Mariana Paes Leme Ferriani

A Multicenter Study of Invasive Fungal Infections in Patients with Childhood-onset Systemic Lupus Erythematosus.

Objective. To study the prevalence, risk factors, and mortality of invasive fungal infections (IFI) in patients with childhood-onset systemic lupus erythematosus (cSLE). Methods. A retrospective multicenter cohort study was performed in 852 patients with cSLE from 10 pediatric rheumatology services. An investigator meeting was held and all participants received database training. IFI were diagnosed according to the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group Consensus Group criteria (proven, probable, and possible). Also evaluated were demographic, clinical, and laboratory data, and disease activity [SLE Disease Activity Index 2000 (SLEDAI-2K)], cumulative damage (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index), treatment, and outcomes. Results. IFI were observed in 33/852 patients (3.9%) with cSLE. Proven IFI was diagnosed in 22 patients with cSLE, probable IFI in 5, and possible IFI in 6. Types of IFI were candidiasis (20), aspergillosis (9), cryptococcosis (2), and 1 each disseminated histoplasmosis and paracoccidioidomycosis. The median of disease duration was lower (1.0 vs 4.7 yrs, p < 0.0001) with a higher current SLEDAI-2K [19.5 (0–44) vs 2 (0–45), p < 0.0001] and current prednisone (PRED) dose [50 (10–60) vs 10 (2–90) mg/day, p < 0.0001] in patients with IFI compared with those without IFI. The frequency of death was higher in the former group (51% vs 6%, p < 0.0001). Logistic regression analysis revealed that SLEDAI-2K (OR 1.108, 95% CI 1.057–1.163, p < 0.0001), current PRED dose (OR 1.046, 95% CI 1.021–1.071, p < 0.0001), and disease duration (OR 0.984, 95% CI 0.969–0.998, p = 0.030) were independent risk factors for IFI (R2 Nagelkerke 0.425). Conclusion. To our knowledge, this is the first study to characterize IFI in patients with cSLE. We identified that disease activity and current glucocorticoid use were the main risk factors for these life-threatening infections, mainly in the first years of disease course, with a high rate of fatal outcome.

Chronic Spontaneous Urticaria: A Survey of 852 Cases of Childhood-Onset Systemic Lupus Erythematosus.

Background: Data regarding the prevalence of chronic spontaneous urticaria (CSU) in childhood-onset systemic lupus erythematosus (cSLE) patients and possible associated factors are limited to a few case reports. The objectives of this study were to assess CSU in a large cSLE population, in order to evaluate the demographic data, clinical manifestations, disease activity/damage, laboratory abnormalities and treatment. Methods: A retrospective multicenter cohort study (Brazilian cSLE group) was performed in 10 Pediatric Rheumatology services and included 852 cSLE patients. CSU was diagnosed according to the guidelines of the European Academy of Allergy and Clinical Immunology, the Global Allergy and Asthma European Network, the European Dermatology Forum and the World Allergy Organization. Patients with CSU (evaluated at urticaria diagnosis) and patients without CSU (evaluated at the last visit) were assessed for lupus clinical/laboratory features and treatment. Results: CSU was observed in 10/852 cSLE patients (1.17%). The median of cSLE duration at urticaria diagnosis was 0 (-3 to 5) years. Comparison of cSLE patients with and without CSU revealed a greater frequency of constitutional symptoms (40 vs. 8%, p = 0.006), reticuloendothelial system involvement (30 vs. 3%, p = 0.003), mucocutaneous (90 vs. 28%, p < 0.0001) and musculoskeletal manifestations (50 vs. 6%, p < 0.0001) and methylprednisolone pulse therapy use (60 vs. 9%, p < 0.0001) in the former group. The frequency of immunosuppressive treatment was lower in patients with CSU (p = 0.018). The median SLE Disease Activity Index 2000 (12 vs. 2, p < 0.0001) and erythrocyte sedimentation rate (40 vs. 19 mm/1st hour, p = 0.024), was higher in patients with CSU. Conclusions: To our knowledge, this is the first study with evidence that CSU may be linked to cSLE. We also demonstrated that this particular skin manifestation occurs predominantly at disease onset and is associated with lupus moderate/high disease activity without major organ involvement.

Evans Syndrome at Childhood-Onset Systemic Lupus Erythematosus Diagnosis: A Large Multicenter Study.

Evans syndrome (ES) in childhood‐onset systemic lupus erythematosus (cSLE) patients has been rarely reported and limited to small populations.

