Autoantibodies identify primary Sjögren's syndrome in patients lacking serum IgG specific for Ro/SS-A and La/SS-B.

OBJECTIVE: Identify autoantibodies in anti-Ro/SS-A negative primary Sjögren's syndrome (SS). METHODS: This is a proof-of-concept, case-control study of SS, healthy (HC) and other disease (OD) controls. A discovery dataset of plasma samples (n=30 SS, n=15 HC) was tested on human proteome arrays containing 19 500 proteins. A validation dataset of plasma and stimulated parotid saliva from additional SS cases (n=46 anti-Ro+, n=50 anti-Ro-), HC (n=42) and OD (n=54) was tested on custom arrays containing 74 proteins. For each protein, the mean+3 SD of the HC value defined the positivity threshold. Differences from HC were determined by Fisher's exact test and random forest machine learning using 2/3 of the validation dataset for training and 1/3 for testing. Applicability of the results was explored in an independent rheumatology practice cohort (n=38 Ro+, n=36 Ro-, n=10 HC). Relationships among antigens were explored using Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) interactome analysis. RESULTS: Ro+ SS parotid saliva contained autoantibodies binding to Ro60, Ro52, La/SS-B and muscarinic receptor 5. SS plasma contained 12 novel autoantibody specificities, 11 of which were detected in both the discovery and validation datasets. Binding to ≥1 of the novel antigens identified 54% of Ro- SS and 37% of Ro+ SS cases, with 100% specificity in both groups. Machine learning identified 30 novel specificities showing receiver operating characteristic area under the curve of 0.79 (95% CI 0.64 to 0.93) for identifying Ro- SS. Sera from Ro- cases of an independent cohort bound 17 of the non-canonical antigens. Antigenic targets in both Ro+ and Ro- SS were part of leukaemia cell, ubiquitin conjugation and antiviral defence pathways. CONCLUSION: We identified antigenic targets of the autoantibody response in SS that may be useful for identifying up to half of Ro seronegative SS cases.

Risk Factors for Infection and Health Impacts of the Coronavirus Disease 2019 (COVID-19) Pandemic in People With Autoimmune Diseases.

BACKGROUND: People with autoimmune or inflammatory conditions taking immunomodulatory/suppressive medications may have higher risk of novel coronavirus disease 2019 (COVID-19). Chronic disease care has also changed for many patients, with uncertain downstream consequences. METHODS: We included participants with autoimmune or inflammatory conditions followed by specialists at Johns Hopkins. Participants completed periodic surveys querying comorbidities, disease-modifying medications, exposures, COVID-19 testing and outcomes, social behaviors, and disruptions to healthcare. We assessed whether COVID-19 risk is higher among those on immunomodulating or suppressive agents and characterized pandemic-associated changes to care and mental health. RESULTS: In total, 265 (5.6%) developed COVID-19 over 9 months of follow-up (April-December 2020). Patient characteristics (age, race, comorbidity, medications) were associated with differences in social distancing behaviors during the pandemic. Glucocorticoid exposure was associated with higher odds of COVID-19 in models incorporating behavior and other potential confounders (odds ratio [OR]: 1.43; 95% confidence interval [CI]: 1.08, 1.89). Other medication classes were not associated with COVID-19 risk. Diabetes (OR: 1.72; 95% CI: 1.08, 2.73), cardiovascular disease (OR: 1.68; 95% CI: 1.24, 2.28), and kidney disease (OR: 1.76; 95% CI: 1.04, 2.97) were associated with higher odds of COVID-19. Of the 2156 reporting pre-pandemic utilization of infusion, mental health or rehabilitative services, 975 (45.2%) reported disruptions therein, which disproportionately affected individuals experiencing changes to employment or income. CONCLUSIONS: Glucocorticoid exposure may increase risk of COVID-19 in people with autoimmune or inflammatory conditions. Disruption to healthcare and related services was common. Those with pandemic-related reduced income may be most vulnerable to care disruptions.

Efficacy and safety of abatacept in active primary Sjögren's syndrome: results of a phase III, randomised, placebo-controlled trial.

