Trials In Systemic Sclerosis Research Articles

P144 Extended examination of post-challenge rewarming in patients with systemic sclerosis, as assessed by thermography

Abstract Background/Aims Clinical trials of systemic sclerosis (SSc)-related Raynaud’s phenomenon require better objective outcome measures. Thermography-monitored cold-challenge is a validated imaging technique. Cold-challenge is monitored for 15-minutes during rewarming, however, patients often do not fully rewarm. Knowing rewarming time enables better planning of daily trial protocols (e.g. challenges before and after treatment). The aim of this study was to test the hypotheses that 15-minute rewarming measurements are predictive of two-hour rewarming and that patients rewarm within a two-hour period. Methods Baseline thermography of the hands and cold-challenge was performed (1 minute, 15oC water, gloved hands submerged). Post-cold challenge, images were taken every 15s (to 15 minutes), every 5 minutes (to 30 minutes), every 10 minutes (to 60 minutes) and every 15 minutes (to 120 minutes). Baseline finger temperature (average, eight fingers, Tbase) and distal dorsal difference (DDD, temperature difference between dorsum ofthe hand and distal finger) were calculated from baseline images. Mean finger temperature difference (post-cold challenge-baseline, Tdiff), time to 25% (t25%), 50% (t50%), 100% (t100%) rewarming, maximum temperature achieved (Tmax), time to Tmax (tmax), area under the rewarming curve (AUC), and final temperature (Tf) were calculated. Cox regression assessed associations between Tbase, Tmax, Tf, DDD and AUC. Results Twenty patients with SSc were recruited; median (interquartile range) age 62 (53-69), duration of RP 16 (7-26) years. Fourteen patients (70%) rewarmed within two hours. Data, Table 1. Cox regression showed positive relationship between AUC and t25%, t50% and t100% and a negative relationship between Tbase, t50% and t100%. In the non-rewarming subset, 3/6 and 1/6 achieved t25%, t50% in 15 minutes. 13/14 patients that rewarmed achieved t25% and 11/14 achieved t50% within 15 minutes. Results suggest that the likelihood of longer-term rewarming is predicted the initial 15-minute rewarming. Conclusion Tbase was reached by the majority of patients with SSc in a two-hour window, therefore, a second or third cold challenge could be incorporated into early Phase II study protocols within a study day. Patients reaching t50% within 15 minutes were highly likely to rewarm fully over two hours; thus 15-minute rewarming may aid screening to identify patients who will fully rewarm. Disclosure A. Ndosi: None. G. Dinsdale: None. J. Manning: None. M. Mandzuk: None. S. Wilkinson: None. A. Herrick: None. A. Murray: None.

Back to the future: targeting the extracellular matrix to treat systemic sclerosis.

Fibrosis is the excessive deposition of a stable extracellular matrix (ECM); fibrotic tissue is composed principally of highly crosslinked type I collagen and highly contractile myofibroblasts. Systemic sclerosis (SSc) is a multisystem autoimmune connective tissue disease characterized by skin and organ fibrosis. The fibrotic process has been recognized in SSc for >40 years, but drugs with demonstrable efficacy against SSc fibrosis in ameliorating the lung involvement have only recently been identified. Unfortunately, these treatments are ineffective at improving the skin score in patients with SSc. Previous clinical trials in SSc have largely focused on the cross-purposing of anti-inflammatory drugs and the use of immunosuppressive drugs from the transplantation field, which address inflammatory and/or autoimmune processes. Limited examination has taken place of specific anti-fibrotic agents developed through their ability to directly target the ECM in SSc by, for example, alleviating the persistent matrix stiffness and mechanotransduction that might be required for both the initiation and maintenance of fibrosis, including in SSc. However, because of the importance of the ECM in the SSc phenotype, attempts have now been made to identify drugs that specifically target the ECM, including some drugs that are currently under consideration for the treatment of cancer.

