Background of vasculitides 

Vasculitides are a heterogeneous group of relatively uncommon autoimmune diseases. There are many types of vasculitis, which can vary greatly in symptoms, severity and duration. They are linked by the presence of vascular inflammation, which can lead to vessel wall destruction, causing aneurysms or rupture, or stenosis of the vessel and resultant tissue ischaemia and necrosis. While the inflammatory process may be confined to one organ, it may also involve several organ systems. 

Patients will typically present in one of three ways. Many will have only constitutional and non-specific symptoms such as malaise, weight loss or fever; this can often be mistaken for an infective picture, especially when associated with raised inflammatory markers. Others will develop specific organ manifestations; for example, patients may present with joint pain, erythema nodosum, renal failure, weakness or abdominal pain. Occasionally, a suspicion of vasculitis may be identified incidentally, such as in those with microscopic haematuria. Vasculitis should be considered in patients presenting with palpable purpura, pulmonary infiltrates, unexplained ischemic events and multisystem disease. 

Vasculitis may occur as a primary disease (idiopathic) or a secondary response to an underlying disease (e.g. hepatitis B infection). We do not know what causes most types of vasculitis, but genetic factors are likely significant. Vasculitis can be a part of other rheumatic diseases, including systemic lupus erythematosus, rheumatoid arthritis and Sjögren’s syndrome. 

Common blood tests used in the diagnosis and management of vasculitis 

• Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) – these inflammatory markers are frequently raised at presentation. They are also useful to monitor disease activity in response to treatment.
• Antineutrophil Cytoplasmic Antibodies (ANCA) – are antibodies raised against antigens in the cytoplasm of neutrophil granulocytes. Antigens for p ANCA include myeloperoxidase (MPO) and bacterial permeability-increasing factor. The c-ANCA antigen is specially proteinase 3 (PR3). The presence of PR3 and MPO antibodies are highly important in the diagnosis of ANCA-associated vasculitis. 
• Antinuclear antibody (ANA) – this is an antibody which targets the nuclear components of the cell. It is non-specific and, therefore, not often used for diagnosis of vasculitides but can be an indicator of underlying autoimmune processes.
• Complement levels – the complement cascade is part of the immune system that allows antibodies and phagocytic cells to clear microbes and damaged cells from an organism. In immune-mediated vasculitis, the complement cascade enhances the ability of autoantibodies and phagocytic cells to clear damaged cells. In acute vasculitis, complement C3 and C4 levels are often reduced and normalised as a response to treatment. 

References

• About vasculitis, Vasculitis UK. Available at: https://www.vasculitis.org.uk/about-vasculitis [Accessed 28th January 2022].
• Clunie, G. P. R., Wilkinson, N., Nikiphorou, E., Jadon, D. (2018) Oxford Handbook of Rheumatology 4th edition. Oxford University Press
• Sofat, N., Rutter-Locher, Z., Oakley, H. (2021) Rheumatology – a case based approach to management. Scion Publishing limited 
• Vasculitides, Amboss. Available at: https://www.amboss.com/us/knowledge/Vasculitides/ [Accessed 17th January 2022].Vasculitis, American College of Rheumaology. Available at: https://www.rheumatology.org/I-Am-A/Patient-Caregiver/Diseases-Conditions/Vasculitis [Accessed 17th January 2022].
• Vasculitis, Versus Arthritis. Available at: https://www.versusarthritis.org/about-arthritis/conditions/vasculitis/[Accessed 15th January 2022].
• What is Vasculitis? Johns Hopkins Vasculitis Center. Available at: https://www.hopkinsvasculitis.org/vasculitis/  [Accessed 16th January]

Types of vasculitis

Based on the size of the vessel affected, vasculitides can be classified into small-vessel, medium-vessel or large-vessel vasculitis.

Largest arteries: aorta and major branches

• Giant cell arteritis (temporal arteritis) 
• Takayasu’s arteritis
• Aortitis in Cogan’s syndrome
• Aortitis in spondyloarthropathies
• Isolated aortitis

Medium-sized arteries

• Kawasaki disease
• Polyarteritis nodosa

Small and medium-sized arteries

• ANCA-associated vasculitis: Granulomatosis with polyangiitis (Wegener’s granulomatosis), Microscopic polyangiitis, Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)
• Thromboangiitis obliterans 
• Primary angiitis of the central nervous system

Small arteries

• IgA Vasculitis (Henoch-Schönlein)
• Vasculitis related to rheumatoid arthritis, systemic lupus erythematosus and Sjögren’s syndrome
• Cryoglobulinemic vasculitis
• Drug-induced vasculitis

Arteries and veins of various sizes

• Behçet’s disease
• Relapsing polychondritis

References

• About vasculitis, Vasculitis UK. Available at: https://www.vasculitis.org.uk/about-vasculitis [Accessed 28th January 2022].
• Vasculitides, Amboss. Available at: https://www.amboss.com/us/knowledge/Vasculitides/ [Accessed 17th January 2022].
• Vasculitis, Versus Arthritis. Available at: https://www.versusarthritis.org/about-arthritis/conditions/vasculitis/[Accessed 15th January 2022].

