REVIEW

CURRENT
OPINION Rheumatoid vasculitis: an update
Ashima Makol a, Eric L. Matteson a,b, and Kenneth J. Warrington a

Purpose of review
Rheumatoid vasculitis is the most serious extra-articular complication of rheumatoid arthritis, with high
morbidity and mortality noted in multiple prior reports. Recent studies have expanded our understanding of
this entity in the era of modern immunosuppressive therapy. New clinical predictors and possible protective
factors have also been identified.
Recent findings
This review provides an update on the epidemiology, clinical correlates, predictors, therapy and outcomes
of rheumatoid vasculitis over the past decade. During this time, there has been increasing use of the treat-
to-target management practices and incorporation of biologic response modifiers that have revolutionized
rheumatoid arthritis treatment with better disease control and overall improved outcomes. The incidence of
rheumatoid vasculitis has declined significantly in the past several decades, but morbidity and mortality
continue to remain high, despite aggressive treatment with cyclophosphamide or biologic agents.
Hydroxychloroquine and low-dose aspirin may have a protective role. There is ongoing debate about the
role of newer biological therapies in prevention, treatment or even as a trigger for rheumatoid vasculitis.
Summary
Rheumatoid vasculitis remains a rare yet challenging extra-articular manifestation of rheumatoid arthritis
with high morbidity and mortality, despite aggressive use of disease-modifying therapy.
Keywords
biologics, extra-articular manifestations, rheumatoid arthritis, rheumatoid vasculitis, vasculitis

INTRODUCTION Over the last 10–15 years, remarkable changes

Vascular involvement in rheumatoid arthritis was
first appreciated in 1898 in the works of Bannatyne
[1], who described an inflammatory infiltrate within
the vasa nervorum of a patient with neuritis.
Bywaters and Scott [2] much later reported periph-
eral gangrene and mononeuritis multiplex among
others as clinical presentations of rheumatoid vas-
culitis. Rheumatoid vasculitis is an inflammatory
process that is now recognized to primarily affect
small to medium-sized blood vessels, is highly
heterogenous clinically, can present with wide-
spread organ involvement and is associated with a
dire prognosis. Disease course can be severe and
associated with other extra-articular manifestations
(EAMs), including nodules and pulmonary fibrosis
[3,4]. A number of predictors or predisposing factors
for rheumatoid vasculitis have been recognized over
the years, including certain human leukocyte anti-
gen (HLA) haplotypes, male sex, smoking and long-
standing seropositive nodular erosive disease [4]. It
is undeniably the most serious extra-articular com-
plication of RA with up to 40% of patients dying
within 5 years of disease onset [4,5].
have occurred in the approach to the treatment of
RA. Early diagnosis, treat-to target treatment strat-
egies, widespread use of methotrexate and availabil-
ity of biologic agents [anti-tumor necrosis factor
(TNF) therapy, B-cell-depleting agents, costimula-
tion inhibitors, anti-interleukin (IL) 6 and others]
have led to improved overall clinical outcomes in
patients with RA. It was not known until recently
whether these changes also paralleled changes in
incidence or clinical presentation of the EAMs of RA,
in particular rheumatoid vasculitis.
The focus of this update is to review the epi-
demiology, pathogenesis, risk factors, approach to
clinical diagnosis and management of rheumatoid
a
Division of Rheumatology and bDepartment of Health Sciences
Research, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
Correspondence to Ashima Makol, MD, Assistant Professor of Medicine,
Division of Rheumatology, Department of Internal Medicine, Mayo Clinic,
200 1st St. SW, Rochester, MN 55905, USA. Tel: +1 507 284 1625;
fax: +1 507 284 0564; e-mail: makol.ashima@mayo.edu
Curr Opin Rheumatol 2015, 27:63–70
DOI:10.1097/BOR.0000000000000126

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 Vasculitis syndromes
KEY POINTS
 Incidence of rheumatoid vasculitis has declined in the
past several decades, but clinical presentation has
remained unchanged (cutaneous vasculitis and
vasculitic neuropathy remaining the most common).
 Hydroxychloroquine and low-dose aspirin are
associated with lower odds of developing rheumatoid
vasculitis among RA patients, thus conferring a possible
protective effect.
 Despite aggressive use of CYC and biologics,
rheumatoid vasculitis remains a difficult EAM to treat,
with high relapse rates and mortality that have not
changed in over 40 years.
vasculitis with a highlight on the advances in
knowledge that have been gained over the past
decade, the so-called ‘biologic era’.
EPIDEMIOLOGY AND PATHOGENESIS
A declining trend in the incidence of rheumatoid
vasculitis was noted beginning in the 1990s [6,7]
&&
and reconfirmed in recent studies [8 ]. This is in
contrast to the incidence of other systemic vasculi-
tides (granulomatous with polyangiitis and micro-
scopic polyangiitis) that has remained stable [9].
Population-based data from the Norwich cohort
in the United Kingdom noted a drop in the average
incidence of rheumatoid vasculitis from 9.1 per
million in 1988–2002 to 3.9 per million between
&&
2001 and 2010 [7,8 ]. These declines have been
largely attributed to an improved treatment of RA,
but another explanation may be the decline in rates
of cigarette smoking. Interestingly, in the US-based
cross-sectional study, Bartels et al. [10] noted a sharp
drop in the prevalence of rheumatoid vasculitis (by
53% among inpatients and 31% among outpatients)
around the year 2000, which is the period corre-
sponding to the advent of biologic response modi-
fiers.
Pathogenesis and risk factors
The triggers and pathogenesis of vascular involve-
ment in RA are not completely understood, but a
striking association has been noted between
rheumatoid vasculitis and particular genotypes
of the shared epitope HLA-DRB1:
0401/
0401,


