ObjectivesTo compare 1-year clinical efficacy of (1) initial triple disease-modifying antirheumatic drug therapy (iTDT) with initial methotrexate (MTX) monotherapy (iMM) and (2) different glucocorticoid (GC) bridging therapies: oral versus a single intramuscular injection in early rheumatoid arthritis.MethodsIn a single-blinded randomised clinical trial patients were randomised into three arms: (A) iTDT (methotrexate+sulfasalazine+hydroxychloroquine) with GCs intramuscularly; (B) iTDT with an oral GC tapering scheme and (C) MTX with oral GCs similar to B. Primary outcomes were (1) area under the curve (AUC) of Health Assessment Questionnaire (HAQ) and Disease Activity Score (DAS) and (2) the proportion of patients with radiographic progression.Results281 patients were randomly assigned to arms A (n=91), B (n=93) or C (n=97). The AUC DAS and HAQ were respectively −2.39 (95% CI −4.77 to −0.00) and −1.67 (95% CI −3.35 to 0.02) lower in patients receiving iTDT than in those receiving iMM. After 3 months, treatment failure occurred less often in the iTDT group, resulting in 40% fewer treatment intensifications. The difference in treatment intensifications between the arms required to maintain the predefined treatment goal remained over time. No differences were seen between the two GC bridging therapies. Respectively 21%, 24% and 23% of patients in arms A, B and C had radiographic progression after 1 year. Patients receiving iTDT had more adjustments of their medication owing to adverse events than those receiving iMM.ConclusionsTreatment goals are attained more quickly and maintained with fewer treatment intensifications with iTDT than with iMM. However, no difference in radiographic progression is seen. Both GC bridging therapies are equally effective and, therefore, both can be used.Trial registration numberISRCTN26791028.

Objective. To identify axial spondyloarthritis (SpA) in Dutch primary care patients with chronic low back pain (CLBP), and to design a simple referral model for general practitioners (GPs) that would identify patients at risk for axial SpA. Methods. Patients (ages 20 -45 years) with CLBP were identified from GP records. Assessments included inflammatory back pain questionnaires, medical interviews, physical examinations, HLA-B27, C-reactive protein level, conventional radiography, and magnetic resonance imaging. The outcome measure was axial SpA defined by the Assessment of SpondyloArthritis international Society (ASAS) criteria. Multivariable regression analysis with bootstrapping was used to develop the referral model. Results. A total of 364 patients (mean ؎ SD age 36.3 ؎ 6.8 years) was recruited with a median symptom duration of 9.0 years. Eighty-six patients (24%) fulfilled the ASAS criteria for axial SpA. Of all potential determinants, the ASAS inflammatory back pain questionnaire, good response to nonsteroidal antiinflammatory drugs, family history of SpA, and symptom duration were identified as most relevant for diagnosing axial SpA by multivariable regression analysis related to axial SpA. The shrunken regression coefficients were, respectively, 1.04, 0.83, 0.73, and 0.23. The combination of these 4 items proved a useful area under the receiver operating characteristic curve of 0.75 (SE 0.03). In a simplified score model, at the suggested cutoff value of 1.5, the sensitivity was 83% and specificity was 59%. Conclusion. This study shows that 1 of 4 primary care patients with CLBP was classified as having axial SpA. A preselection in primary care based on a combination of clinical items may be useful to facilitate the identification of patients at risk of axial SpA.

BackgroundVarious cytokines and inflammatory mediators are known to be involved in the pathogenesis of rheumatoid arthritis (RA). We hypothesized that polymorphisms in selected inflammatory response and tissue repair genes contribute to the susceptibility to and severity of RA.MethodsPolymorphisms in TNFA, IL1B, IL4, IL6, IL8, IL10, PAI1, NOS2a, C1INH, PARP, TLR2 and TLR4 were genotyped in 376 Caucasian RA patients and 463 healthy Caucasian controls using single base extension. Genotype distributions in patients were compared with those in controls. In addition, the association of polymorphisms with the need for anti-TNF-α treatment as a marker of RA severity was assessed.ResultsThe IL8 781 CC genotype was associated with early onset of disease. The TNFA -238 G/A polymorphism was differentially distributed between RA patients and controls, but only when not corrected for age and gender. None of the polymorphisms was associated with disease severity.ConclusionsWe here report an association between IL8 781 C/T polymorphism and age of onset of RA. Our findings indicate that there might be a role for variations in genes involved in the immune response and in tissue repair in RA pathogenesis. Nevertheless, additional larger genomic and functional studies are required to further define their role in RA.

