Vasculitis – classification and clinical features

01Definition and overview

Vasculitis is inflammation of the wall of blood vessels, seen under the microscope as inflammatory cells in and around the wall, often with necrosis of the wall. It is a pattern of injury, not one disease. In the systemic vasculitides it is widespread and causes fever, raised inflammatory markers and damage to many organs, and it usually needs glucocorticoids and immunosuppressive drugs.

• Primary vasculitis has no known cause, such as giant cell arteritis or granulomatosis with polyangiitis.
• Secondary vasculitis has a cause or a setting: an infection (hepatitis B, hepatitis C, syphilis), a drug, a cancer, or a systemic disease such as rheumatoid arthritis or lupus.

The Chapel Hill nomenclature

The 2012 International Chapel Hill Consensus Conference gave each vasculitis a name and a definition, mainly by the size of the vessel it affects most. Large vessels are the aorta and its major branches; medium vessels are the main visceral arteries and their first branches; small vessels are the small arteries inside organs, arterioles, capillaries and venules. Each disease reaches beyond its usual size: any vasculitis can hit an artery of any size, so the category names the vessels it affects most, not the only ones.

This topic is the map; the topics after it go deep on each disease:

• IgA vasculitis (Henoch-Schönlein purpura), the immune complex vasculitis of children;
• polyarteritis nodosa, the classic medium vessel vasculitis;
• ANCA-associated vasculitis: granulomatosis with polyangiitis, microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis;
• large vessel vasculitis: giant cell arteritis, Takayasu arteritis, and Buerger disease, which the syllabus lists there although it is not a true large vessel vasculitis;
• Kawasaki disease, the medium vessel vasculitis of children under 5, belongs to paediatrics.

02Etiology and pathophysiology

How vessels are injured

The cause of most primary vasculitis is unknown: a genetic background (HLA-DP variants in PR3-ANCA vasculitis, HLA-B51 in Behçet disease) meets a trigger such as an infection, a drug or an environmental exposure. Three mechanisms explain most of the injury, and they map onto the categories.

Anti-GBM disease is a fourth kind: antibodies against type IV collagen in the glomerular and alveolar basement membranes cause crescentic glomerulonephritis and lung haemorrhage directly. Rare monogenic diseases cause vasculitis too, such as deficiency of adenosine deaminase 2 with a polyarteritis-like picture in the young.

What the injured vessel does

1. 1

   Narrowing and occlusion

   An inflamed, thickened wall or a thrombus on it narrows the lumen: claudication of limbs or jaw, stroke, visual loss, gut ischaemia, and infarcts in the skin, nerves and kidneys.
2. 2

   Weakening

   Necrosis of the wall lets it bulge: microaneurysms in polyarteritis nodosa, aortic and coronary aneurysms in large and medium vessel disease, and bleeding when they rupture.
3. 3

   Leaking

   Inflamed capillaries and venules let red cells out: palpable purpura in the skin, haematuria from the glomeruli, alveolar haemorrhage in the lung.
4. 4

   Systemic inflammation

   Cytokines, interleukin-6 above all, bring fever, weight loss, anaemia and a high CRP and ESR.

Secondary vasculitis has the same mechanisms with a known driver: hepatitis B antigen in the immune complexes of polyarteritis nodosa, hepatitis C in cryoglobulins, drugs such as hydralazine, propylthiouracil and minocycline inducing ANCA, and haematological cancers, lupus and rheumatoid arthritis in the background of others.

03Clinical features

Constitutional features

Most systemic vasculitides start with weeks or months of fever, night sweats, weight loss, fatigue, arthralgia and myalgia, which suggest infection or cancer as much as vasculitis. The clue is a patient who is unwell, with raised inflammatory markers, in whom signs appear in several organs that do not fit one disease.

Features by vessel size

The signs that matter

• Palpable purpura: raised, non-blanching red-purple papules, symmetrical and on the dependent parts (lower legs, buttocks, the back in a patient in bed). Purpura from a low platelet count is flat.
• Livedo: a violet net in the skin. Livedo reticularis is a fine, regular, unbroken net that comes with cold and fades with warmth, often harmless. Livedo racemosa is broken, irregular and persistent, and points to disease of the dermal arteries: polyarteritis nodosa, antiphospholipid syndrome, cholesterol emboli.
• Mononeuritis multiplex: painful, asymmetric damage to individually named nerves (the common peroneal nerve with foot drop, the ulnar or median nerve, the radial nerve with wrist drop), one after another over days to weeks, from infarction of the nerves through their small arteries.
• Glomerulonephritis: microscopic haematuria with dysmorphic red cells and red cell casts, proteinuria, hypertension and a rising creatinine. It causes no symptoms until it is advanced, and it can progress to kidney failure over days or weeks (rapidly progressive glomerulonephritis).
• Alveolar haemorrhage: breathlessness, a falling haemoglobin and diffuse infiltrates on the chest film; haemoptysis is absent in up to a third.

Severity

European recommendations for ANCA-associated vasculitis divide disease into organ- or life-threatening (glomerulonephritis, alveolar haemorrhage, mononeuritis multiplex, mesenteric, heart, retro-orbital, meningeal or brain disease) and non-organ-threatening (nose and sinuses, skin without ulcers, non-cavitating lung nodules, episcleritis), and the division chooses the induction treatment; the same logic guides the other vasculitides.

