TNFi-treated Patients Research Articles

Effect of Tumor Necrosis Factor Inhibitor Therapy on Osteoclasts Precursors in Ankylosing Spondylitis.

IntroductionAnkylosing Spondylitis (AS) is characterized by excessive local bone formation and concomitant systemic bone loss. Tumor necrosis factor (TNF) plays a central role in the inflammation of axial skeleton and enthesis of AS patients. Despite reduction of inflammation and systemic bone loss, AS patients treated with TNF inhibitors (TNFi) have ongoing local bone formation. The aim of this study was to assess the effect of TNFi in the differentiation and activity of osteoclasts (OC) in AS patients.Methods13 AS patients treated with TNFi were analyzed at baseline and after a minimum follow-up period of 6 months. 25 healthy donors were recruited as controls. Blood samples were collected to assess receptor activator of nuclear factor kappa-B ligand (RANKL) surface expression on circulating leukocytes and frequency and phenotype of monocyte subpopulations. Quantification of serum levels of bone turnover markers and cytokines, in vitro OC differentiation assay and qRT-PCR for OC specific genes were performed.ResultsRANKL+ circulating lymphocytes (B and T cells) and IL-17A, IL-23 and TGF-β levels were decreased after TNFi treatment. We found no differences in the frequency of the different monocyte subpopulations, however, we found decreased expression of CCR2 and increased expression of CD62L after TNFi treatment. OC number was reduced in patients at baseline when compared to controls. OC specific gene expression was reduced in circulating OC precursors after TNFi treatment. However, when cultured in OC differentiating conditions, OC precursors from AS TNFi-treated patients showed increased activity as compared to baseline.ConclusionIn AS patients, TNFi treatment reduces systemic pro osteoclastogenic stimuli. However, OC precursors from AS patients exposed to TNFi therapy have increased in vitro activity in response to osteoclastogenic stimuli.

Impact of tobacco smoking on response to tumour necrosis factor-alpha inhibitor treatment in patients with ankylosing spondylitis: results from the Danish nationwide DANBIO registry.

To investigate the association between tobacco smoking and disease activity, treatment adherence and treatment responses in patients with AS treated with their first tumour necrosis factor-alpha inhibitor (TNFi) therapy in routine care. Observational cohort study based on the Danish nationwide DANBIO registry. Kaplan-Meier plots, Cox and logistic regression analyses by smoking status (current/never/previous) were calculated for treatment adherence and BASDAI 50%/20 mm-response. Additional stratified analyses were performed for gender and TNFi-type. Of 1576 AS patients included in the study, 1425(90%) had known smoking status (current/never/previous: 43%/41%/16%). The median follow-up time was 2.02 years (IQR 0.69-5.01). At baseline, current smokers compared with never smokers had longer disease duration (4 years (1-12)/2 years (0-10)), higher BASDAI (61 mm (47-73)/58 mm (44-70)), BASFI (53 mm (35-69)/46 mm (31-66)) and BASMI (40 mm (20-60)/30 mm (10-50)) scores (all P < 0.01). Current and previous smokers had shorter treatment adherence than never smokers (current: 2.30 years (1.81-2.79) (median (95% CI)); previous: 2.48 years (1.56-3.40), never: 4.12 years (3.29-4.95)), P < 0.0001). Similar results were found in multivariate analyses (current versus never smokers, HR 1.41 (95% CI 1.21-1.65), P < 0.001), most pronounced among men. Current smokers had poorer 6 months' BASDAI50%/20 mm-response rate than never smokers (42%/58%, P < 0.001). In multivariate analyses, current smokers had lower odds of achieving BASDAI50%/20 mm-response than never smokers, both overall (OR 0.48 (95% CI 0.35-0.65), P < 0.0001) and for the different TNFi-types (adalimumab 0.45 (0.27-0.76)/etanercept 0.24 (0.10-0.61)/infliximab 0.57 (0.34-0.95)). In this study of TNFi-treated AS patients in clinical practice, current and previous smokers had significantly poorer patient-reported outcomes at baseline, shorter treatment adherence and poorer treatment response compared with never smokers.

Malignancy risk in Australian rheumatoid arthritis patients treated with anti-tumour necrosis factor therapy: analysis of the Australian Rheumatology Association Database (ARAD) prospective cohort study.

