Cutaneous small vessel vasculitis

  

Salient features

·       Palpable purpura, urticarial lesions, and/or hemorrhagic macules or vesicles; occasionally, targetoid lesions, pustules, and ulcerations

 

·       Lesions favor the lower extremities (especially the ankles), dependent areas, or pressure points

 

·       Only involves small vessels, primarily postcapillary venules

 

·       Histopathologically, leukocytoclastic vasculitis is seen

 

·       Extracutaneous involvement occurs in up to 30% of patients, but it is usually mild

Introduction

 

CSVV is a single‐organ ­vasculitis that involves primarily the dermal postcapillary venules and is characterized histologically by leukocytoclastic vasculitis (LCV).  Although CSVV with LCV can be seen in the setting of mixed (small and medium-sized vessel) vasculitides, the term CSVV is generally reserved for small vessel vasculitis of the skin without medium-sized vessel involvement, irrespective of the clinical severity of the skin disease or the underlying etiology. CNV may be restricted to the skin, may occur in association with an underlying chronic disease, may be precipitated by infections or drugs, or may develop for unknown reasons (idiopathic).

 

The American College of Rheumatology (ACR) has produced classification criteria for CSVV. The presence of three of the following five criteria have 84% specificity for CSVV: (i) age greater than 16 years at disease onset; (ii) a precipitating factor such as history of taking a medication at onset; (iii) the presence of palpable purpura; (iv) the presence of a maculopapular rash; and (v) a biopsy demonstrating granulocytes around an arteriole or venule.

Epidemiology

 

CSVV occurs in both sexes and at all ages, but is more common in the adult population with a mean age at onset is between 36 and 56 years. It is estimated that ~10% of those affected are children. The annual incidence of CSVV is ~15 cases per million.

 

Etiology

 

Associated chronic disorders ·       Rheumatoid arthritis ·       Sjögren syndrome ·       Systemic lupus erythematosus ·       Hypergammaglobulinemic purpura ·       Paraneoplastic vasculitis ·       Cryoglobulinemia ·       Ulcerative colitis ·       Cystic fibrosis ·       Antineutrophil cytoplasmic or antiphospholipid antibody syndromes

Precipitating events ·       Bacterial, viral, mycobacterial, and rickettsial infections ·       Therapeutic and diagnostic agents

Idiopathic disorders ·       Henoch–Schönlein purpura ·       Acute hemorrhagic edema of infancy ·       Urticarial venulitis ·       Erythema elevatum diutinum ·       Nodular vasculitis ·       Livedoid vasculopathy ·       Genetic complement deficiencies ·       Eosinophilic vasculitis ·       Idiopathic

 

Pathogenesis

CSVV is mediated by immune complex deposition.

 

Pathology

Ideally, lesions should be biopsied within the first 24 to 48 hours of appearance. When CSVV is suspected, a biopsy specimen for direct immunofluorescence should be obtained as the presence of certain immunoglobulins (e.g. IgA) may suggest a particular diagnosis and influence prognosis.

The classic histopathologic features of CSVV are referred to as leukocytoclastic (Necrotizing) vasculitis with segmental inflammation in an angiocentric pattern, endothelial cell swelling, peivenular and transmural infiltration of the walls of small vessels (primarily postcapillary venules) by neutrophils undergoing karyorrhexis of their nuclei (leukocytoclasia) as well as fibrinoid necrosis of the damaged vessel walls i.e. deposition of eosinophilic material (fibrinoid) in the walls of postcapillary venules in the upper dermis, results from accumulation and conversion of plasma proteins, and extravasated erythrocytes.  However, lesions present for greater than 48 to 72 hours may have a predominantly mononuclear rather than neutrophilic infiltrate. Palpable purpura, the most common clinical lesion of CSVV, can be explained by the infiltrate of leukocytes (palpability) and the resulting extravasation of RBCs from the damaged blood vessel (purpura).

In ~80% of cases of CSVV, direct immunofluorescence (DIF) demonstrates deposition of C3 or IgM, in a granular pattern within the vessel walls. Immunoglobulin deposition is highest (up to 100%) in skin lesions present for ≤48 hours. On the other hand, in 30% of samples obtained 48–72 hours after lesion onset, DIF will be negative for immunoglobulins, and only C3 will be detected in lesions present for >72 hours.

 

Clinical features

The three P’s of small-vessel vasculitis

 

CSVV typically presents 7-10 days after exposure to an triggering agent with a single crop of lesions and are polymorphous; however, the hallmark is palpable purpura that describes as bright red, well-demarcated papules with a central, dot like punctum that is a darker red and do not blanch with a glass slide, indicating hemorrhage. Lesions often begin as purpuric macules or partially blanching urticarial papules that may progress to purpuric papules and plaques. In the case of massive inflammation, purpuric papules convert to hemorrhagic blisters. With even more tissue damage, lesional skin will become necrotic and will eventually detach, leaving superficial ulcers. These ulcers may then become secondarily infected. Sometimes, non purpuric erythematous macules, papules, pustules, and targetoid lesions are seen. Occasionally, there is subcutaneous edema below the area of the dermal lesions.

