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Thalidomide for the Treatment of Oral Aphthous Ulcers in Crohn's Disease

1999; Lippincott Williams & Wilkins; Volume: 28; Issue: 2 Linguagem: Inglês

10.1097/00005176-199902000-00025

1536-4801

Toba Weinstein, James J. Sciubba, Jeremiah Levine,

Chronic Lymphocytic Leukemia Research

Crohn's disease is a chronic inflammatory disease that may involve any part of the gastrointestinal tract from the mouth to the anus. There is a wide spectrum of clinical features and great individual variation in disease course. The incidence of oral lesions in patients with Crohn's disease ranges between 6% and 20% (1-5). Aphthous ulceration of the mouth is the most common oral manifestation described and can lead to significant morbidity. These small areas of frank ulceration can occur on the floor of the mouth, alveolar gingiva, lips, soft palate, buccal mucosa, and uvula (1,6). Oral manifestations of the disease usually correlate with gastrointestinal disease activity, but they can occur before gastrointestinal manifestations or even before the diagnosis of Crohn's disease is made. Treatment of these lesions can be difficult. Thalidomide (α-N-phthalimidoglutarimide) has been espoused in the literature for its role in the treatment of severe recurrent aphthous stomatitis (7-9) and most recently for its use in the treatment of oral aphthous ulcers in patients with human immunodeficiency virus infection (10-13). We report our success with thalidomide in the treatment of a patient with Crohn's disease and severe recurrent oral ulcerations of the aphthous type. CASE REPORT A 13-year-old girl received a diagnosis of Crohn's disease at the age of 5 years when she manifested symptoms including fever, diarrhea, abdominal pain, weight loss, hypoalbuminemia, and an elevated erythrocyte sedimentation rate. An upper gastrointestinal series with small bowel follow-through revealed a nodular and markedly irregular terminal ileum. Colonoscopic evaluation revealed diffuse colitis. Study of pathologic specimens showed noncaseating granuloma, acute and chronic inflammation, and crypt abscess formation. One year after the diagnosis was made, oral aphthous ulcerations developed and persisted despite therapy with sulfasalazine, prednisone, and metronidazole. Further evaluation showed esophageal Crohn's disease. Because of her severe disease course, she was supported by hyperalimentation, an ileostomy was created, and therapy with 6-mercaptopurine (6-MP) and ranitidine was initiated. Six years after treatment with 6-MP was implemented, she continued to have disease exacerbation, predominantly oral aphthous ulcerations, requiring intravenous hydration, methylprednisolone, and hyperalimentation. Colonoscopy and ileoscopy performed through the stoma during a disease exacerbation revealed only mild erythema without pathologic abnormalities. However, punctate ulcerations were present at the stoma site. In light of recalcitrant disease, steroid dependence, and toxicity, the option of treatment with thalidomide was offered. After extensive discussion detailing all the potential risks of thalidomide therapy and obtaining informed consent, treatment with 25 mg thalidomide (0.7 mg/kg daily) was instituted in addition to her regimen of 50 mg 6-MP, 20 mg prednisone, and 75 mg ranitidine twice daily; mesalamine suppository; and folate and calcium supplementation. Laboratory evaluation of the patient, while she was undergoing this regimen and before initiation of therapy revealed leukocytes, 3900 mm3; hematocrit, 36.7%; erythrocyte sedimentation rate, 3 mm/hr; and albumin, 4.1 g/dl. Growth parameters before initiation of therapy were weight, 33.5 kg (10th percentile), and height, 122.5 cm (below the 5th percentile) with a height velocity of less than 3% in a Tanner stage 1 girl with moderate inflammatory bowel disease (score of 54, based on a clinical scoring system for chronic inflammatory bowel disease in children [14]). Thalidomide was provided after obtaining appropriate U.S. Food and Drug Administration and institutional review board approval for compassionate use. One week after implementation of thalidomide therapy, the oral lesions began to resolve. Within a month, all oral and stomal ulcerations had healed. After 8 months of continuous thalidomide therapy she had discontinued steroid therapy completely (for the first time in 8 years) with the following laboratory parameters: leukocytes, 4000 mm3; hematocrit, 37.7%, erythrocyte sedimentation rate, 1 mm/hr; and albumin concentration, 4.4 g/dl. Her growth parameters were weight, 37 kg (10th percentile), height, 131 cm (below the 5th percentile); and height velocity of 97% since drug initiation. Tanner classification remained stage 1 with a juvenile inflammatory bowel disease score of 85, consistent with good disease status (14). After 1 year of thalidomide therapy she had been without oral lesions, had not had any disease exacerbation, and began a regimen of alternate-day dosage of thalidomide. Within 6 weeks she reported a sore throat and had intermittent fever. She had a negative evaluation for mononucleosis and a throat culture that revealed normal flora. Her throat pain persisted, and 1 month later a posterior pharyngeal wall ulceration extending from the level of the base of the tongue toward the epiglottis was noted during otolaryngologic examination. A 1-week course of prednisone was begun that included a rapid taper, and daily thalidomide therapy was resumed. Again, 1 week after implementation of daily thalidomide therapy she was symptom free and her oral lesion began to resolve. She is currently without oral lesions with continued resolution of symptoms and ulceration noted after 1 month of returning to a daily thalidomide regimen. DISCUSSION Thalidomide was used in the late 1950s as an effective sedative, hypnotic, and antiemetic in pregnant women (9,11-13). It appears to selectively inhibit