Key points

Psoriasis is a chronic, immunodysregulatory disease with significant prevalence and a range of severity in its dermatologic and rheumatologic signs and symptoms. Topical agents remain the first-line treatments for mild disease. For patients with greater percent body surface area (BSA) of involvement, or with disease that has significant quality of life impact, systemic therapy or phototherapy is indicated. Strong evidence indicates that psoriasis is an independent risk factor for cardiovascular risk and that the inflammatory comorbidities of psoriasis merit systemic therapy even in the absence of joint disease, though prospective data to assess whether there is a morbidity or mortality benefit to doing so are in their infancy.

Systemic medication for psoriasis can be broadly divided into small molecules, which are usually given orally, and biologics, which are large molecules that must be delivered by injection or infusion. Systemic medications are often used as monotherapy but, in many, instances are combined or used with phototherapy to increase or maintain efficacy; decrease undesired effects; or, out of necessity, for refractory disease. In some cases oral systemics are given in combination with biologics for synergistic effects or to forestall the development of biologic immunogenicity.

The small molecules used in therapy for psoriasis include mature drugs, such as methotrexate, cyclosporine, and acitretin, as well as newer compounds discovered through targeted development and understanding of molecular pathways, such as tofacitinib and apremilast. This article focuses on the, small molecule systemic therapies with clinical data supporting their efficacy.

Patient assessment

A thorough medical history, prior treatment history and focused physical examination should be the starting point from which systemic therapy for psoriasis is considered, with a review of systems that covers the cutaneous, immune, hematologic, cardiac, gastrointestinal, musculoskeletal, neurologic, reproductive, and family and social history. Concerns of the patient regarding mode of administration and risk aversion need to be considered ( Table 1 ). This evaluation should include laboratory investigations, and it is prudent to include baseline studies necessary for the whole spectrum of possible systemic treatments. A suggested list of these tests is included in Table 2 . A complete picture of the patient’s disease severity, impact on their quality of life, overall health and comorbidities, and their willingness to attempt available treatment should coalesce, and a patient-centered, mutually agreeable therapeutic approach enacted. The nonbiologic, nonphototherapy options for modern systemic treatment of psoriasis are as follows.

Patient assessment

A thorough medical history, prior treatment history and focused physical examination should be the starting point from which systemic therapy for psoriasis is considered, with a review of systems that covers the cutaneous, immune, hematologic, cardiac, gastrointestinal, musculoskeletal, neurologic, reproductive, and family and social history. Concerns of the patient regarding mode of administration and risk aversion need to be considered ( Table 1 ). This evaluation should include laboratory investigations, and it is prudent to include baseline studies necessary for the whole spectrum of possible systemic treatments. A suggested list of these tests is included in Table 2 . A complete picture of the patient’s disease severity, impact on their quality of life, overall health and comorbidities, and their willingness to attempt available treatment should coalesce, and a patient-centered, mutually agreeable therapeutic approach enacted. The nonbiologic, nonphototherapy options for modern systemic treatment of psoriasis are as follows.

Methotrexate

Methotrexate is the oldest systemic therapy for moderate to severe psoriasis having been approved over 40 years ago. Its anti-inflammatory effects are primarily mediated through its metabolism to polyglutamate derivatives that are potent inhibitors of 5-aminoimidazole-4-carboxamide ribonucleotide transformylase. In so doing, methotrexate increases the endogenous levels of adenosine, a potent anti-inflammatory compound. Methotrexate also has been shown to decrease primary and secondary antibody responses. Generally, it is available in 2.5 mg tablets and is typically prescribed at 7.5 to 25 mg, taken once weekly; higher doses produce better response. Older dosing schemes were split between 3 administrations, every 12 hours, but this is unnecessary from an efficacy or side-effect standpoint. Additionally, subcutaneous methotrexate dosed once weekly has displayed better bioavailability, efficacy, and tolerability relative to the oral formulation in studies of patients with rheumatoid arthritis. Daily or weekly folic or folinic acid supplements are recommended to decrease side effects (particularly bone marrow suppression) and improve gastrointestinal tolerability.

