Influence of asiatic acid, madecassic acid, and asiaticoside on human collagen I synthesis.

Bonte F, Dumas M, Chaudagne C, Meybeck A. LVMH Recherche, Colombes, France.

Planta Med 1994 Apr;60(2):133-5

Asiatic acid, madecassic acid, and asiaticoside, terpenoids with an ursane skeleton, were tested separately and in combination on skin human fibroblast collagen I synthesis in vitro. In the absence of ascorbic acid, the mixture as well as each individual component stimulated collagen I synthesis to a similar extent. In the presence of ascorbic acid, the level of collagen I secretion was higher for each individual component and for the mixture. A comparison of asiaticoside and asiatic acid shows that the sugar moiety of the molecule does not seem to be necessary for this biological activity.

Increased susceptibility to oxidation of low-densitylipoproteins isolated from patients with systemic sclerosis.

Bruckdorfer KR; Hillary JB; Bunce T; Vancheeswaran R; Black CM Department of Rheumatology, Royal Free Hospital School of Medicine, London, England.

Arthritis Rheum (United States) Aug 1995, 38 (8) p1060-7

OBJECTIVE. To examine the resistance to oxidation of low-density lipoproteins (LDL) from patients with systemic sclerosis (SSc) and primary Raynaud's phenomenon (RP) compared with healthy controls.

METHODS. Plasma LDL were isolated from patients with diffuse cutaneous and limited cutaneous SSc (dcSSc and lcSSc, respectively), patients with primary RP, and healthy control subjects. The lipoproteins were assessed for their resistance to oxidation in the presence of cupric ions, using spectrophotometric assays.

RESULTS. LDL from patients with dcSSc and lcSSc were more susceptible to oxidation than were those from healthy control subjects or patients with RP.

CONCLUSION. Our findings suggest that free radicals may play a role in the pathology of SSc.

Fish - oil dietary supplementation in patients withRaynaud's phenomenon: a double-blind, controlled, prospective study.

DiGiacomo RA; Kremer JM; Shah DM Division of Rheumatology, Albany Medical College, New York 12208.

Am J Med (United States) Feb 1989, 86 (2) p158-64

PURPOSE: The ingestion of omega -3 fatty acids could benefit patients with Raynaud's phenomenon because, among other effects, these fatty acids induce a favorable vascular response to ischemia. The aim of our study was to investigate, in a double-blind, placebo-controlled manner, the effects of fish - oil fatty-acid dietary therapy in patients with rheumatic disease.

PATIENTS AND METHODS: Thirty-two patients with primary or secondary Raynaud's phenomenon were randomly assigned to olive-oil placebo or fish-oil groups. Patients ingested 12 fish-oil capsules daily containing a total of 3.96 g eicosapentaenoic acid and 2.64 g docosahexaenoic acid or 12 olive-oil capsules and were evaluated at baseline and after six, 12, and 17 weeks. All patients ingested olive oil between Weeks 12 to 17. Digital systolic blood pressures and blood flow were measured at room air and water baths of 40 degrees C, 25 degrees C, 15 degrees C, and 10 degrees C using strain gauge plethysmography. Onset of Raynaud's phenomenon was timed with a stop watch and defined as plethysmographic evidence of cessation of blood flow and blood pressure in the study finger.

RESULTS: In the fish-oil group, the median time interval before the onset of Raynaud's phenomenon increased from 31.3 +/- 1.3 minutes baseline to 46.5 +/- 2.1 minutes at six weeks (p = 0.04). Patients with primary Raynaud's phenomenon ingesting fish oil had the greatest increase in the time interval before the onset of the condition. Five of 11 patients (45.5 percent) with primary Raynaud's phenomenon ingesting fish oil in whom the phenomenon was induced at baseline could not be induced to develop Raynaud's at the six- or 12-week visit compared with one of nine patients (11 percent) with primary Raynaud's ingesting olive oil (p = 0.05). The mean digital systolic pressures were higher in the patients with primary Raynaud's phenomenon ingesting fish oil than in patients with primary Raynaud's ingesting olive oil in the 10 degrees C water bath (+32 mm Hg, p = 0.02).

CONCLUSION: We conclude that the ingestion of fish oil improves tolerance to cold exposure and delays the onset of vasospasm in patients with primary, but not secondary, Raynaud's phenomenon. These improvements are associated with significantly increased digital systolic blood pressures in cold temperatures.

[Madecassol treatment of systemic and localized scleroderma]. [Article in Russian]

Guseva NG, Starovoitova MN, Mach ES.

Ter Arkh 1998;70(5):58-61

AIM: The trial of efficacy of 6-month therapy with madecassol (tablets, ointment, powder) of patients with systemic and focal scleroderma (SS and FS).

MATERIALS AND METHODS: 54 patients (49 females and 5 males) aged 15 to 70 years with scleroderma running from 3 months to 15 years entered the study. 30 patients had typical SS, 24 patients had FS. Tablets were given to 18 patients, ointment was applied in 42 patients, powder in 3 and tablets + ointment in 9 patients. Madecassol 10 mg tablets were taken 3 times a day by patients with SS and advanced FS. The ointment was preferred in ulcers and scars on fingers and toes in SS and vascular trophic lesions in FS. In active focal scleroderma the ointment was applied to the skin lesions. The ointment was used 2 times a day (in the morning and evening) for 1-6 months. Madecassol powder was employed rarely, primarily of anal and vulval lesions.

RESULTS: 6-month oral course (30 mg/day) in 12 SS patients brought about a decrease of indurative lesions, hyperpigmentation (8), vascular trophic disorders (6) and improvement of general condition (5). Subjective response was good in 10 patients and corresponded to absence of progression. In progressive disease and diffuse skin lesions the drug was ineffective. The best response was obtained in local application of madecassol ointment on digital ulcers in SS.

CONCLUSION: Madecassol is effective and well tolerated and therefore recommended for oral and local use in combined treatment of SS adn FS. Indications for per os utelization are: chronic or subchronic SS with limited skin involvement, advanced and/or prone to progression FS in which combined administration of the tablets and ointment is proposed.

Dietary intake of micronutrient antioxidants in relation to blood levels in patients with systemic sclerosis.

Herrick AL; Worthington H; Rieley F; Clarke D; Schofield D; Braganza JM; Jayson MI University of Manchester Rheumatic Diseases Centre, Hope Hospital, Salford, UK.

J Rheumatol (Canada) Apr 1996, 23 (4) p650-3

OBJECTIVE. To document habitual intakes of micronutrient antioxidants in patients with systemic sclerosis (SSc) in light of studies reporting subnormal levels of ascorbate and selenium in this patient group.

METHODS. Dietary intakes of vitamin C , selenium, alpha-tocopherol, beta-carotene, and sulfur amino acid precursors of glutathione were assessed using the 7 day weighed record in 12 patients with SSc and in 12 healthy control subjects. The intakes of the first 4 substances were examined in relation to plasma/serum levels, while intakes of sulfur amino acids were examined in relation to urinary inorganic sulfate.

RESULTS. Antioxidant and sulfur amino acid intakes were similar in patients and controls, although the patients had lower levels of selenium (median 74 compared to 87 milligrams in controls; p = 0.014) and of vitamin C in plasma (median 6.0 compared to 11.1 milligrams/l in controls; p = 0.08). Inorganic sulfate concentration in urine was similar in patients and controls.

CONCLUSION. Our results suggest that reduced blood levels of the water soluble antioxidants selenium and ascorbic acid in patients with SSc are not due to dietary deficiency. Other explanations must therefore be sought.

Essential fatty acid metabolism in diseases of connective tissue with special reference to scleroderma and to Sjogren's syndrome.

Horrobin DF

Med Hypotheses (England) Jul 1984, 14 (3) p233-47

Drugs which modify the conversion of essential fatty acids to prostaGLAndins and leukotrienes are the mainstays of treatment in rheumatology. Yet these drugs have little or no action in scleroderma or Sjogren's syndrome and under some circumstances may have adverse effects. Patients with scleroderma have been shown to have very high levels of circulating prostaglandins, coupled with depletion of the prostaglandin precursors, dihomogammalinolenic acid and arachidonic acid. Levels of the metabolites of arachidonic acid, 22:4n-6 and 22:5n-6, which have major roles in maintaining normal cell membrane characteristics were exceptionally low in both plasma and red cell membranes. Others have observed that various functions are highly resistant to normal actions of PGs in scleroderma. This raises the possibility that the high rate of PG formation in scleroderma may be beneficial, in compensation, and that clinical symptoms develop when PG precursors begin to be depleted. Red cell membrane fatty acids patterns in Sjogren's syndrome are almost identical to those in scleroderma. Placebo-controlled trials of supplementation with essential fatty acids have been found to be beneficial in both scleroderma and Sjogren's syndrome.

Essential fatty acid and prostaglandin metabolism in Sjogren's syndrome, systemic sclerosis and rheumatoid arthritis.

Horrobin DF

Scand J Rheumatol Suppl (Sweden) 1986, 61 p242-5

Evidence from biochemical studies and from experimental animals indicates that abnormalities of essential fatty acid (EFA) and eicosanoid metabolism could lead to salivary and lacrimal GLAnd atrophy and to immunological and cardio-vascular defects. Measurements of EFA levels in erythrocytes from patients with primary Sjogren's syndrome have shown that abnormalities are indeed present. Controlled clinical trials of supplementation with gamma-linolenic acid (GLA) as evening primrose oil (Efamol) in both primary Sjogren's syndrome and systemic sclerosis have given positive results. There are strong arguments to indicate that sophisticated manipulation of EFA metabolism may have a role to play, not only in Sjogren's syndrome but also in other rheumatological disorders. (16 Refs.)

Biomechanical stimulation therapy. A novel physiotherapy method for systemic sclerosis.

Klyscz T, Rassner G, Guckenberger G, Junger M. Department of Dermatology, University Hospital of Tubingen, Germany.

Adv Exp Med Biol 1999;455:309-16

To improve the mobility of joints, particularly of the finger joints and the mandibular joint, and to reduce the edema of the skin, various physical therapies have to be used in patients with SSc. As the quality of patients' life depends on the use of their fingers and of their mouth, these therapeutics belong to the basic measures in the treatment of SSc. In addition to the manually performed lymph drainage a new method, the biomechanical stimulation therapy, has proven to be efficacious to improve the mobility of the joints and to reduce the edema in SSc-patients. By devices of various size, longitudinal vibrations are transduced to patients' body: finger, hand, face, mandibular joint, the oral mucosa, the legs and the trunk. In 6 patients we found: significant (p < 0.05) increase of skin score, grip strength, mobility of joints (10-30%). No side effects were observed. We conclude from these data, that skin, mucosa, joints and patients' quality of life are improved by the biomechanical stimulation therapy in a clinical relevant degree.

Management of severe scleroderma with long-term extracorporeal photopheresis.

Krasagakis K, Dippel E, Ramaker J, Owsianowski M, Orfanos CE. Department of Dermatology, University Medical Center Benjamin Franklin, Free University of Berlin, Germany.

Dermatology 1998;196(3):309-15

BACKGROUND: The management of systemic sclerosis remains unsatisfactory. Thus far, the action of extracorporeal photopheresis (ECP) in severe systemic scleroderma has been evaluated in short-term studies, and only limited experience has been obtained with long-term application.

OBJECTIVE: The aim of the present study was to evaluate prospectively the long-term effect of ECP in a group of 16 patients suffering from severe scleroderma, showing visceral involvement and progressive clinical course.

METHODS: Fourteen patients with systemic scleroderma involving several organs, 1 with CREST syndrome and another with scleroderma-myositis overlap syndrome were treated with ECP over a period of 6-45 months. In 3 cases, gamma-IFN was additionally administered. Skin and visceral involvement were assessed by evaluating a series of clinical criteria and results from laboratory, imaging and functional tests.

RESULTS: Overall, clear improvement was encountered in 6 patients, mixed response in 2, stable disease in 3 and continuing progressive course in 5 patients. Four out of 6 patients with improvement were treated with ECP early after onset of scleroderma (< or = 2 years), whereas all patients with a progressive course under ECP had had scleroderma for longer than 2 years. Immunosuppressive drugs previously administered could be reduced or fully withdrawn under ECP treatment in 5 patients, but additional oral medication was introduced in 4 patients due to disease progression. Addition of gamma-IFN to ECP did not reveal further benefit. No side-effects were recorded under ECP treatment.

CONCLUSIONS: Based on this observation, we believe that long-term ECP represents an effective treatment modality in severe scleroderma particularly when started early, with stabilization of the disease course and partial remission of the cutaneous findings, whereas visceral involvement, if present, may rarely improve.

Triterpenes from Centella asiatica stimulate extracellular matrix accumulation in rat experimental wounds.

Maquart FX, Chastang F, Simeon A, Birembaut P, Gillery P, Wegrowski Y. Laboratory of Biochemistry, UPRESA CNRS 6021, IFR-53 Biomolecules, Faculty of Medicine, Reims, France. fmaquart@chu-reims.fr

Eur J Dermatol 1999 Jun;9(4):289-96

Titrated Extract from Centella asiatica (TECA) is a drug which has been used for many years in Europe for the treatment of wound healing defects. It is a reconstituted mixture of 3 triterpenes extracted from the plant, asiatic acid, madecassic acid and asiaticoside. In this report, we studied the effects of TECA and its separated components in the wound chamber model described by Schilling et al. Stainless steel wound chambers were surgically inserted under the skin of rats and received serial injections of either TECA or its purified components. Chambers were collected at days 7, 14, 21 or 28 for biochemical analysis or histological examination. TECA-injected wound chambers were characterized by increased dry weight, DNA, total protein, collagen and uronic acid contents. Peptidic hydroproline was also increased, showing an increased remodeling of the collagen matrix in the wound. The 3 purified components of TECA were all able to reproduce the effects of the complete drug, with some differences depending on the product. Asiatic acid and asiaticoside were the most active of the 3 triterpenes. Asiaticoside exerted a preferential stimulation of collagen synthesis and was active at low doses only. In addition to collagen, the 3 components were also able to stimulate glycosaminoglycan synthesis.

[The effect of dimethyl sulfoxide on the thromboelastographic indices and the microcirculation in patients with rheumatic diseases]

Murav'ev IuV; Loskutova TT; Anikina NV; Shcherbakov AB; Sokolov VB

Ter Arkh (USSR) 1989, 61 (12) p106-9

Using a blind method for assessing the results, a study was made of the effect of dimethylsulfoxide (DMSO) on fibrin formation and microcirculation in 42 patients with rheumatic diseases (rheumatoid arthritis, systemic scleroderma, Raynaud's syndrome). It has been shown that the therapeutic effect of DMSO in rheumatic diseases is determined to a definite degree by its normalizing action on fibrin formation and microcirculation.

Boswellic acids: novel, specific, nonredox inhibitors of 5-lipoxygenase.

Safayhi H, Mack T, Sabieraj J, Anazodo MI, Subramanian LR, Ammon HP. Department of Pharmacology, University of Tuebingen, FRG.

J Pharmacol Exp Ther 1992 Jun;261(3):1143-6

Isomers (alpha- and beta-) of boswellic acids (BAs), 11-keto-beta-BA and their acetyl derivatives were isolated from the gum resin of Boswellia serrata. BA and derivatives concentration dependently decreased the formation of leukotriene B4 from endogenous arachidonic acid in rat peritoneal neutrophils. Among the BAs, acetyl-11-keto-beta-BA induced the most pronounced inhibition of 5-lipoxygenase (5-LO) product formation with an IC50 of 1.5 microM. In contrast to the redox type 5-LO inhibitor nordihydroguaiaretic acid, BA in concentrations up to 400 microM did not impair the cyclooxygenase and 12-lipoxygenase in isolated human platelets and the peroxidation of arachidonic acid by Fe-ascorbate. The data strongly suggest that BAs are specific, nonreducing-type inhibitors of the 5-LO product formation either interacting directly with the 5-LO or blocking its translocation.

Novel functional sets of lipid-derived mediators with anti-inflammatory actions generated from omega-3 fatty acids via cyclooxygenase 2-nonsteroidal antiinflammatory drugs and transcellular processing.

Serhan CN, Clish CB, Brannon J, Colgan SP, Chiang N, Gronert K. Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. cnserhan@zeau.bwh.harvard.edu

J Exp Med 2000 Oct 16;192(8):1197-204

Aspirin therapy inhibits prostaglandin biosynthesis without directly acting on lipoxygenases, yet via acetylation of cyclooxygenase 2 (COX-2) it leads to bioactive lipoxins (LXs) epimeric at carbon 15 (15-epi-LX, also termed aspirin-triggered LX [ATL]). Here, we report that inflammatory exudates from mice treated with omega-3 polyunsaturated fatty acid and aspirin (ASA) generate a novel array of bioactive lipid signals. Human endothelial cells with upregulated COX-2 treated with ASA converted C20:5 omega-3 to 18R-hydroxyeicosapentaenoic acid (HEPE) and 15R-HEPE. Each was used by polymorphonuclear leukocytes to generate separate classes of novel trihydroxy-containing mediators, including 5-series 15R-LX(5) and 5,12,18R-triHEPE. These new compounds proved to be potent inhibitors of human polymorphonuclear leukocyte transendothelial migration and infiltration in vivo (ATL analogue > 5,12,18R-triHEPE > 18R-HEPE). Acetaminophen and indomethacin also permitted 18R-HEPE and 15R-HEPE generation with recombinant COX-2 as well as omega-5 and omega-9 oxygenations of other fatty acids that act on hematologic cells. These findings establish new transcellular routes for producing arrays of bioactive lipid mediators via COX-2-nonsteroidal antiinflammatory drug-dependent oxygenations and cell-cell interactions that impact microinflammation. The generation of these and related compounds provides a novel mechanism(s) for the therapeutic benefits of omega-3 dietary supplementation, which may be important in inflammation, neoplasia, and vascular diseases.

Enhanced lipid peroxidation in systemic scleroderma

Sommerburg O.; Brenke A.; Muller G.-M.; Siems W.; Grune T. Abteilung fur Kindernephrologie, Medizinische Fakultat, Humboldt-Universitat, Schumannstrasse 20/21,10117 Berlin Germany

Zeitschrift fur Dermatologie (Germany) 1996, 182/3 (124+126-128)

Scleroderma, the aetiology of which remains uncertain, is a rare, autoimmunological disease of the vascular system and connective tissues often accompanied by joint pain. It has been shown that in patients with scleroderma, a considerable accumulation of free radicals, and massive lipid peroxidation occurs. The serum of these patients contains levels of 4-hydroxynonenal - an aldehydic product of lipid peroxidation which is toxic at lowdoses - that are three times as high as those seen in healthy subjects. Under treatment with the antioxidant, vitamin E, the concentrations of 4-hydroxynonenal decrease by more than two-thirds, and the subjective feeling of well-being clearly improves.

New innovations in scar management.

Widgerow AD, Chait LA, Stals R, Stals PJ.

Aesthetic Plast Surg 2000 May-Jun;24(3):227-34

As current aesthetic surgical techniques become more standardized and results more predictable, a fine scar may be the demarcating line between acceptable and unacceptable aesthetic results. With this in mind, a scar management program has been adopted based on the modalities of wound support, hydration, and hastened maturity, all factors gleaned from scientific evidence published over the past 25 years. Tension on a scar in one axis will result in a stretched scar, probably initiated by neutrophils and their neutral proteases [18,26]. Tension on a scar from many directions or intermittently will result in a hypertrophic scar, possibly initiated by lymphocytes but definitely related to a prolongation of the inflammatory process, with increased fibroblast activity and overabundant extracellular matrix secretion [24,26]. The common initiating factor is the tension on the scar, and the critical element needed to counteract this tension is scar support. Clinical experience has shown us that the most reliable way to support a scar is by using microporous tape. Hydration is a second beneficial influence on scar control and is the basis of the use of silicone sheeting and gel [7,29,36]. Alpha Centella cream has two main components. The first is an extract from the plant Bulbine frutescens. This increases hydration under the tape by leaving a layer of fatty vesicles of glycoprotein on the skin surface. This also has antibacterial properties. The second component is the principal terpenoids extracted from the Centella asiatica plant. These include asiatic acid, madecassic acid, and asiaticoside. Centella asiatica has been documented to aid wound healing in a large number of scientific reports [5,12,21,22,33,34,40]. The most beneficial effect appears to be the stimulation of maturation of the scar by the production of type I collagen [4,19] and the resulting decrease in the inflammatory reaction and myofibroblast production. Thus these components have been incorporated into the formulation of a scar management program. This publication reviews much of the available literature relating to scar management and describes the formulation and use of a scar management program based on this information.

