Abstract
Objective
Previous analyses of pooled DISCOVER‐1 and DISCOVER‐2 data through Week 24 showed significantly higher rates of dactylitis resolution in patients treated with guselkumab compared with placebo. Here, we investigate associations between dactylitis resolution and other outcomes through 1 year.
Methods
Patients were randomized 1:1:1 to receive subcutaneous injections of guselkumab 100 mg at Week 0, Week 4, and then every 4 or 8 weeks, or placebo with crossover to guselkumab at Week 24. Independent assessors determined dactylitis severity score (DSS; 0‐3/digit; total = 0‐60). Dactylitis resolution (DSS = 0) (prespecified) and at least 20%, at least 50%, and at least 70% DSS improvement from baseline (post hoc) were determined through Week 52 (nonresponder imputation for treatment failure through Week 24 and for missing data through Week 52). ACR50, tender/swollen joints, low disease activity (LDA) as assessed by composite indices, and radiographic progression (DISCOVER‐2 only) were assessed in patients with dactylitis versus without dactylitis resolution at Week 24 and Week 52.
Results
Patients with dactylitis at baseline (473 of 1118) had more severe joint and skin disease than those without dactylitis (645 of 1118). At Week 52, approximately 75% of guselkumab‐randomized patients with dactylitis at baseline had complete resolution; approximately 80% had at least 70% DSS improvement. Through Week 52, new‐onset dactylitis (DSS ≥1) was uncommon among patients with a DSS of 0 at baseline. Guselkumab‐randomized patients with dactylitis resolution were more likely to achieve ACR50, at least 50% reduction in tender and swollen joints, and LDA at Week 24 and Week 52 than those without resolution. At Week 52, patients with dactylitis resolution had numerically less radiographic progression from baseline (DISCOVER‐2).
Conclusion
Through 1 year, approximately 75% of guselkumab‐randomized patients had complete resolution of dactylitis; patients exhibiting resolution were more likely to achieve other important clinical outcomes. Given the high burden of dactylitis, resolution may be associated with better long‐term patient outcomes.
INTRODUCTION
Psoriatic arthritis (PsA) is a chronic, immune‐mediated inflammatory disease that develops in up to 30% of patients with psoriasis (1). Dactylitis, a characteristic feature of PsA, is one of six clinical domains considered in PsA treatment decisions, along with peripheral arthritis, axial disease, enthesitis, skin disease, and nail disease (2). Dactylitis typically presents as swelling of the whole digit, with inflammation in the joints, soft tissues, and tendon sheaths (3, 4, 5, 6). Although dactylitis can occur in patients with other diseases, it is a hallmark feature of PsA, developing in up to 50% of patients at some point during their disease course, with toes affected more often than fingers (5, 6, 7). Imaging studies in patients with PsA revealed that flexor tenosynovitis with diffuse extra‐tendinous inflammation with an epicenter around accessory pulleys is a characteristic feature of dactylitis pathogenesis, helping to differentiate it from rheumatoid and other forms of arthritis (8). Other imaging features of dactylitis that can aid in differential diagnosis of PsA include extracapsular inflammatory changes, enthesitis, diffuse osteitis, and soft‐tissue edema (6, 7, 8).
PsA treatments that provide high levels of dactylitis improvement and resolution are important because dactylitis is a clinical marker for a more severe disease phenotype in patients with early PsA, characterized by higher swollen joint count (SJC), higher C‐reactive protein (CRP) levels, and more synovitis and bone erosions on imaging (5). In patients with chronic PsA, dactylitis is associated with a higher degree of radiographic damage (9). Development of dactylitis is a predictor of future radiographic damage, and patients with PsA with dactylitis and/or enthesitis report higher levels of physical disability, poorer functional status, and greater pain and fatigue than patients without these disease features (10, 11, 12, 13). Furthermore, resolution of dactylitis is associated with improvements in physical function, health‐related quality of life, and pain (14, 15, 16).
Guselkumab, a high‐affinity, fully human monoclonal antibody targeting the p19 subunit of interleukin (IL)‐23, is approved for the treatment of active PsA and moderate‐to‐severe plaque psoriasis (17). The pivotal Phase 3 DISCOVER‐1 and DISCOVER‐2 studies confirmed the safety and efficacy of guselkumab for treating the diverse manifestations of active PsA through 24 (18, 19) and 52 (20, 21) weeks of treatment, and DISCOVER‐2 confirmed low levels of radiographic progression through 2 years of treatment (22). Prespecified analyses of pooled data from DISCOVER‐1 and DISCOVER‐2 at Week 24 demonstrated significantly higher rates of dactylitis resolution with guselkumab every 4 weeks (Q4W; 64%) and every 8 weeks (Q8W; 59%) than with placebo (42%; both P < 0.05) (19). In these same patients, dactylitis response rates were maintained through 1 year (21). Here, we report results from analyses of pooled data from DISCOVER‐1 and DISCOVER‐2 exploring the specific treatment effects of guselkumab through 1 year in patients with PsA with and without dactylitis, including evaluation of relationships between dactylitis resolution and improvements in other domains of disease.
PATIENTS AND METHODS
Study designs and patients
DISCOVER‐1 (NCT03162796) and DISCOVER‐2 (NCT03158285) were multicenter, randomized, double‐blind, placebo‐controlled, Phase 3 studies of guselkumab in patients with active PsA despite treatment with standard therapies (conventional synthetic disease‐modifying antirheumatic drugs [csDMARDs], nonsteroidal anti‐inflammatory drugs [NSAIDs], and apremilast). Eligible participants in DISCOVER‐1 had an SJC of 3 or more, a tender joint count (TJC) of 3 or more, and a CRP level of 0.3 mg/dl or more. Previous exposure to one or two tumor necrosis factor (TNF) inhibitors was permitted in DISCOVER‐1 but was limited to approximately 30% of the study population (18). In DISCOVER‐2, eligible patients had an SJC of 5 or more, a TJC of 5 or more, and a CRP level of 0.6 mg/dl or more and had not received prior biologics for PsA (19). In both studies, concomitant treatment at stable doses was allowed with NSAIDs or other analgesics up to regionally approved doses; oral corticosteroids (prednisone ≤10 mg/day or equivalent); or one csDMARD (methotrexate ≤25 mg/week, sulfasalazine ≤3 g/day, hydroxychloroquine ≤400 mg/day, or leflunomide ≤20 mg/day) (18, 19).
In both studies, patients were randomized 1:1:1 to receive subcutaneous injections of guselkumab 100 mg Q4W, guselkumab 100 mg at Week 0 and Week 4 and then Q8W, or placebo with crossover to guselkumab Q4W at Week 24 (placebo→Q4W). Treatment continued through Week 48 in DISCOVER‐1 and through Week 100 in DISCOVER‐2. Efficacy data collected through Week 52 are included here.
Ethics
These studies were conducted in accordance with the principles of the Declaration of Helsinki and International Council for Harmonization Guidelines for Good Clinical Practice. Each site's governing ethical body approved study protocols, and all patients provided written informed consent, as previously reported (18, 19).
Assessments
Independent joint assessors evaluated each patient for the presence of dactylitis using a dactylitis severity score (DSS) (23) in which each of 20 digits is evaluated on a 0 to 3 scale, where 0 = no dactylitis, 1 = mild dactylitis, 2 = moderate dactylitis, and 3 = severe dactylitis. The total score ranges from 0 to 60 (24), with subscores of 0 to 30 for hands and feet. The same independent joint assessors determined TJC (0‐68) and SJC (0‐66, excluding hips), and evaluated enthesitis using the Leeds Enthesitis Index (0‐6) (25).
Investigators rated global assessment of disease activity on a 0 to 10 cm visual analog scale (VAS) and evaluated skin disease severity using the Psoriasis Area and Severity Index (PASI; score = 0‐72) (26) and percentage of body surface area (BSA) affected by psoriasis. Additionally, patients rated their pain and global impression of disease activity (0‐100 mm VAS) and completed the Health Assessment Questionnaire‐Disability Index (HAQ‐DI; score = 0‐3) (27), Functional Assessment of Chronic Illness Therapy‐Fatigue (FACIT‐Fatigue; score = 0‐52) (28, 29), and 36‐item Short‐Form (SF‐36) questionnaires (30).
In DISCOVER‐2, single radiographs of the hands (posteroanterior) and feet (anteroposterior) were obtained at Weeks 0, 24, and 52 (or at discontinuation if between Weeks 24 and 52; Reading Session 2) and scored by blinded central primary readers using the PsA‐modified van der Heijde‐Sharp (vdH‐S) score (range, 0‐528 based on joint erosion and joint space narrowing scores) (19, 31).