OBJECTIVES: To evaluate efficacy and safety of abatacept in adults with active primary Sjögren's syndrome (pSS) in a phase III, randomised, double-blind, placebo-controlled trial. METHODS: Eligible patients (moderate-to-severe pSS [2016 ACR/European League Against Rheumatism (EULAR) criteria], EULAR Sjögren's Syndrome Disease Activity Index [ESSDAI] ≥5, anti-SS-related antigen A/anti-Ro antibody positive) received weekly subcutaneous abatacept 125 mg or placebo for 169 days followed by an open-label extension to day 365. Primary endpoint was mean change from baseline in ESSDAI at day 169. Key secondary endpoints were mean change from baseline in EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) and stimulated whole salivary flow (SWSF) at day 169. Other secondary clinical endpoints included glandular functions and patient-reported outcomes. Selected biomarkers and immune cell phenotypes were examined. Safety was monitored. RESULTS: Of 187 patients randomised, 168 completed double-blind period and 165 continued into open-label period. Mean (SD) baseline ESSDAI and ESSPRI total scores were 9.4 (4.3) and 6.5 (2.0), respectively. Statistical significance was not reached for primary (ESSDAI -3.2 abatacept vs -3.7 placebo, p=0.442) or key secondary endpoints (ESSPRI, p=0.337; SWSF, p=0.584). No clinical benefit of abatacept over placebo at day 169 was seen with other clinical and PRO endpoints. Relative to baseline, abatacept was associated with significant differences vs placebo in some disease-relevant biomarkers (including IgG, IgA, IgM-rheumatoid factor) and pathogenic cell subpopulations (post hoc analyses). No new safety signals were identified. CONCLUSIONS: Abatacept treatment did not result in significant clinical efficacy compared with placebo in patients with moderate-to-severe pSS, despite evidence of biological activity.

How to treat Sjögren's syndrome.

SS is a chronic, autoimmune disease of unknown aetiology for which there is no known curative treatment. Although dryness of the eyes and mouth are the classically described features, patients often experience drying of other mucosal surfaces and systemic manifestations, including fatigue and arthralgia. There is an association with other autoimmune diseases, especially thyroid disease, coeliac disease and primary biliary cholangitis. Systemic features may affect up to 70% and include inflammatory arthritis, skin involvement, haematological abnormalities, neuropathies, interstitial lung disease and a 5-10% lifetime risk of B cell lymphoma. Treatment should aim to empower patients to manage their condition; conserve, replace and stimulate secretions; prevent damage; and suppress underlying systemic disease activity.

Neuropathic Pain in the Eyes, Body, and Mouth: Insights from the Sjögren's International Collaborative Clinical Alliance.

OBJECTIVE: To evaluate how ocular, oral, and bodily neuropathic pain symptoms, which characterize small fiber neuropathies, are associated with Sjögren's syndrome (SS) classification based on the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria. METHODS: Participants enrolled in the Sjögren's International Collaborative Clinical Alliance (SICCA) registry had ocular, rheumatologic, oral, and labial salivary gland (LSG) biopsy examinations, blood and saliva samples collected, and completed questionnaires at baseline. We used mixed effects modeling with age, country, gender, and depression being fixed effects and study site, a random effect, to determine if neuropathic pain indicators (assessed via questionnaires) were associated with being classified as SS. RESULTS: A total of 3,514 participants were enrolled into SICCA, with 1,541 (52.9%) meeting the 2016 ACR/EULAR classification criteria for SS. There was a negative association between being classified as SS and experiencing bodily neuropathic pain features of needle-like pain, prickling/tingling sensation, ocular neuropathic pain of constant burning, and constant light sensitivity, and having a presumptive diagnosis of neuropathic oral pain. CONCLUSIONS: We found that those classified as SS had lower scores/reports of painful neuropathies compared with those classified as non-SS. Non-SS patients with dry eye disease or symptoms could benefit from pain assessment as they may experience painful small-fiber neuropathies (SFNs). Pain questionnaires may help identify pain associated with SFNs in patients with SS and non-SS dry eye. Future studies would be helpful to correlate self-reports of pain to objective measures of SFNs in those with SS, non-SS dry eye, and healthy controls.

Unique Sjögren's syndrome patient subsets defined by molecular features.

