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Systemic vasculitides. Part 2: Small vessel diseases

Sean M. Conte

Peter R. Vale

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This article was originally published as: Conte, S. M., & Vale, P. R. (2020). Systemic vasculitides. Part 2: Small vessel diseases. Medicine Today, 21 (5), 21-27.

Original article available here: https://medicinetoday.com.au/2020/may/feature-article/systemic-vasculitides-part-2-small-vessel-diseases

This article is posted on ResearchOnline@ND at . For more information, please contact [email protected]. This article originally published: - Conte, S. and Vale, P.R. (2020) Systemic vasculitides. Part 2: Small vessel diseases. Medicine Today, 21(5): 21-27. Permission granted by Medicine Today for use on ResearchOnline@ND. © Medicine Today 2020 (http://www.medicinetoday.com.au). PEER REVIEWED FEATURE

Systemic vasculitides Part 2: Small vessel diseases SEAN M. CONTE BA, MB BS; PETER R. VALE MB BS, FRACP, FCSANZ, FACC, FACP Small vessel vasculitides often manifest as neurological, renal, pulmonary and dermatological KEY POINTS symptoms. Clinical features of systemic vasculitides • The two main categories of small vessel are are often nonspecific; therefore, it is important that antineutrophil cytoplasmic -associated and GPs be aware of the range of symptoms that can -associated disease, best diagnosed help in the differential diagnosis, treatment and with renal and/or pulmonary . management of this diverse group of conditions. • Severe renal failure and pulmonary haemorrhage are high-risk features that require urgent management. • Eosinophilic granulomatosis with polyangiitis can be art one of this two-part series on systemic vasculitides associated with severe cardiac disease including heart covered the large, medium and variable vessel vascu- failure, conduction abnormalities and pericarditis. litides. We saw that most primary vasculitides are These complications account for half of the mortality typified by nonspecific systemic manifestations such as associated with this disease. Pfever, weight loss and lethargy but that classic presentations often • Hypocomplementaemic urticarial vasculitis and aid our diagnostic efforts. We also stressed the importance of cryoglobulinaemic vasculitis are commonly associated with underlying systemic conditions including identifying high-mortality and high-morbidity situations such inflammatory rheumatological disease, chronic viral as visual impairment in (GCA) and coronary hepatitis and haematological malignancies. These artery aneurysms in . should be screened for at the time of diagnosis. Part two will discuss small vessel diseases, a diverse group • Leukocytoclastic vasculitis is the most common of diseases often with neurological, renal, pulmonary and vasculitis encountered in clinical practice, only involves ­dermatological manifestations, which are summarised in Table 1. the skin and is most commonly associated with We will conclude with a summary outlining a general approach medication use. • Patients receiving long-term or immuno­ suppressive therapy require dedicated screening for MedicineToday 2020; 21(5): 21-27 chronic iatrogenic complications such as diabetes mellitus, osteoporosis, , obesity, Dr Conte is a Medical Registrar and RACP Trainee at St Vincent’s Hospital, opportunistic infections and secondary malignancies. Sydney; and Clinical Associate Lecturer at UNSW, Sydney and the University of Notre Dame Australia, Sydney. Professor Vale is a Professor of Medicine at The University of Notre Dame Australia, Sydney; and a Vascular Physician and Cardiologist at Mater

© HEALTH CARE/STOCK.ADOBE.COM Hospital, Sydney, NSW.

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TABLE 1. SUMMARY OF CLINICAL FEATURES AND ASSESSMENT OF SMALL VESICLE DISEASE VASCULITIDES

Disease entity Clinical patient features Investigations and diagnosis Management options

Granulomatosis with • Sinusitis • Cytoplasmic antineutrophil • Induction: + polyangiitis (GPA) / • Haemoptysis cytoplasmic : protease or microscopic • Haematuria 3 (granulomatosis with • Maintenance: , polyangiitis (MPA) polyangiitis), myeloperoxidase methotrexate, rituximab (GPA) (MPA)

Eosinophilic • , • p-ANCA • Induction: corticosteroids +/− granulomatosis with • Mononeuritis multiplex • Eosinophilia cyclophosphamide polyangiitis • Cardiac conduction • Chest imaging (patchy opacities) • Maintenance: azathioprine, abnormalities • Surgical lung biopsy methotrexate, leflunomide • Anti-interleukin-5

