Prevalence of tissue transglutaminase antibodies and IgA deficiency are not increased in juvenile idiopathic arthritis: a case-control study.

BACKGROUND: The prevalence of Celiac Disease (CD) in Juvenile Idiopathic Arthritis (JIA) has been reported to be 0.1-7% in various small studies. As a result of the limited number of research and their inconclusive results there are no clear recommendations for routine CD screening in asymptomatic patients with JIA. Our aim is to estimate the prevalence of IgA deficiency and tissue transglutaminase (tTG) IgA in a cohort of JIA followed in two large academic medical centers. METHODS: Serum was collected and stored from all subjects and analyzed in a reference laboratory for total IgA (Quantitative Nephelometry) and tTG IgA antibody levels (Semi-Quantitative Enzyme-Linked Immunosorbent Assay). Fisher's exact tests were performed for statistical significance. Risk estimates (odds ratios) with 95% confidence intervals were calculated. RESULTS: 808 JIA cases and 140 controls were analyzed. Majority were non-Hispanic whites (72% vs. 68% p = 0.309). A total of 1.2% of cases were IgA deficient compared to none of the controls (p = 0.373). After excluding IgA deficient subjects, 2% of cases had tTG IgA ≥ 4u/mL compared to 3.6% of controls (p = 0.216) (OR = 0.5; 95% C.I = 0.1-1.4); and 0.8% of cases had tTG IgA > 10u/mL compared to 1.4% of controls (p = 0.627) (OR = 0.5; 95%C.I = 0.1-2.9). CONCLUSIONS: Using the largest JIA cohort to date to investigate prevalence of celiac antibodies, the prevalence of positive tTG IgA was 0.8% and of IgA deficiency was 1.2%. The results did not demonstrate a higher prevalence of abnormal tTG IgA in JIA. The study did not support the routine screening of asymptomatic JIA patients for CD.

Selective IgA Deficiency with Multiple Autoimmune Comorbidities: A Case Report and Literature Review.

Case: Individuals with Selective Immunoglobulin-A Deficiency (SIgAD) are often asymptomatic, and symptomatic SIgAD patients often have autoimmune comorbidities. A 48-year-old Han Chinese man presented with abdominal discomfort, hematochezia, and a large tumor in the anogenital region. The primary diagnosis of SIgAD was based on the patient's age, serum IgA concentration (0.067 g/L), and the evidence of chronic respiratory infection. No other immunoglobulin deficiency or evidence of immunosuppression was present. The primary diagnosis of giant condyloma acuminatum was based on human papilloma virus-6-positive laboratory results and histological characteristics. The tumor and adjacent skin lesions were resected. Hemoglobin concentration fell to 5.50 g/dL, and an emergency erythrocyte transfusion was performed. The body temperature increased to 39.8 ºC, suggesting a transfusion reaction, and 5 mg dexamethasone was administered intravenously. Hemoglobin concentration stabilized at 10.5 g/dL. The clinical signs and laboratory results indicated autoimmune hemolytic anemia, systemic lupus erythematosus, and Hashimoto's thyroiditis. Abdominal discomfort and hematochezia subsided. Though uncommon, the manifestation of multiple autoimmune comorbidities can occur in SIgAD patients. Further research is needed regarding the causes of SIgAD and the autoimmune disorders that often occur as comorbidities.

Study of the immune response in celiac patients with selective IgA deficiency who start a gluten-free diet.

Studies are scarce regarding IgG anti-tissue transglutaminase 2 (tTG) normalization in selective IgA deficient (SIgAD) celiac disease (CD) patients after beginning a gluten free diet (GFD). The aim of this study is to analyse the decreasing dynamics of IgG anti-tTG in patients diagnosed with CD who start a GFD. To achieve this objective, IgG and IgA anti-tTG levels at diagnosis and during follow-up in 11 SIgAD CD patients and in 20 IgA competent CD patients were retrospectively evaluated. At diagnosis, statistical differences were not found when comparing IgA anti-tTG levels of IgA competent subjects with IgG anti-tTG levels of SIgAD subjects. Regarding the decreasing dynamics, even though no statistical differences were found (p = 0.06), normalization rates were slower for SIgAD CD patients. After 1 and 2 years on GFD, respectively, only 18.2% and 36.3% of the SIgAD CD patients normalized IgG anti-tTG levels; otherwise, IgA anti-tTG reached values under the reference values in 30% and 80% of the IgA competent patients in the same time-points. Although IgG anti-tTG has demonstrated a high diagnostic efficiency in SIgAD CD pediatric patients, this test does not appear to be as precise for long-term GFD response monitoring as IgA anti-tTG levels in IgA sufficient patients.

