Dapson in the Treatment of Pyoderma Gangrenosum: a Narrative Review

Introduction

Pyoderma gangrenosum (PG) is a rare, debilitating inflammatory skin disease that usually occurs between the third and fifth decade of life. Precise epidemiological data are scarce, its occurrence is estimated between 3 and 10 cases per million annually [1, 2]. As an autoinflammatory neutrophilic dermatosis, it displays a diverse course and clinical presentation. PG association with autoinflammatory syndromes underscores its intricate pathophysiology that involves neutrophil dysfunction, inflammatory mediators and genetic predisposition. It is usually associated with systemic diseases, mainly inflammatory bowel disease (IBD) and other autoimmune and hematologic conditions such as lymphoproliferative diseases and paraproteinemia. [3].
Therapy is usually multimodal and multidisciplinary. It consists of systemic treatments, such as glucocorticosteroids, immunosuppressive agents and biological therapies, alongside local topical medications and proper wound management [4]. However, properly managing this condition often requires many lines of treatment, and the treatment itself is contraindicated in many cases due to numerous adverse effects associated. Currently, there are no established gold standards for the management of this condition due to a lack of high-quality evidence, scarce data from randomised clinical trials and limited evaluation of individual medications [4, 5].
In this review, we focus on dapsone, an immunomodulator commonly employed as a second-line treatment for PG. We delve into its potential pathomechanism and provide a comprehensive summary of the literature concerning its clinical use.

Pyoderma gangrenosum

Clinical characteristics and diagnostic criteria

Pyoderma gangrenosum (PG) is characterized by painful, quickly evolving cutaneous ulcers with irregular, undermined, erythematous-violaceous edges [6, 7]. PG is an autoinflammatory neutrophilic dermatosis that demonstrates different clinical variants, such as the classic ulcerative, bullous, pustular, vegetative, postoperative, and peristomal [6]. PG usually affects the lower limbs, however the lesions may appear on any part of the body [4]. The classical, ulcerative PG starts as a reddish-blue pustule that can be a few millimetres in size. The lesion may be induced by a minor cutaneous trauma (pathergy). Instead of healing, the lesion breaks down and turns into an ulcer [8]. The ulceration grows centrifugally. The centre is usually necrotic, purulent, or granulating and surrounded by elevated borders with bluish margins. Lesions can range in size from a few millimetres to 30 centimetres but sometimes they may be very deep and expose tendons and muscles. PG scars are distinctive, atrophic, and cribriform [9]. Figure 1 presents the possible clinical manifestations of PG.
Approximately 50% of the cases are linked to systemic diseases, mainly inflammatory bowel disease (IBD), rheumatoid arthritis, paraproteinemia, and haematological malignancies. Less common associated diseases include primary biliary cirrhosis, hepatitis, spondyloarthropathies, and systemic lupus erythematosus [10]. There is a female predominance in non-malignancy-associated PG. Males are more likely to be impacted by PG linked to malignancies and have a worse prognosis [11].
Moreover, PG may be a part of autoinflammatory syndromes including PAPA (pyogenic arthritis, PG, and acne), PASH (PG, acne, and suppurative hidradenitis), PAPASH (pyogenic arthritis, PG, acne, and suppurative hidradenitis), PASS (PG, acne, suppurative hidradenitis and ankylosing spondylitis) and PsAPASH (psoriatic arthritis, PG, acne and suppurative hidradenitis) [6, 12]. PG may be also induced by drugs, amongst which the most common are granulocyte colony-stimulating factor (G-CSF), gefitinib, imatinib and sunitinib (tyrosine kinase inhibitors), ipilimumab (immune checkpoint inhibitor), azacitidine, rituximab, interferon-α, retinoids [13, 14]. Moreover, tumor necrosis factor inhibitors (anti-TNF-α antibodies) have been reported to paradoxically induce PG despite their pivotal role in the treatment of this condition and underlying diseases, such as IBD [15]. Most drug-induced PG lesions resolve after discontinuation of the medication [8].
The diagnosis of PG should be considered in any patient with a non-healing ulceration, especially when the patient presents with any systemic disease [10]. Currently, there are no universally accepted diagnostic criteria for PG. The most commonly used criteria are those proposed by Su et al. in 2004, the PARACELSUS score by Jockenhöfer et al. from 2018, and the Delphi consensus by Maverakis et al. from 2018 [5, 9, 16, 17]. The latter demonstrates the highest sensitivity and specificity of 86% and 90%, respectively, among those previously mentioned. Diagnostic criteria for ulcerative PG proposed by Maverakis et al. include one major criterion (biopsy of ulcer edge demonstrating neutrophilic infiltrate) and eight minor criteria: (1) exclusion of infection; (2) pathergy; (3) history of IBD or inflammatory arthritis; (4) history of papule, pustule or vesicle ulcerating within 4 days of appearing; (5) peripheral erythema, undermining border and tenderness at ulceration site; (6) multiple ulcerations, at least one on an anterior lower leg; (7) cribriform scarring at healed ulcer sites; and (8) decreased ulcer size 1 month after implementation of the immunosuppressive agent. A diagnosis is established when the patient meets the major criterion and at least four of the minor criteria.

