Multiple Manifestations of Systemic Sclerosis Affect Walk Distance

To the Editor:

We welcome the novel report on the efficacy of B-cell depletion in the treatment of pulmonary arterial hypertension (PAH) associated with systemic sclerosis (SSc). In this study, the primary outcome measure was change in the 6-minute-walk distance (6MWD) (1). The 6MWD has some disadvantages as a primary outcome measure in a clinical trial of PAH (2), particularly in patients with SSc (3).

A number of factors affect the 6MWD in SSc aside from PAH, including interstitial lung disease (ILD), arthritis, muscle strength, conditioning, peripheral vascular disease, and nutritional status (4). However, the present study did not report the prevalence or the severity of these common SSc manifestations in the cohort, which raises the likelihood of confounding bias.

ILD affects 25–90% of patients with SSc and may precede or develop in parallel with PAH (5). In this study, although subjects with a TLC <70% predicted were excluded, patients with mild fibrosis on high-resolution computed tomography were eligible to participate. Rituximab (RTX) is an immunomodulatory drug that can inhibit ILD progression in SSc. This effect is not limited to patients with moderate or severe disease but has also been reported in subjects with mild ILD (5). Further characterization of pulmonary function of the study participants, including FVC% predicted and its response to treatment, would have been informative in Table 1 as well as Tables E2–7.0 in the work by Zamanian and colleagues.

Erosive arthritis has been reported in 18% and joint inflammation in up to 60% of patients with SSc (6). RTX is an established therapy for polyarthritis in systemic rheumatic diseases, including, but not limited to, rheumatoid arthritis. No data on joint inflammation were reported in this cohort, nor were changes in CRP (C-reactive protein) or erythrocyte sedimentation rate.

The prevalence of skeletal myopathy in SSc has been estimated to be at least 17% and more common in patients with respiratory impairment. RTX is a treatment option for inflammatory myopathies, and current data suggest that it is effective against immune-mediated myositis. It would have been informative to know the prevalence and severity of myopathy among the study participants before and after RTX treatment.

No changes in immunomodulatory background treatment were allowed during the study’s first 24 weeks. It can be speculated that RTX treatment may have alleviated disease activity unrelated to PAH in the RTX arm. The same would not have been possible in the placebo group.

Besides the primary outcome measure, the authors included predefined secondary outcomes. No changes were seen in pulmonary vascular resistance or NTproBNP (N-terminal pro–B-type natriuretic peptide), factors that, in contrast to the 6MWD, are directly associated with the pulmonary circulation (1).

In summary, we conclude that RTX is an immunomodulatory agent that may improve several SSc disease manifestations. The 6MWD is a composite outcome measure to which pulmonary vascular function is only one out of multiple contributing factors (3, 4). Given the systemic nature of this disease (5, 6) and our current knowledge on RTX in rheumatology, we ask the authors to elaborate on changes in measures of ILD, arthritis, and myopathy over the course of the study.