Dermatology

Degos Disease (Kohlmeier Disease, Degos-Kohlmeier Disease, Malignant atrophic papulosis, benign atrophic papulosis, Malignant atrophic papulosis)

Are You Confident of the Diagnosis?

Atrophic papulosis or Degos disease (DD) has 2 variants: 1) a more common, limited, cutaneous type, which can be referred to as benign atrophic papulosis (BAP) and 2) a severe systemic, fatal variant, which can be referred to as malignant atrophic papulosis (MAP). Most cases of eruptions with clinical and histologic findings of DD are benign atrophic papulosis and are confined to the skin alone. The ratio of these variants is unclear but some suggest it is 5:1 to 10:1

Characteristic findings on physical examination

Atrophic porcelain papules are not pathognomic DD. All collagen vascular diseases (CVD) and some types of vasculitis (Wegener granulomatosis) can manifest with the atrophic papules of DD and an identical histology. Sometimes there is an overlap with the CVD and DD and sometimes just a CVD is present. Thus atopic papules themselves do not definitively make a diagnosis of DD. There is currently no laboratory test that defines DD. That said, for those who are familiar with DD, when a patient with DD appears for examination, the diagnosis of DD would be considered by dermatologists in their differential diagnosis.

DD first manifests as erythematosis papules or plaques 2 to 15mm in diameter. Ulcers, necrotic amputations, purpura and cutaneous vasculitis have been found in patients with DD. The classic papules of DD evolve slowly into scars with central, porcelain white atrophic centers, which usually have a peripheral telangiectatic rim. The papules of DD have been reported to have few associated findings except perhaps for a sensation of burning that some patients report.

The papules of DD most commonly occur on the torso and extremities, and on the penis. They can also occur on the palms and soles but only rarely on the face. Most patients with DD have 10 to 40 papules. This includes both BAP and MAP. Fewer or greater numbers of papules than 10 to 40 have been reported.

What to be alert for in the history

The skin is usually the first organ system involved in DD, although cases in which where the internal organs were first noted to have DD-type lesions before skin papules appeared have been reported.

It can take weeks, months or years for the pathology of DD to spread from the skin to the internal organs, if it spreads at all. The most concerning sign in DD is the development of internal symptoms, in particular severe abdominal pain along with the presence of the atrophic papules. This development of systemic findings suggests systemic DD, which is usually fatal in 2 to 3 years.

Expected results of diagnostic studies

If DD is suspected, a punch biopsy of the skin should be performed. The histology of DD has been described. The early papules in DD are skin colored or erythematous and can manifest a primarily lymphocytic cell infiltrate associated with interstitial mucin deposition in a superficial and deep perivascular, periadnexal, and perineural pattern. Eosinophils are rarely present. The mucin that is present appears like the mucin found in the histology of lupus, and like lupus, there can be vacuolar alteration at the dermoepidermal junction.

The atrophic white papules of DD demonstrate wedge-shaped degeneration of collagen, sometimes along with mucin and vacuolar change. Interface dermatitis can occur in DD but is usually limited to the central portion of the specimen. There can be squamatization of the dermoepidermal junction, melanin incontinence, epidermal atrophy and dermal sclerosis, which resembles lichen sclerosis. There can be necrobiosis of the collagen layer, which may remind the histologist of granuloma annulare or necrobiosis lipodica. Abundant acid mucopolysaccharides can manifest in the dermis, mimicking dermal mucinosis.

Indirect immunofluorescence can show involvement of complement factors. Direct immunofluorescence does not yield definitive findings in DD. Perivascular fibrin and complement can be found in specimens of DD. An autopsy in a patient who manifested the clinical diagnosis of DD demonstrated features of thromboangiitis of the Buerger type (ie, bland infarcts of the small intestine and striking perforation of the jejunum).

Microaneurysms of the bulbar conjunctival vessels have been observed histologically.

IMAGING FINDINGS IN MAP

MRI of the brain can show multiple cerebral infarctions accompanied by small hemorrhagic areas and gadolinium-diethylenetriamine pentaacetic acid enhancement of the dura. MRI can show defects in the optic nerve and spinal cord including a loss of myelin, thrombosis and occlusion. MRI can also show intracerebral bleeding, subdural hemorrhage, and cord infarcts. A cerebral angiogram can show narrowing and occlusion of small intracranial arteries, in particular stenosis, ectasia, and aneurysms involving the peripheral branch of arteries in MAP.

