Abstract
Objective and methods
This health technology assessment (HTA) report synthesises systematically randomized controlled studies (RCT) on the therapy of moderate and severe psoriasis vulgaris which were published between 1999 and 2004; it includes some important clinical studies which have been published after 2004 and thus updates the English HTA report by Griffiths et al. [1]. The major objective is the evaluation of the medical effectiveness of different therapeutical approaches and the cost effectiveness with relevance for Germany.
Results
The major conclusions from the results of medical RCT on moderate and severe psoriasis vulgaris are:
Oral fumarates are effective in the treatment of moderate to severe psoriasis vulgaris. However, fumarates quiet frequently cause moderate side effects. Cyclosporine and methotrexate are both effective in the treatment of severe psoriasis vulgaris. Both substances have a different spectrum of side effects which may limit the individual applicability. Acetritin is only moderately effective in the treatment of severe psoriasis of the plaque type. Calcipotriol or UV-radiation used at the same time can increase the clinical effectiveness of acetritin.
Systemic PUVA, balneo-PUVA and UVB therapy are all effective for the treatment of severe psoriasis. The combination of UV therapy with vitamin D3 analogues or with topical steroids is more effective than the treatment with UV radiation alone. Saltwater baths increase the effectiveness of UVB therapy. No RCT on the therapeutical effects of topical tar or of dithranol in combination with UV therapy have been published so far. A continuous therapy with PUVA should not be applied due to its proven photocarcinogenicity.
Three substances from the group of biologicals (Efalizumab, Etanercept, and Infliximab) are now available in Europe and a further substance (Alefacept) is available in the USA for the treatment of moderate to severe psoriasis. All biologicals have been effective in placebo controlled studies. The substances differ in the times until a clinical effect is observable, in the spectrum of side effects and in their efficiency on psoriasis arthritis.
From health-economic studies considering both costs and clinical efficiency oral fumarates appear to be superior to acitretin or cyclosporine (although cyclosporine appears to be more effective in severe psoriasis). From the health economic view methotrexate is equivalent with UVB or PUVA and superior to cyclosporine. The therapy options UVB, UVB plus calcipotriol and PUVA are equivalent and superior to balneo-phototherapy. Biologicals are cost intensive and should be used when other approaches are not sufficient or are not applicable due to their side effects.
The HTA report summarizes some health-economic studies on dithranol, on calcipotriol and on the combination with tar and UV light. No RCT have been published for the treatment of severe psoriasis with these agents alone but it appears to be certain that these substances are effective in severe psoriasis as well.
Discussion
The spectrum of therapeutical options has fortunately increased during the last years. It must be emphasized that a number of therapeutical procedures exist which are not discussed in detail in this HTA. This is due to the search strategy of literature: Only RCT performed with patients with moderate and/or severe psoriasis vulgaris were included into this evaluation. This led to the exclusion of a number of substances which are traditionally used alone or in combination for the treatment of moderate or severe psoriasis vulgaris (e.g. dithranol, salicyc acid, tar, corticosteroids and topical retinoids). Moreover, other approaches which include neither drugs nor UV light are not discussed in this HTA although the authors believe in the importance of psychotherapeutical interventions, educational approaches and combined medical and non-medical approaches in rehabilitational medicine in the management of psoriasis vulgaris.
The transferability of the health economic evaluations is strongly limited by the fact that all included health economic evaluations except one were not aligned to a German setting. A future research question will be the evaluation of the duration of remission and relapse ratios in the context of different therapy options of moderate and severe psoriasis. Moreover, the consideration of combined outcomes such as the improvement of psoriatic symptoms and the decrease of symptoms in accompanying psoriasis arthritis represents a future requirement of health assessment.
Conclusions
From the clinical point of view it is positive that the spectrum of therapeutic procedures for a chronic severe skin disease has increased continuously during the last years. In cases of individual contraindications or individual inefficacies it is now possible to try alternative approaches. Moreover the risk of long-term side effects can be reduced by changing the therapeutical procedure after some time (so-called rotation therapy). The therapeutical algorithm for severe psoriasis vulgaris now includes photo(chemo-)therapy in combination with topical substances, oral fumaric acid esters, retinoids (in combination with phototherapy or topical substances), methotrexate, cylosporine and the new biologics.
