Abstract
Vasculitis broadly refers to inflammation of blood vessel walls. It can affect any size of vessel anywhere in the body and can therefore be associated with a wide variety of clinical conditions and presentations. Some patients may present as an emergency to their GP or to accident and emergency (A&E), others may have symptoms of more insidious onset, and present to primary care with a long history of vague symptoms. Awareness of these presentations and the potentially serious sequelae of many of the underlying differential diagnoses is essential in helping to direct patients to an appropriate secondary care setting for further investigation and prompt treatment.
Clinical case scenario
A 55-year-old woman attends the surgery with persistent unilateral headache, exacerbated by combing her hair and sometimes when chewing her food. On examination, she has a palpable and tender temporal artery on the left side. She also complains of feeling more tired than usual and having generalised aches and pains. Her C-reactive protein (CRP) is mildly elevated. The GP suspects temporal arteritis and discusses the patient immediately with the medical registrar on-call at the local hospital. Subsequently, the patient is admitted urgently via A&E for bloods and assessment by the rheumatology team, who confirm the diagnosis and initiate steroid treatment straight away.
Definition
The term ‘vasculitis’ describes a group of disorders characterised by inflammation and damage of blood vessel walls. The diagnosis can be purely clinical or can be aided by the measurement of antibodies or other biomarkers. Vasculitis also has a characteristic microscopic appearance (Fig. 1).
Photomicrograph of a blood vessel wall showing infiltration by numerous inflammatory cells (seen as small, darkly staining cells scattered throughout the tissue).
Inflammation may be local (for example in purely cutaneous vasculitides), or systemic, involving several organ systems. There are various ways of categorising the vasculitides, for example into disorders affecting small, medium and large vessels, or by aetiology (see below), although there is inevitably some overlap. Around 14 600 new cases of vasculitis (of any cause) are diagnosed in the UK annually (Watts et al., 2014).
Aetiologies
A number of aetiologies of vasculitis have been described, although up to 50% of cases are idiopathic. Immune-mediated inflammation is the most common and can be local or systemic. Mechanisms of immune-mediated vasculitis include immune complex deposition, anti-neutrophil cytoplasmic antibodies and T-cell mediated mechanisms.
Immune complex deposition
Lupus is perhaps one of the best-known autoimmune causes of vasculitis. The disease is characterised by a wide range of autoantibodies, the most characteristic of which are the ANAs (antinuclear antibodies). These largely cause injury by forming immune complexes, which are deposited in small vessels throughout the body, leading to complement-mediated vascular and tissue injury (type III hypersensitivity).
Immune complex deposition is also present in drug hypersensitivity vasculitis (most commonly seen in the skin), and vasculitis secondary to infections (for example, the complex of HBsAg and anti-HBsAG seen in polyarteritis nodosa as a sequel of hepatitis B infection). Another familiar disorder is Henoch-Schönlein purpura (HSP). HSP predominantly affects a younger population, involving the formation of complexes of IgA and complement subsequently deposited in small vessels in the skin and renal glomeruli.
Anti-neutrophil cytoplasmic antibodies
Anti-neutrophil cytoplasmic antibodies (ANCA) are implicated in a variety of autoimmune diseases. They used to be classified according to the intracellular location of the target antigens (with p-ANCA being peri-nuclear, and c-ANCA being cytoplasmic), but are now classified by antigen specificity as:
PR3-ANCA (formerly c-ANCA): Anti-proteinase-3 antibodies, associated with polyangiitis MPO-ANCA (formerly p-ANCA): Anti-myeloperoxidase antibodies, associated with microscopic polyangiitis and Churg-Strauss syndrome
ANCA titres reflect disease activity and can therefore be used for monitoring and detecting recurrence as well as making the initial diagnosis.
T-cell mediated
Autoreactive T cells can respond to antigens in blood vessel walls and trigger inflammation and granuloma formation. Examples include giant cell (temporal) arteritis and Takayasu arteritis. In children, anti-endothelial autoantibodies can predispose to the T-cell mediated inflammation of coronary vessels seen in Kawasaki disease.
Additional mechanisms include the direct invasion of vessel walls by infectious agents, and injury from chemicals or radiation (or indeed physical injury). It should also be noted that in up to 50% of cases no cause can be identified (Patterson, 2016).
Clinical presentation
The generalised inflammatory state seen in systemic vasculitides can lead to constitutional symptoms, such as malaise, fever, arthralgia and myalgia. More specific symptoms and signs can also be seen, depending on the condition and the vessels affected. Key conditions and their presentations are discussed below. Skin rashes are a common and important presentation and will be discussed separately.
A thorough history is essential to elicit the duration and progression of clinical symptoms, which may give important clues to the GP (or to the secondary care physician) as to the possible cause. Given the sometimes, vague presentation, it is worth considering the diagnosis of vasculitis in patients with no clear cause for their symptoms. For example:
Raised inflammatory markers with no clear cause Deteriorating renal function with no clear cause An incidental finding of microscopic haematuria +/− protein on urine dip An atypical rash, or a rash not responding to the usual treatment Multi-system symptoms with no clear cause
Other clues gleaned from examination could include changes in the hands (splinter haemorrhages, ulcers, digital infarcts), hypertension as a manifestation of renal disease, and other more specific signs of end-organ ischaemia (visual changes or loss, transient ischaemic attack (TIA), chest pain).
