Reduced progression of bone erosion in cytomegalovirus seropositive rheumatoid arthritis patients.

BACKGROUND: Human cytomegalovirus (HCMV) seropositivity has been associated with higher inflammation during rheumatoid arthritis (RA). However, no data are available on the impact of HCMV seropositivity on bone erosion progression during RA. METHODS: We selected 487 individuals of ESPOIR cohort who fulfilled the 2010 ACR/EULAR criteria for RA. HCMV serology for these patients was determined using Architect CMV IgG assay. Baseline and 1-year central X-ray reading using modified Total Sharp Score (mTSS), Erosion Sharp Score, and joint space narrowing Sharp score were used to quantify structural damage progression. We performed univariate and multivariate analyses to investigate the association between HCMV status and bone erosion progression. RESULTS: We analyzed 273 HCMV seropositive (HCMV+) and 214 HCMV seronegative (HCMV-) RA patients. At inclusion, HCMV+ patients were less frequently ACPA+ (49.8% versus 58.9%, p < 0.0465) and had a higher DAS28-ESR (5.55 ± 1.24 versus 5.20 ± 1.14, p < 0.0013) in comparison with HCMV-. At 1 year, bone erosion progression (delta erosion Sharp score > 1 point) was lower in HCMV+ patients (16.1% versus 25.2%, p = 0.0128) in comparison with HCMV-. HCMV+ status remained independently associated with lower bone erosion progression in multivariate analysis. CONCLUSIONS: Our findings suggest that, independently of other confounding factors, HCMV seropositivity is associated with a lower progression of bone erosion during RA.

Early-onset granulomatous arthritis, uveitis and skin rash: characterization of skin involvement in Blau syndrome.

BACKGROUND: Blau syndrome (BS) is a rare monogenic autoinflammatory disease caused by NOD2 mutations. BS classically presents in early childhood as a triad of granulomatous polyarthritis, uveitis and skin involvement. Joint and ocular involvement have been characterized by several cohort studies but only very little data are available on skin lesions. OBJECTIVES: We aimed to provide a detailed clinical and microscopic analysis of skin manifestations and to study whether they may contribute to an early diagnosis. METHODS: We conducted a retrospective multicentre study in a French cohort of 21 patients diagnosed with genetically confirmed BS. RESULTS: Skin involvement was the first clinical manifestation of BS in 15/16 patients with dermatological manifestations. The presence of skin lesions was associated with significant shorter age at diagnosis (P = 0.03) and diagnostic delay (P = 0.04). Dermatological assessment allowed an earlier diagnosis (P = 0.001) and reduces the diagnostic delay (P = 0.007). Early skin lesions had a homogeneous, stereotypical clinical presentation, namely non-confluent erythematous or pigmented millimetric papules in 13/14(93%) patients. In contrast, skin lesions occurring during later disease stages had a more heterogeneous clinical presentation, including ichthyosiform dermatosis, panniculitis, livedoid lesions and vasculitis. Whatever their time of occurrence and the clinical aspect, all biopsied showed histologically presence of granuloma. CONCLUSION: Skin involvement in BS is the earliest clinical manifestation of the BS in the large majority of patients. The recognition of dermatological manifestations as granulomatous skin lesions and early dermatological expertise are the key to an early diagnosis of BS. In view of our results, it seems reasonable to propose a simplified view of skin lesions of BS in which the granuloma is the key structure.

Psoriatic arthritis screening by the dermatologist: development and first validation of the 'PURE-4 scale'.

