Recommendations on cutaneous and hematological manifestations of Sjögren's disease by the Brazilian Society of Rheumatology.

Sjogren's disease (SjD) is an autoimmune disease that is characterized not only by the sicca symptoms it causes but also by its systemic nature, which is capable of several and not yet fully understood extraglandular manifestations. To gain a clearer understanding of these manifestations as well as a better practical approach, a panel of experts from the Brazilian Society of Rheumatology conducted a systematic review and meta-analysis on the identification of epidemiologic and clinical features of the extraglandular manifestations present in ESSDAI (EULAR Sjogren´s syndrome disease activity index), followed by a voting panel with recommendations for clinical practice. This publication is complementary to others already published and covers cutaneous and hematological manifestations, with prevalence data generated by a meta-analysis of 13 clinical or laboratory manifestations and 6 clinical management recommendations.

Sicca syndrome/Sjögren's disease associated with cancer immunotherapy: a narrative review on clinical presentation, biomarkers, and management.

INTRODUCTION: Almost one-quarter of immune checkpoint inhibitor (ICI) recipients experience sicca syndrome, while Sjögren's disease (SjD) is estimated at 0.3-2.5%, possibly underreported. AREAS COVERED: This narrative review (Medline/Embase until January/31/2024) addresses the pathophysiology, incidence, demographic/clinical features, biomarkers, labial salivary gland biopsy (LSGB), fulfillment of the idiopathic SjD (iSjD) classificatory criteria, differential diagnosis, and management of sicca syndrome/SjD associated with ICIs. EXPERT OPINION: SjD associated with ICIs is underdiagnosed, since studies that performed the mandatory SjD investigation identified that 40-60% of patients with sicca syndrome associated with ICIs meet the iSjD classificatory criteria. LSGB played a fundamental role in recognizing these cases, as most of them had negative anti-Ro/SS-A antibody. Despite the finding of focal lymphocytic sialoadenitis in LSGB samples mimicking iSjD, immunohistochemical analysis provided novel evidence of a distinct pattern for sicca syndrome/SjD associated with ICIs compared to iSjD. The former has scarcity of B lymphocytes, which are a hallmark of iSjD. Additionally, patients with sicca syndrome/SjD associated with ICIs have demographical/clinical/serological and treatment response dissimilarities compared to iSjD. Dryness symptoms are more acute in the former than in iSjD, with predominance of xerostomia over xerophthalmia, and partial/complete response to glucocorticoids. Dryness symptoms in ICI-treated patients warrant prompt SjD investigation.

Effects of a lifestyle intervention on cardiovascular risk factors in systemic lupus erythematosus patients: The study "Living well with lupus".

OBJECTIVE: The aim of the present study was to investigate the effects of a lifestyle intervention on cardiometabolic risk factors in patients with systemic lupus erythematosus with a high cardiovascular risk profile. METHODS: This trial was conducted in Sao Paulo, Brazil between August 2020 and March 2023. The patients were randomly assigned to lifestyle intervention or control. The intervention was a 6-month multifaced program focused on behavioral changes through personalized recommendations for increasing physical activity (structured and non-structured) and improving eating aspects. Cardiometabolic risk score (primary outcome), anthropometry and visceral fat, aerobic capacity, blood pressure, inflammatory and oxidative stress markers, and blood flow and endothelial function were assessed before and after the intervention. RESULTS: A total of 80 patients were randomized. Twelve and 6 patients dropped out due to personal reasons in the intervention and control groups, respectively. Average adherence rate for the intervention was 56.9%. Intention-to-treat analysis showed no significant difference between groups in the cardiometabolic risk score (intervention group - Pre: 1.7 ± 3.6; Post: -1.6 ± 4.0; control group - Pre: -1.9 ± 3.6; Post: -2.0 ± 3.8; estimated mean difference between groups at post: -0.4; 95% confidence intervals: -2.7; 1.9; p = 0.96). This finding was confirmed by exploratory, per-protocol analysis. No significant differences were observed between adherents vs. non-adherent participants. Secondary outcomes did not change between groups. CONCLUSION: This 6-month, individualized, lifestyle intervention did not improve cardiovascular risk factors in SLE patients with a high cardiovascular risk profile. TRIAL REGISTRATION: clinicaltrials.gov (NCT04431167).

