INTRODUCTION — The treatment of psoriatic arthritis (PsA) involves the use of a variety of interventions, including many of the agents used for the treatment of patients with other forms of inflammatory arthritis, particularly spondyloarthritis and rheumatoid arthritis (RA), and others employed for the management of the cutaneous manifestations of psoriasis.
Although a number of medications are effective in the treatment of both RA and PsA, trials involving some classes of biologic agents indicate that patients with RA and PsA can also experience markedly different responses to some drug classes. Treatment of the different elements of PsA includes coordinated intervention to address the major domains of the disease, including peripheral and axial arthritis, enthesitis, dactylitis, and skin and nail involvement. (See "Clinical manifestations and diagnosis of psoriatic arthritis".)
The treatment of PsA, including peripheral and axial arthritis, enthesitis, and dactylitis, is discussed in this topic review. The treatment of psoriatic skin and nail involvement, the clinical manifestations and diagnosis of PsA, and the pathogenesis of PsA are presented separately. (See "Treatment of psoriasis in adults" and "Nail psoriasis" and "Clinical manifestations and diagnosis of psoriatic arthritis" and "Pathogenesis of psoriatic arthritis".)
MANAGEMENT PRINCIPLES AND PRETREATMENT INTERVENTIONS — The approach to treatment includes therapy for both musculoskeletal disease, including peripheral and axial arthritis, enthesitis, and dactylitis, and disease of the skin and nails, and is aimed at controlling inflammation and preventing discomfort, joint damage, and disability [1,2]. More than one type of musculoskeletal involvement, and frequently cutaneous involvement, often occur in individual patients. General principles of treatment for psoriatic arthritis (PsA) include:
●Patients benefit from evaluation and treatment early in the disease by clinicians with expertise in the care of patients with rheumatologic conditions [3,4] (see 'Prognosis' below), and treatment should be coordinated between the rheumatologist, primary care clinician, and other specialists (eg, the dermatologist). Differences in response to individual therapies between the skin and joints, and between different musculoskeletal manifestations, are commonly observed.
●Treatment is guided initially by an assessment of disease severity, including the degree of disease activity, damage, and impact on the patient for each clinical domain, followed by initial attention to the most severely involved region such as axial or peripheral arthritis. Due to the common involvement of multiple domains (peripheral arthritis, axial inflammation, dactylitis, enthesitis, skin, and nails) in a single patient, additional considerations regarding optimal therapy may be required. Initiation of a biologic agent for the management of one clinical manifestation (eg, axial arthritis or moderate to severe skin disease) may eliminate the need for additional therapies in the treatment of another manifestation (eg, trial[s] of a conventional disease-modifying antirheumatic drug [DMARD] for peripheral arthritis before use of a biologic agent).
●A treat-to-target approach should be employed for peripheral and axial arthritis, with a target of remission/inactive disease or, alternatively, low/minimal disease activity [5-7]. The choice of the target should be made together with the patient; a target of low/minimal disease activity may be more appropriate in some patients with longstanding disease or multiple comorbidities, in whom remission/inactive disease may be particularly difficult to achieve. Evidence suggests that this type of approach can result in improved patient outcomes and reduced disease progression, as progression of damage is predicted by persistent joint inflammation [8-11]. Application of a treat-to-target strategy to the management of PsA is consistent with (and a principal recommendation of) an international task force that has supported this strategy for patients with PsA, as well as nonpsoriatic axial and peripheral spondyloarthritis [6,7].
●Comorbidities (eg, diabetes, metabolic syndrome, fatty liver, coronary artery disease, depression, hyperuricemia) are prevalent in PsA and should be identified because they can affect overall health and treatment selection. Patients should be referred as needed for prevention and medical management of these comorbidities. This last point is particularly important because many patients may be receiving care from a rheumatologist and dermatologist but not a primary care clinician.
●Pretreatment screening for comorbidities and baseline testing before drug administration in all patients should include screening for cardiovascular risk factors (lipids, blood pressure, and smoking), weight loss counseling for patients with elevated body mass index (BMI), and evaluation (eg, ultrasound) of the liver for patients with elevated liver function tests (LFTs); eg, greater than three times the upper limit of normal [12]. Additional testing should include screening for hepatitis in patients initiating methotrexate (MTX) therapy and screening for latent tuberculosis (TB) in patients who may receive biologic agents.
●Patients should undergo vaccinations relevant to treatments that may be planned. (See "Immunizations in autoimmune inflammatory rheumatic disease in adults".)
NONPHARMACOLOGIC TREATMENT — The following nonpharmacologic management strategies are important in the treatment of psoriatic arthritis (PsA) in addition to drug therapy:
●Exercise, physical therapy, and occupational therapy – Patients should be referred for physical therapy (PT) and occupational therapy (OT), encouraged to exercise, referred as needed for orthotics, and educated about joint protection.
●Weight reduction – Obesity and metabolic syndrome are common comorbidities in PsA and may lessen treatment response to disease-modifying antirheumatic drugs (DMARDs) and/or biologic agents [13]. Patients should be counseled about proper eating habits and referred to nutritionists for further counseling if appropriate.
●Patient education
•Patients should be educated as to the nature of their condition and to the effect of stress on their disease, as well as the importance of following up for appropriate management of increased cardiovascular risk associated with the disease and other comorbidities. (See "Clinical manifestations and diagnosis of psoriatic arthritis", section on 'Comorbidities' and "Comorbid disease in psoriasis".)
•Patients should also be instructed about their medications and the proper use of topical and oral medications, as well as the need for regular drug administration and monitoring of disease activity and for side effects of therapies.
PERIPHERAL ARTHRITIS
Overview of approach — The choice of therapy for peripheral arthritis is based upon the severity of disease and the patient's response to treatment. It may also be influenced by comorbidities, patient goals and preferences regarding routes of drug administration and cost of treatment to the patient, and regulatory and insurance requirements. (See 'Management principles and pretreatment interventions' above.)
●Mild arthritis – Patients with mild peripheral arthritis may be effectively treated by use of a nonsteroidal antiinflammatory drug (NSAID). (See 'Mild arthritis/NSAIDs' below.)
●Moderate to severe arthritis or resistant to NSAIDs – Patients with moderate to severe arthritis or who are resistant to initial NSAID therapy alone are usually treated with a conventional disease-modifying antirheumatic drug (DMARD), such as methotrexate (MTX) or leflunomide (LEF), unless a biologic DMARD is required for the treatment of other disease manifestations (see 'Moderate to severe arthritis or resistant to NSAID' below). Some patients with mild to moderate arthritis benefit from apremilast, which can be used instead of a nonbiologic or biologic DMARD. In particular, it can be useful for patients who wish to avoid DMARD therapy, infusions, or injections, although only a portion of patients respond. (See 'Apremilast' below.)
●Severe disease at presentation – In patients presenting with severe disease, such as those with many involved joints, erosive disease at presentation, and functional limitation, we suggest a biologic DMARD (eg, a tumor necrosis factor [TNF] inhibitor) as first line therapy, rather than a conventional nonbiologic DMARD. We prefer this approach because of its capacity to limit joint damage and more rapidly restore function. (See 'Severe peripheral arthritis/adverse prognosis' below.)
●Resistant to nonbiologic DMARD – In patients with peripheral arthritis but an inadequate response to a conventional DMARD, treatment with a biologic DMARD, such as a TNF inhibitor, is usually indicated. An alternative biologic, with a different target, may be required in patients with an inadequate response to TNF inhibitors. Such biologic agents can differ from each other and TNF inhibitors in their efficacy for different disease manifestations. (See 'Resistant to nonbiologic DMARDs' below.)
Since progressive joint damage is more likely in patients with a larger number of inflamed joints at the outset, patients with polyarticular involvement may benefit from early introduction of DMARDs. Notably, however, no conventional synthetic DMARDs have been proven to slow or prevent radiographic damage. Thus, the role of these agents for patients with baseline damage is of uncertain value but is often required when access to TNF inhibitors is limited.
The choice of the DMARD depends, in part, upon whether the patient has active or severe psoriasis as well as arthritis. Medications used for control of psoriasis should be considered in individuals in whom the psoriasis and arthritis are of roughly equal severity. Drugs such as MTX, photochemotherapy with psoralen plus ultraviolet A (PUVA), use of retinoic acid derivatives, and cyclosporine A have been shown to improve both the joint and skin manifestations of psoriasis [1,2,14-16]. However, none of these medications has actually been shown to prevent or retard progression of joint damage. Inhibitors of TNF-alpha may also be effective for both skin and joint disease.
Mild arthritis/NSAIDs — In patients with mild arthritis, defined as disease involving less than four joints, no radiological evidence of damage, and minimal discomfort or functional impairment, we suggest initiating treatment with an NSAID (eg, naproxen 375 to 500 mg twice daily, or celecoxib 200 mg twice daily) rather than starting a DMARD [1,2].
Other NSAIDs that we use in patients with peripheral arthritis include ibuprofen (up to 2400 mg/day), diclofenac (up to 150 mg/day), or ketoprofen (up to 200 mg/day). There is general consensus by experts that NSAIDs, including both nonselective NSAIDs, such as naproxen, and cyclooxygenase (COX)-2 selective NSAIDs, such as celecoxib, can help control the mild inflammatory symptoms of PsA and may also lessen pain and stiffness in spondylitis, although there is very limited evidence from randomized trials in patients with PsA [1,2,17-19]. While there has been some concern that NSAIDs may aggravate the skin psoriasis [14,20], in one randomized trial of a COX-2 selective inhibitor (which was not approved for commercial use) there was no significant difference in an index of skin involvement between the two groups [17].
Comparative studies have not found any difference in efficacy between different NSAIDs. As a result, the choice of an NSAID depends upon the individual clinician's familiarity with a particular drug, patient preference regarding frequency of administration, and individual patient tolerance. The COX-2 selective inhibitor etoricoxib can also be given in a once-daily dose of 60 or 90 mg, but this drug is not available in the United States or Canada.
One difficulty with NSAIDs, particularly in PsA where many patients may already have increased cardiovascular risk, is the additional cardiovascular risk typically associated with the use of these agents. (See "NSAIDs: Adverse cardiovascular effects".)
An alternative agent for use in patients with mild PsA and multiple comorbidities is apremilast, particularly in patients who wish to avoid DMARD therapy, infusions, or injections, although only a portion of patients respond. (See 'Apremilast' below.)
In patients with only one or two swollen joints (mono- or oligoarthritis), we generally perform a joint aspiration and intraarticular glucocorticoid injection. Although there are no randomized trials demonstrating efficacy of intraarticular injections, an observational cohort study revealed effectiveness of intraarticular injections in PsA [21]. Care should be taken in patients who require intraarticular glucocorticoid injections to avoid injection through psoriatic plaques. We generally avoid the use of oral glucocorticoids. (See 'Role of glucocorticoids' below.)
Moderate to severe arthritis or resistant to NSAID
Choice of nonbiologic DMARD and other agents — We take the following approach:
●In patients whose peripheral arthritis remains active (ie, persistent joint inflammation) despite the use of NSAIDs, we suggest starting with a conventional (small molecule) DMARD rather than a biologic agent. We prefer MTX (15 to 25 mg once weekly) in patients with peripheral arthritis who lack axial symptoms or in whom axial symptoms that may be present, such as back pain, are well-controlled with NSAIDs (see 'Methotrexate' below). We also use this approach for initial therapy in patients with more than mild disease who lack erosive joint changes or substantial functional limitations. (See 'Severe peripheral arthritis/adverse prognosis' below.)
