Development Of Macrophage Activation Syndrome Research Articles

Leucine-rich α2-glycoprotein as the acute-phase reactant to detect systemic juvenile idiopathic arthritis disease activity during anti-interleukin-6 blockade therapy: A case series

Objectives: To assess the role of leucine-rich α2-glycoprotein (LRG) as a biomarker for monitoring systemic juvenile idiopathic arthritis (s-JIA) disease activity during interleukin (IL)-6 blockade treatment.Methods: We serially measured serum LRG levels in four s-JIA patients treated with the anti-IL-6 receptor antibody tocilizumab and determined the correlation between clinical symptoms and other inflammatory biomarkers and proinflammatory cytokines, including IL-18, IL-6, neopterin, and tumor necrosis factor-α receptor type I and II. The serum levels of LRG and proinflammatory cytokines were determined using enzyme-linked immunosorbent assay.Results: Serum LRG levels increased concomitantly with s-JIA disease flare-up and macrophage activation syndrome development. Furthermore, even in the clinically inactive phase, serum LRG levels were well above normal values. There were no correlations between serum LRG levels and indicators of s-JIA disease activity other than aspartate aminotransferase. There were significant positive correlations between serum LRG levels and proinflammatory cytokines.Conclusions: Serum LRG levels might be a unique and potential biomarker of s-JIA disease activity during IL-6 blockade treatment.

Primary varicella infection in children with systemic juvenile idiopathic arthritis under tocilizumab therapy

We report the clinical course and outcome of primary varicella infection in six children with systemic juvenile idiopathic arthritis (sJIA) receiving tocilizumab. None had disseminated or fatal varicella infection, but one patient developed macrophage activation syndrome (MAS) and another had an arthritis relapse. All patients had a significant elevation of serum IL-6 levels, and the two children who developed MAS or arthritis relapse showed high serum IL-18 levels, which could cause a sJIA flare-up.

Macrophage activation syndrome associated with hepatitis a virus in a child with systemic onset juvenile idiopathic arthritis: A case report

Macrophage Activation Syndrome (MAS) is a rare but a grave complication of systemic onset juvenile idiopathic arthritis (SOJIA). It occurs as a result of immune dysfunction of macrophages and T lymphocyte. A twelve-year old boy diagnosed case of SOJIA presented with high grade fever, diffuse abdominal pain, vomiting and jaundice. He had high ALT, abnormal coagulation profile and Anti HA V IgM was positive. He had also high ferritin and triglyceride level which were very much suggestive for MAS. Infection especially Epstein Barr Virus, Herpes viruses and drugs are the common triggers for the development of MAS in association with SOJIA patients. MAS associated with hepatitis A virus are very rare. Only a few case reports are available in the literature. Considering its rarity and grave prognosis we are reporting a case of hepatitis A associated Macrophages Activation Syndrome in a systemic onset juvenile idiopathic arthritis.

Inhibition of natural killer cell cytotoxicity by interleukin-6: implications for the pathogenesis of macrophage activation syndrome.

Systemic juvenile idiopathic arthritis (JIA) is associated with high levels of interleukin-6 (IL-6) in the serum and synovial fluid, and impairment of natural killer (NK) cell function is often observed. This study was undertaken to evaluate a possible link between these 2 biologic findings and whether they may be associated with the development of macrophage activation syndrome, a condition frequently observed in systemic JIA. Splenocytes from wild-type (WT) or IL-6-transgenic (Tg) mice were evaluated for NK cell cytotoxicity using a (51) Cr-release assay. Numbers of NK cells and expression of perforin, granzyme B, CD69, and CD107a were evaluated by flow cytometry. Human peripheral blood mononuclear cells (PBMCs) isolated from healthy donors were treated with IL-6 and cultured in the presence or absence of tocilizumab (TCZ), an IL-6 receptor blocker. Human polyclonal NK cells from healthy donor PBMCs were evaluated for cell cytotoxicity and expression of perforin, granzyme B, and CD107a. PBMCs harvested from patients with systemic JIA during periods of active or inactive disease were left untreated or treated with IL-6 in combination with soluble IL-6 receptor and analyzed for the expression of perforin and granzyme B. Splenic NK cell cytotoxicity was reduced in IL-6-Tg mice compared to WT mice. Levels of CD69 and CD107a showed no significant differences, whereas expression of perforin and granzyme B was impaired in NK cells from IL-6-Tg mice. Exposure of human peripheral blood NK cells to IL-6 led to reduced expression of perforin and granzyme B. Culturing human polyclonal NK cells in the presence of TCZ significantly increased cell cytotoxicity, and also increased expression of perforin and granzyme B. In patients with systemic JIA, a reduction in IL-6 plasma levels during disease remission correlated with the rescue of perforin and granzyme B expression in NK cells from these patients. In both mice and humans, IL-6 down-modulated the cytotoxic activity of NK cells. This decrease was associated with reduced perforin and granzyme B levels in the absence of altered granule exocytosis.

