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Rheumatology Advance Access originally published online on May 23, 2006
Rheumatology 2007 46(1):93-96; doi:10.1093/rheumatology/kel175
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The –308 tumour necrosis factor-{alpha} gene polymorphism predicts therapeutic response to TNF{alpha}-blockers in rheumatoid arthritis and spondyloarthritis patients

M. Seitz1, U. Wirthmüller2, B. Möller1 and P. M. Villiger1

1Department of Rheumatology and Clinical Immunology/Allergology and 2Division of Molecular Diagnostics, University Hospital, Inselspital, Berne, Switzerland.

Correspondence to: Michael Seitz, MD, Department of Rheumatology and Clinical Immunology/Allergology, University Hospital, CH-3010 Berne, Switzerland. E-mail: michael.seitz{at}insel.ch


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgement
 References
 
Objective. To examine whether the G-to-A polymorphism at position –308 in the promoter of the tumour necrosis factor-{alpha} (TNF{alpha}) gene influences the therapeutic response to TNF{alpha}-blockers in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS).

Methods. A total of 54 patients with RA, 10 with PsA and 22 with AS were genotyped by polymerase chain reaction for the –308 TNF{alpha} promoter polymorphism. They were treated with infliximab (n = 63), adalimumab (n = 10) or etanercept (n = 13). Clinical response was assessed after 24 weeks by the Disease Activity Score in 28 joints (DAS28) for RA and PsA, and the Bath Ankylosing Spondylitis Activity Index (BASDAI) for AS patients.

Results. All patients with the A/A genotype (n = 3, all RA) and two patients with the A/G genotype (AS) failed to respond to anti-TNF treatment. Irrespective of the underlying disease, moderate response (n = 44) was predominantly associated with the A/G genotype (A/G 18/22, G/G 4/22), whereas good response (n = 59) was exclusively seen in patients with the G/G genotype. The average improvement in the DAS28 score was 0.83 in the A/A, 1.50 in the A/G and 2.64 in the G/G group of RA and PsA patients (P < 0.0001). The BASDAI score in AS improved on average by 1.21 in the A/G and by 3.30 in the G/G group (P < 0.005).

Conclusions. The data suggest that humans with a TNF{alpha} –308 G/G genotype are better responders to anti-TNF{alpha} treatment than those with A/A or A/G genotypes independent of the treated rheumatic disease (RA, PsA or AS).

KEY WORDS: –308 TNF{alpha} promoter polymorphism, Response to TNF{alpha}-blockers


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 Acknowledgement
 References
 
Tumour necrosis factor-{alpha} (TNF{alpha})-neutralizing strategies represent a major breakthrough in the treatment of rheumatoid arthritis (RA) [1], ankylosing spondylitis (AS) and psoriatic arthritis (PsA) [2]. However, there is a large heterogeneity in the response to these agents. Therapy with TNF{alpha}-blockers is expensive and bears substantial risks. Predictors of treatment response would, therefore, be useful to select the appropriate patients for treatment. Recently, a French study showed that RA patients with the –308 TNF{alpha} promoter G/G genotype have a better response to TNF{alpha}-blockade with infliximab than those with the –308A allele [3]. In another study, patients with the rare allele of the promoter polymorphism 196 of the p75 TNF receptor showed a poorer response to anti-TNF{alpha} therapy [4]. In addition, a recent Swedish study demonstrated that the combination of the diplotypes –308 G/G in the TNF{alpha} promoter and of –1087G/G in the interleukin (IL-10) gene was associated with good responsiveness to etanercept [5]. In the present study, we demonstrate a prognostic impact of the –308 TNF{alpha} promoter polymorphism regarding not only the responsiveness of RA patients to infliximab but also to etanercept and adalimumab. In addition, we present data for similar observations in spondyloarthritis patients.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 Acknowledgement
 References
 
A total of 54 patients with RA, 10 patients with PsA and 22 patients with AS diagnosed according to the American College of Rheumatology [6] and modified New York criteria [7] required treatment with infliximab (Essex, Luzern CH), adalimumab (Abbott, Baar, CH) or etanercept (Wyeth, Zug, CH). The patients received infusions of infliximab or subcutaneous injections of adalimumab or etanercept according to standard protocols. Fifty-three RA, 10 PsA patients and 11 AS patients continued with s.c. weekly low-dose methotrexate (MTX). One RA patient received leflunomide (20 mg/day), and three AS patients were comedicated with azathioprine (50–150 mg/day). Three AS patients started with MTX after the onset of TNF{alpha}-blockade. Approval of the study was obtained from the Local Ethical Committee (Canton of Berne), and informed consent was obtained from all patients.