Analyses
Data from DISCOVER‐1 and DISCOVER‐2 were pooled, and baseline demographic and disease characteristics were summarized for patients with and without dactylitis. As prespecified, dactylitis data (total DSS) were pooled across DISCOVER‐1 and DISCOVER‐2 to increase the sample size when determining the proportions of patients achieving dactylitis resolution (DSS = 0).
Post hoc analyses of pooled data assessed dactylitis response using the established indices of improvements of at least 20%, 50%, and 70% from baseline in DSS (24); nominal P values for comparison of DSS improvement with guselkumab Q4W and Q8W versus placebo were generated using the Cochran‐Mantel‐Haenszel test. Dactylitis resolution rates at Weeks 24 and 52 were evaluated in patient subgroups defined by baseline characteristics including sex (male/female), age (<45, ≥45 to <65, ≥65 years), body weight (≤90, >90 kg), body mass index (BMI; <25, ≥25 to <30, ≥30 kg/m2), PsA duration (<1, ≥1 to <3, ≥3 years), TJC (<10, 10 to 15, >15), SJC (<10, 10 to 15, >15), CRP level (<1, ≥1 to <2, ≥2 mg/dl), concomitant baseline csDMARD use (none, any csDMARD use, methotrexate use), PASI score (<12, ≥12 to <20, ≥20), and psoriasis BSA (<3%, ≥3% to <10%, ≥10% to <20%, ≥20%). Through Week 24, patients meeting treatment failure (TF) criteria (ie, discontinued study treatment, terminated study participation, initiated or increased their dose of nonbiologic cDMARDs or oral corticosteroids, or initiated any protocol‐prohibited PsA treatments) or with missing data were imputed as nonresponders. After Week 24 and through Week 52, patients with missing data were imputed as nonresponders without application of TF rules. Additionally, the proportion of patients with new‐onset dactylitis was determined through Week 52 for those without dactylitis (DSS = 0) at baseline using observed data.
Post hoc analyses of achievement of various clinical efficacy outcomes at Weeks 24 and 52 were conducted in the pooled subgroups of patients with (DSS ≥1) and without (DSS = 0) dactylitis at baseline, including proportions of patients achieving improvements of at least 20%, 50%, and 70% in American College of Rheumatology response criteria (ACR20, ACR50, and ACR70, respectively) and FACIT‐Fatigue response (≥4‐point improvement) (29), and changes from baseline in HAQ‐DI and SF‐36 physical and mental component summary (PCS/MCS) scores. Achievement of the following composite measures were also assessed: Disease Activity in Psoriatic Arthritis (DAPSA) and clinical DAPSA (cDAPSA; excluding CRP) low disease activity (LDA; score ≤ 14 and ≤ 13, respectively) and remission (score ≤ 4 for both) (32, 33); Psoriatic Arthritis Disease Activity Score (PASDAS) LDA (score ≤ 3.2) and very low disease activity (VLDA; score ≤ 1.9) (34, 35, 36); and minimal disease activity (MDA), defined as achievement of five of the following seven criteria: TJC of ≤ 1 or less, SJC of ≤ 1 or less, PASI score of ≤ 1 or less, patient pain VAS of ≤ 15 or less, patient global disease activity VAS of ≤ 20 or less, HAQ‐DI of 0.5 or less, and tender entheseal points of ≤ 1 or less (37). For binary endpoints, patients meeting TF criteria and those with missing data were considered nonresponders through Week 24; after Week 24 and through Week 52, patients with missing data were imputed as nonresponders, and no TF rules were applied. For continuous endpoints through Week 24, patients meeting TF criteria were imputed as zero (no change) from baseline, and remaining missing data were assumed to be missing at random and imputed by multiple imputations; after Week 24 and through Week 52, no TF rules were applied, and for patients who discontinued study agent for any reason, the change from baseline, if missing, was set to zero (no change).
Relationships between dactylitis resolution and the following clinical outcomes at Weeks 24 and 52 were assessed using a Chi‐squared analysis: ACR50, 50% or more improvement in TJC and SJC, PASDAS LDA, DAPSA LDA, and MDA.
Within treatment group effect size was determined at Weeks 24 and 52 using Cohen's D (38), defined as the difference between mean baseline DSS and mean Week 24 or 52 DSS divided by the pooled standard deviation (SD) of baseline and Week 24 or 52 DSS, respectively, in the same treatment group. Effect size was calculated for all patients with dactylitis at baseline, with and without concomitant methotrexate use at baseline (yes/no). Effect sizes of 0.2 or less are considered small, values of 0.2 to 0.8 are considered moderate, and values of 0.8 or more are considered large (39).
For patients in DISCOVER‐2 with and without dactylitis at baseline, mean changes in total vdH‐S score were evaluated from Week 0 to 52. For DISCOVER‐2 patients with dactylitis at baseline, mean changes in vdH‐S score from Week 0 to 52 were also evaluated by dactylitis resolution status at Week 24 and 52.
RESULTS
Patients
As previously reported, baseline demographic and disease characteristics were generally consistent across randomized treatment groups in both studies (18, 19). Of 1120 patients in the pooled DISCOVER‐1 and DISCOVER‐2 full analysis population, dactylitis data were available for 1118 patients. At baseline, 42% (473 of 1118) of patients had dactylitis (DSS ≥1), including 43% (159 of 373) in the guselkumab Q4W group, 43% (160 of 374) in the Q8W group, and 42% (154 of 371) in the placebo group. Among patients with dactylitis, 24% (114 of 473) had finger dactylitis, 35% (164 of 473) had toe dactylitis, and 41% (195 of 473) had both finger and toe dactylitis. In the 309 patients with hand dactylitis, mean (SD) dactylitis finger count was 3.4 (3.0), and in the 359 patients with foot dactylitis, mean (SD) dactylitis toe count was 3.2 (2.6).
Relative to the subgroup of patients without dactylitis (DSS = 0) at baseline, the subgroup with dactylitis (mean DSS = 8.2) was characterized by numerically higher proportions of patients who were male (58% vs. 48%); who had enthesitis (75% vs. 58%), a PASI score of 20 or more (16% vs. 11%), and a BMI of less than 30 kg/m2 (64% vs. 57%); and who were receiving csDMARDs (71% vs. 65%) (Table 1). On average, patients with versus without dactylitis at baseline had numerically higher values for indicators of more severe PsA, including SJC (14 vs. 10), TJC (24 vs. 18), PASDAS score (7.2 vs. 6.0), and DAPSA score (53 vs. 42) (Table 1). Patients with dactylitis also had higher mean serum CRP concentration (2.1 vs. 1.5 mg/dl), which is a marker for higher risk of radiographic progression (40). In DISCOVER‐2, mean baseline vdH‐S scores were numerically higher in patients with dactylitis (26‐35 vs. 16‐20 units).
Table 1.
