SCLERODERMA
(Page 3)

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.)

Continued on the next page...