Herpes zoster infection in childhood-onset systemic lupus erythematosus patients: a large multicenter study

Objective The aim of this multicenter study in a large childhood-onset systemic lupus erythematosus (cSLE) population was to assess the herpes zoster infection (HZI) prevalence, demographic data, clinical manifestations, laboratory findings, treatment, and outcome. Methods A retrospective multicenter cohort study (Brazilian cSLE group) was performed in ten Pediatric Rheumatology services in São Paulo State, Brazil, and included 852 cSLE patients. HZI was defined according to the presence of acute vesicular-bullous lesions on erythematous/edematous base, in a dermatomal distribution. Post-herpetic neuralgia was defined as persistent pain after one month of resolution of lesions in the same dermatome. Patients were divided in two groups for the assessment of current lupus manifestations, laboratory findings, and treatment: patients with HZI (evaluated at the first HZI) and patients without HZI (evaluated at the last visit). Results The frequency of HZI in cSLE patients was 120/852 (14%). Hospitalization occurred in 73 (61%) and overlap bacterial infection in 16 (13%). Intravenous or oral aciclovir was administered in 113/120 (94%) cSLE patients at HZI diagnosis. None of them had ophthalmic complication or death. Post-herpetic neuralgia occurred in 6/120 (5%). After Holm–Bonferroni correction for multiple comparisons, disease duration (1.58 vs 4.41 years, p < 0.0001) was significantly lower in HZI cSLE patients compared to those without HZI. Nephritis (37% vs 18%, p < 0.0001), lymphopenia (32% vs 17%, p < 0.0001) prednisone (97% vs 77%, p < 0.0001), cyclophosphamide (20% vs 5%, p < 0.0001) and SLE Disease Activity Index 2000 (6.0 (0–35) vs 2 (0–45), p < 0.0001) were significantly higher in the former group. The logistic regression model showed that four independent variables were associated with HZI: disease duration < 1 year (OR 2.893 (CI 1.821–4.597), p < 0.0001), lymphopenia <1500/mm3 (OR 1.931 (CI 1.183–3.153), p = 0.009), prednisone (OR 6.723 (CI 2.072–21.815), p = 0.002), and cyclophosphamide use (OR 4.060 (CI 2.174–7.583), p < 0.0001). Conclusion HZI is an early viral infection in cSLE with a typical dermatomal distribution. Lymphopenia and immunosuppressive treatment seem to be major factors underlying this complication in spite of a benign course.

Pyomyositis in childhood-systemic lupus erythematosus

Pyomyositis is a pyogenic infection of skeletal muscle that arises from hematogenous spread and usually presents with localized abscess. This muscle infection has been rarely reported in adult-onset systemic lupus erythematous and, to the best of our knowledge, has not been diagnosed in pediatric lupus population. Among our childhood-onset systemic lupus erythematous population, including 289 patients, one presented pyomyositis. This patient was diagnosed with childhood-onset systemic lupus erythematous at the age of 10 years-old. After six years, while being treated with prednisone, azathioprine and hydroxychloroquine, she was hospitalized due to a 30-day history of insidious pain in the left thigh and no apparent trauma or fever were reported. Her physical examination showed muscle tenderness and woody induration. Laboratory tests revealed anemia, increased acute phase reactants and normal muscle enzymes. Computer tomography of the left thigh showed collection on the middle third of the vastus intermedius, suggesting purulent stage of pyomyositis. Treatment with broad-spectrum antibiotic was initiated, leading to a complete clinical resolution. In conclusion, we described the first case of pyomyositis during childhood in pediatric lupus population. This report reinforces that the presence of localized muscle pain in immunocompromised patients, even without elevation of muscle enzymes, should raise the suspicion of pyomyositis. A prompt antibiotic therapy is strongly recommended.

Brazilian Guidelines for Hereditary Angioedema Management - 2017 Update Part 1: Definition, Classification and Diagnosis

Hereditary angioedema is an autosomal dominant disease characterized by recurrent angioedema attacks with the involvement of multiple organs. The disease is unknown to many health professionals and is therefore underdiagnosed. Patients who are not adequately diagnosed and treated have an estimated mortality rate ranging from 25% to 40% due to asphyxiation by laryngeal angioedema. Intestinal angioedema is another important and incapacitating presentation that may be the main or only manifestation during an attack. In this article, a group of experts from the “Associação Brasileira de Alergia e Imunologia (ASBAI)” and the “Grupo de Estudos Brasileiro em Angioedema Hereditário (GEBRAEH)” has updated the Brazilian guidelines for the diagnosis and treatment of hereditary angioedema.

Hereditary Angioedema with Normal C1 Inhibitor and F12 Mutations in 42 Brazilian Families.

