Pyoderma Gangrenosum Pyoderma Gangrenosum

CAZURI CLINICE CLINICAL CASES

PYODERMA GANGRENOSUM

GABRIELA RALUCA MIULESCU*, MARIA MAGDALENA CONSTANTIN**,***, **MIHAI CRISTIAN DUMITRAªCU***,****, RÃZVAN-COSMIN PETCA***,*****, ANA MARIA ALEXANDRA STÃNESCU***, FLORICA ªANDRU*,***

Rezumat Summary Prezentãm cazul unui pacient în vârstã de 65 de ani, We present the case of a 65 years old man, with cu multiple comorbiditãþi, care a dezvoltat o ulceraþie multiple comorbidities, who reffered to our Dermatology ovalarã, cu margini eritemato-violacee, cu baza necroticã, Clinic for the evaluation, of an oval ulceration, with localizatã la nivelul gambei stângi. Întrucât aceasta nu a erythematous-violet margins, with necrotic base, located at rãspuns la tratamentul cu dermatocorticoizi, ºi luând în the level of the left calf. Because the treatment with considerare aspectul clinic, vârsta ºi antecedentele dermatocorticoids was ineffective, and considering the personale patologice, s-a ridicat suspiciunea clinicã de clinical appearance, age and personal history, the clinical pyoderma gangrenosum. S-a efectuat biopsie cutanatã cu suspicion of pyoderma gangrenosum has been raised. Skin examen histopatologic, care a relevat: infiltrate neutrofilice biopsy was performed with histopathological examination, cu aspect supurativ, fibrozã, þesut de granulaþie; coloraþie which revealed: suppurative neutrophilic infiltrate, fibrosis, PAS ce nu a evidenþiat elemente micotice, susþinându-se granulation tissue; PAS staining that did not show a fungal astfel diagnosticul de pyoderma gangrenosum. Tratamentul element, thus supporting the diagnosis of pyoderma sistemic a constat în dapsonã ºi corticoterapie, cu evoluþie gangrenosum. Systemic treatment with dapsone and favorabilã. corticosteroids was initiated, with favorable evolution. Pyoderma gangrenosum (PG) este o patologie Pyoderma gangrenosum (PG) is a rare, chronic, cutanatã ulcerativã, rarã, cronicã, caracterizatã prin ulcerative skin disease, characterized by rapid progression progresia rapidã a unui ulcer dureros, cu margini to a painful ulcer, with irregular, purple margins. The neregulate, violacee. Diagnosticul se stabileºte atât prin diagnosis is established by histopathological examination, examen histopatologic, cât ºi prin excluderea altor cauze de perhaps by excluding other causes of skin ulceration. Also, ulceraþie cutanatã. De asemenea, fenomenul de patergie the phenomenon of patergia precedes the appearance of the precede deseori apariþia leziunii. injury. Managementul unor astfel de pacienþi este unul Managing such patients is extremely difficult, because extrem de dificil, deoarece recãderile sunt frecvente, iar they are common and care pathologies are associated with patologiile care se asociazã numeroase. the number. Cuvinte cheie: pyoderma gangrenosum, boalã Crohn, Keywords: pyoderma gangrenosum, Crohn’s disease, ulceraþie, dapsona, corticosteroizi. ulceration, dapsone, corticosteroids.

Intrat în redacþie: 04.11.2019 Received: 04.11.2019 Acceptat: 07.12.2019 Accepted: 07.12.2019

* Clinica Dermatologie, Spitalul Clinic Universitar de Urgenþã ,,Elias”, Bucureºti, România Department of Dermatology, ”Elias” University Emergency Hospital, Bucharest, Romania ** Clinica II Dermatologie, Spitalul Clinic Colentina, Bucureºti, România Department of Dermatology II, Colentina Clinical Hospital, Bucharest, Romania *** Universitatea de Medicinã ºi Farmacie ,,Carol Davila”, Bucureºti, România ”Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania **** Clinica de Obstetricã ºi Ginecologie, Spitalul Universitar de Urgenþã, Bucureºti, România Department of Obstetrics and Gynecology, University Emergency Hospital, Bucharest, Romania ***** Clinica de Urologie, Spitalul Clinic ,,Prof. DR. Theodor Burghele”, Bucureºti, România Department of Urology, ”Prof. Dr. Theodor Burghele” Clinical Hospital, Bucharest

