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Objective To provide guidelines on the coronavirus disease 2019 (COVID-19) vaccination in patients with immune-mediated rheumatic diseases (IMRD) to rheumatologists considering specific scenarios of the daily practice based on the shared-making decision (SMD) process. Methods A task force was constituted by 24 rheumatologists (panel members), with clinical and research expertise in immunizations and infectious diseases in immunocompromised patients, endorsed by the Brazilian Society of Rheumatology (BSR), to develop guidelines for COVID-19 vaccination in patients with IMRD. A consensus was built through the Delphi method and involved four rounds of anonymous voting, where five options were used to determine the level of agreement (LOA), based on the Likert Scale: (1) strongly disagree; (2) disagree, (3) neither agree nor disagree (neutral); (4) agree; and (5) strongly agree. Nineteen questions were addressed and discussed via teleconference to formulate the answers. In order to identify the relevant data on COVID-19 vaccines, a search with standardized descriptors and synonyms was performed on September 10th, 2021, of the MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and LILACS to identify studies of interest. We used the Newcastle–Ottawa Scale to assess the quality of nonrandomized studies. Results All the nineteen questions-answers (Q&A) were approved by the BSR Task Force with more than 80% of panelists voting options 4—agree—and 5—strongly agree—, and a consensus was reached. These Guidelines were focused in SMD on the most appropriate timing for IMRD patients to get vaccinated to reach the adequate covid-19 vaccination response. Conclusion These guidelines were developed by a BSR Task Force with a high LOA among panelists, based on the literature review of published studies and expert opinion for COVID-19 vaccination in IMRD patients. Noteworthy, in the pandemic period, up to the time of the review and the consensus process for this document, high-quality evidence was scarce. Thus, it is not a substitute for clinical judgment.

ObjectivesTo evaluate risk factors associated with unfavourable outcomes: emergency care, hospitalisation, admission to intensive care unit (ICU), mechanical ventilation and death in patients with immune-mediated rheumatic disease (IMRD) and COVID-19.MethodsAnalysis of the first 8 weeks of observational multicentre prospective cohort study (ReumaCoV Brasil register). Patients with IMRD and COVID-19 according to the Ministry of Health criteria were classified as eligible for the study.Results334 participants were enrolled, a majority of them women, with a median age of 45 years; systemic lupus erythematosus (32.9%) was the most frequent IMRD. Emergency care was required in 160 patients, 33.0% were hospitalised, 15.0% were admitted to the ICU and 10.5% underwent mechanical ventilation; 28 patients (8.4%) died. In the multivariate adjustment model for emergency care, diabetes (prevalence ratio, PR 1.38; 95% CI 1.11 to 1.73; p=0.004), kidney disease (PR 1.36; 95% CI 1.05 to 1.77; p=0.020), oral glucocorticoids (GC) (PR 1.49; 95% CI 1.21 to 1.85; p50 years (PR 1.89; 95% CI 1.26 to 2.85; p=0.002), no use of tumour necrosis factor inhibitor (TNFi) (PR 2.51;95% CI 1.16 to 5.45; p=0.004) and methylprednisolone pulse therapy (PR 2.50; 95% CI 1.59 to 3.92; pConclusionsAge >50 years and immunosuppression with GC and cyclophosphamide were associated with unfavourable outcomes of COVID-19. Treatment with TNFi may have been protective, perhaps leading to the COVID-19 inflammatory process.

