Trial methodology in scleroderma: Avoiding a shot in the dark

SSc (scleroderma) is a rare autoimmune disease with fibrosis, vasculopathy and autoantibodies. When a disease is rare, it is especially important that clinical trial methodology and outcomes be appropriately powered to have a feasible study. The outcomes must be reliable and sensitive to change within the time frame of the trial. Good trial methodology will help to avoid negative studies (Type II errors) or false-negative trials. Many organ manifestations occur in 8–15% of patients with SSc such as interstitial lung disease (ILD), pulmonary arterial hypertension (PAH), muscle involvement and prevalent finger ulcers [1]. We find that highly restrictive inclusion criteria may limit the feasibility of a trial and its generalizability. However, there must be inclusion criteria where patients that are studied have the organ manifestation in question or are at risk of having a new occurrence. In the former instance, there would be the study of ILD that is clinically relevant, and in the latter, there could be prevention of scleroderma renal crisis in SSc patients at high risk of developing this complication. There are now many positive trials in SSc (scleroderma) despite the rarity of the disease. In this supplement, scleroderma experts have written a series of points to consider with respect to multiple organ systems in SSc including skin, ILD, pulmonary hypertension, renal involvement, digital ulcers, Raynaud’s, muscle, heart, gastrointestinal tract, arthritis and quality of life but not necessarily overall disease modification [2–12]. However, in general, we find that immune suppressants may be helpful for skin and overall disease modification and likewise for many trials with treatment for scleroderma-related ILD [13]. Some organ involvement is likely too rare to perform trials and have outcomes that are not surrogates but are clinically relevant. For instance, myocardial involvement at autopsy in SSc is not rare but clinically relevant cardiomyopathy is uncommon and can manifest in many areas of the heart and can result in heart failure, arrhythmia, pericarditis and so on. In large trials of coronary artery disease in the general population, there can be outcomes such as death and hospitalization and recurrent myocardial infarction, but in an SSc population, outcomes would likely be surrogates such as changes in echocardiography, or other cardiac imaging or markers such as brain naturetic peptide, and functional class [6]. Similarly, even though symptomatic ILD is common, often the primary outcome measurements are changes in pulmonary function tests or worsening dyspnoea, but not death, hospitalization or need for transplantation, as these outcomes would require very large numbers of patients and far longer follow-up than 1–2 years [12]. Many PAH trials contain one-quarter to one-third of patients with SSc, and the data are combined with other diseases that cause PAH and idiopathic PAH. These trials have now evolved to have clinically relevant outcomes such as time to clinical worsening, whereas early trials used the 6-minute walk distance which is a surrogate outcome, similarly to changes in BMD translating to fractures in osteoporosis trials. Some studies can be short and others can be long. For example, if there is a scleroderma renal crisis trial, it could be short if there is a lower blood pressure to target and final creatinine at a few weeks, or it can be long in the instance of prevention of dialysis, or maintaining renal function. For improving skin, and lung function stabilization, there may be more improvement in the second year (scleroderma lung study 2 [13], Tociluzimab [14], Rituximab trial [15]), whereas with stem cell transplantation, the modified Rodnan skin score may improve quickly but it takes a couple of years to show a survival benefit compared with Cylcophosphamide [16]. For PAH, there has been a move away from the 6-minute walk distance and towards the use of more relevant end points such as the time to clinical worsening, with various definitions among the trials. However, the standardization of digital ulcers has been problematic. Whether an ulcer is active or fully healed is difficult to ascertain in SSc even with experienced clinicians. There is also the concept of healing ulcers (and this is not the case when using Bosentan) vs preventing new ulcers (the latter was demonstrated in two Bosentan trials) [16]. In general, ulcers that are located only on finger (digital) tips are included, and others located elsewhere on the fingers or other parts of the body, or ulcers thought to be from calcinosis are excluded. This affects the ability to make inferences about treatment beyond digital tip ulcers. The pathophysiology may be different between calcinosis and ischaemic lesions but calcinosis to date is largely untreatable. However, the general principles of avoiding repetitive trauma and treatment of ischaemia may apply. Patients and clinicians welcome trials for this complication in order to give an evidence-based standard of care. The Combined Response Index in Systemic Sclerosis has been validated and may be appropriate for many SSc trials to determine whether other organs are not compromised (or complications are reduced) when having a long trial [17]. The Patient Reported Outcomes Measurement Information System questionnaire for physical function asks, over a range of five possible answers, multiple questions with respect to physical function [18]. It asks about function in more detail than the HAQ Disability Index, which is based upon basic activities of daily living [19]. The Patient Reported Outcomes Measurement Information System includes other domains beyond basic activities of daily living including vigorous exercise and other household tasks (e.g. changing a light bulb). It has more questions and a larger range of answers, which could make it more discriminatory for some functions not questioned in the HAQ Disability Index. This will need to be determined in actual clinical trials. In many cases of SSc, treatment (immune suppressives) and outcomes are borrowed from other diseases. In a treatment trial of SSc patients with inflammatory arthritis, outcomes could mimic the ACR and the DAS responses similarly to RA. There is likely no need to test other new outcomes if the latter are found to be responsive in SSc trials. My opinion is different from that of Clements et al. [3], where primary outcomes were considered via questionnaires of function. I think that trialling these questionnaires would be secondary endpoints, or perhaps even exploratory and using ACR or DAS responses seems logical. Function can be affected in SSc by many problems beyond inflammatory arthritis, such as contractures of deep tissues, tight skin, ulcers, calcinosis and so on, whereas inflammatory arthritis is usually measured by tender and swollen joint counts. Validated composite outcomes would be my approach to designing a trial of inflammatory arthritis in SSc. Indeed, DAS responses have been reported for SSc patients with inflammatory arthritis using tocilizumab and abatacept [20]. A further point to consider is the ethics of trials in SSc. Often, standard of care is denied for early diffuse SSc patients who enrol in trials (such as an active drug vs placebo), and there is an opportunity to have an escape at 6 months in order to add an immune suppressive to the study medication. Studies can be designed adding a therapeutic to the required standard of care, or comparing with the standard of care unless there is a concern about safety. Nonetheless, these points to consider are very helpful for the design of SSc trials. Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: The author has declared no conflicts of interest.

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