Objective: Anticytokine autoantibodies occur across a range of hematologic, pulmonary, and infectious diseases. However, systematic investigation of their presence and significance in autoimmune diseases is lacking. This study was undertaken to examine the distinct functions of anticytokine autoantibodies in patients with systemic lupus erythematosus (SLE) compared to patients with other rheumatic diseases and healthy controls.Methods: Serum samples from patients with SLE (n = 199), patients with primary Sjögren's syndrome (SS) (n = 150), patients with rheumatoid arthritis (RA) (n = 149), and healthy controls (n = 200) were screened for 24 anticytokine autoantibodies using a multiplex bead‐based assay. To evaluate the biologic activity of anticytokine autoantibodies, their ability to block cytokine‐induced signal transduction or protein expression was measured. RNA sequencing was performed on whole blood in a subset of healthy controls and patients with SLE.Results: Patients with SLE and those with SS had a striking excess of autoantibodies against interferons and the interferon‐responsive chemokine interferon‐inducible protein 10 (IP‐10). Only autoantibodies against type I interferon, interleukin‐12 (IL‐12), and IL‐22 exhibited neutralizing activity. In SLE, the presence of anti–interferon‐γ autoantibodies was correlated with more severe disease activity, higher levels of anti–double‐stranded DNA antibodies, and elevated expression of interferon‐α/β–inducible genes. Conversely, in SLE patients with blocking anti–interferon‐α autoantibodies, the type I interferon gene expression signature was normalized. Anti–type III interferon autoantibodies (λ2, λ3) and anti–IP‐10 autoantibodies were newly recognized in SLE patient serum, and autoantibodies against macrophage‐colony stimulating factor, IL‐4, IL‐7, IL‐17, and IL‐22, none of which have been previously identified in rheumatic conditions, were discovered.Conclusion: Anticytokine autoantibodies are associated with distinct patterns of disease in SLE, SS, and RA. Anti‐interferon autoantibodies are overrepresented in patients with SLE and those with SS, and fall into distinct functional classes, with only a subset of anti–type I interferon antibodies exhibiting neutralizing activity. Anti–interferon‐γ autoantibodies are correlated with increased disease activity and interferon‐related gene expression, suggesting that such autoantibodies may contribute to the pathogenesis of SLE.

Objective Primary Sjögren's syndrome (SS) is an autoimmune disease characterized by activation of minor salivary gland (MSG) epithelial cells and B and T lymphocytic infiltrates. These findings have long encouraged the hypothesis that a persistent viral infection of the MSG epithelial cells may drive the autoimmune response; however, the identity of that virus has remained elusive. The aim of this study was to test this hypothesis. Methods We applied the differential display protocol to MSG RNA samples from patients with primary SS and healthy controls. We then used seminested reverse transcriptase–polymerase chain reaction to amplify the 5′-noncoding region (5′-NCR) of the enteroviral genome in 8 patients with primary SS, 9 patients with secondary SS, and 8 control subjects. Immunohistochemistry was performed to study the expression of the VP1 enteroviral capsid protein in MSG biopsy samples from 12 patients with primary SS, 8 patients with secondary SS, and 16 controls. Results Differential display analysis yielded a 94-bp fragment of coxsackievirus B4 (CVB4) P2A gene in the primary SS samples. The 5′-NCR was amplified in 7 samples from patients with primary SS and in no samples from patients with secondary SS or controls. The 7 amplified products were sequenced; 4 of the sequences were found to be 98–99% identical to the 5′- NCR of CVB4, and 3 were found to be 97–98% identical to the 5′-NCR of CVA13. Immunohistochemistry for the enteroviral capsid protein VP1 revealed positive staining in epithelial cells and lymphocytic infiltrates in 11 primary SS samples, 1 secondary SS sample, and no control samples. Conclusion We provide evidence that primary SS may be associated with coxsackievirus infection of the MSG epithelial cells and focal lymphocytic infiltrates. Our findings are formulated in a hypothesis concerning the possible role of coxsackieviruses in the induction and maintenance of autoimmunity in primary SS.

Objective: To evaluate the prevalence of avascular necrosis (AVN), using magnetic resonance imaging (MRI), in patients with primary antiphospholipid syndrome (APS) and in patients with systemic lupus erythematosus (SLE), with or without anticardiolipin antibodies (aCL), who are asymptomatic for AVN and have not taken corticosteroids.Methods: Seventy‐nine subjects who were asymptomatic for AVN were evaluated by MRI of the femoral heads: 30 patients with primary APS who had never received corticosteroids, 19 SLE patients who had never received steroids (divided into 2 groups, aCL positive and aCL negative, in order to examine any association between AVN and aCL), and 30 healthy subjects who were age‐ and sex‐matched with patients with primary APS. Established MRI criteria were used for a diagnosis of AVN.Results: Asymptomatic AVN was evident in 6 (20%) of 30 patients with primary APS: 3 of them (1 man, 2 women) had intermediate bilateral AVN, and 3 (all women) had early AVN (bilateral in 1 patient). Results of hip and pelvis radiography and dynamic scintigraphy were negative. Followup MRI 6 months later revealed no changes. At the time of the initial MRI examination, the mean (±SD) age of patients in whom AVN was identified was 31.2 ± 7.3 years, and that of patients without AVN was 42.4 ± 11.9 years (P = 0.036). Livedo reticularis occurred significantly more commonly in the group with AVN (P = 0.041). None of the healthy subjects and none of the patients with SLE demonstrated AVN on MRI.Conclusion: AVN can be detected by MRI in 20% of patients with primary APS. Younger patients tend to develop AVN more frequently than do older patients, and the presence of livedo reticularis may identify individuals at risk for AVN. Clinicians should be aware of this possible clinical manifestation of primary APS, because early diagnosis can lead to early intervention.