Large vessel vasculitis – Horton disease, Takayasu’s arteriitis, Buerger disease

01Definition and overview

The 2012 Chapel Hill nomenclature defines large-vessel vasculitis as vasculitis that affects the aorta and its major branches more than other arteries, although any size of artery can be involved. Its two diseases share the same granulomatous inflammation of the wall and are told apart above all by age.

Giant cell arteritis

Giant cell arteritis (GCA), named Horton disease after the American physician who described it in 1932 and once called temporal arteritis, is a granulomatous arteritis of people over 50. Two patterns overlap: cranial GCA, of the temporal, occipital, ophthalmic and other branches of the external and internal carotid arteries, and large-vessel GCA, of the aorta and its arch branches, especially the subclavian and axillary arteries.

Takayasu arteritis

Takayasu arteritis, named after the Japanese ophthalmologist who described the retinal changes in 1908, is a granulomatous inflammation of the aorta and its main branches in the young. It is also called pulseless disease and aortic arch syndrome.

Buerger disease

Thromboangiitis obliterans, Buerger disease, is a segmental inflammatory occlusion of the small and medium arteries, veins and nerves of the limbs, almost confined to smokers. It is not a large-vessel vasculitis, nor a classic vasculitis at all: the vessel wall is relatively spared while an inflammatory thrombus fills the lumen. The syllabus groups it here, and it is covered for that reason.

02Etiology and pathophysiology

Giant cell arteritis

Age is the strongest risk factor, and the disease is linked to HLA-DRB1*04 and is commonest in people of northern European descent. The trigger is unknown.

1. 1

   Dendritic cells wake

   Dendritic cells that normally sit quietly in the adventitia of large arteries are activated, perhaps by an infection or by changes of the ageing artery, and fail to switch off because the PD-1 checkpoint pathway is weak.
2. 2

   T cells and macrophages

   They draw in CD4 T cells, which split into Th1 cells making interferon-gamma and Th17 cells making IL-17. Macrophages fuse into multinucleated giant cells and form granulomas, usually along the internal elastic lamina, which they break up.
3. 3

   Systemic inflammation

   IL-6 from the inflamed wall drives the fever, malaise, high ESR and CRP and the anaemia, and is the reason IL-6 blockade works.
4. 4

   Narrowing

   Growth factors from the macrophages make the intima proliferate, and the lumen narrows or closes: of the posterior ciliary arteries (ischaemic optic neuropathy), of the arteries of the jaw muscles (claudication) and of the vertebral arteries (stroke).
5. 5

   Weakening

   In the aorta, destruction of the media weakens the wall, and aneurysms and dissection can follow years later.

Intracranial arteries, which lose their vasa vasorum and external elastic lamina soon after crossing the dura, are rarely involved. Inflammation is patchy, with skip lesions, so a biopsy can miss it.

Takayasu arteritis

The cause is unknown; HLA-B*52 is the strongest genetic link. The same granulomatous panarteritis as in GCA begins in the adventitia and vasa vasorum and spreads inwards. The wall thickens and scars, causing long, smooth stenoses and occlusions; less often it weakens into aneurysms. Collaterals develop slowly, which is why patients can live without radial pulses.

Buerger disease

Tobacco, smoked or chewed, is the essential cause: the disease almost never starts without it and stops when tobacco stops. Cannabis has been linked too. An immune reaction to components of tobacco in susceptible people is suspected.

The acute lesion is a highly cellular, inflammatory thrombus that fills the lumen, with microabscesses and giant cells, while the internal elastic lamina and the wall are relatively preserved, unlike in true vasculitis or atherosclerosis. Later the thrombus organises and fibrosis can bind the artery, vein and nerve together. The disease advances from the distal arteries of the feet and hands upwards.

03Clinical features

Giant cell arteritis

The temporal arteries may be thickened, beaded, tender or pulseless. The eye is the danger: arteritic anterior ischaemic optic neuropathy, from occlusion of the posterior ciliary arteries, gives sudden painless loss of vision with a pale, swollen optic disc; central retinal artery occlusion is less common. Without treatment the second eye often follows within days. Vertebrobasilar stroke, scalp or tongue necrosis and hearing loss are rarer.

Large-vessel GCA without cranial symptoms presents as fever, weight loss, raised inflammatory markers, polymyalgia that responds poorly to steroids, or limb claudication, and is easily missed. Years later it can leave thoracic aortic aneurysm or dissection.