Response was assessed after 24 weeks of treatment. For RA and PsA patients, the modified disease activity score (DAS28) was used [8–10]. Disease activity of AS patients was assessed using the Bath Ankylosing Spondylitis Activity Index (BASDAI) [11]. We used a detailed categorization of response: in RA and PsA moderate response corresponded to a DAS28 improvement of ≥1.2 and ≤2.2, and good response to an improvement of >2.2 from baseline. Consequently, treatment failure was defined as an improvement in DAS28 <1.2.

In the group of AS patients, a moderate response was defined as an improvement in BASDAI of ≥20 and ≤ 50%, and a BASDAI improvement of >50% from baseline corresponded to a good response [11]. Non-responders were defined as having a BASDAI improvement of <20%.

Genomic DNA was extracted from whole blood using a commercially available kit (Qiagen, Hilden, Germany). Genotypes were determined with the use of fluorogenic allele-specific oligonucleotide probes (TaqMan assay I). Primer pairs were designed to match the –308G or –308A allele, resulting in amplification of the target sequence. Genotype calling was carried out with the allelic discrimination analysis module of the ABI PRISM® 7700 SDS (software version 1.7).

Patients, characteristics and quantitative measures are presented as mean ± S.D. compared with Students, two-tailed t-test. A P-value <0.05 was regarded as statistically significant. Association analyses of treatment response with –308 TNF{alpha} promoter diplotypes (A/A, A/G, G/G), the allelic status (–308A absent or present), or the anti-TNF agents used in this study were done by {chi}2 test. All statistics were done with the software package SPSS® version 12.0 (SPSS Munich, Germany).


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 Acknowledgement
 References
 
In Table 1, basis demographics, disease status and drug treatment of RA and AS patients were compared according with their –308 genotype (A/A, A/G, G/G). RA patients with the A/A and A/G genotypes tended to be younger than those with the G/G genotype. There were no significant differences in prednisolone and DMARD comedication at study entry. About 61.1% of RA patients received infliximab, 22.2% etanercept and 16.7% were treated with adalimumab.


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  		TABLE 1. Description of RA and AS patients according to the –308 TNF{alpha} promoter polymorphism genotypes

 
Mean disease duration of AS patients was somehow longer in those with the A/G genotype compared with their G/G-positive counterparts (16.8 vs 9.5 yr; P < 0.025). The vast majority of AS patients was treated with infliximab (94.1%), and only one patient with adalimumab.

Table 2 demonstrates the division of RA, PsA and AS patients according to the –308 genotype that resulted in groups of comparable disease activity at baseline as indicated by the mean DAS28 or the mean BASDAI but of significantly different improvement of DAS28 and BASDAI scores with anti-TNF{alpha} treatment. The clinical outcome of anti-TNF{alpha} treatment in RA patients was closely associated with the –308 TNF{alpha} promoter diplotype (n = 54, {chi}2 = 96.72, P < 0.001) and to the presence or absence of an A allele at locus –308 ({chi}2 = 43,43, P < 0.001). Good response was exclusively observed in patients carrying the –308 G/G diplotype, whereas moderate response was associated with the –308 A/G genotype in 14/14, and unresposiveness with the –308 AA diplotype in 3/3 patients.


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  		TABLE 2. DAS28 scores in RA and BASDAI scores in AS patients improve upon anti-TNF{alpha} treatment in correlation with the polymorphism at position –308 of the TNF{alpha} gene

 
In agreement with the results in RA patients, response to anti-TNF{alpha} treatment was associated with the allelic status (n = 32, {chi}2 = 26.75, P < 0.001) and genotype ({chi}2 = 26.75, P < 0.001) at position –308 in the entire cohort of SpA patients (pooled data of AS and PsA patients) and in AS patients when analysed in separate (n = 20, {chi}2 = 22.00, P < 0.001).

Strong prediction of treatment response was suggested by association analyses for the allelic status (n = 86, {chi}2 = 70.17, P < 0.001) and genotype ({chi}2 = 115.50, P < 0.001) of the entire study cohort.

