A rheumatology perspective on cutaneous vasculitis: assessment and investigation for the non‐rheumatologist

Abstract

Vasculitis, by definition, is inflammation of the vasculature. This inflammation can result in either vessel wall destruction causing aneurysm or rupture, or stenosis causing ischaemia or necrosis. This autoimmune response does not always have a clear cause.

Vasculitis is a heterogeneous group of disorders that has been categorised not only by primary and secondary causes, but also by the size of the affected vessel. The secondary causes that can trigger vasculitis include infection (particularly hepatitis B and C and haemorrhagic fever);cancer, autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and Sjogren's; drugs or allergic reactions. As vasculitis can affect any part of the vasculature, it can result in a wide range of signs and symptoms. However, one of the most common presentations of vasculitis is a rash, due to small vessel vasculitis, which is most common. A vasculitic rash has certain characteristics that are easily identifiable and differentiate it from other rashes.

This is a review from a rheumatologist's perspective of how to identify vasculitis skin changes. If cutaneous vasculitis is suspected, this article identifies other areas of skin that can be affected that need identification, in addition to what to screen for in the history and other differential diagnoses to consider. Subsequently, the article addresses the key investigations to request and a brief overview of the treatment principles for primary vasculitis.

Introduction

Vasculitis, by definition, is inflammation of the vasculature. This inflammation can result in either vessel wall destruction causing aneurysm or rupture or stenosis causing ischaemia or necrosis. This autoimmune response does not always have a clear cause.

This heterogeneous group of disorders has been categorised not only by primary and secondary causes but also by the size of the affected vessel; small – capillaries and intraparenchymal arteries, arteries and venules; medium – visceral arteries; large – aorta and its main branches (see Table 1) 1. The secondary causes that can trigger vasculitis include infection (particularly, hepatitis B and C and haemorrhagic fever); cancer; autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and Sjogren's syndrome; drugs or allergic reactions. As vasculitis can affect any part of the vasculature, it can result in a wide range of signs and symptoms. However, one of the most common presentations of vasculitis is a rash, due to small vessel vasculitis, which is most common. A vasculitic rash has certain characteristics that are easily identifiable and differentiate it from other rashes.

Table 1.

Primary Vasculitis: Summary of main features and treatments

Condition	Size of affected vessel	Symptoms	Treatments
Behcet's syndrome	Small	Mouth and genital ulcers with scarring, erythema nodosum, folliculitis and cutaneous pustular vasculitis. Uveitis and pathergy present. Age 20s–30s	Triamcinolone acetonide cream, NSAIDs, colchicine, steroids, azathioprine, mycophenolate, methotrexate. Anti‐TNF and rituxumab
Henoch Schönlein purpura	Small	Abdominal pain, arthritis, purpura on buttocks, legs and feet. Haematuria	Hydration, rest and analgesics; majority of cases are self‐limiting. Steroids. Azathioprine. Cyclophosphamide. Plasmapheresis
Cryoglobulinaemia	Small	Purpura on lower extremities, polyarthritis, weakness, associated with hepatitis B/C and myeloma, arthritis, weakness and neuropathy	Steroids +/− cyclophosphamide or rituximab. Treat any underlying cause: anti‐viral therapy for hepatitis C or anti‐retroviral therapy for HIV. Consider plasma exchange
Microscopic polyangiitis	Small/medium	Fever, purpura and LR. Proteinura and haematuria. Haemoptysis and fever	Steroids with methotrexate. Cyclophosphamide or rituximab 9.
Buerger's disease (Thromboangiitis obliterans)	Small/medium	Extremities affected with pain and ulcers. Specific geographical distribution being more prevalent in Asia	Smoking cessation is the definitive treatment
Eosinophilic granulomatosis with polyangiitis (Churg‐Strauss)	Small/medium	Cutaneous granulomata along elbows and fingers ‘Churg Strauss nodules’. Asthma, allergic rhinitis, nasal polyps neuropathy	Steroids, cyclophosphamide. Azathioprine, methotrexate, leflunomide, mycophenolate mofetil, IV immunoglobulins, hydroxyurea, rituximab, interferon‐alpha 9
Granulomatosis with polyangiitis (Wegener's granulomatosis)	Small/medium	Palpable purpura, necrotic papules, LR, pyoderma gangrenosum. Epistaxis, painless oral ulcers, chronic sinusitis, nasal stuffiness. Haematuria or red cell casts. Neuropathy	Steroid, cyclophosphamide, plasma exchange, rituximab 10
Polyarteritis nodosa	Medium	Purpura, ‘punched out’ skin ulcers in the lower extremities, myalgia and arthritis, abdominal haemorrhage, fever, weight loss, renal infarction	Steroids, cyclophosphamide, azathioprine, methotrexate 10
Kawasaki disease	Medium	Erythema of palms and soles with desquamation, macular‐papular rash, purpura. Persistent fever, bilateral conjunctival injection, anterior uveitis, strawberry tongue.	Intravenous immunoglobulin, aspirin
Giant cell arteritis	Large/medium	Age >50, tender scalp, jaw claudication, absent neck and arm pulses, blurred or double vision, blindness. Associated with PMR	Steroids, methotrexate
Takayasu's arteritis	Large	Aorta, young women. Numb and cold extremities, decreased or absent pulses, hypertension, headaches and visual disturbances	Steroids, methotrexate, leflunomide, mycophenolate mofetil, tocilizumab/anti‐TNF agents, azathioprine, cyclophosphamide. Treatment of hypertension, heart failure or angioplasty for aortic stenosis

