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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 32  |  Issue : 1  |  Page : 40-46

A clinical study of acute-phase reactants and immunological markers in patients of chronic inflammatory arthritis in a tertiary care setting


Department of Medicine, Dr. D. Y. Patil Medical College, Pune, Maharashtra, India

Date of Web Publication18-Jun-2018

Correspondence Address:
Dr. Varsha Shirish Dabadghao
F 5/10, Salunke Vihar, Pune, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jms.jms_113_16

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  Abstract 

Context: Chronic inflammatory arthritis (IA) refers to a joint disease with pain, morning stiffness more than 30 min, redness, and swelling, lasting for more than 6 weeks.
Aims: This study was conducted to evaluate the pattern of joint involvement of these patients, evaluate etiologies, and delineate acute-phase reactants and immunological markers. An attempt was made to correlate the severity of joint involvement with acute-phase reactants and immunological markers.
Settings and Design: This was a descriptive, cross-sectional study conducted for 24 months.
Subjects and Methods: One hundred patients with clinically diagnosed chronic IA fulfilling criteria for inflammation and lasting more than 6 weeks were studied clinically and by laboratory parameters. Patients with vague, noninflammatory, periarticular or acute disease were excluded from the study.
Statistical Analysis Used: Data was collected and analyzed using Epi Info version 7. Chi-square and Fisher's exact tests were applied.
Results: The mean age of affection was 40 ± 15 years. A total of 77 patients were female and 23 were male. Seventy-six patients had rheumatoid arthritis (RA), seven had ankylosing spondylitis, six had systemic lupus erythematosus, four had mixed connective tissue disease (MCTD), four had gout, one had juvenile idiopathic arthritis, one had systemic sclerosis, and one had overlap syndrome. Erythrocyte sedimentation rate was raised in 66% of patients, and C-reactive protein (CRP) was raised in 57%. Of the RA patients, 42.1% were rheumatoid factor (RF) positive and 91.5% were anti-cyclic citrullinated polypeptide (CCP) positive. Out of 44 patients who were RF negative, positivity for anti-CCP was 86.1%, which was found significant. Nearly 6.52% of the patients were seronegative. Overall, the correlation of severity of joint involvement with CRP was significant. In RA, severity correlated with CRP, RF, and anti-CCP.
Conclusions: RA was the most common etiology (76%) and in it, the positivity of RF was 42.1% and anti-CCP was 91.5%. Overall, the severity of joint involvement was significantly correlated with CRP.

Keywords: Acute-phase reactants, anti-cyclic citrullinated polypeptide, inflammatory arthritis, joint involvement


How to cite this article:
Dabadghao VS, Sharma SK, Malik SK, Kakrani AL, Naik DG. A clinical study of acute-phase reactants and immunological markers in patients of chronic inflammatory arthritis in a tertiary care setting. J Med Soc 2018;32:40-6

How to cite this URL:
Dabadghao VS, Sharma SK, Malik SK, Kakrani AL, Naik DG. A clinical study of acute-phase reactants and immunological markers in patients of chronic inflammatory arthritis in a tertiary care setting. J Med Soc [serial online] 2018 [cited 2021 Apr 17];32:40-6. Available from: https://www.jmedsoc.org/text.asp?2018/32/1/40/211094


  Introduction Top


Articular syndrome refers to a disease of the joints which is diagnosed by the fact that pain emerges from all movements of the joint and has similar intensity with active and passive movements.[1]

Inflammatory arthritis is a part of “articular syndrome” in which there are signs of inflammation in the affected joints, that is, presence of swelling, redness, early morning stiffness, restriction of movements, and systemic symptoms such as fever, loss of weight, and extra-articular symptoms. It is said to be chronic if symptoms last for more than 6 weeks.[1]

There are three types of arthritis: monoarthritis, oligoarthritis, and polyarthritis. Involvement of one single joint is monoarthritis, of four or less joints is oligoarthritis, and of more than four joints (five or more) is polyarthritis. There are several inflammatory causes of each arthritis. Gout, pseudogout, and septic arthritis are the main causes of monoarthritis. Seronegative spondyloarthropathies and sometimes crystal arthropathies are the etiologies of oligoarthritis. The main causes of polyarthritis are rheumatoid arthritis (RA) and connective tissue diseases such as systemic lupus erythematosus (SLE), scleroderma, Sjogren's, mixed connective tissue disease (MCTD), and various overlap syndromes.[2]

