Significant energy has been invested over the past 15 years into the development of biologic agents for the treatment of immune-mediated inflammatory disorders. These drugs are highly effective first-line therapeutic agents, as well as second-line agents for patients whose disease is inadequately controlled by traditional systemic therapies. But where does one turn when a patient’s disease is refractory even to biologics?
The addition of systemic agents to biologic monotherapy is routine in clinical studies in rheumatology and gastroenterology, as compared to psoriasis where all studies of biological agents have purely involved monotherapy. The 4 biologic agents currently in clinical use for psoriasis include the 3 tumor necrosis factor-alpha (TNF-α) inhibitors etanercept (Enbrel), infliximab (Remicade) and adalimumab (Humira) and the interleukin-12/23 inhibitor, ustekinumab (Stelara). These agents are also being used off-label to treat a multitude of dermatologic conditions including hidradenitis suppurativa, pyoderma gangrenosum, sarcoidosis and vitiligo.
In this article, we will examine the current literature and personal experience from our Psoriasis Specialty Clinic in Dallas regarding the role of methotrexate as an adjunctive treatment to biologic therapy for the treatment of psoriasis. The evidence for the efficacy and safety of biologics with methotrexate in psoriasis is derived purely from post-marketing research. In dermatological Phase II and Phase III studies, patients suspend the use of all treatments other than dilute topical corticosteroids prior to commencing the biologic agent under evaluation.
The only exception to this protocol is in psoriatic arthritis studies where methotrexate and systemic steroids at stable doses are used in up to 50% of cases. This difference is important when comparing data between specialties. Crucial aspects to consider are: 1) the development of psoriatic arthritis during therapy for psoriasis with biologic agents and 2) the development of “drug resistance” with biologic monotherapy.
Etanercept and Methotrexate
The addition of etanercept to the treatment regimen of psoriasis patients not adequately controlled on methotrexate monotherapy results in significant clinical improvement.1
In a pilot study, patients with moderate-to-severe plaque psoriasis were randomly assigned to 1 of 2 treatment groups: etanercept with methotrexate tapered until discontinued or etanercept with continuous methotrexate.1 Fifty-one patients completed the study and after 24 weeks of therapy, Psoriasis Area and Severity Index 75 (PASI 75) response was achieved in 70% of patients in the etanercept and continuous methotrexate group in contrast to a PASI 75 response of 36% in the etanercept and methotrexate taper group.1
There was no significant difference in the incidence of adverse events (AEs) between the groups, no new safety signals and no observed cases of tuberculosis, malignancies or opportunistic infections.1
A subsequent randomized, double-blind, placebo-controlled study of 239 patients who received etanercept at a dose of 50 mg twice weekly for 12 weeks followed by 50 mg of etanercept once weekly together with 7.5 mg to 15 mg of methotrexate weekly versus placebo, revealed a PASI 75 response in 77.3% of patients in the etanercept and methotrexate group compared with a PASI 75 response in 60.3% of patients in the etanercept and placebo group after 24 weeks.2
In contrast to the previous study, the overall proportion of patients reporting AEs was higher in the combination group (74.9%) compared with the monotherapy group (59.8%).2 The majority of these AEs were mild or moderate and included nasopharyngitis, headache, upper respiratory tract infection and nausea.2 Of note, the incidence of elevated hepatic transaminases was slightly higher in the combination therapy group compared with the monotherapy group − 2.9% versus 1.7%, respectively.2
Additionally, 4 further publications have revealed no safety issues with the concurrent use of methotrexate and etanercept.3-6
In a separate study of 261 patients with psoriatic arthritis, simultaneous use of methotrexate with all 3 TNF-α inhibitors resulted in a longer duration of use with these drugs as compared with biologic monotherapy.7
Mease et al evaluated etanercept and concomitant methotrexate for the treatment of psoriatic arthritis and concluded that etanercept with methotrexate did not appear to improve clinical responses versus etanercept as monotherapy.8
Infliximab and Methotrexate
Infliximab is a chimeric TNF-α monoclonal antibody. In the United States, the Phase III psoriasis clinical study of infliximab monotherapy at a dose of 5 mg/kg showed a reduction in PASI 75 from 75.5% at week 10 to 59% at week 52.9 To date, there has not been a randomized, double-blind, placebo-controlled trial to evaluate the use of infliximab in combination with methotrexate for the treatment of psoriasis. The use of the combination is frequently preferred to monotherapeutic infliximab with a reduction in anti-chimeric antibody formation being noted.10-13
In a prospective, single-center, open-label trial involving 11 patients, dual therapy with methotrexate and infliximab reduced clinical signs and ameliorated the symptoms of psoriasis and psoriatic arthritis.14 In this study, methotrexate was maintained at stable doses of between 5 mg and 20 mg per week and infliximab infusion was added at 3 mg/kg at weeks 2, 6, 14 and 22.14
