Psoriatic arthritis

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Treatment of psoriatic arthritis (PsA) aims to control symptoms, improve quality of life, and prevent structural damage and complications. A multidisciplinary approach is often required, including dermatologists and rheumatologists, and shared decision-making with patients is an important principle.[38][50][54]

PsA may become polyarticular over time and develop erosive changes.[55][56] Initial onset as polyarthritis is associated with significant progression and poor outcome, as is the presence of dactylitis.[50][57][58]

A uniform approach to treatment is impractical, due to the variable manifestations of PsA, for example:

peripheral arthritis
dactylitis
enthesitis
axial disease.

Treat-to-target approach

A treat-to-target approach can achieve better control of symptoms and improved patient outcomes.[59] PsA-specific composite measures such as the Disease Activity index for Psoriatic Arthritis (DAPSA), the Psoriatic Arthritis Joint Activity Index (PsAJAI), and the Composite Psoriatic Disease Activity Index (CPDAI) can help to assess disease activity and guide a treat-to-target approach.[38]

Using a standardised strategy of more frequent patient visits and progression of therapies to achieve disease control is recommended.[50][60][61][62]

Treat-to-target guidelines recommend that disease-modifying anti-rheumatic drugs (DMARDs) should show at least 50% improvement in signs and symptoms within 3 months and achieve the target of clinical remission of musculoskeletal and extra-articular manifestations within 6 months of initiating treatment.[60]

Assessment of the specific musculoskeletal manifestations and their severity to assist in the development of individualised treatment plans is recommended.[60][61] Consideration should also be given to non-musculoskeletal manifestations, such as psoriasis, uveitis, and inflammatory bowel disease, as well as comorbidities such as cardiovascular disease, metabolic syndrome, and depression.[60] Special management issues arise in patients with HIV and PsA.[63]

Supportive measures

All patients should receive supportive measures as part of management.

Smoking cessation is strongly recommended for all patients, particularly in view of the increased risk of cardiovascular disease with PsA.[50]

Low-impact exercise is recommended for patients without contraindications, such as existing muscle/tendon injury or multiple inflamed joints with pain that is worse with exercise.[50] High-impact exercise may also be considered according to patient preference.[50]

Physiotherapy reduces pain, improves range of motion, and strengthens muscles of joints with associated periarticular muscle atrophy. Consequently, patients with limited disease may not necessarily require physiotherapy. Other non-pharmacological treatments that may be beneficial include weight loss in patients who are overweight or obese, occupational therapy, and alternative therapies, such as massage therapy and acupuncture.[50]

Peripheral arthritis

Treatment options for patients with peripheral arthritis include conventional synthetic DMARDs, biological agents, or targeted synthetic DMARDs. Initial treatment choice is based on severity of disease and/or the patient's response to treatment. Recommended first-line treatment varies; check local guidelines.

All patients with peripheral arthritis may be treated with adjunct treatments including non-steroidal anti-inflammatory drugs (NSAIDs) and/or corticosteroids.[60][61] NSAIDs and intra-articular corticosteroid injections may improve symptoms in patients with progressive disease (polyarthritis, joint erosions, or oligoarthritis), but treatment with disease-modifying therapies is required to arrest or modify the disease process.

NSAIDs

NSAIDs may be used to relieve musculoskeletal symptoms of PsA, with careful consideration of the risk:benefit ratio, in view of the increased cardiovascular risk in patients with PsA.[60][61]

However, symptom relief, for the most part, is only partial with NSAIDs. US guidelines recommend NSAIDs for patients who do not have severe PsA or severe psoriasis, and for those who are at risk of liver toxicity.[50] NSAID monotherapy should not be used for more than 1 month if symptoms persist.[60]

No studies have demonstrated an advantage of one NSAID over another; choice will depend on patient preference and clinical experience.

Corticosteroids

Intra-articular corticosteroid injections may be offered as adjunctive therapy for patients with peripheral arthritis.[60][61] The benefit of intra-articular corticosteroid injection for PsA has been demonstrated in an observational cohort study.[64] There is a lack of randomised controlled trial (RCT) evidence. Long-acting agents (e.g., triamcinolone hexacetonide) should be avoided in superficial joints, where there is a high risk of subcutaneous atrophy. In this situation, methylprednisolone acetate is preferred.

