The Pathophysiology and Treatment of Pyoderma Gangrenosum-Current Options and New Perspectives.

1. Introduction

Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis characterized by a painful, aseptic ulcer. Typically, the disease begins with a papule, pustule, blister, or nodule following trauma, which then rapidly progresses to painful ulceration with a characteristic violaceous border ( Figure 1 ) [ 1 , 2 , 3 ]. The most common localizations of PG are the lower extremities. However, PG could also appear in the regions around a stoma, postoperative wounds, trunk, face, or upper extremities, depending on the disease subtype ( Figure 1 ) [ 4 , 5 ]. In over fifty percent of cases, PG is accompanied by systemic disease [ 6 ].

Six clinical variants of PG can be distinguished: ulcerative, bullous, pustular, vegetative, peristomal, and postoperative [ 1 , 5 , 7 , 8 ]. The most frequent is ulcerative PG, also referred to as classical PG, described as an inflammatory pustule or nodule that transforms into a necrotic ulcer, usually occurring on the lower limbs. Bullous PG presents fast-growing, painful bulla on the face or upper limbs that transform into erosion or ulcer. A pustule on the leg or trunk is typical for pustular PG. Vegetative PG manifests with a specific pattern of lesions on the trunk, typically a single ulcer that is less painful, more superficial, and progresses more slowly with a good response to therapy. A papule located directly by the stoma transforming into an ulcer represents peristomal PG. After the surgery on the abdomen or breast, postoperative PG can occur in the form of erythema and unhealing wounds that unite, forming the ulcer.

The specific epidemiology of PG is difficult to estimate since only a few cross-sectional studies have been conducted so far. In a recent American study, the prevalence of PG was evaluated at 58 individuals with PG per 1 million adults [ 9 ]. The United Kingdom research indicated an incidence rate of 0.63 per 100,000 person years [ 10 ]. PG occurs mostly around the age of 50, with a higher prevalence and incidence among women than men [ 9 , 11 , 12 ]. It has been reported that the mortality of patients with PG could be threefold higher than in the control group after adjustments for sex and age [ 10 ]. There are also data indicating the negative influence of PG on quality of life [ 13 ].

The proposed pathophysiology of PG is associated with the interplay between innate and adaptive immunity and the state of autoinflammation with the crucial role of neutrophils [ 6 , 14 , 15 , 16 , 17 , 18 , 19 ]. Indicators of the autoimmune character of PG are its correlations with other immune-mediated disorders. Data indicate that over fifty percent of individuals with PG suffer from other autoimmune diseases such as inflammatory bowel disease, rheumatoid arthritis, or hematological malignancies [ 10 ]. Pathergy, which is the induction or exacerbation of skin lesions due to trauma, is one of the described phenomena [ 20 ]. Certain aspects of PG development are still to be fully discovered.

Diagnosing PG may be demanding, especially when distinguishing between PG and skin infections, and vascular or malignant lesions [ 21 , 22 , 23 ]. A novel diagnostic tool for PG, the PARACELSUS score is based on the prevalence of the characteristics in the population with PG and consists of major, minor, and additional criteria, each awarded with points differently. Criteria A score of at least 10 points corresponds to a high probability of suffering from PG [ 2 ]. Other diagnostic criteria are international PG diagnostic criteria with the use of the Delphi method. They contain four sections—histology, history, clinical examination, and response to therapy. A score of at least 5 points suggests the diagnosis of PG [ 1 ]. It is worth noting that results from diagnostic criteria have to be considered with the clinical data.

The treatment of PG is arduous; however, new therapeutic strategies are continuously evolving. The basis of the new therapies derives from the current knowledge of PG molecular pathophysiology. In this literature review, we focus on the latest discoveries regarding the pathophysiology and summarize the treatment of PG to raise awareness and improve the management of this rare disease.

2. Pathophysiology

Pathogenesis of PG remains unclear. However, based on the existing research, it can be affirmed that it is a complex and multifactorial process ( Figure 2 ). Possible aberrant origins of inflammation encompass neutrophils, T cells, inflammasomes, keratinocyte apoptosis, and modifications in epigenetic patterns. PG is most commonly considered a disease in the spectrum of neutrophilic dermatoses (ND) [ 14 ]. ND is a group of skin disorders characterized by sterile lesions such as papules, pustules, plaques, or nodules caused by neutrophilic infiltration [ 24 ]. This might be explained by numerous mechanisms as neutrophil chemotaxis is one of the final stages of the inflammatory cascade [ 14 , 17 ].

Based on the existing reports, it can be inferred that genetic predisposition plays a significant role in the pathogenesis of PG. An animal model with the pathogenic gene of tyrosine-protein phosphatase non-receptor type 6 (PTPN6) and the diminished activity of its protein presented autoinflammatory, neutrophilic skin lesions similar to PG. PTPN6 is known to modulate signals from tyrosine-phosphorylated cell membranes and T cell receptors [ 25 , 26 , 27 ]. The results were supported by a study with human participants [ 28 ]. Another gene with its mutation correlated with PG is considered to be the proline–serine–threonine phosphatase interacting protein 1 gene (PSTPIP1) [ 28 , 29 ]. The pathogenic variant may lead to PSTPIP1-pyrin binding of higher affinity and therefore to the activation of the inflammasome [ 30 ]. Inflammasome activates interleukin 1β (IL-1β) that indirectly recruits neutrophils, causing an autoinflammatory state [ 16 , 31 , 32 , 33 ]. Data indicate an association between this pathway and pyogenic arthritis, PG, and acne syndrome (PAPA) [ 34 ].

PAPA spectrum disorders, such as PASH (PG, acne and hidradenitis suppurativa), PAPASH (PASH and pyogenic sterile arthritis), PsAPASH (PASH and psoriatic arthritis), PASS (PG, acne, and ankylosing spondylitis, with or without hidradenitis suppurativa), and PAC (PG, acne and ulcerative colitis), are associated with genes or chromosomal alterations [ 35 ].

Growing evidence suggests that individuals with a genetic predisposition and abnormal activation of the innate immune system create a conducive environment for the development of PG. Genetic defects play a crucial role in disrupting molecular pathways in the discussed diseases. Different molecular pathways are altered depending on the severity of PG [ 36 , 37 ].

Immune system dysregulation plays a crucial role in PG pathophysiology. Based on the abnormalities observed in lesional skin, the role of the inflammatory mediators IL-1β, IL-8, IL-17, and TNF-α has been previously delineated. In PG lesions, abnormal neutrophils and T-cells have been identified.

PG may be induced or exacerbated by trauma (pathergy phenomenon). Physical injury can cause the release of IL-36 and autoantigens from damaged keratinocytes and upregulate the expression of IL-8 and IL-17. The aforementioned mechanism in the presence of predisposing factors may induce PG [ 15 , 38 , 39 , 40 ].

PG syndromes suggest the pathophysiological pathways of this disease. The occurrence of PG together with the autoinflammatory disorder—hidradenitis suppurativa, pyogenic arthritis, PG, acne, and hidradenitis suppurativa syndrome (PAPASH) and PG, acne, and hidradenitis suppurativa syndrome (PASH)—can be an indicator of autoinflammation in PG [ 41 , 42 , 43 , 44 ].

Although IL-1α and IL-1β are acknowledged as one of the main inflammatory cytokines, only the first cytokine contributes to the development of PG. A missense mutation of the Ptpn6 gene in mice led to the stimulation of IL-1α pathways, including the receptor-interacting serine/threonine-protein kinase 1 (RIPK1) that caused chronic neutrophilic suppurative inflammation similar to PG [ 45 , 46 , 47 ]. The study also revealed the involvement of mitogen-activated protein kinase 7 (MAP3K7) and MAP3K5, together with caspase recruitment domain-containing protein 9 (CARD9), in this process [ 45 , 46 , 47 , 48 ].

Cytokines suspected of contributing to PG are IL-36A and IL-36G, which are produced by epithelial cells when inflammation occurs. They are known for their role in many autoimmune diseases, including psoriasis, hidradenitis suppurativa, acute generalized pustulosis, Crohn’s disease, or ulcerative colitis, associated with PG [ 49 , 50 , 51 , 52 , 53 ]. It might be hypothesized that minor trauma leads to the release of RNA by keratinocytes, activation of the innate immune response, and degranulation of neutrophils, as well as the release of IL-36 and activation of this cytokine by IL-36 neutrophil-derived proteases. IL-36 has a pro-inflammatory effect by stimulating neutrophils to increase the expression of pro-inflammatory cytokines and by promoting the differentiation of naive T cells towards the Th1 lineage [ 49 , 53 ].

It has been reported that another cytokine associated with neutrophils and the development of PG may be IL-25, also known as IL-17E [ 18 ]. Many engaged in inflammation cells produce IL-25—these include dendritic cells, basophils, eosinophils, T helper 2 cells (Th2), as well as keratinocytes [ 54 ]. IL-25 triggers macrophages to the production of chemokines CXCL1, CXCL10, and CCL20, which attract neutrophils [ 55 ]. Other neutrophil-recruiting molecules with higher expression in PG are IL-8, CCL3, CCL5, or IL-16 [ 15 , 41 , 56 , 57 , 58 ]. The latter acts indirectly on neutrophils by causing the production of neutrophile-chemoattractive substances [ 19 ].

The importance of IL-6, IL-8, IL-17, and IL-23 in PG pathomechanisms was suggested by Rubas et al. [ 59 ]. They observed increased serum levels of all studied interleukins in a group of 48 PG patients. However, only IL-6 and IL-8 presented an association with studied parameters (localization of skin lesion and CRP for IL-6, age for IL-8) [ 59 ].

Therapy with the use of tumor necrosis factor (TNF) succeeded in treating PG and therefore underlined the possible importance of this cytokine in the pathophysiology of PG. TNF triggers the expression of adhesion molecules on blood vessels, which promotes the migration of neutrophils. The priming of the inflammasome is also enabled by the binding of TNF to its receptor, which leads to the characteristic of PG autoinflammation.

The association between PG and adaptive immunity has not been fully established. However, some data that support this theory exist. It has been observed that T cell lymphocytes dominate over other immune cells in the border region of the PG ulcer [ 60 ]. T cell clones also occur in this site, suggesting the possible mechanism of response to follicular or dermal antigens in PG development [ 15 , 61 ]. Biopsy of early PG papule revealed an elevated gene expression of T cells attracting chemokines and cytokines, including CXCL9, CXCL10, CXCL11, TNF, interferon gamma (IFNG), IL-17A, IL-8, and IL-36G [ 15 ]. T cells accumulated there around vessels and pilosebaceous units [ 15 ]. The upregulation of a signal transducer and activator of transcription 1 ( STAT1 ) and STAT4 genes, which induce the production of Th1 transcription factors, and downregulation of the GATA binding protein 3 ( GATA3 ) gene, which enhances the expression of the Th2 transcription factor, suggest the promotion of Th1 over Th2 response in the early stages of PG [ 15 ].

Another lymphocyte imbalance in PG might be the higher level of Th17-promoting cytokines and the reduction of regulatory lymphocytes T (Treg) [ 15 , 60 ]. IL-23 could have an influence on the predominance of Th17 by triggering pathways including STAT3 and the Janus Kinase 2 (JAK2) [ 28 , 61 ]. Consequently, IL-17A is produced and it recruits neutrophils [ 62 , 63 ]. These processes create the IL-23-IL-17 axis, which may indicate an association between adaptive and innate immunity in the evolution of PG.

