Rheumatology

Leukocytoclastic vasculitis

Does this patient have leukocytoclastic vasculitis?

Leukocytoclastic vasculitis (LCV) is a frequently-misused histopathologic term that describes the microscopic changes seen in various types of vasculitis affecting the skin and internal organs. However, LCV more typically refers to small-vessel vasculitis of the skin. The terms cutaneous LCV, cutaneous small-vessel vasculitis, and cutaneous leukocytoclastic angiitis are all used interchangeably for this type of skin-predominant vasculitis, which most commonly presents with palpable purpura on the lower extremities.

The 1994 Chapel Hill nomenclature defined cutaneous leukocytoclastic angiitis as an isolated, skin-limited disease without systemic vasculitis or glomerulonephritis. The revised 2012 Chapel Hill nomenclature now lists cutaneous leukocytoclastic angiitis and cutaneous arteritis as two of the single-organ vasculitides (i.e. with no features that indicate that it is a limited expression of a systemic vasculitis). The exact way to differentiate between cutaneous leukocytoclastic angiitis and cutaneous arteritis is not clearly specified, which further exemplifies the lingering ambiguity behind the terms of LCV. The nomenclature also clearly emphasizes that some patients originally diagnosed with cutaneous vasculitis can later progress to manifest symptoms of systemic vasculitis. Therefore, a diagnosis of cutaneous LCV based on typical clinical and histologic findings, one must rule out systemic involvement and search for underlying causes and associated diseases.

Epidemiology

Cutaneous LCV is not rare. In all, 38-55 per million adults per year are diagnosed with the condition, as compared with 5-10 per million diagnosed annually with granulomatosis with polyangiitis. Cutaneous LCV affects both sexes equally, and all ages. The possible underlying causes are multiple. It is often a skin-limited and benign condition of undetermined origin, but it can become chronic and/or feature recurrent flares, with significant psycho-social impact.

It can also represent the first manifestation of a more severe disease with extra-cutaneous and potentially life-threatening complications, including systemic vasculitides, but also infections, connective tissue diseases, and malignancies.

Clinical presentation

The disease classically presents with purpuric papules a few millimeters in diameter, predominately located on the lower legs and other dependent areas, but also often involving the thighs, buttocks, and lower abdomen. The upper body is less frequently affected. These skin lesions may be subtly palpable or indurated, necrotic and/or ulcerated, and occasionally confluent and ecchymotic. There is often a halo of erythema around the lesions and associated edema of the affected limb.

Vesicles, pustules, and urticarial papules are sometimes seen, but larger hemorrhagic bullae, subcutaneous nodules, and livedo reticularis are less common and should raise suspicion of vasculities involving medium-sized vessels. Figure 1, Figure 2, Figure 3, and Figure 4 show presentations of cutaneous LCV.

Figure 1.

Figure 2.

Figure 3.

Figure 4.

The first skin lesions usually develop rapidly in crops over 1 to 2 days. This acute eruption may suggest a preceding associated trigger. Other lesions arise over subsequent days or weeks. The number of lesions is extremely variable, ranging from few to hundreds.

Individual lesions typically last 2-3 weeks before fading away, leaving hyperpigmented and/or atrophic scar-like areas. New lesions may appear almost daily until treatment is initiated or a trigger withdrawn. Successive flares can occur at various intervals, interspaced from days or weeks to sometimes years. Ulcerated lesions, particularly those on the lower limbs, may be slow to heal.

Cutaneous LCV may be chiefly an aesthetic concern. The purpuric lesions are rarely painful unless they become ulcerated. They can be itchy or accompanied by an aching discomfort or heaviness, especially when the eruption leads to soft-tissue edema. Arthralgias of adjacent joints, mainly the ankles, are common during and/or before the flares. Frank synovitis or arthritis is rare and suggests the presence of systemic disease.

Careful review of preceding or accompanying symptoms - especially fever, abdominal pain, numbness or tingling of the hands or feet, presence of gross hematuria or bloody stools, and cough or shortness of breath - is important for prompt identification of potentially severe extra-cutaneous manifestations of vasculitis.

