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Efficacy and safety of ustekinumab in psoriatic arthritis patients with peripheral arthritis and physician-reported spondylitis: post-hoc analyses from two phase III, multicentre, double-blind, placebo-controlled studies (PSUMMIT-1/PSUMMIT-2)
  1. Arthur Kavanaugh1,
  2. Lluis Puig2,
  3. Alice B Gottlieb3,
  4. Christopher Ritchlin4,
  5. Yin You5,
  6. Shu Li5,
  7. Michael Song6,
  8. Bruce Randazzo6,7,
  9. Proton Rahman8,
  10. Iain B McInnes9
  1. 1Division of Rheumatology, Allergy, and Immunology, University of California-San Diego, La Jolla, California, USA
  2. 2Department of Dermatology, Hospital de la Santa Creu I Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain
  3. 3Department of Dermatology, Tufts Medical Center, Boston, Massachusetts, USA
  4. 4Department of Dermatology, University of Rochester, Rochester, New York, USA
  5. 5Department of Biostatistics, Janssen Research & Development, LLC, Spring House, Pennsylvania, USA
  6. 6Department of Immunology, Janssen Research & Development, LLC, Spring House, Pennsylvania, USA
  7. 7University of Pennsylvania, Philadelphia, Pennsylvania, USA
  8. 8Department of Dermatology, Memorial University, St. Johns, Newfoundland, Canada
  9. 9College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
  1. Correspondence to Professor Arthur Kavanaugh, Department of Rheumatology, University of California-San Diego, 9500 Gilman Drive, MC 0943, La Jolla, CA 92093-0943, USA; akavanaugh{at}ucsd.edu

Abstract

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.

  • Psoriatic Arthritis
  • DMARDs (biologic)
  • Spondyloarthritis
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Introduction

Psoriatic arthritis (PsA), a chronic inflammatory arthritis characterised by skin and nail psoriasis, synovitis, enthesitis and dactylitis, can occur in up to 20%–30% of patients with psoriasis.1 Inflammatory axial involvement/spondylitis has been reported in 25%–75% of patients with PsA. Most cases of spondylitis are accompanied by peripheral arthritis.2–4

While methotrexate (MTX) has been the disease-modifying antirheumatic drug (DMARD) of choice for PsA, anti-tumour necrosis factor (TNF) biologics are now largely viewed as more effective for the varied PsA manifestations. Additionally, success with biologics has spurred interest in newer therapies, including the anti-interleukin (IL)-12/IL-23 monoclonal antibody ustekinumab, which has demonstrated efficacy in PsA, particularly for active or severe skin manifestations.1 Ustekinumab efficacy and safety in PsA were primarily established in phase III PSUMMIT-15 and PSUMMIT-26 trials evaluating patients with active disease despite conventional and/or biological anti-TNF (PSUMMIT-2 only) treatment. Ustekinumab significantly inhibited radiographic progression of joint damage in PsA.7

In observational studies, etanercept and adalimumab demonstrated efficacy in improving axial manifestations of PsA.8 ,9 Treatments for PsA axial disease have not yet been well studied, partially because standardised, prospectively applied selection criteria for identifying such patients are lacking.10 The Assessment of SpondyloArthritis international Society (ASAS), however, has identified several measures to assess spondyloarthritis activity in clinical trials, including the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)11 and the Ankylosing Spondylitis Disease Activity Score incorporating C reactive protein (ASDAS-CRP).12 The BASDAI includes assessments of fatigue, spinal pain, peripheral arthritis, enthesitis, morning stiffness and its second question pertaining to overall levels of neck, back, hip pain is recommended for spondyloarthritic pain assessment.13 We performed post-hoc analyses of data related to these and other outcomes from PSUMMIT-1 and PSUMMIT-2 to assess the efficacy and safety of ustekinumab in a subset of PsA patients with peripheral arthritis and physician-reported spondylitis.

