1. Introduction
Pyoderma gangrenosum (PG) is an uncommon, noninfectious neutrophilic dermatosis characterized by recurrent, sterile, necrotic ulcers of unknown etiology. It can occur idiopathically or secondary to various systemic conditions, notably inflammatory bowel diseases, rheumatological disorders, and hematological malignancies [1]. PG is rare in childhood, accounting for only 4% of cases [2].
Due to its rarity, the precise disease mechanism is not well understood, and although systemic glucocorticoids are generally considered the first‐line therapy, there is limited clinical evidence regarding second‐line or subsequent treatment for refractory cases, especially in childhood. Here, we present a case of a 9‐month‐old boy diagnosed with idiopathic PG that was refractory to conventional interventions but showed successful improvement with the addition of an anti‐TNF‐alpha antibody. We also performed exploratory cytokine profiling of this patient to provide descriptive immunological context, together with a comparison with Kawasaki disease as a representative pediatric inflammatory condition.
2. Case Report
A previously healthy 9‐month‐old boy was referred to our hospital with multiple pustules and ulcers on his face and extremities. The patient had received the Bacillus Calmette–Guérin (BCG) vaccine at 7 months of age. Several days after vaccination, pustules developed at the inoculation site.
These pustules rapidly expanded within a few days, progressing to ulceration, and subsequently disseminated to multiple areas within a month. He also developed a high fever. Due to a lack of response to empirical treatment with broad‐spectrum antibiotics and antituberculosis agents, he was admitted to our department.
At the time of admission, he was in good general condition but irritable due to pain. He presented with a 10‐cm diameter violaceous‐red flat‐elevated plaque with undermined ulcers surrounded by edema at the site of the BCG vaccination on his upper left arm (Figure 1A). He also had multiple ulcerative plaques and some impetigo‐like papules and pustules on his face and legs (Figure 1B,C).
Notably, the sites of blood draw and venous access developed nodules within a few days, indicative of pathergy (Figure 1D).
Blood tests revealed an inflammatory reaction with neutrophilic leukocytosis, but no abnormalities were found in lymphocytes or globulin subsets (Table 1). No pathogens were detected in cultures from the multiple lesions or by the PCR test for the Mycobacterium tuberculosis complex. A skin biopsy from an ulcer on the left lower leg showed dense inflammatory cell infiltrates throughout all layers of the dermis.
The epidermis was markedly thickened, and folliculitis with pseudocarcinomatous proliferation of follicular epithelium within the dermis was also observed (Figure 1E). In high‐power fields, the infiltrating leukocytes were predominantly neutrophils (Figure 1F). No evidence of vasculitis was observed, and staining with Grocott, Ziehl–Neelsen, and auramine–rhodamine stains yielded negative results.
No underlying condition, such as inflammatory bowel disease or malignancies, was identified through investigations including an FDG‐PET scan (Figure 1G) and a bone marrow examination. We also conducted whole‐exome sequencing to investigate potential genetic abnormalities associated with autoinflammatory syndromes known to be associated with PG, including PAPA, PASH, and PAPASH syndromes. Genes involved in inflammatory pathways, including inflammasome activation, IL‐1β signaling, and TNF‐related pathways, were also analyzed.
However, no significant mutations that could explain the pathophysiology were detected. Thus, we diagnosed the patient with idiopathic PG. We started treatment with intravenous immunoglobulin (IVIG) and 2 mg/kg of prednisolone (PSL), considering the severe systemic inflammatory presentation and the need for rapid immunomodulatory intervention.
After initiation of the initial treatment, the emergence of new lesions and pathergy decreased; however, tapering of PSL led to a rebound increase in inflammatory markers. Thus, methylprednisolone (mPSL) pulse therapy was administered, and cyclosporine was subsequently introduced. In addition, diaminodiphenyl sulfone and colchicine were added to the treatment due to the recurrence of skin lesions.
Although the patient partially responded to these treatments, there was a tendency for relapses at 3 months after the start of treatment during PSL tapering. Therefore, we initiated infliximab (IFX) at a dose of 5 mg/kg at baseline, at Weeks 2 and 6, and every 8 weeks thereafter. Following IFX initiation, the disease was controlled and remained in remission (Figure 2A).