The North American experience with photopheresis.

Zic JA, Miller JL, Stricklin GP, King LE Jr. Division of Dermatology, Vanderbilt University School of Medicine/Nashville Veterans Affairs Medical Center, Tennessee, USA.

Ther Apher 1999 Feb;3(1):50-62

Photopheresis or extracorporeal photochemotherapy (ECP) is a novel immunomodulatory therapy based upon pheresis of light-sensitive cells. Whole blood is removed from patients who have previously ingested the photosensitizing agent 8-methoxypsoralen (8-MOP) followed by leukapheresis and exposure of the 8-MOP containing white blood cells (WBCs) extracorporeally to an ultraviolet A (UVA) light source prior to their return to the patient. In 1988, the Food and Drug Administration (FDA) approved photopheresis for the treatment of cutaneous T-cell lymphoma (CTCL). Treatment of CTCL with photopheresis has been reported in over 300 patients worldwide. Photopheresis has also demonstrated encouraging results in the treatment of solid organ transplant rejection, graft versus host disease, scleroderma, and other autoimmune diseases although fewer patients have been studied. This review will focus on the North American experience with photopheresis.

SUGGESTED READING

Effect of N-acetyl-L-cysteine on peroxynitrite and superoxide anion production of lung alveolar macrophages in systemic sclerosis.

Failli P, Palmieri L, D'Alfonso C, Giovannelli L, Generini S, Rosso AD, Pignone A, Stanflin N, Orsi S, Zilletti L, Matucci-Cerinic M. Department of Preclinical and Clinical Pharmacology, University of Florence, Viale Pieraccini 6, 50139, Firenze, Italy. failli@server1.pharm.unifi.it

Nitric Oxide. 2002 Dec;7(4):277-82.

Lung macrophages may play a relevant role in oxidative processes producing both superoxide anion (O(2)(-)) and NO. In this view, an antioxidant therapy can be useful in the treatment of systemic sclerosis (SSc) patients. N-Acetylcysteine (NAC) is able to expand natural antioxidant defenses by increasing intracellular gluthatione concentration and it has been proposed as an antioxidant therapy in respiratory distress syndromes. The aim of our study was to determine whether lung macrophages obtained from SSc patient bronchoalveolar lavage (BAL) express the inducible form of nitric oxide synthase (iNOS) and whether NAC can reduce the peroxynitrite (ONOO(-)) and O(2)(-) production of these cells. Alveolar macrophages were isolated from BAL of 32 patients and used for the immunocytochemical determination of iNOS, and the production of ONOO(-) and O(2)(-) was measured by fluorimetric or spectrophotometric methods, respectively. Lung macrophages obtained from SSc patients expressed a higher level of iNOS compared to healthy subject cells. NAC preincubation (5 x 10(-5)M, 24h) significantly reduced (-21%) the ONOO(-) production in formyl Met-Leu-Phe (fMLP)-activated cells and slightly reduced it under resting conditions, whereas NAC preincubation was unable to modify the release of O(2)(-) both in basal condition and in fMLP-stimulated cells. We conclude that since SSc lung macrophages express high levels of iNOS and produce a significant quantity of ONOO(-), NAC administration reduces ONOO(-) production and can be an useful treatment to alleviate SSc symptoms.

Activin, a grape seed-derived proanthocyanidin extract, reduces plasma levels of oxidative stress and adhesion molecules (ICAM-1, VCAM-1 and E-selectin) in systemic sclerosis.

Kalin R, Righi A, Del Rosso A, Bagchi D, Generini S, Cerinic MM, Das DK. Cardiovascular Research Center, University of Connecticut School of Medicine, Farmington 06030-2110, USA.

Free Radic Res. 2002 Aug;36(8):819-25.

This study evaluated whether a new generation antioxidant Activin derived from the grape seed proanthocyanidins, could reduce the induction of the adhesion molecules as a result of inflammatory response in the plasma of systemic sclerosis (SSc) patients. SSc patients were divided into two groups: one group was treated with Activin, a grape seed-derived proanthocyanidins, while the other group served as control. Patients were given Activin 100 mg/day orally for one month after which the blood samples were withdrawn from both groups of the patients. Blood was also taken from normal human volunteers. Plasma was obtained in fasting state between 8 to 9 A.M. from two groups of SSc patients and controls. Soluble adhesion molecules including ICAM-1, VCAM-1, E-selectin and P-selectin as well as malonaldehyde, a marker for oxidative stress, were measured. The results of our study demonstrated up-regulation of these soluble adhesion molecules except for P-selectin, in the plasma of the SSc patients compared to those obtained from human volunteers. Activin significantly attenuated the increased expression of these adhesion molecules. In addition, there was a significant increase in the amount of malondialdehyde formation in the plasma of the SSc patients, which was also attenuated by Activin. The results of this study demonstrated that Activin could reduce the inflammatory response and the oxidative stress developed in SSc patients.

Emerging potentials for an antioxidant therapy as a new approach to the treatmentof systemic sclerosis.

Simonini G, Pignone A, Generini S, Falcini F, Cerinic MM, Gabriele S, Alberto P, Sergio G, Fernanda F, Marco MC. Department of Pediatrics, University of Florence, Institute of Internal Medicine, Italy.

Toxicology. 2000 Nov 30;155(1-3):1-15.

Oxidative stress, favoring disease progression by a rapid degeneration of endothelial cell function is deeply involved in Systemic Sclerosis (SSc) pathogenesis. Raynaud's phenomenon (RP), present in 90% of patients with SSc, provoking frequent daily episodes of hypoxia-reperfusion injury, produces several episodes of free radicals-mediated endothelial derangement. These events results in a positive feedback effect of luminal narrowing and ischemia and therefore to the birth of a vicious cycle of oxygen free radicals (OFR) generation, leading to endothelial damage, intimal thickening and fibrosis. Thus ischemia and reperfusion are two criticals events that may induce oxidative stress and inactivation of antioxidant enzymes. In RP and SSc, a reduced concentration of ascorbic acid, alpha-tocopherol and beta-carotene as well as low values of Selenium have been reported. This antioxidative potential deficiency increases the propensity to oxidative stress. favoring the development of injury mediated by OFR. We reviewed several antioxidant compounds, aiming at their capacity of reverting endothelial dysfunction and damage, scavenging lipid peroxidation and reducing multiple episodes of hypoxia-reperfusion injury. In order to interrupt SSc vicious cycle, we propose a main strategy for SSc treatment by a supplementation of antioxidants and different kind of drugs with antioxidant property, such as Lazaroids, Resveratrol, Melatonin and Probucol.

Probucol improves symptoms and reduces lipoprotein oxidation susceptibility in patients with Raynaud's phenomenon.

Denton CP, Bunce TD, Darado MB, Roberts Z, Wilson H, Howell K, Bruckdorfer KR, Black CM. Academic Unit of Rheumatology, Royal Free Hospital School of Medicine, London, UK.

Rheumatology (Oxford). 1999 Apr;38(4):309-15.

OBJECTIVE: Reactive oxygen species have been implicated in the pathogenesis of inflammatory and vascular disease. We have undertaken a controlled trial to evaluate probucol, a synthetic antioxidant, as a potential therapy for Raynaud's phenomenon.

METHODS: The study cohort included patients with systemic sclerosis (SSc; n = 20), primary Raynaud's phenomenon (n = 15) or 'autoimmune Raynaud's' (n = 5). Patients were allocated to receive either probucol (500 mg daily) or nifedipine (20 mg daily) for 12 weeks. Clinical and biochemical variables at baseline were compared with those at completion of treatment. Evaluation included assessment of Raynaud's attack frequency and severity by visual analogue scale, measurement of low-density lipoprotein (LDL) oxidation lag time, and plasma concentrations of cholesterol, triglyceride, vitamin E and vitamin C.

RESULTS: There was a significant reduction of both the frequency and severity of Raynaud's attacks in the patients who received probucol, but not in the control group. LDL oxidation lag time, reflecting in vitro susceptibility to oxidation, was also increased by probucol therapy and serum cholesterol levels were significantly reduced. Similar changes were observed in both SSc- and non-SSc-associated Raynaud's cases.

CONCLUSION: These data suggest that probucol may be useful for the symptomatic treatment of Raynaud's phenomenon and also reduces LDL oxidation susceptibility. Since oxidized lipoproteins may mediate vascular damage in SSc, the use of probucol could have additional disease-modifying benefits. Based upon the results of this pilot study, further evaluation of this novel form of therapy is warranted.

Effect of melatonin on normal and sclerodermic skin fibroblast proliferation.

Carossino AM, Lombardi A, Matucci-Cerinic M, Pignone A, Cagnoni M. Institute of Internal Medicine IV, University of Florence, Italy.

Clin Exp Rheumatol. 1996 Sep-Oct;14(5):493-8.

OBJECTIVE: We studied the effect of melatonin (MLT) (N-acetyl 5-methoxytryptamine) on the growth rate of normal skin fibroblasts and of fibroblasts from involved and apparently uninvolved skin of patients affected by systemic sclerosis (SSc).

METHODS: The growth rate was evaluated on the basis of growth curves and a 3H-thymidine incorporation assay.

RESULTS: Our results demonstrate that a dose of 200 micrograms/ml of MLT inhibits (> 80%) both control and SSc fibroblasts. Inhibition was dose-dependent and was greater than 70% for MLT concentrations of 100 micrograms/ml, 200 micrograms/ml and 400 micrograms/ml. 3H-thymidine incorporation was correlated with the effect on thegrowth curves (81% at 200 micrograms/ml of MLT). In contrast, at a low dosage of 6 micrograms/ml, MLT exerted a stimulatory effect on cell proliferation in all the cell lines analyzed. Cell viability was not affected by MLT at any of the concentrations tested. A recovery study indicated that replacement of MLT-containing medium with MLT-free medium resulted in a re-establishment of cell growth.

CONCLUSIONS: These results suggest that MLT, at higher dosages, is a potent inhibitor of the proliferation of fibroblasts derived from the skin of healthy and SSc patients.

Gastrointestinal function in patients with progressive systemic sclerosis.

Akesson A; Akesson B; Gustafson T; Wollheim F

Clin Rheumatol (Belgium) Dec 1985, 4 (4) p441-8

In 24 patients with progressive systemic sclerosis (PSS) the pentagastrin-stimulated gastric acid secretion was determined to investigate if acid hypersecretion is associated with reflux-oesophagitis--the most common complication to oesophageal involvement in PSS. Gastro-oesophageal reflux was observed in 12, reflux-oesophagitis in 9 and oesophageal mycosis in 8 patients. Gastric acid secretion was increased in 13 (54%) patients and tended to be higher in patients with oesophagitis. Patients with reflux and increased acid secretion seemed to be free from oesophageal mycosis. Bacterial overgrowth and malabsorption are known complications to intestinal scleroderma and these items were investigated using non-invasive methods. Four patients had increased bile acid deconjugation, 3 had increased (14C)xylose degradation indicating bacterial overgrowth and 7 patients had decreased fat absorption in the triolein breath test. Nutritional status with respect to selenium, folate, cobalamin and fat-soluble vitamins was essentially normal.

Stingl G.; Holubar K.; Scherak O.; et al.
Abt. Exp. Dermatol., I. Univ. Hautklin., Wien Austria
H+G Zeitschrift fur Hautkrankheiten 1975, 50/2 (83-95)

The clinical, serologic and immunologic data of 5 patients with the recently recognized 'mixed connective tissue disease' are reported. Clinically, it includes symptoms of certain collagenases such as lupus erythematosus, dermatomyositis, and scleroderma and sometimes of rheumatoid arthritis. Immunologically antinuclear antibodies are found which show a 'speckled pattern' by the indirect immunofluorescence method, a high titre of hemagglutinating antibodies against extracted nuclear antigen, inhibition of hemagglutination or extinction of the indirect immunofluorescence if pretreated with RNAase. The clinical and immunologic characteristics found by Sharp et al. are confirmed. In order to determine whether there is a renal involvement, kidney biopsies were undertaken and a moderate immune complex precipitation together with a high antinuclear antibody titre was found. The prognosis of this syndrome and comparison with lupus erythematosus are discussed.

Huang PP; Wang SG; Hua GX
Hospital of Hematology, Chinese Academy of Medical Sciences, Tianjin.
Chung Kuo Chung Hsi I Chieh Ho Tsa Chih (China) Feb 1994, 14 (2) p86-8, 68

The blood flow change of 34 progressive systemic scleroderma (PSS) patients were examined. The amplitude proved to be lowered markedly than healthy subjects. All patients were treated with the basic prescription of PSS as the principal method, combined with infusion of Mailuoning injection in 500 ml of 5% glucose. The course of treatment lasted three months to one year. The result of treatment showed that the abnormal blood flow of extremities of all patients were improved remarkably. Marked improvement rate and total effective rate were 70.5% and 100% respectively. Significant improvements in clinical and laboratory parameters were observed. It revealed that there was a close relationship between the occurrence and development of PSS and blood circulation. It is assumed that the pathogenic mechanism of PSS is Deficiency of vitality and Excess of pathogenic factor (Stasis of Blood), and the Qi tonifying and Blood activating, hard lump softening and mass dissolving medicinal herbs according to Syndrome Differentiation of TCM should be used.

Serup J; Hagdrup H
Acta Derm Venereol (Sweden) 1985, 65 (4) p343-5

Vitamin D metabolites in serum were analysed in 20 patients with generalized scleroderma. The concentration of 1,25-dihydroxyvitamin D was normal, however, significantly lower concentrations (p less than 0.05) were found in 7 patients with cutaneous calcinosis in comparison with 13 patients with no calcinosis. Concentrations of 25-hydroxyvitamin D, 24-25-dihydroxyvitamin D, and vitamin D-binding protein (Gc globulin) were all within the normal range. The 24,25-dihydroxy-vitamin D level correlated with the duration of disease (r = 0.4453, p less than 0.05), and 25-hydroxyvitamin D tended to correlate (r = 0.3016, NS). The study strongly indicates that cutaneous synthesis, intestinal absorption and hepatic hydroxylation of vitamin D are not deficient in scleroderma. A relative but specific decrease in the renal hydroxylation to 1,25-dihydroxyvitamin D, i.e. the active hormone, as the disease progresses and calcinosis occurs, is suspected.

Ohta A; Uitto J
Arthritis Rheum (United States) Apr 1987, 30 (4) p404-11

Recent studies have demonstrated that retinoids (synthetic vitamin A analogs) can modulate connective tissue metabolism in human skin fibroblast cultures. In this study, we examined the effects of 3 retinoids, all-trans-retinoic acid (RA), 13-cis-RA, and an aromatic retinoid, RO-10-9359, on collagen gene expression in scleroderma fibroblast cultures and matched control fibroblast cultures. The results indicated that all-trans-RA and 13-cis-RA significantly reduced procollagen production both in control and scleroderma fibroblast cultures in a dose-dependent manner. The reduction in procollagen production was paralleled by a similar decrease in steady-state levels of type I and type III procollagen messenger RNAs, which suggests that there is coordinate inhibition on the transcriptional level. In contrast, RO-10-9359 elicited only limited effects on collagen production, and such effects were variable. The results suggest that further development of retinoids might provide an effective means to counteract tissue deposition of collagen in scleroderma and other fibrotic diseases.

Horrobin DF
Med Hypotheses (England) Jul 1984, 14 (3) p233-47

Drugs which modify the conversion of essential fatty acids to prostaglandins and leukotrienes are the mainstays of treatment in rheumatology. Yet these drugs have little or no action in scleroderma or Sjogren's syndrome and under some circumstances may have adverse effects. Patients with scleroderma have been shown to have very high levels of circulating prostaglandins, coupled with depletion of the prostaglandin precursors, dihomogammalinolenic acid and arachidonic acid. Levels of the metabolites of arachidonic acid, 22:4n-6 and 22:5n-6, which have major roles in maintaining normal cell membrane characteristics were exceptionally low in both plasma and red cell membranes. Others have observed that various functions are highly resistant to normal actions of PGs in scleroderma. This raises the possibility that the high rate of PG formation in scleroderma may be beneficial, in compensation, and that clinical symptoms develop when PG precursors begin to be depleted. Red cell membrane fatty acids patterns in Sjogren's syndrome are almost identical to those in scleroderma. Placebo-controlled trials of supplementation with essential fatty acids have been found to be beneficial in both scleroderma and Sjogren's syndrome.

Serup J; Hagdrup HK
Arch Dermatol Res (Germany, West) 1984, 276 (2) p91-5

Parathyroid hormone (PTH) in serum and biochemical parameters of calcium metabolism were analysed in 45 patients with systemic sclerosis. Calcification of the skin and subcutaneous tissue was assessed by X-ray examination of the hands. Analyses disclosed secondary hyperparathyroidism (increased PTH in serum, low calcium 'ion' in serum, decreased urinary excretion of calcium and phosphate), in particular in patients with calcinosis (P less than 0.05) as compared to those with no calcinosis. The duration of systemic sclerosis was longer in patients with calcinosis (P less than 0.05). The calcinosis type of systemic sclerosis is characterized by secondary hyperparathyroidism developed during the progression of the disease. A hypothesis is made regarding calcium metabolism in the early no-calcinosis (with increased synthesis of Vitamin D) and late calcinosis types. PTH may stimulate aberrant calcification. The hypothesis implicates that prophylactic treatment with Vitamin D in low dose may prevent calcinosis.

De Antoni A; Muggeo M; Costa C; Allegri G; Crepaldi G
Acta Vitaminol Enzymol (Italy) 1976, 30 (4-6) p134-9

The tryptophan metabolism "via" kynurenine was studied in five patients with scleroderma after aminoacid loading. Four of these patients had abnormal tryptophan metabolism, characterized by a large urinary excretion of kynurenine and kynurenic acid in two cases, of kynurenine, 3-hydroxykynurenine and kynurenic acid in one case and of 3-hydroxyanthranilic acid in another case and generally a reduced excretion of xanthurenic acid and its 8-methyl ether in comparison with a group of healthy controls. Only two of the four patients had a normal response to tryptophan loading after pyridoxine administration, while no one of these responded to nicotinamide supplementation. But the simultaneous administration of pyridoxine and nicotinamide to three of these patients normalized the excretory picture after tryptophan loading. This suggested the presence of a combined vitamin deficiency in seleroderma. As four out of five patients showed total excretory values of kynurenine, kynurenic acid and acetylkynurenine higher than that of the controls, the sum of these values might be considered as a characteristic index of scleroderma.

Jablonska S.; Blaszczyk M.
Dr. S. Jablonska, Department of Dermatology, Warsaw School of Medicine, Koszykowa 82a, 02-008 Warsaw Poland
Seminars in Cutaneous Medicine and Surgery (United States) 1998, 17/1 (65-76)

Scleroderma-like disorders are widely disparate conditions mimicking either systemic scierosis or cutaneous localized scleroderma, not infrequently displaying features of both. Some are exclusively sclerotic, some scleroatrophic with prevailing scierosis or atrophies. The recognition of scieroderma-like disorders is of practical importance because by establishing the cause of the disease, it is possible to introduce an effective therapy, as in scieredema Buschke or scieredema diabeticorum, scierodermiform porphyria, Borrelia burgdorferiinduced scierodermiform acrodermatitis atrophicans, scierodermitorm phenylketonuria, drug-induced conditions, and so on. Soieroderma-like disorclers strongly suggest that the pathogenesis of skin sclerosis and internal involvement may be divergent, and of various causes. Some of them, such as atrophoderma Pasini-Pierini or progressive facial herniatrophy, frequently overlapping with scieroderma, make the differentiation very difficult, it at all possible, and the diagnosis is often arbitrary. Some, as scierodermiform graft-versushost reaction, point to the autoimmune origin of scieroderma. The amply-covered congenital scierodermiform conditions present a large spectrum of still not widely known and extremely heterogeneous syndromes, associated with numerous anomalies and/or malignancies.

