Treatment of Pyoderma Gangrenosum in Pediatric Inflammatory Bowel Disease

Pyoderma gangrenosum (PG) is a rare, necrotizing dermatologic condition associated with neoplastic and immune dysregulatory states, including adult and pediatric inflammatory bowel disease (IBD). Over the last decade, the elucidation of inflammatory mediators in PG has led to a plethora of localized and systemic corticosteroid sparing therapies including antibiotics, antiinflammatory, and immunomodulatory agents. Herein, we describe the case of a 17-year-old female with ulcerative colitis in clinical remission, who presented with a long-standing, large, deep, and painful lower extremity PG lesion. Following failed attempts both at local and at systemic therapies, her PG was successfully treated with the tumor necrosis factor-alpha (TNF-α) monoclonal antibody adalimumab, and the lesion remains in remission after four years of subcutaneous anti-TNF therapy. This case serves as the basis for our presenting a review of the pathogenesis, diagnostic criteria, differential diagnosis, therapies and treatment outcomes for pediatric IBD-associated PG. Our experience adds to earlier reports suggesting anti-TNF-α biologic therapy is most likely to achieve long-term resolution of IBD-associated PG in children and adolescents with severe lesions or who failed other treatments.


CASE REPORT
A 17-year-old female, a recent émigré from Jamaica, was referred to the Pediatric Gastroenterology service at the Children's Hospital, SUNY-Downstate Medical Center, for management of ulcerative colitis (UC) in clinical remission. Her treatment comprised only oral prednisone 5 mg daily at the time of consultation. A diagnosis of UC had been made at age 10 years, and, at 13 years of age, she was diagnosed with a left lower extremity "venous stasis ulcer," which had progressed despite multiple courses of therapy with antibiotics and topical corticosteroids. At the time of referral, she denied symptoms of weight loss, diarrhea, bleeding and abdominal pain, and her Pediatric Ulcerative Colitis Activity Index (PUCAI) score was 0. Her chief complaint was the painful leg "ulcer." Physical examination demonstrated a well-developed, well-nourished young woman, Tanner Stage V. The remainder of the examination was remarkable only for a deep, left lower leg lateral and pretibial ulcerating lesion measuring approximately 15 × 7 cm (Fig. 1). The ulceration was characterized by a violaceous border, purulent exudate, and areas of necrosis, with what appeared to be exposed connective tissue. These physical findings were consistent with severe Pyoderma gangrenosum (PG) in the setting of UC, and the diagnosis of PG was confirmed histopathologically.
Initial laboratory studies included a hemoglobin of 12.0 gm/ dL, serum albumin of 4.4 g/dL (normal 3.5-5.7 g/dL) and marked elevations both of the erythrocyte sedimentation rate (>130 mm/h) and of C-reactive protein (>40 mg/L). Serologic evaluation demonstrated elevated perinuclear antineutrophil cytoplasmic antibody (p-ANCA) and negative anti-Saccharomyces cerevisiae antibody (ASCA) titers. Colonoscopy showed some loss of the normal vascular pattern but appeared otherwise unremarkable (Mayo endoscopic score 1). Histopathology showed mild acute and chronic inflammation with occasional cryptitis in the rectosigmoid and descending colon. Ileal biopsies were normal. These endoscopic findings of mild colitis were consistent with her prior UC diagnosis, and treatment was started with an oral 5-aminosalicylic acid (5-ASA) derivative.
Over a 1-year period, the PG lesion was refractory to multiple therapies, including oral and intralesional corticosteroids, topical and oral tacrolimus, topical dapsone, oral antibiotics (including metronidazole and doxycycline), and intralesional interleukin-10 (IL-10). Subsequently, the family sought consultation at a regional burn center, where autologous skin grafting was performed and was unsuccessful. Her colitis remained in clinical remission, with a persistent PUCAI score of 0. Subcutaneous adalimumab (ADA) monotherapy was then initiated, using a standard induction and maintenance protocol. Significant improvement in the PG ulcer was observed within 1 month of commencing treatment, with almost complete healing after 6 months (Fig. 2). Adalimumab therapy was continued at 40 mg subcutaneously every 2 weeks. Both UC and PG have remained in clinical remission after 4 years, and no new PG lesions have appeared.

