Life-Threatening Gastrointestinal Mucosal Necrosis during Methotrexate Treatment for Rheumatoid Arthritis
An 82-year-old woman was referred to our hospital for constipation and lower abdominal pain 3 days after she had taken her last dose of MTX. She had been diagnosed with RA at the age of 74 and was being treated with nonsteroidal anti-inflammatory drugs (NSAIDs; 180 mg/day loxoprofen sodium hydrate), prednisolone (4–6 mg/day) and low-dose MTX (8 mg/week). At the first visit to our hospital, physical examination showed fullness and slight tenderness of the lower abdomen. Blood tests showed that she had anemia (hemoglobin [Hb] 10.0 g/dl) and mild inflammation (white blood cell [WBC] count and C-reactive protein [CRP] levels were 18,600/μl and 0.95 mg/dl, respectively). Her platelet count was 388,000/μl, and biochemical examination showed no significant abnormality. Computed tomography of the abdomen showed slight thickening of the descending colonic wall and no organic lesions resembling neoplasms. Lower gastrointestinal endoscopy showed mucosal petechiae in the descending colon, and the patient was believed to have colitis caused by fecal impaction (fig. ). Her symptoms were immediately relieved once she defecated after receiving laxative treatment. Antibiotics were not administered. To provide bowel rest, ingestion of enteral nutrients and parenteral nutrition were started.\nNine days after the first visit, the patient again complained of nausea, epigastralgia and abdominal fullness. The next day, she developed a fever (38.6°C) and ulcerative oral mucositis. Laboratory examination showed a WBC count of 900/μl, a Hb level of 7.6 g/dl, a platelet count of 120,000/μl and a CRP level of 14.45 mg/dl. Upper gastrointestinal endoscopy showed severe mucosal necrosis covering a large area (almost the entire circumference) of the lower esophagus, linear erosive gastritis and multiple duodenal ulcers. Lower gastrointestinal endoscopy was performed again, and mucosal necrosis with sloughing was observed along the entire circumference of the descending colon (fig. ). Contrast-enhanced computed tomography showed wall thickening along the entire circumference of the lower esophagus and descending colon, with mild pleural effusion. Microscopic examination of biopsy specimens from the esophagus and descending colon also revealed necrotic mucosa. On fecal culture analysis conducted at the same time, methicillin-resistant Staphylococcus aureus (MRSA) was detected, but Clostridium difficile or Candida albicans was not. Therapy with granulocyte colony-stimulating factor and empiric antibiotics was initiated. Eleven days after the first visit, the patient developed pancytopenia; her WBC count was 400/μl, Hb was 6.1 g/dl and platelet count was 59,000/μl. Severe inflammation and renal injury were observed (CRP 27.99 mg/dl; blood urea nitrogen 84 mg/dl; creatinine level 1.18 mg/dl). Blood transfusion and intravenous administration of meropenem, vancomycin, gamma-globulin, recombinant human soluble thrombomodulin and a proton pump inhibitor were started for the pancytopenia and infection. Leucovorin rescue was also initiated with a 3-mg intravenous bolus every 8 h, since the involvement of MTX was suspected. However, since the patient's general condition did not improve immediately, continuous hemodiafiltration with polymyxin B-immobilized fibers was performed. After 2 days of this blood purification therapy, the patient's general condition improved gradually.\nThe DLST was performed for MTX, NSAIDs and prednisolone. MTX showed a strong positive reaction, with a stimulation index of 443% compared to drug-free normal controls. The patient resumed oral intake 30 days after her first visit but had developed cicatricial stricture of the esophagus and colon (fig. ). Therefore she required balloon dilatation, twice for the esophagus and once for the descending colon. She was discharged from our hospital 15 weeks after admission (fig. ).