PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of f1000medLatest ContentReportsReportsReports
 
F1000 Med Rep. 2009; 1: 30.
Published online 2009 May 8. doi:  10.3410/M1-30
PMCID: PMC2924720

The role of TNF inhibitors in psoriasis therapy: new implications for associated comorbidities

Abstract

Over the past several years, tumor necrosis factor (TNF) antagonists have become first-line agents in the treatment of moderate-to-severe psoriasis. These medications are highly effective in treating both psoriasis and psoriatic arthritis and may also reduce the risk of cardiovascular events in patients with chronic inflammatory disorders. In this article we review the use of anti-TNF therapy in psoriasis and its implications in regards to the co-morbid conditions associated with psoriasis.

Introduction and context

Psoriasis is a common, chronic inflammatory disease of the skin affecting 1-3% of the general population and characterized by complex alterations in epidermal growth and differentiation with multiple biochemical, immunological, and vascular abnormalities [1]. Although the exact etiology of psoriasis remains unclear, current evidence indicates that it is T-cell driven. Individuals with active skin disease have elevated levels of tumor necrosis factor alpha (TNFα) in both blood and lesional skin [2]. TNFα, which is secreted by both T cells and antigen-presenting cells within lesional skin, has emerged as a key mediator in the disease process. Specifically, TNFα is a pro-inflammatory cytokine that amplifies inflammation through several distinct pathways: facilitating entry of inflammatory cells into lesional skin through induction of adhesion molecules on vascular endothelial cells; stimulating keratinocyte production of other pro-inflammatory mediators [3]; and finally activating dermal macrophages and dendritic cells (Figure 1). Recently, the efficacy of TNFα inhibitors in treating psoriasis has been attributed to their inhibition of Th17 T cells [2], a newly identified population of T cells now thought to be central to psoriasis pathogenesis.

Figure 1.
The biological effects of TNFα [27]

Currently, three TNFα antagonists are available for use in psoriasis: infliximab (Remicade®), etanercept (Enbrel®), and adalimumab (Humira®). While all three block TNFα in vivo, they differ significantly in structure and exact mechanism of action. Infliximab is a chimeric human/murine monoclonal antibody that can bind both soluble and membrane-bound TNFα and effectively neutralize its activity [4]. Adalimumab, a fully human antibody [5], functions in the same way as infliximab, binding both soluble and membrane bound TNFα. In contrast, etanercept is a receptor fusion protein and is composed of two human TNFα receptors fused to the Fc portion of a human antibody. Etanercept binds free TNFα and weakly inhibits TNFα trimers in vivo [4]. Of these three antagonists, etanercept is the least effective [6]. Infliximab, due to its non-human (chimeric) structure, carries higher risk of inducing neutralizing antibodies, particularly in patients on intermittent therapy, and this can lead to decreased efficacy and lack of response to treatment [7]. Consequently, some dermatologists recommend concomitantly treating patients with methotrexate [8-13], although no clear guidelines exist.

As mentioned above, there is a slight difference in the way that these agents work. Additionally, the dosing regimens for these three agents differ significantly (Figure 2 and Table 1). TNF antagonists cause immunosuppression and are contraindicated in patients with chronic leg ulcers, persistent or recurrent chest infections, indwelling catheters, demyelinating diseases, congestive cardiac failure (New York Heart Association classes III and IV) and malignancy (except adequately treated non-melanoma skin cancer) [14]. Latent tuberculosis can also reactivate during treatment, although this has been shown to be lower for etanercept [12] compared to the other two agents. Therefore, patients with untreated or latent tuberculosis should receive a full 9-month course of isoniazid before initiating treatment with TNF antagonists [12]. Furthermore, screening with the tuberculin skin test is recommended in all individuals prior to treatment [12], and patients receiving treatment are encouraged to undergo yearly tuberculosis screenings for the duration of the regimen [12].

Figure 2.
Dosing regimens for the three TNF antagonists
Table 1.
Clinical guidelines for TNF inhibitor use [5]

Due to the substantial cost and risks associated with TNF-inhibitor therapy, several guidelines have been published for their use in psoriasis [5,12]. It is recommended that these agents only be used in patients with extensive skin disease or in patients with limited skin disease unresponsive to topical and/or targeted phototherapy. There are limited data regarding the use of these medications in children except for etanercept [5,13].

