Dissertations / Theses on the topic 'Rheumatic'

Rheumatic Heart Disease remains one of the most neglected cardiac conditions in children and young adults around the world. The pathogenesis is complex and remains elusive, and the clinical characteristics vary around the world. This thesis concentrates on different aspects of the disease in Egypt, where it is known to have a high incidence. The methodology included epidemiological studies in school children in Aswan and investigation of RHD in a population with history of RF, using newly developed echocardiographic criteria. Concomitantly, the pattern of immune response in RF and RHD was determined in serum and excised valves. In this series RF presents in children and young adults, as well as adults, (0.2-44 years, 10.69 ± 6.24) with polyarthritis being the most common clinical presentation (87.9%) and recurrences of RF being very common (98.2%). RHD affected 23 in 1000 school children in Aswan with over 90% of the cases being subclinical and developed in up to 69.2% of the individuals with history of RF, predominantly as mitral regurgitation. Risk factors for the development and severity of RHD were shown to be low disease awareness, non-compliance to penicillin prophylaxis or a regimen of longer than 15-days. Resistance to antibiotic regimens, including Penicillin and Vancomicin seems to lead to development and recurrences of RF in Egypt. This series showed the presence of immune activation and ongoing immunological reaction in an apparently quiescent phase of the disease with distortion of normal valvular architecture, histology and composition. This work has served to define the epidemiology, pattern of disease, immune reponse and predisposing factors in a population with no previous data, also contributing to the improvement of the echocardiographic diagnostic criteria. Standardization of the criteria will allow comparison of prevalence in different areas and improve case detection.

Class of 2012
Specific Aims: To evaluate the presence of statistical information from clinical studies in official product labeling specific for disease-modifying anti-rheumatic drugs (DMARDs) used in the treatment of rheumatoid arthritis. Methods: Data were abstracted from official product labeling DMARDs with FDA approval for treatment of rheumatoid arthritis. Each document was examined for the presence of statement regarding a priori type 1 error rate, p-values, and measures of variance. Medications were classified as either biologic or non-biologic. Main Results: A total of 14 DMARDs, 7 biologics (50%) and 7 non-biologics (50%), were found to be FDA approved for the treatment of rheumatoid arthritis. Primary outcomes consisted of American College of Rheumatology (ACR) response rates, radiographic changes, and health assessment questionnaire score (HAQ). Any measure of variance and the presence of a p-value were both found in six (43%) of the drug labels. Inclusion of p- values was found to be significantly greater in biologics compared to non-biologics for both ACR and radiographic results. Inclusion of variance was found to be significantly greater in biologics compared to non-biologics for radiographic changes only. No package inserts contained statements regarding the a priori type I error rate. Conclusions: Measures of variance are not frequently included in product labeling for either biologic or non-biologic DMARDs. However, inclusion of variance and p-values for ACR response rates and radiographic changes were more likely to be reported for biologics therapies as compared to non-biologics. A statement regarding Type 1 error rates were absent from labels regardless of outcome assessed.

Class of 2012 Abstract
Specific Aims: To evaluate the presence of statistical information from clinical studies in official product labeling specific for disease-modifying anti-rheumatic drugs (DMARDs) used in the treatment of rheumatoid arthritis. Methods: Data were abstracted from official product labeling DMARDs with FDA approval for treatment of rheumatoid arthritis. Each document was examined for the presence of statement regarding a priori type 1 error rate, p-values, and measures of variance. Medications were classified as either biologic or non-biologic. Main Results: A total of 14 DMARDs, 7 biologics (50%) and 7 non-biologics (50%), were found to be FDA approved for the treatment of rheumatoid arthritis. Primary outcomes consisted of American College of Rheumatology (ACR) response rates, radiographic changes, and health assessment questionnaire score (HAQ). Any measure of variance and the presence of a p-value were both found in six (43%) of the drug labels. Inclusion of p-values was found to be significantly greater in biologics compared to non-biologics for both ACR and radiographic results. Inclusion of variance was found to be significantly greater in biologics compared to non-biologics for radiographic changes only. No package inserts contained statements regarding the a priori type I error rate. Conclusions: Measures of variance are not frequently included in product labeling for either biologic or non-biologic DMARDs. However, inclusion of variance and p-values for ACR response rates and radiographic changes were more likely to be reported for biologics therapies as compared to non-biologics. A statement regarding Type 1 error rates were absent from labels regardless of outcome assessed.

This is a collaboration project between the Nepal Heart Foundation (NHF) and the University of Greenwich (UoG), United Kingdom (UK). Our mutual aim, agreed at the outset, has been to analyse, design and develop a cost effective Clinical Decision Support System (CDSS) for diagnosis and recognition of Acute Rheumatic Fever (ARF) and Rheumatic Heart Disease (RHD) at an early stage by developing/adopting UK’s and NHF’s treatment practices and procedures that would be appropriate for the Nepalese environment and lifestyle. The Application we developed was designed for use by community health workers and doctors in the rural areas of Nepal where laboratory facilities, expert services and technology are often deficient. The research undertaken investigated three problems that previously had not been addressed in the Artificial Intelligence (AI) community. These are: 1) ARF in Nepal has created a lot of confusion in diagnosis and treatment, due to the lack of standard procedures; 2) the adoption of foreign guidelines is often not effective and does not suit the Nepali environment and lifestyle and 3) the value of combining (our proposed) Hybrid Approach (Knowledge-based System (KBS), Temporal Theory (TT) and Fuzzy Logic (FL)) to design and develop an application to diagnose ARF cases at an early stage in English and Nepali. This research presents, validates and evaluates a proposed Hybrid Approach to diagnose ARF at three different stages: 1) Detected; 2) Suspected and 3) Not-detected and also to identify the severity level of detected ARF in the forms of Severe Case, Moderate Case or Mild Case. The Hybrid Approach is a combination of the KBS/Boolean Rule Model, Temporal Model and Fuzzy Model. The KBS/Boolean Rule Model has four components for design and implementation of KBS. These are: identifying the ARF stage in a case; Rule Pattern Matching; New Rule Formation and Rule Selection Mechanism. The Temporal Model has four components namely: Descriptive Explanation of ARF symptoms; Temporal Lookup-Table/Rules and Temporal Reasoning which produce a Temporal Template for demonstrating the relationship between the signs and ARF. The Fuzzification, Fuzzy Inferences and Defuzzification components are applied to design and implement a Fuzzy Model. The research undertaken divided the overall ARF diagnosis problem, in effect its requirements, into several sub-problems and each model of the Hybrid Approach addressed particular sub-problems for example, Identify the stage of the ARF component of the KBS/Boolean Rule Model used to solve the question of identifying the stage of ARF based on the symptoms presented. Each problem was therefore handled using a particular model’s components. This significantly helped to improve maintainability, reliability and the overall quality of our final ARF Diagnosis Application. The developed ARF Diagnosis Application was experimentally tested and evaluated by NHF’s experts and users through applying NHF’s data sets consisting of 676 real patients’ records. The ARF Diagnosis Application was found to match 99% of the cases derived from NHF’s datasets. The overall ARF diagnostics performance and accuracy was 99.36%. Therefore, the experiments and evaluations of our ARF Diagnosis Application proved that it was logically and technically feasible to employ the Hybrid Approach for developing a new and practical ARF Diagnosis Application. The Application was ultimately developed and succeeded in embracing NHF’s requirements and guidelines thereby matching the Nepalese setting and making it suitable for use in Nepal having fully by met the exigencies of the Nepalese environment and lifestyle. Application of a new ARF diagnosis system (ours) proved that the Hybrid Approach, applied methods of diagnosis of ARF, medication and treatment plan, including help and supporting information which were identified and defined, were shown to be appropriate to support effectively community health workers and doctors who actively care for ARF and RHD cases in rural Nepal.