BackgroundMalignancy risk with tumour necrosis factor inhibitor (TNFi) therapy remains unclear. Our primary aim was to assess malignancy risk with TNFi therapy in a cohort of Australian patients with rheumatoid arthritis (RA). We also assessed risk in a biologic-naïve group.MethodsDemographic data of all RA patients enrolled in the Australian Rheumatology Association Database before 25 October 2010 were matched to national cancer records in July 2010 (linkage complete to 2007). Verified self-reported malignancies occurring between 1 January 2008 and 25 October 2010 were also included in the analysis. Standardised incidence ratios (SIRs) were used to compare malignancy incidence in biologic-naïve and TNFi-exposed ARAD participants to the general population using site-, age- and sex-specific rates by calendar year. Rate ratios (RRs) were used to compare malignancy incidence in TNFi-exposed participants to biologic-naïve RA patients, and a composite RA cohort that included pre-TNFi person years, both adjusted for age, gender, smoking, methotrexate use and prior malignancy.ResultsForty-four malignancies were reported after 5752 person-years in the TNFi-exposed group (N = 2145) and 32 malignancies were reported after 1682 person-years in the biologic-naïve group (N = 803). No overall increased risk of malignancy in TNFi-treated RA patients was found when compared with the general population or with biologic-naïve RA patients. Compared to the biologic naïve group, without the inclusion of pre-TNFi years in the comparator group, the relative risk of female breast cancer was reduced in TNFi-treated patients (RR 0.17 (95 % CI 0.03 to 0.95)). It was no longer significant when adding pre-TNFi years in the comparator group. The risk of melanoma was increased for both biologic naïve and TNFi-treated patients when compared with the general population (SIR 2.72 (95 % CI 1.13 to 6.53) and SIR 2.03 (95 % CI 1.09 to 3.78) respectively). The relative risk of melanoma was not increased in the TNFi-exposed group compared with biologic naïve patients (RR 0.54, 95 % CI 0.12, 2.40). Inclusion of pre-TNFi person years in the comparator group did not change these results.ConclusionsMalignancy incidence was low in this RA cohort and biologic exposure did not increase the risk of malignancy. Melanoma risk was increased in both TNFi-treated and biologic-naïve RA patients compared with the general population suggesting that RA status, and possibly methotrexate exposure, may be responsible.

Estimation of heritability of different outcomes for genetic studies of TNFi response in patients with rheumatoid arthritis

ObjectivesPharmacogenetic studies of tumour necrosis factor inhibitors (TNFi) response in patients with rheumatoid arthritis (RA) have largely relied on the changes in complex disease scores, such as disease activity score...

TNF inhibitor therapy and risk of breast cancer recurrence in patients with rheumatoid arthritis: a nationwide cohort study

ObjectiveTo investigate the risk of breast cancer recurrence in rheumatoid arthritis (RA)—patients with tumour necrosis factor inhibitor (TNFi) treatment and a history of breast cancer, taking several breast cancer, comorbidity...

FRI0277 Predicting Future Response to Tumor Necrosis Factor Inhibitors by the Distribution of Affected Joints in Rheumatoid Arthritis Patients

BackgroundAchieving remission is essential for avoiding joint destruction and disability in patients with rheumatoid arthritis (RA). Tumor necrosis factor inhibitors (TNFi) therapies represent an important advancement in therapy for RA....

Lack of validation of genetic variants associated with anti–tumor necrosis factor therapy response in rheumatoid arthritis: a genome-wide association study replication and meta-analysis

IntroductionIn this study, our aim was to elucidate the role of four polymorphisms identified in a prior large genome-wide association study (GWAS) in which the investigators analyzed the responses of patients with rheumatoid arthritis (RA) to treatment with tumor necrosis factor inhibitors (TNFi). The authors of that study reported that the four genetic variants were significantly associated. However, none of the associations reached GWAS significance, and two subsequent studies failed to replicate these associations.MethodsThe four polymorphisms (rs12081765, rs1532269, rs17301249 and rs7305646) were genotyped in a total of 634 TNFi-treated RA patients of Spanish Caucasian origin. Four outcomes were evaluated: changes in the Disease Activity Score in 28 joints (DAS28) after 6 and 12 months of treatment and classification according to the European League Against Rheumatism (EULAR) response criteria at the same time points. Association with DAS28 changes was assessed by linear regression using an additive genetic model. Contingency tables of genotype and allele frequencies between EULAR responder and nonresponder patients were compared. In addition, we combined our data with those of previously reported studies in a meta-analysis including 2,998 RA patients.ResultsNone of the four genetic variants showed an association with response to TNFi in any of the four outcomes analyzed in our Spanish patients. In addition, only rs1532269 yielded a suggestive association (P = 0.0033) with the response to TNFi when available data from previous studies were combined in the meta-analysis.ConclusionOur data suggest that the rs12081765, rs1532269, rs17301249 and rs7305646 genetic variants do not have a role as genetic predictors of TNFi treatment outcomes.