Does autoimmune thyroid disease affects rheumatoid arthritis disease activity or response to methotrexate?

Publisher's version (útgefin grein)Objective: To investigate if autoimmune thyroid disease (AITD) impacts rheumatoid arthritis (RA) disease activity or response to methotrexate. Methods A nationwide register-based cohort study of 9 004 patients with new-onset RA from the Swedish Rheumatology Quality Register year 2006-2016, with linkage to other nationwide registers to identify comorbidity with AITD defined as thyroxine prescription before RA diagnosis, excluding non-autoimmune causes. We compared RA disease activity using 28-joint Disease Activity Score (DAS28) and its components, and EULAR response, between patients with and without AITD, using logistic regression. Results At diagnosis, patient reported outcome measures (PROMs; patient global, Health Assessment Questionnaire Disability Index and pain) but not objective disease activity measures (erythrocyte sedimentation rate and swollen joint count) were significantly higher (p<0.05 for all PROMs) among RA patients with AITD compared with those without. The level of DAS28 was 5.2 vs 5.1. By contrast, AITD had little influence on EULAR response to methotrexate at 3 months (OR of non/moderate response=0.95, 95% CI 0.8 to 1.1), nor at 6 months. When stratified by age, however, AITD was more common among EULAR non/moderate responders at 3 and 6 months in patients below 45 years resulting in ORs of non/moderate response of 1.44 (0.76-2.76) and 2.75 (1.04-7.28). Conclusion At diagnosis, RA patients with concomitant AITD score worse on patient reported but not on objective RA disease activity measures, while DAS28 was only marginally elevated. The overall chance of achieving a EULAR good response at 3 or 6 months remains unaffected, although among a limited subgroup of younger patients, AITD may be a predictor for an inferior primary response. © Author(s) (or their employer(s))This work was supported by research grants from the Swedish Research Council, the Swedish Cancer Society, the Swedish HeartLung Foundation, Nordforsk, Vinnova and FOREUM. Financial support information: Dr Askling has acted or acts as PI in agreements between Karolinska Institutet and the following entities, mainly related to the safety monitoring of immunomodulators in rheumatology: Abbvie, BMS, Eli Lilly, Merck, Pfizer, Roche, Samsung Bioepis, Sanofi.Peer Reviewe

Mannan binding lectin as an adjunct to risk assessment for myocardial infarction in individuals with enhanced risk

Inflammation can predispose to myocardial infarction (MI), and mannan binding lectin (MBL) promotes phagocytic clearance of inflammatory agents, but the predictive value of MBL levels for MI is not known. MBL was analyzed in subgroups of the population-based Reykjavik study, a cohort of 19,381 participants recruited from 1967. MBL levels were very stable over time (self correlation: 0.86). In a cross-sectional group from the original cohort (n = 987), high MBL (>1,000 μg/L) was associated with a greatly lowered odds ratio for MI (0.64, P < 0.001). To verify this finding, a nested case control sample (n = 1,309) was randomly selected from the cohort. High MBL at recruitment was also associated with decreased MI risk in this follow-up group, but to a lesser extent and not significant for the whole group, smokers, or hypertensive individuals. However, high MBL was as in the cross-sectional group, associated with greatly decreased MI risk in diabetic (P = 0.02) or hypercholesterolemic individuals (P = 0.004). This also applied to raised erythrocyte sedimentation rate (P = 0.007). Diabetic patients with high MBL did not have a higher MI risk than nondiabetic individuals. Our findings indicate that high MBL may predict decreased likelihood of MI, particularly in diabetics, and are consistent with the possibility that MBL may promote clearance of atherogenic agents

Evaluation of hand bone loss by digital X-ray radiogrammetry as a complement to clinical and radiographic assessment in early rheumatoid arthritis: results from the SWEFOT trial

