Pyoderma gangrenosum: a review with special emphasis on Latin America literature^☆,☆☆

Abstract

Pyoderma gangrenosum is a neutrophilic dermatosis characterized by chronic ulcers due to an abnormal immune response. Despite the existence of diagnostic criteria, there is no gold standard for diagnosis or treatment. In Latin America, recognizing and treating pyoderma gangrenosum is even more challenging since skin and soft tissue bacterial and non-bacterial infections are common mimickers. Therefore, this review aims to characterize reported cases of pyoderma gangrenosum in this region in order to assist in the assessment and management of this condition. Brazil, Mexico, Argentina, and Chile are the countries in Latin America that have reported the largest cohort of patients with this disease. The most frequent clinical presentation is the ulcerative form and the most frequently associated conditions are inflammatory bowel diseases, inflammatory arthropaties, and hematologic malignancies. The most common treatment modalities include systemic corticosteroids and cyclosporine. Other reported treatments are methotrexate, dapsone, and cyclophosphamide. Finally, the use of biological therapy is still limited in this region.

KEYWORDS
Inflammatory bowel diseases; Latin America; Pyoderma gangrenosum; Skin ulcer

Introduction

Pyoderma gangrenosum (PG) is an inflammatory disease, most commonly characterized by painful cutaneous ulcers with irregular, violaceous borders located on the lower limbs. It is frequently associated with inflammatory bowel diseases (IBD), inflammatory arthropathies, and hematologic malignancies.^1,2 The worldwide incidence is estimated to be around two to three cases per 100,000 habitants per year,³ but this might be underestimated due to lack of a diagnostic gold standard. Pathogenesis is not well understood, but studies have suggested an abnormal immune response in patients with genetic predisposition, hence PG is classified within the spectrum of neutrophilic and auto-inflammatory syndromes.^4,5

Other pathologic conditions in the clinical differential diagnosis - including infections, vasculitis/vasculopathy, and neoplastic disorders - should be ruled out with the assistance of laboratory testing, as well as histopathologic and microbiological studies.⁶ First-line treatment includes systemic corticosteroids and cyclosporine. Second-line and third-line therapeutic options comprise immunosuppressive, immunomodulatory, and biologic agents.⁷ The present study aimed to review the literature in order to recommend the best approach when facing patients with PG in Latin America (LA).

Methods

A systematic review was performed of the case-reports and case-series studies of PG from countries in LA published in MEDLINE (PubMed) and LILACS from inception to October 2018. The search strategies are available in Table 1.

Table 1
Search strategy

Database	PubMed: (https://www.ncbi.nlm.nih.gov/pubmed/) Date: October 23rd, 2018.		Results
Strategy	#1	Search (chile OR brazil OR peru OR brasil OR colombia OR mexico OR ecuador OR venezuela OR uruguay OR cuba OR puerto rico OR costa rica OR latin america OR argentina)	702779
	#2	Search Pyoderma Gangrenosum[tiab]	2853
	#3	Search (#1 AND #2)	61
Database	LILACS (http://pesquisa.bvsalud.org/portal/) Date: October 23rd, 2018.		Results
Strategy	#1	(tw:(pyoderma gangrenosum)) AND (instance:"regional") AND (db:("LILACS"))	141

Epidemiology

PG is considered a rare disease of with estimated prevalence of two to three cases per 100,000 people and an adjusted incidence rate of 0.63 per 100,000 person-years. Risk of death is three times higher than general controls.⁸ It tends to have a slight predominance for females.^8,9 Differences in comorbid conditions and differential diagnoses to consider vary significantly depending on geographic regions and local disease prevalence. Reports from LA are scarce and mostly consist of case reports or case series.¹⁰

Pathogenesis

Neutrophilic dysfunction has been implicated in the pathogenesis of PG.⁹ In addition, pathergy, which is defined as a nonspecific increase of neutrophil activity reaction, is present in other neutrophilic dermatoses (e.g., Behcet's disease and Sweet's syndrome) but it has been described in at least 30% of patients.^11,12 Neutrophilic dysfunction shares the same pro-inflammatory effectors found in auto-inflammatory syndromes. Both are characterized by an over-activated innate immune system leading to the increased assembly of inflammasomes.² Inflammasomes are responsible for the activation of the caspase 1, a protease that cleaves the pro-interleukin IL-1β into functionally active IL-1β. The overproduction of IL-1β triggers the release of several pro-inflammatory cytokines and chemokines, inducing the recruitment and activation of neutrophils and subsequent neutrophil-mediated inflammation.⁵ IL-17 appears to be crucial in the recruitment of neutrophils in auto-inflammation and acts synergistically with tumor necrosis factor (TNF).^13,14 Finally, IL-1β, IL-17, and TNF-α activate and increase the production of matrix metalloproteinases (MMPs), which are overexpressed in the inflammatory infiltrate of PG, causing an inflammatory insult and the consequent destruction of the involved tissue.^2,5

In conclusion, PG is the result of innate immune system over-activation via inflammasomes, coupled with the activation of the adaptive immune system, triggered by an external insult (e.g., pathergy) and/or a possible internal trigger in a genetically predisposed individual.¹⁵

Histopathologic findings

PG has non-specific histopathologic findings. Presence of perifollicular inflammation, edema, and neutrophilic inflammation are the initial features seen in untreated and expanding PG lesions. Polymorphonuclear leukocyte infiltration can lead to abscess formation and necrosis of the tissue with mixed inflammatory infiltrate. Additional findings may include giant cells, secondary thrombosis of small- and medium-sized vessels, and hemorrhage. Secondary leukocytoclastic vasculitis is present in around 40% of cases. Direct immunofluorescence also yields non-specific findings such as deposition of IgM, C3, and fibrin in the papillary and reticular dermal vessels. Due to the non-specific findings, skin biopsies are more useful to rule out other causes of ulceration that may present with similar clinical findings, such as infections, vasculitis, vasculopathies, or malignancies.^12,16-18

Clinical features

PG is classified into four clinical subtypes: classic (ulcerative) (Figs. 1 and 2), bullous, pustular, and vegetative (Figs. 3 and 4). Ulcerative or classic PG often starts as an inflammatory erythematous violaceous pustule of a few millimeters in size, which enlarges forming an ulceration that gradually increases both in size and depth. The ulcer discharges a purulent and hemorrhagic exudate, easily detectable by applying pressure on its border. The purulent and malodorous exudate can be attributable to a bacterial colonization or to an actual superinfection. The border is well demarcated, elevated, and slowly progressive, with a violaceous color. An erythematous, edematous, and infiltrated halo extends up to 2cm from the border of the ulcer.^2,5,19 The lesion is usually solitary, but multiple ulcers can occur; they are typically painful, ranging from a few millimeters to 30cm or more, localized mostly in extensor surface of the legs, but they can affect any anatomic site. They may be deep enough to expose tendons, fasciae, and muscles.^5,20 Lesions start in healthy skin and may be provoked by trauma (pathergy). Therefore, postoperative PG (Figs. 5 and 6), peristomal PG, and worsening of lesions after sharp or surgical debridement frequently occur.²¹ The ulcer can propagate rapidly, showing a serpentine configuration.^3,19 PG has been classically associated with inflammatory colitis (IBD and diverticulitis), hematological malignancies (myelodysplastic syndrome, monoclonal gammopathy, chronic myeloid leukemia, etc.), autoimmune inflammatory disease (seronegative polyarthritis, rheumatoid arthritis), and solid tumors (prostate and colon adenocarcinoma).^4,8 Finally, sterile neutrophilic infiltrates have been found to affect internal organs supporting the concept of PG being a systemic disease.²²

Figure 1
Classic or ulcerative pyoderma gangrenosum.

Figure 2
Classic or ulcerative pyoderma gangrenosum.

Figure 3
Vegetative or verrucous pyoderma gangrenosum in a patient with Behcet's disease.

Figure 4
Vegetative or verrucous pyoderma gangrenosum in a patient with Behcet's disease.

Figure 5
Pyoderma gangrenosum after abdominoplasty.

Figure 6
Multiple pyoderma gangrenosum ulcers at the sites of sclerotherapy injections.

Results

In LA, 118 studies were found from 1981 to 2018, with 232 cases of PG. Brazil was the country with the largest report of case-series, with 96 (41.4%) cases of PG. The next highest total was from Argentina, which has 69 (29.7%) reported cases of PG, followed by Chile and Mexico, which have a similar number of reported cases, with 21 (9.1%) and 17 (7.3%), respectively. In addition, the results of the systematic review show that ulcerative PG was the most frequent type of PG reported, and that the others had similar prevalence. Bullous, vegetative (granulomatous), and pustular PG were reported in nine (3.9%), eight (3.5%), and five (2.1%) cases. The rest of PG cases did not report the subtype (Table 2).