Osteoporosis and fragility fractures are recognized complications of inflammatory rheumatic diseases. This is thought to result from the effects of chronic inflammation, relative immobility and corticosteroid use. A rare syndrome of osteoporosis in a patient with coeliac disease has been described which results from production of neutralizing antibodies to the bone protective protein osteoprotegerin (OPG). The aim of my thesis is to evaluate prevalence and clinical predictors of osteoporosis in a contemporary cohort of patients with rheumatoid arthritis (RA) and to investigate the role of OPG autoantibodies in the pathogenesis of osteoporosis in rheumatic diseases. In a retrospective cohort study, I found that the overall prevalence of osteoporosis in patients with RA was 29.9% which is in keeping with older reports that recorded a prevalence rate between 17% and 36%. In our contemporary cohort osteoporosis was significantly more common than in a gender and age matched control cohort (17.4%). Further analysis showed that only age and BMI were independent predictors of osteoporosis in RA. A predictive tool based on age and BMI was developed which had 91.4% sensitivity for the detection of osteoporosis in an independent RA population. I went on to screen for the presence of autoantibodies to OPG in patients with various rheumatic diseases. In a study of 75 patients with rheumatoid arthritis and 199 healthy controls OPG autoantibodies were detected in two controls (1%) compared with seven patients with RA (9.3%). The RA patients with detectable OPG antibodies had a longer disease duration, higher DAS28 scores and higher levels of the bone resorption marker CTX than RA patients who did not have autoantibodies. Purified IgG from patients with high levels of OPG antibodies blocked the ability of recombinant OPG to inhibit RANKL induced NFκB activation in a HEK293 cell based assay indicating that they were functional. In a further study of 134 patients with ankylosing spondylitis (AS), 16 patients (11.9%) had detectable OPG antibodies. The presence of OPG-Ab was independently associated with reduced hip bone mineral density and an increased risk of fractures in this population. In patients with a longer disease duration we have also observed that there was a higher discrepancy between spinal and hip BMD in OPG-Ab positive patients compared with OPG ab negative patients (p=0.003). In order to investigate if OPG antibodies affected measurement of serum RANKL concentrations as detected by ELISA using OPG as the capture reagent, I measured OPG ab and free RANKL concentrations in 55 rheumatic disease patients. Surprisingly there was a significant positive correlation between free RANKL and OPG Ab concentrations (r=0.430, p=0.001) which was the opposite to what I had expected. These findings reject the hypothesis that OPG ab block binding of synthetic OPG to RANKL in the ELISA. In conclusion, I have shown that osteoporosis is a common complication in RA and I have developed a new risk prediction tool for the use in clinical practice. I have also found that OPG antibodies are produced more commonly in patients with RA and AS than in healthy controls and that antibody levels correlate with bone resorption markers in RA and bone mineral density in AS patients. In vitro studies have shown that some OPG antibodies have functional effects on RANKL signalling. These findings raise the possibility that OPG antibodies may contribute to the pathogenesis of local and systemic bone loss in rheumatic diseases and signal the need to study the relationship between these antibodies and bone disease in large-scale longitudinal studies.

The group A beta-haemolytic streptococcus is known to be the aetiologic agent in acute rheumatic fever, but the exact pathogenesis remains obscure. A review of the histopathology of the Aschoff body suggests that the cardiac pathology is a granulomatous hypersensitivity reaction. However the streptococcus has not been found in the lesions, and the agent responsible for the granuloma has not yet been identified. Circulating immune complexes have previously been measured in some children with acute rheumatic fever. The normal or raised complement components measured by some workers in acute rheumatic fever suggests that the immune complexes may not be complement fixing. Considering that the usual assays for measuring immune complexes depend on complement fixation, the failure of the immune complexes to fix complement might produce false negative results. A physical, non-complement fixing assay (polyethylene glycol precipitation - PEG), was therefore used to measure circulating immune complexes. Results were expressed as total IgG precipitated (g/L), or as a percentage of serum IgG. Immune complexes were also measured by two complement dependent assays, a Clq binding assay (ClqBA), and conglutinin binding assay (CBA). Complexes were assayed in 15 children with acute rheumatic carditis (ARC), 11 with non-active, chronic rheumatic heart disease (CRHD), 13 with acute poststreptococcal glomerulonephritis (APSGN), and 15 normal children and adults (NORMAL). Total haemolytic complement, complement components as well as the complement breakdown product C3d, were measured.

Rheumatic heart disease (RHD), the permanent damage of the heart valves caused by an untreated 'strep throat' infection, is the leading cause of cardiovascular mortality and morbidity in children and young adults worldwide. Simple penicillin treatment after the early diagnosis of RHD can stop recurring bouts of the condition, which lead to the most severe valvulopathy, and ultimately, heart failure. However, RHD is an under-diagnosed condition in the developing world, as such a diagnosis requires, at a minimum, a trained clinician to perform auscultation to detect pathological heart sounds. Trained medical personnel are scarce in the countries where RHD is most prevalent. A low-cost, mobile phone-based automatic diagnostic tool offers a potential solution, allowing a non-medically trained individual to screen for RHD in those countries. An essential feature of such a device is feedback on the signal quality of heart sound recordings. The first major contribution of this thesis is the investigation of features and algorithms for the automatic signal quality assessment of heart sound recordings. These algorithms are able to differentiate between good- and poor-quality recordings in over 80% of cases when using both a low-cost mobile phone-based stethoscope and an electronic stethoscope. Once the quality of recordings is ensured, the positions of the first and second heart sounds need to be located in a process called segmentation. This thesis extends the state-of-the art hidden semi-Markov models by: investigating additional features; extending the Viterbi algorithm; incorporating logistic regression into the model to form a hybrid generative-discriminative model; and investigating a discriminative duration-dependent probabilistic model - a conditional random field. These extensions are found to outperform the state-of-the-art method. Lastly, the period between the first and second heart sounds can be analysed for the presence of a pathological murmur. This thesis presents automated systolic murmur classification algorithms based on wavelet and mel-frequency cepstral coefficient-based features along with denoising via cycle averaging. These algorithms outperform three methods from the literature when detecting valvulopathy, while also outperforming a cardiologist and commercial software when detecting RHD in mobile phone-based heart sound recordings.