Several other features help in the characterization of the inflammatory arthritis (IA). They may be acute versus chronic, additive versus migratory, persistent versus recurrent, symmetrical versus asymmetrical, and with or without systemic manifestations.[2]

Various joints may be involved in IA depending on the cause. In addition to clinical features, by which most arthritis can be delineated, laboratory parameters such as acute-phase reactants and immunological markers help in differentiation of the various arthropathies and hence help in making the final diagnosis so that specific treatment can be initiated. Acute-phase reactants such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) help in establishing the inflammatory nature of articular syndrome. Markers such as rheumatoid factor (RF), anti-cyclic citrullinated polypeptide (anti-CCP), anti-nuclear antibody (ANA), and extractable nuclear antibodies (ENAs) help in further diagnosing the etiology.[2]

This study attempts to evaluate the pattern of acute-phase reactants and immunological markers in all patients of IA of various causes, diagnosed on clinical evaluation, attending rheumatology outpatient department (OPD) in a tertiary care center. It also delineates the etiologies and pattern of joint involvement of these patients. An attempt is made to correlate the severity of clinical features with the acute-phase reactants and the presence of specific immunological markers.


  Subjects and Methods Top


This was a descriptive, cross-sectional study conducted for 24 months. Institutional Ethics Committee approval was obtained before the study, and written informed consent was obtained from each patient studied. One hundred patients with clinically diagnosed chronic IA, attending the rheumatology and medicine OPD and wards of a tertiary care center in western India were studied.

Arthritis was diagnosed as inflammatory if patients clinically had joint disease with pain, swelling, early morning stiffness of more than 30 min, and restriction of movement. It was chronic if the history was more than 6 weeks' duration. All patients with vague, noninflammatory joint disease, periarticular diseases, and acute arthritis were excluded from the study. Patients fulfilling inclusion criteria were enrolled and subjected to detailed history and physical examination including general, musculoskeletal, and systemic features.

Joint counts (swollen and tender), types of joints involved, and pattern of joint involvement were evaluated. Further, investigations such as hemogram, ESR, CRP (qualitative), renal function tests, liver function tests, blood sugars, proteins, urine examination, and uric acid were conducted. ESR was done by Westergren's method with normal values (0–15 mm in males; 0–20 mm in females).

RF (quantitative), anti-CCP, human leukocyte antigen (HLA) B 27, ANA, and ENAs were done in all relevant cases. RF was done by nephelometry. Anti-CCP was done by ELISA technique and titers were obtained. ANA was done by immunofluorescence assay and ENA by line immunoassay. Data were collected and compiled in Epi Info version 7 (Atlanta, USA). Percentages, mean, and standard deviation were calculated. Statistical tests of significance (Chi-square and Fisher's exact test) were applied.


  Results Top


A total of 100 patients of clinically diagnosed chronic IA were studied. The ages of affection ranged between 3 and 79 years, with a mean age of affection of 40 ± 15 years. Seventy-seven patients were female and 23 were male [Table 1]. Out of the 100 patients of IA, 76 patients had RA, seven had ankylosing spondylitis (AS), six had SLE, four had mixed connective tissue disorder (MCTD), four had gout, one had juvenile idiopathic arthritis (JIA), one had systemic sclerosis (SSc), and one had overlap syndrome (scleroderma/polymyositis [PM]) [Table 2].
Table 1: Sex involved

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Table 2: Diagnosis

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Of a total of 100 patients, 89 had polyarthritis, seven had oligoarthritis, and four had monoarthritis [Table 3]. Out of the 89 patients who had polyarthritis, 76 (86.36%) had RA, 6 (5.68%) had SLE, 4 (4.55%) had MCTD, and one each (1.14%) had JIA, SSc, and overlap syndrome (Ssc/PM). Six patients of oligoarthritis had AS while one had gout. Three patients of monoarthritis had gout while one had AS.
Table 3: Type of joints involved (number)

