Although Crohn disease (CD) primarily involves the small and large intestine, approximately 7% to 24% of affected children experience extraintestinal manifestations (1). After musculoskeletal involvement, dermatologic lesions are the second most common extraintestinal manifestation of CD. The spectrum, pathogenesis, and natural history of dermatologic lesions associated with CD are not well defined. In many patients, skin lesions precede the development of typical CD gastrointestinal symptoms, and there may be no correlation between intestinal disease activity and the presentation and severity of the skin manifestations. Dermatologic lesions commonly associated with CD include erythema nodosum, pyoderma gangrenosum, and cutaneous CD (2). Less common manifestations are Melkersson-Rosenthal syndrome, oral-facial granulomatosis, and inflammatory lymphedema (3). Treatment of these dermatologic conditions is empiric and has involved primarily topical and systemic corticosteroids and immunomodulatory agents (4). In many of these conditions, specifically blistering skin lesions such as pyoderma gangrenosum (PG), response to therapy is poor, even with high-dose, continuous corticosteroid therapy (5).
Treatment with antibodies targeting the cytokine TNF-α has been efficacious for luminal and fistulizing CD in both adults and children (6–8). Infliximab (Remicade; Centocor, Malvern, PA), the chimeric monoclonal antibody against TNF-α, has been used successfully to treat extraintestinal manifestations in adult patients, including PG (9–11). The favorable response of patients with PG suggests that TNF-α may also play a role in the molecular mechanisms underlying the dermatologic manifestations of CD. Currently, there is limited information on the use of anti-TNF-α therapy (i.e., infliximab) in children with dermatologic manifestations of CD (12). In this article, we report four children with skin manifestations of CD who were successfully treated with anti–TNF-α antibody (infliximab) after they had no response to standard corticosteroid and 6-mercaptopurine (6-MP) therapy.
A 13-year-old boy was seen in the Dermatology Clinic with a pustular lesion of his lower left leg. The lesion had begun as a 7-mm pustule, which rapidly became a deep ulcer with undermined edges and purple discoloration around the periphery (Fig. 1 A). Several courses of antibiotics and topical corticosteroid treatment over 1 year were not beneficial. He initially had no gastrointestinal complaints. His height and weight were normal for age, and he had no musculoskeletal symptoms.
One year after the appearance of the lesion, a skin biopsy showed characteristic histopathologic features of PG. Because no underlying systemic disease had been identified that could be targeted for therapy, a course of intralesional corticosteroid injections was administered without benefit. Repeat laboratory evaluation at that time of intralesional therapy revealed a normal erythrocyte sedimentation rate (ESR) and serum albumin. Complete blood count showed a hemoglobin of 12.1 g/dL (normal, 12.5–16 g/dL) and mean corpuscular volume (MCV) of 67 fl (normal, 78–95 fl). These results suggesting mild iron deficiency anemia prompted a gastroenterologic evaluation.
Terminal ileal and right colonic ulcerations and inflammatory changes consistent with CD were found during colonoscopy. An upper endoscopy was normal. The patient was started on 6-MP at a dose of 1.5 mg/kg. Despite 6-MP therapy, new PG lesions appeared on the other leg. The patient's previous poor response to corticosteroids and 6-MP for 3 months led us treat with infliximab at 5 mg/kg. Three doses of infliximab were given at 0, 2, and 6 weeks. There was a complete resolution of the PG lesions (Fig. 1 B). One year later, there was no recurrence of PG. The patient has been continued to receive 6-MP at 1.5 mg/kg.
A 9-year-old boy came to Dermatology Clinic with intermittent episodes of facial swelling and red crusted perioral lesions. A provisional diagnosis of Melkersson-Rosenthal syndrome was made, and he was treated with antibiotics and topical corticosteroids intermittently for 3 years. At the age of 12 years, he experienced perianal lesions with intermittent purulent discharge. A gastrointestinal consultation was obtained at that time.