0401/
0404 and
0101/
0401 [11,12]. Association
with HLA-C
03 is independent of linkage disequili-
brium with the shared epitope [13] and likely due to
interactions between HLA-C molecules and killer
immunoglobulin-like receptors on CD28 null T cells
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implicated in the pathogenesis of EAMs of RA,
particularly [14].
Smoking has remained the most consistently
demonstrated environmental risk factor for rheuma-
&&
toid vasculitis [13,15 ,16], particularly in male
seropositive patients. The mechanism remains
poorly understood, but a combination of B-cell and
T-cell-mediated damage to arterial intima, endo-
thelial dysfunction or damage leading to occlusive
vasculopathy, and possible role of p53 gene muta-
tions induced by smoking, have been implicated [17].
A high prevalence of autoantibodies [rheuma-
&& &&
toid factor (RF) [4,8 ,15 ], anticitrullinated peptide
antibodies (ACPA) [18], antinuclear antibody] and
circulating or tissue-deposited immune complexes
are seen in patients with rheumatoid vasculitis and
thought to have a role in causation. However, many
RA patients with high titers of RF and ACPA do not
develop rheumatoid vasculitis [19], and these were
not found to be independent predictors of risk for
&&
rheumatoid vasculitis in a recent study [15 ]. The
role of proinflammatory cytokines, particularly
TNF-alpha remains unclear, as anti-TNF therapy
has been used as a treatment, but has also been
implicated as a trigger for rheumatoid vasculitis.
&&
In a recent study [15 ] on patients with RA
comparing 86 rheumatoid vasculitis cases with
172 controls (RA without vasculitis) diagnosed
between 2001 and 2010, we confirmed the pre-
viously known higher risk for rheumatoid vasculitis
was associated with male sex [7,20,21], long-
&&
standing disease [8 ] and current smoking at RA
diagnosis (OR, 1.98). In addition, we found a higher
risk of rheumatoid vasculitis among RA patients
with peripheral vascular disease (OR, 3.98) and
cerebrovascular disease (OR, 6.48), demonstrating
the high burden of atherosclerosis and vascular dis-
ease in this subset of RA patients. Severe RA, defined
as the presence of nodules, radiographic erosions
and requirement for joint surgery, doubled the odds
of rheumatoid vasculitis (OR, 2.02). We also noted a
significantly higher risk with the use of biologics for
RA (OR, 2.80), but after reviewing individual cases,
we found that this was primarily attributed to dis-
ease severity (confounding by indication) rather
than drug-induced vasculitis in the majority of
the cases.
&&
Another new observation of this study [15 ]
was a protective effect associated with the use of
hydroxychloroquine (HCQ) (OR, 0.54) and the use
of low-dose aspirin (OR, 0.42) in cardioprotective
doses. The numerous immunomodulatory actions
of HCQ mediated in part by toll-like receptor
antagonism, including its antilipidemic, antiangio-
genic and antithrombotic effects, may be respon-
sible for this benefit [22]. This finding needs to be
Volume 27  Number 1  January 2015

