Mentoring in IBD is an innovative and successful educational program for Canadian gastroenterologists that now includes an annual national meeting, regional satellites in both official languages, a website, an educational newsletter series, and regular electronic communications answering key clinical questions with new research. This issue is based on the presentation made by the issue editors at the annual national meeting, Mentoring in IBD XVII: The Master Class, held November 4, 2016 in Toronto, Ontario.
Inflammatory bowel disease (IBD) is the most common systemic disease associated with pyoderma gangrenosum (PG). Typically, PG is more common in long-standing IBD with colonic disease; in women than in men; in Crohn’s disease (CD, 1.3%) than in ulcerative colitis (UC, 0.8%); and in association with other extraintestinal manifestations, such as uveitis, arthritis, and spondylitis.(1–4)
Many variants of PG can be seen in IBD, including classic ulcerative, pustular, peristomal, postsurgical, mucosal, and extracutaneous (Table 1).(1–5) Classic ulcerative PG lesions have a gun-metal grey border and are often undermined (Figure 1); they tend to heal with cribriform scarring and can be seen in both CD and UC. Pustular PG is more commonly associated with UC and presents with slowly creeping pustular lesions on an infiltrated erythematous base (Figure 2). The extremely rare mucosal PG variant, more commonly known as pyostomatitis vegetans, typically presents with a snail-track appearance to mucosal erosions and is almost exclusively restricted to UC. Peristomal PG is seen in association with IBD about 93% of the time, in contrast to postsurgical PG, which is seen most commonly after breast reduction surgery and uncommonly in IBD.(6,7) Peristomal PG may take several months to develop, and it has a 61% recurrence rate, whereas postsurgical PG tends to develop about 11 days postoperatively and rarely recurs.
PG is a diagnosis of exclusion, made clinically with histopathologic support in patients who satisfy identified diagnostic criteria (Table 2).(8) The differential diagnosis for PG includes infections (fungi such as disseminated blastomycosis, mycobacteria, tertiary syphilis), vasculitis (granulomatosis with polyangiitis, Behçet’s disease), immunodeficiencies (leukocyte adhesion deficiency, chronic granulomatous disease), toxins (loxoscelism from recluse spiders), malignancies (squamous cell carcinoma, lymphomas), and metastatic or dystrophic calcification (calciphylaxis).
A biopsy for culture and histopathology is commonly taken from the active border of the lesion to exclude other diseases, and intralesional triamcinolone acetonide is often injected into the biopsy site at the time of the procedure due to the risk of pathergy.
PG often requires aggressive therapy for initial disease control and ulcer healing and an appropriate maintenance management strategy to retain control of this chronic condition. The basic principles of management of PG are suppression of neutrophilic inflammatory disease activity, promotion of wound healing, treatment of secondary infections and associated disease, and control of pain.(9)
Topical, intralesional, and systemic therapies are used to suppress the inflammation of PG.
Topical: Topical therapies are primary therapy for limited PG and adjunctive therapy for more severe disease.(9,10) Appropriate topical corticosteroids include potent agents, such as clobetasol propionate, halobetasol, betamethasone dipropionate, or fluocinonide. Calcineurin inhibitor ointments or creams, such as tacrolimus or pimecrolimus, may be useful. Dapsone is available in a topical acne formulation(11), and sodium cromoglycate in an otic or optic formulation can be used before applying an antibiotic to inhibit neutrophil activity.
