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Keywords:

  • antineutrophil cytoplasmic autoantibody;
  • anti-phosphatidylserine–prothrombin complex antibodies;
  • cutaneous polyarteritis nodosa;
  • Henoch–Schönlein purpura;
  • KAWAKAMI algorithm;
  • livedo racemosa;
  • palpable purpura

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Seven diseases based on a new algorithm for primary cutaneous vasculitis (kawakami algorithm)
  5. Main cutaneous manifestations of primary cutaneous vasculitis
  6. Diagnostic algorithm of primary cutaneous vasculitis (kawakami algorithm)
  7. Mechanisms of primary cutaneous vasculitis
  8. Treatment of cutaneous polyarteritis nodosa and henoch–schönlein purpura
  9. Concluding remarks
  10. Acknowledgments
  11. References

Palpable purpura tends to indicate involvement of small vessel vasculitis in the upper dermis. Livedo racemosa, nodular lesion and skin ulceration are indicative of involvement of small to medium-sized vessel vasculitis in the lower dermis to subcutaneous fat. We set out to establish a new algorithm (KAWAKAMI algorithm) for primary cutaneous vasculitis based on the Chapel Hill Consensus Conference classification and our research results, and apply to the diagnosis. The first step is to measure serum antineutrophil cytoplasmic antibodies (ANCA) levels. If myeloperoxidase-ANCA is positive, Churg–Strauss syndrome or microscopic polyangiitis can be suspected, and if the patient is positive for proteinase 3-ANCA, Wegener’s granulomatosis is most likely. Next, if cryoglobulin is positive, cryoglobulinemic vasculitis should be suspected. Third, if direct immunofluorescence of the skin biopsy specimen reveals immunoglobulin A deposition within the affected vessels, Henoch–Schönlein purpura is indicated. Finally, the presence of anti-phosphatidylserine–prothrombin complex antibodies and/or lupus anticoagulant and histopathological necrotizing vasculitis in the upper to middle dermis (leukocytoclastic vasculitis) indicates cutaneous leukocytoclastic angiitis, whereas if necrotizing vasculitis exists in the lower dermis and/or is associated with the subcutaneous fat, cutaneous polyarteritis nodosa is indicated. The KAWAKAMI algorithm may allow us to refine our earlier diagnostic strategies and allow for efficacious treatment of primary cutaneous vasculitis. In cutaneous polyarteritis nodosa, warfarin or clopidogrel therapies should be administrated, and in cases that have associated active inflammatory lesions, corticosteroids or mizoribine (mycophenolate mofetil) therapy should be added. We further propose prophylactic treatment of renal complications in patients with Henoch–Schönlein purpura.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Seven diseases based on a new algorithm for primary cutaneous vasculitis (kawakami algorithm)
  5. Main cutaneous manifestations of primary cutaneous vasculitis
  6. Diagnostic algorithm of primary cutaneous vasculitis (kawakami algorithm)
  7. Mechanisms of primary cutaneous vasculitis
  8. Treatment of cutaneous polyarteritis nodosa and henoch–schönlein purpura
  9. Concluding remarks
  10. Acknowledgments
  11. References

Systemic vasculitides represent a rare inflammatory condition in the blood vessel walls. There have been a number of important developments in the diagnosis of these conditions, including recognition of dominant blood vessel size, distinction between primary and secondary vasculitis, and incorporation of pathogenic markers such as antineutrophil cytoplasmic antibodies (ANCA). In 1990, the American College of Rheumatology (ACR) published classification criteria for vasculitis.1–3 Although the criteria did not include microscopic polyangiitis or ANCA, the importance of these indications in accurate diagnosis has subsequently been recognized. In 1994, the Chapel Hill Consensus Conference (CHCC) introduced definitions for the major types of vasculitis as follows: giant cell (temporal) arteritis and Takayasu arteritis as large vessel vasculitis; polyarteritis nodosa and Kawasaki disease as medium-sized vessel vasculitis; Wegener’s granulomatosis, Churg–Strauss syndrome, microscopic polyangiitis, Henoch–Schönlein purpura (HSP), essential cryoglobulinemic vasculitis and cutaneous leukocytoclastic angiitis (CLA) as small vessel vasculitis.4 The CHCC proposed three disorders, Wegener’s granulomatosis, Churg–Strauss syndrome and microscopic polyangiitis, as ANCA-associated vasculitides. Subsequently, ANCA has become increasingly important as a clinical marker for Wegener’s granulomatosis, Churg–Strauss syndrome and microscopic polyangiitis.5 Hypersensitivity angiitis resulting from vasculitis induced by external agents such as drugs was once considered an established disease entity. In fact, it was listed as one of the seven selected vasculitis syndromes reported by the ACR in 1990,6 which is 4 years before the CHCC classification and diagnostic standards were published. However, the CHCC classification does not list hypersensitivity angiitis, and as a result, this term has not been as widely applied or gained as much popularity as the CHCC classification.

