Pyoderma gangrenosum: Clinical Guidelines

List of Abbreviations

DNA – deoxyribonucleic acid

IL – interleukin

TNF – tumor necrosis factor

PAPA – Pyogenic Arthritis, Pyoderma gangrenosum, Acne (genetic syndrome including pyogenic arthritis, pyoderma gangrenosum, acne)

PAPASH – Pyogenic Arthritis, Pyoderma gangrenosum, Acne, Suppurativa Hidradenitis (a genetic syndrome comprising pyogenic arthritis, pyoderma gangrenosum, acne, and hidradenitis suppurativa)

PASH – Pyoderma gangrenosum, Acne, Suppurativa Hidradenitis (a genetic syndrome comprising pyoderma gangrenosum, hidradenitis suppurativa, and acne)

PASS – Pyoderma gangrenosum, Acne conglobata, Suppurativa hidradenitis, seropositive Spondyloarthropathies (a genetic syndrome comprising pyoderma gangrenosum, acne conglobata, hidradenitis suppurativa, and seropositive spondyloarthropathy)

PsAPASH – Psoriatic Arthritis, Pyoderma gangrenosum, Acne, Suppurativa Hidradenitis (a genetic syndrome comprising psoriatic arthritis, pyoderma gangrenosum, acne, and hidradenitis suppurativa)

Th – T helper cell

Terms and Definitions

Pyoderma gangrenosum is an autoinflammatory skin disease characterized mainly by sterile pustules and/or ulcers, driven by excessive neutrophil activation and dysfunction, which is accompanied by increased production of cytokines and chemokines in the lesions.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Pyoderma gangrenosum is an autoinflammatory skin disease characterized mainly by sterile pustules and/or ulcers, driven by excessive neutrophil activation and dysfunction, which is accompanied by increased production of cytokines and chemokines in the lesions.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Initially, pyoderma gangrenosum was classified among pyodermas; however, it was subsequently established that ulcers in this disease are primarily sterile, and the detection of microorganisms on their surface is due to secondary colonization, meaning that pyoderma gangrenosum is not an infectious disease [1].

The development of pyoderma gangrenosum is associated with neutrophil abnormalities, dysregulation of innate and adaptive immune responses, and genetic factors [1–3]. Although clonal expansion of T lymphocytes is observed even in the early stages of pyoderma gangrenosum lesion formation, a particular significance in the pathogenesis of this disease is attributed to neutrophils [3–5]. The crucial role of neutrophils in the pathogenesis of pyoderma gangrenosum is evidenced by the presence of a large number of these cells in the lesions, where neutrophil abscesses form and purulent inflammation develops [6]. The increase in neutrophil count within pyoderma gangrenosum lesions is attributed to the elevated production of corresponding chemoattractants in the affected areas, namely interleukin-6 (IL-6), IL-8/CXCL8, and CXCL1, CXCL2, CXCL3 [7–9]. At the same time, there is evidence of functional defects in neutrophils present in the lesions, resulting in impaired chemotaxis, adhesion, trafficking, and phagocytosis [1]. The pathogenetic importance of neutrophils is also confirmed by the association of pyoderma gangrenosum with other conditions characterized by impaired neutrophil function, such as inflammatory bowel disease, rheumatoid arthritis, seronegative arthritis, hematological disorders, and malignancies like acute myeloid leukemia [1–3].

The pathergy phenomenon observed in pyoderma gangrenosum—the appearance of typical disease lesions at the site of trauma—is linked to increased neutrophil activity in the affected areas [1].

The inflammatory response in pyoderma gangrenosum lesions is driven by the production of various cytokines by infiltrating cells—IL-1α, IL-1β, tumor necrosis factor alpha (TNF-α), interferon-γ, IL-8, and IL-36α, endothelial and leukocyte selectins, as well as chemokines IL-8, CXCL16, and RANTES [10–13]. In addition, elevated levels of IL-23 (which promotes the differentiation of Th17 lymphocytes) and IL-17 (produced by Th17 lymphocytes) have been detected in pyoderma gangrenosum lesions [10, 14].

A decrease in the ratio of regulatory T cells to Th17 lymphocytes in pyoderma gangrenosum lesions also plays a pathogenetic role. Regulatory T cells help prevent autoinflammatory reactions; therefore, a reduction in their numbers can lead to the uncontrolled activation of pro-inflammatory cells and cytokines, such as IL-17-producing Th17 lymphocytes [15].

Cytokine action is associated with the activation of pattern recognition receptor (PRR) intracellular signaling pathways—identified in the affected skin of pyoderma gangrenosum—and increased expression of Janus kinases (JAK) 1–3 and signal transducers and activators of transcription (STAT) by dermal infiltrate cells [16, 17].

Pyoderma gangrenosum is characterized by the overexpression of matrix metalloproteinases, which not only play a major role in the damage and destruction of the extracellular matrix leading to ulcer formation, but also contribute to increased production of neutrophil chemokines [1, 18].

A hypothesis has been proposed suggesting that the development of pyoderma gangrenosum is driven by an abnormal immune response targeting pilosebaceous units. Unlike psoriasis and venous stasis, ulcers in pyoderma gangrenosum never occurred at the site of previously existing ulcers, and biopsies of healed lesions and unaffected skin resulted in ulceration as a pathergy phenomenon only when unaffected skin was biopsied [13]. It has been suggested that this occurs due to the loss of a target autoantigen that may be located in follicular skin appendages. This theory is supported by the absence of ulceration in pyoderma gangrenosum in areas devoid of follicular skin appendages, such as the nipple-areola complex, palm, and sole [13].

The importance of genetic factors in the pathogenesis of pyoderma gangrenosum is demonstrated by genetic syndromes associated with the condition. All mutations leading to pyoderma gangrenosum-associated genetic syndromes are linked to a state that facilitates the development of autoinflammatory reactions. PAPA, PASH, and PAPASH syndromes, one of whose manifestations is pyoderma gangrenosum, are associated with mutations in the PSTPIP1 and NCSTN genes. These mutations are linked to an uncontrolled increase in IL-1 production, leading to autoinflammatory reactions [19–22]. In cases of pyoderma gangrenosum associated with inflammatory bowel disease, genetic abnormalities in the IL8RA, TIMP3, and TRAF3IP2 gene loci have occasionally been detected, which encode the IL-8 receptor, matrix metalloproteinase inhibitor, and an IL-17 signal transduction protein, respectively [20].

Familial cases of pyoderma gangrenosum have been described both with and without an associated disease, as well as cases where skin lesions in family members developed following trauma or surgical interventions [23–27].

1.3 Epidemiology of the Disease or Condition

Pyoderma gangrenosum is a rare skin disease; exact data on its incidence and prevalence are lacking due to a scarcity of epidemiological studies. The incidence of pyoderma gangrenosum is estimated to be 3 to 10 cases per million population per year [18, 28, 29]. In the UK, the incidence of pyoderma gangrenosum was 0.63 cases per 100,000 population per year [30]. The mean age of onset for pyoderma gangrenosum is 51.6 years [31].

The prevalence of pyoderma gangrenosum in the United States was 0.0058%, or 5.8 cases per 100,000 adults, with the prevalence in women (7.1 cases per 100,000 adults) being nearly twice as high as in men (4.4 cases per 100,000 adults) [32]. The highest prevalence of pyoderma gangrenosum was observed in the 70–79 age group at 9.8 per 100,000 of the corresponding population, and individuals aged 50 years and older accounted for 69.5% of pyoderma gangrenosum cases [32]. Pediatric patients account for approximately 4% of patients with pyoderma gangrenosum [18, 28].

