Anti-adalimumab antibodies kinetics: an early guide for juvenile idiopathic arthritis (JIA) switching.

OBJECTIVE: To assess the longitudinal production of anti-adalimumab antibody (AAA) and baseline risk factors for this antibody development in juvenile idiopathic arthritis (JIA) patients initiating adalimumab (ADA). METHOD: Thirty consecutive JIA patients under ADA therapy were prospectively followed. JIA clinical/laboratorial/treatment data and sera for ADA and AAA assays (ELISA and bridging ELISA) were obtained at baseline (BL), 2 months (2M), 3 months (3M), 6 months (6M), 12 months (12M), and 24 months (24M). Patients with therapy failure requiring ADA withdrawn had their sera evaluated at their last medical visit prior to biologic switch (blinded to ADA and AAA levels). RESULTS: AAA was absent at BL, first detected at 2M after ADA initiation in 2/30 (7%) patients with a significant increase at 3M (10/29 (34%), p = 0.013) and no major change in 6M (11/30 (37%)) and 12M (9/26 (35%)). Of note, at 3M, AAA levels correlated negatively with ADA levels (r = - 0.781, p = 0.0001). Analysis of BL predictors revealed a significantly higher risk of developing AAA in patients with female gender (OR 21; 95% CI 1.08-406.57; p = 0.044), ESR > 30 mm/1st hour (OR 5.44; 95% CI 1.04-28.53; p = 0.045), and leflunomide use (OR 9.33; 95% CI 1.51-57.66; p = 0.016). In contrast, concomitant use of methotrexate was protective for AAA appearance (OR 0.08; 95% CI 0.01-0.53; p = 0.009). After 12M of ADA, 60% of AAA-positive patients required drug switch for drug failure compared with 15% in AAA-negative group (p = 0.03). CONCLUSIONS: This study provides novel evidence of AAA production kinetics demonstrating a timely significant increase starting at 3M and stable throughout 24M. We also identified female gender, increased ESR, and leflunomide use as relevant risk factors for AAA production at BL, whereas methotrexate was protective. Early systematic monitoring of AAA at 3M may, therefore, guide drug switching in these patients.Key Points• Anti-adalimumab antibodies (AAA) production kinetics demonstrated a timely significant increase starting at 3M in juvenile idiopathic arthritis (JIA) patients under adalimumab therapy• Female gender, increased ESR, and leflunomide use were identified as relevant risk factors for AAA production in JIA, whereas methotrexate was protective.

High rate of serious infection in juvenile idiopathic arthritis patients under biologic therapy in a real-life setting.

OBJECTIVES: To assess the rate of serious and/or opportunistic infections in juvenile idiopathic arthritis (JIA) patients from a single tertiary center under biologic therapy and to identify possible risk factors associated to these complications. METHODS: A total of 107 JIA patients followed at the biologic therapy center of our tertiary university hospital using a standardized electronic database protocol including demographic data, clinical and laboratorial findings and treatment at baseline and at the moment of infection. Opportunistic infections included tuberculosis, herpes zoster and systemic mycosis. RESULTS: A total of 398 patient-yrs(py) were included. The median time of biologic exposure was 3.0 years (0.15-11.5). We observed 35 serious/opportunistic infectious events in 27 (25%) patients: 31(88.6%) were serious infections and four (11.4%) opportunistic infections. Serious/opportunistic infections rates were 10.6/100py for ETN, 10.9/100py for ADA, 2.6/100py for ABA and 14.8/100py for TCZ. Comparison of 27 patients with and 80 without infection showed a higher frequency of systemic-onset JIA, lower age at biologic therapy initiation and a history of previous serious infection (p < .05) in the former group. CONCLUSIONS: This study demonstrated a high rate of serious infections in JIA patients under biologic therapy in a real-life setting. Systemic-onset JIA, lower age at biologic therapy start and history of previous serious infections were important risk factors for these complications. Also, higher rates of severe infections comparing to the former studies was possibly due to elevated MTX doses in our patients.

