A dissertation submitted to the Faculty of Health Science, University of the Witwatersrand, Johannesburg, in fulfillment of the requirements for the degree of Master of Science in medicine. Johannesburg 2014 / Introduction: The presence of pain during sleep causes patients with chronic daily pain, such as in Rheumatoid and Osteoarthritis, to experience insomnia, fragmented sleep and an increased number of night-time awakenings. This poor sleep results in an increased sensitivity to pain during the day. The effect of improving sleep on pain, sleep and mood after taking Zolpidem MR was the aim of this study. Methods: 11 patients from Chris Hani Baragwanath Hospital in Soweto South Africa who reported insomnia and daily pain spent 4 weeks in this crossover design, double blinded, placebo controlled study. Week 1- baseline, week 2 and 4 were Intervention weeks – either placebo or Zolpidem MR, week 3 was a Washout week. Data collected included actigraphy, McGill Pain Questionnaire, PSQI, BDI, physical activity questionnaire and daily sleep and pain diaries containing VAS scales for sleep and pain. Results: No significant changes were found in the pain or physical activity levels in any of the patients. Sleep quality, as measured by an isolated PSQI question, was improved by Zolpidem MR (p=0.0075). PSQI was decreased in the final week of the study compared to baseline (8.7 vs. 11.3, p=0.0106) and BDI was lower in week 4 than baseline (7.7 vs. 15.85, p=0.0003), BDI was also lower in week 4 compared to week 2 (7.7 vs. 12.8, p<0.05). However the changes in PSQI and BDI were a result of the order of the weeks, with patients interacting with the researcher and were not due to either Zolpidem MR or placebo. Anecdotal reports include feeling more energised and capable of living life. Conclusion: This study has shown that human interaction is an important component of treatment for insomnia and chronic pain as there is a positive effect on sleep disruption and depression.

Made available in DSpace on 2014-06-11T19:27:57Z (GMT). No. of bitstreams: 0 Previous issue date: 2001Bitstream added on 2014-06-13T19:15:40Z : No. of bitstreams: 1 siqueira_rca_me_botfm.pdf: 744727 bytes, checksum: a3899d53afe3ee28af93a9231f3eaefc (MD5) / O presente trabalho teve como objetivo principal padronizar o teste de contraimunoeletroforese (CIE) para detecção dos autoanticorpos contra os antígenos SS-A/Ro e SS-B/La. Como complementação, realizou-se a padronização da obtenção dos antígenos Ro e La à partir de baço de cão. Para consecução dos objetivos, foram realizadas as seguintes etapas: 1. Extração dos antígenos Ro e La à partir de baço de cão 2. Padronização da CIE com os antígenos obtidos: 2.1 Padronização da técnica CIE propriamente dita; 2.2 Teste qualitativo dos antígenos Ro e La obtidos com padrão USP-SP e ELISA-kit comercial para esses antígenos. 3. Escolha dos casos de doença reumática (diagnosticados por biópsia - 40 pacientes) e controles (soro de doadores de sangue - 10 doadores). As doenças selecionadas tiveram a seguinte distribuição: 3.1 Lúpus Eritematoso Sistêmico = 29 casos 3.2 Lúpus Eritematoso Discóide = 4 casos 3.3 Esclerodermia = 3 casos 3.4 Síndrome de Sjögren = 4 casos 4. Realização dos testes CIE e ELISA-kit. 5. Obtenção dos resultados dos testes de imunofluorescência indireta (IFI) para fator anti-núcleo (FAN) e anti-DNA, ELISA- RNP e ELISA- Sm, realizados na rotina diagnóstica de doenças autoimunes no Laboratório de Imunopatologia do Departamento de Patologia- FMB-UNESP. 6. Comparação e estatística dos resultados obtidos pela CIE com os demais testes. Os resultados e as conclusões obtidas foram as seguintes: 1. Na padronização e nos testes dos soros dos pacientes reumáticos, a CIE apresentou, em geral, apenas uma linha de precipitação bem definida. Somente em dois casos ocorreram duas linhas de precipitação. A presença de uma linha de precipitação impossibilitou a caracterização da presença de anticorpos anti-Ro e anti-La. A detecção de apenas uma linha de precipitação pode ter sido devida: a) aos baixos níveis de... / The main objective of the present work was to standardize the counterimmunoelectrophoresis assay for the detection of autoantibodies to the SS-A/Ro and SS-B/La autoantigens. As a complementary objective, the extraction of both antigens from dog's spleen was also standardized. To accomplish these objectives, the following steps was performed: 1. Extraction of the Ro e La antigens from dog's spleen. 2. CIE standardization with the extracted antigens: 2.1 Standardization of CIE test; 2.2 Qualitative and quantitative analysis of the Ro e La antigens present in the extract of the spleens with a gold-standard (positive serum against Ro and La antigens + Ro and La antigens obtained from spleen dog) obtained from the University of São Paulo-SP and with a commercial ELISA-kit for detection of autoantibodies against these antigens. 