Hyperspectral imaging in systemic sclerosis-associated Raynaud phenomenon

Background/purposeLack of robust, feasible, and quantitative outcomes impedes Raynaud phenomenon (RP) clinical trials in systemic sclerosis (SSc) patients. Hyperspectral imaging (HSI) non-invasively measures oxygenated and deoxygenated hemoglobin (oxyHb and deoxyHb) concentrations and oxygen saturation (O2 sat) in the skin and depicts data as oxygenation heatmaps. This study explored the potential role of HSI in quantifying SSc-RP disease severity and activity.MethodsPatients with SSc-RP (n = 13) and healthy control participants (HC; n = 12) were prospectively recruited in the clinic setting. Using a hand-held camera, bilateral hand HSI (HyperMed™, Waltham, MA) was performed in a temperature-controlled room (22 °C). OxyHb, deoxyHb, and O2 sat values were calculated for 78-mm2 regions of interest for the ventral fingertips and palm (for normalization). Subjects underwent a cold provocation challenge (gloved hand submersion in 15 °C water bath for 1 min), and repeated HSI was performed at 0, 10, and 20 min. Patients completed two patient-reported outcome (PRO) instruments: the Raynaud Condition Score (RCS) and the Cochin Hand Function Scale (CHFS) for symptom burden assessment. Statistical analyses were performed using the Mann-Whitney U test and a mixed effects model (Stata, College Station, TX).ResultsNinety-two percent of participants were women in their 40s. For SSc-RP patients, 69% had limited cutaneous SSc, the mean ± SD SSc duration was 11 ± 5 years, and 38% had prior digital ulcers—none currently. Baseline deoxyHb was higher, and O2 sat was lower, in SSc patients versus HC (p < 0.05). SSc patients had a greater decline in oxyHb and O2 sat from baseline to time 0 (after cold challenge) with distinct rewarming oxyHb, O2 sat, and deoxyHb trajectories versus HCs (p < 0.01). There were no significant correlations between oxyHb, deoxyHb, and O2 sat level changes following cold challenge and RCS or CHFS scores.ConclusionHyperspectral imaging is a feasible approach for SSc-RP quantification in the clinic setting. The RCS and CHFS values did not correlate with HSI parameters. Our data suggest that HSI technology for the assessment of SSc-RP at baseline and in response to cold provocation is a potential quantitative measure for SSc-RP severity and activity, though longitudinal studies that assess sensitivity to change are needed.

Emerging Evidence and Treatment Perspectives from Randomized Clinical Trials in Systemic Sclerosis: Focus on Interstitial Lung Disease.

Systemic sclerosis (SSc) is a complex rare autoimmune disease with heterogeneous clinical manifestations. Currently, interstitial lung disease (ILD) and cardiac involvement (including pulmonary arterial hypertension) are recognized as the leading causes of SSc-associated mortality. New molecular targets have been discovered and phase II and phase III clinical trials published in the last 5 years on SSc-ILD will be discussed in this review. Details on the study design; the drug tested and its dose; the inclusion and exclusion criteria of the study; the concomitant immunosuppression; the outcomes and the duration of the study were reviewed. The two most common drugs used for the treatment of SSc-ILD are cyclophosphamide and mycophenolate mofetil, both supported by randomized controlled trials. Additional drugs, such as nintedanib and tocilizumab, have been approved to slow pulmonary function decline in SSc-ILD. In this review, we discuss the therapeutic alternatives for SSc management, offering the option to customize the design of future studies to stratify SSc patients and provide a patient-specific treatment according to the new emerging pathogenic features of SSc-ILD.

Contribution of monocytes and macrophages to the pathogenesis of systemic sclerosis: recent insights and therapeutic implications.

To discuss recent studies addressing the role of monocytes and macrophages in the pathogenesis of systemic sclerosis (SSc) based on human and mouse models. Studies indicate that monocyte adhesion could be increased in SSc secondary to an interferon-dependent loss of CD52, and chemotaxis up-regulated through the CCR3/CCL24 pathway. Beyond the conventional M1/M2 paradigm of macrophage subpopulations, new subpopulations of macrophages have been recently described in skin and lung biopsies from SSc patients. Notably, single-cell ribonucleic acid sequencing has provided evidence for SPP1+ lung macrophages or FCGR3A+ skin macrophages in SSc. Impaired pro-resolving capacities of macrophages such as efferocytosis, i.e. the ability to phagocyte apoptotic cells, could also participate in the inflammatory and autoimmune features in SSc. Through their potential pro-fibrotic and pro-inflammatory properties, macrophages are at the cross-road of key SSc pathogenic processes and associated manifestations. Investigative drugs targeting macrophage polarization, such as pan-janus kinase inhibitors (tofacitinib or ruxolitinib) impacting both M1 and M2 activations, or Romilkimab inhibiting IL-4 and IL-13, have shown promising results in preclinical models or phase I/II clinical trials in SSc and other fibro-inflammatory disorders. Macrophage-based cellular therapy may also represent an innovative approach for the treatment of SSc, as initial training of macrophages may modulate the severity of fibrotic and autoimmune manifestations of the disease.

