The latest medical research on Rheumatology

The research magnet gathers the latest research from around the web, based on your specialty area. Below you will find a sample of some of the most recent articles from reputable medical journals about rheumatology gathered by our medical AI research bot.

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Risk of Prostate Cancer in U.S. Veterans with Rheumatoid Arthritis.

Arthritis Care Res

Patients with rheumatoid arthritis (RA) have an increased risk of select cancers, including lymphoma and lung cancer. Whether RA influences prostate cancer risk is uncertain. We aimed to determine the risk of prostate cancer in patients with RA compared to patients without RA in the Veterans Health Administration (VA).

We performed a matched (up to 1:5) cohort study of males with and without RA in the VA from 2000 to 2018. RA status, as well as covariates, were obtained from national VA databases. Prostate cancer was identified through linked VA cancer databases and the National Death Index. Multivariable Cox models compared prostate cancer risk between RA and non-RA, including models that accounted for retention in the VA system.

We included 56,514 veterans with RA and 227,284 veterans without RA. During 2,337,104 patient-years of follow-up, 6,550 prostate cancers occurred. Prostate cancer incidence (per 1,000 patient-years) was 3.50 (95% CI 3.32, 3.69) in RA and 2.66 (95% CI 2.58, 2.73) in non-RA. After accounting for confounders and censoring for attrition of VA healthcare, RA was modestly associated with a higher prostate cancer risk (adjusted HR 1.12 [95% CI 1.04, 1.20]). There was no association between RA and prostate cancer mortality (adjusted HR 0.92 [95% CI 0.73, 1.16]).

RA was associated with a modestly increased risk of prostate cancer, but not prostate cancer mortality, after accounting for relevant confounders and several potential sources of bias. However, even minimal unmeasured confounding could explain these findings.

Risk of cardiovascular events in patients having had acute calcium pyrophosphate crystal arthritis.

Annals of the Rheumatic Diseases

Calcium pyrophosphate deposition (CPPD) disease, broadly defined, has been associated with increased risk of cardiovascular (CV) events. We investigated risk of CV events in patients with acute CPP crystal arthritis, the acute manifestation of CPPD.

Cohort study using Mass General Brigham electronic health record (EHR) data, 1991-2017. Patients with acute CPP crystal arthritis were identified using a published machine learning algorithm with positive predictive value 81%. Comparators were matched on year of EHR entry and index date of patients with acute CPP crystal arthritis (first positive synovial fluid CPP result or mention of 'pseudogout', or matched encounter). Major adverse cardiovascular event (MACE) was a composite of non-fatal CV event (myocardial infarction, acute coronary syndrome, coronary revascularisation, stroke) and death. We estimated incidence rates (IRs) and adjusted hazard ratios for MACE, non-fatal CV event and death, allowing for differential estimates during years 0-2 and 2-10. Sensitivity analyses included: (1) patients with acute CPP crystal arthritis diagnosed during outpatient visits, (2) patients with linked Medicare data, 2007-2016 and (3)patients matched on number of CV risk factors.

We matched 1200 acute CPP crystal arthritis patients to 3810 comparators. IR for MACE in years 0-2 was 91/1000 person-years (p-y) in acute CPP crystal arthritis and 59/1000 p-y in comparators. In years 2-10, IR for MACE was 58/1000 p-y in acute CPP crystal arthritis and 53/1000 p-y in comparators. Acute CPP crystal arthritis was significantly associated with increased risk for MACE in years 0-2 (HR 1.32, 95% CI 1.01 to 1.73) and non-fatal CV event in years 0-2 (HR 1.92, 95% CI 1.12 to 3.28) and years 2-10 (HR 2.18, 95% CI 1.27 to 3.75), but not death. Results of sensitivity analyses were similar to the primary analysis; in the outpatient-only analysis, risk of non-fatal CVE was significantly elevated in years 2-10 but not in years 0-2.

Acute CPP crystal arthritis was significantly associated with elevated short and long-term risk for non-fatal CV event.

In vivo generating SSA/Ro-antigen specific regulatory T cells improves experimental Sjögren's syndrome in mice.

Arthritis Rheumatol

Sjögren's syndrome (SS) is a systemic autoimmune disease and T cells play an important role in the initiation and perpetuation of the disease. Here, we developed an immunotherapy for SS-like NOD/Ltj mice by combining a transient depletion of CD4+ T cells together with the administration of autoantigen-specific peptide Ro480.