Assessment of hydroxychloroquine blood levels in Sjögren's disease patients: drug adherence and clinical associations.

Hydroxychloroquine (HCQ) has been used to treat Sjögren's disease (SjD) patients. However, there are no studies evaluating drug adherence through HCQ blood levels, pharmacy refill (PR) and medication adherence questionnaires. The relationship of HCQ blood levels with glandular/extraglandular disease parameters was also poorly assessed. This cross-sectional observational study included 74 adult SjD patients, who were receiving a stable HCQ dose (4-5.5 mg/kg/day, actual weight) for at least 3 months before study inclusion. HCQ blood levels were quantified by high-performance liquid chromatography coupled to mass spectrometry. Adherence was assessed by PR and Medida de Adesão aos Tratamentos (MAT) questionnaire. The following parameters were evaluated: Xerostomia Inventory, Ocular Surface Disease Index, EULAR (European League Against Rheumatism) Sjögren's Syndrome Disease Activity Index, EULAR Sjögren's Syndrome Patient Reported Index, Schirmer's I test and non-stimulated/stimulated salivary flow rates. HCQ blood levels were 775.3(25.0-2,568.6)ng/mL. Eleven patients (14.9%) had HCQ blood levels < 200ng/mL (non-adherent group); 11(14.9%), 200-499ng/mL (sub-therapeutic levels group); and 52(70.2%), ≥ 500ng/mL (adherent group). PR classified incorrectly all non-adherent/sub-therapeutic patients and 2/52(3.9%) adherent patients. Using MAT, the overall misclassification was 24/52(46.2%) in the adherent group, and were correctly identified 9/11(81.8%) patients in non-adherent and 7/11(63.6%) in sub-therapeutic groups. MAT sensitivity and specificity to identify non-adherent/sub-therapeutic patients were 72.7% and 53.9%, respectively. The three groups were comparable regarding glandular/extraglandular disease parameters (p > 0.05). The assessment of HCQ blood levels is a promising tool for evaluating drug adherence in SjD. This is particularly crucial as one-third of patients exhibited non-adherence/sub-therapeutic levels, and neither PR nor MAT reliably identified these patients.

Post-acute COVID-19 in three doses vaccinated autoimmune rheumatic diseases patients: frequency and pattern of this condition

Abstract Background Data on post-acute COVID-19 in autoimmune rheumatic diseases (ARD) are scarce, focusing on a single disease, with variable definitions of this condition and time of vaccination. The aim of this study was to evaluate the frequency and pattern of post-acute COVID-19 in vaccinated patients with ARD using established diagnosis criteria. Methods Retrospective evaluation of a prospective cohort of 108 ARD patients and 32 non-ARD controls, diagnosed with SARS-CoV-2 infection (RT-PCR/antigen test) after the third dose of the CoronaVac vaccine. Post-acute COVID-19 (≥ 4 weeks and > 12 weeks of SARS-CoV-2 symptoms) were registered according to the established international criteria. Results ARD patients and non-ARD controls, balanced for age and sex, had high and comparable frequencies of ≥ 4 weeks post-acute COVID-19 (58.3% vs. 53.1%, p = 0.6854) and > 12 weeks post-acute COVID-19 (39.8% vs. 46.9%, p = 0.5419). Regarding ≥ 4 weeks post-acute COVID-19, frequencies of ≥ 3 symptoms were similar in ARD and non-ARD controls (54% vs. 41.2%, p = 0.7886), and this was also similar in > 12 weeks post-acute COVID-19 (68.3% vs. 88.2%, p = 0.1322). Further analysis of the risk factors for ≥ 4 weeks post-acute COVID-19 in ARD patients revealed that age, sex, clinical severity of COVID-19, reinfection, and autoimmune diseases were not associated with this condition (p > 0.05). The clinical manifestations of post-acute COVID-19 were similar in both groups (p > 0.05), with fatigue and memory loss being the most frequent manifestations. Conclusion We provide novel data demonstrating that immune/inflammatory ARD disturbances after third dose vaccination do not seem to be a major determinant of post-acute COVID-19 since its pattern is very similar to that of the general population. Clinical Trials platform (NCT04754698).

