Pyoderma gangrenosum: update and guidance
Pioderma gangrenoso: atualização e orientação

Pyoderma gangrenosum and the spectrum of neutrophilic dermatoses

Pyoderma gangrenosum (PG) belongs to a group of conditions characterized by polymorphous skin manifestations that include pustules, blisters, abscesses, papules, nodules, plaques and ulcers, whose histopathological substrate shows intense inflammatory infiltrate with a predominance of neutrophils, being, therefore, called dermatoses neutrophils¹. Due to the possible occurrence of extracutaneous manifestations and neutrophilic infiltration in different organs and systems, they would be more adequately defined as neutrophilic diseases².

In addition to PG, neutrophilic diseases include acute febrile neutrophilic dermatosis (Sweet’s syndrome), diurnal raised erythema, neutrophilic eccrine hidradenitis, subcorneal pustular dermatosis, IgA pemphigus, amicrobial pustulosis of the folds, and Behçet’s disease, among others^1,3. These diseases manifest in isolation, but it is not surprising that some of these conditions eventually occur concomitantly or sequentially, considering that they share the same inflammatory infiltrate and are usually associated with the same systemic diseases⁴.

There is also a possible association with several systemic conditions, such as inflammatory bowel diseases, hematological diseases, rheumatological diseases, upper airway and gastrointestinal tract infections, and drug reactions. Neutrophilic diseases share clinical and anatomopathological peculiarities with the so-called autoinflammatory diseases, characterized by recurrent episodes of inflammation in affected organs in the absence of infection, allergy or autoimmunity^1,3.

Pathergy

The phenomenon of pathergy refers to a condition of exaggerated tissue reactivity that occurs in response to minimal trauma and leads to the appearance of new lesions or the worsening of previous lesions. It is most commonly seen in pyoderma gangrenosum and occasionally in Sweet’s syndrome. Generally, pathergy is provoked by biopsies, injections, venipunctures, vascular access, surgical debridement and various surgeries, but minor trauma caused by abrasions, insect bites, and removal of skin adhesives can also trigger pathergy reactions⁵.

This phenomenon is also observed and used in diagnosing Behçet’s disease through skin injury caused by a needle, the so-called pathergy test⁶.

Although the precise mechanism of this phenomenon is not known, it is assumed that the abnormal inflammatory response triggered by tissue injury is due to the exaggerated release of pro-inflammatory cytokines and chemokines by keratinocytes and other cells present in the epidermis and dermis, resulting in the intense perivascular inflammatory infiltrate of polymorphonuclear cells, observed on histopathological examination⁷.

Epidemiology

PG is rare, with an estimated prevalence of 58 cases/1 million adults in the US population, and an incidence of 6.3 cases/1 million individuals/year, according to a British study^8,9.

The disease is even rarer in children, affecting mainly individuals around 50 years of age, with a slight predominance of females, with an average age of 44.6 years (±19.7) of onset of the disease^10,11.

Mortality is also higher in PG patients, with a risk three times higher compared to age-matched controls⁹. However, studies are lacking in understanding why this increased mortality and how much it could be attributed to associated comorbidities, immunosuppression, infections and iatrogenic events¹².

A survey carried out in Germany with specialists in wound care, which included 31,619 patients with chronic leg ulcers, showed that PG accounted for 3% of all cases¹³.

Clinical condition

The classic and predominant form of PG begins with an erythematous papule or pustule that evolves into a painful ulceration that progresses rapidly, with typical characteristics of detached violaceous edges and surrounding erythema. The ulcer can reach large dimensions and go deep into the subcutaneous tissue, less frequently reaching the fascia and exposing muscles and tendons. The ulcer bed may be exudative, purulent, necrotic, or show exuberant granulation tissue. Ulcers usually appear in areas of trauma, more frequently on the lower limbs, are solitary or multiple, may converge, and tend to resolve with atrophic scars type “cigarette paper” or cribriform type.

The classic form of PG may be associated with inflammatory bowel disease, hematological malignancies, inflammatory arthropathies and monoclonal gammopathies. The syndromic types of PG related to autoinflammatory diseases also manifest with the ulcerative form of the disease^14-16. In addition to the classic presentation of PG, we have other forms that are necessary to know (Chart 1 and Figures 1 and 2)¹.

Chart 1 - Clinical variants of Pyoderma Gangrenosum¹.

Figure 1 - Clinical variants: ulcerative (a), bullous (b), pustular (c), vegetative (d), peristomal (e) and postoperative (f).

Figure 1 - Clinical variants: ulcerative (a), bullous (b), pustular (c), vegetative (d), peristomal (e) and postoperative (f).

Figure 2 - Peripheral erythema with violaceous edges (a), multiple ulcers (b), cribriform scar (c) and pathergy (d).

Figure 2 - Peripheral erythema with violaceous edges (a), multiple ulcers (b), cribriform scar (c) and pathergy (d).

PG can evolve with an abrupt onset and rapid progression of the lesions, when it usually presents with intense pain and general manifestations of fever, adynamia, myalgia and arthralgia, or follow an indolent course, with gradual progression of the lesions, usually without presenting general manifestations. Lymphangitis and lymphadenitis are usually not present¹⁷.

