1. Department of Dermatology, University of Virginia, Charlottesville, VA, USA
2. Department of Dermatology, University of California, San Francisco, CA, USA
3. Center for Dermatology Research, Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
To date, the US FDA has approved three tumor necrosis factor (TNF)-a inhibitors for use in dermatology. Etanercept (Enbrel®, Amgen-Wyeth), a fully human fusion protein of TNF receptor II bound to the Fc component of human IgG1, is approved for use in psoriasis (2004) and psoriatic arthritis (2002). Infliximab (Remicade®, Centocor) is a chimeric monoclonal antibody that is approved for use in psoriasis (2006) and psoriatic arthritis (2005), and adalimumab (Humira®, Abbott Laboratories), a fully human monoclonal antibody, is approved for use in psoriatic arthritis (2005). While data regarding the efficacy and safety of these therapies is abundant, it proves nearly impossible to objectively compare and contrast agents as there are no head-to-head trials. Clinical experience and post-marketing reporting has allowed dermatologists to identify the relative strengths and limitations of each agent. The well-founded enthusiasm for these agents, because of their excellent initial efficacy and safety profile, is reasonably tempered by concerns about declining efficacy over time, the risk of infection, lymphoma and demyelinating disorders, and cost. The distinct and targeted mechanism of action of the TNF inhibitors allows dermatologists to customize therapy to match the individual needs and characteristics of patients who are candidates for systemic or phototherapy.
TNF inhibitors, tumor necrosis factor, etanercept, infliximab, adalimumab
The efficacy of the tumor necrosis factor (TNF) inhibitors for the treatment of chronic plaque psoriasis and psoriatic arthritis has been well established in clinical trials and through real world experience. The improvements in the psoriasis area and severity index (PASI) and American College of Rheumatology (ACR) scores are comparable, and in many cases superior, to traditional antipsoriatic drugs and disease-modifying antirheumatic drugs (DMARDs), respectively. Clinical trials also demonstrate improvement in physical and health-related quality of life (HRQoL) measures in psoriasis patients who were treated with biologics when compared with placebo.1
Long-term studies objectively demonstrating continued efficacy for plaque-type psoriasis are limited, given the relatively recent FDA approval of the individual agents for this use. Tyring and colleagues recently reported extended efficacy of etanercept (50mg twice weekly) out to 96 weeks of continuous therapy.2 Clinical experience suggests that a percentage of patients on long-term therapy with TNF inhibitors may begin to show a decline in original efficacy. Long-term trial data is necessary to further explore this clinical observation.
Assessing efficacy of the TNF inhibitors from trial data is accomplished with relative ease, while safety assessments are much more difficult. Interdrug comparison is difficult because of the lack of head-to-head trials, the differences in trial design and patient characteristics, and the lack of consistency in mandatory postmarketing reporting of adverse events. Anti-TNF agents act with greater target specificity than traditional systemic agents and to date, more than 1 million patients have been exposed across indications, allowing a reasonable degree of confidence in the safety of these drugs. Given the molecular role that TNF plays in the immune system, the primary safety concerns regarding the use of these drugs include risk of infection and malignancy.
The most common adverse events in the short-term are injection site (etanercept and adalimumab) and infusion reactions (infliximab). The most concerning short-term risk is serious infection, which includes sepsis, infection from opportunistic organisms, and reactivation of latent tuberculosis. All anti-TNF agents carry a warning about reactivation of tuberculosis (black box for infliximab and adalimumab; bold letter for etanercept).3-6 The risk of infection is higher in patients with predisposing underlying conditions, such as diabetes mellitus, congestive heart failure, a history of active or chronic infections, or concurrent use of immunosuppressive drugs.
Other Safety Concerns
Other class-wide safety concerns include the risk of malignancy, demyelinating disease, and exacerbation or development of congestive heart failure.7,8 The risk of lymphoma among patients treated with anti-TNF agents remains controversial. The incidence of lymphoma was higher in anti-TNF treated patients compared with controls during the controlled portion of trials of all approved agents. In patients with psoriasis, no clear findings identify whether lymphoma risk is associated with disease severity, treatment, other unidentified factors, or a combination of factors.9 To date, there is no consensus on the estimated risk of lymphoma with anti-TNF therapy. Although nonmelanoma skin cancer and lymphoma rates are greater in patients treated with anti-TNF agents, conclusions are difficult to draw in light of the pre-existing association of lymphomas with severe rheumatoid arthritis, psoriasis, and systemic inflammation. Furthermore, prior systemic therapies and environmental risk factors, such as sun exposure and smoking, confound the data. National registries to date show no increase in solid cancers vs. the general population.