Giant cell arteritis (temporal arteritis)

Background 

Epidemiology 

Giant cell arteritis (GCA) or temporal arteritis is the most common form of vasculitis in adults. Almost all patients with GCA are over the age of 50, with a peak incidence of 70-90 years of age. There is a female predominance. Although it can occur in all racial groups, it is most common in people of Scandinavian descent. Around 22 people per 100,000 aged over the age of 50 will develop GCA.

Aetiology

The exact cause of the condition is unknown. Possible contributing factors include genetic predisposition (e.g. human leukocyte antigen HLA-DR4) and viral infections (e.g. parvovirus B19). Up to 50% of patients with giant cell arteritis also have polymyalgia rheumatica (PMR).

Pathophysiology

The activation of dendritic cells in the blood vessel walls leads to the recruitment of lymphocytes and monocytes. The differentiation of monocytes into macrophages and giant cells augments the inflammatory process by producing cytokines. This process leads to the destruction of vessel wall structures and concentric intimal hyperplasia. There is resultant reduction in blood flow and ischaemia. GCA commonly involves external carotid artery branches (especially temporal artery), as well as the aorta and vertebral arteries.

Clinical features

Patients can commonly present with non-specific constitutional symptoms such as fever, weight loss, night sweats, malaise, fatigue, myalgia and arthralgia (mainly of the shoulders and hip joints). 

Other features include those specific to arterial inflammation, such as new onset unilateral or bilateral headache. This is typically over the temples, which can be pulsatile, throbbing or dull in nature. Other symptoms include jaw claudication (jaw pain when chewing) and vision loss, which can present with scintillating scotoma, amaurosis fugax or even permanent loss of vision. Clinical examination may reveal hardened or tender temporal artery. 

Those with large vessel GCA involving the aorta and its primary branches may present with angina pectoris/acute coronary syndrome, abdominal pain or limb claudication. Signs may include asymmetrical pulses and blood pressure readings, vascular bruits, aortic regurgitation murmur and features of aortic aneurysm or dissection. 

Patients with co-existing PMR may present with symptoms of this, such as pain and stiffness of the shoulders or hips with associated limitations on movement. 

Diagnosis

If GCA is highly suspected, it is crucial not to delay the initiation of high-dose glucocorticoids to minimise the risk of vision loss. Initial laboratory tests such as low red cell count and raised ESR and CRP can be suggestive of the disease. 

Doppler ultrasound of the temporal arteries is the first line imaging technique for suspected GCA. Oedema and thickening of the vessel wall (halo sign), non-compressible artery (compression sign) and stenosis and occlusion of the vessels are all supportive of the diagnosis. However, this is operator-dependent, and other modalities such as high-resolution MRI, MRA, CTA, and PET scans can also be used. 

The gold standard for diagnosis is a temporal artery biopsy. Typical findings include panarteritis, proliferation of the intima and subsequent stenosis of the artery, necrosis of the media, and mononuclear infiltration of the vessel wall with formation of the giant cells. Despite this, histopathology may be falsely negative due to skip lesions and biopsy of the contralateral temporal artery may be required. 

Patients with PMR with no symptoms of GCA above the neck can be diagnosed clinically without a temporal artery biopsy.

Treatment

High-dose glucocorticoid therapy (prednisolone 40-60mg once a day) for 2-4 weeks is indicated for all newly diagnosed and recurrent disease. Most patients improve dramatically within 1-3 days. However, blindness is usually irreversible, which highlights the importance of early detection and treatment. Prednisolone is then tapered down to a maintenance dose to control the symptoms, generally up to 2 years. Rarely, steroid-sparing therapies such as methotrexate can be used in patients who do not respond, relapse or are at high risk of complications from long-term steroid therapy. PMR generally responds well to low-dose prednisolone. 

References

• Giant Cell Arteritis, Johns Hopkins Vasculitis Center. Available at: https://www.hopkinsvasculitis.org/types-vasculitis/giant-cell-arteritis/ [Accessed 16th January].
• Vasculitides, Amboss. Available at: https://www.amboss.com/us/knowledge/Vasculitides/ [Accessed 17th January 2022].

Takayasu’s arteritis (aortic arch syndrome)

Background 

Epidemiology 

This is a rare disease with a 9:1 female predominance. It typically occurs in people aged between 15-45 years and is more commonly seen in those of Asian heritage.