3. Selection of the cases with rheumatic disease (diagnosed by biopsys - 40 patients) and normal individual for control serum (blood donors - 10 donors). The diseases and the number of each one in the forty selected cases was distributed as follow: 3.1 Systemic erithematous lupus = 29 cases 3.2 Discoid erithematous lupus = 4 cases 3.3 Scleroderma = 3 cases 3.4 Sjögren syndrome = 4 cases 4. Performance of the CIE e the ELISA-kit tests. 5. Obtaining the results of the following tests: IFI , AAN anti-DNA, ELISA- RNP and ELISA- Sm, registered in the files of the service of autoimmune diseases of the Laboratory of Immunopathology, Department of Pathology - UNESP University - Botucatu Medical School. 6. Statistical analysis and comparison of the results of CIE and other tests. The results and conclusions were the following: 1. In the standardization for the Ro and La antigens in the extract of the spleens and in the tests performed in the serum of rheumatic patients, the CIE in general expressed only one well-defined line of precipitation. Only... (Complete abstract, click electronic access below)

Made available in DSpace on 2014-06-11T19:29:34Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-09-02Bitstream added on 2014-06-13T19:38:45Z : No. of bitstreams: 1 carvalho_sm_me_botfm.pdf: 851185 bytes, checksum: eea10cd209e9c4f24efd8d9bd0d1f8fb (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / A febre reumática (FR) é uma doença pós-infecciosa, causada pelo Streptococus β hemolítico do Grupo A de Lancefield, de mecanismo auto-imune. As suas manifestações clínicas principais são denominadas sinais maiores, incluindo a artrite, cardite, coréia, nódulos subcutâneos e eritema marginado. Entre as manifestações denominadas sinais menores estão o aumento do intervalo P-R no eletrocardiograma, febre, provas de fase aguda positivas, como a VHS e a proteína C reativa. A comprovação de infecção recente pelo estreptococo é considerada um critério essencial. A FR é ainda prevalente nos países em desenvolvimento e emergentes, tendo como complicações crônica o dano valvular causado pela cardite. A sua prevenção é realizada com a erradicação do estreptococo na orofaringe, por meio da profilaxia primária com penicilina benzatina e a profilaxia secundária com a manutenção da penicilina benzatina em intervalos de 21 dias, de acordo com a recomendação da OMS. Como a FR pode apresentar seqüelas, impacto social e na qualidade de vida, justifica-se a avaliação do desfecho clínico e as suas manifestações em longo prazo. Examinar a epidemiologia, as características clínicas e o desfecho da FR em uma série de casos, nos últimos 20 anos em uma unidade acadêmica dedicada à reumatologia pediátrica (HC-FMB-UNESP). 178 casos foram identificados no período de 1986 a 2007 e destes, 134 foram revisados de acordo com um protocolo listando as manifestações clínicas e laboratoriais, o uso de medicação, o período de acompanhamento e os episódios de recorrência durante o seguimento para vigilância da profilaxia secundária. Os dados demográficos, assim como as manifestações clínicas, laboratoriais e de desfecho são apresentados por meio de freqüência para os dados categóricos e pela estatística descritiva para variáveis contínuas. A probabilidade... / Rheumatic Fever (RF) is a post-infectious disease caused by group A Streptococcus, with autoimmune mechanism. The main clinical features are named major signs as arthritis, carditis, chorea, subcutaneous nodules and erythema marginatum. Among other features, there are the minor signs as increased P-R interval on electrocardiogram (ECG), fever and acute phase reaction measured by erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP). Evidence of previous streptococcal infection is considered a core criteria. RF is highly prevalent in developing countries, where the main complication is damaged heart valves due to carditis. Prophylaxis is called primary when long-acting benzyl penicilin is administered for the first time after diagnosis and it is called secondary prophylaxis for maintenance treatment with long-acting benzyl penicilin every 3 weeks, according to the WHO guidelines. As RF may result in heart damage with both quality of life and social impact, it is valuable to assess its long term outcome. To examine epidemiology , clinical features and outcome of RF in a paediatric case series, seen in an academic unit dedicated to paediatric rheumatology (HC-FMB-UNESP) during the last 20 years. 178 cases were identified from 1986 to 2007, of those 134 were fully revised according to a standardized protocol checking for clinical and laboratorial features, treatment, follow up and acute RF relapse during follow up for prophylaxis surveillance. Demographics, clinical and laboratorial features as well as outcome data are reported by frequency for categorical variables. Continuous variables are presented by descriptive statistics. The probability of carditis, valve damage and RF relapses were examined by survival analysis with actuarial survival plots. Of 134 revised cases, age at onset was from 4 to 13.8 years, follow up duration was from 1.1 to 16.9 years mean 6.8 SD (3.6) and median... (Complete abstract click electronic access below)

