SAT0485 What is the effect of cyclophosphamide iv pulse therapy in patients with diffuse cutaneous systemic sclerosis on skin involvement: an observational study (original) (raw)
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State-of-the-art evidence in the treatment of systemic sclerosis
Nature Reviews Rheumatology
Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease with multi-organ involvement, fibrosis and vasculopathy. Treatment in SSc, including early diffuse cutaneous SSc (dcSSc) and the use of organspecific therapies, has improved, as evident from randomized clinical trials. Treatments for early dcSSc include immunosuppressive agents such as mycophenolate mofetil, methotrexate, cyclophosphamide, rituximab and tocilizumab. Patients with rapidly progressive early dcSSc might be eligible for autologous haematopoietic stem cell transplantation, which can improve survival. Morbidity from interstitial lung disease and pulmonary arterial hypertension is improving with the use of proven therapies. Mycophenolate mofetil has surpassed cyclophosphamide as the initial treatment for SSc-interstitial lung disease. Nintedanib and possibly perfinidone can be considered in SSc pulmonary fibrosis. Pulmonary arterial hypertension is frequently treated with initial combination therapy (for example, with phosphodiesterase 5 inhibitors and endothelin receptor antagonists) and, if necessary, the addition of a prostacyclin analogue. Raynaud phenomenon and digital ulcers are treated with dihydropyridine calcium channel blockers (especially nifedipine), then phosphodiesterase 5 inhibitors or intravenous iloprost. Bosentan can reduce the development of new digital ulcers. Trial data for other manifestations are mostly lacking. Research is needed to develop Nature Reviews Rheumatology Review article as pulmonary arterial hypertension (PAH), inflammatory arthritis, calcinosis, myopathy and/or myositis, cardiomyopathy, sicca symptoms and scleroderma renal crisis (SRC). Owing to the relatively high frequency of certain disease complications and the fact that early intervention can change the natural history of these complications, screening for ILD and PAH is recommended (Table 1). In patients with early dcSSc, blood pressure should be monitored, especially if the patient has anti-RNA polymerase III antibodies (anti-RNAPIII), in order to detect and treat SRC early. Selected screening can also be performed when the index of suspicion of certain manifestations, such as cardiac involvement (beyond echocardiography, which is done for PAH screening, such as for arrhythmias), and paraneoplastic SSc, is high where cancer screening is performed. Several SSc clinical trials and consensus statements guide treatments, and the order of their use, for various organ-based manifestations of SSc. Of note, randomized controlled trials (RCTs) of treatments that modify the overall disease (that is, improve the natural history and pathophysiology) and skin fibrosis generally consider only patients in the dcSSc subset and often only within 2-5 years from the onset of the first non-Raynaud phenomenon features, whereas RCTs of treatments for organ-based manifestations, such as ILD, PAH, Raynaud phenomenon and digital ulcers, include patients in either subset provided that they meet the entry criteria for the trials. This article reviews and summarizes the current management of SSc, including screening for and treatment of organ-based manifestations such as skin, lung (ILD and PAH) and Raynaud phenomenon and digital ulcers, as well as consideration of overall disease modification with autologous haematopoietic stem cell transplantation (AHSCT). Although patients with SSc can also be affected by other symptoms, including gastrointestinal manifestations, SRC, arthritis, myopathy and cardiac involvement, these have not been included in this Review because data from RCTs are mostly lacking; we direct the reader to treatment algorithms devised by SSc experts that address these symptoms 15. In addition, several treatments can improve disease pathophysiology and thus be considered to modify the overall disease, but in this article treatments are discussed according to the outcome measures used in studies; for example, mycophenolate mofetil (MMF) and cyclophosphamide might improve ILD and skin manifestations, whereas for AHSCT data are available on improvements in survival as well as skin, function and ILD. There may be a survival advantage when treating patients with early dcSSc with immunosuppressives, especially those not eligible for AHSCT, but proof within RCTs is lacking for immunosuppressive therapies. Management of skin manifestations Skin fibrosis is one of the dominant clinical features of SSc. The designations dcSSc and lcSSc are used as surrogates of disease severity and prognosis, but both subsets are associated with high functional and psychosocial impact. The extent of skin fibrosis in SSc is most commonly assessed using the modified Rodnan skin score (mRSS), which measures skin thickness on a scale of 0 to 3 at 17 anatomical sites (score range 0-51). The minimal clinically important difference in mRSS has been estimated to range between 3.5 and 5.3 points 16. In dcSSc, mRSS generally increases over the first 4 years of the disease and regresses somewhat over time thereafter, although many patients do not follow this pattern as they may worsen later or not improve after 4 years of disease. It is difficult to predict which patients with early dcSSc will improve or worsen during a clinical trial with respect to skin involvement, but a large response to