Lesions are scattered, discrete or confluent, and favor areas prone to stasis such as lower legs and the ankles or over other dependent areas such as the back and gluteal regions as well as areas affected by trauma (Koebner phenomenon) or under tight-fitting clothing, reflecting the influence of hydrostatic pressure and stasis on the pathophysiology. Although they are usually asymptomatic, the lesions can be associated with burning, pain or pruritus. Palpable purpura persists for 1-4 weeks and resolves at times with hyperpigmentation and/or atrophic scars. Residual post inflammatory hyperpigmentation may take months to resolve. The clinical lesions are episodic and may recur over weeks to years.

An episode of skin lesions may be accompanied by constitutional symptoms, such as fevers, weight loss and myalgia irrespective of a defined underlying or associated disease. Systemic involvement of the small blood vessels most commonly occurs in the synovia, gastrointestinal tract, voluntary muscles, peripheral nerves, and kidneys.  In general, signs or symptoms of gastrointestinal, renal, or neurologic involvement should increase the clinical suspicion for a systemic vasculitis. 

While the prognosis of patients with CSVV depends upon the severity of systemic involvement, approximately 90% of patients will have spontaneous resolution of cutaneous lesions within several weeks or a few months, while another 10% will have chronic or recurrent disease at intervals of months to years.

 

Laboratory Findings

 

The laboratory evaluation of patients with CSVV depends on information obtained from the history and physical examination. An elevated erythrocyte sedimentation rate is the most consistent abnormal laboratory finding. The platelet count is usually normal. Other abnormalities reflect either a coexistent chronic disorder or the involvement of additional organ systems. Occasionally, leukocytosis, anemia, thrombocytosis, an abnormal urine sediment, circulating immune complexes, rheumatoid factor, and antinuclear antibodies have been reported in idiopathic disease.

Laboratory Evaluation of CSVV

 

·       Erythrocyte sedimentation rate ·       Complete blood count with differential analysis ·       Platelet count ·       Urinalysis ·       24-hour urine protein and creatinine clearance ·       Blood chemistry profile ·       Serum protein electrophoresis ·       Immunoelectrophoresis ·       Hepatitis B antigen and hepatitis A and C antibodies ·       Cryoglobulins ·       CH50 ·       Antinuclear antibody ·       Rheumatoid factor ·       Antineutrophil cytoplasmic antibodies ·       Antiphospholipid antibodies ·       Circulating immune complexes ·       Stool guaiac test ·       Skin biopsy

 

 

Treatment

 

Therapeutic approaches may be divided into removal of the antigen, treatment of an underlying disease, and treatment of CSVV. Therapeutic approaches in the treatment of necrotizing vasculitis consist of prevention of the deposition of immune complexes, suppression of the inflammatory response, modulation of underlying immunopathologic mechanisms, and local therapy. When the eruption is associated with a precipitating event, withdrawal of the medication or treatment of the infection results in resolution of the cutaneous lesions. Efforts to minimize stasis, such as use of compression hosiery and the elevation of dependent areas may reduce symptoms. If a coexistent chronic disease is present, treatment of the underlying disease may be associated with improvement in the cutaneous vascular lesions. In many cases, CNV is a self-limited condition, so treatment is often unnecessary.

H1 antihistamines are used in patients with palpable purpura to alleviate lesional symptoms and perhaps to reduce tissue deposition of circulating immune complexes. Nonsteroidal anti-inflammatory agents are combined with the H1 antihistamine.

The need for and choice of additional treatments depends on the severity of the cutaneous involvement, chronicity and whether or not systemic involvement is present.

Chronic (>4 weeks’ duration) or more severe cutaneous disease may require more aggressive systemic therapy. Colchicine and dapsone may be used either alone or in combination. Oral colchicine (0.6 mg two to three times daily) is helpful for both skin and joint manifestations. However, gastrointestinal side effects are fairly common, even at low doses. Oral dapsone (50–200 mg/day) can lead to improvement of mild to moderate chronic lesions.

Patients with severe, ulcerating or painful progressive cutaneous lesions who require rapid control of symptoms can be treated with a short course of high-dose oral corticosteroids (e.g. up to 1 mg/kg/day of prednisone). Because of the multiple adverse effects of long-term oral corticosteroids, a taper over 4 to 6 weeks should be attempted. If the patient develops recurrent CSVV as the dosage is decreased, addition of a steroid-sparing agent is warranted. Immunosuppressive agents such as azathioprine (1-2 mg/kg/day) and methotrexate (15–25 mg weekly) have been reported to be useful in recalcitrant CSVV.