Baseline characteristics in patients with PsA with or without dactylitis at baseline
| All patients | Patients with dactylitis | Patients without dactylitis | |
|---|---|---|---|
| Pooled randomized, treated patients, N | 1120 a | 473 | 645 |
| Age (y), mean (SD) | 46.6 (11.6) | 45.1 (11.2) | 47.7 (11.8) |
| Sex, % | |||
| Male | 52.1 | 57.7 | 48.1 |
| Female | 47.9 | 42.3 | 51.9 |
| Weight (kg), mean (SD) | 84.9 (19.3) | 84.2 (20.0) | 85.4 (18.7) |
| BMI (kg/m2), mean (SD) | 29.2 (6.1) | 28.6 (6.1) | 29.6 (6.0) |
| Normal (<25), % | 25.5 | 29.8 | 22.5 |
| Overweight (≥25 and <30), % | 34.5 | 33.8 | 34.9 |
| Obesity (≥30), % | 40.0 | 36.4 | 42.6 |
| PsA disease duration (y), mean (SD) | 5.9 (6.1) | 5.5 (5.7) | 6.2 (6.3) |
| Joint counts, mean (SD) | |||
| Swollen (0‐66) | 11.4 (7.4) | 13.8 (8.5) | 9.7 (6.0) |
| Tender (0‐68) | 20.6 (13.3) | 24.0 (14.0) | 18.1 (12.2) |
| Enthesitis at baseline, % b | 65.1 | 74.6 | 58.1 |
| Enthesitis (LEI) score (1‐6), mean (SD) b | 2.8 (1.6) | 2.9 (1.6) | 2.7 (1.5) |
| Dactylitis at baseline, % | 42.3 a | 100 | 0 |
| Dactylitis (DSS) score (0‐60), mean (SD) | 8.2 (9.6) | 8.2 (9.6) | 0 |
| CRP (mg/dl), mean (SD) | 1.8 (2.3) | 2.1 (2.6) | 1.5 (2.0) |
| HAQ‐DI score (0‐3), mean (SD) | 1.2 (0.6) c | 1.3 (0.6) | 1.2 (0.6) |
| FACIT‐Fatigue score (0‐52), mean (SD) | 30.0 (10.0) c | 29.4 (9.7) | 30.4 (10.1) |
| SF‐36 MCS score, mean (SD) | 47.6 (10.9) c | 47.5 (10.7) | 47.6 (11.1) |
| SF‐36 PCS score, mean (SD) | 33.4 (7.7) c | 32.8 (7.3) | 33.8 (7.9) |
| DAPSA score, mean (SD) | 46.3 (20.6) | 52.9 (22.3) | 41.5 (17.8) |
| ≤14, % | 0.5 | 0.4 | 0.6 |
| >14 and ≤28, % | 14.4 | 7.2 | 19.7 |
| >28, % | 85.1 | 92.4 | 79.7 |
| cDAPSA score, mean (SD) | 44.6 (20.2) | 50.8 (21.8) | 40.0 (17.6) |
| ≤13, % | 0.6 | 0.4 | 0.8 |
| >13 and ≤27, % | 14.8 | 7.8 | 20.0 |
| >27, % | 84.6 | 91.8 | 79.2 |
| PASDAS score, mean (SD) d | 6.5 (1.1) | 7.2 (1.0) | 6.0 (0.8) |
| ≤3.2, % | 0.1 | 0 | 0.2 |
| >3.2 and <5.4, % | 15.3 | 5.1 | 22.8 |
| ≥5.4, % | 84.6 | 94.9 | 77.0 |
| PASI score (0‐72), mean (SD) | 9.5 (10.6) c | 10.4 (11.4) | 8.7 (10.0) |
| <12, % | 74.4 | 72.7 | 75.7 |
| ≥12 and <20, % | 12.9 | 11.6 | 13.8 |
| ≥20, % | 12.7 | 15.6 | 10.5 |
| Psoriasis BSA, mean (SD) e | 16.1 (19.5) | 17.9 (21.0) | 14.7 (18.3) |
| <3%, % | 21.1 | 18.0 | 23.3 |
| ≥3% and <10%, % | 32.4 | 32.3 | 32.5 |
| ≥10% and <20%, % | 19.9 | 20.5 | 19.4 |
| ≥20%, % | 26.6 | 29.2 | 24.7 |
| csDMARD use at baseline, % | 67.8 | 71.5 | 65.1 |
| Methotrexate | 58.4 | 61.7 | 56.0 |
| Other f | 9.4 | 9.7 | 9.1 |
| NSAID use at baseline, % | 64.4 | 64.5 | 64.3 |
Note: Results are pooled across DISCOVER‐1 and DISCOVER‐2.
Abbreviations: BMI, body mass index; BSA, body surface area; cDAPSA, clinical DAPSA (excludes CRP); CRP, C‐reactive protein; csDMARD, conventional synthetic disease‐modifying antirheumatic drug; DAPSA, Disease Activity in Psoriatic Arthritis; DSS, dactylitis severity score; FACIT‐Fatigue, Functional Assessment of Chronic Illness Therapy‐Fatigue; HAQ‐DI, Health Assessment Questionnaire‐Disability Index; LEI, Leeds Enthesitis Index; NSAID, nonsteroidal anti‐inflammatory drug; PASDAS, Psoriatic Arthritis Disease Activity Score; PASI, Psoriasis Area and Severity Index; PsA, psoriatic arthritis; SD, standard deviation; SF‐36 PCS/MCS, 36‐item Short‐Form health survey physical/mental component summary; y, years.
Among 1120 patients, 1118 were included in the dactylitis analysis.
All patients, N = 1118 with baseline LEI score, n = 720 with LEI score >0; patients with dactylitis, n = 349 with LEI score >0; patients without dactylitis, n = 371 with LEI score >0.
N = 1119.
All patients, N = 1108; patients with dactylitis, n = 469; patients without dactylitis, n = 639.
All patients, N = 1116; patients with dactylitis, n = 473; patients without dactylitis, n = 643.
Includes hydroxychloroquine, sulfasalazine, and leflunomide.
Dactylitis resolution and improvement
Prespecified pooled DISCOVER‐1 and DISCOVER‐2 results showed that among patients with dactylitis at baseline, significantly higher proportions of patients in the Q4W (63.5% [95% confidence interval (CI): 55.7‐71.3]) and Q8W (59.4% [51.5‐67.3]) groups achieved resolution of dactylitis at Week 24 compared with placebo (42.2% [34.1‐50.3]); both P < 0.05 (19). Least‐squares mean (95% CI) changes in DSS from baseline to Week 24 were − 6.0 (−6.8 to −5.1) in the Q4W group, −6.1 (−6.9 to −5.3) in the Q8W group, and − 4.2 (−5.0 to −3.4) in the placebo group (19).
From Week 24 to 52 (nonresponder imputation), dactylitis resolution rates increased to 74.8% (67.8‐81.9) in the Q4W group, 75.6% (68.7‐82.6) in the Q8W group, and 70.1% (62.6‐77.7) in the placebo→Q4W group. Least‐squares mean (95% CI) changes in DSS from baseline to Week 52 were − 6.5 (−7.1 to −5.8) in the Q4W group, −7.1 (−7.8 to −6.5) in the Q8W group, and –6.6 (−7.3 to −5.9) in the placebo→Q4W group.
More than half of all guselkumab‐randomized patients achieved 20% or more DSS improvement by Week 4, 50% or more improvement by Week 8, and 70% or more improvement by Week 16 (Figure 1). Owing to relatively high placebo responses at Weeks 4 and 8, separation between guselkumab and placebo first became apparent (nominal P < 0.05) at Week 16. By Week 52, approximately 80% of guselkumab‐randomized patients achieved 70% or more improvement in DSS (Figure 1).
Figure 1.
Proportions of patients with ≥20% (A), ≥50% (B), and ≥ 70% (C) improvement in DSS from baseline over time. Data pooled for patients with DSS 1 or higher at baseline across DISCOVER‐1 and DISCOVER‐2. DSS is a total score of the presence and severity of dactylitis in each digit scored from 0 (no dactylitis) to 3 (severe dactylitis); final score range = 0 to 60. Treatment group comparisons through Week 24 were not adjusted for multiplicity of testing; all reported P values are nominal. Through Week 24, patients meeting TF criteria or with missing data were imputed as nonresponders. After Week 24 and through Week 52, patients with missing data were imputed as nonresponders without application of TF rules. DSS, dactylitis severity score; GUS, guselkumab; PBO, placebo; Q4/8W, every 4/8 weeks; TF, treatment failure.
Dactylitis resolution/improvement by baseline characteristics
At Week 24, higher rates of dactylitis resolution were observed with guselkumab Q4W and Q8W versus placebo across most demographic and disease‐specific subgroups with sufficient sample size for evaluation, including subgroups of patients that are more difficult to treat (eg, those with longer PsA duration, more extensive joint and skin involvement, and higher body weight) (Figure 2). At Week 24, guselkumab treatment was associated with numerically greater improvements in both hand and foot DSS subscores compared with placebo, suggesting similar treatment effects regardless of anatomical location. Although dactylitis was more common in males than females (Table 1), there were no notable differences in dactylitis resolution by sex (Figure 2). From Week 24 to 52, dactylitis resolution rates were maintained or increased across all subgroups (Figure 2).
Figure 2.
Dactylitis resolution at Week 24 and Week 52 by baseline characteristics in patients with PsA with dactylitis at baseline. Data pooled across DISCOVER‐1 and DISCOVER‐2. BMI, body mass index; BSA, body surface area of psoriasis; CI, confidence interval; CRP, C‐reactive protein; csDMARD, conventional synthetic DMARD; DMARD, disease‐modifying antirheumatic drug; GUS, guselkumab; MTX, methotrexate; NSAID, nonsteroidal anti‐inflammatory drug; PASI, Psoriasis Area and Severity Index; PBO, placebo; PsA, psoriatic arthritis; Q4/8W, every 4/8 weeks.
Effect size
At Week 24, effect sizes were 0.84 in the guselkumab Q4W group and 0.77 in the Q8W group, indicating a moderate to large treatment effect, and 0.56 in the placebo group, suggesting a moderate placebo effect (Table 2). Among guselkumab‐treated patients, effect sizes at Week 24 were moderate (0.71‐0.74) for patients with concomitant methotrexate use and large (0.85‐1.03) for patients without concomitant methotrexate use. By Week 52, effect sizes were large in all guselkumab treatment groups (0.99‐1.02), including the placebo→guselkumab crossover group, and similar for patients with and without concomitant methotrexate use at baseline (Table 2).
Table 2.
