Elisabetta Miserocchi
Dr. Elisabetta Miserocchi is a consultant ophthalmologist, based at University Hospital San Raffaele Milan, Italy. After graduating with a medical degree from the University of Milan in 1996, Dr. Miserocchi completed a four-year residency in the Department of Ophthalmology at the San Raffaele Hospital, including a research fellowship at the Massachusetts Eye and Ear Infirmary, part of Harvard Medical School, Massachusetts, USA, with Dr. Stephen Foster.Her main areas of interest and activity are diagnosis and treatment of uveitis, pediatric uveitis associated with rheumatic diseases, ocular cicatricial pemphigoid, and herpetic ocular disease. Dr. Miserocchi is also currently participating in many international multicenter clinical trials on systemic immunosuppressive agents for non-infectious uveitis.Dr. Miserocchi is a member of the International Uveitis Study Group in 2014 and the American Uveitis Society. She is widely published in peer-reviewed journals and has presented her work at a number of national and international congresses; she was awarded the SOI-SOE Lecture at the Società Oftalmologica Italiana 2012 annual meeting in Rome for new treatments in non-infectious uveitis. Dr. Miserocchi has conducted research and applied new therapies to further the diagnosis and treatment of non-infectious uveitis.
Lorenzo Iuliano
Dr. Lorenzo Iuliano is a consultant ophthalmologist at the San Raffaele Scientific Institute of Milan, Italy. He graduated in 2010 at the Medical School of the Vita-Salute University of Milan and completed his five-year residency program in the Ophthalmology Department of the San Raffaele Scientific Institute of Milan, Italy. He is also a Fellow of the European Board of Ophthalmology.Dr. Iuliano’s main areas of interest are posterior segment diseases and uveitis, with a particular focus on vitreoretinal surgery. He is also currently participating as investigator in different international multicenter clinical trials on systemic immunosuppressive agents for non-infectious uveitis.Dr. Iuliano is also widely active in spontaneous clinical research, which results are widely published in peer-reviewed journals. He also presented his work in different national and international congresses.
Giulio Modorati
Dr. Giulio Modorati is a senior consultant ophthalmologist, based at University Hospital San Raffaele Milan, Italy. Graduated with a medical degree from the University of Milan, Dr Modorati completed a four-year residency in the Department of Ophthalmology at the San Raffaele Hospital.Dr. Modorati’s main areas of interest and activity are diagnosis and treatment of uveitis, AIDS, ocular oncology, and dry eye diseases. He is also currently involved as principal investigator in many international multicenter clinical trials on systemic immunosuppressive agents for noninfectious uveitis and ocular tumors.Dr. Modorati is the Head of Ocular Oncology and Immunopathology Service at the San Raffaele Scientific Institute in Milan (Italy). He is widely published in peer-reviewed journals and has presented his work at a number of National and International Congresses.
Introduction
Pyoderma gangrenosum, first described by Brocq [1] and named by Brunsting [2] in 1930, is a rare, ulcerating, neutrophilic dermatosis primarily affecting patients aged 25–54 years, without a clear gender predilection. Epidemiologic data establishing disease incidence have yet to be published [3, 4].
Clinical Presentation
A pyoderma gangrenosum lesion typically starts as a tender nodule, plaque, or sterile pustule that enlarges and erodes, over a course of days, into a sharply marginated ulcer with undermined, violaceous borders and a surrounding zone of erythema; pain is a characteristic feature. The skin and subcutis become necrotic, creating a friable wound bed often with a hemorrhagic or purulent exudate, sometimes extending as deep as the muscle. Cribriform or “sieve-like” atrophic scars often form as the lesions heal. Lesions typically are multiple and recurrent and tend to occur at areas of trauma, a process known as pathergy.
A hallmark of pyoderma gangrenosum is the purulent aspect of lesions, which seems to be infectious. No microorganism growth can be detected, but the caseating necrotic aspect of lesions is confounding about possible mycobacterial infection (“pseudotuberculous appearance”) [5–10].
Pyoderma gangrenosum lesions in adults most frequently affect the lower extremities, but any anatomic site can be affected. In children (approximately 4 % of cases), it typically involves the lower extremities, buttocks, and perineal region, as well as the head and neck.
Pyoderma gangrenosum may also involve extracutaneous sites such as the eye, the lungs (aseptic pulmonary nodules), the spleen, and the musculoskeletal system in the form of sterile pyoarthrosis and neutrophilic myositis [4].
Physiopathology
The pathophysiology of pyoderma gangrenosum remains poorly understood though is now believed to involve loss of innate immune regulation and altered neutrophil chemotaxis.
T-cells are involved in the regulation of both macrophage and neutrophil function, and helper T-cell abnormalities have been demonstrated in patients with pyoderma gangrenosum [11, 12]. It is not known whether the skin ulcers occur secondary to this immune dysfunction or if the lesions are the result of an inappropriate inflammatory response against some factor in the skin. Furthermore, emerging evidence of the clinical efficacy of tumor necrosis factor (TNF) alpha inhibitor therapy strongly suggests a key role for this cytokine in this disease [3, 13, 14].
Association
Pyoderma gangrenosum is associated with underlying systemic diseases in at least half of patients; the remainder of cases are considered idiopathic. Inflammatory bowel disease (IBD), arthritis, and hematologic disorders are the most common disease associations [15, 16]. Although in most cases pyoderma gangrenosum was diagnosed after the associated disease, it may also precede or be the presenting sign of an underlying disease. The courses of the two diseases are sometimes, but not necessarily, parallel [17, 18].
