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Keywords:

  • combination therapy;
  • psoriasis

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Objectives
  5. Methods
  6. Results
  7. Comments
  8. Acknowledgements
  9. Conflict of interest
  10. References

In addition to topical monotherapy for mild and systemic monotherapy for moderate to severe psoriasis, combination therapy plays an important role in daily practice. Although clinical trials almost exclusively evaluate monotherapy regimens, in real life psoriasis patients are usually treated with combination therapies. All combinations are used, topical/topical, topical/UV-light, topical/systemic or UV-light/systemic. Often not only two but more drugs/therapies are combined. Not every combination provides additive or synergistic effects. Some combinations are not possible and may be regarded as contraindications. Data on a benefit-risk-assessment are much more sparse in medical literature as compared to monotherapies. We summarize current knowledge about the use of combination therapies in psoriasis on the basis of published literature in the form of a table to show which combinations are possible, useful or which can not be recommended. This provides a quick overview of available options.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Objectives
  5. Methods
  6. Results
  7. Comments
  8. Acknowledgements
  9. Conflict of interest
  10. References

In recent years, the treatment of psoriasis vulgaris has undergone significant changes. The current standard of care for psoriasis patients is based on the S3 guideline published in 2006 by the German Society of Dermatology (DDG) and the Federal Association of German Dermatologists (BVDD) which is currently being revised [1, 2]. The European S3 guideline, which builds on the German guideline, has also been available since October 2009 [3]. The creation of guidelines was necessary for several reasons:

  • • 
    Increasing need for treatments based on evidence-based medicine,
  • • 
    Availability of various new drugs,
  • • 
    Inadequate care of psoriasis patients.

An important aspect is the formulation of treatment goals which were discussed for the first time in the guidelines and then in subsequent publications [4].

Significant improvements in psoriasis care have been made thanks to the guidelines as well as the advent of various biological therapies (currently three approved TNFa inhibitors, as well as ustekinumab which is the first p40 antagonist) and improved topical galenicals and the potential for use in topical combination therapies (e.g., Elosalic®, Daivobetc®/Psorcutanc® beta). Improvements in care are also reflected in preliminary survey results (e.g., the “National Care Study on Psoriasis – PsoHealth” 2007) [5]. Despite all efforts and advancements, however, in moderate-to-severe disease in particular, which affects as many as 50% of psoriasis patients, treatment is not always adequate or long-lasting which further reduces the satisfaction of patients with available therapy options [6, 7].

Combining medications and therapies is one possible alternative for improving treatment effectiveness and for reducing potential side effects which may limit treatment. At present, due to lacking data, the choice of a combination therapy is often based only on its anticipated effect and personal experience rather than on evidence-based criteria. It is thus vital that recommendations be made for combination therapies with the most commonly-used treatment options in order to enhance long-term disease management while minimizing the risks associated with necessary long-term therapy. Furthermore, psoriasis is no longer seen as merely a disease of the skin, but rather is viewed as an inflammatory systemic disease with associated co-morbidities [8–10]. Long-term, sustained control of the systemic inflammatory reaction is considered increasingly important particularly for reducing associated cardiovascular disease. This underscores the need to develop safe and effective long-term strategies, including combination therapies.

Objectives

  1. Top of page
  2. Summary
  3. Introduction
  4. Objectives
  5. Methods
  6. Results
  7. Comments
  8. Acknowledgements
  9. Conflict of interest
  10. References

The aim of the present paper was to provide an overview of the current information on possible therapy combinations in the treatment of psoriasis. The intention is not to conduct a meta-analysis in the sense of a Cochrane review but rather to produce a useful table for practical usage of combination therapies for psoriasis. We have intentionally omitted any discussion or analysis of the data. For more detail, the reader is referred to the cited references.

Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Objectives
  5. Methods
  6. Results
  7. Comments
  8. Acknowledgements
  9. Conflict of interest
  10. References

A thorough search of the literature was made using Medline/PubMed with the keywords psoriasis, (combination-) therapy, and also by individual drug name/ therapy name. The results are summarized in Table 1. For the majority of possible combination therapies, there were either no or only very limited data and virtually no evidence-based studies. Some therapy combinations, such as topical vitamin D3/corticosteroid (Daivobet®/Psorcutan® beta) and corti-costeroid/salicylic acid (Elosalic®), which are now commercially-available combination therapies, have been thoroughly tested and may be recommended on the basis of current study results.

