Vasculitis and familial Mediterranean fever: Description of 22 French adults from the juvenile inflammatory rheumatism cohort.

Objective: The frequency of vasculitis may be increased in patients with Familial Mediterranean Fever (FMF), according to several studies. Our aim was to assess the characteristics of French adult patients with both diseases. Methods: Patients with vasculitis were selected from patients followed for FMF in the French JIR-cohort. Results: Twenty-two patients were included [polyarteritis nodosa (PAN) n = 10, IgA vasculitis n = 8, unclassified vasculitis n = 2, granulomatosis with polyangiitis n = 1, and microscopic polyangiitis n = 1]. Pathogenic mutations in exon 10 were found in all 21 patients (96%) for which MEFV testing results were available, and 18 (82%) had two pathogenic mutations. Histology showed vasculitis in 59% of patients. Most patients with FMF-associated PAN were HBV-negative and had an inactive FMF before PAN onset, and 40% had a peri-renal or central nervous system bleeding. Most patients with FMF-associated IgA vasculitis had an active FMF before vasculitis onset, and 25% had digestive bleeding. Both patients with unclassified vasculitis had ischemic and/or hemorrhagic complications. Conclusion: This study confirms the predominance of PAN and IgA vasculitis in patients with FMF and the high frequency of bleeding in FMF-associated PAN. FMF should be considered in case of persistent symptoms and/or inflammatory syndrome despite vasculitis treatment in Mediterranean patients.

Efficacy and Safety of Tocilizumab for Polyarticular-Course Juvenile Idiopathic Arthritis in the Open-Label Two-Year Extension of a Phase III Trial.

OBJECTIVE: To report the 2-year efficacy and safety of tocilizumab (TCZ) in patients with polyarticular-course juvenile idiopathic arthritis (JIA). METHODS: Patients ages 2-17 years with active polyarticular-course JIA, in whom treatment with methotrexate was unsuccessful, received 16 weeks of open-label intravenous TCZ in part 1 (once every 4 weeks: 8 mg/kg or 10 mg/kg for body weight [BW] <30 kg; 8 mg/kg for BW ≥30 kg). Assessments were based on the JIA-American College of Rheumatology (ACR) response (defined as percentage of improvement in ≥3 of the 6 JIA core response variables [CRVs]). Patients with at least a JIA-ACR30 response (defined as ≥30% improvement in ≥3 of the 6 JIA CRVs without worsening in >1 of the remaining JIA CRVs by >30%) at week 16 were randomly assigned (1:1) to receive TCZ or placebo in part 2. Patients remained in part 2 until either week 40 or the occurrence of JIA flare. Upon starting part 3, all patients received open-label TCZ. At week 104 of the study, efficacy was assessed using JIA-ACR50/70/90 response rates (defined as 50%, 70%, or 90% improvement, respectively), achievement of inactive disease, and the Juvenile Arthritis Disease Activity Score in 71 joints (JADAS-71). Safety was assessed in the all-exposure population per 100 patient-years of exposure. RESULTS: Overall, 188 patients entered part 1, 166 patients entered part 2, and 160 patients entered part 3. By week 104, among the 188 patients in the modified intent-to-treat group who received TCZ, JIA-ACR50/70/90 response rates were 80.3%/77.1%/59.6%, respectively, the median JADAS-71 score decreased from 3.6 at week 40 to 0.7 at week 104, 51.1% of patients had achieved inactive disease, and 31 of 66 patients who had been receiving glucocorticoids discontinued them. Adverse event (AE) and serious AE rates were 406.5 per 100 patient-years and 11.1 per 100 patient-years, respectively. The infection rate was 151.4 per 100 patient-years, and the serious infection rate was 5.2 per 100 patient-years. CONCLUSION: Patients treated with TCZ for polyarticular-course JIA showed high-level disease control for up to 2 years. The TCZ safety profile was consistent with that previously reported.

Serious adverse events in children with juvenile idiopathic arthritis and other rheumatic diseases on tocilizumab - a real-world experience.

