The purpose of this study is to evaluate the efficacy (improvement of signs and symptoms) and safety of ustekinumab in patients with psoriatic arthritis.
INTERVENTION: Trade Name: Stelara Product Name: ustekinumab Product Code: CNTO1275 Pharmaceutical Form: Solution for injection Current Sponsor code: ustekinumab Other descriptive name: Human Anti‐IL‐12 Antibody Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 90‐ Pharmaceutical form of the placebo: Solution for injection Route of administration of the placebo: Subcutaneous use CONDITION: Psoriatic arthritis ; MedDRA version: 12.1 Level: LLT Classification code 10037160 Term: Psoriatic arthritis PRIMARY OUTCOME: Main Objective: The primary objectives of this study are to evaluate the efficacy of ustekinumab in subjects with active PsA including those previously treated with biologic anti‐TNFa agent(s) by assessing the reduction in signs and symptoms of PsA and to evaluate the safety of ustekinumab in this population. Primary end point(s): The primary endpoint is the proportion of subjects achieving an ACR 20 response at Week 24. Secondary Objective: The secondary objectives of this study are to evaluate the efficacy of ustekinumab in:; 1. Improving physical function;; 2. Improving psoriatic skin lesions; and; 3. Inhibiting the progression of structural damage. INCLUSION CRITERIA: • Men or women between 18 and 99 years of age, inclusive. • Have had PsA at least 6 months prior to the first administration of study agent. • Have a diagnosis of active PsA as defined by: – 5 or more swollen joints and 5 or more tender joints at screening and at baseline ‐AND‐ – C‐reactive protein (CRP) = 0.3 mg/dL at screening. • Have at least 1 of the PsA subsets: • Have active plaque psoriasis or a documented history of plaque psoriasis. • Have active PsA despite current or previous DMARD and/or NSAID therapy. • Subjects previously treated with a biologic anti‐ TNFa agent, must have: – received at least an 8‐week dosage regimen of etanercept, adalimumab, golimumab, or certolizumab pegol; or – received at least a 14‐week dosage regimen of infliximab; or – received less than an 8‐week dosage regimen of etanercept, adalimumab, golimumab, or certolizumab pegol or less than a 14‐week dosage regimen of infliximab
Background Ustekinumab (UST)has demonstrated efficacy in pts with active psoriatic arthritis (PsA) at wk24 in the Phase 3, multicenter, PBO-controlled PSUMMIT2 trial. Results through wk52 PSUMMIT 2 are presented herein. Methods 312 adults with active PsA were randomized to UST 45mg or 90mg at wk0, wk4, and q12w or PBO at wks0, 4, and 16 followed by crossover to UST 45mg at wk24, wk28, and wk40. Randomization was stratified by site, weight (≤100kg, >100kg) and baseline MTX use, and pts previously treated with biologic anti-TNF agents were eligible. At wk16, pts with <5% improvement in both tender/swollen joint counts entered blinded early escape (PBO→UST 45mg, 45mg→90mg, 90mg→90mg). The primary endpoint was ACR20 at wk24. Secondary endpoints were HAQ-DI, ACR50, ACR70, and ≥75% improvement in the Psoriasis Area and Severity Index (PASI75). Results Anti-TNF-experienced pts had more active disease at baseline than anti-TNF-naïve pts. More UST (43.8%>combined, 43.7%>45mg, 43.8%>90mg) than PBO (20.2%) treated pts had ACR20 at wk24 (all P<0.001). Significant differences were observed for ACR50 and PASI75 response at wk24 (table). Efficacy was sustained through wk52. At wk52, 51% and 44% of pts who were and were not, respectively, receiving MTX at baseline had ACR20. UST efficacy at wk52 was more robust in anti-TNF-naïve (ACR20 59-73%) than anti-TNF-experienced (37-41%) pts and pts who had previously received 1 (50-55%) vs. 2 (13-39%) or ≥3 (13-30%) anti-TNF agents. UST was generally well tolerated, with no deaths or TB and similar rates of AEs (78.6%>45mg, 77.9%>90mg), SAEs (5.8%>45mg, 5.8%>90mg), and AEs leading to discontinuation (5.8%>45mg, 3.8%>90mg) reported across doses through wk60. 2 pts, both anti-TNF-experienced, had malignancies (breast-45mg, squamous cell carcinoma-90mg); 2/287 (0.7%) of UST-treated pts (both 90mg) had serious infections. 3 pts (2-45mg, 1-90mg) had MACE (myocardial infarctions) through wk60, all had multiple CV risk factors and prior anti-TNF experience. Conclusions Both UST doses (45/90 mg q12w) yielded significant and sustained improvements in PsA signs/symptoms with favorable and comparable safety profiles. UST was effective in both anti-TNF-naïve and anti-TNF-experienced pts, with greater efficacy in anti-TNF naïve pts and anti-TNF-experienced pts previously treated with 1 or 2 anti-TNF agents. (Figure Presented).