At week 10 of the study, PASI 50 was achieved by 91%, PASI 75 was achieved by 82% and PASI 90 was achieved by 18%.14 Only mild AEs of bursitis, cold, headache, dry eyes and restless feet were reported.14
A retrospective chart review of 23 patients with moderate-to-severe psoriasis concluded that infliximab at doses of 3 mg/kg used concurrently with methotrexate or azathioprine is a fast-acting and sustained mode of managing moderate-to-severe psoriasis.15 AEs in this study included the development of a pulmonary embolism after 2 infusions of infliximab in 1 patient.15 No hepatoxicity or bone marrow suppression was seen.15
There have been 6 additional studies describing the effective treatment of psoriasis with or without psoriatic arthritis using an infliximab-methotrexate combination.16-21 These included 1 case of pustular psoriasis and 1 case of erythrodermic psoriasis.17,18 AEs in these patients consisted of symptoms of pyrexia attributed to infection, diarrhea and vomiting.16,18 Elevated hepatic enzymes and elevated serum type II pro-collagen levels were also reported.19 Due to the not infrequent infliximab antibody production issue, many clinicians do initiate infliximab infusions for psoriasis with methotrexate ab initio.21
Adalimumab and Methotrexate
In Phase III studies of adalimumab following 16 weeks of treatment with adalimumab monotherapy, 71% of patients achieved a PASI score of 75% or greater.22 To date, only 1 study has been published evaluating adalimumab and methotrexate combination therapy in psoriasis.23
This was a prospective, observational cohort examining options for increasing adalimumab therapy effectiveness.23 With the addition of methotrexate at an average dose of 9.5 mg ± 3.2 mg per week to adalimumab 40 mg every other week, an additional 9% of patients achieved PASI 50 after 12 and 24 weeks and an additional 18% achieved PASI 50 at 24 weeks.23 Following escalation of adalimumab monotherapy dosing from 40 mg every other week to 40 mg weekly, an additional 25% of patients achieved PASI 50 after 12 weeks of treatment and 35% achieved PASI 50 after 24 weeks of treatment.23
Two serious AEs occurred following adalimumab dose escalation.23 The first was a fatality due to hemorrhage of esophageal varices, and the second was an exacerbation of psoriasis which occurred 13 months following dose escalation.23
Personal Clinical Experience: Baylor, Dallas Tertiary Referral Clinic
To date, a total of 1,725 patients with moderate-to-severe psoriasis are receiving systemic and biologic therapy at the Baylor Psoriasis Specialty Clinic.
Of the 895 patients on the 3 TNF-α biologic agents, approximately 40% are receiving concomitant methotrexate either due to loss of psoriasis clinical response with individual biologic agents as monotherapy or due to significant psoriatic joint disease either at initiation of the TNF-α agent or subsequently during the course of therapy.
In addition, in a study from our clinic published in 2011, of the 120 psoriasis patients maintained on infliximab for more than 1 year, 62 (52%) patients required concomitant methotrexate or an increase in infliximab dosage to maintain clinical response.21
In comparison, as adalimumab is a fully human protein, the development of antibodies to this drug is indeed lower than with infliximab. Despite this, combination with methotrexate is certainly used frequently, especially in patients with psoriatic joint disease. Likewise, a number of our patients on ustekinumab also require the addition of methotrexate to both reduce flares prior to the set 12-weekly injections and/or to improve the response in patients with concomitant psoriatic joint disease.
There is good evidence for both the efficacy and safety of methotrexate and etanercept combination therapy in psoriasis. The use of infliximab, adalimumab and ustekinumab in conjunction with methotrexate while commonplace, has not been as extensively studied as etanercept. Safety issues with etanercept monotherapy, (eg, serious infections such as tuberculosis) are generally slightly lower than with infliximab and adalimumab.
However, etanercept monotherapy PASI 75 scores are lower in the large Phase III clinical studies. Thus, with each of these 3 agents as well as ustekinumab combination with methotrexate can be actively considered with few apparent safety issues. This may be particularly relevant in patients on ustekinumab with psoriatic joint symptoms as the American College of Rheumatology (ACR) 20 score with this drug (recently approved for psoriatic arthritis) is approximately 25% lower than with the 3 TNF-α agents.
Dr. Haugh is with the University Hospital Limerick in Limerick, Ireland.
Dr. Ryan is with the division of dermatology at Baylor Research Institute in Dallas, TX.
Dr. Menter is with the division of dermatology at Baylor Research Institute in Dallas, TX.
Disclosure: The authors have no conflict of interest to report.
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2. 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(3):649-657.
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17. Barland C, Kerdel FA. Addition of low-dose methotrexate to infliximab in the treatment of a patient with severe, recalcitrant pustular psoriasis. Arch Dermatol. 2003;139(7):949-950.
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