Soluble hemoglobin-haptoglobin scavenger receptor CD163 as a lineage-specific marker in the reactive hemophagocytic syndrome

Reactive hemophagocytic syndrome (RHS) is a disease of overwhelming macrophage activity triggered by infection, malignancy or autoimmune disorders. Currently used laboratory markers for the quantitative assessment of monocyte/macrophage activation lack lineage-restricted expression patterns and thus specificity. Serum levels of the macrophage specific scavenger receptor CD163 were determined by enzyme-linked immunosorbent assay (ELISA) and were found to be highly increased in patients with RHS (median 39.0 mg/L). Significantly lower levels were determined in patients with sepsis (median 9.1 mg/L), acute mononucleosis (median 8.2 mg/L), Leishmania infection (median 6.7 mg/L) and healthy controls (median 1.8 mg/L). Follow-up of patients with a relapsing course of the disease revealed close correlations of sCD163 with clinical disease activity, serum ferritin and other markers of macrophage activity. Large sinusoidal accumulations of CD163 expressing macrophages actively engaged in phagocytosis of blood cells were detected in spleen sections of RHS patients. Our data suggests sCD163 to be a macrophage-specific marker in patients with disorders of inappropriate macrophage activation.     

Plasma exchange successfully treated macrophage activation syndrome in rheumatoid factor‐positive polyarticular juvenile idiopathic arthritis with co‐existing pneumonia

Macrophage activation syndrome (MAS) is one of the serious complications associated with rheumatic diseases, especially systemic juvenile idiopathic arthritis (sJIA). Here we describe a 9‐year‐old girl with rheumatoid factor (RF)‐positive polyarticular JIA, not sJIA, combined with pneumonia who was successfully treated by plasma exchange. She was diagnosed with RF‐positive polyarticular JIA based on positive RF and multiple joint swelling and tenderness 3 years ago. She was admitted in our hospital with myalgia for 2 days and a high fever for half a day. Physical examination revealed relapsing joints symptoms and rough breathing sounds of lungs. The laboratory examination showed increased liver enzymes, elevated serum ferritin and procalcitonin (PCT), decreased percentage of nature killer (NK) cells and fibrinogen, and activated macrophage phagocytosing hematopoietic elements in bone marrow. The elevated PCT and chest computed tomography scan confirmed she also had pneumonia. Intravenous methylprednisolone and oral cyclosporine A followed by intravenous immunoglobulin were added on the basis of antibiotics therapy, but clinical symptoms and laboratory findings did not improve. Finally, we changed to plasma exchange once every other day for a total of three times. Within 1 week, the girl recovered from the MAS completely.     

Clinical practice guidance for juvenile idiopathic arthritis (JIA) 2018

Juvenile idiopathic arthritis (JIA) is the most common disease in pediatric rheumatism. There is no specific symptom or examination finding for JIA, and the diagnosis is made by exclusion and differentiation. Because non-pediatric rheumatologists are sometimes involved in medical care, ‘proposal for JIA guidance on diagnosis and treatment for primary care pediatricians and non-pediatric rheumatologists’ was first published in 2007. In these 10 years, a number of new findings on pathophysiology and treatment of JIA have been published; therefore, we propose this guidance of 2018th edition aiming at updating and standardization of JIA medical care in Japan. This edition included the management of uveitis, macrophage activation syndrome, infectious diseases before and during treatment. Moreover, details of biologics are also described. Although this guidance is tailored to adaptation of examinations and drugs, we do not purpose to limit the physicians' discretion in clinical practice. This guidance should be viewed as recommendations and be individualized according to the condition of the patient. We hope that medical care for JIA will advance and more patients will get benefit based on this guidance. Then, further revisions are needed due to changes in future conditions.     