BACKGROUND: Dermatologists are recommended to ask psoriasis patients about musculoskeletal complaints to allow early detection and treatment of psoriatic arthritis (PsA). Screening tools have been developed to help identify patients warranting further rheumatologic assessment, but evidence suggests room for improvement in their diagnostic value and ease of use for outpatient practice. OBJECTIVE: To develop and internally validate a brief tool for dermatologists to screen patients to refer to a rheumatologist for PsA diagnosis. METHODS: After the literature review, 23 items were selected, covering pain at various locations and inflammatory signs of PsA. The validation study was conducted in medically diagnosed psoriasis patients consecutively recruited between 2012 and 2014 (Saint Joseph Hospital, Paris, France). Patients were enrolled by a dermatologist who helped to complete the questionnaire. Diagnosis of PsA was established by a rheumatologist based on CASPAR criteria. Multivariate logistic regression models were performed to build the scale, assessing discrimination through sensitivity, specificity and area under the ROC curve (AUC). Final model was internally validated using bootstrapping techniques. RESULTS: One hundred and sixty-eight patients were recruited, of whom nine were excluded for known PsA and 21 did not attend the rheumatologist consultation. Of 137 included patients (median age 43 years, 59.6% men), 21 (15.3%) had a PsA diagnosis. Final regression model retained four independent items, including evocative signs of dactylitis, inflammatory heel pain, bilateral buttock pain and peripheral joint pain with swelling in patients aged <50. A total score (the PURE-4) was computed (0-4 points) that demonstrated excellent discriminative power (AUC = 87.6%; Sensitivity = 85.7% and Specificity = 83.6% at the threshold of ≥1/4 points), with no evidence for over-optimism in bootstrapped internal validation. CONCLUSION: These findings demonstrate the good diagnostic properties of a new screening scale using only four easy-to-collect items. If confirmed in other populations, it may prove useful in outpatient dermatology clinics for triage of psoriasis patients requiring further assessment by the rheumatologist.

Association between RANK, RANKL and OPG polymorphisms with ACPA and erosions in rheumatoid arthritis: results from a meta-analysis involving three French cohorts.

OBJECTIVES: The RANK/RANKL/osteoprotegerin (OPG) system plays a central role in the pathogenesis of bone erosions in rheumatoid arthritis (RA). The aim of this study was to test the association between 11 single-nucleotide polymorphisms (SNPs) located on RANK, RANKL and OPG genes and anticitrullinated peptide antibody (ACPA) presence or erosions in RA. PATIENTS: This work was performed on three independent samples of French patients with RA: the Etude de Suivi des PolyArthrites Indifférenciées Récentes (ESPOIR) (n=632), Rangueil Midi-Pyrénées (RMP) (n=249) and French Rheumatoid Arthritis Genetic Consortium (FRAGC) (n=590) cohorts. Genotyping: the genotyping of 11 SNPs located on RANK, RANKL and OPG were performed by PCR. STATISTICAL ANALYSES: The association between the genotypes with ACPA or erosions was first tested in the ESPOIR cohort using a χ(2) test and, in the case of significant association, replicated in the RMP and FRACG cohorts. A meta-analysis on the three cohorts was performed using the Mantel-Haenszel method. RESULTS: One SNP on RANK (rs8086340) and three SNPs on RANKL (rs7984870, rs7325635, rs1054016) were significantly associated with ACPA presence, while one SNP on OPG (rs2073618) and one SNP on RANKL (rs7325635) were significantly associated with erosions in the ESPOIR cohort. Following meta-analysis performed on the three samples, the SNP on RANK and the GGG haplotype of the three SNPs located on RANKL were both significantly associated with ACPA presence, while only the SNP on OPG remained significantly associated with erosions. CONCLUSIONS: This study identified one SNP located on RANK, one haplotype on RANKL associated with ACPA presence, and one SNP located on OPG associated with erosions in three different samples of French patients with RA.

Predictive risk factors of serious infections in patients with rheumatoid arthritis treated with abatacept in common practice: results from the Orencia and Rheumatoid Arthritis (ORA) registry.

OBJECTIVES: Little data are available regarding the rate and predicting factors of serious infections in patients with rheumatoid arthritis (RA) treated with abatacept (ABA) in daily practice. We therefore addressed this issue using real-life data from the Orencia and Rheumatoid Arthritis (ORA) registry. METHODS: ORA is an independent 5-year prospective registry promoted by the French Society of Rheumatology that includes patients with RA treated with ABA. At baseline, 3 months, 6 months and every 6 months or at disease relapse, during 5 years, standardised information is prospectively collected by trained clinical nurses. A serious infection was defined as an infection occurring during treatment with ABA or during the 3 months following withdrawal of ABA without any initiation of a new biologic and requiring hospitalisation and/or intravenous antibiotics and/or resulting in death. RESULTS: Baseline characteristics and comorbidities: among the 976 patients included with a follow-up of at least 3 months (total follow-up of 1903 patient-years), 78 serious infections occurred in 69 patients (4.1/100 patient-years). Predicting factors of serious infections: on univariate analysis, an older age, history of previous serious or recurrent infections, diabetes and a lower number of previous anti-tumour necrosis factor were associated with a higher risk of serious infections. On multivariate analysis, only age (HR per 10-year increase 1.44, 95% CI 1.17 to 1.76, p=0.001) and history of previous serious or recurrent infections (HR 1.94, 95% CI 1.18 to 3.20, p=0.009) were significantly associated with a higher risk of serious infections. CONCLUSIONS: In common practice, patients treated with ABA had more comorbidities than in clinical trials and serious infections were slightly more frequently observed. In the ORA registry, predictive risk factors of serious infections include age and history of serious infections.