Pathophysiology

PG has a complex aetiology that includes neutrophilic dysfunction, inflammatory mediators, and genetic predisposition. The currently proposed pathophysiological process begins with an internal or external trigger that stimulates the immune system directly or through necrosis of epithelial cells and keratinocytes, leading to neutrophilic infiltration into the epidermis and dermis [18]. Overexpression of IL-8, IL-17 and TNF-α, and matrix metalloproteinases (MMP) 2 and 9 has been observed in PG lesions [19–21]. Additionally, there is an increase in IL-1β and its receptor, indicating a potential role for autoinflammation via inflammasome formation [21]. These factors, particularly IL-8, which is a potent chemotactic agent for neutrophils, promote myeloperoxidase-positive neutrophilic recruitment and the formation of ulcers. Apoptosis and necrosis of keratinocytes result in the release of damage-associated molecular patterns (DAMPs), driving sterile inflammation with macrophage and T-cell infiltration. These cells further secrete chemotactic cytokines, such as IL-1β, IL-8, CCL5, and TNF-α. T-cells are also polarized towards Th1/Th17 cells, which secrete IL-17, which acts synergistically with TNF-α [22]. IL-17 is a strong stimulus for the production of IL-1β, IL-8, CCL5, TNF-α, G-CSF, and GM-CSF, thus prolonging the lifespan of neutrophils and further skin damage. The pathogenesis of PG is illustrated in Figure 2.
Moreover, specific genetic loci linked to an increased risk of IBD are correlated with the development of PG, such as loci IL-8RA (a mediator of neutrophil migration), PR domain-containing protein 1 (associated with autoimmune disease development), and tissue inhibitor of metalloproteinase 3 [23]. They are frequently observed in PG as well as in IBD. Genetic loci known to be linked to IBD, TRAF-interacting protein 2, and its variations raise the risk of concomitant PG and erythema nodosum development.
PG is found in a variety of genetic disorders, which provides insight into its aetiology [10, 21].
Previously mentioned genetic syndromes associated with PG, such as PASH, PAPA, PAPASH, PsAPASH, and PASS, are considered to be caused by a mutation of genes related to autoinflammatory diseases, such as PSTPIP1 [12, 24]. Patients with this mutation exhibit elevated levels of circulating neutrophils, leading to formation of neutrophil extracellular traps (NETs) in the skin, which further stimulate production of pro-inflammatory cytokines such as IL-1β, IL-6, IL-8, and IL-17 that drive the process of PG formation [22].

