Fachklinik 360°

Weight gain and hypertension are well known adverse effects of treatment with high-dose glucocorticoids. To evaluate the effects of 2 years of low-dose glucocorticoid treatment in rheumatoid arthritis (RA). Pooled analysis of 5 randomized controlled trials with 2-year interventions allowing concomitant treatment with disease-modifying antirheumatic drugs. 12 countries in Europe. Early and established RA. Glucocorticoids at 7.5 mg or less prednisone equivalent per day. Coprimary end points were differences in change from baseline in body weight and mean arterial pressure after 2 years in intention-to-treat analyses. Difference in the change of number of antihypertensive drugs after 2 years was a secondary end point. Subgroup and sensitivity analyses were done to assess the robustness of primary findings. A total of 1112 participants were included (mean age, 61.4 years [SD, 14.5]; 68% women). Both groups gained weight in 2 years, but glucocorticoids led, on average, to 1.1 kg (95% CI, 0.4 to 1.8 kg; P<0.001) more weight gain than the control treatment. Mean arterial pressure increased by about 2 mm Hg in both groups, with a between-group difference of -0.4 mm Hg (CI, -3.0 to 2.2 mm Hg; P= 0.187). These results were consistent in sensitivity and subgroup analyses. Most patients did not change the number of antihypertensive drugs, and there was no evidence of differences between groups. Body composition was not assessed, and generalizability to non-European regions may be limited. This study provides robust evidence that low-dose glucocorticoids, received over 2 years for the treatment of RA, increase weight by about 1 kg but do not increase blood pressure. None.

BackgroundInflammatory bowel disease (IBD) is a chronic and recurring intestinal inflammatory disease, that includes Crohn’s disease (CD) and ulcerative colitis (UC). There is no known cure for IBD and its subtypes. It is essential to identify modifiable risk factors and seek potential treatments to slow down the progression or even prevent the onset of these diseases. As one of these factors, physical activity and sedentary time have recently aroused much research interest in the coming years. However, previous observational studies designed to examine the relationship between physical activity, sedentary time and inflammatory bowel diseases have mostly yielded inconsistent results. Furthermore, whether observed associations are causal remains elusive due to reverse causation and residual confounding noted in observational studies.ObjectivesMendelian randomization (MR) assesses causality by using genotypes to simulate randomized trial groups. Herein, we assessed whether lifelong physical activity (i.e., moderate to vigorous intense physical activity [MVPA]) or sedentary time (sedentary behavior at work, sedentary commuting, and leisure screen time [LST]) has the potential causal relationship with the risk for IBD and its subtypes, using a genetically informed method.MethodsInstrumental variables (IVs) for the main exposures in our study were extracted from the latest published meta-analysis of up to 703,901 European individuals in 51 studies on a genome-wide-association study (GWAS) for self-reported MVPA, LST, sedentary commuting, and sedentary behavior at work (minimum n = 159,606; maximum n = 608,595)[1]. Summary statistics for IBD, CD, and UC were retrieved from the up-to-date studies in European ancestry (cases/controls for IBD: 25042/34915; CD: 12194/28072; UC: 12366/33609)[2]. The inverse variance weighted (IVW) method was utilized as the primary MR analysis. Weighted median and MR-Egger were then implemented as complements to the IVW.ResultsMendelian randomization evidence suggested a protective relationship between MVPA and IBD (Figure 1a) (IBD: odds ratio [OR]: 0.67, 95% confidence interval [CI]: 0.47 to 0.95, P = 0.03) and CD (Figure 1b) (OR: 0.53, 95% CI: 0.30 to 0.94, P = 0.03). Greater genetically-predicted LST was associated with higher risks of IBD (Figure 1c) (IBD: OR: 1.21, 95% CI: 1.06 to 1.38, P = 0.004) and CD (Figure 1d) (OR: 1.25, 95% CI: 1.07 to 1.45, P = 0.004). In contrast, there was no statistically significant relationship between MVPA and UC (OR: 0.76, 95% CI: 0.49 to 1.18, P = 0.23). A similar insignificant association was found between LST and UC (OR: 1.12, 95% CI: 0.95 to 1.32, P = 0.18). Furthermore, there was no significant relationship between sedentary behavior at work and IBD (including CD and UC) or between sedentary commuting and IBD (including CD and UC) with a P-value > 0.05.ConclusionOur study provides strong evidence that greater MVPA and lower LST are likely to reduce the risks for IBD and CD. Particular attention should be given to reducing LST and encouraging proper physical activities during the management and treatment of IBD and CD.