Hunzelmann N.; Kochanek K.S.; Hager C.; Krieg T.
Dr. T. Krieg, Department of Dermatology, University of Cologne, 50924 Cologne Germany
Seminars in Cutaneous Medicine and Surgery (United States) 1998, 17/1 (34-40)

Localized scleroclerma denotes a spectrum of conditions characterized by circumscribed fibrotic areas involving different levels of the dermis, subcutis, and sometimes underlying soft tissue and bone. Although the clinical course of the disease is often benign, widespread lesions and disabling joint contractures may lead to significant complications. The pathogenesis of the different types of localized scieroderma is still unknown. Numerous therapeutic agents have been reported to be effective in this disease spectrum, but controlled studies are rare. The purpose of this review is to summarize previous experience and to discuss recent advances in the management of localized scleroderma.

Breier F.; Klade H.; Stanek G.; Poitschek C.; Kirnbauer R.; Dorda W.; Aberer E.
Department of Dermatology, University of Vienna Medical School, Waehringer Guertel 18-20,A-1090 Vienna Austria
British Journal of Dermatology (United Kingdom) 1996, 134/2 (285-291)

Humoral immune responses to Borrelia burgdorferi (Bb) have been reported to occur in certain patients with circumscribed scleroderma (CS) (morphoea). Together with the isolation of spirochaetes from CS skin biopsies, this finding was taken to suggest Bb as the aetiological agent of CS. Since there is cellular immunoreactivity to Bb in patients with chronic Lyme borreliosis (LB), Bb-specific lymphocytic responses were tested in patients with CS. For this purpose, peripheral blood mononuclear cells from CS patients and, as controls, from patients with various manifestations of LB, and from healthy volunteers without any evidence of Bb infection, were exposed to Bb organisms for 5 days and then assayed for DNA synthesis. Stimulation indices (SI) > 10 were scored positive. By performing lymphocyte proliferation tests we found:

(i) that not only patients with various manifestations of LB but also a considerable percentage of seropositive (five of 13 = 38%) and seronegative (six of 26 = 23%) CS patients exhibit an elevated Bb-induced lymphocyte proliferation;
(ii) that the magnitude of the cellular response seen in CS patients is comparable to that encountered in patients with established Bb manifestations; and
(iii) that, within a given patient, antibiotic therapy can result in a significant reduction of this response.

These results support a causative role of Bb in at least some CS patients. Bb-induced lymphocyte responses were also seen in both seropositive and seronegative erythema chronicum migrans patients. These findings show that the pattern of Bb-specific immune responses is more complex than previously thought, and underscore the importance of lymphocyte function assays in evaluating the diagnosis of potential Bb infection in seronegative patients.

Fushimi M.; Ogai M.; Furukawa F.
Division of Dermatology, Fujinomiya City General Hospital,Fujinomiya Japan
Acta Dermatologica - Kyoto (Japan) 1995, 90/1 (109-112)

Sairei-to, a Chinese-Japanese herbal medicine, has been used for the treatment of various diseases for about 3,000 years in China, and is well known to improve the symptoms of rheumatoid arthritis and other collagen diseases. We encountered an 18-year-old man with localized scleroderma. He was treated with 8.1 g/day of Sairei-to (Kanebo) and topical corticosteroids. Skin lesions were improved gradually and the titer of anti-single stranded DNA antibody in sera reduced from 270 U/ml to 89 U/ml after 7-month treatment. Herein, we describe his clinical course and discuss the efficacy of Sairei-to for the localized scleroderma.

Smiley J.D.
Arthritis Consultation Center, Presbyterian Hospital of Dallas, 8200 Walnut Hill Lane,Dallas, TX 75231 United States
American Journal of the Medical Sciences (United States) 1992, 304/5 (319-333)

This review integrates the clinical aspects of systemic sclerosis (SSc; scleroderma) and scleroderma-like conditions with new knowledge of the control of blood vessel tone and the role of anoxia in the activation of connective tissues leading to fibrosis. Serologic tests, high resolution computed tomographic scanning, bronchoalveolar lavage, and physiologic assessment of pulmonary gas diffusion are compared as diagnostic tools and as means of quantitating internal organ involvement. Treatment of Raynaud's disease and phenomenon, management of scleroderma renal crisis, and new means for improving gastrointestinal function with octreotide, the somatostatin analogue, also are discussed. The relationship between idiopathic forms of SSc and eosinophilic fasciitis/eosinophilia-myalgia syndrome caused by L- tryptophan ingestion and the scleroderma-like disease associated with silicone breast implants also is discussed.

Humbert P.G.; Dupond J.L.; Rochefort A.; Vasselet R.; Lucas A.; Laurent R.; Agache P.
Department of Dermatology, Centre Hospitalier, Universitaire St-Jacques,25030 Besancon Cedex France
Clinical and Experimental Dermatology (United Kingdom) 1990, 15/5 (396-398)

1,25-Dihydroxyvitamin Dinf 3 (1,25(OH)inf 2 Dinf 3) may be an immunomodulatory drug which could have a role in controlling collagen depositioin, and inducing reversal of fibrosis in some tissues. These observations prompted a study of the possible use of this hormone for the treatment of scleroderma. A 35-year-old woman, who had been suffering from localized scleroderma for 2 years, was given oral 1,25(OH)inf 2Dinf 3 for 6 months. The effects of the treatment were evaluated using clinical and physical measurements (skin thickness, extensibility properties of the skin). The evolution of the patient's condition during the 6-month therapy suggests that 1,25(OH)inf 2 Dinf 3 is beneficial in localized scleroderma. The mechanisms of action are discussed in relation to the literature, which suggests both immunoregulatory and inhibitory effects on fibroblast growth. The presence of cutaneous receptors for 1,25-dihydroxyvitamin Dinf 3 (1,25(OHinf 2)Dinf 3) suggested that the skin was not only the site for vitamin -D synthesis, but also a target organ for this hormone. The observations that cultured human dermal fibroblasts possess receptors for 1,25(OH)inf 2Dinf 3 and that this hormone is extremely potent in inhibiting their proliferation, prompted an exploration of the possible use of the hormone in the treatment of scleroderma.

Xie Y.; Jingde L.; Wenjie C.; et al.
Capital Hosp., Chinese Acad. Med. Sci., Beijing China
Chinese Medical Journal (China) 1981, 94/2 (85-93)

We have successfully treated 2 series of patients with the 'incurable disease' scleroderma with Chinese traditional medicine according to the traditional medicine principle of stimulating circulation to end stasis (SCES) (Huoxue huayu) and have found it useful. Its value was first seen in the first series of 104 cases treated from May 1960 to March 1966 and later confirmed in a second series of 123 cases. In the second series, in addition to the decoction, we added intralesional and/or acupuncture point injections of herbal extracts. Of the 123, 43 had systemic scleroderma and 80 circumscribed scleroderma. In the systemic group, the effective rate was 97.7%, of which 37.2% had marked improvement, while in the 80 cases of circumscribed scleroderma the figures were 97.5% and 46.3%. The histopathologic changes under light and electron microscopy confirmed the therapeutic efficacy of the combined treatment. The main SCES therapeutic effect appears to be improvement of circulation, especially the microcirculation, and connective tissue metabolism.

Rowell N.
Gen. Infirm., Leeds United Kingdom
Practitioner (United Kingdom) 1977, 219/1314 (820-825)

The important recent developments in diseases in which scleroderma is a feature can be summarized as follows. The distinction between morphoea (localized or generalized) and systemic sclerosis is valid. The former tends to improve over the years without treatment. Patients with systemic sclerosis usually die from the disease but may live for over 30 years after diagnosis. The prognosis is worse in males than in females. The presence of histocompatibility antigen B8 and impairment of cellular immunity in a patient with systemic sclerosis are other adverse prognostic factors. There is still no specific treatment for sclerodermatous disorders. Systemic steroids may help patients with mixed connective tissue disease and eosinophilic fasciitis. Occupational scleroderma occurs in industry after exposure to vinyl chloride and pesticides.

Szczepanski A.; Dabrowska H.; Moskalewska K.
Klin. Dermatol., AM, Warszawa Poland
Przeglad Dermatologiczny 1974, 61/4 (525-527)

Fifteen cases of scleroderma (8 of acroscleroderma type, 2 of diffuse scleroderma, 5 of circumscribed scleroderma) were treated with piascledine. In part of cases of acrosclerosis treated over a period of a few months in a dose from 3 to 6 capsules an improvement was obtained. It was characterized mainly by a decrease in the intensity of arthralgia and a better movability of fingers and, in circumscribed scleroderma, by a lessening of skin indurations. In all cases but one in which transient gastrointestinal disturbances and papular eruption occurred drug tolerance was very good.

Teh LS; Johns CW; Shaffer JL; Booth EJ; Aarons L; Bennett RJ; Herrick AL; Jayson MI
Rheumatic Diseases Centre, Radioisotope Department, University of Manchester, UK.
J Rheumatol (Canada) Dec 1997, 24 (12) p2353-7

OBJECTIVE. To investigate whether reduced circulating levels of ascorbic acid in patients with systemic sclerosis (SSc) are a result of malabsorption.

METHODS. Eight patients with SSc, but with no evidence of bacterial overgrowth, and 8 healthy controls were recruited. On the first day of study, each subject was given orally an aliquot of [14C] ascorbic acid, which was then "flushed out" by oral intake of unlabeled ascorbic acid for the following 7 days. Plasma samples were collected at specified intervals and urine was collected continuously over the 8 day study period. [14C] content of plasma and urine were measured by scintillation counting. For each subject, a plasma [14C] decay curve was drawn. Each subject's ascorbic acid absorption was assessed using the area under the curve (AUC) and the apparent renal clearance (CLr[app]). Ascorbic acid intake was assessed using dietary history and food composition tables.

RESULTS. There were no differences in the dietary intake of vitamin C (p = 0.16) and body mass indices (p = 0.91) between patients and controls. The plasma [14C] AUC and CLr(app) were similar between patients and controls [AUC patient mean (standard deviation, SD) = 37.1 (6.8), AUC control mean (SD) = 38.6 (9.9), p = 0.74; CLr(app) patient mean (SD) = 0.57 (0.24), CLr(app) control mean (SD) = 0.47 (0.27), p = 0.45].

CONCLUSION. There was no evidence of impaired absorption of ascorbic acid in patients with SSc without bacterial overgrowth compared to healthy controls.

Stainforth JM; Layton AM; Goodfield MJ
Department of Dermatology, General Infirmary, Leeds, United Kingdom.
Acta Derm Venereol (Norway) Mar 1996, 76 (2) p144-6

Systemic sclerosis is a multi system disorder, for which there is no satisfactory treatment. Theoretically, dietary supplementation with essential fatty acids may lead to an increase in their derivatives, the vasoactive prostaglandins, which benefit the acute and chronic ischaemic lesions of this disease. We assessed the value of concentrated essential fatty acids in patients with systemic sclerosis, concentrating particularly on vascular symptoms and objective tests of vascular reactivity. Twenty-five patients with systemic sclerosis were randomised to receive concentrated essential fatty acids or placebo, for 6 months in a double-blind parallel group study. There was no significant difference between the active and placebo groups in terms of maximum blood flow after warming, minimum blood flow after cooling or the recovery time after cooling. There were no significant differences between the groups in the other parameters measured. Dietary essential fatty acids have no role in the treatment of vascular symptoms in established systemic sclerosis.

Herrick AL; Worthington H; Rieley F; Clarke D; Schofield D; Braganza JM; Jayson MI
University of Manchester Rheumatic Diseases Centre, Hope Hospital, Salford, UK.
J Rheumatol (Canada) Apr 1996, 23 (4) p650-3

OBJECTIVE. To document habitual intakes of micronutrient antioxidants in patients with systemic sclerosis (SSc) in light of studies reporting subnormal levels of ascorbate and selenium in this patient group.

METHODS. Dietary intakes of vitamin C, selenium, alpha-tocopherol, beta-carotene, and sulfur amino acid precursors of glutathione were assessed using the 7 day weighed record in 12 patients with SSc and in 12 healthy control subjects. The intakes of the first 4 substances were examined in relation to plasma/serum levels, while intakes of sulfur amino acids were examined in relation to urinary inorganic sulfate.

RESULTS. Antioxidant and sulfur amino acid intakes were similar in patients and controls, although the patients had lower levels of selenium (median 74 compared to 87 milligrams in controls; p = 0.014) and of vitamin C in plasma (median 6.0 compared to 11.1 milligrams/l in controls; p = 0.08). Inorganic sulfate concentration in urine was similar in patients and controls.

CONCLUSION. Our results suggest that reduced blood levels of the water soluble antioxidants selenium and ascorbic acid in patients with SSc are not due to dietary deficiency. Other explanations must therefore be sought.

Bruckdorfer KR; Hillary JB; Bunce T; Vancheeswaran R; Black CM
Department of Rheumatology, Royal Free Hospital School of Medicine, London, England.
Arthritis Rheum (United States) Aug 1995, 38 (8) p1060-7

OBJECTIVE. To examine the resistance to oxidation of low-density lipoproteins (LDL) from patients with systemic sclerosis (SSc) and primary Raynaud's phenomenon (RP) compared with healthy controls.

METHODS. Plasma LDL were isolated from patients with diffuse cutaneous and limited cutaneous SSc (dcSSc and lcSSc, respectively), patients with primary RP, and healthy control subjects. The lipoproteins were assessed for their resistance to oxidation in the presence of cupric ions, using spectrophotometric assays.

RESULTS. LDL from patients with dcSSc and lcSSc were more susceptible to oxidation than were those from healthy control subjects or patients with RP.

CONCLUSION. Our findings suggest that free radicals may play a role in the pathology of SSc.

Herrick AL; Rieley F; Schofield D; Hollis S; Braganza JM; Jayson MI
University of Manchester Rheumatic Diseases Centre, Hope Hospital, Salford, UK.
J Rheumatol (Canada) Aug 1994, 21 (8) p1477-83

OBJECTIVE. To investigate the possibility that micronutrient antioxidant status is an important factor in determining the severity of Raynaud's phenomenon (RP) and in differentiating between patients with primary Raynaud's phenomenon (PRP) and those in whom Raynaud's is secondary to systemic sclerosis (SSc).

METHODS. Four micronutrient antioxidants (selenium, vitamin E, beta-carotene and ascorbic acid) and 2 "markers" of free radical associated activity were assayed in peripheral blood from 10 patients with PRP, 9 with limited cutaneous SSc (ISSc), 9 with diffuse SSc (dSSc) and 15 healthy control subjects.

RESULTS. Plasma ascorbic acid was reduced in all 3 groups of patients: median level 10.6 mg/l in controls, 4.8 mg/l in PRP (p < 0.01), 2.5 mg/l in ISSc (p < 0.01) and 6.8 mg/l in dSSc (p < 0.05). A reduction in serum selenium was especially found in dSSc (median 75 micrograms/l compared to 100 micrograms/l in controls, p < 0.05). In keeping with these deficiencies, the serum concentration of 9, 11, linoleic acid was elevated in RP patients: median values for the molar ratio of the isomer to the parent fatty acid were 1.91% in controls, 3.70% in ISSc (p < 0.05) and 3.85% in dSSc (p < 0.01). Smoking patients showed lower levels of ascorbic acid and higher levels of the linoleic isomer than nonsmokers.

CONCLUSION. Deficiencies of ascorbic acid and selenium may predispose towards irreversible tissue injury in RP patients and cigarette smoke may be an independent risk factor. Micronutrient antioxidant supplements may be of therapeutic value.

Lundberg AC; Akesson A; Akesson B
Department of Rheumatology, University of Lund, Sweden.
Ann Rheum Dis (England) Oct 1992, 51 (10) p1143-8

Oesophageal dysmotility and abnormalities of intestinal function are important manifestations in systemic sclerosis and may have a significant effect on nutrient absorption and nutritional status. In this study 30 patients with systemic sclerosis with symptoms from the gastrointestinal tract were compared with matched healthy control subjects with respect to nutrient intake (four day record), anthropometric measurements, and biochemical nutritional status. The intake of energy (8.1 and 8.4 MJ/day) and its distribution among nutrients did not differ between patients and control subjects, but the lower intake of dietary fibre among patients with systemic sclerosis suggests that they avoided food with a coarse structure, such as coarse bread. The intake of vegetables and fruit also tended to be lower among patients with systemic sclerosis. Half of the patients had a subnormal arm muscle circumference, and two patients also had a subnormal triceps skinfold thickness, indicating severe malnutrition. The concentration of ascorbic acid, alpha-tocopherol, carotene, selenium, and also the proportion of linoleic acid (18:2) in serum phosphatidylcholine was lower in patients than in control subjects.

Horrobin DF
Scand J Rheumatol Suppl (Sweden) 1986, 61 p242-5

Evidence from biochemical studies and from experimental animals indicates that abnormalities of essential fatty acid (EFA) and eicosanoid metabolism could lead to salivary and lacrimal gland atrophy and to immunological and cardio-vascular defects. Measurements of EFA levels in erythrocytes from patients with primary Sjogren's syndrome have shown that abnormalities are indeed present. Controlled clinical trials of supplementation with gamma-linolenic acid (GLA) as evening primrose oil (Efamol) in both primary Sjogren's syndrome and systemic sclerosis have given positive results. There are strong arguments to indicate that sophisticated manipulation of EFA metabolism may have a role to play, not only in Sjogren's syndrome but also in other rheumatological disorders. ( 16 Refs.)

Halle O.; Schaeverbeke T.; Bannwarth B.; Dehais J.
O. Halle, Institut Bergonie, 180, Rue Saint-Genes, 33076 Bordeaux France
Revue de Medecine Interne (France) 1997, 18/3 (219-229)

The etiology of scleroderma remains unknown. Although a genetic susceptibility seems to play a role, some environmental and iatrogenic factors have been suggested to trigger the disease. Contact for many months or years with natural or synthetic 'toxic' products (by inhalation, cutaneous contact, injection, swallowing or surgical implant) could be implicated in the development of typical scleroderma or pseudo-scleroderma. These products are either occupational or non occupational like those used at home in daily life. We will sum up the knowledges about this subject.

Czirjak L.; Nagy Z.; Szegedi G.
3rd Department of Medicine, University Medical School,H-4004 Debrecen Hungary
Clinical Rheumatology (Belgium) 1992, 11/4 (483-485)

In our study, the characteristics of 114 patients with systemic sclerosis (SSc) are discussed with emphasis on the subgroup of cases whose onset of disease occurred above the age of 60 years. Seven out of the 9 cases showed symptoms of diffuse cutaneous systemic sclerosis with an extensive skin involvement, and 5 of these cases died within 2 years following the onset of SSc. Seven of the 9 cases showed a rapid disease course with symptoms of cardiac, pulmonary and/or renal involvement, while no secondary Sjogren's syndrome, subcutaneous calcinosis and myositis were demonstrated among these patients.

Fleischmajer R.; Pollock J.L.
Hahnemann Med. Coll. Hosp., Philadelphia, Pa. United States
Clinics in Rheumatic Diseases (United States) 1979, 5/1 (243-261)

Pseudoscleroderma is a term coined in the medical literature to encompass a collection of diseases characterized by skin induration or atrophy resembling that encountered in progressive systemic sclerosis (PSS) or localized scleroderma. A broad spectrum of aetiologically unrelated disorders has been included in the pseudosclerodermas. The skin induration in this heterogeneous group is due to a variety of factors, including an increase in collagen and glycosaminoglycans, deposition of amyloid, and changes in the fatty acid composition of the subcutaneous tissue (Jablonska, 1975). In this chapter, the term pseudoscleroderma will be restricted to a group of disorders characterized by skin induration due to fibrosis of the dermis and/or the subcutaneous tissue. We include among the pseudosclerodermas: scleredema, diffuse fasciitis with blood eosinophilia, progeria, Werner's disease, carcinoid syndrome, chronic graft-versus-host disease, porphyria cutanea tarda, phenylketonuria, scleromyxoedema, scleroderma-like lesions due to bleomycin therapy, occupational sclerodermas and melorheostosis with linear scleroderma. The clinical picture and pathogenesis of each disease are reviewed, and the cutaneous manifestations resembling scleroderma are described in detail.

