A 6-month, multicenter, open-label study of fixed dose naproxen/esomeprazole in adolescent patients with juvenile idiopathic arthritis.

BACKGROUND: Juvenile idiopathic arthritis (JIA) is an inflammatory arthritis of unknown etiology, which lasts for greater than 6 weeks with onset before 16 years of age. JIA is the most common chronic rheumatic disease in children. NSAIDs have been the mainstay of initial management with naproxen (NAP) being commonly used, but they may cause serious side effects such as gastric ulcers which can be reduced by concomitant administration of proton pump inhibitors, such as esomeprazole (ESO). METHODS: Primary objective was to evaluate the safety and tolerability of 3 fixed doses of NAP/ESO in JIA patients aged 12 to 16 years. Forty-six children and adolescents with JIA by International League of Associations for Rheumatology criteria, mean age of 13.6 years, from 18 US sites were prospectively enrolled over 2 years and followed for up to 6 months. Doses of the NAP/ESO fixed combination were based on baseline weight. The exploratory efficacy outcome was assessed with the ACR Pediatric-30, - 50, - 70, - 90 Response and the Childhood Health Assessment Questionnaire (CHAQ) discomfort and functional scores at months 1, 3, and 6 as change from baseline. Occurrence and causality were assessed for treatment emergent AEs (TEAEs) and discontinuations were monitored monthly. RESULTS: Forty-six patients received at least 1 dose of naproxen/esomeprazole and 36 completed the trial. Thirty-seven (80.4%) had at least 1 treatment emergent adverse event (TEAE) and, with the exception of 2 events in one patient, all of the TEAEs were mild or moderate. Frequent TEAEs (≥5% of patients) were upper respiratory tract and gastrointestinal related. Eleven (23.9%) had at least 1 TEAE considered to be related to study drug. Four patients (8.7%) discontinued due to a TEAE with one of these being the only serious AE reported, acute hepatitis. Mean number of active joints at baseline was 3.1. Improvement in JIA signs and symptoms occurred at most assessments and by month 6, the percentage of patients with an ACR Pediatric-30, - 50, - 70, and - 90 Response was 47.1, 38.2, 32.4, and 17.6%, respectively. The percent of patients achieving ACR Pediatric response increased over time. CHAQ discomfort improved at each assessment and functional scores improved at all assessments for 'Arising, Walking, and Activities' with several improved for 'Dressing and Grooming, Eating, Hygiene, and Grip'. There was no indication of a dose-related efficacy effect. CONCLUSION: NAP/ESO was well tolerated in JIA patients aged 12 to 16 years with high levels of response to ACR criteria. No new safety signals were identified for the well-characterized components of this fixed dosed JIA treatment, which was developed to reduce the risk of gastric ulcers. TRIAL REGISTRATION: Clinicaltrials.gov, NCT01544114 . Registered February 21, 2012.

Neurological Complications of Rheumatic Disease.

Rheumatic disease represents a broad spectrum of systemic conditions manifested by multisystem involvement and mediated by autoimmunity and inflammation. Their neurological complications may occur at any point in the disease process and are diagnostically challenging. For years central nervous system (CNS) was considered as a system uniquely protected from effects of the immune system because of the blood-brain barrier. Indeed, under physiological conditions immune access to CNS is tightly regulated. Over the past decade, new scientific discoveries highlighted pathways by which immune and neurological systems interact, including a variety of mechanisms controlling permeability of blood-brain barrier, and specific roles that CD4+ and CD8+ T-lymphocytes play in initiation of specific adaptive immune response to neural specific antigens. This leads to release of proinflammatory cytokines (interleukin 1, interleukin 6, and tumor necrosis factor alpha). In addition, B-cells involved in CNS inflammation produce antibodies against membrane bound and soluble antigens. This article describes specific neurological manifestations of the most common autoimmune rheumatic disorders.

Physicians' perspectives on the diagnosis and management of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome.

