The French version of the Juvenile Arthritis Multidimensional Assessment Report (JAMAR).

The Juvenile Arthritis Multidimensional Assessment Report (JAMAR) is a new parent/patient reported outcome measure that enables a thorough assessment of the disease status in children with juvenile idiopathic arthritis (JIA). We report the results of the cross-cultural adaptation and validation of the parent and patient versions of the JAMAR in the French language. The reading comprehension of the questionnaire was tested in 10 JIA parents and patients. Each participating centre was asked to collect demographic, clinical data and the JAMAR in 100 consecutive JIA patients or all consecutive patients seen in a 6-month period and to administer the JAMAR to 100 healthy children and their parents. The statistical validation phase explored descriptive statistics and the psychometric issues of the JAMAR: the three Likert assumptions, floor/ceiling effects, internal consistency, Cronbach's alpha, interscale correlations and construct validity (convergent and discriminant validity). A total of 100 JIA patients (23% systemic, 45% oligoarticular, 20% RF negative polyarthritis, 12% other categories) and 122 healthy children, were enrolled at the paediatric rheumatology centre of the Necker Children's Hospital in Paris. Notably, none of the enrolled JIA patients is affected with psoriatic arthritis. The JAMAR components discriminated well healthy subjects from JIA patients. All JAMAR components revealed good psychometric performances. In conclusion, the French version of the JAMAR is a valid tool for the assessment of children with JIA and is suitable for use both in routine clinical practice and clinical research.

Inflammatory manifestations in a single-center cohort of patients with chronic granulomatous disease.

BACKGROUND: Chronic granulomatous disease (CGD) is a rare phagocytic disorder that results in not only infections but also potentially severe inflammatory manifestations that can be difficult to diagnose and treat. OBJECTIVE: To describe inflammatory manifestations in a single-center cohort of patients with CGD. METHODS: Medical records of patients treated at Necker-Enfants Malades Hospital (Paris, France) between 1968 and 2009 and registered at the French National Reference Center for Primary Immunodeficiencies (CEREDIH) were retrospectively reviewed. RESULTS: In a study population of 98 patients, a total of 221 inflammatory episodes were recorded in 68 individuals (69.4%). The incidence rate of inflammatory episodes was 0.15 per person-year (0.18 in patients with X-linked [XL] CGD and 0.08 in patients with autosomal-recessive [AR] CGD). The most commonly affected organs were the gastrointestinal tract (in 88.2% of the patients), lungs (26.4%), the urogenital tract (17.6%), and eyes (8.8%). Inflammation at other sites (the skin, central nervous system, and tympanum) and autoimmune manifestations (lupus, arthritis, etc) were recorded in 19.1% and 10.3% of the patients, respectively. Granuloma was found in 50% of the 44 histological analyses reviewed. The risk of inflammatory episodes was 2-fold higher in patients with XL-CGD than in patients with AR-CGD (relative risk, 2.22; 95% CI, 1.43-3.46). CONCLUSIONS: Patients with XL-CGD have a higher risk of developing inflammatory episodes than do patients with AR-CGD. Although the most commonly affected organ is the gastrointestinal tract, other sites can be involved, making the management of patients with CGD a complex, multidisciplinary task.

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.

The identification of MAFB mutations in eight patients with multicentric carpo-tarsal osteolysis supports genetic homogeneity but clinical variability.

Multicentric carpo-tarsal osteolysis (MCTO) with or without nephropathy is a rare osteolysis disorder beginning in early childhood and involving mainly carpal and tarsal bones. Renal disease appears later in life in the majority of cases and evolves quickly to end stage renal failure. Autosomal dominant (AD) inheritance has been demonstrated, with a high frequency of sporadic cases. Recently, mutations in a highly conserved region of the MAFB gene (v-maf musculoaponeurotic fibrosarcoma oncogene ortholog B) have been identified in MCTO patients by exome sequencing. MafB, known as a regulator of various developmental processes, is essential for osteoclastogenesis and renal development. We report here the molecular screening of MAFB in eight MCTO patients from six families. We identified MAFB mutations in all, including three novel missense mutations clustering within the hot spot mutation region. Among the eight patients, six only presented renal disease. Our report confirms the genetic homogeneity of MCTO and provides data underlying the clinical variability of this disorder.