Table 1. Clinical presentation of rheumatoid vasculitis
based on organ system involved
Organ system Clinical presentation
Skin (most common) Purpura
Nail fold infarcts
Digital ischemia/gangrene
Cutaneous ulcers (upper or lower
extremity)
Peripheral nervous system Mononeuritis multiplex
Distal asymmetric/symmetric
sensory and/or mixed
polyneuropathy
Eye Episcleritis
Scleritis (anterior/posterior,
nodular/diffuse, nonnecrotizing/
necrotizing scleromalacia
perforans)
Peripheral ulcerative keratitis (with
or without corneal melt)
Retinal vasculitis
Heart Pericarditis
Myocarditis (presenting as
arrhythmias – atrial fibrillation,
ventricular arrhythmias and
complete heart block)
Coronary vasculitis (presenting as
myocardial infarction)
Lung Pulmonary angiitis/capillaritis
(presenting as alveolar
hemorrhage)
Kidney Pauci-immune glomerulonephritis
Medium vessel vasculitis (without
microaneurysms)
Gastrointestinal tract Mesenteric vasculitis
Bowel (commonly ileal or sigmoid)
ischemia and/or perforation
Central nervous system Hypertrophic pachymeningitis
Central nervous system vasculitis
(presentations include seizures,
cranial nerve palsies, strokes and
myelopathy)
confirmed in other cohorts of rheumatoid vasculitis.
Whether combination therapies that include
Hydroxychloroquine will prove beneficial for
patients with risk factors for rheumatoid vasculitis
also remains an area of future investigation.
CLINICAL PRESENTATION AND
APPROACH TO DIAGNOSIS
Rheumatoid vasculitis typically occurs in patients
with long-standing, erosive, deforming RA. The
mean duration between the diagnosis of RA and
the onset of vasculitic symptoms is 10–14 years
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Rheumatoid vasculitis: an update Makol et al.
&&
[15 ,20], and presentation within the first 5 years
of the RA diagnosis is unusual but has been reported.
Patients often have rheumatoid nodules and are
positive for rheumatoid factor [4] and/or ACPA.
Rheumatoid vasculitis often develops at a time
when the inflammatory arthritis is burned out
and hence the patient may not have significantly
&&
swollen or tender joints on examination [15 ] and
joint disease activity scores may be low. These
patients, however, seem to have a high burden of
comorbidities (cardiovascular and peripheral vascu-
lar disease) and EAMs (Felty’s syndrome, pulmonary
fibrosis).
The onset of rheumatoid vasculitis is often her-
alded by constitutional symptoms (fever, weight
loss), an escalation of the acute-phase markers
(erythrocyte sedimentation rate and/or C-reactive
protein), thrombocytosis and anemia of chronic
disease [23]. Although complement levels are nor-
mal or elevated in RA, hypocomplementemia is
often seen in patients with rheumatoid vasculitis
[5]. However, the significance of this finding for
monitoring disease activity is not well defined.
Rheumatoid vasculitis is heterogenous in its
clinical presentation (Table 1), depending on the
size of blood vessels and type of organ affected. Skin
(Fig. 1) and peripheral nerve involvement are the
most common followed by eye and pericardium.
Involvement of the bowels, lung, kidney and central
nervous system is much rarer but can be organ-
threatening or life-threatening. Involvement in
multiple organ systems can also be seen simul-
taneously or sequentially. Recurrences are common
&&
[15 ] and may affect the same or different organ
systems. The clinical presentation of rheumatoid
&& &&
vasculitis in the recent decade [8 ,15 ] continues
to remain similar to that reported in prior studies
[7,20].
Histopathology
Rheumatoid vasculitis primarily affects small to
medium-sized vessels and shares many features with
polyarteritis nodosa, albeit without the develop-
ment of microaneurysms [24]. Histopathologic
examination reveals mononuclear or neutrophilic
infiltration of the vessel walls in association with
features of vessel wall destruction (necrosis, leuko-
cytoclasis and disruption of the elastic laminae).
Isolated capillaritis or perivascular infiltrates with-
out vessel wall involvement can be seen in RA, but
are not adequate for a histopathologic diagnosis of
rheumatoid vasculitis [19]. Involvement of more
than three cell layers of the vessel is a sensitive
and specific finding to distinguish rheumatoid vas-
culitis from RA without rheumatoid vasculitis [25].
www.co-rheumatology.com 65
 Vasculitis syndromes
FIGURE 1. Cutaneous vasculitis presenting as poorly healing lower extremity ulcers in a patient with rheumatoid arthritis.
Approach to diagnosing rheumatoid
vasculitis
There are no validated diagnostic or classification
criteria for rheumatoid vasculitis. Scott and Bacon
[20] defined systemic rheumatoid vasculitis as one
or more of the following in a patient with RA: first,
mononeuritis multiplex or peripheral neuropathy;
second, peripheral gangrene; third, biopsy evidence
of acute necrotizing arteritis in addition to systemic
illness (e.g. fever and weight loss) and finally, deep
cutaneous ulcers or extra-articular disease (e.g.
pleurisy, pericarditis and scleritis) if associated with
typical digital infarcts or biopsy evidence of vascu-
litis. Other causes of such lesions, such as infection
(disseminated herpes zoster, HIV, viral hepatitis,
tuberculosis and endocarditis), atherosclerosis,
trauma, arterial or venous insufficiency and diabetes
mellitus, need to be excluded.
Laboratory tests are only supportive and have
no role in the diagnosis of rheumatoid vasculitis.
Anemia of chronic inflammation, leukocytosis,
thrombocytosis, elevation of erythrocyte sedimen-
tation rate or C-reactive protein and polyclonal
hypergammaglobulinemia are often seen. Hypo-
complementemia and cryoglobulinemia can be
rarely demonstrated. A high prevalence of RF and
ACPA in RA without rheumatoid vasculitis has only
modest positive predictive value for the develop-
ment of rheumatoid vasculitis, but their absence has
a high negative predictive value in circumstances
when the clinical suspicion is not high.
Antineutrophil cytoplasmic antibodies are seen
in 50–85% of patients with various types of primary
small vessel vasculitides, and typical or atypical peri-
nuclear (p)-antineutrophil cytoplasmic antibodies,
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in particular, has been observed in 36–48% patients
&&
with rheumatoid vasculitis [15 ,26]. Specific enzyme
immunoassays for antimyeloperoxidase and anti-
proteinase-3 are typically negative, but antilactofer-
rin antibodies have been demonstrated [26].
Definitive diagnosis of rheumatoid vasculitis
requires histologic evidence of small–medium
vessel vasculitis in the affected organ. Skin biopsy
is the least invasive procedure for tissue evaluation
and has a high yield (up to 75%) [19]. An electro-
physiological evaluation of peripheral nerves can
help direct appropriate nerve and/or muscle biopsy
(commonly sural nerve-gastrocnemius muscle or
peroneal nerve, peroneus brevis muscle). Other
affected organs can be biopsied if safely feasible,
but blind rectal biopsies advocated previously have
low yield and are no longer done.
Angiography is a suitable tool for the evaluation
of mesenteric vasculitis or medium vessel vasculitis
affecting the extremities (similar to polyarteritis
nodosa). In certain circumstances, if biopsy and/
or angiography are not feasible, treatment may need
to be initiated based on strong clinical suspicion for
rheumatoid vasculitis alone, but excluding mimics
is critical. The extent and severity and chronicity of
vasculitic manifestations are important to assess
prior to making decisions on therapy. Additionally,
assessment of other EAMs can also help in making
decisions regarding appropriate treatment strategies.
TREATMENT
The lack of validated classification criteria and
heterogeneity of clinical presentation has been a
significant obstacle to pursing therapeutic trials in
Volume 27  Number 1  January 2015