TNF has been implicated in multiple sclerosis (MS) pathogenesis, has been identified in active MS lesions, and is known to be toxic to oligodendrocytes in vitro. A double-blind, placebo-controlled phase II study of an anti-TNF molecule (lenercept, a recombinant TNF receptor p55 immunoglobulin fusion protein) conducted in MS patients documented significantly increased and earlier occurrences of MS exacerbations and more severe neurologic deficits in the lenercept treatment groups compared to placebo.10 Although a causal relationship between TNF inhibitors and demyelinating disease remains unclear, optic neuritis, transverse myelitis, MS, seizures, and Parkinson’s disease have been reported in patients taking TNF inhibitors. The drugs should be withheld from any patient who has a history of, or first degree relative with a demyelinating disease; Patients should be monitored vigilantly for suspicious signs or symptoms.
Congestive Heart Failure
TNF inhibitors were previously evaluated as a therapy for congestive heart failure (CHF), but trials were halted due to lack of efficacy. Although data from one of the etanercept CHF trials suggested higher mortality in treated patients vs. placebo, analyses did not identify any specific risk factors. Postmarketing reports of CHF have included:
- new onset cases
- cases with no identifiable risk factors, such as previous myocardial infarction, coronary artery disease, or hypertension
- cases in patients under the age of 50.11
Most patients improved or symptoms resolved once therapy was stopped, though rare fatal incidences have been recorded.
The issue of autoimmunity requires further study. Autoantibody formation (ANA, anti-dsDNA, and anticardiolipin) appears to be more common with infliximab than with etanercept; only limited reports exist for adalimumab. Development of human antihuman antibodies and human antichimera antibodies also seem to be slightly more common with infliximab than with other agents. Infliximab data suggests that development of these antibodies is loosely associated with reduced efficacy and a higher incidence of infusion reactions.12 The impact of long-term treatment with anti-TNF agents on the development of autoimmune diseases is unknown.
Pregnancy and Breastfeeding
All anti-TNF agents are pregnancy category B (no human studies conducted, but no adverse effects noted in animal studies). Because human data is not available, therapy should be avoided, if possible, in pregnant or breastfeeding women.
Primary Issues of Concern
Two primary issues of concern facing the clinicians who are prescribing these agents include long-term safety and the appropriate choice of screening/ monitoring tests. Long-term safety profiles remain to be established. Patient selection is key; not all patients are good candidates for treatment with anti-TNF agents. Patients must be predetermined to be reliable, compliant with follow-up visits, and able to self assess and report the onset of new signs or symptoms that may herald the onset of an adverse event. Although guidelines regarding objective screening and monitoring are yet to be established, a reasonable approach includes a detailed history and physical examination, TB testing (US FDA-mandated for adalimumab and infliximab), and additional baseline lab tests that are deemed appropriate as a result of the history and examination. Close and routine follow-up is warranted to assess both the continued efficacy and safety of these drugs in individual patients.
Compared with traditional treatments for psoriasis, such as phototherapy and methotrexate, treatment with the anti-TNF drugs represents a tremendous financial burden. A year of methotrexate at 15mg/week costs an average of $375 USD (not including lab fees), while a year of biologic therapy can vary between $10,000 USD and $25,000 USD (or more) based on the dosage and treatment regimen prescribed.13 Moreover, insurance carriers often require failure of, or contraindications to, one or more standard therapies prior to approval of coverage for a biologic agent, thus presenting a major obstacle to patients in need. Cost is not only a concern to patients, but to their dermatologists and the entire healthcare system in general. The cost of treatment is a primary reason many dermatologists do not consider biologic agents as first-line therapy for moderate-to-severe or socially disabling psoriasis, and reinforces the first-line use of more traditional, efficacious, and cost effective treatments such as ultraviolet light.14 In the case of psoriatic arthritis, however, the low cost of time-proven agents, such as methotrexate, may no longer be considered worth the risk of potential toxicity.
