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.

Spine abnormalities associated with bone edema on sacroiliac joints MRI in patients with non-inflammatory chronic back pain.

OBJECTIVE: To investigate whether bone marrow edema (BME) fulfilling the ASAS definition of magnetic resonance imaging (MRI) sacroiliitis is associated with non-inflammatory spine abnormalities in patients with definite mechanical chronic back pain (CBP). METHODS: Patients with definite mechanical CBP, according to the physician, started before the age of 45 and be lasting for more than 3months but less than 3years underwent a protocolized MRI and radiographs of sacroiliac joint (SIJ) and spine. BME and structural changes were scored, by three readers, for SIJ as well as non-inflammatory abnormalities for spine, including degenerative lesions and static disorders. Univariate analysis by Chi2 test was performed to search a statistical association between BME fulfilling the ASAS definition of MRI sacroiliitis and the presence of at least one non-inflammatory spine abnormality. RESULTS: A total of 94 patients were analyzed, 27 (29%) patients had BME and 16 (17%) patients had BME fulfilling the ASAS definition of MRI sacroiliitis; 86 (91.5%) patients had at least one non-inflammatory spine abnormality which are associated into 3 distinct clusters. BME was slightly more frequent at the lower and posterior part of the SIJ. MRI sacroiliitis was associated with interspinous bursitis, facet joint effusion and lateral spinal deviation and was more likely in patients with at least one non-inflammatory spine abnormality (OR: 4.96, 95% CI [1.47; 16.72]). CONCLUSIONS: BME fulfilling the ASAS definition of MRI sacroiliitis is significantly associated with non-inflammatory spine abnormalities in patients with mechanical CBP.

Immunomodulation with IL-17 and TNF-α in spondyloarthritis: focus on the eye and the central nervous system.

Tumor necrosis factor alpha (TNF-α) and interleukin-17 (IL-17) are two pro-inflammatory cytokines involved in the pathophysiology of spondyloarthritis (SpA). Therapies targeting TNF-α or IL-17 are used as a second line among SpA patients failing non-steroidal anti-inflammatory drugs. The choice of such treatment has to take into account the patient's comorbidities. Neurologic diseases are common and their association with SpA deserves to be studied. Therefore, the role of TNF-α and IL-17 cytokines is worth investigating in these neuropsychiatric diseases. This review aimed to explore the role of TNF-α and IL-17 in the pathogenesis of uveitis, multiple sclerosis, neuromyelitis optica, Alzheimer's disease, Parkinson's disease and depression. This update is critical to guide the therapeutic management of these co-morbidities in SpA patients.

Variability of rituximab and tocilizumab trough concentrations in patients with rheumatoid arthritis.

Patients with rheumatoid arthritis (RA) are eligible for treatment with therapeutic monoclonal antibodies (mAbs) that target tumor necrosis factor α (TNFα), as well as others, such as rituximab (RTX) and tocilizumab (TCZ). Although pharmacokinetic variability and the link between concentration-clinical response of anti-TNFα mAbs have been well-described, little is known about RTX and TCZ. We aimed to evaluate the variability of RTX and TCZ serum concentrations in RA patients treated in second-line and the relationship between RTX/TCZ concentrations and the clinical response. Serum mAb trough concentrations of RA patients treated with RTX (n = 35) or TCZ (n = 46) were determined at week 24 by liquid chromatography-tandem mass spectrometry. The clinical response was assessed at week 24 by the change in the disease activity score in the 28 joints-erythrocyte sedimentation rate from baseline (ΔDAS28-Erythrocyte Sedimentation Rate) and according to the European League Against Rheumatism (EULAR) recommendations. RTX and TCZ trough concentrations were highly variable, with a coefficient of variation of 171.3% for RTX (median [10th-90th percentiles]: <1.0 µg/mL [<1.0-5.1]) and 132.6% for TCZ (median [10th-90th percentiles]: 5.4 µg/mL [<1.0-27.8]). Univariate analysis did not identify any determinants of such variability, except cotreatment with methotrexate, which was associated with lower RTX concentrations (P = 0.03). The response to treatment was not related to the RTX or TCZ trough concentration. RTX and TCZ trough concentrations at 24 weeks were highly variable in RA patients treated in the second line, without any link concentration-clinical response having been demonstrated.

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.

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.

Rheumatoid Meningitis a Rare Extra-Articular Manifestation of Rheumatoid Arthritis: Report of 6 Cases and Literature Review.