Pyoderma gangrenosum is often associated with certain internal organ diseases that may occur before, concurrently with, or after the diagnosis of pyoderma gangrenosum [20, 33–36]. Associated diseases were identified in 66.9% of patients with pyoderma gangrenosum [31]. Inflammatory bowel disease (Crohn's disease or ulcerative colitis) was present in 41.0% of patients with pyoderma gangrenosum, inflammatory arthritis in 20.5%, internal organ malignancies in 6.5%, hematological malignancies (lymphomas, leukemias, multiple myeloma) in 5.9%, and other hematological diseases, monoclonal gammopathy of undetermined significance, myelodysplastic syndrome, and polycythemia vera in 4.8% of patients [31]. Inflammatory bowel disease was more common in patients with pyoderma gangrenosum younger than 65 years (47.7% compared with 26.6% of cases aged 65 years and older). Rheumatoid arthritis (13.3% of cases vs. 6.2% of cases under 65), visceral malignancies (13.3% of cases vs. 3.3% of cases under 65), hematological malignancies (9.7% of cases vs. 4.1% of cases under 65), and other blood disorders (10.6% of cases vs. 2.1% of cases under 65) were more frequently observed in patients with pyoderma gangrenosum aged 65 years and older [31]. Depression was diagnosed in 14% of patients with pyoderma gangrenosum, and psoriasis in 11% [36].

Patients with pyoderma gangrenosum have a 3-fold increased risk of death [30]. The overall mortality of patients with pyoderma gangrenosum over an 8-year follow-up period was 16% [36].

1.4 Features of Coding the Disease or Condition

L88 – Pyoderma gangrenosum

1.5 Classification of the disease or condition

Depending on the nature of the skin lesions, 4 clinical forms of pyoderma gangrenosum are distinguished [37]:

1. Ulcerative (classic).

2. Bullous.

3. Pustular.

4. Vegetative.

In addition, two more clinical forms of pyoderma gangrenosum are distinguished, taking into account the origin of the lesions, which in these cases represent a manifestation of the pathergy phenomenon [3]:

5. Peristomal.

6. Postoperative [2, 3].

The features of various clinical forms of pyoderma gangrenosum include their localization, the degree of clinical aggressiveness, and the presence of associations with specific systemic diseases [3].

1.6 Clinical presentation of the disease or condition

Pyoderma gangrenosum lesions can appear anywhere except the nipple-areolar complex, palms, and soles. The primary lesion of pyoderma gangrenosum is a soft erythematous nodule, plaque, vesicle, or sterile pustule, at the site of which ulcers rapidly form. Ulcers in pyoderma gangrenosum are usually aseptic, although superinfection may occur [38, 39].

The course of the disease is extremely variable. In most cases, there are one to three lesions that slowly increase in size and typically occupy less than 5% of the total body surface area [3]. In other patients, the disease manifests with the sudden appearance of multiple rapidly enlarging lesions. In such cases, a severe course of the disease is possible with multiple large ulcerating lesions [40].

The appearance of lesions may be accompanied by fever, malaise, myalgia, and arthralgia. Approximately one-third of patients with pyoderma gangrenosum exhibit the pathergy phenomenon—the appearance of typical disease lesions at the site of trauma. Pathergy was more frequently observed in patients older than 65 years, but its frequency may be underestimated if there was no trauma capable of triggering the pathergy phenomenon [3, 31, 36].

Pyoderma gangrenosum lesions are painful, sometimes severely so, especially during the growth of the ulcers [41].

Healing of ulcerated lesions occurs through the extension of epithelial strands from the edges of the ulcer toward its center—the Gulliver sign [42, 43]. As a result, they heal with cribriform scars or "cigarette paper" scars [2, 6].

Ulcerative (classic) pyoderma gangrenosum is the most common form of the disease. In adults, the characteristic localization of lesions in ulcerative pyoderma gangrenosum is the shins, although lesions may also appear in other anatomical areas [40, 44]. In children, lesions are usually located on the lower extremities, buttocks, perineum, and head and neck [45].

Initially, a soft nodule, plaque, or sterile pustule appears on a background of erythema. Within a few days, the primary lesion increases in size and transforms into a sharply demarcated, painful ulcer with undermined, overhanging reddish-purple or dark purple edges surrounded peripherally by a zone of erythema and infiltration. The edges of the ulcers may be elevated or consist of necrotic tissue. The base of the ulcer is usually filled with granulation tissue, and sometimes necrotic tissue, and covered with hemorrhagic or purulent exudate.

Two stages of the pathological process are distinguished in the ulcerative form of the disease: the active ulcerative stage and the wound healing stage [18]. In the active stage, ulcer lesions increase in size, sometimes rapidly. At this time, pain may intensify. Furthermore, disease progression can occur with the appearance of pustules at the periphery of existing lesions. During progression, the underlying dermis and subcutaneous tissue down to the muscles may undergo necrosis.

In the healing stage, cord-like epithelial extensions spread from the edges of the ulcer into its central part (Gulliver sign), leading to the formation of cribriform or "cigarette paper" scars [2, 6, 42, 43].

The ulcerative form of pyoderma gangrenosum is typically associated with inflammatory bowel disease, arthritis, and myeloproliferative disorders.

Pustular pyoderma gangrenosum is characterized by multiple sterile pustules with a surrounding erythematous halo, usually located on the trunk and extensor surfaces of the extremities. Ulcer formation at the site of pustules is considered atypical in pustular pyoderma gangrenosum [46]. This form of the disease is usually associated with inflammatory bowel disease, and if therapeutic control of the bowel disease is achieved, remission of skin lesions may also occur [18, 46–48].

Bullous pyoderma gangrenosum typically presents as lesions on the dorsal hands, extensor surfaces of the upper extremities, or the head, where grouped vesicles appear that rapidly spread and merge into large bullae, subsequently forming ulcers with central necrosis and a peripheral erythematous halo. The bullous form is mainly observed in patients with lymphoproliferative disorders as a paraneoplastic manifestation. An association between bullous pyoderma gangrenosum and myeloproliferative diseases, particularly acute myeloid leukemia, is possible [2]. Pyoderma gangrenosum in patients with hematological disorders may indicate malignant transformation and point to a poor prognosis or aggressive course of the blood disease [6, 18].

Vegetative or superficial granulomatous pyoderma gangrenosum is characterized by a solitary, erythematous, ulcerated plaque lacking the purplish coloration of the borders typically seen in the classic ulcerative form [33, 38]. This is the rarest and most benign form of the disease, rarely associated with other conditions and generally demonstrating a good response to therapy [18, 39, 49].

Postoperative pyoderma gangrenosum develops following surgical interventions. Most frequently, the development of pyoderma gangrenosum is described after breast and thoracic surgeries, including cardiac surgery [2]. The risk of skin lesion development is higher after extensive surgical procedures and in the presence of chronic diseases in patients [3]. It has been noted that 15.1% of patients with a prior diagnosis of pyoderma gangrenosum who underwent surgery developed postoperative pyoderma gangrenosum lesions or experienced an exacerbation of pre-existing skin lesions [50]. The time between surgery and the first manifestations of postoperative pyoderma gangrenosum averages 11 days, although skin lesions can develop immediately after surgery [2, 3]. If skin lesions in postoperative pyoderma gangrenosum are misdiagnosed as a wound infection, the patient may undergo surgical wound debridement, which can worsen the patient's condition, as the course of postoperative pyoderma gangrenosum—being a manifestation of the pathergy phenomenon—worsens following skin trauma.

Peristomal pyoderma gangrenosum develops in patients with stomas, most commonly created for inflammatory bowel disease, but it can also occur in patients with urostomas [2, 51]. The onset of peristomal pyoderma gangrenosum lesions can occur at any time following stoma creation—ranging from a few weeks to several years. Peristomal pyoderma gangrenosum manifests as a deep, painful nodule or a superficial pustule with purulent-hemorrhagic contents, appearing spontaneously or after minimal trauma. Subsequently, necrosis develops at the site, forming a crateriform ulcer with purulent discharge. The resulting ulcer may be single, or multiple ulcers may form. In most cases, the size of the ulcers does not exceed 3 cm in diameter, though large ulcers up to 30 cm in diameter can form [52].

Pyoderma gangrenosum may be accompanied by various cutaneous appendage and joint disorders, forming corresponding syndromes (Table 1).

Table 1. Syndromes associated with pyoderma gangrenosum

Secondary infection should be considered a complication of pyoderma gangrenosum therapy, manifesting as abundant purulent discharge from the ulcers, increased erythema, and edema in the affected areas [18].

