Pyoderma gangrenosum in rheumatoid arthritis treated with combined immunomodulatory and antimicrobial therapy: A case report

INTRODUCTION

Pyoderma gangrenosum (PG) is a rare, non-infectious neutrophilic dermatosis characterized by rapidly progressive, painful cutaneous ulcers with undermined violaceous borders.^[1,2]It most commonly affects individuals between the third and sixth decades of life and occurs with similar frequency in both sexes.^[1] Although the exact etiology remains unclear, PG is widely regarded as an autoinflammatory condition driven by dysregulated immune responses and neutrophilic infiltration.^[2,3]

A significant proportion of PG cases are associated with systemic diseases, particularly inflammatory conditions such as rheumatoid arthritis (RA).^[4,5] Epidemiological studies have demonstrated a higher prevalence of RA among patients with PG compared to the general population, suggesting a strong pathogenic link between these entities.^[4,6] Both conditions share overlapping immunological mechanisms, including cytokine dysregulation and activation of neutrophil-mediated inflammatory pathways.^[7,8] Clinically, PG in patients with RA may present later in life and often poses diagnostic and therapeutic challenges due to its resemblance to other cutaneous manifestations of RA and potential resistance to conventional therapies.^[9,10]

Recent advances in understanding the immunopathogenesis of PG have led to the exploration of targeted therapies, including Janus kinase (JAK) inhibitors, which modulate key inflammatory signaling pathways.^[11,12] Among these, tofacitinib has emerged as a promising option in refractory cases, particularly when traditional immunosuppressive agents are contraindicated or ineffective.^[13,14]

In this context, we report a case of PG in a patient with RA successfully managed with a combination regimen centered on a JAK inhibitor, highlighting both the clinical association and evolving therapeutic strategies for this challenging condition.

CASE REPORT

A 70-year-old Indian woman with a two-year history of RA on irregular treatment presented with a two-month history of painful, itchy skin lesions involving both upper and lower extremities. The lesions began insidiously over the ankle and heel regions and progressed rapidly to involve the extensor surfaces and interdigital web spaces of the hands.

Her past medical history revealed inconsistent use of nonsteroidal anti-inflammatory drugs and oral methotrexate over the preceding six months. This poor adherence was associated with worsening morning stiffness, joint pain, and progressive joint deformities in both upper and lower limbs. She also reported recent-onset anorexia, dysphagia, and generalized weakness.

On physical examination, multiple tender ulcers of varying sizes and stages were observed. These ulcers were well-defined, with erythematous bases, undermined edges, and violaceous borders. Laboratory evaluation showed significantly elevated inflammatory markers: erythrocyte sedimentation rate (ESR) of 100 mm/hr (reference: 0–10 mm), C-reactive protein (CRP) 64.9 mg/dL (reference: 0–6 mg/dL), anti-cyclic citrullinated peptide antibodies >358 U/mL (positive >17 U/mL), and rheumatoid factor 64.9 IU/mL (reference: 1–20 IU/mL). Hematological parameters revealed hemoglobin 8.4 g/dL (reference: 12–15 g/dL), total leukocyte count 21,400/mL (reference: 4,000–11,000/mL), platelet count 121,000/cumm (reference: 150,000–410,000/cumm), and a markedly elevated neutrophil-to-lymphocyte ratio (NLR) of 14.8 (reference: 0.78–3.53).^[15] Peripheral smear examination showed macrocytic anemia with bicytopenia.

Histopathological examination of a skin biopsy revealed reactive epidermal atypia with hyperplasia, and a mixed acute and chronic inflammatory infiltrate in the dermis, consistent with PG. Wound swabs taken from the lesions were sterile on routine aerobic culture.

Considering the patient’s bicytopenia, prior methotrexate exposure, and financial constraints, a comprehensive treatment strategy was formulated [Figure 1], and treatment was initiated with tofacitinib 10 mg/day in two divided doses, sulfasalazine 1 g/day in two divided doses, doxycycline, dapsone, and topical 0.1% tacrolimus ointment applied twice daily. Topical tacrolimus at 0.1% was selected to provide potent localized T-cell inhibition and decrease the secretion of inflammatory cytokines without the systemic risks involved with the use of high-potency topical corticosteroids. Supportive wound care and pain management were also provided. This comprehensive treatment regimen resulted in notable clinical improvement, including resolution of joint pain and morning stiffness, significant healing of skin ulcers [Figures 2 and 3], and marked reduction in inflammatory markers [Figures 4-6].

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Figure 1:

Schematic management pathway: refractory pyoderma gangrenosum in rheumatoid arthritis (elderly/bicytopenic). RA: Rheumatoid arthritis, ESR: Erythrocyte sedimentation rate, CRP: C-reactive protein, PG: Pyoderma gangrenosum, NFkB: NF-κB: Nuclear factor kappa B, NLR: Neutrophil-to-lymphocyte ratio, DMARD: Disease-modifying antirheumatic drugs, IL: Interleukin.

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Figure 2:

(a) Ulcer on the thenar eminence. (b) Ulcer resolved after one month of treatment.

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Figure 3:

(a) Ulcer on the medial aspect of the ankle. (b) Ulcer resolved after one month of treatment

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Figure 4:

Laboratory values for erythrocyte sedimentation rate plotted against the days of treatment.

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Figure 5:

Laboratory values for C-reactive protein plotted against the days of treatment

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Figure 6:

Laboratory values for neutrophil-lymphocyte (NLR) ratio plotted against the days of treatment.

