Expert Insights on Psoriatic Arthritis From ACR Convergence 2020

Which psoriatic arthritis (PsA) research findings presented at the American College of Rheumatology (ACR) 2020 annual meeting have the potential for the most meaningful clinical impact?

There were several interesting abstracts presented at this year’s ACR annual meeting from a therapy standpoint, some of which were also presented at the 2020 European League Against Rheumatism (EULAR) annual meeting.

One of the new agents for PsA is upadacitinib. There were 2 phase 3 studies presented at ACR 2020: SELECT – PsA 1 (ClinicalTrials.gov Identifier: NCT03104400) and SELECT – PsA 2 (ClinicalTrials.gov Identifier: NCT03104374). SELECT – PsA 1 was a study conducted among biologic-naive patients with PsA, and SELECT – PsA 2 was conducted among patients with PsA who had an inadequate response to treatment with a tumor necrosis factor (TNF) inhibitor. The SELECT – PsA 1 study also included adalimumab as a comparator.

We were surprised to find the efficacy of Janus kinase (JAK) inhibitors on the skin. JAK inhibitors have been approved for the treatment of rheumatoid arthritis (RA), and we know that they are fairly good with respect to the peripheral joints because of our experience with them in RA. In this case, as well, it wasn’t any different that upadacitinib worked well on the musculoskeletal component of PsA. The surprise was that compared to adalimumab, which is a very good drug even for the skin, the response rate (Psoriasis Area and Severity Index [PASI] 90, PASI 100) with upadacitinib was found to be better than with adalimumab.¹  

The other abstract addressed upadacitinib in patients with inadequate response to TNF inhibitors; this study showed that patients with PsA demonstrated a good response to upadacitinib.²

Long-term data (week 52 and 100) from a study on another JAK1 inhibitor, filgotinib, showed that this drug works and maintains its efficacy in the long term. Minimal disease activity with filgotinib was found to be about 31% at week 100.³

Guselkumab, an interleukin (IL)-23 p19 inhibitor, has been effective in PsA, as demonstrated by the results of phase 2 and phase 3 studies published in the Lancet. What was reported at the ACR 2020 meeting was the effect of guselkumab on axial disease in PsA. These data were presented earlier at EULAR 2020, but this was the first time they were presented at ACR. It is thought that IL-23 inhibitors have no effect on the axial skeleton based on 2 studies: the first one included risankizumab, another IL-23 p19 inhibitor, and the second one was on ustekinumab, an IL-12/23 inhibitor. Neither of these agents was found to be effective in patients with axial spondyloarthritis (SpA). 

Researchers of the 2 guselkumab 1-year trials pooled data and studied patients who had axial symptoms and evidence of imaging-based sacroiliitis. They assessed changes in BASDAI (Bath Ankylosing Spondylitis Disease Activity Index), and, when guselkumab was compared to placebo, there was a statistically significant difference. They also evaluated individual components of BASDAI.⁴ These findings are quite interesting and make us think that perhaps axial PsA is different than axial SpA.

Currently, there is no good way of defining axial PsA, although the Assessment of SpA International Society (ASAS) and the Group for Research and Assessment of Psoriasis and PsA (GRAPPA) are conducting a larger international study, the Axial Involvement in PsA Cohort (AXIS) study (ClinicalTrials.gov Identifier: NCT04434885), to define axial PsA and how to quantify these patients.

How can clinicians differentiate patients with axial PsA from those with axial SpA and provide care, accordingly?

The real clinical question is how to differentiate between a patient who has ankylosing spondylitis (AS) with skin psoriasis and a patient who has PsA and axial symptoms. There are many differences in the presentation of these patients. Approximately 6% to 7% of patients with AS have psoriasis as well. However, radiographic examination of these patients will demonstrate symmetric sacroiliitis. If these patients have syndesmophytes, they are thin and run from the lower end of a vertebra to the upper end of the lower vertebra. In axial PsA, patients typically have asymmetric sacroiliitis and “chunky,” asymmetric, osteophyte-looking changes in the spine that run from the middle of the vertebra to the next vertebra. So, symmetric vs asymmetric sacroiliitis and thin vs chunky syndesmophytes would be 1 way of differentiating between axial PsA and axial SpA. Approximately 80% of patients with AS have the HLA-B27 gene, and only approximately 50% of patients with axial PsA have the HLA-B27. 