OBJECTIVES: To assess the incidence rate and type of serious adverse events (SAE) in children with rheumatic inflammatory diseases treated with the interleukin 6 blocker tocilizumab (TCZ). METHODS: A retrospective review of all consecutive patients diagnosed with an inflammatory rheumatic disease and receiving at least one dose of TCZ was performed in two French tertiary pediatric rheumatology centers between 01/2007 and 06/2019. SAE were defined as a life-threatening event and/or an event requiring hospital admission, leading to permanent disability or treatment discontinuation. RESULTS: One hundred four children (64 female) were included. Most children suffered from systemic (n = 43) or polyarticular-course juvenile idiopathic arthritis (n = 43). Median age at TCZ start was 8.9 years (IQR 4.7 - 12.1), most children had received prednisone (81%), and/or a biologic agent (84%) prior to TCZ. Median TCZ treatment duration was 1.6 years (IQR 0.5 - 2.7), total TCZ exposure 215 patient years. Thirty-three SAE were observed in 26 (25%) children (SAE 15.3/100 patient years), mostly infections and infusion reactions. Children with SAE were significantly younger at disease onset (p = 0.034) and TCZ initiation (p = 0.016). Children experiencing infusion reactions were more likely to have systemic JIA or another autoinflammatory disease (p = 0.021), they all had active disease. At last follow up, 61 (59%) children remained on TCZ. CONCLUSION: In this cohort, SAE and most commonly serious infections were observed in a quarter of children. Severe infusion reactions were associated with persistently active autoinflammatory disease. Ongoing careful monitoring of TCZ-treated patients, especially young children with marked systemic inflammation is required.

Persistent osteoarticular pain in children: early clinical and laboratory findings suggestive of acute lymphoblastic leukemia (a multicenter case-control study of 147 patients).

BACKGROUND: The aim of this study was to identify early clinical and laboratory features that distinguish acute lymphoblastic leukemia (ALL) from juvenile idiopathic arthritis (JIA) in children presenting with persistent bone or joint pain for at least 1 month. METHODS: We performed a multicenter case-control study and reviewed medical records of children who initially presented with bone or joint pain lasting for at least 1 month, all of whom were given a secondary diagnosis of JIA or ALL, in four French University Hospitals. Each patient with ALL was paired by age with two children with JIA. Logistic regression was used to compare clinical and laboratory data from the two groups. RESULTS: Forty-nine children with ALL and 98 with JIA were included. The single most important feature distinguishing ALL from JIA was the presence of hepatomegaly, splenomegaly or lymphadenopathy; at least one of these manifestations was present in 37 cases with ALL, but only in 2 controls with JIA, for an odds ratio (OR) of 154 [95%CI: 30-793] (regression coefficient: 5.0). If the presence of these findings is missed or disregarded, multivariate analyses showed that non-articular bone pain and/or general symptoms (asthenia, anorexia or weight loss) (regression coefficient: 4.8, OR 124 [95%CI: 11.4-236]), neutrophils < 2 × 109/L (regression coefficient: 3.9, OR 50 [95%CI: 4.3-58]), and platelets < 300 × 109/L (regression coefficient: 2.6, OR 14 [95%CI: 2.3-83.9]) were associated with the presence of ALL (area under the ROC curve: 0.96 [95%CI: 0.93-0.99]). CONCLUSIONS: Based on our findings we propose the following preliminary decision tree to be tested in prospective studies: in children presenting with at least 1 month of osteoarticular pain and no obvious ALL in peripheral smear, perform a bone marrow examination if hepatomegaly, splenomegaly or lymphadenopathy is present. If these manifestations are absent, perform a bone marrow examination if there is fever or elevated inflammatory markers associated with non-articular bone pain, general symptoms (asthenia, anorexia or weight loss), neutrophils < 2 × 109/L or platelets < 300 × 109/L.

Etanercept treatment for extended oligoarticular juvenile idiopathic arthritis, enthesitis-related arthritis, or psoriatic arthritis: 6-year efficacy and safety data from an open-label trial.