To assess the practice patterns of pediatric rheumatology and infectious diseases subspecialists in the diagnosis and treatment of periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome. An online survey assessing diagnostic and treatment approaches was sent to 424 members of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) and 980 members of the Pediatric Infectious Disease Society (PIDS). 277 physicians (123 from CARRA and 154 from PIDS representing 21% of the total membership) completed the survey. To diagnose PFAPA, most respondents agreed that patients must have the following features of the diagnostic criteria: stereotypical fever episodes (95%), asymptomatic intervals between episodes (93%), and normal growth and development (81%). However, 71% of the respondents did not require age of onset <5 years, 33% did not require regular intervals between episodes, and 79% did not require the concomitant signs of aphthous stomatitis, adenitis, or pharyngitis during episodes as long as episodes were regular. Over half (58%) considered episode resolution with steroids to be diagnostic of PFAPA. Corticosteroids, antipyretics, tonsillectomy, and cimetidine were the most commonly prescribed treatments, while steroids and tonsillectomy were most effective. Subspecialists in pediatric rheumatology and infectious diseases showed limited adherence to the complete published criteria for diagnosing PFAPA suggesting heterogeneity in the characteristics of patients diagnosed with the disorder. These findings emphasize the need to develop consensus diagnostic and treatment guidelines in well-characterized patient populations.

Childhood primary angiitis of the central nervous system with metachronous hemorrhagic infarcts: a postmortem study with clinicopathologic correlation.

This neuropathologic case study illustrates the discovery of metachronous hemorrhagic infarcts insinuating round mass-like lesions by magnetic resonance imaging in the setting of childhood primary angiitis of the central nervous system (cPACNS) raising diagnostic awareness of this unusual presentation in a clinical and neuroimaging context. The report underscores the importance of recurrent vasculitis-induced ischemic brain damage as a pathologic correlate of relapsing cPACNS and offers a critical reappraisal of common imitators as well as a clinicopathologic approach to differential diagnosis. Attention is drawn to the caveat that although magnetic resonance imaging findings at initial presentation may not be typical for stroke, they later exhibit attributes of cerebral infarction at both the subacute and chronic stages. A pattern of cPACNS characterized predominantly by multiple petechial-like cortical hemorrhages with pathologic features of hemorrhagic infarcts is recognized. The present study lends credence to the practice of a rigorous autopsy-based approach aimed at a better understanding of the anatomic pathology and biology of cPACNS and at facilitating prospective neuroimaging and biopsy-based surgical pathology correlations, ultimately enhancing diagnostic accuracy in clinical settings. Although PACNS is, by definition, a diagnosis of exclusion, it should be considered from the outset in the differential diagnosis of ischemic stroke or hemorrhagic stroke or of unusual and relapsing intra-axial mass-like CNS lesions in children, necessitating appropriate pathologic evaluation of brain biopsy specimens.

Safety of celecoxib and nonselective nonsteroidal anti-inflammatory drugs in juvenile idiopathic arthritis: results of the Phase 4 registry.

BACKGROUND: This study aimed to assess long-term safety and developmental data on juvenile idiopathic arthritis (JIA) patients treated in routine clinical practice with celecoxib or nonselective nonsteroidal anti-inflammatory drugs (nsNSAIDs). METHODS: Children aged ≥2 to <18 years with rheumatoid-factor-positive or -negative polyarthritis, persistent or extended oligoarthritis, or systemic arthritis were enrolled into this prospective, observational, multicenter standard-of-care registry. Eligible patients were newly or recently prescribed (≤6 months) an nsNSAID or celecoxib. Enrolled patients were followed to the end of the study, whether they remained on the original NSAID, switched, or discontinued therapy altogether. All adverse events (AEs) regardless of severity were captured in the database. RESULTS: A total of 274 patients (nsNSAID, n = 219; celecoxib, n = 55) were observed for 410 patient-years of observation. Naproxen, meloxicam, and nabumetone were the most frequently used nsNSAIDs. At baseline, the celecoxib group was older, had a numerically longer median time since diagnosis, and a numerically higher proportion of patients with a history of gastrointestinal-related NSAID intolerance. AEs reported were those frequently observed with NSAID treatment and were similar across groups (nsNSAIDs: 52.0%; celecoxib: 52.9%). Twelve unique patients experienced a total of 18 serious AEs; the most frequent were infections, and none was attributed to NSAID use. CONCLUSIONS: The safety profile of celecoxib and nsNSAIDs appears similar overall. The results from this registry, ongoing pharmacovigilance, and the phase 3 trial that led to the approval of celecoxib for children with JIA provide evidence that the benefit-risk for celecoxib treatment in JIA remains positive. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00688545.

