Abstract
Objective Several advanced therapies have been licensed across the related conditions of psoriatic arthritis (PsA), Crohn disease (CD), ulcerative colitis (UC), and noninfectious uveitis. We sought to summarize results from randomized controlled trials (RCTs) investigating the efficacy and safety of advanced therapies for these related conditions in patients with PsA.
Methods We updated the previous systematic search conducted in 2013 with literature reviews of MEDLINE, Embase, and the Cochrane Library (from February 2013 to August 2020) on this subject; only those new studies are presented here. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework.
Results The number of RCTs meeting eligibility criteria were 12 for CD, 15 for UC, and 5 for uveitis. The tumor necrosis factor inhibitor (TNFi) class appears to be efficacious and safe across CD, UC, and uveitis, with the exception of etanercept. Interleukin 12/23 inhibitors (IL-12/23i) are efficacious for CD and UC. Phase II and III RCTs of Janus kinase inhibitors (JAKi) and IL-23i in CD and UC are promising in terms of efficacy and safety. IL-17i must be used with great caution in patients with PsA at high risk of inflammatory bowel disease (IBD). RCTs in uveitis have mainly studied adalimumab.
Conclusion We have identified 32 recent RCTs in IBD and uveitis and updated recommendations for managing patients with PsA and these related conditions. A multispecialty approach is essential to effectively, safely, and holistically manage such patients. Advanced therapies are not equally efficacious across these related conditions, with dosing regimens and safety varying.
Psoriatic arthritis (PsA) is known to have a shared pathogenesis with inflammatory bowel diseases (IBD), such as Crohn disease (CD), ulcerative colitis (UC), and IBD-unclassified (IBD-U), and different forms of inflammatory eye disease. The evidence for this is derived from epidemiological and genetic studies showing shared heritability and familial clustering.1-4
Cohort studies and metaanalyses estimate a lifetime risk of incident IBD in patients with spondyloarthritis (SpA) to be 4% to 14%, and perhaps higher in axial compared with peripheral SpA.1,3,4 Macroscopic intestinal inflammation is estimated to affect 30-44%2,5 and microscopic inflammation 46-66%2,6 of patients with SpA in general, but especially those with axial predominant SpA (axSpA).
Uveitis is characterized by inflammation of the uvea and is anatomically classified into anterior, intermediate, posterior, and panuveitic eye inflammation types. Approximately 30% to 40% of patients with uveitis have an associated immune-mediated inflammatory disease (IMID),7,8 while other infectious etiologies (viral, fungal, or bacterial) or injuries exist. A large number of uveitis cases do not fit into any well-defined diagnostic category and are labeled idiopathic. One of the differences between PsA and axSpA is that in PsA, the acute anterior form of uveitis is less common.9 IMID has therefore been proposed as a more precise term for these and other overlapping conditions.10
Our objectives were to summarize results from recent RCTs in patients with IBD and/or uveitis and investigate the efficacy and safety of advanced therapies, which have also been tested in patients with PsA, to inform treatment choices in patients with PsA.
METHODS
Literature search. A systematic search was conducted in 2013 to inform the 2014 GRAPPA treatment recommendations for PsA.11 We conducted an update of the 2013 systematic review to inform the 2021 update of the GRAPPA treatment recommendations regarding related conditions.12 These related conditions included CD, UC, and uveitis (including noninfectious etiologies of acute and chronic anterior uveitis, posterior uveitis, and panuveitis). In the present paper, we present only the results of studies published since February 2013 until August 2020.
Inclusion/exclusion criteria. We sought to identify RCTs in patients with IBD or uveitis who were treated with pharmaceutical drugs recognized as treatments for PsA and that had a placebo comparator arm. Eligibility criteria are detailed in Table 1. Comprehensive searches were conducted of 3 bibliographic databases (MEDLINE, Embase, and the Cochrane Library; see Supplementary Table 1 for MEDLINE search, available with the online version of this article) from February 19, 2013, to August 28, 2020. Open-label extension (OLE) and long-term extension (LTE) studies meeting eligibility criteria, but found to no longer have a control treatment arm, were excluded from further analysis.
Eligibility criteria for searches of RCTs in patients with IBD or uveitis treated with pharmaceutical drugs recognized as treatments for PsA.