A phase II, multicenter, open-label study evaluating dosing and preliminary safety and efficacy of canakinumab in systemic juvenile idiopathic arthritis with active systemic features.

OBJECTIVE: To assess dosing, preliminary safety, and efficacy of canakinumab, a fully human anti-interleukin-1ß (anti-IL-1ß) antibody, in children with systemic juvenile idiopathic arthritis (JIA) and active systemic features. METHODS: In this phase II, multicenter, open-label, dosage-escalation study, children with systemic JIA who were ≥4 years of age, had fever, and were receiving ≤0.4 mg/kg/day of corticosteroids were administered a single subcutaneous dose of canakinumab, 0.5-9 mg/kg of body weight, and were redosed upon relapse. Response to treatment was assessed according to an adaptation of the American College of Rheumatology (ACR) pediatric criteria for improvement. RESULTS: A total of 23 children ages 4-19 years with active disease were enrolled. Of these, 1 patient was excluded from analysis, and 3 of the reenrolled patients were included twice in the efficacy analysis. By day 15 of the first treatment cycle, 15 of 25 patients (60%) had achieved an adapted ACR Pediatric 50 response, with 4 of them achieving inactive disease status. Response was sustained over time, with 11 of 13 patients able to maintain their response throughout the study. In 8 of the 11 responders who had been receiving steroids at baseline, the steroid dosage was decreased from a mean of 0.38 mg/kg/day to 0.13 mg/kg/day over the first 5 months, and 4 of them were able to discontinue steroids. At a dose of 4 mg/kg of canakinumab given subcutaneously every 4 weeks, the median percentage of patients predicted to relapse within 4 weeks was estimated to be 6% (95% confidence interval 1-21). Therapy was generally well tolerated and few patients experienced injection-site reactions. CONCLUSION: Canakinumab has a promising preliminary safety and efficacy profile in this limited cohort. Based on the findings of this trial, further studies in a larger population of children with systemic JIA are warranted.

Targeting the chemokine receptor CXCR4 with histamine analog to reduce inflammation in juvenile arthritis.

Introduction: Among immune cells, activated monocytes play a detrimental role in chronic and viral-induced inflammatory pathologies, particularly in Juvenile Idiopathic Arthritis (JIA), a childhood rheumatoid arthritis (RA) disease. The uncontrolled activation of monocytes and excessive production of inflammatory factors contribute to the damage of bone-cartilage joints. Despite the moderate beneficial effect of current therapies and clinical trials, there is still a need for alternative strategies targeting monocytes to treat RA. Methods: To explore such an alternative strategy, we investigated the effects of targeting the CXCR4 receptor using the histamine analog clobenpropit (CB). Monocytes were isolated from the blood and synovial fluids of JIA patients to assess CB's impact on their production of key inflammatory cytokines. Additionally, we administered daily intraperitoneal CB treatment to arthritic mice to evaluate its effects on circulating inflammatory cytokine levels, immune cell infiltrates, joints erosion, and bone resorption, as indicators of disease progression. Results: Our findings demonstrated that CXCR4 targeting with CB significantly inhibited the spontaneous and induced-production of key inflammatory cytokines by monocytes isolated from JIA patients. Furthermore, CB treatment in a mouse model of collagen-induce arthritis resulted in a significant decrease in circulating inflammatory cytokine levels, immune cell infiltrates, joints erosion, and bone resorption, leading to a reduction in disease progression. Discussion: In conclusion, targeting CXCR4 with the small amino compound CB shows promise as a therapeutic option for chronic and viral-induced inflammatory diseases, including RA. CB effectively regulated inflammatory cytokine production of monocytes, presenting a potential targeted approach with potential advantages over current therapies. These results warrant further research and clinical trials to explore the full therapeutic potential of targeting CXCR4 with CB-like molecules in the management of various inflammatory diseases.