Aside from the above history, the patient reported no additional gastrointestinal symptoms. Weight and height velocities had been normal. On physical examination, marked facial swelling involving the upper lip and philtrum was noted. The upper lip was diffusely swollen with superficial scaling and erythema (Fig. 2 A). The gingiva was hypertrophied. No oral ulcerations were seen. Results of the abdominal examination were normal. With the patient supine, a perianal fistula was noted at the 3 o'clock position without surrounding inflammation. Laboratory results included hemoglobin of 12.5 g/dL and serum albumin of 4.0 g/dL. The ESR was elevated at 35 mm/h (normal, <20 mm/h). A small bowel follow-through x-ray was normal without stricture, ulceration, or mucosal abnormalities. Computed tomography (CT) scan showed no evidence of bowel wall thickening or inflammatory changes around the ileum. Colonoscopic examination revealed aphthous and linear ulcers consistent with CD throughout the colon. Biopsies showed granulomas consistent with CD.
A diagnosis of CD colitis was made, and a regimen of 6-MP was begun. After transient improvement, the patient experienced progressive worsening of his facial swelling and perianal fistula, despite 7 months of 6-MP therapy with therapeutic serum 6-thioguanine (6-TG) levels. Corticosteroids were added without benefit after 2 months. Because of the refractory fistulizing disease, 3 infliximab infusions (5 mg/kg) were administered (at 0, 2, and 6 weeks). The patient experienced a rapid and dramatic reduction of swelling of his lips, face, and gums, and he was able to close his lips around his teeth within 10 days of the initial infusion. Complete resolution of orofacial (Fig. 2 B) and gingival swelling and the perianal fistula was seen 2 months after the initial dose of infliximab. 6-MP therapy was continued at the dose of 1.5 mg/kg for the next 10 months, when a relapse of both colitis and facial swelling occurred. Another course of systemic corticosteroids was not beneficial. The patient was given a fourth infliximab infusion with a good therapeutic response. At this writing 12 months later, he has continued to receive infliximab infusions every 10 weeks and 6-MP with no recurrence of symptoms.
A 16-year-old boy with a 2-year history of ileocolonic CD had a 3-week history of low-grade fever, worsening diarrhea, and weight loss. He also had painful, swollen lesions of both lower extremities. Before this presentation, his disease had been controlled with 6-MP. Physical examination revealed several lesions on the extensor aspects of both legs suggestive of erythema nodosum (EN). Laboratory results included an ESR of 100 mm/h, hemoglobin of 9.5 g/dL, and serum albumin of 2.5 g/dL. Because of deteriorating clinical condition and fevers he was admitted to the hospital and given IV corticosteroids. An upper gastrointestinal series and small bowel follow-through radiologic examination showed terminal ileal disease similar to examinations 2 years previously. Abdominal and pelvic CT scans were normal. Two weeks of IV corticosteroids had no impact on either the EN or the gastrointestinal symptoms. He was given an infliximab infusion at 5 mg/kg. Significant improvement of the EN was seen within 3 days, and he was discharged with a rapidly tapering steroid course prescribed. Complete resolution of the EN was seen after a second dose of infliximab 4 weeks later. He has continued to receive 6-MP alone and has had no recurrence of the EN for 18 months.
A 13-year-old boy with a 7-year history of ileal CD experienced bilateral leg swelling (right > left), associated with painful induration of the skin over the lower extremities. He had undergone an ileal resection several years before and was not receiving any treatment at the time of this presentation. Although he had no gastrointestinal symptoms, the patient underwent colonoscopy and ileoscopy, which showed active ileal disease at the anastomotic site. An upper gastrointestinal series with a small bowel follow-through confirmed the disease recurrence at the anastomosis. No stricture was seen. Serum albumin was normal at 3.7 g/dL. Abdominal and pelvic CT scan, ultrasound with Doppler studies, and coagulation study results were normal. A venogram of both lower extremities was normal. He was treated with corticosteroids and 6-MP.
