Ustekinumab in psoriatic arthritis: need for studies from real-world evidence

ABSTRACT

Ustekinumab (UST) is a recently approved drug for the treatment of psoriatic arthritis (PsA). The ACR response rates in randomized clinical trials (RCTs) with this drug have been slightly lower than that reported in RCTs of anti-TNF and anti-IL17 therapies. Therefore, the position that this drug may occupy in the treatment algorithms of PsA is not clear. More information is needed on the true efficacy of this agent under real clinical practice conditions. In this review of real-world evidence studies, it is shown that UST is effective and safe to treat PsA; nevertheless, it is necessary to homogenize the way in which the main outcomes and treatment objectives of these studies are presented.

KEYWORDS:

• Psoriasis
• psoriatic arthritis
• ustekinumab
• real-world evidence

Psoriatic arthritis (PsA) is a chronic inflammatory musculoskeletal disease, usually seronegative for rheumatoid factor, associated with psoriasis, with a prevalence of 0.02–0.42% in the general population and 13.8–30% among patients with psoriasis [1]. PsA is a heterogeneous condition with articular and extra-articular manifestations, including a combination of peripheral arthritis, axial disease, enthesitis, dactylitis and skin and nail disease. This phenotypic variability has been a permanent challenge when evaluating the different domain outcomes of the disease as well as when estimating the efficacy of the different treatments on these domains [2].

Thanks to new knowledge about disease pathogenesis, in recent years, new therapeutic agents with novel mechanisms of action have been incorporated into the market, which has significantly broadened the offer of treatments for these patients. The advent of new therapeutic agents that act via mechanisms independent of tumoral necrosis factor (TNF) blockade, or by inhibition of phosphodiesterase 4 (apremilast), has not only increased the chances of successful treatment for these patients but has forced different work groups, such as EULAR or GRAPPA, to redesign their treatment recommendations for this entity [3].

Ustekinumab (UST) is one of the drugs recently incorporated into the repertoire of treatments for PsA. Ustekinumab is a fully human IgG1 monoclonal antibody that binds with high affinity to the shared p40 subunit of human IL-12 and IL-23, inhibiting their binding to the IL-12Rβ1 receptor on the surfaces of T cells, NK cells and antigen presenting cells. It has been used for treating moderate-to-severe psoriasis, and it has been recently approved for PsA as well. Its safety and efficacy have been evaluated in two multicentric, double-blind, placebo-controlled trials (PSUMMIT 1 and PSUMMIT 2). At week 24, there was a significant improvement in ACR 20 in PSUMMIT 1 (UST 90 mg 50%, UST 45 mg 42%, placebo 23%) as well as in PSUMMIT 2 (UST 90 mg 44%, UST 45 mg 44%, placebo 20%). Ustekinumab use was associated with remarkable improvements on other PsA domains, such as enthesitis, dactylitis, pain, quality of life, physical function and inhibition of radiological damage [4].

Although UST is a well-defined treatment option for PsA, recent observations have indicated that some psoriatic patients may experience new onsets of PsA or worsening of pre‐existent PsA [5]. It has been suggested that patients with high BMIs or those previously treated with anti-TNFα drugs more often develop UST-induced PsA [5]. However, in a recent study, authors found that 22 out of 327 patients with plaque psoriasis developed PsA during treatment with biologic drugs. In particular, 6 (27.2%) PsA patients were under etanercept therapy, 10 (45.4%) under adalimumab, 4 (18.2%) under ustekinumab and 2 (9.2%) under infliximab [6]. However, the ACR20 response rates in different randomized controlled trials (RCTs) with biological therapies for PsA showed lower values in this respect in patients treated with UST compared to those treated with TNFα inhibitors or inhibitors of IL-17A [4]. Due in part to these findings, it has been difficult to properly position UST in the different therapeutic algorithms proposed for this condition. In fact, EULAR recommendations for PsA treatment tend to place the anti-TNFα drugs family one step ahead of other biological drugs, including UST [3]. These findings have reinforced the notion that UST may be less efficient than other biologics for PsA treatment.

It is necessary to gather information about the real effectiveness of UST in the management of PsA. Therefore, we can review the information provided by the meta-analyses of RCTs, the post-marketing observational studies and, above all, the experiences obtained from real clinical practice with this agent.

This leads to the challenge of comparing the efficacy and safety of the latest drugs incorporated into PsA treatment according to the evidence provided by the corresponding RCTs. Conventional meta-analysis is incapable of comparing three or more treatments; therefore, it is difficult to integrate information on the relative efficacy of all tested regimens. However, a network meta-analysis (NMA) can provide a comprehensive and coherent set of comparisons based on available evidence. There have been some recent NMAs that have compared these aspects between apremilast, secukinumab, abatacept and UST. Song et al. compared apremilast, secukinumab and UST for induction of ACR20 responses and safety profiles in the overall population included in clinical trials, and they found no significant differences between treatments [7]. In another recent NMA, the combined ranking of ACR20 and serious adverse events among patients from the overall population and anti-TNF-α-naive subpopulation revealed that secukinumab and UST were the best treatments. Ustekinumab was not as efficacious as secukinumab but was a safer option. Among anti-TNF-α-failure and anti-TNF-α-experienced subpopulations, apremilast and UST were the best treatment options [8]. Another important point to be considered is the used dose of each drugs, since higher doses may suppose a more intense blockade of the pathway, but at the same time associate a higher rate of adverse events. For example, in the study cited earlier, secukinumab 75 mg, which is the lowest dose used in clinical trials, was the safest drug in terms of any adverse event [8].

