Cost-utility of tofacitinib in the treatment of moderate-to-severe rheumatoid arthritis in France: a multi-state Markov model analysis.

OBJECTIVES: This study aimed to evaluate the cost-effectiveness of introducing tofacitinib in second-line therapies after methotrexate failure for rheumatoid arthritis in France. METHODS: Using a Markov model, we simulated a cohort of 10,000 patients based on literature data to compare various treatment strategies. The reference strategy included the four classes of biologics commonly used in France (TNFi, tocilizumab, abatacept, rituximab). The trial strategies additionally included tofacitinib at different introduction positions. The cycle duration was set at 6 months, and the time horizon was a lifetime. The data for severe adverse effects were sourced from the ORAL Surveillance study. RESULTS: Compared to the reference strategy, introducing tofacitinib is a dominant strategy, regardless of its introduction position. Introducing it as the first-line treatment results in the greatest cost savings (€1,679 per patient) while increasing quality-adjusted life years (QALYs) by 0.29. According to the one-way sensitivity analysis, the discount rate and the cost of TNFi were the two variables that most influenced costs, while the change in HAQ score and the discount rate were the two variables that most influenced QALYs. CONCLUSIONS: Our study represents the first assessment of the cost-effectiveness of tofacitinib in France and incorporates the latest adverse effects reported in the literature. It reinforces previously obtained results from other countries. Our study has some limitations, mainly related to the use of data from clinical trials. Our analysis is limited to severe adverse effects, and their cost is extrapolated from the average hospitalisation cost. The estimated costs are therefore underestimated for chronic diseases such as cancer.

New-onset inflammatory bowel diseases among IL-17 inhibitor-treated patients: results from the case-control MISSIL study.

OBJECTIVES: To describe new-onset IBD (new IBD) in patients treated with IL-17 inhibitors (IL-17i), to assess their incidence and to identify their risk factors in real life. METHODS: A French national registry (MISSIL) aimed to report all cases of new IBD in patients treated with IL-17i from January 2016 to December 2019. Using the estimated number of patients treated by IL-17 in France during the study period, the annual incidence rates of new IBD was reported in IL-17i-treated patients. A case-control study was performed with two controls per new IBD case matched by gender, age and underlying inflammatory disease. RESULTS: Thirty-one cases of new IBD under IL-17i were collected: 27 patients treated for spondyloarthritis and four patients for psoriasis. All were observed with secukinumab (SEK). The median time to onset of new IBD symptoms was 4.0 (1.5-7.5) months. SEK was discontinued in all patients. The evolution was favourable with complete resolution (17/31), improvement (7/31) or stabilization (5/31). Two patients died: one due to a massive myocardial infarction and one due to post-colectomy complications. The incidence of new IBD decreased from 0.69/100 patient-years [PY] (7/1010) in 2016 to 0.08/100 PY (6/7951) in 2019. No previous treatment with etanercept (odds ratio [OR] = 0.33, 95% CI: 0.14-0.80, P = 0.014) and low number of previous biologic therapies (OR = 0.67, 95% CI: 0.47, 0.94, P = 0.021) were significantly associated with new IBD. CONCLUSION: The incidence of new IBD was low and decreased from 2016 to 2019. The outcome was favourable in 24 out of 31 patients, but two patients died.

Cut-off value to identify a flare using the Flare Assessment in Rheumatoid Arthritis (FLARE-RA) questionnaire: analysis of the TOSCA study.

OBJECTIVE: The Flare Assessment in RA (FLARE-RA) self-administered questionnaire aims to identify patients who had flare in the interval between two consultations. This study aimed to establish a threshold for FLARE-RA score to identify RA flare. METHODS: The Tocilizumab SubCutAneous study evaluated the efficacy and safety of s.c. tocilizumab (TCZ) to patients with active RA. Disease activity was assessed with the DAS28ESR at baseline and at week 2 (W2), W4, W12 and W24. The FLARE-RA questionnaire was administered at W12 and W24. Patient satisfaction, assessed at baseline and W24 with the Patient Acceptable Symptom State (PASS), was used as a surrogate marker of no flare. A correlation was sought between the FLARE-RA score at W12 and W24 and the area under the receiver operating characteristic (ROC) curve (AUC) for monthly DAS28ESR. The optimal FLARE-RA cut-off below which patient satisfaction reached the PASS was explored with an ROC curve. RESULTS: A total of 139 patients were included (mean age 57.3 ± 13.8 years, 74.1% women, mean RA duration 10.8 ± 9.2 years, mean DAS28ESR 5.8 ± 1.1). The correlation between the FLARE-RA score and DAS28ESR AUC was moderate at all times: ρ = 0.41 at W12 (P < 0.0001) and 0.51 at W24 (P < 0.0001). The optimal cut-off for the FLARE-RA score to identify absence of flare (i.e. an acceptable situation based on the PASS) was 2.3 with an AUC of 0.81. CONCLUSION: FLARE-RA and DAS28ESR assessment differ; we propose a FLARE-RA cut-off of 2.3, below which the situation (i.e. without flare) is acceptable for patients.

