Othmane Mejjad

Gene profiling in white blood cells predicts infliximab responsiveness in rheumatoid arthritis

As indicators of responsiveness to a tumour necrosis factor (TNF)α blocking agent (infliximab) are lacking in rheumatoid arthritis, we have used gene profiling in peripheral blood mononuclear cells to predict a good versus poor response to infliximab. Thirty three patients with very active disease (Disease Activity Score 28 >5.1) that resisted weekly methotrexate therapy were given infliximab at baseline, weeks 2 and 6, and every 8th week thereafter. The patients were categorized as responders if a change of Disease Activity Score 28 = 1.2 was obtained at 3 months. Mononuclear cell RNAs were collected at baseline and at three months from responders and non-responders. The baseline RNAs were hybridised to a microarray of 10,000 non-redundant human cDNAs. In 6 responders and 7 non-responders, 41 mRNAs identified by microarray analysis were expressed as a function of the response to treatment and an unsupervised hierarchical clustering perfectly separated these responders from non-responders. The informativeness of 20 of these 41 transcripts, as measured by qRT-PCR, was re-assessed in 20 other patients. The combined levels of these 20 transcripts properly classified 16 out of 20 patients in a leave-one-out procedure, with a sensitivity of 90% and a specificity of 70%, whereas a set of only 8 transcripts properly classified 18/20 patients. Trends for changes in various transcript levels at three months tightly correlated with treatment responsiveness and a down-regulation of specific transcript levels was observed in non-responders only. Our gene profiling obtained by a non-invasive procedure should now be used to predict the likely responders to an infliximab/methotrexate combination.

Impact of Three Anti-TNFα Biologics on Existing and Emergent Autoimmunity in Rheumatoid Arthritis and Spondylarthropathy Patients

ObjectiveThe objective of this study was to analyze the effects of 3 anti-TNFα agents on markers of autoimmunity in rheumatoid arthritis (RA) and spondylarthropathy (SPA) patients.MethodsFirst-time anti-TNFα biologics (infliximab, etanercept, or adalimumab) were prescribed to 156 RA and 95 SPA (58 ankylosing spondylarthritides, 37 psoriatic arthritides). During 1–2xa0years of follow-up, clinical, biological [antinuclear (ANA) and anti-double-stranded (dsDNA) antibodies, rheumatoid factors (RF), and anti-cyclic citrullinated peptide (CCP) for RA], and therapeutic data were collected biannually.ResultsANA appeared or ANA and anti-dsDNA titers increased significantly (Pu2009<u20090.001) more under infliximab than etanercept in both rheumatisms and than adalimumab in RA patients. During the 2-year follow-up, ANA appeared more in RA patients taking adalimumab than etanercept (Pu2009=u20090.003), but independently of the anti-TNFα used; anti-dsDNA titers rarely became positive. Under etanercept or infliximab, ANA and anti-dsDNA were not influenced by the underlying pathology nor were they affected by infliximab intensification over 18xa0months. Only one case of cutaneous lupus was observed in a patient having IgG anti-dsDNA. The therapeutic responses were independent of ANA and anti-dsDNA titers for all rheumatisms and biologics. In RA patients, RF titers, but not anti-CCP levels, declined with the therapeutic response for all biologics.ConclusionThis is the first study that has evaluated the impact of three TNFα blockers on ANA and anti-dsDNA antibodies in RA and SPA patients. Autoimmunity was more induced with infliximab than etanercept and to a lesser degree to adalimumab but, more importantly, this emergent autoimmunity was exceptionally associated to clinical manifestations of lupus.

Association between the TNFRII 196R allele and diagnosis of rheumatoid arthritis.

