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.

IntroductionPain remains the most important problem for people with rheumatoid arthritis (RA). Active inflammatory disease contributes to pain, but pain due to non-inflammatory mechanisms can confound the assessment of disease activity. We hypothesize that augmented pain processing, fibromyalgic features, poorer mental health, and patient-reported 28-joint disease activity score (DAS28) components are associated in RA.MethodsIn total, 50 people with stable, long-standing RA recruited from a rheumatology outpatient clinic were assessed for pain-pressure thresholds (PPTs) at three separate sites (knee, tibia, and sternum), DAS28, fibromyalgia, and mental health status. Multivariable analysis was performed to assess the association between PPT and DAS28 components, DAS28-P (the proportion of DAS28 derived from the patient-reported components of visual analogue score and tender joint count), or fibromyalgia status.ResultsMore-sensitive PPTs at sites over or distant from joints were each associated with greater reported pain, higher patient-reported DAS28 components, and poorer mental health. A high proportion of participants (48%) satisfied classification criteria for fibromyalgia, and fibromyalgia classification or characteristics were each associated with more sensitive PPTs, higher patient-reported DAS28 components, and poorer mental health.ConclusionsWidespread sensitivity to pressure-induced pain, a high prevalence of fibromyalgic features, higher patient-reported DAS28 components, and poorer mental health are all linked in established RA. The increased sensitivity at nonjoint sites (sternum and anterior tibia), as well as over joints, indicates that central mechanisms may contribute to pain sensitivity in RA. The contribution of patient-reported components to high DAS28 should inform decisions on disease-modifying or pain-management approaches in the treatment of RA when inflammation may be well controlled.

The prevalence of rheumatoid arthritis was studied in the adult Indian population. As the first step, a house-to-house survey of a rural population near Delhi was conducted by two trained health workers. The target population comprised 44,551 adults (over 16 years old). The health workers identified the possible cases of rheumatoid arthritis (RA) using a questionnaire. These cases were then further evaluated by the authors using the 1987 revised ARA criteria for the diagnosis of RA. A response rate of 89.5% was obtained and 3393 persons were listed as possible cases of RA by the health workers. Of these, 299 satisfied the revised ARA criteria for the diagnosis of RA, giving a prevalence of 0.75%. Projected to the whole population, this would give a total of about seven million patients in India. The prevalence of RA in India is quite similar to that reported from the developed countries. It is higher than that reported from China, Indonesia, Philippines and rural Africa. These findings are in keeping with the fact that the north Indian population is genetically closer to the Caucasians than to other ethnic groups.

Background: Osteoporotic hip fractures have been extensively studied in women, but they have been relatively ignored in men. Objective: To study the mortality, morbidity, and impact on health related quality of life of male hip fractures. Methods: 100 consecutive men aged 50 years and over, with incident low trauma hip fracture, admitted to Royal Cornwall Hospital, UK during 1995-97, were studied. 100 controls were recruited from a nearby general practice. Mortality and morbidity, including health status assessed using the SF-36, were evaluated over a 2 year follow up period. Results: Survival after 2 years was 37% in fracture cases compared with 88% in controls (log rank test 62.6, df = 1, p = 0.0001). In the first year 45 patients died but only one control. By 2 years 58 patients but only 8 controls had died. Patients with hip fracture died from various causes, the most common being bronchopneumonia (21 cases), heart failure (9 cases), and ischaemic heart disease (8 cases). Factors associated with increased mortality after hip fracture included older age, residence before fracture in a nursing or residential home, presence of comorbid diseases, and poor functional activity before fracture. Patients with fracture were often disabled with poor quality of life. By 24 months 7 patients could not walk, 12 required residential accommodation, and the mean SF-36 physical summary score was 1.7SD below the normal standards. Conclusions: Low trauma hip fracture in men is associated with a significant increase in mortality and morbidity. Impaired function before fracture is a key determinant of mortality after fracture.

Covalent protein modifications by electrophilic acyl glucuronide (AG) metabolites are hypothetical causes of hypersensitivity reactions associated with certain carboxylate drugs. The complex rearrangements and reactivities of drug AG have been defined in great detail, and protein adducts of carboxylate drugs, such as diclofenac, have been found in liver and plasma of experimental animals and humans. However, in the absence of definitive molecular characterization, and specifically, identification of signature glycation conjugates retaining the glucuronyl and carboxyl residues, it cannot be assumed any of these adducts is derived uniquely or even fractionally from AG metabolites. We have therefore undertaken targeted mass spectrometric analyses of human serum albumin (HSA) isolated from diclofenac patients to characterize drug-derived structures and, thereby, for the first time, have deconstructed conclusively the pathways of adduct formation from a drug AG and its isomeric rearrangement products in vivo. These analyses were informed by a thorough understanding of the reactions of HSA with diclofenac AG in vitro. HSA from six patients without drug-related hypersensitivities had either a single drug-derived adduct or one of five combinations of 2-8 adducts from among seven diclofenac N-acylations and three AG glycations on seven of the protein's 59 lysines. Only acylations were found in every patient. We present evidence that HSA modifications by diclofenac in vivo are complicated and variable, that at least a fraction of these modifications are derived from the drug's AG metabolite, and that albumin adduction is not inevitably a causation of hypersensitivity to carboxylate drugs or a coincidental association.