BACKGROUND: To describe the 6-year safety and efficacy of etanercept (ETN) in children with extended oligoarticular juvenile idiopathic arthritis (eoJIA), enthesitis-related arthritis (ERA), and psoriatic arthritis (PsA) METHODS: Patients who completed the 2-year, open-label, phase III CLinical Study In Pediatric Patients of Etanercept for Treatment of ERA, PsA, and Extended Oligoarthritis (CLIPPER) were allowed to enroll in its 8-year long-term extension (CLIPPER2). Children received ETN at a once-weekly dose of 0.8 mg/kg, up to a maximum dose of 50 mg/week. Efficacy assessments included the JIA core set of outcomes, the JIA American College of Rheumatology response criteria (JIA-ACR), and the Juvenile Arthritis Disease Activity Score (JADAS). Efficacy data are reported as responder analyses using a hybrid method for missing data imputation and as observed cases. Safety assessments included treatment-emergent adverse events (TEAEs). RESULTS: Out of 127 patients originally enrolled in CLIPPER, 109 (86%) entered CLIPPER2. After 6 years of trial participation (2 years in CLIPPER and 4 years in CLIPPER2), 41 (32%) patients were still taking ETN, 13 (11%) entered the treatment withdrawal phase after achieving low/inactive disease (of whom 7 had to restart ETN), 36 (28%) discontinued treatment for other reasons but are still being observed, and 37 (29%) discontinued treatment permanently. According to the hybrid imputation analysis, proportions of patients achieving JIA ACR90, JIA ACR100, and JADAS inactive disease after the initial 2 years of treatment were 58%, 48%, and 32%, respectively. After the additional 4 years, those proportions in patients who remained in the trial were 46%, 35%, and 24%. Most frequently reported TEAEs [n (%), events per 100 patient-years] were headache [28 (22%), 5.3], arthralgia [24 (19%), 4.6], and pyrexia [20 (16%), 3.8]. Number and frequency of TEAEs, excluding infections and injection site reactions, decreased over the 6-year period from 193 and 173.8, respectively, during year 1 to 37 and 61.3 during year 6. A single case of malignancy (Hodgkin's lymphoma) and no cases of active tuberculosis, demyelinating disorders, or deaths were reported. CONCLUSIONS: Open-label etanercept treatment for up to 6 years was safe, well tolerated, and effective in patients with eoJIA, ERA, and PsA. TRIAL REGISTRATION: ClinicalTrials.gov: CLIPPER, NCT00962741 , registered 20 August, 2009, CLIPPER2, NCT01421069 , registered 22 August, 2011.

Treatment of active rheumatoid arthritis: comparison of patients younger vs older than 75 years (CORPUS cohort).

Objectives: Little information is available on the characteristics of elderly patients starting TNFα antagonist treatment for rheumatoid arthritis (RA). The objective of this work was to compare prescription patterns in RA patients younger vs. older than 75 years. Methods: Biologic-naive patients with active RA (DAS28 > 3.2) despite first-line therapy were included between 2007 and 2009 in the prospective, multicentre, longitudinal, observational, population-based CORPUS-RA cohort. TNFα antagonist users were defined as having received at least one TNFα antagonist during the first study year. The groups < 75 years and ≥ 75 years were compared regarding comorbidities, inflammation (CRP and ESR), disease activity (DAS28), disability (HAQ-DI), number of physician visits, and treatment. To verify the impact of the cut off, we also compared patients aged 70 years or more to patients younger than 70 years. Results: Of 543 RA patients, 382 had complete one-year follow-up data, including 114 TNFα antagonist users, 3 (6%) among the 49 patients aged 75 years or over and 111 (32%) of the 333 patients younger than 75 years (p < 0.01). Disease activity in the two age groups was similar at inclusion and after one year. Comorbidities and a history of auto-immunity were more common in the older group. Compared to their younger counterparts, the older patients received glucocorticoids more often (p = 0.003) and synthetic disease-modifying anti-rheumatic drugs less often (p = 0.01). Conclusion: TNFα antagonists are used less often and glucocorticoids more often in elderly patients with active RA compared to their younger counterparts. The fact that this study was performed in 2007-9 is a limitation in terms of relevance to today's patients and further studies should be conducted in new cohorts of active RA.

Clinical features of children with enthesitis-related juvenile idiopathic arthritis / juvenile spondyloarthritis followed in a French tertiary care pediatric rheumatology centre.

BACKGROUND: Childhood-onset spondyloarthropathies usually start with enthesitis and peripheral arthritis. However, axial disease may develop afterward. Patients are most often classified, following revised (Edmonton 2011) ILAR criteria, as enthesitis-related arthritis, psoriatic arthritis, or unclassified juvenile idiopathic arthritis, particularly in cases of psoriasis in the patient or a first-degree relative. In adults, peripheral spondyloarthritis is classified by ASAS criteria. METHODS: We retrospectively studied patients with childhood-onset spondyloarthropathies followed for more than one year in our referral centre. We did not exclude patients with a personal or familial history of psoriasis. RESULTS: We included 114 patients followed between January 2008 and December 2015 for a median of 2.5 years (IQR = 2.3). Sixty-nine per-cent of patients fulfilled the revised ILAR classification criteria for enthesitis-related arthritis, and 92% the ASAS criteria for peripheral spondyolarthritis (p <  0.001). Axial disease and sacroiliitis were rare at disease onset. However, they appeared during follow-up in 63% and 47% of cases respectively, after a median disease duration of 2.6 (IC 95% [2.2-4.4]) and 5.3 years (IC 95% [4.1-7.7]), respectively. Multivariable analysis showed that familial history of spondyloarthritis was associated with the presence of sacroiliitis and active disease at the latest follow-up (OR = 3.61 [1.5-8.7], p <  0.01 and 2.98 [1.2-7.3], p = 0.02, respectively). CONCLUSION: Axial involvement developed in most patients within five years. Revised Edmonton criteria were less sensitive than ASAS criteria to classify patients as having childhood-onset spondyloarthropathies. The main risk factor for both sacroiliitis and persistent active disease was a familial history of spondyloarthritis.

