A STUDY OF EXTRA ARTICULAR MANIFESTATIONS OF RHEUMATOID ARTHRITIS

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1 A STUDY OF EXTRA ARTICULAR MANIFESTATIONS OF RHEUMATOID ARTHRITIS By Dr. SANDEEP R. SHARMA,M.B.B.S. Dissertation Submitted to the Rajiv Gandhi University of Health Sciences, Karnataka, Bangalore In partial fulfillment of the requirements for the degree of DOCTOR OF MEDICINE in GENERAL MEDICINE Under the guidance of Dr. MOHAMMED GHOUSE SHARIFF,MD Professor of Medicine DEPARTMENT OF MEDICINE MYSORE MEDICAL COLLEGE AND RESEARCH INSTITUTE MYSORE APRIL 2012

2 RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA, BANGALORE DECLARATION BY THE CANDIDATE I hereby declare that this dissertation entitled A STUDY OF EXTRA ARTICULAR MANIFESTATIONS OF RHEUMATOID ARTHRITIS is a bonafide and genuine research work carried out by me under the guidance of Dr. MOHAMMED GHOUSE SHARIFF, M.D., Professor, Department of Medicine, Mysore Medical College and Research Institute, Mysore. ii

3 CERTIFICATE BY THE GUIDE This is to certify that the dissertation entitled A STUDY OF EXTRA ARTICULAR MANIFESTATIONS OF RHEUMATOID ARTHRITIS is a bonafide research work done by Dr. SANDEEP R. SHARMA, in partial fulfillment of the requirement for the degree of Doctor of Medicine in General Medicine. iii

4 ENDORSEMENT BY THE HEAD OF THE DEPARTMENT AND THE DIRECTOR AND DEAN This is to certify that the dissertation entitled A STUDY OF EXTRA ARTICULAR MANIFESTATIONS OF RHEUMATOID ARTHRITIS is a bonafide research work done by Dr. SANDEEP R. SHARMA, under the guidance of Dr. MOHAMMED GHOUSE SHARIFF,M.D., Professor, Department of Medicine, Mysore Medical College and Research Institute, Mysore. iv

5 COPYRIGHT Declaration by the candidate I hereby declare that the Rajiv Gandhi University of Health Sciences, Karnataka, Bangalore shall have the rights to preserve, use and disseminate this dissertation in print or electronic format for academic/research purpose. RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES v

6 ACKNOWLEDGEMENTS With deep sense of gratitude and thankfulness, I express my indebtedness to my revered teacher, Dr. MOHAMMED GHOUSE SHARIFF, Professor, Department of Medicine, Mysore Medical College and Research Institute, Mysore, who has been a constant source of inspiration and encouragement and had provided invaluable guidance in the successful completion of this dissertation. I am thankful to Dr. H. VASUDEVA NAIK, Professor and Head, Department of Medicine, Mysore Medical College and Research Institute, Mysore, for his support and encouragement during the study period. I would like to thank Dr. M.A. SHEKAR, Dr. N. GUNASEELAN, Dr. M. SRINIVASA, Dr. A.G. RAVISHANKAR, Dr. C. RAJAN and Dr. SHETTY SHIVAKUMAR M., Professors; Dr. S. HIMAMANI and Dr. REKHA, Associate Professors; Dr. LAXME GOWDA, Dr. J. INBANATHAN, Dr. S.S. RAMESH, Dr. RANGASWAMY, Dr. MANJULA, Dr. S.P. YOGANNA, Dr. D.K. SUNEETHA, Dr. M.M. BASAVARAJU and Dr. DINESHA B., Assistant Professors; Dr. JAYASHEELAN, Dr. DEVARAJ R., Dr. VIKAS L., Senior Residents; Dr. SURESH K., Neurologist, for their suggestions in preparing this dissertation. I also express my gratitude to the Director and Dean and the Ethical Committee of Mysore Medical College and Research Institute; Superintendent, K.R. Hospital, Mysore, for granting me permission to conduct this study. I also thank my Post-Graduate colleagues, for their immense help in the preparation of this dissertation. vi

7 I am thankful to my parents, for their moral support and encouragement. I thank Mr. B.K. VENKATESH, M/S Kowshik DTP centre, for his efficient and excellent computer work. Last, but not least, I would like to thank my patients without whose consent and cooperation, this would have been an incomplete accomplishment. vii

8 LIST OF ABBREVIATIONS AP view Antero-posterior view CRP C-reactive peptide ESR Erythrocyte sedimentation rate HLA Human leukocyte antigen IFN Interferon IL Interleukin MCP Metacarpophalangeal joint MHC Major histocompatibility complex MTP Metatarsophalangeal joint PIP Proximal interphalangeal joint RA Rheumatoid arthritis RANK Receptor activated nuclear factor Kappa B RF Rheumatoid factor TNF Tumour necrosis factor viii

9 ABSTRACT BACKGROUND AND OBJECTIVE Rheumatoid arthritis is a common systemic inflammatory disease. Extra-articular manifestations are a common occurrence and are part of the spectrum of the disease. The manifestations are diverse and involve almost all the major systems of the body, including cardiovascular, respiratory, neurological and hematological systems. A wide variety of extra-articular features have been documented in various studies. However, there are considerable variations in the type of extra-articular manifestations reported. The present study was taken up to observe the extent of extraarticular manifestations noted in our patients. The aim is to document the occurrence of extra-articular involvement in patients suffering from Rheumatoid Arthritis. The objective is to study and document extra-articular manifestations by clinical examination, biochemical, pathological and radiological studies. METHODS The study was performed on patients attending the outpatient departments as well as on patients admitted in K.R. Hospital, Mysore, attached to Mysore Medical College and Research Centre, Mysore. A total of 50 patients were studied. The study was conducted between November 2009 and August After clinical evaluation and laboratory investigations, those patients satisfying the modified 1987 American College of Rheumatology criteria were included in the study. Patients not satisfying the modified 1987 American College of Rheumatology criteria were not included in the study. ix

