
S. Pirzada, MD1; Z. Tomi, MD, FRCPC2; W. Gulliver, MD, FRCPC2,3
1. Dalhousie University, Halifax, Canada
2. Division of Dermatology, Department of Medicine, Memorial University, St. John’s, Canada
3. Newlab Research, St. John’s, Canada
ABSTRACT
Moderate-to-severe psoriasis is known to affect millions of people around the globe. This chronic disease substantially impacts patients by impairing their quality of life, causing psychosocial distress, and creating an ongoing financial burden. The biologics are the newest and most effective therapeutic weapon in the treatment of moderate-to-severe psoriasis and psoriatic arthritis that can significantly alter the course of the disease in a relatively short period of time. There is a need to review the recommended treatment guidelines for moderate- to-severe psoriasis and psoriatic arthritis as the perception and demands of patients are constantly changing. Real world experience with this class of drugs is expanding and more new biologics are becoming available.
Key Words:
Psoriasis, Immunomodulators, Infliximab, Etanercept, Efalizumab, Alefacept, Adalimumab
Psoriasis is a very common skin disease affecting up to 2.5% of people worldwide including over one million adults in Canada,1 and more then 250,000 new cases are diagnosed each year. Thirty-five percent of this population has been estimated to have moderate-to-severe disease, affecting between 2%-10% of total body surface area.2
According to the Canadian Consensus Statement, moderate-to-severe psoriasis significantly diminishes quality of life regardless of the amount of body surface area involved. A survey conducted by the National Psoriasis Foundation in the U.S. found that the stigma around psoriasis caused many sufferers to avoid social interactions or activities, especially if their lesions may attract undesirable attention or negative comments.3 Of the patients surveyed, 10% admitted to contemplating suicide as a result of their condition.
The psychosocial impact of psoriasis is increasingly being recognized by treating physicians and further reinforced by patients’ experiences. The result is a continuing demand for quick and effective treatment options, no matter how short term the benefits and what the financial implications are on the health care system.
Pathogenesis
Psoriasis has been widely recognized as an immune mediated disease of the skin, where T-cells play a central role in its pathogenesis. Pathophysiology of psoriasis involves an abnormal activation of several types of leukocytes that control cellular immunity and the T-cell-dependent inflammatory process in the skin that accelerates the growth of epidermal and vascular cells in psoriasis lesions.
Psoriatic Arthritis (PsA)
Up to 30% of Canadians with psoriasis develop psoriatic arthritis (PsA).4 Up to 20% of PsA patients suffer from deforming and destructive effects as the disease advances.5 PsA can lead to progressive and often irreversible bone and joint damage, making it crucial to diagnose early and initiate treatment to interfere with disease progression. Consequently, early intervention is important in preventing or slowing the long term effects, since it is estimated that half of those with PsA have already experienced serious joint damage (e.g., bone loss) upon first diagnosis.
Standard Systemic Therapies for Psoriasis
Standard systemic therapies for psoriasis that have been in use by dermatologists for decades include methotrexate, cyclosporine, oral retinoids (acitretin), hydroxyurea (rare), mycophenolate mofetil (rare), PUVA and RE-PUVA. Some standard treatment options (e.g., methotrexate, cyclosporine, acitretin and hydroxyurea) can safely be used in combination with certain of the newer biologic therapies. Given the chronic nature of the disease, it is necessary to give more then one course of any systemic treatment if chosen.
New Systemic Therapies for Psoriasis
A number of systemic biologic therapies have been used for the past several years by dermatologists and rheumatologists, and newer targeted biologic therapies are currently under investigation.
Biologics are immunomodulators and bioengineered proteins (such as antibodies, fusion proteins, or recombinant cytokines) that target the pathological effects of T cells directly. The mechanism of action of these targeted therapies follows one of four strategies:6,7,8
- Inhibiting T-cell activation and migration.
- Eliminating activated T cells.
- Inhibiting postsecretory cytokines.
- Inducing immune deviation.
The following biologics have received regulatory approval from the US FDA and Health Canada for the treatment of psoriasis and PsA:
- Infliximab (Remicade®, Schering Canada/ Centocor USA)
- Etanercept (Enbrel®, Amgen/Wyeth)
- Efalizumab (Raptiva®, Serono Canada/Genentech)
- Alefacept (Amevive®, Astellas)
- Adalimumab (Humira®, Abbott)
Infliximab
Infliximab is a chimeric (75% human and 25% murine) monoclonal antibody that specifically targets and binds to TNFá, which has been shown to play a role in rheumatoid arthritis (RA), Crohn’s disease (CD), ankylosing spondylitis (AS), psoriasis and psoriatic arthritis (PsA).2 It is approved by the US FDA for the treatment of active PsA, moderate-to-severe plaque psoriasis, CD, and RA.