Glucocorticoid-sparing effect of first-year anti-TNFα treatment in rheumatoid arthritis (CORPUS Cohort).

OBJECTIVES: Anti-TNFα agents are indicated in selected patients with rheumatoid arthritis (RA) who respond inadequately to methotrexate and particularly when glucocorticoids are mandatory. We evaluated whether a glucocorticoid-sparing effect occurred during the first year of anti-TNF-α therapy. METHODS: Between 2007 and 2009, the French multicentre, longitudinal, prospective, observational, population-based CORPUS cohort included biologic-naive patients with inflammatory joint disease. Patients with active RA treated with glucocorticoids were included. Patients who received at least one anti-TNFα injection during follow-up were compared to anti-TNF-α non-users. RESULTS: Among the 205 patients, 76.1% were women, mean disease duration was 7.7±8.3 years, mean DAS28 was 5.2±1.3, mean follow-up was 13.1±2.8 months, and mean prednisone dose was 9.9±9.6 mg/day. The 75 (36.6%) anti-TNF-α recipients were younger, had a longer RA duration, more often tested positive for rheumatoid factor and anti-citrullinated peptide antibody, more often received previous DMARDs, received a higher methotrexate dosage, had fewer intra-articular glucocorticoid injections at baseline and were more often followed by hospital practitioners than non-recipients. Mean prednisone dosage decreased from 11.8±12.7 to 5.9±9.7 mg/day in recipients and from 8.7±7.1 to 5.0±4.4 mg/day in non-recipients. Prednisone was stopped more often among recipients (21/59, 35.6%) than among non-recipients (16/94, 17.0%) (p=0.01). By multivariate analysis, factors independently associated with lower prednisone requirements were baseline daily prednisone dosage, a CRP >10 mg/l and not to be followed by an office-based practitioner. CONCLUSIONS: This study showed a significantly higher glucocorticoid discontinuation rate among anti-TNF-α recipients than among non-recipients. However, the glucocorticoid-sparing effect was small and not observed by multivariate analysis.

Arthritis in children: comparison of clinical and biological characteristics of septic arthritis and juvenile idiopathic arthritis.

AIM: Childhood arthritis arises from several causes. The aim of this observational study is to compare the clinical and biological features and short-term outcome of different types of arthritis because they have different treatment and prognoses. METHODS: Children <16 years of age hospitalised in a French tertiary care centre for a first episode of arthritis lasting for less than 6 weeks who underwent joint aspiration were retrospectively included. We performed non-parametrical tests to compare groups (septic arthritis (SA), juvenile idiopathic arthritis (JIA) and arthritis with no definitive diagnosis). The time before apyrexia or C reactive protein (CRP) <10 mg/L was analysed using the Kaplan-Meier method. RESULTS: We studied 125 children with a sex ratio (M/F) of 1.1 and a median age of 2.2 years (range 0.3 to 14.6). SA was associated with a lower age at onset (1.5 years, IQR 1.2-3.0 vs 3.6 years, IQR 2.2-5.6), shorter duration of symptoms before diagnosis (2 days, IQR 1-4 vs 7 days, IQR 1-19) and higher synovial white blood cell count (147 cells ×103/mm3, IQR 71-227, vs 51 cells ×103/mm3, IQR 12-113), than JIA. Apyrexia occurred later in children with JIA (40% after 2 days, 95% CI 17% to 75%) than children with SA (82%, 95% CI 68% to 92%), as did CRP<10 mg/L (18% at 7 days, 95% CI 6.3% to 29.6% vs 82.1%, 95% CI 76.1% to 89.7%, p=0.01). CONCLUSIONS: There were no sufficiently reliable predictors for differentiating between SA and JIA at onset. The outcomes were different; JIA should be considered in cases of poor disease evolution after antibiotic treatment and joint aspiration.

Which patients with rheumatoid arthritis, spondyloarthritis, or juvenile idiopathic arthritis receive TNF-α antagonists in France? The CORPUS cohort study.