●We initiate or continue NSAIDs as bridging or adjunctive therapy as needed in patients begun on DMARDs. (See 'Mild arthritis/NSAIDs' above.)
●In patients who are intolerant of MTX, unwilling to use this agent (eg, because they perceive it as "chemotherapy"), or unresponsive to MTX, we use LEF (20 mg daily) (see 'Leflunomide' below). However, unlike MTX, which is also effective for psoriasis in some patients, LEF is generally not beneficial for the skin disease.
●Other medications may be used occasionally in individuals with PsA unable to use MTX or LEF and in whom the psoriasis does not pose a particular problem. Included in this group are sulfasalazine (SSZ), antimalarials, and azathioprine. We usually use SSZ as an alternative to MTX in patients with a contraindication to MTX or LEF (eg, refusal or inability to give up alcohol intake), but the likely degree of benefit is low. (See 'Sulfasalazine' below.)
●Some patients with arthritis benefit from apremilast, which can be used instead of a nonbiologic or biologic DMARD. It may be useful for patients who wish to avoid DMARD therapy, infusions, or injections, although only a portion of patients respond. It should not be used in patients with erosive disease, as the capacity of apremilast to prevent joint injury has not been established. (See 'Apremilast' below.)
Methotrexate
MTX use and efficacy — MTX should be increased rapidly as tolerated to 15 mg orally once weekly then as required up to the 25 mg once weekly. Patients receiving MTX should also be treated with folic acid (1 mg daily) to reduce the risk of adverse effects. (See "Use of methotrexate in the treatment of rheumatoid arthritis".)
Prior to initiating MTX therapy, patients should undergo routine laboratory testing, including hematology and biochemistry to confirm normal liver function. They should also have their hepatitis status tested, as well as a chest radiograph. Any required vaccinations should be administered before initiating DMARD therapy. The use of MTX in patients with obesity and/or type II diabetes mellitus should be avoided, if possible, given the increased risk of hepatic fibrosis in patients with these comorbidities [22]. (See 'MTX safety and monitoring' below.)
In patients with an inadequate response to doses of MTX greater than 17.5 mg weekly given orally, we switch to the subcutaneous route, which improves absorption of the medication, as shown in rheumatoid arthritis (RA), and which patients may self-administer. Alternatively, splitting the oral dose over a 24-hour period (morning, evening, and next morning) may improve pharmacokinetics and pharmacodynamics (see "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Dosing and administration'). With the correct dose, a response should occur within eight weeks of initiating therapy.
In patients using parenteral rather than oral MTX, the subcutaneous route may be more beneficial than the intramuscular route and is more convenient for patients who can self-administer the medication. Parenteral MTX can be increased up to 25 or, rarely, 30 mg/week.
Folic acid supplementation should be provided to all patients taking MTX. Patients who do not have a satisfactory response to folic acid or who poorly tolerate it may instead be prescribed leucovorin (folinic acid), usually the day after MTX. (See "Major side effects of low-dose methotrexate", section on 'Prevention of side effects with folate' and "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Folic acid supplementation'.)
MTX is the most commonly used first-line DMARD in PsA, although only limited data are available supporting its efficacy in PsA. Despite the lack of randomized trial evidence of efficacy, observational studies and our clinical experience indicate that MTX may be effective for some patients in clinical practice [23-25]. Expert opinion also supports use of MTX as a first-line DMARD, including treatment guidelines of the European Alliance of Associations for Rheumatology (EULAR; formerly European League Against Rheumatism) [18,26] and the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) [27]; we prefer it as well based upon ease of use, tolerability, and proven efficacy in psoriasis. (See "Treatment of psoriasis in adults", section on 'Methotrexate'.)
While most randomized trials and other studies using MTX have not shown significant benefit, they have all had significant limitations, including the use of lower (sometimes much lower) doses of MTX than are routinely used in practice; patient populations with very longstanding disease, often more than 10 years' duration; small numbers of subjects; trials of short duration; and other elements of poor study design. For example, the largest randomized controlled trial with MTX was the Methotrexate in Psoriatic Arthritis (MIPA) trial, which failed to show that MTX was superior to placebo [24]. Although this trial did not show efficacy of MTX over placebo, the maximum dose was only 15 mg weekly given orally, the burden of joint involvement was low, and the high dropout rate may have reduced the strength of the trial. The Etanercept and Methotrexate in Combination or as Monotherapy in Psoriatic Arthritis trial (also termed the SEAM trial; ClinicalTrials.gov identifier: NCT02376790) is a randomized trial that is ongoing and will provide additional evidence to inform treatment choices. Prevention of radiologic joint injury has not been demonstrated.
The maximal response to MTX is usually achieved within three months of treatment with the drug. Patients who do not respond to MTX 25 mg/week for six to eight weeks are unlikely to respond to more prolonged therapy. On the other hand, discontinuation of MTX in responders is often associated with severe flares of both skin and joint disease. We thus suggest that patients who wish to discontinue MTX do so using a slow taper. (See "Use of methotrexate in the treatment of rheumatoid arthritis".)
MTX safety and monitoring — The most serious potential side effects of MTX include liver toxicity, interstitial lung disease, and bone marrow suppression. Data are not available for prevalence of liver toxicity in PsA. However, in a study of 71 psoriasis patients on MTX, 169 serial biopsies were analyzed, and type 2 diabetes and obesity were major risk factors for progressive fibrosis even at lower doses of MTX [22]. The role of liver biopsy in monitoring hepatotoxicity in patients treated with MTX has been controversial. One study of 54 patients with psoriasis or PsA treated with MTX for a mean of 6.9 years found that the use of laboratory tests alone could adequately identify liver toxicity [28].
National organizations have published different recommendations concerning the role of liver biopsies:
●The American Academy of Dermatology (AAD) and the National Psoriasis Foundation do NOT require liver biopsies in all patients administered MTX [29,30]. There are no specific guidelines for patients with PsA [31,32]. (See "Treatment of psoriasis in adults", section on 'Hepatotoxicity'.)
●The American College of Rheumatology (ACR) has recommended pretreatment liver biopsies only for patients with a significant history of alcohol consumption, with persistently elevated liver enzymes, or with a history of chronic hepatitis B or C infection; and repeat biopsies as indicated by liver test abnormalities [33]. The latter guidelines were originally developed specifically for patients with RA, who may have different liver sensitivity to MTX than patients with PsA.
We generally follow the guidelines of the ACR with regard to pretreatment biopsies, but we tend to perform repeat biopsies more commonly in patients with PsA than in those with RA. (See "Hepatotoxicity associated with chronic low-dose methotrexate for nonmalignant disease".)
Caution is necessary in patients with impaired renal function. Patients with severely reduced glomerular filtration rates (GFR; eg, GFR <20 mL/min, serum creatinine >3.4 mg/dL [300 micromol/L]) should not receive MTX; those with less marked impairment may cautiously take the drug at a reduced dose with close monitoring. (See "Chemotherapy nephrotoxicity and dose modification in patients with kidney impairment: Conventional cytotoxic agents", section on 'Methotrexate'.)
Leflunomide — We use LEF (20 mg daily, taken orally) in patients who have persistent joint inflammation despite three months of treatment with MTX (in maximal doses up to 25 mg weekly subcutaneously) and in patients who are unable to tolerate MTX due to adverse effects, such as liver toxicity. LEF can also be prescribed as a first-line DMARD for patients with a low skin burden of psoriasis. In addition, the use of LEF following an inadequate response to MTX may be required by some insurers or regulatory agencies prior to the approval of a biologic DMARD. The dosing, adverse effects, and monitoring of LEF are the same as in patients with RA and are discussed in detail separately. We do not use a loading dose, as reported in some studies [34], because of the higher rate of gastrointestinal side effects with this approach. (See "Pharmacology, dosing, and adverse effects of leflunomide in the treatment of rheumatoid arthritis" and 'Monitoring' below.)
The benefits of LEF in patients with PsA have been shown in a small number of randomized trials and observational studies [34-38]. In our experience, LEF is effective in about 40 percent of patients. It also improves skin disease, but may be less effective for the skin changes than MTX [38]. Treatment for a total of three months is usually adequate to determine the maximal degree of benefit. Effects on progression of radiologic joint damage have not been demonstrated.
In one representative randomized trial involving 190 patients with PsA, in which the efficacy of LEF was compared with placebo, a significantly higher proportion of LEF-treated (100 mg/day loading dose for three days followed by 20 mg daily), patients were classified as responders at 24 weeks, based upon scores on the PsA Response Criteria (PsARC), an index of PsA activity (59 versus 30 percent) [34]. LEF was also effective in controlling skin disease, as measured by greater improvement in Psoriasis Area and Severity Index (PASI) scores (22 versus 2 percent). Diarrhea and increased serum aminotransferase levels were more frequent in the group receiving LEF, as has been observed in RA (see "Pharmacology, dosing, and adverse effects of leflunomide in the treatment of rheumatoid arthritis"). Effects on progression of joint damage were not assessed in this trial.
Apremilast — In patients with PsA and nonerosive inflammatory arthritis, particularly those with multiple comorbidities, we suggest apremilast (30 mg twice daily following an up-titration at a rate of 10 mg daily over six days), a novel, orally administered phosphodiesterase-4 inhibitor. Apremilast may also be of benefit in patients with enthesitis and dactylitis early in disease course (see 'Enthesitis and dactylitis' below). It may be particularly appropriate for PsA patients with multiple comorbidities, given the excellent safety profile and documented efficacy in randomized trials for both psoriasis and PsA. It is also useful for patients who wish to avoid DMARD therapy, infusions, or injections, although only a portion of patients respond. Some patients require up to four months of treatment to achieve a maximal response to the drug.
Apremilast should not be used in patients with erosive disease, as the capacity of apremilast to prevent joint injury has not been established or adequately examined in PsA or in other forms of inflammatory arthritis. Routine laboratory monitoring is not required, but baseline serum creatinine is important because the dose should be reduced to 30 mg once daily in patients with creatinine clearance estimated at less than 30 mL/min. The role of apremilast in PsA remains to be determined as greater experience is gained with this agent. We generally do not combine it with biologic agents because of the lack of information on benefit and risk with these combinations as well as the substantial costs.
Apremilast is available for the treatment of PsA in the United States, Canada, and Europe [39]; it is under review in other regions as well. The drug modifies multiple proinflammatory mediators and cytokines involved in the innate and adaptive immunity [40-42]. It is not known whether it has disease-modifying properties, such as the ability to prevent or reduce joint damage. Apremilast is also available for the treatment of psoriasis and the beneficial impact on skin disease is similar to MTX, but the drugs have not been directly compared. It has gained favor with dermatologists based upon the low toxicity profile. (See "Treatment of psoriasis in adults", section on 'Apremilast'.)
