WITHDRAWN: ACRALLY DISTRIBUTED DERMATOSES Vascular dermatoses (purpura and vasculitis)

WITHDRAWN: ACRALLY DISTRIBUTED DERMATOSES Vascular dermatoses (purpura and vasculitis)

    TEMPORARY REMOVAL: ACRALLY DISTRIBUTED DERMATOSES Vascular dermatoses (purpura and vasculitis) Jana Kazandjieva MD, PhD, Dimitar Anto...

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    TEMPORARY REMOVAL: ACRALLY DISTRIBUTED DERMATOSES Vascular dermatoses (purpura and vasculitis) Jana Kazandjieva MD, PhD, Dimitar Antonov MD, Jivko Kamarashev MD, Nikolay Tsankov MD, PhD PII: DOI: Reference:

S0738-081X(16)30229-2 doi: 10.1016/j.clindermatol.2016.09.010 CID 7095

To appear in:

Clinics in Dermatology

Please cite this article as: Kazandjieva Jana, Antonov Dimitar, Kamarashev Jivko, Tsankov Nikolay, TEMPORARY REMOVAL: ACRALLY DISTRIBUTED DERMATOSES Vascular dermatoses (purpura and vasculitis), Clinics in Dermatology (2016), doi: 10.1016/j.clindermatol.2016.09.010

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ACRALLY DISTRIBUTED DERMATOSES

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Vascular dermatoses (purpura and vasculitis)

Department of Dermatology and Venereology, Medical University Sofia, Sofia, Bulgaria 2 3 4

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Jana Kazandjieva1,MD, PhD Dimitar Antonov2,MD Jivko Kamarashev3, MD Nikolay Tsankov4 MD, PhD

Department of Dermatology, University Hospital Jena, Jena, Germany

Department of Dermatology, University Hospital Zurich, Zurich, Switzerland

Department of Dermatology and Venereology, Tokuda Hospital Sofia, Sofia, Bulgaria

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Abstract

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[email protected]>

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Purpuric lesions appear in acral distriburion in a variety of conditions and often provide clues to the clinical diagnosis. Purpuric means hemorrhagic, i.e. the lesions do not blanche from pressure. This review focuses on dermatoses which produce hemorrhagic lesions in acral distribution from the large groups of the vasculitic diseases and their mimics. Cutaneous small vessel vasculitis is confined to the skin, involves mainly postcapillary venules, and has the hallmark manifestation of palpable purpura. Henoch-Schönlein purpura (HSP) is an immune complex mediated systemic vasculitis of the small vessels with manifestations from the skin, joints, kidneys and the gastrointestinal system. Only cases where the immune complexes contain IgA type are classified as HSP. Cryoglobulinemic vasculitis is induced by the deposition of cold-precipitated immune complexes in the small vessels. Urticarial vasculitis comprises a spectrum of conditions with the characteristic course of chronic urticaria, with wheals that persist longer than 24 hours, leave hyperpigmentation, and show leukocytoclastic vasculitits on histology. Polyarteritis nodosa is a rare multisystem, segmential necrotizing vasculitis of mainly the medium sized vessels.

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Pigmented purpuric dermatoses (PPDs) are chronic benign dermatoses characterized by petechiae, purpura, and increased skin pigmentation. The hallmark of PPDs is their orange-brown, speckled, cayenne pepper–like discoloration.

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Keywords

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Purpura, acrally distributed dermatoses, pigmented purpuric dermatoses

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Introduction and Classification

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Purpuric lesions appear in acral distribution in a variety of conditions and often provide clues to the clinical diagnosis. This review focuses on dermatoses, which produce hemorrhagic lesions in acral distribution from the large groups of the vasculitic diseases and their mimics.

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Purpuric means hemorrhagic, i.e. the lesions do not blanche from pressure. Table 1 presents the conditions usually showing acral distribution, which are subject of this review. The classification of vasculitis is a controversial matter, as these nosologic entities show many overlapping features and there are different classification and diagnostic criteria. We have used the revised Chapel Hill Consensus nomenclature together with the established eponyms 1,2 and the classification is adjusted to the needs of this chapter.

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Table 1. Vasculitis and vascular dermatoses with acral distribution.

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Immune-complex small-vessel vasculitis Cutaneous small vessel vasculitis

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Henoch-Schönlein purpura (IgA Vasculitis) Cryoglobulinemic vasculitis

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Urticarial Vasculitis Other small vessel vasculitis Collagen vascular disease associated vasculitis Septic vasculitis ANCA small vessel vasculitis ANCA Vasculitis Microscopic polyangiitis Granulomatosis with polyangiitis (Wegener’s granulomatosis) Eosinophilic granulomatosis with polyangiitis (Churg Strauss) Medium vessel vasculitis Polyarteritis nodosa (PAN)

ACCEPTED MANUSCRIPT Important vasculitis mimics (pseudovasculitis) Purpura fulminans

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embolic conditions (including septic emboli, left atrial myxoma, cholesterol emboli), endothelial and rickettsial infections, ecthyma gangrenosum.

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Lymphocytic vasculitis (pigment purpura such as lichen aureus, Schamberg’s disease)

Cutaneous small vessel vasculitis (CSVV)

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Synonyms: hypersensitivity vasculitis/angiitis, cutaneous necrotizing vasculitis, necrotizing venulitis, IgA negative small vessel vasculitis3,4. This condition is the most common type of vasculitis in the dermatological practice. It is confined to the skin, involves mainly postcapillary venules, and has the hallmark manifestation of palpable purpura.

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In many patients the condition is associated with an offending drug (most commonly antibiotics and NSAIDs) or infection, such as upper respiratory tract infection of viral or bacterial origin, streptococcal infection, viral hepatitis, and others.

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CSVV lesions usually appear in crops. The most typical are the palpable purpuric lesions, which may be flat at the onset. They are of various sizes, from pinpoint to a few millimeters in diameter. Initially, the lesions might be urticarial or like a maculopapular eruption. With progression, they tend to coalesce and form large plaques. They quickly become partially or completely haemorrhagic and do not blanche with pressure. In their evolution there may be necrosis with formation of necrotic vesicles and bullae, and ulceration, usually shallow. The lower aspects of the legs are mainly affected, as well as dependent areas and areas under pressure, including acral areas such as the fingers and the toes. (Figures 1 to 4). The eruption may spread to the buttocks and arms, rarely to the trunk. The intertriginous areas are typically spared, and mucous membranes are rarely involved. The appearance of lesions may be associated with pruritus and burning, as well as with systemic symptoms such as fever, malaise, synovitis, myalgia, or abdominal pain 3,4. The presence of signs of systemic vasculitis precludes the diagnosis of CSVV which by definition should be limited to the skin. The course of CSVV is self-limiting, but in a small proportion of patients it may recur or become remittent. Lesions generally resolve within a few weeks, leaving postlesional hyperpigmentation or atrophic scars at the sites of ulceration.

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The major histologic features are segmental areas of transmural neutrophilic infiltration with karyorrhexis (leukocytoclasia), fibrinoid necrosis, and extravasation of erythrocytes. Direct immunofluorescence (DIF) from fresh lesions may reveal perivascular depositions of IgM and C3. Finding IgA immune complexes means the condition should be classified as HenochSchönlein purpura5.

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There may be an elevated erythrocyte sedimentation rate (ESR) and/or CRP, usually without hypocomplementemia. Thrombocytopenia and ANCA antibodies must be ruled out. Urinalysis and other appropriate tests must be undertaken to exclude systemic vasculitis (especially as an association with autoimmune connective tissue disease, dysproteinemias, or neoplasms) and to search for etiologic factors.

