Management of systemic sclerosis‐associated interstitial lung disease in the current era

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154421/1/apl13799_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154421/2/apl13799.pd

Emerging drugs for the treatment of scleroderma: a review of recent phase 2 and 3 trials

International audienceINTRODUCTION: Systemic sclerosis (SSc) has the highest case-specific mortality of all connective tissue diseases. Its underlying disease mechanism affects several organs and remains incompletely understood. Ongoing work clarifying its etiopathogenesis is helping to develop targeted therapy. AREAS COVERED: Several clinical trials have evaluated the safety and efficacy of agents targeting different mechanisms of this disease. This review article reviews those mechanisms and surveys four key recent phase II or III clinical trials that are contributing to the landscape of SSc therapy. The reported trials primarily focus on patients with systemic sclerosis in the early phase of disease. EXPERT OPINION: Traditional therapies for SSc center on immunosuppressive and cytotoxic agents. A new cadre of therapies is borne from improved understandings of SSc pathobiology and target the inflammatory-fibrotic pathways. Scleroderma trials have entered the initial phase of personalized medicine, recognizing molecular subsets that will improve upon cohort enrichment and maximize the measurable benefit of future therapies

Therapeutic Approaches to Systemic Sclerosis: Recent Approvals and Future Candidate Therapies

International audienceSystemic sclerosis is the rheumatic disease with the highest individual mortality. The severity of the disease is determined by the extent of fibrotic changes to cutaneous and internal organ tissues, the most life-threatening visceral manifestations being interstitial lung disease, SSc-associated-pulmonary arterial hypertension and myocardial involvement. The heterogeneity of the disease has initially hindered the design of successful clinical trials, but considerations on classification criteria have improved patient selection in trials, allowing the identification of more homogeneous groups of patients based on progressive visceral manifestations or the extent of skin involvement with a focus of patients with early disease. Two major subsets of systemic sclerosis are classically described: limited cutaneous systemic sclerosis characterized by distal skin fibrosis and the diffuse subset with distal and proximal skin thickening. Beyond this dichotomic subgrouping of systemic sclerosis, new phenotypic considerations based on antibody subtypes have provided a better understanding of the heterogeneity of the disease, anti-Scl70 antibodies being associated with progressive interstitial lung disease regardless of cutaneous involvement. Two targeted therapies, tocilizumab (a monoclonal antibody targeting interleukin-6 receptors (IL-6R)) and nintedanib (a tyrosine kinase inhibitor), have recently been approved by the American Food and Drug Administration to limit the decline of lung function in patients with SSc-associated interstitial lung disease, demonstrating that such better understanding of the disease pathogenesis with the identification of key targets can lead to therapeutic advances in the management of some visceral manifestations of the disease. This review will provide a brief overview of the pathogenesis of SSc and will present a selection of therapies recently approved or evaluated in this context. Therapies evaluated and approved in SSc-ILD will be emphasized and a review of recent phase II trials in diffuse cutaneous systemic sclerosis will be proposed. We will also discuss selected therapeutic pathways currently under investigation in systemic sclerosis that still lack clinical data in this context but that may show promising results in the future based on preclinical data

Systemic Sclerosis Associated Interstitial Lung Disease: A Conceptual Framework for Subclinical, Clinical, and Progressive Disease

OBJECTIVES Establish a framework by which experts define disease subsets in systemic sclerosis associated interstitial lung disease (SSc-ILD). METHODS A conceptual framework for subclinical, clinical, and progressive ILD was provided to eighty-three experts, asking them to use the framework and classify actual SSc-ILD patients. Each patient profile was designed to be classified by at least 4 experts in terms of severity and risk of progression at baseline; progression was based on 1-year follow-up data. A consensus was reached if ≥ 75% of experts agreed. Experts provided information on which items were important in determining classification. RESULTS Forty-four experts (53%) completed the survey. Consensus was achieved on the dimensions of severity (75%, 60 of 80 profiles), risk of progression (71%, 57 of 80 profiles) and progressive ILD (60%, 24 of 40 profiles). For profiles achieving consensus, most were classified as clinical ILD (92%), low risk (54%), and stable (71%). Severity and disease progression overlapped in terms of framework items that were most influential in classifying patients (forced vital capacity, extent of lung involvement on high resolution chest CT (HRCT)); risk of progression was influenced primarily by disease duration. CONCLUSIONS Using our proposed conceptual framework, international experts were able to achieve a consensus on classifying SSc-ILD patients along the dimensions of disease severity, risk of progression, and progression over time. Experts rely on similar items when classifying disease severity and progression: a combination of spirometry and gas exchange and quantitative HRCT

Tocilizumab Prevents Progression of Early Systemic Sclerosis–Associated Interstitial Lung Disease

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/168321/1/art41668.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/168321/2/art41668_am.pd