Objectives To examine the impact of ustekinumab (UST) treatment on patient reported outcomes in patients with active psoriatic arthritis (PsA) using week 24 data from two Phase 3 clinical studies, PSUMMIT I and II. Methods Adult patients with active PsA despite DMARD and/or NSAID therapy (PSUMMIT I, n=617) or previously treated with anti-TNFα therapy (PSUMMIT II, n=312) were randomized to receive UST 45mg, 90mg, or placebo (PBO) at wks 0, 4, and q12wks, thereafter. Patient reported outcomes were measured using the Health Assessment Questionnaire (HAQ), Dermatology Quality Life Index (DLQI), SF-36health survey questionnaire (SF-36), Visual Analogue Scales (VAS) for impact of PsA on work productivity (0-10), patient assessment of pain (0-10), and disease activity (0-10). Sub-analyses were conducted by combining both studies into 3 mutually exclusive groups based on treatment history: MTX naïve, previously treated with MTX therapy, and previously treated with anti-TNF therapy. Results At baseline, patients in both studies had moderate to severe physical disability and impaired health related quality of life with a mean HAQ score of ≥1.25, mean DLQI score of ≥10 and mean SF-36 PCS and MCS below 50 (normal population score). In PSUMMIT I, UST-treated patients achieved statistically significantly greater improvements in HAQ (- 0.31 and -0.4 vs. -0.1), DLQI (-6.6 and -7.5 vs. -1.4), and SF-36 PCS (4.9 and 6.2 vs. 1.4), for the UST 45mg, 90mg, vs. PBO groups, respectively. When compared to PBO, greater proportions of UST-treated patients achieved clinical meaningful improvements in HAQ (≥0.3) (47.8% and 47.5% vs. 28.2%), DLQI (≥5) (58.6% and 63.1% vs. 32.9%), and SF-36 PCS (≥5) (45.5%, and 53.3% vs. 26.0%), for the UST 45mg, 90mg, vs. PBO groups, respectively. Similar results were observed in PSUMMIT II and in the sub-analyses by MTX naïve, prior MTX experienced, and prior anti-TNFα experienced patients. Similar results were also observed in SF-36 sub-scales, especially in bodily pain and physical health. In the anti-TNF naïve population, statistically significantly greater improvement in SF-36 MCS was observed in the combined UST 45mg and 90mg group vs PBO Additionally, UST-treated patients achieved statistically significantly greater improvements in patient assessment of pain, patient assessment of disease activity, and greater reduction in impact of disease on work productivity vs PBO-treated patients. Conclusions UST improves physical function, improves general, arthritis and skin-related quality of life, and reduces the impact of disease on work productivity in patients with active PsA regardless of current or prior MTX use or prior anti-TNF experience.
Objectives To evaluate the effect of ustekinumab (UST), an IL-12/23 p40 inhibitor, on inhibition of progression of structural damage in patients with active psoriatic arthritis (PsA) at wk24 and wk52 in the PSUMMIT 1 and PSUMMIT 2 trials. Methods Adult PsA patients with active disease (≥5 SJC and ≥5 TJC; CRP≥0.3mg/dL [ULN 1.0 mg/dL]) despite DMARD and/or NSAID therapy (PSUMMIT 1, n=615; PSUMMIT 2, n=132) or previously treated with DMARD and/or NSAID, and prior anti-TNFα therapy (PSUMMIT 2, n=180) were randomized to UST45mg, 90mg, or PBO at wks 0, 4, and q12wks, thereafter. At wk16, patients with <5% improvement in TJC & SJC entered blinded early escape [EE] (PBO$→ $UST45mg; UST45mg$→ $90mg; 90mg$→ $90mg). No concomitant DMARDs with the exception of MTX (approximately 50% of patients in each study) were permitted. Radiographs of hands and feet were taken at wks 0, 24, and 52 regardless of EE status, or at the time of study drug discontinuation (unless radiographs were completed within the prior 8wks). Erosions and joint space narrowing (JSN) were evaluated by independent readers blinded to treatment, patient IDs and image time sequence using PsA modified van der Heijde-Sharp (vdH-S) method (total score ranging from 0-528). The major secondary endpoint of change from baseline in total vdH-S scores at wk24 was analyzed based on a pre-specified integrated data analysis using data combined from both studies. Imputation of missing data was done using linear extrapolation or median change of 0. Results Baseline disease characteristics including total vdH-S, TJC, SJC and CRP were comparable between PSUMMIT 1 & 2. In the integrated analyses, both UST 45 mg and 90 mg treated patients demonstrated a significant difference in change from baseline in total vdH-S scores at wk24 vs PBO (Table). Moreover, continued inhibition was demonstrated through wk 52; patients randomized to PBO who initiated UST at wk16 or 24 demonstrated slowing of radiographic progression by wk52 (mean change in total vdH-S wk24 to wk52 of 0.08). These observations were reproduced when PSUMMIT 1 was evaluated alone. In PSUMMIT 2, a demonstrable effect of UST on inhibition of structural damage progression could not be discerned; these results may have been impacted by missing radiographic data, especially among PBO-treated patients (23% missing radiographs). Conclusions Based upon the pre-specified integrated data analysis, ustekinumab inhibits radiographic progression at wk24. (Figure Presented).