10 RESULTS Extra-articular manifestations were noted in all cases of Rheumatoid Arthritis in the study. Anemia was the most common extra-articular manifestation noted in the study. Other manifestations noted were cardiac abnormalities, ocular abnormalities, lymphadenopathy, purpura, peripheral neuropathy and glomerulonephritis. CONCLUSION Rheumatoid arthritis is a systemic disease. Hence, it may result in a variety of extraarticular manifestations. Extra-articular manifestations may develop anytime during the clinical course of Rheumatoid arthritis. Patients most likely to develop extra-articular disease test positive for serum Rheumatoid Factor. Extra-articular manifestations contribute significantly to the morbidity and mortality in Rheumatoid arthritis. KEYWORDS: Rheumatoid Arthritis; American College of Rheumatology Criteria; Extra-articular manifestations; Rheumatoid Factor; Rheumatoid Nodules x

11 TABLE OF CONTENTS PAGE NO. 1. INTRODUCTION 1 2. OBJECTIVES 2 3. REVIEW OF LITERATURE 3 4. METHODOLOGY RESULTS DISCUSSION CONCLUSION SUMMARY BIBLIOGRAPHY ANNEXURES (i) PROFORMA 59 (ii) KEY TO MASTER CHART 62 (iii) MASTER CHART 63 xi

12 LIST OF TABLES Table No. Title Page No. 1 Non Class II Major Histocompatibility Complex Associations in Rheumatoid Arthritis 7 2 Extra-Articular Manifestations of Rheumatoid Arthritis 14 3 Modified American College of Rheumatology Criteria Criteria for inclusion as extra-articular manifestation of RA 17 5 Age and Gender Distribution of Cases 26 6 Symptom Distribution related to Extra-Articular Manifestations 28 7 Duration of Disease 30 8 Clinical Examination findings related to Extra-Articular Manifestations 31 9 Laboratory Investigation Findings in Cases Rheumatoid factor Extra-Articular Manifestations noted in the Study Comparison with other studies 46 xii

13 LIST OF FIGURES Figure No. Title Page No. 1 2 Roles of Innate and Adaptive Immunity in Etiology and Pathogenesis of Rheumatoid Arthritis Roles of Innate and Adaptive Immunity in Etiology and Pathogenesis of Rheumatoid Arthritis Rheumatoid arthritis 13 4 Extra-articular manifestations of rheumatoid arthritis 15 5 Purpura 20 6 Rheumatoid nodules 21 7 Age distribution of cases 27 8 Gender distribution of cases 27 9 Symptoms of extra articular manifestations Duration of disease Clinical examination Hemoglobin Peripheral smear Chest X-ray D echocardiography Electrocardiogram Slit lamp examination Rheumatoid factor Extra-articular manifestations 39 xiii

14 INTRODUCTION Rheumatoid Arthritis is a chronic systemic disease of unknown etiology. It is characterized by peripheral symmetrical polyarthritis. It has a progressive course with exacerbations and remissions being part of its natural history. Its onset could be any age; it usually starts in the fourth decade of life. Overall, there is a 3:1 female preponderance, but the excess is greater in young people and the age related incidence is approximately equal in elderly people. 1 Though being principally a disease of joints, several extra-articular manifestations are also noted. The systemic manifestations include involvement of cardiac, pulmonary, hematological, ocular, and neurological systems. The prevalence of Rheumatoid arthritis is between 0.7% and 1.5%. Malviaya et al. found the prevalence in Indian rural population to be 0.75%. 2 1

15 OBJECTIVES 1. To document the occurrence of extra-articular involvement in patients suffering from Rheumatoid Arthritis. 2. To study and document extra-articular manifestations by clinical examination, biochemical, pathological and radiological studies. 2

16 REVIEW OF LITERATURE HISTORICAL ASPECTS Soranus, an Epherian, who lived in the 2 nd century AD, wrote a treatise describing a polyarthritis with morning stiffness in which the joints become twisted sideways or bent over backwards, or resting immovable upon their neighbours. 3 Charaka, in India, two thousand years ago described a chronic disease with joint swellings and subcutaneous nodules. The problem with accepting this or other earlier descriptions as being first case reports of Rheumatoid arthritis is that each of them has clear references to what might have been tophaceous gout. In the translation from Latin by Short, of Syndenhams (1676) description of a polyarticular disease characterized by remissions and exacerbations, and his observation that the joints of his fingers have been as it were inverted and bulging out with the knots showing in their inner rather than the outer aspects of the fingers ; the first description of swan neck deformity is made. 4 The first detailed case report of Rheumatoid arthritis was that by a French medical student in 1850, Augustine Jacob Landre-Beauvais, who described acute onset of polyarthritis in a 35 year old female, which gradually ceased leaving behind deformity of the wrists and hands, only to recur. Garrod coined the term Rhematoid arthritis in However, the term came into use in 1941, prior to that was known by many different terms such as proliferative arthritis, atrophic arthritis etc

17 PREVALENCE OF RHEUMATOID ARTHRITIS Rheumatoid arthritis occurs worldwide with variable incidence and severity. Overall the prevalence ranges from %. The highest prevalence is seen in the Pima Indians, USA. In most Western countries, it affects up to 1-3% of the population, although many are not severely affected and may not seek medical advice at all. In India the prevalence of rheumatoid arthritis 2 in rural population is 0.7 % according to Malaviya et al. (1993). 4