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Introducere Introduction PG reprezintã o dermatozã neutrofilicã rarã, PG is a rare, non-infectious, recurrent non-infecþioasã, recurentã, cu aspect morfologic neutrophilic dermatosis with distinct distinct, ºi asociatã, de cele mai multe ori, cu o morphological appearance, and most often patologie sistemicã [1]. Existã patru forme clinice associated with systemic pathology [1]. There are de PG: ulcerativã, buloasã, pustuloasã, granulo- four clinical forms of PG: ulcerative, bullous, matoasã superficialã. Cel mai frecvent, aceastã pustular, superficial granulomatous. Most dermatozã debuteazã printr-o pustulã, localizatã commonly, this dermatosis begins with a pustule, pe un fond eritemato-violaceu, printr-un nodul located on an erythematous-purple background, eritematos, sau printr-o bulã. În timp, aceastã through an erythematous node, or through a leziune evolueazã într-o ulceraþie cu margine bubble. Over time, this lesion develops into an necroticã, ºi cu baza purulentã sau vegetativã [2]. ulceration with a necrotic margin, and with a Conform unor studii, incidenþa a fost purulent or vegetative base [2]. raportatã la 3-10 cazuri la 1 milion de persoane, According to some studies, the incidence was pe an. PG se poate manifesta la orice vârstã, însã reported in 3-10 cases per 1 million people, per cel mai frecvent apare la indivizi între 40 ºi 60 de year. PG can occur at any age, but most ani. De asemenea, aceastã patologie dermato- commonly occurs in individuals between 40 and logicã este mai des întâlnitã la femei [3-7]. 60 years. Also, this dermatological pathology is Etiopatogeneza PG nu este pe deplin more common in women [3-7]. elucidatã. În prezent, existã mai multe teorii prin The etiopathogenesis of PG is not fully care aceastã dermatoza s-ar produce. În primul elucidated. Currently, there are several theories rând, fiind o dermatozã neutrofilicã, este by which this dermatosis would occur. First, recunoscut rolul disfuncþiei neutrofilelor în being a neutrophilic dermatosis, the role of declanºarea bolii. Acest fapt este susþinut ºi de neutrophil dysfunction in triggering the disease rãspunsul benefic al PG la agenþi anti-neutrofilici, is recognized. This fact is also supported by the cum ar fi dapsona [8]. În al doilea rând, factorul beneficial response of PG to anti-neutrophilic genetic joacã un rol extrem de important: au fost agents, such as dapsone [8]. Second, the genetic raportate cazuri familiale de PG [9, 10]. Conform factor plays an extremely important role: familial literaturii de specialitate, sindromul PAPA se cases of PG have been reported [9, 10]. According manifestã prin: artritã piogenicã sterilã, PG ºi to the literature, PAPA syndrome is manifested acnee. Gena implicatã în dezvoltarea acestui by: pyogenic arthritis, PG and acne. The gene sindrom este localizatã pe cromozomul 15q, involved in the development of this syndrome is gena PSTPIP1/CD2BP1 care codeazã prolina/ located on chromosome 15q, the PSTPIP1 / serina/proteina 1 care interacþioneazã cu fosfatul CD2BP1 gene that encodes proline / serine / treoninei. Se considerã cã tocmai mutaþiile din threonine phosphatase-interacting protein. It is aceastã genã sunt cele care declanºeazã ºi considered that it is precisely the mutations in menþin procesul inflamator [11, 12]. Dupã cum this gene that trigger and maintain the am menþionat anterior, procesul inflamator, ºi inflammatory process [11, 12]. As mentioned anume asocierea cu boli inflamatorii sistemice above, the inflammatory process, namely the (boalã inflamatorie intestinalã, artritã) este association with systemic inflammatory diseases frecventã în cazul pacienþilor cu PG. Studiile (inflammatory bowel disease, arthritis) is demonstreazã creºterea producþiei de citokine common in patients with PG. Studies show (IL-8, IL-23). Ca ºi în cazul dapsonei, rãspunsul increased cytokine production (IL-8, IL-23). As terapeutic favorabil la terapii biologice (agenþi with dapsone, the favorable therapeutic response anti-TNF-α), susþine rolul TNF-α în etiologia bolii to biological therapies (anti-TNF-α agents) [8, 13, 14]. supports the role of TNF-α in the etiology of the Diagnosticul PG este în primul rând unul de disease [8, 13, 14]. excludere, realizându-se diagnosticul diferenþial The diagnosis of PG is primarily one of cu alte ulceraþii, întrucât aspectul clinic, exclusion, the differential diagnosis being made examinãrile paraclinice ºi analizele de laborator with other ulcerations, since the clinical aspect,

