Response to: ‘Correspondence on ‘Interleukin 6 receptor inhibition in primary Sjögren syndrome: a multicentre double-blind randomised placebo-controlled trial’’ by de Wolff et al

Abstract

We read with interest the correspondence on our article 'Interleukin 6 receptor inhibition in primary Sjögren syndrome: a multicentre double-blind randomised placebo-controlled trial' by Wolff et al 1 in which the use of a composite endpoint, combining disease activity, functional and serological parameters, the newly developed CRESS 2 in future primary Sjögren's syndrome (pSS) trials is discussed, to lower placebo response and facilitate inclusions in clinical trials.As suggested by Wolff et al, a composite endpoint including multiple important pSS features might reveal more appropriate than only Eular Sjögren Syndrome Disease Activity index (ESSDAI) or only gland function as primary endpoint in this complex and heterogeneous disease to lower placebo response. We agree this is an important point to consider for future trials. As mentioned in our reply 3 to the correspondence from Wang et al, 4 NECESSITY, a European initiative, will combine data from our trial 5 with those of previous randomised trials to determine new clinical composite outcomes in pSS, capturing both systemic and glandular features of the disease. An initiative from OMERACT on clinical outcomes in pSS is also ongoing on this crucial topic.Wolff et al also suggest that another advantage of a composite endpoint might be to facilitate a broader inclusion of patients with pSS in clinical trials, that is, to allow the inclusion of patients with either an active systemic disease or a high burden of symptoms such as fatigue or dryness. However, in pSS, the pathogenesis of fatigue and dryness remains uncertain, with no key pathogenic cytokine or cell population identified to date. Targeting a unique goal to achieve a relevant improvement concomitantly in systemic activity, fatigue and dryness remain a great challenge in pSS. Indeed, even in the few recent positive phase II clinical trials, no drug was capable to improve all these three dimensions of the disease. Therefore, focusing on the evaluation of symptoms or systemic manifestations related to the pathway targeted might reveal more straightforward than a composite outcome. To increase the odds of finding effective drugs, biomarkers are also needed to stratify patients according to a molecular endotype amenable to a specific targeted therapy.We therefore definitively hope that a relevant composite score will emerge from CRESS, NECESSITY and OMERACT initiatives and that the ongoing collective effort to clarify the pathogenesis of the disease will allow to make pSS enter the individualised medicine age.

Pulmonary Manifestations of Sjögren's Disease

“…125 However, a recent large, doubleblind RCT of tocilizumab use in moderate to high systemic disease activity showed no superiority over placebo. 126 Furthermore, IL-6 inhibition did not improve serum immunoglobulin levels as has been demonstrated in trials involving rituximab and abatacept. 113,123 The future direction of treatment in systemic/pulmonary SjD lies in immune-targeted therapies, with several promising studies emerging.…”

Biological Therapy in Primary Sjögren's Syndrome: Effect on Salivary Gland Function and Inflammation

“…Findings from the most recent RCT testing tocilizumab in a cohort of pSS patients (NCT01782235) has failed to meet its primary endpoint with no response observed at week 24. There was no effect on UWSF or circulating immunoglobulins or complement, suggesting that IL-6 may not be the main driver of B-cell hyperactivity in pSS (35). Limiting the primary outcome to a 3-point reduction in ESSDAI, however, lead to a high placebo effect, reinforcing the need to validate this outcome measure for use in RCTs.…”

Genetics and epigenetics of primary Sjögren syndrome: implications for future therapies

“…Ongoing and completed randomized controlled trials (RCTs) generally use targeted approaches aimed at depleting specific cell populations, inhibiting co-stimulation, blocking cytokine-receptor interactions or targeting kinases important for intracellular signalling. Therapies evaluated in major RCTs for pSS (trials with >100 patients) include infliximab (a TNF inhibitor) 162 , rituximab (an anti-CD20, B cell-depleting antibody) 163,164 , abatacept (a fusion protein that blocks CD28-CD80/CD86 co-stimulation) 165 , tocilizumab (an IL-6 inhibitor) 166 and ianalumab (a BAFF inhibitor and B cell-depleting antibody) 167 (Fig. 6).…”