Anti-tumor necrosis factor alpha monoclonal antibody (infliximab) for the treatment of Pyoderma gangrenosum associated with Crohn’s disease

ARTICLE

Auteur(s) : Alessandro ZACCAGNA¹, Alberto BERTONE², Paolo PUIATTI¹, Franco PICCIOTTO¹, Tatiana SPRUJEVNIK², Renato SANTUCCI², Francesco Paolo ROSSINI²

Reprints: F. Picciotto Fax: (+39) 0119933225 E-mail : fpicciottomauriziano.it

Article accepted on 6/2/2003

Infliximab, a chimeric anti-tumour necrosis factor α (TNF-α) monoclonal antibody (Remicade ; Centocor BV, Leiden, the Netherlands), is an IgG antibody whose efficacy has been amply demonstrated in the treatment of inflammatory bowel disease and rheumatoid arthritis [1-4]. Encouraging results have recently emerged also for inflammatory skin conditions such as Sneddon-Wilkinson disease [5], Behcet’s disease [6-11], severe psoriasis [12-16], psoriatic arthritis [17-18], fistulas and hidradenitis in patients with Crohn’s disease [19-22]. 
The use of infliximab for Pyoderma gangrenosum (PG) has, up until now only been described in 17 cases (7 peristomal PG) [3, 23-29]. In this work, we describe a case of PG associated with severe Crohn’s disease, successfully treated with infliximab.

Case report

A 53-year old man with an 11-year history of Crohn’s disease localized in the sigmoid colon came to us on relapse. Symptoms were abdominal pain, severe diarrhoea, (10 movements a day) difficulty in control and tenesmus, blood in stools, overall poor health and temperature over 38°C. Routine blood chemistry showed slight anaemia and a marked increase in the inflammatory index (erythrocyte sedimentation rate 100 mm/h, reactive C protein 29.3 mg/L, fibrinogen 683 mg/dl). Rectoscopy revealed signs of severe Crohn’s disease (Crohn’s Disease Activity Index CDAI = 275) [30]. 
Further physical examination also revealed a perianal abscess and a rounded ulceration on the dorsal side of the left foot of approximately 5 cm diameter with purple-red thickened raised borders (Fig. 1); the base of the ulcer was covered by a pseudomembrane which on removal showed the typical cribriform characteristic of PG. Histology revealed an epidermis with acanthosis, totally lacking a long section in the ulcer region. The skin surface showed signs of neutrophil invasion and lymphohistiocytes separating the connective tissue. Although not a diagnostic proof, the histology was compatible with the clinical diagnosis of PG and excluded other possible causes (Fig. 2). Hematochemical values excluded lymphoproliferative disease and bacteriological skin tests showed no signs of bacterial superinfection as an eventual cause of the ulcerative lesion. 
The patient was thus given antibiotics (Metronidazole + Imipenem) and methylprednisolone i.v. infusion (60 mg/day) showing a rapid improvement in his general condition, normal temperature and reduction in diarrhoea although blood was still present in the stools and inflammatory indices were persistently elevated. Colonoscopy carried out four days after the start of therapy revealed that there were still deep ulceration and coagulation. Furthermore, the lesion on the back of the foot was unaltered. One day later, due to persistent rectal bleeding and acute anaemia, we decided to administer a dose of 5 mg/kg intravenous infliximab, that resulted in no side effects. 
During the following days, diarrhoea slowly disappeared; blood was no longer present in stools, body weight increased, and colonoscopy performed at day 10 showed an improvement in the ulceration. At this point, the skin lesion had improved both in terms of size and depth. Three weeks after a further 5 mg/kg dose of i.v. infliximab was administered; follow up visit at one month showed complete endoscopic remission of Crohn’s disease, and a complete epithelial regrowth of the ulcer with pigmented scar tissue (Fig. 3). The patient then underwent maintenance therapy with oral methylprednisolone at 8 mg/day and oral 5-aminosalicylic acid (5-ASA) at 800 mg × 3/day.
After 8 months there were no signs of cutaneous relapse of PG, and bowel movements were normal.