Serological screening for coeliac disease in patients with juvenile idiopathic arthritis

Background and study aimsJuvenile idiopathic arthritis (JIA) is characterized by autoimmune aetiology. A gene locus 4q27 related to rheumatoid arthritis, psoriatic arthritis, and coeliac disease is associated with susceptibility to JIA. There are reports indicating several patients with JIA had been diagnosed with CD. We aimed to assess the frequency of coeliac disease (CD) in patients with juvenile idiopathic arthritis (JIA).Patients and methodsThis prospective study was carried out from October 2015 to August 2016 and included 96 patients with JIA. All patients were evaluated in terms of clinical and laboratory findings of CD. Levels of total IgA and tissue transglutaminase antibody (tTG) IgA were measured in all patients. Those with increased level of tTG IgA were further tested for anti-endomysium IgA antibodies (EMA). Gastroduodenoscopy were planned for a definite diagnosis of CD in patients with positive EMA.ResultsOf the 96 patients in our study, 34 (35.4%) had oligoarticular form of JIA, 29 (30.2%) had polyarticular form, 12 (12.5%) had ERA form, 11 (11.5%) had systemic form, and 10 (10.4%) had psoriatic form. Sixteen of our patients (16.6%) were not using any drugs during the study. Neither EMA IgA antibodies were analysed nor gastro-duodenoscopy was performed because no patients were positive for tTG IgA. There was no difference in terms of tTG levels between the patients using NSAIDs or other drugs.ConclusionWe did not find CD in children with JIA. Long term studies with more JIA patients are needed to provide more precise interpretation.     

Serum interleukin-18 level as a possible early diagnostic marker of systemic juvenile idiopathic arthritis

Early diagnosis of systemic juvenile idiopathic arthritis (s-JIA) is a prerequisite for therapeutic efficacy. However, it is often challenging because most patients with s-JIA do not show arthritis at disease onset and are simply diagnosed with fever of unknown origin. Serum ferritin levels have commonly been used to diagnose s-JIA because they increase in patients with this condition by more than 5 times their normal value. However, there are no definite biomarkers for s-JIA, which makes the clinical diagnosis of s-JIA difficult. We report a case of s-JIA in which interleukin (IL)-18 elevation was observed before ferritin elevation at the early phase of s-JIA. We propose serum IL-18 levels as a more useful biomarker for the early diagnosis of s-JIA compared to serum ferritin levels.     

Neprilysin levels in plasma and synovial fluid of juvenile idiopathic arthritis patients

Objective Neprilysin (neutral endopeptidase, 3:4:24:11, CD10) (NEP) is a Zn metallopeptidase linked to controlling inflammation through the degradation of neuropeptides involved in neurogenic inflammation of chronic rheumatic diseases. The aim of our study was to evaluate circulating activity and cellular expression of NEP in the plasma of 58 children with juvenile idiopathic arthritis (JIA) and 52 controls. In 20 subjects requiring local steroid injection, NEP was measured in synovial fluid.Methods Plasma and synovial NEP were evaluated using a fluorimetric technique. Neprilysin, expressed as the antigen CD10, was determined on circulating and synovial fluid cells as mean fluorescence intensity (MFI) and as percentage of positive cells by two-color immunofluorescence.Results Circulating NEP levels were lower in JIA patients than in controls (42.0±16.6 vs 76.5±24 pmol/ml per min, P<0.001), while synovial fluid NEP values were higher than circulating levels (241.4±86.2 vs 40±15.3 pmol/ml per min, P<0.001). In monocytes, the percentage of CD10-positive circulating cells and the MFI in JIA were lower than in controls (11.6±5.2% vs 41.4±13%, P<0.001 and 18.1±7.5 vs 31.2±5.4, P<0.05, respectively). On synovial monocytes, the percentage of CD10-positive cells and the MFI were higher than on circulating monocytes (35.2±14.6% vs 9.1±2.4%, P<0.001 and 66.4±5.4 vs 22.8±14.7, P<0.001, respectively).Conclusions The downregulation of CD10 expression in monocytes and the reduction in NEP activity may be linked to the enzymes role in the control of peptides involved in the inflammation. The increased levels of NEP, MFI, and CD10-positive monocytes in synovial fluid, even though in plasma, might reflect a reactive effort to control synovial proliferation.     

