Early Improvements with Guselkumab Associate with Sustained Control of Psoriatic Arthritis: Post hoc Analyses of Two Phase 3 Trials
verfasst von:
Jeffrey R. Curtis, Atul Deodhar, Enrique R. Soriano, Emmanouil Rampakakis, May Shawi, Natalie J. Shiff, Chenglong Han, William Tillett, Dafna D. Gladman
Patterns of treatment response can inform clinical decision-making. This study assessed the course and impact of achieving minimal clinically important improvement (MCII) in clinical measures and patient-reported outcomes (PROs) with guselkumab in patients with active psoriatic arthritis (PsA).
Methods
Post hoc analyses evaluated 1120 patients with PsA receiving guselkumab every 4 or 8 weeks (Q4W/Q8W) or placebo from DISCOVER-1 (31% tumor necrosis factor inhibitor-experienced) and DISCOVER-2 (biologic-naïve). Achievement of MCII in clinical Disease Activity Index for PsA (cDAPSA), patient global assessment (PtGA) of arthritis, PtGA of psoriasis, patient-reported pain, Functional Assessment of Chronic Illness Therapy-Fatigue, Health Assessment Questionnaire-Disability Index, 36-item Short-Form Health Survey Physical Component Summary score, PtGA Arthritis + Psoriasis, and PsA Disease Activity Score (PASDAS) was compared between the guselkumab and placebo groups using Cox regression. Logistic regression adjusting for baseline factors evaluated associations between early (W4/W8) MCII achievement and stringent response (≥%50/%70 improvement in American College of Rheumatology response criteria, cDAPSA low disease activity [LDA], PASDAS LDA, and minimal disease activity) at W24/W52 among guselkumab-randomized patients.
Results
Among patients with highly active PsA (baseline cDAPSA = 44.1–45.0, PASDAS = 6.4–6.5), times to MCII were significantly faster for guselkumab vs. placebo (hazard ratios 1.3–2.5; P < 0.05). Across measures, at first timepoint assessed, MCII rates were significantly higher with guselkumab (Q4W/Q8W 28–68%/29–65%) vs. placebo (19–47%; both P < 0.05). Early (W4/W8) MCII with guselkumab associated with higher odds of achieving stringent responses at W24/W52 (odds ratios 1.4–17.2/1.4–5.4).
Conclusions
In a mixed PsA population, significant proportions of patients treated with guselkumab achieved early (W4/W8) MCII across clinical and PRO measures, which associated with a higher likelihood of attaining clinically relevant improvements and low levels of disease activity at W24/W52.
Prior Presentation: This manuscript is based on work previously presented at EULAR 2023: Curtis J, Deodhar A, Soriano E, et al. AB1084 Guselkumab provides rapid clinically meaningful improvements in clinical and patient-reported outcomes and sustained disease control of psoriatic arthritis. Ann Rheum Dis 2023;82:1762-3.
Key Summary Points
Why carry out this study?
In the phase 3 DISCOVER-1 and DISCOVER-2 studies, the fully human interleukin-23p19 inhibitor guselkumab demonstrated significantly greater improvements across signs and symptoms of psoriatic arthritis (PsA) compared with placebo through 6 months, with response rates sustained or further enhanced through up to 2 years of treatment.
Using data from the DISCOVER studies, these post hoc analyses were conducted to assess achievement of minimal clinically important improvement (MCII) and time to MCII achievement with guselkumab across various clinical and patient-reported measures and to evaluate associations between attainment of early MCII with guselkumab and future PsA disease control.
What was learned from the study?
Among patients with active PsA, significantly greater proportions of patients treated with guselkumab vs. placebo attained early MCII at the first timepoints assessed (week 4 or 8) in measures of joint and skin involvement, pain, fatigue, physical function, and overall disease activity.
Achievement of MCII after one or two doses of guselkumab associated with a higher likelihood of attaining low levels of PsA disease activity at 6 months and 1 year.
Early improvements in individual PsA domains with guselkumab may be indicative of better patient outcomes.
Introduction
Psoriatic arthritis (PsA) is a systemic inflammatory disease affecting multiple domains: peripheral arthritis, enthesitis, dactylitis, axial disease, skin psoriasis, and nail involvement [1]. PsA is associated with impairment of functional status and negative impact on health-related quality of life (HRQoL) [2]. Delays in PsA diagnosis and treatment have been associated with progressive joint damage and long-term disability [3]. Thus, rapid assessment and early introduction of therapies that address all PsA manifestations may lead to improved patient outcomes [4].
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Clinical and patient-reported outcome (PRO) indices are used to assess the extent and severity of PsA across disease domains, the impact of disease on patients’ lives, and changes in disease states with treatment interventions [5]. The minimal clinically important improvement (MCII), defined as the smallest improvement in an outcome perceived as beneficial at the individual-patient level, has been derived for several PsA outcome measures [6]. The time to achieve this clinically meaningful improvement in disease activity, functional status, HRQoL, and the relationship between achieving MCII and the subsequent attainment of stringent disease control is of interest to both patients with PsA and health care providers.
