Tab Application Banner
  • Users Online: 1135
  • Home
  • Print this page
  • Email this page
Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 

 
ORIGINAL ARTICLE
Ahead of print publication  

A study of serum YKL-40 and its correlation with traditional biomarkers in rheumatoid arthritis patients


 Department of Biochemistry, Sri Ramachandra Institute of Higher Education and Research (Deemed to be University), Chennai, Tamil Nadu, India

Correspondence Address:
Vinod Narayan,
Department of Biochemistry, Sri Ramachandra Institute of Higher Education and Research (Deemed to be University), Porur, Chennai - 600 116, Tamil Nadu
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_44_19

  Abstract 


Background: This study was aimed to measure the serum levels of YKL-40 among early and late rheumatoid arthritis (RA) patients along with other disease activity measures in RA patients.
Materials and Methods: It was a cross-sectional study involving 152 RA patients based on the 1987 American College of Rheumatology criteria for the diagnosis of RA and 68 age- and sex-matched healthy controls. The patient group was further subdivided into 75 early (<2 years disease duration) and 77 late (>2 years) RA patients based on the duration of the disease. Clinical examination was performed on RA patients, and traditional markers to measure the disease activity such as Disease Activity Score (DAS)-28, Visual Analog Score (VAS), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), anti-cyclic citrullinated peptide (CCP), and rheumatoid factor (RF) were assessed. Serum YKL-40 level was measured using ELISA method. All the values were expressed as median (25th–75th percentile).
Results: In our study, there was a significant increase in serum YKL-40 level in RA patients (200.8 [141.24–282.7] ng/ml) compared to healthy controls (82.2 [49.01–123.78] ng/ml) with P < 0.001. There was no significant difference in serum YKL-40 levels among early and late RA patients. The traditional inflammatory markers such as ESR, CRP, and measures of disease activity such as DAS-28 and VAS were significantly increased in late RA patients than early RA (P < 0.001). Serum YKL-40 levels were not correlated with disease activity measures such as DAS-28, VAS, CRP, and ESR in RA patients.
Conclusion: Serum YKL-40 level was significantly higher in RA. However there was no difference between early and late RA. It does not correlate with measures of disease activity.

Keywords: Anti-cyclic citrullinated peptide, early and late rheumatoid arthritis, rheumatoid arthritis, rheumatoid factor, YKL-40



How to cite this URL:
Narayan V, Pallinti V, Ganesan N. A study of serum YKL-40 and its correlation with traditional biomarkers in rheumatoid arthritis patients. Indian J Rheumatol [Epub ahead of print] [cited 2019 Oct 22]. Available from: http://www.indianjrheumatol.com/preprintarticle.asp?id=267920




  Introduction Top


Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease involving chronic inflammation principally affecting the joints. Diagnosing the disease in the early stages followed by combative treatment is the best means of avoiding joint destruction, organ damage, and disability.[1] The exact mechanisms that provoke the autoimmune responses, eventually leading to joint destruction, are not fully known. Nevertheless, at the early phases of the pathogenic process, some exogenous and autologous antigens presented to T-cells by antigen-presenting cells, and interestingly, one such candidate autoantigen, which can elicit an immune response, is YKL-40.[2]

YKL-40 is chitinase-like glycoprotein, having a molecular weight of 40 kDa. It is associated with inflammation and secreted at the site of inflammation by vascular smooth muscle cells and macrophages.[3] However, YKL-40 established its role in the remodeling of highly dynamic structures such as the extracellular matrix and the development of new blood vessels.[4] This puts forward YKL-40 as a marker of inflammation and endothelial dysfunction. A couple of studies proved that there is an increased level of YKL-40 in the serum of RA patients compared to normal controls.[5],[6],[7] Supporting the above views, one study reported that in the joint synovium, YKL-40-positive cells were found in the synovial lining, macrophages, and chondrocytes of arthritic cartilage, and the number of YKL-40-positive cells was related to the degree of synovial inflammation.[8] Although several other studies have reported elevated YKL-40 levels in RA patients, there are no such published studies of serum YKL-40 on patients with RA in the Indian population. This made us assess the serum YKL-40 level in our cohort of RA patients as our primary objective of the study.

