Advances in the management of psoriatic arthritis in adults
BMJ 2024; 387 doi: https://doi.org/10.1136/bmj-2024-081860 (Published 21 November 2024) Cite this as: BMJ 2024;387:e081860
- Fadi Kharouf, medical doctor, clinical fellow1 2,
- Dafna D Gladman, professor of medicine, senior scientist1 2
- 1University of Toronto, Psoriatic Arthritis Program, University Health Network, Toronto Western Hospital, Toronto, ON, Canada
- 2Gladman-Krembil Psoriatic Disease Program, Toronto Western Hospital, Toronto, ON, Canada
- Correspondence to: D D Gladman dafna.gladman{at}utoronto.ca
Abstract
Psoriatic arthritis is an inflammatory arthritis that affects around 30% of patients with psoriasis. The disease spectrum includes peripheral arthritis, enthesitis, tenosynovitis, dactylitis, axial involvement, and skin and nail psoriasis in most patients. In addition to the cutaneous and musculoskeletal manifestations, several comorbidities can complicate the disease course, including cardiovascular disease, diabetes mellitus, metabolic syndrome, gout, anxiety, and depression. The management of patients with psoriatic arthritis begins with a careful assessment of the skin and joints and screening for comorbidities. This review describes the assessment tools and outcome measures used in the evaluation of patients with psoriatic arthritis. It summarizes the approach to therapy, including non-medicinal interventions such as education, lifestyle changes, physiotherapy, and occupational therapy. It discusses the evidence on pharmacologic treatments, including drugs used for symptomatic relief such as non-steroidal anti-inflammatory drugs, and those used to control the disease process; this last group comprises conventional synthetic disease modifying anti-rheumatic drugs (DMARDs), including methotrexate, leflunomide, and sulfasalazine, and biologic and targeted DMARDs, including anti-tumor necrosis factor (TNFα), anti-interleukin-17 (IL-17), anti-IL-12/23, and anti-IL-23 agents, as well as Janus kinase (JAK) inhibitors and phosphodiesterase 4 (PDE4) antagonists. Although these drugs are usually tailored to the clinical profile of the patient, biomarkers predictive of response to therapy are needed so that a more personalized approach can be followed.
Introduction
Psoriatic arthritis is an immune mediated inflammatory musculoskeletal disease affecting around 30% of patients with psoriasis. Most patients with psoriatic arthritis develop psoriasis before or simultaneously with joint involvement. The disease comprises several domains, including peripheral arthritis, enthesitis, dactylitis, axial disease, and skin and nail psoriasis.1 It may also be associated with several comorbidities, including obesity, metabolic syndrome, cardiovascular disease, anxiety, and depression.2 Psoriatic arthritis was recognized as a distinct entity owing to the efforts of Moll and Wright.3 Although it was initially thought to be a mild disease, more recent studies have shown that patients with psoriatic arthritis can develop significant joint damage.1
This review summarizes the clinical features and comorbidities characteristic of psoriatic arthritis. We describe how to assess disease activity of the skin and joints and detail advances in the management of the disease. The review is intended for clinicians managing patients with psoriatic disease and clinical researchers who are studying the condition.
Sources and selection criteria
We searched PubMed and Medline databases for articles dated from 1 January 1976 until 1 July 2024. We used a range of sources, including recent systematic literature reviews, Cochrane reviews, randomized controlled trials, and observational/registry data. We then refined the articles to focus on the most informative clinical and therapeutic data. We prioritized systemic reviews, meta-analyses, primary randomized controlled trials, and well designed observational studies, with the aim of providing an overview of clinical disease aspects, current practice, and future fields of interest. We excluded case studies, case series, and reports.
Epidemiology
Psoriatic arthritis has an annual incidence of 2.7-3.2% in patients with psoriasis, with no prominent sex predominance.4 It affects 0.1-1% of the general population and 6-42% of patients with psoriasis56; the reported prevalence varies depending on the study design and geographic location.2 Since the classification criteria for psoriatic arthritis (CASPAR) 7 were published (table 1), more consistent estimates of 30% of patients with psoriasis developing psoriatic arthritis have been reported.58 In most patients, the onset of skin disease precedes that of arthritis by an average of 10 years.1 However, in about 15% of the cases, the skin and joint manifestations appear simultaneously9; in 7-20% of cases, arthritis precedes the skin disease.910 Potential risk factors for the development of psoriatic arthritis in patients with psoriasis include nail dystrophy, obesity, trauma, and severe psoriasis, among others.2
CASPAR classification criteria for psoriatic arthritis 7
Pathophysiology
Although the exact cause of psoriatic arthritis is unknown, several factors involved in its pathogenesis have been recognized. These include environmental triggers, such as trauma, infection, and alterations in the microbiome.111 Genetic factors are thought to play an important role in the development of both psoriasis and psoriatic arthritis, and certain genes, especially human leukocyte antigen (HLA) genes, seem to identify patients with psoriasis likely to develop psoriatic arthritis. These include HLA-B*27, HLA-B*8, and HLA-B*38, which are more prevalent in patients with psoriatic arthritis than in those with psoriasis without arthritis, and HLA-C*06, which seems to be more common in patients with psoriasis.12HLA-B*27, HLA-B*38, and HLA-C*06 occur more frequently in patients with psoriatic arthritis than in healthy controls.13 Non-HLA associations have also been identified using genome-wide association studies and exome sequences. These include several genes associated with psoriasis and others more specific for psoriatic arthritis. The second group includes IL23R encoding the interleukin 23 (IL-23) receptor, AIP3 encoding the tumor necrosis factor (TNF) regulated protein A20, TRAF3IP2 encoding the receptor protein Act1, which regulates cellular activation on IL-17 receptor signaling, and PTPN22 encoding a tyrosine-protein phosphatase non-receptor type 22, a single nucleotide polymorphism within the 5q31 susceptibility locus.11 These factors are all involved in the immune response. Elevated concentrations of pro-inflammatory cytokines have also been found in the tissues and blood of patients with psoriatic arthritis, providing substrates for therapeutic interventions. Figure 1 describes the sequence of events leading to disease evolution and progression.