Table 1.  Assessment of possible therapy combinations for the treatment of psoriasis with literature references. +/−= Combination is useful/not useful, ?= no publications, (+)/(−) = case reports with positive/negative results.
 Calcineurin inhibitorsDithranolCorticosteroidsTarVitamin D3TazaroteneSalicylic acidUreaCyclosporineFumaric acid esterMethotrexateRetinoidsAdalimumabEtanerceptInfliximabUVBPUVA
Calcineurin ???(+)1?+2??????????
Dithranol? +3−/(+)4+5+6++7(+)8??????+9(+)10
Corticosteroids?+3 (+)11+12+13+14????+15?(+)16?17+/−18
Tar?−/(+)4(+)11 (+)19??????????+20−/(+)21
Vitamin D3(+)1+5+12(+)19 +22??+/(+)23+24+25+26?+27?+28+29
Tazarotene?+6+13?+22 ?????????+30+31
Salicylic acid+2++14??? ????????3233
Urea?+7????? ?????????
Cyclosporine?(+)8??+/(+)23??? (+)34+35+/(+)36?+/(+)37(−)38(+)39(+)40
Fumaric acid ester????+24???(+)34 (+)41(+)42?????
Methotrexate????+25???+35(+)41 +/(+)43?+/(+)44+/(+)45+46+47
Retinoids??+15?+26???+/(+)36(+)42+/(+)43 (+)48+/(+)49(+)50+51+52
Adalimumab???????????(+)48 ????
Etanercept??(+)16?+27???+/(+)37?+/(+)44+/(+)49? ?+53?
Infliximab????????(−)38?+/(+)45(+)50?? ??
UVB?+917+20+28+3032?(+)39?+46+51?+53? +54
PUVA?(+)10+/−18−/(+)21+29+3133?(+)40?+47+52???+54 
1[19]12[11, 15, 21–26]23[38, 46–51]34[53]45[74, 78–84]
2[40]13[15, 24, 28–38]24[52]35[38, 55–58]46[38, 58, 103]
3[11–13]14[15, 21, 41–43]25[49, 54]36[38, 62, 63]47[38, 58, 125–127]
4[14–16]15[38]26[38, 49, 59–61]37[67–71]48[64]
5[20]16[65]27[66]38[77]49[64, 65, 71, 75, 76]
6[27]17[38, 91, 92]28[38, 49, 85, 86, 88, 95–99]39[38]50[81]
7[44]18[38, 91,114–116]29[38, 49, 96, 98, 118–120]40[38, 123, 124]51[38, 58, 62, 104–110]
8[45]19[17]30[33, 36, 38, 85, 100, 101]41[53]52[38, 58, 62, 104, 106, 108, 110, 128, 129]
9[86–90]20[89, 93, 94]31[36, 38, 118, 121]42[53]53[111, 112]
10[38, 113]21[38, 114, 117]32[42, 102]43[39, 58, 62]54[38]
11[17, 18]22[35, 38]33[122]44[69–74]  

It is therefore still not possible to present complete data and recommendations on potential or improper combinations.

The table provided here reflects current knowledge from scientific publications and is thus a preliminary overview of potential future recommendations.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Objectives
  5. Methods
  6. Results
  7. Comments
  8. Acknowledgements
  9. Conflict of interest
  10. References

The results of our literature search are summarized in Table 1. Combination therapies for which there are as yet no published results (e.g., randomized studies, case reports, reviews, etc.) have been marked with a “?”. Randomized studies with a positive or negative assessment of the investigated therapy were marked with “+” or “−”. If only case reports or small case series have been published, the assessment was placed in parentheses.

Comments

  1. Top of page
  2. Summary
  3. Introduction
  4. Objectives
  5. Methods
  6. Results
  7. Comments
  8. Acknowledgements
  9. Conflict of interest
  10. References

The following comments apply to the table:

  • • 
    Salicylic acid inactivates vitamin D3 analogues (calcipotriol, calcitriol, and tacalcitol) and should therefore not be combined with them (latency period after salicylic acid and prior to vitamin D3 analogue use: 3 days).
  • • 
    The combination of salicylic acid with systemic therapies such as cyclosporine, methotrexate, and fumaric acid esters can lead to nephrotoxic side effects. These therapies should only be used if absolutely necessary and should be administered under careful surveillance.
  • • 
    For the combination of UV therapy (PUVA or UVB) and topical cal-cineurin inhibitors, a warning has been published in the product information about increased photocarcinogenicity Concomitant use of these therapies is not advised.
  • • 
    The use of salicylic acid-based topical therapies immediately prior to UV therapy diminishes the effectiveness of phototherapy due to absorption of UV by the chemical. An interval of at least 12 hours between the two therapies is recommended.
  • • 
    The combination of cyclosporine and UV therapy is contraindicated given an increased risk of cancer.
  • • 
    The combination of methotrexate and UV therapy is not advised given a possible increased risk of the development of epithelial skin tumors.
  • • 
    Combination use of topical corticosteroids and calcineurin inhibitors is conceivable and appears useful but there are still no published data for psoriasis.
  • • 
    Dithranol-based topical therapies are often available in a salicylic base as this improves stability.
  • • 
    Although the S3 guideline on psoriasis therapy does not advise the use of tarbased therapies given insufficient evidence of their effectiveness, tar-based therapies are nevertheless used under special circumstances. Results for combination therapies with tar-based products have thus been included in the table.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Objectives
  5. Methods
  6. Results
  7. Comments
  8. Acknowledgements
  9. Conflict of interest
  10. References

Funding for this paper was provided by a stipend from the German Psoriasis Association e. V, Hamburg.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Objectives
  5. Methods
  6. Results
  7. Comments
  8. Acknowledgements
  9. Conflict of interest
  10. References
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