Vol. 118 No. 3 September 2014
Treatment of a Crohn’s diseaseerelated cutaneous facial lesion with topical tacrolimus Neha P. Shah, BDS,a Rishi M. Goel, MBBS, BSc, MRCP, SCE,b and Michael Escudier, MD, BDS, FDS, FDS (OM), RCSc John Radcliffe Hospital, Oxford, England; Guy’s and St Thomas’ Hospital, London, England; King’s College London Dental Institute, London, England
We report a case of an orofacial lesion in Crohn’s disease successfully treated with tacrolimus ointment. A 22-yearold woman with Crohn’s disease presented with a discharging lesion on the right side of her face. Intraorally, there was a resultant loss of the sulcal depth. She reported a 1-year history of variable right-sided facial swelling for which she had undergone extraoral incision and drainage, resulting in localized paresthesia and nonhealing of the incision site. Following exclusion tests, a treatment of twice-daily extraoral application of tacrolimus 0.1% ointment was commenced. Upon review, the lesion had reduced in size, with minimal discharge. Further improvement over 12 months of tacrolimus use resulted in a satisfactory cosmetic result as well as resolution of the intraoral features and reestablishment of the full sulcal depth. This case illustrates the successful use of topical tacrolimus to treat a cutaneous manifestation of Crohn’s disease. (Oral Surg Oral Med Oral Pathol Oral Radiol 2014;118:e71-e73)
Tacrolimus 0.1% ointment is commonly used in the treatment of inflammatory dermatoses such as allergic contact dermatitis and psoriasis.1 Successful intraoral use of the ointment has been reported in several mucosal conditions, including erosive oral lichen planus, oral psoriasis, and immunobullous disorders.2-4 We report a case of an orofacial lesion in Crohn’s disease that was successfully treated with tacrolimus ointment.
CASE REPORT A 22-year-old woman was referred from Gastroenterology to the Oral Medicine department complaining of a discharging lesion on the right side of her face. She reported a 1-year history of variable right-sided facial swelling, which extended from the inferior border of her mandible to her right eye. A mass was palpable within her right cheek; it was firm and approximately 4 cm in diameter. Six months previously, she had undergone incision and drainage of the swelling via an extraoral approach, resulting in localized paresthesia and nonhealing of the incision site. Subsequently a lesion developed which discharged periodically. Her medical history included intraoral and fistulating ileocolonic Crohn’s disease diagnosed at age 16 years. She had previously undergone surgery with an ileal resection and This case was presented as a poster presentation at the British Society of Oral Medicine Annual Scientific Meeting, Birmingham, England, May 2-3, 2013. a Senior House Officer in Oral and Maxillofacial Surgery, John Radcliffe Hospital, Oxford University Hospitals. b Clinical Research Fellow, Department of Gastroenterology, Guy’s and St Thomas’ Hospital. c Senior Lecturer and Honorary Consultant, Oral Medicine Unit, King’s College London Dental Institute; Deputy Director of Education (Assessment), Guy’s and St Thomas’ Hospitals Trust. Received for publication Feb 12, 2014; returned for revision May 12, 2014; accepted for publication May 16, 2014. Ó 2014 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2014.05.018
right hemicolectomy and was now maintained on azathioprine, adalimumab, and vitamin B12 injections. She had recently commenced a cinnamon- and benzoate-free diet, which had significantly improved her recurrent aphthae and lip swelling but had no effect on her cutaneous lesion. Extraoral examination revealed a puckered, erythematous lesion of the right cheek measuring approximately 2 3 cm. The lesion was very tender, with a central area of crusting and a purulent discharge. There was no associated lymphadenopathy or facial swelling. Intraoral examination revealed healthy unrestored dentition, good oral hygiene, and a well-lubricated oral mucosa with normal papillated tongue. In the lower right quadrant adjacent to the premolar teeth, the buccal mucosa immediately below the extraoral lesion was attached to the lateral aspect of the mandible. There was resultant loss of the sulcal depth, and the surrounding areas were firm. Other areas of the oral cavity were normal. Plain film radiography ruled out dental or bony pathology. It was agreed that an incisional biopsy could further compromise the area, located in the cosmetic zone; for this reason, the patient was unwilling to have a biopsy unless the lesion was unresponsive to treatment. Routine blood tests were unremarkable. A swab of the cutaneous lesion showed no evidence of infective