SPIN2019

Conference summaries


PSORIASIS

Combined therapy in psoriasis

Presented by: Pablo Coto-Segura, MD, PhD
Hospital Vital Álvarez-Buylla, Mieres, Spain
  • Psoriasis (PsO) is a chronic, systemic, inflammatory condition for which a variety of treatment modalities exist.
  • Combinations of therapies are used often in clinical practice to enhance efficacy and reduce drug toxicities.
  • Traditional systemic therapies for PsO are often not able to meet desired treatment goals, and high-dose and/or long-term use is associated with toxicities that can result in end-organ damage.
  • Despite remarkable improvements in PsO treatment outcomes with biologic therapy, many patients still do not achieve the desired goals, have a prolonged time to response, or fail to maintain efficacy improvements over time.
  • Treatment cycles identified as combined therapy range from 9.9% (PSONET registry [1]) to 25.1% (BADBIR registry – the inclusion of patients on bridging therapy (21.4%) may partly explain this difference [2]).
  • Rather than increasing the dosage of monotherapies, which may be limited due to concerns of accumulating toxicity, combined therapy is often employed by many dermatologists to improve overall treatment response and minimize adverse effects associated with higher doses.
  • Most patients will not need this kind of approach however there are specific groups that can benefit (see Table 1).
  • In sub-optimal responders, who would require high doses of the systemic agent associated with tolerability or safety concerns, combined therapies can be considered.
  • The main reason identified in registries to use combined therapy was psoriatic arthritis (in up to 30% of patients) as they may benefit from a broader immunosuppressive effect.
  • European consensus guidelines recommend that combined therapy should be considered for individuals who are switching to a biologic agent and in whom it may be useful to taper previous systemic therapy before discontinuation to prevent a disease flare.
  • In patients with a well-controlled systemic agent who unexpectedly experience a rebound or a flare, rather than switching to another drug we may consider the use of combined therapy for a short period.
  • Combined therapy may also be helpful in the prevention or treatment of adverse events in certain patients (e.g., use of retinoids in a patient at high risk of non-melanoma skin cancer, or methotrexate (MTX) in under treatment with interferon to prevent antidrug-antibodies formation).
  • Combined therapy with retinoids, is an old, well-known combination that provide better results than each regimen alone.
  • Both cyclosporine and phototherapy are associated with an increased carcinogenic risk, so this combination has not been widely used or studied.
    • In a small study, patients underwent concomitant treatment with cyclosporin-A (CsA) and UVB. The therapeutic synergism of the two treatments allowed to initiate treatment with a CsA and a lower dosage phototherapy than used in a monotherapy scenario (2.5 mg/kg/day instead of 3.5-4 mg/kg/day, and UVB twice a week) [3].
  • Few studies found small statistically significant differences in favor of UV-B/psoralen plus ultraviolet A (PUVA) plus MTX [4-5].
  • Apremilast is an oral small molecule phosphodiesterase-4 (PDE4) inhibitor and clinical trials report an efficacy range of between 29-33% PASI 75 at week 16 [6].
  • In a small study (n = 29) that combine UVB plus apremilast, after 12 weeks, 73% of the patients achieved PASI 75, and 45% achieved a PASI 90.
  • Of note is that the therapeutic effect of the apremilast−narrowband (NB)-UVB combination was greater than that reported with apremilast alone [7].
  • Apremilast has been combined with many therapies, and the best results seem to be with phototherapy (see Figure 1).
  • One of the problems with fumaric acid esters (FAE) is the long time to response (up to 24 weeks).
  • However, it has been proven that combining a short course of NB-UVB to FAE both accelerates and increases the therapeutic response during the early phase of treatment [8].
  • There is a lack of evidence for other combinations, but expert opinion suggests that in combination with infliximab or MTX there may be an increased risk of immunosuppression [9].
  • A number of uncontrolled clinical trials have shown positive results when NB-UVB therapy was combined with etanercept, adalimumab, and ustekinumab.
  • The best evidence is for NB.
    • Two retrospective studies evaluated NB-UVB combined with etanercept in plaque psoriasis patients found a comparable PASI 75 response at week 12. Up to 85% achieved PASI 75 [6,10].
    • However, others found that obese patients treated with etanercept + NB-UVB may not result in significant benefit [11-12].
  • One of the main problems of combining phototherapy with biologic agents is the low adherence to the treatment (21%).
  • Systemics:
    • Retinoids: a well-known combination with the highest quality of evidence.
    • MTX: slight increase in efficacy.
    • CsA: non recommended due to increased risk of skin cancer, except short-cycles.
    • Apremilast: works better with phototherapy than alone.
    • FAE: a short-term cycle (4-6 weeks) may enhance efficacy.
  • Biologics:
    • Etanercept: problems with the adherence to the treatment and less efficacious in obese patients.
  • Among the biologics, etanercept and MTX combination therapy is the most well studied, and this combination is more effective than either etanercept or MTX alone, but adverse events are high (74.9 % combination therapy vs. 59.8 % etanercept monotherapy) [13].
  • Infliximab: in the IMPACT2 study at week 54, PASI 75 MTX + infliximab was 53% vs. 48% infliximab only (no P value reported) and the incidence of infusion reactions was significantly lower in combination MTX + infliximab [14].
  • Adalimumab: a small study (n = 45) of combination therapy MTX + adalimumab vs. adalimumab dose escalation reported PASI 50 at 12 weeks of 9 % vs. 25% and at 24 weeks 18 % vs. 35%, respectively, suggesting that at least for some patients, adalimumab dose escalation may be more beneficial than adding MTX [15].
  • There is no difference with adding CMX.
  • MTX + etanercept improves efficacy with slight increase in adverse event.
  • MTX + infliximab does not improve efficacy but prevents drug infusion reactions.
  • Adalimumab dose escalation may be a better strategy than adding MTX.
  • Adding MTX to CMX does not improve efficacy.
  • Other biologics agents do not benefit of combining with MTX.
  • Acitretin is a traditional systemic treatment for PsO with antiproliferative and immunomodulatory properties.
  • Acitretin may contribute to additive effectiveness when combined with a biologic and could be considered in patients for whom immunosuppression is not desirable.
  • Therefore, with concomitant use of acitretin, the dosing of etanercept can be reduced to maintain similar levels of efficacy [16-17] (see Figure 2).