Functional status in severe juvenile idiopathic arthritis in the biologic treatment era: an assessment in a French paediatric rheumatology referral centre.

OBJECTIVES: To investigate the functional status of difficult-to-treat JIA patients, including patients receiving biotherapies, and to correlate functional status to disease activity. METHODS: All JIA patients consecutively evaluated in a paediatric rheumatology referral centre (November 2008 to March 2009) were enrolled in an observational cross-sectional study. The Childhood HAQ (CHAQ), physician's assessment of overall disease activity, parent's assessment of well-being and pain, and active and limited joint numbers were measured. RESULTS: We enrolled 95 patients [27% systemic, 29% polyarticular, 22% enthesitis-related arthritis (ERA) and 23% oligoarticular JIA]. Median disease duration was 3.5 years. Treatment included NSAIDs (56%), MTX (23%), CSs (21%) and biologics (45%). Of all patients, 31 and 56%, respectively, had inactive and minimally active disease. The median CHAQ score was 0.375 (range 0-3). Most patients had no or mild functional disability (61%), impaired well-being (63%) or pain (55%); 10% reported severely impaired function and well-being, 19% severe pain. ERA patients reported worse well-being and pain. CHAQ scores correlated with disease activity. Long-lasting disease and biologic treatment were associated with better well-being and pain scores. CONCLUSION: Despite the high proportion of severe JIA patients in this cohort, CHAQ values are within the lower range of recent reports, probably related to new therapeutic approaches. Impaired function and well-being remain a challenge for at least 10% of the patients. Impaired well-being and pain in ERA patients require further study. The strong correlation between functional status and well-being underlines the importance of improving function to optimize quality of life.

Invasive mold infections in chronic granulomatous disease: a 25-year retrospective survey.

BACKGROUND: Invasive fungal infection (IFI) represents a life-threatening condition for patients with chronic granulomatous disease (CGD) and causes one-third of deaths in this population. This study offers a descriptive review of invasive mold infection (mIFI) in children with CGD over an extended period of time. METHODS: In a cohort of patients with CGD registered in the French National database for Primary Immunodeficiency, we performed a retrospective review of proven mIFI episodes (European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group 2008 criteria) occurring from 1984 through 2009. RESULTS: Twenty-nine proven mIFIs were identified in 24 patients. Thirteen (54%) of 24 children were receiving itraconazole prophylaxis. Seven episodes were caused by Aspergillus fumigatus, 10 by Aspergillus nidulans, 2 by Aspergillus species, and 6 by other opportunistic molds (4 patients only had positive pathological examination findings). First proven mIFI occurred later in the group that received itraconazole than in the group without (median time to mIFI, 10 vs 4 years; P < .01), with a higher proportion of infections due to A. nidulans and other opportunistic molds (P < .05). Course of IFI was complex, with the median duration of therapy and hospitalization reaching 446 and 153 days, respectively. Combined antifungal therapy was commonly used. Four patients received geno-identical hematopoietic stem cell transplantation as salvage therapy. Global cure rate among the cohort reached 75%, but sequelae were frequent. Prognosis has improved over time (43% mortality during 1985-1990 vs 6% thereafter; P = .06). Mortality tended to be lower in the group that recieved itraconazole prophylaxis but at the cost of a longer duration of therapy among cured patients. CONCLUSIONS: Management of mIFI remains challenging in patients with CGD, but significant improvements have been made over the past decade.

Adalimumab with or without methotrexate in juvenile rheumatoid arthritis.

