Per Larsson

Early psoriatic arthritis: short symptom duration, male gender and preserved physical functioning at presentation predict favourable outcome at 5-year follow-up. Results from the Swedish Early Psoriatic Arthritis Register (SwePsA)

Objective The Swedish Early Psoriatic Arthritis Register describes the course of early psoriatic arthritis (PsA) in a real life clinical setting in Sweden. The aim of this study was to obtain information on predictors of clinical outcomes over a 5-year period with special focus on effects of gender, joint patterns, diagnostic delay and initial disease activity. Methods In six centres, patients with signs suggestive of PsA were included in the Swedish Early Psoriatic Arthritis Register within 2 years of symptom onset. CASPAR (classification for psoriatic arthritis) criteria were fulfilled by 197 patients who had passed the 5-year follow-up. Disease activity was measured by the Disease Activity Score including 28 joints (DAS28) and the Disease Activity Index for Psoriatic Arthritis (DAPSA). Remission and minimal disease activity (MDA) were used as outcome measures. Results Mean age at inclusion was 46 years, younger in male than female patients (43 vs 48 years). Mean DAS28 was 3.7 and 3.0 at inclusion and 2.8 and 2.1 at follow-up for women and men, respectively—significantly higher in women at both visits. Likewise, DAPSA scores were significantly higher in women. The degree of improvement (change in DAS28 and DAPSA) was similar. Men achieved MDA or remission (50% vs 33%, 25% vs 13%, respectively) more often, and women had significantly more polyarthritis at inclusion (49% vs 27%) and after 5 years (25% vs 15%). Axial or mono/oligoarticular disease was predominant in men. Independent predictors of MDA at the 5-year follow-up were: shorter symptom duration; greater general well-being (global visual analogue scale); and low Health Assessment Questionnaire at inclusion. Conclusions In early PsA, short delay between onset of symptoms and diagnosis, preserved function, and male gender are the most important predictors of favourable clinical outcome at the 5-year follow-up. Early recognition of PsA and active treatment may be important, particularly in women with polyarticular disease.

The inflammatory milieu in the rheumatic joint reduces regulatory T-cell function.

Regulatory T cells (Tregs) are important for maintaining immune homeostasis, but many studies suggest that Tregs are functionally impaired in autoimmune and chronic inflammatory disorders. In addition, effector T cells may vary in sensitivity toward Treg suppression. Herein, we have studied the interplay between T effectors and Tregs in the rheumatic joint. Synovial Tregs demonstrated a high degree of FOXP3 demethylation and displayed only marginal IL‐17 and virtually no IFN‐γ production following in vitro stimulation, altogether indicating suppressive capacity. Still, the frequency of FOXP3 expression could not predict the degree of suppression. Instead, the inflammatory milieu in the joint, i.e. proliferative capacity of effector T cells and in situ levels of pro‐inflammatory cytokines influenced Treg function. Indeed, blocking IL‐6 or TNF increased the suppression by Tregs in co‐cultures. Additionally, approximately 30% of the synovial FOXP3+ T cells were Ki67+ and hence actively dividing, but proliferation did not overlap with cytokine production, suggesting that these cells represent functional Tregs having met their cognate antigen and expanded in an attempt to alleviate joint inflammation. Overall, our data argue against a general functional deficit in joint‐derived Tregs and instead emphasize the importance of the inflammatory milieu to set the threshold for immune regulation.

Polymorphisms in peptidylarginine deiminase associate with rheumatoid arthritis in diverse Asian populations: evidence from MyEIRA study and meta-analysis

IntroductionThe majority of our knowledge regarding disease-related mechanisms of uncontrolled citrullination and anti-citrullinated protein antibody development in rheumatoid arthritis (RA) was investigated in Caucasian populations. However, peptidylarginine deiminase (PADI) type 4 gene polymorphisms are associated with RA in East Asian populations and weak or no association was found in Caucasian populations. This study explores the association between the PADI4 polymorphisms and RA risk in a multiethnic population residing in South East Asia with the goal of elucidating generalizability of association in non-Caucasian populations.MethodsA total of 320 SNPs from the PADI locus (including PADI1, PADI2, PADI3, PADI4 and PADI6 genes) were genotyped in 1,238 RA cases and 1,571 control subjects from the Malaysian Epidemiological Investigation of Rheumatoid Arthritis (MyEIRA) case-control study. Additionally, we conducted meta-analysis of our data together with the previously published studies of RA from East Asian populations.ResultsThe overall odds ratio (ORoverall) for the PADI4 (rs2240340) allelic model was 1.11 (95% confidence interval (CI) = 1.00 to 1.23, P = 0.04) and for the genotypic model was 1.20 (95% CI = 1.01 to 1.44, P = 0.04). Haplotype analysis for four selected PADI4 SNPs revealed a significant association of one with susceptibility (P = 0.001) and of another with a protective effect (P = 0.02). The RA susceptibility was further confirmed when combined meta-analysis was performed using these data together with data from five previously published studies from Asia comprising 5,192 RA cases and 4,317 control subjects (ORoverall = 1.23 (95% CI = 1.16 to 1.31, Pheterogeneity = 0.08) and 1.31 (95% CI = 1.20 to 1.44, Pheterogeneity = 0.32) in allele and genotype-based models, respectively). In addition, we also detected a novel association of PADI2 genetic variant rs1005753 with RA (ORoverall = 0.87 (95% CI = 0.77 to 0.99)).ConclusionOur study demonstrates an association between PADI4 and RA in the multiethnic population from South East Asia and suggests additional association with a PADI2 gene. The study thus provides further support for the notion that polymorphisms in genes for enzymes responsible for citrullination contribute to RA development in multiple populations of Asian descent.