International guidelines conditionally recommend systemic corticosteroids.[61] However, there is evidence to suggest that systemic corticosteroids should be avoided, as there is a risk of post-exposure psoriasis flare and an increased risk of cardiovascular disease, even at low doses of <5 mg/day prednisolone.[65] In practice, corticosteroids should be avoided; however, in acute polyarticular arthritis, a brief course of a low-dose oral corticosteroid may be considered to reduce pain/suffering of the patients if clinically appropriate, in conjunction with conventional synthetic DMARDs.

DMARDs

International and US guidelines recommend conventional synthetic DMARDs or biological agents as first-line treatment options.[50][61] In contrast, European guidelines recommend a stepwise approach to treatment with DMARDs, beginning with conventional DMARDs, such as methotrexate, sulfasalazine, or leflunomide, and then progressing to biological agents.[60]

Conventional synthetic DMARDs

International guidelines suggest that conventional synthetic DMARDs (methotrexate, sulfasalazine, or leflunomide) may be used as first-line treatment for treatment-naive patients with peripheral arthritis, with regular assessment of clinical response (every 12-24 weeks) and early escalation of therapy (between 12 and 24 weeks) advised as necessary.[61] If the patient has an inadequate response to initial conventional synthetic DMARD treatment, switching to an alternative conventional synthetic DMARD is conditionally recommended.[61]

US guidelines conditionally recommend that a conventional synthetic DMARD should be considered as first-line treatment for patients who are treatment naive without severe PsA or severe psoriasis, based on patient preference, or for patients who have contraindications to tumour necrosis factor (TNF)-alpha inhibitors (e.g., congestive heart failure, previous serious infection, recurrent infection, demyelinating disease).[50]

European guidelines recommend a conventional synthetic DMARD as first-line treatment.[60] Methotrexate is preferred, due to ease of administration (i.e., once-weekly dosing) and relatively rapid onset of action, particularly in patients with psoriasis.[60] Alternatives include leflunomide and sulfasalazine, which are less beneficial in treating skin symptoms.[60] An initial trial of methotrexate should last for 3 months and if the treatment target is not reached within 6 months, a different strategy should be pursued.[60] Methotrexate does not appear to increase the risk of respiratory adverse events in PsA.[66] Folic acid supplementation is required.

Methotrexate is recommended as monotherapy in most cases but may be used in combination with a biological agent if the patient has severe skin manifestations or concomitant uveitis (as uveitis may respond to methotrexate).[50] However, this combination is not supported by other major guidelines.[60][61]

One Cochrane review demonstrated that low-dose oral methotrexate for 6 months may be more effective than placebo for PsA patients, although the evidence quality was considered to be low.[67] An absolute improvement of 16% was seen with methotrexate for disease response (using the psoriatic arthritis response criteria), 10% for function (using the health assessment questionnaire), and 3% for mean disease activity (using the disease activity score 28 ESR) compared with placebo.[67]

An alternative conventional synthetic DMARD is conditionally recommended for patients with diabetes, due to an increased risk of liver toxicity and fatty liver disease with methotrexate.[50]

Ciclosporin may be an option in some locations, but it is not recommended for PsA patients with peripheral arthritis in international or European guidelines.[60][61]

Biological agents

Biological agents include TNF-alpha inhibitors, interleukin (IL) inhibitors, and abatacept (a T-cell co-stimulation inhibitor), and are a suitable first-line option in some patients. Recommended first-line treatment varies; check local guidelines.

International guidelines recommend biological agents as first-line treatment for peripheral arthritis. TNF-alpha inhibitors may be the preferred first-line therapy for treatment-naive patients, as emergent evidence demonstrated their efficacy over conventional synthetic DMARDs, especially for patients with early disease.[61]

For patients with previous experience of biological agents, TNF-alpha inhibitors, IL-17 inhibitors, IL-23 inhibitors, or Janus kinase (JAK) inhibitors are strongly recommended to treat patients with an inadequate response to conventional synthetic DMARDs, and abatacept is recommended for patients who experience treatment failure with other biologicals.[50][60][61][68]

If patients do not respond to initial biological agents or targeted synthetic DMARD treatment, switching to a TNF-alpha inhibitor, IL-17 inhibitor, IL-23 inhibitor, or JAK inhibitor is strongly recommended, while IL-12/23 inhibitors, abatacept, and the targeted synthetic DMARD apremilast are conditionally recommended as alternatives.[61]