The presence of autoantibodies is a distinctive feature of RA. It has been reported that even before the beginning of clinical symptoms, there is the presence of circulating antibodies such as anti-cyclic citrullinated peptides (CCPs) and rheumatoid factor (RF), due to breaking in immune tolerance both in systemic circulation as well as synovial tissue leading to nonspecific inflammatory synovium, and eventually forms established RA synovium. These early histological changes in the (presumed) unaffected joints of RA patients are subclinical in nature.[9] This triggered us to make a ground plan to establish the role of YKL-40 and other traditional markers in early and late RA patients.

All these observations strengthen our thought to study YKL-40 levels and traditional markers in both male and female RA patients. The present study aimed to examine serum YKL-40 levels in patients with early and late RA compared to healthy controls and to search a correlation between serum YKL-40 concentrations with traditional inflammatory markers and disease characteristics in RA.


  Materials and Methods Top


The total number of participants for the entire study included 220 individuals, which consist of 152 RA patients with ages between 23 and 70 years attending the Rheumatology Clinic at Sri Ramachandra Medical College and Research Institute at Chennai from October to December 2010. The primary inclusion criterion was definite RA fulfilling the 1987 American College of Rheumatology criteria and disease duration of 6 months onward.

The control group consists of 68 age- and sex-matched healthy staff and faculties working in the institution with no other forms of inflammatory rheumatic disease. The exclusion criteria for both the groups include physiological statuses such as pregnancy, lactation, and individuals with habitual smoking and alcohol consumption excluded as they are known to affect the levels of inflammatory markers such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP).[10] We also excluded individuals with known infectious disease and other diseases such as diabetes mellitus, hypertension, thyroid dysfunction, neurological disorders, cancer, secondary osteoarthritis (OA), and any other forms of arthritis from the study.

The patient group is further divided as early RA with the disease duration of <2 years from the onset of initial symptoms and late RA with the disease duration of more than 2 years from the onset of initial symptoms. All these early RA and late RA patients also retrospectively met the new 2010 RA classification criteria.[11] The patient history, physical activity, and Visual Analog Score (VAS) were obtained by a personal interview of all the patients along with relevant clinical data, and the treatment history was collected using the Health Assessment Questionnaire (HAQ). The number of swollen and tender joints was recorded with the help of a rheumatologist. After 12-h overnight fasting, the blood sample of 5 mL with and without anticoagulant was collected from RA patients and normal healthy individuals. The serum sample was collected and kept at a temperature of −70°C for further biochemical analysis. The patients and controls were similar in ethnicity and nutritional habits. All patients were under uniform dosage of nonsteroidal anti-inflammatory drugs and disease-modifying antirheumatic drugs as per treatment protocol.

Other than autoantibodies, the conventional markers in RA consist of the various Disease Activity Scores (DASs) which include composite parameters such as counts of tender and swollen joints and levels of serum CRP or ESR. The DAS-28–CRP combination is widely used nowadays because CRP is very much handy and is responsive to even minimal changes in systemic inflammatory activity.[12] We have included both ESR and CRP as inflammatory markers in our study. Traditional markers of disease activity in RA including DAS-28, ESR, and CRP were analyzed using standard laboratory methods.[13],[14],[15] The values for physical activity, VAS, number of swollen and tender joints, disease duration, and treatment were recorded in the HAQ under the guidance of the rheumatologist. The biochemical markers analyzed were anti-CCP, RF, and YKL-40 in both patients and controls. All these parameters were analyzed by in vitro quantitative ELISA method in batches from the stored samples within 30 days.

Ethical approval

The Research Ethics Committee of Sri Ramachandra Institute of Higher Education and Research (SRIHER), Chennai, approved the study protocol (MEC/06/51/23). All patients gave written informed consent prior to their enrollment in this study.

Statistical analysis

Statistical analysis of our study was performed using the SPSS® statistical program version 16.0 (SPSS Inc., Chicago, Illinois, USA). Because most of the variables did not follow a normal distribution, all the statistical analyses had done using nonparametric tests. In our study group, nonnormally distributed quantitative variables were presented as median (interquartile range). Comparison of biochemical marker concentration between groups was calculated by nonparametric significant Kruskal–Wallis test, followed by Bonferroni-adjusted Mann–Whitney test for unpaired differences. The Wilcoxon signed-rank test was used to assess the changes in parameters between subgroups. Spearman's Rho test and P ≤ 0.05 were considered statistically significant when we calculated the correlation between different parameters.