18 ETIOLOGY The etiology of rheumatoid arthritis remains unclear, but there is evidence of genetic predisposition to the disease. The presence of HLA-DR4 is significantly commoner among sufferers of rheumatoid arthritis who are white. Rheumatoid arthritis is associated with only certain subtypes of HLA-DR4 (HLA-Dw4 and HLA-Dw14); susceptibility is related to a shared epitope on the HLA molecule (HLA DR B1). Role of HLA-DR in the Susceptibility to and Severity of Rheumatoid Arthritis The structure of class II MHC molecules in antigen presenting cells is associated with increased susceptibility and severity of RA and accounts for about 40% of the genetic influence. A genetic link between HLA-DR and RA was initially described in the 1970s with the observation that HLA-DR4 occurred in 70% of RA patients compared with about 30% of controls, giving a relative risk of having RA of approximately 4 to 5 to individuals with HLA-DR4. The susceptibility to RA is associated with the third hypervariable region of DRβ-chains, from amino acids 70 through The epitope is glutamine-leucine-arginine-alanine-alanine (QKRAA), a sequence found in DR4 and DR14 (in which RA is more prevalent), in addition to some DR1β-chains. Current nomenclature attempts to clarify these ambiguities by including information on the specific DRβ sequences. The DR4β-chains with the greatest association with RA are referred to as DRB*0401, DRB*0404, DRB*0101 and DRB*1;

19 Additional Polymorphisms: Cytokines, Citrullinating Enzymes, PTPN22, and Others The clear genetic influences on RA have led to studies evaluating non-mhc genes. Single-nucleotide polymorphisms (SNPs) in promoter regions or coding regions have been extensively investigated in RA. SNPs in promoter regions could lead to altered gene regulation as a result of variable binding of transcription factors to promoters, whereas SNPs in coding regions directly change the amino acid sequence of the encoded protein. A second method for assessing genetic associations involves the evaluation of microsatellite sequences near key genes that are implicated in the disease. Microsatellites are tandem repeated sequences in the DNA that are primarily (but not exclusively) located in noncoding regions. Considerable heterogeneity exists in the length of each microsatellite, which can indirectly alter gene expression or be in linkage disequilibrium with other undefined genetic 9, 20 polymorphisms. Gender 21 Rheumatoid Arthritis is one of many autoimmune diseases that is predominant in women. The ratio of female-to-male patients (2:1 to 3:1) is significant. The role of estrogens has been explored by various methods. Autoantibody-producing B cells exposed to estradiol are more resistant to apoptosis, suggesting that autoreactive B cell clones might escape tolerance. The effect on T lymphocytes is more difficult to reconcile with the female preponderance in Rheumatoid Arthritis because estrogens tend to bias T cell differentiation toward the T helper type 2 (Th2) phenotype. Estrogen receptors are expressed on fibroblast-like synoviocytes (FLS) and, when 6

20 stimulated, increase production of metalloproteinases in the synovium. In macrophage cell lines, estrogen can enhance production of TNF-α. Taken together, these data suggest that the hormone milieu can have significant effects on the cells known to participate in RA. The effects are complex, however, and the specific mechanisms responsible for increased susceptibility to RA in women are uncertain. Table 1: Non Class II Major Histocompatibility Complex Associations in Rheumatoid Arthritis 20 Gene Region of Gene Studied Associated with Rheumatoid Arthritis * PTPN22 Coding + PADI4 Coding + STAT4 Intron + TRAF1-C5 Intron + TNF-α Promoter + IL-1 Coding region; association with IL-1β strongest IL-1Ra Coding region + IL-3 Promoter + IL-4 IntronPromoter +- IL-6 Promoter - IL-10 Promoter - IL-12 3 untranslated region - IFN-γ Intron microsatellite +/- CCR5 CCRδ32 allele + RANTES Promoter + MIF Promoter + RAGE Ligand-binding domain + CTLA4 3 untranslated region + TGF-β Coding region + FcRγIII Coding region + CCR5, chemokine receptor 5; c-5, complement 5; FcRγIII, Fc receptor γiii; IFN-γ, interferon-γ; IL, interleukin; IL-1Ra, interleukin-1 receptor antagonist; MIF, macrophage inhibitory factor; RAGE, receptor for advanced glycosylation end products; RANTES, regulated on activation, normally T cell expressed and secreted; TGF-β, transforming growth factor-β; TNF-α, tumor necrosis factor-α; TRAF1, TNF-receptor associated factor 1. * +, association observed; -, no association observed; +/-, association observed in some studies, but not in others. +/- 7

21 Tobacco 22 Numerous environmental factors certainly contribute to RA susceptibility, although no specific exposure has been identified as a pivotal agent. Smoking is the best defined environmental risk factor for seropositive Rheumatoid Arthritis in certain populations. The reason for its influence on the development of synovitis is not fully defined, but could involve the activation of innate immunity. Citrullinated peptides have been detected in bronchoalveolar lavage samples of smokers, and this could provide a stimulus for generation of anticitrullinated peptide antibodies in susceptible individuals. Repeated activation of innate immunity, especially in an individual with underlying genetically determined autoreactivity, potentially could contribute to autoreactivity and the initiation of RA. 8

22 PATHOGENESIS OF RHEUMATOID ARTHRITIS The CD4+ cells are the main orchestrators of cell-mediated immune responses, and are responsible for release and activation of a cascade of cytokines that are responsible for the disease whether it is at local site of destruction at the joint synovial membrane or the diffuse attack at the other organ systems, responsible for the many extra-articular manifestations. 23 In genetic studies, rheumatoid arthritis is strongly linked to the majorhistocompatibility-complex class II antigens HLA-DRB1*0404 and DRB1*0401. Innate immunity activates fibroblast-like synoviocytes (FLS), dendritic cells (DC), and macrophages (MΦ) in the earliest phases in individuals with underlying immune hyperreactivity as evidenced by the production of autoantibodies. DC can migrate to the central lymphoid organs to present antigen and activate T cells, which can activate B cells. These lymphocytes can migrate back to the synovium and enhance adaptive immune responses in the target organ. In addition, repeated activation of innate immunity can lead directly to chronic inflammation and possibly antigen presentation in the synovium. In the latter phases of disease, many cell types activate osteoclasts (OC) through the receptor activator of nuclear factor κb (NFκB)/receptor activator of NFκB ligand (RANK/RANKL) system, although FLS and T cells likely provide the greatest stimulus. 9