Data extraction. Unique article titles and abstracts were screened by a single coauthor against predefined eligibility criteria (Table 1). Full-text articles of those remaining were independently assessed by pairs of coauthors (formed based upon volunteering for this duty) for eligibility, with a third reviewer (DRJ or MEH) consulted in the case of disagreements. No significant disagreements were encountered. Included studies underwent data extraction and assessment for risk of bias using the Cochrane risk of bias tool by 1 coauthor and were independently checked by a second coauthor (NC), with a third reviewer (DRJ or MEH) consulted in the case of disagreements.13 No significant disagreements were encountered.
GRADE rating. Each eligible trial was assessed using the GRADE-level assessment of quality of evidence.14 Several coauthor group meetings were undertaken to reach a consensus on recommendation for (strong/weak), recommendation against (strong/weak), or no recommendation (no, insufficient, or conflicting evidence) for each agent. The GRADE recommendations were made based on prior reviews and the updated RCTs.12
Ethics. This paper does not require ethical or institutional review board approval.
RESULTS
We screened 311 full-text articles and reviewed 72 potential RCTs (Figure); 40 were excluded because of lack of controls or missing outcome data. We included 32 eligible RCTs for review: 12 RCTs for CD (Table 2), 15 RCTs for UC (Table 3), and 5 RCTs for uveitis (Table 4).
Flowchart of the study selection process for RCTs of CD, UC, and uveitis with treatments used in PsA. CD: Crohn disease; PsA: psoriatic arthritis; RCT: randomized controlled trial; UC: ulcerative colitis.
Advanced therapy PBO-controlled RCTs in Crohn disease. Efficacy and safety results for new studies from February 2013 to August 2020.
Advanced therapy PBO-controlled RCTs in UC. Efficacy and safety for new studies from February 2013 to August 2020.
Advanced therapy PBO-controlled RCTs in noninfectious uveitis. Efficacy and safety in new studies from February 2013 to August 2020.
RCTs of CD
Twelve RCTs met eligibility criteria for final reporting, as shown in Table 2.15-26 Since 2013, no new primary studies comparing adalimumab (ADA) or golimumab (GOL) with placebo have been published. Several treatments had OLE or LTE studies without a placebo arm and were excluded. No study reported if the subjects had concomitant PsA, SpA, inflammatory arthritis, psoriasis, or uveitis.
TNFi. The PREVENT RCT15 studied 297 biologic-experienced cases with ileocolonic resection and anastomosis (Table 2). Participants randomized to infliximab (IFX) vs placebo were no more likely to attain the study’s primary endpoint of no clinical recurrence at week 76, nor was efficacy found for most secondary endpoints. IFX was only statistically significantly better than placebo as measured by the probability of endoscopic recurrence.
IL-12/23i: Ustekinumab. The phase III UNITI portfolio of RCTs testing ustekinumab (UST) induction and maintenance therapy in patients with CD who are TNFi-naïve (n = 761) and TNFi-inadequate responders (IR; n = 397) showed consistent and statistically significant efficacy of UST (p40-specific subunit inhibitors of IL-23) over placebo for the primary and most secondary endpoints, without new safety signals, both at week 6 and week 44 (Table 2).16,17
IL-23i: Risankizumab. A phase II RCT of risankizumab (RZB; p19-specific subunit inhibitors of IL-23) enrolled 121 CD cases and stratified by steroid-IR, conventional synthetic-IR, and TNFi-IR.18 RZB at 600 mg (but not 200 mg) was significantly more efficacious than placebo across all primary and secondary endpoints, with no new safety signals.18 A phase III study for this agent is in progress.
IL-23i: MEDI2070. A phase IIa RCT of MEDI2070 (IL-23i, subsequently called brazikumab) enrolled 121 TNFi-IR cases and stratified by lines of TNFi previously used.19 MEDI2070 was significantly more likely than placebo to attain the primary endpoint (100-point improvement in the Crohn’s Disease Activity Index [CDAI] at week 8) and efficacy was also found for several secondary endpoints. Phase III studies for this agent are in progress.