Effect size a of mean change from baseline to Week 24 and Week 52 in DSS for all patients with dactylitis at baseline and stratified by concomitant MTX use at baseline
| Guselkumab Q4W | Guselkumab Q8W | Placebo | |
|---|---|---|---|
| Patients with dactylitis at baseline, N | 159 | 160 | 154 |
| Week 24 results | |||
| Patients with DSS data at Week 24, N | 159 | 159 | 153 |
| Effect size at Week 24 | 0.84 | 0.77 | 0.56 |
| With concomitant MTX use | |||
| Patients with DSS data at Week 24, N | 103 | 89 | 99 |
| Effect size at Week 24 | 0.74 | 0.71 | 0.65 |
| Without concomitant MTX use | |||
| Patients with DSS data at Week 24, N | 56 | 70 | 54 |
| Effect size at Week 24 | 1.03 | 0.85 | 0.52 |
| Week 52 results | Guselkumab Q4W | Guselkumab Q8W | Placebo→Guselkumab Q4W |
| Patients with DSS data at Week 52, N | 157 | 159 | 153 |
| Effect size at Week 52 | 0.99 | 0.99 | 1.02 |
| With concomitant MTX use | |||
| Patients with DSS data at Week 52, N | 102 | 90 | 99 |
| Effect size at Week 52 | 0.92 | 0.94 | 1.10 |
| Without concomitant MTX use | |||
| Patients with DSS data at Week 52, N | 55 | 69 | 54 |
| Effect size at Week 52 | 1.11 | 1.09 | 1.01 |
Note: Results are pooled across DISCOVER‐1 and DISCOVER‐2.
Abbreviations: DSS, dactylitis severity score; MTX, methotrexate; Q4/8W, every 4/8 weeks; SD, standard deviation.
Effect size within treatment groups is based on Cohen's D, defined as the difference between the mean baseline DSS and the mean Week 24 or Week 52 DSS divided by the pooled SD of the baseline and Week 24 or 52 DSS, respectively.
New‐onset dactylitis
In patients without dactylitis at baseline, new‐onset dactylitis was uncommon. Among patients in each treatment group with a DSS of 0 at baseline, only a small proportion had a DSS of greater than 0 at any assessment time point from Week 4 to 52 (Figure 3).
Figure 3.
New‐onset dactylitis through Week 52 in patients with PsA without dactylitis (DSS = 0) at baseline. Observed data pooled across DISCOVER‐1 and DISCOVER‐2. DSS, dactylitis severity score; GUS, guselkumab; PBO, placebo; PsA, psoriatic arthritis; Q4/8W, every 4/8 weeks.
Relationships between dactylitis at baseline and achievement of clinical efficacy endpoints
ACR20 response at Week 24 (primary endpoint) was achieved by similar proportions of guselkumab‐treated patients with (58%‐62%) and without (61%‐63%) dactylitis at baseline; in the placebo group, the ACR20 response rate was the same (29%) for patients with and without dactylitis at baseline (Table 3). Among guselkumab‐randomized patients, response rates (nonresponder imputation) were sustained through Week 52, at which time approximately 70% of patients with and without dactylitis at baseline achieved ACR20 response (Table 3).
Table 3.
Clinical response a through Week 52 in randomized treated patients with PsA with or without dactylitis at baseline
| W | Patients with dactylitis | Patients without dactylitis | |||||
|---|---|---|---|---|---|---|---|
| Guselkumab 100 mg | Placebo (W0‐24) → Q4W (W24‐52) | Guselkumab 100 mg | Placebo (W0‐24) → Q4W (W24‐52) | ||||
| Q4W | Q8W | Q4W | Q8W | ||||
| N | 159 | 160 | 154 | 214 | 214 | 217 | |
| ACR20, % (95% CI) b | 24 | 61.6 (53.8‐69.5) | 58.1 (50.2‐66.1) | 29.2 (21.7‐36.7) | 62.6 (55.9‐69.3) | 61.2 (54.5‐68.0) | 29.0 (22.8‐35.3) |
| 52 | 69.8 (62.4‐77.3) | 70.0 (62.6‐77.4) | 55.8 (47.7‐64.0) | 72.9 (66.7‐79.1) | 69.2 (62.7‐75.6) | 65.4 (58.9‐72.0) | |
| ACR50, % (95% CI) b | 24 | 28.9 (21.6‐36.3) | 29.4 (22.0‐36.7) | 10.4 (5.2‐15.5) | 37.9 (31.1‐44.6) | 32.2 (25.7‐38.7) | 13.8 (9.0‐18.6) |
| 52 | 46.5 (38.5‐54.6) | 45.6 (37.6‐53.7) | 33.8 (26.0‐41.6) | 50.0 (43.1‐56.9) | 44.9 (38.0‐51.8) | 39.6 (32.9‐46.4) | |
| ACR70, % (95% CI) b | 24 | 8.8 (4.1‐13.5) | 15.6 (9.7‐21.6) | 7.1 (2.8‐11.5) | 20.6 (14.9‐26.2) | 16.8 (11.6‐22.1) | 2.8 (0.4‐5.2) |
| 52 | 20.8 (14.1‐27.4) | 28.1 (20.8‐35.4) | 20.8 (14.0‐27.5) | 31.8 (25.3‐38.2) | 26.6 (20.5‐32.8) | 14.7 (9.8‐19.7) | |
| HAQ‐DI, LS mean (95% CI) b change from baseline | 24 | −0.4 (−0.5 to −0.3) | −0.4 (−0.5 to −0.3) | −0.2 (−0.3 to −0.1) | −0.4 (−0.4 to −0.3) | −0.3 (−0.4 to −0.2) | −0.0 (−0.1 to 0.0) |
| 52 | −0.5 (−0.6 to −0.4) | −0.5 (−0.6 to −0.4) | −0.4 (−0.5 to −0.3) | −0.5 (−0.5 to −0.4) | −0.4 (−0.4 to −0.3) | −0.3 (−0.3 to −0.2) | |
| SF‐36 PCS, LS mean (95% CI) b change from baseline c | 24 | 6.6 (5.4‐7.8) | 7.8 (6.6‐9.0) | 3.5 (2.3‐4.7) | 7.0 (6.0‐7.9) | 6.0 (5.0‐7.1) | 2.2 (1.2‐3.2) |
| 52 | 7.9 (6.6‐9.3) | 8.7 (7.4‐10.0) | 7.5 (6.2‐8.9) | 8.7 (7.6‐9.8) | 7.2 (6.1‐8.4) | 5.8 (4.6‐6.9) | |
| SF‐36 MCS, LS mean (95% CI) b change from baseline c | 24 | 4.9 (3.4‐6.3) | 4.7 (3.3‐6.1) | 3.3 (1.9‐4.7) | 3.3 (2.1‐4.4) | 3.1 (2.0‐4.3) | 1.4 (0.2‐2.5) |
| 52 | 5.2 (3.9‐6.6) | 5.2 (3.9‐6.5) | 4.5 (3.2‐5.8) | 3.8 (2.7‐4.9) | 3.9 (2.7‐5.0) | 3.9 (2.7‐5.0) | |
| FACIT‐Fatigue response, d % (95% CI) b | 24 | 65.4 (57.7‐73.1) | 65.6 (58.0‐73.3) | 44.8 (36.6‐53.0) | 57.5 (50.6‐64.3) | 52.8 (45.9‐59.7) | 40.1 (33.3‐46.8) |
| 52 | 68.6 (61.0‐76.1) | 68.1 (60.6‐75.7) | 61.7 (53.7‐69.7) | 59.3 (52.5‐66.2) | 57.9 (51.1‐64.8) | 59.0 (52.2‐65.8) | |
| DAPSA LDA, e % (95% CI) b | 24 | 32.7 (25.1‐40.3) | 33.1 (25.5‐40.7) | 13.0 (7.4‐18.6) | 45.8 (38.9‐52.7) | 43.9 (37.0‐50.8) | 21.2 (15.5‐26.9) |
| 52 | 46.5 (38.5‐54.6) | 45.0 (37.0‐53.0) | 40.9 (32.8‐49.0) | 59.8 (53.0‐66.6) | 57.9 (51.1‐64.8) | 49.8 (42.9‐56.7) | |
| DAPSA remission, e % (95% CI) b | 24 | 3.8 (0.5‐7.0) | 5.0 (1.3‐8.7) | 3.2 (0.1‐6.4) | 15.0 (9.9‐20.0) | 10.7 (6.4‐15.1) | 1.4 (0.0‐3.2) |
| 52 | 10.7 (5.6‐15.8) | 15.0 (9.2‐20.8) | 9.7 (4.7‐14.7) | 23.8 (17.9‐29.8) | 19.6 (14.1‐25.2) | 12.0 (7.4‐16.5) | |
| cDAPSA LDA, f % (95% CI) b | 24 | 31.4 (23.9‐39.0) | 31.9 (24.3‐39.4) | 12.3 (6.8‐17.9) | 44.4 (37.5‐51.3) | 44.4 (37.5‐51.3) | 21.7 (15.9‐27.4) |
| 52 | 45.9 (37.9‐54.0) | 46.3 (38.2‐54.3) | 39.6 (31.6‐47.7) | 61.2 (54.5‐68.0) | 57.9 (51.1‐64.8) | 49.8 (42.9‐56.7) | |
| cDAPSA remission, f % (95% CI) b | 24 | 3.8 (0.5‐7.0) | 5.6 (1.7‐9.5) | 3.9 (0.5‐7.3) | 19.6 (14.1‐25.2) | 11.7 (7.1‐16.2) | 1.8 (0.0‐3.9) |
| 52 | 11.3 (6.1‐16.6) | 17.5 (11.3‐23.7) | 13.0 (7.4‐18.6) | 28.0 (21.8‐34.3) | 23.4 (17.5‐29.3) | 13.8 (9.0‐18.6) | |
| PASDAS LDA, g % (95% CI) b | 24 | 18.2 (11.9‐24.6) | 26.3 (19.1‐33.4) | 9.1 (4.2‐14.0) | 35.0 (28.4‐41.7) | 33.2 (26.6‐39.7) | 8.8 (4.8‐12.7) |
| 52 | 39.6 (31.7‐47.5) | 39.4 (31.5‐47.3) | 33.8 (26.0‐41.6) | 49.5 (42.6‐56.5) | 43.9 (37.0‐50.8) | 38.7 (32.0‐45.4) | |