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The diagnosis of CSVV is one of exclusion; systemic involvement must be ruled out by careful history and appropriate tests. The presence of systemic manifestations means the condition could be an initial phase of HenochSchönlein purpura, microscopic polyangiitis, polyarrteriitis nodosa, or Wegener’s granulomatosis. CSVV is a single organ vasculitis and should be distinguished from a limited form of systemic vasculitis which may further progress to a full blown systemic disease 2. Such distinction can only be done retrospectively, after no progression has been observed over time, A period of 6 months follow up with no progression has been suggested 2.

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Purpuric lesions, sometimes palpable, may be seen in non-vasculitic disorders, such as thrombocytopenic purpura (very rarely palpable lesions), drug eruptions with thrombocytopenia, disseminated intravascular coagulation (DIC) with purpura fulminans, embolic conditions (including septic emboli, left atrial myxoma, cholesterol emboli), and some infections where the endothelial cells of the small vessels become infected such as Rickettsia infections (e.g. Rocky Mountain spotted feber). The inducing agent should be removed or treated, if identified. Supportive care, including rest, leg elevation, and warmth may suffice for mild cases. Antihistamines and NSAIDS may provide symptomatic relief. For more extensive disease, systemic corticosteroids are indicated, with other options being colchicine or dapsone. Alternatively, azathioprine, methotrexate, or cyclophosphamide may be used, usually in combination with oral corticosteroids.

Henoch-Schönlein purpura (HSP) Synonyms: IgA Vasculitis, Schönlein-Henoch purpura, anaphylactoid purpura 2,3 .

ACCEPTED MANUSCRIPT HSP is an immune complex mediated systemic vasculitis of the small vessels, affecting mainly children, but also adults, with manifestations from the skin, joints, kidneys and the gastrointestinal system. Only cases where the immune complexes contain IgA type are classified as HSP.

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HSP is the most common vasculitis in childhood with more than 50% of all cases occurring before the age of 5years6. Other authors report an incidence in adults much higher than expected7.

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HSP frequently follows an upper respiratory tract infection, especially one with group A streptococci. Hence the seasonal variation in incidence with most cases occurring in the period between January and March.The latency period is 1-3 weeks. Medicinal products are less frequently associated with HSP. IgA is considered central for the pathogenesis. Aberrant glycosilation of IgA1 hinders its clearance by the liver and facilitates the accumulation of IgA1 and IgA1 containing immune complexes. HSP is very rarely associated with malignancy and in many studies patients with neoplasias were excluded.

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HSP usually has an acute onset. The most common initial manifestations are an eruption, arthralgia, and colicky-type abdominal pain. While the cutaneous manifestations are always present, not all of the rest of target organs: joints, the kidneys and the gastrointestinal tract, may be involved. The skin manifestations start as small erythematous macules and edematous papules dispersed mainly on the exterior aspects of legs and to lesser extent arms that usually become hemorrhagic (palpable purpura) and fade for 3 to 10 days 3,4,6. Such lesions appear in “crops” and may extend proximally to the buttocks and the trunk, the clinical presentation on the skin is very similar to the CSVV. The spread of lesions above the waist bears the prognosis of heavier kidney involvement 3. Additional such indicators are the presence of fever and elevated ESR. Other cutaneous signs might be urticarial, erythematous, or angioedematous lesions. In evolution there might be vesicular and bullous lesions and formation of necrotic ulcers. The joint manifestations are usually arthralgias and/or arthritis, with edema most frequently of the knees and ankles, resolving without sequele. From the gastrointestinal system, there might be abdominal pain, nausea, vomiting, diarrhea (eventually constipation) with mucus and blood in the stools. The gastrointestinal manifestations may start later in the disease course. The kidney involvement is usually mild glomerulonephritis manifesting with mild proteinuria, microscopic hematuria, and erythrocyte cell casts in the sediment. The glomerulonephritis is self-limiting, but in some cases the disease may recur. In 1-5% of patients it may be progressive and lead to end-stage renal disease which is more common in adults. Other manifestations may be scrotal edema and orchitis. In patients with IgA gammopathy there may be middle-vessel involvement.

ACCEPTED MANUSCRIPT Histology shows small-vessel necrotizing vasculitis as in CSVV. DIF reveals deposition of IgA and C3. The laboratory studies are nonspecific. An elevated ESR is considered a prognostic factor for kidney involvement. Serum IgA might be elevated.

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Differential diagnosis may be made with CSVV and the other systemic vasculitis. As the diagnosis of HSP is reserved to IgA-mediated vasculitis only, demonstration of IgA depositions may be useful to differentiate HSP from other vasculitis. , in many cases, especially in children, the diagnosis can be made only clinically without DIF.

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In most cases, symptomatic and supportive care is sufficient8; patients should be monitored for systemic complications which usually occur within 4 weeks after disease onset. In cases with more severe systemic or renal involvement corticosteroids are indicated, although there is no evidence that they have any effect on purpura, disease duration or likelihood of recurrences 3. They do not prevent progressive disease 6. Crescentic nephritis is treated aggressively with high doses corticosteroids, alone or combined with immunosuppressants; alternatives include high doses IVIG. Anecdotal evidence suggests that dapsone may shorten the disease duration.

Cryoglobulinemic vasculitis

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This is a vasculitis induced by the deposition of cold-precipitated immune complexes in the small vessels (usually in type II and II cryoglobulinemia).

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Chronic HCV infection is the major etiologic factor for mixed cryoglobulinemia, but other infections, including HIV, and connective tissue diseases are also associated, such as systemic lupus erythematosus, Sjögren’s syndrome, systemic sclerosis, rheumatoid arthritis. Lymphoproliferative disorders and hematologic malignancies may also cause mixed cryoglobulinemia. Type II cryoglobulins (monoclonal IgM directed against IgG) and type III cryoglobulins (polyclonal IgM against IgG) are grouped together as mixed cryoglobulins. They are present in the body as immune complexes and their deposition in blood vessels leads to complement activation and systemic vasculitis3. It is usually manifested with palpable purpura and hemorrhages, urticarial lesions, arthralgias, and malaise. The lesions are cold-induced and have mainly acral distribution and on the lower extremities. The acral involvement might include a widespread hemorrhagic necrosis and gangrene. A contact to cold objects, cold weather or even sudden changes in temperature such as in spring may trigger the precipitation. Peripheral neuropathy and renal involvement, such as nephritic syndrome or membranoproliferative glomerulonephritis, are also common. Type I ceryoglobulinemia (monoclonal immunoglobulins and light chains, without rheumatoid factor activity, usually

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associated with malignant hematologic disease) induces less-pronounced inflammation with vascular occlusion being the leading pathogenic factor. Livedo reticularis, cutaneous necrosis and gangrene, Raynaud’s phenomenon and cold-induced acrocyanosis (refered to as pseudo Raynaud phenomenon, because the phase changes are lacking, but pain and even acral ulceration may occur) are more common with type I cryoglobulinemia but may be present together with the vasculitis symptoms in the mixed cryoglobulinemias. It is questionable if the type I cryoglobulinemia may induce true vasculitis beyond vasculopathy4. Diagnostic cirteria for cryoglobulinemic vasculitis has been proposed9.

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In mixed cryoglobulinemia, the histology reveals necrotizing leukocytoclastic vasculitis affecting vessels from dermis to subcutaneous fat. In type I cryoglobulinemia – an occlusion of vessels with eosinophylic precipitates. These precipitates are distinguished from fibrin with periodic acid – Schiff reaction.

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The treatment is directed at the underlying primary disease. Recognizing the underlying condition is very important, but there are idiopathic (i.e. essential) forms as well. Supportive and symptomatic measures as well as antiinflammatory treatment are recommended. Plasmapheresis is useful to deplete immunoglobulins. Rituximab is reported to be effective in mixed cryoglobulinemia.

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Urticarial Vasculitis (UV)

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UV comprises a spectrum of conditions with the characteristic course of chronic urticaria, with wheals that persist longer than 24 hours, leave hyperpigmentation, and show leukocytoclastic vasculitits on histology.