organisms. Treatment with tacrolimus 0.1% ointment was commenced, applied thinly over the extraoral lesion twice daily (14 applications per week). Upon 12-week review, the extraoral lesion had reduced in size and was less tender, with minimal discharge (Figure 1). Intraorally, the area of attachment had softened, with some improvement in the sulcal depth. The patient did not report any adverse effects of using topical tacrolimus when questioned (either local or systemic effects). A repeat swab of the facial lesion confirmed the absence of any infection. Routine hematologic assays were taken at 3-month intervals to monitor any immunosuppression caused by azathioprine or topical tacrolimus therapy. Further improvement occurred over the following year (Figure 2), with total resolution of the lesion at 12 months of tacrolimus use, resulting in a satisfactory cosmetic outcome extraorally as
e71
ORAL MEDICINE e72 Shah, Goel and Escudier
OOOO September 2014
Fig. 1. Cutaneous lesion at 3 months after treatment with tacrolimus ointment.
Fig. 2. Cutaneous lesion at 13 months after treatment with tacrolimus ointment.
Fig. 3. Cutaneous lesion at 33 months after treatment with tacrolimus ointment. well as resolution of the intraoral features and reestablishment of the full sulcal depth. Improvement in color and texture of the remnant scar took a further 20 months of simple massage of the area on a daily basis (Figure 3).
DISCUSSION Crohn’s disease is a chronic inflammatory bowel disease characterized by localized areas of nonspecific, noncaseating granulomas.5 It may affect any part of the gastrointestinal tract, but it most frequently affects the ileocecal region. Oral Crohn’s disease may manifest as aphthae, diffuse lip and buccal mucosal swelling, oral cobblestoning, buccal sulcus ulceration, and banding, mucosal tags, and tongue fissuring.6 Recurrent buccal space abscesses have been reported, and orocutaneous fistulas may rarely occur.7,8 Fibrous banding in the oral sulci has been found to correlate well with the presence of gut Crohn’s disease.9
Extraintestinal complications of Crohn’s disease may involve the musculoskeletal, ophthalmic, and dermatologic systems,10 with the most commonly reported cutaneous manifestations of Crohn’s disease being erythema nodosum and pyoderma gangrenosum.11 Sterile granulomatous skin lesions have been termed ‘metastatic Crohn’s disease’ and present as solitary or multiple lesions, primarily involving the limbs and less frequently the face.12 The most common histologic findings in metastatic Crohn’s lesions are both superficial and deep nonsuppurative granulomas.13 The differential diagnoses included an epidermoid cyst and extraoral sinus of odontogenic origin. The lack of associated odontogenic pathology and the failure to respond to surgical and antibiotic therapy made these unlikely. Although microscopic confirmation was unobtainable in this case, the dramatic response to tacrolimus confirmed our clinical suspicion that this was a cutaneous
OOOO Volume 118, Number 3
lesion related to Crohn’s disease which persisted as a recurrent abscess at the site of the incision scar. Recent studies have shown systemic tacrolimus to be effective in inflammatory bowel disease,14 including fistulating disease.15 Safe and effective use of topical tacrolimus has been demonstrated in cases of perianal Crohn’s disease16 and parastomal pyoderma gangrenosum.17 Tacrolimus inhibits T-cell activation and proliferation and improves skin inflammation when applied topically. It is absorbed better through the epidermal barrier than cyclosporine, and serum levels remain low or undetectable at this concentration even when the drug is applied to broken skin or mucosa.18 Compared with topical corticosteroids, tacrolimus does not affect collagen synthesis and is therefore not associated with atrophy of the skin19; in fact, there is evidence that tacrolimus improves collagen synthesis and increases skin thickness.20 The most commonly recorded adverse events for topical use of this drug are a localized burning sensation or pruritus, both of which are usually mild to moderate in intensity and transient, occurring in the first few days of treatment and decreasing in intensity over time and use.21 There is very little evidence to show that long-term topical use of tacrolimus increases the incidence of cutaneous malignancies or cutaneous infections as a result.22 We recommend twice-daily use of topical tacrolimus for cutaneous Crohn’s lesions until complete resolution. In small lesions such as this one, this regimen would indicate a total of 60 g of the ointment. Failure to respond to tacrolimus treatment within 12 weeks should warrant further investigation.