OBJECTIVE: To address heterogeneity complicating primary SS (pSS) clinical trials, research and care by characterizing and clustering patients by their molecular phenotypes. METHODS: pSS patients met American-European Consensus Group classification criteria and had at least one systemic manifestation and stimulated salivary flow of ⩾0.1 ml/min. Correlated transcriptional modules were derived from gene expression microarray data from blood (n = 47 with appropriate samples). Patients were clustered based on this molecular information using an unbiased random forest modelling approach. In addition, multiplex, bead-based assays and ELISAs were used to assess 30 serum cytokines, chemokines and soluble receptors. Eleven autoantibodies, including anti-Ro/SSA and anti-La/SSB, were measured by Bio-Rad Bioplex 2200. RESULTS: Transcriptional modules distinguished three clusters of pSS patients. Cluster 1 showed no significant elevation of IFN or inflammation modules. Cluster 2 showed strong IFN and inflammation modular network signatures, as well as high plasma protein levels of IP-10/CXCL10, MIG/CXCL9, BLyS (BAFF) and LIGHT. Cluster 3 samples exhibited moderately elevated IFN modules, but with suppressed inflammatory modules, increased IP-10/CXCL10 and B cell-attracting chemokine 1/CXCL13 and trends toward increased MIG/CXCL9, IL-1α, and IL-21. Anti-Ro/SSA and anti-La/SSB were present in all three clusters. CONCLUSION: Molecular profiles encompassing IFN, inflammation and other signatures can be used to separate patients with pSS into distinct clusters. In the future, such profiles may inform patient selection for clinical trials and guide treatment decisions.

Sicca Syndrome Associated with Immune Checkpoint Inhibitor Therapy.

BACKGROUND: The objective of this study was to characterize the clinicopathologic features of sicca syndrome associated with immune checkpoint inhibitor (ICI) therapy. SUBJECTS, MATERIALS, AND METHODS: Consecutive patients with new or worsening xerostomia in the setting of ICI treatment for benign or malignant neoplastic disease were evaluated, including labial salivary gland biopsy (LSGB). RESULTS: Twenty patients (14 male; median age 57 years) had metastatic melanoma (n = 10), metastatic carcinoma (n = 6), or recurrent respiratory papillomatosis (n = 4) and were being treated with avelumab (n = 8), nivolumab (n = 5), pembrolizumab (n = 4), nivolumab/ipilimumab (n = 2), and M7824, a biologic targeting programmed cell death ligand 1 (PD-L1) and transforming growth factor ß (n = 1). Four had pre-existing autoimmune disease. Nineteen had very low whole unstimulated saliva flow; six had new dry eye symptoms. The median interval between ICI initiation and dry mouth onset was 70 days. Rheumatoid factor and anti-Sjögren's Syndrome-related Antigen A (Anti-SSA) were both positive in two subjects. LSGB showed mild-to-severe sialadenitis with diffuse lymphocytic infiltration and architectural distortion. There were lymphocytic aggregates in eight patients, composed mainly of CD3+ T cells with a slight predominance of CD4+ over CD8+ T cells. ICI targets (e.g., programmed cell death 1 and PD-L1) were variably positive. In direct response to the advent of the sicca immune-related adverse event, the ICI was held in 12 patients and corticosteroids were initiated in 10. Subjective improvement in symptoms was achieved in the majority; however, salivary secretion remained very low. CONCLUSION: ICI therapy is associated with an autoimmune-induced sicca syndrome distinct from Sjögren's syndrome, often abrupt in onset, usually developing within the first 3 months of treatment, and associated with sialadenitis and glandular injury. Improvement can be achieved with a graded approach depending on severity, including withholding the ICI and initiating corticosteroids. However, profound salivary flow deficits may be long term. IMPLICATIONS FOR PRACTICE: Sicca syndrome has been reported as an immune-related adverse event (irAE) of immune checkpoint inhibitor therapy (ICI) for neoplastic diseases. Severe dry mouth (interfering with eating or sleeping) developed abruptly, typically within 90 days, after initiation of ICI therapy. Salivary gland biopsies demonstrated mild-to-severe sialadenitis distinct from Sjögren's syndrome, with diffuse T-cell lymphocytic infiltration and acinar injury. Recognition of the cardinal features of ICI-induced sicca will spur appropriate clinical evaluation and management, including withholding of the ICI and corticosteroid, initiation. This characterization should help oncologists, rheumatologists, and oral medicine specialists better identify patients that develop ICI-induced sicca to initiate appropriate clinical evaluation and therapy to reduce the likelihood of permanent salivary gland dysfunction.

Renal involvement in primary Sjögren's syndrome: natural history and treatment outcome.

