Methotrexate for urticarial vasculitis and angioedema with cryoglobulinemia

Background: Cryoglobulinemia (CG) is associated with a leukocytoclastic vasculitis primarily affecting the kidneys, skin and peripheral nerves.  Urticaria, but not usually angioedema, is a potential presentation for CG.  Cryoglobulins are usually associated with infectious, autoimmune and lymphoproliferative disorders; therefore, treatment options are varied.  We report a patient with corticosteroid (CS)-dependent urticaria and angioedema (U/AE) who was able to discontinue CS therapy following weekly oral methotrexate (MTX).

Results:  57-year- old Caucasian male presented with a seven month history of recurring symptoms of generalized urticaria and facial angioedema.  The symmetrical rash initially developed after a dental procedure requiring penicillin therapy.  The findings were attributed to penicillin, but persistence of the rash prompted a skin biopsy which demonstrated a leukocytoclastic vasculitis.  Prednisone, 10 mg twice daily, resulted in minimal improvement of the rash, but arthritic pain in the hands and knees developed.   An immunologic and rheumatologic evaluation showed type 3 mixed CG without monoclonal protein, 2+ urinary protein, decreased C3 (50 mg/dL; normal 90 – 180 mg/dL) and CH50 (13 U/mL; normal 31-66 U/mL).  Negative studies included serum rheumatoid factor, hepatitis antibodies, anti-nuclear antibody, anti-neutrophil cytoplasmic antibody and CT scan of the abdomen.

Treatment with daily doxepin, 100 mg, meloxicam, 7.5 mg, hydroxycloroquine, 400 mg, and prednisone, 20 mg, was ineffective for the U/AE.  Exacerbations occurred when the dose of prednisone was reduced.  Oral MTX, 25 mg weekly, facilitated a prednisone taper, which was discontinued completely within 6 months without U/AE exacerbations.  The cryoglobulin quantification remained unchanged. 

Conclusion:  The differential diagnosis of U/AE includes a variety of less common immunologic conditions.  The mechanism of action of weekly, oral MTX is not completely understood. Suppression of cell replication is probably not the primary mechanism of action.  Weekly MTX is a minimally immunosuppressive therapy that may be effective for U/AE associated with CG.  Evaluation for CG should be considered in subjects with U/AE requiring chronic CS therapy or with features of leukocytoclastic vasculitis.