Treatment of refractory pyoderma gangrenosum with hyperbaric oxygen therapy and adalimumab

Dear Editor,

Pyoderma gangrenosum (PG) is a neutrophilic dermatosis characterised by rapidly progressing, painful skin ulcers with erythematous, undermined borders. Onset typically occurs between the ages of 30-40 years with no gender preference. There is no definitive treatment. We report a case of refractory PG successfully managed with hyperbaric oxygen therapy (HBOT) and adalimumab.

A 60-year-old man presented with multiple non-healing ulcers on the left foot since 8 months, progressively increasing in size and number over the past 6 months. He reported similar painful lesions in the past that resolved with treatment (details unavailable), no episode lasting beyond 6 months. On examination, there were three tender, punched-out ulcers with undermined edges and surrounding erythema affecting the right foot [Figure 1a and 1b]. Inflammatory markers like C Reactive Protein (CRP), Erythrocyte Sedimentation rate (ESR); coagulation function; Anti Nuclear Antibody (ANA), antibodies against extractable nuclear antigens, anti‐cardiolipin antibodies, Anti-Neutrophil Cytoplasmic Antibodies (ANCA), rheumatoid factor, protein‐C & S, anti‐thrombin‐III, and homocysteine levels were normal. The Factor‐V Leiden mutation was absent. Colour Doppler study of the lower limbs was normal. Bacterial and fungal cultures were negative. Skin biopsy revealed sloughing off of epidermis with dense neutrophil-rich infiltrate in dermis with perivascular inflammatory infiltrate, extravasated RBCs, and dilated vessels [Figures 2a & 2b]. Based on the above findings, the patient was diagnosed with PG. The patient was initially treated with prednisolone and colchicine, leading to partial pain relief by day 45, though ulcers persisted. Prednisolone was tapered by day 45 due to elevated blood sugar, and colchicine was discontinued for lack of efficacy. Cyclosporine (3 mg/kg) was introduced but caused persistent hypertension by day 60, necessitating its discontinuation. Tofacitinib (5 mg twice daily) was then administered; however, symptoms worsened, and ulcers persisted. On day 75, adalimumab was initiated (80 mg initial dose, followed by 40 mg at week 1 and then 40 mg every two weeks), resulting in a reduction in pain by around 70% from the baseline and signs of ulcer reepithelialisation were also visible after the eighth dose. However, no further improvement was seen over the subsequent eight weeks. HBOT was then commenced, achieving complete ulcer reepithelialisation by the tenth session on Day 252 [Figure 3a & 3b]. Once the ulcer healed and sugar levels normalised without hypoglycaemic agents, a low dose of prednisolone was started. Other immunomodulators were withheld to assess follow-up compliance, as prednisolone was easier to monitor in rural settings.

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Figure 1:

Ulcer with undermined edges and pinkish granulation tissue on the floor with a reepithelization line affecting the a) lateral aspect of the right foot and b) the dorsal aspect of the right foot.

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Figure 2a:

Histopathology revealed sloughing of epidermis in the center with dilated vessels, extravasated RBCs, and dense dermal infiltrate (Haematoxylin and eosin, 100x)

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Figure 2b:

Histopathology revealed sloughing off of epidermis with dense neutrophil-rich infiltrate in dermis with perivascular mixed inflammatory infiltrate (Haematoxylin and eosin, 200x)

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Figure 3:

Shows complete re-epthelisation of ulcer over a) lateral aspect of the right foot and b) dorsum of the right foot.

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Treating PG poses challenges with various combinations of anti-inflammatory and immunomodulatory therapies utilised by different experts.¹ Prednisolone and cyclosporine are the most common immunomodulators used in the management of PG; however, our patient developed adverse effects to both.

The patient was initially prescribed colchicine, despite its lower recommendation grade compared to immunomodulators like cyclosporine and Mycophenolate mofetil (MMF), due to concerns about follow-up adherence and perceived effectiveness of colchicine in managing PG.² Initially non-diabetic and normotensive, the patient developed uncontrolled blood sugar levels after starting prednisolone and hypertension with low-dose cyclosporine. Despite the suggestion to add antihypertensive medication, the patient declined, fearing lifelong medication use. Tofacitinib was introduced for its anti-inflammatory properties but was discontinued due to an unsatisfactory response.³ Adalimumab has shown immense potential in refractory PG. A phase 3 randomised open-label study to assess the efficacy, safety, and pharmacokinetics of a 40 mg weekly dose of adalimumab over 52 weeks in Japanese patients with active ulcers of PG has been conducted.⁴ In this study, 15 of 22 patients achieved complete ulcer re-epithelialisation, 12 by week 26 and 3 more by week 34. Our patient responded partially to adalimumab, as suggested by partial reepithelialization and pain control.

HBOT, which has been approved by the Undersea and Hyperbaric Medical Society and the European Committee for chronic wounds, enhances tissue oxygenation, promotes fibroblast proliferation, collagen synthesis, and angiogenesis.⁵ This process, known as the hyperoxia-hypoxia paradox, activates cellular mechanisms associated with hypoxia through the production of free radicals and their scavengers. A systematic review reported that among 48 patients treated with HBOT for PG, 58.4% experienced complete lesion healing, while 20.8% showed lesion improvement.⁶

Our report is unique as for the first time HBOT with adalimumab have been combined to treat refractory PG in the Indian scenario. We also noticed the lack of response of PG to tofacitinib, contrary to the existing reports. The authors do acknowledge that the observed improvement could simply be attributed to the passage of time or continued use of Adalimumab, rather than the addition of HBOT. Hence, the regimen requires further validation in more cases to establish its efficacy and safety.