26th February 2025

Primary vasculitides

Overview of primary vasculitides

Primary vasculitides are a group of conditions characterised by inflammation within blood vessels. These can be primary or secondary to another condition, such as SLE or rheumatoid arthritis. They are classified by the size of vessel they generally affect; however, this is not absolute.

Large-vessel vasculitis

There are two main types of primary large-vessel vasculitis: giant cell arteritis (GCA) and Takayasu’s arteritis. Large vessel generally refers to the aorta or its main branches. We will discuss the two main primary causes here; however, there are other secondary causes, such as infection. Clinical features depend on which vessel is involved.

Giant cell arteritis

GCA is the most common form of vasculitis. It generally occurs in middle-aged (>50) Caucasians and has a 2:1 female-to-male ratio. There is an association with polymyalgia rheumatica. This is one of the few rheumatological emergencies, particularly when associated with eye involvement, as there is a very high risk of blindness.

Classical presentation is with a new headache, scalp or temporal artery tenderness, and jaw claudication. Headache can occur anywhere but is most commonly temporal. Visual loss may be present, and this is irreversible. Patients may describe amaurosis fugax as a ‘curtain coming down’ on their vision. The best predictor for future visual loss is previous episodes of visual loss.

Blood tests generally show elevated CRP and ESR. US of the temporal artery is often performed, which may show a ‘halo’ around the artery. Gold standard diagnosis is with temporal artery biopsy; however, a negative biopsy does not rule out the disease, as there is a ‘skip lesion’ pattern, and also, often, patients will have had some treatment by the time they have the biopsy. PET-CT may be performed to look for other areas of large vessel involvement. If there is any suggestion of visual involvement, urgent ophthalmological assessment should be arranged.

Anterior ischaemic optic neuropathy is the most common ocular manifestation of GCA. Posterior ischaemic optic neuropathy can occur but is less common. Central retinal vein occlusion can be seen, but this is much rarer.

Treatment is with high-dose glucocorticoids such as 60 mg oral prednisolone or, if there is visual involvement, 1000 mg IV methylprednisolone for 3 days before stepping down to oral. Steroids can then slowly be weaned over around 12 months, depending on response. Given these patients will be on high-dose steroids for a long period of time, bone protection and gastroprotection should be prescribed. In patients who have steroid-resistant or dependent disease, DMARDs such as methotrexate or biologic agents such as tocilizumab can be used.

Polymyalgia rheumatica (PMR)

Polymyalgia rheumatica as an autoinflammatory condition with an unknown pathophysiology which affects the shoulder and hip girdle. This is not a form of vasculitis; however, it shares some common features with GCA, and 10-20% of patients with PMR will go on to develop GCA. PMR occurs in a similar patient group to GCA, as described above. 

Patients typically present with symmetrical muscle pain and stiffness in the hip and shoulder girdle, which is worst in the morning. This can be so severe it can limit activities of daily living, for example, with tasks that require patients to lift their arms above their head. Systemic symptoms such as malaise, anorexia, and fatigue are common. Low-grade fever can be seen; however, if present, this should prompt thorough investigation to rule out infection. It is important to rule out concomitant GCA when assessing someone presenting with PMR symptoms.

CRP and ESR are almost always raised, and normal values should prompt investigation for an alternative diagnosis. There are no associated autoantibodies.

Treatment is with low-dose prednisolone (15-20 mg), and patients often feel significant symptomatic relief even after one dose. If there is no response to steroids, another diagnosis should be considered. Prednisolone is subsequently weaned slowly.

Takayasu’s arteritis

Takayasu’s is a granulomatous arteritis which affects the aorta and its main branches. It generally affects young women from the ages of 20-40 and is most common in Japan and Southeast Asia. 

Classical findings are manifestations of the consequences of vascular inflammation, such as bruits, claudication and asymmetrical or absent pulses.

Investigation is with cross-sectional imaging and angiography.

