A Project of UKIVAS, the Vasculitis Rare Disease Group of the UK and Ireland.
Vasculitis – Clinician Information
- Types of Vasculitis
Vasculitis is a group of disorders characterised by inflammation and fibrinoid necrosis in blood vessels. Where no underlying cause is found, the vasculitis is termed primary. Commonly, vasculitis is classified by the size of the blood vessels that are affected: i.e. large arteries (aorta and its major branches and corresponding veins), medium sized arteries and veins supplying visceral organs, or small blood vessels (small arteries, arterioles, venules, capillaries). A new classification system for vasculitis has been approved by the 2012 Chapel Hill Consensus Conference.
The major groups of vasculitic diseases are listed below. Clinical descriptions of the diseases can be found by clicking on the attached links to the Vasculitis UK webpages.
Small vessel vasculitides
Primary small vessel vasculitidies are strongly associated with anti-neutrophil cytoplasmic antibodies (ANCA). In the kidney these conditions manifest as a necrotizing glomerulonephritis without significant immune deposits (pauci-immune), which may be rapidly progressive. Three major clinical syndromes of ANCA-associated (AAV) small vessel vasculitis are recognised:
- Granulomatosis with polyangiitis (GPA) formerly known as Wegener’s granulomatosis
- Microscopic polyangiitis (MPA)
- Eosinophilic granulomatosis with polyangiitis (EGPA) formerly known as Churg-Strauss syndrome
A separate form of primary small vessel vasculitis, not associated with ANCA is IgA vasculitis (formerly known as Henoch-Schoenlein purpura), which is the commonest form of vasculitis in children. It is characterized by skin rashes and kidney and gut involvement, with IgA deposition in the histological lesions.
Anti-Glomerular Basement Membrane disease (formerly known as Goodpasture’s disease)
This is a small vessel vasculitis distinct from the AAV and distinguished by the presence of circulating anti-glomerular basement membranes (anti-GBM) antibodies (present in up to 92% of cases). Clinical presentation is usually with rapidly progressive glomerulonephritis and diffuse alveolar haemorrhage. These organs are targeted due to the presence of the autoantigen, the alpha 3 chain of type IV collagen, in the basement membranes.
Anti-GBM disease is a rare disease with an annual incidence of around 1 per million. Risk factors for disease development are smoking and HLA DR15 or DR4 positivity. There is a bimodal age incidence, with peaks in the third and seventh decades.
Kidney biopsy typically shows a severe acute necrotizing and crescentic glomerulonephritis, with immunofluorescence confirming the presence of IgG in a linear pattern on the GBM. Up to 55% of patients will require renal replacement therapy (RRT) at presentation, and this is a strong predictor of the ongoing need for RRT.
Treatment is similar to that of other organ/life- threatening small vessel vasculitides, in this case with focus on reduction/removal of antibody and blockade of the inflammatory/destructive consequences. This is achieved with initial high dose steroids (pulsed methylprednisolone may be used if life threatening disease, followed by 1mg/kg daily of oral prednisolone, typically limited to a maximum dose of 60mg, then reducing) and oral cyclophosphamide 2 mg/kg daily. In addition prompt institution of plasmapheresis is recommended, with up to 14 sessions, ideally daily, or until anti-GBM antibody cannot be detected.
Other treatments used in the setting of first line treatment failure or contraindication include rituximab and mycophenolate mofetil. The role of newer biologics and other agents to control the inflammatory process remains to be clarified.
Treatment differs from the other small vessel vasculitides in that maintenance immunosuppression therapy is rarely needed due to the low relapse rate (2-3%) once removal of the pathogenic antibody has been achieved. Corticosteroids are usually tapered and discontinued by 6 months post-presentation, with cyclophosphamide duration typically limited to around 3 months.
Although life-threatening, pulmonary haemorrhage can usually be controlled within a number of days by prompt and comprehensive treatment, Extra Corporeal Membrane Oxygenation is now an option to sustain life in the early days of management.
