PURPOSE OF THE REVIEWOne of the most perplexing features of systemic-onset juvenile rheumatoid arthritis is the association with macrophage activation syndrome, a life-threatening complication caused ...by excessive activation and proliferation of T cells and macrophages. The main purpose of the review is to summarize current understanding of the relation between macrophage activation syndrome and other clinically similar hemophagocytic disorders.
RECENT FINDINGSClinically, macrophage activation syndrome has strong similarities with familial and virus-associated reactive hemophagocytic lymphohistiocytosis. The better understood familial hemophagocytic lymphohistiocytosis is a constellation of rare, autosomal recessive immune disorders. The most consistent immunologic abnormalities in patients with familial hemophagocytic lymphohistiocytosis are decreased natural killer and cytotoxic cell functions. In approximately one third of familial hemophagocytic lymphohistiocytosis patients, these immunologic abnormalities are secondary to mutations in the gene encoding perforin, a protein that mediates cytotoxic activity of natural killer and cytotoxic CD8 T cells. Several recent studies have suggested that profoundly depressed natural killer cell activity and abnormal levels of perforin expression may be a feature of macrophage activation syndrome in systemic-onset juvenile rheumatoid arthritis as well. Although it has been proposed that in both hemophagocytic lymphohistiocytosis and macrophage activation syndrome, natural killer and cytotoxic cell dysfunction may lead to inadequate control of cellular immune responses, the exact nature of such dysregulation and the relation between macrophage activation syndrome and hemophagocytic lymphohistiocytosis still remain to be determined.
Systemic juvenile idiopathic arthritis (SJIA) is a severe childhood arthropathy with features of autoinflammation. Monocytes and macrophages in SJIA have a complex phenotype with both pro‐ and ...anti‐inflammatory properties that combine features of several well characterized in vitro conditions used to activate macrophages. An important anti‐inflammatory phenotype is expression of CD163, a scavenger receptor that sequesters toxic pro‐inflammatory complexes that is highly expressed in both active SJIA and macrophage activation syndrome (MAS). CD163 is most strongly up‐regulated by IL‐10 (M(IL‐10)), and not by other conditions that reflect features seen in SJIA monocytes such as M(LPS+IC). MicroRNA plays key roles in integrating cellular signals such as those in macrophage polarization, and as such we hypothesize microRNAs regulate macrophage functional responses in SJIA including CD163 expression. We find that 2 microRNAs previously found to be elevated in active SJIA, miR‐125a‐5p and miR‐181c, significantly reduced macrophage CD163 expression through 2 distinct mechanisms. Neither microRNA was elevated in M(IL‐10) with robust CD163 expression, but were instead induced in M(LPS+IC) where they restricted CD163 mRNA expression. Mir‐181 species directly targeted CD163 mRNA for degradation. In contrast, miR‐125a‐5p functions indirectly, as transcriptome analysis of miR‐125a‐5p overexpression identified “cytokine‐cytokine receptor interactions” as the most significantly repressed gene pathway, including decreased IL10RA, required for IL‐10‐mediated CD163 expression. Finally, overexpression of miR‐181c inhibited CD163 anti‐inflammatory responses to hemoglobin or high mobility group box 1 (HMGB1) complexes. Together, these data show that microRNA utilizes multiple mechanisms to integrate well‐characterized polarization phenotypes and regulate macrophage functional properties seen in SJIA.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Haemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening systemic hyperinflammatory syndromes that can develop in most inflammatory contexts. They can ...progress rapidly, and early identification and management are critical for preventing organ failure and mortality. This effort aimed to develop evidence-based and consensus-based points to consider to assist clinicians in optimising decision-making in the early stages of diagnosis, treatment and monitoring of HLH/MAS.
A multinational, multidisciplinary task force of physician experts, including adult and paediatric rheumatologists, haematologist/oncologists, immunologists, infectious disease specialists, intensivists, allied healthcare professionals and patients/parents, formulated relevant research questions and conducted a systematic literature review (SLR). Delphi methodology, informed by SLR results and questionnaires of experts, was used to generate statements aimed at assisting early decision-making and optimising the initial care of patients with HLH/MAS.
The task force developed 6 overarching statements and 24 specific points to consider relevant to early recognition of HLH/MAS, diagnostic approaches, initial management and monitoring of HLH/MAS. Major themes included the simultaneous need for prompt syndrome recognition, systematic evaluation of underlying contributors, early intervention targeting both hyperinflammation and likely contributors, careful monitoring for progression/complications and expert multidisciplinary assistance.
These 2022 EULAR/American College of Rheumatology points to consider provide up-to-date guidance, based on the best available published data and expert opinion. They are meant to help guide the initial evaluation, management and monitoring of patients with HLH/MAS in order to halt disease progression and prevent life-threatening immunopathology.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Follistatin-like protein 1 (FSTL-1) is a secreted glycoprotein overexpressed in certain inflammatory diseases. Our objective was to correlate FSTL-1 levels with gene expression, known biomarkers, and ...measures of disease activity in systemic juvenile idiopathic arthritis (sJIA), including macrophage activation syndrome (MAS).