The formation of extracutaneous neutrophil infiltrates in the bones, liver, lungs, pancreas, spleen, kidneys, and central nervous system is possible, though rare [18, 38, 53, 54]. Ocular involvement (scleritis and corneal ulceration), pulmonary involvement (aseptic nodules with or without cavities, interstitial lung disease, and pleural effusion), and musculoskeletal involvement (sterile pioarthrosis, neutrophilic myositis) have been described [2, 3, 55–60].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Pyoderma gangrenosum is diagnosed clinically; there are no specific laboratory (serological, histological) markers for pyoderma gangrenosum. However, the ulcerative skin lesions in pyoderma gangrenosum may be visually indistinguishable from ulcerations caused by infectious skin diseases, certain neoplasms, vascular disorders, autoimmune diseases, and other autoinflammatory conditions (Table 2). Therefore, the diagnosis of pyoderma gangrenosum is a diagnosis of exclusion, established after ruling out other potential causes of cutaneous ulceration, which requires laboratory evaluation [61, 62].

Table 2. Differential diagnosis of pyoderma gangrenosum

The minimum diagnostic workup for a patient with pyoderma gangrenosum must include a thorough history taking, a complete physical examination, and a pathological examination of skin biopsy material [55]. Analysis of anamnestic data helps determine the presence of the patergy phenomenon (whether lesions appeared at sites of trauma), the clinical course (triggering factors, ulcer growth rate), and the results of prior therapy. A complete physical examination is necessary to assess the morphological character of the skin lesion and its location, as well as to evaluate the patient for associated conditions, including genetic syndromes such as PAPA, PASH, PASS, PAPASH, and PsAPASH (acne, hidradenitis suppurativa, arthritis). Clinical and anamnestic signs pointing toward a diagnosis of pyoderma gangrenosum have been identified. These include pain associated with cutaneous ulcer defects, rapid enlargement, prolonged persistence, lack of response to systemic antibacterial therapy, clinical worsening after surgical treatment (manifestation of the patergy phenomenon), and the presence of typical associated conditions [55].

The primary method for differential diagnosis between pyoderma gangrenosum and skin neoplasms is the pathological examination of skin biopsy material, which is also important for differentiating pyoderma gangrenosum from infectious skin ulcers. To rule out infectious etiologies and identify the causative agent, standard hematoxylin and eosin staining of histological specimens, as well as special stains, may be required [55]. If an infectious etiology of the skin ulcer needs to be excluded, a microbiological (culture) examination of purulent discharge for aerobic and facultatively anaerobic microorganisms, Mycobacterium tuberculosis complex, and skin scrapings for fungi (yeasts, molds, dermatophytes) may also be necessary. Pathological examination of skin biopsy material using immunofluorescence methods may be required in the differential diagnosis of cutaneous ulceration between pyoderma gangrenosum, vasculitis, and other autoimmune diseases [63].

Diagnostic criteria for ulcerative pyoderma gangrenosum have been developed. The diagnostic criteria for ulcerative pyoderma by W. Su et al. (2004) include 2 major and 4 minor criteria [41] (Appendix G1). The diagnostic criteria for classical (ulcerative) pyoderma of the Delphi Consensus of international experts include 1 major and 8 minor criteria [64] (Appendix G2).

When evaluating a patient with pyoderma gangrenosum, the presence of associated diseases should be assessed, as this association may influence treatment selection [29, 37, 65]. A thorough history and complete physical examination can suggest the presence of an associated disease. As an initial screen for hematological disorders and liver and kidney dysfunction—which may result from potential associated conditions—a complete blood count (CBC) with differential leukocyte count, general biochemical blood analysis (including blood electrolytes and liver function tests), and a routine urinalysis are used [55]. It should be noted that nonspecific changes in the CBC are common in pyoderma gangrenosum, have no diagnostic value, and rather reflect disease severity—namely, an elevated erythrocyte sedimentation rate and elevated blood neutrophils [55, 66]. If pyoderma gangrenosum is suspected to be associated with vasculitis or another autoimmune disease, serum C-reactive protein levels, antiphospholipid antibodies, antinuclear and anti-DNA antibodies, and antineutrophil cytoplasmic antibodies may be required.

If signs of an associated disease are detected in a patient with pyoderma gangrenosum, or if such a condition is suspected, consultations with relevant specialists are required: an internal medicine physician, gastroenterologist, rheumatologist, hematologist, and oncologist, who may order further investigations if necessary.

Criteria for establishing the diagnosis/condition:

Due to the absence of pathognomonic features for pyoderma gangrenosum, its diagnosis is based on identifying typical features of pyoderma gangrenosum and excluding other causes of such lesions using:

1) anamnestic data,

2) physical examination,

3) laboratory investigations,

4) pathological examination of skin biopsy material.

2.1 Complaints and Anamnesis

Complaints and anamnesis are described in Section 1.6. "Clinical presentation of the disease or condition (group of diseases or conditions)"

2.2 Physical Examination

Physical examination findings are described in Section 1.6. "Clinical presentation of the disease or condition (group of diseases or conditions)"

2.3 Laboratory Diagnostics

There are no specific laboratory criteria for diagnosing pyoderma gangrenosum. Therefore, pyoderma gangrenosum should be considered a clinical diagnosis of exclusion, as its clinical manifestations can be indistinguishable from other ulcerative skin lesions of infectious, neoplastic, or autoimmune origin, necessitating laboratory evaluation in patients with pyoderma gangrenosum [6, 67]. Laboratory workup is also essential to detect associated conditions and to monitor the safety of systemic therapy.

Comments: To identify associated conditions, it is necessary to assess the erythrocyte sedimentation rate (ESR) and perform a differential leukocyte count [18]. It should be noted that elevated ESR and neutrophilia often develop as manifestations of pyoderma gangrenosum, though they lack diagnostic specificity and rather reflect disease severity [55, 66]. Performing a complete blood count to monitor the safety of therapy with #prednisolone**, #cyclosporine**, #dapsone**, #mycophenolate mofetil**, #methotrexate**, #infliximab**, #adalimumab**, #etanercept**, #ustekinumab** is necessary due to their potential to affect hematopoiesis, causing anemia and/or neutropenia and/or thrombocytopenia [68–74].

Comments: Performing a routine general biochemical blood test to monitor the safety of therapy with #dapsone**, #cyclosporine**, #methotrexate**, #adalimumab**, #infliximab** is necessary due to the potential impact on liver function, lipid metabolism, and water-electrolyte balance [68, 70, 71, 73, 75–81].

Comments: An elevated serum C-reactive protein level may occur in patients with pyoderma gangrenosum [18]. However, its levels can also rise in vasculitis and other autoimmune disorders, whose clinical manifestations may be identical to those of pyoderma gangrenosum.

Comments: Clinically, skin lesions in antiphospholipid syndrome may be indistinguishable from pyoderma gangrenosum, but antiphospholipid syndrome is characterized by elevated blood levels of antiphospholipid antibodies.

Comments: Skin lesions in vasculitis and other autoimmune diseases may be clinically indistinguishable from pyoderma gangrenosum, but elevated levels of antinuclear and anti-DNA antibodies may indicate an autoimmune disease.

Comments: Skin involvement in ANCA-associated vasculitis can be clinically indistinguishable from pyoderma gangrenosum, whereas elevated blood levels of antineutrophil cytoplasmic antibodies serve as a laboratory marker of ANCA-associated vasculitis.

Comments: In systemic vasculitis, where skin lesions may clinically resemble those of pyoderma gangrenosum, protein may be detected in the urine. Immunosuppressive therapy with #cyclosporine**, #adalimumab**, or #infliximab** predisposes patients to infectious diseases of the kidneys and urinary tract [70, 82, 83].

Comments: Ulcerative skin lesions in pyoderma gangrenosum and ulcers of bacterial etiology may be clinically indistinguishable, necessitating microbiological (culture) examination for differential diagnosis.

Comments: Although ulcers in pyoderma gangrenosum are initially sterile, secondary infection may occur, requiring antibacterial therapy and the selection of a systemic antimicrobial agent to which the bacterial flora is susceptible.

Comments: Microbiological (culture) examination of purulent discharge for Mycobacterium tuberculosis complex is required in patients with clinical manifestations of pyoderma gangrenosum when it is necessary to rule out cutaneous tuberculosis as the cause of the ulcerative skin lesion

Comments: Ulcerative skin lesions in pyoderma gangrenosum can be clinically identical to fungal skin infections, necessitating microbiological (culture) examination for differential diagnosis.

