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1.  Cardiovascular co-morbidity in rheumatic diseases 
Patients with rheumatic disorders have an increased risk of cardiovascular disease (CVD). This excess co-morbidity is not fully explained by traditional risk factors. Disease severity is a major risk factor for CVD in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Shared disease mechanisms in atherosclerosis and rheumatic disorders include immune dysregulation and inflammatory pathways, which are potential targets for therapy. Lessons from RA and SLE may have implications for future research on the pathogenesis of atherosclerotic vascular disease in general. Recent data indicate that suppression of inflammation reduces the risk of CVD morbidity and mortality in patients with severe RA. The modest, but clinically relevant, efficacy of atorvastatin treatment in RA adds to the evidence for important anti-inflammatory properties for statins. There is increased recognition of the need for structured preventive strategies to reduce the risk of CVD in patients with rheumatic disease. Such strategies should be based on insights into the role of inflammation in CVD, as well as optimal management of life style related risk factors. In this review, the research agenda for understanding and preventing CVD co-morbidity in patients with rheumatic disorders is discussed.
PMCID: PMC2515420  PMID: 18827910
rheumatoid arthritis; systemic lupus erythematosus; cardiovascular disease; inflammation
2.  Rheumatic fever pathogenesis: Approach in research needs change 
Annals of Pediatric Cardiology  2012;5(2):169-178.
Despite identifying that rheumatic fever (RF) is the result of an immunological reaction following group-A beta-hemolytic streptococcal infection, the pathogenesis remains elusive. RF has been incorrectly designated as causing pancarditis, since it does not cause myocarditis. Research directed toward myocarditis, targeting myosin to unravel the pathogenesis has not succeeded in more than 60 years. RF causes permanent damage to cardiac valves. The mitral valve (MV), derived from the wall of the left ventricle, is composed of a central core of connective tissue, covered on both sides by endothelium. The left ventricle does not have either myocardial or intermyocardial connective tissue involvement in RF. By exclusion, therefore, the primary site of RF damage appears to be the endothelium. Evaluation of the histopathology and immunopathology indicates that RF is a disease of the valvular and vascular endothelium. It is not a connective tissue disorder. Research to identify pathogenesis needs to be focused toward valvular endothelium.
PMCID: PMC3487207  PMID: 23129908
Endothelium; pathogenesis; poststreptococcal; acute glomerulonephritis; myocarditis; myosin; rheumatic fever
3.  Role of Adipokines in Atherosclerosis: Interferences with Cardiovascular Complications in Rheumatic Diseases 
Mediators of Inflammation  2012;2012:125458.
Patients with rheumatic diseases have an increased risk of mortality by cardiovascular events. In fact, several rheumatic diseases such as rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, and ankylosing spondylitis are associated with a higher prevalence of cardiovascular diseases (CVDs). Although traditional cardiovascular risk factors have been involved in the pathogenesis of cardiovascular diseases in rheumatic patients, these alterations do not completely explain the enhanced cardiovascular risk in this population. Obesity and its pathologic alteration of fat mass and dysfunction, due to an altered pattern of secretion of proinflammatory adipokines, could be one of the links between cardiovascular and rheumatic diseases. Indeed, the incidence of CVDs is augmented in obese individuals with rheumatic disorders. Thus, in this paper we explore in detail the relationships among adipokines, rheumatic diseases, and cardiovascular complications by giving to the reader a holistic vision and several suggestions for future perspectives and potential clinical implications.
PMCID: PMC3403095  PMID: 22910888
4.  MicroRNAs in systemic rheumatic diseases 
MicroRNAs (miRNAs) are endogenous, non-coding, single-stranded RNAs about 21 nucleotides in length. miRNAs have been shown to regulate gene expression and thus influence a wide range of physiological and pathological processes. Moreover, they are detected in a variety of sources, including tissues, serum, and other body fluids, such as saliva. The role of miRNAs is evident in various malignant and nonmalignant diseases, and there is accumulating evidence also for an important role of miRNAs in systemic rheumatic diseases. Abnormal expression of miRNAs has been reported in autoimmune diseases, mainly in systemic lupus erythematosus and rheumatoid arthritis. miRNAs can be aberrantly expressed even in the different stages of disease progression, allowing miRNAs to be important biomarkers, to help understand the pathogenesis of the disease, and to monitor disease activity and effects of treatment. Different groups have demonstrated a link between miRNA expression and disease activity, as in the case of renal flares in lupus patients. Moreover, miRNAs are emerging as potential targets for new therapeutic strategies of autoimmune disorders. Taken together, recent data demonstrate that miRNAs can influence mechanisms involved in the pathogenesis, relapse, and specific organ involvement of autoimmune diseases. The ultimate goal is the identification of a miRNA target or targets that could be manipulated through specific therapies, aiming at activation or inhibition of specific miRNAs responsible for the development of disease.