The efficacy and safety of apremilast for the treatment of PsA has been shown in several randomized trials in which ACR composite criteria for at least 20 percent improvement, termed an ACR20 response, was achieved in patients receiving 30 mg twice daily after 16 weeks in about 40 percent of patients [42-44]. As examples:
●In a phase 3 randomized trial involving 504 patients with active PsA, the Psoriatic Arthritis Long-term Assessment of Clinical Efficacy (PALACE-1) trial, apremilast (20 or 30 mg twice daily) was significantly more likely than placebo to result in an ACR20 (31 and 40 versus 19 percent) at week 16 [42]. Benefit was observed in patients on both background traditional DMARDs (eg, MTX, LEF, and/or SSZ) and in patients not on DMARDs. A minority of the patients had previously received a biologic DMARD; some of these patients showed benefit, although less than the biologic-naïve patients. Statistically significant functional improvement with apremilast, compared with placebo, was also observed (Health Assessment Questionnaire (HAQ) disability index [HAQ-DI] changes of -0.20 and -0.25 versus -0.09). Benefit was sustained in patients continuing apremilast for 52 weeks (ACR20 on the lower and higher apremilast doses in 55 and 63 percent, respectively), and responses were also maintained for secondary outcomes including skin psoriasis severity and physical function [45].
The most common adverse effects in the PALACE-1 trial were mild gastrointestinal symptoms, including diarrhea and nausea. Headache also occurred. Side effects usually occurred early and were self-limited. Less than 2 percent of patients receiving apremilast had weight loss that was thought to be drug-related. No significant laboratory changes were observed. Adverse events were similar over 52 weeks to those seen at 24 weeks, although diarrhea and nausea typically occurred early in therapy and were self-limited.
●Additional information demonstrating the relatively rapid onset of the clinical response to apremilast monotherapy and efficacy for enthesitis was reported in a randomized trial involving 219 biologic-naïve patients with active PsA who received either apremilast (30 mg twice daily) or placebo after discontinuation of conventional synthetic DMARD therapy, if such treatment was ongoing [46]. Clinical benefit was documented by week 2 (ACR20 of 16 versus 6 percent), at similar levels to findings in other phase 3 trials at week 16 (38 versus 20 percent), and sustained through the 52-week trial period. Reduced enthesopathy was also noted by week 2 (Gladman Enthesitis Index [GEI] -1.1 versus -0.4) and further improved by week 16 (GEI -1.5 versus -0.4), with sustained benefit at week 52 [47].
Patients treated with apremilast should have their weight monitored regularly, as significant and otherwise unexplained weight loss may require discontinuation of treatment [39]. Use of apremilast has also been associated with an increase in reports of depression compared with placebo [39]. Risks of drug use during pregnancy are unknown.
Severe peripheral arthritis/adverse prognosis — In patients presenting with severe disease who already have erosive disease and functional limitation, we suggest a TNF inhibitor as first-line therapy, rather than a conventional nonbiologic DMARD. Other biologic DMARDs (eg, secukinumab or ustekinumab) are alternatives to a TNF inhibitor. The approach in these patients is the same as that used for patients who have already had an inadequate response to nonbiologic DMARDs. (See 'Resistant to nonbiologic DMARDs' below.)
We prefer this approach because of the capacity of the TNF inhibitors and other biologic agents, demonstrated in multiple randomized trials and in contrast to MTX and the other conventional nonbiologic DMARDs, to limit joint damage and more rapidly restore function (see 'Resistant to nonbiologic DMARDs' below and 'TNF inhibitor use and efficacy' below and 'Secukinumab' below and 'Ustekinumab' below and 'MTX use and efficacy' above). This approach is also supported by the 2021 GRAPPA recommendations [27]; however, not all experts favor this approach [26].
Resistant to nonbiologic DMARDs — In patients whose joint counts do not improve substantially after three months of treatment with a conventional nonbiologic DMARD (eg, MTX) or who still have more than three tender and swollen joints, we recommend a TNF inhibitor, rather than sequential trials of other conventional DMARDs, unless required to use another conventional synthetic DMARD (eg, LEF) before obtaining approval for use of a biologic agent. We prefer a TNF inhibitor in this setting because of the greater experience that exists with these agents, as well as the greater number of trials providing evidence of benefit. (See 'Choice of nonbiologic DMARD and other agents' above and 'Choice of TNF inhibitor' below.)
Typically patients require up to three months of therapy to achieve a maximal response, but many respond sooner, as illustrated in multiple randomized trials with these drugs (see 'TNF inhibitor use and efficacy' below). Assessment of the treatment response should be individualized to incorporate other domains of disease activity in addition to arthritis, such as psoriatic skin involvement, dactylitis, and enthesitis, particularly in patients with moderate to severe involvement in these other domains. With respect to the musculoskeletal manifestations, a target of minimal disease activity (MDA) is desirable, but these manifestations may not be the most prominent aspects of disease in some patients. (See 'Other assessment measures' below.)
We initially add the TNF inhibitor, while continuing the conventional DMARD (eg, MTX). However, in contrast to RA, MTX generally can be discontinued in PsA patients who respond to TNF-inhibitor therapy, with one important exception, which is infliximab; some experts also prefer that patients receiving adalimumab should also continue MTX. Patients treated with infliximab, and perhaps adalimumab, should continue concomitant MTX, when possible, to lessen the likelihood of a reduced response to infliximab over time [48]. Evidence from registries has not shown increased efficacy with the combination over TNF inhibitor monotherapy, although drug survival with combined treatment was increased slightly for most agents, and most markedly for patients on infliximab [48].
It is not uncommon for patients on TNF inhibitor monotherapy to experience sustained responses in the skin and joints, and the efficacy of TNF inhibitors for the peripheral arthritis of PsA is supported by multiple randomized trials with these agents. (See 'TNF inhibitor use and efficacy' below.)
Other cytokine inhibitors such as anti-interleukin (IL) 12/23 (ustekinumab) and anti-IL-17 (secukinumab and ixekizumab) have also been approved for the treatment of PsA. These agents work extremely well for the skin disease, and are especially useful in patients with contraindications to use of anti-TNF agents (eg, patients with significant heart failure or multiple sclerosis). Either of these agents may also be of benefit in patients resistant to TNF inhibitor therapy. (See 'Peripheral arthritis resistant to initial TNF inhibitor' below.)
Choice of TNF inhibitor — All five of the original TNF inhibitors (etanercept, adalimumab, infliximab, certolizumab pegol, and golimumab) are available for use in patients with PsA in the United States, in the European Union, and in many other countries. The efficacy of the drugs for the arthritis appears comparable (see 'TNF inhibitor use and efficacy' below), and the choice of agent is based upon patient preferences for route (subcutaneous versus intravenous) and frequency of administration, regulatory and payor requirements and limitations, and potential cost to the patient. There may be a differential effect on the skin, which should be incorporated into the choice of agent made in collaboration with the patient's dermatologist. (See "Treatment of psoriasis in adults", section on 'Biologic agents'.)
TNF inhibitor use and efficacy — The five original TNF inhibitors and their respective dosing regimens are:
●Etanercept – 50 mg as a subcutaneous injection once weekly. Etanercept is a dimeric p75 TNF-alpha receptor Fc fragment fusion protein that binds TNF. An initial dose of 50 mg twice weekly for the first three months of therapy may be used in patients requiring treatment for moderate to severe psoriatic skin disease.
●Infliximab – 5 mg/kg administered by intravenous infusion at zero, two, and six weeks, followed by 5 mg/kg every eight weeks thereafter. It may be given either with or without MTX. Infliximab is a human / mouse chimeric anti-TNF-alpha antibody.
●Adalimumab – 40 mg subcutaneously once every two weeks. Adalimumab is a human monoclonal anti-TNF antibody.
●Golimumab – 50 mg subcutaneously once monthly. Golimumab is a human monoclonal anti-TNF antibody.
●Certolizumab pegol – Initial dose of 400 mg (administered as two 200 mg injections subcutaneously), with this dose repeated two and four weeks after the initial dose; maintenance with 200 mg once every other week, but may alternatively treat with 400 mg every four weeks. Certolizumab pegol is a pegylated Fab fragment of a humanized anti-TNF monoclonal antibody.
Screening for latent tuberculosis (TB) prior to beginning therapy with anti-TNF agents is necessary, and those with evidence of disease usually require prophylactic anti-TB therapy (see "Treatment of tuberculosis infection in nonpregnant adults without HIV infection"). We avoid TNF inhibitors in patients with first-degree relatives with multiple sclerosis.
The efficacy of the TNF inhibitors in patients with PsA has been well-documented in meta-analyses involving several of the agents [49] and in multiple clinical trials with all of the agents, including etanercept [50-53], infliximab [14,54-58], adalimumab [59-64], golimumab [65,66], and certolizumab pegol [67,68], compared with placebo. In one retrospective analysis, monotherapy with a TNF inhibitor was superior to MTX monotherapy after controlling for multiple variables [69]. Benefits in trials included reduced activity of arthritis, with ACR20 responses in 50 to 65 percent of patients within three months; reduced radiographic progression; and improved physical function and health-related quality of life measures. In long-term follow-up studies, benefit is maintained in most patients who have responded to therapy. Enthesitis, dactylitis, and cutaneous findings also improved in TNF inhibitor-treated patients. (See 'Enthesitis and dactylitis' below.)
Higher initial doses of etanercept (50 mg twice weekly for 12 weeks, then once weekly) than are required for the joint disease may be of benefit for treatment of the skin manifestations. (See "Treatment of psoriasis in adults", section on 'Etanercept'.)
Sustained benefit from these drugs has been shown among patients with PsA studied using several drug registries and several other studies [70-75]. As an example, in the Danish registry of 764 PsA patients treated with their first TNF-alpha inhibitor in clinical practice, the median drug survival was 2.9 years. The ACR50 response rate was 45 percent. Increased CRP at baseline was associated both with good treatment responses and with continued treatment [73].
In addition to improvement in clinical signs and symptoms, these agents also reduce radiographic progression of disease, as indicated by the data from the individual trial. A meta-analysis of five randomized trials involving 1110 patients found that significantly fewer patients with PsA who were treated with TNF inhibitors (including etanercept, adalimumab, infliximab, and golimumab) exhibited radiographic disease progression at week 24 of treatment compared with patients who received placebo (15 versus 31 percent); it was uncertain whether MTX provided additional benefit [76].
Peripheral arthritis resistant to initial TNF inhibitor
Choice of agent
●Resistant to one TNF inhibitor – We switch to a second TNF inhibitor in patients who experience an inadequate response to the first TNF inhibitor used, rather than trying a different class of biologic agent (see 'Choice of TNF inhibitor' above and 'TNF inhibitor use and efficacy' above). Most patients achieve maximal benefit after about three to four months of therapy.
We prefer to switch from one of the antibody-based agents (eg, infliximab, adalimumab, golimumab, or certolizumab) to the soluble TNF receptor (etanercept) and vice versa, although formal evidence to support or refute this strategy is lacking. For example, in patients with an inadequate response to etanercept, the second agent should be one of the other four agents, while patients on an anti-TNF antibody should switch to etanercept. An alternative to using a second TNF inhibitor is another biologic agent that has been shown to be effective in this population, such as secukinumab or ustekinumab.
●Resistant to two TNF inhibitors – In patients who do not respond adequately to two different TNF inhibitors, we use an IL-17 inhibitor (ie, secukinumab or ixekizumab) or the IL-12/23 inhibitor ustekinumab. (See 'Secukinumab' below and 'Ixekizumab' below and 'Ustekinumab' below.)
Secukinumab may be given with or without MTX, and in patients with marked improvement in joint and skin disease with the addition of secukinumab an effort can be made to gradually reduce or discontinue MTX. In clinical trials, secukinumab may have greater benefit for PsA than ustekinumab, but they have not been directly compared for this indication.
