Introduction
Pyoderma gangrenosum (PG) is a rare neutrophilic cutaneous disorder characterized
by single or multiple inflammatory nodules, papules, or pustules, which rapidly ulcerate
with undermined borders, tenderness, and cribriform scarring upon healing.
1
It is a challenging condition to identify, given initial misdiagnosis and mismanagement
with physical debridement, propensity for superinfection, and rarity.
2
Furthermore, once the correct diagnosis is recognized, therapeutic challenges include
promptly implementing an effective treatment to prevent rapid progression with concomitant
morbidity and distress to the patient. Treatment options include topical and intralesional
steroids, systemic glucocorticoids, conventional immunosuppressants, biologics, and
intravenous immunoglobulin.
3
We present the novel use of guselkumab, a monoclonal antibody targeting interleukin
(IL)-23, as an effective and safe treatment option for severe and recalcitrant PG.
Case report
A 60-year-old woman presented to the dermatology clinic with a 1-year history of lower-leg
ulcers. The patient's clinical history was significant for a monoclonal gammopathy
of undetermined significance and type 2 diabetes. She was previously followed at a
wound care center for the management of presumed venous stasis ulcers. The patient
failed treatments, including local wound care with silver sulfadiazine, compression
wraps, and clobetasol ointment. Physical examination revealed a purulent ulceration
with jagged undermined violaceous borders on the left lower leg. A bacterial culture
was performed, and the patient was prescribed ciprofloxacin and triamcinolone cream
for presumed superinfection and inflammation, respectively. Despite treatment, the
ulceration on her left leg enlarged significantly with surrounding edema. Intralesional
steroid injections were administered, and a class I topical steroid was prescribed
without improvement. Tissue was sampled and sent for both histology and culture to
exclude occult infection or malignancy. Pathology revealed ulceration with underlying
acute and chronic inflammation and tissue necrosis. These features along with a negative
culture were not diagnostic, but consistent with PG.
2
In light of her history of monoclonal gammopathy of undetermined significance along
with the clinical presentation, the ulcer was diagnosed as PG.
3
Biologic therapy was chosen for management, given the large size of the ulcer, the
rapid progression of disease, medication safety profile, and availability of product
samples from pharmaceutical companies in the office. Biologics were the preferred
treatment choice for immune modulation, given her history of gammopathy and favorable
side effect profile.
3
Furthermore, newer biologics such as ustekinumab, which targets IL-12/23, have emerging
case studies demonstrating support for the treatment of PG.
4
,
5
Ustekinumab manufacturer product samples were readily available in-office and administered
initially. Shortly thereafter, the ulceration deepened, exuding a strong odor with
exposure of tendons, ligaments, and muscle, prompting hospital admission. A Pseudomonas
superinfection was identified and treated with intravenous antibiotics. Ustekinumab
administration was temporarily suspended focusing on local wound care. Following stabilization,
ustekinumab was restarted. The patient experienced rapid improvement with minimal
pain and nearly complete re-epithelialization.
Sixteen months later, a relapse occurred while the patient still received ustekinumab
with ulceration and associated pain. Assuming development of neutralizing autoantibodies
against ustekinumab, the patient was placed on and failed both adalimumab and infliximab
sequentially. The ulcer expanded to approximately 60% of her left lower leg circumference
with re-exposure of tendon and muscle (Fig 1). The patient was then administered intravenous
immunoglobulin by her oncologist for potential management of both the monoclonal gammopathy
of undetermined significance and PG. In addition, prednisone was instituted which
arrested disease progression.
Fig 1
Severe PG involving the left lower extremity with muscle and tendon exposure in May
2019 when ustekinumab was initiated. PG, Pyoderma gangrenosum.
Given the previous response to an IL-12/23 antagonist and failure of 2 tumor necrosis
factor alfa inhibitors, we speculated that inhibiting IL-23 with guselkumab might
halt and even reverse disease progression. Within weeks of starting guselkumab at
100 mg monthly dosing, the ulcer bed began retreating from underlying exposed muscles
and tendons. Within 3 months, the ulcer was virtually non-existent. Re-epithelialization
was notable over 95%of the original ulcer. The response was found to be durable, with
continued remission of her PG after 15 months (Fig 2).
Fig 2
Severe PG involving the left lower extremity with muscle and tendon exposure in May
2019 after failing ustekinumab, adalimumab, and infliximab. PG, Pyoderma gangrenosum.
Discussion
PG should always be included in the differential diagnosis of a chronic ulcer that
does not heal with conventional therapies. The Su et al criteria, The Delphi Consensus
of International Experts, and PARACELSUS (Progressing disease, Assessment of relevant
differential diagnoses, Reddish-violaceous wound border, Amelioration by immunosuppressant
drugs, Characteristically irregular shape of ulceration, Extreme pain, Localization
of lesion at the site of the trauma, Suppurative inflammation in histopathology, Undermined
wound borders, and Systemic disease associated) score are helpful diagnostic tools.
3
Criteria for diagnosis comprises the exclusion of other similar presenting disorders
such as venous stasis ulcers, infectious processes, and malignancy.
2
,
3
Additional diagnostic criteria includes a typical clinical presentation, histopathology
findings, improvement with immunosuppressants, and a history of pathergy.
3
The presence of an associated typical systemic disease, such as inflammatory bowel
disease, rheumatoid arthritis, monoclonal gammopathy, or hematologic malignancy is
helpful for diagnosis.
3
Once a diagnosis is made, treatment presents a challenge because defined management
is lacking in the literature.
2
Treatment modalities focus on local wound care, infection control, avoidance of pathergy,
pain management, topical or intralesional steroids, oral immunosuppressants, and biologics.
3
Case reports and expert opinions have mentioned prednisone, cyclosporine, methotrexate,
mycophenolate, and azathioprine as treatment options.
3
Regarding biologic management, only one randomized, double-blinded, placebo-controlled
study has been performed, analyzing the efficacy of the biologic infliximab versus
placebo, with support for the use of 5 mg/kg dosing regimen of infliximab.
6
More recently, the focus on PG treatment has been newer biologics. Genova et al
4
evaluated a woman with PG on the lower extremity, which had failed topical therapy
in addition to oral steroids. Upon evaluation of the tissue on biopsy, a marked increase
in expression of IL23A was found when compared with healthy tissue. This prompted
a trial of ustekinumab, which targets IL-12/23. Following 14 weeks of treatment, the
lesion had healed completely. Since then, there have been other studies evaluating
ustekinumab with promising results for the treatment of recalcitrant PG.
5
In this case, the patient initially responded well to ustekinumab, but presumably
developed neutralizing autoantibodies after 16 months of use. Fortunately, her PG
responded to IL-23 blockade with guselkumab, a monoclonal antibody targeting IL-23
and currently indicated for the treatment of moderate to severe plaque psoriasis and
psoriatic arthritis.
This case demonstrates a common conundrum among providers treating patients with recalcitrant
PG. Case reports have identified IL-1/IL-6 antagonists, janus kinase-signal transducer
and activator of transcription inhibitors, and phosphodiesterase type 4 inhibitors,
but none have evaluated guselkumab despite the significance of IL-23 expression.
3
PG can be a severely debilitating disease, and the need for evidence-based treatment
is crucial. A larger trial analyzing the effect of IL-23 targeting biologics for the
treatment of PG would be helpful in further defining the role of this medication within
the existing treatment algorithm.
Conflicts of interest
None disclosed.