Intralesional: Intralesional triamcinolone acetonide, 20 to 40 mg/mL, injected into active or undermined edges every 2 weeks can help to limit lesion progression.(9)
Systemic: Systemic therapy is indicated for more severe cases.(9,12,13) A high degree of immunosuppression is critical in severe disease, as ulcers can rapidly erode to muscle and bone. Prednisone, 1 mg/kg/day, possibly with the addition of a pulsed intravenous corticosteroid for the first 3 days, is a useful option, as is cyclosporine, 2 to 5 mg/kg/day, starting at the higher dose and tapering as ulcer expansion decreases. Both of these agents have a rapid onset of action, making them appropriate for initial therapy. As a steroid-sparing strategy, patients can be transitioned for maintenance to mycophenolic acid or mycophenolate mofetil, as these agents have a slow onset of effect, about 8 weeks. Intravenous immunoglobulin, 2 g/kg initially followed by 1 g/kg every 4 weeks, has demonstrated efficacy in treating PG but a relatively slow onset of effect. Other systemic immunomodulators that have successfully treated cases of PG include dapsone, sulfasalazine, and colchicine. The tumour necrosis factor-α (TNF-α) inhibitors infliximab and adalimumab have been reported to be effective in at least two-thirds of cases.(14) Case reports indicate that high-dose ustekinumab may be effective.(15) The interleukin (IL)-1 antagonists gevokizumab, anakinra, and canakinumab also appear promising.(14)
PG is invariably associated with tissue edema, and the use of compression to minimize edema is a basic principle of management. Before applying compression, it is critical to determine the amount of compression that can be used, by performing an ankle-brachial index, toe pressure, and oxygen saturation measurements. Short-stretch non-elastic compression bandages are used in patients with a compromised arterial supply, whereas high-stretch elastic bandages are used in patients with minimal vascular disease. Hyperbaric oxygen has been shown to be beneficial in managing PG.(16)
Pseudomonas colonization is common in PG lesions, and daily washes with dilute acetic acid (1:5 to 1:10 dilution as tolerated) may be useful in management. Alginate dressings can manage exudative PG lesions. Potentially useful antibacterial dressings include those containing activated silver, iodine, or crystal violet. The use of bacterial binding resins can assist in management of biofilms. Very deep swabs or biopsy for culture can determine appropriate systemic antibiotic therapy.
In patients with IBD, treatment with a TNF-α inhibitor can treat both the gastrointestinal disease and the PG. An immunosuppressive agent, such as mycophenolate mofetil or cyclosporine, can be added to prolong the duration of action of the TNF-α inhibitor.(13)
Appropriate pain control is necessary to allow effective compression therapy. After short-acting morphine has been titrated to an effective dose, treatment can be converted to a long-acting opioid with the addition of a short-acting agent to manage breakthrough pain.
PG is a chronic, often severe and disfiguring, inflammatory dermatologic manifestation of numerous chronic diseases, including IBD. Aggressive immunosuppression is frequently required to achieve and maintain control of PG, which may best be managed in conjunction with a dermatologist.
TNF-α is one of the principal inducers of inflammation in many gastrointestinal diseases, including IBD. Immunologic interference with TNF-α levels, using biologics, decreases the inflammatory response and clinical manifestations. As a class, TNF-α inhibitors, however, are associated with development or exacerbation of dermatologic lesions in 20 to 30% of patients with IBD and reports of these adverse events have increased over time (Figure 1).(1) Patients who develop dermatologic adverse reactions may be undergoing TNF-α inhibitor treatment for gastrointestinal, rheumatologic, or dermatologic diseases. These dermatologic adverse effects were first identified in early clinical trials of infliximab in rheumatoid arthritis.(2) Most of the affected individuals have no personal or family history of skin diseases. Severely affected individuals may discontinue TNF-α inhibitor therapy.(3)
Adverse dermatologic effects of TNF-α inhibitors are classified as local or systemic reactions, skin infection, malignancy, and immune-mediated effects (Table 1).(4–9)
Local or systemic dermatologic reactions are common.(4) Injection-site reactions have been reported in 30 to 40% of studies. Infusion reactions can be modulated by pretreating with anti-inflammatory agents and by altering infusion rates.
Skin infections are seen during treatment with any immunomodulators and encompass a broad range of bacterial, viral, and fungal infections (Table 1).(5)
TNF-α, in addition to its important role in inflammation, has an impact on tumour biology. A cohort study assessed the risk of squamous cell carcinoma in 46,409 patients with rheumatoid arthritis (RA), who had not been exposed to TNF-α inhibitors, in comparison with 12,558 patients with RA treated with TNF-α inhibitors and 379,666 matched individuals from the general population.(6) The study also assessed the risk of basal cell carcinoma in 43,675 patients with RA, who had not been exposed to TNF-α inhibitors, in comparison with 8,827 patients with RA treated with TNF-α inhibitors and 364,584 matched individuals from the general population.