2.4 Instrumental Diagnostics

Not applicable.

2.5 Other Procedures

Because the clinical manifestations of pyoderma gangrenosum can be identical to those of ulcerative skin lesions caused by infectious, neoplastic, or autoimmune diseases, differential diagnosis may require pathomorphological examination of a skin biopsy specimen, which is the primary diagnostic method for pyoderma gangrenosum. The sample should be obtained from the edge of the ulcer and adjacent skin. There are no definitive histological criteria for diagnosing pyoderma gangrenosum; it is a diagnosis of exclusion [6, 67].

Comments: The initial lesion preceding ulceration is characterized histologically by deep purulent, often folliculocentric inflammation with dense neutrophilic infiltrates; leukocytoclastic vasculitis is frequently detected [41]. The undermined border of the ulcer contains a mixed infiltrate with a predominance of neutrophils, while the base of the lesion typically shows signs of necrosis and hemorrhage. A specimen obtained from the area of erythema surrounding the ulcer may reveal a neutrophil-predominant infiltrate, necrosis, and blood vessel thrombosis [41]. Edema and neutrophilic abscesses in the dermis may be present, and purulent inflammation can extend from the dermis into the subcutaneous adipose tissue. Pustular pyoderma gangrenosum presents with a neutrophilic dermal infiltrate and subcorneal neutrophilic micropustules. Vegetative pyoderma gangrenosum is characterized by granulomas centered by neutrophilic inflammation, palisaded by a rim of histiocytes, which in turn is surrounded by a lymphocytic infiltrate. Special histological stains to identify fungi, protozoa, and bacteria may be required for differential diagnosis with ulcers of infectious etiology [6, 67].

Comments: In pyoderma gangrenosum, deposition of IgM, the C3 complement component, and fibrin in vessel walls is detected in the majority of cases [55, 63, 84].

Comments: It should be noted that a disease or neoplasm associated with pyoderma gangrenosum may develop either before or after skin manifestation.

Comments: Inflammatory bowel disease associated with pyoderma gangrenosum may develop both before and after the manifestation of skin lesions. It should be kept in mind that manifestations of inflammatory bowel disease may be mild, which requires a careful medical history and a thorough physical examination of patients with pyoderma gangrenosum. Even mild, infrequent abdominal pain and occasional episodes of mild diarrhea, which the patient might ignore, can be manifestations of inflammatory bowel disease.

Comments: Hematologic disease or neoplasm associated with pyoderma gangrenosum may develop both before and after the manifestation of skin lesions.

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: Inflammatory joint disease associated with pyoderma gangrenosum may develop both before and after the manifestation of skin lesions. It should be kept in mind that manifestations of inflammatory joint disease may be mild, which requires a careful medical history and a thorough physical examination of patients with pyoderma gangrenosum. Even mild, infrequent pain and occasional episodes of erythema and swelling in the joint area can be manifestations of arthritis associated with pyoderma gangrenosum.

Comments: During therapy with tumor necrosis factor-alpha (TNF-alpha) inhibitors or interleukin inhibitors, reactivation of mycobacterial infection with the development of pulmonary and extrapulmonary tuberculosis is possible, which necessitates a repeat consultation with a phthisiatrician before initiating treatment with these drugs and periodically (every 6 months) during therapy. The risk of mycobacterial infection activation is higher when using tumor necrosis factor-alpha (TNF-alpha) inhibitors.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

The mainstay of therapy for patients with pyoderma gangrenosum is conservative treatment using systemic and topical medications. Conservative treatment aims to achieve regression of skin lesions, prevent or eliminate complications (primarily secondary infection or severe pain in the skin lesion areas), and its prescription must take into account the absence or presence of associated diseases that may influence the choice of therapy. In addition, despite the potential manifestation of the pathergy phenomenon, patients with pyoderma gangrenosum may require surgical treatment.

Pyoderma gangrenosum therapy is often long-term and may require changing medications, making it appropriate to establish realistic expectations for the ongoing therapy with patients from the outset. According to data from an analysis of the disease course in 86 patients, it takes an average of 12 months for patients with pyoderma gangrenosum receiving therapy to recover [65].

3.1 Conservative Treatment

Patients with pyoderma gangrenosum are prescribed both systemic and topical therapy. Topical therapy is administered to all patients with pyoderma gangrenosum, whether they have solitary, localized skin lesions or widespread rashes. Topical therapy for pyoderma gangrenosum may include dermatological corticosteroids as well as non-corticosteroid dermatitis medications (#tacrolimus**, #pimecrolimus**). These medications should be applied to the inflamed border of the ulcer rather than its base [55]. However, there is a report of #pimecrolimus** cream application to the ulcer after the elimination of bacterial infection and clearance of purulent discharge [87]. Topical therapy alone may be used in patients with solitary, localized skin lesions, such as peristomal pyoderma gangrenosum, but systemic therapy is required if its efficacy is insufficient or in patients with widespread skin involvement.

The primary systemic medications for patients with pyoderma gangrenosum are systemic corticosteroids, which can be prescribed orally or intravenously as pulse therapy. Short-term systemic corticosteroid pulse therapy is administered, and if its effect is insufficient, therapy may be continued with oral systemic corticosteroids, #cyclosporine**, #dapsone**, or #mycophenolate mofetil**. In case of monotherapy failure, combination therapy using systemic corticosteroids and #methotrexate** or #cyclosporine** may be prescribed. If this proves ineffective, immunosuppressants such as tumor necrosis factor-alpha (TNF-alpha) inhibitors or interleukin inhibitors may be prescribed.

Patients with pyoderma gangrenosum may require therapy to manage complications of the disease (secondary infection) and symptomatic treatment if the patient develops pain at the skin lesion sites. In the presence of a secondary infection with purulent discharge, antibiotics and antimicrobial agents used in dermatology may be used to treat patients with pyoderma gangrenosum, which can be combined with antiseptics and disinfectants or other antibacterial drugs. If there is profuse purulent discharge or widespread skin involvement accompanied by purulent discharge, systemic antibacterial drugs are required. When a patient develops pain in the areas of skin lesions, nonsteroidal anti-inflammatory and antirheumatic drugs are prescribed.

An important component of therapy for patients with pyoderma gangrenosum is adequate care for ulcerative skin lesions, as their healing may be delayed by bacterial superinfection, edema, and circulatory insufficiency [88, 89]. Therefore, regular dressing changes with adequate compression are necessary [89].

Comments: A prospective cohort study involving adult patients noted healing of 43.8% of ulcers after 6 months of topical therapy with clobetasol, and the median time to ulcer healing was 145 days, although 15% of patients experienced a relapse [94].

• or

  clobetasol 0.05% ointment, cream for external use in pediatric patients: apply in a thin layer and gently rub in, covering the entire affected area, 1–2 times a day [95]

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: In a 1-year-old child, clobetasol therapy led to significant improvement as early as the second day of treatment [95]. A contraindication to prescribing 0.05% clobetasol cream and ointment is age under 1 year.

• or

  #tacrolimus** 0.03% / 0.1% ointment for external use is applied in a thin layer to the affected skin areas 2 times a day. After improvement or after healing of erosive and ulcerative lesions, it is possible to switch to less frequent applications of the ointment 1 time a day for 2 months and thereafter 2 times a week for 6–12 months, or to use #tacrolimus** 0.03% ointment for external use [96–99]

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: Treatment with #tacrolimus** in five patients with pyoderma gangrenosum involving no more than 5% of the body surface area and having no more than 3 lesions has been shown to achieve complete remission on average 6 weeks after treatment initiation [96]. A case of peristomal pyoderma gangrenosum has been described where in a female patient with a 3 cm ulcer, a reduction in the size of the skin ulcer was observed 2 months after starting therapy with 0.1% #tacrolimus** ointment, after which applications of 0.03% #tacrolimus** ointment were initiated [97].

