Indian Journal of Rheumatology

ORIGINAL ARTICLE
Year
: 2018  |  Volume : 13  |  Issue : 1  |  Page : 33--37

Effect of HLA-B27 status and body mass index on the clinical response to infliximab in ankylosing spondylitis patients


Mohammed Hadi Al-Osami1, Ekhlas Khalid Hameed2, Ali Mohammed Al-Hamadani3,  
1 Department of Medicine, Rheumatology and Medical Rehabilitation Unit, College of Medicine, University of Baghdad, Baghdad, Iraq
2 Department of Clinical Biochemistry, Al-Kindy College of Medicine, University of Baghdad, Baghdad, Iraq
3 Ministry of Health, Baghdad, Iraq

Correspondence Address:
Ekhlas Khalid Hameed
Department of Clinical Biochemistry, Al-Kindy College of Medicine, University of Baghdad, Baghdad
Iraq

Abstract

Background: Tumor necrosis factor-alpha inhibitors (infliximab) have changed the therapeutic approach to ankylosing spondylitis (AS). Body mass index (BMI) and HLA-B27 status may affect the response to infliximab. Methods: One hundred and seventy AS patients with active disease were enrolled in the study. Age, sex, disease duration, HLA-B27 status, and other demographics were obtained. Patients were classified according to their BMI to three groups clinical response was monitored using Bath AS disease activity index, at the time of initiation of treatment and 6 months later. Clinical response was defined as BASDAI50. Results: At baseline, all the groups were comparable. The median BMI of the responders was 25.4 kg/m2 while for the nonresponders it was 27 kg/m2. The normal weight and overweight AS patients have achieved the BASDAI 50 response after 6 months of infliximab treatment (P < 0.001) while the obese AS patients fail to achieve this response by infliximab alone and they need another drug (nonsteroidal anti-inflammatory drugs). The response was higher in HLA-B27 positive patients (42.5%) compared to the HLA-B27 negative patients (29%), the difference, however, was statistically insignificant. Conclusion: Obese AS patients are less likely to achieve a response to infliximab than normal weight AS patients.



How to cite this article:
Al-Osami MH, Hameed EK, Al-Hamadani AM. Effect of HLA-B27 status and body mass index on the clinical response to infliximab in ankylosing spondylitis patients.Indian J Rheumatol 2018;13:33-37


How to cite this URL:
Al-Osami MH, Hameed EK, Al-Hamadani AM. Effect of HLA-B27 status and body mass index on the clinical response to infliximab in ankylosing spondylitis patients. Indian J Rheumatol [serial online] 2018 [cited 2019 Dec 10 ];13:33-37
Available from: http://www.indianjrheumatol.com/text.asp?2018/13/1/33/222119


Full Text



 Introduction



Overweight and obesity are increasing all over the world reaching about one-third of the world's population. Obesity is associated with increased risk of many diseases including the rheumatologic diseases as rheumatoid arthritis and psoriatic arthritis incidence; in addition, it also portends greater disease activity, higher radiographic joint damage, and reduced therapeutic response.[1]

Ankylosing spondylitis (AS) is a chronic, progressive inflammatory rheumatic disease involving primarily the sacroiliac joints and the axial skeleton. It is characterized by back pain and progressive stiffness of the spine. Oligoarthritis of the hips and shoulders, enthesopathy, and anterior uveitis are common, patients with AS can experience significant long-term functional impairment and disability, with reduced quality of life and an increased risk of comorbid conditions.[2],[3] HLA-B27 is known to be the major AS-susceptibility gene, its prevalence differ among different populations. It is assumed that AS is triggered by an environmental factor in individual who is genetically predisposed.[4]

Tumor necrosis factor-alpha (TNF α)-inhibitor treatment is currently the only effective therapy in AS for whom conventional therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) has failed.[3],[5],[6] Infliximab is one of the five TNF α-inhibitors (etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol). It is a chimeric (human-murine) monoclonal IgG1 anti-TNF alpha antibody; the current recommended dose is 5-mg/kg infusion at weeks 0, 2, and 6, followed by infusions every 8 weeks.[7],[8],[9] Although Infliximab has a weight-dependent dose; inter-individual serum concentration differs as reported in different inflammatory diseases.[10],[11]

The pharmacokinetics of an obese person is different from a normal person regarding the absorption, distribution, metabolism, and excretion. Increased level of serum proteins changes the metabolism in obese patients that leads to different half-lives of the drug in an obese patient from a normal person[12],[13] all the above factors may affect the response to treatment, we hypothesized that the body weight and HLA-B27 status could have an effect on the clinical responses to infliximab in AS patients. This study aimed to evaluate whether the response to infliximab differs according to body mass index (BMI) and HLA-B27 status in AS patients.

