Development of Pyoderma Gangrenosum in a Patient with Acquired Reactive Perforating Collagenosis

Abstract

Introduction

Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis associated with systemic diseases, but its pathogenesis remains unclear. Acquired reactive perforating collagenosis (ARPC) is characterized by transepidermal elimination of degenerated collagen and is usually linked to diabetes mellitus or renal dysfunction. ARPC is not recognized as a precursor to PG. We report a rare case of PG occurring in a patient with ARPC, successfully treated with adalimumab.

Case Presentation

An 80-year-old woman with diabetes presented with generalized erythema and later developed multiple papules and nodules with central crusting. Histology confirmed ARPC. Despite topical corticosteroids, lesions ulcerated and progressed into painful necrotic ulcers on her extremities. Laboratory findings showed neutrophilia and elevated C-reactive protein, but no infection or autoimmune markers. Histopathology of the ulcers revealed dense neutrophilic infiltration with transepidermal elimination of collagen, consistent with PG. Diagnostic criteria (Delphi, Su, Paracelsus) supported PG secondary to ARPC. Topical corticosteroids were ineffective. Due to comorbid diabetes, high-dose systemic corticosteroids were avoided; instead, low-dose prednisolone with adalimumab was initiated. The patient received adalimumab induction (160 mg at week 0, 80 mg at week 2) followed by 40 mg weekly. The ulcers rapidly improved, and by 12 weeks, near-complete epithelialization was achieved without recurrence during steroid tapering.

Conclusion

This case represents PG occurring in a patient with ARPC, suggesting that persistent epidermal injury in ARPC may trigger neutrophilic dermatosis. Adalimumab proved effective, offering a safe therapeutic option in PG patients with comorbidities limiting corticosteroid use. Recognition of this association may aid earlier diagnosis and optimize treatment strategies.

Introduction

Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis often associated with systemic diseases such as inflammatory bowel disease, rheumatoid arthritis, and hematologic malignancies [1]. However, its exact pathogenesis remains unclear. Acquired reactive perforating collagenosis (ARPC) is characterized by transepidermal elimination of degenerated collagen fibers and is primarily observed in patients with diabetes mellitus or chronic renal failure [2]. ARPC is not typically considered a precursor to PG, but we present an extremely rare case of PG occurring in a patient with ARPC. This report highlights the clinical transition between the two diseases and the successful treatment with adalimumab.

Case Report

An 80-year-old woman with a history of diabetes visited a dermatology clinic 6 months prior to presentation at our hospital, with generalized erythema accompanied by pruritus. She had no history of inflammatory bowel disease, rheumatoid arthritis, myelodysplastic syndrome, or occult malignancy. Three months before presentation, multiple papules and nodules with central crusting appeared on her extremities (Fig. 1a). Histological examination of a nodule revealed transepidermal elimination of degenerated collagen fibers (Fig. 2a, b), leading to a diagnosis of ARPC. She was treated with topical corticosteroids for a few weeks, but the lesions ulcerated, enlarged, and became painful, prompting her referral to our hospital. Physical examination revealed multiple well-demarcated ulcers with black necrotic tissue predominantly on her lower extremities (Fig. 1b). Laboratory tests showed an elevated white blood cell count (9,410/μL) with neutrophil predominance (5,890/μL), elevated HbA1c (7.0%), and C-reactive protein (0.40 mg/dL; reference range: 0.00–0.14 mg/dL). There was no renal dysfunction (creatinine: 0.64 mg/dL), and IgA (345 mg/dL) was within the normal range. Rheumatoid factor, antinuclear antibody, MPO-ANCA, and PR3-ANCA were negative. The soluble interleukin (IL)-2 receptor level was within the institutional reference range. A culture test on the ulcerated area revealed the absence of bacteria, fungi, and acid-fast bacilli. Histopathological examination of the skin ulcers and surrounding areas revealed dense neutrophilic infiltration in the dermis and subcutaneous tissue, along with extrusion of degenerated collagen bundles through the epidermis (Fig. 3a–c). No evidence of venous dilatation or histological features suggestive of vasculitis, such as fibrinoid degeneration, was observed. The patient was diagnosed with PG based on the Delphi consensus (meeting the major criteria and four of eight minor criteria), the Su criteria (meeting two major criteria and two minor criteria), and the Paracelsus score (meeting 12 points) (Table 1). Initial treatment with topical betamethasone butyrate propionate failed to halt ulcer progression. Due to her diabetes, high-dose systemic corticosteroids were considered unsuitable; the combination therapy with low-dose prednisolone (10 mg/day) and adalimumab was started. Adalimumab was administered as 160 mg at week 0, 80 mg at week 2, and then 40 mg weekly thereafter. The ulcers gradually improved, and pain was reduced. By 12 weeks after initiating adalimumab, the ulcers were nearly completely epithelialized (Fig. 4). Therefore, prednisolone has been tapered without any recurrence of the ulcer. Furthermore, we are considering discontinuing adalimumab.