BACKGROUND Patients with immune-mediated rheumatic diseases (IMRD) are at increased risk of infections, including significant morbidity and high mortality. Considering the potential for unfavorable outcomes of SARS-CoV-2 infection in patients with IMRD, several questions were raised regarding the impact of COVID-19 at the start of the pandemic. OBJECTIVE This paper presents the protocol of a study that aims to prospectively evaluate patients with IMRD and a confirmed COVID-19 diagnosis (using criteria provided by the Brazilian Ministry of Health). METHODS The study comprised a prospective, observational cohort (patients with IMRD and COVID-19) and a comparison group (patients with only IMRD), with a follow-up time of 6 months to evaluate differences in health outcomes. The primary outcomes will be changes in IMRD disease activity after SARS-CoV-2 infection at 4 time points: (1) at baseline, (2) within 4-6 weeks after infection, (3) at 3 months after the second assessment (±15 days), and (4) at 6 months (±15 days). The secondary outcomes will be the progression rate to moderate or severe forms of COVID-19, need for intensive care unit admission and mechanical ventilation, death, and therapeutic changes related to IMRD. Two outcomes—pulmonary and thromboembolic events in patients with both IMRD and SARS-CoV-2 infection—are of particular interest and will be monitored with close attention (clinical, laboratory, and function tests as well as imaging). RESULTS Recruitment opened in May 2020, with 1300 participants recruited from 43 sites as of November 2020. Patient recruitment will conclude by the end of December 2020, with follow-up occurring until April 2021. Data analysis is scheduled to start after all inclusion data have been collected, with an aim to publish a peer-reviewed paper in December 2020. CONCLUSIONS We believe this study will provide clinically relevant data on the general impact of COVID-19 on patients with IMRD. CLINICALTRIAL Brazilian Registry of Clinical Trials RBR-33YTQC; http://www.ensaiosclinicos.gov.br/rg/RBR-33ytqc/ INTERNATIONAL REGISTERED REPORT DERR1-10.2196/24357

Introdução: O HPV causa uma grande variedade de lesões e neoplasias, a maioria envolvendo a região anogenital. Infecção persistente por tipos oncogênicos de HPV é responsável pela quase totalidade dos cânceres de colo de útero. Mulheres imunossuprimidas apresentam maior risco de câncer cervical do que mulheres saudáveis, devido ao uso prolongado de imunossupressores. A segurança, imunogenicidade e eficácia das vacinas HPV em imunossuprimidos não são bem conhecidas. Métodos: Foi realizada revisão sistemática e metanálise para avaliar a segurança e imunogenicidade das vacinas HPV em imunocomprometidos, excluindo pessoas vivendo com HIV/aids. Foi realizada busca nas bases de dados mais relevantes (PubMed, Embase, Scopus, LILACS, Web of Science, Clinical Trials, International Clinical Trials Registry Platform, OpenGrey), até julho de 2020. Foram incluídos estudos que avaliaram a imunogenicidade (taxas de soroconversão e títulos médios geométricos [GMT] de anticorpos para os tipos de HPV vacinais) ou segurança de qualquer vacina HPV. Resultados: Foram identificados 3.467 artigos, dos quais 23 foram selecionados para revisão. Foram incluídos ensaios clínicos abertos não randomizados e estudos de coorte, que avaliaram as vacinas HPV bivalente (HPV2v) e quadrivalente (HPV4v), em pessoas com doenças inflamatórias imunomediadas, principalmente lúpus eritematoso sistêmico (LES), mas também dermatomiosite juvenil (DMJ), artrite idiopática juvenil (AIJ) e doença inflamatória intestinal (DII); transplantados de órgãos sólidos (TOS) e transplantados de células tronco-hematopoiéticas (TCTH). A maioria dos estudos que avaliou a vacina HPV em doenças inflamatórias imunomediadas envolveu mulheres jovens com baixa atividade da doença; os estudos com receptores de TOS envolveram homens e mulheres. A qualidade dos estudos foi classificada como boa. Cinco artigos avaliaram a imunogenicidade de vacinas HPV em mulheres com LES um mês após a última dose da vacina e foram incluídos na metanálise. As taxas de soroconversão nas participantes com LES foram de 89,3% (IC95%, 0,25-0,85) para HPV6; 92,4% (IC95%, 0,82-1,02) para HPV11; 96,4% (IC95%, 0,93-0,98) para HPV16; e 91,8% (IC95%, 0,85-0,98) para HPV18. A metanálise da imunogenicidade em TOS incluiu quatro