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UV is strongly associated with connective tissue diseases, such as Sjögren’s syndrome, SLE and others3,4. Other associations and etiologies include serum sickness, infections (such as HCV, HBV and others), drugs, physical urticaria to cold, light, malignancies such as hematologic malignancies and colon cancer, gammopathies and others. UV is considered an immune-complex mediated type III hypersensitivity reaction like serum sickness3. It is divided into normo- and hypocomplementemic (NUV and HUV), NUV being more common. UV comprises a spectrum of conditions. On one end of the spectrum are skin-limited NUV cases, followed by HUV with systemic involvement, and on the other end of the spectrum are cases that fulfill the diagnostic criteria for SLE. Corresponding to this distribution is the gender difference. While in NUV there is a slight female predominance, the patients with HUV are almost exclusively women.

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The urticarial wheals are located mainly on the trunk and proximal extremities. They are edematous, raised and with symptoms of burning and tenderness rather than itching. The lesions look exactly as the wheals of urticarial but are distinguished from it in that they persist longer than 24 hours and change shape slowly, may contain visible purpuric areas or may reveal purpura on blanching, and resolve with more or less pronounced hyperpigmentation. Angioedema may be present. Systemic symptoms such as arthralgias and joint swelling, fever, abdominal pain, diarrhea, vomiting and dyspnea occur more often with HUV3, 10 While NUV is usually confined to the skin9, systemic involvement with glomerulonephritis, ocular manifestation (iritis, episleritis, uveitis), lymphadenopathy and bronchospasms or obstructive pulmonary disease may be present in patients with HUV. The course of the disease is unpredictable, usually chronic with recurrent episodes of urticarial eruptions.

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The diagnosis of UV requires a histological confirmation or the detection of C1q antibodies in serum. Fresh lesions are needed for biopsy and sometimes biopsies on a couple of recurrences are needed to prove the diagnosis. Histology reveals interstitial and perivascular neutrophilic infiltrates. The signs of vascular injury and leukocytoclasia are usually mild.

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ESR is often raised. In the HUV syndrome there are additionally anti-C1q antibodies. In HUV, the hypocomploementemic UV, the hypocomplementemia may not always be evident. ANA and other lupus serology may be positive. Some patients may have microhematuria and proteinuria.

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In the differential diagnosis chronic urticaria, serum sickness, and other vasculititdes should be excluded. Diseases known to be associated with UV must be sought for.

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Milder cases may be self-lmited. H1 and H2 blockers are helpful in the treatment of UV, as well as NSAIDs. Corticosteroids are effective, but given the recurrent course of UV, other medications, such as colchicine, hydroxychloroquine and dapsone, should be included to reduce corticosteroid usage and side effects. Mycophenolate mofetil and cytotoxic agents may also be used.

Collagen vascular disease associated vasculitis Vasculitic changes can be found in patients with autoimmune diseases such as systemic lupus erythematosus (SLE), Sjögren’s syndrome, rheumatoid arthritis, systemic scleroderma, CREST and others 3,4,11. In SLE vessels of any size can be affected by vasculitits, but small-sized vessels predominate. Lesions usually include palpable purpura, urticaria, digital microinfarcts. Splinter hemorrages represent longitudinal purpura of the nail bed and may result from the digital microinfarcts; however, the splinter hemorrhages

ACCEPTED MANUSCRIPT are generally very unspecific and seen in a variety of benign dermatologic conditions or trauma and are of limited diagnostic value.

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The systemic vasculitis associated with connective tissue diseases may be severe. In Sjögren’s syndrome large and small vessels can be affected too. The cutaneous lesions may be palpable purpura, urticaria, and hemorrhages on the lower extremities, Raynaud’s phenomenon and erythematous nodules. In rheumatoid arthritis usually patients with advanced disease and high rheumatoid factor develop vasculitis. The skin and peripheral nerves (as mononeuritis multiplex) are typically involved. Skin lesions include nailfold infarctions, purpura, livedo reticularis and livedo racemosa, nodules and ulcers.

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Eosinophilic vasculitis has been distinguished from Churg Strauss Syndrome and other eosinophilic conditions12. The patients develop recurrent itching papules and wheels as well as angioedema. Hypocomplementemia and an association with rheumatoid arthritis and collagenoses are common.

Septic vasculitis

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Within both the clinical and histopathologic manifestations of sepsis and bacteriemia, true immune complex vasculitis may be present 9,13. It usually accompanies the predominant pathogenetic process of vascular injury due mainly to thrombosis, coagulopathy and/or embolisation. It nevertheless obscures the situation where a choice should be made to apply broad spectrum antibiotics or corticosteroids. Clinically, there could be palpable purpura or hemorrhagic nodules with rapid deterioration of the patient’s general condition. Pustules might develop within the hemorrhagic lesions and the causative microorganisms may sometimes be isolated from the skin lesions. The skin manifestations may progress to purpura fulminans. Histologically, there is neutrophilic vasculitis with scant or missing nuclear debris. The small and medium sized as well as the superficial and deep vessels of the dermis and subcutis are involved. Additionally, perivascular fibrin and fibrin thrombi are observed 12. Blood cultures should be obtained in such patients and the clinicians should be on alert for signs of sepsis including fever attacks, blood pressure fall, tachycardia and somnolence.

ANCA Vasculitis This is a group of ANCA antibodies associated vasculitis which are characterized with scant or no detectable deposits of antibodies or complement in the vessels on direct immunofluorescence, hence “pauci-immune”1,3.

Microscopic Poliangiitis (MPA) This is a systemic necrotizing vasculitis of predominantly small vessels, but small and medium arteritis may also be affected 1.

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In contrast to classical pan arteritis nodosa, in MPA there are often pulmonary symptoms and necrotizing glomerulonephritis. p-ANCA are considered to play a role in its pathogenesis. The inflammation is focused on the blood vessels without granuloma formation; there is no tissue or blood eosinophilia 10. Skin involvement is reported in up to 65% of patients and consists of mostly palpable purpura similar to the clinical picture of small vessel cutaneous vasculitis and Henoch-Schönlein purpura, but livedo and nodules are also reported 10.

Granulomatous vasculitis

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Granulomatosis with polyangiitis (Wegener’s granulomatosis) and eosinophilic granulomatosis with polyangiitis (Churg-Strauss disease) are included in the group of the ANCA antibody associated granulomatous vasculitides.

Granulomatosis with polyangiitis

Synonyms: Granulomatous polyangitis, Wegener’s granulomatosis

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Granulomatous polyangitis(GPA) is a systemic small to medium vessel necrotizing vasculitis with granuloma formation and typical predilection to affect the upper airways and the kidneys 3,10.

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In the disease progression there might be phases of limited GPA and of severe, acute, multiorgan disease 10. Only a minority of the patients with limited GPA, up to 15%, may show cutaneous involvement including palpable purpura and ulcers. Skin lesions are more common in the severe multiorgan disease, where up to 50% of the patients develop cutaneous signs. These are variable and correspond to the involved vessels10 - palpable purpura as a sign of the small vessel vasculitis; subcutaneous nodules, livedo, ulcers and digital infarcts resulting from vasculitis of the medium sized vessels; polymorphous necrotic papules and nodules (papulonecrotic lesions), favoring the extensor surfaces of the extremities3. Additional signs include mouth ulcers and gingival hyperplasia. An important feature are the pyoderma gangrenosum like ulcerated nodules, which distinguish GPA from other vasculitis 10. Over 80% of patients with GPA are positive for cANCA. The skin histology requires deep biopsies and is dependent on the phase of the disease. The typical changes of neutrophilic vasculitis and granulomatous inflammation are characteristic to different phases and are usually found separately 10.

Eosinophilic granulomatosis with polyangiitis (EGPA) Synonyms: Churg-Strauss disease, Churg –Strauss syndrome, allergic granulomatosis3,10. EGPA is a small vessel granulomatous systemic vasculitis typically associated with asthma and eosinophilia.

