Speaker- April W Armstrong

In the development of psoriatic arthritis (PsA), patients typically begin with psoriasis, as this is the case for most individuals. These patients are often genetically predisposed to PsA and may experience further aggravating factors, such as mechanical stress or certain infections, which drive the progression toward PsA. A second "hit" can also occur, triggered by comorbidities or microbiome-related events, increasing the risk of PsA over time. Studies indicate that it generally takes an average of 10 years from the onset of psoriasis for PsA to manifest. This timeline has several stages, ranging from psoriasis to preclinical PsA, subclinical PsA, prodromal PsA, and finally, the full development of PsA. Rheumatologists, particularly those specializing in psoriasis, have recognized that subclinical inflammation may occur in the synovium or areas affected by enthesitis even before a patient experiences symptoms. Dermatologists are crucial in screening and identifying individuals at an earlier stage, potentially before progressing to full-blown PsA, allowing for earlier intervention. 

According to the guidelines from the American Academy of Dermatology and the National Psoriasis Foundation (NPF), it is recommended that patients with psoriasis be screened for PsA during every visit. It highlights the importance of vigilance in preventing the progression of psoriasis into PsA. When we examine the pharmacotherapies used to treat PsA, many are familiar to dermatologists, as they overlap significantly with treatments for psoriasis. A few drugs are more specific to PsA and less commonly used in psoriasis, but most medications are employed in both conditions. It includes several FDA-approved biologics, with a new approval for PsA recently granted in the US. When addressing whether psoriasis treatments can prevent the development of PsA, it is crucial to consider the broader pathogenesis of psoriatic disease. Psoriatic disease is often visualized as a Venn diagram with three overlapping circles: cutaneous manifestations (psoriasis), synovial manifestations of PsA, and entheseal and axial disease (a smaller yet significant part of the PsA spectrum). These three disease manifestations share considerable overlap in terms of affected cell types and cytokines, which play a role in their pathogenesis. Thus, systemic treatments for psoriasis could theoretically help prevent the progression to PsA by targeting shared pathogenic pathways across these overlapping disease areas. However, further study is needed to conclusively determine the effectiveness of psoriasis treatments in preventing PsA.

Initially, whether biologics or oral Disease-modifying antirheumatic drugs (DMARDs) used to treat psoriasis can prevent or increase the risk of developing PsA might seem straightforward. However, when examining the literature, the evidence presents a mixed picture. Some key studies support the idea that biologics or oral DMARDs reduce the risk of PsA. For example, treatment with biologics, non-biologic systemic agents, and continuous biologic therapy for more than five years has been associated with a decreased risk of developing PsA. Similarly, treatments like narrowband Ultraviolet B (UVB) phototherapy have also shown potential protective effects.

On the other hand, other studies suggest that biologics, systemic therapies, or phototherapy might increase the risk of PsA. These findings are more evident when biologics are used as a surrogate marker for mild, moderate, or severe psoriasis, showing that those treated with biologics or non-biologics may still experience an increased risk of PsA. Data indicates that patients treated with topicals or those receiving no treatment might be at higher risk. Given this conflicting evidence, many in the field debate whether these treatments truly reduce the risk of PsA or, paradoxically, are linked to increased risk due to the severity of the disease in patients requiring these therapies. However, understanding both sides of the argument is crucial before forming a clear position 

During a patient consultation, a case presented involved a psoriasis patient reporting joint issues, specifically morning stiffness lasting 15 to 20 minutes. Upon reviewing the patient's medical history, the clinician noted the absence of a formal diagnosis of PsA. Given the patient's reported joint symptoms, there was an increased likelihood that the clinician would consider prescribing a biologic or an oral DMARD, which is effective for psoriasis and PsA. In such instances, a phenomenon known as protopathic bias could occur. The bias arises when treatment is initiated for early, undiagnosed disease symptoms. Suppose a clinician prescribes a biologic or DMARD for joint stiffness without a confirmed diagnosis of PsA. In that case, subsequent epidemiological studies might misclassify the treatment as a potential cause of PsA development. This misclassification occurs because the treatment was aimed at addressing early manifestations of the disease rather than causing the disease itself. Thus, while there may be an observed association between the use of biologics and the incidence of PsA, it is essential to recognize that this does not imply causation. Rather, the treatment may have been prescribed in response to initial symptoms indicative of an underlying disease that had not yet been diagnosed. This distinction is crucial when interpreting epidemiological data regarding the relationship between psoriasis treatments and the risk of PsA.

