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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

## 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].

### 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

## 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.

### 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].

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].

### 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].

### 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

### 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

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].

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.

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.
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.
3. , , , , , . Urticaria and angioedema: An update on classification and pathogenesis. Clin Rev Allergy Immunol. 2018;54:88-101.
4. . Omalizumab (Xolair) for treatment of asthma. Am Fam Physician. 2005;71:341-2.
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.
6. , . Yella Pragada Subbarow-the unsung Indian biochemist behind methotrexate and other drugs. Indian J Dermatol Venereol Leprol. 2017;83:733-5.
7. . Methotrexate in corticosteroid-resistant urticaria. Ann Intern Med. 1989;110:848.
8. , , , . Anti-arthritic effect of methotrexate: Is it really mediated by adenosine? Eur J Pharm Sci. 2000;9:333-43.
9. , , , , , , et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev. 2015;4:1.
10. , , , , , , et al. Assessing the quality of reports of randomized clinical trials: Is blinding necessary? Control Clin Trials. 1996;17:1-12.
11. , , , , , . Methodological index for non-randomized studies (MINORS): Development and validation of a new instrument. ANZ J Surg. 2003;73:712-6.
12. , , . Use of nonbiologic treatments in antihistamine-refractory chronic urticaria: A review of published evidence. J Dermatolog Treat. 2018;29:80-97.
13. , , , . Urticaria autoinmunitaria. Tratamiento con metotrexato [Autoimmune urticaria Treatment with methotrexate] Rev Alerg Mex. 2004;51:167-72.
14. . Methotrexate in autoimmune urticaria. Indian J Dermatol Venereol Leprol. 2004;70:377.
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.
16. , . Effectiveness, safety and tolerability of methotrexate in chronic urticaria: At a tertiary care center. Int J Contemp Med Res. 2017;4:1952-5.
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.
18. , , , , , , et al. EAACI/GA(2)LEN/EDF/WAO guideline: Definition, classification and diagnosis of urticaria. Allergy. 2009;64:1417-26.
19. , , , , , . Evidence for methotrexate as a useful treatment for steroid-dependent chronic urticaria. Acta Derm Venereol. 2011;91:303-6.
20. , , . Methotrexate: A useful steroid-sparing agent in recalcitrant chronic urticaria. Br J Dermatol. 2010;162:191-4.
21. , , , . Methotrexate-responsive chronic idiopathic urticaria: A report of two cases. Br J Dermatol. 2001;145:340-3.