Impact of disease activity and treatments on ovarian reserve in patients with rheumatoid arthritis in the ESPOIR cohort.

OBJECTIVES: Patients with RA have a higher prevalence of infertility than the general population. This study sought to examine the impact of RA disease activity and treatments on ovarian reserve measured by serum anti-Müllerian hormone (AMH) levels in the ESPOIR cohort. We sought to better define the indications for fertility preservation. METHODS: Patients and serum analysis data were derived from the French national cohort ESPOIR. Enrolled patients (n = 102; 18-37-year-olds) fulfilled ACR/EULAR 2010 criteria for RA. Serum AMH levels were measured at T0, T6, T12, T24 and T36 months post-diagnosis. The impacts of RA activity (DAS28 and CRP level) and treatments (MTX only or with other medications) were evaluated at each study visit. RESULTS: A gradual decrease in patients' serum AMH levels was observed over time, in line with the descending curve described for healthy women. Serum AMH levels of RA patients in comparison with the values considered normal for age did not reveal any significant differences (P > 0.05). We did not observe any impact of RA treatments. We demonstrated an inverse correlation between AMH variation and disease activity (DAS28: r = -0.27, P = 0.003; CRP: r = -0.16, P = 0.06). CONCLUSION: This is the first study to determine serum AMH levels of a large cohort of RA patients over 36 months. Rapid disease activity control appears to be required to limit changes in the ovarian reserve. Fertility preservation is not likely to be necessary if inflammation is promptly controlled. CLINICALTRIALS.GOV IDENTIFIER: NCT03666091.

Evaluation of the impact of a nurse-led program of patient self-assessment and self-management in axial spondyloarthritis: results of a prospective, multicentre, randomized, controlled trial (COMEDSPA).

OBJECTIVE: To evaluate the impact of a nurse-led program of self-management and self-assessment of disease activity in axial spondyloarthritis. METHODS: Prospective, randomized, controlled, open, 12-month trial (NCT02374749). Participants were consecutive axial spondyloarthritis patients (according to the rheumatologist) and nurses having participated in a 1-day training meeting. The program included self-management: educational video and specific video of graduated, home-based exercises for patients; and self-assessment: video presenting the rationale of tight monitoring of disease activity with composite scores (Ankylosing Spondylitis Disease activity Score, ASDAS/Bath Ankyslosing Spondylitis Disease Activity Index, BASDAI). The nurse trained patients to collect, calculate and report (monthly) ASDAS/BASDAI. Treatment allocation was by random allocation to this program or a comorbidities assessment (not presented here and considered here as the control group). RESULTS: A total of 502 patients (250 and 252 in the active and control groups, respectively) were enrolled (age: 46.7 (12.2) years, male gender: 62.7%, disease duration: 13.7 (11.0) years). After the one-year follow-up period, the adherence to the self-assessment program was considered good (i.e. 79% reported scores >6 times). Despite a lack of statistical significance in the primary outcome (e.g. coping) there was a statistically significant difference in favor of this program for the following variables: change in BASDAI, number and duration of the home exercises in the active group, and physical activity (international physical activity score, IPAQ). CONCLUSION: This study suggests a short-term benefit of a nurse-led program on self-management and self-assessment for disease activity in a young axial spondyloarthritis population in terms of disease activity, exercises and physical activity.

Foot-Worn Inertial Sensors Are Reliable to Assess Spatiotemporal Gait Parameters in Axial Spondyloarthritis under Single and Dual Task Walking in Axial Spondyloarthritis.