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EGPA typically evolves through 3 phases over ears or decades. The first stage represents allergic rhinitis, nasal polyps, and asthma and other atopic conditions and may have prolonged course. There are, however, rare non-asthmatic cases or cases with late onset asthma10. In the second phase, there develops tissue eosinophilia affecting the blood and one or more organs (for example eosinophilic pneumonia). Frequent relapses are typical. In the third phase vasculitis develops involving multiple organs, but less frequently than other vasculitis the kidneys and more frequently the heart, which is the leading cause of death 10. The skin is involved in approximately 50% of patients of all phases. In the vasculitis phase, the skin involvement is often present together with neurologic involvement, usually mononeuritis multiplex 3,10. Palpable purpura, subcutaneous nodules and livedo as well as papulonecrotic lesions as in GPA might be present, the scalp and the extensor surfaces of the limbs are typically affected. Less frequently described are urticarial lesions, new onset Raynaud phenomenon and other.

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Histologically there are eosinophil rich neutropilic vasculitis, together with granulomatous dermatitis and tissue eosinophilie, the granulomatous and the vasculitic features can be seen on the same biopsy preparation3,10.

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Only 25% of patients with EGPA have positive ANCA antibodies, but 75% of patients with any kind of renal involvement and 100% of patients with necrotizing glomerulonephritis have ANCAs1.

Polyarteriitis Nodosa (PAN)

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Synonyms: Periarteriitis Nodosa, Panarteriitis Nodosa, Kussmaul-Maier Disease.

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PAN is a rare multisystem, segmential necrotizing vasculitis of mainly the medium sized vessels. The etiology is unknown, association with infections, such as streptococcal and viral hepatitis (C, B) is suspected. It has been suggested that the sheer mechanical stress on the bifurcation of arteries plays a role in the pathogenesis of PAN. With the development of effective vaccines and treatment of viral hepatitis, the incidence is expected to decrease 13. Because PAN is a multisystemic vasculitis, there usually are constitutional symptoms such as fever, malaise, arthralgias, weight loss, and abdominal pain. The variety of affected organs and systems accounts for the diversity of symptoms, including musculoskeletal symptoms (muscle wasting and myalgias), nervous (mononeuritis multiplex with mixed motor/sensory symptoms, cerebrovascular accident), cardiovascular (congestive heart failure and hypertension), gastrointestinal (gastrointestinal bleeding and infarction)3,14. Classical PAN does not usually affect the lungs. When present, the renal involvement is typically at the level of pre-glomerular arteries causing renal hypertention and/or renal insufficiency, with elevated BUN and decreased

ACCEPTED MANUSCRIPT creatinine clearance, but without glomerulonephritis which is the manifestation of the involvement of the smaller vessels. Testicular pain and tenderness are more typical for the hepatitis-associated PAN.

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Skin lesions develop in up to 60% of PAN patients (15 to 50% in most sources). In some cases they may be the first manifestation of the systemic PAN. The cutaneous lesions are typically located on the legs, less frequently on the arms and trunk. Palpable purpura might be present, but it is a result of the involvement of the small vessels. Typical are livedo reticularis and livedo racemosa (with fixed not blanchable livedo or “starburst” pattern of livid to haemorrhagic reticular streaks). The livid areas often involve the fingers and toes. Subcutaneous nodules 0.5 to 2 cm in diameter and clusters of nodules forming painful plaques along the involved superficial arteries are also typical and lead frequently to ulceration with ‘pinched out’ ulcers. The overlying skin may be bright red to bluish or normal. Such nodules develop typically on the lower legs and on the back of the feet. Digital necrosis and gangrene follow vascular involvement of the middle sized vessels of the fingers and toes.

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Histologic picture consists of polymorphonuclear panarteriitis and periarteriitis with fibrinoid necrosis of the vessel’s wall that may lead to thrombosis and occlusion. The histology is most typical if taken from a deep subcutaneous nodule. Otherwise it is of a small vessel leucocytoclastic vasculitis with necrosis and thrombosis of the vessels’ walls13.

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Commonly neutrophilic leukocytosis, possibly anemia and elevated ESR, hematuria and proteinuria are present. In many patients the arteriolar inflammation leads to aneurismal dilatations of the hepatic, renal and visceral vasculature, which are visible on angiography, but are not specific for PAN. PANCAs were reported in some patients with PAN from earlier studies, but are more common in MPA and in the current classification of vasculitis, PAN is not associated with ANCA and patients with ANCA should not be classified as having PAN1. ANCA, rheumatic factors, and ANA are typically negative. The differential diagnosis should be made with other systemic vasculitides and panniculitides. When nongranulomatous vasculitis of the lung is present or necrotizing glomerulonephritis is found, the diagnosis of microscopic poliangiitis (MPA) should be considered. Systemic corticosteroids are the mainstay of therapy. Cyclophosphmide is added in severe cases. Viral-hepatitis associated cases are treated with the respective antiviral regimens.

Cutaneous PAN Synonyms: benign cutaneous PAN, livedo with nodules

ACCEPTED MANUSCRIPT Cutaneous PAN is a rare variant of polyarteriitis nodosa with better prognosis. In cutaneous PAN mainly the skin is affected. Some cases may be initial or more limited forms of systemic PAN.

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There may be constitutional symptoms as in systemic PAN, such as fever, malaise, arthralgias, as well as mild muscular and peripheral neural involvement, but no other systems are affected. Skin lesions are the same as in systemic PAN, but subcutaneous nodules are more common, typically located on the lower legs, sometimes extend proximally and on the arms. The nodules are painful and may ulcerate. The nodules can be less pronounced in some cases. Additional features are “starburst” livedo reticulris with active nodules or inflammation within the livedo. The prognosis is favorable but the course may be protracted and intermittent. The histology is the same as in the systemic PAN.

Pseudovasculitis Purpura fulminans

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The term purpura fuminans has been used in the literature to denote different but overlapping conditions. It is usually used for the skin manifestations of DIC (disseminated intravascular coagulation) and septic shock; however,, it has been also used for the disseminated necrotizing infections similar to the necrotizing fasciits and Fornier gangrene which usually require surgical treatment additional to the broad spectrum antibiotics. The current classification encompasses three groups of cases as true purpura fulminans: 1) acute infectious with DIC; 2) neonatal purpura fulminans resulting from protein S or protein C deficiency without infection 3) idiopathic post infectious or with unknown cause 15 . A wide range of microorganisms might cause the septic purpura fulminans, the most common being Neisseria meningitides, followed by streptococcal species and staphylococcus aureus and various gram negative microorganisms 16. Purpura fulminans might show the clinical picture of palpable purpura at the beginning, which rapidly progresses to involve large acral areas, and the skin involvement might precede the onset of the septic shock, for example in approximately 50% of the patients with pneumococcal sepsis 15. Petechiae, hemorrhagic papuels and plaques, vesicules, bullae, pustules and nodules have been observed in such patients15,17. The hemorrhagic areas (echymoses) affect for example the whole fingers or hands and bluish of black necrosis form within such areas, these might be dry necroses (eschars) or gangrene. These areas are typically much broader than the digital infarcts of the medium sized vasculitis and are usually symmetric (symmetrical gangrene), with sharp borders and “geographic” irregular forms. Not only the acral areas, but also areas of pressure, lips, cheeks and broad areas on the trunk might be affected. A different

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pattern of skin necrosis has been observed – in septic purpura fulminans these start from the distal tips or parts of the acral areas (fingers, toes, earlobes, nose) and move proximal in patchy distribution. In the idiopathic purpura fulminans, the thigs, buttocks and trunk are preferably affected 15. Laboratory workup includes coagulation parameters such as fibrinogen, D-dimers, platelets, PT, aPTT, protein C, protein S and antithrombin III levels. Purpura fulminans has a high mortality rate and the survivors might have severe sequelae including amputations and loss of fingers, toes or limbs18.

