Difficult-to-Treat Psoriatic Arthritis Characteristics
Despite utilizing guideline-recommended treatment and management strategies, some patients with psoriatic arthritis (PsA) struggle to be successfully treated. These patients often experience multiple treatment failures and may be categorized as difficult-to-treat (D2T).
Gaps in the literature exist concerning this subset of patients with PsA, including the categorization of a patient as D2T, the prevalence of D2T PsA, and the best way for health care practitioners to manage these patients.
To answer these questions, researchers conducted a comparative analysis of the characteristics of D2T PsA.
Lead study author, Cécile Philippoteaux, MD, MSc, PharmD, answers these questions and more about her team’s recent comparative analysis examining the characteristics of D2T PsA. Dr Philippoteaux is part of the Department of Rheumatology at Lille University Hospital (Lille, France).
Consultant360: Please provide an overview of your study and your session at ACR Convergence 2023.
Cécile Philippoteaux: While there has been an increase in available therapeutics for inflammatory rheumatic diseases in recent years, some patients still do not respond to treatments and therefore are categorized as D2T. D2T rheumatoid arthritis (RA) has been defined by the European Alliance of Associations for Rheumatology (EULAR) as “the persistence of signs of activity within the failure of at least 2 b/tsDMARDs (biologic and targeted synthetic disease modifying antirheumatic drugs) with 2 mechanisms of action.” Several challenges exist as this definition has not yet been extrapolated with consensus in PsA and we have limited data in the real-world setting.
The absence of a temporal criterion is a limitation in the D2T RA EULAR definition. The primary endpoint of our analysis was to study the prevalence and the characteristics of patients with D2T PsA using the EULAR definition. The second objective was to study a sub-group of patients with a more stringent definition, which included a temporal criterion.
We performed a retrospective study at the Lille University Hospital in France, which is a tertiary center. D2T PsA was defined as the persistence of activity perceived as problematic and the failure of two or more b/tsDMARDs with different mechanisms of action. Very D2T PsA was defined as the same, with a treatment failure criteria of two or more b/tsDMARDs in 2 years or less. Patients with D2T and very D2T PsA were compared with patients with non-D2T PsA in univariate and multivariate analysis.
A total of 150 patients with PsA were included from 2004 to 2018, for a total of 49 patients in the D2T PsA group and 101 patients in the non-D2T PsA group. A higher prevalence of axial involvement (p = 0.030), axial and/or peripheral structural damage (p=0.007) at baseline, and more bDMARDs discontinuation due to poor dermatological control (p=0.005) was observed in the D2T PsA group. In multivariate analysis, peripheral structural damage at baseline was found to be a predictive factor for D2T PsA with an OR of 2.57 (1.16 to 5.69; p=0.020). There was no significant difference between the D2T and non-D2T groups regarding comorbidities such as obesity, smoking status, fibromyalgia, or depression. A total of 17 (11.3%) patients with PsA were categorized as very D2T PsA. The proportion of obesity was higher (p=0.015), and axial involvement was more prevalent in the very D2T PsA group (p=0.020) when compared with the non-D2T PsA group.
There are limitations in applying the EULAR D2T definition for RA to PsA. These include the clinical heterogeneity of PsA, the lack of a temporal criteria for treatment failure criteria, and the lack of consideration for comorbidities. The very D2T PsA group represented a low proportion of patients, suggesting the need to build a better definition for more stringent criteria. Pending the PsA D2T definition by the European and American societies, this study highlights some characteristics that may help practitioners better identify patients who are considered D2T.
Our study has been recently accepted for publication in Seminars in Arthritis and Rheumatism, and we were able to share our findings with the international scientific community at the American College of Rheumatology Convergence.
C360: The results of your study showed that of the 150 patients included, 32.7% were characterized as having D2T PsA after applying the EULAR definition. Was this prevalence anticipated by your team, or did this result surprise you?
CP: We were surprised by the high proportion of patients with D2T PsA in our cohort, which contrasts with real-world studies in RA that demonstrated a lower D2T prevalence of between 7% to 10%. Yet, Perrota and colleagues have shown a D2T PsA prevalence of 33.9%, which is similar to ours.
These results can raise the limit of the extrapolation of the D2T RA definition in PsA because of the clinical heterogeneity of this inflammatory rheumatic disease, with a remission more complex to assess, thus the need to properly characterize the clinical subset of patients. Since there are also limitations to the EULAR definition itself (mainly because of the lack of a time criterion), we studied a sub-group of patients selected after applying a more stringent definition, including a time criterion. The very D2T PsA prevalence drastically lowered to 11.3%, which is close to the data available in RA. In psoriasis, Loft and colleagues identified 6.5% of patients as D2T.
