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Combination Therapies for Psoriasis
Key points
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Combination therapies of biologics and systemic agents for psoriasis treatment can potentially enhance efficacy of treatment, increase onset of remission, and decrease side effects by allowing for dose reductions.
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Potential therapeutic combinations examined include methotrexate paired with biologics; cyclosporine paired with biologics; acitretin paired with biologics; or phototherapy paired with biologics.
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Randomized clinical trials, case series, and case reports chronicling these therapeutic combinations have demonstrated good safety and efficacy data, indicating an important future role for combination therapy in the treatment of psoriasis.
Introduction
Psoriasis is a chronic inflammatory disease that negatively affects approximately 2% of the US population with significant impact on quality of life. Approximately 20% of these patients have moderate-to-severe disease. Its systemic effects include cardiovascular, metabolic, rheumatologic, and psychiatric comorbidities with older studies showing 25% to 38% of patients with psoriasis dissatisfied with their traditional treatments. Of those affected with psoriasis, 17% require treatment beyond traditional topical corticosteroids, such as phototherapy or systemic agents. More traditional systemic treatments include methotrexate, cyclosporine, and acitretin with newer biologic treatments, such as ixekizumab, secukinumab, ustekinumab, adalimumab, etanercept, and infliximab, quickly becoming important players in the therapeutic arena. A new oral agent, apremilast, has also been in use since 2014, with a few case reports of its use in combination with other therapies.
As treatment methods progress for this chronic disease, clinicians have been forced to expand therapeutic regimens and explore new combination therapies for patients with recalcitrant disease or dose-related cumulative toxicity from traditional treatments. Combination treatment of biologics with systemic agents, such as methotrexate, cyclosporine, and acitretin, can potentially enhance efficacy, hasten onset of remission, and decrease potential side effects by allowing for dose reductions ( Table 15.1 ). When combining immunosuppressive agents, the possibility of additive immunosuppression should be considered, and the dosage and period of overlap of more than one immunosuppressive medication should be minimized. This chapter investigates different combination therapies with biologics and traditional oral treatments.
Table 15.1
Traditional treatments and biologics for combination therapies in patients with psoriasis
Data from Refs.
| Combination Therapy | Source | Dosing | Comparisons | Study Type |
|---|---|---|---|---|
| Methotrexate + Ustekinumab | Puig, 2012 | Ustekinumab 90 mg (transient increase in injection frequency) + methotrexate 10 mg/wk | None | Case report |
| Methotrexate + Adalimumab | Philipp et al, 2012 | Standard dosing adalimumab + methotrexate 12.4 ± 4.5 mg/wk | None | Retrospective chart review |
| Methotrexate + Infliximab | Dalaker & Bonesronning, 2009 | 3 mg/kg infliximab at week 0, 2, 6, then q 8 wk + methotrexate 7.5–15 mg/wk | None | Retrospective chart review |
| Wee et al, 2012 | 3 mg/kg or 5 mg/kg infliximab at week 0, 2, 6, then q 8 wk + methotrexate 5–20 mg/wk | None | Retrospective chart review | |
| Methotrexate + Etanercept | Gottlieb et al, 2012 | Etanercept (50 mg twice weekly × 12 wk then 50 mg/wk × 12 wk) + methotrexate (7.5–15 mg/wk) | Etanercept monotherapy (50 mg twice weekly × 12 wk then 50 mg/wk × 12 wk) | Randomized, controlled trial |
| Zachariae et al, 2008 | Etanercept (50 mg twice weekly × 12 wk then 25 mg twice weekly × 12 wk) + methotrexate (stable dosing × 3 mo) | Etanercept (50 mg twice weekly × 12 wk then 25 mg twice weekly × 12 wk) + methotrexate (stable dosing × 3 mo then 4 wk taper) | Randomized, controlled trial, open label | |
| Gelfand et al, 2008 | Etanercept (50 mg twice weekly × 12 wk, then continuous or interrupted etanercept 50 mg/wk × 12 wk) + stable dose of methotrexate | Etanercept monotherapy (50 mg twice weekly × 12 wk, then continuous or interrupted etanercept 50 mg/wk for 12 wk) | Randomized, controlled trial, open label | |
| Driessen et al, 2008 | Etanercept (50 mg twice weekly × 12 wk, then etanercept 25 mg/wk twice weekly × 12 wk) + methotrexate (2.5–35 mg/wk) | None | Case series | |