TNF-alpha inhibitors

TNF-alpha inhibitors are the most widely used group of biological agents. Etanercept, adalimumab, infliximab, golimumab, and certolizumab have been shown to improve joints, skin, daily function, and rate of progression of radiographic erosions in placebo-controlled RCTs.[69][70] There is some evidence of better adherence to golimumab compared with other TNF-alpha inhibitors in patients with inflammatory arthritis, although guidelines do not recommend one TNF-alpha inhibitor over another.[50][60][71] In patients who have concomitant inflammatory bowel disease or inflammatory eye disease (uveitis), it is strongly recommended that monoclonal antibody TNF-alpha inhibitors are chosen over etanercept.[50]

Contraindications to TNF-alpha inhibitors include congestive heart failure, previous serious or recurrent infections, and demyelinating disease.[50][72] TNF-alpha inhibitors carry a warning against their use in patients with frequent serious infections.[50] Number needed to harm has been calculated as 59 for serious infection (within a treatment period of 3-12 months), and 154 for cancer (within a treatment period of 6-12 months) for patients treated with TNF-alpha inhibitors.[72] Prior to initiation of TNF-alpha inhibitor therapy, a baseline chest x-ray should be obtained, along with an assessment of tuberculin and hepatitis B infection status.

For patients who have active disease despite using a TNF-alpha inhibitor, US guidelines conditionally recommend switching to an alternative TNF-alpha inhibitor before moving on to other biological agents.[50]

IL inhibitors

There are several IL inhibitors approved to treat PsA: the IL-17 inhibitors secukinumab and ixekizumab; the IL-12/23 inhibitor ustekinumab; and the IL-23 inhibitors guselkumab and risankizumab.

International guidelines suggest that IL inhibitors may be considered for use after TNF-alpha inhibitors, based on one small trial that demonstrated a lack of superiority of IL inhibition compared with TNF inhibition in peripheral joint domains.[61]

US guidelines conditionally recommend secukinumab and ixekizumab (IL-17 inhibitors) for use after TNF-alpha inhibitors, but note that they may be used earlier if there are contraindications to TNF-alpha inhibitors or in patients with severe psoriasis.[50][68] They are not recommended in patients who have concomitant inflammatory bowel disease due to a lack of evidence for their effectiveness.[50] European guidelines recommend that IL-17 and IL-12/23 inhibitors may be preferred over other biological agents when a patient has relevant skin involvement.[60]

A 52-week RCT comparing secukinumab and adalimumab found similar ACR20 response rates between groups.[73] An open-label trial comparing ixekizumab with adalimumab found similar ACR50 response rates at 24 weeks.[74]

Ustekinumab is conditionally recommended for use after secukinumab and ixekizumab; however, it may show benefit if used earlier in patients with concomitant inflammatory bowel disease or those who prefer less frequent dosing.[50]

Guselkumab and risankizumab have demonstrated efficacy and safety versus placebo in phase 3 studies, with sustained improvements reported at 1 and 2 years in both treatments.[75][76][77][78][79][80][81] IL-23 inhibitors provide a further treatment option in patients with an inadequate response or intolerance to at least one conventional synthetic DMARD, although they are not yet included in many treatment guidelines. The National Institute for Health and Care Excellence (NICE) in the UK recommends guselkumab or risankizumab alone or with methotrexate as an option for adults with active PsA (with ≥3 tender and ≥3 swollen joints and psoriasis that is moderate to severe [body surface area ≥3% and Psoriasis Area and Severity Index {PASI} >10]), who have experienced treatment failure or are intolerant to two conventional synthetic DMARDs and at least one biological agent.[82][83] If guselkumab is being considered, a biological agent need not be trialled if TNF-alpha inhibitors are contraindicated.[83]

Although the efficacy of IL inhibitors in rheumatological conditions is established, they are associated with an increased risk of serious infections, opportunistic infections, and cancer.[84][85] Number needed to harm has been calculated as 67 for serious infection (within a treatment period of 3-12 months), and 250 for cancer (within a treatment period of 6-12 months) for patients treated with IL inhibitors.[84] However, the US Food and Drug Administration (FDA) considers IL inhibitors to carry less risk of infection than TNF-alpha inhibitors.

