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CUTANEOUS VASCULITIS
1. INTRODUCTION
Vasculitides comprise of heterogeneous entities of vasculitic processes of diverse aetiologies and manifestations. The vasculitic process can be confined to the skin only, or involve vital organs such as kidney, lung, nervous system and gut. The underlying pathogenesis is often immunological, the detail mechanisms have not be fully elucidated in every case yet. Vasculitis is strictly defined as a process through which inflammatory destruction of the of blood vessels walls occurs. Nowadays, most clinicians use the term vasculitis in a broad sense to mean a condition/process in which blood vessel walls are inflamed and destroyed.
2. AETIOLOGY
A causative agent can sometimes be implicated in small and medium vessel vasculitis. Examples include: (i) Drug, e.g., aspirin, NSAID, penicillin etc. (ii) Infection, e.g., Hepatitis B, Streptococcus etc. (iii) Blood disorder, e.g., essential mixed cryoglobulinaemia (iv) Neoplastic, e.g., multiple myeloma, lymphoma. In large vessel vasculitis, a causative agent is not identified yet, e.g. Temporal arteritis, Takayashu's disease.
3. HISTOPATHOLOGY
3.1 Major Features
The main histopathological features are fibrinoid necrosis of the affected vessel wall and inflammatory cells within the vessel wall. Accompanying extravasation of red cells are frequent and responsible for palpable purpura observed clinically.
3.2 Minor Features
The minor histopathological features that often but not invariably accompany vasculitis include thrombosis occluding the vessel lumen; associated inflammation and damage to surrounding tissue (e.g. panniculitis, ischaemia, necrosis); direct immunofluorescence staining showing immunoglobulin Ig G/A/M and C3 deposition within the vessel wall *.
3.3 Vessel Size
The small vessels (postcapillary venules) are involved in leuco-cytoclastic or hypersensitivity (allergic) vasculitis. The medium size vessels are involved in polyarteritis nodosa. The large arteries are involved in giant cell arteritis.
PS : Pitfall - Perivascular lymphocytic infiltration without involving the vessel wall itself is commonly seen in many conditions and should not be regarded as vasculitis.
3.4 Type of Inflammatory Cells
The type/s of inflammatory cells present differ in different types of vasculitis and differ at different age of the lesion. The different types of inflammatory cells and the clinical conditions in which they are found are outlined below :
Leucocytoclastic vasculitis :
Neutrophils are predominant. Examples are Henoch-Scholein Purpura, drug-induced vasculitis, erythema elevatum diutinum, granuloma faciale, hypocomplementemic vasculitis, polyarteritis nodosa, acute febrile neutrophilic dermatosis (Sweet Syndrome)**.
Lymphocytic vasculitis :
Lymphocytes are predominant. Examples include erythema nodosum, lupus erythematosus, pityriasis lichenoides.
Eosinophilic vasculitis :
Churg-Strauss is an example. Eosinophils are predominant.
Granulomatous vasculitis :
Wegeners Granulomatosis and Churg-Strauss Angiitis***. Cells include histiocytes, plasma cells, lymphocytes and occasional giant cells.
Giant cells arteritis :
Are found in cranial and temporal arteritis and polymyalgia rheumatica. Multinucleated giant cells are predominant.
* The optimum specimen selected for biopsy should be an early established lesion about 18-36 hours old.
** The traditional view that Sweet Syndrome is a form of vasculitis is now being challenged. Many dermatopathologist no longer consider this condition a true vasculitis, because the histopathology merely consists of dense dermal perivascular neutrophilic aggregates, without fibrinoid necrosis of the vessel wall.
*** Churg-Strauss (Granulomatosis) Angiitis has features of a necrotising granulomatosus and eosinophilic vasculitis.
4. PATHOGENESIS
Immune Complex Deposition :
Following exposure to an antigenic stimulus, antibodies, usually of IgG or IgM class, are formed and complex with the antigen in the circulation. These complexes circulate without any difficulty until reaching certain sites, where local factors (eg antigen excess in gravitational dependent areas) causes them to deposit and bind to the vessel wall.
