Randy Q. Cron

2011 American College of Rheumatology Recommendations for the Treatment of Juvenile Idiopathic Arthritis: Initiation and Safety Monitoring of Therapeutic Agents for the Treatment of Arthritis and Systemic Features

Guidelines and recommendations developed and/or endorsed by the American College of Rheumatology (ACR) are intended to provide guidance for particular patterns of practice and not to dictate the care of a particular patient. The ACR considers adherence to these guidelines and recommendations to be voluntary, with the ultimate determination regarding their application to be made by the physician in light of each patient’s individual circumstances. Guidelines and recommendations are intended to promote beneficial or desirable outcomes but cannot guarantee any specific outcome. Guidelines and recommendations developed or endorsed by the ACR are subject to periodic revision as warranted by the evolution of medical knowledge, technology, and practice.

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.

Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment

Macrophage activation syndrome (MAS) is a severe, frequently fatal complication of systemic juvenile idiopathic arthritis (sJIA) with features of hemophagocytosis leading to coagulopathy, pancytopenia, and liver and central nervous system dysfunction. MAS is overt in 10% of children with sJIA but occurs subclinically in another 30–40%. It is difficult to distinguish sJIA disease flare from MAS. Development of criteria for establishing MAS as part of sJIA are under way and will hopefully prove sensitive and specific. Mutations in cytolytic pathway genes are increasingly being recognized in children who develop MAS as part of sJIA. Identification of these mutations may someday assist in MAS diagnosis. Defects in cytolytic genes have provided murine models of MAS to study pathophysiology and treatment. Recently, the first mouse model of MAS not requiring infection but rather dependent on repeated stimulation through Toll-like receptors was reported. This provides a model of MAS that may more accurately reflect MAS pathology in the setting of autoinflammation or autoimmunity. This model confirms the importance of a balance between pro- and anti-inflammatory cytokines. There has been remarkable progress in the use of anti-pro-inflammatory cytokine therapy, particularly against interleukin-1, in the treatment of secondary forms of MAS, such as in sJIA.

High prevalence of temporomandibular joint arthritis at disease onset in children with juvenile idiopathic arthritis, as detected by magnetic resonance imaging but not by ultrasound.

OBJECTIVE To determine the prevalence of temporomandibular joint (TMJ) disease in a cohort of children with new-onset juvenile idiopathic arthritis (JIA), and to compare magnetic resonance imaging (MRI) with ultrasound (US) for the detection of acute and chronic changes of TMJ arthritis. METHODS Between January 2005 and April 2007, children with newly diagnosed JIA were prospectively evaluated for TMJ arthritis. Prior to imaging, jaw pain and disability were assessed with questionnaires and physical examination. The TMJs of all patients were imaged with MRI and US within 8 weeks of diagnosis. RESULTS Of the 32 patients enrolled, 78% were female, and the median age was 8.6 years (range 1.5-17.2 years). Acute TMJ arthritis was diagnosed in 75% of the children by MRI and in none by US; chronic arthritis was diagnosed in 69% by MRI and in 28% by US. Findings of both acute and chronic TMJ disease were detected by MRI in 53% of the patients. Of those with acute TMJ arthritis, 71% were asymptomatic, and 63% had normal findings on jaw examination. Fifty-six percent of patients with acute disease had an improved maximal incisal opening after corticosteroid injection. Among these responders, 56% had been asymptomatic and had normal jaw examination findings. CONCLUSION TMJ arthritis was present in the majority of patients with new-onset JIA. Findings on MRI along with responses to treatment among asymptomatic patients with normal jaw examination findings suggest that a history review and physical examination are not sufficient to screen for TMJ disease. Our results also suggest that MRI and US findings are not well correlated, and that MRI is preferable for the detection of TMJ disease in new-onset JIA.

Successful treatment of severe paediatric rheumatic disease-associated macrophage activation syndrome with interleukin-1 inhibition following conventional immunosuppressive therapy: case series with 12 patients