Recent advances

Over the past several years it has become apparent that psoriasis is associated with several co-morbidities, including lymphoma [14], myocardial infarction [15], and metabolic diseases such as obesity, diabetes, and hypertension [16]. The risk of these co-morbid conditions appears to be higher in individuals with more severe disease [14,15] and, not surprisingly, psoriasis has been associated with increased mortality [17]. While the majority of affected individuals are successfully managed with topical therapies, 20-30% of cases have severe extensive disease necessitating systemic treatment [7].

It remains unclear whether treatment with systemic agents can decrease the risk of co-morbid conditions associated with psoriasis. This is still a largely unexplored area of research in psoriasis, but several recently published studies have begun to provide some insights into this problem. Psoriasis has a complex relationship with metabolic diseases such as obesity [16]. Adipose tissue, including adipocytes and resident macrophages, may serve as a significant source of TNFα in obese individuals [16,18,19]. This source of circulating TNFα can create a pro-inflammatory state elsewhere in the body and can further amplify pre-existing inflammatory processes. Moreover, elevated levels of TNFα have also been suggested to disrupt normal adipocyte function, ultimately leading to increased total body adiposity and further metabolic dysregulation [19]. It is not surprising, therefore, that a correlation between body mass and psoriasis has been identified and obese patients seem to have decreased responses to systemic treatments [20]. Interestingly, TNF antagonists may also contribute to obesity [21-23]. Due to the association between obesity and higher levels of circulating TNFα [24], the efficacy of fixed dose anti-TNF agents (etanercept and adalimumab) has been questioned in obese individuals [25].

Few studies exist on whether TNF antagonists have any effect on glucose control. In a recent study of 12 psoriasis patients with two or more risk factors for type 2 diabetes mellitus, treatment with etanercept was shown to slightly lower fasting insulin levels [26]. However, no difference was seen in insulin secretion and insulin sensitivity while on treatment [26].

As more evidence emerges correlating elevated C-reactive protein levels directly with increased risk of cardiovascular disease, suppressing chronic inflammation has become a top priority in the treatment of psoriasis. Since TNFα is a recognized mediator of systemic inflammation, it has been hypothesized that TNF antagonists may have cardioprotective properties [25]. Although insufficient data exist to reach any definitive conclusions in this regard, one recent study demonstrated that etanercept significantly reduced C-reactive protein levels in obese patients with moderate-to-severe plaque psoriasis, indicating that adequately treated patients may have decreased risk for future cardiovascular events [18]. However, it is not clear whether this ‘protective’ effect lasts once treatment is discontinued.

Implications for clinical practice

Anti-TNFα antagonists continue to be one of the most effective medications in treating psoriasis, significantly decreasing the overall burden of the disease. Furthermore, with recent data suggesting that these drugs may decrease cardiovascular risk in patients with chronic inflammatory diseases, TNF antagonists may play a larger role in psoriasis treatment in the future. However, given the potential risks of infection and malignancy, the use of these agents should be carefully evaluated.

Abbreviations

TNF
tumor necrosis factor

Notes

The electronic version of this article is the complete one and can be found at: http://F1000.com/Reports/Medicine/content/1/30

Notes

Competing interests

The authors declare that they have no competing interests.