Future studies should address therapeutical approaches which can not easily be studied by RCT, e.g. physical, balneological, climate approaches, educational programs and complex rehabilitation therapy which all may have positive effects on individuals with severe psoriasis.
As in medical therapy management of moderate and severe psoriasis the economic evaluation also points out the way of a strategic therapy concept which corresponds to a large extent to the algorithm in medical practice.
Abstract
Fragestellung und Methodik
Der HTA-Bericht fasst kontrollierte klinische Studien aus den Jahren 1999 bis 2004 sowie einen publizierten HTA-Bericht von 2000 von Griffiths et al. [1] zur Therapie der mittelschweren bis schweren Psoriasis vulgaris systematisch zusammen. Wichtige klinische Studien, die nach Abschluss der systematischen Literatursuche 2004 publiziert wurden, wurden möglichst ebenfalls berücksichtigt. Ziel ist es, anhand der aktuellen Literatur zu kontrollierten Studien die medizinische Effektivität und Kosteneffektivität mit Relevanz für Deutschland zu bewerten.
Ergebnisse
Hinsichtlich der medizinischen Effektivität ist aus publizierten kontrollierten Studien zusammenfassend abzuleiten:
Orale Fumarate sind wirksam in der Therapie der mittelschweren bis schweren Psoriasis, verursachen allerdings relativ häufig leichtere unerwünschte Arzneimittelwirkungen. Ciclosporin und Methotrexat sind wirksam in der Behandlung der schweren Psoriasis. Die beiden Substanzen weisen unterschiedliche Nebenwirkungsspektren auf, die die Anwendung im Einzelfall limitieren. Acetritin ist bei schwerer Plaque-Psoriasis als Monotherapie nur mäßig wirksam, Calcipotriol (CAL) oder eine gleichzeitig angewandte UV-Therapie können die klinische Wirksamkeit von Acetritin jedoch verstärken.
Die systemische PUVA, die Bade-PUVA und die UVB-Therapie sind wirksam zur Behandlung der schweren Psoriasis. Die Kombination von UV-Therapie mit Vitamin D3 Analoga oder mit topischen Steroiden ist wirksamer als die Behandlung mit jeweils einem Therapieprinzip allein. Starksolebäder erhöhen die Effektivität der UVB-Therapie. Es gibt keine auswertbaren kontrollierten Studien, die die Effekte von zusätzlichem topischen Teer oder von Dithranol zur UV-Therapie vergleichen. Eine Dauertherapie mit PUVA verbietet sich aufgrund der nachgewiesenen Photokarzinogenität.
In den letzten Jahren wurden in Europa aus der Gruppe der so genannten Biologics drei Substanzen (Efalizumab, Etanercept, Infliximab) und in den USA zusätzlich Alefacept zur Behandlung der mittelschweren bis schweren Psoriasis vulgaris zugelassen. Die genannten Substanzen erwiesen sich in placebokontrollierten Studien als unterschiedlich wirksam, allerdings fehlen direkt vergleichende Studien zu anderen Therapieprinzipien und zu den Biologics untereinander. Unterschiede zwischen den vier Biologics bestehen im Hinblick auf die Stärke der therapeutischen Wirksamkeit, den Wirkungseintritt, das Nebenwirkungsspektrum sowie die Effektivität der Mitbehandlung einer gegebenenfalls gleichzeitig bestehenden Psoriasis-Arthritis.
Aus den gesundheitsökonomischen Studien, die sowohl die Kosten als auch die Effektivität einbeziehen, ist abzuleiten, dass Fumarate im direkten Vergleich günstiger als Acitretin und Ciclosporin sind (wobei bei der schweren Psoriasis Ciclosporin individuell deutlich effektiver sein kann als die beiden anderen Substanzen). Methotrexat ist aus ökonomischer Sicht gleichwertig mit UVB oder PUVA und günstiger als Ciclosporin. Die Therapieoptionen UVB, UVB plus CAL und PUVA sind aus gesundheitsökonomischer Sicht als etwa gleichwertig zu beurteilen und in dieser Hinsicht der Balneo-Phototherapie überlegen. Die relativ neu verfügbaren Biologics sind aufgrund der derzeitigen Preise am wenigsten kosteneffektiv, so dass sie aus ökonomischer Sicht zurzeit erst nach den vorgenannten Therapieoptionen bei der mittelschweren bis schweren Psoriasis vulgaris eingesetzt werden sollten.
