Inhibition of radiographic progression in psoriatic arthritis by adalimumab independent of the control of clinical disease activity

Evidence is provided for a disconnect between disease activity and radiographic progression in PsA patients receiving adalimumab.

Disease activity correlated with radiographic progression in patients receiving placebo, but not patients receiving adalimumab.

Concomitant methotrexate treatment appeared to have little influence on radiographic progression.

PsA, an inflammatory peripheral joint disease associated with psoriasis, is often characterized by structural damage as a result of cartilage degradation, bone resorption and osteoproliferation [ 1 , 2 ]. Therapies for PsA, which include conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) and biologic agents (bDMARDs), aim to reduce the underlying inflammation, thereby also preventing structural damage. bDMARDs, such as TNF inhibitors as well as IL-12/23 and IL-17 inhibitors, are effective in controlling the signs and symptoms of PsA and have been shown to inhibit radiographic progression [ 3–6 ], whereas csDMARDs have not shown effective inhibition of structural damage [ 3 , 4 , 7–9 ].

In RA, inhibition of radiographic progression under TNF inhibitor therapy has been shown to be greater than expected based on the control of clinical disease activity. This ‘disconnect’ phenomenon, an uncoupling between inflammation and structural progression, has been observed in subjects with RA treated with infliximab in combination with MTX in the ATTRACT and ASPIRE trials [ 10 , 11 ], as well as after treatment with etanercept in the TEMPO trial [ 12 ]. However, this phenomenon has yet to be explored in PsA.

In the ADEPT trial of subjects with PsA, adalimumab (ADA) significantly inhibited structural progression over 24 weeks compared with placebo (PBO), and the inhibitory effect was maintained in a 2-year open-label extension period [ 13 ]. Preliminary results showed that a disconnect phenomenon, similar to that observed in subjects with RA, may also be seen in subjects with PsA following ADA therapy [ 14 ]. The objective of this analysis was to further examine the relationship between inhibition of structural progression and control of clinical disease activity in subjects with PsA treated with ADA within the ADEPT trial, and to assess the impact of concomitant MTX usage.

ADEPT was a double-blind, randomized, PBO-controlled, parallel-group, 24-week trial comparing the efficacy and safety of ADA therapy with PBO in subjects with active PsA. Details of subjects, methods and the primary results of the ADEPT study have been published previously [ 15 ].

In brief, subjects included in ADEPT were ⩾18 years old and had moderately to severely active PsA (⩾3 swollen joints and ⩾3 tender or painful joints) with either active psoriatic skin lesions or a documented history of psoriasis. Subjects had a history of inadequate response or intolerance to non-steroidal anti-inflammatory drug therapy and were TNF inhibitor naive. MTX use was allowed prior to and during the study if it had been taken for ⩾3 months with stable dosage for ⩾4 weeks prior to the baseline visit. Use of csDMARDs other than MTX was not permitted. Subjects were grouped according to MTX use and degree of psoriasis at baseline [⩾3% or ⩽3% of body surface area (BSA)], and were randomized 1:1 to receive ADA or PBO 40 mg subcutaneously every other week. This post hoc analysis included subjects who had evaluable radiographs at baseline and week 24.

All research was conducted in compliance with the Declaration of Helsinki, and the protocol was approved by the institutional review boards of the participating centres. Investigators at each site enrolled patients into the trial, and all patients gave their written informed consent before participating in the study.

The following composite measures of PsA disease activity were used: Disease Activity Score of 28 joints with CRP [DAS28(CRP)] [ 16 ]; Disease Activity Index for Psoriatic Arthritis (DAPSA) [ 17 , 18 ]; and Psoriatic Arthritis Disease Activity Score (PASDAS) [ 19 , 20 ]. Disease activity was categorized as follows: DAS28(CRP) remission (<2.6), low (⩾2.6–<3.2), moderate (⩾3.2–⩽5.1) and high (>5.1) disease activity; DAPSA remission (⩽4), low (>4–⩽14), moderate (>14–⩽28) and high (>28) disease activity [ 21 ]; and PASDAS low (⩽3.2), moderate (>3.2–<5.4) and high (⩾5.4) disease activity [ 22 ]. Subjects were also categorized by achieving or not achieving minimal disease activity (MDA) [ 23 ].

Radiographic progression was measured by the modified total Sharp score (mTSS) on the radiographs of hands and feet taken at baseline and week 24.

