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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