Complement Activation and consumption :
The Fc portion of the immunoglobulin molecule binds complement and initiates the complement cascade. Subsequent elaboration of the potent chemotactic factor C5a attracts neutrophils into the vessel wall. Tissue injury occurs as the activated neutrophils phagocytize the immune complexes and thereby release destructive proteolytic enzymes. The resulting inflammation, necrosis, and haemorrhage appear clinically as palpable purpura when they occur on the skin.
Lymphocytic infiltration :
Following exposure to antigenic material, tissue lymphocytes and histiocytes become activated to produce various cytokines and inflammatory mediators. Their interaction with intercellular adhesion molecules on cell surfaces will initiate and regulate cell mediated immunity, leading to further lymphocyte proliferation and macrophage aggregation at the site of inflammation.
Granulomatous inflammation and giant cell formation :
Failure to clear the antigen will perpetuate the inflammatory processes and eventually lead to epithelioid giant cell and granuloma formation.
5. CLINICAL PRESENTATION
5.1 Cutaneous features
Morphology of skin lesions :
Persistent urticaria, tender palpable purpura, papules, nodules, haemorrhagic bulla, Ulcers, atrophie blanche, livedo reticularis, nail fold-telangiectasia, infarct, digital gangrene.
Distribution of Skin lesions :
Often start on dependent areas initially (eg lower legs, buttocks, back) before becoming generalised. This is due to the effect of hydrostatic force on the post-capillary venules, leading to the preferential deposition of immune complexes in these sites.
Course of skin lesions :
Occur in successive crops, evolving from papules, nodules to palpable purpura which resolve leaving pronounced post-inflammatory hyperpigmentation. Depending on the aetiology, the course may be acute, resolving within few days to few weeks; or it may be chronic and recurrent, persisting from months to years.
5.2 Extracutaneous features
General : Fever, malaise, mucous membrane ulcers
Renal : Glomerulonephritis - proteinuria, haematuria, hypertension
Pulmonary : Pneumonitis and haemorrhage - haemoptysis, dyspnoea
GI tract : Melaena, abdominal pain
Musculoskeletal : Joint pain, myalgia
Neurological : Mononeuritis multiplex, Myelopathy, CVA.
Eye : Iritis, Uveitis
Cardiac : Pericarditis, endocarditis, myocarditis and infarct
6. INVESTIGATION
Investigations are performed to : a) confirm the diagnosis of vasculitis and determine the predominant cell infiltrate by skin biopsy. b) Screen for any extra-cutaneous organ involvement and hence the systemic nature of vasculitis. c) Exclude an offending causative agent and remove it if possible e.g. drug. d) Screen for and treat any underlying disease process that may be responsible for the vasculitis e.g. Infection, connective tissue disease or malignancy.
Skin biopsy for histopathological studies.
Blood Tests for
Complete blood count & Erythrocyte sedimentation rate.
Antinuclear Factor Screen
Rheumatoid Factor
Complements C3, C4
Liver and Renal biochemistry profile
C-Reactive Protein
Anti-streptolysin O Titre
Cryoglobulins
Anticardolipin Antibody (Quantitative VDRL)
Immunoglobulin pattern and Serum protein electrophoresis
Hepatitis B Antigen
Throat swab for culture
Urinalysis for proteinuria, Red blood Cell, White cell, and Casts
Stool for Occult Blood
Chest X ray
Nerve Conduction Studies and/or Nerve Biopsy
NB : More invasive investigations like Renal or lung Biopsy may be useful but should not be taken lightly unless clearly indicated and in conjunction with the physician.
7. TREATMENT
7.1 Cutaneous
Supportive
Bed rest, elevation of dependent parts and avoidance of trauma and cold
Anti-inflammatory agents
Include topical steroids, nonsteroid anti-inflammatory drug e.g. Indomethacin, Colchicine 0.5 mg bd or tds, dapsone 50-100 mg qd (esp erythema elevatum diutinum), sulphapyridine, Minocin.