Sequence of events and outcomes in evolution and progression of psoriatic disease. HLA=human leukocyte antigen
Clinical features
Initial descriptions of psoriatic arthritis by Moll and Wright identified five clinical patterns among patients with psoriatic arthritis: a distal predominant pattern affecting primarily the distal interphalangeal joints; an oligoarticular asymmetrical arthritis often affecting the joints of the lower extremities; a polyarticular rheumatoid arthritis-like pattern; predominant spondylitis; and arthritis mutilans, a very destructive form of arthritis. However, although these patterns may be observed at presentation, they do not persist.14
Many patients presenting with oligoarthritis develop polyarthritis. Likewise, patients may present with axial disease but subsequently develop peripheral arthritis, and patients may present with distal involvement and then develop proximal disease; arthritis mutilans can occur with any of the peripheral patterns.15 For that reason, the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) defined the six domains of the disease16: peripheral arthritis, dactylitis, enthesitis, axial involvement, skin disease, and nail psoriasis.
Arthritis presents as inflammatory joint pain, often accompanied by swelling. Notably, a unique feature of psoriatic arthritis is the occasional presence of a purplish discoloration over the affected joint. The distribution of joint involvement may be monoarticular, asymmetric oligoarticular, or polyarticular; these patterns commonly merge along the disease course. Severe destructive cases may manifest as the so-called arthritis mutilans. Dactylitis, or inflammation of the whole digit, occurs in almost 50% of patients.17 Often, all joints of the digit are inflamed, as well as the tendons and soft tissue structures. Enthesitis, or inflammation at the insertion of tendons and ligaments into bone, occurs in more than 40% of patients. The most common sites are the insertion of the Achilles and plantar fascia into the calcaneus.18
Axial disease is often associated with inflammatory-type back pain, although not as frequently or severely as in the prototype form of spondylitis, ankylosing spondylitis.19 Isolated axial disease occurs in up to 4% of patients with psoriatic arthritis, but most of the 25-70% who have spinal involvement also have peripheral disease. Compared with axial spondyloarthritis, axial psoriatic arthritis usually presents at an older age, with a lower male predominance. It is more often asymptomatic, with more prevalent cervical and peripheral involvement. Syndesmophytes are usually non-marginal and asymmetrical and may be accompanied by paravertebral ossifications; the association with HLA-B*27 is less frequent than in axial spondyloarthritis.20
Skin manifestations
Skin psoriasis occurs in almost all patients with psoriatic arthritis, although some may first present with joint manifestations.1 Nail lesions are more common among patients with psoriatic arthritis than in patients with psoriasis without arthritis, and they have been recognized as a predictor of the development of psoriatic arthritis among patients with psoriasis.4 Nail lesions occur in about 80% of patients with psoriatic arthritis. Appreciating the different domains of psoriatic arthritis is important, as they all need to be assessed in each patient and managed accordingly. The choice of therapy is based, among other things, on the specific domains involved.
Extra-musculoskeletal manifestations
In addition to the different disease domains, patients may have extra-musculoskeletal manifestations. These include the presence of mucous membrane lesions, which may occur in 5-10% of the patients; uveitis, which affects 8% of patients21; inflammatory bowel disease, which occurs in 5% of the patients; and, rarely, aortic root dilatation. These manifestations are common to all forms of spondyloarthritis, and psoriatic arthritis is classified among this group.
Radiographic findings
Radiographs can aid in the initial assessment of patients with psoriatic arthritis, as they may show typical disease features such as erosions, periosteal bone proliferation, tuft resorption, enthesophytes, and, in severe cases, pencil-in-cup deformities, subluxations, and ankylosis (fig 2); erosive and bone proliferative changes can also appear in the sacroiliac joints (fig 3) and along the spine. Notably, ultrasonography and magnetic resonance imaging (MRI) scans provide better assessment of the joints and surrounding soft tissue, such as in cases of enthesitis, tenosynovitis, and dactylitis; MRI is extremely useful in the evaluation of axial disease.