All good responders were identified in the group of G/G-positive patients irrespective of their disease, whereas moderate responders mostly carried the A/G genotype (90%) and much less the G/G genotype (6.3%). In contrast, non-responders belonged either to the A/A (three RA patients) or to the A/G group (two AS patients). Robustness of these results was further supported by separate analyses for both genders (female: n = 45, {chi}2 = 72.38, P < 0.001; male: n = 42, {chi}2 = 42.00, P < 0.001) or by analyses only of female RA patients (n = 37, {chi}2 = 26.56, P < 0.001) or of male SpA patients (n = 24, {chi}2 = 24.00, P < 0.001). However, association analyses of the treatment response to infliximab, adalimumab or etanercept were not significantly different (n = 86, {chi}2 = 4.93).


   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
Acknowledgement
 References
 
In the present study, 54 patients with RA, 10 with PsA and 22 with AS who were treated with TNF{alpha}-blocking agents, either with infliximab, adalimumab or with etanercept, were followed up. We examined whether the clinical response at 24 weeks could be predicted by the TNF{alpha} promoter genotype at position –308. Our analysis supports previous findings [3] on the importance of the –308 TNF promoter polymorphism for the response to infliximab of RA patients. In addition, our results provide evidence for similar associations in other inflammatory conditions and for the other two currently available TNF-blocking agents, etanercept and adalimumab.

When we analysed patients according to their clinical response (moderate and good responses), carriers of the G/G genotype by far outweighed patients with the A/G genotype in the group of good responders. In contrast, A/G carriers had a 14-fold higher probability of achieving only a moderate response compared with patients with the G/G genotype. The rare A/A genotype was strongly associated with non-response in our RA patients. In fact, we calculated a 10-fold higher probability of non-response in this group of patients compared with patients with the A/G genotype.

This is the first study reporting the importance of a TNF{alpha} polymorphism predicting response to TNF{alpha}-blocking agents not only in RA but also in PsA and AS. A previous study in Crohn's disease did not find any influence of –308 TNF{alpha} gene polymorphism on the response to infliximab [12], and a Swedish group found that only a combination of the G/G genotype of the –308 TNF{alpha} promoter and the –1087 G/G genotype of IL-10 was associated with good responsiveness to etanercept in RA patients [5]. Our patients were comparable with regard to age and disease duration, but in contrast to the Swedish study, our RA patients were all on parenteral MTX, which is known to have a higher bioavailability compared with oral MTX [13]. One can argue that the more intensive MTX comedication had an impact on baseline inflammtory cytokine levels before starting with TNF{alpha}-blockers, rendering patients more sensitive to TNF{alpha} neutralization. This hypothesis is supported by our own studies on the effect of MTX on the IL-1 pathway [14]. It suggests a synergistic role of the two therapeutic strategies regarding the proinflammatory cytokine network. Another explanation is the inhibitory effect of MTX on the production of neutralizing antibodies to the TNF{alpha}-blocking molecules. Furthermore, it has previously been reported that MTX reduces the clearance of TNF{alpha}-blocking antibodies and thereby increases the bioactivity and the clinical response [15]. These mechanisms could also explain the substantially higher response rate of our RA patients with A/G or G/G genotypes compared with a French cohort of patients [3].

Our data furthermore support the previous observation [16] that a rapid CRP reduction upon TNF{alpha}-blockade was associated with the clinical response in RA patients (data not shown).

The results of clinical studies [16, 17] showing that some patients not responding to one TNF{alpha}-blocker may respond to the treatment with another TNF{alpha}-blocking agent, however, are not supported and cannot be explained by our data. Whether it is the locus investigated here, the presence of distinct TNF haplotypes or MHC genes linked to –308 A/G as discussed elsewhere remains to be elucidated [3, 18, 19]. Similar results in RA and SpA, diseases of completely different genetic background, give rise to the assumption that the TNF{alpha} gene, rather than the class I or class II MHC genes, is of importance for the response to TNF{alpha}-blockade.

Collectively, the presented results illustrate that the TNF{alpha} promoter is important determinant of treatment response irrespective of genetic associations of the underlying diseases.


   Acknowledgement
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgement
References
 
This study has been supported by a research grant from Abbott AG, Baar, Switzerland.