• or

  #pimecrolimus** 1% cream for external use in adult patients: apply in a thin layer to the affected surface 2 times a day and gently rub in until fully absorbed [87]

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: A case has been described where the effect of therapy with 1% #pimecrolimus** cream became noticeable 15 days after treatment initiation (reduction in erythema, ulcer size, and pain), and complete healing of the patient's two existing ulcers occurred at 8 and 12 weeks, respectively [87]. A contraindication to prescribing #pimecrolimus** ointment is age under 3 months.

• or

  dexamethasone 2–5 mg/kg body weight in adult patients intravenously as an infusion once daily for 3–5 days [100]

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

• or

  #dexamethasone 2–5 mg/kg body weight in pediatric patients intravenously as an infusion once daily for 3–5 days [100]

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

• or

  #methylprednisolone** 1 g in 150 ml of 5% dextrose** solution in adult patients intravenously as infusions lasting 60–90 minutes for 1–5 days [53, 101–103]

Level of Recommendations CLevel of Evidence 3Level of Recommendation C (Level of Evidence – 3)

Comments: Improvement in patient condition, manifested by a decrease in erythema intensity, pus formation, reduction of pain in the areas of skin lesions, and cessation of the appearance of new rashes, may be noted as early as 24–48 hours after starting pulse therapy with systemic corticosteroids [100]. After its completion, systemic corticosteroid therapy must be continued orally.

Comments: In a group of 53 patients with pyoderma gangrenosum treated with #prednisolone** at a daily dose of 0.75 mg/kg body weight, which was increased if necessary up to 1 mg/kg body weight per day, complete ulcer healing after 6 weeks of therapy was observed in 21% of patients, and after 6 months in 47% of patients [105].

• or

  #methylprednisolone** orally at 0.5–1.0 mg/kg body weight per day [53, 55, 108]

GCR CLoE 3Grade of Recommendation C (Level of Evidence – 3)

Comments: After achieving the effect of ulcer scarring, systemic corticosteroid therapy should be continued, gradually reducing the daily dose of the medicinal product over several months. During treatment with systemic corticosteroids, adverse events may develop, requiring safety monitoring of therapy (Appendix A3).

• or

  #cyclosporine** 3–5 mg/kg body weight per day in adult patients orally 2 times a day [105, 109–112]

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: A comparative study showed that the efficacy of #cyclosporine** in treating patients with pyoderma gangrenosum is comparable to that of #prednisolone** [105]. In a group of 59 patients with pyoderma gangrenosum treated with #cyclosporine** at a daily dose of 4 mg/kg body weight, complete ulcer healing after 6 weeks of therapy was observed in 15% of patients, and after 6 months in 47% of patients [105]. #Cyclosporine** may have an advantage over #prednisolone** when choosing therapy for patients with pyoderma gangrenosum and concomitant diabetes mellitus [112].

During treatment with #cyclosporine**, adverse events may develop, requiring safety monitoring of therapy (Appendix A3).

• or

  #dapsone** 50–200 mg per day in adult patients orally [55, 113, 114]

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: There are only isolated case reports demonstrating the efficacy of #dapsone** in pyoderma gangrenosum [113, 114]. In these cases, complete ulcer healing took from 4 weeks to 2 months of #dapsone** therapy [113, 114].

During treatment with #dapsone**, adverse events may develop, requiring safety monitoring of therapy (Appendix A3).

• or

  #mycophenolate mofetil** in adult patients orally at an initial dose of 0.5–1 g per day, and a maximum dose ranging from 0.5 g 4 times a day to 1.5 g 2 times a day [115]

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: The results of treating 7 patients with pyoderma gangrenosum using #mycophenolate mofetil** are described, according to which the therapeutic effect of the drug becomes noticeable 4–12 weeks after treatment initiation [115]. Improvement in condition was noted in 6 out of 7 patients, and complete ulcer healing in 4 patients [115].

• or

  #prednisolone** 0.6 mg/kg per day orally combined with #cyclosporine** 3 mg/kg per day orally and #minocycline 100 mg per day orally in adult patients [116]

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

• or

  #prednisolone** 40 mg per day orally combined with #methotrexate** 15 mg once a week orally, subcutaneously, or intramuscularly in adult patients [117]

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: #Infliximab** is administered intravenously over 2 hours. If infusion reactions do not occur, it can also be administered over 1 hour. During the infusion and for 1 hour after it, patients must be monitored for the presence of infusion reactions. Increasing the intervals between infusions increases the likelihood of antibody formation against #infliximab** and a decrease in therapeutic efficacy.

A randomized study showed that 2 weeks after the first infusion of #infliximab**, a reduction in the severity of the condition and/or ulcer size was observed in 46% of patients with pyoderma gangrenosum. By week 6 of therapy, improvement was noted in 20 out of 29 (69%) patients treated with #infliximab**, with complete regression of rashes occurring in 6 out of 29 (21%) patients [118]. Treatment with #infliximab** was ineffective in 31% of patients [118].

Therapy with #infliximab** may be accompanied by the development of adverse events; therefore, before and during treatment with infliximab**, the safety of the ongoing therapy should be monitored (Appendix A3).

#infliximab**lyophilized powder for concentrate for solution for infusion 5 mg/kg body weight for pediatric patients intravenously according to the administration schedule: weeks 0, 2, and 10 [123, 150]

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: A contraindication to the prescription of #infliximab** is pediatric age under 18 years (except for Crohn's disease and ulcerative colitis, for which #infliximab** is contraindicated under 6 years of age). Therefore, #infliximab** may be prescribed to pediatric patients with pyoderma gangrenosum if they are also diagnosed with Crohn's disease or ulcerative colitis.

• or

  #adalimumab** solution for subcutaneous injection for adult patients subcutaneously 80 mg or 160 mg on day 1, 80 mg after 2 weeks, then 40 mg once every 1–2 weeks [124–127]

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: Cases of ulcer healing in patients with pyoderma gangrenosum 2 months after the initiation of #adalimumab** therapy have been described [125, 126].

Adalimumab** therapy is associated with the development of adverse events; therefore, before and during treatment with #adalimumab**, the safety of the ongoing therapy should be monitored (Appendix A3).

• or

  #etanercept** subcutaneously for adult patients 25–50 mg twice a week or 50 mg once a week [128–132]

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: In a group of 7 patients with pyoderma gangrenosum who had 11 ulcers, treatment with #etanercept** at a dose of 25–50 mg twice a week led to the resolution of 8 out of 11 ulcer lesions in an average of 12.5 weeks, while the remaining 3 ulcers significantly decreased in size [128]. Cases of ulcer healing 8 weeks and 4 months after starting #etanercept** therapy at 25 mg twice a week have been described [129, 130]. Treatment with #etanercept** is contraindicated in patients under 12 years of age and with a body weight of less than 62.5 kg.

Therapy with #etanercept** is associated with the development of adverse events; therefore, before and during treatment with #etanercept**, the safety of the ongoing therapy should be monitored (Appendix A3).

• or

  #ustekinumab** solution for subcutaneous injection for adult patients 45 mg for patients with a body weight of no more than 100 kg or 90 mg for patients with a body weight of more than 100 kg subcutaneously according to the injection schedule: weeks 0, 4, and then every 12 weeks [14, 133]

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: A case of complete remission in a patient with pyoderma gangrenosum 14 weeks after the initiation of #ustekinumab** treatment has been described [14]. In another patient, almost complete regression of rashes was observed 22 weeks after the first #ustekinumab** injection [133].

Therapy with #ustekinumab** is associated with the development of adverse events; therefore, before and during treatment with #ustekinumab**, the safety of the ongoing therapy should be monitored (Appendix A3).

• or

  #canakinumab** solution for subcutaneous injection subcutaneously for adult patients at week 0 at a dose of 150 mg, then at week 2 (if the therapeutic response is insufficient) at a dose of 150 mg, then at week 8 at a dose of 150 mg or 300 mg [12]

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: In a group of 5 patients with pyoderma gangrenosum who received 2 or 3 injections of #canakinumab** over 8 weeks, when assessing the therapeutic effect at week 16 from the start of treatment (8 weeks after the last injection), 3 patients achieved complete remission and another showed an improvement in condition [12].

Therapy with #canakinumab** is associated with the development of adverse events; therefore, before and during treatment with #canakinumab**, the safety of the ongoing therapy should be monitored (Appendix A3).