Plain radiograph of hands showing advanced changes in psoriatic arthritis. Arrowheads: pencil-in-cup deformities; thin arrows: periarticular erosions; thick arrows: ankylosis at left fifth distal interphalangeal joint and subluxation at first interphalangeal joints
Plain radiograph of pelvis in patient with axial psoriatic arthritis, showing left sided grade 3 sacroiliitis with erosive changes and some degree of bone proliferation
Comorbidities
Psoriatic arthritis does not just affect the skin and joints but is also associated with several comorbidities. Most prominent is cardiovascular disease, which is also a major cause of death.22 The cumulative probability of developing cardiovascular disease is 20% by age 70 and 30% by age 80.23 The risk of cardiovascular disease was markedly increased in a meta-analysis of 11 studies including 32 973 patients (pooled odds ratio 1.43, 95% confidence interval (CI) 1.24 to 1.66).24 Inflammation is associated with the extent of the atherosclerotic disease burden as detected by carotid ultrasonography.25
Diabetes mellitus is more common in patients with psoriatic arthritis than in the general population,26 which further increases the cardiovascular risk. Risk factors for development of diabetes mellitus in patients with psoriatic arthritis include elevated measures of disease activity such as the tender joint count and erythrocyte sedimentation rate, severity of psoriasis, and dactylitis count.27 Metabolic syndrome is also associated with psoriatic arthritis. In one study of 283 patients, 44% had evidence of metabolic syndrome.28 This was significantly associated with disease severity, smoking, and worse quality of life. Interestingly, some evidence suggests that weight loss can ameliorate pre-existing psoriasis and psoriatic arthritis and even prevent the onset of psoriasis in obese patients.29
In a longitudinal cohort study, liver abnormalities were detected in 32% of patients with psoriatic arthritis and were associated with more severe disease, higher body mass index, and use of methotrexate and anti-TNFα agents; drug induced hepatitis and fatty liver disease were the most common causes.30 Depression and anxiety are also prevalent among patients with psoriatic arthritis, more so than in patients with psoriasis alone, and are associated with disease related features.31 Moreover, patients with psoriatic arthritis also have a high frequency of hyperuricemia; one third of patients in one study had hyperuricemia, whereas only 3.4% had evidence of gout.32 Hyperuricemia was associated with more severe psoriasis and obesity. Importantly, many of these comorbidities are associated with disease activity and severity, which affects the choice and success of therapeutic interventions. Controlling disease activity while preventing the development of these comorbidities is therefore vital; once they have developed, appropriate management strategies should be tailored.
Prognosis
Although arthritis mutilans was recognized as a distinct pattern of psoriatic arthritis, the severity of the disease as a whole was not recognized until the past few decades, when it was linked to progressive joint damage, impaired function, and reduced quality of life.1 Risk factors for the development and progression of damage include inflammatory disease activity at baseline and at each visit, as well as the presence of existing damage.33 HLA genes were also found to have prognostic significance in disease progression. Whereas HLA-B*22 is protective, HLA-B*27 (in the presence of HLA-DR*7), HLA-B*39, and HLA-DQw*3 (in the absence of HLA-DR*7) are predictive of subsequent damage.34
Psoriatic arthritis is associated with an increased mortality risk.35 Risk factors for early mortality include evidence of previously active and severe disease, as reflected by the previous use of medications and radiologic changes, as well as high erythrocyte sedimentation rate (ESR) at presentation to the clinic.35 Given the disease severity and associated comorbidities, and the fact that inflammatory activity is a risk factor for several untoward outcomes, psoriatic arthritis should be diagnosed and treated early. Several studies have shown that late presentation, and therefore treatment, is associated with detrimental outcomes.363738
Assessment and outcome measures
The assessment of patients with psoriatic arthritis must include all the domains of the disease, as they all need to be considered in the creation of a therapeutic plan. The assessment of peripheral joints is based on the number of tender and swollen joints; 68 joints for tenderness and 66 joints for swelling (excluding the hip joints) should be included. This is the recommended joint count by Outcome Measures in Rheumatology (OMERACT) and GRAPPA.39
Peripheral arthritis
On the basis of the actively inflamed (swollen or tender) joint count, two outcome measures are available for peripheral arthritis. The first is the American College of Rheumatology 20% (ACR20) response, which was initially developed for rheumatoid arthritis but has been used as the primary outcome measure in most clinical trials in psoriatic arthritis.40 For a patient to be considered a responder, the tender and swollen joint counts must decrease by at least 20%, as well as ≥20% reduction in three of five additional items, including patient assessment of pain, patient’s global assessment of disease activity, physician’s global assessment of disease activity, patient’s assessment of physical function, and an acute phase reactant (C reactive protein (CRP) or ESR). In more recent trials, the primary outcome has been a second measure, the ACR50, for which a 50% reduction is required for a patient to be considered a responder.