Rarely, some patients may have extracutaneous neutrophilic infiltration, either asymptomatic or accompanied by clinical manifestations, depending on the organ affected. It may occur in patients with hematological, intestinal, or rheumatic comorbidities and those without associated systemic disease. Extracutaneous manifestations are more common in the lungs and eyes, less common in the kidneys, spleen and bones, and rarer in muscles, mucous membranes (buccal, tongue, pharynx, larynx and genitalia)⁴, the central nervous system, the cardiovascular system and in the gastrointestinal tract¹⁸.

Clinical associations

Systemic diseases are frequently observed in patients with PG, but the frequency is quite variable in the different series published in the literature (33-78%)^9,11,19-21. In a systematic review of the literature and a multicenter study that evaluated a large number of patients with PG, the main systemic diseases associated with PG were inflammatory bowel disease, inflammatory arthropathies, solid tumors, and malignant and non-malignant hematological diseases (Chart 2)^21,22. In a large study that evaluated PG in 56,097 patients with inflammatory bowel disease, the frequency of PG was 0.5%, and this manifestation was more frequently associated with Crohn’s disease compared to ulcerative colitis²³. PG may occur concomitantly with the diagnosis of the systemic disease, or it may occur independently of the activity of the associated disease²⁴.

Chart 2 - Systemic diseases associated with pyoderma gangrenosum^21,22.

PG can also occur as a manifestation of different autoinflammatory syndromes, also referred to as syndromes related to neutrophilic dermatitis. These monogenic autoinflammatory syndromes present PG as part of their clinical manifestations. Also, variants in classically autoinflammatory genes are observed in patients with neutrophilic dermatitis, which draws attention to this clinical manifestation as part of the spectrum of polygenic autoinflammatory conditions¹⁶. Chart 3 describes the main autoinflammatory syndromes associated with PG manifestations, clinical manifestations, and related genes. In most syndromes, there is a mutation in the PSTPIP1 gene that encodes the CD2-binding protein, which leads to less inhibition of the inflammasome, with greater production of IL-1 and IL-18 and neutrophilic activation²⁵. The association with PG is seen in two other syndromes: the PASS syndrome (pyoderma gangrenosum, acne conglobata, hidradenitis suppurativa and axial spondyloarthritis) and the PsAPASH syndrome (pyoderma gangrenosum, acne, hidradenitis suppurativa and psoriatic arthritis), but there are no known genetic variants in association²⁶.

Chart 3 - Autoinflammatory syndromes that evolve with pyoderma gangrenosum^20,26.

Diagnosis

The diagnosis of PG is challenging and considered a diagnosis of exclusion since there are no specific clinical aspects and laboratory markers of the disease. Therefore, all differential diagnoses, in principle, should be systematically ruled out. The spectrum of conditions that deserve to be distinguished from PG is wide, which reinforces the complexity of its diagnosis and justifies the high frequency of diagnostic delays and errors, generally exposing patients to risks related to treatments^14,25,27.

Chart 4 lists the main differential diagnoses of PG, especially the classic form. The bullous form must be differentiated, particularly from autoimmune bullous dermatoses, erythema multiforme and dyshidrosiform dermatitis, while the pustular form deserves distinction, essentially, from bacterial pyoderma, pustular psoriasis, subcorneal pustular dermatosis and pustular eruptions caused by drugs.

Chart 4 - Main differential diagnoses of the classic ulcerated form of pyoderma gangrenosum.

Historically considered a diagnosis of exclusion, it would imply that all possible causes of cutaneous ulcers should be ruled out before confirming the diagnosis of PG, an impracticable and costly strategy today¹⁶. In order to resolve this impasse, proposals for the validation of diagnostic instruments have emerged to refine diagnostic accuracy. In 2004, Su et al.²⁸ were the first to propose diagnostic criteria guide for PG, which maintains the requirement of excluding other causes of skin ulceration.

A more complete diagnostic instrument, proposed by an international panel of specialists, resulted from a consensus using the Delphi method and is shown in Chart 5. This instrument also scores the criteria classified into four categories (histology, history, clinical examination and therapeutic response), and it guaranteed a sensitivity of 86% and a specificity of 90%. It could serve as a diagnostic guide for clinicians to reduce diagnostic errors and improve the selection of patients for clinical trials²⁹.

Chart 5 - Diagnostic tool for the classic ulcerated form of pyoderma gangrenosum (PG)^*.

Laboratory evaluation

The first step in the face of a suspected case of PG is to perform a deep incisional biopsy of the edge of the ulcer, including the adipose tissue. If this is not possible, a 4mm punch should be used for the biopsy. The sample taken must be divided into two fragments, one intended to execute cultures for bacteria, mycobacteria and fungi and the other fixed in formalin for histological processing. In addition to hematoxylin-eosin, special stains for bacteria, mycobacteria, fungi and protozoa, such as Gram, Fite, PAS and Giemsa, or corresponding ones, should be performed³⁰.

