Anti-TGFß1 (CAT 192)
Imatinib Mesylate (Gleevec)
Penicillamine, Cuprimine, Depen
Disproven treatments for systemic scleroderma include alpha interferon, imatinib mesylate, minocycline (the "antibiotic cure"), penicillamine, and relaxin.
Due to the relapsing and remitting natural course of scleroderma, it is easy to attribute any treatment or lifestyle change as being a cure, so things are usually perceived as being a cure until the last phase of large scale, double-blind clinical trials.
Skeptical researchers say that no drug has been proven totally worthless until it has been tried for scleroderma, so sometimes scleroderma trials are a last-ditch effort for drugs that have failed in all other applications.
Survival has improved dramatically in recent years and is due to the effectiveness of treatments directed at specific internal organ features. These include drugs for pulmonary hypertension (flolan, bosentan) ; renal (kidney) involvement (angiotensin converting enzyme inhibitors) ; and pulmonary (lung) inflammation (cyclophosphamide).
Systemic sclerosis developing in association with the use of interferon alpha therapy for chronic viral hepatitis. We speculate that the immunomodulatory effects of IFNalpha triggered the clinical manifestations of SSc in this patient. To our knowledge, this is the second case of SSc developing after therapy with IFNalpha and the first in a patient treated for chronic viral hepatitis C. PubMed, Clin Exp Rheumatol. 2004 Sep-Oct;22(5):625-8. (Also see Causes of Scleroderma: Medications and Liver Involvement)
1998: Alpha Interferon: Study done, no effect on Scleroderma. (1)
Recombinant human anti-transforming growth factor beta1 antibody therapy in systemic sclerosis: a multicenter, randomized, placebo-controlled phase I/II trial of CAT-192. In this pilot study, CAT-192, in doses up to 10 mg/kg, showed no evidence of efficacy. The utility of clinical and biochemical outcome measures and the feasibility of multicenter trials of early dcSSc were confirmed. PubMed, Arthritis Rheum. 2007 Jan;56(1):323-33.
Chlorambucil/5-flourouracil - study done, no effect on Scleroderma.
FDA Public Health Advisory Interferon gamma-1b (marketed as Actimmune). The INSPIRE study of Actimmune for treating idiopathic pulmonary fibrosis (IPF) was stopped because an interim analysis showed that patients with IPF who received Actimmune did not benefit. FDA 03-05-07.
No good study yet for Scleroderma. (1)
There used to be an article in the Archives of Dermatology, entitled, "Systemic Scleroderma: Multicenter Trial of 1 Year of Treatment With Recombinant Interferon Gamma."
Imatinib mesylate (Gleevec) in scleroderma-associated diffuse skin fibrosis: a phase II multicentre randomized double-blinded controlled trial. This study failed to demonstrate the efficacy of imatinib 400 mg daily to improve skin fibrosis of diffuse scleroderma after 6 months of treatment based on validated outcome measurements. PubMed, Br J Dermatol, 2012 Nov;167(5):1138-1144.
Proof of Concept Trial of Gleevec (Imatinib) in Active Diffuse Scleroderma. This study was terminated due to frequent adverse events that occurred early in treatment with poor tolerability. Study NCT01545427. ClinicalTrials.gov. 03/01/12.
Scleroderma Clinical Trials: Completed, Negative: Minocycline (Doxicycline) Antibiotic Treatment. This has been proven to be ineffective for the treatment of systemic scleroderma by reliable scientific study. ISN.
Until very recently, Penicillamine (aka Cuprimine, Depen, or d-penicillamine was commonly used for this purpose in Systemic Scleroderma, but in 1997, a large multi-center clinical trial in the U.S. proved that there was no difference between high-dose and low-dose Penicillamine in the treatment of Scleroderma.
This study only tested the difference between high-dose and low-dose. It was not designed to determine if penicillamine is effective in the treatment of Scleroderma, so further studies need to be conducted.
Rapid Progression of Scleroderma Possibly Associated with Penicillamine Therapy "...This case raises the possibility that penicillamine may even be harmful in certain patients, and may perhaps be associated with acceleration of the decline in the course of the disease. The mechanism may involve either immune dysregulation or the generation of free radicals, directly toxic to the endothelium and leading to fibrotic tissue repair and intimal thickening." Article was on Medscape.com 1/1/98 (2)
A word of caution regarding single-center, retrospective studies. Patients frequently improve on placebo. Patients who are improving usually attribute it to their therapy and thus stay with it. Thus uncontrolled cohorts become enriched for "responders" while failures seek other paths.