Takayasu arteritis

The disease often starts with a systemic, prepulseless phase of fever, malaise, weight loss, joint pains and pain over the arteries (carotidynia), which may pass unrecognised. The occlusive phase follows:

• arm claudication, dizziness or visual blurring on raising the arms, weak or absent radial and brachial pulses;
• a difference of more than 10 mmHg in systolic pressure between the arms, and bruits over the subclavian, carotid and abdominal arteries;
• hypertension, from renal artery stenosis or a narrowed aorta, in about half, more in some Asian series; the pressure must be measured in all four limbs, because it may be falsely low in a stenosed arm;
• transient ischaemic attacks, stroke, syncope and visual loss;
• aortic regurgitation from a dilated root, angina from stenosis of the coronary ostia, heart failure; pulmonary artery disease; abdominal angina.

Buerger disease

• A young man, nearly always a heavy smoker, with ischaemia of the distal limbs: foot or instep claudication, often taken for an orthopaedic problem, then rest pain, ulcers and gangrene of the toes or fingers.
• Two or more limbs, with the hands involved in many; an abnormal Allen test.
• Migratory superficial thrombophlebitis, red tender cords in the skin, in about 40 per cent, and Raynaud phenomenon in about 40 per cent.
• Normal proximal pulses, with absent foot or wrist pulses.

04Diagnosis and management

Giant cell arteritis

Tests. ESR and CRP are almost always raised, often very high, and are normal in only a few per cent; platelets are high, with a normocytic anaemia and a raised alkaline phosphatase. These tests support but do not prove the diagnosis, which needs imaging or histology.

1. 1

   Treat

   With a strong suspicion, glucocorticoids are started the same day, without waiting for confirmation.
2. 2

   Refer within 24 hours

   A fast-track pathway sends the patient to a specialist the same or next day; such clinics have reduced permanent visual loss. Visual symptoms need same-day ophthalmology.
3. 3

   Ultrasound first

   Ultrasound of both temporal and both axillary arteries, ideally within a week of starting glucocorticoids, looks for the halo sign (dark, homogeneous thickening of the wall round the lumen) and the compression sign (the wall stays visible when the artery is pressed flat). With a high clinical probability, a positive scan confirms GCA without biopsy; with a low probability, a negative scan makes it unlikely.
4. 4

   Biopsy or other imaging when needed

   Temporal artery biopsy, at least 1 cm long and within about two weeks of starting steroids, shows granulomatous inflammation with giant cells and a broken internal elastic lamina; skip lesions mean a negative biopsy does not exclude GCA. High-resolution MRI of the cranial arteries, and FDG-PET-CT for the aorta and its branches (and, with modern scanners, the cranial arteries), are alternatives. Imaging of the large vessels is also used when large-vessel GCA is suspected.

The 2022 ACR/EULAR classification criteria are for research, not diagnosis: they apply once a medium- or large-vessel vasculitis has been diagnosed and its mimics excluded, in people aged 50 or more at diagnosis, and classify GCA at 6 points or more: morning stiffness of the shoulders or neck +2, sudden visual loss +3, jaw or tongue claudication +2, new temporal headache +2, scalp tenderness +2, an abnormal temporal artery on examination +2; a maximum ESR of 50 mm/h or more or CRP of 10 mg/L or more +3, a positive temporal artery biopsy or halo sign +5, bilateral axillary involvement on imaging +2, and FDG uptake throughout the aorta on PET +2.

Glucocorticoids. Prednisolone 40 to 60 mg a day, the higher dose with jaw claudication or visual symptoms. Intravenous methylprednisolone, 250 to 1000 mg a day for three days, is often given for evolving visual loss or amaurosis fugax, although established loss rarely recovers. Symptoms settle within days. The dose is tapered to 15 to 20 mg a day by 2 to 3 months, then slowly, aiming to stop within 12 to 18 months.

Steroid-sparing drugs. Relapses come in up to half of patients during the taper, and glucocorticoid harms (diabetes, fractures, cataract, infection, hypertension) are common at this age, so an add-on drug is used for refractory or relapsing disease and for patients at high risk of steroid harm:

Supportive care. Bone protection with calcium, vitamin D and a bisphosphonate; blood pressure, glucose and eyes checked; a proton pump inhibitor where there is a gastrointestinal risk; a steroid card. Aspirin is no longer given routinely, because it has not been shown to prevent ischaemic events; it is kept for patients with another reason, such as critical narrowing of the carotid or vertebral arteries.

Follow-up. Symptoms, ESR and CRP guide the taper. A minor relapse returns the dose to the last one that worked; a major relapse, with ischaemia, returns it to induction doses. Because of the late risk of aortic aneurysm, the aorta is imaged at intervals, especially in large-vessel GCA.

Takayasu arteritis

Tests. ESR and CRP are raised in most, but normal values do not exclude activity. Imaging makes the diagnosis: MR or CT angiography of the aorta and its branches shows wall thickening, stenoses, occlusions and aneurysms; FDG-PET shows active wall inflammation; ultrasound shows the long, bright, concentric thickening of the carotid wall. Catheter angiography is kept for intervention and pressure measurement.