The renal prognosis differs from acute kidney secondary to AAV in that recovery of renal function is unusual in patients who require dialysis or are oligo-anuric at onset. On the other hand prompt treatment usually succeeds in maintaining independent renal function in patients with plasma creatinine <500micromol/L at presentation. Renal transplantation is a successful treatment option in suitable candidates whose renal function does not recover. Patients can be considered for transplantation once they are anti-GBM antibody negative, although common practice is to wait for 12 months from control of disease activity.
Around 30% of patients with anti-GBM disease may also have ANCA antibodies. It is suggested that the anti-GBM antibodies and overt disease manifestations in these ‘double positive’ patients may develop following damage caused by previously undetected AAV.
Such patients have an initial outcome similar to that of anti-GBM disease alone, and should be treated accordingly. However, they may relapse due to the ANCA, and therefore require maintenance immunosuppressive treatment, similar to those with AAV alone.
Giant Cell Arteritis
Giant cell arteritis (GCA) is the commonest form of vasculitis in the UK, with an incidence of 2.2 cases/ 10000 person- years in those over the age of 40. GCA is caused by inflammation of the medium and large blood vessels, particularly around the head and neck. It typically presents with sudden onset headache, scalp tenderness, jaw claudication, and systemic upset with visual loss due to anterior ischaemic optic neuropathy in up to 20%. There is an overlap with polymyalgia rheumatics (PMR), with 50% of patients with GCA also describing PMR features.
Medium vessel vasculitis
Large vessel vasculitis:
Variable vessel vasculitis
- Clinical Guidelines
The British Society for Rheumatology 2014 guidelines for the management of ANCA associated vasculitis have been produced with the collaboration of the Vasculitis RDG. They can be accessed online here. The 2007 guidelines can be accessed here and the European League against Rheumatism (EULAR) guidelines for the management of medium and small vessel vasculitis can be accessed here. A consensus statement on the use of Rituximab in ANCA-associated vasculitis has recently been produced by experts in the field.
- Management of systemic corticosteroids
- Monitoring adverse events in corticosteroid therapy
Management of large vessel vasculitis
Management of Behcet’s disease
- Investigation, Diagnosis and Classification
Small Vessel Vasculitis
Small vessel vasculitides are rare conditions that are strongly associated with anti-neutrophil cytoplasm antibodies (ANCA). In the kidney, the process predominantly affects the glomeruli, leading to a pauci-immune necrotising crescentic glomerulonephritis. Patients can present with rapidly progressive glomerulonephritis, and other systemic features, including pulmonary haemorrhage, which can have a fulminant presentation. Since the introduction of immunosuppression, most patients with vasculitis have a relapsing/remitting chronic course. Over the past 20 years, the management of ANCA-associated vasculitis has been informed by a number of randomised controlled clinical trials. Aims of therapy are to induce and maintain disease remission and prevent organ damage, whilst avoiding side effects of treatment.
Vasculitis may present in non-specific ways, with malaise, fatigue, arthralgia, myalgia and weight loss.
Granulomatosis with polyangiitis (GPA) is characterised by upper respiratory tract involvement, lung disease (including pulmonary infiltrates or nodules, haemoptysis, pulmonary haemorrhage, pleuritis, dyspnoea) and renal involvement. Granulomatous tissue destruction can occur especially in the upper airways (nose and sinuses). Peri-orbital masses and ocular disease (scleritis, episcleritis, uveitis, retinal vasculitis) can also occur. Disease localised to the upper airways and eyes/orbits without systemic involvement is also recognised.
Microscopic polyangiitis is characterized by renal and lung involvement, without granulomatous tissue destruction. The lung disease is often more of a fibrosing, restrictive pattern. Pulmonary haemorrhage with fulminant presentation also occurs.
Eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss syndrome) is characterized by marked hyper-eosinophilia and tissue eosinophil infiltration, associated with granulomata and vasculitis. Allergic rhinitis and asthma precede the development of EGPA. Peripheral nerve, cardiac and gastrointestinal involvement can occur.
It is important to consider other systemic diseases, including subacute bacterial endocarditis, malignancy, drugs, HIV and viral hepatitis in the differential diagnosis of vasculitis.