Tumour necrosis factor (TNF)-α plays a key role in the pathogenesis of rheumatoid arthritis (RA). It binds to two receptors, namely TNF receptor (TNFR)I and TNFRII. Several studies have suggested an association between TNFRII 196R/R genotype and RA. The objective of the present study was to evaluate the predictive value of the TNFRII 196R allele for RA diagnosis and prognosis in a cohort of patients with very early arthritis. We followed up a total of 278 patients recruited from the community, who had swelling of at least two joints that had persisted for longer than 4 weeks but had been evolving for less than 6 months, and who had not received disease-modifying antirheumatic drugs or steroid therapy. At 2 years, patients were classified according to the American College of Rheumatology criteria. All patients were genotyped with respect to TNFRII 196M/R polymorphism. Radiographs of hands and feet (read according to the modified Sharp method) and the Health Assessment Questionnaire were used to quantify structural and functional severity. The cohort of 278 patients was found to include 156 and 122 RA and non-RA patients, respectively. The TNFRII 196R allele was found to be associated with RA (P = 0.002). However, progression of radiographic severity and Health Assessment Questionnaire scores over 1 year did not differ between carriers of the 196R allele and noncarriers. Our findings suggest that the TNFRII 196R allele may be associated with RA diagnosis but that it does not predict early radiographic progression or functional severity in patients with very early, unclassified arthritis.

Serum IgA rheumatoid factor and pyridinoline in very early arthritis as predictors of erosion(s) at two years: A simple model of prediction from a conservatively treated community-based inception cohort

To identify, in conservatively treated, very early arthritis patients, predictors of ≥1 erosion(s) at 2 years, and to construct a prediction model.

Osteocalcin is not a marker of progress in multiple myeloma

Abstract: The aim of this study was to evaluate the usefulness of serum osteocalcin (OC) levels in multiple myeloma (MM) in order to assess its significance and activity, and to predict its course. Serum OC was measurement in 117 patients with MM and 116 healthy controls matched for age and sex. Serum OC levels were weakly correlated with Karnofsky index (r = 0.22; p<0.03). Lowest OC levels were observed when lytic bone lesions increased (p <0.05). There was no relationship between serum OC levels and vertebral crush fractures, serum calcium concentrations or stage of MM, neither was there any relationship between initial serum OC levels and survival. Progression of the disease was associated with a clear fall of serum OC in 61.5% of the “progressive” patients, versus 41% of the persisting “stabilized” cases. Serum OC level was strongly correlated with bone formation (p = 0.005), but not with bone resorption. Serum OC level is a sensitive marker of osteoblast activity, but a poor marker of the severity of MM. We do not consider it as a marker of MM activity or prognosis.

Combining anti-cyclic citrullinated peptide with the American College of Rheumatology 1987 criteria failed to improve early rheumatoid arthritis diagnosis in the community-based very early arthritis cohort

OBJECTIVESnTo test the performances of combining anti-CCP second generation (CCP2) with ACR 1987 classification criteria and to diagnose early RA in a community-based very early arthritis (VErA) patient cohort.nnnMETHODSnThe VErA cohort comprised 310 patients (median age 52 years; 68.1% women; median symptom duration 4.2 months; glucocorticoid- and DMARD naïve) conservatively treated during the first 2 years. At 6 years of follow-up, a three-expert committee classified the patients into three groups: RA, other classified arthritis (OCA) or unclassified arthritis (UA). We calculated the performances of the different sets, including anti-CCP2 positivity, while retaining or deleting RF and rheumatoid nodule components with ACR 1987 criteria for early RA diagnosis. Models were subjected to receiver operating characteristics curve and logistic regression analyses to try to identify relevant sets able to classify very early RA.nnnRESULTSnAt 6 years, 149 patients were diagnosed as RA and 119 as non-RA (95 OCA and 24 UA). The original ACR 1987 criteria had 77.9% sensitivity and 64.7% specificity for the RA diagnosis at 6 years. The modified set excluding rheumatoid nodules, including anti-CCP2 positivity and retaining RF performed significantly better than ACR 1987 criteria, with 79.9% sensitivity and 64.7% specificity and with a larger area under the curve. However, in the zone of interest, i.e., ≥4/7 criteria, the curves for these sets were superimposed.nnnCONCLUSIONSnAdding anti-CCP2 positivity and deleting rheumatoid nodules failed to improve the performances of ACR 1987 classification criteria for the diagnosis of early RA.