OBJECTIVES: Limited information is available about the characteristics of patients with active inflammatory rheumatic diseases who start TNF-α antagonist therapy. Our objective was to assess TNF-α antagonist prescription patterns in this context in France. METHODS: Between 2007 and 2009, 102 rheumatologists, internists, and pediatricians in French university hospitals and private practice prospectively recruited biologics-naïve patients with active rheumatoid arthritis (RA) (DAS28>3.2 despite methotrexate therapy), spondyloarthritis (SA) (BASDAI≥4 despite non-steroidal anti-inflammatory drug [NSAID] use), and juvenile idiopathic arthritis (JIA) (unresponsive to methotrexate). Patients were monitored prospectively for 1 year. RESULTS: Of the 543 RA, 287 SA, and 53 JIA patients included in the study, 382 RA, 171 SA, and 28 JIA patients had complete follow-up data available after 1 year. Among these patients, 110/382 (28.8%) with RA, 81/171 (47.4%) with SA, and 26/28 (92.9%) with JIA received at least one TNF-α antagonist dose during the 1-year follow-up. The main physician-reported reason for not starting TNF-α antagonists in patients with RA or SA was low disease activity (72% for RA and 67% for SA); absence of TNF-α antagonist therapy was due to patient refusal in only 10% and to contraindications in 6% to 7% of cases. CONCLUSIONS: In France, TNF-α antagonists, which are fully reimbursed by the national health insurance system, were used almost routinely in JIA patients unresponsive to methotrexate and were given to about half the SA patients with BASDAI≥4 despite NSAID use and a third of RA patients with DAS28>3.2 despite methotrexate therapy.

Long-term safety, efficacy, and quality of life in patients with juvenile idiopathic arthritis treated with intravenous abatacept for up to seven years.

OBJECTIVE: The efficacy and safety of abatacept in patients with juvenile idiopathic arthritis (JIA) who experienced an inadequate response to disease-modifying antirheumatic drugs were previously established in a phase III study that included a 4-month open-label lead-in period, a 6-month double-blind withdrawal period, and a long-term extension (LTE) phase. The aim of this study was to present the safety, efficacy, and patient-reported outcomes of abatacept treatment (10 mg/kg every 4 weeks) during the LTE phase, for up to 7 years of followup. METHODS: Patients enrolled in the phase III trial could enter the open-label LTE phase if they had not achieved a response to treatment at month 4 or if they had received abatacept or placebo during the double-blind period. RESULTS: One hundred fifty-three (80.5%) of 190 patients entered the LTE phase, and 69 patients (36.3%) completed it. The overall incidence rate (events per 100 patient-years) of adverse events decreased during the LTE phase (433.61 events during the short-term phase [combined lead-in and double-blind periods] versus 132.39 events during the LTE phase). Similar results were observed for serious adverse events (6.82 versus 5.60), serious infections (1.13 versus 1.72), malignancies (1.12 versus 0), and autoimmune events (2.26 versus 1.18). American College of Rheumatology (ACR) Pediatric 30 (Pedi 30) responses, Pedi 70 responses, and clinically inactive disease status were maintained throughout the LTE phase in patients who continued to receive therapy. Improvements in the Child Health Questionnaire physical and psychosocial summary scores were maintained over time. CONCLUSION: Long-term abatacept treatment for up to 7 years was associated with consistent safety, sustained efficacy, and quality-of-life benefits in patients with JIA.

Old treatments for new insights and strategies: proposed management in adults and children with alkaptonuria.

Alkaptonuria (AKU) is caused by deficiency of the enzyme homogentisate 1,2 dioxygenase. It results in an accumulation of homogentisate which oxidizes spontaneously to benzoquinone acetate, a highly oxidant compound, which polymerises to a melanin-like structure, in a process called ochronosis. Asymptomatic during childhood, this accumulation will lead from the second decade of life to a progressive and severe spondylo-arthopathy, associated with multisystem involvement: osteoporosis/fractures, stones (renal, prostatic, gall bladder, salivary glands), ruptures of tendons/muscle/ligaments, renal failure and aortic valve disease. The pathophysiological mechanisms of AKU remain poorly understood, but recent advances lead us to reconsider the treatment strategy in AKU patients. Besides the supporting therapies (pain killers, anti-inflammatory drugs, physiotherapy, joints replacements and others), specific therapies have been considered (anti-oxidant, low protein diet, nitisinone), but clinical studies have failed to prove efficiency on the rheumatological lesions of the disease. Here we propose a treatment strategy for children and adults with AKU, based on a review of the latest findings on AKU and lessons from other aminoacipathies, especially tyrosinemias.

Aetiology of arthritis in hospitalised children: an observational study.