The study by Alexis Ogdee's group analyzed the timing of PsA diagnosis and treatment initiation. The findings indicated that patients receiving systemic therapies, such as oral medications and biologics, often received a PsA diagnosis within the first one to two years of treatment. Specifically, the data revealed that the blue line, representing patients starting oral therapies, and the green line for those beginning biological therapies showed a notable spike in diagnoses shortly after treatment initiation, likely due to prompt referrals to rheumatology. The concept of survival bias was also relevant in this context. Patients prescribed systemic therapies typically had undergone multiple topical treatments and phototherapy before starting biologics. This prior treatment cycle suggested that these patients had been living with psoriasis longer without developing PsA, increasing their likelihood of being observed in the biological treatment group. Consequently, the extended duration of their psoriasis might enhance the risk of developing PsA, skewing the results when comparing them to patients on topical therapies only. A study at the Keck School of Medicine involved tracking psoriasis patients undergoing phototherapy without any history of arthritis. This cohort was monitored over time to assess the incidence of PsA development in patients who continued phototherapy compared to those who switched to biologic therapy. Following the exclusion of individuals diagnosed with PsA in the first year, the results demonstrated that patients receiving biologics had a lower risk of developing PsA than those on phototherapy.

Further investigation into which class of biologics may be more effective in preventing PsA involved an analysis using the Trinetics database, which contains extensive coded data primarily from the United States. The study, published in Lancet Rheumatology, compared various biologic classes, examining their effectiveness in reducing the incidence of PsA among patients receiving treatment over time.

Based on recent findings, inhibitors of interleukin-23 (IL-23) may demonstrate superior efficacy in preventing the onset of inflammatory arthritis compared to other biologics. However, it is crucial to consider the potential for protopathic bias in these observations. For instance, clinicians may prescribe IL-17 inhibitors to patients with symptoms suggestive of an increased likelihood of developing PsA. At the same time, those treated with IL-23 may not show the same level of concern. This differential treatment approach complicates the interpretation of data regarding the effectiveness of these biologics. When assessing whether systemic treatments for psoriasis can prevent the development of PsA, the biological plausibility of this relationship remains high. Despite the complexities introduced by protopathic bias and survival bias observed in some observational studies, the underlying mechanisms suggest a strong rationale for the preventive potential of these therapies. A prospective study is underway to investigate the efficacy of   Guselkumab (Gacel QMAB) in preventing PsA among patients with psoriasis. The randomized controlled trial compares the outcomes of Gacel QMAB against placebo and standard care, excluding biologic therapy. The study, referred to as the  Psoriasis and Musculoskeletal Pain Assessment (PAMPA) study, aims to provide definitive evidence on this important question. The study protocol has already been published, and results are anticipated. While the nuances of treatment bias must be acknowledged, the overarching message is clear: treating PsA may also confer preventive benefits against its development. 

The discussion regarding prospective studies to assess whether PsA is delayed or prevented by specific drugs has highlighted concerns raised by rheumatologists. They often express difficulties with readouts, stating that while visible changes can be observed in the skin, significant joint symptoms may not be as readily apparent. It raises the question of whether the studies incorporate advanced techniques like needle biopsies or single-cell analysis. In response, it was noted that needle biopsies are not included in the study protocols, particularly in the PAMPA study. Instead, these studies utilize imaging techniques like ultrasound to monitor joint changes. The reasoning behind this approach is that it may take longer than the study duration, which is typically 96 weeks, for observable joint symptoms to manifest significantly. While imaging is a useful tool for detection, the absence of tissue sampling limits the capacity to gather detailed biomarker information. This information could potentially provide deeper insights into the disease's underlying mechanisms. As a result, integrating advanced techniques may enhance the understanding of treatment effects on PsA and improve the reliability of study outcomes.

33, European Academy of Dermatology and Venereology Congress, 25-28 September 2024, Amsterdam