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We read with interest the correspondence related to our article, ‘Interleukin 6 receptor inhibition in primary Sjögren syndrome: a multicentre double-blind randomised placebo-controlled trial’, by Wang et al 1 who discuss the disappointing results of recent trials of primary Sjögren syndrome (pSS).
To explain recent negative results of tocilizumab and abatacept, apart from the inefficacy of these biologicals in pSS, Wang et al discuss the contribution of the design of the study. First, they discuss the choice of a primary endpoint based on the EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI). As mentioned by the authors, this score captures only the systemic complications of the disease, observed in 30%–50% of patients with pSS overall, but in all patients in our trials (requiring ESSDAI ≥5 at inclusion).2 Until now, 17 controlled trials have used ESSDAI as the primary endpoint (table 1), including at least three positive trials (leflunomide and hydroxychloroquine, iscalimab, ianalumab).3–6
Second, Wang et al propose to use exocrine gland-centred outcome measures such as salivary gland biopsy and salivary gland ultrasonography. We agree that salivary gland ultrasonography requires improved standardisation. In addition, there might be a disconnect between salivary gland biopsy and salivary gland function findings. We preferred to use the routine Schirmer’s test and unstimulated salivary flow in this academic multicentre trial as well as a patient-reported outcome visual analogue scale score for dryness. In our trial, none of these exocrine gland-centred outcomes revealed any effect of tocilizumab on pSS, but missing data on Schirmer test and unstimulated salivary flow limit the interpretation of these results.
Finally, Wang et al suggest that the poor response to treatment of pSS in terms of glandular function may be due to damage rather than activity in advanced stages of the disease. They suggest including patients at earlier disease stages. Of note, for more than half of the patients included in our trial, the disease duration was <5 years after diagnosis. In addition, restricting the study to patients with recently diagnosed pSS would make inclusion in clinical trials of pSS even more difficult.
Thus, regardless concerns regarding trial design in pSS, our negative results for clinical, patient-reported and also immunological outcomes indicate that interleukin 6 does not represent a relevant therapeutic target in pSS.
However, we agree with Wang et al that we have to continue our efforts to improve the design of future trials. NECESSITY, a European initiative, will combine data from our trial 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 progressing on this crucial topic.
Contributors All authors contributed to the concept, design and writing of the letter and have approved the final version.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Patient consent for publication Not required.
Provenance and peer review Commissioned; internally peer reviewed.
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