Clinical Rheumatology

https://doi.org/10.1007/s10067-020-05459-9

REVIEW ARTICLE

Biological therapy in rheumatoid vasculitis: a systematic review

Débora Patrícia Alves de Cerqueira 1 & Ana Luisa Souza Pedreira 1,2 & Marcelo Gomes de Cerqueira 2 &
Mittermayer Barreto Santiago 1,2

Received: 21 August 2020 / Revised: 1 October 2020 / Accepted: 8 October 2020

# International League of Associations for Rheumatology (ILAR) 2020

Abstract
Rheumatoid vasculitis (RV) is one of the most severe extra-articular manifestations of rheumatoid arthritis, with significant
morbidity and mortality, requiring aggressive treatment with corticosteroids and/or immunosuppressants. Recently, biological
drugs were included in its therapeutic armamentarium. The objective of this study was to perform a systematic review on the use
of biological drugs in the treatment of RV. A systematic literature review was performed based on PRISMA (Preferred Reporting
Items for Systematic Reviews and Meta-Analyses) recommendations and searching articles in MEDLINE/PubMed, Cochrane,
SciELO, Scopus, and Virtual Health Library electronic databases. Secondary references were also evaluated. The methodological
quality of the selected studies was evaluated by the Strengthening the Reporting of Observational Studies in Epidemiology
(STROBE) criteria. Altogether, five articles, assessing the use of biological drugs, were included. Globally, 35 patients partic-
ipated in the studies, of which 21 were treated with rituximab (RTX) in cycles of 1000 mg every 2 weeks; 9 used infliximab 5
mg/kg; 3 used infliximab 3 mg/kg; and 2 used etanercept 25 mg twice/week. In general, an improvement in clinical picture,
reduction of the mean daily dose of corticosteroids, and improvement in the Birmingham Vasculitis Activity Score was achieved
by the end of the treatment. Complete remission occurred in almost 70% of the cases. The adverse effect rate was 34%, mainly
due to infections. There were two deaths, one due to sepsis and the other due to uncontrolled vasculitis, after the biological drug
withdrawal, following the development of sepsis. Based on the results of the present review, we believe that the use of biological
therapy such as RTX and anti-tumor necrosis factor α can be beneficial in treating this complication.

Keywords Anti-TNF . Biological drugs . Biological therapy . Rheumatoid vasculitis . Systematic review

Introduction
Rheumatoid vasculitis (RV) is a potentially severe extra-
articular manifestation of rheumatoid arthritis (RA), which
affects approximately 2 to 5% of long-term disease patients
(longer than 10 years). The 5-year mortality rate of RV is 30–
50% in addition to high rates of morbidity due to complica-
tions or treatment-associated toxicity [1].
RV can involve any organ, but usually involves the skin,
representing approximately 90% of the cases, characterized by
petechiae and purpura, skin ulcerations that can be deep, is-
chemia, and peripheral gangrene [2]. Peri- and/or epineural
* Ana Luisa Souza Pedreira
analupedreira@gmail.com
1
Escola Bahiana de Medicina e Saúde Pública, Av Dom João VI, 275
– Brotas, Salvador, BA 40290-000, Brazil
2
Universidade Federal da Bahia, Salvador, BA, Brazil
arteritis is also observed in about half of the cases; they cause
peripheral nerve lesions that may manifest as acute symmet-
rical and sensory peripheral neuropathy or multiple
mononeuritis [3]. The involvement of the heart, lungs, central
nervous system, gastrointestinal tract, and kidneys occurs in
less than 1% of patients with RV.
The criteria for systemic RV were developed by Scott and
Bacon in 1984. According to these criteria, the diagnosis of
RV depends on the presence of one or more of the following
findings: (1) mononeuritis multiplex; (2) peripheral gangrene;
(3) biopsy evidence of acute necrotizing arteritis plus systemic
illness (such as weight loss and fever); and (4) deep cutaneous
ulcers or active extra-articular disease (e.g., pleurisy, pericar-
ditis, scleritis), if associated with typical digital infarcts or
biopsy evidence of vasculitis [4].
The treatment of mild to moderate RV, in which the disease
is limited to cutaneous manifestations, is carried out with glu-
cocorticoid induction therapy and maintenance therapy with
disease-modifying anti-rheumatic drugs (DMARDs) such as