The aim of this study was (1) to evaluate the relative and absolute reliability of gait parameters during walking in single- and dual-task conditions in patients with axial spondyloarthritis (axSpA), (2) to evaluate the absolute and relative reliability of dual task effects (DTE) parameters, and (3) to determine the number of trials required to ensure reliable gait assessment, in patients with axSpA. Twenty patients with axSpa performed a 10-m walk test in single- and dual-task conditions, three times for each condition. Spatiotemporal, symmetry, and DTE gait parameters were calculated from foot-worn inertial sensors. The relative reliability (intraclass correlation coefficients-ICC) and absolute reliability (standard error of measurement-SEM and minimum detectable change-MDC) were calculated for these parameters in each condition. Spatiotemporal gait parameters showed good to excellent reliability in both conditions (0.59 < ICC < 0.90). The reliability of symmetry and DTE parameters was low. ICC, SEM, and MDC were better when using the mean of the second and the third trials. Spatiotemporal gait parameters obtained from foot-worn inertial sensors assessed in patients with axSpA in single- and dual-task conditions are reliable. However, symmetry and DTE parameters seem less reliable and need to be interpreted with caution. Finally, better reliability of gait parameters was found when using the mean of the 2nd and the 3rd trials.

A single nucleotide polymorphism of IL6-receptor is associated with response to tocilizumab in rheumatoid arthritis patients.

Biological disease-modifying anti-rheumatic drugs (bDMARDs) have changed care of patients with rheumatoid arthritis (RA). However, bDMARDs are costly, can lead to serious infections, and induce a sustained remission in only 30% of RA patients. In this study, we sought to determine if the clinical response to treatment with Tocilizumab (TCZ), an IL-6 inhibitor, varied with genetic background. The efficacy of TCZ was assessed using the European League Against Rheumatism (EULAR) response criteria, measured after 3 months of treatment in two samples of French RA patients (TOCI and ROC studies). Single nucleotide polymorphisms (SNPs) in 21 candidate genes were genotyped using KasPar method (LGC-genomics, UK) and then analyzed to determine their contribution to variation in the response to treatment. One hundred twenty-three patients in the TOCI group (79.8%) and 48 patients in the ROC group (80%) experienced good or moderate EULAR response. The clinical response to treatment was associated with SNP genotype in the gene IL6R, with patients with the homozygous AA-genotype for rs12083537 (IL6R) showing a significantly better response than homozygous or heterozygous patients with the G allele [TOCI: 87.5% of responders for AA genotype vs. 72.2% for AG or GG genotype (p = 0.018); ROC patients: 89.2% of responders for AA genotype vs. 65.2% for AG or GG genotype, p = 0.044]. A meta-analysis combining data from the two cohorts confirmed the lower response rate in patients carrying a copy of the G allele (OR (95% CI) = 0.35 (0.16-0.61), p = 0.001). No association was found with any of the other SNPs tested.

Calprotectin discriminates septic arthritis from pseudogout and rheumatoid arthritis.

OBJECTIVE: We aimed to determine whether calprotectin and α-defensins could discriminate septic from other inflammatory arthritides. METHODS: Synovial fluids with a predominance of neutrophils from patients with septic arthritis, pseudogout and RA were prospectively collected. Neutrophil-related proteins calprotectin and human neutrophil α-defensins levels were assessed in synovial fluids. Demographic parameters and biomarkers with P-value ⩽0.05 for differentiating septic from non-septic arthritis were included in a multivariable model. Multivariable logistic regression with stepwise selection was performed to build the final combined model. RESULTS: A total of 74 patients were included: septic arthritis (n = 26), pseudogout (n = 28) and RA (n = 20). Patients with septic arthritis were more likely to be male and young, and to display higher synovial neutrophil count. Calprotectin was significantly increased in patients with septic arthritis. The multivariable model included calprotectin, synovial fluid neutrophil count and gender. Calprotectin was the only biomarker that discriminated septic arthritis from non-septic inflammatory arthritides, with 76% sensitivity, 94% specificity and a positive likelihood ratio = 12.2 at the threshold for calprotectin of 150 mg/l. CONCLUSION: Synovial fluid calprotectin is a relevant biomarker to discriminate septic arthritis from other inflammatory arthritides. This biomarker should be tested in an independent cohort.