Diagnostic random bladder biopsies: Reflections from a population-based cohort of 538 patients

Abstract Objective. To assess whether diagnostic random bladder biopsies and the detection of concomitant carcinoma in situ (CIS) have an impact on the frequency of intravesical bacille Calmette–Guérin (BCG) instillations or radical cystectomy; and whether this affects the cancer-specific survival in patients with pTaG3 or pT1G1–G3 transitional cell carcinoma of the urinary bladder. Material and methods. A population-based cohort of 538 patients with newly diagnosed bladder cancer was prospectively registered in the Stockholm County during 1995 and 1996 and followed for more than 5 years. Results. Random biopsies were recommended in all patients but the decision to take biopsies was made by the treating urologist and hence performed in 326 out of 538 patients (61%), which revealed concomitant CIS in 47 patients(14%). Sixty out of 103 (58%) patients with pTaG3 or pT1G1–G3 tumours, in whom random biopsies were performed, received intravesical BCG compared with five out of 22 patients (23%) where random biopsies were not taken (p = 0.004). Moreover, 23 out of 103 patients (22%) with pTaG3 or pT1G1–G3 tumours in whom random biopsies were performed underwent radical cystectomy compared with none out of 22 patients (0%) without random biopsies (p = 0.013). The Cox proportional hazard ratio for death due to bladder cancer in patients with pTaG3 or pT1G1–G3 tumours among patients not having versus having undergone random biopsies was 2.5 (95% confidence interval 1.1–5.6). Conclusion. Patients diagnosed in Stockholm in 1995 or 1996 with pTaG3 or pT1G1–G3 bladder tumours having undergone random bladder biopsies more frequently underwent BCG treatment and radical cystectomy and had higher cancer-specific survival than patients who did not undergo random biopsies.

The Swedish Early Psoriatic Arthritis Registry 5-year Followup: Substantial Radiographic Progression Mainly in Men with High Disease Activity and Development of Dactylitis.

Objective. To describe early radiographic findings in patients from the Swedish psoriatic arthritis (SwePsA) registry, progression of destruction, correlations with clinical disease variables, and predictors of destruction. Methods. Hand and foot radiographs were available for 72 of 197 SwePsA patients followed for 5 years. Clinical data were collected according to the SwePsA protocol. Results. Disease characteristics and clinical improvement were similar in men and women. Radiographic abnormalities were more pronounced in men. Total Wassenberg radiographic score at baseline was 0 in 45% of men and 51% of women. One man and one woman had a score > 10. At 5 years, total score was 0 in 14% of men and 40% of women (p = 0.018); 17% of men and 7% of women had scores > 10. Mean total scores for men and women had increased. Baseline erythrocyte sedimentation rate was associated with baseline total radiographic score. In men, swollen joint count was positively, and in women tender joint count negatively, correlated to total radiographic score. After 5 years, only male scores, mainly hand scores, significantly correlated with 28-joint Disease Activity Score and Disease Activity Index for Psoriatic Arthritis scores, swollen joint count, and dactylitis. Achieving remission or minimal disease activity after 5 years protected against structural damage, mainly in men. Conclusion. Radiographic progression in early PsA was generally slow but substantial. Male sex appears to be a risk factor for early radiographic damage while the presence of baseline radiographic damage and dactylitis developing during followup seem to predict further destruction. Hand and foot radiograph scoring cannot be substituted with clinical signs.

A multicentre, randomised, controlled, open-label pilot study on the feasibility of discontinuation of adalimumab in established patients with rheumatoid arthritis in stable clinical remission.