23 Figure 1: Roles of Innate and Adaptive Immunity in Etiology and Pathogenesis of Rheumatoid Arthritis 23 arthritis. Schematic diagram of disease mechanisms that likely occur in rheumatoid 10

24 Figure 2: Roles of Innate and Adaptive Immunity in Etiology and Pathogenesis of Rheumatoid Arthritis Cytokine Signaling Pathways Involved in Inflammatory Arthritis The major cell types and cytokine pathways believed to be involved in joint destruction mediated by TNF-α and interleukin-1 are shown. Th 2 denotes type 2 helper T cell; Th 0 is precursor of type 1 and type 2 helper T cells. 11

25 PATHOGENESIS OF EXTRA-ARTICULAR MANIFESTATIONS OF RHEUMATOID ARTHRITIS RA is associated with elevated systemic levels of Rheumatoid factor (RF), CRP, and cytokines (TNF-alpha, IL-1, and IL-6). RF and each of these cytokines play a direct pathogenic role in the development of several of the extra-articular manifestations of RA TNF-alpha and IL-1 promote fibroblast activation and adhesion and stimulate the production of other cytokines. 24, 25 IL-6 promotes B-cell activation and stimulates systemic production of inflammatory mediators, such as CRP. The importance of TNF-alpha, IL-1, and IL-6 in the pathogenesis of RA is highlighted by the effectiveness of therapies directed at neutralizing these cytokines The extra-articular manifestations of RA are closely associated with RF levels and circulating immune complexes that contain complement components (C1q, C3, C4); this is especially true for RA-associated vasculitis for which a direct pathogenic role for RF has been demonstrated. 32, 33 Other extra-articular manifestations that are associated with RF levels include Felty s syndrome, rheumatoid nodules, and secondary Sjögren s syndrome

26 CLINICAL FEATURES 1 The start of the disease is usually insidious but can be episodic or acute. Rheumatoid arthritis usually presents as a polyarthritis affecting small joints or small and large joints. Early disease is characterized by pain and other cardinal signs of inflammation (heat, swelling, functional loss, and possible erythema over the joints) but not by damage and deformity. If the disease remains active and uncontrolled the inflammation will usually spread to additional joints and gradual irreversible tissue damage will occur, causing deformity and instability of joints. Inflammation of other synovial structures is common, and a similar process may occur in tendon sheaths, progressing to serious dysfunction and rupture. The typical rheumatoid deformities such as ulnar deviation of the fingers, deformity of the thumb, and swan neck and Boutonniere deformities - are mostly due to damage or displacement of tendons. Palpable thickening or nodularity of tendons is common. Figure 3: Rheumatoid arthritis Effect of rheumatoid arthritis on the hand: (left) early changes and (right) later deformity 13

27 EXTRA-ARTICULAR MANIFESTATIONS OF RHEUMATOID ARTHRITIS Table 2: Extra-Articular Manifestations of Rheumatoid Arthritis 10 Organ System Cardiovascular Hematologic Systemic Manifestation Coronary artery disease, pericarditis, conduction defects, aortic root dilatation Anemia, thrombocytosis, Felty s syndrome, large granulocytic leukemia, non-hodgkin s lymphoma Pulmonary Vascular Bone Pleural effusion, nodules, interstitial lung disease Vasculitis, neuropathy Osteopenia and osteoporosis Ocular Keratoconjunctivitis sicca, scleritis, episcleritis, peripheral ulcerative keratitis Salivary glands Secondary Sjögren s syndrome with dry eyes and mouth Skin Cutaneous vasculitis, nodules, pyoderma gangrenosum 14

28 Figure 4: Extra-articular manifestations of rheumatoid arthritis 15

29 MODIFIED AMERICAN COLLEGE OF RHEUMATOLOGY CRITERIA This is 92% sensitive and 89.3% specific. At least 4 criteria must be present of the following in a given patient and criteria 1 4 should be present for a period of six weeks to make a diagnosis of Rheumatoid arthritis. Table 3: Modified American College of Rheumatology Criteria Morning stiffness Morning stiffness in and around the joints, lasting at least 1 hour before maximal improvement 2. Arthritis of 3 or Atleast 3 joint area s (out of 14 possible areas; right or left more Joints PIP, MCP, wrist, elbow, knee, ankle, and MTP joints). Simultaneously should have had soft tissue swelling or fluid (no bony growth) as observed by physician. Atleast one area swollen (as defined above) in wrist MCP, PIP joints 3. Arthritis of hand joints 4. Symmetric arthritis Simultaneous involvement of the same joint areas (as defined in 2) on both sides of the body (bilateral involvement of PIPs, MCP, MTP without absolute symmetry is acceptable. 5. Rheumatoid nodules Subcutaneous nodules over the bony prominences or extensor aspect, or juxta articular regions as observed by physician. 6. Serum rheumatoid factor 7. Radiographic criteria Demonstration of abnormal serum rheumatoid factor by any method for which the result has been positive and is less than 5 % of normal control subjects. AP hand and wrist x-rays, must include erosions, juxta articular or generalized osteoporosis, subluxation, and secondary osteoarthritis. 16

