Therapeutic options abound as PsA treatment armamentarium expands
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The emergence of new treatments and therapeutic approaches for psoriatic arthritis is improving physicians’ ability to treat a complicated, multifaceted disease.
Many patients with PsA start their treatment journey with dermatologists to address skin symptoms before being referred to rheumatologists as the disease progresses. Typically, dermatologists will use topical treatments, ultraviolet therapy and, perhaps briefly, methotrexate, for treatment of psoriasis but some dermatologists may not be ready to pull the trigger on more advanced therapies, such as biologics and targeted synthetic disease-modifying antirheumatic drugs, according to Philip J. Mease, MD, MACR, director of rheumatology research at Swedish Medical Center/Providence St. Joseph Health and clinical professor at the University of Washington School of Medicine in Seattle.
There is often a lag time between onset of PsA symptoms and diagnosis. Although diagnosis may come later than one would hope, there are a large number of effective treatment options to choose from as we work closely with our dermatology colleagues, Mease noted.
Current treatment landscape
Based on safety and efficacy data, the clinical practice guideline from the American College of Rheumatology and the National Psoriasis Foundation recommends initiating therapy with a TNF inhibitor over MTX in patients with PsA who are treatment-naïve. However, most insurance companies require treatment with MTX before use of a more expensive biologic, according to Mease.
Unfortunately, Mease noted, many patients do not experience adequate benefits with MTX, or they have intolerable side effects. Therefore, the treatment period is often brief, usually lasting only a few months, before progression to other therapies.
“From a biologic treatment point of view, we really have a number of drugs to choose from,” Mease said. “Currently, there are five TNF inhibitors, two interleukin-17 inhibitors, two interleukin-23 inhibitors and one interleukin-12/23 inhibitor, so it really is a matter of what the patient is comfortable with.”
Clinical trial data indicate that efficacy among these drugs in the musculoskeletal domain is fairly similar, but IL-17 and IL-23 inhibitors appear superior to TNF inhibitors for skin symptoms. They also have a slightly better safety profile overall, including a lower rate for serious infections and no signal for malignancy, according to Mease.
Even so, access to these medications may prove challenging, as insurance companies often require patients to first try adalimumab (Humira, AbbVie), the most commonly used TNF inhibitor. However, patients with non-Medicaid or Medicare insurance may be able to receive IL-17 or IL-23 inhibitors through manufacturer programs free of charge for some period of time, according to Mease.
Another effective treatment option is JAK inhibitors, including tofacitinib (Xeljanz, Pfizer) and upadacitinib (Rinvoq, AbbVie). As once-daily oral medications, patients are often attracted to their convenience, Mease noted. However, signals regarding increased risks for blood clots, serious heart-related events and cancer prompted the FDA to add boxed warnings to tofacitinib and upadacitinib, among others not approved for PsA. Therefore, JAK inhibitors have been relegated to second-line treatment, particularly among older patients who may have comorbidities that place them at greater risk for cardiovascular complications or malignancies, according to Mease.
One newer treatment that falls under the umbrella of JAK inhibitors is deucravacitinib (Sotyktu, Bristol Myers Squibb), which is a tyrosine kinase 2 inhibitor that has been approved for moderate to severe plaque psoriasis. Although not yet approved for use in PsA, rheumatologists are starting to see patients who have been prescribed deucravacitinib by their dermatologists.
“We know from the phase 2 trial in PsA that it’s highly effective in the musculoskeletal manifestations,” Mease said.
Notably, deucravacitinib does not carry the same safety warnings from the FDA as the other available JAK inhibitors, meaning that it could be used as first-line therapy and does not require lab monitoring except in patients with liver disease, according to Mease.
“It’s likely going to be a pretty popular drug when it gets approval for PsA down the road,” Mease said.
Promise of combination therapy
Although some patients respond remarkably well to their initial therapy, a fairly large group achieve only a partial response in which they experience a diminution in the number of tender and painful joints and some improvement in skin symptoms but perhaps have not returned to normal daily functioning, according to Mease.
He noted that whereas the former type of patient may remain on his or her current treatment for several years before the effect starts to wane, those experiencing only a partial response will likely switch drugs much earlier, perhaps after 1 year or so.
Other patients face even greater challenges and cycle through four or five medications relatively quickly without significant success.
“Then we have a little bit more trouble finding options for them,” Mease said.
For this type of patient, off-label combination therapy, which involves use of two biologics or tsDMARDs, may offer some benefit. However, when deciding which drugs to use, safety concerns are paramount, Mease noted.
“If a patient is on a drug that may not be quite as pristine from a safety perspective, we try to pair that with one that has a more pristine safety profile to improve efficacy without adding safety burden,” he said.
For instance, a dermatologist could add apremilast (Otezla, Amgen) to the treatment regimen of a patient who is already using a TNF inhibitor prescribed by their rheumatologist but is not achieving a full response in their joints or skin, according to Mease, noting that this is one of the more common combinations used in PsA.
“Given its safety profile, it would be quite reasonable from a safety perspective to use along with the biologic, so I would say let’s see if it can get through insurance. Sometimes insurance actually will approve the use of two different medications like this, partly because the prescribers are from two different disciplines,” Mease said.
For patients on a TNF inhibitor who have experienced significant improvement in their arthritis but continue to struggle with their skin symptoms, another option would be the addition of an IL-23 inhibitor. Again, Mease said, IL-23 inhibitors have a good safety profile and are only administered once every 2 or 3 months, lessening the additional burden to the patient.
Notably, researchers are conducting a trial in which they are comparing golimumab (Simponi, Janssen), a TNF inhibitor, plus guselkumab (Tremfya, Janssen), an IL-23 inhibitor, with guselkumab alone in patients with PsA.