IL-17i: Brodalumab. Targan et al demonstrated a detrimental effect of brodalumab (BRO; IL-17A receptor antagonist) on CD in a study of 130 steroid-IR, conventional synthetic-IR, and biologic-naïve CD cases (Table 2).20 Despite eligibility criteria only permitting the recruitment of patients with mild severity CD, patients treated with placebo were far more likely to achieve the primary endpoint (150 point improvement in CDAI at week 6) than all BRO dose groups. Placebo and BRO groups were not statistically different for secondary endpoints.
IL-6i: PF-04236921. PF-04236921 (IL-6i) was tested in a dose-ranging phase II RCT of 247 TNFi-IR cases with CD.21 The 50 mg dose was more likely than placebo to attain the primary endpoint (70-point improvement in CDAI at week 12), but few secondary endpoints showed efficacy (Table 2).
JAKi: Tofacitinib. The JAKi tofacitinib (TOF), has been tested in 1 phase II RCT22,23 reported at week 4 and at week 24, as shown in Table 2. The 139 steroid-IR, conventional synthetic-IR, and/or biologic-IR cases were stratified by baseline CDAI, then randomized to TOF 1 mg/day, 5 mg/day, 15 mg/day, or placebo. The primary endpoint (70-point improvement in CDAI at week 4) was statistically no different in the TOF arms vs the placebo arm. The secondary endpoints (100-point improvement in CDAI and 10-item IBD Questionnaire) did not show efficacy.22 TOF has not attained regulatory approvals for CD, and no phase III studies are in progress.
JAKi: Filgotinib. A phase II RCT of another JAKi, filgotinib (FILGO), recruited 174 conventional synthetic-IR cases with CD and randomized participants to either FILGO (100 mg 4 times daily [QID] or 200 mg QID) or placebo.24 FILGO (200 mg) was found to be significantly more likely than placebo to attain the primary endpoint of CDAI improvement at week 10 and most secondary endpoints. The safety profile was clinically acceptable and risk of bias was low.24 Phase III RCTs are in progress.
JAKi: Upadacitinib. A phase II dose-ranging RCT tested 5 doses of upadacitinib (UPA; JAKi) in 220 steroid-IR, conventional synthetic-IR, and/or biologic-IR cases (Table 2).25 During the 16-week induction, the higher doses of UPA were most efficacious, without altering safety profiles. However, by week 52 there was no significant difference in the primary endpoint (clinical remission) between the UPA arms and placebo.26 Endoscopic remission was statistically more likely with higher-dose UPA than placebo.26 Phase III RCTs are in progress.
Summary of treatments for CD. Coauthor consensus meetings reviewed the several large high-quality RCTs of TNFi and 1 large RCT of UST and made a strong recommendation for both (Table 5). For IL-23i, good efficacy was seen for RZB and MEDI2070, but this was only supported by 1 RCT for each; thus, the group made a weak recommendation for IL-23i in CD, pending the publication of further results. JAKi treatments (UPA and FILGO) have weak recommendations for, whereas TOF, which did not show efficacy in CD, was given a weak recommendation against use. The group agreed on a strong recommendation against IL-17i in CD, given the lack of improvement in CD seen with BRO compared with placebo. As there was only 1 medium-sized RCT of IL-6i, there was insufficient evidence to make a recommendation. No recent studies were found for GOL or etanercept (ETN).
Summary of GRADE recommendations for advanced treatments for CD, UC, and uveitis.
RCTs of UC
A total of 23 studies were screened and 15 were eligible for review, as shown in Table 3,27-41 with 8 studies excluded because of long-term maintenance or a lack of control group.
