Efficacy and Safety of Methotrexate in Psoriasis Vulgaris Long-Term Treatment: A Real-World Observation Study

Abstract

Background:

Methotrexate (MTX) in the therapy of psoriasis vulgaris (PV) is a well and long-established treatment option.

Aims:

To assess the long-term experience of individual patients in the real world with regard to the efficacy and safety of MTX in PV therapy.

Patients and Methods:

In a retrospective study, MTX as a weekly used monotherapy in PV was examined. Clinical data including the Psoriasis Area Severity Index (PASI), prevalence of psoriatic-arthritis (PsA), Investigator Global Assessment (IGA), laboratory parameters, occurrence of adverse events (AEs), dosing of MTX and characteristics of patients treated for at least 24 months were collected.

Results:

A total of 55 patients with 247 patient-years under MTX therapy were included. The mean PASI reduction was 51.2% with a significant (P < 0.001) improvement in the skin condition in the first 6 months of treatment, remaining stable thereafter. The mean MTX dose increased from 11.8 ± 3.7 mg to 12.9 ± 3.8 mg in the first year of therapy, with a constant mean dose in the following years. In 247 patient-years, no serious AE was documented. Gastrointestinal side effects or fatigue were commonly detected. The liver parameter alanine aminotransferase/ glutamate-pyruvate transaminase (ALT/GPT) (baseline 35.8 ± 22.0 U/L) increased after 3 years of therapy (42.0 ± 22.4 U/L; P = 0.013) without clinical significance.

Conclusion:

In this patient collective, MTX in low doses was effective and safe in long-term therapy. The improved skin condition was steady and reached by an unvarying dose. New data showed a better efficacy of MTX in higher doses; however, additional data must be collected on the long-term efficacy and safety of MTX with a higher dose regime.

Introduction

Psoriasis vulgaris (PV), a chronic inflammatory skin disease, is accompanied by psoriatic arthritis (PsA) in 20–30% of patients.[1] MTX as a traditional drug is recommended as induction and long-term treatment for moderate-to-severe PV and PsA.[2,3] MTX causes an inhibition of the inflammatory response by activating adenosine receptors, such as the A2A receptor.[4] Furthermore, MTX is believed to decrease the nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κΒ) activity and interleukin (IL)-17 expression.[5,6]

Although the use of MTX is common, only a few trials are available. A study by Kirby et al. observed a lower drug survival of MTX compared to biological therapies.[3] Yet, the case series of MTX in psoriasis showed that MTX has been used safely and effectively for over 20 years.[3] Despite expanding therapeutic options for managing PV- and PsA-patients, undertreatment remains a challenge. The use of biologics is often limited due to high costs. Surveys in the US showed that biologics are used in less than 10% of psoriasis patients.[1]

The burden of psoriasis was recognized as serious by the World Health Organization (WHO) in 2014.[7] Health care needs to be improved among others by treating psoriasis worldwide with accessible, cost-effective medicines such as MTX,[8] which is included on the WHO Model List of Essential Medicines.[7] Therefore, the question arises as to how well MTX is tolerated and whether the effect can be maintained over several years under real-world conditions.

Patients and Methods

Patients with PV treated with MTX-monotherapy for ≥24 months between December 2009 and October 2016 in the departments of dermatology at the universities of Bonn and Göttingen were retrospectively identified by a chart review. The study was performed according to the principles of the Declaration of Helsinki and approved by the ethics committees.

Following data were collected: patient characteristics (age, sex, body mass index [BMI], nicotine/alcohol consumption, family history, comorbidity, comedication), PsA (with a definite diagnosis by a rheumatologist), Psoriasis Area Severity Index (PASI), Investigator Global Assessment (IGA) (both if available: before treatment, after 6 months, 1 year, then annually), mode and dose of MTX administration, therapy duration, systemic PV pre-medication, reasons for discontinuing MTX, AEs and laboratory values during MTX therapy.

The comparison of two groups was performed in the case of normally distributed samples using the t-test, and the Wilcoxon rank-sum test was used in the case of not normally distributed related samples. All tests were two-sided. A P < 0.05 is considered statistically significant.

The correlation between the two groups was determined using the correlation coefficient according to Spearman’s or Pearson’s correlation. All statistical calculations were performed with SPSS version 24.

Results

We identified 55 patients representing 247 treatment years. The mean treatment duration (±SD) was 54 ± 34 months, with a minimum of 24 months and a maximum of 14 years and 9 months. Patient characteristics are summarized in Table 1. MTX application was exclusively oral in 16.4%, subcutaneous in 56.4%, and 27.3% switched between the application modalities. Folic acid was given orally with 5 mg 24 h later.

