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Background We investigated sensitivity of the 2020 Revised Comprehensive Diagnostic Criteria (RCD) and the 2019 ACR/EULAR classification criteria across the four identified IgG4-related disease (IgG4-RD) phenotypes: “Pancreato-Hepato-Biliary”, “Retroperitoneum and Aorta”, “Head and Neck-limited” and “Mikulicz’ and Systemic” in a well-characterized patient cohort. Methods We included adult patients diagnosed with IgG4-RD after comprehensive clinical assessment at Oslo University Hospital in Norway. We assigned patients to IgG4-RD phenotypes based on pattern of organ involvement and assessed fulfillment of RCD and 2019 ACR/EULAR classification criteria. Differences between phenotype groups were analyzed using one-way ANOVA for continuous variables, and contingency tables for categorical variables. Results The study cohort included 79 IgG4-RD patients assigned to the “Pancreato-Hepato-Biliary” (22.8%), Retroperitoneum and Aorta” (22.8%) “Head and Neck-limited” (29.1%), and “Mikulicz’ and Systemic” (25.3%) phenotype groups, respectively. While 72/79 (91.1%) patients in total fulfilled the RCD, proportion differed across phenotype groups and was lowest in the “Retroperitoneum and Aorta” group (66.7%, p  < 0.001). Among the 57 (72.2%) patients meeting the 2019 ACR/EULAR classification criteria, proportion was again lowest in the “Retroperitoneum and Aorta” group (27.8%, p  < 0.001). Conclusion The results from this study indicate that IgG4-RD patients having the “Retroperitoneum and Aorta” phenotype less often fulfill diagnostic criteria and classification criteria than patients with other IgG4-RD phenotypes. Accordingly, this phenotype is at risk of being systematically selected against in observational studies and randomized clinical trials, with potential implications for patients, caregivers and future definitions of IgG4-RD.

AimTo identify subgroups of early rheumatoid arthritis (RA) based on comorbidities and RA manifestations and to investigate their associated risks of cardiovascular events and mortality.MethodsWe included patients with incident RA, diagnosed during 2002–2013 and followed through 2022. Latent class analysis was performed using 29 variables (excluding age) to identify subgroups 1 year after RA diagnosis. Risk of major cardiovascular events (4p-MACE), death, acute coronary syndrome and stroke was compared between groups using Cox regression adjusting for age and sex.ResultsFour subgroups were identified in a cohort of 873 patients with early RA: a ‘cardiometabolic’ group (19%), characterised by a high prevalence of cardiovascular disease (CVD) and diabetes; an ‘elderly-onset’ group (20%), with a high prevalence of polymyalgia rheumatica, anticitrullinated protein antibodies (ACPAs) negativity and less use of disease-modifying antirheumatic drugs (DMARDs); a ‘classic’ group (26%) with extensive joint involvement and the highest C reactive protein (CRP) levels and a ‘young-onset’ group (35%) characterised by ACPA positivity and palindromic arthritis.Compared to the ‘young-onset’ subgroup, both the ‘cardiometabolic’ (HR 2.14, 95% CI 1.20 to 3.79) and ‘elderly-onset’ subgroups (HR 1.89, 95% CI 1.07 to 3.35) had increased MACE risk. However, only the ‘cardiometabolic’ subgroup had increased mortality risk (HR 1.79, 95% CI 1.12 to 2.87).ConclusionFour distinct subgroups were identified with different clinical profiles and outcomes. This underscores the feasibility of data-driven classification in early RA. The ‘cardiometabolic’ and ‘elderly-onset’ subgroups had similarly high MACE risk, but the latter used less DMARDs, antihypertensives and statins, suggesting undertreatment of both RA and CVD risk factors.

