Associations of pain sensitisation with tender and painful joint counts in people with hand osteoarthritis: results from the Nor-Hand study

ObjectiveTo examine associations of pain sensitisation with tender and painful joint counts and presence of widespread pain in people with hand osteoarthritis (OA).MethodsPressure pain thresholds (PPT) at a painful finger joint and the tibialis anterior muscle, and temporal summation (TS) were measured in 291 persons with hand OA. We examined whether sex-standardised PPT and TS values were associated with assessor-reported tender hand joint count, self-reported painful hand and total body joint counts and presence of widespread pain using linear and logistic regression analyses adjusted for age, sex, body mass index, education and OA severity.ResultsPeople with lower PPTs at the painful finger joint (measure of peripheral and/or central sensitisation) had more tender and painful hand joints than people with higher PPTs. PPT at tibialis anterior (measure of central sensitisation) was associated with painful total body joint count (beta=−0.82, 95% CI −1.28 to –0.35) and presence of widespread pain (OR=0.57, 95% CI 0.43 to 0.77). The associations between TS (measure of central sensitisation) and joint counts in the hands and the total body were statistically non-significant.ConclusionThis cross-sectional study suggested that pain sensitisation (ie, lower PPTs) was associated with joint counts and widespread pain in hand OA. This knowledge may be used for improved pain phenotyping of people with hand OA, which may contribute to better pain management through more personalised medicine. Further studies are needed to assess whether a reduction of pain sensitisation leads to a decrease in tender and painful joint counts.

Immunogenicity of BNT162b2 mRNA SARS-CoV-2 vaccine in patients with psoriatic arthritis on TNF inhibitors

BackgroundScanty data on the immunogenicity of the BNT162b2 vaccine in patients with psoriatic arthritis (PsA) on Tumor Necrosis Factor inhibitors (TNFi) have been published.ObjectiveTo investigate the humoral response to BNT162b2 vaccination patients with PsA on TNFi, comparing immunogenicity with healthy controls.MethodsForty patients with classified PsA on TNFi undergoing vaccination with the BNT162b2 mRNA SARS-CoV-2 vaccine (BioNTech/Pfizer) were enrolled. Fifteen days after the second shot, serum IgG levels against SARS-CoV-2 (Abbott ARCHITECT i2000SR, positivity cut-off 50 AU/mL) were assayed in all patients. Clinimetrics and treatment data were gathered. TNFi treatment was not discontinued throughout the whole period, whereas methotrexate (MTX) was discontinued for 1 week after each shot in those on combination therapy. Sera from healthcare professionals were considered as healthy controls for 1:1 propensity score matching; any of them was taking medication.Student’s t-test and logistic regression were used for investigating differences in immunogenicity between groups and predictors of antibody response.ResultsClinical Disease Activity Index did not change before and after vaccination (7.06±5.23 to 7.10±5.27, p=0.92).Patients with PsA achieved a positive anti-SARS-CoV-2 IgG level with a mean (±SD) of 13794.44±15 815.42 AU/mL. Although lower, the antibody level was not significantly different from matched controls (19227.4±11.8460.45 AU/mL, p=0.08). In the overall sample, those on MTX (12/80, 15%) had a trend toward lower immune response (p=0.07); glucocorticoid therapy (11/80, 13.8%) predicted lower antibody levels (p=0.04).ConclusionsContinuing TNFi in patients with PsA throughout the vaccination did not hamper immunogenicity.

Immune responses to mRNA vaccines against SARS-CoV-2 in patients with immune-mediated inflammatory rheumatic diseases

BackgroundPatients with immune-mediated rheumatic diseases (IMRDs) are commonly treated with immunosuppressors and prone to infections. Recently introduced mRNA SARS-CoV-2 vaccines have demonstrated extraordinary efficacy across all ages. Immunosuppressed patients were excluded from phase III trials with SARS-CoV-2 mRNA vaccines.AimsTo fully characterise B-cell and T-cell immune responses elicited by mRNA SARS-CoV-2 vaccines in patients with rheumatic diseases under immunotherapies, and to identify which drugs reduce vaccine’s immunogenicity.MethodsHumoral, CD4 and CD8 immune responses were investigated in 100 naïve patients with SARS-CoV-2 with selected rheumatic diseases under immunosuppression after a two-dose regimen of SARS-CoV-2 mRNA vaccine. Responses were compared with age, gender and disease-matched patients with IMRD not receiving immunosuppressors and with healthy controls.ResultsPatients with IMRD showed decreased seroconversion rates (80% vs 100%, p=0.03) and cellular immune responses (75% vs 100%, p=0.02). Patients on methotrexate achieved seroconversion in 62% of cases and cellular responses in 80% of cases. Abatacept decreased humoral and cellular responses. Rituximab (31% responders) and belimumab (50% responders) showed impaired humoral responses, but cellular responses were often preserved. Antibody titres were reduced with mycophenolate and azathioprine but preserved with leflunomide and anticytokines.ConclusionsPatients with IMRD exhibit impaired SARS-CoV-2 vaccine immunogenicity, variably reduced with immunosuppressors. Among commonly used therapies, abatacept and B-cell depleting therapies show deleterious effects, while anticytokines preserved immunogenicity. The effects of cumulative methotrexate and glucocorticoid doses on immunogenicity should be considered. Humoral and cellular responses are weakly correlated, but CD4 and CD8 tightly correlate. Seroconversion alone might not reflect the vaccine’s immunogenicity.

