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Table of Contents
ORIGINAL ARTICLES
Year : 2021  |  Volume : 18  |  Issue : 3  |  Page : 241-244

Raised inflammatory markers as predictors of response to anti-tumor necrosis factor drugs (etanercept and infliximab) in a sample of Iraqi patients with ankylosing spondylitis


1 Department of Medicine, Baaquba Teaching Hospital, Diyala, Iraq
2 Department of Medicine, Baghdad Teaching Hospital, Baghdad, Iraq
3 Department of Medicine, Merjan Teaching Hospital, Babil, Iraq

Date of Submission20-Apr-2021
Date of Acceptance29-Jul-2021
Date of Web Publication29-Sep-2021

Correspondence Address:
Anmar Abdulwahhab Khaleel Al-Bayati
Department of Medicine, Merjan Teaching Hospital, Babil.
Iraq
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/MJBL.MJBL_27_21

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  Abstract 

Background: Ankylosing spondylitis (AS) is a chronic systemic inflammatory disorder mainly affecting the axial skeleton, although peripheral joints, entheses, and extra-articular tissues such as eyes, heart, and lungs may also be involved. Raised inflammatory markers in patients with AS at the start of anti-tumor necrosis factor (anti-TNF) therapy are associated with more clinical response. Objectives: The aim of this article is to assess the role of raised inflammatory markers in predicting response to anti-TNF drugs in patients with AS. Materials and Methods: The prospective cohort study enrolled a total of 71 patients with AS. Nineteen patients were excluded from the study due to discontinuation of anti-TNF therapy and 52 patients continued in the study and were followed for 3 months. Results: The mean age of the patients was 35.2±9.6 years, males constitute 84.6% of them and the median disease duration was 5 (3–10) years. Univariate analysis showed that the predictors of response to anti-TNF drugs were raised baseline C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), Bath Ankylosing Spondylitis Disease Activity Index, and Bath Ankylosing Spondylitis Functional Index. Multivariate analysis showed that the only independent predictor for response to anti-TNF drugs was raised baseline CRP. The optimal cut point for CRP to predict response was >7.5 mg/L, whereas that for ESR was >32 mm/h. Conclusion: Raised inflammatory markers at baseline predict better response to anti-TNF drugs in AS patients. CRP had better prediction of response to anti-TNF drugs than ESR.

Keywords: Ankylosing spondylitis, inflammatory, Iraq, tumor necrosis factor


How to cite this article:
Al-Shaibani SR, Jassim NA, Al-Bayati AK. Raised inflammatory markers as predictors of response to anti-tumor necrosis factor drugs (etanercept and infliximab) in a sample of Iraqi patients with ankylosing spondylitis. Med J Babylon 2021;18:241-4

How to cite this URL:
Al-Shaibani SR, Jassim NA, Al-Bayati AK. Raised inflammatory markers as predictors of response to anti-tumor necrosis factor drugs (etanercept and infliximab) in a sample of Iraqi patients with ankylosing spondylitis. Med J Babylon [serial online] 2021 [cited 2021 Dec 3];18:241-4. Available from: https://www.medjbabylon.org/text.asp?2021/18/3/241/327035




  Introduction Top


Ankylosing spondylitis (AS) is a chronic systemic inflammatory disorder mainly affecting the axial skeleton, although peripheral joints, entheses, and extra-articular tissues may also be involved, such as eyes, heart, and lungs.[1]

The prevalence of AS varies worldwide from 0 to 1.8% and is highest in northern European populations and lowest in sub-Saharan Africa.[2] AS is more common in males, with a male: female ratio of 2:1 to 3:1.[3] The peak age of onset is in the second and third decades of life.[4] The estimated prevalence of AS in Iraq is 0.07%; 84% of Iraqi patients with AS are HLA-B27-positive, whereas 2.1% of healthy Iraqi populations are HLA-B27-positive.[5]

Raised inflammatory marker levels including C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) might identify patients with more active disease who are more likely to benefit from anti-tumor necrosis factor (TNF) treatment than patients with chronic, less active disease.[6] Several studies concluded that raised inflammatory markers (CRP or ESR) in patients with AS at the start of anti-TNF therapy are associated with more clinical response.[7],[8],[9]

The aim of this study is to assess the role of raised inflammatory markers (CRP and ESR) in predicting response to anti-TNF drugs in patients with AS.


  Patients and Methods Top


Study design and population

A prospective cohort study was conducted at the Rheumatology Unit in Baghdad Teaching Hospital during the period between September 2016 and June 2017.

A total of 71 Iraqi patients with AS were enrolled in the study; all of them were fulfilling the modified New York criteria for AS[10] and ASAS classification criteria for diagnosing spondyloarthropathy.[11] Nineteen patients were excluded from the study due to discontinuation of anti-TNF therapy and 52 patients continued in the study and were followed for 3 months.

Ethical issue, approval, and official permission

Prior to data collection, a signed consent from each of the participants was obtained after explaining the purpose of the study and ensuring privacy of the data.

The study protocol was reviewed; approval and official permission were obtained from the Ministry of Higher Education and Scientific Research, Baghdad University, College of Medicine to conduct the present study.