Conclusions

  • Specific groups may benefit from combined therapy.
  • Combinations with phototherapy are safe and may work either with systemic (retinoids, apremilast, FAE) or biological agent (etanercept).
  • MTX is the most frequent used in combined therapy although the data that support it use to enhance efficacy are mainly limited to etanercept.
  • Apremilast and retinoids are also suitable to combine with other therapies with an increase in efficacy ratios and a good safety profile.


References

References


  1. Busard CI, Cohen AD, Wolf P, et al. Biologics combined with conventional systemic agents or phototherapy for the treatment of psoriasis: real-life data from PSONET registries. J Eur Acad Dermatol Venereol. 2018;32:245-53.
  2. Iskandar IYK, Ashcroft DM, Warren RB, et al. Patterns of biologic therapy use in the management of psoriasis: cohort study from the British Association of Dermatologists Biologic Interventions Register (BADBIR). Br J Dermatol. 2017;176; 1297-307.
  3. Franchi C, Cainelli G, Frigerio E, et al. Association of cyclosporine and 311 nM UVB in the treatment of moderate to severe forms of psoriasis: A new strategic approach. Int J Immunopathol Pharmacol. 2004;17:401-6.
  4. Mahajan R, KaurI, KanwarAJ. Methotrexate/narrowband UVB phototherapy combination vs. narrowband UVB phototherapy in the treatment of chronic plaque-type psoriasis: a randomized single-blinded placebo-controlled study. J Eur Acad Dermatol Venereol. 2010;24:595-600.
  5. Asawanonda P, Nateetongrungsak Y. Methotrexate plus narrowband UVB phototherapy versus narrowband UVB phototherapy alone in the treatment of plaque-type psoriasis: a randomized, placebo-controlled study. J Am Acad Dermatol. 2006;54:1013-8.
  6. Kircik L, Bagel J, Korman N, et al. Utilization of narrow-band ultraviolet light B therapy and etanercept for the treatment of psoriasis (UNITE): efficacy, safety, and patient-reported outcomes. J Drugs Dermatol. 2008;7:245-53.
  7. De Simone C, D’Agostino M, Capizzi R, et al. Combined treatment with etanercept 50 mg once weekly and narrow-band ultraviolet B phototherapy in chronic plaque psoriasis. Eur J Dermatol. 2011;21:568-72.
  8. Mrowietz U, Adamczyk A, Augustin M, et al. New information about fumaric acid esters (Fumaderm): results of a workshop of experts - German]. J Dtsch Dermatol Ges. 2011;9:1-13.
  9. Tzaneva S, Geroldinger A, Trattner H, Tanew A. Fumaric acid esters in combination with a 6- week course of narrow-band UVB provides for an accelerated response as compared to fumaric acid esters monotherapy in patients with moderate to severe plaque psoriasis: A randomized prospective clinical study. Br J Dermatol. 2018;178:682-8.
  10. Nast A, Gisondi P, Ormerod AD, et al. European S3-Guidelines on the systemic treatment of psoriasis vulgaris--Update 2015--Short version--EDF in cooperation with EADV and IPC. J Eur Acad Dermatol Venereol. 2015 Dec;29(12):2277-94.
