Peripheral neuropathy can be the first and only manifestation of necrotising primary immune-mediated vasculitis which, carries a high mortality. A clear idea of how to both recognise and treat peripheral nervous system vasculitis is important. We provide a practical approach to immediate and longer term treatment protocols.
- Treatment vasculitic neuropathy
- Treatment mononeuritis multiplex
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In a third of patients, neuropathy is the initial manifestation of necrotising primary immune-mediated vasculitis.1 The range of classification systems is confusing: some considering the size of the affected blood vessel,2 ,3 others referring to types of organ involvement and autoantibody profiles. From the neurologists’ point of view, what is useful to know is whether peripheral nervous system (PNS) vasculitis is likely to be part of a systemic process or whether it is non-systemic and localised. Another useful division concerns the underlying immune process: whether it is antineutrophil cytoplasmic antibody (ANCA) associated or immune complex driven. This will help the clinician to make an unifying diagnosis, allowing appropriate investigation and relevant involvement of other specialists, usually rheumatologists or renal physicians. Before the introduction of steroids and cyclophosphamide (CYC) in the early 1970s, survival rates from primary immune-mediated vasculitis were low. Induction of remission is now achieved in over 90% of patients by 6 months,4 and 5-year survival rates are around 75%.5 However, even with best available therapy, relapse rates remain high at up to 50% over 5 years,6 as does treatment related morbidity and mortality.
How to identify PNS vasculitis clinically
Multiple mononeuropathy is the mode of presentation in up to 30% of cases.7 This can be as a series of complete mononeuropathies presenting acutely over a few days, or with slow accumulation of asymmetric multifocal neurological deficits, sometimes punctuated by acute events. Occasionally the progression of mononeuropathies can be so rapid that the presenting picture can be mistaken for that of a symmetric polyneuropathy. PNS vasculitis can also present with an isolated mononeuropathy, a chronic distal symmetric sensorimotor axonal polyneuropathy or a radiculoplexus neuropathy. The range of potential causes is large (table 1).
PNS vasculitis: is it part of a systemic or localised process?
While multi-organ involvement in primary immune-mediated vasculitides is the rule, the ANCA associated conditions have predominant ‘kidney–chest’ involvement, and immune complex types have a ‘kidney–skin’ involvement. Microscopic polyangiitis, a subtype of polyarteritis nodosa, is highly likely to affect the PNS, a neuropathy being seen in up to 50% of all cases within a few months of diagnosis.8 In Wegener's granulomatosis and Churg–Strauss syndrome, PNS involvement occurs as a secondary phenomenon, the primary stage typically involving chest and upper airways.
There is also PNS-specific vasculitis. Long term follow-up studies have shown that this remains localised to the PNS9 and despite the occasional presence of systemic markers (raised CRP, etc), carries no risk of multi-organ failure.
How to diagnose and when to treat PNS vasculitis
Histological evidence remains the ‘gold-standard’ for the diagnosis of PNS vasculitis. Of patients ultimately diagnosed with vasculitic neuropathy, sural nerve biopsy alone is confirmatory in 40%–50% of cases. A combined nerve–muscle biopsy gives a positive result in 60%–70% of cases.10 Biopsy should only be considered if the possibility of vasculitis is high and the blood tests are uninformative. Delay in starting treatment should be avoided.
How to treat PNS vasculitis
The treatment of vasculitis depends on its cause. The use of CYC and other immunosuppressive agents has transformed the prognosis of the primary immune-mediated vasculitides. There is no available evidence from randomised controlled studies to support the use of CYC in isolated PNS vasculitis. There are two main phases in the treatment of PNS vasculitis.11
Remission-induction therapy: An initial treatment that results in resolution of the manifestations of active vasculitis.
Remission-maintenance therapy: A continuation of treatment for a prolonged period with the aim of maintaining control and reducing the likelihood of clinical relapses.
Glucocorticoids and CYC form the basis of initial treatment. Oral prednisolone is prescribed at 1 mg/kg/day from onset of treatment. When rapid effect is needed, intravenous methylprednisolone 1g/day for the first 3 days, then oral prednisolone at 1 mg/kg/day can be used.12 Markers of poor prognosis in vasculitis include advanced renal impairment at presentation and the presence of c-ANCA with anti-proteinase 3 (which is highly suggestive of Wegener's granulomatosis) rather than p-ANCA with anti-myeloperoxidase (more commonly seen in microscopic polyangiitis and Churg–Strauss syndrome).12 While there is no clear guidance to advise us on the intensity of steroid use we feel the presence of poor prognostic indicators would justify intravenous steroids early in this initial phase.
The CYCLOPS trial showed that a single pulse of intravenous CYC 15 mg/kg (max dose 1.2 g) repeated every 2 weeks for the first three pulses, then at 3 weekly intervals until remission and then for another 3 months was equal to oral CYC at its normal dosing regimen (2 mg/kg/day for 3 months and then 1.5 mg/kg/day for another 3 months, with dose adjustment for age) in providing remission-induction, but with fewer side effects.11 Patients should be monitored clinically every 8 weeks during this initial remission period. The dose of intravenous CYC should be adjusted according to age and renal function, as shown in table 2. Usually in clinical practice, we find 6–10 pulses are required over a period of 3–6 months.