OBJECTIVES: Overt renal disease in primary Sjögren's syndrome (pSS) manifests as interstitial nephritis and glomerulonephritis. This single centre study aims to describe the natural history and treatment outcome of renal disease in pSS. METHODS: pSS patients with renal disease were identified, and clinical features, renal biopsy findings, treatment details and renal outcome were recorded. RESULTS: Of the 20 pSS patients with renal disease, 14 had interstitial nephritis (IN), 3 had glomerulonephritis (GN) and 3 had both entities. In the IN group, 3 patients presented with chronic kidney disease (CKD), 4 with renal tubular acidosis (RTA), 2 with symptomatic hypokalaemia, 4 with renal colic and 1 with haematuria/proteinuria. Eight of 14 patients with IN received systemic immunosuppression (IS) during renal disease course and in 6 patients no beneficial effect was observed on renal function, hypokalaemia and RTA. Six of 14 IN patients developed CKD while 5 of them preserved normal renal function during follow-up. In the GN group, 2 patients presented with CKD, 3 with proteinuria/haematuria and 1 with nephrotic proteinuria. GN renal biopsy findings revealed membranoproliferative (MPGN) (n=3), focal segmental glomerulosclerosis (n=1) and fibrillary glomerulopathy (n=1). All 3 MPGN patients had cryoglobulinaemia and in 1 patient cryoglobulinaemic MPGN was clinically diagnosed. All GN patients were treated with immunosuppressive therapy, with stabilisation or improvement of renal function in the 4 cryoglobulinaemia-associated GN patients only. CONCLUSIONS: Interstitial nephritis follows a slow course and does not improve with systemic immunosuppression while GN has a favourable treatment response in those with MPGN pathology.

Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab.

OBJECTIVES: Immune checkpoint inhibitors (ICIs) targeting the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) pathways have demonstrated survival improvements in multiple advanced cancers, but also cause immune-related adverse events (IRAEs). IRAEs with clinical features similar to rheumatic diseases have not been well described. We report patients with inflammatory arthritis and sicca syndrome secondary to ICIs. METHODS: We report patients evaluated in the Johns Hopkins Rheumatology clinics from 2012 to 2016 identified as having new rheumatological symptoms in the context of treatment with ipilimumab (anti-CTLA-4) and/or nivolumab (anti-PD-1) for solid tumours. RESULTS: We identified 13 patients who received ICIs and developed rheumatological IRAEs. Mean age was 58.7 years. Cancer types included melanoma, non-small cell lung cancer, small cell lung cancer and renal cell carcinoma. ICI regimens included nivolumab or ipilimumab as monotherapy (n=5), or combination nivolumab and ipilimumab (n=8). Nine of 13 patients developed an inflammatory arthritis, 4 with synovitis confirmed on imaging (3 ultrasound, 1 MRI) and 4 with inflammatory synovial fluid. Four patients developed sicca syndrome with severe salivary hypofunction. Other IRAEs included: pneumonitis, colitis, interstitial nephritis and thyroiditis. Antinuclear antibodies were positive in 5 out of 13 patients. All 13 patients were treated with corticosteroids with varying response. Two patients were treated with methotrexate and antitumor necrosis factor therapy for inflammatory arthritis. CONCLUSIONS: As ICIs are increasingly used for a range of malignancies, new cases of rheumatic IRAEs are likely to emerge. Further research is required to understand mechanisms, determine risk factors and develop management algorithms for rheumatic IRAEs.

PUF60: a prominent new target of the autoimmune response in dermatomyositis and Sjögren's syndrome.

OBJECTIVES: Autoantibodies are used clinically to phenotype and subset patients with autoimmune rheumatic diseases. We detected a novel 60 kDa autoantibody specificity by immunoblotting using a dermatomyositis (DM) patient's serum. Our objective was to identify the targeted autoantigen and to evaluate disease specificity and clinical significance of this new autoantibody. METHODS: A new 60 kDa specificity was detected by immunoblotting HeLa cell lysates. The targeted autoantigen was identified as poly(U)-binding-splicing factor 60 kDa (PUF60) using (i) a human protein array and (ii) two-dimensional gel electrophoresis and liquid chromatography tandem mass spectrometry peptide sequencing. Anti-PUF60 antibodies were assayed by ELISA using sera from patients with primary Sjögren's syndrome (SS; n=84), systemic lupus erythematosus (SLE; n=71), DM (n=267), polymyositis (n=45), inclusion body myositis (n=45) and healthy controls (n=38). RESULTS: PUF60 was identified as a new autoantigen. Anti-PUF60 antibodies were present in 25/84 (30%) patients with SS, 6/71 (8.5%) patients with SLE and 2/38 (5.0%) control subjects (SS vs controls, p=0.002; SLE vs controls, p=0.711). Anti-PUF60 antibodies were present in 48/267 (18.0%) patients with DM versus 4/45 (8.9%) and 5/45 (11.1%) patients with inclusion body myositis and polymyositis, respectively. The antibody was significantly associated with anti-Ro52 antibodies, rheumatoid factor and hyperglobulinemia in the patients with primary SS. In patients with DM, the antibody was associated with anti-transcription intermediary factor 1 gamma seropositivity and Caucasian race. CONCLUSIONS: PUF60 represents a novel autoantigen in patients with SS and DM. PUF60 antibodies are associated with distinct clinical features and different immune responses in different diseases.

