IL-27 promotes pathogenic T cells in a mouse model of Sjögren's disease.

Sjögren's disease (SjD) is a chronic autoimmune disease characterized by focal lymphocytic inflammation in lacrimal and salivary glands. We recently identified IL-27 as a requisite signal for the spontaneous SjD-like manifestations in nonobese diabetic (NOD) mice. Here, we define T cell-intrinsic effects of IL-27 in lacrimal gland disease in NOD mice. IL-27 receptor was required by both CD4 T effector (Te) cells and CD8 T cells to mediate focal inflammation. Intrinsic IL-27 signaling was associated with PD-1 and ICOS expressing T follicular helper (Tfh)-like CD4 Te cells within lacrimal glands, including subsets defined by CD73 or CD39 expression. CD8 T cells capable of IL-27 signaling also expressed PD-1 with subsets expressing ICOS and CD73 demonstrating a T follicular cytotoxic (Tfc)-like cell phenotype and others expressing a CD39hi exhausted-like phenotype. These findings suggest IL-27 is a key early signal driving a follicular-type response in lacrimal gland inflammation in NOD mice.

Treatment strategies for Sjögren's syndrome with childhood onset: a systematic review of the literature.

OBJECTIVES: SS with childhood onset is a rare autoimmune disease characterized by heterogeneous presentation. The lack of validated classification criteria makes it challenging to diagnose. Evidence-based guidelines for treatment of juvenile SS are not available due to the rarity of disease and the paucity of research in this patient population. This systematic review aims to summarize and appraise the current literature focused on pharmacological strategies for management of SS with childhood onset. METHODS: PubMed and MEDLINE/Scopus databases up to December 2020 were screened for suitable reports highlighting pharmacological treatment of SS with childhood onset using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2009 reporting checklist. Animal studies were excluded. RESULTS: A total of 43 studies (34 case reports, 8 mini case series and 1 pilot study) were eligible for analysis. The studies retrieved included girls in 88% (120/137) of cases and had very low confidence levels. HCQ was prescribed for parotid swelling, as well as in association with MTX and NSAIDs in patients with arthritis and arthralgia. Corticosteroids such as long courses of oral prednisone and i.v. methylprednisolone were commonly prescribed for children with severe disease presentations. Rituximab was mainly indicated for mucosa-associated lymphoid tissue lymphoma and renal and nervous system complications. Other conventional DMARDs were prescribed in selected cases with extraglandular manifestations. CONCLUSION: Various therapies are used for the management of juvenile SS and are prescribed based on expert clinician's opinion. There are currently no good-quality studies that allow clinical recommendations for treatment of SS with childhood onset.

A distinguishing profile of chemokines, cytokines and biomarkers in the saliva of children with Sjögren's syndrome.

OBJECTIVE: SS is an autoimmune disease most commonly diagnosed in adults but can occur in children. Our objective was to assess the presence of chemokines, cytokines and biomarkers (CCBMs) in saliva from these children that were associated with lymphocyte and mononuclear cell functions. METHODS: Saliva was collected from 11 children diagnosed with SS prior to age 18 years and 16 normal healthy children. A total of 105 CCBMs were detected in multiplex microparticle-based immunoassays. ANOVA and t test (0.05 level) were used to detect differences. Ingenuity Pathway Analysis (IPA) was used to assess whether elevated CCBMs were in annotations associated with immune system diseases and select leukocyte activities and functions. Machine learning methods were used to evaluate the predictive power of these CCBMs for SS and were measured by receiver operating characteristic (ROC) curve and area under curve (AUC). RESULTS: Of the 105 CCBMs detected, 43 (40.9%) differed in children with SS from those in healthy study controls (P < 0.05) and could differentiate the two groups (P < 0.05). Elevated CCBMs in IPA annotations were associated with autoimmune diseases and with leukocyte chemotaxis, migration, proliferation, and regulation of T cell activation. The best AUC value in ROC analysis was 0.93, indicating that there are small numbers of CCBMs that may be useful for diagnosis of SS. CONCLUSION: While 35 of these 43 CCBMs have been previously reported in SS, 8 CCBMs had not. Additional studies focusing on these CCBMs may provide further insight into disease pathogenesis and may contribute to diagnosis of SS in children.