BACKGROUND: To investigate hand bone loss (HBL) measured by digital X-ray radiogrammetry (DXR) in patients with early rheumatoid arthritis (RA) receiving different treatment regimens, and to evaluate if DXR change rates during the first 12 months correlate with radiological damage after 24 months. METHODS: From the total SWEFOT trial population, 159 patients had hand radiographs correctly timed and taken with same modality to be analyzed with DXR. All patients started treatment with methotrexate. After 3–4 months, patients with DAS28 > 3.2 were randomized to add sulfasalazine and hydroxychloroquine (triple therapy) or infliximab (MTX + INF). Those with DAS28 ≤3.2 were followed in regular care. Radiographic progression over 24 months was scored according to the Sharp van der Heijde score (SHS) and defined as >5 increase in T-SHS over 24 months. Hand bone mineral density (BMD) was measured by DXR at inclusion and 12 months and a change ≥2.5 mg/cm(2)/month was used as a cut-off for HBL. RESULTS: In the MTX responders, triple therapy, and MTX + INF groups, the proportions with HBL were 4.1%, 22.2% and 16.4%, respectively (p = 0.01), and the mean (SD) radiological progression in these groups was 3.91 (6.72), 7.40 (14.63) and 2.72 (4.55) respectively (p = 0.06). Patients with HBL had significantly greater risk for radiographic progression, compared with patients without HBL (odds ratio 3.09, 95% CI =1.20–7.79, p = 0.02). CONCLUSIONS: Non-responders to MTX had a significantly greater risk of HBL than MTX-responders, despite the add-on therapies. Patients with HBL during the 12 months had greater risk of radiographic progression after 24 months. Evaluation of HBL may help to identify patients who are at risk of radiographic progression

Mannan Binding Lectin (MBL) genotypes coding for high MBL serum levels are associated with rheumatoid factor negative rheumatoid arthritis in never smokers

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field.INTRODUCTION: Previous studies have provided inconsistent results on whether variants in the MBL2 gene, coding for the complement-activating mannan-binding lectin (MBL) protein, associate with rheumatoid arthritis (RA). We re-evaluated this in context of the main environmental and genetic risk factors (smoking, HLA-DRB1 'shared epitope' (SE), PTPN22*620W), which predispose to rheumatoid factor (RF) and/or anti-citrullinated-protein antibody (ACPA)-positive RA. METHODS: In this population-based EIRA study, rheumatoid factor (RF), ACPA, smoking, SE and PTPN22*620W status was determined in incident RA cases and matched controls. MBL-high (n = 1330) and MBL-low (n = 1257) genotypes predicting MBL levels were constructed from four promoter and exon-1 polymorphisms in the MBL2 gene. Odds ratios with 95% confidence interval (OR, 95% CI) were calculated by logistic regression. In extended families (n = 316), previously reported data were re-analyzed, considering RF and smoking. RESULTS: MBL-high genotypes tended to be associated with RF-negative (OR = 1.20, 95% CI 0.96-1.51) but not RF-positive (OR = 1.00, 95% CI 0.83-1.20) RA. Results divided by ACPA status did not differ. When stratified for smoking, MBL-high genotype was strongly associated with RF-negative RA in never smokers (OR = 1.82, 95% CI 1.24-2.69) but not in ever smokers (OR = 0.96, 95% CI 0.73-1.30). In never smokers, the association was observed in both the RF-negative/ACPA-negative (OR = 1.67, 95% CI 1.10-2.55) and RF-negative/ACPA-positive subgroups (OR = 3.07, 95% CI 1.37-6.89), and remained on an SE/PTPN22*620W negative background. In the extended families, the reported association between high MBL and RA was in fact confined to never smokers. CONCLUSIONS: High MBL may predispose to RF-negative RA but only in individuals who have never smoked. This illustrates the importance of phenotypic subgrouping in genetic studies.Stockholm county Swedish Medical Research Council Stockholm County Council Flight Attendant Medical Research Institute Swedish Council for Working Life and Social Research King Gustaf V's 80-year foundation Swedish Rheumatism Association Swedish COMBINE project E

Combined Conventional Synthetic Disease Modifying Therapy vs. Infliximab for Rheumatoid Arthritis : Emulating a Randomized Trial in Observational Data