rheumatoid vasculitis. In the absence of established
guidelines to help guide therapy, treatment has
been largely empirical and entails sustained
aggressive immunosuppression. Chlorambucil and
D-penicillamine used as therapies for rheumatoid
vasculitis in the 1960s are not employed anymore,
primarily in view of their adverse effects profile
and, especially for D-penicillamine, doubtful effi-
cacy. The use of high-dose glucocorticoids, in com-
bination with cyclophosphamide (CYC) employed
by Scott and Bacon [20] in their initial studies, has
continued to remain the primary regimen for
rheumatoid vasculitis based on its success in severe
cases (vasculitic neuropathy, necrotizing arteritis
on biopsy) and long clinical experience with this
regimen.
Data reported from the Norfolk vasculitis regis-
ter suggested that high-dose glucocorticoids with
intravenous (i.v.) CYC were used as the treatment
strategy for 94% rheumatoid vasculitis patients
&&
treated between 2001 and 2010 [8 ]. Despite this,
however, mortality rates were high at 12% at 1 year
and 60% at 5 years. Infection and organ damage
from active vasculitis are the leading causes of early
death. The partial efficacy and the toxicity of these
therapeutic regimens indicate a need for alternative
therapies in patients with this life-threatening
complication of RA. The availability of a wider
armamentarium for RA treatment has somewhat
broadened the options for the management of
rheumatoid vasculitis.
Among 86 patients treated for rheumatoid
vasculitis at Mayo Clinic between 2000 and 2010
&&
[15 ], 99% received glucocorticoids (oral or i.v. or
both), 29% received CYC (oral or i.v.), 55% received
another disease-modifying antirheumatic drug
(methotrexate, azathioprine, mycophenolate mofe-
til, hydroxychloroquine, minocycline) and 28%
received a biologic agent (anti-TNF, rituximab,
abatacept, anakinra). Conclusions regarding the
efficacy of one DMARD or biologic over another
are difficult to make due to small sample sizes,
heterogeneity of disease manifestations treated
and variable clinical response. Our approach to
the management of rheumatoid vasculitis is out-
lined in Fig. 2 and is primarily based on its extent,
severity and presence of other EAMs. In our experi-
ence, patients without EAMs or with primarily
limited cutaneous disease may respond to a lesser
degree of immunosuppression. On the other hand,
patients with severe disease often experience sub-
optimal response or relapses, despite the conven-
tional therapy.
The role of biologics in rheumatoid vasculitis
treatment is not well established, but is gaining a
wider acceptance. There are reports of efficacy in
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Rheumatoid vasculitis: an update Makol et al.
refractory cases, but also as initial therapy for induc-
tion. The prevalence of high autoantibody titers
and circulating immune complexes in rheumatoid
vasculitis supports a rationale for B-cell depletion
therapy. Given its efficacy in other small vessel
vasculitides [27] and successful use in individual
rheumatoid vasculitis cases [28,29], there has been
a significant interest in the use of rituximab for
rheumatoid vasculitis. Seventeen patients enrolled
in the French Autoimmunity and Rituximab
Registry were treated with rituximab (as a primary
induction therapy in seven, for rheumatoid vascu-
litis relapse in six and in four as salvage therapy
after failure of conventional treatment) for active
systemic rheumatoid vasculitis [30]. At 6 months, 12
patients achieved complete remission, four had a
partial response and one died with uncontrolled
vasculitis. The mean prednisone dosage was reduced
from 19.2 to 9.7 mg/day. At 12 months, 14 patients
(82%) remained in sustained complete remission.
Severe infection occurred in three patients, corre-
sponding to a 6.4 per 100 patient-years rate. Among
six patients, who received further rituximab as a
maintenance therapy between months 6 and 12,
no relapse of vasculitis was observed, whereas
among the nine patients who did not, a relapse
was observed in three patients treated with metho-
trexate alone. Remission was reestablished by
reintroducing rituximab in two cases. Rituximab
represents a suitable therapeutic option to induce
remission in RV, but maintenance therapy seems to
be necessary.
The role of anti-TNF therapy in rheumatoid
vasculitis is much more debatable. With their
efficacy in RA and with TNF implicated in the patho-
genesis of rheumatoid vasculitis [31], anti-TNF
therapy seems to be a logical option for the manage-
ment of rheumatoid vasculitis. There are numerous
reports of successful use of anti-TNF therapy in refrac-
tory rheumatoid vasculitis [32,33], but many authors
have raised concerns about these agents’ potentially
triggering vasculitis, with more than 200 such cases
in the literature [34–38].
There are several hypotheses to explain the
occurrence of vasculitis in association with TNFa
antagonist therapy. First, type III hypersensitivity
reaction from immune complexes (containing the
drug and its target) depositing on vessel walls,
inducing local activation of the complement.
Second, decreased CD23 expression at the surface
of activated B cells among RA patients treated with
anti-TNF agents. Third, induction of a cytokine
imbalance by shifting the T helper 1 pattern (e.g.
IL1, TNF and interferon gamma) to a T helper 2
pattern (e.g. IL-4, IL-5, IL-6, IL-10 and IL-13) pro-
moting antibody-mediated immunity. These cases,
www.co-rheumatology.com 67
 Vasculitis syndromes