Childhood-onset of primary Sjögren's syndrome: phenotypic characterization at diagnosis of 158 children.

OBJECTIVES: To characterize the phenotypic presentation at diagnosis of childhood-onset primary SS. METHODS: The Big Data Sjögren Project Consortium is an international, multicentre registry using worldwide data-sharing cooperative merging of pre-existing clinical SS databases from the five continents. For this study, we selected those patients in whom the disease was diagnosed below the age of 19 years according to the fulfilment of the 2002/2016 classification criteria. RESULTS: Among the 12 083 patients included in the Sjögren Big Data Registry, 158 (1.3%) patients had a childhood-onset diagnosis (136 girls, mean age of 14.2 years): 126 (80%) reported dry mouth, 111 (70%) dry eyes, 52 (33%) parotid enlargement, 118/122 (97%) positive minor salivary gland biopsy and 60/64 (94%) abnormal salivary US study, 140/155 (90%) positive ANA, 138/156 (89%) anti-Ro/La antibodies and 86/142 (68%) positive RF. The systemic EULAR Sjögren's syndrome disease activity index (ESSDAI) domains containing the highest frequencies of active patients included the glandular (47%), articular (26%) and lymphadenopathy (25%) domains. Patients with childhood-onset primary SS showed the highest mean ESSDAI score and the highest frequencies of systemic disease in 5 (constitutional, lymphadenopathy, glandular, cutaneous and haematological) of the 12 ESSDAI domains, and the lowest frequencies in 4 (articular, pulmonary, peripheral nerve and CNS) in comparison with patients with adult-onset disease. CONCLUSIONS: Childhood-onset primary SS involves around 1% of patients with primary SS, with a clinical phenotype dominated by sicca features, parotid enlargement and systemic disease. Age at diagnosis plays a key role in modulating the phenotypic expression of the disease.

Childhood Sjögren syndrome: features of an international cohort and application of the 2016 ACR/EULAR classification criteria.

OBJECTIVE: Sjögren syndrome in children is a poorly understood autoimmune disease. We aimed to describe the clinical and diagnostic features of children diagnosed with Sjögren syndrome and explore how the 2016 ACR/EULAR classification criteria apply to this population. METHODS: An international workgroup retrospectively collected cases of Sjögren syndrome diagnosed under 18 years of age from 23 centres across eight nations. We analysed patterns of symptoms, diagnostic workup, and applied the 2016 ACR/EULAR classification criteria. RESULTS: We identified 300 children with Sjögren syndrome. The majority of patients n = 232 (77%) did not meet 2016 ACR/EULAR classification criteria, but n = 110 (37%) did not have sufficient testing done to even possibly achieve the score necessary to meet criteria. Even among those children with all criteria items tested, only 36% met criteria. The most common non-sicca symptoms were arthralgia [n = 161 (54%)] and parotitis [n = 140 (47%)] with parotitis inversely correlating with age. CONCLUSION: Sjögren syndrome in children can present at any age. Recurrent or persistent parotitis and arthralgias are common symptoms that should prompt clinicians to consider the possibility of Sjögren syndrome. The majority of children diagnosed with Sjögren syndromes did not meet 2016 ACR/EULAR classification criteria. Comprehensive diagnostic testing from the 2016 ACR/EULAR criteria are not universally performed. This may lead to under-recognition and emphasizes a need for further research including creation of paediatric-specific classification criteria.

Characterization of Type I Interferon-Associated Chemokines and Cytokines in Lacrimal Glands of Nonobese Diabetic Mice.

