Psoriatic arthritis (PsA) is a complex multidomain disease, and many patients continue to experience significant disease activity despite treatment. Complex-to-manage PsA often necessitates adjunctive therapy beyond traditional DMARDs to address persistent symptoms and contributing factors, while true treatment-refractory PsA frequently requires a multi-immunomodulatory therapeutic approach. A better clinical understanding of PsA is necessary to navigate the ever-expanding therapeutic landscape with the goal of achieving individualized patient care.

When considering treatment approaches for patients with PsA, it is important to distinguish between complex-to-manage PsA and true treatment-refractory PsA. The broader group, which the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) is calling “complex-to-manage PsA,” is defined by the concomitant presence of comorbidities, overlapping conditions, psychosocial factors, or treatment-related challenges that may be contributing to a patient’s pain, increasing their fatigue, and reducing their overall response to the medications that we are using.

Various comorbidities are inherently part of the PsA process. Patients with PsA are at higher risk for cardiovascular disease, obesity, hyperlipidemia, and fibromyalgia, which may influence their disease activity. Many patients experience central pain or central sensitization. In fact, approximately 30% of patients with rheumatic inflammatory disease also have fibromyalgia. To address this, we can use nonpharmacologic approaches and provide exercise recommendations (while working with physical therapists and psychologists), along with using some of the US Food and Drug Administration (FDA)–approved medications for fibromyalgia, such as duloxetine.

We also know that patients with obesity present with more severe disease and often experience a dampened treatment response. For these patients, we are increasingly using dual or triple therapies and are considering GLP-1 receptor agonists, which are targeted to improve obesity and, as emerging evidence shows, may in their own right have immunomodulatory effects.

We also see cases of treatment-refractory PsA in some patients over the course of their disease, and, under the new GRAPPA definition, this is characterized by persistent symptoms even after at least 3 different therapies. In these cases, we have tried and had a good effect from a number of different mechanisms (eg, TNF, IL-17, and IL-23 inhibition), but patients have lost their response, either because of changes in overall immune response or the development of antidrug antibodies or other factors. And this is evident by an increased number of tender and swollen joints, increased skin psoriasis severity, and objective measures, including ultrasound evidence of inflammation.

These individuals are considered the truly treatment-refractory patients who have a resurgence of immunologic disease and sometimes need more aggressive therapy, including dual therapy combining 2 immunologic-modifying agents together. For example, if a patient is not getting the full benefit from an IL-23 inhibitor, we may want to couple that with a TNF inhibitor. From emerging data in the AFFINITY trial, we see efficacy with this combination compared with immunomodulatory therapy alone.

Overall, it takes a village to care for a patient with PsA, bringing in experts in obesity, diabetes, cardiovascular disease, and other clinical disciplines, alongside a more in-depth and granular understanding of PsA to better treat patients who are not experiencing the full benefit from treatment.

When I first started my practice, treating PsA was about assessing a patient’s laboratory values and x-rays, and then choosing the right biologic based on that. Now, there is a whole literature base on addressing comorbidities and safety risks that we have to incorporate into our treatment decisions. We are now looking at how active some of these comorbidities are and at how bidirectional their effects are.

It is interesting that some of the lifestyle factors that we have been talking about for decades are now supported by evidence-based data (eg, that a patient with an elevated body mass index may not respond as well to treatment). Another example is cardiovascular risk. Based on recent studies, including the ORAL study in rheumatoid arthritis, we know to shy away from some of the JAK inhibitors in older patients with cardiovascular risk. Central pain is also an important comorbidity to consider. Many patients with PsA experience pain, which may be inflammatory or noninflammatory. So, how do we optimize the treat-to-target strategy? If they have central pain, could an additional medication help address that pain while they stay on their current medicine for PsA?

Regarding a patient who is not responding, I think that our previous definitions were very simple: response or no response. And now we are really asking: Is this a primary nonresponse? Is this a loss of response over time? Is this some intolerance of the medication and the patient is not taking it as prescribed? Is there maybe just one aspect of an uncontrolled domain and all the other domains are really well treated?

So, I think that having a conversation about the complexity of PsA and defining what response looks like (ie, whether it is truly treatment refractory or just complex to manage) are much more at the forefront. And I think that this has really helped us conduct better trials, communicate better with patients, and select the right medications. Overall, I think that these nuances are important; it is important to understand what it means when a patient is not really at target so that we can make the right treatment decisions moving forward.