Background: To examine the impact of ustekinumab (UST) treatment on patient reported outcomes in patients with active PsA using week 24 data from two Phase 3 clinical studies, PSUMMIT I and II. Methods: Adult patients with active PsA despite DMARD and/or NSAID therapy (PSUMMIT I, n=617) or previously treated with anti‐ TNFalpha therapy (PSUMMIT II, n=312) were randomized to receive UST 45 mg, 90 mg, or placebo (PBO) at weeks 0, 4, and q12weeks, thereafter. Patient reported outcomes were measured using the Health Assessment Questionnaire (HAQ), Dermatology Quality Life Index (DLQI), SF‐36 health survey questionnaire (SF‐36), Visual Analogue Scales (VAS) for impact of PsA on work productivity (0‐10), patient assessment of pain (0‐10), and disease activity (0‐10). Sub‐analyses were conducted by combining both studies into 3 mutually exclusive groups based on treatment history: MTX naive, previously treated with MTX therapy, and previously treated with anti‐TNF therapy Results: At baseline, patients in both studies had moderate to severe physical disability and impaired health related quality of life with a mean HAQ score of >1.25, mean DLQI score of >10 and mean SF‐36 PCS and MCS below 50 (normal population score). In PSUMMIT I, UST‐treated patients achieved statistically significantly greater improvements in HAQ (‐0.31 and ‐0.4 vs ‐0.1), DLQI (‐6.6 and ‐7.5 vs ‐1.4), and SF‐36 PCS (4.9 and 6.2 vs 1.4), for the UST 45 mg, 90 mg, vs PBO groups, respectively . When compared with PBO, greater proportions of UST‐treated patients achieved clinical meaningful improvements in HAQ (>0.3) (47.8% and 47.5% vs 28.2%), DLQI (>5) (58.6% and 63.1% vs 32.9%), and SF‐36 PCS (>5) (45.5%, and 53.3% vs 26.0%), for the UST 45 mg, 90 mg, vs PBO groups, respectively. Similar results were observed in PSUMMIT II and in the sub‐analyses by MTX naive, prior MTX experienced, and prior anti‐ TNFalpha experienced patients. Similar results were also observed in SF‐ 36 sub‐scales, especially in bodily pain and physical health. In the anti‐ TNF naive population, statistically significantly greater improvement in SF‐36 MCS was observed in the combined UST 45mg and 90mg group vs PBO Additionally, UST‐treated patients achieved statistically significantly greater improvements in patient assessment of pain, patient assessment of disease activity, and greater reduction in impact of disease on work productivity vs PBO‐treated patients. Conclusion: UST improves physical function, improves general, arthritis and skin‐related quality of life, and reduces the impact of disease on work productivity in patients with active PsA regardless of current or prior MTX use or prior anti‐TNF experience.
Objective Evaluate ustekinumab, an anti-interleukin (IL)-12 and IL-23 antibody, effects on radiographic progression in psoriatic arthritis (PsA). Methods: We conducted preplanned integrated analyses of combined radiographic data from PSUMMIT-1 and PSUMMIT-2 phase 3, randomised, controlled trials. Patients had active PsA despite prior conventional and/or biologic disease-modifying antirheumatic drugs (≥5/66 swollen, ≥5/68 tender joints, C-reactive protein ≥3.0 mg/L, documented plaque psoriasis). Patients (PSUMMIT-1, n=615; PSUMMIT-2, n=312) were randomised to ustekinumab 45 mg, 90 mg, or placebo, at weeks (wk) 0, 4 and every (q) 12 wks. At wk 16, patients with <5% improvement in tender/swollen joint counts entered blinded early escape. All other placebo patients received ustekinumab 45 mg at wk 24 and wk 28, then q 12 wks. Radiographs of hands/feet at wks 0/24/52 were assessed using PsA-modified van der Heijde-Sharp (vdH-S) scores; combined PSUMMIT-1 and PSUMMIT-2 changes in total vdH-S scores from wk 0 to wk 24 comprised the prespecified primary radiographic analysis. Treatment effects were assessed using analysis of variance on van der Waerden normal scores (factors=treatment, baseline methotrexate usage, and study). Results: Integrated data analysis results indicated that ustekinumab-treated patients (regardless of dose) demonstrated significantly less radiographic progression at wk 24 than did placebo recipients (wk 0-24 total vdH-S score mean changes: 0.4-combined/ individual ustekinumab dose groups, 1.0-placebo; all p<0.02). From wk 24 to wk 52, inhibition of radiographic progression was maintained for ustekinumab-treated patients, and progression was substantially reduced among initial placebo recipients who started ustekinumab at wk 16 or wk 24 (wk 24 - wk 52, total vdH-S score mean change: 0.08). Conclusions: Ustekinumab 45 and 90 mg treatments significantly inhibited radiographic progression of joint damage in patients with active PsA.
