The presentation of R.T. is representative of asymmetric oligoarthritis.

Traditionally, treatment of this form of PsA consists of an NSAID, local

corticosteroid injections, and immunosuppressive agents, including TNF inhibitors.

Despite scant clinical evidence of efficacy, NSAIDs are commonly used to suppress

the musculoskeletal symptoms of PsA, but do not induce remissions.

89 Systemic

corticosteroids are avoided because they destabilize psoriasis (transformation to

pustular forms), induce resistance to other effective therapies, and re-exacerbate the

skin disease during withdrawal.

91 PUVA and acitretin have negligible anti-arthritic

efficacy.

Methotrexate

Methotrexate is one of the most common agents used to produce symptomatic benefits

(approximately 30%) in patients with PsA, but data on its efficacy to inhibit articular

damage are limited.

91,92 TNF-α inhibitors have also been demonstrated to slow down

or halt radiographic progression.

93 For mild joint disease, NSAIDs and intraarticular glucocorticoid injections may be adequate, whereas moderate-to-severe

joint disease optimally will be treated with systemic oral disease-modifying

antirheumatic drugs or biologics.After a sufficient trial of an NSAID, initiation of a

second-line agent such as methotrexate before progression to a biologic intervention

is a reasonable approach to manage R.T.’s arthralgias in his shoulders, knees, and

hands, as well as his active skin disease.

After obtaining the history and physical examination, baseline laboratory tests

should be obtained, which include a complete blood count, platelets, renal function

tests (serum creatinine, BUN), liver function tests (LFTs: alanine aminotransferase,

aspartate aminotransferase, alkaline phosphatase, and bilirubin), HIV antibody

determination, and a purified protein derivative (PPD). Although standard in the past

for all patients about to receive methotrexate therapy, a baseline aspiration needle

biopsy of the liver, not an innocuous procedure, is obtained currently only in those

patients with preexisting severe liver disease.

77 Patients with one or more risk

factors for hepatic fibrosis (e.g., persistent abnormal liver chemistries, previous

exposure to hepatotoxic agents, obesity, hyperlipidemia, diabetes mellitus, and

family history of inheritable liver disease) should receive a baseline liver biopsy and

a biopsy every 2 to 6 months until the drug’s efficacy and a lack of toxicity have been

established. A repeat liver biopsy after 1.0 to 1.5 g of methotrexate has been

received is appropriate because it is rare for life-threatening liver disease to develop

at this lower cumulative dose.

94

Therapy with methotrexate usually is initiated with a 2.5- to 5-mg test dose.

77

If no

idiosyncratic reaction occurs, doses are gradually increased to a maintenance dose of

10 to 25 mg/week. Methotrexate is best given in a single weekly oral dose or in three

2.5- to 7.5-mg doses at 12-hour intervals during a 24-hour period (e.g., 8 AM, 8 PM,

and again at 8 AM). With the introduction of biologic agents in the management of

psoriasis and its associated conditions, an increased level of monitoring has

developed. Hepatotoxicity, however, may not be apparent on routine laboratory

evaluation. Every 4 to 12 weeks, LFTs should be obtained, preferably at least 1

week after the last methotrexate dose because these values are often elevated 1 to 2

days after therapy. If a significant abnormality in the LFTs is noted, therapy should be

withheld for 1 to 2 weeks, and the LFT testing should be repeated. LFT values should

return to normal in 1 to 2 weeks. If significantly abnormal LFTs persist for 2 to 3

months, a liver biopsy should be considered. As noted previously, a liver biopsy is

recommended when the cumulative dosage level reaches 1.0 to 1.5 g, as well as after

each subsequent 1.5-g increase in the cumulative dose. Liver function abnormalities

may improve after cessation of methotrexate therapy for 6 months.

Immunomodulatory Therapy

CASE 41-3, QUESTION 2: During a follow-up visit to his family physician several months later, R.T. had

several somatic complaints that led to a diagnosis of recurrent depression. Subsequent history reveals that he

also has resumed use of alcohol. He tends to drink four to five beers a night on weekends or when he is feeling

low, although he does admit that his level of alcohol use is sometimes higher. His skin lesions are relatively well

controlled, but joint complaints have persisted. What additional options now exist for R.T.?

Methotrexate should be discontinued because the risks probably now exceed the

benefits, particularly because rheumatic complaints have not been controlled and

alcohol consumption has resumed. Agents such as methotrexate and cyclosporine may

reduce inflammatory joint activity in the short term, but evidence of their ability to

modify the long-term disease process remains elusive. Close monitoring of the

effects of these agents is also required because the toxicities often limit long-term

use. R.T. should be referred for physical and occupational therapy, encouraged to

exercise regularly, and, if needed, referred for orthotics. An NSAID can be given for

symptomatic relief. Sulfasalazine and hydroxychloroquine might be beneficial for

mild joint symptoms alone, but the cutaneous manifestations may be controlled with

topical agents. Other alternative second-line agents include immunomodulatory

agents, anticytokines, TNF-α inhibitors, infliximab, and etanercept. In the case of

R.T., it is clear that better therapies for PsA are necessary.