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Embolic conditions

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Septic emboli could arise not only within the acute setting of sepsis but also in patients in better general conditions such as subacute endocarditis. Painful hemorrhagic nodules are seen on the fingers and toes, usually on the distal phalanges, as a consequence of infected thrombotic embolisations originating from the endocarditis. These are known as Osler nodules. Another acral manifestation is petechae on the palms and soles, called Jeneway macules. Such petechiae are also the reason for splinter hemorrhages. Small petechiae could be seen not only on the acral areas, but on the mucous membranes including the conjunctive. In bacteriemia of any origin, there could be septic thrombi on the skin or hematogenic dissemination to the skin, where the lesions appear as hemorrhagic papules and nodules with the tendency to central necrosis and ulceration. These could be similar to palpable purpura and as discussed in the paragraph on septic vasculitis, such lesions could show true vasculitis on histology 9. A broad range of microorganisms might cause such lesions19. An example could be the disseminated gonococcal infection, where a few disseminated macules with a hemorrhagic component, develop to hemorrhagic papules or pustules with central necrosis. These develop together with fever attacks and have predominantly acral distribution. Another example is ecthyma gangrenosum, where usually immunosuppressed or neutropenic individuals develop anywhere on the body (perianal areas could be preferred) macules and plaques which progress to hemorrhagic necroses und ulcers18. Pseudomonas aeruginosa is a frequent and the initially described cause, but a wide range of bacterial and fungal infections can cause the same clinical picture20. Embolic conditions of noninfectious etiology such as cholesterin emboli 21 or in atrial myxoma may also cause hemorrhagic lesions in acral distribution and are important differential diagnosis to vasculitis22.

Pigmented purpuric dermatoses Since 1896, a group of pigmented purpuric eruptions has been described in the dermatologic literature. They have variable clinical features, similar histopathologic alterations and many synonyms such as capillaritis, purpura simplex, inflammatory purpura without vasculitis etc.

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Pigmented purpuric dermatoses (PPDs) are rare chronic benign dermatoses characterized by petechiae, purpura, and increased skin pigmentation23. The hallmark of PPDs is their orange-brown, speckled, cayenne pepper–like discoloration. The cause is unknown, but cell-mediated immunity might play a role24. PPDs have been traditionally divided into 5 clinical entities: Schamberg's purpura (typically presenting as "cayenne pepper" spots on lower extremities), Majocchi's purpura (described as purpura annularis telangiectoides), lichen aureus (characterized by a solitary golden-colored patch with purpura), Gougerot-Blum purpura (typically presenting as lichenoid papules with purpura on lower extremities) and eczematid-like purpura of Doucas and Kapetanakis (characterized by itching and orange-colored pigmentation25. Other different subtypes such as itching purpura of Lowenthal, lichen purpuricus, transitory pigmented purpuric dermatosis, linear pigmented purpuric dermatosis, and granulomatous variant of PPDs have been recognized. PPDs most commonly occur on the lower extremities and may be asymptomatic or pruritic. Dermatoscopic examination of PPDs shows multiple red to purple globules or dots over a purpuric, and later, orange-brown background26

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All chronic pigmented purpuric dermatoses (PPDs) are inflammatory in nature. Although the extent, the density and the distribution of the inflammatory infiltrate can vary considerably, it is always concentrated in the upper dermis and is dominated by lymphocytes and macrophages. The lymphocytes are predominantly of the CD4+ helper phenotype and along with that occasional CD1a+ dendritic cells are present27. Plasma cells and neutrophils are sporadically found as well. Whether the chronic pigmented purpuric dermatoses can be regarded as lymphocytic vasculitis or at least as a lymphocytic capillaritis has been a controversial issue for many years. Though vascular changes are usually very mild, endothelial cell proliferation and oedema, focal karyorrhectic debris, as well as narrowing of vessel lumens may sometimes be observed in active pronounced lesions28. Notably, features of leukocytoclastic vasculitis (e.g., leukocytoclasia and fibrinoid necrosis of vessel walls) are absent. Red blood cell extravasations in the papillary dermis in early lesions and a variable degree of hemosiderin deposition in macrophages in the dermal papillae in mature lesions are typical findings, considered as important diagnostic histological criteria. It should be born in mind though, that the degree of hemosiderin deposition may be variable, and it can be minimal in early lesions29. Histochemical staining with Perls stain to demonstrate iron (hemosiderin) and Masson-Fontana stain to exclude melanin pigment may be useful to confirm the diagnosis. Hemosiderin depositions in the dermis are seen only in the upper dermis in PPDs, whereas it is present in all dermal layers in stasis dermatitis, which is a useful differentiating feature. Another useful feature for this differentiation is the lobular proliferation of relatively thick-walled vessels in the superficial dermis typical of stasis dermatitis.

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Because of the presence of hemorrhage, leukocytoclastic vasculitis is often a relevant differential diagnosis; however, in leukocytoclastic vasculitis, the inflammatory infiltrate is composed of neutrophils and eosinophils with associated leukocytoclasis and the vessels show fibrin deposition and sometimes frank necrosis. The histologic aspect of PPDs could be similar to the appearance of patch stage Kaposi sarcoma, but the promontory sign, dermal lymphangiectasia and peritumoral plasmocytosis of the latter condition are lacking in PPDs, and endothelial cells in the latter conditions do not stain for HHV8.

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Mycosis fungoides can present with purpuric lesions, and rare patients who initially seemed to have a PPD have subsequently developed frank mycosis fungoides. Both mycosis fungoides and PPDs can have solitary lymphocytes in the lower half of the epidermis, along with a few small collections, but large intraepidermal groups of lymphocytes anywhere in the epidermis or many lymphocytes in the upper spinous layer point to a diagnosis of mycosis fungoides. The intraepidermal lymphocytes in mycosis fungoides are larger than normal and show as a rule a variable degree of nuclear atypia. Although PPDs can usually be differentiated histopathologically from patch stage mycosis fungoides in some cases, a reliable distinction between the two can be extremely difficult. In a study of 43 patients with PPDs, Magro et al found monoclonality and diminished CD7 expression in 18 participants, correlating with large surface area involvement. Approximately 40% of patients in this study had histologic findings consistent with mycosis fungoides, suggesting that T-cell gene rearrangement studies should be obtained for prognostic evaluation in patients with widespread disease30.

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The histologic differences between the clinical entities of the chronic pigmented purpuric dermatoses lie in the number, pattern, and distribution of lymphocytes and number of siderophages. In Schamberg’s disease and in purpura annulare telangiectoides or Majocchi’s disease, there is usually a mild to moderate perivascular and interstitial lymphocytic infiltrate admixed with extravasated erythrocytes and siderophages. The epidermis is usually unchanged but sometimes a mild spongiosis may be noted in those variants. More persistent and extensive is the spongiosis in eczematous-like purpura of Doucas and Kapetanakis. In this variant, areas of parakeratosis often accompany it. The inflammatory infiltrate is band-like and heavy in lichen aureus and lichenoid purpura of Gougerot and Blum. In the latter variant there might be a significant exocytosis of lymphocytes in the lower layers of the mildly spongiotic epidermis, whereas in lichen aureus a thin layer of uninvolved connective tissue separates the under surface of the epidermis from the inflammatory infiltrate below (Grenz zone) is often present. A rare granulomatous histological variant of PPD has been reported31.

ACCEPTED MANUSCRIPT Because the clinical and histopathological differences between PPDs are minor and frequently overlap, differentiation is often difficult.

Schamberg's Disease

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Synonyms: Progressive pigmentary dermatosis of Schamberg, Purpura pigmentosa progressiva, Schamberg's purpura Schamberg’s purpura (SP) is the most common type of PPDs.

