Abstract
Pyoderma gangrenosum (PG) is a chronic inflammatory neutrophilic dermatosis often presenting as a solitary enlarging painful ulcer with red to violaceous undermined borders. This report delves into the role of doxycycline in the treatment of PG in a 44-year-old male COVID-19 positive patient who has concomitant active tuberculosis infection and end-stage kidney disease, for which both first-line treatments (systemic corticosteroid and cyclosporine) are contraindicated. After three months on doxycycline and topical corticosteroids, there was resolution of the ulcers and no note of recurrence up to three months from completion of the treatment regimen.
Keywords: pyoderma gangrenosum, doxycycline, nonhealing ulcer, neutrophillic dermatosis
INTRODUCTION
Pyoderma gangrenosum is an uncommon chronic inflammatory neutrophilic dermatosis commonly presenting as a solitary enlarging painful ulcer with violaceous undermined borders.1 Diagnosis is clinical and done upon exclusion of other causes of non-healing ulcers such as chronic bacterial and deep fungal infections, vasculitis and other vascular problems, and malignancy. History of pathergy and histologic findings of dense neutrophilic infiltrate, as well as pustule and abscess formation will support this diagnosis.2
Treatment for pyoderma gangrenosum is mainly medical, with mild localized or unilesional forms of the disease with <5% body surface area (BSA) involvement responsive to topical/intralesional immunosuppressants like corticosteroids and calcineurin inhibitors (Level 2B Evidence). More severe disease with three or more lesions or those with more than 5% BSA involved require systemic therapy, with systemic corticosteroid and/or cyclosporine as first-line (Level 1B Evidence).3 Despite several treatment options for pyoderma gangrenosum, its prognosis varies from case to case; some would require chronic pharmacologic treatment and some would respond to medications but would still relapse.4 Systemic treatments for pyoderma gangrenosum, when chronic use is indicated, would require close monitoring for adverse effects.
CASE PRESENTATION
This is a case of a 44-year-old male with a six-week history of gradually enlarging ulcers on his right calf, admitted for severe COVID-19 infection. He had Stage 5 chronic kidney disease from hypertensive kidney disease for the last eight years but was non-compliant to maintenance hemodialysis and his prescribed medications namely: calcium carbonate, calcitriol, telmisartan, spironolactone, carvedilol, atorvastatin, and enoxaparin. He had a history of cerebrovascular disease 15 years ago with left-sided residuals. Both his parents had diabetes, hypertension, and a history of stroke. He was a former occasional smoker and alcoholic beverage drinker, had been unemployed since he was diagnosed with chronic kidney disease (CKD), and lived with his daughter and her family who were his primary carers and financially supported his treatments.
During the admission, he had an incidental diagnosis of pulmonary tuberculosis infection (PTB) and was started on anti-tuberculosis medications. Patient was also diagnosed with uncontrolled diabetes further contributing to his CKD and for which hemodialysis was initiated. The non-healing wound was initially managed as a case of cellulitis with several antibiotic regimen including: ceftriaxone, clindamycin, piperacillin-tazobactam, meropenem, and levofloxacin, providing no resolution of the lesion. Wound discharge culture studies done prior to starting antibiotics revealed no growth after five days. He also underwent regular wound debridement while admitted, but in the interim, the ulcer continued increasing in size and depth, and becoming more exudative. Upon referral to dermatology, multiple well-defined irregularly-shaped tender ulcers with hyperpigmented undermined borders localized on the right leg were appreciated (Figures 1A and 2A). Punch biopsy was taken from the edge of an ulcer, which revealed dermal edema and diffuse dense infiltrate composed mostly of neutrophils, with accompanying eosinophils, histiocytes, and plasma cells, and areas of hemorrhage/extravasated erythrocytes superficial to deep dermis (Figures 3A and 3B), consistent with pyoderma gangrenosum. Tissue culture studies revealed no growth. Since patient was not cleared to receive systemic steroids, he was prescribed doxycycline 100 mg/capsule twice daily combined with halobetasol propionate 0.05% cream applied twice daily. He was discharged from the hospital after two weeks and instructed to continue with his treatments at home.
Figure 1.