| PASDAS VLDA, g % (95% CI) b | 24 | 3.1 (0.1‐6.2) | 6.3 (2.2‐10.3) | 1.3 (0.0‐3.4) | 13.6 (8.7‐18.4) | 9.3 (5.2‐13.5) | 0.9 (0.0‐2.4) |
| 52 | 8.2 (3.6‐12.7) | 17.5 (11.3‐23.7) | 9.1 (4.2‐14.0) | 23.4 (17.5‐29.3) | 21.0 (15.3‐26.7) | 12.9 (8.2‐17.6) | |
| MDA, % (95% CI) b | 24 | 12.6 (7.1‐18.0) | 20.0 (13.5‐26.5) | 7.8 (3.2‐12.4) | 30.4 (24.0‐36.8) | 27.6 (21.3‐33.8) | 7.8 (4.0‐11.6) |
| 52 | 29.6 (22.2‐37.0) | 28.8 (21.4‐36.1) | 26.6 (19.3‐33.9) | 40.7 (33.8‐47.5) | 32.2 (25.7‐38.7) | 29.0 (22.8‐35.3) | |
| vdH‐S, mean (SD) change from baseline h | 24 | 0.3 (2.5) | 1.0 (3.2) | 1.2 (2.7) | 0.6 (2.4) | 0.5 (1.7) | 0.9 (3.5) |
| 52 | 1.2 (4.1) | 1.5 (4.6) | 1.5 (3.7) | 0.9 (3.6) | 0.5 (2.5) | 1.1 (3.4) | |
Note: Results are pooled across DISCOVER‐1 and DISCOVER‐2.
Abbreviations: ACR20/50/70, ≥20/50/70% improvement in American College of Rheumatology response criteria; cDAPSA, clinical DAPSA (excludes C‐reactive protein); CI, confidence interval; DAPSA, Disease Activity in Psoriatic Arthritis; FACIT‐Fatigue, Functional Assessment of Chronic Illness Therapy‐Fatigue; HAQ‐DI, Health Assessment Questionnaire‐Disability Index; LDA, low disease activity; LS, least‐squares; MDA, minimal disease activity; PASDAS, Psoriatic Arthritis Disease Activity Score; PsA, psoriatic arthritis; Q4/8W, every 4/8 weeks; SD, standard deviation; SF‐36 PCS/MCS, 36‐item Short‐Form health survey physical/mental component summary; vdH‐S, PsA‐modified van der Heijde‐Sharp score; VLDA, very low disease activity; W, week.
For binary endpoints, patients meeting treatment failure criteria and with missing data were considered nonresponders through Week 24; after Week 24 and through Week 52, patients with missing data were imputed as nonresponders and no treatment failure rules were applied. For continuous endpoints through Week 24, patients meeting treatment failure criteria were imputed as zero (no change) from baseline, and remaining missing data were assumed to be missing at random and imputed by multiple imputations; after Week 24 and through Week 52, after patients discontinued study agent for any reason, the change from baseline, if missing, was set to zero (no change), and no treatment failure rules were applied after Week 24.
95% CIs based on the Wald statistic.
LS mean determined using an analysis of covariance model.
Defined as ≥4‐point improvement in FACIT‐Fatigue score.
DAPSA LDA defined as score ≤ 14; DAPSA remission defined as score ≤ 4.
cDAPSA LDA defined as score ≤ 13; cDAPSA remission defined as score ≤ 4.
PASDAS LDA defined as score ≤ 3.2; PASDAS VLDA defined as score ≤ 1.9.
Collected in DISCOVER‐2 only, Read Campaign 2; scores are based on observed data. Patients with dactylitis at baseline: guselkumab Q4W, n = 114; guselkumab Q8W, n = 108; Placebo→Guselkumab Q4W, n = 92. Patients without dactylitis at baseline: guselkumab Q4W, n = 118; guselkumab Q8W, n = 130; Placebo→Guselkumab Q4W, n = 138.
Patients with dactylitis at baseline were less likely to achieve more rigorous disease activity measures of the magnitude of disease resolution, including ACR50, ACR70, DAPSA and cDAPSA LDA and remission, PASDAS LDA and VLDA, and MDA, at Weeks 24 and 52 (Table 3). These composite indices include assessments of several joint‐related components that are more likely to be affected in patients with versus without dactylitis (eg, SJC, pain, elevated CRP levels, enthesitis, and tender dactylitis count). Of note, baseline DAPSA, cDAPSA, and PASDAS scores were substantially higher in those with versus without dactylitis, suggesting more severe disease (Table 1).
Although baseline FACIT‐Fatigue and SF‐36 MCS scores were similar for patients with and without dactylitis (Table 1), patients with dactylitis at baseline were more likely to achieve FACIT‐Fatigue response (≥4‐point improvement) and had greater least‐squares mean improvements in SF‐36 MCS scores. Least‐squares mean improvements in HAQ‐DI and SF‐36 PCS scores at Weeks 24 and 52 were generally similar for patients with and without dactylitis at baseline (Table 3).
Relationships between dactylitis resolution and other clinical responses
Analyses of primary efficacy endpoint results in the subset of guselkumab‐randomized patients with dactylitis at baseline showed that at Week 24, 73% (140 of 193) of ACR20 responders and 53% (63 of 119) of ACR20 nonresponders achieved dactylitis resolution. In the placebo group, dactylitis resolution was achieved by 68% (32 of 47) of ACR20 responders and 38% (37 of 97) of ACR20 nonresponders. In guselkumab‐randomized patients at Week 52, dactylitis resolution was achieved by 86% (191 of 223) of ACR20 responders and 66% (49 of 74) of ACR20 nonresponders.
Patients who achieved dactylitis resolution at Week 24 were more likely (P < 0.05) to achieve other criteria for clinical response, including ACR50, 50% or more improvement in TJC and SJC, PASDAS LDA, and DAPSA LDA (Figure 4). Among guselkumab‐randomized patients, these patterns of response were maintained at Week 52. In the guselkumab Q4W and Q8W groups, dactylitis resolution at Week 24 was predictive of 50% or more improvement in TJC and SJC, PASDAS LDA, and DAPSA LDA at Week 52 (Figure 4), suggesting that earlier treatment of dactylitis was associated with long‐term improvements in composite measures of disease activity.
Figure 4.
Clinical response at Week 24 and Week 52 by dactylitis resolution status.* Data pooled across DISCOVER‐1 and DISCOVER‐2.*Based on observed data; post hoc P values calculated based on Chi‐squared statistics. ACR 50, 50% or more improvement in American College of Rheumatology response criteria; DAPSA, Disease Activity in Psoriatic Arthritis; DR, dactylitis resolution; GUS, guselkumab; LDA, low disease activity; MDA, minimal disease activity; PASDAS, Psoriatic Arthritis Disease Activity Score; PBO, placebo; Q4/8W, every 4/8 weeks; SJC, swollen joint count; TJC, tender joint count.
In DISCOVER‐2, patients with dactylitis resolution at Week 24 showed less radiographic progression at Week 52 than those without dactylitis resolution at Week 24 (mean [SD] changes in vdH‐S score from Week 0 to 52: Q4W: 1.0 [3.7] vs. 1.6 [5.0]; Q8W: 0.5 [2.5] vs. 3.1 [6.3]). Similar results were observed for patients with versus without dactylitis resolution at Week 52 (Q4W: 0.9 [3.7] vs. 2.6 [5.7]; Q8W: 1.4 [4.4] vs. 1.9 [5.6]).