PMCID: PMC3239341  PMID: 21787439
5.  Rheumatic fever & rheumatic heart disease: The last 50 years 
Rheumatic fever (RF) and rheumatic heart disease (RHD) continue to be a major health hazard in most developing countries as well as sporadically in developed economies. Despite reservations about the utility, echocardiographic and Doppler (E&D) studies have identified a massive burden of RHD suggesting the inadequacy of the Jones’ criteria updated by the American Heart Association in 1992. Subclinical carditis has been recognized by E&D in patients with acute RF without clinical carditis as well as by follow up of RHD patients presenting as isolated chorea or those without clinical evidence of carditis. Over the years, the medical management of RF has not changed. Paediatric and juvenile mitral stenosis (MS), upto the age of 12 and 20 yr respectively, severe enough to require operative treatement was documented. These negate the belief that patients of RHD become symptomatic ≥20 years after RF as well as the fact that congestive cardiac failure in childhood indicates active carditis and RF. Non-surgical balloon mitral valvotomy for MS has been initiated. Mitral and/or aortic valve replacement during active RF in patients not responding to medical treatment has been found to be life saving as well as confirming that congestive heart failure in acute RF is due to an acute haemodynamic overload. Pathogenesis as well as susceptibility to RF continue to be elusive. Prevention of RF morbidity depends on secondary prophylaxis which cannot reduce the burden of diseases. Primary prophylaxis is not feasible in the absence of a suitable vaccine. Attempts to design an antistreptococcal vaccine utilizing the M-protein has not succeeded in the last 40 years. Besides pathogenesis many other questions remain unanswered.
PMCID: PMC3724245  PMID: 23703332
Antistreptococcal vaccine; heart disease; myocarditis; rheumatic fever; rheumatic heart disease; streptococcal infections; subclinical carditis
6.  Glucocorticoid Receptor: Implications for Rheumatic Diseases “Glucocorticoids in Rheumatic Diseases” 
Clinical and experimental rheumatology  2011;29(5 0 68):S32-S41.
The glucocorticoid receptor (GR), a member of the nuclear receptor superfamily, mediates most of the known biologic effects of glucocorticoids. The human GR gene consists of 9 exons and expresses 2 alternative splicing isoforms, the GRα and GRβ. GRα is the classic receptor that binds to glucocorticoids and mediates most of the known actions of glucocorticoids, while GRβ does not bind to these hormones and exerts a dominant negative effect upon the GRα-induced transcriptional activity. Each of the two GR splice isoforms has 8 translational variants with specific transcriptional activity and tissue distribution. GRα consists of three subdomains, translocates from the cytoplasm into the nucleus upon binding to glucocorticoids, and regulates the transcriptional activity of numerous glucocorticoid-responsive genes either by binding to its cognate DNA sequences or by interacting with other transcription factors. In addition to these genomic actions, the GR also exerts rapid, non-genomic effects, which are possibly mediated by membrane-localized receptors or by translocation into the mitochondria. All these actions of the GR appear to play an important role in the regulation of the immune system. Specifically, the splicing variant GRβ may be involved in the pathogenesis of rheumatic diseases, while the circadian regulation of the GR activity via acetylation by the Clock transcription factor may have therapeutic implications for the preferential timing of glucocorticoid administration in autoimmune inflammatory disorders.
PMCID: PMC3630375  PMID: 22018181
7.  Rheumatic disorders in Zimbabwe: a prospective analysis of patients attending a rheumatic diseases clinic. 
Annals of the Rheumatic Diseases  1990;49(6):400-402.