Pain intensity, psychological inflexibility, and acceptance of pain as predictors of functioning in adolescents with juvenile idiopathic arthritis: a preliminary investigation.

Juvenile Idiopathic Arthritis (JIA) is a chronic rheumatic disease associated with pain and maladjustment. This study investigated whether pain, acceptance of pain, and psychological inflexibility uniquely predicted functional disability, anxiety, general quality of life (QOL), and health-related quality of life (HQOL) among adolescents with JIA. Twenty-three adolescents with JIA and pain were recruited from a pediatric rheumatology clinic. Participants completed self-report measures pertaining to the key study variables. A series of multiple regression analyses demonstrated that higher pain uniquely predicted higher functional disability. Greater psychological inflexibility uniquely predicted higher anxiety, lower general QOL, and lower HQOL. Increases in acceptance of pain were found to be uniquely related to increases in general QOL. These data confirm prior findings that pain impacts functioning, and provide preliminary findings that psychological inflexibility and acceptance may be important targets of psychological intervention for youth with JIA and pain to improve functioning and QOL.

Pachydermatodactyly mimics polyarticular juvenile idiopathic arthritis.

Pachydermatodactyly is an infrequently recognized disorder characterized by painless swelling of the soft tissues around the proximal interphalangeal joints. We report 2 cases erroneously diagnosed as polyarticular juvenile idiopathic arthritis, then referred to pediatric rheumatology for further assessment because of lack of improvement after initial treatment.

Successful treatment of severe or methotrexate-resistant juvenile localized scleroderma with mycophenolate mofetil.

OBJECTIVE: To evaluate the efficacy of mycophenolate mofetil (MMF) in the treatment of severe refractory juvenile localized scleroderma (JLS). METHODS: A retrospective chart review was performed in patients with JLS who had been treated with MMF after the failure of a combination of MTX and corticosteroids for at least 4 months, or whose JLS had concomitant severe extracutaneous manifestations. Outcome was assessed through clinical examination and thermography. Adverse events were recorded. RESULTS: Ten patients (six females and four males) were enrolled in the study. JLS clinical subtypes were deep morphoea (two patients with disabling pansclerotic morphoea), generalized morphoea (three patients), linear scleroderma (five patients) affecting the limbs in two and face in three patients (en coup de sabre). The age at onset of disease was 8 (range 2-16) years, and the disease duration at the time of treatment with MMF was 18 (range 8-62) months. All MMF-treated patients experienced clinical improvement that allowed withdrawal or reduction of doses of corticosteroids and MTX. Over a follow-up of 27 (range 6-36) months, mild abdominal discomfort was reported in only one patient. CONCLUSIONS: MMF appears to be effective in arresting disease progression in severe or MTX-refractory JLS and is generally well tolerated. Further controlled studies are needed to confirm these data.

Long-term open-label preliminary study of the safety and efficacy of leflunomide in patients with polyarticular-course juvenile rheumatoid arthritis.