Teste de antigliadina deaminada IgG para crianças com até 2 anos de idade e com suspeita de doença celíaca / IgG deaminated antigliadin test for children aged 2 years or older with suspected celiac disease

INTRODUÇÃO: A Doença Celíaca (DC) é uma doença autoimune crônica do intestino delgado caracterizada por intolerância permanente ao glúten. A sua prevalência global é de aproximadamente 1%. No Brasil, essa prevalência foi relatada em cerca de 0,54% em crianças (1-14 anos). O rastreamento por sorologia associado à confirmação por biópsia duodenal é padrão ouro para o diagnóstico em adultos e em crianças, mas a biópsia precisa ser bem indicada na prática pediátrica por ser um procedimento invasivo e potencialmente de alto risco. Os testes sorológicos para detectar anticorpos IgA são comumente utilizados, porém indivíduos com deficiência de IgA não podem ser diagnosticados/rastreados por esses testes, justamente porque apresentam déficit na síntese de todas as imunoglobulinas do tipo A. Uma alternativa de triagem para esses indivíduos, bem como para os menores de 2 anos, é a dosagem sérica dos anticorpos IgG, como o teste antigliadina deaminada IgG. PERGUNTA DE PESQUISA: O uso do teste sorológico antigliadina deaminada IgG para triagem é mais acurado e custo-efetivo em pacientes com deficiência de IgA e suspeita de doença celíaca e crianças menores de dois anos quando comparado à triagem com antitransglutaminase IgA e confirmação por biópsia de duodeno por via endoscópica (endoscopia digestiva alta + biópsia)? EVIDÊNCIAS CIENTÍFICAS: Este relatório incluiu oito estudos que avaliaram se o uso do teste sorológico antigliadina deaminada IgG é mais acurado em pacientes com deficiência de IgA e suspeita de doença celíaca de qualquer idade e crianças menores de dois anos quando comparado à biópsia de duodeno por via endoscópica para diagnóstico da doença celíaca. Segundo os resultados das metanálises apresentadas neste relatório, para as análises da acurácia obtidas por meio da sensibilidade e especificidades combinadas, destaca-se a boa especificidade do teste antigliadina deaminada IgG em crianças menores de dois anos, utilizando o ponto de corte determinado pelo fabricante (97,8%; IC95% 95,6% - 98,9%). Já a especificidade combinada foi máxima (100,0%; IC95%:0,0 - 100,0%), potencializando o valor preditivo negativo do teste antigliadina deaminada IgG neste grupo populacional. Estes achados mostram que a adição do teste antigliadina deaminada IgG pode melhorar a acurácia diagnóstica da detecção de DC em crianças menores de dois anos de idade. AVALIAÇÃO ECONÔMICA (AE): Conduziu-se análise de custo-efetividade para comparar os testes diagnósticos com base em suas efetividades e seus custos, por meio da razão de custoefetividade incremental (RCEI). Considerando-se as diferenças observadas no desempenho do teste para crianças menores de dois anos e indivíduos com deficiência de IgA e suspeita de doença celíaca, foram propostas duas árvores de decisão. No caso de indivíduos com deficiência de IgA, a realização de teste antigliadina deaminada associada à EDA com biópsia, comparada à antigliadina deaminada isolada resultaria em razão de custo-efetividade incremental (RCEI) de R$ 108,17 por biópsia evitada. Para a comparação entre antigliadina deaminada isolada e EDA com biópsia, a RCEI seria de R$ 2.063,16 por biópsia evitada. ANÁLISE DE IMPACTO ORÇAMENTÁRIO (AIO): Considerando a população elegível total e suspeita de doença celíaca, o cenário alternativo 01 (market share variando de 30% a 50%) provocaria uma economia de R$ 30.671.133,25, no caso da incorporação do teste antigliadina em substituição aos testes atuais. Já o cenário alternativo 02 (market share de 50% a 70%) de substituição dos testes atuais pelo teste da antigliadina provocaria também economia de R$ 46.018.687,48. Já no cenário em que o teste antigliadina seja adicionado aos testes atuais, ao invés de substituí-los, o impacto orçamentário acumulado em cinco anos seria de R$ 14.410.515,92. CONSIDERAÇÕES FINAIS: Segundo os resultados das metanálises apresentadas neste relatório, destaca-se a boa especificidade do teste de antigliadina deaminada IgG em crianças menores de dois anos, utilizando o ponto de corte determinado pelo fabricante (97,8%; IC95% 95,6% - 98,9%). Já a especificidade combinada foi máxima (100,0%; IC95%:0,0 ­ 100,0%), potencializando o valor preditivo negativo do teste de antigliadina deaminada IgG