NOD/Ltj mice were treated with single anti-CD4 mAb followed 2 days later by a series of 6 injections (i.p.) of Ro480-494 every other day. Salivary flow rates were determined pre- and post-treatment once a week. Mice were sacrificed 6 weeks post initial anti-CD4 mAb treatment, salivary glands (SG) were collected for analyses of histological disease scores and inflammatory cell infiltration, PCR determination of genes and flow cytometry analysis including MHC class II tetramer staining of immune cells. In addition, adoptive transferring of Tregs was administrated to investigate the function of the newly generating Treg in vivo.

The combination of anti-CD4 mAb with autoantigen-specific peptide Ro480 generates SSA/Ro-antigen specific Tregs in vivo, which can suppress IFN-γ production of CD4+ T cells and the inflammation infiltration in SG, and maintain the function of SG.

Our findings provide a new approach to generating antigen-specific Tregs in vivo for SS treatment, which should have implications for potential therapy for patients with SS.

Patterns of arthritis flare reveal joint-specific memory together with sustained risk for new joint accumulation.

Arthritis Rheumatol

Inflammatory arthritides exhibit hallmark patterns of affected and spared joints, but in each individual, arthritis affects only a subset of all possible sites. We studied patient-specific joint flare patterns to distinguish local from systemic drivers of disease chronicity.

Patients with juvenile idiopathic arthritis followed without interruption from onset into adulthood were identified across two large academic centers. Joints inflamed at each visit were established by medical record review. Flare was defined as physician-confirmed joint inflammation following documented inactive disease.

Among 222 adult candidates, 95 had complete serial joint examinations since disease onset as children. Mean follow-up was 12.5 years (IQ range 7.9-16.7 years). 90 of 95 patients (95%) achieved inactive disease, after which 81% (73 patients) flared at least once. Among 940 joints affected in 253 flares, 74% had been involved previously. In flares affecting easily observed large joint pairs where only one side had been involved before (n=53), the original joint was affected in 83% and the contralateral joint in 17% (p<0.0001 vs. random laterality). However, disease extended to at least one new joint in approximately 40% of flares, a risk that remained stable even decades after onset and was greatest in flares that occurred off medications (54% vs. 36% on therapy, odds ratio 2.09, p=0.015).

Arthritis flares preferentially affect previously inflamed joints but carry an ongoing risk of disease extension. These findings confirm joint-specific memory and suggest that prevention of new joint accumulation should be an important target for arthritis therapy.

Biological insights into systemic lupus erythematosus through an immune cell-specific transcriptome-wide association study.

Annals of the Rheumatic Diseases

Genome-wide association studies (GWAS) have identified >100 risk loci for systemic lupus erythematosus (SLE), but the disease genes at most loci remain unclear, hampering translation of these genetic discoveries. We aimed to prioritise genes underlying the 110 SLE loci that were identified in the latest East Asian GWAS meta-analysis.

We built gene expression predictive models in blood B cells, CD4+ and CD8+ T cells, monocytes, natural killer cells and peripheral blood cells of 105 Japanese individuals. We performed a transcriptome-wide association study (TWAS) using data from the latest genome-wide association meta-analysis of 208 370 East Asians and searched for candidate genes using TWAS and three data-driven computational approaches.

TWAS identified 171 genes for SLE (p<1.0×10-5); 114 (66.7%) showed significance only in a single cell type; 127 (74.3%) were in SLE GWAS loci. TWAS identified a strong association between CD83 and SLE (p<7.7×10-8). Meta-analysis of genetic associations in the existing 208 370 East Asian and additional 1498 cases and 3330 controls found a novel single-variant association at rs72836542 (OR=1.11, p=4.5×10-9) around CD83. For the 110 SLE loci, we identified 276 gene candidates, including 104 genes at recently-identified SLE novel loci. We demonstrated in vitro that putative causal variant rs61759532 exhibited an allele-specific regulatory effect on ACAP1, and that presence of the SLE risk allele decreased ACAP1 expression.

Cell-level TWAS in six types of immune cells complemented SLE gene discovery and guided the identification of novel genetic associations. The gene findings shed biological insights into SLE genetic associations.