Disease activity in psoriatic arthritis
The disease activity in psoriatic arthritis (DAPSA) score was developed specifically for patients with psoriatic arthritis. It provides a continuous score based on the tender (n=68) and swollen (n=66) joint counts, patient’s assessment of pain, patient’s global assessment, and CRP. Patients can be classified as having high, moderate, or low disease activity or remission on the basis of the total score. Many clinical trials have included the DAPSA as a secondary outcome measure.
Dactylitis
The assessment of dactylitis is based on the number of swollen digits and the demonstration of tenderness in these digits. In recent clinical trials, the Leeds Dactylitis Index, which measures digital swelling using a dactylometer, has been used.41
Axial disease
Axial disease is assessed at the bedside by cervical and lumbar spine lateral flexion, chest expansion from full expiration to full inspiration, and the Schober test measuring forward flexion of the lumbar spine.42 Axial disease activity has been assessed in clinical trials by the Bath Ankylosing Spondylitis Disease Activity Index (BADAI) or the Ankylosing Spondylitis Disease Activity Score (ASDAS).4344
Enthesitis
Tenderness at the insertion of tendons and ligaments into bone is examined by applying pressure at the site of insertion. Two instruments have been routinely used to record enthesitis, the Leeds Enthesitis Index, which records tenderness at six sites,45 and the Spondyloarthritis Research Consortium Canada enthesitis index,46 which includes 18 sites.
Skin and nail disease
The assessment of skin disease is of paramount importance. It can be measured by the body surface area (BSA), whereby the extent of psoriasis is assessed on the basis of the number of palms that cover the areas affected by psoriasis (each palm is considered to be 1% BSA) or by the Psoriasis Area Severity Index (PASI), which accounts for the degree of erythema, induration, and scaling in four separate areas of the body—the head, the trunk, and the upper and lower extremities. Rheumatologists can use the PASI score as well as dermatologists.47 Both BSA and PASI have been used in clinical trials.
Nail disease in psoriatic arthritis is assessed using the Nail Assessment of Psoriasis Index (NAPSI), which records the presence of nail bed and matrix lesions, including onycholysis, hyperkeratosis, pitting, and leukonychia, among others. NAPSI has proven reliable when used by both dermatologists and rheumatologists.41
Composite measures of disease activity
In addition to the individual domain assessment, composite measures of disease activity have been developed and are increasingly used in clinical trials. The minimal disease activity (MDA) criteria encompass seven items. Patients are considered to be in MDA if they achieve five of the following seven criteria: tender joint count ≤1, swollen joint count ≤1, enthesitis count ≤1, PASI ≤1 or BSA ≤3, patient’s global visual analog score (VAS) ≤20 mm, patient’s pain VAS ≤15 mm, and health assessment questionnaire (HAQ) ≤0.5.48 Very low disease activity (VLDA) describes a situation in which all seven criteria are met.
The Psoriatic Arthritis Disease Activity Score (PASDAS) is a weighted index developed using a similar methodology to the rheumatoid arthritis disease activity score (DAS).49 PASDAS includes seven components identified on principal component analysis (arthritis, enthesitis, dactylitis, CRP, and patient reported outcomes). It requires a calculation, which is easily computed.
The Composite Psoriatic Disease Activity Index is based on the GRAPPA domains of psoriatic arthritis.50 Each domain (peripheral joints, entheses, dactylitis, axial disease, and skin) is assessed, and they are added together to create a total score of 0-15.
The updated psoriatic arthritis core domain set endorsed by OMERACT members in 2016 included musculoskeletal disease activity, skin disease activity, pain, patient global, physical function, health related quality of life, fatigue, and systemic inflammation.51 Although these are commonly used in clinical trials and observational cohorts, assessment in the real life setting should be comprehensive and clinically oriented to cover the various disease domains and the patient’s complaints; these include the swollen and tender joint counts; the presence of enthesitis, dactylitis, and clinically damaged joints; measurement of axial metrology in cases of axial disease; and evaluation for nail lesions and skin psoriasis (PASI, BSA, or both).
Treat-to-target approach
When treating psoriatic disease, clinicians should aim to reach a predefined state of disease control, with consideration of the various domains. Although the goal of therapy is to achieve remission, no well accepted and validated definition of remission is yet available for psoriatic arthritis. Moreover, even if one defines remission as the “absence of disease activity,” the frequency of such a state is low, occurring in 18% of patients at one visit and only 9% on two to three subsequent visits.52 Therefore, states of low disease activity are alternative targets, and the instruments identified as being appropriate include MDA, VLDA, and DAPSA.5354 The tight control of inflammation in early psoriatic arthritis (TICOPA) study was a multicenter, open label, randomized controlled trial which showed that tight control of psoriatic arthritis disease activity using a treat-to-target approach, which is MDA based, significantly improved joint and skin outcomes for patients with newly diagnosed psoriatic arthritis. For instance, the odds of achieving an ACR20 response at 48 weeks were higher in the tight control arm than in the standard control arm (odds ratio 1.91, 95% CI 1.03 to 3.55; P=0.04).55
Treatment
Non-pharmacologic interventions
The first step in the management of patients with psoriatic arthritis is education. Patients need to understand the nature of their disease, with emphasis on the inflammatory component. Patients need to appreciate that controlling inflammation, and thereby alleviating symptoms, is of paramount importance not only to prevent joint damage but also to prevent the development of comorbidities associated with the disease.