Method of Review
In collecting reports of PG diagnosis and management in pediatric inflammatory bowel disease (IBD), data were accessed from MedlinePlus and the National Institutes of Health US National Library of Medicine, to review IBD-associated PG treatment in children and adolescents, reported in English language articles published between 2002 and 2018. Inclusion criteria comprised: (1) age ≤19 years at diagnosis of histopathologically confirmed PG; (2) PG associated with a confirmed case of IBD; (3) indication of specific PG treatments and outcomes. We reviewed prospective, randomized controlled trials, population-based and observational studies, metaanalyses and systematic reviews appearing in peer reviewed journals and cited at https://www.ncbi.nlm.nih.gov/pubmed/. This search included pediatric patients reported in adult case series. Thirty-one references were identified, of which 9 were eliminated as lacking a discussion of specific clinical cases. Ten references 1-10 were excluded because they did not satisfy all of the above inclusion criteria. Twelve published studies met all search criteria and described a total of 19 patients (13 females, 6 males). These reported cases included 13 patients with Crohn's disease (CD) and 6 with UC.

Clinical Presentation and Diagnosis
Pyoderma gangrenosum is a neutrophilic dermatosis that may develop de novo or, more commonly, in the clinical setting of an underlying inflammatory or neoplastic disease. The worldwide incidence of PG is estimated to be 3-10 cases per 1,000,000 population per year 11 and 4% are in children. 12 In adults, approximately 60% of reported PG cases occur in association with a systemic disorder, including rheumatoid arthritis, autoimmune hepatitis, and malignancy. Up to 50% are associated with IBD 11-13 ; however, <5% of patients with IBD develop PG. 11,13 In IBD patients, PG is diagnosed most frequently in association with UC, but it is also reported in CD. 12,13 It is more common in female patients and in those with active colitis. 12 The lesion's characteristics include a deep, extremely painful, papulopustular, necrotic cutaneous ulcer with an undermined and violaceous border that frequently heals with cribiform scarring. 12,13 The occurrence and severity of PG lesions may not directly parallel IBD clinical activity. 12,14,15 In adults, PG most commonly occurs on the lower extremities, whereas in children, it frequently appears on the head and in the genital, peristomal, and perianal regions. [16][17][18] Lesions may develop acutely or over the course of months to years and may recur after apparently successful treatment. 13,14 A diagnosis of PG is based on clinical features and the exclusion of other causes of cutaneous ulcerations including infection, vascular disease, other neutrophilic dermatoses, and malignancy, 13,14,16,[18][19][20] as listed in Table 1. Histologically, the PG lesion is composed of a dense neutrophilic dermal infiltrate, with marked tissue necrosis at the base of the ulcer. 21 Up to 30% of cases mimic the cutaneous findings seen in neoplastic and in other inflammatory disorders . 13,14,16 Diagnostic criteria for PG were proposed in 2018, through a consensus of selected international experts, using Delphi methodology, and these are presented in Table 2. 20 A confirmed case of PG requires identification of the 1 major criterion and at least 4 of 8 minor clinical, histologic, and treatment criteria.

Pathogenesis/Genetics
The Th1 type of inflammatory process noted in PG is characterized by a complex interplay of cytokines, neutrophils, and T lymphocytes. 13,[22][23][24] Dysfunction both of the innate and of the adaptive immune systems causes upregulation of granulocyte-colony stimulating factor (GCSF) and of diverse cytokine/chemokine/interleukin (IL) moieties, including Tumor necrosis factor-alpha (TNFα). Pathergy, a condition in which an environmental trigger, such as minor trauma, results in an exaggerated immune response, represents one of the PG minor criteria. 13,23 This cascade of immune-mediated events may explain why PG has commonly been associated with other autoimmune diseases. 13,15,23,25 Genome wide studies, examining the association of IBD with PG, have identified potential etiopathogenic factors, including regulatory sites for IL-8Rα (IL-8 receptor α, a mediator of neutrophil migration), PR domain-containing protein 1 (associated with the pathogenesis of autoimmune disease), and tissue inhibitor of metalloproteinase. 23 Possible interrelationships among these varied inflammatory mediators and genetic determinants are presented in Figure 3.