Immunomodulatory Agents

With advances in biotechnology immunomodulatory therapy, important treatment

alternatives are becoming available for moderate-to-severe plaque psoriasis and

PsA that is resistant to other systemic therapies. These agents are thought to target the

immune-mediated and elevated levels of TNF found in psoriasis.

MONOCLONAL ANTIBODIES AND TNF-α INHIBITORS: INFLIXIMAB,

ETANERCEPT, ADALIMUMAB, GOLIMUMAB, USTEKINUMAB,

SECUKINUMAB, and IXEKIZUMAB

As a potent cytokine, TNF-α is involved in inflammation and joint damage. Inhibition

of TNF-α reduces direct actions as well as the action of other proinflammatory

cytokines. The TNF-α inhibitors,

p. 842

p. 843

infliximab, etanercept, and adalimumab, are FDA approved for the treatment of both

plaque and PsA. Golimumab is approved only for PsA. Ustekinumab is approved for

both psoriasis and PsA, whereas secukinumab is currently approved only for plaque

psoriasis. The mechanism of action of these agents is through blocking the interaction

of TNF-α with cell-surface TNF receptors.

95 Ustekinumab is a specific inhibitor of

interleukin-12 (IL-12) and anti-interleukin-23 (IL-23).

95 Secukinumab and

ixekizumab inhibit interleukin-17A. Dosing is either subcutaneous injection or

intravenous infusion (infliximab), on a biweekly, weekly, every other week, or

monthly schedule during the initiation phase.

In a 24-week trial to assess the efficacy and safety of etanercept 50 mg

administered once weekly in patients with moderate-to-severe plaque psoriasis, at

week 12, 37.5% of patients achieved a PASI 75 response, with 71.1% achieving

PASI 75 at week 24. No deaths, serious infections, opportunistic infections,

demyelinating disorders, or malignancies were reported.

96 Antibody production has

been reported in up to 18% of patients; however, they do not impact the efficacy of

etanercept.

97

Infliximab is a human/mouse chimeric anti-TNF-α antibody. One hundred eightysix patients were given infliximab for moderate-to-severe plaque and nail psoriasis

for 46 weeks. A PASI of 75 was demonstrated in 74.6% of patients, and a PASI of

90 was demonstrated in 54.1% at week 50.

98

In spite of clinically significant

improvements, induction of antinuclear antibodies and anti–double-stranded DNA

antibodies is frequently observed in patients receiving infliximab. To investigate the

development of autoimmunity in patients receiving infliximab for severe, recalcitrant

forms of psoriasis, 28 patients with psoriasis refractory to three or more systemic

treatments were given infliximab 5 mg/kg for 22 weeks.

99 Detection of antinuclear

antibodies and of IgM and IgG anti–double-stranded DNA antibodies was performed

at baseline and at week 22. The prevalence of positive detection of antinuclear

antibodies increased from 12% at baseline to 72% at week 22 and was also

observed for IgM anti–double-stranded DNA antibodies. Three patients exhibited

nonerosive polyarthritis, without any other criteria for systemic lupus. This study

suggests that the incidence of biologic autoimmunity is high in patients with

refractory psoriasis receiving infliximab.

99

In a 52-week trial to assess the efficacy and safety of adalimumab 80 mg load

followed by 40 mg administered every other week in patients with psoriasis, at week

16, 71% achieved an improved PASI score. Only 5% of patients continued on

adalimumab until week 52 lost response to adalimumab.

100 Antibody formation for

adalimumab, a human monoclonal antibody, occurs in up to 50% of patients, which

may reduce the efficacy of this medication.

97

In phase 3 trials, ixekizumab was superior to etanercept for mild-to-moderate

psoriasis. By 12 weeks of ixekizumab dosed every other week, 90% of patients

achieved a PASI of 75% versus 48% with etanercept. The most common adverse

reactions were infection (26%) and injection site reactions (10%).

101

Pharmacotherapy with TNF-α inhibitors has the best ratio of number-needed-totreat-to-benefit (NNTB) to number-needed-to-harm (NNTH) of all disease-modifying

antirheumatic drugs (DMARDs) in psoriatic arthritis, and is able to induce clinical

remission in at least 30% of patients. Of interest, however, is that in many of these

clinical studies, the NNTB presented comparisons with placebo. Many studies of

TNF-α inhibitor therapies have allowed inclusion of patients who had not received

other systemic therapies beyond topical therapies alone.

