Philip Mease is a rheumatologist based in Seattle, Washington, and has been in practice since 1982. Here, he discusses the management of psoriatic arthritis and findings from the DISCOVER-2 trial.
Philip Mease has an interest in psoriatic arthritis (PsA), which arose after working alongside a dermatology department in Seattle where he treated many patients referred by dermatologists for the treatment of their arthritic component. His work on PsA took off after undertaking a clinical trial with etanercept in 2000.
Since then, he has continued to play an active role in clinical research on PsA, as well as mentoring clinicians and was involved in the establishment of GRAPPA, a multidisciplinary, non-profit, organisation that promotes and disseminates information on PsA.
Understanding psoriatic arthritis
As Dr Mease explained, ‘psoriatic arthritis is a condition that occurs in people with psoriasis’ and that in the US and Western Europe, psoriasis occurs in around three out of 100 individuals and, of those, ‘one out of the three will have manifestations of PsA.’ He described how PsA is a unique presentation in that any joint in the body can become inflamed. A key feature of PsA Dr Mease added, was how patients can get inflammation where tendons or ligaments insert into bone. For many, the Achilles tendon is affected and this is referred to as enthesitis and which, he says, ‘can be quite disabling for patients, especially low extremity enthesitis.’ A further hallmark presentation, dactylitis, occurs on fingers or toes in which the whole digit swells, becoming sausage-like, reflecting inflammation in both the synovium and bone. Another area of the bone affected in 40-50% of patients he said, was the spine and whilst quite disabling, he finds this is often missed because of the belief that back pain invariably occurs due to degenerative arthritis of the spine as opposed to an immunologic inflammation.
Given the combination of a painful arthritis and an unsightly skin and nail disease, Dr Mease is unsurprised that such patients experience a significant detriment in their quality of life, characterised by a higher incidence of depression and suicidal ideation than for most other chronic disease.
As Dr Mease explained, rheumatoid arthritis tends to be more common in women and is predominately restricted to inflammation of the synovial lining tissue of the joints and without some of the defining features (e.g. enthesis) of PsA. In contrast, PsA is equigender – occurring equally in males and females – and tends to present in fewer joints. He also noted that PsA rarely occurs in the absence of the cutaneous manifestation of psoriasis that sometimes the arthritis precedes the development of skin-related symptoms. On average, he says, ‘people will develop psoriasis about 10 years before they develop the arthritis manifestations.’
Diagnosing PsA
Unfortunately, and unlike rheumatoid arthritis, Dr Mease revealed how there are no specific clinical biomarkers indicative of PsA. Consequently, the diagnosis is a clinical one and rests on the presence of specific symptoms and the presence of concomitant psoriasis.
While there are some biomarkers that are elevated in PsA, none of these are particularly informative. For instance, inflammatory markers such as C-reactive protein are sometimes elevated, but as he says, ‘this only happens in around 40% of the time, even in patients with very active disease.’ Occasionally, he added, a gene marker, HLA b27 is measured when investigating the presence of spinal involvement but again, ‘maybe about 30% of patients with spinal involvement will have the presence of this particular gene marker.’
While disabling, as Dr Mease explained, the symptoms of PsA such as joint pain, stiffness and swelling can vary considerably among sufferers. For some patients, these symptoms can be particularly burdensome, occurring daily, whereas for others, symptoms may persist for several weeks at a time before quiescence. A further complication is PsA is degenerative, resulting in the destruction of bones and joints, leading to constant, debilitating pain.
He believes that PsA can be diagnosed by both dermatologists and rheumatologists although recognises how many dermatologists freely admit to being unable to differentiate between PsA and osteoarthritis or sometimes, might not even enquire about the presence of musculoskeletal symptoms in their psoriasis patients.
Patient burden and prognosis
With a cosmetically disfiguring skin disease and associated painful joints, the burden upon PsA sufferers is huge, severely impacting on social and occupational activities and ultimately their quality-of-life. Dr Mease discussed how in practice patients become overburdened by heightened levels of pain and fatigue together with social embarrassment due to the visible nature of their skin condition.
Although untreated, PsA becomes degenerative over a period of several years, Dr Mease mentioned how in a patient who first presents with dactylitic digit, ‘we can see within a year the destruction of the joint within that finger or toe.’
Although the presence of psoriasis, particularly severe disease, is known to be linked with a higher risk of cardiovascular disease, the association with PsA is less well defined. Nevertheless, as Dr Mease noted, ‘we know that the deeper the inflammatory burden that the patient has, the greater likelihood of associated cardiovascular risk.’ Moreover, given how there is already a genetically predisposed risk for cardiovascular risk in both PsA and psoriasis patients, he sees it as vital to educate both patients and clinicians about this potential higher cardiovascular risk.