The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgement
 References
 

  1. Maini R, St Clair EW, Breedfeld F, et al. (1999) Infliximab (chmireic anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexat: a randomised phase III trial. Lancet 354:1932–9.[CrossRef][Web of Science][Medline]
  2. Anandarajah A and Ritchlin CT. (2005) Treatment update on spondyloarthropathy. Curr Opin Rheumatol 17:247–56.[CrossRef][Web of Science][Medline]
  3. Mugnier B, Balandraud N, Darque A, et al. (2003) Polymorphism at position –308 of the tumour necrosis factor {alpha} gene influences outcome of infliximab therapy in rheumatoid arthritis. Arthritis Rheum 48:1849–52.[CrossRef][Web of Science][Medline]
  4. Fabris M, Tolusso B, Di Poi E, et al. (2002) Tumour necrosis factor receptor II polymoprhism in patients from southern Europe with mild-moderate and severe rheumatoid arthritis. J Rheumatol 29:1847–50.[Abstract/Free Full Text]
  5. Padyukov L, Lampa J, Heimbürger M, et al. (2003) Genetic markers for the efficacy of tumour necrosis factor blocking therapy in rheumatoid arthritis. Ann Rheum Dis 62:526–9.[Abstract/Free Full Text]
  6. Arnett FC, Edworthy SM, Bloch DA, et al. (1988) The American Rheumatism Association 1987 revised criteria of rheumatoid arthritis. Arthritis Rheum 25:2524–30.
  7. Van der Linden S, Valkenburg HA, Cats A, et al. (1984) Evaluation of diagnostic criteria for ankylosing spondylitis: a proposal for modification of the New York criteria. Arthritis Rheum 27:361–8.[Web of Science][Medline]
  8. Antoni CE, Kavanaugh A, Kirkham B, et al. (2005) Sustained benefits of infliximab therapy for dermatologic and articular manifestations of psoriatic arthritis. Results from the infliximab multinational psoriatic arthritis controlled trial (IMPACT). Arthritis Rheum 52:1227–36.[CrossRef][Web of Science][Medline]
  9. Prevoo MLL, van't Hof MA, Kuper HH, et al. (1995) Modified disease activity scores that include twenty-eight-joint counts: development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 38:44–8.[Web of Science][Medline]
  10. Smolen J, Breedfeld F, Burmester G, et al. (2000) Consensus statement on the initiation and continuation of TNF blocking therapies in rheumatoid arthritis. Ann Rheum Dis 59:504–5.[Free Full Text]
  11. Rudwaleit M, Listing J, Brandt J, et al. (2004) Prediction of a major clinical response (BASDAI 50) to tumour necrosis factor {alpha} blockers in ankylosing spondylitis. Ann Rheum Dis 63:665–70.[Abstract/Free Full Text]
  12. Louis E, Vermeire S, Rutgeerts P, et al. (2002) A positive response to infliximab in Crohn's disease: association with higher systemic inflammation before treatment but not with –308 TNF gene polymorphism. Scand J Gastroenterol 37:818–24.[Web of Science][Medline]
  13. Oguey D, Kölliker F, Gerber NJ, et al. (1992) Effect of food on the bioavailability of low-dose methotrexate in patients with rheumatoid arthritis. Arthritis Rheum 35:611–4.[Web of Science][Medline]
  14. Seitz M, Zwicker M, Villiger PM. (2003) Pretreatment cytokine profiles of peripheral blood mononuclear cells and serum from patients with rheumatoid arthritis in different American College of Rheumatology Response Groups to methotrexate. J Rheumatol 30:28–35.[Abstract/Free Full Text]
  15. Maini RN, Breedveld FC, Kalden JR, et al. (1998) Therapeutic efficacy of multiple intravenous infusions of anti-tumour necrosis factor {alpha} monoclonal antibody combined with low dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum 41:1552–63.[CrossRef][Web of Science][Medline]
  16. Buch MH, Seto Y, Bingham SJ, et al. (2005) C-reactive protein as a predictor of infliximab treatment outcome in patients with rheumatoid arthritis: defining subtypes of nonresponse and subsequent response to etanercept. Arthritis Rheum 52:42–8.[Medline]
  17. von Vollenhoven R, Harju A, Brannemark S, Klasrekog L. (2003) Treatment with infliximab (Remicade) when etanercept (Enbrel) has failed or vice versa: data from the STURE registry showing that switching tumour necrosis factor alpha blockers can make sense. Ann Rheum Dis 62:1195–8.[Abstract/Free Full Text]
  18. Martinez A, Salido M, Bonilla G, et al. (2004) Association of the major histocompatibility complex with response to infliximab therapy in rheumatoid arthritis patients. Arthritis Rheum 50:1077–82.[CrossRef][Web of Science][Medline]
  19. Bridges SL Jr. (2004) Genetic markers of treatment response in rheumatoid arthritis. Arthritis Rheum 50:1019–22.[CrossRef][Web of Science][Medline]
Submitted 26 January 2006; revised version accepted 18 April 2006.
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