Background Anti-citrullinated protein antibody (ACPA) reactivities precede clinical onset of rheumatoid arthritis (RA), and it has been suggested that ACPA reactivities towards distinct target proteins may be associated with differences in RA phenotypes. We aimed to assess the prevalence of baseline ACPA reactivities in an inception cohort of patients with early RA, and to investigate their associations with disease activity, treatment response, ultrasound findings and radiographic damage. Methods Disease-modifying antirheumatic drug (DMARD)-naïve patients with early RA, classified according to the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) criteria, were included in the ARCTIC trial and assessed in the present analysis. During follow up, patients were monitored frequently and treatment was adjusted according to a predetermined protocol, starting with methotrexate monotherapy with prednisolone bridging. Analysis of 16 different ACPA reactivities targeting citrullinated peptides from fibrinogen, alpha-1 enolase, vimentin, filaggrin and histone was performed using a multiplex chip-based assay. Samples from 0, 3, 12 and 24 months were analysed. Controls were blood donors with similar characteristics to the patients (age, gender, smoking status). Results A total of 217 patients and 94 controls were included. Median [25, 75 percentile] number of ACPA reactivities in all patients was 9 [4, 12], and were most prevalent in anti-cyclic citrullinated peptide /rheumatoid factor-positive patients 10 [7, 12]. Disease activity measures and ultrasound scores at baseline were lower in ACPA reactivity-positive compared to ACPA reactivity-negative patients. ACPA reactivity levels decreased after 3 months of DMARD treatment, most pronounced for fibrinogenβ 60–74 to 62% of baseline antibody level, with least change in filaggrin 307–324 to 81% of baseline antibody level, both p  < 0.001. However, outcomes in disease activity measures, ultrasound and radiographic scores after 12 and 24 months were not associated with baseline levels or changes in ACPA reactivity levels and/or seroreversion after 3 months. Conclusions The clinical relevance of analysing ACPA reactivities in intensively treated and closely monitored early RA was limited, with no apparent associations with disease activity, prediction of treatment response or radiographic progression. Further studies in larger patient materials are needed to understand the role of ACPA reactivities in patients with RA classified according to the 2010 ACR/EULAR criteria and treated according to modern treatment strategies. Trial registration www.ClinicalTrials.gov, NCT01205854 . Registered on 21 September 2010.

ObjectivesEvidence as to whether or not giant cell arteritis (GCA) confers added risk of cancer or death is conflicting. Our aim was to identify factors predicting death or cancer in a large Norwegian GCA-cohort.MethodsThis is a retrospective observational cohort study including patients diagnosed with GCA in Western Norway during 1972–2012. Patients were identified through computerized hospital records using the International Classification of Diseases coding. Medical records were reviewed and data about registered deaths and cancer occurrences were extracted from the Norwegian Cause of Death Registry and the Cancer Registry of Norway. We investigated predicting factors using Cox proportional hazards regression.ResultsWe identified 881 cases with a validated diagnosis of GCA (60% biopsy-verified). 490 patients (56%) died during the study period. Among 767 patients with no registered cancer prior to GCA diagnosis, 120 (16%) were diagnosed with cancer during the study period. Traditional risk factors were the main predictors of death; age at time of GCA-diagnosis [hazard ratio (HR) 2.81], smoking (HR 1.61), hypertension (HR 1.48) and previous cardiovascular disease (HR 1.26). Hemoglobin (Hb) level was also associated with risk of death with increasing Hb-levels at time of GCA-diagnosis indicating decreased risk of death (HR 0.91). Other GCA-related factors were not predictive of death. We did not identify any predictors of cancer risk.ConclusionIn our cohort of GCA-patients, the risk of death was predominantly predicted by age and traditional risk factors. We found no significant associations with regards to the risk of incident cancer.

ObjectivesThe reproductive health of men with inflammatory joint disease (IJD) has been a topic of debate in recent years, due to conflicting findings in existing research. In this study, we investigated childlessness and number of children per man, according to the joint diseases psoriatic arthritis (PsA), rheumatoid arthritis (RA) and axial spondylarthritis (axSpA). Furthermore, we studied the timing of fathering and risk factors associated with childlessness.MethodsThis is a nationwide, population-based cohort study. Male patients aged 25–65 years with PsA (n=2649), RA (n=1716) and axSpA (n=2766) from the Norwegian Arthritis Registry were individually matched 1:5 with men without IJDs obtained from the National Population Register (n=35 655). Information on children was obtained from the Medical Birth Registry of Norway. Fertility rates were compared between the patient/IJD groups and matched controls.ResultsIn all IJD groups, fewer men were childless compared with the control groups (p<0.001). Similarly, the mean number of children per man was higher in all diagnostic groups, and this difference was evident before the IJD diagnosis (p<0.001). AxSpA patients had a slightly higher proportion of childless men compared with patients with PsA (p<0.001). Also, men with IJD were younger than the respective controls when fathering for the first time (p<0.001).ConclusionThis large nationwide study revealed that men with PsA, RA and axSpA were less childless compared with the general population, a difference that occurred before the onset of the IJD. These findings are novel, suggesting a notable difference in fertility patterns between those with and without IJDs.

