Generic selectors
Exact matches only
Search in title
Search in content
Search in posts
Search in pages
Filter by Categories
15th National Conference of the IAOMFP, Chennai, 2006
Abstract
Abstracts from current literature
Acne in India: Guidelines for management - IAA Consensus Document
Addendum
Announcement
Art & Psychiatry
Article
Articles
Association Activities
Association Notes
Award Article
Book Review
Brief Report
Case Analysis
Case Letter
Case Letters
Case Notes
Case Report
Case Reports
Clinical and Laboratory Investigations
Clinical Article
Clinical Studies
Clinical Study
Commentary
Conference Oration
Conference Summary
Continuing Medical Education
Correspondence
Corrigendum
Cosmetic Dermatology
Cosmetology
Current Best Evidence
Current View
Derma Quest
Dermato Surgery
Dermatopathology
Dermatosurgery Specials
Dispensing Pearl
Do you know?
Drug Dialogues
e-IJDVL
Editor Speaks
Editorial
Editorial Remarks
Editorial Report
Editorial Report - 2007
Editorial report for 2004-2005
Errata
Erratum
Focus
Fourth All India Conference Programme
From Our Book Shelf
From the Desk of Chief Editor
General
Get Set for Net
Get set for the net
Guest Article
Guest Editorial
History
How I Manage?
IADVL Announcement
IADVL Announcements
IJDVL Awards
IJDVL AWARDS 2015
IJDVL Awards 2018
IJDVL Awards 2019
IJDVL Awards 2020
IJDVL International Awards 2018
Images in Clinical Practice
In Memorium
Inaugural Address
Index
Knowledge From World Contemporaries
Leprosy Section
Letter in Response to Previous Publication
Letter to Editor
Letter to the Editor
Letter to the Editor - Case Letter
Letter to the Editor - Letter in Response to Published Article
LETTER TO THE EDITOR - LETTERS IN RESPONSE TO PUBLISHED ARTICLES
Letter to the Editor - Observation Letter
Letter to the Editor - Study Letter
Letter to the Editor - Therapy Letter
Letter to the Editor: Articles in Response to Previously Published Articles
Letters in Response to Previous Publication
Letters to the Editor
Letters to the Editor - Letter in Response to Previously Published Articles
Letters to the Editor: Case Letters
Letters to the Editor: Letters in Response to Previously Published Articles
Medicolegal Window
Messages
Miscellaneous Letter
Musings
Net Case
Net case report
Net Image
Net Letter
Net Quiz
Net Study
New Preparations
News
News & Views
Obituary
Observation Letter
Observation Letters
Oration
Original Article
ORIGINAL CONTRIBUTION
Original Contributions
Pattern of Skin Diseases
Pearls
Pediatric Dermatology
Pediatric Rounds
Perspective
Presedential Address
Presidential Address
Presidents Remarks
Quiz
Recommendations
Regret
Report
Report of chief editor
Report of Hon : Treasurer IADVL
Report of Hon. General Secretary IADVL
Research Methdology
Research Methodology
Resident page
Resident's Page
Resident’s Page
Residents' Corner
Residents' Corner
Residents' Page
Retraction
Review
Review Article
Review Articles
Revision Corner
Self Assessment Programme
SEMINAR
Seminar: Chronic Arsenicosis in India
Seminar: HIV Infection
Short Communication
Short Communications
Short Report
Special Article
Specialty Interface
Studies
Study Letter
Supplement-Photoprotection
Supplement-Psoriasis
Symposium - Contact Dermatitis
Symposium - Lasers
Symposium - Pediatric Dermatoses
Symposium - Psoriasis
Symposium - Vesicobullous Disorders
SYMPOSIUM - VITILIGO
Symposium Aesthetic Surgery
Symposium Dermatopathology
Symposium-Hair Disorders
Symposium-Nails Part I
Symposium-Nails-Part II
Tables
Technology
Therapeutic Guidelines
Therapeutic Guidelines - IADVL
Therapeutics
Therapy
Therapy Letter
View Point
Viewpoint
What’s new in Dermatology
View/Download PDF
CROSSMARK LOGO Buy Reprints
PDF

Translate this page into:

Original Article
ARTICLE IN PRESS
doi:
10.25259/IJDVL_1145_20

The therapeutic role of methotrexate in chronic urticaria: A systematic review

Department of Dermatology, Venereology and Leprology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India
Corresponding author: Dr. Jaspriya Sandhu, Assistant Professor, Department of Dermatology, Venereology and Leprology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India. sandhu.jaspriya@gmail.com
Licence
This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

How to cite this article: How to cite this article: Sandhu J, Kumar A, Gupta SK. The therapeutic role of methotrexate in chronic urticaria: A systematic review. Indian J Dermatol Venereol Leprol, doi: 10.25259/IJDVL_1145_20

Abstract

Background:

Chronic urticaria, in many cases, has an unsatisfactory response to antihistamines. The current recommendations in urticaria do not mention the dose and duration for methotrexate.

Aims:

This study aims to systematically review the use/efficacy of methotrexate in chronic urticaria.

Methods:

A systematic search in four databases, that is, PubMed/Medline, Cochrane central, Google Scholar and Clinicaltrials.gov was done to identify studies on the use of methotrexate in chronic urticaria using key words “methotrexate [MeSH terms]” and “urticaria” or “urticaria, chronic” or “urticaria, chronic spontaneous.”