Sleep problems in rheumatoid arthritis over 12 years from diagnosis: results from the Swedish EIRA study

ObjectiveMost studies of rheumatoid arthritis (RA) and sleep have focused on established RA. We here investigate sleep quality and sleep duration in patients with newly diagnosed RA and during 1–12 years after diagnosis.MethodsData were collected on sleep 1–12 years after diagnosis from patients diagnosed 1998–2018 in the Swedish study Epidemiological Investigation of RA. Six sleep domains (sleep problems, non-restorative sleep, insomnia, insufficient sleep, sleep quality perceived as poor and sleep considered a health problem); a global sleep score and time spent in bed were estimated. Using logistic regression, ORs were calculated for each sleep outcome by disease duration. We explored whether pain (low (Visual Analogue Scale=0–20 mm, reference), intermediate=21–70, high=71–100) or functional impairment (Health Assessment Questionnaire>1.0) was associated with problems.ResultsWe had sleep data on 4131 observations (n=3265 individuals). Problems with ≥1 sleep domain (global sleep score) was reported in 1578 observations (38%) and increased with disease duration (OR 1.04, 95% CI 1.02 to 1.07). Median time in bed was 8 hours (Q1-Q3: 7.5–9.0). High-grade pain increased the likelihood of sleep problems ~3–9 fold, and increased functional impairment ~4–8 fold.ConclusionIn this cohort of newly diagnosed patients with RA with access to the current treatment from diagnosis, we did not find any major problems with sleep, and existing sleep problems related mainly to pain and reduced function. Treatment of sleep problems in RA should be guided towards treating the underlying problem causing the sleep disturbance.

Role of synovial fibroblast subsets across synovial pathotypes in rheumatoid arthritis: a deconvolution analysis

ObjectivesTo integrate published single-cell RNA sequencing (scRNA-seq) data and assess the contribution of synovial fibroblast (SF) subsets to synovial pathotypes and respective clinical characteristics in treatment-naïve early arthritis.MethodsIn this in silico study, we integrated scRNA-seq data from published studies with additional unpublished in-house data. Standard Seurat, Harmony and Liger workflow was performed for integration and differential gene expression analysis. We estimated single cell type proportions in bulk RNA-seq data (deconvolution) from synovial tissue from 87 treatment-naïve early arthritis patients in the Pathobiology of Early Arthritis Cohort using MuSiC. SF proportions across synovial pathotypes (fibroid, lymphoid and myeloid) and relationship of disease activity measurements across different synovial pathotypes were assessed.ResultsWe identified four SF clusters with respective marker genes: PRG4+ SF (CD55, MMP3, PRG4, THY1neg); CXCL12+ SF (CXCL12, CCL2, ADAMTS1, THY1low); POSTN+ SF (POSTN, collagen genes, THY1); CXCL14+ SF (CXCL14, C3, CD34, ASPN, THY1) that correspond to lining (PRG4+ SF) and sublining (CXCL12+ SF, POSTN+ + and CXCL14+ SF) SF subsets. CXCL12+ SF and POSTN+ + were most prominent in the fibroid while PRG4+ SF appeared highest in the myeloid pathotype. Corresponding, lining assessed by histology (assessed by Krenn-Score) was thicker in the myeloid, but also in the lymphoid pathotype + the fibroid pathotype. PRG4+ SF correlated positively with disease severity parameters in the fibroid, POSTN+ SF in the lymphoid pathotype whereas CXCL14+ SF showed negative association with disease severity in all pathotypes.ConclusionThis study shows a so far unexplored association between distinct synovial pathologies and SF subtypes defined by scRNA-seq. The knowledge of the diverse interplay of SF with immune cells will advance opportunities for tailored targeted treatments.

