Study of Bone Mineral Density (BMD) in Patients with Rheumatoid Arthritis and its Corelation with Severity of the Disease

26 ORIGINAL ARTICLE Study of Bone Mineral Density (BMD) in Patients with Rheumatoid Arthritis and its Corelation with Severity of the Disease Liyakat Ali Gauri 1, Qadir Fatima 2, Sharanbasu Diggi 3, Asim Khan 4, Ambreen Liyakat 5, BR Ajay 3 Abstract Introduction: Rheumatoid arthritis (RA) is a chronic inflammatory disease of unknown etiology marked by a symmetric, peripheral polyarthritis. 1-3 People with rheumatoid arthritis are at increased risk of osteoporosis. Hence this article intends to highlight the importance of BMD measurement in patients with RA as a tool for assessment of disease activity and severity. Objectives: To evaluate Bone Mineral Density in patients of Rheumatoid Arthritis and Co-relate it with severity of disease. Materials and Methods: Hand bone density was measured on the plain radiographs of the right hand using digital x-ray radiogrammetry (Pronosco Xposure System 2.0). This BMD was correlated with markers of disease activity using DAS 28 Scoring system. 4 Results: In our study there were 200 patients with equal number of controls. 70 patients in study group and 131 patients in control group were <45 years old and had normal Z-score while in age group >45 years 26 and 20 cases in study and control groups respectively had their Z-score within normal range. There were total 21 and 2 cases of study and control groups respectively (age <45 years) who had osteoporosis while in age group >45 years 12 and 10 cases in study and control groups respectively had osteopenia. Conculsion: Patients with RA are more susceptible for bone loss in comparison to normal age and gender related subjects. Patients with longer duration and higher disease activity are more susceptible for developing osteopenia and osteoporosis. Occurrence of joint deformities increases with longer disease duration. Limitation of physical activity impairs the bone mineral density. Patient taking anti-rheumatic therapy (steroids and Disease-modifying antirheumatic drugs) are at increased risk of bone loss. All these factors contribute to bone loss independent of each other. Introduction R heumatoid arthritis (RA) is a chronic inflammatory disease of unknown etiology marked by a symmetric, peripheral Editorial Viewpoint Limitation of physicl activity nd anti-rheumatic drug therapy impairs Bone Mineral Density in RA patients. Seropositive RA patients are more prone to osteopenia and osteoporosis. Decreased BMD is more common in patients with early, active, erosive disease. polyarthritis. It is the most common form of chronic inflammatory arthritis and often results in joint damage and physical disability. Because it is a systemic disease, RA may result in a variety of extra articular manifestations, including fatigue, subcutaneous nodules, lung involvement, pericarditis, peripheral neuropathy, vasculitis, and hematologic abnormalities. 1-3 The incidence of RA increases between 25 and 55 years of age, after which it plateaus until the age of 75 and then decreases. The presenting symptoms of RA typically result from inflammation of the joints, tendons, and bursae. Patients often complain of early morning joint stiffness lasting more than 1 Senior Professor, Department of Medicine, 2 Professor, Department of Pathology, 3 Post graduate Student, Department of Medicine, S.P. Medical College, Bikaner, Rajasthan; 4 Senior Resident, Department of Ophthalmology, SMS College, Jaipur, Rajasthan; 5 Consultant Radiologist, SDMH, Jaipur, Rajasthan Received: 20.07.2015; Revised: 07.11.2016; Accepted: 03.12.2016

27 1 hour and easing with physical activity. The earliest involved joints are typically the small joints of the hands and feet. The initial pattern of joint involvement may be monoarticular, oligoarticular (2-4 joints), or polyarticular (>5 joints), usually in a symmetric distribution. Some patients with an inflammatory arthritis will present with too few affected joints and other characteristic features to be classified as having RA so-called undifferentiated inflammatory arthritis. Increased bone loss is only part of the story in RA, as decreased bone formation plays a crucial role in bone remodeling at sites of inflammation. Recent evidence shows that inflammation suppresses bone formation. The proinflammatory cytokine Tumor necrosis factor-α plays a key role in actively suppressing bone formation by enhancing the expression of dickkopf-1 (DKK-1). DKK-1 is an important inhibitor of the Wnt pathway, which acts to promote osteoblast differentiation and bone formation. Osteoporosis is a condition in which the bone becomes less dense and more likely to fracture. The World Health Organization (WHO) operationally defines osteoporosis as a bone density that falls 2.5 standard deviations (SD) below the mean for young healthy adults of the same gender also referred to as a T-score of 2.5. Studies have found an increased risk of bone loss in individuals with rheumatoid arthritis. People with rheumatoid arthritis are at increased risk of osteoporosis for many reasons. The glucocorticoids medications often prescribed for the treatment of rheumatoid arthritis can trigger significant bone loss. In addition, pain and loss of joint function caused by the disease can result in inactivity, further increasing osteoporosis risk. Osteoporosis is defined by the World Health Organization (WHO) as a bone mineral density that is 2.5 standard deviations or more below the mean peak bone mass (average of young, healthy adults) as measured by DXA; the term established osteoporosis includes the presence of a fragility fracture. 