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.

Serum calprotectin and renal function decline in ANCA-associated vasculitides: a post hoc analysis of MAINRITSAN trial.

OBJECTIVE: Serum calprotectin appears to be an interesting biomarker associated with renal vascular disease activity in antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV). The aim of this study was to assess whether serum calprotectin levels can predict decline in renal function in AAV patients receiving maintenance therapy. METHODS: Serum calprotectin levels were assessed at inclusion and month 6 in AAV patients, in complete remission after induction therapy, randomly assigned to rituximab or azathioprine. Renal function decline was defined as a 25% decrease in estimated glomerular filtration rate (eGFR) and a change in the eGFR category, or a decrease of 15 mL/min/1.73 m2. Relapse was defined as a Birmingham Vasculitis Activity Score >0 attributable to active vasculitis. RESULTS: Seventy-six AAV were included. Serum calprotectin increased from baseline to month 6 in patients with renal function decline (7940 (-226.0, 28 691) ng/ml vs -4800 (-18 777, 3708) ng/ml; p<0.001). An increase of calprotectin level was associated with a higher risk of subsequent renal function decline even after adjustment (OR 6.50 (95% CI 1.7 to 24.9) p=0.006). A significantly higher risk of relapse was observed in proteinase 3- AAV patients with an increase of serum calprotectin levels (OR 5.6 (95% CI 1.0 to 31.2), p=0.03). CONCLUSION: An increase in serum calprotectin by month 6 compared with inclusion during remission-maintenance therapy in AAV was associated with a higher risk of renal function decline in the following 12 months. TRIAL REGISTRATION NUMBER: NCT00748644.

Survey of adolescents' needs and parents' views on sexual health in juvenile idiopathic arthritis.

BACKGROUND: Although the advent of new therapeutics for juvenile idiopathic arthritis (JIA) patients has considerably lessened the impact of the disease and reduced its sequelae, the outcomes of JIA remain important in their lives. Disease repercussions and side effects of treatments may affect sexual health and cause psychological distress. This aim of the study was to determine the expectations of adolescent JIA patients and the perceptions of their parents regarding knowledge and communication with healthcare providers (HCPs) in the field of sexual health (SH). METHODS: In France, from September 2021 to April 2022, a survey was conducted, using anonymous self-administered questionnaires, among JIA patients (adults (aged 18-45 years) to provide insights from their recollection of their adolescence) and their parents in nine rheumatology centers and three patient associations. RESULTS: The responses to the 76 patient questionnaires and 43 parent questionnaires that were collected were analyzed. Half of the patients thought JIA impacted their romantic relationships, but the results were less clear-cut for their sexual activity; and 58.7% of the patients said they would be comfortable discussing the subject with HCPs, but only 26.3% had done so, mainly regarding biomedical issues. The patients and their parents thought that ideally, the topic should be addressed in an individual patient education session at the hospital (51.3% and 34.9%, respectively), in a regular consultation (47.4% and 53.5%), or in a dedicated consultation requested by the adolescent without the adolescent's parents being informed (38.2% and 20.9%). Most of the respondents thought HCPs should be proactive in SH (77.6% of the patients and 69.8% of their parents). More patients than parents said the following digital information tools must be used: videos (29.0% vs. 9.3%, p = 0.0127) and smartphone applications (25.0% vs. 9.3%, p = 0.0372). CONCLUSION: HCPs should consider addressing the unmet need for SH discussions during their patient encounters. To meet this need, we propose concrete actions in line with the wishes of patients and parents. CLINICAL TRIAL REGISTRATION NUMBER: NCT04791189.

Systematic assessment of heart valves and cardiac function by echocardiography in axial spondyloarthritis: A systematic review and meta-analysis.

OBJECTIVES: Axial Spondyloarthritis (ax-SpA) is associated with increased risk of cardiovascular disease (CVD)-specific deaths. We aimed to assess the prevalence of left ventricular (LV) systolic and diastolic dysfunction and valvular heart disease (VHD) by transthoracic echocardiography (TTE) in ax-SpA patients without history of CVD. METHODS: A systematic literature review was performed in PUBMED, Embase, Cochrane Library databases published before April 2020. We included all controlled studies assessing myocardial function and heart valve by TTE in ax-SpA without history of CVD. A meta-analysis was performed with random or fixed effects model estimating mean differences (MD) and odds ratio (OR). RESULTS: Literature search selected 189 abstracts and 28 articles were included (1471 ax-SpA and 1115 controls). ax-SpA had a statistically slight alteration of LV ejection fraction (MD=0.64%, 95%CI: 0.14-1.14). ax-SpA had more frequently LV diastolic dysfunction (OR=3.43, 95%CI: 1.78-6.59) and an alteration of E/A ratio (MD=0.15, 95%CI: 0.08-0.21), deceleration time (MD=13.07ms, 95%CI: 7.75-18.40), isovolumetric relaxation time (MD=7.90ms, 95%CI: 4.50-11.30), left-ventricular end diastolic (MD=0.57mm, 95%CI: 0.19-0.95) and systolic (MD=0.77mm, 95%CI: 0.36-1.17) diameters. Three studies (15%) used a combination of TTE parameters to diagnose LV diastolic dysfunction. Prevalence of mitral regurgitation and aortic regurgitation were similar in ax-SpA patients and healthy individuals. CONCLUSION: ax-SpA have a non-clinically relevant alteration of LV ejection fraction and similar prevalence of VHD compared to healthy individuals. LV diastolic TTE parameters are altered in ax-SpA. However, most studies do not combine set of parameters to recognize diastolic dysfunction. The clinical relevance of diastolic dysfunction observed by TTE remains to be determined in future longitudinal studies.