Despite the absence of high level evidence on non-pharmacologic interventions in psoriatic arthritis, we generally advise regular exercise, weight reduction, and other lifestyle changes such as stopping smoking, avoiding excess alcohol intake, and proper sleep hygiene. We also recommend physiotherapy and occupational therapy for patients with stiffness and articular limitations, as well as appropriate pain management. Although evidence in spondyloarthritis is less robust than in rheumatoid arthritis, we also recommend mindfulness based stress reduction programs, yoga, Tai Chi, and relaxation, which seem to ameliorate patients’ symptoms and improve reported outcomes.56 In a randomized controlled trial implementing self‐help interventions in 130 patients with psoriasis (including patients with psoriatic arthritis), approaches based on compassion and mindfulness were found to reduce feelings of shame and improve quality of life.57
Several studies have evaluated the role of non-pharmacologic interventions. A cross sectional study found that lack of adherence to a Mediterranean diet was linked to higher psoriatic arthritis disease activity.58 Additionally, a cohort study found that using a very low energy diet to achieve short term weight loss was linked to positive effects on the musculoskeletal domain.59
The effect of smoking, alcohol consumption, and sleep abnormalities on the course and treatment of psoriatic arthritis has also been studied. A study of 267 patients who had had psoriatic arthritis for at least 10 years found an association between smoking and poor physical function, as measured by the HAQ.60 Poor sleep has also been associated with higher joint counts, greater peripheral and axial disease, fatigue, anxiety, and depression.61 A study of 82 672 US women found that excessive alcohol intake was associated with an increased risk of incident psoriatic arthritis in a cohort of US women.62An Iskandar correlation between alcohol misuse and a worse response to systemic therapies (including biologics) in patients with psoriasis has also been reported.63
Regarding physical activity, an uncontrolled intervention study showed that home based programs of exercise improved self-reported health and mental assessments in patients with well treated psoriatic arthritis on stable therapy.64 Additionally, in a randomized controlled trial from Brazil involving 41 patients with psoriatic arthritis, resistance exercises improved functional capacity, disease activity, and the overall quality of life.65 Of note, an open label controlled clinical study including 36 patients showed that spa therapy was associated with a reduction of residual synovial inflammation on ultrasonography and favorable joint and skin effects for patients treated with TNFα inhibitors.66
Despite these results, a systematic review including eight studies focusing on lifestyle modifications and non-pharmacologic interventions did not provide high quality evidence to guide patients for non-drug treatments of psoriatic arthritis; the authors concluded that the effectiveness of these interventions has therefore not been established, but physical activity seemed to have a positive effect on disease activity and psychological wellbeing.67 Additionally, a review on the use of complementary and alternative medicine (CAM) in psoriatic arthritis, including interventions such as massage, homeopathy, acupuncture, and yoga, found that despite common use, a significant knowledge gap remains, with a critical need for more research to ensure safe and effective use of CAM in patients with psoriatic arthritis.68
Drug therapy
The treatment of psoriatic arthritis requires attention to the active domains present in each patient. If the major active domain is peripheral arthritis, treatment usually begins with non-steroidal anti-inflammatory drugs (NSAIDs) to control symptoms of pain and mild inflammation. However, if a patient has a comorbidity that is a contraindication for an NSAID, such as cardiovascular disease or chronic kidney disease, then NSAIDs should be avoided. In this situation, pain medication may be prescribed instead. Of note, no evidence is available for the efficacy of NSAIDs in psoriatic arthritis, and no reason exists to prefer a specific NSAID.
If these drugs fail to control disease activity, a conventional synthetic disease modifying anti-rheumatic drug (csDMARD) is usually prescribed, most commonly methotrexate. Evidence on the efficacy of methotrexate mostly comes from widespread experience and observational studies.69707172 Despite contrasting results in clinical trials, the drug is included in all treatment recommendations and guidelines owing to its demonstrated effectiveness in real world settings, as well as recognized limitations in trial designs.737475 Leflunomide and sulfasalazine have also been used in the management of peripheral joint disease.49 European Alliance of Associations for Rheumatology (EULAR) guidelines on the management of psoriatic arthritis with drug therapies recommend that if patients do not achieve a satisfactory response within three months of starting a csDMARD, treatment should be escalated and advanced therapies should be considered.76
Although the exact cause of psoriatic arthritis is unclear, genetic, environmental, and immunologic factors play a role. One cannot change genetics, and avoiding environmental factors is often not possible. Therefore, advanced therapy is based on disease related immunologic aberrations. Several cytokines have been implicated in the development and perpetuation of the inflammatory process, and many of the therapies that have become available since 2000 are based on targeting these cytokines (table 2).