neste grupo populacional. Para a população de indivíduos com deficiência de IgA, a sensibilidade combinada foi de 76,7% (IC 95%: 54,7% a 90,0%) e a especificidade de 73,3% (IC 95%: 60,6% a 83,0%). A taxa de falsos positivos global correspondeu a 26,7% (IC 95%: 17,0% a 39,4%). Contudo, os achados devem ser interpretados com cautela, uma vez que os estudos primários incluídos foram considerados de qualidade metodológica baixa e muito baixa qualidade da evidência. Um dos estudos incluídos neste relatório é uma revisão sistemática cujo divergiu do encontrado na meta-análise feita pelo grupo elaborador. Enquanto a sensibilidade para o teste antigliadina deaminada IgG em relação à biópsia duodenal foram de 0,96 (IC 95% 0,91 a 0,98) na revisão sistemática, a metaanálise deste relatório teve como resultado 0,48 (IC de 95%: 0,23 a 0,97). Essa divergência está relacionada ao ponto de corte utilizado para a inclusão dos estudos nas metaanálises. Em relação à confiança nos resultados da revisão sistemática em questão, os resultados estão associados a uma baixa confiabilidade. RECOMENDAÇÃO PRELIMINAR DA CONITEC: O tema foi avaliado na 113ª Reunião Ordinária da Conitec em 5 de outubro de 2022. A recomendação inicial foi desfavorável à incorporação do teste de antigliadina deaminada IgG para pessoas com deficiência de IgA por considerar que os testes atualmente disponíveis no SUS já atendem satisfatoriamente a população. Ademais, a recomendação inicial foi favorável à incorporação do teste de antigliadina deaminada IgG para pessoas menores de 2 anos de idade por evitar as hospitalizações necessárias para realização de endoscopia digestiva alta nessa população. CONSULTA PÚBLICA: Foram recebidas 18 contribuições, sendo cinco pelo formulário para contribuições técnico-científicas e 13 pelo formulário para contribuições sobre experiência ou opinião de pacientes, familiares, amigos ou cuidadores de pacientes, profissionais de saúde ou pessoas interessadas no tema. Em relação às contribuições de cunho técnico-científico, quatro concordaram que o teste antigliadina deaminada IgG deve ser incorporado ao SUS e uma não concordou. A Federação Nacional das Associações de Celíacos do Brasil (FENACELBRA) se manifestou contrária à recomendação de incorporação do teste diagnóstico e a favor de seguir a Sociedade Europeia de Gastroenterologia, Hepatologia e Nutrição Pediátrica (ESPGHAN), que sugere que seja realizada a dosagem de IgA total e antitransglutaminase IgA (antitTG) enquanto o paciente estiver consumindo glúten diariamente por cerca de 2 a 3 meses. No caso de crianças com concentração de IgA baixa, a contribuição indicou a necessidade de uma das seguintes sorologias IgG: antigliadina deaminada IgG, antiendomísio IgG ou antitransglutaminase IgG. Um participante foi contrário à premissa de que o resultado para o teste antigliadina deaminada IgG positivo deveria substituir a endoscopia e biópsia, o que foi corroborado por um especialista que participou do grupo elaborador. Dessa forma, uma avaliação econômica e análise de impacto orçamentário adicional foram realizadas com o objetivo de avaliar o impacto dessa premissa. A AE resultou numa RCEI custo-efetiva (R$ 1.254 por QALY ganho) e a AIO resultou em impacto orçamentário positivo de R$ 17.460.094 ao longo de cinco anos. Quanto às contribuições referentes ao formulário de experiência ou opinião, todos foram favoráveis à incorporação. RECOMENDAÇÃO FINAL DA CONITEC: As contribuições da consulta pública foram apresentadas à Conitec por ocasião da 117ª Reunião Ordinária, realizada em 29 de março de 2023. Os membros presentes deliberaram, por unanimidade, recomendar a incorporação do teste de antigliadina deaminada IgG para crianças com até 2 anos de idade e com suspeita de doença celíaca, porque, para essa população, o teste anti-gliadina tem alta acurácia diagnóstica, enquanto para os deficientes de IgA a acurácia diagnóstica foi considerada moderada e de impacto clínico incerto. O teste anti-gliadina deaminada IgG para crianças de até 2 anos de idade deverá ser incorporado conforme Protocolo Clínico do Ministério da Saúde. Por fim, foi assinado o Registro de Deliberação Nº 811 / 2023. DECISÃO: ncorporar, no âmbito do Sistema Único de Saúde - SUS, o teste de antigliadina deaminada IgG para crianças com até 2 anos de idade e com suspeita de doença celíaca, publicada no Diário Oficial da União nº 74, seção 1, página 195, em 18 de abril de 2023.