Because methotrexate use for psoriasis predates the modern drug approval process, there have been, until the last decade, a lack of robust clinical data regarding its efficacy. This, however, is no longer the case. A multicenter, prospective, randomized, double-blind, placebo-controlled study involved 110 subjects receiving methotrexate doses from 7.5 to 25 mg/wk (plus folate 5 mg 2 days after the methotrexate dose). At 16 weeks, using the Psoriasis Area and Severity Index (PASI), 35.5% of subjects achieved a 75% reduction in PASI (PASI 75). A similar response rate, PASI 75 of 39.9% at 24 weeks, was seen in a comparison study of methotrexate and briakinumab. These results parallel the largest single study involving methotrexate, in which 41.9% of the 215 subjects taking methotrexate (in an open-label, nonblinded manner) achieved PASI 75 at 16 weeks. Although these PASI 75 response rates are somewhat lower than reported in other clinical trials, they represent the best quality data, and a reasonable expectation of oral methotrexate efficacy is that approximately 40% will achieve PASI 75. The advent of pharmacogenomics and identification of gene polymorphisms conferring a better response to methotrexate may facilitate patient screening and increase the percentage achieving optimal control, once such testing becomes more readily available.

The most common clinical side effects of methotrexate at the low doses used for psoriasis are nausea, diarrhea, fatigue, and headache. Supplementation with folic and/or folinic acid may either mitigate or eliminate these adverse effects, which tend to become less severe with time. Monitoring for rarer and more severe side effects is an integral part of every follow-up appointment. Liver function tests (LFTs) should be checked every 4 to 12 weeks because the first signs of hepatotoxicity may manifest as an elevation in transaminases. For long-term monitoring of hepatotoxicity, the general movement has been away from routine liver biopsy and toward noninvasive measurement of classic and newly validated serum biomarkers, such as type III procollagen amino terminal propeptide, which is currently standard in most European countries. In some jurisdictions, liver biopsy may be recommended before methotrexate initiation in patients with hepatic disease risk factors, and by American Academy of Dermatology (AAD) guidelines once a cumulative dose of 3.5 to 4 g is reached. Particular vigilance to hepatic monitoring is necessary because psoriasis has been identified as an independent risk factor for nonalcoholic fatty liver disease and the comorbidities often found in psoriatic patients can place them at higher risk of methotrexate-induced hepatic injury.

A complete blood count is necessary to warn of myelosuppression, whereas adequate kidney function must be verified because most methotrexate is renally excreted. Dose adjustments can be made for decreased glomerular filtration rate, but this should be done with care because these patients are at increased risk of cytopenia. Screening for any changes in pulmonary status, including breathing difficulty or persistent cough, is a requirement because of the rare side-effect of idiosyncratic pneumonitis or pulmonary fibrosis. Other adverse effects include alopecia (higher or, inadvertently, daily doses), mouth ulcers (particularly in the setting of neutropenia), and (rarely) radiation recall and/or acral erythema. In patients with rheumatoid arthritis, an increased frequency of melanoma, non-Hodgkin lymphoma and lung cancer has been reported ; however, these findings have not been well-substantiated.

Methotrexate has numerous potential interactions with other drugs. Care should be taken with concurrent salicylates, regular use and overuse of nonsteroidal anti-inflammatory drugs, and certain types of antibiotic use (particularly sulfonamides), and it is recommended to check a current interaction database before initiating new therapy.

Methotrexate is pregnancy category X; pregnancy and lactation are absolute contraindications. Individual accounts of accidental in utero exposure without any observed sequelae exist, but all patients (male and female) should discontinue methotrexate 3 months before any planned attempts at pregnancy, and those pregnancies conceived while on methotrexate should be considered high-risk until proven otherwise.