Emerit I; Filipe P; Meunier P; Auclair C; Freitas J; Deroussent A; Gouyette A; Fernandes A
Institut Biomedical des Cordeliers, Universite Paris VI, et CNRS, France.
Dermatology (Switzerland) 1997, 194 (2) p140-6

BACKGROUND: Scleroderma patients exhibit increased chromosomal instability due to circulating clastogenic plasma factors (CF). Formation and action mechanisms of CF are mediated by superoxide. In addition, previous work detected inosine triphosphate (ITP) in the plasma of 2 patients, and the enzyme adenosine deaminase (ADA) was found to be increased.

OBJECTIVE: To study correlations between CF, ITP and ADA levels, CF and disease activity, as well as other biomarkers of oxidative stress.

METHODS: Clastogenic activity was evaluated by means of cytogenetic methods in 48 patients and 55 healthy subjects. ITP was detected by mass spectrometry and electrospray ionisation. ADA was measured with a colorimetric assay and malondialdehyde using the Yagi method.

RESULTS: Clastogenic activity was significantly increased in patients' plasma compared to controls. In 10 patients CF, ITP and ADA were studied simultaneously. All three parameters were increased in the 7 patients of subgroups 2 (skin and esophagus involvement) and 3 (skin plus multiple organ involvement). ITP was not detected in 2 patients of subgroup 1 (skin involvement only) with low ADA and CF values.

CONCLUSION: ITP, the deamination product of ATP, is one of the clastogenic and superoxide generating components of CF. The formation of this deamination product of ATP is probably related to the increase in ADA. CF are biomarkers of oxidative stress and can be used for evaluation of antioxidant treatments in scleroderma.

Stein CM; Tanner SB; Awad JA; Roberts LJ 2nd; Morrow JD
Vanderbilt University, Nashville, Tennessee 37232, USA.
Arthritis Rheum (United States) Jul 1996, 39 (7) p1146-50

OBJECTIVE. Free radical-induced oxidative stress with consequent lipid peroxidation and resultant tissue damage has been suggested as a potential mechanism of the pathogenesis of scleroderma. However, because reliable measurement of lipid peroxidation in vivo is difficult, it has not been possible to adequately examine this hypothesis. We have previously described a series of bioactive prostaglandin F2-like compounds, termed F2-isoprostanes, produced in vivo in humans by the non-cyclooxygenase, free radical-catalyzed, peroxidation of arachidonic acid and have shown them to be a reliable measure of lipid peroxidation in vivo. In the present study, we determined whether scleroderma is associated with enhanced oxidative stress.

METHODS. As a measure of oxidative stress, we determined urinary concentrations of a tetranor-dicarboxylic acid metabolite of F2-isoprostanes (F2IP-M) by mass spectrometry in 8 patients with scleroderma (representing a wide spectrum of disease, including limited disease with refractory digital ulceration or pulmonary hypertension, and diffuse disease) and in 10 healthy control subjects.

RESULTS. F2IP-M concentrations were significantly higher in patients with scleroderma (mean +/- SEM 3.41 +/- 0.64 ng/mg of creatinine) than in healthy controls (1.22 +/- 0.14 ng/mg of creatinine) (P = 0.002). These elevations occurred in patients with limited disease and in those with diffuse disease.

CONCLUSION. The increased level of urinary F2IP-M supports the hypothesis that free radical-induced oxidative injury occurs in scleroderma and provides a biologic marker whose relationship to disease activity and disease therapy may be important. These findings may also provide a rationale for exploring whether antioxidant therapy may influence the natural course of the disease.

Howe S; Eaker EY; Sallustio JE; Peebles C; Tan EM; Williams RC Jr
Department of Medicine, University of Florida, Gainesville 32610.
J Clin Invest (United States) Aug 1994, 94 (2) p761-70

The pathogenesis of gastrointestinal (GI) dysmotility in scleroderma is incompletely understood, although previous studies have proposed a neuropathic mechanism. We studied patients with scleroderma as compared with other connective tissue disease patients and normal controls for the presence of circulating antibodies to myenteric neurons. Serial dilutions of sera were overlaid on rat intestine, double-labeled with antineurofilament antibody as a myenteric plexus marker, and imaged using indirect immunofluorescence techniques. High titer sera (> or = 1:50) from 19 out of 41 scleroderma patients stained myenteric neurons, whereas none of 22 normals or 5 patients with idiopathic GI dysmotility were positive. Although 6 out of 20 SLE and 6 out of 10 mixed connective tissue disease patients' sera stained myenteric plexus neurons, when positive sera were absorbed with calf thymus extract to remove antinuclear antibody, 15 scleroderma sera, 0 SLE, and 2 mixed connective tissue disease patients retained positive staining of myenteric neurons. Western blotting using actin and neuronal intermediate filament preparations failed to show immunoreactivity with scleroderma sera containing antimyenteric neuronal antibodies. Paraneoplastic sera associated with GI dysmotility stained myenteric neurons in a different pattern than seen with scleroderma sera. A positive correlation between the presence of Raynaud's phenomenon and antimyenteric neuronal antibodies was observed in scleroderma patients. Our results indicate that IgG antibodies reacting with myenteric neurons are present in many patients with scleroderma. Although the neuronal antigen has not yet been identified, the presence of myenteric neuronal antibodies in patients with GI dysmotility and scleroderma suggests a neuropathic process.

Suchkova TN; Sharova NM; Suchkov SV
Vestn Dermatol Venerol (USSR) 1990, (2) p47-50

To help the physicians choose a rational scheme of combined therapy of patients with various immunopathologic forms of focal scleroderma, the authors present a clinical and immunologic assessment of the efficacies of 2 combined therapeutic courses, enzyme immunotherapy and penicillin immunotherapy, as well as of the individual course of tactivin immunotherapy. Inclusion of tactivin in any complex therapeutic scheme appears to be necessary. In patients suffering from the condition for a long time, with multiple foci of involvement, tactivin should be combined with enzymic drugs, like hyaluronidase (lydase). Enzyme immunotherapy promoted a more active resolution of the skin process. Penicillin immunotherapy alone is disputable, and further studies of such treatment are necessary. Enzyme immunotherapy should be considered as the optimal scheme of rational combined treatment for focal scleroderma.

Wilson TJ; Van de Water J; Mohr FC; Boyd RL; Ansari A; Wick G; Gershwin ME
Department of Internal Medicine, University of California, Davis 95616.
J Autoimmun (England) Jun 1992, 5 (3) p261-76

T cell activation is dependent upon calcium influx and protein kinase C activation, with subsequent lymphocyte proliferation dependent upon IL-2. Abnormalities in T cell proliferation, including abnormal calcium influx and defective protein kinase C activation, have been identified in aged mice and humans and many autoimmune diseases including diabetes, lupus and scleroderma. Since UCD line 200 chickens, which spontaneously develop a scleroderma-like disease, have both thymic defects and a diminished peripheral blood lymphocyte response to IL-2, we have further investigated T cell function in these birds. Interestingly, line 200 T cells respond poorly in vitro to a variety of diversely acting T cell mitogens including concanavalin A, phytohemagglutinin and anti-chicken CD3 monoclonal antibody. Moreover, they do not respond well even to phorbol myristate acetate in conjunction with ionomycin. Addition of exogenous IL-2-containing supernatant concurrently with mitogenic stimulation also had no significant effect. Analysis of intracellular free calcium demonstrated that the lymphocytes from diseased birds had a reduced influx of calcium (or release for intracellular stores) following stimulation. These data clearly reflect a unique defect in T cell activation associated with avian scleroderma. Analysis of chicken CD3, CD4 and CD8 expression revealed a 39% decrease in peripheral blood CD4+ cells in scleroderma birds, although this decrease was not sufficient to explain the 80-90% decrease observed in proliferation assays and calcium influx. Our data support the hypothesis that avian scleroderma is mediated via abnormal function of lymphocyte co-stimulatory molecules or intracellular calcium regulators.

Suchkova TN; Sharova NM; Cheknev SB; Suchkov SV
Vestn Dermatol Venerol (USSR) 1990, (3) p35-8

Studies of the function of cyclic nucleotide system in the lymphocytes of patients with focal scleroderma have revealed that this condition is characterized by growth of the intracellular cAMP/cGMP ratio, correlating with the process duration, severity, and dissemination. A correlation between lymphocyte regulatory function defect and the presence of immunodeficiency syndrome was demonstrated. Sensitivity of lymphocytic cyclic nucleotides in focal scleroderma patients to thymoptin, a thymic agent, was examined. Manifest clinical effect of this drug is based on stabilization of the function of lymphocytic cyclic nucleotides system and, consequently, on normalization of the immunologic parameters. Potentialities and prospects of thymic factors immunotherapy of focal scleroderma patients are discussed.

de Clerck LS; Dequeker J; Francx L; Demedts M
Arthritis Rheum (United States) Jun 1987, 30 (6) p643-50

Sequential lung function tests were performed on 17 scleroderma patients who were treated with D-penicillamine (DP) (total of 66 treatment years) and on 10 control scleroderma patients who were not treated or were treated with low-dose prednisone (total of 25 treatment years). Cusum plots showed significant differences between the 2 groups in their cumulative changes in carbon monoxide diffusing capacity (DLCO) (P less than 0.005) and in DLCO/lung volume (P less than 0.02). The end value of the DLCO was greater than 10% lower than the initial value in 3 of the 17 DP-treated patients versus 5 of the 10 control patients (P less than 0.01, Fisher's exact probability test); in 3 DP-treated patients and 8 control patients (P less than 0.003, Fisher's exact probability test), the end value of the DLCO/lung volume was greater than 10% lower than the initial value. We conclude that DP has a beneficial effect on interstitial lung disease in patients with scleroderma.

Binnick SA; Shore SS; Corman A; Fleischmajer R
Arch Dermatol (United States) Oct 1977, 113 (10) p1398-402

Nineteen patients with systemic scleroderma and five with localized scleroderma were treated with topical dimethyl sulfoxide by painting and immersion techniques. Partial control was obtained by using a very low concentration (5%) on one side when involvement was symmetrical. Duration of treatment ranged from 3 to 15 months. Topical dimethyl sulfoxide did not improve the skin induration, range of motion, or Raynaud's phenomenon in the scleroderma patients. No substantial beneficial effect was noted on the healing of ischemic ulcers, and the continuous application of dimethyl sulfoxide did not prevent new ulceratins from developing. Relief of pain was noted in ten of 16 patients, probably due to the local analgesic effect of dimethyl sulfoxide.

Davis P.; Bleehen S.S.
Dept. Med., Univ. Alberta, Edmonton Canada
British Journal of Dermatology 1976, 94/6 (705-711)

D Penicillamine (B'B'' dimethylcysteine) is a drug widely known for its clinical therapeutic benefit in the treatment of Wilson's disease and cystinuria. A number of recent studies have demonstrated that penicillamine may be therapeutically active in other diseases including rheumatoid arthritis (RA), progressive systemic sclerosis (PSS), morphea and active chronic hepatitis, as well as acting as a chelator of a number of heavy metals. The increasing number of therapeutic indications for D penicillamine therapy need to be clearly defined and its ill effects plainly identified. This review concentrates on the present value of this drug in the treatment of rheumatoid arthritis and progressive systemic sclerosis.

Morita A; Minami H; Sakakibara N; Sato K; Tsuji T
Department of Dermatology, Nagoya City University, Medical School Nagoya, Japan.
J Dermatol Sci (Ireland) Mar 1996, 11 (3) p196-201

Injury to vessel walls, especially microvascular damage due to free radicals, has been a focus of interest concerning the pathogenesis of systemic sclerosis. Excess reactive oxygen species may induce antioxidant defenses. We therefore measured plasma superoxide dismutase (SOD) activity in patients with systemic sclerosis and found average SOD activity of plasma in 16 patients with systemic sclerosis (5.00 +/- 3.10 U/ml) to be significantly (P < 0.001) higher than those in 89 healthy volunteers (1.56 +/- 0.234 U/ml). Patients with Raynaud's phenomenon and/or skin sclerosis had particularly high SOD activity. These findings suggest that plasma SOD activity may serve as a useful parameter for assessment of sclerotic progression and the presence of Raynaud's phenomenon.

Marchiori PE; Scaff M; Cossermelli W; De Assis JL
Arq Neuropsiquiatr (Brazil) Dec 1984, 42 (4) p380-3

The development of autoimmune diseases in some patients treated with D-penicillamine (DPA) suggests that the reported occurrence of a conduction disorder at the neuromuscular junction and the development of a reversible myasthenia gravis in rheumatoid disease, progressive systemic sclerosis or Wilson's disease after the use of DPA are part of a general predisposition for autoimmune disease related to DPA therapy. The case reported is an example. The DPA- induced myasthenia gravis (MG) is similar to the spontaneous MG clinically and electrophysiologically, though ocular signs prevail in the former. Antibodies to acetylcholine receptor have been demonstrated and thymic hyperplasia also has been formed. Regarding the onset of myasthenic manifestations the duration of the treatment with DPA varies from 6 to 10 months. The action of DPA on the neuromuscular junction is different from that occurring in spontaneous MG. The pathogenesis of the DPA induced MG is still obscure. The chemical properties of DPA permit it to react with many proteins and some alteration of proteins may appear, with structural changes in the composition and antigenicity of the collagen fibers. In vitro DPA causes disorder of acetylcholine receptor bridges to alpha, beta, gamma sub-units with reduction of the S-S bridges in the gamma-subunit. This decreases the linkage of high affinity and abolishes its positive cooperative system, reducing the S-S connection in the alpha-unit near the acetylcholine linkage. The interaction between DPA and receptor may induce antigenic alteration in this latter, starting the autoimmune phenomena. The other possibility is the stimulation of prostaglandin E-1 synthesis by DPA may fill the allosteric place of ACh receptor, interfering on the neuromuscular junction.

Carter J; Ewen SW; Gray E; Beck JS
J Pathol (England) May 1973, 110 (1) p97-100

No abstract.

Pope J
University of Western Ontario, London, Canada.
Curr Opin Rheumatol (United States) Nov 1993, 5 (6) p792-801

Although there have been no major breakthroughs in scleroderma therapy, new treatments have been tested in patients with systemic sclerosis, including both interferon alfa and interferon gamma. These biologic agents can reduce collagen synthesis, which is a rational target for scleroderma therapy. Debate about the use of photopheresis continues, and it was suggested in a recent editorial that photopheresis is no better than D-penicillamine in the treatment of scleroderma and is more expensive. Cyclosporine appears to have frequent renal toxicity when used to treat scleroderma. Outcome measurements have been concentrated on in scleroderma trials. Several types of scleroderma classifications were compared, and the classification of diffuse and limited scleroderma was strongly related to disease severity. Skin score was systematically compared with mapping the surface area of involved skin, and the skin score was found to be more reliable. A possible prognostic indicator in scleroderma is high-resolution pulmonary computed tomography, which is sensitive in early detection of scleroderma-associated interstitial lung disease. Classification of Raynaud's phenomenon into primary and secondary forms has been proposed, and further testing of the criteria and long-term follow-up is necessary to validate this classification. Over the past year, treatment of vasospasm with prostacyclin analogues has been efficacious with iloprost but not with low-dose oral cicaprost. Tissue plasminogen activator is not beneficial in the treatment of Raynaud's phenomenon. A report of radical microarteriolysis for the treatment of refractory Raynaud's phenomenon seems promising, warranting further investigation. (70 Refs.)

Sattar MA; Guindi RT; Sugathan TN
Department of Medicine, Faculty of Medicine, Kuwait University.
Clin Rheumatol (Belgium) Dec 1990, 9 (4) p517-22

In a 36-month prospective trial 21 patients with systemic sclerosis (diffuse systemic sclerosis 16 patients and 5 subjects with limited cutaneous subtype) were treated with D-penicillamine. In all patients with diffuse systemic sclerosis there was objective improvement. The degree and extent of skin involvement decreased significantly (p less than 0.001), whereas no objective improvement was noted in patients with limited cutaneous subtype. Further, no systemic progression of the disease was observed during the study period. Our results suggest that a prolonged treatment with D-penicillamine in small doses is not only beneficial and effective but also free of side-effects, if used at an earlier stage.

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Alarcon-Segovia D.
Dept. Immunol. Rheumatol., Inst. Nac. Nutric., Mexico City Mexico
Clinics in Rheumatic Diseases (United States) 1979, 5/1 (294-302)

Our studies indicate that colchicine appears to halt the progression of PSS, and probably of the localized forms of scleroderma as well, and causes improvement in a substantial proportion of patients. Such improvement takes place mainly in the skin and has been significant enough to be corroborated by the histological examination of skin biopsies evaluated without knowledge of the clinical situation. Some improvement has also occurred at sites of involvement other than the skin, particularly in regard to dysphagia and Raynaud's phenomenon. The nature of our study did not allow us to determine if treatment with colchicine may prevent the development of renal or lung involvement. Patients who were begun on treatment with colchicine earlier in the course of their disease had significantly greater improvement than those who were first treated after disease of longer duration. Long-term treatment appeared to be required as evaluated by the correlation between improvement and total colchicine dose received. The apparent innocuity of long-term treatment with colchicine and the beneficial effects which have been observed warrant the use of this agent in the treatment of PSS. Early and prolonged use appear particularly desirable.

DiGiacomo RA; Kremer JM; Shah DM
Division of Rheumatology, Albany Medical College, New York 12208.
Am J Med (United States) Feb 1989, 86 (2) p158-64

PURPOSE: The ingestion of omega -3 fatty acids could benefit patients with Raynaud's phenomenon because, among other effects, these fatty acids induce a favorable vascular response to ischemia. The aim of our study was to investigate, in a double-blind, placebo-controlled manner, the effects of fish - oil fatty-acid dietary therapy in patients with rheumatic disease.

PATIENTS AND METHODS: Thirty-two patients with primary or secondary Raynaud's phenomenon were randomly assigned to olive-oil placebo or fish - oil groups. Patients ingested 12 fish -oil capsules daily containing a total of 3.96 g eicosapentaenoic acid and 2.64 g docosahexaenoic acid or 12 olive-oil capsules and were evaluated at baseline and after six, 12, and 17 weeks. All patients ingested olive oil between Weeks 12 to 17. Digital systolic blood pressures and blood flow were measured at room air and water baths of 40 degrees C, 25 degrees C, 15 degrees C, and 10 degrees C using strain gauge plethysmography. Onset of Raynaud's phenomenon was timed with a stop watch and defined as plethysmographic evidence of cessation of blood flow and blood pressure in the study finger.

RESULTS: In the fish -oil group, the median time interval before the onset of Raynaud's phenomenon increased from 31.3 +/- 1.3 minutes baseline to 46.5 +/- 2.1 minutes at six weeks (p = 0.04). Patients with primary Raynaud's phenomenon ingesting fish oil had the greatest increase in the time interval before the onset of the condition. Five of 11 patients (45.5 percent) with primary Raynaud's phenomenon ingesting fish oil in whom the phenomenon was induced at baseline could not be induced to develop Raynaud's at the six- or 12-week visit compared with one of nine patients (11 percent) with primary Raynaud's ingesting olive oil (p = 0.05). The mean digital systolic pressures were higher in the patients with primary Raynaud's phenomenon ingesting fish oil than in patients with primary Raynaud's ingesting olive oil in the 10 degrees C water bath (+32 mm Hg, p = 0.02).

CONCLUSION: We conclude that the ingestion of fish oil improves tolerance to cold exposure and delays the onset of vasospasm in patients with primary, but not secondary, Raynaud's phenomenon. These improvements are associated with significantly increased digital systolic blood pressures in cold temperatures.

Zarafonetis CJ; Dabich L; Negri D; Skovronski JJ; DeVol EB; Wolfe R
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor.
J Clin Epidemiol (England) 1988, 41 (2) p193-205

Demographic and survival data are presented for 390 patients with scleroderma . For the entire group an estimated 81.4% survived 5 years from diagnosis and 69.4% survived 10 years. Life-table analyses revealed that adequate treatment with potassium para-aminobenzoate (Potaba KPAB) was associated with improved survival (p less than 0.01); 88.5% 5 year survival rate and 76.6% 10 year survival rate for adequately treated patients. Five and ten year survival rates for patients never treated with KPAB were 69.8 and 56.6%, respectively. Similar findings were obtained by comparing observed to expected mortality for these patients; again, KPAB therapy showed prolongation of survival. The Cox proportional hazards model was also applied to this retrospective study adjusting for baseline clinical involvement, demographics and KPAB treatment. There were some interesting results including a high significance for skin involvement per se as a prognostic indicator: the greater the extent of skin involvement the poorer prognosis. Time from first diagnosis to first University Hospital visit or admission when included as a covariate did not influence survival.