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Of the total patients, 42 (42%) had anemia. ESR was raised in 66 patients (66%) while it was normal in 34 (34%). Out of these patients in whom ESR was raised, 48 had RA (72.73%), four had SLE (6.06%), four had MCTD (6.06%), four had AS (6.06%), four had gout (6.06%), and one each had overlap syndrome and SSc (1.52%) [Table 4]. Of the 76 patients of RA, 48 (63.16%) had raised ESR; of the six patients of SLE, 4 (66.67%) had raised ESR; of the seven patients of AS, 4 (57.1%) had raised ESR; of the four patients of gout, all had raised ESR; and of the four patients of MCTD, all had raised ESR.
Table 4: Erythrocyte sedimentation rate level with diagnosis

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Nearly 43% of the patients had a negative CRP and 57 (57%) had a positive CRP. Out of those who had a positive CRP, 45 had RA (78.94%), three had MCTD (5.26%), three had SLE (5.26%), two had gout (3.51%), two had AS (3.51%), one had JIA (1.75%), and one had SSc (1.75%) [Table 5].
Table 5: C-reactive protein with diagnosis

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In RA, the pattern of joint involvement varied. Thirty-eight patients (50%) had involvement of metacarpophalangeal (MCP), proximal interphalangeal (PIP), and wrist while 29 (38.15%) had MCP, PIP, wrist, elbows, and knees involved. Six patients (7.89%) had MCP, PIP, and knees involved. AS patients maximally had knee and ankle involvement (71.42%) while SLE patients had MCP, PIP, and wrist joint involvement. Patients of MCTD had joint involvement pattern similar to SLE. Gout involved first MTP joint most commonly and one patient had additionally a wrist joint involvement.

Eleven (11%) patients had <5 joints involved, of whom seven had AS (63.63%) and 4 (36.36%) had gout. Out of 37 patients with 5–10 joints involved, 24 had RA (64.10%), six had SLE (15.38%), four had MCTD (12.82%), one had JIA (2.56%), one had overlap syndrome (2.56%), and one had SSc. Out of 52 patients with more than 10 joints involved, all had RA [Table 6].
Table 6: Relation between number of joints (range) and diagnosis (percentage)

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Out of the 37 patients with 5–10 joints involved, 15 patients (40.54%) had a positive CRP. However, among the 52 patients of more than 10 joints involved, 38 (73.08%) had a positive CRP. Out of 37 patients with 5–10 joints involved, 22 (59.46%) had a raised ESR, and out of 52 patients of more than 10 joints involved, 37 (71.5%) had a raised ESR. The correlation of number of joints with CRP was found to be significant by Chi square test with P = 0.002 [Table 7]. The trend toward significance was seen with ESR as well, but it was not statistically relevant.
Table 7: Relation between number of joints (range) and C-reactive protein

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RA formed the single largest group of all patients of IA. Among the 76 cases of RA, 33 patients had anemia (43.4%) and 43 did not (57.33%). CRP was positive in 44 patients (57.89%) and negative in the rest [Table 8]. ESR was raised in 49 (64.47%) patients while it was normal in the rest.
Table 8: C-reactive protein profile (in rheumatoid arthritis)

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Out of 76 patients, 32 were RF positive (42.1%) [Table 9]. About 17 patients could not afford anti-CCP testing; 71.05% were positive and 6.57% were negative [Table 10]. Out of 59 patients who underwent the test, 54 were positive (91.5%) and 5 were negative (8.47%). Out of 32 RF-positive patients, 23 were anti-CCP positive and 9 did not undergo the test. Out of 44 patients who were RF negative, 36 patients underwent anti-CCP testing, of which, 31 (86.1%) were anti-CCP positive. This fact was found statistically significant (P = 0.03) [Table 11]. Hence, among RF-negative patients, anti-CCP was a good way of confirming the possibility of RA. There were still five patients who were negative for both RF and anti-CCP (6.57%), the seronegative RA group.
Table 9: Rheumatoid factor profile (in rheumatoid arthritis)

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Table 10: Anti-cyclic citrullinated polypeptide profile (in rheumatoid arthritis)

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Table 11: Relation between profile of rheumatoid factor and anti-cyclic citrullinated polypeptide (in rheumatoid arthritis)