Classifying primary cutaneous vasculitis has proven both challenging and controversial. There has yet to emerge a single, unified system that can be applied to clinical diagnosis.7,8 For most physicians, cutaneous vasculitis evokes a crop of lower-extremity palpable purpura that correlates histologically with small vessel necrotizing vasculitis.9 For dermatologists, it would be preferable to devise a classification system dedicated to those vasculitides that present cutaneously.8 Given the current lack of knowledge regarding the pathogenesis, vessel size has been used to diagnose this condition because size can be ascertained relatively easily by clinical and histopathological examination. As a result, most authorities accept the CHCC for classification of vasculitis on the basis of vessel size.4 We set out to establish a new algorithm for primary cutaneous vasculitis (KAWAKAMI algorithm) based on the CHCC classification and our research results. The algorithm was approved by the Guideline Committee of Vasculitis 2008 within the Japanese Dermatological Association. We have taken great measures to ensure that the new algorithm is easier to understand by dermatologists and physicians.

Seven diseases based on a new algorithm for primary cutaneous vasculitis (kawakami algorithm)

  1. Top of page
  2. Abstract
  3. Introduction
  4. Seven diseases based on a new algorithm for primary cutaneous vasculitis (kawakami algorithm)
  5. Main cutaneous manifestations of primary cutaneous vasculitis
  6. Diagnostic algorithm of primary cutaneous vasculitis (kawakami algorithm)
  7. Mechanisms of primary cutaneous vasculitis
  8. Treatment of cutaneous polyarteritis nodosa and henoch–schönlein purpura
  9. Concluding remarks
  10. Acknowledgments
  11. References

The kidney is an organ that contains a maze of vessels, and the incidence of nephropathy in systemic vasculitis is high. Consequently, renal histopathological findings obtained from kidney biopsies have been frequently used in the characterization of systemic vasculitis. While the CHCC classification has been developed primarily on the basis of renal histopathology findings, it is presently used most often to classify systemic vasculitis. The renal arteries are made up of arcuate arteries that become interlobular arteries and then afferent arterioles–glomerulus–efferent arterioles, and these vessels connect to the venous system. This arrangement closely resembles dermal vessels. Renal arcuate arteries are medium-sized vessels that are equivalent to small arteries in the subcutaneous fat below the skin. In the periphery, interlobular arteries and afferent–glomerulus–efferent arterioles are small-size vessels that are equivalent to cutaneous arterioles, capillaries and venules in the skin. Based on these vascular similarities between the kidney and skin, we can deduce that a number of types of systemic vasculitis can also occur in cutaneous vessels. In other words, systemic vasculitis and cutaneous vasculitis often have overlapping symptoms. Therefore, when examining vasculitis from the standpoint of dermatology, it may be appropriate to apply the CHCC classification to cutaneous vasculitis.