Type I interferons (IFNs) are required for spontaneous lacrimal gland inflammation in the nonobese diabetic (NOD) mouse model of Sjögren's disease, but the consequences of type I IFN signaling are not well-defined. Here, we use RNA sequencing to define cytokine and chemokine genes upregulated in lacrimal glands of NOD mice in a type I IFN-dependent manner. Interleukin (IL)-21 was the highest differentially expressed cytokine gene, and Il21 knockout NOD mice were relatively protected from lacrimal gland inflammation. We defined a set of chemokines upregulated early in disease including Cxcl9 and Cxcl10, which share a receptor, CXCR3. CXCR3+ T cells were enriched in lacrimal glands with a dominant proportion of CXCR3+ regulatory T cells. Together these data define the early cytokine and chemokine signals associated with type I IFN-signaling in the development of lacrimal gland inflammation in NOD mice providing insight into the role of type I IFN in autoimmunity development.

Alagille Syndrome and Chronic Arthritis: An International Case Series.

We describe 10 children with Alagille syndrome and inflammatory arthritis. In our centers, the prevalence of chronic arthritis in patients with Alagille syndrome is approximately 50 times higher compared with the general population. Arthritis was refractory to most treatment. Patients with Alagille syndrome should routinely be screened for musculoskeletal symptoms.

Toll-Like Receptor 7 Is Required for Lacrimal Gland Autoimmunity and Type 1 Diabetes Development in Male Nonobese Diabetic Mice.

Sjögren syndrome (SS) is an immunologically complex, chronic autoimmune disease targeting lacrimal and salivary glands. Nonobese diabetic (NOD) mice spontaneously develop inflammation of lacrimal and salivary glands with histopathological features similar to SS in humans including focal lymphocytic infiltrates in the affected glands. The innate immune signals driving lymphocytic infiltration of these glands are not well-defined. Here we evaluate the role of Toll-like receptor (TLR) 7 in the development of SS-like manifestations in NOD mice. We created a Tlr7 knockout NOD mouse strain and performed histological and gene expression studies to characterize the effects of TLR7 on autoimmunity development. TLR7 was required for male-specific lacrimal gland inflammation but not for female-specific salivary gland inflammation. Moreover, TLR7 was required for type 1 diabetes development in male but not female NOD mice. RNA sequencing demonstrated that TLR7 was associated with a type I interferon (IFN) response and a type I IFN-independent B cell response in the lacrimal glands. Together these studies identify a previously unappreciated pathogenic role for TLR7 in lacrimal gland autoimmunity and T1D development in male NOD mice adding to the growing body of evidence supporting sex differences in mechanisms of autoimmune disease in NOD mice.

Salivary-gland-protective regulatory T-cell dysfunction underlies female-specific sialadenitis in the non-obese diabetic mouse model of Sjögren syndrome.

Immune cell-mediated destruction of salivary glands is a hallmark feature of Sjögren syndrome. Similar to the female predominance in humans, female non-obese diabetic (NOD) mice develop spontaneous salivary gland autoimmunity. However, in both humans and mice it is unclear what factors contribute to the initial immune infiltration of the salivary glands. Here, we used an adoptive transfer model of Sjögren syndrome to determine if female mice harbor a sex-specific defect in salivary-gland-protective regulatory T (Treg) cells. Transfer of cervical lymph node (LN) cells from female NOD mice into sex-matched NOD-severe combined immunodeficient (SCID) recipients resulted in sialadenitis, regardless of the presence or absence of Treg cells. In contrast, transfer of cervical LN cells from male NOD mice into sex-matched NOD-SCID recipients only resulted in sialadenitis when Treg cells were depleted before transfer, suggesting that male NOD mice have functional salivary-gland-protective Treg cells. Notably, the host environment affected the ability of Treg cells to prevent sialadenitis with testosterone promoting salivary gland protection. Treg cells from male mice did not protect against sialadenitis in female recipients. Testosterone treatment of female recipients of bulk cervical LN cells decreased sialadenitis, and Treg cells from female mice were capable of protecting against development of sialadenitis in male recipients. Hence, our data demonstrate that female NOD mice develop sialadenitis through a defect in salivary-gland-protective Treg cells that can be reversed in the presence of testosterone.