TREATMENT OF PYODERMA GANGRENOSUM
Treatment of PG is targeted at ameliorating the inflammatory process causing the ulcerative lesion. Several factors may influence therapeutic choices, including the number and size of PG lesions, the clinical course of disease (indolent vs more rapidly progressive), the presence of associated illnesses, and other comorbid conditions. Published reports in adult PG populations have shown relatively small and slowly progressive PG lesions often may be successfully managed with local therapy, including the use of topical corticosteroids, calcineurin inhibitors, and antibiotics. 26 Systemic treatment has generally been required for larger and more aggressive cases. Because of the paucity of well-controlled studies, particularly in pediatric subjects, definitive PG treatment guidelines have not been established. As described above, Table 3 lists the 12 published reports of pediatric IBD-associated PG that include patient characteristics, histopathologically confirmed IBD and IBD-associated PG, cutaneous location of PG lesion(s), as well as initial and second-line PG therapies. Most cases of severe PG did not respond either to local wound care or to intralesional injections, but multiple pediatric cases of IBD-associated PG achieved a complete clinical response with an anti-TNF-α biologic agent.

Topical/intralesional Agents
In the management of PG, topical/intralesional agents, including calcineurin inhibitors and corticosteroids (most commonly triamcinolone) have been used in combination with a systemic drug. 12,38 In the present review, 3 patients receiving topical tacrolimus responded completely when combined with systemic corticosteroids; and, one patient achieved a complete PG remission with topical tacrolimus monotherapy. 28,38 Local therapy of pediatric PG with topical or with intralesional agents may be expected to ameliorate smaller and more indolent lesions, as indicated in prior reports of adult IBD-associated PG. 26

Corticosteroids
High-dose, systemic corticosteroids are effective in halting the progression of PG and, therefore, have been recommended as firstline treatment. 13,14,39 However, frequent PG exacerbations/recurrences following treatment discontinuation may compromise steroid utility in long-term PG management, particularly in pediatric patients. 39 In the present review, 11 patients received systemic corticosteroids for management of PG, with only 1 patient experiencing a complete response with monotherapy. 18,28,30,31,36

Calcineurin Inhibitors
Cyclosporine-A (CSA) has been recommended as a first-line treatment for IBD-associated PG, because of its role in inhibiting T-cell activation, inflammatory cell proliferation, and proinflammatory cytokine production. 13,14,39 In a randomized controlled trial comparing systemic corticosteroids to CSA for treating PG in adults, both treatments were associated with a clinical response rate of approximately 50%. 39 In the present review, CSA monotherapy was  Minor criteria: 1. At least 1 ulcer on an anterior lower leg (with multiple ulcerations).
2. Codiagnosis of inflammatory bowel disease or inflammatory arthritis.
4. Decrease in ulcer size within 1 month of initiating immunosuppressive therapy.
*Diagnosis of PG requires the major criterion and at least four of eight minor criteria. 10 Vaidy et al successful in achieving a complete response in only 1 of 4 patients with PG. 28,31,33,36 Tacrolimus, a potent calcineurin inhibitor, was administered orally to 2 reported pediatric patients, either alone or in combination with other immunomodulators. Of these, 1 patient achieved a complete response with systemic tacrolimus monotherapy. 18,28

Thiopurines and Methotrexate
The thiopurine drugs 6-mercaptopurine and azathioprine have commonly been used in the treatment of IBD-associated PG. However, despite their immunomodulatory effects, thiopurines alone have generally not been shown to be effective in treating IBD-associated PG, either in adults or in the 5 reported pediatric patients. 15 The 1 pediatric case that showed clinical improvement also received systemic corticosteroids. 18 Interestingly, 4 pediatric patients have been described who developed PG while undergoing thiopurine treatment for IBD, a complication previously seen in adults. 27,29,32,36 Methotrexate monotherapy has not been widely used in the management of PG in the setting of IBD. Table 1 includes the report of a pediatric IBD patient who received methotrexate in combination with systemic corticosteroids and with anti-TNF-α biologic agents. The PG reached clinical resolution after 18 months of this combination therapy. 18