Anti-glomerular • Haemoptysis • p-ANCA • Critical/Emergent: intubation, • Haematuria • Myeloperoxidase dialysis disease • Acute renal failure • Antibodies against type IV • Initial: + on ELISA, western blot, corticosteroid + and immunofluorescence of renal cyclophosphamide or pulmonary biopsy • Alternate: rituximab or mycophenolate • Maintenance: low-dose prednisolone +/− second agent

IgA-related vasculitis • Asian populations • Renal function • Uncomplicated: NSAIDs, rest, • Palpable on lower • Urine sediment hydration limbs and buttocks • Urine protein • : ACE inhibitor or ARB • Migratory oligoarthralgia • Immunofluorescence of biopsy • Prolonged: low-dose prednisolone • Abdominal pain specimen (IgA) • Severe or marked renal • IgA nephropathy dysfunction: mycophenolate +/− cyclophosphamide

Hypocomplementaemic • Constitutional symptoms • Low C3 and C4 • Mild: NSAIDs and antihistamines urticarial vasculitis • Chronic obstructive • Leukocytoclastic vasculitis on • Moderate: prednisolone + pulmonary disease biopsy colchicine, dapsone, • Mild renal dysfunction • Renal function and urinalysis hydroxychloroquine • Migratory polyarthritis • Hepatitis serology • Severe: mycophenolate • Associations: SLE, Sjögren’s • ANCA, antinuclear antibody, disease, drugs, HCV and extractable nuclear antigens, etc. HBV, complement deficiency, • Serum protein electrophoresis haematological malignancies and immunofixation

Cryoglobulinaemic • Cutaneous manifestations • Screening for connective tissue • Mild: NSAIDs, rest hydration vasculitis • Arthralgias (hands, knees, diseases (SLE, Sjögren’s) • Proteinuria: ACE inhibitor or ARB ankles) • Screening for haematological • Moderate: low-dose prednisolone • Peripheral neuropathy malignancy (multiple myeloma, • Severe/prolonged: • Waldenström’s) cyclophosphamide +/− • Evaluation of renal function and mycophenolate proteinuria • Renal biopsy

Leukocytoclastic • Temporal relationship to new • Absence of evidence of major • Supportive care vasculitis or changed medication visceral involvement • Cessation of offending • • Exclusion of medication • Maculopapular rash or infection • Perivascular neutrophils • Fibrinoid necrosis

Abbreviations: ARB = angiotensin-receptor blocker; c-ANCA = cytoplasmic antineutrophil cytoplasmic antibodies; ELISA = enzyme-linked immunosorbent assay; HBV = hepatitis B virus; HCV = hepatitis C virus; IgA = immunoglobin A; p-ANCA = peripheral antineutrophil cytoplasmic antibodies; SLE = systemic erythematosus.