References

1. Gudjonsson JE, Elder J. Psoriasis. In: Wolff K, Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, editors. Fitzpatrick's Dermatology in General Medicine. 7. New York: McGraw-Hill; 2008. p. 169.
2. Zaba LC, Cardinale I, Gilleaudeau P, Sullivan-Whalen M, Suárez-Fariñas M, Fuentes-Duculan J, Novitskaya I, Khatcherian A, Bluth MJ, Lowes MA, Krueger JG. Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses. J Exp Med. 2007;204:3183–94. doi: 10.1084/jem.20071094. [PMC free article] [PubMed] [Cross Ref] F1000 Factor 3.0 Recommended
Evaluated by David Fiorentino 16 Jul 2008
3. Gottlieb AB, Chamian F, Masud S, Cardinale I, Abello MV, Lowes MA, Chen F, Magliocco M, Krueger JG. TNF inhibition rapidly down-regulates multiple proinflammatory pathways in psoriasis plaques. J Immunol. 2005;75:2721–9. [PubMed]
4. Gisondi P, Girolomoni G. Biologic therapies in psoriasis: a new therapeutic approach. Autoimmun Rev. 2007;6:515–9. doi: 10.1016/j.autrev.2006.12.002. [PubMed] [Cross Ref]
5. Menter A, Gottlieb A, Feldman SR, Van Voorhees AS, Leonardi CL, Gordon KB, Lebwohl M, Koo JY, Elmets CA, Korman NJ, Beutner KR, Bhushan R. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol. 2008;58:826–50. doi: 10.1016/j.jaad.2008.02.039. [PubMed] [Cross Ref]
6. Schmitt J, Zhang Z, Wozel G, Meurer M, Kirch W. Efficacy and tolerability of biologic and nonbiologic systemic treatments for moderate-to-severe psoriasis: meta-analysis of randomized controlled trials. Br J Dermatol. 2008;159:513–26. doi: 10.1111/j.1365-2133.2008.08732.x. [PubMed] [Cross Ref]
7. Thaçi D. Long-term data in the treatment of psoriasis. Br J Dermatol. 2008;159(2):18–24. doi: 10.1111/j.1365-2133.2008.08781.x. [PubMed] [Cross Ref]
8. Kirby B, Marsland AM, Carmichael AJ, Griffiths CE. Successful treatment of severe recalcitrant psoriasis with combination infliximab and methotrexate. Clin Exp Dermatol. 2001;26:27–9. doi: 10.1046/j.1365-2230.2001.00753.x. [PubMed] [Cross Ref]
9. Barland C, Kerdel FA. Addition of low-dose methotrexate to infliximab in the treatment of a patient with severe, recalcitrant pustular psoriasis. Arch Dermatol. 2003;139:949–50. doi: 10.1001/archderm.139.7.949. [PubMed] [Cross Ref]
10. Ahmad K, Rogers S. Three years' experience with infliximab in recalcitrant psoriasis. Clin Exp Dermatol. 2006;31:630–3. doi: 10.1111/j.1365-2230.2006.02170.x. [PubMed] [Cross Ref]
11. Doherty SD, Van Voorhees A, Lebwohl MG, Korman NJ, Young MS, Hsu S. National Psoriasis Foundation consensus statement on screening for latent tuberculosis infection in patients with psoriasis treated with systemic and biologic agents. J Am Acad Dermatol. 2008;59:209–17. doi: 10.1016/j.jaad.2008.03.023. [PubMed] [Cross Ref]
12. Paller AS, Siegfried EC, Langley RG, Gottlieb AB, Pariser D, Landells I, Hebert AA, Eichenfield LF, Patel V, Creamer K, Jahreis A. Etanercept treatment for children and adolescents with plaque psoriasis. N Engl J Med. 2008;358:241–51. doi: 10.1056/NEJMoa066886. [PubMed] [Cross Ref]Changes Clinical Practice
F1000 Factor 9.0 Exceptional
Evaluated by Joel Gelfand 19 Feb 2008
13. Gelfand JM, Shin DB, Neimann AL, Wang X, Margolis DJ, Troxel AB. The risk of lymphoma in patients with psoriasis. J Invest Dermatol. 2006;126:2194–201. doi: 10.1038/sj.jid.5700410. [PubMed] [Cross Ref]
14. Smith CH, Anstey AV, Barker JN, Burden AD, Chalmers RJ, Chandler D, Finlay AY, Griffiths CE, Jackson K, McHugh NJ, McKenna KE, Reynolds NJ, Ormerod AD. British Association of Dermatologists guidelines for use of biological interventions in psoriasis 2005. Br J Dermatol. 2005;153:486–97. doi: 10.1111/j.1365-2133.2005.06893.x. [PubMed] [Cross Ref]