Aetiology 

The cause is unknown, with evidence suggestive of infection of some kind (viral, bacterial, other) predisposing to the disease. 

Pathophysiology

Granulomatous inflammation of the aorta and its major branches occur. This results in thickening and stenosis of the involved blood vessels. The chronic inflammation then causes subsequent vascular symptoms. 

Clinical features

Patients initially present with systemic symptoms associated with an active inflammatory illness. Typical features include generalised malaise, fever, arthralgia, weight loss and night sweats. There can be tenderness overlying the affected arteries. 

As the disease develops, patients begin to develop symptoms associated with narrowing of the affected arteries. Specific vascular symptoms and signs include: syncope, angina pectoris, bilateral carotid bruits, headache, impaired vision, movement-induced muscular pain in one or more limbs and Raynaud phenomenon. Hypertension is common, but blood pressure readings can be falsely low, associated with decreased bilateral brachial and radial pulses. Skin manifestations include erythema nodosum and urticaria.

Major complications associated with the disease include aortic aneurysms, aortic root dilatation, critical limb ischemia and stroke. 

Diagnosis

Blood tests demonstrating raised inflammatory markers, primarily a high ESR is indicative of disease. Angiography is the gold standard for diagnosis, which detects vascular stenosis in the large arteries. Biopsy of the affected vessel will demonstrate granulomatous thickening of the aortic arch, plasma cells and lymphocytes in media and adventitia and vascular fibrosis. These findings are indistinguishable with giant cell arteritis. 

The diagnosis of Takayasu’s arteritis requires three or more of the following criteria to be fulfilled: 

• Age of onset: ≤ 40 years
• Claudication of upper or lower extremities while in use
• Audible bruit over the subclavian artery or abdominal aorta
• Decreased brachial artery pulse
• Blood pressure difference > 10 mm Hg between arms
• Abnormal arteriography of the aorta or large blood vessels in the extremities that is not due to arteriosclerosis or fibromuscular dysplasia

Image Source: Wikipedia (2021). Takayasu’s_arteritis, Licensed under a creative commons licence. Available for free at:  https://en.wikipedia.org/wiki/Takayasu%27s_arteritis (Accessed: 16 February 2022).

Treatment 

The mainstay of treatment is prednisolone, with a generally good response. This is tapered down to reduce the side effects of long-term steroid use. Steroid-sparing agents such as methotrexate, cyclophosphamide and azathioprine can also be used. 

Surgical interventions such as aortic valve or large vessel repair may be required. Bypass surgery may be performed if critical stenosis of the aortic arch or its branches occurs. 

References

• About vasculitis, Vasculitis UK. Available at: https://www.vasculitis.org.uk/about-vasculitis [Accessed 28th January 2022].
• Takayasu’s Arteritis, Johns Hopkins Vasculitis Center. Available at: https://www.hopkinsvasculitis.org/?s=+Takayasu%E2%80%99s+arteritis+ [Accessed 16th January].
• Vasculitides, Amboss. Available at: https://www.amboss.com/us/knowledge/Vasculitides/ [Accessed 17th January 2022].

Polyarteritis nodosa (PAN)

Background

Epidemiology

Polyarteritis nodosa can occur at any age, with the peak incidence being 45-65 years of age. There is a male predominance of 2:1. 

Aetiology

The cause is largely unknown (idiopathic); however, some cases are associated with active hepatitis B. 

Pathophysiology 

Necrotising vasculitis of medium-sized vessels leads to microaneurysm formation, especially at the bifurcations of vessels. This can cause end-organ damage by aneurysmal rupture and thrombosis of the vessel. PAN most commonly affects the skin, peripheral nerves, muscles, joints, gastrointestinal tract and kidneys. 

Clinical features 

Non-specific symptoms such as fever, weight loss and malaise, along with muscle and joint pains, may develop sub-acutely over weeks or months. PAN may affect every organ of the body with a predisposition for the skin, kidneys, nerves and gastrointestinal tract. 

Renal involvement occurs in around 60% of patients, which can present with hypertension and impaired renal function. Skin involvement occurs in 40%, mainly on the legs and can be very painful. Common findings include purpura, livedo reticularis, ulcers, nodules or gangrene. Neurological involvement includes polyneuropathy (mononeuritis multiplex) along with central nervous system presentations such as seizures and stroke. Gastrointestinal involvement can cause abdominal pain, malaena, nausea and vomiting. More serious complications can occur, such as bowel infarction and perforation. Coronary artery involvement occurs in 35% with an increased risk of myocardial infarction. 