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The entity is named after the prominent dermatologist from Philadelphia Jay Frank Schamberg (1870-1934), who described purpura pigmentosa in 1901. Schamberg reported a 15-year-old boy with a 5-year history of “diffuse, reddishbrown, non-elevated, irregular oval patches with borders consisting of pin-head size, reddish-brown, scarcely elevated puncta or cayenne-pepper spots”32. SP affects individuals of all ages. It is occasionally observed before puberty33 and more common in man.

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Rare familial cases of SP have been reported in the literature, implying a genetic cause in a minority of patients. Some cases may be attributed to medications, venous hypertension, gravitational dependency, capillary fragility, contact allergy to wool or clothing dyes, trauma, or exercise34.

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SP is typically observed on the legs, but can extend to the rest of the body. It is usually irregularly distributed on both sides with few or many patches. The skin changes consist of multiple oval or irregular plaques and patches with orangebrown color. Some of the plaques may become darker, but some may spontaneously clear. The color is due to hemosiderin, with characteristic "cayenne pepper" macules appearing within and at the edge of the old lesions. The macules represent petechiae and persist with diascopy. The disease is chronic and lasts for years. SP is generally asymptomatic. There may be a subgroup of SP called transitory PPD or Schamberg-like dermatitis, where, transitory PPD is pruritic and tends to clear within a few months after onset35. Many topical and systemic drugs have been tried without consistent results. Colchicine treatment has been successfully used to prevent recurrence of the clinical manifestations. There are anecdotal reports of response to treatment with large doses of vitamin C. An encouraging effect of pentoxifylline has been described36. Narrowband UVB therapy has been suggested37 as an effective for SP. Case of SP was reported to respond dramatically to PUVA38. Favorable results occurredin five patients with Advanced Fluorescence Technology pulsed light39.

Majocchi's purpura

ACCEPTED MANUSCRIPT Synonyms: Purpura annularis telangiectodes, Majocchi capillaritis, Majocchi's disease, Majocchi's purpura,

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Purpura annularis telangiectodes of Majocchi(PATM) is a less common variant of PPDs. In 1896 Domenico Majocchi (1849-1929)observed slowly progressing unusual hemorrhagic eruption on the lower part of the legs of a 21 year old man. He called the disorder "purpura annularis telangiectodes" 40.

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PATM affects predominantly children and young adults with female predilection. PATM has no known cause. Viral41 or bacterial42 infections may be a risk factor for the condition. The origin of the disease is speculated as genetic because of the several described familial cases. Drugs such as aspirin, carbamazepine, acetaminophen have been found to be a common cause. The role of gravity and increased venous pressure is also discussed.43

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In PATM the lesions appear symmetrically on both legs. PATM is characterized by punctate telangiectatic macules progressing to annular, hyperpigmented patches with central clearing and infrequent atrophy. The patches are wellcircumscribed, about 1-3 cm in size . Within time, the lesions slowly spread to the rest of the body. The condition is neither painful nor itchy.

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Treatment is difficult. Mainline is the use of topical corticosteroids. If the lesions are widespread, systemic steroid treatment may be administered for a short time. Some authors report the effectiveness of NB-UVB and PUVA therapy44. For resistant cases ascorbic acid, antihistamins, stanozolol, griseofulvin, cyclosporine, colchicine45, supportive socks, and carbon dioxide snow have been proposed46. Methotrexate may offer a therapeutic alternative to patients with highly symptomatic pigmented purpuric dermatosis refractory to other, more conservative, treatment modalities47. The prognosis of PATM is generally good, though it may be present for several years.

Eczematid-like purpura of Doucas and Kapetanakis Synonyms: eczematoid purpura, eczematoid-like purpura, itchy purpura; disseminated pruriginous angiodermatitis Eczematid-like purpura of Doucas and Kapetanakis (EPDK) is a subtype of the PPDs with eczematous changes in the purpuric surface. Christoforus Doucas(1890-1974) and Joanis Kapetanakis(1913-1987) first described EPDK in 1953. They reported 49 patients with clinical picture similar but not quite the same as pigmented purpuric lichenoid dermatitis of Gougerot Blum and Schamberg’s purpura.

ACCEPTED MANUSCRIPT In a retrospective review of 174 cases of PPDs, eczematous-like purpura of Doucas and Kapetanakis only account for 10% of the cases48. According to the same review, the mean age of the patients is 54.2 years with a slight female predominance. EPDK is rare in children49.

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Risk factors are unknown. Increased venous pressure, capillary fragility, contact dermatitis to aniline paints; exercises, focal infections, chemical foods, and alcohol consumption are discussed. Some drugs like infliximab 50 were reported to induce EPDK.

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The Doucas and Kapetanakis subtype of PPDs is recognized clinically by its extensive distribution, eczematous appearance, scales on the surface of the plaques and associated pruritus51. Trunk is often involved together with the extremities. Doucas and Kapetanakis described the lesions as “stippling hemorrhagic spots which are close to each other, red in color, of a pin-head size and did not disappear upon pressure…Later the eruption grow brown and yellow and gradually disappeare; however,, a new eruption of bright red color appeared and followed the same course”52. The lesions are extremely pruritic, that’s why lichenification could be observed .

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Various therapy options have been tried in the treatment of EPDK. According to some authors, narrow band UVB53 and PUVA are effective. Other reported modalities include topical corticosteroids and tacrolimus. Systemic treatment consists of oral cyclosporin, griseofulvin, oral bioflavonoids and ascorbic acid. An option is symptomatic treatment with antihistamines, corticosteroids, and support stockings

Lichen aureus

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Synonyms: Lichen Purpuricus; Localized Variant of Pigmented Purpuric Dermatitis Lichen aureus (LA) is a rare clinical condition of unknown origin, categorized in the group of PPDs. In 1958 Martin54 first published case of LA as a case for diagnosis. Charles D.Calnan (1916-2012)55 used the term lichen aureus to describe this localized persistent form of PPDs. LA usually occurs in younger individuals, though older patients have been reported. Both males and females are affected; however, the condition is seen at a higher incidence in males. Lichen Aureus is observed worldwide. There is no racial or ethnic predilection. The etiology of LA is unknown. The risk factors include varicose veins and/or recent trauma; however,, not all cases of LA are associated with either varicose veins or a history of trauma. Drugs are also thought to be one of the

ACCEPTED MANUSCRIPT causes56. Case of LA induced by interferon-alpha plus ribavirin has been described57.

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LA begins once of a sudden, usually on the lower legs. It often overlies a varicose vein. Seldom, LA may be seen on the forearms and trunk. LA occurs unilateral, usually as a solitary lesion or a localized group of hyperpigmented lesions. The skin lesions are presented with macules, papules or plaques of varying sizes with golden-brown, rust, cupric to purple color58. The patches are well circumscribed. Petechiae could be observed in and around the patches. Linear or segmental forms of lichen aureus have been reported 59. The lesions, in most cases, are asymptomatic, but the patients may experience local pain or itch in the affected area60.

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Dermatoscopy shows a diffuse copper background (dermal lymphohistiocytic infiltrate), with red globules, plaques and round-to-oval dots (dilated blood capillaries), some gray dots and a network of interconnected pigmented lines (basal layer hyperpigmentation and incontinentia pigmenti)61.

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Differential diagnoses are other pigmented purpuric eruptions, traumatic bruises, purpura caused by drugs, contact dermatitis, mycosis fungoides and atypical forms of histiocytosis.

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Topical therapy of LA consists of application of potent corticosteroid creams. Some authors disagree and consider them as an ineffective62. Other treatment modalities include application of local calcineurin inhibitors twice daily63 and PUVA therapy64. When present, associated venous stasis should be treated. In cases of severe pruritus, oral antihistamines should be added to the topical therapy.

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The prognosis is generally good, though, as mentioned, LA is a chronic recurrent condition and may become chronic regardless of the treatment. It may cause cosmetic issues and the affected individuals may face a lot of emotional stress. According to some authors, LA belongs to the expanding spectrum of socalled clonal dermatoses, and a possible evolution to mycoses fungoides cannot be ruled out65. Therefore, close patient follow-up observation is recommended.