Anti-TNF-α Biologics
TNF-α is a potent inflammatory mediator found in PG lesions. 21,[23][24][25] This cell signaling protein upregulates proinflammatory factors, including IL-1β and IL-8, 40 that act as mediators of inflammation in IBD and in PG. 15,17-20,41 TNF-α also may stimulate cutaneous recruitment of inflammatory cells via enhanced vasculature expression of adhesion molecules, including the metalloproteinases MMP-9 and MMP-10. 21,24,25 The use of anti-TNF-α biologics as firstline therapy for IBD-associated PG has been recommended, as PG severity may be independent of IBD clinical activity. 15,[42][43][44][45][46] Clinical reports also have demonstrated the efficacy of infliximab and adalimumab therapy of PG in other immune-mediated disorders, 19,30,33 The nine reported pediatric and adolescent patients who received an anti-TNF-α biologic agent for IBD-associated PG are listed in Table 3. Eight achieved complete PG resolution with monotherapy, including those who failed other therapeutic regimens. 18,27,[29][30][31]34,36 These results are consistent with findings from larger studies in adults. In 1 review, all 13 adult patients with medically refractory PG responded to standard induction dosing with infliximab. 47 The only randomized control trial of PG treatment to date included 29 adult subjects and reported a 69% PG response rate to infliximab. 48 In the largest systematic review in the literature, anti-TNF-α PG therapy was associated with a 92% response rate among 40 adult IBD patients. 15

Other Therapies
In the present review, 6 patients received a 5-ASA drug (1 as monotherapy), without clinical improvement. 18,27,30,31,36 Granulocyte and monocyte adsorption apheresis (GCAP) involves extracorporeal adsorption and removal of active granulocytes and monocytes from the circulation. 49,50 Several small case series in adults and in 1 pediatric patient have demonstrated some efficacy in treating IBDassociated PG with GCAP. 32,49,50 Intravenous immunoglobulin (IVIG) has been shown to result in a complete or partial clinical response in up to 87.8% of adults with refractory PG. However, only 1 reported pediatric patient with idiopathic (non-IBD related) PG has received such treatment. 38,51 As in the case presented here, skin grafting has proven ineffective in both adults and pediatric patients with PG, and it may lead to worsening of PG as the consequence of tissue injury associated with the grafting procedure. 35 Ustekinumab, a human monoclonal antibody targeting the p40 subunit of IL-12 and IL-23 has been used successfully in several adult cases of PG. 52

CONCLUSIONS
Pediatric PG is a rare extraintestinal manifestation of IBD that carries significant physical and psychologic morbidity and is often refractory to multiple treatments. Previously, management of pediatric PG has emphasized local wound care and the use of immunomodulatory drugs, including corticosteroids and calcineurin inhibitors, 18,28,33,35,37,38 as well as systemic and topical antiinfective age nts. 18,28,35,37,38 However, earlier reports demonstrated little consistency in treatment protocols or in therapeutic efficacy. 18,28,33,35,37,38 More recently, elucidation of the inflammatory cascade involved in the etiology and progression of PG has established a prominent role for TNF-α dysregulation; this observation serves as the basis for the use of anti-TNF-α biologics as first-line PG treatment. Although milder, indolent PG lesions may respond to local therapy, the case detailed herein, along with other published reports, have confirmed the effectiveness of TNF-α monoclonal antibodies in more extensive pediatric IBD-associated PG. Ideally, an organized, multicenter study could evaluate therapeutic alternatives in a randomized, controlled trial of systemic PG treatments in pediatric IBD subjects. However, until such an investigation can be conducted, currently available published data support using an anti-TNF-α biologic agent as first-line therapy for severe PG therapy in pediatric IBD, as well as for those cases that have not responded to local therapies. *Second-line therapy not listed where either not required or not stated. †Time in parenthesis, interval between treatment initiation and response, where indicated. 5-ASA, 5-aminosalicylate; 6-MP, 6-mercaptopurine; Abx, antibiotics; ADA, adalimumab; AZA, azathioprine; CD, Crohn disease; CLX, chlorhexidine; CR, complete response; CS, corticosteroids (systemic); CSA, cyclosporine-A; ETC, etanercept; GCAP, Granulocyte and monocyte adsorption apheresis; IFX, infliximab; IL, intralesional; LE, lower extremity; MMF, mycophenylate mofitil; MNZ, metronidazole; MTX, methotrexate; n/a, not available; NR, no response; PR, partial response; SSD, silver sulfadiazine; SSZ, sulfasalazine; TAC, tacrolimus; UC, ulcerative colitis; UE, upper extremity.