A CASE REPORT OF THE USE TOCILIZUMAB IN REFRACTORY SYSTEMIC JUVENILE ARTHRITIS WITH PULMONARY INVOLVEMENT AND MACROPHAGE ACTIVATION SYNDROME

The paper describes a patient with refractory systemic juvenile arthritis treated with tocilizumab (TCZ). Specific features of therapeutic response in real clinical practice, aspects of individual TCZ safety in the development of macrophage activation syndrome and concurrent therapy are discussed.

Interleukin-18 for predicting the development of macrophage activation syndrome in systemic juvenile idiopathic arthritis

To assess the role of IL-6/IL-18 in the pathogenesis of systemic juvenile idiopathic arthritis (s-JIA) and to investigate the clinical significance of serum IL-18 levels for predicting macrophage activation syndrome (MAS) development, we measured the serum IL-6/IL-18 levels in 76s-JIA patients, including 15 with MAS, and compared them with the clinical features. We identified 2 distinct subsets on the basis of serum IL-6/IL-18 levels. The IL-18-dominant subset had more patients who developed MAS. Serum IL-18 levels during active phase in patients with MAS were significantly higher than those without MAS. The cutoff value of serum IL-18 levels for predicting MAS development was 47750pg/ml. The patients with IL-18 dominant subset at their disease onset were significantly more likely to develop MAS after TCZ therapy started. IL-18 might have a key role in the pathogenesis of MAS. Serum IL-18 levels >47750pg/ml might be useful to predict MAS development.

Cytokines in systemic juvenile idiopathic arthritis and haemophagocytic lymphohistiocytosis: tipping the balance between interleukin-18 and interferon-γ.

To study the role of IFN-γ in the pathogenesis of systemic JIA (sJIA) and haemophagocytic lymphohistiocytosis (HLH) by searching for an IFN-γ profile, and to assess its relationship with other cytokines. Patients with inactive (n = 10) and active sJIA (n = 10), HLH [n = 5; of which 3 had sJIA-associated macrophage activation syndrome (MAS)] and healthy controls (n = 16) were enrolled in the study. Cytokines and IFN-γ-induced genes and proteins were determined in plasma, in patient peripheral blood mononuclear cells (PBMCs) and in lymph node biopsies of one patient during both sJIA and MAS episodes. IFN-γ responses were investigated in healthy donor PBMCs, primary fibroblasts and endothelial cells. Plasma IFN-γ, IL-6 and IL-18 were elevated in active sJIA and HLH. Levels of IFN-γ and IFN-γ-induced proteins (IP-10/CXCL-10, IL-18BP and indoleamine 2,3-dioxygenase) in HLH were much higher than levels in active sJIA. Free IL-18 and ratios of IL-18/IFN-γ were higher in active sJIA compared with HLH. HLH PBMCs showed hyporesponsiveness to IFN-γ in vitro when compared with control and sJIA PBMCs. Endothelial cells and fibroblasts expressed IFN-γ-induced proteins in situ in lymph node staining of a MAS patient and in vitro upon stimulation with IFN-γ. Patients with active sJIA and HLH/MAS show distinct cytokine profiles, with highly elevated plasma levels of IFN-γ and IFN-γ-induced proteins typically found in HLH/MAS. In addition to PBMCs, histiocytes, endothelial cells and fibroblasts may contribute to an IFN-γ profile in plasma. Increasing levels of IFN-γ compared with IL-18 may raise suspicion about the development of MAS in sJIA.