 Methods



This was a cross-sectional study, 170 AS patients attending the Department of Rheumatology in Baghdad teaching hospital (national level referral institute) who received biologics were enrolled in this study.

Patients

All the patients included in the study fulfilled the modified New York criteria for classification of AS,[14] with active AS at the imitation and bath AS disease activity index (BASDI) equal or more than 4 despite at least 3 months of daily treatment with NSAIDs (scale 0–10, 0 meaning no activity, and 10 high disease activities).[14]

Following were excluded;

Patients who did not receive infliximab on schedule during the first 6 months of therapyPatients who were taking corticosteroids before initiation of treatmentPatients who were taking disease-modifying anti-rheumatic drugs (DMARDs) before initiation of infliximab therapyThose with hypertension, diabetes mellitus, rheumatoid arthritis, systemic lupus erythematosus, overlap, history of eye infection or trauma, patients on corticosteroids and elderly.

For inclusion, patients had to have high disease activity (BASDAI ≥4) while they were on treatment with NSAIDs. Clinical response was defined as BASDAI 50 (at least 50% improvement of the initial BASDAI) after 6 months of treatment with infliximab.

Data collected include age, sex, disease duration, HLA-B27 status, and smoking historyBMI was calculated according to the formula BMI = body weight (kg)/body height (m)[2]The BMI was categorized into three classes according to the National Institutes of Health classification as normal weight; BMI 20–25 kg/m2, Overweight; BMI 25–30 kg/m2, and obese: BMI >30 kg/m2[15]BASDI was calculated at the time of initiation of treatment and 6 months laterHistory of NSAIDs intake at the time of initiation of treatment and 6 months later was noted.

HLA-B27

A volume of 2 ml of blood sample was collected from each individual kept in EDTA tube for DNA extraction. The HLA genotyping done by polymerase chain reaction sequence-specific oligonucleotides (PCR-SSO) method according to the manufacturer's instructions in the HLA-typing laboratory of Al-Karama teaching hospital, Baghdad (PCR-SSO kit: Innogenetics-Line Probe Assay, INNO—LiPA; Belgium).

Statistical analysis

Data were analyzed using SPSS 17.0 for Windows (SPSS, Chicago, IL, USA) and Graph Pad Prism 5.0 software (Graph Pad Software, La Jolla, CA, USA). Categorical and quantitative variables were described as frequencies, percentages, and mean (standard deviation). The nonparametric Mann–Whitney U-test was used to compare the continuous variables. Categorical variables were analyzed using the Chi-squared test or Fisher's exact test. Differences between groups were analyzed using the nonparametric Mann–Whitney test. Linear correlations between continuous variables were evaluated using Spearman's rho coefficient. A logistic multivariate regression model with step-wise backward Wald elimination to study the associations.

Ethical approval

The study was approved by the ethics committee of the institute. Informed written consent was obtained from all patients before their enrollment in this study.

 Results



Age, gender, and BMI data of the 170 AS patients enrolled in the study are summarized in [Table 1], the mean age was 36.1 years ± 9. One hundred and fifty-eight patients (92.9%) were male and twelve (7.1%) were female, and the mean BMI was 27.2 kg/m2 ± 4.9. The distribution of AS patients according to their BMI is shown in [Table 2] as 35.3% of the studied AS population were normal weight, 34.7% overweight, and 30% obese.{Table 1}{Table 2}

[Table 3] shows that 68 participants (40%) were HLA B-27 positive, with insignificant difference in the prevalence between the three BMI categories. By comparing the BASDI before and 6 months after treatment with infliximab [Table 4], it shows that the median BASDAI decreased significantly (P< 0.001) in the three BMI categories but the decrease in the BASDI in normal weight and overweight patients was achieved by infliximab alone, whereas in the obese group, 50% of the patients could not achieve this response by the use of infliximab alone and they need another drug (NSAID).{Table 3}{Table 4}

[Table 5] shows that 94 (55.29%) AS patients were responders and achieved the BASDAI 50 response, whereas 76 (44.7%) were nonresponders at 6 months follow-up interval and the median BMI of the responders was statistically lower than that of the nonresponders (25.2 [22.9–28.4] vs. 29.0 [25.3–32.5], P < 0.001), whereas HLA B-27 was positive in 41.5% of the responders versus 38.2% of the nonresponders (P = 0.753). Hence, the prevalence of B27 positivity was higher in the responders but not to a degree of statistical significance.{Table 5}

Logistic regression analysis of the effect of BMI on clinical response (depending on BASDAI and using of NSAID) of AS patients after 6 months of treatment with infliximab is shown in [Table 6].{Table 6}