Late-onset neutropenia after treatment with rituximab for rheumatoid arthritis and other autoimmune diseases: data from the AutoImmunity and Rituximab registry.

OBJECTIVES: To evaluate the prevalence of late-onset neutropenia and its complications in patients treated with rituximab (RTX) for rheumatoid arthritis (RA) and other autoimmune diseases (AIDs) in a prospective registry. METHODS: The AutoImmunity and Rituximab registry is an independent 7-year prospective registry promoted by the French Society of Rheumatology. For each episode of neutropenia, data were validated by the clinician in charge of the patient. RESULTS: Among 2624 patients treated with RTX for refractory AIDs, and at least 1 follow-up visit (a total follow-up of 4179 patient-years in RA and 987 patient-years in AIDs), late-onset neutropenia was observed in 40 patients (25 RA (1.3% of patients with RA, 0.6/100 patient-years), and AIDs in 15 (2.3% of patients with AIDs, 1.5/100 patient-years)). 6 patients (15%) had neutrophils <500/mm(3), 8 (20%) had neutrophils between 500 and 1000/mm(3), and 26 (65%) had neutrophils between 1000 and 1500/mm(3). Neutropenia occurred after a median period of 4.5 (3-6.5) months after the last RTX infusion in patients with RA, and 5 (3-6.5) months in patients with AIDs. 5 patients (12.5%), 4 of them with neutrophils lower than 500/mm(3), developed a non-opportunistic serious infection and required antibiotics and granulocyte colony-stimulating factor injections, with a favourable outcome. After resolution of their RTX-related neutropenia, 19 patients (47.5%) were re-treated, and neutropenia reoccurred in 3 of them. CONCLUSIONS: Late-onset neutropenia might occur after RTX and may result in serious infections. Thus, monitoring of white cell count should be performed after RTX. However, in this large registry of patients with AIDs, the frequency of RTX-induced neutropenia was much lower than that previously reported in patients treated for blood malignancies or AIDs.

In ACPA-positive RA patients, antibodies to EBNA35-58Cit, a citrullinated peptide from the Epstein-Barr nuclear antigen-1, strongly cross-react with the peptide ß60-74Cit which bears the immunodominant epitope of citrullinated fibrin.

Although several infectious agents and particularly Epstein-Barr virus (EBV) have been suspected to be involved in aetiology of rheumatoid arthritis (RA), their role still remains elusive. Almost 80% of RA sera contain antibodies to citrullinated proteins/peptides. Among them, the autoantibodies to citrullinated human fibrinogen (AhFibA) are composed of two non-cross-reactive subsets directed to immunodominant epitopes borne by the α36-50Cit and ß60-74Cit fibrin peptides. RA sera also contain antibodies towards the citrullinated EBNA35-58Cit peptide derived from the EBNA-1 protein of EBV. Here, using a large cohort of RA patients and controls, we showed that for a diagnostic specificity of 98.5%, 47% of the AhFibA-positive patients were anti-EBNA35-58Cit-positive and that almost all (98.5%) the anti-EBNA35-58Cit-positive were AhFibA-positive, whereas 86% were anti-ß60-74Cit-positive and only 43% anti-α36-50Cit-positive. AhFibA, anti-EBNA35-58Cit- and anti-ß60-74Cit-antibody titres were significantly correlated. Competition assays showed that anti-EBNA35-58Cit antibodies are highly cross-reactive with the ß60-74Cit peptide. The demonstration that a citrullinated peptide derived from the EBNA-1 protein of EBV presents a molecular mimicry with human citrullinated fibrin constitutes an additional argument for a possible role of EBV in RA aetiopathogeny.