3.2 Surgical Treatment

Patients with pyoderma gangrenosum may require surgical treatment, the purpose of which may be to remove necrotic tissue or accelerate the healing of existing skin ulcer defects using tissue transplantation methods. Surgical treatment in pyoderma gangrenosum should be used with caution due to the possible manifestation of the pathergy phenomenon characteristic of this disease—the appearance of typical rashes at the site of trauma. Consequently, surgical trauma can serve as a triggering factor for the appearance of pyoderma gangrenosum lesions [6, 90, 135, 136]. Any surgical intervention must be performed against the background of immunosuppressive therapy and only in those patients whose disease progression has been halted [136]. Immunosuppressive therapy should be continued until complete healing of the ulcers and the donor site, if skin autologous grafting was performed [137].

Comments: It is necessary to consider the possibility of patients with pyoderma gangrenosum developing new rashes at the site of trauma, including surgical trauma.

Comments: A case has been described where a patient underwent surgical wound debridement with the removal of necrotic tissue under general anesthesia [138]

Comments: A prerequisite for the effectiveness of autologous skin grafting in patients with pyoderma gangrenosum is local and/or systemic immunosuppressive therapy [140].

3.3 Other Treatment

To prevent secondary infection of pyoderma gangrenosum lesions, antiseptics and disinfectants or other antibacterial agents (hydroxymethylquinoxalinedioxide) can be used, which can also be prescribed together with antibiotics and antimicrobial agents used in dermatology in the event of secondary infection of the lesions manifested by an increase in the amount of purulent discharge, increased intensity of erythema and edema. In case of secondary infection of pyoderma gangrenosum lesions with the development of bacterial tissue damage (lymphangitis, phlegmon) or widespread skin damage, the patient is prescribed systemic antibacterial drugs taking into account the sensitivity of microorganisms to them. If rashes are accompanied by pain, nonsteroidal anti-inflammatory and antirheumatic drugs must be prescribed.

Comments: There are no restrictions on the use of hydrogen peroxide** in children.

• or

  hydrogen peroxide 3% spray for external use – damaged areas of the skin are irrigated by pressing the spray nozzle in an amount sufficient to thoroughly moisten them [52]

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: There are no restrictions on the use of hydrogen peroxide** in children.

• or

  hydroxymethylquinoxalinedioxide 5 mg/ml (0.5%), 10 mg/ml (1%) solution for intracavity, local and external use for adult patients: for the treatment of superficial infected purulent wounds, gauze pads moistened with a 0.5%–1% solution of the drug are applied to the wound. Deep wounds, after treatment, are loosely packed with tampons moistened with a 1% solution of the drug, and if a drainage tube is present, 20 to 100 ml of a 0.5% solution of the drug is injected into the cavity [141].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

• or

  hydroxymethylquinoxalinedioxide 5% ointment for external use for adult patients is applied in a thin layer directly to the affected area, previously cleaned of purulent-necrotic masses, or used to pre-coat gauze pads 2–3 mm thick. Procedures are carried out daily or every other day [141].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: Mupirocin is effective against gram-positive bacteria, including methicillin-resistant staphylococci [55]. The frequency of application and duration of treatment depend on the dynamics of the clinical picture. The drug should not be used for more than 10 days. There are no restrictions on use in children.

• or

  dioxomethyltetrahydropyrimidine + chloramphenicol 40 mg/g + 7.5 mg/g ointment for external use for adult patients: sterile gauze pads are impregnated with the drug and used to loosely fill the wound. Dressings are performed daily, once a day [141]

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: Contraindication to the prescription of the drug is infancy under 1 year of age.

• or

  silver sulfadiazine 1% cream for external use for adults and children over 2 years of age: the damaged surface, after wound cleansing, is smeared with a 2 mm thick layer of cream 2 times a day; large damaged skin surfaces are covered with a sterile dressing changed 2 times a day, in severe cases up to 4 times [55, 142].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: Before each re-application, the previous layer of the drug must be removed with a stream of water or an antiseptic solution (antiseptics and disinfectants). Silver sulfadiazine is effective against most bacteria, including gram-negative bacilli [55]. A contraindication for prescribing 1% silver sulfadiazine cream is infancy under 2 years of age.

• or

  silver sulfathiazole 2% cream for external use for adult patients is applied to the skin defect after cleansing and surgical debridement under sterile conditions in a layer 2–3 mm thick 2–3 times a day [143]

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: The skin defect must be completely covered with cream during treatment. If part of the skin defect becomes exposed, additional cream must be applied. Application of an occlusive dressing is possible, but not mandatory. Contraindications for the prescription of silver sulfathiazole are prematurity and infancy under 2 months of age (risk of kernicterus).

• or

  minocycline 200–300 mg per day orally for pediatric patients for several weeks [55]

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: A contraindication for prescribing minocycline is childhood under 8 years of age.

• or

  amoxicillin + [clavulanic acid]** for adult patients orally [141]

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: The dosing regimen is established individually depending on age, body weight, and severity of the infection.

• or

  co-trimoxazole [sulfamethoxazole + trimethoprim]** 400 mg + 80 mg tablets 2 times a day for adult patients orally [127]

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: Pain in the area of ulcerative lesions is a common sign of pyoderma gangrenosum. During the active period of appearance and growth of lesions, pain may increase and be extremely intense, which requires pain relief. A decrease in pain intensity may be the first sign of healing even before the appearance of signs of ulcer re-epithelialization [55]

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Medical rehabilitation for patients with pyoderma gangrenosum has not been developed.

5. Prevention and Dispensary Observation

Primary prevention of pyoderma gangrenosum is absent.

Comments: Patients with pyoderma gangrenosum must be warned that skin trauma can lead to the appearance of new rashes.

6. Organization of Medical Care

Medical care for patients with pyoderma gangrenosum is provided in the form of:

- primary health care;

- specialized, including high-tech, medical care.

Medical care for patients with pyoderma gangrenosum may be provided in the following settings:

- on an outpatient basis (under conditions not providing for round-the-clock medical observation and treatment);

- in a day hospital (in settings providing medical observation and treatment during daytime hours, not requiring round-the-clock medical observation and treatment);

- inpatiently (in settings providing round-the-clock medical observation and treatment).

Primary health care includes measures for the prevention, diagnosis, and treatment of patients with pyoderma gangrenosum, medical rehabilitation, and the promotion of a healthy lifestyle.

Primary health care includes:

- primary general medical care;

- primary specialized health care.

Primary general medical care is provided in medical organizations by a district general practitioner, district pediatrician, or general practitioner (family physician) in outpatient settings.

Within the framework of primary general medical care, district general practitioners, district pediatricians, and general practitioners (family physicians) refer patients with pyoderma gangrenosum to a medical organization to receive primary specialized health care, and also provide medical care in accordance with the recommendations of a dermatovenereological medical organization, in the absence of medical indications for referral to it.

Primary specialized health care for patients is provided by dermatovenereologists or surgeons.

If it is impossible to provide medical care in an outpatient setting and there are medical indications, a patient with pyoderma gangrenosum is referred to a medical organization providing inpatient medical care.

Specialized medical care for patients with pyoderma gangrenosum is provided by dermatovenereologists or surgeons and includes prevention, diagnosis, and treatment using special methods and complex medical technologies, as well as medical rehabilitation.

In the presence of medical indications, the treatment of patients with pyoderma gangrenosum is carried out with the involvement of medical specialists in the fields provided for by the Nomenclature of Specialties of Specialists with Higher and Postgraduate Medical and Pharmaceutical Education in the Healthcare Sector of the Russian Federation.

In the presence of indications for surgical treatment in a surgical inpatient setting, patients with pyoderma gangrenosum are referred by a district general practitioner, district pediatrician, general practitioner (family physician), or dermatovenereologist for an appointment (examination, consultation) with a surgeon.

Indications for planned hospitalization in a dermatovenereological medical organization:

1) Indications for providing medical care in a day hospital setting:

- insufficient effectiveness of treatment performed in an outpatient setting, in case of limited skin lesions;

2) Indications for inpatient medical care;

- insufficient effectiveness of outpatient treatment in patients with pyoderma gangrenosum.