Data suggest that PG has a characteristic of an autoimmune disease course of relapses and remissions. Evidence supporting this theory might be the observation of some PG ulcers that disappear without any treatment [ 62 ]. The possible explanation of this process could be the presence of anti-inflammatory IL-10 and the upregulation of the forkhead box 3 (FOX3) transcription factor of Treg in the ulcers [ 15 , 63 ]. The healing process of PG should be explored in more detail in future studies to reveal new possible therapeutic strategies.

3. Treatment

First, PG is a challenging dermatosis, as there are no national or international guidelines regarding the treatment in this dermatological entity. As a rare disease, there are limited studies considering therapeutic options. To date, only two randomized trials have been conducted [ 64 , 65 ]. Frequently, clinicians are prompted to explore alternative therapeutic approaches for patients who are unresponsive to standard treatments, based on new pathophysiological findings. The primary objective of treatment is to arrest the abnormal inflammatory process, and, typically, this objective is realized through the implementation of immunosuppressive measures. Given that PG often coexists with other autoimmune diseases, reports indicate the effective application of modern therapies in treating accompanying conditions while simultaneously achieving the healing of PG lesions. In this paper, we conduct a review of existing therapeutic methods.

3.1. Wound Management

Wound care is an integral part of the treatment [ 66 ]. The main principles involve proper cleansing with sterile saline or antiseptic and dressing changes. The dressing should be nonadherent to the wound bed and promote a moist environment that is not overly dry or wet. Moreover, it should be easy to remove to prevent trauma and subsequent pain. Surgical procedures and surgical wound management should be limited to avoid pathergy [ 67 ]. Gentle mechanical and autolytic debridement is recommended. Compression therapy reduces localized inflammation and tissue swelling, resulting in increased blood circulation, both directly and indirectly, by promoting better mobility [ 68 ].

Negative pressure wound therapy (NPWT) is a method of wound management in which a wound dressing is attached to a vacuum suction machine, applying controlled negative pressure that results in better healing. The role of NPWT is still controversial due to the pathergy effect; however, an increasing number of studies prove its effectiveness. Almeida et al. [ 69 ] conducted a systematic review in which improvement was observed in 85.1% of the patients treated with this method. Numerous case reports demonstrated that NPWT has resulted in rapid healing and satisfactory clinical outcomes [ 70 , 71 , 72 ]. On the other hand, some authors indicate that NPWT alone, without skin grafting, does not accelerate healing time [ 73 ].

3.2. Topical Therapies

For patients with mild PG, topical therapy can serve as a first-line treatment option. The data regarding this therapeutic approach are, in fact, limited. The most commonly used topical therapy is clobetasol propionate twice daily, but other high-potency or superpotent topical corticosteroids can be administered. Besides corticosteroids, topical calcineurin inhibitors are also described in the literature as a treatment regimen. Thomas et al. [ 74 ] conducted a prospective cohort study aimed at estimating the effectiveness of topical therapies (topical corticosteroids [classes I–III] and tacrolimus 0.03% or 0.1%) in the treatment of PG. The study involved 66 PG patients, with 49 treated with clobetasol propionate 0.05%, 10 with tacrolimus 0.03% or 0.1%, and 8 using other topical preparations. In the clobetasol group, twenty patients (43%) benefited from the treatment. However, due to comorbidities, nine of them received additional systemic therapy (azathioprine, TNFα inhibitor, and tetracyclines) that might have influenced the treatment outcomes. The median healing time was 145 days. In the topical tacrolimus group, resolution of lesions was observed in half of the group [ 74 ]. The comparison between the effectiveness of studied topical regimens was not analyzed as the study was not randomized. Another study compared the effectiveness of topical corticosteroids and topical tacrolimus in the management of peristomal PG. In total, 13 patients received topical clobetasol 0.05%, and 11 received topical tacrolimus 0.3%. Topical tacrolimus showed significantly better effectiveness in managing peristomal PG than corticosteroids. Moreover, the studied calcineurin inhibitor was more effective in the management of lesions larger than 2 cm in diameter [ 75 ].

3.3. Intralesional Therapies

In the literature, reports indicate the effectiveness of intralesional drug administration in pyoderma gangrenosum. However, this approach is controversial due to the potential risk of pathergy. The implemented therapy in such cases may result in an adverse outcome by inducing the formation of new ulcers or enlarging existing ones. Nevertheless, existing case reports describe the successful administration of intralesional corticosteroids, methotrexate, and cyclosporine A [ 76 , 77 ]. The latest report described a successful intralesional application of infliximab in a patient with PG and systemic lupus erythematosus (SLE) [ 78 ].

3.4. Systemic Therapies

In the case of extensive, rapidly progressing, or treatment-resistant skin lesions, systemic treatment is recommended. The therapy usually begins with the use of fast-acting immunosuppressive agents, primarily systemic steroids, or CyA, but other immunosuppressive and immunomodulatory drugs are also used in everyday practice.

3.4.1. Corticosteroids

Systemic corticosteroids are the most common first-line treatment option, as the advantage of the mentioned therapy is, in most cases, rapid response [ 79 ]. The dose of prednisone ranges from 0.5 to 2 mg/kg per day [ 80 ]. Usually, the initial dose starts from 40 to 80 mg daily. Higher doses can be administered in case of rapidly progressing ulcers. In times when disease activity is controlled, a gradual reduction of the dosage is recommended [ 77 , 81 ]. In severe cases, intravenous pulse corticosteroids (0.5–1 g methylprednisolone per day for one to five days) can be administered [ 82 , 83 ].

Despite the frequent usage of corticosteroids in clinical practice, the majority of data regarding their efficacy are derived from case reports and nonrandomized studies. However, a STOP GAP study, designed to determine whether CsA is superior to prednisolone for the treatment of pyoderma gangrenosum, was one of the randomized controlled trials that provided high-quality research outcomes. A total of 53 patients were included in the prednisolone group. Patients were treated with a prednisolone dose of 0.75 mg/kg/d (maximum 75 mg/d). Investigators analyzed the speed of healing over six weeks, time of healing, global treatment response, resolution of inflammation, self-reported pain, quality of life, number of treatment failures, adverse reactions, and time to recurrence. The conclusion indicated that prednisolone and CsA do not differ across reported outcomes. By six months, ulcers had healed in 47% of patients in the prednisolone group. Furthermore, wound healing progressed within a comparable timeframe in both groups. In the prednisolone group, 66% of patients suffered from adverse effects, most commonly infections requiring hospital admission or parenteral antibiotics [ 84 ].

Prolonged corticosteroid therapy is associated with several side effects, such as infections, hyperglycemia, osteoporosis, hypertension, and others, which is why steroid-sparing agents are added to the therapy. Typically CsA, MMF, or dapsone are included as a second agent to maintain an improvement as the steroid is withdrawn [ 85 ]. In patients who do not respond to other therapeutic options and require long-term corticosteroid therapy, deflazacort may be the best option.

3.4.2. Cyclosporine A (CsA)

As mentioned above, CsA is considered one of the initial treatments in patients with PG. The recommended initial dose of CsA is 2.5 to 5 mg/kg/d, which can be subsequently tapered as tolerated [ 86 ]. The effectiveness of CsA was also presented in several case reports where patients were successfully treated with CsA [ 87 , 88 , 89 ].

During the discussion on corticosteroid use in PG, reference was made to the STOP GAP study. Within the group receiving cyclosporine, a total of 59 patients were included. Patients were administered a dosage of 4 mg/kg/day (maximal dose 400 mg/d). As mentioned before, CsA and prednisolone seem to have similar effectiveness. The results of this study demonstrated that, by six months, ulcers had healed in 47% of participants in the CsA group [ 84 ]. CsA side effects were noted in 68% of patients, and the most common was renal toxicity. This study showed that the efficacy of both prednisolone and CsA is similar in PG patients, but less than 50% of them noticed healing of lesions by six months in both groups. Moreover, approximately one-third of patients in both treatment groups experienced a recurrence after a median duration of 582 days. Based on all the above, when selecting a therapeutic option, it is essential to consider comorbidities and patient preferences.

3.4.3. Other Immunosuppressants

There are reports of using conventional immunosuppressants such as mycophenolate mofetil, methotrexate, and azathioprine in the PG treatment.

Mycophenolate Mofetil (MMF)

Mycophenolate mofetil (MMF) demonstrated satisfactory therapeutic effects in patients with PG. Most data are derived from retrospective studies. This medication is typically administered in conjunction with other therapeutics. Eaton et al. [ 90 ] described a series of 7 cases treated with MMF. The dosage regimen started from 0.5 mg daily to 1 mg twice daily. The maximal dose ranged from 0.5 mg 4 times a day to 2 mg twice daily. In 6 out of 7 patients, they observed a reduction in ulcer size, and in 4, they observed complete healing. The onset of response ranged from 4 to 12 weeks. In two patients, MMF was the only systemic treatment. Among the reported adverse effects, anemia has been documented in one patient [ 90 ].

Another retrospective study was conducted by Li et al. [ 91 ] to examine the efficacy and safety of MMF in PG patients. In 11 (42.3%) patients, MMF was the first steroid-sparing agent. The initial dose ranged from 1 g to 2 g daily, reaching 2 g or 3 g daily. In total, 22 out of 26 patients benefited from the therapy. The mean time of treatment was 12.1 months. Researchers categorized patients into excellent, good, and no-clear response groups. In excellent responders, the average time to heal was 9.71 months, while in good responders it was 30.8 months. More than half of the patients experienced adverse effects, most often gastrointestinal ( n = 6) and hematologic ( n = 3) adverse effects, and infections ( n = 3) [ 91 ].

Most recent report of MMF use in PG as a adjunctive therapy was reported by Hrin et al. [ 92 ]. In the 10-year retrospective study, they identified 14 patients treated with MMF and prednisone. The initial and maximal dosage of MMF ranged from 1 g to 2.5 g daily. Improvement of skin lesions was observed in 93% within 12 months. Total healing was noticed in 5 patients, while significant improvement was reported in 4 of them. Half of the subjects experienced adverse effects such as hematologic suppression (21%), gastrointestinal upset (21%), edema (14%), and shortness of breath (14%) [ 92 ].

The above studies suggest that mycophenolate mofetil (MMF) is particularly effective in individuals for whom previously employed preferred treatment methods have proven unsuccessful. The addition of MMF to therapy resulted in an improvement in skin lesions.

Methotrexate (MTX)

Data on the efficacy and safety of MTX in the treatment of PG are limited. Recently, Williams et al. [ 93 ], in their retrospective study, presented 33 patients treated with MTX. The initial dose ranged from 5 mg to 20 mg weekly. Most patients (97%) received concomitant prednisone. Complete response after 4 months was observed in 6% of patients, while partial response was noted in 52% of patients. Side effects were observed in 21% of patients, such as mild gastrointestinal upset, infection, mouth ulcers, and fatigue. This study suggests that MTX may be used in PG patients and has the potential to decrease the corticosteroid dose in the treatment of PG. Moreover, MTX is well tolerated by patients and is characterized by a low incidence of adverse effects [ 93 ].