Objectives Treatment with tumour necrosis factor (TNF) blockers, once started as therapy for rheumatoid arthritis (RA), is usually continued indefinitely. The aim of this trial was to assess the possibility of discontinuing treatment with adalimumab (ADA) while maintaining remission in patients with RA with established disease in stable remission on combination therapy with ADA and methotrexate (MTX). Methods In a randomised, controlled, open-label pilot study of patients with RA in stable remission treated with ADA+MTX, patients were randomised in a 1:1 ratio to continue with ADA plus MTX (arm AM) or MTX monotherapy (arm M) for 52 weeks. Flare was defined as Disease Activity Score (DAS28) ≥2.6 or a change in DAS28 (ΔDAS28) of >1.2 from baseline at any time. Patients in arm M with a flare restarted ADA. The primary end point was the proportion of patients in remission at week 28. Results 31 patients were enrolled in the study and randomised to arm AM (n=16) or arm M (n=15). At 28 weeks, 15/16 patients (94%) and 5/15 patients (33%) in arms AM and M, respectively, were in remission (p=0.001). During the first 28 weeks, 50% (8/16) in the AM arm and 80% (12/15) in the M arm had a flare (p=0.08). The number of patients in the AM and M arms with ≥1 ΔDAS28 >1.2 during the first 28 weeks was 1/16 (6%) and 8/15 (53%), respectively (p=0.005). Conclusions In this study, remission was rarely maintained in patients with long-standing disease who discontinued ADA. Discontinuation may be feasible in only a minority of patients with established RA in stable clinical remission. Trial registration number NCT00808509.

FRI0587 Magnetic Resonance Imaging of the Sacro-Iliac Joints (SI-MRI) in Axial-Spondyloarthritis (AX-SPA): Correlations Between Imaging Findings and Clinical Characteristics

Background SI-MRI is essential for diagnosing and monitoring ax-SpA. How the imaging findings relate to clinical characteristics is still poorly understood. Objectives To clarify the relationships between the findings observed on SI-MRI and the clinical characteristics in ax-SpA. Methods We selected 47 SI-MRI performed on ax-SPA patients between 1994 and 2013. An experienced radiologist reviewed and scored the images according to a modified version of the SPARCC1,2 scoring system for SI-MRI. SI joints were assessed for bone marrow edema (BME), erosions, joint space irregularities subchondral cysts, and contrast enhancement after Gadolinium-DTPA administration. Demographic and clinical data at the time of imaging were collected retrospectively. MRI findings were analysed for correlation with clinical parameters. Results At the time of imaging the patients had mean ± SEM age of 37.4±1.7 and mean disease duration of 9.0±1.6 years. Fifty-three percent were male while the prevalence of HLA-B27 positivity was 52%. Mean disease activity as measured by the BASDAI was 5.4±0.6, while mean ASDAS-ESR was 3.0±0.3 and ASDAS-CRP was 3.1±0.3. The mean BASFI was 4.2±0.8. Mean CRP was 10.1±2.6 mg/L and mean ESR was 17.5±2.6 mm. Twenty-eight percent of the patients received TNF blockers and 60% NSAIDs. Imaging analysis revealed a prevalence of BME of 66% with a mean score of 2.4±0.4. Erosions were detected in 53% of the cases (mean score 1.4±0.3). Subchondral cysts were present in 30%, and joint space irregularities in 45% of the cases. Ankylosis was observed in 8 cases. Contrast enhancement had been performed in 15 scans and its mean score accounted for 1.2±0.3. Interestingly, this feature was significantly associated with systemic inflammation (for CRP: R=0.64, p=0.03; for ESR: R=0.84, p=0.003). The score for BME only showed a trend towards an association with ESR (R=0.30, p=0.09), while it did not associate with the CRP levels (R=0.08, p=0.64), nor with the BASDAI score (R=-0.4, p=0.13) or the ASDAS-ESR (R= -0.3, p=0.42) and ASDAS-CRP ASDAS-CRP (R=-0.38, p=0.25). Chronic damage, as expressed by the erosion mean score was not associated with disease duration (R=0.17, p=0.34) nor with the BASFI index (R=-0.03, p=0.94). Carrying the HLA-B27 antigen did not associate with a higher burden of MRI detectable inflammation or damage. Mean scores of BME in carriers compared to non-carriers (3.5±0.8 vs 2.8±0.7, p=0.47) and of erosions (2.0±0.6 vs 1.6±0.7, p=0.53) did not show statistically significant differences. HLA-B27 positivity was instead associated with a trend towards higher clinical activity by ASDAS-ESR and ASDAS-CRP (p=0.08). Conclusions In patients with ax-SpA SI-MRI findings show poor associations with clinical parameters. Although not routinely performed, the degree of contrast enhancement after Gadolinium-DTPA administration is strongly correlated with the degree of systemic inflammation. This association underlines the importance of its use in the clinical evaluation of ax-SpA patients. References Maksymowych WP, et al, Arthritis Rheum 2005 Oct 15;53(5):703-9. Wick MC, et al, J Rheumatol 2010;37(3):622-7. Disclosure of Interest None declared