Gougerot–Blum syndrome Synonyms: Pigmented purpuric lichenoid dermatitis, Pigmented purpuric lichenoid dermatitis of Gougerot and Blum Gougerot-Blum syndrome (GBS) is a variant of pigmented purpuric dermatitis. This form of capillaritis is less common, benign, generally pruritic. GBS tends to be chronic with remissions and flares. Henri Gougerot(1881-1955) and Paul Blum(1878-1933) in 1925 published the first case of this rare entity, describing it as “purpura angiosclereux prurigineux avec elements lichenoїdes”66. In 1929 they described additionally 4 cases of

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pigmented and purpuric lichenoid dermatitis which they regarded as a clinical entity. It is characterized clinically by a male predominance; It most commonly affects males age 40-60 years. The ethiopathogenesis is unclear like the other PPDs. In a patient with GBS the lesions disappeared when the diltiazem hydrochloride that he had been taking was discontinued67. The eruption predominantly affects the lower legs. In some cases only one leg remain involved, but in other cases the eruption spreads over the arms and thrunk. GBS resembles progressive pigmented purpura, but with characteristic small shiny slightly raised lichenoid papules that become confluent and thickened. The papules are initially pink, but slowly become orange and then brown. Wickham striae are absent. The lesions are pruritic. The term lichenoid describes the clinical appearance rather than a histologic feature. Prompt clinical response to topical steroid have been documented in many cases. In a series of seven patients with Gougerot–Blum's disease, PUVA treatments were administered to achieve clearance. It is commented that UV radiation alters the distribution and function of lymphocytes and leads to dissappearance of epidermal Langerhans cells68. Other possibility is narrowband UVB therapy, preferable because of the fewer side effects69.

Granulomatous variant of PPDs

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The granulomatous variant of PPDs was first described in 1996 by Saito and Matsuoka70. Since that time, 17 additional cases have been published in the literature. In terms of etiologic theories related to the granulomatous variant, hyperlipidemia is proposed as a possible association. Like other PPDs, the lesions of granulomatous PPDs are chronic and localized on the legs. In contrast to the conventional types, dorsa of the feet are described as the most common site of involvement. However, characteristic eruptions of other body sites has been reported71 The clinical picture persists of red to brown macules and papules72.

Itching purpura of Lowenthal Synonyms: disseminated pruriginous angiodermatitis Alphonse Lowenthal(1903-1983) described it in 1954 as “purpura of fairly acute onset”. The condition begins symmetrically on the front, sides of both ankles and extends upwards73.

ACCEPTED MANUSCRIPT Itching purpura is reported very rare and most of the authors consider it as an itching variant of Schamberg's disease.

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Unilateral linear capillaritis

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Unilateral linear capillaritis, also named quadrantic capillaropathy or unilateral pigmented purpuric eruption, is clinically characterized by an extensive linear or segmental distribution of pigmented purpuric macules and a favorable course23.

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There are more than 20 entities in the big family of acrally distributed vascular dermatoses. They have many synonyms, different clinical characteristics and variable histopathologic alterations. This review focuses on their particularities and treatment options.

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References: 1

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Jennette JC, Falk RJ, Bacon PA et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis and rheumatism 2013; 65: 1-11.

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Mahr A, de Menthon M. Classification and classification criteria for vasculitis: achievements, limitations and prospects. Current opinion in rheumatology 2015; 27: 1-9. Fiorentino DF. Cutaneous vasculitis. JEADV 2003; 48: 311-340.

SC

3 4

MA NU

Sunderkotter C, Pappelbaum KI, Ehrchen J. Cutaneous symptoms of various vasculitides. Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete 2015; 66: 589-598. 5

Ratzinger G, Zelger BG, Carlson JA et al. Vasculitic wheel - an algorithmic approach to cutaneous vasculitides. Journal der Deutschen Dermatologischen Gesellschaft, JDDG 2015; 13: 1092-1117.

6

Roberts PF, Waller TA, Brinker TM et al. Henoch-Schonlein purpura: a review article. Southern medical journal 2007; 100: 821-824.

7

PT

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Hocevar A, Rotar Z, Jurcic V et al. IgA vasculitis in adults: the performance of the EULAR/PRINTO/ PRES classification criteria in adults. Arthritis research & therapy 2015; 18: 58.

8

9

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Tsankov N, Angelova I, Кazandjieva J. Topical modalities for the treatment of cutaneous vasculities. Clin Dermatol, 1999, 17, 6, 649-654. Damoiseaux J. The diagnosis and classification of the cryoglobulinemic syndrome. Autoimmunity reviews 2014; 13: 359-362.

10

11

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Chen KR, Carlson JA. Clinical approach to cutaneous vasculitis. Am J Clin Dermatol 2008; 9: 71-92.

Carlson JA, Chen KR. Cutaneous vasculitis update: small vessel neutrophilic vasculitis syndromes. Am J D ermatopathol 2006; 28: 486-506.

12

Chen KR, Su WP, Pittelkow MR et al. Eosinophilic vasculitis syndrome: recurrent cutaneous eosinophilic necrotizing vasculitis. Seminars dermatol 1995; 14: 106-110.

13

Carlson JA. The histological assessment of cutaneous vasculitis. Histopathology 2010; 56: 3-23. 14

Carlson JA, Chen KR. Cutaneous vasculitis update: neutrophilic muscular vessel and eosinophilic, granulomatous, and lymphocytic vasculitis syndromes. Am J Dermatopathol 2007; 29: 32-43.

15

Adcock DM, Brozna J, Marlar RA. Proposed classification and pathologic mechanisms of purpura fulminans and skin necrosis. Seminars in thrombosis and hemostasis 1990; 16: 333340.

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Betrosian AP, Berlet T, Agarwal B. Purpura fulminans in sepsis. American journal of the medical sciences 2006; 332: 339-345.

17

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Delgado-Jimenez Y, Fraga J, Requena C et al. Acute bacterial septic vasculopathy. Int J Dermatol 2013; 52: 1071-1080.

18

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Mazzone L, Schiestl C. Management of septic skin necroses. European journal of pediatric surgery : official journal of Austrian Association of Pediatric Surgery . Zeitschrift fur Kinderchirurgie 2013; 23: 349-358.

19

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Pagnoux C, Cohen P, Guillevin L. Vasculitides secondary to infections. Clin Exp Rheumatol 2006; 24: S71-81.

20

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Vaiman M, Lazarovitch T, Heller L et al. Ecthyma gangrenosum and ecthyma-like lesions: review article. European journal of clinical microbiology & infectious diseases 2015; 34: 633-639. 21

Ogbechie OA, Morley KW, Sugai D et al. Limited cutaneous pseudovasculitis: a mild variant of cholesterol emboli syndrome. Circulation 2015; 131: 514-5

22

Carlson JA, Chen KR. Cutaneous pseudovasculitis. Am J Dermatopathol 2007; 29: 44-55. Samuel J, Nichamin A, Brough J. Chronic Progressive Pigmentary PurpuraPurpura Annulares Telangiectodes of Majocchi-Schamberg. Am J Dis Child 1968;116:429-433

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28

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Mun JH, Jwa SW, Song M, Kim HS, Ko HC, Kim BS, Kim MB. Extensive Pigmented Purpuric Dermatosis Successfully Treated with Pentoxifylline. Ann Dermatol 2012; 24: 363– 365. 25 Zvulunov A, Avinoach I, Hatskelzon L, Halevy S. Pigmented purpuric dermatosis (Schamberg's purpura) in an infant. Dermatology Online J 1999; 5: 2 26 Vazquez-Lopez F, Garcíia-Garcíia B, Sanchez-Martin J, Argenziano G. Dermoscopic patterns of purpuric lesions. Arch Dermatol 2010;146:938. 27 Smoller BR, Kamel OW. Pigmented purpuric eruptions: immunopathologic studies supportive of a common immunophenotype. J Cutan Pathol 1991;18:423-427. Weedon D. The vasculopathic reaction pattern. In: Weedon's Skin Pathology, 3rd ed, Elsevier Limited, 2010. p.195.

