Lyn C. Guenther, MD, FRCPC
Division of Dermatology, University of Western Ontario, London, ON, Canada
The Guenther Dermatology Research Centre, London, ON, Canada
Although biologics are very efficacious as monotherapy in patients with psoriasis, combination treatment with traditional systemic and topical therapies may increase the speed of onset and enhance efficacy without significant additional toxicity. In contrast, in psoriatic arthritis, the addition of methotrexate to anti-tumour necrosis factor-alpha therapy does not enhance efficacy in either the skin or joints.
acitretin, adalimumab, alefacept, biologics, calcipotriol, combination therapy, cyclosporine, etanercept, infliximab, methotrexate, phototherapy, psoriasis
Psoriasis is a chronic inflammatory disorder that is associated with a number of comorbidities including arthritis, cardiovascular risk factors, and inflammatory bowel disease.1 Patients with moderate to severe disease usually require phototherapy, traditional systemic medications (e.g. methotrexate, acitretin, and cyclosporine), or biologic agents (e.g., adalimumab, alefacept, etanercept, infliximab, and ustekinumab) for adequate control.2 Alefacept binds to CD2 on CD45RO+ effector T lymphocytes, inhibiting their activation and inducing apoptosis of these T cells, while adalimumab, etanercept, and infliximab inhibit tumour necrosis alpha, a cytokine that is elevated in patients with psoriasis, and ustekinumab inhibits interleukins 12 and 23, which are also elevated in psoriasis.3 Although biologics are generally used as monotherapy, in Europe the concurrent use of traditional systemic agents can be found in up to 30% of cases.4 Addition of a biologic to traditional systemic therapy can enhance efficacy, or permit discontinuation or dose reduction of the traditional systemic agent without compromising disease control. On the other hand, addition of a systemic agent, phototherapy, or topical therapy to a biologic can enhance efficacy, including speed of onset, degree of clearing, and in some cases duration of remission or improve safety. Since acitretin can suppress the development of skin cancers, such as squamous cell carcinoma in high risk patients,5 addition to at-risk individuals receiving biologic treatment might enhance safety.
In rheumatoid arthritis (RA) and psoriatic arthritis patients, methotrexate is routinely used with tumour necrosis factor-alpha (TNF-alpha) inhibitors without additional toxicity.6,7 In contrast to the psoriasis and RA investigations, studies in patients with psoriatic arthritis have shown that concurrent methotrexate and anti-TNF agents (adalimumab,8 etanercept,9 infliximab10) does not enhance efficacy in either the skin or joints. Some efficacy and safety data in psoriasis are available for combination therapy with adalimumab, alefacept, etanercept, and infliximab, but not for ustekinumab.
Combination Therapy with Adalimumab (Humira®)
Calcipotriol + Betamethasone Dipropionate
Adalimumab used in combination with calcipotriol + betamethasone dipropionate (Dovobet®) showed a more rapid and higher PASI 75 response at week 4 (40.7% vs. 32.4%, p=0.021) compared with adalimumab monotherapy.11 However, at week 16, there was no significant difference in PASI 75 response (64.8% with combination therapy vs. 70.9% with adalimumab monotherapy, p=0.086).
Adalimumab in combination with methotrexate results in down regulation of more inflammatory markers in psoriatic plaques than monotherapy with either agent.12 In the ADEPT psoriatic arthritis trial, at week 48, PASI 50, 75, 90, and 100 response rates were greater in the with-methotrexate subgroups (n=29) compared to the adalimumab without methotrexate subgroup (n=40), but only the PASI 50 results were statistically significant (PASI 50 in 83% vs. 55 %, p<0.05).13
Combination Therapy with Alefacept (Amevive®)
Alefacept has Health Canada approval for use in combination with mid- to high-potency topical agents, ultraviolet B (UVB) phototherapy, methotrexate, cyclosporine, and systemic retinoids.14 The Canadian AWARE study showed that alefacept allowed for a reduction in dosage or discontinuation of concomitant systemic agents or phototherapy.15
In an open-label study of 1-3 courses of alefacept (n=449), combination therapy with topical agents occurred in approximately one-third and combination treatment with phototherapy or traditional systemic agents was also used in approximately one-third of patients [UVB (n=24), methotrexate (n=63), cyclosporine (n=42), systemic retinoids (n=23), and prednisone (n=7)].16 When alefacept was added to existing treatment regimens, ≥30% achieved a response of mild or better. Concurrent therapy with methotrexate or cyclosporine resulted in lower response rates than with other agents. A physician global improvement (PGA) of at least two categories was achieved by 20-21% on methotrexate, 31-43% on cyclosporine, 50-64% on systemic retinoids, 43-62% on mid- to high-potency topical agents, and 55-77% on UVB. There was no increased risk of infection or malignancy when alefacept was used in combination with methotrexate or cyclosporine. The lower response rates with methotrexate combination therapy may be secondary to the study requirement for discontinuation of methotrexate within 4 weeks of initiation of alefacept and the fact that many patients experienced flares as soon as it was discontinued. Cyclosporine was also initially suspended within the first 4 weeks of alefacept therapy; however, due to flares, the protocol was amended so that cyclosporine could be discontinued within 6 weeks after the 12-week alefacept dosing period. Other therapies could be continued throughout the treatment courses.