30 Table 4: Criteria for inclusion as extra-articular manifestation of RA 12 17

31 IMPORTANT EXTRA-ARTICULAR MANIFESTATIONS OF RHEUMATOID ARTHRITIS Cardiovascular Disease Cardiovascular disease is one of the major causes of increased mortality in patients with Rheumatoid Arthritis. 34,35 Twenty-seven percent of Rheumatoid Arthritis patients developed clinical evidence of cardiovascular disease over a 7-year period between 1999 and 2006 in a study done by Hochberg et al. 38 Accelerated atherosclerosis, as measured by carotid intima-medial thickness, also occurs in Rheumatoid Arthritis patients with early disease and is directly correlated with CRP levels. 36 The increased incidence of cardiovascular disease in Rheumatoid Arthritis patients may be a consequence of the increased systemic inflammation that occurs 34, 36, 37 outside the joints of these patients. Hematological Disease Hematologic abnormalities, especially anemia, are present in the majority of RA patients. 39, 40 Anemia of chronic disease is commonly present in patients with RA, and its severity is directly related to high levels of inflammatory cytokines, including 39, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, and IL-6. Thrombocytosis is another common hematologic finding in RA patients, and it correlates to markers of disease activity and inflammation. 44 There is an association of high RF levels with the development of Felty s syndrome (RA, splenomegaly, and neutropenia), with large granulocytic leukemia 39, 45 and the development of non-hodgkin s lymphoma. 18

32 Pulmonary Disease The lungs are commonly affected in patients with RA. Pleural effusions and pulmonary rheumatoid nodules are common, and there is an association of these pulmonary manifestations of RA with, high titers of RF. 46,47,48 Patients with RA also develop interstitial lung disease that is characterized by an early inflammatory phase associated with pulmonary mononuclear cell infiltrates. The later phases of interstitial lung disease are characterized by the development of pulmonary fibrosis. 49 Risk factors for the development of interstitial lung disease includes disease severity and smoking. Symptomatic interstitial lung disease occurs in approximately 3% to 14% of RA patients, whereas detailed pulmonary function testing and autopsy studies have indicated that 35% to 60% of RA patients have evidence of interstitial lung disease and pulmonary fibrosis. 26,50,51 Osteopenia and Osteoporosis Osteopenia and osteoporosis are very common in patients with RA. 56 The development of osteopenia in RA patients appears to occur independent of corticosteroid use and is directly linked to elevated levels of the receptor activator of nuclear factor-kappa B (RANK) ligand, which is expressed by T cells and promotes osteoclastic bone resorption. 56,57,58 Osteopenia in RA is directly associated with markers of inflammation. The periarticular osteopenia that occurs in RA patients is likely related to high local levels of IL-1 and TNF-alpha, which are produced in inflamed RA synovium and which augment RANK ligand production

33 Vascular Disease The vasculitis associated with RA is often manifested as a neuropathy (distal sensory neuropathy or sensorimotor neuropathy [mononeuritis multiplex]) or as nailfold infarcts, skin ulcerations, or gangrene. 52 There is a strong association between RF levels and the development of vasculitis in patients with RA. 26,53 The development of vasculitis in RA patients is associated with the intravascular deposition of immune complexes containing RF and immunoglobulin and associated with complementmediated vascular damage. 53,54,55 Ocular Disease Figure 5: Purpura 60, 61 Ocular involvement is another major manifestation of RA. The most important ocular manifestation is scleritis, which is associated with the development of anterior uveitis and with peripheral ulcerative keratitis or corneal melt. 60, 61 These disorders are associated with mononuclear cell infiltrates in the eye that produce inflammatory cytokines. Unlike many of the other systemic manifestations of RA, ocular involvement can predate the development of arthritis and may be independent of the RA disease activity

34 RA patients also develop secondary Sjögren s syndrome, which can be associated with the development of keratoconjunctivitis sicca; 63 there is an association between RF levels and keratoconjunctivitis sicca in RA patients. 64 Rheumatoid Nodules One of the most common manifestations of extra-articular disease is the development of rheumatoid nodules. They occur most frequently in RF positive patients, and rarely in seronegative patients. Typically seen over areas of the body exposed to mechanical pressure, particularly the elbows and extensor surfaces of the forearm, but can also occur on pressure points over tendons and bone on the fingers, feet, knees, scalp and back. 65,66 Peripheral nodules can ulcerate and serve as a portal for bacteremia. Nodules can also form in some organs (e.g. heart, lung, eye, etc.), where they may have a greater propensity for causing symptoms. Figure 6: Rheumatoid nodules FACTORS ASSOCIATED WITH POORER PROGNOSIS IN RHEUMATOID ARTHRITIS 1. Insidious polyarticular onset 2. Male patients 3. Extra-articular manifestations 4. Rheumatoid nodules 21

35 5. Functional disability at one year after start of disease- grade 3 or 4 6. Substantially raised concentration of rheumatoid factors 7. Positive anticitrullinated protein in serum 8. Presence of HLA-DR4 9. Presence of the shared epitope (QKRAA) on class II major histocompatibility genes 10. Radiographic evidence of erosions within three years of start of disease 11. Persistent elevation of ESR and CRP 12. Early age of onset ACR CRITERIA FOR CLINICAL REMISSION OF RHEUMATOID ARTHRITIS 68 A minimum of 5 of the following criterion should be present for at least two consecutive months. 1. Morning stiffness not to exceed 15 minutes 2. No fatigue 3. No joint pain 4. No joint tenderness or pain on movements 5. No soft tissue swelling in joints or tendon sheath 6. ESR less than 30 mm/1 hour (females) and < 20 mm/1 hour (males) 22