BACKGROUND AND OBJECTIVE: Arthritis in children has many causes and includes septic and viral arthritis, reactive arthritis and juvenile idiopathic arthritis (JIA). We aimed to describe the different types of arthritis among children hospitalised for a first episode of arthritis. DESIGN: Retrospective, descriptive case series study. SETTING: A French tertiary care centre. PATIENTS: Children under 16 years of age hospitalised for an arthritis episode between 1 January 2008 and 31 December 2009. MAIN OUTCOME MEASURES: Demographic and clinical features were compared with χ(2) or Fisher's exact tests and non-parametric tests. RESULTS: 173 children were hospitalised for a first episode of arthritis during the study period, with a male/female ratio of 1.14. The most frequent cause of hospitalisation was septic arthritis (43.4% of cases, 69.3% of which were due to Kingella kingae and 10.7% to Staphylococcus aureus). JIA was responsible for 8.1% of cases and arthritis without any definitive diagnosis for 40.4%. Median age at diagnosis was 2.7 years (IQR 0.3-14.6) and was lower in the septic arthritis group (1.5 years; 1.1-3.4) than in the JIA group (4.7 years; 2.5-10.9) (p<0.01). Septic arthritis involved a single joint in 97.3% of cases, while JIA involved four joints in 14.3% of cases and two to four joints in 28.6% of cases (p<0.01). CONCLUSIONS: Septic arthritis was the most frequent cause of arthritis in hospitalised children. Despite the increasing application of microbiological molecular methods to synovial fluid analysis, further measures are required to improve the diagnosis of arthritis of unknown cause.

Anticyclic citrullinated peptide antibodies in rheumatoid and nonrheumatoid rheumatic disorders: experience with 1162 patients.

OBJECTIVE: Anticyclic citrullinated peptide antibodies (anti-CCP) are considered specific markers of rheumatoid arthritis (RA) and have been included in the revised classification criteria for RA diagnosis. However, these antibodies have also been detected in patients with other types of chronic inflammatory rheumatism. Our objectives were to identify the prevalence of positive anti-CCP patients in non-RA diseases, to determine the diagnostic value of anti-CCP for the diagnosis of RA, to specify the clinical characteristics of non-RA patients positive for anti-CCP, and to determine the discriminatory value of the levels of anti-CCP in patients among the various diseases. METHODS: We carried out an observational and descriptive study. All the determinations of anti-CCP requested by the 2 rheumatology departments at Cochin Hospital over a period of 18 months were analyzed. Such determinations were requested for 1162 patients in total. Anti-CCP levels were determined with the Euro Diagnostica ELISA kit, with values ≥ 25 U for this test being considered positive. The diagnosis of rheumatic conditions was the responsibility of the treating physician. RESULTS: Anti-CCP antibodies were detected in 357 (30.7%) of the 1162 patients. The prevalence of anti-CCP was 292/417 (70.0%) in RA, 13/122 (10.6%) in patients with psoriatic arthritis, 13/62 (20.9%) in patients with unclassified rheumatism, 11/33 (33.3%) in patients with primary Sjögren syndrome, 5/30 (16.6%) in patients with systemic lupus erythematosus, 3/28 (10.7%) in patients with mixed connective tissue disorder, 3/36 (8.3%) in patients with systemic sclerosis, 7/44 (15.9%) in patients with juvenile arthritis, and 6/220 (2.7%) in patients with noninflammatory diseases. In the population of patients positive for anti-CCP, mean anti-CCP levels were 869.4 (± 978.4) U/ml, with no significant difference between RA [854.8 (± 959.8) U/ml] and any of the non-RA conditions [922.7 (± 1070.0) U/ml]. CONCLUSION: Anti-CCP are a hallmark of RA, but may be observed in other inflammatory, systemic, or mechanical diseases. In this large cohort of patients, the presence of second-generation anti-CCP (anti-CCP2) antibodies is useful in diagnosing RA (70% sensitivity, 91.3% specificity), but examining the levels of these antibodies does not appear to offer further discriminatory power among patients who are anti-CCP2-positive.

Efficacy and safety of open-label etanercept on extended oligoarticular juvenile idiopathic arthritis, enthesitis-related arthritis and psoriatic arthritis: part 1 (week 12) of the CLIPPER study.