Due to their unique protein structures, biologics have varying capacities to generate anti-drug antibodies (ADAbs), which may affect clinical outcomes, and may link to the sustainability of efficacy and drug survival. In a recent systematic literature review conducted to explore the immunogenicity of biologics in PsA, ADAb rates varied widely among studies of biologics in PsA, with the highest frequency in studies of adalimumab (7–54%) and infliximab (15–33%) and the lowest in studies of etanercept (0%) and secukinumab (0–0.2%). Patients with ADAbs against adalimumab, infliximab and UST had lower serum drug levels and poorer efficacy outcomes than those without antibodies. However, the high persistence rate shown by UST in the PSOLAR registry makes it unlikely that the immunogenicity against UST could be relevant in terms of its survival [9,10]

However, the information obtained from conventional RCTs and NMAs only refers to the efficacy and safety data in the short term, being necessary to look for additional information about what happens in the middle- and long-term scenarios with these newest agents. Biologics have been shown to be highly effective for the initial treatment of psoriatic disease; however, response may wane over time and lead to the stopping/switching of treatment. In fact, the most common reason for discontinuing biologics is lack of effectiveness. In that sense, drug survival can be influenced by a range of factors, including safety, treatment effectiveness, side-effects, cost, convenience, quality-of life, access and other patient-oriented factors [10]. In one of the largest post-marketing surveillance studies of biological therapies for psoriatic disease published so far, the proportion of patients in the PsA subgroup who discontinued therapy was lower for patients treated with UST compared with each anti-TNF agent across the first-, second- and third-line cohorts. Multivariate analyses showed that comparisons of drug survival did not reach statistical significance for infliximab, adalimumab or etanercept for first-line therapy; however, the comparison between UST and all three biologics for second-line therapy and between UST and etanercept for third-line therapy showed significantly better survival for UST in the PsA subgroup [10].

The information obtained from RCTs and their meta-analyses, as well as that of postmarketing surveillance studies, is undoubtedly relevant for positioning the different drugs available in PsA treatment algorithms. However, the third source of information in this context comes from real-world evidence studies. These allow analysis of the use of each drug in a context that explores the effectiveness and safety of the treatments, collecting information that is not usually contemplated in the RCTs. Therefore, practicing clinicians especially welcome these studies. Real-life data indicate that there is still a need for improvement in today’s treatment of PsA. In a recent observation, only a few patients fulfilled the DAPSA, PASDAS, and CPDAI remission criteria, and about a quarter fulfilled the MDA criteria. Considerably fewer patients fulfilled PsA-specific remission criteria versus non-PsA specific remission criteria. Still, patient satisfaction was good, and PASI and DLQI were low [11]. From the analysis of the few published studies on UST under conditions of real clinical practice, it is deduced that the drug works by improving the different domains of PsA (axial and peripheral arthritis, dactylitis, enthesitis, skin, physical function, pain and quality of life). The safety profile is optimal, and drug survival is much better in patients naive to TNFi. Regarding the results expressed in terms of MDA, it should be noted that, in these studies, between 30 to 70% of patients achieved this stringent goal (Table 1) [12–16]. In real clinical practice, TNFi treated patients reach MDA in 50 to 60% of cases [17]. Therefore, results in these terms are quite similar between classic TNFi and UST.

Table 1. Main real-world evidence studies with ustekinumab.

Author, year	Design, patients and study period	Prior use of BT	Main results	Other outcomes
Napolitano, 2017	Single center, observational, prospective. N: 34 (23 ♂, 11 ♀) Jan–Dec 2015	1 TNFi: 70.5% 2 TNFi: 17.4% 3 TNFi: 29.4%	MDA: 70.5% at W24	Significant ↓: TJC, SJC, PASI, BSA, pain, TEP, HAQ.
Almirall, 2017	Multicenter, observational, retrospective. N: 58 (33 ♂, 25 ♀) 2009–2015	TNF-IR: 82.8% ≥ 2 TNFi: 54.2%	14 out of 30 patient with DAS28 measurement in clinical remission (DAS28 ≤ 2.6)	Discontinuation associated with obesity and number of prior BT
Chimenti, 2018	Multicenter, observational, prospective. N: 65 (28 ♂, 37 ♀) 2015–17	UST 1st line: 20% 2nd line:33.8% 3rd line: 26.5% 4th line: 15.4% 5th line: 4.6%	MDA: 30.7% (6 Mo) 47% (12 Mo) 34% (24 Mo) MDA Predictors: Mono-oligoarthritis	Significant ↓: TJC, SJC, PASI, LEI, Pain, BASDAI, HAQ
Iannone, 2018	Biologic registry (BIOPURE). N: 160 (76 ♂, 84 ♀). 2014–16.	1st line: 33.8% 66.2% TNF-IR	DAPSA rem. (biologic-naïve): 34% DAPSA rem. (TNF-IR): 17% 12-month drug survival significantly higher in naïve (87%) than in TNF-IR (68%)	Significant ↓: HAQ, PASI. Naïve patients had the lowest risk of UST discontinuation (HR 0.27, p = 0.01)
Queiro, 2018	Single center, observational, retrospective. N: 50 (27 ♀, 23 ♂) 2015–2017	1st line: 18% 1 TNFi: 52% ≥ 2 TNFi: 30%	MDA: 54% Predictors: Lower basal PASI, longer use of UST, previous failure to one TNFi	Significant ↓: PASI, HAQ, PsAID. 70.4% reached patient-acceptable symptoms state