Pediatric Celiac Disease and Selective IgA Deficiency: Unexpected Sequence of Events.

PURPOSE: Selective IgA deficiency (IgAD) is the most common primary immunodeficiency, frequently leading to only minor clinical complaints. IgAD may be associated with autoimmune diseases such as celiac disease (CeD). Although IgAD is thought to precede CeD and autoimmunity, the association between the two conditions has not been clarified. METHODS: Routine techniques were used to measure serum IgA and celiac diagnostic markers as transglutaminase 2 IgA (TG2-IgA) and deamidated gliadin IgG and for immunohistochemistry for IgG, IgM, and IgA. RESULTS: We report two childhood cases of complete IgA deficiency that evolved after the diagnosis of CeD and the start of a gluten-free diet. Histology showed persistence of IgA in the intestinal mucosa. CONCLUSION: Both children with CeD showed IgA deficiency that unexpectedly developed after the initiation of a gluten-free diet. This supports IgA deficiency as a process that develops gradually and occurs due to specific defects in immunoregulation.

IgA deficiency and autoimmune comorbidities in Juvenile Idiopathic Arthritis.

OBJECTIVES: (1) To describe the prevalence of IgA deficiency (IgAD), uveitis, coeliac disease (CD) and thyroid disorders in a multicentric cohort of patients diagnosed with JIA and, (2) to evaluate whether patients with JIA and IgAD present other autoimmune diseases more frequently than patients with normal serum levels of IgA. METHODS: Retrospective chart review of a cohort of patients diagnosed with JIA followed at the paediatric rheumatology units of two hospitals in Madrid, Spain. RESULTS: A total of 193 patients were included. Of them, 123 were females (64%). Median age at disease onset was 5.6 years (IQR 2.5-9.7) and the median time of follow-up was 5.1 years (IQR 2.2-8.1). The three most common ILAR categories were oligoarticular (53%), polyarticular RF negative (20%) and enthesitis related arthritis (10%). Serum IgA levels were available in 172/193 (89%); 25/172 (15%) had selective (<7mg/dl, n=8) or partial (7-69mg/dl, n=17) IgAD. All the patients had periodic eye exams. Eighteen children (9%) had anterior uveitis, 15/18 chronic and 3/18 acute. Serum anti transglutaminase IgA, or IgG in IgAD were obtained in 135/193 (70%). Four children (3%) were diagnosed with CD either by intestinal biopsy (n=3) or by the combination of characteristic clinical, serological and genetic features (n=1); two of them had IgAD (p=0.12; OR=6.4; 95% CI 0.9-47.6). Only 1/153 (0.7%) patient had hyperthyrotropinemia with positive anti-thyroid antibodies and required replacement therapy. CONCLUSION: Patients with JIA frequently present autoimmune comorbidities. IgAD does not seem to increase their prevalence, with the possible exception of CD.

Anti-tissue transglutaminase (tTG) screening using relative light units to identify IgA deficiency.

IgA deficiency is more common in patients with coeliac disease (CD). Total IgA levels are often recommended as part of first line coeliac testing along with anti-tissue transglutaminase (tTG) IgA, to identify these patients and reduce falsely negative results. This study aimed to identify patients with complete IgA deficiency by determining a cut-off threshold on chemiluminescent tTG IgA testing. A chemiluminescent assay QUANTA Flash h-tTG was reviewed using the BIO-FLASH automated platform. tTG relative light units (RLU) were analysed in relation to total IgA levels. Correlation analysis was performed and distributions of tTG RLU were compared between the IgA deficient and IgA detectable groups, and ROC analysis was performed to identify a suitable threshold. A total of 203 samples were reviewed in our initial cohort. There was a strong correlation between IgA and tTG RLU levels (Pearson correlation coefficient 0.495, p<0.001). There was a statistically significant difference of 170.57 RLU between the means of the IgA deficient and IgA detectable group (p<0.001, 156.50-184.64). A receiver operating characteristic (ROC) curve was generated with area under the curve of 0.997. A cut-off of less than 300 tTG RLU for identification of IgA deficiency was chosen, which had a sensitivity and specificity of 100% and 98.9%, respectively. A prospective validation cohort was conducted which confirmed the initial results. Our study has validated an algorithm to identify complete IgA deficiency by implementing a threshold of 300 RLU during tTG IgA testing by chemiluminescent immunoassay. This approach resulted in a sensitivity of 100% to detect patients with complete IgA deficiency. Widespread uptake would result in improved workflow, workload and turnaround time, and reduce the need for unnecessary blanket testing of total IgA in the screening for coeliac disease.

