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Pharmacotherapy is the cornerstone of management of PsA. Drug therapy depends on the severity and stage of the arthritis and severity of skin disease. Patients should ideally be under the care of a team of health professional comprising rheumatologists, dermatologists, physiotherapists, and occupational therapists. However, if the primary problem is skin disease and the arthritis is mild, the subject may be managed by a dermatologist after a complete assessment by a rheumatologist. Periodic assessment by a rheumatologist in such cases would be ideal. On the other hand, if the primary problem is joint disease, the rheumatologist should primarily manage the patient, with the dermatologist confirming the diagnosis of psoriasis and providing input if skin disease remains poorly controlled.
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Drug therapy for psoriatic arthritis may be classified as in Box 19-3.
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Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
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NSAIDs are useful in the treatment of PsA and give relief to symptoms such as pain and stiffness. However, NSAIDs do not prevent disease progression, and may worsen skin lesions. They may be used as sole therapy in treating mild PsA and for symptomatic management of pain, inflammatory swelling and morning stiffness. With the recent reports of increased risk of myocardial infarction and stroke with long term use of COX-2 inhibitors, the use of nonselective NSAIDs like naproxen, ibuprofen, diclofenac, indomethacin, or aspirin (with or without misoprostol/H2-blockers/proton pump inhibitors) is preferable. If symptoms persist, or if more joints accrue after adequate trials with two different NSAIDs, Disease Modifying Antirheumatic Drug (DMARD) use should be considered.
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Corticosteroid therapy in the form of intra-articular injections of corticosteroids (triamcinolone, methylprednisolone) into the joints either at the bedside in the clinic or under ultrasound guidance is often used for rapid relief of symptoms when only one or a few joints are affected. This form of therapy has been proven effective in PsA.66 Oral corticosteroids are used occasionally for symptom relief when there is polyarthritis or when there is inadequate response to NSAIDs and there is significant disability. However, glucocorticosteroids need to be used with extreme caution with slow taper, since psoriasis worsens in many instances and could occasionally evolve into more severe forms like pustular psoriasis. Treatment with oral steroids is usually resorted to as short-term therapy, until other longer acting drugs take effect. Long-term steroid therapy is associated with significant toxicity such as high blood pressure, cataracts, weight gain, diabetes, osteoporosis, and avascular necrosis of bone.
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Disease Modifying Drug Therapy
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There is a paucity of clinical trials with traditional disease modifying agents (DMARDs) in PsA.67 A recently published systematic review and meta-analysis of efficacy and toxicity of DMARDs and biological agents for PsA showed that treatment was more effective than placebo (RR = 0.35; 95% CI 0.25, 0.49) but caused more toxicity (RR = 2.33; 95% CI 1.61, 3.37).67
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Although methotrexate is used most commonly to treat PsA, oral methotrexate (MTX) has been evaluated in only one RCT.68 This 12-week placebo-controlled trial of low-dose oral MTX given at a dose of 2.5–5.0 mg every 12 hours in three consecutive doses per week was terminated early after recruiting only 37 patients. MTX significantly improved physician global assessment, but there were no significant effects on tender and swollen joint scores, patient global assessment, and ESR. However, a retrospective analysis of PsA patients treated with MTX for 24 months therapy compared to a matched cohort not thus treated did not show any difference in radiographic progression scores in the two groups.69 A reappraisal from the same cohort showed that in the last decade treatment with MTX has changed to include patients with shorter disease duration and less damage, at increased dose, and that there may be better response with less progression of damage.70 In spite of lack of evidence from RCTs, based on efficacy in RA and psoriasis, rheumatologists have been using MTX as a first-line DMARD. Patients on MTX require regular monitoring of blood counts, liver function tests, and creatinine. Significant test abnormalities require adjustment of dose or treatment cessation. Although liver toxicity can occur in the absence of abnormal serum liver function tests, regular liver biopsies are not typically ordered by rheumatologists as they may be by dermatologists. The occurrence of liver fibrosis and cirrhosis seem to be higher in patients with psoriasis when compared to patients with RA, reflected in the differing guidelines in rheumatology and dermatology. There is increased prevalence of obesity, metabolic syndrome and type-2 diabetes in patients with psoriasis. Patients with psoriasis treated with MTX and having risk factors for liver disease, especially diabetes type 2 or obesity, are at higher risk of developing severe liver fibrosis compared to those without such risk factors, even when lower cumulative methotrexate doses are given.71 These risk factors are important for nonalcoholic steatohepatitis even when there is no exposure to MTX. Thus it is unclear whether weekly low-dose MTX independently increases risk for cirrhosis. In clinical practice, it will thus be prudent to get serial liver biopsies after a cumulative MTX dose of 1.5 g especially in those patients who have risk factors for fibrosis and cirrhosis such as obesity, metabolic syndrome, type 2 diabetes, viral hepatitis, and significant alcohol use.