Antiplatelet agents
Such as aspirin or dipyridamole are sometimes used
Systemic corticosteroids given as a short course may be useful in an acute severe episode to reduce morbidity and produce early resolution of lesions
7.2 Systemic
Systemic vasculitis with widespread involvement of internal organs (e.g. renal, heart, lung) may result in life-threatening complications (e.g. acute renal failure). Prompt treatment with high dose systemic steroids and immunosuppressives, e.g. cyclophosphamide are required to reduce morbidity and are often life-saving. Monitoring of electrolytes, haematological picture, and hepato-renal function is necessary during treatment.
7.3 Life-Threatening System Vasculitis
IV Pulse Methylprednisolone, 1g QD for 3-5 days
IV Cyclophosphamide 2mg/kg/day, for 5-7 days
Plasmaphoresis, plasma exchange
These agents are indicated in emergency situations where immediate control of the disease activity is imperative to prevent mortality and preserve organ (e.g. renal) function.
IV Cyclophosphamide may cause haemorrhagic cystitis. Careful monitoring of fluid and electrolyte balance is necessary during administration. Any infection should be identified and treated promptly.
8. APPENDIX : EXAMPLES OF VASCULITIS WITH SIGNIFICANT SKIN INVOLVEMENT
8.1 Leucocytoclastic Vasculitis
This is a heterogeneous disorder with hypersensitivity reaction and immune complex deposition, following exposure to an antigen, foreign (infectious agent/drug) or endogenous. The small vessels (post-capillary venules) are infiltrated with neutrophils and their nuclear debris (Leucocytoclasis) in the acute stages. Skin lesions occur on gravitational dependent areas : lower extremities of ambulatory patients or sacral area of bed-ridden patients. These include palpable purpura, macules, papules, vesicles, bullae, subcutaneous nodules, ulcers, recurrent or chronic urticaria. The ankles and lower limb may be swollen. Constitutional symptoms include fever, malaise, arthralgia, myalgia, haematuria, GI bleeding and neuropathy. Investigations reveal mild leucocytosis and elevated ESR; cryoglobulins and rheumatoid factor may also be detected.
Henoch-Schoenlein purpura (anaphylatoid purpura) is a variant that occurs in children and young adults after an upper respiratory infection. It is characterized by purpuric skin eruptions on the extensor surface of lower limbs and buttocks, arthritis, abdominal pain, and glomerulo-nephritis with haematuria. Raised serum IgA and IgA immune deposits are found on the affected vessel walls. Platelet count is normal distinguishing this condition from thrombocytopenic purpura.
Treatment :
(i) Bed rest and elevation of the dependent parts,
(ii) NSAID to control inflammation and relief joint pain.
(iii) Monitor for systemic involvement like blood pressure and urinalysis, stool for occult blood etc.
(iv) Screen and treat the underlying cause if possible
Only when the function of vital organs (e.g. renal) are compromised should systemic steroids be necessary.
8.2 Narcotizing Vasculitis
8.2.1 Classic Polyarteritis Nodosa (PAN)
This is a multisystem, narcotizing vasculitis of small and medium sized muscular arteries with characteristic involvement of renal and visceral arteries. 30% are HBsAg +ve. The mean age of onset is 45 years with a male preponderance (M/F 2.5 to 1). Systemic features include fever, malaise, arthralgia, myalgia, abdominal pain, melaena, CVA, neuropathy, hypertension and renal failure. Cutaneous lesions occur in 50% of cases with painful subcutaneous nodules, purpura, ulcers, infarct and gangrene along the course of arteries and a livedo reticularis pattern. Microscopic PAN is a variant with small vessel vasculitis and focal segmented glomerulonephritis.