Risk factors for lung function decline in systemic sclerosis-associated interstitial lung disease in a large single-center cohort

International audienceOBJECTIVES: The aim of this study was to identify risk factors of percent predicted forced vital capacity (ppFVC) decline in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD). METHODS: We identified 484 patients with SSc who had HRCT Chest, of which 312 with ILD. Those with serial pulmonary function tests were included in a longitudinal analysis (n = 184). Linear mixed effect models were fitted to assess the decline in ppFVC over time, and to explore the effect of demographics and baseline characteristics on ppFVC decline. RESULTS: The majority of SSc-ILD patients were female (76.3%) and 51.3% had diffuse cutaneous subset. The mean (SD) age was 53.6 (12.7) years, median disease duration since first non-RP symptoms was 2.6 years, and 48.4% of the patients had ILD extent >20% on HRCT. In the univariate analysis, longer disease duration (>2.37 years), ILD extent > 20%, and anti-topoisomerase I (ATA) positivity were significantly associated with ppFVC decline. In the multivariate analysis, the only statistically significant variable associated with ppFVC decline was ATA positivity. The overall group’s mean decline in ppFVC was -0.28% (p-value 0.029), with -0.13% (N = 163) in those who were alive and -8.28% (p-value 0.0002 for the change in ppFVC trajectory) in patients who died within 2 years. CONCLUSION: Our study confirms that ppFVC is a marker of survival in SSc-ILD, supporting its use for risk stratification to identify patients who may benefit from earlier interventions and treatment. Our study also supports the role of ATA positivity as a predictive marker for ppFVC decline in this population

Systemic Sclerosis–Associated Interstitial Lung Disease: How to Incorporate Two Food and Drug Administration–Approved Therapies in Clinical Practice

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SYSTEMIC SCLEROSIS-ASSOCIATED INTERSTITIAL LUNG DISEASE: How to incorporate two Food and Drug Administration-approved therapies in clinical practice

International audienceSystemic sclerosis (SSc; scleroderma) has the highest individual mortality of all rheumatic diseases and interstitial lung disease (ILD) is among the leading causes of SSc-related death. Two drugs are now approved by the Food and Drug Administration (FDA) and indicated for slowing the rate of decline in pulmonary function in patients with SSc-ILD: nintedanib (a tyrosine kinase inhibitor) and tocilizumab (the first biologic agent targeting the interleukin-6 pathway in SSc). In addition, two generic drugs with cytotoxic and immunoregulatory activity, mycophenolate mofetil and cyclophosphamide, have shown comparable efficacy in a Phase II trial but are not FDA-approved for SSc-ILD. In light of the heterogeneity of the disease, the optimal therapeutic strategy in the management of patients with SSc-ILD is still to be determined. The objectives of this review are two-fold: (1) review the body of research focused on the diagnosis and treatment of SSc-ILD; and (2) propose a practical approach for diagnosis, stratification, management, and therapeutic decision-making in this clinical context. This review presents a practical classification of SSc patients in terms of disease severity (subclinical vs. clinical ILD) and associated risk of progression (low vs. high risk). The pharmacological and non-pharmacological options as first and second-line therapy, as well as potential combination approaches, are discussed in light of the recent approval of tocilizumab for SSc-ILD

Domains and outcome measures for the assessment of limited cutaneous systemic sclerosis: an international collaborative scoping review

International audienceOBJECTIVES: to comprehensively identify instruments within relevant domains employed to assess limited cutaneous systemic sclerosis (lcSSc) since the endorsement of its consensus definition in 1988. The overall objective is to inform the creation of a combined response index for lcSSc (Combined response index for scleroderma trial assessing limited scleroderma (CRISTAL)). METHODS: MEDLINE and EMBASE were searched with terms selected to comprehensively retrieve titles/abstracts mentioning both lcSSc and dcSSc along with those only mentioning lcSSc, SSc sine scleroderma, limited SSc and/or CREST/CRST. Because our initial assessment of the literature revealed that very few studies included only lcSSc subjects, we assessed literature that included either only lcSSc or both cutaneous subsets. 3964 Titles and Abstracts were screened by two reviewers. 270 articles were selected for data extraction. RESULTS: We identified 27 domains encompassing 459 instruments. Instruments from "Skin involvement", "Pulmonary involvement" and "Health-related quality of life and general functioning" were the most frequently retrieved. Among the 15 most represented instruments announced as primary endpoints in efficacy or effectiveness studies, 7 were Clinician Reported Outcomes (RO), 7 were patient ROs and one was a Performance outcome (6 min-walk test). The mean proportion of lcSSc patients in studies including both lc and dcSSc, was 56.4% demonstrating that this subset is underrepresented in the literature. CONCLUSION: This scoping literature review provides a comprehensive identification of domains and outcomes used to assess lcSSc. Our results also highlight that lcSSc is under-represented in the literature