Evaluation of the Usefulness of a Serological Test for Diagnosis of Celiac Disease Simultaneously Detecting Specific Antibodies and Total IgA.

The diagnosis of celiac disease (CD) at the first diagnostic step requires the detection of specific class A antibodies to tissue transglutaminase type-2 (TG2 IgA) and the measurement of total immunoglobulin A (tIgA) to exclude IgA deficiency. The aim of the study was to evaluate the new quantitative immunoassay panel allowing for the detection of celiac-specific antibodies with the simultaneous determination of tIgA from the same sample of blood at one time. This retrospective study included 104 pediatric patients divided into groups with recognized CD and IgA deficiency (n = 20; 19%), immunocompetent children with CD (n = 28; 27%), children with IgA deficiency and without CD (n = 28; 27%), and the control group of immunocompetent children without CD (n = 28; 27%). Intestinal biopsy with histopathological evaluation (except five patients with CD who were diagnosed without biopsy) and measurement of reference celiac specific antibodies were performed in all children. Multiparametric quantitative immunoassay Polycheck® Celiac IgA plus total IgA test was used to evaluate its usefulness in CD screening and IgA deficiency diagnosis. The statistical analysis showed the high sensitivity and specificity of both TG2 IgA and tIgA on the multiparametric panel (sensitivity 96% and 100%; specificity 100% and 79%, respectively). The accuracy and area under the ROC curve for tIgA were 0.904 and 0.955, while for TG2 IgA they were 0.982 and 1.000, respectively. Although the sensitivity of IgA antibodies against deaminated gliadin peptides was low (20%), the specificity reached 100%. The study showed that Polycheck® Celiac IgA plus total IgA test is a specific and sensitive tool for simultaneous serological CD screening and recognition of IgA deficiency.

The Prevalence of Selective and Partial Immunoglobulin A Deficiency in Patients with Autoimmune Polyendocrinopathy.

BACKGROUND: Autoimmune disorders are reported as presenting signs in patients with immunoglobulin A (IgA) deficiency. Herein, we aim to evaluate serum IgA among patients with autoimmune polyendocrinopathy. METHODS: Patients with two or more autoimmune endocrinopathies were selected and the serum IgA levels were measured. Patients with an isolated low serum IgA (<7 mg/dL) after exclusion of other causes of hypogammaglobulinemia were considered as selective IgA deficiency (SIgAD), while partial IgA deficiency (PIgAD) was defined as IgA levels below lower limits of IgA normal range for age but higher than 7 mg/dL. RESULTS: Fifty-three patients (19 [35.8%] male and 34 [64.2%] female) with autoimmune polyendocrinopathy enrolled in the study. Parental consanguinity and positive family history of autoimmunity were reported in 38.0% and 52.9% of patients, respectively. Overall, IgA deficiency was observed in 5 (9.4%) patients including PIgAD in 3 (5.7%) and SIgAD in 2 (3.8%) patients. Among IgA deficient patients, the first autoimmune disorder was developed at earlier ages (p = .002), and the prevalence of infection (p = .002), lymphoproliferation (p = .021), and overlap between insulin-dependent diabetes mellitus and autoimmune thyroiditis (p = .032) were significantly higher than patients with normal IgA. Also, the number of autoimmune comorbidities was closely correlated with the occurrence of IgA deficiency (p = .008). CONCLUSION: The prevalence of IgA deficiency in patients with autoimmune polyendocrinopathy is higher than that in the general population. In these patients, immunologic workup may lead to early diagnosis of inborn error of immunity, which can positively impact the evolution of complications and even management of the autoimmune disorders.

IgA Deficiency Is Not Systematically Ruled Out in Patients Undergoing Celiac Disease Testing.