MRI lesions of the spine in patients with axial spondyloarthritis: an update of lesion definitions and validation by the ASAS MRI working group.

Annals of the Rheumatic Diseases

Spinal MRI is used to visualise lesions associated with axial spondyloarthritis (axSpA). The ASAS MRI working group (WG) updated and validated the definitions for inflammatory and structural spinal lesions in the context of axSpA.

After review of the existing literature on all possible types of spinal MRI pathologies in axSpA, the group (12 rheumatologists and two radiologists) consented on the required revisions of lesion definitions compared with the existing nomenclature of 2012. In a second step, using 62 MRI scans from the ASAS classification cohort, the proposed definitions were validated in a multireader campaign by global (absent/present) and detailed (inflammation and structural) lesion assessment at the vertebral corner (VC), vertebral endplate, facet joints, transverse processes, lateral and posterior elements. Intraclass correlation coefficient (ICC) was used for analysis.

Revisions were made for both inflammatory (bone marrow oedema, BMO) and structural (fat, erosion, bone spur and ankylosis) lesions, including localisation (central vs lateral), extension (VC vs vertebral endplate) and extent (minimum number of slices needed), while new definitions were suggested for the type of lesion based on lesion maturity (VC monomorphic vs dimorphic). The most reliably assessed lesions were VC fat lesion and VC monomorphic BMO (ICC (mean of all 36 reader pairs/overall 9 readers): 0.91/0.92; 0.70/0.67, respectively.

The lesion definitions for spinal MRI lesions compatible with SpA were updated by consensus and validated by a group of experienced readers. The lesions with the highest frequency and best reliability were fat and monomorphic inflammatory lesions at the VC.

Mechanism of action of baricitinib and identification of biomarkers and key immune pathways in patients with active systemic lupus erythematosus.

Annals of the Rheumatic Diseases

To elucidate the mechanism of action of baricitinib, a Janus kinase (JAK) 1/2 inhibitor, and describe immunological pathways related to disease activity in adults with systemic lupus erythematosus (SLE) receiving standard background therapy in a phase II trial.

Patients with SLE were treated with baricitinib 2 mg or 4 mg in a phase II randomised, placebo-controlled study. Sera from 239 patients (baricitinib 2 mg: n=88; baricitinib 4 mg: n=82; placebo: n=69) and 49 healthy controls (HCs) were collected at baseline and week 12 and analysed using a proximity extension assay (Target 96 Inflammation Panel (Olink)). Interferon (IFN) scores were determined using an mRNA panel. Analytes were compared in patients with SLE versus HCs and in changes from baseline at week 12 between baricitinib 2 mg, 4 mg and placebo groups using a restricted maximum likelihood-based mixed models for repeated measures. Spearman correlations were computed for analytes and clinical measurements.

At baseline, SLE sera had strong cytokine dysregulation relative to HC sera. C-C motif chemokine ligand (CCL) 19, C-X-C motif chemokine ligand (CXCL) 10, tumour necrosis factor alpha (TNF-α), TNF receptor superfamily member (TNFRSF)9/CD137, PD-L1, IL-6 and IL-12β were significantly reduced in patients treated with baricitinib 4 mg versus placebo at week 12. Inflammatory biomarkers indicated correlations/associations with type I IFN (CCL19, CXCL10, TNF-α and PD-L1), anti-double stranded DNA (dsDNA) (TNF-α, CXCL10) and Systemic Lupus Erythematosus Disease Activity Index-2000, tender and swollen joint count and worst joint pain (CCL19, IL-6 and TNFRSF9/CD137).

These results suggest that baricitinib 4 mg downregulated key cytokines that are upregulated in patients with SLE and may play a role in a multitargeted mechanism beyond the IFN signature although clinical relevance remains to be further delineated.

NCT02708095.

Lung Ultrasound in Children with Systemic Juvenile Idiopathic Arthritis Associated Interstitial Lung Disease.

Arthritis Care Res

Lung disease associated with Systemic Juvenile Idiopathic Arthritis (sJIA-LD) is a potentially life threating complication in children with sJIA. Although high resolution computed tomography (HRCT) is considered the gold standard imaging modality for evaluating interstitial lung disease (ILD), lung ultrasound (LUS) has shown utility for ILD screening in adults with connective tissue diseases (CTD) at lower cost and without utilizing ionizing radiation. The goals of this pilot study were to describe LUS features in children with known SJIA-LD and to assess the feasibility of LUS in this population.