Azathioprine

The use of azathioprine in the treatment of PG has been reported. Similarly to MTX, the data regarding this treatment regimen are ambiguous. The majority of them originate from case reports [ 94 , 95 ]. Azathioprine is particularly effective in patients with coexisting conditions such as IBD, rheumatoid arthritis, and other autoimmune disorders, for which this medication is employed as a standard therapeutic approach.

3.4.4. Immunosuppressive Antibiotics

Several antibiotics, besides their antimicrobial properties, present anti-inflammatory effects. The representatives, i.e., dapsone and minocycline, are successfully used in neutrophil-mediated diseases [ 96 ].

Dapsone

The literature regarding PG treatment with dapsone is sparse and includes several case reports and a retrospective analysis of 27 patients treated with dapsone [ 97 , 98 , 99 , 100 ]. It is hypothesized that the effectiveness of this drug in neutrophilic dermatoses is related to its ability to inhibit neutrophil adherence to antibodies. In published studies, dapsone is commonly used as an adjuvant and steroid-sparing agent in doses ranging from 50 to 150–200 mg daily. In their retrospective study, Din et al. [ 100 ] analyzed 27 individuals treated with dapsone. In their population, patients received dapsone in combination with other therapies. The study demonstrated a 96.9% response rate with complete healing noted in 15.6% and a partial improvement seen in 81.3% of the patients. The average time to respond was 5.3 weeks. Approximately one-third of the patients experienced adverse events, with hemolytic anemia being the most common [ 100 ]. Screening for glucose-6-phosphate dehydrogenase (G6PD) deficiency should precede dapsone therapy since it increases the risk for hematologic toxicity. This therapeutic option works especially well in people who have small-diameter and superficial lesions.

Minocycline

Minocycline is a drug that inhibits protein synthesis by binding ribosomal subunits of bacteria and can be used in the treatment of PG. In the available literature, minocycline is usually administered at a dose of 100 mg twice daily and used in combination with other therapeutics, such as oral prednisolone and sulfasalazine [ 101 , 102 ]. In one case, minocycline caused adverse effects such as hyperpigmentation [ 103 ].

3.4.5. Intravenous Immunoglobulin (IVIG)

The favorable safety profile of intravenous immunoglobulin (IVIG) renders it an attractive therapeutic alternative for individuals with severe PG who cannot endure the adverse effects of conventional immunosuppressive agents or are already significantly immunocompromised.

In a systematic review, Song et al. [ 104 ] summarized data from cases and case series. A total of 49 patients were included of which 43 had complete or partial response. Complete healing was reported in over half of the population ( n = 26). It should be mentioned that in 43 patients systemic corticosteroids were administered regardless of IVIG treatment. Nearly three-quarters of the patients were treated with 2 g/kg or higher dosage. The average time to initial response was 3.5 weeks and the duration of the treatment was 5.9 months. Authors indicated that the time to initial response was dose dependent—the higher the dose, the shorter the time to response. There were some adverse effects reported, such as nausea (12%) and headache (4%) [ 104 ].

A summary of discussed systemic therapies is presented in Table 1 .

3.4.6. Tumor Necrosis Factor-α (TNF-α) Inhibitors

Infliximab

Infliximab is a chimeric mouse/human monoclonal IgG1 antibody against TNF-α. It prevents the binding of TNF-α to its receptors by interacting with both the soluble and transmembrane forms of the cytokine [ 105 ].

Regarding TNF-α inhibitors in PG therapy, the most scientific data concern the use of infliximab. It is warranted in the context of coexisting IBD, as infliximab is recommended in the treatment of the mentioned medical condition. A randomized placebo-controlled trial assessing the efficacy of infliximab in 30 patients with PG and IBD was conducted. After randomization at week 0, one group ( n = 13) received an infusion of infliximab, and the second group ( n = 17) received a placebo. At week 2, significantly more patients in the infliximab group observed improvement (46%) compared with the placebo group (6%). Patients from the placebo group, without a response, were offered infliximab. Overall, 29 patients received infliximab, with 69% demonstrating adequate results. The remission rate at week 6 was 21% [ 64 ]. In PG, infliximab is administered in standard doses, i.e., 5 mg/kg at weeks 0, 2, and 6, followed by infusions every 6 to 8 weeks.

Several retrospective analyses were performed in patients with PG receiving infliximab. A retrospective study of 13 patients with IBD and PG treated with infliximab demonstrated complete healing of the skin lesions. The mean time to respond was 11 days and the mean time to complete healing was 86.1 days. All patients received standard doses of infliximab [ 106 ]. Another retrospective observational study presented the data of 67 patients treated due to PG. Infliximab was used in 24 patients and, in 22 of them, it contributed to complete remission [ 107 ].

The above are just the largest reported studies regarding infliximab use in PG. Other studies are presented in Table 2 .

Adverse effects of infliximab treatment include infusion reactions, infections, demyelinating disease, and heart failure [ 108 ].

Adalimumab

Adalimumab is a fully human monoclonal antibody against TNF-α. The use of adalimumab is supported by a 52-week, phase 3 open-label study of 22 patients with PG. Patients received adalimumab during a 26-week treatment period and another 26-week extension period. The dosage regimen was 160 mg at week 0, 80 mg at week 2, and 40 mg every week from week 4. At week 26, 12 of 22 patients (54.5%) reached a satisfactory outcome. In this study, an adverse effect, which was an infection in one patient, was observed. Based on the results of this trial, we can assume that adalimumab is effective in PG treatment [ 113 ]. Moreover, in a retrospective observational study, the healing of PG lesions after adalimumab was observed in 7 IBD patients [ 107 ]. There are also a few case reports where the use of adalimumab shows adequate effects [ 114 , 115 , 116 ]. Nevertheless, some reports suggested that adalimumab may paradoxically provoke PG, which is why this therapeutic method should be administered with caution [ 117 , 118 , 119 ]. Currently, there is an ongoing observational study of adalimumab for the treatment of pyoderma gangrenosum [ 120 ].

A summary of clinical studies concerning adalimumab is presented in Table 3 .

Etanercept

Even though etanercept seems to be effective in PG treatment, there were no randomized clinical trials conducted. Etanercept is used in a dose of 50 mg once or twice a week, and then 50 mg every other week for 6 months [ 66 ]. There are cases described in the literature where etanercept was successfully used [ 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 ]. Ben Abdallah et al. [ 130 ], in a semi-systematic review, summarized available data regarding the efficacy of TNF inhibitors in PG and compared the clinical effectiveness of etanercept, adalimumab, and infliximab. Etanercept was used in 36 patients and constituted the smallest subgroup. The response rate was estimated at 83%, while a complete response was noted in half of the patients. In total, 17% of patients did not respond to the treatment. There were no significant differences between the groups; however, etanercept presented less favorable responses [ 130 ].

Importantly, as in the case of adalimumab, there is a report of the development of PG in a patient treated with etanercept due to psoriatic arthritis, which indicates an ambiguous role of this drug in PG therapy [ 131 ].

A summary of clinical studies concerning adalimumab is presented in Table 4 .

3.4.7. Ustekinumab

Ustekinumab is an IL-12/IL-23 antagonist that can be used in PG management. According to the world literature, there are currently 13 cases of successful treatment with ustekinumab reported [ 118 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 ]. The suggested dose of ustekinumab is 90 mg, twice at 4-week intervals, then the same dose every 8 weeks. A summary of clinical studies concerning adalimumab is presented in Table 5 .

3.4.8. IL-1 Antagonists

IL-1 antagonists utilized in PG treatment include canakinumab and anakinra [ 66 ]. Canakinumab, a human anti-IL- 1b monoclonal antibody was used in a prospective, open-labeled study of 5 patients with PG. Canakinumab was administered in a dose of 150 mg at weeks 0 and 2, and 150–300 mg at week 4 if needed. Four of them were completely healed [ 145 ]. Cases of complete resolution of skin lesions after the use of canakinumab have also been reported in the literature [ 146 , 147 ]. Anakinra, a recombinant, non-glycosylated form of IL-1 receptor antagonist used in a dose of 100 mg once a day from 8 weeks to 10 months, was administered only to a few patients described in case reports [ 148 ]. A summary of clinical studies concerning adalimumab is presented in Table 6 .

3.4.9. IL-17 Inhibitors

IL-17 inhibitors are a group of novel biological drugs that inhibit the activity of IL-17. The available literature describes the effects of treatment with three representatives of this group (secukinumab, ixekizumab, and brodalumab) [ 149 , 150 , 151 ]. The reports regarding the use of this group of biologic drugs and PG is ambiguous. Secukinumab, a first-in-class fully human monoclonal antibody against interleukin-17A, was successfully used in several case reports [ 149 , 152 , 153 ]. However, there are existing data on the paradoxical reactions to it. Few authors reported the development of PG in patients treated with secukinumab [ 141 , 154 , 155 ]. There is one case report on the successful use of brodalumab, another human monoclonal antibody to the interleukin-17A receptor [ 151 ]. Interestingly, Sadik et al. [ 156 ] reported induction of PG, palmoplantar pustulosis, and sacroiliitis after switching from secukinumab to brodalumab in plaque psoriasis patients. Kao et al. [ 150 , 157 ] documented effective treatment of PG lesions in four patients after ixekizumab therapy. Nonetheless, there is a case report of PG manifestation in a patient undergoing ixekizumab treatment [ 158 ]. The majority of reported cases of PG induction are associated with the alteration of biologic drugs in patients with psoriasis. Therefore, transitioning from one medication to another should be approached judiciously. The existing case reports and case series on their successful use of IL-17 inhibitors are presented in Table 7 .

IL-23 Inhibitors

IL-23 inhibitors, including guselkumab, tildrakizumab, and risankizumab, are a group of new biological drugs targeting the IL-23 pathway, widely used in the treatment of moderate to severe psoriasis and, partially, psoriatic arthritis (to date, only risankizumab and guselkumab are registered for this indication) [ 159 ]. Guselkumab is a fully human monoclonal antibody specifically targeting the p19 subunit of IL-23. Risankizumab is a fully human immunoglobulin (Ig)G monoclonal antibody that binds with high affinity to the p19 sub-unit of IL-23. Tildrakizumab is another high-affinity, humanized, IgG1-κ antibody targeting the p19 subunit of IL-23. Despite these representing a novel class of medications, there are several cases reporting successful use of this group of biologics in PG treatment [ 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 ]. A summary of clinical studies concerning adalimumab is presented in Table 8 .

4. Future Directions

Undoubtedly, the future of PG treatment lies in targeted therapies. Ongoing research on the pathogenesis of the disease and emerging insights into the pathomechanisms provide hope for the integration of both existing and novel molecules in the treatment paradigm.

4.1. Janus Kinase Inhibitors (JAKi)

As in many other dermatological conditions, Janus Kinase inhibitors (JAKi) may be the future of the treatment of PG. Tofacitinib is an oral JAK-1 and JAK-3 inhibitor that has been approved for the treatment of rheumatoid arthritis and ulcerative colitis, plaque psoriasis, atopic dermatitis, vitiligo, and alopecia areata. Cases are reporting successful resolution of PG ulcers in patients treated with JAKi due to concomitant medical conditions. Other JAKi including tofacitinib, baricitinib, upadacitinib, and ruxolitinib were reported as effective treatment options [ 168 , 169 , 170 , 171 ]. We present available case reports in Table 9 .