BACKGROUND: Guidelines for celiac disease (CD) testing recommend total serum IgA determination alongside anti-transglutaminase IgA antibodies. It is not well known if lack of serum IgA determination is a common finding in clinical practice. AIM: To determine the prevalence of lack of serum IgA determination among patients screened for celiac disease. MATERIALS AND METHODS: We identified all subjects who underwent serum anti-transglutaminase IgA and/or other CD-related antibodies determination at a single teaching hospital in Buenos Aires from October 2019 to February 2020. Medical records were reviewed to select adult patients who were tested for celiac disease. The primary outcome was the proportion of patients with inadequate testing for celiac disease due to lack of serum IgA determination. We retrieved the following variables from each patient's record: age, gender, body mass index, symptoms present at screening, first-grade family history of CD, history of type-1 diabetes mellitus, autoimmune hypothyroidism, Down's syndrome. RESULTS: Overall, 1122 patients were included for analysis. Lack of serum IgA determination prevalence was 20.49%. Among patients who did have serum IgA determination, the prevalence of IgA deficiency was 5.16%. The following variables were independently associated with a significantly increased odds of serum IgA determination: diarrhea [OR 1.55 (1.01-2.34)] and abdominal pain [OR 2.28 (1.44-3.63)]; higher body mass index [OR 0.91 (0.85-0.98)], osteoporosis [OR 0.49 (0.28-0.89)], hypothyroidism [OR 0.18 (0.07-0.45)], arthralgia/arthritis [OR 0.47 (0.27-0.85)], or testing by endocrinologist [OR 0.46 (0.23-0.91)] and gynecologist [OR 0.14 (0.06-0.31)] were inversely associated. CONCLUSION: IgA deficiency is not systematically ruled out in a relatively high proportion of patients undergoing serological screening of celiac disease.

Serum Protein Electrophoresis May Be Used as a Screening Tool for Antibody Deficiency in Children and Adolescents.

Background: Patients with antibody deficiency may experience exceptionally long diagnostic delays, increasing the risk of life-threatening infections, end-organ damage, mortality, and health costs. Objective: This study aimed to analyze serum protein electrophoresis and verify the correlation between calculated globulin (CG, total protein minus albumin levels) or electrophoretically determined serum gamma globulin fraction (Gamma) with IgG levels in children and adolescents under 18 years old (yo). Methods: We analyzed serum protein electrophoresis (GC or Gamma) and IgG levels from 1215 children and adolescents under 18 yo, classified into 5 age groups. We verified the correlation between CG or Gamma with serum IgG levels. Results: Serum IgG levels varied according to age groups (from 4.3 ± 2.3 g/l in children under 6 months old to 11.4 ± 3.2 g/l in adolescents in the 10-<18 yo group). CG sensitivity and specificity to detect IgG below the reference range for all patients were 93.1% and 81.8%, respectively, and varied according to age group. Gamma sensitivity and specificity for all patients were 100% and 87.8%, respectively, and varied according to age group as well. We found serum IgG levels below the age reference level in 29 patients (2.4% of the cases) using CG or Gamma levels. Conclusion: Both CG and Gamma levels may be of utility as a screening tool for earlier diagnosis of antibody deficiency in children and adolescents under 18 yo.

[Selective IgA deficiency]. / Le déficit sélectif en IgA.

Selective IgA deficiency (SIgAD) is defined by the European Society for Immunodeficiencies (ESID) as a serum IgA of less than 0.07g/L in patients greater than 4 years old with normal levels of IgG and IgM, normal vaccine responses, and with the exclusion of secondary causes of hypogammaglobulinemia. When serum IgA level is higher than 0.07g/L but two standard deviations below normal for age, the condition may be referred to as partial IgA deficiency, which is quite common. SIgAD is the most common primary immunodeficiency in Europe (1/600 in France) and most patients with SIgAD are asymptomatic (75-90%). The clinical complications associated with SIgAD include recurrent respiratory infections (in particular involving Haemophilus influenza and Streptococcus pneumoniae) and gastrointestinal (mainly due to Giardialamblia), autoimmune and allergic manifestations (anaphylaxis if blood products with IgA are administrated), inflammatory gastrointestinal disease. There is no specific treatment for SIgAD and each patient must be managed individually. While asymptomatic subjects do not need any treatment, it is still necessary for them to be up-to-date with vaccinations. If the patient experiences recurrent infections, prophylactic antibiotics may be beneficial. Immunoglobulin replacement therapy should be considered in patients with SIgAD and concomitant IgG subclass deficiency. Treatment for autoimmune and allergic manifestations is based on current standards of care for specific disease entities. To improve quality of life and reduce morbidity, an interdisciplinary team approach is essential.