CONCLUSION We report a case of a facial cutaneous lesion related to Crohn’s disease effectively treated with topical tacrolimus. Our experience suggests topical tacrolimus is a safe and effective therapy for such lesions. Delay in the diagnosis and alternative treatments can lead to increased chronicity of the lesion and cosmetic defects, as in this case.
REFERENCES 1. Wollina U. The role of topical calcineurin inhibitors for skin diseases other than atopic dermatitis. Am J Clin Dermatol. 2007;8: 157-173. 2. Thomson MA, Hamburger J, Stewart DG, Lewis HM. Treatment of erosive oral lichen planus with topical tacrolimus. J Dermatolog Treat. 2004;15:308-314. 3. Morrison L, Kratochvil FJ 3rd, Gorman A. An open trial of topical tacrolimus for erosive oral lichen planus. J Am Acad Dermatol. 2002;4:617-620. 4. Hodgson TA, Malik F, Hegarty AM, Porter SR. Topical tacrolimus: a novel therapeutic intervention for recalcitrant labial pemphigus vulgaris. Eur J Dermatol. 2003;13:142-144.
CASE REPORT Shah, Goel and Escudier e73 5. Gagoh OK, Qureshi RM, Hendrickse MT. Recurrent buccal space abscesses: a complication of Crohn’s disease. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1999;88:33-36. 6. Zbar A, Ben-Horin S, Beer-Gabel M, Eliakim R. Oral Crohn’s disease: is it a separable disease from orofacial granulomatosis? A review. J Crohns Colitis. 2012;6:135-142. 7. Leão JC, Hodgson T, Scully C, Porter R. Review article: orofacial granulomatosis. Aliment Pharmacol Ther. 2004;20:1019-1027. 8. Mills CC, Amin M, Manisali M. Salivary duct fistula and recurrent buccal space infection: a complication of Crohn’s disease. J Oral Maxillofac Surg. 2003;61:1485-1487. 9. Campbell H, Escudier M, Patel P, et al. Distinguishing orofacial granulomatosis from Crohn’s disease: two separate disease entities? Inflamm Bowel Dis. 2011;17:2109-2115. 10. Levine JS, Burakoff R. Extraintestinal manifestations of inflammatory bowel disease. Gastroenterol Hepatol (NY). 2011;7: 235-241. 11. Tavarela Veloso F. Review article: skin complications associated with inflammatory bowel disease. Aliment Pharmacol Ter. 2004;20:50-53. 12. Hackzell-Bradley M, Hedblad MA, Stephansson EA. Metastatic Crohn’s disease: report of 3 cases with special reference to histopathologic findings. Arch Dermatol. 1996;132:928. 13. Emanuel PO, Phelps RG. Metastatic Crohn’s disease: a histopathologic study of 12 cases. J Cutan Pathol. 2008;35: 457-461. 14. Benson A, Barrett T, Sparberg M, Buchman AL. Efficacy and safety of tacrolimus in refractory ulcerative colitis and Crohn’s disease: a single-center experience. Inflamm Bowel Dis. 2008;14:7-12. 15. Sandborn WJ, Present DH, Isaacs KL, et al. Tacrolimus for the treatment of fistulas in patients with Crohn’s disease: a randomized, placebo-controlled trial. Gastroenterology. 2003;125:380-388. 16. Hart AL, Plamondon S, Kamm MA. Topical tacrolimus in the treatment of perianal Crohn’s disease: exploratory randomized controlled trial. Inflamm Bowel Dis. 2007;13:245-253. 