Currently, there is an ongoing phase 2 open-label, proof-of-concept, study of baricitinib for the treatment of pyoderma gangrenosum [ 172 ] ( Table 10 ).

4.2. Spesolimab

An example of medications that may find application in PG includes IL-36 inhibitors. Recently, Guénin et al. [ 175 ] reported successful use of spesolimab in two patients with refractory PG. Patients were administered 900 mg of spesolimab intravenously every 4 weeks. During therapy, one patient developed epididymitis without further complications after antibiotic therapy. Another report of successful spesolimab use was presented by Ma et al. [ 176 ]. Currently, there is an ongoing clinical study to evaluate the feasibility of spesolimab in PG treatment [ 177 ]. Estimated enrollment is approximately 20 participants and the completion of the trial is planned for 09.2025 ( Table 10 ).

4.3. Vilobelimab

Vilobelimab, also known as IFX-1, is a complement C5a inhibitor that was tested in phase IIa open-label trial [ 178 ]. Nineteen patients were enrolled in the study and were divided into three arms. The first cohort ( n = 6) received 800 mg of IFX-1 twice weekly for 12 weeks, following an initial phase involving 3 doses of 800 mg on days 1, 4, and 8 of the study, with a subsequent three-month observational period. The second cohort ( n = 6) received vilobelimab 1600 mg every 2 weeks, with the option to increase the dose from day 57 to 2400 mg every two weeks, and the third cohort ( n = 7) received 2400 mg every 2 weeks. After the promising results of phase II, phase III randomized, double-blind, placebo-controlled, multicenter trial is currently recruiting patients [ 179 ]. Estimated enrollment is approximately 90 participants and the completion of the trial is planned for February 2026 ( Table 10 ).

5. Conclusions

Treatment of PG is difficult and complex, and the lack of clear recommendations supported by large randomized studies is one of the problems faced by patients with PG. Even though there are currently many therapeutic methods with greater or lesser effectiveness, the key first-line drugs appear to be fast-acting immunosuppressants, such as systemic steroids and cyclosporine to reduce the disease burden, followed by slow-acting immunosuppressive agents with more favorable safety profiles and biologics. However, it is worth emphasizing that targeted therapies seem to be the most promising future option for the effective treatment of PG. Most scientific evidence refers to TNFα inhibitors—infliximab and adalimumab. Numerous case reports support the use of ustekinumab. As in many dermatological conditions, JAKi seems to be a future valuable therapeutic option in PG treatment. Ongoing clinical trials may yield new treatment alternatives, such as spesolimab or vilobelimab.

It is worth noting that rare pathological entities should not be overlooked, and only collaborative efforts across multiple centers can yield credible research results and bring about changes in the treatment of PG.

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Author Contributions

Conceptualization, M.Ł. and A.J.-K.; methodology, M.Ł. and A.J.-K.; writing—original draft preparation, M.Ł., A.R., M.K. and J.K.; writing—review and editing, M.Ł., A.R., M.K., J.K. and A.J.-K.; visualization M.Ł.; supervision, A.J-K. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Patients in this study provided consent for publication.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflicts of interest.

References

1. Maverakis E. Ma C. Shinkai K. Fiorentino D. Callen J.P. Wollina U. Marzano A.V. Wallach D. Kim K. Schadt C. Diagnostic Criteria of Ulcerative Pyoderma Gangrenosum: A Delphi Consensus of International Experts JAMA Dermatol. 2018 154 461 466 10.1001/jamadermatol.2017.5980 29450466

2. Jockenhöfer F. Wollina U. Salva K.A. Benson S. Dissemond J. The PARACELSUS score: A novel diagnostic tool for pyoderma gangrenosum Br. J. Dermatol. 2019 180 615 620 10.1111/bjd.16401 29388188

3. Haag C. Hansen T. Hajar T. Latour E. Keller J. Shinkai K. Ortega-Loayza A.G. Comparison of Three Diagnostic Frameworks for Pyoderma Gangrenosum J. Investig. Dermatol. 2021 141 59 63 10.1016/j.jid.2020.04.019 32445742

4. Hughes A.P. Jackson J.M. Callen J.P. Clinical features and treatment of peristomal pyoderma gangrenosum JAMA 2000 284 1546 1548 10.1001/jama.284.12.1546 11000649

5. Tolkachjov S.N. Fahy A.S. Cerci F.B. Wetter D.A. Cha S.S. Camilleri M.J. Postoperative Pyoderma Gangrenosum: A Clinical Review of Published Cases Mayo Clin. Proc. 2016 91 1267 1279 10.1016/j.mayocp.2016.05.001 27489052

6. Borda L.J. Wong L.L. Marzano A.V. Ortega-Loayza A.G. Extracutaneous involvement of pyoderma gangrenosum Arch. Dermatol. Res. 2019 311 425 434 10.1007/s00403-019-01912-1 30923901

7. George C. Deroide F. Rustin M. Pyoderma gangrenosum—A guide to diagnosis and management Clin. Med. 2019 19 224 228 10.7861/clinmedicine.19-3-224 PMC6542232 31092515

8. Honma M. Sugawara M. Ueno N. Honma M. Hinooka R. Tani C. Clinical Characteristics of Peristomal Pyoderma Gangrenosum: A Single Center Retrospective Observational Study J. Dermatol. 2022 49 1178 1182 10.1111/1346-8138.16504 35789032

9. Xu A. Balgobind A. Strunk A. Garg A. Alloo A. Prevalence estimates for pyoderma gangrenosum in the United States: An age- and sex-adjusted population analysis J. Am. Acad. Dermatol. 2020 83 425 429 10.1016/j.jaad.2019.08.001 31400451

10. Langan S.M. Groves R.W. Card T.R. Gulliford M.C. Incidence, mortality, and disease associations of pyoderma gangrenosum in the United Kingdom: A retrospective cohort study J. Investig. Dermatol. 2012 132 2166 2170 10.1038/jid.2012.130 22534879

11. Monari P. Moro R. Motolese A. Misciali C. Baraldi C. Fanti P.A. Caccavale S. Puviani M. Olezzi D. Zampieri P. Epidemiology of pyoderma gangrenosum: Results from an Italian prospective multicentre study Int. Wound J. 2018 15 875 879 10.1111/iwj.12939 29877043 PMC7949684

12. Kolios A.G. Gübeli A. Meier B. Maul J.-T. Kündig T. Nilsson J. Hafner J. Guenova E. Kerl K. Anliker M. Clinical Disease Patterns in a Regional Swiss Cohort of 34 Pyoderma Gangrenosum Patients Dermatology 2017 233 268 276 10.1159/000481432 29130957

13. Ighani A. Al-Mutairi D. Rahmani A. Weizman A.V. Piguet V. Alavi A. Pyoderma gangrenosum and its impact on quality of life: A multicentre, prospective study Br. J. Dermatol. 2019 180 672 673 10.1111/bjd.17347 30362501

14. Marzano A.V. Borghi A. Wallach D. Cugno M. A Comprehensive Review of Neutrophilic Diseases Clin. Rev. Allergy Immunol. 2018 54 114 130 10.1007/s12016-017-8621-8 28688013

15. Wang E.A. Steel A. Luxardi G. Mitra A. Patel F. Cheng M.Y. Wilken R. Kao J. de Ga K. Sultani H. Classic Ulcerative Pyoderma Gangrenosum Is a T Cell-Mediated Disease Targeting Follicular Adnexal Structures: A Hypothesis Based on Molecular and Clinicopathologic Studies Front. Immunol. 2018 8 1980 10.3389/fimmu.2017.01980 29379508 PMC5775228

16. Weiss D.I. Ma F. Merleev A.A. Maverakis E. Gilliet M. Balin S.J. Bryson B.D. Ochoa M.T. Pellegrini M. Bloom B.R. IL-1β Induces the Rapid Secretion of the Antimicrobial Protein IL-26 from Th17 Cells J. Immunol. 2019 203 911 921 10.4049/jimmunol.1900318 31235553 PMC6684376

17. Satoh T.K. Mellett M. Contassot E. French L.E. Are neutrophilic dermatoses autoinflammatory disorders? Br. J. Dermatol. 2018 178 603 613 10.1111/bjd.15105 27905098

18. Senra L. Mylonas A. Kavanagh R.D. Fallon P.G. Conrad C. Borowczyk-Michalowska J. Wrobel L.J. Kaya G. Yawalkar N. Boehncke W.-H. IL-17E (IL-25) Enhances Innate Immune Responses during Skin Inflammation J. Investig. Dermatol. 2019 139 1732 1742 10.1016/j.jid.2019.01.021 30738055

19. Smith S. Wu P.W. Seo J.J. Fernando T. Jin M. Contreras J. Montano E.N. Gabhann J.N. Cunningham K. Widaa A. IL-16/miR-125a axis controls neutrophil recruitment in pristane-induced lung inflammation JCI Insight 2018 3 e120798 10.1172/jci.insight.120798 30089723 PMC6129123

20. Ergun T. Pathergy Phenomenon Front. Med. 2021 8 639404 10.3389/fmed.2021.639404 PMC8185024 34113630

21. Le S.T. Wang J.Z. Alexanian C.C. Johng S.Y. Patel F.B. Wang E.A. Ma C. Wilken R. Cheng M.Y. Maverakis E. End stage scurvy in the developed world: A diagnostic conundrum but not to be mistaken for pyoderma gangrenosum Int. Wound J. 2019 16 1024 10.1111/iwj.13149 31154667 PMC7949452

22. Haag C.K. Nutan F. Cyrus J.W. Satpathy J. Shinkai K. Loayza A.G.O. Pyoderma gangrenosum misdiagnosis resulting in amputation: A review J. Trauma Acute Care Surg. 2019 86 307 313 10.1097/TA.0000000000002096 30358767

23. Bradsher R.W. The Endemic Mimic: Blastomycosis An Illness Often Misdiagnosed Trans. Am. Clin. Climatol. Assoc. 2014 125 188 25125734 PMC4112704

24. Wallach D. Vignon-Pennamen M.D. From acute febrile neutrophilic dermatosis to neutrophilic disease: Forty years of clinical research J. Am. Acad. Dermatol. 2006 55 1066 1071 10.1016/j.jaad.2006.07.016 17097401

25. Lorenz U. SHP-1 and SHP-2 in T cells: Two phosphatases functioning at many levels Immunol. Rev. 2009 228 342 359 10.1111/j.1600-065X.2008.00760.x 19290938 PMC2669678

26. Zhang J. Somani A.K. Siminovitch K.A. Roles of the SHP-1 tyrosine phosphatase in the negative regulation of cell signalling Semin. Immunol. 2000 12 361 378 10.1006/smim.2000.0223 10995583

27. Nesterovitch A.B. Szanto S. Gonda A. Bardos T. Kis-Toth K. Adarichev V.A. Olasz K. Ghassemi-Najad S. Hoffman M.D. Tharp M.D. Spontaneous insertion of a b2 element in the ptpn6 gene drives a systemic autoinflammatory disease in mice resembling neutrophilic dermatosis in humans Am. J. Pathol. 2011 178 1701 1714 10.1016/j.ajpath.2010.12.053 21435452 PMC3078426

