Abstract Objective A minority of patients with ankylosing spondylitis (AS) fail to respond to infliximab treatment. This study compared the circulating infliximab concentration and the presence of clinical symptoms in patients continuously treated with infliximab or after treatment interruption. Methods Patients with active AS were randomly assigned at week 0 to receive infliximab either at weeks 4, 6, 10, and then every 6 weeks (continuous treatment), or at weeks 4, 6, and 10 and then upon symptom recurrence (on‐demand treatment). The circulating concentration of infliximab was determined early during treatment and at weeks 46 and 52 for the continuous treatment group or upon relapse for the on‐demand group. Response in the continuous treatment group was defined at week 58 using the ASsessment in AS International Working Group Criteria for 20% improvement. Results Among the 93 patients in the continuous treatment group, treatment failure was not associated with a low circulating concentration of infliximab, either during early treatment or at 1 year. Eleven (39.2%) of the 28 nonresponders had an infliximab concentration of >10 μg/ml at week 52, whereas 9 (13.8%) of the 65 responders had an infliximab concentration of <1 μg/ml. In the on‐demand group, the infliximab concentration at relapse closely correlated with the time to relapse. However, 24 (36.9%) of 65 patients had a resurgence of clinical symptoms at an infliximab concentration of >10 μg/ml, whereas 25 patients (38.4%) had a relapse at an infliximab concentration of <0.5 μg/ml. Conclusion Responsiveness to infliximab treatment is highly heterogeneous among individuals with AS, and this parameter overcomes the circulating infliximab concentration to explain treatment success or failure.
La prophylaxie des accidents thromboemboliques a pris, ces dernieres annees, une importance dont temoignent de nombreux consensus ou articles de synthese publies sur ce theme [1-5]. Pourtant, deux enquetes realisees dans les hopitaux de l’Assistance publique-Hopitaux de Paris (AP-HP) durant les annees 1993 et 1994 ont montre l’existence de nombreuses variations de pratiques cliniques dans la prophylaxie thromboembolique en milieu chirurgical [6]. Ces variations sont conformes avec ce que d’autres auteurs, dans d’autres domaines de la medecine, ont mis en evidence depuis plus de vingt ans [7].
Periodontal infections are hypothesized to increase the risk of adverse systemic outcomes through inflammatory mechanisms. The magnitude of effect, if any, of anti-infective periodontal treatment on systemic inflammation is unknown, as are the patient populations most likely to benefit. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to test the hypothesis that anti-infective periodontal treatment reduces systemic c-reactive protein (CRP).MEDLINE, EMBASE, CENTRAL and CINAHL databases were searched using sensitivity-enhancing search terms. Eligible RCTs enrolled patients with periodontal infection, compared a clearly defined anti-infective periodontal intervention (experimental group) to an "inactive control" (no periodontal intervention) or to an "active control" (lower treatment intensity than the experimental group). Mean differences in final CRP values at the earliest post-treatment time point (typically 1-3 months) between experimental and control groups were analyzed using random-effects regression. Among 2,753 possible studies 20 were selected, which included 2,561 randomized patients(median=57). Baseline CRP values were >3.0 mg/L in 40% of trials. Among studies with a control group receiving no treatment, the mean difference in CRP final values among experimental treatment vs. control groups was -0.37 mg/L [95%CI=-0.64, -0.11], (P=0.005), favoring experimental treatment. Trials for which the experimental group received antibiotics had stronger effects (P for interaction=0.03) and the mean difference in CRP final values among experimental treatment vs. control was -0.75 mg/L [95%CI=-1.17,-0.33]. No treatment effect was observed among studies using an active treatment comparator. Treatment effects were stronger for studies that included patients with co-morbidities vs. studies that included "systemically healthy" patients, although the interaction was not significant (P=0.48).Anti-infective periodontal treatment results in short-term modest reductions in systemic CRP.
A persistent dilemma when performing meta-analyses is whether all available trials should be included in the meta-analysis.
Objectives
To compare treatment outcomes estimated by meta-analysis of all trials and several alternative analytic strategies: single most precise trial (ie, trial with the narrowest confidence interval), meta-analysis restricted to the 25% largest trials, limit meta-analysis (a meta-analysis model adjusted for small-study effect), and meta-analysis restricted to trials at low overall risk of bias.
Data Sources
One hundred sixty-three meta-analyses published between 2008 and 2010 in high-impact-factor journals and between 2011 and 2013 in the Cochrane Database of Systematic Reviews: 92 (705 randomized clinical trials [RCTs]) with subjective outcomes and 71 (535 RCTs) with objective outcomes.
Data Synthesis
For each meta-analysis, the difference in treatment outcomes between meta-analysis of all trials and each alternative strategy, expressed as a ratio of odds ratios (ROR), was assessed considering the dependency between strategies. A difference greater than 30% was considered substantial. RORs were combined by random-effects meta-analysis models to obtain an average difference across the sample. An ROR greater than 1 indicates larger treatment outcomes with meta-analysis of all trials. Subjective and objective outcomes were analyzed separately.