BACKGROUND: Tumor necrosis factor (TNF) has a pathogenic role in juvenile rheumatoid arthritis. We evaluated the efficacy and safety of adalimumab, a fully human monoclonal anti-TNF antibody, in children with polyarticular-course juvenile rheumatoid arthritis. METHODS: Patients 4 to 17 years of age with active juvenile rheumatoid arthritis who had previously received treatment with nonsteroidal antiinflammatory drugs underwent stratification according to methotrexate use and received 24 mg of adalimumab per square meter of body-surface area (maximum dose, 40 mg) subcutaneously every other week for 16 weeks. We randomly assigned patients with an American College of Rheumatology Pediatric 30% (ACR Pedi 30) response at week 16 to receive adalimumab or placebo in a double-blind fashion every other week for up to 32 weeks. RESULTS: Seventy-four percent of patients not receiving methotrexate (64 of 86) and 94% of those receiving methotrexate (80 of 85) had an ACR Pedi 30 response at week 16 and were eligible for double-blind treatment. Among patients not receiving methotrexate, disease flares (the primary outcome) occurred in 43% of those receiving adalimumab and 71% of those receiving placebo (P=0.03). Among patients receiving methotrexate, flares occurred in 37% of those receiving adalimumab and 65% of those receiving placebo (P=0.02). At 48 weeks, the percentages of patients treated with methotrexate who had ACR Pedi 30, 50, 70, or 90 responses were significantly greater for those receiving adalimumab than for those receiving placebo; the differences between patients not treated with methotrexate who received adalimumab and those who received placebo were not significant. Response rates were sustained after 104 weeks of treatment. Serious adverse events possibly related to adalimumab occurred in 14 patients. CONCLUSIONS: Adalimumab therapy seems to be an efficacious option for the treatment of children with juvenile rheumatoid arthritis. (ClinicalTrials.gov number, NCT00048542.)

Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis.

BACKGROUND: Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high. CASE REPORT: A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs. CONCLUSION: Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.

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.

Long-term outcomes in patients with polyarticular juvenile idiopathic arthritis receiving adalimumab with or without methotrexate.

OBJECTIVES: Long-term safety and efficacy of adalimumab among patients with juvenile idiopathic arthritis (JIA) was evaluated through 6 years of treatment. METHODS: Children aged 4-17 years with polyarticular JIA were enrolled in a phase III, randomised-withdrawal, double-blind, placebo-controlled trial consisting of a 16-week open-label lead-in period, 32-week randomised double-blind period and 360-week long-term extension. Patients were stratified by baseline methotrexate use. Adverse events (AEs) were monitored, and efficacy assessments included JIA American College of Rheumatology (JIA ACR) 30%, 50%, 70% or 90% responses and the proportions of patients achieving 27-joint Juvenile Arthritis Disease Activity Score (JADAS27) low disease activity (LDA, ≤3.8) and inactive disease (ID, ≤1). RESULTS: Of 171 patients enrolled, 62 (36%) completed the long-term extension. Twelve serious infections in 11 patients were reported through 592.8 patient-years of exposure. No cases of congestive heart failure-related AEs, demyelinating disease, lupus-like syndrome, malignancies, tuberculosis or deaths were reported. JIA ACR 30/50/70/90 responses and JADAS27 LDA were achieved in 66% to 96% of patients at week 104, and 63 (37%) patients achieved clinical remission (JADAS27 ID sustained for ≥6 continuous months) during the study. Attainment of JIA ACR 50 or higher and JADAS27 LDA or ID in the initial weeks were the best predictors of clinical remission. Mean JADAS27 decreased from baseline, 22.5 (n=170), to 2.5 (n=30) at week 312 (observed analysis). CONCLUSIONS: Through 6 years of exposure, adalimumab was well tolerated with significant clinical response (up to clinical remission) and a relatively low retention rate.

Leflunomide or methotrexate for juvenile rheumatoid arthritis.