| Cyclosporine + Etanercept | Yamauchi & Lowe, 2008 | Cyclosporine (200 mg BID until PASI-50), then etanercept (50 mg weekly while cyclosporine tapered) | None | Case series |
| Lee et al, 2010 | Cyclosporine (200 mg daily) + etanercept (50 mg weekly) | None | Case series | |
| Cyclosporine + Adalimumab | Karanikolas et al, 2011 | Cyclosporine (2.5–3.75 mg/kg/d) + Adalimumab (40 mg weekly) | Cyclosporine (2.5–3.75 mg/kg/d) monotherapy or adalimumab (40 mg weekly) | Nonrandomized, open-label clinical trial |
| Acitretin + Etanercept | Gisondi et al, 2008 | Etanercept (25 mg weekly) + oral acitretin (0.4 mg/kg daily) | Etanercept monotherapy (25 mg weekly) or oral acitretin (0.4 m/kg daily) | Randomized, controlled trial |
Methotrexate
Methotrexate is the most frequently used oral treatment for psoriasis and has been found to be significantly effective in randomized, controlled trials, open-label studies, and retrospective studies. Combination therapy of methotrexate with biologics is an emerging field of treatment with many considerations. Importantly, combining biologic therapies with methotrexate has not been shown to increase the bone marrow toxicity or hepatotoxicity of methotrexate. Although there is no published literature about the combination of methotrexate with the newer anti-interleukin-17 (IL-17) drugs, secukinumab or ixekizumab, one would expect the combination to be more effective than monotherapy with either agent.
Methotrexate and Ustekinumab
Ustekinumab is a human monoclonal immunoglobulin G antibody that binds to the p40 subunit of IL-12 and IL-23. Dosing is weight based with a 45-mg or 90-mg dose every 12 weeks for a patient weighing 100 kg or less or greater than 100 kg, respectively. For patients who are not adequately treated with ustekinumab alone, combination therapy has been seen to be useful particularly in those suffering from psoriatic arthritis, as a bridging therapy, for palmoplantar disease control or for recalcitrant disease.
The success of the combination of methotrexate and ustekinumab was highlighted in a case report of a patient who had failed therapy with psoralen and UV-A (PUVA), cyclosporine, infliximab, etanercept, and various combination therapies, including etanercept/methotrexate, etanercept/methotrexate/acitretin, adalimumab/efalizumab/cyclosporine, cyclosporine/efalizumab/cyclosporine/methotrexate, and cyclosporine/adalimumab. Responses to all these regimens and combinations had slowly lost their efficacy, usually after just a few months. Treatment with ustekinumab showed improvement within 1 month, although response was eventually lost as with the patient’s other therapies. By adding methotrexate 10 mg to the regimen along with a slight increase in injection frequency, the patient regained response with persistent control.
Methotrexate and Adalimumab
Adalimumab is a fully human monoclonal antibody approved for use with plaque psoriasis at a dose of 80 mg at week 0, 40 mg at week 1, and then 40 mg every other week. A retrospective chart review examined responses to combination therapy with standard dosing of adalimumab, without loading doses for some patients, and methotrexate dosing at 12.4 ± 4.5 mg per week. In 27 of 32 patients, a very good to moderate response, defined as a Physician’s Global Assessment (PGA) score of 0, 1, 2, or 3 was seen. In fact, a reduction in methotrexate dosage was possible in 5 patients. Combination therapy showed a good safety profile with AEs limited to mild infections, abdominal complaints, and diarrhea. Adalimumab was stopped in 1 patient due to recurrent infection; gastrointestinal effects were ameliorated with methotrexate dosage adjustments. de Groot and colleagues evaluated inflammatory markers in psoriatic lesional skin with decreased markers seen in combination therapy compared with methotrexate or adalimumab alone.
Data from clinical trials for rheumatoid arthritis show increased levels of adalimumab in patients treated with combination therapy as compared with adalimumab alone. Thus, levels of adalimumab may be increased by an unknown mechanism when using it in combination with methotrexate. In fact, tumor necrosis factor-α (TNF-α) antagonists used with methotrexate have been approved for the use of rheumatologic diseases. Studies have also shown a decrease in antiadalimumab antibody formation in patients on combination therapy.
Overall, larger trials are lacking, but positive results have been seen in multiple case series with psoriasis or psoriatic arthritis as well as randomized trials for those with rheumatoid arthritis. Certainly, more data are needed to fully elucidate risks and benefits of this combination therapy.
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