In patients without an adequate response to secukinumab, we suggest ustekinumab (see 'Ustekinumab' below). Ustekinumab may be given with or without MTX, and in patients with marked improvement in joint and skin disease with the addition of ustekinumab an effort can be made to gradually reduce or discontinue MTX.
●Resistant to multiple biologics – In patients who have not responded adequately to TNF inhibitor therapy and to other biologics such as secukinumab and ustekinumab, another treatment option is abatacept, the costimulation blocker, which has become available for use in PsA. (See 'Abatacept' below.)
Anti-IL-17 therapies — Several drugs that inhibit IL-17 are available for use in PsA and/or psoriasis:
●Secukinumab – Secukinumab is a human anti-IL-17A monoclonal antibody available for the treatment of PsA and psoriasis in the United States, the European Union, and a number of other countries. It was shown to be effective by a number of measures for the treatment of PsA in a series of phase 3 randomized trials [77-79]. (See 'Secukinumab' below.)
●Ixekizumab – Ixekizumab, which is available in the United States, Canada, and the European Union for the treatment of moderate to severe plaque psoriasis, is also an IL-17A monoclonal antibody, which demonstrated efficacy in both psoriasis and PsA. (See 'Ixekizumab' below.)
●Brodalumab – Brodalumab is an anti-IL-17 receptor antibody that is approved by the US Food and Drug Administration (FDA) for use in psoriasis and has shown efficacy in trials for PsA [77-83]. (See 'Brodalumab' below and "Treatment of psoriasis in adults", section on 'Brodalumab'.)
Secukinumab — Secukinumab is administered by subcutaneous injection, usually with a loading dose of 150 mg at weeks 0, 1, 2, 3, and 4, followed by 150 mg every four weeks; it may be increased to 300 mg every four weeks in patients who have failed TNF inhibitors or who continue to have active arthritis despite 150 mg every four weeks. In patients with severe psoriasis, the usual dose is 300 mg every four weeks. Therapy may also be initiated without a weekly loading dose with 150 mg every four weeks from the beginning of therapy. In patients with coexistent moderate to severe plaque psoriasis, the drug is given as 300 mg once weekly at weeks 0, 1, 2, 3, and 4, followed by 300 mg every four weeks, although some patients may only require 150 mg per dose. Patients usually achieve a maximal response within three to four months of treatment.
Patients should be screened for latent TB prior to use of this agent and should be treated appropriately, if screening positive, by initiation of anti-TB therapy before starting secukinumab, although there are no data, in contrast to TNF-blocker therapy, of latent TB reactivation under secukinumab treatment. (See "Treatment of tuberculosis infection in nonpregnant adults without HIV infection" and "Tuberculosis infection (latent tuberculosis) in adults: Approach to diagnosis (screening)".)
Regimens for dosing and drug administration have varied between the trials:
●In a multicenter phase 3 randomized trial involving 397 patients with active PsA, secukinumab was superior to placebo in achieving significant improvement in joint and skin symptoms and findings and in physical function and quality of life [79]. Secukinumab (300, 150, or 75 mg administered subcutaneously) or placebo were given weekly for the first four weeks and then every four weeks. A significantly higher proportion of patients treated with secukinumab (300 and 150 mg), compared with placebo-treated patients, achieved an ACR20 response at week 24 (54, 51, and 29 versus 15 percent). Responses by weeks 12 to 16 were similar to those at week 24, and benefit was sustained at 52 weeks. The drug was well-tolerated, with similar types and frequencies of adverse events in patients treated with either the drug or placebo. Patients who were inadequate responders to TNF inhibitors demonstrated a better response to the 300 mg dose than the 150 mg dose.
●Clinical and radiographic benefit was shown in a randomized trial involving 606 patients [78]. Patients who received secukinumab (three loading doses of 10 mg/kg, followed by subcutaneous administration of either 75 or 150 mg/dose) were significantly more likely compared with patients receiving placebo to achieve the composite clinical endpoint of an ACR20 response (50 and 51 versus 17 percent) at week 24. ACR50 and ACR70 responses were also significantly more frequent in patients receiving secukinumab (31 and 35 versus 7 percent and 17 and 19 versus 2 percent, respectively). Responses were sustained at week 52. In this trial, responses to 300 mg were more frequent than to 150 mg in patients who had prior inadequate responses to TNF inhibitors (ACR20 46 versus 30 percent, ACR50 27 versus 19 percent, and ACR70 15 versus 11 percent). Treatment with secukinumab also significantly reduced radiographic progression compared with placebo and reduced the frequency of enthesitis and dactylitis.
Ixekizumab — Ixekizumab is an anti-IL-17A monoclonal antibody available for use in patients with plaque psoriasis (see "Treatment of psoriasis in adults", section on 'Ixekizumab'); it has also shown efficacy for PsA in several clinical trials [84,85]:
●In a randomized trial involving 417 patients with active PsA, most of whom had previously received a conventional nonbiologic DMARD, ixekizumab (160 mg initially, then 80 mg every two or four weeks by subcutaneous injection) was more likely than placebo to achieve an ACR20 response at week 24 (62 and 58 versus 30 percent) and achieved results comparable to adalimumab (40 mg every two weeks by subcutaneous injection) [84]. Ixekizumab reduced radiographic progression compared with placebo and improved psoriatic skin disease. A similar adverse event profile was seen with ixekizumab and adalimumab.
●In another randomized trial involving 363 patients with active PsA who were either refractory, had loss of efficacy, or were intolerant to a TNF inhibitor, ixekizumab (160 mg initially, then 80 mg every two or four weeks by subcutaneous injection) was more likely than placebo to achieve an ACR20 response at week 24 (48 and 53 versus 20 percent) [85]. Serious infections occurred in three patients on ixekizumab (all on the every-two-week regimen). Improved physical function was more frequent with the active drug. Radiographic changes were not evaluated.
Ustekinumab — Ustekinumab is a human monoclonal antibody to the shared p40 subunit of IL-12 and IL-23, which interferes with receptor binding to immune cells. It is commercially available for the treatment of both psoriasis and PsA and is administered by subcutaneous injection (45 mg, given initially and four weeks later, then every 12 weeks). A higher dose of ustekinumab is used for patients with coexistent moderate-to-severe plaque psoriasis weighing greater than 100 kg (220 lbs) (90 mg initially and four weeks later, followed by 90 mg every 12 weeks) [86,87]. IL-23 is important in triggering the production of IL-17, which has a role in immune regulation and in mediating joint injury. IL-23 also triggers the release of IL-22, which has been implicated in keratinocyte proliferation and new bone formation in an animal model of enthesitis [88]. (See "Treatment of psoriasis in adults", section on 'Ustekinumab'.)
The efficacy and safety of ustekinumab for PsA has been demonstrated in several randomized trials, which included patients who had active PsA despite having received either NSAIDs, a conventional nonbiologic DMARD, or a TNF inhibitor [89-91]. As examples:
●In the multicenter PSUMMIT 1 trial, 615 patients with active PsA despite use of an NSAID or a traditional DMARD (without prior use of a TNF inhibitor) were randomly assigned to receive either ustekinumab (90 or 45 mg) or placebo at weeks 0 and 4, followed by every 12 weeks; at week 16, patients without at least 5 percent improvement in both tender and swollen joint counts were increased to 90 mg of ustekinumab if they had been receiving 45 mg, or 45 mg of ustekinumab if they had been receiving placebo [89]. At week 24, the primary outcome, ACR20, was achieved significantly more often by the patients receiving either 90 or 45 mg of ustekinumab compared with those receiving placebo (ACR20 in 50 and 42 versus 23 percent), and responses were maintained at week 52. Clinically and statistically significant improvement in function at week 24 was also achieved more often in the patients receiving ustekinumab (HAQ-DI increase of at least 0.3 in 48 and 48 versus 28 percent). Statistically significant improvement in psoriasis, dactylitis, and enthesitis was also noted.
No opportunistic infections (including TB), malignancies, or deaths were reported. Active therapy was discontinued by less than 2 percent of patients, and serious infections (all after week 24) included two patients with cholecystitis and one each with salpingitis, erysipelas, and a pharyngolaryngeal abscess. During the placebo phase of the trial, there was one patient on placebo who experienced angina and one on ustekinumab who had a nonfatal stroke; later in the trial, two patients on ustekinumab had myocardial infarctions.
●In another phase 3 randomized trial with a similar design to that above (the PSUMMIT 2 trial), benefit was also seen among the 58 percent of trial patients who had previously received TNF inhibitor therapy [91]. In this multicenter trial, involving 312 patients with active PsA despite use of either traditional nonbiologic DMARDs or anti-TNF therapy, ustekinumab (initially at a dose of 45 or 90 mg at weeks 0 and 4, then every 12 weeks) was significantly more likely than placebo to result in an ACR20 response at week 24 (44 versus 20 percent). Concomitant therapy with MTX was permitted in patients on a stable dose of this agent. Significant benefit compared with placebo was seen at week 24 in the subgroup that had previously received at least one TNF inhibitor (ACR20 in 36 versus 15 percent). Improvement in function was also seen at week 24 (HAQ-DI change of -0.25 versus 0.00). Benefits in composite measures of disease activity and function were sustained at week 52.
Serious adverse events occurred in 5.2 percent (15 of 287) of patients treated for 60 weeks with ustekinumab (11.82 per 100 patient-years). These included serious infections, but no cases of TB and no deaths.
●Combined data from the PSUMMIT 1 and PSUMMIT 2 trials also indicated that treatment with ustekinumab resulted in a statistically significant reduction of radiographic progression of joint injury compared with placebo from baseline to week 24 (modified van der Heijde-Sharp score increase of 0.4 versus 1.0) [92]. Inhibition of progression was maintained at week 52.
Abatacept — Abatacept (CTLA4-Ig), a selective T-cell costimulation modulator used for the treatment of RA, has also shown benefit for patients with PsA in limited published randomized trials. PsA became an FDA-approved indication for its use in 2017 [93], and it was also approved for this indication in the European Union. We would use abatacept in situations where other drugs have failed or have contraindications. Published reports showed the following:
●Efficacy and safety of abatacept (125 mg administered by subcutaneous injection once weekly) were analyzed in a phase 3 randomized trial comparing abatacept with placebo in 424 patients with active PsA and plaque psoriasis and an inadequate response or intolerance to at least one nonbiologic DMARD [94]. About 60 percent had prior exposure to a TNF inhibitor; concomitant therapy with a nonbiologic DMARD, low-dose oral glucocorticoid, and topical steroids was allowed. ACR composite criteria for at least 20 percent improvement (an ACR20) response was achieved more often in the patients receiving abatacept at week 24 (39 versus 22 percent), after which patients were given the active drug in an open-label extension. A nonsignificant trend suggesting improvement in physical function and only modest benefit for the psoriasis were seen, although the improvement in the arthritis was sustained over one year. The frequency of adverse effects were similar in the treatment and control groups.
●In a previous phase 2 trial of abatacept (administered by intravenous infusion), 170 patients with an inadequate response to a nonbiologic DMARD (usually MTX), a biologic agent (usually a TNF inhibitor), or both were randomly assigned to receive one of three doses of abatacept or placebo; an ACR20 response was achieved significantly more often after six months of therapy among patients treated with abatacept (10 mg/kg administered intravenously in three initial doses at two-week intervals and then every four weeks) compared with those receiving placebo (48 versus 19 percent) [95].