Identification of the best cutoff points and clinical signs specific for early recognition of macrophage activation syndrome in active systemic juvenile idiopathic arthritis

ObjectivesThe purpose of our study was to detect early clinical and laboratory signs that help to discriminate macrophage activation syndrome (MAS) from active systemic juvenile idiopathic arthritis (SJIA) without MAS. MethodsOur retrospective study was based on reviewing the medical charts of the children admitted to the rheumatology department with active SJIA and definite MAS (n = 18) and without MAS (n = 40). We evaluated the data related to SJIA and MAS at the moment of the patient׳s admission. If the patient had signs of MAS since admission or developed definite MAS later during this flare, he was referred to the main group. The children who did not have MAS during the flare episode and did not have MAS in the past medical history were in the control group. We calculated the cutoff points for MAS parameters, performed the analysis of sensitivity and specificity, identified the predictors, and provided the preliminary diagnostic rule through “the-number-of-criteria-present” approach. ResultsThe clinical signs were relevant to MAS in SJIA: oligoarticular disease course (OR = 5.6), splenomegaly (OR = 67.6), hemorrhages (OR = 33.0), and respiratory failure (OR = 11.3). The involvement of wrist (OR = 0.2), MCP (OR = 0.1), and PIP joints (OR = 0.1) was protective against MAS development. The best cutoffs for laboratory parameters were PLT ≤ 211 × 109/l, WBC ≤ 9.9 × 109/l, AST > 59.7U/l, LDH > 882U/l, albumin ≤ 2.9g/dl, ferritin > 400μg/l, fibrinogen ≤ 1.8g/l, and proteinuria. The laboratory variables were more precise in the discrimination of early MAS than clinical: any 3 or more laboratory criteria provided the highest specificity (1.0) and sensitivity (1.0) and OR = 2997. ConclusionsWe detected clinical and laboratory markers and created preliminary diagnostic (laboratory) guidelines for early discrimination of MAS in active SJIA.

Treatment of MAS and HLH

Macrophage activation syndrome (MAS) is a life-threatening complication of inflammatory disease, occurring secondary to a complex interplay of genetic factors, drugs, infectious agents and immunological anomalies. Early identification and aggressive treatment are mandatory to prevent fatal evolution. Precipitating factors should be looked for and eventually removed such as infections (leishmania, EBV, Parvo B19…) or drug exposure. Epstein Barr Virus (EBV) is a major cause of MAS and anti-EBV therapies can be helpful to control MAS. First line therapies usually include high-dose steroids associated to cyclosporine. In the context of primary hemophagocytic lymphohistiocytosis (HLH), bone marrow transplantation is the only treatment able to cure the disease. In inflammatory disease with secondary HLH, a few case reports indicate an efficacy of anti-cytokine treatment (anti-IL1, anti-IL6, anti-TNFα). However, a role of these cytokines in MAS development remains unproven. To investigate whether the IL-1 pathway might contribute to MAS, we compared IL-1RA-/- to wild type mice after stimulation with CpG, a TLR9 activator. TLR9-induced MAS was similar in the two groups, suggesting that IL-1 excess is not a major inducer of MAS. More interestingly, recent data implicate IFNγ as a crucial factor in MAS onset. Thus, the inhibition of secreted IFNγ might represent an interesting therapeutic avenue worthy of further investigation.

Biologic agents therapy for Saudi children with rheumatic diseases: indications and safety.

To report the indications and safety of biologic agents in childhood rheumatic diseases at a tertiary hospital. Children with rheumatic diseases treated with biologic agents at King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia, from January 2001 to December 2011 were included. All patients were reviewed for: demographic characteristics, diagnosis, concomitant treatment and indications of using biologic agents, age at start of therapy and side effects during the treatment period. In all, 134 children (89 female) with various rheumatic diseases were treated with biologic agents. Mean age at starting biologic treatment was 9.3 (4.25-14) years and mean therapy duration was 14.7 (3-88) months. Juvenile idiopathic arthritis (JIA) was the most frequent diagnosis (70.1%) followed by systemic lupus erythematosus (12.7%) and vasculitis (4.5%). All patients received concomitant therapy (corticosteroids and disease-modifying antirheumatic drugs). In total, 273 treatments with biologic agents were used, (95 etanercept, 52 rituximab, 47 adalimumab, 37 infliximab, 23 anakinra, 10 tocilizumab and nine abatacept). Therapy was switched to another agent in 57 (42.5%) patients, mainly because of inefficacy (89.4%) or adverse event (10.6%). A total of 95 (34.8%) adverse events were notified; of these, the most frequent were infusion-related reactions (33.7%) followed by infections (24.2%) and autoantibody positivity (10.6%). One patient developed macrophage activation syndrome. Biologic agents were used in children with a range of rheumatic diseases. Of these, the most frequent was JIA. Off-label use of biologic agents in our cohort is common. These agents seem safe. However, they may associated with various adverse events. Sequential therapy seems well tolerated. However, this should be carefully balanced and considered on an individual basis.