Results:

Nine articles (study participants 127), including three randomized control trials, one prospective interventional trial without control, three retrospective reviews and two case reports, were identified and finally included in the systematic review. There was a paucity of literature and the three randomized control trials did not show any benefit of methotrexate over antihistamines alone. However, in studies where steroid-dependent cases were given methotrexate, marked benefit was reported with steroid-sparing effect, particularly on methotrexate dose escalation.

Limitations:

Due to a paucity of published literature on methotrexate in urticaria, a meta-analysis could not be done.

Conclusion:

In chronic recalcitrant or steroid-dependent cases, methotrexate may be a therapeutic agent of interest; however, current evidence does not point to any added advantage in efficacy over antihistamines. More evidence based on larger, well-executed randomized control trials is needed in the future to get more definitive answers.

Keywords

Chronic urticaria
methotrexate
non-biological therapy in urticaria
systematic review
urticarial

Plain Language Summary

Chronic urticaria is the appearance of weal or “hives” on the skin that occur on most days for a period longer than 6 weeks. The disease affects less than 1% of the population; however, it can affect the daily life of patients to a great extent. The researchers of this paper are based in India and the work was carried out in the Dayanand Medical College & hospital, Ludhiana, Punjab. The aim of the study was to scientifically review the existing published literature to examine the use of methotrexate (a drug which affects the replication of immune cells in the body by affecting the DNA synthesis during cell division) in chronic urticaria. The authors independently reviewed scientific databases available to look for published articles. Four databases, i.e., PubMed/Medline, Cochrane Central, Google Scholar and Clinicaltrials.gov was done to identify studies on the use of methotrexate in chronic urticaria using certain key words {“methotrexate [MeSH terms]” AND “urticaria” OR “urticaria, chronic” OR “urticaria, chronic spontaneous”}. Only nine relevant studies were included and analyzed; there was a paucity of available literature. The evidence for use of methotrexate was not found in the randomized controlled trials; only few studies showed some benefit in patients who were on oral steroids. To conclude, in chronic recalcitrant or steroid-dependent cases, methotrexate may be a useful therapeutic modality; however, more studies to investigate its role in urticaria are needed to strengthen evidence for its use.

Introduction

Urticaria, defined as a recurrent, evanescent eruption of wheals, can be a rather frustrating condition to treat for a dermatologist. The word urticaria has its roots in the Latin word urtica; which means “to burn.” Patients, referred by general practitioners, often recant a long list of previously prescribed anti-histamines, when they first reach the dermatologist’s office. It always comes back: is a common grievance and they seek a more “permanent cure.” When urticaria occurs almost every day for six weeks or more, it is then called chronic urticaria. Chronic urticaria can further be classified as spontaneous (specific trigger/cause cannot be identified) and inducible (urticaria can be elicited following a specific trigger).1

In the United States, the prevalence of chronic urticaria has been estimated to be 0.23% and is twice as common in women.2 In a vast majority of cases, a specific cause may not always be found.3 Treatment can sometimes be unsatisfactory with either a partial or poor response to antihistamines. As per EAACI/GA2LEN/ EDF/WAO (EAACI, European academy of allergology and clinical immunology; GA2LEN, global asthma and allergy European network; EDF, European dermatology forum and WAO, World Allergy Organization) guidelines, omalizumab (anti-IgE) has been shown to be very effective and safe in the treatment of CSU. It has also been reported to be effective in chronic inducible urticaria including cholinergic urticaria, cold urticaria and solar urticaria among others.1 However, the cost is often prohibitive, particularly for patients in developing countries (monthlycost$541–$2706).4 Furthermore, certain subset of patients may not be suitable candidates for biological therapy or may develop adverse effects to the same.5 There is good evidence to support the use of cyclosporine in antihistamine refractory chronic urticaria and guidelines also recommend its use as third-line therapy; but its problematic adverse effect profile and cost can, on occasion, limit its clinical utility.1

Methotrexate was first synthesized by Yellapragada Subbarao, an Indian-American Harvard graduate from Andhra Pradesh.6 The first reported use of methotrexate in chronic urticaria was by Weiner in 1989; he successfully achieved complete remission with methotrexate in a patient with chronic, steroid-dependent, recalcitrant urticaria.7 Methotrexate may be an affordable, easily available and well-tolerated alternative to achieve remission in refractory chronic urticaria; its effect in chronic urticaria is through its effect on adenosine and inhibition cytokines, oxidative burst and leukocyte chemotaxis.8

The current recommendation in urticaria does not detail the dose and duration for methotrexate. There is a paucity of systematic reviews devoted to evaluation of the use of methotrexate in chronic urticaria. Hence, the aim of this study was to systematically review the use/efficacy of methotrexate in chronic urticaria.

Methods

This systematic review was done following Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) recommendations.9

Data sourcing

This systematic review was conducted in the Department of Dermatology, Dayanand Medical College and Hospital, Ludhiana (Punjab). Two investigators (J.S.and A.K.) independently conducted a systematic search in four databases, that is, PubMed/Medline, Cochrane Central, Google Scholar and Clinicaltrials.gov on April 6, 2020, using keywords “methotrexate [MeSH terms]” AND “urticaria” OR “urticaria, chronic” OR “urticaria, chronic spontaneous.”