Esophageal abnormalities in juvenile localized scleroderma: is it associated with other extracutaneous manifestations? / Anormalidades esofágicas na esclerodermia localizada juvenil: associação com outras manifestações extracutâneas?

Abstract Objective: To assess esophageal involvement (EI) in juvenile localized scleroderma (JLS) population and the possible association between this gastrointestinal manifestation and demographic data, clinical features, laboratory exams, treatments and outcomes. Methods: For a period of 30 years, 5881 patients with rheumatic diseases were followed in our Pediatric Rheumatology Division. EI was defined by the presence of symptoms (solid/liquid dysphagia, heartburn, esophageal regurgitation, nausea/vomiting and epigastralgia) and confirmed by at least one EI exam abnormality: barium contrast radiography, upper gastrointestinal endoscopy and 24-hour esophageal pH-monitoring. Results: JLS was observed in 56/5881 patients (0.9%), mainly linear morphea subtype. EI was observed in 23/56(41%) of JLS patients. Eight(35%) of 23 EI patients with JLS were symptomatic and presented heartburn(5/8), solid and liquid dysphagia(3/8), nausea and epigastralgia(1/8). The frequency of any cumulative extracutaneous manifestations (calcinosis, arthritis/arthralgia, central nervous system, interstitial pneumonitis, mesangial nephritis and/or arrhythmia) was significantly higher in JLS patients with EI compared to those without this complication (56% vs. 24%, p = 0.024). No differences were evidenced in demographic data, JLS subtypes and in each extracutaneous manifestation in both groups (p > 0.05). The frequency of methotrexate use was significantly higher in JLS patients with EI compared to those without (52% vs. 12%, p = 0.002). Autoantibody profile (antinuclear antibodies, anti-SCL-70, rheumatoid factor, anticentromere, anti-cardiolipin, anti-Ro/SSA and anti-La/SSB) was similar in both groups (p > 0.05). Conclusions: Our study demonstrated that EI was frequently observed in JLS patients, mainly in asymptomatic patients with linear subtype. EI occurred in JLS patients with other extracutaneous manifestations and required methotrexate therapy.

Resumo Objetivo: Avaliar o envolvimento do esôfago (EE) na população com esclerodermia localizada juvenil (ELJ) e a possível associação entre essa manifestação gastrointestinal e dados demográficos, características clínicas, exames laboratoriais, tratamentos e desfechos. Métodos: Durante 31 anos, 5.881 pacientes com doenças reumáticas foram acompanhados em nossa Divisão de Reumatologia Pediátrica. O EE foi definido pela presença de sintomas (disfagia para sólidos/líquidos, azia, regurgitação esofágica, náuseas/vômitos e epigastralgia) e confirmado com pelo menos um exame que revelou EE: radiografia contrastada com bário, endoscopia digestiva alta e pHmetria esofágica de 24 horas. Resultados: Observou-se ELJ em 56/5.881 pacientes (0,9%), principalmente do subtipo morfeia linear. O EE foi observado em 23/56 (41%) dos pacientes com ELJ. Oito (35%) dos 23 pacientes com ELJ com EE eram sintomáticos e apresentavam azia (5/8), disfagia para sólidos e líquidos (3/8), náuseas e epigastralgias (1/8). A frequência de quaisquer manifestações extracutâneas cumulativas (calcinose, artrite/artralgia, envolvimento do sistema nervoso central, pneumonite intersticial, nefrite mesangial e/ou arritmias) foi significativamente maior em pacientes com ELJ com EE em comparação com aqueles sem essa complicação (56% vs. 24%, p = 0,024). Não foi evidenciada diferença nos dados demográficos, subtipos de ELJ e quaisquer manifestações extracutâneas entre os grupos (p > 0,05). A frequência de uso de metotrexato foi significativamente maior em pacientes com ELJ com EE em comparação com aqueles sem EE (52% vs. 12%, p = 0,002). O perfil de autoanticorpos (anticorpos antinucleares, anti-SCL-70, fator reumatoide, anticentrômero, anticardiolipina, anti-Ro/SSA e anti-La/SSB) foi semelhante nos dois grupos (p > 0,05). Conclusões: Este estudo demonstrou que o EE foi frequentemente observado em pacientes com ELJ, principalmente naqueles assintomáticos com o subtipo linear da doença. O EE ocorreu em pacientes com ELJ com outras manifestações extracutâneas e exigiu tratamento com metotrexato.