After 11 years, initial COBRA combination therapy resulted in numerically lower mortality and similar prevalence of comorbidity compared with initial SSZ monotherapy. In addition, lower progression of joint damage suggests long-term disease modification.

Background Long term studies with treat-to-target therapy are essential to guide treatment strategies. Objectives To compare clinical and radiographic outcomes of 4 treatment strategies in early rheumatoid arthritis (RA) patients after 10 years. Methods The BeSt study enrolled 508 patients with early RA. Patients were randomized to: 1 sequential monotherapy, 2 step-up therapy, 3 initial combination with prednisone, 4 initial combination with infliximab. Treatment adjustments were based on 3-monthly disease activity score (DAS) measurements (DAS>2.4: next step; DAS≤2.4 for ≥6 months: taper to maintenance dose, next if DAS<1.6 for ≥6 months: stop last drug). Functional ability (Health Assessment Questionnaire, HAQ) over time was analyzed with a linear mixed model (LMM). Annual X-rays were scored ine one session by 2 blinded readers with the Sharp van der Heijde Score (SHS). SHS progression was categorized per year into “no” (<0.5), “little” (≥0.5 - ≤5) and “much” (>5) and analyzed over time with a generalized LMM. Results 10 year follow-up was completed by 313 patients (62%). Drop-out rates were lowest in arm 4. Mean age of completers was 61 years and 67% were female. Mean (SD) DAS was 1.6 (0.8) and mean (SD) HAQ was 0.6 (0.6). 82% had a DAS≤2.4, 53% had a DAS<1.6, 15% were in drug-free remission (DFR) with a mean (median) duration of 52 (58) months. After 10 years, 38% were still on the initial treatment step, others had changed medication at least once. Toxicity was similar in all arms. Table 1 shows outcomes per treatment arm. The initial functional improvement achieved during year 1 was maintained during 10 years. Over time HAQ was significantly lower in arm 4 than in arm 2 (0.52 vs 0.70, p=0.03, other differences non-significant). Ten year progression rates were low in all arms. Over time, patients in arm 3 less often developed progression compared to arm 1 (p=0.03, other comparisons non-significant). If progression was present, estimates were 8, 11, 8 and 5 SHS progression in 10 years in arm 1 to 4, respectively. At t=10 years Arm 1 Arm 2 Arm 3 Arm 4 p N=126 N=121 N=133 N=128 DAS, mean ± SD* 1.7±0.7 1.7±0.8 1.5±0.8 1.6±0.8 0.333 HAQ, mean ± SD* 0.6±0.6 0.7±0.6 0.5±0.5 0.5±0.6 0.121 DAS≤2.4, n (%)* 61 (85) 43 (71) 59 (84) 75 (84) 0.102 DAS<1.6, n (%)* 36 (50) 28 (46) 40 (57) 50 (56) 0.507 DFR, n (%)* 11 (14) 11 (15) 12 (15) 13 (13) 0.604 On initial treatment, n (%)* 21 (28) 13 (19) 33 (42) 52 (58) <0.001 Current infliximab use, n (%)* 14 (18) 8 (12) 9 (12) 23 (25) 0.075 Drop out, n (%) 50 (40) 54 (45) 55 (41) 36 (28) 0.041 Patients with SAE, n (%) 62 (49) 51 (42) 61 (46) 66 (52) 0.473 ΔSHS, median (IQR)* 2.0 (0.0–11.0) 2.5 (0.0–13.5) 3.0 (0.3–11.3) 1.5 (0.0–6.0) 0.390 ΔSHS >5, n (%)* 24 (38) 23 (42) 27 (42) 21 (27) 0.190 ΔSHS >10, n (%)* 16 (25) 16 (29) 18 (28) 12 (15) 0.196 *Completers analysis. Conclusions 10 year follow-up in the BeSt study shows the benefit of continued treat-to-target therapy, steering at low disease activity. After initial improvement...

