A genome-wide association study identifies a new locus associated with the response to anti-TNF therapy in rheumatoid arthritis.

Anti-Tumor Necrosis Factor (anti-TNF) drugs are biologic agents commonly used to treat rheumatoid arthritis (RA). However, anti-TNFs are not effective in approximately one out of four treated patients. We conducted a Genome-Wide Association Study (GWAS) to identify the genetic variation associated with the response to anti-TNF therapy in RA. In the discovery stage, 372 RA patients treated with an anti-TNF agent (infliximab, adalimumab or etanercept) were analyzed and treatment response was defined at 12 weeks of therapy. We found a genome-wide significant association in the MED15 gene with the response to etanercept (P<1.5e-8). Using an independent cohort of 245 RA patients, we performed a replication study of the most significant GWAS associations. We replicated the association at the MED15 locus and found suggestive evidence of association in the previously associated MAFB locus. The results of this study suggest novel mechanisms associated with the response to anti-TNF therapies.

IL-6 blockade reverses the abnormal STAT activation of peripheral blood leukocytes from rheumatoid arthritis patients.

Considering the interplay of multiple STATs in response to cytokines, we investigated how IL-6 and its blocking affect STAT signaling in rheumatoid arthritis (RA). Leukocytes obtained from RA patients before and after tocilizumab treatment and healthy donors (HDs) were cytokine-stimulated and STAT phosphorylation was analyzed by cytometry. RA patients had significantly fewer pSTAT1+, pSTAT3+, and pSTAT6+ monocytes and pSTAT5+ lymphocytes than HDs. After 24weeks of treatment, percentages of IFNγ-induced pSTAT1+ and IL-10-induced pSTAT3+ monocytes in RA patients increased, reaching levels comparable to HDs. pSTAT1+ and pSTAT3+ cells correlated inversely with RA disease activity index and levels of pSTAT+ cells at baseline were higher in patients with good EULAR response to tocilizumab. IFNγ-induced pSTAT1+ cells correlated inversely with memory T cells and anti-CCP levels. IL-10-induced pSTAT3+ cells correlated with Treg/Teff ratio. Our findings suggest that IL-6 blocking reduces the inflammatory mechanisms through the correction of STAT1 and STAT3 activation status.

Is thiopurine methyltransferase genetic polymorphism a major factor for withdrawal of azathioprine in rheumatoid arthritis patients?

OBJECTIVE: To determine whether the presence of thiopurine methyltransferase (TPMT) alleles associated with reduced or absent activity of thiopurine methyltransferase is a major factor for withdrawal of azathioprine (AZA) in rheumatoid arthritis (RA) patients. METHODS: The TPMT genotype, including the variable number of tandem repeats (VNTR) pattern in the 5' untranslated region, was analysed in 111 patients with long-standing RA. Azathioprine (AZA) therapy was used in 40 patients (36%) as a disease-modifying anti-rheumatic drug. RESULTS: Seven out of 111 RA patients (6.3%) were carriers of a mutant allele, TPMT3A (G(460)-->A, A(719)-->G) being the mutant allele observed most frequently. In the group of 40 AZA-treated patients, therapy was discontinued in six patients because of side-effects and in 26 patients because of lack of efficacy. Three patients presented moderate side-effects and were homozygous for the wild-type TPMT allele, whereas the remaining three patients, who developed gastrointestinal effects with severe nausea and vomiting, were TPMT3A carriers. CONCLUSION: In this observational study, the absence of response, probably due to the low-dose scheme used, was the major cause of AZA withdrawal in our series of RA patients. TPMT genotyping may allow the use of high doses of AZA in patients with normal TPMT alleles to improve the efficacy of this immunosuppressive drug. Our data support the relationship between gastrointestinal intolerance and thiopurine metabolic imbalance.

Group B Streptococcal sacroiliitis: case report and review.

Streptococcus agalactiae, or group B Streptococcus (GBS), is the major cause of neonatal meningitis and sepsis but is an uncommon infection in adults. GBS arthritis is rare, and axial involvement with sacroiliitis is even more uncommon. Microbiological diagnosis frequently relies upon positive blood cultures as synovial fluid cultures are usually negative. Severe joint damage may result due to delay in the initiation of antibiotic treatment.

[Aplasia after azathioprine administration: role of the thiopurine methyltransferase genetic polymorphism]. / Aplasia medular tras administración de azatioprina: papel de polimorfismo genético de la tiopurina metiltransferasa.

BACKGROUND: Azathioprine is an immunosuppressor drug widely used in the treatment of autoimmune diseases. Adverse effects during treatment are related to the activity of thiopurine methyltransferase (TPMT), an enzyme which plays a role in azathioprine metabolism. The presence of the allelic variants of the TPMT gene allows us to classify patients into three different groups: high, moderate and low risk of myelosuppression after receiving standard doses of azathioprine. PATIENTS AND METHODS: Study of the allelic variants of the TPMT gene in the positions 460 and 719 with PCR methods in a patient with Crohn's disease, who developed aplasia after receiving azathioprine. The study was extended to his relatives. RESULTS: The patient under study carried the most frequent variant allele of the TPMT gene associated with low enzymatic activity. The mother and one sister of the patient were also carriers of this allelic variant. CONCLUSIONS: Genotyping the allelic variants of the TPMT gene is a useful method to identify patients at moderate or high risk of myelosuppression after administration of azathioprine.

Allelic variants of the thiopurine S-methyltransferase deficiency in patients with ulcerative colitis and in healthy controls.

OBJECTIVE: Thiopurine S-methyltransferase (TPMT) is a cytosolic enzyme that catalyzes the inactivation of mercaptopurine, azathioprine, and thioguanine. The genetic polymorphisms in the TPMT gene that regulate TPMT activity are inherited as an autosomal recessive trait and patients with genetically determined low levels of TPMT activity develop severe myelosuppression when treated with standard doses of the above-mentioned drugs. We have analyzed the frequencies of the allelic variants of the TPMT gene in a white European population of healthy blood donors from Spain and The Netherlands, and in a group of patients suffering from ulcerative colitis (UC) with a similar genetic background. METHODS: Two hundred and thirteen unrelated healthy individuals (HC) and 146 UC patients were typed for the polymorphic sites at positions 460 (G-->A) and 719 (A-->G) of the TPMT gene using specific polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) methods. RESULTS: There were no significant differences between the allele frequencies observed in the group of UC patients and those of the control group (10% of cases were heterozygous carriers of a TPMT mutant allele). The most frequent mutant allele in both UC and HC groups was TPMT3A (A460-->G719) (60% of carriers). TPMT3B (A460-->A719) and TPMT3C (G460-->G719) alleles were more often found in our study than in previously reported studies, reflecting the different genetic backgrounds of the European populations analyzed. CONCLUSIONS: Genotyping methods provide a simple and reliable screening to identify patients with a high risk of developing severe bone marrow toxicity if treated with thiopurine drugs. In UC patients, TPMT genotype should be determined before the initiation of azathioprine therapy.