The pattern of rheumatic disease in Africa differs from that in Europe and the United States and these differences may provide clues to its cause or pathogenesis. In a six month prospective analysis of 141 patients (83 female) attending a rheumatic diseases clinic rheumatoid arthritis was the commonest disorder, occurring in 49 patients. Twenty seven of the 49 (55%) were seropositive, 25 (51%) had erosive disease with rheumatoid nodules (13/49, 27%), and extra-articular complications (6/49, 12%), indicating a pattern of disease unlike the early reports from Africa. Systemic lupus erythematosus found in 18/141 (13%), gout in 12 (9%), ankylosing spondylitis in six (4%), and Reiter's syndrome in five (4%), in contrast with their rarity in previous reports from Africa, were not uncommon, whereas tropical polyarthritis was seldom diagnosed. The pattern of rheumatic disease in Harare, a large city, is changing to approximate more closely the pattern seen in developed countries.
PMCID: PMC1004109  PMID: 2383064
8.  Current treatment of hepatitis C-associated rheumatic diseases 
The hepatitis C virus (HCV) is both hepatotropic and lymphotropic, responsible for a great number of hepatic and extrahepatic immune-system disorders that comprise the so-called HCV syndrome. HCV-associated rheumatic diseases are characterized by frequent clinico-serological overlap; therefore, correct classification of individual patients is necessary before therapeutic decisions are made. This is particularly difficult to do, however, because of the coexistence of viral infection and complex autoimmune alterations. In this context, mixed cryoglobulinemia syndrome (MCs) represents the prototype of virus-related autoimmune-lymphoproliferative diseases. MCs can be treated at different levels by means of etiological treatment with antivirals (peg-interferon-alpha plus ribavirin) aimed at HCV eradication and/or pathogenetic/symptomatic treatments directed to both immune-system alterations and the vasculitic process (rituximab, cyclophosphamide, steroids, plasmapheresis, and so on). In clinical practice, the therapeutic strategy should be modulated according to severity/activity of the MCs and possibly tailored to each individual patient's conditions. Cryoglobulinemic skin ulcers may represent a therapeutic challenge, which should be managed by means of both local and systemic treatments. HCV-associated arthritis should be differentiated from the simple comorbidity of HCV infection and classical rheumatoid arthritis. It may be treated with low doses of steroids and/or hydroxychloroquine; the use of biologics (rituximab) may be considered in more severe cases. Primary Sjögren's syndrome is rarely associated with HCV infection, while sicca syndrome and myalgia are frequently detectable in hepatitis C patients, with or without cryoglobulinemic vasculitis. Other autoimmune rheumatic disorders (poly/dermatomyositis, polyarteritis nodosa, osteosclerosis, fibromyalgia, and so on) have been reported as potentially associated with HCV infection in patient populations from different countries, suggesting the role of genetic and/or environmental co-factors. The therapeutic approach to these disorders should be decided according to each individual patient's evaluation, including hepatic, virological, and immunological findings.
PMCID: PMC3446515  PMID: 22731694
9.  Proteomic analysis of human plasma in chronic rheumatic mitral stenosis reveals proteins involved in the complement and coagulation cascade 
Clinical Proteomics  2014;11(1):35.
Rheumatic fever in childhood is the most common cause of Mitral Stenosis in developing countries. The disease is characterized by damaged and deformed mitral valves predisposing them to scarring and narrowing (stenosis) that results in left atrial hypertrophy followed by heart failure. Presently, echocardiography is the main imaging technique used to diagnose Mitral Stenosis. Despite the high prevalence and increased morbidity, no biochemical indicators are available for prediction, diagnosis and management of the disease. Adopting a proteomic approach to study Rheumatic Mitral Stenosis may therefore throw some light in this direction. In our study, we undertook plasma proteomics of human subjects suffering from Rheumatic Mitral Stenosis (n = 6) and Control subjects (n = 6). Six plasma samples, three each from the control and patient groups were pooled and subjected to low abundance protein enrichment. Pooled plasma samples (crude and equalized) were then subjected to in-solution trypsin digestion separately. Digests were analyzed using nano LC-MSE. Data was acquired with the Protein Lynx Global Server v2.5.2 software and searches made against reviewed Homo sapiens database (UniProtKB) for protein identification. Label-free protein quantification was performed in crude plasma only.
A total of 130 proteins spanning 9–192 kDa were identified. Of these 83 proteins were common to both groups and 34 were differentially regulated. Functional annotation of overlapping and differential proteins revealed that more than 50% proteins are involved in inflammation and immune response. This was corroborated by findings from pathway analysis and histopathological studies on excised tissue sections of stenotic mitral valves. Verification of selected protein candidates by immunotechniques in crude plasma corroborated our findings from label-free protein quantification.