Initial treatment is with medium-dose glucocorticoids, such as 40-60 mg prednisolone, and then DMARDs, such as methotrexate, azathioprine, or MMF, if the features are steroid-resistant.

Medium-vessel vasculitis

Polyarteritis nodosa (PAN)

This is a rare condition; however, questions are relatively common in examinations. 

Systemic features such as fever, weight loss, arthralgia and fatigue are very common. Cutaneous manifestations, including ulcers, livedo reticularis, and purpura, occur in around 50% of patients. Other common features include non-specific abdominal pain, orchitis and mononeuritis multiplex. Up to half of all patients will have some renal involvement, usually renal ischaemia causing hypertension due to activation of the renin-angiotensin-aldosterone pathway. Renal artery aneurysms can also be present.

Antibodies are typically negative, although p-ANCA is sometimes positive. Inflammatory markers can be elevated. Treatment is generally with glucocorticoids, and then steroid-sparing agents such as cyclophosphamide can be used.

There is a correlation with hepatitis B infection, and this should be screened for at diagnosis.

Kawasaki’s disease

This generally occurs in children; however, sequelae can cause morbidity and mortality in the adult population. Classical features include fever over 40 degrees for over 5 days, widespread erythematous rash, strawberry tongue, desquamation to the hands and feet and bilateral conjunctival erythema. The most important complication to be aware of is coronary artery aneurysms, so monitoring with echocardiography is essential. Treatment is with IVIG and aspirin; urgent treatment is important to avoid the development of cardiovascular complications.

Small-vessel vasculitis

ANCA-associated vasculitides

These conditions are classically severe small-vessel vasculitides associated with anti-neutrophil proteins. However, confusingly, not all patients are ANCA-positive. They most commonly affect older adults.

These often start off with systemic features, including malaise, fevers, night sweats, weight loss, anorexia and arthralgia, which are commonly misdiagnosed before presenting with more classical symptoms.

Glucocorticoids are generally used to induce remission, followed by ongoing treatment to maintain remission, such as cyclophosphamide and rituximab.

The three key subtypes are granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA).

Granulomatosis with polyangiitis

GPA was formerly known as Wegener’s granulomatosis.

Clinical features are as follows:

• Up to 90% of patients have ENT involvement, such as nasal crusting, sinusitis, rhinorrhoea, otorrhoea or otitis media. Hearing loss is common and can be conductive or sensorineural. Nasal bone and cartilage destruction can lead to saddle-nose deformity or nasal septal perforation.
• Renal involvement affects up to 90% of patients, usually as a rapidly progressive glomerulonephritis.
• Lung involvement can occur, affecting the airways or parenchyma, and presents with haemoptysis, dyspnoea, stridor or wheeze. Imaging can show nodules, pulmonary infiltrates or hilar lymphadenopathy.
• Cutaneous vasculitis is seen in around half of patients, commonly presenting as purpuric lesions on the lower limbs.
• Mononeuritis multiplex can be seen, but less commonly than in microscopic polyangiitis. It is usually associated with a worse prognosis.

Investigation findings include:

• If the disease is flaring, blood tests will often show elevated WCC, platelets and inflammatory markers.
• ANCA is positive in around 80-90% of patients, and GPA is most commonly associated with PR3-ANCA (C-ANCA). However, up to 20% are MPO-ANCA positive, and some are ANCA negative, particularly if the disease is quiescent.
• Urinalysis and microscopy may show microscopic haematuria or red cell casts.
• Diagnosis is confirmed by biopsy of involved tissue, usually renal or skin, which shows granulomatous inflammation. Renal biopsy will show ‘pauci-immune’ glomerulonephritis, meaning there are few immune deposits in the glomeruli.

Microscopic polyangiitis (MPA)

This shares many features with GPA; however, lacks the granulomatous inflammation. It is one of the pulmonary-renal syndromes, along with anti-GBM disease, and haemoptysis and renal involvement are the most common features.

Eighty percent of patients are ANCA-positive. This is usually an MPO-ANCA antibody with a P-ANCA (perinuclear) pattern on immunofluorescence.

