Emergent high fatality lung disease in systemic juvenile arthritis.

OBJECTIVE: To investigate the characteristics and risk factors of a novel parenchymal lung disease (LD), increasingly detected in systemic juvenile idiopathic arthritis (sJIA). METHODS: In a multicentre retrospective study, 61 cases were investigated using physician-reported clinical information and centralised analyses of radiological, pathological and genetic data. RESULTS: LD was associated with distinctive features, including acute erythematous clubbing and a high frequency of anaphylactic reactions to the interleukin (IL)-6 inhibitor, tocilizumab. Serum ferritin elevation and/or significant lymphopaenia preceded LD detection. The most prevalent chest CT pattern was septal thickening, involving the periphery of multiple lobes ± ground-glass opacities. The predominant pathology (23 of 36) was pulmonary alveolar proteinosis and/or endogenous lipoid pneumonia (PAP/ELP), with atypical features including regional involvement and concomitant vascular changes. Apparent severe delayed drug hypersensitivity occurred in some cases. The 5-year survival was 42%. Whole exome sequencing (20 of 61) did not identify a novel monogenic defect or likely causal PAP-related or macrophage activation syndrome (MAS)-related mutations. Trisomy 21 and young sJIA onset increased LD risk. Exposure to IL-1 and IL-6 inhibitors (46 of 61) was associated with multiple LD features. By several indicators, severity of sJIA was comparable in drug-exposed subjects and published sJIA cohorts. MAS at sJIA onset was increased in the drug-exposed, but was not associated with LD features. CONCLUSIONS: A rare, life-threatening lung disease in sJIA is defined by a constellation of unusual clinical characteristics. The pathology, a PAP/ELP variant, suggests macrophage dysfunction. Inhibitor exposure may promote LD, independent of sJIA severity, in a small subset of treated patients. Treatment/prevention strategies are needed.

Therapeutic role of anakinra, an interleukin-1 receptor antagonist, in the management of secondary hemophagocytic lymphohistiocytosis/sepsis/multiple organ dysfunction/macrophage activating syndrome in critically ill children*.

OBJECTIVES: Secondary hemophagocytic lymphohistiocytosis, macrophage activating syndrome, and sepsis share the same inflammatory phenotype leading often to multiple organ dysfunction syndrome needing intensive care. The goal of this article is to describe our experience with anakinra (Kineret), a recombinant interleukin-1 receptor antagonist, in decreasing the systemic inflammation. DESIGN: Retrospective case series. SETTING: The PICU at the Helen DeVos Children's Hospital (Grand Rapids, MI). PATIENTS: The records of eight critically ill children presumed to have secondary hemophagocytic lymphohistiocytosis at our institution between January 1, 2011, and July 31, 2012, were reviewed. INTERVENTIONS: All of the patients were treated with anakinra (Kineret) and in some cases systemic corticosteroids as first-line therapy for secondary hemophagocytic lymphohistiocytosis. MEASUREMENTS AND MAIN RESULTS: Patients had a median age of 14 years and a median Pediatric Risk of Mortality score of 11.5. Four were previously healthy and four had underlying diseases that could have made them susceptible to secondary hemophagocytic lymphohistiocytosis. Indications for PICU transfer were respiratory distress 50% (4 of 8), cardiovascular instability 37.5% (3 of 8), and chest pain (1 of 8). Five of the patients (62.5%) were mechanically ventilated and 62.5% (5 of 8) received vasoactive infusions. Inflammatory markers were assessed linearly at the start of therapy and 7 days later. Baseline C-reactive protein was 206 ± 50 mg/L (mean ± SEM) at the start of anakinra and decreased by 67.1% to 68 ± 36 mg/L (p = 0.03). Ferritin decreased by 63.8% to 3,210 ± 1,178 ng/mL (p = 0.30), and fibrinogen decreased by 42% to 158 ± 41 mg/dL (p = 0.03). Absolute neutrophil count (p = 0.38) and absolute lymphocyte count (p = 0.69) did not change significantly. No infections were attributed to anakinra therapy. One patient died long after treatment with anakinra while receiving pre-hematopoietic stem cell transplant chemotherapy. CONCLUSIONS: Anakinra could represent a promising therapeutic approach in these life-threatening disorders that are likely underdiagnosed and often difficult to treat.