Dual-energy computed tomography has limited sensitivity for non-tophaceous gout: a comparison study with tophaceous gout.

BACKGROUND: Dual-energy computed tomography (DECT) is a new diagnostic tool for gout, but its sensitivity has not been established. Our goal was to assess the sensitivity of DECT for the detection of monosodium urate (MSU) deposits in non-tophaceous and tophaceous gout, both at the level of the patient and that of the individual joint or lesion. METHODS: DECT was performed on 11 patients with crystal-proven non-tophaceous gout and 10 with tophaceous gout and included both the upper and lower extremities in 20/21 patients. DECT images were simultaneously acquired at 80 and 140 kV and then processed on a workstation with proprietary software using a two-material decomposition algorithm. MSU deposits were color coded as green by the software and fused onto grey-scale CT images. The number and location of these deposits was tallied independently by two DECT-trained radiologists blinded to the clinical characteristics of the patient. Sensitivity of DECT was defined as the proportion of patients with a confirmed diagnosis of gout which was correctly identified as such by the imaging technique. All patients provided informed consent to participate in this IRB-approved study. RESULTS: MSU deposits were detected by DECT in ≥1 joint area in 7/11 (64 %) patients with non-tophaceous gout, but were only detected in 3/12 (25 %) joints proven by aspiration to be affected with gout. Inclusion of the upper extremity joints in the scanning protocol did not improve sensitivity. All 10 patients with tophaceous gout had MSU deposits evident by DECT. The sensitivity of DECT for individual gouty erosions was assessed in 3 patients with extensive foot involvement. MSU deposits were detected by DECT within or immediately adjacent to 13/26 (50 %) erosions. CONCLUSIONS: A DECT protocol that includes all lower extremity joints has moderate sensitivity in non-tophaceous and high sensitivity in tophaceous gout. However, DECT has lower sensitivity when restricted to individual crystal-proven gouty joints in non-tophaceous disease or individual erosive lesions in tophaceous gout. The detection of MSU deposits by DECT relates to their size and density and the detection parameters of the DECT scanner and adjustment of the latter might improve sensitivity.

The SSB-positive/SSA-negative antibody profile is not associated with key phenotypic features of Sjögren's syndrome.

OBJECTIVE: To determine whether the Sjögren's syndrome B (SSB)-positive/Sjögren's syndrome A (SSA)-negative antibody profile is associated with key phenotypic features of SS. METHODS: Among registrants in the Sjögren's International Collaborative Clinical Alliance (SICCA) with possible or established SS, we compared anti-SSA/anti-SSB reactivity profiles against concurrent phenotypic features. We fitted logistic regression models to explore the association between anti-SSA/anti-SSB reactivity profile and each key SS phenotypic feature, controlling for potential confounders. RESULTS: Among 3297 participants, 2061 (63%) had negative anti-SSA/anti-SSB, 1162 (35%) had anti-SSA with or without anti-SSB, and 74 (2%) anti-SSB alone. Key SS phenotypic features were more prevalent and had measures indicative of greater disease activity in those participants with anti-SSA, either alone or with anti-SSB, than in those with anti-SSB alone or negative SSA/SSB serology. These between-group differences were highly significant and not explained by confounding by age, race/ethnicity or gender. Participants with anti-SSB alone were comparable to those with negative SSA/SSB serology in their association with these key phenotypic features. Among SICCA participants classified with SS on the basis of the American-European Consensus Group or American College of Rheumatology criteria, only 2% required the anti-SSB-alone test result to meet these criteria. CONCLUSIONS: The presence of anti-SSB, without anti-SSA antibodies, had no significant association with SS phenotypic features, relative to seronegative participants. The solitary presence of anti-SSB antibodies does not provide any more support than negative serology for the diagnosis of SS. This serological profile should thus be interpreted cautiously in clinical practice and potentially eliminated from future classification criteria.

