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Background: Macrophage activation syndrome (MAS) is a severe and potentially lethal complication of several inflammatory diseases but seems particularly linked to systemic juvenile idiopathic arthritis (sJIA). Standardized diagnostic and treatment guidelines for MAS in sJIA are currently lacking. The aim of this systematic literature review was to evaluate currently available literature on diagnostic criteria for MAS in sJIA and provide an overview of possible biomarkers for diagnosis, disease activity and treatment response and recent advances in treatment. Methods: A systematic literature search was performed in MEDLINE, EMBASE and Cochrane. 495 papers were identified. Potentially relevant papers were selected by 3 authors after which full text screening was performed. All selected papers were evaluated by at least two independent experts for validity and level of evidence according to EULAR guidelines. Results: 27 papers were included: 7 on diagnosis, 9 on biomarkers and 11 on treatment. Systematic review of the literature confirmed that there are no validated diagnostic criteria for MAS in sJIA. The preliminary Ravelli criteria, with the addition of ferritin, performed well in a large retrospective case-control study. Recently, an international consortium lead by PRINTO proposed a new set of diagnostic criteria able to distinguish MAS from active sJIA and/ or infection with superior performance. Other promising diagnostic biomarkers potentially distinguish MAS complicating sJIA from primary and virus-associated hemophagocytic lymphohistiocytosis. The highest level of evidence for treatment comes from case-series. High dose corticosteroids with or without cyclosporine A were frequently reported as first-line therapy. From the newer treatment modalities, promising responses have been reported with anakinra. Conclusion: MAS in sJIA seems to be diagnosed best by the recently proposed PRINTO criteria, although prospective validation is needed. Novel promising biomarkers for sJIA related MAS are in need of prospective validation as well, and are not widely available yet. Currently, treatment of MAS in sJIA relies more on experience than evidence based medicine. Taking into account the severity of MAS and the scarcity of evidence, early expert consultation is recommended as soon as MAS is suspected. [ABSTRACT FROM AUTHOR]

Context: Novel therapies have improved the remission rate in chronic inflammatory disorders including juvenile idiopathic arthritis (JIA). Therefore, strategies of tapering therapy and reliable parameters for detecting subclinical inflammation have now become challenging questions.Objectives: To analyze whether longer methotrexate treatment during remission of JIA prevents flares after withdrawal of medication and whether specific biomarkers identify patients at risk for flares.Design, Setting, and Patients: Prospective, open, multicenter, medication-withdrawal randomized clinical trial including 364 patients (median age, 11.0 years) with JIA recruited in 61 centers from 29 countries between February 2005 and June 2006. Patients were included at first confirmation of clinical remission while continuing medication. At the time of therapy withdrawal, levels of the phagocyte activation marker myeloid-related proteins 8 and 14 heterocomplex (MRP8/14) were determined.Intervention: Patients were randomly assigned to continue with methotrexate therapy for either 6 months (group 1 [n = 183]) or 12 months (group 2 [n = 181]) after induction of disease remission.Main Outcome Measures: Primary outcome was relapse rate in the 2 treatment groups; secondary outcome was time to relapse. In a prespecified cohort analysis, the prognostic accuracy of MRP8/14 concentrations for the risk of flares was assessed.Results: Intention-to-treat analysis of the primary outcome revealed relapse within 24 months after the inclusion into the study in 98 of 183 patients (relapse rate, 56.7%) in group 1 and 94 of 181 (55.6%) in group 2. The odds ratio for group 1 vs group 2 was 1.02 (95% CI, 0.82-1.27; P = .86). The median relapse-free interval after inclusion was 21.0 months in group 1 and 23.0 months in group 2. The hazard ratio for group 1 vs group 2 was 1.07 (95% CI, 0.82-1.41; P = .61). Median follow-up duration after inclusion was 34.2 and 34.3 months in groups 1 and 2, respectively. Levels of MRP8/14 during remission were significantly higher in patients who subsequently developed flares (median, 715 [IQR, 320-1 110] ng/mL) compared with patients maintaining stable remission (400 [IQR, 220-800] ng/mL; P = .003). Low MRP8/14 levels indicated a low risk of flares within the next 3 months following the biomarker test (area under the receiver operating characteristic curve, 0.76; 95% CI, 0.62-0.90).Conclusions: In patients with JIA in remission, a 12-month vs 6-month withdrawal of methotrexate did not reduce the relapse rate. Higher MRP8/14 concentrations were associated with risk of relapse after discontinuing methotrexate.Trial Registration: isrctn.org Identifier: ISRCTN18186313. [ABSTRACT FROM AUTHOR]

Lysosomal storage disorders (LSDs), a heterogeneous group of inborn metabolic disorders, are far more common than most doctors presume. Although patients with a severe LSD subtype are often readily diagnosed, the more attenuated subtypes are frequently missed or diagnosis is significantly delayed. The presenting manifestations often involve the bones and/or joints and therefore these patients are frequently under specialist care by (paediatric) rheumatologists, receiving inadequate treatment. Since effective disease-specific treatments, including enzyme replacement therapy and stem cell transplantation, have become available for certain LSDs and timely initiation of these treatments is necessary to prevent the development of severe, disabling and irreversible manifestations, early diagnosis has become essential. The challenge is to raise awareness for better recognition of the presenting signs and symptoms of LSDs by all doctors who may encounter these patients, including rheumatologists. [ABSTRACT FROM PUBLISHER]