Esophageal abnormalities in juvenile localized scleroderma: is it associated with other extracutaneous manifestations?

OBJECTIVE: To assess esophageal involvement (EI) in juvenile localized scleroderma (JLS) population and the possible association between this gastrointestinal manifestation and demographic data, clinical features, laboratory exams, treatments and outcomes. METHODS: For a period of 30 years, 5881 patients with rheumatic diseases were followed in our Pediatric Rheumatology Division. EI was defined by the presence of symptoms (solid/liquid dysphagia, heartburn, esophageal regurgitation, nausea/vomiting and epigastralgia) and confirmed by at least one EI exam abnormality: barium contrast radiography, upper gastrointestinal endoscopy and 24-hour esophageal pH-monitoring. RESULTS: JLS was observed in 56/5881 patients (0.9%), mainly linear morphea subtype. EI was observed in 23/56(41%) of JLS patients. Eight(35%) of 23 EI patients with JLS were symptomatic and presented heartburn(5/8), solid and liquid dysphagia(3/8), nausea and epigastralgia(1/8). The frequency of any cumulative extracutaneous manifestations (calcinosis, arthritis/arthralgia, central nervous system, interstitial pneumonitis, mesangial nephritis and/or arrhythmia) was significantly higher in JLS patients with EI compared to those without this complication (56% vs. 24%, p=0.024). No differences were evidenced in demographic data, JLS subtypes and in each extracutaneous manifestation in both groups (p>0.05). The frequency of methotrexate use was significantly higher in JLS patients with EI compared to those without (52% vs. 12%, p=0.002). Autoantibody profile (antinuclear antibodies, anti-SCL-70, rheumatoid factor, anticentromere, anti-cardiolipin, anti-Ro/SSA and anti-La/SSB) was similar in both groups (p>0.05). CONCLUSIONS: Our study demonstrated that EI was frequently observed in JLS patients, mainly in asymptomatic patients with linear subtype. EI occurred in JLS patients with other extracutaneous manifestations and required methotrexate therapy.

Latent tuberculosis infection screening in juvenile idiopathic arthritis patients preceding anti-TNF therapy in a tuberculosis high-risk country.

OBJECTIVES: To evaluate, in an endemic country, the long-term efficacy of latent tuberculosis infection (LTBI) screening and primary prophylaxis in patients with JIA receiving TNF blockers. METHODS: This was a retrospective cohort that included JIA patients eligible to anti-TNF therapy. Patients were screened for LTBI prior to anti-TNF using tuberculin skin test (TST), chest X-ray and history of exposure to TB. Subjects were regularly followed at 2-month intervals. RESULTS: Sixty-nine JIA patients with current age of 17.4±5.8 years, mean disease duration of 5.0±4.9 years were included. Forty-seven patients received a single anti-TNF, while 22 patients switched to another anti-TNF once or twice: 57 were treated with etanercepte, 33 patients with adalimumab and 3 infliximab. LTBI screening was positive in three patients: one had TST-positive and history of TB exposure and two had solely TST-positive. No active TB was diagnosed during the study period (median of follow-up was 3.8 years). CONCLUSION: Long-term evaluation revealed that LTBI screening and primary prophylaxis before anti-TNF treatment was effective in a high-risk country and TST was the most sensitive parameter to identify these patients.