Background We have previously reported the efficacy and safety results of ustkeinumab (UST), an IL-12/23 p40 inhibitor, in patients with active psoriatic arthritis up to two years of UST treatment from the PSUMMIT 1 and PSUMMIT 2 trials. Objectives Here, we further describe the sustained effects of UST using the modified Psoriatic Arthritis Response Criteria (PsARC) response. Although not validated, the PsARC has been widely used in psoriatic arthritis clinical trials. Methods Adult PsA patients with active disease (≥5 SJC and ≥5 TJC; CRP≥0.3mg/dL [ULN 1.0 mg/dL]) despite DMARD and/or NSAID therapy (PSUMMIT 1, n=615; PSUMMIT 2, n=312 [of which 180 pts were previously treated with DMARD and/or NSAID, and prior anti-TNFα therapy]) were randomized to UST45mg, 90mg, or PBO at wks 0, 4, and q12wks, thereafter. PBO-treated pts were crossed over to UST45mg at wks24 and 28 followed by q12wk dosing. At wk16, patients with <5% improvement in TJC & SJC entered blinded early escape [EE] (PBO$→ $UST45mg; UST45mg$→ $90mg; 90mg$→ $90mg). No concomitant DMARDs with the exception of MTX (approximately 50% of patients in each study) were permitted. Patients were considered a responder using the modified PsARC if improvement was demonstrated in at least 2 (including at least 1 of the joint criteria) of the following criteria and no deterioration was noted in the other criteria: ≥30% decrease in the swollen joint count, ≥30% decrease in the tender joint count, ≥20% improvement in the patient's overall assessment (VAS), and ≥20% improvement in the physician's overall assessment (VAS). Proportions of patients with PSARC response were assessed at wks 4, 8, 12, 24, 28, 40, and 52. Results PSARC results are summarized in Table 1. Statistically significantly higher PSARC response rates were observed as early as wk4 for both UST groups compared to PBO in the PSUMMIT 1 trial and statistically significantly higher responses were also observed at wks 8, 12 and 24 for both UST dose groups compared to PBO in both trials. Responses in both UST dose groups continued to increase after wk24, reached a plateau at wk 28 and were maintained through wk52. Patients who were initially randomized to PBO and crossed over to 45mg achieved similar responses to those originally randomized to UST. Higher PSARC responses were consistently observed at wk8-24 for both UST groups compared with the placebo group regardless of baseline MTX status. The early onset of PSARC responses observed was consistent with early onset of ACR 20 responses. UST was generally well-tolerated. Conclusions Significantly higher PSARC responses were observed as early as wk4-8 for both UST dose groups compared with PBO. Improvements observed at wk24 continued to increase at wk28 and were sustained through wk52. (Figure Presented).
Objective Assess ustekinumab efficacy (week 24/week 52) and safety (week 16/week 24/week 60) in patients with active psoriatic arthritis (PsA) despite treatment with conventional and/or biological anti-tumour necrosis factor (TNF) agents. Methods: In this phase 3, multicentre, placebocontrolled trial, 312 adults with active PsA were randomised (stratified by site, weight (≤100 kg/ >100 kg), methotrexate use) to ustekinumab 45 mg or 90 mg at week 0, week 4, q12 weeks or placebo at week 0, week 4, week 16 and crossover to ustekinumab 45 mg at week 24, week 28 and week 40. At week 16, patients with <5% improvement in tender/swollen joint counts entered blinded early escape ( placebo→45 mg, 45 mg→90 mg, 90 mg→90 mg). The primary endpoint was ≥20% improvement in American College of Rheumatology (ACR20) criteria at week 24. Secondary endpoints included week 24 Health Assessment Questionnaire-Disability Index (HAQ-DI) improvement, ACR50, ACR70 and ≥75% improvement in Psoriasis Area and Severity Index (PASI75). Efficacy was assessed in all patients, anti-TNF-naïve (n=132) patients and anti- TNF-experienced (n=180) patients. Results: More ustekinumab-treated (43.8% combined) than placebo-treated (20.2%) patients achieved ACR20 at week 24 ( p<0.001). Significant treatment differences were observed for week 24 HAQ-DI improvement (p<0.001), ACR50 (p≤0.05) and PASI75 (p<0.001); all benefits were sustained through week 52. Among patients previously treated with ≥1 TNF inhibitor, sustained ustekinumab efficacy was also observed (week 24 combined vs placebo: ACR20 35.6% vs 14.5%, PASI75 47.1% vs 2.0%, median HAQ-DI change -0.13 vs 0.0; week 52 ustekinumab-treated: ACR20 38.9%, PASI75 43.4%, median HAQ-DI change -0.13). No unexpected adverse events were observed through week 60. Conclusions: The interleukin-12/23 inhibitor ustekinumab (45/90 mg q12 weeks) yielded significant and sustained improvements in PsA signs/symptoms in a diverse population of patients with active PsA, including anti-TNF-experienced PsA patients.
