Hypersensitivity vasculitis

Synonyms: leukocytoclastic vasculitis, cutaneous vasculitis, urticarial vasculitis, small-vessel vasculitis

What is hypersensitivity vasculitis?¹

This is a disorder of the skin caused by small-vessel vasculitis. It is part of the spectrum of vasculitides.

Vasculitis is a disorder in which there are inflamed blood vessels. These may include capillaries, arterioles, venules and lymphatics. Small vessel vasculitis is the most common form of vasculitis affecting arterioles and venules.

Small vessel vasculitis is also called immune complex small vessel vasculitis. The term hypersensitivity vasculitis is used for cutaneous small vessel vasculitis due to known drug or infection.

Pathogenesis

• The disorder can be acute or chronic.

• Internal organs such as the kidneys, gastrointestinal tract and joints may also be affected.

• The pathology is probably mediated by immune complexes.²

The calibre of the affected vessels predominantly involved strongly influences the clinical features of the different forms of vasculitis and therefore is one major criterion for classification. Distinction must be made between antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) and non-ANCA vasculitides. Hypersensitivity vasculitis is an AAV. AAVs are classified according to the Chapel Hill classification revised in 2012.³

Hypersensitivity vasculitis aetiology

No cause is found in a third to half of all cases.

Many drugs have been reported to cause the condition. Examples include:

• Antibiotics.

• Non-steroidal anti-inflammatory drugs (NSAIDs).

• Letrozole.⁴

• Orlistat.⁵

Other implicated causes include:

• Upper respiratory tract infections. As symptoms do not present until after the illness, if an antibiotic is used, it is often impossible to know if it was the illness or the medication that caused them.

• Severe bacterial infection, especially bacterial endocarditis.

• Food and food additives.

How common is hypersensitivity vasculitis?(Epidemiology)

The disease is in many ways similar to Henoch-Schönlein purpura.

• One study of 297 adults (over the age of 20) at a single centre between 1975 and 2012 found that 195 patients (104 men/91 women) were diagnosed with hypersensitivity vasculitis.⁶

• The condition does occur in children but is often labelled as Henoch-Schönlein purpura, as the latter is more common in children. The opposite is true in adults.^{7 8}

Hypersensitivity vasculitis symptoms (presentation)¹

History

The patient may complain of itching, burning or pain but often the lesions are asymptomatic. The most common complaint is of the rash - purpura.

History may reveal an underlying cause with signs and symptoms both dependent on this and the disease process. They may include:

• Fever and flu-like symptoms.

• Abdominal pain, diarrhoea, blood in the stool.

• Chronic cough or haemoptysis.

• Paraesthesia, weakness, or haematuria.

• Arthralgia or myalgia.

Look at past medical history, including possible intravenous drug use, hepatitis, transfusion and travel.

Ask about inflammatory bowel disease including Crohn's disease and ulcerative colitis along with collagen vascular disorders, particularly rheumatoid arthritis, systemic lupus erythematosus, or Sjögren's syndrome.

Take a full drug history, also enquiring into any recent changes in medication.

Examination

Examine the heart, lungs, and musculoskeletal system and perform abdominal examination to seek associated conditions:

• The most common lesion is palpable purpura:
  

  • The lesions are usually 1-3 mm in diameter but may coalesce to form plaques.

  • Rarely they may ulcerate.

  • The most common place for palpable purpura is the legs.

• Sometimes there is urticaria:
  

  • This is different from the usual pattern of urticaria in that it tends to last for more than 24 hours and may leave ecchymoses or pigmentation.

  • The sensation is burning rather than itching.

  • It may be helpful to mark the lesions by circling them with a marker such as a ballpoint pen and asking the patient to note how long they last.

• Livedo reticularis (pink-blue mottled, 'net-like' pattern) is rare but suggests small-vessel vasculitis:
  

  • It occurs with occlusive or inflammatory disease of small-sized vessels.

  • Nodular lesions may also appear.

• Ulceration suggests involvement of larger vessels but it can occur with very intense purpura.

Investigations

After the condition is confirmed, the purpose of investigation is to discover if there is systemic involvement and if there is an associated disease. As underlying causes are more common in adults, investigations are more appropriate in this group:

• Biopsy is the gold standard not only for diagnosis but also for detection of cutaneous vascular immune complexes by direct immunofluorescence.⁹ A list of relevant differential diagnoses can be generated from:
  

  • The type of vessel disrupted by inflammation (small and/or muscular).

  • The distribution of vasculitis in the dermis and subcutis.

  • The predominating inflammatory cell-type mediating vessel wall damage.

  
  It is often omitted in children.

• FBC, ESR, blood chemistry and urinalysis are basic. ESR is often raised and complement is low.

• Stool should be tested for occult blood. Further examination of the gut may be required if occult bloods are positive.

• Autoantibodies and anti-streptolysin O (ASO) titre should be taken.

• Of the various forms of hepatitis that should be considered, hepatitis C is the most important.

• Positive rheumatoid factor may suggest possible cryoglobulinaemia.

• IgA levels are often raised in Henoch-Schönlein purpura.

• CXR may be carried out as part of the examination of the chest.

Hypersensitivity vasculitis treatment and management

General measures

• If there is an underlying cause that has been established, it needs to be managed.

• If a drug is implicated, its discontinuation usually results in resolution in around two weeks.¹

• As the legs are most commonly affected, elevation of the legs, or compression stockings, may be of value. Avoiding standing, cold temperatures and tight-fitting clothing are also advised.

• If there is a personal or family history of allergy, perhaps with immune complexes and complement consumption, an elimination diet may identify offending food or additives with long-term benefit.¹⁰

Pharmacological

• If only the skin is involved with no systemic involvement, colchicine and dapsone have been utilised.

• Antihistamines may help pruritus. Sometimes the older, sedating ones are better. NSAIDs are sometimes beneficial.

• The first-choice agents for mild recurrent disease are colchicine, dapsone and prednisolone.

• If there is severe systemic involvement, high-dose steroid may be required. In addition, immunosuppressive drugs such as azathioprine, cyclophosphamide and methotrexate may be required. Plasmapheresis/plasma exchange and intravenous immunoglobulin are potential therapies for refractory disease.¹¹

• Treatments that work via cytokine blockade or lymphocyte depletion, such as tumour alpha inhibitor infliximab and the anti-B-cell antibody rituximab, are showing benefit in certain vasculitic conditions and may also be options for the future.¹²

Prognosis

The majority of cases are short-lived; in one paper around 60% of patients had symptoms resolving in under three months.¹³ The outlook will depend on the underlying cause. If none is found and only skin and joints are affected, the prognosis is good, although recurrence is not uncommon.

• Paraesthesia, fever and absence of painful lesions have been found to be risk factors for systemic involvement.

• Cryoglobulins, arthralgia and normal temperature are risk factors for chronic cutaneous disease.¹⁴

• Where the vasculitis presents on a background of GPA, polyarteritis nodosa, Churg-Strauss syndrome or severe necrotising vasculitis, it can be fatal. Steroids and immune modulators may be life-saving.