Indications for planned hospitalization in a surgical medical organization:

1) Indications for inpatient medical care;

- Non-healing large-area skin ulcer defects — for autodermoplasty.

Indications for patient discharge from a medical organization:

Partial or complete regression of rashes.

7. Additional Information

Important factors that can increase the effectiveness of the therapy include the patient quitting smoking, controlling blood glucose levels in diabetes mellitus, optimizing nutrition, and minimizing edema (if present, for example, in venous insufficiency) [3, 55]. There is evidence of an increased incidence of wound infection and decreased healing rates of postoperative wounds in tobacco smokers [147].

In the case of an associated malignant neoplasm in a patient with pyoderma gangrenosum, immunosuppressive therapy is undesirable. It should be borne in mind that a malignant neoplasm associated with pyoderma gangrenosum may manifest later than pyoderma gangrenosum; therefore, immunosuppressive therapy, especially with tumor necrosis factor alpha (TNF-alpha) inhibitors and interleukin inhibitors, should be administered with caution, taking all risks into account [14, 18].

The disease often has a chronic, relapsing, unpredictable course, and therefore deciding on the duration of treatment and when to discontinue it can be difficult. Patients who experience a rapid therapeutic effect and complete regression of lesions frequently experience relapses [148]. It is believed that careful management of chronic conditions associated with pyoderma gangrenosum is crucial for preventing relapses and exacerbations after cessation of therapy [19].

Factors associated with an unfavorable prognosis in pyoderma gangrenosum include disease severity, advanced age at diagnosis, ulcerated and bullous variants, non-responsiveness to the treatment of the associated disease, secondary infection, and sepsis [149].

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Kubanov Alexey Alekseevich – Academician of the RAS, Doctor of Medical Sciences, Professor, President of the Russian Society of Dermatovenereologists and Cosmetologists, Director of the State Research Center of Dermatovenereology and Cosmetology of the Russian Ministry of Health. There is no conflict of interest.

2. Olisova Olga Yuryevna – Corresponding Member of the RAS, Doctor of Medical Sciences, Professor, Member of the Russian Society of Dermatovenereologists and Cosmetologists.

3. Grabovskaya Olga Valentinovna – Doctor of Medical Sciences, Member of the Russian Society of Dermatovenereologists and Cosmetologists.

4. Lyudmila F. Znamenskaya – Doctor of Medical Sciences, Member of the Russian Society of Dermatovenereologists and Cosmetologists. No conflict of interest.

5. Karamova Arfenya Eduardovna – Candidate of Medical Sciences, Member of the Russian Society of Dermatovenereologists and Cosmetologists. No conflict of interest.

6. Chikin Vadim Viktorovich – Doctor of Medical Sciences, Member of the Russian Society of Dermatovenereologists and Cosmetologists. No conflict of interest.

Conflict of Interest: The authors declare no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Dermatovenereologists.

2. Surgeons.

3. Residents and trainees of continuing professional education programs in the specified specialties.

Table 1. Level of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Scale for evaluating the levels of evidence (LE) for prevention, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitative interventions)

Table 3. Scale for evaluating the levels of recommendation certainty (LRC) for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on natural healing factors (preventive, diagnostic, therapeutic, and rehabilitation interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

These clinical guidelines have been developed taking into account the following regulatory and legal documents:

1. Order of the Ministry of Health of the Russian Federation No. 924n dated November 15, 2012, "On Approval of the Procedure for Providing Medical Care to the Population in the Profile 'Dermatovenereology'."

2. Order of the Ministry of Health of the Russian Federation No. 922n dated November 15, 2012 (as amended on February 21, 2020) "On Approval of the Procedure for Providing Medical Care to the Adult Population in the Profile 'Surgery'."

Table 1. Nonsteroidal anti-inflammatory and antirheumatic drugs that can be used to reduce pain intensity in pyoderma gangrenosum.

In preparing these clinical guidelines, instructions for the medical use of medicinal products and scientific literature data were used, which determined the procedure for monitoring the safety of therapy in patients with pyoderma gangrenosum.

During systemic corticosteroid therapy with #prednisolone** and #methylprednisolone**, adverse effects may develop, such as leukocytosis, lymphopenia and eosinopenia, impaired glucose tolerance, steroid diabetes mellitus, and electrolyte metabolism disorders. To monitor these, a complete blood count (CBC) and a general clinical blood chemistry panel must be performed before and during treatment.

Before prescribing #cyclosporine** and during treatment with #cyclosporine**, patients' conditions should be monitored to identify contraindications to the drug's prescription and due to the potential development of adverse events during treatment, such as infection activation, increased blood pressure, nephrotoxic effects with an increase in plasma creatinine levels, changes in blood electrolyte levels, elevated blood lipids and uric acid, and increased activity of "liver" transaminases. Regular monitoring of plasma creatinine concentration is necessary—an increase may indicate a nephrotoxic effect and require a dose reduction: by 25% if the creatinine level increases by more than 30% from baseline, and by 50% if it doubles. If reducing the dose over 4 weeks does not lead to a decrease in creatinine levels, #cyclosporine** is discontinued. Monitoring of blood pressure, blood levels of potassium, uric acid, bilirubin, transaminases, and the lipid profile is required.

Therapy with #dapsone** may be accompanied by adverse events, including hemolytic anemia, methemoglobinemia, eosinophilia, agranulocytosis, albuminuria without proteinuria, and nephrotic syndrome. Therefore, regular dynamic monitoring of the blood picture is necessary (complete blood count weekly at the start of therapy, and monthly after a few months). In the event of a significant decrease in leukocyte count, platelet count, or bone marrow depression, treatment with #dapsone** should be interrupted [68, 69, 71]. Before starting therapy with #dapsone**, a general clinical blood chemistry panel should also be performed to monitor liver function via blood aspartate aminotransferase and alanine aminotransferase activity, along with a routine urinalysis [71]. Subsequently, the general clinical blood chemistry panel should be performed once every 3 months; if blood aspartate aminotransferase and alanine aminotransferase activity exceeds the upper limit of normal by 4 times, therapy with #dapsone** should be discontinued.

Therapy with tumor necrosis factor-alpha (TNF-alpha) inhibitors (#infliximab**, #adalimumab**, #etanercept**) is associated with adverse events, some of which require laboratory monitoring: urinary tract infections (including pyelonephritis), leukopenia or leukocytosis, anemia, thrombocytopenia, elevated lipid levels, hypokalemia, elevated uric acid, abnormal blood sodium levels, hypocalcemia, hyperglycemia, hypophosphatemia, elevated liver enzymes, elevated bilirubin, coagulation disorders, and hemorrhagic disorders. Activation of chronic infections, including tuberculosis and viral hepatitis, is possible [72, 76–83, 85, 86]. Therefore, patients should be carefully monitored for the appearance of infections, including tuberculosis, before treatment, during treatment, and after the completion of treatment with #adalimumab**, including for 4 months after the last injection of the drug. Appropriate screening tests (tuberculin skin test and targeted chest radiography) must be performed in all patients (local guidelines may be applied). A consultation with a phthisiatrician may be required. Therefore, before starting therapy with tumor necrosis factor-alpha (TNF-alpha) inhibitors, the following tests are required:

1. Complete blood count (CBC), including leukocyte differential and platelet count.

2. General clinical blood chemistry panel, including testing levels of creatinine, urea, bilirubin, and determining the activity of aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, and alkaline phosphatase

3. Urinalysis (general clinical urine test).

4. Targeted chest radiography in 2 projections, tuberculin skin test, consultation with a phthisiatrician to rule out tuberculosis infection.

5. Determination of hepatitis B virus surface antigen (HbsAg) in the blood

6. Determination of antibodies of classes M, G (IgM, IgG) to human immunodeficiency virus HIV 1 in the blood.

7. Determination of antibodies of classes M, G (IgM, IgG) to human immunodeficiency virus HIV 2 in the blood.

8. Determination of hepatitis C virus antigen in the blood.

9. Pregnancy test (e.g., urine test for chorionic gonadotropin).

Therapy with tumor necrosis factor-alpha (TNF-alpha) inhibitors should not be carried out during pregnancy. Therefore, before starting therapy with tumor necrosis factor-alpha (TNF-alpha) inhibitors, women of childbearing potential must obtain a negative pregnancy test result. When undergoing therapy with tumor necrosis factor-alpha (TNF-alpha) inhibitors and for at least 6 months after its completion, women of childbearing potential must use reliable methods of contraception.