Guselkumab, a fully human monoclonal antibody that selectively inhibits the p19 subunit of interleukin (IL)-23, is approved for the treatment of patients with moderate-to-severe plaque psoriasis as well as those with active PsA [7]. The DISCOVER-1 and DISCOVER-2 phase 3 studies demonstrated significant improvements in signs and symptoms of PsA with guselkumab through week 24, with responses sustained or further enhanced through up to 2 years of treatment [8‐11]. Significant improvements were also reported with guselkumab across several composite measures of disease activity and PROs, with substantial proportions of patients achieving minimal disease activity (MDA) at 1 and 2 years [10‐12].
The current post hoc analyses, utilizing data from the DISCOVER studies, aimed to determine the effect of guselkumab versus placebo on time to, and achievement of, MCII across multiple clinical and patient-reported measures, and the association between early (week 4/8 depending on first timepoint assessed) achievement of MCII with guselkumab and future disease control in patients with active PsA.
Methods
Patients and Study Design
These post hoc analyses included participants of the DISCOVER-1 and DISCOVER-2 studies. Details of study design, inclusion and exclusion criteria, and primary results have been reported [8, 9]. Briefly, the DISCOVER studies were randomized, double-blind, placebo-controlled trials of guselkumab in patients with active PsA despite standard therapies. In DISCOVER-1, eligibility criteria were swollen and tender joint counts (SJC [0–66 joints]/TJC [0–68 joints]) each ≥ 3, C-reactive protein (CRP) levels ≥ 0.3 mg/dl, and current or documented history of psoriasis; approximately 30% of enrolled patients could have previously received 1–2 tumor necrosis factor inhibitors (TNFi). In DISCOVER-2, eligible patients were those with SJC/TJC each ≥ 5, CRP ≥ 0.6 mg/dl, and current or documented skin psoriasis; previous exposure to biologics or Janus kinase inhibitors prohibited enrollment. Patients in both studies were randomized 1:1:1 to guselkumab 100 mg every 4 weeks (Q4W); guselkumab 100 mg at week 0, 4, then Q8W; or placebo with crossover to guselkumab 100 mg Q4W starting at week 24.
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Ethics
The DISCOVER-1 (NCT03162796) and DISCOVER-2 (NCT03158285) studies were conducted in accordance with the principles of the Declaration of Helsinki and International Council for Harmonization Guidelines for Good Clinical Practice. Each participating site's governing ethical body approved study protocols, and all patients provided written informed consent.
Outcomes
Early Treatment Targets
Details of clinical and PRO measures and conservative MCII thresholds are summarized in Table 1. Joint disease activity was evaluated using clinical Disease Activity Index for Psoriatic Arthritis (cDAPSA), and patient global assessment of arthritis activity (PtGA Arthritis; 0–100 mm visual analog scale [VAS]). cDAPSA is a validated composite measure with scores ranging from 0–154, based on the sum of TJC, SJC, PtGA Arthritis, and patient assessment of arthritic pain (0–100 mm VAS) [13]. Higher cDAPSA scores represent more severe disease activity. The first timepoint of assessment for cDAPSA and PtGA Arthritis was week 4. Skin psoriasis was assessed with the patient global assessment of psoriasis (PtGA Psoriasis; 0–100 mm VAS), with first assessment performed at week 8.
Table 1
Summary of early outcomes assessed in DISCOVER-1 and DISCOVER-2 and corresponding MCII thresholds utilized in the present analysis
cDAPSA clinical Disease Activity Index for Psoriatic Arthritis, FACIT-Fatigue Functional Assessment of Chronic Illness Therapy–Fatigue, HAQ-DI Health Assessment Questionnaire–Disability Index, MCII minimal clinically important improvement, PASDAS Psoriatic Arthritis Disease Activity Score, PtGA patient global assessment, SF-36 PCS 36-item Short-Form Health Survey Physical Component Summary, US United States, VAS visual analog scale
aThreshold predicated on anchor-based (minimal important change = 0.67) [22] and distribution (minimal clinically important difference = 0.76) [23] methods, and indicative of a moderate response in majority of patients with psoriatic arthritis[20]
Other PRO measures assessed included patient-reported pain (Patient Pain; 0–100 mm VAS), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), Health Assessment Questionnaire Disability Index (HAQ-DI), and the 36-item Short-Form Health Survey Physical Component Summary (SF-36 PCS) score. FACIT-Fatigue, a patient-reported measure of fatigue and its impact on daily activities and function during the previous week, is a 13-item validated measure with scores ranging from 0 to 52, with higher scores indicative of less fatigue [14, 15]. The HAQ-DI is an accepted instrument for evaluating physical function in PsA with scores ranging from 0 to 3 [16, 17]. The PCS score of the validated SF-36 health instrument is derived from individual scores of the four SF-36 subscales (physical functioning, role-physical, bodily pain, general health,), with higher scores representing better physical status [18, 19]. The first timepoint of assessment for Patient Pain and HAQ-DI was week 4. SF-36 PCS and FACIT-Fatigue were first assessed at week 8.