Occult macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis

OBJECTIVE: Macrophage activation syndrome (MAS) is a well described, but purportedly uncommon manifestation of systemic juvenile idiopathic arthritis (SJIA). There is evidence to suggest that macrophage activation is integral to the pathogenesis of SJIA. Accordingly, many patients with SJIA may have evidence of mild MAS that is not appreciated clinically. We investigated the prevalence of occult MAS in children with SJIA by reviewing bone marrow aspirates (BMA). METHODS: Patients diagnosed with SJIA who underwent bone marrow aspiration were identified retrospectively. Patients admitted with a diagnosis of fever of unknown origin and discharged with a diagnosis other than SJIA or malignancy, and who had a BMA, were identified as controls. The BMA were reviewed by a single hematopathologist for evidence of MAS, ranging from activated macrophages to frank hemophagocytic cells. RESULTS: Eight of 15 (53%) patients with SJIA had BMA suggestive of MAS. Two of 15 patients (13%) were diagnosed clinically with MAS. Three patients (20%) were noted to have frank hemophagocytosis, only one of whom was diagnosed with MAS clinically. There were no statistically significant differences in the laboratory values for the patients with and without evidence of MAS on BMA. There was no evidence of increased macrophage activity or hemophagocytosis in any of the control BMA. CONCLUSION: Occult MAS appears to be common in patients with SJIA who undergo BMA. This suggests that macrophage activation may be integral to the pathogenesis of SJIA, with implications for treatment.     

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

Abstract

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.     

Clinical characteristics of influenza virus infection in juvenile idiopathic arthritis patients treated with tocilizumab

Background

Inhibition of interleukin-6 (IL-6) signaling by tocilizumab is highly effective for treatment of refractory juvenile idiopathic arthritis (JIA). It appears that IL-6 plays an important role in the immune response to the influenza virus, but it is not clear whether treatment with tocilizumab affects the severity of influenza.

Methods

We retrospectively collected clinical and laboratory data from JIA patients (n = 33) treated with tocilizumab. Ten patients who developed influenza (tocilizumab group; 10.1 %, 10/99 patient-years) were analyzed. Eleven JIA patients who experienced influenza during conventional treatments, without tocilizumab (control group), were compared with the tocilizumab group.

Results

Of the 10 patients in the tocilizumab group, 6 patients did not have high fever (>38 °C), and the other 4 febrile patients recovered from fever in 1 day. White blood cell counts and lymphocyte counts were significantly lower at the acute phase of infection compared with data from before influenza infection. The degree of fever and level of C-reactive protein in the tocilizumab group were significantly reduced compared with the control group.

Conclusions

IL-6 inhibition by tocilizumab reduced inflammation associated with infection and resulted in mild symptoms during influenza. Leukopenia might be a useful indicator of viral infection, including influenza, during tocilizumab treatment.     

Soluble CD163 in patients with liver diseases: very high levels of soluble CD163 in patients with fulminant hepatic failure

Background The levels of several cytokines and chemokines are elevated in various liver diseases, especially in fulminant hepatic failure (FHF). Activated macrophages may have a role in the production of these immune modulators. CD163 is a member of a scavenger receptor family and is expressed mainly on activated macrophages, and a soluble form of CD163 (sCD163) is released from activated macrophages. The aim of this study was to assess sCD163 levels in patients with FHF and to evaluate their clinical significance.Methods The levels of sCD163 in the sera were measured in 21 patients with FHF, 17 patients with acute hepatitis (AH), 22 patients with chronic hepatitis (CH), and 14 normal healthy controls (NC), by an enzyme-linked immunosorbent assay. The levels of sCD163 were observed serially in patients with FHF and AH.Results The levels of sCD163 in the sera from patients with FHF were significantly higher than those in patients with AH and CH and the NC group (P < 0.0001). There was a good correlation between serum levels of sCD163 and prothrombin time (r = –0.677; P < 0.0001). A kinetic study revealed that the levels of sCD163 decreased in patients with AH and in survivors of FHF, whereas the levels of sCD163 progressively increased in nonsurvivors of FHF.Conclusions This study shows that the products of activated macrophages may be involved in the pathogenesis of FHF. This study also inspires optimism that sCD163 may possess prognostic importance in FHF.     

Isolated proximal tibiofibular joint arthritis in a patient with juvenile idiopathic arthritis: A case report

We report the case of a 14-year-old girl of juvenile idiopathic arthritis (JIA) with isolated and chronic proximal tibiofibular (PTF) joint arthritis. The clinical history, magnetic resonance imaging, and pathological findings of the patient are presented. We should be careful to evaluate the patient for chronic lateral knee pain, and consider concomitant evaluation for JIA, including rheumatoid arthritis.     