After 3 months, the lower extremity swelling progressively worsened in association with increasingly painful, indurated skin overlying both thighs. Further evaluation of the patient leg lesions was initiated. A radionucleotide lymphoscintigram showed bilateral lymphatic obstruction (Fig. 3 A). Because no anatomic source of lymphatic obstruction was found, an idiopathic inflammatory lymphedema in association with systemic inflammatory process was suspected. The inadequate response to 6-MP and corticosteroids prompted treatment with a 5-mg/kg infliximab infusion. The patient experienced dramatic response with resolution of pain and leg swelling within 2 weeks. Two additional infusions of infliximab were administered (2 and 6 weeks after the initial infusion). After the third infusion, a repeat lymphoscintigram demonstrated no further obstruction (Fig. 3 B). No recurrence of lymphedema or gastrointestinal symptoms occurred during 11 months of follow-up. He continued to receive therapy with 6-MP only.
Dermatologic extraintestinal manifestations of CD are a significant complicating feature that may exhibit a clinical course independent of bowel disease activity. Therapy for the dermatologic complications of CD has remained undefined, and many patients have disease refractory to standard therapy (2,13). Our four patients, whose skin manifestations of CD responded poorly to corticosteroids, immunomodulators, and antibiotic treatment, all experienced rapid improvement after infusions of infliximab. In addition to the recognized dermatologic conditions associated with CD (pyoderma gangrenosum, erythema nodosum, and orofacial granulomas), we also describe a beneficial response to anti–TNF-α therapy in a child with bilateral inflammatory lymphedema of the lower extremities, a rare extraintestinal manifestation of CD.
Pyoderma gangrenosum occurs in approximately 2% of adults with ulcerative colitis (UC) and a smaller number patients with CD (14). Our patient had a typical large lesion (Fig. 2 A) on the left leg and early lesions on the right leg before infliximab infusion. Favored sites for the appearance of PG include the lower limbs, near surgical scars (peristomal sites), or at sites of trauma (venipuncture sites) (15,16). Treatment of PG with immunosuppression, including high-dose corticosteroids, is often met with limited success. Previously reported therapy has included such immunosuppressing agents as chlorambucil, cyclophosphamide, cyclosporine, methotrexate, and thalidomide. Recently, systemic and topical tacrolimus have shown some promise. Although most of the reported cases treated with tacrolimus took about 12 weeks to show healing, one 11-year-old boy reported by Kimble et al. experienced healing in 5 weeks (17). The decision to treat our patient with infliximab was driven partly by concerns about toxicity associated with strong immunosuppressive agents and by the need for rapid, effective therapy. There is precedence in the use of infliximab for the treatment of PG in both children and adults. Recently, Batres et al. reported inducing complete resolution of a severe peristomal PG with infliximab in a 13-year-old patient (12).
Orofacial CD in children has been described sporadically as case reports. Therefore, the natural history and response to therapy are not well defined (18). “Orofacial CD” and “orofacial granulomatosis” are terms often used interchangeably. Orofacial granulomatosis encompasses what previously was described as “oral Crohn disease.” Some affected patients do not have gastrointestinal symptoms and signs of CD. However, many patients who experience orofacial granulomatosis as an isolated phenomenon will later exhibit features of intestinal Crohn disease (19). Other associations of orofacial granulomatosis include sarcoidosis, mycobacterial infections, and hypersensitivity reactions (20). The differential diagnosis includes Melkersson-Rosenthal syndrome, a condition that results from lymphatic stasis, which produces granulomatous inflammation of the lips, tongue and gingival mucosa, and sometimes facial palsy (21). Characteristic findings of orofacial granulomatosis include raised plaques of hyperplastic mucosa, which may have a cobblestone appearance. Painful chronic cheilitis can occur, such as in our patient (Fig. 2 A).