Data extraction

A total number of items found on search were 6188 (741– Google Scholar, 4959 –PubMed/Medline, 485 – Cochrane Central and 3 – www.clinical trials.gov) [Figure 1].

Figure 1:: Flow diagram and literature review

Selection criteria/eligibility

Articles were screened by title and abstract. The articles included were randomized control trials, case–control studies, prospective intervention studies, retrospective reviews, case series and case reports. Descriptive reviews, guidelines and expert opinions were excluded. Both the investigators independently assessed the articles for their eligibility. After removing duplicates and applying the selection criteria, we obtained nine articles [Figure 1]. The full text of the selected literature was studied by both the investigators independently. A detailed proforma was prepared by the investigators wherein following data from the available literature were tabulated– study type, mean age, gender ratio, sample size, type of urticaria, disease duration, inclusion criteria, treatment protocol, tool(s) used for assessment of response, side effects and follow-up.

Bias assessment

Quality and bias of the included studies were assessed using the Oxford Quality Scoring System for the randomized control trials and methodological index for non-randomized control trials for the rest.10,11

Outcome analysis

The level of evidence on the efficacy of methotrexate in chronic urticaria was assessed by a numerical scale– the Copenhagen Evidential Scale of Treatments introduced by Holm et al., based on parameters including study design, number of studies, study participants and treatment efficacy [Table 1].12

Table 1:: Copenhagen evidential scale of treatments(Adapted from Holm et al.)12
Parameters Level of evidence (points) Specification for calculation
Study design
Randomized controlled trial 3 Each study scored (mean acrossstudies used)
Prospective intervention 2
Caseseries 1
Single-casereport 0
Number of studies identified
10<–Strong evidence 2 Each treatment scored
5<×≤10–Intermediate evidence 1
5≤–Weak evidence 0
Number of patients treated
50< 2 Number of patients treated in total
20<×≤50 1
≤20 0
Effect of treatment
↑↑↑ 3 Average across all patients treated (total score/number of patients). Studies without exact measures or indicative of variations in efficacy will not be included and the patients cut from the equation
↑↑ 2
1
0
–1
Total score(maximum of 10 points) 7≤-A A – Very strong evidence
5.5≤×<7-B B – Strong evidence
4.5≤×<5.5-C C–Intermediate evidence
3≤×<4.5-D D – Weak evidence
<3-C E–Very weak evidence

Results

The nine selected articles included three randomized control trials, one uncontrolled prospective interventional trial, three retrospective reviews and two case reports. The quality and risk of bias of selected articles are presented in Table 2.

Table 2:: Risk of bias assesment for the included studies
(a) Quality and risk of bias assessment of included RCTs10
Randomization Randomization scheme Double blinded Blinding scheme Dropouts/withdrawals
Leducq et al., 202015
Yadav et al., 201716 - - -
Sharma et al., 201317 -
(b) Quality and risk of bias assessment of included non-RCTs11
A stated aim of the study Inclusion of consecutive patients Prospective collection of data End point appropriate to the study aim Unbiased evaluation of end points Follow-up period appropriate Loss to follow- up not exceeding 5%
Mora
et al., 2004 13
2 2 2 2 0 0 2
Perez
et al., 200920
2 0 0 1 0 0 0
Sagi et al., 201119 0 0 0 0 0 0 0
Godse, 200421 0 0 0 0 0 0 0
Prospective calculation of the study size A control group having the criterion standard intervention Contemporary groups Baseline equivalence of groups Prospective calculation of the sample size Statistical analyses adapted to the study design Total
Mora
et al., 2004 13
0 0 0 0 0 2 12
Perez
et al., 200920
0 0 0 0 0 1 4
Sagi et al., 201119 0 0 0 0 0 0 0
Godse, 200421 0 0 0 0 0 0 0

Patient selection criteria/profile

The total number of patients in all the studies included were 127(n). The age of the patients across the studies varied from 15 to 75 years. Female predominance was seen in most of the studies. The disease duration of the patients varied from few weeks up to 24 years. The study population (n=127) included 93 patients with chronic urticaria, 21 with chronic urticaria (steroid-dependent), 11 with chronic autoimmune urticaria and two angioedema [Table 3].

Table 3:: Demographic and clinical profile of the study participants (n=127)
Author Study design Age mean/range Male:female ratio Type of urticaria Mean duration of urticaria
Leducq et al.,202015 RCT 46.4 11:28 CSU=39 4.9 yrs.
Yadav et al.,201716 RCT 35.33±4.53 yrs. (mean) 17:23 CU=40 1.8 yrs.
Sharma et al., 201317 RCT 34.21 ±10.42 yrs. (mean) 6:8 CSU=14 1.9 yrs.
Sagi et al.,201119 Retrospective review 54±19/(18–74 yrs.) 2:6 Steroid-dependent CU=8 12 ± 8 mo.
Perez et al.,*200920 Retrospective review 49yrs/(30–75 yrs.) 3:9 Steroid-dependent CU=10 Angioedema=2 48.5 mo.
Godse, 200414 Case series 15–55 yrs. 3:1 CAU=4 NR
Mora et al., 200413 Uncontrolled Prospective,interventional trial NR 2:5 CAU=7 NR
Gach et al., 200121 Case report Case1=42 yrs.
Case 2= 37 yrs.
1:1 Steroid-dependent CIU + Angioedema Case 1=intermittent episodes since childhood Case 2=8 mo.
Weiner, 19897 Case report 48 yrs. 1 male Steroid-dependent CU 24 yrs.
12 patients with chronic urticaria and angioedema were included in our review; four patients with urticarial vasculitis were excluded from this analysis. NR: Not reported by author, CU: Chronic urticaria, CSU: Chronic spontaneous urticaria, CAU: Chronic autoimmune urticaria, RCT: Randomized controlled trial, yrs.: Years, mo: Months

