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

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 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].

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Figure 1:

Flow diagram and literature review

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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.

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.