THERAPEUTIC INTERVENTIONS
How to recognise and treat
1
Department of Neurology, Royal
Gwent Hospital, Newport, UK
2
Department of Neurology,
University Hospital of Wales,
Cardiff, UK
3
Department of Pharmacy,
University Hospital of Wales,
Cardiff, UK
Correspondence to
Dr E A Marsh, Department of
Neurology, Royal Gwent
Hospital, Newport, NP20 2UB,
UK;
eleanor.marsh@wales.nhs.uk
Published Online First
10 May 2013
To cite: Marsh EA,
Davies LM, Llewelyn JG. Pract
Neurol 2013;13:408–411.
408
peripheral nervous system vasculitis
E A Marsh,1,2 L M Davies,3 J G Llewelyn1,2
ABSTRACT
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.
INTRODUCTION
In a third of patients, neuropathy is
the initial manifestation of necrotising
primary immune-mediated vasculitis.1
The range of classification systems is con-
fusing: some considering the size of the
affected blood vessel,2 3 others referring
to types of organ involvement and auto-
antibody 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 con-
cerns the underlying immune process:
whether it is antineutrophil cytoplasmic
antibody (ANCA) associated or immune
complex driven. This will help the clin-
ician to make an unifying diagnosis,
allowing appropriate investigation and
relevant involvement of other specialists,
usually rheumatologists or renal physi-
cians. 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
Marsh EA, et al. Pract Neurol 2013;13:408–411. doi:10.1136/practneurol-2012-000464
can be as a series of complete mono-
neuropathies presenting acutely over a
few days, or with slow accumulation of
asymmetric multifocal neurological defi-
cits, 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 polyneur-
opathy 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’ involve-
ment, 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 diagno-
sis.8 In Wegener’s granulomatosis and
Churg–Strauss syndrome, PNS involve-
ment 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 vascu-
litis. Of patients ultimately diagnosed
with vasculitic neuropathy, sural nerve
biopsy alone is confirmatory in 40%–50%

Table 1 Causes of peripheral nervous system (PNS) vasculitis
A primary immune-mediated vasculitic ANCA associated
process
Immune complex
driven
A vasculitic process resulting from other types
of autoimmune conditions
A vasculitic process resulting from other Diabetes
non-autoimmune conditions Drugs
Viral infections
Bacterial infections Infective endocarditis, Strep pneumoniae, Haemophilus influenzae, Salmonella typhi,
Fungal infections
Protozoa infections Toxoplasma gondii, Plasmodium falciparum
Radiation
Paraneoplastic
Malignancy
Chronic
inflammatory
ANCA, antineutrophil cytoplasmic antibody.
of cases. A combined nerve–muscle biopsy gives a posi-
tive 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 treat-
ment for a prolonged period with the aim of maintaining
control and reducing the likelihood of clinical relapses.
REMISSION-INDUCTION THERAPY
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 granulomato-
sis) 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
Marsh EA, et al. Pract Neurol 2013;13:408–411. doi:10.1136/practneurol-2012-000464
THERAPEUTIC INTERVENTIONS
Wegener’s granulomatosis, Churg–Strauss syndrome, polyarteritis nodosa and
microscopic polyangiitis
Henoch-Schönlein purpura and essential cryoglobulinaemic vasculitis
Rheumatoid arthritis, systemic sclerosis, Sjögren’s syndrome, essential
cryoglobulinaemia
Diabetic radiculoplexus neuropathy
Amphetamine, propylthiouracil, hydralazine, interferons, non-steroidal
anti-inflammatory drugs, penicillin, allopurinol, cocaine, heroin, sulfonamides and
phenytoin
Cytomegalovirus, human T-lymphotropic virus 1, hepatitis, human immunodeficiency
virus, Herpes simplex virus, Varicella zoster virus, Epstein-Barr virus, cytomegalovirus
alpha haemolytic strep, Lyme, Mycobacterium tuberculosis, leprosy, Treponema
pallidum
Aspergillus, coccidoides, mucormycosis, histoplasma capsulatum
Sarcoidosis
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 adjust-
ment for age) in providing remission-induction, but
with fewer side effects.11 Patients should be moni-
tored clinically every 8 weeks during this initial remis-
sion 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, subse-
quent 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 main-
tain the total WCC in a safe range so as to minimise
the risk of infection.
Table 2 Dose adjustment of intravenous cyclophosphamide
(IV CYC) according to age and renal function11
Creatine mmol/l
Age <300 300–500 >500
<60 15 mg/kg/pulse 12.5 mg/kg/pulse Consider alternative
to IV CYC
60–70 12.5 mg/kg/pulse 10 mg/kg/pulse
>70 10 mg/kg/pulse 7.5 mg/kg/pulse
409
 THERAPEUTIC INTERVENTIONS
Box 1 Adjustment of intravenous cyclophospha-
mide (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 admi-
nistered intravenously immediately before the intra-
venous 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 rou-
tinely carried out prior to each dose to monitor for
bladder toxicity. Patients are given antiemetic medica-
tion 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 mmol/l) should be treated with plasma
exchange in addition to the standard treatment regi-
mens (with oral prednisolone and intravenous CYC).13
Oral methotrexate (MTX) has been shown to have
similar success rates to CYC for remission-induction
Table 3 Oral prednisolone calculator chart: adapted from CYCLOPS trial protocol16
Time from entry Prednisolone dosage
(weeks) (mg/kg/day)
0 1
1 0.75
2 0.5
3 0.4
6 0.33
8 0.25
Prednisolone dosage
(mg/day)
At end of month 3 12.5
At month 6 10
During months 12–15 7.5
During months 15–18 5
410
for early non-life threatening disease without signifi-
cant 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 moni-
toring 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.