The patients included in various studies, often did not respond to first- and second-generation antihistamine therapy and were subsequently put on second-/third-line immunosuppressive agents. Some even needed injectable (subcutaneous) adrenaline and corticosteroids (hydrocortisone) for severe, acute flares [Table 4].

Table 4:: Selection criteria/clinical profile of patients in various studies
Author Patient selection/clinical profile Therapeutic agents given before MTX
Leducq et al., 202015 1. CU treated with threedifferent anti-H1 molecules
or
2. Combination of twodifferent anti-H1 molecules
or
3.One anti-H1 molecule used at double dose for ≥3 months
4. With persistency of at least sevendays with urticarial lesions in the previous month
Antihistamines
Multiple
Leukotriene inhibitor
Montelukast
Corticosteroid
Oral
Others
Colchicine
Yadav et al., 201716 Patients with chronic spontaneous urticaria. NR
Sharma et al., 201317 Antihistamine-resistant chronic spontaneous urticaria was defined as less than 50% reduction in urticaria activity score (UAS) with:
Five milligrams of levocetirizine or tenmilligramscetirizine BD for 15 days
+
Combination of fexofenadine 180 mg and hydroxyzine 25 mg for another 15 days
Antihistamines
Levocetirizine
Cetirizine
Fexofenadine
Hydroxyzine
Sagi et al., 201119 Patient with steroid-dependent chronic urticaria (biopsy performed) Antihistamines*
Corticosteroid
Oral prednisolone (30–40 mg/day)
Intravenous hydrocortisone
Others
Doxepin
Colchicine
Dapsone
Perez et al., 200920 Patients with steroid dependent, recalcitrant chronic urticaria Antihistamines*
Second generation
Corticosteroid
Oral prednisolone (10–60 mg/day)
Leukotriene inhibitor
Montelukast
Immunomodulator
Azathioprine
Ciclosporin
Others
Colchicine
Hydroxychloroquine
Sulfasalazine
Dapsone, Doxepin
I/v immunoglobulins
Godse,200414 Patient with recalcitrant CU + positive ASST Antihistamines
Fexofenadine
Cetirizine
Hydroxyzine
Mora et al., 200413 Patients with chronic autoimmune urticaria with positive ASST Antihistamines
Hydroxyzine
Montelukast
Desloratadine
Author Patient selection/clinical profile Therapeutic agents given prior to MTX
Gach et al., 200121 Case 1: CU + angioedema, arthralgia, myalgia, eye soreness, breathlessness, arthritis; negative ASST. Challenge test for delayed pressure urticaria was positive(biopsy performed)
Case 2:CU + angioedema, negative ASST. Challenge test for delayed pressure urticaria was positive. Cushingoid features, adrenal insufficiency seen
Antihistamines
Chlorpheniramine
Astemizole
Fexofenadine
Acrivastine
Corticosteroid
Oral prednisolone (40–60 mg/day)
Immunomodulator
Ciclosporin
Others
Doxepin
Dapsone
Adrenaline
Ephedrine spray
Weiner, 19897 Patient with chronic urticaria + angioedema, high fevers, arthralgias, arthritis Antihistamines
Cyproheptadine
Corticosteroid
Subcutaneous hydrocortisone
Others
Adrenaline
Details of antihistamines not reported in published article, NR: Not reported

Treatment protocol

Methotrexate was used in variable doses in different studies, the maximum dose being 25mg/week [Table 5]. The route of administration was oral for all patients except two patients who could not tolerate oral methotrexate due to gastrointestinal side effects. Methotrexate was administered as a once weekly dose in all studies except in cases reports by Weiner, Montero et al. and Godse who gave methotrexate for two–three days/week.7,13,14 The duration of treatment varied from few weeks to over six months [Table 5].