OBJECTIVE: To evaluate ustekinumab efficacy and safety in psoriatic arthritis (PsA) patients with peripheral arthritis and physician-reported spondylitis (termed the 'spondylitis subset').
METHODS: Adults with active PsA (PSUMMIT-1/PSUMMIT-2, n=615/312) were randomised to ustekinumab 45 mg, 90 mg or placebo at week 0/week 4/q12 week. At week 16, patients with <5% improvement in tender and swollen joints entered blinded early escape. A subset of patients with physician-identified spondylitis was evaluated with spondylitis-specific assessments, including Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Ankylosing Spondylitis Disease Activity Score employing C reactive protein (ASDAS-CRP), through week 24.
RESULTS: 256/927 (27.6%) PSUMMIT-1/PSUMMIT-2 patients (placebo/ustekinumab, n=92/164) comprised the evaluable spondylitis subset. At week 24, in this analysis subset, significantly more patients achieved BASDAI20/50/70 responses (54.8%/29.3%/15.3% vs 32.9%/11.4%/0%; p≤0.002), improvement in BASDAI question 2 concerning axial pain (1.85 vs 0.24; p<0.001) and mean per cent ASDAS-CRP improvements (27.8% vs 3.9%; p<0.001) for ustekinumab versus placebo recipients, respectively. Comparable to the overall study population, significant improvements were also achieved in psoriasis, peripheral arthritis, enthesitis, dactylitis, physical function and peripheral joint radiographs in the spondylitis subset.
CONCLUSIONS: In this post-hoc analysis of PsA patients with baseline peripheral arthritis and physician-reported spondylitis, ustekinumab-treated patients demonstrated significant improvements in axial signs and symptoms through week 24.
TRIAL REGISTRATION NUMBER: PSUMMIT-1 (NCT01009086, EudraCT 2009-012264-14) and PSUMMIT-2 (NCT01077362, EudraCT 2009-012265-60); post-study results.
OBJECTIVE: To examine the effects of ustekinumab on patient‐reported outcomes (PROs) in PSUMMIT 1 and PSUMMIT 2 patients with active psoriatic arthritis (PsA) who were methotrexate (MTX) naive, MTX experienced, or anti‐tumor necrosis factor (TNF) experienced. METHODS: Patients in the phase 3, PSUMMIT 1 (n = 615) and PSUMMIT 2 (n = 312) studies randomly (1:1:1) received placebo, ustekinumab 45‐mg, or ustekinumab 90‐mg subcutaneous injections at weeks 0, 4, 16, 28, 40, and 52. The PROs (Health Assessment Questionnaire [HAQ] disability index [DI], Dermatology Life Quality Index [DLQI], 36‐Item Short Form [SF‐36] health survey physical (PCS) and mental component summary scores, patient assessments of pain and disease activity, and impact of disease on productivity) were assessed at weeks 0, 24, and 52. In these post hoc analyses, outcomes were compared between the ustekinumab and placebo groups for 3 mutually exclusive antecedent‐exposure populations from the combined studies: MTX/anti‐TNF naive (placebo, n = 56; 45 mg, n = 58; and 90 mg, n = 66), MTX experienced, biologic agent naive (placebo, n = 192; 45 mg, n = 190; and 90 mg, n = 185), and anti‐TNF experienced with or without MTX (placebo, n = 62; 45 mg, n = 60; and 90 mg, n = 58). RESULTS: At week 24, mean improvements from baseline in HAQ DI, DLQI, and SF‐36 PCS scores were significantly greater in both ustekinumab groups versus placebo across antecedent‐exposure groups. Greater proportions of ustekinumab‐treated than placebo‐treated patients (all P < 0.05) had clinically meaningful improvements in HAQ DI (≥0.3), DLQI (≥5), and SF‐36 (≥5) scores at week 24, irrespective of drug exposure. Improvements in pain, disease activity, and impact of disease on productivity were similar, and benefits were maintained through week 52. CONCLUSION: Significant improvements in PROs with ustekinumab versus placebo were observed in 3 antecedent‐exposure populations of PsA patients, including those with prior MTX and anti‐TNF use.