Includes bibliographical references / Rheumatic Heart Disease (RHD) is a leading cause of heart disease in children and young adults in the developing world, with significant associated morbidity and mortality. Early secondary prophylaxis may retard the deleterious progression from its antecedent, acute rheumatic fever to permanent heart valve damage, and thus several echocardiographic screening programmes to detect asymptomatic RHD and institute early prophylaxis have been conducted. While effective interventions are available for ameliorating the effects of RHD, research on their use in different settings is scant. Key questions remain regarding the natural history of asymptomatic RHD and the optimal method for early detection. In addition, there is a lack of contemporary estimates of mortality and morbidity among the symptomatic population in the developing world. The primary purpose of the thesis was to determine the outcomes of asymptomatic and symptomatic RHD. More specifically, I sought to quantify the incidence, prevalence and outcomes of RHD in South Africa over the past two decades, determine the natural history of asymptomatic RHD and validate a focused protocol for screening in schoolchildren from Cape Town. In addition, I determined the baseline characteristics, prevalent sequelae and gaps in evidence-based implementation in children and adults from14 developing countries. Finally, I investigated the independent predictors for mortality and morbidity of RHD over a two-year period in patients from Cape Town, South Africa. My thesis has five key findings. Firstly, a systematic review of the literature showed that the incidence and prevalence of RHD over the past two decades in South Africa remains high, although there is evidence of falling cause-specific mortality at a population level. Secondly, asymptomatic RHD has a variable natural history that ranges from regression to a normal state, to persistence of disease, and progression to symptomatic RHD. Thirdly, a focused hand-held echocardiography protocol shows promising levels of sensitivity and specificity for detecting subclinical RHD. Fourthly, the baseline data from the global rheumatic heart disease registry demonstrates significant gaps in the implementation of medical and surgical interventions of proven effectiveness in low- and middle-income countries. Finally, the annual mortality rate for children and adults with RHD in Cape Town over a two-year period is 4.1%with cardiovascular events occurring at a rate of 0.18 events per patient per year. The findings encapsulated in this thesis have important implications for policy, practice and research related to the management of asymptomatic and symptomatic RHD in the world.

Objective. Since 2010, the rheumatology community has developed guidelines and tools to improve healthcare transition. In this study, we aimed to compare current transition practices and beliefs among Childhood Arthritis and Rheumatology Research Alliance (CARRA) rheumatology providers with transition practices from a provider survey published in 2010. Methods. In 2018, CARRA members completed a 25-item online survey about healthcare transition. Got Transition's Current Assessment of Health Care Transition Activities was used to measure clinical transition processes on a scale of 1 (basic) to 4 (comprehensive). Bivariate analyses were used to compare 2010 and 2018 survey findings. Results. Over half of CARRA members completed the survey (202/396), including pediatric rheumatologists, adult- and pediatric-trained rheumatologists, pediatric rheumatology fellows, and advanced practice providers. The most common target age to begin transition planning was 15-17 years (49%). Most providers transferred patients prior to age 21 years (75%). Few providers used the American College of Rheumatology transition tools (31%) or have a dedicated transition clinic (23%). Only 17% had a transition policy in place, and 63% did not consistently address healthcare transition with patients. When compared to the 2010 survey, improvement was noted in 3 of 12 transition barriers: availability of adult primary care providers, availability of adult rheumatologists, and pediatric staff transition knowledge and skills (P < 0.001 for each). Nevertheless, the mean current assessment score was < 2 for each measurement. Conclusion. This study demonstrates improvement in certain transition barriers and practices since 2010, although implementation of structured transition processes remains inconsistent.