P151 Self-assessment of scleroderma skin thickness: development and evaluation of the PASTUL questionnaire

Background/Aims Evaluation of skin is central to both clinical practice and trials in systemic sclerosis (SSc). This is generally done with the modified Rodnan Skin Score (mRSS). Remote consultations are now widely implemented in response to the COVID-19 pandemic, which has inevitably limited evaluation of skin. To monitor skin during this pandemic and to further explore ways to assess skin, we developed the PASTUL (Patient self-Assessment of Skin Thickness in Upper Limb) questionnaire. The aim of this study was to evaluate feasibility and validity of the PASTUL in SSc. Methods The PASTUL questionnaire specifies a simple grading of skin as normal, mild, moderate, or severely thickened at eight sites of upper limb corresponding to mRSS. Assessed grades were converted to an integer scale [0, 1, 2, 3]. Detailed instructions for patients were provided. Scleroderma Skin PRO (SSPRO) and Scleroderma Health Assessment Disability Index (SHAQ-DI) were also completed. The mRSS was done in a selection of patients. Construct validity was evaluated by examining the correlation between PASTUL, mRSS, SSPRO and SHAQ-DI using Pearson’s correlation coefficient. Content validity was evaluated by scoring relevance, clarity and practical difficulty. Test-retest reliability was estimated using intraclass correlation coefficient (ICC). Results In total, 107 patients were invited of which 83 (77.6%) completed the questionnaires. The mRSS was undertaken in 61 patients. The PASTUL was completed by patients (83.1%) or by a partner/friend (16.9%). Mean PASTUL score was 11 (SD 6), mean HAQ-DI 1.47 (SD 0.76) and mean SSPRO 49.8 (SD 26.6). PASTUL and SSPRO physical limitations correlated strongly (0.62, p < 0.001). Correlations between PASTUL and total SSPRO and mRSS upper limbs were moderate to weak (0.59, 0.50 and 0.32 respectively). Correlation between PASTUL and mRSS was stronger in lcSSc compared to dcSSc patients (0.61 vs 0.29) and when assessed by a partner/friend compared to patients themselves (0.98 vs 0.45). The PASTUL demonstrated excellent test-retest reliability (ICC of 0.92) and good content validity. P151 Table 1:Correlation of PASTUL score with other outcome measuresOutcome measurePearson's correlation coefficientP-valuemRSS0.48<0.001mRSS upper limbs0.50<0.001SHAQ-DI0.320.004VAS pain0.180.107VAS GI0.130.239VAS breathing0.130.236VAS RP0.090.406VAS DU0.090.466VAS limitations0.250.026SSPRO0.59<0.001SSPRO subdomain PE0.56<0.001SSPRO subdomain PL0.62<0.001SSPRO subdomain EE0.49<0.001SSPRO subdomain SE0.370.001DU, digital ulcers; EE, emotional effects; GI, gastrointestinal; HAQ-DI, Health Assessment Questionnaire Disability Index; mRSS, modified Rodnan skin score; PE, physical effects; PL, physical limitations; RP, Raynaud's phenomenon; SE, social effects Conclusion Moderate and significant correlations of PASTUL scores with total SSPRO, physical limitation scores and mRSS support the usefulness of PASTUL as an outcome measure and indicates it’s potential for use in virtual clinical settings Disclosure J. Spierings: None. V.H. Ong: None. C.P. Denton: None.

An update on recent randomized clinical trials in systemic sclerosis.

Systemic sclerosis (SSc) is an autoimmune disorder characterized by a remarkable clinical heterogeneity and variable disease course. In this multifactorial condition, the interaction of several pathogenic pathways related to inflammation, vasculopathy and fibrosis promote organ damage. The understanding of the pathogenesis of SSc has improved in recent years leading to the identification of relevant therapeutic targets. Over the last few years, insightful clinical trials have been published and great progress has been made in developing effective therapeutic options. The positive results of the Safety and Efficacy of Nintedanib in Systemic SClerosIS (SENSCIS) trial have led to the approval by drug agencies of the first drug for SSc-related interstitial lung disease. However, the majority of clinical trials have focused on immunosuppressive therapy. Although benefit trends have been observed, outstanding results have not been achieved and to date no immunosuppressant has been approved in SSc. Clinical trial design has evolved regarding inclusion criteria with the aim to enrich for progressive patients. Endpoints have also been revised to better cover the fields of patients' feelings and functioning. Finally, background synthetic immunosuppressants have been allowed in some trials evaluating targeted therapies opening the door to combination therapies. Herewith, we provide an overview of the most significant clinical trials developed in recent years for the management of SSc.