  Results Top


The demographic data, including disease activity measures and serum biomarker levels, were compared between the RA patient group and control group, as shown in [Table 1]. Our study group included 152 RA patients and 68 age- and sex-matched normal healthy controls consisting of 113 females and 39 males in the patient group and 50 males and 18 females in the control group (74% of females and 26% of males in both groups). All the values are calculated as the median (25th–75th percentile). The age of the study participants for RA patients and healthy controls was 47 (39–53) and 50.5 (39–59.25) years, respectively, and patients had disease duration of 2.6 (1–6.25) years. In our study, serum YKL-40 level was significantly increased in RA patients (200.8 [141.24–282.7]) than normal healthy controls (82.2 [49.01–123.78]), P < 0.001 [Figure 1]. However, there was no significant change among early and late RA groups [Figure 2]. The markers of inflammation such as ESR and CRP levels were significantly elevated in RA patients than healthy controls (P < 0.001) [Table 1].
Table 1: Demographic data and serum biomarker levels of all participants

Click here to view
Figure 1: Serum YKL-40 level in rheumatoid arthritis patients and normal healthy controls. The figure represents the serum YKL-40 level in rheumatoid arthritis patients and normal controls. A significant increase (P < 0.001) in YKL-40 level was observed in rheumatoid arthritis patients when compared to normal controls

Click here to view
Figure 2: Serum YKL-40 levels in early and late rheumatoid arthritis patients. The figure reveals no significant difference in serum YKL-40 level between early and late rheumatoid arthritis patients

Click here to view


In line with expectations, the serum anti-CCP and RF values, the traditional markers of RA disease, are significantly elevated in the patient group than healthy controls (P < 0.001). The demographic data of subgroups of RA patients and normal controls were shown in [Table 2]. The results from the subgroups, which consist of 75 early RA and 77 late RA patients, showed that disease activity measures and inflammatory markers of RA were significantly elevated in late RA patients than early RA. Correlation analysis was performed between serum YKL-40 and other measures of disease activity, as shown in [Table 3]. In our study, we observed that there was no noteworthy correlation between serum YKL-40 levels with demographic characteristics and inflammatory measurements including ESR and CRP.
Table 2: Demographic data of subgroups of rheumatoid arthritis (early and late) participants and normal healthy controls

Click here to view
Table 3: Correlation between YKL-40 and other measures of disease activity in rheumatoid arthritis

Click here to view



  Discussion Top


In clinically suspected cases of RA, immunological tests such as RF and anti-CCP, along with traditional markers of disease activity such as ESR, CRP, and joint count, are performed to confirm the disease activity in patients. Based on these tests and further clinical examination of the patients, the physician would rule out other possibilities of other autoimmune diseases.[16] In this study, we investigated the role of serum YKL-40 in RA patients, and the major findings of this study were as follows: (a) serum YKL-40 concentration increased in RA, whereas there is no significant difference in its level between early and late RA patients and (b) YKL-40 was positively correlated with the traditional markers such as anti-CCP and RF but no correlation with disease activity measures such as DAS-28, joint count, CRP, and ESR in RA patients.

YKL-40 in rheumatoid arthritis patient

In RA, the synovial membrane-lining layer is the predominant site of inflammation. This is due to a surge in bioenergetic and biosynthetic needs during sustained inflammation and drastic changes in oxygen and other essential nutrient availabilities in damaged synovium. This metabolic disruption ultimately ends up damaging the joints and synovial tissue.[17] For several years YKL-40 has been studied in joint pathologies concluding, this protein is secreted by chondrocytes and synovial cells surrounding the joints. It is well documented that the serum concentration of YKL-40 is undoubtedly elevated in patients with RA. Moreover, YKL-40 levels in synovial fluid were higher in RA patients with moderate/severe or none/slight synovitis of the joint. This synovial-derived YKL-40 might potentially influence the serum level of YKL-40. Since it is involved in the pathophysiology of the arthritic processes and reflects local disease activity, YKL-40 is considered as an important marker of synovial inflammation in RA.[18]