Correspondence to Dr Maria Karolina Jonsson, Bergen Group of Epidemiology and Biomarkers in Rheumatic Disease, Department of Rheumatology, Haukeland University Hospital, Bergen 5021, Norway; jonssonmk@gmail.com We appreciate the additional data regarding calprotectin and radiographic progression provided by Chevreau et al 1 as an eLetter addressing our published research paper.2 It is important to explore new biomarkers in different cohorts of patients with early and established rheumatoid arthritis (RA). When introducing baseline van der Heijde modified Sharp erosion score in the multivariate model (including erythrocyte sedimentation rate, C reactive protein, age, gender, Clinical Disease Activity Index and rheumatoid factor (RF)), baseline erosion score was a significant predictor of radiographic progression (OR 1.14, 95% CI 1.02 to 1.28; table 1). CDAI, Clinical Disease Activity Index; CRP, C reactive protein; ESR, erythrocyte sedimentation rate; h, hour; L, liter; mg, milligram; mm, millimeter; OR, odds ratio; Ref, reference category (lowest quartile as reference); RF, rheumatoid factor; µg, microgram; vdHS, van der Heijde modified Sharp.

Background In Norway, an annual tender system for the prescription of biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) has been used since 2007. This study aimed to explore annual b/tsDMARDs costs and disease outcomes in Norwegian rheumatoid arthritis (RA) patients between 2010 and 2019 under the influence of the tender system. Methods RA patients monitored in ordinary clinical practice were recruited from 10 Norwegian centers. Data files from each center for each year were collected to explore demographics, disease outcomes, and the prescribed treatment. The cost of b/tsDMARDs was calculated based on the drug price given in the annual tender process. Results The number of registered RA patients increased from 4909 in 2010 to 9335 in 2019. The percentage of patients receiving a b/tsDMARD was 39% in 2010 and 45% in 2019. The proportion of b/tsDMARDs treated patients achieving DAS28 remission increased from 42 to 67%. The estimated mean annual cost to treat a patient on b/tsDMARDs fell by 47%, from 13.1 thousand euros (EUR) in 2010 to 6.9 thousand EUR in 2019. The mean annual cost to treat b/tsDMARDs naïve patients was reduced by 75% (13.0 thousand EUR in 2010 and 3.2 thousand EUR in 2019). Conclusions In the period 2010–2019, b/tsDMARD treatment costs for Norwegian RA patients were significantly reduced, whereas DAS28 remission rates increased. Our data may indicate that the health authorities’ intention to reduce treatment costs by implementing a tender system has been successful.

