Comment on: Equal rights in autoimmunity: is Sjögren's syndrome ever ‘secondary’?

Dear Editor, In their interesting article, Kollert and Fisher comprehensively outlined pathophysiological, clinical and serological features characterizing patients with isolated Sjögren’s syndrome (SS) compared with those with a concomitant immuno-mediated rheumatic disease (IM-RD) [1]. SS is the IM-RD most commonly occurring in overlap or association with systemic (e.g. RA, SLE and coeliac disease) and organ-specific (e.g. thyroid disease) IM conditions [2] and may also be characterized by severe life-threatening manifestations and poor prognostic comorbidities [3, 4]. This overlap makes it difficult to distinguish whether specific clinical features, such as interstitial lung disease, arthritis and serositis, represent extra-glandular manifestations of SS or rather an overlap of two different diseases, as illustrated in the Table 2 of the article. The term ‘secondary’ SS has been recently replaced by ‘associated’ SS (aSS) since the former was considered obsolete to indicate patients fulfilling both the 2012 ACR or 2016 ACR/EULAR SS classification criteria and those of another systemic or organ-specific autoimmune disease. Although created for primary SS (pSS) and not validated in patients with aSS, a recent study involving 300 patients with SLE, RA and scleroderma (SSc) demonstrated that the 2016 ACR/EULAR criteria show the best performance for classifying patients with aSS in comparison to 2002 American European Consensus Group (AECG) and 2012 ACR criteria [5]. As reported by the authors [1] and in line with a previous study, the autoantibody profile and the histological features of salivary gland biopsies are similar between patients with isolated and aSS [6]. Moreover, salivary gland biopsy is not a mandatory criterion for diagnosing aSS according to 2002 AECG criteria, thus hampering the correct classification of ‘secondary’ SS patients when these criteria are applied.

Taking into account the above mentioned evidence, we performed a retrospective analysis and compared our cohort of pSS patients to that of patients with SS and another IM-RD (aSS), both classified according to the 2002 AECG criteria. As shown in Table 1, 18 patients (8%) were classified as aSS. Age at SS diagnosis and gender were not significantly different between the two groups and, in line with the findings by Kollert et al. [1], prevalence of rheumatoid factor, anti-Ro/SSA and La/SSB antibodies was similar. In aSS patients, the interval between the diagnosis of the two conditions was 3 (6) [mean (s.d.)] years. Interestingly, in more than half of patients (10/18, 55%), the diagnosis of SS and the other IM-RD was simultaneous. In all the remaining patients except one, the diagnosis of SS resulted subsequent to the other IM-RD. All patients with aSS that underwent salivary gland biopsies fulfilled the 2002 AECG histological criterion. On this basis, it may be assumed that in patients with systemic IM-RDs, SS should not be considered an adjunctive manifestation of the disease but rather a distinct entity.

Almost all clinical trials on biologic therapies in RDs have associated autoimmune diseases as exclusion criteria. The data of our cohort and the reflections of Kollert about including aSS in pSS clinical trials deserve to be appraised in this setting. The RA with Orencia Trial towards Sjögren's syndrome Endocrinopathy (ROSE) [7] represents one of the few trials that included patients with RA and aSS, the latter according to the revised Japanese criteria [8]. Notwithstanding some methodological pitfalls, including eligibility criteria (subjective dryness) and lack of information regarding the actual timing of SS onset compared with RA diagnosis, this trial allowed indirect witnessing of the effects of abatacept in SS. With the lack of solid data about novel biologic therapies in pSS and based on the assumption that these compounds being evaluated or already in use for other conditions such as RA or SLE may be effective also in pSS, the question remains of whether including patients with aSS in RA or SLE trials rather than in pSS ones may be a more appropriate option. We acknowledge that pSS and aSS patients have similar demographic, serological and histological features, but the range of compounds under evaluation in RA and SLE is consistently higher compared with the few therapeutic approaches that reach that stage for pSS. It is therefore tempting to speculate that the inclusive approach that we propose may allow the unmasking of potential therapeutic approaches for pSS while saving the costs of setting up dedicated clinical trials in pSS only for those proving to provide at least a minimum effect. Standardized inclusion criteria, as well as a thorough characterization of aSS, ideally including histological features, would be advisable in such a setting.

Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript.

Disclosure statement: The authors have declared no conflicts of interest.

Data availability statement

Data are available upon reasonable request by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA). All data relevant to the study are included in the article.

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