Table 5:: Summary of treatment protocol, efficacy, follow-up and adverse effects in the various studies
Author Cases Controls Treatment protocol MTX Dose Duration of treatment Response* Follow-up and dropout Adverse effects
Leducq
et al., 202015
39 36 MTX +antihistamines;Placebo +antihistamines 0.2 mg/kg/wk. (↑ by 0.25mg/kg/wk., if no response) 18 weeks 3×↑↑↑
11×↑↑
ND
dropout – none
17 had gastrointestinal symptoms
Yadav et al., 201716 40 40 MTX;Placebo 15 mg/ week 8–12 weeks 40×↑↑ ND
dropout– none
NR
Sharma
et al., 201317
14 15 MTX + levocetirizine 5 mg daily
Placebo + levocetirizine 5 mg daily
15 mg/week 12 weeks 1×↑↑↑
2×↑↑
3.5±2.4 months
Dropout=12 (fourcases, eightcontrols)
Uncontrollable nausea,vomiting=1(withdrew from study)raised transaminase level-2
Sagi et al., 2/01119 8 NA MTX + antihistamines+ 5 mg folic acid once weekly(steroid tapered gradually) 15mg/week (non-responder: up to
25 mg/week)
4.5±3 months 7×↑↑↑
1×→
8.25±4.6months
Dropouts–NA
GI intolerance=2
Raised LFT=1
Weakness =1
Perez et al., 200920 12 NA MTX + antihistamines+ 5 mg folic acid once weekly(steroid tapered gradually) 10–15 mg/week (non-responder: up to
25 mg/week)
Variable§ 1×↑↑↑
5×↑↑
3×↑
3×→
ND
Dropouts– NA
Hair thinning and fatigue
Godse, 200414 4 NA MTX + antihistamines+1.5 mg folic acid daily 10mg/week in divided doses 8 weeks 4×↑↑ One relapse after two weeks of stopping MTX NR
Mora et al., 200413 7 NA MTX 10–15mg/week in divided doses 6 weeks 6×↑↑↑
1×↑↑
ND Headache and nausea
Gach et al., 200121 2 NA Case1=MTX +antihistamines(oral cyclosporine tapered and stopped)
Case 2=MTX + antihistamines (oral steroids tapered off gradually)
15mg/week
20mg/week
NR
NR
2×↑↑ ND NR
Weiner, 19897 1 NA MTX(oral steroids tapered off gradually) 15mg/week in divided doses NR 1×↑↑↑ Relapse after sixmonths MTX again started Slight elevation in SGPT/SGOT
Mild leukopenia
Effects of treatment as per CEST (Copenhagen evidential scale of treatments). †Twelvepatients with chronic urticaria and angioedema were included in our review; four patients with urticarial vasculitis were excluded from this analysis. §Patients were given cumulative dose of 174.7 mg MTX, duration varying from three weeks to >six months. MTX: Methotrexate, CYA: Cyclosporine A, ND: Not done, N/A: Not applicable, NR: Not reported, SGOT: Serum glutamic oxaloacetic transaminase, SGPT: Serum glutamic pyruvate transaminase

Response to treatment

The outcome measures varied across different studies [Table 5]. In a randomized control trial conducted by Leducq et al. on antihistamine-refractory urticaria, the outcome measures were based on the reduction of urticarial wheals and decrease in the intensity of pruritus with methotrexate. They chose a stringent criterion for response to treatment, that is, complete remission was defined as no new lesions within 30 days of stopping treatment. In their study, with 39 cases and 36 controls, respectively, three cases achieved complete remission with methotrexate whereas none of the placebo group had complete remission while 11 cases on methotrexate and six from placebo group had partial remission.15 Both Sharma et al. and Yadav et al. measured outcomes using urticaria severity assessment, which included scoring the number, size, frequency and duration of wheals as well as severity of pruritus.16-18

In a placebo-controlled randomized control trial conducted by Sharma et al., with 14 cases and 15 controls, there was significant improvement in urticaria severity assessment score in the methotrexate group; however, no additional benefits over antihistamines were seen (urticaria severity assessment score; pruritus and wheal score, P = 0.923 and 0.929, respectively).17 Similarly, in a randomized control trial conducted by Yadav et al. with 40 cases and controls each, they concluded that though both groups showed a significant improvement in all parameters of urticaria severity assessment score; there was no statistically significant difference between the methotrexate and placebo groups (urticaria severity assessment score, pruritus/wheal score, P>0.05).16

Sagi et al., in a retrospective review, reported good response to methotrexate in eight patients with steroid-dependent chronic urticaria. They reported that 87% of patients had complete remission with methotrexate at 15–25 mg/week.19 Doses of steroids could be gradually tapered.

Perez et al. reported on the benefits of methotrexate in patients with steroid-dependent chronic urticaria with gradual reduction in steroid doses. Among 12 patients, reviewed retrospectively, 16.7% showed complete clearance of urticaria, 58% had considerable benefit and 25% of patients showed some benefit after methotrexateuse.20

Montero et al. conducted a prospective interventional study on seven patients with chronic urticaria. They reported benefit in all the seven patients by the end of six weeks with significant improvement in itching and wheal score (P= 0.003 and 0.004, respectively).14

Godse also reported a case series of four patients with recalcitrant autoimmune urticaria who had a positive autologous serum skin test. He observed marked improvement with methotrexate.14 Gach et al. and Weiner also reported cases with good response to methotrexate.7,21

Tests for functional antibodies (i.e.,autologous serum skin testand basophil histamine release assay} were done in a few studies; however,no significant correlation was seen between presence of functional antibodies and response to methotrexate [Table 6].14,20