Background Treat-to-target therapy (T2T) is recommended in the treatment of rheumatoid arthritis (RA), but appears not yet fully implemented in daily practice. Objectives To evaluate adherence to a T2T strategy and to determine the rheumatologist's opinion about the study protocol steps, suppression of RA and performance of disease activity score (DAS). Methods During 10 year follow-up rheumatologists in 20 clinics treated 508 early RA patients enrolled in the BeSt study as part of their daily outpatient practice. The protocol required treatment adjustments based on 3-monthly DAS measurements, with treatment intensification aiming to achieve low disease activity (DAS ≤2.4) and tapering and discontinuation steps when the target was met and sustained. Rheumatologists filled in questionnaires about satisfaction with level of RA suppression, agreement with the next protocol step and the DAS as representation of disease activity. We checked adherence to the treatment protocol over time and investigated if questionnaire responses and hypothetical conditions (see results) where rheumatologists might disagree with the DAS were associated with protocol violations, using generalized estimating equations. Results Protocol adherence decreased over time from almost 100% in year 1 to ±60% per visit in year 10, with an average of 79% per visit over 10 years. Rheumatologists mostly agreed with DAS (80-90% of visits over time), and were satisfied with treatment steps in the protocol (75-90% over time) and the level of RA suppression (85-90% over time). Although even then the protocol was mostly followed, the odds for PV increased when the rheumatologist felt the DAS underestimated (Odds Ratio, OR 2.1, 95% confidence interval, CI 1.7-2.5) or overestimated (OR 2.0, 95% CI 1.7-2.3) true disease activity, when the rheumatologist disagreed with the study protocol (OR 2.5, 95% CI 2.1-2.9) or was dissatisfied with the level of RA suppression (OR 1.4, 95% CI 1.2-1.6). The odds for PV were also higher in some specific conditions: when swollen joint count (SJC) was ≤1 and erythrocyte sedimentation rate (ESR) was ≥28 (OR 1.3, 95% CI 1.1-1.5), or when the visual analogue scale of global health of the patient (VASpt) was ≥20 millimetre (mm) higher than the VAS of the physician (VASph) (OR 1.3, 95%CI 1.2-1.5). Other specified conditions as SJC ≤1 and tender joint count ≥2, or SJC ≤1 and VASpt ≥20 mm, or VASph ≥20 mm higher than the VASpt, did not increase the risk of PV. Conclusions Rheumatologists adhered well to the treat-to-target strategy of the BeSt protocol, although over time adherence decreased. This may be because in later years, physicians started taking part in the study who had not taken part in designing the protocol. Rheumatologists mostly agreed with how the DAS represented disease activity and with the treatment protocol steps, and were satisfied with the level of RA suppression. However, when they did not agree or were dissatisfied, protocol deviation was more likely. These results prove the feasibility of DAS targete...