We propose that this protein profile of blood plasma, or any of the individual proteins, could serve as a focal point for future mechanistic studies on Mitral Stenosis. In addition, some of the proteins associated with this disorder may be candidate biomarkers for disease diagnosis and prognosis. Our findings might help to enrich existing knowledge on the molecular mechanisms involved in Mitral Stenosis and improve the current diagnostic tools in the long run.
Electronic supplementary material
The online version of this article (doi:10.1186/1559-0275-11-35) contains supplementary material, which is available to authorized users.
PMCID: PMC4193131  PMID: 25379033
Rheumatic fever; Mitral Stenosis; Plasma proteomics; Inflammation; Immunotechniques
10.  Biologic treatments for systemic rheumatic diseases 
Oral diseases  2008;14(3):206-216.
Many rheumatologic disorders, most notably Sjögren's syndrome, are associated with dental complications and in some cases oral diseases may trigger or drive connective tissue disease. During the past three decades the treatment in rheumatology was revolutionized by the introduction of disease-modifying anti-rheumatic drugs. Advances in our understanding of the pathogenesis of rheumatic diseases have led to the discovery of critical mechanisms of inflammation and autoimmunity and the invention of new target-specific biologic agents. In this review, we will summarize the current state of biologic therapies in rheumatology and discuss the implications of these on oral health and disease.
PMCID: PMC2766248  PMID: 18282173
autoimmunity; biologic therapies; monoclonal antibodies; rheumatic diseases; Sjögren's syndrome
11.  Inflammatory Rheumatic Disorders and Bone 
Current Rheumatology Reports  2012;14(3):224-230.
Inflammatory joint diseases such as rheumatoid arthritis, as well as other rheumatic conditions, such as systemic lupus erythematosus (SLE) and ankylosing spondylitis, comprise a heterogeneous group of joint disorders that are all associated with extra-articular side effects, including bone loss and fractures. The concept of osteoimmunology is based on growing insights into the links between the immune system and bone. The pathogenesis of osteoporosis in these patients is multifactorial. We have, more or less as an example, described this extensively for patients with SLE. High disease activity (inflammation) and immobility are common factors that substantially increase fracture risk in these patients, on top of the background fracture risk based on, among other factors, age, body mass index, and gender. Although no fracture reduction has been shown in intervention studies in patients with inflammatory rheumatic diseases, we present treatment options that might be useful for clinicians who are treating these patients.
PMCID: PMC3338911  PMID: 22477520
Osteoporosis; Fractures; Rheumatoid arthritis; Systemic lupus erythematosus; SLE; Ankylosing spondylitis; Metabolic bone disease; Inflammation; Bone; Medicine & Public Health; Rheumatology
12.  Transcription profiling of rheumatic diseases 
Rheumatic diseases are a diverse group of disorders. Most of these diseases are heterogeneous in nature and show varying responsiveness to treatment. Because our understanding of the molecular complexity of rheumatic diseases is incomplete and criteria for categorization are limited, we mainly refer to them in terms of group averages. The advent of DNA microarray technology has provided a powerful tool to gain insight into the molecular complexity of these diseases; this technology facilitates open-ended survey to identify comprehensively the genes and biological pathways that are associated with clinically defined conditions. During the past decade, encouraging results have been generated in the molecular description of complex rheumatic diseases, such as rheumatoid arthritis, systemic lupus erythematosus, Sjögren syndrome and systemic sclerosis. Here, we describe developments in genomics research during the past decade that have contributed to our knowledge of pathogenesis, and to the identification of biomarkers for diagnosis, patient stratification and prognostication.
PMCID: PMC2688218  PMID: 19232067
13.  Global research priorities in rheumatic fever and rheumatic heart disease 
We now stand at a critical juncture for rheumatic fever (RF) and rheumatic heart disease (RHD) control. In recent years, we have seen a surge of interest in these diseases in regions of the world where RF/RHD mostly occur. This brings real opportunities to make dramatic progress in the next few years, but also real risks if we miss these opportunities. Most public health and clinical approaches in RF/RHD arose directly from programmes of research. Many unanswered questions remain, including those around how to implement what we know will work, so research will continue to be essential in our efforts to bring a global solution to this disease. Here we outline our proposed research priorities in RF/RHD for the coming decade, grouped under the following four challenges: Translating what we know already into practical RHD control; How to identify people with RHD earlier, so that preventive measures have a higher chance of success; Better understanding of disease pathogenesis, with a view to improved diagnosis and treatment of ARF and RHD; and Finding an effective approach to primary prevention. We propose a mixture of basic, applied, and implementation science. With concerted efforts, strong links to clinical and public health infrastructure, and advocacy and funding support from the international community, there are good prospects for controlling these RF and RHD over the next decade.