17. Khurrum Baig M, Marquez H, Nogueras JJ, Weiss EG, Wexner SD. Topical tacrolimus (FK506) in the treatment of recalcitrant parastomal pyoderma gangrenosum associated with Crohn’s disease: report of two cases. Colorectal Dis. 2004;6:250-253. 18. Rice SA, Woo PN, El-Omar E, Ronald KA, Anthony OD. Topical tacrolimus 0.1% ointment for treatment of cutaneous Crohn’s Disease. BMC Res Notes. 2013;6:19. 19. Sehgal VN, Srivastava G, Dogra S. Tacrolimus in dermatologyd pharmacokinetics, mechanism of action, drug interactions, dosages, and side effects, part I. Skinmed. 2008;1:27-30. 20. Kyllonen H, Remitz A, Mandelin JM, Elg P, Reitamo S. Effects of 1-year intermittent treatment with topical tacrolimus monotherapy on skin collagen synthesis in patients with atopic dermatitis. Br J Dermatol. 2004;150:1174-1181. 21. Reitamo S, Wollenberg A, Schöpf E, et al. Safety and efficacy of 1 year of tacrolimus ointment monotherapy in adults with atopic dermatitis. The European Tacrolimus Ointment Study Group. Arch Dermatol. 2000;136:999-1006. 22. Rustin M. The safety of tacrolimus ointment for the treatment of atopic dermatitis: a review. Br J Dermatol. 2007;157:861-873.
Reprint requests: Neha P. Shah, BDS Department of Oral and Maxillofacial Surgery John Radcliffe Hospital Headley Way Oxford OX3 9 DU United Kingdom [email protected]
Treatment of a Crohn’s diseaseerelated cutaneous facial lesion with topical tacrolimus Neha P. Shah, BDS,a Rishi M. Goel, MBBS, BSc, MRCP, SCE,b and Michael Escudier, MD, BDS, FDS, FDS (OM), RCSc John Radcliffe Hospital, Oxford, England; Guy’s and St Thomas’ Hospital, London, England; King’s College London Dental Institute, London, England
We report a case of an orofacial lesion in Crohn’s disease successfully treated with tacrolimus ointment. A 22-yearold woman with Crohn’s disease presented with a discharging lesion on the right side of her face. Intraorally, there was a resultant loss of the sulcal depth. She reported a 1-year history of variable right-sided facial swelling for which she had undergone extraoral incision and drainage, resulting in localized paresthesia and nonhealing of the incision site. Following exclusion tests, a treatment of twice-daily extraoral application of tacrolimus 0.1% ointment was commenced. Upon review, the lesion had reduced in size, with minimal discharge. Further improvement over 12 months of tacrolimus use resulted in a satisfactory cosmetic result as well as resolution of the intraoral features and reestablishment of the full sulcal depth. This case illustrates the successful use of topical tacrolimus to treat a cutaneous manifestation of Crohn’s disease. (Oral Surg Oral Med Oral Pathol Oral Radiol 2014;118:e71-e73)
Tacrolimus 0.1% ointment is commonly used in the treatment of inflammatory dermatoses such as allergic contact dermatitis and psoriasis.1 Successful intraoral use of the ointment has been reported in several mucosal conditions, including erosive oral lichen planus, oral psoriasis, and immunobullous disorders.2-4 We report a case of an orofacial lesion in Crohn’s disease that was successfully treated with tacrolimus ointment.
