Evaluation of clinical outcomes in systemic juvenile idiopathic arthritis patients treated with biological agents in Turkey: the TURSIS study.

OBJECTIVES: Biological drugs are one of the most effective treatment methods for systemic juvenile idiopathic arthritis (SJIA) and can significantly prevent morbidity and mortality. This study aimed to evaluate the efficacy and safety of biologics in patients with SJIA and provide real-life data that might help improve the outcomes. METHODS: TURSIS was a retrospective multicentre study carried out in patients with SJIA for whom a biological treatment had been initiated between 1st March 2013 and 30th December 2018. Data include patients' characteristics, laboratory-clinical results, outcomes, and safety-related variables. The 24-month follow-up data of the patients and the efficacy and safety of biological drugs were evaluated. RESULTS: 147 patients were enrolled. The clinical course of the disease was as follows; it was monocyclic in 38.1%, polycyclic in 49%, and persistent in 12.9% of patients. First-choice biologics were interleukin (IL)-1 blockers in the majority of patients (56.5%), followed by the anti-IL-6 (25.2%) and anti-TNF-alpha drugs (18.4%). Anakinra was the most preferred biologic agent in patients with macrophage activation syndrome (MAS), and tocilizumab was used more frequently in patients with persistent type (p=0.000 and p=0.003). The most frequent switch rate was seen in patients receiving anakinra (n=40/68, 58.8%), and it was most frequently switched to canakinumab (n=32/40, 80%). Better physician's global assessment scores were achieved in patients treated with anakinra in Month 3, compared to other treatments (p=0.04). CONCLUSIONS: The results of our study support the efficacy of biological drugs in particular anti-IL-1 and anti-IL-6 drugs, in the treatment of SJIA. These treatments resulted in improvement in activity of disease and provide a considerable decrease in the frequency of MAS.

Anakinra and hepatotoxicity in pediatric rheumatology: a case series.

BACKGROUND: Anakinra is a recombinant interleukin-1 (IL-1) receptor antagonist used in systemic juvenile idiopathic arthritis (sJIA), refractory Kawasaki disease (KD) and cryopyrin-associated autoinflammatory syndrome (CAPS). Anakinra associated hepatotoxicity, while rare, has been described in several cases in daily practice. ​In this case series the authors describe three pediatric patients with this side effect in the setting of severe macrophage activation syndrome (MAS) in KD and sJIA. CASE PRESENTATION: The first patient was a 12-year-old boy who presented with fever, maculo-papular exanthema and polyarthralgia. Tonsillitis, distal limb induration and tender cervical lymph nodes were observed. Erythrocyte-sedimentation rate (ESR), C-reactive protein (CRP), ferritin (11,975 ng/mL), D-dimers (5,98 mg/L FEU) and soluble CD25 (3645 pg/mL) levels were elevated. Exclusion of sepsis / toxic shock syndrome warranted introduction of IV methylprednisolone and immunoglobulin (IG IV), with partial response. A MAS secondary to KD was assumed, and anakinra 2 mg/kg/day was introduced. Twenty days later he developed new-onset nausea and severe cyto-cholestasis, normalizing after 2 months of drug discontinuation. Posterior onset of polyarthritis and evanescent lead to a final diagnosis of sJIA. The second patient was a 2-year-old boy with a 10-day history of fevers, generalized rash, hepatosplenomegaly and strawberry tongue. Leucocytosis with neutrophilia and elevated CRP were observed. Initial treatment with IVIG in the setting of incomplete KD was ineffective. Mild anaemia, leukopenia and very high serum ferritin (maximum 26,128 ng/mL) ensued. Presumptive sJIA associated MAS was treated with IV methylprednisolone and anakinra 2 mg/kg/day, with prompt response. Four weeks later transaminitis was detected, and temporary anakinra suspension led to normalisation of laboratorial values. The third case related to a 4-year-old boy presenting with fever, maculopapular rash and cervical lymphadenopathy. CRP and ESR were elevated, and KD was diagnosed. IVIG and methylprednisolone were initiated with clinical worsening, warranting for anakinra introduction at 2 mg/kg/day. After three weeks, liver enzymes progressively elevated, resolving on 2 weeks of anakinra discontinuation. CONCLUSIONS: To the best of our knowledge, this is the first case series describing anakinra associated hepatotoxicity in pediatric patients with rheumatic diseases other than sJIA, bringing additional insight to therapeutic monitoring in patients undergoing this treatment.