Patients evaluated their overall disease activity with the patient global assessment of arthritis and psoriasis (PtGA Arthritis + Psoriasis; 0–100 mm VAS). Overall disease activity was also assessed using the Psoriatic Arthritis Disease Activity Score (PASDAS) that comprises patient and physician global scores of skin and joint disease, TJC, SJC, Leeds Enthesitis Index, tender dactylitis count, SF-36 PCS score, and CRP level, with scores ranging from 0 to 10 and worse disease activity represented by higher scores [20, 21]. A PASDAS MCII threshold of ≥ 0.8 improvement/reduction from baseline was selected as a more conservative cut-off than that identified with anchor-based (minimal important change = 0.67) [22] and distribution (minimal clinically important difference = 0.76) [23] methods and found to indicate a moderate response among most patients with PsA [20]. The first timepoint of assessment for both PtGA Arthritis + Psoriasis and PASDAS was week 8. A ≥ 15 mm improvement/reduction from baseline was selected as the MCII for PtGA Arthritis, PtGA Psoriasis, PtGA Arthritis + Psoriasis, and Patient Pain based on prior literature showing that a value of 15% of a PRO measurement instrument score range, including a 0–100 mm VAS, is a plausible threshold for a noticeable change [24].
Stringent Treatment Targets
Stringent disease control was determined using the ≥ 50%/≥ 70% improvement in the American College of Rheumatology response criteria (ACR50/ACR70), cDAPSA low disease activity (LDA; score ≤ 13) [13], PASDAS LDA (score ≤ 3.2) [5, 21], and MDA [25]. MDA is defined as achievement of at least five of the following seven criteria: SJC ≤ 1, TJC ≤ 1, psoriasis area and severity index (PASI) ≤ 1 [26], Patient Pain ≤ 15 mm, PtGA Arthritis + Psoriasis ≤ 20 mm, HAQ-DI ≤ 0.5, and tender entheseal points ≤ 1 [25].
Statistical Analyses
Data were pooled from both DISCOVER studies through week 52, representing the final efficacy assessment in DISCOVER-1. For each outcome, analyses were limited to patients with baseline values above the MCII threshold for the respective score to avoid a floor effect, as patients with baseline scores near normal and smaller than the MCII would not be able to achieve the requisite amount of improvement. Time to MCII (as the outcome) among patients receiving guselkumab Q4W or Q8W compared with placebo was assessed using Cox regression, adjusting for baseline levels of the respective outcome, prior TNFi use, and baseline use of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). MCII response rates were evaluated at the first timepoint of assessment for each outcome, either week 4, following one guselkumab dose, or week 8, after two doses. Proportions of patients achieving MCII were reported using nonresponder imputation (NRI) and compared between each guselkumab group and the placebo group using logistic regression adjusting for baseline levels of the respective outcome, prior TNFi use, and baseline csDMARD use.
In separate models, associations between MCII achievement at first timepoints assessed (as the main independent variable) and stringent disease control at weeks 24 and 52 (as the outcome), determined with NRI, were analyzed in guselkumab-randomized patients (combined Q4W and Q8W) using logistic regression, adjusting for prior TNFi use and baseline csDMARD use. All P values are nominal.
Results
Patient Disposition and Characteristics
A total of 1120 patients were randomized and treated in the DISCOVER-1 (n = 381) [8] and DISCOVER-2 (n = 739) [9] phase 3 studies. Across both studies, 373, 375, and 372 patients were randomized to receive guselkumab Q4W, Q8W, or placebo, respectively (Table 2). Baseline demographic and disease characteristics were similar across the pooled treatment groups, with a mean duration of PsA of 6 years; mean CRP levels of 1.6–1.9 mg/dl; mean SJC and TJC of 11–12 and 20–21, respectively; 79–83% of patients having Investigator’s Global Assessment of psoriasis (IGA) scores indicative of mild to severe skin disease; mean BSA of 15–17%; and mean PASI scores ranging from 9–10. The baseline cDAPSA and PASDAS scores indicated high levels of joint and overall disease activity, respectively. Approximately 93% of guselkumab-randomized patients completed study agent through 1 year across the DISCOVER studies [10, 27].