Management

There are no universally accepted standards for the management of PG. The 2022 guidelines from the Japanese Dermatologic Society by Yamamoto et al. recommend systemic corticosteroids, such as oral prednisone (0.5–1 mg/kg/day) or intravenous pulse corticosteroids (1000 mg/day), as first-line treatments for progressive and severe PG [4]. Treatment effects can typically be observed within 2 to 3 days. Often used as a second-line treatment, cyclosporine (2.5–5 mg/kg/day) may also be efficacious, particularly in cases where corticosteroids are not working or as a corticosteroid-sparing agent [25]. Dapsone (1.0–1.5 mg/kg/day) has been shown to be a useful alternative in the second-line setting. Additionally, there have been reports of the effective use of tacrolimus, azathioprine, methotrexate, mycophenolate mofetil, sulfasalazine, colchicine, and cyclophosphamide [26]. Targeted therapies, notably with TNF-a inhibitors (infliximab, adalimumab, etanercept) and IL-1 antagonists (canakinumab, anakinra, gevokizumab) have been used successfully in PG treatment [27]. There are ongoing trials investigating the potential use of IL-17 antagonists, IL-23 antagonists, JAK inhibitors, spesolimab (IL-36 inhibitor) and vilobelimab (C5a inhibitor) [28]. Topical treatment for PG is usually of second importance and includes the use of topical and intralesional corticosteroids [4, 26]. Treatment with topical tacrolimus has also proven effective; however, its efficacy is comparable to that of medium-potency topical corticosteroids. Additional local/topical therapies that have been documented include topical dapsone, nicotine, sodium cromoglycate, and 5-aminosalicylic acid [4, 26, 29]. Current studies suggest the potential application of topical infliximab; however, this has not yet been evaluated in clinical trials [30, 31]. Surgical debridement is contraindicated due to pathergy; however, proper wound management, according to the TIME protocol (based on the tissue, infection, moisture balance, and epithelization) is essential [32].

Dapsone

Mechanism of action

Dapsone (4-4´-diaminodiphenylsulfone, DDS), derived synthetically from aniline, is the most basic sulfone structurally, featuring a sulfonyl functional group with a sulfur atom bonding to two carbon atoms [33, 34]. Over the past 70 years, dapsone and other sulfones have served dual roles as antibacterial and anti-inflammatory agents. It is the primary component in the multidrug leprosy treatment recommended by the World Health Organization. Subsequently, its effectiveness in addressing numerous dermatological and systemic conditions, often characterized by the buildup and infiltration of neutrophils and eosinophils, was recognized, and its usage has broadened [35].
Dapsone absorption is typically slow but generally efficient. Peak concentrations of dapsone following oral intake occur within a range of 2 to 6 h. The extent of absorption is estimated to be between 70% and 80%. Approximately 70% to 90% of circulating dapsone is bound to proteins [33, 36]. Following absorption, dapsone undergoes enterohepatic circulation and metabolic transformations in both the liver and activated polymorphonuclear leukocytes (PML) or mononuclear cells. In the liver, its primary metabolic pathways entail acetylation by N-acetyltransferase to generate monoacetyldapsone (MADDS), and hydroxylation by cytochrome P-450 enzymes, leading to the formation of dapsone hydroxylamine (DDS-NOH). Hydroxylation of dapsone also takes place in the dermis in inflammatory dermatoses (involving PML). DDS-NOH is considered the active metabolite, mainly acting to inhibit chemotaxis, thus contributing to the anti-inflammatory properties of dapsone in many skin diseases [37].
The generation of DDS-NOH is crucial for both the drug’s efficacy and the incidence of adverse reactions, particularly in cutaneous inflammatory processes mediated by activated PML [34, 38]. Dapsone is extensively distributed throughout the body, traversing physiological barriers such as the blood-brain barrier and placenta, and is detectable in the breast milk. Approximately 20% of dapsone is excreted unchanged in urine, while 70% to 85% is eliminated as water-soluble metabolites [37]. A minor fraction may also be excreted in faeces.
As an antibiotic, dapsone operates similarly to sulfonamides by impeding the synthesis of dihydrofolic acid by competitively inhibiting para-aminobenzoate at the active site of dihydropteroate synthetase. Consequently, dapsone restrains the growth of microorganisms reliant on internal folic acid synthesis [34, 37]. As an anti-inflammatory/immunomodulatory drug dapsone exerts multiple effects on neutrophils, including interference with chemotactic migration and β2 integrin-mediated adherence. It inhibits the G-protein (Gi type) involved in signal transduction, reducing neutrophil recruitment and the production of harmful respiratory and secretory products [39]. Dapsone also inhibits myeloperoxidase (MPO) in neutrophils, crucial for generating a strong oxidant – hypochlorous acid. Dapsone interacts with MPO, causing its inactivation, which effectively safeguards cells against oxidative injury. Additionally, dapsone reduces leukotriene B4-stimulated inflammation by suppressing its binding to neutrophil receptors. It also inhibits the generation of leukotrienes and prostaglandins by multiple mechanisms. Dapson inhibits the synthesis of interleukin-8 (IL-8), interleukin-1β (IL-1β), and tumor necrosis factor-a (TNF-a). The mechanism of action of dapsone is illustrated in Figure 2.