Background: The epidemiological, genetic and host immunogenetic association between Group A P haemolytic Streptococcal (GAS) pharyngotonsillitis and the subsequent development of Acute Rheumatic Fever (ARF) and Rheumatic Heart Disease (RHD) is an area of major interest. RHD still remains an important contributor to cardiovascular disease in children and adults in Yemen. Aims: The purpose of this study was to determine: (i) the prevalence ofRHD among primary school children in Aden City, Yemen, (ii) the prevalence of GAS and Non Group A β haemolytic Streptococcal (SNA) pharyngotonsillitis among patients attending primary health care centres, (iii) the distribution of emm genotypes and selected superantigen prophage exotoxin anasofgenes among GAS and SNA , (iv) the antimicrobial susceptibility pattern of GAS and SNA in patients with a history of ARF and RHD, (v) comparision of a profile of selected cytokines and chemokines between ARF and recurrent rheumatic fever (RRF) patients. Methods: A cross-sectional case-finding survey of RHD was conducted in 6000 school children aged 5 - 16 years in Aden City to determine the prevalence of RHD. A cross- sectional descriptive survey was undertaken in 730 children aged 1- 16 years with acute pharyngotonsillitis to determine the prevalence of GAS and SNA infections. Thirty four throat culture isolates from patients with GAS and SNA pharyngotonsillitis with history of ARF and echo-proven cases of RHD were analyzed by a multiplex PCR method to determine the emm genotypes, presence of superantigen prophage-associated virulence genes and so! genes. Antibiotic sensitivity tests were conducted on 24 GAS and SNA throat culture isolates using the BSAC disc diffusison method. Fourteen serum cytokine and chemokine concentrations including interleukin-Iβ (IL-lβ), interleukin-6 (IL-6), interleukin-7 (IL-7), interleukin-8 (IL-8), interleukin-9 (IL-9), interleukin-10 0 (IL-I0), interleukin-12p70 (IL-12p70), tumor necrosis factor (TNF-α), interferon gamma (IFN- γ), chemokines monocyte chemotactic protein-I (MCP-1), macrophage inflammatory protein-I a (MIP-1 a), macrophage inflammatory protein-I P (MIP-I P), human interferon inducable protein-I 0 (IP-IO) and regulated upon activation, normal T-cell expressed and secreted (RANTES) protein levels from children with ARF and RRF were analyzed by the BD F ACS Array Bioanalyzer using FCAP Array Software. Results: The prevalence of RHD was 36.5/1000 school children which is one of the highest reported among school echo cardiography surveys in the world. RHD had a high preponderance in 10-16 years old students. 49.8% had mitral regurgitation (MR) lesions, 26.6% had MR with mitral valve prolapse (MVP) and 17.8% with combined MR and aortic regurgitation (AR) lesions. RI--ID was diagnosed in more than one family member in 53 (24.2%) of the children. A high prevalence of GAS pharyngotonsillitis (41.5%) was noticed in children of 11 - 15 years of age. A red erythematous uvula and petechie on the soft palate were observed significantly more commoinlyin GAS pharyngotonsillitis. Group B (GBS), Group C (GCS) and Group Gβ haemolytic streptococci (GGS) were isolated from pharyngotonsillitis in 4.3% patients with history of ARF/RHD. The most frequent GAS isolates among ARF and RI-ID patients with pharyngotonsillitis were emm87, emm12, emm28 and emm5. This is the first report of emm87 and emm28 genotypes to be potentially rheumatogenic. The 11 emm87 GAS isolates shared a common PFGE pattern and profile of five exotoxin prophage genes spec, spdl, sdn, sUC and silD with the sof 87 sequence. emm12 and emm28 GAS strains were positive for gene sof , spec and spd1. This is the first report to describe the pattern of exotoxin prophage genes of spec, spd1, sdn, silC and silD among emm87,-emm12, emm28 and emm5 GAS and SNA (GBS, GCS and GGS) isolates with history of ARF and RHD. The genotypic characteristics of GBS, GCS and GGS isolates confirmed seven new emm sequence types first detected among children with acute pharyngotonsillitis. GAS and SNA isolates were susceptible to the β-lactam antimicrobials, penicillin and amoxicillin. Erythromycin resistance was detected in so! positive emm 12 and emm28 in 50% and 33% of isolates respectively. Chemokine MCP-l was significantly correlated with cytokines, IL-lβ, IL-6, IL-l0, IL- 12p70, TNF-α, IFN-γ and RANTES in patients with RRF. This suggests that MCP-l could serve as a potential inflammatorybiomarker for patients with RRF having underlying RHD. MIP-1~ had significant correlations with IL-8, IL-lO, IL-12p70, IP- 10, TNF-α and IFN-γ in patients with ARF. MIP-l~ may serve as a potential inflammatory biomarker in patients with ARF without RHD. Conclusions: The high prevalence of RHD is an alarming public health problem in Yemen. Urgent screening surveys and a preventive RHD prophylactic program with appropriate management of GAS pharyngotonsillitis are required. Future studies are needed to confirm the rheumatogenic GAS and SNA strains with their exotoxin prohage genes and the role of the chemokines and cytokines as biomarkers for ARF within the complex network of auto immune reactions in RF/RHD. This study hopes to provide a further small step in elucidating the pathogenesis of this complex immunological disease.

Introduction Rheumatic disease is an autoimmune disorder with an unpredictable course of exacerbation and remission. There is no known cure for the disease at the moment. The patients’ conditions may progressively deteriorate despite intensive therapies, and runs an erratic course with the possibility of disfiguration and alteration in body image. Pain, disabilities and psychological distress are common. Rheumatic patients may respond differently to the same level of pain and physical symptoms. The understanding of the needs of rheumatic patients and how they successfully manage the disease and optimize psychological adjustment can help develop effective psychosocial interventions. Aims The aims of the study are (1) to identify the needs of rheumatic patients and perceptions of their disease, (2) to develop a conceptual framework for psychological adjustment, and (3) to identify factors associated with resilience in rheumatic patients. Methods The present study consisted of two phases. The first phase was a focus group interview, aiming to understand the patients’ feelings and to design a questionnaire. The second phase was a prospective questionnaire survey that includes a baseline study and a six-month follow-up study. Patients were recruited from support groups in Hong Kong. The baseline questionnaire was self-administrated, and the follow-up questionnaire was administrated by telephone interview. The self-regulation model was chosen as the basis for the conceptual framework for psychological adjustment. The questionnaire included demographics, illness representation, coping efforts, appraisal of coping efforts, sense of coherence, quality of care, functional disability, and health-related quality of life. The outcome measures were functional and psychological health, change in adjustment, and positive and negative resilience. Results Having a good and caring doctor, more information on the disease, and public understanding of the disease were the needs of rheumatic patients. The patients perceived that the disease was chronic, cyclical, and had poor consequences. They perceived that the disease caused great pain, stress, depression and anxiety, and affected their daily activities, appearance, and relationship with family and friends. Poor adjustment was associated with chronic and cyclical timeline, and poor perception of personal and treatment control. The analysis of resilience shows that positive perception of treatment control and disease consequence, correct understanding of disease causes, and high sense of own value and importance to the society, were protective. While those who lacked family support and blamed themselves or their families to be the cause of disease, were vulnerable. Discussion and conclusions The present study lends support to the validity of self-regulation model in psychological adjustment to disease, but coping efforts could only partially mediate the relationship of illness representation to appraisal of coping efforts, implying that the coping style might not sufficiently capture the underlying differences in individual coping styles. An effective psychosocial intervention can be developed based on the factors associated with better adjustment and resilience, and targeted at non-working older patients with rheumatoid arthritis. Last but not least, support from the community, and public understanding of the disease are important for rheumatic patients.
published_or_final_version
Psychiatry
Doctoral
Doctor of Philosophy

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.

Rheumatic heart disease is an inflammatory heart disease that affects millions of people around the world. Especially high rates of the disease can be found in Oceania, including the island nation of Samoa. Genetic studies of immune response genes have provided insight into a possible genetic link to increased susceptibility to rheumatic heart disease, including the genes that code for the toll-like receptor (TLR) protein family. One of the functions of TLR proteins is to recognize the presence of bacteria via identification of bacterial flagella. My evaluation of a Samoan family identified a variant in the TLR-5 gene that would inhibit this ability. However, further study showed this variant to not be statistically significant in relation to rheumatic heart disease susceptibility. My contribution to a regional genome-wide association study of Oceania resulted in the discovery of a variant in the IGHV4-61 gene affecting the ability of antibodies to properly bind to bacterial antigens. This variant was associated with a 1.4-fold increased risk of rheumatic heart disease development. The success of this study warrants further investigation of the IGHV4-61 variant in other populations and illustrates the benefits of utilizing a genome-wide association study to study rheumatic heart disease.