News and failures from recent treatment trials in systemic sclerosis.

There have been many recent trials in systemic sclerosis (SSc) that have explored treatment for skin or lung. Some have been encouraging, but there has also been disappointment reflecting potential limitations of treatment effect of study design. These trials are discussed and reviewed. Studies conducted in SSc are described and discussed with a focus on endpoint selection and trial design as well as potential mechanism of action and treatment effect. Studies have included very encouraging trials of interleukin 6 blockade, immunosuppression, and broad-spectrum tyrosine kinase inhibition. Other trials including recent studies of peroxisome proliferator-activated receptor agonists and specific intracellular signaling inhibitors such as imatinib or anti-transforming growth factor beta blocking strategies have been more disappointing. Trial design is improving, and overall, there are now almost positive trials using agents with great promise, and studies are also providing important biological insight into SSc. It is hoped that ongoing studies will further progress the field and move it toward better treatments for SSc that still represent a major unmet medical need.

Scope and Consistency of Outcomes Reported in Trials of Patients With Systemic Sclerosis.

The core outcome set for trials in systemic sclerosis (SSc) was developed in 2008 and comprises 11 domains and 31 measures, leading to the development of the Combined Response Index in Diffuse Cutaneous Systemic Sclerosis (CRISS). We aimed to assess the scope and consistency of outcomes reported in trials of SSc and the uptake of this core set and the CRISS. Medline, the Cochrane Central Register of Controlled Trials, Embase, and ClinicalTrials.gov were searched to identify randomized trials published from January 1, 2000 to April 29, 2018 in adults with limited or diffuse SSc. Outcomes and measures were recorded for each trial, classified into domains and the frequency of outcomes before after publication of the publication of the core set calculated. From 152 trials, 4,193 outcomes were classified into 84 domains. The 3 most common domains were health-related quality of life (HRQoL) and function (59%, 130 measures), skin (47%, 59 measures), and pulmonary (45%, 168 measures). After the publication of the core outcome set, no trial reported the complete core set with adherence to each of the 11 domains, ranging from 6.1% to 54.4% and adherence to each of the 31 measures ranging from 0% to 48.1%. The 5 measures required for the CRISS were reported completely in 11% of trials. Despite recognition that uniform acquisition and reporting of outcomes would enable a better evaluation of proposed SSc therapeutics, the outcome domains and measures reported in randomized trials in SSc remain very inconsistent, with little impact of the core outcome set.

Assessment of skin disease in scleroderma: Practices and opinions of investigators studying scleroderma.

The modified Rodnan skin score is a common primary outcome measurement tool in clinical trials of systemic sclerosis (scleroderma). However, it is unknown how often physicians perform the modified Rodnan skin score in clinical practice or what precise approach is most often used when assessing each of the 17 sites included in the modified Rodnan skin score (i.e. "maximizing," "averaging," "representative area"). This study assessed the experiences, perceptions, training, and practices of individuals studying scleroderma with regard to modified Rodnan skin score. An invitation with an online survey link was sent electronically to 282 individuals who are part of the Scleroderma Clinical Trials Consortium. The 46-item survey included three sections: participant demographics, modified Rodnan skin score background/training, and modified Rodnan skin score assessment practices. The survey was accessible for 5 weeks (October-November 2019). The response rate was 41% (116 of 282 individuals). The majority of participants perform the modified Rodnan skin score in clinical care (>99%) and practice at academic institutions (90%) in North America (41%) or Europe (40%). Nearly all participants felt that the modified Rodnan skin score is either "somewhat important" (43%) or "essential" (56%) to the care of patients with systemic sclerosis. In total, 91% of participants reported having received modified Rodnan skin score training. The majority (60%) of those who had not received training were interested in receiving modified Rodnan skin score training, and 39% of participants felt either "uncomfortable" or only "somewhat comfortable" performing the modified Rodnan skin score. The modified Rodnan skin score approach varied: 44% used "maximizing," 28% used "averaging," and 18% used "representative area." A majority of participants feel that the modified Rodnan skin score is "essential" to the care of patients with systemic sclerosis; however, the method used to measure modified Rodnan skin score varies greatly among systemic sclerosis investigators. These results indicate a continued role of modified Rodnan skin score for care and research in systemic sclerosis, support ongoing efforts to increase opportunities for modified Rodnan skin score training, and highlight a potential need to harmonize the technical approach to measuring the modified Rodnan skin score.