Abatacept

Abatacept is conditionally recommended for patients who experience treatment failure with other biological agents.[60][61]

In the US, abatacept can be considered for patients with active disease despite treatment with TNF-alpha inhibitors, instead of switching to a different TNF-alpha inhibitor, or for patients with recurrent or severe infection who do not have severe psoriasis.[50][68] Evidence from RCTs suggests that abatacept significantly improved ACR20 response at 24 weeks versus placebo.[86][87]

Targeted synthetic DMARDs

Targeted synthetic DMARDs include tofacitinib (a Janus kinase [JAK] inhibitor) and apremilast (a phosphodiesterase-4 inhibitor).

JAK inhibitors

In patients with peripheral arthritis who have an inadequate response to at least one conventional synthetic DMARD and at least one biological agent, or when a biological agent is not appropriate, a JAK inhibitor (e.g., tofacitinib, upadacitinib) may be considered.[60][61] There are also concerns of intolerance and adverse effects with the existing conventional synthetic DMARDS and biological agents. In that respect JAK inhibitors offer new options for many patients with PsA.

Results from a large randomised safety clinical trial comparing tofacitinib with TNF-alpha inhibitors in patients with rheumatoid arthritis who were 50 years of age or older and had at least one other cardiovascular risk factor found an increased risk of death, blood clots, myocardial infarction, and cancer with the lower dose of tofacitinib (5 mg twice daily); this serious event had previously been reported only with the higher dose (10 mg twice daily) in the preliminary analysis.[88]

Subsequently, the FDA, the European Medicines Agency (EMA), and the UK's Medicines and Healthcare products Regulatory Agency (MHRA) have issued warnings about the increased risk of serious cardiovascular events, malignancy, thrombosis, and death with JAK inhibitors compared with TNF-alpha inhibitors.[89][90][91]

The FDA advises clinicians to:[89]

Reserve JAK inhibitors for patients who have had an inadequate response or are intolerant to one or more TNF-alpha inhibitors
Consider the patient's individual benefit-risk profile when deciding to prescribe or continue treatment with these medications, particularly in patients who are current or past smokers, patients with other cardiovascular risk factors, those who develop a malignancy, and those with a known malignancy (other than a successfully treated non-melanoma skin cancer).

Apremilast

Apremilast is recommended as either first-line therapy for treatment-naive patients, or as treatment for patients who experience an inadequate response to at least one conventional synthetic DMARD.[50][60][61]

Axial disease

Axial disease is treated with NSAIDs first line. Biological agents or JAK inhibitors are second-line options. Intra-articular corticosteroid injections may be offered as adjunctive therapy.

NSAIDs

NSAIDs are effective for symptoms of pain and stiffness and should be used first line (continuously rather than on-demand), taking into consideration the patient's symptom severity, preferences, and comorbidities (particularly gastrointestinal, renal, and cardiovascular).[61]

US guidelines state that NSAIDs are considered to have failed if two or more different NSAIDs have been trialled at maximum dose over 1 month or there has been an incomplete response to two or more different NSAIDs over 2 months.[50] European guidelines recommend that NSAIDs can be tried for up to 12 weeks, as long as there has been some symptomatic relief by 4 weeks.[60]

Biological agents

Biological agents (TNF-alpha inhibitors, IL-17 inhibitors) are recommended for patients with axial symptoms who have not responded to treatment with NSAIDs and supportive measures.[50][60][61] NSAIDs may need to be continued as an adjunct treatment in some patients.

No TNF-alpha inhibitor is recommended over any other for the typical patient.[50] However, infliximab is not recommended for patients with an increased risk of tuberculosis exposure or a history of recurrent infections. In patients with recurrent uveitis or inflammatory bowel disease, monoclonal antibody TNF-alpha inhibitors are recommended over etanercept.[50][60] Patients who relapse after initially responding to one TNF-alpha inhibitor should be switched to a second TNF-alpha inhibitor.[50][60]

The IL-17 inhibitors secukinumab and ixekizumab are recommended for patients with severe psoriasis or contraindications to TNF-alpha inhibitors, or for those who are primary non-responders to TNF-alpha inhibitors.[50][60] Secukinumab has been specifically evaluated for efficacy in axial manifestations of PsA and demonstrated significant improvements compared with placebo for both signs and symptoms of axial disease and objective measures of axial inflammation.[92] Both ixekizumab and secukinumab are indicated for the treatment of axial spondyloarthritis.