Objective: to assess the prevalence of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and spondyloarthropathy (SpA) in Vilnius, Lithuania. Methods: 3 prevalence studies were conducted: 1. Registry-based study of the prevalence of RA and SLE; 2. Population-based study of the prevalence of RA and SLE (interview conducted by mail); 3. Poulation-based study of the prevalence of RA and SpA (interview conducted by telephone). Results: according to the Vilnius RA and SLE registry, the prevalence of RA in Vilnius at the end of year 2004 was 0,14% (95% CI 0,13-0,15), and the prevalence of SLE was 0,0174% or 17,4/100 000 (95% CI 0,0137-0,0218). The population-based study, conducted by mail, revealed 15 RA and 2 SLE cases, accounting for a prevalence rate of RA of 0,37% (95% CI 0,21-0,62), and a prevalence of SLE rate of 0,0498% (95% CI 0,006-0,180). The standardized prevalence rate according to age and sex in the Vilnius population showed an RA prevalence of 0,32% (95% CI 0,18-0,57). The population-based study, conducted be telephone, detected 16 RA and 13 SpA cases, resulting in a crude prevalence of 0,76% (95% CI 0,44-1,24) for RA and 0,62% (95% CI 0,33-1,06) for SpA. The standardized prevalence rate according to age and sex in the Vilnius population showed an RA prevalence of 0,51% (95% CI 0,29-0,96) and a SpA prevalence of – 0,75% (95% CI 0,38-1,40).
Darbo tikslas: nustatyti reumatoidinio artrito (RA), seronegatyvių spondiloartropatijų (SpA) bei sisteminės raudonosios vilkligės (SRV) paplitimą Vilniaus mieste. Darbo metodika: Buvo atlikti 3 tyrimai: 1. RA ir SRV paplitimo Vilniaus mieste apskaičiavimas, remiantis Vilniaus miesto RA ir SRV sergančių asmenų duomenų baze; 2. RA ir SRV paplitimo Vilniaus mieste populiacinis tyrimas, apklausiant Vilniaus miesto gyventojus paštu; 3. RA ir SpA paplitimo Vilniaus mieste populiacinis tyrimas, apklausiant Vilniaus miesto gyventojus telefonu. Rezultatai: remiantis Vilniaus miesto RA ir SRV sergančiųjų duomenų baze, RA paplitimas Vilniaus mieste 2004m. pabaigoje buvo 0,14% (95% PI 0,13-0,15). Apskaičiuotas SRV paplitimas Vilniuje 2004m. pabaigoje buvo 0,0174% arba 17,4/100 000 gyventojų (95% PI 0,0137-0,0218). Atlikus RA ir SRV paplitimo tyrimą (apklausą paštu), nustatyta, kad RA paplitimas Vilniuje yra 0,37% (95% PI 0,21-0,62), o SRV paplitimas – 0,0498% (95% PI 0,006-0,180). RA paplitimas buvo standartizuotas pagal amžių ir lytį, remiantis 2004m. pradžios Vilniaus miesto populiacija, apskaičiuotas standartizuotas RA paplitimas yra 0,32% (95% PI 0,18-0,57). Atlikus RA ir SpA paplitimo tyrimą (apklausą telefonu), apskaičiuotas RA paplitimas buvo 0,76% (95% PI 0,44-1,24), o SpA paplitimas - 0,62% (95% PI 0,33-1,06). RA ir SpA paplitimas buvo standartizuotas pagal amžių ir lytį, remiantis 2004m. pradžios Lietuvos populiacija, apskaičiuotas standartizuotas RA paplitimas yra 0,51% (95%... [toliau žr. visą tekstą]

Immune complexes (IC) have key pathological roles in both autoimmune and infectious diseases. In this thesis functional mechanisms behind IC-driven inflammation in rheumatic diseases and tropical infections have been studied, with special focus on the contribution of autoantibodies and cytokine-inducing properties of IC. In the autoimmune disease SLE, increased levels of IC-induced cytokines were associated with both increased classical complement activation and the occurrence of the autoantibodies anti-SSA and anti-SSB, both directed against RNA-associated antigens. In addition, complement activation and anti-SSA synergistically predisposed to higher levels of IC in sera. In the following study it was demonstrated that also other autoantibodies against RNA-associated autoantigens were more enriched than anti-dsDNA in SLE IC. Sudanese Visceral Leishmaniasis (VL) patients had elevated IC levels, and precipitated IC induced higher levels of GM-CSF, IL10, IL6 and IL1RA than control IC. Levels of IC were especially prominent in severely ill patients receiving antimony treatment, and a parallel association with IC induction of GM-CSF was demonstrated. Leishmania-infected patients were often rheumatoid factor (RF) positive and a substantial number displayed reactivity towards cyclic citrullinated peptide (CCP) antigens. Contrary to what was seen in Sudanese RA sera, the CCP reactivity was not restricted to citrulline but reacted equally well with arginine-containing control peptides. Levels of anti-CCP among VL patients were not due to cross-reactions with, or CCP-reactivity bound to IC. I have demonstrated that IC are associated with the presence of autoantibodies in both SLE and in Leishmania infection. In SLE, autoantibodies against RNA-associated antigens were more prone to form circulating IC than anti-dsDNA. In Leishmania infection false reactivity against the CCP-autoantigen correlated to IC levels although the IC themselves did not contain such reactivity. In both diseases higher IC levels were associated with a more active disease, and purified IC induced key cytokines in disease pathogeneses.

Background: Determinants of response and relapse to B cell depletion in rheumatic diseases is poorly understood, but necessary to improve its clinical use. Objectives: The aims of this study were (1) to test peripheral blood biomarkers for non-response in RA and systemic lupus erythematosus; (2) to evaluate variations in treatment regimen using these biomarkers; (3) to correlate peripheral blood findings with synovial tissue Results: In both RA and SLE, peripheral blood B cell subsets were predictive of response and relapse. Increase numbers of.memory B cells and plasma blasts before or immediately after rituximab were predictive of worse responses, and numbers of these subsets in early repopulation were predictive of relapse. Differences in pattern of depletion and re population were observed between these diseases. These markers correlated with improved response when combining rituximab with alternative DMARDs, when altering rituximab dose, or using early retreatment to improve poor response. Changes in antibodies were studied: these did not correlate with clinical response, but persistently high levels of rheumatoid factor after rituximab were predictive of earlier relapse, as was persistence of synovial plasma cells. Baseline levels of BAFF and IL-6 were predictive of clinical response. Abnormalities ofT cell homeostasis were partially reversed by rituximab, which also correlated with clinical response. Pilot data indicate changes in B cell phenotype in some patients whose importance in clinical response is as yet undetermined. In SLE, some subtypes of disease were less responsive to rituximab. Conclusions: Increased B cell numbers before and after rituximab predict worse clinical response, but this can be overcome by dose, combination DMARD or retreatment interval. Markers of B cell activation prior to rituximab predict good response to treatment. However, after rituximab, these markers, as well as B cell repopulation, also predict earlier relapse and the need for retreatment. These observations provide a rationale for future attempts to improve clinical use of rituximab.

