The goals of treatment in patients with PsA are to control symptoms and signs of inflammation and to prevent progression of joint damage. The present post hoc
analysis has extended previous studies of joint damage in PsA [6
] by identifying factors that independently predicted radiographic progression in a randomized, placebo-controlled study of PsA (ADEPT). Furthermore, it determined whether these factors had similar effects for patients treated with adalimumab versus those treated with placebo. The principal finding, obtained from a multivariate linear regression analysis, was that an elevated baseline CRP concentration was the dominant independent risk factor for radiographic progression in PsA. Treatment with adalimumab was the dominant predictor for reduced radiographic progression.
Univariate analyses demonstrated that elevated baseline CRP was strongly associated with radiographic progression only for placebo-treated patients. In contrast, while almost no radiographic progression occurred among adalimumab-treated patients with baseline CRP < 1.0 mg/dl, those with baseline CRP ≥2.0 mg/dl had the best overall radiographic outcomes; that is, the lowest mean ΔmTSS. These results indicate that the baseline CRP concentration was a predictor of which patients with PsA were at risk for subsequent joint damage, that adalimumab was effective for preventing most joint damage in PsA, and that the greatest radiographic benefit from adalimumab occurred for patients with the greatest baseline CRP concentrations.
Cumulative probability plots demonstrated that adalimumab prevented nearly all radiographic progression among patients with baseline CRP < 1.0 mg/dl and, compared with placebo, most radiographic progression among patients with baseline ≥CRP 1.0 mg/dl (Figure ). They also illustrated that the mTSS did not increase for a substantial portion of placebo-treated patients, including some with baseline CRP ≥1.0 mg/dl. This finding was not attributable to concomitant use of methotrexate [14
] and was too frequent to have been caused only by spontaneous improvements in clinical arthritis activity [13
]. Instead, the absence of radiographic progression in some patients probably reflects true disease heterogeneity, plus several quantitative factors - including the tendency for PsA to cause radiographically detectable joint damage less frequently than RA, the limited duration of placebo-controlled observation in ADEPT (24 weeks), and the ability of radiographs to detect only a portion of total joint damage [21
The magnitude of radiographic benefit observed here with adalimumab is probably a low estimate compared with what might have been observed if adalimumab and placebo had been compared over a longer period of time. Consistent with this expectation, adalimumab inhibited radiographic progression in patients from ADEPT to 48 weeks [14
] and to 2 years [22
]. Although baseline CRP was < 1.0 mg/dl in a smaller portion of patients treated with placebo (60%) than adalimumab (66%; P
= 0.282) in ADEPT, the overall radiographic efficacy of adalimumab [13
] cannot be explained by this difference because mean ΔmTSS was significantly lower with adalimumab, regardless of whether baseline CRP was < 1.0 mg/dl or ≥1.0 mg/dl.
This analysis also found that radiographic joint damage at baseline was an independent predictor of radiographic progression. The magnitude of this association was small in the multivariate analysis, both in absolute terms and when compared with the results for baseline CRP variables (Table ). Baseline joint damage also predicted progression of damage in a previous observational cohort study [6
]. In that study, tender and swollen joints were identified as independent predictors of radiographic progression [6
]; in the current study, however, TJC and SJC were predictive of progression only in the univariate analysis, not in the multivariate analysis. This disparity between studies may be related to the finding that CRP was a stronger predictor of joint damage than were the physical examination-based indicators of arthritic inflammation. The disparity may also be related to the greater joint counts at baseline in ADEPT (mean values of 24 tender joints and 14 swollen joints), compared with the observational cohort study [6
The present study focused mainly on evaluating baseline measures as predictors of joint damage. It also examined the role of treatment effect, by assessing patients in terms of their 24-week time-averaged CRP. For placebo-treated patients, the association between ΔmTSS and time-averaged CRP was similar to that observed between ΔmTSS and baseline CRP, probably because an elevated CRP tends to remain elevated without treatment (Figure ). For adalimumab-treated patients, the mean ΔmTSS was inhibited regardless of the concentration of time-averaged CRP. Adalimumab thus appeared to inhibit radiographic progression not only by reducing inflammation, but also via effects that were not entirely dependent on control of inflammation. These findings are consistent with evidence that TNF antagonists can directly inhibit the osteoclast pathway in patients with PsA [23
], and with radiographic outcomes observed in patients with RA [21
]. Further research is needed to understand variations in responses to TNF antagonists, not only for individual patients, but also with respect to destructive versus proliferative joint disease in PsA.
The main limitation of the analyses presented here is that they were designed post hoc
. ADEPT is a unique resource because it is the only randomized controlled trial of a TNF antagonist in PsA that continued placebo therapy for 24 weeks without an escape option. The 24-week duration limited the ΔmTSS in placebo-treated patients to a mean value of 1.0, however, and did not allow radiographic efficacy to be assessed in the full study population after an initial period of therapy. The number of adalimumab-treated patients with radiographic progression was small, which precluded subset analyses in this group. The mTSS used for ADEPT was modified for PsA by including the distal interphalangeal joints, but it only measured erosions and joint space narrowing and only in peripheral joints. Other PsA-related radiographic findings were assessed in ADEPT, such as juxtaarticular periostitis and pencil-in-cup. They changed by amounts that were too small to warrant their inclusion in the present analysis [14