Funding Information: This work was supported by the Swedish Research Council (grant 2016‐01355). S.C.K. is supported by the National Institutes of Health (NIH; grant K24AR078959). Publisher Copyright: © 2022 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.Observational studies are often considered unreliable for evaluating relative treatment effectiveness, but it has been suggested that following target trial protocols could reduce bias. Using observational data from patients with rheumatoid arthritis (RA) in the Swedish Rheumatology Quality Register (SRQ), between 2006 and 2020, we emulated the protocol of the Swedish Farmacotherapy trial (SWEFOT) and compared the results. SWEFOT was a pragmatic trial nested in SRQ, between 2002 and 2005, where methotrexate (MTX) insufficient responders were randomized to receive additional infliximab or sulfasalazine (SSZ) + hydroxychloroquine (HCQ). Patients with RA initiating infliximab (N = 313) or SSZ + HCQ (N = 196) after MTX were identified in SRQ and the Prescribed Drugs Register, mimicking the SWEFOT eligibility criteria. The primary outcome was the proportion of European Alliance of Associations for Rheumatology (EULAR) good responders at 9 months, classifying patients who discontinued treatment as “nonresponders.” Through sensitivity analyses, we assessed the impact of relaxing eligibility criteria. The observed proportions reaching EULAR good response were close to those reported in SWEFOT: 39% (vs. 39% in SWEFOT) for infliximab and 28% (vs. 25%) for SSZ + HCQ. The crude observed response ratio was 1.39 (95% confidence interval (CI) 1.04–1.86), increasing to 1.48 (95% CI 0.98–2.24) after confounding adjustment, compared to 1.59 (95% CI 1.10–2.30) in SWEFOT. Results remained close to SWEFOT when relaxing eligibility criteria until allowing prior disease-modifying anti-rheumatic drug (DMARD) use which reduced the observed difference between treatments. By applying a prespecified trial emulation protocol to observational clinical registry data, we could replicate the results of SWEFOT, favoring infliximab over SSZ + HCQ combination therapy at 9 months.Peer reviewe

Does persistence to methotrexate treatment in early rheumatoid arthritis have a familial component?

Funding Information: Open access funding provided by Karolinska Institute. HW received support for the project from Stiftelsen Anna och Emil Olssons fond, Reumatikerförbundet [grant no R-940868]; Stiftelsen Professor Nanna Svartz Fond [grant no 2020-00334]; Kung Gustav V:s 80 year foundation [grant no FAI-2020-0666]; Karolinska Institutet foundations [grant no 2020-02508 and 2020-02398]. TF and SS were supported by the Swedish Research Council [DNR 2016-01355 and DNR 2018-02803, respectively]. JA was supported by the Swedish Research Council; Nordforsk; Vinnova; Region Stockholm/Karolinska Institutet Funds (ALF) and the Swedish Heart Lung Foundation. Publisher Copyright: © 2022, The Author(s).Objectives: To assess whether persistence to treatment with methotrexate (MTX) in early rheumatoid arthritis (RA) is shared among first-degree relatives with RA and to estimate any underlying heritability. Methods: First-degree relative pairs diagnosed with RA 1999–2018 and starting MTX (in monotherapy) as their first disease-modifying anti-rheumatic drug (DMARD) treatment were identified by linking the Swedish Rheumatology Quality Register to national registers. Short- and long-term persistence to MTX was defined as remaining on treatment at 1 and 3 years, respectively, with no additional DMARDs added. We assessed familial aggregation through relative risks (RR) using log-binomial regression with robust standard errors and estimated heritability using tetrachoric correlations. We also explored the familial aggregation of EULAR treatment response after 3 and 6 months. To mimic the clinical setting, we also tested the association between having a family history of MTX persistence and persistence within the index patient. Results: Familial persistence was not associated with persistence at 1 (RR=1.02, 95% CI 0.87–1.20), only at 3 (RR=1.41, 95% CI 1.14–1.74) years. Heritability at 1 and 3 years was estimated to be 0.08 (95% CI 0–0.43) and 0.58 (95% CI 0.27–0.89), respectively. No significant associations were found between family history and EULAR response at 3 and 6 months, neither overall nor in the clinical setting analysis. Conclusions: Our findings imply a familial component, including a possible genetic element, within the long-term persistence to MTX following RA diagnosis. Whether this component is reflective of characteristics of the underlying RA disease or determinants for sustained response to MTX in itself will require further investigation.Peer reviewe

Cartilage Acidic Protein 1 in Plasma Associates With Prevalent Osteoarthritis and Predicts Future Risk as Well as Progression to Joint Replacements : Results From the UK Biobank Resource