Introdução: As doenças reumáticas pediátricas compreendem um grupo heterogêneo de doenças cujas causas são multifatoriais. Pacientes portadores dessas doenças apresentam maior risco de desenvolver infecções devido ao comprometimento da resposta imune causado pela doença e também pelo uso de drogas com potencial imunossupressor. Em vista deste fato, a vacinação torna-se uma ferramenta eficaz na prevenção de doenças infecciosas e suas complicações. Contudo, ainda não existe consenso sobre as indicações e contra-indicações dessas vacinas neste grupo particular. Há poucos trabalhos publicados sobre imunogenicidade e segurança de vacinas em crianças e adolescentes com doenças reumáticas e freqüentemente esses pacientes não recebem as vacinas recomendadas para sua idade. Objetivo: Avaliar a situação vacinal de crianças e adolescentes com doenças reumáticas, as possíveis causas de atraso vacinal e o impacto da orientação específica feita pelo reumatologista pediátrico visando à atualização das vacinas segundo o calendário proposto pelo Ministério da Saúde. Materiais e Métodos: Foi realizado um inquérito com os pacientes e seus responsáveis, consulta dos cartões vacinais e revisão de prontuários dos pacientes em seguimento nos ambulatórios de Reumatologia Pediátrica do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto (HCFMRP-USP) durante o período de abril de 2008 a março de 2009, que possuíssem o cartão vacinal. Para os pacientes com atraso vacinal, prescrição específica de vacina foi feita pelo reumatologista pediátrico, e um novo registro da situação vacinal foi verificado após seis meses. O projeto foi submetido e aprovado pelo Comitê de Ética em Pesquisa do HCFMRP-USP. Resultados: Duzentos e sete pacientes (58% do sexo feminino; média de idade: 10,9 anos) foram incluídos e apresentavam os seguintes diagnósticos: 86 artrite idiopática juvenil (AIJ); 30 lúpus eritematoso sistêmico (LES); 21 dermatomiosite juvenil (DMJ); 10 esclerodermia; 20 vasculites; 10 síndrome de anticorpo anti-fosfolípide (SAAF); 6 doença mista do tecido conjuntivo ou síndrome de sobreposição (DMTC); 24 outras doenças. Anteriormente à intervenção, a cobertura vacinal segundo o calendário brasileiro de vacinação infantil foi: tuberculose (BCG): 100%; sarampo, caxumba e rubéola (SCR): 98,1%; poliomielite (Sabin - VOP): 95,2%; difteria, tétano e coqueluche: 92,8%; hepatite B: 89,4%; e febre amarela: 85%. Noventa dos 207 pacientes incluídos (43,5%) tinham atraso de pelo menos uma dose de alguma vacina recomendada. O atraso da imunização ocorreu, respectivamente, em 43%, 70%, 42,9%, 60%, 45%, 66,7% e 16,7% dos pacientes com AIJ, LES, DMJ, esclerodermia, vasculite, DMTC/síndrome de sobreposição e outras doenças reumáticas. As proporções de crianças que receberam vacinas fora do calendário básico (especiais) foram: hepatite A (9,6%); influenza (24%); meningocócica (10,6%); pneumocócica (15%), e 52,8% para varicela (38/72 pacientes suscetíveis). Em 20,8% dos pacientes a vacinação foi contraindicada pela equipe médica: 88,4% contra febre amarela e 11,6% contra SCR. O atraso da vacinação causado por receio das conseqüências das vacinas ocorreu em 25%. Prescrição específica das vacinas atrasadas foi fornecida a 44/60 pacientes (73,3%) com vacinação incompleta. A atualização completa da vacinação foi verificada após 6 meses em 75% destas crianças. Conclusão: A freqüência de atraso vacinal em pacientes com doenças reumáticas é alta e preocupante. A prescrição específica de vacinas durante o seguimento clínico desses pacientes tem impacto positivo na cobertura vacinal e deve ser implementada com o objetivo de diminuir a morbidade associada às infecções preveníveis. / Background: Pediatric rheumatic diseases comprise a heterogeneous group of diseases with multifactorial causes. These patients present high risk of infection due to impaired immune response and use of immunosuppressive drugs and vaccination is an effective tool for preventing infectious diseases and their sequelae. However, there is still no consensus on the recommendations of vaccines in this group. There are limited data on safety and immunogenicity of vaccines in children and adolescents with rheumatic diseases and frequently these patients do not receive adequate age-recommended vaccines. Objective: To assess the immunization status and possible causes of delayed immunization in children and adolescents with rheumatic diseases, evaluating the impact of physician specific intervention for missing vaccines. Material and Methods: We performed a survey with patients/caregivers, review of charts and immunization cards of patients with rheumatic diseases who were receiving care in a Brazilian Pediatric Rheumatology Center (HCFMRP-USP) from April/08 to March/09 and had an immunization card. For patients with delayed immunization, specific vaccine prescription was made by the pediatric rheumatologist and the new immunization status was recorded after 6 months. Results: Two hundred