OBJECTIVES: Central neurological manifestations of rheumatoid arthritis (RA) like rheumatoid meningitis (RM) are rare, little known and have a high rate of morbi-mortality. METHODS: We described six cases of RM that were directly related to RA activity after exhaustive assessment. RESULTS: They were mainly women, aged of 50 to 69. All were positive for anti-cyclic citrullinated peptide antibodies and half for rheumatoid factors. RA activity, duration, and treatments were heterogeneous including oral steroids, conventional synthetic disease modifying anti-rheumatic drugs (DMARDs) and biologic DMARDs. Symptoms were various, with acute or progressive beginning; main were: generalized or focal seizure (4/6), fever (3/6), headaches (3/6), and frontal syndrome (2/6). Imaging lesions were four leptomeningitis, one pachymeningitis, and one association of both. MRI usually showed hypersignal in various territories in T2-FLAIR (fluid attenuated inversion recovery) mode, and enhancement in T1-weighted mode after gadolinium injection. All patients had lumbar puncture that found sterile cerebrospinal fluid, no neoplasic cell, elevated cell count in 5/6 cases and elevated proteins concentration in 3/6 cases. Cerebral biopsy was possible for three patients, and definitively confirmed the diagnosis of aseptic lepto- or pachymenintis, excluding vasculitis and lymphoma. Different treatments were used like intravenous high dose steroids, immunoglobulins or biologic DMARDs, with variable clinical and imaging outcome: one death, one complete recovery, and four recoveries with sequelae. CONCLUSIONS: Clinical symptoms, imaging, lumbar puncture, and serological studies are often nonspecific, only histologic examination can confirm the diagnosis of RM. Any central neurological manifestation in RA patients, even in quiescent and ancient RA, should warn the physician.

Prealbumin, platelet factor 4 and S100A12 combination at baseline predicts good response to TNF alpha inhibitors in rheumatoid arthritis.

OBJECTIVES: Tumour necrosis factor-alpha inhibitors (TNFi) are effective treatments for Rheumatoid Arthritis (RA). Responses to treatment are barely predictable. As these treatments are costly and may induce a number of side effects, we aimed at identifying a panel of protein biomarkers that could be used to predict clinical response to TNFi for RA patients. METHODS: Baseline blood levels of C-reactive protein, platelet factor 4, apolipoprotein A1, prealbumin, α1-antitrypsin, haptoglobin, S100A8/A9 and S100A12 proteins in bDMARD naive patients at the time of TNFi treatment initiation were assessed in a multicentric prospective French cohort. Patients fulfilling good EULAR response at 6 months were considered as responders. Logistic regression was used to determine best biomarker set that could predict good clinical response to TNFi. RESULTS: A combination of biomarkers (prealbumin, platelet factor 4 and S100A12) was identified and could predict response to TNFi in RA with sensitivity of 78%, specificity of 77%, positive predictive values (PPV) of 72%, negative predictive values (NPV) of 82%, positive likelihood ratio (LR+) of 3.35 and negative likelihood ratio (LR-) of 0.28. Lower levels of prealbumin and S100A12 and higher level of platelet factor 4 than the determined cutoff at baseline in RA patients are good predictors for response to TNFi treatment globally as well as to Infliximab, Etanercept and Adalimumab individually. CONCLUSION: A multivariate model combining 3 biomarkers (prealbumin, platelet factor 4 and S100A12) accurately predicted response of RA patients to TNFi and has potential in a daily practice personalized treatment.

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.

Impact of gender on the response and tolerance to abatacept in patients with rheumatoid arthritis: results from the 'ORA' registry.

OBJECTIVE: The impact of gender on the response and tolerance to abatacept was assessed in a large prospective cohort during 2 years of follow-up. METHODS: From the 1017 patients included in the Orencia and Rheumatoid Arthritis registry, disease activity was assessed at baseline, 6, 12 and 24 months. The relationship between the European League Against Rheumatism (EULAR) response, Disease Activity Score 28 (DAS28) remission, rate of adverse events and gender was explored in multivariate analysis. RESULTS: 990 patients, 79.3%female, with at least one follow-up visit were analysed. At baseline, women had longer disease duration, higher disease activity and more often received antitumour necrosis factor (TNF) drugs. The remission was not different between men and women during the follow-up after adjustment on age, disease duration and activity, rheumatoid factor and anti-cyclic citrullinated pyeptide (CCP) positivity, and current disease-modifying antirheumatic drugs (DMARDs), previous TNF blockers and corticosteroids use. The proportion of men and women achieving EULAR good-or-moderate response at any endpoints was similar (52.4% vs 55.5%), as well as time to achieving EULAR response (5.4±4.9 vs 5.6±5.2 months). Moderate EULAR response was more frequent in women at 6 months (OR=1.80, p=0.02) but was no longer significant at 12 or 24 months. During the follow-up, the DAS28, the tender joint count score and the patient global assessment remained higher in women (p=0.001, 0.04 and 0.06, respectively). Drug retention and safety were comparable. CONCLUSION: In this large daily practice cohort of established rheumatoid arthritis treated with abatacept, women achieved similar remission and EULAR response than men despite higher disease activity and tender joint count during the treatment course.