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Five RCTs have evaluated sulfasalazine (SSZ) in the treatment of PsA; its benefits were moderate.67 In the largest of these, 221 PsA patients were treated with SSZ, 2 g/day, for 36 weeks.72 The psoriatic arthritis response criteria (PsARC) developed specifically for this study showed statistically significant improvement in the treatment group (57.8% for SSZ compared with 44.6% for placebo, P = 0.05). But, the only individual measure within the responder index to do so was the patient global assessment, and longitudinal analysis revealed only a trend favoring SSZ treatment. A systematic review revealed that the effect size for SSZ was less than 0.2, the level required to confirm response.73 SSZ has not been shown to prevent progression of joint damage.74
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The efficacy of
leflunomide is similar to sulfasalazine.
75 In this study on 188 PsA patients, the PsARC response was met by 59% of leflunomide-treated patients compared with 29.7% of placebo-treated patients (
P < 0.0001). ACR 20 response was achieved by 36.3% and 20%, respectively (
P = 0.0138). PASI 75 response was seen in 17.4% and 7.8%, respectively (
P = 0.048). Unfortunately, radiographs were not included in the study; therefore, the effect of
leflunomide on progression of joint damage has not been studied. Liver toxicity is the major side effect; therefore, liver function tests need to be monitored.
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Cyclosporine A (CsA) is effective in controlling psoriasis. A three-arm RCT comparing CsA 3 mg/kg/day added to standard therapy, SSZ 2 g/day added to standard therapy, and standard therapy alone, showed that CsA was well tolerated and was more efficacious that standard therapy and SSZ.76 In the most recently published RCT, CsA was compared to placebo as an add-on treatment, in patients with PsA demonstrating an incomplete response to MTX monotherapy. There was significant improvement at 12 months in the swollen joint count, C-reactive protein, PASI, and synovitis detected by high-resolution ultrasound. There was no improvement in the Health Assessment Questionnaire or pain scores.77 Thus, CsA has a role in the management of PsA either on its own or as an add-on treatment to MTX. However, it is not well tolerated. Its effect on joint damage has not been assessed.
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Although not shown to protect from progression of joint damage, Gold has been used in the treatment of PsA, with intramuscular gold being more efficacious.78 With significant concern about toxicity, slow mode of action, problems with availability, and availability of more effective drugs, it is seldom used nowadays.
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Apremilast is a new potent, orally active phosphodiesterase 4 (PDE4) and TNF-α inhibitor, and suppresses multiple proinflammatory mediators and cytokines.
79 A phase 2 RCT with
Apremilast in 204 subjects randomized to
Apremilast 20 mg BID,
Apremilast 40 mg QD, or placebo showed ACR 20 response in 43.5%, 35.8%, and 11.8%, respectively at 12 weeks.
80 The common adverse events are nausea, diarrhea, headache, nasopharyngitis, and fatigue. Larger trials are needed to characterize the optimum dose, efficacy, and safety of
Apremilast for treatment of PsA.
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(See also Chapter 234.) Anti-TNF agents have revolutionized the management of PsA. There are currently four agents marketed for the treatment of PsA. In the placebo-controlled portion of the phase 3 Etanercept trial in PsA (n = 205), ACR 20 response was achieved by 59% of Etanercept treated patients versus 15% in the placebo group (P < 0.0001).81 Skin response, as measured by the PASI score in patients with body surface area (BSA) involvement at least 3% showed a 75% improvement in 23% and 3%, respectively at 24 weeks (P = 0.001). Measures of function and quality of life significantly improved. Significant inhibition of progression of joint space narrowing and erosions was shown. In the open label extension of this study, at 2 years, effectiveness was maintained. The drug was well tolerated. A more recent trial compared Etanercept 50 mg twice weekly for 12 weeks, followed by 50 mg weekly, compared with 50 mg weekly throughout in 752 patients with psoriasis affecting >10% of body surface area and at least two swollen and tender joints.82 There was no difference in the response to arthritis at week 12 or 24, although the skin response was better at week 12. No difference in skin response was evident at week 24. Dactylitis and enthesitis also showed improvement from baseline.