22 MedicineToday ❙ MAY 2020, VOLUME 21, NUMBER 5 Downloaded for personal use only. No other uses permitted without permission. © MedicineToday 2020. to investigating and managing systemic 2. in those with pulmonary vasculitides. haemorrhage 3. in the presence of concomitant ­ Classification and clinical anti-glomerular basement features membrane antibodies.3 Antineutrophil cytoplasmic Maintenance therapy is started once antibody-associated vasculitis corticosteroids are tapered, usually after Granulomatosis with polyangiitis and three to six months, and preferred agents are azathioprine or methotrexate. Rituxi- Granulomatosis with polyangiitis (GPA), mab is an alternative agent for maintenance formerly known as Wegener’s disease, therapy but is not recommended for MPO- Figure 1. CT of the chest in a patient with and microscopic polyangiitis (MPA) most ANCA positive disease.4 granulomatosis with polyangiitis. commonly occur in patients over the age Case courtesy of Radswiki, Radiopaedia.org, rID: 12079. of 65 years and more often in Caucasian Eosinophilic granulomatosis with populations, affecting men and women polyangiitis pulmonary biopsy. Surgical lung biopsy equally. GPA affects the respiratory and Eosinophilic granulomatosis with poly- revealing extravascular granulomas with glomerular epithelia producing haemop- angiitis (EGPA), formerly known as eosinophilic pneumonia is the gold stand- tysis and haematuria, respectively. Ear, Churg-Strauss syndrome, is a multi­system ard diagnostic test for EGPA and is superior nose and throat (ENT) manifestations vasculitis of the small and medium-sized in demonstrating typical histopathology such as sinusitis, otitis media, ulcers, vessel with gradual onset in the second or to a transbronchial approach.6 Spirometry polychondritis and subglottic stenosis third decade of life. EGPA is typified by and pulmonary function testing typically are also classically seen. Dermatologic chronic rhinosinusitis, asthma and atopy demonstrate obstruction, w­ ith asthmat- and ophthalmologic involvement can in the context of peripheral eosinophilia. ic-range reversibility with decreased lung occur with variable frequency. Cytoplas- Atopic and eosinophilic phases of the volumes and impairment of gas transfer. mic antineutrophil cyto­plasmic anti­ illness generally predate nonspecific signs Electrocardiography,­ echocardiography bodies (c-ANCA) are seen in over 80% of systemic vasculitis such as fevers, weight and occasionally endomyocardial biopsy of patients with GPA and MPA and are loss and lassitude by as much as a decade. are prognostically useful tests for deter- typically associated with protease 3 in Cardiac involvement in the form of heart mining the extent of organ involvement GPA and myeloperoxidase (MPO) in failure, conduction abnormalities or and guiding therapy.7 MPA.1 Urinalysis discloses haemoglobin ­pericarditis accounts for roughly half of Initially, treatment with corticosteroids and red-cell casts indicating glomerular the mortality associated with EGPA. Mon- achieves remission without the use of inflammation. CT of the head, sinuses oneuritis multiplex is a classic neurological ­adjuvant therapy in the majority of patients and chest is recommended in cases with manifestation of EGPA and may be a clue with EGPA. Cyclophosphamide is added ENT manifestations and pulmonary to differentiate the disease from simple when severe multiorgan involvement is disease to ­clarify the site and severity of asthma or sinusitis in its early phase. Renal present. Maintenance therapy with disease and guide biopsy (­ Figure 1).2 GPA involvement is present in most patients ­azathioprine, methotrexate or leflunomide and MPA are best diagnosed and differ- with variable histopathology. Finally, it is is reserved for severe disease without entiated on biopsy, ­usually renal or pul- worth noting that patients with EGPA are ­multiorgan involvement and is continued monary, and defined by the presence of at a significantly increased risk of venous for 12 to 18 months.8 Anti-interleukin-5 granulomatous inflammation. thromboembolism compared with the monoc ­lonal antibody therapy (mepoli- The goals of therapy are to reduce the general population.5 Patients with EGPA zumab and reslizumab) has shown promise incidence of renal failure and haemoptysis, have a raised peripheral eosinophil count, in treating EGPA.9 and induce remission. Initial therapy usually above 1500 mcmol/L, and roughly begins with corticosteroids in combina- half have a positive peripheral antineu- Immune complex-associated tion with cyclophosphamide, rituximab trophil cytoplasmic antibodies (p-ANCA). vasculitis or methotrexate for mild nonorgan- A case study on the diagnosis of EGPA is Anti-glomerular basement membrane threaten ­ing disease. Plasma exchange ther- outlined in the Box. disease apy should be added in three situations: Chest imaging, especially CT, typically Anti-glomerular basement membrane 1. when patients have rapidly progressive demonstrates transient patchy opacities, (GBM) disease, also known as Good­ renal impairment or renal failure at peribronchial and septal thickening, and pasture’s disease, is a small vessel vasculitis the point of requiring dialysis helps guide bronchoalveolar lavage and characterised by the presence of anti-GBM