Dermatologists generally encounter two types of adult patients, those who present with small vessel vasculitis and those with medium-sized vessel vasculitis, based on biopsy findings of samples taken to the depth of the small arteries in the subcutaneous fat (medium-sized vessels). Consequently, primary cutaneous vasculitis is based on the small vessel and medium-sized vessel levels of the CHCC classification: ANCA-associated vasculitides, HSP, cryoglobulinemic vasculitis, CLA and cutaneous polyarteritis nodosa (CPN). Because it is impossible to distinguish cutaneous manifestations of polyarteritis nodosa from those of CPN, there has been much debate on whether CPN can progress to polyarteritis nodosa. Approximately half the CPN patients in our study showed extracutaneous symptoms such as arthralgia, myalgia and mononeuritis.10 However, we found CPN did not progress to polyarteritis nodosa, which showed a chronic relapsing benign course in the study. This Japanese study introduced new drafts for CPN diagnostic criteria and described CPN as a distinct clinical entity with benign and chronic courses without systemic involvement.11 Based on these findings, CPN and polyarteritis nodosa can be considered different entities, whereby CPN does not necessarily progress to polyarteritis nodosa. In CLA, necrotizing vasculitis occurs in small vessels, namely, arterioles, capillaries and venules (also referred to as leukocytoclastic vasculitis because the vascular walls are thin and fibrinoid degeneration occurs in conjunction with collapse of the neutrophils); in addition, it lacks systemic vasculitis and affects only the skin. However, some dermatologists have disagreed about the disease description as “CLA” adopted by the CHCC classification. They feel uncomfortable with using a histological description such as “leukocytoclasia” as a clinical diagnosis.12–14 However, many agree with the CHCC concept to describe the disease entity, and find this description easy to understand in the context of vasculitis syndrome. Because the present classification system is based on the CHCC classification, it routinely refers to CLA.15

Livedo vasculopathy is diagnosed based on such clinical features as livedo appearance, recurrent skin ulcer, atrophie blanche, purpura and partial pigmentation on the lower extremities.16 Because it can be diagnosed based on cutaneous manifestations, it can be easily diagnosed in a clinical setting. A skin biopsy is used to confirm that there is no histopathological evidence of necrotizing vasculitis. Confusion can occur due to inconclusive skin biopsy findings, failing to prove vasculitis in some cases. We often perform “deeper cut” pathological examinations for the presence of histological necrotizing vasculitis findings at each 50th, 100th, 150th and 200th cut specimen, when there is no conclusive evidence of necrotizing vasculitis in the standard skin biopsy specimen.

Main cutaneous manifestations of primary cutaneous vasculitis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Seven diseases based on a new algorithm for primary cutaneous vasculitis (kawakami algorithm)
  5. Main cutaneous manifestations of primary cutaneous vasculitis
  6. Diagnostic algorithm of primary cutaneous vasculitis (kawakami algorithm)
  7. Mechanisms of primary cutaneous vasculitis
  8. Treatment of cutaneous polyarteritis nodosa and henoch–schönlein purpura
  9. Concluding remarks
  10. Acknowledgments
  11. References

The size and depth of the vessel that runs between the rash and primary cutaneous vasculitis was determined based on the dermatological findings. Cutaneous symptoms are easy to notice, and by interpreting the cutaneous manifestations, dermatologists can ascertain the depth of the lesion or the types of affected vessels. Palpable purpura tends to indicate involvement of small vessel vasculitis in the upper dermis. On the other hand, livedo racemosa, nodular lesions and skin ulcerations are indicative of involvement of small to medium-sized vessel vasculitis in the lower dermis to subcutaneous fat. In addition, we sometimes find palisading granulomas on the elbow and knee of patients with cutaneous vasculitis.

Palpable purpura

Palpable purpura is defined by slightly elevated purpura with palpable swelling (Fig. 1a). While each lesion appears independent, the color, elevation and infiltration of purpura match the disease progression. Furthermore, involvement is frequently seen in areas of pressure or friction, such as waistbands, belts, shoulder straps or sock collars, thus resulting in “Köbner phenomenon”. When confronted with such rashes, it is important to assume skin-localized necrotizing vasculitis in the upper dermis or leukocytoclastic vasculitis. In leukocytoclastic vasculitis, the vascular lumen becomes narrow, particularly peripheral to cutaneous small vessels, and as a result, fibrinoid necrosis is less likely to occur and neutrophilic infiltration is more notable (Fig. 2). In other words, palpable purpura is a term indicating leukocytoclastic vasculitis in the skin. In the elderly, age lowers the skin’s elasticity and palpable purpura lesions are not very elevated. Furthermore, because age loosens collagen fibers and elastin fibers in the dermis, bleeding from necrotizing vasculitis leads to spreading of the purpura and can cause ecchymosis (Fig. 1b).

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Figure 1.  (a) Palpable purpura on the lower extremities. Purpura occurs linearly, matching a sock, and is referred to as “Köbner phenomenon”. (b) Palpable purpura in elderly patients.