The optimal treatment response was at the same dose used for RA in adults and for juvenile idiopathic arthritis (10 mg/kg). Modest improvements in skin disease were also seen, as were improvements in findings on magnetic resonance imaging (MRI) of affected joints in the hands or feet. Safety profiles and drug discontinuation rates were similar among treatment and placebo groups.
Guselkumab — Guselkumab, which is commercially available for the treatment of moderate to severe psoriasis and for active psoriatic arthritis (PsA), is an anti-IL-23-specific monoclonal antibody that targets the p19-protein subunit of IL-23; it has shown efficacy for PsA. In a randomized phase 2 trial involving 149 patients with active PsA and plaque psoriasis, ACR composite criteria for at least 20 percent improvement (an ACR20 response) at week 24 was achieved more frequently in the patients allocated to receive guselkumab compared with placebo (58 versus 18 percent; percentage difference of 39.7, 95% CI, 25.3-54.1) [96]. The drug was well tolerated over 44 weeks of treatment, and rates of adverse events, including infection, were similar in the two groups. (See "Treatment of psoriasis in adults", section on 'Guselkumab'.)
Janus kinase inhibitors
Tofacitinib — Tofacitinib, an oral inhibitor of Janus kinase (JAK), has demonstrated efficacy in the treatment of PsA in several randomized trials, including both patients with an inadequate response to a conventional synthetic DMARD [97] and patients with an inadequate response to TNF inhibitor therapy [98]. It is commercially available for the treatment of PsA in the United States for patients who have had an inadequate response or intolerance to MTX or other DMARDs. It is under study for several conditions. Tofacitinib inhibits cytokine pathways important in PsA and psoriasis through its effects on JAK3 and JAK1. The major published trials include the following:
●In a randomized phase 3 trial (Oral Psoriatic Arthritis Trial [OPAL] Broaden), involving 422 patients with active PsA, an inadequate response to at least one conventional DMARD, and who were TNF inhibitor-naïve, the addition of either tofacitinib (5 mg twice daily and 10 mg twice daily) or adalimumab (40 mg by subcutaneous injection every two weeks) resulted in superior efficacy compared with placebo after three months of treatment (ACR20 of 50, 61, and 52 versus 33 percent, respectively) [97]. Physical function was also improved at three months (change in Health Assessment Questionnaire Disability Index [HAQ-DI] of -0.35, -0.40, and -0.38 versus -0.18, respectively). Patients were followed through month 12, responses were maintained, and there were similar rates of serious adverse effects with either of the active drugs. Greater benefit with tofacitinib (5 or 10 mg twice daily) versus placebo was seen by week 2 (ACR20 of 22 and 32 versus 6 percent).
●In another randomized phase 3 trial (OPAL Beyond), involving 395 patients with active PsA and an inadequate response to a TNF inhibitor, treatment with tofacitinib (5 mg or 10 mg twice daily) resulted in greater benefit compared with placebo at three months (ACR20 of 50 and 47 versus 24 percent) [98]. Greater improvements in physical function at three months were also observed in the tofacitinib-treated patients (change in HAQ-DI of -0.39 and -0.35 versus -0.14). Responses were maintained through the six-month trial. Adverse effects with tofacitinib were similar to those seen in other trials in patients with RA or psoriasis.
Other JAK inhibitors — Other JAK inhibitors, including the selective JAK1 inhibitor, filgotinib, are under investigation. (See 'Other therapies' below.)
AXIAL DISEASE — The choice of therapy for axial disease (ie, involving the sacroiliac joints and spine) is based upon the severity of disease and the patient's response to treatment. Patients with mild symptoms may be effectively treated by use of a nonsteroidal antiinflammatory drug (NSAID) (see 'Mild arthritis/NSAIDs' above), while patients with moderate to severe arthritis or who are resistant to NSAIDs alone are usually treated with a biologic disease-modifying antirheumatic drug (DMARD) such as a tumor necrosis factor (TNF) inhibitor.
Treatment choices are also be influenced by the need to treat psoriatic skin and nail disease and psoriatic peripheral arthritis, enthesitis, and dactylitis; comorbidities; patient goals and preferences regarding routes of drug administration, needed rapidity and completeness of response, and cost of treatment; and regulatory and insurance requirements.
Use of the TNF inhibitors for axial disease in patients with psoriatic arthritis (PsA) is supported by evidence of benefit for axial spondyloarthritis in trials involving patients with ankylosing spondylitis [99] (see "Treatment of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults"), as well as by expert opinion [18,19,26]. Conventional nonbiologic DMARDs have not been shown to be effective for controlling either symptoms or radiographic disease progression of sacroiliac or spinal arthritis. There are no studies specifically for the axial disease in PsA.
Mild axial symptoms — In patients with mild symptoms of axial disease, which includes patients with inflammatory back pain that does not interfere with function, we suggest the use of NSAIDs in antiinflammatory dose regimens (eg, naproxen 375 to 500 mg twice daily, indomethacin 100 to 150 mg daily in divided doses, celecoxib 200 mg twice daily). NSAIDs can lessen pain and stiffness in spondylitis, although support for their use for axial manifestations of PsA is based upon their demonstrated benefit in patients with ankylosing spondylitis, expert opinion, and clinical experience [1,2,26,99,100]. (See "Treatment of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults", section on 'Initial drug therapy with NSAIDs'.)
Moderate to severe axial disease — In patients with axial symptoms that do not respond adequately to treatment with NSAIDs, such as those with prolonged morning stiffness and severe pain, interfering with function, we recommend a TNF inhibitor rather than a traditional nonbiologic DMARD, as the latter have been shown to be ineffective for spondylitis. The choice of agent and dosing are the same as those used for peripheral arthritis. (See 'Choice of TNF inhibitor' above and 'TNF inhibitor use and efficacy' above and "Treatment of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults", section on 'TNF inhibitors'.)
Severity of spondylitis is often assessed by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) (calculator 1). Spondylitis is considered severe when the BASDAI is greater than 4. (See 'Resistant to nonbiologic DMARDs' above.)
Axial disease resistant to initial TNF inhibitor — In patients with axial symptoms that do not respond adequately to initial therapy with a TNF inhibitor, we use the same approach described for peripheral arthritis, switching to a second TNF inhibitor and, if that is inadequate, to an alternative biologic agent such as secukinumab or ustekinumab. (See 'Peripheral arthritis resistant to initial TNF inhibitor' above.)
Two phase 3 randomized trials, named MEASURE 1 and 2, have shown a clear benefit of the interleukin (IL) 17 blocker secukinumab, compared with placebo, in ankylosing spondylitis [101], providing evidence of benefit for this agent for spondyloarthritis, although direct evidence for the axial manifestations in PsA is lacking. There are limited data supporting the use of the IL-12/23 inhibitor ustekinumab in patients with spondylitis; the trials have generally been limited to patients with ankylosing spondylitis. (See "Treatment of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults", section on 'Secukinumab' and "Treatment of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults", section on 'Inadequate response or intolerance to initial biologic'.)
ENTHESITIS AND DACTYLITIS — Enthesitis and dactylitis often benefit from the therapies being used to treat other clinical manifestations.
Enthesitis — In patients with enthesitis, which often affects the plantar fascia and the Achilles tendon insertion, we suggest initial treatment with nonsteroidal antiinflammatory drugs (NSAIDs) (see 'Mild arthritis/NSAIDs' above). Local measures, including physical therapy and local glucocorticoids, are sometimes beneficial, but their use has not been systematically evaluated in patients with psoriatic arthritis (PsA).
In patients in whom NSAIDs, local measures, and treatments for other manifestations are insufficient to control the inflammation, particularly those with functional limitation due to enthesitis, we suggest biologic agents (eg, a tumor necrosis factor [TNF] inhibitor), rather than conventional nonbiologic disease-modifying antirheumatic drugs (DMARDs). There is no evidence that the traditional DMARDs work for this condition, and most of the biologic DMARDS used for peripheral arthritis have also been reported to be effective for enthesitis in trials in which these outcomes are also reported [102] (see 'TNF inhibitor use and efficacy' above and 'Secukinumab' above and 'Ustekinumab' above). This approach is consistent with expert opinion and our clinical experience [19,26].
Apremilast has also been shown to improve enthesitis and may be useful in patients who do not otherwise require a biologic agent. (See 'Apremilast' above.)
Dactylitis — Dactylitis, or inflammation of the whole digit, may respond to NSAIDs and some traditional DMARDs (eg, methotrexate [MTX] 15 to 25 mg once weekly). If it is severe, affecting a number of digits or interfering with function, biologic DMARDs are usually indicated, as in patients with enthesitis, as improvements in dactylitis are reported as secondary outcomes in the randomized trials of these agents [103] (see 'TNF inhibitor use and efficacy' above and 'Secukinumab' above and 'Ustekinumab' above). Glucocorticoid injections are sometimes used, but their efficacy has been examined in a systematic fashion.
ROLE OF GLUCOCORTICOIDS — Use of oral glucocorticoids in patients with psoriatic arthritis (PsA) should generally be avoided, since their use is associated with an increased chance of developing erythroderma or pustular psoriasis; in addition, there appears to be interference with the effect of other drugs [14,104]. Rarely, oral glucocorticoids are prescribed for patients with severe flares unresponsive to conventional or biologic disease-modifying antirheumatic drugs (DMARDS). It is important, however, to taper the glucocorticoids slowly and with close observation in these patients to help avoid development of erythroderma or pustular psoriasis. In patients requiring systemic glucocorticoids, such as oral prednisone, the lowest dose necessary should be employed.
Injection of glucocorticoids into tendon insertions should not be performed because of a risk of tendon rupture, and data supporting efficacy of this approach are not available. Likewise, some clinicians inject dactylitic digits with glucocorticoids, but no data are published demonstrating efficacy.
Intraarticular glucocorticoids are sometimes used, and care should be taken in patients who require such injections to avoid injection through psoriatic plaques.
RESISTANT TO OR INTOLERANT OF STANDARD THERAPIES — Other modalities are reserved for patients with psoriatic arthritis (PsA) who either do not respond to or demonstrate toxic reactions to the usual medications. These include:
●Alternative conventional disease-modifying antirheumatic drugs (DMARDs), such as sulfasalazine (SSZ), azathioprine, or cyclosporine (see 'Alternative conventional DMARDs' below)
●Agents used primarily for psoriatic skin disease, such as psoralen plus ultraviolet A (PUVA) and retinoic acid derivatives (see 'Agents used primarily for skin disease' below)
●Biologic agents or kinase inhibitors being studied in PsA that are available for other indications, such as brodalumab, an IL-17 inhibitor (see 'Biologic agents and kinase inhibitors used for other disorders' below)
●Other medications supported by very limited evidence (see 'Other therapies' below)
Alternative conventional DMARDs
Sulfasalazine — SSZ (gradually increased to 1000 mg twice daily) is used infrequently given the availability of more effective and well-tolerated agents, including methotrexate (MTX), leflunomide (LEF), the tumor necrosis factor (TNF) inhibitors, and others. Some patients require a dose of 3 g/day to obtain a therapeutic benefit. SSZ may be required prior to the use of biologics in some jurisdictions. One needs to confirm that the patient is not allergic to sulfa medications prior to initiating SSZ. Routine monitoring of laboratory tests, as in patients with rheumatoid arthritis (RA), is required as SSZ may lead to leukopenia. (See "Sulfasalazine: Pharmacology, administration, and adverse effects in the treatment of rheumatoid arthritis".)