Table 2
Prevalence of Latin American pyoderma gangrenosum cases reported in the literature

	Total (n)	%	Ulcerative	Granulomatous	Pustular	Bullous
Brazil	96	41.38	76	3	1	3
Argentina	69	29.74	57	2	2	3
Bolivia	1	0.43	1	-	-	-
Chile	21	9.05	20	-	1	-
Colombia	16	6.90	14	-	-	-
Costa Rica	1	0.43	1	-	-	-
Cuba	2	0.86	1	1	-	-
Mexico	17	7.33	5	1	-	-
Paraguay	1	0.43	-	-	-	1
Peru	5	2.16	2	-	1	2
Venezuela	3	1.29	2	1	-	-
TOTAL	232	100	179	8	5	9
%	100	-	77.16	3.45	2.16	3.88

In addition, the systematic review found that there was a high prevalence of PG cases associated with comorbidities. Overall, 149 (64.5%) and 37 (16%) of the patients included in the analysis had PG associated to a condition or surgery, respectively. In the rest of PG patients, no other conditions or disease associations were reported. IBD was the most frequent conditions associated (53/149, 35.6%), then ulcerative colitis (UC) (32/149, 21.5%) and Crohn's disease (10/149, 6.7%). Other inflammatory diseases were also frequent (54/149, 36.2%); among them, rheumatoid arthritis (RA) (17/149, 11.4%), antiphospholipid syndrome (APS) (15/149, 10.1%), systemic erythematous lupus (4/149, 2.7%), and Takayasu's arteritis (4/149, 2.7%) were reported. Several malignances were reported in association with PG (19/149, 12.8%), in particular hematologic malignancies (14/149, 9.4%) and solid-organ malignancies (5/149, 3.4%). Other conditions were also reported (23/149, 15.4%), including the presence of pulmonary nodules (5/149, 3.4%) of unknown etiology. In regard to surgical procedures, reduction mammoplasty (9/149, 6.0%), laparotomy (6/149, 4.0%), and skin grafting (4/149, 2.7%) were the more frequent triggers of PG. It is important to mention that due to the limited information in the reports and the scarce number of PG cases, only descriptive statistical analysis was performed (Table 3).

Table 3
Prevalence of the conditions associated with pyoderma gangrenosum reported in the Latin American literature

Condition	n	%
IBD
No specified	11	7.4
UC	32	21.5
CD	10	6.7
Subtotal	53	35.6
Malignancy
Hematologic malignancy	14	9.4
Solid-organ malignancy	5	3.4
Subtotal	19	12.8
Inflammatory
Antiphospholipid syndrome	15	10.1
Rheumatoid arthritis	17	11.4
Lupus erythematosus	4	2.7
Takayasu's arteritis	4	2.7
Other	14	9.4
Subtotal	54	36.2
Other conditions
Pulmonary nodules	5	3.4
Cocaine consumption	2	1.3
Diverticular disease	2	1.3
Pregnancy	2	1.3
Other	12	8.1
Subtotal	23	15.4
Total	149	64.5a
Secondary to surgery
Reduction mammoplasty	9	22.5
Laparotomy	6	15.0
Abdominoplasty	4	10.0
Skin grafts	4	10.0
Total surgery	37	16.0b

• ^a
  Total of patients with comorbidities/total of patients with PG × 100.
• ^b
  Total of patients with PG secondary to surgery/total of patients with PG × 100.
  IBD, inflammatory bowel disease; UC, ulcerative colitis; CD, Crohn's disease.

Thus, the systematic review of PG case-series from LA helped to elucidate the main associated conditions. In Table 4, all the studies where PG was reported to be associated with clinical or surgical conditions are listed.

Table 4
Conditions associated with pyoderma gangrenosum (PG) reported in the Latin American literature