One of the main limitations of CYC is its ability to reduce the white cell count (WCC). Therefore, subsequent pulses should be adjusted (in addition to renal function) according to the lowest WCC, referred to as nadir, typically seen 10–14 days after the pulse, as shown in box 1. This dose adjustment aims to maintain the total WCC in a safe range so as to minimise the risk of infection.
Adjustment of intravenous cyclophosphamide (IV CYC) doses according to white cell count (WCC) nadir13
WCC: 1–2×109/L reduce IV CYC for next dose by 40%
WCC: 2–3×109/L reduce IV CYC for next dose by 20%
WCC: >3×109/L keep IV CYC dose the same
In addition, the pulse of intravenous CYC is only given if the WCC on the day of the pulse is >4 × 109/l and neutrophils >2 × 109/l. If this is not the case, the pulse is postponed until the WCC is in range, normally rechecking full blood count on a weekly basis.
Mesna (2-mercaptoethanesulfonate sodium) is administered intravenously immediately before the intravenous CYC infusion. Two further oral doses are given at 2 and 6 h after the start of the infusion to reduce the urotoxic side effects of a metabolite of CYC.13 Prehydration with a litre of normal saline is usually given before the CYC pulse. Urinalysis is routinely carried out prior to each dose to monitor for bladder toxicity. Patients are given antiemetic medication on a ‘when required’ basis for the initial 48 h. Pneumocystis jiroveci infection can be a complication in immunocompromised patients. In patients receiving CYC and glucocorticoids there is some evidence to support the use of prophylactic co-trimoxazole 960 mg given orally three times a week.13
It has been recommended that patients with severe/life threatening vasculitis and significant renal failure (creatine >500 µmol/l) should be treated with plasma exchange in addition to the standard treatment regimens (with oral prednisolone and intravenous CYC).13
Oral methotrexate (MTX) has been shown to have similar success rates to CYC for remission-induction for early non-life threatening disease without significant renal disease. However, it has been seen to result in more relapses at 18 months and an increased risk of progression to more widespread disease than with CYC.14 MTX is prescribed orally at 10 mg once a week, gradually increasing to 20–25 mg once a week over 1–2 months if tolerated. Folic acid (5 mg once a week) should be prescribed to be taken 1–2 days after MTX to minimise some side effects. A baseline chest x-ray is usually carried out and routine blood monitoring for full blood count, liver and renal function is also required throughout treatment. We feel this represents a good option for treatment in patients with isolated non-systemic PNS vasculitis without renal impairment.
This second phase of treatment is achieved with a combination of oral prednisolone and a steroid-sparing agent. Azathioprine (AZA) at 2 mg/kg/day has been shown to be as effective as oral CYC (1.5 mg/kg/day) in preventing relapse at 18 months, but with a lower risk of serious adverse effects (10% vs 18%).15 AZA is started at a low dose, for example, 25 mg daily and increased gradually over a few weeks to target dose provided pretreatment thiopurine methyltransferase levels are normal. We take a pragmatic view that remission-maintenance therapy (with AZA, CYC or MTX) should be continued for 24 months, although evidence for this duration of treatment only exists for ANCA positive vasculitis.12
Oral prednisolone should be started at a dose of 1 mg/kg/day—see Remission-induction therapy section above. The dose is then gradually tapered; however, the dose should not go below 15 mg/ day for the first 3 months. When a dose of 15 mg/day is reached, the steroid taper is continued at a slower rate (see table 3). With prolonged use of steroids, it is our routine practice to provide adequate bone (bisphosphonate, calcium, vitamin D) and gastrointestinal (proton pump inhibitor) protection.
Oral MTX continuing at 20–25 mg/week as an alternative to AZA can be used if it had been started in the remission-induction phase.17
What to tell patients about treatment
Once the diagnosis of PNS vasculitis has been discussed, the patient must be informed before treatment of the side effects of steroids and advised to carry a steroid treatment card at all times.
CYC, MTX and AZA are immunosuppressant medicines with a major risk of bone marrow suppression and associated infection. Liver toxicity is a possible adverse effect of MTX and AZA therapy. Patients must be made aware that blood test monitoring (full blood count, liver function and renal function as appropriate) is required regularly throughout treatment to ensure safety. This is usually started in hospital and once stable the responsibility is transferred to the GP using agreed local shared care protocols. We encourage patients to keep their own record of blood results. Patients should be advised on how to recognise and act on any symptoms that may suggest infection, thrombocytopenia, liver toxicity, MTX-induced pneumonitis or CYC-induced urotoxicity. Other potential adverse effects associated with these medicines include nausea, rash, secondary malignancy, teratogenicity and hair loss. CYC treatment is associated with infertility and the possibility of egg/sperm harvesting should be discussed with appropriate patients. It is recommended that patients receiving immunosuppressants should receive pneumococcal and influenza vaccination. Live vaccines should generally be avoided due to reduced response and risk of infection. Patient collaboration through being thoroughly informed and motivated is critical to minimising clinical risk and optimising treatment outcome.
Contributors JGL had a role in planning the project and editing the manuscript for presentation. LMD had a role in pharmacotherapy-related contents and recommendations for minor editing (typographical/grammatical). EAM takes responsibility for the planning and overall content.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed. This paper was reviewed by Neil Scolding, Bristol, UK.