 Discussion



Adipose tissue is considered as an active tissue with endocrine and immune-modulating effects. It plays an important role in producing many proinflammatory cytokines, including TNF-a, IL-1 and IL-6, which are targets of new classes of drugs that antagonize the biologic effects of these molecules. In addition, adipose tissue produce proinflammatory and anti-inflammatory adipocytokines as leptin, resistin, adiponectin, and visfatin with a well-documented role in immunity and inflammation.[16]

We selected the BASDAI 50 (at least 50% improvement of the initial BASDAI) as the measure to define a good clinical response because BASDAI 50 was one of the outcome measures in many trials,[8],[9] in addition the international ASAS consensus recommends the use of BASDAI 50 as a primary measure to decide whether to continue anti-TNF treatment in AS.[17] In the current study, the median BMI of the responders was 25.4 kg/m2, while for the nonresponders, it was 27 kg/m2. Both the normal weight and overweight, AS patients have achieved the BASDAI 50 response after 6 months of infliximab treatment (P< 0.001), whereas the obese AS patients failed to achieve this response by infliximab alone and they needed another drug (NSAIDs) to achieve the same clinical response.

The response to infliximab depends on both the serum concentrations of the drug and the volume of distribution.[18] The volume of distribution correlates with the intravascular space which is rather small in individuals who are obese compared to normal weight individuals,[19] although it is well-known that the calculation of infliximab is dosed as per body weight, we expect that the serum level of infliximab is higher in obese AS patients compared to normal weight AS patients, but their clinical response showed to be less, this may be explained by the fact that the adipose tissue might create an infliximab-resistant state. On the other hand, the proinflammatory adipocytokine leptin increase with the increase in the BMI, leptin increases the production of TNF-α which suppresses the transcription of adiponectin, which has anti-inflammatory properties.[16] Liver and kidney are the most important organs for the excretion of the drug. Any change in the physiology may affect the clearance of the drug. Furthermore, obesity can cause fatty liver which impairs the blood flow, this affect the clearance in the liver. According to Han et al.,[20] obese patients demonstrate higher clearance than nonobese. The kidney weight, renal blood flow glomerular filtration rate is higher in obese people hence clearance is high.[12],[13]

Similar findings related to the effect of the BMI on the clinical response to infliximab in patients with rheumatoid arthritis were reported in previous studies.[21],[22] In patients with psoriatic arthritis, similar results were noticed in obese patients, with the probability of obtaining minimal disease activity being lower than in normal weight patients.[23],[24]

The response rate for BASDAI50 in this study was 55.2% which is in line with other study in which the response rate to infliximab was around 50%.[25],[26] HLA-B27 was positive in 68 (40%) of AS patients. The response of AS patients to achieve BASDAI 50 was higher in HLA-B27 positive patients (42.5%) compared to the response rate in HLA-B27 negative patients (29%), the difference, however, was insignificant. This may be due to the inadequate sample size; similar findings were reported in other studies.[25]

It is well-known that a good clinical response of AS to infliximab depends on a high serum infliximab levels and the lack of anti-infliximab antibodies. A study showed that the absence of HLA B27 is correlated with the formation of anti-infliximab antibodies which decrease the efficacy of infliximab in AS. The decrease in efficacy can be explained by the lower serum infliximab levels, probably caused by enhanced clearance due to immune complex formation of anti-infliximab antibodies and infliximab.[27] Extended studies, using direct quantification of the body fat mass by skinfold measurement, and bioelectrical impedance analysis, in addition to assessment of the adipocytokines and pharmacokinetics, to further reveal the role of obesity in AS clinical response to infliximab.

The main limitations of the study were the small sample of the patients and being cross-sectional so cause and effect could not be determined, and the assumption that body fat was estimated by BMI and not by impendensitometry.