C360: How might health care practitioners alter their approach to treatment of these patients, based on the higher prevalence of axial involvement, structural damage, and therapeutic discontinuation that were observed among this population in this study?
CP: The main findings of our study may help health care practitioners to better consider the predominant clinical pattern in PsA and the possible structural damage to identify potential patients who are D2T. Clinical heterogeneity and potential modification over time may need to be considered when categorizing the clinical subset of patients with PsA. Adequately targeting the predominant symptomatic pattern (axial and/or peripheral) is especially important after tumor necrosis factor (TNF) inhibitor failure.
The higher frequency of b/tsDMARDs discontinuation in both D2T groups compared with the non-D2T group can be partially explained by the high proportion of patients treated with TNF inhibitors. The number of available therapeutics increased during the time of our study, and a lot of patients have received TNF inhibitors before the market authorization of ustekinumab and secukinumab in France (November 2015 and July 2016, respectively). Head-to-head studies have shown less dermatological efficacy of TNF inhibitors compared with other interleukin inhibitors for patients with psoriasis. Individuals on long-term maintenance therapy are now able to reach the Psoriasis Area and Severity Index goal score of 90/100. Thus, the absence of dermatological satisfaction can encourage the patient or the practitioner to make a therapeutic switch, hoping for a better outcome.
C360: What are some clinical pearls that you use in your practice for managing patients with D2T PsA?
CP: In cases of multiple treatment failure, it is essential to reevaluate whether the correct diagnosis has been made, whether the symptoms not controlled by the different therapeutic lines are attributable to the inflammatory rheumatic disease activity, and, of course, whether the treatments are well taken. Non-adherence to treatment has been found to be more frequent in patients with D2T RA, which underlines the need to better understand the barriers that can prevent patients from proper adherence. The D2T PsA concept is complex and multifactorial, as extra-musculoskeletal manifestations (psoriasis, uveitis, inflammatory bowel diseases), bio-psycho-social factors, and comorbidities can impact the response to treatments. It is therefore crucial to consider all these aspects to better manage and treat patients with a D2T disease.
C360: Your study notes that a task force from the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) is currently developing a consensual definition for D2T PsA. Once this has been achieved, what are the next steps for research in this area?
CP: Yes, a GRAPPA task force is currently working on proposing a consensual D2T PsA definition. We were happy to join a discussion group organized by GRAPPA during the ACR Convergence Congress in San Diego that aimed to raise discussions on a D2T PsA definition. This definition is important for the next steps of clinical research (randomized controlled trials and observational studies), as it would help identify factors associated with the D2T character, the analysis of cohorts of patients with PsA treated worldwide, and the use of a standardized definition. With the development of new therapeutic options, the D2T phenomenon might intensify in the future, raising the need to have a more stringent D2T treatment failure criteria in the definition, potentially including temporal criteria.
Additional next steps for research include the difference between patients who are considered D2T and refractory, as the difference is not clear at this time. We anticipate that all patients who are D2T are not refractory. We consider a distinction based on the challenging aspects of treating patients with D2T PsA, such as a history of some treatment failures and/or the presence of comorbidities. In contrast, patients who are refractory would have failed multiple therapeutic lines, and in some cases, all available therapies. Currently, there is no distinction between the two definitions. Loft and colleagues used the term treatment-refractory psoriasis while using a D2T definition.
Finally, discussions are emerging on the possibility of inflammatory rheumatic disease endotypes that could explain b/tsDMARD failure. An innovative randomized controlled trial was conducted in RA, with randomization and stratification according to the patient's endotype after a synovial tissue biopsy. This trial represents a paradigm shift with a new way of thinking about therapeutic choices in inflammatory rheumatic diseases. We could develop this approach in patients with D2T PsA, identified with the consensual D2T definition, to study the effects of specific immune treatments and better apprehend molecular or cellular responses.
Many challenges are yet to come in D2T PsA, and the objectives are to lower the global economic and medical burden.
References:
1. Philippoteaux C, Marty-Ane A, Cailliau E, et al. Characteristics of difficult-to-treat psoriatic arthritis: a comparative analysis. Semin Arthritis Rheum. 2023;63:152275. doi:10.1016/j.semarthrit.2023.152275.
2. Philippoteaux C, Marty-Ane A, Cailliau E, et al. Spondyloarthritis including psoriatic arthritis – treatment I: PsA. American College of Rheumatology Convergence; November 10-15, 2023; San Diego, CA. Accessed November 16, 2023. https://acrabstracts.org/abstract/characteristics-of-difficult-to-treat-psoriatic-arthritis-a-comparative-analysis/