L’artrite reumatoide, la spondilite anchilosante e l’artrite psoriasica sono malattie infiammatorie croniche, progressive e invalidanti che colpiscono le articolazioni provocando dolore e disabilità. I recettori dell’adenosina giocano un ruolo fondamentale nel meccanismo infiammatorio, in particolare l’attivazione dei sottotipi recettoriali A2A e A3 è spesso associata ad una riduzione dello stato infiammatorio. Il primo obiettivo di questo studio è stato quello di indagare il coinvolgimento dei recettori adenosinici nei pazienti affetti da artrite reumatoide all’esordio della patologia (non ancora in cura), artrite reumatoide, spondilite anchilosante ed artrite psoriasica. L’analisi dell’RNA messaggero (mRNA) e gli esperimenti di saturazione del binding hanno indicato una sovraespressione dei recettori A2A e A3 dell’adenosina nei linfociti ottenuti dai pazienti, comparati con soggetti di controllo sani. Gli agonisti dei recettori adenosinici A2A e A3 sono stati in grado di inibire l’attivazione di NF-κB, un complesso proteico funzionante come fattore di trascrizione. Inoltre hanno ridotto il rilascio di citochine pro infiammatorie, come ad esempio TNF-α, IL-1β e IL-6. Per di più l’attivazione dei sottotipi recettoriali A2A e A3 è stata in grado di mediare una riduzione delle metalloproteasi (MMP)-1 e MMP-3. L’effetto degli agonisti è stato annullato grazie alla somministrazione di antagonisti recettoriali selettivi, dimostrando così il diretto coinvolgimento di questi sottotipi recettoriali. Questi dati confermano l’implicazione dei recettori dell’adenosina nelle patologie reumatiche cronico degenerative evidenziando la possibilità di utilizzare i recettori A2A e A3 dell’adenosina come target terapeutici, con lo scopo di limitare la risposta infiammatoria spesso associata ad artrite reumatoide, spondilite anchilosante ed artrite psoriasica. Lo scopo del secondo capitolo di questa tesi, è stato quello di valutare la modulazione dei recettori A2A e A3 dell’adenosina nei pazienti affetti dalle patologie prese in esame nel primo capitolo, dopo diversi trattamenti farmacologici. Abbiamo indagato sulla densità e la funzionalità recettoriale nella progressione delle patologie attraverso uno studio longitudinale nei pazienti affetti da artrite reumatoide, spondilite anchilosante ed artrite psoriasica prima e dopo le terapie in uso, quali metotressato, agenti anti-TNFα o rituximab. I recettori A2A e A3 dell’adenosina sono stati analizzati attraverso esperimenti di saturazione del binding nei linfociti dei pazienti presi in esame, durante un periodo di ricerca della durata di 24 mesi. Nei linfociti ottenuti dai pazienti affetti da artrite reumatoide, la sovraespressione dei sottotipi recettoriali A2A e A3 dell’adenosina è stata gradualmente ridotta in funzione del tempo di trattamento. Questi risultati confermano il coinvolgimento dei recettori adenosinici A2A e A3 nella progressione delle patologie reumatiche cronico degenerative, sottolineando che gli agonisti dei recettori A2A e A3 dell’adenosina potrebbero rappresentare un’alternativa terapeutica per il trattamento dell’artrite reumatoide.
Rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) are chronic inflammatory rheumatic diseases that affect joints, causing debilitating pain and disability. Adenosine receptors (ARs) play a key role in the mechanism of inflammation, and the activation of A2A and A3AR subtypes is often associated with a reduction of the inflammatory status. The first aim of this study was to investigate the involvement of ARs in patients suffering from early-RA (ERA), RA, AS and PsA. Messenger RNA (mRNA) analysis and saturation binding experiments indicated an upregulation of A2A and A3ARs in lymphocytes obtained from patients when compared with healthy subjects. A2A and A3AR agonists inhibited nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) activation and reduced inflammatory cytokines release, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6. Moreover, A2A and A3AR activation mediated a reduction of metalloproteinases (MMP)-1 and MMP-3. The effect of the agonists was abrogated by selective antagonists demonstrating the direct involvement of these receptor subtypes. These data confirmed the involvement of ARs in chronic autoimmune rheumatic diseases highlighting the possibility to exploit A2A and A3ARs as therapeutic targets, with the aim to limit the inflammatory responses usually associated with RA, AS and PsA. The purpose of the second chapter of this thesis, was to evaluate the modulation of A2A and A3ARs in patients suffering from RA, AS and PsA after different pharmacological treatments. We investigated A2A and A3AR density and functionality in pathologies progression by using a longitudinal study in RA, AS and PsA patients before and after methotrexate (MTX), anti-TNFa agents or rituximab treatments. A2A and A3ARs were analyzed by saturation binding assays in lymphocytes from patients throughout the 24-month study timeframe. In lymphocytes obtained from RA patients, the A2A and A3AR up-regulation was gradually reduced in function of the treatment time. Taken together, these data confirmed the involvement of A2A and A3ARs in chronic inflammatory rheumatic disease progression and highlighted that A2A and A3AR agonists could represent a physiological-like therapeutic alternative for RA treatment.

Human endogenous retroviruses are the remnants of ancient retroviral infections present within our genome. These molecular fossils show similarities with present day exogenous retroviruses but act as typical Mendelian elements that are passed vertically between generations. Despite being repeatedly linked to a number of autoimmune diseases and disorders, no conclusive proof has been identified. Rheumatoid arthritis (RA) is one such disease which has been associated with an increase in HERV expression, compared to controls. In order to elucidate a clear role for HERVs in RA pathogenesis, autoantigens implicated in disease pathogenesis were scanned for sequence homology to retroviral genes. Such epitopes would induce antibodies cross reactive with host proteins, resulting in disease. Short peptides mimicking these regions were synthesised and the prevalence of anti-HERV antibodies was determined in RA patients and disease controls. Additionally, a novel real-time Polymerase Chain Reaction (PCR) assay was developed to accurately quantify levels of HERV-K (HML-2) gag expression, relative to normalised levels of housekeeping gene expression. Both serological and molecular assays showed significant increases in HERV-K (HML-2) activity in RA patients compared to disease controls with CD4+ lymphocytes harbouring the highest activity. The real-time assay was also used to determine whether factors within the synovium could modulate HERVs, resulting in their upregulation. Exogenous viral protein expression and pro-inflammatory cytokines were shown to exert a significant modulatory effect over HERV-K (HML-2) transcription. From this data, it is clear that RA patients have increased levels of HERV-K (HML-2) gag activity compared to controls. Despite this it is likely that factors within the synovium such as exogenous viral expression and pro-inflammatory cytokines also influence HERV-K (HML-2) transcription possibly contributing to a role of bystander activation, i.e. being influenced by external factors, rather than actively contributing to disease processes. The exact role of HERVs in RA pathology remains elusive; however this research proposes several mechanisms by which HERV-K (HML-2) may contribute to disease.

Neuropsychiatric (NP) symptoms are relatively common in patients with SLE. The diverse and dramatic clinical presentations, the unclear pathogenesis, the lack of diagnostic test/s and uncertainties about the optimal management are some problems facing a clinician. When serum anti P antibodies were claimed to be highly correlated to lupus psychosis, this needed confirmation. An ELISA for measuring anti P antibodies was developed and validated. The prevalence of anti P antibodies was determined in different patient groups in a large retrospective study. Although anti P antibodies were highly specific for SLE, there was no correlation between the presence of these antibodies and lupus psychosis or other NP symptoms. Two prospective studies were carried out to eliminate any bias in our retrospective study. In one, none of the patients developed psychosis and these antibodies were not found to be specific for lupus depression or anxiety. In the other, anti P antibodies were measured in Malaysian Chinese SLE patients. No correlation was found between these antibodies and NP-SLE but a high prevalence of these antibodies was demonstrated in this group. Genetic studies showed that there was an increase in HLA-Dr2w16X subtype allele in anti P-positive patients but this did not reach significance. The usefulness of measuring antineuronal antibodies in helping to diagnose NP-SLE was examined but these antibodies were not better indicators of NP-SLE. Although the clinical correlations of anti P antibodies remain controversial, anti P antibodies were found to selectively bind to neuroblastoma cell surfaces in vitro but the nature of the surface antigen was not determined. Finally, sera from patients with lupus psychosis were found to significantly influence the response of neuroblastoma cells to agonist-induced stimulation and if confirmed, would offer an explanation for the reversible changes in cell function associated with psychiatric lupus.

This study surveyed healthcare professionals and rheumatic heart disease (RHD) female participants in two hospitals located in central Afghanistan to examine the effects of communication among healthcare professionals, ethnicity and socioeconomic status, and the health quality of life. The social ecological models (SEM) of health promotion was utilized in the individual (communication between healthcare professionals), community (health quality of life), and societal factors (ethnicity and socioeconomic status). Three research questions were explored in this study: the significance of RHD healthcare professional's education to their RHD female patients ages 16 to 45 years; a correlation between ethnicity and socioeconomic status among the targeted participants; and a correlation between health-related quality of life and RHD education among the targeted participants. This study was a cross-sectional quantitative survey design with 138 participants to determine the factors of RHD education, communication training, and beliefs of the targeted population in assessing RHD effects. McNamara's, Pearson's, and Chi test was used for determining correlation and relation of the research variables. The results of this study showed a correlation between healthcare professional communications and RHD but no correlations for ethnicity and socioeconomic status, and health quality of life and RHD. This study promotes positive social change through training healthcare professional to educate their female RHD patients about prevention and living with the disease. This research showed that the onset of healthcare professional education could reduce the effects of the disease. Moreover, the need for funding of the society would also control the RHD effected population.