Ulcerative pyoderma gangrenosum, superior portion of the wound. (A) Baseline photo on day of dermatology referral; (B) Photo after one month of doxycycline 100 mg twice a day and halobetasol propionate 0.05% cream twice a day; (C) Photo following month 2 on doxycycline 100 mg once a day and halobetasol propionate 0.05% cream twice a day; (D) Photo following month 3 on doxycycline 100 mg once a day and halobetasol propionate 0.05% cream twice a day.
Figure 2.
Ulcerative pyoderma gangrenosum, inferior portion of the wound. (A) Baseline photo on day of dermatology referral; (B) Photo after one month of doxycycline 100 mg twice a day and halobetasol propionate 0.05% cream twice a day; (C) Photo following month 2 on doxycycline 100 mg once a day and halobetasol propionate 0.05% cream twice a day; (D) Photo folllowing month 3 on doxycycline 100 mg once a day and halobetasol propionate 0.05% cream twice a day.
Figure 3.
Histopathologic results, punch biopsy taken from the edge of the ulcer. (A) LPO view shows dermal edema and a dense diffuse infiltrate from the superficial to deep dermis (B) HPO view reveals that the dense infiltrate is composed mainly of neutrophils, with accompanying eosinophils, histiocytes, plasma cells, and extravasated erythrocytes.
After one month on this regimen, there was significant re-epithelialization of the ulcer noted on out-patient follow up (Figures 1B and 2B). Dose was decreased to 100 mg daily for two more months, allowing the ulcer to heal completely (Figures 1C-D and 2C-D). Patient reported that he was able to take doxycycline as prescribed and his caretaker helped him with the application of halobetasol throughout the treatment course. No significant side effects (e.g., abdominal discomfort, nausea, cutaneous drug reactions, photosensitivity, diarrhea, etc.) were noted throughout the treatment and no recurrence was noted up to three months after the completion of treatment.
DISCUSSION
High-dose systemic corticosteroids (e.g. prednisone 1 mg/kg/day) is indicated in pyoderma gangrenosum. Fifty percent reduction in ulcer size is expected within one month on this regimen and is actually considered one of the minor criteria in the diagnosis of the disease. Cyclosporine is the alternative first-line medication for pyoderma gangrenosum but was also contraindicated in this case due to the concomitant renal failure.5 If the response to corticosteroid or cyclosporine is not sufficient, other anti-inflammatory steroid sparing agents like minocycline, dapsone, mycophenolate mofetil and azathioprine are given as alternative or adjunct.6 Although there are other cases of pyoderma gangrenosum associated with chronic renal failure reported in literature, the presence of concomitant infections posted a challenge in the management of our case.7,8
Tetracyclines like doxycycline have been used as a steroid-sparing agent due to its anti-inflammatory properties in certain conditions like rosacea, bullous pemphigoid, perioral dermatitis, and in granulomatous and other neutrophilic dermatoses.9,10 Furthermore, its use in neutrophilic dermatoses like pyoderma gangrenosum can be attributed to its synergistic ability to inhibit monocyte chemoattractant protein-1 (MCP-1), one of the key chemokines responsible for neutrophil migration; and decrease pro-inflammatory cytokine interleukin-8 (IL-8), a neutrophil chemotactic factor.11 Doxycycline is mainly excreted extrarenally, hence, is considered relatively safe to give to patients with renal failure.9 Although minocycline is considered as an adjunctive treatment for PG, the response of PG to other tetracyclines like doxycycline as monotherapy is poorly documented in literature.10 To the authors’ knowledge, this was the only documented case of extensive ulcerative pyoderma gangrenosum in the Philippines that was managed without the use of any of the first-line systemic treatments. Doxycycline was the alternative non-immunosuppressive treatment given in this case, which provided a rapid and dramatic response, but could have been confounded by the concomitant use of topical halobetasol.
CONCLUSION
This report suggests that the anti-inflammatory effect of doxycycline has a role in the treatment of pyoderma gangrenosum in patients with contraindications to receiving systemic steroids and cyclosporine. It is an easily accessible and affordable medication, which is relatively safe to prescribe to patients with active tuberculosis and COVID-19 infection. Clinical trials would better compare the efficacy and safety of the doxycycline and systemic steroids in patients with pyoderma gangrenosum.
Statement of Authorship
All authors certified fulfillment of ICMJE authorship criteria.
Author Disclosure
All authors declared no conflicts of interest.
Funding Source
None.
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