The mainstays of treatment
According to Dr Mease, ‘psoriatic arthritis is considered to be an auto-immune disease due to the activation of predominately T lymphocytes but also to some extent, B lymphocyte as well as other immune cells such as natural killer cells.’ Each of these different cells have the capacity to over-produce key pro-inflammatory cytokines including tumour necrosis factor (TNF) and interleukins 17, 23 and, to a lesser extent, interleukin-6. These inflammatory molecules migrate to areas of inflammation and stimulate cells to become overactive. Consequently, these molecules have become a key target for treatment.
While initial management for a psoriasis patient who complains of joint aches and pains might be over-the-counter or prescribed non-steroidal anti-inflammatory agents, by the time they reach a rheumatologist, many will no longer find these drugs to be effective.
While the next step in the UK is the use of immunosuppressants such as methotrexate, Dr Mease described that in the US, recent guidance suggested earlier use of an anti-TNF agent. This he says, is because anti-TNF agents are known to be more effective than immunosuppressants such as methotrexate and help to delay both disease progression and ultimately destruction of joints, making them more cost-effective.
However, Dr Mease depicted how there is a reluctance to use biologics before drugs like methotrexate due to the higher cost of the former agents. Nonetheless, he thinks that this stance may well change in the future after more widespread adoption of biosimilars, which while still expensive, are considerably cheaper than their original reference products and therefore serve to increase patient access to treatment.
The rationale of the DISCOVER-2 trial
Dr Mease described how the overarching aim of the DISCOVER-2 trial was to investigate the ‘safety and efficacy of guselkumab, an IL-23 inhibitor, in treating the various clinical domains of PsA including the ability to inhibit structural damage progression or not.’ The trial itself included over 700 patients with psoriatic arthritis and enabled researchers to document safety and efficacy for the drug and which would form part of the submission required for regulatory approval.
The main efficacy and safety outcomes were assessed after 24 weeks but further assessments were made at 52 and 100 weeks. He stated that an important part of the analysis was the use of non-responder imputation. Using this approach, participants who discontinued therapy for any number of different reasons would be counted as a non-responder.
This was a more stringent test and, as Dr Mease explained, given that ‘three-quarters of the patients had an ACR20 [a composite efficacy measure] response, it was a comment about the efficacy and longevity of the effect of the medication.’
Quick responses
The trial also found how patients responded quickly, with responses seen as early as one month after starting treatment. In addition, Dr Mease described how there was also a climbing response over time, ‘so that an ACR20 response was achieved by about two-thirds of patients at the 24-week mark and by about 50% of patients at the 16-week mark’ and continued to climb as the study continued and were even higher at the 100-week mark.
Dr Mease thinks that the trial showed how treatment with guselkumab not only provides a relatively fast onset of action but also that the response continues to increase over time and probably becomes maximal after 52 weeks. As well as clinical efficacy, Dr Mease described how guselkumab produced a statistically superior response to placebo for all the quality-of-life measures assessed in the trial.
While clearly the response to treatment wanes over time, he noted how biologic registry data, which include thousands of patients, suggests that for this class of drugs, the persistency of response is between 1.5 and 3 years. A further and reassuring point he added was that the emerging registry data tend to mirror the safety profile of agents observed in clinical trials.
Dr Mease also said that there are currently several other drugs being considered for the management of PsA, including interleukin (IL)-17 and -23 inhibitors and TNF inhibitors. Nevertheless, he thinks that IL-23 is a somewhat attractive target for PsA given how blockage of this cytokine is effective against both cutaneous and arthritic symptoms. He mentioned how it was also effective in a subgroup of patients with psoriatic spondylitis in their spine.
Next steps for psoriatic arthritis management
Dr Mease described the emergence of therapies with different molecular targets. One intracellular pathway target is tyrosine kinase 2, which is part of the Janus kinase (JAK) family. The use of an inhibitor of this pathway, deucravacitinib, has been shown to be well tolerated and improves disease severity. In addition, two oral JAK inhibitors, tofacitinib and upadacitinib, have already received FDA approval for PsA. Finally, although not currently available, neurokinin 2 inhibitors are under development for the treatment of not only PsA, but also rheumatoid arthritis and lupus.
Dr Mease believes that the last 25 years has witnessed a significant improvement in both the understanding and treatment of PsA and that today, is what he described as a ‘terrific time to treat people with the condition because we can actually often get them into remission or low disease activity.’