36 METHODOLOGY The study was performed on patients attending the outpatient departments as well as on patients admitted in K.R. Hospital, Mysore, attached to Mysore Medical College and Research Centre, Mysore. A total of 50 patients were studied. The study was conducted between November 2009 and August Inclusion Criteria After clinical evaluation and laboratory investigations, those patients satisfying the modified 1987 American College of Rheumatology criteria were included in the study. Exclusion Criteria Patients not satisfying the modified 1987 American College of Rheumatology criteria were not included in the study. All patients were evaluated with Detailed history Age, sex, duration of rheumatoid arthritis, presence and duration of morning stiffness, presence of other systemic disease, and history of symptoms of extraarticular manifestations of rheumatoid arthritis were documented. Treatment history was also documented. Examination All patients were examined in detail, looking for physical signs suggestive of extra-articular manifestations. Cardiovascular, respiratory, abdominal, neurological and integumental system examination was done in detail. 23

37 Investigations All relevant investigations to search for extra-articular manifestations were done. Routine investigations Complete hemogram, peripheral smear, erythrocyte sedimentation rate, blood urea, serum creatinine, blood sugar, and urine for albumin were done in all patients. Chest Radiography All patients were subjected to chest X-ray, postero-anterior view. Ultrasonogram All patients were subjected to abdominal ultrasonogram. Electrocardiogram A 12 lead electrocardiogram was taken in all patients. Echocardiography Patients with symptoms suggestive of cardiac involvement were subjected to 2D-echocardiography. Histopathology Patients with features suggestive of renal disease were subjected to renal biopsy. Patients with lymphadenopathy were subjected to fine needle aspiration and biopsy. 24

38 Slit Lamp Examination All patients with features suggestive of ocular disease were subjected to examination by slit lamp. Rheumatoid Factor (IgG) A quantitative assay was performed using a latex fixation lab kit in all patients. 25

39 RESULTS Age Distribution In the current study, 5 patients are under the age of 35 years, 24 patients are between the age group of 35 to 45 years, and, 21 patients are over the age of 45 years. Gender Distribution In the current study, of the 50 patients studied, 12 are males and 38 are female patients. Table 5: Age and Gender Distribution of Cases Age group (years) Number of patients < > Gender Number of patients Males 12 Females 38 26

40 Figure 7: Age distribution of cases Figure 8: Gender distribution of cases 27

41 Symptoms The symptoms related to extra-articular manifestations of RA noted in this study are malaise (20 patients), fatigue (23 patients), subcutaneous nodules (12 patients), dryness of eyes (9 patients), dryness of mouth (8 patients), eye pain (9 patients), skin rash (8 patients) and Raynaud s phenomenon (7 patients). Table 6: Symptom Distribution related to Extra-Articular Manifestations Symptoms Number of patients Malaise 20 Fatigue 23 Subcutaneous Nodules 12 Dry Eyes 9 Dry Mouth 8 Eye Pain 9 Skin Rash 8 Raynaud s phenomenon 7 28

42 Figure 9: Symptoms of extra articular manifestations 29

43 Duration of Disease The duration of disease in the cases in the study ranged from 4 to 17 years. A disease duration of less than 5 years is seen in 4 patients, a duration between 5 and 10 years is seen in 20 patients, a duration between 10 to 15 years is seen in 24 patients and a duration of more than 15 years is seen in 2 patients. Table 7: Duration of Disease Duration in years Number of Patients Figure 10: Duration of disease 30

44 Physical Examination The clinical examination findings in the study patients revealed pallor in 26 patients, pedal edema in 9 patients, lymphadenopathy in 10 patients, purpuric rash in 8 patients, rheumatoid nodules in 7 patients, keratitis in 3 patients, episcleritis in 3 patients, scleritis in 3 patients, mild splenomegaly in 2 patients, peripheral neuropathy in 2 patients, pericardial rub in 1 patient and muffled heart sounds in 1 patient. Table 8: Clinical Examination findings related to Extra-Articular Manifestations Clinical examination Number of patients Pallor 26 Pedal Edema 9 Lymphadenopathy 10 Purpuric Rash 8 Rheumatoid Nodules 7 Corneal Opacity 3 Episcleritis 3 Scleritis 3 Splenomegaly 2 Pericardial rub 1 Muffled Heart Sounds 1 Peripheral Neuropathy 2 31

45 Figure 11: Clinical examination 32

46 Investigations Hemoglobin is between 7 and 10 g/dl in 26 patients, between 10 and 12 g/dl in 15 patients, and the rest showed a hemoglobin of more than 12 g/dl. Peripheral smear showed a Normochromic Normocytic blood picture in 47 patients and a Microcytic Hypochromic blood picture in 3 patients. Chest X ray showed Mild Cardiomegaly in 5 patients and Pericardial effusion in 2 patients. Urine examination showed Albumin trace in 3 patients. Ultrasonography showed Grade I Medical renal disease in 3 patients. Kidney biopsy suggested Glomerulonephritis in 3 patients. Electrocardiogram showed Non-specific ST-T changes in 4 patients and First Degree Heart Block in 2 patients. 2D Echocardiography showed Pericardial effusion in 2 patients, Left Ventricular Diastolic Dysfunction in 5 patients, and, Pulmonary Hypertension in 1 patient. Slit Lamp Examination showed Keratitis in 3 patients, Scleritis in 3 patients and Episcleritis in 3 patients. Table 9: Laboratory Investigation Findings in Cases Laboratory investigations Number of patients < 7 0 Hemoglobin 7 to to > 12 9 Peripheral smear NCNC 47 MCHC 3 Chest X-ray Mild Cardiomegaly 5 Pericardial Effusion 2 Urine Examination Albumin Trace 3 USG Abdomen Grade I MRD 3 Renal Biopsy Glomerulonephritis 3 Pericardial Effusion 2 2d echocardiography LVDD 5 Pulm. Hypertension 1 ECG Non Sp. ST-T changes 4 First Degree Heart Block 2 Keratitis 3 Slit lamp examination Scleritis 3 Episcleritis 3 33