Table 2
Baseline demographic and disease characteristics in the pooled DISCOVER-1 and DISCOVER-2 populations
Guselkumab Q4W (N = 373)
Guselkumab Q8W (N = 375)
Placebo
(N = 372)
Demographics
Age, years
46.5 (11.5)
46.2 (11.9)
47.2 (11.5)
Male, n (%)
208 (55.8)
197 (52.5)
178 (47.8)
BMI, kg/m2
29.4 (5.8)
29.1 (6.3)
29.2 (6.1)
PsA characteristics
PsA duration, years
5.9 (6.1)
5.6 (5.7)
6.2 (6.4)
CRP, mg/dl
1.6 (2.0)
1.9 (2.4)
1.9 (2.4)
SJC (0–66)
11.4 (7.5)
11.4 (7.7)
11.5 (7.0)
TJC (0–68)
20.8 (13.6)
19.9 (12.8)
21.0 (13.5)
LEI (1–6)
3.0 (1.6)
2.7 (1.5)
2.8 (1.6)
DSS (1–60)
8.8 (10.3)
8.1 (9.7)
7.7 (8.7)
IGA ≥ 2 (mild-severe disease), n (%)
311 (83.4)
295 (78.7)
301 (81.1)a
BSA with psoriasis (%)
17.1 (19.7)
15.7 (20.0)b
15.4 (18.9)a
PASI (0–72)
10.4 (11.2)
9.2 (11.1)
8.8 (9.5)
cDAPSA (0–154)a
44.6 (20.3)
44.1 (20.4)
45.0 (19.9)
PASDAS (0–10)b
6.4 (1.1)
6.5 (1.1)
6.5 (1.0)
Patient-reported outcomes
PtGA Arthritis (VAS 0–100 mm)
62.9 (19.8)
65.3 (19.5)
63.8 (19.6)
Patient Pain (VAS 0–100 mm)
60.5 (19.8)
62.0 (20.1)
61.2 (19.5)
HAQ-DI (0–3)c
1.2 (0.6)
1.3 (0.6)
1.3 (0.6)a
PtGA Psoriasis (VAS 0–100 mm)
61.0 (22.8)
60.0 (25.3)
61.2 (24.7)
PtGA Arthritis + Psoriasis (VAS 0–100 mm)
66.2 (19.8)
67.9 (20.1)
66.6 (19.8)
FACIT-Fatigue (0–52)
31.0 (9.8)
29.4 (10.4)
29.5 (9.6)
SF-36 PCS (US norm = 50)
34.2 (7.6)
33.1 (7.8)
32.9 (7.6)
Medication use at baseline, n (%)
csDMARDs
252 (67.6)
253 (67.5)
254 (68.3)
Methotrexate
218 (58.4)
209 (55.7)
227 (61.0)
Prior TNFi, n (%)
38 (10.2)
41 (10.9)
39 (10.5)
Data presented are mean (SD) unless otherwise specified. aN = 371. bN = 372
BMI body mass index, BSA body surface area, cDAPSA clinical Disease Activity Index for Psoriatic Arthritis, CRP C-reactive protein, csDMARD conventional synthetic disease-modifying antirheumatic drug, DSS dactylitis severity score, FACIT-Fatigue Functional Assessment of Chronic Illness Therapy-Fatigue, HAQ-DI Health Assessment Questionnaire-Disability Index, IGA Investigator’s Global Assessment of psoriasis, LEI Leeds Enthesitis Index, PASDAS Psoriatic Arthritis Disease Activity Score, PASI Psoriasis Area and Severity Index, PsA psoriatic arthritis, PtGA patient global assessment, Q4W every 4 weeks, Q8W every 8 weeks, SD standard deviation, SF-36 PCS 36-item Short-Form Health Survey Physical Component Summary, SJC swollen joint count, TJC tender joint count, TNFi tumor necrosis factor inhibitor, VAS visual analog scale
acDAPSA disease activity states are defined as: remission (≤ 4), low disease activity (> 4 to ≤ 13), moderate disease activity (> 13 to ≤ 27), and high disease activity (> 27) [13]
bPASDAS disease activity states are defined as: very low (≤ 1.9), low (> 1.9 to ≤ 3.2), moderate (score > 3.2 to < 5.4), and high disease activity (≥ 5.4) [5, 21]
cHAQ-DI score of 0–1 indicates mild difficulties to moderate disability, score of 1–2 indicates moderate-to-severe disability, and score of 2–3 indicates severe to very severe disability [17]
Time to and Achievement of MCII
Times to achieve MCII for all outcomes assessed were significantly faster for both guselkumab Q4W and Q8W compared with placebo (Fig. 1). At the first timepoints assessed (week 4, i.e., following one dose of guselkumab, or week 8, i.e., after two doses), MCII response rates across PsA domains were significantly higher in both guselkumab groups than in the placebo group (Table 3).
