The Long Road to a PsA Prevention Trial

Jennifer Lubell

September 04, 2020

About one-third of all patients with psoriasis will develop psoriatic arthritis (PsA), a condition that comes with a host of vague symptoms and no definitive blood test for diagnosis. Prevention trials could help to identify higher-risk groups for PsA, with a goal to catch disease early and improve outcomes. The challenge is finding enough participants in a disease that lacks a clear clinical profile, then tracking them for long periods of time to generate any significant data.

Dr Christopher Ritchlin

Researchers have been taking several approaches to improve outcomes in PsA, Christopher Ritchlin, MD, MPH, chief of the allergy/immunology and rheumatology division at the University of Rochester (N.Y.), said in an interview. "We are in the process of identifying biomarkers and imaging findings that characterize psoriasis patients at high risk to develop PsA."

The next step would be to design an interventional trial to treat high-risk patients before they develop musculoskeletal inflammation, with a goal to delay onset, attenuate severity, or completely prevent arthritis. The issue now is "we don't know which agents would be most effective in this prevention effort," Dr. Ritchlin said.

Biologics that target specific pathways significant in PsA pathogenesis are an appealing prospect. However, "it may be that alternative therapies such as methotrexate or ultraviolet A radiation therapy, for example, may help arrest the development of joint inflammation."

Underdiagnosis Impedes Research

Several factors may undermine this important research.

For one, psoriasis patients are often unaware that they have PsA. "Many times they are diagnosed incorrectly by nonspecialists. As a consequence, they do not get access to appropriate medications," said Lihi Eder, MD, PhD, staff rheumatologist and director of the psoriatic arthritis research program at the University of Toronto's Women's College Research Institute.

Dr Lihi Eder

The condition also lacks a good diagnostic tool, Dr. Eder said. There's no blood test that identifies this condition in the same manner as RA and lupus, for example. For these conditions, a general practitioner such as a family physician may conduct a blood test, and if positive, refer them to a rheumatologist. Such a system doesn't exist for PsA. "Instead, nonspecialists are ordering tests and when they're negative, they assume wrongly that these patients don't have a rheumatic condition," she explained.

Many clinicians aren't that well versed in PsA, although dermatology has taken steps to become better educated. As a result, more dermatologists are referring patients to rheumatologists for PsA. Despite this small step forward, the heterogeneous clinical presentation of this condition makes diagnosis especially difficult. Unlike RA, which presents with inflammation in the joints, PsA can present as back or joint pain, "which makes our life as rheumatologists much more complex," Dr. Eder said.

Defining a Risk Group

Most experts agree that the presence of psoriasis isn't sufficient to conduct a prevention trial. Ideally, the goal of a prevention study would be to identify a critical subgroup of psoriasis patients at high risk of developing PsA.

However, this presents a challenging task, Dr. Eder said. Psoriasis is a risk factor for PsA, but most patients with psoriasis won't actually develop it. Given that there's an incidence rate of 2.7% a year, "you would need to recruit many hundreds of psoriasis patients and follow them for a long period of time until you have enough events."

Dr George Schett

Moving forward with prevention studies calls for a better definition of the PsA risk group, according to Georg Schett, MD, chair of internal medicine in the department of internal medicine, rheumatology, and immunology at Friedrich‐Alexander University, Erlangen, Germany. "That's very important, because you need to define such a group to make a prevention trial feasible. The whole benefit of such an approach is to catch the disease early, to say that psoriasis is a biomarker that's linked to psoriatic arthritis."

Indicators of risk other than psoriasis, such as pain, inflammation seen in ultrasound or MRI, and other specificities of psoriasis, could be used to define a population where interception can take place, Dr. Schett added. Although it's not always clinically recognized, the combination of pain and structural lesions can be an indicator for developing PsA.

One prospective study he and his colleagues conducted in 114 psoriasis patients cited structural entheseal lesions and low cortical volumetric bone mineral density as risk factors in developing PsA. Keeping these factors in mind, Dr. Schett expects to see more studies in biointervention in these populations, "with the idea to prevent the onset of PsA and also decrease pain and subcutaneous inflammation."

Researchers are currently working to identify those high-risk patients to include in an interventional trial, Dr. Ritchlin said.

That said, there's been a great deal of "clinical trial angst" among investigators, Dr. Ritchlin noted. Outcomes in clinical trials for a wide range of biologic agents have not demonstrated significant advances in outcomes, compared with initial studies with anti–tumor necrosis factor–alpha (TNF-alpha) agents 20 years ago.