ObjectivesCalprotectin is an inflammatory marker of interest in rheumatoid arthritis (RA). We evaluated whether the level of calprotectin was associated with disease activity, and if it was predictive of treatment response and radiographic progression in patients with early RA.MethodsPlasma from disease-modifying antirheumatic drug (DMARD)-naïve patients with RA fulfilling 2010 American College of Rheumatology/European League Against Rheumatism classification criteria with symptom duration <2 years was analysed for calprotectin at baseline, and after 1, 3 and 12 months. All patients received treat-to-target therapy, as part of a randomised controlled strategy trial (ARCTIC). The association between calprotectin, erythrocyte sedimentation rate (ESR) and C reactive protein (CRP) and measures of disease activity were assessed by correlations. We used likelihood ratios and logistic regression models to assess the predictive value of the baseline inflammatory markers for treatment response and radiographic damage.Results215 patients were included: 61% female, 82% anti-citrullinated peptide antibody positive, mean (SD) age 50.9 (13.7) years and median (25, 75 percentile) symptom duration 5.8 (2.8, 10.5) months. Calprotectin was significantly correlated with Clinical Disease Activity Index (r=0.32), ESR (r=0.50) and ultrasonography power Doppler (r=0.42) before treatment onset. After 12 months of treatment, calprotectin, but not ESR and CRP, was significantly correlated with power Doppler (r=0.27). Baseline levels of calprotectin, ESR and CRP were not predictive of treatment response, but high levels of calprotectin were associated with radiographic progression in multivariate models.ConclusionsCalprotectin was correlated with inflammation assessed by ultrasound before and during DMARD treatment, and was also associated with radiographic progression. The data support that calprotectin may be of interest as an inflammatory marker when assessing disease activity in different stages of RA.Trial registration numberNCT01205854; Post-results.

Background Biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) are highly effective in treating rheumatoid arthritis (RA), albeit high drug cost has restricted their use in many countries. As a countermeasure, Norway implemented pharmaceutical tendering as a cost-reducing strategy. The aim of this study was to assess the annual proportion of different b/tsDMARDs registered to treat RA patients under the influence of a Norwegian pharmaceutical tendering between 2010 and 2019. Method The data is collected from ten Norwegian outpatient centers. The included patients are categorized as naïve, non-naïve, and current b/tsDMARD users. 13 individual b/tsDMARDs are assessed and compared with the tender rankings from each year. Overview of subcutaneous (sc) with per oral vs. intravenous (iv) and biosimilars vs. non-biosimilar are also described. Result The tender-winning b/tsDMARD was the most or second most used drug in nine out of ten years for naïve users, seven for non-naïve users, and twice for current users. The average sum of the highest and second highest proportion among naïve, non-naïve, and current b/tsDMARD users were 75%, 53%, and 50% during the ten years, respectively. The tender-winning drug was iv in eight out of ten years. However, the average total proportion of sc and per oral b/tsDMARDs was about 70% for naïve b/tsDMARD users, 50% for non-naïve b/tsDMARD users, and 60% for current b/tsDMARD users. The main contributors to sc and per oral b/tsDMARD were etanercept (reference and biosimilar) and certolizumab pegol. The main contributors to iv b/tsDMARD were rituximab reference and infliximab biosimilar. Despite low-ranking offers, rituximab reference (offered as a second-line drug) often achieved a high proportion among non-naïve and current b/tsDMARD users. After the introduction of biosimilars, their average proportion was about 40%, 40%, and 20% for naïve, non-naïve, and current b/tsDMARD users, respectively. Conclusion Based on observed data, a higher tender rank was associated with a higher proportion among naïve and non-naïve b/tsDMARD users. However, in most cases, sc b/tsDMARDs achieved a higher proportion with lower tender ranks than iv b/tsDMARDs with higher tender ranks.

Objectives Although TNF-α inhibitors’ striking effect on clinical symptoms have revolutionised the treatment of ankylosing spondylitis (AS), no certain influence on the development of spinal ankylosis and joint destruction has been documented. We wished to investigate whether improved treatment has affected the use of hip arthroplasty surgery. Methods Using the Norwegian Arthroplasty Register, we selected hip prosthesis procedures performed in patients with AS in 1988–2010 (n=534), and compared the trend in the number of procedures being performed annually in 1988–2002 versus 2003–2010. Patients with osteoarthritis (OA) (n=95094) were used as a control group. Results The frequency of hip prosthesis surgery increased significantly in both groups up until 2002. In 2003–2010, although not statistically significant (p=0.087), there was a trend towards a reduced frequency in the AS group when compared with the expected continued increase as was seen among patients with OA. Mean age at surgery increased significantly (p<0.001) from 49.9 years to 56.4 years when comparing patients with AS up until and after 2002. Conclusions TNF-α inhibitors were introduced to patients with AS in Norway in 2000–2003, and our findings suggest that they may have altered the prognosis by inhibiting or slowing large joint arthritis and thus reducing the need for hip replacement surgery.