CASE REPORT A 22-year-old woman was referred from Gastroenterology to the Oral Medicine department complaining of a discharging lesion on the right side of her face. She reported a 1-year history of variable right-sided facial swelling, which extended from the inferior border of her mandible to her right eye. A mass was palpable within her right cheek; it was firm and approximately 4 cm in diameter. Six months previously, she had undergone incision and drainage of the swelling via an extraoral approach, resulting in localized paresthesia and nonhealing of the incision site. Subsequently a lesion developed which discharged periodically. Her medical history included intraoral and fistulating ileocolonic Crohn’s disease diagnosed at age 16 years. She had previously undergone surgery with an ileal resection and This case was presented as a poster presentation at the British Society of Oral Medicine Annual Scientific Meeting, Birmingham, England, May 2-3, 2013. a Senior House Officer in Oral and Maxillofacial Surgery, John Radcliffe Hospital, Oxford University Hospitals. b Clinical Research Fellow, Department of Gastroenterology, Guy’s and St Thomas’ Hospital. c Senior Lecturer and Honorary Consultant, Oral Medicine Unit, King’s College London Dental Institute; Deputy Director of Education (Assessment), Guy’s and St Thomas’ Hospitals Trust. Received for publication Feb 12, 2014; returned for revision May 12, 2014; accepted for publication May 16, 2014. Ó 2014 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2014.05.018
right hemicolectomy and was now maintained on azathioprine, adalimumab, and vitamin B12 injections. She had recently commenced a cinnamon- and benzoate-free diet, which had significantly improved her recurrent aphthae and lip swelling but had no effect on her cutaneous lesion. Extraoral examination revealed a puckered, erythematous lesion of the right cheek measuring approximately 2 3 cm. The lesion was very tender, with a central area of crusting and a purulent discharge. There was no associated lymphadenopathy or facial swelling. Intraoral examination revealed healthy unrestored dentition, good oral hygiene, and a well-lubricated oral mucosa with normal papillated tongue. In the lower right quadrant adjacent to the premolar teeth, the buccal mucosa immediately below the extraoral lesion was attached to the lateral aspect of the mandible. There was resultant loss of the sulcal depth, and the surrounding areas were firm. Other areas of the oral cavity were normal. Plain film radiography ruled out dental or bony pathology. It was agreed that an incisional biopsy could further compromise the area, located in the cosmetic zone; for this reason, the patient was unwilling to have a biopsy unless the lesion was unresponsive to treatment. Routine blood tests were unremarkable. A swab of the cutaneous lesion showed no evidence of infective organisms. Treatment with tacrolimus 0.1% ointment was commenced, applied thinly over the extraoral lesion twice daily (14 applications per week). Upon 12-week review, the extraoral lesion had reduced in size and was less tender, with minimal discharge (Figure 1). Intraorally, the area of attachment had softened, with some improvement in the sulcal depth. The patient did not report any adverse effects of using topical tacrolimus when questioned (either local or systemic effects). A repeat swab of the facial lesion confirmed the absence of any infection. Routine hematologic assays were taken at 3-month intervals to monitor any immunosuppression caused by azathioprine or topical tacrolimus therapy. Further improvement occurred over the following year (Figure 2), with total resolution of the lesion at 12 months of tacrolimus use, resulting in a satisfactory cosmetic outcome extraorally as
e71
ORAL MEDICINE e72 Shah, Goel and Escudier
OOOO September 2014
Fig. 1. Cutaneous lesion at 3 months after treatment with tacrolimus ointment.
Fig. 2. Cutaneous lesion at 13 months after treatment with tacrolimus ointment.
Fig. 3. Cutaneous lesion at 33 months after treatment with tacrolimus ointment. well as resolution of the intraoral features and reestablishment of the full sulcal depth. Improvement in color and texture of the remnant scar took a further 20 months of simple massage of the area on a daily basis (Figure 3).