Evidence-based recommendations on the role of dermatologists in the diagnosis and management of psoriatic arthritis: systematic review and expert opinion.

BACKGROUND: Psoriatic arthritis (PsA) can develop at any time during the course of psoriasis. AIMS: The aims of these practical recommendations are to help dermatologists identify patients at risk of PsA, to diagnose PsA in collaboration with rheumatologists and to gain a better understanding of initial PsA management. MATERIALS AND METHODS: A scientific committee consisting of 10 dermatologists and a rheumatologist selected clinically relevant questions to be addressed by evidence-based recommendations using the DELPHI method. For each question, a systematic literature review was performed in Medline, Embase and the Cochrane Library databases. The levels of evidence of all selected and reviewed articles were appraised according to the Oxford levels of evidence. RESULTS: An expert board of 30 dermatologists reviewed and analysed the evidence and developed recommendations for the selected questions. Agreement among participants was assessed on a 10-point scale, and the potential impact of the recommendations on clinical practice was evaluated. Among the 6960 references identified, 190 relevant articles were included in the reviews. Three recommendations regarding risk factors for PsA and one regarding PsA prevalence were issued. The mean agreement score between participants varied from 7.8 to 9.6. Three recommendations on PsA screening tools that can be used by dermatologists were issued. The mean agreement score between participants varied from 7.7 to 9.4. Initial PsA treatment options according to published guidelines were critically appraised for axial and peripheral involvement and enthesitis/dactylitis. Three recommendations were issued. The mean agreement score between participants varied from 7.6 to 8.7. DISCUSSION: The systematic literature research and meta-analyses did not provide high-quality evidence to support recommendations regarding PsA screening. Conversely, PsA treatment options were supported by strong evidence. CONCLUSION: Cooperation between dermatologists and rheumatologists should be emphasized to better identify and manage PsA patients.

Treatment for palmoplantar pustular psoriasis: systematic literature review, evidence-based recommendations and expert opinion.

BACKGROUND: Palmoplantar pustular psoriasis (PPPP) is a variant of psoriasis whose the association with psoriatic arthritis (PsA) has been recently described. There is limited evidence regarding how to best reduce palmoplantar pustular psoriasis severity and to maintain remission once achieved. OBJECTIVE: The aim of this study was to elaborate evidence-based recommendations for PPPP treatment supported by a systematic literature review. METHODS: A systematic literature search was carried out in Embase, Medline and Cochrane Library databases from 1980 to February 2013 searching for any trial in patients with PPPP assessing therapeutic interventions not including a systemic biotherapy. The selection of articles was limited to human subjects and English or French languages. RESULTS: Among the 675 articles identified, 29 including one Cochrane review were analysed. The Cochrane review summarised 23 randomised controlled trials (RCTs) in chronic PPPP until February 2003, including 724 patients. The authors concluded that oral retinoid therapy (acitretin), photochemotherapy or combination of both, low dose of ciclosporin or topical corticosteroids under occlusion appeared to be helpful in relieving symptoms of PPPP. Since the publication of this review, 9 open studies on PPPP treatment have been published. Three new studies evaluated the benefits of PUVA on PPPP. They all showed a better efficacy of PUVA compared to UVB therapy. One open study concluded that a retinoid treatment with an arotinoid ethylesther showed a good efficacy. Five prospective studies (level of evidence of 3) assessed Laser Excimer UVB-NB (Excimer 308 nm) in PPPP. The combined analysis of these studies showed that 64% of patients experienced an improvement of 70% at the end of treatment. CONCLUSION: Phototherapy, ciclosporin and topical corticosteroids seem to be able to control PPPP. However, the standard of care for PPPP remains an issue and there is a strong need for reliable RCTs to better define treatment strategies for PPPP.

Is there a psoriasis skin phenotype associated with psoriatic arthritis? Systematic literature review.

