Michael Binks

Imperial College London, London, ENG, United Kingdom

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Publications (18)73.57 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: RATIONAL AND OBJECTIVE: Dynamic contrast enhanced (DCE)-MRI has great potential to provide quantitative measure of inflammatory activity in rheumatoid arthritis. There is no current benchmark to establish the stability of signal in the joints of healthy subjects when imaged with DCE-MRI longitudinally, which is crucial so as to differentiate changes induced by treatment from the inherent variability of perfusion measures. The objective of this study was to test a pixel-by-pixel parametric map based approach for analysis of DCE-MRI (Dynamika) and to investigate the variability in signal characteristics over time in healthy controls using longitudinally acquired images. MATERIALS AND METHODS: 10 healthy volunteers enrolled, dominant wrists were imaged with contrast enhanced 3T MRI at baseline, week 12, 24 and 52 and scored with RAMRIS, DCE-MRI was analysed using a novel quantification parametric map based approach. Radiographs were obtained at baseline and week 52 and scored using modified Sharp van der Heidje method. RAMRIS scores and dynamic MRI measures were correlated. RESULTS: No erosions were seen on radiographs, whereas MRI showed erosion-like changes, low grade bone marrow oedema and low-moderate synovial enhancement. The DCE-MRI parameters were stable (baseline scores, variability) (mean±st.dev); in whole wrist analysis, MEmean (1.3±0.07, -0.08±0.1 at week 24) and IREmean (0.008±0.004, -0.002±0.005 at week 12 and 24). In the rough wrist ROI, MEmean (1.2±0.07, 0.04±0.02 at week 52) and IREmean (0.001±0.0008, 0.0006±0.0009 at week 52) and precise wrist ROI, MEmean (1.2±0.09, 0.04±0.04 at week 52) and IREmean (0.001±0.0008, 0.0008±0.001 at week 24 and 52). The Dynamic parameters obtained using fully automated analysis demonstrated strong, statistically significant correlations with RAMRIS synovitis scores. CONCLUSION: The study demonstrated that contrast enhancement does occur in healthy volunteers but the inherent variability of perfusion measures obtained with quantitative DCE-MRI method is low and stable, suggesting its suitability for longitudinal studies of inflammatory arthritis. These results also provide important information regarding potential cut-off levels for imaging remission goals in patients with RA using both RAMRIS and DCE-MRI extracted parametric parameters.
    European journal of radiology 04/2013; · 2.65 Impact Factor
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    ABSTRACT: To test the sensitivity to change of ultrasonographic endpoints in early phase clinical trials in subjects with active rheumatoid arthritis (RA). A double-blind, placebo and comparator controlled, randomised, two-centre study investigated the effect on synovial thickness and vascularity of 28 days repeat daily oral dosing of 60 mg of the inducible nitric oxide synthase inhibitor GW274150 or 7.5 mg prednisolone in RA. Fifty patients with DAS28 scores ≥4.0 were assigned to 3 treatment arms of 17, 19 and 14 (on placebo, GW274150 and prednisolone respectively). Synovial thickness and vascularity of all 10 metacarpophalangeal joints were assessed by ultrasonography using a semi-quantitative scale at baseline (Day 1), Day 15 and Day 28. Vascularity was also measured quantitatively by power Doppler area. At Day 28, the GW274150 group showed a trend towards reduction in synovial thickness compared with placebo, with an adjusted mean decrease of 33% (p=0.072); the prednisolone group decreased significantly by 44% (p=0.011). Similarly, there was a trend to reduced synovial vascularity with GW274150 by 42% compared with placebo (p=0.075); prednisolone resulted in a statistically significant decrease of 55% (p=0.012). There was a 55% decrease in power Doppler area for GW274150, compared with placebo although the result was not statistically significant (p=0.375). Prednisolone 7.5 mg resulted in a highly statistically significant decrease of 95% (p=0.003). This study advocates the use of ultrasonographic measures of metacarpophalangeal joint synovitis as an endpoint for clinical studies assessing therapeutic potential of new compounds in small patient cohorts over 28 days.