Table 6:: Functional antibody results done in various studies
Author ASST BHRA Remarks
+ve –ve +ve –ve
Sharma et al., 201317 ASST negative (with MTX):
Mean wheal scores: ↓ in 30% patients
Mean pruritus scores: ↓ in 40% patients ASST positive (with MTX):
Mean wheal scores: ↓ in 14.2% patients
Mean pruritus scores: ↓ in 28.4% patients
In the placebo group, the ASST-positive group showed a better response.
Case=10 7 3 ND ND
Control=7 3 4 ND ND
Perez et al., 200920 n=12(threeout of 12 patients not tested) 4 2 2 2 Five patients with considerable benefit (i.e.,↓ wheals, symptoms, ↓ steroid dose), one had -ve ASST andBHRA, while one had -ve BHRA(ASST=ND), one was +ve for ASST (BHRA=ND) and the rest were not tested
In threepatients with no benefit on MTX, twohad +veASST while one had not been tested
Mora et al. 200413
n=7
7 nil ND ND ASST was positive in the sevenpatients included in the study
At the end of sixweeks, good response was seen in all of the patients with methotrexate
Godse, 200414
n=4
4 nil ND ND In antihistamine-resistant CAU patients, there was marked improvement after treatment for onemonth
Gach et al., 200121
n=2
0 2 nil 2 Good response in steroid-dependent cases who had developed adrenal insufficiency andCushingoid features due to chronic steroid use

ASST: Autologous serum skin test, BHRA: Basophil histamine release assay, MTX: Methotrexate, ND: Not done, CAU: Chronic autoimmune urticarial

Quality of life

Leducq et al. reported improvement in dermatology life quality index from baseline to week 18 in both groups which was not statistically significant (P=0.57).15 However, Montero reported statistically significant improvement in impact on daily activity at the end of six weeks with methotrexate (P= 0.003).13

Adverse effects

In the largest randomized control trial with 75 cases conducted by Leducq et al., a number of side effects were reported. These included gastrointestinal side effects, deranged LFTs, bone marrow depression, nasopharyngitis and asthenia among others.15Among other reviewed studies, only minor side effects were observed; only one patient had uncontrolled nausea and vomiting due to methotrexate given at 15mg/ week dose following which it had to be withdrawn [Table 3].

Clinical outcome, follow-up and relapse

Complete remission, seen in three patients (methotrexate group), was defined as no urticarial lesions within the 30 days; partial remission, seen in 11 cases (methotrexate group), was defined as <7 days of urticarial lesions within 30 days before the 18-week end point by Leducq et al. Treatment with methotrexate was discontinued after 18 weeks and patients were followed up till 26 weeks.15

Sharma et al. followed up ten of their patients; at the end of six months follow-up, one patient (methotrexate group) had complete remission, that is, no lesions without antihistamines, two had partial remission, that is, reduction in antihistamine dose (one from each group), while the rest had relapsed immediately after stoppage of therapy.17

Sagi et al. followed up patients up to ten months (range 1-10 months), 71.4% (5/7) achieved complete remission after stopping methotrexate (i.e. no lesions after stopping treatment), while two patients were still on methotrexate at the time of analysis.19

Godse et al. noted that one patient out of four relapsed two weeks after stopping methotrexate.14 Weiner reported a relapse at six months post-methotrexate and the drug had to be restarted.7

Evidence for methotrexate use

After evaluating the articles, the evidence for methotrexate use was calculated with the Copenhagen evidential scale of treatments; the score obtained for methotrexate using selected literature was 6.7.12 As per the scale, this score is considered as strong evidence (B)[Tables1 and 7].

Discussion

On our literature search, there were limited articles on methotrexate use in chronic urticaria, majority being retrospective reviews and case series. The total participants in all the studies included were 127. Till date, only three randomized control trials (n=93) have been published and there is considerable heterogeneity in their methods. Therefore, due to the small number of studies of limited quality, a meta-analysis could not be done [Table 2a].

The largest and highest quality randomized control trial in our review was by Leducq et al., which included 39 cases and 36 controls; however, they chose an arbitrary measure for treatment response which did not compare well with other randomized control trials. Since they chose a stringent criterion for the treatment response, only three patients achieved complete remission in the methotrexate group. Although no dropouts were reported, the total number of patients finally recruited in the two groups were less than the initially proposed sample size of 110.15A treatment goal with a stringent criterion of no lesion in the past 30 days is perhaps too ambitious for any therapeutic modality. In real life, unless a motivated patient keeps a symptom diary, this may neither be accurate nor feasible. This is precisely why that with a less stringent criterion (i.e., partial remission–no lesions in the past 14 days), 14 patients reported benefits with methotrexate. Sharma et al. reported no additional benefit of methotrexate over antihistamines alone. The dropout rate was also high with 28.6% and 53.3% for cases and controls, respectively. One patient withdrew early from the study due to uncontrolled nausea and vomiting.17

In terms of selection criteria, Leducq et al. included patients who had received multiple anti-H1 molecules or a single anti-H1 molecule at double dose for more ≥ three months. Some even received immunosuppressants and leukotriene inhibitors. Thus, their patient population had more chronic, severe and recalcitrant course. In comparison, Sharma et al. gave a shorter course with no reported history of immunosuppressants.15,17 The authors opine that the difference in their response to methotrexate could be attributed to this fact.

The randomized control trial by Yadav et al. had no defined patient selection criteria. Furthermore, there was no documentation of dropouts or follow-up of patients for relapse.16 Hence, the finding reported by them should be taken with a grain of salt.