Combination Biologics

One approach that's generated some interest is the use of combination biologics medications. Sequential inhibition of cytokines such as interleukin-17A and TNF-alpha is of interest given their central contribution in joint inflammation and damage. "The challenge here of course is toxicity," Dr. Ritchlin said. Trials that combined blockade of IL-1 and TNF-alpha in a RA trial years ago resulted in significant adverse events without improving outcomes.

Comparatively, a recent study in The Lancet Rheumatology reported success in using the IL-17A inhibitor secukinumab (Cosentyx) to reduce PsA symptoms. Tested on patients in the FUTURE 2 trial, investigators demonstrated that secukinumab in 300- and 150-mg doses safely reduced PsA signs and symptoms over a period of 5 years.

Secukinumab also outperformed the TNF-alpha inhibitor adalimumab in 853 PsA patients in the 52-week, randomized, head-to-head, phase 3b EXCEED study, which was recently reported in The Lancet. Articular outcomes were similar between the two therapies, yet the secukinumab group did markedly better in Psoriasis Area and Severity Index scores, compared with the adalimumab group.

Based on these findings, "I suspect that studies examining the efficacy of combination biologics for treatment of PsA will surface in the near future," Dr. Ritchlin said.

Yet another approach encompasses the spirit of personalized medicine. Clinicians often treat PsA patients empirically because they lack biomarkers that indicate which drug may be most effective for an individual patient, Dr. Ritchlin said. However, the technologies for investigating specific cell subsets in both the blood and tissues have advanced greatly over the last decade. "I am confident that a more precision medicine–based approach to the diagnosis and treatment of PsA is on the near horizon."

Diet as an Intervention

Other research has looked at the strong link between metabolic abnormalities and psoriasis and PsA. Some diets, such as the Mediterranean diet, show promise in improving the metabolic profile of these patients, making it a candidate as a potential intervention to reduce PsA risk. Another strategy would be to focus on limiting calories and promoting weight reduction.

One study in the British Journal of Dermatology looked at the associations between PsA and smoking, alcohol, and body mass index, identifying obesity as an important risk factor. Analyzing more than 90,000 psoriasis cases from the U.K. Clinical Practice Research Datalink between 1998 and 2014, researchers identified 1,409 PsA diagnoses.

Among this cohort, researchers found an association between PsA and increased body mass index and moderate drinking. This finding underscores the need to support weight-reduction programs to reduce risk, Dr. Eder and Alexis Ogdie, MD, of the University of Pennsylvania, Philadelphia, wrote in a related editorial.

While observational studies such as this one provide further guidance for interventional trials, confounders can affect results. "Patients who lost weight could have made a positive lifestyle change (e.g., a dietary change) that was associated with the decreased risk for PsA rather than weight loss specifically, or they could have lost weight for unhealthy reasons," Dr. Eder and Dr. Ogdie explained. Future research could address whether weight loss or other interventional factors may reduce PsA progression.

To make this work, "we would need to select patients that would benefit from diet. Secondly, we'd need to identify what kind of diet would be good for preventing PsA. And we don't know that yet," Dr. Eder further elaborated.

As with any prevention trial, the challenge is to follow patients over a long period of time, making sure they comply with the restrictions of the prescribed diet, Dr. Eder noted. "I do think it's a really exciting type of intervention because it's something that people are very interested in. There's little risk of side effects, and it's not very expensive."

In other research on weight-loss methods, an observational study from Denmark found that bariatric surgery, especially gastric bypass, reduced the risk of developing PsA. This suggests that weight reduction by itself is important, "although we don't know that yet," Dr. Eder said.

A Risk Model for PsA

Dr. Eder and colleagues have been working on an algorithm that will incorporate clinical information (for example, the presence of nail lesions and the severity of psoriasis) to provide an estimated risk of developing PsA over the next 5 years. Subsequently, this information could be used to identify high-risk psoriasis patients as candidates for a prevention trial.

Other groups are looking at laboratory or imaging biomarkers to help develop PsA prediction models, she said. "Once we have these tools, we can move to next steps of prevention trials. What kinds of interventions should we apply? Are we talking biologic medications or other lifestyle interventions like diet? We are still at the early stages. However, with an improved understanding of the underlying mechanisms and risk factors we are expected to see prevention trials for PsA in the future."

This article originally appeared on, part of the Medscape Professional Network.


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