Dosage and Monitoring
The preferred RA dose is 5mg/kg IV over 2 hours at week-0, -2, and -6, then 5mg/kg q8 wks. Improvement can be seen after the first few weeks. Screening for latent TB (through a PPD and/or chest x-ray) should be done at baseline. Other optional tests conducted at baseline include: BUN, Creatinine, SGOT, SGPT, Hepatitis C serology, and¨Mor ¦Â-HCG. Consider periodic CBC and clinical follow up every 3 months.
Efficacy
In the phase III multi-centre, double blind EXPRESS trial at 32 centres in Europe and Canada, 378 patients were enrolled; trial assessments included skin and nail changes using the Psoriasis Area Severity Index (PASI) and Nail Psoriasis Severity Index (NAPSI). At week-10, 80% of patients treated with infliximab achieved at least a 75% improvement from baseline, and 57% achieved at least a 90% improvement, compared with 3% and 1% in the placebo group (p<0.0001). At week-24, PASI 75 (82% for infliximab versus 4% for placebo) and PASI 90 (58% versus 1% for placebo) were maintained (p<0.0001). At week 50, 61% achieved PASI 75 and 45% achieved PASI 90 in the infliximab group.9 The EXPRESS trial also evaluated the impact of long term infliximab maintenance therapy on health related quality of life (HRQoL) in patients with psoriasis.
The IMPACT 2 trial evaluated 200 patients with active PsA who were unresponsive to previous treatments.10 At week-14, 58% of patients receiving infliximab and 11% of those receiving placebo achieved arthritis response criteria improvement of 20% (ACR 20) and 77% of infliximab patients and 27% of placebo patients achieved no improvements according to the psoriatic arthritis response criteria (PsARC) (both with p<0.001). Among the 85% of patients with psoriasis involvement of at least 3% body surface area at baseline, 64% of patients receiving infliximab had at least 75% improvement in PASI compared with 2% of patients receiving placebo at week-14 (p<0.001). These therapeutic effects were maintained through week-24. This study also reported that fewer infliximab patients than placebo patients had dactylitis and enthesopathy.
Adverse Effects
Common adverse effects include nausea, abdominal pain, back pain, arthralgia, fatigue, and headache. More serious side-effects include hypersensitivity reactions, infusion reactions, worsening of congestive heart failure (CHF), invasive fungal infections, and a lupus-like syndrome. There is a high risk of infection with pre-existing or recent onset of CNS demyelinating disease, seizure disorders, or those who have received live virus vaccines.2
Contraindications
Contraindications include hypersensitivity to infliximab or murine products, CHF (Class III/IV based on guidelines of the New York Heart Association). The pregnancy category is B and lactation safety is not known.2
Infliximab can be used in conjunction with methotrexate.
Etanercept
This immunomodulator is a fusion protein of the Fc of human IgG1 and the extracellular TNF receptor. It binds soluble TNF and blocks its interaction with cell surface receptors.2 It is indicated for moderate-to-severe plaque psoriasis in adults; psoriatic, rheumatoid, and juvenile rheumatoid arthritis; and ankylosing spondylitis.
Dosage and Monitoring
The appropriate dosing for etanercept is 50mg SC b.i.w. for 12 weeks then 50mg SC weekly. The US FDA does not require any monitoring, but it is recommended that the following tests be undertaken at baseline: PPD and or/chest x-ray, BUN, creatinine, SGOT, SGPT, hepatitis C serology, and¢Aor £]-HCG. Consider 3 periodic CBC, ESR and clinical follow up every 3 months.2
Efficacy
In clinical studies2 47% of patients achieved PASI 75 at 3 months and 54% at 6 months. At 3 months, 71% of patients achieved PASI 50, and 47% achieved a static physician’s global assessment (sPGA) rating of “almost clear” or “clear”. The median time to PASI 50 and PASI 75 was 1 and 2 months respectively, after start of treatment. Of those patients achieving a PASI 75 at 3 months with 50mg SC b.i.w. for 3 months, 77% maintained their improvement at month-6 with 25mg SC qw.