The available evidence, including randomized trial data [105-108], suggests only very modest benefit for the joint or skin disease, although improvement can be seen in both domains [105,106,109-111].
The largest study of SSZ in PsA randomly assigned 221 patients with PsA to SSZ (2 g/day) or placebo [110]. Using the Psoriatic Arthritis Response Criteria (PsARC) to identify patients who responded to the medication, favorable responses were more frequent in the SSZ group than in the placebo group (response rates of 58 versus 45 percent).
Adverse effects may be a limiting factor for the use of SSZ. In one study, 40 percent of patients discontinued SSZ within three months [111]. Some findings also suggest that the dose of SSZ required to control PsA may be higher than that used in RA; as a result, many patients with PsA do not tolerate SSZ, despite it being effective in some patients able to take it [105,106,110,111]. The major reasons for discontinuation of therapy are gastrointestinal side effects. In addition, the onset of drug-induced lupus and toxic epidermal necrolysis has been described in patients with psoriasis treated with SSZ [112,113].
Cyclosporine — Cyclosporine is a conventional nonbiologic DMARD, available commercially for use in psoriasis refractory to other therapies and in severe RA. Cyclosporine is used in lower doses for psoriasis and PsA than for organ transplantation. Most patients receive between 2.5 and 5 mg/kg/day, usually in divided doses. The time to response is three to four months. Renal toxicity is a limiting factor, and renal function and blood pressure need to be closely monitored (see "Cyclosporine and tacrolimus nephrotoxicity"); thus, use of cyclosporine has been largely supplanted by other more potent and safer therapies for the treatment of PsA. However, it is an effective agent for psoriatic skin disease. (See "Treatment of psoriasis in adults", section on 'Cyclosporine'.)
Evidence for the efficacy of cyclosporine for PsA includes an uncontrolled study suggesting it improved symptoms and findings of arthritis [114]; an open-label trial, in which it was compared with SSZ and with "usual care" (nonsteroidal antiinflammatory drugs [NSAIDs], low-dose prednisone, and analgesics), in which only very modest benefit was observed compared with the other treatments [115]; and a randomized trial in patients continuing MTX, to which they had had an inadequate response, in which there was improvement in the activity of the joint disease and less progression of joint damage compared with patients receiving placebo [116].
Azathioprine — Azathioprine is a conventional nonbiologic DMARD available commercially for use in RA; it is used only infrequently in RA, given the availability of more effective and better-tolerated agents, and there is only one randomized trial of azathioprine in PsA [117]. This was a double-blind crossover study for 12 months, with patients randomly assigned to drug or to placebo for the first six months. Marked improvement in joint counts, grip strength, and morning stiffness was recorded in four of six patients studied, and moderate response was recorded in the other two. Complete clearing of skin lesions was noted in two of the six patients, and partial clearing was noted in four of the six. No improvement in skin or joint disease was noted in those on placebo. In our clinical experience, we have found this drug to be effective even in individuals unresponsive to other drugs. Indeed, in an uncontrolled study of 28 patients using azathioprine in our clinic, the drug was well-tolerated, and an improvement in actively inflamed joints was noted [118]. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases".)
Agents used primarily for skin disease
Psoralen and ultraviolet light — Suggestion of benefit from PUVA therapy in PsA was noted in an uncontrolled series [119]. Although the arthritis improved, it seemed to do so primarily in those patients whose psoriasis improved. Thus, PUVA is used primarily in patients with severe psoriasis. (See "Treatment of psoriasis in adults", section on 'Ultraviolet light'.)
Many patients receive the combination of PUVA and a conventional DMARD. The efficacy and side effects associated with this approach are unclear. In our clinic, we have not noted any unusual adverse events combining PUVA with azathioprine, MTX, or SSZ. A group of experts has recommended that aggressive immunosuppression should not follow extensive phototherapy, especially PUVA, because of a heightened risk of malignant melanoma and of nonmelanoma skin cancer in this setting [100]. It has not been determined whether biologic agents should be used in combination with PUVA; we avoid using them simultaneously because of concern regarding risk of cutaneous malignancy.
In addition to the usual contraindications to the use of anti-TNF therapies, a guideline from the British Society of Rheumatology also recommended caution in use of these agents in patients with prior PUVA therapy (>1000 joules), due to an increased risk of nonmelanoma skin cancer; in patients with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), due to a general lack of data on the safety of anti-TNF therapy in this setting; and in patients with heart failure of American Heart Association grade III or IV [120].
Retinoic acid derivatives — The value of the retinoic acid derivative acitretin in PsA is uncertain; we do not use these agents specifically for the treatment of arthritis, but they are sometimes used in combination with other drugs to treat psoriasis. (See "Treatment of psoriasis in adults", section on 'Acitretin'.)
Retinoic acid derivatives take about four months to produce a response [121]. They are given in doses of 25 to 100 mg/day, in either single or divided daily doses. Their main side effects include extreme dryness of the skin and mucous membranes and hyperlipidemia. Clinical trials were performed with etretinate, an agent that has been withdrawn from the market due to toxicity. It should be noted that retinoic acid derivatives can produce extraskeletal bone deposition and can lead to joint pain in patients with psoriasis.
Biologic agents and kinase inhibitors used for other disorders
Brodalumab — Brodalumab, like secukinumab and ixekizumab, is an anti-IL-17 agent that has been studied in PsA, with evidence of benefit [83]. Brodalumab has become commercially available for use in psoriasis but has not been approved by the FDA for use in PsA. For use in patients with psoriasis, the patients must enter a risk evaluation and mitigation strategy (REMS) program with use in the United States because of concerns about suicidal ideation and completed suicides in the clinical trials for psoriasis and PsA. Due to such concerns, at least one manufacturer has discontinued their development program for this agent. The overall level of risk for suicidality associated with the anti-IL-17 agents is unknown. Additional trials will be helpful to further clarify the efficacy and safety of this agent. (See "Treatment of psoriasis in adults", section on 'Brodalumab'.)
Rituximab — The use of rituximab has been explored in a small number of patients, with variable results [122,123].
Other therapies — Additional medications and other modalities have been studied, with the following observations:
●Filgotinib – Filgotinib is a selective Janus kinase 1 (JAK1) inhibitor under investigation for PsA, as well as for RA, inflammatory bowel disease, spondyloarthritis, and several other conditions. The effects of filgotinib were evaluated in a multicenter phase 2 randomized trial involving 131 patients with active PsA and an inadequate response or intolerance to at least one conventional synthetic DMARD; the addition of filgotinib (200 mg orally once daily) to existing stable therapy resulted in a greater proportion achieving an American College of Rheumatology (ACR) composite criteria for at least 20 percent improvement (an ACR20 response) at week 16, compared with placebo (80 versus 33 percent, treatment difference 47 percent, 95% CI 30.2-59.6) [124].
Psoriatic skin disease, enthesitis, and several patient-reported outcomes were more improved with the active drug. Adverse events were of similar frequency and severity in the two groups. Larger studies of greater duration will be of interest.
●Colchicine – Conflicting results have been noted for colchicine treatment. Two controlled studies with random patient assignment have been reported; in one there was benefit, while in the other there was not [125,126]. A systematic review concluded that further trials were needed [108].
●Fish oil and plant seed oils – Controlled trials of fish oil or a combination of fish and plant seed oils have not shown benefit in PsA or psoriasis, despite promising results in observational studies and measurable alterations in prostaglandin metabolism [127-129].
●Other medications and interventions – Small observational studies or case reports have suggested benefit with various agents that require further evaluation. These include oral vitamin D3, bromocriptine, extracorporeal photochemotherapy, and mycophenolate mofetil [130-133].
The addition of balneotherapy (mud packs and sulfur baths) to bathing in the Dead Sea and sun exposure provides additional benefit to that seen with bathing and sun alone in three- or four-week treatment programs, particularly for inflammatory back pain [134,135]. Benefits can still be observed in arthritis and back pain, regardless of the addition of balneotherapy, six months following treatment [135].
MONITORING
Assessment for clinical care — Patients require monitoring at regular intervals to assess the response to therapy for the psoriatic arthritis (PsA) and related morbidities and to adjust therapy based upon the treatment response. In addition, patients need regular monitoring for adverse effects of medications. Patients should be monitored more closely when new medications are being initiated, depending upon the expected response time. We monitor patients at three-month intervals when the disease is more active and under changing treatment. Stable patients may be monitored at six-month intervals. Depending upon the medication, laboratory monitoring may be required more often, sometimes at monthly intervals.
●Disease activity – Disease activity should be assessed by use of joint counts for detection of painful and swollen joints. A 68/66 (tender/swollen) joint count is ideal, as it can be done relatively quickly and includes the ankles and feet, which are excluded from a 28 joint count (as used, for example, to calculate a DAS28, the disease activity score in 28 joints). (See 'Other assessment measures' below.)
In addition to a joint count, the severity of periarticular involvement can be determined by the number of areas affected by enthesitis, with particular attention, at a minimum, to the Achilles tendon insertions and the plantar fascia in each foot, as well as the epicondyles, since these areas have been shown to be most commonly affected [136], and identification and a count of the number of digits affected by dactylitis. Taken together this information is usually sufficient to provide a good estimate of the extent and severity of articular and periarticular disease in our experience. The effects of joint disease, enthesitis, and dactylitis on function should also be ascertained.
Composite measures, particularly the Minimal Disease Activity (MDA) measure, are helpful in assessment of disease activity and guiding a treat-to-target approach; in patients with peripheral arthritis only, lacking axial disease, enthesitis, or dactylitis, the Disease Activity Index for Psoriatic Arthritis (DAPSA) can be employed as an alternative. (See 'Other assessment measures' below.)
Other measures created for use in rheumatoid arthritis (RA), such as the RAPID3 (a modification of the Routine Assessment of Patient Index Data) and the DAS28-CRP (Disease Activity Score using a 28 joint count and C-reactive protein), may be helpful, but they only reflect peripheral arthritis, and active PsA may still be present in patients with a good response based upon these measures; thus, they cannot be used alone as a sufficient rationale to stop escalation of therapy. (See 'Other assessment measures' below.)
●Imaging and joint injury – In clinical practice, plain film radiography of clinically involved peripheral joints, the sacroiliac joints, and the spine are used to assess the extent and progression of disease at these sites.
●Laboratory testing – Laboratory testing depends primarily upon the specific therapeutic agents being used. Acute phase measures (eg, the sedimentation rate and C-reactive protein [CRP]) should be included in the initial assessment, in part because of their prognostic implications.
A treat-to-target approach, in which a therapeutic goal such as inactive disease or MDA is targeted and treatment is adjusted at frequent and defined intervals if the target is not met, has been suggested for patients with PsA. The benefits of this strategy were supported by the first randomized trial to test this approach in PsA, a multicenter open-label trial in the United Kingdom involving 206 patients with recent-onset active PsA who had not previously received disease-modifying antirheumatic drug (DMARD) therapy [11]. Patients who were assigned to tight control (every four week visits with pre-specified treatment escalation if MDA criteria were not met) were significantly more likely to achieve American College of Rheumatology (ACR) composite criteria for at least 20 percent improvement (an ACR20 response) at 48 weeks, compared with patients receiving standard care (as defined by their treating clinician; odds ratio [OR] 1.91, 95% CI 1.03-3.55, ACR20 in 44 versus 18 percent).