Diagnosis

Blood tests such as raised ESR, anaemia, leukocytosis and a negative ANCA screen are important for the diagnosis of this condition. Hepatitis serology needs to be carried out in all patients, given the association with active hepatitis B infections. Urine analysis can show proteinuria and haematuria. 

If there is skin, muscle or nerve involvement, a biopsy of the tissue will greatly aid in diagnosis. Muscle biopsy can demonstrate transmural inflammation of the arterial wall with leukocytic infiltration and fibrinoid necrosis. Angiography commonly demonstrates numerous small aneurysms and stenosis of small and medium-sized vessels of the involved organs, most commonly seen in the renal arteries. 

Treatment

PAN is fatal within weeks to months without treatment as a result of kidney, heart or gastrointestinal complications. Immunomodulation with glucocorticoids is used initially. Immunosuppressive therapies such as cyclophosphamide can also be added to therapy. Antiviral therapy may be required if the patient is positive for hepatitis B. PAN does not relapse following completed treatments. 

References

• About vasculitis, Vasculitis UK. Available at: https://www.vasculitis.org.uk/about-vasculitis [Accessed 28th January 2022].
• Bessant, R., Borms, J., Ford, C., 2020.Medicine for MRCP. Oxford Specialty Training 
• Polyarteritis Nodosa, Johns Hopkins Vasculitis Center. Available at: https://www.hopkinsvasculitis.org/?s=polyarteritis [Accessed 16th January 2022]
• Vasculitides, Amboss. Available at: https://www.amboss.com/us/knowledge/Vasculitides/ [Accessed 17th January 2022].https://www.amboss.com/us/knowledge/Vasculitides/

Granulomatosis with polyangiitis (Wegener’s granulomatosis)

Background 

Epidemiology

Granulomatosis with polyangiitis, which was formerly known as Wegener’s granulomatosis, affects equal numbers of males and females. The peak incidence is around 40-60 years of age. Prevalence is approximately 3 per 100,000 population.

Aetiology

Idiopathic.

Pathophysiology

Aberrant epigenetic expression of PR-3 on the cell membranes of neutrophils binds to c-ANCA. This activates neutrophils to release neutrophilic inflammatory markers. This process damages the endothelial cells of the small blood vessels. 

Clinical features

Granulomatosis with polyangiitis can affect virtually any site in the body with predisposition to certain organs such as the upper respiratory tract, lungs and kidneys. Constitutional features such as fever, night sweats, weight loss and arthralgia will commonly occur.

Ear, nose and throat involvement are often the first clinical manifestation of disease. Commonly, patients have chronic rhinitis or sinusitis, which are slow to resolve. This causes nasopharyngeal ulcerations and nasal septum perforation, leading to depression of the nasal dorsum (saddle nose deformity). Others can present with chronic otitis (decreased hearing), mastitis, oral ulcers or gingival hyperplasia (strawberry gingivitis). 

Skin lesions such as papules, vesicles and ulcers may occur. Palpable purpura of the lower extremities may lead to Raynaud’s phenomenon, necrotising vasculitis and dry gangrene of digits. Ocular involvement includes conjunctivitis, episcleritis, retinal vasculitis and corneal ulcerations. 

Life-threatening complications of the disease include those with renal involvement causing pauci-immune glomerulonephritis. This can progress to rapidly progressive (crescentic) glomerulonephritis with possible pulmonary-renal syndrome if not aggressively managed. These patients have proteinuria, haematuria, and red cell casts in the urine. 

Patients can also present with pneumonia-like symptoms caused by pulmonary fibrosis, pulmonary hypertension and pulmonary haemorrhage. Cardiac involvement can lead to pericarditis and myocarditis. Disease in the coronary arteries are complicated by myocardial infarction and death. 

Image Source: Wikipedia (2021). Granulomatosis with polyangiiti, Licensed under a creative commons licence. Available for free at: https://en.wikipedia.org/wiki/Granulomatosis_with_polyangiitis (Accessed:16 February 2022).

Diagnosis

Blood tests can demonstrate an acute kidney injury with a rise in urea and creatinine. Inflammatory markers are typically raised. PR3, c-ANCA is highly sensitive and positive in around 90% of patients. Patients can also have normocytic normochromic anaemia. Urinalysis typically shows microscopic haematuria and mild to moderate proteinuria, with urine sediments of dysmorphic RBC and RBC casts (nephrotic sediment) with sterile pyuria. 

CXR or CT chest are done to look for bilateral cavitating nodule lesions and pulmonary haemorrhage. 

Diagnosis of condition is typically by biopsy of the affected tissue (primarily lung or kidney), which can show necrotic, partially granulomatous vasculitis of small and medium-sized vessels with necrotising granulomas.