Patient with rheumatoid arthritis

Constitutional symptoms (fever, weight loss)

Elevated acute-phase markers (ESR, CRP)
Normocytic anemia, leukocytosis/thrombocytosis
End organ dysfunction

? rheumatoid vasculitis (RV)

If biopsy not feasible

Characteristic histopathology on biopsy • Consider angiography (mesenteric or extremity ischemia)
(skin, nerve +/– muscle, other affected organ) • Exclude mimics
• Consider treating based on strong clinical suspicion of RV

Assess for
• RV extent and severity
• Other extra-articular manifestations (EAMs)

Mild–moderate RV Severe RVa

Limited disease (cutameous, pericarditis) Multi-organ-system involvement
0–1 EAMs 2 or more EAMs

Induction therapy
Induction therapy
Oral GC (40–60 mg/kg daily) +/– IV pulse
Oral GC (20–40 mg/day prednisone equivalent) GC 0.5–1 g/day for 3 days
+ Refractory
+
Oral DMARD (1st line- MTX 10–25 mg/week; CYC (daily oral/monthly IV) 36 months
alternative-AZA 2 mg/kg) or rituximab 1g IV 2 weeks apart
or anti-TNF agentb

Maintainance therapy Maintainance therapy

MTX/AZA/LEF MTX/AZA/LEF/rituximab

Refractory cases/
relapsing disease

Consider alternate biologics

• Rituximab if not used previously
• Switching to alternate anti-TNF agent
• Tocilizumab or abatacept or anakinra
Addition of plasmapheresis or IVIG therapy

FIGURE 2. Our approach to diagnosis and management of rheumatoid vasculitis. AZA, azathioprine; CRP, C-reactive protein;
CYC, cyclophosphamide; DMARD, disease-modifying antirheumatic drugs; ESR, erythrocyte sedimentation rate; GC,
glucocorticoid; i.v., intravenous; IVIG, intravenous immunoglobulin; LEF, leflunomide; MTX, methotrexate; TNF, tumor necrosis
factor. aSevere RV includes RV with necrotizing arteritis on histo-pathology or with major end organ involvement [Digital or
extremity ischemia, scleritis, peripheral ulcerative keratitis, mononeuritis multiplex, involvement of the heart (besides
pericarditis) lung, kidney, central nervous system or GI tract]. bIf temporal association of anti-TNF therapy and high suspicion
for drug induced vasculitis, consider discontinuing the anti-TNF medication and switching to a different biologic.