DISCUSSION
Results of the current analyses of pooled data from DISCOVER‐1 and DISCOVER‐2 indicate that guselkumab treatment resolved or reduced the severity of dactylitis by 70% or more in the majority of patients with dactylitis at baseline, and these improvements were sustained through 1 year of treatment. At Week 16, greater mean improvement in dactylitis was achieved with guselkumab compared with placebo. By Week 52, approximately 75% of guselkumab‐randomized patients had complete resolution, and approximately 80% had an improvement in DSS of at least 70%. Furthermore, new‐onset dactylitis was uncommon in patients with a DSS of 0 at baseline, with 1.4% of these patients having a DSS ≥ 0 at Week 52.
In these studies, patients with baseline dactylitis had more severe disease, on average, than those without dactylitis, including higher prevalence of enthesitis, more severe psoriasis, higher numbers of swollen and tender joints, higher CRP levels, and higher overall disease activity based on PASDAS and DAPSA scores. These findings are consistent with previous observations that dactylitis is a marker of more severe disease manifestations in PsA (5, 6, 7, 9, 11, 41). Also consistent with published literature (5, 9), in the DISCOVER studies, dactylitis was more common in toes than in fingers. This finding supports the hypothesis that physical trauma or stress is a contributor to dactylitis pathophysiology (ie, the loadbearing function of toes makes them more predisposed to physical‐injury‐induced dactylitis than fingers) (42).
Dactylitis resolution occurred more frequently in guselkumab‐treated patients who achieved ACR20 response at Week 24 (73%) than in ACR20 nonresponders (53%), compared with 68% and 38%, respectively, in the placebo group. However, it is noteworthy that roughly half of guselkumab‐treated patients who did not achieve ACR20 did achieve resolution of dactylitis, suggesting that failure to achieve ACR20 does not preclude meaningful improvement in specific PsA core domains. This finding is consistent with a recent study by Mease et al (43) showing that substantial proportions of patients with PsA who failed to achieve ACR20 with apremilast had sustained improvements in several PsA core domains, including dactylitis.
Patients in DISCOVER‐2 with dactylitis at baseline had more preexisting structural damage in their hands and feet than those without dactylitis. This finding supports observations of more active disease progression and greater structural damage in patients with PsA with versus without dactylitis (10, 11). Results of this analysis further show that, among guselkumab‐treated patients, mean changes in vdH‐S scores from Week 0 to 52 were smaller, indicating numerically less radiographic progression, in those who achieved dactylitis resolution at Weeks 24 and 52 than in those who did not achieve resolution. As such, findings suggest that attenuating chronic pathophysiologic inflammatory responses with guselkumab may provide resolution of the clinical symptoms of dactylitis and diminish the rate of structural damage progression in the hands and feet of patients with active PsA.
Patients with dactylitis tended to have higher baseline CRP levels (mean 2.1 vs. 1.5 mg/dl), which is an independent indicator of poor radiographic outcomes (40). Subgroup analyses showed high dactylitis resolution rates at Week 52 in guselkumab‐randomized patients with baseline CRP level of 1 to less than 2 mg/dl (74%‐80%) and 2 mg/dl or more (76%‐83%), which were consistent with response rates for all patients with dactylitis at baseline.
Although there has been considerable improvement in understanding the micro‐anatomical basis for dactylitis, the underlying immunopathogenesis remains incompletely understood. It is thought that enhanced innate immune responses to biomechanical stress and subsequent T cell migration triggers dactylitis (44). The high levels of dactylitis resolution with guselkumab observed in the current analyses reinforce findings from animal models of experimental dactylitis supporting a key role of the IL‐23/IL‐17 axis in the pathogenesis of dactylitis and associated enthesitis, osteitis, and nail disease (6, 45, 46, 47). The central roles of IL‐23 and IL‐17 in PsA, and specifically in dactylitis, have been confirmed in large‐scale clinical development programs that established the robust efficacy of monoclonal antibodies targeting these cytokines (18, 19, 48, 49, 50, 51, 52, 53). The rates of dactylitis resolution observed in DISCOVER‐1 and DISCOVER‐2 are generally consistent with rates observed in clinical trials of other therapies targeting dactylitis pathogenesis (eg, IL‐17A, TNF, IL‐23, and Janus kinase inhibition) (53, 54, 55, 56, 57, 58).
Dactylitis assessment tools, including the DSS and the Leeds Dactylitis Index (LDI), have been used in PsA clinical trials and in real‐world clinical practice to identify and monitor this hallmark feature of PsA. The LDI (58, 59) is a validated outcome measure that includes assessment of digit size and tenderness and is sensitive to change. In practice, the LDI can be relatively time‐consuming, and intra‐ and interobserver variability has been reported (59, 60, 61, 62). The DSS is a numerical rating scale of dactylitis severity based on digit size and tenderness, with scores summed across each of the 20 digits, that has demonstrated responsiveness in PsA clinical trials (24, 57, 62).
Limitations
Clinical assessment of dactylitis is inherently subjective. In a clinical trial setting, assessors may have been more likely to overestimate the prevalence of dactylitis than in real‐world settings, potentially contributing to the relatively high placebo response observed in these studies. Specifically, the DSS lacks objective assessments of digit size and tenderness, formal validation, and an established minimally clinically important difference. In the DISCOVER studies, the independent joint assessors were not given specific instructions not to include dactylitic digits in the SJC, so the observed differences in mean SJC in patients with versus without dactylitis (14 vs. 10) may have been due to dactylitis itself, which by definition is swelling of and swelling between the metacarpophalangeal and proximal interphalangeal and distal interphalangeal joints, such that each dactylitic digit contributes 2 or 3 swollen joints (6). Additionally, prevalent use of NSAIDs at baseline (reported by 64% of patients with and 64% of patients without dactylitis) may have reduced pain and swelling in dactylitic joints, potentially confounding DSS measurements. The high prevalence of overweight and obesity in these studies (74% of patients had a BMI ≥25 kg/m2 at baseline) may also have confounded dactylitis diagnosis and assessment, as BMI has been shown to be a source of variability in digital subcutaneous tissue thickness, and inflammation in this tissue is a characteristic feature of dactylitis (63). Despite these limitations, the predominant focus of the current analyses was dactylitis resolution, which is a rigorous binary endpoint. The response indices of 20% or more, 50% or more, and 70% or more improvement in DSS were first used in the GO‐DACT Phase 3b trial of golimumab in patients with PsA, in which these thresholds provided discrimination between treatment arms, helping confirm superiority of active treatment over placebo for the treatment of dactylitis (24). Reassuringly, guselkumab treatment effects were generally maintained across baseline demographic subgroups, including normal, overweight, and obese BMI categories.
The current analyses of dactylitis resolution in DISCOVER‐1 and DISCOVER‐2 were limited to a relatively short 1‐year time frame. However, DISCOVER‐2 continued through 2 years, and dactylitis resolution rates were maintained from Week 52 to 100 (72%‐83% across treatment groups at Week 100) (22).
In conclusion, dactylitis is a PsA disease domain associated with more severe disease activity and worse patient outcomes. Guselkumab treatment is effective in resolving dactylitis in a broad range of patients with PsA, highlighting the role of IL‐23 inhibition in controlling this important disease domain and emphasizing the importance of IL‐23 in PsA pathophysiology and therapy. By selectively inhibiting the p19 subunit of IL‐23, guselkumab promotes sustained resolution of dactylitis, which is associated with achievement of LDA, lower rates of radiographic progression, and achievement of other important treatment goals that may improve overall long‐term outcomes in patients with PsA.
AUTHOR CONTRIBUTIONS
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. McGonagle had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study conception and design
McGonagle, McInnes, Deodhar, Schett, Shawi, Chakravarty, Kollmeier, X. Xu, Sheng, S. Xu, Ritchlin, Rahman, Mease.
Acquisition of data
McGonagle, McInnes, Deodhar, Schett, Ritchlin, Rahman, Mease.
Analysis and interpretation of data
McGonagle, McInnes, Deodhar, Schett, Shawi, Chakravarty, Kollmeier, X. Xu, Sheng, S. Xu, Ritchlin, Rahman, Mease.
ROLE OF THE STUDY SPONSOR
Employees of the funder had a role in the study design and in the collection, analysis, and/or interpretation of the data, the writing of the manuscript, and the decision to submit the manuscript for publication. The corresponding author had full access to all study data and had final responsibility to submit for publication.
Supporting information
Disclosure Form
ACKNOWLEDGMENTS
Medical writing support was provided by Cherie Koch, PhD, of Janssen Scientific Affairs, LLC, under the direction of the authors in accordance with Good Publication Practice guidelines (Ann Intern Med 2022;175:1298‐304). The authors thank Cynthia Guzzo, MD, a paid consultant for Janssen, for substantive manuscript review.