Eosinophilic granulomatosis with polyangiitis (EGPA)

This was formerly known as Churg-Strauss syndrome.

Although classified as an ANCA-associated vasculitis, only around 50% of patients have a detectable ANCA antibody. It is a triad of features including late-onset asthma, eosinophilia and systemic vasculitis.

Specific clinical features are as follows:

• Respiratory involvement is the most common presentation of EGPA, with asthma generally presenting 8-10 years prior to systemic vasculitis. The asthma is often difficult to control, and patients will have required multiple courses of oral steroids. Leukotriene inhibitors such as montelukast have been associated with unmasking EGPA. Imaging can reveal ‘fleeting’ pulmonary infiltrates, nodules or pleural effusion.
• Cutaneous ulcers and nodules are common.
• Cardiac involvement can occur in severe disease and is an important cause of mortality, causing around half of all deaths. This can manifest with pericarditis, arrhythmias or heart failure. 
• Mononeuritis multiplex may be seen.

Investigation findings include:

• Eosinophilia, usually >1.5 x 109/L.
• In uncontrolled disease, there is often a leucocytosis with elevated inflammatory markers.
• ANCA is positive in around half of patients, and this will usually be MPO-ANCA.

Immune complex-associated vasculitides

Anti-glomerular basement membrane (GBM) disease

This is also called Goodpasture disease.

This is another pulmonary-renal syndrome. It affects pulmonary and glomerular capillaries and is caused by deposition of anti-basement membrane antibodies.

Most patients present with rapidly progressive glomerulonephritis, occasionally with concomitant pulmonary haemorrhage. Other manifestations of respiratory involvement include dyspnoea and cough.

Blood tests show an AKI, and anti-GBM antibodies may be present. Urinalysis shows proteinuria and haematuria, with red cell and granular casts on microscopy. Chest imaging may show pulmonary infiltrates. Lung function testing may show an increased DLCO if pulmonary haemorrhage is present. Renal biopsy is required for formal diagnosis unless contraindicated. This will reveal linear deposition of IgG along glomerular capillaries.

IgA vasculitis (Henoch Schönlein purpura, HSP) 

This is classically described in children; however can occur in people at any age.

Palpable purpura is the most common presenting symptom, usually over the buttocks and legs, alongside arthritis, abdominal pain and renal involvement. Arthritis is usually oligoarticular and involves large joints of the lower limbs. GI involvement can range from mild abdominal pain with nausea and vomiting to intussusception, although this is rare in adults. Renal involvement is more common in adults and carries a higher risk of ESRF than in children.

There are no specific blood tests for HSP, although serum IgA can be raised. Biopsy is generally not required in children; however, is often necessary in adult patients. 

HSP is generally self-limiting, and management is supportive. The use of glucocorticoids is controversial.

Hypocomplimentaemic urticarial vasculitis

This is a rare condition which causes a combination of urticaria and cutaneous vasculitis, with purpura and livedo reticularis. Extra-cutaneous manifestations can occur similarly to other forms of vasculitis, with arthralgia or arthritis, pulmonary involvement, and proteinuria or haematuria. 

Blood tests will often show raised ESR, reduced complement, positive ANA and positive C1q antibodies.

Cryoglobulinaemic vasculitis

This is a rare form of vasculitis caused by the presence of cryoglobulin immune complexes in blood vessels. Most commonly, this involves the skin, kidneys and peripheral nerves. There are three types of cryoglobulins:

