J. Merlijn van den Berg

Chronic Granulomatous Disease: The European Experience

CGD is an immunodeficiency caused by deletions or mutations in genes that encode subunits of the leukocyte NADPH oxidase complex. Normally, assembly of the NADPH oxidase complex in phagosomes of certain phagocytic cells leads to a “respiratory burst”, essential for the clearance of phagocytosed micro-organisms. CGD patients lack this mechanism, which leads to life-threatening infections and granuloma formation. However, a clear picture of the clinical course of CGD is hampered by its low prevalence (∼1∶250,000). Therefore, extensive clinical data from 429 European patients were collected and analyzed. Of these patients 351 were males and 78 were females. X-linked (XL) CGD (gp91phox deficient) accounted for 67% of the cases, autosomal recessive (AR) inheritance for 33%. AR-CGD was diagnosed later in life, and the mean survival time was significantly better in AR patients (49.6 years) than in XL CGD (37.8 years), suggesting a milder disease course in AR patients. The disease manifested itself most frequently in the lungs (66% of patients), skin (53%), lymph nodes (50%), gastrointestinal tract (48%) and liver (32%). The most frequently cultured micro-organisms per episode were Staphylococcus aureus (30%), Aspergillus spp. (26%), and Salmonella spp. (16%). Surprisingly, Pseudomonas spp. (2%) and Burkholderia cepacia (<1%) were found only sporadically. Lesions induced by inoculation with BCG occurred in 8% of the patients. Only 71% of the patients received antibiotic maintenance therapy, and 53% antifungal prophylaxis. 33% were treated with γ-interferon. 24 patients (6%) had received a stem cell transplantation. The most prominent reason of death was pneumonia and pulmonary abscess (18/84 cases), septicemia (16/84) and brain abscess (4/84). These data provide further insight in the clinical course of CGD in Europe and hopefully can help to increase awareness and optimize the treatment of these patients.

Divergent effects of tumor necrosis factor α on apoptosis of human neutrophils

Apoptosis of neutrophils is a key mechanism to control the intensity of the acute inflammatory response. Previously, the cytokine tumor necrosis factor α (TNF‐α) was reported by some to have pro‐apoptotic and by others to have anti‐apoptotic effects on neutrophils. The aim of this study was to explain these contradictory results. We found that TNF‐α at low concentrations strongly decreased apoptosis of neutrophils. However, at higher concentrations, TNF‐α lost its protective effects, and also reversed the protective effects of interferon‐γ (IFN‐γ) and granulocyte‐macrophage colony‐stimulating factor (GM‐CSF). This pro‐apoptotic effect of TNF‐α was blocked by anti‐CD11b and was absent in neutrophils from patients with chronic granulomatous disease, which cannot produce toxic oxygen metabolites. Under these circumstances, we found that TNF‐α retained its anti‐apoptotic effects even at high concentrations. In conclusion, the protective effects against apoptosis of IFN‐γ, GM‐CSF, and TNF‐α itself are overruled when the concentration of TNF‐α is high enough to produce a respiratory burst. These dual, concentration‐dependent effects of TNF‐α provide an explanation for previous controversial reports and support a dominant role for TNF‐α in neutrophil apoptosis.

Induction of regulatory T cells by macrophages is dependent on production of reactive oxygen species

The phagocyte NAPDH–oxidase complex consists of several phagocyte oxidase (phox) proteins, generating reactive oxygen species (ROS) upon activation. ROS are involved in the defense against microorganisms and also in immune regulation. Defective ROS formation leads to chronic granulomatous disease (CGD) with increased incidence of autoimmunity and disturbed resolution of inflammation. Because regulatory T cells (Tregs) suppress autoimmune T-cell responses and are crucial in down-regulating immune responses, we hypothesized that ROS deficiency may lead to decreased Treg induction. Previously, we showed that in p47phox-mutated mice, reconstitution of macrophages (Mph) with ROS-producing capacity was sufficient to protect the mice from arthritis. Now, we present evidence that Mph-derived ROS induce Tregs. In vitro, we showed that Mph ROS-dependently induce Treg, using an NADPH-oxidase inhibitor. This finding was confirmed genetically: rat or human CGD Mph with mutated p47phox or gp91phox displayed hampered Treg induction and T-cell suppression. However, basal Treg numbers in these subjects were comparable to those in controls, indicating a role for ROS in induction of peripheral Tregs. Induction of allogeneic delayed-type hypersensitivity with p47phox-mutated Mph confirmed the importance of Mph-derived ROS in Treg induction in vivo. We conclude that NAPDH oxidase activity in Mph is important for the induction of Tregs to regulate T cell-mediated inflammation.