Includes abstract.
Includes bibliographical references.
Rheumatic heart disease is still the most common cause of valvular heart lesions requiring replacement or repair procedures worldwide. In South Africa, where there is an interesting mix of first and third world dynamics, factors sustaining the epidemic of rheumatic disease are still commonplace. The choice of appropriate valve procedure and prosthesis in our setting will depend on an adequate knowledge of short and long term outcomes of valve replacement and repair. The aim of this thesis was to evaluate the demographics and presentation of our rheumatic and non-rheumatic patients and to determine if our current implantation choices could be validated.

Острая ревматическая лихорадка – постинфекционное осложнение тонзиллита или фарингита, вызванных b-гемолитическим стрептококком группы А, в виде системного воспалительного заболевания соединительной ткани с преимущественной локализацией в сердечно–сосудистой системе, суставах, мозге и коже, развивающееся главным образом у лиц молодого возраста (7–15 лет). Данное заболевание склонное к рецидивированию и формированию пороков сердца. Таким образом, лечение ревматизма является чрезвычайно актуальной проблемой.

Background: SARDs (Systemic Autoimmune Rheumatic Diseases) are a group of rare, chronic conditions (systemic vasculitis, systemic lupus erythematosus, scleroderma, Sjogren's disease, and poly/dermatomyositis) associated with high health resource consumption. However, estimates of their healthcare burden are sparse, with most determined at tertiary centres over short periods. Studying them separately has also limited research progress. Here we grouped the SARDs, for the first time ever, to quantify their collective, longitudinal (twelve-year) burden at the population-level. Methods: A population-based cohort of SARDs cases was identified from the administrative database of BC’s single-payer health system (PopDataBC). A detailed algorithm, with time and specialist parameters, was used to enhance diagnostic specificity. From PopDataBC, all provincially-funded health services, and all prescriptions (regardless of funding source), consumed from 1996 -2007 were captured. Costs for outpatient services and prescriptions were summed directly from paid claims; case-mix methodology was used for most hospitalizations. To quantify their net burden, costs were summed for claims attributable (under broad and narrow definitions) to SARDs. Costs are reported in 2007 Canadian dollars. Results: 18,741 SARDs cases were identified, contributing 82,140 patient-years(PY). After inflation adjustments, the annual mean per-PY direct medical costs of SARDs averaged $6,954/PY, with $1,882/PY(27%) from outpatient, $3,551/PY(51%) from hospital, and $1,521/PY(22%) from prescriptions. Over twelve years, annual costs decreased by 32%, from $8,901/PY in 1996 to $6,087/PY in 2007. Outpatient costs and encounters decreased by 26% ($2,205-$1,641/PY) and 19% (34-27/PY), respectively. Mean annual hospital costs decreased by half ($5,579-$2,776/PY), and admissions by 46% (0.89-0.48/PY). Despite these decreases, the annual mean number of dispensed prescriptions increased by 49% (23-34/PY), and their costs by 50% ($1,117-$1,670/PY). The annual net per-PY costs of SARDs, mainly from hospitalizations(18-43% of costs) and prescriptions(48-76%), averaged $2,011-$3,202/PY. Conclusions: SARDs impart a substantial healthcare burden at the population level, and in 2007 were directly responsible for ≥44% of cases’ gross mean annual healthcare costs ($6,087/PY). Most costs have decreased over twelve years; however, medication costs are rising (by 4% annually, on-average), which suggests comorbidity burdens are too. As demand grows for expensive but potentially-better SARDs therapies, research to assess their impact on long-term comorbidity risk is needed.

Group A Streptococcal pharyngitis is a common illness in the pediatric population. Penicillin or amoxicillin remain the standard therapy. In nonanaphylactic cases of penicillin allergy, a first-generation cephalosporin may be used.

Background: Rheumatic heart disease (RHD) remains a major public health concern in African countries due to the high rates of complications such as atrial fibrillation, stroke, infective endocarditis, and heart failure, all of which can result in premature death. In 2015, RHD was estimated to affect 33 million people globally and resulted in at least 320,000 deaths, nearly all of which were in low and middle-income countries. Comparing to other non-communicable diseases (NCDs), RHD imposes economic burden on households that if measures are not in place to mitigate this, it can impoverish such household. However, there are several literatures on the intergenerational economic consequences of other chronic diseases. But, there is no study regarding the household economic of RHD. This mini-dissertation sets out to estimate the household economic impact of RHD. Methods: This study was a follow-on study from the Global Rheumatic Heart Disease Registry (REMEDY), which was a multi-center, international, hospital-based prospective registry of patients with RHD. It was designed as a cohort study to document the disease characteristics and outcomes of individuals with RHD across many countries. We recruited participants in the REMEDY study who were resident in Cape Town and received care at Groote Schuur Hospital (GSH). This study made use of patient and household member surveys to estimate the economic consequences of RHD among households in which REMEDY participants reside. REMEDY registry participants (index cases), their caregivers, and other household members were considered as respondents. 100 REMEDY participants receiving care at GSH was sampled. This sample size was chosen to balance feasibility and precision and to align with a parallel study of the cost of RHD to the health system that aimed to sample medical records from the same 100 REMEDY participants. Patient and household data collection was carried out between September 2017 to December 2017. Direct costs, indirect costs, and the downstream economic behaviors (coping strategies) that lead to medical impoverishment and other consequences were estimated. Cost of illness (COI) was used to assess the effect of ill-health and health-related expenditure on the consumption possibilities of households. Direct costs comprise both medical and nonmedical costs, which may include both the financial cost of resources as well as opportunity costs (e.g., of capital items). Human capital approach was used to calculate indirect cost. Implicit in the human capital approach is the assumption that changes in health status of household members can be reflected by losses in productivity, and losses in income generation. Productivity losses was estimated using the new South Africa minimum wage rate per month as proxy. Coping was estimated with the direct costs (e.g., borrowing from friends or relatives, or taking out formal loans) or indirect costs (e.g., intra-household labor substitution) and can be cost prevention strategies (e.g., ignoring illness, non-treatment) to cost management strategies (e.g., borrowing, selling assets, or labor substitution). Economic costs were valued in United State dollar (USD) converted from South African rand (ZAR) in 2017. Results: Direct medical cost was estimated to ZAR 0, because all patients were exempt from medical fees. Total direct non-medical cost for outpatient and inpatient visits was estimated to be ZAR 27,000 (USD 2000) and 29,000 (USD 2200) (respectively) over 302 and 74 encounters (respectively), an average of ZAR 270 (USD 20) and ZAR 290 (USD 22) per patient (respectively). Indirect costs incurred over the 302 outpatient encounters and 74 hospital admissions were estimated to be ZAR 41,000 (USD 3100) and ZAR 26,000 (USD 1900) (respectively), an average of ZAR 410 (USD 31) and ZAR 260 (USD 19) per patient. Direct cost had a very high impact on the household and they were compelled to adopt coping. Households observed in the study recorded that seventeen percent of households took out loans at an average of ZAR 1200 (USD 91) per loan (range ZAR 100 to ZAR 7000) (range USD 7 to 500). Fifteen percent received financial gifts at an average of ZAR 800 (USD 61) per gift. Two percent sold assets valued at ZAR 5600 (USD 120) on average. Five percent engaged in multiple coping strategies. Also, HH had to cope with indirect cost of illness as 15% of household caregivers changed jobs and 10% worked extra hours. About 4% of household members dropped out of school. Four percent adopted more than one coping strategy. A considerable share of participants reported that they had reduced education to take care of the affected patient. Most of the caregivers of patients with RHD were spouses and children, and 6 % were heads of household. The total cost of RHD to the average affected household is valued at about ZAR 1600 annually. In total, the overall annual economic impact of RHD in this sample of 100 households affected by RHD was estimated at ZAR 160,000 (USD 12200) (ZAR 1600 per household) (USD 120), representing 4.4% of annual household income or 4.9% of annual household expenditure patient spending that exceeded 10% threshold was estimated to be 8% and increasing the threshold to 40 % of non- food expenditure reduced the prevalence of catastrophic spending to 4%. Conclusions: The economic impact of RHD in South Africa is substantial despite government efforts to provide free care. The total cost of RHD to the average affected household is valued at about ZAR 1600 annually. A broader and more robust range of social policies will be required to mitigate non-medical and indirect costs and reduce distortions in household economic activity.