Ocular and systemic morbidity in a longitudinal cohort of Sjögren's syndrome.

PURPOSE: To report vision-threatening ocular manifestations of primary Sjögren's syndrome (SS). DESIGN: Retrospective review. PARTICIPANTS: Consecutive patients evaluated at an SS center between January 2007 and May 2011. METHODS: Data collection was completed in March 2013. The 2002 American-European consensus criteria were used for diagnosis of SS. MAIN OUTCOME MEASURES: Frequency of extraglandular ocular findings and timing of their diagnosis relative to that of SS and dry eye were assessed. RESULTS: One hundred sixty-three patients were included. Almost all patients (98%) had a history of dry eye for an average of 10.4 years (median, 7.9 years) before presentation. One or more extraglandular ocular manifestations were present in 40 patients (25%), and vision-threatening findings were present in 22 patients (13%). Twelve patients (55%) with a vision-threatening ocular finding did not have a diagnosis of SS at presentation. Sixty-eight patients (42%) had extraglandular systemic manifestations of SS. Patients with vision-threatening ocular findings were 3.9 times more likely to have systemic involvement (95% confidence interval, 1.4-11.0; P = 0.010). Peripheral neuropathy, interstitial nephritis, and vasculitis were more common in those with vision-threatening ocular findings compared with patients without (P < 0.05 for all). CONCLUSIONS: These results from a tertiary referral-based cohort demonstrate that primary SS frequently is associated with ocular and systemic complications. Dry eye precedes these findings on average by 1 decade. Therefore, ophthalmologists should consider assessing for SS in patients with clinically significant dry eye.

Precise probes of type II interferon activity define the origin of interferon signatures in target tissues in rheumatic diseases.

Elucidating the molecular pathways active in pathologic tissues has important implications for defining disease subsets, selecting therapy, and monitoring disease activity. The development of therapeutics directed at IFN-α or IFN-γ makes the discovery of probes that report precisely on the activity of different IFN pathways a high priority. We show that, although type I and II IFNs induce the expression of a largely overlapping group of molecules, precise probes of IFN-γ activity can be defined. Used in combination, these probes show prominent IFN-γ effects in Sjögren syndrome (SS) tissues. In contrast, dermatomyositis muscle shows a dominant type I IFN pattern. Interestingly, heterogeneity of IFN signatures exists in patients with SS, with some patients demonstrating a predominant type I pattern. The biochemical patterns largely distinguish the target tissues in patients with SS from those with dermatomyositis and provide a relative weighting of the effects of distinct IFN pathways in specific biopsies. In SS, type I and II IFN effects are localized to the same epithelial cells, surrounded by inflammatory cells expressing IFN-γ-induced proteins, suggesting reinforcing interactions. Precise probes of the different IFN pathways active in tissues of complex rheumatic diseases will be critical to classify disease, elucidate pathogenesis, and select therapy.

Racial differences in gout incidence in a population-based cohort: Atherosclerosis Risk in Communities Study.

We examined racial differences in gout incidence among black and white participants in a longitudinal, population-based cohort and tested whether racial differences were explained by higher levels of serum urate. The Atherosclerosis Risk in Communities Study is a prospective, US population-based cohort study of middle-aged adults enrolled between 1987 and 1989 with ongoing annual follow-up through 2012. We estimated the adjusted hazard ratios and 95% confidence intervals of incident gout by race among 11,963 men and women using adjusted Cox proportional hazards models. The cohort was 23.6% black. The incidence rate of gout was 8.4 per 10,000 person-years (15.5/10,000 person-years for black men, 12.0/10,000 person-years for black women, 9.4/10,000 person-years for white men, and 5.0/10,000 person-years for white women; P < 0.001). Black participants had an increased risk of incident gout (for women, adjusted hazard ratio (HR) = 1.69, 95% confidence interval (CI): 1.29, 2.22; for men, adjusted HR = 1.92, 95% CI: 1.44, 2.56). Upon further adjustment for uric acid levels, there was modest attenuation of the association of race with incident gout (for women, adjusted HR = 1.62, 95% CI: 1.24, 2.22; for men, adjusted HR = 1.49, 95% CI: 1.11, 2.00) compared with white participants. In this US population-based cohort, black women and black men were at increased risk of developing gout during middle and older ages compared with whites, which appears, particularly in men, to be partly related to higher urate levels in middle-aged blacks.

