Clinical Trials In Systemic Sclerosis Research Articles

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.

Composite measures to assess disease damage, disease severity and treatment response in systemic sclerosis clinical trials.

The aim of this study was to summarize the composite outcome measures available to assess disease damage, severity and treatment response in systemic sclerosis (SSc). There have been many recent efforts to rigorously develop and validate composite outcome measures to assess the totality of the impact of SSc on patients. All initiatives have used both consensus and data-driven methods. Recently developed are a SSc-specific damage index, a patient-reported disease impact questionnaire (ScleroID) and a treatment response index (ACR-CRISS). Multiorgan, composite measures are being increasingly applied to assess treatment efficacy in clinical trials. Although a fully validated, disease-specific composite measure is not yet available, there has been significant recent progress towards developing measures of treatment response, damage and overall impact of SSc for application in randomized controlled trials.

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.

Imaging techniques for assessment of vascular involvement in systemic sclerosis.

Vascular assessment in systemic sclerosis (SSc) is included in classification criteria for this disease, thus routinely used in the evaluation of patients in which this diagnosis is being considered. In this review, imaging techniques for assessment of vascular involvement in SSc hands and skin are discussed. Longitudinal use of imaging techniques has important implications for understanding the progressive vasculopathy and fibrotic transition in SSc. Nailfold and oral capillaroscopy as well as laser speckle contrast analysis are established techniques for vascular functional assessment, but longitudinal use is challenged by equipment costs and clinical time constraints. Ultrasound techniques are well described but require technical training. Advances in mobile infrared thermography and optical coherence tomography could potentially provide a point-of-care, quantitative outcome measure in clinical trials and practice. The equipment cost, technical training, data standardization, and invasiveness of vascular assessment techniques that quantify morphological (microangiopathy) and functional (blood flow reduction) are critical for implementation into SSc clinical trials and practice to understand progressive vasculopathy, such as wound development.

Plasma protein correlates of skin severity in systemic sclerosis.

Systemic sclerosis is an autoimmune disease associated with widespread fibrosis in skin and internal organs. The extent of skin involvement affects quality of life and an improvement in skin thickening predicts better survival.1 Moreover, skin involvement is the primary or secondary outcome in many systemic sclerosis clinical trials. Currently, the extent of skin fibrosis is measured using a palpitation-based, semi-quantitative scoring system called the modified Rodnan skin score (mRSS). Although the mRSS is a validated outcome measure, it requires extensive training and has a high inter-observer variability.

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.

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.

Durometry in SSc: The hard facts. A systematic literature review and additional pilot study.

To investigate the reliability of durometry in systemic sclerosis (SSc), by means of a systematic review and additional pilot study. Literature was systematically reviewed according to the PRISMA guidelines to identify all original studies assessing the reliability of durometry in SSc. Additionally, in the pilot study, intra-rater reliability was evaluated in a first cohort of 74 SSc patients (61 female, 13 LSSc/53 LcSSc/8 DcSSc). In a second separate set of 30 SSc patients (21 female, 4 LSSc/20 LcSSc/6 DcSSc), intra- and inter-rater reliability were evaluated. Only two unique records identified through the systematic review were qualified to generate conclusions. Regarding intra-rater reliability, Kissin reported excellent intra-class correlation coefficient values (ICC, 0.86-0.94) for measurements at nine skin sites in two DcSSc patients. Merkel and Kissin described, both in five DcSSc patients, good to excellent inter-rater reliability (ICC, 0.82-0.96 and 0.61-0.85) for measurements at respectively, six and nine skin sites. In our pilot study, ICC for intra-rater reliability at 17 standardized skin sites were excellent in both cohorts, ranging 0.93-0.99 and 0.78-0.98, respectively. ICC for inter-rater reliability at 17 standardized skin sites were good to excellent 0.63-0.93, except for the feet (0.48 and 0.52). The preliminary findings in the literature are supported by our pilot study in which we have attested the reliability of durometry in SSc patients. However, prior to including durometry as an (additional) outcome measure in SSc clinical trials, its validation status in the assessment of skin fibrosis needs to be completely attested.