This dynamic underlies virtually all therapeutic "breakthroughs" which is why large scale double-blinded clinical trials are crucial for determining valid scleroderma treatments.
A retrospective randomly selected cohort study of D-penicillamine treatment in rapidly progressive diffuse cutaneous systemic sclerosis of recent onset. In a population of patients with diffuse cutaneous systemic sclerosis, with progressive disease of recent onset, D-penicillamine treatment at a median dose of 750 mg per day caused a statistically significant reduction in skin involvement and improvement of renal, cardiac and pulmonary involvement. (PubMed) Br J Dermatol. 2008 Feb 16. (Also see Scleroderma Treatments, and Skin Fibrosis)
Pulmonary-renal syndrome (PRS) in systemic sclerosis: a report of three cases and review of the literature. Clinical courses of the patients with PRS with thrombotic microangiopathy suggest that high-dose corticosteroid therapy is a trigger of diffuse alveolar hemorrhage in patients with diffuse SSc with signs of thrombotic microangiopathy. PubMed, Mod Rheumatol. 2007;17(1):37-44. (Also see Renal Involvement, Pulmonary Involvement,and Medications)
Myasthenia gravis and scleroderma: Two cases and a review of the literature. Myasthenia gravis is uncommon in patients with scleroderma, and when diagnosed is usually associated with previous use of d-penicillamine. Clinically, both myasthenia and scleroderma may present with fatigue, weakness and bulbar symptoms, so one of diagnoses may be delayed. PubMed, Clin Neurol Neurosurg. 2007 Feb 3. (Also see Myasthenia Gravis)
High-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis trial: lessons learned. After analysis, we were not able to tell whether either dose was effective or ineffective. Even in studies that are therapeutically "negative," careful evaluation of the data can examine other hypotheses and thereby provide important insights into other aspects of trial design, outcome measures, patient function, and trial conduct. PubMed, Semin Arthritis Rheum. 2004 Feb;33(4):249-63.
Study proved no effect on Scleroderma. (1)
The routine use of ACE inhibition in treating upper-limb digital ulcers or other vascular manifestations in patients with systemic sclerosis is not advisable.
Relaxin failed Phase III clinical trials and will not be pursued any further as a treatment for scleroderma. See Relaxin by ISN.
Study Results: Evaluation of the Pharmacodynamic Effect of the Combination of Sildenafil and Riociguat on Blood Pressure and Other Safety Parameters. There were 3 fatalities out of 12 participants, and none in the placebo arm, so this study was terminated by the sponsor. ClinicalTrials.gov. Posted 2015.
Evaluation of the Pharmacodynamic Effect of the Combination of Sildenafil and Riociguat on Blood Pressure and Other Safety Parameters. Inhalation of Nitric Oxide, which activates sGC is used to treat PAH, but its effect wears off as soon as inhalation stops. Direct stimulation of sGC using this new compound Riociguat may be a new approach for the treatment of PAH. ClinicalTrials.gov. Posted 2012.
Open label trial of tamoxifen in scleroderma. Previous reports have suggested that treatment with the selective estrogen antagonist tamoxifen may be effective in diminishing primary and secondary Raynaud's vasospasm, including cases occurring in the setting of scleroderma. Tamoxifen treatment has also been associated with improvement of retroperitoneal fibrosis and desmoid tumors, conditions also associated with abnormal fibroblast proliferation. Tamoxifen increases production of the immunosuppressive cytokine TGF beta which modulates fibroblast activity. The potential effect of tamoxifen on vascular reactivity and fibrotic lesions raised questions about its utility as a therapeutic agent in scleroderma. CONCLUSION: Based on these results, we would not recommend tamoxifen for further large scale studies in scleroderma. PubMed, Clin Exp Rheumatol 2003 Jan-Feb;21(1):99-102 (Also see Clinical Trials: Ineffective or Unproven)
(1) Source:1998 SF pamphlet "About Medications"
(2) Medscape requires (free) sign up and password. You do not need to be a medical professional to use Medscape. However this makes for slower access to the site for first-time users.
Also see related page, Scleroderma Treatments and Clinical Trials.
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