the production of human monocyte tumor necrosis factor-α (TNF-α). Tumor necrosis factor-α production by human blood monocytes is inhibited by thalidomide without influencing general protein synthesis, interleukin-1β, interleukin-6, or granulocyte/macrophage colony-stimulating factor (15). It is thought to have anti-inflammatory and immunomodulating effects and the property of angiogenesis inhibition (10,16). In vivo studies in animals have shown that thalidomide is a potent inhibitor of angiogenesis induced by basic fibroblast growth factor (16). Its use for treatment of erythema nodosum leprosum is well established (7,10,12,15,17); however, the drug is better known for its teratogenicity, which caused its withdrawal from pharmaceutical use in the early 1960s (9,11,12). In addition, peripheral neuropathy can occur with long-term use and may be irreversible. Other adverse effects include drowsiness, constipation, xerostomia, cutaneous dryness, distal edema, hypothyroidism, rash, and other hypersensitivity reactions (7-10,12). Currently, there appears to be strong confirmation in the literature about the usefulness of thalidomide in treating recurrent oral aphthous ulcers, especially in patients who have recalcitrant disease, steroid toxicity, or both (7-13). Several of these case reports have included treatment of oral lesions in children (7,8,13,18). Patients with Crohn's disease and chronic mucosal ulceration can experience extreme pain and significant morbidity, particularly when their disease is refractory to treatment. Our patient had severe oral, esophageal, terminal ileal, and colonic Crohn's disease requiring long-term therapy with steroids and 6-MP, with intermittent parenteral nutritional support and surgical intervention. The oral aphthous ulcerations were causing severe morbidity requiring frequent hospitalization and intravenous fluid therapy for dehydration and malnutrition. These exacerbations responded to an increase in steroid dosage but with each attempt at discontinuation of steroid dosage her oral lesions would recur, and she began to experience corticosteroid toxicity. Once thalidomide therapy was implemented, the patient's steroids were discontinued without disease exacerbation. Only after an alternate-day thalidomide regimen was implemented did she have recurrence of oral ulceration, which responded to therapy with oral steroids and a daily thalidomide regimen. While receiving daily doses of thalidomide, she rapidly discontinued steroid therapy and has remained without disease exacerbation. In addition, she has exhibited excellent growth, with a height velocity of 97% since thalidomide therapy was initiated and marked improvement in the juvenile inflammatory bowel disease clinical score from moderate to good clinical status. We are aware of one other patient with Crohn's disease whose oral lesions were treated with an initial thalidomide dose of 100 mg/day (19). In the adult literature there are two reports of thalidomide's use as a therapeutic agent in patients with inflammatory bowel disease. In 1979 there was a report of a 33-year-old woman with ulcerative colitis who was treated with thalidomide (initial dose of 300 mg/day, increased to 400 mg/day) with steady disease improvement (20) and a recent report of a 55-year-old woman with recalcitrant Crohn's disease who was treated with an initial thalidomide dose of 300 mg/day with resolution of intestinal ulcerations (21). Thalidomide should be considered an effective agent in the treatment of refractory oral aphthous ulcers in patients with Crohn's disease who have not responded to other therapeutic regimens. As in any therapeutic regimen, the patient and parents (caretakers) must be fully aware of the potential side effects of this drug. Teratogenicity is a well-known effect of thalidomide, and all patients with childbearing potential must be educated regarding this adverse outcome. Even though our patient was classified as Tanner stage 1, the risks associated with pregnancy were discussed fully. If thalidomide is given to female patients with childbearing potential, effective birth control must be practiced, informed consent (which should include counseling procedures and monitoring in the event that pregnancy occurs) must be obtained, and periodic monitoring for potential pregnancy should be scheduled. In addition, because of the irreversible nature of the peripheral neuropathy, all patients should receive careful screening and follow-up. If distal paresthesia or neurologic deficits are noted, immediate neurologic evaluation including nerve conduction studies should be performed. Decisions regarding discontinuation of the medication should be made as soon as neurologic signs or symptoms are detected. In addition to treatment of refractory oral aphthous ulcerations in patients with Crohn's disease, thalidomide may represent a potential treatment option for patients with moderate to severe Crohn's disease. In uncontrolled trials, thalidomide seemed to be effective in patients with Behĉet's disease, inflammatory dermatoses, and refractory rheumatoid arthritis (7,9,12). Thalidomide has been a very successful agent in the treatment of erythema nodosum leprosum. The success of this drug appears to be linked to reduction of TNF-α levels, which are known to be elevated in patients with erythema nodosum leprosum who have active inflammation (15). Recent studies have suggested that TNF-α may play a central role in the inflammatory process in at least two thirds of patients with Crohn's disease (22,23). Thalidomide's mechanism involves inhibition of the synthesis of TNF-α and angiogenesis. The marked improvement exhibited in this patient with thalidomide therapy suggests a potential role for thalidomide therapy in patients with moderate to severe Crohn's disease. Further study of this anti-inflammatory and immunomodulating drug should be considered in a select group of patients with Crohn's disease.