Children <18 years with sJIA-LD and healthy controls were enrolled. LUS acquisition was performed at 14 lung positions. Demographic, clinical, and HRCT data were collected and reviewed. Feasibility was assessed through patient surveys. LUS findings were qualitatively and semi-quantitatively assessed and compared to HRCT findings.

LUS was performed in 9 children with sJIA-LD and 6 healthy controls and took 12 minutes on average to perform. LUS findings in sJIA-LD included focal to diffuse pleural irregularity, granularity, and thickening, with associated scattered or coalesced B-lines, and subpleural consolidations. LUS findings appeared to correspond to HRCT findings.

LUS in sJIA-LD reveals highly conspicuous abnormalities in the pleura and sub-pleura that appear to correlate with peripheral lung findings on HRCT. LUS is a feasible imaging tool in children even from an early age. This study suggests a potential role of LUS in sJIA-LD screening, diagnosis, and/or prognostication.

The impact of clinical association between gout and dementia: a nationwide population-based cohort study in Korea.

Arthritis Care Res

Hyperuricemia might have neuroprotective or neurodegenerative effects on dementia via oxidative stress or inflammatory response regulation. Few studies have explored the association of hyperuricemia or gout with dementia. This retrospective cohort study aimed to investigate the association between gout and dementia in Korea.

Altogether, 5,052 gout patients and 25,260 age- and sex-matched controls were selected from the National Health Insurance Service-National Sample Cohort (NHIS-NSC) database. The incidence and risk of dementia was evaluated by reviewing the NHIS record. We also performed a subgroup analysis according to age group (<65 or ≥65 years old) based on the age of 65, the standard for elderly and non-elderly groups and sex.

During follow-up, 81 and 558 participants in the gout and control cohorts developed dementia, respectively. The mean follow-up duration was 4.38 years in gout patients and 4.94 years in controls. Gout patients showed hazard ratio (HR) 0.79 for overall dementia [95% confidence interval (CI): 0.62-1.00] and significantly lower Alzheimer's disease (AD) risk (HR: 0.73; 95% CI: 0.54-0.98) after adjusting for age, sex, household income, and comorbidities. In subgroup analysis stratified by age and sex, the inverse association between gout and risk of overall dementia (HR: 0.71; 95% CI: 0.52-0.97) and AD (HR: 0.67; 95% CI: 0.46-0.97) were observed in the elderly male group. On the other hand, age, sex-adjusted analysis showed that the HR for vascular dementia of gout patients was 2.31 (95% CI: 1.02-5.25) in non-elderly male group age.

Gout decreased the risk of incident AD-type dementia, especially in elderly patients. The association between gout and dementia risk may differ according to age and disease duration.

Remission and Low-Disease Activity in Granulomatosis with Polyangiitis and Microscopic Polyangiitis: Prevalence and Impact on Damage Accrual.

Arthritis Care Res

To assess the prevalence and impact on damage accrual of different levels of disease activity in patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA).

Patients with GPA and MPA followed for ≥5 years in two different centers were included. Disease activity and damage were assessed using Birmingham Vasculitis Activity Score (BVAS) and Vasculitis Damage Index (VDI), respectively. Three levels of remission were defined: complete remission (CR) [(BVAS=0), negative ANCA, off treatment], clinical remission off therapy [(BVAS=0), positive ANCA] (CROffT) and clinical remission on therapy [(BVAS=0), +/-ANCA, glucocorticoids ≤5 mg/day and/or immunosuppressant] (CROnT). Low-disease activity state (LDAS) was defined as 0<BVAS≤3, low-dose glucocorticoids (≤7.5 mg/day) and/or immunosuppressant. Remission or LDAS were defined as prolonged when lasting ≥2 consecutive years.

167 patients were included: 128 (76.6%) GPA, 39 (23.4%) MPA, mean age 51.0±16.7 years. During 5-year follow-up, 10 (6.0%) patients achieved prolonged CR, 6 (3.6%) prolonged CROffT, 89 (53.3%) prolonged CROnT, 42 (25.1%) prolonged LDAS and 20 (12.0%) never achieved LDAS. VDI at 5 years progressively worsened according to increasing levels of disease activity targets (CR, CROffT, CROnT, LDAS). Mean 5-year VDI was higher in patients not achieving prolonged remission compared to those who did (3.7±2.0 vs. 2.2±1.9, P<0.0001). By multivariate analysis, baseline ENT (P=0.006) and lung involvement (P=0.047) were negative predictors of prolonged remission.