In clinical practice, I believe that this distinction may not matter that much, as both TNF and IL-17 inhibitors would probably work on both conditions. The MAXIMISE study (ClinicalTrials.gov Identifier: NCT02721966) found secukinumab to be effective in patients with axial PsA, so it may not really matter to differentiate between the 2 conditions in day-to-day practice. However, there are several clinical, genetic, and radiographic differences between axial PsA and axial SpA, and this is an active area of research.

One of the biggest clinical challenges is identifying risk factors for progression and when psoriasis may progress to PsA. What is your perspective on the early diagnosis and screening for PsA?

There were many studies that addressed “pre-PsA,” similar to pre-RA in patients with some arthralgias and a positive cyclic citrullinated peptide (CCP) test. For PsA, we do not have any antibodies such as rheumatoid factor or anti-CCP. However, we do have a biomarker, and that is skin psoriasis.

There is a lot of work being conducted on standardizing the terminology for pre-PsA. A presentation at ACR 2020 looked at the terminology in detail.⁵ In addition, there is an organization, PPACMAN (the Psoriasis & Psoriatic Arthritis Clinics Multicenter Advancement Network), in the United States that includes clinics in dermatology and rheumatology that is exploring pre-PsA terminology because unless these patients are defined carefully, it becomes challenging to study their condition.

There was another presentation at ACR 2020 on whether there are risk factors in patients with skin psoriasis who develop PsA. There were 2 parts to this study: the first was at year 1 when patients developed PsA after they were initiated into the study, and the second was at year 5. At 1 year, predictors of development of PsA included arthralgia, joint aches and pains, and fatigue. At 5 years, it became challenging to identify what the risk factors were, although 1 risk factor that stood out was nail disease at baseline, which was something we already knew.

Can you discuss the current state of targeted therapies for PsA?

Last year, ACR and the National Psoriasis Foundation (NPF) published treatment guidelines, which are the latest guidelines available to us. GRAPPA is working on their treatment guidelines, which are expected to be released at the end of 2021.

Results of the SEAM study (Etanercept and Methotrexate in Combination or as Monotherapy in Psoriatic Arthritis; ClinicalTrials.gov Identifier: NCT02376790) were published last year and presented at the 2019 ACR annual meeting. The study assessed whether the combination of methotrexate and etanercept was superior to etanercept alone. The study found no difference between the combination treatment and etanercept alone. The researchers indicated that methotrexate seems to have good efficacy in PsA, although the study had limitations because there was no placebo and it could be claimed that the methotrexate response was because of the placebo. However, there was a significant ACR50/70 response in patients who received methotrexate alone.

There are also several types of drugs and there are many different classes of each drug: conventional synthetic disease-modifying antirheumatic drugs (DMARDs); TNF inhibitors (there are 5 of them); the IL-12/23 inhibitor (ustekinumab); IL-17 inhibitors (secukinumab and ixekizumab); pure IL-23 inhibitors (there are 3 of them; 1 has been approved for PsA [guselkumab], but rizankizumab and tildrakizumab are being studied in phase 2 trials presented at the ACR 2020 meeting); JAK inhibitors; the phosphodiesterase-4 (PDE4) inhibitor apremilast; and abatacept (a T-cell inhibitor that is mainly used for RA but has been approved for the treatment of PsA). This totals to up to as many as 12 different targeted novel molecules that we have for the treatment of PsA, so it has become a fairly rich field of treatment options besides the usual conventional synthetic DMARDs.

What effect does the plethora of available PsA treatments have on your decision-making process? How do you select the appropriate medication based on patients’ disease stage? Further, how can treatment for PsA be tailored to suit individual patient needs?

This is where the treatment guidelines are very important. The ACR and NPF guidelines are very practical, and they answer exactly this question.

There is a hierarchy to follow depending on the severity of the patient’s PsA. If the disease is mild, you can use methotrexate. If it is more severe and there is involvement of numerous joints with polyarticular inflammation and skin involvement, you directly use a TNF inhibitor and avoid methotrexate.

According to the ACR-NPF treatment guidelines, which are a significant departure from older treatment guidelines and EULAR recommendations, patients with severe disease can directly receive a TNF inhibitor. If treatment with the TNF inhibitor fails, the class could be changed if it were a primary failure, and it can remain in the same class if it were a secondary failure. One would also take into account whether there is significant skin involvement, as we know that IL-17 and IL-23 inhibitors are superior to TNF inhibitors with respect to the skin.

A couple of head-to-head studies were published in the past year, although not presented at ACR 2020, which compared ixekizumab vs adalimumab and secukinumab vs adalimumab. These studies showed that ixekizumab and secukinumab were superior to adalimumab with regard to the skin, and both drugs were both noninferior to adalimumab with regard to the joints. In clinical practice, my decision will depend on how severe the patient’s musculoskeletal disease and skin disease are.