n	Author	Year	Country	Number of patients	Clinical type	Associated disease	Secondary to surgery or drugs
1	Corti et al.59	1981	Argentina	1	Ulcerative	Crohn's disease	No
2	Della-Giovanna et al.60	1991	Brazil	4	Ulcerative	Two patients with ulcerative colitis, one with pregnancy	No
3	Moreno et al.61	1994	Argentina	2	Ulcerative	Two patients with rheumatoid arthritis	No
4	Vignale et al.62	1996	Argentina	4	Ulcerative	Three patients with Crohn's disease, two with seronegative arthritis, and one with ulcerative colitis	No
5	Saraceno et al.63	2002	Argentina	6	Ulcerative	One patient with myelodysplastic syndrome, one with rheumatoid arthritis, one with hemophagocytic syndrome and hepatitis C	No
6	Plaza64	2004	Argentina	1	Ulcerative	Rheumatoid arthritis	No
7	Simon et al.65	2005	Argentina	1	Ulcerative	Ulcerative colitis	Peristomal after total colectomy
8	Vazquez et al.66	2009	Argentina	1	Ulcerative	Chronic osteomyelitis	Knee prosthesis replacement
9	Sommerfleck et al.67	2014	Argentina	1	Not reported	Ulcerative colitis	No
10	Achenbach et al.68	2014	Argentina	1	Ulcerative	Crohn's disease	Sulfasalazine
11	Curmona et al.69	2014	Argentina	2	Ulcerative	One patient with metastatic ovarian cancer	Abdominal tumor resection
12	Pereyra et al.70	2014	Argentina	1	Ulcerative	Renal transplant	No
13	Fassi et al.71	2015	Argentina	1	Ulcerative	Rheumatoid arthritis and ulcerative colitis	No
14	Silva-Feistner et al.72	2015	Argentina	1	Ulcerative	None	Cesarean
15	Galimberti et al.73	2016	Argentina	1	Ulcerative	Ulcerative colitis	No
16	Vacas et al.1	2017	Argentina	27	Ulcerative	Ten patients with IBD, seven with hematologic malignances, five with rheumatoid or seronegative arthritis, and one with cocaine consumption	No
				2	Bullous
				2	Pustular
17	Vega et al.74	2018	Argentina	1	Ulcerative	Retroperitoneal fibrosis	Exploratory mid-laparotomy
18	Vacas et al.75	2018	Argentina	1	Bullous	Acute and chronic myeloid leukemia	No
19	Pires et al.76	1987	Brazil	1	Ulcerative	Chronic hepatitis	No
20	Lana et al.77	1990	Brazil	1	Ulcerative	Multiple sclerosis	No
21	Pessato et al.78	1996	Brazil	9	Not reported	Five patients with comorbidities	No
22	Souza et al.79	1999	Brazil	11	Predominantly ulcerative	One patient with ulcerative colitis, one with rheumatoid arthritis, one with Grave's disease, one with diabetes mellitus	No
23	Cabral et al.80	2004	Brazil	4	Ulcerative	Four patients with ulcerative colitis, one with additional primary sclerosing cholangitis, one with seronegative arthritis	No
24	Martinez et al.81	2005	Brazil	1	Ulcerative	Ulcerative colitis	No
25	Costa et al.82	2005	Brazil	1	Ulcerative	Rheumatoid Arthritis	No
26	Fraga et al.83	2006	Brazil	1	Superficial granulomatous	Psoriasis	No
27	Coltro et al.84	2006	Brazil	1	Ulcerative in donor site	None	Skin graft for varicose ulcers
28	Batista et al.85	2006	Brazil	1	Bullous	Myelodysplastic syndrome	No
29	Meyer et al.86	2006	Brazil	1	Ulcerative	Crohn's disease	Infraumbilical median laparotomy
30	Franca et al.87	2006	Brazil	1	Ulcerative	Gastric adenocarcinoma	No
31	Burkieviecz et al.88	2007	Brazil	1	Ulcerative	Systemic lupus erythematosus/antiphospholipid syndrome	No
32	Barbato et al.89	2008	Brazil	13	Ulcerative	Two patients with Crohn's disease, two with diabetes, two with collagenosis, one with leukemia.	No
				2	Superficial granulomatous
				1	Bullous
33	Tinoco et al.90	2008	Brazil	1	Ulcerative	Acne	Isotretinoin
34	Dornelas et al.91	2008	Brazil	1	Ulcerative	None	Reduction mammoplasty and abdominoplasty
35	Bonamigo et al.92	2008	Brazil	1	Ulcerative	None	Breast implant with silicone prosthesis and facial surgery
36	Coelho et al.93	2009	Brazil	2	Ulcerative	Inflammatory arthritis/splenomegaly	No
37	Berbert et al.94	2009	Brazil	1	Superficial granulomatous	None	Donor site after skin grafting for burns.
38	Furtado et al.95	2010	Brazil	1	Ulcerative	None	Reduction mammoplasty and abdominoplasty
39	Avelar et al.96	2011	Brazil	1	Ulcerative	Breast cancer	Breast quadrantectomy and radiotherapy
40	Fonseca et al.97	2011	Brazil	1	Bullous	Ulcerative colitis	No
41	Grillo et al.98	2012	Brazil	1	Ulcerative	None	Reduction mammoplasty
42	Maia et al.99	2012	Brazil	1	Ulcerative	Cocaine use	No
43	Cunha et al.100	2012	Brazil	1	Ulcerative	None	Laparoscopy
44	Bittencourt et al.101	2012	Brazil	1	Ulcerative	Pulmonary nodules	No
45	Andrade et al.102	2012	Brazil	1	Ulcerative	Inflammatory bowel disease	No
46	Carvalho et al.103	2013	Brazil	1	Ulcerative	Splenic and renal impairment	No
47	Kruger et al.104	2013	Brazil	1	Ulcerative	Ulcerative colitis	No
48	Soares et al.105	2013	Brazil	1	Ulcerative	None	Reduction mammoplasty and abdominoplasty
49	Beber et al.106	2014	Brazil	1	Ulcerative	Rheumatoid arthritis	No
50	Marchiori et al.107	2014	Brazil	1	Ulcerative	Pulmonary nodules	No
51	Rosseto et al.108	2015	Brazil	1	Ulcerative	None	Abdominoplasty
52	de Souza et al.109	2015	Brazil	1	Ulcerative	Myelodysplastic syndrome	No
53	Sempertegui et al.110	2015	Brazil	1	Ulcerative	Breast cancer	Breast quadrantectomy and radiotherapy
54	Soncini et al.111	2016	Brazil	1	Ulcerative	None	Augmentation mastopexy
55	Dantas et al.55	2017	Brazil	1	Ulcerative	Autoimmune hepatitis	No
56	Freitas et al.112	2017	Brazil	1	Ulcerative	Iliac vein compression syndrome	No
57	Gabe et al.113	2018	Brazil	1	Ulcerative	Pyogenic arthritis	No
58	Bittencourt et al.114	2018	Brazil	1	Ulcerative	Multiple myeloma	Autologous stem cell transplantation and then laparoscopic cholecystectomy
59	Clemente et al.115	2018	Brazil	2	Ulcerative	Two patients with atypical Takayasu's arteritis	No
60	Perez et al.116	2001	Chile	2	Ulcerative	None	Cesarean
61	Lopez de Maturana et al.54	2001	Chile	3	Ulcerative	Two patients with diverticular disease, one patient with Crohn's disease, one patient with rheumatoid arthritis	No
				1	Pustular
62	Hevia et al.117	2004	Chile	1	Ulcerative	Ulcerative colitis	Peristomal after total colectomy
63	Eulufi et al.118	2006	Chile	3	Ulcerative	None	Two patients after skin graft, one patient after reduction mammoplasty
64	Calderon et al.119	2011	Chile	1	Ulcerative	Ulcerative colitis	No
65	Fernandez-Castillo et al.120	2012	Chile	1	Ulcerative	Wegener granulomatosis/chronic kidney disease	Arteriovenous fistula
66	Gosch et al.121	2012	Chile	1	Ulcerative	None	Reduction mammoplasty
67	Melo and Fernandez 122	2013	Chile	1	Ulcerative	None	Foot and ankle surgery
68	Calderon et al.123	2013	Chile	3	Ulcerative	None	After reduction mammoplasty
69	Bannura et al.124	2014	Chile	1	Ulcerative	Ulcerative colitis	Laparotomy/ileostomy
70	Erlij et al.125	2018	Chile	1	Ulcerative	Erythema induratum and large B-cell non-Hodgkin's lymphoma	No
71	Penaloza et al.126	1988	Colombia	1	Ulcerative	Ulcerative colitis	No
72	Restrepo et al.127	2006	Colombia	2	Ulcerative	Two patients with ulcerative colitis	No
73	Jaime-Lopez et al.128	2009	Colombia	1	Ulcerative	Ulcerative colitis	Infliximab
74	Cañas et al.129	2010	Colombia	7	Ulcerative	Seven patients with antiphospholipid syndrome	No
75	Cadavid et al.130	2012	Colombia	1	Ulcerative	Ulcerative colitis	None
76	Severiche et al.131	2014	Colombia	1	Ulcerative	Breast phyllodes tumor (paraneoplastic)	No
77	Acon-Ramirez et al.132	2017	Costa Rica	1	Ulcerative	Rheumatoid arthritis	No
78	Moreira-Preciado et al.133	2001	Cuba	1	Superficial granulomatous	Renal failure	No
79	Hernandez-Urra et al.134	2010	Cuba	1	Ulcerative	Ulcerative colitis	No
80	Zonana-Nacach et al.135	1994	Mexico	2	Not reported	Two patients with rheumatoid arthritis	No
81	Reynoso-von Dratein et al.58	1997	Mexico	9	Not reported	Three patients with rheumatoid arthritis and two patients with systemic lupus erythematosus	No
82	Chacek et al.136	1998	Mexico	1	Ulcerative	Inferior cava vein syndrome due to thrombosis and antiphospholipid syndrome	No
83	Muñiz-Gonzalez et al.137	2007	Mexico	1	Ulcerative	Ulcerative colitis, diverticular disease	No
84	Contreras-Ruiz et al.138	2008	Mexico	1	Ulcerative	Rheumatoid arthritis	No
85	Barrera-Vargas et al.139	2015	Mexico	2	Ulcerative	Two patients with pulmonary nodules and Takayasu's arteritis	No
86	Contreras-Verduzco et al.140	2018	Mexico	1	Superficial granulomatous	Pulmonary nodules and nodular scleritis	No
87	Real-Delor et al.141	2011	Paraguay	1	Bullous	Ulcerative colitis	No
88	Dominguez et al.142	2009	Peru	1	Pustular	Ulcerative colitis	No
89	Carrillo-Nanez et al.143	2014	Peru	1	Bullous	Ulcerative colitis	No
90	Deza-Araujo et al.144	2014	Peru	1	Ulcerative	Systemic lupus erythematosus	No
91	Fermin et al.145	1989	Venezuela	2	Ulcerative	One patient with ulcerative colitis	No
92	Valecillos et al.146	1998	Venezuela	1	Superficial granulomatous	Pregnancy	No

Infectious PG-mimickers to be considered in LA and/or from LA

In general, ulcerative entities resembling PG fall into one of six disease categories: (a) primary deep cutaneous infections (e.g., sporotrichosis, cutaneous tuberculosis, leishmaniasis, etc.) (Figs. 7 and 8); (b) vascular occlusive or venous disease (e.g., APS, venous stasis ulceration, etc.); (c) vasculitis (e.g., Wegener's granulomatosis, polyarteritis nodosa, etc.); (d) malignant processes involving the skin (e.g., angiocentric T-cell lymphoma, anaplastic large-cell T-cell lymphoma, etc.); (e) drug-induced or exogenous tissue injury (factitial disorder, loxoscelism, etc.); and (f) other inflammatory disorders (cutaneous Crohn's disease, ulcerative necrobiosis lipoidica, etc.). However, in LA, the most common differential diagnoses include deep cutaneous infections, vascular occlusive disease, and metabolic disorders.²³ It is crucial for the management of PG in this region to rule out infection, as immunosuppressive medications used to treat PG may be contraindicated in these patients.²⁴ Depending on the specific region, infectious ulcers can be caused by Leishmania parasites, atypical Mycobacterium species, deep fungal infections (sporotrichosis, chromoblastomycosis and, mycetoma), myasis, and cutaneous amebiasis.³

Figure 7
Cutaneous leishmaniasis lesions can mimic classic pyoderma gangrenosum lesions.

Figure 8
Cutaneous leishmaniasis lesions can mimic classic pyoderma gangrenosum lesions.

Cutaneous leishmaniasis (CL) is a common skin disease in developing countries, such as Brazil and Peru.²⁵ Lesions may start as a papule or a nodule that develops into an ulcer with or without a scar (Figs. 7 and 8). They are usually painless, but when painful, secondary infection is generally present. The initial diagnosis of CL is based on the clinical presentation and the patient's history of visiting an endemic area. Diagnostic work up includes multiple components in order to provide the highest likelihood of confirmation. Biopsy specimens should be obtained for impression smears, histopathologic slides with hematoxylin and eosin, Giemsa stain and special stains for other microbes, culture, and polymerase chain reaction (PCR) analysis if diagnosis is challenging.²⁶

Ulcerating cutaneous lesions can be caused by mycobacterial infections including Mycobacterium ulcerans, M. marinum, and M. tuberculosis. M. ulcerans is the third most common agent of mycobacterial disease (after tuberculosis and leprosy) and the most common mycobacterium causing cutaneous ulceration.²⁷ Buruli ulcers, which are caused by M. ulcerans, are endemic in foci in West Africa and have been reported as an imported disease in countries of LA such as Peru, Brazil, Guiana, and Mexico.²⁸ Microscopy and PCR are used for routine diagnosis, while culture is less useful given time requirements and lack of species specificity.²⁹ Treatment is generally surgical, although a combination of rifampicin and streptomycin may be effective in the early stage.