254 DermatoVenerol. (Buc.), 64(4): 253-259 nu sunt specifice acestei dermatoze. Tocmai din the paraclinical examinations and the laboratory aceastã cauzã, se recomandã efectuarea unei analyzes are not specific to this dermatosis. anamneze atente (fenomene de patergie în Precisely for this reason, it is recommended to istoricul pacientului), examen obiectiv general perform a careful history (patergia phenomena in (asocierea unor posibile patologii), biopsie the patient’s history), general objective exa- cutanatã ºi examen histopatologic [8]. mination (association of possible pathologies), skin biopsy and histopathological examination Prezentare de caz [8].

Prezentãm cazul unui pacient în vârstã de 65 Case presentation de ani, cunoscut cu multiple comorbiditãþi, care s-a prezentat în clinicã noastrã pentru o ulceraþie We present the case of a patient aged 65 years, ovalarã, dureroasã, localizatã la nivelul gambei known with multiple comorbidities, who stângi, în evoluþie de 4 luni. Tratamentul anterior presented in our clinic with an oval ulceration, prezentãrii în clinica noastrã, cu dermato- painful, located at the level of the left leg, corticoizi, nu a condus la ameliorarea leziunilor. evolving for 4 months. Treatment, prior to Din istoricul pacientului, reþinem: hipertensiune presentation in our clinic, with dermatocorticoids arterialã grad II ºi dislipidemie mixtã. Antece- did not lead to amelioration of the lesions. From dentele heredo-colaterale sunt nesemnificative. the patient’s history, we retain: hypertension La domiciliu, pacientul urmeazã tratament cu grade II and mixed dyslipidemia. Hereditary- statine ºi antihipertensiv. collateral history is insignificant. At home, the În cadrul examenului obiectiv general, am patient is receiving statin and antihypertensive observat obezitate grad I (IMC=31,5kg/m²). treatment. Examenul cutanat local a evidenþiat ulceraþie During the general objective examination, we ovalarã, cu detritusuri necrotice, uºoarã epite- observed obesity grade I (BMI = 31.5kg / m²). lizare centralã , margini violacee, deprimate, Local skin examination revealed oval neregulate, eritem perilezional, localizatã la ulceration, with necrotic debris, mild central nivelul gambei stângi. (Fig. 1) epithelialization, purple, depressed, irregular Analizele de laborator au fost în limite margins, perileional erythema, located at the normale, cu excepþia: dislipidemie mixtã level of the left leg. (Fig. 1) (nivelurile colesterolului seric ºi trigliceridelor Laboratory analyzes were within normal serice crescute), sindrom inflamator (VSH limits, except: mixed dyslipidemia (high serum crescut, fibrinogen crescut, leucocitoza, neutro- cholesterol and triglyceride levels), inflammatory filie). De asemenea, pentru a exclude alte cauze syndrome (increased VSH, increased fibrinogen, leukocytosis, neutrophilia). Also, to exclude other causes of ulceration, we performed neutrophil antibodies (to exclude granulomatous vasculitis), coagulation tests and antiphospholipid antibodies (to exclude an antiphospholipid syndrome), but all of these laboratory examinations were limited normal. At the same time, the patient did not have stigma due to venous insufficiency, and the arterial pulse was present, so we excluded venous, arterial or mixed ulcerations. We performed a bacteriological and mycological examination, with the antibiogram, respectively the antifungigram; bacterial / fungal Figura 1. Ulceraþie ovalarã, cu margini eritemato-violacee, colonies were not developed on the seeded elevate, localizatã la nivelul gambei stângi culture media, thus excluding infectious ulcers. Figure 1. Oval ulceration, with erythematous-purple Radiological examination and abdominal-pelvic margins, elevated, located at the level of the left leg ultrasound were within normal limits.