REMISSION-MAINTENANCE THERAPY
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 methyl-
transferase 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,
Prednisolone dosage
Prednisolone dosage (mg/day for 60 kg) (mg/kg for 90 kg)
60 80
45 70
30 45
25 35
20 30
15 20
Maximum 80 mg a day
Round dose to nearest 5 mg above 20 mg
Round dose to nearest 2.5 mg below 20 mg
Marsh EA, et al. Pract Neurol 2013;13:408–411. doi:10.1136/practneurol-2012-000464

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 (bispho-
sphonate, 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 dis-
cussed, 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 medi-
cines 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 treat-
ment to ensure safety. This is usually started in
hospital and once stable the responsibility is trans-
ferred to the GP using agreed local shared care proto-
cols. 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 asso-
ciated 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 gener-
ally be avoided due to reduced response and risk of
infection. Patient collaboration through being thor-
oughly informed and motivated is critical to minimis-
ing 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.
Marsh EA, et al. Pract Neurol 2013;13:408–411. doi:10.1136/practneurol-2012-000464
THERAPEUTIC INTERVENTIONS
REFERENCES
1 Said G, Lacroix C, Lozeron P, et al. Inflammatory vasculopathy
in multifocal diabetic neuropathy. Brain 2003;126:376–85.
2 Hunder GG, Arend WP, Bloch DA, et al. The American
College of Rheumatology 1990 criteria for the classification of
vasculitis. Arthritis Rheum 1990:33,1065–67.
3 Jeanette JC, Faulk RJ, Andrassy K, et al. Nomenclature of
systemic vasculitides. Proposal of an international consensus
conference. Arthritis Rheum 1994;37:187–92.
4 Jayne D, Rasmussen N, Andrassy K, et al. A randomized trial
of maintenance therapy for vasculitis associated with
antineutrophil cytoplasmic autoantibodies. N Engl J Med
2003;349:36–40.
5 Matteson EL, Gold KN, Bloch DA, et al. Long-term survival of
patients with Wegener’s granulomatosis from the American
College of Rheumatology Wegener’s Granulomatosis
Classification Criteria Cohort. Am J Med 1996;101:129–34.
6 Westman KW, Bygren PG, Olsson H, et al. Relapse rate, renal
survival, and cancer morbidity in patients with Wegener’s
granulomatosis or microscopic polyangiitis with renal
involvement. J Am Soc Nephrol 1998;9:842–52.
7 Zivkovic SA, Ascgerman D, Lacomis D. Vasculitic neuropathy
—electrodiagnostic findings and association with malignancies.
Acta Neurol Scand 2007;115:432–36.
8 Schaublin GA, Michet CJ Jr, Dyck PJ, et al. An update on the
classification and treatment of vasculitic neuropathy. Lancet
Neurol 2005;4:853–65.
9 Dyck PJ, Benstead TJ, Conn DL, et al. Nonsystemic vasculitic
neuropathy. Brain 1987;110:843–53.
10 Collins MP, Mendell JR, Periquet MI, et al. Superficial
peroneal nerve/ peroneous brevis muscle biopsy in vasculitic
neuropathy. Neurology 2000;55:636–43.
11 De Groot K, Harper L, Jayne DRW, et al. EUVAS (European
Vasculitis Study Group). CYCLOPS trial. Pulse versus daily oral
cyclophosphamide for induction of remission in
antineurtrophil cyctoplasmic antibody-associated vasculitis: a
randomised trial. Ann Intern Med 2009;150:670–80.
12 Hamour S, Salama AD, Pusey CD. Management of
ANCA-associated vasculitis: current trends and future
prospects. Ther Clin Risk Manag 2010;6:253–64.
13 Lapraik C, Watts R, Bacon P, et al. BSR and BHPR guidelines
for the management of adults with ANCA associated vasculitis.
Rheumatology 2007;46:1–11.
14 De Groot K, Rasmussen N, Bacon P, et al. Randomisation trial
of cyclophosphamide versus methotrexate for induction of
remission in early systemic antineutrophil cytoplasmic antibody
associated vasculitis. Arthritis Rheum 2005;52:2462–8.
15 Mukhtyar C, Guillevin L, Cid MC, et al. EULAR
recommendations for the management of primary small and
medium vessel vasculitis. Ann Rheum Dis 2009;68:310–17.
16 De Groot K, Harper L, Jayne DRW, et al. EUVAS (European
Vasculitis Study Group). CYCLOPS trial protocol. http://www.
vasculitis.nl/media/documents/cyclops.pdf
17 Reinhold-Keller E, Fink CO, Herlyn K, et al. High rate of
renal relapse in 71 patients with Wegener’s granulomatosis
under maintenance of remission with low-dose methotrexate.
Arthritis Rheum 2002;47:326–32.
411