In accordance with other studies, we found that in our study, serum YKL-40 was significantly increased in RA patients compared to age- and sex-matched normal healthy participants [Figure 1], suggesting that they are released locally by arthritic joints followed by a secondary increase in serum YKL-40 level.[19],[20] One such study had reported that there is an increased expression of YKL-40 by connective tissue cells such as synoviocytes and, activated synovial fibroblasts present within synovial joints of RA patients, which reflects the level of YKL-40 in serum.[21] There are several studies on serum level of YKL-40 in OA patients but not in RA patients of Indian origin, even though it is established as a surrogate marker for inflammatory and degenerative joint diseases.[22] We could not assess the serum level of YKL-40 in male and female RA patients separately as it was not the primary objective of our study. However, studies suggested that YKL-40 levels were not associated with gender signifying age and genotypes are all strong independent factors affecting serum concentrations of YKL-40.[23]

YKL-40 in subgroups of rheumatoid arthritis

Not many published studies are available supporting elevated serum YKL-40 level leading to joint destruction in early and late RA patients. However, a study provides evidence about increased serum inflammatory marker YKL-40 levels correlating with disease activity in early RA patients.[5] Contrary to that, in our study, we found no significant changes in the serum YKL-40 level among early and late RA patients [Figure 2]. We could not assess any correlation between YKL-40 with disease activity measures separately in our early RA and late RA patients but with total RA patients [Table 3]. Again, there are no published data on serum YKL-40 levels in late RA patients or its association with any biomarker. According to the study on OA patients, it was reported that serum levels of YKL-40 are significantly increased in late stages when compared to early stages of OA, indicating that its level in serum directly reflects the articular cartilage degradation and the degree of synovial inflammation in the knee joint of OA patients.[24]

Correlation between YKL-40 with traditional markers of disease activity in rheumatoid arthritis

Contrary to our studies, Bulgarian RA patients showed a positive correlation between the serum YKL-40 level with CRP and ESR.[25],[26] However, we could not establish any relation between these markers and YKL-40 levels in RA patients [Table 3]. Although the exact mechanism is not known, consumption of alcohol and smoking was found to be associated with an increase in serum YKL-40 level in RA patients.[27] Interestingly, as per the exclusion criteria, all the participants are nonsmokers and nonalcoholics in our study. Therefore, we have no explanation for this outcome.

Moreover, we could not establish any correlation between YKL-40 with any other disease activity measures such as DAS-28, VAS, joint count, ESR, and CRP in RA patients [Table 3]. Therefore, we presume that serum YKL-40 level could provide a different and a restricted view of the inflammatory process than traditional biomarkers such as CRP, ESR, and RF. We could not ascertain the exact role of YKL-40 in inflammatory and noninflammatory conditions in RA patients. Since our study shows poor correlation with disease activity measures, the role of YKL-40 for monitoring disease activity is still unclear.

This study had few limitations too.

  1. We had carefully selected RA patients with a uniform drug dosage regimen. Despite our study group, about nine late RA and seven early RA patients were treated with immunosuppressive drugs such as steroids at the time of the investigation. This might have affected the outcome of the study (around 10% of total RA patients)
  2. We did not follow the recent definition of early RA (the disease duration <6 months)[28] in our study population
  3. The number of study participants was limited, and the status of YKL-40 in the synovial fluid and tissue needs to be understood to correlate with the serum YKL-40
  4. The assessment of YKL-40 levels in a comprehensive follow-up study from initial stages until later stages of RA, through treatment, may give a better understanding of the role of YKL-40 and its potential as a marker or therapeutic target
  5. As we could not collect radiographic images of the hands and feet of RA patients, the erosive status of the disease and extent of damage was not measured in our study participants.



  Conclusion Top


The findings from our study suggested that the higher levels of serum YKL-40 are observed in RA. We are unable to conclude on its specific role as an inflammatory marker in the different stages such as early and late RA. Even though we proved the correlation between YKL-40 with RF and anti-CCP, its importance in diagnosis and prognosis of RA is uncertain, suggesting that further, large prospective, longitudinal clinical studies needed to determine if plasma YKL-40 is a new RA biomarker or is mainly a biomarker of inflammation.

Acknowledgments

The authors wish to thank all the individuals for their participation in this research.