Fig. 1
Time to achieve MCII in joints (A, B), skin (C), pain (D), and overall disease activity (E, F) through week 24 among patients receiving guselkumab Q4W and Q8W vs. placebo. cDAPSA, Clinical Disease Activity Index for Psoriatic Arthritis, CI confidence interval, HR hazard ratio, MCII minimal clinically important improvement, PASDAS Psoriatic Arthritis Disease Activity Score, PBO placebo, PtGA patient global assessment, Q4W every 4 weeks, Q8W every 8 weeks. Time to MCII among patients receiving guselkumab Q4W or Q8W compared with placebo was assessed using Cox regression, adjusting for baseline levels of the respective outcome, prior tumor necrosis factor inhibitor use, and baseline use of conventional synthetic disease-modifying antirheumatic drugs
Table 3
Proportions of patients achieving MCII in the guselkumab Q4W, Q8W, and placebo treatment groups
PsA domain
Outcome measure
Week
Guselkumab Q4W
Guselkumab Q8W
Placebo
Joints
cDAPSA, N
–
371
373
370
4
58.5%**
57.9%**
46.8%
8
73.9%†
72.1%†
56.8%
PtGA Arthritis, N
–
364
370
365
4
31.9%**
34.1%†
21.1%
8
45.3%†
45.7%†
30.7%
Skin psoriasis
PtGA Psoriasis, N
–
356
348
349
8
64.0%†
62.1%†
35.2%
PROs
Patient Pain, N
–
360
367
359
4
27.8%**
29.4%**
18.9%
8
44.7%†
44.1%†
28.1%
FACIT-Fatigue, N
–
358
367
364
8
51.1%*
53.1%**
43.4%
HAQ-DI, N
–
336
338
344
4
33.9%**
30.5%*
22.7%
8
41.7%†
42.6%†
27.6%
SF-36 PCS, N
–
373
375
372
8
43.2%**
41.6%
35.8%
Overall disease activity
PtGA Arthritis + Psoriasis, N
–
365
369
365
8
53.4%†
53.7%†
32.9%
PASDAS, N
–
367
370
364
8
68.4%†
64.9%†
44.0%
cDAPSA Clinical Disease Activity Index for PsA, csDMARD conventional synthetic disease-modifying antirheumatic drug, FACIT-Fatigue Functional Assessment of Chronic Illness Therapy-Fatigue, HAQ-DI Health Assessment Questionnaire-Disability Index, MCII minimal clinically important improvement, PASDAS Psoriatic Arthritis Disease Activity Score, PBO placebo, PRO, patient-reported outcome, PsA psoriatic arthritis, PtGA patient global assessment, Q4W every 4 weeks, Q8W every 8 weeks, SF-36 PCS, 36-item Short-Form Health Survey Physical Component Summary, TNFi tumor necrosis factor inhibitor
*P < 0.05; **P < 0.01; †P ≤ 0.0001 vs. PBO; all nominal. ‡cDAPSA, PtGA Arthritis, Patient Pain, and HAQ-DI were first assessed at week 4. PtGA Psoriasis, FACIT-Fatigue, SF-36 PCS, PtGA Arthritis + Psoriasis, and PASDAS were first assessed at week 8. Response rates determined using nonresponder imputation and compared between each guselkumab group and the placebo group using logistic regression adjusting for baseline levels of the respective score, prior TNFi use, and baseline csDMARD use
×
Joint Disease Activity
For outcomes assessing joint disease activity, namely cDAPSA and PtGA Arthritis, time to achieve MCII was significantly shorter for patients receiving either guselkumab dosing regimen than for those receiving placebo. The hazard ratios (HRs; 95% confidence intervals [CIs]) for the guselkumab Q4W and Q8W groups versus placebo were 1.7 (1.5–2.0) and 1.6 (1.4–1.9), respectively, for cDAPSA and 1.9 (1.6–2.2) and 1.8 (1.5–2.1), respectively, for PtGA Arthritis (all P < 0.0001; Fig. 1A, B).
At week 4, the first timepoint at which cDAPSA was assessed, significantly greater proportions of patients receiving guselkumab Q4W (58.5%) and Q8W (57.9%) achieved MCII than those receiving placebo (46.8%; both P < 0.01). Likewise, response rates for achieving MCII in PtGA Arthritis were significantly higher in patients treated with guselkumab Q4W (31.9%, P < 0.01) and Q8W (34.1%, P = 0.0001) than in those receiving placebo (21.1%) at the first timepoint assessed (week 4; Table 3).
Skin Psoriasis
Time to achieve MCII in PtGA Psoriasis was significantly faster for both guselkumab Q4W and Q8W vs. placebo, with respective HRs (95% CIs) of 2.5 (2.1–3.0) and 2.2 (1.9–2.7) (both P < 0.0001; Fig. 1C). Significantly greater proportions of patients in the guselkumab Q4W (64.0%) and Q8W (62.1%) vs. placebo (35.2%; both P < 0.0001) groups achieved MCII in PtGA Psoriasis when first assessed at week 8 (Table 3).
Pain and Fatigue
The time to achievement of MCII in Patient Pain was significantly shorter with guselkumab Q4W and Q8W vs. placebo, with HRs (95% CIs) of 1.7 (1.4–2.1) and 1.6 (1.3–1.9), respectively (both P < 0.0001; Fig. 1D). At first assessment (week 4), significantly greater proportions of patients in the Q4W (27.8%) and Q8W (29.4%) groups achieved MCII in Patient Pain VAS versus the placebo group (18.9%; both P < 0.01; Table 3).
With both guselkumab Q4W and Q8W, the time to achieve MCII in the FACIT-Fatigue score was significantly reduced when compared with placebo; respective HRs (95% CIs) were 1.4 (1.2–1.7) (P < 0.0001) and 1.3 (1.1–1.6) (P = 0.0017) (Supplementary Fig. S1A). At week 8, the first assessment of FACIT-Fatigue, significantly greater proportions of guselkumab-treated patients achieved MCII (Q4W 51.1%, P < 0.05; Q8W 53.1%, P < 0.01) compared with placebo (43.4%; Table 3).