DISCUSSION Crohn’s disease is a chronic inflammatory bowel disease characterized by localized areas of nonspecific, noncaseating granulomas.5 It may affect any part of the gastrointestinal tract, but it most frequently affects the ileocecal region. Oral Crohn’s disease may manifest as aphthae, diffuse lip and buccal mucosal swelling, oral cobblestoning, buccal sulcus ulceration, and banding, mucosal tags, and tongue fissuring.6 Recurrent buccal space abscesses have been reported, and orocutaneous fistulas may rarely occur.7,8 Fibrous banding in the oral sulci has been found to correlate well with the presence of gut Crohn’s disease.9
Extraintestinal complications of Crohn’s disease may involve the musculoskeletal, ophthalmic, and dermatologic systems,10 with the most commonly reported cutaneous manifestations of Crohn’s disease being erythema nodosum and pyoderma gangrenosum.11 Sterile granulomatous skin lesions have been termed ‘metastatic Crohn’s disease’ and present as solitary or multiple lesions, primarily involving the limbs and less frequently the face.12 The most common histologic findings in metastatic Crohn’s lesions are both superficial and deep nonsuppurative granulomas.13 The differential diagnoses included an epidermoid cyst and extraoral sinus of odontogenic origin. The lack of associated odontogenic pathology and the failure to respond to surgical and antibiotic therapy made these unlikely. Although microscopic confirmation was unobtainable in this case, the dramatic response to tacrolimus confirmed our clinical suspicion that this was a cutaneous
OOOO Volume 118, Number 3
lesion related to Crohn’s disease which persisted as a recurrent abscess at the site of the incision scar. Recent studies have shown systemic tacrolimus to be effective in inflammatory bowel disease,14 including fistulating disease.15 Safe and effective use of topical tacrolimus has been demonstrated in cases of perianal Crohn’s disease16 and parastomal pyoderma gangrenosum.17 Tacrolimus inhibits T-cell activation and proliferation and improves skin inflammation when applied topically. It is absorbed better through the epidermal barrier than cyclosporine, and serum levels remain low or undetectable at this concentration even when the drug is applied to broken skin or mucosa.18 Compared with topical corticosteroids, tacrolimus does not affect collagen synthesis and is therefore not associated with atrophy of the skin19; in fact, there is evidence that tacrolimus improves collagen synthesis and increases skin thickness.20 The most commonly recorded adverse events for topical use of this drug are a localized burning sensation or pruritus, both of which are usually mild to moderate in intensity and transient, occurring in the first few days of treatment and decreasing in intensity over time and use.21 There is very little evidence to show that long-term topical use of tacrolimus increases the incidence of cutaneous malignancies or cutaneous infections as a result.22 We recommend twice-daily use of topical tacrolimus for cutaneous Crohn’s lesions until complete resolution. In small lesions such as this one, this regimen would indicate a total of 60 g of the ointment. Failure to respond to tacrolimus treatment within 12 weeks should warrant further investigation.
CONCLUSION We report a case of a facial cutaneous lesion related to Crohn’s disease effectively treated with topical tacrolimus. Our experience suggests topical tacrolimus is a safe and effective therapy for such lesions. Delay in the diagnosis and alternative treatments can lead to increased chronicity of the lesion and cosmetic defects, as in this case.
REFERENCES 1. Wollina U. The role of topical calcineurin inhibitors for skin diseases other than atopic dermatitis. Am J Clin Dermatol. 2007;8: 157-173. 2. Thomson MA, Hamburger J, Stewart DG, Lewis HM. Treatment of erosive oral lichen planus with topical tacrolimus. J Dermatolog Treat. 2004;15:308-314. 3. Morrison L, Kratochvil FJ 3rd, Gorman A. An open trial of topical tacrolimus for erosive oral lichen planus. J Am Acad Dermatol. 2002;4:617-620. 4. Hodgson TA, Malik F, Hegarty AM, Porter SR. Topical tacrolimus: a novel therapeutic intervention for recalcitrant labial pemphigus vulgaris. Eur J Dermatol. 2003;13:142-144.