Recommendations for evaluation and diagnosis of extra-glandular manifestations of primary sjogren syndrome: results of an epidemiologic systematic review/ meta-analysis and a consensus guideline from the Brazilian Society of Rheumatology (articular, pulmonary and renal)

Abstract Sjogren's Syndrome (SS) is an autoimmune disease characterized by lymphocytic infiltration of the exocrine glands and other organs, associated with sicca syndrome but also with systemic involvement with varying degrees of severity. Despite their importance, these systemic manifestations are not routinely evaluated and there is no homogenous approach to their diagnosis or evaluation. To close this gap, a panel of experts from the Brazilian Society of Rheumatology conducted a systematic review and meta-analysis on the identification of epidemiologic and clinical features of these manifestations and made recommendations based on the findings. Agreement between the experts was achieved using the Delphi method. The first part of this guideline summarizes the most important topics, and 11 recommendations are provided for the articular, pulmonary, and renal care of SS patients.

Recommendations for evaluation and diagnosis of extra-glandular manifestations of primary Sjögren syndrome: results of an epidemiologic systematic review/ meta-analysis and a consensus guideline from the Brazilian society of rheumatology (hepatic, gastrointestinal and pancreatic)

Abstract Sjogren's syndrome (SS) is an autoimmune disease characterized by lymphocytic infiltration of the exocrine glands and other organs, associated with sicca syndrome but also with systemic involvement with varying degrees of severity. Despite their importance, some systemic manifestations, mainly liver, gastrointestinal, and pancreatic are not routinely evaluated. To address these manifestations, the Sjögren's Syndrome Committee of the Brazilian Society of Rheumatology conducted a broad systematic review of the literature on studies investigating prevalence and diagnosis of these symptoms in Sjogren´s patients and made recommendations based on the findings. Agreement between the experts was achieved using the Delphi method. This is the second part of this guideline, providing 6 recommendations for liver, gastrointestinal, and pancreatic care of SS patients.

VI Brazilian consensus guidelines for detection of anti-cell autoantibodies on HEp-2 cells

Abstract Background: The VI Brazilian Consensus on Autoantibodies against HEp-2 cells for determination of autoantibodies against cellular constituents on HEp-2 cells was held on September, 2019, in Fortaleza (CE, Brazil). The guidelines in this edition were formulated by the group of Brazilian experts discussing the classification of complex patterns, the classification of the nuclear discrete dots (few and multiple), the identification of the discrete fine speckled pattern (AC-4a) and improvements on the ANA report. Mainbody: Sixteen Brazilian researchers and experts from universities and clinical laboratories representing the various geographical regions of Brazil participated in the meeting. Four main topics were discussed: (1) How to classify patterns with fluorescence in more than one cell compartment considering three relevant categoris: composite patterns, mixed patterns and multiple patterns; (2) The splitting of the discrete nuclear dots pattern into the multiple discrete nuclear dots (AC-6) and few discrete nuclear dots (AC-7) patterns, respectively; (3) Inclusion of a novel nuclear pattern characterized by discrete fine speckled pattern highly associated with antibodies to SS-A/Ro60, classified as AC-4a. In addition, adjustments on the Brazilian Consensus nomenclature were implemented aiming to harmonize the designation of some patterns with the International Consensus on ANA Patterns (ICAP). Furthermore, the designations of the PCNA-like pattern (AC-13), CENP-F-like pattern (AC-14) and Topo I-like pattern (AC-29) were adjusted in accordance to ICAP. Finally, there was a recommendation for adjustment in the test report in order to address the status of nuclear envelope staining. For all topics, the aim was to establish specific guidelines for laboratories and clinicians. All recommendations were based on consensus among participants. All recommendations from the V Consensus were maintained and there was relevant progress in the BCA/HEp-2 guidelines and further harmonization with ICAP. Conclusion: The VI BCA/HEp-2 edition was successful in establishing important recommendations regarding the classification of complex patterns, in supporting the identification of a novel pattern within the AC-4 group and in the harmonization process with the ICAP terminology.