Good results have been reported with methotrexate in steroid-dependent chronic urticaria in retrospective reviews and anecdotal case reports.19-21

Sagi et al. and Perez et al. up-dosed methotrexate for nonresponders up to 25mg/week, which may have contributed to better response compared to other studies where lower doses were given.19,20 In this review, 20 patients included were steroid-dependent cases; it appears that in these patients, methotrexate is beneficial especially at higher doses.19-21

Various authors have suggested that chronic spontaneous urticaria may be an autoimmune condition in a substantial proportion of cases.22 Autologous serum skin test was done to investigate for autoimmune urticaria in studies by Sharma et al. and Perez et al.17,20 However, response rate to methotrexate was not influenced by autologous serum skin test results. Since we expect methotrexate to alter the level of functional antibodies, larger studies may be done in the future to further investigate its role in autoimmune urticaria.

Methotrexate is a relatively safe drug when used at lower doses for dermatological diseases with very few adverse effects; severe adverse drug reaction (bone marrow depression and pulmonary fibrosis) is generally not seen in the doses used for urticaria. Severe gastrointestinal symptoms usually presented early in the course of treatment and were easily identified and managed.17 Parenteral route is an option for patients who do not tolerate the drug orally [Table 8].

Table 7:: Application of Copenhagen evidential scale of treatments to the findings of present systematic review12
Scale parameters Factor Findings of present systematic review Score Mean
Study design
Randomized controlled trial 3 3 9 14/9 1.6
Prospective intervention 2 1 2
Caseseries 1 3 3
Single-casereport 0 2 0
No. of studies identified - 9 1 - 1
No. of patients treated - 127 2 - 2
Effect of treatment*
↑↑↑ 3 19 57 190/91
↑↑ 2 65 130
1 3 3
0 4 0
-1 0 0
Total 6.7
Treatment response was clearly mentioned for 91 cases out of 127 in the studies reviewed
Table 8:: Common side effects of methotrexate
System Side effect
Gastrointestinal Nausea
Vomiting
Diarrhea
Anorexia
Ulcerative stomatitis
Hepatic Transaminitis
Cirrhosis
Hematological Thrombocytopenia
Neutropenia
Pancytopenia
Myelosuppression
Pulmonary Acute pneumonitis
Pulmonary fibrosis
Reproductive Teratogenicity
Abortifacient
Renal Renal papillary necrosis
Others Alopecia
Headache
Fatigue
Risk of malignancy

Cyclosporine is another effective and commonly used drug in recalcitrant cases, but its side effects can be troublesome. In a meta-analysis by Kulthanan et al., cyclosporine was found to be an effective modality to treat urticaria in low-to-moderate doses; though, adverse events were seen in patients receiving moderate doses (4–5mg/kg/day) of cyclosporine (elevated creatinine, hypertension, headache, hirsutism, infections and paresthesia).23 Although methotrexate scores over cyclosporine in terms of safety and cost; the question of its efficacy is still subject to the availability of more scientific evidence.

Omalizumab has drastically altered treatment paradigms for chronic urticaria patients, wherein a few injections can lead to a potential cure. In a meta-analysis conducted by Zhao et al., it was seen that omalizumab was significantly more effective in reducing weekly wheal score and weekly itch score as compared to placebo. It also showed complete resolution (i.e. a post-treatment UAS7 score of 0) in 36% of patients at 300mg dosing.5 However, it may not be a silver bullet in all cases; being a chimeric monoclonal antibody, there remains a risk of immunological reactions.24,25 Although a highly effective alternative in refectory cases of urticaria; its high-cost limits use in developing nations where health insurance coverage may not be universal.

Recently, a systematic review of the effects of add-on methotrexate has been reported by Patil et al.; they concluded that though well tolerated, there may be no add-on benefit of methotrexate in difficult to treat urticaria with the caveat that this recommendation is based on limited data.26

Current Indian guidelines still recommend methotrexate, even with the paucity of good evidence, due to its suitability from the Indian perspective with respect to cost, availability, dosing schedule and good acceptance.27

On reviewing the available literature, we concur that application of methotrexate may be limited to cases where antihistamines have failed or the patient may have become steroid-dependent. Although omalizumab has considerably better efficacy in many of these cases, nonetheless methotrexate is still an additional tool in the dermatologist’s armamentarium. Cyclosporine, with good efficacy and reasonable safety, is another popular alternative; however, no randomized control trials to compare cyclosporine with methotrexate are currently available. The limitation of our study is that due to the paucity of literature, a meta-analysis could not be performed.

Conclusion

We conclude that all patients may not be good candidates for methotrexate; more evidence from as larger, well-executed randomized control trials is needed in order to give more definitive answers. Patients with prolonged disease course, not responding to multiple antihistamines, and steroid-dependent cases may be the potential candidates where methotrexate may prove useful.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