Patient and methods

The PSUMMIT-1 (NCT01009086, EudraCT 2009-012264-14)5 and PSUMMIT-2 (NCT01077362, EudraCT 2009-012265-60)6 studies were conducted according to the Declaration of Helsinki/International Committee on Harmonisation good clinical practices. Protocols were approved by each site's governing ethical body; all patients provided written informed consent.

Adult patients with active PsA (≥5/66 swollen and ≥5/68 tender joints), for ≥6 months despite ≥3 months of DMARDs and/or ≥4 weeks of non-steroidal anti-inflammatory drugs, were enrolled. PSUMMIT-1 included 615 patients with no prior biological treatment. In PSUMMIT-2, 180/312 randomised patients received anti-TNF agents previously. All patients were randomised to receive ustekinumab 45 mg, 90 mg or placebo at week 0, week 4 and every 12 weeks (q12 weeks). Early escape was established at week 16. Placebo patients received ustekinumab, beginning at week 24 per protocol. Further details of trial conduct have been published5 ,6 and are summarised in online supplementary material.

The current report evaluates ustekinumab treatment through week 24 in a subset of PSUMMIT-1 and PSUMMIT-2 PsA patients with baseline physician-reported spondylitis. The presence of spondylitis was based solely on the treating physician's assessment and was not contingent upon radiographic/imaging evidence.

Disease activity was assessed via BASDAI, a self-assessment tool for ankylosing spondylitis (AS),11 comprising the six questions detailed in table 2. The minimum clinically important difference in BASDAI score from the patient's perspective has been reported as 10 mm/1 point.14 Although BASDAI is not adequately validated in PsA, in patients with axial PsA, ASDAS and BASDAI scores show similar good-to-moderate discriminative ability and correlation with different constructs of disease activity.15 The ASDAS-CRP,12 determined post hoc, is a composite score incorporating BASDAI questions 2, 3, and 6; the patient-reported global assessment of disease activity during the previous week (0=not active, 10=very active); and CRP (mg/L). Additional clinical assessments are detailed in online supplementary material.

Physical function was assessed using the Health Assessment Questionnaire Disability Index (HAQ-DI, 0–3).16 Quality of life was assessed via the Dermatology Life Quality Index (DLQI) score (0–30)17 among patients with ≥3% body surface area (BSA) affected by psoriasis at baseline. Radiographs of the hands and feet were scored using the PsA-modified (to include scores for the distal interphalangeal hand joints and pencil-in-cup and gross osteolysis deformities) van der Heijde–Sharp (vdH-S) method18 by two independent readers.7

Treatment differences were assessed using Cochran–Mantel–Haenszel tests and analyses of variance on the van der Warden score adjusted for baseline MTX usage. Treatment failure and early escape rules were applied as detailed in the online supplementary material and described previously.5–7

Results

Patient disposition and baseline characteristics

The PSUMMIT trials were conducted between November 2009 and January 2013.7 Among the 1771 patients screened, 927 were randomised. Patient disposition has been described.5 ,6

Of the 927 randomised patients with PsA, 256 (27.6%) were reported by their physicians as having baseline spondylitis. Patient/disease characteristics were consistent between this spondylitis subset and the overall study population, as well as across randomised treatment groups (table 1). The proportions of patients with baseline enthesitis/dactylitis in this spondylitis subset (table 1) were consistent with the overall population, that is, 80.5% vs 71.4% (662/927), respectively, for enthesitis, and 51.6% vs 45.6% (423/927) for dactylitis, respectively.5 ,6

Table 1

Summary of baseline patient and disease characteristics among randomised PsA patients with peripheral arthritis with and without physician-reported spondylitis at baseline in PSUMMIT-1 and PSUMMIT-2

Clinical responses

Significantly higher proportions of ustekinumab-treated than placebo-treated spondylitis subset patients achieved BASDAI20 (54.8% vs 32.9%; p=0.002), BASDAI50 (29.3% vs 11.4%; p=0.002) and BASDAI70 (15.3% vs 0%; p<0.001) responses at week 24. Mean improvements from baseline in BASDAI scores at weeks 12/24 exceeded the minimal clinically important difference (MCID) (1.0) for ustekinumab-treated (1.78/2.05) but not placebo-treated (0.62/0.74) patients, and mean improvements from baseline to week 24 in BASDAI questions were numerically greater in ustekinumab-treated than placebo-treated patients (table 2).