PMCID: PMC3104531  PMID: 21677798
Rheumatic fever; rheumatic heart disease; prevention
14.  Pain Patterns in the Rheumatic Disorders* 
British Medical Journal  1972;4(5834):213-216.
Pain patterns vary greatly in the different types of arthritis, from the localized agony without mental overtones in acute gout to the diffuse disorder we call rheumatoid arthritis, where inflammation of many joints, systemic illness, anaemia, anxiety, and depression are usually all present in some degree. Each pain pattern calls for a different therapeutic approach, physical, psychological, and pharmacological. Few patients suffer as much pain and suffering over many years as do chronic arthritics. It is all the more important to instruct them in the essentials of their own treatment. A patient with an occupied and instructed mind usually suffers less than an ignorant and depressed one, fearful of her disease and its complications and of the dark uncertain future that lies ahead.
PMCID: PMC1786467  PMID: 4117170
15.  Prevention and control of rheumatic fever and rheumatic heart disease: the Cuban experience (1986–1996–2002) 
Cardiovascular Journal of Africa  2008;19(3):135-140.
Rheumatic fever (RF) and rheumatic heart disease (RHD) are still major medical and public health problems mainly in developing countries. Pilot studies conducted during the last five decades in developed and developing countries indicated that the prevention and control of RF/RHD is possible. During the 1970s and 1980s, epidemiological studies were carried out in selected areas of Cuba in order to determine the prevalence and characteristics of RF/RHD, and to test several long-term strategies for prevention of the diseases.
Between 1986 and 1996 we carried out a comprehensive 10-year prevention programme in the Cuban province of Pinar del Rio and evaluated its efficacy five years later. The project included primary and secondary prevention of RF/RHD, training of personnel, health education, dissemination of information, community involvement and epidemiological surveillance. Permanent local and provincial RF/RHD registers were established at all hospitals, policlinics and family physicians in the province. Educational activities and training workshops were organised at provincial, local and health facility level. Thousands of pamphlets and hundreds of posters were distributed, and special programmes were broadcast on the public media to advertise the project.
There was a progressive decline in the occurrence and severity of acute RF and RHD, with a marked decrease in the prevalence of RHD in school children from 2.27 patients per 1 000 children in 1986 to 0.24 per 1 000 in 1996. A marked and progressive decline was also seen in the incidence and severity of acute RF in five- to 25-year-olds, from 18.6 patients per 100 000 in 1986 to 2.5 per 100 000 in 1996. There was an even more marked reduction in recurrent attacks of RF from 6.4 to 0.4 patients per 100 000, as well as in the number and severity of patients requiring hospitalisation and surgical care. Regular compliance with secondary prophylaxis increased progressively and the direct costs related to treatment of RF/RHD decreased with time. The implementation of the programme did not incur much additional cost for healthcare. Five years after the project ended, most of the measures initiated at the start of the programme were still in place and occurrence of RF/RHD was low.
PMCID: PMC3974561  PMID: 18568172
16.  D8/17 and CD19 Expression on Lymphocytes of Patients with Acute Rheumatic Fever and Tourette's Disorder 
D8/17, an alloantigen found on B lymphocytes, has been reported to be elevated in patients susceptible to rheumatic fever and may be associated with autoimmune types of neuropsychiatric disorders. The pediatric-autoimmune-neuropsychiatric-disorders-associated-with-streptococci model is a putative model of pathogenesis for a group of children whose symptoms of obsessive-compulsive disorder and Tourette's disorder (TD) are abrupt and may be triggered by an infection with group A streptococci. As a test of this model, we have examined D8/17 levels on the B cells of patients with TD and acute rheumatic fever (ARF) along with those on the B cells of normal controls by flow cytometry. We have utilized several different preparations of D8/17 antibody along with a variety of secondary antibodies but have been unable to show an association with an elevated percentage of D8/17-positive, CD19-positive B cells in either ARF or TD. We did find, however, that the percentages of CD19-positive B cells in ARF and TD patients were significantly elevated compared to those in normal controls. Group A streptococcal pharyngitis patients also had an elevated percentage of CD19 B cells, however. These studies failed to confirm the utility of determining the percentage of B cells expressing the D8/17 alloantigen in ARF patients or our sample of TD patients. In contrast, the percentage of CD19-positive B cells was significantly elevated in ARF and TD patients, as well as group A streptococcal pharyngitis patients, suggesting a role for inflammation and/or autoimmunity in the pathogenesis of these disorders.