Chronic inflammatory diseases, subclinical atherosclerosis, and cardiovascular diseases: Design, objectives, and baseline characteristics of a prospective case-cohort study ‒ ELSA-Brasil

Abstract Objectives This analysis describes the protocol of a study with a case-cohort to design to prospectively evaluate the incidence of subclinical atherosclerosis and Cardiovascular Disease (CVD) in Chronic Inflammatory Disease (CID) participants compared to non-diseased ones. Methods A high-risk group for CID was defined based on data collected in all visits on self-reported medical diagnosis, use of medicines, and levels of high-sensitivity C-Reactive Protein >10 mg/L. The comparison group is the Aleatory Cohort Sample (ACS): a group with 10% of participants selected at baseline who represent the entire cohort. In both groups, specific biomarkers for DIC, markers of subclinical atherosclerosis, and CVD morbimortality will be tested using weighted Cox. Results The high-risk group (n = 2,949; aged 53.6 ± 9.2; 65.5% women) and the ACS (n=1543; 52.2±8.8; 54.1% women) were identified. Beyond being older and mostly women, participants in the high-risk group present low average income (29.1% vs. 24.8%, p < 0.0001), higher BMI (Kg/m2) (28.1 vs. 26.9, p < 0.0001), higher waist circumference (cm) (93.3 vs. 91, p < 0.0001), higher frequencies of hypertension (40.2% vs. 34.5%, p < 0.0001), diabetes (20.7% vs. 17%, p = 0.003) depression (5.8% vs. 3.9%, p = 0.007) and higher levels of GlycA a new inflammatory marker (p < 0.0001) compared to the ACS. Conclusions The high-risk group selected mostly women, older, lower-income/education, higher BMI, waist circumference, and of hypertension, diabetes, depression, and higher levels of GlycA when compared to the ACS. The strategy chosen to define the high-risk group seems adequate given that multiple sociodemographic and clinical characteristics are compatible with CID.

2021 recommendations of the Brazilian Society of Rheumatology for the gynecological and obstetric care of patients with Sjogren's syndrome

Abstract Sjogren's syndrome (SS) is an autoimmune disease characterized by lymphocytic infiltration of the exocrine glands and other organs. Women with SS often experience gynecological symptoms due to the disease and need extra care regarding their sexual activity, reproductive health and during pregnancy, conditions that are not properly conducted in the clinical practice. To cover this gap, a panel of experts from the Brazilian Society of Rheumatology conducted a systematic review and meta-analysis on the identification of symptoms, diagnosis, monitoring, prognosis, and treatment of these manifestations. A Focus Group meeting was held and included experts in the field and methodologists, based on a previously developed script, with themes related to the objective of the study. The most important topics were summarized and 11 recommendations were provided.

V Brazilian consensus guidelines for detection of anti-cell autoantibodies on hep-2 cells

Abstract Background: The V Brazilian Consensus for determination of autoantibodies against cellular constituents on HEp-2 cells, held in Brasilia (DF, Brazil) on August 27, 2016, discussed the harmonization between the Brazilian Consensus on ANA (BCA) guidelines and the International Consensus on ANA Patterns (ICAP) recommendations (www.anapatterns.org). Initial guidelines were formulated by the group of Brazilian experts with the purpose of guiding and enabling Brazilian clinical laboratories to adopt recommendations and to provide a common standard for national and international consensuses. Mainbody: Twenty Brazilian researchers and experts from universities and clinical laboratories representing the various geographical regions of the country participated in the meeting. Three main topics were discussed, namely the harmonization between the BCA guidelines and latest recommendations of the ICAP initiative, the adjustment of the terminology and report on HEp-2 patterns, and a reassessment of quality assurance parameters. For the three topics, our aim was to establish specific guidelines. All recommendations were based on consensus among participants. There was concrete progress in the adjustment of the BCA guidelines to match the ICAP guidelines. To a certain extent, this derives from the fact that ICAP recommendations were largely based on the algorithm and recommendations of the IV Brazilian ANA Consensus, as consistently recognized in the ICAP publications and presentations. However, although there is great overlap between the two Consensuses, there are some point divergences. These specific items were individually and extensively discussed, and it was acknowledged that in several points ICAP improved recommendations previously issued by the Brazilian ANA Consensus and these changes were readily implemented. Regarding some specific topics, the BCA panel of experts felt that the previously issued recommendations remained relevant and possibly will require further discussion with ICAP. The term anti-cell antibodies was adopted as the recommended designation, recognizing that the assay addresses antibodies against antigens in the nucleus and in other cell compartments. However, the acronym ANA HEp-2 was maintained due to historical and regulatory reasons. It was also signalized that the latest trend in ICAP is to adopt the term Indirect Immunofluorescent Assay on HEp-2 cell substrate (HEp-2 IIFA). In addition, the quality assurance strategies previously presented were ratified and emphasized. Conclusion: The V BCA edition was successful in establishing an overall harmonization with the ICAP recommendations for interpretation of the HEp-2 IIFA test, pinpointing the perspectives in filling the remaining gaps between both initiatives.