Table 5 Classification of cryoglobulinaemia

References

• Clunie GPR, Wilkinson N, Nikiphorou E, Deepak Jadon. Oxford handbook of rheumatology. Oxford: Oxford University Press; 2018
• Lyons HS, Quick V, Sinclair AJ, Nagaraju S, Mollan SP. A new era for giant cell arteritis. Eye [Internet]. 2019 Oct 3 [cited 2022 Jan 21];34:1013–26. Available from: https://www.nature.com/articles/s41433-019-0608-7
• Camellino D, Matteson EL, Buttgereit F, Dejaco C. Monitoring and long-term management of giant cell arteritis and polymyalgia rheumatica. Nature Reviews Rheumatology [Internet]. 2020 Sep 1 [cited 2022 Jan 11];16(9):481–95. Available from: https://www.nature.com/articles/s41584-020-0458-5
• Salvarani C, Muratore F. Clinical Manifestations and Diagnosis of Polymyalgia Rheumatica [Internet]. Warrington KJ, Ramirez Curtis M, editors. UpToDate. 2022 [cited 2022 Jan 24]. Available from: https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polymyalgia-rheumatica
• Johnston SL, Lock RJ, Gompels MM. Takayasu arteritis: a review. Journal of Clinical Pathology [Internet]. 2002 Jul 1 [cited 2021 Oct 8];55(7):481–6. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1769710/
• Merkel PA. Clinical Manifestations and Diagnosis of Polyarteritis Nodosa in Adults [Internet]. Hunder GG, Ramirez Curtis M, editors. UpToDate. 2021 [cited 2022 Apr 13]. Available from: https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polyarteritis-nodosa-in-adults
• Harnden A, Takahashi M, Burgner D. Kawasaki disease. BMJ [Internet]. 2009 May 5 [cited 2022 May 13];338(may05 1):b1514–4. Available from: https://www.bmj.com/bmj/section-pdf/186211
• Greco A, Marinelli C, Fusconi M, Macri G, Gallo A, De Virgilio A, et al. Clinic manifestations in granulomatosis with polyangiitis. International Journal of Immunopathology and Pharmacology. 2015 Dec 18;29(2):151–9
• Falk RJ, Merkel PA, King Jr TE. Granulomatosis with Polyangiitis and Microscopic Polyangiitis: Clinical Manifestations and Diagnosis [Internet]. Glassock RJ, Appel GB, Lam AQ, Ramirez Curtis M, editors. UpToDate. 2022 [cited 2022 Apr 13]. Available from: https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-clinical-manifestations-and-diagnosis
• Gioffredi A, Maritati F, Olivia E, Buzio C. Eosinophilic granulomatosis with polyangiitis: an overview. Frontiers in Immunology [Internet]. 2014 Nov 3 [cited 2022 Mar 13];5:1664–3224. Available from: https://www.frontiersin.org/article/10.3389/fimmu.2014.00549
• Kaplan AA, Appel GB, Pusey CD. Anti-GBM (Goodpasture) disease: Treatment and prognosis [Internet]. Glassock RJ, Fervenza FC, Lam AQ, editors. UpToDate. 2022 [cited 2022 Mar 13]. Available from: https://www.uptodate.com/contents/anti-gbm-goodpasture-disease-treatment-and-prognosis
• Merkel PA. Overview of and Approach to the Vasculitides in Adults [Internet]. Matteson EL, Ramirez Curtis M, editors. UpToDate. 2021 [cited 2022 Mar 13]. Available from: https://www.uptodate.com/contents/overview-of-and-approach-to-the-vasculitides-in-adults
• Kitching AR, Anders H-J, Basu N, Brouwer E, Gordon J, Jayne DR, et al. ANCA-associated vasculitis. Nature Reviews Disease Primers [Internet]. 2020 Aug 27 [cited 2022 Jan 13];6(1). Available from: https://www.nature.com/articles/s41572-020-0204-y
• Braun GS, Horster S, Wagner KS, Ihrler S, Schmid H. Cryoglobulinaemic vasculitis: Classification and Clinical and Therapeutic Aspects. Postgraduate Medical Journal [Internet]. 2007 Feb 1 [cited 2022 Jun 13];83(976):87–94. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2805946/
• Brewer JD, Davis MD. Urticarial vasculitis [Internet]. Callen J, Ramirez Curtis M, Ofori AO, editors. UpToDate. 2021 [cited 2022 Feb 13]. Available from: https://www.uptodate.com/contents/urticarial-vasculitis