OBJECTIVE: To obtain preliminary data regarding the efficacy and long-term safety of leflunomide in patients with refractory polyarticular-course juvenile rheumatoid arthritis (JRA). METHODS: Twenty-seven patients were entered into the initial 26-week open-label study of leflunomide therapy; 17 entered the extension phase (maximum 107 weeks). Mean disease duration at study entry was 7.0 years. All patients had >or=5 joints with active arthritis and had received methotrexate for a mean of 36.0 months. Following a loading dose, patients initially received leflunomide at a dosage of 10 mg/1.73 m(2)/day, which could be increased to 20 mg/1.73 m(2)/day (maximum 20 mg/day) beginning at week 8. The primary efficacy outcome was the American College of Rheumatology (ACR) Pediatric 30 (Pedi 30) criteria for improvement. Last observation carried forward (LOCF) analysis was used, and all patients were entered into an intent-to-treat analysis. Intraarticular corticosteroids (maximum of 2 in the initial 26 weeks) were allowed, but no new disease-modifying antirheumatic drug or change in nonsteroidal antiinflammatory drug was allowed throughout the study. RESULTS: Seventeen of the 27 patients (63%) completed the initial 26-week study. Fourteen patients (52%) met the ACR Pedi 30 response criteria at week 26. Seventeen patients entered into the extension phase (13 who met response criteria and 4 who failed to meet response criteria but decided to continue). Nine of the 17 patients (53%) who entered the extension phase either completed all 30 months of study or the study ended prior to the month 30 visit. Five patients withdrew because of failure to maintain efficacy, 2 withdrew their consent, and 1 withdrew because of an adverse event. Using LOCF analysis, 65% of patients met ACR Pedi 30 response criteria at 1 year and 2 years (weeks 50 and 106, respectively) and 53% at the end of the study. Good response rates were also seen using ACR Pedi 50 and ACR Pedi 70 criteria (47% and 24% at week 106, respectively). CONCLUSION: In this open-label study of JRA patients who either failed to respond to, or were intolerant of, methotrexate, the majority met the ACR Pedi 30 response criteria at week 26. The response was durable, since 53% of patients who entered into the extension phase (maximum 30 months) responded at the end of this phase. Our findings support the further study of the role of leflunomide in the treatment of polyarticular-course JRA.

Pulmonary capillaritis with hemorrhage due to propylthiouracil therapy in a child.

We report on a case of pulmonary capillaritis with diffuse alveolar hemorrhage in a child due to propylthiouracil (PTU). PTU treatment is a rare cause of pulmonary capillaritis in adults; we report on the first case in a pediatric patient. The treatment of pulmonary capillaritis often requires corticosteroid therapy, other immunosuppressive medications, or withdrawal of the causative agent. Our patient recovered completely after treatment with a limited course of corticosteroids and removal of PTU.

De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases.

OBJECTIVE: Neonatal-onset multisystem inflammatory disease (NOMID; also known as chronic infantile neurologic, cutaneous, articular [CINCA] syndrome) is characterized by fever, chronic meningitis, uveitis, sensorineural hearing loss, urticarial skin rash, and a characteristic deforming arthropathy. We investigated whether patients with this disorder have mutations in CIAS1, the gene which causes Muckle-Wells syndrome and familial cold autoinflammatory syndrome, two dominantly inherited disorders with some similarities to NOMID/CINCA syndrome. METHODS: Genomic DNA from 13 patients with classic manifestations of NOMID/CINCA syndrome and their available parents was screened for CIAS1 mutations by automated DNA sequencing. Cytokine messenger RNA (mRNA) levels were assessed by real-time polymerase chain reaction on peripheral blood leukocyte mRNA, and serum cytokine levels were assayed by enzyme-linked immunosorbent assay. Protein expression was assessed by Western blotting of lysates from plastic-adherent peripheral blood mononuclear cells. RESULTS: In 6 of the 13 patients, we found 6 heterozygous missense substitutions in CIAS1. Five of the 6 mutations are novel. None of these sequence changes was observed in a panel of >900 chromosomes from healthy controls. Two distinct nucleotide changes in a single codon in unrelated patients resulted in the same amino acid change. In 4 mutation-positive children whose parental DNA was available, no mutation was found in the parental DNA, supporting the conclusion that the mutations arose de novo. Consistent with the recently discovered role of CIAS1 in the regulation of interleukin-1 (IL-1), we found evidence of increased IL-1beta, as well as tumor necrosis factor, IL-3, IL-5, and IL-6, but not transforming growth factor beta, in a mutation-positive patient compared with normal controls. CONCLUSION: Our data increase the total number of known germline mutations in CIAS1 to 20, causing a spectrum of diseases ranging from familial cold autoinflammatory syndrome to Muckle-Wells syndrome to NOMID/CINCA syndrome. Mutations in CIAS1 were only found in approximately 50% of the cases identified clinically as NOMID/CINCA syndrome, which raises the possibility of genetic heterogeneity. IL-1 regulation by CIAS1 suggests that IL-1 receptor blockade may constitute a rational approach to the treatment of NOMID/CINCA syndrome.