68 www.co-rheumatology.com Volume 27  Number 1  January 2015

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however, represent only a small fraction of RA
patients treated with anti-TNF agents [39].
It is very difficult to separate rheumatoid vascu-
litis from drug-induced vasculitis based on clinical
presentation or histopathology. A temporal associ-
ation with a short interval between treatment
initiation and vasculitis onset, prompt resolution
of the vasculitis upon treatment discontinuation
and relapses upon reinitiation of the medication
lend support to a drug-induced vasculitic process.
Additionally, drug-induced hypersensitivity or idi-
osyncratic reactions can occur. It is also important
to remember that these associations between the
drug and disease manifestation can be confounded
by disease severity. Rheumatoid vasculitis can
develop in patients with severe seropositive RA with
EAMs, who are much more likely to require biologic
therapy.
There are several reports of successful use of
tocilizumab [40–42] and abatacept in refractory
rheumatoid vasculitis [43]. Only longer clinical
experience with these newer medications will
help demonstrate whether they can replace conven-
tional treatment regimens with CYC for induction
and/or maintenance of remission in rheumatoid
vasculitis. At this time, tocilizumab and abatacept
are generally reserved for refractory rheumatoid
vasculitis cases.
The risk of comorbid cardiovascular disease,
which is known to be highly prevalent among
patients with RA [44], is even higher among those
with severe EAMs [45]. The high burden of vascular
disease in patients with rheumatoid vasculitis [15 ],
&&
thus, necessitates close monitoring and interven-
tion for traditional risk factors (hypertension, smok-
ing, diabetes, hyperlipidemia and obesity), besides
aggressively managing the underlying inflamma-
tory process with disease-modifying antirheumatic
drug and biologics.
OUTCOMES
Unfortunately, despite the decrease in incidence
and widespread use of CYC and biologics, the
clinical presentation, severity and 5-year mortality
have not remarkably changed since the 1980s. We
recently reported a 5-year mortality of 26% among a
large retrospective US cohort of rheumatoid vascu-
litis patients evaluated at the Mayo Clinic between
&&
2000 and 2010 [15 ]. Poor outcomes were similarly
&&
reported by Ntatsaki et al. [8 ] using 2001–2010
data from the Norfolk vasculitis register in which
1-year mortality was 12% and 5-year mortality
was 60%, which is very high and not significantly
different from the 1988–2000 cohort (14 and
51%, respectively, P ¼ 0.134). Thus, despite all the
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Rheumatoid vasculitis: an update Makol et al.
improvements and successes in RA treatment,
rheumatoid vasculitis continues to remain a chal-
lenging complication to manage.
CONCLUSION
Rheumatoid vasculitis remains a difficult-to-
manage EAM of RA. Although its incidence has
declined in the past several decades, clinical pres-
entation has not significantly changed. Outcomes
of rheumatoid vasculitis remain grim, despite the
aggressive use of CYC, newer disease-modifying
drugs and biologics. The effect of TNF inhibitors
and other biologics on the occurrence of rheuma-
toid vasculitis, and their role in the induction or
maintenance therapy of severe, active rheumatoid
vasculitis, require further investigation.
Acknowledgements
None.
Financial support and sponsorship
This work was funded by the Mayo Clinic Margaret
Harvey Schering Clinician Career Development Award
Fund for Arthritis Research.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED
READING
Papers of particular interest, published within the annual period of review, have
been highlighted as:
& of special interest
&& of outstanding interest
1. Bannatyne GA. Rheumatoid arthritis: its pathology, morbid anatomy, and
treatment. 2nd ed Bristol: John Wright; 1898; 73.
2. Bywaters EG, Scott JT. The natural history of vascular lesions in rheumatoid
arthritis. J Chronic Dis 1963; 16:905–914.
3. Scott DG, Bacon PA, Tribe CR. Systemic rheumatoid vasculitis: a clinical
and laboratory study of 50 cases. Medicine (Baltimore) 1981; 60:288–
297.
4. Voskuyl AE, Zwinderman AH, Westedt ML, et al. Factors associated with the