Short-term Efficiency and Tolerance of Ketoprofen and Methylprednisolone in Acute Sciatica: A Randomized Trial.

OBJECTIVE: Although anti-inflammatory drugs are commonly used in acute discogenic sciatica, data regarding their efficacy are scarce and controversial. We compared the efficacy and safety of intravenous ketoprofen and methylprednisolone with placebo in sciatica. DESIGN: Multicenter, double-blinded randomized controlled trial. SUBJECTS: Patients with confirmed discogenic acute sciatica, without neurologic deficit, were randomized into three arms. METHODS: Besides standard-of-care analgesic therapy, they received intravenous injections of methylprednisolone (60 mg/d) or ketoprofen (200 mg/d) or placebo for five days. The primary outcome was leg pain over five days. Secondary outcomes were clinical responses at days 3 and 5, lumbar pain, Straight Leg Raise Test and lumbar flexion index, analgesic consumption, realization of lumbar spine injections, and surgery during the study period. RESULTS: Fifty-four patients were randomized, and 50 completed the study. In patients admitted to the hospital for pain control with acute lumbar radicular pain due to intervertebral disc herniation and receiving an oral analgesic protocol including paracetamol, nefopam, tramadol, and morphine, there was no additional analgesic effect seen between groups. There was no significant difference in leg pain between the three groups over the study period. In the methylprednisolone group, however, we observed a higher rate of clinically relevant responses at day 3. No difference was observed on other secondary efficacy outcomes and safety. CONCLUSION: No significant difference in leg pain was observed between groups. However, there was a higher proportion of patients relieved with intravenous methylprednisolone at day 3, compared with ketoprofen or placebo.

Gait as predictor of physical function in axial spondyloarthritis: the prospective longitudinal FOLOMI (Function, Locomotion, Measurement, Inflammation) study protocol.

Axial spondyloarthritis (axSpA) is a chronic inflammatory rheumatic disease affecting predominantly sacroiliac joints and axial skeleton. axSpA progression being irregular and hardly predictable, identifying functional decline is particularly important in patient with axSpA to allow delivery of timely and targeted interventions. Pain, reduced range of motion or altered posture can have adverse consequences on gait. Although gait has previously been used as a sensitive measure of physical outcomes in elderly and pathological populations, to the best of our knowledge, no study has used gait as a predictor of physical function in patients with axSpA. The objective of our study is hence to determine if gait parameters measured in patients with axSpA could predict the evaluation at 18 months of physical function as assessed by the Bath Ankylosing Spondylitis Functional Index (BASFI). This is a prospective and longitudinal study. Sixty patients with axSpA and 30 healthy age- and sex-matched controls will be included. Patients should be aged 18-65 years at time of their first evaluation, followed at Grenoble Alpes University Hospital for axSpA or ankylosing spondylitis, able to walk 180 m without technical help and with stable treatment for at least 12 months. Clinical characteristics, BASFI, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), clinical and laboratory measurements of gait will be assessed during four visits (at baseline and at months 6, 12, and 18). Similar assessments will be performed once for the healthy control group. A linear mixed model at 6, 12 and 18 months will be constructed to answer to the first objective, with the BASFI as dependent variable and gait parameters as explanatory variables. The data collection started in August 2018 and will be completed with the inclusion and follow-up of all the participants. We believe that the combination of clinical and laboratory measurements of gait in patients with axSpA could strengthen the capacity to monitor disease's evolution and to predict changes in patients' physical function. Results of the present study could ultimately allow delivering targeted, timely, personalized interventions and treatment in patients with axSpA.Trial registration: The study was approved by local ethic committee (CPP Ile De France 1, RCB: 2017-A03468-45, date of agreement: July 17th, last version: V4.0, 2018, March 5th, 2019) and is retrospectively registered in Clinical trials (NCT03761212).

A randomised, double-blind, placebo-controlled study assessing the efficacy of high doses of vitamin D on functional disability in patients with rheumatoid arthritis.