Vessel inflammation and morphological changes in patients with large vessel vasculitis: a retrospective study

ObjectiveThe aim was to identify any association between imaging signs of vessel wall inflammation (positron emission tomography–CT (PET-CT) score and CT/MR wall thickening) and synchronous and subsequent vascular damage (stenoses/dilations) in patients with large vessel vasculitis (LVV).MethodsConsecutive patients with LVV referred to a tertiary centre in 2007–2020 with baseline PET-CT and morphological imaging (CT/MR angiography) performed within 3 months were included. All available PET-CT and CT/MR scans were reviewed to assess PET-CT uptake (4-point semi-quantitative score), wall thickening, stenoses and dilations for 15 vascular segments. The associations of baseline PET score and CT/MR wall thickening with synchronous and incident stenoses/dilations at CT/MR performed 6–30 months from baseline were evaluated in per-segment and per-patient analyses. Respective areas under the receiver operating characteristic curve (AUC) were calculated.ResultsWe included 100 patients with LVV (median age: 48 years, 22% males). Baseline PET score and wall thickening were strongly associated (Cuzick non-parametric test for trend across order groups (NPtrend) <0.001). The association with synchronous stenoses/dilations was weak for PET score (NPtrend=0.01) and strong for wall thickening (p<0.001). In per-patient analyses, sensitivity/specificity for ≥1 synchronous stenoses/dilations were 44%/67% for PET score ≥2 and 66.7%/60.5% for wall thickening. Subsequent CTs/MRs were available in 28 patients, with seven incident stenoses/dilations. Baseline PET score was strongly associated with incident stenoses/dilations (p=0.001), while baseline wall thickening was not (p=0.708), with AUCs for incident stenoses/dilations of 0.80 for PET score and 0.52 for wall thickening.ConclusionPET score and wall thickening are strongly associated, but only baseline PET score is a good predictor of incident vessel wall damage in LVV.

Role of clinical and biochemical inflammation in structural progression of patients with psoriatic arthritis

ObjectiveTo determine the contribution of clinical and biochemical inflammation to structural progression of patients with psoriatic arthritis (PsA).MethodsWe analysed patients from the Infliximab Multinational Psoriatic Arthritis Controlled Trial 2 trial (infliximab vs placebo). We obtained total modified Sharp/van-der-Heijde Scores from baseline and year one images, and swollen joint counts (SJC) and levels of C reactive protein (CRP) throughout the second half of year 1 (5 measurements) from 74 placebo-treated patients. We computed radiographic progression, time-averaged SJC (taSJC) and CRP (taCRP) values and assessed their impact on structural progression by logistic regression analysis. We further categorised patients as ‘active’ (+) or ‘inactive’ (−) based on their taSJC (cut-off point: 2/66 joints) and taCRP (cut-off point: 0.5 mg/dL) and compared radiographic progression across three groups (double inactive, single active, double active).ResultsORs for progression were 1.24 (95 % CI 1.04 to 1.47; p=0.016) for taSJC and 6.08 (95 % CI 1.12 to 33.03; p=0.036) for taCRP. When predictors were dichotomised (+ vs −), differences were maintained between taSJC+ and taSJC− patients (1.05±3.21 and 0.56±2.30, respectively), as well as for taCRP+ vs taCRP− patients (1.14±3.23 and 0.05±2.37, respectively). Progression was intermediate in the presence of abnormalities of one but not the other inflammatory variable, indicating increasing radiographic progression with increasing inflammation (p=0.05).ConclusionIn patients with PsA, both clinical and biochemical inflammation have an impact on structural progression. Overall, progression is smallest in the absence of both clinical and biochemical inflammation, higher when either clinical or biochemical inflammation is present and highest with both clinical and biochemical inflammation.