Es werden im HTA-Bericht weiterhin gesundheitsökonomische Studien zu den Therapieprinzipien Dithranol, CAL-Monotherapie sowie Kombinationstherapien mit Teer und UV-Licht dargestellt, die wahrscheinlich wirksam in der Therapie der mittelschweren Psoriasis sind, auch wenn hierzu bislang keine kontrollierten Studien zur Effektivität vorliegen.
Diskussion
Das Therapiespektrum hat sich für die mittelschwere bis schwere Psoriasis vulgaris in den letzten Jahren - erfreulicherweise - kontinuierlich vergrößert. Es ist hervorzuheben, dass Therapieverfahren, die hier nicht dargestellt werden, nicht automatisch untauglich für die Therapie der schweren Psoriasis vulgaris sind, denn die Suchstrategie - Einschluss nur von RCT, die mit Patienten mit mittelschwerer oder schwerer Psoriasis vulgaris durchgeführt worden waren - führte zum Ausschluss vieler etablierter ergänzender Verfahren, die in Kombination mit anderen Verfahren auch zur Behandlung der mittelschweren bis schweren Psoriasis vulgaris eingesetzt werden. Hierzu gehören u. a. die topischen Wirkstoffe Dithranol, Salizylsäure, Teerbestandteile, Kortikosteroide und topische Retinoide. Weiterhin wurden Ansätze, in denen weder Medikamente noch UV-Strahlen untersucht wurden, nicht in den Bericht aufgenommen, obwohl die Autoren den hohen Stellenwert gezielter psychotherapeutischer Interventionen, interdisziplinärer Schulungsansätze oder kombinierter medikamentöser und nicht-medikamentöser rehabilitativer Ansätze inklusive Klimatherapie anerkennen.
Die Übertragbarkeit der dargestellten Studienergebnisse aus den gesundheitsökonomischen Evaluationen wird deutlich durch die Tatsache eingeschränkt, dass die Studien bis auf eine Ausnahme nicht auf ein deutsches Setting ausgerichtet waren. Eine zukünftige Forschungsfrage muss auch aus gesundheitsökonomischer Sicht die Bewertung von Remissionsdauer und Rückfallquoten im Rahmen der einzelnen Therapieverfahren der mittelschweren und schweren Psoriasis sein. Auch die Berücksichtigung eines kombinierten Outcomes wie verbessertes Hautbild, Erhöhung der Lebensqualität und/oder Rückgang der Symptomatik einer gleichzeitigen Psoriasis-Arthritis, stellt eine Herausforderung für künftige gesundheitsökonomische Studien dar.
Schlussfolgerung
Zusammenfassend ist es aus medizinischer Sicht zu begrüßen, dass sich das Spektrum der therapeutischen Verfahren für eine schwere chronische Hautkrankheit wie die schwere Psoriasis vulgaris in den letzten Jahren kontinuierlich vergrößert hat. Dieses schafft Ausweichmöglichkeiten bei Kontraindikationen oder bei individueller Unwirksamkeit bestimmter Verfahren und die Möglichkeit, durch abwechselnde Verfahren (Rotationstherapie) das Risiko einzelner Nebenwirkungen zu verringern. Für die schwere Plaque-Psoriasis hat sich, in Abhängigkeit von den individuellen Erfahrungen der Therapeuten und bestehenden Kontraindikationen der Patienten ein therapeutischer Algorithmus etabliert, der als wirksame Interventionstherapien Photo(-chemo-)therapien in Kombination mit externen Wirkstoffen, Fumarsäureester, gegebenenfalls Retinoide (in Kombination mit Phototherapien und externen Wirkstoffen), Methotrexat, Ciclosporin und seit kurzer Zeit auch die neueren Biologics beinhaltet.