Psoriatic arthritis (PsA) is associated with psoriasis with a prevalence varying from 5.94% to 23.9%. The aim of this study was to assess if some psoriatic skin features are associated with a higher risk of PsA. A systematic literature search was carried out from 1980 to January 2013, in the Embase and Pubmed databases, using a combination of keywords including (Psoriasis) AND (PsA). Of the 2746 articles retrieved, 25 references were selected. Meta-analysis was performed when possible. Mean age at psoriasis onset appeared to be similar among patients with skin disease alone and in those with PsA. There was no clinical type of psoriasis specifically associated with PsA, including pustular psoriasis of palms and soles. Nonetheless specific psoriasis localizations were significantly associated with an increased risk of developing PsA in one cohort study: scalp lesions [Hazard Ratio (HR) 3.89 (95% confidence interval (CI):2.18-6.94)] and intergluteal/perianal lesions [HR 2.35 (95%CI:1.32-4.19)]. A similar association was found in two cross-sectional studies. Nail involvement was significantly associated with PsA in the meta-analysis [Odds Ratio (OR) 2.92 (95% CI 2.34-3.64)], particularly onycholysis [OR 2.38 (95% CI 1.74-3.26)]. Moreover, nail psoriasis was also associated with distal interphalangeal joint arthritis. The extent of psoriasis appeared to be associated with PsA in one cohort study [≥3 sites: HR 2.24 (95% CI 1.23-4.08)], one case-control study [body surface area >75%: OR 2.52 (95% CI 1.33-4.75)] and three cross-sectional studies. The meta-analysis suggested a trend for an association between high PASI and PsA risk [mean difference 3.39 (95% CI 0.94-5.83)]. Therefore, psoriasis patients with such clinical features may require a particular attention for early and close detection of PsA during the course of the cutaneous disease.

Symptoms dermatologists should look for in daily practice to improve detection of psoriatic arthritis in psoriasis patients: an expert group consensus.

BACKGROUND: Up to 29% of patients with psoriasis seen by dermatologists have undiagnosed psoriatic arthritis (PsA). As early detection of PsA may be associated with improved joint and skin outcomes, it is essential for dermatologists to improve their ability to diagnose PsA. Skin and nail features of psoriasis associated with PsA are well known to dermatologists but they may feel less confortable assessing other symptoms and they rarely use PsA screening questionnaires. OBJECTIVE: To develop a limited list of clinical signs and symptoms that a dermatologist should be looking for in a psoriasis patient in addition to specific skin features and nail involvement, to improve PsA detection. METHODS: A systematic search was performed in Pubmed, Cochrane and Embase databases to identify clinical key symptoms associated with PsA. It yielded 27 studies in which we extracted a list of clinical signs and symptoms observed in PsA and submitted it to a panel of dermatology experts through a DELPHI selection process. The experts had to determine which minimal set of signs and symptoms dermatologists should look for in daily practice to improve detection of PsA in patients with psoriasis. RESULTS: The four items that received a score higher than 90% in the DELPHI process were finally selected. Those items were as follows: peripheral inflammatory pain (100%), axial inflammatory pain (95.3%), dactylitis (93%), buttock and sciatic pain (90.7%). The remaining items: distal interphalangeal joints (DIPs) involvement (83.7%), Talalgia (79.1%), swollen Achille's tendon (41.9%), costo-chondral involvement (32.6%), uveitis (7%), mouth ulcerations (2.3%), were not retained. CONCLUSION: We propose a set of four items to screen psoriasis patients for psoriatic arthritis for routine clinical use by dermatologists.

Treatment (biotherapy excluded) of psoriatic arthritis: an appraisal of methodological quality of international guidelines.

BACKGROUND: Some international guidelines have been published to provide the best care for patients with psoriatic arthritis (PsA) but little is known about their quality. OBJECTIVE: The primary aim of this study was to examine the quality of guidelines that concern treatment (biotherapy exluded) of PsA. The secondary aim was to review studies published since the publication of the most recent guideline. METHODS: A systematic literature search was carried out from 2007 to February 2013, in the Embase, Medline and Cochrane Library databases, in English and French using a combination of keywords including 'Arthritis, Psoriatic/therapy' NOT 'Biological Therapy' OR 'Antibodies, Monoclonal' OR 'Recombinant Fusion Proteins' OR 'tumour necrosis factor-alpha'. The AGREE instrument (Appraisal of Guidelines Research and Evaluation) was used by four reviewers to evaluate the quality of selected guidelines according to the proposed methodology. RESULTS: Of the 518 identified references, six guidelines and two studies were selected. There was considerable variation in the quality of clinical guidelines across the AGREE domains. The least well-addressed domains were 'applicability', 'stakeholder involvement', 'scope and purpose' and 'quality of development', whereas 'editorial independence' and 'clarity and presentation' were less problematic. CONCLUSION: Although guidelines development was of good quality, many of the studies that they included are of poorer quality. This work indicates that the current guidelines can be improved, particularly the stakeholder domain and the applicability domain. The prospective use of the AGREE instrument should improve the guideline quality. More controlled trials should be required but are unlikely to be conducted, given the lack of interest in studying old drugs.