Cutaneous tuberculosis (CTB) is an infection caused by M. tuberculosis complex, M. bovis, and in immunocompromised hosts, by bacillus Calmette-Guérin (BCG) vaccination.³⁰ An increase in its incidence has been described in several countries of LA in recent years, especially in urban centers and regions with high prevalence of human immunodeficiency virus (HIV) infection. Lupus vulgaris is a form of CTB that initiates as smoldering papular or tuberous lesions and progresses to plaques with necrosis and ulceration, with or without cicatricial deformities and mutilations.³¹ Diagnostic approaches to CTB include skin biopsy with acid fast bacilli stain and culture, as well as PCR amplification testing of biopsy tissue.³²

Sporotrichosis is one of the most common deep mycoses; it may be accompanied by ulceration.³³ Most cases of sporotrichosis are currently being reported in South and Central America, with recent outbreaks transmitted by cats.³⁴ The primary cutaneous lesions may appear as papular, nodular, or pustular lesions that develop into either a superficial ulcer or a verrucous plaque. During progression, the lymphocutaneous form displays multiple subcutaneous nodules that are formed along the course of locally draining lymphatics (sporotrichoid spread). In contrast, the localized form shows no lymphatic spread and is characterized by indurated or verrucous plaques and occasional ulcers.^35,36 Diagnosis of sporotrichosis is primarily clinical due to its distinguished presentation, but in difficult cases, culture is the gold standard.³⁷Sporotrichosis is treated with systemic itraconazole.³⁸

Mycetoma is a chronic subcutaneous fungal infection caused by inoculation via organic matter such as splinters or thorns. Given the ubiquitous nature of causative fungi, there may be a genetic predisposition to developing the disease.³⁹ In South America, the most common pathogens are Trematosphaeria grisea, Madurella mycetomatis, and Scedosporium apiospermum. The clinical manifestations of mycetoma include painless slow growing subcutaneous nodules, which may evolve into necrotic abscesses with sinus tracts. Lesions are most commonly located on exposed areas, especially the lower extremities. The expression of black granules and debris from the lesions is highly suggestive of fungal mycetoma.⁴⁰ Diagnostic work up includes tissue microscopy using potassium hydroxide, as well as deep tissue biopsies for culture on Sabouraud dextrose agar kept at both room temperature and 37 °C. As fungal cultures can take several weeks, histopathologic evaluation may expedite the diagnosis but may not aid in identifying the causative species.

Furuncular myiasis is most commonly caused by larval tissue penetration by Dermatobia hominis, the botfly, and Cordylobia anthropophaga, the tumbu fly. Lesions slowly evolve into periodically painful nodules. They may present with multiple nodules containing larvae, and removal of the larvae typically relieves symptoms.

Cutaneous amebiasis is a rare extracutaneous manifestation of Entamoeba histolytica infection. It can occur independently through direct inoculation or along with other tissue involvement. There is predilection of the disease in the perineal region due to direct inoculation from stool, leading to ulcerations, but lesions can be present anywhere on the body.⁴¹ Notable clinical features include one or more painful and malodorous ulcers with a necrotic base.⁴² The edges of the lesions are often raised and red in color. Progression of the ulcers is often rapid, with destruction in all planes.⁴² Confirmation of the diagnosis can be made with identification of the pathogen on tissue biopsy of the ulcer. Cytologic smears may also be useful in identifying the trophozoites.⁴²

Chromoblastomycosis infection is causes by fungal spore implantation into the skin at sites of trauma. The fungus is ubiquitous in the soil and vegetation and therefore is highly associated with trauma occurring in the outdoors.^43,44 This inoculation leads to a chronic granulomatous reaction. The infection initially begins as an inflamed macule, which evolves into a papule and eventually develops into one of several morphologic subtypes, including nodular, verrucous, tumorous, cicatricial, or plaque types.⁴⁵ Disease progression is very slow and is usually limited to the skin and subcutaneous tissue. Due to the mechanism of inoculation, it most commonly occurs on the lower extremities. One rare complication in chronic lesions is squamous cell carcinoma transformation.^44,45 Diagnosis is made by identifying muriform cells on microscopy.^44-48 Samples can be obtained via scrapings, tape preparation, wet mounts, tissue biopsy, or culture. Treatment is dependent on the stage at diagnosis; early lesions can be treated effectively with surgery or cryotherapy. Pharmacologic treatment options are systemic antifungals for refractory or extensive disease.^44,47,49

Treatment of PG in LA

There is no gold standard therapy for PG, but treatment should be guided by extension and depth of the ulcer, associated systemic diseases, the patient's performance status, and availability of medications.^3,50 Topical therapy is the first choice for small lesions in the early stages (papules, pustules, nodules, or superficial ulcers). It includes dressings, topical immunomodulators, and intralesional corticosteroid injections.⁵¹ A report from Chile showed an excellent and rapid respond to cyclosporin 5%, clobetasol 0.05%, and gentamycin 0.2% ointment applied twice daily, after 18 weeks.⁵²

In patients with severe forms of PG, or with rapid expansion and resistance to topical treatment, systemic therapy is the treatment of choice. Corticosteroids are the first line drugs in the acute phase and should be initiated at high doses (1-2 mg/kg).^3,53 A steroid-sparing drug should be used in the initial phases to minimize long-term steroid toxicity and side effects. Agents including dapsone, sulfasalazine, methotrexate, azathioprine, mycophenolate mofetil, cyclophosphamide, cyclosporine, and biologics may be employed.^2,53

In LA, systemic corticosteroids are, by far, the most frequent first-line therapy. In a cohort of patients with PG, systemic corticosteroids were administered to 87% of patients (n = 27), at a dose-range of 1-1.5 mg/kg/day, for two to 14 months.¹ In another cohort, these drugs were initiated in 81.8% of the patients (n = 9); after 60 months, only two patients had been recurrence free, while the others had multiple recurrences, treated with sulfamethoxazole and trimethoprim, minocycline, topical corticosteroids, and cyclophosphamide.⁵⁴ In addition, corticosteroids and local treatment were preferred when PG was associated with autoimmune diseases, such as autoimmune hepatitis.⁵⁵

Cyclosporine is less frequently used as a first-line therapy due to its side effects. Cyclosporine monotherapy induces a rapid remission of the disease at a dose of 3-5 mg/kg/day after a few weeks of treatment and complete resolution of the lesion after one to three months, but long-term therapy might be problematic.³ In one report from LA, it was used in 13% (n = 4) of the patients, for one to six months, with a dose of 1.5-3 mg/kg/day, with no relapses after four years of treatment.¹

Experience with methotrexate in LA is scarce, and it is generally used as a steroid-sparing drug in severe or refractory disease.⁵⁶ However, a case report from Chile showed a remarkable response with intralesional methotrexate. After 40 days of oral prednisolone, followed by eight weeks of 10 mg weekly intramuscular methotrexate, the PG ulcers failed to improve. After seven injections of methotrexate (25 mg/week) administered intralesionally in the erythematous border of the ulcers, almost 90% of the ulcer was healed.⁵⁷

In Mexico, an open-label trial assessed intravenous bolus cyclophosphamide in a dose of 500 mg/m² of body surface area monthly for a total of three or six doses in nine patients with PG. Seven patients had complete remission, one experienced failure, one had partial remission, and three had relapses after three and twelve months.⁵⁸ However, rare but severe side effects, such as infertility, hemorrhagic cystitis, and secondary tumors, might limit its use.³

Dapsone and sulfasalazine were reported only in two patients with PG in Chile.⁵⁴ However, recurrence occurred on multiple occasions and each patient was eventually transitioned to systemic steroids and cyclosporine.

For steroid-resistant PG, biological agents are now increasingly used in LA. TNF-α inhibitors are preferred due to availability and long-term safety data, but the high cost of these medications is still a limitation in this region.

Conclusion

Based on the current studies, PG in LA is still an under-reported disease and there is a lack of robust studies. The most frequent form of PG is the ulcerative subtype, which is most commonly associated with IBD. An accurate diagnosis in LA is even more challenging, as the prevalence of cutaneous infections that mimic all forms of PG is higher compared to developed countries. Being aware of the epidemiological variations of infectious diseases might provide clinical clues in the diagnosis of PG-like lesions, not only in people from these areas but also in immigrants and travelers. Treatment of PG is primarily with systemic corticosteroids; however, some positive outcomes have been reported with cyclosporine and methotrexate. In LA, biological therapy data is scarce and apparently reserved for severe forms of PG non-responsive to steroids due to high cost and limited access.

• Financial support
  None declared.
• ☆
  How to cite this article: Rodríguez-Zúñiga MJM, Heath MS, Gontijo JRV, Ortega-Loayza AG. Pyoderma gangrenosum: a review with special emphasis on Latin America literature. An Bras Dermatol. 2019;94:729-43.
• ☆☆
  Study conducted at the Oregon Health and Sciences University, Portland, United States; and at the Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.