Practical use

The oral dosage of dapsone for sulfone-sensitive conditions needs personalized adjustment to determine the optimal daily dose for disease control. Typically, adults commence with 50–100 mg per day orally. Dapsone can be gradually increased up to 200–300 mg daily if needed to achieve the desired effect. Upon achieving a favourable response, doses should be reduced to the minimum effective levels, usually 25–50 mg daily, which can be continued for years [38]. In children, it is recommended to administer dapsone at a dose of 2 mg/kg body weight per day [40]. Topical dapsone gel, available in 5% and 7.5% formulations, typically recommended for managing acne agminate, turned out to be effective in treating PG [33]. There are also reports of successful treatment of peristomal PG with topical crushed dapsone [29]. For children younger than 9, topical dapsone is not recommended [40].
Dapsone therapy can lead to various adverse effects (pharmacologic, dose-dependent, allergic, or idiosyncratic reactions). Among these, haematological side effects such as methemoglobinemia, haemolysis, and anemia are particularly prevalent. Typically, haemoglobin levels decrease after initiation of dapsone – around 1 g/dl in 4 weeks, which is considered not dangerous and a clinician should not worry about it. These effects are common even at low daily dosages of 100 mg and are more pronounced in patients with genetic enzyme deficiencies like glucose-6-phosphate dehydrogenase or glutathione reductase. They typically manifest in a mild and inconsequential manner, often escaping clinical detection by the patient. Long-term use of dapsone at standard doses typically results in methemoglobinemia, which, although usually not clinically significant, is caused by hydroxylamine metabolites of dapsone.
Moreover, antioxidants, including vitamins C and E, have been investigated for their potential to improve dapsone-induced haemolytic anemia [41]. While initial findings regarding vitamin E efficacy were inconclusive, recent investigations suggest a plausible protective effect against haemolysis, particularly in selecting patient populations. Nevertheless, further clinical trials are imperative to comprehensively validate these observations.
Consideration should also be given to determining the methaemoglobin (metHb) level and urinalysis. Yet, there is an absence of a precisely defined upper threshold for met-Hb levels in patients undergoing dapsone treatment. The Polish Dermatological Society defines normal met-Hb levels as 2–3%, however, some clinicians advise against routine metHb monitoring, advocating for assessments solely upon the emergence of clinical symptoms [42]. The most reliable approach is to measure metHb levels 14 days after starting therapy [40]. MetHb levels below 10% are typically asymptomatic [43]. Levels exceeding 10% may cause cyanosis, while levels above 30% can result in dyspnoea, dizziness, syncope, headache, and fatigue. MetHb levels above 50% may lead to metabolic acidosis, arrhythmias, seizures, and coma, and levels above 70% can be fatal. Asymptomatic patients with elevated metHb levels can be monitored without treatment [43, 44]. Symptomatic patients with high metHb levels (defined usually in the literature as above 20%) should receive oxygen therapy and intravenous methylene blue, supplemented with ascorbic acid. If there is no improvement after repeated doses of methylene blue, therapeutic whole-blood exchange or hyperbaric oxygen therapy should be considered.
Agranulocytosis, another severe adverse effect, is thought to be an unpredictable, idiosyncratic reaction and is more common in patients with dermatitis herpetiformis. Another rare side effect, named dapsone hypersensitivity syndrome (DHS) that occurs with the incidence rate between 0.5% to 3.6%, typically manifests 4 or more weeks after therapy initiation [34, 45, 46]. Symptoms may include a rash resembling mononucleosis, fever, and lymphadenopathy. Moreover, can be also involved, presenting symptoms like hepatomegaly, icterus, hepatitis, and hepatic encephalopathy. Also, eosinophilia can be present. In such instance, drug rash with eosinophilia and systemic symptoms (DRESS syndrome) should be diagnosed. The disease course varies, with some cases lasting 4 weeks or more, fatalities are also being reported. Exanthematous skin eruptions usually resolve within 2 weeks of discontinuing dapsone. Patients, who develop Stevens-Johnson syndrome or toxic epidermal necrolysis have increased morbidity and mortality rates [40].
Dapsone is contraindicated in patients with severe glucose-6-phosphate dehydrogenase (G6PD) deficiency, severe hepatic abnormality, known hypersensitivity to sulfonamides, sulfones, patients with severe anaemia and porphyria. It also should be avoided during pregnancy and breastfeeding.
Although dapsone is contraindicated in patients with G6PD deficiency, routine screening for G6PD status is not typically advised in the Caucasian population due to its low prevalence [47]. Studies indicate that the prevalence of G6PD deficiency ranges from approximately 1.4% to 7.9%, predominantly affecting individuals of Asian and African-American descent. It is usually mild, and not all patients with G6PD deficiency develop haemolytic anemia after initiation of dapsone. However, in the case of patients with not known G6PD status who are prescribed dapsone, close monitoring and frequent complete blood counts (CBC) are recommended to detect any potential hematologic complications.
Laboratory evaluation before starting dapsone treatment includes CBC count with differential, white blood cell count, and reticulocyte count; liver and renal function tests.
During follow-up appointments, patients should be monitored for adverse effects, and regular neurological function screening is advised, with special attention to fatigue, dizziness and syncope. During the initial 1 month, laboratory tests such as CBC count with differential, reticulocyte count, liver and renal function and urinalysis tests should be performed every week, followed by testing every month for 3 months, every 3 months. Monitoring diabetic patients using glycosylated haemoglobin (HbA1c) levels may be unreliable (usually lower) due to the potential interference of metHb with HbA1c measurements [48, 49].
Special caution when treating patients with dapsone must be considered in those who are receiving or have been exposed to other drugs or agents that are capable of inducing metHb production or haemolysis [34, 38]. Table 1 summarizes the most essential information regarding the use of dapsone in clinical practice.