28. Nesterovitch A.B. Gyorfy Z. Hoffman M.D. Moore E.C. Elbuluk N. Tryniszewska B. Rauch T.A. Simon M. Kang S. Fisher G.J. Alteration in the gene encoding protein tyrosine phosphatase nonreceptor type 6 (PTPN6/SHP1) may contribute to neutrophilic dermatoses Am. J. Pathol. 2011 178 1434 1441 10.1016/j.ajpath.2010.12.035 21406173 PMC3078441

29. Nesterovitch A.B. Hoffman M.D. Simon M. Petukhov P.A. Tharp M.D. Glant T.T. Mutations in the PSTPIP1 gene and aberrant splicing variants in patients with pyoderma gangrenosum Clin. Exp. Dermatol. 2011 36 889 895 10.1111/j.1365-2230.2011.04137.x 21790734

30. Smith E.J. Allantaz F. Bennett L. Zhang D. Gao X. Wood G. Kastner D.L. Punaro M. Aksentijevich I. Pascual V. Clinical, Molecular, and Genetic Characteristics of PAPA Syndrome: A Review Curr. Genom. 2010 11 519 10.2174/138920210793175921 21532836 PMC3048314

31. Kastner D.L. Aksentijevich I. Goldbach-Mansky R. Autoinflammatory disease reloaded: A clinical perspective Cell 2010 140 784 790 10.1016/j.cell.2010.03.002 20303869 PMC3541025

32. Marzano A.V. Borghi A. Meroni P.L. Cugno M. Pyoderma gangrenosum and its syndromic forms: Evidence for a link with autoinflammation Br. J. Dermatol. 2016 175 882 891 10.1111/bjd.14691 27106250

33. Dinarello C.A. A clinical perspective of IL-1β as the gatekeeper of inflammation Eur. J. Immunol. 2011 41 1203 1217 10.1002/eji.201141550 21523780

34. Wise C.A. Gillum J.D. Seidman C.E. Lindor N.M. Veile R. Bashiardes S. Lovett M. Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder Hum. Mol. Genet. 2002 11 961 969 10.1093/hmg/11.8.961 11971877

35. Genovese G. Moltrasio C. Garcovich S. Marzano A.V. PAPA spectrum disorders G. Ital. Dermatol. Venereol. 2020 155 542 550 10.23736/S0392-0488.20.06629-8 32618443

36. Moura R.R. Brandão L. Moltrasio C. Agrelli A. Tricarico P.M. Maronese C.A. Crovella S. Marzano A.V. Different molecular pathways are disrupted in Pyoderma gangrenosum patients and are associated with the severity of the disease Sci. Rep. 2023 13 4919 10.1038/s41598-023-31914-z 36966241 PMC10039684

37. Marzano A.V. Genovese G. Moltrasio C. Tricarico P.M. Gratton R. Piaserico S. Garcovich S. Boniotto M. Brandão L. Moura R. Whole-Exome Sequencing in 10 Unrelated Patients with Syndromic Hidradenitis Suppurativa: A Preliminary Step for a Genotype-Phenotype Correlation Dermatology 2022 238 860 869 10.1159/000521263 35034021

38. Henry C.M. Sullivan G.P. Clancy D.M. Afonina I.S. Kulms D. Martin S.J. Neutrophil-Derived Proteases Escalate Inflammation through Activation of IL-36 Family Cytokines Cell Rep. 2016 14 708 722 10.1016/j.celrep.2015.12.072 26776523

39. Takeuchi F. Streilein R.D. Hall R.P. Increased E-selectin, IL-8 and IL-10 gene expression in human skin after minimal trauma Exp. Dermatol. 2003 12 777 783 10.1111/j.0906-6705.2003.00088.x 14714557

40. Maverakis E. Van Den Elzen P. Sercarz E.E. Self-reactive T cells and degeneracy of T cell recognition: Evolving concepts-from sequence homology to shape mimicry and TCR flexibility J. Autoimmun. 2001 16 201 209 10.1006/jaut.2000.0493 11334484

41. Marzano A.V. Damiani G. Ceccherini I. Berti E. Gattorno M. Cugno M. Autoinflammation in pyoderma gangrenosum and its syndromic form (pyoderma gangrenosum, acne and suppurative hidradenitis) Br. J. Dermatol. 2017 176 1588 1598 10.1111/bjd.15226 27943240

42. Braun-Falco M. Kovnerystyy O. Lohse P. Ruzicka T. Pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH)--a new autoinflammatory syndrome distinct from PAPA syndrome J. Am. Acad. Dermatol. 2012 66 409 415 10.1016/j.jaad.2010.12.025 21745697

43. Marzano A.V. Ishak R.S. Colombo A. Caroli F. Crosti C. Pyoderma gangrenosum, acne and suppurative hidradenitis syndrome following bowel bypass surgery Dermatology 2012 225 215 219 10.1159/000343602 23171584

44. Marzano A.V. Ceccherini I. Gattorno M. Fanoni D. Caroli F. Rusmini M. Grossi A. De Simone C. Borghi O.M. Meroni P.L. Association of pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH) shares genetic and cytokine profiles with other autoinflammatory diseases Medicine 2014 93 e187 10.1097/MD.0000000000000187 25501066 PMC4602806

45. Lukens J.R. Kanneganti T.-D. SHP-1 and IL-1α conspire to provoke neutrophilic dermatoses Rare Dis. 2014 2 e27742 10.4161/rdis.27742 25054090 PMC4091500

46. Lukens J.R. Vogel P. Johnson G.R. Kelliher M.A. Iwakura Y. Lamkanfi M. Kanneganti T.-D. RIP1-driven autoinflammation targets IL-1α independently of inflammasomes and RIP3 Nature 2013 498 224 10.1038/nature12174 23708968 PMC3683390

47. Tartey S. Gurung P. Dasari T.K. Burton A. Kanneganti T.D. ASK1/2 signaling promotes inflammation in a mouse model of neutrophilic dermatosis J. Clin. Investig. 2018 128 2042 2047 10.1172/JCI98446 29629899 PMC5919885

48. Tartey S. Gurung P. Samir P. Burton A. Kanneganti T.-D. Cutting Edge: Dysregulated CARD9 Signaling in Neutrophils Drives Inflammation in a Mouse Model of Neutrophilic Dermatoses J. Immunol. 2018 201 1639 1644 10.4049/jimmunol.1800760 30082320 PMC6483079

49. Johnston A. Xing X. Wolterink L. Barnes D.H. Yin Z. Reingold L. Kahlenberg J.M. Harms P.W. Gudjonsson J.E. IL-1 and IL-36 are dominant cytokines in generalized pustular psoriasis J. Allergy Clin. Immunol. 2017 140 109 120 10.1016/j.jaci.2016.08.056 28043870 PMC5494022

50. Carrier Y. Ma H.-L. Ramon H.E. Napierata L. Small C. O’Toole M. Young D.A. Fouser L.A. Nickerson-Nutter C. Collins M. Inter-regulation of Th17 cytokines and the IL-36 cytokines in vitro and in vivo: Implications in psoriasis pathogenesis J. Investig. Dermatol. 2011 131 2428 2437 10.1038/jid.2011.234 21881584

51. Russell S. Horan R. Stefanska A. Carey A. Leon G. Aguilera M. Statovci D. Moran T. Fallon P. Shanahan F. IL-36α expression is elevated in ulcerative colitis and promotes colonic inflammation Mucosal Immunol. 2016 9 1193 1204 10.1038/mi.2015.134 26813344

52. Boutet M.-A. Bart G. Penhoat M. Amiaud J. Brulin B. Charrier C. Morel F. Lecron J.-C. Rolli-Derkinderen M. Bourreille A. Distinct expression of interleukin (IL)-36α, β and γ, their antagonist IL-36Ra and IL-38 in psoriasis, rheumatoid arthritis and Crohn’s disease Clin. Exp. Immunol. 2016 184 159 10.1111/cei.12761 26701127 PMC4837235

53. Hessam S. Sand M. Gambichler T. Skrygan M. Rüddel I. Bechara F.G. Interleukin-36 in hidradenitis suppurativa: Evidence for a distinctive proinflammatory role and a key factor in the development of an inflammatory loop Br. J. Dermatol. 2018 178 761 767 10.1111/bjd.16019 28975626

54. Pappu R. Ramirez-Carrozzi V. Sambandam A. The interleukin-17 cytokine family: Critical players in host defence and inflammatory diseases Immunology 2011 134 8 16 10.1111/j.1365-2567.2011.03465.x 21726218 PMC3173690

55. Senra L. Stalder R. Martinez D.A. Chizzolini C. Boehncke W.H. Brembilla N.C. Keratinocyte-Derived IL-17E Contributes to Inflammation in Psoriasis J. Investig. Dermatol. 2016 136 1970 1980 10.1016/j.jid.2016.06.009 27329229

56. Marzano A.V. Fanoni D. Antiga E. Quaglino P. Caproni M. Crosti C. Meroni P.L. Cugno M. Expression of cytokines, chemokines and other effector molecules in two prototypic autoinflammatory skin diseases, pyoderma gangrenosum and Sweet’s syndrome Clin. Exp. Immunol. 2014 178 48 56 10.1111/cei.12394 24903614 PMC4360193

57. Yeon H.B. Lindor N.M. Seidman J.G. Seidman C.E. Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome maps to chromosome 15q Am. J. Hum. Genet. 2000 66 1443 1448 10.1086/302866 10729114 PMC1288212

58. Oka M. Berking C. Nesbit M. Satyamoorthy K. Schaider H. Murphy G. Ichihashi M. Sauter E. Herlyn M. Interleukin-8 overexpression is present in pyoderma gangrenosum ulcers and leads to ulcer formation in human skin xenografts Lab. Investig. 2000 80 595 604 10.1038/labinvest.3780064 10780675

59. Rubas K. Reich A. Nowicka-Suszko D. Maj J. The role of interleukins 6, 8, 17 and 23 in the pathogenesis of pyoderma gangrenosum J. Eur. Acad. Dermatol. Venereol. 2023 37 e660 e662 10.1111/jdv.18683 36268700

60. Su W.P.D. Sctiroeter A.L. Perry H.O. Powell F.C. Histopathologic and immunopathologic study of pyoderma gangrenosum J. Cutan. Pathol. 1986 13 323 330 10.1111/j.1600-0560.1986.tb00466.x 3537032

61. Brooklyn T.N. Williams A.M. Dunnill M.G.S. Probert C.S. T-cell receptor repertoire in pyoderma gangrenosum: Evidence for clonal expansions and trafficking Br. J. Dermatol. 2007 157 960 966 10.1111/j.1365-2133.2007.08211.x 17935516

62. Gaffen S.L. Jain R. Garg A.V. Cua D.J. The IL-23-IL-17 immune axis: From mechanisms to therapeutic testing Nat. Rev. Immunol. 2014 14 585 600 10.1038/nri3707 25145755 PMC4281037

63. Langrish C.L. Chen Y. Blumenschein W.M. Mattson J. Basham B. Sedgwick J.D. McClanahan T. Kastelein R.A. Cua D.J. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation J. Exp. Med. 2005 201 233 240 10.1084/jem.20041257 15657292 PMC2212798