• The Birmingham Vasculitis Activity Score (version 3) scores the features of active vasculitis in nine organ systems, 56 items in all. A score of 0 means remission.
• The Vasculitis Damage Index records irreversible damage present for at least 3 months since the vasculitis began, whether from the disease or its treatment (deafness, kidney failure, diabetes, osteoporosis). It only rises, and a high score predicts death.

04Diagnosis and management

The approach

Vasculitis is suspected in a multisystem illness with raised inflammatory markers, or from one of its signature signs: palpable purpura, mononeuritis multiplex, an active urine sediment, alveolar haemorrhage, absent pulses. The work-up then finds every organ involved, excludes the mimics, and proves the disease with serology and with tissue or vascular imaging. When an organ is threatened, treatment starts the same day, after blood cultures and before the biopsy result if need be.

Tests

The meaning of each antibody, and how ANCA are tested, is in humoral immunity in rheumatic diseases. A positive ANCA in a patient without a fitting clinical picture is often a false lead: infections, drugs and other autoimmune diseases cause low titres.

The mimics to exclude

Antiphospholipid syndrome, thrombotic microangiopathy, calciphylaxis, fibromuscular dysplasia and atrial myxoma can imitate vasculitis too.

Treatment principles

1. 1

   Treat the cause

   In secondary vasculitis the cause is treated first: antivirals for hepatitis B or C, the infection treated, the drug or cocaine stopped, the cancer treated.
2. 2

   Induce remission

   Severity sets the strength. Organ- or life-threatening disease is treated at once with glucocorticoids, often as intravenous methylprednisolone pulses first, with a second drug: rituximab or cyclophosphamide in ANCA vasculitis, cyclophosphamide in severe polyarteritis nodosa. Giant cell arteritis starts on high-dose glucocorticoids alone, adding tocilizumab for relapsing disease or when glucocorticoid harm is likely. Plasma exchange has a place in anti-GBM disease, severe cryoglobulinaemia, hepatitis B-associated polyarteritis nodosa and selected ANCA vasculitis with severe kidney failure. Milder disease takes glucocorticoids, with rituximab, methotrexate or mycophenolate in ANCA vasculitis, and methotrexate or azathioprine in polyarteritis nodosa when glucocorticoids alone do not suffice.
3. 3

   Maintain it

   Once in remission, usually in 3 to 6 months, glucocorticoids are tapered and a less toxic drug keeps the remission: rituximab every 6 months, azathioprine or methotrexate, for 18 months to several years by disease.
4. 4

   Limit the harm

   Glucocorticoid doses are kept as low and short as control allows, because treatment causes much of the long-term damage.

Intensive immunosuppression also brings screening for hepatitis B and C, HIV and latent tuberculosis first, co-trimoxazole against Pneumocystis pneumonia, non-live vaccines, bone protection, control of cardiovascular risk, and advice on fertility before cyclophosphamide.

Behçet disease

Behçet disease is a variable vessel vasculitis of arteries and veins of any size, commonest along the old Silk Road from the Mediterranean to Japan and linked to HLA-B51. Its mark is recurrent painful oral ulcers. The International Criteria for Behçet's Disease give points, and 4 or more classify the patient:

Arthritis of the knees and ankles, gut ulcers and a raised CRP are common; autoantibodies are absent. Treatment follows the organ: colchicine for skin, mucosa and joints, apremilast for oral ulcers, azathioprine (or ciclosporin, interferon alfa or a TNF inhibitor) for disease of the back of the eye, with high-dose glucocorticoids and infliximab or interferon alfa for sight-threatening uveitis, and immunosuppression rather than anticoagulation alone for venous thrombosis. Uveitis and pulmonary artery aneurysms decide the outcome in Behçet disease: repeated attacks of uveitis cause blindness, and a ruptured aneurysm kills.

Cogan syndrome, the other variable vessel vasculitis, pairs interstitial keratitis with sensorineural deafness and vertigo in young adults, sometimes with aortitis.

05Epidemiology

Each vasculitis has its own age, sex and geography:

06Prognosis

Before glucocorticoids and cyclophosphamide, systemic necrotising vasculitis was usually fatal within a year or two. Today most patients enter remission, and 5-year survival in ANCA-associated vasculitis is about 75 to 85 per cent. Deaths in the first year come mostly from infection and active disease, especially kidney failure and alveolar haemorrhage; later deaths come from cardiovascular disease, infection and cancer.

What decides the outlook:

• the organs involved and how much is lost before treatment, the kidney above all: the creatinine at diagnosis predicts kidney survival;
• age over 65, and heart or gut involvement, which the Five-Factor Score counts in the necrotising vasculitides;
• relapse, common in PR3-ANCA vasculitis and in giant cell arteritis, rare in hepatitis B-associated polyarteritis nodosa once the virus is controlled; IgA vasculitis of children recurs in a quarter to a third, usually within months, but most recurrences are mild and the illness rarely lasts;
• the treatment itself: diabetes, osteoporosis, infection and cataract from glucocorticoids, infertility and bladder cancer from cyclophosphamide.

Follow-up checks the urine, blood pressure and creatinine at every visit and watches for relapse and the harms of treatment. A rising ANCA titre alone does not change treatment, but calls for closer review.