JEADV
LETTER TO THE EDITOR
Finally, recurrent pyoderma gangrenosum treated with Adalimumab: case report and review of the literature Editor Pyoderma Gangrenosum (PG) is a rare disorder belonging to neutrophilic dermatoses, characterized by chronic and relapsing clinical course, often related to the recurrence of the underlying undiagnosed disease, as lymphoproliferative disorders, rheumatologic or inflammatory bowel diseases (IBD).1 Although PG is morphologically classified into four clinical variants (ulcerative, bullous, pustular and vegetative), the most frequently detected one is the ulcerative form in the pretibial area of the lower limbs.1 Treatment of PG is a great challenge for dermatologists and actually there are nostandardized guidelines on this topic. Topical and systemic corticosteroids are considered the first therapeutic option, whereas immunosuppressor and cytostatic drugs can be used as steroid-sparing agents.2 In the last decades, the biological therapies have dramatically changed the clinical course of several inflammatory and
immune-mediated diseases and their off-label use has been reported in PG.3–5 We report a case of a severe recalcitrant PG in Crohn’s disease treated successfully with Adalimumab. A 51-year-old woman came to our attention for an oedematous, ulcerative and vegetative lesion of about 13 9 10 cm on the right tibial area, appeared 1 month previously (Fig. 1a). The lesion was painful, spontaneously bleeding and showed a fibrinous exudate. In a peripheral hospital, it was considered as a venous ulcer with secondary infection, thus it had been treated with systemic antibiotic therapy and surgical debridement. Despite the above procedures, the skin lesion had rapidly worsened, leading the clinicians to a misdiagnosis of gangrene, with the risk of limb amputation. Based on clinical signs and anamnestic data, we suspected a vegetative PG showing painful, necrotic ulcer with irregular cyanotic borders. A lesional culture swab was performed and it was negative for microbial infection; moreover, an echo Doppler revealed a patent arterio-venous circulation. Blood parameters were within normal ranges apart from a microcytic normochromic anaemia, increased Reactive CProtein (11 m/dL) and faecal calprotectin (254 lg/g).
(a)
(b)
(c)
Figure 1 (a) Ulcerative and vegetative lesion of the right tibial area. (b) Anatomopathological findings of the ulcerative lesion (H&E staining 209): non-specific ulceration, abscesses, acute and chronic inflammation features with superficial and deep dermis acute vasculitis. (c) Improvement of PG after 24 weeks of corticosteroids therapy.
JEADV 2014
© 2014 European Academy of Dermatology and Venereology
Letter to the Editor
2
Although systemic corticosteroids are mostly used in the treatment of PG associated with IBD, therapeutic failures and side-effects oblige the clinicians to shift them to alternative longterm therapies.8 The rationale of the use of TNF-alpha-inhibitors (Infliximab, Etanercept, Adalimumab) lies in the known role of this cytokine in both PG and IBD.9,10 Although contradictory results, Adalimumab could be a valuable alternative for the treatment of PG, with comparable efficacy to infliximab.9,10 Although a recent systematic review stated that anti-TNF alpha therapy should be considered as a first-line agent for PG, studies on larger population are lacking and the prohibitive costs could reduce the use of biologics in off-label regimen for this disease.5 Figure 2 After 12 weeks of treatment with Adalimumab.
A. Campanati,1,† V. Brisigotti,1,† G. Ganzetti,1,* E. Molinelli,1 K. Giuliodori,1 V. Consales,1 S. Racchini,2 E. Bendia,3 A. Offidani1 2
Colonscopy revealed multiple inflammatory foci in colon and small intestine with some aphtoid ulcers according to Crohn’s disease (CD); histopathology showed a non-specific ulceration with abscesses, neutrophilic inflammation and acute vasculitis in superficial and deep dermis (Fig. 1b). A diagnosis of PG in inflammatory bowel disease was carried out. Thus, we started a systemic corticosteroid therapy (betamethasone dipropionate 6 mg/die for 2 weeks), with gradual tapering; furthermore, we applied a hydrogel and a hydrocellular foam dressing. After 24 weeks, therapeutic response was excellent with a great improvement of the skin lesion of more than half in size (Fig. 1c). However, the patient developed an iatrogenic Cushing-like syndrome, leading us to a gradually reduction of steroid and to add azathioprine 100 mg twice a day. The healing process properly improved for further 6 weeks; when the dose was tapered off to 2 mg/day, a rapid relapse occurred. According to the gastroenterologist, we discontinued steroid and azathioprine and started Adalimumab with the following regimen: an induction dose of 160 mg at week 0, 80 mg at week 1 and 40 mg every 2 weeks. After the second dose of Adalimumab, a rapid clinical improvement both of the skin lesion and gastrointestinal symptoms was obtained, with a complete PG healing after 12 weeks of treatment (Fig. 2). The patient was on Adalimumab for the control of CD. PG has been reported to occur in 2–12% of IBD patients and, as in our case, it represents the first sign of an underlying intestinal disease.6,7 Data on literature show that treatment of the underlying intestinal disease can bring about improvement of extra-intestinal manifestation in PG.8
JEADV 2014
1 Dermatological Unit, Department of Clinical and Molecular Sciences, Institute of Pathological Anatomy and Histopathology, and 3Department of Gastroenterology, Polytechnic University of the Marche Region, Ancona, Italy *Correspondence: G. Ganzetti. E-mail: [email protected] † These two authors contributed equally to this work.