and seven patients (58% women; mean age: 10.9 years) were enrolled: 86 with juvenile idiopathic arthritis (JIA); 30 systemic lupus erythematosus (SLE); 21 juvenile dermatomyositis (JDM); 10 scleroderma; 20 vasculitis; 10 antiphospholipid antibody syndrome (APS); 6 mixed connective tissue disease (MCTD); 24 with other diseases. Prior to intervention, vaccines of the routine Brazilian childhood immunization schedule had been received among these children as follows: tuberculosis (BCG): 100%; mumps, measles and rubella (MMR): 98.1%; poliomyelitis (Sabin): 95.2%; tetanus, pertussis and diphtheria: 92.8%; hepatitis B: 89.4%; and yellow fever: 85%. With respect to the routine schedule 90/207 (43.5%) enrolled patients missed at least one dose of any vaccine. Delayed immunization occurred, respectively, in 43%, 70%, 42.9%, 60%, 45%, 66.7%, and 16.7% of the patients with JIA, SLE, JDM, scleroderma, vasculitis, MCTD and other rheumatic diseases. The proportions of non-routinely scheduled (special) vaccines received amongst the 207 children were: hepatitis A (9.6%); influenza (24%); meningococcal (10.6%); pneumococcal (15%), and 52.8% for varicella (38/72 susceptible patients). In 20.8% of patients vaccination was contraindicated by the physician: 88.4% for yellow fever and 11.6% for MMR. Delayed immunization caused by family/patient fear or omission occurred in 25%. Specific prescription for the missing vaccines were given to 44/60 patients (73.3%) with incomplete immunization. The complete updated vaccination was verified after 6 months in 75% of these children. Conclusion: The frequency of delayed immunization in pediatric patients with rheumatic diseases is high and worrying. Specific vaccine prescription given during the follow-up is effective and should be performed with the aim of reducing complications associated with preventable infections.

Cerebral small vessel disease (SVD) is a distinct microvascular disorder that can lead to lacunar stroke, an important stroke subtype that accounts for a quarter of all ischaemic strokes. SVD is associated with imaging biomarkers such as white matter hyperintensities (WMH). The cause of SVD is largely unknown, although inflammation and blood-brain barrier failure via endothelial dysfunction have been implicated. Elevated plasma biomarkers of inflammation are associated with coronary heart disease and large vessel stroke but the role of inflammation in SVD is less well understood. Our hypothesis is that inflammation plays a role in SVD and we sought to examine this by reviewing the literature for evidence of this, and by conducting a brain imaging study of patients with a known inflammatory disease and reviewing the images for evidence of inflammation and SVD, and comparing findings with controls groups. Section A: This thesis begins with a systematic review and meta-analysis of 13 plasma biomarkers of four physiological processes (coagulation, fibrinolysis, endothelial dysfunction and inflammation) in lacunar stroke versus non-lacunar stroke (to control for having any stroke) and non-stroke (to compare to the general population). We sought to know if there were differences in these biomarkers between lacunar stroke and other stroke subtypes and non-stroke controls as a way of generating hypotheses for the disease mechanisms that might lead to lacunar stroke. Findings revealed differences in several biomarkers between lacunar stroke and healthy controls but only fibrinogen, D-dimer, von Willebrand factor and interleukin-6 were different (all significantly lower in lacunar stroke) between lacunar stroke and other stroke subtypes. There was heterogeneity between studies, including variations in the definition of lacunar stroke and most studies measured the biomarkers in the acute phase post stroke, which is potentially confounding. To further examine plasma biomarkers of inflammation and endothelial dysfunction in SVD, we used data from a prior study of mild stroke conducted at the Brain Research Imaging Centre, University of Edinburgh, UK. Lacunar stroke patients were compared to cortical stroke patients. The lacunar group had lower levels of tissue plasminogen activator independent of age, sex and vascular risk factors but we found no difference in the other plasma biomarkers. Section B: Non-resolving systemic inflammation is a feature of inflammatory autoimmune rheumatic diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). These patients are at increased risk of stroke but much knowledge relates to stroke in general; less is known about associations with stroke subtypes including SVD, or when in life stroke risk is greatest. Consequently, we sought to better understand the influence of inflammatory rheumatic diseases on stroke and SVD. The review and meta-analysis of cerebrovascular disease in rheumatic diseases showed an excess risk of stroke in RA, SLE, ankylosing spondylitis, gout and psoriasis over the general population. Meta-analyses of stroke