Herouy Y; May AE; Pornschlegel G; Stetter C; Grenz H; Preissner KT; Schopf E; Norgauer J; Vanscheidt W
Department of Dermatology, University-Hospital, Freiburg, Germany.
J Invest Dermatol (United States) Nov 1998, 111 (5) p822-7

Lipodermatosclerosis refers to skin induration of the lower extremities and is associated with patients preceding venous ulcerations. To better understand the pathogenesis of ulcer formation we investigated the expression of matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMP) in lipodermatosclerosis. By preparing biopsies from healthy skin and liposclerotic lesions, MMP-1, MMP-2, MMP-9, TIMP-1, and TIMP-2 were analyzed by using reverse transcriptase-polymerase chain reaction, western blot, zymography, hydrolysis of [3H]labeled collagens, and immunohistochemistry. Our investigations provide evidence that mRNA and protein expression of MMP-1, MMP-2, and TIMP-1 were significantly increased in lipodermatosclerosis, whereas the total amount of MMP-9 and TIMP-2 mRNA and protein was not altered. Western blot of liposclerotic lesions revealed an inactive proMMP-1-TIMP-1 complex, whereas MMP-2 was prominent as an active 66 kDa band. Increased proteolytic activity of MMP-2 could be proven in lesional in comparison with healthy skin by zymography and [3H] collagen degradation. Increased diffuse staining was found for MMP-1 in the epidermis and dermis in comparison with controls. In lipodermatosclerosis, MMP-2 was predominantly localized in the basal and suprabasal layers of the epidermis, in perivascular regions, and in the reticular part of the dermis. Furthermore, MMP-2 was imbalanced by locally reduced expression of TIMP-2 in the basement membrane zone of lesional skin. Our findings indicate lipodermatosclerosis to be characterized by elevated matrix turnover.

LeRoy EC
J Invest Dermatol (United States) Jul 1982, 79 Suppl 1 p87s-89s

Increasing interest in the vascular features of scleroderma has led to the hypothesis that the blood vessel is the major target tissue and that the endothelial cell is the principal cell target. Useful observations stemming from the vascular hypothesis include the use of microvascular abnormalities in the early detection of the patient destined to develop classical scleroderma, the discovery of a serum protease selectively cytotoxic to endothelial cells, and the study of a serum mitogenic activity for fibroblasts in scleroderma patients. Immune events related to the vascular lesions are under active study but have not as yet provided a unique immunological lesion in scleroderma patients. The possibility that immunity to basement membrane (type IV) collagen may be selective for scleroderma patients deserves further study. Persistent immunity to endothelial basement membrane structures would provide a basis for continued endothelial injury. Techniques to quantify endothelial injury are useful to assess activity of the vascular lesions and to monitor therapies designed to block further vascular injury. The definition of pre-fibrotic vascular lesions may have future therapeutic and preventive implications for scleroderma .

Matsuoka LY; Dannenberg MJ; Wortsman J; Hollis BW; Jimenez SA; Varga J
Department of Dermatology, Jefferson Medical College, Philadelphia, PA 19107.
J Rheumatol (Canada) Aug 1991, 18 (8) p1196-8

Progressive systemic sclerosis (PSS) is a predominantly dermal disorder which may be associated with epidermal atrophy. We investigated epidermal function in 8 patients with PSS and their healthy controls matched for age, sex and racial group. We measured the vitamin D3 photosynthetic response to whole body irradiation with ultraviolet light B (UVB). There were no significant differences in basal serum vitamin D3 levels (mean +/- SEM: PSS 1.2 +/- 0.2 ng/ml; controls 0.8 +/- 0.1 ng/ml; p greater than 0.1) or post UVB blood values (PSS 5.2 +/- 1.4 ng/ml; controls 6.9 +/- 1.1 ng/ml; p greater than 0.1); although the increases post-UVB were significant in both groups (p less than 0.01). In an additional group of 19 patients with PSS and their corresponding matched healthy controls, we performed determination of random levels of the active vitamin D metabolites, 25-hydroxyvitamin D (25-OH-D) and 1,25-dihydroxyvitamin D [1,25-(OH)2-D]. Similar levels were observed in both groups: 25-OH-D PSS 28 +/- 3 ng/ml, controls 29 +/- 3 ng/ml; 1,25-(OH)2-D PSS 27 +/- 2 pg/ml, controls 31 +/- 2 pg/ml (p greater than 0.1). None of the correlations between skin area involved and vitamin D3 formation or active circulating metabolites reached statistical significance (p greater than 0.1). We conclude that global epidermal synthesis of vitamin D is retained in PSS and, that the hepatic and renal vitamin D hydroxylating mechanisms function normally in that condition.

Humbert P; Dupond JL; Agache P; Laurent R; Rochefort A; Drobacheff C; de Wazieres B; Aubin F
Department of Dermatology and Vascular Diseases, Hopital St Jacques, Besancon, France.
Acta Derm Venereol (Sweden) Dec 1993, 73 (6) p449-51

1,25-dihydroxycholecalciferol (1,25 (OH)2 D3) causes dose-dependent inhibition of fibroblast growth and collagen synthesis and has numerous immunoregulatory activities. We assessed the effects of oral 1,25 (OH)2 D3 in the treatment of patients with systemic sclerosis (SS). Eleven patients with SS entered an open prospective study. Oral 1,25(OH)2 D3 was given at a mean dose of 1.75 micrograms/day. The effects of the treatment were evaluated using clinical examination and physical measurements. After the treatment period (6 months to 3 years), a significant improvement, as compared with baseline values, was observed. No serious side-effects were observed. These results suggest that high-dose 1,25 (OH)2 D3 may be a useful therapeutic agent for scleroderma .

Humbert PG; Dupond JL; Rochefort A; Vasselet R; Lucas A; Laurent R; Agache P
Department of Dermatology, Centre Hospitalier Universitaire St-Jacques, Besancon, France.
Clin Exp Dermatol (England) Sep 1990, 15 (5) p396-8

1, 25 - Dihydroxyvitamin D3 [1,25(OH)2 D3] may be an immunomodulatory drug which could have a role in controlling collagen deposition, and inducing reversal of fibrosis in some tissues. These observations prompted a study of the possible use of this hormone for the treatment of scleroderma . A 35-year-old woman, who had been suffering from localized scleroderma for 2 years, was given oral 1,25(OH)2 D3 for 6 months. The effects of the treatment were evaluated using clinical and physical measurements (skin thickness, extensibility properties of the skin). The evolution of the patient's condition during the 6-month therapy suggests that 1,25(OH)2 D3 is beneficial in localized scleroderma . The mechanisms of action are discussed in relation to the literature, which suggests both immunoregulatory and inhibitory effects on fibroblast growth.

Adams JS; Singer FR; Gacad MA; Sharma OP; Hayes MJ; Vouros P; Holick MF
J Clin Endocrinol Metab (United States) May 1985, 60 (5) p960-6

Hypercalcemia and hypercalciuria in sarcoidosis are thought to result from the endogenous overproduction of an active vitamin D metabolite. We employed primary cultures of pulmonary alveolar macrophages from two patients with biopsy-proven pulmonary sarcoidosis and a recent or current clinical abnormality in calcium metabolism to synthesize in vitro a 1,25 - dihydroxyvitamin D3 [1,25-(OH)2D3]-like metabolite from 25-hydroxyvitamin D3 (25OHD3). The macrophage metabolite cochromatographed with [3H]1,25-(OH)2D3 on normal phase and reverse phase high performance liquid chromatography and was bound with high affinity by the chick intestinal receptor for 1,25-(OH)2D3. On UV spectroscopy, the metabolite possessed the carbon-5,7,10 (19) cis-triene chromophore characteristic of a vitamin D sterol. Electron impact mass spectrometry of trimethylsilyl ether derivatives of the metabolite revealed a mass fragmentation pattern similar to that of the trimethylsilyl ether derivative of authentic 1,25-(OH)2D3. The incubation of cultured macrophages from two patients with idiopathic pulmonary fibrosis and two with scleroderma with [3H]25OHD3 did not result in production of a metabolite with the chromatographic identity of 1,25-(OH)2D3. These data indicate that the metabolite of 25OHD3 synthesized by sarcoid macrophages in vitro is 1,25-(OH)2D3 and that the macrophage is a synthetic source of the sterol metabolite in sarcoidosis.

Torres MA; Furst DE
University of Medicine and Dentistry, New Jersey, Robert Wood Johnson Medical School, New Brunswick.
Rheum Dis Clin North Am (United States) Feb 1990, 16 (1) p217-41

Over the years, many encouraging uncontrolled studies extolling treatments of SSc have appeared, but initial impressions were not corroborated when controlled trials were done. This article points out that certain recent studies have effectively ruled out the use of some specific therapies for the general treatment of systemic sclerosis. Thus, sufficient data has been generated to rule out the use of n-acetylcysteine, colchicine, chlorambucil, cyclofenil, and DMSO, at least in disease of longer duration. Ketanserin and prostaglandin infusions probably also belong in this group, as they affect only Raynaud's phenomenon. Angiotensin enzyme inhibitors, while probably life-saving in renal crises, do not seem to affect the underlying systemic sclerosis per se. Another group of drugs has only limited supportive data and await well-controlled trials to prove or disprove their effectiveness. These include: 5-fluorouracil, D-penicillamine, drugs affecting platelet function (dipyridamole), and para-aminobenzoic acid. There are a few treatments which have potential. Factor XIII has only limited data using controlled trials, but what does exist seems positive. Apheresis is encouraging, although the success of this treatment modality may be dependent upon a "combination" approach. Ongoing studies with gamma-interferon, photopheresis, and the mast cell stabilizer ketotifen appear exciting, and we await reports of their use in scleroderma . On another level, new insights into genomic alterations in skin fibroblasts and T-cell proto-oncogene expression have contributed to the understanding of the pathogenesis of this disease at the cellular level and new methods to measure change in disease will help gauge response to therapy. Thus, we look forward to more definitive treatment of SSc in the future. (129 Refs.)

Murav'ev IuV; Loskutova TT; Anikina NV; Shcherbakov AB; Sokolov VB
Ter Arkh (USSR) 1989, 61 (12) p106-9

Using a blind method for assessing the results, a study was made of the effect of dimethylsulfoxide (DMSO) on fibrin formation and microcirculation in 42 patients with rheumatic diseases (rheumatoid arthritis, systemic scleroderma, Raynaud's syndrome). It has been shown that the therapeutic effect of DMSO in rheumatic diseases is determined to a definite degree by its normalizing action on fibrin formation and microcirculation.

Williams HJ; Furst DE; Dahl SL; Steen VD; Marks C; Alpert EJ; Henderson AM; Samuelson CO Jr; Dreyfus JN; Weinstein A; et al
Arthritis Rheum (United States) Mar 1985, 28 (3) p308-14

A prospective, randomized, double-blind trial compared topical therapy with 0.85% normal saline, 2% dimethyl sulfoxide (DMSO), and 70% DMSO for treatment of digital ulcers in 84 patients with systemic sclerosis. There were no statistically significant differences among the 3 treatment groups in the improvement in the total number of open ulcers, total surface area of open ulcers, average surface area per open ulcer, number of infected ulcers, number of inflamed ulcers, or patient pain assessment. While some patients improved during the study, improvement could not be attributed to a specific treatment. Over one-quarter of the patients treated with 70% DMSO were withdrawn for significant skin toxicity.

Scherbel AL
Ann N Y Acad Sci (United States) 1983, 411 p120-30

DMSO exerts a palliative, therapeutic effect on healing of cutaneous ulcers in systemic sclerosis. The therapeutic response was variable and, therefore, the concentration of DMSO, as well as frequency and duration of treatments, should be individualized to obtain maximum healing effect with a minimum of adverse reactions. There was no evidence of ocular toxicity or other serious toxicity manifestations in this group of patients treated with topical DMSO for one year or longer. Delayed improvement was observed in the untreated extremity in the majority of patients studied. In no instance did improvement in the untreated extremities exceed improvement in the treated, bilateral counterpart. It is believed this resulted from a systemic, carry-over effect of DMSO rather than spontaneous improvement in the disease course. DMSO is a worthwhile, supplemental, therapeutic agent providing the limitations of therapy are understood.

Namaka M.; Briggs C.
Health Sciences Centre,Winnipeg, Man. Canada
Canadian Pharmaceutical Journal (Canada) 1994, 127/5 (248-249+255)

Dimethylsulfoxide, more commonly referred to as DMSO, was discovered in 1866. A clear, colorless, odorless industrial solvent, it is hygroscopic in nature and miscible with water and organic solvents. In the mid 1960s, DMSO became popular for its potential as a therapeutic agent and a pharmaceutical solvent. Known as a wonder drug, it was alleged useful in a variety of indications ranging from arthritis to mental retardation. In 1965, the legal use of DMSO was restricted because of ocular toxicity produced in animals during various investigational studies. This side effect was not confirmed in humans and DMSO is currently approved in Canada for two indications: scleroderma and interstitial cystitis. Various experiments have looked at the external and systemic adverse effects of topical application of DMSO . Hemolysis, CNS toxicity, nephrotoxicity and hepatotixicity have occurred after IV administration of DMSO in humans. Similar toxicities have appeared when DMSO was given orally. The route of administration influenced the nature and degree of toxicity observed. Ocular toxicity was more prone to develop in animals when DMSO was given orally. Teratogenic effects of DMSO have been demonstrated in rabbits and chickens, but not observed in other species.

Alyabyeva A.P.; Muravyev Y.V.
Inst. Rheum., USSR Acad. Med. Sci., AMN Moscow Russia
Annals of the New York Academy of Sciences (United States) 1983, Vol. 411/- (309-315)

This is a report of control trials using DMSO in 199 patients. Seventy patients were diagnosed as suffering from rheumatoid arthritis (RA), and ranged in age from 17 to 75 years. Thirty-five children ages 5-13 were diagnosed with juvenile chronic arthritis (JCA). The diagnosis was made according to American Rheumatology Association (ARA) criteria. Sixty-five patients ranging in age from 18-65, had Sjogren's syndrome. The diagnosis was based on clinical and laboratory findings. Twenty-nine patients suffered from systemic scleroderma with pronounced and extensive skin involvement. In 6 patients, ulcerations of fingers were seen. All 199 patients continued basic anti-inflammatory therapy: 60 received corticosteroids (20-30 mg by mouth), 40 received intra-articular hydrocortisone injections (due to resistant synovitis) which were, however, ineffective. The key selective principle was the absence or a slight effect in response to the basic therapy. Before DMSO application, all patients had undergone a tolerance test: 50% DMSO (always diluted with distilled water) was applied on the back of the hand and 30% solution over the parotid glands. The follow-up lasted for 24 hours. Dermatitis on the tested areas was seen in only two cases. These patients were excluded from the trial. Patients and physicians knew that they were receiving DMSO application but not the concentration or drug combinations. These details were known only to the chief of the experimental trial, Dr. A.P. Alyabyeva. The course of treatment lasted for two weeks. Each patient received 200 ml of 50% DMSO .

Kappert A.
Dept. Clin. Angiol., Univ. Med. Sch., Bern Switzerland
Annals of the New York Academy of Sciences 1975, Vol. 243/- (403-407)

The topical use of dimethyl sulfoxide (DMSO) as a trigger substance for the accumulation of antiinflammatory, analgesic, and venotropic compounds in regions of the extremities that have acute or chronic venous disorders offers a new approach to this still neglected therapeutic field. The clinical results are in accordance with the experimental findings and with the known properties of DMSO itself.

Levin M.S.
Department of Medicine, Washington University, School of Medicine, Box 8124, 660 South Euclid Ave,St Louis, MO 63110 United States
Current Opinion in Gastroenterology (United Kingdom) 1992, 8/2 (224-231)

Issues in the medical management of small intestinal disease that were addressed in the recent scientific literature include the following: 1) bile acid malabsorption, including the etiologic role of an ileal brush-border bile salt carrier and the diagnostic value of the sup 7sup 5Se homocholic acid taurine test; 2) small bowel bacterial overgrowth, including the role of bacteria in vitamin B12 malabsorption in atrophic gastritis and in pathogenesis of hepatobiliary complications; 3) short bowel syndrome, including the effects of somatostatin analogue therapy; 4) small intestinal tumors, including the diagnostic value of small bowel enteroscopy and plasma postheparin diamine oxidase measurements and therapy for carcinoid syndrome and primary intestinal lymphoma; 5) prevention and treatment of radiation enteropathy; and 6) pathogenesis and diagnosis of nonsteroidal anti-inflammatory drug enteropathy.

Calas M.E.; Sayag J.; Castelain P.Y.; et al.
France
Marseille Med. 1975, 112/7-8 (419)

There was a presentation of several slides corresponding to 5 cases aged from 60 to 70 years, similar to 9 cases collected by the Dermatological School of Bordeaux and published in No 4 of 1972 of Annales de Dermatologie. It is the mixing of other products (adrenoxyl, reptilase, vitamin B12) with vitamin K1 that seems to produce a pharmacodynamic incompatibility in subjects, mostly cirrhotics, with a haemorrhagic syndrome. The lumbo gluteal infiltrations appear in the months following the injections. They spread out in plaques of scleroderma, like a belt of armour, right up to the trochanteric regions. They develop for several years and no treatment is really efficacious.

Hallgren R; Berne C
Acta Med Scand (Sweden) 1983, 213 (5) p351-5

Nine of 16 patients with inflammatory connective tissue diseases (rheumatoid arthritis, polymyalgia rheumatica, scleroderma and mixed connective tissue disease) had glucose intolerance defined a a K-rate less than one but a normal early insulin response to intravenous glucose loading. The degree of the impaired glucose handling was related to the degree of inflammatory activity as defined by acute phase reactants. Glucocorticoid therapy induced within three days an improved and normalized glucose tolerance and an augmented early insulin response (p less than 0.001). The glucocorticoid effect was still present up to six months of ongoing therapy. It is suggested that glucose intolerance in chronic inflammation is a consequence of a peripheral insulin antagonism and an inhibition of insulin secretion. This inhibition may be mediated directly or indirectly by inflammatory cell products and may be sensitive to glucocorticoids.

Alonso-Llamazares J; Ahmed I
Department of Dermatology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, USA.
J Am Acad Dermatol (United States) Feb 1998, 38 (2 Pt 2) p322-4

We describe a 45-year-old white man in whom distinctive clinical and histologic features of localized scleroderma developed at sites of injection of vitamin K1 (phytonadione). A direct immunofluorescence test demonstrated prominent linear deposition of IgA along the basement membrane zone. No circulating antibasement membrane zone IgA antibodies were identified on indirect immunofluorescence testing. We believe that the unusual immunofluorescence finding in our patient is nonspecific and represents an epiphenomenon caused by cutaneous injury. (18 Refs.)

Sheng FY; Ohta A; Yamaguchi M
Department of Internal Medicine, Saga Medical School.
Intern Med (Japan) Aug 1994, 33 (8) p466-71

The in vitro effect of one traditional Chinese herbal medicine (Japanese name: "Keishi-bukuryo-gan"), which has been empirically used in scleroderma patients in China and Japan, on collagen production in fibroblast cultures was studied. Fibroblasts from 3 scleroderma patients and 2 normal controls were incubated with various concentrations of "Keishi-bukuryo-gan" and collagen production was then determined by a radiochemical method. "Keishi-bukuryo-gan" significantly and selectively inhibited collagen synthesis in a dose-dependent manner, with a tendency of a stronger effect on scleroderma fibroblasts than control cells. The results may explain the clinical usefulness of this medicine, and it may become a promising new agent for the treatment of scleroderma.

Poskitt LB; Duffill MB; Rademaker M
Department of Dermatology, Waikato Public Hospital, Hamilton, New Zealand.
Clin Exp Dermatol (England) May 1994, 19 (3) p264-7

The case of a 53-year-old man who developed chloracne, palmoplantar keratoderma and scleroderma after many years of exposure to a variety of chloracnegens is reported. Chloracne is a rare but important acneiform eruption associated with exposure to halogenated aromatic compounds used primarily in agriculture. However, to our knowledge, the association of palmoplantar keratoderma and scleroderma with exposure to chloracnegens has not been previously reported.