8 Aims and Objectives 1. To evaluate bone mineral density in patients of Rheumatoid arthritis and equal number of controls. 2. Correlation of BMD with severity of the disease. Material and Methods The present study was a case control study conducted in the Rheumatology Division, Department of Medicine, S.P. Medical College, Bikaner during July 2009 to January 2012 after explaining the objective of the study and taking an informed consent from the patients or from guardian family members. Hand bone density was measured on the plain radiographs of the right hand using digital x-ray radiogrammetry (Pronosco Xposure System 2.0) a computerized version of the traditional technique of radiogrammetry. A standard x ray image of the hand scanned by an x ray scanner into a PC. In order to estimate the BMD value, the digitized image analysed via PRONOSCO SOFTWARE 5. mean surrogate bone density value was calculated from cortical thickness from regions of interest measured at the center of the second, third, and fourth metacarpals. This surrogate bone density measurement (expressed as grams per square centimeter) was based on measurement of the outer and inner diameter, measuring combined cortical thickness. This BMD was correlated with markers of disease activity using DAS 28 Scoring system 9.Other laboratory investigations (eg. Complete blood count, renal function test, liver function test, random blood sugar, serum lipid profile, thyroid function test, erythrocyte sedimentation rate, Rheumatoid factor, C-reactive protein etc.) were done. Appropriate statistical analysis was applied as and when required using statistical software (SPSS version 10.0). Number of patients: Over 200 controls subjects with no known history of disease and equal number of cases recruited as per the following inclusion and exclusion criteria. Inclusion Criteria Patients of rheumatoid arthritis diagnosed as per American College of Rheumatology (ACR) criteria 1987 were included in the study. Exclusion Criteria 1. All patients of rheumatoid arthritis with association illnesses like malignancy, renal failure, liver failure, bronchial asthma, chronic obstructive pulmonary disease, diabetics, coronary artery disease, hypertension, thyroid disorders, dyslipidemia or any other endocrinopathy excluded from this study. 2. Patients of RA with other connective tissue disorders like scleroderma, systemic lupus erythematosus, poliomyelitis etc. (overlap syndrome) excluded from this study. 3. All pregnant and lactating mothers having RA excluded from this study. 4. All patients of RA who smoke excluded from this study. Observations Mean age in study group was 43.59+13.00 and in control group 42.79+12.87 years. Mean hemoglobin was 9.77+1.52 and 10.03+1.44 in study and control groups respectively. Mean BMD was 0.53+0.01 and 0.57+0.08 in study and control groups respectively while mean T-score was -1.42+1.94 in study group and -0.15+0.08 in control group. Mean Z-score in study group was -0.50+1.79 and in control group 0.51+1.54.

28 Table 1: Distribution of cases and controls according to Z-score in relation to age Z Score Age group <45 years >45 years Study group Control group Study group Control group Normal (> -0.99) 70 (56.9) 131 (92.3) 26 (33.8) 20 (34.5) Osteopenia (-1 to -2.49) 32 (26.0) 9 (6.3) 39 (50.6) 28 (48.3) Osteoporosis (< -2.5) 21 (17.1) 2 (1.4) 12 (15.6) 10 (17.2) Total 123 (100) 142 (100) 77 (100) 58 (100) Mean Z-score -0.26 1.09-0.88-0.89 SD 1.91 1.08 1.52 1.61 T -7.179 0.026 P <0.001 0.980 On statistical comparison, the difference was statistically highly significant in BMD, T-score, Z-score between study and control groups (p<0.001) while it was insignificant in age, hemoglobin and platelet count (p>0.05). Among the male, there were total 29 patients each in study and control group who had normal Z-score while among females, 67 and 95 cases in study and control groups respectively had their Z-score within normal range and there were total 22 patients each in study and control group who had osteopenia while among females, 49 and 31 cases in study and control groups respectively had osteopenia. There were total 13 patients each in study and control group who had osteoporosis in male group while among females, 20 and 10 cases in study and control groups respectively had Osteoporosis. On statistical comparison of study vs control groups, there was highly significant difference in Z-score among males and females (p<0.001). There were total 96 cases who had their Z-score within normal range and out of these 96 patients joint deformity