Financial support and sponsorship

The result of this article was derived from the Ph.D (Faculty of Medicine) thesis of Dr. Vinod Narayan registered in the SRIHER Deemed to be University, Chennai, Tamil Nadu, India, and this was a self-funded project.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Guo Q, Wang Y, Xu D, Nossent J, Pavlos NJ, Xu J. Rheumatoid arthritis: Pathological mechanisms and modern pharmacologic therapies. Bone Res 2018;6:15.  Back to cited text no. 1
    
2.
van Bilsen JH, van Dongen H, Lard LR, van der Voort EI, Elferink DG, Bakker AM, et al. Functional regulatory immune responses against human cartilage glycoprotein-39 in health vs. proinflammatory responses in rheumatoid arthritis. Proc Natl Acad Sci U S A 2004;101:17180-5.  Back to cited text no. 2
    
3.
Väänänen T, Vuolteenaho K, Kautiainen H, Nieminen R, Möttönen T, Hannonen P, et al. Glycoprotein YKL-40: A potential biomarker of disease activity in rheumatoid arthritis during intensive treatment with csDMARDs and infliximab. Evidence from the randomised controlled NEO-RACo trial. PLoS One 2017;12:e0183294.  Back to cited text no. 3
    
4.
Rathcke CN, Johansen JS, Vestergaard H. YKL-40, a biomarker of inflammation, is elevated in patients with type 2 diabetes and is related to insulin resistance. Inflamm Res 2006;55:53-9.  Back to cited text no. 4
    
5.
Matsumoto T, Tsurumoto T. Serum YKL-40 levels in rheumatoid arthritis: Correlations between clinical and laborarory parameters. Clin Exp Rheumatol 2001;19:655-60.  Back to cited text no. 5
    
6.
Peltomaa R, Paimela L, Harvey S, Helve T, Leirisalo-Repo M. Increased level of YKL-40 in sera from patients with early rheumatoid arthritis: A new marker for disease activity. Rheumatol Int 2001;20:192-6.  Back to cited text no. 6
    
7.
Volck B, Johansen JS, Stoltenberg M, Garbarsch C, Price PA, Ostergaard M, et al. Studies on YKL-40 in knee joints of patients with rheumatoid arthritis and osteoarthritis. Involvement of YKL-40 in the joint pathology. Osteoarthritis Cartilage 2001;9:203-14.  Back to cited text no. 7
    
8.
Kumar HA, Kumar JS, Mahavir Y, Archana T. Expression of YKL-40, an inflammatory glycoprotein and its prognostic implications in cancer. J Mol Biomark Diagn 2012;3:130.  Back to cited text no. 8
    
9.
Hitchon CA, El-Gabalawy HS. The synovium in rheumatoid arthritis. Open Rheumatol J 2011;5:107-14.  Back to cited text no. 9
    
10.
Roseman C, Truedsson L, Kapetanovic MC. The effect of smoking and alcohol consumption on markers of systemic inflammation, immunoglobulin levels and immune response following pneumococcal vaccination in patients with arthritis. Arthritis Res Ther 2012;14:R170.  Back to cited text no. 10
    
11.
Heidari B. Rheumatoid arthritis: Early diagnosis and treatment outcomes. Caspian J Intern Med 2011;2:161-70.  Back to cited text no. 11
    
12.
Doǧan M, Küçüksaraç S, Tüfekçi O, Feyzioǧlu B, Özdemir M, Baykan M, et al. Comparison of the diagnostic values in rheumatoid arthritis: Anti-CCP antibodies and other serological tests. Biomed Res 2014;25:381-6.  Back to cited text no. 12
    
13.
Lee CG, Da Silva CA, Dela Cruz CS, Ahangari F, Ma B, Kang MJ, et al. Role of chitin and chitinase/chitinase-like proteins in inflammation, tissue remodeling, and injury. Annu Rev Physiol 2011;73:479-501.  Back to cited text no. 13
    
14.
Falconer J, Murphy AN, Young SP, Clark AR, Tiziani S, Guma M, et al. Review: Synovial cell metabolism and chronic inflammation in rheumatoid arthritis. Arthritis Rheumatol 2018;70:984-99.  Back to cited text no. 14
    
15.
Salomon J, Matusiak ł Nowicka-Suszko D, Szepietowski JC. Chitinase-3-like protein 1 (YKL-40) is a biomarker of severity of joint involvement in psoriatic arthritis. Postepy Dermatol Alergol 2018;35:485-9.  Back to cited text no. 15
    