Table 1.

Patient characteristics and details of MTX therapy

Parameters	Mean±SD or n (%)
Gender
Male	38 (69.1)
Female	17 (30.9)
Age at beginning of treatment (in years)	51±11.7
Smoker status
Smoker	15 (27.3)
Non-smoker	14 (25.5
Not available	26 (47.3)
BMI	29.3±6.3
Family history
Yes	18 (32.7)
No	15 (27.3)
Not available	22 (40.0)
Psoriatic arthritis (PsA)
Diagnosed PsA	26 (47.3)
Suspicious for PsA	6 (10.9)
None	15 (27.3)
Not available	8 (14.5)
Diabetes
Yes	11 (20.0)
Insulin-dependent	2 (18.0)
No	41 (74.5)
Not available	3 (5.5)
Cardiovascular diseases
Yes	25 (45.6)
No	27 (49.1)
Not available	3 (5.5)
Therapy
Duration of therapy (in months)	55±34
Dose (per week in mg)	11.9±2.8
MTX as
First-line-therapy	28 (51.0)
Second-line-therapy	17 (31.0)
Third-line-therapy	0 (0.0)
Fourth-line-therapy	2 (3.5)
Not available	8 (14.5)

Efficacy

Six months after the initiation of MTX, the PASI improved significantly from 13.7 ± 6.9 to 6.0 ± 3.2 (mean ± SD; P < 0.001); mean PASI reduction was 51.2%; 52.5% of patients achieved a PASI50; PASI75 was achieved by 16%; thereafter, until the fourth year, the PASI remained stable [Figure 1a].

Figure 1.

(a + b): Efficacy of long-term low-dose methotrexate. Error bar chart representing mean ± 1 standard error of PASI (a) and IGA (b) data. The mean dose is shown in Figure 1a in interval timeframes

In 10 cases without PASI values, the IGA improved significantly (P = 0.016) from 3.2 ± 0.4 to 2.0 ± 0.9 after 6 months of therapy [Figure 1b]. Also, 30.0% discontinued the therapy due to loss of efficacy after 46.5 ± 22.5 (mean ± SD) months, 15.0% due to improved skin condition after 38.0 ± 8.7 (mean ± SD) months, 30% discontinued the therapy due to loss of efficacy, 15% due to improved skin condition and 20% due to other reasons *(thrombocytopaenia, leukopaenia, feared teratogenicity, discontinued by another physician, respiratory complaints) [Figure 2a and b]. The mean MTX dose per week was 11.9 ± 2.8 mg (ranging from 7.5 mg to 19.5 mg) and increased significantly (P = 0.016) from 11.8 ± 3.7 mg to 12.9 ± 3.8 mg in the first year [Figure 1a]. There was no statistically significant correlation between MTX dose and PASI. Patients with PsA received a higher MTX dose of 12.9 ± 3 mg (mean ± SD) in 57.5 ± 38.7 (mean ± SD) months. Patients without PsA received 11.1 ± 2.2 mg (mean ± SD) per week for 50.4 ± 30.9 (mean ± SD) months.

Figure 2.

(a + b): Reasons for discontinuation of MTX therapy and distribution of adverse events. (a)*None >1.4 mg/dL (b) *Other reasons (*thrombocytopaenia, leukopaenia, feared teratogenicity, discontinued by another physician, respiratory complaints); AE = Adverse events; GPT = Glutamate-pyruvate transaminase; GIT = Gastrointestinal

Safety

No serious adverse events (SAEs) were documented during 247 cumulative treatment years. Most frequently, AEs were gastrointestinal adverse events (25%), fatigue (22%) and slightly increased ALT/GPT concentrations (50–100 U/L) (27%) [Figure 2a]. These were also the most common AEs causing the discontinuation of MTX. There was no significant change in ALT/GPT concentration, except between baseline (35.8 ± 22 U/L) and year 3 (42 ± 22.4 U/L; P = 0.013). Aspartate aminotransferase (AST/GOT) concentration only increased significantly between the second (23.6 ± 12.1) and third (34.2 ± 18.1; P = 0.008) years. Gamma-GT, blood count and renal parameters remained largely stable during MTX therapy. Laboratory controls were usually made every 3 months.