estudos, com as seguintes taxas de soroconversão: 54,6% (IC95%, 0,77-1,02) para HPV6; 73,8% (IC95%, 0,59-0,89) para HPV11; 85,1% (IC95%, 0,69-1,01) para HPV16; e 61% (IC95%, 0,24-0,99) para HPV18. Os artigos que avaliaram outros imunossuprimidos, assim como os resultados dos títulos de anticorpos foram incluídos na análise qualitativa. Dor no local da injeção foi o evento adverso (EA) mais comum. Não foi relatado nenhum EA grave associado à vacina HPV nos artigos revistos. Cinco estudos que avaliaram exacerbação do LES após vacinação foram incluídos em metanálise. A taxa de exacerbação do LES foi de 12,6% (IC95%, 0,04-0,21). Metanálise da taxa de rejeição aguda do órgão transplantado após vacinação nos receptores de TOS incluiu seis artigos e encontrou taxa de 8,4% (IC95%, 0,02-0,15). Conclusões: Poucos estudos, com amostra pequena, avaliaram as vacinas HPV em imunossuprimidos. Mulheres com LES tiveram taxas de soroconversão semelhante à da população saudável. Os TOS apresentaram taxas de soroconversão menores que a população saudável, principalmente para HPV6 e HPV11. Em geral, os títulos de anticorpos foram mais baixos nos imunossuprimidos. As vacinas HPV foram seguras nessas populações. Introduction: HPV causes a wide variety of lesions and neoplasms, most of which involve the anogenital area. Oncogenic HPV persistent infection is responsible for almost all cervical cancers. Immunosuppressed women are at higher risk of cervical cancer than healthy women, due to the long use of immunosuppressors. The safety, immunogenicity, and efficacy of HPV vaccines in immunosuppressed persons are not well known. Methods: A systematic review and meta-analysis was performed to evaluate the safety and immunogenicity of HPV vaccines in immunocompromised individuals, excluding persons living with HIV/AIDS. The search was conducted in the most relevant databases (PubMed, Embase, Scopus, LILACS, Web of Science, Clinical Trials, International Trials Registry Platform, Open Grey), up to July 2020. Studies that evaluated the immunogenicity (seroconversion rates and antibody geometric mean titers [GMT] of HPV vaccine types) or safety of any HPV vaccine were included. Results: We identified 3,467 articles, of which 23 articles were selected for review. Open-label not randomized clinical trials and cohort studies that assessed bivalent or quadrivalent HPV recombinant vaccines in persons with immune-mediated inflammatory diseases, mainly Systemic Lupus Erythematosus(SLE), but also juvenile dermatomyositis (JDM), juvenile idiopathic arthritis (JIA), and inflammatory bowel disease (IBD); solid organ transplantation (SOT) and hematopoietic stem-cell transplantation (HSCT). Most studies that evaluated immune-mediated inflammatory diseases involved young women with low activity disease, whereas studies with SOT recipients involved both men and women. The quality of the reviewed studies was considered as good. Five articles evaluated HPV vaccine immunogenicity in the SLE women, a month after the last vaccine dose, and were included in a meta-analysis. Seroconversion rates among SLE participants were 89.3% (95%CI, 0.25-0.85) for HPV6; 92.4% (95%CI, 0.82-1.02) for HPV11; 96.4% (95%CI, 0.93-0.98) for HPV16; and 91.8% (95%CI, 0.85-0.98) for HPV18. A meta-analysis of SOT recipients included four studies and the following seroconversion rates were found: 54.6% (95%CI, 0.77-1.02) for HPV6; 73.8% (95%CI, 0.59-0.89) for HPV11; 85.1% (95%CI, 0.69-1.01) for HPV16; and 61% (95%CI, 0.24-0.9) for HPV18. Other articles, that evaluated other immunosuppressed diseases were included in the qualitative analysis only. Pain at the injection site was the most common adverse event (AE). No serious AE were seen in the reviewed articles. A meta-analysis of SLE flare after HPV vaccination included five studies and found SLE flare rate of 12.6% (95% CI, 0.04-0.21). Meta-analysis of acute rejection of the transplanted organ including six studies found a rejection rate of 8.4% (95%CI, 0.02-0.15). Conclusions: Few studies with a small sample size evaluated HPV vaccines in the immunosuppressed population. Women with SLE had seroconversion rates similar to healthy population. SOT recipients had lower seroconversion rates as compared to healthy persons, particularly to HPV6 and HPV18. Immunosuppressed persons had lower antibody GMT. HPV vaccines were safe in these population.