References 1 Wollina U. Pyoderma gangrenosum:a review. Orphanet J Rare Dis 2007; 2: 19. 2 Kontochristopoulos GJ, Stavropoulos PG, Gregoriou S, Zakopoulou N. Treatment of Pyoderma gangrenosum with low-dose colchicine. Dermatology 2004; 209: 233–236. 3 Campanati A, Ganzetti G, Di Sario A et al. The effect of etanercept on hepatic fibrosis risk in patients with non-alcoholic fatty liver disease, metabolic syndrome, and psoriasis. J Gastroenterol 2013; 48: 839–846. 4 Campanati A, Giuliodori K, Ganzetti G, Liberati G, Offidani AM. A patient with psoriasis and vitiligo treated with etanercept. Am J Clin Dermatol 2010; 11(Suppl 1): 46–48. 5 Agarwal A, Andrews JM. Systematic review: IBD-associated pyoderma gangrenosum in the biologic era, the response to therapy. Aliment Pharmacol Ther 2013; 38: 563–572. 6 Ganzetti G, Campanati A, Offidani A. Alopecia Areata: a possible extraintestinal manifestation of Crohn’s disease. J Crohns Colitis 2012; 6: 962– 963. 7 Ruocco E, Sangiuliano S, Gravina AG, Miranda A, Nicoletti G. Pyoderma gangrenosum: an updated review. J Eur Acad Dermatol Venereol 2009; 23: 1008–1017. 8 Wollina U, Tchernev G. Pyoderma gangrenosum: pathogenetic oriented treatment approaches. Wien Med Wochenschr 2014; 164: 263–273. 9 Hubbard VG, Friedmann AC, Goldsmith P. Systemic pyoderma gangrenosum responding to infliximab and adalimumab. Br J Dermatol 2005; 152: 1059–1061. 10 Kleinpenning MM, Langewouters AM, Van De Kerkhof PC, Greebe RJ. Severe pyoderma gangrenosum unresponsive to etanercept and adalimumab. J Dermatolog Treat 2011; 22: 261–265. DOI: 10.1111/jdv.12703
© 2014 European Academy of Dermatology and Venereology
LETTER TO THE EDITOR
Finally, recurrent pyoderma gangrenosum treated with Adalimumab: case report and review of the literature Editor Pyoderma Gangrenosum (PG) is a rare disorder belonging to neutrophilic dermatoses, characterized by chronic and relapsing clinical course, often related to the recurrence of the underlying undiagnosed disease, as lymphoproliferative disorders, rheumatologic or inflammatory bowel diseases (IBD).1 Although PG is morphologically classified into four clinical variants (ulcerative, bullous, pustular and vegetative), the most frequently detected one is the ulcerative form in the pretibial area of the lower limbs.1 Treatment of PG is a great challenge for dermatologists and actually there are nostandardized guidelines on this topic. Topical and systemic corticosteroids are considered the first therapeutic option, whereas immunosuppressor and cytostatic drugs can be used as steroid-sparing agents.2 In the last decades, the biological therapies have dramatically changed the clinical course of several inflammatory and
immune-mediated diseases and their off-label use has been reported in PG.3–5 We report a case of a severe recalcitrant PG in Crohn’s disease treated successfully with Adalimumab. A 51-year-old woman came to our attention for an oedematous, ulcerative and vegetative lesion of about 13 9 10 cm on the right tibial area, appeared 1 month previously (Fig. 1a). The lesion was painful, spontaneously bleeding and showed a fibrinous exudate. In a peripheral hospital, it was considered as a venous ulcer with secondary infection, thus it had been treated with systemic antibiotic therapy and surgical debridement. Despite the above procedures, the skin lesion had rapidly worsened, leading the clinicians to a misdiagnosis of gangrene, with the risk of limb amputation. Based on clinical signs and anamnestic data, we suspected a vegetative PG showing painful, necrotic ulcer with irregular cyanotic borders. A lesional culture swab was performed and it was negative for microbial infection; moreover, an echo Doppler revealed a patent arterio-venous circulation. Blood parameters were within normal ranges apart from a microcytic normochromic anaemia, increased Reactive CProtein (11 m/dL) and faecal calprotectin (254 lg/g).
(a)
(b)
(c)
Figure 1 (a) Ulcerative and vegetative lesion of the right tibial area. (b) Anatomopathological findings of the ulcerative lesion (H&E staining 209): non-specific ulceration, abscesses, acute and chronic inflammation features with superficial and deep dermis acute vasculitis. (c) Improvement of PG after 24 weeks of corticosteroids therapy.