Methods

The following data were obtained using data sheet:

  1. Sociodemographic data: include name, age, gender, weight (in kg), height (in m), body mass index (BMI), and smoking status.


  2. Clinical data: include disease duration from onset of symptoms, current treatment and presence of peripheral arthritis, enthesitis, or uveitis.


  3. Disease activity: evaluated at baseline and after 3 months of treatment with anti-TNF drugs by using Bath Ankylosing Spondylitis Disease Activity Index (BASDAI).[12] The response to anti-TNF drugs is determined by improvement in BASDAI ≥ 2 score from baseline till 3 months.[13]


  4. Functional status: This is evaluated at baseline and after 3 months of treatment with anti-TNF drugs by using Bath Ankylosing Spondylitis Functional Index (BASFI).[14]


  5. Investigation data: These include baseline CRP, ESR, white blood cell (WBC), Hb, and platelets.


Statistical analysis

The Anderson darling test was done to assess whether continuous variables follow normal distribution; if they follow normal distribution, then mean and standard deviation are used, and if they did not follow normal distribution, then median and interquartile range will be used to present the data. Discrete variables are presented using number and percentage to present the data; the χ2 test is used to analyze the discrete variable or Fisher’s exact test is used to analyze the distribution between two groups. Two samples t-test was used to analyze the differences in means between the two groups. Mann–Whitney U-test was used to analyze the differences in median of the two groups. Binary logistic regression analysis was used to calculate odds ratio (OR) and their 95% confidence intervals, when the outcome can be categorized into two binary levels.

Receiver operating characteristics (ROCs) are used to see the validity of different parameters in separating cases with responders from non-responders. The trapezoidal method was used to calculate the curve.

SPSS 20.0.0, Minitab 17.1.0, MedClac 14.8.1, and GraphPad Prism 7.0 software package are used to make the statistical analysis; P-value is considered when appropriate to be significant if it is less than 0.05.


  Results Top


The study included 52 patients with AS: 28 of them were receiving etanercept and 24 were receiving infliximab. There was no significant difference between patients in the infliximab and etanercept groups in their demographic variables, disease duration, response, use of drugs, and presence of peripheral arthritis, enthesitis, or uveitis as illustrated in [Table 1] and [Table 2].
Table 1: Demographic variables of AS patients according to therapy

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Table 2: Disease characteristics and use of drugs in patients according to therapy

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In the univariate analysis, four variables were predictors of good response in all subjects which are raised baseline BASDAI, BASFI, ESR, and CRP. In patients receiving etanercept, three variables were the predictors of good response which are raised baseline BASDAI, ESR, and CRP. In the infliximab-receiving patients, two variables were the predictors of good response which are raised baseline ESR and CRP, as illustrated in [Table 3].
Table 3: Univariate logistic regression analysis for predictors of response to anti-TNF drugs in AS patients according to therapy

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In the multivariate analysis, only raised baseline CRP remained an independent predictor of response after 3 months of anti-TNF therapy, as illustrated in [Table 4].
Table 4: Multivariate logistic regression analysis of predictors of response to anti-TNF drugs to all patients

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CRP had better prediction of 3 months response than ESR with an optimal cut point of >7.5 mg/L for CRP (and >32 mm/h for ESR), as illustrated in [Table 5].
Table 5: ROC analysis of predictors of response to anti-TNF drugs after 3 months in AS patients

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  Discussion Top


This study showed in the univariate analysis that patients with raised baseline CRP and ESR had better response to anti-TNF drugs after 3 months of therapy than those with normal CRP and ESR. This agrees with the results of Arends et al.[7] and Lord et al.[8] Whereas in the multivariate analysis, only a raised baseline CRP value remained an independent predictor of response to anti-TNF drugs in AS patients. This is close to the results of Rudwaleit et al.’s study,[15] which showed that raised baseline CRP is associated with better response.

The optimal cut point of CRP to predict response to anti-TNF drugs is >7.5 mg/L. This disagrees with the results of Glintborg et al.’s study,[6] which concluded that AS patients responded to anti-TNF when the baseline CRP was >14 mg/L. This difference may be due to different laboratory processes, disease activity, or genetic components.

This study also showed that raised BASDAI and BASFI at baseline can predict response to anti-TNF drugs. This partially disagrees with the result of Rudwaleit et al.’s study,[9] which showed that raised BASDAI and low BASFI at baseline predict better response to anti-TNF drugs. This difference may be attributed to the fact that BASFI depends only on patients’ evaluation of limitation in daily activities, and this limitation occurs either due to pain from active disease which responds to treatment or due to structural damage which does not respond to treatment, so patients in our study might have high baseline BASFI due to higher disease activity not due to structural damage, so that they responded better.

The better response of patients with raised inflammatory markers might identify patients with more active disease who are more likely to benefit from anti-TNF treatment than patients with chronic, less active disease.[6] This was shown in Visvanathan et al.’s study,[16] which showed that patients with raised inflammatory markers had more spinal inflammation detected by MRI.