Influence of patient characteristics on perceived risks and willingness to take a proposed anti-rheumatic drug.

BACKGROUND: The causes of the underutilization of disease modifying anti-rheumatic drugs (DMARDS) for rheumatoid arthritis (RA) are not fully known, but may in part, relate to individual patient factors including risk perception. Our objective was to identify the determinants of risk perception (RP) in RA patients and predictors of their willingness to take a proposed DMARD (DMARD willingness). METHODS: A cross-sectional mail survey of RA patients in a community rheumatology practice. Patients were presented a hypothetical decision scenario where they were asked to consider switching DMARDs. They evaluated how risky the proposed medication was and how likely they would be to take it. RESULTS: The completed sample included 1009 RA patients. The overall survey response rate was 71%. PATIENT CHARACTERISTICS: age 61.6 years (range 18-93), 75% female, minority 6.5%, low or marginal health literacy 8.8%, depression 15.0%, duration RA 13.1 years (range 0.5 - 68). Regression models demonstrated that health literacy, independent of low educational achievement or other demographic (including race), was a common predictor of both RP and DMARD willingness. There was partial mediation of the effects of HL on DMARD willingness through RP. Depression and happiness had no significant effect on RP or DMARD willingness. RP was influenced by negative RA disease and treatment experience, while DMARD willingness was affected mainly by perceived disease control. CONCLUSIONS: Risk aversion may be the result of potentially recognizable and correctable cognitive defect. Heightened clinician awareness, formal screening for low health literacy or cognitive impairment in high-risk populations, may identify patients could benefit from additional decision support.

Anakinra as first-line disease-modifying therapy in systemic juvenile idiopathic arthritis: report of forty-six patients from an international multicenter series.

OBJECTIVE: To examine the safety and efficacy of the interleukin-1 (IL-1) receptor antagonist anakinra as first-line therapy for systemic juvenile idiopathic arthritis (JIA). METHODS: Patients with systemic JIA receiving anakinra as part of initial disease-modifying antirheumatic drug (DMARD) therapy were identified from 11 centers in 4 countries. Medical records were abstracted using a standardized instrument, and resulting data were analyzed to characterize concomitant therapies, clinical course, adverse events, and predictors of outcome. RESULTS: Among 46 patients meeting inclusion criteria, anakinra monotherapy was used in 10 patients (22%), while 67% received corticosteroids and 33% received additional DMARDs. Outcomes were evaluated at a median followup interval of 14.5 months. Fever and rash resolved within 1 month in >95% of patients, while C-reactive protein and ferritin normalized within this interval in >80% of patients. Active arthritis persisted at 1 month in 39% of patients, at 3 months in 27%, and at >6 months of followup in 11%. Approximately 60% of patients, including 8 of 10 receiving anakinra monotherapy, attained a complete response without escalation of therapy. Disease characteristics and treatment were similar in partial and complete responders, except that partial responders were markedly younger at onset (median age 5.2 years versus 10.2 years; P = 0.004). Associated adverse events included documented bacterial infection in 2 patients and hepatitis in 1 patient. Tachyphylaxis was not observed. CONCLUSION: Anakinra as first-line therapy for systemic JIA was associated with rapid resolution of systemic symptoms and prevention of refractory arthritis in almost 90% of patients during the interval examined. These results justify further study of IL-1 inhibition as first-line, rather than rescue, therapy in systemic JIA.

Emerging ideas: prevention of posttraumatic arthritis through interleukin-1 and tumor necrosis factor-alpha inhibition.