[Prevalence and characteristics of selective IgA deficiency in celiac patients]. / Prevalencia y características de la deficiencia selectiva de IgA en pacientes celíacos.

INTRODUCTION: Celiac disease is a multisystemic autoimmune disease that mainly affects the small intestine. Selective Immunoglobulin A deficiency is the most common primary immunodeficiency in the general population, with an incidence of 1%. It is estimated that it affects 2%-3% of celiac disease and 6.5% of patients with this deficit have celiac disease, observing the important association between both. OBJECTIVES: To determine the prevalence of selective Immunoglobulin A deficiency in celiac patients. Describe the clinical, serological, and histological presentation and its association with autoimmune diseases. MATERIALS AND METHODS: Cross-sectional, descriptive, and retrospective study in celiac patients with Immunoglobulin A dosing in the period from March 2005 to March 2020, at the Gastroenterology Clinic, Hospital de Clínicas, Montevideo-Uruguay. RESULTS: 343 patients were included. Seven patients presented selective Immunoglobulin A deficiency (2%). All were female with a mean age of 20 years (4-36). Selective total immunoglobulin A deficiency was observed in 6 patients (85%) and only 1 (15%) had partial deficiency. Tissue transglutaminase antibody immunoglobulin A and antiendomysium antibody were negative in patients with selective total immunoglobulin A deficiency and positive in those with partial deficiency. All presented villous atrophy, gastrointestinal symptoms, and a lower incidence of autoimmune diseases compared to the reference literature. CONCLUSIONS: The prevalence of selective immunoglobulin A deficiency in this celiac population (2%) is similar to that reported in other populations, reaffirming the importance of including immunoglobulin A dosing for the diagnosis of CD.

Diagnosing and Monitoring Celiac Patients with Selective IgA Deficiency: Still an Open Issue.

Although, the association between celiac disease (CD) and selective immunoglobulin A deficiency (SIgAD) has been known for more than fifty years, the procedures for diagnosing and monitoring patients with both conditions are still far from definitive. When serological markers were introduced as pre-bioptic investigations, it was immediately clear that searching for specific IgA antibodies without checking total serum IgA could lead to a failure in diagnosing IgA-deficient CD patients, while specific IgG antibodies could be useful as additional tests, because they are frequently found in the serum of affected patients. Nonetheless, until recently the diagnosis of CD in IgA-deficient patients was based on the few, fragmentary and often contradictory data available in literature. The introduction of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) guidelines in 2012 provided the current criteria for diagnosing CD in IgA-deficient patients, although some issues remained open, such as the selection of patients who should undergo specific IgG antibody testing and the choice of the most reliable IgG-based test for both diagnosis and follow-up. A real-life study recently assessed the impact of the 2012 ESPGHAN guidelines in diagnosing and monitoring CD in SIgAD patients, highlighting several pitfalls that can lead to operational uncertainties and difficulties in patient management. In the present report, the evolution of diagnostic tools and criteria for CD in SIgAD patients has been critically assessed, both strengths and open issues have been highlighted, and future perspectives for improving the current diagnostic protocols have been suggested.

Antithyroid Drug-Induced Lupus Erythematosus and Immunoglobulin A Deficiency.

BACKGROUND Antithyroid drugs, namely methimazole, are well-known causes of drug-induced lupus erythematosus. This is, however, an infrequent adverse effect. Selective Immunoglobulin A (IgA) deficiency, in contrast, is the most common primary immunodeficiency. Patients with IgA deficiency are at risk of developing infectious diseases, but also autoimmune diseases such as Grave's disease or systemic lupus erythematosus. CASE REPORT We report a case of methimazole-induced lupus erythematosus in a 32-year-old man with renal involvement and concomitant selective IgA deficiency. Symptoms promptly resolved after treatment with hydroxychloroquine and corticosteroids after discontinuation of methimazole. Lupus nephritis required treatment with cyclophosphamide followed by maintenance therapy with mycophenolate mofetil. CONCLUSIONS Drug-induced lupus erythematosus usually develops after a few months or years of exposure to the causative agent. No specific symptoms exist. The diagnosis is not based on particular specific tests, but relies on a set of arguments evoking the role of the medication inducing the condition. The first step in treatment is to stop the causative drug. The therapeutic management of the various manifestations does not differ from that of idiopathic systemic lupus erythematosus. We briefly discuss the relationship between drug-induced lupus erythematosus, Grave's disease, and IgA deficiency, and suggest that IgA deficiency may act as a potential risk factor. Testing for IgA deficiency could be helpful in patients being treated with drugs known to be associated with drug-induced lupus erythematosus.