BACKGROUND: We compared the safety and efficacy of leflunomide with that of methotrexate in the treatment of polyarticular juvenile rheumatoid arthritis in a multinational, randomized, controlled trial. METHODS: Patients 3 to 17 years of age received leflunomide or methotrexate for 16 weeks in a double-dummy, blinded fashion, followed by a 32-week blinded extension. The rates of American College of Rheumatology Pediatric 30 percent responses (ACR Pedi 30) and the Percent Improvement Index were assessed at baseline and every 4 weeks for 16 weeks and every 8 weeks during the 32-week extension study. RESULTS: Of 94 patients randomized, 86 completed 16 weeks of treatment, 70 of whom entered the extension study. At week 16, more patients in the methotrexate group than in the leflunomide group had an ACR Pedi 30 response (89 percent vs. 68 percent, P=0.02), whereas the values for the Percent Improvement Index did not differ significantly (-52.87 percent vs. -44.41 percent, P=0.18). In both groups, the improvements achieved at week 16 were maintained at week 48. The most common adverse events in both groups included gastrointestinal symptoms, headache, and nasopharyngeal symptoms. Aminotransferase elevations were more frequent with methotrexate than with leflunomide during the initial study and the extension study. CONCLUSIONS: In patients with polyarticular juvenile rheumatoid arthritis, methotrexate and leflunomide both resulted in high rates of clinical improvement, but the rate was slightly greater for methotrexate. At the doses used in this study, methotrexate was more effective than leflunomide.

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.

Long-term outcome of children with pediatric-onset cutaneous and visceral polyarteritis nodosa.

OBJECTIVE: To assess the prognostic impact of clinical presentation in children with polyarteritis nodosa (PAN). METHODS: Children diagnosed between 1986 and 2006 in a tertiary care pediatric rheumatology center were classified as "cutaneous PAN" (group 1), "cutaneous PAN with significant extra-cutaneous features" (group 2) or "visceral childhood PAN" (group 3). OUTCOME MEASURES: (1) clinical remission off-therapy at last follow-up, (2) requirement and length of glucocorticoid therapy, (3) presence of disease-related sequelae. RESULTS: Twenty-nine children were included. Sixteen met the Ankara criteria for PAN. Nine patients were qualified as group 1, 11 as group 2, and 9 as group 3. At last follow-up, 15 children were in clinical remission off-therapy: 4 from group 1 (44%), 4 from group 2 (36%) and 7 from group 3 (78%). Glucocorticoid therapy was required for 8 (89%), 7 (64%) and 7 (78%) patients from groups 1, 2 and 3, respectively. Seven children did not require any glucocorticoid therapy. Time-dependent probability of achieving glucocorticoid-free clinical remission was similar between the three groups. Three patients (one from each group) had digital ischemia leading to amputation. There were no significant between-group differences in outcome based on the three outcome measures addressed. CONCLUSION: Outcome was not strikingly predictable from initial presentation in children with PAN. The organ distribution-based distinction between cutaneous and visceral PAN had little prognostic power in this series.

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.

Clostridium difficile-associated reactive arthritis in two children.

In adults, reactive arthritis (ReA) following Clostridium difficile-enterocolitis has been documented. In children, only one case of C. difficile-associated ReA has been reported. We now describe two other cases of ReA associated with C. difficile in children. The characteristics of ReA due to C. difficile appear to be similar in adults and children. Both children show polyarthritis after an episode of diarrhoea with positive stool cultures for C. difficile. Arthritis is asymmetrical with a self-limiting course. Nonsteroidal antiinflammatory drug (NSAID) therapy is sufficient. One case is remarkable because of its prolonged course of ReA despite NSAID therapy, and its association with the presence of HLA-B27 antigen.

Effect of biologic treatments on growth in children with juvenile idiopathic arthritis.

OBJECTIVE: Growth retardation is a frequent complication of severe juvenile idiopathic arthritis (JIA). Biologic treatments may improve growth velocity by controlling systemic inflammation and reducing corticosteroids. Our goals were to compare growth velocity before and after the onset of biologic therapy and to determine whether the JIA subtype, the use of steroids, the requirement of one or several biologic agents, or the disease activity influenced growth velocity. METHODS: We retrospectively analyzed the growth of children with JIA who never received growth hormone treatment, who started biologic treatment before puberty, and who were followed for at least 6 months afterward. RESULTS: We included 100 children (33 boys). Median patient age was 7.1 years (range: 1.6-15.7) at the onset of biologic treatment and 11.0 years (range: 2.3-19.5) at the latest followup. Forty-six patients had received corticosteroid and 34 had received more than 1 biologic agent. Patient median height expressed as SD score (SDS) was 0.31 (range: -2.47 to 5.46) at disease onset, -0.24 (-3.63 to 2.90) at biologic therapy onset (p < 0.0001), and -0.15 (-4.95 to 3.52) at the latest followup (p = 0.171 compared to biologic treatment onset). Patients who required several biologics and systemic patients had a significantly lower growth velocity after the onset of biologic treatment. At the latest followup, 18% of our study group had low growth velocities and 19% were below -2SD or shorter than genetically programmed. CONCLUSION: In a subset of patients, particularly systemic JIA patients and patients who required more than 1 biologic, biologic therapy may be insufficient to restore normal growth velocity.

