Paivi Miettunen

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.

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

Macrophage activation syndrome in juvenile systemic lupus erythematosus: A multinational multicenter study of thirty‐eight patients

OBJECTIVE To describe the clinical and laboratory features of macrophage activation syndrome as a complication of juvenile systemic lupus erythematosus (SLE). METHODS Cases of juvenile SLE-associated macrophage activation syndrome were provided by investigators belonging to 3 pediatric rheumatology networks or were found in the literature. Patients who had evidence of macrophage hemophagocytosis on bone marrow aspiration were considered to have definite macrophage activation syndrome, and those who did not have such evidence were considered to have probable macrophage activation syndrome. Clinical and laboratory findings in patients with macrophage activation syndrome were contrasted with those of 2 control groups composed of patients with active juvenile SLE without macrophage activation syndrome. The ability of each feature to discriminate macrophage activation syndrome from active disease was evaluated by calculating sensitivity, specificity, and area under the receiver operating characteristic curve. RESULTS The study included 38 patients (20 with definite macrophage activation syndrome and 18 with probable macrophage activation syndrome). Patients with definite and probable macrophage activation syndrome were comparable with regard to all clinical and laboratory features of the syndrome, except for a greater frequency of lymphadenopathy, leukopenia, and thrombocytopenia in patients with definite macrophage activation syndrome. Overall, clinical features had better specificity than sensitivity, except for fever, which was highly sensitive but had low specificity. Among laboratory features, the best sensitivity and specificity was achieved using hyperferritinemia, followed by increased levels of lactate dehydrogenase, hypertriglyceridemia, and hypofibrinogenemia. Based on the results of statistical analysis, preliminary diagnostic guidelines for macrophage activation syndrome in juvenile SLE were developed. CONCLUSION Our findings indicate that the occurrence of unexplained fever and cytopenia, when associated with hyperferritinemia, in a patient with juvenile SLE should raise the suspicion of macrophage activation syndrome. We propose preliminary guidelines for this syndrome in juvenile SLE to facilitate timely diagnosis and correct classification of patients.

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).

Consensus treatment plans for induction therapy of newly diagnosed proliferative lupus nephritis in juvenile systemic lupus erythematosus

To formulate consensus treatment plans (CTPs) for induction therapy of newly diagnosed proliferative lupus nephritis (LN) in juvenile systemic lupus erythematosus (SLE).

Incident vertebral fractures among children with rheumatic disorders 12 months after glucocorticoid initiation: a national observational study.

To determine the frequency of incident vertebral fractures (IVF) 12 months after glucocorticoid (GC) initiation in children with rheumatic diseases and to identify children at higher risk.

Dramatic pain relief and resolution of bone inflammation following pamidronate in 9 pediatric patients with persistent chronic recurrent multifocal osteomyelitis (CRMO)

BackgroundChronic recurrent multifocal osteomyelitis (CRMO) is an inflammatory, non-infectious osteopathy that affects predominantly patients ≤ 18 years of age. There is no uniformly effective treatment. Our objective is to describe clinical, magnetic resonance imaging (MRI), and bone resorption response to intravenous pamidronate in pediatric CRMO.MethodsWe report our prospectively documented experience with all CRMO patients treated with pamidronate between 2003 and 2008 at a tertiary pediatric centre. Pamidronate was administered as intravenous cycles. The dose of pamidronate varied among subjects but was given as monthly to every 3 monthly cycles depending on the distance the patient lived from the infusion center. Maximum cumulative dose was ≤ 11.5 mg/kg/year. Pamidronate treatment was continued until resolution of MRI documented bone inflammation. Visual analog scale for pain (VAS) and bone resorption marker urine N-telopeptide/urine creatinine (uNTX/uCr) were measured at baseline, preceding each subsequent pamidronate treatment, at final follow-up, and/or at time of MRI confirmed CRMO flare. MRI of the affected site(s) was obtained at baseline, preceding every 2nd treatment, and with suspected CRMO recurrence.ResultsNine patients (5 F: 4 M) were treated, with a median (range) age at treatment of 12.9 (4.5–16.3) years, and median (range) duration of symptoms of 18 (6–36) months. VAS decreased from 10/10 to 0–3/10 by the end of first 3–day treatment for all patients. The mean (range) time to complete MRI resolution of bone inflammation was 6.0 (2–12) months. The mean (confidence interval (CI)) baseline uNTX/uCr was 738.83 (CI 464.25, 1013.42)nmol/mmol/creatinine and the mean (CI) decrease from baseline to pamidronate discontinuation was 522.17 (CI 299.77, 744.56)nmol/mmol/creatinine. Median (range) of follow-up was 31.4 (24–54) months. Four patients had MRI confirmed CRMO recurrence, which responded to one pamidronate re-treatment. The mean (range) uNTX/uCr change as a monthly rate from the time of pamidronate discontinuation to flare was 9.41 (1.38–19.85)nmol/mmol/creatinine compared to -29.88 (-96.83–2.01)nmol/mmol/creatinine for patients who did not flare by the time of final follow-up.ConclusionPamidronate resulted in resolution of pain and MRI documented inflammation in all patients. No patient flared while his/her uNTX/uCr remained suppressed. We propose that pamidronate is an effective second-line therapy in persistent CRMO.