PMCID: PMC371196  PMID: 15013984
17.  Crucial Role of the CB3-Region of Collagen IV in PARF-Induced Acute Rheumatic Fever 
PLoS ONE  2009;4(3):e4666.
Acute rheumatic fever (ARF) and rheumatic heart disease are serious autoimmune sequelae to infections with Streptococcus pyogenes. Streptococcal M-proteins have been implicated in ARF pathogenesis. Their interaction with collagen type IV (CIV) is a triggering step that induces generation of collagen-specific auto-antibodies. Electron microscopy of the protein complex between M-protein type 3 (M3-protein) and CIV identified two prominent binding sites of which one is situated in the CB3-region of CIV. In a radioactive binding assay, M3-protein expressing S. pyogenes and S. gordonii bound the CB3-fragment. Detailed analysis of the interactions by surface plasmon resonance measurements and site directed mutagenesis revealed high affinity interactions with dissociation constants in the nanomolar range that depend on the recently described collagen binding motif of streptococcal M-proteins. Because of its role in the induction of disease-related collagen autoimmunity the motif is referred to as “peptide associated with rheumatic fever” (PARF). Both, sera of mice immunized with M3-protein as well as sera from patients with ARF contained anti-CB3 auto-antibodies, indicating their contribution to ARF pathogenesis. The identification of the CB3-region as a binding partner for PARF directs the further approaches to understand the unusual autoimmune pathogenesis of PARF-dependent ARF and forms a molecular basis for a diagnostic test that detects rheumatogenic streptococci.
PMCID: PMC2646144  PMID: 19252743
18.  Genetics of rheumatic disease 
Many of the chronic inflammatory and degenerative disorders that present to clinical rheumatologists have a complex genetic aetiology. Over the past decade a dramatic improvement in technology and methodology has accelerated the pace of gene discovery in complex disorders in an exponential fashion. In this review, we focus on rheumatoid arthritis, systemic lupus erythematosus and ankylosing spondylitis and describe some of the recently described genes that underlie these conditions and the extent to which they overlap. The next decade will witness a full account of the main disease susceptibility genes in these diseases and progress in establishing the molecular basis by which genetic variation contributes to pathogenesis.
PMCID: PMC2787281  PMID: 19849816
19.  The Relationship Between Genetics and Environment in the Pathogenesis of Rheumatic Diseases 
Western Journal of Medicine  1979;131(3):205-218.
Major developments have taken place to further our understanding of the relationship between genetics and the environment in the pathogenesis of rheumatic disorders. The association between HLA markers and human disease is becoming clearer. For instance, HLA-DRW4 frequently occurs in patients with rheumatoid disease, and penicillamine and gold toxicity are seen most often in patients with HLA-DRW2 or DRW3. Antisera to B alloantigens help define the genetic differences between systemic lupus erythematosus and rheumatoid arthritis. As yet, the most dramatic link is that between HLA-B27 and primary ankylosing spondylitis. This same antigen is related, to varying degrees, with other members of the seronegative spondylarthritides and there is strong evidence that this association is related to HLA-B27, itself, rather than an associated disease gene. Nevertheless, some data refute a single gene theory. We are just beginning to learn more about interactions between different genes on the sixth chromosome and genes on other chromosomes.
The sex ratio of the spondylarthritides is now better defined. Sacroiliitis may have a comparable sex distribution although females have more peripheral joint disease and males have greater spinal involvement. Unfortunately, the explanation for these differences remains elusive.
The specific infective agents related to the development of rheumatic disorders are becoming clarified. Chlamydia, Salmonella, Yersinia and Shigella flexneri types 1b and 2a are arthritogenic, while Shigella sonnei appears not to cause disease. Although the Reiter syndrome is now considered a chronic disease, the reason for remissions and relapses remains unclear.