Funding Information: Supported by deCODE genetics/Amgen Inc. Publisher Copyright: © 2022 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.OBJECTIVE: The level of cartilage acidic protein 1 (CRTAC1) in plasma was recently discovered to be associated with osteoarthritis (OA) risk and progression to joint replacement in Iceland. This study was undertaken to validate these findings in an independent population. METHODS: In this study, 1,462 plasma proteins were measured in 54,265 participants from the UK Biobank on the Olink Explore platform. We analyzed the association of plasma proteins with prevalent OA, incident OA, and progression to joint replacement. We assessed the specificity of OA association through comparison of associations with inflammatory joint diseases and with previous joint replacement. RESULTS: The CRTAC1 protein showed the strongest association with prevalent knee OA (odds ratio [OR] 1.34 [95% confidence interval (95% CI) 1.27, 1.41]) and was associated with hip OA (OR 1.19 [95% CI 1.11, 1.28]). It predicted incident diagnosis of OA in the knee (hazard ratio [HR] 1.40 [95% CI 1.35, 1.46]) and hip (HR 1.25 [95% CI 1.19, 1.31]), as well as progression to joint replacement (HR 1.20 [95% CI 1.08, 1.33] for the knee and HR 1.22 [95% CI 1.08, 1.38] for the hip), while no association was found with inflammatory joint diseases. Individuals in the highest quintile of risk based on CRTAC1 level, age, sex, and body mass index had a 10-fold risk of knee or hip OA within 5 years compared to those in the lowest quintile. Adding aggrecan core protein (ACAN) and neurocan core protein (NCAN) to the model improved the prediction of OA but not joint replacement. Furthermore, we replicated the association of CUB domain-containing protein 1 with prior joint replacement. CONCLUSION: Plasma CRTAC1 is a specific biomarker for OA and a predictor of OA risk and progression to joint replacement. Adding ACAN and NCAN protein levels to the CRTAC1 model improved the prediction of OA.Peer reviewe

Social Investment. As a new charity finance tool: using both head and heart

Presenting associations between individual amino acid residues and EULAR response. (DOCX 23 kb

Predicting risk for radiographic damage in rheumatoid arthritis:comparative analysis of the multi-biomarker disease activity score and conventional measures of disease activity in multiple studies

Pathophysiology and treatment of rheumatic disease

Drug Tolerant Anti-drug Antibody Assay for Infliximab Treatment in Clinical Practice Identifies Positive Cases Earlier

Publisher's version (útgefin grein)A subgroup of patients treated with infliximab lose response to the treatment and one reason for this is the development of anti-drug antibodies (ADA). If used optimally, measuring drug and ADA level could lead to a more personalized and efficient treatment regime, and enable identification of ADA-positive patients before the underlying disease flares or allergic reactions occur. With the use of a drug-tolerant ADA assay which can detect ADA irrespective of drug levels in the sample, we determined the impact of ADA on treatment failure to infliximab. The aims of this study were to estimate the real-life optimal serum infliximab (sIFX) level and set a clinical threshold value for a drug-tolerant ADA assay. Trough levels of sIFX were measured with ELISA. Free ADA was measured with two drug-sensitive methods (ELISA and a bioassay) and one drug-tolerant method (PandA). Two real-life cohorts treated with infliximab were included; a cross-sectional cohort including patients with inflammatory rheumatic diseases (n = 270) and a prospective cohort of rheumatoid arthritis (RA) patients (n = 73) followed for 1 year. Normal range of sIFX was estimated from the prospective cohort and an arbitrary optimal drug level was set to be between 1 and 6 μg/mL. Using this range, optimal sIFX was found in only 60% (163/270) of the patients in the cross-sectional cohort. These patients had significantly better treatment response than those with a drug level under 1 μg/mL, who had an ADA frequency of 34% (19/56) using the drug-tolerant method. In the prospective cohort, the drug-tolerant assay could identify 34% (53/155 samples) as ADA positive in samples with sIFX level >0.2 μg/mL. ADA were seldom detected in patients with >1 μg/mL sIFX, with three interesting exceptions. A clinically relevant ADA threshold was determined to be >3 RECL as measured with the drug-tolerant assay. In a real-life setting, there was a substantial number of patients with suboptimal drug levels and a proportion of these had ADA. Both too low and too high drug levels correlated with worse disease, but for different reasons. Adding a drug-tolerant assay enabled detection of ADA earlier and regardless of drug level at time of sampling.We would like to thank all patients for their participation in this study. We would also like to thank Consuelo Gomez, Pascual Gonzalez, Anna G. Mattsson, Arne St?hl, and Yousra Rehouma for excellent technical assistance. Funding. The research leading to these results has received support from Swelife, Stockholm County Council (ALF project) #20140333 and the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115303, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies' in kind contribution. This work was also supported by the grants from Aina (Ann) Wallstr?ms och Mary-Ann Sj?bloms Foundation for Medical Research, Professor Nanna Svartz Foundation, the Gothenburg Medical Society (GLS-889421 to RP), the Swedish Rheumatism Association (R-862061 and R-663511 to RP), Adlerbertska research Foundation and the Regional agreement on medical training and clinical research between the Western G?taland county council and the University of Gothenburg (ALFGBG-926621).Peer Reviewe