Fig. 1.

a Clinical presentation 3 months before the first visit to our hospital. Red pruritic papular eruptions across her entire body. b Clinical presentation at the initial consultation. Multiple well-demarcated ulcers with black necrotic tissue predominantly on her lower extremities.

Fig. 2.

Histopathological findings of nodule taken from the leg 3 months before the initial consultation revealed transepidermal elimination of degenerated collagen fibers (hematoxylin and eosin stain; original magnification, ×200 (a)). Elastica van Gieson staining revealed a superficial transepidermal elimination pattern, showing pale pink-stained collagen fibers along with a small number of black-stained elastic fibers (original magnification, ×200 (b)).

Fig. 3.

Histopathological findings of the skin ulcers and peripheral areas at the initial visit to our hospital. Dense dermal and subcutaneous infiltration of inflammatory cells, predominantly neutrophils (a, b) and the extrusion of degenerated collagen bundles through the epidermis (c) (hematoxylin and eosin stain; original magnification, ×40 (a), ×200 (b), ×200 (c)).

Table 1.

Fulfillment of diagnostic criteria for PG in the present case

Diagnostic system	Criterion met (basis in this case)
Delphi consensus	Major criterion (biopsy showing neutrophilic infiltrate)
	Minor: exclusion of infection (sterile culture and no histologic evidence of infection)
	Minor: pathergy (ulcer progression after trauma/scratching over ARPC lesions)
	Minor: multiple ulcers including anterior lower leg
	Minor: peripheral erythema/undermined border/tenderness
Su criteria	Major: rapid progression of painful, necrolytic cutaneous ulcers with an irregular, violaceous, and undermined border
	Major: exclusion of other causes (infection, vasculitis, malignancy excluded clinically and histologically)
	Minor: history suggestive of pathergy (ulcer progression after trauma/scratching over ARPC lesions)
	Minor: histopathological findings (sterile dermal neutrophilia with mixed inflammation)
Paracelsus score (12 ≥10 = highly likely)	Major: progressive course
	Major: reddish-violaceous wound border
	Minor: amelioration with immunosuppression (adalimumab and prednisolone)
	Minor: severe pain (VAS >4)
	Minor: localized pathergy (at prior ARPC sites after scratching)
	Minor: suppurative neutrophilic histology
	Minor: undermined wound margin

The patient fulfilled the major criteria and four minor criteria of the Delphi consensus, two major and two minor criteria of the Su criteria, and achieved 12 points in the Paracelsus score, supporting a highly probable diagnosis of PG.

Fig. 4.

Clinical course of the current patient. The patient was treated with adalimumab (ADA) and prednisolone (PSL). The ulcers gradually improved, and pain was reduced after initiating ADA. By 12 weeks, the ulcers were nearly completely epithelialized, allowing for tapering of PSL without any recurrence. Discontinuation of ADA is also being considered.

Discussion

PG is characterized by neutrophil-mediated sterile inflammation [3]. In this case, we hypothesize that ARPC-induced epidermal damage triggered PG. ARPC leads to transepidermal elimination of degenerated collagen fibers, resulting in sustained epidermal injury [4]. This injury causes the release of alarmins, which stimulate the production of pro-inflammatory cytokines such as IL-1β, IL-6, and tumor necrosis factor-alpha (TNF-α). These cytokines activate innate lymphocytes and T cells, promoting a type 1 immune response. This immune activation enhances neutrophil infiltration and abnormal neutrophil activation, contributing to PG lesion formation [5].