The fibrin-derived citrullinated peptide ß60-74Cit60,72,74 bears the major ACPA epitope recognised by the rheumatoid arthritis-specific anticitrullinated fibrinogen autoantibodies and anti-CCP2 antibodies.

OBJECTIVES: To evaluate the proportions of rheumatoid arthritis (RA) sera containing anticitrullinated proteins autoantibodies (ACPA) reactive to α36-50Cit38,42 and/or ß60-74Cit60,72,74, two peptides identified as bearing the immunodominant epitopes of their major target, citrullinated fibrin. To analyse the relationships of anti-α36-50Cit38,42 and anti-ß60-74Cit60,72,74 autoantibodies with autoantibodies reactive to the complete citrullinated human fibrinogen molecule (AhFibA) and with anti-CCP2 antibodies. METHODS: 617 sera from 181 patients with established RA and 436 with non-RA rheumatic diseases were tested by ELISA for AhFibA, anti-CCP2, anti-α36-50Cit38,42, anti-ß60-74Cit60,72,74 autoantibodies, and by nephelometry for rheumatoid factor (RF). Diagnostic indexes, correlations and concordances between tests were analysed. Crossreactivity of anti-α36-50Cit38,42 and anti-ß60-74Cit60,72,74 autoantibodies was assessed in competition experiments. RESULTS: At a diagnostic specificity of 95%, the diagnostic sensitivity of AhFibA (83%) was significantly higher than that of all other tests. The diagnostic sensitivity of anti-ß60-74Cit60,72,74 (71%) was significantly higher than that of anti-α36-50Cit38,42 autoantibodies (51%) but similar to that of anti-CCP2 (74%). Titres of RF, anti-α36-50Cit38,42 and anti-ß60-74Cit60,72,74 autoantibodies were weakly correlated with each other, whereas titres of anti-ß60-74Cit60,72,74 were strongly correlated with those of AhFibA (r=0.633) and anti-CCP2 (r=0.634). Anti-α36-50Cit38,42 and anti-ß60-74Cit60,72,74 mainly corresponded to two non-crossreactive subfamilies of ACPA. More than 90% of AhFibA-positive or anti-CCP2-positive sera recognised the α36-50Cit38,42 and/or the ß60-74Cit60,72,74 peptide. CONCLUSIONS: Autoantibodies reactive to α36-50Cit38,42 and ß60-74Cit60,72,74 form two distinct, non-overlapping subfamilies of ACPA that, together, cover practically all the ACPA reactivity to citrullinated fibrinogen and to CCP2 antigens. In established RA, anti-ß60-74Cit60,72,74 autoantibodies show diagnostic indexes similar to those of anti-CCP2.

Positivity for anti-cyclic citrullinated peptide is associated with a better response to abatacept: data from the 'Orencia and Rheumatoid Arthritis' registry.