IL-12/23 and IL-23 inhibitors are not recommended for axial disease as they have not shown efficacy in clinical trials.[50][60]

JAK inhibitors

JAK inhibitors are also recommended as an option for patients with axial symptoms who have not responded to treatment with NSAIDs and supportive measures.[50][60][61] NSAIDs may need to be continued as an adjunct treatment in some patients.

Both tofacitinib and upadacitinib are indicated for ankylosing spondylitis for patients who have had an inadequate response or are intolerant to one or more TNF-alpha inhibitors.[61]

Tofacitinib showed a significant benefit in axial symptoms in one phase 3 study and is an option in patients with co-existing ulcerative colitis if TNF-alpha inhibitors are not an option.[93][94] However, the safety concerns discussed above should be considered.

Enthesitis

NSAIDs, local corticosteroid injections, and physiotherapy are commonly used as first-line therapies for enthesitis, despite a lack of high-quality trials of their efficacy for patients with PsA, especially for localised enthesitis.[61]

TNF-alpha inhibitors, IL-17 inhibitors, IL-12/23 inhibitors, IL-23 inhibitors, JAK inhibitors, and apremilast are recommended as options to treat patients who have an inadequate response to NSAIDs.[61] Abatacept is conditionally recommended as an alternative option.[61]

Conventional synthetic DMARDs are conditionally recommended for the treatment of active enthesitis in some countries, but in others (including the US) they are not recommended for patients with predominant enthesitis.[50][61] Methotrexate is the preferred conventional synthetic DMARD, due to ease of administration (i.e., once-weekly dosing) and relatively rapid onset of action, particularly in patients with psoriasis.[60] A trial of methotrexate should last for 3 months and if the treatment target is not reached within 6 months, a different strategy should be pursued.[60] Methotrexate does not appear to increase the risk of respiratory adverse events in PsA.[66] Daily folic acid supplements are required.

In patients who have predominant enthesitis, US guidelines conditionally recommend that NSAIDs, TNF-alpha inhibitors, and tofacitinib are used as initial treatment.[50] Apremilast is recommended as an alternative for patients who have contraindications to these medications, or as an alternative to NSAIDs in patients with severe psoriasis. Patients who have an inadequate response or contraindications to TNF-alpha inhibitors or who have severe psoriasis may benefit from IL-17 inhibitors, or from IL-12/23 inhibitors if they have inflammatory bowel disease or prefer less frequent drug administration.[50]

Dactylitis

Dactylitis (inflammation of the whole digit) in PsA is associated with disease severity and an increased risk of radiographic progression, particularly in men.[60][95]

Physiotherapy improves overall physical function and provides relief of pain and stiffness in patients with dactylitis. It is strongly recommended by guidelines, with conditional recommendations for active physiotherapy over passive, and land-based physiotherapy over water-based.[50]

TNF-alpha inhibitors, IL-17 inhibitors, IL-12/23 inhibitors, IL-23 inhibitors, JAK inhibitors, and apremilast are recommended as treatment options for dactylitis in PsA, with abatacept conditionally recommended as an alternative option.[61]

Evidence from meta-analyses demonstrates that both TNF-alpha inhibitors and IL inhibitors are effective in resolving dactylitis compared with placebo, and that both treatments are associated with higher dactylitis resolution rates.[95][96] Analysis of dactylitis outcomes in patients with PsA in subsequent trials report significantly more resolution for guselkumab and ixekizumab compared with placebo, and golimumab with methotrexate compared with methotrexate monotherapy.[97][98]

Although there is a lack of clinical trials to specifically evaluate therapeutic interventions for dactylitis, methotrexate has shown some efficacy, and is conditionally recommended to treat dactylitis.[60][61] However, US guidelines suggest that a conventional synthetic DMARD should be considered, with progression to biological agents in patients with an inadequate response at 3-6 months.[50][60]

Methotrexate is the preferred conventional synthetic DMARD, due to ease of administration (i.e., once-weekly dosing) and relatively rapid onset of action, particularly in patients with psoriasis.[60] A trial of methotrexate should last for 3 months and if the treatment target is not reached within 6 months, a different strategy should be pursued.[60] Methotrexate does not appear to increase the risk of respiratory adverse events in PsA.[66] Daily folic acid supplements are required.

NSAIDs and localised corticosteroid injections are recommended as an adjunct treatment for dactylitis.[61]

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