Food and Drug Administration approved biologic and targeted synthetic disease modifying anti-rheumatic drugs for treatment of psoriatic arthritis
Anti-TNFα agents
The first biologics that became available for the treatment of psoriatic arthritis were the anti-TNFα agents. TNFα is elevated in both the skin and the synovium of patients with psoriatic arthritis, so it was perceived as a good target for inhibition. To date, five anti-TNFα agents are available in most jurisdictions: etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol. They all inhibit the TNFα pathway, but etanercept is a soluble TNFα receptor whereas the others are monoclonal antibodies directed against TNFα.
All anti-TNFα agents are effective for the management of psoriatic arthritis; however, they vary in their effect on psoriasis, with the anti-TNFα antibodies being generally more effective than etanercept7778798081; doubling the dose of etanercept has been shown to provide better skin control.82 Etanercept is also considered less effective for other extra-articular disease manifestations, including inflammatory bowel disease and uveitis.83Table 3 presents data on the responses to anti-TNFα agents in the pivotal phase 3 trials, with details on the most common and remarkable side effects.
Details of approved biologic and targeted synthetic disease modifying anti-rheumatic drugs including structure, target, clinical trial efficacy, and most common adverse events
The major side effects of anti-TNFα agents include injection site or infusion reactions and susceptibility to infections, especially upper respiratory tract infections.7778798081 Reactivation of tuberculosis and concerns about neurologic complications, including demyelinating disease, are also noteworthy.102103 However, these effects are infrequently seen nowadays, especially in the context of appropriate screening and history taking. In psoriatic arthritis, unlike in rheumatoid arthritis, concomitant use of methotrexate does not seem to have a major advantage,104 but its continued use while using anti-TNFα monoclonal antibodies has been suggested in an attempt to reduce the production of anti-drug antibodies.105
Anti-IL-17/23 agents
The next available biologics in the market were directed against the T helper-17 (Th-17) axis. First came the IL-12/23 agent ustekinumab,84 followed by the anti-IL-17 agents brodalumab,106 secukinumab,107 and ixekizumab.88 Bimekizumab, which neutralizes IL-17A, IL-17F, and IL-17AF has been approved for psoriasis and more recently for psoriatic arthritis90 (table 3).
Despite it not emerging as a major problem in clinical trials in psoriatic arthritis, concern exists about anti-IL-17 therapy and the exacerbation of inflammatory bowel disease108; in a phase 2 study of brodalumab in inflammatory bowel disease, exacerbations of inflammatory bowel disease were seen more commonly in patients receiving the drug than in those receiving placebo.109 Avoiding these drugs is recommended if Crohn’s disease or ulcerative colitis is suspected. Fungal infections, also infrequently reported in the pivotal trials, are an additional concern, as IL-17 is an important cytokine in defense against fungi.110 Reports on the association between ustekinumab and cardiovascular events are contrasting.111112
The IL-23 p19 subunit specific agents guselkumab and risankizumab have been approved for psoriatic arthritis.9294 Although these agents work well in psoriasis and are superior to the anti-TNFα agents in this domain, they seem to have a similar efficacy for musculoskeletal manifestations, excluding axial disease, for which they failed to show efficacy in axial spondyloarthritis trials.113114 Anti-IL-23 agents have a relatively favorable safety profile (table 3).
Phosphodiesterase-4 antagonists
A new mechanism of action was introduced when the phosphodiesterase-4 antagonist apremilast was approved.100 Unlike the previously described drugs, this is an oral agent given twice daily. Apremilast is generally less effective than both anti-TNFα and anti-IL-17/23 agents when considering the cutaneous and musculoskeletal domains. However, its advantage is that it is given orally, which many patients may prefer. Furthermore, its safety profile is good; it has been mainly associated with diarrhea and headache (table 3).
Janus kinase inhibitors
Inhibition of Janus kinase was subsequently developed, with three drugs available for psoriatic arthritis. These agents, like apremilast, are oral drugs. Tofacitinib inhibits Janus kinase 1 and 2, and upadacitinib preferentially inhibits Janus kinase 1. Major concerns with the Janus kinase inhibitors relate to increases in lipid concentrations, cardiovascular events, cancer, and herpes zoster infections; although these have not been major problems in the pivotal trials (table 3), the results of the ORAL SURVEILLANCE study in rheumatoid arthritis contributed to much of the concern.115 This study compared tofacitinib with anti-TNFα agents in a population enriched for patients at higher risk of cardiovascular disease and found that the risks of major adverse cardiovascular events and cancers were higher with tofacitinib, failing to show non-inferiority of the drug; hazard ratios were 1.33 (95% CI 0.91 to 1.94) for major adverse cardiovascular events and 1.48 (1.04 to 2.09) for cancers. Patients are recommended to receive zoster vaccines before starting a Janus kinase inhibitor.
