Sjögren’s syndrome is a systemic autoimmune disease characterized by lymphocytic infiltration of exocrine glands and a range of extra-glandular features. In this study, we analyzed data collected systematically from 1,927 participants enrolled in the international SICCA registry. The depth and breadth of data collected on both pSS and non-pSS participants allowed us to study many extra-glandular disease manifestations (EGM) reportedly associated with SS based on application of the AECG criteria as well as by specific objective features of SS.
Our results document a strong association between pSS and certain immunologic findings such as hypergammaglobulinemia, low C4 levels and certain autoantibodies. We also find that hematologic abnormalities (leukopenia, anemia and thrombocytopenia) are common and significantly associated with pSS case status, as was the physical exam finding of cutaneous vasculitis. These findings highlight clinically important extra-glandular manifestations in pSS. However, our results also suggest that the prevalence of EGM such as thyroid, liver and kidney disease may be lower than reported previously. Further, while rheumatologic symptoms may be common among pSS patients, these symptoms were not significantly more frequent among individuals with pSS, at least when compared to non-pSS individuals who underwent the same extensive process of phenotypic characterization but did not meet AECG or other objective criteria for pSS.
This study provides an opportunity to examine EGM in the context of salivary gland histopathology. In those patients with a diagnosis of focal lymphocytic sialdenitis, we examined the relationship between the degree of salivary gland inflammation, measured by the focus score, and the presence of EGM. Individuals with higher focus scores were more likely to have anemia and certain immunologic abnormalities. Additional details of relationships between salivary gland histopathology and phenotypic characteristics of SS among this cohort were recently reported (10
Prior reports of EGM in SS have consisted primarily of descriptions of case cohorts comprised exclusively of pSS patients. For example, Ramos-Casals et al. (15
) described the presence of certain EGM among a collection of 1,010 Spanish patients with SS. They employed laboratory studies and detailed objective tests to document the frequency of immunologic, lung, peripheral nerve and renal abnormalities. Similarly, Skopouli et al. (16
) characterized specific lung, peripheral nerve, renal and liver abnormalities in a collection of 261 Greek patients with pSS seen between 1981 and 1995 and studied at six month intervals. These studies lacked comparative or control data and therefore are limited in their ability to quantify associations of specific abnormalities with SS.
Comparison of EGM reported for different pSS cohorts also reveals substantial variability. For example, Raynaud’s phenomenon was described in 48% of the Greek cohort, 18% of the Spanish cohort and 14% of the SICCA pSS cases. Similarly, arthritis was detected in 23% of Greek, 15% of Spanish, and only 9% of SICCA pSS cases. Possible reasons for these differences include variation in the specific populations studied, recruitment sources, and methods for assessing EGM. Further, the definition of SS has been evolving over the past several decades, introducing another potentially important source of variation in prior studies of EGM in pSS. The various criteria employed in these and other studies encompass a wide range of symptoms, signs, and disease severity. Thus, it is difficult to assess the comparability of SS case groups without additional details of specific disease features. Indeed, this lack of specificity led us to examine the association between EGM and more specific, objective disease features ().
The association of neurologic disorders with pSS has attracted a lot of attention as a result of prior reports, such as those by Delalande et al (17
) and Kieko Mori et al (18
). Data from the SICCA registry indicate a very high frequency of neurological motor and sensory symptoms in pSS patients. However, we noted a similarly high frequency of neurological symptoms among non-pSS participants. A limitation of the SICCA collection is the lack of objective neurological testing on participants. Thus, the prevalence of neurologic involvement in pSS remains unclear.
Strengths of the current study include the large size and international nature of the SICCA cohort. Participants are recruited from a wide range of clinical and non-clinical sources, including rheumatologic, ophthalmologic, oral medicine and various lay and patient organizations. The availability of a subset of participants with a high prevalence of non-specific symptoms of dry eyes and dry mouth but absence of objective findings to support SS is a unique feature of the SICCA collection.
A limitation of the current study is the lack of a completely healthy (asymptomatic) control group of individuals. Although it would be of interest to study such a group, it is not feasible to assemble a sufficiently large, population-based control group characterized by the breadth of relevant variables, including the objective serologic, ocular and oral measures obtained as part of this study. On the other hand, the diversity of the SICCA cohort should enhance the representativeness of the pSS cases because it minimizes the selection bias that can result from enrolling patients only at certain sites or based on specific criteria, such as presence of neurologic or other systemic manifestations.
The large size and international nature of the SICCA registry strengthened our analysis, but also limited our ability to carefully characterize some of the EGM. For example, we were not able to review details of some of the disorders, such as thyroid function tests or antibodies, or results of renal or liver biopsy. Instead, we had to rely on the confirmation of diagnoses by treating physicians. We also did not perform screening tests of serum or urine to identify new diagnoses of renal tubular acidosis or other disorders. For these reasons, we may have underestimated the prevalence of some systemic disorders. In particular, the prevalence of sub-clinical disease such as hypothyroidism may be underestimated because participants were not specifically screened for these conditions. However, the use of self-report diagnoses of thyroid and other disorders is common in large studies such as the National Health and Nutrition Examination Study (NHANES) (19
), and a strength of the current study was the systematic effort to confirm all reported diagnoses of thyroid and other conditions by treating physicians.
Although the duration of symptoms at the time of SICCA enrollment was substantial (6 to 7 years on average), the current analyses were limited to prevalent data at the time of enrollment. Some of these individuals may still develop one or more of these EGM in the future. Previous studies suggest that at least some of these disorders, such as lymphoma, may not occur until many years of disease have elapsed (6
). Although follow-up data on SICCA participants is currently limited, a subset of patients is being recalled after two years for a complete reevaluation. These follow up data may improve our ability to capture incident cases of rare conditions such as lymphoma and primary biliary cirrhosis.
In conclusion, data from the international SICCA registry support the systemic nature of pSS, manifest primarily in terms of specific autoantibody production and various immunologic and hematologic abnormalities. The concurrence of other systemic disorders among this cohort is relatively uncommon and previously reported associations may be more specific to select patient subgroups, such as those referred for evaluation of neurologic, rheumatologic or other systemic manifestations. Longer term follow up of patients in the SICCA registry and other pSS populations will increase our understanding of rarer extra-glandular features in pSS.
Significance and Innovation
Although the hallmark features of primary Sjögren’s Syndrome (pSS) include glandular manifestations, there is convincing evidence that pSS is a systemic disease with various extra-glandular manifestations (EGM).
We assess the prevalence of specific EGM among over 1,900 participants in the Sjögren’s International Collaborative Clinical Alliance (SICCA) registry.
Our results support the systemic nature of pSS, primarily based on the presence of several immunologic and hematologic abnormalities. We also find that the prevalence of specific organ manifestations in pSS is relatively low and these abnormalities may be more common among select patient subgroups.