Treatment 

Urgent treatments with glucocorticoids along with immunosuppressive agents such as methotrexate, cyclophosphamide or rituximab are required to initiate remission. In severe disease such as those with pulmonary haemorrhage, intravenous immunoglobulins and plasmapheresis may be used. Remission maintenance requires immunosuppressive drugs such as azathioprine, rituximab and methotrexate. 

Without adequate treatment, the 1-year survival rate is < 20%. 5-year survival with adequate treatment is approx. 80%. 

References

• Granulomatosis with Polyangiitis, Johns Hopkins Vasculitis Center. Available at: https://www.hopkinsvasculitis.org/?s=polyarteritis [Accessed 16th January 2022].
• Vasculitides, Amboss. Available at: https://www.amboss.com/us/knowledge/Vasculitides/ [Accessed 17th January 2022].
• Vasculitis, Versus Arthritis. Available at: https://www.versusarthritis.org/about-arthritis/conditions/vasculitis/[Accessed 15th January 2022].
• Wallace, Z.S. and Miloslavsky, E.M., 2020. Management of ANCA associated vasculitis. BMJ, 368.

Microscopic polyangiitis

Background

Epidemiology 

This disease may affect all ethnic backgrounds in any age group, with the typical patient being middle-aged males or females. 

Aetiology

The disease is mediated by the immune system, with no obvious cause of the immune hyperactivity identified.

Pathophysiology

Microscopy polyangiitis is an ANCA-associated vasculitis. ANCA resides in neutrophils and macrophages and leads to destruction of white blood cells at the site of disease with release of enzymes within blood vessel walls, causing damage to the blood vessels. 

Clinical features

Manifestations are similar to those with granulomatous polyangiitis; however, the nasopharynx is usually not affected. The majority of patients have renal involvement with pauci-immune glomerulonephritis with hypertension. The inflammation also commonly affects the peripheral nervous system causing mononeuritis multiplex with presentations such as foot drop, pins and needles or numbness. Approximately half of the patients have skin involvement, which is typically a dependent palpable purpuric rash. Often, patients will also have constitutional symptoms such as fever and weight loss. Lung involvement can be life-threatening with inflammatory infiltrates and alveolar haemorrhage presenting with haemoptysis. 

Diagnosis

Laboratory findings of anti-MPO, pANCA are present in around 70% of cases. ESR and CRP are typically raised to suggest an inflammatory process. CT scan can demonstrate lung involvement. Diagnosis of the condition involves biopsy of the involved organ, typically the kidney skin, nerve, muscle or lung. This will demonstrate fibrinoid necrosis with infiltration of neutrophils with no evidence of granulomas.

Treatment

Immunosuppression with corticosteroids and steroid-sparing agents such as cyclophosphamide is usually first-line. Following the control of disease, a course of maintenance therapy is required to maintain remission.

References

• About vasculitis, Vasculitis UK. Available at: https://www.vasculitis.org.uk/about-vasculitis [Accessed 28th January 2022].
• Vasculitides, Amboss. Available at: https://www.amboss.com/us/knowledge/Vasculitides/ [Accessed 17th January 2022].
• Wallace, Z.S. and Miloslavsky, E.M., 2020. Management of ANCA associated vasculitis. BMJ, 368.

Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)

Background

Epidemiology 

This disease typically affects middle-aged individuals, with equal distribution of disease amongst males and females. 

Aetiology

Unknown, however, the cause is likely multifactorial with genetic, environmental and infective precipitants. 

Pathophysiology 

Unidentified allergens stimulate an adaptive immune response, leading to a B-cell response and IgG4, IgE and ANCA production. This process guides eosinophils to the tissues and stimulates degranulation of activated eosinophils, causing damage and necrosis of tissues and vessels. 

Clinical features

The chief presentation in patients is severe allergic asthma attacks. This is often associated with allergic rhinitis, nasal polyps or sinusitis. These symptoms can present long before the onset of vasculitis, which may involve the skin, lungs, nerves, kidney and other organs. Approximately 30% of patients have pulmonary infiltrates with some developing pulmonary haemorrhage. Kidneys are frequently affected with pauci-immune glomerulonephritis with associated hypertension. Other complications include impaired mental status, mononeuritis multiplex (75%), pericarditis, congestive heart failure, myocardial infarction, gastrointestinal bleed, ischaemia and perforation. Skin nodules and palpable purpura can present in around 50% of cases. 

Diagnosis 

The clinical history and associated asthma, mono/poly-neuropathy and paranasal sinus abnormalities aid diagnosis. Peripheral blood eosinophilia (>1.5×109/L) and raised IgE levels are characteristic of the disease, with 40% having positive anti-MPO pANCA levels. CXR to look for pulmonary infiltrates, as well as other imaging may be required according to the clinical presentation. Diagnosis is confirmed by tissue biopsy (typically of the lung, skin, nerve or kidney) with eosinophilia, necrotising vasculitis and necrotising granuloma.