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Among 24 patients having 5–10 joints involved, only 6 (25%) had a positive CRP and 50% had a positive ESR. Among the 52 patients of more than 10 joints involved, 38 (73.08%) had a positive CRP and 37 (71.15%) had a positive ESR. By the application of Chi-square and Fisher's exact tests, the relation between joint involvement and CRP positivity was found to be statistically significant (P = 0.0002 and 0.00009, respectively) [Table 12].
Table 12: Relation between joints involved and C-reactive protein (in rheumatoid arthritis)

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Among 24 patients of RA with 5–10 joints involved, 17 (70.83%) had a positive anti-CCP while four had a negative one and three could not undergo the test. Among 52 patients with more than 10 joints involved, 37 (71.15%) had a positive anti-CCP. In patients with >10 joint involvement vis-a-vis those with <10 joints, Fisher's exact test was applied. This was statistically significant (P = 0.049) [Table 13].
Table 13: Number of joints (range) with anti-cyclic citrullinated polypeptide (in rheumatoid arthritis)

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Out of 24 patients of RA with 5–10 joints involved, 18 (75%) had a negative RF while only 6 had a positive one (25%). In 52 patients with more than 10 joints involved, exactly 50% had a positive RF. The odds ratio was 3 (95% confidence interval: 1.03–8.76).

Hence, the more severe the joint involvement in RA, the more were chances of a positive CRP, RF, and anti-CCP, showing a positive correlation.

Ten patients had a positive ANA, of which two had a positive dsDNA and four had positive anti-Ro/SSA with nucleosome. Six of them were diagnosed as SLE and four as MCTD (all of whom had a strongly positive U1 RNP). Seven patients who were clinically diagnosed as having AS had HLA-B27 positive in varying titers.


  Discussion Top


Musculoskeletal disorders are common in general adult population, irrespective of age, and can be very disabling.[3] They can be inflammatory or noninflammatory, acute or chronic, and articular or periarticular. Most of these disorders are noninflammatory, degenerative diseases such as osteoarthritis or soft-tissue rheumatism (periarticular). Inflammatory arthritis forms a small but important part, mostly around 6%–10% of all musculoskeletal or rheumatic disorders.[3]

The age of involvement in our study was 3–79 years, with a mean age of 40 ± 15 years. In many studies done on arthritis, it was noted that IA affected population in 3rd and 4th decades.[3] The female-to-male ratio was 3.34:1. In a study by Owino et al. conducted only on RA, the female-to-male ratio was 6.5:1, and in another study done only on seronegative spondyloarthropathy patients, there was a male-to-female ratio of 5.5:1; the prevalence was more in ages <45 years.[4],[5] The present study was on all types of IA, and hence the figures are different. The prevalence of SLE among females was 6 times higher compared to males in a study done by Feldman et al.[6]

Among the types of IA, the cause in the present study was found to be RA in 76%, AS in 7%, SLE in 6%, gout in 4%, mixed connective tissue disorder in 4%, JIA in 1%, SSc in 1%, and overlap syndrome (SSc/PM) in 1% of the patients. Of a total of 100 patients, 89 had polyarthritis, seven had oligoarthritis, and four had monoarthritis. Out of 89 patients who had polyarthritis, 76 (86.36%) had RA, 6 (5.68%) had SLE, 4 (4.55%) had MCTD, and 1 each (1.14%) had JIA, SSc, and overlap syndrome (Ssc/PM). All six patients of oligoarthritis had AS while one had gout. Three patients of monoarthritis had gout while one had AS.

In a study done by Joshi and Chopra, the World Health Organization-International League of Associations for Rheumatology Community Oriented Program for Control of Rheumatic Diseases Bhigwan Model, the major disorders among urban cases were RA (0.2%), undifferentiated IA (0.3%), SSA (0.3%), and gout (0.06%); the corresponding rates in Bhigwan were RA (0.5%), undifferentiated IA (0.8%), SSA (0.3%), and gout (0.1%).[3] RA is the most common IA worldwide with a prevalence of 1%–2%[7] The prevalence of SLE was found to be 72.8 per 100,000 persons.[8] The prevalence of AS per 10,000 persons (from 36 eligible studies) was 23.8 in Europe and 16.7 in Asia.[9]