PSL, DDS, and colchicine were discontinued at 12, 13, and 15 months after disease onset, respectively. Thereafter, treatment was continued with IFX and cyclosporine. No serious adverse events or infections were observed during IFX therapy, and no new lesions appeared.
The ulcers subsequently became completely epithelialized (Figure 2B), and his development was age appropriate. Following clinical resolution, subsequent vaccinations were carried out without any adverse events. IFX was discontinued 3 years after disease onset due to gastrointestinal adverse effects (intolerable nausea), and the patient has remained in remission thereafter.
2.1. Additional Examination
We also conducted cytokine profiling of this patient by evaluating serum cytokines using the Bio‐Plex multiplex assay system (Bio‐Rad, CA, USA). Human cytokine assay kits for interleukin‐6 (IL‐6) (#171B5006M), soluble tumor necrosis factor receptor (sTNFR)‐1 (#171BL034M), sTNFR‐2 (#171BL035M), interleukin‐18 (IL‐18) (#171B6023M), and interferon‐gamma–induced protein 10 (IP‐10) (#171B5020M) were individually purchased and evaluated simultaneously according to the manufacturer’s recommendations. The assays were performed on serum samples from this patient (two samples obtained before treatment initiation), healthy adults (n = 11), and patients with Kawasaki disease who had a typical clinical course (n = 15) as inflammatory disease controls.
In this context, the term “typical clinical course” of Kawasaki disease refers to the following: (1) meeting more than 5 out of 6 of the clinical diagnostic criteria, (2) achieving improvement with the initial immunoglobulin therapy, and (3) the absence of residual coronary artery complications. As a result, we found the following: (A) no cytokines were elevated in healthy adults; (B) the cytokine profile in Kawasaki disease showed increases in a wide range of proinflammatory cytokines, including IL‐6, sTNFR‐1, sTNFR‐2, IL‐18, and the interferon‐responsive chemokine IP‐10; and (C) The cytokine pattern of this patient also showed a broad elevation of proinflammatory cytokines, which closely resemble that of typical Kawasaki disease (Figure 3).
3. Discussion
We presented a case of an infant with idiopathic PG who showed sustained clinical improvement after the addition of IFX. Additionally, we provided an analysis of cytokine profiling, which may provide immunological context for the underlying inflammatory processes in infantile PG. PG in infancy is an exceptionally rare disease, with available information primarily limited to case reports and literature reviews [2].
Infantile PG has unique characteristics compared to adult cases: The proportion of comorbidities is lower (33% in infants, 75% in adults), while multiple or disseminated lesions and systemic signs such as fevers, anemia, and failure to thrive are more common [3]. Pathergy is also observed more frequently in infants (71% in infants, 33% in adults) [3]. Table 2 summarizes 17 cases of idiopathic infantile PG reported in the literature [3–16].
The age of onset ranges from 3 weeks to 11 months (median 8 months), with PG occurring during the neonatal period in two cases. Our case, presenting at 9 months with multiple ulcerative lesions, systemic signs, and pathergy, may represent the typical manifestations of infantile PG.
The diagnosis of PG is primarily clinical, supported by histological findings and exclusion of alternative diagnoses, as no pathognomonic histological features have been established. Although the association between BCG vaccination and the onset of PG in our case could not be defined, there have been reports of infantile PG developing after minor trauma [9] and respiratory tract infections [4, 10]. It is possible that the vaccine acted as a trigger rather than as the primary cause of the disease.
Regarding treatment, all patients received systemic glucocorticoids, including PSL or mPSL pulse therapy, with approximately half of the cases achieving remission with steroid monotherapy, while the other half were unresponsive or experienced relapses, necessitating combination therapy with immunosuppressants or biologic agents. For combination therapy, cyclosporine was the most used agent, administered in five cases. IFX was also used as a second‐line treatment in several cases.