Macrophage activation syndrome and cytokine-directed therapies.

Macrophage activation syndrome (MAS) is an episode of overwhelming inflammation that occurs most commonly in children with systemic juvenile idiopathic arthritis (SJIA). It is characterized by expansion and activation of T lymphocytes and hemophagocytic macrophages and bears great similarity to hemophagocytic lymphohistiocytosis (HLH). This disorder has substantial morbidity and mortality, and there is frequently a delay in recognition and initiation of treatment. Here, we will review what is known about the pathogenesis of MAS and, in particular, its similarities to HLH. The development of MAS is characterized by a cytokine storm, with the elaboration of numerous pro-inflammatory cytokines. We will examine the evidence for various cytokines in the initiation and pathogenesis of MAS and discuss how new biologic therapies may alter the risk of MAS. Finally, we will review current treatment options for MAS and examine how cytokine-directed therapy could serve as novel treatment modalities.

Very low density lipoprotein, chylomicron, and lipoprotein (a) are more useful to detect the development of macrophage activation syndrome in adult‐onset still's disease as compared with cytokines and triglyceride

Very low density lipoprotein, chylomicron, and lipoprotein (a) are more useful to detect the development of macrophage activation syndrome in adult‐onset still's disease as compared with cytokines and triglyceride

Differentiating Macrophage Activation Syndrome in Systemic Juvenile Idiopathic Arthritis from Other Forms of Hemophagocytic Lymphohistiocytosis

To identify measures distinguishing macrophage activation syndrome (MAS) in systemic juvenile idiopathic arthritis (sJIA) from familial hemophagocytic lymphohistiocytosis (FHL) and virus-associated hemophagocytic lymphohistiocytosis (VA-HLH) and to define appropriate cutoff values. To evaluate suggested dynamic measures differentiating MAS in patients with sJIA from sJIA flares. In a cohort of patients referred for evaluation of hemophagocytic lymphohistiocytosis, we identified 27 patients with sJIA and MAS (MAS/sJIA) fulfilling the criteria of the proposed preliminary diagnostic guideline for the diagnosis of MAS in sJIA. Ten measures at diagnosis were compared between the MAS/sJIA group and 90 patients with FHL and 42 patients with VA-HLH, and cutoff values were determined. In addition, 5 measures were analyzed for significant change from before MAS until MAS diagnosis. Neutrophil count and C-reactive protein were significantly higher in patients with MAS/sJIA compared with patients with FHL and patients with VA-HLH, with 1.8×10(9)/L neutrophils (sensitivity 85%, specificity 83%) and 90 mg/L C-reactive protein (74%, 89%) as cutoff values. Soluble CD25<7900 U/L (79%, 76%) indicated MAS/sJIA rather than FHL/VA-HLH. Platelet (-59%) and white blood cell count (-46%) displayed a significant decrease, and neutrophil count (-35%) and fibrinogen (-28%) showed a trend during the development of MAS. However, a substantial portion of patients had values at diagnosis of MAS within or above the normal range for white blood cells (84%), neutrophils (77%), platelets (26%), and fibrinogen (71%). Readily available measures can rapidly differentiate between MAS/sJIA and FHL/VA-HLH. The findings substantiate that a decline of measures may facilitate the distinction of MAS from flares of sJIA.

