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Published on 20 September 2010

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Long-term efficacy of biologics in psoriasis

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Intermittent dosing of the anti-TNF-alpha fusion protein, etanercept, can be a safe and cost-effective option for long-term treatment of moderate-severe psoriasis

Robert Strohal
MD
Associate Professor of Dermatology, Head of Department of Dermatology, Federal University Teaching Hospital, Feldkirch, Austria

Biologics have transformed the treatment of psoriasis in recent years offering the hope of effective treatment to people with moderate to severe disease that has not responded well or showed intolerance to other treatment. Now that a number of products have been available for five years, questions about their role in long-term treatment need to be addressed.
Chronic plaque psoriasis is a chronic inflammatory skin disease that follows a relapsing and remitting course. Some patients experience frequent relapses or the disease never clears completely and treatment is needed for much of the time. The severity of psoriasis can also vary considerably. Many patients have mild disease that can be controlled with suitable topical treatments. A substantial proportion of patients have moderate to severe disease that requires either intermittent courses of ultraviolet light treatment – UVB, most often narrowband, or UVA plus psoralen (PUVA) or immunomodulatory systemic treatment with ciclosporin, methotrexate or acitretin. Patients whose disease has failed to respond to such treatments or who are unable to tolerate such treatments can benefit from treatment with certain biologics – monoclonal antibodies directed against cytokines involved in the psoriatic inflammation (adalimumab, infliximab, ustekinumab), or an anti-TNF-alpha fusion protein (etanercept).
There is no generally accepted definition of long-term treatment for psoriasis but, given that psoriasis represents a chronic disease, it makes sense clinically to think in terms of treatment that continues for more than 50 weeks. Patients and prescribers have a number of quite different expectations for such treatment. The drug must be effective both for inducing remission and controlling disease; it must have sustained efficacy and produce sustained improvements in day-to-day quality of life. In addition, it is certainly of utmost importance to adapt treatment to meet patients’ individual needs and treatment should be flexible enough to accommodate life events such as undergoing a surgical operation, planning for a family, or the administration of live vaccines. Furthermore, it should have good long-term safety profile and re-treatment with the drug should be safe and as efficient as initial treatment.
Four biologics are currently available in Europe (see Table 1).
When considering strategies for the long-term treatment with biologics a key question is whether it should be continuous or intermittent. It is of interest that when used for treatment of psoriatic arthritis, biologics are always given continuously.
The monoclonal antibodies (adalimumab, infliximab, ustekinumab) are all not approved by the EMEA to be used intermittently. Infliximab, when given intermittently and the gap (infliximab-free interval) exceeds a period of 20 weeks, carries a substantial risk of hypersensitivity reactions, ranging from mild to severe anaphylactic reactions, which is clearly explained in the prescribing information.[1] The CRYSTEL study (Clinical Randomized Year-long STudy assessing the safety and efficacy of EnbreL in psoriasis) was designed to compare the safety and efficacy of intermittent and continuous etanercept treatment.[2] A total of 720 patients with moderate-to-severe plaque psoriasis were randomised to receive continuous etanercept 25mg twice weekly or ‘paused’ etanercept for 54 weeks. The paused group received etanercept 50mg twice weekly for up to 12 weeks until reaching the treatment goal of a physician’s global assessment (PGA) of 2 or less (corresponding to mild or better), when treatment was paused; when the disease relapsed (PGA ≥ 3), etanercept was restarted at 25mg twice weekly until a PGA of 2 or less was regained. The primary efficacy endpoint was mean PGA over 54 weeks. Although this was statistically significantly lower in the continuous etanercept therapy group than in the paused etanercept therapy group (1.98 vs 2.51, respectively), the clinical difference was marginal. There were no problems with stopping and restarting treatment during the 54-week study period although patients were, in the beginning, somewhat less satisfied with intermittent treatment. Patients in the paused group received etanercept for 31 weeks compared with 54 weeks in the control group. In the UK the National Institute for Health and Clinical Excellence (NICE) stated that intermittent treatment with etanercept (25mg twice weekly) was the most cost-effective option.[3] In fact, intermittent treatment can cost 45% less than continuous treatment, which makes this strategy a reliable option for the physician and for patients.
Long-term infliximab treatment is associated with a progressive loss of efficacy that can be as much as 30%.[4,5] Consequently, today infliximab therapy is usually started together with methotrexate to minimise the risk of antibody formation.

[[HPE52.19]]

Long term adalimumab treatment is also associated with – although to a much lesser extent – the formation of antibodies which might have the potential to impair long term efficacy.
Long-term experience with ustekinumab is largely limited to two main studies (PHOENIX 1 and 2 trials[6,7]) with a 5% rate of antibody formation the impact of which will have to be clarified on the basis of future post-marketing and study experiences.
Etanercept was first introduced in 2004 and there is now extensive experience with its use. Five trials have reported long-term (54–232 weeks) treatment with etanercept (see Table 2).

[[HPE52.19a]]

We can now say with some confidence that infections represent the most commonly reported adverse event, but the number of severe infections per patient year – being 0.04 – is quite low.[12] Moreover, during the 4.6 years of follow-up in the Canadian safety study, no episodes of lymphoma, tuberculosis and opportunistic infections were reported. The development of tuberculosis especially is an important concern with all biologics and needs certain pre-treatment assessment before starting this kind of therapy. In addition, although non-neutralising antibodies to etanercept are found in a proportion of patients, these have no apparent effect on safety or efficacy.[13]
Long-term treatment is necessary for some patients who have moderate-severe psoriasis that has failed to respond to or were intolerant of UV or traditional systemic agents. At present the most cost-effective treatment appears to be intermittent etanercept. Nevertheless, in order to gain a more thorough understanding of the safety, effectiveness and tolerability of long-term treatment for moderate-severe psoriasis, treatment registers and post-marketing surveillance data are of utmost importance.

References
1. Remicade SPC.
2. Ortonne JP, Griffiths CEM, et al. Expert Rev Dermatol 2008;3:657–65.
3. NICE technology appraisal guidance 103 Etanercept and efalizumab for the treatment of adults with psoriasis. July 2006. www.nice.org.uk/TA103
4. Reich K, Nestle FO, et al. Lancet 2005;366:1367–1374.
5. Menter A, Feldman SR, et al. J Am Acad Dermatol 2007;56:31.e1–31.e15.
6. Leonardi C, Kimball AB, et al. Lancet 2008;371:1665–1674.
7. Papp KA, Langley RG, et al. Lancet 2008;371:1675–1684.
8. Paller AS, Siegfried EC, et al. J Am Acad Dermatol 2010 Jun 2 (epublication).
9. Elewski B et al. Extension study 115. Presented at AAD Annual Meeting March 2006 San Francisco. Poster 2908
10. Tyring S et al. Extension study 117. Presented at AAD 2007 Washington DC. Poster P2731
11. Papp K et al . Etanercept extension study. Presented at 17th EADV 2008, Paris, France abstract FP1386
12. US Etanercept prescribing information. Immunex Corporation, Seattle, Washington. October 2002.
13. Tyring S, Gordon KB, et al. Arch Dermatol 2007 Jun;143(6):719–26.



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