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.

Clinical, radiographic, and scintigraphic abnormalities of the knee joint have been correlated in a cross sectional study of 100 patients with osteoarthritis. The group comprised 73 women and 27 men with a mean age of 65.7 years. One hundred and ninety one of the 200 knees had clinical (175) or radiographic (185) evidence ofosteoarthritis, or both (161). Scintigraphic images of the knees were obtained 4-5 minutes (early phase) and 2.5-3.5 hours (late phase) after intravenous injection of 600 mBq of technetium-99m diphosphonate. Abnormal images were recorded in 162 knees (81%), and six different patterns were detected. Generalised isotope retention around the knee (early or late phase) was less common than focal areas of uptake around the joint margin (early or late phase) or in the patella or subchondral bone (late phase). Some knees with abnormal scans were normal on radiography (n=7), or vice versa (n=21). Different scan patterns correlated with different clinical and radiographic features: the generalised pattern correlated with pain (odds ratio (OR)=45.1) and osteophytes (OR=48-3); joint line retention correlated with subchondral bone sclerosis on radiography (OR=62-1); and subchondral bone retention correlated with more severe radiographic changes. It is concluded that different patterns of scintigraphic abnormality reflect various aspects of the disease process of osteoarthritis.

The repeatability of physical signs used to assess osteoarthritis of the knee has not been systematically examined. The within and between observer variation of 10 commonly used physical signs to determine osteoarthritis of the knee has been assessed here. The results obtained show variation in the repeatability of these signs. For those examining the tibiofemoral joints the repeatability was greater than for those examining the patellofemoral joint. It would therefore seem vital to take note of the repeatability of physical signs in detennining the number of subjects to be studied in epidemiological studies and therapeutic studies in osteoarthritis. Five observers (two consultants, three trainees) participated in the study. They had varying degrees of experience in rheumatology. The observers agreed on the examination techniques to be used to elicit the 10 physical signs, but no training was undertaken to try to improve between observer agreement.In one three hour session both knees of each patient were examined twice by each observer in constrained random order, supervised by a study controller. At least 30 minutes and several other patient examinations elapsed between the two examinations made by any one observer of any one patient. The following physical signs were graded present or absent: bony swelling, non-bony swelling, tibiofemoral crepitus, patellofemoral crepitus, medial tenderness, lateral tenderness, patellofemoral tenderness, mediolateral instability, anteroposterior instability. Active ranges of flexion and extension were measured with a goniometer.Within and between observer reproducibility were estimated for the 10 variables. Within observer reproducibility was assessed (a) using all 80 pairs of observations (to examine overall reliability ignoring the different observers), and (b) for each individual observer (to examine the range of reliability within different observers). Between observer reproducibility was likewise estimated (a) for the grouped results of the five observers as a whole, and (b) for each of the 10 possible combinations of observers (A v B, and B v C, etc).The level of observer agreement was measured using the kappa (x) statistic3 for dichotomous variables and by estimating mean differences between paired observations for continuous variables.Results Table 1 shows the overall within observer agreement for the nine dichotomous variables on 80 replicate readings. Reproducibility was best for the detection of bony swelling (x=0 74)

Twelve knees with a range of severity of knee osteoarthritis were assessed by magnetic resonance imaging (MRI) and technetium-99m labelled hydroxymethylene diphosphonate scintigraphy. Five magnetic resonance pulse sequences were evaluated. Proton density (TR= 1000, TE=26 ms) The knee with exertional pain at the time of the study was examined for tenderness, swelling, crepitus, and deformity. Plasma viscosity and rheumatoid factor were also measured. RADIOGRAPHYRecent anteroposterior weightbearing, and lateral knee radiographs were available in all cases. The presence of joint space narrowing, sclerosis, remodelling, cysts, and effusion was recorded in each compartment of the knee joint and graded on a 0-3 severity scale. These scores were then summated to provide an overall severity score relating to each compartment.

Eighty-nine patients with established OA of the knee joint, already on regular NSAIDs for joint pain, were randomly allocated to receive 100 mg/day of slow release diclofenac (45 patients) or matching placebo (44), in place of their NSAID, for 2 years. Thirty-eight patients withdrew or dropped out of the study. The major causes for withdrawal were lack of efficacy (three active, 12 placebo, P < 0.01) or side effects (six active, five placebo), and most withdrawals occurred within the first 6 months. Long term follow up of these patients was not possible. Fifty-one patients completed the study (31 active, 20 placebo), 35 of whom reported that they were the same or better at the end of the 2-year period than at the beginning. Most of the recorded clinical parameters showed little or no change over 2 years in these 51 subjects, and in 70% there was no detectable change in the radiographs. We conclude that long term placebo-controlled trials are both feasible and ethical in knee OA, but that conventional clinical and radiographic techniques detect very little change in joint structure or function over a 2-year time period. This may reflect the insensitivity of the methods used to assess progression rather than absence of change. The fact that 20 of 44 patients changed from an NSAID to placebo completed the 2-year study without any symptomatic penalty indicates that not all patients entered needed or responded to NSAIDs.