Other association [3]:
Less common: hematologic malignancy and other hematologic abnormality, monoclonal gammopathy, arthritis
Rare: hidradenitis suppurativa, pyogenic arthritis, pyoderma gangrenosum and acne (PAPGA) syndrome, pulmonary disease, systemic lupus erythematosus, thyroid disease, solid organ malignancy, autoimmune hepatitis, sarcoidosis
Diagnosis
Pyoderma gangrenosum remains a clinical diagnosis; it lacks specific serologic or histologic markers. Although no clinical criteria have been formally adopted, one proposed set requires the fulfillment of two major criteria [18–21]:
- 1.
Rapid progression (margin expansion of 1–2 cm per day, or 50 % increase in ulcer size within 1 month) of a painful, necrolytic, cutaneous ulcer with an irregular, violaceous, and undermined border
- 2.
Exclusion of other causes of cutaneous ulceration
and at least two minor criteria:
- 1.
A history suggestive of pathergy or a clinical finding of cribriform scarring
- 2.
Systemic diseases associated with PG
- 3.
Histopathologic findings (sterile dermal neutrophilia, mixed inflammation, lymphocytic vasculitis)
- 4.
Treatment response (rapid response to systemic corticosteroid treatment)
Ocular Involvement
Ophthalmic involvement is rare. Isolated ocular localization of pyoderma gangrenosum is very rare, while an ophthalmic extension if other simultaneous cutaneous lesions are present makes the diagnosis easier. Pyoderma gangrenosum may involve the sclera, cornea, orbit, and ocular adnexa. Different ophthalmic segments may also be concurrently interested.
Scleral involvement clinically presents as a necrotizing scleritis (Fig. 25.1), where an abscess formation is the hallmark of the disease. Severe cases of sclerocorneal extension of the disease may result in cutaneous and scleral fistula, associated with hypopyon in the anterior chamber.
Fig. 25.1
Two cases of necrotizing scleritis in patients with pyoderma gangrenosum associated with Crohn’s disease. (a) Acute scleritis at presentation. Both episcleral and deep scleral vessels are markedly inflamed. Note the white circumscribed avascular area of necrosis. (b) Advanced phase. The uvea is visible under marked scleral thinning, next to an area of scleritis
Regarding corneal involvement, cases of peripheral ulcerative keratitis (PUK) have been reported (Fig. 25.2). Pyoderma gangrenosum-associated PUK shares many similarities with collagen vascular disease-associated PUK. Residual corneal scarring with conjunctivalization and contiguous scleral thinning may be present after sclerokeratitis resolution [22–28].
Fig. 25.2
Typical clinical pictures of peripheral ulcerative keratitis. (a) A 52-year-old woman with rheumatoid arthritis. The lesion has a bullous-like aspect, invading the cornea and with adjacent dilated conjunctival vessels. (b) A 39-year-old woman with acute myeloid leukemia. The ulcerative keratitis is adjacent to an area of scleritis. (c) A 48-year-old man with Crohn’s disease. Severe peripheral ulcerative keratitis in advanced phase, with stromal opacity, corneal neovascularization, and scleritis
Orbital involvement includes the eyelid, lacrimal sac, and the deep post-septal orbital tissues, including the lacrimal gland. Intraorbital (post-septal) extension is rare and tends to occur deep to the lateral canthus. Lacrimal sac involvement may be clinically confused with a chronic dacryocystitis. In the eyelid, necrosis appears characteristically to spare the marginal bar of upper lid tarsus (alongside the tarsomarginal artery) and to favor the central one-third of the upper lid and lateral two-thirds of the lower lid (Fig. 25.3). Healing process of periocular wounds may result also in a cicatricial ectropion [29–35].
Fig. 25.3
Diagram of eyelid involvement in pyoderma gangrenosum. The necrosis typically spares the marginal bar of upper lid tarsus (alongside the tarsomarginal artery) and favors the central one-third of the upper lid and lateral two-thirds of the lower lid
Workup
Once diagnosis has been done, it is imperative to exclude infection or malignancy as part of the initial workup, especially if the patient will undergo systemic immunosuppression.
Routine laboratory tests as an initial screen for hematologic disorders and liver or kidney dysfunction related to a variety of possible associated conditions.
Systemic vasculitis: antinuclear antibody, coagulopathy panel including antiphospholipid antibody test, cryoglobulins, rheumatoid factor, circulating antineutrophil cytoplasmic antibodies
IBD: fecal occult blood test and sigmoidoscopy/colonoscopy
Hematologic disease: serum protein electrophoresis, urine spot protein, or urine protein electrophoresis, immunofixation electrophoresis, peripheral smear, bone marrow biopsy
Infectious causes: HIV test, hepatitis serologies, and rapid plasma regain (if risk factors exist)
Radiologic examination (chest X-rays, computed tomography, magnetic resonance imaging) should be performed according to the clinical suspect. MRI is a powerful tool for evaluating the extent of extracutaneous pyoderma gangrenosum lesions in the periocular tissues. Acute inflammation shows marked homogeneous hyperintensity on fat-saturated T2-weighted image and hypointensity on T1-weighted image. Fibrosis reveals marked hypointensity on T2-weighted image and hyperintensity on T1-weighted image.
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