255 DermatoVenerol. (Buc.), 64(4): 253-259 ale ulceraþiei, am efectuat anticorpi anticito- Considering the patient’s history, clinical plasma neutrofile (pentru a exclude o vasculitã appearance, evolution and laboratory analysis, granulomatoasã), teste de coagulare ºi anticorpi the clinical suspicion of PG was raised. Skin antifosfolipidici (pentru a exclude un sindrom biopsy was collected and the histopathological antifosfolipidic), însã toate aceste examinãri de examination revealed: irregular epidermis, with laborator au fost în limite normale. Totodatã, infundibular invagination, epithelial hyperplasia, pacientul nu prezenta stigmate de insuficienþã suppurative-looking neutrophilic infiltrates, venoasã cronicã, iar pulsul arterial era prezent, fibrosis, granulation tissue; PAS color did not deci am exclus ulceraþiile venoase, arte- reveal fungal elements. (Fig. 2, Fig. 3). The riale sau mixte. Am efectuat examen bacterio- histopathological examination established the logic ºi micologic, cu antibiogramã, respectiv diagnosis of PG. antifungigramã; pe mediile de culturã însã- Corroborating the anamnestic, clinical and mânþate nu s-au dezvoltat colonii bacte- paraclinical data, the diagnosis of PG was riene/fungice, excluzând astfel ºi ulceraþiile de established. naturã infecþioasã. Examenul radiologic ºi To exclude inflammatory bowel disease, a ecografia abdomino-pelvinã au fost în limite gastroenterological consultation was performed, normale. and colonoscopy revealed no pathological Având în vedere istoricul pacientului, elements. aspectul clinic, evoluþia ºi analize de laborator, s- The general condition of the patient and the a ridicat suspiciunea clinicã de PG. S-a recoltat severity of the lesion were evaluated, and the biopsie cutanatã cu examen histopatologic, care a following therapeutic objectives were proposed: relevat: epiderm neregulat, cu invaginare reducing the aberrant inflammatory response to infundibularã, hiperplazie epitelialã, infiltrate promote ulcer healing (systemic / local control of neutrofilice cu aspect supurativ, fibrozã , þesut de the inflammatory process); minimizing the granulaþie; coloraþia PAS nu a evidenþiat adverse effects of drugs, but also developing a elemente micotice. (Fig. 2, Fig. 3). Examenul long-term therapeutic strategy. Thus, during the histopatologic a stabilit diagnosticul de PG. hospitalization, systemic cortisone treatment Coroborând datele anamnestice, clinice ºi with prednison 0.5 mg / kg body was initiated, paraclinice s-a stabilit diagnosticul de PG. slowly decreasing, associated with gastric protec- Pentru a exclude o boalã inflamatorie tion, proton pump inhibitor (pantoprazole intestinalã, s-a efectuat consult gastroenterologic, 20 mg/day). Given the normal level of serum iar colonoscopia nu a relevat elemente patologice. reticulocytes and the normal activity of glucose-6 S-au evaluat starea generalã a pacientului ºi phosphate-dehydrogenase, dapsone 50 mg/day severitatea leziunii, ºi au fost propuse urmã- was associated. Locally, the lesion was

Figura 3. Epiderm neregulat, cu invaginare infundibularã; Figura 2. Ameliorarea semnificativã a aspectului leziunii hiperplazie epitelialã Figure 2. Significant improvement of the appearance of the Figure 3. Irregular epidermis, with infundibular lesion invagination; epithelial hyperplasia