Pacientes com doenças autoimunes tem maior risco de contrair infecção pelo HPV e evoluírem para lesões pré-neoplásicas e neoplásicas. Este estudo teve por objetivo determinar a segurança da vacinação contra o HPV em meninas e adolescentes com Lúpus Eritematoso Sistêmico Juvenil (LESJ) e Dermatomiosite Juvenil (DMJ), através da verificação da ocorrência dos eventos adversos pós-vacinação (EAPVs) e da avaliação da atividade das doenças antes e depois da vacina. Estudo de intervenção prospectivo multicêntrico em meninas e adolescentes (9-20 anos) com diagnóstico de LESJ ou DMJ. A vacina utilizada foi a HPV quadrivalente no esquema de 3 doses (0-2-6 meses). Um diário de possíveis EAPVs foi entregue a todos os vacinados para ser preenchido por 14 dias consecutivos após cada dose da vacina. A atividade das doenças foi avaliada antes e após as doses por meio de um conjunto de medidas clínicas e laboratoriais e índices de atividade das doenças (o Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) para pacientes com LESJ, o Childhood Myositis Activity Score (CMAS) e o Manual Muscle Testing (MMT) para pacientes com DMJ) validados internacionalmente. Para verificar se houve diferença na ocorrência dos relatos dos EAPVs entre os grupos de pacientes com LESJ e com DMJ foi utilizado o cálculo da razão de prevalência e, para a analisar se houve influência de alguma variável na ocorrência dos EAPVs pós 1ª, 2ª e 3ª doses foi empregado o algoritmo conditional inference trees. Foram incluídas 222 com LESJ, 41 com DMJ e 40 controles. Observou-se que a frequência dos EAPVs locais foi semelhante em pacientes e controles. Nenhum evento adverso grave (EAG) foi relatado durante o estudo. Não foi identificada piora da doença de base relacionada à vacinação. A vacina mostrou ser bem tolerada e segura nessas pacientes. Patients with autoimmune diseases have increased risk of HPV infection and development of metaplastic and neoplastic lesions. The aim of this study was to determine the safety of HPV vaccination in girls and adolescents with Juvenile Systemic Lupus Erythematosus (JSLE) and Juvenile Dermatomyositis (JDM), through evaluating the occurrence of post-vaccination adverse events following vaccination (AEFVs) and assessment of disease activity before and after the vaccine. It was a multicenter prospective intervention study including girls and adolescents (9-20 years old) with diagnosis of JSLE or JDM. The vaccine used was quadrivalent HPV in the 3 doses schedule (0-2-6 months). A diary of possible AEFV was handed out to all vaccinated patients and controls, to be filled for 14 consecutive days following each dose of the HPV vaccine. Disease activity was assessed before and after each dose, using a core set of clinical and laboratorial measures and disease activity indexes (o Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) for patients with JSLE, o Childhood Myositis Activity Score (CMAS) e o Manual Muscle Testing (MMT) for patients with JDM) internationally validated. In order to verify if there was difference between the groups of patients with JSLE and with JDM on the occurrence of AEFV we used the prevalence ratio. In addition, the conditional inference trees algorithm was used to analyze if there was influence of any variables on the occurrence of AEFVs after 1st, 2nd and 3rd doses. We have included 222 patients with JSLE, 41 with JDM and 40 health controls. It was observed that the frequency of local AEFV was similar between patients and controls. No serious adverse events were reported during the study. Worsening or flares-up of underlying disease was not related to vaccination. The vaccine has been shown to be well tolerated and safe in these patients.