Adult onset Still's disease: experience from a tertiary care rheumatology unit

Adult-onset Still's disease (AOSD) is a rare chronic inflammatory disorder presenting with prolonged fever and polyarthritis. Retrospective study of patients with AOSD, seen between 1992 and 2009 at a large tertiary care hospital. Twenty-nine patients (18 female) with median age at onset of 28 (17-58) years were seen. The clinical features included fever in 29, inflammatory polyarthritis in 26, sore throat in eight and typical rash in 13. Lymphadenopathy was present in 15, hepatomegaly in 15, splenomegaly in 13 and serositis in five patients. Anemia was present in 22, neutrophilic leukocytosis in 28 and thrombocytosis in 13 patients. Acute phase reactants were elevated in all. Fifteen patients had transaminitis. Low titer antinuclear antibodies were present in 6/28 patients. On median follow-up (25 patients) of 23.7 months (range: 3-84) one patient had self-limited or monocyclic pattern, eight had polycyclic and 16 had chronic articular pattern. All patients received non-steroidal anti-inflammatory drugs and 25 received methotrexate and/or prednisolone. During the course 14 patients had remission and of these six were in remission on drugs at last follow-up. One patient received tociliziumab and was in clinical remission. One patient developed macrophage activation syndrome and one had atlanto-axial dislocation. Three patients developed tuberculosis and two died of infection associated with immunosuppression. AOSD is an uncommon disorder with 1-2 patients seen at a large tertiary care rheumatology unit. Overall AOSD has a fair outcome with significant morbidity and most needing long-term therapy with steroids and methotrexate.

Patients with early-onset systemic juvenile idiopathic arthritis show more inflammation and worse outcome

Methods Retrospective analysis of clinical data. Early-onset (EO) was defined as the start of SJIA prior to age 18 months. Variables included: demographic and clinical features at onset and outcome variables during disease course (pattern of course, presence of clinical joint damage [using the Juvenile Arthritis Damage Index or JADI], radiographic joint damage [erosions], destructive hip disease, disability [CHAQ > 0.5], growth retardation, development of macrophage activation syndrome [MAS], need for biologic agents, and death). Patients with EO were compared with patients with disease onset at age ≥ 18 months. Chi square and Mann-Whitney tests were used for comparisons.

Macrophage Activation Syndrome

We recently treated a patient with adult-onset Still's disease who developed macrophage activation syndrome (MAS) secondary to disseminated histoplasmosis while being treated with adalimumab. The gastroenterology service was consulted early, before diagnosis, as the patient presented with elevated liver enzymes and disseminated intravascular coagulation. MAS is an exaggerated immune response that can develop as a primary condition or secondary to infections, drugs and various diseases, resulting in liver dysfunction, encephalopathy, pancytopenia and disseminated intravascular coagulation. The development of MAS has also been reported in patients with inflammatory bowel disease and post-liver transplantation and has been triggered by medications used by gastroenterologists, particularly sulfasalazine and anti-tumor necrosis factor biologic modifiers. Therefore, we present a review on etiology, pathogenesis, clinical and laboratory features, and treatment of MAS with a focus on gastrointestinal aspects and presentations. MAS is a life threatening condition with a high mortality rate if untreated. Therefore it is important to recognize this condition early. As these patients may occasionally present to gastroenterologists we hope this review will increase awareness of this rare, but serious syndrome.

RE: Reactive macrophage activation syndrome (MAS) in a patient with parvovirus B19 infection, lymphocytic lichenoid vasculitis, urticaria and angioedema