256 DermatoVenerol. (Buc.), 64(4): 253-259 toarele obiective terapeutice: reducerea rãspun- sului inflamator aberant pentru a favoriza vindecarea ulcerului (controlul sistemic/local al procesului inflamator); minimizarea efectelor adverse ale medicamentelor , dar ºi elaborarea unei strategii terapeutice pe termen lung. Astfel, pe durata spitalizãrii, s-a iniþiat tratament sistemic cortizonic cu prednison 0,5 mg/kg corp, cu scãdere lentã, asociat cu protecþie gastricã, inhibitor de pompã de protoni (pantoprazol 20 mg/zi). Având în vedere nivelul normal al reticulocitelor serice ºi activitatea normalã a glucozo-6 fosfat-dehidrogenazei, s-a asociat dapsonã 50 mg/zi. Local, leziunea a fost dezinfectatã cu acid boric soluþie 2%, urmatã de Figura 4. Infiltrate neutrofilice cu aspect supurativ; fibrozã aplicarea alternativã a preparatelor: sulfadiazinã Figure 4. Suppurative-looking neutrophilic infiltrates; de argint 1%, acid hialuronic 0,2%. Terapia a fost fibrosis bine toleratã, iar tabloul clinic a fost ameliorat semnificativ. disinfected with boric acid 2% solution, followed Pacientul s-a prezentat la control, la o luna de by alternative application of the preparations: la externare. Leziunea era amelioratã semnifi- silver sulfadiazine 1%, hyaluronic acid 0.2%. The cativ, iar pacientul a negat simptomatologia therapy was well tolerated and the clinical (Fig. 2). Recomandarea a fost de continuare a picture was significantly improved. corticoterapiei, în scãdere conform schemei The patient presented to the control one iniþiale, ºi a dapsonei. month after discharge. The lesion was significantly improved and the patient denied the Discuþii symptoms (Fig. 2). The recommendation was to continue corticosteroids, decreasing according to În ceea ce priveºte tratamentul PG, acesta the initial scheme, and dapsone. depinde de numãrul ºi severitatea leziunilor. În cazurile uºoare de boalã, se poate opta pentru: Discussions dermatocorticoizi sau corticosterozi administraþi intralezional, inhibitori topici de calcineurinã [15- Regarding the treatment of PG, it depends on 17]. În schimb, în formele severe, cu leziuni the number and severity of the lesions. In mild severe ºi extinse, este necesarã terapie sistemicã: cases, dermatocorticoids or corticosteroids glucocorticoizi, ciclosporinã, azatioprinã, meto- administered intralesionally, topical calcineurin trexat, infliximab, dapsonã sau minociclinã [8, 16, inhibitors [15-17] can be chosen. In contrast, in 18-20]. severe forms, with severe and extensive lesions, Diagnosticul PG reprezintã o provocare, systemic therapy is required: glucocorticoids, deoarece, aceastã dermatozã poate mima o serie cyclosporine, azathioprine, methotrexate, inflix- de alte patologii. Nu existã analize de laborator, imab, dapsone or minocycline [8, 16, 18-20]. elemente histopatologice specifice pentru PG, de PG diagnosis is a challenge, because this aceea diagnosticul este unul de excludere. dermatosis can mimic a number of other Diferenþierea de ulcerele gambiere de etiologie pathologies. There are no laboratory tests, vascularã primeazã: ulcer venos, ulcer arterial, specific histopathological elements for PG, so the ulcer mixt; vasculite: poliarteritã nodoasã diagnosis is one of exclusion. Differentiation of cutanatã, poliangeitã microscopicã, vasculite the foot ulcers of vascular etiology primates: granulomatoase. Totodatã, PG poate mima ulcere venous ulcer, arterial ulcer, mixed ulcer; vascu- gambiere de etiologie infecþioasã: infecþii litis: cutaneous nodular polyteritis, microscopic bacteriene (ectima gangrenosum), infecþii polyangiitis, granulomatous vasculitis. At the