BACKGROUND Hereditary angioedema (HAE) with normal C1 inhibitor (C1-INH) is a rare condition with clinical features similar to those of HAE with C1-INH deficiency. Mutations in the F12 gene have been identified in subsets of patients with HAE with normal C1-INH, mostly within families of European descent. OBJECTIVES Our aim was to describe clinical characteristics observed in Brazilians from 42 families with HAE and F12 gene mutations (FXII-HAE), and to compare these findings with those from other populations. METHODS We evaluated a group of 195 individuals, which included 102 patients clinically diagnosed with FXII-HAE and their 93 asymptomatic relatives. RESULTS Genetic analysis revealed that of the 195 subjects, 134 individuals (77.6% females) carried a pathogenic mutation in F12. The T328K substitution was found in 132 individuals, and the c.971_1018+24del72 deletion was found in 2 patients. The mean age at onset of symptoms in patients with FXII-HAE was 21.1 years. The most common symptoms were subcutaneous edema (85.8% of patients), abdominal pain attacks (69.7%), and upper airway edema (32.3%). Of male individuals carrying F12 mutations, 53.3% (16 of 30) were symptomatic. Compared with reports from Europe, fewer female patients (68.6%) reported an influence of estrogen on symptoms. CONCLUSIONS Our study included a large number of patients with FXII-HAE, and, as the first such study conducted in a South American population, it highlighted significant differences between this and other study populations. The high number of symptomatic males and patients with estrogen-independent FXII-HAE found here suggests that male sex and the absence of a hormonal influence should not discourage clinicians from searching for F12 mutations in cases of HAE with normal C1-INH.

129 Panniculitis in childhood-onset systemic lupus erythematosus: a multicentric cohort study

Background and Aims To evaluate prevalence, clinical manifestations, laboratory abnormalities, treatment and outcome in a multicenter cohort of childhood-onset systemic lupus erythematosus(cSLE) patients with and without panniculitis. Methods Panniculitis was diagnosed due to painful subcutaneous nodules and/or plaques in deep dermis/subcutaneous tissues and lobular/mixed panniculitis with lymphocytic lobular inflammatory infiltrate in skin biopsy. Statistical analysis was performed using Bonferroni correction(p<0.004). Results Panniculitis was observed in 6/847 (0.7%) cSLE. Painful subcutaneous erythematosus and indurated nodules were observed in 6/6 panniculitis patients and painful subcutaneous plaques in 4/6. Generalised distribution was evidenced in 3/6 and localised in upper limbs in 2/6 and face in 1/6. Histopathology features showed lobular panniculitis without vasculitis in 5/6(one of them had concomitant obliterative vasculopathy due to antiphospholipid syndrome) and panniculitis with vasculitis in 1/6. Comparison between cSLE with panniculitis and 60 cSLE without panniculitis with same disease duration [2.75 (0–11.4) vs. 2.83 (0–11.8) years, p=0.297], showed higher frequencies of constitutional involvement (67% vs. 10%,p=0.003), leukopenia (67% vs. 7%, p=0.002) and median C-reactive protein (10.5 vs. 0.5 mg/L, p=0.001). Cutaneous atrophy and hyperpigmentation occurred in 83% of patients. Conclusions Panniculitis is a rare skin manifestation of cSLE occurring in the first three years of disease with considerable sequelae. The majority of patients have concomitant mild lupus manifestations.

Anafilaxia a cloridrato de benzidamina: relato de caso

RESUMO 1. Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto, Departamentos de Clínica Médica e Pediatria, Ribeirão Preto, SP, Brasil. 316 Reações de hipersensibilidade a medicamentos (RHM) podem induzir manifestações clínicas heterogêneas, desde leves até graves. São classificadas em imunológicas ou alérgicas quando mediadas por anticorpos ou linfócitos T, e não imunológicas quando decorrentes de efeitos farmacológicos da droga, incluindo inibição da enzima cicloxigenase (Cox). Os dois grupos mais frequentemente implicados nas RHM são os anti-inflamatórios não esteroidais (AINEs), e os antibióticos betalactâmicos. O manejo adequado das reações aos AINEs depende da identificação do mecanismo fisiopatológico envolvido, que permitirá classificar em reator seletivo (indivíduo que reage a um único fármaco e a outros com estrutura química similar), ou reator múltiplo ou intolerante cruzado (aquele que reage a múltiplos fármacos de estrutura química não relacionada). O cloridrato de benzidamina (CBZ) é um AINE de uso frequente e relativamente seguro, sem descrições de reações graves associadas ao seu uso. Atua inibindo as enzimas Prostaglandina Endoperoxidase H Sintase 1 e/ou 2, e a Fosfolipase A2. Em pacientes com história de reações aos AINEs, o teste de provocação é a ferramenta diagnóstica padrão ouro para confirmar ou excluir a reatividade cruzada a outros AINEs e definir um fármaco alternativo seguro. Descreveremos um caso raro de anafilaxia ao CBZ durante teste de provocação oral. Descritores: Benzidamina, anti-inflamatórios não esteroidais, hipersensibilidade a drogas, anafilaxia. Hypersensitivity drug reactions (HDRs) may induce mild to severe heterogeneous clinical manifestations. They are classified as immunological or allergic when mediated by antibodies or T lymphocytes, and non-immunological when resulting from pharmacological effects of the drug, including inhibition of the cyclooxygenase (Cox) enzyme. The two groups of drugs most frequently implicated in HDRs are non-steroidal anti-inflammatory drugs (NSAIDs) and beta-lactam antibiotics. Appropriate management of NSAID reactions depends on identification of the pathophysiological mechanism involved, which will allow to classify the patient as selective reactor (patient reacting to a single drug and others with similar chemical structure) or multiple or cross-intolerant reactor (patient reacting to multiple drugs with unrelated chemical structure). Benzydamine hydrochloride (BZH) is a frequently used, relatively safe NSAID for which descriptions of severe reactions are not available. BZH acts inhibiting the enzymes prostaglandin endoperoxide H synthase (PGHS) 1 and/ or 2 and phospholipase A2. In patients with a history of NSAID reactions, the challenge test is the gold standard diagnostic tool to confirm or exclude cross-reactivity to other NSAIDs, and to define a safe alternative drug. In this paper, we describe a rare case of anaphylaxis to BZH during an oral drug provocation test.