Treatment 

The disease process is usually responsive to high-dose prednisolone (e.g. 40-60mg/day). This is usually tapered down, and other immunosuppressive drugs such as azathioprine, methotrexate, cyclophosphamide or rituximab may be used in addition. ESR and eosinophil count are often useful markers for monitoring of disease activity. 

References

• Wallace, Z.S. and Miloslavsky, E.M., 2020. Management of ANCA associated vasculitis. BMJ, 368.
• About vasculitis, Vasculitis UK. Available at: https://www.vasculitis.org.uk/about-vasculitis [Accessed 28th January 2022].
• Bessant, R., Borms, J., Ford, C., 2020.Medicine for MRCP. Oxford Specialty Training 
• Vaglio, A., Buzio, C. and Zwerina, J., 2013. Eosinophilic granulomatosis with polyangiitis (Churg–Strauss): state of the art. Allergy, 68(3), pp.261-273.
• Vasculitides, Amboss. Available at: https://www.amboss.com/us/knowledge/Vasculitides/ [Accessed 17th January 2022].
• Vasculitis, American College of Rheumaology. Available at: https://www.rheumatology.org/I-Am-A/Patient-Caregiver/Diseases-Conditions/Vasculitis [Accessed 17th January 2022].

Thromboangiitis obliterans (Buerger disease)

Background

Epidemiology 

Most commonly affects adult males with significant history of cigarette smoking (most significant risk factor). Onset is usually before the age of 45 years. Prevalence is up to 20 cases per 100,000 individuals; however, it is more common in Asia and less common among African Americans. 

Aetiology

The exact cause of Buerger’s disease is unknown; however, tobacco use, particularly cigarette smoking, is an overwhelming predisposing factor for disease. It is thought that the disease is triggered by chemicals in tobacco which irritate the lining of blood vessels. 

Pathophysiology 

Thromboangiitis obliterans affects both small and medium-sized arteries and veins. It localises in the distal arteries of the upper and lower extremities.

Inflammation of the tunica intima with neutrophilic infiltration and micro-abscess formation can spread to the tunica media with the internal elastic lamina usually intact. The development of cell-rich, inflammatory thrombi in the lumen occludes the vessel. This is followed by reorganisation of the thrombus and perivascular fibrosis. Contiguous extension of the inflammatory process to the adjacent structures results in the encasement of the artery, vein and nerve in a fibrous sheath. 

Clinical features

Patients may present with acute limb ischaemia or symptoms of peripheral vascular disease. Early manifestations include superficial thrombophlebitis (often migratory) with tender nodules along the course of the vein, intermittent claudication and Raynaud phenomenon. Later stages of the disease may present with severe rest pain, cold peripheral extremities, trophic nail changes, ulceration or gangrene of the digits, which may autoamputate. Symptoms typically begin in the extremities but radiate more to the proximal parts of the body. Patients typically have normal brachial and popliteal pulses but poor or absent distal pulsations. 

Diagnosis

Typical laboratory findings include normal ESR and CRP levels with absent autoantibodies and normal hypercoagulability screen. A decreased ankle-brachial index is suggestive of the disease. Arteriography is the imaging modality of choice and can show extensive arterial occlusive disease with corkscrew collateral vessels around the site of occlusion. Confirmation of diagnosis requires excisional skin biopsy; however, this is rarely performed. 

Treatment 

The most important management is the complete cessation of smoking and tobacco products. Conservative management for Raynaud’s phenomenon, such as protecting fingers and toes from the cold is important. Ulcerations may need debridement, antibiotic treatments, and amputation may be required in extreme cases. 

Medications such as Iloprost, calcium channel blockers (nifedipine, amlodipine) and hyperbaric oxygen therapy can at times be used. 

References

• About vasculitis, Vasculitis UK. Available at: https://www.vasculitis.org.uk/about-vasculitis [Accessed 28th January 2022].
• Buerger’s Disease, Johns Hopkins Vasculitis Center. Available at: https://www.hopkinsvasculitis.org/types-vasculitis/buergers-disease/ [Accessed 16th January 2022].
• Knipe. H., 2021. Buerger disease, Radiopaedia. Available at: https://radiopaedia.org/articles/buerger-disease?lang=gb [Accessed 3rd February 2022].
• Vasculitides, Amboss. Available at: https://www.amboss.com/us/knowledge/Vasculitides/ [Accessed 17th January 2022].

IgA Vasculitis/Henoch-Schönlein Purpura (HSP)

Background

Epidemiology 

Children are most often affected, but Henoch-Schönlein Purpura (HSP) can affect adults of all ages. Half the affected children are under the age of 5. Kidney involvement is more likely to be severe in older children and adults. It affects both sexes equally.