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image

Figure 2.  Microscopic examination of palpable purpura shows deposition of fibrinogen in the walls of the postcapillary venules in the upper dermis, along with a perivenular and intramural inflammatory infiltrate consisting predominantly of neutrophils, consistent with leukocytoclastic vasculitis (hematoxylin–eosin stain, original magnification ×200).

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Livedo racemosa

Livedo appearance refers to a clinical feature where reticular erythema spreads over a wide area. Livedo consists of macular violaceous connecting rings that form a netlike pattern. There are many potential causes, and this can make the evaluation of a patient presenting with cutaneous manifestations very difficult.17 Livedo reticularis is characterized by reticular cyanotic cutaneous discoloration surrounding a pale central area. The term “livedo reticularis” is often used indiscriminately.18,19 Livedo racemosa is characterized by a striking violaceous netlike pattern on the skin similar to livedo reticularis, from which it differs according to its shape (irregular or broken) (Fig. 3). Despite important clinical differences, in the English language published work the term “livedo reticularis” is still used to describe all types of livedo, whereas the term “livedo racemosa” is rarely used.20 In the recent update of classification criteria for antiphospholipid syndrome, livedo reticularis was defined as “persistent, not reversible with rewarming, violaceous, red or blue, reticular or mottled pattern of the skin of trunk, arms or legs, consisting of regular unbroken circles (regular livedo reticularis) or irregular-broken circles (livedo racemosa)”.21 In our studies, livedo racemosa was significantly associated with skin ulceration and arthralgia compared to regular livedo reticularis.22 Serum C-reactive protein (CRP) titers in patients with livedo racemosa were significantly higher than in regular livedo reticularis patients. CRP is an inflammatory marker and an elevated CRP titer likely contributes to the aggressive clinical condition. We found that patients with livedo racemosa seem to have more severe clinical symptoms compared to patients with regular livedo reticularis. These findings suggest that livedo reticularis and livedo racemosa should be viewed as separate entities. In addition, the presence of anti-phosphatidylserine–prothrombin complex (anti-PS/PT) antibodies plays some role in the pathogenesis of livedo racemosa. Interestingly, in the anti-PS/PT antibodies positive group, we observed a higher frequency of histopathological cutaneous vasculitis compared with the anti-PS/PT antibodies negative group. Patients with cutaneous vasculitis confirmed by skin biopsy also showed a significantly higher titer of anti-PS/PT antibodies compared to patients without cutaneous vasculitis (Fig. 4).

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Figure 3.  Livedo racemosa with irregular broken circles.

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Figure 4.  Microscopic examination of livedo racemosa reveals fibrinoid degeneration, nuclear dust, neutrophilic infiltration and erythrocyte extravasation, characteristic of necrotizing vasculitis in the subcutaneous fat (hematoxylin–eosin stain, original magnification ×20).

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Sneddon syndrome is characterized by the association of livedo appearance and ischemic cerebrovascular events, including stroke and transient ischemic attack. Livedo was noted before cerebrovascular events in more than half of the patients with Sneddon syndrome in two reported studies.20,23 In our series, a statistically significant association between histopathological necrotizing vasculitis in the skin biopsy specimen and ischemic cerebrovascular events was found among patients in whom livedo was noted. These findings indicate that histopathological cutaneous necrotizing vasculitis may be a useful parameter to define the risk of ischemic cerebrovascular events. Performing a skin biopsy to determine the presence of cutaneous vasculitis could be an important prognostic indicator of the risk of ischemic cerebrovascular events in livedo patients.22 These findings may shed further light on how to treat patients with livedo, especially those who showed histopathological necrotizing vasculitis using skin biopsy.

Nodular lesion

This condition is characterized by a skin rash that is slightly elevated and feels light to the touch due to the vasculitis in the lower dermis and/or subcutaneous fat. When the localized arteries are occluded due to the vasculitis, the peripheral vessels become dilated and take on slight erythema with a nodular lesion. Nodular lesion indicates involvement of small and/or medium-sized vessels, sometimes associated with livedo racemosa due to the same histopathogenesis. When confronted with such a rash, it is necessary to consider necrotizing vasculitis from the lower dermis to the subcutaneous fat (Fig. 4).