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CASE STUDY. SMALL VESSEL DISEASE VASCULITIS

A 39-year-old woman with a history of asthma presents with a 3-month history of progressive exertional dyspnoea and cough. She has noticed relief from two courses of oral corticosteroids prescribed by her general practitioner for asthma exacerbation management but worsens when she ceases these after one week. On examination, a prolonged expiratory phase, mild diffuse wheeze and a mild left-sided foot drop is noted. Laboratory investigations reveal a serum creatinine level of 120 mcg/dL, peripheral eosinophil count of 2350 mcmol/L and a positive peripheral antineutrophil cytoplasmic antibody test. CT of the chest is remarkable for multilobar patchy opacities and septal thickening. Sputum microbiology, serum Aspergillus precipitins and skin prick testing are negative. What diagnosis is most likely? The constellation of asthma, renal impairment, eosinophilia and peripheral neuropathy Figure 2. Linear deposition is highly suggestive of eosinophilic granulomatosis with polyangiitis. in the basement membrane of glomerular capillaries pathognomonic of anti-glomerular What other investigations should be undertaken? basement membrane vasculitis. This patient requires an electrocardiogram and potentially an echocardiogram to Reproduced from Silva N, Oliveira L, Frutuoso M, evaluate for cardiac involvement as this is responsible for up to half the mortality in Morgado T. Anti-glomerular basement membrane disease: this disease. Pulmonary function testing and imaging is prudent and can guide surgical a case report of an uncommon presentation. J Clini Nephrol. 2019; 3: 61-65 under the terms of the Creative biopsy if diagnosis is uncertain as this is the gold standard diagnostic test. Commons Attribution License. How should the patient be managed initially? Corticosteroids are the best initial therapy and, if severe, can be combined with Haematuria and an active urinary sedi- cyclophosphamide to induce remission. ment are typically found and renal dys- function is typically self-­limited.17 Markers antibodies, usually directed against the Patients are managed initially with a of poor prognosis include prolonged NC1 domain of type IV collagen found combination of corticosteroids and ­abnormalities of the urinary sediment, primarily in the renal and respiratory either cyclophosphamide, rituximab or heavy proteinuria, hypertension and tracts.10 Acute renal failure is the most mycophenolate mofetil for three to six impairment of renal function with an common presenting illness and roughly months, as well as up to six weeks of elevated serum creatinine level. Serum half of affected patients have clinical intensive ­plasmapheresis to remove IgA levels are elevated in approximately ­evidence of alveolar haemorrhage with ­circulating anti-GBM­ antibodies.15 Anti- half of cases and are a­ ssociated with renal cough, pro­gressive dyspnoea or overt GBM antibody levels, together with dysfunction.18 IgA deposition on immuno­ ­haemoptysis.11 ­Concurrent systemic vas- ­clinical response, guides the need for fluorescence of skin or renal biopsy culitis is suggested clinically by the repeat plasmapheresis. Maintenance ­specimens is usually required to make the presence­ of constitutional symptoms ­therapy with low-dose prednisolone with diagnosis in adult patients. such as fevers, weight loss and malaise, or without a second agent such as azathi- and by the presence of positive ANCA, oprine or mycophenolate mofetil is usually M­ PO-ANCA, which is found in ­recommended for nine months. up to a third of patients with anti-GBM vasculitis.12 Immunoglobulin A vasculitis Demonstration of serum, pulmonary Immunoglobulin A (IgA) vasculitis, also or renal anti-GBM antibodies using direct known as Henoch-Schönlein purpura enzyme-linked immunoassay (ELISA) (HSP), is a small-vessel vasculitis more and confirmed with western blot is common in Asian populations that ­diagnostic. Renal biopsy should always ­predominantly affects children under be performed if possible as it is more 15 years old.16 The major clinical mani­ accurate and guides treatment. Immuno­ festations include palpable purpura fluorescence of biopsy specimens reveals ­primarily on the buttocks and lower limbs Figure 3. Classic palpable purpura of the pathognomonic linear immuno­ (Figure 3), non-deforming migratory immunoglobulin A vasculitis. globulin G (IgG) deposition in the base- ­oligoarthralgia of the lower limb large Reproduced with permission from the Mayo Foundation for Medical Education and Research. © Mayo Foundation ment membrane of glomerular capillaries joints, colicky abdominal pain some- for Medical Education and Research. All rights reserved. (Figure 213).14 times with bleeding and renal disease.