Type I Interferon Signaling Is Required for Dacryoadenitis in the Nonobese Diabetic Mouse Model of Sjögren Syndrome.

Nonobese diabetic (NOD) mice spontaneously develop lacrimal and salivary gland autoimmunity similar to human Sjögren syndrome. In both humans and NOD mice, the early immune response that drives T-cell infiltration into lacrimal and salivary glands is poorly understood. In NOD mice, lacrimal gland autoimmunity spontaneously occurs only in males with testosterone playing a role in promoting lacrimal gland inflammation, while female lacrimal glands are protected by regulatory T cells (Tregs). The mechanisms of this male-specific lacrimal gland autoimmunity are not known. Here, we studied the effects of Treg depletion in hormone-manipulated NOD mice and lacrimal gland gene expression to determine early signals required for lacrimal gland inflammation. While Treg-depletion was not sufficient to drive dacryoadenitis in castrated male NOD mice, chemokines (Cxcl9, Ccl19) and other potentially disease-relevant genes (Epsti1, Ubd) were upregulated in male lacrimal glands. Expression of Cxcl9 and Ccl19, in particular, remained significantly upregulated in the lacrimal glands of lymphocyte-deficient NOD-severe combined immunodeficiency (SCID) mice and their expression was modulated by type I interferon signaling. Notably, Ifnar1-deficient NOD mice did not develop dacryoadenitis. Together these data identify disease-relevant genes upregulated in the context of male-specific dacryoadenitis and demonstrate a requisite role for type I interferon signaling in lacrimal gland autoimmunity in NOD mice.

CD8 T cells contribute to lacrimal gland pathology in the nonobese diabetic mouse model of Sjögren syndrome.

Sjögren syndrome is an autoimmune disease characterized by targeted destruction of the lacrimal and salivary glands resulting in symptoms of severe ocular and oral dryness. Despite its prevalence, the mechanisms driving autoimmune manifestations are unclear. In patients and in the nonobese diabetic (NOD) mouse model of Sjögren syndrome, lymphocytic infiltrates consist of CD4 and CD8 T cells, although the role of CD8 T cells in disease pathogenesis has been largely unexplored. Here, we evaluated the contribution of CD8 T cells to lacrimal and salivary gland autoimmunity. Within the lacrimal and salivary glands of NOD mice, CD8 T cells were proliferating, expressed an activated phenotype, and produced inflammatory cytokines. Transfer of purified CD8 T cells isolated from the cervical lymph nodes (LNs) of NOD mice into NOD-severe combined immunodeficiency recipients resulted in inflammation of the lacrimal glands, but was not sufficient to cause inflammation of the salivary glands. Lacrimal gland-infiltrating CD8 T cells displayed a cytotoxic phenotype, and epithelial cell damage in the lacrimal glands was observed in recipients of CD8 T cells regardless of the presence of CD4 T cells. Collectively, our results demonstrate that CD8 T cells have a pathogenic role in lacrimal gland autoimmunity. The gland-specific pathogenicity of CD8 T cells makes them a valuable resource to further understand the mechanisms that discriminate lacrimal versus salivary gland autoimmunity and for the development of new therapeutics that target the early stages of disease.

Features of childhood Sjögren's syndrome in comparison to adult Sjögren's syndrome: considerations in establishing child-specific diagnostic criteria.