102 When interpreting the

NNTB for TNF-α inhibitors, it is important to compare them with the NNTB for

other systemic therapies. Also, having a comparable outcome measure (e.g., PASI

75) is necessary, especially because most established treatments have not been

compared with placebo.

103 To determine which TNF-α inhibitor to use in a patient,

consider the results from three meta-analyses. Infliximab was most likely to achieve

a PASI of 75. Also, ustekinumab and adalimumab achieve significantly higher PASI

75 scores than etanercept. It is important to note this evaluation was based on 16

weeks of therapy.

104–106

For a patient like R.T., whose disease cannot be treated successfully or safely with

methotrexate, proceeding with a TNF-α inhibitor remains an option. These agents

produce rapid, well-tolerated, beneficial responses compared with placebo. Benefit

is seen anywhere from 2 to 12 weeks, with a PASI 75 being obtained in at least 80%

of patients after 10 weeks of infliximab, at least 50% after 12 weeks of etanercept,

and at least 50% after 48 weeks of adalimumab treatment.

107,108 R.T. does not have

any contraindications to therapy, such as active infection or New York Heart

Association (NYHA) class III or IV heart failure. If available, etanercept (25–50 mg

subcutaneously twice weekly [3 or 4 days apart] for the first 3 months, followed by

50 mg once a week) may be preferred for convenience; however, in a recent

comparative trial of ustekinumab (administered at weeks 0 and 4) and etanercept

(administered twice weekly for 12 weeks), ustekinumab patients experienced a

superior improvement in PASI 75 scores.

109

Screening for tuberculosis before beginning therapy with anti-TNF agents is

prudent, and those with evidence of prior tuberculous chest infection or with a

positive skin test for tuberculosis should be offered prophylactic antitubercular

therapy.

Phosphodiesterase 4 (PDE4) Inhibitors

Apremilast was recently approved by the FDA for the treatment of active PsA

because clinical trials demonstrated moderate efficacy in the reduction of symptoms

of PsA, including tender and swollen joints. Results from both phase II and phase III

clinical trials demonstrated improvement in symptoms, quality of life, and pain in

patients randomized to apremilast compared with placebo.

110 Of the patients enrolled

in the phase III clinical studies, over half received concomitant therapy with

DMARDS (e.g., methotrexate) and 10% to 15% had failed therapy with TNF-α

inhibitors.

111

Dosing is similar to that of plaque psoriasis, a titration up to 30 mg twice daily.

The most common adverse effects reported in the clinical trials were gastrointestinal

(i.e., diarrhea, nausea), fatigue, headache, and nasopharyngitis. The gastrointestinal

adverse events were transient in nature and often occurred early on in therapy.

85

Combination Therapy

The National Psoriasis Foundation recommendations for combination treatments

include methotrexate and a TNF-α inhibitor (etanercept or infliximab), acitretin and

infliximab, then a TNF-α inhibitor (etanercept or adalimumab) and phototherapy.

112

There is no evidence as yet to support using two biologics or a biologic with

cyclosporine.

112

KEY REFERENCES AND WEBSITES

A full list of references for this chapter can be found at

http://thepoint.lww.com/AT11e. Below are the key references and websites for this

chapter, with the corresponding reference number in this chapter found in parentheses

after the reference.

Key References

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878. (49)

p. 843

p. 844

Armstrong AW et al. Combining biologic therapies with other systemic treatments in psoriasis. JAMA Dermatol.

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biologic therapies in the treatment of psoriasis and psoriatic arthritis. Curr Med Chem. 2015;22:1930–1942. (60)

Gladman DD et al. Psoriatic arthritis: epidemiology, clinical features, course, and outcome. Ann Rheum Dis.

2005;64(Suppl 2):ii–14. (18)

Jabbar-Lopez ZK, Reynolds NJ. Newer agents for psoriasis in adults. BMJ. 2014;349:g4026. (61)

Menter A et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 5. Guidelines of

care for the treatment of psoriasis with phototherapy and photochemotherapy. J Am Acad Dermatol.

2010;62:114. (57)

Naldi L. Scoring and monitoring the severity of psoriasis. What is the preferred method? What is the ideal method?

Is PASI passé? Facts and controversies. Clin Dermatol. 2010;28:67. (26)

Pariser DM et al. National Psoriasis Foundation clinical consensus on disease severity. Arch Dermatol.

2007;143:239. (28)

Key Websites

American Academy of Dermatology Current Psoriasis Guidelines. https://www.aad.org/education/clinicalguidelines.

American Academy of Dermatology Current Psoriasis Pharmacotherapy Reviews.

https://www.aad.org/dermatology-a-to-z/diseases-and-treatments/mp/psoriasis.

Arthritis Foundation (psoriatic arthritis). http://www.arthritis.org/about-arthritis/types/psoriatic-arthritis/.

National Psoriasis Foundation. http://www.psoriasis.org.

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