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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.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.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.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.

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.

Objective Biomarkers for diagnosis and progression of osteoarthritis (OA) are lacking. This study was undertaken to identify circulating biomarkers for OA that could predict disease occurrence and/or progression to joint replacement. Methods Using the SomaScan platform, we measured 4,792 proteins in plasma from 37,278 individuals, of whom 12,178 individuals had OA and 2,524 had undergone joint replacement. We performed a case-control study for identification of potential protein biomarkers for hip, knee, and/or hand OA, and a prospective study for identification of biomarkers for joint replacement. Results Among the large panel of plasma proteins assessed, cartilage acidic protein 1 (CRTAC1) was the most strongly associated with both OA diagnosis (odds ratio 1.46 [95% confidence interval 1.41-1.52] for knee OA, odds ratio 1.36 [95% confidence interval 1.29-1.43] for hip OA, and odds ratio 1.33 [95% confidence interval 1.26-1.40] for hand OA) and progression to joint replacement (hazard ratio 1.40 [95% confidence interval 1.30-1.51] for knee replacement and hazard ratio 1.31 [95% confidence interval 1.19-1.45] for hip replacement). Patients with OA who were in the highest quintile of risk of joint replacement, based on known risk factors (i.e., age, sex, and body mass index) and plasma CRTAC1 level, were 16 times more likely to undergo knee replacement within 5 years of plasma sample collection than those in the lowest quintile, and 6.5 times more likely to undergo hip replacement. CRTAC1 was not associated with other types of inflammatory arthritis. A specific protein profile was identified in those patients who had undergone joint replacement prior to plasma sample collection. Conclusion Through a hypothesis-free approach, we identified CRTAC1 in plasma as a novel promising candidate biomarker for OA that is both associated with occurrence of OA and predictive of progression to joint replacement. This biomarker might also be useful in the selection of suitable patients for clinical trial enrollment.

OBJECTIVE To compare the pain course between methotrexate (MTX)-refractory early rheumatoid arthritis (RA) patients randomized to infliximab (IFX) versus sulfasalazine (SSZ) plus hydroxychloroquine (HCQ). METHODS The randomized, controlled, open-label Swedish Pharmacotherapy (SWEFOT) trial enrolled new-onset RA patients from October 2002 to December 2005. After 3 months of receiving MTX, patients not reaching low disease activity (Disease Activity Score in 28 joints score ≤3.2) were randomized to adding IFX (n = 128) or SSZ plus HCQ (n = 130) and followed for 21 months. Here, outcomes included area under the curve (AUC) for visual analog scale (VAS) scores for pain, unacceptable pain (VAS pain score >40 mm [range 0-100]), and unacceptable pain despite inflammation control (refractory pain; VAS pain score >40 plus C-reactive protein level

Publisher's version (útgefin grein), Objective: To investigate the relationship between anti–citrullinated protein antibodies (ACPAs), specific ACPA subspecificities, rheumatoid factor (RF) isotypes, and incident cardiovascular (CV) events in patients with rheumatoid arthritis (RA). Methods: Serum samples from Swedish patients with new-onset RA (diagnosed within 1 year of symptom onset between 1996 and 2009) were centrally typed for anti–cyclic citrullinated peptide 2 (anti-CCP2) antibodies, 20 ACPA subspecificities, and RF isotypes. Patients were followed up longitudinally in nationwide registers to monitor the occurrence of acute coronary syndrome (ACS), stroke, CV-related death, and major adverse CV events (MACE). The association between each serologic marker and CV outcome, and the impact of adjustment for the Disease Activity Score in 28 joints (DAS28), smoking status, and income at baseline, were assessed using Cox proportional hazards models. In addition, associations of serologic markers with all-cause mortality were explored. Results: In total, 2,814 patients with RA were included in the study. The median follow-up was 13 years, during which the CV end points of ACS, stroke, or CV-related death were reported to occur in 375 patients. Occurrence and/or levels of anti-CCP2 were associated with risk of incident ACS (hazard ratio [HR] 1.46, 95% confidence interval [95% CI] 1.03–2.06), stroke (HR 1.47, 95% CI 1.03–2.10), CV-related death (P = 0.024 for association with anti-CCP2 levels), and MACE (HR 1.34, 95% CI 1.06–1.70). Similarly, an association with the number of ACPA subspecificities was observed; however, this could not be attributed to any individual or group of ACPA subspecificities. Presence of IgM-RF was associated with all CV end points except ACS, and IgA-RF was exclusively associated with CV-related death. Adjustment for smoking status, income, and DAS28 scores decreased most of the HRs, whereas IgA-RF remained associated with CV-related death (HR 1.61, 95% CI 1.05–2.48). All of the assessed serologic makers were associated with all-cause mortality. Conclusion: RF isotypes and ACPAs are associated with future CV events in patients with RA. ACPA levels and number of subspecificities seem more important than the occurrence of particular subspecificities, and these associations were not explained by a history of ever smoking., Karolinska institutet (strategic research area epidemiology), The nordic research council (nordforsk), The rheumatology research foundation (foreum), Stiftelsen för Strategisk Forskning, Vetenskapsrådet, Stockholms Läns Landsting, The swedish heart lung foundation