The study found that patients with RA have a moderately increased risk of basal cell carcinoma and almost double the risk of squamous cell carcinoma compared with the general population (Figure 2).(6) TNF-α inhibitors confer no additional risk of basal cell carcinoma but increase the risk of squamous cell carcinoma by about 30%.
Psoriasiform dermatitis, pustular palmoplantar psoriasis, eczematous dermatitis, acneiform eruptions and other immune-mediated conditions may develop in patients with no history of these skin problems. A case-control study conducted among 521 patients with IBD being treated with TNF-α inhibitor found 18 patients (3.5%) developed psoriasiform lesions, 50% of whom discontinued therapy.(9) Other immune-mediated reactions that have been reported with TNF-α inhibitor therapy include cutaneous lupus or lupus-like syndrome; cutaneous vasculitis (7); erythema multiforme; toxic epidermal necrolysis, including Stevens-Johnson syndrome; and alopecia.(8)
Several possible mechanisms have been proposed for the development of psoriasis with TNF-α inhibitor therapy. The most commonly accepted explanation involves the uncontrolled release of interferon-α (IFN- α) by plasmacytoid dendritic cells in genetically predisposed individuals, which activates autoreactive CD3 T cells and stimulates secretion of IL-12 and -23. (Figure 3).(10)
Another hypothesis involves the initiation of apoptosis in response to binding of the monoclonal antibody Fab fragment to the membrane-associated TNF-α receptor and activation of macrophages by the antibody binding to the Fc-γ receptor on macrophages (Figure 4).(11) This binding induces secretion of IL-23, which stimulates T lymphocytes to release IL-17 and -22, ILs that are required for development of psoriasiform skin lesions. A potential treatment may combine the use of ustekinumab, an anti-IL-12/23 antibody. Ustekinumab binding to the p40 subunit of IL-12 and IL-23 neutralizes both cytokines and reduces the psoriasis-induced lesions.
Finally, another possible mechanism is the hypothesis that treatment with TNF-α inhibitors affects the composition of the microbiome, which correlates with the development of dermatologic adverse effects.(12)
It is important for gastroenterologist to be familiar with the presentation of these dermatologic manifestations, options for their management, and the pathophysiology of these harmful adverse events. As TNF-α inhibitors may increase the risk of skin cancer, it is essential to advise patients to use sun protection. Given the risk of treatment discontinuation with severe dermatologic reactions, it is also vital to counsel patients about the signs and symptoms of cutaneous reactions and to advise patients to contact her or his gastroenterologist if they develop a skin reaction. It is advisable to have patients with IBD treated with a TNF-α inhibitor see a dermatologist regularly. Rapid access to a dermatologist can support optimal management of dermatologic adverse effects of TNF-α inhibitors.
As the use of TNF-α inhibitors continues to increase, the diagnosis and management of cutaneous side-effects will become an increasingly important challenge.
John K. Marshall, MD MSc FRCPC AGAF, Chief of Gastroenterology Clinical Service, Hamilton Health Sciences; Professor of Medicine, Division of Gastroenterology, McMaster University, Hamilton, ON
Richard N. Fedorak, MD FRCPC FRCP (London) FRCP (Edinburgh) FRCS, Dean, Faculty of Medicine & Dentistry; Professor of Medicine, Division of Gastroenterology, University of Alberta, Edmonton, AB
Scott Walsh, MD PhD FRCPC DABD, Assistant Professor, Division of Dermatology, Department of Medicine, University of Toronto, Sunnybrook Health Sciences Centre, Toronto, ON
Hermenio Lima, MD PhD, Associate Clinical Professor, Division Director, Division of Dermatology, Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON
Alain Bitton, MD FRCPC, McGill University, Montreal, QC
Brian Bressler, MD MS FRCPC, University of British Columbia, Vancouver, BC
Anne M. Griffiths, MC FRCPC, University of Toronto, Toronto, ON
Steven E. Gruchy, MD MSc FRCPC, Dalhousie University, Halifax, ON
Remo Panaccione, MD FRCPC, University of Calgary, Calgary, AB
Craig Render, MD FRPCP, University of British Columbia, University of Alberta, Kelowna, BC
Hillary Steinhart, MD MSc FRCPC, University of Toronto, Toronto, ON
Jennifer Stretton, ACNP MN BScN, St. Joseph’s Healthcare, Hamilton, ON
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