29

Sardana K, Sarkar R, Sehgal VN. Pigmented purpuric dermatoses: an overview. Int J Dermatol. 2004;43:482-488.

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Magro CM, Schaefer JT, Crowson AN, et al. Pigmented purpuric dermatosis: classification by phenotypic and molecular profiles. Am J Clin Pathol 2007;128:218-229.

31

Saito R, Matsuoka Y. Granulomatous pigmented purpuric dermatosis. J Dermatol 1996;23:551-555. 32 Schamberg JF. A peculiar progressive pigmentary disease of the skin. Br J Dermatol 1901; 13: 1-5. 33 Torrelo A, Requena C, Mediero IG, Zambrano A. Schamberg's purpura in children: A review of 13 cases. J Am Acad Dermatol 2003;48:31-33. 34 Leung AKC, Leung AAM, Barankin B. Schamberg Disease in a 54-Year-Old Chinese Woman. Int J Dermatol Clin Res 2015;1: 18-19.

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Osment LS, Noojin RO, Lewis RA, Lupton CH. Transitory pigmented purpuric eruption of the lower extremities. Arch Dermatol 1960;81:591–598 36 Wahba-Yahav AV. Schamberg's purpura: association with persistent hepatitis B surface antigenemia and treatment with pentoxifylline. Cutis. 1994;54:205–206. 37 Lasocki AL, Kelly RI. Narrowband UVB therapy as an effective treatment for Schamberg's disease. Australas J Dermatol 2008;49:16-88. 38

Seckin D, Yazici Z, Senol A, Demircay Z. A case of Schamberg's disease responding dramatically to PUVA treatment. Photodermatol Photoimmunol Photomed. 2008;24:95-96.

39

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Manolakos DA,Weiss J, Glick B, Weiss KD, Weiss E. Treatment of Schamberg's Disease with Advanced Fluorescence Technology. JDD 2012; 11;528. 40

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Kass I, Sneid P, Slavin M. Report of a case of purpura annularis telangiectodes (Majocchi's disease) and its treatment with cortisone. Ann Intern Med. 1954;41:349-357. 41 Erbagcý Z, Tuncel A. HCV enfeksiyonlu iki olguda pigmente purpurik dermatoz geliþimi (in Turkish). Turkiye Klinikleri J Med Sci 2003;23:238-241 42 Satoh T, Yokozeki H, Nishioka K. Chronic pigmented purpura associated with odontogenic infection. J Am Acad Dermatol 2002;46:942-944 43 Goyal T, Varshney A, Zawar V. Purpura annularis telangiectodes in a child: An uncommon entity. J Appl Hematol 2014;5:71-72 44 Dhali TK, Chahar M, Haroon MA. Phototherapy as an effective treatment for Majocchi’s disease - Case report. An Bras Dermatol 2015;90:96-99. 45 Pandhi R, Jain R, Radotra BD, Kumar B. Purpura annularis telangiectoides with vasculitic ulcers treated with colchicines. Int J Dermatol 2002;41:388-389 46 Ozturk P, Ataseven A, Ozturk U, Demiroren K, Dagli F. Majocchi disease in a child. Indian J Dermatol 2006;51:275-277

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Hoesly FJ, Huerter CJ, Shehan JM. Purpura annularis telangiectodes of Majocchi: case report and review of the literature. Int J Dermatol 2009;48:1129–1133. 48 Ratnam KV, Su WP, Peters MS. Purpura simplex (inflammatory purpura without vasculitis): a clinicopathologic study of 174 cases. J Am Acad Dermatol 1991;25:642-647. 49 Vedak P, Nazarian R, Kroshinsky D. A case of eczematid-like purpura of Doucas and Kapetanakis in a child. Pediatric Dermatology 2015; 32:291-292. 50 Wang LC, Medenica MM, Shea CR, Busbey S. Infliximab-induced eczematid-like purpura of Doucas and Kapetenakis. J Am Acad Dermatol 2003;49:157-158. 51 Sardana K, Sarkar R, Sehgal VN. Pigmented purpuric dermatoses: an overview. Int J Dermatol 2004;43:482– 488. 52 Doucas C, Kapetanakis J. Eczematid-Like Purpura. Dermatologica 1953;106:86–95 53 Karadag A, Bilgili S, Onder S, Calka O. Two cases of eczematid-like purpura of Doucas and Kapetanakis responsive to narrow band ultraviolet B treatment. Photodermatology, Photoimmunology & Photomedicine 2013; 29:97-99. 54 Martin RH. Case for diagnosis. Trans Rep St Johns Hosp Dermatol Soc Lond 1958;40:98 55 Price ML, Wilson JE, Calnan C. Lichen aureus: a localized persistent form of pigmented purpuric dermatosis. Br J Dermatol. 1984;112:307-314. 56 Sardana K, Sarkar R, Sehgal VN. Pigmented purpuric dermatoses: an overview. Int J Dermatol 2004;43:482–488

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González-Sixto B, García-Dova I, Conde A, Mayo E, Pardavila R, De la Torre C, Cruces M. Lichen Aureus Induced By Interferon-Alpha plus Ribavirin. Acta Dermatovenereologica, 2006,87,87-88 58 Nico M, Rivitti E. Líquen Áureo. An Bras Dermatol. 1996;71:47–49. 59 Dippel E, Schröder K, Goerdt S. Zosteriformer Lichen aureus. Hautarzt. 1998;49:135–138. 60 Cunha RR, Filho, Schwartz J, Zanol J. Líquen aureus "algesiogênico". An Bras Dermatol. 2006;81:163–165 61 Portela PS, Melo DF, Ormiga P, Olivera FJG, Freitas NK, Bastos CSj. Dermoscopy of lichen aureus. An Bras Dermatol. 2013; 88: 253–255. 62 Rudolph RI. Lichen aureus. J Am Acad Dermatol 1983;8:722 63 Bohm M, Bonsmann G, Luger T. Resolution of lichen aureus in a 10-year-old child after topical pimecrolimus. Br J Dermatol 2004;151:519 64 Ling TC, Goulden V, Goodfield MJD. PUVA therapy in lichen aureus. J Am Acad Dermatol 2001;45:145 65

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Prosser Thomas EW, Rook E. Pigmented Purpuric Lichenoid Dermatitis of Gougerot and Blum. Proc R Soc Med. 1948;41:530–531. 67 Inui S, Itami S, Yoshikawa K. A case of lichenoid purpura possibly caused by diltiazem hydrochloride. J Dermatol 2001;28:100-102 68 Krizsa J, Hunyadi J, Dobozy A. PUVA treatment of pigmented purpuric lichenoid dermatitis (Gougerot–Blum). J Am Acad Dermatol 1992;27:778–780. 69 Kocaturk, E., Kavala, M., Zindanci, I., Zemheri, E., Sarigul, S. and Sudogan, S. Narrowband UVB treatment of pigmented purpuric lichenoid dermatitis (Gougerot–Blum). Photodermatology, Photoimmunology & Photomedicine,2009;25:55–56. 70 . Saito R, Matsuoka Y. Granulomatous pigmented purpuric dermatosis. J Dermatol 1996; 23:551 71 Battle L, Shalin S, Gao L. Granulomatous pigmented purpuric dermatosis. Clin Exp Dermatol [serial online]. 2015;40(4):387-390 72 Macquarrie E, Pasternak S, Torok M, Veerassamy S, Walsh N. Persistent pigmented purpuric dermatitis: granulomatous variant. J Cutan Pathol 2011; 38:979-983. 73 Loewenthal LJA. Itching purpura. Brit J Dermatol 1954;66: 95–103.