Objective To investigate the frequency of remaining pain in early rheumatoid arthritis (RA) after 3 months of treatment with methotrexate as the only disease modifying antirheumatic drug, with a special focus on patients with a good clinical response. Methods The study base was cases reported to a population-based early RA cohort who had followup data from the Swedish Rheumatology Quality Register (n = 1,241). The Disease Activity Score in 28 joints European League Against Rheumatism (EULAR) response criteria were used to evaluate clinical response to treatment as good, moderate, and no response. The primary end point was remaining pain at the 3-months followup visit, defined as pain >20 mm on a 100-mm visual analog scale (VAS). Results Remaining pain in spite of a EULAR good response at followup was associated with higher baseline disability, using the Health Assessment Questionnaire (adjusted odds ratio [OR] 2.2 [95% confidence interval (95% CI) 1.4–3.4] per unit increase), and less baseline inflammation, using the erythrocyte sedimentation rate (adjusted OR 0.81 [95% CI 0.70–0.93] per 10-mm increase). Similar associations were detected for remaining pain at followup in spite of low inflammatory activity, defined as a C-reactive protein level

Objective Rheumatoid arthritis (RA) clinical trials often exclude patients who have low C‐reactive protein (CRP) levels, which slows enrollment into the trial. The purpose of this study was to determine whether high Multi‐Biomarker Disease Activity (MBDA) scores (>44) in RA patients with low CRP levels (≤10 mg/liter) could be used as a complement to CRP levels >10 mg/liter to enhance patient recruitment without affecting clinical trial outcomes. Methods We evaluated patients from the Swedish Pharmacotherapy (SWEFOT) trial, which did not include any selection criteria for CRP levels. Clinical outcomes were assessed after 3 months of methotrexate (MTX) monotherapy in MTX‐naive RA patients (n = 220) and after 3–10 months of add‐on therapy in patients who were incomplete responders to MTX alone (MTX‐IR) (n = 127). Radiographic outcomes were assessed at 1 year in all patients. Within each cohort, the outcomes were compared between patients with a CRP level of ≤10 mg/liter and an MBDA score of >44 at the start of the respective treatment interval versus those with a CRP level of >10 mg/liter. Results Patients with both a CRP level of ≤10 mg/liter and an MBDA score of >44 at baseline had clinical and radiographic outcomes that were comparable to those in patients with a CRP level of >10 mg/liter at baseline. This broadened definition of the inclusion criteria identified an additional 24% of patients in the MTX‐naive cohort and 47% in the MTX‐IR cohort. Conclusion Patient recruitment into RA clinical trials may be substantially enhanced, without any decrease in clinical and radiographic outcomes, by using as an inclusion criterion “a CRP level of >10 mg/liter and/or an MBDA score of >44.”