Cutaneous ulceration

Cutaneous ulcerations with purpuric painful lesions over the lower extremities are found in primary cutaneous vasculitis, especially CPN (Fig. 5). Recalcitrant cutaneous ulcerations are associated with myalgias and arthralgias, and elevated serum CRP levels. Cutaneous ulcerations heal with porcelain-white, stellate, atrophic scarring and hyperpigmentation (atrophie blanche) during the follow-up clinical course.

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Figure 5.  Recalcitrant cutaneous ulcerations with livedo racemosa on the lower extremities of a patient with cutaneous polyarteritis nodosa.

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Palisading granuloma on the elbow and knee

Although small nodules on the elbow and knee are not common, they are relevant cutaneous manifestations of vasculitis (Fig. 6).24–26 This disease resembles rheumatoid nodules. Microscopic examination of the skin biopsy reveals a palisade arrangement of histiocytes in the dermis, called palisading granulomas. Because it often occurs in the extremities, such as the elbow and knee, which are often subjected to external stimulation, chronic recurrent vasculitis and external force result in granulomatous changes.

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Figure 6.  Palisading granuloma on the elbow of a patient with Churg-Strauss syndrome.

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Diagnostic algorithm of primary cutaneous vasculitis (kawakami algorithm)

  1. Top of page
  2. Abstract
  3. Introduction
  4. Seven diseases based on a new algorithm for primary cutaneous vasculitis (kawakami algorithm)
  5. Main cutaneous manifestations of primary cutaneous vasculitis
  6. Diagnostic algorithm of primary cutaneous vasculitis (kawakami algorithm)
  7. Mechanisms of primary cutaneous vasculitis
  8. Treatment of cutaneous polyarteritis nodosa and henoch–schönlein purpura
  9. Concluding remarks
  10. Acknowledgments
  11. References

When one examines the above features of the cutaneous manifestations, one can suspect cutaneous vasculitis and use the proposed diagnosis algorithm shown in Figure 7 (KAWAKAMI algorithm). The algorithm deals only with primary cutaneous vasculitis and excludes collagen disease, cancer, infection and drug-induced secondary vasculitis. In addition, the algorithm excludes urticarial vasculitis, erythema elevatum diutinum and facial granuloma with characteristic dermatological features.

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Figure 7.  Diagnosis algorithm for primary cutaneous vasculitis (KAWAKAMI algorithm). ANCA, antineutrophil cytoplasmic antibody; Ig, immunoglobulin; MPO, myeloperoxidase; PR3, proteinase 3; SLE, systemic lupus erythematosus.

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The first step is to measure serum ANCA levels. If myeloperoxidase (MPO)-ANCA is positive, Churg–Strauss syndrome or microscopic polyangiitis can be suspected. Churg–Strauss syndrome is characterized by a past history of asthma or allergic rhinitis, blood eosinophilia, increased immunoglobulin (Ig)E and eosinophilic infiltration upon histopathological examination, and this needs to be differentiated from microscopic polyangiitis. Microscopic polyangiitis generally has a rapid to intermediate progressive clinical course which eventually results in renal failure and pulmonary hemorrhage. However, a slowly progressive clinical course, the smoldering type, is generally manifested by slow increases in serum MPO-ANCA and CRP levels.25,27,28 These patients often first visit the dermatology department rather than the internal medicine department because their cutaneous manifestations tend to be noticed as an initial abnormal finding during the slowly progressive clinical course. If the patient is positive for proteinase 3 (PR3)-ANCA and the upper and lower respiratory tracts are affected, Wegener’s granulomatosis is most likely. Next, if cryoglobulin is positive, cryoglobulinemic vasculitis should be suspected and its underlying diseases sought, particularly hepatitis B, hepatitis C, systemic lupus erythematosus and Sjögren’s syndrome.29–31 Third, direct immunofluorescence of the skin biopsy specimen is used to examine IgA deposition in the affected vessels. If we find IgA deposition in the vessels, especially small vessels in the dermis, HSP is indicated (Fig. 8). Most patients who present with HSP have palpable purpura on the lower extremities.15 If IgA deposition is absent, it is necessary to measure lupus anticoagulant (LAC) and anti-PS/PT antibody (in particular IgM), and if histopathological examination reveals necrotizing vasculitis (leukocytoclastic vasculitis) in the upper to middle dermis, CLA is indicated, whereas if necrotizing vasculitis exists in the lower dermis and/or the subcutaneous fat, CPN is indicated (Fig. 7).10,15 The algorithm as a clinical diagnosis of primary cutaneous vasculitis artificially divides patients into groups depending on clinical symptoms and histopathological findings based on the skin biopsy specimen. Some patients may have positive findings for more than one element of the algorithm. The algorithm also needs to be tested further in patients with less well-defined disease during the clinical course.