HIV, human immunodeficiency virus; LR, livedo reticularis; NSAIDs, Non‐Steroidal Anti‐Inflammatories.

What makes a rash vasculitic?

The most common presentation of cutaneous vasculitis is purpura (Figure 1). When describing it, the definition of purpura is 3–10 mm (petechiae measure <3 mm and ecchymoses >1 cm). This is commonly palpable and non‐blanching, often demonstrated by applying pressure with a glass tumbler. Purpura signifies extravasation of red blood cells. These may become bullous and ulcerate.

Figure 1.

Lower limb vasculitic purpuric rash.

Other aspects to look for in cutaneous vasculitis include red macules, wheals, papules, nodules, vesicles and blisters. Small and medium vasculitis can cause reticulate patterns and nail fold infarcts.

Medications and infections are common causes of small vessel vasculitis. Allergic vasculitis manifests as non‐blanching haemorrhagic papules, purpuric macules, plaques, bullae, ulcers, mainly affecting the lower leg. The lesions appear almost always synchronously with regard to the time of onset and progression, whereas primary vasculitis lesions progress independently and appear at different time. Large vessel vasculitis normally has no cutaneous manifestations because of the size of the vessels. Large vessel vasculitis could cause larger areas of skin to be affected because of the large size of supplying vessel, but this is very rare. This could result in widespread necrosis and purpura.

In antiphospholipid syndrome (APLS), cutaneous manifestations can mimic vasculitis with livedo reticularis (LR) and thrombophlebitis. In a series of 1000 patients with primary or secondary APLS, 20% had LR 2. Another study of 200 patients in 2005 found that LR was observed in 25·5% of APLS patients, and this was significantly associated with the arterial subset of APLS 3. However, livedo racemosa, similar to reticularis but with an appearance of irregular and/or broken circles rather than full circles of reticularis, is thought to be significantly more associated with an underlying vasculitis 4.

APLS can be primary or secondary, often due to SLE. Vascular thrombosis of any organ and recurrent spontaneous foetal loss are the associated complications. However LR can occur in normal young women without systemic involvement 5, so this is by no means pathognomonic of APLS. Physiologic LR is more often found in neonates, fair‐skinned women and usually only affects the lower extremities 6. Physiologic LR is also known as cutis marmorata.

Which part of the body is affected?

Most commonly, these changes are found in the legs, but can occur anywhere. Particular areas to be aware of are those of trauma or pressure. Mucosal surfaces are rarely affected but sometimes haemorrhagic blisters, ulcers or petechiae can occur.

Oral ulcers are a part of the diagnostic criteria for Behcet's disease 7 and SLE. SLE oral ulcers are often painless, shallow and occur on the soft and hard palate of the mouth. Behcet's oral ulcers are painful and can occur anywhere in the mouth and can last up to 3 weeks. Crohn's oral ulcers in contrast, cannot be distinguished from the common aphthous ulcers.

