Funding source: None.
Low-dose methotrexate – a therapeutical kick in TNF-alpha antagonist treatment for recalcitrant psoriasis vulgaris
Article first published online: 2 APR 2013
© 2013 Wiley Periodicals, Inc.
Volume 27, Issue 1, pages 55–59, January/February 2014
How to Cite
Wilsmann-Theis, D., Fronhoffs, K., Ehler, L.-K., Wenzel, J., Bieber, T. and Klingmueller, K. (2014), Low-dose methotrexate – a therapeutical kick in TNF-alpha antagonist treatment for recalcitrant psoriasis vulgaris. Dermatologic Therapy, 27: 55–59. doi: 10.1111/dth.12046
Conflict of interest:
D. Wilsmann-Theis received financial support for performing clinical trials, has served as a consultant for or has received speakers' honoraria and travel scholarships from Abbott GmbH & Co. KG and Pfizer GmbH.
K. Klingmueller, Th.Bieber, L.Ehler, K.Fronhoffs, and J.Wenzel declare no conflict of interest.
- Issue published online: 6 FEB 2014
- Article first published online: 2 APR 2013
- psoriasis vulgaris;
- TNF-alpha inhibitor
In contrast to the treatment of rheumatoid arthritis, there are few data in psoriasis vulgaris regarding the efficacy of combining tumor necrosis factor (TNF)-alpha inhibitors and methotrexate (MTX). Indeed, combination of MTX with different TNF-alpha inhibitors may enhance the therapeutic effects and reduce side effects because of less dosage of the single agent. The present authors present five cases in which low-dose MTX combined with TNF-alpha inhibitors led to impressive improvement in Psoriasis Area and Severity Index scores. Here, the present authors initiated very low-dose MTX treatment in addition to existing TNF-alpha inhibitor therapy to exhaust current therapy and prevent premature change of the biologic. These observations support the concept of combined treatment in recalcitrant cases of psoriasis, which need a systemically lifelong treatment when both first-line and second-line monotherapies fail to provide sufficient clinical response.
More than 30% of psoriasis vulgaris patients suffer from severe forms requiring systemic therapy [1, 2]. Tumor necrosis factor (TNF)-alpha inhibitors have shown great impact on the management of psoriasis vulgaris and psoriasis arthritis with fewer systemic side effects during the treatment course. However, if efficacy is the goal to aim for, sometimes, these treatments alone fail to reach that purpose. Therefore, in rheumatology, the combination of TNF-alpha inhibitors and traditional therapies, like methotrexate (MTX), is a common therapeutic concept [3-5]. This is in sharp contrast to the management of persistent moderate to severe psoriasis vulgaris where less data are available.
Patients and methods
The present authors observed retrospectively five cases of patients with psoriasis vulgaris, who received low-dose MTX combined to an existing TNF-alpha blocker therapy.
The mean age of the four male and one female psoriasis patients was 50.8 ± 6.7 years (Table 1). All five patients were presented with plaque-type psoriasis, including one patient with painful palmoplantar lesions. The mean disease duration was 15.4 ± 5.0 years. Patient 2 showed symptoms of psoriasis arthritis, since more than 6 weeks with dactylitis (three finger joints), and morning stiffness but no findings of rheuma factors in serology or radiographic changes.
|Pat no||Sex||Age||Psoriasis-arthritis||Type of psoriasis||Former therapies||MTX naïve||Reason for discontinuation or contraindication of MTX monotherapy||Monotherapy||Time (and dose) on monotherapy||Time of efficacy onset (and dose) on combination to MTX||PASI baseline||PASI after monotherapy||PASI after combination|
|1||Male||49||no||Plaque type psoriasis||Fumaric acid, acitretin, efalizumab||Yes||Elevated liver enzymes||Adalimumab||24 weeks (40 mg every 2 weeks)||8 weeks (10 mg oral every 2 weeks, later 7,5 mg every 2 weeks)||28.4||14.8||5.2|
|2||Male||54||yes||Plaque type psoriasis||MTX||No||Nausea||Etanercept||12 weeks (50 mg twice weekly)||6 weeks (5 mg oral weekly)||24.6||20.7||5.2|
|3||Male||42||no||Plaque type psoriasis||Fumaric acid, efalizumab||Yes||History of pancreatitis||Etanercept||23 weeks (50 mg once-twice weekly)||4 weeks (5 mg oral weekly)||17.7||9.2||4.7|
|4||Female||49||no||Plaque type psoriasis||Fumaric acid, PUVA, MTX||No||Inefficacy||Etanercept||16 weeks (50 mg twice weekly)||12 weeks (5 mg oral weekly)||12.8||9.6||5.3|
|5||Male||60||no||Plaque type psoriasis mostly located on palms and soles||Acitretin, PUVA, efalizumab, cyclosporine||Yes||Elevated serum creatinine||Etanercept||12 weeks (50 mg twice weekly)||12 weeks (7.5 mg s.c. weekly, after-wards 5 mg p.o. weekly)||6.3||5.7||1.7|
Three of five patients had at least one comorbidity, patient 1 had high liver enzymes, patient 3 had a pancreatitis in his anamnesis, and patient 5 had an increase of blood pressure and serum creatinine after a cyclosporine therapy.