Systemic lupus erythematosus
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with protean manifestations (Table 1). This is a reflection of the widespread immune complex deposition described above. Estimates of prevalence range from 12 to 28 per 100 000 population, with a 9:1 female to male preponderance, and a peak age of onset between 15–40 years (lupusuk.org.uk).
Clinical and pathological manifestations of SLE.
Adapted from Kumar et al., 2021.
Unfortunately, as seen in Table 1, the symptoms and signs of lupus can be rather non-specific. However, the clinician can be alerted to the possibility in young female patients presenting with constitutional symptoms, rashes (especially the characteristic ‘butterfly’ rash seen in up to 50% of patients (Fig. 2)), joint and muscle pains, chest pains and perhaps even recurrent foetal loss or deep vein thrombosis as seen in the anti-phospholipid syndrome.
Butterfly rash as seen in systemic lupus erythematosus.
Diagnosis is by these clinical clues and serology to detect the culprit autoantibodies (ANA, anti-dsDNA, anti-Sm and antiphospholipid). Renal function testing is also essential, as lupus nephritis (which may need to be confirmed with a renal biopsy) can be one of many serious consequences of active disease. Treatment is usually with steroids for acute flares, and long-term steroid sparing immunosuppressant medications.
Giant cell (temporal) arteritis
Giant cell arteritis is caused by granulomatous inflammation of medium- to large-sized arteries and is most common in patients over 50 years old. It can be associated with polymyalgia rheumatica in up to 60% of patients (Li et al., 2021). The name temporal arteritis comes from the characteristically palpable and tender (and readily biopsied) temporal artery, which is one of the hallmarks of this disease; however, the inflammation also affects the vertebral and ophthalmic arteries, with the latter potentially leading to sudden and permanent blindness. Other common symptoms include constitutional symptoms, facial pain, headache and jaw claudication. Diagnosis is based on clinical findings, raised inflammatory markers and biopsy findings, and treatment is with steroids (often oral prednisolone, although pulsed IV methylprednisolone can be given in more urgent situations when sight may be threatened).
Microscopic polyangiitis with granulomatosis (formerly Wegener’s granulomatosis)
This disease, associated with PR3-ANCA, is rare (approximately 13–20 cases per million population (understandaav.com)), is slightly more common in men and has an average age of onset of about 40 years. Necrotising and granulomatous inflammation occurs in a triad of sites, leading to characteristic clinical features:
Upper respiratory tract: Causing chronic sinusitis, mucosal ulceration of the naso- and oropharynges, and sometimes collapse of the nasal bridge Lower respiratory tract: Bilateral pneumonitis, pulmonary nodules and cavitations, and haemoptysis (sometimes life-threatening haemorrhage) Renal glomeruli: Glomerulonephritis
This can be a rapidly fatal disease without prompt immunosuppression.
Churg-Strauss syndrome
Associated with MPO-ANCA in some (but not all cases), this syndrome is characterised by an eosinophilic inflammatory infiltration of vessels and tissues (which can also be detected in the peripheral blood). Clinically, is manifests as asthma, allergic rhinitis, palpable cutaneous purpura, gastrointestinal bleeding, renal disease and cardiomyopathy. Treatment is also with immunosuppression.
Henoch-Schönlein purpura (HSP)
This disorder, most common in children, is also known as IgA vasculitis, and involves deposition of IgA and complexes of IgA, IgG and complement. The classic clinical features are of palpable purpura of the extensor surfaces of the limbs and buttocks (Fig. 3), abdominal pain (sometimes with intestinal bleeding), arthralgia and renal involvement ranging from nephrotic syndrome to glomerulonephritis with visible haematuria. Treatment is often supportive, with steroids sometimes given to reduce the risk of severe renal impairment (which can proceed to chronic renal failure in a minority of patients).
Palpable purpura as seen in Henoch-Schönlein purpura.
Kawasaki disease
Kawasaki disease is a large- to medium-vessel vasculitis that affects infants and children, with the large majority of patients being under 5 years old. The trigger is unknown, but is widely believed to be a viral agent. Children present with fever, conjunctivitis, oral erythema and blistering, a desquamative rash with erythematous palms and soles, and cervical lymphadenopathy. Vasculitis of the coronary arteries can cause coronary artery ectasia and aneurysms, some of which can rupture, thrombose and lead to myocardial infarction. These vascular sequelae can occur in up to 20% of patients (Kumar et al., 2021) and can be largely prevented with prompt treatment with aspirin and intravenous immunoglobulin.