BACKGROUND: Despite surgical and mechanical stabilization of an acutely injured joint through ligament reconstruction, meniscus repair, or labral repair, the risk of posttraumatic arthritis remains high. Joint injury triggers three phases of pathogenic events: the early (acute) phase involves joint swelling, hemarthrosis, expression of inflammatory cytokines (especially interleukin-1 [IL-1] and tumor necrosis factor-α [TNF-α]), and biomarkers of cartilage catabolism; an intermediate phase is characterized by reduction of joint inflammation, ongoing joint catabolism, but no evidence yet for typical features of radiographic osteoarthritis (OA); and a late phase characterized by radiographic OA. HYPOTHESES: We hypothesize that the early phase of acute knee injury represents a window of opportunity for providing biologic treatment to promote healing and to slow or prevent a subsequent cascade of destructive joint processes leading to OA. PROPOSED PROGRAM: We propose a phase II, randomized, placebo-controlled, double-blinded, clinical trial to treat acute knee injuries with intraarticular injection of an IL-1 inhibitor. Patient-centered outcomes will include pain reduction and improvement of knee function. MR imaging and measurement of biochemical markers will be monitored during the subsequent 2 years to determine if the structural response to injury can be reversed. SIGNIFICANCE: If this model is validated, modulation of the molecular pathways responsible for articular cartilage breakdown will augment current reconstructive procedures in the treatment of acute joint injuries and prevent the development of injury-related arthritis.

Severe paediatric systemic lupus erythematosus nephritis--a single-centre experience.

BACKGROUND: Paediatric patients with systemic lupus erythematosus (SLE) often have severe presentations including lupus nephritis (LN). Few paediatric studies have evaluated the anticardiolipin antibody (aCL) and renal histology. The purpose of this study was to evaluate clinicopathologic features, including aCL, short-term clinical and renal histologic outcomes of paediatric patients with new-onset SLE nephritis. METHODS: We conducted a single centre, retrospective inception cohort study. Charts were reviewed at presentation (initial renal biopsy), 6-month (follow-up biopsy) and 12-month follow-up. RESULTS: The population consisted of 21 patients (median age, 14.5 years): 19/21 were female, 6/21 African American, 3/21 Asian, 9/21 Caucasian and 3/21 Hispanic. At presentation, 19/21 had elevated aCL, 15/21 hypertensive, 12/21 nephrotic and 7/21 required haemodialysis (HD)-2/7 HD patients had thrombotic microangiopathy, 1/7 crescentic glomerulonephritis. Two patients had thromboembolism: both had aCL, were taking oral contraceptives and required HD, one was nephrotic and the other had elevated lupus anticoagulant. Initial biopsies revealed 6/21 ISN/RPS class II nephritis, 3/21 class III, 7/21 class IV and 5/21 class V. Treatment consisted of methylprednisolone, corticosteroids, cyclophosphamide or mycophenolate mofetil. Follow-up biopsies revealed 12/13 to have improved histology. Indication for a follow-up biopsy was severe illness at presentation. At 12-month follow-up, no patients were nephrotic (P < 0.001) or required HD (P < 0.001), and 3/14 had elevated aCL (P < 0.001). CONCLUSION: Elevated aCL, hypertension, nephrotic syndrome and need for HD were common presentations among our paediatric SLE nephritis population. Renal histology and aCL were helpful in the therapeutic management.

Comparison of the Effects of a Pharmaceutical Industry Decision Guide and Decision Aids on Patient Choice to Intensify Therapy in Rheumatoid Arthritis.