Giant Cell Arteritis
The 1990 ACR classification criteria were not designed as diagnostic criteria but are useful as a descriptor of clinical features, including:
- Age at disease onset >=50 years
- New headache
- emporal artery abnormality (tenderness to palpation or decreased pulsation unrelated to cervical arteritis)
- Elevated erythrocyte sedimentation rate (>=50 mm/hour by the Westergren method)
- Abnormal artery biopsy (biopsy specimen with artery showing vasculitis characterized by a predominance of mononuclear cell infiltration or granulomatous inflammation, usually with multinucleated giant cells).
The presence of any 3 or more criteria yields a sensitivity of 93.5% and a specificity of 91.2%.
False-negative temporal artery biopsies (TAB) can be due to skip lesions or suboptimal technique; biopsy samples should be at least 1cm long, preferably >2cm, and be taken within one week of starting treatment with glucocorticoids. A positive TAB gives prognostic information, being associated with neuro-opthalmic complications, and TAB is currently the gold standard for diagnosis. Vascular ultrasound is currently under investigation as an alternative diagnostic tool. The Diagnosis and Classification Criteria of Systemic Vasculitis (DCVAS) study is a multinational project to redefine classification and diagnostic criteria for GCA is currently underway.
- Management: Treatment and Monitoring
Induction therapy for ANCA-associated vasculitis (GPA and MPA)
Classically a combination of cyclophosphamide and high dose oral corticosteroids (1mg/kg initially (max 60mg/day), tapered to 10mg/day by 3-6 months) have been used to induce remission in active ANCA-associated vasculitis, giving a remission rate of 90% at 6 months.
Pulsed cyclophosphamide given every 2 weeks for the first 3 doses, and then every 3 weeks for up to 7 more doses in combination with corticosteroids was as effective as daily oral cyclophosphamide in inducing disease remission in a randomized controlled trial, with a substantially lower total cyclophosphamide dose. The relapse rate with the lower dose cyclophosphamide was somewhat higher, but due to reduced toxicity intravenous cyclophosphamide is generally preferred. (de Groot et al, 2009)
Cyclophosphamide dose reductions are required for age and poor renal function – please see BSR 2007 guidelines.
In 2010, two randomized controlled clinical trials were published (Jones et al; Stone et al), showing that depletion of B cells using an anti-CD20 monoclonal antibody (Rituximab), in combination with corticosteroids, with or without low dose cyclophosphamide, was as effective at inducing remission as traditional cyclophosphamide-based regimens. Rituximab is preferred to cyclophosphamide in cases of on-going chronic infection, malignancy, or in young patients who wish to preserve their fertility. There is evidence that Rituximab is particularly effective in relapsing and refractory disease.
The utility of plasma exchange in active renal ANCA-associated vasculitis and/or pulmonary haemorrhage is currently being assessed in PEXIVAS, a multicentre randomized controlled trial. Where patients are not suitable for this trial, adjuvant plasma exchange, in addition to induction immunosuppression, is commonly used for patients with severe renal failure (serum creatinine>500µmol/l) and/or significant pulmonary haemorrhage, based on the results of the MEPEX trial
The MYCYC trial, comparing mycophenolate mofetil to cyclophosphamide in the induction of remission in ANCA-associated vasculitis will report in 2013.
Methotrexate induction therapy can be used but should be reserved for disease with no systemic organ involvement and no tissue destruction.
Patient monitoring during induction therapy
Adverse events are common during induction therapy, particularly infections, and patients should be monitored closely and have rapid access to the specialist centre, particularly in the event of fever.
Patients on oral cyclophamide should have their full blood count monitored weekly, and cyclophosphamide should be discontinued if the total white count falls below 4 x 109/l, only restarting at a lower dose when the white count recovers. Patients on pulsed IV cyclophosphamide should have their leucocyte count checked between 7-10 days after each dose. If the wbc count falls below 4 x 109/l, cyclophosphamide should be discontinued and restarted at a lower dose once the count has recovered.