lettersRE: Reactive macrophage activation syndrome (MAS) in a patient with parvovirus B19 infection, lymphocytic lichenoid vasculitis, urticaria and angioedema Luis Gonzalez-Granado Luis Gonzalez-Granado Search for more papers by this author Published Online:3 Jun 2010https://doi.org/10.4103/0256-4947.62827SectionsPDF ToolsAdd to favoritesDownload citationTrack citations ShareShare onFacebookTwitterLinked InRedditEmail AboutIntroductionTo the Editor: I read with keen interest the article published by Soldo-Juresa et al in the last issue of the journal.1 I would like to make some comments: First, Still disease should be kept in mind whenever macrophage activation syndrome is considered in a patient with the clinical picture shown. In fact the patient's condition fulfills the criteria published by Yamagushi for Still disease.2 I would like to remark that the measurement of soluble IL-2R (also known as CD25s) could be helpful in distinguishing between Still disease and MAS.3 Furthermore, the development of MAS in Still disease is not infrequent and intravenous gamma globulins have shown promising results in treatment.4,5 Second, as the authors rule out a C1q-linked vasculitis, C4 and alternative complement pathway activity should be measured. It is well known that in esterase inhibitor type II levels of C1-inhibitor esterase are normal although C4 is decreased due to low functional C1-inhibitor levels.6 Hypocomplementemic vasculitis has been also described in patients with factor I deficiency.7 I have attended recently a patient with vasculitis secondary to factor I deficiency. This factor was not measured by the author in this patient. Third, the authors recognize that DNA of parvovirus B-19 can persist in bone marrow for years. This is why we should distinguish between MAS secondary to viral infection or underlying Still disease that needs long-term treatment and follow-up.ARTICLE REFERENCES:1. Soldo-Juresa D, Radman M, Pejsa V, Bozikov V. "Reactive macrophage activation syndrome in a patient with parvovirus B19 infection, lymphocytic lichenoid vasculitis, urticaria and angioedema" . Ann Saudi Med. 2010; 30:88-9. Google Scholar2. Yamaguchi M, Ohta A, Tsunematsu T, Kasukawa R, Mizushima Y, Kashiwagi H, Kashiwazaki S, Tanimoto K, Matsumoto Y, Ota T. "Preliminary criteria for classification of adult Stills disease" . J Rheumatol. 1992; 19:424-430. Google Scholar3. Bleesing J, Prada A, Siegel DM, Villanueva J, Olson J, Ilowite NT, Brunner HI, Griffin T, Graham TB, Sherry DD, Passo MH, Ramanan AV, Filipovich A, Grom AA. "The diagnostic significance of soluble CD163 and soluble interleukine-2 receptor a -chain in macrophage activation syndrome and untreated new-onset systemic juvenile idiopathic arthritis" . Arthritis Rheum. 2007; 56:965-71. Google Scholar4. García-Consuegra Molina J, Merino Muñoz R, de Inocencio Arocena J. "Grupo de Estudio del Síndrome de Activación Macrofágica y Artritis Idiopática Juvenil de la Sociedad Española de Reumatología Pediátrica. Macrophage activation syndrome and juvenile idiopathic arthritis. A multicenter study" . An Pediatr (Barc). 2008; 68:110-6. Google Scholar5. Vignes S, Wechsler B, Amoura Z, Papo T, Francès C, Huong DL, Veyssier P, Godeau P, Piette JC. "Intravenous immunoglobulin in adult Still's disease refractory to non-steroidal anti-inflammatory drugs" . Clin Exp Rheumatol. 1998; 16:295-8. Google Scholar6. Zuraw BL, Christiansen SC. "Pathogenesis and laboratory diagnosis of hereditary angioedema" . Allergy Asthma Proc. 2009; 30:487-92. Google Scholar7. Sadallah S, Gudat F, Laissue JA, Spath PJ, Schifferli JA. "Glomerulonephritis in a patient with complement factor I deficiency" . Am J Kidney Dis. 199906 33(6):1153-7. Google Scholar Previous article Next article FiguresReferencesRelatedDetails Volume 30, Issue 3May–Jun 2010 Metrics History Published online3 June 2010 InformationCopyright © 2010, Annals of Saudi MedicineThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.PDF download

Mutations in the perforin gene can be linked to macrophage activation syndrome in patients with systemic onset juvenile idiopathic arthritis

Macrophage activation syndrome (MAS) in systemic onset juvenile idiopathic arthritis (SoJIA) is considered to be an acquired form of familial haemophagocytic lymphohistiocytosis (fHLH). FHLH is an autosomal recessive disorder, characterized by diminished NK cell function and caused by mutations in the perforin gene (PRF1) in 20-50% of patients. Interestingly, SoJIA patients display decreased levels of perforin in NK cells and diminished NK cell function as well. Here, we analysed PRF1 and its putative promoter in SoJIA patients with or without a history of MAS. DNA of 56 SoJIA patients (41 Italian and 15 Dutch) was isolated. Of these, 15 (27%) had a confirmed history of MAS. We sequenced PRF1 and 1.5 kb of the 5'-upstream region. DNA sequence variations in the promoter region were functionally tested in transfection experiments using a human NK cell line. We detected a previously undescribed sequence variation (-499 C > T) in the promoter of PRF1 in 18% of the SoJIA patients. However, transfection experiments did not show functional implications of this variation. Secondly, we found that 11 of 56 (20%) SoJIA patients were heterozygous for missense mutations in PRF1. In particular, we found a high prevalence of the Ala91Val mutation, a variant known to result in defective function of perforin. Interestingly, the prevalence of Ala91Val in SoJIA patients with a history of MAS (20%) was increased compared with SoJIA patients without MAS (9.8%). One SoJIA patient, heterozygous for Ala91Val, showed profound decreased perforin levels at the time of MAS. These findings suggest that PRF1 mutations play a role in the development of MAS in SoJIA patients.