Recommendations from the Brazilian society of rheumatology for the diagnosis of Sjögren's syndrome (Part I): glandular manifestations (systematic review)

Abstract Background: Primary Sjögren's syndrome (pSS) is a systemic immune-mediated disease whose main characteristic is exocrine gland inflammation and, subsequent reduction in tear and saliva production. A delayed diagnosis is common due to the nonspecific clinical manifestations of disease. The aim of the present study was to develop recommendations for the diagnosis of glandular manifestations of pSS based on evidence and expert opinion. Main body of the abstract: We conducted a systematic literature review to retrieve the best evidence available on the accuracy of diagnostic tests for pSS. We also held two in-person meetings with experts (rheumatologists, pathologists, ophthalmologists and dentists) to establish their level of agreement using the Delphi method. Ultimately, we generated 18 recommendations that aim to facilitate the diagnosis of the glandular manifestations of pSS. Conclusion: The diagnosis of glandular manifestations of pSS is complex and multidisciplinary. It requires specific knowledge in the field of ophthalmology, immunology, pathology and imaging, making it compulsory for the rheumatologist to work with professionals from these different areas in order to improve accuracy and early diagnosis. Glandular dysfunction tests, ANA, RF, Anti-Ro, protein electrophoresis, urinalysis, blood count, C-Reactive protein, complement, testing for syphilis and viruses (HCV, HIV) and SGUS should be investigated when dryness or systemic manifestation are present. Minor salivary gland biopsy is recommended for all anti-Ro negative or incomplete criteria cases.

Effects of periodontal treatment on primary sjogren's syndrome symptoms

Abstract The aim of this longitudinal prospective study was to evaluate the effects of periodontal treatment on the clinical, microbiological and immunological periodontal parameters, and on the systemic activity (ESSDAI) and subjective (ESSPRI) indexes in patients with primary Sjögren’s Syndrome (pSS). Twenty-eight female patients were divided into four groups: pSS patients with or without chronic periodontitis (SCP, SC, respectively), and systemically healthy patients with or without chronic periodontitis (CP, C, respectively). Periodontal clinical examination and immunological and microbiological sample collection were performed at baseline, 30 and 90 days after nonsurgical periodontal treatment (NSPT). Levels of interleukin IL-1β, IL-8 and IL-10 in saliva and gingival crevicular fluid (GCF) were evaluated by ELISA, as well as the expression of Porphyromonas gingivalis (Pg), Aggregatibacter actinomycetemcomitans, (Aa) Tannerella forsythia (Tf), and Treponema denticola (Td), by qPCR. Systemic activity and pSS symptoms were evaluated by ESSDAI and ESSPRI. NSPT resulted in improved periodontal clinical parameters in both SCP and CP groups (p>0.05). Pg, Aa, and Tf levels decreased after NSPT only in CP patients (p<0.05). Significantly greater levels of IL-10 in GCF were verified in both SCP and CP groups (p<0.05). SCP patients showed increased salivary flow rates and decreased ESSPRI scores after NSPT. In conclusion, NSPT in pSS patients resulted in improved clinical and immunological parameters, with no significant effects on microbiological status. pSS patients also showed increased salivary flow and lower ESSPRI scores after therapy. Therefore, it can be suggested that NSPT may improve the quality of life of pSS patients.

Recomendações para o tratamento da síndrome de Sjögren / Recommendations for the treatment of Sjögren's syndrome

RESUMOAs recomendações propostas pela Comissão de Síndrome de Sjögren da Sociedade Brasileira de Reumatologia para tratamento da síndrome de Sjögren foram baseadas em uma revisão sistemática da literatura nas bases de dados Medline (PubMed) e Cochrane até outubro de 2014 e opinião de especialistas na ausência de artigos sobre o assunto. Foram incluídos 131 artigos classificados de acordo com Oxford & Grade. Essas recomendações foram elaboradas com o objetivo de orientar o manejo adequado e facilitar o acesso aos tratamentos para aqueles pacientes com adequada indicação de recebê-los, considerando o contexto socioeconômico brasileiro e os medicamentos disponíveis no país.