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.

Gait and Axial Spondyloarthritis: Comparative Gait Analysis Study Using Foot-Worn Inertial Sensors.

BACKGROUND: Axial spondyloarthritis (axSpA) can lead to spinal mobility restrictions associated with restricted lower limb ranges of motion, thoracic kyphosis, spinopelvic ankylosis, or decrease in muscle strength. It is well known that these factors can have consequences on spatiotemporal gait parameters during walking. However, no study has assessed spatiotemporal gait parameters in patients with axSpA. Divergent results have been obtained in the studies assessing spatiotemporal gait parameters in ankylosing spondylitis, a subgroup of axSpA, which could be partly explained by self-reported pain intensity scores at time of assessment. Inertial measurement units (IMUs) are increasingly popular and may facilitate gait assessment in clinical practice. OBJECTIVE: This study compared spatiotemporal gait parameters assessed with foot-worn IMUs in patients with axSpA and matched healthy individuals without and with pain intensity score as a covariate. METHODS: A total of 30 patients with axSpA and 30 age- and sex-matched healthy controls performed a 10-m walk test at comfortable speed. Various spatiotemporal gait parameters were computed from foot-worn inertial sensors including gait speed in ms-1 (mean walking velocity), cadence in steps/minute (number of steps in a minute), stride length in m (distance between 2 consecutive footprints of the same foot on the ground), swing time in percentage (portion of the cycle during which the foot is in the air), stance time in percentage (portion of the cycle during which part of the foot touches the ground), and double support time in percentage (portion of the cycle where both feet touch the ground). RESULTS: Age, height, and weight were not significantly different between groups. Self-reported pain intensity was significantly higher in patients with axSpA than healthy controls (P<.001). Independent sample t tests indicated that patients with axSpA presented lower gait speed (P<.001) and cadence (P=.004), shorter stride length (P<.001) and swing time (P<.001), and longer double support time (P<.001) and stance time (P<.001) than healthy controls. When using pain intensity as a covariate, spatiotemporal gait parameters were still significant with patients with axSpA exhibiting lower gait speed (P<.001), shorter stride length (P=.001) and swing time (P<.001), and longer double support time (P<.001) and stance time (P<.001) than matched healthy controls. Interestingly, there were no longer statistically significant between-group differences observed for the cadence (P=.17). CONCLUSIONS: Gait was significantly altered in patients with axSpA with reduced speed, cadence, stride length, and swing time and increased double support and stance time. Taken together, these changes in spatiotemporal gait parameters could be interpreted as the adoption of a so-called cautious gait pattern in patients with axSpA. Among factors that may influence gait in patients with axSpA, patient self-reported pain intensity could play a role. Finally, IMUs allowed computation of spatiotemporal gait parameters and are usable to assess gait in patients with axSpA in clinical routine. TRIAL REGISTRATION: ClinicalTrials.gov NCT03761212; https://clinicaltrials.gov/ct2/show/NCT03761212. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1007/s00296-019-04396-4.

The effects of a secondary task on gait in axial spondyloarthritis.

Studies on the effects of dual tasking in patients with chronic inflammatory rheumatic diseases are limited. The aim of this study was to assess dual tasking while walking in patients with axial spondyloarthritis (axSpA) in comparison to healthy controls. Thirty patients with axSpA and thirty healthy controls underwent a 10-m walk test at a self-selected comfortable walking speed in single- and dual-task conditions. Foot-worn inertial sensors were used to compute spatiotemporal gait parameters. Analysis of spatiotemporal gait parameters showed that the secondary manual task negatively affected walking performance in terms of significantly decreased mean speed (p < 0.001), stride length (p < 0.001) and swing time (p = 0.008) and increased double support (p = 0.002) and stance time (p = 0.008). No significant interaction of group and condition was observed. Both groups showed lower gait performance in dual task condition by reducing speed, swing time and stride length, and increasing double support and stance time. Patients with axSpA were not more affected by the dual task than matched healthy controls, suggesting that the secondary manual task did not require greater attention in patients with axSpA. Increasing the complexity of the walking and/or secondary task may increase the sensitivity of the dual-task design to axial spondyloarthritis.

