What is the role of methotrexate (MTX) in the treatment of chronic urticaria?

Methotrexate in Chronic Urticaria

Methotrexate has only anecdotal evidence supporting its use in chronic urticaria and should be reserved as a last-resort option for steroid-dependent cases unresponsive to antihistamines, ciclosporin, and omalizumab. 1

Evidence Quality and Guideline Recommendations

The British Association of Dermatologists guidelines explicitly state that evidence for methotrexate in chronic urticaria is limited to anecdotal reports and case reports only, with no randomized controlled trials supporting its efficacy. 1 This stands in stark contrast to ciclosporin, which has Quality of evidence I and Strength of recommendation A for chronic urticaria. 1

Treatment Algorithm for Refractory Chronic Urticaria

First-Line Therapy

• Standard-dose second-generation H1 antihistamines should be initiated first 2
• If inadequate control, updose antihistamines to 4-fold the standard dose 2

Second-Line Therapy

• Omalizumab 300 mg subcutaneously every 4 weeks is the preferred second-line agent for antihistamine-refractory chronic spontaneous urticaria 3, 2
• Omalizumab demonstrates clear clinical benefit with excellent safety profile and prevents angioedema episodes 2

Third-Line Therapy

• Ciclosporin 4 mg/kg daily is the best-studied immunosuppressive drug for chronic urticaria, effective in approximately two-thirds of patients with severe autoimmune urticaria unresponsive to antihistamines 1
• Treatment duration of 16 weeks shows fewer therapeutic failures than 8 weeks 1

Fourth-Line Consideration: Methotrexate

• Consider methotrexate only for steroid-dependent chronic urticaria that has failed antihistamines, omalizumab, and ciclosporin 4, 5
• Typical dosing: 10-15 mg weekly 5

Clinical Evidence for Methotrexate

Retrospective Studies Show Mixed Results

• One retrospective series of 8 patients achieved complete response in 87% (7/8 patients) with mean dose of 15 mg/week for 4.5 months 4
• A larger retrospective review of 16 steroid-dependent patients showed 75% response rate (12/16 patients), with doses of 10-15 mg weekly 5

Randomized Controlled Trial Shows No Benefit

• The only randomized, double-blind, placebo-controlled trial found no additional benefit of methotrexate 15 mg weekly over antihistamines alone 6
• Primary outcome (>2/3 reduction in urticaria scores) was achieved in similar proportions: methotrexate group vs placebo group (P > 0.05) 6

Potential Role After Omalizumab Failure

• One retrospective study of 10 patients unresponsive to omalizumab + high-dose antihistamines showed 70% complete or well-controlled response with methotrexate 15 mg weekly subcutaneously 7
• Mean treatment duration was 5.1 months, and methotrexate was well tolerated in 80% of patients 7

Critical Caveats and Pitfalls

Evidence Quality Issues

• The positive retrospective studies lack placebo controls, making it impossible to distinguish methotrexate's effect from natural disease fluctuation 4, 5
• The single RCT contradicts the retrospective data, suggesting publication bias in case series 6
• Functional autoantibodies do not predict response to methotrexate 5

Safety Monitoring Requirements

• Weekly monitoring initially: full blood count, liver function tests, serum creatinine 1
• Interval can be extended to every 1-2 months once stable 1
• Contraception required in both men and women due to teratogenicity 1
• Risk of hepatic fibrosis with cumulative dosing 1

Alternative Agents to Consider First

• Tacrolimus and mycophenolate mofetil have shown similar overall responses to ciclosporin in open studies 1
• Plasmapheresis and intravenous immunoglobulins may be effective in severe autoimmune chronic urticaria 1

Practical Recommendation

Given the lack of RCT evidence and the availability of better-studied alternatives (omalizumab, ciclosporin), methotrexate should only be considered in the rare patient with steroid-dependent chronic urticaria who has documented failure of omalizumab and ciclosporin. 1, 7 In such cases, use 10-15 mg weekly with appropriate monitoring, recognizing that the evidence base is weak and response is unpredictable. 5, 7