Investigations include skin biopsy of nodular lesions, sural nerve biopsy and nerve conduction study. Blood test showed raised ESR, leucocytosis with neutophilia, anaemia of chronic disease, hypergammaglobulinaemia, and positive Hep B surface antigen. Renal and visceral artery involvement are demonstrated by small aneurysmal dilatations on visceral angiography. Classic PAN does not involve pulmonary arteries; granuloma and significant eosinophilia are not part of the syndrome.
Treatment and course :
The clinical course is characterized by progressive deterioration with intermittent acute flare ups. Death usually results from renal failure. The 5 year survival of untreated patients is 13%, but with combined systemic steroid and cyclophosphamide therapy there may be a 90% long term remission rate even after discontinuing therapy.
8.2.2 Cutaneous Polyarteritis Nodosa
A more benign form PAN where vasculitis is chiefly confined to the skin only. Cutaneous manifestation is similar but milder than classic PAN; nodules and livedo, with accompanying fever, arthralgia and neuropathy occasionally.
Treatment includes low dose systemic steroids. The prognosis is good with no significant mortality even without treatment.
8.2.3 Churg-Strauss (Allergic Granulomatous) Angiitis
Churg-Strauss is a systemic vasculitis which shares many features with classic PAN, but distinguished by the following features :
(i) Frequent involvement of the lung.
(ii) Vasculitis of blood vessels of various types and sizes.
(iii) Intravascular and extravascular granuloma formation with eosinophil infiltration.
(iv) Strong association with severe asthma and peripheral eosinophilia.
(v) Skin lesions occur in 70% of cases but renal disease is less common or severe as PAN.
The 5 year survival of untreated Churg-Strauss is 25%. The cause of death is often related to cardio-pulmonary involvement as opposed to renal and gastro-intestinal involvement of PAN.
Glucocorticoid therapy alone improves 5 year survival to 50%. Combination regimen of cyclophosphamide and alternate day prednisolone is required for more severe cases and may result in high rate of remission approaching that of classic PAN.
8.2.4 Kawasaki Disease (Mucocutaneous Lymph Node Syndrome)
Is an acute vasculitis of unknown aetiology that most frequently affects infants and children between 5 years of age. It is probably initiated by an yet unidentified infective agent. The clinical picture is characterized by fever, palpable cervical lymph node, bilateral conjunctivitis, red cracked lips with strawberry tongue, and generalized erythematous desquamative rash especially on extremities. It affects the coronary arteries in 30% of cases. Overall mortality is 1-2% due to cardiovascular complications : acute coronary thrombosis and late sequel of coronary artery aneurysm.
High dose aspirin remains the mainstay of treatment. Recent studies in Japan and USA have shown that high dose IV gamma globulin is effective in reducing coronary artery abnormalities when given early in the course of the disease. Systemic steroids are contraindicated because they increase risk of coronary complications.
8.3 Livedo Vasculitis and Atrophie Blanche
Atrophie blanche are peculiar porcelain white scars studded with pepper like red macules and telangiectasia seen around the medial malleolus of both ankles. They are frequently the result of chronic venous stasis in varicose vein disorder, yet sometimes they represent the healed result of painful infarction.
Livedo reticularis describes the blotchy, mottled, net-like pattern of skin cyanosis seen in cutaneous vasculitis as a result of reduced and sluggish cutaneous blood flow. A similar but reversible appearance may be seen as a physiological response to cold on the exposed lower limbs of young girls during winter. Livedo reticularis may be secondary to cutaneous polyarteritis, lupus vasculitis, and vasculitis associated with antiphospholipid antibody syndrome. In the latter, livedo may occur together with atrophie blanche. Livedo vasculitis associated with atrophie blanche is considered as a distinct entity by North American Dermatologists.
Treatment :
The disorder is associated with a decrease in fibrinolytic activity in skin and increase platelet adhesiveness. Phenformin and ethylestrenol in combination are effective because of their enhancement of fibrinolytic activity. Combination of aspirin (300 mg/day) and dipyridamole (50 mg tds) which affect platelet function are helpful. Pentoxifylline (Trental) 400 mg tds has also been used with some success.
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