Kohlmeier Degos disease I77.8

Köhlmeier-Degos disease, also known as "papulosis maligna atrophicans", is a rare, thrombo-obliterative microangiopathy, of unknown etiology, affecting the skin, gastrointestinal tract, central nervous system and, less commonly, other organs (kidney, heart, eyes). Dermatologically, disseminated satin red, flat papules, are characterized by their bizarre, central, spatter-like, "porcelain white" sunken atrophic zones and a surrounding telangiectatic rim. This clinical morphology, although not unique, is nonetheless characteristic and pathognomonic of the clinical picture. In this respect, the dermatologist, knowing this constellation, has the special task of an early clinical (diagnostic and therapeutic) course setting.

The following classification has emerged for this clinical picture:

• sporadic, systemic (malignant) KDK (60%)
• hereditary, autosomal dominant (mostly benign) KDK (8%)
• benign monoorganic cutaneous KDK (40%)
• (?) monoorganic or polyorganic KDK without cutaneous involvement (so far not described disease)

Although "atrophic papulosis" was first described by the Viennese pathologist Walter Kund in 1941 and by the Parisian dermatologist Robert Degos in 1942, the etiology and pathogenesis of the disease remain unclear. There is clear evidence (for a proportion <10% relative to the total collketive) of a genetic predisposition based on reports in family members, sometimes over several generations. First-degree family members are more frequently affected, suggesting an autosomal dominant mode of inheritance (Katz SK et al 1997).

Apart from a genetic predisposition, there are several main hypotheses for the etiology of the disease: vasculitis, coagulopathy, a primary endothelial cell dysfunction, an interferonopathy (nonsense mutation in the IFNAR1 gene/Becker et al.2022). Recently, the proximity to systemic lupus erythematosus is discussed by the detection of antiphospholipid antibodies.

Several theories exist for the pathogenesis of KDK:

• Vasculitis
• Coagulopathy
• primary dysfunction of endothelial cells
• Interferonopathy (gain-of-function mutation in the interferon-alpha/beta receptor subunit of IFNAR1).

Vasculopathy: Su et al described"lymphocyte-associated necrotic vasculitis" as the dominant cutaneous feature of skin lesions (Su WP et al 1985). Magro et al.(2011) discovered pathological deposits of C5b-9 in the skin, gastrointestinal tract and cerebral vasculature in some patients with atrophic papulosis. In addition, all patients with high C5b-9 deposits had high expression of interferon alpha, endothelial tubuloreticular inclusions, and an interferon gene signature in peripheral blood mononuclear cells.

Coagulopathy: Other authors observed fibrinolytic dysfunction in individual patients. They considered thrombosis in the deep reticular dermis as the precipitating event (Páramo JA et al 1985). The resulting ischemia leads to endothelial cell damage, resulting in mucin deposition and mononuclear cell aggregation. Tribble et al (1986) found abnormal swelling and proliferation of the vascular endothelium with thrombosis in skin, the gastrointestinal tract, and the central nervous system. In addition, increased plasminogen activator inhibitor-1 activity resulted in decreased serum plasminogen levels. A sustained increase in thrombin-antithrombin III and plasmin-a-2 plasmin inhibitor complexes also suggests coagulopathy as a possible pathogenetic primary.

Microbial infections: Furthermore, viral or bacterial infections could be the origin of the endothelial cell changes, a concept supported by the discovery of intracytoplasmic paramyxovirus-like inclusions on the electron microscope in skin lesions of patients with atrophic papulosis (Howard RO et al (1969). However, there is no polymerase chain reaction detection of paramyxovirus DNA in biopsy specimens.

Genetic predisposition: Familial clustering of cases, sometimes over several generations, suggests a genetic predisposition for a proportion of cases. First-degree family members are more frequently affected, suggesting an autosomal dominant mode of inheritance (Katz SK et al 1997). An association of Köhlmeier-Degos disease with a factor V Leiden mutation was reported in an older report (Darwich E et al. 2011).

Interferonopathy: This suggestion is based in Köhlmeier-Degos disease on evidence of a gain-of-function mutation in the interferon-alpha/beta receptor subunit of IFNAR1. This mutant leads to overactivation of the interferon signaling pathway. It is suspected that this may result in a systemic inflammatory response and cause organ damage (Becker et al.2022).

Occurrence is possible at any age. Peak of manifestation 20-50 years of age . (Mean value from a larger study: 33.3 years). However, the disease can occur at any age. Children and adolescents may also be affected. Single case reports of atrophic papulosis in neonates are available (Vicktor C et al. 2001). It appears that the female sex slightly predominates (1.6/1.0) (Kaleta KP et al. 2022).

There are also single case reports of the occurrence of KDK in newborns (Vicktor C et al. 2001).