The 2022 ACR/EULAR classification needs age at diagnosis of 60 or under and imaging evidence of vasculitis, then 5 points or more from: female sex +1, angina +2, arm or leg claudication +2, a vascular bruit +2, a weak upper limb pulse +2, a weak or tender carotid +2, a systolic difference of 20 mmHg or more between the arms +1; one arterial territory affected +1, two +2, three or more +3; symmetric involvement of paired arteries +1; disease of the abdominal aorta with renal or mesenteric arteries +3.

Treatment.

• Glucocorticoids, prednisolone 40 to 60 mg a day, tapered to 15 to 20 mg by 2 to 3 months and stopped, if possible, within 12 to 18 months.
• A conventional steroid-sparing drug in every patient from the start: methotrexate, azathioprine, mycophenolate mofetil or leflunomide.
• For refractory or relapsing disease, tocilizumab or a TNF inhibitor (infliximab or adalimumab); American guidance prefers TNF inhibitors.
• Control of hypertension, cardiovascular risk and, where needed, antiplatelet therapy.
• Revascularisation, by bypass (better long-term patency) or angioplasty and stenting (fewer early strokes), only in quiescent disease, except for emergencies such as critical ischaemia or dissection.
• Imaging is repeated regularly to judge activity and damage, because symptoms and blood tests miss progression.

Buerger disease

Buerger disease is a diagnosis of exclusion. The Shionoya criteria require all five of: a smoking history, onset before 50, occlusions of the arteries below the knee, involvement of the arms or migratory phlebitis, and no atherosclerotic risk factor other than smoking. Olin's criteria add the exclusion of an embolic source, thrombophilia, diabetes and autoimmune disease.

• Tests: normal ESR, CRP, glucose, lipids and autoantibodies; screening for antiphospholipid antibodies and other thrombophilia; echocardiography and proximal imaging to exclude emboli.
• Angiography: segmental occlusions of the small and medium distal arteries, normal arteries above them without atheroma, and corkscrew collaterals around the blocks, suggestive but not specific.
• Biopsy is rarely needed, mainly in atypical cases, of an inflamed superficial vein.

Stopping all tobacco is the only treatment that halts the disease and prevents amputation. That means every cigarette, cigar, pipe, chewed tobacco and, ideally, cannabis; even one or two cigarettes a day keep it active. Nicotine itself may keep the disease active, so some experts avoid nicotine replacement and prefer varenicline or bupropion with behavioural support; the evidence for either choice is thin.

Around that: foot and wound care, pain control, calcium channel blockers for vasospasm, and intravenous iloprost, a prostacyclin analogue, for critical ischaemia. Revascularisation is rarely possible because the disease is distal; sympathectomy, spinal cord stimulation and experimental cell therapies are options in specialist centres, and amputation, usually of digits, when gangrene sets in. Glucocorticoids have no proven role.

05Epidemiology

Giant cell arteritis

GCA is the commonest systemic vasculitis in adults in Europe and North America. A meta-analysis found about 10 new cases per 100,000 people over 50 a year, highest in Scandinavia at about 20, and a prevalence of about 50 per 100,000 over 50. It is rare before 50, peaks between 70 and 80, and affects women two to three times as often as men. It is much less common in people of Asian and African descent.

Takayasu arteritis

Takayasu arteritis affects about 1 to 2 people per million a year in Europe, more in Japan, China, India, Turkey and Mexico. In Norway its prevalence was about 22 per million in people of northern European descent and several times higher in those of Asian or African descent. About 80 to 90 per cent of patients are women, with onset usually between 15 and 40.

Buerger disease

Buerger disease accounts for under 1 to about 5 per cent of patients with peripheral arterial disease in western Europe, but far more in India, South-East Asia and the Middle East, where tobacco use is high. Onset is usually before 45, and men predominate, although the share of women has risen as more women smoke. It has become less common where smoking has fallen.

06Prognosis

Giant cell arteritis

With prompt treatment, most patients do well, and life expectancy is close to normal. Blindness, once present, rarely recovers, and is now uncommon once glucocorticoids have started. Most patients need glucocorticoids for one to two years and some for longer, and relapses affect up to half. The long-term burden comes from glucocorticoid toxicity and from the aorta: thoracic aortic aneurysm and dissection are several times commoner than in people of the same age, years after the diagnosis.

Takayasu arteritis

Takayasu arteritis is chronic and relapsing, but with treatment most patients survive for decades, with 10-year survival of about 90 per cent or more. Complications decide the outlook: hypertension, aortic regurgitation and heart failure, stroke, coronary disease and aneurysms. Pregnancy is possible but needs specialist care and blood pressure control.

Buerger disease

Life expectancy is close to normal, because the coronary and cerebral arteries are rarely involved. The limbs depend on tobacco: those who stop completely seldom need a major amputation, while those who keep smoking face repeated ulcers and amputations, about two in five eventually losing part of a limb.