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Figure 8.  Direct immunofluorescence testing reveals immunoglobulin A deposition in the walls of the involved blood vessels.

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Note 1

Churg–Strauss syndrome is an ANCA-associated vasculitis, but approximately half of all patients test negative for ANCA. Purpura and petechiae accompanied by paresthesias due to lower extremity mononeuritis multiplex is a useful dermatological finding in early-stage Churg–Strauss syndrome.24,32

Note 2

In general, microscopic polyangiitis progresses rapidly, but there is a slowly progressive type in which the clinical course advances relatively slowly. Skin biopsy specimens of smoldering type reveal leukocytoclastic vasculitis with more moderate neutrophilic infiltration in the superficial dermis compared with that of regular microscopic polyangiitis.25,33

Note 3

Cryoglobulins are cold-precipitating Ig that persist in the serum and resolubilize when rewarmed.29,30 There is no standard method to measure cryoglobulin. Histological examination in a cryoglobulinemic vasculitis patient reveals microvascular thrombus and leukocytoclastic vasculitis in the dermis.16 Anti-PS/PT antibodies are detected in serum samples taken from the patient. The anti-PS/PT antibodies levels in cryoprecipitates of cryoglobulinemia are reportedly elevated in comparison with those in cryoglobulin-free sera.31 The presence of such underlying diseases as hepatitis B, hepatitis C, systemic lupus erythematosus and Sjögren’s syndrome need to be conclusively ruled out by examination.

Note 4

The presence of palpable purpura in the lower extremities is required to confirm the diagnosis of adult HSP. Serum IgA and anti-cardiolipin antibody IgA and anti-PS/PT antibody IgA are elevated in the initial active stage of adult HSP. Higher levels of serum anti-cardiolipin antibody IgA are significantly associated with arthralgia and proteinuria according to urinalysis.15,34 In patients with abdominal complications (bloody stool, diarrhea and abdominal pain), levels of clotting factor XIII tend to be lower than normal.

Note 5

Blood samples should be filtered and checked to confirm that there are no residual platelets when measuring the plasma LAC. According to the guidelines recommended by the Subcommittee on Lupus Anticoagulant/Phospholipid Dependent Antibodies, LAC is screened by measuring diluted Russell’s viper venom time and kaolin clotting time and is confirmed by mixing studies and the demonstration of phospholipid dependence.35 The presence of anti-PS/PT antibodies and/or LAC could serve as markers of CLA and CPN.10,15 The anti-PS/PT antibody is closely related to the pathogenic factors that trigger the development.

Mechanisms of primary cutaneous vasculitis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Seven diseases based on a new algorithm for primary cutaneous vasculitis (kawakami algorithm)
  5. Main cutaneous manifestations of primary cutaneous vasculitis
  6. Diagnostic algorithm of primary cutaneous vasculitis (kawakami algorithm)
  7. Mechanisms of primary cutaneous vasculitis
  8. Treatment of cutaneous polyarteritis nodosa and henoch–schönlein purpura
  9. Concluding remarks
  10. Acknowledgments
  11. References

ANCA-associated cutaneous vasculitides

If ANCA causes the vasculitis in vasculitic conditions, the autoantibodies interact with neutrophils and monocytes in the circulation, resulting in activation, microvascular adherence of leukocytes, and subsequent vascular inflammation and necrosis (ANCA–cytokine sequence theory).36–38 Neutrophils play an important role in the pathogenesis and predominate at the site of tissue injury and they are the main target cells of the ANCA antigens. ANCA interacts with primary granule constituents (i.e. PR3, MPO) on the surface of apoptotic neutrophils. Subsequent inflammatory mediators and adhesion molecules activate around the vascular conditions, which is indicative of vasculitis. The potential pathogenic role of ANCA is that ANCA in combination with exogenous factors aggravate a clinical inflammatory process and may result in systemic vasculitis.