257 micobacteriene, botriomicozã; infecþii parazitare: same time, PG can mimic leg ulcers of infectious leishmaniasis. Nu în ultimul rând, trebuie excluse etiology: bacterial infections (ectima gangreno- ºi ulcere gambiere din cadrul neoplaziilor sum), mycobacterial infections, botriomycosis; cutanate: CSC, CBC, limfom cutanat cu celule parasitic infections: leishmaniasis. Last but not T/B; fasciita necrotizantã reprezintã un alt least, limb ulcers should be excluded from the diagnostic diferenþial [2, 21, 22]. skin neoplasms: CSC, CBC, cutaneous T / B cell PG se poate asocia cu o serie de alte patologii. lymphoma; necrotizing fasciitis is another Tocmai din aceastã cauzã, este importantã differential diagnosis [2, 21, 22]. evaluarea completã, interdisciplinarã a pacien- PG can be associated with a number of other tului: anamnezã, examen clinic, biopsie cutanatã pathologies. Precisely for this reason, it is (þesut suficient în profunzime, pentru coloraþii important the complete, interdisciplinary eva- speciale, culturi), evaluare gastroentero-logicã luation of the patient: anamnesis, clinical exa- (colonoscopie, biopsie, radiografie, funcþia mination, skin biopsy (tissue sufficiently deep, hepaticã), evaluare hematologicã (hemoleuco- for special stains, cultures), gastroenterological evaluation (colonoscopy, biopsy, radiography, gramã, biopsie medularã în cazuri selecþionate), liver function), hematological evaluation ( teste serologice (electroforeza proteinelor serice, hemolithogram, bone marrow biopsy in selected ANA, ANCA), radiografie toracicã [2]. Conform cases), serological tests (serum protein electro- unui studiu recent, cele mai frecvente patologii phoresis, ANA, ANCA), chest radiography [2]. care se asociazã cu PG sunt: bolile inflamatorii According to a recent study, the most common intestinale (boalã Crohn, rectocolita ulcero- pathologies that are associated with PG are: hemoragicã), artritã inflamatorie, neoplasme, inflammatory bowel disease (Crohn’s disease, leucemii [23]. De asemenea, se pare cã pacienþii ulcer-hemorrhagic rectocolitis), inflammatory peste 65 de ani, aºa cum este ºi cazul pacientului arthritis, neoplasms, leukemias [23]. It also seems nostru, au un risc mai mare de a asocia artritã that patients over 65 years , as is the case with our inflamatorie, spondilitã anchilozantã, neoplasme, patient, they have a higher risk of associating comparativ cu pacienþii tineri, care sunt dia- inflammatory arthritis, ankylosing spondylitis, gnosticaþi frecvent cu boalã inflamatorie intesti- neoplasms, compared with young patients, who nalã [8, 24]. are frequently diagnosed with inflammatory bowel disease [8, 24]. Concluzii În concluzie, în faþa unui pacient cu ulceraþie Conclusions gambierã, trebuie sã luãm în considerare ºi In conclusion, in front of a patient with limb diagnosticul de PG, deoarece, aceastã patologie ulceration, we must also consider the diagnosis este subdiagnosticatã într-o treime din cazuri. of PG, because, this pathology is underdiagnosed Totodatã, existã posibilitatea asocierii unei in one third of the cases. At the same time, there patologii. De aceea, este necesarã, de multe ori, is the possibility to associate a pathology. abordarea interdisciplinarã a pacientului cu PG, Therefore, it is often necessary to interdisci- în vederea stabilirii diagnosticului ºi tratamen- plinary approach of the patient with PG, in order tului comorbiditãþilor. to establish the diagnosis and treatment of Având în vedere evoluþia cronicã ºi refractarã comorbidities. a PG, urmãrirea periodicã ºi atentã a acestor Considering the chronic and refractory pacienþi reprezintã unul dintre obiectivele evolution of PG, the periodic and careful follow- principale ale echipei medicale. up is one of the main goals of the medical team.

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Conflict de interese Conflict of interest NEDECLARATE NONE DECLARED

Adresa de corespondenþã: Mihai Cristian Dumitraºcu Splaiul Independentei, nr. 169, Bucharest, Romania E-mail: [email protected]

Correspondance address: Mihai Cristian Dumitraºcu Splaiul Independentei, no 169, Bucharest, Romania E-mail: [email protected]

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