was present in 23 patients. Out of these 23 patients 4 had their disease duration <1 years while remaining 19 patients had their disease duration 1-5 years. In osteopenia group, there were total 71 patients were found and out of them joint deformity was present in 39 patients. Out of these 39 patients 30 patients had their disease duration >10 years while 7 patients had their disease duration 1-5 years. One patient each was also found in disease duration groups <1 and >5-10 years. In osteoporosis group, there were total 33 patients were found and out of them joint deformity was present in 23 patients. Out of these 23 patients 18 patients had their disease duration >10 years while 3 patients had their disease duration >5-10 years and 2 patients had their disease duration 1-5 years while no patient was found in disease duration <1 year. There were total 96 cases who had their Z-score within normal range and out of these 96 patients joint deformity was present in 9 males and 17 females. Out of these 39 patients with deformities, 14 were males and 25 were females. In osteoporosis group there were total 33 patients were found and out of them joint deformity was present in 23 patients. Out of these 23 patients 11were males and 12 were females. Rheumatoid factor was positive in total 148 patients out of them 37.2% patients had osteopenia, 20.9% had osteoporosis while in patients with negative rheumatoid factor 30.8% had osteopenia and 3.8% had osteoporosis. On statistical comparison t test was applied and the difference was statistically highly significant between Z-score and rheumatoid factor (p<0.001). Rest all the co relations are depicted and presented in Tables 1-3. Table 2: Distribution of newly diagnosed cases and correlation of their Z-score with disease duration (N=51) Age (yrs.) Sex Z-score Discussion Disease duration (yrs.) Newly diagnosed patients <45 Female Normal <1 13 (56.5) 1-5 10 (43.5) Osteopenia <1 1 (33.3) 1-5 1 (33.3) >5-10 0 >10 1 (33.3) Osteoporosis <1 0 1-5 2 (100) Male Normal <1 6 (85.7) 1-5 1 (14.3) Osteopenia 0 Osteoporosis 0 >45 Female Normal <1 3 (37.5) 1-5 5 (62.5) Osteopenia <1 3 (100) >1 0 Osteoporosis <1-10 0 >10 1 (100) Male Normal <1 1 (25) 1-5 3 (75) Osteopenia 0 Osteoporosis 0 Osteoporosis and fragilityrelated fractures are one of the most common complications seen in patients with RA and dramatically affect quality of life 6. The present study was designed to evaluate BMD changes in patients with RA, as well as the effect of severity and drugs (steroids and Diseasemodifying antirheumatic drugs) on these changes. In our study, there were 200 patients with equal number of controls. There were total 70 patients in study group and 131 patients in control group who

29 Table 3: Distribution of cases according to Z-Score in relation to disease duration and rheumatoid nodules Z Score Duration of disease group (years) Rheumatoid nodules Total < 1 1-5 >5-10 >10 Present Absent Normal (> -0.99) 23 (85.2) 67 (77.9) 3 (30) 3 (3.9) 3 (50) 93 (47.9) 96 (48) Osteopenia (-1 to -2.5) 4 (14.8) 16 (18.6) 4 (40) 47 (61) 3 (50) 68 (35.1) 71 (35.5) Osteoporosis (< -2.5) 0 3 (3.5) 3 (30) 27 (35.1) 0 33 (17) 33 (16.5) Total 27 86 10 77 6 194 200 Mean 1.09 0.44-1.46-1.99 0.02-0.52 SD 1.13 1.39 2.11 1.03 1.41 1.81 t 0.711 P <0.001 HS 0.478NS had their age <45 years had normal Z-score while in age group >45 years 26 and 20 cases in study and control groups respectively had their Z-score within normal range. There were total 32 and 9 cases of study and control groups respectively (age <45 years) who had osteopenia while in age group >45 years 39 and 28 cases in study and control groups respectively had osteopenia. There were total 21 and 2 cases of study and control groups respectively (age <45 years) who had osteoporosis while in age group >45 years 12 and 10 cases in study and control groups respectively had osteopenia. On statistical comparison of study vs control groups, there was highly significant difference in Z-score in age <45 years group and in age group >45 years the difference of Z-score between study and control group was insignificant (p>0.05). There were total 51 newly diagnosed cases. There was no specific treatment history in these patients. On the basis of duration of symptoms, patients were divided into 4 groups i.e. <1, 1-5, >5-10 and >10 years. On the basis of age we divided patients into two groups i.e. <45 and >45 years. Among females there were total 40 newly diagnosed cases out of them 28 were from age group <45 years while remaining 12 cases were from >45 years of age group. Out of total 28 patients who had their age group <45 years 23 patients who had their Z-score within normal range and out of these 23 patients 13 were from disease duration <1 years while remaining 10 patients were from disease duration 1-5 years. There were total 12 females who had their age >45 years out of them 8 females had their Z-score within normal range and out of them 3 were from disease duration <1 years and 5 were from disease duration 1-5 years. Out of remaining 4 females, 3 had osteopenia and 1 had osteoporosis and they came from