In an open label study of 60 patients, greater efficacy and a more rapid onset of action were noted with a combination of alefacept and narrowband (nb) or broadband (bb) UVB compared with alefacept monotherapy.17 Four weeks after treatment was started, PASI 50 was achieved at the US site in 0% on monotherapy vs. 22% on bb UVB + alefacept, and at the French site 44% on monotherapy vs. 82-90% on nb UVB + alefacept. Similarly in a half-side comparison alefacept/nb UVB study (n=14), the side treated with nb UVB had accelerated and improved clearance.18
A case series of two patients who had previously been unresponsive to ultraviolet phototherapy, methotrexate, and acitretin showed that combination therapy of alefacept with low dose (10 mg, 25 mg) acitretin shortened the onset of improvement to 4-5 weeks (compared with the usual 8 weeks) and improved inverse and palmoplantar psoriasis.19 In one patient with a history of squamous cell carcinoma (SCC) who developed three SCCs every 2 weeks while on etanercept monotherapy, after acitretin 25 mg every other day was added only actinic keratoses developed during the 18 month follow-up.20
Combination Therapy with Etanercept (Enbrel®)
The addition of calcipotriol cream twice daily for 4 weeks, then once daily for 8 weeks, in patients with psoriasis and psoriatic arthritis who had not achieved PASI 50 at week 12 (n=45 patients) with etanercept 50 mg twice weekly, allowed 31.1% (14 patients) to become PASI 75 responders and 51.1% (23 patients) to become PASI 50 responders at week 24 despite a dose reduction in etanercept to 25 mg twice weekly at week 12.21
Narrowband UVB enhances efficacy irrespective of whether it is used from the start (12 week PASI 75 in 90% vs. 40% on etanercept 25 mg twice weekly monotherapy)22 or added after 6 weeks to patients who had not attained PASI 75 response with etanercept 50 mg twice weekly (after 6 weeks of combination therapy: mean PASI=1.6 vs. 4.7 for non-UVB treated body half, p=0.0192).
In the EASE trial, the odds ratio of a ‘clear’/’almost clear’ PGA was 2.246 (95% confidence interval (CI) 1.25, 4.0; p=0.0069) for concomitant methotrexate/etanercept when compared with etanercept monotherapy.23 In this study, 30% of patients could reduce their weekly dose of methotrexate and 16% could stop it altogether. In the EDUCATE study, 29% could discontinue methotrexate and 7% could lower their dose.24 In cases of inadequate response to methotrexate, in one study continuation of the methotrexate when etanercept was initiated resulted in greater efficacy with a similar safety profile than when the methotrexate was tapered and discontinued during the first 4 weeks (PGA ‘clear’ or ‘almost clear’ at 24 weeks in 66.7% vs. 37.0% respectively, p=0.025).25
A small study (n=60) showed that etanercept 25 mg twice weekly and etanercept 25 mg once weekly + acitretin 0.4 mg/kg/day had similar efficacy at week 24 (PASI 75: 45% and 44% respectively; mean BSA reduction: 80% and 78.2% respectively), suggesting that concomitant use of acitretin can lower the required dose of etanercept.26
Small case series suggest that etanercept can maintain control when cyclosporine discontinuation is needed.23,27 In a small psoriatic arthritis study, addition of cyclosporine 3.0 mg/kg/day to 11 patients whose arthritis was in remission, but who had an insufficient skin response, resulted in 9/11 achieving PASI 75 at week 24.28
Combination with Infliximab (Remicade®)
Warren et al. used methotrexate in one patient and cyclosporine in two patients at transition to infliximab therapy in order to prevent a flare.29 Dalaker and Bonesrønning treated 17 patients with infliximab 3 mg/kg + methotrexate 7.5-15 mg/wk, one with infliximab 5 mg/kg + methotrexate, and five patients with infliximab 5 mg/kg + azathioprine 50 mg/day.30 At week 14, 69.6% achieved PASI 75 and 39.1% PASI 90. Two patients on methotrexate + infliximab stopped treatment because of loss of response, one after 14 months and one after 3 years.