Patients with cutaneous LCV sometimes identify triggering or exacerbating factors such as intake of a particular drug or food, alcohol ingestion, prolonged standing, heat or humidity, menstruation, upper respiratory infection, or other uncomplicated infectious illnesses. Seldom are these factors the sole cause of the vasculitis. However, a thorough patient interview is essential, because identifying such triggers can play an important role in long-term management.

The extent and precise characteristics of cutaneous LCV lesions do not reliably predict their cause or the likelihood of finding more severe extra-cutaneous manifestations. Thus, a thorough, extensive, and systematic diagnostic work-up must be conducted.

What tests to perform?

Lab testing

Fundamentally, the diagnosis of LCV is histopathologic. When lesions clinically suspicious for LCV are noted on examination, the first and most important diagnostic test is often a skin biopsy.

Once the finding of LCV is confirmed histologically, the physician’s work has only just begun. A thorough review of systems and physical exam should be followed by a targeted work-up to identify possible underlying causes and rule out systemic disease. In about half of adult patients, an underlying cause can be found: infection (15-20%), inflammatory disease (15-20%), medication or drug (10-15%), and malignancy (<5%), with the remaining 45-55% idiopathic.

Basic or first-line tests include complete blood cell count with differential, serum creatinine level, C-reactive protein level and/or sedimentation rate, liver enzymes, and urinalysis (with microscopic review). Stool guaiac testing may be useful to screen for gastrointestinal involvement.

If suspicion of systemic vasculitis or a particular underlying disease is high or if there is no obvious cause of the vasculitis, additional tests may be ordered, including tests for antinuclear antibodies (ANA) and antibodies against extractable nuclear antigens (anti-ENA), anti-neutrophil cytoplasmic antibodies (ANCA), C3 and C4 complement components, rheumatoid factor, as well as cryoglobulin screening, serum protein electrophoresis, determination of activated partial thromboplastin time, and viral serologies (hepatitis B and particularly C virus and HIV).

Depending on the context and the results of these first investigations, other tests may be ordered, such as tests for cryofibrinogen, lupus anticoagulant, anti-B2-glycoprotein I, anti-cardiolipin, anti–double-stranded DNA, anti-cyclic citrullinated peptide, and serum IgA levels as well as immunoelectropheresis of serum protein, tests for celiac disease, cold agglutinin, specific serologies, echocardiography, and blood and/or urine culture if an infection, particularly endovascular or neisserial, is suspected.

Biopsy

In cases of suspected cutaneous vasculitis, a biopsy is almost always necessary to confirm the suspected diagnosis and to guide further management. Histologic findings are dynamic, so a biopsy performed too early or too late in lesion evolution may be non-diagnostic. Generally, a biopsy should be directed at a relatively new or fresh lesion, approximately 12-48 hours old, and every effort should be made to perform the biopsy the same day the patient is seen if there are new lesions.

The classic findings of LCV include vascular and perivascular infiltration of superficial and mid-dermal small blood vessels with neutrophils and granulocytic debris or nuclear dust (leukocytoclasis), fibrinoid necrosis and disruption of vessel walls, and extravasation of red blood cells ( Figure 5). Other mixed inflammatory cells such as lymphocytes or eosinophils may be present.

Figure 5.

This histologic pattern is not specific to any one entity; it can be seen in any vasculitic syndrome. It also may be seen in various infections, neutrophilic dermatoses, ulcer beds, or insect bite reactions. Therefore, the clinical–pathologic correlation must be established before arriving at a final diagnosis.

Importantly, when cutaneous LCV is suspected, a biopsy for direct immunofluorescence analysis should also be performed to detect immune complex deposition (complement [C3] and/or immunoglobulin [Ig] deposits [IgA, IgG, or IgM, and cryoglobulin precipitates]). The predominant presence of IgA suggests a diagnosis of IgA vasculitis (Henoch-Schonlein purpura).

Immunofluorescence studies may also help rule out conditions that can sometimes be associated with secondary skin vasculitis, such as systemic lupus erythematosus (lupus band test, with IgG and complement deposition at the dermoepidermal junction).

Finally, the term “leukocytoclastic vasculitis” is sometimes improperly used to describe isolated perivascular inflammatory infiltrates (i.e. with no infiltration of the vessel wall or fibrinoid necrosis and therefore no real vasculitis). Therefore, the detailed pathology report must be read, checking whether a direct immunofluorescence study was done and not relying solely on the line diagnosis.

