5 research outputs found
Genetics of Behçet's disease
No full textPURPOSE OF REVIEW: This article discusses recent genetic and epigenetic associations involved in the pathogenesis of Behçet's disease.RECENT FINDINGS: Genetic studies have supported the strong association of human leukocyte antigen-B and Behçet's disease, and high production of tumour necrosis factor and low production of interleukin (IL)-10, which have led to therapy based on controlling these effects. Polymorphisms that affect the response to pathogens (TLR and FUT2) are leading to increased interest in responses to microbiomes. Inflammation in Behçet's disease results in vascular damage and several single nucleotide polymorphisms in chemokine and adhesion molecules may be involved in this process. Increased levels of inflammatory cytokines including IL-1β and IL-17 have been linked to altered expression of microRNAs, miR155, miR21 and miR23b. DNA methylation changes in monocytes and lymphocytes have been described that affect the function of these cells.SUMMARY: Genetic and epigenetic changes affecting cells and molecules involved in Behçet's disease offer new pathways for research, including cytoskeletal protein function, that will provide new targets for therapy, and potentially address the ethnic differences seen in validation of gene studies.</p
Analysis of Fcγ receptor haplotypes in rheumatoid arthritis: FCGR3A remains a major susceptibility gene at this locus, with an additional contribution from FCGR3B
No full textThe Fcγ receptors play important roles in the initiation and regulation of many immunological and inflammatory processes, and genetic variants (FCGR) have been associated with numerous autoimmune and infectious diseases. The data in rheumatoid arthritis (RA) are conflicting and we previously demonstrated an association between FCGR3A and RA. In view of the close molecular proximity with FCGR2A, FCGR2B and FCGR3B, additional polymorphisms within these genes and FCGR haplotypes were examined to refine the extent of association with RA. Biallelic polymorphisms in FCGR2A, FCGR2B and FCGR3B were examined for association with RA in two well characterized UK Caucasian and North Indian/Pakistani cohorts, in which FCGR3A genotyping had previously been undertaken. Haplotype frequencies and linkage disequilibrium were estimated across the FCGR locus and a model-free analysis was performed to determine association with RA. This was followed by regression analysis, allowing for phase uncertainty, to identify the particular haplotype(s) that influences disease risk. Our results reveal that FCGR2A, FCGR2B and FCGR3B were not associated with RA. The haplotype with the strongest association with RA susceptibility was the FCGR3A–FCGR3B 158V-NA2 haplotype (odds ratio 3.18, 95% confidence interval 1.13–8.92 [P = 0.03] for homozygotes compared with all genotypes). The association was stronger in the presence of nodules (odds ratio 5.03, 95% confidence interval 1.44–17.56; P = 0.01). This haplotype was also more common in North Indian/Pakistani RA patients than in control individuals, but not significantly so. Logistic regression analyses suggested that FCGR3A remained the most significant gene at this locus. The increased association with an FCGR3A–FCGR3B haplotype suggests that other polymorphic variants within FCGR3A or FCGR3B, or in linkage disequilibrium with this haplotype, may additionally contribute to disease pathogenesis
Infliximab versus alpha interferon in the treatment of Behçet's disease: the BIO BEHÇET'S RCT
No full textBackground
While biologic therapy, typically with infliximab or Roferon, was used for Behçet syndrome after first-line immunosuppressants, no high-quality randomised trials or predictive biomarkers were available.
Objective
To undertake a randomised controlled clinical trial of infliximab versus Roferon in Behçet syndrome and identify potential biomarkers for response.
Design
Pragmatic, standard of care, single-masked, randomised, two-arm, parallel head-to-head trial, with exploratory study on potential role of interferon lambda 3 and interferon lambda 4 single nucleotide polymorphisms and urinary metabolomics biomarkers.
Setting
Three national UK Behçet syndrome centres and allied clinics.
Participants
Patients with active Behçet syndrome, fulfilling International Study Group 1990 criteria, with inadequate response to or intolerance of first-line treatment.
Intervention
Randomisation to infliximab (5 mg/kg intravenous infusion) or Roferon (subcutaneous injection), utilising the UK Behçet syndrome drug pathway protocol.
Outcomes
Primary outcome: modified Behçet’s disease activity index at 12 weeks of therapy. Secondary outcomes: (1) modified Behçet’s disease activity index score at 24 weeks and (2) significant improvement at 12 and 24 weeks from baseline in vitreous haze and best corrected visual acuity change, oral ulcer severity score, number of genital ulcers, arthritis pain, adverse events, reduction in dose of glucocorticoid, quality-of-life scores and Physician’s Global Assessment of disease activity.
Sample size
Utilising a Bayesian analysis of covariance model (80% credible interval), initial sample size was 45/arm (Bayesian power 90%). With an anticipated 10% dropout rate, 100 patients were to be recruited. Following recommendations to reduce the overall length of the trial, this was revised down to 80 patients (36 in each arm, allowing for 10% dropout): 80% equi-tailed credibility interval, Bayesian power 88%. In total, 79 patients were eventually recruited for the study.