The activity of orofacial granulomatosis does not always correlate with that of the underlying intestinal disease. The response to conventional treatment with corticosteroids and immunomodulators is typically poor. Our patient experienced no response to standard therapy with corticosteroids and 6-MP. We did not consider our patient a candidate for thalidomide therapy. Mahadevan and Sandborn reported a 25-year-old woman with orofacial CD with an excellent response to infliximab who had initially experienced no improvement with mesalamine and corticosteroid therapy (10).
Erythema nodosum occurs in as many as 15% of patients with CD and in approximately 4% of those with UC (2,14). Erythema nodosum may precede the intestinal disease, but more often its activity parallels that of the underlying bowel disorder. Occasionally it may occur as an adverse reaction to drugs such as 5-aminosalicylates. Although our patient with EN was receiving mesalamine at the time of presentation, discontinuation of mesalamine therapy did not result in improvement. The illness often remits after 2 to 4 weeks but clearly persisted beyond this time in our patient, despite intravenous corticosteroid therapy. Other medical therapeutic options, such as dapsone, thalidomide, and cyclosporine, have been described in the literature with variable responses. Our decision to chose infliximab was based on the need for a rapidly acting drug and safety issues.
Lymphedema is a rare manifestation of CD (22,23). It has also been described in association with rheumatoid arthritis and polyarticular juvenile rheumatoid arthritis (24–26). The pathogenesis of lymphedema in these chronic inflammatory illnesses is unclear, and both mechanical obstruction and lymphangitis have been suggested as causes (24). There is no definitive treatment of the lymphedema associated with rheumatoid arthritis and juvenile rheumatoid arthritis, and to date, there have been no previous reports of the use of infliximab in this condition. Careful evaluation revealed that our patient did not have mechanical lymphatic obstruction. This suggests that alternative mechanisms are involved in lymphedema associated with CD. The dramatic and rapid improvement following anti–TNF-α therapy in our patient suggests that a direct anticytokine effect on the lymphatics promoted the clinical improvement.
In summary, we report four clinically distinct and refractory dermatologic manifestations of CD in children who subsequently experienced response to infliximab treatment. All of these children had experienced no improvement with conventional therapy. Dermatologic improvement was an unexpected outcome in our patient with lymphedema, where underlying bowel disease prompted the initiation of biologic anti–TNF-α treatment. The rapid and dramatic improvement in these CD-associated dermatologic conditions supports the concept that TNF-α may play a role in the pathogenesis of these skin lesions, and anti–TNF-α agents may represent an important therapeutic strategy. Our experience suggests that therapy with infliximab should be considered in children with CD who have skin manifestations and in whom standard treatment approaches fail.
Conflict of interest: S. Kugathasan and D. G. Binion have served in Centocor's speakers bureau.
1. Shashidhar H, Integlia M, Grand RJ. Clinical manifestations of pediatric inflammatory bowel disease. In: Kirsner JB, ed. Inflammatory Bowel Disease. Philadelphia: WB Saunders; 2000:326–41.
2. Levine JB, Lukawski-Trubish D. Extraintestinal considerations in inflammatory bowel disease. Gastroenterology 1995; 24:633–46.
3. Williams AJ, Wray D, Ferguson A. Orofacial granulomatosis. Lancet 1991; 338:20–1.
4. Plauth M, Jenss H, Meyle J. The clinical entity of orofacial Crohn's disease. Q J Med 1991; 79:451–8.
5. Powell RJ, Holbrook MR, Stevens A. Pyoderma gangrenosum and its treatment. Lancet 1997; 350:1720–1.
6. Targan SR, Hanauer SB, van Deventer SJ, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease. Crohn's Disease cA2 Study Group. N Engl J Med 1997; 337:1029–35.