Randomised controlled trials in systemic sclerosis: patient selection and endpoints for next generation trials.

The heterogeneity in the natural history of systemic sclerosis is a major issue in both clinical management and trial design and is dictated by the complex and multifactorial pathogenesis of the disease. Systemic sclerosis is an autoimmune disease and therefore many trials for the disease have targeted immune activation pathways; however, the phase 3 trials that have been positive have targeted pathways directly linked to tissue damage rather than systemic immune activation. On one hand, these results represent enormous progress that has led to the first approved drugs for this extremely challenging condition. On the other hand, they have revealed a possible selection bias in our current approach to trial design. In this Series paper, we describe randomised controlled trials from the past 4 years we believe to be most relevant to future strategies in systemic sclerosis. Based on advances in our understanding of the pathogenesis and natural history of disease, we will also identify important points to consider in the design of the next generation of systemic sclerosis trials.

Patient-reported outcome instruments in clinical trials of systemic sclerosis.

Patient-reported outcome instruments provide valuable insight into disease-related morbidity known only to the patient and complement more objective outcome tools in the clinical trial setting. They are of particular importance in systemic sclerosis owing to the challenges around defining disease activity, the episodic nature of many disease-specific manifestations and the paucity of validated objective surrogate outcome measures for use in clinical trials. Early clinical trials of systemic sclerosis often incorporated legacy patient-reported outcome instruments, but the last 20 years has witnessed the emergence of several scleroderma-specific instruments that are now being routinely used alongside other outcomes in systemic sclerosis clinical trials. More recently, the value of patient-reported outcomes has been highlighted by their prominence in the American College of Rheumatology Combined Response Index for Systemic Sclerosis that has been utilized as the primary endpoint of recent clinical trials of early diffuse systemic sclerosis. This review considers the role and performance of the various patient-reported outcome instruments utilized in systemic sclerosis clinical trials, the current positioning of patient-reported outcome instruments within clinical trial endpoint models across the range of systemic sclerosis disease manifestations and, where applicable, we shall highlight areas for future research.

Challenges in systemic sclerosis trial design

Systemic sclerosis (scleroderma; SSc) is an autoimmune rheumatic disease with high clinical burden and unmet need due to connective tissue fibrosis and vascular damage. It has the highest case specific mortality of any rheumatic disease, with approximately half of patients diagnosed eventually dying as a direct result of SSc. There are no approved diseases modifying treatments. This is partly related to the difficulty of conducting clinical trials for regulatory approval.Traditionally skin thickness has been assessed using the modified Rodnan skin score (MRSS) that has been shown to correlate with survival and risk of complications in SSc. However recent trials have highlighted the limitations of MRSS which often improves over time, even on placebo.A new composite measure integrating changes in multiple domains of lung function, skin, patients and physician global and HAQ disability index has been developed, the CRISS (Composite Response Index for Systemic Sclerosis). This measure looks promising and has provisional acceptance by American College of Rheumatology (designated ACR CRISS) but is unlikely to be strongly persuasive to Health Authorities in isolation unless there are also clinically meaningful changes in relevant domains that reflect how patients feel, function or survive.

Predictors of disease worsening defined by progression of organ damage in diffuse systemic sclerosis: a European Scleroderma Trials and Research (EUSTAR) analysis

ObjectivesMortality and worsening of organ function are desirable endpoints for clinical trials in systemic sclerosis (SSc). The aim of this study was to identify factors that allow enrichment of patients...