Imaging

A chest X-ray, if not performed recently, should be ordered. Depending on the context and associated clinical findings, other examinations may be indicated. CT angioscan of the abdominal, celiac and renal artery (or conventional angiography) may be useful with suspected involvement of medium-sized renal or other visceral vessels.

CT scan of the chest, abdomen, and pelvis may be indicated to search for malignancies, particularly in older patients, infectious processes, or manifestations of a systemic vasculitis or other disease. Younger patients are more likely to have an isolated and benign condition or IgA vasculitis (Henoch-Schonlein purpura), but older patients (>40 years old at disease onset) should undergo more extensive investigation for underlying hematologic or solid malignancies.

Overall interpretation of test results

The prognosis of small-vessel vasculitis depends largely on the underlying syndrome, if any, and the presence or absence of systemic vasculitis and/or associated major organ disease. Cutaneous small-vessel vasculitis is, by definition, restricted to the skin and joints and is not associated with more morbid systemic complications. Physical examination and laboratory testing must be thorough and systematic so that the term LCV is applied accurately and appropriate treatment and follow-up can be arranged.

Controversies in diagnostic testing

There are often few specific signs or symptoms of individual disorders that cause cutaneous vasculitis, and the clinical features and histologic findings can overlap. The size of involved vessels continues to be the backbone of most classification schemes.

How should patients with leukocytoclastic vasculitis be managed?

Patients with “idiopathic” cutaneous LCV may exhibit various disease patterns. Most cases self-resolve within 3-4 weeks. Some patients may flare only intermittently, perhaps for 2 weeks every other year; others have recurrent flares every 3-6 months or intractable disease with new lesions almost every day or week for years.

Identifying and controlling triggers or exacerbating factors such as prolonged standing, alcohol use, or specific drug use can help, as can wearing compression stockings and keeping the feet elevated. Bed rest can accelerate the regression of skin lesions but is rarely feasible in active patients.

Topical treatments

Topical treatments such as emollients or corticosteroid creams are sometimes prescribed and may transiently alleviate pruritus when present. The efficacy of such treatments is not supported by any data and is highly variable.

Systemic pharmacological therapies

Systemic pharmacological therapies should be considered after careful discussion with the patient and should be driven by the frequency of flares, the associated discomfort, and the psycho-social impact of the disease. Several different agents must often be tried before finding one that will help limit the frequency and/or intensity of the disease, and for many patients, cure remains an elusive goal.

Glucocorticoids

Although cutaneous small-vessel vasculitis is not rare, few epidemiological studies and no large controlled therapeutic trials have been conducted. Short courses of systemic glucocorticoids can be prescribed for severe flares of cutaneous disease (prednisone, 0.5 to 1 mg/kg/day for 1 week, followed by a rapid tapering over 2-3 weeks). However, the response is not universal and usually requires relatively high doses, so recurrence with tapering and glucocorticoid-dependency are common. Out of concern for adverse side effects, glucocorticoid therapy should be avoided for skin-limited disease except for short periods.

Other long-term treatments

Initial long-term treatment options include colchicine (0.6 mg once or twice daily), which has been useful for cutaneous and joint symptoms in open label studies but not in a small randomized controlled study of 20 patients. There has been so far no other randomized controlled study for cutaneous vasculitis.

The use of dapsone (50 to 200 mg daily) is supported by anecdotal evidence and small case series and may be combined with colchicine. Its use is contra-indicated in patients with glucose-6-phosphate dehydrogenase deficiency, and it may cause methemoglobinemia and anemia with or without hemolysis. Hydroxychloroquine (100 to 300 mg daily), pentoxifylline (400 to 1200 mg daily), and non-steroidal anti-inflammatory agents such as indomethacin may help alleviate symptoms, but their use is supported by only case series and anecdotal data.

Immunosuppressive drugs can be considered, especially when none of the previously mentioned treatments (i.e., colchicine, dapsone, hydroxychloroquine) has been effective or tolerated. Azathioprine (2 mg/kg/day), methotrexate (15-25 mg/week, with folic acid supplementation), mycophenolate mofetil (2 g/day), or leflunomide (20 mg/day) may be considered. The risks of these agents must be cautiously balanced against the severity of skin symptoms.