Anakinra for Systemic Juvenile Arthritis

Poor outcomes in systemic juvenile arthritis have been associated with persistent thrombocytosis, increased sedimentation rates, anemia, polyarthritis, and prolonged steroid use. Off-label treatment with recombinant interleukin-1 receptor antagonist therapy (anakinra) has become more common since reports of its association with reduced systemic symptoms and arthritis scores, improved laboratory parameters of inflammation, and decreased corticosteroid requirements. To examine the efficacy and safety of anakinra in a regional cohort of systemic juvenile arthritis patients. We performed a retrospective case series of systemic juvenile arthritis patients (n = 33) treated with anakinra at 3 Pediatric Rheumatology centers. The effect of anakinra on corticosteroid dose, sedimentation rate, platelet count, albumin, hemoglobin, arthritis joint counts, and height Z score was determined using the paired t test. We evaluated differences in change in these variables between patient groups within the sample determined by: age of onset, anakinra dose, and duration from diagnosis until anakinra treatment. Treatment was associated with decreases in corticosteroid dosage and sedimentation rate and increases in hemoglobin and albumin (P < 0.02). There were decreases in large joint arthritis counts (P < 0.04) but not small joint counts after 3 to 4 months. There were greater decreases in sedimentation rates from pre to post (1-2 months) in patients on high versus low dose anakinra (P < 0.001). Fever and rash, present in 7 cases before treatment, was resolved. Eight patients had periods of arthritis, 1 developed macrophage activation syndrome, and another Epstein Barr virus. Over half of patients reported localized pain or swelling at their injection site. Treatment with anakinra was associated with short-term improvements in large joint counts and laboratory parameters of active disease. Higher anakinra doses may be more efficacious in treating the systemic inflammatory response in systemic onset juvenile idiopathic arthritis patients. A subset of patients had periods of arthritis during treatment, and local side-effects were frequent. Our experience supports the continued use of interleukin-1 inhibition in systemic juvenile arthritis and the search for more effective and more tolerable forms of interleukin-1 inhibition.

Gene expression profiling of peripheral blood from patients with untreated new‐onset systemic juvenile idiopathic arthritis reveals molecular heterogeneity that may predict macrophage activation syndrome

Systemic juvenile idiopathic arthritis (JIA) is frequently associated with the development of macrophage activation syndrome. This study was undertaken to better understand the relationship between systemic JIA and macrophage activation syndrome. Gene expression profiles were examined in 17 patients with untreated new-onset systemic JIA, 5 of whom showed evidence of subclinical macrophage activation syndrome (of whom 2 eventually developed overt macrophage activation syndrome). Peripheral blood mononuclear cells (PBMCs) were separated on Ficoll gradients, and purified RNA was analyzed using Affymetrix GeneChip expression arrays. A fraction of the PBMCs were used for flow cytometry to define the cellular composition of the samples. Two hundred twenty-five differentially expressed genes (P < 0.05) that distinguished patients with systemic JIA from healthy controls (n = 30) were identified. Clustering analysis indicated that expression patterns correlated with serum ferritin levels. Three main clusters distinguished systemic JIA patients with highly elevated ferritin levels (including those with subclinical macrophage activation syndrome) from those with normal or only moderately elevated ferritin levels. The first cluster comprised genes involved in the synthesis of hemoglobins and structural proteins of erythrocytes. This transcriptional profile was consistent with immature nucleated red blood cells, likely reflective of high red blood cell turnover. Also included were transcripts indicating immature granulocytes. The second cluster was enriched for genes involved in cell cycle regulation. The third cluster was enriched for genes involved in innate immune responses, including those involved in the negative regulation of Toll-like receptor/interleukin-1 receptor-triggered inflammatory cascades and markers of the alternative pathway of macrophage differentiation. Additional differentially expressed genes of interest were those involved in the cytolytic pathway, including SH2D1A and Rab27a. These data indicate that gene expression profiling can be a useful tool for identifying early macrophage activation syndrome in patients with systemic JIA.