Objectives: To assess the relationship between changes in enthesopathy and in function/health-related quality of life (HRQoL) in anti-TNF-naïve patients (pts) with psoriatic arthritis (PsA) receiving treatment with ustekinumab (UST). Methods: Adult pts in 2 Phase 3 trials (n=747 anti-TNF naive) with active PsA (≥5 SJC and ≥5 TJC;CRP≥0.3mg/dL) despite DMARD and/or NSAIDs were randomized to UST45mg, 90mg, or PBO at weeks 0, 4, and q12weeks. Stable concomitant MTX was permitted but not mandated. At week16, pts with <5% improvement in TJC & SJC entered blinded early escape (PBO→UST45mg; UST45mg→90mg; 90mg→90mg). Presence or absence of enthesopathy, HAQDI, and SF-36 were assessed at baseline and week 24. In this post-hoc analysis, enthesopathy of the Achilles tendon and plantar fascia was assessed as present or absent. Pts were categorized thereafter as follows: improved (enthesopathy present at baseline, but not at week 24), worsened (enthesopathy present at week 24, but not at baseline), and unchanged. Pts with an enthesopathy assessment missing at either time point were included in the unchanged category; those with enthesopathy data missing at both time points were excluded. Early escape pts were also excluded from this analysis. Improvements in HRQoL (assessed by the SF-36 PCS and MCS and physical function (HAQ-DI) were assessed by enthesopathy response category. Results: A total of 591 anti-TNF-naïve pts from both trials were included in the analysis; 45% of pts were female, mean age was 47 years, mean PsA duration was 6.7 years, and 74% had ≥3% body surface area affected at baseline. The proportion of pts with enthesopathy at baseline was similar in the combined UST (46.5%) and placebo (49.4%) groups. At week 24, the proportions of pts with enthesopathy were 22.8% and 35.9% for the combined UST and placebo groups, respectively. Across all pts, those who had an improvement in enthesopathy had a greater improvement in functioning and HRQoL, compared with those who did not (p<0.05; Table). When the analysis was restricted to those who achieved an ACR 20 response, pts with an improvement in enthesopathy showed a trend of greater improvement in functioning and HRQoL compared to those who had worsened (Table). Conclusions: There is an association between improvement in enthesopathy of the Achilles tendon and plantar fascia and improvement in physical function and quality of life in anti-TNF-naïve pts with PsA in 2 UST trials. Some, but not all, of this improvement may be explained by improvements in peripheral arthritis. (Table Presented).
OBJECTIVE: To evaluate the associations of C-reactive protein (CRP) and circulating Th17-associated cytokine levels with psoriatic arthritis (PsA) disease activity and therapeutic response to ustekinumab.
METHODS: Interleukin-17A (IL-17A), IL-17F, IL-23, and CRP concentrations were measured in serum samples collected as part of the 2 PSUMMIT phase III studies of ustekinumab in PsA (n = 927). In post hoc analyses, relationships of IL-17A, IL-17F, and CRP levels at baseline, week 4, and week 24 with baseline skin and joint disease activity and response to therapy were evaluated using generalized linear models and Pearson's product-moment correlation tests.
RESULTS: Baseline serum levels of IL-17A and IL-17F were positively correlated with baseline skin disease scores (r = 0.39-0.62). IL-23 levels were correlated with skin disease scores to a lesser extent (r = 0.26-0.31). No significant correlations were observed between these cytokine or CRP levels and baseline joint disease activity. There was no significant association of baseline levels of IL-17A, IL-17F, IL-23, or CRP with therapeutic response to ustekinumab in either the skin or joints. Significant reductions from baseline in levels of IL-17A, IL-17F, and CRP were seen in patients treated with ustekinumab compared to those treated with placebo. Ustekinumab-treated patients in whom 75% improvement in the Psoriasis Area and Severity Index score or 20% improvement according to the American College of Rheumatology criteria was achieved after 24 weeks of treatment had greater reductions in CRP level (geometric mean decreases of 51-58% versus 32-33%; P < 0.05), but not IL-17A or IL-17F levels, than nonresponders.
CONCLUSION: Baseline serum IL-23/IL-17 levels correlated with skin, but not joint, disease activity, suggesting tissue-specific variation. However, neither baseline Th17-associated cytokine levels nor CRP level were predictive of therapeutic response to ustekinumab in the skin or joints, despite rapid reductions in their levels following ustekinumab therapy.
OBJECTIVE: Evaluate enthesitis, physical function, and health-related quality of life (HRQOL) among patients with psoriatic arthritis (PsA) who are naive to anti-tumor necrosis factor agents.
METHODS: In PSUMMIT 1 and 2, patients with PsA were randomized to placebo or ustekinumab 45 mg or 90 mg. Enthesitis was assessed at weeks 0 and 24 (Maastricht Ankylosing Spondylitis Enthesitis Score). Assessments included Health Assessment Questionnaire-Disability Index (HAQ-DI), Medical Outcomes Study Short Form-36 (SF-36) physical component summary/mental component summary (PCS/MCS), and American College of Rheumatology 20 (ACR20).