16.
Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, et al. 2010 rheumatoid arthritis classification criteria: An American College of Rheumatology/European League against Rheumatism Collaborative Initiative. Ann Rheum Dis 2010;69:1580-8.  Back to cited text no. 16
    
17.
Eker YÖ, Pamuk ÖN, Pamuk GE, Dönmez S, Çakır N. The frequency of anti-CCP antibodies in patients with rheumatoid arthritis and psoriatic arthritis and their relationship with clinical features and parameters of angiogenesis: A comparative study. Eur J Rheumatol 2014;1:67-71.  Back to cited text no. 17
    
18.
Kazakova M, Sarafian V. YKL-40 in health and disease: A challenge for joint inflammation. Biomed Rev 2013;24:49-56.  Back to cited text no. 18
    
19.
Ballara S, Taylor PC, Reusch P, Marmé D, Feldmann M, Maini RN, et al. Raised serum vascular endothelial growth factor levels are associated with destructive change in inflammatory arthritis. Arthritis Rheum 2001;44:2055-64.  Back to cited text no. 19
    
20.
Jafari-Nakhjavani MR, Ghorbanihaghjo A, Bagherzadeh-Nobari B, Malek-Mahdavi A, Rashtchizadeh N. Serum YKL-40 levels and disease characteristics in patients with rheumatoid arthritis. Caspian J Intern Med 2019;10:92-7.  Back to cited text no. 20
    
21.
Knorr T, Obermayr F, Bartnik E, Zien A, Aigner T. YKL-39 (chitinase 3-like protein 2), but not YKL-40 (chitinase 3-like protein 1), is up regulated in osteoarthritic chondrocytes. Ann Rheum Dis 2003;62:995-8.  Back to cited text no. 21
    
22.
Conrozier T, Carlier MC, Mathieu P, Colson F, Debard AL, Richard S, et al. Serum levels of YKL-40 and C reactive protein in patients with hip osteoarthritis and healthy subjects: A cross sectional study. Ann Rheum Dis 2000;59:828-31.  Back to cited text no. 22
    
23.
Nielsen KR, Steffensen R, Boegsted M, Baech J, Lundbye-Christensen S, Hetland ML, et al. Promoter polymorphisms in the chitinase 3-like 1 gene influence the serum concentration of YKL-40 in Danish patients with rheumatoid arthritis and in healthy subjects. Arthritis Res Ther 2011;13:R109.  Back to cited text no. 23
    
24.
Johansen JS, Hvolris J, Hansen M, Backer V, Lorenzen I, Price PA, et al. Serum YKL-40 levels in healthy children and adults. Comparison with serum and synovial fluid levels of YKL-40 in patients with osteoarthritis or trauma of the knee joint. Br J Rheumatol 1996;35:553-9.  Back to cited text no. 24
    
25.
Maria K, Anastas B, Tanya D, Nonka M, Zlatimir K, Victoria S. Relationship between sonographic parameters and YKL-40 levels in rheumatoid arthritis. Rheumatol Int 2012;4:11-3.  Back to cited text no. 25
    
26.
Nielsen KR, Steffensen R, Boegsted M, Baech J, Lundbye-Christensen S, Hetland ML, et al. Promoter polymorphisms in the chitinase 3-like 1 gene influence the serum concentration of YKL-40 in Danish patients with rheumatoid arthritis and in healthy subjects. Arthritis Res Ther 2011;13:R109.  Back to cited text no. 26
    
27.
Yang JD, Kim E, Pedersen RA, Kim WR, Pungpapong S, Roberts LR, et al. Utility of serum YKL-40 as a tumor-specific marker of hepatobiliary malignancies. Gut Liver 2010;4:537-42.  Back to cited text no. 27
    
28.
Singh JA, Furst DE, Bharat A, Curtis JR, Kavanaugh AF, Kremer JM, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken) 2012;64:625-39.  Back to cited text no. 28
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

 
Top
 
 
  Search
 
     Search Pubmed for
 
    -  Narayan V
    -  Pallinti V
    -  Ganesan N
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
Abstract
Introduction
Materials and Me...
Results
Discussion
Conclusion
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed46    
    PDF Downloaded5    

Recommend this journal