64. Brooklyn T.N. Dunnill M.G.S. Shetty A. Bowden J.J. Williams J.D.L. Griffiths C.E.M. Forbes A. Greenwood R. Probert C.S. Infliximab for the treatment of pyoderma gangrenosum: A randomised, double blind, placebo controlled trial Gut 2006 55 505 509 10.1136/gut.2005.074815 16188920 PMC1856164

65. Craig F.F. Thomas K.S. Mitchell E.J. Williams H.C. Norrie J. Mason J.M. Ormerod A.D. UK Dermatology Clinical Trials Network’s STOP GAP trial (a multicentre trial of prednisolone versus ciclosporin for pyoderma gangrenosum): Protocol for a randomised controlled trial Trials 2012 13 51 10.1186/1745-6215-13-51 22540770 PMC3423010

66. Alavi A. French L.E. Davis M.D. Brassard A. Kirsner R.S. Pyoderma Gangrenosum: An Update on Pathophysiology, Diagnosis and Treatment Am. J. Clin. Dermatol. 2017 18 355 372 10.1007/s40257-017-0251-7 28224502

67. Miller J. Yentzer B.A. Clark A. Jorizzo J.L. Feldman S.R. Pyoderma gangrenosum: A review and update on new therapies J. Am. Acad. Dermatol. 2010 62 646 654 10.1016/j.jaad.2009.05.030 20227580

68. Croitoru D. Naderi-Azad S. Sachdeva M. Piguet V. Alavi A. A Wound Care Specialist’s Approach to Pyoderma Gangrenosum Adv. Wound Care 2020 9 686 694 10.1089/wound.2020.1168 PMC7698649 32320358

69. Almeida I.R. Coltro P.S. Gonçalves H.O.C. Westin A.T. Almeida J.B. Lima R.V.K.S. Silva M.F. Junior J.A.F. The role of negative pressure wound therapy (NPWT) on the treatment of pyoderma gangrenosum: A systematic review and personal experience Wound Repair Regen. 2021 29 486 494 10.1111/wrr.12910 33772964

70. Bazaliński D. Krawiec A. Kucharzewski M. Więch P. Negative Pressure Wound Therapy in Pyoderma Gangrenosum Treatment Am. J. Case Rep. 2020 21 1 6 10.12659/AJCR.922581 PMC7304651 32520925

71. Yamaguchi Y. Yanagi T. Sato K. Yoshimoto N. Hirata Y. Ujiie I. Nishimura M. Natsuga K. Shiiya C. Tsukinaga I. Portable negative-pressure wound therapy for pyoderma gangrenosum: Report of two cases J. Dermatol. 2018 45 483 486 10.1111/1346-8138.14180 29235669

72. Mulholland O. Middleton D. Hunter H. Negative-pressure wound therapy as an adjunct to treating pyoderma gangrenosum J. R. Coll. Physicians Edinb. 2022 52 260 262 10.1177/14782715221126768 36369817

73. Eisendle K. Thuile T. Deluca J. Pichler M. Surgical Treatment of Pyoderma Gangrenosum with Negative Pressure Wound Therapy and Skin Grafting, Including Xenografts: Personal Experience and Comprehensive Review on 161 Cases Adv. Wound Care 2020 9 405 425 10.1089/wound.2020.1160 32320362 PMC7307671

74. Thomas K.S. Ormerod A.D. Craig F.E. Greenlaw N. Norrie J. Mitchell E. Mason J.M. Johnston G.A. Wahie S. Williams H.C. Clinical outcomes and response of patients applying topical therapy for pyoderma gangrenosum: A prospective cohort study J. Am. Acad. Dermatol. 2016 75 940 949 10.1016/j.jaad.2016.06.016 27502313

75. Lyon C.C. Stapleton M. Smith A.J. Mendelsohn S. Beck M.H. Griffiths C.E.M. Topical tacrolimus in the management of peristomal pyoderma gangrenosum J. Dermatol. Treat. 2001 12 13 17 10.1080/095466301750163518 12171681

76. Chow R.K.P. Ho V.C. Treatment of pyoderma gangrenosum J. Am. Acad. Dermatol. 1996 34 1047 1060 10.1016/S0190-9622(96)90285-6 8647970

77. Mrowieiz U. Christophers E. Clearing of pyoderma gangrenosum by intralesional cyclosporin A Br. J. Dermatol. 1991 125 499 10.1111/j.1365-2133.1991.tb14783.x 1751361

78. Ahmadi K. Aflaki E. Akbarzade Jahromi M. Dastgheib L. Successful Treatment of Classic Pyoderma Gangrenosum with Intralesional Infliximab Injection: A Case Report Australas. J. Dermatol. 2023 64 e252 e255 10.1111/ajd.14072 37192138

79. Cozzani E. Gasparini G. Parodi A. Pyoderma gangrenosum: A systematic review G. Ital. Dermatol. Venereol. 2014 149 587 600 Available online: https://pubmed.ncbi.nlm.nih.gov/25213386/ (accessed on 20 April 2023) 25213386

80. Pyoderma Gangrenosum: Treatment and Prognosis—UpToDate Available online: https://www.uptodate.com/contents/pyoderma-gangrenosum-treatment-and-prognosis (accessed on 20 April 2023)

81. Holt P.J. Davies M.G. Saunders K.C. Nuki G. Pyoderma gangrenosum: Clinical and laboratory findings in 15 patients with special reference to polyarthritis Medicine 1980 59 114 133 Available online: https://pubmed.ncbi.nlm.nih.gov/7360040/ (accessed on 20 April 2023) 10.1097/00005792-198003000-00003 7360040

82. Yamauchi T. Ishida K. Iwashima Y. Ikegaya S. Kawai Y. Ueda T. Wakahara M. Kumakiri M. Successful treatment of pyoderma gangrenosum that developed in a patient with myelodysplastic syndrome J. Infect. Chemother. 2003 9 268 271 10.1007/s10156-003-0254-6 14513399

83. Ambooken B. Khader A. Muhammed K. Rajan U. Snigdha O. Malignant pyoderma gangrenosum eroding the parotid gland successfully treated with dexamethasone pulse therapy Int. J. Dermatol. 2014 53 1536 1538 10.1111/ijd.12519 25312614

84. Ormerod A.D. Thomas K.S. Craig F.E. Mitchell E. Greenlaw N. Norrie J. Mason J.M. Walton S. Johnston G.A. Williams H.C. Comparison of the two most commonly used treatments for pyoderma gangrenosum: Results of the STOP GAP randomised controlled trial BMJ 2015 350 h2958 10.1136/bmj.h2958 26071094 PMC4469977

85. Perry H.O. Pyoderma gangrenosum South. Med. J. 1969 62 899 907 10.1097/00007611-196908000-00001 5798325

86. Callen J.P. Jackson J.M. Pyoderma gangrenosum: An update Rheum. Dis. Clin. N. Am. 2007 33 787 802 10.1016/j.rdc.2007.07.016 18037117

87. Graziano F. Macaluso F.S. Cassata N. Citrano M. Orlando A. Pyoderma Gangrenosum in An Ulcerative Colitis Pediatric Patient During Vedolizumab Therapy Successfully Treated with Oral Cyclosporine Inflamm. Bowel. Dis. 2021 27 E110 E111 10.1093/ibd/izab106 34003258

88. Vidal D. Puig L. Gilaberte M. Alomar A. Review of 26 cases of classical pyoderma gangrenosum: Clinical and therapeutic features J. Dermatol. Treat. 2004 15 146 152 10.1080/09546630410031909 15204146

89. Hasselmann D.O. Bens G. Tilgen W. Reichrath J. Pyoderma gangrenosum: Clinical presentation and outcome in 18 cases and review of the literature JDDG J. Der Dtsch. Dermatol. Ges. 2007 5 560 564 10.1111/j.1610-0387.2007.0328.x 17610605

90. Eaton P.A. Callen J.P. Mycophenolate mofetil as therapy for pyoderma gangrenosum Arch. Dermatol. 2009 145 781 785 10.1001/archdermatol.2009.57 19620559

91. Li J. Kelly R. Treatment of pyoderma gangrenosum with mycophenolate mofetil as a steroid-sparing agent J. Am. Acad. Dermatol. 2013 69 565 569 10.1016/j.jaad.2013.05.028 23850090

92. Hrin M.L. Bashyam A.M. Huang W.W. Feldman S.R. Mycophenolate mofetil as adjunctive therapy to corticosteroids for the treatment of pyoderma gangrenosum: A case series and literature review Int. J. Dermatol. 2021 60 e486 e492 10.1111/ijd.15539 33739458

93. Williams J.A. Hrin M.L. Bowers N.L. Jorizzo J.L. Feldman S.R. Huang W.W. Methotrexate for pyoderma gangrenosum: A retrospective case series of 33 patients J. Am. Acad. Dermatol. 2023 90 642 644 10.1016/j.jaad.2023.10.063 37972652

94. Sardar P. Guha P. Das N.K. Gharami R.C. Majumdar S. Banerjee D. Banerjee R. Ulcerative pyoderma gangrenosum in mixed connective tissue disorder: A rare association and role of azathioprine in the management Indian J. Dermatol. 2011 56 600 602 10.4103/0019-5154.87172 22121294 PMC3221239

95. Nazir A. Zafar A. Management of Idiopathic Pyoderma Gangrenosum with Azathioprine As the Primary Adjunct in an Asian Man: A Case Report Cureus 2022 14 e25177 10.7759/cureus.25177 35746991 PMC9209338

96. Wozel G. Blasum C. Dapsone in dermatology and beyond Arch. Dermatol. Res. 2014 306 103 124 10.1007/s00403-013-1409-7 24310318 PMC3927068

97. Galun E. Flugelman M.Y. Rachmilewitz D. Pyoderma gangrenosum complicating ulcerative colitis: Successful treatment with methylprednisolone pulse therapy and dapsone Am. J. Gastroenterol. 1986 81 988 989 Available online: https://pubmed.ncbi.nlm.nih.gov/3766502/ (accessed on 20 April 2023) 3766502

98. Brown R.E. Lay L. Graham D. Bilateral pyoderma gangrenosum of the hand: Treatment with dapsone J. Hand Surg. Br. 1993 18 119 121 10.1016/0266-7681(93)90209-X 8436847

99. Teasley L.A. Foster C.S. Baltatzis S. Sclerokeratitis and facial skin lesions: A case report of pyoderma gangrenosum and its response to dapsone therapy Cornea 2007 26 215 219 10.1097/ICO.0b013e31802eb078 17251816

100. Din R.S. Tsiaras W.G. Li D.G. Mostaghimi A. Efficacy of Systemic Dapsone Treatment for Pyoderma Gangrenosum: A Retrospective Review J. Drugs Dermatol. 2018 17 1058 1060 Available online: https://pubmed.ncbi.nlm.nih.gov/30365585/ (accessed on 20 April 2023) 30365585

101. Shenefelt P.D. Pyoderma gangrenosum associated with cystic acne and hidradenitis suppurativa controlled by adding minocycline and sulfasalazine to the treatment regimen Cutis 1996 57 315 319 Available online: https://pubmed.ncbi.nlm.nih.gov/8726710/ (accessed on 20 April 2023) 8726710