Table 2

Summary of efficacy at weeks 12 and 24 among randomised PsA patients with peripheral arthritis and physician-reported spondylitis at baseline in PSUMMIT-1 and PSUMMIT-2

Improvements in BASDAI question 2 (‘How would you describe the overall level of neck, back or hip pain you have had?’) at week 24 were greater with ustekinumab (1.85) than with placebo (0.24; p<0.001) (table 2). Regardless of baseline MTX use, ustekinumab-treated patients demonstrated consistent improvement across all BASDAI questions versus placebo (see online supplementary table S1).

At weeks 12 and 24, ustekinumab-treated spondylitis subset patients experienced significant (p<0.001) improvement in ASDAS-CRP. Mean per cent improvements from baseline to week 24 approached 30% among ustekinumab-treated patients versus <5% with placebo (figure 1).

Figure 1

Mean Ankylosing Spondylitis Disease Activity Score incorporating C reactive protein (ASDAS-CRP) (A) and mean per cent improvement from baseline (B) at weeks 12 and 24 among randomised patients with peripheral arthritis and physician-reported spondylitis at baseline in PSUMMIT-1 and PSUMMIT-2.

Consistent with the overall PSUMMIT-1 and PSUMMIT-2 study populations,5 ,6 significantly higher proportions of ustekinumab-treated than placebo-treated patients with spondylitis achieved at least 20% improvement in the American College of Rheumatology response criteria (43.9% vs 22.8%; p<0.001) and at least 75% improvement in the Psoriasis Area and Severity Index response criteria (63.5% vs 11.6%; p<0.001) at week 24. Additionally, significantly larger mean per cent improvements with ustekinumab than with placebo treatment were observed in Maastricht Ankylosing Spondylitis Enthesitis Score index (46.7% vs 16.0%; p=0.017) and dactylitis (57.5% vs 11.0%; p<0.001) scores at week 24.

Physical function and quality of life

Ustekinumab treatment of PsA spondylitis subset patients resulted in significant improvement in physical function from baseline to week 24 (mean improvements in HAQ-DI of 0.33 for ustekinumab vs 0.11 for placebo; p<0.001; table 2).

Quality of life, assessed by the DLQI in patients with ≥3% of BSA baseline psoriasis involvement, was significantly improved with ustekinumab versus placebo at week 24 (mean improvements of 8.09 for ustekinumab vs 1.97 for placebo; p<0.001; table 2).

Radiographic response

Consistent with the overall population,7 significantly less peripheral (hands/feet) radiographic progression was observed at week 24 in PsA spondylitis subset patients treated with ustekinumab versus placebo (mean changes in PsA-modified vdH-S score from baseline of 0.00 to 1.51; p=0.003; see online supplementary figure S1).

Adverse events

During placebo control (week 0–16), adverse event (AE) rates were generally comparable between combined ustekinumab and placebo for all AEs (34.8% vs 41.3%), serious AEs (1.2% vs 2.2%), discontinuations due to AEs (0.6% vs 3.3%) and infections (13.4% vs 16.3%) (see online supplementary table S2).

Discussion

As established in the phase III PSUMMIT-15 and PSUMMIT-26 trials, the anti-IL-12/IL-23 monoclonal antibody ustekinumab is safe and effective for patients with active PsA. Axial involvement/spondylitis can occur in a substantial proportion of patients with PsA.2–4 The IL-23/IL-17 axis is emerging as an important inflammatory pathway in axial spondyloarthritis. Strong genetic associations with IL23R and polymorphisms have been shown in AS,19 ,20 suggesting that IL-23 may be involved in the pathology of AS.21

The current report, derived from 256/927 (27.6%) randomised PSUMMIT-1/PSUMMIT-2 PsA patients with peripheral arthritis and physician-reported spondylitis, is the first evaluation of ustekinumab in a spondylitis subset of patients with PsA. The post-hoc analyses included clinical measures identified by ASAS for use in clinical trials of spondyloarthritis (BASDAI, ASDAS-CRP).

