PATIENT NO 1

A 27 year old Caucasian receptionist presented with severe oropharyngeal and genital ulceration, and a pustular rash on the neck, back, and upper limbs in April 1999. She was a non-smoker with no family history of inflammatory bowel disease. Three months later she developed abdominal pain, bloody diarrhoea, 15 kg weight loss, and ankle synovitis. Her C reactive protein (CRP) was 72 mg/l; autoantibodies (including dsDNA) were negative. Barium follow through was normal. Colonoscopy revealed serpiginous and aphthoid ulceration in the hepatic flexure, descending, and sigmoid colon. The rectum was normal. Biopsy of a deeply ulcerated area at the hepatic flexure was reported as possible Crohn's disease without granulomata. In view of the pustular rash and severe orogenital ulceration however a diagnosis of Behçet's was made and she was treated with prednisolone 40 mg daily with modest improvement. Her weight remained unchanged (49 kg, body mass index (BMI) 17 kg/m²) and her CRP decreased to 45 mg/l.

In June 1999, she relapsed with fever, severe abdominal pain, recurrence of large painful oral ulcers, a painful punched out vulval ulcer, and a deep posterior perianal fistula. She also had synovitis of the left knee, right elbow, and several proximal interphalangeal joints, vasculitis of the toes, and superficial thrombophlebitis of each forearm. Her CRP was 70 mg/l. Double contrast barium enema revealed a perforation and abscess formation at a segment of narrowing and mucosal irregularity in the proximal sigmoid colon. The pyrexia settled on parenteral antibiotics and a computed tomography scan confirmed resolution of the abscess. Synovitis and orogenital ulceration did not respond to three pulses of methyl prednisolone (500 mg) and there was limited improvement of abdominal pain, bloody diarrhoea, and oral ulceration on thalidomide 400 mg daily for six weeks.

After discussion with the patient, thalidomide was discontinued and infliximab (3 mg/kg, dose reduced because of recent sepsis) was administered in September 1999. Within 10 days the perianal fistula and genital ulcers healed completely, single formed motions daily replaced frequent episodes of bloody diarrhoea, and appetite and energy levels returned to normal. Synovitis, thrombophlebitis, and the rash resolved completely and weight increased by 3 kg. Six weeks later, abdominal pain and occasional loose stools recurred with a CRP of 29 mg/l despite sustained improvement in weight. Thalidomide was restarted. A second infusion of infliximab (3 mg/kg) was given in November 1999, eight weeks after the initial dose, with symptomatic improvement. A repeat barium enema showed persistent narrowing and irregularity in the sigmoid colon but no abscess cavity. Areas of ulceration and mucosal irregularity in the transverse colon and hepatic flexure were thought to be more marked than previously. Nevertheless, 12 weeks later CRP was 12 mg/l and was <6 mg/l after six months. Weight returned to normal (56 kg) and digital vasculitis improved slowly. Thalidomide 100 mg daily was continued, with prednisolone 4 mg daily. As of March 2001, she had no complaints, had needed no further infliximab (17 months after the second dose), and was keen to stop the small doses of thalidomide and prednisolone.

PATIENT NO 2

A 30 year old Caucasian bank cashier presented in August 1998 with recurrent oral and vulval ulceration for four years. She then developed a pustular erythematous rash over the trunk and limbs, bilateral ankle synovitis, and conjunctivitis. She was a non-smoker with no family history of inflammatory bowel disease. Antinuclear antigen and antineutrophil cytoplasmic antibody were negative. Behçet's syndrome was diagnosed and treatment with prednisolone 20–40 mg/day relieved the conjunctivitis and synovitis, with a reduction in CRP from 109 to 25 mg/l over eight weeks. Addition of colchicine 0.5–1 mg/day had no effect on orogenital ulceration. In November 1998 she had diarrhoea and rectal bleeding, with recurrence of the rash and arthritis. Her CRP increased to 73 mg/l, weight decreased to 58 kg (BMI 18 kg/m²), haemoglobin declined to 8.6 g/dl, and colonoscopy showed punched out ulcers throughout the colon. Colonic biopsies showed chronic inflammation with focal acute inflammation but no granulomas. Small bowel radiology was normal. In June 1999, arthritis and diarrhoea recurred when prednisolone was reduced to less than 20 mg/day. Cyclosporin up to 300 mg/day (5 mg/kg) was ineffective and symptom control was inadequate on prednisolone up to 60 mg/day. Her CRP remained elevated at 41 mg/l. In September 1999, colonoscopy again showed punched out and linear ulcers throughout the colon, most prominently in the sigmoid colon, but with normal intervening mucosa. Colonic biopsies from the areas of ulceration confirmed a focal chronic inflammatory infiltrate with no granulomas and normal intervening mucosa. A 1.5 cm×0.75 cm ulcer (fig 1) was noted in the natal cleft.

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Figure 1

Ulcer in the natal cleft (case No 2) before (A) and three weeks after (B) infusion of infliximab.

After full discussion with the patient, an infusion of infliximab (5 mg/kg) was administered (December 1999). She experienced myalgia for three days but then noted a dramatic improvement in symptoms. Rectal bleeding stopped and bowel frequency decreased from six to 2–3 times daily. Arthritis and the rash resolved. Anorexia, oral ulcers, and fatigue disappeared. CRP declined from 53 to <6 mg/l. Three weeks after infusion, flexible sigmoidoscopy showed that the rectosigmoid ulcers had epithelialised and the natal cleft ulcer had healed (fig 1). Thalidomide 300 mg/day was started after normal nerve conduction studies and prednisolone reduced. Steroids were withdrawn over 10 weeks although she experienced dizzy spells, myalgia, and mood disturbance. Diarrhoea, and mouth and genital ulcers did not recur. A short Synacthen test was normal and symptoms resolved when thalidomide was stopped. She became asymptomatic for the first time in five years, on no immunosuppression until October 2000, when synovitis and then diarrhoea gradually recurred, with perianal ulceration, 4 kg weight loss, and fatigue. CRP increased to 36 mg/l. Another infusion of infliximab (5 mg/kg, December 2000) led to resolution of diarrhoea and perianal ulcer, with normal inflammatory markers. No further immunosuppression was introduced, but in March 2001 (12 weeks after the second infusion), diarrhoea, ulceration, and synovitis recurred with a CRP of 63 mg/l. A third infusion of infliximab has been administered with reintroduction of low dose (100 mg/day) thalidomide.