OBJECTIVES: Very limited data are available regarding the efficacy of abatacept (ABA) in real life. The aims of this study were to determine the efficacy of ABA in rheumatoid arthritis and predicting factors of efficacy in common practice. METHODS: The Orencia and Rheumatoid Arthritis" (ORA) prospective registry, promoted by the French Society of Rheumatology, has included 1003 patients with RA. RESULTS: 773 patients had already fulfilled the 6-month follow-up visit. Only 21.3% of patients would have fulfilled inclusion criteria used in pivotal controlled trials. The European League Against Rheumatism (EULAR) response, was observed in 330 (59.1%) of the 558 assessed patients (good response: 20.4%, moderate response: 38.7%) and was similar in patients who did and in patients who did not fulfill inclusion criteria of controlled trials. Among EULAR responders, initial 28-joint disease activity score (5.4 (4.7-6.5) in responders vs 4.9 (4.0-6.0) in non responders, p< 0.0001), the proportion of rheumatoid factor (75.6% vs 66.7%, p= 0.03) and the proportion of anti-cyclic citrullinated peptide antibody (anti-CCP)-positivity (75.9% vs 62.2%, p= 0.001) were significantly higher. In multivariate analysis adjusted on initial 28-joint disease activity score and CRP, anti-CCP positivity was associated with EULAR response (OR=1.9;95% CI=1.2 to 2.9, p=0.007), but not rheumatoid factor (OR=1.0;95% CI=0.6 to 1.6, p=0.9). Anti-CCP positivity was also significantly associated with a higher ABA retention rate at 6 months. CONCLUSIONS: Real life efficacy of ABA in the ORA registry was similar as that reported in clinical trials. Anti-CCP positivity was associated with a better response to ABA, independently from disease activity.

Efficacy of rituximab in primary Sjogren's syndrome with peripheral nervous system involvement: results from the AIR registry.

OBJECTIVE: To evaluate rituximab (RTX) in primary Sjögren's syndrome (pSS) with peripheral nervous system (PNS) involvement. METHODS: Patients with pSS and PNS involvement who were included in the French AIR registry were analysed. RESULTS: 17 patients (age 60 years (44-78 years); 14 were female) were analysed. Neurological improvement was noted in 11 patients (65%) at 3 months. Rankin scale decreased from 3 (1-5) to 2 (1-5), 2 (1-5) and 2 (1-6) after 3, 6 and 9 months (p=0.02). European Sjögren's Syndrome Disease Activity Index decreased from 18 (10-44) to 11 (5-20), 11 (5-29) and 12 (5-30) after 3, 6 and 9 months (p<0.05). RTX was effective in neurological involvement in 9/10 patients with vasculitis or cryoglobulinaemia (90%) (group 1) at 3 months and in 2/7 cases (29%) without cryoglobulinaemia and vasculitis (p=0.03). Rankin and European Sjögren's Syndrome Disease Activity Index scales decreased significantly in group 1. CONCLUSION: RTX seems effective in cryoglobulinaemia or vasculitis-related PNS involvement in pSS.

Cytosolic phospholipase A2α gene silencing in the myeloid lineage alters development of Th1 responses and reduces disease severity in collagen-induced arthritis.

OBJECTIVE: Several lines of evidence implicate cytosolic phospholipase A(2)α (cPLA(2)α) as a critical enzyme in inflammatory disorders, including rheumatoid arthritis. Since cells from the myeloid compartment regulate local and systemic disease pathogenesis, the present study was undertaken to examine the effect of cPLA(2)α inhibition in experimental arthritis, using a delivery system tailored to target monocyte functions by RNA interference (RNAi). METHODS: Mice with collagen-induced arthritis (CIA) were injected intravenously with an anti-cPLA(2)α small interfering RNA (siRNA) sequence (siPLA2) formulated as lipoplexes with the RPR209120/DOPE cationic liposome and a carrier DNA. The clinical course of joint inflammation was assessed, and the immunologic balance was analyzed by measuring T helper cell frequencies and cytokine expression. Biodistribution studies of siRNA were also performed. RESULTS: Weekly systemic injection of siPLA2 lipoplexes significantly reduced the incidence and severity of CIA, in both preventive and curative settings, as compared with findings in control animals. Histologic scores for inflammation and cartilage damage were reduced. The clinical effect was associated with local inhibition of tumor necrosis factor α secretion and lower cPLA(2)α expression and activity. The siPLA2 lipoplexes enabled triggering of in vivo RNAi-mediated gene silencing of cPLA(2)α in CD11b+ cells recovered from the spleen. While the treatment had no effect on anti-type II collagen (anti-CII) antibodies, CII-specific T helper cells producing interferon-γ, but not interleukin-17, in draining lymph node cells were decreased. CONCLUSION: Our findings indicate that systemic RNAi-mediated cPLA(2)α gene silencing in CD11b+ cells is effective in the treatment of CIA, and Th1 suppression is one of the potential underlying mechanisms, whereas Th17 suppression is not.

Risk factors for severe infections in patients with rheumatoid arthritis treated with rituximab in the autoimmunity and rituximab registry.