Serious adverse effects occurred in 14 and 6 percent of patients in the tight control and standard care groups, respectively. Further studies are needed to identify the optimal therapeutic regimens, although these data provide evidence to further support the benefits of achieving MDA and of a treat-to-target approach [137]. It is important to note, however, that combination therapies prescribed in this trial for some patients, including cyclosporine and combined treatment with methotrexate (MTX) and leflunomide (LEF), are not commonly prescribed in the United States for PsA.
Other assessment measures — Several validated assessment tools have been designed for use in patients with PsA, including the MDA and DAPSA [6]. Measures that were developed to assess the response to treatment in RA have also been used for PsA [100]. RA response criteria used for clinical trials in PsA include the ACR20, ACR50, and ACR70 (from the ACR), as well as the DAS28 and the European Alliance of Associations for Rheumatology (EULAR) response criteria. However, although the DAS28 clearly distinguishes between drug- and placebo-treated patients in clinical trials, it may not be appropriate for PsA patients, many of whom have foot and distal interphalangeal (DIP) joint involvement that is not recorded in the DAS28. (See "Assessment of rheumatoid arthritis disease activity and physical function", section on 'Composite indices for disease activity assessment' and "Assessment of rheumatoid arthritis disease activity and physical function".)
A detailed review of assessment methods that have been used and/or proposed for research purposes to guide development of drugs and biologic agents is beyond the scope of this topic. However, a review published in 2004 addressed the issue and highlighted the need to develop standardized approaches to assessing the activity of disease in the following domains [138]:
●Peripheral arthritis (joint pain, tenderness, and swelling). It is essential to evaluate the feet and the DIP joints of the hands and feet because they are commonly involved in PsA.
●Clinical severity of joint damage (including restricted motion, ankylosis, or unstable joints).
●Measures of spinal mobility.
●Dactylitis.
●Tendonitis.
●Enthesitis.
●Skin disease.
●Functional ability (disability).
●Fatigue.
A module from the Outcome Measures in Rheumatology Clinical Trials (OMERACT) on PsA recommended the following "core set" of domains to be included in clinical trials and observational cohort studies in PsA: peripheral joint assessment, skin assessment, patient global assessment, pain, physical function, and quality of life. The following domains were considered important but not mandatory: dactylitis, enthesitis, nail assessment, spinal assessment, radiology, physician global assessment, and acute phase reactants [139].
Use of the following instruments has been proposed for supporting treat-to-target management in PsA [6,7]:
●MDA – An outcome that is particularly relevant to patients with PsA is a state of MDA, which is associated with reduced progression of damage both in an observational cohort and in drug trials [140-142]. MDA has been formally defined as follows: "A patient is classified as achieving MDA when meeting 5 of the 7 following criteria: tender joint count < or =1; swollen joint count < or =1; Psoriasis Area and Severity Index < or =1 or body surface area < or =3 percent; patient pain visual analogue score (VAS) < or =15; patient global disease activity VAS < or =20; health assessment questionnaire < or =0.5; tender entheseal points < or =1" [5,143]. Patients can be further classified as achieving very low disease activity (VLDA) when they meet all seven of the criteria. Further study is required to determine the utility of these definitions of MDA and VLDA as targets for treatment.
●DAPSA – Another composite index for PsA disease activity, which is limited to the assessment of peripheral arthritis, is the DAPSA [144-146]. This score is the sum of the swollen joint count of 66 joints, the tender joint count of 68 joints, the patient global assessment on a 10 cm VAS (in cm), pain score on a 10 cm VAS (in cm), and the CRP (mg/dL). Disease activity states are defined as follows: remission, ≤4; low disease activity, >4 and ≤14; moderate disease activity, >14 and ≤28; and high disease activity, >28 [144].
In addition to the MDA and DAPSA for PsA and those measures originally developed for the study of RA are additional PsA composite measures for disease activity and response to therapy that were developed more specifically for studying treatment responses in patients with PsA (eg, the Psoriatic Arthritis Response Criteria [PsARC]). A study analyzing the data from the first etanercept and infliximab randomized controlled trials demonstrated that all these indices function well in PsA. It was also shown that CRP did not function well in PsA. Although the DAS28 functioned well, a reduction of joint count to 28 would eliminate 25 percent of the patients included in the clinical trials [147].
A simplified composite measure for evaluating clinical trial outcomes, the Psoriatic Arthritis Joint Activity Index (PsAJAI), has been developed based upon the data from phase III randomized trials [148]. The PsAJAI rated responses based upon a weighted sum of 30 percent improvement in core measures with weights of 2 given to the joint count measure, the CRP laboratory measure, and the physician global assessment of disease activity measure, while 30 percent improvement in measures of pain, patient global assessment of disease activity, and the Health Assessment Questionnaire (HAQ) are given 1.
Another outcome measure to assess response in PsA in clinical trials, the Composite Psoriatic Disease Activity Index (CPDAI), was developed, based upon the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) treatment recommendation grid [100,149,150]. Numerical values were assigned to the different grades of the disease manifestations proposed by GRAPPA to up to a maximum score of 15.
The Psoriatic Arthritis Disease Activity Score (PASDAS) was developed through a GRAPPA study in which patients were followed for one year and changes in treatment were documented [146]. Based on a statistical model similar to that used for the development of the disease activity score for RA, a formula was established that includes tender and swollen joints, physician and patient global scores, enthesitis, dactylitis, and CRP. It requires computation, which can be done on computer. It provides both a state and a score, and levels of disease activity have been defined.
Plain film radiography, MRI, and ultrasonography may provide useful information for responding to treatment and for assessing the effect of therapy on preventing joint destruction or ankylosis. There are no validated indices based upon these imaging techniques that can be recommended. However, in randomized trials, the Sharp method for evaluating radiographs and the van der Heijde modification of that method have been used successfully [151].
ROLE OF SURGERY — There is a paucity of reports concerning the epidemiology and efficacy of surgery in patients with psoriatic arthritis (PsA). One study of 440 patients with PsA revealed that 31 (7 percent) had undergone musculoskeletal surgery [152]. The probability for surgery increased with disease duration. Compared with those not requiring an operative procedure, surgery patients had more active inflammation and radiological evidence of damage. However, quality of life was similar between the two groups.
Joint replacements have been performed when PsA leads to damage that limits movement and that impairs function [153]. A review of the types of procedures performed in a cohort of patients with PsA documented the following [154]:
●Patients with oligoarticular disease usually underwent hip or knee surgery
●Those with distal joint disease usually had hand surgery
●Patients with polyarticular disease underwent a variety of procedures
It is not clear whether PsA poses an additional risk, particularly for infection; the study reported only one infection in 71 procedures [154].
While initial results for total hip replacement in one survey were noted to be good, there appeared to be excess bone proliferation with a decrease in mobility [155]. We have also been disappointed with small joint arthroplasty in these patients, since they appear to fibrose around the prosthesis. In general, patients with PsA do not do as well as expected with post-reconstructive surgery [154].
RECOMMENDATIONS OF MAJOR ORGANIZATIONS — Our approach to treatment is generally consistent with recommendations from several major groups, although these vary somewhat depending in part upon the dates when several agents became available for use in clinical practice. These include:
●GRAPPA recommendations – These recommendations are from an international group of rheumatologists and dermatologists, the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA), which has made treatment recommendations in 2009, 2015, and 2021 for psoriasis and psoriatic arthritis (PsA) [19,27,100,156,157].
●EULAR treatment recommendations – The 2012 guidelines, with a 2015 update, from the European Alliance of Associations for Rheumatology (EULAR) are centered on five overarching principles, 10 specific recommendations, and a treatment algorithm (which was also updated in 2015) [18,26]. Specific treatment recommendations are outlined for peripheral arthritis, axial disease, dactylitis, and enthesitis, along with a consideration of comorbidities in the treatment approach.
●Canadian Rheumatology Association and Spondyloarthritis Research Consortium Canada – The Canadian Rheumatology Association, together with the Spondyloarthritis Research Consortium Canada (SPARCC), issued a revised set of treatment recommendations, which advocate for appropriate treatment depending on the patient's clinical history and physical findings [158,159]. These recommendations include all forms of spondyloarthritis, including PsA.
●International treat-to-target task force on axial and peripheral spondyloarthritis and psoriatic arthritis – An international task force has developed recommendations to treat-to-target in patients with PsA and both axial and peripheral SpA based upon systematic literature review and an expert consensus process [6]. These were updated in 2017 [7].
PROGNOSIS — Psoriatic arthritis (PsA) was once considered a mild disease for which clinicians were reluctant to use disease-modifying antirheumatic drugs (DMARDs); however, it has since become clear that the disease is more severe than previously described [160]. Two years after disease onset in an early disease cohort, 47 percent of patients had radiographic erosions in the hands and feet, and 56 percent were taking DMARDS. In another prospective cohort study of 100 PsA patients, the majority of patients showed progression in the number of joints involved, and 68 percent manifested radiographic progression at five years [73,161]. (See "Clinical manifestations and diagnosis of psoriatic arthritis".)
Patients appear to benefit from evaluation and treatment early in the disease by a rheumatologist [3,4]. One study involving 283 patients demonstrated that those who saw a rheumatologist within six months of onset of symptoms had better radiographic and functional outcomes compared with patients first seen by a rheumatologist at least six months after symptom onset [3]. Similarly, another study found that patients who presented to a clinic specializing in the care of PsA within two years of diagnosis had less progression of joint damage than those who presented more than two years after diagnosis [4].
Some clinical and genetic risk factors for disease progression have been identified. Such information can help to prospectively identify patients who will benefit from aggressive early treatment. Severe disease may adversely affect survival.
Risk factors for progressive joint damage — A systematic literature review and consensus process has identified the following factors predicting a poor prognosis with respect to progression of peripheral joint injury [100]:
●Increased numbers of actively inflamed joints
●Elevated erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP)
●Failure of previous medication trials
●The presence of joint damage (clinically or radiographically)
●Loss of function (by Health Assessment Questionnaire [HAQ])
●Diminished quality of life
Observations that support these findings above and that identify other prognostic factors include the following:
●Polyarticular rather than oligoarticular presentation, higher tender and swollen joint counts, a high number of joint effusions, and the damage present predict progression of clinical and radiologic damage [162-166]. Of 129 patients with PsA identified in an early arthritis clinic, the number of patients with at least one erosion in the hands or feet increased from 27 percent at baseline to 47 percent by the two-year follow-up [167].
●A high level of past medication use (particularly glucocorticoids) predicts progression of clinical damage [162,163].
●A low ESR generally indicates that the patient is at low risk for progression [165]. In addition, each mm/hour increase in the ESR is associated with a 2 percent increased risk of progression of both clinical and radiological damage [166].
●The importance of aggressive treatment of inflammatory joint disease is supported by the finding that inflammation in a particular joint predicts progression of damage in that joint [168].
