Introduction

This review summarizes the current understanding of psoriatic arthritis (PsA), its comorbidities, and evolving treatment strategies, and highlights educational gaps for healthcare professionals involved in its management.

PsA represents a heterogeneous, chronic, and potentially debilitating spondyloarthropathy linked to psoriasis. ^{{Al Hammadi, 2018, p.14, ¶2}} In patients with psoriasis, estimates of PsA prevalence vary widely, ranging from 6% to 41%. ^{{Singh, 2019, p.3, col 1, ¶1}} Yet once PsA develops, a significant percentage of patients (40%) go on to develop irreversible erosive and deforming arthritis. ^{{Al Hammadi, 2018, p.15, ¶7}}

Clinical Signs and Symptoms

Plaque-subtype psoriasis typically precedes the musculoskeletal symptoms of PsA by about 10 years. The characteristic initial musculoskeletal symptoms of PsA include enthesitis, dactylitis, spondylitis, and peripheral arthritis, along with nail changes such as pitting or detachment. ^{{Singh, 2019, p.2, col 1, ¶1; Ogdie, 2015, p.3, ¶3; Husni, 2016, p.1, ¶1; Kaine, 2019, p.122, col 2, ¶1}}

Manifestations such as these help distinguish PsA from other inflammatory arthropathies, including rheumatoid arthritis (RA). Indeed, the presence of these manifestations, as well as a negative serological test for RA, is a salient diagnostic feature of PsA. ^{{Kerschbaumer, 2016, p.791, col 2, ¶1}} Further, enthesitis—inflammation at the insertion of tendons or ligaments into bone—appears to be an early diagnostic sign of more severe PsA. It appears in up to 50% of patients, is associated with a poor outcome, and is more common in PsA than in other inflammatory arthropathies. ^{{Kaeley, 2018, p.35,¶4, p.36, col 1,¶2}}

Pathogenesis

The pathogenesis of PsA remains poorly understood, but likely involves a complex interplay among genetic susceptibility, environmental triggers, and dysregulated innate and adaptive immune responses. ^{{Veale, 2018, p.2281, col 2, ¶2}}Yet psoriasis and PsA appear to share an overlapping immune-mediated etiology. ^{{Kerschbaumer, 2016, p.792, col 2, ¶1; Veale, 2018, p.2273, col 1, ¶2; p.2227, col 1, ¶1}} The synovium in patients with PsA shows dense T cell, B cell, macrophage infiltrates and elevated levels of inflammatory cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-12, IL-17 and IL-23, with TNF-α and IL-23 also fundamental immunogenic drivers in psoriasis.

In addition, persistent synovial inflammation leads to the release of matrix‑degrading enzymes, including matrix metalloproteinases, which contribute to cartilage and bone damage, bone resorption, and ultimately joint deformity and functional impairment. Together, these inflammatory processes result in bone resorption and, in turn, joint deformity and subsequent loss of function.

Conceptually, PsA can be viewed either as a systemic autoimmune disease or as an enthesis‑driven process in which microtrauma at tendon and ligament insertions initiates inflammation at the enthesis and adjacent bone. This enthesis‑organ model helps explain the close relationship between mechanical stress, entheseal inflammation, and the development of peripheral arthritis and axial disease in PsA. ^{{Kerschbaumer, 2016, p.792, col 2, ¶1}}

Comorbidities

Over the past decade, however, recognition of PsA as a systemic inflammatory disease has expanded, revealing strong associations with multiple comorbidities.^{{Ogdie, 2015, p.7, ¶4}} Patients with PsA exhibit elevated risks of metabolic syndrome components (obesity, hypertension, dyslipidemia, type 2 diabetes), cardiovascular disease (coronary artery disease, cerebrovascular events), and other immune‑mediated conditions, including multiple sclerosis.^{{Kaine, 2019, p.122, col 1, ¶3; Shah, 2017, p.1, col 1, ¶3}} Additional comorbidities that impair quality of life—such as fatigue, depression, anxiety, osteoporosis, uveitis, eczema, and gout—are also prevalent.