Discussion

PG, first described by Brocq in 1916 and later recognized as a disease entity in 1930 by Brunsting [31], is an idiopathic, painful and destructive condition that usually presents as an ulceration on the pretibial region of the legs. It is considered among the neutrophilic dermatoses and its aetiology is currently unknown. The infectious hypothesis has now been abandoned while PG association with immunological disorders such as inflammatory bowel disease, paraproteinaemia and rheumatoid arthritis, and its clinical response to immunomodulating agents such as corticosteroids and cyclosporine suggest its immune aetiology [32]. The signs of pus and high neutrophil count on biopsy suggest that the polymorphonuclear leukocytes play a fundamental role in PG lesion development and in the consequent tissue destruction [32]. 
Recent studies suggest that release of cytokines and in particular of tumour-necrosis-factor-α (TNF-α) may be fundamental in the development of many inflammatory dermatoses including the neutrophilic dermatoses [33-34]. TNF-α belongs to the family of proinflammatory cytokines and it is produced mainly by stimulated mononuclear phagocytes, but also by many cutaneous cells, including keratinocytes, mast cells and Langerhans cells. It has been shown how intradermal administration of recombinant human TNF-α (rHuTNF-α) can cause an inflammatory cell infiltrate characterized by many neutrophils, thus confirming findings in animal studies where a predominantly neutrophilic response to TNF-α was observed [33]. The mechanism causing rHuTNF-α to recruit neutrophil leukocytes is largely due to the induction of adhesion molecules on vascular endothelium [33]. These molecules are, on the one hand, ICAM-1 and 2 (intercellular adhesion molecules 1 and 2) and VCAM-1 (vascular cell adhesion molecule 1) and on the other, selectin ELAM-1 (E-selectin endothelial leukocyte adhesion molecule 1) and P-selectin (CD62P). Both E- and P-selectin mediate neutrophil recruitment [34]. 
In some neutrophilic dermatoses the TNF-α endothelial cell activation produced by macrophages and lymphocytes activated by several stimuli including interleukin-1 (IL-1), leads to the expression of E-selectin and intercellular adhesion molecule-1 (ICAM-1) on the endothelial cell surface, promoting adhesion and subsequent rolling of neutrophils on the endothelial surface [35]. 
Infliximab (Remicade) is a humanized-murine monoclonal anti-TNF-α antibody consisting of the variable domain (Fab) of mouse IgG attached to the constant region (Fc) of human IgG1. The antibody binds both the soluble subunit and the membrane-bound precursor of TNF-α, thereby neutralizing the biological activity of TNF-α in vivo [36]. 
Its efficacy has been clearly demonstrated in rheumatoid arthritis and inflammatory bowel disease such as Crohn’s disease [1-4]. Patients with Crohn’s disease have increased levels of TNF-α, TNF-α-producing lamina propria cells, and soluble TNF receptors. Treatment with Infliximab decreases TNF-α levels in inflamed areas of the intestine, decreases the infiltration by inflammatory cells, and lowers interleukin 6 (IL-6) and C-reactive protein concentrations, resulting in a rapid reduction in mucosal inflammation [24]. Moreover, some recent studies have shown promising results with infliximab in the treatment of many inflammatory skin disorders such as Sneddon-Wilkinson disease [5], Behcet’s disease [6-11], severe psoriasis [12-16], psoriatic arthritis [17, 18], fistulas and hidradenitis in patients with Crohn’s disease [19-22]. 
In the case described herein, intravenous infusion of two 5 mg/kg doses of infliximab, with a three week interval between each dose, caused an almost total regression of the ulcer on the back of the foot. Treatment was well tolerated and had no side effects, even if in the literature possible complications have been reported, in particular hypersensitivity reactions such as urticaria, hypotension and dyspnea [24] or infections [5]. 
The efficacy of infliximab in our patients provides support to the important role of neutrophilic activation by TNF-α in the pathogenesis of PG. 
We conclude that infliximab may be a valid therapeutic choice in patients with PG associated with Crohn’s disease, particularly in those who do not respond to conventional treatment. The efficacy of infliximab in PG either associated or not with Crohn’s disease, deserves further assessment in larger studies. n

References

1. Targan SR, Hanauer SB, van Deventer SJ Mayer L, Present DH, Braakman T, DeWoody KL, Schaible TF, Rutgeerts PJ. 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.