Dysregulated neutrophil function plays a crucial role in PG pathogenesis. TNF-α is known to activate neutrophils and promote IL-8 production, which further enhances neutrophil recruitment. This mechanism is a key contributor to PG pathophysiology, as increased TNF-α levels have been reported in PG lesions [1, 6]. In our case, neutrophil-dominant inflammation was observed in both ARPC and PG lesions, suggesting that neutrophil dysfunction played a role in disease progression.

Adalimumab, a fully human monoclonal antibody that targets TNF-α, has been reported as an effective treatment for PG by suppressing neutrophil activation and inflammatory cytokine production. Studies have suggested that TNF-α inhibitors may be particularly useful in patients with PG that is refractory to conventional therapies or in cases where systemic corticosteroids pose significant risks due to comorbidities such as diabetes, as seen in our patient. TNF-α inhibitor, including adalimumab, certolizumab pegol, etanercept, infliximab, and golimumab, have been used for the treatment of PG. Among these agents, adalimumab appears to demonstrate a higher response rate. Indeed, a phase III open-label study reported a response rate of 54.5% in patients receiving adalimumab after 6 months of treatment [7]. Furthermore, TNF-α inhibitors have been demonstrated to reduce tissue destruction by modulating the overactive inflammatory response, preventing excessive neutrophilic infiltration and subsequent tissue damage. Given that PG is often associated with underlying systemic inflammation, TNF-α inhibitors may be particularly beneficial in patients with concurrent autoimmune disorders or metabolic syndromes that exacerbate inflammatory responses [8].

The potential link between ARPC and PG raises questions about whether ARPC may belong to the broader spectrum of neutrophilic dermatoses. Traditionally, ARPC is classified as a perforating disorder rather than an inflammatory neutrophilic disease. However, our case suggests that persistent epidermal injury from ARPC, combined with neutrophilic infiltration, may facilitate the development of PG. This raises the possibility that ARPC may, in certain circumstances, act as a trigger for neutrophilic dermatoses, particularly in predisposed individuals.

In addition to TNF-α inhibitors, other targeted therapies for PG include IL-1 inhibitors, IL-17 inhibitors, IL-23 inhibitors, IL-36 receptor inhibitors, or complement factor C5a inhibitors, all of which modulate inflammatory pathways involved in neutrophil activation [7]. Among IL-17 inhibitors, ixekizumab, an anti-IL-17A monoclonal antibody, has been reported to be a safe and effective treatment for PG [9]. However, TNF-α inhibitors remain among the most widely used biologics for PG due to their ability to rapidly reduce inflammation and promote wound healing. Future studies should focus on identifying biomarkers that predict responsiveness to TNF-α inhibition, as well as on understanding the long-term outcomes of PG treatment with biologics.

To our knowledge, no prior well-documented cases of PG associated with ARPC have been published. This case represents PG occurring in a patient with ARPC, where chronic transepidermal elimination and scratching may have acted as pathergic triggers. Additionally, it supports the efficacy of adalimumab in PG treatment, particularly in patients with comorbidities that limit corticosteroid use.

This is a single case report and the findings cannot be generalized. As with all case reports, no causal or statistical conclusions can be drawn. Although validated diagnostic frameworks were applied and alternative causes were excluded, a definitive diagnostic gold standard for PG is lacking. Therefore, the interpretation of this case should be considered within the limitations of observational, anecdotal evidence. Further studies are needed to clarify the relationship between ARPC and PG and to explore the broader implications of neutrophilic inflammation in perforating disorders. Increased awareness of this potential association may lead to earlier diagnosis and optimized therapeutic strategies for affected patients.

Statement of Ethics

The patient has given informed consent and the study was done according to the Declaration of Helsinki. Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images. Ethical approval is not required for this study in accordance with local guidelines. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000550460).

Conflict of Interest Statement

The authors have no conflicts of interest to disclose.

Funding Sources

No funding was received for this study.

Author Contributions

The data were collected and the initial manuscript was written by Yuki Mizutani. Keiichi Yamanaka assessed and edited the manuscript, offering valuable feedback and contributing to the final version. Kyoko Sugioka and Tomoko Akeda provided medical treatment to the patient. Akinobu Hayashi contributed to histological analysis and diagnosis of the patient.

Funding Statement

No funding was received for this study.

Data Availability Statement

All data generated or analyzed during this study are included in this article and its online supplementary material. Further inquiries can be directed to the corresponding author.