Anakinra pharmacokinetics in children and adolescents with systemic-onset juvenile idiopathic arthritis and autoinflammatory syndromes.

BACKGROUND: Anakinra pharmacokinetics and pharmacodynamics were investigated in children and adolescents treated for systemic-onset juvenile idiopathic arthritis (SJIA) and autoinflammatory syndromes. METHODS: Anakinra was given subcutaneously at doses between 2 and 10 mg/kg (maximum 100 mg) per day. Anakinra concentrations were recorded in patients, as well as C-reactive protein (CRP) levels, on different occasions. The data were fitted to a pharmacokinetic-pharmacodynamic model via a population approach using Monolix. RESULTS: A total of 87 children and adolescents, 8 months to 21 years old, were available for pharmacokinetic evaluation. A one compartment model with linear absorption and elimination described the pharmacokinetics. Taking into account bodyweight to explain variations in apparent clearance (CL/F) and distribution volume (V/F) significantly reduced the associated between-subject and between-occasion variabilities. The final estimates were 6.24 L/h/70 kg and 65.2 L/70 kg for CL/F and V/F respectively. A mixture pharmacodynamic model described the CRP level change during anakinra treatment for the SJIA patients with 2 subpopulations, patients with high baseline and large CRP decrease and patients with low baseline and small CRP decrease followed by a re-increase in CRP levels. There was no significant effect of the combined anti-inflammatory treatment. The proportion of patients for which the development of a resistance to treatment was significant was 62% and the corresponding time was approximately 60 days. CONCLUSIONS: Based on effects in SJIA, a prospective dosage adjustment was proposed based on a 0.4 mg/L Css target in order to obtain a CRP decrease to 10 mg/L or below.

Epidemiology and outcome of invasive fungal diseases in patients with chronic granulomatous disease: a multicenter study in France.

BACKGROUND: Chronic granulomatous disease (CGD) is a rare inherited phagocytic disorder resulting in an increased susceptibility to infections including invasive fungal diseases (IFDs) and inflammatory complications. This study is aimed at assessing the incidence, prevalence, and outcome of IFDs among CGD patients followed in France. METHODS: CGD patients were identified through the French national registry for primary immunodeficiencies (PID) held by the French national reference Centre of PID (Centre de Référence Déficits Immunitaires Héréditaires), which comprises a total of 3083 patients including 155 with CGD followed between 1976 and 2008. A questionnaire was filled out for each episode of IFD. Information retrieved included a description of the IFD using the 2008 European Organization for Research and Treatment of Cancer/Mycoses Study Group IFD definition criteria. RESULTS: Of CGD patients, 42.6% (66/155) developed at least 1 episode of IFD. Overall incidence of IFD was 0.040/patient-years (1862 patient-years of total follow-up). IFD incidence was found to be significant while receiving itraconazole prophylaxis compared with no prophylaxis (0.027 vs. 0.053 IFD/patient-years; P < 0.01). Median age at IFD diagnosis was 6.5 years (3.3-11.3). The most common fungal genus was Aspergillus sp. accounting for 40% of all IFDs. Of the IFDs, 42.5% were proven, 30.0% probable, and 27.5% possible. Of all IFD episodes, 52.5% were treated by antifungal monotherapy, mostly by amphotericin B. Survival was reduced in IFD patients compared with those without it (log-rank 0.04). CONCLUSIONS: IFDs are a frequent and life-threatening complication in CGD patients. Itraconazole significantly reduces its incidence and should be recommended in absence of better alternatives.