The discovery, use, and great clinical success of anti-TNF molecules for the treatment of moderate-to-severe psoriasis and psoriatic arthritis have engendered well-founded enthusiasm, but the cost of therapy and unknown long-term safety and efficacy profile gives us pause. The addition of these agents to the available therapeutic modalities for treating psoriasis, which can be physically, psychologically, and socially devastating, is excitedly welcomed. However, as with any new drug class, the high price of therapy and the unknown long-term effects represent major obstacles to selection of these drugs as first-line agents in all patients with moderate-to-severe or debilitating psoriasis/ arthritis. The excellent initial efficacy seems to hold up fairly well over 12-36 months, but a trend toward declining efficacy thereafter is being observed in some cases. Combination therapy with methotrexate is observed to maintain the efficacy of infliximab, but the additional cost and risk of combination may not be appropriate for all patients.
The major focus of concern now and in the future remains safety. Objective screening and monitoring guidelines are needed, as current clinical practice varies from no screening to indiscriminate panel testing. Given safety data, including postmarketing reports, a reasonable approach to patient selection and monitoring includes specific tests for all patients and additional tests based on individual patient need. A thorough history and physical examination with careful assessment for neurologic abnormalities and a baseline tuberculin skin test (PPD), complete blood count, and metabolic profile are a minimum. Additional laboratory testing and subsequent monitoring should be selected individually given the patient, region of practice, and drug to be utilized. Frequent in-office follow-up to assess efficacy and safety is warranted.
- Katugampola RP, Lewis VJ, Finlay AY. The Dermatology Life Quality Index: assessing the efficacy of biological therapies for psoriasis. Br J Dermatol 156(5):945-50 (2007 May).
- Tyring S, Gordon KB, Poulin Y, et al. Long-term safety and efficacy of 50mg of etanercept twice weekly in patients with psoriasis. Arch Dermatol 143(6):719-26 (2007 Jun).
- Immunex Corporation. Enbrel® (etanercept) package insert; 2005. Thousand Oaks, CA, USA.
- Centocor Inc. Remicade® (infliximab) package insert; 2005. Malvern, PA, USA.
- Abbott Laboratories. Humira® (adalimumab) package insert; 2006. Chicago, IL, USA.
- Keane J. TNF-blocking agents and tuberculosis: new drugs illuminate an old topic. Rheumatology (Oxford). 44(6):714-20 (2005 Jun).
- Scheinfeld N. A comprehensive review and evaluation of the side-effects of the tumor necrosis factor alpha blockers etanercept, infliximab and adalimumab. J Dermatolog Treat 15(5):280–94 (2004 Sep).
- Hochberg MC, Lebwohl MG, Plevy SE, Hobbs KF, Yocum DE. The benefit/risk profile of TNF-blocking agents: findings of a consensus panel. Semin Arthritis Rheum 34(6):819-36 (2005 Jun).
- Gelfand JM, Berlin J, Van Voorhees A, Margolis DJ. Lymphoma rates are low but increased in patients with psoriasis: results from a population-based cohort study in the United Kingdom. Arch Dermatol 139(11):1425-9 (2003 Nov).
- Arnason BGW, et al. The Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. Neurology 53(3):457-65 (1999 Aug 11).
- Kwon HJ, Coté TR, Cuffe MS, Kramer JM, Braun MM. Case reports of heart failure after therapy with a tumor necrosis factor antagonist. Ann Intern Med 138(10):807-11 (2003 May).
- Kapetanovic MC, Geborek P, Saxne T, et al. Development of antibodies against infliximab during infliximab treatment in rheumatoid arthritis: relation to infusion reactions and treatment response. Arthritis Rheum 52(suppl):S543 [abstract 1440] (2005).
- Prices based on those found at http://www.drugstore.com, last accessed August 22, 2007.
- Miller DW, Feldman SR. Cost-effectiveness of moderate-to-severe psoriasis treatment. Expert Opin Pharmacother 7(2):157-67 (2006 Feb).