Methotrexate often is combined with other systemic therapies or phototherapy to achieve either additive or synergistic effects. Combination allows lower doses; minimized toxicity; augmented efficacy; and, via the reduction in immunogenicity, the preservation of the activity of biologic therapies. Combination may involve cyclosporine, acitretin (with careful liver monitoring, in appropriate patients), TNF-α inhibitors, and ustekinumab. The combination of methotrexate with another therapy frequently leads to superior and longer lasting efficacy than with either therapy alone.

Cyclosporine

Cyclosporine is a calcineurin inhibitor that is approved to treat moderate to severe psoriasis. Its mechanism of action is to form a complex with cyclophilin, resulting in reduced activity of the nuclear transcription factor, nuclear factor of activated T cells, thus lowering the production of IL-2 and other proinflammatory cytokines, and, consequently, inhibiting T cell activation. In addition cyclosporine inhibits interferon-γ production. At typical doses (2.5–5.5 mg/kg/d) cyclosporine is highly effective for rapidly and consistently treating severe disease. Cyclosporine therapy may be used with many different approaches: (1) intermittently as a short-course (12–16 week) therapy with minimal renal and hypertensive toxicity, (2) continuously to maintain remission in a minority of patients with refractory disease, (3) as a crisis intervention (4–8 weeks) to reduce flare or treat severe disease, and (4) as a part of sequential and rotational therapy to help minimize toxicity and optimize efficacy. The treatment regimen should be tailored to the needs and medical history of the individual patient.

Unlike methotrexate, cyclosporine has not been used as a comparator in any modern, large, multicenter, randomized, placebo-controlled clinical trials. There are, however, several moderate-size clinical trials that demonstrate the drug’s high efficacy ( Tables 3 and 4 ). Studies have established a clear dose-response curve in which 5 mg/kg/d is the inflection point that balances safety and side effects with impressive clearance; cyclosporine at this dose reliably results in average PASI 75 rates of 70%. Further, there seems to be improved benefit in starting at this dose, then titrating down as the disease is controlled.

Table 4

Select additional clinical studies evaluating cyclosporine

Study, Year	Agent	Number of Subjects Evaluated	Study Type	Outcome Measure	Results	P	Comments
Ellis et al, 1991	CsA (2.5 –7.5 mg/kg/d) vs placebo	85	RDPCT	PGA and Global Severity Score	At 8 wk, 36%, 65%, and 85% were clear or almost clear on doses of 2.5 mg/kg/d, 5 mg/kg/d, or 7.5 mg/kg/d, respectively	P <.0001	Higher doses associated with more renal toxicity, hypertension, intolerance
Reitamo et al, 2001	CsA	34	RDPCT	PASI improvement	At 16 wk, CsA 1.25 mg/kg 33%; CsA 5 mg/kg 71%	P <.001	—
Yoon & Youn, 2007	CsA	61	Open-label	PASI 75	At 12 wk, 75% of step-down subjects and 51.5% of standard subjects achieved PASI 75	P <.05	Standard regimen 2.5 mg/kg/d titrated up vs step-down regimen of 5 mg/kg/d titrated down
Pedraz et al, 2006	CsA vs MMF	8	Sequential	PASI improvement	At 16 wk CsA PASI 75 85%, MMF PASI 75 50%	NA	CsA 4 mg/kg/d, MMF 30 mg/kg/d
Beissart et al, 2009	CsA vs MMF	37 (21 CsA)	Multicenter open-label RCT	PASI 75	At 12 wk CsA PASI 75 58%, MMF PASI 75 18%	P <.01	2.5 mg/kg CsA 2 g/d MMF; dose escalation at 6 wk if <25% improvement in PASI

Only gold members can continue reading. Log In or Register to continue

Share this:

• Click to share on Twitter (Opens in new window)
• Click to share on Facebook (Opens in new window)

Related

Related posts:

Genetics of Psoriasis The Immunopathogenesis of Psoriasis Psoriasis and the Life Cycle of Persistent Life Effects Phototherapy and Photochemotherapy for Psoriasis Ten Years On Psoriatic Arthritis for the Dermatologist

Stay updated, free articles. Join our Telegram channel

Join