    Clinical and experimental rheumatology 02/2012; 30(2):254-61. · 2.66 Impact Factor
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    ABSTRACT: Purpose: To investigate the effects of single doses of losmapimod, dilmapimod (inhibitors of p38 MAPK) and prednisolone on biomarkers of systemic inflammation (serum C-reactive pro-tein (CRP) and interleukin (IL)-6) in subjects with active rheumatoid arthritis (RA). Methods: Two randomized, double blind, placebo controlled, parallel group, single dose studies investigated the CRP and IL-6 dose-response relationships for losmapimod (study A) and dilmapimod and prednisolone (study B) in patients with active RA on stable weekly doses of methotrexate. CRP, IL-6 and other exploratory biomarkers were measured in blood at baseline and up to 72 hours post-dosing. Results: In study A, 51 sub-jects were randomized to receive losmapimod (7.5, 20 and 60 mg) or placebo and in study B, 77 subjects were randomized to receive dilmapi-mod (7.5, 15 and 25 mg) or prednisolone (10, 20 and 50 mg) or placebo. Single doses of predni-solone caused a decrease in circulating IL-6 detectable at 3 and 24 hours post-dose as well as a CRP single-dose relationship at 48 hours post-dose in patients with active RA. All doses of losmapimod produced a statistically signifi-cant reduction in serum IL-6, 3 hours post-dose but had no effect on CRP. Dilmapimod had no effect on IL-6 or CRP at any dose or time. Con-clusion: This single-dose response clinical study design could be useful in the early clinical development of anti-inflammatory agents for the treatment of rheumatoid arthritis. Inhibition of both circulating IL-6 and CRP would increase confidence that a new chemical entity may have the potential to deliver clinical benefit in RA. Trial registration: [clinicaltrials.gov: NCT00256919 and NCT00134693].
    Open Journal of Immunology 02/2012; 2(3):85.
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    ABSTRACT: To investigate the stability over 2 weeks of ultrasonographic assessments of synovial thickness and vascularity in all 10 metacarpophalangeal joints of subjects with rheumatoid arthritis (RA) with a range of disease activities as measured by the validated Disease Activity Score-28 joint score (DAS28-ESR). And in subjects with severe disease activity, to compare the sensitivity of these measurements, acute-phase markers, and vascular endothelial growth factor to change in response to 2 weeks of oral prednisolone (7.5 mg daily). A group of 38 subjects with RA were enrolled, 13 (mean DAS28 2.1), 14 (mean DAS28 5.2), and 11 (mean DAS28 5.7) meriting oral corticosteroid treatment. Synovial thickness and vascularity were assessed by ultrasonography at 3 timepoints. Images were ranked by semiquantitative scale. Vascularity was also measured by quantitative determination of the power Doppler area (PDA). In the whole RA cohort, baseline indices of synovial thickness and vascularity correlated with DAS28, as did PDA (r = 0.42, p < 0.05). In the RA groups on stable therapy, synovial thickness and vascularity showed little variation over 2 weeks. In the corticosteroid group, PDA had fold changes of -1.9-fold (p < 0.05) after 1 week and -2.2-fold (p < 0.05) after 2 weeks. These were the largest fold changes of all measured variables. Ultrasonographic measures can differentiate disease severity in RA correlating closely with DAS28. Quantitative power Doppler signal was significantly reduced within 1 week of oral prednisolone, a rapid kinetic suggesting that PDA may have value as a sensitive early marker of therapeutic response.