development of vasculitis in rheumatoid arthritis: results of a case-control
study. Ann Rheum Dis 1996; 55:190–192.
5. Puechal X, Said G, Hilliquin P, et al. Peripheral neuropathy with necrotizing
vasculitis in rheumatoid arthritis: a clinicopathologic and prognostic study of
thirty-two patients. Arthritis Rheum 1995; 38:1618–1629.
6. Myasoedova E, Crowson CS, Turesson C, et al. Incidence of extraarticular
rheumatoid arthritis in Olmsted County Minnesota, in 1995–2007 versus
1994: a population-based study. J Rheumatol 2011; 38:983–989.
7. Watts RA, Carruthers DM, Symmons DP, Scott DG. The incidence of
rheumatoid vasculitis in the Norwich Health Authority. Br J Rheumatol
1994; 33:832–833.
8. Ntatsaki E, Mooney J, Scott DG, Watts RA. Systemic rheumatoid vasculitis in
&& the era of modern immunosuppressive therapy. Rheumatology (Oxford) 2014;
53:145–152.
This study based on prospectively collected data on a stable cohort of patients in
the United Kingdom provides an update on the incidence and mortality of
rheumatoid vasculitis. It demonstrates a significant decline in incidence of rheu-
matoid vasculitis over last 40 years, without much change in the mortality that
remains high despite the utilization of intense immunosuppressive strategies.
9. Watts RA, Mooney J, Skinner J, et al. The contrasting epidemiology of
granulomatosis with polyangiitis (Wegener’s) and microscopic polyangiitis.
Rheumatology (Oxford) 2012; 51:926–931.
www.co-rheumatology.com 69
 Vasculitis syndromes
10. Bartels C, Bell C, Rosenthal A, et al. Decline in rheumatoid vasculitis
prevalence among US veterans: a retrospective cross-sectional study.
Arthritis Rheum 2009; 60:2553–2557.
11. Gorman JD, David-Vaudey E, Pai M, et al. Particular HLA-DRB1 shared epitope
genotypes are strongly associated with rheumatoid vasculitis. Arthritis Rheum
2004; 50:3476–3484.
12. Turesson C, Schaid DJ, Weyand CM, et al. The impact of HLA-DRB1 genes
on extra-articular disease manifestations in rheumatoid arthritis. Arthritis Res
Ther 2005; 7:R1386–R1393.
13. Turesson C, Schaid DJ, Weyand CM, et al. Association of HLA-C3 and
smoking with vasculitis in patients with rheumatoid arthritis. Arthritis Rheum
2006; 54:2776–2783.
14. Martens PB, Goronzy JJ, Schaid D, Weyand CM. Expansion of unusual CD4þ
T cells in severe rheumatoid arthritis. Arthritis Rheum 1997; 40:1106–1114.
15. Makol A, Crowson CS, Wetter DA, et al. Vasculitis associated with rheuma-
&& toid arthritis: a case–control study. Rheumatology (Oxford) 2014; 53:890–
899.
This is the largest single-center case series of rheumatoid vasculitis to date and
provides an update on the clinical presentation, treatment, outcomes and risk
factors of rheumatoid vasculitis in the era of modern immunosuppresive therapy,
particularly since the advent of biologics. It also suggested for the first time the
protective effect of hydroxychloroquine and low-dose aspirin in a case–control
study.
16. Struthers GR, Scott DL, Delamere JP, et al. Smoking and rheumatoid
vasculitis. Rheumatol Int 1981; 1:145–146.
17. Albano SA, Santana-Sahagun E, Weisman MH. Cigarette smoking and
rheumatoid arthritis. Semin Arthritis Rheum 2001; 31:146–159.
18. Laskari K, Ahmadi-Simab K, Lamken Mea. Are anti-cyclic citrullinated peptide
autoantibodies seromarkers for rheumatoid vasculitis in a cohort of patients
with systemic vasculitis? Ann Rheum Dis 2010; 69:469–471.
19. Bartels CM, Bridges AJ. Rheumatoid vasculitis: vanishing menace or target for
new treatments? Curr Rheumatol Rep 2010; 12:414–419.
20. Scott DG, Bacon PA. Intravenous cyclophosphamide plus methylpredniso-
lone in treatment of systemic rheumatoid vasculitis. Am J Med 1984; 76:377–
384.
21. Vollertsen RS, Conn DL, Ballard DJ, et al. Rheumatoid vasculitis: survival and
associated risk factors. Medicine (Baltimore) 1986; 65:365–375.
22. Wallace DJ, Gudsoorkar VS, Weisman MH, Venuturupalli SR. New insights
into mechanisms of therapeutic effects of antimalarial agents in SLE. Nat Rev
Rheumatol 2012; 8:522–533.
23. Turesson C, Matteson ME. Extraarticular features of rheumatoid arthritis and
systemic involvement. In: Hochberg MC, Smolen JS, Weinblatt ME, Weisman
MH, editors. Rheumatology, 5th ed Philadelphia: Mosby; 2011. pp. 839–
847.
24. Pagnoux C, Mahr A, Cohen P, Guillevin L. Presentation and outcome of