Of all the patients, 42 had anemia. ESR was raised in 66 patients (66%) while 57 (57%) had a positive CRP. Out of these, the single largest group belonged to RA (78.9%), while MCTD and SLE accounted for 5.26%, gout for 3.5%, AS for 3.5%, JIA for 1.75%, and SSc for 1.75%. In a study done by Keenan et al., up to 40% of RA patients at presentation had normal ESR or CRP. Specifically, among RA patients, 46% had an elevated CRP and a similar percentage had an elevated ESR. In contrast, SLE patients had a higher percentage of ESR abnormality than CRP (62% vs. 46%) in this study.[10]

In RA, the pattern of joint involvement varied. Thirty-eight patients (50%) had involvement of MCP, PIP, and wrist while 29 (38.15%) had MCP, PIP, wrist, elbows, and knees involved. AS patients maximally had knee and ankle involvement (71.42%) while SLE had MCP, PIP, and wrist joint involvement commonly. In a study conducted by Penserga et al., the most common joints involved in RA were MCP, PIP, and wrist symmetrically.[11] In a study by Messuti et al., SLE involved the same joints (MCP, PIP, and wrists).[12]

In this study, RA formed the single largest group of all patients of IA. In all cases of RA, 33 patients had anemia (43.4%) and CRP was positive in 44 patients (57.89%). In a study conducted by Ganna, anemia was observed in 57 (64%) patients.[13] In a study by Keenan et al., in RA patients, 46% had an elevated CRP and a similar percentage had an elevated ESR.[10]

Thirty-two patients were RF positive (42.1%). In a study conducted by Penserga et al. on Filipino patients, RF was positive in two-third of the cases.[11]

Out of 59 patients who underwent the test, 54 were positive (91.5%) and 5 were negative (8.47%). In the TIRA study, 242 patients of RA were followed up for 3 years. Of them, 67% were anti-CCP positive.[14] In the present study, out of 32 RF-positive patients, 23 were anti-CCP positive and nine did not undergo the test. Out of 44 patients who were RF negative, 36 patients underwent anti-CCP testing, of which, 31 (86.1%) were anti-CCP positive. This fact was found significant by mid-P exact test and trend toward significance by Fisher's exact test. Around 6.57% of patients were seronegative RA, that is, negative for both RF and anti-CCP. In the TIRA study, there was a significant propensity for anti-CCP antibody-positive patients to be positive also for RF (P < 0.001). Nearly 78% of the RF-positive and 40% of the RF-negative TIRA patients were anti-CCP antibody positive.[13]

Among the 52 patients of more than 10 joints involved, 37 (74%) had a positive CRP and 70% had a positive ESR. By application of Chi-square test, the relation between CRP positivity and joint involvement was found to be significant. According to literature, serum CRP concentration closely reflects activity of RA and is of value in its objective assessment. ESR followed the same pattern as CRP levels.[15]

Among 24 patients of RA with 5–10 joints involved, 16 (69.57%) had a positive anti-CCP, and among 52 patients with more than 10 joints involved, 37 (71.15%) had a positive anti-CCP. A trend toward significance was seen. In the TIRA study, DAS28 scores were higher in anti-CCP-positive patients, showing a positive correlation between joint counts and anti-CCP.[14]


  Conclusions Top


Among the 100 patients studied, 89% of the patients had polyarthritis. Nearly 76% had RA, the single largest group. Rest had AS, SLE, MCTD, JIA, SSc, and overlap syndrome in smaller percentages. About 42 patients had anemia. ESR was raised in 66 patients (66%) while 57 (57%) had a positive CRP. In RA, the pattern of joint involvement varied. Thirty-eight patients (50%) had involvement of MCP, PIP, and wrist while 29 (38.15%) had MCP, PIP, wrist, elbows, and knees involved. AS patients maximally had knee and ankle involvement (71.42%) while SLE had MCP, PIP, and wrist joint involvement commonly. The relation between CRP positivity and joint involvement was found to be significant in all patients of chronic IA. In RA, CRP was positive in 44 patients (57.89%), ESR in 64.47%, and RF in 42.1% of the patients. Anti-CCP positivity was found in 91.5% of the patients who underwent the test. Of 44 patients who were RF negative, 36 patients underwent anti-CCP testing, of which, 31 (86.1%) were anti-CCP positive, a fact found statistically significant. Hence, in RF-negative patients, anti-CCP is a good way to confirm the diagnosis of RA. Severity of joint involvement was found to be positively correlated with CRP, RF, and anti-CCP. The limitation of this study was that, due to financial constraints, anti-CCP could not be done in few patients, which had some impact on the results.