    The Journal of Rheumatology 10/2010; 37(12):2493-501. · 3.26 Impact Factor
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    ABSTRACT: The aim of the present study was to determine the in vivo efficacy of p38 mitogen-activated protein kinase (MAPK) inhibitors, namely GW856553X and GSK678361, in murine models of arthritis. The effect of p38 MAPK inhibitors was tested in 2 variants of the collagen-induced arthritis model (CIA) in DBA/1 mice, acute arthritis induced by heterologous collagen and chronic relapsing arthritis induced by homologous collagen. Animals were treated after onset of arthritis. Furthermore, post-onset disease efficacy of GSK678361 was tested in the chronic model, so as to determine the effects on established arthritis. In vitro studies were carried out with GW856553X, using human umbilical vein endothelial cells, to determine potential effects of GW856553X on the vasculature. In both acute and chronic arthritis, GW856553X reduced signs and symptoms of disease, and protected joints from damage. The effect of GW856553X in chronic CIA was confirmed using an alternative compound, GSK678361. Importantly, treatment with GSK678361 from 14 days post-onset of chronic arthritis completely reversed signs of established disease and joint destruction. Mechanism of action studies demonstrated that GW856553X inhibited endothelial cell migration and angiogenesis in vitro, with reduced pro-inflammatory cytokine production. Suppression of murine CIA by the p38 MAPK inhibitors GW856553X and GSK678361 suggests that they may have therapeutic potential for future use in RA if safe clinical dosing achieves adequate compound exposure.
    Clinical and experimental rheumatology 01/2010; 28(2):176-85. · 2.66 Impact Factor
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    Arthritis & Rheumatology 07/2009; 60(7):2207-2208. · 7.48 Impact Factor
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    ABSTRACT: Methionine aminopeptidase-2 (MetAP-2) inhibitors have potent anti-angiogenesis activity and are being developed for the treatment of solid tumours. The recently observed specific expression of MetAP-2 in germinal centre B cells suggests that it has a role in regulating B cell function. We have demonstrated a potent MetAP-2-dependent inhibitory effect on the antibody secretion from B cell receptor and CD40 co-stimulated primary human B cells in the presence of interleukin-21. The effect of MetAP-2 inhibition on antibody secretion was due to a block in differentiation of B cells into plasma cells. Immunohistochemical analysis of germinal centres from human, mouse and marmoset spleen showed a similar expression pattern of MetAP-2 in the marmoset and man, whereas mouse spleen showed no detectable expression. In a marmoset, T dependent immunization model, the MetAP-2 inhibitor suppressed an antigen-specific antibody response. Furthermore, histological analysis showed loss of B cells in the spleen and disrupted germinal centre formation. These results provide experimental evidence to support a novel role for MetAP-2 in immunomodulation. These effects of MetAP-2 are mediated by disruption of the germinal centre reaction and a block in the differentiation of B cells into plasma cells.
    Clinical & Experimental Immunology 01/2009; 155(3):514-22. · 3.41 Impact Factor
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    ABSTRACT: The HLA-DRB1 locus within the major histocompatibility complex (MHC) at 6p21.3 has been identified as a susceptibility gene for rheumatoid arthritis (RA); however, there is increasing evidence of additional susceptibility genes in the MHC region. The aim of this study was to estimate their number and location. A case-control study was performed involving 977 control subjects and 855 RA patients. The HLA-DRB1 locus was genotyped together with 2,360 single-nucleotide polymorphisms in the MHC region. Logistic regression was used to detect DRB1-independent effects. After adjusting for the effect of HLA-DRB1, 18 markers in 14 genes were strongly associated with RA (P<10(-4)). Multivariate logistic regression analysis of these markers and DRB1 led to a model containing DRB1 plus the following 3 markers: rs4678, a nonsynonymous change in the VARS2L locus, approximately 1.7 Mb telomeric of DRB1; rs2442728, upstream of HLA-B, approximately 1.2 Mb telomeric of DRB1; and rs17499655, located in the 5'-untranslated region of DQA2, only 0.1 Mb centromeric of DRB1. In-depth investigation of the DQA2 association, however, suggested that it arose through cryptic linkage disequilibrium with an allele of DRB1. Two non-shared epitope alleles were also strongly associated with RA (P<10(-4)): *0301 with anti- cyclic citrullinated peptide-negative RA and *0701 independently of autoantibody status. These results confirm the polygenic contribution of the MHC to RA and implicate 2 additional non-DRB1 susceptibility loci. The role of the HLA-DQ locus in RA has been a subject of controversy, but in our data, it appears to be spurious.