OBJECTIVES: To evaluate the short-term efficacy of vitamin D (cholecalciferol) supplementation on functional disability in RA patients. METHODS: 1) Patients: RA (ACR 1987 revised criteria) in non-remission (DAS28 >2.6) whose treatment was not expected to be changed over a 3-month period following inclusion and presenting with vitD deficits (serum 25OHD <30ng/mL). 2) Study design: prospective randomised placebo-controlled trial (NCT02243800). 3) Study arms: either vitD ampoules (cholecalciferol 100,000IU) or placebo. 4) Outcome measures: primary: improvement in patients' functional disability using the Health Assessment questionnaire (HAQ); secondary: improvement in DAS28ESR, DAS28CRP, ESR, CRP, RAID score, fatigue (EVA and FACIT), and SF36. RESULTS: Overall, 59 patients were included, 83.1% females, aged 59.8±10.9 years on average, with RA for 17.0±9.7 years. Thirty patients received placebo and 29 vitD. At 6 months, HAQ scores tended to be increased in the placebo group (+0.08±0.25), while slightly numerically decreased in the vitD group (-0.03±0.23) (p=0.11). After adjusting for age, gender, season, and initial vitD status, the between-group difference achieved statistically significance (p=0.046). After adjusting for age, gender, season, and initial vitD status, there was no significant difference in the secondary criteria between the 2 groups except for ESR and CRP (p=0.002 and 0.04, respectively). CONCLUSIONS: In this randomised, double-blind, placebo-controlled clinical trial in patients with RA and VitD deficiency, high doses of cholecalciferol resulted in a statistically significant improvement in functional disability at month 6, which, however, was clinically not relevant.

Safety of surgery in patients with rheumatoid arthritis treated by abatacept: data from the French Orencia in Rheumatoid Arthritis Registry.

Objective: To investigate the frequency and risk factors of postoperative complications in RA patients treated with abatacept (ABA). Methods: The Orencia RA registry recruited 1012 patients receiving ABA for RA in routine care. Data from patients treated with ABA who underwent surgery were reviewed to describe the frequency of postoperative complications. Characteristics of patients and surgeries with and without complications were compared to identify factors associated with complications. Results: We identified 205 (20.3%) patients who underwent 263 surgeries, including 176 (66.9%) orthopaedic surgeries. Nineteen (7.2%) surgeries, in 19 patients (9.3%), entailed complications, including 7 delayed wound healing (2.7% of surgeries) and 6 surgical site infections (2.3% of surgeries). The median time between the last infusion of ABA and surgery was 5.9 weeks (range: 0.3-12.0 weeks), with no significant difference between patients with and without complications. The median corticosteroids daily dosage was higher in the group with complications [10.0 (6.25-15.0) vs 6.0 (5.0-10.0) mg/day, P = 0.042]. In multivariate analysis, only the duration of ABA treatment was significantly associated with postoperative complications [adjusted odds ratio (aOR) = 0.94 (95% CI: 0.89, 0.99) for each month of treatment], as were orthopaedic surgeries compared with other kinds of surgery [aOR = 4.45 (95% CI: 1.01, 20.2)]. Conclusion: In RA patients treated with ABA, the rate of surgical complications was low: 7.2% and higher in case of orthopaedic procedure and a more recent initiation of ABA. The median time between surgery and the last infusion of ABA was short and did not influence the rate of postoperative complications.

Step-down strategy of spacing TNF-blocker injections for established rheumatoid arthritis in remission: results of the multicentre non-inferiority randomised open-label controlled trial (STRASS: Spacing of TNF-blocker injections in Rheumatoid ArthritiS Study).

UNLABELLED: Tumour necrosis factor (TNF)-blocker tapering has been proposed for patients with rheumatoid arthritis (RA) in remission. OBJECTIVE: The trial aims to compare the effect of progressive spacing of TNF-blocker injections (S-arm) to their maintenance (M-arm) for established patients with RA in remission. METHODS: The study was an 18-month equivalence trial which included patients receiving etanercept or adalimumab at stable dose for ≥1 year, patients in remission on 28-joint Disease Activity Score (DAS28) for ≥6 months and patients with stable joint damage. Patients were randomised into two arms: maintenance or injections spacing by 50% every 3 months up to complete stop. Spacing was reversed to the previous interval in case of relapse, and eventually reattempted after remission was reachieved. The primary outcome was the standardised difference of DAS28 slopes, based on a linear mixed-effects model (equivalence interval set at ±30%). RESULTS: 64 and 73 patients were included in the S-arm and M-arm, respectively, which was less than planned. In the S-arm, TNF blockers were stopped for 39.1%, only tapered for 35.9% and maintained full dose for 20.3%. The equivalence was not demonstrated with a standardised difference of 19% (95% CI -5% to 46%). Relapse was more common in the S-arm (76.6% vs 46.5%, p=0.0004). However, there was no difference in structural damage progression. CONCLUSIONS: Tapering was not equivalent to maintenance strategy, resulting in more relapses without impacting structural damage progression. Further studies are needed to identify patients who could benefit from such a strategy associated with substantial cost savings. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT00780793; EudraCT identifier: 2007-004483-41.