We are now also observing that guselkumab, at least according to the results of DISCOVER-1 (ClinicalTrials.gov Identifier: NCT03162796) and DISCOVER-2 (ClinicalTrials.gov Identifier: NCT03158285) trials, has been found to have a strikingly good safety profile. However, one has to take this with a “pinch of salt” when one is looking at clinical trials that assess safety, as longer-term follow-up in postmarketing experience is needed.

Data that will contribute to our decision-making may include considering the severity of musculoskeletal disease, the severity of skin disease, and the safety of the treatment. Shared decision-making is very important. It is very important to assess the patients’ status in terms of how comfortable they are with the route of administration (oral vs injection), their risk tolerance, their insurance, etc.

There was a very interesting study at the ACR meeting about the safety and efficacy of JAK inhibitors in PsA, particularly in patients who are intolerant or who lack response to DMARDs. What is your treatment of choice for patients who do not respond to 1 or more TNF inhibitors?

If a patient has not responded to treatment with 1 or more TNF inhibitors, then I would probably use IL-17 inhibitors first, only because they have a longer track record compared to the JAK inhibitors. In the United States, unfortunately, treatment also depends on what the insurance company will approve and patients’ out-of-pocket expenses. I might then consider the IL-12/23 inhibitor ustekinumab because that drug has been in the market for quite some time and it is a very good drug with respect to the skin, although in my experience it is not as good a drug as TNF inhibitors for the joints. As I mentioned earlier, there are head-to-head studies showing that IL-17 inhibitors are as effective as TNF inhibitors; they are noninferior and superior in the skin.

A phase 2 randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of the novel tyrosine kinase type 2 (Tyk2) inhibitor deucravacitinib and was presented in a late-breaking abstract at ACR 2020.⁶ Tyk2 is part of the Janus kinases. The ACR50/70 responses with deucravacitinib 6 and 12 mg per day administered orally were found to be superior to placebo. There was also a slight dose response with the 12-mg dose being slightly better than the 6-mg dose, although the difference between the 2 doses did not reach statistical significance. The investigators also looked at enthesitis resolution, minimal disease activity, and Health Assessment Questionnaire Disability Index. So, this is another new and interesting class of drugs that we can look forward to.

Disclosure: Dr Atul A. Deodhar declared affiliations with the pharmaceutical industry.

References

1. McInnes I, Anderson JK, Magrey M, et al. Efficacy and safety of upadacitinib versus placebo and adalimumab in patients with active psoriatic arthritis and inadequate response to non-biologic disease-modifying anti-rheumatic drugs: a double-blind, randomized controlled phase 3 trial.  Presented at: ACR Convergence 2020; November 5-9, 2020. Abstract 2026.
2. Mease P, Lertratanakul A, Strober B, et al. Efficacy of upadacitinib in patients with psoriatic arthritis stratified by number of prior biologic disease-modifying anti-rheumatic drugs. Presented at: ACR Convergence 2020; November 5-9, 2020. Abstract 1356.
3. Coates L, Gladman D, Van de Bosch F, et al. Long-term outcomes with filgotinib, an oral selective Janus kinase 1 inhibitor: 100-week data from an open-label extension (OLE) study in patients with active psoriatic arthritis (PsA). Presented at: ACR Convergence 2020; November 5-9, 2020. Abstract 907.
4. Mease P, Helliwell P, Gladwell D, et al. Efficacy of guselkumab, a monoclonal antibody that specifically binds to the p19 subunit of il-23, on axial-related endpoints in patients with active psa with imaging-confirmed sacroiliitis: week-52 results from two phase 3, randomized, double-blind, placebo-controlled studies. Presented at: ACR Convergence 2020; November 5-9, 2020. Abstract 2025.
5. Haberman R, Perez-Chada L, Chandran V, et al. A Delphi consensus study to standardize terminology for the pre-clinical phase of psoriatic arthritis. Presented at: ACR Convergence 2020; November 5-9, 2020. Abstract 305.
6. Mease P, Deodhar A, van der Heijde D, et al. Efficacy and safety of deucravacitinib (BMS-986165), an oral, selective tyrosine kinase 2 inhibitor, in patients with active psoriatic arthritis: results from a phase 2, randomized, double-blind, placebo-controlled trial. Presented at: ACR Convergence 2020; November 5-9, 2020. Abstract LO3.