Supported by Janssen Research & Development, LLC.
The data sharing policy of Janssen Pharmaceutical Companies of Johnson & Johnson is available at https://www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through the Yale Open Data Access (YODA) Project site at http://yoda.yale.edu.
Author disclosures are available at https://onlinelibrary.wiley.com/action/downloadSupplement?doi=10.1002%2Facr2.11537&file=acr211537-sup-0001-Disclosureform.pdf.
REFERENCES
- 1. Ritchlin CT, Colbert RA, Gladman DD. Psoriatic arthritis. N Engl J Med 2017;376:957–70. [DOI] [PubMed] [Google Scholar]
- 2. Coates LC, Kavanaugh A, Mease PJ, et al. Group for Research and Assessment of Psoriasis and Psoriatic Arthritis 2015 treatment recommendations for psoriatic arthritis. Arthritis Rheumatol 2016;68:1060–71. [DOI] [PubMed] [Google Scholar]
- 3. Gladman DD, Ziouzina O, Thavaneswaran A, et al. Dactylitis in psoriatic arthritis: prevalence and response to therapy in the biologic era. J Rheumatol 2013;40:1357–9. [DOI] [PubMed] [Google Scholar]
- 4. Yamamoto T. Optimal management of dactylitis in patients with psoriatic arthritis. Open Access Rheumatol 2015;7:55–62. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Dubash S, Alabas OA, Michelena X, et al. Dactylitis is an indicator of a more severe phenotype independently associated with greater SJC, CRP, ultrasound synovitis and erosive damage in DMARD‐naive early psoriatic arthritis. Ann Rheum Dis 2022;81:490–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. McGonagle D, Tan AL, Watad A, et al. Pathophysiology, assessment and treatment of psoriatic dactylitis. Nat Rev Rheumatol 2019;15:113–22. [DOI] [PubMed] [Google Scholar]
- 7. Girolimetto N, Macchioni P, Tinazzi I, et al. Predominant ultrasonographic extracapsular changes in symptomatic psoriatic dactylitis: results from a multicenter cross‐sectional study comparing symptomatic and asymptomatic hand dactylitis. Clin Rheumatol 2020;39:1157–65. [DOI] [PubMed] [Google Scholar]
- 8. Tinazzi I, McGonagle D, Macchioni P, et al. Power Doppler enhancement of accessory pulleys confirming disease localization in psoriatic dactylitis. Rheumatology 2020;59:2030–4. [DOI] [PubMed] [Google Scholar]
- 9. Brockbank JE, Stein M, Schentag CT, et al. Dactylitis in psoriatic arthritis: a marker for disease severity? Ann Rheum Dis 2005;64:188–90. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Geijer M, Lindqvist U, Husmark T, et al. The Swedish Early Psoriatic Arthritis Registry 5‐year followup: substantial radiographic progression mainly in men with high disease activity and development of dactylitis. J Rheumatol 2015;42:2110–7. [DOI] [PubMed] [Google Scholar]
- 11. Mease PJ, Karki C, Palmer JB, et al. Clinical characteristics, disease activity, and patient‐reported outcomes in psoriatic arthritis patients with dactylitis or enthesitis: results from the Corrona Psoriatic Arthritis/Spondyloarthritis Registry. Arthritis Care Res 2017;69:1692–9. [DOI] [PubMed] [Google Scholar]
- 12. Kavanaugh A, Helliwell P, Ritchlin CT. Psoriatic arthritis and burden of disease: patient perspectives from the population‐based Multinational Assessment of Psoriasis and Psoriatic Arthritis (MAPP) survey. Rheumatol Ther 2016;3:91–102. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Bagel J, Schwartzman S. Enthesitis and dactylitis in psoriatic disease: a guide for dermatologists. Am J Clin Dermatol 2018;19:839–52. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Kavanaugh A, Puig Sanz L, Gottlieb AB, et al. Long term improvements in physical function are associated with improvements in dactylitis, enthesitis, tender and swollen joint counts, and psoriasis skin involvement: results from a phase 3 study of ustekinumab in psoriatic arthritis patients. Arthritis Rheumatol 2014;66(10 Suppl):S688. [Google Scholar]
- 15. Gladman DD, Orbai A‐M, Klitz U, et al. Ixekizumab and complete resolution of enthesitis and dactylitis: integrated analysis of two phase 3 randomized trials in psoriatic arthritis. Arthritis Res Ther 2019;21:38. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Mease PJ, Gladman DD, Deodhar A, et al. Impact of guselkumab, an interleukin‐23 p19 subunit inhibitor, on enthesitis and dactylitis in patients with moderate to severe psoriatic arthritis: results from a randomised, placebo‐controlled, phase II study. RMD Open 2020;6:e001217. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. TREMFYA® (guselkumab) injection, for subcutaneous use. Horsham, PA: Janssen Biotech, Inc., July 2020. (package insert). [Google Scholar]
- 18. Deodhar A, Helliwell PS, Boehncke W‐H, et al. Guselkumab in patients with active psoriatic arthritis who were biologic‐naive or had previously received TNFα inhibitor treatment (DISCOVER‐1): a double‐blind, randomised, placebo‐controlled phase 3 trial. Lancet 2020;395:1115–25. Erratum in: Lancet 2020;395:114. [DOI] [PubMed] [Google Scholar]
- 19. Mease PJ, Rahman P, Gottlieb AB, et al. Guselkumab in biologic‐naive patients with active psoriatic arthritis (DISCOVER‐2): a double‐blind, randomised, placebo‐controlled phase 3 trial. Lancet 2020;395:1126–36. Erratum in: Lancet 2020;395:1114. [DOI] [PubMed] [Google Scholar]
- 20. Ritchlin CT, Helliwell PS, Boehncke W‐H, et al. Guselkumab, an inhibitor of the IL‐23p19 subunit, provides sustained improvement in signs and symptoms of active psoriatic arthritis: 1 year results of a phase III randomised study of patients who were biologic‐naïve or TNFα inhibitor‐experienced. RMD Open 2021;7:e001457. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. McInnes IB, Rahman P, Gottlieb AB, et al. Efficacy and safety of guselkumab, an interleukin‐23p19‐specific monoclonal antibody, through one year in biologic‐naive patients with psoriatic arthritis. Arthritis Rheumatol 2021;73:604–16. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. McInnes IB, Rahman P, Gottlieb AB, et al. Long‐term efficacy and safety of guselkumab, a monoclonal antibody specific to the p19 subunit of interleukin‐23, through two years: results from a phase III, randomized, double‐blind, placebo‐controlled study conducted in biologic‐naive patients with active psoriatic arthritis. Arthritis Rheumatol 2022;74:475–85. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Antoni CE, Kavanaugh A, Kirkham B, et al. Sustained benefits of infliximab therapy for dermatologic and articular manifestations of psoriatic arthritis: results from the Infliximab Multinational Psoriatic Arthritis Controlled Trial (IMPACT). Arthritis Rheum 2005;52:1227–36. [DOI] [PubMed] [Google Scholar]
- 24. Vieira‐Sousa E, Alves P, Rodrigues AM, et al. GO‐DACT: a phase 3b randomised, double‐blind, placebo‐controlled trial of GOlimumab plus methotrexate (MTX) versus placebo plus MTX in improving DACTylitis in MTX‐naive patients with psoriatic arthritis. Ann Rheum Dis 2020;79:490–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Healy PJ, Helliwell PS. Measuring clinical enthesitis in psoriatic arthritis: assessment of existing measures and development of an instrument specific to psoriatic arthritis. Arthritis Rheum 2008;59:686–91. [DOI] [PubMed] [Google Scholar]
- 26. Fredriksson T, Pettersson U. Severe psoriasis‐‐oral therapy with a new retinoid. Dermatologica 1978;157:238–44. [DOI] [PubMed] [Google Scholar]
- 27. Fries JF, Spitz P, Kraines RG, et al. Measurement of patient outcome in arthritis. Arthritis Rheum 1980;23:137–45. [DOI] [PubMed] [Google Scholar]
- 28. Yellen SB, Cella DF, Webster K, et al. Measuring fatigue and other anemia‐related symptoms with the Functional Assessment of Cancer Therapy (FACT) measurement system. J Pain Symptom Manage 1997;13:63–74. [DOI] [PubMed] [Google Scholar]
- 29. Cella D, Yount S, Sorensen M, et al. Validation of the Functional Assessment of Chronic Illness Therapy Fatigue Scale relative to other instrumentation in patients with rheumatoid arthritis. J Rheumatol 2005;32:811–9. [PubMed] [Google Scholar]