Occurring mainly on the middle trunk. But also on the extremities. Occasionally, the hands may also be affected.

The cutaneous lesions usually occur in disseminated episodes. They initially appear as small (2.0 to max. 5.0 mm), moderately painful, roundish but also elongated, saturated red papules on the trunk or extremities. Rarely, the palms, soles, scalp, and face are affected. Isomorphic irritant phenomena are absent, as are systematized arrangements. Over 2 to 4 weeks, the center of the lesion thickens while the papules continue to enlarge (0.5 to 1.0 cm); the central areas pale to a whitish color and are markedly sunken. The atrophic sunken center is described as "porcelain white." It is surrounded by a dark red rim about 1 mm wide.

Internal symptoms: Gastrointestinal symptoms are predominant. About 75% of gastrointestinal K-D occur together with other systemic manifestations. Of these, CNS involvement is most common (40%). Synchronous neurologic and gastrointestinal symptoms or gastrointestinal manifestations preceding neurologic symptoms are common patterns. In rare cases, neurologic symptoms develop before gastrointestinal ones.

Other systemic manifestations observed with gastrointestinal K-D occur in pleura (25%), pericardium (15%), kidney (nephrotic syndrome/12%), and eye (8%). Multiple organ involvement is the rule.

Associated diseases: K-D may coexist with dermatomyositis, systemic lupus erythematosus, antiphospholipid antibody syndrome , and systemic sclerosis (Jang MS et al. 2017, Pukhalskaya T et al. 2021).

Specific parameters for target-oriented diagnostics are not known! Possible detection of paraproteinemia, anemia or phospholipid antibodies. Inflammatory parameters are clearly elevated (ESR; CRP).

• The lesions initially show a superficial and deep perivascular lymphocytic infiltrate with mucin deposits and subsequently a focal necrosis (necrobiosis) of the dermis due to ischemia. Early thromboembolic occlusions occur at the base of the lesion (Harvell JD et al 2001). The overlying epidermis shows vacuolated degeneration; it is usually atrophic and slightly hyperkeratotic. Sclerosis can often be observed in the dermis in later lesions. Early lesions may resemble lupus erythematosus.
• Immunohistology: Granular IgM deposits are occasionally detectable in early lesions (Pukhalskaya T et al 2021).

• Fine tissue findings of gastrointestinal KDK: Evidence of obliterative intimal arteriopathy leading to occlusive acellular deposition of mucin and collagen and extravascular paucicellular sclerosis resembling (systemic) scleroderma and confined to subserosal adipose tissue. Both C5b-9 and interferon-alpha are expressed in all vascular calibers of the affected gut (Sattler SS et al. 2022; Magro CM et al. 2011). Evidence of an interferon gene signature in peripheral blood mononuclear cells.

• Fine tissue findings of CNS lesions: autopsy studies, demonstrate an obstructive vasculopathy of small and medium vessels with varying degrees of inflammation, sparing the tunica media (Sindhu DM et al. 2021).

For the diagnosis, multidisciplinary cooperation is necessary.

Until now, the diagnosis has always been based on the pathognomonic skin lesions. These require histopathological confirmation.

Important: There are no laboratory abnormalities or serum markers specific for the identification of atrophic papulosis. However, many patients present with blood coagulation disorders (Theodoridis A et al. (2013), individual antibody constellations(antiphospholipid antibodies).

If there is a (obvious) suspicion of organ symptomatology, the investigation focuses on the affected organ. If gastrointestinal involvement is suspected, fecal occult blood tests and endoscopic procedures are required, including laparoscopy in case of doubt.

Magnetic resonance imaging of the brain with contrast, cardiac ultrasonography, thoracic computed tomography with contrast, ocular fundus examination, and renal function tests are required for possible central nervous system, cardiac, respiratory, ocular, and renal involvement, respectively (Rice AS et al. 2023).

leukocytoclastic vasculitis: relapsing and acute course, histology is diagnostic

Papulonecrotic tuberculid: Up to pea-sized, blue-red, centrally softening and necrotizing nodules. Formation of varioliform scars or shallow ulcerations (ulcerative tuberculids) after shedding of the central eschar. Histology is diagnostic.

Lupus erythematosus, systemic: laboratory evidence with positive ANA or DNA acc.

extragenenital lichen sclerosus et atrophicus. In this case, any signs of systemic involvement are absent. White patches and papules. No central splashy scars.

Small-spotted form of circumscritic scleroderma: here any signs of systemic involvement are absent. White patches and papules. No central splashy scars.