The Birmingham Vasculitis Activity Score (BVAS) has been validated as a disease scoring tool for patients with systemic vasculitis. This can be helpful in monitoring a patient’s initial presentation, monitoring response to treatment and identifying remission and relapse.
In addition, the Vasculitis Damage Index has been validated to record damage accruing as a result of the disease and the treatment. Training is required to use these scoring systems accurately. This training can be accessed here.
Remission maintenance therapy in ANCA-associated vasculitis
Following induction of remission, cyclophosphamide should be substituted for maintenance immunosuppression. In a randomized controlled trial, substitution of azathioprine (2mg/kg) for cyclophosphamide after three months was as effective as continuation of cyclophosphamide for a year in maintaining remission, with reduced toxicity (Jayne et al, 2003).
Azathioprine was more effective in remission maintenance in ANCA-associated vasculitis than mycophenolate mofetil, and so mycophenolate mofetil should be reserved for those patients intolerant of azathioprine.
In those with preserved renal function (GFR>30ml/minute), methotrexate is a alternative agent for remission maintenance.
It is unclear how long maintenance therapy should be continued, but most physicians recommend a minimum of 2-3 years of therapy. Relapse (50% by 5 years) can occur at any time and patients should be reviewed regularly (3 monthly) for signs of disease relapse or drug toxicity. Relapse occurs more commonly in granulomatosis with polyangiitis and those who remain ANCA positive.
Management of EGPA (Churg-Strauss syndrome)
Management depends on the severity of the disease. Disease severity can be assessed using the five factor score (1 point for each: creatinine> 140 µmol/l, proteinuria>1g, severe GI involvement, cardiomyopathy and central nervous system signs. Cyclophosphamide induction improves survival in those patient with a 5 factor score of more than 2.
In less severe disease, corticosteroids alone can be used.
Refractory and frequently relapsing ANCA-vasculitis
Minor relapses, without systemic or organ-threatening features may be managed by a temporary increase in corticosteroid dosage.
For major relapses, further induction therapy may be required. Rituximab is emerging as a useful therapy in this group of patients. The RITAZAREM randomized controlled trial will compare Rituximab against standard azathioprine treatment for remission maintenance in relapsing disease. For NICE guidelines on the use of Rituximab in ANCA associated vasculitis click here.
Other therapies have been used in patients with refractory and frequently relapsing disease, and specialist advice should be sought.
Adjunctive treatments and detecting adverse effects of therapy
- Trimethoprim/sulfamethoxazole (or aerolized pentamidine) should used as prophylaxis against pneumocystis jiroveci in patients on induction immunosuppression.
- Anti-fungal prophylaxis (eg oral nystatin) should be used during induction.
- Female patients should be screened for cervical intraepithelial neoplasia.
- Patients should be counselled about the possibility of infertility following cyclophosphamide treatment and prior gamete storage should be offered where appropriate.
- Prophylaxis against osteoporosis should be used in all patients receiving high dose corticosteroids.
- Patients receiving immunosuppression should be screened for tuberculosis.
- Patients receiving immunosuppression should be vaccinated against pneumococcal infection and influenza.
- Cardiovascular and thombotic risk should be assessed and treated where appropriate, as vasculitis has been linked to increased thrombo-embolic and cardiovascular risk.
Giant Cell Arteritis
British Society of Rheumatology (BSR) treatment guidelines divide patients into those with uncomplicated GCA (no visual symptoms or jaw or tongue claudication), who can be treated with oral prednisolone 40-60mg a day, and complicated GCA (evolving visual symptoms, e.g amaurosis fugax or visual loss), who should receive intravenous methylprednisolone 500mg to 1g daily for 3 days followed by 60mg oral prednisolone. Glucocorticoids should not be withheld prior to biopsy as delay may increase the risk of visual loss. Bone and gastric protection should be co-prescribed. Aspirin 75mg a day may reduce the risk of visual loss and cerebrovascular accidents and should be started if there are no contraindications. A sample oral prednisolone reduction plan would be: 40-60mg a day for 4 weeks, then reduce by 10mg every 2 weeks to 20mg a day, then reduce by 2.5mg every 2-4 weeks to 10mg a day, then reduce by 1mg every 1-2 months. Patients may flare on glucocorticoid reduction however so dosages should be individually titrated to disease activity based on the assessment of symptoms, clinical examination and inflammatory markers. There are no specific biomarkers available for GCA diagnosis or monitoring at present.