SIR, Macrophage activation syndrome (MAS) belongs to the haemophagocytic lymphohistiocytic (HLH) disorders, and is one of the most feared complications of paediatric inflammatory diseases with mortality rates up to 53% [1]. Its early recognition and treatment are critical in improving outcome [2]. However, current therapeutics, including corticosteroids, ciclosporin and intravenous immunoglobulin (IVIG), do not work for all children, and the nextline treatments, such as etoposide, are associated with sepsis, a risk of secondary malignancy and up to 44% mortality rate [3]. A less immunosuppressive but effective targeted therapy is in demand. Anakinra, an IL-1 receptor antagonist, has been highly effective in treating systemic juvenile idiopathic arthritis (sJIA) [4], and MAS may occur in up to half of sJIA patients [5]. Recently, three case reports have demonstrated anakinra to effectively treat MAS as part of panniculitis, sJIA and adult onset Still’s disease [6–8]. Herein, we report the benefit of anakinra in 12 children with paediatric rheumatic disease-related MAS (prMAS). All patients at the Alberta Children’s Hospital and the Children’s Hospital of Philadelphia, who received anakinra between 2006 and 2009 for prMAS were studied retrospectively. The diagnosis of MAS was based on the combination of: (i) Ravelli’s preliminary criteria for sJIA-associated MAS [9] and (ii) HLH-2004 criteria for inherited HLH [10]. Resolution of MAS was defined by the HLH-2004 criteria [10], and included no fever, splenomegaly, cytopenia (haemoglobin 590 g/l, platelets 5100 10/l, absolute neutrophil count 5500 cells/ml) or hypertriglyceridaemia (>500 mg/l) and normalization of soluble CD25 (sCD25) if the test was performed. When prMAS occurred, all patients initially received corticosteroids (n1⁄4 12) and other immunosuppressants [IVIG (n1⁄4 9), ciclosporin (n1⁄4 10), etoposide (n1⁄4 2, one dose each) and etanercept (n1⁄4 1)] with limited benefit. Anakinra was given for better prMAS control. Etanercept and etoposide were discontinued when anakinra was initiated. In all other patients, anakinra was added to pre-existing MAS therapy at 2 mg/kg/day s.c. (maximum dose 100 mg/day) once daily. Laboratory measurements as per Ravelli’s and HLH-2004 criteria were measured before and after anakinra administration. CRP was additionally measured in selected patients. During hospitalization for prMAS, five patients were diagnosed with new-onset sJIA by the ILAR criteria, three patients with vasculitis using ACR criteria and one patient with acute rheumatic fever. Institutional Review Board approval was obtained from both institutions before the study for publication of the results of the case series. In total, 12 patients with prMAS were treated with anakinra between 2006 and 2009. Baseline characteristics are shown in Table 1. Before anakinra, five patients required intensive care, and potential infectious triggers were present in seven patients. All patients met diagnostic criteria for Ravelli’s sJIA-associated MAS [9]. Seven of 12 met the HLH-2004 criteria [10], including elevated ferritin (n1⁄4 12/12), haemophagocytosis in the bone marrow (n1⁄4 5/7), abnormal NK cell activity (n1⁄4 1/2) and elevated sCD25 (n1⁄4 4/6). The median hospitalization stay before anakinra was 11 (range 1–27) days. All patients achieved MAS remission after addition of anakinra within a median of 13 (range 2–19) days. Corticosteroids were discontinued by 6 weeks in seven patients. Of all laboratory parameters, CRP and ferritin correlated the best with MAS activity (Table 1). Median (interquartile range) CRP (n1⁄4 9/12) 2 days before the use of anakinra was 125 (95.5–183.5) mg/l compared with median 6.8 (1.9–8.9) mg/l 5 days after the use of anakinra (P1⁄4 0.0039). Patients were followed for a median of 22 (range 2–40) months, and all were in remission of MAS at the final follow-up with excellent control of the underlying rheumatic disease. There were no noted side effects from anakinra administration. We report resolution of severe prMAS following addition of anakinra to conventional immunosuppressive therapy. In these severely ill patients, anakinra was chosen over HLH-2004 treatment with etoposide and high-dose dexamethasone because of concern for sepsis, potential future malignancy and the high mortality rate associated with this protocol [3]. The clinical response was dramatic and rapid, occurring within days. All patients fully recovered, including five who had required intensive care support. In sJIA-related MAS, the mortality rate was reported in 2001 as 28% [2], yet all our patients with sJIA did well. Our three patients with vasculitis and one with rheumatic fever-associated MAS also remitted. Ravelli’s 2005 preliminary MAS criteria [9] allowed for early confirmation of MAS, although we also utilized ferritin, sCD25 and NK cell activity from the HLH-2004 criteria to confirm the diagnosis [10]. We attribute the excellent outcome in our patients to early diagnosis and immediate therapeutic intervention, including early use of anakinra. As all patients were treated with anakinra and traditional therapies, it is possible that the combination of medications contributed to the resolution of MAS. We therefore recommend anakinra in combination with high-dose corticosteroids, ciclosporin and IVIG, rather than as a sole agent. Further studies with larger patient numbers are required to better define

MHCII Is Required for α-Synuclein-Induced Activation of Microglia, CD4 T Cell Proliferation, and Dopaminergic Neurodegeneration