FSTL-1 serum levels were measured by ELISA in 28 patients with sJIA, including 7 patients who developed MAS, and 30 healthy controls. Levels were correlated with erythrocyte sedimentation rate (ESR), ferritin, and soluble interleukin-2 receptor-α (sIL-2Rα). Gene expression based on FSTL-1 levels was analyzed in peripheral blood mononuclear cells (PBMC).
Serum levels of FSTL-1 were elevated at time of presentation of sJIA (mean 200.7 ng/ml) and decreased to normal (mean 133.7 ng/ml) over 24 months (p < 0.01). FSTL-1 levels were markedly elevated during acute MAS (mean 279.8 ng/ml) and decreased to normal following treatment (p < 0.001). FSTL-1 levels correlated with serum markers of inflammation, including sIL-2Rα and ferritin. Ferritin/ESR ratio was superior to ferritin, sIL-2Rα, and FSTL-1 in discriminating MAS from new-onset sJIA. PBMC from patients with FSTL-1 levels > 200 ng/ml showed altered expression of genes related to innate immunity, erythropoiesis, and natural killer cell dysfunction. Two patients with the highest FSTL-1 levels at disease onset (> 300 ng/ml) ultimately developed MAS.
Elevated pretreatment serum FSTL-1 levels in sJIA are associated with dysregulated gene expression suggestive of occult MAS, and may have utility in predicting progression to overt MAS. Ferritin/ESR ratio may be superior to ferritin alone in discriminating overt MAS from new-onset sJIA.
•Uncontrolled, chronic anterior uveitis leads to ocular morbidity in children.•Failed treatment with methotrexate and adalimumab and/or infliximab is not uncommon.•Alternative biologic agents include ...golimumab, tocilizumab, and abatacept.•Nine patients with resistant disease were successfully treated with alternative biologic agents.
A significant number of children with noninfectious, chronic anterior uveitis (CAU) fail to respond to conventional therapy; however, successful alternative biologic treatments (ABT) have not been well described. This study aims to review the clinical and treatment characteristics of children with CAU who require ABT.
Retrospective, nonrandomized clinical study.
Setting: Tertiary center. Study Population: Children with noninfectious CAU. Observation Procedures: Clinical characteristics, uveitis course, complications, and treatment were compared among patients treated with methotrexate (MTX) monotherapy, conventional TNFα inhibitors (cTNFi), and ABT for >3 months. Main Outcome Measure: Success of ABT (abatacept, tocilizumab, and/or golimumab) in children failing conventional treatment.
Of the 52 children with CAU, 75% had juvenile idiopathic arthritis. CAU was controlled in 15 children receiving MTX monotherapy, 28 receiving cTNFi, and 9 receiving ABT (n = 1, abatacept; n = 3, tocilizumab; n = 5, golimumab). Patients in the ABT group had a greater number of total ocular complications per person before ABT than those in the control groups (3.4 vs 0.7 MTX, P < .001, and 1.5 cTNFi, P < .001, respectively). In all 9 children on ABT, treatment led to control of CAU and topical glucocorticoids tapered to ≤2 drops/d with no new ocular complications.
In this study, alternative biologics (abatacept, golimumab, and tocilizumab) were useful for treating CAU in children who fail MTX and cTNFi therapy. Patients who were controlled on ABT had more disease activity, ocular complications, and anti-cTNFi neutralizing antibodies (before ABT) than those managed with conventional therapy. Larger studies are required to confirm these findings.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Objective
To ascertain the role of platelet glycoprotein Ib α‐chain (GPIbα) plasma protein levels in cardiovascular, autoimmune, and autoinflammatory diseases and whether its effects are mediated by ...platelet count.
Methods
We performed a two‐sample Mendelian randomization (MR) study, using both a cis‐acting protein quantitative trait locus (cis‐pQTL) and trans‐pQTL near the GP1BA and BRAP genes as instruments. To assess if platelet count mediated the effect, we then performed a two‐step MR study. Putative associations (GPIbα/platelet count/disease) detected by MR analyses were subsequently assessed using multiple‐trait colocalization analyses.
Results
After correction for multiple testing (Bonferroni‐corrected threshold P ≤ 2 × 10−3), GPIbα, instrumented by either cis‐pQTL or trans‐pQTL, was causally implicated with an increased risk of oligoarticular and rheumatoid factor (RF)–negative polyarticular juvenile idiopathic arthritis (JIA). These effects of GPIbα appeared to be mediated by platelet count and were supported by strong evidence of colocalization (probability of all 3 traits sharing a common causal variant ≥0.80). GPIbα instrumented by cis‐pQTL did not appear to affect cardiovascular risk, although the GPIbα trans‐pQTL was associated with an increased risk of cardiovascular diseases and autoimmune diseases but a decreased risk of autoinflammatory diseases, suggesting that this trans‐acting instrument operates through other pathways.