Former treatments in patient 1 were fumaric acid, acitretin, and efalizumab, which did not provide sufficient improvement. Patient 4 received, in the past, fumaric acid and systemic Psoralene-UVA (PUVA) without success. Patient 5 took acitretin, cream-PUVA, efalizumab, and cyclosporine, which were either ineffective or had side effects such as an increase of blood pressure and serum creatinine.
Thus, these three patients were MTX naïve, i.e., had never received MTX treatment before because of contraindication (like enhanced liver enzymes) of MTX in higher doses (Table 1).
One of the two none-MTX-naïve patients was treated with high dose MTX monotherapy (20 mg s.c. weekly) before changing to TNF-alpha blocker and had to stop the MTX treatment because of persisting nausea, the other one due to insufficient improvement (Table 1).
Used TNF-alpha blockers
Four of the five patients received etanercept in a dose of 50 mg twice (three patients) or once weekly (one patient); and patient 1 took adalimumab 40 mg every second week as TNF-alpha inhibitor. All patients were never treated with a TNF-alpha blocker before.
The treatment duration of TNF-alpha blocker monotherapy before starting the combination with MTX ranged between 12 and 24 weeks (Median 17.4 ± 5.2).
Reason for combination therapy
Although the monotreatment with TNF-alpha blocker showed, in all five cases, a reduction in Psoriasis Area and Severity Index (PASI) of 10–48% (mean 34%) (Table 1), the reason for initiating combination therapy with MTX was insufficient response and the aim to enhance the efficacy of TNF-alpha therapy in all five cases.
PASI was evaluated at baseline before starting TNF-alpha therapy (mean PASI = 18), before starting the combination with MTX (mean PASI = 12), which showed a PASI reduction in average of 34% and in the course of combination therapy of TNF-alpha blocker and MTX (mean PASI = 4), which means a PASI reduction in average of 78% (FIG. 1 and Table 1). In patient 2, we saw a reduction of the dactylitis symptoms but already during the etanercept therapy.
In all five cases, the clinical results were still stable after more than 5 months follow-up.
Low-dose MTX administration
In all patients, MTX low-dose therapy was added to former TNF-alpha blocker therapy. MTX was administered orally right from the beginning of the combination in four cases, in one after 3 months of subcutaneously application. MTX doses ranged from 5 to 7.5 mg weekly initially later reduced, due to treatment success, from 3.75 to 5 mg weekly. MTX in the combination and in this low-dose was well tolerated without any nausea or other side effects.
The observed duration of the combination treatments was between 6 and 24 months (mean 17.6 ± 7.8).
No severe adverse event or increases of infections during the combination treatment appeared in any case. Especially the patients, who had contraindications due to MTX (enhanced liver enzymes, elevated serum creatinine, and pancreatitis in history) were monitored closely without any appearance of adverse events.
In some psoriasis patients, TNF-alpha inhibitor treatment may not lead to a sufficient improvement. Thus, during either induction of therapy or episodes of exacerbation, a combination with conventional systemic therapies may be necessary to control the disease [6-8].
An unblinded, randomized study from Scandinavia  revealed that combination of etanercept with continuous MTX administration compared with tapering administration of MTX achieved significant better efficacy in psoriasis treatment. None of these patients were MTX naïve, which perhaps explains why in average higher doses were dispensed (average 13.7 mg/week) compared with our very low doses (average 6.0 mg/week).
In three of our five cases, MTX first-line monotherapy was not done due to contraindications; in patient 2, MTX in higher doses had caused nausea. The very low MTX doses we administered, however, could be proven to be safe and tolerable. An aspect, that considers the established fact of the psoriatic comorbidities as fatty liver disease in the context of the metabolic syndrome .
Especially for etanercept, a later onset of treatment response compared with other TNF-alpha inhibitors is known . Hence, it could be discussed if maybe in our case series the effect of improvement is due to the prolonged treatment duration of etanercept. In our opinion, the rapid reduction of the psoriatic findings after initiation of MTX shown in FIG. 2 speaks against this theory.
A recently published study  underlines our experiences of the advantage from an MTX combination therapy compared with an etanercept monotherapy. In contrast to this trial, MTX was given from the beginning to the etanercept therapy. We want to highlight the practical aspect, that our individually selected patients received MTX to an existing, but not resoundingly successful anti-TNF-alpha therapy, with the idea to exhaust the treatment and to prevent a biologic hopping. Further on, regarding combination of adalimumab and MTX in treatment of plaque psoriasis, no studies have been performed  until now, although the combination is often discussed in order to prevent the development of neutralizing antibodies , so we presented here a case in which this combination enhanced therapeutic efficacy as well as in the etanercept patients.
In conclusion, low-dose MTX combined with TNF-alpha inhibitors may be a potent enhancer of the therapeutic effect without increasing side effects .
This provides a promising opportunity for treatment of high-need patients with persistent plaque psoriasis when TNF-alpha inhibitor therapy, as second-line therapy, alone has not been sufficient or its response delayed, or when MTX, as first-line monotherapy, at higher doses has shown adverse events or inefficacy. Additionally, concomitant immunomodulators like MTX can reduce the immunogenicity of therapeutic antibodies. Further experience is needed to evaluate whether the expected effect is different in patients being MTX naïve or not. Besides, it needs to be discussed if combination has additive or even synergistic effects. Considering the minimal dose of MTX the present authors needed in the presented limited number of cases, the present authors suppose a rather synergistic effect.
- 12Randomized, 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: 25: 1365–2133., , , et al.