gastrointestinal involvement in systemic necrotizing vasculitides: analysis of
62 patients with polyarteritis nodosa, microscopic polyangiitis, Wegener
granulomatosis, Churg–Strauss syndrome, or rheumatoid arthritis-asso-
ciated vasculitis. Medicine (Baltimore) 2005; 84:115–128.
25. Voskuyl AE, van Duinen SG, Zwinderman AH, et al. The diagnostic value of
perivascular infiltrates in muscle biopsy specimens for the assessment of
rheumatoid vasculitis. Ann Rheum Dis 1998; 57:114–117.
26. Coremans IE, Hagen EC, Daha MR, et al. Antilactoferrin antibodies in patients
with rheumatoid arthritis are associated with vasculitis. Arthritis Rheum 1992;
35:1466–1475.
70 www.co-rheumatology.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
27. Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for
ANCA-associated vasculitis. N Engl J Med 2010; 363:221–232.
28. Hellmann M, Jung N, Owczarczyk K, et al. Successful treatment of rheumatoid
vasculitis-associated cutaneous ulcers using rituximab in two patients with
rheumatoid arthritis. Rheumatology (Oxford) 2008; 47:929–930.
29. Maher LV, Wilson JG. Successful treatment of rheumatoid vasculitis-asso-
ciated foot drop with rituximab. Rheumatology (Oxford) 2006; 45:1450–
1451.
30. Puechal X, Gottenberg JE, Berthelot JM, et al., Investigators of the Auto-
Immunity Rituximab Registry. Rituximab therapy for systemic vasculitis asso-
ciated with rheumatoid arthritis: results from the AutoImmunity and Rituximab
Registry. Arthritis Care Res (Hoboken) 2012; 64:331–339.
31. Flipo RM, Cardon T, Copin MC, et al. ICAM-1, E-selectin, and TNF alpha
expression in labial salivary glands of patients with rheumatoid vasculitis. Ann
Rheum Dis 1997; 56:41–44.
32. Puechal X, Miceli-Richard C, Mejjad O, et al. Antitumour necrosis factor
treatment in patients with refractory systemic vasculitis associated with
rheumatoid arthritis. Ann Rheum Dis 2008; 67:880–884.
33. Unger L, Kayser M, Nusslein HG. Successful treatment of severe rheumatoid
vasculitis by infliximab. Ann Rheum Dis 2003; 62:587–588.
34. Jarrett SJ, Cunnane G, Conaghan PG, et al. Antitumor necrosis factor-alpha
therapy-induced vasculitis: case series. J Rheumatol 2003; 30:2287–2291.
35. Mohan N, Edwards ET, Cupps TR, et al. Leukocytoclastic vasculitis asso-
ciated with tumor necrosis factor-alpha blocking agents. J Rheumatol 2004;
31:1955–1958.
36. Ramos-Casals M, Roberto Perez A, Diaz-Lagares C, et al. Autoimmune
diseases induced by biological agents: a double-edged sword? Autoimmun
Rev 2010; 9:188–193.
37. Saint Marcoux B, De Bandt M; CRI (Club Rhumatismes et Inflammation).
Vasculitides induced by TNFalpha antagonists: a study in 39 patients in
France. Joint Bone Spine 2006; 73:710–713.
38. Sokumbi O, Wetter DA, Makol A, Warrington KJ. Vasculitis associated with
tumor necrosis factor-alpha inhibitors. Mayo Clin Proc 2012; 87:739–
745.
39. Turesson C, Jacobsson C, Geborek P, et al. Extra-articular manifestations in a
community-based sample of patients with rheumatoid arthritis: incidence and
relation to treatment with TNF inhibitors. Arthritis Rheum 2007; 56:S709.
40. Iijima T, Suwabe T, Sumida K, et al. Tocilizumab improves systemic rheuma-
toid vasculitis with necrotizing crescentic glomerulonephritis. Mod Rheumatol
2014. [Epub ahead of print]
41. Sumida K, Ubara Y, Takemoto F, Takaichi K. Successful treatment with
humanised anti-interleukin 6 receptor antibody for multidrug-refractory and
antitumour necrosis factor-resistant systemic rheumatoid vasculitis. Clin Exp
Rheumatol 2011; 29:S133.
42. Yoshida S, Takeuchi T, Sawaki H, et al. Successful treatment with tocilizumab
of pericarditis associated with rheumatoid arthritis. Mod Rheumatol 2014;
24:677–680.
43. Fujii W, Kohno M, Ishino H, et al. The rapid efficacy of abatacept in a patient
with rheumatoid vasculitis. Mod Rheumatol 2012; 22:630–634.
44. Turesson C, Jacobsson LT, Matteson EL. Cardiovascular co-morbidity in
rheumatic diseases. Vasc Health Risk Manag 2008; 4:605–614.
45. Turesson C, McClelland RL, Christianson TJ, Matteson EL. Severe extra-
articular disease manifestations are associated with an increased risk of first
ever cardiovascular events in patients with rheumatoid arthritis. Ann Rheum
Dis 2007; 66:70–75.
Volume 27  Number 1  January 2015