OBJECTIVE: To investigate the efficacy and safety of etanercept (ETN) in paediatric subjects with extended oligoarticular juvenile idiopathic arthritis (eoJIA), enthesitis-related arthritis (ERA), or psoriatic arthritis (PsA). METHODS: CLIPPER is an ongoing, Phase 3b, open-label, multicentre study; the 12-week (Part 1) data are reported here. Subjects with eoJIA (2-17 years), ERA (12-17 years), or PsA (12-17 years) received ETN 0.8 mg/kg once weekly (maximum 50 mg). Primary endpoint was the percentage of subjects achieving JIA American College of Rheumatology (ACR) 30 criteria at week 12; secondary outcomes included JIA ACR 50/70/90 and inactive disease. RESULTS: 122/127 (96.1%) subjects completed the study (mean age 11.7 years). JIA ACR 30 (95% CI) was achieved by 88.6% (81.6% to 93.6%) of subjects overall; 89.7% (78.8% to 96.1%) with eoJIA, 83.3% (67.2% to 93.6%) with ERA and 93.1% (77.2% to 99.2%) with PsA. For eoJIA, ERA, or PsA categories, the ORs of ETN vs the historical placebo data were 26.2, 15.1 and 40.7, respectively. Overall JIA ACR 50, 70, 90 and inactive disease were achieved by 81.1, 61.5, 29.8 and 12.1%, respectively. Treatment-emergent adverse events (AEs), infections, and serious AEs, were reported in 45 (35.4%), 58 (45.7%), and 4 (3.1%), subjects, respectively. Serious AEs were one case each of abdominal pain, bronchopneumonia, gastroenteritis and pyelocystitis. One subject reported herpes zoster and another varicella. No differences in safety were observed across the JIA categories. CONCLUSIONS: ETN treatment for 12 weeks was effective and well tolerated in paediatric subjects with eoJIA, ERA and PsA, with no unexpected safety findings.

Radiological cervical spine involvement in young adults with polyarticular juvenile idiopathic arthritis.

OBJECTIVES: Radiological cervical spine involvement in JIA has already been assessed with a large range of prevalence (5-80%), but most studies were performed a long time ago, in symptomatic JIA and without differentiating subsets of JIA. We set out to describe structural cervical spine involvement in young adults with polyarticular JIA (pJIA) regardless of the cervical symptoms and to compare lesions with those observed in adult RA. METHODS: All consecutive pJIAs followed in a transition programme were included. Standard radiographs of the cervical spine, hands, feet and hip were analysed by two independent radiologists blinded to the diagnosis. An RA control group (<55 years), matched for sex and disease duration, was recruited. RESULTS: Fifty-seven pJIA and 58 RA patients were included. Radiographs showed cervical lesions in 65% of pJIA and 67% of RA patients. In total, 51% of pJIA with radiographic abnormalities had no clinical symptoms. In pJIA, the most frequent structural lesions were anterior atlantoaxial subluxation (33%), erosion of the odontoid process (19%), C1-C2 arthritis (17%) and apophyseal joint arthritis (16%). Cervical lesions in pJIA were similar to those in RA except for ankylosis and hypotrophia (P < 0.05). The presence of cervical lesions correlated with a more severe disease. CONCLUSION: Structural cervical spine involvement is common in pJIA persisting into adulthood, frequently asymptomatic and associated with a more severe disease. We suggest that radiographic assessment of the cervical spine should be done systematically at onset of the disease and regularly during its course regardless of clinical symptoms.

Chronic recurrent multifocal osteomyelitis (CRMO): a longitudinal case series review.

BACKGROUND: Chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory disorder that is currently diagnosed based on clinical, radiologic, pathological and longitudinal findings. OBJECTIVE: To provide detailed descriptions of CRMO lesion patterns seen on radiographs and MRI and to suggest clinical use of whole-body MRI and propose noninvasive diagnostic strategy. MATERIALS AND METHODS: Retrospective longitudinal study (1989-2010) of 31 children (22 girls, 9 boys) diagnosed with CRMO. Imaging data were evaluated by two pediatric radiologists. RESULTS: Mean age at diagnosis was 11 years (3-17). A total of 108 lesions were investigated. The most common sites were the long bone metaphyses (56 lesions in 24 children) especially femoral and tibial (20/24); pelvis (10/31); spine (9/31); clavicle (6/31) and mandible (3/31). In long bones, the radiologic appearance was normal (22/56), mixed lytic and sclerotic (20/56), sclerotic (8/56) or lytic (6/56) often juxtaphyseal (36/56), with hyperostosis or periosteal thickening (10/56). Vertebral involvement was often multifocal (6/9). Medullary edema was seen on MRI (42) with epiphyseal (23/42) or soft-tissue (22/42) inflammation and juxtaphyseal nodule-like appearance (7/42). Whole-body MRI (15/31) was key in detecting subclinical lesions. CONCLUSION: CRMO is a polymorphous disorder in which whole-body MRI is extremely useful for showing subclinical edema. Vertebral collapse requires long-term monitoring.