EEG tests in MAP can show generalized nonspecific slowing. Electromyograms have shown axonal and demyelinating polyneuropathy.

Angiograms of the body in MAP can show stenosis in the celiac artery and the small arteries in the kidney. Chest x-rays in patients with MAP have shown extensive calcification of the pericardium. CT scanning of the abdomen and pelvis with oral and intravenous contrast in patients with MAP can show extensive ascites, nodular thickening of the omentum, small bowel wall thickening and patchy mucosal perfusion and intraluminal jejunal hemorrhage and perforation.

Diagnosis confirmation

The main entities to be considered in the differential diagnosis of DD are lupus, dermatomyositis and antiphospholipid syndrome; the lack of positive serologic tests and characteristic papules of DD help to define pure or primary DD rather than DD overlapping with a CVD, or a CVD with findings of DD-type skin papules. The white macules of DD have a different appearance from the atrophic white papules of atrophie blanche or morphea. Another disease that can resemble DD in the skin is lichen sclerosis, but its white papules and plaques have a different appearance from those of DD, often demonstrating dells and becoming confluent into plaques.

From a mechanistic standpoint, DD is a disease of blood vessels that is a vasculopathy or an endovasculitis. It is not a frank vasculitis but rather an occlusive arteriopathy involving small-caliber vessels. Specifically, DD manifests as a progressive, small- and medium-size arterial-occluding disease, resulting in tissue infarction, initially involving cutaneous blood vessels of the skin and then perforce the skin itself.

Electron microscopy of the white papules can demonstrate interwoven tubular structures within the endothelial cells that have the quality of viral inclusions. To date no virus has been identified. Specifically, paramyxovirus was not found by polymerase chain reaction of tissue of DD with viral inclusions.

No specific laboratory test can be used to definitively define DD. In fact, most laboratory test results in patients with pure DD are normal, with the exception of the blood count in MAP where anemia occurs secondary to intestinal bleeding. It has been suggested that molecular testing can define an interleukin, cytokine and hematologic profile (in particular complement) for DD, but this needs to be studied further.

Gastrointestinal endoscopy can help to define MAP. Endoscopy of the gastrointestinal tract (ie, stomach, esophagus, duodenum, colon, rectum) can show infarcted, necrotic areas or ulcers. Intestinal laparoscopy can demonstrate areas of infarction and necrosis that appear as white plaques with red borders on the serosal surface of the bowel and the peritoneum, omental infarction, or multiple yellow plaques on the serosal surface of the small intestine.

Renal pathology of DD has shown thickening of the afferent glomerular arterioles and thickening of the capillary basement membrane.

Who is at Risk for Developing this Disease?

The risk factors for developing DD are not known. DD has been reported in infants as well as adults. The ratio of benign/purely cutaneous DD to the systemic lethal form of DD is not known but could be 5:1 or 10:1. About 250 cases of DD have been reported in the world literature. Some cases of DD appear to be familial, and about 10 reports of familial DD exist.

What is the Cause of the Disease?

Etiology

Pathophysiology

The cause of DD is not certain. DD seems to be a hematologic and/or endothelial disease. No immune defect has ever been linked consistently to DD and no treatment that suppresses the immune system has consistently been shown to abate DD. Why some cases of DD remain confined to the skin and some are systemic is uncertain. The two categories of DD, one only in the skin and the other in the skin and internal organs, suggests the interaction between the endothelial cells and erythrocytes in the skin vasculature may be different from that of vessels in internal organs.

The author believes that DD could be an acquired intrinsic defect in some endothelial or hematologic gene and the protein or factor thereby expressed. In this context, DD might parallel paroxysmal nocturnal hemoglobinuria (PNH), which is a potentially lethal hematologic disease characterized by complement-induced intravascular hemolytic anemia, red urine (from hemoglobin) and thrombosis.

PNH, a hematopoietic stem cell disorder, arises from a somatic mutation of the phosphatidylinositol glycan-class A (PIG-A) gene. The gene product is required in the biosynthesis of a glycosylphosphatidylinositol (GPI) structure and serves as an anchor for a group of membrane proteins. The PNH cells are characterized by a total or partial lack of the GPI-anchored membrane proteins. Without this structure, intravascular hemolysis occurs due to the inability to regulate the lytic and cell-stimulatory activities of complement on the membrane surface of hematopoietic cells.