Factors Associated With Treatment Response to Etanercept in Juvenile Idiopathic Arthritis

CONTEXT Since the introduction of biologic therapies, the pharmacological treatment approach for juvenile idiopathic arthritis (JIA) has changed substantially, with achievement of inactive disease as a realistic goal. OBJECTIVE To determine the response to therapy after initiation of etanercept therapy among patients with JIA and to examine the association between baseline factors and response to etanercept treatment. DESIGN, SETTING, AND PATIENTS The Arthritis and Biologicals in Children Register, an ongoing prospective observational study since 1999, includes all Dutch JIA patients who used biologic agents. All biologically naive patients who started etanercept before October 2009 were included, with follow-up data to January 2011. Among the 262 patients, 185 (71%) were female, 46 (18%) had systemic-onset, and the median age at initiation of etanercept treatment was 12.4 years. MAIN OUTCOME MEASURES Excellent response (inactive disease or discontinuation earlier due to disease remission), intermediate response (more than 50% improvement from baseline, but no inactive disease), and poor response (less than 50% improvement from baseline or discontinuation earlier due to ineffectiveness or intolerance) evaluated 15 months after initiation of etanercept. RESULTS At 15 months after treatment initiation, 85 patients (32%) were considered excellent responders; 92 (36%), intermediate responders; and 85 (32%), poor responders. Compared with an intermediate or poor response, an excellent response was associated with lower baseline disability score (range, 0-3 points, with 0 being the best score; adjusted odds ratio [OR] per point increase, 0.49; 95% CI, 0.33-0.74); fewer disease-modifying antirheumatic drugs (DMARD) (including methotrexate) used before initiating etanercept (adjusted OR per DMARD used, 0.64; 95% CI, 0.43-0.95), and younger age at onset (adjusted OR per year increase, 0.92; 95% CI, 0.84-0.99). Compared with an intermediate or excellent response, a poor response was associated with systemic JIA (adjusted OR systemic vs nonsystemic categories, 2.92; 95% CI, 1.26-6.80), and female sex (adjusted OR female vs male, 2.16; 95% CI, 1.12-4.18). Within the first 15 months of etanercept treatment, 119 patients experienced 1 or more infectious, noninfectious, or serious adverse events, including 37 among those with an excellent response, 36 with an intermediate response, and 46 with a poor response. Within the first 15 months of treatment, 61 patients discontinued etanercept treatment, including 4 with an excellent response, 0 with an intermediate response, and 57 with a poor response. In a secondary analysis of 262 patients with a median follow-up of 35.6 months after initiation of etanercept, a range of 37% to 49% of patients reached inactive disease. The mean adherence to etanercept was 49.2 months (95% CI, 46.4-52.0) for patients with an excellent response after 15 months, 47.5 months (95% CI, 44.9-50.1) for patients with an intermediate response, and 17.4 months (95% CI, 13.6-21.2) for patients with a poor response. CONCLUSIONS Among patients with JIA who initiated treatment with etanercept, one-third achieved an excellent response, one-third an intermediate response, and one-third a poor response to therapy. Achievement of an excellent response was associated with low baseline disability scores, DMARDs used before initiating etanercept, and younger age at onset of JIA. Achievement of a poor treatment response was associated with systemic JIA and female sex.

β 1 integrin activation on human neutrophils promotes β 2 integrin-mediated adhesion to fibronectin