More than 60% of GPA/MPA achieved prolonged remission, which was associated with better long-term outcomes. In contrast, prolonged LDAS correlated with increased damage accrual and was not a sufficient treatment target.

Rising incidence and prevalence of systemic lupus erythematosus: a population-based study over four decades.

Annals of the Rheumatic Diseases

To determine the trends in incidence, prevalence and mortality of systemic lupus erythematosus (SLE) in a US population over four decades.

We identified all the patients with SLE in Olmsted County, Minnesota who fulfilled the European Alliance of Associations for Rheumatology (EULAR)/American College of Rheumatology (ACR) criteria for SLE during 1976-2018. Age-specific and sex-specific incidence and prevalence dates were adjusted to the standard 2000 projected US population. The EULAR/ACR score was used as a proxy for disease severity. Standardised mortality ratio (SMR) was estimated.

There were 188 incident SLE cases in 1976-2018 (mean age 46.3±SD 16.9; 83% women). Overall age-adjusted and sex-adjusted annual SLE incidence per 100 000 population was 4.77 (95% CI 4.09 to 5.46). Incidence was higher in women (7.58) than men (1.89). The incidence rate increased from 3.32 during 1976-1988 to 6.44 during 2009-2018. Incidence rates were higher among the racial and ethnic minority populations than non-Hispanic whites. The EULAR/ACR score did not change significantly over time. Overall prevalence increased from 30.6 in 1985 to 97.4 in 2015. During the study period, there was no improvement in SMR over time (p=0.31).

The incidence and prevalence of SLE are increasing in this US population. The increase in incidence may be at least partially explained by the rising ethnic/racial diversity of the population. There was no evidence that the severity of SLE has changed over time. The survival gap between SLE and the general population remains unchanged. As the US population grows more diverse, we might continue to see an increase in the incidence of SLE.

Concordance and discordance in SLE clinical trial outcome measures: analysis of three anifrolumab phase 2/3 trials.

Annals of the Rheumatic Diseases

In the anifrolumab systemic lupus erythematosus (SLE) trial programme, there was one trial (TULIP-1) in which BILAG-based Composite Lupus Assessment (BICLA) responses favoured anifrolumab over placebo, but the SLE Responder Index (SRI(4)) treatment difference was not significant. We investigated the degree of concordance between BICLA and SRI(4) across anifrolumab trials in order to better understand drivers of discrepant SLE trial results.

TULIP-1, TULIP-2 (both phase 3) and MUSE (phase 2b) were randomised, 52-week trials of intravenous anifrolumab (300 mg every 4 weeks, 48 weeks; TULIP-1/TULIP-2: n=180; MUSE: n=99) or placebo (TULIP-1: n=184, TULIP-2: n=182; MUSE: n=102). Week 52 BICLA and SRI(4) outcomes were assessed for each patient.

Most patients (78%-85%) had concordant BICLA and SRI(4) outcomes (Cohen's Kappa 0.6-0.7, nominal p<0.001). Dual BICLA/SRI(4) response rates favoured anifrolumab over placebo in TULIP-1, TULIP-2 and MUSE (all nominal p≤0.004). A discordant TULIP-1 BICLA non-responder/SRI(4) responder subgroup was identified (40/364, 11% of TULIP-1 population), comprising more patients receiving placebo (n=28) than anifrolumab (n=12). In this subgroup, placebo-treated patients had lower baseline disease activity, joint counts and glucocorticoid tapering rates, and more placebo-treated patients had arthritis response than anifrolumab-treated patients.

Across trials, most patients had concordant BICLA/SRI(4) outcomes and dual BICLA/SRI(4) responses favoured anifrolumab. A BICLA non-responder/SRI(4) responder subgroup was identified where imbalances of key factors driving the BICLA/SRI(4) discordance (disease activity, glucocorticoid taper) disproportionately favoured the TULIP-1 placebo group. Careful attention to baseline disease activity and monitoring glucocorticoid taper variation will be essential in future SLE trials.

NCT02446912 and NCT02446899.