Two proteins, CD55-decay accelerating factor and CD59-membrane inhibitor of reactive lysis, are known to be tethered to the cell membrane by the GPI-anchor. Additionally, platelets lacking CD59 may cause venous thrombosis with possible Budd-Chiari syndrome. The development of PNH requires a hypoplastic bone marrow, somatic mutation restricted to the PIG-A gene in the stem cell, and clonal expansion of the hematopoietic stem cell pool.

The interaction of complement, red blood cells, platelets, other blood factors and the endothelial cells are complex, and some dysfunction in these systems could underlie DD. The fact that GPI anchor pathology can cause thrombosis would seem to inform our understanding of thrombosis in DD.

Eculizumab (Soliris) is a monoclonal antibody directed against the complement protein C5. This antibody blocks the cleavage of C5 and halts the process of complement-mediated cell destruction. Eculizumab has been shown to be effective in treating PNH. Broadly put, disabling the function of complement can stop a variety of hematologic pathology such that occurs in PNH and DD.

Eculizumab has also been used effectively to treat other hematologic diseases and forms of vascular thrombosis, including hemolytic uremic syndrome, renal allograft rejection, and antiphospholipid syndrome. Eculizumab exhibits its therapeutic activity by binding to the C5 complement protein, thereby blocking its cleavage by the C5 convertase.

Other factors suggested for the etiology of DD include a virus because endothelial cells in DD have viral inclusions, although no virus has been identified. Specifically, paramyxovirus was not found by polymerase chain reaction of tissue of DD with viral inclusions. Some suggest that parvovirus B-19 is involved, but this has not been shown in a rigorous fashion.

Molecular research suggests that DD is a dysregulated interferon-α response combined with membranolytic attack complex deposition that may contribute to the unique vascular changes, and DD thereby could be considered a C5b-9/interferon-α-mediated endotheliopathy syndrome. Some have suggested that DD is a variant of lupus; however, the cause of lupus is not known so this observation does not help define the etiology of DD. Also, as rare diseases are usually single hits and are easier to define, one might imagine that the cause of DD will be defined before the cause of lupus is ascertained.

Commentators have suggested that DD is a vasculitis, a mucinosis, or a thrombotic disorder. In most instances of DD, however, no circulating immune complexes, antiendothelial cell antibodies, or anticardiolipin antibodies can be indentified. However, in some instances of DD, researchers have identified antiphospholipid antibodies of uncertain significance. Others have posited that DD is a primary endothelial cell defect accompanied by secondary thrombosis, causing infarctive changes. Antibodies to components of endothelial cells have not been found.

Medications and toxic chemicals do not seem to induce DD, although a case of a patient with BAP who took an immunosuppressive medication (cyclosporine) and later developed MAP has been reported. One can only speculate whether the drug in this case involved causation.

Some cases of DD are familial and an autosomal dominant mode of inheritance has been posited; however, these cases of DD are uncommon.

Systemic Implications and Complications

Systemic DD (MAP) can manifest in the gastrointestinal tract, neurologic system (including the eyes), cardiopulmonary systems and blood vessels. It seems likely that DD can affect any organ with blood vessels.

The outcome of MAP can be fatal with a median survival of 2 to 3 years. Some patients live more than 3 years; why this is the case is not known.

Reported symptoms relating to the GI tract include abdominal pain, which is usually severe and not subject to remission, abdominal swelling, cramps, nausea, vomiting, diarrhea, or constipation. Findings associated with the GI tract, in particular weight loss, and/or symptoms of malabsorption have been noted.

Diabetes mellitus, histologic findings of DD and hyaline diabetic microangiopathy have been noted in a DD patient.

Neurologic issues include facial and acral paresthesias, seizures, headaches, dizziness, hemiplegia, aphasia, quadraplegia, paraplegia, and gaze palsy. In 1996, a series of 15 patients with DD was analyzed; 10 DD patients developed neurologic manifestations consistent with DD. This pathology included fatal hemorrhage (with or without ischemic strokes) in 5, disabling polyradiculoneuropathy in 1, and nonspecific neurologic symptoms without objective findings in 4. Other pathology included strokes, headaches, epilepsy, or generalized neurologic symptoms (for example memory loss and/or altered sensation).