●Human leukocyte antigen (HLA) typing provides important predictive information, but we do not perform such testing routinely in our practice. However, with further developments, HLA testing may have greater potential to provide clinically useful prognostic information. In univariate analysis, patients who are HLA-B27-, -B39-, or -DQw3-positive are at a higher risk for progression of clinical damage; these antigens are stronger prognostic factors than the clinical variables [169]. The presence of HLA-DR7 appears to be "protective," predicting less progression. The best multivariate model identified the HLA-B27, when -DR7 is present, and -DQw3, when -DR7 is not present, as predicting disease progression. HLA-B39 was associated with progression in early disease [169]. HLA-B22 is protective when all HLA antigens are added to the model [170].
●The presence of a variant of the interleukin (IL) 4 receptor gene is associated with greater severity of erosive disease in patients with PsA [171].
●The presence of antibodies to cyclic citrullinated peptides (anti-CCP) is associated with an increased prevalence of polyarthritis and of erosive joint disease in a cross-sectional study of patients with PsA [172]. In one study of 588 patients with PsA, anti-CCP antibodies were detected in 7 percent [173]. It is not known whether these antibodies are present in early disease and could help predict disease course or if they develop later in the illness.
Remission — Complete relief of joint tenderness and swelling may occur in a substantial minority of treated patients. As an example, among 391 patients, 69 (18 percent) achieved a remission, and nearly one-half remained free of active joint disease without continued use of medication [174]. Periods of remission lasted an average of approximately 2.5 years. However, the majority experienced at least one relapse, after a mean duration of remission of 2.6 years. Male sex, milder disease, and less disability at presentation were each associated with a greater likelihood of achieving a remission.
Morbidity and mortality — Patients with PsA may be at increased risk for cardiovascular disease and/or death.
●In one study, there was a significant increased risk of myocardial infarction, angina, and hypertension in those with PsA versus the general population [175]; the increased risk was associated with severe psoriasis as well as other conventional risk factors.
●Conflicting data exist concerning the association between PsA and increased mortality [176-178]. Survival appears to have improved since the late 1970s and early 1980s, possibly related to more effective therapeutic approaches [176]. A study of 453 patients with PsA in the United Kingdom entered in the database of a single center between 1985 and 2007 found no increase in mortality risk among this cohort compared with the general population of the United Kingdom [179].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Psoriatic arthritis in adults" and "Society guideline links: Spondyloarthritis".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Psoriatic arthritis in adults (The Basics)")
●Beyond the Basics topic (see "Patient education: Psoriatic arthritis (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Treatment of psoriatic arthritis (PsA) should be started early in disease and be coordinated between a rheumatologist, primary care clinician, and other specialists (eg, the dermatologist). Differences in response to individual therapies between the skin and joints, and between different musculoskeletal manifestations, are commonly observed. Treatment is guided initially by an assessment of disease severity, including the degree of disease activity, damage, and impact on the patient for each clinical domain. Attention to the most severely involved region, such as axial or peripheral arthritis, should help guide therapy. (See 'Management principles and pretreatment interventions' above.)
●A treat-to–target approach should be employed for peripheral and axial arthritis, with a target of remission/inactive disease or low/minimal disease activity. Patients should undergo pretreatment screening for comorbidities and baseline testing and appropriate vaccinations before drug administration. They should be referred as needed for prevention and medical management of comorbidities, such as cardiovascular and liver disease and related risk factors. (See 'Management principles and pretreatment interventions' above.)
●Nonpharmacologic management strategies are important in the treatment of PsA in addition to drug therapy; these include physical and occupational therapy, exercise, prescription of orthotics, and education regarding the disease and about joint protection, disease management, and proper use of medications. Patients should receive assistance in weight reduction and management of cardiovascular risk factors and other comorbidities. (See 'Nonpharmacologic treatment' above.)
●In patients with mild peripheral arthritis, defined as disease involving less than four joints, no radiological evidence of damage, and minimal discomfort or functional impairment, we suggest initiating treatment with a nonsteroidal antiinflammatory drug (NSAID; eg, naproxen 375 to 500 mg twice daily, or celecoxib 200 mg twice daily) rather than starting a disease-modifying antirheumatic drug (DMARD) (Grade 2C). NSAIDs can help to control the mild inflammatory symptoms of PsA and may also lessen pain and stiffness in associated spondylitis. A concern that NSAIDs may aggravate the skin psoriasis remains unproven. An alternative that may be effective and safer for some patients, particularly those with multiple comorbidities, is apremilast (30 mg twice daily). (See 'Mild arthritis/NSAIDs' above.)
●In patients whose peripheral arthritis remains active despite the use of NSAIDs or is moderate to severe without erosions or substantial functional limitations, and who lack axial symptoms or have such symptoms as are well-controlled with NSAIDs, we suggest a conventional (small molecule) DMARD, usually methotrexate (MTX; 15 to 25 mg once weekly) rather than a biologic agent (Grade 2C). Limited randomized trial data support the use of a conventional DMARD in PsA, but its use is supported by evidence of benefit in other forms of inflammatory polyarthritis, efficacy for psoriasis, expert opinion, and clinical experience in such patients. We initiate or continue NSAIDs as bridging or adjunctive therapy as needed in patients begun on DMARDs. (See 'Choice of nonbiologic DMARD and other agents' above and 'MTX use and efficacy' above.)
●Alternatives to MTX for the peripheral arthritis include leflunomide (LEF; 20 mg daily) and sulfasalazine (SSZ), which can be tried in patients unable to take either MTX or LEF. However, unlike MTX, which is also effective for psoriasis in some patients, LEF is less helpful than MTX for the skin disease. Another alternative to MTX is apremilast, which may be particularly useful for patients who wish to avoid DMARD therapy, infusions, or injections, although only a portion of patients respond. Apremilast should not be used in patients with erosive disease, as the capacity of apremilast to prevent joint injury has not been established or adequately examined in PsA or in other forms of inflammatory arthritis. (See 'Choice of nonbiologic DMARD and other agents' above and 'Leflunomide' above and 'Apremilast' above and 'Sulfasalazine' above.)
●In patients presenting with severe disease who already have erosive disease and functional limitation, we suggest a tumor necrosis factor (TNF) inhibitor as first-line therapy, rather than a conventional nonbiologic DMARD (Grade 2B). Another biologic DMARD (eg, secukinumab or ustekinumab) is an alternative to a TNF inhibitor in such patients. We prefer this approach because of the capacity of the TNF inhibitors and other biologic agents, demonstrated in multiple randomized trials and in contrast to MTX and the other conventional nonbiologic DMARDs, to limit joint damage and more rapidly restore function. (See 'Severe peripheral arthritis/adverse prognosis' above and 'Choice of TNF inhibitor' above and 'TNF inhibitor use and efficacy' above.)
●In patients whose joint counts do not improve substantially after three months of treatment with a conventional nonbiologic DMARD (eg, MTX), or who still have more than three tender and swollen joints, we recommend a TNF inhibitor rather than sequential trials of other conventional DMARDs (Grade 1B). The choice of the agent is based upon patient preferences for route (subcutaneous versus intravenous) and frequency of administration, regulatory and payor requirements and limitations, and potential cost to the patient. (See 'Resistant to nonbiologic DMARDs' above and 'Choice of TNF inhibitor' above and 'TNF inhibitor use and efficacy' above.)
●In patients with peripheral arthritis who experience an inadequate response to an initial TNF inhibitor, we use a second TNF inhibitor rather than trying a different class of biologic agent. We prefer to switch from one of the antibody-based agents (eg, infliximab, adalimumab, golimumab, or certolizumab) to the soluble TNF receptor (etanercept) and vice versa. (See 'Choice of agent' above.)
●In patients with peripheral arthritis who do not respond adequately to two different TNF inhibitors, we use an alternative biologic agent rather than another TNF inhibitor. We prefer secukinumab (administered by subcutaneous injection, usually with a loading dose of 150 mg given at weeks 0, 1, 2, 3, and 4, followed by 150 mg every four weeks; it may be increased to 300 mg every four weeks in patients who continue to have active arthritis). In patients without an adequate response to secukinumab, we use ustekinumab (by subcutaneous injection, 45 mg, given initially and four weeks later, then every 12 weeks, with a higher dose of 90 mg for patients with coexistent moderate-to-severe plaque psoriasis weighing greater than 100 kg [220 lbs] initially and four weeks later, followed by 90 mg every 12 weeks). Either of these agents may be given with or without MTX. Abatacept and guselkumab are other treatment options for patients in whom other drugs have failed or have contraindications. (See 'Choice of agent' above and 'Secukinumab' above and 'Ustekinumab' above.)
●In patients with mild symptoms of axial disease, which includes patients with inflammatory back pain that does not interfere with function, we suggest NSAIDs in antiinflammatory dose regimens (eg, naproxen 375 to 500 mg twice daily, indomethacin 100 to 150 mg daily in divided doses, celecoxib 200 mg twice daily), rather than a biologic agent (Grade 2B). (See 'Mild axial symptoms' above.)
●In patients with axial symptoms that do not respond adequately to treatment with NSAIDs, such as those with prolonged morning stiffness and severe pain, interfering with function, we recommend a TNF inhibitor rather than a traditional nonbiologic DMARD, as the latter have been shown to be ineffective in spondylitis (Grade 1B). The choice of agent and dosing are the same as those used for peripheral arthritis. (See 'Resistant to nonbiologic DMARDs' above and 'Choice of TNF inhibitor' above and 'TNF inhibitor use and efficacy' above.)
●In patients with axial symptoms that do not respond adequately to initial therapy with a TNF inhibitor, we use the same approach described for peripheral arthritis, switching to a second TNF inhibitor and, if that is inadequate, to an alternative biologic agent such as secukinumab or ustekinumab. (See 'Peripheral arthritis resistant to initial TNF inhibitor' above.)
●In patients with enthesitis or dactylitis, a response is often seen with medications used for other manifestations of PsA. In patients with enthesitis causing functional impairment who do not respond to NSAIDs and local therapy, we use a biologic agent, initially a TNF inhibitor. In patients with dactylitis who do not respond to NSAIDS, a response to a conventional DMARD (eg, MTX 15 to 25 mg once weekly) is sometimes seen, but if a conventional nonbiologic DMARD is inadequate patients should be treated with a biologic agent (eg, a TNF inhibitor). (See 'Enthesitis and dactylitis' above and 'Enthesitis' above and 'Dactylitis' above.)
●Use of oral glucocorticoids in patients with PsA should be avoided, and when required (eg, for severe flares), the dose should be the minimum needed, since their use is associated with an increased chance of developing erythroderma or pustular psoriasis; in addition, there appears to be interference with the effect of other drugs. It is important, however, to taper the glucocorticoids slowly and with close observation for the development of erythroderma or pustular psoriasis. Intraarticular glucocorticoids are sometimes used, and care should be taken in patients who require such injections to avoid injection through psoriatic plaques. (See 'Role of glucocorticoids' above.)
●PsA has variable disease expression; a significant proportion of patients may develop destructive and potentially disabling disease. Factors predicting a poor prognosis include a higher number of actively inflamed joints, an elevated erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP), failure of previous medication trials, the presence of joint damage, loss of function, and diminished quality of life. (See 'Prognosis' above.)
●Clinical monitoring of disease should include joint counts that assess both the upper and lower extremities, and the number of areas involved by enthesitis and by dactylitis. In clinical practice, plain film radiography of clinically involved peripheral joints, the sacroiliac joints, and the spine are used to assess the extent and progression of disease at these sites. (See 'Assessment for clinical care' above.)