Aetiology

In two-thirds of cases, the disease follows an upper respiratory tract infection, with onset an average of 10 days after the start of symptoms. However, no single microorganism or environmental exposure has been confirmed to cause HSP. 

Streptococcus strains and Parainfluenza virus are the most commonly associated pathogens, and in children, Human Parvovirus B19 is a frequent viral trigger.

Pathophysiology 

IgA antibodies act to protect the lining of the airway, throat and gut, hence why HSP is triggered by infections in those organs. IgA binds to and cross-reacts with the endothelial cells following the activation of complement factors. This damages the endothelium. Inflammation of the small blood vessels causes bleeding into the skin and, therefore, produces the typical purpuric rash, primarily seen on the lower limbs. 

Clinical features

Symptoms are typically more severe in adults compared to children. They develop over days to weeks with a widespread rash commonly noted over the backs of the legs, buttocks, trunk and back. This purpuric papular rash can coalesce into patches and cause ulceration in severe cases. Other patients may present with arthralgia, abdominal pain and rectal bleeding. Abdominal symptoms may be severe and be misdiagnosed as appendicitis. Complications of gastrointestinal involvement include intussusception, perforation and bowel infarction. Kidney involvement, such as macroscopic or microscopic haematuria along with proteinuria, will be present along with associated hypertension. This can progress to nephrotic or nephritic syndrome and renal failure. 

Image Source: Wikipedia. (2021). Henoch–Schönlein purpura, Licensed under a creative commons licence. Available for free at:https://en.wikipedia.org/wiki/Henoch%E2%80%93Sch%C3%B6nlein_purpura (Accessed: 16 February 2022).

Diagnosis

The clinical tetrad of purpura, arthritis, kidney inflammation and abdominal pain is highly suggestive of diagnosis. Blood tests may demonstrate a raised IgA level in around one-third of patients. Biopsy of the skin, bowel or kidneys will show IgA deposition in the vessel walls on direct immunofluorescence in 81% of cases. CT scan of the abdomen may demonstrate bowel inflammation or abdominal complications of disease. 

Treatment 

In most cases, HSP resolves spontaneously; however, the disease can often relapse. In children, the disease usually resolves within a few weeks. Symptom management with NSAIDs can be used for joint pains without kidney involvement. Dapsone may be effective in some cases. Corticosteroids can be used to reduce inflammation, especially in adults. Long-term kidney protection, such as blood pressure control, may be required. 

References

• About vasculitis, Vasculitis UK. Available at: https://www.vasculitis.org.uk/about-vasculitis [Accessed 28th January 2022].
• Henoch-Schönlein Purpura, Johns Hopkins Vasculitis Center, Available at: https://www.hopkinsvasculitis.org/types-vasculitis/henochschnlein-purpura/ [Accessed 16th January 2022].
• Hetland, L.E., Sørensen SUSRUD, K., Lindahl, K.H. and Bygum, A., 2017. Henoch-Schönlein Purpura: A Literature Review. Acta dermato-venereologica, 97(10).
• Vasculitides, Amboss. Available at: https://www.amboss.com/us/knowledge/Vasculitides/ [Accessed 17th January 2022].

Cryoglobulinemic vasculitis 

Background

Epidemiology 

Cryoglobulinemia is a rare disease which affects approximately 1 per 100,000 population with significant geographic variations. The disease is more common over the age of 50 and affects females more than males at a ratio of 3:1. 

Aetiology

Cryoglobulinemic vasculitis is the most common extra-hepatic manifestation of hepatitis C. Other associations include multiple myeloma, lymphoproliferative disorders and autoimmune diseases such as systemic lupus erythematosus. 

Pathophysiology 

Cryoglobulins can be transiently detected in asymptomatic individuals without leading to disease. Three types of cryoglobulins are distinguished based on whether the cryoglobulin is monoclonal and has rheumatoid factor activity. Temperature-dependent formation of immune complexes (IgG and IgM) in small and medium-sized blood vessel walls leads to complement activation and inflammation of the involved vessels and surrounding tissue. 

Diagnosis 

Cold-precipitable immunoglobulins or immune complexes and raised rheumatoid factor are characteristic of the condition. The majority of the cases have hypocomplementemia. It is crucial to screen for hepatitis C with associated liver function derangements. Skin or renal biopsy can identify inflammatory vascular changes and renal damage assessed with cryoglobulin deposits of IgG and IgM deposits in the glomeruli. Further tests for underlying causes include WBC, autoimmune antibodies and imaging such as angiography, CT and CXR. 