Evaluation and management of dry mouth and its complications in rheumatology practice.

INTRODUCTION: The symptom of dry mouth has multiple potential etiologies and can be a diagnostic clue to the presence of common systemic diseases encountered in rheumatology practice. The presence of decreased saliva flow (i.e. salivary hypofunction) defines a subset of dry mouth patients in whom there may be reversible drug effects, an iatrogenic insult such as head and neck irradiation, or a disease that directly involves the salivary glands (e.g. Sjögren's disease). The assessment of salivary hypofunction includes sialometry, salivary gland imaging, salivary gland biopsy, and an assessment for relevant systemic diseases. Optimal management of dry mouth requires accurate definition of its cause, followed by general measures that serve to alleviate its symptoms and prevent its complications. AREAS COVERED: Through a literature search on xerostomia and salivary hypofunction, we provide an overview of the causes of dry mouth, highlight the potential impact of salivary hypofunction on oral and systemic health, detail routine evaluation methods and treatment strategies, and emphasize the importance of collaboration with oral health care providers. EXPERT OPINION: Our Expert Opinion is provided on unmet needs in the management of dry mouth and relevant research progress in the field.

CD40 ligand antagonist dazodalibep in Sjögren's disease: a randomized, double-blinded, placebo-controlled, phase 2 trial.

Sjögren's disease (SjD) is a chronic, systemic autoimmune disease with no approved disease-modifying therapies. Dazodalibep (DAZ), a novel nonantibody fusion protein, is a CD40 ligand antagonist that blocks costimulatory signals between T and B cells and antigen-presenting cells, and therefore may suppress the wide spectrum of cellular and humoral responses that drive autoimmunity in SjD. This study was a phase 2, randomized, double-blinded, placebo (PBO)-controlled trial of DAZ with a crossover stage in two distinct populations of participants with SjD. Population 1 had moderate-to-severe systemic disease activity and population 2 had an unacceptable symptom burden and limited systemic organ involvement. All participants had a diagnosis of SjD, with 21.6% and 10.1% having an associated connective tissue disease (rheumatoid arthritis or systemic lupus erythematosus) in populations 1 and 2, respectively. The remaining participants would be considered as having primary Sjögren's syndrome. The primary endpoint for population 1 (n = 74) was the change from baseline in the European League Against Rheumatism Sjögren's Syndrome Disease Activity Index at day 169. The primary endpoint for population 2 (n = 109) was the change from baseline in the European League Against Rheumatism Sjögren's Syndrome Patient Reported Index at day 169. The primary endpoints (least squares mean ± standard error) were achieved with statistical significance for both population 1 (DAZ, -6.3 ± 0.6; PBO, -4.1 ± 0.6; P = 0.0167) and population 2 (DAZ, -1.8 ± 0.2; PBO, -0.5 ± 0.2; P = 0.0002). DAZ was generally safe and well tolerated. Among the most frequently reported adverse events were COVID-19, diarrhea, headache, nasopharyngitis, upper respiratory tract infection, arthralgia, constipation and urinary tract infection. In summary, DAZ appears to be a potential new therapy for SjD and its efficacy implies an important role for the CD40/CD40 ligand pathway in its pathogenesis. ClinicalTrials.gov identifier: NCT04129164 .

GZMK+CD8+ T cells Target A Specific Acinar Cell Type in Sjögren's Disease.

Sjögren's Disease (SjD) is a systemic autoimmune disease without a clear etiology or effective therapy. Utilizing unbiased single-cell and spatial transcriptomics to analyze human minor salivary glands in health and disease we developed a comprehensive understanding of the cellular landscape of healthy salivary glands and how that landscape changes in SjD patients. We identified novel seromucous acinar cell types and identified a population of PRR4+CST3+WFDC2- seromucous acinar cells that are particularly targeted in SjD. Notably, GZMK +CD8 T cells, enriched in SjD, exhibited a cytotoxic phenotype and were physically associated with immune-engaged epithelial cells in disease. These findings shed light on the immune response's impact on transitioning acinar cells with high levels of secretion and explain the loss of this specific cell population in SjD. This study explores the complex interplay of varied cell types in the salivary glands and their role in the pathology of Sjögren's Disease.