Discussion
Köhlmeier–Degos disease, also known as atrophic papulosis, is a rare obliterative vasculopathy that may present in either a benign or malignant form. 1 – 8 Benign, cutaneous KD is characterized by pathognomonic lesions with porcelain-white plaques, atrophic centres, and erythematous borders, which may persist for several weeks or even years. 1 , 2 , 5 , 6 These cutaneous lesions typically involve the trunk and upper extremities and often spare the face and hands. 2 , 6 Benign, cutaneous KD may progress into a severe, multisystem, malignant variant; in three-quarters of people who have malignant progression, KD involves the gastrointestinal system. 4 , 6 Although case series describe visceral perforation as the dominant presentation, patients have preceding gastrointestinal symptoms of abdominal pain, cramping, anorexia or weight loss, vomiting, diarrhea, constipation, or fullness. 2 Involvement of the central nervous system, heart, lung, eyes, or bladder has been described. 4 , 6 Patients with systemic involvement who are left untreated have high mortality, most commonly from abdominal sepsis caused by bowel perforation or strokes caused by lesions of the central nervous system. 2 In the largest case series to date, including 105 patients, the mean age of disease onset was 33 (range 15–50) years with a male-to-female ratio of 1 to 1.6. 6 , 7 Although 41% of patients had cutaneous KD throughout the follow-up period, 59% of patients had malignant KD that progressed from cutaneous to multisystem involvement within a year of symptom onset. 7 This series described a mortality of 22.6%, less than the 50%–75% reported in earlier case series and reviews. 5 , 7
The exact cause and pathophysiology of KD remains unknown. 6 In the large case series, 10% of the 105 patients reported familial occurrence, suggesting a possible genetic predisposition. 7 The disease has also been described in the postinfection or autoimmune context. 4 Pathologically, KD has features of thrombotic microangiopathy and distinctive obliterative arteriopathy. 7 Histopathological studies show lymphocyte-mediated necrotizing vasculitis of the cutaneous venules and arterioles. 4 Heavy deposition of membranolytic attack complex (i.e., C5b-9 complex) within cutaneous vasculature is noted on biopsy. 4 Myxovirus-resistance protein A, a type I interferon–inducible protein, is expressed in the pattern of C5b-9 deposition, suggesting a role for interferon-α in the pathophysiology of KD. 4 Endothelial cell dysfunction and coagulopathy have also been proposed as pathogenic mechanisms, as deep excessive endothelial proliferation — seen in the vessels — may lead to thrombosis and final distal necrosis. 4 Conversely, thrombi may also cause endothelial damage, mucin deposition, and mononuclear cell aggregation. 4 The C5b-9 immunohistochemical stain of frozen sections of our patient’s skin were negative; however, we may have sampled inactive areas, given the absence of thrombi. We did not have any frozen bowel tissue for C5b-9 staining. She also tested positive for antiphosphatidylserine–prothrombin IgG, but negative for IgM and antiphospholipid syndrome markers; the importance of these results is unknown.
The treatment for KD is currently empirical and based on case series data. We started IVIG based on a single case report of successful remission and its availability, although the results have been mixed in other reports. 4 , 8 We also used heparin on the basis of case reports supporting the use of antiplatelets and anticoagulants, preferring an agent that could be immediately stopped to allow for emergency surgery. 4 We specifically avoided steroids as they have been shown to increase the risk of complications. 4 Similarly, cyclosporine, cyclophosphamide, and azathioprine have not been found effective. 4 Eculizumab — a monoclonal antibody that binds to the C5 complement component to prevent the formation of the membranolytic attack complex and partially reverse complement deposition — has shown some promise. 3 , 4 Several case series have shown the effectiveness of eculizumab during the acute phase of the disease, with more prolonged remission when coupled with treprostinil. 2 , 4 Treprostinil is a prostacyclin analogue that inhibits platelet aggregation and causes vasodilation. 4 . The rare incidence and high fatality of systemic KD limits the feasibility of randomized controlled trials of treatments.
Eculizumab is approved by Health Canada to treat paroxysmal nocturnal hemoglobinuria or atypical hemolytic uremic syndrome. 9 The use of eculizumab in the treatment of malignant KD is considered off label and is evaluated on a case-by-case basis. Applications to finance and access eculizumab for emergency use are submitted to and approved by local programs for exceptional access to drug therapies. Approval for using this 2-drug regimen is based on pathology results supporting the diagnosis of KD and provision of literature that demonstrates therapy correlation with prolonged survival. 2
The time-sensitive nature of treatment and the need for a special application to access eculizumab and treprostinil highlight the importance of early recognition by providers. Given this context, diagnosing KD when it is still the benign, cutaneous variant is essential to allow for monitoring of disease progression and early identification of malignant transformation.
Patients with KD should be followed at a specialized centre according to a standardized protocol, including whole-skin exam, skin biopsy, fecal occult blood testing, and ocular fundus exam every 6 months. 4 For patients with KD and any gastrointestinal symptoms, laparoscopy is more sensitive than endoscopy or colonoscopy and should be used to detect complications and confirm progression to malignant disease. 10 Reversal of lesions upon treatment with eculizumab and treprostinil has been shown among patients who have undergone laparoscopy before catastrophic perforation. 2 Further testing — such as esophagogastroduodenoscopy, colonoscopy, brain or spine magnetic resonance imaging, echocardiogram, and CT angiography — may be needed depending on patient symptomatology. Given that transformation of KD from benign to malignant forms most often occurs within the first 7 years of disease, review articles suggest that patients with cutaneous KD be followed up twice per year for the first 7 years, and once per year until the tenth year, after which the risk of malignant transformation is nearly nonexistent. 4
The section Cases presents brief case reports that convey clear, practical lessons. Preference is given to common presentations of important rare conditions, and important unusual presentations of common problems. Articles start with a case presentation (500 words maximum), and a discussion of the underlying condition follows (1000 words maximum). Visual elements (e.g., tables of the differential diagnosis, clinical features or diagnostic approach) are encouraged. Consent from patients for publication of their story is a necessity. See information for authors at www.cmaj.ca .