Non ANCA-associated cutaneous vasculitides

Anionic phospholipids such as cardiolipin and phosphatidylserine (PS) are regular constituents of the inner leaflet of the cell membrane, which are only exposed on the outside of the cell membrane during apoptosis or by damaged endothelial cells.10 Prothrombin (PT) binds specifically to the surface of apoptotic endothelial cells and combines PS.32,33 The complexes may cause anti-PS/PT antibody production in cutaneous vasculitis, which is likely produced locally. Antiphospholipid antibodies, including anti-PS/PT antibodies, are regarded as activating endothelial cells, thus creating a hypercoagulable state and leading to thrombosis.39 Inflammatory mediators, including interleukin-8 and neutrophils, promote coagulation, providing procoagulant surfaces on which to amplify the signal and by inhibiting natural anticoagulant mechanisms.40 In turn, the coagulation reaction with inflammatory mediators occurs on phospholipid surfaces expressing positively-charged phospholipids. Subsequent complement activation might be due to Ig aggregates, which would likely be produced locally, and cutaneous vasculitis.

Generally, IgA abnormalities suggest an immunological basis for the pathogenetic mechanisms underlying HSP.41,42 It may be related to increased production of abnormally glycosylated IgA, which is not sufficiently cleared by the liver and leads to the formation of IgA macromolecules. These accumulate in the circulation and are subsequently deposited on the vessel walls in cutaneous small vessels. Elevated serum IgA anti-cardiolipin antibody and/or IgA anti-PS/PT antibody levels may imply involvement of immunological elements in the pathogenesis of HSP.15,34

Treatment of cutaneous polyarteritis nodosa and henoch–schönlein purpura

  1. Top of page
  2. Abstract
  3. Introduction
  4. Seven diseases based on a new algorithm for primary cutaneous vasculitis (kawakami algorithm)
  5. Main cutaneous manifestations of primary cutaneous vasculitis
  6. Diagnostic algorithm of primary cutaneous vasculitis (kawakami algorithm)
  7. Mechanisms of primary cutaneous vasculitis
  8. Treatment of cutaneous polyarteritis nodosa and henoch–schönlein purpura
  9. Concluding remarks
  10. Acknowledgments
  11. References

It is important for dermatologists to establish how best to treat CPN and HSP given how often these two conditions are encountered by dermatologists during clinical examination.

Treatment for cutaneous polyarteritis nodosa

Anticoagulation and/or anti-aggregant therapies should be administrated in most cases of CPN. Warfarin therapy at a target international normalized ratio (INR) of 3.0 is effective in patients with CPN at an active stage and this should be kept at a target INR of 2.0–3.0 during the stable phase. Vitamin K is an essential factor to a hepatic γ-glutamyl carboxylase that adds a carboxyl group to glutamic acid residues on factors II (prothrombin), VII, IX, X, protein S and protein C (Fig. 9). Warfarin creates a deficiency of reduced vitamin K by blocking vitamin K epoxide reductase, thereby inhibiting maturation of these vitamin K-dependent clotting factors.43 Warfarin treatment has reportedly led to the effective attenuation of anti-PS/PT antibodies related to PT, and leads to improvement in symptoms among these patients. Clopidogrel is known to block the adenosine diphosphate pathway, impair clot retraction and render thrombin-induced platelet aggregates susceptible to disaggregation.44 Clopidogrel is presently the treatment of choice, primarily to prevent stent re-stenosis in coronary artery disease and in the early and long-term prevention of atherothrombotic events. In addition, clopidogrel improves endothelial nitric oxide bioavailability and diminishes biomarkers of oxidant stress and inflammation.45 Clopidogrel treatment leads to impairment of the thrombotic and vasculitis processes, which are triggered in the development of CPN.46

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Figure 9.  Blood coagulation pathway.

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Neither warfarin nor clopidogrel therapy alone can effectively treat CPN with active inflammatory lesions. Systemic glucocorticosteroids represent an anti-inflammatory agent and the mainstay of therapeutic strategies for autoimmune disease. Long-term systemic administration, however, may be limited due to severe adverse effects and its tendency to cause coagulation reactions. Mizoribine is a purine synthesis inhibitor that has recently been developed as a new immunosuppressant in Japan.47 This drug induces selective inhibition of inosine monophosphate dehydrogenase and guanosine monophosphate synthetase, which inhibits T- and B-cell proliferation.48 The pharmacological effects are the same as those of another purine biosynthesis inhibitor, mycophenolate mofetil. It has recently been reported that 14-3-3 proteins, which are mizoribine-binding proteins, interact with the glucocorticoid receptor and may enhance the transcriptional activity of that receptor, suggesting a steroid-sparing effect of mizoribine.49 A serum mizoribine concentration level of more than 2.6 μg/mL has been shown to enhance the interaction of the glucocorticoid receptor significantly.50 When the serum concentration of mizoribine reaches 2.6 μg/mL, mizoribine leads to a dramatic improvement in symptomatology. Monitoring mizoribine concentration is important for achieving effective therapy.