  11. Lynde CW, Gupta AK, Guenther L, et al. A randomized study comparing the combination of nbUVB and etanercept to etanercept monotherapy in patients with psoriasis who do not exhibit an excellent response after 12 weeks of etanercept. J Dermatolog Treat. 2012;23:261-7.
  12. Park KK, Wu JJ, Koo J. A randomized, ‘head-to-head’ pilot study comparing the effects of etanercept monotherapy vs. etanercept and narrowband ultraviolet B (NB-UVB) phototherapy in obese psoriasis patients. J Eur Acad Dermatol Venereol. 2013;27(7):899-906.
  13. Wolf P, Weger W, Legat FJ, et al. Treatment with 311-nm ultraviolet B enhanced response of psoriatic lesions in ustekinumab-treated patients: a randomized intraindividual trial. Br J Dermatol. 2012;166:147-53.
  14. Gottlieb AB, Langley RG, Strober BE, et al. A randomized, double-blind, placebo-controlled study to evaluate the addition of methotrexate to etanercept in patients with moderate to severe plaque psoriasis. Br J Dermatol. 2012;167:649-57.
  15. Kavanaugh A, Krueger GG, Beutler A, et al; IMPACT 2 Study Group. Infliximab maintains a high degree of clinical response in patients with active psoriatic arthritis through 1 year of treatment: results from the IMPACT 2 trial. Ann Rheum Dis. 2007;66:498-505.
  16. Wee JS, Petrof G, Jackson K, et al. Infliximab for the treatment of psoriasis in the U.K.: 9 years’ experience of infusion reactions at a single centre. Br J Dermatol. 2012;167: 411-6.
  17. Gisondi P, Del Giglio M, Cotena C, Girolomoni G. Combining etanercept and acitretin in the therapy of chronic plaque psoriasis: a 24-week, randomized, controlled, investigator-blinded pilot trial. Br J Dermatol. 2008;158:1345-9.
  18. Smith EC, Riddle C, Menter MA, Lebwohl M. Combining systemic retinoids with biologic agents for moderate to severe psoriasis. Int J Dermatol. 2008;47:514-8. 

Presenter disclosure(s): [None provided]

Written by: Johanna Chester, BA

Reviewed by: Martina Lambertini, MD


All report

Welcome to the SPIN 2019 Highlights

Jo Lambert, MD, PhD

With this collection of summaries from selected presentations at SPIN 2019, and interviews with international experts, we hope to share with you some of the highlights of this year’s congress. The international network met … [ Read all ]

SUMMARIES

ATOPIC DERMATITIS & PSORIASIS

Atopic dermatitis and psoriasis: On a spectrum?

Presented by: Emma Guttman-Yassky, MD, PhD

INFLAMMATORY SKIN DISEASES

PSORIASIS

Which drug for which patient?

Presented by: Emilie Sbidian, MD, PhD

PSORIASIS

Effects of biotherapy on vascular disease in psoriasis

Presented by: Nehal N. Mehta, MD, MSCE, FAHA

SYSTEMIC THERAPIES

Classical systemic therapies – Methotrexate

Presented by: Rolland Gyulai, MD, PhD, DSc

SMALL MOLECULES

Small molecules, apremilast, and beyond

Presented by: Richard G.B. Langley, MD

PSORIASIS

Treatment goals in psoriasis

Presented by: Ulrich Mrowietz, MD

PSORIASIS

Combined therapy in psoriasis

Presented by: Pablo Coto-Segura, MD, PhD

MEASURING OUTCOMES

PSORIASIS & ADHERENCE

How can we support optimal medication adherence?

Presented by: Rachael Thorneloe, MD