N: number of patients, BT: biologic therapy, TNFi: tumoral necrosis factor inhibitors, MDA: minimal disease activity, W: week, TJC: tender joint count, SJC: swollen joint count, PASI: psoriasis area and severity index, BSA: body surface area, TEP: tender entheseal points, HAQ: health assessment questionnaire, TNF-IR: tumoral necrosis factor-inadequate responders, DAS: disease activity score, Mo: months, LEI: Leeds enthesitis index, BASDAI: Bath ankylosing spondylitis disease activity index, DAPSA: disease activity in psoriatic arthritis, rem: remission, HR: hazard ratio, UST: ustekinumab, PsAID: psoriatic arthritis impact of disease.

These real-world practice studies undoubtedly help to better position UST in the therapeutic algorithms of PsA. However, it is still necessary to expand this information with new studies coming from daily clinical practice.

1. Conclusions

The information obtained from the RCTs and their meta-analyses, the pharmacovigilance studies and the studies of real clinical practice confirms the effectiveness and safety of UST for the treatment of PsA. Further, the information we could obtain from new real-practice studies would help to refine knowledge on the true efficacy of UST as well as the grade and extension of drug effectiveness on the different faces of psoriatic disease.

2. Expert comment

PsA is a multifaceted disease for which the different modalities to evaluate disease outcomes are an evolving field. Currently, there is no universal consensus on the order in which the drugs available for treatment should be used, nor is there solid evidence on which are the best drugs to manage each domain of the disease. The use of new biologic drugs inhibiting IL-23-IL17 signaling is one of the most promising approaches for the treatment of psoriasis and PsA. Efficacy results of these novel therapies have placed them at the top of the treatment for psoriasis. However, the data from the RCTs with these new agents in PsA show similar (or even lower) results to those obtained with the most classic biological therapies, which raises many doubts about the position that these new drugs should occupy in the therapeutic algorithms for PsA.

Therefore, in addition to the results that these new therapies have achieved in the RCTs in PsA, it is necessary to expand the effectiveness and safety studies, not only with the pertinent biological therapy registries, but, above all, with the studies that arise from the world of routine clinical practice. The few studies carried out with ustekinumab in this last field are still very scarce, and, in fact, most of them come from only two countries (Italy and Spain), where the drug was launched at the same time.

Real-world evidence studies with ustekinumab in PsA show that the drug works and is safe. Unfortunately, the treatment goals set in these studies are very different; some authors have used the classic DAS28, while others have used the more modern outcome tools (DAPSA and/or MDA). Some of these studies have carried out drug survival studies, while others have not. For example, only one study has used the modern PsAID tool to assess the impact that the disease has on patients’ lives. In sum, the outcome measures of these studies have been very heterogeneous, which may add some confusion when making a real estimate of UST effectiveness in PsA.

One of the main tasks that must be done in this type of study is to standardize the way in which outcomes are evaluated. Recently, EULAR has proposed a treat-to-target strategy for these patients and has suggested using DAPSA or MDA as treatment targets. In addition to this, the impact that the disease generates on patients’ lives must be measured. In this way, both the tools that measure disease activity, as well as those that reflect the impact of the disease, should be integrated into the clinical and therapeutic decision-making algorithm.

Therefore, we need to expand the information on the effectiveness and safety of both ustekinumab and the other recently introduced agents for the treatment of PsA, such as IL17-inhibitors. In the coming years, it is foreseeable that the therapeutic arsenal available for patients with PsA will expand markedly, and, again, the clinicians will demand quality information beyond that which comes from RCTs. This information will be useful for clinical practice, as long as the collection of this information is done in a standardized manner. In this sense, both GRAPPA and EULAR are laying the rules to achieve this important objective. Finally, the positioning of UST and other recently introduced molecules in the field of PsA will be one of the main tasks that the national rheumatology societies should undertake (Figure 1).

Figure 1. Proposed algorithm for positioning different therapeutic options in PsA patients.

Poor prognostic factors:- High number of actively involved joints- Radiographic damage- Elevated acute phase reactants- DactylitisPsA; Psoriatic Arthritis; csDMARDS: conventional synthetic Disease-Modifying AntireumaticDrugs; Tbc: Tuberculosis; ANA: Antinuclear Antibodies

Declaration of Interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.