Although the importance of β1 integrin‐mediated binding to adhesion molecules and extracellular matrix (ECM) molecules is well established for most types of leukocytes, the expression patterns and functional importance of β1 integrins on neutrophils have remained controversial. Using flow cytometry, we found that human neutrophils express the α4, α5, α9 and β1 integrin subunits. To examine whether the integrins VLA‐4 (α4/β1) and VLA‐5 (α5/β1) have a functional role on neutrophils, we studied adhesion to their ligand fibronectin. Treatment of neutrophils with antibody 8A2, which specifically binds and activates β1 integrins, resulted in increased binding to fibronectin. However, addition of blocking mAb revealed that 8A2‐induced adhesion did not depend on β1 integrins, but on the β2 integrin CD11b/CD18. Similarly, activation of β1 integrins by 8A2 resulted in CD11b‐dependent binding of neutrophils to fibrinogen. 8A2 treatment increased expression of an activation epitope of CD11b/CD18, which depended on phosphoinositide 3‐OH kinase activity and an adequate concentration of intracellular free Ca2+. These data suggest that engagement of β1 integrins on neutrophils results in a cross‐talk signal that leads to activation of the β2 integrin CD11b/CD18, followed by CD11b‐mediated adhesion. As transmigrated neutrophils are surrounded by both β1 and β2 ligands in the ECM, this integrin cross‐talk could play a role in modifying migration and cellular activation in inflamed tissues.

Tumor necrosis factor-blocking agents for children with enthesitis-related arthritis--data from the dutch arthritis and biologicals in children register, 1999-2010

Objective. To evaluate the effectiveness and safety of biological agents in children with enthesitis-related arthritis (ERA). Methods. All patients with ERA in whom a biological agent was initiated between 1999 and 2010 were selected from the Dutch Arthritis and Biologicals in Children (ABC) register. In this ongoing multicenter observational register, data on the course of the disease and medication use are retrieved prospectively at the start of the biological agent, after 3 months, and yearly thereafter. Inactive disease was assessed in accordance with the Wallace criteria. Results. Twenty-two patients with ERA started taking 1 or more biological agents: 20 took etanercept, 2 took adalimumab (1 switched from etanercept to adalimumab), and 2 took infliximab (1 switched from etanercept to infliximab). Characteristics: 77% were male, 77% had enthesitis, 68% were HLA-B27-positive. The median age of onset was 10.4 (IQR 9.4–12.0) years; median followup from the start of the biological agent was 1.2 (IQR 0.5–2.4) years. Intention-to-treat analysis shows that inactive disease was achieved in 7 of 22 patients (32%) after 3 months, 5 of 13 patients (38%) after 15 months, and 5 of 8 patients (63%) after 27 months of treatment. Two patients discontinued etanercept because of ineffectiveness, and switched to adalimumab (inactive disease achieved) or infliximab (decline in joints with arthritis after 3 months of treatment). One patient discontinued etanercept because of remission, but had flare and restarted treatment, with good clinical response. No serious adverse events occurred. Conclusion. Tumor necrosis factor (TNF)-blocking agents seem effective and safe for patients with ERA that was previously unresponsive to 1 or more DMARD. However, a sustained disease-free state could not be achieved, and none discontinued TNF-blocking agents successfully.

Reliability and responsiveness of the Juvenile Arthritis MRI Scoring (JAMRIS) system for the knee

ObjectivesTo assess the reliability and responsiveness of a new Juvenile Arthritis MRI Scoring (JAMRIS) system for evaluating disease activity of the knee.MethodsTwenty-five juvenile idiopathic arthritis (JIA) patients with clinical knee involvement were studied using open-bore 1-T MRI. MRI features of synovial hypertrophy, bone marrow changes, cartilage lesions and bone erosions were independently scored by five readers using the JAMRIS system. In addition, the JAMRIS system was determined to be a follow-up parameter by two readers to evaluate the response to therapy in 15 consecutive JIA patients.ResultsInter-reader (ICCs 0.86–0.95) and intra-reader reliability (ICCs 0.92–1.00) for the scoring of JAMRIS features was good. Reliability of the actual scores and changes in scores over time was good for all items: ICCs 0.89–1.00, 0.87–1.00, respectively. Concerning therapy response, the mean synovial hypertrophy scores decreased significantly (mean 1.1 point; P < 0.001, SRM = −0.65). No change was observed with respect to bone marrow change, cartilage lesion and bone erosion scores.ConclusionsThe JAMRIS proved to be a simple and highly reliable assessment score in the evaluation of JIA disease activity of the knee. The JAMRIS system may serve as an objective and accurate outcome measure in future research and clinical trials.Key Points• MRI is increasingly used to diagnose and assess juvenile idiopathic arthritis.• A simple and reliable scoring method would help monitor progress and research.• The Juvenile Arthritis MRI Scoring (JAMRIS) system provides reliable objective measures.• JAMRIS evaluates synovial hypertrophy, bone marrow changes, cartilage lesions and bone erosions.• The JAMRIS system can detect therapeutic response and should help future research.