Guidelines and Recommendations Towards Evidence-Based Management of Systemic Sclerosis

The preferred treatment of systemic sclerosis (SSc) is unclear due to an incomplete understanding of disease pathogenesis, variations in disease manifestations and variable quality of evidence to support treatment decisions. The objectives of this article are to discuss the value of clinical practice guidelines, critique guideline development and uptake, compare SSc-specific guidelines and highlight consensus-based treatment algorithms to complement guidelines when recommendations and/or high-quality evidence are lacking. Thirty-nine guidelines or recommendations for the screening, diagnosis, treatment and conduct of trials in SSc have been published. Four publications contained guidance on the treatment of multiple domains. The European League Against Rheumatism and the EULAR Scleroderma Trial and Research group guidelines were published in 2009 and updated in 2017. The British Society of Rheumatology and the British Health Professionals in Rheumatology published guidelines in 2016. The Brazilian Society of Rheumatology published SSc guidelines in 2013. The absence of recommendations for the preferred order of therapy is a limitation of all published guidelines. Treatment algorithms, based on SSc expert consensus, were proposed in 2012 and updated in 2018. These algorithms are complementary to the guidelines, as they provide expert consensus in areas of uncertainty. SSc-specific guidelines and treatment algorithms provide evidence-based and/or expert consensus-based recommendations on how to treat patients with the intention of reducing inappropriate practice variability and improving patient outcomes.

Hematopoietic stem cell transplantation for autoimmune diseases: more than just prolonged immunosuppression.

To summarize the current clinical experience in the use of autologous hematopoietic stem cell transplantation (HSCT) in autoimmune disease and to explore the concept of durable remission induction and tissue de-remodeling via restoration of normal niche function and "immune reset.' Controlled clinical trials in systemic sclerosis, multiple sclerosis, and Crohn's disease as well as extensive uncontrolled trial and registry data have established the unique role of HSCT in selected cases. Although HSCT for multiple sclerosis and systemic sclerosis has recently entered several official treatment guidelines, mechanistic studies are few but indicate some possible modes of action, for example, increase of regulatory T cells. Toxicity of HSCT remains high but is improving with protocol modifications and more precise patient selection. For the first time, it has been demonstrated that strategies exist which may permanently reprogram an autoaggressive immune system to one of self-tolerance independent of ongoing immunosuppression. In addition, some tissues have the capacity to repair damage via normal regenerative processes. The exact mechanism(s) as to how this is achieved in certain cases and not others are emerging. Such knowledge, together with adoption of recently developed less toxic and more targeted regimens from the hematology/oncology field may translate to a safer yet still effective treatment for autoimmune disease.

An Interim Report of the Scleroderma Clinical Trials Consortium Working Groups.

The Scleroderma Clinical Trials Consortium (SCTC) represents many of the clinical researchers in the world who are interested in improving the efficiency of clinical trials in Systemic Sclerosis (SSc). The SCTC has established 11 working groups (WGs) to develop and validate better ways of measuring and recording multiple aspects of this heterogeneous disease. These include groups working on arthritis, disease damage, disease activity, cardiac disease, juvenile SSc, the gastrointestinal tract, vascular component, calcinosis, scleroderma renal crisis, interstitial lung disease, and skin measurement. Members of the SCTC may join any one or more of these groups. Some of the WGs have only recently started their work, some are nearing completion of their mandated tasks and others are in the midst of their projects. All these projects, which are described in this paper, will help to improve clinical trials and observational studies by improving or developing better, more sensitive ways of measuring various aspects of the disease. As Lord Kelvin stated, "To measure is to know. If you cannot measure it you cannot improve it." The SCTC is dedicated to improving the lives of patients with SSc and it is our hope that the contributions of the WGs will be one important step in this process.

Therapeutic interleukin-6 blockade reverses transforming growth factor-beta pathway activation in dermal fibroblasts: insights from the faSScinate clinical trial in systemic sclerosis

ObjectivesSkin fibrosis mediated by activated dermal fibroblasts is a hallmark of systemic sclerosis (SSc), especially in the subset of patients with diffuse disease. Transforming growth factor-beta (TGFβ) and interleukin-6 (IL-6)...

Interstitial lung disease points to consider for clinical trials in systemic sclerosis

Interstitial lung disease causes major morbidity and mortality in patients with systemic sclerosis (SSc-ILD). Large randomized clinical trials in SSc-ILD have provided important information regarding the feasibility, reliability and validity of outcome measures. Forced vital capacity percentage predicted should be considered as a primary outcome measure, with inclusion of appropriate radiological and patient-reported measures. We provide practical recommendations for trial design in SSc-ILD.

Functional disability and other health-related quality-of-life domains: points to consider for clinical trials in systemic sclerosis.

Patients with SSc have the highest mortality among the rheumatic diseases. In addition, SSc is associated with disfigurement, hand contractures, fatigue, poor sleep, severe RP with numbness and tingling of the fingers can lead to decrements in quality of life. This Points to Consider article provides practical considerations for design of trials for functional disability and other health-related quality-of-life issues.