Conclusion
The role of platelets in thrombosis is well‐established; however, our findings provide some novel genetic evidence that platelets may be causally implicated in the development of oligoarticular and RF‐negative polyarticular JIA, and indicate that GPIbα may serve as a putative therapeutic target for these JIA subtypes.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Macrophage activation syndrome (MAS) is a life-threatening cytokine storm complicating systemic juvenile idiopathic arthritis (SJIA) driven by IFN-γ. SJIA and MAS are also associated with an ...unexplained emerging inflammatory lung disease (SJIA-LD), with our recent work supporting pulmonary activation of IFN-γ pathways pathologically linking SJIA-LD and MAS. Our objective was to mechanistically define the potentially novel observation of pulmonary inflammation in the TLR9 mouse model of MAS. In acute MAS, lungs exhibit mild but diffuse CD4-predominant, perivascular interstitial inflammation with elevated IFN-γ, IFN-induced chemokines, and alveolar macrophage (AMϕ) expression of IFN-γ-induced genes. Single-cell RNA sequencing confirmed IFN-driven transcriptional changes across lung cell types with myeloid expansion and detection of MAS-specific macrophage populations. Systemic MAS resolution was associated with increased AMϕ and interstitial lymphocytic infiltration. AMϕ transcriptomic analysis confirmed IFN-γ-induced proinflammatory polarization during acute MAS, which switches toward an antiinflammatory phenotype after systemic MAS resolution. Interestingly, recurrent MAS led to increased alveolar inflammation and lung injury, and it reset AMϕ polarization toward a proinflammatory state. Furthermore, in mice bearing macrophages insensitive to IFN-γ, both systemic features of MAS and pulmonary inflammation were attenuated. These findings demonstrate that experimental MAS induces IFN-γ-driven pulmonary inflammation replicating key features of SJIA-LD and provides a model system for testing potentially novel treatments directed toward SJIA-LD.
Objective
Human leukocyte antigen (HLA)‐DRB1*15:01 has been recently associated with interstitial lung disease (LD), eosinophilia, and drug reactions in systemic juvenile idiopathic arthritis (sJIA). ...Additionally, genetic variants in IL1RN have been linked to poor response to anakinra. We sought to reproduce these findings in a prospective cohort study of patients with new‐onset sJIA treated with anakinra as first‐line therapy.
Methods
HLA and IL1RN risk alleles were identified via whole‐genome sequencing. Treatment responses and complications were compared between carriers versus noncarriers.
Results
Seventeen of 65 patients (26%) carried HLA‐DRB1*15:01, comparable with the general population, and there was enrichment for HLA‐DRB1*11:01, a known risk locus for sJIA. The rates of clinical inactive disease (CID) at 6 months, 1 year, and 2 years were generally high, irrespective of HLA‐DRB1 or IL1RN variants, but significantly lower in carriers of an HLA‐DRB1*11:01 allele. One patient, an HLA‐DRB1*15:01 carrier, developed sJIA‐LD. Of the three patients with severe drug reactions to biologics, one carried HLA‐DRB1*15:01. The prevalence of eosinophilia did not significantly differ between HLA‐DRB1*15:01 carriers and noncarriers at disease onset (6.2% vs 14.9%, P = 0.67) nor after the start of anakinra (35.3% vs 37.5% in the first 2 years of disease).
Conclusion
We observed high rates of CID using anakinra as first‐line treatment irrespective of HLA‐DRB1 or IL1RN variants. Only one of the 17 HLA‐DRB1*15:01 carriers developed sJIA‐LD, and of the three patients with drug reactions to biologics, only one carried HLA‐DRB1*15:01. Although thorough monitoring for the development of drug hypersensitivity and refractory disease courses in sJIA, including sJIA‐LD, remains important, our data support the early start of biologic therapy in patients with new‐onset sJIA irrespective of HLA‐DRB1 background or IL1RN variants.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
It has been increasingly recognized that there is a subset of patients with refractory systemic JIA, who have failed all available medications and may benefit from HSCT. The increasing experience ...with HSCT in SJIA, suggests that despite the complicated post-HSCT course, short-term, the transplanted patients either achieved SJIA remission or reduced burden of disease. Longer follow-up, however, is needed to better define the long-term outcomes. The discussion at the NextGen 2022 conference was focused on the optimal timing for the procedure, the need for a good control of inflammatory SJIA activity prior to HSCT, and the role of the reduced intensity conditioning regimens as there was a remote concern that such regimens might increase the risk of SJIA relapse after the transplantation. There was unanimous agreement about the importance of long-term registries to address these questions.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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