BackgroundBDMARD treatments in patients with psoriatic arthritis (PsA) are initiated after insufficient response to csDMARD either in monotherapy or by in parallel continuing csDMARDs. Here, the value of MTX in combination with bDMARDs in PsA is still unclear. We designed an investigator-initiated, randomized, placebo-controlled trial (IIT) in active PsA to examine the potential impact of MTX-continuation or -initiation parallel to newly started UST on different outcomes beyond clinical examination (MSUS; PsASon22 score [1]).ObjectivesTo compare sensitive imaging efficacy outcomes measured by MSUS changes [PsASon22] from week 4 and 24 to baseline in UST+PBO vs UST+MTX (stratified to ongoing or new onset of MTX treatment).MethodsA total of 186 patients with active PsA (defined as TJC≥4, SJC≥4 [68/66 joint count] and DAS28≥3.2) were screened for eligibility. 173 patients were randomized to UST+MTX (new or ongoing) or UST+PBO. 84 patients were included in the subgroup analysis with MSUS scoring of PsASon22 at BL, weeks 4 and 24. Results were compared between the groups with prior MTX treatment (UST+ ongoing MTX or UST+PBO) and with new initiation of MTX to UST (UST+ new MTX or UST+PBO) according to the study design.ResultsBL data were well-balanced between treatment groups (UST+MTX, n=44; UST+PBO, n=40) and subgroups with exception of slightly higher age (mean age 53.3 years) and more (45%) female patients in the UST with ongoing MTX group. All baseline data are shown in Table 1. After UST initiation, improvement of inflammatory activity measured by MSUS using PsASon22 score was seen early at week 4 in all treatment groups. The improvement was delayed in patients with previous MTX failure (“prior MTX”) and, in overall less pronounced compared to the patients without previous MTX treatment (Figure 1). At week 24, clinical meaningful changes in PsASon22 score were seen in all treatment groups but with most prominent differences in both treatment groups with UST+PBO.ConclusionIL12/23 inhibition with UST is an effective treatment for active PsA independent of MTX use. Data from this IIT indicate that additional MTX has no positive impact on UST efficacy for musculoskeletal manifestations such as arthritis and enthesitis measured sensitively by PsASon22 ultrasound score validated for PsA monitoring. Moreover, by monitoring in MSUS, patients on UST monotherapy seem to benefit best from the treatment.Reference[1]Ficjan, A., et al., Ultrasound composite scores for the assessment of inflammatory and structural pathologies in Psoriatic Arthritis (PsASon-Score). Arthritis Res Ther, 2014. 16(5): p. 476.Table 1.Baseline Characteristics: Subgroup analysis on MSUSParameterswith prior MTX, UST + MTXwith prior MTX, UST + Placebowithout MTX, UST + MTXwithout MTX, UST + PlaceboN=20N=17N=24N=23Age [years]53.3 (SD 10.0)46.8 (SD 15.8)45.5 (SD 14.6)45.2 (SD 15.6)Sex [Female]9 (45.0%)6 (35.3%)9 (37.5%)8 (34.8%)BMI [kg/m²]28.0 (SD 6.1)28.5 (SD 5.5)30.4 (SD 4.7)28.1 (SD 4.8)Age at PsA diagnosis [years]47.8 (SD 12.2)42.5 (SD 15.0)42.0 (SD 14.0)40.6 (SD 16.2)PsASon225.0 (1.5 to 13.0)2.0 (1.0 to 8.0)3.0 (1.0 to 7.0)6.0 (3.0 to 10.0)Presence of Enthesitis [LEI > 0]9 (45.0%)7 (41.2%)16 (66.7%)11 (47.8%)Presence of Dactylitis [LOCF]1 (5.0%)1 (5.9%)13 (54.2%)9 (39.1%)TJC68 [LOCF]14.5 (9.0 to 23.5)13.0 (9.0 to 16.0)10.5 (8.0 to 15.0)13.0 (9.0 to 18.0)SJC66 [LOCF]8.5 (6.5 to 20.5)8.0 (6.0 to 10.0)8.0 (7.0 to 12.0)8.0 (5.0 to 10.0)Nail involvement [mtNAPSI > 0]7 (35.0%)9 (52.9%)17 (70.8%)14 (60.9%)BSA [%]2.0 (1.0 to 6.0)1.0 (1.0 to 3.0)5.5 (1.0 to 12.1)2.0 (1.0 to 5.0)PASI2.5 (0.7 to 5.8)1.8 (0.6 to 3.8)7.1 (2.5 to 10.4)4.2 (0.8 to 8.2)HAQ-DI [LOCF]0.8 (0.4 to 1.4)0.9 (0.3 to 1.5)1.1 (0.4 to 1.6)1.0 (0.4 to 1.3)DLQI [LOCF]5.5 (3.0 to 12.5)6.0 (1.0 to 9.0)11.5 (3.0 to 15.5)6.0 (3.0 to 11.0)EQ5D Health Scale VAS100 [LOCF]47.7 (SD 24.1)50.2 (SD 20.2)54.2 (SD 22.9)59.1 (SD 16.0)Figure 1.Improvement in PsASon22 score from baseline to week 4 and 24 (mITT population)Acknowledgements:NIL.Disclosure of InterestsMichaela Köhm Speakers bureau: Janssen, UCB, Pfizer, Novartis, Consultant of: Janssen, UCB, Pfizer, Novartis, Grant/research support from: Janssen, Pfizer, GSK, BMS, Ann Christina Foldenauer Grant/research support from: Janssen, GSK, BMS, Pfizer, Tanja Rossmanith Grant/research support from: Janssen, GSK, Leo, Pfizer, BMS, Siegfried Wassenberg: None declared, Stephanie Finzel: None declared, Arnd Kleyer: None declared, Raoul Bergner: None declared, Rieke Alten: None declared, Herbert Kellner: None declared, Jochen Walter: None declared, Peter Kästner: None declared, Frank Behrens Speakers bureau: Janssen, Pfizer, UCB, Novartis, Consultant of: Janssen, Pfizer, UCB, Novartis, Grant/research support from: Janssen, Pfizer, UCB, Novartis, GSK, BMS.