Adverse Effects
Common side-effects include injection site reactions, cough and respiratory symptoms, infections, headaches, and positive ANA. More serious adverse effects include allergic reactions, leucopenia, pancytopenia, new onset or exacerbation of CNS demyelinating disorders (rare), and an increased incidence of lymphoma (twice the general risk).2
Contraindications
Contraindications include hypersensitivity to etanercept or its components, live vaccines, active infections or sepsis, CHF, poorly controlled diabetes, or immunosuppression. Precautions should be taken if concomitant medications include anakinara, natalizumab, TNF-blocking agents, or use in patients with malignancy, renal impairment, asthma, CNS demyelinating disease, or blood dyscrasias. The pregnancy category is B, and lactation safety is not known, however it is secreted in breast milk.2
Etanercept can be used in conjunction with methotrexate.
Efalizumab
This biologic is a humanized form of murine antibody directed against CD11a. It inhibits T-cell activation, cutaneous trafficking, and adhesion to keratinocytes through the blockade of LFA-1/ICAM-1 binding. It is indicated for moderate-to-severe plaque psoriasis.
Dosage and Monitoring
Dosing for this immunomodulator should begin at 0.7mg/kg SC for the first week, then hold at 1 mg/kg for the next 11 weeks (to a maximum dosage of 200mg) weekly as maintenance therapy. Improvement can be seen as early as 2 weeks after start of treatment. PASI improvement can be maintained during extended treatment with weekly or every other week dosing. The FDA requires that a platelet count be taken on initiation, then they recommend monthly assessments, that may decrease in frequency with continued treatment (e.g., every 3 months). Other recommended tests conducted at baseline include PPD and¨Mor chest x-ray, ¦Â-HCG, liver function tests, respiratory function tests (RFTs), and CBC with differential.2
Efficacy
In clinical trials,2 22%-39% of patients achieved PASI 75 and 52%-61% achieved PASI 50 at 12 weeks. PASI 50 began 4 weeks after start. At 12 weeks, 19%-32% of patients achieved an sPGA of “almost clear” or “clear”. Seventy seven percent of patients achieving PASI 75 maintained their improvement through a second 12-week treatment period.
Adverse Effects
Common side-effects include headache, flu-like symptoms with first dose (i.e., fever, headache, myalgia, and nausea), infection, and elevated alkaline phosphatase. Serious adverse effects include infection, malignancy, thrombocytopenia, and worsening of psoriasis.2
Contraindications
Contraindications include hypersensitivity to efalizumab or any murine or humanized monoclonal antibody. Avoid combining with natalizumab. Precautions should be taken if concurrent treatment includes thrombocytopenia, immunosuppression, infection, if the patient is elderly, or has received live vaccines, or if there is a history of malignancy. The pregnancy category is C, and it is unsafe to take during lactation.2
A rebound effect is seen with discontinuation in nearly 14% of patients. The median time to relapse is 60-80 days.
Alefacept
Alefacept is a fusion protein of human LFA-3 and the Fc portion of IgG1. It inhibits T-cell activation/proliferation by blocking the LFA-3/CD2 interaction resulting in selective apoptosis of T cells.2 It is indicated for moderate-to-severe plaque psoriasis.
Dosing and Monitoring
This immunomodulator should be given at a weekly dose of 15mg for 12 weeks, wait 12 weeks, and then consider a second 12-week course. A 16-week cycle is currently under investigation. The maximum reduction in psoriasis is seen at 8 weeks after the last dose. The FDA requires that a CD4 level be taken at baseline and then weekly. Alefacept should be held if the CD4 drops below 250 cells/¦ÌL. Other possible tests to undertake include a PPD and ¨Mor chest x-ray, ¦Â-HCG, CBC with differential, liver function test, and RFTs at baseline.2
Efficacy
In clinical trials, 21% of patients achieved PASI 75 and 42% achieved PASI 50 at week-14, with 14% achieving an sPGA of almost clear or clear (2 weeks post dosing). PASI 50 began 60 days after start. Most patients maintained at least a PASI 50 through the 3 month observation period.2
Adverse Effects
Common side-effects include cough, dizziness, nausea, myalgia, chills, pharyngitis, pruritus, injection site reactions, and transaminitis. More serious adverse effects include lymphopenia (10% IM, 22% IV), malignancies, serious infections, hypersensitivity, increased transaminase levels (rare), and cardiovascular events.2
Contraindications
Contraindications include a hypersensitivity to alefacept. Use should be discontinued for 1 month if CD4 drops below 250 cells/¦ÌL. Precautions should be taken if the patient has an infection, a history of malignancy, or has received live vaccines. The pregnancy category is B and lactation safety is not known.2
Adalimumab
This immunomodulator is a recombinant human IgG1 monoclonal antibody against TNFá. It binds to TNF-alpha and blocks its interaction with cell surface TNF receptors.2 It is indicated for PsA and moderate-to-severe RA.