Macrophage activation syndrome triggered by methotrexate-related lymphoproliferative disease in a patient with rheumatoid arthritis.

A 56-year-old woman was treated for rheumatoid arthritis for 17 years with methotrexate (MTX). Night sweats, fever and weight loss made her visit our hospital. Although levofloxacin failed to resolve her fever, she was suspected of having sepsis because of pancytopenia, elevated procalcitonin and a nodular lesion in the lung. After urgent hospitalization, she was diagnosed finally with the methotrexate-related lymphoproliferative disorder (MTX-LPD) associated with macrophage activation syndrome (MAS). Her general condition was improved with MTX withdrawal and 5-day high-dose glucocorticoid administration. Thus, even when the patient was critically ill with MAS, no cytotoxic agents were required to control MTX-LPD.

6-Mercaptopurine and Macrophage Activation Syndrome Case Report and Review of the Literature.

Macrophage activation syndrome is a life-threatening syndrome of uncontrolled immune activation with variable clinical presentation making early diagnosis difficult. It is often manifested by the development of multi-organ failure due to systemic inflammatory response. Patients with ulcerative colitis (UC) on purine antimetabolites are at high risk for severe myelosuppression due to the mechanism of thiopurine toxicity which potentially contributes to the development of macrophage activation syndrome. We present a case of a 39-year-old woman with a 2-year history of UC previously treated with 6-mercaptopurine (6-MP) and recent COVID-19 infection, who was admitted to our emergency department for C. difficile infection and subsequently developed macrophage activation syndrome. This case report also raises the question of whether abrupt discontinuation of 6-MP may have contributed to the worsening of the patient's symptoms of underlying hemophagocytic lymphohistiocytosis (HLH) and her rapid deterioration. Both macrophage activation syndrome and COVID-19 infection can produce a large number of pro-inflammatory cytokines termed "cytokine storm," but a pro-inflammatory cytokine panel breakdown helps to differentiate between the two. Our case report emphasizes the importance of close monitoring of patients on purine antimetabolite therapy who present with signs and symptoms of systemic toxicity.

Severe Immediate and Delayed Hypersensitivity Reactions to Biologics in a Toddler With Systemic Juvenile Idiopathic Arthritis.

Many pediatric rheumatic diseases can be safely managed with biologic therapy. Severe allergic reactions to these medications are uncommon. We report the case of a 2-year-old male with systemic-onset juvenile idiopathic arthritis and secondary macrophage activation syndrome (MAS), whose treatment was complicated by severe allergic reactions to biologics, including drug reaction with eosinophilia and systemic symptoms (DRESS)/drug-induced hypersensitivity reaction (DIHR) likely due to anakinra, and anaphylactoid reaction to intravenous tocilizumab. These required transition to canakinumab, cyclosporine, and corticosteroids, with later development of interstitial lung disease and MAS flare needing transition from canakinumab to tofacitinib, which led to disease control. Whether lung disease is a manifestation of DRESS/DIHR to canakinumab remains unclear. High index of suspicion of hypersensitivity reactions for timely diagnosis and drug discontinuation is critical, especially in patients with active disease who might be at increased risk of these adverse events.

Reintroduction of tocilizumab elicited macrophage activation syndrome in a patient with adult-onset Still's disease with a previous successful tocilizumab treatment.

