Management of juvenile-onset systemic sclerosis with systemic immunosuppressive therapies: An evidence-based review

To the Editor: Juvenile-onset systemic sclerosis (JSSc) is a rare, debilitating, autoimmune condition resulting from inflammation, vascular abnormality, and progressive fibrosis. It affects the connective tissue in multiple organ systems.1Cutolo M. Sulli A. Smith V. Assessing microvascular changes in systemic sclerosis diagnosis and management.Nat Rev Rheumatol. 2010; 6: 578-587https://doi.org/10.1038/nrrheum.2010.104Crossref PubMed Scopus (180) Google Scholar This systematic review examines the use of systemic immunosuppressive therapies in JSSc, with a focus on efficacy for skin thickness. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria, a MEDLINE and Embase OVID search was conducted on November 12, 2021, using variations and synonyms of the keywords “scleroderma” and “pediatric” (Supplementary Table I, available via Mendeley at https://data.mendeley.com/datasets/jpsxp7dwds/4). After the independent screening of 232 articles by 2 reviewers (AA and BDR), 95 patients from 42 studies were included (Fig 1); extracted data are presented in Supplementary Table II (available via Mendeley at https://data.mendeley.com/datasets/jpsxp7dwds/4). The mean patient age was 9.6 years (range, 2-17 years). There were 21 (22.1%) boys and 71 (74.7%) girls; sex was not stated for 3 (3.2%) patients. A total of 121 instances of systemic immunosuppressive therapy use with outcomes were documented in the 95 patients; treatments were categorized as monotherapy (78/121, 64.5%) or combination therapy (43/121, 35.5%). Corticosteroids (27/78, 34.6%), methotrexate (18/78, 23.1%), and D-penicillamine (15/78, 19.2%) were the most common monotherapies. Corticosteroids with methotrexate (24/43, 55.8%), corticosteroids with D-penicillamine and methotrexate (4/43, 9.3%), and corticosteroids with cyclophosphamide (3/43, 7%) were the most frequent combination therapies (Supplementary Table III, available via Mendeley at https://data.mendeley.com/datasets/jpsxp7dwds/4). Treatment duration was described in 30 instances (mean, 6.5 months; range, 0.25-18 months). Outcomes were reported as improved, stabilized (no improvement or worsening), and worsened in 92 (76%), 16 (13.2%), and 13 (10.7%) of the 121 instances, respectively. The modified Rodnan skin score (mRSS), a validated outcome measure for evaluating skin thickness severity in systemic sclerosis (range, 0-52), was the primary focus of this evaluation. Based on clinical trial data in adults with systemic sclerosis, the minimal clinically important difference (MCID) in mRSS is a ≥20% improvement or a reduction by ≥3 points from baseline.2Khanna D. Furst D.E. Clements P.J. et al.Standardization of the modified Rodnan skin score for use in clinical trials of systemic sclerosis.J Scleroderma Relat Disord. 2017; 2: 11-18https://doi.org/10.5301/jsrd.5000231Crossref PubMed Scopus (221) Google Scholar The mRSS was recorded in 49 (51.6%) of the 95 patients with JSSc. The mean change in the mRSS from baseline across treatments was −5.6 points, with 36 (73.5%) of the 49 patients achieving MCID. The most common treatment regimens resulting in the MCID for mRSS were monotherapy with methotrexate (16/49, 32.7%), D-penicillamine (12/49, 24.5%), and corticosteroids (11/49, 22.4%). Treatment-related adverse events were reported in 4 (4.2%) cases, with none resulting in death; no patients discontinued treatment because of adverse events. The Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) initiative recently published recommendations for the management of JSSc, suggesting systemic corticosteroids at the time of diagnosis with subsequent use of methotrexate and then transitioning to mycophenolate mofetil within 6 months if signs/symptoms do not improve.3Foeldvari I. Culpo R. Sperotto F. et al.Consensus-based recommendations for the management of juvenile systemic sclerosis.Rheumatology (Oxford). 2021; 60: 1651-1658https://doi.org/10.1093/rheumatology/keaa584Crossref PubMed Scopus (6) Google Scholar Unfortunately, because of the lack of evidence, other contemporary treatments (eg, tocilizumab) were omitted from the guidelines.4Torok K.S. Updates in systemic sclerosis treatment and applicability to pediatric scleroderma.Rheum Dis Clin North Am. 2021; 47: 757-780https://doi.org/10.1016/j.rdc.2021.07.004Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar Limitations of our systematic review include a small sample size, the lack of follow-up data/standardized outcome metrics, and potential selection bias for cases with reported outcomes. Delayed treatment in some patients with JSSc may also hinder the efficacy of systemic immunosuppressive therapy. Nevertheless, we highlight evidence for the use of systemic immunosuppressive therapy in treating JSSc. Rigorous placebo-controlled and head-to-head clinical trials involving systemic immunosuppressive therapies in populations with JSSc are needed; similar studies in adults have led to comprehensive management guidelines.5Kowal-Bielecka O. Fransen J. Avouac J. et al.Update of EULAR recommendations for the treatment of systemic sclerosis.Ann Rheum Dis. 2017; 76: 1327-1339https://doi.org/10.1136/annrheumdis-2016-209909Crossref PubMed Scopus (598) Google Scholar Dr Prajapati has been an advisor, consultant, speaker, and/or investigator for AbbVie, Actelion, Amgen, AnaptysBio, Aralez, Arcutis, Arena, Aspen, Bausch Health, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Cipher, Concert, Dermavant, Dermira, Eli Lilly, Galderma, GlaxoSmithKline, Homeocan, Incyte, Janssen, LEO Pharma, Medexus, Nimbus Lakshmi, Novartis, Pediapharm, Pfizer, Regeneron, Reistone, Sanofi Genzyme, Sun Pharma, Tribute, UCB, and Valeant. Author Abduelmula and Drs Rankin, and Luca have no conflicts of interest to declare.