Dosing and Monitoring
Adalimumab should be given at 40mg SC over 3-5 minutes every 2 weeks for 12 weeks. The frequency can be increased to weekly doses if the patient is not taking methotrexate. The FDA requires that patients be screened for latent TB (PPD and/or chest x-ray), routine CBC/chemistries at baseline, and anti-dsDNA antibodies if lupus-like symptoms are present. In addition B-HCG, liver function tests, and RFT, can be considered at baseline.2
Adverse Effects
Common side-effects include injection site reaction, and positive ANA. Serious adverse effects include hypersensitivity reactions, confusion, multiple sclerosis, paresthesia, subdural hematoma, tremor, infection ¨M sepsis, malignancy, and TB.2
Efficacy
In a very small trial, two out of two patients achieved PASI 50 by week-12 and week-16 in 2 and by week-20, one out of two patients had achieved PASI 75, which was maintained through week-40.6
In another study of 147 patients, 53% pf patients on 40mg adalimumab every other week, 80% of patients taking adalimumab weekly, and 4% of patients taking placebo achieved 75% improvement in PASI score at 12 weeks. Responses were sustained for 60 weeks.11
Contraindications
Adalimumab is contraindicated in patients with a hypersensitivity to adalimumab or murine products, chronic or recurrent infections, latent TB, or are immunocompromised.
Avoid concomitant therapy with anakinra and TNF-blocking agents. Precautions should be considered if patients have mild CHF (NYHA Class I ¨MII), or if they require close cardiac monitoring. Discontinue in patients who develop a lupus-like syndrome. Exercise caution when treating elderly patients, or those with pre-existing or recent onset of CNS demyelinating disease. Pregnancy category is B and lactation safety is not known.2
Adalimumab can be used in conjunction with methotrexate, steroids, salicylates, and NSAIDs.
References
- Gupta AK, Langley R, Pouline Y, et al. Pathogenesis of psoriasis and current challenges. J Cutan Med Surg (suppl 8):3-7 (2004 Aug).
- Thomas VD, Yang FC, Kvedar JC. Biologics in psoriasis: a quick reference guide. J Am Acad Dermatol 53(2):346-51 (2005 Aug).
- Guenther L, Langley R, Shear NH, et al. Integrating biologic agents into management of moderate-to-severe psoriasis: a consensus of the Canadian Psoriasis Expert Panel. J Cutan Med Surg 8(5):321-37 (2004 Sep-Oct).
- The Arthritis Society. Psoriatic Arthritis. www.arthritis.ca.
- The Arthritis Foundation. Psoriatic Arthritis. www.arthritis.org.
- Lui H, Langley R, Poulin Y, et al. Incorporating biologics into the treatment of psoriasis. J Cutan Med Surg (suppl 8):8-13 (2004 Aug).
- Krueger JG. The immunologic basis for the treatment of psoriasis with new biologic agents. J Am Acad Dermatol 46(1):1-23 (2002 Jan).
- Singri P, West D, Gordon K. Biologic therapy for psoriasis: the new therapeutic frontier. Arch Dermatol 138(5):657-63 (2002 May).
- Reich K, Nestle FO, Papp K, et al. Infliximab induction and maintenance therapy for moderate-to-severe psoriasis: a phase III, multicentre, double-blind trial. Lancet 366(9494):1367-74 (2005 Oct).
- Antoni C, Krueger GG, de Vlam K, et al. Infliximab improves signs and symptoms of psoriatic arthritis: results of the IMPACT 2 trial. Ann Rheum Dis 64(8):1150-7 (2005 Aug).
- Gordon KB, Langley RG, Leonardi C, et al. Clinical response to adalimumab treatment in patients with moderate-to-severe psoriasis: double-blind, randomized controlled trial and open-label extension study. J Am Acad Dermatol 55(4):598-606 (2006 Oct).