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ObjectiveTo investigate whether antidrug antibodies and/or drug non‐trough levels predict the long‐term treatment response in a large cohort of patients with rheumatoid arthritis (RA) treated with adalimumab or etanercept and to identify factors influencing antidrug antibody and drug levels to optimize future treatment decisions.MethodsA total of 331 patients from an observational prospective cohort were selected (160 patients treated with adalimumab and 171 treated with etanercept). Antidrug antibody levels were measured by radioimmunoassay, and drug levels were measured by enzyme‐linked immunosorbent assay in 835 serial serum samples obtained 3, 6, and 12 months after initiation of therapy. The association between antidrug antibodies and drug non‐trough levels and the treatment response (change in the Disease Activity Score in 28 joints) was evaluated.ResultsAmong patients who completed 12 months of followup, antidrug antibodies were detected in 24.8% of those receiving adalimumab (31 of 125) and in none of those receiving etanercept. At 3 months, antidrug antibody formation and low adalimumab levels were significant predictors of no response according to the European League Against Rheumatism (EULAR) criteria at 12 months (area under the receiver operating characteristic curve 0.71 [95% confidence interval (95% CI) 0.57, 0.85]). Antidrug antibody–positive patients received lower median dosages of methotrexate compared with antidrug antibody–negative patients (15 mg/week versus 20 mg/week; P = 0.01) and had a longer disease duration (14.0 versus 7.7 years; P = 0.03). The adalimumab level was the best predictor of change in the DAS28 at 12 months, after adjustment for confounders (regression coefficient 0.060 [95% CI 0.015, 0.10], P = 0.009). Etanercept levels were associated with the EULAR response at 12 months (regression coefficient 0.088 [95% CI 0.019, 0.16], P = 0.012); however, this difference was not significant after adjustment. A body mass index of ≥30 kg/m2 and poor adherence were associated with lower drug levels.ConclusionPharmacologic testing in anti–tumor necrosis factor–treated patients is clinically useful even in the absence of trough levels. At 3 months, antidrug antibodies and low adalimumab levels are significant predictors of no response according to the EULAR criteria at 12 months.

Rheumatoid arthritis (RA) is a chronic inflammatory disease preferentially affecting the joints and leading, if untreated, to progressive joint damage and disability. Cytokines, a group of small inducible proteins, which act as intercellular messengers, are key regulators of the inflammation that characterizes RA. They can be classified into pro-inflammatory and anti-inflammatory groups. Numerous cytokines have been implicated in the regulation of RA with complex up and down regulatory interactions. This paper considers a two-variable model for the interactions between pro-inflammatory and anti-inflammatory cytokines, and demonstrates that mathematical modelling may be used to investigate the involvement of cytokines in the disease process. The model displays a range of possible behaviours, such as bistability and oscillations, which are strongly reminiscent of the behaviour of RA e.g. genetic susceptibility and remitting-relapsing disease. We also show that the dose regimen as well as the dose level are important factors in RA treatments.

The association of celiac disease with fracture is controversial. Recent studies may have underestimated the impact by studying patients with low fracture risk. Since postmenopausal women are at greatest risk of fracture, we have investigated non-spine fracture occurrence in women > or =50 years with celiac disease. Patients were recruited from hospital and general practice as well as from volunteers, controls from general practice. All completed a questionnaire detailing fracture occurrence. Three hundred and eighty-three female celiac patients and 445 female controls aged > or =50 years at time of study were compared. Mean age was 61.4+/-7.8 years in celiac patients and 62.7+/-9.9 years in controls. Celiac patients were lighter but not shorter. Celiac patients displayed greater "all fracture" prevalence (odds ratio [OR], 1.51; confidence interval [CI], 1.13:2.02) and fracture after 50 years (OR, 2.20; CI, 1.49:3.25). Wrist fracture was more frequent (OR, 1.65; CI, 1.12:2.41), but significance was lost once height and weight were taken into account. Celiac patients had more multiple fractures (OR, 2.96; CI, 1.81:4.83). To investigate the association of fracture with time from diagnosis, 324 celiac patients were paired with a control by age. No excess fracture risk was found more than 10 years before diagnosis amongst celiac patients diagnosed after age 50 years, but risk increased in the period from 10 years before diagnosis to 5 years after and remained high more than 5 years after diagnosis ( p<0.05). Wrist fracture only increased in the period more than 5 years after diagnosis ( p<0.05). In women diagnosed before 50 years, no excess fracture risk existed. Fracture risk in female celiac patients >50 years is increased overall but is related largely to the peri-diagnostic period. Wrist fracture risk is partly accounted for by height and weight, but is more common more than 5 years after diagnosis. Celiac testing may be indicated in thin women over 50 years with multiple fractures, and after diagnosis adequate calcium and vitamin D intake should be ensured.

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