2. Maini R, St Clair EW, Breedveld F, Furst D, Kalden J, Weisman M, Smolen J, Emery P, Harriman G, Feldmann M, Lipsky P. Infliximab (chimeric anti-tumor necrosis factor α monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet 1999; 354: 1932-9.

3. Arnott ID, McDonald D, Williams A, Ghosh S. Clinical use of Infliximab in Crohn’s disease: the Edinburg 1 experience. Aliment Pharmacol Ther 2001; 15 (10): 1639-46.

4. Bondeson J, Maini RN. Tumor necrosis factor as a therapeutic target in rheumatoid arthritis and other chronic inflammatory diseases: the clinical experience with infliximab (REMICADE). Int J Clin Pract 2001; 55 (3): 211-6.

5. Voigtländer C, Lftl M, Schuler G, Hertl M. Infliximab (Anti-Tumor Necrosis Factor α Antibody). A novel, highly effective treatment of recalcitrant subcorneal pustolar dermatosis (Sneddon-Wilkinson disease). Arch Dermatol 2001; 137: 1571-4.

6. Fujino Y. Behcet’s disease. Nippon Rinsho 2002; 60 (Suppl.1): 381-8.

7. Rozembaum M, Rosner I, Portnoy E. Remission of Behcet’s syndrome with TNFalpha blocking treatment. Ann Rheum Dis 2002; 61 (3): 283-4.

8. Munoz-Fernandez S, Hidalgo V, Fernandez-Melon J, Schlincker A, Martin-Mola E. Effect of Infliximab on threatening panuveitis in Behcet’s disease. Lancet 2001; 358 (9293): 1644.

9. Travis SP, Czajkowski M, McGovern DP, Watson RG, Bell AL. Treatment of intestinal Behcet’s syndrome with chimeric tumour necrosis factor alpha antibody. Gut. 2001; 49 (5): 725-8.

10. Sfikakis PP, Theodossiadis PG, Katsiari CG, Kaklamanis P, Markomichelakis NN. Effect of infliximab on sight-threatening panuveitis in Behcet’s disease. Lancet 2001; 358 (9278): 295-6.

11. Goossens PH, Verburg RJ, Breedveld FC. Remission of Behcet’s syndrome with tumour necrosis factor alpha blocking therapy. Ann Rheum Dis 2001; 60 (6): 637.

12. Griffiths CE. Immunotherapy for psoriasis: from serendipity to selectivity. Lancet 2002; 359 (9303): 279-80.

13. Tutrone WD, Kagen MH, Barbagallo J, Weinberg JM. Biologic therapy for psoriasis: a brief history, II. Cutis 2001; 68 (6): 367-72.

14. Chaudari U, Romano P, Mulcahy LD, Dooley LT, Baker DG, Gottlieb AB. Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomised trial. Lancet 2001; 357 (9271): 1842-7.

15. Kirby B, Marsland AM, Carmichael AJ, Griffiths CE. Successful treatment of severe recalcitrant psoriasis with combination infliximab and methotrexate. Clin Exp Dermatol 2001; 26 (1): 27-9.

16. Oh CJ, Das KM, Gottlieb AB. Treatment with anti-tumor necrosis factor alpha (TNF-alpha) monoclonal antibody dramatically decreases the clinical activity of psoriasis lesions. J Am Acad Dermatol 2000; 42 (5 Pt 1): 829-30.

17. Girolomoni G, Abeni D. Anti-tumor necrosis factor alpha therapy in psoriatic arthritis and psoriasis. Arch Dermatol 2001; 137 (6): 784-5.

18. Ogilvie AL, Antoni C, Dechant C, Manger B, Kalden JR, Schuler G, Luftl M. Treatment of psoriatic arthritis with anti-tumor necrosis factor-alpha antibody clears skin lesions of psoriasis resistant to treatment with methotrexate. Br J Dermatol 2001; 144 (3): 587-9.