47 Figure 12: Hemoglobin Figure 13: Peripheral smear 34

48 Figure 14: Chest X-ray Figure 15: 2D echocardiography 35

49 Figure 16: Electrocardiogram Figure 17: Slit lamp examination 36

50 Rheumatoid Factor Rheumatoid Factor positivity is seen in all cases in the study. The titres of Rheumatoid Factor ranged from 1/16 to 1/ patients had a titre of 1/16, 19 patients had a titre of 1/32, 9 patients had a titre of 1/64 and 3 patients had a titre of 1/128. Table 10: Rheumatoid factor Rheumatoid factor Titre Number of Patients 1\ \ \64 9 1\128 3 Figure 18: Rheumatoid factor 37

51 Extra Articular Manifestations The following are the various extra articular manifestations seen in the current study, anemia in 41 patients, lymphadenopathy in 10 patients, purpuric rash in 8 patients, rheumatoid nodules in 7 patients, splenomegaly in 2 patients, peripheral neuropathy in 2 patients, pericardial effusion in 2 patients, left Ventricular Diastolic dysfunction in 5 patients, pulmonary Hypertension in 1 patient, glomerulonephritis in 3 patients, keratitis in 3 patients, scleritis in 3 patients and episcleritis in 3 patients. Table 11: Extra-Articular Manifestations noted in the Study Extra-articular manifestations Number of patients Anemia 41 Lymphadenopathy 10 Purpuric Rash 8 Rheumatoid Nodules 7 Splenomegaly 2 Peripheral Neuropathy 2 Pericardial Effusion 2 Left Ventricular Diastolic Dysfunction 5 Pulmunary Hypertension 1 Glomerulonephritis 3 Keratitis 3 Scleritis 3 Episcleritis 3 38

52 Figure 19: Extra-articular manifestations 39

53 DISCUSSION Rheumatoid arthritis (RA) is a systemic inflammatory disease, which is associated with a number of extra-articular organ manifestations. 10 Arthritis is only one manifestation of rheumatoid disease. This multi-system concept was first advanced in 1948 and the term rheumatoid disease was subsequently introduced. Since then extra-articular features have been described in many studies. Possible predictors of extra-articular rheumatoid arthritis manifestations include constitutional factors such as male sex and disease associated HLA genes (in particular homozygosity for certain DRB1*04 subtypes), autoantibodies such as rheumatoid factor and antinuclear antibodies (ANA), and environmental factors such as smoking. The various extra-articular rheumatoid arthritis manifestations described in various studies include anemia, thrombocytosis, pericarditis, pleuritis, major cutaneous vasculitis, Felty s syndrome, neuropathy, ophthalmological manifestations, glomerulonephritis, osteoporosis, lymphadenopathy, non-hodgkin s lymphoma, secondary Sjogren s syndrome and interstitial lung disease and other rare manifestations. Age Distribution The age incidence in the current study is 44.5 ± 9.5. In the study done by Turesson C et al., 12 the mean age of the study group was 58.1 years. The age incidence in this study is higher than the mean age in the current study. 40

54 In the study done by Maione et al., 15 the mean age of the study group was 46.4 years. The age incidence in this study is comparable to the mean age in the current study. In the study done by Kaushal et al., 16 the mean age of the study group was 29 years. The age incidence in this study is lower than the mean age in the current study. Gender Distribution The ratio of male to female patients in the current study is 1:3.16. In the study done by Turesson C et al., 12 the ratio of male to female patients was 1:2.71. The sex ratio in this study is comparable to the same in the current study. In the study done by Maione et al., 15 the ratio of male to female patients was 1:2.2. The sex ratio in this study is lower than the sex ratio in the current study. Duration of Disease The mean duration of disease in the present study is years. In the study done by Fleming A et al., 13 the mean duration of disease was found to be 4.5 years. The mean duration here is lesser than the present study. In the study done by Sahatciu-Meka et al., 14 the mean duration of disease was found to be 9.8 years. This is comparable to the present study. In the study done by Turesson et al., 12 the mean duration of disease was found to be 11.8 years. This is comparable to the present study. 41

55 Rheumatoid Factor In the present study, Rheumatoid factor positivity is found in all cases. Pai et al., 11 Jonsson et al., 45 Sahatciu-Meka et al., 14 Turesson et al., 12 all have found high percentage of their cases to be Rheumatoid factor positive. All have found Rheumatoid factor positivity together with higher percentage of extra-articular manifestations. Extra Articular Manifestations Anemia In the present study, anemia is predominant extra-articular manifestation. 82 % of the cases had anemia. The anemia is predominantly normocytic normochromic type (76%), the other being microcytic hypochromic type (6%). In the study done by Sahatciu-Meka et al., 14 anemia was the predominant manifestation, with 97.8 % of the patients having anemia. This is comparable to the present study. In the study done by Bowman et al. 39 also, anemia was the predominant manifestation. Cardiac Manifestations In the present study, cardiac manifestations are seen in 20% of cases. The manifestations seen are pericardial effusion (4%), left ventricular diastolic dysfunction (10%), pulmonary hypertension (2%) and first degree heart block (4%). In the study done by Maione et al., 15 cardiac manifestations were found in 43% of the patients. Left ventricular diastolic dysfunction was seen in 26% of patients and pericardial effusion was seen in 9% of cases. 42

56 In the study done by Kaushal et al., 16 cardiac manifestations were seen in 20% of cases. This is comparable to the present study. Pericardial effusion was the major manifestation in the above study. Left ventricular diastolic dysfunction was not documented. Dawson et al., 17 have reported a higher percentage of pulmonary hypertension (21%) in their study. Rheumatoid Nodules In the present study, rheumatoid nodules are seen in 14% of the cases. In the study done by Sahatciu-Meka et al., 14 rheumatoid nodules were seen in 12% of cases, this is comparable to the present study. In the study done by Fleming A et al., 13 rheumatoid nodules were seen in 31% of cases. In the study done by Turesson et al., 12 rheumatoid nodules were seen in 34% of cases. Also, in the present study, rheumatoid nodules are seen in cases with high titres of Rheumatoid factor. This is comparable to the study by both Sahatciu-Meka et al. and Turesson et al. Ocular manifestations In the present study, ocular manifestations are seen in 18% of cases. Of these, episcleritis, scleritis and keratitis are observed, each in 6% of the cases. In the study done by Sahatciu-Meka et al., 14 scleritis was observed in 4% of cases. 43