Background Exercise is an important method to control the progression of diabetes. Since diabetes compromises immune function and increases the risk of infectious diseases, we hypothesized that exercise may affect the risk of infection by its immunoprotective effects. However, population-based cohort studies regarding the association between exercise and the risk of infection are limited, especially regarding changes in exercise frequency. The aim of this study was to determine the association between the change in exercise frequency and the risk of infection among patients with newly diagnosed diabetes. Methods Data of 10,023 patients with newly diagnosed diabetes were extracted from the Korean National Health Insurance Service-Health Screening Cohort. Self-reported questionnaires for moderate-to-vigorous physical activity (MVPA) were used to classify changes in exercise frequency between two consecutive two-year periods of health screenings (2009–2010 and 2011–2012). The association between changes in exercise frequency and the risk of infection was evaluated using multivariable Cox proportional-hazards regression. Results Compared with engaging in ≥ 5 times of MVPA/week during both periods, a radical decrease in MVPA (from ≥ 5 times of MVPA/week to physical inactivity) was associated with a higher risk of pneumonia (adjusted hazard ratio [aHR], 1.60; 95% confidence interval [CI], 1.03–2.48) and upper respiratory tract infection (aHR, 1.15; 95% CI, 1.01–1.31). In addition, a reduction of MVPA from ≥ 5 to < 5 times of MVPA/week was associated with a higher risk of pneumonia (aHR, 1.52; 95% CI, 1.02–2.27), whereas the risk of upper respiratory tract infection was not higher. Conclusion Among patients with newly diagnosed diabetes, a reduction in exercise frequency was related to an increase in the risk of pneumonia. For patients with diabetes, a modest level of physical activity may need to be maintained to reduce the risk of pneumonia.

BackgroundRecent studies showed diverging results about mortality trends in patients with rheumatoid arthritis (RA).ObjectivesOur aim was to determine survival after 10 years of treat-to-target therapy in patients with early RA, to compare these survival rates with the general population and to define risk factors for mortality during the 10 years duration of the BeSt study.MethodsThe BeSt study enrolled 508 Dutch patients with early active RA (1987 criteria) who were randomized to: sequential monotherapy, step-up therapy, initial combination including either prednisone or infliximab. During 10 years, all patients were treated-to-target, aiming at a disease activity score (DAS) ≤2.4. Kaplan-Meier curves and the log-rank test were used to compare survival rates in the four treatment strategies. Standardized mortality ratios (SMR) were used to compare the BeSt population to the general Dutch population, matched by age, gender and calendar year. Cox regression analysis was used to calculate hazard ratios (HR) to determine baseline risk factors for increased mortality in the BeSt population. Time dependent Cox regression analysis was used to study DAS during follow-up as a risk factor for mortality.ResultsDuring 10 years, 72 of 508 patients died at a mean age of 75 years. No difference in survival was observed between the treatment strategies (p=0.805) (figure), with 16/126, 15/121, 21/133 and 20/128 deaths in arm 1 to 4, respectively. Based on the general Dutch population, 62 deaths were expected and 72 deaths occurred, resulting in an overall SMR of 1.16 (95% confidence interval, CI 0.92 – 1.46). Comparing the general population to each of the treatment strategies resulted in a SMR (95% CI) of 1.00 (0.61–1.64), 1.02 (0.61–1.69), 1.30 (0.85–1.99) and 1.32 (0.85–2.04) in arm 1 to 4, respectively.In the BeSt population, baseline age (HR 1.13, 95% CI 1.10-1.16), male gender (HR 1.78, 95% CI 1.06-2.99), smoking at baseline (HR 5.19, 95% CI 3.08-8.75) and health assessment questionnaire at baseline (HR 1.89, 95% CI 1.29-2.76) were associated with an increased risk of mortality. Randomization arm was not associated with an increased risk of mortality (arm 1 as reference category; arm 2 HR 0.99, 95% CI 0.49–2.00; arm 3 HR 1.27, 95% CI 0.66–2.44; arm 4 HR 1.25, 95% CI 0.65–2.41). DAS over time showed a trend (HR 1.23, 95% CI 0.96–1.58).ConclusionsAfter 10 years of continued tight controlled treatment in patients with rheumatoid arthritis in the BeSt study, the survival rate was comparable to the general Dutch population, without significant differences between the treatment strategies. Higher age, male gender, smoking and worse functional ability were associated with an increased mortality risk within our study population, as in the general population. These results suggest that treatment targeted at DAS ≤2.4 prevents excess mortality during 10 years after diagnosis, and that the medication used in these strategies does not increase mortality.Disclosure of InterestI. Markusse: None declared, L. Dirven: None declared, H. Han:...