19. Geyer AS, Anhalt GJ, Nousari HC. Effectiveness of infliximab in the treatment of refractory perineal cutaneous Crohn disease. Arch Dermatol 2000; 136 (4): 459-60.

20. Korzenik JR. Infliximab for fistulas: a hole in one ? Inflamm Bowel Dis 2000;6 (1): 62.

21. Present DH, Rutgeerts P, Targan S, Hanauer SB, Mayer L, van Hogezand RA, Podolsky DK, Sands BE, Braakman T, DeWoody KL, Schaible TF, van Deventer SJ. Infliximab for treatment of fistulas in patients with Crohn’s disease. N Engl J Med 1999; 340 (18): 1398-405.

22. Martinez F, Nos P, Benlloch S, Ponce J. Hidradenitis suppurativa and Crohn’s disease: response to treatment with infliximab. Inflamm Bowel Dis 2001; 7 (4): 323-6.

23. Hughes AP, Jackson JM, Callen JP. Clinical features and treatment of peristomal pyoderma gangenosum. JAMA 2000; 284 (12): 1546-8.

24. Tan MH, Gordon M, Lebwohl O, George J, Lebwohl MG. Improvement of Pyoderma gangrenosum and psoriasis associated with Crohn disease with anti-tumor necrosis factor alpha monoclonal antibody. Arch Dermatol 2001; 137 (7): 930-3.

25. Sheldon DG, Sawchuk LL, Kozarek RA, Thirlby RC. Twenty cases of peristomal pyoderma gangrenosum: diagnostic implication and management. Arch Surg 2000; 135 (5): 564-568; discussion 568-9.

26. Grange F, Djilali-Bouzina F, Weiss AM, Polette A, Guillaume JC. Corticosteroid-resistant Pyoderma gangrenosum associated with Crohn disease: rapid cure with infliximab. Dermatology 2002; 205 (3): 278-80.

27. Batres LA, Mamula P, Baldassano RN. Resolution of severe peristomal pyoderma gangrenosum with infliximab child with Crohn disease. J Pediatr Gastroenterol Nutr 2002; 34 (5): 558-60.

28. Triantafillidis JK, Cheracakis P, Sklavaina M, Apostolopoulou K. Favorable response to infliximab treatment in a patient with active Crohn disease and pyoderma gangrenosum. Scand J Gastroenterol 2002; 37 (7): 863-5.

29. Ljiung T, Staun M, Grove O, Fausa O, Vatn MH, Hellstrom PM. Pyoderma gangrenosum associated with Crohn disease: effect of TNF-alpha blockade with infliximab. Scand J Gastroenterol 2002; 37 (9): 1108-10.

30. Yoshida EM. The Crohn’s Disease Activity Index, its derivatives and the Inflammatory Bowel Disease Questionnaire: a review of instruments to assess Crohn’s disease. Can J Gastroenterol 1999; 13 (1): 65-73.

31. Brunsting LA, Goeckerman WH, O’Leary PA. Pyoderma gangrenosum: clinical and experimental observations in five cases occurring in adults. Arch Dermatol 1930; 22: 655-80.

32. Blitz NM, Rudikoff D. Pyoderma gangrenosum. Mt.Sinai J Med 2001; 68 (4-5): 287-97.

33. Groves RW, Allen MH, Ross EL, Barker JNWN, MacDonald DM. Tumor necrosis factor alpha is pro-inflammatory in normal human skin and modulates cutaneous adhesion molecole expression. Br J Dermatol 1995; 132: 345-52.

34. Kupper TS. Immune and inflammatory processes in cutaneous tissues. Mechanism and speculation. J Clin Invest 1990; 86: 1783-9.

35. Terui T, Ozawa M, Tagami H. Role of neutrophils in induction of acute inflammation in T-cell-mediated immune dermatosis, psoriasis: a neutrophil-associated inflammation-boosting loop. Exp Dermatol 2000; 9: 1-10.

36. Knight DM, Trinh H, Le J, Siegel S, Shealy D, McDonough M, Scallon B, Moore MA, Vilcek J, Daddona P, et al. Construction and initial characterization of a mouse-human chimeric anti-TNF antibody. Mol Immunol 1993; 30: 1443-53.