ADA. The efficacy and safety of ADA compared to placebo has been reported in active UC in 4 RCTs.27-30 Two trials, Ulcerative Colitis Long-Term Remission and Maintenance with Adalimumab (ULTRA) 1 (N = 576) and ULTRA 2 (N = 248), evaluated an 8-week induction therapy with ADA and demonstrated better remission, mucosal healing, and quality of life (QOL) compared to placebo.28,29 During the ULTRA 3 trial, an additional trial focusing on TNFi-experienced patients, lower response rates compared to TNFi-naïve patients were observed,29 with similar efficacy and safety seen at year 4.30 A RCT performed in Japan found 23.2% of patients treated with ADA achieved remission by week 52, and 32.5% of the patients were able to taper down corticosteroids.27
GOL. GOL, another TNFi biologic, was studied in 5 RCTs.31-35 The PURSUIT trials included 2 6-week inductions trials, a maintenance study and a study in a Japanese cohort.31,33-35 The PURSUIT-M trial demonstrated early clinical response to GOL treatment.31 The phase III trial, PURSUIT-J (N = 144) demonstrated that subcutaneous GOL maintained clinical efficacy to week 54 among induction responders.32 More patients randomized to GOL in PURSUIT-SC achieved a clinical response at 6 weeks and were more likely to achieve remission and mucosal healing.33 In PURSUIT-IV (N = 291), a single-dose IV administration of GOL in patients with moderate-to-severe UC did not lead to significant improvements in clinical outcomes.35
Methotrexate. Two RCTs determined that methotrexate (MTX) was not superior to placebo in induction of steroid-free remission among patients with UC who are steroid-dependent.36,37 Further, the prevention of UC relapse was not significantly different between groups during the 48-week maintenance part of this trial.37
Apremilast. An oral inhibitor of phosphodiesterase 4, apremilast (APR), was evaluated in a phase II RCT in patients with active UC, but showed no efficacy compared to placebo.38
TOF. The Oral Clinical Trials for Tofacitinib in Ulcerative Colitis (OCTAVE) portfolio of trials studied TOF in adults with active UC.39,40 In the phase II trial (N = 194), patients on TOF (15 mg) reported a significant improvement of symptoms from baseline compared with placebo.39 In the induction trials, TOF (10 mg) twice daily achieved clinical remission in 18.5% of OCTAVE 1 patients and 16.6% of OCTAVE 2 patients.40 The OCTAVE Sustain (N = 593) maintenance phase further confirmed the efficacy of TOF, with 40.6% of patients taking 10 mg twice daily and 34.3% of patients taking 5 mg twice daily achieving clinical remission, compared with only 11.1% of patients taking placebo.40 In terms of safety, there was similar increased risk of herpes zoster as was seen in rheumatoid arthritis and psoriasis trials, with a higher rate of serious infection compared with placebo.40
UST. A large RCT of UST (N = 961) with an 8-week induction and 44-week maintenance found UST was more effective than placebo for reducing UC remissions.41
Summary of treatments for UC. Based on our review and our coauthor consensus meetings (Table 5), a strong recommendation was made for TNFi (ADA and GOL), JAKi (TOF), and IL-12/23i (UST), all with a low risk of bias. For the phosphodiesterase-4 inhibitor (APR), there is a single small study that did not show efficacy in UC and so the group made a weak recommendation against. For MTX, as both RCTs did not show efficacy in UC, a strong recommendation against was given. No recent RCTs for ETN or certolizumab pegol were found.
RCTs of uveitis
A total of 7 RCTs were screened and 5 RCTs (Table 4) were eligible.42-46 Corticosteroids have long been the standard treatment for patients with ocular inflammation; however, their long-term use confers risks to patients.47,48 We sought to summarize the RCTs of uveitis treatments, other than corticosteroids, that are also commonly used to treat patients with PsA.
ADA. Three RCTs assessed the efficacy of ADA in treating flares of uveitis and improvement in visual acuity scores.42-44 In 2 trials, patients received prednisone at baseline along with ADA treatment, which was then tapered and stopped during the trial.42,43 ADA demonstrated steroid-sparing effects and flares of uveitis were delayed compared with the placebo group.42,43 A small RCT in cases of refractory noninfectious uveitis showed significant reduction in ocular inflammation in the ADA group.44
Secukinumab. Secukinumab (SEC; IL-17i) demonstrated efficacy in a small trial of acute-on-chronic noninfectious uveitis.45 Patients with uveitis receiving intravenous (at significantly higher doses than are used in clinical practice) vs subcutaneous SEC responded faster and with greater likelihood of remission.45 Perhaps subcutaneous SEC did not attain sufficient concentrations for uveitis treatment in this trial.
MTX. One RCT evaluated the QOL in patients with uveitis treated with either MTX or mycophenolate mofetil.46 Although the visual symptoms improved, the overall physical health scores did not show improvement and mental health-related QOL scores declined.