Body mass index influences the response to infliximab in ankylosing spondylitis.

INTRODUCTION: The excess of adipose tissue in obese individuals may have immunomodulating properties and pharmacokinetic consequences. The aim of this study was to determine whether body mass index (BMI) affects response to infliximab (IFX) in ankylosing spondylitis (AS) patients. METHODS: In 155 patients retrospectively included with active AS, the BMI was calculated before initiation of IFX treatment (5 mg/kg intravenously). After 6 months of treatment, changes from baseline in BASDAI, Visual Analogue Scale (VAS) pain, C-reactive protein (CRP) level, and total dose of nonsteroidal antiinflammatory drug (NSAID) were dichotomized with a threshold corresponding to a decrease of 50% of initial level of the measure, into binary variables assessing response to IFX (BASDAI50, VAS50, CRP50, NSAID50). Whether the BMI was predictive of the response to IFX therapy according to these definitions was assessed with logistic regression. RESULTS: Multivariate analysis found that a higher BMI was associated with a lower response for BASDAI50 (P = 0.0003; OR, 0.87; 95% CI (0.81 to 0.94)), VAS50 (P < 0.0001; OR, 0.87; 95% CI (0.80 to 0.93)); CRP50 (P = 0.0279; OR, 0.93; 95% CI (0.88 to 0.99)), and NSAID50 (P = 0.0077; OR, 0.91; 95% CI (0.85 to 0.97)), criteria. According to the three WHO BMI categories, similar results were found for BASDAI50 (77.6%, 48.9%, and 26.5%; P < 0.0001), VAS50 (72.6%, 40.4%, and 16.7%; P < 0.0001); CRP50 (87.5%, 65.7%, and 38.5%; P = 0.0001), and NSAID50 (63.2%, 51.5%, and 34.6%; P = 0.06). CONCLUSIONS: This study provides the first evidence that a high BMI negatively influences the response to IFX in AS. Further prospective studies, including assessment of the fat mass, pharmacokinetics, and adipokines dosages are mandatory to elucidate the role of obesity in AS IFX response.

Safety of rituximab in rheumatoid arthritis: a long-term prospective single-center study of gammaglobulin concentrations and infections.

OBJECTIVE: Rituximab seems well tolerated in patients with rheumatoid arthritis (RA). However, variations in the gammaglobulin profile that might increase the infection risk have been reported. Here, our objective was to evaluate gammaglobulin concentrations and the infection risk in patients receiving rituximab therapy for RA in everyday practice. METHODS: Prospective single-center observational study of 65 patients with refractory RA (median age, 59 years; range, 26-83) treated with rituximab 1 g twice 15 days apart, with or without a further 1-g dose at least 6 months later depending on the clinical response. Gammaglobulins were assayed before each rituximab dose. RESULTS: The median cumulative rituximab dose was 4 g (1-16) and the median time to retreatment was 8 months (6-16). Rituximab therapy significantly improved the DAS-28 score. The gammaglobulin concentration decreased significantly between the first and last rituximab dose (from 11.6 g/L [5-26] to 8.2 g/L [3-20], a -2.6 g/L difference; P<0.05). The decrease was larger in the 24 patients with cumulative rituximab doses greater than 5 g than in the 41 other patients (difference of -4 vs. -2.7 g/L; P<0.05). Three patients experienced severe infections, two in the high-dose group and one in the other group (P=0.5). CONCLUSION: These data obtained in everyday practice constitute further evidence that rituximab is well-tolerated in patients with RA. Rituximab therapy was associated with a decrease in gammaglobulin concentrations that was greater in patients receiving higher cumulative doses.

Chronic recurrent multifocal osteomyelitis.

Chronic recurrent multifocal osteomyelitis (CRMO), also known as chronic nonbacterial osteomyelitis, is an orphan disease that manifests as recurrent flares of inflammatory bone pain with or without a fever. The pain is related to one or more foci of nonbacterial osteomyelitis. To distinguish unifocal CRMO from a tumor or an infection, a bone biopsy is required in nearly all patients and a trial of antibiotic therapy in many. CRMO is now considered the pediatric equivalent of SAPHO syndrome, and recent data suggest that CRMO should be classified among the autoinflammatory diseases. The treatment of CRMO is not standardized. Although no randomized placebo-controlled trials are available, there is general agreement that nonsteroidal antiinflammatory drugs constitute the best first-line treatment and that bisphosphonates and biotherapies such as TNFα antagonists are effective in the most severe forms. Although CRMO is considered a benign disease, recent data suggest an up to 50% rate of residual impairments despite optimal management.