The evidence for steroid sparing agents in GCA is not conclusive, although this may be due to trial design, clinically the addition of methotrexate may allow a faster reduction in patients with severe glucocorticoid adverse effects and there are case reports of leflunomide and azathioprine also being used in these circumstances. Randomised controlled trials of biological therapies including anti- tumour necrosis factor (TNF) therapies have not demonstrated efficacy in GCA but results are awaited from the international GiACTA trial which is currently assessing the efficacy and safety of tocilizumab, an interleukin (IL)-6 receptor antagonist, in maintenance of disease remission in patients with GCA.
Patients should be monitored clinically for the development of ischaemic manifestations, including occlusion of limb vessels, aortic involvement and cardiovascular disease, including pulses, bruits and blood pressure measurements. Chest X-rays at baseline and every two years should be performed to exclude the development of aortic aneurysm, which may be present in over 20% of patients with GCA within the first five years. In clinical practice, 18F-Fluorodeoxyglucose (FDG) Positron Emission Tomography (FDG-PET) scanning is currently reserved for patients with ongoing systemic symptoms and high inflammatory markers despite glucocorticoid treatment, although aortitis has been demonstrated in over half of newly diagnosed patients with GCA using this imaging modality. Glucocorticoid adverse events should be monitored and addressed, specifically weight gain, diabetes, hypertension, osteoporosis, glaucoma, infection and dyslipidaemia.
- Paediatric vasculitides
The Oxford Handbook of Paediatric Rheumatology provides information for health professionals including detailed investigation and treatment guidelines for the various forms of paediatric vasculitis, important differential diagnoses, and other specialist information.
- Clinical Trials
- European Vasculitis Study Group (EUVAS)
EUVAS has organised several major international clinical trials over the last two decades. Results of previously published EUVAS trials are available on their website, as well as information about currently active clinical trials in vasculitis.
Plasma exchange and glucocorticoid dosing in the treatment of anti-neutrophil cytoplasm antibody associated vasculitis: an international randomised controlled trial.
Plasma exchange (PLEX), a method of rapidly removing potentially pathogenic anti-neutrophil cytoplasmic antibodies and other mediatorsof inflammation and coagulation, has shown promise as an adjunctive therapy in ANCA-associated vasculitis (AAV) to improve early disease control and improve rates of renal recovery in severe disease. Glucocorticoids (GC) are a standard of care in the treatment of AAV. High doses of GC early in disease although undeniably reduce disease activity due to their anti-inflammatory and immunosuppressive properties, also increase the risk of infection particularly in the elderly and in the presence of uremia. There is no randomized trial data to guide GC dosing.
PEXIVAS is a multicentre, open label, factorial design, randomized controlled trial in severe ANCA-associated vasculitis (active newly diagnosed or relapsed). The primary objectives are to determine the efficacy of plasma exchange (PLEX) in addition to immunosuppressive therapy and glucocorticoids (GC) in reducing death and end-stage renal disease, and to determine the non-inferiority of a reduced-dose glucocorticoid regimen in reducing death and end-stage renal disease. Five hundred participants will be randomized, 1:1, to receive adjunctive plasma exchange (PLEX) in addition to standard immunosuppressive therapy and glucocorticoids (GC) or standard immunosuppressive therapy and GC without PLEX. The same 500 patients will be randomized, 1:1, to receive reduced-dose GC taper or standard-dose GC taper.
Rituximab is now established as an effective drug for anti-neutrophil cytoplasmic antibody (ANCA) vasculitis following major European and US trials reported in 2010. After a time, its effect wears off and the disease can return.