Discussion

In our real-world data of long-term therapy in psoriasis patients receiving MTX monotherapy at least over 2 years, a significant improvement in skin condition within the first 6 months of therapy was observed. After 26 weeks, we observed a PASI50-reduction and a PASI75 in 52.5% and 16.0% of patients, respectively. As reported in a meta-analysis by West et al., with a maximum treatment duration of 24 months (our minimum), PASI75 after 12–16 weeks was achieved in almost 40% of patients with a median dose of 13.75 mg per week and 15 mg in patients with PsA.[9] The PASI50 response in our study was less compared to this study and may be due to the lower median dose of 11.5 mg per week. In the Swiss registry, 18% reached PASI75 measured after a shorter time of 12 weeks.[10] Another study with systemic naïve patients treated with MTX per os (p.o.) up to 15 mg/week observed a PASI75 in 70.4% after 24 weeks.[11]

In 2011, Paul et al. recommended a dosing regimen with MTX in psoriasis initially of 5–10 mg, increasing it as needed to a therapeutic dose of 15–25 mg per week.[12] Recent studies indicate that initially higher MTX doses (at least 17.5 mg) are more effective and safe.[6]

Compared to our results, we assume that higher doses could have led to better efficacy. PsA patients received higher doses, which were administered at least partly to treat this comorbidity. Although the efficacy of MTX has been occasionally studied in short-term use,[6,9,13] fewer data are available on long-term studies, which might indicate that long-term MTX therapy in PV is less common. There are different studies[3,14,15] including partial aspects of MTX long-term therapy and its efficacy and safety. Considering the amount of treatment years, the occurrence of AEs can be described as infrequent. No SAE was documented in 247 treatment years. Van Dooreen-Greebe et al. reported similar results in 22 years of observation in 113 patients and a low mean dose of 10.4 mg per week.[15]

They describe abnormal liver function tests in 33% of 113 patients but no correlation between liver biopsy classification and dosing or treatment duration.[15] We observed only a mild relative increase in liver enzymes after 3 years with low clinical relevance. There are changes in laboratory values in individual cases, perhaps also partly attributable to comorbidities or comedication. Interestingly, regarding metabolic syndrome, low-dose methotrexate has been found to be effective in decreasing the risk of cardiovascular diseases in patients with psoriasis.[16]

The following are the limitations of the study. Patients who discontinued therapy or left the clinic earlier were not followed up. A study by Arnold shows a 1-year drug survival of MTX of 46% showing therapy is often stopped in the first year.[17] As Caldarola et al.[18] described the treatment time over 3 months as a positive predictive factor for drug survival in an MTX cohort, we were interested in the safety of long-term treatment in patients without intolerance in the first 2 years.

With 55 patients, the cohort size of this work was limited, further reduced due to the loss of follow-up over the years.

The therapy of PV with monoclonal antibodies leads to a PASI75 response in the majority of patients that is often not reached by MTX in a low-dose regime. However, MTX is cost-effective and globally accessible, and MTX therapy is often continued by colleagues outside the psoriasis centers, which might be one reason for the loss of follow-up in our study.

There is still a lack of high evidence data¹⁰ in the long-term use of MTX in PV in a real-world setting. Because we can only describe the use of low-dose MTX, it is important to gain further data on the higher-dose treatment regime.

Financial support and sponsorship

Nil.

Conflicts of interest

D. Wilsmann-Theis has been advisor and/or received speakers’ honoraria or travel expense reimbursements and/or received grants and/or participated in clinical trials of the companies AbbVie, Almirall, Amgen, Beiersdorf, Biogen, Boehringer Ingelheim Pharma, Celgene, Forward Pharma, GlaxoSmithKline, Janssen-Cilag, Leo, Lilly, Medac, Merck Sharp and Dohme Corp., Novartis, Pfizer, UCB Pharma, and VBL.

R. Funk has no conflicts of interest to declare.

R. Mössner has been an advisor and/or received speakers’ honoraria and/or received grants and/or participated in clinical trials of the following companies: Abbott/Abbvie, Allmirall, Biogen IDEC GmbH, Böhringer-Ingelheim, Bristol Myers Squibb, Celgene, Essex Pharma GmbH, Janssen-Cilag GmbH, Leo Pharma GmbH, Lilly, Merck Serono GmbH, MSD SHARP and DOHME GmbH, Novartis Pharma GmbH, Pfizer GmbH and UCB.

T. Bieber has no conflict of interest relevant to this work.

J.Wenzel has been an advisor and/or received speakers’ honoraria and/or received grants and/or participated in clinical trials of the following companies: GSK, Novartis, Medac, Merck/Serono, Roche, Actelion, Pfizer, Spirig, ArrayBio, Biogen.