Treatment 

Treatment of the underlying disease such as hepatitis C, hepatitis B and HIV are crucial. Immunosuppression with systemic corticosteroids and rituximab is used in mild disease with organ involvement. Plasmapheresis combined with immunosuppressive therapy is indicated in severe or life-threatening cases. 

References

• About vasculitis, Vasculitis UK. Available at: https://www.vasculitis.org.uk/about-vasculitis [Accessed 28th January 2022].
• Cryoglobulinemia, Vasculitis Foundation. Available at: https://www.vasculitisfoundation.org/education/forms/cryoglobulinemia/ [Available 28th January 2022].
• Davuluri, S. and Bansal, P., 2020. Cryglobulinemic Vasculitis. Stat Pearls Publishing, Treasure Island (FL)
• Vasculitides, Amboss. Available at: https://www.amboss.com/us/knowledge/Vasculitides/ [Accessed 17th January 2022].

Behçet’s disease

Background

Epidemiology 

Behçet’s syndrome is most common along the ancient silk trading routes from the Far East to the Mediterranean and has the highest prevalence in Turkey and surrounding regions. It is very rare in the UK but may occur in people of any nationality and race. Men and women are affected equally. It may occur at any age but is diagnosed most commonly in adults between the age of 20-30.  

Aetiology 

Genetic links with HLA B-51 (which plays a role in immunity) have been associated with the disease. Environmental triggers such as herpes virus, bacterial infections, and smoking have been identified to contribute to the condition. 

Pathogenesis

The pathogenesis of Behçet’s disease is still largely unknown. However, interleukin-driven T-cell responses, along with other inflammatory pathways and mediators, correlate with disease activity.

Clinical features

Recurrent mouth ulcers are the hallmark of Behcet’s syndrome. They can be large, small or multiple. These are often in the inner lips but can also occur on the tongue, the roof of the mouth and occasionally in the throat. Ulcers often resolve within 10-14 days, although replacement with new ulcers can be frequent. Genital ulcers occur less frequently and affect 60-70% of people. Skin redness and pustules can resemble acne. Other skin manifestations include erythema nodosum and pathergy (an exaggerated skin reason occurring after trauma). Other symptoms include blurred vision, painful eyes (caused by anterior/posterior uveitis and retinal vasculitis), fatigue, headaches, myalgia, arthralgia and abdominal pain. 

Complications of disease include decreased vision and blindness, as well as meningitis. Vasculitis predisposes to venous blood clots and arterial aneurysms. 

Image Source: Wikipedia (2009). Aphthous_stomatiti, Licensed under a creative commons licence. Available for free at: https://en.wikipedia.org/wiki/Aphthous_stomatitis#/media/File:Aphtha2.jpg (Accessed:18 September 2023).

Diagnosis 

Diagnosis of the condition is primarily based on clinical suspicion of ocular lesions, genital and oral ulcerations, skin lesions, neurological manifestations, vascular manifestations and a positive pathergy test. A pathergy test is usually performed by applying a sterile needle with multiple pricks to the forearm. A positive test is interpreted by the presence of a large skin bump, pustule or ulceration after 48 hours. Blood tests such as inflammatory markers and HLA B51 expression are of limited value. 

Treatment 

The mainstay of treatment targets organ involvement and the severity of involvement. Male sex and younger age at onset also require more aggressive management.

Topical treatments such as local steroid preparation, chlorhexidine mouth wash and colchicine can be used for ulcerations and skin disease. Systemic corticosteroids may be required for disease exacerbations or chronic diseases. In individuals with organ damage such as eye or central nervous system involvement, high-dose steroids and immunosuppressive agents such as azathioprine, cyclosporine, cyclophosphamide, and TNF-alpha inhibitors are usually necessary.

References

• About vasculitis, Vasculitis UK. Available at: https://www.vasculitis.org.uk/about-vasculitis [Accessed 28th January 2022].
• Behcet’s Disease, Johns Hopkins Vasculitis Center. Available at: https://www.hopkinsvasculitis.org/types-vasculitis/behcets-disease/ [ Accessed 19th January 2022].
• Behcet’s Disease, Vasculitis Foundation. Available at: https://www.vasculitisfoundation.org/education/behcets-disease/ [Accessed 2nd February 2022].
• Davatchi, F., 2012. Diagnosis/classification criteria for Behcet’s disease. Pathology research international, 2012.
• de Chambrun, M.P., Wechsler, B., Geri, G., Cacoub, P. and Saadoun, D., 2012. New insights into the pathogenesis of Behcet’s disease. Autoimmunity reviews, 11(10), pp.687-698.
• Vasculitides, Amboss. Available at: https://www.amboss.com/us/knowledge/Vasculitides/ [Accessed 17th January 2022].