References

• ¹
  Vacas AS, Torre AC, Bollea-Garlatti ML, Warley F, Galimberti RL. Pyoderma gangrenosum: clinical characteristics, associated diseases, and responses to treatment in a retrospective cohort study of 31 patients. Int J Dermatol. 2017;56:386-91.
• ²
  Marzano AV, Ishak RS, Saibeni S, Crosti C, Meroni PL, Cugno M. Autoinflammatory skin disorders in inflammatory bowel diseases, pyoderma gangrenosum and Sweet's syndrome: a comprehensive review and disease classification criteria. Clin Rev Allergy Immunol. 2013;45:202-10.
• ³
  Cozzani E, Gasparini G, Parodi A. Pyoderma gangrenosum: a systematic review. G Ital Dermatol Venereol. 2014;149:587-600.
• ⁴
  Pereira N, Brites MM, Goncalo M, Tellechea O, Figueiredo A. Pyoderma gangrenosum - a review of 24 cases observed over 10 years. Int J Dermatol. 2013;52:938-45.
• ⁵
  Marzano AV, Borghi A, Wallach D, Cugno M. A comprehensive review of neutrophilic diseases. Clin Rev Allergy Immunol. 2018;54:114-30.
• ⁶
  Yasin F, Assad S, Zahid M, Malik SA. Extensive pyoderma gangrenosum: a challenging diagnosis and literature review of management. Cureus. 2017;9:e1486.
• ⁷
  Ahn C, Negus D, Huang W. Pyoderma gangrenosum: a review of pathogenesis and treatment. Expert Rev Clin Immunol. 2018;14:225-33.
• ⁸
  Langan SM, Groves RW, Card TR, Gulliford MC. Incidence, mortality, and disease associations of pyoderma gangrenosum in the United Kingdom: a retrospective cohort study. J Invest Dermatol. 2012;132:2166-70.
• ⁹
  Schmieder SJ, Krishnamurthy K. Pyoderma gangrenosum. In: StatPearls; 2018. Treasure Island (FL).
• ¹⁰
  Soni A, Vora D. Pyoderma gangrenosum: a systemic review of the incidence and prevalence. J Clin Stud. 2015;7:42-5.
• ¹¹
  Budak-Alpdogan T, Alpdogan O, Direskeneli H, Ergun T, Ozturk A, et al. Skin hyperreactivity of Behcet's patients (pathergy reaction) is also positive in interferon alpha-treated chronic myeloid leukaemia patients, indicating similarly altered neutrophil functions in both disorders. Br J Rheumatol. 1998;37:1148-51.
• ¹²
  Ruocco E, Sangiuliano S, Gravina AG, Miranda A, Nicoletti G. Pyoderma gangrenosum: an updated review. J Eur Acad Dermatol Venereol. 2009;23:1008-17.
• ¹³
  Caproni M, Antiga E, Volpi W, Verdelli A, Venegoni L, Quaglino P, et al. The Treg/Th17 cell ratio is reduced in the skin lesions of patients with pyoderma gangrenosum. Br J Dermatol. 2015;173:275-8.
• ¹⁴
  Braswell SF, Kostopoulos TC, Ortega-Loayza AG. Pathophysiology of pyoderma gangrenosum (PG): an updated review. J Am Acad Dermatol. 2015;73:691-8.
• ¹⁵
  McKenzie F, Arthur M, Ortega-Loayza AG. Pyoderma gangrenosum: what do we know now. Curr Derm Rep. 2018;7:147-57.
• ¹⁶
  Su WP, Schroeter AL, Perry HO, Powell FC. Histopathologic and immunopathologic study of pyoderma gangrenosum. J Cutan Pathol. 1986;13:323-30.
• ¹⁷
  Wollina U. Pyoderma gangrenosum - a review. Orphanet J Rare Dis. 2007;2:19.
• ¹⁸
  Weedon D. The vasculopathic reaction pattern. In: Weedon D, editor. Weedon's skin pathology. 3rd ed. London: Churchill Livingstone; 2010. p. 196-244.
• ¹⁹
  Cozzani E, Scaparro M, Rongioletti F, Pierri I, Pimpinelli N, Parodi A. Pyoderma gangrenosum-like CD30 + cutaneous T-cell lymphoma in a patient with mycosis fungoides. J Eur Acad Dermatol Venereol. 2015;29:819-21.
• ²⁰
  Sasor SE, Soleimani T, Chu MW, Cook JA, Nicksic PJ, Tholpady SS. Pyoderma gangrenosum demographics, treatments, and outcomes: an analysis of 2,273 cases. J Wound Care. 2018;27:S4-8.
• ²¹
  Kutlubay Z, Tuzun Y, Wolf R. The pathergy test as a diagnostic tool. Skinmed. 2017;15:97-104.
• ²²
  Borda LJ, Wong LL, Marzano AV, Ortega-Loayza AG. Extracutaneous involvement of pyoderma gangrenosum. Arch Dermatol Res. 2019 [Epub ahead of print].
• ²³
  Wachholz PA, Masuda PY, Nascimento DC, Taira CM, Cleto NG. Quality of life profile and correlated factors in chronic leg ulcer patients in the mid-west of Sao Paulo State Brazil. An Bras Dermatol. 2014;89:73-81.
• ²⁴
  Weenig RH, Davis MD, Dahl PR, Su WP. Skin ulcers misdiagnosed as pyoderma gangrenosum. N Engl J Med. 2002;347:1412-8.
• ²⁵
  Karimkhani C, Wanga V, Coffeng LE, Naghavi P, Dellavalle RP, Naghavi M. Global burden of cutaneous leishmaniasis: a cross-sectional analysis from the Global Burden of Disease Study 2013. Lancet Infect Dis. 2016;16:584-91.
• ²⁶
  Centers for Disease Control and Prevention. Practical guide to laboratory diagnosis of leishmaniasis; 2016.
• ²⁷
  van der Werf TS, van der Graaf WT, Tappero JW, Asiedu K. Mycobacterium ulcerans infection. Lancet. 1999;354:1013-8.
• ²⁸
  Merritt RW, Walker ED, Small PL, Wallace JR, Johnson PD, Benbow ME, et al. Ecology and transmission of Buruli ulcer disease: a systematic review. PLoS Negl Trop Dis. 2010;4:e911.
• ²⁹
  Sakyi SA, Aboagye SY, Darko Otchere I, Yeboah-Manu D. Clinical and laboratory diagnosis of Buruli ulcer disease: a systematic review. Can J Infect Dis Med Microbiol. 2016;2016:5310718.
• ³⁰
  Bellet JS, Prose NS. Skin complications of bacillus Calmette-Guerin immunization. Curr Opin Infect Dis. 2005;18:97-100.
• ³¹
  Dias MF, Bernardes Filho F, Quaresma MV, Nascimento LV, Nery JA, Azulay DR. Update on cutaneous tuberculosis. An Bras Dermatol. 2014;89:925-38.
• ³²
  Hill MK, Sanders CV. Cutaneous tuberculosis. Microbiol Spectr. 2017:5.
• ³³
  Zeegelaar JE, Faber WR. Imported tropical infectious ulcers in travelers. Am J Clin Dermatol. 2008;9:219-32.
• ³⁴
  Ramirez Soto MC, Malaga G. Subcutaneous mycoses in Peru: a systematic review and meta-analysis for the burden of disease. Int J Dermatol. 2017;56:1037-45.
• ³⁵
  Byrd DR, El-Azhary RA, Gibson LE, Roberts GD. Sporotrichosis masquerading as pyoderma gangrenosum: case report and review of 19 cases of sporotrichosis. J Eur Acad Dermatol Venereol. 2001;15:581-4.
• ³⁶
  Charles K, Lowe L, Shuman E, Cha KB. Painful linear ulcers: a case of cutaneous sporotrichosis mimicking pyoderma gangrenosum. JAAD Case Rep. 2017;3:519-21.
• ³⁷
  Barros MB, de Almeida Paes R, Schubach AO. Sporothrix schenckii and sporotrichosis. Clin Microbiol Rev. 2011;24:633-54.
• ³⁸
  Sharkey-Mathis PK, Kauffman CA, Graybill JR, Stevens DA, Hostetler JS, Cloud G, et al. NIAID Mycoses Study Group Treatment of sporotrichosis with itraconazole. Am J Med. 1993;95:279-85.
• ³⁹
  van de Sande WW, Fahal A, Verbrugh H, van Belkum A. Polymorphisms in genes involved in innate immunity predispose toward mycetoma susceptibility. J Immunol. 2007;179:3065-74.