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In the IMPACT II phase 3 study, Infliximab in 200 PsA patients showed significant benefit. At week 14, 58% of Infliximab-treated patients and 11% of placebo patients achieved an ACR 20 response (P < 0.001). Presence of dactylitis and enthesitis decreased significantly in the Infliximab group. At 24 weeks, PASI 75 was achieved by 64% of the evaluable treatment group and 2% of the placebo group (P < 0.001).83 Infliximab also significantly inhibits radiographic progression, and improves function and quality of life.83,84
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In the phase 3 Adalimumab Effectiveness in Psoriatic Arthritis Trial (ADEPT), 313 subjects were studied.85 At 12 weeks, 58% of patients receiving Adalimumab 40 mg every other week achieved ACR 20 response compared with 14% of patients receiving placebo (P < 0.001). PASI 75 was achieved by 59% in the Adalimumab-treated group and 1% in the placebo group (P < 0.001) in those 69 patients in each group who were evaluable for PASI scoring. Radiographic progression of disease was significantly inhibited, and there was improvement in disability and quality of life scores.85
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The latest anti-TNF agent to be approved for PsA is Golimumab. In the GO-REVEAL trial, 405 patients active PsA were randomly assigned to receive subcutaneous injections of placebo (Golimumab 50 mg or Golimumab 100 mg every 4 weeks.86 At week 14, 51% of patients receiving Golimumab 50 mg and 45% of patients receiving Golimumab 100 mg achieved an ACR 20 response, compared with 9% of patients receiving placebo (P < 0.001 for all comparisons). Among the 74% of patients in whom at least 3% of the body surface area was affected by psoriasis at baseline, 40% of those in the Golimumab 50 mg group and 58% of those in the Golimumab 100 mg group had at least 75% improvement in the PASI at week 14, compared with 3% of placebo-treated patients (P < 0.001 for both doses). Improvement was also demonstrated in the HAQ score, SF-36, NAPSI, and enthesitis. There was no difference in the arthritis outcomes between the two doses of Golimumab and it is marked only for PsA at a monthly dose of 50 mg. Significant improvement in dactylitis was seen only in the 100 mg dose, although a trend was evident with the 50 mg dose.86 Golimumab was also shown to inhibit progression of radiographic damage.87
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Thus, the anti-TNF agents have shown the greatest efficacy of any treatment to date in the various clinical aspects of PsA. Their efficacy in joint disease activity, inhibition of structural damage, function, and quality of life are similar, and they are well tolerated, with injection site reactions being the most significant. On comparing with traditional DMARDs, anti-TNF agents had the best efficacy/toxicity ratio (number needed to harm/number needed to treat = 0.25); tolerability was least with gold and leflunomide, and poor with SSZ.67 There are no direct head-to-head trials comparing the efficacy of various anti-TNF agents in PsA. However, a meta-analysis of anti-TNF RCTs showed that the three anti-TNF agents [(1) Infliximab, (2) Etanercept, and (3) Adalimumab] were significantly more effective than placebo.88 There were no significant differences between anti-TNF agents and placebo in the proportions of patients experiencing withdrawal for any reason, due to adverse events, serious adverse or upper respiratory tract infections. Pooled rates for injection site reactions were significantly higher for Adalimumab and Etanercept than for placebo, but there was no significant difference in the proportion of patients experiencing infusion reactions with Infliximab compared against placebo. Indirect analysis did not demonstrate any significant differences between the anti-TNF agents.88
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Data from biologics registries that have been maintained in Europe suggest that drug survival (the length of time a patient continues to take a particular drug) of anti-TNF agents is significantly higher in SpA compared to RA.89,90 Concomitant MTX was associated with better drug survival in RA and PsA, but not for AS.90,91 There is a tendency toward shorter persistence with treatment for Infliximab when compared with Etanercept and Adalimumab.91,92 Risk factors for drug discontinuation include female sex, comorbidity, using Infliximab rather than Etanercept, and absence of concomitant therapy with MTX.91,92
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(See also Chapter 234.) Ustekinumab is a human monoclonal antibody that inhibits receptor binding of IL-12 and IL-23 has been shown to be very efficacious in treating psoriasis and is marketed for this indication.93 A phase 2 trial in 146 subjects with PsA showed that at week 12, 42% of patients in active arm and 14% in the placebo arm achieved an ACR 20 response (p = 0.0002).94 Of 124 participants with psoriasis affecting 3% or more body surface area, 52% in the active arm and three of 5% in the placebo arm had a PASI 75 response (p < 0.0001). The drug was well tolerated.94 A larger phase 3 trial is underway.