CASE REPORT Shah, Goel and Escudier e73 5. Gagoh OK, Qureshi RM, Hendrickse MT. Recurrent buccal space abscesses: a complication of Crohn’s disease. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1999;88:33-36. 6. Zbar A, Ben-Horin S, Beer-Gabel M, Eliakim R. Oral Crohn’s disease: is it a separable disease from orofacial granulomatosis? A review. J Crohns Colitis. 2012;6:135-142. 7. Leão JC, Hodgson T, Scully C, Porter R. Review article: orofacial granulomatosis. Aliment Pharmacol Ther. 2004;20:1019-1027. 8. Mills CC, Amin M, Manisali M. Salivary duct fistula and recurrent buccal space infection: a complication of Crohn’s disease. J Oral Maxillofac Surg. 2003;61:1485-1487. 9. Campbell H, Escudier M, Patel P, et al. Distinguishing orofacial granulomatosis from Crohn’s disease: two separate disease entities? Inflamm Bowel Dis. 2011;17:2109-2115. 10. Levine JS, Burakoff R. Extraintestinal manifestations of inflammatory bowel disease. Gastroenterol Hepatol (NY). 2011;7: 235-241. 11. Tavarela Veloso F. Review article: skin complications associated with inflammatory bowel disease. Aliment Pharmacol Ter. 2004;20:50-53. 12. Hackzell-Bradley M, Hedblad MA, Stephansson EA. Metastatic Crohn’s disease: report of 3 cases with special reference to histopathologic findings. Arch Dermatol. 1996;132:928. 13. Emanuel PO, Phelps RG. Metastatic Crohn’s disease: a histopathologic study of 12 cases. J Cutan Pathol. 2008;35: 457-461. 14. Benson A, Barrett T, Sparberg M, Buchman AL. Efficacy and safety of tacrolimus in refractory ulcerative colitis and Crohn’s disease: a single-center experience. Inflamm Bowel Dis. 2008;14:7-12. 15. Sandborn WJ, Present DH, Isaacs KL, et al. Tacrolimus for the treatment of fistulas in patients with Crohn’s disease: a randomized, placebo-controlled trial. Gastroenterology. 2003;125:380-388. 16. Hart AL, Plamondon S, Kamm MA. Topical tacrolimus in the treatment of perianal Crohn’s disease: exploratory randomized controlled trial. Inflamm Bowel Dis. 2007;13:245-253. 17. Khurrum Baig M, Marquez H, Nogueras JJ, Weiss EG, Wexner SD. Topical tacrolimus (FK506) in the treatment of recalcitrant parastomal pyoderma gangrenosum associated with Crohn’s disease: report of two cases. Colorectal Dis. 2004;6:250-253. 18. Rice SA, Woo PN, El-Omar E, Ronald KA, Anthony OD. Topical tacrolimus 0.1% ointment for treatment of cutaneous Crohn’s Disease. BMC Res Notes. 2013;6:19. 19. Sehgal VN, Srivastava G, Dogra S. Tacrolimus in dermatologyd pharmacokinetics, mechanism of action, drug interactions, dosages, and side effects, part I. Skinmed. 2008;1:27-30. 20. Kyllonen H, Remitz A, Mandelin JM, Elg P, Reitamo S. Effects of 1-year intermittent treatment with topical tacrolimus monotherapy on skin collagen synthesis in patients with atopic dermatitis. Br J Dermatol. 2004;150:1174-1181. 21. Reitamo S, Wollenberg A, Schöpf E, et al. Safety and efficacy of 1 year of tacrolimus ointment monotherapy in adults with atopic dermatitis. The European Tacrolimus Ointment Study Group. Arch Dermatol. 2000;136:999-1006. 22. Rustin M. The safety of tacrolimus ointment for the treatment of atopic dermatitis: a review. Br J Dermatol. 2007;157:861-873.
Reprint requests: Neha P. Shah, BDS Department of Oral and Maxillofacial Surgery John Radcliffe Hospital Headley Way Oxford OX3 9 DU United Kingdom [email protected]