• ⁴⁰
  Gabhane SK, Gangane N. Cytodiagnosis of eumycotic mycetoma: a case report. Acta Cytol. 2008;52:354-6.
• ⁴¹
  Kenner BM, Rosen T. Cutaneous amebiasis in a child and review of the literature. Pediatr Dermatol. 2006;23:231-4.
• ⁴²
  Fernandez-Diez J, Magana M, Magana ML. Cutaneous amebiasis: 50 years of experience. Cutis. 2012;90:310-4.
• ⁴³
  Tschen JA, Knox JM, McGavran MH, Duncan WC. Chromomycosis. The association of fungal elements and wood splinters. Arch Dermatol. 1984;120:107-8.
• ⁴⁴
  Queiroz-Telles F, Nucci M, Colombo AL, Tobon A, Restrepo A. Mycoses of implantation in Latin America: an overview of epidemiology, clinical manifestations, diagnosis and treatment. Med Mycol. 2011;49:225-36.
• ⁴⁵
  Queiroz-Telles F, de Hoog S, Santos DW, Salgado CG, Vicente VA, Bonifaz A, et al. Chromoblastomycosis. Clin Microbiol Rev. 2017;30:233-76.
• ⁴⁶
  Garcia-Martos P, Marquez A, Gene J. Human infections by black yeasts of genus Exophiala. Rev Iberoam Micol. 2002;19:72-9.
• ⁴⁷
  Garnica M, Nucci M, Queiroz-Telles F. Difficult mycoses of the skin: advances in the epidemiology and management of eumycetoma, phaeohyphomycosis and chromoblastomycosis. Curr Opin Infect Dis. 2009;22:559-63.
• ⁴⁸
  Miranda MF, Silva AJ. Vinyl adhesive tape also effective for direct microscopy diagnosis of chromomycosis, lobomycosis, and paracoccidioidomycosis. Diagn Microbiol Infect Dis. 2005;52:39-43.
• ⁴⁹
  Queiroz-Telles F, Esterre P, Perez-Blanco M, Vitale RG, Salgado CG, Bonifaz A. Chromoblastomycosis: an overview of clinical manifestations, diagnosis and treatment. Med Mycol. 2009;47:3-15.
• ⁵⁰
  Patel F, Fitzmaurice S, Duong C, He Y, Fergus J, Raychaudhuri SP, et al. Effective strategies for the management of pyoderma gangrenosum: a comprehensive review. Acta Derm Venereol. 2015;95:525-31.
• ⁵¹
  Feldman SR, Lacy FA, Huang WW. The safety of treatments used in pyoderma gangrenosum. Expert Opin Drug Saf. 2018;17:55-61.
• ⁵²
  Bertolo MS, Ruiz M, Contreras C. Pyoderma gangrenosum: excellent response to topical therapy. Rev Med Chil. 2015;143:130-1.
• ⁵³
  Al Ghazal P, Dissemond J. Therapy of pyoderma gangrenosum in Germany: results of a survey among wound experts. J Dtsch Dermatol Ges. 2015;13:317-24.
• ⁵⁴
  Lopez de Maturana D, Amaro P, Aranibar L, Segovia L. Pyoderma gangrenosum: report of 11 cases. Rev Med Chil. 2001;129:1044-50.
• ⁵⁵
  Dantas SG, Quintella LP, Fernandes NC. Exuberant pyoderma gangrenosum in a patient with autoimmune hepatitis. An Bras Dermatol. 2017;92:114-7.
• ⁵⁶
  Soto Vilches F, Vera-Kellet C. Pyoderma gangrenosum: classic and emerging therapies. Med Clin (Barc). 2017;149:256-60.
• ⁵⁷
  Del Puerto C, Navarrete-Dechent CP, Carrasco-Zuber JE, Vera-Kellet C. Intralesional methotrexate as an adjuvant treatment for pyoderma gangrenosum: a case report. Indian J Dermatol Venereol Leprol. 2017;83:277.
• ⁵⁸
  Reynoso-von Drateln C, Perla-Navarro AV, Gamez-Nava JI, Gonzalez-Lopez L, Galvan-Villegas F, Ramos-Remus C. Intravenous cyclophosphamide pulses in pyoderma gangrenosum: an open trial. J Rheumatol. 1997;24:689-93.
• ⁵⁹
  Corti RE, Outeda JL, Boerr LA, Bai JC, Corti RN. Pioderma gangrenoso en enfermedades de Crohn del colon. Acta Gastroenterol Latinoam. 1981;11:383-90.
• ⁶⁰
  Della Giovanna P, Mion S, Poledore I, Torre J, Cabrera HN. Pioderma gangrenoso: a propósito de 4 casos uno asociado embarazo. Arch Argent Dermatol. 1991;41:261-70.
• ⁶¹
  Moreno JLC, Oliva JA, Pardo Hidalgo RA. Piodermia gangrenosa y artritis reumatoidea. Rev Argent Reumatol. 1994;5:69-72.
• ⁶²
  Vignale RA, Theophile R, Riveiro C, Abulafia J. Pioderma gangrenosum asociado a anticuerpos antifosfolípidos: a propósito de 4 casos. Arch Argent Dermatol. 1996;46:209-18.
• ⁶³
  Saraceno EF, Simionato C, Sánchez G, Coradini N. Pioderma gangrenoso: a propósito de 6 casos. Arch Argent Dermatol. 2002;52:143-52.
• ⁶⁴
  Plaza MG. Pioderma gangrenoso en el geronte asociado a colagenopatias: a proposito de un caso. Rev Argent Dermatol. 2004;85:220-6.
• ⁶⁵
  Simón S, Rivarola E, Abaca H. Pioderma gangrenoso periestomal. Dermatol Argent. 2005;11:31-4.
• ⁶⁶
  Vázquez FJ, Oria I, Saucedo C, Freue J, Aguera D. Pioderma gangrenoso y osteomielitis crónica: una rara asociación. Rev Hosp Ital B Aires (2004). 2009;29:97-8.
• ⁶⁷
  Sommerfleck FA, Schneeberger EE, Suarez Lissi MA, Chiardola F, Sambuelli A, Marconi O, et al. Manifestaciones reumatológicas y sistémicas en pacientes con enfermedad inflamatoria intestinal. Rev Argent Reumatol. 2014;25:36-9.
• ⁶⁸
  Achenbach RE, Sánchez GF, Marina S, Dutto M, Boytenko S, Maggi C. Pioderma gangrenoso extendido asociado a enfermedad de Crohn tratada con adalimumab. Rev Argent Dermatol. 2014;95:36-40.
• ⁶⁹
  Curmona MC, Chiesura VC, Garay IS, Kurpis M, Ruiz Lascano A. Pioderma gangrenoso. Dermatol Argent. 2014;20:164-8.
• ⁷⁰
  Pereyra S, Martínez C, Cano M, Consigli J, Ponssa G. Pioderma gangrenoso en paciente trasplantado renal: respuesta al tratamiento con tacrolimus tópico. Dermatol Argent. 2014;20:56-9.
• ⁷¹
  Fassi MV, Chiesura V, Valente E, Kurpis M, Ruiz Lascano A. Úlcera en pierna en un paciente con artritis reumatoidea y colitis ulcerosa: ¿vasculitis reumatoidea o pioderma gangrenoso ulceroso?: Rheumatoid vasculitis or ulcerous pyoderma gangrenosum? Rev Argent Dermatol. 2015;96:52-64.
• ⁷²
  Silva-Feistner M, Correa GH, Hasbún AP, Vial V. Pioderma gangrenoso como complicación de cicatriz de cesárea: comunicación de un caso y revisión de literatura. Rev Argent Dermatol. 2015;96:43-51.
• ⁷³
  Galimberti RL, Vacas AS, Bollea Garlatti ML, Torre AC. The role of interleukin-1beta in pyoderma gangrenosum. JAAD Case Rep. 2016;2:366-8.
• ⁷⁴
  Vega STDdl, Ortega IJ, Figueroa CE, Rojas FC. Pioderma gangrenoso post-quirúrgico: reporte de un caso en paciente con fibrosis retroperitoneal. Rev Argent Dermatol. 2018;99:1-10.
• ⁷⁵
  Vacas AS, Bollea-Garlatti ML, Torre AC, Galimberti RL. Bullous pyoderma gangrenosum as a predictor of hematological malignancies. An Bras Dermatol. 2018;93:133-4.
• ⁷⁶
  Pires AMKS, Weiss PB, Weissbluth ML, Ramos MC, Hampe SV, Bakos L. Pioderma gangrenoso associado a hepatite crônica ativa. An Bras Dermatol. 1987;62:15-8.
• ⁷⁷
  Lana MA, Moreira PR, Neves LB. Wall-eyed bilateral internuclear ophthalmoplegia (Webino syndrome) and myelopathy in pyoderma gangrenosum. Arq Neuropsiquiatr. 1990;48:497-501.
• ⁷⁸