Humoral protection to SARS-CoV2 declines faster in patients on TNF alpha blocking therapies

BackgroundThe persistence of the SARS-CoV2 pandemic, partly due to the appearance of highly infectious variants, has made booster vaccinations necessary for vulnerable groups. Questions remain as to which cohorts require SARS-CoV2 boosters. However, there is a critical lack of data on the dynamics of vaccine responses in patients with chronic inflammatory diseases (CID) undergoing immunosuppressive/disease modifying anti-rheumatic (DMARD) treatment. Here, we present the first data regarding the decline of the vaccine-induced humoral immune responses in patients with CID.Methods23 patients with CID were monitored clinically and for anti-spike IgG and IgA levels, neutralization efficacy and antigen-specific CD4+ T cell responses over the first 6 months after SARS-CoV2 vaccination. 24 healthy individuals were included as controls.ResultsWhile anti-spike IgG-levels declined in CID patients and healthy controls, patients receiving anti-TNF treatment showed significantly greater declines at 6 months post second vaccination in IgG and especially neutralizing antibodies. IgA levels were generally lower in CID patients, particularly during anti-TNF therapy. No differences in SARS-CoV2 spike-specific CD4+ T-cell frequencies were detected.ConclusionAlthough the long-term efficacy of SARS-CoV2 vaccination in CID patients undergoing disease-modifying therapy is still not known, the pronounced declines in humoral responses towards SARS-CoV2 6 months after mRNA vaccination in the context of TNF blockade should be considered when formulating booster regimens. These patients should be considered for early booster vaccinations.

Genetic variants at the RTP4/MASP1 locus are associated with fatigue in Scandinavian patients with primary Sjögren’s syndrome

ObjectivesFatigue is common and severe in primary Sjögren’s syndrome (pSS). The aim of this study was to identify genetic determinants of fatigue in pSS through a genome-wide association study.MethodsPatients with pSS from Norway, Sweden, UK and USA with fatigue and genotype data available were included. After genotype imputation and quality control, 682 patients and 4 966 157 genetic markers were available. Association analysis in each cohort using linear regression with fatigue as a continuous variable and meta-analyses between the cohorts were performed.ResultsMeta-analysis of the Norwegian and Swedish cohorts identified five polymorphisms within the same linkage disequilibrium block at the receptor transporter protein 4 (RTP4)/MASP1 locus associated with fatigue with genome-wide significance (GWS) (p<5×10−8). Patients homozygous for the major allele scored 25 mm higher on the fatigue Visual Analogue Scale than patients homozygous for the minor allele. There were no variants associated with fatigue with GWS in meta-analyses of the US/UK cohorts, or all four cohorts. RTP4 expression in pSS B cells was upregulated and positively correlated with the type I interferon score. Expression quantitative trait loci effects in whole blood for fatigue-associated variants at RTP4/MASP1 and levels of RTP4 and MASP1 expression were identified.ConclusionGenetic variations at RTP4/MASP1 are associated with fatigue in Scandinavian pSS patients. RTP4 encodes a Golgi chaperone that influences opioid pain receptor function and MASP1 is involved in complement activation. These results add evidence for genetic influence over fatigue in pSS.

Risk factors for progression of juvenile-onset non-radiographic axial spondyloarthritis to juvenile-onset ankylosing spondylitis: a nested case–control study

ObjectiveTo evaluate the clinical characteristics of juvenile-onset non-radiographic axial spondyloarthritis (nr-axSpA) and to investigate risk factors associated with progression to juvenile-onset ankylosing spondylitis (JoAS).MethodsA nested case–control study was conducted using the retrospectively collected data of 106 patients with juvenile-onset nr-axSpA (age at disease onset, <16 years) in the Clinical characteristic and Outcome in Chinese Axial Spondyloarthritis study cohort. Baseline demographic and clinical characteristics and prognosis were reviewed. Logistic regression analyses were performed to investigate risk factors associated with progression to JoAS.ResultsOverall, 58.5% of patients with juvenile-onset nr-axSpA presented with peripheral symptoms at disease onset. In 82.1% of these patients, axial with peripheral involvement occurred during the disease course. The rate of disease onset at >12 years and disease duration of ≤10 years were significantly higher in those with progression to JoAS than in those without progression to JoAS (83.0% vs 52.8%, p=0.001; 92.5% vs 56.6%, p<0.001, respectively). Multivariable logistic regression analysis revealed that inflammatory back pain (IBP) (OR 13.359 (95% CI 2.549 to 70.013)), buttock pain (OR 10.171 (95% CI 2.197 to 47.085)), enthesitis (OR 7.113 (95% CI 1.670 to 30.305)), elevated baseline C reactive protein (CRP) levels (OR 7.295 (95% CI 1.984 to 26.820)) and sacroiliac joint-MRI (SIJ-MRI) positivity (OR 53.821 (95% CI 9.705 to 298.475)) were significantly associated with progression to JoAS.ConclusionPeripheral involvement was prevalent in juvenile-onset nr-axSpA. IBP, buttock pain, enthesitis, elevated baseline CRP levels and SIJ-MRI positivity in patients with the disease are associated with higher risk of progression to JoAS.