Multimorbidity is common: approximately 40% of PsA patients have at least three simultaneous comorbidities.^{{Ogdie, 2015, p.7, ¶4}} Shared inflammatory pathways, particularly those involving IL‑23/IL‑17 and TNF‑α, likely contribute to the development of cardiometabolic comorbidities. ^{{Shah, 2017, p.3, col 2, ¶2}} Delayed PsA diagnosis and suboptimal disease control exacerbate comorbidity burden, joint damage, functional decline, and impaired quality of life.^{{Van den bosch, 2018, p. 2285, col 2, ¶1}} Early, comprehensive management addressing both PsA and comorbidities is therefore critical to mitigate long‑term morbidity.

Treatment

In the treatment of PsA, both clinicians and patients seek approaches that provide durable effectiveness with an acceptable safety profile. PsA and RA have historically shared a similar basic treatment approach. However, there is now a movement to view PsA and RA as distinct disease entities with increasingly divergent treatment pathways. ^{{Weaver, 2018, p.2}}

DMARDS

Conventional disease‑modifying antirheumatic drugs (DMARDs)—methotrexate, leflunomide, sulfasalazine, and ciclosporin—have been used to treat PsA according to schedules similar to those used in RA. ^{{van der Bosch, 2018, p. 2287, col. 1, ¶2}}Yet, for most of these agents, clinical trials in PsA have been uncontrolled and have included only a small number of subjects. Leflunomide remains the only DMARD with efficacy in the management of PsA supported by a double-blind, placebo-controlled trial. In routine practice, however, rheumatologists usually prescribe methotrexate as first‑line therapy for PsA, a strategy supported by European League Against Rheumatism (EULAR) guidelines.

Biological Therapy

Biologic therapies (Table 1), such as TNF‑α inhibitors, have demonstrated efficacy in the management of PsA and appear to prevent or slow structural damage in patients with peripheral disease. ^{{van der Bosch, 2018, p.2288, col 1, ¶1}}

Table 1: Biologic Therapies Approved by the FDA for Treatment of Psoriatic Arthritis

Biologic agent
TNF-α inhibitors
Brand	Generic
ENBREL	Etanercept
ERELZI	Etanercept-szzs (biosimilar for Enbrel)
REMICADE	Infliximab
INFLECTRA	Infliximab-dyyb (biosimilar for Remicade)
HUMIRA	Adalimumab
CYLTEZO	Adalimumab-adbm (biosimilar for Humira)
AMJEVITA	Adalimumab-atto) (biosimilar for Humira)
ORENCIA	Abatacept
SIMPONI ARIA	Golimumab
CIMZIA	Certolizumab pegol
IL-17 inhibitors
COSENTYX	Secukinumab
SILIQ	Brodalumab
TALTZ	Ixekizumab
IL-12/IL-23 inhibitor
STELARA	Ustekinumab
SKYRIZI	Risankizumab
TREMFYA	Guselkumab
Phosphodiesterase 4 inhibitor^a
OTEZLA	Apremilast
Janus kinase inhibitor^a
XELJANZ	Tofacitinib

^aBlocks pathway involved in synthesis of inflammatory mediators such as TNF-α, IL-12, IL-17, and IL-23 ^{{Gooderham, 2015, p.327, col 1, ¶1; Veale, 2019, p.200, Figure 2}}

In 2018, the American College of Rheumatology and the National Psoriasis Foundation (ACR/NPF) issued updated guidelines for the treatment of PsA. ^{{Singh, 2019}} These guidelines include a conditional recommendation for TNF-α blockers over conventional small-molecule DMARDs, such as methotrexate, as first-line therapy in patients with active PsA. ^{{Singh, 2019, p.9, Figure 3}} This recommendation represents a major shift, as other treatment guidelines, including EULAR, still advocate methotrexate as first-line treatment, followed by the stepwise deployment of biologic agents as needed.