Aims: The importance of inflammation in the development of joint damage and subsequent functional limitation, together with the increasing awareness that clinical assessment is insensitive at detecting synovitis, has led to the use of modern imaging modalities such as ultrasonography (US) in rheumatology. This with an emphasis on improved detection of synovitis and earlier, more effective therapeutic intervention. The aim of this thesis was to investigate the role of US in routine practice, by validating its role in diagnosis, prognosis and therapeutic intervention, across a range ofcommon rheumatological clinical scenarios. Methods: Construct validity for US-detected synovitis in knee arthritides was examined by comparison with clinical assessment and arthroscopy. In order to examine the benefits of US-guided joint injections, the accuracy of guided shoulder injections was observed. As well, the efficacy of US-guided corticosteroid injections in hip osteoarthritis and predictors of outcome were also assessed. The sensitivity of US over clinical examination was assessed in a cohort of rheumatoid arthritis patients with low disease activity levels. The diagnostic and therapeutic predictive value of US-detected synovitis in inflammatory hand pain was examined in a large cohort. Finally the clinical utility of US at altering diagnosis and management in clinical rheumatology practice was prospectively examined. Results: For detection of knee synovitis, using arthroscopy as the gold-standard, US had higher sensitivity (98 vs 85%) and specificity (75 vs 25%) than clinical assessment. Kappa values for inter- and intra-reader reliability of US were 0.71 and 0.85 respectively. In the shoulder US-guided injections were 100% accurate, but 55% had evidence of extrabursal contrast limited to the tissue planes adjacent to the bursa. Outcome following hip injection was poor, but synovitis without osteophytes on US was the best predictor of short term benefit. In rheumatoid arthritis patients in clinical remission, the majority satisfying established remission criteria, US detected gray-scale and power Doppler (PD) synovitis in 85% and 60% patients respectively. The kappa value for inter-reader reliability was 0.60 for gray-scale, and intra-reader reliability was 0:60 for gray-scale and 0.62 for PD.Most inflammatory hand pain patients without clinical evidence of an inflammatory arthritis had US synovitis (55%); and US (p < O.OOl), but not clinical, synovitis was significantly associated with response to parenteral corticosteroid therapy. The site-specific diagnosis (53%) and management (53%) was altered in most patients referred for US in a routine clinic. Conclusion: Ultrasonography is now well validated in synovitis detection in small and large joints, and this has substantial implications for the accurate and early diagnosis of inflammatory arthritis, as well as in monitoring outcomes to therapy in rheumatoid arthritis. Ultrasonography can aid prognosis as well as improving placement of guided intra-articular therapies. This work has demonstrated that US has a significant role to play in rheumatology practice.