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(See also Chapter 234.) Alefacept is a fully human lymphocyte function associated antigen-3/immunoglobulin G1 fusion protein that targets memory-effector T cells is an effective therapy for psoriasis.95 In combination with MTX, Alefacept is efficacious in PsA. In a phase 3 trial with 185 patients, 54% of patients in the Alefacept plus MTX group achieved an ACR 20 response, compared with 23% of patients in the placebo plus MTX group (P ≤ 0.001) at week 24.96 In patients with psoriasis involving ≥3% BSA (n = 87), a PASI 50 response at week 14 was achieved by 53% of patients receiving Alefacept plus MTX compared with 17% of those receiving placebo plus MTX (P < 0.001).96 Alefacept in combination with MTX is thus a treatment option in patients failing standard therapy.
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Abatacept (CTLA4-Ig) is a recombinant human fusion protein that binds to the CD80/86 receptor on an antigen-presenting cell, thus blocking the second signal activation of the CD28 receptor on the T-cell. It is approved for use in RA.97 Results from a phase 2 study using Abatacept in PsA show that Abatacept at 10 mg/kg significantly improved ACR 20 and physical function in PsA patients. Abatacept treatment also resulted in less joint damage by MRI evaluation.98
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There are few studies addressing surgery in patients with PsA. It has been reported that about 7% of the patients with PsA require surgery and that the likelihood of surgery increased with disease duration.99 The average disease duration at the time of surgery was 13 years. The most common surgical procedure was total hip replacement followed by total knee replacement. Joint replacement in the metacarpophalangeal joints was also performed, followed by fusion surgery for the fingers, wrists, and ankles. Few patients had synovectomies, including knee, wrist, and elbow. The majority of the patients had only one procedure, but in 28% several procedure were performed. The upper and lower extremities were involved in a similar number of patients with few patients having both upper and lower extremity surgery. Surgery was predicted by the number of actively inflamed joints and the extent of X-ray damage at presentation to the clinic. Patients with the highest number of severely affected joints both clinically and on radiographs were more likely to have surgery. Although patients who had surgery had more severe disease, their health outcomes were not worse than those who did not have surgery.99 In another study of the type and outcome of reconstructive surgery for different patterns of psoriatic arthritis over a 10-year period was studied.100 The patients were divided into three groups: (1) distal joint involvement, (2) oligoarticular, and (3) polyarticular. It was shown that the majority of patients had polyarticular disease. The majority of the operations done in this group of patients included complex hand and foot reconstruction, followed by hip replacements, and surgical fusion of different joints. In the oligoarticular group most of the procedures involved joint replacement, usually the hip or knee. Patients with distal arthritis had fusions in the distal joints. Patients with polyarticular disease had lower level of physical functioning according to the scores on the physical function domain of a quality of life questionnaire. Patients with severe axial arthritis may develop marked deformity of the spine and on occasion require surgery to correct this deformity. While there are no reported studies specifically describing spinal surgery in patients with PsA, the procedures are similar to those performed in patients with AS.
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Recommendations from GRAPPA
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Based on formal literature reviews of therapies for peripheral joints, spine, skin and nails, enthesitis, and dactylitis, the GRAPPA group has developed a treatment grid categorizing each domain as mild, moderate, or severe based on measures of disease severity and impact on function and quality of life in order to help clinicians with treatment decisions.101 GRAPPA recommends that all domains of the disease be considered to define severity of “psoriatic disease.” The worst individual domain should guide the management of all domains of PsA. Thus, if the skin domain is severe, but the peripheral arthritis is mild, the patient is classified as heaving severe disease and treated for severe psoriasis as appropriate. GRAPPA has also suggested treatment strategies applicable to patients worldwide.