Yuan X; Li JD
Chung Hsi I Chieh Ho Tsa Chih (China) Jan 1989, 9 (1) p19-21, 5

Of 725 cases of scleroderma, 265 were of systemic type (the sex ratio being 1M:6F) and 460 of circumscribed type (the sex ratio being 1M:9F). The patients were divided into three groups and treated with three different stimulating circulation to end stasis (SCES) prescriptions. Satisfactory therapeutic effects were obtained in all. According to the clinical practice and laboratory findings, although SCES therapy exerted manifold actions on the disease, it not only softened the indurated connective tissues, tonified the body and improved the symptoms, but also improved laboratory indexes as follows: nailfold bed capillary, parameter of the peripheral blood stream in patients, content of urinary 2-ketol, 17-KS, free corten, serum joint-hexose, amino-hexose and histopathology including ultrastructure of the skin. The main effect was the improvement of circulation, especially the microcirculation and regulation of the metabolism of the connective tissues. Great attention should be paid to the drug's function of softening the indurated connected tissues. For further investigation, the authors have stressed three important points: screening of clinical symptoms and signs, examination of blood circulatory disturbances, and examination of pathological changes of the connective tissue. The necessity of developing new criteria for judging the therapeutic effects was emphasized.

Baron M; Keystone EC; Gladman DD; Lee P; Poplonski L
Clin Exp Immunol (England) Oct 1981, 46 (1) p70-6

T lymphocyte subpopulations were studied in 40 patients with scleroderma (PSS), 26 of whom were studied simultaneously for lymphoproliferative responses to phytohaemagglutinin (PHA), concanavalin A (Con A) and pokeweed mitogen (PWM). PSS patients exhibited a reduction relative to 42 age- and sex-matched controls in the absolute number and percentage of early E rosettes, late E rosettes and E rosettes formed with aminoethylisothiouronium bromide (AET) treated sheep red blood cells. There was no difference between patients and controls in the proportions of B lymphocytes. PSS patients exhibited normal lymphocyte transformation responses to PHA and ConA and an augmented response to PWM. The mitogen responses did not correlate with the absolute number or percentage of lymphocytes or T and B lymphocyte subpopulations. No correlation was observed between any immunological variable studied and the extent of skin or organ involvement, disease duration or therapy.

Horwitz DA; Garrett MA
Clin Exp Immunol (England) Jan 1977, 27 (1) p92-9

The mitogenic reactivity of lymphocytes from subjects with systemic lupus erythematosus, rheumatoid arthritis and scleroderma was studied. Cultures containing either unseparated or separated lymphocytes were stimulated with phytohaemagglutinin, Con A and pokeweed mitogen after inhibitory serum factors were eluted from the cell surface. Incorporation of [3H]thymidine in patient cultures was compared to that of normal controls. Greatly decreased reactivity was found in SLE to all three mitogens. Significantly decreased values to some mitogens was also observed in rheumatoid arthritis and scleroderma, but the defect was less severe. Cultures of study subjects contained significantly fewer small lymphocytes than normal controls and this finding explained at least in part the decreased mitogenic reactivity.

Mittal BR; Wanchu A; Das BK; Ghosh PP; Sewatkar AB; Misra RN
Department of Nuclear Medicine, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.
Clin Nucl Med (United States) May 1996, 21 (5) p379-82

Gastric emptying studies, using an indigenously prepared radiolabeled solid food marker in the form of Indian bread called Chapati, were performed on 13 patients with systemic sclerosis. Six patients had limited cutaneous disease and seven had diffuse cutaneous disease. Earlier, the procedure was standardized in 30 healthy volunteers. Seven of the 13 (54%) patients (five with diffuse and two with limited cutaneous disease) had delayed gastric emptying. Most of these patients had gastric symptoms. This pattern of gastric emptying may be clinically significant, particularly in patients with diffuse cutaneous disease.

Yuan X; Chen M
PUMC Hospital, CAMS, Beijing.
Chin Med Sci J (England) Jun 1991, 6 (2) p107-9

Forty cases of overlap syndrome of progressive systemic sclerosis and polymyositis (OS PSS-PM) are reported in this paper. All of these cases had manifestations of both PSS and PM as well as Raynaud's phenomenon. The sclerodermatous skin changes were diffused over the whole body in most cases. All cases had muscular weakness, elevated skeletal muscle enzyme levels and muscle damage as seen on the electromyogram. Histopathologic changes showed characteristics of myositis. There was noticeable systemic involvement, especially with the digestive and circulatory systems. Serologic examination frequently revealed autoantibodies. The patients responded well to traditional Chinese medicines and corticosteroids.

Chun WH; Bang D; Lee SK
Department of Dermatology, Yonsei University College of Medicine, Seoul, Korea.
J Dermatol (Japan) May 1996, 23 (5) p347-51

We report a case of secondary antiphospholipid syndrome (APS) occurring in a progressive systemic sclerosis (PSS) patient who took herbal medication. Clinical findings compatible with APS included positive IgM anticardiolipin antibody (ACL), thrombocytopenia, and obstruction of the left radial artery on digital subtraction angiography (DSA). Clinical findings compatible with PSS included sclerodactyly and digital ulcers, Raynaud's phenomenon, pulmonary fibrosis and pulmonary hypertension, proteinuria and renal mesangial reaction, and myocarditis.

Bostrom H.; Herbai G.
Med. Klin., Akad. Sjukh., Uppsala Sweden
Lakartidningen (Sweden) 1979, 76/4 (207-210)

Scleroderma is an uncommon but complex disease. The onset is slow and the progress chronic. The main pathophysiological changes vary, affecting blood vessels, connective tissue, collagen fibres, fibrin deposition and inflammatory reactions. There may be early oedema and a wide spectrum of organic involvement. Clinically, all the fibril-containing and connective tissue organs are subject to various degrees of attack. The most common organic manifestations are: the Raynaud phenomenon in the arms and hands, vascular fibrosis, stiff and hard facial skin, restriction of joint movement by pericapsular hardening, calcium deposition and capsular rigidity. In the gastro-intestinal tract, muscular atrophy, collagen and connective tissue damage are common, especially at the cardia of the stomach. Malabsorption may occur. Progressive pulmonary fibrosis leads to formation of cor pulmonale and respiratory insufficiency. The liver, kidneys and endocrine glands are seldom involved, however. Therapeutic trials have been performed using many different groups of drugs: experiment to influence connective tissue, thyroxine, and a variety of anti-rheumatic agents. In the last decade the best short-term clinical results have been achieved with penicillamine, some vasodilators, chlorambucil (Leukeran), and, recently a potent anti-oestrogen: cyclofenil, which has marked connective tissue and collagen metabolism influencing properties. Good therapeutic effects without serious sideeffects have been achieved.

Langtry JA; Rowland Payne CM; Staughton RC; Stewart JC; Horrobin DF
Department of Dermatology, Westminster Hospital, London, UK.
Clin Exp Dermatol (England) Sep 1997, 22 (5) p216-9

A randomised, double-blind, placebo-controlled trial with lithium succinate ointment was conducted in patients with AIDS-associated facial seborrhoeic dermatitis. Twice daily applications of the ointment brought about a rapid (2.5 days) and highly significant (P = 0.007) improvement in the severity of the condition. Lithium succinate ointment is well tolerated and can be a useful treatment for seborrhoeic dermatitis in this group of patients.

Cunningham BB; Landells ID; Langman C; Sailer DE; Paller AS
Department of Pediatrics, Northwestern University Medical School, Chicago, Illinois, USA.
J Am Acad Dermatol (United States) Aug 1998, 39 (2 Pt 1) p211-5

BACKGROUND: Morphea and linear scleroderma are characterized by erythema, induration, telangiectasia, and dyspigmentation. There is no universally effective treatment. Oral calcitriol has been beneficial in the treatment of localized and extensive morphea/scleroderma, but the use of topical calcipotriene has not been reported.

OBJECTIVE: The purpose of this study was to evaluate the efficacy and safety of topical calcipotriene 0.005% ointment in the treatment of localized scleroderma.

METHODS: In a 3-month open-label study, 12 patients aged 12 to 38 years with biopsy-documented active morphea or linear scleroderma applied calcipotriene ointment under occlusion twice daily to plaques for 3 months. The condition of each patient had previously failed to respond to potent topical corticosteroids and, for some patients, systemic medications. Efficacy was assessed at baseline, 1 month, and 3 months. Levels of serum ionized calcium, intact parathyroid hormone, and 1,25-dihydroxyvitamin D and of random urinary calcium excretion were measured.

RESULTS: During the 3-month trial, the condition of all 12 patients showed statistically significant improvement in all studied features. No adverse effects were reported or detected through laboratory monitoring of mineral metabolism.

CONCLUSION: Topical calcipotriene 0.005% ointment may be an effective treatment for localized scleroderma, but double-blind placebo controlled studies are needed for confirmation.

Krasagakis K; Dippel E; Ramaker J; Owsianowski M; Orfanos CE
Department of Dermatology, University Medical Center Benjamin Franklin, Free University of Berlin, Germany.
Dermatology (Switzerland) 1998, 196 (3) p309-15

BACKGROUND: The management of systemic sclerosis remains unsatisfactory. Thus far, the action of extracorporeal photopheresis (ECP) in severe systemic scleroderma has been evaluated in short-term studies, and only limited experience has been obtained with long-term application.

OBJECTIVE: The aim of the present study was to evaluate prospectively the long-term effect of ECP in a group of 16 patients suffering from severe scleroderma, showing visceral involvement and progressive clinical course.

METHODS: Fourteen patients with systemic scleroderma involving several organs, 1 with CREST syndrome and another with scleroderma-myositis overlap syndrome were treated with ECP over a period of 6-45 months. In 3 cases, gamma-IFN was additionally administered. Skin and visceral involvement were assessed by evaluating a series of clinical criteria and results from laboratory, imaging and functional tests.

RESULTS: Overall, clear improvement was encountered in 6 patients, mixed response in 2, stable disease in 3 and continuing progressive course in 5 patients. Four out of 6 patients with improvement were treated with ECP early after onset of scleroderma (< or = 2 years), whereas all patients with a progressive course under ECP had had scleroderma for longer than 2 years. Immunosuppressive drugs previously administered could be reduced or fully withdrawn under ECP treatment in 5 patients, but additional oral medication was introduced in 4 patients due to disease progression. Addition of gamma-IFN to ECP did not reveal further benefit . No side-effects were recorded under ECP treatment.

CONCLUSIONS: Based on this observation, we believe that long-term ECP represents an effective treatment modality in severe scleroderma particularly when started early, with stabilization of the disease course and partial remission of the cutaneous findings, whereas visceral involvement, if present, may rarely improve.

Kanekura T; Fukumaru S; Matsushita S; Terasaki K; Mizoguchi S; Kanzaki T
Department of Dermatology, Kagoshima University Faculty of Medicine, Japan.
J Dermatol (Japan) Jul 1996, 23 (7) p455-9

PUVA therapy was carried out on four patients with scleroderma; three of them had cutaneous manifestations of progressive systemic sclerosis and one other exhibited generalized morphea. PUVA therapy was given with daily doses of 0.25J/cm2 or 0.4J/cm2 for 3-8 weeks, resulting in total doses between 3.5J/cm2 and 9.6J/cm2. All four patients responded well to this treatment; improvements of hand closure, skin sclerosis index, and flexion of fingers or knee joints were obtained. Thus, PUVA appeared to be beneficial for treating scleroderma.

Boelsma E; Pavel S; Ponec M
Department of Dermatology, University Hospital Leiden, The Netherlands.
Dermatology (Switzerland) 1995, 191 (3) p226-33

BACKGROUND: Scleroderma is a fibrotic disorder of unknown etiology that is characterized by excessive collagen synthesis and its deposition in the skin and various internal organs.

OBJECTIVE: To examine whether an overproduction of extracellular matrix molecules is a result of either increased fibroblast proliferation or increased collagen synthesis. As results of clinical trials with 1,25-dihydroxyvitamin D3 (calcitriol) have suggested beneficial effect in the treatment of scleroderma patients, the effects of calcitriol on fibroblasts derived from scleroderma and normal skin has been examined as well.

METHODS: Cultures of fibroblasts were established from biopsies from involved and uninvolved skin of scleroderma patients and from skin of healthy subjects, and compared with respect to proliferation, collagen synthesis and collagen lattice contraction.

RESULTS: No significant differences in cell proliferation and in the extent of fibroblast-induced collagen lattice contraction have been found between scleroderma patients exhibited a disorganized growth pattern in a monolayer culture in contrast to normal fibroblasts. Collagen synthesis tends to be higher in scleroderma fibroblasts as compared with controls. Calcitriol exerted an antiproliferative and antisynthetic effect on fibroblasts, which, however, did not discriminate healthy fibroblasts from fibroblasts derived from involved or uninvolved scleroderma plaques.

CONCLUSIONS: Our findings suggest that collagen accumulation may not result from increased proliferation or altered dynamic properties of fibroblasts in a scleroderma lesion but from increased collagen biosynthesis. We additionally found that calcitriol does not selectively affect scleroderma fibroblasts.

Takeda K; Hatamochi A; Arakawa M; Ueki H
Department of Dermatology, Kawasaki Medical School, Kurashiki, Japan.
Arch Dermatol Res (Germany) 1993, 284 (8) p440-4

Recent studies have demonstrated that tumor necrosis factor-alpha (TNF-alpha) selectively decreases production of collagens I and III, the major types of collagen in the dermis, and increases production of collagenase in cultured dermal fibroblasts. The effects of TNF-alpha on collagens I, III and VI, fibronectin and collagenase gene expression by fibroblasts derived from normal individuals and patients with systemic sclerosis (SSc) were studied. SSc is characterized by excessive accumulation of collagen in the skin and in certain organs. TNF-alpha inhibited collagen production and mRNA levels of collagens I and III and of fibronectin, and stimulated collagenase activity and collagenase mRNA levels in SSs fibroblasts. Levels of mRNA for alpha 1 (VI) and alpha 3 (VI) collagen and for beta-actin were unaltered in SSc fibroblasts incubated with TNF-alpha. Similar results were observed for mRNA levels in normal fibroblasts incubated with TNF-alpha. These results suggest that TNF-alpha could be expected to be beneficial in the treatment of SSc. In addition, our results indicated that collagen-VI expression is regulated independently from expression of collagens I and III, and expression of fibronectin and collagens I and III are regulated in parallel in fibroblasts treated with TNF-alpha.

Ruthlein HJ; Riegger G; Auer IO
Medizinische Universitatsklinik Wurzburg.
Z Rheumatol (Germany) Jan-Feb 1991, 50 (1) p16-20

Eleven patients with severe Raynaud's syndrome were treated with intravenous infusion of prostacyclin (Prostaglandin I2). Raynaud's syndrome was caused by inflammatory diseases such as progressive systemic sclerosis (N = 9) or thromboangiitis obliterans (N = 2). Five patients had acral ulcerations. Treatment with prostacyclin lead to immediate cessation of acral pain in all patients if doses of 5-6 ng/kg/min were tolerated. In 7 out of 11 patients there was a long-term analgesic effect with clinical improvement of Raynaud's syndrome. In three of five patients we achieved healing of the ulcerations within a few weeks. Plasmaconcentrations of prostaglandin F1-alpha, the main metabolite of prostacyclin, were about 10 times above normal during infusion and returned to normal levels within 30 min after the end of the infusion, in spite of the prolonged clinical effect. Therefore, prostacyclin alone cannot be responsible for the long-term clinical benefit . (Parts of this publication were published as an abstract and presented at the 23rd Congress of the Deutsche Gesellschaft fur Rheumatologie (15).

Gruber BL; Kaufman LD
Department of Medicine, State University of New York, Stony Brook 11794-8161.
Arthritis Rheum (United States) Mar 1991, 34 (3) p362-6

To determine the efficacy of the mast cell-stabilizing drug ketotifen in scleroderma, we conducted a 6-month, randomized, prospective, double-blind, placebo-controlled trial in 24 patients. No significant improvement in the clinical parameters, pulmonary function, global assessments, and mast cell releasability was noted. Pruritus tended to improve in the group taking the active drug. Six months of treatment with ketotifen (6 mg/day), therefore, produced no apparent benefit in patients with early scleroderma. We were unable to address the role of mast cells in scleroderma since mast cell suppression was not achieved.

Paye M; Read D; Nusgens B; Lapiere CM
Laboratory of Experimental Dermatology, Tour de Pathologie, CHU du Sart Tilman, University of Liege, Belgium.
Br J Dermatol (England) Mar 1990, 122 (3) p371-82

The administration of Factor XIII (FXIII) produces a beneficial effect on the skin lesions in about 50% of the treated patients with progressive systemic sclerosis (PSS). The effect of FXIII on various skin fibroblast functions (proliferation, attachment, biosynthetic activity and mechanical properties) was investigated in vitro using normal and PSS strains. In cell culture, most of the PSS fibroblast strains synthesized excessive amounts of collagen. Other cell functions such as adhesion to collagen I or III, to fibronectin, retraction of collagen lattices, proliferation in low serum concentration and degradation of newly synthesized collagen were not significantly different. The addition of FXIII (I U/ml) inhibited the synthesis of collagen by normal fibroblasts and reduced it in PSS fibroblasts to a level similar to that of normal fibroblasts. This effect was observed for cells cultured on plastic or in a collagen lattice. In the latter, an increased amount of collagen degradation was observed. No significant effect of FXIII on the other cell functions was noted. Excessive collagen production by PSS fibroblasts can be repressed by FXIII in vitro by at least two distinct mechanisms: a reduction of collagen synthesis and an increased degradation of the newly synthesized collagen.

Casas JA; Saway PA; Villarreal I; Nolte C; Menajovsky BL; Escudero EE; Blackburn WD; Alarcon GS; Subauste CP
Department of Medicine, Universidad Peruana Cayetano Heredia, Lima, Peru.
Ann Rheum Dis (England) Nov 1990, 49 (11) p926-8

A six month controlled study of 5-fluorouracil in the treatment of scleroderma showed a modest benefit in skin scores, Raynaud's phenomenon, and patients' global assessment. Visceral organ and hand function were unaffected. Mild to moderate toxicity was common in the 5-fluorouracil treated patients but usually responded to dose reduction. Two patients receiving 5-fluorouracil died from causes seemingly unrelated to treatment. Significant clinical improvement in scleroderma was not noted in the first six months of treatment with 5-fluorouracil.

Krieg T; Meurer M
Dermatology Clinic and Polyclinic, Ludwig-Maximilian University of Munchen, FRG.
J Am Acad Dermatol (United States) Mar 1988, 18 (3) p457-81

Systemic scleroderma is a generalized disease of connective tissue involving mainly the skin, the gastrointestinal tract, the lungs, the heart, and the kidneys. It can be present in different forms, of which acroscleroderma, with limited cutaneous and extracutaneous involvement, and diffuse scleroderma within a more rapid progression are most characteristic. Circulating antibodies against antinucleolar antigens are present in most patients with systemic scleroderma. They are helpful for establishing a classification and for determining the prognosis of the disease; their involvement in the pathogenesis, however, is still unclear. Alterations of the blood vessels and induction of fibroblasts by potent mediators are thought to play an important role in the early phase of scleroderma. Therefore early diagnosis is required, which then can initiate vasoactive therapy. In patients with systemic scleroderma, who also suffer from additional myositis, interstitial lung diseases, or arthritis, anti-inflammatory treatment with prednisolone and azathioprine is suggested. Development and progression of fibrosis cannot yet be influenced sufficiently. Only D-penicillamine affecting cross-linking of collagen has been widely used in scleroderma and has some beneficial effect. (160 Refs.)

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Schmidt C; Schooneman F; Siebert P; Weber M; Dureux JB; Streiff F; Schmitt J
Secteur d'Angeiologie, Medecine H, Hopital Central, CHRU Nancy.
Ann Med Interne (Paris) (France) 1988, 139 Suppl 1 p20-2

Generalized scleroderma (GS) is associated with dysimmunity anomalies suggesting possible benefits of plasma exchange (PE) therapy. Nineteen patients with GS were treated by PE (volume of plasma exchange equivalent to 5-6% body weight and replacement by 4% human albumin), initially three times weekly, then weekly, bi-monthly and monthly (total duration 12-18 months). Clinical and paraclinical follow up was for an average of more than 2 years after the end of PE (mean number 17 per patient). Clinical results were assessed as positive and lasting in 11 cases (57.9%), two cases remaining stable and three cases worsening (one death from heart failure). The remaining three cases were failures in application of treatment (difficult venous approach). Improvement was noted in cutaneous sclerosis (62% of cases), trophic disorders (recovery in 6 of 7 cases) and articular manifestations. Vasomotor disorders were improved in only 20% of cases and visceral lesions unaltered. Results of capillaroscopy showed improvement in 5 of 11 cases. Biological values could not be correlated with either the course or the therapeutic efficacy. General tolerance to PE was good but the venous approach must be of good quality. These findings suggest the need for a randomized trial to define the place of PE in the treatment of GS.