Results
Treatment outcomes were larger in the meta-analysis of all trials than in the single most precise trial (combined ROR, 1.13 [95% CI, 1.07-1.19]) for subjective outcomes and 1.03 (95% CI, 1.01-1.05) for objective outcomes). The difference in treatment outcomes between these strategies was substantial in 47 of 92 (51%) meta-analyses of subjective outcomes (meta-analysis of all trials showing larger outcomes in 40/47) and in 28 of 71 (39%) meta-analyses of objective outcomes (meta-analysis of all trials showing larger outcomes in 21/28). The combined ROR for subjective and objective outcomes was, respectively, 1.08 (95% CI, 1.04-1.13) and 1.03 (95% CI, 1.00-1.06) when comparing meta-analysis of all trials and meta-analysis of the 25% largest trials, 1.17 (95% CI, 1.11-1.22) and 1.13 (95% CI, 0.82-1.55) when comparing meta-analysis of all trials and limit meta-analysis, and 0.94 (95% CI, 0.86-1.04) and 1.03 (95% CI, 1.00-1.06) when comparing meta-analysis of all trials and meta-analysis restricted to trials at low risk of bias.
Conclusions and Relevance
Estimation of treatment outcomes in meta-analyses differs depending on the strategy used. This instability in findings can result in major alterations in the conclusions derived from the analysis and underlines the need for systematic sensitivity analyses.
Objective. To study the effect of age on the risk–benefit balance of abatacept in RA. Methods. Data from the French orencia and RA registry, including a 2-year follow-up, were used to compare the effectiveness and safety of abatacept according to age. Results. Among the 1017 patients, 103 were very elderly (⩾75 years), 215 elderly (65–74), 406 intermediate aged (50–64) and 293 very young (<50). At baseline, elderly and very elderly patients had longer disease duration, higher CRP levels and higher disease activity. These age groups showed a lower incidence of previous anti-TNF therapy and less common concomitant use of DMARDs, but a similar use of corticosteroid therapy. After adjusting for disease duration, RF/ACPA positivity, use of DMARDs or corticosteroids and previous anti-TNF treatment, the EULAR response (good or moderate) and the remission rate were not significantly different between the four age groups. At 6 months, the very elderly had a significantly lower likelihood of a good response than the very young (odds ratio = 0.15, 95% CI: 0.03, 0.68). The decrease in DAS28-ESR over the 24-month follow-up period did not differ by age. Increasing age was associated with a higher rate of discontinuation for adverse events, especially severe infections (per 100 patient-years: 1.73 in very young, 4.65 in intermediates, 5.90 in elderly, 10.38 in very elderly; P < 0.001). Conclusion. The effectiveness of abatacept is not affected by age, but the increased rate of side effects, especially infections, in the elderly must be taken into account.
In the course of our PubMed searches and preprints from MedRxiv, we identified a number of protocols for RCTs on preventive measures and treatments for Covid-19. This file is updated regularly.
Hand osteoarthritis (HOA) is a frequent painful polyarticular disease which may not respond to any classical therapeutics, leaving the practitioners without any solution.
Objectives
To evaluate anti TNF blocker in patients with painful HOA refractory to analgesics and NSAIDs
Methods
The digital osteoarthritis in refractory hand OA study (DORA), is a phase 3 randomized superiority, double-blind (patients and outcome assessors), parallel, placebo controlled, 26 weeks, multicenter trial (conducted in 16 French clinical site) using TNF blocker adalimumab (2 sub cutaneous injections at week 0 and week 2) Patients meeting the American College of Rheumatology for hand OA with pain over 40mm on a 100mm VAS, (involving at least 3 interphalangeal joints) with at least 3 OA joints at Kellgren Lawrence (KL) grade > 2 on a recent X Rays, and who do not respond to analgesics and NSAIDs, were recruited. The primary endpoint was the proportion of patients with at least 50% improvementin their baseline painscore at week 6. Secondary outcomes were number of spontaneous painful joints, number of painful joints on pressure, number of swollen joints, morning stiffness, patient and practitioner global assessments, functional index of Dreiser and Cochin hand functional index, consumption of analgesics were recorded ( acetaminophen up to 3g/D was the only rescue medication allowed until week 6). Serum markers (COMP, PIINP, AH, usCRP, cytokines level of TNF, IL-6, IL-1) and urine level of CTX-II were measured at W0 and W6.
Results
On the 99 patients selected, 85 were randomized (42 in the placebo group, 41 in the adalimumab group and 2 unknown treatment received). 37 patients in the placebo group and 41 in adalimumab group received at least one injection and were evaluated at week 6 (n=78) (mITT). 35 patients in the placebo group and 38 in the adalimumab group received the two injections. Mean (SD) age was 62.5 (6.9), 85 % of women, mean (SD) level of pain was 65.4 (12.9) mm. At week 6, primary outcome was achieved by 31.7% of adalimumab treated patients compared with 24.3% of placebo-treated patients (relative risk, 1.05; 95% confidence interval, 0.93-1.17). No statistically significant differences were foundfor any of the secondary outcomes. Post hoc analysis in sub group of patients with more than 3 swollen IP at baseline did not shown any difference between groups. Consumption of analgesics was not different between groups. There were no safety concerns. There was none variations of any biological markers between the 2 groups. TNF alpha serum level was not correlated with clinical outcome in the group of patients treated with adalimumab.
Conclusions
In a group of patients with refractory hand OA, TNFalpha blockers (adalimumab, 2 sc injections) failed to demonstrate any clinical improvement
Acknowledgements
Funding academic study supported by The French Section on Osteoarthritis Labortaory Abbott, Inserm Pro A