Objective To investigate the association between life events and the risk for rheumatoid arthritis (RA) with and without antibodies to citrullinated protein (ACPAs). Methods We used data from a population-based case–control study of individuals ages 18–70 years living in geographically defined parts of Sweden between May 1996 and November 2009. We included incident cases (n = 2,774) diagnosed by rheumatologists according to the American College of Rheumatology 1987 criteria for RA and randomly selected controls (n = 3,911) matched to the cases by age, sex, and area of residence. All of the participants answered a questionnaire consisting of questions about 15 life events. We calculated odds ratios (ORs) and 95% confidence intervals (95% CIs) from unconditional logistic regression models adjusted for matching variables and confounding factors. Results Having experienced a life event was weakly associated with ACPA-positive RA as well as ACPA-negative RA (OR 1.1, 95% CI 1.0–1.2 and OR 1.2, 95% CI 1.0–1.4, respectively). The association with ACPA-negative RA was stronger with an increasing number of events (OR 1.4, 95% CI 1.1–1.7 for having experienced ≥3 events versus none). Several particular life events were associated with RA (e.g., “conflict at work,” “change of residence,” “change of work place,” and “increased responsibility at work”). The results were more consistent in women than in men. Conclusion Our study lends support to the concept that certain stressful conditions, here measured as life events, are associated with an increased risk of developing RA.

Objective Production of anti–citrullinated protein antibodies (ACPAs) is an important biomarker for rheumatoid arthritis (RA). We undertook this study to determine whether genetic factors (HLA—DRB1 alleles) are associated with extreme ACPA levels in individuals with ACPA-positive RA, and to ascertain whether there are any phenotypic characteristics associated with these subgroups of RA. Methods HLA–DRB1 allelic groups were genotyped in 1,073 ACPA-positive RA patients from the Swedish Epidemiological Investigation of Rheumatoid Arthritis study. We found that 283 patients (26.4%) had high ACPA levels (defined as >1,500 units/ml using the Euro-Diagnostica anti-CCP2 test), while the rest of the patients had moderate ACPA levels and served as the comparison group. A replication group consisted of 235 RA patients. Results No significant differences in baseline disease activity were observed between patients with high and those with moderate ACPA levels. However, the HLA–DRB1*15 allele was associated with high ACPA levels (P = 0.0002). A similar trend was detected in HLA–DRB1*15–positive patients in the replication cohort, with meta-analysis of the discovery and replication cohorts demonstrating an overall effect of HLA–DRB1*15 on development of high ACPA levels in both the discovery and replication cohorts (P < 0.0001 by Mantel-Haenszel test with a fixed-effects model). Conclusion Our data indicate that HLA–DRB1*15 may promote the production of high ACPA levels. Due to the high value of ACPA level scores in the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for RA, the presence of HLA–DRB1*15 may, at least in part, contribute to fulfilling the criteria for RA. This illustrates the complex nature of the genetic regulation of ACPA levels. Additional mechanistic studies of the regulation of ACPAs and ACPA-positive RA are pending.

Objective Anti–tumor necrosis factor α (anti-TNF) therapy is a mainstay of treatment in rheumatoid arthritis (RA). The aim of the present study was to test established RA genetic risk factors to determine whether the same alleles also influence the response to anti-TNF therapy. Methods A total of 1,283 RA patients receiving etanercept, infliximab, or adalimumab therapy were studied from among an international collaborative consortium of 9 different RA cohorts. The primary end point compared RA patients with a good treatment response according to the European League Against Rheumatism (EULAR) response criteria (n = 505) with RA patients considered to be nonresponders (n = 316). The secondary end point was the change from baseline in the level of disease activity according to the Disease Activity Score in 28 joints (▵DAS28). Clinical factors such as age, sex, and concomitant medications were tested as possible correlates of treatment response. Thirty-one single-nucleotide polymorphisms (SNPs) associated with the risk of RA were genotyped and tested for any association with treatment response, using univariate and multivariate logistic regression models. Results Of the 31 RA-associated risk alleles, a SNP at the PTPRC (also known as CD45) gene locus (rs10919563) was associated with the primary end point, a EULAR good response versus no response (odds ratio [OR] 0.55, P = 0.0001 in the multivariate model). Similar results were obtained using the secondary end point, the ▵DAS28 (P = 0.0002). There was suggestive evidence of a stronger association in autoantibody-positive patients with RA (OR 0.55, 95% confidence interval [95% CI] 0.39–0.76) as compared with autoantibody-negative patients (OR 0.90, 95% CI 0.41–1.99). Conclusion Statistically significant associations were observed between the response to anti-TNF therapy and an RA risk allele at the PTPRC gene locus. Additional studies will be required to replicate this finding in additional patient collections.