Methods
Patients with refractory active Behçet syndrome underwent stratified block randomisation, based on randomly permuted blocks with random block sizes of two and four, allocating treatment to either infliximab or Roferon. Follow up with symptom-directed examination at weeks 12 and 24 according to standard of care. Analysis of the primary end point was undertaken using a Bayesian analysis of covariance approach. Informative priors for the anticipated treatment effect were derived from a cohort of six international experts prior to the start of the study.
Results
In this first prospective head-to-head randomised controlled clinical trial of two biologic drugs in Behçet syndrome, both infliximab and Roferon were equally effective [mean difference (80% credibility interval) = 0.13 (–0.19 to 0.46)], with a trend for minor benefit in favour of infliximab in terms of tolerability and treatment persistence. Genetic data suggested a potential association between patient outcome and carriage of either rs4803221 or rs7248668 variants in the interferon lambda 3 (interleukin 28B) gene locus in the Roferon-treated arm. However, with the relatively small sample size, statistical significance of the association was lost when correcting for multiple tests. Metabolomic analysis identified potential markers of a metabolic response to treatment with infliximab.
Limitations
Single-masked design. Slow recruitment with fewer patients recruited in total, limiting the strength of analysis for secondary outcomes and mechanistic studies.
Conclusion
We report clinical efficacy in both infliximab and Roferon in refractory active Behçet syndrome, together with the potential for a novel metabolomic biomarker identifying response to infliximab.
Future work
Further work will characterise the appropriate metabolite(s) from existing samples to inform future prospective trials to study this in more detail clinically. The efficacy of Roferon in Behçet syndrome may support future manufacture of this drug.
Trial registration
This trial is registered as EudraCT Number: 2014-005390-36; ISRCTN49793874.
Funding
This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 12/205/46) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 17. See the NIHR Funding and Awards website for further award information
Predicting response to infliximab and interferon-α in Behçet’s syndrome:An exploratory analysis from the BIO-BEHÇET’S randomized controlled trial
No full textBackground and Objectives: Biologic therapy has been used for Behçet’s Syndrome after first-line immunomodulation, but in the absence of high-quality evidence or predictive biomarkers. BIO-BEHÇET’S was a randomized controlled clinical trial to compare the two most widely used biologics for Behçet’s Syndrome at that time, infliximab versus interferon-α2a, and identify potential biomarkers for response. Methods: A total of 79 patients with active Behçet’s Syndrome were randomized to either infliximab (REMICADE) or interferon-α2a (ROFERON) according to the UK national treatment pathway, and follow-up with symptom-directed examination undertaken at Weeks 12 and 24. The head-to-head trial included an exploratory analysis on the potential role of single nucleotide polymorphisms (SNPs) and urinary metabolomic to act as biomarkers for drug response. Genotypic analysis was performed to determine whether four SNPs in IFNL3 and IFNL4 – selected based on known effects – impacted primary and secondary outcomes. For metabolomic analyses, urine samples were analyzed by nuclear magnetic resonance spectroscopy and principal component analysis. Results: Genetic data suggested potential association between outcomes and carriage of rs4803221 or rs7248668 variants in the IFNL3 (IL-28B) gene locus for interferon-α2a patients; however, with the relatively small sample, statistical significance was lost when corrected for multiple testing. Metabolomic analysis identified potential markers of metabolic response to infliximab. Conclusion: BIO-BEHÇET’S suggests there is potential for a novel metabolomic biomarker that can identify response to infliximab in patients with Behçet’s Syndrome. Further work will characterize the appropriate metabolite (s) from existing samples to inform future prospective trials to study this in more detail clinically
The BILAG multi-centre open randomized controlled trial comparing ciclosporin vs azathioprine in patients with severe SLE.
No full textObjective. To determine whether low-dose ciclosporin was a more effective corticosteroid-sparing agent than AZA in patients with SLE. Methods. Patients with SLE requiring a change or initiation of a corticosteroid-sparing agent and who were taking >/=15 mg of prednisolone/day were randomized to receive either ciclosporin or AZA during this 12-month open-label multi-centre trial. There were strict guidelines for the reduction of prednisolone. The primary outcome was the absolute mean change in prednisolone. Results. Eighty-nine patients were randomized. Using an intention-to-treat analysis, the absolute mean change in prednisolone dose between baseline and 12 months, adjusted for baseline prednisolone dose, was 9.0 mg for ciclosporin (95% CI 7.2, 10.8) and 10.7 mg for AZA (95% CI 8.8, 12.7). The difference in the change between treatment groups was -1.7 mg (95% CI -4.4, 0.9; P = 0.2). No significant differences were detected for the secondary outcomes: change in disease activity [classic British Isles Lupus Assessment Group (BILAG) index], number of flares, development of new damage or change in quality of life. A similar number of patients in each arm stopped the study drugs due to adverse events and ineffectiveness. No patient developed severe hypertension or a persistent rise in creatinine. One patient in the ciclosporin arm developed a significant increase in proteinuria due to disease activity. Conclusions. Both drugs were effective corticosteroid-sparing agents. Ciclosporin was not a more effective corticosteroid-sparing agent. Ciclosporin may be considered in patients who are unable to tolerate AZA. Patients on ciclosporin require close monitoring of blood pressure and creatinine. Trial registration. Current Controlled Trials, http://www.controlled-trials.com/, ISRCTN35919612