Variations in the metabolome in response to disease activity of rheumatoid arthritis.

BACKGROUND: Anti-Tumor Necrosis Factor (TNF) therapies are able to control rheumatoid arthritis (RA) disease activity and limit structural damage. Yet no predictive factor of response to anti-TNF has been identified. Metabolomic profile is known to vary in response to different inflammatory rheumatisms so determining it could substantially improve diagnosis and, consequently, prognosis. The aim of this study was to use mass spectrometry to determine whether there is variation in the metabolome in patients treated with anti-TNF and whether any particular metabolomic profile can serve as a predictor of therapeutic response. METHODS: Blood samples were analyzed in 140 patients with active RA before initiation of anti-TNF treatment and after 6 months of Anti-TNF treatment (100 good responders and 40 non-responders). Plasma was deproteinized, extracted and analyzed by reverse-phase chromatography-QToF mass spectrometry. Extracted and normalized ions were tested by univariate and ANOVA analysis followed by partial least-squares regression-discriminant analysis (PLS-DA). Orthogonal Signal Correction (OSC) was also used to filter data from unwanted non-related effects. Disease activity scores (DAS 28) obtained at 6 months were correlated with metabolome variation findings to identify a metabolite that is predictive of therapeutic response to anti-TNF. RESULTS: After 6 months of anti-TNF therapy, 100 patients rated as good responders and 40 patients as non-responders according to EULAR criteria. Metabolomic investigations suggested two different metabolic fingerprints splitting the good-responders group and the non-responders group, without differences in anti-TNF therapies. Univariate analysis revealed 24 significant ions in positive mode (p < 0.05) and 31 significant ions in negative mode (p < 0.05). Once intersected with PLS results, only 35 ions remained. Carbohydrate derivates emerged as strong candidate determinants of therapeutic response. CONCLUSIONS: This is the first study describing metabolic profiling in response to anti-TNF treatments using plasma samples. The study highlighted two different metabolic profiles splitting good responders from non-responders.

Tocilizumab induces corticosteroid sparing in rheumatoid arthritis patients in clinical practice.

OBJECTIVE: . The aim of this study was to evaluate the impact of introducing tocilizumab (TCZ) as co-therapy with CS in patients with RA. METHODS: This study was an open, observational, retrospective multicentre study. RA patients treated with oral CS for >3 months who started treatment with TCZ between December 2009 and June 2011 in five centres were included. Variables included demographic data, disease history, co-treatments, disease activity and dose of CS at inclusion and at weeks 4, 8, 12 and 24. The evolution of disease activity and of the dose of CS (analysis of variance with repeated measures) were analysed, searching for factors correlated with changes in the dose of CS. RESULTS: Inclusion of 130 patients [women 80.8%, mean age 56.7 years (s.d. 14.0), RA duration 16.3 years (s.d. 10.4), mean baseline 28-joint DAS (DAS28) 5.1 (s.d. 1.4), mean baseline dose of CS 10.0 mg/day (s.d. 8.2) prednisone equivalent. Decreases in the mean daily dose of CS and in the DAS28 were observed during follow-up [respectively 6.5 mg (s.d. 4.8) at week 24 (P < 0.0001) and 3.0 mg (s.d. 1.4) at week 24 (P < 0.0001)]. The only variable that correlated with the decrease in the dose of CS was the initial dose of the drug (r = 0.82, P < 0.001). CONCLUSION: The introduction of TCZ led to rapid and long-lasting CS sparing that did not correlate with the reduction in disease activity. It is possible that in patients treated with high-dose CS, the main objective of the clinician is to reduce dosage of CS rather than RA activity.

[NADPH oxidases, Nox: new isoenzymes family]. / Les NADPH oxydases, Nox - Une nouvelle famille d'isoenzymes.

