Spotlight on latent tuberculosis infection screening for juvenile idiopathic arthritis in two countries, comparing high and low risk patients

Abstract Background: Rheumatic diseases are associated with an increase in overall risks of tuberculosis (TB). The aim of this study was to evaluate the frequency of TB and the frequency of latent TB infection (LTBI), in clinical practice, for juvenile idiopathic arthritis (JIA) patients from high and low risk of TB incidence endemic countries. Methods: This is an international, multicenter, cross-sectional, observational study of data collection from Brazil and Registry of Portugal at REUMA.PT. The inclusion criteria were patients with Juvenile Idiopathic Arthritis (JIA) with age ≤ 18 years who underwent screening for Mycobacterium tuberculosis infection [tuberculin skin test (TST) and/or interferon gamma release assay (IGRA)]. Chest X-rays and history of exposure to TB were also assessed. Results: 292 JIA patients were included; mean age 14.3 years, mean disease duration 7.5 years, 194 patients (66.4%) performed only TST, 14 (4.8%) only IGRA and 84 (28.8%) both. The frequency of LTBI (10.6%) and TB was similar between the two countries. The reasons for TB screening were different; in Brazil it was performed more often at JIA onset while in Portugal it was performed when starting Disease Modified Anti-Rheumatic Drugs (DMARD) treatment (p < 0.001). Isoniazid therapy was prescribed in 40 (13.7%) patients (31 with LTBI and 9 with epidemiologic risks and/or due to contact with sick people). Only three patients (1%) developed active TB. Conclusion: We found nearly 10% of patients with LTBI, a small percentage of patients with treatment due to epide-miologic risks and only 1% with active TB. Distinct reasons and screening methods for LTBI were observed between the two countries.

Granulomatosis with Polyangiitis in Adolescence: Two Distinct Presentations.

Introduction. Granulomatosis with polyangiitis (GPA) is a rare disease in pediatric age. We report two cases with distinct presentations. Case Reports. A seventeen-year-old male with prolonged febrile syndrome, cough, and constitutional symptoms. CT-scan showed cavitated lesions of the lung and bronchial biopsy a necrotizing inflammatory process. The remaining investigation revealed hematoproteinuria and positive C-ANCA and anti-PR3. Complications: Bilateral acute pulmonary thromboembolism, splenic infarction, and extensive popliteal and superficial femoral deep vein thrombosis. He was treated with corticosteroids, immunoglobulin, rituximab, and anticoagulation. Rituximab was maintained every six months during the first two years. Control angio-CT was performed with almost complete resolution of previous findings. In a twelve-year-old female with inflammatory signs of the limbs, investigation showed myositis of the thigh and tenosynovitis of the wrist, normocytic normochromic anemia (Hg 9.4 g/dL), mild elevation of inflammatory markers, and high creatine kinase. During hospitalization, she presented an extensive alveolar hemorrhage associated with severe anemia and positive C-ANCA and anti-PR3. Clinical deterioration prompted intravenous methylprednisolone pulses and plasmapheresis. Induction therapy with rituximab and prednisolone showed good results. Rituximab was maintained every six months, for 18 months, with gradual tapering of corticoids. Discussion. GPA is a systemic disease with variable clinical presentation and severity. Pediatric patients have similar clinical manifestations to adults but different frequencies of organ involvement; constitutional symptoms are also more common. We highlight the different presentation of these two cases, as well as the need for an individualized approach. Rituximab has been used for both induction-remission and maintenance therapy, with good results, particularly in young patients.

Inherited p40phox deficiency differs from classic chronic granulomatous disease.

Biallelic loss-of-function (LOF) mutations of the NCF4 gene, encoding the p40phox subunit of the phagocyte NADPH oxidase, have been described in only 1 patient. We report on 24 p40phox-deficient patients from 12 additional families in 8 countries. These patients display 8 different in-frame or out-of-frame mutations of NCF4 that are homozygous in 11 of the families and compound heterozygous in another. When overexpressed in NB4 neutrophil-like cells and EBV-transformed B cells in vitro, the mutant alleles were found to be LOF, with the exception of the p.R58C and c.120_134del alleles, which were hypomorphic. Particle-induced NADPH oxidase activity was severely impaired in the patients' neutrophils, whereas PMA-induced dihydrorhodamine-1,2,3 (DHR) oxidation, which is widely used as a diagnostic test for chronic granulomatous disease (CGD), was normal or mildly impaired in the patients. Moreover, the NADPH oxidase activity of EBV-transformed B cells was also severely impaired, whereas that of mononuclear phagocytes was normal. Finally, the killing of Candida albicans and Aspergillus fumigatus hyphae by neutrophils was conserved in these patients, unlike in patients with CGD. The patients suffer from hyperinflammation and peripheral infections, but they do not have any of the invasive bacterial or fungal infections seen in CGD. Inherited p40phox deficiency underlies a distinctive condition, resembling a mild, atypical form of CGD.

Chronic granulomatous disease as a risk factor for cutaneous lupus in childhood.

Chronic granulomatous disease (CGD) is a primaryimmunodeficiency disorder that affects the phagocyticcells of the innate immune system. It is characterizedby recurrent or persistent infections with granulomaformation. Lupus-like lesions have been reported incarriers of CGD and less frequently, in patients withCGD. Immunological study in these patients areusually negative. We describe the case of an 8-yearoldboy with CGD who developed chronic and acutecutaneous lupus erythematous with angular cheilitis,oral ulcers, Raynaud phenomenon, and positiveserologies for antinuclear, anticentromere, and anti-Saccharomyces cerevisiae antibodies.