102. Reynolds N.J. Peachey R.D. Response of atypical bullous pyoderma gangrenosum to oral minocycline hydrochloride and topical steroids Acta. Derm. Venereol. 1990 138 538 539 Available online: https://pubmed.ncbi.nlm.nih.gov/1981437/ (accessed on 20 April 2023) 10.2340/00015555-70538539 1981437

103. Miralles E.S. Nunez M. Perez B. Ledo A. Minocycline hydrochloride hyperpigmentation complicating treatment of pyoderma gangrenosum J. Dermatol. 1994 21 965 967 10.1111/j.1346-8138.1994.tb03320.x 7868770

104. Song H. Lahood N. Mostaghimi A. Intravenous immunoglobulin as adjunct therapy for refractory pyoderma gangrenosum: Systematic review of cases and case series Br. J. Dermatol. 2018 178 363 368 10.1111/bjd.15850 28742926

105. Chaudhari U. Romano P. Mulcahy L.D. Dooley L.T. Baker D.G. Gottlieb A.B. Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: A randomised trial Lancet 2001 357 1842 1847 10.1016/S0140-6736(00)04954-0 11410193

106. Regueiro M. Valentine J. Plevy S. Fleisher M.R. Lichtenstein G.R. Infliximab for treatment of pyoderma gangrenosum associated with inflammatory bowel disease Am. J. Gastroenterol. 2003 98 1821 1826 10.1111/j.1572-0241.2003.07581.x 12907338

107. Argüelles-Arias F. Castro-Laria L. Lobatón T. Aguas-Peris M. Rojas-Feria M. Acosta M.B.-D. Soto-Escribano P. Calvo-Moya M. Ginard-Vicens D. Chaparro-Sánchez M. Characteristics and treatment of pyoderma gangrenosum in inflammatory bowel disease Dig. Dis. Sci. 2013 58 2949 2954 10.1007/s10620-013-2762-2 23828140

108. Tumor Necrosis Factor-Alpha Inhibitors: An Overview of Adverse Effects—UpToDate Available online: https://www.uptodate.com/contents/tumor-necrosis-factor-alpha-inhibitors-an-overview-of-adverse-effects (accessed on 20 April 2023)

109. Ljung T. Staun M. Grove O. Fausa O. Vatn M.H. Hellström P.M. Pyoderma gangrenosum associated with crohn disease: Effect of TNF-alpha blockade with infliximab Scand. J. Gastroenterol. 2002 37 1108 1110 10.1080/003655202320378338 12374238

110. Salehzadeh F. Mohammadikebar Y. Enteshary A. Ghanbarpour O. Mirzarahimi M. Infliximab in treatment of idiopathic refractory childhood pyoderma gangrenosum (PG) Biologics 2019 13 97 99 10.2147/BTT.S203753 31239637 PMC6554516

111. Kaur M.R. Lewis H.M. Severe recalcitrant pyoderma gangrenosum treated with infliximab Br. J. Dermatol. 2005 153 689 691 10.1111/j.1365-2133.2005.06812.x 16120178

112. Betetto L.Đ. Točkova O. Suhodolčan A.B. Mucocutaneous pyoderma gangrenosum: A case report and literature review Acta Dermatovenerol. Alp. Pannonica Adriat. 2022 31 S10 S13 10.15570/ACTAAPA.2022.S4 35339135

113. Yamasaki K. Yamanaka K. Zhao Y. Iwano S. Takei K. Suzuki K. Yamamoto T. Adalimumab in Japanese patients with active ulcers of pyoderma gangrenosum: Final analysis of a 52-week phase 3 open-label study J. Dermatol. 2022 49 479 487 10.1111/1346-8138.16337 35243682 PMC9313851

114. Seishima M. Sasaki M. Sugie S. Successful treatment of pyoderma gangrenosum using adalimumab in a patient undergoing hemodialysis J. Dermatol. 2022 49 e435 e436 10.1111/1346-8138.16526 35862244

115. Ohmura S. Homma Y. Hanai S. Otsuki Y. Miyamoto T. Successful switching treatment of adalimumab for refractory pyoderma gangrenosum in a patient with rheumatoid arthritis with prior use of tumour necrosis factor inhibitors: A case report and review of the literature Mod. Rheumatol. Case Rep. 2023 7 9 13 10.1093/mrcr/rxac023 35285489

116. Campanati A. Brisigotti V. Ganzetti G. Molinelli E. Giuliodori K. Consales V. Racchini S. Bendia E. Offidani A. Finally, recurrent pyoderma gangrenosum treated with Adalimumab: Case report and review of the literature J. Eur. Acad. Dermatol. Venereol. 2015 29 1245 1247 10.1111/jdv.12703 25200926

117. Kikuchi N. Hiraiwa T. Ohashi T. Hanami Y. Satoh M. Takenoshita H. Yamamoto T. Pyoderma gangrenosum possibly triggered by adalimumab Eur. J. Dermatol. 2012 22 804 805 10.1684/ejd.2012.1849 23107608

118. Benzaquen M. Monnier J. Beaussault Y. Rouby F. Berbis P. Pyoderma gangrenosum arising during treatment of psoriasis with adalimumab: Effectiveness of ustekinumab Australas J. Dermatol. 2017 58 e270 e271 10.1111/ajd.12545 28660635

119. Tan Y. Kavaklieva S. Wood F. Pyoderma gangrenosum induced by adalimumab in a seropositive rheumatoid arthritis patient: A paradoxical effect of adalimumab? Rheumatology 2021 60 e288 e289 10.1093/rheumatology/keab194 33836074

120. A Study to Assess Adverse Events and Change in Disease State in Adult Participants Being Treated with Humira in Participants Diagnosed with Pyoderma Gangrenosum (PG) Available online: https://clinicaltrials.gov/study/NCT04750213?cond=Pyoderma%20Gangrenosum&rank=4&limit=10&aggFilters=status:rec%20not&page=1 (accessed on 2 January 2024)

121. Ariane M. Bouaziz J.D. de Masson A. Jachiet M. Bagot M. Lepelletier C. Efficacy and safety of etanercept for postoperative pyoderma gangrenosum after infliximab serum sickness Dermatol. Ther. 2019 32 e12774 10.1111/dth.12774 30341800

122. Kim F.S. Pandya A.G. The use of etanercept in the treatment of peristomal pyoderma gangrenosum Clin. Exp. Dermatol. 2012 37 442 443 10.1111/j.1365-2230.2011.04234.x 22582915

123. Roy D.B. Conte E.T. Cohen D.J. The treatment of pyoderma gangrenosum using etanercept J. Am. Acad. Dermatol. 2006 54 S128 S134 10.1016/j.jaad.2005.10.058 16488326

124. Rogge F.J. Pacifico M. Kang N. Treatment of pyoderma gangrenosum with the anti-TNFalpha drug—Etanercept J. Plast. Reconstr. Aesthet. Surg. 2008 61 431 433 10.1016/j.bjps.2006.11.011 18358433

125. Haridas V. Shetty P. Dsouza L.C. Dinesh U.S. Haridas K. Bargale A. Pyoderma gangrenosum in Sjögren’s syndrome and its successful treatment with topical application of etanercept Int. J. Rheum. Dis. 2017 20 657 659 10.1111/1756-185X.13086 28419761

126. Goldenberg G. Jorizzo J.L. Use of etanercept in treatment of pyoderma gangrenosum in a patient with autoimmune hepatitis J. Dermatol. Treat. 2005 16 347 349 10.1080/09546630500424722 16428159

127. Pastor N. Betlloch I. Pascual J.C. Blanes M. Bañuls J. Silvestre J.F. Pyoderma gangrenosum treated with anti-TNF alpha therapy (etanercept) Clin. Exp. Dermatol. 2006 31 152 153 10.1111/j.1365-2230.2005.01972.x 16309525

128. McGowan J.W. 4th Johnson C.A. Lynn A. Treatment of pyoderma gangrenosum with etanercept J. Drugs Dermatol. 2004 3 441 444 Available online: https://pubmed.ncbi.nlm.nih.gov/15303791/ (accessed on 20 April 2023) 15303791

129. Guedes R. Moreira A. Menezes N. Baptista A. Varela P. Treatment of thalidomide resistant pyoderma gangrenosum with etanercept Acta Dermatovenerol. Croat. 2012 20 175 180 Available online: https://pubmed.ncbi.nlm.nih.gov/23069303/ (accessed on 20 April 2023) 23069303

130. Abdallah H.B. Fogh K. Bech R. Pyoderma gangrenosum and tumour necrosis factor alpha inhibitors: A semi-systematic review Int. Wound J. 2019 16 511 521 10.1111/iwj.13067 30604927 PMC7949186

131. Kowalzick L. Bertolini J. Baumann C. Walther B. Truhm B. Eickenscheidt L. Paradoxical Reaction to Etanercept: Development of Pyoderma Gangraenosum during Therapy of Psoriasis Arthritis J. Dtsch. Dermatol. Ges. 2013 11 447 449 10.1111/ddg.12032 23343137

132. Kleinpenning M.M. Langewouters A.M.G. Van De Kerkhof P.C.M. Greebe R.J. Severe pyoderma gangrenosum unresponsive to etanercept and adalimumab J. Dermatol. Treat. 2011 22 261 265 10.3109/09546631003797106 20673157

133. Vallerand I.A. Hardin J. Ustekinumab for the treatment of recalcitrant pyoderma gangrenosum: A case report SAGE Open Med. Case Rep. 2019 7 2050313X1984520 10.1177/2050313X19845206 PMC6498760 31080598

134. González J.L. Sáez M.L. Moraleda I.M. Martínez Á.H. Pyoderma gangrenosum solved by ustekinumab therapy Gastroenterol. Hepatol. 2021 44 299 300 10.1016/j.gastre.2020.06.021 33069432

135. Fahmy M. Ramamoorthy S. Hata T. Sandborn W.J. Ustekinumab for peristomal pyoderma gangrenosum Am. J. Gastroenterol. 2012 107 794 795 10.1038/ajg.2012.42 22552250

136. Low Z.M. Mar A. Treatment of severe recalcitrant pyoderma gangrenosum with ustekinumab Australas J. Dermatol. 2018 59 131 134 10.1111/ajd.12744 29205260

137. Cámara P.G. Ara M.L.Z. López S.G. Ustekinumab in a patient with pyoderma gangrenosum and refractory Crohn’s disease Med. Clin. 2019 153 e35 e36 10.1016/J.MEDCLI.2018.12.004 30795905

138. Piqueras-García J. Sahuquillo-Torralba A.J. Torres-Navarro I. Botella-Estrada R. Pyoderma Gangrenosum with Ulcerative Colitis Successfully Treated with Ustekinumab Actas Dermosifiliogr. 2019 110 776 778 10.1016/j.ad.2018.03.034 31151671

139. Nieto D. Sendagorta E. Rueda J.M. Herranz P. Successful treatment with ustekinumab and vacuum-assisted closure therapy in recalcitrant myelodysplastic syndrome-associated pyoderma gangrenosum: Case report and literature review Clin. Exp. Dermatol. 2019 44 116 119 10.1111/ced.13679 29851121