    Arthritis & Rheumatology 12/2008; 60(1):53-62. · 7.48 Impact Factor
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    ABSTRACT: Selenoprotein-S (SELS) is involved in the stress response within the endoplasmic reticulum (ER) and inflammation. Recently, promoter variants in the SELS gene were shown to be associated with plasma levels of interleukin (IL)6, IL1beta and tumour necrosis factor (TNF). It was hypothesised that these variants could influence rheumatoid arthritis (RA) susceptibility and may interact with functional single nucleotide polymorphisms (SNPs) in the genes for IL1, IL6 and TNF. Genotyping was performed in 988 unrelated healthy controls and 965 patients with RA. Stratified analysis was used to test for interactions. Single gene effects and evidence of epistasis were investigated using the Mantel-Haenszel (M-H) test and the linkage disequilibrium (LD)-based statistic. No association of SELS -105 genotype and RA susceptibility was detected. Stratification of SELS -105 genotypes by IL1 -511 genotypes showed that the disease risk (comparing AA/GA to GG at the SELS -105 locus) in individuals with the GG/AG genotype at the IL1beta -511 locus was significantly lower than that in individuals having the AA genotype at the IL1beta -511 locus (odds ratio (OR): 0.9 and 2.3, respectively; p = 0.004 by M-H test). Significant epistasis was also detected using the LD-based statistic (p = <0.001). No interaction was observed between SELS -105 and IL6 or TNF variants. Our results reveal evidence of strong epistasis in two genes in the IL1 production pathway and highlight the potential importance of gene-gene interactions in the pathogenesis of RA.
    Annals of the rheumatic diseases 09/2008; 68(9):1494-7. · 8.11 Impact Factor
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    ABSTRACT: To determine whether the plasma levels of a range of inflammatory proteins have utility as biomarkers of disease activity in rheumatoid arthritis (RA) patients. Plasma proteins (n = 163) were profiled in 44 patients with RA diagnosed according to the American College of Rheumatology 1987 criteria (22 with active and 22 with quiescent disease) and in 16 age- and sex-matched healthy controls. The utility of a subset of differentially expressed proteins as predictors of RA disease activity was investigated using partial least-squares discriminant analysis, and their response to therapeutic intervention was evaluated in plasma from an additional cohort of 16 patients with active RA treated with anti-tumor necrosis factor alpha (anti-TNFalpha). The protein profiling study identified 25 proteins that were differentially expressed in plasma samples from patients with active RA (P for the false discovery rate < or = 0.01) compared with those with quiescent RA, including the previously described interleukin-6 (IL-6), oncostatin M, and IL-2, and the 5 less-established markers macrophage colony-stimulating factor (M-CSF), tumor necrosis factor receptor superfamily member 9, CCL23, transforming growth factor alpha, and CXCL13. Systemic levels of these 5 markers correlated with the C-reactive protein level, erythrocyte sedimentation rate, rheumatoid factor level, tender joint count in 68 joints, and Disease Activity Score in 28 joints (DAS28), and their combined plasma levels were shown to be good predictors of disease activity (kappa = 0.64). In anti-TNFalpha-treated RA patients, plasma levels of CXCL13 were reduced after 1 and 7 days of therapy, and levels of CCL23, M-CSF, and CXCL13 showed a statistically significant positive correlation with the DAS28 score. This exploratory study for biomarker discovery led to the identification of several proteins predictive of RA disease activity that may be useful in the definition of disease subphenotypes and in the measurement of response to therapy in clinical studies.
    Arthritis & Rheumatology 08/2008; 58(8):2257-67. · 7.48 Impact Factor
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    ABSTRACT: To investigate the association of a recently described classification of Human leukocyte antigen (HLA)-DRB1 shared epitope alleles with rheumatoid factors (RF) and anti-cyclic citrullinated peptide (CCP) production and radiological severity in rheumatoid arthritis (RA). Patients with RA (n = 962) were studied. Genotyping of DRB1 alleles and assays for RF and anti-CCP were performed. Radiological severity was measured using the modified Larsen score. In accordance with previous reports, we found carriage of S2 alleles (K-R-A-A at positions 71-74) to be associated with more severe disease with a gene-dose effect (p = 0.0059), and also associated with the presence of anti-CCP and RF (p<0.001). Carriage of S1 alleles (D-E-R-A-A at positions 70-74) was associated with less severe disease (p = 0.01), however there was no association between S1 and either anti-CCP or RF, suggesting that the basis for this possible protective effect was not related to autoantibody-producing B cells. These data suggest that multiple biological mechanisms underlie the DRB1 association with rheumatoid arthritis severity.