High Incidence of Vertebral Fractures in Children With Acute Lymphoblastic Leukemia 12 Months After the Initiation of Therapy

PURPOSE Vertebral fractures due to osteoporosis are a potential complication of childhood acute lymphoblastic leukemia (ALL). To date, the incidence of vertebral fractures during ALL treatment has not been reported. PATIENT AND METHODS We prospectively evaluated 155 children with ALL during the first 12 months of leukemia therapy. Lateral thoracolumbar spine radiographs were obtained at baseline and 12 months. Vertebral bodies were assessed for incident vertebral fractures using the Genant semiquantitative method, and relevant clinical indices such as spine bone mineral density (BMD), back pain, and the presence of vertebral fractures at baseline were analyzed for association with incident vertebral fractures. RESULTS Of the 155 children, 25 (16%; 95% CI, 11% to 23%) had a total of 61 incident vertebral fractures, of which 32 (52%) were moderate or severe. Thirteen (52%) of the 25 children with incident vertebral fractures also had fractures at baseline. Vertebral fractures at baseline increased the odds of an incident fracture at 12 months by an odds ratio of 7.3 (95% CI, 2.3 to 23.1; P = .001). In addition, for every one standard deviation reduction in spine BMD Z-score at baseline, there was 1.8-fold increased odds of incident vertebral fracture at 12 months (95% CI, 1.2 to 2.7; P = .006). CONCLUSION Children with ALL have a high incidence of vertebral fractures after 12 months of chemotherapy, and the presence of vertebral fractures and reductions in spine BMD Z-scores at baseline are highly associated clinical features.

2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis: A European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborative Initiative

To develop criteria for the classification of macrophage activation syndrome (MAS) in patients with systemic juvenile idiopathic arthritis (JIA).

The outcomes of juvenile idiopathic arthritis in children managed with contemporary treatments: results from the ReACCh-Out cohort

Objective To describe clinical outcomes of juvenile idiopathic arthritis (JIA) in a prospective inception cohort of children managed with contemporary treatments. Methods Children newly diagnosed with JIA at 16 Canadian paediatric rheumatology centres from 2005 to 2010 were included. Kaplan–Meier survival curves for each JIA category were used to estimate probability of ever attaining an active joint count of 0, inactive disease (no active joints, no extraarticular manifestations and a physician global assessment of disease activity <10 mm), disease remission (inactive disease >12 months after discontinuing treatment) and of receiving specific treatments. Results In a cohort of 1104 children, the probabilities of attaining an active joint count of 0 exceeded 78% within 2 years in all JIA categories. The probability of attaining inactive disease exceeded 70% within 2 years in all categories, except for RF-positive polyarthritis (48%). The probability of discontinuing treatment at least once was 67% within 5 years. The probability of attaining remission within 5 years was 46–57% across JIA categories except for polyarthritis (0% RF-positive, 14% RF-negative). Initial treatment included joint injections and non-steroidal anti-inflammatory drugs for oligoarthritis, disease-modifying antirheumatic drugs (DMARDs) for polyarthritis and systemic corticosteroids for systemic JIA. Conclusions Most children with JIA managed with contemporary treatments attain inactive disease within 2 years of diagnosis and many are able to discontinue treatment. The probability of attaining remission within 5 years of diagnosis is about 50%, except for children with polyarthritis.