placebo (and many active therapies) is unlikely. Some prediction models Key points • Treatment of systemic sclerosis (SSc) is organ-based or aimed at disease modification. • Autologous haematopoietic stem cell transplantation can improve survival in patients with early diffuse cutaneous SSc who are at high risk of mortality, such as those with very high skin scores (as measured by the modified Rodnan skin score) or moderate skin involvement and worsening interstitial lung disease (ILD). • Immunosuppressives and some biologic agents can soften skin and change the natural history of early diffuse cutaneous SSc. • Appropriate treatment for patients with early limited cutaneous SSc is unknown, and further research is needed. • ILD is usually treated by the use of mycophenolate mofetil as the initial therapy and then other immunosuppressives or biologic agents, but if ILD is fibrotic and progressing, anti-fibrotic therapy can be added, such as nintedanib (and possibly pirfenidone). • Raynaud phenomenon in SSc is treated with calcium channel blockers and then phosphodiesterase 5 inhibitors or intravenous iloprost. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author selfarchiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
JAMA, 2014
; for the EBMT/EULAR Scleroderma Study Group IMPORTANCE High-dose immunosuppressive therapy and autologous hematopoietic stem cell transplantation (HSCT) have shown efficacy in systemic sclerosis in phase 1 and small phase 2 trials. OBJECTIVE To compare efficacy and safety of HSCT vs 12 successive monthly intravenous pulses of cyclophosphamide. DESIGN, SETTING, AND PARTICIPANTS The Autologous Stem Cell Transplantation International Scleroderma (ASTIS) trial, a phase 3, multicenter, randomized (1:1), open-label, parallel-group, clinical trial conducted in 10 countries at 29 centers with access to a European Group for Blood and Marrow Transplantation-registered transplant facility. From March 2001 to October 2009, 156 patients with early diffuse cutaneous systemic sclerosis were recruited and followed up until October 31, 2013. INTERVENTIONS HSCT vs intravenous pulse cyclophosphamide. MAIN OUTCOMES AND MEASURES The primary end point was event-free survival, defined as time from randomization until the occurrence of death or persistent major organ failure. RESULTS A total of 156 patients were randomly assigned to receive HSCT (n = 79) or cyclophosphamide (n = 77). During a median follow-up of 5.8 years, 53 events occurred: 22 in the HSCT group (19 deaths and 3 irreversible organ failures) and 31 in the control group (23 deaths and 8 irreversible organ failures). During the first year, there were more events in the HSCT group (13 events [16.5%], including 8 treatment-related deaths) than in the control group (8 events [10.4%], with no treatment-related deaths). At 2 years, 14 events (17.7%) had occurred cumulatively in the HSCT group vs 14 events (18.2%) in the control group; at 4 years, 15 events (19%) had occurred cumulatively in the HSCT group vs 20 events (26%) in the control group. Time-varying hazard ratios (modeled with treatment × time interaction) for event-free survival were 0.35 (95% CI, 0.16-0.74) at 2 years and 0.34 (95% CI, 0.16-0.74) at 4 years. CONCLUSIONS AND RELEVANCE Among patients with early diffuse cutaneous systemic sclerosis, HSCT was associated with increased treatment-related mortality in the first year after treatment. However, HCST conferred a significant long-term event-free survival benefit.
Outcome of pulse oral cyclophosphamide therapy in scleroderma interstitial lung disease
Clinical Rheumatology, 2020
Introduction Standard regimens for scleroderma interstitial lung diseases (SSc-ILDs) are pulse intravenous (IV) and oral daily cyclophosphamide (CYC). However, IV CYC has limited access to diffuse cutaneous SSc, and oral daily CYC is associated with febrile neutropenia and hemorrhagic cystitis. Pulse oral CYC regimen has never been studied. Objective To determine the effectiveness of pulse oral CYC therapy in SSc-ILDs, predictors of effectiveness, and side-effects. Methods A historical cohort study enrolled SSc-ILDs from the SSc database registry at Srinagarind Hospital, Thailand from 1 January 2012 to 1 October 2018. All patients received monthly oral dosages of CYC 600-750 mg/m 2 , Mesna, and daily prednisolone of 10 mg for 2 years. Changes of FVC, chest radiography, HRCT, 6MWT, and side effects were recorded for the baseline and at the end of the treatment. Response to treatment was defined by (a) stable FVC or a decline ≤ 10% of predicted, (b) unchanged or improved radiographic findings, or (c) a decline 6MWT of ≤ 30 m compared with the baseline. Results A total of 76 patients with female 52 patients (68.4%) and with a median age of 54.2 years (IQR 46.6-59.6). The majority was dcSSc subset (59 patients; 78.6%). Fifty-four patients (71%) were defined as responsive to therapy. The mean FVC improvement was 1 ml (SD 9.5). The only factor associated with treatment response was limited cutaneous SSc (OR 7.69, 95% CI (1.01, 339.68), p = 0.029). Hemorrhagic cystitis was found in 1 patient. Conclusions Nearly three-quarters of SSc-ILDs patients had a good response to the pulse oral CYC therapy for 2 years with a few serious side effects. Pulse oral CYC therapy had been effective for SSc-ILDs in case of difficult IV access. Key Point • Pulse oral cyclophosphamide has been used for scleroderma lung disease. It has shown efficacy and safety in scleroderma patients. In patients who have difficulty with intravenous access, pulse oral cyclophosphamide can be an alternative regimen.