Other disorders of note
Other well-characterised vasculitic disorders which could present to primary care include:
Behçet’s disease (the hallmark of which is orogenital ulceration) Buerger’s disease (thromboarteritis obliterans, chiefly affecting the tibial and radial arteries of young smokers, and causing vascular insufficiency of the extremities) Polyarteritis Nodosa (PAN): One-third of patients with PAN have hepatitis B, with immune complexes of HBsAg and its corresponding antibody implicated in the inflammation (the cause of the remainder of cases is unknown); the inflammation preferentially affects the renal and visceral circulations, with secondary hypertension and abdominal pain (associated with intestinal bleeding) being common presentations, along with symptoms of myalgia and peripheral neuritis. Takayasu arteritis: Medium- to large-vessel arteritis causing inflammation of the aorta and main branches, and characteristically leading to pulseless extremities and visual disturbances, as well as myocardial infarction, renal artery stenosis and peripheral vascular insufficiency.
The vasculitic rash
Presentations to primary care for dermatological issues are very common, and an unusual skin rash may be the first manifestation of a vasculitic process. This may be limited to the skin, or the cutaneous signs could be a manifestation of a systemic vasculitis.
DermNetnz.org helpfully categorises the cutaneous vasculitides and their clinical manifestations according to vessel size (along with a comprehensive photo library). Capillaritis presents with pigmented (rather than palpable) purpura or petechiae, which can leave behind haemosiderin deposits as they resolve. Small vessel vasculitis can present with palpable purpura, for example in HSP (discussed above). Medium vessel vasculitis can be associated with nodules and livedo reticularis (Fig. 4), for example in lupus, rheumatoid arthritis and cryoglobulinaemia.
Livedo reticularis.
As previously mentioned, there are many causes of vasculitic rashes. The following are possibly the most common to be considered, although there are many others.
Infection
Vasculitis associated with infection is most common with upper respiratory tract infection, especially Streptococcal. Other possible culprits include influenza, Mycobacterium, hepatitis B, HSV, Herpes zoster/varicella, CMV, parvovirus, HIV and malaria.
Vasculitic rashes can also be caused by disseminated infection and sepsis, for example in meningococcal disease (the classic, much-dreaded and thankfully uncommon ‘non-blanching’ rash), gonococcus, Pseudomonas, infective endocarditis (especially when caused by Staphylococcus), and secondary syphilis.
Drugs and chemicals
Numerus drugs have been implicated, and a partial list is provided in Box 1. Although this kind of rash is a rare side effect, any new rash would normally prompt a thorough drug history, and consideration of suspension of any drugs suspected if safe to do so. A full blood count may also be helpful, as it can reveal a peripheral blood eosinophilia in these cases. Partial list of drugs causing vasculitic rash.
Malignancy
Both solid and haematological cancers can be the underlying cause of a vasculitic rash. Examples include the lymphomas, myelodysplastic syndrome, hairy cell and chronic lymphocytic leukaemias, myeloma, Waldenström’s macroglobulinaemia and mycosis fungoides among the haematological disorders, and solid gastrointestinal (GI) tumours, mesothelioma and squamous cell carcinoma of the lung among the non-haematological malignancies.
Systemic
Apart from the disorders discussed above, vasculitic rashes can also be seen in other autoimmune disorders (for example, dermatomyositis, Coeliac disease, inflammatory bowel disease, Sjögren’s syndrome and rheumatoid arthritis), as well as in connective tissue diseases, sarcoidosis and alpha-1 anti-trypsin deficiency. As previously discussed, cryoglobulinaemia of any cause (most commonly hepatitis C, but also associated with other infections as well as haematological disorders and lupus) can lead to livedo reticularis and palpable purpura, as well as more serious ischaemic skin lesions. Exercise-induced vasculitis (involving exposed skin and sometimes associated with urticaria and oedema) can be a worrisome complaint for a patient, but is a completely benign condition and resolves spontaneously within 3–4 weeks.
Investigations
Although vasculitides are most likely to be referred to secondary care for further investigation and treatment, there are a number of preliminary tests to be considered in primary care when considering a diagnosis of vasculitis. A basic blood panel comprising a full blood count, urea and electrolytes (U&E) and inflammatory markers will highlight the extent of systemic disease and possible renal impairment, with a simple urine dip for blood and protein also contributing to the clinical picture if renal involvement is suspected. More specialised tests could also be considered, such as an autoantibody panel and hepatitis serology.
Referral
Clinical findings suspicious of a vasculitic process should be discussed with a secondary care specialist, such as a dermatologist, rheumatologist or paediatrician as appropriate. Appropriate tests and treatment (for example supportive care, steroids or other immunosuppressive drugs, and plasmapheresis/plasma exchange to reduce the burden of injurious antibodies in severe cases) can then be initiated to prevent permanent organ damage or even death.
Key points
Vasculitis can be due to a wide range of aetiologies, including autoimmune processes, drugs, infection and malignancy, with a significant proportion being idiopathic The clinical manifestations are very varied, with skin rashes being a common presentation in primary care Some patients present as an emergency, others have symptoms more insidious in onset with a long history of vague symptoms The sequelae of vasculitic inflammation can be serious or even life threatening Early recognition is essential so that appropriate secondary care referral can be made for further investigation and treatment Preliminary tests can be considered in primary care when a diagnosis of vasculitis is possible