OBJECTIVE: To compare the effects a pharmaceutical industry decision guide and International Patient Decision Aids Standard (IPDAS) compliant patient decision aids (PtDA) on patient medication beliefs and choice to intensify therapy. METHODS: Rheumatoid arthritis (RA) patients, who had never taken etanercept (Enbrel), took part in a mail survey. They were presented with a hypothetical decision scenario where they were asked to consider adding etanercept to their current regimen. Each patient was randomized to review 1 of 3 forms of an etanercept-specific decision support: a long PtDA (LONG DA), a short PtDA (SHORT DA), or the manufacturer's Enbrel decision guide (Pharm Booklet). RESULTS: We had 402 RA patients participate in the study (response rate, 52%). Of the patients randomized to the Pharm Booklet, 30.6% elected to initiate etanercept. Only 14.6% and 14.0% of patients who reviewed the LONG DA or SHORT DA choose to take etanercept (χ2 = 15.7; P < 0.001). Patients who reviewed the LONG DA or SHORT DA had a greater increase in knowledge about etanercept than those who reviewed the Pharm Booklet. There was no difference in decisional conflict among the groups. A logistic regression model explained 44.2% (R2 = 0.442) of patient choice to intensify therapy by initiating etanercept. The strongest predictor of choice to intensify therapy were beliefs about etanercept's ability to improve symptoms (OR = 2.56, 96%CI [1.71, 3.80]), and its use by others like the respondent (OR = 2.24, 95%CI [1.49, 3.35]). Mediation analysis confirmed the presence of a partial mediating effect of decision support on patients' intent to take etanercept (OR = 0.59, 95%CI [0.39, 0.89]). CONCLUSIONS: Patients supported by the Pharm Booklet were twice as likely to choose to intensify therapy. The Pharm Booklet's effects are partially mediated through persuasive communication techniques that influence patients' beliefs that symptoms will improve, and increase social normative beliefs, rather than by increasing the relevant knowledge, clarifying patient values about positive or negative treatment outcomes, or increasing their self-efficacy.

High dose Anakinra for treatment of severe neonatal Kawasaki disease: a case report.

We report an 11-week-old female who presented with Kawasaki disease (KD) complicated by macrophage activation syndrome (MAS). The infant presented to the hospital with persistent fever, cough, diarrhea, and emesis, among other symptoms. Her condition quickly began to decompensate, and she developed classic features (conjunctivitis, rash, cracked lips, distal extremity edema) prompting a diagnosis of acute KD. The patient was treated with standard therapy for KD including three doses of intravenous immunoglobulin (IVIG), aspirin, and high dose glucocorticoids with no change in her condition. Due to a high suspicion for MAS, high dose anakinra therapy was initiated resulting in dramatic clinical improvements. She also received one dose of infliximab for concern for coronary artery changes, and over the course of several months, anakinra and high dose glucocorticoids were tapered. Nearly complete reversal of echocardiogram changes were observed after 8 months, and the infant is now off all immunosuppressive therapy. In this case report, we briefly review the importance of early recognition of MAS in pediatric patient populations with rheumatic diseases, and we suggest early initiation of anakinra therapy as a rapid and effective treatment option.

Randomized, double-blind, placebo-controlled trial of the efficacy and safety of rilonacept in the treatment of systemic juvenile idiopathic arthritis.

OBJECTIVE: To assess the efficacy and safety of rilonacept, an interleukin-1 inhibitor, in a randomized, double-blind, placebo-controlled trial. METHODS: An initial 4-week double-blind placebo phase was incorporated into a 24-week randomized multicenter design, followed by an open-label phase. Seventy-one children who had active arthritis in ≥2 joints were randomized (1:1) to the 2 arms of the study. Patients in the rilonacept arm received rilonacept (loading dose 4.4 mg/kg followed by 2.2 mg/kg weekly, subcutaneously) beginning on day 0. Patients in the placebo arm received placebo for 4 weeks followed by a loading dose of rilonacept at week 4 followed by weekly maintenance doses. The primary end point was time to response, using the adapted American College of Rheumatology Pediatric 30 criteria coupled with the absence of fever and taper of the dosage of systemic corticosteroids, using prespecified criteria. RESULTS: The time to response was shorter in the rilonacept arm than in the placebo arm (χ(2) = 7.235, P = 0.007). The secondary analysis, which used the same response criteria, showed that 20 (57%) of 35 patients in the rilonacept arm had a response at week 4 compared with 9 (27%) of 33 patients in the placebo arm (P = 0.016). Exacerbation of systemic juvenile idiopathic arthritis (JIA) was the most common severe adverse event. More patients in the rilonacept arm had elevated liver transaminase levels (including levels more than 3 times the upper limit of normal) compared with those in the placebo arm. Adverse events were similar in the 2 arms of the study. CONCLUSION: Rilonacept was generally well tolerated and demonstrated efficacy in active systemic JIA.