Acknowledgment

The authors would like to acknowledge the Department of Community Medicine for biostatistical support.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Woolf AD. How to assess musculoskeletal conditions. History and physical examination. Best Pract Res Clin Rheumatol 2003;17:381-402.  Back to cited text no. 1
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2.
Cush JJ, Lipsky PE. Approach to articular and musculoskeletal disease. Harrison's Rheumatology. 2nd ed. New York: The McGraw-Hill Companies, Inc.; 2010. p. 210-22.  Back to cited text no. 2
    
3.
Joshi VL, Chopra A. Is there an urban-rural divide? Population surveys of rheumatic musculoskeletal disorders in the Pune region of India using the COPCORD Bhigwan model. J Rheumatol 2009;36:614-22.  Back to cited text no. 3
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Owino BO, Oyoo GO, Otieno CF. Socio-demographic and clinical aspects of rheumatoid arthritis. East Afr Med J 2009;86:204-11.  Back to cited text no. 4
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van Tubergen A, Weber U. Diagnosis and classification in spondyloarthritis: Identifying a chameleon. Nat Rev Rheumatol 2012;8:253-61.  Back to cited text no. 5
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Feldman CH, Hiraki LT, Liu J, Fischer MA, Solomon DH, Alarcón GS, et al. Epidemiology and sociodemographics of systemic lupus erythematosus and lupus nephritis among US adults with Medicaid coverage, 2000-2004. Arthritis Rheum 2013;65:753-63.  Back to cited text no. 6
    
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Bajraktari IH, Teuta BÇ, Vjollca SM, Bajraktari H, Saiti V, Krasniqi B, et al. Demographic features of patients with rheumatoid arthritis in Kosovo. Med Arch 2014;68:407-10.  Back to cited text no. 7
    
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Somers EC, Marder W, Cagnoli P, Lewis EE, DeGuire P, Gordon C, et al. Population-based incidence and prevalence of systemic lupus erythematosus: The Michigan Lupus Epidemiology and Surveillance program. Arthritis Rheumatol 2014;66:369-78.  Back to cited text no. 8
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Dean LE, Jones GT, MacDonald AG, Downham C, Sturrock RD, Macfarlane GJ. Global prevalence of ankylosing spondylitis. Rheumatology 2014;53:650-7.  Back to cited text no. 9
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Keenan RT, Swearingen CJ, Yazici Y. Erythrocyte sedimentation rate and C-reactive protein levels are poorly correlated with clinical measures of disease activity in rheumatoid arthritis, systemic lupus erythematosus and osteoarthritis patients. Clin Exp Rheumatol 2008;26:814-9.  Back to cited text no. 10
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Penserga EG, Natividad TA, Salido ES; RADAR Study Group. Clinical profile of 266 Filipino patients with rheumatoid arthritis included in the rheumatoid arthritis database and registry (RADAR) of the Philippine General Hospital. Int J Rheum Dis 2015;18:433-8.  Back to cited text no. 11
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Messuti L, Zoli A, Gremese E, Ferraccioli G. Joint involvement in SLE: The controversy of RHUPUS. Int Trends Immun 2014;2:155-61.  Back to cited text no. 12
    
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Ganna S. The prevalence of anemia in rheumatoid arthritis. Rev Bras Reumatol 2014;54:257-9.  Back to cited text no. 13
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Kastbom A, Strandberg G, Lindroos A, Skogh T. Anti-CCP antibody test predicts the disease course during 3 years in early rheumatoid arthritis (the Swedish TIRA project). Ann Rheum Dis 2004;63:1085-9.  Back to cited text no. 14
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Mallya RK, de Beer FC, Berry H, Hamilton ED, Mace BE, Pepys MB. Correlation of clinical parameters of disease activity in rheumatoid arthritis with serum concentration of C-reactive protein and erythrocyte sedimentation rate. J Rheumatol 1982;9:224-8.  Back to cited text no. 15
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10], [Table 11], [Table 12], [Table 13]



 

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