  Pessato S, Bonamigo RR, Leite CM, Brodt C, Sperhacke C, Bakos L. Piodema gangrenoso: uma revisão de cinco anos em um hospital universitário. Rev AMRIGS. 1996;40:49-51.
• ⁷⁹
  Souza CdS, Chioss MPdV, Takada MH, Foss NT, Roselino AMF. Pioderma gangrenoso: casuística e revisão de aspectos clínico-laboratoriais e terapêuticos. An Bras Dermatol. 1999;74:465-72.
• ⁸⁰
  Cabral VLR, Miszputen SJ, Catapani WR. Anticorpo anticitoplasma de neutrófilos (ANCA) em pioderma gangrenoso, um marcador sorológico para associação com doenças sistêmicas: estudo de oito casos. An Bras Dermatol. 2004;79:39-44.
• ⁸¹
  Martinez CAR, Priolli DG, Ramos RFB, Nonose R, Schmidt KH. Remissão completa do pioderma gangrenoso após colectomia total em doente portador de retocolite ulcerativa inespecífica. Arq Med ABC. 2005;30:106-10.
• ⁸²
  Costa IMC, Nogueira LS-C. Pioderma gangrenoso e artrite reumatóide: relato de caso. An Bras Dermatol. 2005;80:81-2.
• ⁸³
  Fraga JCS, Souza VLd, Valverde RV, Gamonal A. Pioderma gangrenoso: apresentação atípica. An Bras Dermatol. 2006;81.S305-S8.
• ⁸⁴
  Coltro PS, Valler CS, Almeida PCCd, Gomez DdS, Ferreira MC. O papel da patergia no pioderma gangrenoso em áreas doadoras de enxertos cutâneos: relato de caso. Rev Soc Bras Cir Plást (1997). 2006;21:231-5.
• ⁸⁵
  Batista MD, Fernandes RL, Rocha MADd, Ikino JK, Pinheiro RF, Chauffaille MdLLF, et al. Pioderma gangrenoso bolhoso e síndrome mielodisplásica. An Bras Dermatol. 2006;81:S309-12.
• ⁸⁶
  Meyer TN. Pioderma gangrenoso: grave e mal conhecida complicação da cicatrização. Rev Soc Bras Cir Plást (1997). 2006;21:120-4.
• ⁸⁷
  Franca AE, Salvino LK, Leite SH, Ferraz JG, Rocha TD, Cintra ML, et al. Pyoderma gangrenosum as first clinical manifestation of gastric adenocarcinoma. J Eur Acad Dermatol Venereol. 2006;20:440-1.
• ⁸⁸
  Burkieviecz CJC, Schmidt L, Silva MB, Skare TL. Pioderma gangrenoso e lúpus eritematoso sistêmico. Rev Bras Reumatol. 2007;47:296-9.
• ⁸⁹
  Barbato MT, Bakos L, Masiero NCMS, Bolson P. Perfil clinicopatológico dos pacientes com pioderma gangrenoso do Hospital das Clínicas de Porto Alegre (RS) ‒ Brasil (2000-2006). An Bras Dermatol. 2008;83:431-6.
• ⁹⁰
  Tinoco MP, Tamler C, Maciel G, Soares D, Avelleira JC, Azulay D. Pyoderma gangrenosum following isotretinoin therapy for acne nodulocystic. Int J Dermatol. 2008;47:953-6.
• ⁹¹
  Dornelas MT, Guerra MCdS, Maués GL, Luiz JOMP, Arruda FRd, Corrêa MdPD. Pioderma gangrenoso: relato de caso. HU Rev. 2008;34:213-6.
• ⁹²
  Bonamigo RR, Behar PR, Beller C, Bonfa R. Pyoderma gangrenosum after silicone prosthesis implant in the breasts and facial plastic surgery. Int J Dermatol. 2008;47:289-91.
• ⁹³
  Coelho LF, Correia FG, Ottoni FA, Santos FPST, Pereira LB, Lanna CCD. Pyoderma gangrenosum: a challenge to the rheumatologist. Rev Bras Reumatol. 2009:49.
• ⁹⁴
  Berbert ALCV, Mantese SAdO, Rocha A, Rezende J, Cunha TFR. Pioderma granulomatoso superficial: relato de caso de variante rara do pioderma gangrenoso. An Bras Dermatol. 2009;84:285-8.
• ⁹⁵
  Furtado JG, Furtado GB. Pioderma gangrenoso em mastoplastia e abdominoplastia. Rev Bras Cir Plást. 2010;25:725-7.
• ⁹⁶
  Avelar JTC, Sempértegui A, Bronzat E, Farmetano R, Ferrari B, Moscardini LMdO, et al. Pioderma gangrenoso após quadrantectomia de mama comradioterapia intraoperatória: relato de caso. Rev Bras Mastol. 2011;21:86-90.
• ⁹⁷
  Fonseca CB, Motta GL, Rampazzo A, Cantarelli Junior JC, Fagundes RB. Pyoderma gangrenosum as a initial manifestation of ulcerative proctocolitis. J Coloproctol (Rio J., Impr). 2011;31:301-5.
• ⁹⁸
  Grillo MA, Cavalheiro TT, da Silva Mulazani M, Rocha JL, Semchechen D, da Cunha CA. Postsurgical pyoderma gangrenosum complicating reduction mammaplasty. Aesthetic Plast Surg. 2012;36:1347-52.
• ⁹⁹
  Maia CBdC, Felix F, Paes V, Azevedo JAd, Grangeiro ERN, Riccio JLN, et al. Perfuração de septo nasal em paciente com pioderma gangrenoso. Int Arch Otorhinolaryngol (Impr). 2012;16:278-81.
• ¹⁰⁰
  Cunha VS, Magno V, Wendt LR, Furian TQ, Passos EP. Pyoderma gangrenosum postlaparoscopy: a rare complication. Surg Laparosc Endosc Percutan Tech. 2012;22:e45-7.
• ¹⁰¹
  Bittencourt MdeJ, Soares LF, Lobato LS, Mancano AD, Leandro HS, Fonseca DM. Multiple cavitary pulmonary nodules in association with pyoderma gangrenosum: case report. An Bras Dermatol. 2012;87:301-4.
• ¹⁰²
  Andrade P, Brites MM, Figueiredo A. Synchronous pyoderma gangrenosum and inflammatory bowel disease, healing after total proctocolectomy. An Bras Dermatol. 2012;87:637-9.
• ¹⁰³
  Carvalho LR, Zanuncio VV, Gontijo B. Pyoderma gangrenosum with renal and splenic impairment - case report. An Bras Dermatol. 2013;88:150-3.
• ¹⁰⁴
  Kruger NA, De Marchi JJ, Souza MMd. Biological therapy for pyoderma gangrenosum. J Coloproctol (Rio J, Impr). 2013;33:232-5.
• ¹⁰⁵
  Soares JM, Rinaldi AE, Taffo E, Alves DG, Cutaiti RdCC, Estrada EdOD. Pioderma gangrenoso pós-mamoplastia redutora: relato de caso e discursão. Rev Bras Cir Plást. 2013;28:511-4.
• ¹⁰⁶
  Beber AAC, Knob CF, Shons KRR, Neumaier W, Silva JCNd, Monticielo OA. Pioderma gangrenoso associado à artrite reumatoide: descrição de caso. Rev Bras Reumatol. 2014;54:322-5.
• ¹⁰⁷
  Marchiori E, Hochhegger B, Guimarães M, Zanetti G. A cutaneous ulceration with pulmonary mass; 2014.
• ¹⁰⁸
  Rosseto M, Costa SCD, NarvÁEz PLV, Nakagawa CM, Costa GOD. Pioderma gangrenoso em abdominoplastia: relato de caso. Rev Bras Cir Plást. 2015;30:654-7.
• ¹⁰⁹
  de Souza EF, da Silva GA, Dos Santos GR, Motta HL, Cardoso PA, de Azevedo MC, et al. Pyoderma gangrenosum simulating necrotizing fasciitis. Case Rep Med. 2015;2015:504970.
• ¹¹⁰
  Sempértegui A, Vasquez ISV, Fernandes Neto ALRG, Santos LMLd, Alvarenga BCF, Ueda WJ, et al. Pioderma gangrenoso após quadrantectomia de mama com radioterapia intraoperatória: relato de caso. Rev Bras Cir Plást. 2015;30:138-42.
• ¹¹¹
  Soncini JA, Grassi Salles A, Frizzo Neto JA, Gemperli R. Successful treatment of pyoderma gangrenosum after augmentation mastopexy using vacuum therapy. Plast Reconstr Surg Glob Open. 2016;4:e1072.
• ¹¹²
  Freitas VMP, Pereira SM, Enokihara M, Cestari S. Pyoderma gangrenosum associated with left iliac vein compression syndrome: presentation of difficult diagnosis. An Bras Dermatol. 2017;92:129-31.
• ¹¹³
  Gabe MB, Borchardt BC, Barella RP, Schipanski CV, Filho AMdS, Antero DC. Pioderma gangrenoso associado à poliartrite piogênica. ACM Arq Catarin Med. 2018;47:216-21.
• ¹¹⁴