Stronger and more toxic agents such as cyclophosphamide may be effective, but their use is clearly excessive absent systemic symptoms, unless chronic pain or ulceration are debilitating. Rituximab has been tried with some promising results but is an expensive biologic agent that should be considered in rare circumstances.

What happens to patients with leukocytoclastic vasculitis?

Patients with small-vessel vasculitis of the skin may experience a highly variable disease course. Generally, the prognosis is good, but if systemic organs are involved, more significant morbidity is possible. Chronic relapsing purpura and ulcerations may be life-altering.

When cutaneous disease is one component of a systemic vasculitis, treatment is aimed at controlling the systemic process. Most of the time, if that treatment is effective in controlling systemic disease, the skin lesions will rapidly regress in parallel. With cutaneous LCV limited to the skin, the duration and outcome depend largely on the underlying associated syndrome, if any, and whether a particular trigger (infection, drug, etc.) is responsible. In this case, cutaneous LCV is usually self-limiting and regresses if the infection is cured or the causative agent is stopped.

How to utilize team care?

Specialty consultations

Dermatologists, internists, and rheumatologists may be involved at one time or another in the care of patients with cutaneous LCV.

Nurses

Wound care by experienced nurses may be required for patients with ulcerations.

Pharmacists

As for any condition, pharmacists help limit the risk of drug interactions and provide useful advice to patients to improve treatment tolerance and compliance.

Therapists

Apart from compression stockings and avoidance of prolonged standing, other types of therapy, including massage or physiotherapy, have no proven benefit. As for other conditions, patients may be tempted by naturopathy, homeopathy, acupuncture, and other kinds of alternative medicine, but such treatments rarely yield sustained benefit with this condition.

Are there clinical practice guidelines to inform decision making?

There are no guidelines for the diagnosis, treatment, and follow-up of cutaneous LCV. Larger series with substantial follow-up duration and controlled therapeutic trials are needed before considering the development of evidence-based recommendations.

Other considerations

Typical length of stay

Patients may be hospitalized with acute flares of cutaneous LCV, which can be rather dramatic, particularly during the initial diagnostic phase or until systemic vasculitis is ruled out. Most inpatient stays are short in the absence of confounding issues. Patients with chronic relapsing cutaneous LCV rarely require hospitalization except in the case of severely painful flares, infectious complications of therapy, or superinfection of ulcerated wounds.

What is the evidence?

Sais, G, Vidaller, A, Jucgla, A, Gallardo, F, Peyri, J. "Colchicine in the treatment of cutaneous leukocytoclastic vasculitis. Results of a prospective, randomized controlled trial". Arch Dermatol. vol. 131. 1995. pp. 1399-1402.

Garcia-Porrua, C, Gonzalez-Gay, MA. "Cutaneous vasculitis as a paraneoplastic syndrome in adults". Arthritis Rheum. vol. 41. 1998. pp. 1133-1135.

Gonzalez-Gay, MA, Garcia-Porrua, C, Salvarani, C, Lo Scocco, G, Pujol, RM. "Cutaneous vasculitis: a diagnostic approach". Clin Exp Rheumatol. vol. 21. 2003. pp. S85-88.

Jennette, JC, Falk, RJ, Bacon, PA, Basu, N, Cid, MC, Ferrario, F, Flores-Suarez, LF, Gross, WL, Guillevin, L, Hagen, EC, Hoffman, GS, Jayne, DR, Kallenberg, CG, Lamprecht, P, Langford, CA, Luqmani, RA, Mahr, AD, Matteson, EL, Merkel, PA, Ozen, S, Pusey, CD, Rasmussen, N, Rees, AJ, Scott, DG, Specks, U, Stone, JH, Takahashi, K. " Watts RA2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides". Arthritis Rheum. vol. 65. 2013. pp. 1-11.

Micheletti, RG, Werth, VP. "Small vessel vasculitis of the skin". Rheum Dis Clin North Am. vol. 41. 2015. pp. 21-232.

Pina, T, Blanco, R, Gonzalez-Gay, MA. "Cutaneous vasculitis: a rheumatologist perspective". Curr Allergy Asthma Rep. 2013.

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