Effectiveness of a Web-Based Application to Monitor Health-Related Quality of Life

BACKGROUND AND OBJECTIVE: Monitoring health-related quality of life (HRQoL) by using electronic patient-reported outcomes (ePROs) has been only minimally evaluated in pediatrics. Children with juvenile idiopathic arthritis (JIA) are at risk for HRQoL problems. The aim of this study was to investigate the effectiveness of ePROs in clinical pediatric rheumatology care. METHODS: All children (aged 0–18 years) with JIA visiting any of the 4 pediatric rheumatology clinics in Amsterdam between February 2009 and February 2010 were eligible for this sequential cohort intervention study. Before an outpatient consultation, children (aged 8–18 years) or parents (of children aged 0–7 years) completed web-based questionnaires. The resulting ePROfile was provided to the pediatric rheumatologist (PR). The study was divided into a control period in which the ePROfile was not discussed during consultation, and an intervention period in which the ePROfile was provided and discussed during consultation. Effectiveness was evaluated in terms of communication about different HRQoL topics, referral to a psychologist, and satisfaction with the consultations. RESULTS: Out of the eligible JIA patients, 176 (65%) participated in the study. Use of the ePROfile increased discussion of psychosocial topics (P < .01), as well as the PR’s satisfaction with provided care during consultation (P < .01). The use of ePROfiles did not affect referrals to a psychologist or parental satisfaction. Parents and PRs evaluated the use of the ePROfile as positive in 80% to 100% of the consultations. CONCLUSIONS: Our web-based application to systemically monitor HRQoL problems in pediatric rheumatology contributed significantly to communication about psychosocial issues in a positive way. We recommend implementation of ePROs in pediatric clinical practice.

A twice daily posaconazole dosing algorithm for children with chronic granulomatous disease.

Posaconazole (PSZ) may be an attractive alternative for antifungal prophylaxis in children with chronic granulomatous disease. Experience with PSZ in pediatric patients is limited, and no specific dose recommendations exist. A twice daily dosing algorithm based on allometric scaling (body-weight based) for PSZ results in adequate exposure and appears to be safe in children with chronic granulomatous disease.

The diagnostic accuracy of unenhanced MRI in the assessment of joint abnormalities in juvenile idiopathic arthritis

AbstractObjectivesTo assess the diagnostic accuracy and reliability of MRI without contrast enhancement in the evaluation of JIA knee joint abnormalities.MethodsJIA patients with clinically active knee involvement were prospectively studied using an 1-T open-bore magnet. MRI features were independently evaluated by two readers using the JAMRIS system. The first reading included unenhanced images, whereas complete image sets were available for the second reading.ResultsImaging findings from 73 patients were analysed. Agreement between Gd-enhanced (+Gd) and Gd-unenhanced (−Gd) MRI scores of bone marrow changes, cartilage lesions and bone erosions was good concerning sensitivity, specificity, negative predictive value and positive predictive value. Inter-observer agreement was good for both −Gd and +Gd scores (ICC = 0.91–1.00, 0.93–1.00, respectively). Regarding the assessment of synovial hypertrophy, specificity of −Gd was high (0.97), but the sensitivity of unenhanced MRI was only 0.62. Inter-reader agreement for +Gd MRI was ICC = 0.94; however, omitting post-Gd acquisitions increased inter-reader variation (ICC = 0.86).ConclusionsIf Gd-enhanced MRI is the reference standard, omitting Gd contrast medium is irrelevant for the assessment of bone marrow changes, cartilage lesions and bone erosions as joint abnormalities in JIA. Omitting intravenous Gd in the MRI assessment of joints in JIA is inadvisable, because it decreases the reliability of detecting synovial disease.Key Points• Magnetic resonance imaging is increasingly used to assess juvenile idiopathic arthritis. • Synovial hypertrophy, a marker of JIA activity, is well shown by MRI. • Omitting intravenous contrast medium decreases the reliability of synovial hypertrophy scores. • Bone marrow, cartilage and erosions can be reliably evaluated without contrast enhancement. • In the evaluation of JIA disease activity, unenhanced MRI is inadvisable.