Notably, studies from recent years indicate an increasing preference for IFX in managing refractory pediatric PG cases [15, 17]. Interestingly, there have been two cases of infantile PG showing an incomplete response to anakinra, an anti–interleukin‐1 receptor antibody, with subsequent resolution after switching to IFX [3, 14]. This observation may suggest that IL‐1 inhibition alone is insufficient in some infantile PG cases and that TNF‐mediated inflammatory pathways may also play an important role.
As treatment options for adult PG, the efficacy of glucocorticoids and cyclosporine has been well demonstrated [18]. Also, TNF‐α inhibitors, particularly IFX, have become established as a first‐line option in specific clinical settings, supported by a randomized controlled trial [19, 20]. IVIG is positioned as an adjunct therapy in refractory PG [21].
However, in infantile PG, recent literature indicates that systemic corticosteroids remain the mainstay of first‐line therapy, while other agents such as cyclosporine, DDS, and biologics are typically reserved for steroid‐refractory cases [17].
Our treatment approach was consistent with this stepwise strategy for infantile PG. Although IVIG was introduced early in the clinical course because of its favorable safety profile in pediatric inflammatory diseases [22], treatment was initiated with glucocorticoids, and due to disease recurrence, additional therapies including cyclosporine, DDS, colchicine, and ultimately IFX were introduced. Thus, in the present case, the addition of IFX was associated with sustained clinical improvement, although the contribution of IFX cannot be distinguished from that of the concomitant immunosuppressive therapies.
Nevertheless, the association between IFX initiation and subsequent disease control raises the possibility that TNF inhibition contributed to the favorable outcome in this refractory case.
We performed exploratory cytokine profiling in this case to characterize the inflammatory milieu and to provide retrospective immunological context for the clinical course. We found that a broad range of proinflammatory cytokines—including IL‐6, soluble TNF receptors, IL‐18, and IP‐10, an interferon‐inducible protein—was elevated. Although the precise pathology of PG remains unclear, it is hypothesized that excessive activation of the innate immune system may play a significant role based on histological findings and the nature of the comorbidities [1].
The cytokine profile observed in this patient was generally consistent with this hypothesis and showed similarities to a previously reported case of infantile idiopathic PG [14].
This cytokine profile showed partial overlap with that observed in Kawasaki disease. Kawasaki disease is a systemic vasculitis syndrome in children, in which overactivation of the innate immune system and the resulting overproduction of proinflammatory cytokines have been well characterized [23]. Because IFX has been demonstrated to be effective as a second‐line or later therapy for refractory Kawasaki disease [24], the similarity of these cytokine patterns in infantile PG may provide further rationale for using IFX in this condition.
However, these findings should be interpreted cautiously because they are derived from a single patient. In addition, the broad elevation of cytokines may reflect nonspecific inflammatory responses rather than a shared disease mechanism. Further investigation is required to establish the treatment strategy for infantile PG.
Nevertheless, we believe that the clinical course and additional cytokine analysis in this patient suggest that TNF‐mediated inflammation may represent a relevant therapeutic target in refractory infantile PG, supporting the consideration of TNF inhibition as part of combination immunosuppressive therapy in selected cases.
4. Conclusion
This case demonstrated a favorable outcome of idiopathic infantile PG treated with an anti–TNF‐α antibody in addition to glucocorticoids and cyclosporine. Cytokine analysis revealed increases in multiple proinflammatory cytokines, resembling the pattern observed in Kawasaki disease, suggesting overlapping inflammatory pathways in this rare condition. Infliximab may represent a potential therapeutic option for infantile PG, although further studies are needed.
Funding
This study was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI (grant number 24K11037).
Ethics Statement
Cytokine analysis was conducted with approval from the Ethics Committee of Asahikawa Medical University (Accession No. #23183) and in accordance with the Declaration of Helsinki. Written informed consent was obtained from the patient’s parents for the publication of this case report and cytokine analysis. For the parents of patients with Kawasaki disease, informed consent was obtained through an opt‐out consent procedure on our website.
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting Information
Additional supporting information can be found online in the Supporting Information section.
Supporting information