OBJECTIVES: To describe the clinical features of childhood Sjögren's syndrome (SS) in comparison to adult SS and to evaluate possible child-specific modifications to existing adult criteria for use in diagnosing childhood SS. METHODS: We retrospectively identified children (age <18 years) with SS and compared the clinical, laboratory, and histopathological features of these children based on presence or absence of parotitis. We compared these features to adults with SS and evaluated the applicability of existing classification criteria in diagnosing childhood SS. Child-specific modifications to existing criteria were evaluated. RESULTS: Twenty-six children were included in our childhood SS group. Sixteen children had parotitis at or before presentation. Absence of parotitis was associated with greater degree of organ damage based on SS disease damage index. Compared to 413 adult SS patients, childhood SS was more commonly associated with parotitis, positive serologies, neurologic and nephrologic manifestations, and non-specific features (fever, lymphadenopathy) but less commonly associated with dry mouth and dry eyes. Only a minority of these children met previously established criteria for adult SS. Inclusion of child-specific features such as parotitis and the presence of any focal lymphocytic sialadenitis on minor salivary gland biopsy increased the proportion of children meeting these criteria. CONCLUSIONS: Childhood SS features may be different than adult SS features necessitating child-specific criteria for better diagnosis of childhood SS, a key step towards better understanding the features, prognosis, and outcomes in this disease.

Reversible lacrimal gland-protective regulatory T-cell dysfunction underlies male-specific autoimmune dacryoadenitis in the non-obese diabetic mouse model of Sjögren syndrome.

CD4(+) CD25(+) Foxp3(+) regulatory T (Treg) cells are required to maintain immunological tolerance; however, defects in specific organ-protective Treg cell functions have not been demonstrated in organ-specific autoimmunity. Non-obese diabetic (NOD) mice spontaneously develop lacrimal and salivary gland autoimmunity and are a well-characterized model of Sjögren syndrome. Lacrimal gland disease in NOD mice is male-specific, but the role of Treg cells in this sex-specificity is not known. This study aimed to determine if male-specific autoimmune dacryoadenitis in the NOD mouse model of Sjögren syndrome is the result of lacrimal gland-protective Treg cell dysfunction. An adoptive transfer model of Sjögren syndrome was developed by transferring cells from the lacrimal gland-draining cervical lymph nodes of NOD mice to lymphocyte-deficient NOD-SCID mice. Transfer of bulk cervical lymph node cells modelled the male-specific dacryoadenitis that spontaneously develops in NOD mice. Female to female transfers resulted in dacryoadenitis if the CD4(+) CD25(+) Treg-enriched population was depleted before transfer; however, male to male transfers resulted in comparable dacryoadenitis regardless of the presence or absence of Treg cells within the donor cell population. Hormone manipulation studies suggested that this Treg cell dysfunction was mediated at least in part by androgens. Surprisingly, male Treg cells were capable of preventing the transfer of dacryoadenitis to female recipients. These data suggest that male-specific factors promote reversible dysfunction of lacrimal gland-protective Treg cells and, to our knowledge, form the first evidence for reversible organ-protective Treg cell dysfunction in organ-specific autoimmunity.

Childhood Sjögren syndrome: insights from adults and animal models.

PURPOSE OF REVIEW: Sjögren syndrome is a chronic autoimmune disease affecting lacrimal and salivary glands that often is accompanied by extraglandular disease manifestations. Although common in adults, the prevalence and prognosis of childhood Sjögren syndrome are unknown, in part due to lack of child-specific diagnostic and classification criteria. This review discusses difficulties in diagnosing childhood Sjögren syndrome and highlights recent findings in Sjögren syndrome treatment and pathogenesis from studies in adults and animal models over the past 18 months. RECENT FINDINGS: Studies of rituximab show some therapeutic potential in adult Sjögren syndrome, whereas newer modalities including gene therapy and mesenchymal stem cell transfer are promising. The pathogenesis of Sjögren syndrome is emerging, including roles of T and B lymphocytes, autoantibodies, interferons, and glandular epithelial cells. Specific recent notable findings in Sjögren syndrome pathogenesis include identification of a type II interferon signature in salivary glands of Sjögren syndrome patients, characterization of salivary gland-infiltrating T-cell subsets, and characterization of antimuscarinic acetylcholine receptor type 3 autoantibodies. SUMMARY: Childhood Sjögren syndrome is a poorly defined and underdiagnosed autoimmune disease that requires child-specific criteria in order to study disease burden and prognosis. Studies in adults and animal models continue to elucidate new potential diagnostic and therapeutic targets, which may be relevant for childhood Sjögren syndrome. VIDEO ABSTRACT: http://links.lww.com/COR/A3.