Summary of treatments for uveitis. Uveitis presents a challenge to make definitive recommendations, as studies were done in a uveitis cohort and extrapolated to PsA. The 2 large RCTs and 1 smaller RCT of ADA in uveitis, with low risk of bias, allowed the group to make a weak recommendation for TNFi (Table 5), except for ETN, with a weak recommendation against. A small comparison trial led to a weak recommendation for MTX based on improved QOL indicators. There was only 1 small trial in SEC that met our criteria, and the consensus was that there was insufficient evidence to make a recommendation from this single study.
DISCUSSION
In keeping with our eligibility criteria, in this review we have only reported on RCTs in the Results section. In the forthcoming Discussion, we will highlight and signpost the reader to notable non-RCT studies for further reading.
Our review of the literature demonstrated that not all treatments used for PsA are also effective for IBD and/or uveitis, dosing regimens can vary, there can be safety considerations, and reimbursement depends upon the indication. We propose that the outcomes of these trials may be extrapolated to patients with PsA with comorbid IBD or uveitis, and thus be used to personalize their treatment, keeping in mind that we are currently lacking RCTs conducted in people with PsA and these related conditions.
Given the varying clinical phenotypes and natural histories that our patients with IMIDs can manifest, a multispecialty approach is essential to effectively, safely, and holistically manage these patients. As a result, therapeutic algorithms are becoming more complex, with an increasing proportion of patients needing a more personalized approach, independent of algorithms.49 This is an approach increasingly advocated by international recommendations, including GRAPPA 2021,12 the American College of Rheumatology,50 and the European Alliance of Associations for Rheumatology 2019 treatment recommendations for PsA.51 The aim is to more effectively diagnose different IMID manifestations, intervene early to prevent clinical sequelae — especially those that are irreversible, reduce disease activity in multiple domains to prevent morbidity and irreversible damage, prevent disease related complications, and improve prognosis and QOL.
Treatment choices for PsA may be affected by treatments for comorbid conditions. For example, IL-17i has been shown to exacerbate known CD. There is now strong evidence based upon 2 independent phase II RCTs that IL-17 antagonists exacerbate CD20,52 and would therefore be contraindicated in patients with PsA and active CD. The same may be applied to IL-17i use in UC.
There are numerous high-quality studies supporting TNFi use (except ETN) in UC, both as monotherapy and combined with conventional synthetic agents. The JAKi TOF has proven effective in UC, albeit not in CD. Further studies of other JAKi (UPA and FILGO) and IL-23i are in progress for UC and CD. Although MTX has been widely used in clinical practice for UC, only recently have there been well-designed RCTs evaluating MTX in UC. Surprisingly, both RCTs did not support MTX to induce steroid-free remission or prevent relapses, compared to placebo.36
The RCTs of uveitis discussed in this review should serve to inform treatment choices in patients with PsA suffering with uveitis in the absence of specific studies in PsA. In severe or untreated cases of uveitis, for example, one must initiate prompt treatment in order to prevent vision loss, which still accounts for 10% to 15% causes of legal blindness in the United States and carries significant personal and societal impact.7,47 ADA is the first TNFi approved for intermediate, posterior, and panuveitis. However, there is still a major need for more RCTs to better inform treatment recommendations. In particular, there are few/no RCTs in the various subsets of uveitis and no studies of prognosis of uveitis in patients with PsA. ETN use is not recommended in patients with PsA with concomitant uveitis because of its poor efficacy for uveitis and the risk uveitis poses for irreversible eye damage, including blindness. Some studies (not eligible for our review) found anti-TNF agents in ankylosing spondylitis and juvenile idiopathic arthritis, and azathioprine in Behcet disease were effective for uveitis.53,54 Efforts to convene international expert consensus are underway to develop guidance on biologic therapy for noninfectious uveitis.47
In conclusion, we have identified recent RCTs in IBD and uveitis that should be considered when managing patients with PsA and these related conditions. For some classes of treatment there is consistent efficacy, whereas for other classes there appears to be differential efficacy across IMID domains. One must be cognizant of differences in safety profiles between different biologics, and the emerging small-molecule therapies. Small-molecule therapies might be more prone to off-target effects that may make their efficacy and safety more difficult to handle as a class. As our therapeutic armamentarium for IMIDs is increasing, we are entering an exciting era of greater multispecialty collaboration, which will also pose unique challenges.
Footnotes
DRJ acknowledges research support from the Cambridge Arthritis Research Endeavour and the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014).