subtypes (ischaemic and haemorrhagic) in RA and SLE showed an excess risk of stroke over the general population. Stroke risk across rheumatic diseases was highest in those aged < 50 years and reduced with ageing. We then requested data from NHS Lothian covering 15 years so that we could assess stroke, including stroke subtypes, among patients diagnosed with various arthropathies. We linked 6,613 rheumatology patients’ records with stroke admission records, grouped the various rheumatic diseases into the two main types of arthritis, inflammatory and non-inflammatory, and also compared the strokes in these rheumatology patients to general population data. There was no difference in stroke prevalence between inflammatory and degenerative (non-inflammatory) arthropathies, although the strokes occurred up to two decades earlier than in the general population. Section C: Lastly, we conducted MRI neuroimaging in patients with SLE and reviewed and meta-analysed diffusion tensor imaging (DTI) (an imaging technique used to assess sub-visible white matter microstructure damage) in SLE to place our findings into context. The research question here was to ascertain if patients with a known inflammatory disease had brain imaging evidence of SVD, and to compare findings to controls. We compared imaging markers of SVD and DTI between SLE patients and age-matched healthy controls and sought associations between the imaging biomarkers and plasma biomarkers of inflammation and endothelial dysfunction, measures of fatigue and cognition, and scores of rheumatic disease activity. Fifty-one patients were recruited. There was higher mean diffusivity in all white matter tracts versus controls indicating a diffuse increase in brain water mobility in SLE. Meta-analysis confirmed higher mean diffusivity in SLE patients versus controls. Fatigue in SLE was significantly higher than a normal reference range and was associated with depression, anxiety, higher body mass index, lower mean diffusivity and some blood markers of inflammation and endothelial dysfunction. The most fatigued were youngest which explained the association with lower mean diffusivity. Damage to the brain’s white matter microstructure may be accelerated in SLE as the age-related declines in the general population are normally seen much later in life. The aging pattern is consistent with inflammation-related microvascular-mediated brain damage where the inflammation is systemic in origin. Summary: This thesis has demonstrated an increase in SVD burden in the inflammatory rheumatic disease SLE and increased stroke risk at younger ages in other inflammatory rheumatic diseases. Thus, systemic inflammation as seen in inflammatory rheumatic diseases could have effects on the brain directly, including influencing stroke risk which is clinically noteworthy and would benefit from further testing in appropriately designed studies such as an inception cohort that follows inflammatory rheumatic patients from diagnosis, with regular brain imaging to track brain changes and correlates with inflammatory profiles and impact on cognition.

Introdução: As doenças reumáticas pediátricas compreendem um grupo heterogêneo de doenças cujas causas são multifatoriais. Pacientes portadores dessas doenças apresentam maior risco de desenvolver infecções devido ao comprometimento da resposta imune causado pela doença e também pelo uso de drogas com potencial imunossupressor. Em vista deste fato, a vacinação torna-se uma ferramenta eficaz na prevenção de doenças infecciosas e suas complicações. Contudo, ainda não existe consenso sobre as indicações e contra-indicações dessas vacinas neste grupo particular. Há poucos trabalhos publicados sobre imunogenicidade e segurança de vacinas em crianças e adolescentes com doenças reumáticas e freqüentemente esses pacientes não recebem as vacinas recomendadas para sua idade. Objetivo: Avaliar a situação vacinal de crianças e adolescentes com doenças reumáticas, as possíveis causas de atraso vacinal e o impacto da orientação específica feita pelo reumatologista pediátrico visando à atualização das vacinas segundo o calendário proposto pelo Ministério da Saúde. Materiais e Métodos: Foi realizado um inquérito com os pacientes e seus responsáveis, consulta dos cartões vacinais e revisão de prontuários dos pacientes em seguimento nos ambulatórios de Reumatologia Pediátrica do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto (HCFMRP-USP) durante o período de abril de 2008 a março de 2009, que possuíssem o cartão vacinal. Para os pacientes com atraso vacinal, prescrição específica de vacina foi feita pelo reumatologista pediátrico, e um novo registro da situação vacinal foi verificado após seis meses. O projeto foi submetido e aprovado pelo Comitê de Ética em Pesquisa do HCFMRP-USP. Resultados: Duzentos e sete pacientes (58% do sexo feminino; média de idade: 10,9 anos) foram incluídos e apresentavam os seguintes diagnósticos: 86 artrite idiopática juvenil (AIJ); 30 lúpus eritematoso sistêmico (LES); 21 dermatomiosite juvenil (DMJ); 10 esclerodermia; 20 vasculites; 10 síndrome de anticorpo anti-fosfolípide (SAAF); 6 doença mista do tecido conjuntivo ou síndrome de sobreposição (DMTC); 24 outras doenças. Anteriormente à intervenção, a cobertura vacinal segundo o calendário brasileiro de vacinação infantil foi: tuberculose (BCG): 100%; sarampo, caxumba e rubéola (SCR): 98,1%; poliomielite (Sabin - VOP): 95,2%; difteria, tétano e coqueluche: 92,8%; hepatite B: 89,4%; e febre amarela: 85%. Noventa dos 207 pacientes incluídos (43,5%) tinham atraso de pelo menos uma dose de alguma vacina recomendada. O atraso da imunização ocorreu, respectivamente, em 43%, 70%, 42,9%, 60%, 45%, 66,7% e 16,7% dos pacientes com AIJ, LES, DMJ, esclerodermia, vasculite, DMTC/síndrome de sobreposição e outras doenças reumáticas. As proporções de crianças que receberam vacinas fora do calendário básico (especiais) foram: hepatite A (9,6%); influenza (24%); meningocócica (10,6%); pneumocócica (15%), e 52,8% para varicela (38/72 pacientes suscetíveis). Em 20,8% dos pacientes a vacinação foi contraindicada pela equipe médica: 88,4% contra febre amarela e 11,6% contra SCR. O atraso da vacinação causado por receio das conseqüências das vacinas ocorreu em 25%. Prescrição específica das vacinas atrasadas foi fornecida a 44/60 pacientes (73,3%) com vacinação incompleta. A atualização completa da vacinação foi verificada após 6 meses em 75% destas crianças. Conclusão: A freqüência de atraso vacinal em pacientes com doenças reumáticas é alta e preocupante. A prescrição específica de vacinas durante o seguimento clínico desses pacientes tem impacto positivo na cobertura vacinal e deve ser implementada com o objetivo de diminuir a morbidade associada às infecções preveníveis. / Background: Pediatric rheumatic diseases comprise a heterogeneous group of diseases with multifactorial causes. These patients present high risk of infection due to impaired immune response and use of immunosuppressive drugs and vaccination is an effective tool for preventing infectious diseases and their sequelae. However, there is still no consensus on the recommendations of vaccines in this group. There are limited data on safety and immunogenicity of vaccines in children and adolescents with rheumatic diseases and frequently these patients do not receive adequate age-recommended vaccines. Objective: To assess the immunization status and possible causes of delayed immunization in children and adolescents with rheumatic diseases, evaluating the impact of physician specific intervention for missing vaccines. Material and Methods: We performed a survey with patients/caregivers, review of charts and immunization cards of patients with rheumatic diseases who were receiving care in a Brazilian Pediatric Rheumatology Center (HCFMRP-USP) from April/08 to March/09 and had an immunization card. For patients with delayed immunization, specific vaccine prescription was made by the pediatric rheumatologist and the new immunization status was recorded after 6 months. Results: Two hundred and seven patients (58% women; mean age: 10.9 years) were enrolled: 86 with juvenile idiopathic arthritis (JIA); 30 systemic lupus erythematosus (SLE); 21 juvenile dermatomyositis (JDM); 10 scleroderma; 20 vasculitis; 10 antiphospholipid antibody syndrome (APS); 6 mixed connective tissue disease (MCTD); 24 with other diseases. Prior to intervention, vaccines of the routine Brazilian childhood immunization schedule had been received among these children as follows: tuberculosis (BCG): 100%; mumps, measles and rubella (MMR): 98.1%; poliomyelitis (Sabin): 95.2%; tetanus, pertussis and diphtheria: 92.8%; hepatitis B: 89.4%; and yellow fever: 85%. With respect to the routine schedule 90/207 (43.5%) enrolled patients missed at least one dose of any vaccine. Delayed immunization occurred, respectively, in 43%, 70%, 42.9%, 60%, 45%, 66.7%, and 16.7% of the patients with JIA, SLE, JDM, scleroderma, vasculitis, MCTD and other rheumatic diseases. The proportions of non-routinely scheduled (special) vaccines received amongst the 207 children were: hepatitis A (9.6%); influenza (24%); meningococcal (10.6%); pneumococcal (15%), and 52.8% for varicella (38/72 susceptible patients). In 20.8% of patients vaccination was contraindicated by the physician: 88.4% for yellow fever and 11.6% for MMR. Delayed immunization caused by family/patient fear or omission occurred in 25%. Specific prescription for the missing vaccines were given to 44/60 patients (73.3%) with incomplete immunization. The complete updated vaccination was verified after 6 months in 75% of these children. Conclusion: The frequency of delayed immunization in pediatric patients with rheumatic diseases is high and worrying. Specific vaccine prescription given during the follow-up is effective and should be performed with the aim of reducing complications associated with preventable infections.