Site-specific accumulation of recently activated CD4+ Foxp3+ regulatory T cells following adoptive transfer.

CD4(+) Foxp3(+) regulatory T (Treg) cells are required for the maintenance of self-tolerance, as demonstrated by profound autoimmunity in mice and humans with inactivating Foxp3 mutations. Recent studies demonstrate that Treg cells are anatomically compartmentalized within secondary lymphoid organs based on their TCR repertoire and specific organ-protective function; however, whether this reflects differential homing or in situ selection is not known. Here, using Foxp3-GFP reporter mice, we have examined the ability of polyclonal Treg cells from cervical LNs to return to their site-of-origin following adoptive transfer to nonlymphopenic congenic recipients. We find that bulk cervical LN Treg cells do not home directly to cervical LNs but rather accumulate site specifically over time following transfer. Site-specific enrichment is both more rapid and more pronounced among a population of recently activated (CD69(+) ) Treg cells. These data suggest that compartmentalization of Treg cells within secondary lymphoid organs may be governed by antigen recognition and implicate CD69 as a potential marker of recently activated Treg cells recognizing locally expressed antigens.

Pediatric rheumatologists' perspectives on diagnosis, treatment, and outcomes of Sjögren disease in children and adolescents.

BACKGROUND: Sjögren disease in children and adolescents (pedSD) presents differently than adult disease. Diagnosis and classification are controversial, optimal treatment is unknown and outcomes are poorly understood. Here, we describe the current perspectives of pediatric rheumatologists on diagnosis, treatment, and outcomes of pedSD. METHODS: A voluntary, 17-question survey was distributed to providers in the Childhood Arthritis and Rheumatology Research Alliance and/or the American College of Rheumatology Childhood Sjögren's Study Group at the 2020 Convergence Virtual Conference. Findings are reported using descriptive statistics and chi-square testing. RESULTS: Of 465 eligible providers, 157 (34%) responded with 135 (29%) completing the survey. The majority (85%) saw five or fewer patients with pedSD in the past year. Parotitis, dry eye and/or dry mouth, and constitutional symptoms were among the most specific and common clinical features. Most providers (77%) used clinical judgment guided by adult criteria for diagnosis. The vast majority (86-99%) of survey participants indicated routine use of serologic testing, while salivary gland ultrasound, minor salivary gland biopsy and other diagnostic tests were less often used. The most commonly prescribed systemic immunomodulators were hydroxychloroquine, corticosteroids, methotrexate, rituximab, and mycophenolate. Seven providers reported malignancy in a patient with pedSD, including one death. CONCLUSIONS: Pediatric rheumatologists diagnose and treat pedSD; however, most only see a few patients per year and rely on clinical judgment and laboratory testing for diagnosis. Treatment frequently includes systemic immunomodulators and malignancies are reported. More studies are needed to better understand natural history, risk factors, and the impact of interventions on outcomes.

Recurrent or persistent salivary gland enlargement in children: When is it Sjögren's?