What makes an ulcer vasculitic?

Ulcers have a multifactorial aetiology and there are many clues to differentiate these. Some more common ulcers are due to venous hypertension. Location is important as 95% of the ulcers occur in the gaiter area of the leg, with an ulcer bed of granulation tissue surrounded by an irregular, gently sloping edge and pitting oedema is often present.

Arterial ulceration is more often located in the heels, toes and bony prominences of the foot. The ulcers look ‘punched out’ with well‐demarcated edges and a pale, non‐granulating, often necrotic base.

Neuropathic ulcers are often related to loss of sensation, which makes them often painless (unless they are infected or have an arterial component). The margins are even and well defined, with variable necrotic and granulation tissue. They are more often located in weight‐bearing surfaces, such as the plantar surface of the foot, metatarsal heads and heels, where minor repetitive trauma is more likely to occur.

Vasculitic ulcers are mainly found distal to the malleolus in the dorsal region of the foot. They are shallow, but can be deep and punched out, and normally have intense surrounding erythematous areas. They can be necrotic with marked vascularity with a mixture of red granulation and necrotic tissue on the wound bed. The borders are irregular with a blistering edge, which can be haemorrhagic. The changes can be subtle, with just purple‐red shade initially and can also be accompanied by atrophie blanche, LR and often by hyperpigmentation. Another clue that they might be vasculitic ulcer is scarring in the surrounding areas. This is due to the repetitive recurrence and poor healing (Figure 2).

Figure 2.

Right foot vasculitic ulcer with violaceous border.

What to ask in the history?

Constitutional symptoms that are consistent with any vasculitis include fever, fatigue, weight loss, myalgia, arthralgia and loss of appetite.

Symptoms to screen for

Any system can be affected in vasculitis; so having a systematic approach is the key:

• Ear, nose and throat: epistaxis, nasal crusting, sinusitis or deafness.

• Respiratory: non‐expectorant cough, haemoptysis, wheeze, chest pain and dyspnoea.

• Gastrointestinal: mouth ulcers, diarrhoea, haemorrhage or abdominal pain from bowel infarction or mesenteric angina.

• Neurological: peripheral sensory or motor impairment. Screen for mononeuritis multiplex.

• Vascular: check pulses, ask about angina symptoms and previous thrombosis, also ask specifically about claudication, scalp tenderness and temporal headache.

• Ophthalamic: vision changes.

Potential underlying causes within secondary vasculitis to consider

Vasculitis can often be a result of infection or exposure to chemicals. Particular culprits include Neisseria meningitidis, hepatitis B/C and chemicals such as amphetamines and cocaine. Medications can also be an underlying cause. More common culprits include Non‐Steroidal Anti‐Inflammatories (NSAIDs), antibiotics, thiazide diuretics and warfarin. Paraneoplastic manifestations are an important consideration, with particular mention of lymphomas and multiple myeloma. Existing auto‐inflammatory conditions such as RA and SLE can present with a vasculitis picture.

Which investigations to request?

Antibodies (this is not an exhaustive list):

• The most important antibody to test for is antineutrophil cytoplasmic antibody (ANCA). A positive ANCA test is associated with medium to small vessel involvement.

• Anticardiolipin antibodies, anti‐beta‐2‐glycoprotein 1 and lupus anticoagulant (APLS). Anti‐beta‐2‐glycoprotein 1 is the most specific of these.

• Anti‐nuclear antibodies (ANA) and extractable nuclear antigens (ENA): SLE or other autoimmune disorders.

• Anti‐streptococcal antibodies: indicates recent streptococcal infection.

• Cryogobulins: detect abnormal antibodies in the blood that precipitate in the cold in cryoglobulinaemia

• dsDNA and low levels of complement (C3/4): SLE.

• Rheumatoid factor.

• Glomerular basement membrane antibody

• Anti‐CCP (ACPA): RA.

Other investigations:

• Hepatitis B/C, Q fever, Lyme and CMV serology.