Physical Function and HRQoL
Patients receiving guselkumab Q4W and Q8W had a significantly faster time to achieve MCII in HAQ-DI than did patients receiving placebo, as reflected by respective HRs (95% CIs) of 1.7 (1.4–2.1) and 1.5 (1.2–1.8) (both P < 0.0001; Supplementary Fig. S1B). Response rates for achieving MCII in HAQ-DI at week 4 (first time point assessed) were significantly greater for guselkumab-treated patients (Q4W 33.9%, P < 0.01; Q8W 30.5%, P < 0.05) compared with patients receiving placebo (22.7%; Table 3).
Similarly, HRs (95% CI) for time to achievement of MCII in the SF-36 PCS score with guselkumab Q4W and Q8W versus placebo were 1.5 (1.3–1.8) and 1.6 (1.3–1.9), respectively (both P < 0.0001; Supplementary Fig. S1C). At the first SF-36 PCS assessment (week 8), the MCII response rate among guselkumab-treated patients was significantly higher for the Q4W regimen (43.2%, P < 0.01) and numerically higher for the Q8W regimen (41.6%) as compared with placebo (35.8%; Table 3).
Overall Disease Activity
Guselkumab-treated participants also had significantly shortened times to achievement of MCII in both PtGA Arthritis + Psoriasis and PASDAS, with HRs (95% CI) for guselkumab Q4W and Q8W versus placebo of 1.9 (1.6–2.2) and 1.7 (1.4–2.0), respectively, for PtGA Arthritis + Psoriasis and 1.9 (1.6–2.3) and 1.7 (1.5–2.0), respectively, for PASDAS (all P < 0.0001; Fig. 1E, F). Significantly greater proportions of patients treated with guselkumab Q4W and Q8W versus placebo achieved MCII in PtGA Arthritis + Psoriasis (53.4% and 53.7% vs. 32.9%; both P ≤ 0.0001) and PASDAS (68.4% and 64.9% vs. 44.0%; both P ≤ 0.0001) at week 8, the earliest timepoint assessed for both outcomes (Table 3).
Associations Between Achievement of MCII and Stringent Disease Control with Guselkumab
Joint Disease Activity
Achievement of MCII in cDAPSA at week 4 with guselkumab associated with a significantly higher likelihood of achieving all stringent disease control endpoints, namely ACR50, ACR70, cDAPSA LDA, PASDAS LDA, and MDA, at both week 24 (ORs 1.9–3.5; all P < 0.001; Fig. 2A) and week 52 (ORs 1.4–2.3; all P < 0.05; Supplementary Fig. S2A). Among guselkumab-treated patients achieving cDAPSA MCII at week 4, 30.7–58.9% achieved disease control at week 52 (Supplementary Fig. S2A). Similar associations were observed between achievement of MCII in PtGA Arthritis at week 4, after one dose of guselkumab, and later achievement of overall disease control at weeks 24 (Fig. 2B) and 52 (Supplementary Fig. S2B); 35.1–59.1% of patients with PtGA Arthritis MCII at week 4 achieved stringent disease targets at week 52 (Supplementary Fig. S2B).
Fig. 2
Associations between early MCII achievement, at first timepoint assessed, in joints (A, B), skin (C), pain (D), and overall disease activity (E, F) and stringent response (ACR50, ACR70, cDAPSA LDA, PASDAS LDA, and MDA) at week 24 among guselkumab-randomized patients (combined Q4W and Q8W). ACR50/70 ≥ 50%/70% improvement in American College of Rheumatology response criteria, cDAPSA clinical Disease Activity Index for Psoriatic Arthritis, CI confidence interval, csDMARD conventional synthetic disease-modifying antirheumatic drug, LDA low disease activity, MCII minimal clinically important improvement, MDA minimal disease activity, OR odds ratio, PASDAS Psoriatic Arthritis Disease Activity Score, PtGA patient global assessment, Q4W every 4 weeks, Q8W every 8 weeks, TNFi tumor necrosis factor inhibitor, W week. Response rates for achieving MCII at week 24 were determined for W4/W8 responders and nonresponders using nonresponder imputation and compared using logistic regression, adjusting for prior TNFi use and baseline csDMARD use
×
Skin Psoriasis
For patients achieving MCII in PtGA Psoriasis at week 8, after two doses of guselkumab, ORs for achieving all stringent disease control endpoints ranged from 2.1–2.4 at week 24 (all P < 0.001; Fig. 2C) and 1.5–2.0 at week 52 (all P < 0.05; Supplementary Fig. S2C).
Pain and Fatigue
Achieving MCII in Patient Pain at week 4 after one dose of guselkumab was significantly associated with later achievement of all stringent response targets, with ORs of 2.8–3.7 at week 24 (all P < 0.0001; Fig. 2D) and 1.6–2.4 at week 52 (all P < 0.01; Supplementary Fig. S2D), when 34.1–62.0% attained treatment targets.
Achievement of MCII in FACIT-Fatigue at week 8 of guselkumab treatment associated with attainment of stringent efficacy responses at week 24 (OR range 1.4–1.9; all P < 0.01 except for MDA; Supplementary Fig. S3A) and week 52 (ORs 1.4–1.8; all P < 0.01 except for cDAPSA LDA and MDA; Supplementary Fig. S2E).