Thurm RH; Alexander JC
Arch Intern Med (United States) Apr 1984, 144 (4) p733-5

Scleroderma is a disease of unknown cause characterized by interstitial fibrosis and vascular lesions in many organ systems. Renal failure, often associated with malignant hypertension, may ensue as a life-threatening component of this disorder. Activation of the renin-angiotensin-aldosterone system has been hypothesized as a cause of this complication. Captopril has been used in 23 patients with this condition. Of this group, 20 (87%) responded favorably with a decrease of the supine diastolic BP to less than 90 mm Hg and a reduction in the serum creatinine level in 14 patients. During long-term therapy (median, 29 months), 11 of the 23 patients continued to have a good clinical response while receiving captopril. Six patients died and six patients were alive after captopril therapy was discontinued. These data suggest that captopril is beneficial in the treatment of scleroderma renal crisis.

Javier R; Dumler F; Levin NW
South Med J (United States) May 1980, 73 (5) p657-9

A patient with scleroderma and severe renal failure was initially treated with hemodialysis and minoxidil (Loniten) without any improvement in her skin involvement. At a later date bilateral nephrectomy and a successful cadaveric renal transplant were performed. Her cutaneous manifestations have improved remarkably during the four years since transplantation. Because these patients do not tolerate hemodialysis very well, renal transplantation appears to be the most effective form of treatment, with the possible added benefit of cutaneous improvement.

Herbai G; Blom B; Bostrom H
Acta Med Scand (Sweden) 1977, 201 (3) p203-6

Cyclofenil is a new diphenyl ethylene derivative related to stilboestrol without oestrogenicity but with marked effects on connective tissue metabolism. The drug has been tested, in a daily dose of 200mg X3, in six patients with progressive systemic sclerosis (PSS) to analyze the expected beneficial effects on the PSS symptoms. The typical skin hardness, joint and muscle rigidity, and reduced breathing capacity were improved to varying dgrees. The only side-effect was a slight transient liver enzyme elevation in 1 out of 6 patients. A slight increase was found in urinary calcium and hydroxyproline excretion. In several cases serum calcium, cholesterol, triglyceride and in some cases the serum uric acid levels were decreased. The ANF titres diminished to varying degrees in 4 out of 6 patients. These results indicate that further detailed clinical and laboratory studies on the therapeutic potential of cyclofenil in PSS and other diseases affecting connective tissue seen to be justified.

Thompson MA; Summers R
JAMA (United States) Apr 19 1976, 235 (16) p1715-7

Two patients with scleroderma of the bowel experienced life-threatening barium impaction after upper intestinal x-ray studies. Although the frequency of this complication is unknown, the difficulty of managing it when it occurs makes prevention imperative. X-ray studies should be performed only after careful consideration of the risks and benefits . When x-ray studies are performed, the patient should be vigorously purged soon thereafter, and a follow-up roentgenogram should be obtained to confirm adequate removal of barium.

Rudolph RI; Leyden JJ
Arch Dermatol (United States) Jul 1976, 112 (7) p995-7

When linear scleroderma traverses several joints, severe and mutilating deformities and contractures, with loss of limb function, can result. Drugs and surgical procedures are usually of little benefit in ameliorating the deformities. Physiatrics on the other hand, is a readily available modality than can restore much useful function and reverse the contractures and is probably the most effective means of treating patients with deforming linear scleroderma. This type of therapy should be instituted at the inception of the disease process so that the development and progression of any contraction can be minimized or prevented.

Akesson A.
Dr. A. Akesson, Department of Rheumatology, Lund University Hospital, S-221 85 Lund Sweden
Current Opinion in Rheumatology (United States) 1998, 10/6 (579-583)

Pulmonary manifestations are the most common cause of death in patients with scleroderma. Consequently, the importance of treatment of both interstital lung disease and pulmonary hypertension has become increasingly evident. Until a placebo-controlled study of any drug has shown its beneficial effect on pulmonary dysfunction, cyclophosphamide may be useful for the treatment of scleroderma lung disease.

Hornstein O.P.; Steffan C.; Diepgen T.L.; Hiller D.; Albrecht H.-P.; Gruschwitz M.S.
Dermatologische Universitatsklinik, Hartmannstrasse 14,91052 Erlangen Germany
H+G Zeitschrift fur Hautkrankheiten (Germany) 1993, 68/7 (437-442)

Patients with progressive systemic scleroderma (PSS) are usually treated with antifibrotic, antiinflammatory and/or vasoactive drugs. As good therapeutic experience by Staehelin using calcitonin in PSS was reported 15 years ago, we treated during the last 10 years 40/44 patients in different stages of PSS with 284 turns of intravenous calcitonin application (100 I.U. salmon calcitonin/day for 10 days, two or three times a year). This regimen was well-tolerated and resulted mostly in reduced finger-swellings and decreased frequencies of Raynaud's attacks. Concomitant side effects like nausea, headache or lowered blood pressure were rare, allergic reactions of other long-term side effects were not observed so far. Disease progress (intermittent inflammatory reactivity) occured in only 4/40 patients, whereas 36/40 remained within their former stage of PSS. The vasoactive profile of calcitonin was evaluated by determination of cutaneous microcirculation using noninvasive methods as well as by investigation of prostaglandin F(1a) serum levels during calcitonin application. Our results strongly suggest that intravenous calcitonin treatment is of therapeutical benefit in the majority of patients suffering from PSS.

Elsmann H.-J.; Rabe E.; Schuler-Pyrtek P.; Bauer R.
Universitats-Hautklinik und Poliklinik, Rheinische Friedrich-Wilhelms-Universitat, Sigmund-Freud-Str. 25, 5300 Bonn 1 Germany
H+G Zeitschrift fur Hautkrankheiten (Germany) 1991, 66/6 (533-535)

Prostaglandin Einf 1 was administered intravenously to 17 patients with progressive systemic sclerosis and secondary Raynaud's phenomenon. Microcirculation was measured by Laser-Doppler immediately before and the day after therapy 3 weeks later. Skin blood flow in resting state and during postocclusive reactive hyperemia was taken at the dorsum of the middlefinger. Assessment of the pre- and post-ischemic flux- and time parametes indicated a statistically significant improvement after PGEinf 1 therapy. In 14 out of 17 patients (82%) the number and severity of Raynaud attacks were reduced. The results show the benefit of intravenous PGEinf 1 therapy for patients with Raynaud's phenomenon in scleroderma and the usefulness of Laser-Doppler-flowmetry in evaluating the efficacy of vasoactive drugs in clinical practice.

Asboe Hansen G.
Afd. Hudsygdomme, Rigshosp., Kobenhavn
Ugeskr.Laeg. 1976, 138/22 (1325-1329)

One hundred and three patients with generalized scleroderma were followed up regularly for a period of 15 yr. Of these, 93 were treated with D penicillamine, benzyl penicillin diethyl amino ethylester hydroiodide, corticosteroids, d-thyroxine, hydralazine or 'mixed drug therapy' (one or more of the drugs administered after one another or simultaneously). The effect of d-thyroxine could not be assessed in this investigation. No lasting benefit was observed after treatment with corticosteroids. Hydralazine appears to have a favourable effect. D-penicillamine resulted in improvement occurred in 12 out of 16 improvement in 25 out of 34 patients treated, while improvement treated with Leocillin. In 6 patients, the dermal sclerosis yielded completely. In 16 patients, complete regression was observed with the exception of sclerosis of the fingers. In 32 patients, partial regression occurred. In 20 patients, progression of the disease occurred, but no evidence of regression was observed and 19 patients did not experience any benefit from the treatment. The prognosis was better in young than in older patients. The age at diagnosis was lowest in the good groups. Better results were observed with higher total doses. The duration of the treatment is probably of significance. Short term cases had better prognosis than long term cases. Twenty one untreated patients showed continued progression. Side effects leading to withdrawal of therapy occurred quite frequently, particularly after d penicillamine. Twelve deaths which occurred during the period of observation did not appear to be causally related to the treatment administered. The results have not been obtained in controlled clinical trials. Such trials, probably comprising several departments, would be desirable.

Schwartz J; Gonzalez J; Palangio M; Klainer AS; Bisaccia E
Department of Internal Medicine and Dermatology, Morristown Memorial Hospital, NJ 07962-1956, USA.
Int J Dermatol (United States) May 1997, 36 (5) p380-5

BACKGROUND: Extracorporeal photochemotherapy (photopheresis), an immune-modulating therapy, has been demonstrated to elicit a therapeutic response in the treatment of several autoimmune disorders. We evaluated the use of photopheresis in the treatment of patients with progressive systemic sclerosis (PSS; scleroderma).

METHODS: Five patients with early-onset, diffuse PSS were treated with photopheresis on 2 successive days monthly for an average of 59 months (range 54-89 months). We initially reported the response this group of patients had to photopheresis treatment at an average of 11 months (range 6-21 months).

RESULTS: An improvement or stabilization was noted in most patients in skin thickening, joint mobility, pulmonary function studies, oral aperture, functional index, as well as symptoms including Raynaud's phenomenon, dyspnea, fatigue, dysphagia, arthralgias, and cutaneous ulcers. Renal function tests remained within normal range. A total of 296 monthly treatments were administered without significant toxicity.

CONCLUSIONS: This study suggests that extended use of extracorporeal photochemotherapy in the management of early-onset, diffuse PSS is well tolerated and may provide an increasingly beneficial clinical outcome.

Di Spaltro FX; Cottrill C; Cahill C; Degnan E; Mulford GJ; Scarborough D; Franks AJ Jr; Klainer AS; Bisaccia E
Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York.
Int J Dermatol (United States) Jun 1993, 32 (6) p417-21

BACKGROUND. Extracorporeal photochemotherapy, an immune-modulating form of therapy, has been shown to be effective in the treatment of autoimmune diseases. We evaluated the effects of extracorporeal photochemotherapy in the treatment of patients with progressive systemic sclerosis (PSS).

METHODS. Nine patients with active progressive systemic sclerosis were treated with extracorporeal photochemotherapy on 2 successive days monthly. The duration of therapy ranged from 6 to 21 months.

RESULTS. A significant improvement was noted in the skin, musculoskeletal system, functional index, and symptoms including Raynaud's phenomenon, dyspnea, fatigue, dysphagia, and arthralgias, as well as improvement of cutaneous ulcers. Stabilization of the pulmonary function studies was also noted in the majority of patients over the course of therapy. No serious side effects were noted throughout the course of therapy in the 9 patients.

CONCLUSIONS. The results suggest that photopheresis may be beneficial in selected early cases of progressive systemic sclerosis.

Akesson A; Wollheim FA; Thysell H; Gustafson T; Forsberg L; Pahlm O; Wollmer P; Akesson B
Department of Rheumatology, University Hospital, Lund, Sweden.
Scand J Rheumatol (Sweden) 1988, 17 (5) p313-23

In a two-year prospective therapeutic trial, 15 patients with progressive systemic sclerosis (PSS) were treated with immunosuppressive drug therapy with or without long-term plasmapheresis. Before the trial all patients had severe involvement of either the esophagus, lungs or kidneys. One patient died of renal failure and another 2 patients withdrew unimproved. In the remaining 12 patients, objective improvement occurred in all but one. The degree and extent of skin involvement decreased significantly (p less than 0.01). Cineradiography revealed increased esophageal motility in 4 patients. Pulmonary function measured as total lung capacity and static lung compliance improved (p less than 0.01). In 4 patients the number of premature atrial or ventricular contractions at 24 h ECG monitoring decreased, as did the concentrations of immunoglobulins and ANA titres in serum. Although it could not be ascertained whether the clinical improvement was associated with combined therapy or immunosuppressive drug treatment alone, our results suggest that immunosuppressive therapy is beneficial in advanced PSS.

Martin MF; Tooke JE
Br Med J (Clin Res Ed) (England) Dec 11 1982, 285 (6356) p1688-90

The effects of prostaglandin E1 infusion on nailfold capillary haemodynamics were studied in eight patients with Raynaud's phenomenon secondary to progressive systemic sclerosis. Using a modified Landis microinjection technique the mean (+/- SEM) transcapillary pressure gradient was increased during and six weeks after infusion by 13.9 +/- 3.2 cm H2O (p less than 0.05) and 5.5 +/- 2.5 cm H2O (p less than 0.05) respectively. Capillary red cell velocity measured in two patients by video television microscopy also increased during and after infusion with prostaglandin E1. Six patients claimed subjective benefit and in three their ulcers healed. These findings support the observed beneficial effect of prostaglandin E1 and suggest that it improves the nutritive capillary circulation by lowering precapillary resistance.

Nassonova V.A.; Ivanova M.M.
Inst. Rheum., Acad. Med. Sci. USSR, Moscow Russia
Clinics in Rheumatic Diseases (United States) 1979, 5/1 (277-288)

Objective assessment of the efficacy of D-penicillamine (DPA) in the treatment of PSS is complicated by the absence of control trials. Our analysis of the available data suggests the following:

1. Application of DPA is indicated in rapidly progressive cases of PSS.

2. DPA exerts a pronounced effect on skin induration and, to a lesser extent, on visceral disturbances.

3. The beneficial effects of DPA are manifested no earlier than two months after initiation of therapy and are correlated with duration of treatment (2.5 years on average).

4. A maintenance dose of 300 to 600 mg DPA a day is recommended.

5. Clinical experience has demonstrated the expediency of combining DPA and corticosteroids for increasing the efficacy of treatment and reducing the frequency of side effects, especially of allergic reactions, and especially during the first few weeks of treatment.

6. The efficacy of therapy with DPA increases with early use of the drug, and falls in cases of more advanced PSS.

7. Side effects, both early (allergic) and late (toxic as a rule), are common during the course of treatment with DPA, necessitating that the physician exert the greatest possible care in choosing this form of treatment and in maintaining close surveillance of the patient during the entire course of such therapy.

Hughes P; Holt S; Rowell NR; Dodd J
Br J Dermatol (England) Nov 1976, 95 (5) p469-73

Circulating thymus -dependent (T) lymphocytes were estimated in twenty-seven patients with progressive systemic sclerosis (PSS) and in forty-five normal controls using the property of T lymphocytes to form rosettes with sheep red blood cells. The patients with PSS were found to have a reduction of T lymphocytes which correlated with the extent of visceral involvement by the disease, those with the lowest counts having the most extensive disease. These findings support the suggestion that immunological factors may be involved in the pathogenesis of PSS.

Sambo P; Jannino L; Candela M; Salvi A; Donini M; Dusi S; Luchetti MM; Gabrielli A
Institute of Internal Medicine, Hematology and Clinical Immunology, University of Ancona, Italy.
J Invest Dermatol (United States) Jan 1998, 112 (1) p78-84

It has been suggested that toxic oxygen free radicals can be involved in the pathogenesis of systemic sclerosis (scleroderma) (SSc). Because the cells that contribute to the generation of free radicals are not known, our aim was (i) to evaluate the ability of unmanipulated and phorbol 12-myristate 13-acetate-stimulated monocytes and polymorphonucleate neutrophils of SSc patients to generate superoxide anion (O2*-); and (ii) to investigate whether the O2*- produced by these cells involved the activation of nicotinamide-adenine dinucleotide diphosphate oxidase biochemical pathway. Employing the superoxide dismutase-inhibitable reduction of cytochrome c to evaluate the generation of O2*-, unmanipulated monocytes of SSc patients generated more O2*- than primary Raynaud's phenomenon patients and normal control monocytes (p = 0.0001), and the release was higher in patients with diffuse cutaneous involvement and 5 y or less disease duration (p = 0.02). The involvement of nicotinamide-adenine dinucleotide diphosphate oxidase in the enhanced 02*- production was demonstrated by the finding that the cytosolic components of the enzyme, p47phox and p67phox, were both translocated to the plasma membrane of enriched but otherwise unmanipulated monocytes of SSc patients. The involvement of mitochondrial oxidases was excluded by the lack of inhibition of O2*- production when monocytes were incubated in the presence of rotenone, a mitochondrial oxidase inhibitor. Upon stimulation with phorbol 12-myristate 13-acetate, monocytes of SSc patients produced more O2*- than controls. In SSc patients untreated polymorphonucleate neutrophils generated significantly less O2*- than monocytes (p = 0.0001) and only slightly more than polymorphonucleate neutrophils of primary Raynaud's phenomenon patients and normal controls (p = 0.03). In conclusion, we demonstrate that in patients with scleroderma, unmanipulated and phorbol 12-myristate 13-acetate-stimulated monocytes release in vitro increased amounts of superoxide anion through the activation of nicotinamide-adenine dinucleotide diphosphate oxidase and, thus, contribute to the oxidative stress found in this disease.

Steen VD; Medsger TA Jr
Georgetown University School of Medicine, Washington, DC 20007-2197, USA.
Arthritis Rheum (United States) Nov 1997, 40 (11) p1984-91

OBJECTIVE: To determine the validity and usefulness of a modified Health Assessment Questionnaire (HAQ) for measurement of disease status and changes in disease status over time in patients with systemic sclerosis (SSc).

METHODS: Since 1985, 1,250 patients attending the University of Pittsburgh Scleroderma Clinic have completed a modified HAQ annually. In addition to the standard HAQ questions about disability, the questionnaire includes visual analog scales (VAS) to evaluate SSc organ system symptoms, Raynaud's phenomenon, gastrointestinal (GI) tract and lung involvement, pain, and overall disease severity. In this study, the disability index (DI) (from the HAQ) and the VAS scores (on a 0-3 scale) were compared with various clinical and laboratory features recorded within 3 months of administration of the HAQ and VAS, using t-tests and Spearman's correlation tests.

RESULTS: The HAQ DI correlated directly with skin involvement, scleroderma heart or kidney disease, tendon friction rubs, hand contractures, and proximal muscle strength. Over time, the DI correlated with changes in skin score and was a good predictor of survival. There was a significant improvement in the DI during a 2-year time period in patients treated with D-penicillamine. The VAS for digital ulcers, GI symptoms, and lung symptoms correlated very closely with subjective and objective findings for these organ systems. The presence of new digital ulcers or improvement in digital ulcers showed significant associations with the Vascular scale, new GI symptoms or improvement in GI symptoms and institution of H2-blockers showed appropriate strong correlations with the GI scale, and changes in the forced vital capacity had an excellent correlation with the Lung scale (r = 0.58, P < 0.001). By Cox regression analysis, the HAQ DI was one of the best predictors of survival.

CONCLUSION: These data provide convincing evidence that a self-administered questionnaire is an accurate and inexpensive tool to measure disease status changes in SSc. Prospective studies with the HAQ administered at regular intervals, as in controlled trials, should be performed to further assess the benefits and limitations of this instrument.

