Sjögren Syndrome: A Forgotten or an Overdiagnosed Entity?

Autoantibodies in SS

In accordance with the 2016 European Alliance of Associations for Rheumatology/American College of Rheumatology (EULAR/ACR) classification criteria of SS, seropositive SS is defined by the presence of anti-SSA/Ro antibodies.⁵ In the majority of academic literature available on the topic, this concerns between 60% and 80% of patients with SS. One of the shortcomings of the 2016 EULAR/ACR classification criteria, for which I bear responsibility as one of the original designers, is the absence of a clear differentiation between anti-Ro60 and anti-Ro52. Indeed, it is important to note that only the presence of anti-Ro60 is a hallmark indicator of SS. Fortunately, most patients with SS who have anti-Ro52 are also anti-Ro60 positive. Nonetheless, the presence of anti-Ro52 alone without anti-Ro60 is not specific enough to SS and can be observed in any connective tissue disease (CTD).⁶ In a number of CTDs, anti-Ro52, in addition to other autoantibodies, are considered as a marker of more active disease.⁷ At present, having only anti-Ro52 antibodies without anti-Ro60 is considered a positive component in the 2016 EULAR/ACR classification criteria, adding 3 points to the criteria’s total count. It might be worth considering a revision that restricts the serological domain of the classification to solely anti-Ro60 positivity rather than any anti-Ro positivity.

In the 2016 classification, we excluded anti-SSB/La positivity, not because they are uncharacteristic of SS but because when anti-SSB/La is detected in isolation without anti-SSA/Ro, it is either a borderline false positive (very close to the threshold) or not specific of SS.⁸ Thus, in SS, anti-SSB/La antibodies are always the consequence of a spreading from anti-SSA/Ro alone to anti-SSA/Ro + anti-SSB/La. Interestingly, the genetic association with HLA is different between the 2 endotypes: HLA-DR15 is for the anti-SSA/Ro alone, and HLA-DR3 is for the anti-SSA/Ro + anti-SSB/La endotype.⁹

My other comment about autoantibodies in SS concerns patients without any anti-SSA antibodies but who have other autoantibodies, such as nonspecific antinuclear antibody (ANA) or rheumatoid factor (RF). The traditional methodology of using immunofluorescence for determining positivity of ANA is dependent on the interpretation of the biologist and it is worth noting that the threshold for positivity at 1/80 as an entry criterion for the EULAR/ACR systemic lupus erythematosus classification¹⁰ is considered negative by numbers of immunology laboratories and experts in the field of autoimmunity. Likewise, RF positivity may be present in rheumatoid arthritis and in many other systemic autoimmune diseases. However, RF is an important biomarker in SS that is not considered specific for diagnosis, but that is predictive of lymphoma occurrence.¹¹ Further, RF titer is sensitive to change with new immunomodulatory drugs, with a presence of a high titer being possibly associated with more severe systemic complications like cryoglobulinemia-associated vasculitis. For these reasons, RF has been included in the biological domain of the new composite scores: Composite of Relevant Endpoints for Sjögren’s Syndrome (CRESS) and Sjögren’s Tool for Assessing Response (STAR), both of which aim to measure activity of the disease.¹² Last, even if nonspecific ANA and RF positivity do not define seropositive SS, it is probable that a patient with nonspecific ANA, RF, hypergammaglobulinemia, and sicca symptoms has SS. Interestingly, although the majority of industrial clinical trials mandate the inclusion of patients with anti-SSA antibodies, some of them also admit seronegative individuals with RF or a high titer of ANA so long as they meet SS criteria, confirmed through a positive minor salivary gland biopsy (MSGB).

Salivary gland histology in SS

By definition, a patient with seronegative SS can meet the EULAR/ACR criteria for SS only if MSGB is positive, meaning that the patient’s biopsy presents at least one aggregate of 50 immune cells/4 mm² (focus score [FS] ≥ 1).⁵ The hindering challenge is that a number of clinical pathologists have limited experience in interpreting these kinds of biopsies. The prevalence of this challenge was highlighted in a study that reexamined 60 biopsies from 58 patients by a trained pathologist of a tertiary center for SS in Philadelphia, leading to a revision of the initial diagnosis in 32/60 (53%) cases.¹³ Most of the mistakes came from a lack of or incorrect use of the FS. Likewise, in the Tolerance and Efficacy of Rituximab in Primary Sjögren’s Syndrome (TEARS) clinical trial, when the MSGBs were reexamined centrally by a trained pathologist, there was evidence of overestimations of the FS by the local pathologist.¹⁴ Last, for patients referred to our reference center for SS and having already had a MSGB, we systematically ask for a reexamination of the biopsy, and in around half of the cases, our experienced pathologist is unable to reconfirm a FS > 1. In all these instances, if these patients do not have anti-SSA antibodies, they do not meet the criteria for SS and thus the diagnosis of SS cannot be confirmed. A high proportion of these patients who are living with sicca symptoms (not linked to medications), and with no anti-SSA antibodies nor foci, have a fibromyalgia (FM)-like syndrome that includes sicca. We had proposed in the past (without great success) to use the term sicca asthenia polyalgia syndrome (SAPS) for this condition.¹⁵