Polymorphism at position -308 of the tumour necrosis factor   gene and rheumatoid arthritis pharmacogenetics

Abstract

W e present a case of recurrent auricular chondritis, which developed after two injections of a luteinising hormone-releasing hormone (LH-RH) analogue buserelin combined with oral treatment of a pure antiandrogen bicalutamide (Casodex). The patient was treated successfully with a continuous moderate dose of corticosteroids together with azathioprine and methotrexate. Complete repair of the deformed ear followed 7 months after starting the treatment.Relapsing polychondritis (RP) is a chronic autoimmune cartilaginous inflammation. Auricular chondritis is a presenting sign in over 85% of patients, in which patients' ears become red, swollen, and tender. We observed a painless form of recurrent auricular chondritis complicated by severe cartilage damage. CASE REPORTA 69 year old man had a history of old myocardial infarction and prostatic adenocarcinoma (Gleason score VI, stage T2B NO MO). He underwent two injections of an LH-RH analogue buserelin (Suprefact Depot, Aventis Pharma), combined with a pure antiandrogen bicalutamide (Casodex; AstraZeneca).Five months after starting treatment he presented with a painless redness and swelling of his right ear, which spared the lobe. This inflammation, showing inflammatory mononuclear infiltrate, progressed to include dropping and deformity of the upper part of the ear, and resolved spontaneously after 3 months (figs 1A and 2). The patient was then referred to the rheumatologist.Besides the dropped pinna, no systemic manifestations were found on physical examination and the patient's neurological status was unremarkable, including normal pain perception. Retinal screening showed no vasculitic changes. Routine laboratory investigation was normal except for raised inflammatory markers: erythrocyte sedimentation rate and C reactive protein. Serum immunoelectrophoresis, antinuclear antibodies, antineutrophil cytoplasmic antibodies, rheumatoid factor, prostate-specific antigen were normal. Viral serology, tuberculin test, and Venereal Disease research Laboratory test were negative. Ultrasound of large vessels and echocardiography were normal. A chest x ray examination and computed tomography (CT), abdominal CT, and bone scan were unremarkable.Owing to serious coronary disease, the lack of active auricular inflammation and systemic disease, and because buserelin treatment had been stopped, it was decided to observe the patient without treatment. However, painless auricular chondritis of the opposite side occurred 3 months later, supporting an initial suspicion of relapsing polychondritis. Prednisone 40 mg/day and azathioprine 100 mg/day were given. Corticosteroids were tapered to 20 mg/day for 1 month after reduction of inflammation in the opposite ear. Azathioprine treatment was stopped when the liver enzyme level was significantly raised after 2 months of treatment. A daily dose of prednisone 20 mg/day was continued, and oral methotrexate 7.5 mg/week was started after the liver function returned to normal. Partial repair of the auricular cartilage was noted 2 months later and f...

Genome-Wide Association Scan Identifies Candidate Polymorphisms Associated with Differential Response to Anti-TNF Treatment in Rheumatoid Arthritis

“…All of the 17 studies focused on polymorphisms in genes known to be involved in RA pathogenesis, genes encoding TNF-α receptors, or genes implicated in TNF-α metabolism. Several groups reported that a single nucleotide polymorphism (SNP), -308G > A, in the promoter of TNFA is associated significantly with the outcome to anti-TNF treatment (5,(8)(9)(10)(11)(12)(13)(14). This positive association also is supported by a meta-analysis that was performed using 311 patients combined from several studies (13).…”

TNF-α −308 G/A polymorphism and responsiveness to TNF-α blockade therapy in moderate to severe rheumatoid arthritis: a systematic review and meta-analysis

“…Three TNF-a inhibitors were included in the meta-analysis: adalimumab, etanercept and infliximab. Although the raw data was not available in one study, 11 counts were derived from Figure 1 of the metaanalysis carried out by Lee et al…”

“…Visual inspection of the forest plot ( Figure 3) revealed that the difference estimates from two studies (11,14) had much smaller standard errors than the other four studies. We contacted the authors of these two studies, who reconfirmed their data.…”

“…7 At present, there are a handful of small studies that have set out to examine whether the G to A polymorphism at position À308 in the promoter of the TNFa gene influences clinical response to TNF blockade in patients with moderate-to-severe RA. [8][9][10][11][12][13][14][15][16] Owing to the relatively small number of patients exposed to anti-TNF-a agents in all of the pharmacogenetic studies in RA to date, each individual study had insufficient power to conclusively determine if the À308 variant of the TNF-a gene would be helpful in predicting patients that respond poorly to TNF-a blockade. Lee et al 17 carried out a metaanalysis investigating the association of TNF-a À308 G/A polymorphism with responsiveness to TNF-a-blockers in RA.…”

Influence of promoter region of TNF-α gene polymorphisms on anti-TNF treatment in rheumatoid arthritis: Preliminary report

“…Several studies suggested that promotor polymorphisms of TNF gene could predict the variations in TNF-α production and hence have an impact on severity of RA and response of the treatment [12][13][14].…”