Physical Function and HRQoL
Patients achieving HAQ-DI MCII at week 4 with guselkumab were significantly more likely to achieve all measures of disease control at week 24 (OR range 2.3–3.6; all P < 0.0001; Supplementary Fig. S3B) and week 52 (ORs 1.5–2.2; all P < 0.05; 36.4–60.4%; Supplementary Fig. S2F). Similar findings were observed for the association of achieving MCII in SF-36 PCS at week 8 and later disease control endpoints at week 24 (OR range 2.7–3.9; P < 0.001; Supplementary Fig. S3C) and week 52 (OR 2.3–3.0; P < 0.0001; Supplementary Fig. S2G).
Overall Disease Activity
When assessing overall PsA disease activity, patients reporting MCII in PtGA Arthritis + Psoriasis with guselkumab at week 8 showed significantly higher odds of achieving all stringent disease activity targets at both week 24 (OR range 2.9–3.6, all P < 0.0001; Fig. 2E) and week 52 (ORs 2.3–2.9, all P < 0.0001; Supplementary Fig. S2H). Among patients reporting MCII in PtGA Arthritis + Psoriasis with guselkumab at week 8, 36.9–62.8% also achieved disease control at week 52 (Supplementary Fig. S2H).
Achievement of PASDAS MCII at week 8 with guselkumab also significantly associated with attaining all stringent response endpoints at week 24 (ORs 5.4–17.2; P < 0.0001; Fig. 2F) and week 52 (ORs 3.5–5.4; all P < 0.0001; Supplementary Fig. S2I), when 35.4–64.0% of patients achieved these endpoints (Supplementary Fig. S2I).
Achievement of Stringent Disease Control at Weeks 24 and 52 with Guselkumab in Patients Not Achieving MCII at First Assessment
Stringent levels of response were also attained at week 24 (9.4–29.1%) and week 52 (22.3–46.9%) by patients who did not achieve cDAPSA MCII at the first timepoint of assessment and patients who did not achieve PtGA Arthritis MCII at the first assessment (11.5–31.5% and 24.1–50.4%, respectively). Similar trends were observed for patients who did not achieve MCII at the first assessment of Patient Pain, FACIT-Fatigue, HAQ-DI, SF-36, PtGA Arthritis + Psoriasis, and PASDAS.
Discussion
The DISCOVER studies demonstrated that guselkumab treatment significantly improved signs and symptoms of PsA, with sustained disease control through week 52 in DISCOVER-1 [10, 12] and week 100 in DISCOVER-2 [11]. Significant efficacy with guselkumab was observed across patient- and physician-reported indices. In these post hoc analyses of data from the DISCOVER studies, treatment with guselkumab associated with early onset of clinically important improvements (as early as week 4, i.e., following one dose of guselkumab, or week 8, i.e., after two doses) in measures encompassing joint and skin symptoms, pain, fatigue, physical function, and overall disease activity. At the first timepoints assessed (week 4 or 8), significantly higher proportions of patients in the guselkumab Q4W and Q8W treatment groups achieved MCII across all outcomes compared with placebo. Early achievement of MCII in each measure with guselkumab associated with a higher likelihood of attaining stringent disease targets at 6 months, a clinically relevant timepoint [28], as well as at 1 year suggesting continued therapy with guselkumab may provide better outcomes. Although some patients did not achieve MCII with guselkumab at the first timepoint of assessment, meaningful proportions of these individuals (between one-third and one-half of patients) nevertheless were still able to attain stringent disease control at week 52. This important observation suggests that lack of an early response at week 4 or 8 is likely not sufficient evidence to be cause for concern nor to warrant changing PsA treatments.
The clinical measures and PROs utilized in this study encompass several key PsA domains, as recognized by the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) [4], and assess the impact of disease from both the health care provider and patient perspectives. Recent studies have identified peripheral joint pain, skin symptoms, fatigue, and physical disability as some of the most bothersome aspects of PsA from a patient perspective, with patients prioritizing treatment addressing these manifestations [29, 30]. As it signifies meaningful change perceptible at an individual patient level [6, 31], the achievement of MCII in a clinical outcome is an important first step in assessing therapeutic utility of PsA treatments. Findings of the present study suggest that early improvements with guselkumab across PsA domains, including clinical and PRO endpoints, were a significant predictor of disease control within the first 6–12 months of therapy as assessed by ACR50/70, cDAPSA LDA, PASDAS LDA and MDA. The durability of clinically meaningful improvements in peripheral joint, skin, and overall disease activity measures observed with the guselkumab Q8W dosing regimen, approved by the United States Food and Drug Administration, was demonstrated in analyses using data from the 2-year DISCOVER-2 study [32]. Among the DISCOVER-2 population (biologic-naïve patients with active PsA), 93%-99% of patients maintained clinical improvement in cDAPSA between consecutive Q8W dosing visits through week 52. Notably, the estimated probabilities of maintenance of MCII achieved by week 24 at 2 years ranged from 68% for IGA to 89% for PASDAS, and the estimated mean durations of maintenance of improvement ranged between 52 and 77 weeks (median time to loss of response not reached) [32]. The early improvements with guselkumab in aspects of disease important to patients demonstrated in the present analysis may encourage treatment persistence and allow for incremental improvements over time. This, in turn, can lead to the achievement of stringent levels of disease control within 1 year, which has been shown to be associated with better long-term patient outcomes [33].