Unexpected function of the phagocyte NADPH oxidase in supporting hyperglycolysis in stimulated neutrophils: key role of 6-phosphofructo-2-kinase.

The phagocyte NADPH oxidase 2 (Nox2) is an enzymatic complex that is involved in innate immunity, notably via its capacity to produce toxic reactive oxygen species. Recently, a proteomic analysis of the constitutively active Nox2 complex, isolated from neutrophil fractions, highlighted the presence of 6-phosphofructo-2-kinase (PFK-2). The purpose of this work was to study the relationship between PFK-2 and NADPH oxidase in neutrophils. Data have underlined a specific association of the active phosphorylated form of PFK-2 with Nox2 complex in stimulated neutrophils. In its active form, PFK-2 catalyzes the production of fructose-2,6-bisphosphate, which is the main allosteric activator of phosphofructo-1-kinase, the limiting enzyme in glycolysis. Pharmacologic inhibition of PFK-2 phosphorylation and cell depletion in PFK-2 by a small interfering RNA strategy led to a decrease in the glycolysis rate and a reduction in NADPH oxidase activity in stimulated cells. Surprisingly, alteration of Nox2 activity impacted the glycolysis rate, which indicated that Nox2 in neutrophils was not only required for reactive oxygen species production but was also involved in supporting the energetic metabolism increase that was induced by inflammatory conditions. PFK-2 seems to be a strategic element that links NADPH oxidase activation and glycolysis modulation, and, as such, is proposed as a potential therapeutic target in inflammatory diseases.-Baillet, A., Hograindleur, M.-A., El Benna, J., Grichine, A., Berthier, S., Morel, F., Paclet, M.-H. Unexpected function of the phagocyte NADPH oxidase in supporting hyperglycolysis in stimulated neutrophils: key role of 6-phosphofructo-2-kinase.

Collection and management of selected comorbidities and their risk factors in chronic inflammatory rheumatic diseases in daily practice in France.

INTRODUCTION: In chronic inflammatory rheumatic diseases (CIRDs), comorbidities such as cardiovascular disease and infections are sub-optimally managed. EULAR recently developed points to consider to collect and report comorbidities. The objective of this present study was to develop a pragmatic guide to collect, report and propose management recommendations for comorbidities, from a rheumatologist perspective. METHODS: The collection and reporting of comorbidities and risk factors was adapted from the EULAR points to consider. To develop management recommendations, the process comprised (1) systematic literature reviews by 3 fellows and (2) a 2-day consensus process involving 110 experts (rheumatologists and health professionals). Votes of agreement (Likert 1-5 where 5 indicates full agreement) were obtained. RESULTS: The six selected comorbidities were ischemic cardiovascular diseases, malignancies, infections, diverticulitis, osteoporosis and depression. The literature review retrieved 97 articles or websites, mostly developed for the general population. The consensus process led to reporting presence of comorbidities, current treatment, risk factors (e.g. hypertension), screening (e.g. mammography) and prevention (e.g. vaccination). Management recommendations include physical examination (e.g. blood pressure or lymph node examination), prescribing screening procedures, and interpreting results to refer in a timely manner to appropriate other health professionals. Agreement was high (mean±standard deviation, 4.37±0.33). CONCLUSIONS: Using an evidence-based approach followed by expert consensus, this initiative furthers the dissemination in France of the EULAR points to consider, and clearly defines what part of the management of comorbidities is potentially within the remit of rheumatologists. This initiative should facilitate systematic management of patients with CIRDs.

Risk of postoperative infections and the discontinuation of TNF inhibitors in patients with rheumatoid arthritis: A meta-analysis.

OBJECTIVE: To determine whether continuation of tumor necrosis factor inhibitors (TNFi) before surgery increases the risk of surgical site infection (SSI) in rheumatoid arthritis (RA) patients. METHODS: A systematic review of the literature was conducted from January 2000 to May first 2014, using the databases of PubMed, Cochrane review, Embase, and manual research of abstracts presented in scientific congresses. Most included studies were retrospective. We compared the risk of SSI in the case of discontinuation of TNFi versus continuing TNFi treatment before a surgery. RESULTS: Six studies, with a total of 2743 patients (1360 in the group continuing TNFi agent and 1383 in the group discontinuing TNFi) were included. There was a decreased risk of SSI in patients stopping TNFi (relative risk [RR]=0.62 [95% confidence interval [CI] 0.43-0.89], P=0.99, I2=0%). Concerning overall complications, there was also a decreased risk in patients discontinuing TNFi treatment (RR=0.60 [95% CI 0.42-0.87], P=0.26, I2=25%). CONCLUSION: This meta-analysis showed an increased risk of SSI in patients under TNF inhibitor, and a decreased risk of SSI in case of interruption of treatment during the perioperative time.