In the case of i.v. injection, argatroban or lipoprostaglandin E1 (Lipo-PGE1) is used. Argatroban is a synthetic monovalent direct anticoagulant/thrombin inhibitor,51 and can lead to remarkable improvement in microcirculation. Prostaglandin E1 (PGE1) is a prostanoid that has numerous biological actions such as inhibition of receptor-mediated stimulation of platelet aggregation, cytoprotection, vasodilation and suppression of antibody formation.52,53 Lipo-PGE1 is a particle preparation of PGE1, which is incorporated in a lectin liposome and is believed to prevent rapid destruction of PGE1 and accumulate in vascular lesions.54

Treatment for Henoch–Schönlein purpura

Corticosteroids, given early in the course of illness, seem to produce consistent benefits for several major clinically relevant HSP outcomes. Early intervention in the course of HSP has been shown to improve patient outcomes for both children and adults and reduce chronic renal disease.55 Mizoribine has recently been proven clinically effective and safe for the treatment of nephrotic syndrome,49 IgA nephropathy56 and lupus nephritis.47 Therefore, we propose prophylactic treatment of renal complications in patients with HSP.

Concluding remarks

  1. Top of page
  2. Abstract
  3. Introduction
  4. Seven diseases based on a new algorithm for primary cutaneous vasculitis (kawakami algorithm)
  5. Main cutaneous manifestations of primary cutaneous vasculitis
  6. Diagnostic algorithm of primary cutaneous vasculitis (kawakami algorithm)
  7. Mechanisms of primary cutaneous vasculitis
  8. Treatment of cutaneous polyarteritis nodosa and henoch–schönlein purpura
  9. Concluding remarks
  10. Acknowledgments
  11. References

Cutaneous symptoms are easy to notice, and by interpreting the cutaneous manifestations, dermatologists can ascertain the type of affected vessels. When compared to kidney and lung biopsies, skin biopsies are less invasive and more convenient. If it is possible to detect necrotizing vasculitis at an early stage by skin biopsy based on cutaneous manifestations, this could lead to more accurate and earlier diagnosis, as well as efficacious treatment of vasculitis. The proposed algorithm (KAWAKAMI algorithm) for vasculitis patients may allow us to refine our earlier diagnostic strategies and provide more efficacious treatment of primary cutaneous vasculitis.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Seven diseases based on a new algorithm for primary cutaneous vasculitis (kawakami algorithm)
  5. Main cutaneous manifestations of primary cutaneous vasculitis
  6. Diagnostic algorithm of primary cutaneous vasculitis (kawakami algorithm)
  7. Mechanisms of primary cutaneous vasculitis
  8. Treatment of cutaneous polyarteritis nodosa and henoch–schönlein purpura
  9. Concluding remarks
  10. Acknowledgments
  11. References

I thank Professor Y. Soma (St Marianna University School of Medicine) and Professor M. Mizoguchi (formerly of St Marianna University School of Medicine) as well as our colleagues at St Marianna University School of Medicine for their assistance with validation and providing constructive feedback. I am also grateful to the chief member of the Committee, Professor K. Katsuoka (Chief; Kitazato University) and thank the Guideline Committee of Vasculitis 2008 within the Japanese Dermatological Association.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Seven diseases based on a new algorithm for primary cutaneous vasculitis (kawakami algorithm)
  5. Main cutaneous manifestations of primary cutaneous vasculitis
  6. Diagnostic algorithm of primary cutaneous vasculitis (kawakami algorithm)
  7. Mechanisms of primary cutaneous vasculitis
  8. Treatment of cutaneous polyarteritis nodosa and henoch–schönlein purpura
  9. Concluding remarks
  10. Acknowledgments
  11. References