NADPH oxidases, Nox, are a family of isoenzymes, composed of seven members, whose sole function is to produce reactive oxygen species (ROS). Although Nox catalyze the same enzymatic reaction, they acquired from a common ancestor during evolution, specificities related to their tissue expression, subcellular localization, activation mechanisms and regulation. Their functions could vary depending on the pathophysiological state of the tissues. Indeed, ROS are not only bactericidal weapons in phagocytes but also essential cellular signaling molecules and their overproduction is involved in chronic diseases and diseases of aging. The understanding of the mechanisms involved in the function of Nox and the emergence of Nox inhibitors, require a thorough knowledge of their nature and structure. The objectives of this review are to highlight, in a structure/function approach, the main similar and differentiated properties shared by the human Nox isoenzymes.

Predictors of response and remission in a large cohort of rheumatoid arthritis patients treated with tocilizumab in clinical practice.

OBJECTIVE: The objective of this study was to identify predictors of response and remission to tocilizumab (TCZ) in RA patients seen in daily routine clinical practice. METHODS: The efficacy of TCZ was evaluated after 12 and 24 weeks of treatment by the European League Against Rheumatism (EULAR) response criteria. Regression analysis was performed to study the association between remission or EULAR response and the following characteristics: gender, age, current smokers, prior cardiovascular disease (CVD), 28-joint disease activity score (DAS28), CRP, RF or ACPA positivity, combination therapy with DMARDs and TCZ as the first biological therapy or after failure of at least one biological therapy. RESULTS: In total, 204 patients were included with a mean DAS28 score of 5.14. EULAR response and remission were obtained in 86.1% and 40% of patients, respectively, at week 24. In multiple regression analysis, a high baseline CRP level [odds ratio (OR) 4.454 (95% CI 1.446, 13.726)] was significantly associated with EULAR response at week 24 and, inversely, age >55 years [OR 0.285 (95% CI 0.086, 0.950)] and prior CVD [OR 0.305 (95% CI 0.113, 0.825)] were significantly associated with lower EULAR response at week 24. Older age was also associated with less remission at week 24 [OR 0.948 (95% CI 0.920, 0.978)]. No additional effectiveness was found when TCZ was used in combination with a DMARD or when patients were naive to biological agents. CONCLUSION: In daily practice we identified three predictors of a better response for TCZ therapy in RA: a younger age, a high baseline CRP level and no history of CVD.

Towards the Lowest Efficacious Dose: Results From a Multicenter Noninferiority Randomized Open-Label Controlled Trial Assessing Tocilizumab or Abatacept Injection Spacing in Rheumatoid Arthritis in Remission.

OBJECTIVE: We assess the clinical and structural impact at two years of progressively spacing tocilizumab (TCZ) or abatacept (ABA) injections versus maintenance at full dose in patients with rheumatoid arthritis in sustained remission. METHODS: This multicenter open-label noninferiority (NI) randomized clinical trial included patients with established rheumatoid arthritis in sustained remission receiving ABA or TCZ at a stable dose. Patients were randomized to treatment maintenance (M) at full dose (M-arm) or progressive injection spacing (S) driven by the Disease Activity Score in 28 joints every 3 months up to biologics discontinuation (S-arm). The primary end point was the evolution of disease activity according to the Disease Activity Score in 44 joints during the 2-year follow-up analyzed per protocol with a linear mixed-effects model, evaluated by an NI test based on the one-sided 95% confidence interval (95% CI) of the slope difference (NI margin 0.25). Other end points were flare incidence and structural damage progression. RESULTS: Overall, 202 of the 233 patients included were considered for per protocol analysis (90 in S-arm and 112 in M-arm). At the end of follow-up, 16.2% of the patients in the S-arm could discontinue their biologic disease-modifying antirheumatic drug, 46.9% tapered the dose and 36.9% returned to a full dose. NI was not demonstrated for the primary outcome, with a slope difference of 0.10 (95% CI 0.10-0.31) between the two arms. NI was not demonstrated for flare incidence (difference 42.6%, 95% CI 30.0-55.1) or rate of structural damage progression at two years (difference 13.9%, 95% CI -6.7 to 34.4). CONCLUSION: The Towards the Lowest Efficacious Dose trial failed to demonstrate NI for the proposed ABA or TCZ tapering strategy.