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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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