New and emerging options

Despite the established efficacy of TNF-α inhibitors in the treatment of PsA, a subset of patients fail to respond adequately or consistently or experience unacceptable side effects. As a result, other, newer biological treatments with disparate anti-inflammatory mechanisms have emerged in recent years (Table 1). These agents inhibit proinflammatory cytokines upregulated in the diseased synovium, such as IL-12, IL-17, and IL-23, or inhibit pathways involved in their overproduction, such as phosphodiesterase-4 and Janus kinase (JAK).

For instance, ustekinumab, a monoclonal antibody that targets IL-12 and IL-23, has demonstrated efficacy in alleviating enthesitis and dactylitis, as well as the dermatologic manifestations of PsA. ^{{van der Bosch, 2018, p. 2288, col 2, ¶1; p.2289, col 1, ¶3}} Additionally, tofacitinib, an oral JAK inhibitor, and ixekizumab, a selective IL-17 inhibitor, improve symptoms in patients with PsA with an inadequate response to TNF-α inhibitors or patients without prior exposure to these agents. ^{{van der Bosch, 2018, p2289, col 1, ¶3; Orbai, 2018, ACR abstract 2561}} Moreover, agents that block the IL 17/IL 23 pathway, such as secukinumab, brodalumab, and ixekizumab can provide durable improvement in the joint and skin manifestations of PsA for up to 52 weeks. ^{{Husni, 2019, abstract; Orbai, 2018, ACR abstract 2560; McInnes, 2018, ACR abstract 2608; Foulkes, 2019p.3, col 2, ¶4}}

As of May 2019, ClinicalTrials.gov listed 92 ongoing clinical trials related to PsA treatment. Novel agents currently in Phase III testing are listed in Table 2. These agents target either IL-17 or JAK.

Table 2: Agents in Late Clinical Phase Testing for the Treatment of Psoriatic Arthritis

Agent	Mechanism of action	Manufacturer
Bimekizumab	Monoclonal antibody against IL-17	UCB Pharma
BCD-085	Monoclonal antibody against IL-17	JSC BIOCAD
Upadacitinib	Oral JAK-selective inhibitor	AbbVie

Treatment approach

ACR/NPF guidelines advocate a treat-to-target strategy―that is, adjusting therapy based on objective measures of disease activity until a predefined therapeutic target is achieved. The treat-to-target approach should, however, be tempered by consideration of the impact of more intensive treatment on the patient, including greater severity or frequency of adverse events, higher therapy costs, or an increased medication dosing burden. ^{{Singh, 2019, p.18, ¶1}} Given the complexity and range of therapeutic options for PsA, a multidisciplinary approach that includes collaboration between rheumatologists and dermatologists, with active patient input, may help achieve optimal treat‑to‑target outcomes. ^{{Visalli, 2019, p.806}}

Gaps and Educational Needs

Gap 1: Delayed PsA diagnosis is common and can result in poor long-term outcomes.

For patients with PsA, the delay between disease onset and diagnosis still averages a disconcerting 5 years. ^{{Garrido-Cumbrera, 2017, p.221, col 2, ¶3}} Clinical data show that early PsA diagnosis improves outcomes and delayed diagnosis worsens outcomes, with an increased risk for joint damage and disability. Early diagnosis of PsA remains challenging for many clinicians and, as a result, patients are often misdiagnosed or remain undiagnosed. The majority of rheumatologists and dermatologists (>85%) acknowledge that failure to recognize the link between skin and joint symptoms underlies the underdiagnosis of PsA. In addition, delayed PsA diagnoses may result in the failure to recognize early and aggressively treat the common comorbidities associated with PsA, such as diabetes, hypertension, and obesity, further contributing to an increased risk for future morbidity. ^{{Eder, 2018, p.2, ¶1}}

To overcome diagnostic delays, all patients with psoriasis should be screened for PsA, perhaps through the routine use of patient questionnaires completed before or during the physician visit. ^{{Jesitus, 2018, p.1, ¶4}}

Educational need: Healthcare professionals involved in the management of PsA would benefit from educational initiatives that delineate its heterogeneous and complex clinical presentation and highlight the need to screen all patients with psoriasis for PsA routinely.

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