Studienbedarf besteht weiterhin zu den Therapieansätzen, die sich schlecht oder gar nicht mit randomisierten kontrollierten Studiendesigns untersuchen lassen. Als Beispiele seien genannt: physikalische, balneologische Ansätze, Klimatherapien, Patientenschulung und auch die komplexe rehabilitative Therapie, für die wahrscheinlich günstige therapeutische Effekte in Bezug auf die Psoriasis bestehen.
Wie im Therapiemanagement in der medizinischen Praxis weist auch die ökonomische Bewertung den Weg eines strategischen Therapiekonzepts, der weitgehend dem Algorithmus der medizinischen Praxis entspricht.
Executive Summary
1. Introduction
Psoriasis is a non life-threatening chronic or chronically relapsing inflammatory skin disease. The prevalence rate is 1% to 2% which means that about 1.5 millions Germans are affected by psoriasis. Psoriasis cannot be healed. Mild psoriasis is usually treated with topical substances. The treatment of moderate and severe psoriasis is primarily performed with photo(chemo)therapy and systemic agents. All systemic drugs may cause side effects. This means that individual benefits and risks have to be considered.
2. Objective
The health technology assessment (HTA) report focuses on clinical effectiveness and cost-effectiveness of therapy options for the treatment of moderate and severe psoriasis. Thus the HTA report represents an update of the English HTA report by the authors Griffiths et al. in 2000 [1]. New literature published between 1999 and June 2004 was systematically evaluated regarding medical effectiveness and the cost effectiveness with relevance for Germany. Important articles which have been published after 2004 were also included into the report.
3. Medical assessment
3.1 Methods
The search strategy included randomized, controlled studies (RCT) on moderate to severe forms of psoriasis. This means that the search strategy may have led to the exclusion of some well established therapeutical procedures which are believed to be effective alone or in combination with other procedures when no RCT are available.
RCT published between 1999 and June 2004 were systematically evaluated regarding medical effectiveness. Important articles which have been published after 2004 were also included into the report. Special forms of psoriasis, in particular psoriasis palmoplantaris pustulosa, psoriasis guttata and psoriasis arthritis, were not evaluated in this report.
Each section contains a summary with most important contents the HTA report from the year 2000. We adapted to the inclusion and exclusion criteria of the former report to make the update comparable to the HTA report from Griffiths et al. [1].
3.2 Results
The major conclusions from the results of medical RCT on moderate and severe psoriasis vulgaris are:
Oral fumarates are effective in the treatment of moderate to severe psoriasis vulgaris. However, fumarates quiet frequently cause moderate side effects which may limit their usefulness. Cyclosporine and methotrexate are both effective in the treatment of severe psoriasis vulgaris as has been shown by one RCT. Both substances have a different spectrum of side effects which may limit the individual applicability.
Acetritin is only moderately effective in the treatment of severe psoriasis of the plaque type even in high concentrations (75 mg or 1 mg/kg). This means that a monotherapy is rarely performed with this substance in plaque psoriasis. Of note the substance is more effective in psoriasis pustulosa and when used in combination with UV radiation or with calcipotriol.
Systemic PUVA, balneo-PUVA and UVB therapy are all effective for the treatment of severe psoriasis. The combination of UV therapy with vitamin D3 analogues or with topical steroids is more effective than the treatment with UV radiation alone. Saltwater baths increase the effectiveness of UVB therapy. No RCT on the therapeutical effects of topical tar or of dithranol in combination with UV therapy have been published so far. A continuous therapy with PUVA should not be applied due to its proven photocarcinogenicity.
Three substances from the group of biologicals (Efalizumab, Etanercept, Infliximab) are now available in Europe and a further substance (Alefacept) is available in the USA for the treatment of moderate to severe psoriasis. All biologicals have been effective in placebo controlled studies. The substances differ in the times until a clinical effect is observable, in the spectrum of side effects and in their efficiency on psoriasis arthritis.