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.

High-throughput quantitative histology in systemic sclerosis skin disease using computer vision

BackgroundSkin fibrosis is the clinical hallmark of systemic sclerosis (SSc), where collagen deposition and remodeling of the dermis occur over time. The most widely used outcome measure in SSc clinical trials is the modified Rodnan skin score (mRSS), which is a semi-quantitative assessment of skin stiffness at seventeen body sites. However, the mRSS is confounded by obesity, edema, and high inter-rater variability. In order to develop a new histopathological outcome measure for SSc, we applied a computer vision technology called a deep neural network (DNN) to stained sections of SSc skin. We tested the hypotheses that DNN analysis could reliably assess mRSS and discriminate SSc from normal skin.MethodsWe analyzed biopsies from two independent (primary and secondary) cohorts. One investigator performed mRSS assessments and forearm biopsies, and trichrome-stained biopsy sections were photomicrographed. We used the AlexNet DNN to generate a numerical signature of 4096 quantitative image features (QIFs) for 100 randomly selected dermal image patches/biopsy. In the primary cohort, we used principal components analysis (PCA) to summarize the QIFs into a Biopsy Score for comparison with mRSS. In the secondary cohort, using QIF signatures as the input, we fit a logistic regression model to discriminate between SSc vs. control biopsy, and a linear regression model to estimate mRSS, yielding Diagnostic Scores and Fibrosis Scores, respectively. We determined the correlation between Fibrosis Scores and the published Scleroderma Skin Severity Score (4S) and between Fibrosis Scores and longitudinal changes in mRSS on a per patient basis.ResultsIn the primary cohort (n = 6, 26 SSc biopsies), Biopsy Scores significantly correlated with mRSS (R = 0.55, p = 0.01). In the secondary cohort (n = 60 SSc and 16 controls, 164 biopsies; divided into 70% training and 30% test sets), the Diagnostic Score was significantly associated with SSc-status (misclassification rate = 1.9% [training], 6.6% [test]), and the Fibrosis Score significantly correlated with mRSS (R = 0.70 [training], 0.55 [test]). The DNN-derived Fibrosis Score significantly correlated with 4S (R = 0.69, p = 3 × 10− 17).ConclusionsDNN analysis of SSc biopsies is an unbiased, quantitative, and reproducible outcome that is associated with validated SSc outcomes.

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.

A Machine Learning Classifier for Assigning Individual Patients With Systemic Sclerosis to Intrinsic Molecular Subsets.

High-throughput gene expression profiling of tissue samples from patients with systemic sclerosis (SSc) has identified 4 "intrinsic" gene expression subsets: inflammatory, fibroproliferative, normal-like, and limited. Prior methods required agglomerative clustering of many samples. In order to classify individual patients in clinical trials or for diagnostic purposes, supervised methods that can assign single samples to molecular subsets are required. We undertook this study to introduce a novel machine learning classifier as a robust accurate intrinsic subset predictor. Three independent gene expression cohorts were curated and merged to create a data set covering 297 skin biopsy samples from 102 unique patients and controls, which was used to train a machine learning algorithm. We performed external validation using 3 independent SSc cohorts, including a gene expression data set generated by an independent laboratory on a different microarray platform. In total, 413 skin biopsy samples from 213 individuals were analyzed in the training and testing cohorts. Repeated cross-fold validation identified consistent and discriminative markers using multinomial elastic net, performing with an average classification accuracy of 87.1% with high sensitivity and specificity. In external validation, the classifier achieved an average accuracy of 85.4%. Reanalyzing data from a previous study, we identified subsets of patients that represent the canonical inflammatory, fibroproliferative, and normal-like subsets. We developed a highly accurate classifier for SSc molecular subsets for individual patient samples. The method can be used in SSc clinical trials to identify an intrinsic subset on individual samples. Our method provides a robust data-driven approach to aid clinical decision-making and interpretation of heterogeneous molecular information in SSc patients.

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...

History of skin thickness assessment and the Rodnan skin thickness scoring method in systemic sclerosis.