57 This is comparable to the present study. There is no report of keratitis and episcleritis in the above study. In the study done by Fleming A et al., 13 episcleritis was observed in 9% of the cases, scleritis was observed in 4% of cases. This is comparable to the present study. In the study done by Turesson et al., 12 scleritis, keratitis, and, episcleritis were reported. Scleritis was observed in 0.8% of cases. Episcleritis was observed in 1% of cases. Keratitis was observed in 11.6% of cases. Purpura In the present study, purpuric rash is observed in 16% of the cases. In the study done by Sahatciu-Meka et al., 14 purpura was observed in 12% of cases. This is comparable to the present study. In the study done by Turesson et al., 12 purpura was observed in 3.6% of cases. Glomerulonephritis In the present study, glomerulonephritis is observed in 6% of cases. In the study done by Harper et al., 69 glomerulonephritis was observed in 8% of the cases. This is comparable to the present study. In the study done by Turesson et al., 12 glomerulonephritis was reported in 1.1% of cases. In the study done by Boers et al., 70 glomerulonephritis was reported in 3% of the cases. 44

58 Peripheral Neuropathy In the present study, peripheral neuropathy is seen in 4% of cases. In the study done by Turesson et al., 12 peripheral neuropathy was observed in 2.1% of cases. This is comparable to the present study. In the study done by Sahatciu-Meka et al. 14 and Fleming A et al., 13 peripheral neuropathy was observed in a higher percentage of cases. It was observed in 16.8% and 18% of the cases respectively. Other Hematological Manifestations In the present study, lymphadenopathy and splenomegaly are the notable hematologic manifestations seen, other than the presence of anemia. Lymphadenopathy is observed in 20% of the cases. Two cases subjected to biopsy showed reactive lymphadenitis. Splenomegaly is observed in 4% of cases. In the study done by Fleming A et al., 13 lymphadenopathy and splenomegaly was observed in 41% and 2% of cases respectively. This is comparable to the present study. In the study done by Turesson et al., 12 splenomegaly (as a part of Felty s syndrome) was observed in 1.6% of cases. Lymphadenopathy was not reported. In the study done by Motulsky AG et al., 18 Hart FD et al., 19 lymphadenopathy was observed in 41-82% of cases. 45

59 Table 12: Comparison with other studies Comparison Present Study Turesson et al. 12 Sahatciu-Meka et al. 14 Fleming A et al. 13 Maione et al. 15 Number of Patients Age(yrs) Mean ± SD 44.5± ±15.6 Sex ratio (M:F) 1:3.16 1:2.71-1:31 1:2.2 Disease Duration (yrs) Rheumatoid Factor 100% - 100% % Anemia 82% % - - Cardiac manifestations 20% % Rheumatoid Nodules 14% 34% 12% 31% - Ocular Manifestations Scleritis 6% 0.80% 4% 4% - Episcleritis 6% 1% - 9% - Keratitis 6% 11.60% Purpura 16% 3.60% 12% - - Glomerulonephritis 6% 1.10% Peripheral Neuropathy 4% 2.10% 16.80% 18% - Lymphadenopathy 20% % - Splenomegaly 4% 1.60% - 2% - 46

60 The overall presence of majority of the extra-articular manifestations is lesser in the present study as compared to the other studies. This could be attributed to the following reasons: 1. The incidence of extra-articular manifestations is much lower in Indian patients as evidenced by the Kaushal et al. 16 study. 2. The duration of disease was much lower in this study as compared to the other studies. 3. The number of cases in the present study is much lower compared to the other studies. 47

61 CONCLUSION Extra-articular manifestations were found in all 50 cases of rheumatoid arthritis. The highest number of patients were found in the age group of 35 to 45 years. The male to female ratio was 1:3.16. The mean duration of disease was found to be years, with maximum number of cases having disease duration between 10 and 15 years. Anemia was found to be the most commonly seen extra-articular manifestation. Forty-one patients had anemia. Normocytic normochromic type of anemia was the most common type of anemia documented. Other extra-articular manifestations noted in the study were cardiac manifestations - 10 patients (left ventricular diastolic dysfunction, pericardial effusion, pulmonary hypertension and first degree heart block), ocular manifestations - 9 patients (scleritis, keratitis, episcleritis), rheumatoid nodules - 7 patients, purpura - 8 patients, peripheral neuropathy - 2 patients, glomerulonephritis - 3 patients, lymphadenopathy - 10 patients and splenomegaly - 2 patients. Rheumatoid factor positivity was seen in all patients. 48

62 SUMMARY Rheumatoid arthritis is a chronic inflammatory disease of unknown etiology marked by a symmetric, peripheral polyarthritis. It is a systemic disease. Hence, it may result in a variety of extraarticular manifestations, including fatigue, subcutaneous nodules, lung involvement, pericarditis, peripheral neuropathy, vasculitis, and hematologic abnormalities. Extra-articular manifestations may develop during the clinical course of Rheumatoid arthritis, even prior to the onset of arthritis. Patients most likely to develop extra-articular disease have a history of smoking, early onset of significant physical disability, and test positive for serum Rheumatoid Factor. Extra-articular manifestations contribute significantly to the morbidity and mortality in Rheumatoid arthritis. Careful screening of all patients for extra-articular manifestations may help reduce the same. 49

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