The efficacy of oral cyclophosphamide plus prednisolone in early diffuse systemic sclerosis
Clinical rheumatology, 2003
Pharmacological treatment of diffuse systemic sclerosis (SSc) directed at the tissue fibrosis has generally been ineffective. Many immunosuppressive drugs have been tried as therapy for SSc, regardless of the disease subtype and/or stage. The aim of this study was to show the efficacy and the toxicity of oral cyclophosphamide and prednisolone therapy on the prevention of fibrosis-based tissue damage in the early stages of the diffuse SSc. Twenty-seven patients with early diffuse SSc were treated with oral cyclophosphamide (1-2 mg/kg/day) plus oral prednisolone (40 mg/every other day) between the years 1995 and 1998. The results regarding the efficacy and toxicity of cyclophosphamide were compared with those of 22 early SSc patients who had been treated with oral D-penicillamine between 1992 and 1995. All the patients were evaluated using clinical and laboratory parameters every 6 months for 2 years. There was a significant improvement on the skin score, maximal oral opening, flexion...
Annals of the rheumatic diseases, 2017
The rarity of early diffuse cutaneous systemic sclerosis (dcSSc) makes randomised controlled trials very difficult. We aimed to use an observational approach to compare effectiveness of currently used treatment approaches. This was a prospective, observational cohort study of early dcSSc (within three years of onset of skin thickening). Clinicians selected one of four protocols for each patient: methotrexate, mycophenolate mofetil (MMF), cyclophosphamide or 'no immunosuppressant'. Patients were assessed three-monthly for up to 24 months. The primary outcome was the change in modified Rodnan skin score (mRSS). Confounding by indication at baseline was accounted for using inverse probability of treatment (IPT) weights. As a secondary outcome, an IPT-weighted Cox model was used to test for differences in survival. Of 326 patients recruited from 50 centres, 65 were prescribed methotrexate, 118 MMF, 87 cyclophosphamide and 56 no immunosuppressant. 276 (84.7%) patients completed 1...
New Therapeutic Strategies for Systemic Sclerosis—a Critical Analysis of the Literature
Clinical and Developmental Immunology, 2005
Systemic sclerosis (SSc) is a multi-system disease characterized by skin fibrosis and visceral disease. Therapy is organ and pathogenesis targeted. In this review, we describe novel strategies in the treatment of SSc. Utilizing the MEDLINE and the COCHRANE REGISTRY, we identified open trials, controlled trials, for treatment of SSc from 1999 to April 2005. We used the terms scleroderma, systemic sclerosis, Raynaud's phenomenon, pulmonary hypertension, methotrexate, cyclosporin, tacrolimus, relaxin, low-dose penicillamine, IVIg, calcium channel blockers, losartan, prazocin, iloprost, N-acetylcysteine, bosentan, cyclophosphamide, lung transplantation, ACE inhibitors, anti-thymocyte globulin, and stem cell transplantation. Anecdotal reports were omitted.
Annals of the Rheumatic Diseases, 2009
Purpose:The optimal treatment of systemic sclerosis (SSc) is a challenge because the pathogenesis of SSc is unclear and it is an uncommon and clinically heterogeneous disease affecting multiple organ systems. The aim of the European League Against Rheumatism (EULAR) Scleroderma Trials and Research group (EUSTAR) was to develop evidence-based, consensus-derived recommendations for the treatment of SSc.Methods:To obtain and maintain a high level of intrinsic quality and comparability of this approach, EULAR standard operating procedures were followed. The task force comprised 18 SSc experts from Europe, the USA and Japan, two SSc patients and three fellows for literature research. The preliminary set of research questions concerning SSc treatment was provided by 74 EUSTAR centres.Results:Based on discussion of the clinical research evidence from published literature, and combining this with current expert opinion and clinical experience, 14 recommendations for the treatment of SSc wer...