DRJ has received research grants, education grants, and/or speaker/advisory board honoraria from pharmaceutical companies, including from AbbVie, Amgen, Biogen, Celgene, Lilly, Ferris, Fresenius Kabi, Galapagos/Gilead, GSK, Celltrion, Janssen, Merck, Novartis, Pfizer, Roche, Sandoz, and UCB. ERS has participated in advisory boards, given conferences, or received grants from AbbVie, Amgen, BMS, Lilly, GSK, Janssen, Novartis, Pfizer, Sandoz, Roche, and UCB. AK has been a consultant to AbbVie, Amgen, Lilly, Janssen, Novartis, and UCB. TR has received research/educational grants and/or speaker/consultation fees from AbbVie, Arena, Aslan, AstraZeneca, BI, BMS, Celgene, Ferring, Galapagos, Gilead, GSK, Heptares, LabGenius, Janssen, Mylan, MSD, Novartis, Pfizer, Sandoz, Takeda, and UCB. FR has provided consulting or been on the advisory board for Adnovate, Agomab, Allergan, AbbVie, Arena, BI, Celgene/BMS, CDISC, Cowen, Ferring, Galapagos, Galmed, Genentech, Gilead, Gossamer, Guidepoint, Helmsley, Horizon Therapeutics, Image Analysis, Index, Jannsen, Koutif, Mestag, Metacrine, Morphic, Organovo, Origo, Pfizer, Pliant, Prometheus Biosciences, Receptos, RedX, Roche, Samsung, Surmodics, Surrozen, Takeda, Techlab, Theravance, Thetis, UCB, Ysios, and 89Bio. S. Siebert has received institutional research funding from Amgen (previously Celgene), BI, BMS, Lilly, Janssen, and UCB; and honoraria/speaker fees from AbbVie, Biogen, Celgene, GSK, Janssen, Novartis, and UCB. MZ has been on the research/speaker/advisory boards for AbbVie, Amgen, Janssen, Lilly, Merck, Novartis, Sandoz, and Pfizer. S. Schwartzman has been a speaker for AbbVie, Jannssen, Lilly, Pfizer, Novartis, and UCB; a consultant for AbbVie, Janssen, Lilly, Myriad, Novarits, Regeneron, Sanofi, UCB, Stelexis, Jubilant, and Teijin; and is a board member of the National Psoriasis Foundation and is on the scientific advisory board of Myriad. JTR has provided consulting for Gilead, AbbVie, Novartis, Revolo, Affibody, Neoluekin, Corvus, Horizon, Roivant, and Priovant; received research support from Horizon, Pfizer, and the Malassezia Foundation; received royalties from UpToDate; and been on the data monitoring committee for Celgene/BMS and Clinical Endpoints Committee for Lilly. BM received a research grant from Novartis. RL received a research grant, an education grant, and has been a speaker for Lilly, AbbVie, and Novartis. MML has received research grants, education grants, and/or speaker/advisory board honoraria from pharmaceutical companies, including AbbVie, Amgen, Lilly, Galapagos/Gilead, Janssen, Novartis, and Pfizer. MS has been a consultant for Novartis. JAS has received consultant fees from Schipher, Crealta/Horizon, Medisys, Fidia, PK Med, Two Labs, Adept Field Solutions, Clinical Care Options, Clearview Healthcare Partners, Putnam Associates, Focus Forward, Navigant Consulting, Spherix, MedIQ, Jupiter Life Science, UBM, Trio Health, Medscape, WebMD, Practice Point Communications, the National Institutes of Health, and the American College of Rheumatology; received institutional research support from Zimmer Biomet; food and beverage payments from Intuitive Surgical/Philips Electronics North America; owns stock options in TPT Global Tech, Vaxart, Atyu BioPharma, Adaptimmune Therapeutics, GeoVax Labs, Pieris, Enzolytics, Seres, Tonix, Charlotte’s Web; and is on the speaker’s bureau of Simply Speaking. JR received support for attending meetings or travel from AbbVie, Novartis, and UCB. MEH received speaker and advisory fees from AbbVie, BMS, Pfizer, Novartis, Lilly, Janssen, and UCB. The remaining authors declare no conflicts of interest relevant to this article.
- Accepted for publication June 28, 2022.
- Copyright © 2023 by the Journal of Rheumatology
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