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heterogeneous group of diseases caused TABLE 2. COMMON SITES OF EXTRACUTANEOUS MANIFESTATIONS IN PATIENTS by the precipitation of blood proteins, WITH HYPOCOMPLEMENTAEMIC URTICARIAL VASCULITIS chiefly immunoglobulin and comple- Site Manifestations ment. The systemic inflammation result- ing from the precipitation of these Joints • Migratory polyarthritis and arthralgias sometimes accompanied by proteins primarily affects medium and Jaccoud’s deforming nonerosive arthropathy small vessels. Cutaneous manifestations Eyes • Episcleritis are nearly universal.25 Arthralgias are • Uveitis also common with a proclivity for meta- • Conjunctivitis carpophalangeal and proximal phalan- Lungs • Cough geal joints, knees and ankles.26 Peripheral • neuropathy and renal involvement, • Chronic obstructive pulmonary disease (COPD) ­primarily in the form of membranopro- Gastrointestinal • Abdominal pain liferative glomerulonephritis, a sub­ tract • Nnausea clinical small airways disease, also affects • Vomiting a sizable minority of patients with • Diarrhoea without bleeding cryoglobulinaemia. Kidneys • Mild nonprogressive renal disease with haematuria and light Investigations are aimed at diagnosis proteinuria of underlying connective tissue disease (SLE, Sjögren’s), monoclonal haematolo­ Hydration, rest and simple analgesia The clinical course is prolonged, usually gical disorder (multiple myeloma, with NSAIDs are first line management occurring over months to years. Roughly Waldenström’s macroglobulinaemia) or strategies for symptomatic control. For half of patients with HUV experience chronic viral infections (HCV or HBV). patients with heavy proteinuria, therapy constitutional symptoms and the most C4 complement levels are almost always with an ACE inhibitor or angiotensin- common sites of extracutaneous mani- reduced in cryoglobulinaemic vasculi- receptor blocker (ARB) is recommended. festations are summarised in Table 2. tis.27 Detection of cryoglobulins is a pre- Low-dose prednisolone may be consid- A skin biopsy should be undertaken cise and complex laboratory process ered in more severe or prolonged disease. early to guide further investigation and which must be executed correctly to avoid Monitoring renal function and urinary treatment. Should the diagnosis of false positives. A cryocrit greater than sediment is a mainstay of management HUV be confirmed on biopsy, inflamma­ 0.5% or cryoglobulin concentration throughout.19 Patients with severe or pro- tory markers, renal function, urinalysis, greater than 50 mcg/mL is considered longed disease (greater than six months) ­hepatitis serology, ANCA and an auto­ clinically significant.­ 28 Management of should undergo renal biopsy to demon- antibody panel, complement protein levels cryoglobulinaemic vasculitis consists of strate active inflammation and, if pres- with C1q precipitin (anti-C1q antibody), identification and treatment of the ent, immunosuppressive therapy with immunofixation electrophoresis and underlying condition. cyclophosphamide or mycophenolate is ­cryoglobulin levels should be obtained. recommended.20 Most disease is mild and responds Leukocytoclastic vasculitis well to supportive treatment with anti­ Leukocytoclastic vasculitis (LCV), also Hypocomplementaemic urticarial histamines and NSAIDs. Corticosteroids referred to as vasculitis, vasculitis with the addition of dapsone, ­colchicine is the commonest vasculitis encountered Hypocomplementaemic urticarial vas- or hydroxychloroquine may be indicated in clinical practice. It is a skin-isolated culitis (HUV) describes a wide range of in cases where symptomatic treatment is vasculitis of the small vessels and may be clinical syndromes characterised by the inadequate. Severe disease, defined by the idiopathic or secondary. The term ‘leuko­ presence of urticaria and dermatological presence of end-organ dysfunction, typ- cytoclastic’ refers to the death and break- biopsy evidence of leukocytoclastic ically requires longer term immunosup- down of neutrophils after degranulation. ­vasculitis. Immune complex deposition pressive therapy with mycophenolate LCV presents most commonly with pal- in vessel walls activates complement mofetil or another steroid-­sparing agent.24 pable purpura of the lower limbs without ­proteins, which stimulates mast cell haematuria or other evidence of major degranulation and clinical urticaria.21 Cryoglobulinaemic vasculitis visceral involvement. It is important to Complement protein levels are reduced Cryoglobulinaemic vasculitis is a man- exclude systemic vasculitis or infection in more severe or widespread disease. ifestation of cryoglobulinaemia, a in cases of suspected LCV. Diagnosis is