disease duration group <1 years and >10 years respectively. Among males there were total 11 newly diagnosed cases out of them 7 were from age group <45 years while remaining 4 cases were from >45 years of age group. Out of total 7 patients who had their age group <45 years all had their Z-score within normal range and disease duration <5 years. There were total 4 males who had their age >45 years all of these patients had their Z-score within normal and disease duration <5 years. This observation supported the fact that patients with RA are more susceptible for bone loss in comparison to normal age and gender related subjects. These findings are in agreement with those of Brand et al 10 who reported that patients with RA have a higher risk of low BMD than normal ageand gender matched populations. Similarly, a study reported by Kim et al 11 showed an increased risk of osteoporotic fractures in RA patients in all age groups, regardless of gender, and at various anatomical sites compared with individuals without RA. In contrast, Curtis et al 10 found that the proportion of their RA patients meeting t score criteria for osteoporosis (t score <-2.5 at either the lumbar spine or femoral neck) was only 4%, and Yoon et al1 5 reported that 52% of their patients with early-onset RA had osteoporosis and 39% were classified as having osteopenia. Our results are also consistent with those of Güler-Yüksel et al 11 who reported that RA patients with early, active, erosive disease and a positive rheumatoid factor had more aggressive joint disease and decreased BMD. Laan et al 12 PLAN concluded that BMD may be affected in patients with recent onset rheumatoid arthritis by disease dependent mechanism. Kim et al 9 also observed an increased risk of osteoporosis associated with a positive RF and elevated acute phase reactants, although this was not statistically significant. While Solomon et al. 13 have found that BMD at the total hip was significantly lower in rheumatoid factor-positive women than in rheumatoid factor-negative women. However, values at the lumbar spine were almost identical for rheumatoid factor-positive and -negative women. Conculsion Patients with RA are more susceptible to bone loss in comparison to normal age and gender related subjects. Patients with longer duration of disease are more susceptible for developing osteopenia and osteoporosis.

30 Patients with higher disease activity are more susceptible for bone loss. Occurrence of joint deformities increases with longer disease duration. Patients who test positive for rheumatoid factor are also more prone to osteopenia and osteoporosis. Limitation of physical activity impairs the bone mineral density. Patient taking anti rheumatic therapy (steroids and Disease-modifying antirheumatic drugs) are at increased risk of bone loss. All these factors contribute to bone loss independent of each other emphasizing the initiation of osteo-protective therapy in rheumatoid arthritis patients as soon as possible. References 1. Felson DT et al. American College of Rheumatology/European League Against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Arthritis Rheum 2011; 63:573. 2. Goldring MB, Marcu KB. Cartilage homeostasis in health and rheumatic diseases. Arthritis Res Ther 1009; 11:224. 3. Goldring SR, Goldring MB. Eating bone or adding it: The Wnt pathway decides. Nat Med 207; 13:133. 4. The Disease Activity Score and the EULAR response criteria- J. Fransen, P.L.C.M. van Riel Radboud University Nijmegen Medical Centre, Department of Rheumatology. Clin Exp Rheumatol 2005; 23(Suppl. 39):S93-S99. 5. Peter E. Lipsky. Rheumatoid arthritis. Harrison s Principles of Internal Medicine, 17th Edition - Anthony Fauci et al(eds). New York: McGraw-Hill, Medical Pub. Division.2008.Page no-2089. 6. WHO. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a WHO Study Group. World Health Organization technical report series 1994; 843:1 129. 7. Neogi T. Rheumatoid arthritis classification criteria: An American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010; 62:2569. 8. Brand C, Lowe A, Hall S. The utility of clinical decision tools for diagnosing osteoporosis in postmenopausal women with rheumatoid arthritis. BMC Musculoskelet Disord 2008; 9:13. 9. Kim SY, Schneeweiss S, Liu J, et al. Risk of osteoporotic fracture in a large populationbased cohort of patients with rheumatoid arthritis. Arthritis Res Ther 2010; 12:R154. 10. Bonjour JP. Dietary protein: An essential nutrient for bone health. Journal of the American College of Nutrition 2005; 24(6Suppl):526S 536S. 11. Turesson C et al. Extra-articular disease manifestations in rheumatoid arthritis: incidence trends and risk factors over 46 years. Ann Rheum Dis 2003; 62:722. 12. Goronzy JJ, Weyand CM. Developments in the scientific understanding of rheumatoid arthritis. Arthritis Res Ther 2009; 11:249. 13. Solomon DH, Finkelstein JS, Shadick N, et al. The relationship between focal erosions and generalized osteoporosis in postmenopausal women with rheumatoid arthritis: The Osteoporosis in Rheumatoid Arthritis (OPiRA) Cohort Study. Arthritis Rheum 2009; 60:1624 31.