Approximately one-third of randomised patients were identified by their treating physicians as having spondylitis, which is at the lower end of the reported prevalence range, that is, 25%–75% of patients with PsA,2–4 indicating this subset is not likely an overestimate of the disease state by physician assessment.

Significantly higher proportions of combined ustekinumab-treated than placebo-treated spondylitis subset patients achieved BASDAI20/50/70 responses at week 24. Improvements in BASDAI question 2 relating to overall spondylitis status at week 24 also were significantly greater with ustekinumab than placebo. The consistent improvement with ustekinumab versus placebo across all BASDAI questions was not impacted by baseline MTX use.

BASDAI findings were confirmed by ASDAS-CRP results, with ustekinumab-treated patients with spondylitis experiencing significant improvement at weeks 12 and 24 versus placebo. Furthermore, safety findings in the spondylitis subset are consistent with the overall PsA populations of PSUMMIT-1 and PSUMMIT-2.5 ,6

These post-hoc analyses are limited by patient spondylitis status being based on the treating physician's judgement and not determined by baseline axial radiographs. These patients also had severe peripheral arthritis; changes in quality-of-life/physical function could be confounded by changes in peripheral disease. Thus, large, long-term, prospective, phase III trials of ustekinumab in patients with PsA and imaging-documented spondylitis are needed to confirm these preliminary findings.

Acknowledgments

The authors thank Michelle Perate, MS, a paid consultant for Janssen Scientific Affairs, LLC, and Julie Thomas, PharmD, an employee of Janssen Scientific Affairs, LLC, for writing and editorial support.

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Footnotes

  • Handling editor Tore K Kvien

  • Contributors All authors fulfilled each of the four ICMJE criteria for authorship, including approving the revised draft for resubmission to the journal.

  • Funding Janssen Research & Development, LLC (Spring House, Pennsylvania, USA) provided funding for the studies contributing data to the reported analyses.

  • Competing interests AK has received funding for clinical research sponsored by Abbott, Amgen, Janssen and UCB and consultancy fees from AbbVie, Amgen, Janssen, Novartis and Pfizer. LP has received research support from/served as a clinical trial principal investigator for AbbVie, Amgen, Janssen, Lilly, Novartis, Pfizer and VBL; served as a consultant/speaker for AbbVie, Amgen, Boehringer, Celgene, Janssen, Leo-Pharma, Lilly, MSD, Merck-Serono, Novartis, Pfizer and Sandoz; and has been a Speakers Bureau/Advisory Board member for Celgene, Janssen, Novartis and Pfizer. ABG has consulting/advisory board agreements in place with Abbott Labs (AbbVie), Actelion, Akros, Amgen, Astellas, Baxalta, Beiersdorf, Bristol Myers Squibb Co, Canfite, Catabasis, Celgene, Coronado, CSL Behring Biotherapies for Life, Dermipsor, Genentech, Glaxo Smith Kline, Incyte, Janssen, Karyopharm, Lilly, Meiji Seika Pharma Co, Mitsubishi Tanabe Pharma Development America, Novartis, Novo Nordisk, Pfizer, Takeda, TEVA, UCB, Vertex and Xenoport; and has received research/educational grants (paid to Tufts Medical Center) from Amgen, Abbott (AbbVie), Baxalta, Celgene, Coronado, Dermira, Janssen, Levia, Lilly, Merck, Novartis, Pfizer and Xenoport. CR has received grant/research support from Janssen. YY, SL, MS and BR are employees of Janssen Research and Development, LLC. PR has received grant/research support from Janssen and has served as a speaker/consultant for AbbVie, BMS, Janssen, Novartis, Pfizer and UCB. IBM has received grant/research support from Astra Zeneca, BMS, Janssen, Pfizer and UCB and has served as a speaker/consultant for AbbVie, Astra Zeneca, BMS, Janssen, Novartis, Pfizer and UCB.

  • Ethics approval Multicentre trials.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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