Use of adalimumab in patients with juvenile idiopathic arthritis refractory to etanercept and/or infliximab

To analyse the effectiveness and safety of adalimumab in a group of patients with juvenile idiopathic arthritis (JIA) who had failed treatment with etanercept and/or infliximab in a single paediatric rheumatology clinic. Patients with JIA with active polyarthritis refractory to metotrexate (MTX) (≥20 mg/m²/week) for at least 3 months and to etanercept (up to 1 mg/kg twice weekly) and/or infliximab (up to 10 mg/kg every 4 weeks) for at least 6 months were included. All patients received adalimumab 24 mg/m²/week concomitantly with MTX 7.5–10 mg/week. Evaluation of efficacy included improvement as defined by the ACR paediatric 30 criteria, 50% and 70% improvement and remission. Six patients were included. Three patients met improvement criteria; 50% and 70% improvement occurred in two children. Improvement was sustained for 12, 24 and 36 months, respectively. Remission occurred in one patient. Adalimumab was discontinued due to lack of efficacy in three patients. No side effects were observed. Adalimumab appears to be effective and safe in patients with JIA refractory to other anti-TNF agents. Further controlled studies are needed in order to assess efficacy of adalimumab in children with refractory JIA.     

Switching the therapy from etanercept to infliximab in a child with rheumatoid factor positive polyarticular juvenile idiopathic arthritis

Tumor necrosis factor α (TNFα)-blocking agents have been used increasingly in the treatment of severe refractory juvenile idiopathic arthritis (JIA). However, some patients have been forced to discontinue these agents because of the lack of efficacy or adverse events. In these situations, cases of switching from one TNF-blocking agent to another are reported in rheumatoid arthritis, but there are few cases in JIA. This report documents the case of a patient with JIA who improved following a switch from etanercept to infliximab.     

Switching the therapy from etanercept to infliximab in a child with rheumatoid factor positive polyarticular juvenile idiopathic arthritis

Abstract

Tumor necrosis factor α (TNFα)-blocking agents have been used increasingly in the treatment of severe refractory juvenile idiopathic arthritis (JIA). However, some patients have been forced to discontinue these agents because of the lack of efficacy or adverse events. In these situations, cases of switching from one TNF-blocking agent to another are reported in rheumatoid arthritis, but there are few cases in JIA. This report documents the case of a patient with JIA who improved following a switch from etanercept to infliximab.     

Anti-endothelial cell antibodies are prevalent in juvenile idiopathic arthritis: implications for clinical disease course and pathogenesis

To determine the prevalence of anti-endothelial cell antibodies (AECA) in children with juvenile idiopathic arthritis (JIA) versus healthy control children. Twenty-eight children with active JIA were studied (ten each with polyarticular and oligoarticular disease, and eight with systemic onset disease). AECA were determined by a cell-based ELISA from samples obtained every 3 months over a 2 year period in each subject. These levels were compared against previously determined levels of von Willebrand factor antigen, fibrin d-dimer, and soluble forms of ICAM-1 and E-selectin, as well as clinical measures of disease activity. AECA were detected in 5/10 oligoarticular, 6/10 polyarticular, and 7/8 systemic JIA subjects and 0/14 controls. Mean levels of AECA were significantly higher in subjects with oligoarticular, and especially systemic disease as compared to polyarticular and control groups when analyzed by ANOVA. AECA are prevalent in JIA and are present more often and at higher levels in systemic disease. Dr. Bloom supported by a Rhode Island Foundation Medical Sciences Grant and a Lifespan Developmental Grant.     

Survey of the awareness of adult rheumatologists regarding transitional care for patients with juvenile idiopathic arthritis in Japan

Abstract

Objectives: To understand the current status of adult rheumatology care for patients who had previously had juvenile idiopathic arthritis (JIA) (excluding systemic JIA), and to identify issues interfering with the transition from pediatric to adult care in Japan.

Methods: Questionnaire-based survey among 30 adult rheumatologists.

Results: Eighty-seven percent of adult rheumatologists responded that they had provided medical care to adults who had had JIA; 44% of them had felt hesitation or anxiety when providing such care. The reasons for this included lack of independence of the patients, lack of knowledge and experience among adult rheumatologists, and lack of preparation for accepting such patients. Many adult rheumatologists believed that the timing of transition from pediatric to adult rheumatology care must be considered based on therapeutic regimens or clinical conditions/disease states, not solely chronological age. A majority of adult rheumatologists showed great interest in transitional care for JIA patients and desired to communicate better with pediatric rheumatologists.

Conclusion: Transitional care for JIA patients is not sufficiently developed in Japan. Education and advocate campaign of transitional care is required for adult rheumatologists as well as patients and their parents.