Update of EULAR recommendations for the treatment of systemic sclerosis
The aim was to update the 2009 European League against Rheumatism (EULAR) recommendations for the treatment of systemic sclerosis (SSc), with attention to new therapeutic questions. Update of the previous treatment recommendations was performed according to EULAR standard operating procedures. The task force consisted of 32 SSc clinical experts from Europe and the USA, 2 patients nominated by the pan-European patient association for SSc (Federation of European Scleroderma Associations (FESCA)), a clinical epidemiologist and 2 research fellows. All centres from the EULAR Scleroderma Trials and Research group were invited to submit and select clinical questions concerning SSc treatment using a Delphi approach. Accordingly, 46 clinical questions addressing 26 different interventions were selected for systematic literature review. The new recommendations were based on the available evidence and developed in a consensus meeting with clinical experts and patients. The procedure resulted in 16 recommendations being developed (instead of 14 in 2009) that address treatment of several SSc-related organ complications: Raynaud's phenomenon (RP), digital ulcers (DUs), pulmonary arterial hypertension (PAH), skin and lung disease, scleroderma renal crisis and gastrointestinal involvement. Compared with the 2009 recommendations, the 2016 recommendations include phosphodiesterase type 5 (PDE-5) inhibitors for the treatment of SSc-related RP and DUs, riociguat, new aspects for endothelin receptor antagonists, prostacyclin analogues and PDE-5 inhibitors for SSc-related PAH. New recommendations regarding the use of fluoxetine for SSc-related RP and haematopoietic stem cell transplantation for selected patients with rapidly progressive SSc were also added. In addition, several comments regarding other treatments addressed in clinical questions and suggestions for the SSc research agenda were formulated. These updated data-derived and consensus-derived recommendations will help rheumatologists to manage patients with SSc in an evidence-based way. These recommendations also give directions for future clinical research in SSc.
A randomized, controlled trial of methotrexate versus placebo in early diffuse scleroderma
Arthritis & Rheumatism, 2001
Objective. Early diffuse scleroderma (systemic sclerosis; SSc) has no proven treatment. This study was undertaken to examine the efficacy of methotrexate (MTX) in improving the skin and other disease parameters in early diffuse SSc. Methods. Seventy-one patients with diffuse SSc of <3 years' duration were enrolled in a multicenter, randomized, placebo-controlled, double-blind trial. Thirty-five patients were treated with MTX and 36 with placebo. Treatment was administered for 12 months. The primary outcome measures were skin score (as determined with 2 different indices) and physician global assessment. Results. At baseline, there were no statistically significant differences in skin scores, carbon monoxide diffusing capacity (DLCO), physician global assessment, or other secondary outcome measurements between the 2 treatment groups. At study completion, results slightly favored the MTX group (mean ؎ SEM modified Rodnan skin score 21.4 ؎ 2.8 in the MTX group versus 26.3 ؎ 2.1 in the placebo group [P < 0.17]; UCLA skin score 8.8 ؎ 1.2 in the MTX group versus 11.0 ؎ 0.9 in the placebo group [P < 0.15]; DLCO in the MTX group 75.7 ؎ 4.6 versus 61.8 ؎ 3.4 in the placebo group [P < 0.2]). In addition, physician global assessment results favored MTX (P < 0.035), whereas patient global assessment did not differ significantly between groups. When between-group differences for changes in scores from baseline to 12 months were examined using intentto-treat methodology, MTX appeared to have a favorable effect on skin scores (modified Rodnan score ؊4.3 in the MTX group versus 1.8 in the placebo group [P < 0.009]; UCLA score ؊1.2 in the MTX group versus 1.2 in the placebo group [P < 0.02]), but differences in the degree of change in the DLCO and physician global assessment were not significant. For the UCLA skin score, these differences in results were not statistically significant after adjustment for baseline differences in sex distribution and steroid use. Dropout rates were similar in the 2 groups. Conclusion. Although results of this trial demonstrated a trend in favor of MTX versus placebo in the treatment of early diffuse SSc, the between-group differences were small and the power to rule out falsenegative results was only 50%. Our findings do not provide evidence that MTX is significantly effective in the treatment of early diffuse SSc. Scleroderma (systemic sclerosis; SSc) is a connective tissue disease that causes fibrosis of the skin and visceral organs such as the lungs, gastrointestinal tract, and heart (1). There are 2 major forms of SSc: diffuse and limited. Limited cutaneous SSc (lcSSc) has been