Ophthamologic findings include diplopia, ptosis, blindness and visual-field defects. In addition, posterior subcapsular cataracts, third cranial nerve palsies, blepharoptosis, and optic atrophy can be associated with DD. Optical neuritis, papilledema, and scleral plaques have occurred in DD patients Another series noted ophthalmologic pathology occurred in 35 of 105 extant reports of DD. The sclera, the episclera, the retina, the choroid, the optic nerve, and/or the neuro-ophthalmologic apparatus in this series of 105 patients had eye damage consistent with DD.

Pulmonary symptoms include shortness of breath, wheezing, pleural pathology, chest pain, bilateral pleural effusion. DD can likely be related to the development of pulmonary hypertension.

Cardiac issues include heart failure and pericardial and endocardial pathology. Specific findings include constrictive pericarditis, perhaps related to pericardial vasculitis, and perhaps causing a left ventricular heart wall motion abnormality.

Vasculitis has been noted in patients with DD.

The liver and the kidneys may show the pathology of DD with the associated DD-type vascular changes.

Treatment Options

Until recently there were no effective treatment options for DD. Immunosuppressive treatments are the mainstays of dermatologic therapy, but as DD is not a disease of immunity, these treatments, including immunoglobulin, have minimal effect on DD. Some have suggested that aspirin or dipyridamole can help reduce or abate the papules of DD, but this is antecdotal and this regimen has no affect on systemic DD/ MAP.

Eculizumab, which is FDA approved for PNH, has been reported to have abated systemic DD/MAP in 3 patients who took this medication and remain on the drug. While this series is antecdotal it is of tremendous promise. The effectiveness of eculizumab suggests that DD might not be a collagen-vascular disease, but instead is an endothelial, hematologic or complement-mediated disease. Eculizumab is extremely expensive, thereby complicating its use. It might be possible that eculizumab could be obtained on a compassionate-use basis. The optimal dosing for eculizumab needs to be defined. Just as eculizumab does not work for every case of PNH it might not work for every case of MAP.

Eculizumab is a complex medication and should not be used in patients with limited/purely cutaneous/benign DD (ie, BAP).

Optimal Therapeutic Approach for this Disease

In the one series noting 3 patients who used eculizumab, eculizumab worked immediately and was life saving with continued use.

Patient Management

The key question that must be answered with patients is whether the patient has benign/limited/purely cutaneous DD/BAP or systemic/malignant DD/MAP. A patient with skin findings of DD and a skin biopsy suggesting DD should be queried for abdominal pain or neurologic findings. A stool guaiac should be done. If no findings or blood are present, the patient should be monitored. If there are abdominal findings, a diagnostic laparotomy can be done. If neurologic symptoms are present an MRI can be considered. If other internal pathology is suggested it should be investigated with appropriate testing of the involved organ system. If a diagnosis of MAP is made treatment options can be explored.

Unusual Clinical Scenarios to Consider in Patient Management

As DD is rare, all scenarios are unique.

What is the Evidence?

Scheinfeld, N. "Degos' disease is probably a distinct entity: a review of clinical and laboratory evidence". J Am Acad Dermatol. vol. 52. 2005. pp. 375-6.

(A short summary of why DD is a distinct entity and not just a variant of lupus. The content of this letter has been confirmed by the findings of Magro's article, which is discussed below.)

Scheinfeld, N. "Pairing and comparing nine diseases with Degos Disease (Malignant Atrophic Papulosis): an attempt to illustrate our understanding and direct future inquiry". Dermatol Online J. vol. 15. 2009. pp. 10.

(A discussion of how DD differs from other dermatologic entities.)

Scheinfeld, N. "Malignant atrophic papulosis". Clin Exp Dermatol. vol. 32. 2007. pp. 483-7.

(A thorough review of the clinical findings, variants and course of DD.)

Magro, CM, Poe, JC, Kim, C, Shapiro, L, Nuovo, G, Crow, MK. "Degos disease: a C5b-9/interferon-α-mediated endotheliopathy syndrome". Am J Clin Pathol. vol. 135. 2011. pp. 599-610.

(The most important basic research article ever published on DD. It provides a basis for understanding DD as a hematologic disease. It also notes the use of eculizumab for the first time in the peer review literature, which itself makes it a most notable work.)

Magro, C, Shapiro, L, Johnson, B, Salmon, J, Whelan, P. "Degos disease". Rheumatology grand rounds, Hospital for Special Surgery. Feb 10, 2010.

(While the text of this meeting is not available, this meeting noted three cases of systemic DD abated with eculizumab. This report is extremely promising and publication of this data is anticipated.)
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