The limitation of the study is the short duration of follow-up. However, this should not affect the results as 2016 Update of the ASAS-EULAR Management Recommendations for axial spondyloarthritis recommended that patients should be evaluated after 12 weeks of starting anti-TNF therapy and if there is no response, he/she should be switched to another anti-TNF or IL-17 inhibitor.[13]


  Conclusions Top


  1. Raised inflammatory markers (CRP and ESR) at baseline predict better response to anti-TNF drugs in AS patients.


  2. CRP had better prediction of response to anti-TNF drugs than ESR.


Recommendations

  1. Inflammatory markers can be checked before starting anti-TNF in AS patients, especially CRP to predict patients with good response to the treatment.


  2. A study with longer duration and larger sample size is recommended to confirm the results of this study.


Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Braun J, Sieper J. Ankylosing spondylitis. Lancet 2007;369:1379-90.  Back to cited text no. 1
    
2.
Khan MA. A worldwide overview: The epidemiology of HLA-B27 and associated spondyloarthritides. In: Calin A, Taurog JD, editors. The Spondyloarthritides. Oxford, UK: Oxford University Press; 1998. pp. 17-26.  Back to cited text no. 2
    
3.
Lee W, Reveille JD, Weisman MH. Women with ankylosing spondylitis: A review. Arthritis Rheum 2008;59:449-54.  Back to cited text no. 3
    
4.
Khan MA. Clinical features of ankylosing spondylitis. In: Hochberg MC, Silman AJ, Smolen JS, Weinblatt ME, Weisman MH, editors. Rheumatology. Philadelphia: Elsevier Ltd; 2003. pp. 1161-81.  Back to cited text no. 4
    
5.
Al-Rawi ZS, Al-Shakarchi HA, Hasan F, Thewaini AJ. Ankylosing spondylitis and its association with the histocompatibility antigen HL-A B27: An epidemiological and clinical study. Rheumatol Rehabil 1978;17:72-5.  Back to cited text no. 5
    
6.
Glintborg B, Ostergaard M, Krogh NS, Dreyer L, Kristensen HL, Hetland ML. Predictors of treatment response and drug continuation in 842 patients with ankylosing spondylitis treated with anti-tumour necrosis factor: Results from 8 years’ surveillance in the Danish nationwide DANBIO registry. Ann Rheum Dis 2010;69:2002-8.  Back to cited text no. 6
    
7.
Arends S, Brouwer E, van der Veer E, Groen H, Leijsma MK, Houtman PM, et al. Baseline predictors of response and discontinuation of tumor necrosis factor-alpha blocking therapy in ankylosing spondylitis: A prospective longitudinal observational cohort study. Arthritis Res Ther2011;13:94.  Back to cited text no. 7
    
8.
Lord PA, Farragher TM, Lunt M, Watson KD, Symmons DP, Hyrich KL; BSR Biologics Register. Predictors of response to anti-TNF therapy in ankylosing spondylitis: Results from the British Society for Rheumatology Biologics Register. Rheumatology (Oxford) 2010;49:563-70.  Back to cited text no. 8
    
9.
Rudwaleit M, Listing J, Brandt J, Braun J, Sieper J. Prediction of a major clinical response (BASDAI 50) to tumour necrosis factor alpha blockers in ankylosing spondylitis. Ann Rheum Dis 2004;63:665-70.  Back to cited text no. 9
    
10.
van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York Criteria. Arthritis Rheum 1984;27:361-8.  Back to cited text no. 10
    
11.
Rudwaleit M. New classification criteria for spondyloarthritis. Int J Adv Rheumatol 2010;8:1-7.  Back to cited text no. 11
    
12.
Sieper J, Rudwaleit M, Baraliakos X, Brandt J, Braun J, Burgos-Vargas R, et al. The Assessment of Spondyloarthritis International Society (ASAS) handbook: A guide to assess spondyloarthritis. Ann Reum Dis 2009;68:1-44.  Back to cited text no. 12
    
13.
Van der Heijde D, Ramiro S, Landewé R, et al. 2016 Update of the ASAS-EULAR Management Recommendations for axial spondyloarthritis. Ann Rheum Dis 2017;76:978-91.  Back to cited text no. 13
    
14.
Calin A, Garrett S, Whitelock H, Kennedy LG, O’Hea J, Mallorie P, et al. A new approach to defining functional ability in ankylosing spondylitis: The development of the Bath Ankylosing Spondylitis Functional Index. J Rheumatol 1994;21:2281-5.  Back to cited text no. 14
    
15.
Rudwaleit M, Schwarzlose S, Hilgert ES, Listing J, Braun J, Sieper J. MRI in predicting a major clinical response to anti-tumour necrosis factor treatment in ankylosing spondylitis. Ann Rheum Dis 2008;67:1276-81.  Back to cited text no. 15
    
16.
Visvanathan S, Wagner C, Marini JC, Baker D, Gathany T, Han J, et al. Inflammatory biomarkers, disease activity and spinal disease measures in patients with ankylosing spondylitis after treatment with infliximab. Ann Rheum Dis 2008;67:511-7.  Back to cited text no. 16
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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Introduction
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