The analyses were performed using as-observed data.

Disease activity by continuous measures (DAS28, DAPSA and PASDAS) was averaged over the period from baseline to week 24: time-averaged (TA) data were calculated as area under the curve for each disease activity measure and standardized by the length of the observation (24 weeks). The achievement of MDA, which is a binary measure (yes/no), was considered as a point assessment at week 24.

The interaction between treatment (ADA or PBO) and disease activity on ΔmTSS was evaluated using an analysis of covariance model adjusting for baseline mTSS, with disease activity, treatment and their interaction included in the model. TA-DAS28(CRP), TA-DAPSA and TA-PASDAS were modelled as continuous variables and MDA as a categorical variable. The different disease activity measures were introduced in separate models.

Changes in mTSS from baseline to week 24 in subjects categorized by TA disease activity or MDA status were compared between the treatments received (ADA or PBO).

The correlation between disease activity and ΔmTSS was assessed by Pearson [TA-DAS28(CRP), TA-DAPSA or TA-PASDAS as continuous variable] or biserial (MDA status as binary variable) correlation coefficients.

To assess the impact of MTX on the relationship between disease activity and structural progression, the same analyses were performed taking into account the presence or absence of concomitant MTX therapy in subjects treated with either ADA or PBO.

The α level of all statistical analyses was 0.05.

Of the 315 subjects randomized to receive treatment in ADEPT, 313 had evaluable radiographs at baseline and week 24. Of these, 151 received ADA and 162 PBO; approximately half of the subjects in both the ADA and PBO groups received concomitant MTX. Subjects’ baseline demographic and disease characteristics were comparable between the treatment groups. Baseline characteristics based on MTX use ( Table 1 ) were also comparable across subgroups; only the frequency of baseline psoriasis BSA ⩾3% was lower in subjects receiving MTX.

We first assessed the interaction between treatment (ADA or PBO) and disease activity on the change in mTSS at week 24. The interaction term was significant for TA-DAS28(CRP), TA-DAPSA and TA-PASDAS ( P = 0.002, P = 0.008 and P = 0.006, respectively), indicating that the relationship between disease activity and radiographic progression did indeed differ between the subjects treated with ADA or PBO. No significant interaction between treatment and disease activity on structural progression could be observed by using MDA status at week 24 rather than TA measures of disease activity. This led us to further investigate the changes in radiographic progression across different levels of disease activity in patients receiving ADA or PBO.

At week 24, the mean change in mTSS was low in subjects with remission or low disease activity, and increased in those with moderate or high disease activity ( Fig. 1A–D ). The subjects treated with ADA experienced lower mean changes in mTSS in all disease activity categories and by all disease activity measures compared with PBO ( Fig. 1A–D ). Remarkably, there was significantly less progression on ADA than PBO in subjects with moderate or high disease activity based on TA-DAPSA and -PASDAS or achievement of MDA at week 24. Although the numerical differences between radiographic progression on ADA and PBO were the largest with TA-DAS28, statistical significance was not reached, which could be due to low patient numbers in the categories of moderate and high disease activity ( Fig. 1A–D ). Similar results were seen with changes in both erosion and joint space narrowing scores across the TA-DAS28(CRP) disease activity categories ( Supplementary Fig. 1 , available at Rheumatology online). In subjects receiving PBO, there was a medium sized and statistically significant positive correlation between TA disease activity expressed by all disease activity measures and change in mTSS at week 24 ( Table 2 ). No such relationship was observed in subjects treated with ADA. There was also no correlation between disease activity and structural progression for subjects treated with either ADA or PBO using MDA status at week 24 as a binary PsA disease activity measure, possibly due to the low number of patients achieving MDA in the PBO group.

Irrespective of the presence or absence of MTX, the subjects treated with ADA experienced numerically less radiographic progression than those treated with PBO within all disease activity categories and by all disease activity measures ( Fig. 2A–D ). Further, concomitant MTX did not appear to markedly influence structural progression in subjects treated with ADA. Although not formally tested, there was also little difference between structural progression on PBO+MTX compared with PBO alone ( Fig. 2A–D ). The present analyses confirmed that treatment with ADA inhibited radiographic progression to a larger extent than might be expected based on the control of clinical disease activity alone, and that this was irrespective of concurrent MTX use. We first showed that the interaction terms for […]

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