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DISCUSSION

PG was first described in 1908 by Louis Brocq as “geometric phagedenic,” due to the geometric configuration and rapid progression of the ulcers.^[3] The term “PG” was later introduced by Brunsting, Goecke man, and O’Leary in 1930, initially thought to be of infectious origin—a theory now disproven, as PG is recognized as a non-infectious, autoinflammatory condition.^[16] PG has several clinical variants, including ulcerative, pustular, bullous, vegetative, peristomal, and postsurgical forms. The classic ulcerative type is the most common, often initiated by minor trauma (pathergy), and typically presents as painful, rapidly progressing ulcers with undermined violaceous borders, predominantly on the lower limbs. Histologically, PG is marked by dense neutrophilic infiltration in the dermis, often with abscess formation, hemorrhage, and epidermal necrosis. Early lesions may also show features of vasculitis, such as endothelial swelling and fibrinoid necrosis.^[2] There is a well-documented association between PG and systemic inflammatory conditions, particularly RA . A population-based case-control study found RA in 4.7% of PG patients compared to 1.5% in controls, indicating over a threefold increased risk.^[4,6] Moreover, PG in RA patients typically presents later in life, with joint symptoms often preceding PG by about 10 years.^[6,17] In some cases, PG may even be the initial manifestation of RA in elderly patients.^[9]This case is unique in its presentation of PG alongside methotrexate-induced bicytopenia, necessitating a shift from traditional disease-modifying antirheumatic drugs (DMARDs) to a JAK-inhibitor-based regimen.

Diagnosing PG in patients with RA is often challenging due to overlap with other RA-associated cutaneous manifestations, such as rheumatoid vasculitis and ulcerative lesions of vascular origin, which can closely mimic PG in both appearance and progression. The presence of pathergy and the lack of specific histopathological features further complicate differentiation, often making PG a diagnosis of exclusion and potentially delaying appropriate treatment.^[10]In addition, management in this subset of patients can be difficult, as they may show suboptimal or variable responses to conventional therapies such as corticosteroids and traditional DMARDs, particularly in the context of longstanding disease or prior immunosuppressive exposure, thereby necessitating alternative therapeutic strategies.^[9]

Inflammatory markers such as CRP, NLR, and interleukin-23 (IL-23) have been shown to correlate with disease activity and wound healing, particularly in inflammatory arthritis.^[18–20]In contrast, ESR tends to be less reliable due to its complex relationship with disease activity.^[21] Monitoring these biomarkers may help clinicians assess disease progression and tailor treatment strategies.

Both PG and RA involve neutrophilic-driven inflammation and cytokine dysregulation. Elevated levels of tumor necrosis factor alpha (TNF-α), IL-1β, IL-8, IL-12, IL-15, IL-17, and IL-23 have been detected in PG lesions, contributing to neutrophil activation and persistent inflammation.^[7] These same cytokines are implicated in RA, particularly in the synovial tissue, suggesting a shared immunopathogenic mechanism. Additionally, PG shows increased expression of pattern recognition receptors, JAK2, and signal transducer/activator of transcription (STAT1) pointing to both innate and adaptive immune system involvement.^[7,11]In RA, autoantibody production and T-cell-mediated responses further support this immune overlap.^[8]

The rationale for our specific combination therapy stems from the need to address the autoinflammatory nature of PG while managing the patient's underlying RA and preventing secondary infection. Tofacitinib and sulfasalazine target the JAK-STAT and NF-κB pathways, respectively, while doxycycline and dapsone provide secondary antimicrobial and anti-neutrophilic benefits. Supporting evidence for using tofacitinib in refractory neutrophilic dermatoses highlights its ability to modulate the IL-23/IL-17 axis effectively.^[13]Recent treatment approaches for PG, especially in patients with comorbid inflammatory diseases like RA, have expanded beyond corticosteroids and cyclosporine. While these remain standard first-line agents, biologic therapies are increasingly used earlier in the disease course. TNF-α inhibitors (e.g., infliximab, adalimumab), IL-1 inhibitors (e.g., canakinumab), and IL-17 inhibitors (e.g., secukinumab) have demonstrated efficacy in PG.^[12] JAK inhibitors, such as tofacitinib, have also shown promise, with reports of complete healing and minimal relapses.^[10,14,22] In this case, tofacitinib proved effective alongside sulfasalazine and topical tacrolimus. This suggests that a JAK-inhibitor-centric protocol may serve as a viable primary strategy for elderly patients with RA who present with significant hematological or metabolic contraindications to systemic steroids.

Effective wound care remains a cornerstone of PG management. Gentle cleansing to remove necrotic tissue, maintaining a moist wound environment, and avoiding sharp debridement are essential to reduce the risk of pathergy. Topical therapies such as tacrolimus, corticosteroids, and non-adherent dressings support local healing.^[7,23-25] The patient remained under observation for a follow-up period of 12 months, during which no recurrence of PG was noted, and the joint disease remained stable, suggesting an excellent long-term prognosis with this individualized regimen.

CONCLUSION

This case highlights the important association between PG and RA, emphasizing the diagnostic and therapeutic challenges when these conditions coexist. Clinicians should maintain a high index of suspicion for PG in patients with RA who present with atypical skin lesions. Early recognition and individualized treatment—addressing both systemic inflammation and wound care—are essential for optimal outcomes.