Dapsone in the treatment of pyoderma gangrenosum

The data regarding the use of dapsone in the treatment of PG are limited. The literature includes only observational studies with retrospective reviews of patient series and case descriptions, with no proper clinical trial. A systematic review by Partridge et al. in 2018 [50] investigating the effectiveness of different systemic treatments in PG – dapsone was studied in 11 studies, which is less than systemic steroids, cyclosporine, and biological therapy. Nevertheless, it is widely used in clinical practice. In published articles, dapsone is commonly prescribed in either of the following scenarios: (1) first-line treatment as a steroid-sparing agent; (2) adjuvant therapy to either systemic steroids or biological treatments; (3) second-line therapeutic option when first-line treatment is ineffective or discontinued, because of the side effects. Assessing the efficacy of dapsone in monotherapy presents challenges owing to the widespread necessity for multimodal treatment in the majority of patients with PG. For example, in the study by Binus et al., all 103 patients with PG received combination therapy, multiple systemic drugs with proper wound management and topical treatments [51]. In 29 cases, three or more systemic drugs were used simultaneously, the most common being steroids (72.8%) followed by infliximab (14.6%), mycophenolate (14.6%), minocycline (13.6%), cyclosporine (13.6%), doxycycline (9.7%), azathioprine (7.8%), adalimumab (5.8%), dapsone (5.8%) and others. Local treatment consisted mostly of topical and intralesional steroids, calcineurin inhibitors, and wound management – debridement, skin grafting, and proper dressings. However, owing to the favourable safety profile of dapsone and the absence of available biological therapies due to age-related limitations, its utilization is more prevalent in the paediatric population. In a review of 170 paediatric patients (mean age: 9.5 years), 42.5% were treated with systemic corticosteroids alone, and 16.7% of the patients received adjuvant therapy [52]. The most common agents were dapsone (34.9%) and cyclosporine (30.4%). Dapsone was used in a dose of 12–100 mg/day. Among the steroid-sparing drugs, dapsone showed the highest clinical improvement rate – 82.6% (however, there was no significant difference from cyclosporine). Moreover, there are numerous cases describing the successful use of dapsone in the management of paediatric PG. Crouse et al. present a review of 21 cases of infantile PG. Seven of them received dapsone combined with other systemic therapy, such as systemic steroids, colchicine, azathioprine, tacrolimus, cyclosporine, and infliximab [53]. Among the cases mentioned, 4 of the patients reached a total resolution of lesions, 2 of them reached partial response, and in 1 patient, lesions were recurrent, and the patient died due to the underlying condition.
There are several studies regarding the use of dapsone in the treatment of adult PG. Din et al. conducted a retrospective analysis involving 27 adult patients diagnosed with PG who underwent treatment with dapsone in conjunction with additional therapeutic modalities [54]. The study reported a complete remission rate of 16% (n = 4), with partial remission observed in 81% (n = 22) of cases, while 3% (n = 1) exhibited no response to treatment. The mean duration until the initial therapeutic response was noted to be 5.3 weeks. Adverse drug reactions were documented in 9 (33%) patients, resulting in the discontinuation of therapy for one individual. Kolios et al. conducted an analysis of 34 adult cases of PG, identifying the most frequently utilized systemic therapies. Systemic steroids were administered in 68.3% of cases, dapsone and cyclosporine each in 31.7%, and infliximab in 13.3%. Complete resolution of PG was observed in 50.8% of cases