Objective: We undertook an observational study to obtain a complete overview of the long-term effectiveness and safety of etanercept in patients with different juvenile idiopathic arthritis (JIA) subtypes. Methods: At baseline we collected patient and disease characteristics of all Dutch patients with JIA who started treatment with etanercept. Disease activity was evaluated (at start of the study, after 3 months and then yearly) according to the JIA core set of the American College of Rheumatology paediatric definition for 30, 50 and 70% improvement (ACR Pedi 30, 50 and 70). Use of etanercept and concomitant drugs was monitored. Adverse events were recorded. Results: We included 146 patients with JIA with a median follow-up of 2.5 years per patient (range 0.3–7.3). JIA subtypes represented: 27% systemic, 8% polyarticular rheumatoid factor positive, 38% polyarticular rheumatoid factor negative, 19% oligoarticular extended, 3% enthesitis-related and 5% psoriatica. Most patients (77%) met the criteria of the ACR Pedi 30 in the first 3 months of treatment. For the majority of patients this improvement was sustained; 53 (36%) of all patients met the remission criteria. No other second-line agents were needed in 43 patients. Although patients with systemic JIA responded initially less to etanercept therapy than patients from other subtypes, those who did respond showed equal effectiveness in the long term. Serious adverse events rate was low (0.029 per patient year). Conclusions: Etanercept is effective and safe in JIA, even for a large proportion of the patients with systemic JIA. The greatest improvement occurred in the first 3 months of treatment, and was sustained for a long time in most patients (up to 75 months). [ABSTRACT FROM PUBLISHER]

OBJECTIVE: Fever of unknown origin is a diagnostic challenge in children, especially for differentiation of systemic-onset juvenile idiopathic arthritis (systemic-onset JIA) and infectious diseases. We undertook this study to analyze the relevance of myeloid-related proteins (MRPs) 8 and 14, endogenous activators of Toll-like receptor 4, in diagnosis and pathogenesis of systemic-onset JIA. METHODS: Serum concentrations of MRP-8/MRP-14 were analyzed in 60 patients with systemic-onset JIA, 85 patients with systemic infections, 40 patients with acute lymphoblastic leukemia, 5 patients with acute myeloblastic leukemia, 18 patients with neonatal-onset multisystem inflammatory disease (NOMID), and 50 healthy controls. In addition, we investigated the link between interleukin-1beta (IL-1beta) and MRP-8/MRP-14 in systemic-onset JIA. RESULTS: Serum MRP-8/MRP-14 concentrations were significantly (P < 0.001) elevated in patients with active systemic-onset JIA (mean +/- 95% confidence interval 14,920 +/- 4,030 ng/ml) compared with those in healthy controls (340 +/- 70 ng/ml), patients with systemic infections (2,640 +/- 720 ng/ml), patients with acute lymphoblastic leukemia (650 +/- 280 ng/ml), patients with acute myeloblastic leukemia (840 +/- 940 ng/ml), and patients with NOMID (2,830 +/- 580 ng/ml). In contrast to C-reactive protein levels, MRP-8/MRP-14 concentrations distinguished systemic-onset JIA from infections, with a specificity of 95%. MRP-14 in serum of patients with systemic-onset JIA was a strong inducer of IL-1beta expression in phagocytes. CONCLUSION: The analysis of MRP-8/MRP-14 in serum is an excellent tool for the diagnosis of systemic-onset JIA, allowing early differentiation between patients with systemic-onset JIA and those with other inflammatory diseases. MRP-8/MRP-14 and IL-1beta represent a novel positive feedback mechanism activating phagocytes via 2 major signaling pathways of innate immunity during the pathogenesis of systemic-onset JIA. [ABSTRACT FROM AUTHOR]

Children with juvenile idiopathic arthritis (JIA) often have significant physical impairment. A minority is unresponsive to combinations of medications, and a possible treatment of resistant JIA is intense immunosuppression followed by autologous hematopoietic SCT (ASCT). Children resistant to conventional therapy have a poor prognosis with regard to long-term outcome of joint function, exercise tolerance and quality of life. It has previously been shown that ASCT can induce long-term remissions in such children. The long-term effects of this treatment are still largely unknown. This retrospective study investigates the exercise tolerance and functional ability in children with JIA who have undergone ASCT compared to healthy subjects. Ten children with JIA who received ASCT between 1997 and 2003 participated in this study. Patients were tested during their regular clinical follow-up. Exercise tolerance was determined using a maximal exercise test. Functional ability was measured using the Childhood Health Assessment Questionnaire and joint status. The study group showed significantly reduced exercise tolerance compared to healthy subjects. Functional ability and joint status were also decreased in patients after ASCT. Children with JIA postASCT have impaired exercise tolerance even 9 years postASCT.Bone Marrow Transplantation (2008) 42, 351–356; doi:10.1038/bmt.2008.171; published online 30 June 2008 [ABSTRACT FROM AUTHOR]