140. Goldminz A.M. Botto N.C. Gottlieb A.B. Severely recalcitrant pyoderma gangrenosum successfully treated with ustekinumab J. Am. Acad. Dermatol. 2012 67 e237 e238 10.1016/j.jaad.2012.04.045 23062936

141. Petty A.J. Whitley M.J. Balaban A. Ellington K. Marano A.L. Pyoderma gangrenosum induced by secukinumab in a patient with psoriasis successfully treated with ustekinumab JAAD Case Rep. 2020 6 731 733 10.1016/j.jdcr.2020.06.011 32715064 PMC7369520

142. Cosgarea I. Lovric Z. Körber A. Dissemond J. Successful treatment of refractory pyoderma gangrenosum with ustekinumab only after excision of renal cell carcinoma Int. Wound J. 2016 13 1041 1042 10.1111/iwj.12377 25294697 PMC7949558

143. Guenova E. Teske A. Fehrenbacher B. Hoerber S. Adamczyk A. Schaller M. Hoetzenecker W. Biedermann T. Interleukin 23 expression in pyoderma gangrenosum and targeted therapy with ustekinumab Arch. Dermatol. 2011 147 1203 1205 10.1001/archdermatol.2011.168 21680759

144. Nunes G. Patita M. Fernandes V. Refractory Pyoderma Gangrenosum in a Patient with Crohn’s Disease: Complete Response to Ustekinumab J. Crohns Colitis 2019 13 812 813 10.1093/ecco-jcc/jjy200 30535292

145. Kolios A. Maul J. Meier B. Kerl K. Traidl-Hoffmann C. Hertl M. Zillikens D. Röcken M. Ring J. Facchiano A. Canakinumab in adults with steroid-refractory pyoderma gangrenosum Br. J. Dermatol. 2015 173 1216 1223 10.1111/bjd.14037 26471257

146. Acierno S. Angrisani F. Marino A. Caporali R.F. Cimaz R. Giani T. Canakinumab treatment in a young girl with refractory chronic recurrent multifocal osteomyelitis associated with pyoderma gangrenosum Int. J. Rheum. Dis. 2022 25 1333 1338 10.1111/1756-185X.14425 36004431

147. Jaeger T. Andres C. Grosber M. Zirbs M. Hein R. Ring J. Traidl-Hoffmann C. Pyoderma gangrenosum and concomitant hidradenitis suppurativa--rapid response to canakinumab (anti-IL-1β) Eur. J. Dermatol. 2013 23 408 410 10.1684/ejd.2013.2018 23816498

148. O’Connor C. Gallagher C. Hollywood A. Paul L. O’Connell M. Anakinra for recalcitrant pyoderma gangrenosum Clin. Exp. Dermatol. 2021 46 1558 1560 10.1111/ced.14809 34137070

149. Coe J. Kudva S. Shams K. Matching the dose to the disease: Successful treatment of recalcitrant pyoderma gangrenosum using high-dose secukinumab Dermatol. Ther. 2022 35 e15669 10.1111/dth.15669 35762275

150. Kao A.S. King A.D. Bardhi R. Daveluy S. Targeted therapy with ixekizumab in pyoderma gangrenosum: A case series and a literature overview JAAD Case Rep. 2023 37 49 53 10.1016/j.jdcr.2023.05.002 37492426 PMC10363659

151. Tee M.W. Avarbock A.B. Ungar J. Frew J.W. Rapid resolution of pyoderma gangrenosum with brodalumab therapy JAAD Case Rep. 2020 6 1167 1169 10.1016/j.jdcr.2020.08.033 32953958 PMC7489266

152. McPhie M.L. Kirchhof M.G. Pyoderma gangrenosum treated with secukinumab: A case report SAGE Open Med. Case Rep. 2020 8 2050313X2094043 10.1177/2050313X20940430 PMC7370553 32733679

153. García M.M. González M.M. Lobato J.M.P. Secukinumab for pyoderma gangrenosum: A case report Med. Clin. 2019 152 246 10.1016/j.medcli.2018.06.011 30144933

154. Zhou Q. Zhou S. Xiong H. Yang J. Yang Z. Zhou N. Mao J. Li M. A Case of Paradoxical Reactions to Biologic Therapy for Psoriasis Clin. Cosmet. Investig. Dermatol. 2023 16 1493 1497 10.2147/CCID.S412520 37333515 PMC10275371

155. Orita A. Hoshina D. Hirosaki K. Pyoderma gangrenosum caused by secukinumab successfully treated with risankizumab: A case report and literature review Clin. Exp. Dermatol. 2022 47 1372 1374 10.1111/ced.15183 35298047

156. Sadik C.D. Thieme M. Zillikens D. Terheyden P. First emergence of pyoderma gangraenosum, palmoplantar pustulosis and sacroiliitis in a psoriasis patient associated with switching from secukinumab to brodalumab J. Eur. Acad. Dermatol. Venereol. 2019 33 e406 e407 10.1111/jdv.15714 31131924

157. Kao A.S. King A.D. Daveluy S. Successful treatment of cabozantinib-induced pyoderma gangrenosum with ixekizumab therapy: A case report Dermatol. Ther. 2022 35 e15716 10.1111/dth.15716 35837805

158. Pollack I.R. Wolner Z.J. Hammett J. Swerlick R.A. Pyoderma gangrenosum in a patient on ixekizumab JAAD Case Rep. 2021 16 152 154 10.1016/j.jdcr.2021.08.021 34621941 PMC8484731

159. Yang K. Oak A.S.W. Elewski B.E. Use of IL-23 Inhibitors for the Treatment of Plaque Psoriasis and Psoriatic Arthritis: A Comprehensive Review Am. J. Clin. Dermatol. 2021 22 173 192 10.1007/s40257-020-00578-0 33301128 PMC7727454

160. Yamanaka K. New treatment of pyoderma gangrenosum and hidradenitis suppurativa: A review J. Dermatol. 2023 51 172 179 10.1111/1346-8138.17031 38009911 PMC11483966

161. Leow L.J. Zubrzycki N. Recalcitrant Ulcerative Pyoderma Gangrenosum of the Leg Responsive to Tildrakizumab: A Case Report Clin. Cosmet. Investig. Dermatol. 2022 15 1729 1736 10.2147/CCID.S374534 PMC9419888 36039180

162. John J.M. Sinclair R.D. Tildrakizumab for treatment of refractory pyoderma gangrenosum of the penis and polymyalgia rheumatica: Killing two birds with one stone Australas. J. Dermatol. 2020 61 170 171 10.1111/ajd.13196 31729012

163. Çalışkan E. Edek Y.C. Adışen E. İlter N. Peristomal pyoderma gangrenosum treated with interleukin 23 inhibitor treatment: A case report J. Eur. Acad. Dermatol. Venereol. 2023 10.1111/jdv.19555 37804076

164. Baier C. Barak O. Guselkumab as a treatment option for recalcitrant pyoderma gangrenosum JAAD Case Rep. 2020 8 43 46 10.1016/j.jdcr.2020.12.005 33490346 PMC7810910

165. Reese A.M. Erickson K. Reed K.B. Ortega-Loayza A.G. Modified dose of guselkumab for treatment of pyoderma gangrenosum JAAD Case Rep. 2022 21 38 42 10.1016/j.jdcr.2021.11.030 35146098 PMC8818803

166. Burgdorf B. Schlott S. Ivanov I.H. Dissemond J. Successful treatment of a refractory pyoderma gangrenosum with Risankizumab Int. Wound J. 2020 17 1086 1088 10.1111/iwj.13359 32266771 PMC7948586

167. Piñeiro L.V. Martínez M.L. Pin A.I.C. Off-label use of guselkumab for pyoderma gangrenosum Med. Clin. 2023 161 226 227 10.1016/J.MEDCLI.2023.04.029 37271670

168. Castro L.G.M. JAK inhibitors: A novel, safe, and efficacious therapy for pyoderma gangrenosum Int. J. Dermatol. 2023 62 1088 1093 10.1111/ijd.16676 37118975

169. Dos Santos M.R.D. Ianhez M. Ribeiro B.N. de Queiroz B.B. Miot H.A. Refractory pyoderma gangrenosum associated with rheumatoid arthritis successfully treated with upadacitinib. Comments on: ‘JAK inhibitors: A novel, safe, and efficacious therapy for pyoderma gangrenosum Int. J. Dermatol. 2023 62 e595 e598 10.1111/ijd.16791 37424391

170. Scheinberg M. Machado L.A. Castro L.G.M. Ferreira S.B. Michalany N. Successful treatment of ulcerated pyoderma gangrenosum with baricitinib, a novel JAK inhibitor J. Transl. Autoimmun. 2021 4 100099 10.1016/j.jtauto.2021.100099 33997753 PMC8100614

171. Nasifoglu S. Heinrich B. Welzel J. Successful therapy for pyoderma gangrenosum with a Janus kinase 2 inhibitor Br. J. Dermatol. 2018 179 504 505 10.1111/bjd.16468 29451690

172. Baricitinib in the Treatment of Adults with Pyoderma Gangrenosum (PG) Available online: https://clinicaltrials.gov/study/NCT04901325?cond=Pyoderma%20Gangrenosum&rank=8&limit=10&aggFilters=status:rec%20not&page=1 (accessed on 2 January 2024)

173. Kochar B. Herfarth N. Mamie C. Navarini A.A. Scharl M. Herfarth H.H. Tofacitinib for the Treatment of Pyoderma Gangrenosum Clin. Gastroenterol. Hepatol. 2019 17 991 993 10.1016/j.cgh.2018.10.047 30404036

174. Olavarría P.S. Iturria S.R. Castillejo Ó.N. Tofacitinib, a useful option for the treatment of pyoderma gangrenosum in an ulcerative colitis patient Rev. Esp. De Enfermedades Dig. 2021 113 733 734 10.17235/REED.2021.7977/2021 33845581

175. Guénin S.H. Khattri S. Lebwohl M.G. Spesolimab use in treatment of pyoderma gangrenosum JAAD Case Rep. 2023 34 18 22 10.1016/j.jdcr.2023.01.022 36936866 PMC10015112

176. Ma L. Chen X. Guo Q. Qiao Z. Wang N. Pai P. Liu X. Rapid Response to Spesolimab in a Patient with severe refractory Pyoderma Gangrenosum Clin. Exp. Dermatol. 2023 49 82 84 10.1093/ced/llad317 37706345

177. Spesolimab in Pyoderma Gangrenosum Available online: https://clinicaltrials.gov/study/NCT06092216?cond=Pyoderma%20Gangrenosum&rank=2&limit=10&aggFilters=status:rec%20not&page=1 (accessed on 2 January 2024)

178. Exploratory Study of IFX-1 in Patients with Pyoderma Gangrenosum Available online: https://clinicaltrials.gov/study/NCT03971643?cond=Pyoderma%20Gangrenosum&rank=12&limit=10&page=2 (accessed on 2 January 2024)

179. Phase III Trial to Investigate Efficacy and Safety of Vilobelimab in Ulcerative Pyoderma Gangrenos Available online: https://clinicaltrials.gov/study/NCT05964413?cond=Pyoderma%20Gangrenosum&rank=5&limit=10&aggFilters=status:rec%20not&page=1 (accessed on 2 January 2024)