TNF-A Inhibitors and Efalizumab for the Treat- Ment of Skin Diseases

TNF-a inhibitors and efalizumab for the treatment of skin diseases

This is an excerpt from the full technical report, which is written in Norwegian. The excerpt provides the report’s main messages in English. N0. 15–2007 Systematic reviews and health economic evaluation Title TNF-α inhibitors and efalizumab for the treatment of skin diseases Norwegian title TNF-hemmere og efaluzimab ved behandling av hudsykdommer Institution Norwegian Knowledge Centre for the Health Services (Nasjonalt kunnskapssenter for helsetjenesten) John-Arne Røttingen, Director Authors Ingvil Sæterdal, Researcher, (Project leader) Nils-Jørgen Mørk, Senior Consultant, (Professional manager) Morten Dalaker, Senior Consultant Tor Langeland, Dermatologist Erlend Tolaas, Senior Consultant Espen Movik, Health economist Jan Odgaard-Jensen, Statistician Anita Lyngstadaas, Senior Advisor Marianne Klemp Gjertsen, Research manager

ISBN 978-82-8121-164-3 ISSN 1890-1298 Report No. 15 – 2007 Project number 353 Type of report Systematic reviews and health economic evaluation No. of pages 83 (137 incl. attachments) Client The Regional Health Authorities “Commissioners” Forum Subject heading Efalizumab; Skin Diseases; Tumor Necrosis Factor-alpha (MeSH) Citation Sæterdal I, Mørk NJ, Dalaker M, Langeland T, Tolaas E, Movik E, Odgaard- Jensen J, Lyngstadaas A, Gjertsen MK. TNF-α inhibitors and efalizumab for the treatment of skin diseases. Report from Kunnskapssenteret no. 15−2007. Oslo: Norwegian Knowledge Centre for the Health Services, 2007.

Norwegian Knowledge Centre for the Health Services summarizes and disseminates evidence concerning the effect of treatments, methods, and interventions in health services, in addition to monitoring health service quality. Our goal is to support good decision making in order to provide patients in Norway with the best possible care. The Centre is organized under The Norwegian Directorate for Health, but is scientifically and professionally independent. The Centre has no authority to develop health policy or responsibility to implement policies.

We would like to thank all contributers for their expertise in this project. Norwegian Knowledge Centre for the Health Services assumes final responsibility for the content of this report.

Norwegian Knowledge Centre for the Health Services Oslo, May 2007

E Key messages ng li s h TNF-α inhibitors and efalizumab for the treatment of skin diseases

Background: Skin diseases like psoriasis, pyoderma gangrenosum and Behçets disease are often chronic with the need for continuous treatment and follow-up. Traditional treatment like phototherapy or systemic therapy with ciclosporin, me- totrexate and retinoids are not always effective or cause long-term side effects. New biological agents, which targets pathologic T cell activity, have been developed. This report deals with the biological agents’ tumour necrosis factor alpha (TNF-α) inhibitors (infliximab (Remicade®), adalimumab (Humira®), etanercept (Enbrel®) and efalizumab (Raptiva®) which is a T cell modulator. Methods: The systematic review was performed according to procedures described in the Norwegian Knowledge Centre for the Health Services’ handbook (1). The work was carried out together with a review team of external professionals. The literature was identified by a systematic search in electronic databases. The pharmaceutical companies were also invited to dispatch documentation. A health economic consideration based on available literature was written. Results: 26 publications were included in the report. 24 of the publications were on psoriasis, one on pyoderma gangrenosum and one on Behçets disease. Sixteen of the studies are RCTs and ten are follow-up studies or separate publications of the included RCTs. The results show that both the TNF-α inhibitors and efalizumab are significantly more effective than placebo for the treatment of moderate to severe psoriasis at week 10-12. The quality of life was also improved compared to placebo treatment. There is lack of RCTs concerning other skin diseases than psoriasis. Long term data for evaluation of adverse events were not identified, and conclusions regarding long-term safety cannot be drawn. Conclusions: There is good evidence that TNF-α inhibitors and efalizumab is efficacious in the treatment of moderate to severe psoriasis. We did not find studies comparing TNF- α inhibitors and efalizumab with traditional treatment. Limited data is available concerning safety in long-term use. One study on health economics performed in England indicates that etanercept and efalizumab is cost-effective for patients with severe psoriasis and low quality of life that re- sponds well to the treatment.

E Executive summary ng li s h TNF-α inhibitors and efalizumab for the treatment of skin diseases

BACKGROUND

Skin diseases like psoriasis, pyoderma gangrenosum and Behçets disease are often chronic with the need for continuous treatment and follow-up.

Recent research has shown that the immune system and T cells in particular, are important for the development of psoriasis. The plaques that characterise the most common form of psoriasis are often infiltrated with T cells The T cells initiate a complex process that leads to inflammation and over production of keratinocytes. The T cells produce tumour necrosis factor alpha (TNF-α) which plays an important role in the process.