    Annals of the rheumatic diseases 08/2008; 67(7):980-3. · 8.11 Impact Factor
  • Clinical Immunology - CLIN IMMUNOL. 01/2008; 127.
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    ABSTRACT: Recent evidence has highlighted a major genetic contribution to radiographic damage in rheumatoid arthritis (RA). The objective of this study was to determine whether genetic variants in the loci for interleukin-1 (IL-1), IL-6, IL-10, protein tyrosine phosphatase N22 (PTPN22), and selenoprotein S are associated with radiographic damage. Modified Larsen scores of radiographic damage were determined in a cross-sectional population of patients with RA (n = 964). Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) were also assayed. The Kruskal-Wallis nonparametric test was used to compare median radiographic damage scores across genotype groups, followed by the Cuzick nonparametric test for trend to assess gene-dose effects. An allele-dose association of IL-6 -174G with increasing radiographic damage was present (P = 0.005), but only in patients who were RF positive (P = 0.004) or anti-CCP positive (P = 0.01). Patients with the IL-10 -592CC genotype had more extensive radiographic damage than did those with the AC or AA genotype (P = 0.006), but this was observed only among patients who were RF negative (P = 0.002) or anti-CCP negative (P = 0.002). However, RF status and anti-CCP status were not associated with the IL-6 or IL-10 genotype. No other genetic associations were detected, apart from a marginal association of PTPN22 +1858T with increased radiographic damage. The reported associations of IL-6 -174G with high IL-6 production and IL-10 -592 with low IL-10 production and our own results support a role of genetically determined dysregulated cytokine production in disease severity. The lack of association of these genotypes with RF and anti-CCP antibody status suggests that they act downstream of autoantibody production. We conclude that IL-6 and IL-10 genotypes may be useful in predicting disease severity in autoantibody-positive and autoantibody-negative patients, respectively.
    Arthritis & Rheumatology 09/2007; 56(8):2549-56. · 7.48 Impact Factor
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    ABSTRACT: The enzyme methionine aminopeptidase-2 (MetAP-2) is thought to play an important function in human endothelial cell proliferation, and as such provides a valuable target in both inflammation and cancer. Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with increased synovial vascularity, and hence is a potential therapeutic target for angiogenesis inhibitors. We examined the use of PPI-2458, a selective non-reversible inhibitor of MetAP-2, in disease models of RA, namely acute and chronic collagen-induced arthritis (CIA) in mice. Whilst acute CIA is a monophasic disease, CIA induced with murine collagen type II manifests as a chronic relapsing arthritis and mimics more closely the disease course of RA. Our study showed PPI-2458 was able to reduce clinical signs of arthritis in both acute and chronic CIA models. This reduction in arthritis was paralleled by decreased joint inflammation and destruction. Detailed mechanism of action studies demonstrated that PPI-2458 inhibited human endothelial cell proliferation and angiogenesis in vitro, without affecting production of inflammatory cytokines. Furthermore, we also investigated release of inflammatory cytokines and chemokines from human RA synovial cell cultures, and observed no effect of PPI-2458 on spontaneous expression of cytokines and chemokines, or indeed on the angiogenic molecule vascular endothelial growth factor (VEGF). These results highlight MetAP-2 as a good candidate for therapeutic intervention in RA.