Head-to-head studies
Several head-to-head studies were carried out in psoriatic arthritis. For instance, in the SPIRIT-H2H trial,116 ixekizumab was superior to adalimumab in achieving simultaneous improvement of joint and skin disease (ACR50 and PASI100) at week 24 (36% v 28%; P=0.04) in 566 patients with psoriatic arthritis and inadequate response to csDMARDs. Looking more closely, the drug was non-inferior for the ACR50 response (ixekizumab 51%; adalimumab 47%; treatment difference 3.9%) and superior for the PASI100 response (ixekizumab 60%; adalimumab 47%; P=0.001). The EXCEED trial,117 on the other hand, evaluated the efficacy and safety of secukinumab versus adalimumab for 52 weeks in 853 patients with active psoriatic arthritis, with an ACR20 response as the outcome. Although secukinumab did not meet statistical significance for superiority versus adalimumab, it was associated with a higher treatment retention rate. The results of these two studies show the superior skin response and comparable joint response with anti-IL-17 agents compared with anti-TNFα biologics; the SPIRIT-H2H trial met its primary outcome and the EXCEED trial did not, which is likely related to the design and outcome selection. In the ECLIPSA trial comparing ustekinumab and anti-TNFα agents, the former achieved significantly superior responses with respect to enthesitis and psoriatic skin disease, but not for arthritis.118 As shown in table 3, tofacitinib and adalimumab achieved comparable results in the OPAL Broaden study in terms of ACR20 and PASI75.119
Briefly, comparative studies showed anti-IL-23, anti-IL-12/23, and anti-IL-17 agents to achieve better skin responses than anti-TNFα biologics.118120121122 As shown in table 3, the anti-IL-23 agents guselkumab and risankizumab achieved excellent PASI scores in clinical trials, better than those of ustekinumab. In comparative trials in moderate-to-severe plaque psoriasis, secukinumab, ixekizumab, and bimekizumab showed greater efficacy than ustekinumab.123124125126127 A few trials compared anti-IL-17 and IL-23 agents in psoriasis, with differences in short term responses (in favor of anti-IL-17) and long term responses (in favor of anti-IL-23) but no significant differences between the two groups.128129130131
Practical algorithm
Clinicians should combine their clinical knowledge, revised guidelines, and available resources to provide the best care possible for the individual patient. This process begins with diagnosing psoriatic arthritis on solid grounds, defining the disease extent, and determining the involved domains and associated extra-articular features and comorbidities. Then the arsenal of therapies should be considered, incorporating local legislations and an interdisciplinary approach that is focused on the management of the patient and not only on treating active disease. Figure 4 provides a practical algorithm that we recommend using when managing a patient with psoriatic arthritis.
Algorithm of practical approach to patients with psoriatic arthritis in clinical practice. CBC=complete blood count; CRP=C reactive protein; ESR=erythrocyte sedimentation rate; HBV=hepatitis B virus; HCV=hepatitis C virus; HLA=human leukocyte antigen; MRI=magnetic resonance imaging; NSAID=non-steroidal anti-inflammatory drug; csDMARD=conventional synthetic disease modifying anti-rheumatic drug; TNFα=tumor necrosis factor; IL=interleukin; JAK=Janus kinase; mAb=monoclonal antibody; PDE4=phosphodiesterase-4
Unmet needs
Despite the advances achieved in the field of psoriatic arthritis, several unmet needs remain. These include reliable markers for diagnosis and prediction of response to therapy. Additionally, well accepted and standardized definitions are lacking for axial disease, a treat-to-target approach, remission state, and difficult-to-treat disease. Evidence is also scarce in several other fields, including drug tapering and withdrawal, safety and efficacy of dual advanced therapy, and the role of biologics in the prevention of progression of psoriasis to psoriatic arthritis.
Emerging treatments
The arsenal of therapies for psoriatic disease is expected to expand further to satisfy the unmet needs and provide better care. In addition, ongoing trials aim to better understand disease subsets and specific aspects of psoriatic arthritis. For instance, the STAR study (ClinicalTrials.gov NCT04929210) examining the efficacy and safety of guselkumab is a phase 4, randomized, double blinded, placebo controlled trial that was carried out to prospectively assess efficacy outcomes in patients with psoriatic arthritis with MRI confirmed axial inflammation132; the results are still pending. The PASTOR trial (NCT04062695) is also ongoing and aims to evaluate the efficacy of tofacitinib in the reduction of inflammation detected on MRI in patients with axial psoriatic arthritis.133 Additionally, the AXIS study (NCT04434885) is a prospective, multicenter, cross sectional study that is recruiting patients in an attempt to evaluate clinical and imaging manifestations suggestive of axial involvement in patients with psoriatic arthritis and develop classification criteria and a unified nomenclature for axial psoriatic arthritis.43 Of note, a study of guselkumab and golimumab combination therapy in patients with active psoriatic arthritis (NCT05071664) is active.