The pathology of skin involvement in systemic sclerosis (or scleroderma) was first described in detail in 1892. In this article, we trace the history of cutaneous scleroderma and the evolution of thinking of scholars who have addressed this topic. We focus on skin histopathologic abnormalities and both clinical and laboratory techniques proposed for quantifying skin thickening and mobility. We examine the development of the simple bedside physical examination method of Dr Gerald Rodnan, first published in the 1970s and subsequently modified by others in the early 1990s (modified Rodnan skin score). This method has been found to be the only completely validated technique for assessing skin thickness in systemic sclerosis. Now nearly 50 years later, the modified Rodnan skin thickness scoring system remains the gold standard for use in both systemic sclerosis clinical trials and observational studies.

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.

Should all digital ulcers be included in future clinical trials of systemic sclerosis-related digital vasculopathy?

Digital ulcers (DU) are a common manifestation of systemic sclerosis (SSc) and occur at a variety of locations including the fingertips and over the extensor aspects of the hands. However, most recent clinical trials have included only fingertip DUs as these are believed to be ischaemic in aetiology, and therefore likely to benefit from treatment with vasoactive drug therapies. There is an emerging evidence base to suggest that all DUs in SSc could share an ischaemic component which is potentially responsive to vascular therapy. Our hypothesis is that is that DUs occurring at sites other than the fingertips, in particular, those overlying the extensor aspect of the hands, may also have a potentially reversible ischaemic component. We review the evidence under the headings: ‘microvascular imaging’, ‘structural microvascular’ and, ‘functional vascular disease’, ‘macrovascular involvement’ and ‘vascular associates’. Based upon the current evidence, we would encourage the expert SSc community to reconsider the rationale for including only fingertip DUs in future SSc clinical trials, and suggest an agenda for future research.

Blockade of TGF-\u03b2/Smad signaling by the small compound HPH-15 ameliorates experimental skin fibrosis

BackgroundTransforming growth factor-β (TGF-β)/Smad signaling is well known to play a critical role in the pathogenesis of systemic sclerosis (SSc). We previously developed an artificial molecule, the histidine-pyridine-histidine ligand derivative HPH-15, which may have an antifibrotic effect. The purpose of the present study was to clarify the effects of this drug in human skin fibroblasts and in a preclinical model of SSc.MethodsThe effects of HPH-15 on expression of extracellular matrix components and TGF-β signaling in human dermal fibroblasts were analyzed. The antifibrotic properties of HPH-15 and its mechanisms were also examined in a bleomycin-induced skin fibrosis mouse model.ResultsHPH-15 suppressed the TGF-β-induced phosphorylation of Smad3 and inhibited the expression of collagen I, fibronectin 1, connective tissue growth factor, and α-smooth muscle actin induced by TGF-β in cultured human skin fibroblasts. In the bleomycin-induced skin fibrosis model, oral administration of HPH-15 protected against the development of skin fibrosis and ameliorated established skin fibrosis. Additionally, HPH-15 suppressed the phosphorylation of Smad3 in various cells, including macrophages in the bleomycin-injected skin. Further, in the treated mice, dermal infiltration of proinflammatory macrophages (CD11b+Ly6Chi) and M2 profibrotic macrophages (CD11b+CD204+ or CD11b+CD206+) was significantly decreased during the early and late stages, respectively. HPH-15 treatment resulted in decreased messenger RNA (mRNA) expression of the M2 macrophage markers arginase 1 and Ym-1 in the skin, whereas it inversely augmented expression of Friend leukemia integration 1 and Krüppel-like factor 5 mRNAs, the transcription factors that repress collagen synthesis. No apparent adverse effects of HPH-15 were found during the treatment.ConclusionsHPH-15 may inhibit skin fibrosis by inhibiting the phosphorylation of Smad3 in dermal fibroblasts and possibly in macrophages. Our results demonstrate several positive qualities of HPH-15, including oral bioavailability, a good safety profile, and therapeutic effectiveness. Thus, this TGF-β/Smad inhibitor is a potential candidate therapeutic for SSc clinical trials.

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.