Macrophage activation syndrome (MAS) is a form of secondary hemophagocytic lymphohistiocytosis and is a rapidly progressive, life-threatening complication of adult-onset Still's disease (AOSD). An anti-IL-6 receptor monoclonal antibody, tocilizumab, has shown to be effective in the treatment of AOSD but may precipitate MAS in patients with AOSD. The precise mechanism of MAS developed during anti-cytokine biologic agents remains unknown, but selective inhibition of a subset of pathways could impact other immune signalling pathways and trigger MAS. We herein describe a case of AOSD with the opposite outcomes of tocilizumab therapy, remission and development of MAS, after tocilizumab treatment at the initial flare and the relapse. From the comparison of clinical characteristics and concomitant treatment around the time of starting tocilizumab in both flares, the type and intensity of concomitant immunosuppressive therapy might strongly affect MAS development during tocilizumab therapy.

E-cigarette or Vaping-Associated Acute Lung Injury and Hemophagocytic Lymphohistiocytosis.

In this report, we describe the case of a 17-year-old boy with progressive respiratory failure requiring extracorporeal support who met clinical criteria for a presumptive diagnosis of electronic cigarette or vaping-associated acute lung injury (EVALI), with clinical, pathologic, and laboratory evidence of hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS). The patient in our report had a history of tetrahydrocannabinol and nicotine electronic cigarette use for months leading up to his presentation of fever, headache, emesis, and weight loss with respiratory distress. Multiple potential diagnoses were explored, and the patient's respiratory status improved, and he was initially discharged from the hospital. Roughly one week later, the patient was readmitted for worsening respiratory distress. The patient then met sufficient criteria for a potential diagnosis of HLH and MAS (elevated ferritin level, inflammatory markers, and cytopenia) to warrant a bone marrow aspirate, which revealed rare hemophagocytic cells. Given the severity of his symptoms and laboratory evidence of HLH and MAS, the patient was started on a course of steroids and anakinra. Although laboratory markers improved after treatment, the patient's respiratory failure worsened, ultimately progressing to a need for mechanical ventilation and extracorporeal support and leading to worsening multiorgan system failure and, ultimately, death. To the best of our knowledge, this is the first report of a patient with a presumptive diagnosis of EVALI with evidence of HLH and MAS, raising the possibility that macrophage activation may play a role in the pathogenesis of EVALI.

Tocilizumab treatment in juvenile idiopathic arthritis patients: A single center experience.

Demir S, Sönmez HE, Arslanoglu-Aydin E, Özen S, Bilginer Y. Tocilizumab treatment in juvenile idiopathic arthritis patients: A single center experience. Turk J Pediatr 2019; 61: 180-185. Tocilizumab is a monoclonal antibody against interleukin-6 that has recently emerged as an alternative treatment modality for juvenile idiopathic arthritis (JIA). In the present study, we aimed to discuss the clinical and laboratory findings and treatment response of JIA cases to tocilizumab therapy. This retrospective study included 20 JIA patients aged between 0-18 years who were followed up from 2014 to 2016 and received tocilizumab treatment in our clinic. Treatment response could be not evaluated in two patients since they developed anaphylactic reactions due to tocilizumab. Of the remaining 18 patients, seven of them (38.9%) had polyarticular JIA, and eleven (61.1%) had systemic JIA. Platelet counts, erythrocyte sedimentation rate and C-Reactive protein (CRP) levels, active joint counts, and Juvenile Arthritis Disease Activity Score 71 (JADAS71) were significantly decreased at the third month in both polyarticular and systemic JIA, while there were not any significant differences between the third and sixth months. All of the patients with polyarticular JIA had low disease activity at six months. Eight patients with systemic JIA had an inactive disease at six months, whereas the remaining three patients had high levels of CRP without presence of any clinical symptoms. Steroid treatment was terminated at the sixth month in all patients except for three patients who continued to receive 0.05-0.25 mg/kg steroid treatment. Two patients developed thrombocytopenia, one patient developed macrophage activation syndrome, and one patient had elevated transaminases due to tocilizumab treatment. Previous studies have shown that tocilizumab treatment is well-tolerated, effective, and safe for use in JIA patients. In the present study, we also demonstrated the efficacy of tocilizumab treatment in JIA patients from our clinic.

