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 populationsTime 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 groupsJoint 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 GuselkumabJoint 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.