7. Kugathasan S, Werlin SL, Martinez A, et al. Prolonged duration of response to infliximab in early but not late pediatric Crohn's disease. Am J Gastroenterol 2000; 95:3189–94.
8. Serrano MS, Schmidt-Sommerfield E, Kilbaugh TJ, et al. Use of infliximab in pediatric patients with inflammatory bowel disease. Ann Pharmacother 2001; 4: 823–8.
9. Tan MH, Gordon M, Lebwohl O, et al. Improvement of pyoderma gangrenosum and psoriasis associated with Crohn's disease with anti-tumor necrosis factor alpha monoclonal antibody. Arch Dermatol 2001; 137:930–3.
10. Mahadevan U, Sandborn WJ. Infliximab for the treatment of orofacial Crohn's disease. Inflamm Bowel Dis 2001; 7: 38–42.
11. Smith JR, Levinson RD, Holland GN, et al. Differential efficacy of tumor necrosis factor inhibition in the management of inflammatory eye disease and associated rheumatic disease. Arthritis Rheum 2001; 45:252–7.
12. Batres LA, Mamula P, Baldassano RN. Resolution of severe peristomal pyoderma gangrenosum with infliximab in a child with Crohn's disease. J Pediatr Gastroenterol Nutr 2002; 34:558–560.
13. Danzi JT. Extraintestinal manifestations of idiopathic inflammatory bowel disease. Arch Intern Med 1988; 148:297–302.
14. McCord M, Hall R. Cutaneous manifestations of inflammatory bowel disease. In: Targan SR, Shanahan F, eds. Inflammatory Bowel Disease: From Bench to Bedside. Baltimore: Williams & Wilkins; 1994:682–94.
15. Keltz M, Lebwohl M, Bishop S. Peristomal pyoderma gangrenosum. J Am Acad Dermatol 1992; 27:360–4.
16. Dwarakanath A, Yu L, Brookes C. Sticky neutrophils, pathergic arthritis and response to heparin in pyoderma gangrenosum complicating ulcerative colitis. Gut 1995; 37:585.
17. Kimble RM, Tucker AD, Nicholls VS, et al. Successful topical tacrolimus therapy in a child with pyoderma gangrenosum. J Pediatr Gastroenterol Nutr 2002; 34:555–7.
18. Somech R., Harel A, Rothstein MS, et al. Granulomatosis chelitis and Crohn's disease. J Pediatr Gastroenterol Nutr 2001; 32:339–41.
19. Field EA, Tyldesley WR. Oral Crohn's disease revisited: 10 year review. Br J Oral Maxillofac Surg 1989; 27:114–23.
20. Wiesenfeld D, Ferguson MM, Mitchell DN. Oro-facial granulomatosis: a clinical and pathological analysis. Q J Med 1985; 54:101–13.
21. Zimmer WM, Rogers 3rd, RS Reeve CM, et al. Orofacial manifestations of Melkersson-Rosenthal syndrome. A study of 42 patients and review of 220 cases from the literature. Oral Surg Oral Med Oral Pathol 1992; 74:610–9.
22. Bel-Pla S, Garcia-Patos Briones V, Garcia Fernandez D, et al. Vulvar lymphedema: unusual manifestation of metastatic Crohn's disease. Gastroenterol Hepatol 2001; 24:297–9.
23. Monk BE, Mortimer PS. Lymphoedema and Crohn's disease. J R Soc Med 1999; 92:136–7.
24. Joos E, Bourgeois P, Famaey JP. Lymphatic disorders in rheumatoid arthritis. Semin Arthritis Rheum 1993; 22:392–8.
25. Bardare M, Falcini F, Hertberger C, et al. Idiopathic limb edema in children with chronic arthritis: a multicenter report of 12 cases. J Rheumatol 1997; 24:384–8.
26. Athreya BH, Ostrov BE, Echenfeld AH, et al. Lymphedema associated with juvenile rheumatoid arthritis. J Rheumatol 1989; 16:1338–40.