“Historically, we haven’t seen combination therapy studied much because of concerns about additive safety issues, but [the researchers] felt pretty confident based on the safety profile of guselkumab as well as the results of the VEGA trial in which the TNF inhibitor and IL-23 inhibitor were used successfully in combination in patients with inflammatory bowel disease,” Mease told Healio.
“For the recalcitrant patients, this is the future. Either we, as rheumatologists, will be given permission to prescribe two treatments at the same time or we will do so in conjunction with a specialist from another discipline,” Mease said. “In this way, we’re becoming a bit more like cancer physicians who often mix and match agents with different mechanisms of action when trying to put cancer into remission.”
A full pipeline
In addition to existing drugs, a number of novel therapies are in development for treatment of PsA.
One particularly promising treatment is bimekizumab, a monoclonal immunoglobulin G (IgG) antibody that inhibits both IL-17A and IL-17F.
“Historically, the thought was that maybe the IL-17A member of the IL-17 family was the most pro-inflammatory cytokine, but we are now beginning to learn that IL-17F is also an important player,” Mease told Healio.
Results from two phase 3 studies — BE OPTIMAL and BE COMPLETE — published in The Lancet showed significant improvements in joint, skin and radiographic outcomes with bimekizumab compared with placebo in patients with psoriatic arthritis who were naïve to biologic DMARDs and in patients who were not responsive or intolerant to TNF inhibitors, respectively. Additionally, a pooled analysis of data from both trials, which was presented at ACR Convergence 2022, linked bimekizumab to improvements in overall disease activity, regardless of prior DMARD treatment.
Bimekizumab is already approved for treatment of psoriasis in Europe, and U.S. physicians are anticipating its approval by the FDA for psoriasis later this year. The hope is that it will subsequently be approved for treatment of PsA and axial spondyloarthritis as well, according to Mease.
Other therapies, including nanobodies, may be further from FDA approval but are “intriguing,” Mease noted. Specifically, izokibep, which is a 16-kilodalton molecule that binds to IL-17A and albumin, to prolong its half-life, has demonstrated promise in a phase 2 trial that was presented at ACR Convergence 2022.
“It’s thought that we have the potential to achieve higher dosing and greater penetrance into difficult-to-penetrate tissue with these nanobodies. We still have to prove that experimentally, but that’s the hope at least,” Mease said.
Notably, data from the successful phase 2 trial showed that there was 50% complete resolution of enthesitis with the low dose of izokibep and 88% complete resolution with the higher dose. This dose effect, Mease noted, has led researchers to plan studies to further investigate whether there actually is better penetrance with izokibep.
The drug is currently beginning a phase 3 trial in PsA, according to Mease.
Another nanobody in development include sonelokimab, which is a nanomolecule which binds to IL-17A and IL-17F as well as albumin, and is currently conducting a PsA trial after showing success in psoriasis. Tildrakizumab (Ilumya, Sun Dermatology) isan IL-23 inhibitor that currently has FDA approval to treat psoriasis and is in development for PsA.
Though not quite as advanced in development as other therapies in the pipeline, researchers are investigating the potential of MK-2 inhibitors. These oral medications work in the NF kappa beta pathway to reduce immune cell activation, with current studies examining this mechanism in PsA and rheumatoid arthritis, according to Mease.
Although the availability of effective treatments for PsA is exciting, Mease highlighted the importance of having this relatively full pipeline.
“It gives us more choices as we find ourselves in the position of having to cycle medications. There is value in having these additional medicines as well as mechanisms for that reason,” Mease said.
Looking ahead
Researchers are making strides in identifying novel therapies for PsA, but other areas that would help optimize treatment are still lacking, according to Mease.
“The biggest unmet needs have to do with biomarker development,” he told Healio. “We do not have any biomarker that is diagnostic for PsA like we do for RA or lupus, so that leaves dermatologists and rheumatologists struggling when they’re initially trying to make a diagnosis.”
Furthermore, Mease noted that this lack of biomarkers leaves rheumatologists without a way to predict disease progression.
“We don’t have biomarkers that we could apply at that very first stage when we are picking the first biologic to use,” he said. “It would be nice if we had biomarkers that could steer us more reliably and effectively toward or away from a particular therapy.”
Despite this need for more research, the growing number of therapeutic options paints an optimistic picture for the field of PsA, according to Mease.
“This is a terrific time in the treatment of PsA. We have many highly effective treatment options. Many of the newer treatment options have improved safety profiles and many of the treatments can treat all of the various clinical domains of this complex disease —arthritis, spine disease, skin disease and more,” Mease said. “It’s a good time to be actively managed and get the disease into a target of remission or low disease activity.”
References
- Behrens F, et al. Abstract 1597. Presented at: ACR Convergence 2022; Nov. 11-14, 2022; Philadelphia (hybrid meeting).
- Feagan BG, et al. Lancet Gastroenterol Hepatol. 2023;doi:10.1016/ S2468-1253(22)00427-7.
- McInnes IB, et al. Lancet. 2022;doi:10.1016/ S0140-6736(22)02302-9.
- Mease PJ, et al. Abstract 2117. Presented at: ACR Convergence 2022; Nov. 11-14, 2022; Philadelphia (hybrid meeting).
- Mease PJ, et al. Abstract 2151. Presented at: ACR Convergence 2022; Nov. 11-14, 2022; Philadelphia (hybrid meeting).
- Mease PJ, et al. Ann Rheum Dis. 2022;doi: 10.1136/annrheumdis-2021-221664.
- Merola JF, et al. Lancet. 2022;doi:10.1016/ S0140-6736(22)02303-0.
- Singh JA, et al. Arthritis Rheumatol. 2018;doi:10.1002/art.40726.
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