Tyndall A
Department of Rheumatology, Basle University, Switzerland.
J Rheumatol Suppl (Canada) May 1997, 48 p94-7

Hematopoietic stem cells (HSC) are increasingly available as an alternative to whole marrow aspirate for bone marrow transplantation (BMT). They may be derived from an HLA matched individual (allogeneic) or from the patient (autologous). Allogeneic BMT is associated with a 15 to 35% mortality, largely due to graft versus host disease. Autologous HSC are used to rescue the patient after severe immunosuppression, and the transplant related mortality is 3 to 5%. The opportunity to ablate severe autoimmune disease with increased safety is particularly attractive for necrotizing vasculitides, polymyositis/dermatomyositis, primary Sjogren's syndrome, systemic juvenile arthritis, relapsing polychondritis, and Behcet's disease, where correct selection of cases would ensure an acceptable benefit /risk ratio. Rheumatoid arthritis (RA), psoriasis associated arthritis (PsA) and some non-rheumatic diseases such as inflammatory bowel disease (IBD), multiple sclerosis, and type 1 diabetes mellitus may also be candidates, but careful selection of patients with a poor prognosis is necessary. There are allogeneic BMT data from patients with aplastic anemia or leukemia and concurrent RA, PsA, and IBD and also autologous HSC BMT data from animal models to support the concept of cure. Patient studies should proceed using recently published protocol guidelines and centralized data collection. (25 Refs.)

van den Hoogen FH; van de Putte LB
Department of Rheumatology, University of Nijmegen, The Netherlands.
Curr Opin Rheumatol (United States) Nov 1994, 6 (6) p637-41

The treatment of systemic sclerosis remains therapeutically challenging. Until just recently, no disease-modifying intervention was proved to be effective. Over the past year, much effort has gone into setting up proposals for outcome measures and response criteria in clinical trials. Several intervention studies were published. Aminobenzoate potassium was found to be ineffective in a double-blind, placebo-controlled trial. Possible efficacy for antithymocyte globulin was suggested in two small open studies, and the dispute about the use of extracorporeal photopheresis continues. The results of another open trial of methotrexate showed improvement of skin involvement in the majority of patients, and attention was drawn to the nephrotoxic side effects of cyclosporine. Combination therapy with cyclophosphamide and low-dose corticosteroids seems promising for improving pulmonary function in scleroderma patients with progressive lung involvement. Iloprost was shown to be superior to placebo in the treatment of Raynaud's phenomenon secondary to scleroderma. Anecdotal data indicate a possible beneficial effect of octreotide treatment in pseudoobstruction intestinalis due to scleroderma. (49 Refs.)

Sfikakis PP; Kyriakidis MK; Vergos CG; Vyssoulis GP; Psarros TK; Kyriakidis CA; Mavrikakis ME; Sfikakis PP; Toutouzas PK
Cardiac Department, Hippokration Hospital, Athens, Greece.
Am J Med (United States) May 1991, 90 (5) p541-6

PURPOSE: This prospective study was performed to evaluate the response of the cardiopulmonary vasculature to two vasodilators in patients with systemic sclerosis and either minimal or no central hemodynamic abnormalities.

PATIENTS AND METHODS: Twenty patients with systemic sclerosis, Raynaud's phenomenon (19 of 20 patients), and clinically normal cardiac function underwent right heart catheterization. Rest and exercise hemodynamic measurements, including cardiac output by thermodilution, were performed before and after oral administration of nifedipine 20 mg and captopril 25 mg.

RESULTS: Half of the patients had normal hemodynamics (Group A); the other half (Group B) had abnormal baseline elevations in pulmonary vascular resistance and four of them showed "borderline" pulmonary arterial hypertension. Group A, with significantly shorter disease duration compared with Group B, responded poorly to nifedipine and captopril. However, Group B had significant decreases in pulmonary vascular resistance (from 148 +/- 20 to normal levels of 94 +/- 21 dynes.second.cm-5) and pulmonary mean pressure in response to nifedipine treatment but not to captopril.

CONCLUSION: These observations show a short-term beneficial effect of nifedipine in the cardiopulmonary vasculature of patients with systemic sclerosis and suggest that a potentially reversible vasoconstrictive element is included in the vascular lesion of this disorder.

van den Hoogen FH; Boerbooms AM; van de Putte LB
Department of Rheumatology, University Hospital Nijmegen, The Netherlands.
Clin Rheumatol (Belgium) Sep 1990, 9 (3) p319-24

We reviewed studies concerning immunomodulating therapy in systemic sclerosis. These comprise mostly uncontrolled trials and case reports. Some of these studies hint at a possible beneficial effect of antimetabolites (azathioprine, 5-fluoro-uracil and methotrexate), cyclosporine and interferon-gamma. However, to give a clearcut answer on the efficacy of these drugs in systemic sclerosis, controlled studies are urgently needed. (32 Refs.)

Kahan A; Devaux JY; Amor B; Menkes CJ; Weber S; Venot A; Strauch G
Department of Rheumatology, Rene Descartes University, School of Medicine, Hopital Cochin, Paris, France.
Clin Pharmacol Ther (United States) Apr 1990, 47 (4) p483-9

In systemic sclerosis, abnormalities of myocardial perfusion are common and may be caused by a disturbance of the coronary microcirculation. We evaluated the long-term effect of captopril (75 to 150 mg per day) on thallium 201 myocardial perfusion in 12 normotensive patients with systemic sclerosis. Captopril significantly decreased the mean (+/- SD) number of segments with thallium 201 myocardial perfusion defects (6.5 +/- 1.9 at baseline and 4.4 +/- 2.7 after 1 year of treatment with captopril; p less than 0.02) and increased the mean global thallium score (9.6 +/- 1.7 at baseline and 11.4 +/- 2.1 after captopril; p less than 0.05). In a control group of eight normotensive patients with systemic sclerosis who did not receive captopril, no significant modification in thallium results occurred. Side effects with captopril included hypotension (six patients), taste disturbances (one patient), and skin rash (one patient). These side effects subsided when the dosage was reduced. These findings demonstrate that captopril improves thallium 201 myocardial perfusion in patients with systemic sclerosis and may therefore have a beneficial effect on scleroderma myocardial disease.

Halkier-Sorensen L; Ternowitz T; Bjerring P; Poulsen JH; Alsbirk KE; Herlin T; Ravnsbaek J; Zachariae E; Zachariae H
Acta Derm Venereol (Sweden) 1986, 66 (2) p177-9

Ten patients with systemic sclerosis were treated with benoxaprofen, a potent lipoxygenase inhibitor, for a period of 6 months. In an attempt to evaluate the efficacy a number of physical disease parameters were followed during the trial. None of these parameters revealed any significant differences. There was, however, a trend for a change towards normalisation of a defect monocyte chemotaxis. In view of the slow and progressive nature of systemic sclerosis the present study leaves undetermined whether benoxaprofen exerts a beneficial effect on systemic sclerosis.

O'Dell JR; Steigerwald JC; Kennaugh RC; Hawkins R; Holers VM; Kotzin BL
Department of Medicine, University of Colorado Health Science Center, Denver.
J Rheumatol (Canada) Aug 1989, 16 (8) p1050-4

Six patients with systemic sclerosis and internal organ involvement were randomized to receive total lymphoid irradiation (TLI) or to serve as untreated controls. Despite evidence of profound immunosuppression, we were unable to detect any longlasting clinical benefit in the treated patients, with follow-ups ranging from 1-4 years after TLI. Moreover, the results suggest that this therapy may accelerate pulmonary and gastrointestinal deterioration in scleroderma.

Kahan A; Amor B; Menkes CJ; Strauch G
Department of Rheumatology, Rene Descartes University, School of Medicine, Paris, France.
Am J Med (United States) Sep 1989, 87 (3) p273-7

PURPOSE: Recombinant interferon-gamma (IFN-gamma) is a potent and selective inhibitor of collagen production by dermal fibroblasts in vitro and has numerous immunoregulatory activities. We assessed the effects of recombinant IFN-gamma in the treatment of patients with systemic sclerosis.

PATIENTS AND METHODS: Ten patients entered the study and nine completed the six-month study period. Recombinant IFN-gamma was administered once daily for seven days per week by intramuscular injections: 10 micrograms/day for 10 days, 25 micrograms/day for 10 days, 50 micrograms/day for 10 days, and 100 micrograms/day for the next five months.

RESULTS: After the six-month treatment period, a significant improvement, as compared with base-line values, was observed in total skin score, maximal oral opening, range of motion of wrists and elbows, grip strength, functional index, dysphagia, and creatinine clearance. No serious side effects were observed; however, a significant decrease in white blood cell counts and in peripheral blood lymphocytes was noted.

CONCLUSION: These results suggest that recombinant IFN-gamma may be beneficial in the treatment of patients with systemic sclerosis.

Maurice PD; Bunker CB; Dowd PM
Department of Dermatology, Middlesex Hospital, London, U.K.
Br J Dermatol (England) Sep 1989, 121 (3) p367-74

Thirteen patients with systemic sclerosis were treated with isotretinoin. Nine patients completed between 6 and 14 months of treatment and all showed an improvement in the cutaneous manifestations of their disease. The drug did not appear to benefit internal organs affected by the disease. Most patients experienced the well-recognized side-effects of retinoids, which in three cases necessitated withdrawal from the study within 3 months. Serum levels of type III procollagen aminopropeptide did not show a consistent decline during treatment, despite a clinical improvement. The mode of action of the reported therapeutic effect of isotretinoin in systemic sclerosis is unclear. There may be a preferential suppression of the synthesis of type I collagen, or the drug may be acting by an unrelated mechanism.

Guillevin L; Leon A; Levy Y; Bletry O; Gayraud M; Andreu G; Godeau P
Int J Artif Organs (Italy) Nov 1983, 6 (6) p315-8

Seven patients, 4 women and 3 men afflicted with severe progressive systemic sclerosis (PSS) were treated with Plasma Exchange after failure of different other treatment. All patients presented Raynaud phenomenon and arthritis, 6 patients presented extensive skin lesions, 5 of them digestive manifestations, 3 pulmonary fibrosis. In one case PSS was associated with polymyositis, one patient presented bilateral recurrent cornea ulcerations, (Sjogren Syndrome++) and one patient numerous skin ulcerations. In 5 patients adjuvant corticosteroid therapy was given during the course of PE. In 3 patients PE must be stopped after one or two sessions because of insufficient venous access. Among the 4 other patients 8 to 20 PE were performed: the patient with cornea ulcerations became blind during the treatment, skin ulcerations and severe Raynaud phenomenon did not improved in two other patients. Benefit of PE was noted in only one patient with regressive myositis, and improvement of articular and cutaneous symptoms. Therefore, PE are not useful in most patients afflicted with PSS, they are difficult to realize in numerous patients and did not improve clinical symptoms in most cases.

Jayson MI; Lovell C; Black CM; Wilson RS
University of Bristol Department of Medicine.
Proc R Soc Med (England) 1977, 70 Suppl 3 p82-8

Twenty-two patients with progressive systemic sclerosis were treated with D-penicillamine in doses ranging up to 1250 mg/day for periods varying between a few months and four years. Side-effects occurred in 7 patients, necessitating drug withdrawal in 2. Cutaneous benefit occurred in 15 patients, but owing to side-effects from the drug, relapses, and development, persistence or advancement of visceral complications, an overall good result only occurred in 5. Seven patients showed improvements in joint function, but only 3 were regarded as having an overall good result. Peripheral vascular disease and visceral involvement seemed not to be influenced by D-penicillamine and sometimes appeared or advanced during treatment. Six patients died from visceral manifestations of systemic sclerosis and one from another cause. D-penicillamine is of limited value for the cutaneous features of progressive systemic sclerosis, but probably of no value for the vascular and visceral manifestations of the disease.

Grassegger A.; Schuler G.; Hessenberger G.; Walder-Hantich B.; Jabkowski J.; Macheiner W.; Salmhofer W.; Zahel B.; Pinter G.; Herold M.; Klein G.; Fritsch P.O.
A. Grassegger, Department of Dermatology, University of Erlangen, Erlangen Germany
alfred.grassegger@uibk.ac.at
British Journal of Dermatology (United Kingdom) 1998, 139/4 (639-648)

We report the results of a randomized controlled multicentre study on interferon-gamma (IFN-gamma) treatment of systemic sclerosis as determined by skin sclerosis, renal and other organ involvement, global assessment, subjective symptoms and quality of life. Forty-four patients were enrolled into the trial, 27 in the treatment group and 17 in the control group. All patients presented with type I or type II scleroderma. Twenty-nine patients (64%) finished the study. The mean duration of Raynaud's phenomenon and skin sclerosis was 15.3 and 10.8 years, respectively. The skin scores tended to improve in the treatment group (P > 0.05). Mouth aperture increased significantly from 38.5 to 47.7 mm in the treatment group (P < 0.001). Subanalysis of IFN-gamma treated patients with normalized skin sclerosis scores <=1 showed significant improvement in both skin involvement and subjective symptoms (P < 0.05). Organ involvement improved in eight of 18 treatment patients and in three of 11 control patients. It worsened in three of 18 treatment patients and in four of 11 control patients. One control patient died due to cardiorespiratory failure during the study. No deterioration of renal function occurred during IFN-gamma treatment. There was a significant improvement in quality of life parameters in the control group but not in the treatment group. Plasma levels of neopterin increased significantly during IFN-gamma treatment but not in the control group, whereas N-terminal procollagen III peptide levels did not change in either group. There was a high frequency of mild to moderate influenza-like adverse events during IFN-gamma treatment. Only four of nine drop-out patients, however, experienced symptoms most probably associated with IFN-gamma treatment. We conclude that IFN-gamma therapy has mild beneficial effects on skin sclerosis and disease-associated symptoms in type I and II scleroderma. IFN-gamma treatment was associated with acceptable tolerability and did not induce major renal dysfunction in our patients.

Lee S.-H.; Park Y.-M.; Oh E.-S.; Min J.-K.; Park S.-H.; Cho C.-S.; Kim H.-Y.
Department of Internal Medicine, Kangnam St. Mary's Hospital, Catholic University Medical College,Seoul South Korea
Journal of Korean Society for Clinical Pharmacology and Therapeutics (South Korea) 1996, 4/1 (29-34)

Background: Prostaglandin E1 (PGE1), a potent vasodilator and an inhibitor of platelet aggregation, has been reported to be useful in the treatment of peripheral vascular diseases and severe Raynaud's phenomenon. Lipo-PGE1 which is a drug preparation of PGE1 incorporated in lipid microspheres has advantage for its longer action and smaller requirement dosage because of less inactivation in the lung than original PGE1.

Methods: We evaluated the efficacy and safety of Lipo-PGE1 in the treatment of peripheral vascular diseases including ulcer, gangrene, and severe Raynaud's phenomenon in systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). The study population included 25 patients (mean age: 36.7 +/- 12.8, F:M = 23:2; SLE (13), systemic sclerosis (12)). Intravenous Lipo-PGE1 (10 mug) was infused every day for 4 weeks. The assessment of efficacy was monitored by patient's subjective questionnaire, ulcer size and digital hemodynamics using finger systolic pressure.

Results: The overall patient's assessment by subjective symptoms including coldness, numbness or rest pain were improved in 17 patients (68%), but not changed in 8 patients. The decreases of ulcer or gangrene size were noted in 21 patients, but 4 patients remained unchanged. There was a significant increase in the finger systolic pressure at 15 minutes following cold stimuli after the treatment (P < 0.01). Significant adverse reactions were not found except pain on injected site (2), mild transaminase elevation (1) and fever (1).

Conclusion: These data suggested that Lipo-PGE1 is relatively safe and beneficial as well as convenient for administration in the treatment of peripheral vascular disease secodary to connective tissue diseases.

Gruschwitz M.S.; Collenberg C.; Albrecht H.-P.
Div. of Connective Tissue Research, Dept. of Dermatology, Medical School, University of Erlangen-Nuremberg, Hartmannstrasse 14,91052 Erlangen Germany
Journal of the European Academy of Dermatology and Venereology (Netherlands) 1996, 7/2 (139-148)

Background: Treatment of scleroderma (systemic sclerosis, SSc) patients (stages I-III) with intravenous (i.v.) calcitonin for 10 days (100 IU/day, Karil(R), Sandoz AG, Germany) 3 times/year leads to subjective and objective improvement of microcirculatory parameters determined by Laser-Doppler fluxmetry and cutaneous pOinf 2 (pcuOinf 2) measurement.

Aim: As previously suggested some rheologic effects of calcitonin might be mediated by vasoactive metabolites of the arachidonic acid metabolism. Alterations of eicosanoid plasma levels were determined in 15 SSc patients during i.v. calcitonin therapy.

Methods: Peripheral blood was obtained on the 1st and 9th days of therapy during a 2 h intravenous calcitonin administration. Samples were taken after 45, 90, 135 and 160 min as well as 1, 5 and 19 days after therapy was stopped. Serum levels of 6-keto-prostaglandin F(1alpha) (6-keto-PGF), a stable end product of prostacyclin synthesis, prostaglandin Einf 2 (PGEinf 2), leukotriene Binf 4 (LTBinf 4), and thromboxane Binf 2 (TXBinf 2) were determined by enzyme- or radio-linked assays.

Results: In contrast to healthy controls we measured elevated 6-keto-PGF, LTBinf 4 and PGEinf 2 serum levels in SSc patients before i.v. treatment, whereas TXBinf 2 levels showed no significant differences. Calcitonin administration led to an increase of plasma 6-keto-PGF after 45 min falling back to the starting level during further treatment as well as to a longer-lasting increase of PGEinf 2 on both the 1st and 9th days of therapy. Calcitonin treatment decreased LTBinf 4, but did not influence TXBinf 2 levels significantly during intravenous administration.

Conclusion: Our data suggest a compensatory mechanism of the damaged vascular system with respect to the PGIinf 2 (prostacyclin) and PGEinf 2 formation in SSc patients measured by a constant elevation of these vasodilatory metabolites. LTBinf 4 may be involved in the microvascular damage in SSc. Calcitonin administration leads to a short-lasting elevation of 6-keto-PGF(1alpha) and an increase of PGEinf 2 combined with a reduction of LTBinf 4 resulting in longer-lasting beneficial effects on microcirculatory functions in diseased skin. Since non-steroidal anti-inflammatory agents had no influence on long-term vasoactive effects, improvement of microcirculatory properties by calcitonin may be additionally mediated by smooth muscle relaxation of arterioles.

Rubisz-Brzezinska J.; Lis A.; Kucharz E.; Brzeziinska-Wcislo L.; Kulawik I.
I Klinika Dermatologiczna, Slaska Akademia Medyczna, ul. Francuska 20/24,40-027 Katowice Poland
Przeglad Dermatologiczny (Poland) 1995, 82/5 (459-464)

Nine patients with progressive systemic sclerosis lasting for 1 to 10 years were treated with cyclosporin A at dosages 2.0-3.5 mg/kg/day, for 4-7 months. Patients were classified according to Holzmann: as type III - 5 patients and as type IV - 4 patients. In 6 patients there was observed marked improvement. Beneficial therapeutic effects included softening of the involved skin (6/9, 67%, improvement of muscle and joint pains (3/6, 60%), and healing of persistent digital ulcers (3/5, 60%). In 3 patients no improvement was noted. The progression of the disease did not occur in any of the patients. In no case serious side effects requiring discontinuation of the therapy were noted.

Fierlbeck G.; Schreiner T.; Rassner G.
Liebermeisterstrasse 25,D-72076 Tubingen Germany
Allergologie (Germany) 1994, 17/8 (389-392)

The results of Interferon-gamma therapy for systemic sclerosis (SSc) are reported in this paper. 25 patients were evaluated after a median follow up of three and a half years and a significant improvement of the skin score could be demonstrated in early forms of SSc. Visceral manifestations of SSc did not improve in general, whereas individual patients also benefited from therapy. Interferon-gamma therapy was generally well tolerated, only flue-like symptoms occured.

Degiannis D, Seibold JR, Czarnecki M, Raskova J, Raska K Jr
Department of Pathology, UMDNJ--Robert Wood Johnson Medical School, Piscataway 08854.
Clin Immunol Immunopathol 1990 Aug;56(2):259-70

The peripheral blood lymphocyte pattern, the lymphocyte responses in vitro, as well as the soluble markers of immune activation were studied in 24 patients with systemic sclerosis (SSc patients). The proportions of total T cells (CD3), their CD4 subset, as well as B lymphocytes were within the normal range. The relative proportion of CD8 lymphocytes, however, was significantly reduced. Patients with SSc had a slightly lower percentage of CD4/4B4+ cells, whereas their proportion of CD4/2H4+ cells was elevated as compared to healthy controls. The proportion of lymphocytes expressing the interleukin-2 receptor (IL-2R) was significantly higher in SSc patients. The proliferative responses of peripheral blood mononuclear cells to PHA stimulation were reduced in the patient group, while expression of IL-2R on lymphocytes after such in vitro stimulation was comparable to that of controls. Expression of IL-2R on patient but not control lymphocytes was increased after in vitro exposure to laminin. Such exposure failed to induce IL-2 production or cell proliferative responses. Soluble plasma IL-2R level (sIL-2R) and soluble CD8 (sCD8) molecule levels in SSc patients were significantly elevated. These results indicate the presence of an ongoing lymphocyte activation in this disease process.