Latent tuberculosis infection screening in juvenile idiopathic arthritis patients preceding anti-TNF therapy in a tuberculosis high-risk country / Rastreamento da infecção latente por tuberculose em pacientes com artrite idiopática juvenil previamente à terapia anti-TNF em um país de alto risco para tuberculose

Abstract Objectives: To evaluate, in an endemic country, the long-term efficacy of latent tuberculosis infection (LTBI) screening and primary prophylaxis in patients with JIA receiving TNF blockers. Methods: This was a retrospective cohort that included JIA patients eligible to anti-TNF therapy. Patients were screened for LTBI prior to anti-TNF using tuberculin skin test (TST), chest X-ray and history of exposure to TB. Subjects were regularly followed at 2-month intervals. Results: Sixty-nine JIA patients with current age of 17.4 ± 5.8 years, mean disease duration of 5.0 ± 4.9 years were included. Forty-seven patients received a single anti-TNF, while 22 patients switched to another anti-TNF once or twice: 57 were treated with etanercepte, 33 patients with adalimumab and 3 infliximab. LTBI screening was positive in three patients: one had TST-positive and history of TB exposure and two had solely TST-positive. No active TB was diagnosed during the study period (median of follow-up was 3.8 years). Conclusion: Long-term evaluation revealed that LTBI screening and primary prophylaxis before anti-TNF treatment was effective in a high-risk country and TST was the most sensitive parameter to identify these patients.

Resumo Objetivo: Avaliar, em um país endêmico, a eficácia em longo prazo do rastreamento à procura de infecção latente por tuberculose (ILTB) e profilaxia primária em pacientes com AIJ em uso de bloqueadores do TNF. Métodos: Trata-se de uma coorte retrospectiva que incluiu pacientes com AIJ elegíveis para a terapia anti-TNF. Os pacientes foram rastreados à procura de ILTB previamente ao uso de anti-TNF por meio do teste tuberculínico (TT), radiografia de tórax e história de exposição à TB. Os indivíduos foram acompanhados regularmente em intervalos de dois meses. Resultados: Incluíram-se 69 pacientes com AIJ com idade atual de 17,4 ± 5,8 anos, com média de duração da doença de 5 ± 4,9 anos; 47 pacientes receberam um único anti-TNF, enquanto 22 foram transferidos para outro anti-TNF uma ou duas vezes: 57 foram tratados com etanercepte, 33 com adalimumabe e três com infliximabe. O rastreamento à procura de ILTB foi positivo em três pacientes: um era TT positivo e tinha história de exposição à TB e dois apenas eram TT positivo. Não foi diagnosticado caso de TB ativa durante o período de estudo (mediana de seguimento de 3,8 anos). Conclusão: A avaliação em longo prazo revelou que o rastreamento à procura de ILTB e a profilaxia primária antes do tratamento com anti-TNF foram eficazes em um país de alto risco para TB e o TT foi o parâmetro mais sensível para identificar esses pacientes.

CANDLE syndrome: chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature-a rare case with a novel mutation.

UNLABELLED: We described herein a patient with chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome and a novel mutation in PSMB8 gene. This patient had multiple visceral inflammatory involvements, including rare manifestations, such as Sweet syndrome and pericarditis. A 3-year-old male, Caucasian, was born to consanguineous healthy parents. At the age of 11 months, he presented daily fever (temperature >40 °C), irritability, hepatomegaly, splenomegaly; and tender and itching, erythematous papular and edematous plaque lesions. Echocardiogram showed mild pericarditis. Skin biopsy revealed a neutrophil infiltrate without vasculitis suggesting Sweet syndrome. Mutational screening of PSMB8 gene revealed homozygous c.280G>C, p.A94P mutation. He responded partially to high doses of oral glucorticoid and intravenous methylprednisolone. Colchicine, azathioprine, methotrexate, cyclosporine, and intravenous immunoglobulin were not efficacious. At the age of 3 years and 1 month, tocilizumab was administered resulting in remission of daily fever and irritability. However, there was no improvement of the skin tenderness and itching lesions. CONCLUSION: A new mutation in a CANDLE syndrome patient was reported with pericarditis and mimicking Sweet syndrome. The disease manifestations were refractory to immunosuppressive agents and partially responsive to tocilizumab therapy. WHAT IS KNOWN: • Proteasome-associated autoinflammatory syndromes (PRAAS) include four rare diseases. • Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome was seldom reported. What is New: • We described a Brazilian patient with CANDLE syndrome possessing a novel mutation in the PSMB8 gene. • This patient had multiple visceral inflammatory involvements, including rare manifestations, such as pericarditis and mimicking Sweet syndrome.