Unopposed IL-18 signaling leads to severe TLR9-induced macrophage activation syndrome in mice.

The term macrophage activation syndrome (MAS) defines a severe, potentially fatal disorder characterized by overwhelming inflammation and multiorgan involvement. Interleukin-18 (IL-18) is a proinflammatory cytokine belonging to the IL-1 family, the activity of which is regulated by its endogenous inhibitor IL-18 binding protein (IL-18BP). Elevated IL-18 levels have been reported in patients with MAS. Herein, we show that on repeated toll-like receptor 9 (TLR9) stimulation with unmethylated cytosine guanine dinucleotide containing single-stranded DNA (CpG), IL-18BP-/- mice display severe MAS manifestations, including increased weight loss, splenomegaly, anemia, thrombocytopenia, hyperferritinemia, and bone marrow hemophagocytosis as compared with wild-type mice. Serum-free IL-18 was detected in CpG-treated IL-18BP-/- mice only. Levels of interferon-γ (IFN-γ) and of IFN-γ signature genes, such as the chemokine Cxcl9 or the transcription factor CIIta, were significantly increased in IL-18BP-/- mice. Blocking IL-18 receptor signaling attenuated the severity of MAS and IFN-γ responses in IL-18BP-/- mice. Blocking IFN-γ had comparable effects to IL-18 inhibition on most MAS manifestations. Our data indicate that endogenous IL-18BP exerts a protective role in CpG-induced MAS and that IL-18, which acts upstream of IFN-γ, is involved in the severity of MAS.

Effect of Biologic Therapy on Clinical and Laboratory Features of Macrophage Activation Syndrome Associated With Systemic Juvenile Idiopathic Arthritis.

OBJECTIVE: To assess performance of the 2016 macrophage activation syndrome (MAS) classification criteria for patients with systemic juvenile idiopathic arthritis (JIA) who develop MAS while treated with biologic medications. METHODS: A systematic literature review was performed to identify patients with MAS while being treated with interleukin (IL)-1 and IL-6 blocking agents. Clinical and laboratory information was compared to a large previously compiled historical cohort. RESULTS: Eighteen publications were identified, and after removing duplicates, 35 patients treated with canakinumab and 49 patients with tocilizumab were available for analysis; 5 anakinra-treated patients were excluded due to limited numbers. MAS classification criteria were less likely to classify tocilizumab-treated patients as having MAS compared to the historical cohort or canakinumab-treated patients (56.7%, 78.5%, and 84%, respectively; P < 0.01). Patients who developed MAS while treated with canakinumab trended towards lower ferritin at MAS onset than the historical cohort (4,050 versus 5,353 ng/ml; P = 0.18) but had no differences in other cardinal clinical or laboratory features. In comparison, patients who developed MAS while treated with tocilizumab were less likely febrile and had notably lower ferritin levels (1,152 versus 5,353 ng/ml; P < 0.001). Other features of MAS were more pronounced in patients treated with tocilizumab, including lower platelet counts, lower fibrinogen, and higher aspartate aminotransferase levels. Mortality rates for patients with MAS treated with tocilizumab or canakinumab were not significantly different from the historical cohort. CONCLUSION: These findings show substantial alterations in MAS features that may limit utility of defined criteria for diagnosis of systemic JIA patients treated with biologic agents.

[Macrophage activation syndrome secondary to tocilizumab: Myth or reality?]. / Syndrome d'activation macrophagique sous tocilizumab : mythe ou réalité ?