- 30. Ware JE Jr, Sherbourne CD. The MOS 36‐Item Short‐Form health survey (SF‐36). I. Conceptual framework and item selection. Med Care 1992;30:473–83. [PubMed] [Google Scholar]
- 31. van der Heijde D, Sharp J, Wassenberg S, et al. Psoriatic arthritis imaging: a review of scoring methods. Ann Rheum Dis 2005;64 Suppl 2:ii61–4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32. Schoels M, Aletaha D, Funovits J, et al. Application of the DAREA/DAPSA score for assessment of disease activity in psoriatic arthritis. Ann Rheum Dis 2010;69:1441–7. [DOI] [PubMed] [Google Scholar]
- 33. Schoels MM, Aletaha D, Alasti F, et al. Disease activity in psoriatic arthritis (PsA): defining remission and treatment success using the DAPSA score. Ann Rheum Dis 2016;75:811–8. [DOI] [PubMed] [Google Scholar]
- 34. Helliwell PS, FitzGerald O, Fransen J, et al. The development of candidate composite disease activity and responder indices for psoriatic arthritis (GRACE project). Ann Rheum Dis 2013;72:986–91. [DOI] [PubMed] [Google Scholar]
- 35. Helliwell PS, FitzGerald O, Fransen J. Composite disease activity and responder indices for psoriatic arthritis: A report from the GRAPPA 2013 meeting on development of cutoffs for both disease activity states and response. J Rheumatol 2014;41:1212–7. [DOI] [PubMed] [Google Scholar]
- 36. Coates LC, Helliwell PS. Defining low disease activity states in psoriatic arthritis using novel composite disease instruments. J Rheumatol 2016;43:371–5. [DOI] [PubMed] [Google Scholar]
- 37. Coates LC, Fransen J, Helliwell PS. Defining minimal disease activity in psoriatic arthritis: a proposed objective target for treatment. Ann Rheum Dis 2010;69:48–53. [DOI] [PubMed] [Google Scholar]
- 38. Husted JA, Cook RJ, Farewell VT, et al. Methods for assessing responsiveness: a critical review and recommendations. J Clin Epidemiol 2000;53:459–68. [DOI] [PubMed] [Google Scholar]
- 39. Oak SR, Strnad GJ, Bena J, et al. Responsiveness comparison of the EQ‐5D, PROMIS Global Health, and VR‐12 questionnaires in knee arthroscopy. Orthop J Sports Med 2016;4:2325967116674714. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40. van der Heijde D, Gladman DD, FitzGerald O, et al. Radiographic progression according to baseline C‐reactive protein levels and other risk factors in psoriatic arthritis treated with tofacitinib or adalimumab. J Rheumatol 2019;46:1089–96. [DOI] [PubMed] [Google Scholar]
- 41. Li S‐S, Du N, He S‐H, et al. Dactylitis is associated with more severe axial joint damage and higher disease activity in axial psoriatic arthritis. J Rheumatol 2022;49:1012–9. [DOI] [PubMed] [Google Scholar]
- 42. Wilkins RA, Siddle HJ, Redmond AC, et al. Plantar forefoot pressures in psoriatic arthritis‐related dactylitis: an exploratory study. Clin Rheumatol 2016;35:2333–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43. Mease PJ, Gladman DD, Kavanaugh A, et al. Articular and extra‐articular benefits in ACR20 non‐responders at Week 104 treated with apremilast: pooled analysis of three randomized controlled trials. Rheumatol Ther 2021;8:1677–91. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44. Kaeley GS, Eder L, Aydin SZ, et al. Dactylitis: a hallmark of psoriatic arthritis. Semin Arthritis Rheum 2018;48:263–73. [DOI] [PubMed] [Google Scholar]
- 45. Siegel EL, Orbai A‐M, Ritchlin CT. Targeting extra‐articular manifestations in PsA: a closer look at enthesitis and dactylitis. Curr Opin Rheumatol 2015;27:111–7. [DOI] [PubMed] [Google Scholar]
- 46. Chen L, Deshpande M, Grisotto M, et al. Skin expression of IL‐23 drives the development of psoriasis and psoriatic arthritis in mice. Sci Rep 2020;10:8259. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47. Mortezavi M, Thiele R, Ritchlin C. The joint in psoriatic arthritis. Clin Exp Rheumatol 2015;33(Suppl 93):S20–5. [PubMed] [Google Scholar]
- 48. Mease PJ, McInnes IB, Kirkham B, et al. Secukinumab inhibition of interleukin‐17A in patients with psoriatic arthritis. N Engl J Med 2015;373:1329–39. [DOI] [PubMed] [Google Scholar]
- 49. McInnes IB, Mease PJ, Kirkham B, et al. Secukinumab, a human anti‐interleukin‐17A monoclonal antibody, in patients with psoriatic arthritis (FUTURE 2): a randomised, double‐blind, placebo‐controlled, phase 3 trial. Lancet 2015;386:1137–46. [DOI] [PubMed] [Google Scholar]
- 50. Mease PJ, van der Heijde D, Ritchlin CT, et al. Ixekizumab, an interleukin‐17A specific monoclonal antibody, for the treatment of biologic‐naive patients with active psoriatic arthritis: results from the 24‐week randomised, double‐blind, placebo‐controlled and active (adalimumab)‐controlled period of the phase III trial SPIRIT‐P1. Ann Rheum Dis 2017;76:79–87. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 51. Nash P, Kirkham B, Okada M, et al. Ixekizumab for the treatment of patients with active psoriatic arthritis and an inadequate response to tumour necrosis factor inhibitors: results from the 24‐week randomised, double‐blind, placebo‐controlled period of the SPIRIT‐P2 phase 3 trial. Lancet 2017;389:2317–27. [DOI] [PubMed] [Google Scholar]
- 52. Östör A, Van den Bosch F, Papp K, et al. Efficacy and safety of risankizumab for active psoriatic arthritis: 24‐week results from the randomised, double‐blind, phase 3 KEEPsAKE 2 trial. Ann Rheum Dis 2022;81:225–31. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 53. Kristensen LE, Keiserman M, Papp K, et al. Efficacy and safety of risankizumab for active psoriatic arthritis: 24‐week results from the randomised, double‐blind, phase 3 KEEPsAKE 1 trial. Ann Rheum Dis 2022;81:225–31. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 54. Smolen JS, Mease P, Tahir H, et al. Multicentre, randomised, open‐label, parallel‐group study evaluating the efficacy and safety of ixekizumab versus adalimumab in patients with psoriatic arthritis naïve to biological disease‐modifying antirheumatic drug: final results by week 52. Ann Rheum Dis 2020;79:1310–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 55. Mourad A, Gniadecki R. Treatment of dactylitis and enthesitis in psoriatic arthritis with biologic agents: a systematic review and metaanalysis. J Rheumatol 2020;47:59–65. [DOI] [PubMed] [Google Scholar]
- 56. Simons N, Degboé Y, Barnetche T, et al. Biological DMARD efficacy in psoriatic arthritis: a systematic literature review and meta‐analysis on articular, enthesitis, dactylitis, skin and functional outcomes. Clin Exp Rheumatol 2020;38:508–15. [PubMed] [Google Scholar]
- 57. Giles JT, Ogdie A, Gomez‐Reino JJ, et al. Impact of baseline body mass index on the efficacy and safety of tofacitinib in patients with psoriatic arthritis. RMD Open 2021;7:e001486. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 58. Orbai A‐M, McInnes IB, Coates LC, et al. Effect of secukinumab on the different GRAPPA‐OMERACT core domains in psoriatic arthritis: a pooled analysis of 2049 patients. J Rheumatol 2020;47:854–64. [DOI] [PubMed] [Google Scholar]
- 59. Coates LC, Helliwell PS. Disease measurement—enthesitis, skin, nails, spine and dactylitis. Best Pract Res Clin Rheumatol 2010;24:659–70. [DOI] [PubMed] [Google Scholar]
- 60. Helliwell PS, Firth J, Ibrahim GH, et al. Development of an assessment tool for dactylitis in patients with psoriatic arthritis. J Rheumatol 2005;32:1745–50. [PubMed] [Google Scholar]
- 61. Healy PJ, Helliwell PS. Measuring dactylitis in clinical trials: which is the best instrument to use? J Rheumatol 2007;34:1302–6. [PubMed] [Google Scholar]
- 62. Gladman DD, Inman RD, Cook RJ, et al. International spondyloarthritis interobserver reliability exercise‐‐the INSPIRE study: II. Assessment of peripheral joints, enthesitis, and dactylitis. J Rheumatol 2007;34:1740–5. [PubMed] [Google Scholar]
- 63. Rebollo‐Giménez A, Martínez‐Estupiñán L, Olivas‐Vergara O, et al. How variable is the volar subcutaneous tissue of the digits on B‐mode and color Doppler ultrasound in non‐psoriatic individuals and could it be included in a dactylitis score? Ultraschall Med 2021;42:643–51. [DOI] [PubMed] [Google Scholar]
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