Hurler's syndrome (HS), the most severe form of mucopolysaccharidosis type-I, causes progressive deterioration of the central nervous system and death in childhood. Allogeneic stem cell transplantation (SCT) before the age of 2 years halts disease progression. Graft failure limits the success of SCT. We analyzed data on HS patients transplanted in Europe to identify the risk factors for graft failure. We compared outcomes in 146 HS patients transplanted with various conditioning regimens and grafts. Patients were transplanted between 1994 and 2004 and registered to the European Blood and Marrow Transplantation database. Risk factor analysis was performed using logistic regression. ‘Survival’ and ‘alive and engrafted’-rate after first SCT was 85 and 56%, respectively. In multivariable analysis, T-cell depletion (odds ratio (OR) 0.18; 95% confidence interval (CI) 0.04–0.71; P=0.02) and reduced-intensity conditioning (OR 0.08; 95% CI 0.02–0.39; P=0.002) were the risk factors for graft failure. Busulfan targeting protected against graft failure (OR 5.76; 95% CI 1.20–27.54; P=0.028). No difference was noted between cell sources used (bone marrow, peripheral blood stem cells or cord blood (CB)); however, significantly more patients who received CB transplants had full-donor chimerism (OR 9.31; 95% CI 1.06–82.03; P=0.044). These outcomes may impact the safety/efficacy of SCT for ‘inborn-errors of metabolism’ at large. CB increased the likelihood of sustained engraftment associated with normal enzyme levels and could therefore be considered as a preferential cell source in SCT for ‘inborn errors of metabolism’.Bone Marrow Transplantation (2007) 40, 225–233; doi:10.1038/sj.bmt.1705718; published online 28 May 2007 [ABSTRACT FROM AUTHOR]

The article assesses the safety and efficacy of intensive immunosuppression followed by T cell-depleted autologous hematopoietic stem cell transplantation (ASCT) for induction of disease remission in children with refractory progressive juvenile idiopathic arthritis (JIA). The study found that intensive immunosuppression followed by ASCT resulted in sustained complete remission or marked improvement in 15 of 22 patients with progressive refractory JIA.

Hurler syndrome (MPS 1H) is the severe form of mucopolysaccharidosis type 1 (MPS 1). Haematopoietic cell transplantation (HCT) is the treatment of choice, but carries a high incidence of graft failure and morbidity. The use of enzyme replacement therapy (ERT) might improve the clinical signs and symptoms before HCT, resulting in less transplantation-related complications. Moreover, clearance of glycosaminoglycans (GAG's) from the bone marrow might improve engraftment. Twenty-two patients with MPS 1H received one or more HCT procedures in combination with ERT. One patient with severe cardiomyopathy improved significantly after ERT. All children were in a relatively good clinical condition before HCT. Of patients 59, 82 and 86% were alive and engrafted after one, two and three HCT procedures, respectively. Two patients died after repetitive HCT. No serious ERT-infusion-related toxicity occurred. ERT with HCT was well tolerated. Neither a positive nor a negative effect on the number of patients who are alive and engrafted after receiving ERT before HCT as compared to a historic cohort was noted. However, patients in a poor clinical condition before HCT might benefit from ERT.Bone Marrow Transplantation (2006) 38, 17–21. doi:10.1038/sj.bmt.1705401; published online 22 May 2006 [ABSTRACT FROM AUTHOR]

Summary:Experimental data and early phase I/II studies suggest that high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (HSCT) can arrest progression of severe autoimmune diseases. We have evaluated the toxicity and disease response in 473 patients with severe autoimmune disease treated with autologous HSCT between 1995 and 2003, from 110 centers participating in the European Group for Blood and Marrow Transplantation (EBMT) autoimmune disease working party database. Survival, transplant-related mortality, treatment response and disease progression were assessed. In all, 420 patients (89%; 86±4%at 3 years, median follow-up 20 months) were alive, 53 (11%) had died from transplant-related mortality (N=31; 7±3%at 3 years) or disease progression (N=22; 9±4%at 3 years). Of 370 patients, 299 evaluable for response (81%) showed a treatment response, which was sustained in 213 (71%of responders). Response was associated with disease (P<0.001), was better in patients who received cyclophosphamide during mobilization (relative risk (RR)3.28 (1.57-6.83)) and was worse with increasing age (>40 years, RR0.29 (0.11-0.82)). Disease progression was associated with disease (P<0.001) and conditioning intensity (high intensity, RR1; intermediate intensity, RR1.81 (0.96-3.42)); low intensity, RR2.34 (1.074-5.11)). These data from the collective EBMT experience support the hypothesis that autologous HSCT can alter disease progression in severe autoimmune disease.Bone Marrow Transplantation (2005) 35, 869-879. doi:10.1038/sj.bmt.1704892 Published online 14 March 2005 [ABSTRACT FROM AUTHOR]