INTRODUCTION: Some authors have reported macrophage activation syndrome (MAS) secondary to infusion of tocilizumab, a monoclonal antibody that blocks interleukin-6 (IL-6). The pathophysiology of MAS is however linked to uncontrolled activation of innate immunity, mediated in part by IL-6. We conducted a study for macrophage activation biomarkers in a cohort of patients treated with tocilizumab. RESULTS: Twenty-seven patients were included prospectively in our center. Levels of neutrophils, platelets, CRP and fibrinogen were lower at the end of treatment than at initiation (P<0.05); other biomarkers were stable. There was neither clinical sign of SAM nor hemophagocytosis in myelogram. CONCLUSION: Laboratory abnormalities are related to direct blockade of IL-6 by tocilizumab and decrease hepatic protein synthesis. Tocilizumab is not responsible for MAS and associations described are more likely to be related to the autoimmune underlying disease, rather than treatment.

Rate and Clinical Presentation of Macrophage Activation Syndrome in Patients With Systemic Juvenile Idiopathic Arthritis Treated With Canakinumab.

OBJECTIVE: In pivotal trials, canakinumab has been shown to be effective in the treatment of systemic juvenile idiopathic arthritis (JIA), but reported adverse events have included macrophage activation syndrome (MAS). This study was undertaken to assess the impact of canakinumab on MAS incidence. METHODS: An independent MAS Adjudication Committee (MASAC), consisting of 3 of the authors, was convened, and a search of databases from clinical studies of canakinumab treatment in systemic JIA was performed using MASAC-specified adverse event terms to identify potential MAS events. These were then adjudicated as "probable MAS," "possible MAS," or "MAS unlikely," using criteria developed by the MASAC. MAS rates were expressed as numbers of cases per 100 patient-years. RESULTS: Of 72 potential MAS cases identified, 21 events (19 with canakinumab treatment; 2 with placebo treatment) in 19 patients were adjudicated as being probable MAS and 10 events in 9 patients as being possible MAS. Systemic JIA was well controlled in the majority of canakinumab-treated patients at the time of MAS. The time period between initiation of canakinumab treatment and onset of MAS ranged from 3 to 1,358 days (median 292 days). When the rates of probable MAS events were compared between canakinumab-treated patients (2.8 per 100 patient-years) and placebo-treated patients (7.7 per 100 patient-years), the difference was not significant (-4.9 [95% confidence interval -15.6, 5.9]). There were 3 deaths due to MAS-related complications (2 in patients receiving canakinumab; 1 in a patient receiving placebo); full recovery was reported in all other patients. Infections were the most common trigger of MAS, and the clinical features of MAS were not modified by canakinumab. CONCLUSION: Canakinumab does not have a significant effect on MAS risk or its clinical features in patients with systemic JIA. Infections are the most common trigger, and MAS occurs even in patients whose systemic JIA is well controlled with this treatment.

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

OBJECTIVE: To report the indications and safety of biologic agents in childhood rheumatic diseases at a tertiary hospital. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Possible macrophage activation syndrome following initiation of adalimumab in a patient with adult-onset Still's disease.

Macrophage activation syndrome (MAS) has been rarely reported in the course of adult-onset Still's disease (AOSD) and in the majority of cases, it was triggered by an infection. Here, we report, to our knowledge, the first case of MAS occurring after adalimumab treatment initiation and not triggered by an infection. A 26-yearold woman with classical features of AOSD developed persistent fever, severe bicytopenia associated with extreme hyperferritinemia, hyponatremia and abnormal liver function tow months after the initiation of adalimumab treatment. The diagnosis of MAS was made without histological proof. The patient was treated with methylprednisolone pulse therapy and her condition improved. During the disease course, extensive studies could not identify any viral infection or other known underlying etiology for the reactive MAS. The adalimumab was incriminated in this complication. Currently, the patient is in remission on tocilizumab and low-dose prednisolone.