An 89 year old male presented with itchy red rash over the body since two weeks. His past medical history was significant for Rheumatoid Arthritis (RA) managed with 2.5 mg weekly oral Methotrexate and 200mg daily Hydroxychloroquine for RA. Examination revealed multiple annular purpuric lesions with central erosion on lower extremities, upper extremities and back. Rest of the Physical Examination was unremarkable. Labs were significant for Pancytopenia with WBC 3500/µL, Hemoglobin 7.8g/dL and platelet count of 24K. Serum creatinine was 2.4 mg/dL with history of chronic kidney disease. His blood smear showed macrocytosis without any overt dysplasia. Reticulocyte count was 0.2%, Reticulocyte production index 0.1 and fibrinogen 292 mg/dL. Vit B12 was 347 pg/ml, Ferritin 426ng/mL, LDH was mildly elevated (291 IU/L) at admission which decreased to normal after five days (150 IU/L). Histoplasma antigen, Cryptococcal Antigen, Parvo virus and Human immunodeficiency virus studies were negative. Blood cultures for bacterial and fungus remained negative. Immunologic work up showed increased C Reactive Protein (59.9mg/L), negative ANA Screen, normal Rheumatoid factor level (12 IU/mL) and elevated cyclic citrullinated antibody (250u). Methotrexate drug levels were undetectable.
Lab work done three months prior to presentation showed normal cell counts with WBC 10,000/µL, Hemoglobin 12.6 g/dL and platelet count of 295K. Methotrexate and Hydroxychloroquine were stopped at admission. He was started on folic acid and leucovorin therapy. The skin lesions were biopsied which showed mixed cell type interface dermatitis, seen in drug reaction particularly with methotrexate. After discontinuing the methotrexate, cell counts started to improve with platelets rising to 239 K and WBC upto 7.6K in one and two weeks, respectively. The drug rash also improved considerably in one week of hospital stay.
Discussion: Methotrexate is the preferred disease- modifying antirheumatic drug administered once weekly. Side effects of methotrexate involve gastrointestinal, hematological and hepatic systems. Severe adverse effects are common with the higher doses of methotrexate. The lowest recommended dose for RA is 7.5mg weekly with 50% dose reduction for creatinine clearance between 10-50ml/minute. Our patient was taking 2.5mg weekly oral Methotrexate. In the literature, degree of myelosupression and skin rash is mostly dose dependent and compounded with renal insufficiency. However, myelosupression and other side effects can also occur with very low dose of Methotrexate particularly with kidney function impairment. To our knowledge, Methotrexate toxicity has not been reported with such low dose. Hematological and other side effects of methotrexate can also occur as late manifestation.
Conclusions:
With increasing long term use of methotrexate, it is important that patients be monitored for hematological and other side effects as it can occur at any dose and as late manifestation. This is particularly vital as these side effects can be quickly progressive and fatal.