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Strengths of the current study include the randomized, double-blind, placebo-controlled study designs; the conservative NRI approach for missing response rate data, and adjustment for select baseline factors in regression analyses. The analysis also employed multiple validated disease activity and PRO measures and associated MCII thresholds reflecting several domains of PsA, which are of interest to patients and their healthcare providers. Moreover, the use of MCIIs provides insight into clinically relevant patient-level improvements provided by guselkumab treatment. However, as MCII estimates vary based on methods used to derive them and across different populations, as well as with disease severity and other factors, a rigorous examination of the MCII threshold is required prior to application in clinical decision making [34, 35]. At the time the current analyses were performed, an MCII of 5.7 was the only such value reported for cDAPSA [36]. An updated MCII of 3.25 was recently reported [37]; however, given that the cut-off used here is a more conservative estimate, it is not anticipated that the conclusions reached from the current analyses would be altered by applying the new MCII value. Use of the higher threshold may have, however, underestimated the proportion of patients achieving early onset of cDAPSA MCII in the present analysis. Similarly, the upper bound of the SF-36 PCS MCII range (2.5–5.0) [19] was utilized in this study potentially resulting in lower estimates of proportions of patients achieving a clinically meaningful improvement in health status.
In line with the post hoc nature of these analyses, all P values are nominal and should be used for hypothesis generation rather than testing. The DISCOVER studies were not powered to detect associations of early response with sustained disease control; therefore, certain associations may have been missed. Additionally, clinical trial cohorts may not be representative of a broader population of patients with PsA.
Conclusions
In these post hoc analyses of data from the phase 3 DISCOVER-1 and -2 studies of patients with active PsA, significant proportions of patients achieved early MCII across PsA domains with guselkumab. Early achievement of MCII after one or two doses of guselkumab associated with attainment of future overall disease control at 6 months and 1 year. Thus, early improvements in individual domains of PsA with guselkumab may portend durable achievement of important patient outcomes.
Medical Writing/Editorial Assistance
Medical writing support was provided by Joanna Dembowy, PhD, of JSS Medical Research, under the direction of the authors in accordance with Good Publication Practice guidelines (Ann Intern Med 2022;175:1298–304) and was funded by Janssen Scientific Affairs, LLC.
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Declarations
Conflict of interest
Jeffrey R Curtis: received grant/research support from AbbVie, Amgen, Bristol Myers Squibb, CorEvitas, Eli Lilly, Janssen, Myriad, Novartis, Pfizer, Sanofi, UCB, and NIAMS P30AR072583; consulting fees from AbbVie, Amgen, Bristol Myers Squibb, CorEvitas, Eli Lilly, Janssen, Myriad, Novartis, Pfizer, Sanofi, and UCB. Atul Deodhar: received consulting fees for participation in advisory boards from AbbVie, Bristol Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, and UCB; research grant funding from AbbVie, Eli Lilly, Novartis, Pfizer, and UCB; speaker fees from Eli Lilly, Janssen, Novartis, Pfizer, and UCB. Enrique R Soriano: speakers bureau for AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly, Janssen, Novartis, Pfizer, Roche, and UCB; consulting fees from AbbVie, Janssen, Novartis, and Roche; grant/research support from AbbVie, Janssen, Novartis, Pfizer, Roche, and UCB. Emmanouil Rampakakis: consulting fees from Janssen; employee of JSS Medical Research. May Shawi: shareholder of Johnson & Johnson; employee of Janssen Research & Development, LLC. Natalie J Shiff: shareholder of AbbVie, Gilead, Iovance, Jazz Pharmaceuticals, Johnson & Johnson, Novavax, and Viatris; employee of Janssen Scientific Affairs, LLC, a Johnson & Johnson company, at the time this work was performed (current employee of Alpine Immune Sciences, a Vertex company). Chenglong Han: shareholder of Johnson & Johnson; employee of Janssen Global Services, LLC. William Tillett: received consulting fees from AbbVie, Amgen, Eli Lilly, Janssen, MSD, Novartis, Ono-Pharma, Pfizer, and UCB; grant/research support from AbbVie, Amgen, Eli Lilly, Janssen, Pfizer, and UCB; speaker fees from AbbVie, Amgen, Eli Lilly, Janssen, MSD, Novartis, Pfizer, and UCB. Dafna D Gladman: grant support from AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Pfizer and UCB; consulting fees from AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, and UCB.
Ethical Approval
The DISCOVER-1 (NCT03162796) and DISCOVER-2 (NCT03158285) studies were conducted in accordance with the principles of the Declaration of Helsinki and International Council for Harmonization Guidelines for Good Clinical Practice. Each participating site's governing ethical body approved study protocols, and all patients provided written informed consent.
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