Histopathological findings are not diagnostic; however, in addition to helping to exclude differential diagnoses of PG, they are usually very suggestive, showing edema, and intense neutrophil infiltration, with the formation of microabscesses, hemorrhage and necrosis in the dermis, which can extend to the hypodermis, usually without the presence of vasculitis and leukocytoclasia. Specific stains for microorganisms are PG¹⁵ negative.

Although there is no standardized guideline for laboratory evaluation of suspected cases of PG, a series of preliminary tests can be recommended to rule out potential differential diagnoses and investigate the presence of possible associated conditions. Blood count, erythrocyte sedimentation rate, C-reactive protein, liver function, kidney function, electrophoresis of serum proteins, cryoglobulins, VDRL, autoantibodies (antinuclear, antineutrophil cytoplasmic, antiphospholipid), rheumatoid factor, routine urine and chest X-ray¹⁶.

Depending on any clinical manifestations associated with the suspected PG picture, the laboratory investigation should be extended with the request of specific tests, which may include vascular Doppler ultrasound, colonoscopy, radiographic images of affected joints, blood smear, myelogram, immunoelectrophoresis, coagulation tests, abdominal ultrasound and chest tomography, among others. Screening for malignant neoplasms is recommended according to the patient’s age, considering that PG can be a paraneoplastic manifestation^12,30.

Treatment

The treatment of pyoderma gangrenosum should be based on the characteristics of the lesion (location, number, size), extracutaneous manifestations, diseases associated with pyoderma, the presence of comorbidities²⁵, and the severity of the condition³¹. It ranges from local care, analgesia, topical medications, systemic treatment, and immunosuppressive agents to immunobiological agents^25,31,32 (Figure 3).

Figure 3 - Schematization of the treatment of pyoderma gangrenosum.

Figure 3 - Schematization of the treatment of pyoderma gangrenosum.

Topical treatment is indicated in cases of small lesions or localized pyoderma^25,32 and can be performed with high-potency topical corticosteroids, intralesional injection in the active edges of the lesion, or tacrolimus^25,31,32. Other options for topical use include sodium cromoglycate, nicotine, dapsone, and 5-aminosalicylic acid (5-ASA)^25,31.

Systemic treatment should be reserved for the most severe cases and is performed with corticosteroids, at a dose of 0.5 to 1.0mg/kg/day of prednisolone or equivalent, as a first-line drug^25,31. Intravenous pulse therapy with methylprednisolone (1g/day, 2 to 3 days)²⁵ may be prescribed as a measure of rapid response, in association with immunosuppressants³¹, such as methotrexate (2.5-25mg/week)²⁵, cyclophosphamide (0.5 -1.0g/day)²⁵, azathioprine (50-100mg/2xs day)²⁵, mycophenolate mofetil (1.0-1.5g/2xs day)²⁵ or IV immunoglobulins (2.0-3.0g/kg)²⁵.

Cyclosporine (2.5-5.0mg/kg/day)²⁵ can be used alone or as a corticosteroid-sparing agent, especially in cases where there is a need for prolonged treatment³¹. Topical or systemic antibiotics and antineutrophil agents such as dapsone (100mg/day) and colchicine (0.5-1.0mg/day) may be beneficial. Antineutrophil agents have anti-inflammatory and prophylactic effects against Pneumocystis jiroveci infection³².

Several immunobiological agents have been proposed to treat PG, with anti-TNF alpha agents being the most studied³². Ben Abdallah et al.³³, in a semi-systematic review of 222 articles, including 356 patients, demonstrated significant efficacy of these agents in adult individuals, with no statistically significant difference between infliximab, adalimumab or etanercept. The recommended doses are infliximab, 5mg/kg, EV²⁵; adalimumab, 40mg every other week, SC²⁵; etanercept, 50mg/week, SC³⁴.

Other biologic therapy options include ustekinumab (anti-IL 12/IL23)^25,35, secukinumab (anti-IL 17)³⁵, canakinumab (anti-IL 1beta)^25,35, anakinra (IL-1 receptor antagonist)^25,35, tocilizumab (anti-IL-6 receptor)^25,35, tofacitinib and ruxolitinib (ruxolitinib?) (JAK inhibitors)³⁵, and apremilast (phosphodiesterase 4 inhibitor)³⁵.

Regarding the wound, surgical debridement is contraindicated as soon as the diagnostic hypothesis is formulated. Differentiation in the approach is crucial, as postoperative patients are almost always managed with a surgical site infection; with antibiotics and aggressive wound manipulation, inadequate therapy leads to worsening PG cases. Care must be centered on using chemical-biological dressings (calcium alginate, hydrogel, among others) with minimal manipulation, giving preference to long-lasting and non-adherent dressings. Routine skin care, such as hygiene, hydration and related to the prevention of pressure ulcers, should be redoubled.

Negative pressure therapy may be used, and hyperbaric oxygen therapy may be indicated for those who are intolerant or unresponsive to corticosteroid therapy. In patients with chronic wounds, a dermal matrix can and should be considered an alternative to promote wound closure.