15. Gelfand JM, Neimann AL, Shin DB, Wang X, Margolis DJ, Troxel AB. Risk of myocardial infarction in patients with psoriasis. JAMA. 2006;296:1735–41. doi: 10.1001/jama.296.14.1735. [PubMed] [Cross Ref]
16. Azfar RS, Gelfand JM. Psoriasis and metabolic disease: epidemiology and pathophysiology. Curr Opin Rheumatol. 2008;20:416–22. doi: 10.1097/BOR.0b013e3283031c99. [PubMed] [Cross Ref]
17. Gelfand JM, Troxel AB, Lewis JD, Kurd SK, Shin DB, Wang X, Margolis DJ, Strom BL. The risk of mortality in patients with psoriasis: results from a population-based study. Arch Dermatol. 2007;143:1493–9. doi: 10.1001/archderm.143.12.1493. [PubMed] [Cross Ref] F1000 Factor 6.0 Must Read
Evaluated by Johann Gudjonsson 22 Feb 2008
18. Strober B, Teller C, Yamauchi P, Miller JL, Hooper M, Yang YC, Dann F. Effects of etanercept on C-reactive protein in psoriasis and psoriatic arthritis. Br J Dermatol. 2008;159:322–30. doi: 10.1111/j.1365-2133.2008.08628.x. [PubMed] [Cross Ref]
19. Cawthorn WP, Sethi JK. TNF-alpha and adipocyte biology. FEBS Lett. 2008;582:117–31. doi: 10.1016/j.febslet.2007.11.051. [PubMed] [Cross Ref]
20. Naldi L, Addis A, Chimenti S, Giannetti A, Picardo M, Tomino C, Maccarone M, Chatenoud L, Bertuccio P, Caggese E, Cuscito R. Impact of body mass index and obesity on clinical response to systemic treatment for psoriasis. Evidence from the psocare project. Dermatology. 2008;217:365–73. doi: 10.1159/000156599. [PubMed] [Cross Ref]
21. Briot K, Gossec L, Kolta S, Dougados M, Roux C. Prospective assessment of body weight, body composition, and bone density changes in patients with spondyloarthropathy receiving anti-tumor necrosis factor-α treatment. J Rheumatol. 2008;35:855–61. [PubMed]
22. Gisondi P, Cotena C, Tessari G, Girolomoni G. Anti-tumour necrosis factor-alpha therapy increases body weight in patients with chronic plaque psoriasis: a retrospective cohort study. J Eur Acad Dermatol Venereol. 2008;22:341–4. doi: 10.1111/j.1468-3083.2007.02429.x. [PubMed] [Cross Ref]
23. Saraceno R, Schipani C, Mazzotta A, Esposito M, Di Renzo L, De Lorenzo A, Chimenti S. Effect of anti-tumor necrosis factor-alpha therapies on body mass index in patients with psoriasis. Pharmacol Res. 2008;57:290–5. doi: 10.1016/j.phrs.2008.02.006. [PubMed] [Cross Ref]
24. Fain JN. Release of interleukins and other inflammatory cytokines by human adipose tissue is enhanced in obesity and primarily due to the nonfat cells. Vitam Horm. 2006;74:443–77. doi: 10.1016/S0083-6729(06)74018-3. [PubMed] [Cross Ref]
25. Clark L, Lebwohl M. The effect of weight on the efficacy of biologic therapy in patients with psoriasis. J Am Acad Dermatol. 2008;58:443–6. doi: 10.1016/j.jaad.2007.11.011. [PubMed] [Cross Ref]
26. Martínez-Abundis E, Reynoso-von Drateln C, Hernández-Salazar E, González-Ortiz M. Effect of etanercept on insulin secretion and insulin sensitivity in a randomized trial with psoriatic patients at risk for developing type 2 diabetes mellitus. Arch Dermatol Res. 2007;299:461–5. doi: 10.1007/s00403-007-0784-3. [PubMed] [Cross Ref]
27. Tan JK, Aphale A, Malaviya R, Sun Y, Gottlieb AB. Mechanisms of action of etanercept in psoriasis. J Investig Dermatol Symp Proc. 2007;12:38–45. doi: 10.1038/sj.jidsymp.5650037. [PubMed] [Cross Ref]

Articles from F1000 Medicine Reports are provided here courtesy of Faculty of 1000 Ltd