Background/Purpose: Systemic sclerosis (SSc) is a chronic disease characterized by multi-organ involvement. Excess collagen deposition and fibrosis is thought to result from a complex interplay between vasculopathy and inflammation. Skin fibrosis, and its extent, is a cardinal feature of SSc, and permits its classification in diffuse and limited subsets. Evidence for the pharmacologic management of skin involvement is limited and there is a need for further clinical guidance. Cyclophosphamide is an alkylating agent with potent immunomodulating effects, commonly used in rheumatic diseases. The objective of this systematic review was to assess the efficacy of Cyclophosphamide in the treatment of skin fibrosis in patients with SSc.

Methods: Embase, MEDLINE and Cochrane Central Register of Controlled Trials were searched for all randomized control trials (RCTs), quasi-randomized studies, case-control studies, controlled before-after studies, prospective and retrospective cohort studies, case series and cross-sectional studies on February 7, 2019. Case reports were excluded. The Health Canada registry, clinicaltrials.gov, the ISRCTN registry, and the World Health Organization (WHO) international clinical trials registry were searched for grey literature. Studies pertaining to patients with a diagnosis of SSc were included with no limitation on specific classification criteria. The main intervention of interest was Cyclophosphamide with no limitation of regimens or route of administration. Comparators were other standard disease modifying agents or placebo. The outcome of interest was extent of skin fibrosis defined by the modified Rodnan skin score (mRss). Two review authors completed independent and duplicate abstract and full text screening. Data extraction and quality appraisal were completed independently by two review authors. Meta-analysis was performed for the primary outcome (mRSS) through random-effects models.

Results: Thirty-one studies conducted between 1994 and 2018 were included: 11 RCTs, 13 case series, 4 retrospective cohort studies and 3 prospective cohort studies. The majority of the 11 RCTs showed some concerns in regards to risk of bias. After 12 months of treatment with Cyclophosphamide, mean mRSS decreased 6.30 points (95% CI, 4.95 to 7.64). The effect remained significant when pooling both 6- and 12-month outcomes – mRSS decreased 4.11 points (95% CI, 0.97, 7.25). Heterogeneity of comparators, use of steroids, and outcome endpoints did not allow for subgroup analyses to be completed as planned.

Conclusion: Statistically and clinically significant improvements in mRSS with administration of Cyclophosphamide were demonstrated in patients with SSc. The effect was greater at 12 months of follow-up. The lack of consistent standard of care for the treatment of skin fibrosis in SSc was highlighted by the variability in the type and duration of comparator treatments used in clinical trials. Although the use of Cyclophosphamide for skin fibrosis in SSc is justified by these results, there is a need for more consistent recommendations regarding treatment regimens, and longer clinical follow-up to better understand the role of immunosuppression as a treatment for this disease manifestation.

« Back to 2019 ACR/ARP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/cyclophosphamide-for-the-treatment-of-skin-fibrosis-in-systemic-sclerosis-a-systematic-review/