Background Rheumatoid arthritis (RA) is an autoimmune chronic disease characterized by inflammation of peripheral joints with a various degree of systemic involvement. The pathogenesis is partly understood. Adaptive immunity plays indeed a pivotal role in inducing and maintaining the inflammatory process. Several cells belonging to the adaptive immune system have been associated to specific histological synovial patterns and clinical findings; among these, T helper (Th) lymphocytes have been exhaustively studied in RA due to their capability of producing cytokines and chemokines, migrating into articular sites and activating other immune or resident cells. The pool of Th cells comprehends many subsets, each of which plays a precise role in inducing, tuning and repressing the immune response. Over the past twenty years, five distinct Th cell populations, properly named Th1, Th2, Th17, Th22 and Th9 cells, along with a counterpart of T cells with immune-repressive properties (T regulatory cells) have been described and characterized. Th9 cells develop under stimulation with Tissue Growth Factor-beta (TGF-β) and Interleukin-4 (IL-4) either from naïve or primed Th lymphocytes. They prevalently synthetize IL-9, but, in vitro, the production of IL-10, IL-17, IL-21 and IL-22 has been also reported. Th9 lymphocytes seem to be involved in the immunological responses underlying parasitic infections and allergic diseases. Neutralization of IL-9 worsens the symptomatic course of infestations while ameliorating the allergic manifestations. Some authors have demonstrated that Th9 cells take part to the pathogenesis of experimental autoimmune encephalomyelitis, systemic lupus erythematosus, systemic sclerosis, psoriatic arthritis and RA. Th9 lymphocytes are increased in the bloodstream and in the synovial membranes of RA patients, being their percentage directly related to the degree of lymphoid organisation and to the production of autoantibodies, like anti-citrullinated peptide antibodies (ACPAs). However, it is unclear whether Th9 lymphocytes could be involved in the response to the therapy, or in the immunogenicity of biologic agents. Aim Primary objective: to evaluate the prevalence of Th9 lymphocytes in the peripheral blood of RA patients, assigned or not to an immunosuppressant treatment (including conventional drugs and infliximab), and to assess the immunogenicity of infliximab by detecting changes in Th9 percentages following an in vitro stimulation test. Secondary objective: to compare the Th9-related immunogenicity of infliximab originator with that of its biosimilar compound (CT-P13, Remsima®), and to evaluate the influence of demographic and clinical features and concomitant medications on Th9 percentages. Methods We collected peripheral blood mononuclear cells (PBMCs) from 55 consecutive RA outpatients according to ACR/EULAR 2010 criteria and 10 healthy controls. We enrolled 15 subjects affected by RA not treated with immunosuppressive drugs, 20 patients successfully treated with branded infliximab, and 20 patients who discontinued branded infliximab due to adverse events or inefficacy. Allowed drugs included prednisone (< 10 mg/day), methotrexate (< 15 mg/week), sulphasalazine (< 3 g/day), hydroxychloroquine (< 400 mg/day) and, in the group of non responder patients, intravenous (i.v.) abatacept (10 mg/kg every 4 weeks), i.v. tocilizumab (8 mg/kg every 4 weeks), subcutaneous (s.c.) etanercept (50 mg once a week) and s.c. certolizumab pegol (200 mg every other week). The PBMCs were cultured with/without 50 μg/mL infliximab originator (Remicade®) or 50 μg/mL infliximab biosimilar (Remsima®), 50 μg/mL Human IgG1kappa and 50 μg/mL recombinant Human IgG Fc for 18 hours, and the percentage of Th9 cells was assessed by means of flow cytometry. Th9 lymphocytes were firstly identified as IFNγ-, IL-4-, IL-17-, IL-9- secreting CD4+ T cells, and, in a second time, as PU.1+, IRF4+, IL-9+ CD4+ cells. Furthermore, the markers CCR7 and CD45RA were used to distinguish naïve from memory IL-9-producer cells. Results In unstimulated condition, untreated RA patients showed the highest percentages of Th9 lymphocytes, either assessed according to cytokine or transcriptional profile, which was also higher in overall RA patients than in healthy controls. The higher frequency of Th9 cells in RA patients was not associated with higher levels of anti-nuclear autoantibodies or other autoantibody subsets, or with a higher likelihood of experiencing an adverse event or lack of efficacy on infliximab treatment. The percentage of PU.1+, IRF4+ Th9 cells, but not that of IL-9+, IFNγ-, IL-4-, IL- 17- CD4+ cells, increased following the exposure to branded infliximab in the group of non responder RA patients, although these data were not confirmed after biosimilar infliximab exposure. Furthermore, when IL-9 producing T cells were subdivided according to the expression of the markers CD45RA and CCR7, CCR7+, CD45RA- central memory and CCR7-, CD45RA- effector memory IL-9-producer lymphocytes increased in non responder RA patients after branded infliximab exposure, whereas CCR7+, CD45RA+ naïve and CCR7-, CD45+ terminal effector memory Th9 cells, although being more represented in RA patients than in healthy subjects, did not vary after drug stimulation. In line with the previous experiment, the exposure to biosimilar infliximab did not induce an increase in the percentage of memory Th9 cell in non responder patients. Conclusions IL-9 levels are increased in RA patients, in whom this cytokine plays indeed a crucial role. Th9 cells are the major producers of IL-9, and their prevalence is higher in RA patients than in healthy subjects. According to our results, PU.1+, IRF4+ Th9 cells may be involved in orchestrating the immune response against the epitopes of branded infliximab; and this condition could rely on the recall and stimulation of both central and effector memory cells. On the other hand, biosimilar infliximab seems not able to activate these pools of cells. However, no significant difference was noticed in the PU.1+, IRF4+ Th9 cell percentages in Remicade®-responder patients after stimulation test either with biosimilar and branded infliximab, proving that in vitro both the two drugs seem to have a comparable efficacy. Our results carry a novel point of view in the immunogenicity of anti-TNF agents, routinely based on the detection of anti-drug antibodies. However, since actual knowledge is still scarce, these data, highlighting a discrepancy between the Th9- driven immunogenicity of branded and biosimilar infliximab, indeed deserve further investigations.
Introduzione L’artrite reumatoide (AR) è una patologia cronica autoimmune con interessamento delle articolazioni diartrodiali. I meccanismi patogenetici alla base della malattia sono ancora poco chiari. Diverse cellule del sistema immunitario contribuiscono all’innesco e al mantenimento del processo infiammatorio. Tra di esse, i linfociti T helper (Th) svolgono un importante ruolo nella produzione di citochine, chemochine, nel reclutamento di cellule dal torrente circolatorio e nell’attivazione di cellule residenti. Tra i linfociti Th, le cellule Th9, che si sviluppano sotto l’azione combinata del Tissue Growth Factor-beta (TGF-β) e dell’interleuchina 4 (IL-4) a partite da cellule Th naive e Th2, sintetizzano IL-9 e, in minime quantità, IL-10, IL-17, IL-21 e IL-22, e sembrerebbero essere coinvolte nelle risposte immunitarie in corso di infestazioni parassitarie e allergie. Recentemente è stato dimostrato che queste cellule sono anche coinvolte nella patogenesi di patologie autoimmuni, come il lupus eritematoso sistemico, la sclerosi sistemica, l’artrite psoriasica e l’AR. In particolare, in corso di AR, i linfociti Th9 potrebbero dirigere la formazione dei centri linfoidi nel tessuto sinoviale e favorire la produzione di autoanticorpi come gli anticorpi anti-peptide ciclico citrullinato (ACPAs). Non è invece noto il ruolo di tali cellule nella risposta al trattamento con farmaci biologici e nei processi di immunogenicità. Scopo Obiettivo primario: valutare la prevalenza dei linfociti Th9 nel sangue periferico di pazienti con AR, in trattamento o meno con farmaci immunosoppressori (DMARDs convenzionali, steroidi o infliximab) e valutare l’immunogenicità di infliximab relativamente alle risposte Th9 dopo test di stimolazione in vitro, confrontando un gruppo di pazienti con AR responder a infliximab (Remicade®) con un gruppo di pazienti con AR non responder al farmaco. Obiettivo secondario: confrontare, con un test in vitro, l’immunogenicità Th9-correlata di infliximab originator Remicade® con quella del suo biosimilare (CT-P13, Remsima®). Valutare l’influenza delle variabili demografiche, cliniche e farmacologiche sulla variazione delle percentuali linfocitarie Th9. Metodi: Abbiamo arruolato 55 pazienti affetti da AR secondo i criteri ACR/EULAR 2010 e 10 controlli sani. I pazienti con AR erano suddivisi in un gruppo di 15 pazienti naive a terapie immunosoppressive, inclusi gli steroidi; un gruppo di 20 pazienti in trattamento con farmaci convenzionali, steroidi e infliximab (Remicade®) con buona risposta clinica e un gruppo di 20 pazienti che avevano fallito in passato la terapia con Remicade® per eventi avversi o inefficacia e che praticavano altre terapie biologiche (abatacept 10 mg/kg e.v. ogni 4 settimane in 13 casi; tocilizumab 8 mg/kg e.v. ogni 4 settimane in 5 casi; etanercept 50 mg a settimana s.c. in un caso e certolizumab pegol 200 mg ogni 2 settimane s.c. in un caso) oltre a DMARDs e steroidi. Era consentito l’uso di prednisone (< 10 mg/die), methotrexate (< 15 mg/settimana), sulfasalazina (< 3g/die), idrossiclorochina (< 400 mg/die). Dopo firma del consenso informato, le cellule mononucleate ottenute da sangue periferico (PBMCs) di ciascun soggetto sono state poste in coltura con aggiunta o meno di 50 μg/ml di infliximab originator (Remicade®) o 50 μg/ml di infliximab biosimilare (Remsima®), 50 μg/ml di IgG1kappa umane e 50 μg/ml di IgG Fc umane per 18 ore. La percentuale di linfociti Th9 cells è stata valutata per mezzo di indagini citofluorimetriche. I linfociti Th9 sono stati inizialmente identificati come cellule T CD4+ producenti IL-9 ma non esprimenti interferon-gamma (IFNγ), IL-4 e IL-17; e secondariamente come cellule T CD4+ PU.1+, IRF4+ e IL-9+. Sono state valutate inoltre le percentuali dei linfociti Th9 in accordo ai marcatori CCR7 e CD45RA al fine di distinguere le cellule naive dal pool delle cellule di memoria. Risultati Al basale, le percentuali di linfociti Th9, sia valutate in base al profilo citochinico che ai fattori trascrizionali, erano significativamente più alte nel gruppo di pazienti con AR rispetto ai controlli, e tra i pazienti, nel gruppo dei non trattati. Le percentuali di cellule Th9 non erano tuttavia significativamente correlate con lo sviluppo di eventi avversi o inefficacia, né con la comparsa di autoanticorpi non specifici per l’AR (es. anticorpi anti-nucleo). Dopo stimolazione con infliximab originator, la percentuale di linfociti Th9 PU.1+, IRF4+ ma non di quella dei linfociti IL-9+, IFNγ-, IL-4-, IL-17- aumentava significativamente rispetto al basale solo nel gruppo dei non responder. Questo evento non è stato registrato invece dopo stimolazione con infliximab biosimilare. Inoltre, quando i linfociti Th9 sono stati suddivisi in accordo all’espressione delle molecole CD45RA e CCR7, le cellule CCR7+ e CD45RA- (central memory) e quelle CCR7- e CD45RA- (effector memory) aumentavano significativamente rispetto al basale nel gruppo dei non responder dopo stimolazione con infliximab originator ma non biosimilare; al contrario nessuna variazione è stata registrata nelle percentuali dei linfociti CCR7+ e CD45RA+ (naive) nè in quella dei linfociti CCR7- e CD45+ (terminal effector memory). Conclusioni I nostri dati dimostrano che la percentuale di linfociti Th9, che rappresentano i maggiori produttori di IL-9, è maggiore nei pazienti con AR rispetto ai controlli sani. L’IL-9 potrebbe infatti giocare un ruolo fondamentale nel processo patogenetico della malattia. Inoltre, i nostri risultati dimostrano che i linfociti Th9, valutati attraverso i fattori trascrizionali PU.1 e IRF4, potrebbero essere implicati nella risposta immunitaria contro gli epitopi di infliximab originator, attraverso fenomeni di recalling di cellule di memoria. Al contrario, nonostante diversi studi abbiano dimostrato una sostanziale comparabilità dal punto di vista biomolecolare e quindi del profilo di immunogenicità relativo alla produzione di anticorpi anti-farmaco tra infliximab originator e biosimilare, dopo stimolazione in vitro con Remsima® non abbiamo osservato variazioni nelle percentuali delle cellule Th9 rispetto al basale nel gruppo dei non responder. Il nostro lavoro si è incentrato su una diversa prospettiva immunologica nell’ambito dell’immunogenicità di un farmaco biologico anti-TNF, valutando anche la presunta sovrapponibilità del farmaco originator al suo biosimilare. Tuttavia, la conoscenza attuale sull’argomento è ancora scarsa e merita ulteriori ricerche.