Background: The optimal dose of rituximab in combination with leflunomide in patients with rheumatoid arthritis (RA) is not known. Methods: In Part 1 (previously reported) of the investigator-initiated AMARA study (EudraCT 2009-015950-39; ClinicalTrials.gov NCT01244958), improvements at week (W)24 were observed in patients randomized to rituximab + leflunomide compared with placebo + leflunomide. In the study reported here (Part 2), Part 1 responders received rituximab 500 or 1000 mg at W24/26 plus ongoing leflunomide. Patients were randomized at baseline to their eventual W24 treatment group. The Part 2 primary outcome was the mean Disease Activity Score-28 joints (DAS28) at W52, based on the last observation carried forward (LOCF) analyses and a two-sided analysis of variance. Patient-reported outcomes (PROs) and adverse events were evaluated. Results: Eighty-three patients received rituximab at W24/26 (31 rituximab→rituximab 1000 mg; 29 rituximab→rituximab 500 mg; 10 placebo→rituximab 1000 mg; 13 placebo→rituximab 500 mg). At W52, there were no significant differences in DAS28 between rituximab doses in patients originally treated with rituximab or those originally treated with placebo. In the Part 1 placebo group, the higher rituximab dose was associated with greater improvements in ACR response rates and some PROs. Adverse events were similar regardless of rituximab dose. Conclusions: Retreatment with rituximab 500 mg and 1000 mg showed comparable efficacy, whereas an initial dose of rituximab 500 mg was associated with lower response rates versus 1000 mg. Reduced treatment response with the lower dose in patients initially treated with placebo may have been influenced by small numbers and baseline disease activity.

To investigate long-term effectiveness and safety of subcutaneous tocilizumab (TCZ-SC) in the routine clinical care of patients with rheumatoid arthritis (RA). ARATA (ML29087) was a prospective, multicentre, observational study of adult patients with active RA initiating therapy with TCZ-SC. The primary effectiveness outcome was the proportion of patients achieving DAS28-ESR <2.6 at week 104. Additional efficacy outcomes included individual DAS28-dcrit responses (improvement of ≥1.8 from baseline), CDAI remission (≤2.8), and patient-reported outcomes (PROs), including Work Productivity and Activity Impairment scores. Adverse event rates were used to evaluate safety and tolerability. Between May 2014 and July 2018, 114 study centres in Germany enrolled 1,300 patients with RA who received at least one dose of TCZ-SC (mean age 57.3 [SD 12.5] years, mean DAS28-ESR of 4.9 [SD 1.3]). At week 104, 58.7% (365/622) patients achieved DAS28-ESR <2.6, 64.0% had an individual DAS28-dcrit response, and 31.4% (241/767) achieved CDAI remission. PROs, including patient global assessment, pain, and fatigue, showed marked improvements from baseline. Work outcomes, including absenteeism (missed work) and presenteeism (productivity while at work), also improved. Injection reactions were rare and no new safety signals occurred. Patients expressed a high level of satisfaction with treatment. Baseline patient characteristics and outcomes were similar for ARATA and ICHIBAN (an observational study of TCZ-IV in Germany), despite different formulations and time periods. The safety and effectiveness of TCZ-SC is maintained over 2 years during routine clinical care. TCZ-SC represents a convenient and effective option for RA patients who prefer SC administration.