by the time of hospital discharge. However, mean time until hospital discharge was not mentioned by the authors. Among those cases with complete disease resolution, dapsone was employed in 29.5%. The average duration for complete ulcer healing was recorded as 7.1 months without subdivision into treatment groups [55]. Bhat et al. documented 18 cases of PG with 61.1% (n = 11) receiving dapsone treatment. All exhibited improvement, achieving either complete or partial responses [56]. Lyon et al. analyzed 26 PG cases, with 19.2% (n = 5) treated with dapsone, either alone or in combination with other therapies; among these, 1 patient showed complete response, three demonstrated partial responses, and one had no response [57]. Pereira et al. identified that all patients receiving dapsone, which was 12.5% (n = 3) of the 24 patients analysed, achieved complete responses [58]. Hughes et al. reported seven PG cases, 3 of which were treated with dapsone; 2 achieved complete responses and 1 a partial response [59]. Hilton et al. reviewed cases of post-caesarean PG, including 4 patients treated with dapsone in combination with systemic steroids (2 cases) or systemic steroids and cyclosporine (2 cases), followed by surgery [60]. All patients achieved complete wound healing. Table 2 summarizes studies on the systemic use of dapsone.
As previously indicated, dapsone can also be administered topically. Li et al. conducted a study utilizing 5% dapsone gel applied to PG lesions in 21 patients [61]. The outcomes showed that 9.5% (n = 2) of the patients exhibited complete response, while 85.7% (n = 18) achieved a partial response. The mean time to response following treatment initiation was 4.3 weeks. No adverse effects were reported. Handler et al. presented a case of a 27-year-old male with peristomal PG [29]. The patient initially responded well to oral dapsone; however, due to elevated liver enzymes, the medication had to be discontinued. Subsequently, the treatment was switched to crushed dapsone tablets applied topically, leading to complete healing after 6 months.

Conclusions

Dapsone stands as a safe and well-tolerated therapeutic agent commonly employed in clinical settings. Notably, the most promising evidence supports the utilization of multimodal therapy in PG, incorporating various systemic agents, including systemic steroids, immunosuppressants such as cyclosporine, and dapsone, together with biologics. However, the studies presented within this review exhibit limitations such as small sample sizes, a high risk of bias, and substantial heterogeneity in patient populations and interventions. While our review primarily focuses on systemic therapies, it is imperative to acknowledge that these represent only one facet of the comprehensive treatment approach for PG. Although our review contributes insights into the practical use of dapsone and highlights gaps in the literature concerning systemic PG treatment, it is constrained by the scarcity of evidence and the limited quality of available studies. Existing data predominantly comprise small retrospective reviews and case reports characterized by inherent bias and a lack of standardization. Moreover, the absence of long-term follow-up, inconsistency in response measurement, and adverse effect reporting further compound the limitations. We shed light on the potential mechanisms through which dapsone modulates PG’s underlying pathophysiology, albeit acknowledging the prevailing gaps in its action. Moving forward, future research should prioritize randomized clinical trials or retrospective analyses involving larger, well-defined patient cohorts with clearly defined outcomes to advance our understanding and management of PG.

Funding

No external funding.

Ethical approval

Not applicable.

Conflict of interest

The authors declare no conflict of interest.

References