The National Institute for Health and Clinical Excellence (NICE) guidelines recommend concurrent use of methotrexate with infliximab to enhance efficacy, reduce the development of antibodies to infliximab, and in cases where it is need, to associated arthritis.31 Co-administration of methotrexate with infliximab may result in higher infliximab serum levels.31
Combination therapy of biologics with topicals, phototherapy, and/or traditional systemics is commonplace and may enhance efficacy including speed of onset and maintenance of response. Moreover, biologics can permit discontinuation or dose reduction of traditional systemic agents. Conversely, traditional systemic agents may permit lowering of the biologic dose. Rather than changing biologic agents, combination therapy should be considered in circumstances of inadequate efficacy or relapses/ flares with monotherapy.
- Guenther L, Gulliver W. Psoriasis comorbidities. J Cutan Med Surg 13(Suppl 2):S77-87 (2009 Sep-Oct).
- Guenther L, Langley RG, Shear NH, et al. Integrating biologic agents into management of moderate-to-severe psoriasis: a consensus of the Canadian Psoriasis Expert Panel. February 27, 2004. J Cutan Med Surg 8(5):321-37 (2004 Sep-Oct).
- Menter A, Gottlieb A, Feldman SR, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol 58(5):826-50 (2008 May).
- Driessen RJ, Boezeman JB, van de Kerkhof PC, et al. Three-year registry data on biological treatment for psoriasis: the influence of patient characteristics on treatment outcome. Br J Dermatol 160(3):670-5 (2009 Mar).
- Marquez C, Bair SM, Smithberger E, et al. Systemic retinoids for chemoprevention of non-melanoma skin cancer in high-risk patients. J Drugs Dermatol 9(7):753-8 (2010 Jul).
- Greenberg JD, Reed G, Kremer JM, et al. Association of methotrexate and tumour necrosis factor antagonists with risk of infectious outcomes including opportunistic infections in the CORRONA registry. Ann Rheum Dis 69(2):380-6 (2010 Feb).
- Kristensen LE, Gulfe A, Saxne T, et al. Efficacy and tolerability of anti-tumour necrosis factor therapy in psoriatic arthritis patients: results from the South Swedish Arthritis Treatment Group register. Ann Rheum Dis 67(3):364-9 (2008 Mar).
- Mease PJ, Gladman DD, Ritchlin CT, et al. Adalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: results of a doubleblind, randomized, placebo-controlled trial. Arthritis Rheum 52(10):3279-89 (2005 Oct).
- Mease PJ, Kivitz AJ, Burch FX, et al. Continued inhibition of radiographic progression in patients with psoriatic arthritis following 2 years of treatment with etanercept. J Rheumatol 33(4):712-21 (2006 Apr).
- Kavanaugh A, Krueger GG, Beutler A, et al. 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 66(4):498-505 (2007 Apr).
- Thaci D, Ortonne JP, Chimenti S, et al. A phase IIIb, multicentre, randomized, double-blind, vehicle-controlled study of the efficacy and safety of adalimumab with and without calcipotriol/betamethasone topical treatment in patients with moderate to severe psoriasis: the BELIEVE study. Br J Dermatol 163(2):402-11 (2010 Aug).
- De Groot M, Teunissen MBM, Picavet DI, et al. Adalimumab in combination with methotrexate more effectively reduces the numbers of different inflammatory cell types in lesional psoriatic skin than does single treatment with adalimumab or methotrexate. Br J Dermatol 158(6):1401 (2008 Dec).
- Gladman DD, Mease PJ, Ritchlin CT, et al. Adalimumab for long-term treatment of psoriatic arthritis: forty-eight week data from the adalimumab effectiveness in psoriatic arthritis trial. Arthritis Rheum 56(2):476-88 (2007 Feb).