26 MedicineToday ❙ MAY 2020, VOLUME 21, NUMBER 5 Downloaded for personal use only. No other uses permitted without permission. © MedicineToday 2020. made with a combination of clinical and In the case of small vessel disease and/ especially when combination immuno- skin biopsy findings and is described or vasculitis occurring in the context of suppressive or high-dose corticosteroid by the American College of Rheumatol- another suspected systemic inflammatory therapy is used. Furthermore, patients ogy criteria.29 These criteria are met if at condition, autoimmune serology should with high burdens of corticosteroid least three out of five of the following are be obtained, including ANCA with pro- ­therapy should be screened for systemic observed: tease 3 and MPO staining, antinuclear complications such as diabetes mellitus, 1. age over 16 years old antibody, rheumatoid factor and comple- hypertension, obesity and osteoporosis, 2. temporal relationship to new or ment protein levels. More specific serol- and managed appropriately. changed medication ogy should be performed to confirm Diagnosis, management and monitor- 3. palpable purpura diagnoses suggested by the initial screen, ing take place primarily in the community, 4. maculopapular rash including anti-double stranded deoxyri- thus the general practitioner is integral to 5. perivascular neutrophils and bonucleic acid antibodies, extractable the management of most patients with fibrinoid necrosis seen on skin nuclear antigens and anti-cyclic citrulli- vasculitis. Vasculitis accompanying sys- biopsy. nated peptide antibodies. In the presence temic disorders such as rheumatoid arthri- Skin biopsy occasionally reveals eosin- of haemo­ptysis, plain chest radio­graphy tis or viral hepatitis often merit specialist ophils, which strongly suggest a phar- and high-resolution CT scan of the chest involvement and regular follow up. Early macological aetiology. The most com- should be undertaken to guide subsequent and urgent referral to a vascular or other mon medications implicated are sulfon- ­therapy. In large vessel vasculitis and relevant physician specialist such as an amides such as frusemide and thiazide ­suspected , CT or immunologist or a rheumatologist should diuretics, penicillin and cephalosporin magnetic resonance angiography is be obtained for patients who have evidence antibiotics, allopurinol, and phenytoin.30 ­usually undertaken to visualise sites of of progressive disease and in those with In most cases, management is supportive involvement and confirm the presence of end-organ dysfunction. In patients with in addition­ to cessation of the offending complications such as aneurysms, dissec- haemoptysis, severe renal impairment or agent if known and possible. tions or occlusions. Tissue sampling is suspected GCA with visual compromise, often integral to diagnosis: temporal arter- immediate hospitalisation is indicated. Investigations ies in suspected GCA, renal biopsy in the Although clinical features of systemic context of renal dysfunction or an active Conclusion vasculitis are usually nonspecific, symp- urinary sediment, and skin biopsy with The vasculitides are a diverse group of toms such as haemoptysis, haematuria, dermatological manifestations such as conditions whose specific manifestations renal failure, asthma and jaw claudication Henoch-Schönlein purpura or HIV. generally depend on the size of vessels can help sharpen the differential. Like- involved. Important complications of wise, features of systemic disease such as Therapy and outcomes these varied diseases such as visual com- SLE, , HIV or infec- Management of primary systemic vas- promise, renal dysfunction, pulmonary tive endocarditis can be helpful in direct- culitides involves the induction and haemorrhage and vascular aneurysms ing investigations and therapy. Initial maintenance of remission, as well as must be considered. Specialist involve- laboratory tests should include inflam- prevention and management of compli- ment is crucial and should be obtained matory markers (erythrocyte sedimen- cations and end-organ dysfunction urgently if such complications are present. tation rate and C-reactive protein), as resulting from vascular injury. Corticos- In patients receiving long-term corticos- well as measures of organ function such teroids form the backbone of induction teroid or immunosuppressive therapy, as serum creatinine level and liver func- regimens, often in high doses compared dedicated screening for chronic iatrogenic tion tests. Serology for HBV, HCV, HIV with systemic rh­ eumatologic conditions. complications such as diabetes mellitus, and cryoglobulins is typically under- In patients requiring prolonged mainte- osteoporosis, hypertension, obesity, taken as well. Urine specimens should nance therapy, steroid-sparing agents opportunistic infections and secondary be sent for routine analysis, microscopy including thiopurines, mycophenolate malignancies is crucial to achieve optimal and examination of the sediment. Micro- and calcineurin inhibitors are preferred health outcomes. MT biological cultures, serology and imaging to long-term ­steroids. In secondary dis- guided by symptoms should be obtained ease, management focuses on the under- References to exclude simple infections. A careful lying condition (i.e. cryoglobulinaemic A list of references is included in the online version of this article (www.medicinetoday.com.au). medication and exposure history should vasculitis in HCV). be undertaken in consideration of a reac- It is important to adhere to vaccination tive process. and infection prophylaxis guidelines, COMPETING INTERESTS: None.

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