3.3 Discussion
The spectrum of therapeutical options has fortunately increased during the last years. It must be emphasized that a number of therapeutical procedures exist which are not discussed in detail in this HTA report. This is due to the search strategy of literature: Only RCT performed with patients with moderate and/or severe psoriasis vulgaris were included into this evaluation. This led to the exclusion of a number of substances which are traditionally used alone or in combination for the treatment of moderate or severe psoriasis vulgaris (e.g. dithranol, salicyc acid, tar, corticosteroids and topical retinoids). Moreover, other approaches which include neither drugs nor UV light are not discussed in this HTA report although the authors believe in the importance of psychotherapeutical interventions, educational approaches and combined medical and non-medical approaches in rehabilitational medicine in the management of psoriasis vulgaris.
Future studies should address therapeutical approaches which can not easily be studied by RCT, e.g. physical, balneological, climate approaches, educational programs and complex rehabilitation therapy which all may have positive effects on individuals with severe psoriasis.
4. Economic assessment
4.1 Methods
For identification of all relevant literature, the HTA database of the International Network of Agencies for Health Technology Assessment and the Centre for Reviews and Dissemination, University of York, were accessed and scanned for relevant literature and current projects. Additionally a systematic literature search was conducted in electronic data bases. A manual search in non-MEDLINE German (health economics) journals without time limits and references of literature hints completed the electronic literature research. About 20 German pharmaceuticals companies were asked for information about innovations in therapy of psoriasis und so far unpublished reports.
The presentation of results is carried out separately for each included health economic evaluation as a structured summary. Selected excluded economic analyses are also characterised within the appendix. In a synthesis the results of the health-economic evaluations are combined in an ordinal rank order.
4.2 Results
A numerically meaningful scientific discussion about economic questions in therapy of moderate and severe psoriasis in terms of publications started at end of the 90ies. Beside economic analysis also estimations of health care cost or analysis of treatment cost can be found. The literature research identifies 15 full health economic evaluations, of which three should be classified as so called grey literature. Regarding the methodology employed and use of primary and secondary data the included publications represent a wide and mixed spectrum.
The therapy options UVB, UVB plus calcipotriol and PUVA are equivalent and dominate (superiority in an economic sense) balneo-phototherapy, UVB plus tar externals and short-contact dithranol. The relationship of the mono therapy calcipotriol and short therapy dithranol is ambivalent. Methotrexat is equivalent to UVB and PUVA and outperforms UVB plus tar externals as well as ciclosporin. Fumarates exceed ciclosporin and acitretin. Unfortunately the relationship of fumarates and methotrexat is not analysed yet. In health economic evaluations the new biologics are shown less cost effective, so that they should be used as a last resort.
4.3 Discussion
The transferability of the health economic evaluation results is strongly limited by the fact that all included health economic evaluations except one were not aligned to a German setting, but the relationships of individual intervention groups in respect to their control groups are less affected.
It should be viewed critically that economic outcomes are frequently applied only remission as an economic endpoint. A future research question will be the evaluation of duration of remission and relapse ratios in the context of different therapy options of moderate and severe and psoriasis. Also the consideration of combined outcomes, improvement of psoriatic symptoms and decrease of symptoms in accompanying psoriasis arthritis, represents a future requirement.
5. Conclusions
From the clinical point of view it is positive that the spectrum of therapeutic procedures for a chronic severe skin disease has increased continuously during the last years. In cases of individual contraindications or individual inefficacies it is now possible to try alternative approaches. Moreover the risk of long-term side effects can be reduced by changing the therapeutical procedure after some time (so-called rotation therapy). The therapeutical algorithm for severe psoriasis vulgaris now includes photo(chemo-)therapy in combination with topical substances, oral fumaric acid esters, retinoids (in combination with phototherapy or topical substances), methotrexate, cylosporine and the new biologics.
As in medical therapy management of moderate and severe psoriasis the economic evaluation also points out the way of a strategic therapy concept which corresponds to a large extent to the algorithm in medical practice. If a therapeutic change of a primary therapy is necessary, subordinate secondary and afterwards tertiary therapy options are available from economic point of view. The rank order of primary, secondary and tertiary therapies correspond largely with medical practice.
References
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