OBJECTIVES: To describe characteristic features in children with recurrent or persistent salivary gland enlargement and to propose a diagnostic algorithm with specific consideration for Sjögren's disease (SD). METHODS: In this single-center, prospective study, 45 patients < 18 years, with recurrent or persistent salivary gland enlargement of unknown etiology were enrolled from 2006 to 2019. We collected detailed clinical information to characterize this group of patients including specific details of their major salivary gland signs and symptoms. We compared clinical, laboratory and radiological parameters between 4 groups based on the results of labial salivary gland biopsy (LSGB) and between patients who met existing SD criteria or not. RESULTS: 44 patients, with a mean age of 6.8 years and female to male ratio 21:23 were observed over a mean of 3.8 years. Characteristics of salivary gland swelling episodes varied considerably between individuals, but the majority experienced ≤5 episodes per year, lasting ≤ 1 week, with swelling affecting either or both glands. Ocular and oral dryness symptoms were observed only in 25% and 59% patients, respectively. The majority were positive for ANA, but negative for SD-specific antibodies. A total of 75% patients fulfilled at least one of the existing SD criteria. CONCLUSION: SD is a major cause of recurrent salivary gland enlargement in children. For children meeting adult criteria, the diagnosis of SD is clear. However, for the many children without dryness symptoms, objective dryness, or SD-specific antibodies, further workup including a combination of salivary gland imaging and histopathological examination can help establish the diagnosis of SD.

Sex differences in comorbidities associated with Sjögren's disease.

Background: Little is known about the association of comorbidities with sex and age at diagnosis in Sjögren's disease. We tested the hypothesis that sex differences occur in comorbidities in patients with Sjögren's disease. Methods: Patients with Sjögren's disease were identified from 11/1974 to 7/2018 in the Mayo Clinic electronic medical record and assessed for 22 comorbidities according to sex and age at diagnosis. Results: Of the 13,849 patients identified with Sjögren's disease, 11,969 (86%) were women and 1,880 (14%) men, primarily white (88%) with a sex ratio of 6.4:1 women to men. The mean age at diagnosis was 57 years for women and 59.7 years for men, and 5.6% had a diagnosis of fibromyalgia at Sjögren's diagnosis. Men with Sjögren's disease were more likely than women to be a current or past smoker. The average time to diagnosis of comorbidities after diagnosis of Sjögren's disease was 2.6 years. The top comorbidities in patients with Sjögren's disease were fibromyalgia (25%), depression (21.2%) and pain (16.4%). Comorbidities that occurred more often in women were hypermobile syndromes (31:1), CREST (29:1), migraine (23:1), Ehlers-Danlos syndrome (EDS) (22:1), Raynaud's syndrome (15:1), SLE (13:1), systemic sclerosis (SSc) (13:1), and fibromyalgia (12:1). Women with Sjögren's disease were at increased risk of developing hypermobile syndromes (RR 7.27, CI 1.00-52.71, p = 0.05), EDS (RR 4.43, CI 1.08-18.14, p = 0.039), CREST (RR 4.24, CI 1.56-11.50, p = 0.005), migraine (RR 3.67, CI 2.39-5.62, p < 0.001), fibromyalgia (RR 2.26, CI 1.92-2.66, p < 0.001), Raynaud's syndrome (RR 2.29, CI 1.77-2.96, p < 0.001), SLE (RR 2.13, CI 1.64-2.76, p < 0.001), and SSc (RR 2.05 CI 1.44-2.92; p < 0.001). In contrast, men with Sjögren's were at increased risk for developing myocardial infarction (RR 0.44, CI 0.35-0.55, p < 0.001), atherosclerosis/CAD (RR 0.44, CI 0.39-0.49, p < 0.001), cardiomyopathy (RR 0.63, CI 0.46-0.86, p = 0.003), stroke (RR 0.66 CI 0.51-0.85, p = 0.001), and congestive heart failure (RR 0.70, CI 0.57-0.85, p < 0.001). Conclusions: The top comorbidities in Sjögren's disease were fibromyalgia, depression, and pain. Women with Sjögren's disease had a higher relative risk of developing fibromyalgia, depression, pain, migraine, hypermobile syndrome, EDS and other rheumatic autoimmune diseases. Men with Sjögren's disease had higher risk of developing cardiovascular diseases.