JEADV 2014
© 2014 European Academy of Dermatology and Venereology
Letter to the Editor
2
Although systemic corticosteroids are mostly used in the treatment of PG associated with IBD, therapeutic failures and side-effects oblige the clinicians to shift them to alternative longterm therapies.8 The rationale of the use of TNF-alpha-inhibitors (Infliximab, Etanercept, Adalimumab) lies in the known role of this cytokine in both PG and IBD.9,10 Although contradictory results, Adalimumab could be a valuable alternative for the treatment of PG, with comparable efficacy to infliximab.9,10 Although a recent systematic review stated that anti-TNF alpha therapy should be considered as a first-line agent for PG, studies on larger population are lacking and the prohibitive costs could reduce the use of biologics in off-label regimen for this disease.5 Figure 2 After 12 weeks of treatment with Adalimumab.
A. Campanati,1,† V. Brisigotti,1,† G. Ganzetti,1,* E. Molinelli,1 K. Giuliodori,1 V. Consales,1 S. Racchini,2 E. Bendia,3 A. Offidani1 2
Colonscopy revealed multiple inflammatory foci in colon and small intestine with some aphtoid ulcers according to Crohn’s disease (CD); histopathology showed a non-specific ulceration with abscesses, neutrophilic inflammation and acute vasculitis in superficial and deep dermis (Fig. 1b). A diagnosis of PG in inflammatory bowel disease was carried out. Thus, we started a systemic corticosteroid therapy (betamethasone dipropionate 6 mg/die for 2 weeks), with gradual tapering; furthermore, we applied a hydrogel and a hydrocellular foam dressing. After 24 weeks, therapeutic response was excellent with a great improvement of the skin lesion of more than half in size (Fig. 1c). However, the patient developed an iatrogenic Cushing-like syndrome, leading us to a gradually reduction of steroid and to add azathioprine 100 mg twice a day. The healing process properly improved for further 6 weeks; when the dose was tapered off to 2 mg/day, a rapid relapse occurred. According to the gastroenterologist, we discontinued steroid and azathioprine and started Adalimumab with the following regimen: an induction dose of 160 mg at week 0, 80 mg at week 1 and 40 mg every 2 weeks. After the second dose of Adalimumab, a rapid clinical improvement both of the skin lesion and gastrointestinal symptoms was obtained, with a complete PG healing after 12 weeks of treatment (Fig. 2). The patient was on Adalimumab for the control of CD. PG has been reported to occur in 2–12% of IBD patients and, as in our case, it represents the first sign of an underlying intestinal disease.6,7 Data on literature show that treatment of the underlying intestinal disease can bring about improvement of extra-intestinal manifestation in PG.8
JEADV 2014
1 Dermatological Unit, Department of Clinical and Molecular Sciences, Institute of Pathological Anatomy and Histopathology, and 3Department of Gastroenterology, Polytechnic University of the Marche Region, Ancona, Italy *Correspondence: G. Ganzetti. E-mail: [email protected] † These two authors contributed equally to this work.
References 1 Wollina U. Pyoderma gangrenosum:a review. Orphanet J Rare Dis 2007; 2: 19. 2 Kontochristopoulos GJ, Stavropoulos PG, Gregoriou S, Zakopoulou N. Treatment of Pyoderma gangrenosum with low-dose colchicine. Dermatology 2004; 209: 233–236. 3 Campanati A, Ganzetti G, Di Sario A et al. The effect of etanercept on hepatic fibrosis risk in patients with non-alcoholic fatty liver disease, metabolic syndrome, and psoriasis. J Gastroenterol 2013; 48: 839–846. 4 Campanati A, Giuliodori K, Ganzetti G, Liberati G, Offidani AM. A patient with psoriasis and vitiligo treated with etanercept. Am J Clin Dermatol 2010; 11(Suppl 1): 46–48. 5 Agarwal A, Andrews JM. Systematic review: IBD-associated pyoderma gangrenosum in the biologic era, the response to therapy. Aliment Pharmacol Ther 2013; 38: 563–572. 6 Ganzetti G, Campanati A, Offidani A. Alopecia Areata: a possible extraintestinal manifestation of Crohn’s disease. J Crohns Colitis 2012; 6: 962– 963. 7 Ruocco E, Sangiuliano S, Gravina AG, Miranda A, Nicoletti G. Pyoderma gangrenosum: an updated review. J Eur Acad Dermatol Venereol 2009; 23: 1008–1017. 8 Wollina U, Tchernev G. Pyoderma gangrenosum: pathogenetic oriented treatment approaches. Wien Med Wochenschr 2014; 164: 263–273. 9 Hubbard VG, Friedmann AC, Goldsmith P. Systemic pyoderma gangrenosum responding to infliximab and adalimumab. Br J Dermatol 2005; 152: 1059–1061. 10 Kleinpenning MM, Langewouters AM, Van De Kerkhof PC, Greebe RJ. Severe pyoderma gangrenosum unresponsive to etanercept and adalimumab. J Dermatolog Treat 2011; 22: 261–265. DOI: 10.1111/jdv.12703
© 2014 European Academy of Dermatology and Venereology