<p>Immune complexes (ICs) are produced during normal immune responses and facilitate clearance of foreign antigens. ICs not efficiently cleared from the circulation can cause tissue damage. This might happen if ICs are formed with autoantibodies and autoantigens. Well described effects of ICs are neutralization of antigen, classical complement activation or FcR-mediated phagocytosis, whereas cytokine inducing effects of ICs in human clinical settings are less well described. I have investigated cytokine-inducing properties <i>in vitro</i> of ICs from patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and cryoglobulinemia in association with lymphoproliferative diseases. </p><p>Cryoglobulin (CG)-induced cytokine production varied with changes in temperature and ionic strength in parallel to CG precipitation. IgG CG-induced cytokine production was also mediated via FcγIIa on monocytes. Blockade of the complement system, resembling the <i>in vivo</i> situation of complement consumption in CG-associated diseases, increased IgG CG induced IL-10 and decreased TNF-α production. This represents hitherto not described mechanisms for CG-associated inflammation.</p><p>ICs from SLE patients induced IL-10 and IL-6 production from PBMC cultures via FcγRIIa. Occurrence of anti-SSA autoantibodies and signs of <i>in vivo</i> complement activation contributed to increased levels of circulating ICs in SLE patients, corresponding to increased amounts of IC-induced IL-10 <i>in vitro</i>. This represents a possible vicious cycle that might perpetuate antibody dependent pathology in SLE, and put anti-SSA in a new pathological context.</p><p>RF-associated ICs from RA joints and ICs formed with antibodies against collagen type II from RA serum induced pro-inflammatory cytokine production from monocytes via FcγRIIa, showing how specific autoantibodies might induce or perpetuate joint inflammation in RA. </p><p>I have described how ICs can induce significant amounts of pathophysiologically important monocyte-derived cytokines in three major IC-dependent diseases. Blockade of FcγRIIa and suppression of monocytes/macrophages might be a means of reducing pathogenic IC-induced cytokine production in these diseases. </p>

Immune complexes (ICs) are produced during normal immune responses and facilitate clearance of foreign antigens. ICs not efficiently cleared from the circulation can cause tissue damage. This might happen if ICs are formed with autoantibodies and autoantigens. Well described effects of ICs are neutralization of antigen, classical complement activation or FcR-mediated phagocytosis, whereas cytokine inducing effects of ICs in human clinical settings are less well described. I have investigated cytokine-inducing properties in vitro of ICs from patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and cryoglobulinemia in association with lymphoproliferative diseases. Cryoglobulin (CG)-induced cytokine production varied with changes in temperature and ionic strength in parallel to CG precipitation. IgG CG-induced cytokine production was also mediated via FcγIIa on monocytes. Blockade of the complement system, resembling the in vivo situation of complement consumption in CG-associated diseases, increased IgG CG induced IL-10 and decreased TNF-α production. This represents hitherto not described mechanisms for CG-associated inflammation. ICs from SLE patients induced IL-10 and IL-6 production from PBMC cultures via FcγRIIa. Occurrence of anti-SSA autoantibodies and signs of in vivo complement activation contributed to increased levels of circulating ICs in SLE patients, corresponding to increased amounts of IC-induced IL-10 in vitro. This represents a possible vicious cycle that might perpetuate antibody dependent pathology in SLE, and put anti-SSA in a new pathological context. RF-associated ICs from RA joints and ICs formed with antibodies against collagen type II from RA serum induced pro-inflammatory cytokine production from monocytes via FcγRIIa, showing how specific autoantibodies might induce or perpetuate joint inflammation in RA. I have described how ICs can induce significant amounts of pathophysiologically important monocyte-derived cytokines in three major IC-dependent diseases. Blockade of FcγRIIa and suppression of monocytes/macrophages might be a means of reducing pathogenic IC-induced cytokine production in these diseases.