Marine habitat use and feeding ecology of introduced anadromous brown trout at the colonization front of the sub-Antarctic Kerguelen archipelago.

In 1954, brown trout were introduced to the Kerguelen archipelago (49°S, 70°E), a pristine, sub-Antarctic environment previously devoid of native freshwater fishes. Trout began spreading rapidly via coastal waters to colonize adjacent watersheds, however, recent and unexpectedly the spread has slowed. To better understand the ecology of the brown trout here, and why their expansion has slowed, we documented the marine habitat use, foraging ecology, and environmental conditions experienced over one year by 50 acoustically tagged individuals at the colonization front. Trout mainly utilized the marine habitat proximate to their tagging site, ranging no further than 7 km and not entering any uncolonized watersheds. Nutritional indicators showed that trout were in good condition at the time of tagging. Stomach contents and isotope signatures in muscle of additional trout revealed a diet of amphipods (68%), fish (23%), isopods (6%), and zooplankton (6%). The small migration distances observed, presence of suitable habitat, and rich local foraging opportunities suggest that trout can achieve their resource needs close to their home rivers. This may explain why the expansion of brown trout at Kerguelen has slowed.

Recommendations for the pragmatic use of ultrasound in rheumatoid arthritis by the GEISPER French group.

OBJECTIVE: To develop recommendations for the appropriate use of ultrasound in the management of rheumatoid arthritis (RA) in routine practice based on data from the literature and of experts opinion. METHODS: Based on a systematic literature review, a scientific committee decided on themes and relevant questions to draw up an initial draft of recommendations. These recommendations were submitted to a group of experts in ultrasound in rheumatic and musculoskeletal diseases using a Delphi method, which produced preliminary recommendations. These were submitted to an expanded group of ultrasound experts for relevance, comprehensibility and comprehensiveness. The level of agreement of the experts were recorded during a face-to-face meeting. RESULTS: Following two rounds of the Delphi, a consensus was reached on three overarching principles, including definitions of joints, tendons and articular sites to be examined, and 10 recommendations. These recommendations underline the benefit of ultrasound for the diagnosis of RA in cases of inflammatory arthralgia or undifferentiated arthritis as well as in assessing the extent of initial structural and inflammatory damage. They also define the role of ultrasound during follow-up or when considering treatment reduction once clinical remission has been achieved. Lastly, they illustrate the utility of ultrasound in facilitating technical procedures. CONCLUSION: These 10 consensus-based recommendations should harmonize and optimize clinical practice and thus improve the management of RA patients.

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.

Mediation of Interleukin-23 and Tumor Necrosis Factor-Driven Reactive Arthritis by Chlamydia-Infected Macrophages in SKG Mice.

OBJECTIVE: ZAP-70W163C BALB/c (SKG) mice develop reactive arthritis (ReA) following infection with Chlamydia muridarum. Since intracellular pathogens enhance their replicative fitness in stressed host cells, we examined how myeloid cells infected with C muridarum drive arthritis. METHODS: SKG, Il17a-deficient SKG, and BALB/c female mice were infected with C muridarum or C muridarum luciferase in the genitals. C muridarum dissemination was assessed by in vivo imaging or genomic DNA amplification. Macrophages were depleted using clodronate liposomes. Anti-tumor necrosis factor (anti-TNF) and anti-interleukin-23p19 (anti-IL-23p19) were administered after infection or arthritis onset. Gene expression of Hspa5, Tgtp1, Il23a, Il17a, Il12b, and Tnf was compared in SKG mice and BALB/c mice. RESULTS: One week following infection with C muridarum, macrophages and neutrophils were observed to have infiltrated the uteri of mice and were also shown to have carried C muridarum DNA to the spleen. C muridarum load was higher in SKG mice than in BALB/c mice. Macrophage depletion was shown to reduce C muridarum load and prevent development of arthritis. Compared with BALB/c mice, expression of Il23a and Il17a was increased in the uterine and splenic neutrophils of SKG mice. The presence of anti-IL-23p19 during infection or Il17a deficiency suppressed arthritis. Tnf was overexpressed in the joints of SKG mice within 1 week postinfection, and persisted beyond the first week. TNF inhibition during infection or at arthritis onset suppressed the development of arthritis. Levels of endoplasmic reticulum stress were constitutively increased in the joints of SKG mice but were induced, in conjunction with immunity-related GTPase, by C muridarum infection in the uterus. CONCLUSION: C muridarum load is higher in SKG mice than in BALB/c mice. Whereas proinflammatory IL-23 produced by neutrophils contributes to the initiation of C muridarum-mediated ReA, macrophage depletion reduces C muridarum dissemination to other tissues, tissue burden, and the development of arthritis. TNF inhibition was also shown to suppress arthritis development. Our data suggest that enhanced bacterial dissemination in macrophages of SKG mice drives the TNF production needed for persistent arthritis.