PMCID: PMC1271771  PMID: 18748470
20.  IL-6 Amplifies TLR Mediated Cytokine and Chemokine Production: Implications for the Pathogenesis of Rheumatic Inflammatory Diseases 
PLoS ONE  2014;9(10):e107886.
The role of Interleukin(IL)-6 in the pathogenesis of joint and systemic inflammation in rheumatoid arthritis (RA) and systemic juvenile idiopathic arthritis (s-JIA) has been clearly demonstrated. However, the mechanisms by which IL-6 contributes to the pathogenesis are not completely understood. This study investigates whether IL-6 affects, alone or upon toll like receptor (TLR) ligand stimulation, the production of inflammatory cytokines and chemokines in human peripheral blood mononuclear cells (PBMCs), synovial fluid mononuclear cells from JIA patients (SFMCs) and fibroblast-like synoviocytes from rheumatoid arthritis patients (RA synoviocytes) and signalling pathways involved. PBMCs were pre-treated with IL-6 and soluble IL-6 Receptor (sIL-6R). SFMCs and RA synoviocytes were pre-treated with IL-6/sIL-6R or sIL-6R, alone or in combination with Tocilizumab (TCZ). Cells were stimulated with LPS, S100A8-9, poly(I-C), CpG, Pam2CSK4, MDP, IL-1β. Treatment of PBMCs with IL-6 induced production of TNF-α, CXCL8, and CCL2, but not IL-1β. Addition of IL-6 to the same cells after stimulation with poly(I-C), CpG, Pam2CSK4, and MDP induced a significant increase in IL-1β and CXCL8, but not TNF-α production compared with TLR ligands alone. This enhanced production of IL-1β and CXCL8 paralleled increased p65 NF-κB activation. In contrast, addition of IL-6 to PBMCs stimulated with LPS or S100A8-9 (TLR-4 ligands) led to reduction of IL-1β, TNF-α and CXCL8 with reduced p65 NF-κB activation. IL-6/IL-1β co-stimulation increased CXCL8, CCL2 and IL-6 production. Addition of IL-6 to SFMCs stimulated with LPS or S100A8 increased CXCL8, CCL2 and IL-1β production. Treatment of RA synoviocytes with sIL-6R increased IL-6, CXCL8 and CCL2 production, with increased STAT3 and p65 NF-κB phosphorylation. Our results suggest that IL-6 amplifies TLR-induced inflammatory response. This effect may be relevant in the presence of high IL-6 and sIL-6R levels, such as in arthritic joints in the context of stimulation by endogenous TLR ligands.
PMCID: PMC4182736  PMID: 25271853
21.  microRNA-mediated regulation of innate immune response in rheumatic diseases 
miRNAs have been shown to play essential regulatory roles in the innate immune system. They function at multiple levels to shape the innate immune response and maintain homeostasis by direct suppression of the expression of their target proteins, preferentially crucial signaling components and transcription factors. Studies in humans and in disease models have revealed that dysregulation of several miRNAs such as miR-146a and miR-155 in rheumatic diseases leads to aberrant production of and/or signaling by inflammatory cytokines and, thus, critically contributes to disease pathogenesis. In addition, the recent description of the role of certain extracellular miRNAs as innate immune agonist to induce inflammatory response would have direct relevance to rheumatic diseases.
PMCID: PMC3672773  PMID: 23582400
22.  What is the prevalence of rheumatic disorders in general medical inpatients? 
Postgraduate Medical Journal  2001;77(914):774-777.
It has been suggested that rheumatological disorders are underdiagnosed in patients with medical problems and that this might be rectified by incorporating a standard brief screening examination as part of the routine assessment of all patients admitted to hospital with medical conditions. Therefore the GALS screening examination was used to assess the prevalence of rheumatic disease in 100 patients admitted with acute medical problems and in a further 100 in the rehabilitative phase of their disease. The nature of locomotor dysfunction in all patients with a positive result was defined by an independent review and then sensitivity and specificity of the screening test was calculated for rheumatic disease in both populations.
The median age of the two populations were 63 and 78 years respectively, with more females in the rehabilitation group. The overall prevalence of a positive screening test was 53% in the acute and 94% in the chronic disease groups, although the false positive rate in the rehabilitation patients was 30% due to factors other than rheumatic disorders limiting locomotor function (mainly orthopaedic and neurological conditions). The diagnosis of a rheumatological disorder was made de novo in a significant minority (10%) of patients and was usually amenable to treatment. The commonest rheumatic disorder was osteoarthritis which accounted for 55% of all rheumatic disease, followed by inflammatory joint disease (16%), and osteoporosis (12%). In addition to osteoporosis, Paget's disease of bone and polymyalgia rheumatica were found more frequently in those patients undergoing rehabilitation than in those admitted with an acute medical problem. A number of clinically important associations between medical and rheumatic disorders were found, such as stroke disease with shoulder capsulitis and heart failure with gout.