Primary Humoral Immune Deficiencies: Overlooked Mimickers of Chronic Immune-Mediated Gastrointestinal Diseases in Adults.

In recent years, the incidence of immune-mediated gastrointestinal disorders, including celiac disease (CeD) and inflammatory bowel disease (IBD), is increasingly growing worldwide. This generates a need to elucidate the conditions that may compromise the diagnosis and treatment of such gastrointestinal disorders. It is well established that primary immunodeficiencies (PIDs) exhibit gastrointestinal manifestations and mimic other diseases, including CeD and IBD. PIDs are often considered pediatric ailments, whereas between 25 and 45% of PIDs are diagnosed in adults. The most common PIDs in adults are the selective immunoglobulin A deficiency (SIgAD) and the common variable immunodeficiency (CVID). A trend to autoimmunity occurs, while gastrointestinal disorders are common in both diseases. Besides, the occurrence of CeD and IBD in SIgAD/CVID patients is significantly higher than in the general population. However, some differences concerning diagnostics and management between enteropathy/colitis in PIDs, as compared to idiopathic forms of CeD/IBD, have been described. There is an ongoing discussion whether CeD and IBD in CVID patients should be considered a true CeD and IBD or just CeD-like and IBD-like diseases. This review addresses the current state of the art of the most common primary immunodeficiencies in adults and co-occurring CeD and IBD.

Seronegative Coeliac Disease Masquerading as Irritable Bowel Syndrome type Symptoms.

Coeliac disease affects 1% of the population but internationally delays in diagnosis are frequent. A relationship between irritable bowel syndrome type symptoms and coeliac disease is well established and most IBS guidelines recommend that patients presenting with IBS type symptoms should be tested serologically for coeliac disease. Seronegative coeliac disease accounts for 3-5% of all cases of coeliac disease and it is a diagnostic challenge which requires a high level of clinical suspicion and consideration of duodenal biopsies prior to confidently excluding this diagnosis. We report the first case of seronegative coeliac disease masquerading as IBS type symptoms. We suggest that if patients have evidence of haematinic deficiency, subsequent weight loss, features of malabsorption or a family history of coeliac disease, then a duodenal biopsy should be considered irrespective of negative serology.

Influence of the 2012 European Guidelines in Diagnosis and Follow-up of Coeliac Children With Selective IgA Deficiency.

OBJECTIVES: The aim of the study was to describe diagnostic criteria used in children with coeliac disease (CD) and selective IgA deficiency; to determine if the publication of the 2012 ESPGHAN criteria prompted any changes; to evaluate the evolution of serological markers. METHODS: Multicenter, retrospective, descriptive study of a cohort of children under 15 years with selective IgA deficiency diagnosed with CD (January 2006 to December 2016). Demographic, clinical, genetic, histological and IgG-based antibodies were collected at diagnosis and follow-up. RESULTS: Eighty-six children were included, 60 diagnosed after the guide. Two groups were established: G1 (n = 63) and G2 (n = 23) with or without diagnostic biopsy respectively. In G1: 87.3% were symptomatic, 87.3% had human leukocyte antigan (HLA) DQ2/DQ8 typing (all positive), all had IgG serology positive (71.5% ATG, 35% EMA, 19% DPG, 9.5% AGA), and all had villous atrophy (Marsh-Oberhuber 2-3). Follow-up data were available in 58 children, 34 after 2 years on a gluten-free diet. Fifty-two percentage remained ATG IgG-positive despite good dietary adherence and symptom remission. Regarding G2: all were diagnosed post-2012, had typical symptoms, HLA DQ2/DQ8 positive and ATG IgG × 10 ULN. Additionally, EMA IgG was performed in 14 (60%), all positive. CONCLUSIONS: In our cohort of children with selective IgA deficiency and diagnosed with CD, children without a diagnostic biopsy suggests that IgG serology was considered the equivalent as IgA isotype, even when this is not addressed in the aforementioned guidelines. Great heterogeneity was observed in the IgG serology used at diagnosis. After 2 years of a gluten-free diet, half of children remained with a positive serology.