ABSTRACTThe recommendations proposed by the Sjögren's Syndrome Committee of the Brazilian Society of Rheumatology for the treatment of Sjögren's syndrome were based on a systematic review of literature in Medline (PubMed) and the Cochrane databases until October 2014 and on expert opinion in the absence of studies on the subject. 131 articles classified according to Oxford & Grade were included. These recommendations were developed in order to guide the management and facilitate the access to treatment for those patients with an appropriate indication, considering the Brazilian socioeconomic context and pharmacological agents available in this country.

Sjogren's syndrome: An underdiagnosed condition in mixed connective tissue disease

OBJECTIVE: To determine the prevalence of sicca symptoms, dry eye, and secondary Sjögren's syndrome and to evaluate the severity of dry eye in patients with mixed connective tissue disease. METHODS: In total, 44 consecutive patients with mixed connective tissue disease (Kasukawa's criteria) and 41 healthy controls underwent Schirmer's test, a tear film breakup time test, and ocular surface staining to investigate dry eye. In addition, the dry eye severity was graded. Ocular and oral symptoms were assessed using a structured questionnaire. Salivary gland scintigraphy was performed in all patients. Classification of secondary Sjögren's syndrome was assessed according to the American-European Consensus Group criteria. RESULTS: The patients and controls had comparable ages (44.7±12.4 vs. 47.2±12.2 years) and frequencies of female gender (93 vs. 95%) and Caucasian ethnicity (71.4 vs. 85%). Ocular symptoms (47.7 vs. 24.4%) and oral symptoms (52.3 vs. 9.7%) were significantly more frequent in patients than in controls. Fourteen (31.8%) patients fulfilled Sjögren's syndrome criteria, seven of whom (50%) did not have this diagnosis prior to study inclusion. A further comparison of patients with mixed connective tissue disease with or without Sjögren's syndrome revealed that the former presented significantly lower frequencies of polyarthritis and cutaneous involvement than did the patients without Sjögren's syndrome. Moderate to severe dry eye was found in 13 of 14 patients with mixed connective tissue disease and Sjögren's syndrome (92.8%). CONCLUSIONS: Sjögren's syndrome, particularly with moderate to severe dry eye, is frequent in patients with mixed connective tissue disease. These findings alert the physician regarding the importance of the appropriate diagnosis of this syndrome in such patients. .

Avaliaçäo em larga escala do diclofenaco colestiramina em síndromes dolorosas lombares / Post-marketing of diclofenac cholestyramine in low back pain

Os autores descrevem os resultados da observaçäo em larga escala, relatando a experiência pós-comercializaçäo de uma nova formulaçäo galênica de um AINE (diclofenaco-colestiramina - Flotac) utilizado como terapia em casos de síndrome dolorosa lombar. Foram observados por cerca de 500 médicos generalistas de todo o Brasil um total de 1.852 pacientes com lombalgia inespecífica. Os pacientes receberam o diclofenaco-colestiramina na dose de uma capsula a cada doze horas durante 10 dias. Todos os sintomas regrediram após o tratamento de forma estatísticamente significativa, com 80 porcento dos pacientes voltando a ter atividades diárias normais ao final do tratamento. O escore médio de dor no início do tratamento foi de 6,81 pela Escala Visual Analógica e, ao final do tratamento, foi de 1,42, uma reduçäo estatísticamente significativa. Considerando-se a avaliaçäo global de eficácia, 93,7 porcento dos médicos e 91,3 porcento dos pacientes relataram o tratamento como sendo eficaz. Em relaçäo à avaliaçäo global de tolerabilidade, 90,9 porcento dos médicos e 88,7 porcento dos pacientes relataram o tratamento como sendo bem tolerado. Os eventos adversos ocorridos foram os esperados para um AINE e foram considerados leves e somente 1,8 porcento dos pacientes interromperam o tratamento por causa deles. Em conclusäo, o diclofenaco colestiramina (FLOTAC) foi considerado um tratamento adjuvante eficaz para os quadros de síndrome dolorosa lombar onde a sintomatologia inflamatória-dolorosa é um grande incomodo para o paciente, e bem tolerado, tanto para a avaliaçäo do médico como pelo paciente, sem nenhum evento adverso que näo fosse desconhecido.(au)