RESULTS: At Week 24, 21 had worsened enthesitis, 158 had improved enthesitis, and 412 had unchanged enthesitis. Improved enthesitis was associated with improvements in HAQ-DI and SF-36 MCS. Results were similar for ACR20 responders and nonresponders.
CONCLUSION: Improvement in enthesitis at Week 24 was associated with improvements in physical function/HRQOL regardless of ACR20 response.
Objective To evaluate the efficacy of ustekinumab by prior treatment exposure and disease duration in tumour necrosis factor inhibitor (TNF)-naïve patients with psoriatic arthritis (PsA) in the PSUMMIT 1 and PSUMMIT 2 studies. Methods In the phase 3, randomised, placebo-controlled PSUMMIT 1 and PSUMMIT 2 studies, adults with active PsA for ≥6 months despite conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and/or non-steroidal anti-inflammatory drugs (NSAIDs) (PSUMMIT 1) or csDMARDs, NSAIDs and/or anti-TNF agents (PSUMMIT 2) were enrolled. Patients were randomised to subcutaneous injections of placebo, ustekinumab 45 mg or ustekinumab 90 mg at weeks 0 and 4 and every 12 weeks. Efficacy was assessed at week 24 using the American College of Rheumatology criteria and 28-joint count disease activity score using C reactive protein (DAS28-CRP); radiographical progression, enthesitis, and dactylitis were also assessed in this post hoc analysis. Results A total of 747 patients were included; all 747 were TNF-naïve, of which, 179 were methotrexate-naïve and TNF-naïve, and 146 were all csDMARD-naïve and TNF-naïve. At week 24, greater proportions of ustekinumab-treated patients had ≥20%/50%/70% improvement in American College of Rheumatology criteria (ACR20/ACR50/ACR70) responses, DAS28-CRP response and DAS28-CRP remission versus placebo in all three prior-treatment populations, with similar differences between treatment groups. Greater proportions of ustekinumab-treated patients also had complete resolution of enthesitis and dactylitis at week 24 across the three prior-treatment populations. Mean changes from baseline in total van der Heijde-Sharp Score at week 24 were generally smaller for ustekinumab-treated patients versus placebo but were statistically significant only in the full TNF-naïve population. Response rates for ACR20/ACR50/ACR70 were similar for TNF-naïve patients with PsA durations of <1 year, ≥1 to <3 years, and ≥3 years. Conclusion Ustekinumab-treated patients demonstrated greater clinical response at week 24 compared with placebo regardless of prior treatment exposure and PsA disease duration.
INTRODUCTION: Theoretical risks of biologic agents remain under study.
OBJECTIVE: The aim of this study was to integrate 1-year safety data from 12 ustekinumab registrational trials.
METHODS: Patients had moderate-to-severe plaque psoriasis, active psoriatic arthritis (PsA) (± methotrexate), or moderate-to-severe Crohn's disease (CD; failed/intolerant of immunomodulators/corticosteroids). Psoriatic patients received subcutaneous ustekinumab 45/90 mg or placebo, generally at week 0, week 4, then every 12 weeks thereafter, while those with CD received a single intravenous ustekinumab dose (130 mg or weight range-based dosing of approximately 6 mg/kg) or placebo induction dose at week 0, followed by subcutaneous ustekinumab 90 mg at week 8 and every 8/12 weeks thereafter. The incidence rates of a priori-defined safety events were integrated post hoc (adjusted for duration of follow-up, reported per 100 patient-years [PYs]).
RESULTS: Among 6280 enrolled patients, 5884 ustekinumab-treated patients (psoriasis: 3117; PsA: 1018; CD: 1749) contributed 4521 PYs versus 674 PYs in placebo-treated patients through year 1 (829 PYs and 385 PYs during 8- to 16-week controlled periods). Combined across diseases among ustekinumab- versus placebo-treated patients, respective incidences/100 PYs (95% confidence intervals) of infections were 125.4 (122.2-128.7) versus 129.4 (120.9-138.3) through year 1, and not meaningfully increased in patients who did versus those who did not receive methotrexate (92.5 [84.2-101.5] vs. 115.3 [109.9-121.0]), or significantly increased in patients who did versus those who did not receive corticosteroids (116.3 [107.3-125.9] vs. 107.3 [102.0-112.8]) at baseline. Major adverse cardiovascular events (0.5 [0.3-0.7] vs. 0.3 [0.0-1.1]), malignancies (0.4 [0.2-0.6] vs. 0.2 [0.0-0.8]), and deaths (0.1 [0.0-0.3] vs. 0.0 [0.0-0.4]) were rare across indications.
CONCLUSIONS: Ustekinumab demonstrated a favorable and consistent safety profile across registrational trials in approved indications.
TRIAL REGISTRATIONS: ClinicalTrials.gov identifier: NCT00320216, NCT00267969, NCT00307437, NCT00454584, NCT00267956, NCT01009086, NCT01077362, NCT00265122, NCT00771667, NCT01369329, NCT01369342, and NCT01369355.