The cause of pyoderma gangrenosum and Behçets disease is unknown but we assume that they are immunomediated.

Traditional treatment like phototherapy or systemic therapy with ciclosporin, me- totrexate and retinoids are not always effective or cause long-term side effects.

This systematic review deals with the biological agents tumour necrosis factor alpha (TNF-α) inhibitors and efalizumab which all target pathologic T cell activity and is used for the treatment of inflammatory skin diseases. The TNF-α inhibitors comprise infliximab (Remicade®), adalimumab (Humira®) and etanercept (Enbrel®). Efalizumab (Raptiva®) is a T cell modulator.

The primary outcomes in the review were efficacy and safety of the treatment. The efficacy was assessed by the proportion of patient’s achieving a 50, 75 or 90 % reduction in the Psoriasis Area Severity Index (PASI). The PASI is an assessment score, representing the extent, redness, thickness and scaliness of a person’s psoriasis on a single scale. Qual- ity of life was also considered.

METHODS

The systematic review was performed according to procedures described in the Norwe- gian Knowledge Centre for the Health Services’ handbook (1). The work was carried out together with a review team of external professionals. The literature was identified by a systematic search in electronic databases. The pharmaceutical companies were also invited to dispatch documentation.

All identified publications were assessed for relevance according to predefined criteria. Quality of relevant publications was assessed by the use of checklists.

The results were summarized for the predefined outcomes and both as a descriptive summary and quantitatively with meta analysis.

A health economic consideration based on available literature was written.

RESULTS

26 publications were included in the report. 24 of the publications were on moderate to severe psoriasis, one on pyoderma gangrenosum and one on Behçets disease. Sixteen of the studies are RCTs and ten are follow-up studies or separate publications of the included RCTs. 4 studies for the health economic evaluation ere included.

Our analysis shows that TNF-α inhibitors and efalizumab are significantly more effective than placebo for the treatment of psoriasis at week 10-12. This was assessed by PASI improvement and reported for PASI 50, 75 and 90.

Treatment of psoriasis using infliximab resulted in 70-88 % of patients in the study groups and 2-18 % in the control groups achieved PASI 75 at week 10. At week 12 achieved 53 % of the patients treated with adalimumab every second week, 80 % of the patients treated with adalimumab every week and 4 % of the patients receiving placebo 75 % improvement in PASI score. Treatment of psoriasis using etanercept resulted in achievement of PASI 75 with 14 - 49 % in the study groups and 2-5 % in the control groups at week 12. The results for achieving PASI 75 after treatment with efalizumab are 22–39 % in the study groups and 2–5 % in the control groups at week 12. The results are analysed independently of dose.

The results show that TNF-α inhibitors and efalizumab significantly improves quality of life compared with placebo, assessed by improved DLQI (the Dermatology Life Quality Index).

Due to limited safety data and short term studies, it is not possible to conclude on long- term safety issues. The included studies did not report on significant differences in adverse events between study group and control group.

No studies (RCTs) comparing the different TNF-α infibitors were identified. Studies comparing TNF-α inhibitors or efalizumab with traditional treatment were also not found. Neither did we identify studies were TNF-α inhibitors or efalizumab were tested with and without co-treatment with an other immunosuppresive agent. There is also a need for long-term safety data.

Relatively few health economic evaluations of TNF-α inhibitors for psoriasis were identified. We included one study from the UK and three from the US. The UK study was based on a complex model, which showed that, in a 10-year perspective, treatment with etanercept and efalizumab are generally not cost-effective as treatment for the average psoriasis patient, but may be so for those patients with a low quality of life and good response,. Three short-term American studies were also considered, but the results from these are

not easily transferable to Norway because of different cost structures in the US health care system.

CONCLUSIONS

There is good evidence that TNF-α inhibitors and efalizumab is efficacious in the treatment of moderate to severe psoriasis. We did not find studies comparing TNF-α inhibitors and efalizumab with traditional treatment. Limited data is available concerning safety in long-term use.

One study on health economic performed in England indicates that etanercept and efalizumab is cost-effective for patients with severe psoriasis and low quality of life that re- sponds well to the treatment.

Norwegian Knowledge Centre for the Health Services summarizes and disseminates evidence concerning the effect of treatments, methods, and interventions in health services, in addition to monitoring health service quality. Our goal is to support good decision making in order to provide patients in Norway with the best possible care. The Centre is organized under The Directorate for Health and Social Affairs, but is scientifically and professionally independent. The Centre has no authority to develop health policy or responsibility to implement policies.

Norwegian Knowledge Centre for the Health Services PB 7004 St. Olavs plass N-0130 Oslo, Norway Telephone: +47 23 25 50 00 E-mail: [email protected] Full report (pdf): www.kunnskapssenteret.no