    Arthritis research & therapy 02/2007; 9(6):R127. · 4.27 Impact Factor
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    ABSTRACT: An important feature of autoimmune diseases is the overlap of pathophysiological characteristics. Clustering of autoimmune diseases in families suggests that genetic variants may contribute to autoimmunity. The aim of the present study was to investigate the role of the interferon induced with helicase domain 1 (IFIH1) A946T (rs1990760 A>G) variant in rheumatoid arthritis (RA), as this was recently associated with susceptibility to type 1 diabetes. A total of 965 Caucasians with RA and 988 healthy controls were genotyped for IFIH1 A946T. Gene expression of IFIH1 was measured in peripheral blood leukocytes using real-time PCR. Genotypes were equally distributed in both RA cases and healthy controls (odds ratio for allele C = 0.9, 95% confidence interval = 0.8-1.0, P = 0.3). No association was detected after stratification by sex, age at onset, rheumatoid factor status, anti-cyclic citrullinated peptide status or radiological joint damage. Levels of IFIH1 mRNA were approximately twofold higher in blood leucocytes of RA cases compared with healthy controls (P < 0.0001). These results indicate that the IFIH1 is upregulated in RA but that the A946T variant does not contribute significantly to the genetic background of RA.
    Arthritis research & therapy 02/2007; 9(2):R40. · 4.27 Impact Factor
  • Vascular Pharmacology - VASC PHARMACOL. 01/2006; 45(3).
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    ABSTRACT: Several recent publications have established a strong association between anti-cyclic citrullinated peptide antibody (anti-CCP)-positive rheumatoid arthritis (RA) and carriage of shared epitope (SE) alleles. Although anti-CCP have also been associated with more severe RA, the issue of whether this is independent of rheumatoid factor (RF) has not been addressed. To identify associations between RF, anti-CCP, SE status and radiological damage, we studied a large cross-sectional cohort with longstanding RA. Individuals (n = 872) enrolled in the study all fulfilled the American College of Rheumatology criteria for RA, had a minimum disease duration of 3 years, and at least one definite radiographic erosion was present in hands or feet. Radiographs were scored blind at study entry by a single musculoskeletal radiologist using a modified Larsen's score. Anti-CCP and RF levels were determined using enzyme-linked immunosorbent assay, and DRB1 typing was performed using polymerase chain reaction based methodology. Both anti-CCP and RF levels were strongly associated with radiographic severity (P < 0.0001). In subgroups stratified for both anti-CCP and RF status, evidence of independent associations of both antibodies with radiographic outcome was found (P < 0.0001). An association of SE alleles with radiographic severity was present only in RF-negative individuals. Anti-CCP positivity was associated with SE status with evidence of a gene-dose effect, most markedly in RF-negative individuals (P < 0.01). Anti-CCP and RF status are independent severity factors for RA, with SE alleles playing at most a secondary role. Our data support the view that previously described associations between SE and radiological severity, especially in RF-negative patients, may be indirect and due to an association with anti-CCP.
    Arthritis research & therapy 01/2006; 8(4):R128. · 4.27 Impact Factor
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    ABSTRACT: Objective: Selenoprotein-S (SELS) is involved in the stress response within the endoplasmic reticulum (ER) and inflammation. Recently, promoter variants in the SELS gene were shown to be associated with plasma levels of interleukin (IL)6, IL1β and tumour necrosis factor (TNF). It was hypothesised that these variants could influence rheumatoid arthritis (RA) susceptibility and may interact with functional single nucleotide polymorphisms (SNPs) in the genes for IL1, IL6 and TNF. Methods: Genotyping was performed in 988 unrelated healthy controls and 965 patients with RA. Stratified analysis was used to test for interactions. Single gene effects and evidence of epistasis were investigated using the Mantel–Haenszel (M–H) test and the linkage disequilibrium (LD)-based statistic. Results: No association of SELS −105 genotype and RA susceptibility was detected. Stratification of SELS −105 genotypes by IL1 −511 genotypes showed that the disease risk (comparing AA/GA to GG at the SELS −105 locus) in individuals with the GG/AG genotype at the IL1β −511 locus was significantly lower than that in individuals having the AA genotype at the IL1β −511 locus (odds ratio (OR): 0.9 and 2.3, respectively; p = 0.004 by M–H test). Significant epistasis was also detected using the LD-based statistic (p = <0.001). No interaction was observed between SELS −105 and IL6 or TNF variants. Conclusion: Our results reveal evidence of strong epistasis in two genes in the IL1 production pathway and highlight the potential importance of gene–gene interactions in the pathogenesis of RA.