Thrombangiitis obliterans: Inflammatory, relapsing, non-atherosclerotic (autoimmunologic?), multilocular, segmental, usually obliterating panarteritis of small and medium-sized arteries and veins, affecting mainly young male smokers. The disease may be diagnosed if the clinical manifestations began before the age of 40, the distal arteries (lower leg, hand-foot) are selectively affected and thrombophlebitis saltans is present. These localizations are not found in Köhlmeier-Degos disease.

So far no specific (and therefore effective) therapy is known. Cooperation with doctors of other specialties according to the clinic. The skin findings usually serve as a diagnostic criterion.

There is no proven effective treatment for atrophic papulosis.

Anticoagulant and circulatory drugs such as acetylsalicylic acid, pentoxifylline, dipyridamole, ticlopidine, and heparin have had positive effects in isolated cases. Therefore, they can be considered an appropriate first-line therapy in newly diagnosed patients.

Immunosuppressive therapies with cyclosporine A, azathioprine, cyclophosphamide, or corticosteroids have not been very promising (Theodoridis A et al. 2013).

Glucocorticosteroids: Their efficacy is controversial (possibly increased rate of intestinal perforations).

Eculizumab, which binds to the C5 protein of the complement system and thus blocks the so-called terminal activation, reduces the deposition of the C5b-9 membrane attack complex. The medication was able to improve the initial skin and intestinal lesions in individual cases (Sathiyaraj A et al. 2020). However, progression of KDK was not prevented.

Treprostinil, a stable tricyclic analog of prostacyclin, was successful in one case of eculizumab-resistant malignant atrophic papulosis with intestinal and cerebral manifestations.Trials with the anti-C5 monoclonal antibody eculizumab and the prostaglandin analog trepostinil proved successful in single cases.

Anifrolumab: An individual positive therapeutic trial with the IFNAR1 antibody anifrolumab has been reported (Becker LL et al. 2022).

In a single center cohort study of 39 patients, the probability of developing the benign cutaneous form of the disease was found to be 70%. The probability of benign disease increased to 97% if the disease occurred only on the skin for 7 years. None of the patients with cutaneous limited disease had a fatal outcome. In contrast, the overall mortality for systemic disease was 21%, with a median survival of 0 to 9 years (Theodoridis A et al. 2014). This result differs from a 1989 literature review of 109 patients, which estimated an overall mortality of 48.1% with a median survival of less than five years (Burg G et al. 1989).

Instead of the name "malignant atrophic papulosis" (chosen by R. Degos), the names "atrophic papulosis" or "Köhlmeier-Degos disease" are now favored as more precise and comprehensive disease names.

History: A 31-year-old man presented with a 6-month history of an asymptomatic rash on the limbs and trunk . It consisted of multiple atrophic white scars surrounded by a slightly raised erythematous telangiectatic rim. Otherwise, he was healthy and in good condition. He had no significant medical or family history and was not taking any medications. Physical examination was otherwise without pathologic findings. Mucous membranes were O.K. A neurological examination was also O.K.

Laboratory: presence of a lupus anticoagulant; evidence of a mutation in the factor V gene (factor V Leiden). Basic coagulation parameters (prothrombin time, activated partial thromboplastin time, D-dimer, anti-thrombin, plasma fibrinogen, and platelets) were within the normal range. The following investigations showed normal or negative findings: complete blood count, electrolytes, liver and kidney function tests, glucose, C-reactive protein, antinuclear antibodies, rheumatoid factor, Wassermann reaction, N-terminal procollagen propeptide, serum immunoglobulins, chest X-ray, CT of the brain and ultrasound of the abdomen.

Therapy: Narrow band UV-B therapy without any effect. The patient was treated with 15 mg prednisolone per day after unsuccessful UV therapy. 7 days later, he was hospitalized with acute abdomen. Intraoperatively, a small perforation of the small intestine was noted. The affected part of the small intestine was resected. The patient recovered quickly from surgery and treatment was changed to aspirin 100 mg daily, pentoxifylline 400 mg three times daily, and warfarin. He was well for 6 months after surgery. The rash remained stable except for the development of ulcerating papules on the penis. He then began to complain of fatigue and lost 15 kg of weight over a 2-month period. He was operated on again for acute adomen. Intraoperatively, it was found that the entire intestine, especially the small intestine, was affected. Due to perforation of the appendix, ileo caecum resection was performed.

Histo: Histological examination of intestinal sections showed full-thickness ischemic necrosis of the small bowel wall with dilatation of several layers of the vessel walls, and small thrombotic occlusions were noted in a few vessels.

Course: A few days later, increasing abdominal pain and signs of septicemia appeared, and another operation revealed a new perforation of the small intestine. The patient's condition deteriorated rapidly, and a second operation revealed massive ischemic changes in both the colon and small intestine, together with peritonitis and extensive vasculitic elements. Further therapeutic measures were unsuccessful, and the patient died after 24 hours.

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