The RITAZAREM trial will find out whether repeating rituximab stops vasculitis returning and whether it works better than the older treatments, azathioprine or methotrexate. It will also tell us how long patients remain well after the repeated rituximab treatments are stopped, and if repeated rituximab is safe. We should also learn useful information about the effects of rituximab on quality of life and economic measures. The trial results will help decide the best treatment for future patients who have their vasculitis initially treated with rituximab.
RITAZAREM aims to recruit patients with established ANCA vasculitis whose disease has come back ‘relapsing vasculitis’. All patients will be treated with rituximab and steroids and we anticipate that most will respond well. If their disease is under reasonable control after four months, further treatment with either rituximab (a single dose ever four months for two years) or azathioprine tablets will be chosen randomly. The patients in the rituximab and azathioprine groups will then be compared. Patients will be in the trial for four years.
The study has been designed by members of the European Vasculitis Study group (EUVAS) and the Vasculitis Clinical Research Consortium (VCRC). It will include 190 participants from 30 hospitals in Europe, the USA, Australia and Mexico. RITAZAREM is being funded by Arthritis Research UK, the U.S. National Institutes of Health and by Roche/Genentech.
A Study to Evaluate the Safety and Efficacy of CCX168 in Subjects with ANCA-Associated Renal Vasculitis
The aim of this trial is to optimize the treatment to induce remission for patients with non-life-threatening anti-neutrophil cytoplasmic antibody renal vasculitis (AARV) with mild-to-moderate renal involvement. The intent is to reduce the toxicity of induction therapy by reducing the overall exposure to or eliminating entirely the use of systemic corticosteroids during the induction period with an inhibitor of the complement C5a receptor plus cyclophosphamide.
Rituximab in paediatric ANCA-associated vasculitis
An open label trial of rituximab for the treatment of paediatric ANCA associated vasculitis. This international trial will open in 2013 and aims to recruit 25 children worldwide with ANCA vasculitis (GPA or MPA). The trial is sponsored by Roche.
An international randomised controlled trial of mycophenolate Mofetil versus cyclophosphamide for the induction of remission of polyarteritis nodosa in children. This investigator led trial is funded by ARUK and is in set up 2013.
Diagnostic classification criteria in vasculitis study (DC-VAS)
DCVAS is a multinational, observational study that aims to develop diagnostic criteria and update classification criteria in vasculitis. Clinicians often use a list of signs and symptoms known as diagnostic criteria to determine if a patient has a particular disease. There are currently no diagnostic criteria for vasculitis. Having clear diagnostic criteria will help reduce delays in making the correct diagnosis and starting appropriate therapy. Classification criteria are used to group patients into different types of vasculitis and are useful for studying patients in clinical trials. The current classification criteria were developed before the availability of modern tests such as ANCA testing or MRI. With our increasing understanding of vasculitis, it is now time to revise these criteria.
Funded by the American College of Rheumatology, the European League Against Rheumatism and the Vasculitis Foundation, the study is led and coordinated from the University of Oxford. Over 75 sites across 29 countries in Asia, Australasia, Europe, North America, South America and UK will be included in the study. Sites will recruit a total of 3500 patients, 2000 with a new diagnosis of vasculitis and 1500 with similar symptoms to those with vasculitis. As of February 2012, 928 patients from 55 sites had been recruited into the study and we plan to reach our target by December 2013.
A new project, the aim of which is to collect anonymised information about the clinical and demographic characteristics of patients diagnosed with vasculitis in the UK and Ireland. This information will be used to obtain an overview of the incidence, demographics, organ involvement and outcomes of vasculitis in the UK. The Vasculitis Rare Disease Group is involved in the project and it is supported by Kidney Research UK.
Other sources of information about clinical trials in vasculitis:
- Vasculitis clinical research consortium (USA)
- The French vasculitis study group
- Clinicaltrials.gov (USA) This is an USA-based website funded by the National Institutes of Health. All new clinical trials (for all diseases) should be registered with this organisation before starting and some of the results of the trials should be made available after completion. Even though the site is American, most European clinical trials will also be registered here.
Written by the Vasculitis Rare Disease Group