Introdução: As infecções pelo papiloma vírus (HPV), geralmente são assintomáticas e transitórias, porém, em indivíduos com doenças autoimune, onde há um comprometimento da imunidade causado por mecanismo inerentes a própria doença e pelo tratamento com drogas imunossupressoras, o risco destas infecções evoluírem para lesões metaplásicas e neoplásicas é alto. A forma mais eficiente de prevenção deste tipo de desfecho é a vacinação contra HPV. Assim, a indicação desta vacina seria fundamental para a proteção destes pacientes, porém, devido aos fatores citados, pressupõem-se que a resposta poderia ser menos eficiente. Objetivo: Avaliar a imunogenicidade da vacina contra HPV quadrivalente em pacientes com Lúpus Eritematoso Sistêmico Juvenil (LESJ) e Dermatomiosite juvenil (DMJ). Métodos: Estudo prospectivo de intervenção multicêntrico, onde foram incluídas 328 meninas e adolescentes (9-20 anos) em 13 centros oriundos de diferentes regiões do Brasil. Porém apenas 246 indivíduos preencheram os critérios de inclusão. O protocolo do estudo previa a aplicação de 3 doses da vacina (0,2 e 6 meses). Os grupos foram divididos em: Grupo A (paciente 206 portadoras de LESJ); Grupo B (pacientes 40 portadoras de DMJ); Grupo C (controle 41 indivíduos saudáveis). A avaliação sorológica foi realizada nos momentos 0, 3, 7 e 12 meses do início do estudo e para mensurar os níveis de anticorpos produzidos para subtipos HPV 16 e HPV18 foi utilizado o imunoensaio Luminex. Foram considerados respondedoras as pacientes ou controles que apresentassem anti-HPV 16 acima do cutt-off= 9 mMU/ml e para antiHPV 18 acima de 13 mMU/ml. Resultados: 246 meninas e adolescentes completaram o protocolo do estudo, sendo 206 pacientes do grupo A, 40 pacientes do grupo B e 41 controles grupo C. Ao todo tivemos 39 indivíduos que não responderam a vacina, sendo 23 do grupo A,8 grupo B e 8 grupo C. E 82 descontinuidades do estudo por motivos diversos como: receio a reações a vacina, mudança de cidade, gravidez e óbito. Na análises comparativas feitas entre os grupos. Não foi observado nenhum fator de risco que influenciou na não resposta a vacina dentre as variáveis consideradas: faixa etária (9-13, 14- 20 anos), número de doses (2 ou 3), tipo e atividade da doença de base, além das várias drogas utilizadas no tratamento, analisadas individual e em associações. Conclusão: A vacinação contra HPV parece ser imunogênica para o grupo de pacientes com LESJ ou DMJ, porém parte delas apresentam uma resposta parcial à vacina, com resposta efetiva a apenas um dos sorotipos avaliados (16 ou 18). Nenhum fator de risco foi encontrado que possa ter influenciado na não resposta a vacina. Introduction: Papillomavirus (HPV) infections are generally asymptomatic and transient, but in individuals with autoimmune diseases whom used to have a compromise of the immunity caused by mechanisms inherent to the disease itself in addition to the treatment with immunosuppressive drugs. Thus, the risk of these infections progress for metaplastic and neoplastic lesions is high in these individuals. Vaccination is essential for the protection of these patients, however because the characteristics of their immune system may be less effective. The most efficient way to prevent this type of outcome is vaccination against HPV. Thus, the indication of this vaccine would be fundamental for the protection of these patients, however due to the compromise in the immune system, it is possible to assumed that the response could be less efficient. Objective: To evaluate the immunogenicity of the quadrivalent HPV vaccine in patients with Juvenile Systemic Lupus Erythematosus (JSLE) and Juvenile Dermatomyositis (JDM). Methods: A multicenter prospective study, including 328 girls and adolescents (9-20 years) in 13 centers from different regions of Brazil. The study protocol provided for the application of 3 doses of the vaccine (0.2 and 6 months). During the study blood collections and serological evaluation was performed at time points 0, 3, 7 and 12 months after the start of the study in 206 SLEJ patients (group A), 40 JDM patients (group B) and 41 healthy controls (group C). To evaluate the levels of antibodies produced for HPV 16 and HPV18 subtypes the Luminex immunoassay was used. Patients or controls with anti-HPV 16 cutt-off = 9 anti-HPV 18 = 13 were considered as responders. RESULTS: Of the 328 girls and adolescents included, 246 girls and adolescents completed the study protocol, being 206 patients in group A, 40 patients in group B and 41 controls in group C. In all we had 39 individuals who did not respond to the vaccine, being 23 of group A, 8 group B and 8 group C. E 82 study discontinuities for various reasons such as: fear of reactions to the vaccine, city change, pregnancy and death. In the comparative analyzes made between the groups. No risk factor was observed that influenced the non-response to the vaccine among the variables considered: age range (9-13, 14-20 years), number of doses (2 or 3), type and activity of the underlying disease, Of the various drugs used in the treatment, analyzed individually and in associations. 287 completed the study. Conclusion: the vaccine anti-HPV seems to be immunogenic in JLES and JDM patient, however a percentage of patients have showed a partial response to the vaccine, just a one of the serotypes 16 or 18. No risk factor was found that May have influenced the nonresponse to the vaccine.