The sensitivity of the GALS screening test was extremely high (92% and 100%), while its specificity fell in the rehabilitation group from 83% to 17%. None the less, it is felt that this study indicates that the routine use of this test should be considered as part of the assessment of all hospitalised patients with medical problems, whether acute or chronic.

Keywords: rheumatic disease; general internal medicine; GALS screening test
PMCID: PMC1742213  PMID: 11723316
23.  Macrophage Migration Inhibitory Factor: A Multifunctional Cytokine in Rheumatic Diseases 
Arthritis  2010;2010:106202.
Macrophage migration inhibitory factor (MIF) was originally identified in the culture medium of activated T lymphocytes as a soluble factor that inhibited the random migration of macrophages. MIF is now recognized to be a multipotent cytokine involved in the regulation of immune and inflammatory responses. Moreover, the pivotal nature of its involvement highlights the importance of MIF to the pathogenesis of various inflammatory disorders and suggests that blocking MIF may be a useful therapeutic strategy for treating these diseases. This paper discusses the function and expressional regulation of MIF in several rheumatic diseases and related conditions.
PMCID: PMC3195319  PMID: 22046508
24.  Adipokines, Metabolic Syndrome and Rheumatic Diseases 
Journal of Immunology Research  2014;2014:343746.
The metabolic syndrome (MetS) is a cluster of cardiometabolic disorders that result from the increasing prevalence of obesity. The major components of MetS include insulin resistance, central obesity, dyslipidemia, and hypertension. MetS identifies the central obesity with increased risk for cardiovascular diseases (CVDs) and type-2 diabetes mellitus (T2DM). Patients with rheumatic diseases, such as rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, and ankylosing spondylitis, have increased prevalence of CVDs. Moreover, CVD risk is increased when obesity is present in these patients. However, traditional cardiovascular risk factors do not completely explain the enhanced cardiovascular risk in this population. Thus, MetS and the altered secretion patterns of proinflammatory adipokines present in obesity could be the link between CVDs and rheumatic diseases. Furthermore, adipokines have been linked to the pathogenesis of MetS and its comorbidities through their effects on vascular function and inflammation. In the present paper, we review recent evidence of the role played by adipokines in the modulation of MetS in the general population, and in patients with rheumatic diseases.
PMCID: PMC3987880  PMID: 24741591
25.  Animal Models to Investigate the Pathogenesis of Rheumatic Heart Disease 
Rheumatic fever (RF) and rheumatic heart disease (RHD) are sequelae of group A streptococcal (GAS) infection. Although an autoimmune process has long been considered to be responsible for the initiation of RF/RHD, it is only in the last few decades that the mechanisms involved in the pathogenesis of the inflammatory condition have been unraveled partly due to experimentation on animal models. RF/RHD is a uniquely human condition and modeling this disease in animals is challenging. Antibody and T cell responses to recombinant GAS M protein (rM) and the subsequent interactions with cardiac tissue have been predominantly investigated using a rat autoimmune valvulitis model. In Lewis rats immunized with rM, the development of hallmark histological features akin to RF/RHD, both in the myocardial and in valvular tissue have been reported, with the generation of heart tissue cross-reactive antibodies and T cells. Recently, a Lewis rat model of Sydenham’s chorea and related neuropsychiatric disorders has also been described. Rodent models are very useful for assessing disease mechanisms due to the availability of reagents to precisely determine sequential events following infection with GAS or post-challenge with specific proteins and or carbohydrate preparations from GAS. However, studies of cardiac function are more problematic in such models. In this review, a historical overview of animal models previously used and those that are currently available will be discussed in terms of their usefulness in modeling different aspects of the disease process. Ultimately, cardiologists, microbiologists, immunologists, and physiologists may have to resort to diverse models to investigate different aspects of RF/RHD.
PMCID: PMC4220098  PMID: 25414841
animal models; rheumatic fever; rheumatic heart disease; group A Streptococcus; molecular mimicry; autoimmune responses

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