Accumulation of α-synuclein (α-syn) in the brain is a core feature of Parkinson disease (PD) and leads to microglial activation, production of inflammatory cytokines and chemokines, T-cell infiltration, and neurodegeneration. Here, we have used both an in vivo mouse model induced by viral overexpression of α-syn as well as in vitro systems to study the role of the MHCII complex in α-syn-induced neuroinflammation and neurodegeneration. We find that in vivo, expression of full-length human α-syn causes striking induction of MHCII expression by microglia, while knock-out of MHCII prevents α-syn-induced microglial activation, antigen presentation, IgG deposition, and the degeneration of dopaminergic neurons. In vitro, treatment of microglia with aggregated α-syn leads to activation of antigen processing and presentation of antigen sufficient to drive CD4 T-cell proliferation and to trigger cytokine release. These results indicate a central role for microglial MHCII in the activation of both the innate and adaptive immune responses to α-syn in PD and suggest that the MHCII signaling complex may be a target of neuroprotective therapies for the disease.

Regulation of the Murine Nfatc1 Gene by NFATc2

NFAT proteins play a key role in the inducible expression of cytokine genes in T lymphocytes. NFATc1 and NFATc2 are the predominant NFAT family members in the peripheral immune system. NFATc2 is found abundantly in the cytoplasm of resting T cells, whereasNfatc1 expression is induced during T cell activation. To investigate Nfatc1 regulation, we characterized the structure of the murine Nfatc1 gene and its 5′-flanking region. A 290-bp sequence proximal to the transcription start site is highly conserved between mouse and human and possesses both basal and inducible promoter activities. Multiple binding sites for transcription factors were identified within this region, including a consensus NFAT-binding site. This promoter segment was cyclosporin A-sensitive, and mutation of the NFAT site abrogated inducible promoter activity and inhibited formation of an inducible DNA·protein complex containing NFATc2 in primary T cells. Overexpression of NFATc2 increased inducibleNfatc1 promoter activity, whereas this inducibility was attenuated in NFATc2−/− splenocytes. This study suggests that pre-existing NFATc2 contributes to the subsequent induction ofNfatc1 during T cell activation.

An international consensus survey of diagnostic criteria for macrophage activation syndrome in systemic juvenile idiopathic arthritis.

Objective. To identify candidate diagnostic criteria for macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (sJIA) using international consensus formation through a Delphi questionnaire survey. Methods. A questionnaire listing 28 clinical, laboratory, and histopathologic features of MAS elicited by literature review was sent to 505 pediatric rheumatologists worldwide. Respondents were asked to select the 10 features that they felt were most important and useful in the diagnosis of MAS, and to order the 10 selected features by assigning the number 10 to the most important, and ending with 1 as the least important. Results. The response rate was 46% (232 physicians from 47 countries). The items selected by more than 50% of respondents were, in order of frequency, falling platelet count, hyperferritinemia, evidence of macrophage hemophagocytosis in the bone marrow, increased liver enzymes, falling leukocyte count, persistent continuous fever ≥ 38°C, falling erythrocyte sedimentation rate, hypofibrinogenemia, and hypertriglyceridemia. Conclusion. Our process led to identification of features that were felt to be most important as candidate diagnostic criteria for MAS by a large sample of international pediatric rheumatologists.

Temporomandibular joint arthritis in juvenile idiopathic arthritis: the forgotten joint.

Purpose of reviewThis review explores the prevalence, clinical and radiographic signs, and treatment of temporomandibular joint arthritis in children with juvenile idiopathic arthritis. Recent findingsTemporomandibular joint arthritis seems to be a more frequent manifestation in patients with juvenile idiopathic arthritis than previously believed, in part due to the paucity of clinical symptoms and poor sensitivity of conventional radiographs used for diagnosis. Antinuclear antibody positivity, early onset of disease, and presence of systemic or polyarticular disease are all risk factors for temporomandibular joint arthritis but may underpredict temporomandibular joint involvement in juvenile idiopathic arthritis. Magnetic resonance imaging enhanced with gadolinium is currently the gold standard in detection of temporomandibular joint arthritis, and treatment with intra-articular corticosteroids has been shown to be effective and safe, with minimal side effects. SummaryGiven the paucity of clinical symptoms in temporomandibular joint arthritis, detection of temporomandibular joint inflammation using contrast-enhanced magnetic resonance imaging is essential for instituting appropriate therapy in a timely fashion. The use of intra-articular corticosteroids holds promise for control of temporomandibular joint inflammation and prevention of associated morbidities.

Clinical Features, Treatment, and Outcome of Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis: A Multinational, Multicenter Study of 362 Patients

To describe the clinical, laboratory, and histopathologic features, current treatment, and outcome of patients with macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (JIA).