• Creatine phosphokinase.

• Protein and immunoglobulin electrophoresis: detects blood disorders such as multiple myeloma.

• Check hepatic and renal function.

• Urine test looking for proteinuria, casts and haematuria (consider protein‐creatinine ratio and look for active urinary sediment).

• Full blood count, taking note of eosinophils, WBC and haemoglobin.

• C Reactive Protein (CRP) and Erythrocyte Sedimentation Rate (ESR).

• Angiography looking for large vessel vasculitis.

• Biopsy of affected organs (especially kidney).

Histopathology

Skin biopsy from the most symptomatic, red or purpuric lesion including the subcutis layer is crucial for obtaining the highest yield diagnostic sample. Depth of skin biopsy, tissue diagnosis and clinicopathological features are the key to diagnosis. By identifying the size of the affected vessel and the immune cell mediating the inflammation, the vasculitis can be classified.

In small vessel vasculitis, disruption by inflammatory cells and deposition of fibrin within the lumen and/or vessel wall with nuclear debris 8 are seen. The fibrinoid necrosis of the vessels and fibrin extravasation may be difficult to visualise. Fibrin deposits are a relatively certain sign of vascular injury, and their presence in the context of an infiltrate of inflammatory cells within and around vessel walls signifies vasculitis. Immunofluorescence may be useful to confirm vascular damage as deposition of fibrinogen, C3, IgG and IgM can be seen within vessel walls. Positive IgA is strongly suggestive of Henoch Schönlein Purpura. Neutrophilic or leukocytoclastic vasculitis (neutrophil degeneration) alone is not indicative of primary vasculitis. Histologically, the dermis has a superficial and mid‐perivascular inflammatory pattern population of predominantly neutrophils in a perivascular and interstitial pattern in addition to those undergoing extravasation from the vessels.

In contrast, muscular vessel (arterioles, small arteries and veins) vasculitis can be identified solely by infiltration of its wall by inflammatory cells. Extravasation of red blood cells (purpura) and necrosis are supportive, but not diagnostic of vasculitis because they are also seen in haemorrhagic and vaso‐occlusive disorders 7.

Investigations for vasculitis mimickers:

• Blood cultures.

• Echocardiography looking for infective endocarditis: infective or Libman‐Sachs.

• Chest and sinus X‐rays.

• Consider investigations to rule out malignancy.

Treatment

The scale and selection of treatment depends on the cause of the cutaneous vasculitis. If the aetiology is a new medication, the medication should be withdrawn. Patients should be screened for infection and treated accordingly.

If the underlying pathology is a primary vasculitis, treatment is determined by the severity of vasculitis. Aspects that determine treatment are whether there is systemic involvement and also which particular organ and to what extent it is involved.

If the vasculitis is confined to the skin only, conservative measures can be undertaken. This involves topical, oral or intravenous steroids, or antihistamines. For more severe cases, immunosuppression may be necessary. All new ANCA‐associated vasculitis should be considered as having a potentially organ‐threatening disease and therefore be assessed for treatment with steroid and cyclophosphamide or rituximab 9. Common disease modifying agents that are used are azathioprine, methotrexate and ciclosporin. Other potential agents include leflunomide, sulphsalazine and mycophenolate mofetil. For more severe cases with major organ involvement (including haematological), chemotherapy in the form of cyclophosphamide is an option. Other disease‐specific treatment such as that for cryoglobulinaemias may include plasma exchange to remove these immune complexes. Regarding organ involvement, for gastrointestinal disease, azathioprine is of preference and for renal involvement, cyclophosphamide and/or mycophenolate, and in certain circumstances, rituximab.

Summary

Cutaneous vasculitis can be a manifestation of several vasculitic disorders encompassing a heterogeneous collection of signs and symptoms. This article aims to identify the typical signs to look for within a vasculitic rash or ulcer. Once cutaneous vasculitis has been identified, further examination and assessment should be commenced. Aims that need to be established are whether the vasculitis is due to a primary or secondary process, and whether there is other organ involvement. This can be addressed by completing a thorough history and examination, screening for extra‐cutaneous signs and symptoms and paying particular attention to potential complications and end organs that may be affected.