  1. , , , , , , et al. The EAACI/GA2LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. Allergy. 2018;73:1393-14.
    [CrossRef] [PubMed] [Google Scholar]
  2. , , . Prevalence estimates for chronic urticaria in the United States: A sex-and age-adjusted population analysis. J Am Acad Dermatol. 2019;81:152-6.
    [CrossRef] [PubMed] [Google Scholar]
  3. , , , , , . Urticaria and angioedema: An update on classification and pathogenesis. Clin Rev Allergy Immunol. 2018;54:88-101.
    [CrossRef] [PubMed] [Google Scholar]
  4. . Omalizumab (Xolair) for treatment of asthma. Am Fam Physician. 2005;71:341-2.
    [Google Scholar]
  5. , , , , , et al. Omalizumab for the treatment of chronic spontaneous urticaria: A meta-analysis of randomized clinical trials. J Allergy Clin Immunol. 2016;137:1742-50.e4.
    [CrossRef] [PubMed] [Google Scholar]
  6. , . Yella Pragada Subbarow-the unsung Indian biochemist behind methotrexate and other drugs. Indian J Dermatol Venereol Leprol. 2017;83:733-5.
    [CrossRef] [PubMed] [Google Scholar]
  7. . Methotrexate in corticosteroid-resistant urticaria. Ann Intern Med. 1989;110:848.
    [CrossRef] [PubMed] [Google Scholar]
  8. , , , . Anti-arthritic effect of methotrexate: Is it really mediated by adenosine? Eur J Pharm Sci. 2000;9:333-43.
    [CrossRef] [Google Scholar]
  9. , , , , , , et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev. 2015;4:1.
    [CrossRef] [PubMed] [Google Scholar]
  10. , , , , , , et al. Assessing the quality of reports of randomized clinical trials: Is blinding necessary? Control Clin Trials. 1996;17:1-12.
    [CrossRef] [Google Scholar]
  11. , , , , , . Methodological index for non-randomized studies (MINORS): Development and validation of a new instrument. ANZ J Surg. 2003;73:712-6.
    [CrossRef] [PubMed] [Google Scholar]
  12. , , . Use of nonbiologic treatments in antihistamine-refractory chronic urticaria: A review of published evidence. J Dermatolog Treat. 2018;29:80-97.
    [CrossRef] [PubMed] [Google Scholar]
  13. , , , . Urticaria autoinmunitaria. Tratamiento con metotrexato [Autoimmune urticaria Treatment with methotrexate] Rev Alerg Mex. 2004;51:167-72.
    [Google Scholar]
  14. . Methotrexate in autoimmune urticaria. Indian J Dermatol Venereol Leprol. 2004;70:377.
    [Google Scholar]
  15. , , , , , , et al. Efficacy and safety of methotrexate versus placebo as add-on therapy to H1 antihistamines for patients with difficult-to-treat chronic spontaneous urticaria: A randomized, controlled trial. J Am Acad Dermatol. 2020;82:240-3.
    [CrossRef] [PubMed] [Google Scholar]
  16. , . Effectiveness, safety and tolerability of methotrexate in chronic urticaria: At a tertiary care center. Int J Contemp Med Res. 2017;4:1952-5.
    [Google Scholar]
  17. , , , , . A randomized placebo-controlled double-blind pilot study of methotrexate in the treatment of H1 antihistamine-resistant chronic spontaneous urticaria. Indian J Dermatol Venereol Leprol. 2014;80:122-8.
    [CrossRef] [PubMed] [Google Scholar]
  18. , , , , , , et al. EAACI/GA(2)LEN/EDF/WAO guideline: Definition, classification and diagnosis of urticaria. Allergy. 2009;64:1417-26.
    [CrossRef] [Google Scholar]
  19. , , , , , . Evidence for methotrexate as a useful treatment for steroid-dependent chronic urticaria. Acta Derm Venereol. 2011;91:303-6.
    [CrossRef] [PubMed] [Google Scholar]
  20. , , . Methotrexate: A useful steroid-sparing agent in recalcitrant chronic urticaria. Br J Dermatol. 2010;162:191-4.
    [CrossRef] [PubMed] [Google Scholar]
  21. , , , . Methotrexate-responsive chronic idiopathic urticaria: A report of two cases. Br J Dermatol. 2001;145:340-3.
    [CrossRef] [PubMed] [Google Scholar]
  22. , , , , . A serological mediator in chronic idiopathic urticaria-a clinical, immunological and histological evaluation. Br J Dermatol. 1986;114:583-90.
    [CrossRef] [PubMed] [Google Scholar]
  23. , , , , , et al. Cyclosporine for chronic spontaneous urticaria: A meta-analysis and systematic review. J Allergy Clin Immunol Pract. 2018;6:586-99.
    [CrossRef] [PubMed] [Google Scholar]
  24. , , , . Delayed onset and protracted progression of anaphylaxis after omalizumab administration in patients with asthma. J Allergy Clin Immunol. 2007;120:1378-81.
    [CrossRef] [PubMed] [Google Scholar]
  25. , , , , . Omalizumab for the treatment of chronic idiopathic urticaria: Systematic review of the literature. Pharmacotherapy. 2017;37:464-80.
    [CrossRef] [PubMed] [Google Scholar]
  26. , , . Efficacy of methotrexate as add on therapy to H1 antihistamine in difficult to treat chronic urticaria: A systematic review and meta-analysis of randomized clinical trials. Dermatol Ther. 2020;33:e14077.
    [CrossRef] [Google Scholar]
  27. , , , , , , et al. Consensus statement for the diagnosis and treatment of urticaria: A 2017 update. Indian J Dermatol. 2018;63:2-15.
    [CrossRef] [PubMed] [Google Scholar]
Show Sections