BACKGROUND: The interleukin‐12/23p40‐subunit‐inhibitor ustekinumab significantly improved spondylitis‐related symptoms through Week 24 in psoriatic arthritis (PsA) patients with peripheral arthritis and physician‐reported spondylitis (PA‐PRS) in PSUMMIT‐1&2. We further evaluated ustekinumab's effect on spondylitis‐related endpoints in PSUMMIT‐1&2 tumour necrosis factor‐inhibitor (TNFi)‐naïve patients with PA‐PRS. METHODS: Patients with active PsA (≥5 swollen and ≥5 tender joints, C‐reactive‐protein ≥ 3.0 mg/L) despite conventional (PSUMMIT‐1&2) and/or prior TNFi (PSUMMIT‐2) therapy received subcutaneous ustekinumab 45 mg, 90 mg or placebo (Week 0, Week 4, Week 16). Changes in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) neck/back/hip pain question (#2) and modified BASDAI (mBASDAI, excluding PA) scores and Ankylosing Spondylitis Disease Activity Score (ASDAS) responses were assessed at Weeks 12 and 24. RESULTS: The pooled PSUMMIT‐1&2, TNFi‐naïve (n=747), PA‐PRS (n=223) subset (158 with human‐leucocyte‐antigen (HLA)‐B27 results) presented with moderate‐to‐severe spondylitis‐related symptoms (mean BASDAI‐neck/back/hip pain‐6.51, mBASDAI‐6.54, BASDAI‐6.51, ASDAS‐3.81). Mean Week 24 changes were larger among ustekinumab than placebo‐treated patients for both neck/back/hip pain (‐1.99 vs ‐0.18) and mBASDAI (‐2.09 vs ‐0.59). Improvements in neck/back/hip pain and fatigue appeared numerically greater in HLA‐B27+ than HLA‐B27 ‐ patients; those for other domains were generally consistent. Greater proportions of ustekinumab versus placebo‐treated patients achieved ASDAS clinically important improvement at Week 24 (decrease ≥ 1.1; 49.6% vs 12.7%; nominal p<0.05). CONCLUSIONS: Improvements in BASDAI neck/back/hip pain and mBASDAI among ustekinumab‐treated, TNFi‐naïve, PsA patients with PA‐PRS were clinically meaningful and consistent across assessment tools. Numerically greater improvements in neck/back/hip pain in HLA‐B27+ than HLA‐B27 ‐ patients, noted in the context of similar overall mBASDAI improvements between the subgroups, suggest ustekinumab may improve disease activity in TNFi‐naïve PsA patients likely to exhibit axial disease. CLINICAL TRIAL REGISTRATION NUMBERS: PSUMMIT 1, NCT01009086; PSUMMIT 2, NCT01077362.
OBJECTIVE: To investigate serum protein expression in participants with psoriatic arthritis (PsA) and changes after guselkumab treatment.
METHODS: Participants with PsA were treated with guselkumab or placebo in the DISCOVER-1 and DISCOVER-2 studies. Serum levels of acute phase reactants C reactive protein (CRP) and serum amyloid A (SAA) and inflammatory cytokines/chemokines were measured at weeks 0, 4 and 24 in 300 study participants and 34 healthy controls (HCs). The PSUMMIT studies measured serum interleukin (IL)-17A, IL-17F and CRP after ustekinumab treatment and levels with ustekinumab versus guselkumab treatment were compared.
RESULTS: Baseline serum levels of CRP, SAA, IL-6, IL-17A and IL-17F were elevated in participants with active PsA vs HCs (p<0.05, geometric mean (GM) ≥40% higher). Baseline T-helper cell 17 (Th17) effector cytokines were significantly associated with baseline psoriasis but not joint disease activity. Compared with placebo, guselkumab treatment resulted in decreases in serum CRP, SAA, IL-6, IL-17A, IL-17F and IL-22 as early as week 4 and continued to decrease through week 24 (p<0.05, GM decrease from baseline ≥33%). At week 24, IL-17A and IL-17F levels were not significantly different from HCs, suggesting normalisation of peripheral IL-23/Th17 axis effector cytokines postguselkumab treatment. Reductions in IL-17A/IL-17F levels were greater in guselkumab-treated versus ustekinumab-treated participants, whereas effects on CRP levels were similar.
CONCLUSION: Guselkumab treatment reduced serum protein levels of acute phase and Th17 effector cytokines and achieved comparable levels to those in HCs. In participants with PsA, reductions of IL-17A and IL-17F were of greater magnitude after treatment with guselkumab than with ustekinumab.
The purpose of this study is to evaluate the efficacy (improvement of signs and symptoms) and safety of ustekinumab in patients with psoriatic arthritis.
País»Austria,Canada,France,Germany,Hungary,Poland,Russian Federation,Sweden,United Kingdom,United States
Diseño del estudio»Ensayo controlado aleatorizado (ECA)