SAT0253 Evans Syndrome at Childhood-Onset Systemic Lupus Erythematosus Diagnosis: A Large Multicenter Study

Background Evans syndrome (ES) is an uncommon manifestation characterized by autoimmune destruction of red cells and platelets and concomitant or sequential appearance of immune thrombocytopenia (ITP) and autoimmune hemolytic anemia (AIHA). This involvement has been associated to severe disease activity in adult patients with systemic lupus erythematosus (SLE), particularly at disease onset. However, ES studies in childhood-onset SLE (cSLE) patients have been rarely reported and limited to small populations. Objectives The objective of the present multicenter study was to assess ES in a large cSLE cohort at diagnosis evaluating prevalence, clinical features, laboratory findings and outcomes. Methods A retrospective multicenter cohort study (Brazilian cSLE group) was performed in 10 Pediatric Rheumatology services including 850 patients with cSLE (ACR criteria). None of them had secondary etiologies of autoimmune cytopenias, such as infections, primary immunodeficiencies and malignancies. Patients were divided in two groups for the assessment of lupus manifestations, laboratory exams and treatment at cSLE diagnosis: patients with ES and patients without ES. Results ES was observed in 11/850 (1.3%) cSLE patients at diagnosis. The majority of them had hemorrhagic manifestations (58%) and active disease (82%). All patients with ES were hospitalized and none of them died. Comparisons of cSLE patients with and without ES at diagnosis revealed similar frequencies of female gender, multi-organ involvement, autoantibody profile and low complement levels (p>0.05). Patients with ES had a lower frequency of malar rash (9% vs. 53%, p=0.003) and musculoskeletal involvement (18% vs. 69%, p=0.001) than those without this complication. The median of hemoglobin [7.4 (5.4–9.4) vs. 10.3 (3.5–16.4)g/dL, p<0.001] and platelets [27 (15–54) vs. 231 (2–761)x103/mm3, p=0.005] were significantly lower in ES compared to non-ES patients, whereas lymphocytes were significantly higher in ES patients [1.8 (1–2.38) vs. 1.16 (0.07–7)x103/mm3, p<0.001]. The frequencies of intravenous methylprednisolone (82% vs. 43%, p=0.013) and intravenous immunoglobulin use (64% vs. 3%, p<0.0001) were significantly higher in the former group. Current prednisone dose between the two groups was similar [1.1 (0.76–1.5) vs. 1.0 mg/kg/day (0–30), 0.195]. Conclusions Our large multicenter study identified that ES was a rare and severe cSLE manifestation with a difficult diagnosis due to the absence of typical lupus manifestations, often requiring hospitalization and intravenous treatment. Disclosure of Interest G. Lube: None declared, M. Ferriani: None declared, L. Campos: None declared, M. Terreri: None declared, E. Bonfá: None declared, C. Magalhães: None declared, N. Aikawa: None declared, D. Piotto: None declared, O. Peracchi: None declared, M. C. Santos: None declared, S. Appenzeller: None declared, V. Ferriani: None declared, R. Pereira: None declared, C. Silva Grant/research support from: Conselho Nacional de Desenvolvimento Científico e Tecnolόgico (CNPq 302724/2011–7 to CAS), Federico Foundation (to CAS) and by Núcleo de Apoio à Pesquisa “Saúde da Criança e do Adolescente” da USP (NAP-CriAd) to CAS