Synovium CD20 expression is a potential new predictor of bone erosion progression in very-early arthritis treated by sequential DMARDs monotherapy – A pilot study from the VErA cohort

OBJECTIVEnBecause available biomarkers (rheumatoid factors [RF], anti-cyclic citrullinated autoantibodies [anti-CCP2], erythrocyte sedimentation rate at 1st hour [ESR]/C-reactive peptide [CRP] and bone erosions) are insufficient to predict rheumatoid arthritis (RA) structural damage, to determine whether synovium expression of greater or equal to 1 markers could constitute new prognostic factor(s).nnnMETHODnThe study was conducted on 18 prospectively enrolled disease-modifying anti-rheumatic drug (DMARD)- and glucocorticoid-naïve, VErA cohort patients with very-early arthritis (median duration: 4months). Recorded at baseline were: clinical and biological (serum ESR, CRP, RF-isotypes, anti-CCP2, osteoprotegerin, receptor activator of nuclear κB-ligand [RANK-L] and cartilage oligomeric matrix protein [COMP] levels) data; synovium expression (HLA-DR, CD163, CD3, CD20, VEGF, osteoprotegerin, RANK-L, Bcl2 and global inflammation index) for a metacarpophalangeal joint-synovium biopsy. Baseline and 3-year hand-and-foot X-rays were graded with the van der Heijde-modified-Sharp score; the judgment criterion was its progression during follow-up. Pearsons product moment correlation statistics were used to test for association between paired samples.nnnRESULTSnA baseline, a significant relationship was found between erosive damage and markers of B-cell activation, notably the synovium CD20 expression (r=0.68; P=0.0001). Quantified by the modified-Sharp erosion score variation, the 3-year structural damage progression was significantly correlated with: serum levels of RF-IgG (r=0.75; P=0.0003), -IgM (r=0.69; P=0.001), anti-CCP2 (r=0.53; P=0.02) and RANK-L (r=0.61; P=0.007); synovium CD20 expression (r=0.70; P=0.001).nnnCONCLUSIONnThis analysis of the prognostic value of a large panel of synovium markers in a limited sample of prospectively followed, well-documented patients suggested that both synovial CD20 and serum RANK-L levels might be new predictors of structural damage progression in very-early RA.

Antiepileptic drugs to treat pain in rheumatic conditions. Recommendations based on evidence-based review of the literature and expert opinion

OBJECTIVESnNeuropathic pain is commonly encountered in rheumatology practice, often associated with nociceptive mechanisms. It is caused by nervous system lesions, and the usual treatments with analgesics and anti-inflammatory drugs are mostly ineffective. Antiepileptic drugs (AED) have proved effective in relieving neuropathic pain. AED are recently used by rheumatologists since the role of neuropathic pain in rheumatological conditions has only recently been documented. Nevertheless, the tendency seems to be reversed when these drugs are used inappropriately. The CEDR (Cercle dEtude de la Douleur en Rhumatologie), a specific interest group of the French Society of Rheumatology that focuses on pain in rheumatology, undertook to develop recommendations for the use of AED in Rheumatology.nnnMETHODSnA list of questions concerning the prescription of AED in painful rheumatic conditions was validated by a working group of 7 experts from the CEDR. The list of questions was used to draw up the recommendations. A literature review was performed using electronic databases (Medline, Embase and Cochrane library between 1980 and 2007) without limitations on the type of publication: case reports, clinical trials, literature review and guidelines about therapeutic management of neuropathic pain. Selected studies were scored for quality. Based on the literature and clinical experience, recommendations were developed using the Delphi method.nnnRESULTSnWe identified 29 studies concerning the use of AED in painful rheumatic conditions and 16 studies were considered valid and scored for quality. These few studies, the guidelines published for neuropathic pain treatment and the clinical experience of each expert, were used to develop 11 recommendations for the use of AED in painful rheumatic conditions.nnnCONCLUSIONnThese recommendations can be used as guidelines to help prescribers to use AED for the management of pain in rheumatic conditions until further scientific evidence becomes available.

A shock associated with adult-onset Still’s disease

Only two cases of adult-onset Stills disease associated with shock have been previously described. We report a case of shock in a man with adult-onset Stills disease and discuss the relationship between the two processes by assessing tumor necrosis factor-alpha, procalcitonin and interleukin-6 concentrations.

Un état de choc associé à une maladie de Still de l'adulte

Resume Seuls deux cas de Maladie de Still de L’Adulte associee a un etat de choc d’allure septique ont ete rapportes. Nous decrivons un etat de choc survenu chez un homme atteint d’une maladie de Still de l’Adulte et nous discutons leurs possibles relations, avec l’aide des taux de tumor necrosis factor-alpha, de procalcitonine et de l’interleukine-6.