  Bittencourt MCB, Atanazio MJ, Xavier EM, Costa SF. Postsurgical pyoderma gangrenosum after an autologous stem cell transplantation for multiple myeloma. BMJ Case Rep. 2018;2018.
• ¹¹⁵
  Clemente G, Silva CA, Sacchetti SB, Ferriani VPL, Oliveira SK, Sztajnbok F, et al. Takayasu arteritis in childhood: misdiagnoses at disease onset and associated diseases. Rheumatol Int. 2018;38:1089-94.
• ¹¹⁶
  Pérez L, López P, González R, Améstica O, Urbina F, Benavides A. Pioderma gangrenoso postcesária. Rev Chil Obstet Ginecol. 2001;66:28-33.
• ¹¹⁷
  Hevia CH, Suárez MJ, Vergara AMT. Pioderma periileostómico: caso clínico. Rev Med Chil. 2004;132:747-9.
• ¹¹⁸
  Eulufí MA, Calderón OW, Piñeros BJL, Silva CM, Cuadra CA, Léniz MP, et al. Pioderma gangrenosa en cirugía plástica: comunicación de tres casos. Rev Med Chil. 2006;134:339-44.
• ¹¹⁹
  Calderón HP, Silva PP, Valenzuela AF, Poniachik TJ, Catalán L, Morales HC. Pioderma gangrenoso en paciente con colitis ulcerosa tratada con infliximab. Rev Chil Dermatol. 2011;27:199-202.
• ¹²⁰
  Fernández Castillo R, Fernández Gallegos R, Cañadas de la Fuente GA, González Jiménez E, El Hamed HH. Pioderma gangrenoso en un paciente con insuficiencia renal crónica sobre fístula arteriovenosa secundaria a granulomatosis de Wegener: estudio de un caso. Rev Nefrol Diál Traspl. 2012;32:222-6.
• ¹²¹
  Gosch CM, Guaya IP, Medina KMR, Stefanazzi M, Pinilla PJ, Leyton MG, et al. Pioderma gangrenoso de la mama: reporte de un caso y revisión de la literatura. Rev Chil Dermatol. 2012;28:439-43.
• ¹²²
  Melo Grollmus R, Fernandez de Retana P. Pyoderma gangrenosum following foot and ankle surgery: a case report. Foot Ankle Int. 2013;34:745-8.
• ¹²³
  Calderón OW, Cisternas VJP, Calderón MD, Eulufi MA, Guler GK, Jaramillo RL, et al. Pioderma gangrenoso en mamoplastía de reducción con pedículo inferior. Rev Chil Cir. 2013;65:541-8.
• ¹²⁴
  Bannura CG, Barrera EA, Melo LC. Pioderma gangrenoso gigante de curso fulminante asociado a enfermedad inflamatoria intestinal. Rev Chil Cir. 2014;66:259-63.
• ¹²⁵
  Erlij D, Cuellar C, Rivera A, Badilla N, Moldenhauer N, Foster C, et al. Oligoarthritis, panniculitis and pyoderma gangrenosum associated with non-Hodgkin lymphoma Report of one case. Rev Med Chil. 2018;146:534-7.
• ¹²⁶
  Peñaloza A, Amaya L, Olmos E, Piña R, Moreno C, Franco F. Colitis ulcerativa idiopatica asociada con pioderma gangrenoso: reporte de un caso. Rev Colomb Gastroenterol. 1988;3:151-3.
• ¹²⁷
  Restrepo PAJ, Farfán QY, Angarita O, Cifuentes S, Hormaza N, Marulanda JC, et al. Colitis ulcerativa asociada con manifestaciones cutáneas. Rev Colomb Gastroenterol. 2006;21:300-5.
• ¹²⁸
  Jaimes-Lopez N, Molina V, Arroyave JE, Vasquez LA, Ruiz AC, Castano R, et al. Development of pyoderma gangrenosum during therapy with infliximab. J Dermatol Case Rep. 2009;3:20-3.
• ¹²⁹
  Canas CA, Duran CE, Bravo JC, Castano DE, Tobon GJ. Leg ulcers in the antiphospholipid syndrome may be considered as a form of pyoderma gangrenosum and they respond favorably to treatment with immunosuppression and anticoagulation. Rheumatol Int. 2010;30:1253-7.
• ¹³⁰
  Cadavid M, Palacios Isaza CP, Molina AL, Gómez LM, Restrepo R. Pioderma gangrenoso: reporte de caso. Med UPB. 2012;31:59-62.
• ¹³¹
  Severiche DF, Velandia O, Saldarriaga EL. Pioderma gangrenoso como síndrome paraneoplásico de un tumor tipo Phyllodes borderline. Acta Med Colomb. 2014;39:207-10.
• ¹³²
  Acón-Ramírez E, Argüello-Ruiz D. Pioderma gangrenoso ulceroso asociado a artritis reumatoide: reporte de caso. Acta Med Costarric. 2017;59:28-31.
• ¹³³
  Moreira Preciado M, Díaz Almeida JG, Pérez López A. Pioderma gangrenoso vegetante asociado con insuficiencia renal. Rev Cubana Med Trop. 2001;53:212-6.
• ¹³⁴
  Hernadez Urra MdC, Hernandez Cubas M, Monteagudo Hernandez KY. Colitis ulcerativa y pioderma gangrenoso. Medicentro (Villa Clara). 2010:14.
• ¹³⁵
  Zonana-Nacach A, Jimenez-Balderas FJ, Martinez-Osuna P, Mintz G. Intravenous cyclophosphamide pulses in the treatment of pyoderma gangrenosum associated with rheumatoid arthritis: report of 2 cases and review of the literature. J Rheumatol. 1994;21:1352-6.
• ¹³⁶
  Chacek S, MacGregor-Gooch J, Halabe-Cherem J, Nellen-Hummel H, Quinones-Galvan A. Pyoderma gangrenosum and extensive caval thrombosis associated with the antiphospholipid syndrome - a case report. Angiology. 1998;49:157-60.
• ¹³⁷
  Muñiz-González A, Kresch-Tronik N, Moreno-Sánchez F, Jáuregui-Camargo L, Halabe-Cherem J, Asz-Sigall D. Dolor abdominal difuso, febricula, náusea, malestar general y dermatosis ulcerativa. Gac Med Mex. 2007;143:427-8.
• ¹³⁸
  Contreras-Ruiz J, Kresch-Tronik NS, de la Cruz-Garcia MI, Mercado-Ceja S, Lozano-Platonoff A. Delayed diagnosis of pyoderma gangrenosum: a case study. Ostomy Wound Manage. 2008;54:32-6.
• ¹³⁹
  Barrera-Vargas A, Granados J, Garcia-Hidalgo L, Hinojosa-Azaola A. An unusual presentation of Takayasu's arteritis in two Mexican siblings. Mod Rheumatol. 2015;25:802-5.
• ¹⁴⁰
  Contreras-Verduzco FA, Espinosa-Padilla SE, Orozco-Covarrubias L, Alva-Chaire A, Rojas-Maruri CM, Saez-de-Ocariz M. Pulmonary nodules and nodular scleritis in a teenager with superficial granulomatous pyoderma gangrenosum. Pediatr Dermatol. 2018;35:e35-8.
• ¹⁴¹
  Real Delor RE, Ramírez Torres L, Rojas G, Britos R, Rojas E, Figueredo N, et al. Pioderma gangrenoso de rápida evolución. Rev Nac (Itauguá). 2011;3:43-5.
• ¹⁴²
  Domiguez L, Aldama O, Rivelli V, Gorostiaga G, Mendoza G, Célias L, et al. Lesiones pustulosas en pacientes con colitis ulcerosa. Dermatol Peru. 2009;19:222-5.
• ¹⁴³
  Carrillo-Ñáñez L, Novoa-Millones L, Carrillo-García PL, Cabrera-Castellano X. Pioderma gangrenoso como presentación inicial de colitis ulcerativa. Rev Soc Peru Med Interna. 2014;27:193-9.
• ¹⁴⁴
  Deza-Araujo P, Araujo-Castillo M, Rojas-Plasencia P. Pioderma gangrenoso en nino: reporte de caso. Dermatol Peru. 2014;24:262-4.
• ¹⁴⁵
  Fermín EY, Rondón LAJ. Pioderma gangrenoso: relevancia clínica Reporte de dos casos. revisión de la literatura. Dermatol Venez. 1989;27:27-30.
• ¹⁴⁶
  Valecillos S, Oliver Llull M, Rondón Lugo A, García E, Reyes Jaimes O, Reyes Flores O, et al. Pioderma granulomatoso superficial recalcitrante y embarazo: presentación de un caso y revisión de la literatura. Dermatol Venez. 1998;36:68-72.

Publication Dates

• Publication in this collection
  03 Feb 2020
• Date of issue
   2019

History

• Received
  3 June 2019
• Accepted
  14 June 2019