During therapy with tumor necrosis factor-alpha (TNF-alpha) inhibitors, adverse events are monitored and laboratory parameters are controlled:

1. Clinical evaluation of the patient's condition – every 3–6 months.

2. Consultation with a neurologist every 3–6 months to detect manifestations of neurological diseases, including demyelinating conditions.

3. Consultation with a cardiologist every 3–6 months to detect signs of heart failure.

4. Consultation with a phthisiatrician 2 times a year to rule out the development of tuberculosis.

5. Complete blood count (CBC) once every 3–6 months (for #infliximab** – before each intravenous infusion).

6. General clinical blood chemistry panel (testing levels of creatinine, urea, bilirubin, determining blood activity of aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, and alkaline phosphatase) once every 3–6 months (for #infliximab** – before each intravenous infusion).

7. Routine urinalysis once every 3–6 months (for #infliximab** – before each intravenous infusion).

8. Determination of hepatitis B virus surface antigen (HbsAg) in the blood – every 6 months.

9. Determination of antibodies of classes M, G (IgM, IgG) to human immunodeficiency virus HIV 1 in the blood – every 6 months.

10. Determination of antibodies of classes M, G (IgM, IgG) to human immunodeficiency virus HIV 2 in the blood – every 6 months.

11. Determination of hepatitis C virus antigen in the blood – every 6 months.

12. Pregnancy test, e.g., urine test for chorionic gonadotropin (for #infliximab** – before each intravenous infusion), as well as whenever pregnancy is suspected.

13. Targeted chest radiography 2 times a year.

14. Ultrasound examination of the abdominal organs (comprehensive), pelvic organs (comprehensive), and prostate gland as clinically indicated.

Therapy with #infliximab** should be discontinued if a serious infection or sepsis develops. Patients with signs or symptoms of liver dysfunction should be evaluated for liver injury. In the event of jaundice or an increase in blood alanine aminotransferase activity exceeding 5 times the upper limit of normal, #infliximab** should be discontinued. All patients who develop signs and symptoms of blood dyscrasia (persistent fever, bruising, bleeding, pallor) should be evaluated immediately. In case of severe hematological abnormalities, therapy with #infliximab** must be discontinued.

Cases of serious bacterial and viral infections have been observed in patients treated with #ustekinumab** [134]. Before starting therapy with #ustekinumab**, patients should be evaluated for tuberculosis. #Ustekinumab** should not be used in patients with active tuberculosis. Latent tuberculosis therapy should be administered before initiating #ustekinumab**. To monitor treatment safety, a complete blood count and general clinical blood biochemistry for liver function assessment should be performed before and during #ustekinumab** therapy [73].

Adverse events of #canakinumab** therapy that require monitoring include neutropenia (absolute neutrophil count below 1.5×10⁹/L) and reactivation of Mycobacterium tuberculosis infection. Before initiating treatment with #canakinumab**, 1–2 months after its start, and periodically during therapy, a complete blood count must be performed to detect neutropenia. In patients with neutropenia, treatment with #canakinumab** should be initiated only after neutrophil counts normalize. If a decrease in the absolute neutrophil count is detected during #canakinumab** therapy, appropriate patient monitoring must be ensured and the discontinuation of #canakinumab** treatment should be considered if necessary. Before using #canakinumab**, all patients must be screened for active or latent tuberculosis infection (including taking a medical history and performing appropriate screening tests, such as a tuberculin skin test, IGRA (Interferon-Gamma-Release-Assay) tests, or chest radiography). During treatment with #canakinumab**, patients should be closely monitored for tuberculosis infection. If a tuberculosis infection is detected, treatment with #canakinumab** must not be initiated or continued.

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Pyoderma gangrenosum is a chronic inflammatory skin disease with a relapsing course that may require long-term therapy.

Smoking cessation, blood glucose control in diabetes mellitus, nutritional optimization, and minimizing edema (if present, e.g., in venous insufficiency) can enhance the efficacy of ongoing drug therapy.

Pyoderma gangrenosum may be accompanied by other diseases, most commonly bowel, joint, and blood disorders, which may manifest before the skin lesions appear, simultaneously with them, or after their development. Their treatment can contribute to the resolution of pyoderma gangrenosum; therefore, one should watch for the appearance of even minimal signs of these conditions and report them to the attending physician.

Since the appearance of new lesions may be triggered by skin trauma, any trauma, even minimal, should be avoided.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. Diagnostic criteria for ulcerative pyoderma gangrenosum by W. Su et al. (2004)

Russian name:

Diagnostic criteria for ulcerative pyoderma gangrenosum.

Original title:

Diagnostic criteria of classic, ulcerative pyoderma gangrenosum.

Source (official developer website, validation publication):

Su W.P., Davis M.D., Weenig R.H. et al. Pyoderma gangrenosum: clinicopathologic correlation and proposed diagnostic criteria. Int J Dermatol. 2004; 43 (11): 790–800.

Type (underline):

- rating scale

- index

- questionnaire

- other (specify): Diagnostic criteria.

Prescription:

Diagnosis of ulcerative pyoderma gangrenosum

Content (template):

Major criteria

• Other diseases and conditions presenting with skin ulcers have been excluded (i.e., pathomorphological examination of skin biopsy material and other studies have been performed)

• Typical clinical manifestations of classic pyoderma gangrenosum: rapidly enlarging (by 1–2 cm per day or 50% per month) painful irregular skin ulcers with undermined reddish-purple borders

Minor criteria

• Histological picture (sterile dermal neutrophilia ± mixed inflammation ± lymphocytic vasculitis)

• Presence of a disease associated with pyoderma gangrenosum

• Response to systemic corticosteroid therapy (usually a response to prednisolone** therapy manifested as a 50% reduction in the size of ulcerated lesions within 1 month).

• History of pathergy or cribriform scars

Key (interpretation):

To establish a diagnosis of classic (ulcerative) pyoderma gangrenosum, the presence of one major and two minor criteria is required.

Clarification:

The proposed criteria are used solely for the diagnosis of ulcerative pyoderma gangrenosum.

Appendix G2. Diagnostic criteria for ulcerative pyoderma gangrenosum by the Delphi Consensus of International Experts

Russian name:

Diagnostic criteria for ulcerative pyoderma gangrenosum by the Delphi Consensus of International Experts.

Original title (if applicable):

Diagnostic Criteria for Classic Ulcerative Pyoderma Gangrenosum

Source (official developer website, validation publication):

Maverakis E., Ma C., Shinkai K. et al. Diagnostic criteria of ulcerative pyoderma gangrenosum: a Delphi Consensus of International Experts. JAMA Dermatol. 2018; 154 (4): 461–466.

Type (underline):

- rating scale

- index

- questionnaire

- other (specify): Diagnostic criteria

Prescription:

Diagnosis of ulcerative pyoderma gangrenosum.

Content (template):

Major criterion:

Pathomorphological examination of skin biopsy material (from the ulcer edge) demonstrating a neutrophilic infiltrate

Minor criteria:

1) Infectious etiology has been excluded.

2) Pathergy (ulcers appearing at the site of trauma).

3) History of inflammatory bowel disease or arthritis.

4) History of papules, pustules, or vesicles that rapidly ulcerated (within 4 days of onset).

5) Peripheral erythema, undermined borders, and tenderness in the area of ulceration

6) Multiple ulcerations (at least 1 ulcer located on the anterior surface of the lower leg)

7) Cribriform scars or cigarette paper-like scars at the site of healed ulcers.

8) Reduction in ulcer size within 1 month from the start of immunosuppressive therapy

Key (interpretation):

To establish a diagnosis of classic (ulcerative) pyoderma gangrenosum, the presence of one major and four minor criteria is required.

Clarification:

The criterion was developed for the diagnosis of ulcerative pyoderma gangrenosum. When 4 minor diagnostic criteria and the major criterion are met, diagnostic sensitivity is 86% and specificity is 90%.