The Diagnosing Challenge of a Positive ANCA Vasculitis in the Paediatric Age.

ANCA-positive systemic vasculitides, rare in paediatric age, present multiorganic involvement. A female teenager presented with a history of subglottic stenosis diagnosed at the age of 12. From the investigation carried out, we highlight hematoproteinuria and negative ANCAs. At 15 years old, she was admitted for gastrointestinal symptoms and respiratory distress. She presented poor peripheral perfusion, pulmonary haemorrhage, respiratory failure, and severe renal insufficiency. She was started mechanical ventilation and emergency haemodialysis. The immunological study revealed ANCA MPO positive. A presumptive diagnosis of ANCA-positive vasculitis was made, and she was started corticotherapy, cyclophosphamide, and plasmapheresis. A renal biopsy, performed later, showed crescentic glomerulonephritis with chronicity signs. Positive ANCA vasculitis may progress slowly or suddenly. The diagnosis was confirmed by a biopsy; however, we can make a presumptive diagnosis based on clinical findings and in a positive ANCA test in order to start an early treatment and decrease the associated morbimortality.

Effectiveness and long-term retention of anti-tumour necrosis factor treatment in juvenile and adult patients with juvenile idiopathic arthritis: data from Reuma.pt.

OBJECTIVES: Assess the effectiveness and safety of biologic therapy as well as predictors of response at 1 year of therapy, retention rate in biologic treatment and predictors of drug discontinuation in JIA patients in the Portuguese register of rheumatic diseases. METHODS: We prospectively collected patient and disease characteristics from patients with JIA who started biological therapy. Adverse events were collected during the follow-up period. Predictors of response at 1 year and drug retention rates were assessed at 4 years of treatment for the first biologic agent. RESULTS: A total of 812 JIA patients [65% females, mean age at JIA onset 6.9 years (s.d. 4.7)], 227 received biologic therapy; 205 patients (90.3%) were treated with an anti-TNF as the first biologic. All the parameters used to evaluate disease activity, namely number of active joints, ESR and Childhood HAQ/HAQ, decreased significantly at 6 months and 1 year of treatment. The mean reduction in Juvenile Disease Activity Score 10 (JADAS10) after 1 year of treatment was 10.4 (s.d. 7.4). According to the definition of improvement using the JADAS10 score, 83.3% respond to biologic therapy after 1 year. Fourteen patients discontinued biologic therapies due to adverse events. Retention rates were 92.9% at 1 year, 85.5% at 2 years, 78.4% at 3 years and 68.1% at 4 years of treatment. Among all JIA subtypes, only concomitant therapy with corticosteroids was found to be univariately associated with withdrawal of biologic treatment (P = 0.016). CONCLUSION: Biologic therapies seem effective and safe in patients with JIA. In addition, the retention rates for the first biologic agent are high throughout 4 years.

Chronic alveolar haemorrhage in a paediatric patient: a diagnostic and treatment challenge.

Pulmonary haemosiderosis is characterised by chronic alveolar haemorrhage, which can lead to serious cardiorespiratory complications. Although considered idiopathic in most patients, there are many possible aetiologies. We present a case of an 18-year-old woman with pulmonary haemosiderosis since 4 years of age, with an inconclusive initial study, who was treated with systemic corticosteroids and hydroxychloroquine until the age of 12 years, and azathioprine since then. Multiple exacerbations led to interstitial lung disease with restrictive functional pattern. Unilateral cochlear deafness was diagnosed at the age of 12 years and occasional polyarthralgias were recorded. When she was 16 years of age the study revealed an atypical myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) pattern. Cyclophosphamide and rituximab were administered with resolution of respiratory insufficiency and functional disability, without new episodes of alveolar haemorrhage. This case of chronic pulmonary haemorrhage was revealed to be an ANCA vasculitis, the diagnosis of which was possible only after 12 years of symptoms, with clinical and functional improvement with the association of cyclophosphamide and rituximab.

Reactive oxygen species deficiency induces autoimmunity with type 1 interferon signature.

AIMS: Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by mutations in the phagocyte reactive oxygen species (ROS)-producing NOX2 enzyme complex and characterized by recurrent infections associated with hyperinflammatory and autoimmune manifestations. A translational, comparative analysis of CGD patients and the corresponding ROS-deficient Ncf1(m1J) mutated mouse model was performed to reveal the molecular pathways operating in NOX2 complex deficient inflammation. RESULTS: A prominent type I interferon (IFN) response signature that was accompanied by elevated autoantibody levels was identified in both mice and humans lacking functional NOX2 complex. To further underline the systemic lupus erythematosus (SLE)-related autoimmune process, we show that naïve Ncf1(m1J) mutated mice, similar to SLE patients, suffer from inflammatory kidney disease with IgG and C3 deposits in the glomeruli. Expression analysis of germ-free Ncf1(m1J) mutated mice reproduced the type I IFN signature, enabling us to conclude that the upregulated signaling pathway is of endogenous origin. INNOVATION: Our findings link the previously unexplained connection between ROS deficiency and increased susceptibility to autoimmunity by the discovery that activation of IFN signaling is a major pathway downstream of a deficient NOX2 complex in both mice and humans. CONCLUSION: We conclude that the lack of phagocyte-derived oxidative burst is associated with spontaneous autoimmunity and linked with type I IFN signature in both mice and humans.