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.

Efficacy, safety and cost-effectiveness of a web-based platform delivering the results of a biomarker-based predictive model of biotherapy response for rheumatoid arthritis patients: a protocol for a randomized multicenter single-blind active controlled clinical trial (PREDIRA).

BACKGROUND: Rheumatoid arthritis (RA) is one of the leading chronic inflammatory rheumatism. First-line therapy with synthetic disease-modifying antirheumatic drugs (sDMARD) is insufficiently effective in 40% of cases and these patients are treated with biotherapies. The increased use of these drugs each year is becoming a public health issue with considerable economic burden. This cost is 20 times higher than that of sDMARD. However, among patients treated with biotherapies, clinical practice shows that about one third will not respond to the selected drug. In nonresponse cases, practitioners currently have no choice but to perform an empirical switching between different treatments, because no tool capable of predicting the response or nonresponse to these molecules is currently available. METHODS: The study is a prospective, phase III, controlled, multicenter, and randomized, single-blind (patient) clinical trial, including RA patients with a previous failure to anti-TNF therapies. The main objective is the analysis of the clinical and pharmacoeconomic impact after 6 months of treatment. Intervention arm: prescription of biotherapy (rituximab, adalimumab, abatacept) using SinnoTest® software, a prediction software based on proteomic biomarkers. Control arm: prescription of biotherapy based on current practice, without the SinnoTest® software (any biotherapy). In addition, a substudy will be carried out within this trial to generate a biobank and further analyze the proteomic profile of the patients and their modification throughout the study. DISCUSSION: This clinical trial study will be the first validation study of a biotherapy response prediction software, bringing personalized medicine into the management of RA. We expect that the findings from this study will bring several benefits for the patient and the Health Care System. TRIAL REGISTRATION: ClincalTrials.gov NCT04147026 . Registered on 31 October, 2019.

Increased high molecular weight adiponectin and lean mass during tocilizumab treatment in patients with rheumatoid arthritis: a 12-month multicentre study.

BACKGROUND: Patients with rheumatoid arthritis (RA) have an increased risk of cardiovascular (CV) disease. Adiponectin is involved in the metabolism of glucose and lipids with favourable effects on CV disease, especially its high molecular weight (HMW) isoform. Body composition changes are described in RA with various phenotypes including obesity. The effects of tocilizumab on serum adiponectin and body composition, especially fat mass, in patients with RA are not well determined. METHODS: Patients with active RA despite previous csDMARDs and/or bDMARDs and who were tocilizumab naïve were enrolled in a multicentre open-label study. They were evaluated at baseline, 1, 3, 6 and 12 months. Clinical assessment included body mass index (BMI) and anthropometric measurements. Lipid and metabolic parameters, serum adiponectin (total and HMW), leptin, resistin and ghrelin were measured at each time point. Body composition (lean mass, fat mass, % fat, fat in the android and gynoid regions) was evaluated at baseline, 6 and 12 months. RESULTS: One hundred seven patients were included. Both total and HMW adiponectin significantly increased from baseline to month 3, peaking respectively at month 3 (p = 0.0105) and month 1 (p < 0.0001), then declining progressively until month 6 to 12 and returning to baseline values. Significant elevation in HMW adiponectin persisted at month 6 (p = 0.001). BMI and waist circumference significantly increased at month 6 and 12, as well as lean mass at month 6 (p = 0.0097). Fat mass, percentage fat and android fat did not change over the study period. Lipid parameters (total cholesterol and LDL cholesterol) increased while glycaemia, insulin and HOMA-IR remained stable. Serum leptin, resistin and ghrelin did not change during follow-up. CONCLUSIONS: Tocilizumab treatment in RA patients was associated with a significant increase in total and HMW adiponectin, especially at the onset of the treatment. Tocilizumab also induced a significant gain in lean mass, while fat mass did not change. These variations in adiponectin levels during tocilizumab treatment could have positive effects on the CV risk of RA patients. In addition, tocilizumab may have an anabolic impact on lean mass/skeletal muscle. TRIAL REGISTRATION: The ADIPRAT study was a phase IV open-label multicentre study retrospectively registered on ClinicalTrials.gov under the number NCT02843789 (date of registration: July 26, 2016).