Further phase 3 studies of new drugs for approval in psoriatic arthritis are also still ongoing. These include phase 3 trials of tildrakizumab (NCT04314544 and NCT04314531), a humanized, IgG1 κ antibody, which has been approved for psoriasis, with a positive phase 2b study in psoriatic arthritis.134 Additionally, deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, which has already shown good results in a phase 2 study in psoriatic arthritis,135 is being tested in phase 3 trials in psoriatic arthritis (NCT04908202 and NCT04908189). Moreover, izokibep, a unique anti-IL-17A agent with high potency and small molecular size, and brepocitinib, an oral tyrosine kinase/Janus kinase 1 inhibitor, have already shown efficacy in psoriatic arthritis in phase 2 studies,136137 and are in the pipeline.
Guidelines
We have already discussed the availability of several disease modifying anti-rheumatic drugs (DMARDs) for the treatment of psoriatic arthritis. How should clinicians decide when to use these drugs and which one to start with? Three major treatment recommendations and guidelines have been published and updated in the past few years.76138139 Differences exist among these, particularly when considering csDMARDs. The ACR/National Psoriasis Foundation guidelines advise using an anti-TNFα agent without previous use of csDMARDs138; the GRAPPA recommendations suggest standard “step-up” approaches based on the disease domains, starting with csDMARDs and expedited treatment strategies whereby biologic or targeted synthetic DMARDs can be used as first line therapy when available139; and the EULAR recommendations encourage starting with a csDMARD, preferably methotrexate, before considering advanced DMARDs, which may be selected on the basis of the most active domain, not necessarily starting with anti-TNFα agents.76 Like the EULAR recommendations, and unlike the ACR/National Psoriasis Foundation guidelines, the GRAPPA recommendations do not consider cyclosporine as a csDMARD for treating psoriatic arthritis. Notably, GRAPPA provides a detailed domain centered and extra-articular manifestation centered approach to management, with mention of the recommended treatment options in each clinical scenario. Given that the last ACR/National Psoriasis Foundation guidelines were published in January 2019, before the advent of the most recent biologics in the market, efforts to update them are ongoing.
Despite these differences, the overall concept is very similar in the various guidelines, aiming at the initiation of systemic therapy for the rapid control of disease activity and escalated therapy based on the disease manifestations and involved domains. These recommendations and guidelines should be used by clinicians as an important adjunct when making treatment decisions; however, ultimately, therapy should be selected on the basis of the specific patient’s clinical profile, disease history, and preferences, as well as local legislation, which may not always align with the guidelines.
Conclusion
Psoriatic arthritis is a complex and heterogeneous inflammatory disease, about which our knowledge has expanded significantly over the years, with breakthrough advances in its management over the past two decades. These include both a better understanding of the disease process and associated features and improved availability of advanced therapies. We continue to seek better treatment approaches and meaningful biomarkers, and several unmet needs remain, including better definitions of axial disease, a treat-to-target approach, and difficult-to-treat disease course. Only further research and experience sharing can help us to overcome these challenges. Until then, we should continue to implement our current knowledge in identifying patients at an early phase and providing the best available therapy, with the aim of controlling activity, preventing damage, preserving functionality and quality of life, and reducing mortality.
Glossary of abbreviations
ACR—American College of Rheumatology
BSA—body surface area
CI—confidence interval
CRP—C reactive protein
csDMARD—conventional synthetic disease modifying anti-rheumatic drug
DAPSA—disease activity in psoriatic arthritis
DMARD—disease modifying anti-rheumatic drug
ESR—erythrocyte sedimentation rate
EULAR—European Alliance of Associations for Rheumatology
GRAPPA—Group for Research and Assessment of Psoriasis and Psoriatic Arthritis
HAQ—health assessment questionnaire
HLA—human leukocyte antigen
IL—interleukin 23
MDA—minimal disease activity
MRI—magnetic resonance imaging
NSAID—non-steroidal anti-inflammatory drug
OMERACT—Outcome Measures in Rheumatology
PASI—Psoriasis Area Severity Index
TNF—tumor necrosis factor
VLDA—very low disease activity
Questions for future research
Can we have biologic markers to guide the choice of and response to advanced therapy?
What constitutes treating to target in psoriatic arthritis?
What is the definition and “mechanism” of difficult-to-treat disease?
Can we safely combine advanced therapies in difficult-to-treat cases?
Does biologic use in patients with psoriasis prevent the development of psoriatic arthritis?
How patients were involved in creation of this article
We asked five randomly selected patients attending the clinic about the most important topics to be covered in this review. The answers were focused on clinical presentation, diagnostic evaluation, and advances in therapy. We included all these topics.
Footnotes
Series explanation: State of the Art Reviews are commissioned on the basis of their relevance to academics and specialists in the US and internationally. For this reason they are written predominantly by US authors
Contributors: Both authors contributed to the planning, design, literature review, formatting, and writing of the manuscript, with DDG serving as the supervisor. DDG is the guarantor.
Competing interests: We have read and understood the BMJ policy on declaration of interests and declare the following interests: DDG is a consultant to Abbvie, Amgen, BMS, Eli Lilly, Janssen, Novartis, Pfizer, and UCB and has received grant support from Abbvie, Amgen, Eli Lilly, Novartis, Pfizer, and UCB.
Provenance and peer review: Commissioned; externally peer reviewed.