In conclusion, the results of this study suggests that obese AS patients are less likely to achieve a response to Infliximab than normal weight AS patients. Larger studies are required to validate these findings.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Daïen CI, Sellam J. Obesity and inflammatory arthritis: Impact on occurrence, disease characteristics and therapeutic response. RMD Open 2015;1:e000012.
2Boonen A, van der Linden SM. The burden of ankylosing spondylitis. J Rheumatol Suppl 2006;78:4-11.
3Scotti N, Bascherini V, Caso F, Costa L, Del Puente A, Caso P, et al. TNFα-inhibitors for ankylosing spondylitis and non-radiographic axial spondyloarthritis. Clin Pharm 2017;9.
4Taurog JD, Chhabra A, Colbert RA. Ankylosing spondylitis and axial spondyloarthritis. N Engl J Med 2016;374:2563-74.
5Lorenzin M, Ortolan A, Frallonardo P, Oliviero F, Punzi L, Ramonda R, et al. Predictors of response and drug survival in ankylosing spondylitis patients treated with infliximab. BMC Musculoskelet Disord 2015;16:166.
6Baraliakos X, Koenig AS, Jones H, Szumski A, Collier D, Bananis E, et al. Predictors of clinical remission under anti-tumor necrosis factor treatment in patients with ankylosing spondylitis: Pooled analysis from large randomized clinical trials. J Rheumatol 2015;42:1418-26.
7de Vries HS, van Oijen MG, Driessen RJ, de Jong EM, Creemers MC, Kievit W, et al. Appropriate infliximab infusion dosage and monitoring: Results of a panel meeting of rheumatologists, dermatologists and gastroenterologists. Br J Clin Pharmacol 2011;71:7-19.
8Clark L, Lebwohl M. The effect of weight on the efficacy of biologic therapy in patients with psoriasis. J Am Acad Dermatol 2008;58:443-6.
9Bruner V, Atteno M, Spanò A, Scarpa R, Peluso R. Biological therapies for spondyloarthritis. Ther Adv Musculoskelet Dis 2014;6:92-101.
10St Clair EW, Wagner CL, Fasanmade AA, Wang B, Schaible T, Kavanaugh A, et al. The relationship of serum infliximab concentrations to clinical improvement in rheumatoid arthritis: Results from ATTRACT, a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2002;46:1451-9.
11Krzysiek R, Breban M, Ravaud P, Prejean MV, Wijdenes J, Roy C, et al. Circulating concentration of infliximab and response to treatment in ankylosing spondylitis: Results from a randomized control study. Arthritis Rheum 2009;61:569-76.
12Kaul A, Adil MS. Drug dosing in obese patients: A dilemma. Int J Adv Pharm 2014;3:60-5.
13Adams JP, Murphy PG. Obesity in anesthesia and intensive care. Br J Anaesth 2000;85:91-108.
14van 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.
15Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults – The evidence report. National institutes of health. Obes Res 1998;6 Suppl 2:51S-209.
16Elolemy GG, Ganeb SS, Ghanima AT, Abdelgwad EA. Influence of adipocytokines and IL-6 on ankylosing spondylitis disease activity and functional status. Egypt Rheumatol 2013;35:65-70.
17Braun J, Pham T, Sieper J, Davis J, van der Linden S, Dougados M, et al. International ASAS consensus statement for the use of anti-TNF agents in patients with ankylosing spondylitis. Ann Rheum Dis 2003;62:817-24.
18Maini RN, Breedveld FC, Kalden JR, Smolen JS, Davis D, Macfarlane JD, et al. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum 1998;41:1552-63.
19Klotz U, Teml A, Schwab M. Clinical pharmacokinetics and use of infliximab. Clin Pharmacokinet 2007;46:645-60.
20Han PY, Duffull SB, Kirkpatrick CM, Green B. Dosing in obesity: A simple solution to a big problem. Clin Pharmacol Ther 2007;82:505-8.
21Ferraccioli G, Trotta F, Punzi L, Ferri C, Sarzi-Puttini P, Bambara L, et al. Weight and response to biologics in RA and spondylarthritides: Obesity reduces the rate of remission-response GISEA Registry. Arthritis Rheum 2010;62:297.
22Daïen CI, Morel J. Predictive factors of response to biological disease modifying antirheumatic drugs: Towards personalized medicine. Mediators Inflamm 2014;2014:386148.
23di Minno MN, Peluso R, Iervolino S, Lupoli R, Russolillo A, Scarpa R, et al. Obesity and the prediction of minimal disease activity: A prospective study in psoriatic arthritis. Arthritis Care Res (Hoboken) 2013;65:141-7.
24Eder L, Thavaneswaran A, Chandran V, Cook RJ, Gladman DD. Obesity is associated with a lower probability of achieving sustained minimal disease activity state among patients with psoriatic arthritis. Ann Rheum Dis 2015;74:813-7.
25Rudwaleit 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.
26Ottaviani S, Allanore Y, Tubach F, Forien M, Gardette A, Pasquet B, et al. Body mass index influences the response to infliximab in ankylosing spondylitis. Arthritis Res Ther 2012;14:R115.
27de Vries MK, Wolbink GJ, Stapel SO, de Vrieze H, van Denderen JC, Dijkmans BA, et al. Decreased clinical response to infliximab in ankylosing spondylitis is correlated with anti-infliximab formation. Ann Rheum Dis 2007;66:1252-4.