OBJECTIVE: The risk of severe infection is a crucial factor in the assessment of the short-term risk:benefit ratio of biologic drugs in rheumatoid arthritis (RA). There is no increase in severe infections in RA patients treated with rituximab (RTX) in controlled trials, but this has not yet been assessed in daily practice. We undertook this study to investigate the occurrence of and risk factors for severe infections in off-trial patients using data from the AutoImmunity and Rituximab (AIR) registry. METHODS: The AIR registry was set up by the French Society of Rheumatology. The charts of patients with severe infections were reviewed. RESULTS: Of the enrolled patients, 1,303 had at least 1 followup visit at 3 months or later, with a mean ± SD followup period of 1.2 ± 0.8 years (1,629 patient-years). Eighty-two severe infections occurred in 78 patients (5.0 severe infections per 100 patient-years), half of them in the 3 months following the last RTX infusion. Multivariate analysis showed that chronic lung disease and/or cardiac insufficiency (odds ratio 3.0 [95% confidence interval 1.3-7.3], P = 0.01), extraarticular involvement (odds ratio 2.9 [95% confidence interval 1.3-6.7], P = 0.009), and low IgG level (<6 gm/liter) before initiation of RTX treatment (odds ratio 4.9 [95% confidence interval 1.6-15.2], P = 0.005) were significantly associated with increased risk of a severe infection. CONCLUSION: The rate of severe infections in current practice is similar to that reported in clinical trials. The risk factors for severe infections include chronic lung and/or cardiac disease, extraarticular involvement, and low IgG before RTX treatment. This suggests that serum IgG should be checked and the risk:benefit ratio of RTX discussed for patients found to have low levels of IgG.

IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial.

OBJECTIVES: The phase III RADIATE study examined the efficacy and safety of tocilizumab, an anti-IL-6 receptor monoclonal antibody in patients with rheumatoid arthritis (RA) refractory to tumour necrosis factor (TNF) antagonist therapy. METHODS: 499 patients with inadequate response to one or more TNF antagonists were randomly assigned to receive 8 mg/kg or 4 mg/kg tocilizumab or placebo (control) intravenously every 4 weeks with stable methotrexate for 24 weeks. ACR20 responses, secondary efficacy and safety endpoints were assessed. RESULTS: ACR20 was achieved at 24 weeks by 50.0%, 30.4% and 10.1% of patients in the 8 mg/kg, 4 mg/kg and control groups, respectively (less than p<0.001 both tocilizumab groups versus control). At week 4 more patients achieved ACR20 in 8 mg/kg tocilizumab versus controls (less than p = 0.001). Patients responded regardless of most recently failed anti-TNF or the number of failed treatments. DAS28 remission (DAS28 <2.6) rates at week 24 were clearly dose related, being achieved by 30.1%, 7.6% and 1.6% of 8 mg/kg, 4 mg/kg and control groups (less than p = 0.001 for 8 mg/kg and p = 0.053 for 4 mg/kg versus control). Most adverse events were mild or moderate with overall incidences of 84.0%, 87.1% and 80.6%, respectively. The most common adverse events with higher incidence in tocilizumab groups were infections, gastrointestinal symptoms, rash and headache. The incidence of serious adverse events was higher in controls (11.3%) than in the 8 mg/kg (6.3%) and 4 mg/kg (7.4%) groups. CONCLUSION: Tocilizumab plus methotrexate is effective in achieving rapid and sustained improvements in signs and symptoms of RA in patients with inadequate response to TNF antagonists and has a manageable safety profile. TRIAL REGISTRATION NUMBER: NCT00106522.

Distal renal tubular acidosis and ovalocytosis: a case report.

A 23-year-old man presented with osteoporosis, revealed by femoral fractures, and a history of nephrolithiasis, short stature, metabolic acidosis, hypokalemia and ovalocytosis, a red blood cell abnormality common in malaria endemic regions. Biological investigations led to the diagnosis of type 1 distal renal tubular acidosis (dRTA). Ovalocytosis and dRTA may co-exist in the same patient, since both can originate in mutations of the anion-exchanger 1 (AE1) gene, which codes for band 3, the bicarbonate/chloride exchanger, present in both the red cell membrane and the basolateral membrane of the collecting tubule alpha-intercalated cell.