- Searles G, Bissonnette R, Landells I, et al. Patterns of combination therapy with alefacept for the treatment of psoriasis in Canada in the AWARE study. J Cutan Med Surg 13(Suppl 3):S131-8 (2009 Dec).
- Alefacept (Amevive®) product monograph. June 1, 2006. Astellas Pharma Canada, Inc., Markham, ON, Canada.
- Krueger GG, Gottlieb AB, Sterry W, et al. A multicenter, open-label study of repeat courses of intramuscular alefacept in combination with other psoriasis therapies in patients with chronic plaque psoriasis. J Dermatolog Treat 19(3):146-55 (2008).
- Ortonne JP, Khemis A, Koo JY, et al. An open-label study of alefacept plus ultraviolet B light as combination therapy for chronic plaque psoriasis. J Eur Acad Dermatol Venereol 19(5):556-63 (2005 Sep).
- Legat FJ, Hofer A, Wackernagel A, et al. Narrowband UV-B phototherapy, alefacept, and clearance of psoriasis. Arch Dermatol 143(8):1016-22 (2007 Aug).
- Moore A, Wright E, Slay D, et al. Alefacept and low-dose acitretin therapy for inverse psoriasis and palmar/plantar psoriasis shortens the onset of action. Poster 5288 at: 21st World Congress of Dermatology (September 30-October 5, 2007), Buenos Aires, Argentina.
- Smith EC, Riddle C, Menter MA, et al. Combining systemic retinoids with biologic agents for moderate to severe psoriasis. Int J Dermatol 47(5):514-8 (2008 May).
- Campione E, Mazzotta A, Paterno EJ, et al. Effect of calcipotriol on etanercept partial responder psoriasis vulgaris and psoriatic arthritis patients. Acta Derm Venereol 89(3):288-91 (2009).
- De Simone C, D’Agostino M, Capponi A, et al. Combined treatment with etanercept and narrow band UVB phototherapy for chronic plaque psoriasis. Poster 5259 at: 21st World Congress of Dermatology (September 30-October 5, 2007), Buenos Aires, Argentina.
- Foley PA, Quirk C, Sullivan JR, et al. Combining etanercept with traditional agents in the treatment of psoriasis: a review of the clinical evidence. J Eur Acad Dermatol Venereol 24(10):1135-43 (2010 Oct).
- Gottlieb AB, Kircik L, Eisen D, et al. Use of etanercept for psoriatic arthritis in the dermatology clinic: the Experience Diagnosing, Understanding Care, and Treatment with Etanercept (EDUCATE) study. J Dermatolog Treat 17(6):343-52 (2006).
- Zachariae C, Mork NJ, Reunala T, et al. The combination of etanercept and methotrexate increases the effectiveness of treatment in active psoriasis despite inadequate effect of methotrexate therapy. Acta Derm Venereol 88(5):495-501 (2008).
- Gisondi P, Del Giglio M, Cotena C, et al. Combining etanercept and acitretin in the therapy of chronic plaque psoriasis: a 24-week, randomized, controlled, investigator-blinded pilot trial. Br J Dermatol 158(6):1345-9 (2008 Jun).
- Yamauchi PS, Lowe NJ. Cessation of cyclosporine therapy by treatment with etanercept in patients with severe psoriasis. J Am Acad Dermatol 54(3 Suppl 2):S135-8 (2006 Mar).
- D’Angelo S, Cutro MS, Lubrano E, et al. Combination therapy with ciclosporin and etanercept in patients with psoriatic arthritis. Ann Rheum Dis 69(5):934-5 (2010 May).
- Warren RB, Brown BC, Lavery D, et al. Biologic therapies for psoriasis: practical experience in a U.K. tertiary referral centre. Br J Dermatol 160(1):162-9 (2009 Jan).
- Dalaker M, Bonesronning JH. Long-term maintenance treatment of moderateto- severe plaque psoriasis with infliximab in combination with methotrexate or azathioprine in a retrospective cohort. J Eur Acad Dermatol Venereol 23(3):277-82 (2009 Mar).
- Smith CH, Anstey AV, Barker JN, et al. British Association of Dermatologists’ guidelines for biologic interventions for psoriasis 2009. Br J Dermatol 161(5):987- 1019 (2009 Nov).