methotrexate, azathioprine, or leflunomide. Meanwhile, in se-
vere RV, which is characterized by systemic involvement of
multiple organs, treatment is performed with an induction
therapy with high doses of glucocorticoids and cyclophospha-
mide, as suggested by Scott and Bacon [4], together with
maintenance therapy with DMARDs, cyclophosphamide or
biological. In refractory cases or severe RV relapse, the use
of rituximab (RTX) if not previously used, anti-Tumor
Necrosis Factor α (anti-TNFα), or other biological molecules
such as tocilizumab, abatacept, and anakinra should be con-
sidered [5]. However, these recommendations are not based
on robust scientific evidence [6].
Regarding the specific use of biological drugs, there is no
standardization of preferential class choice, although the use
of anti-TNFα and RTX has been reported more frequently [7].
Given this scenario, the objectives of this review were to
describe the use of biological drugs in RV therapy, as well as
to evaluate their efficacy and safety, according to the studies
available to date.
Methods
A systematic review was performed according to the PRISMA
(Preferred Reporting Items for Systematic Reviews and Meta-
Analyses) recommendations [8].
Eligibility criteria
Studies considered eligible were as follows: those, including
patients diagnosed with RA, based on the classification
criteria of the American Rheumatism Association (ARA)
1987 [9], or the American College of Rheumatology (ACR)/
the European League Against Rheumatism (EULAR) 2010
[10]; with a RV diagnosis according to the Scott and Bacon
criteria [4], or biopsy confirmation of the affected site; and
over the age of 18 years and having evaluated the use of
biological drugs, including anti-TNFα, RTX, tocilizumab,
abatacept, and anakinra for the treatment of RV. Studies in-
volving patients with other rheumatological diseases (includ-
ing primary vasculitis), studies with vasculitis secondary to
infection or vasculitis resulting from the use of anti-TNFα,
review studies, and isolated case report articles were excluded.
Search strategy and search of studies
The Cochrane Register of Controlled Trials, MEDLINE (Via
PubMed), Cochrane, Virtual Health Library (VHL), Europe
PMC, and Scopus databases were used to search for potential-
ly eligible articles, from 1988 until April 2019, in English,
Portuguese, or Spanish. In addition, studies on the reference
list of the included articles were also searched.
Clin Rheumatol
The descriptors used were as follow: Rheumatoid Arthritis,
Vasculitis, Rheumatoid Vasculitis, Biological Therapy,
Treatment, Drug Therapy, Anakinra, Rituximab, Abatacept,
To cilizumab , Anti-TNF, Etanercept, Infliximab,
Adalimumab, Certolizumab, and Golimumab.
Study selection and data mining
Three independent researchers read the titles, abstracts, and
conclusions of the pre-selected studies in the databases, sepa-
rately identifying articles, which responded to the eligibility
criteria. After this step, each researcher read the complete ar-
ticles and selected those that were compatible with the sys-
tematic review criteria. Subsequently, data were also collected
individually in a standard form. In case of disagreement be-
tween the authors, a fourth researcher was consulted.
Evaluation of the quality of the included studies
The methodological quality and the risk of bias of the selected
studies were evaluated by the Strengthening the Reporting of
Observational Studies in Epidemiology (STROBE) criteria
for observational studies [11].
Results
Altogether, 4513 articles in the databases were screened, 1161
articles in MEDLINE/PubMed, 57 in Cochrane, 1784 in
Scopus, 1296 in VHL, 213 in Europe PMC, and 2 manual
references from other articles. Finally, 5 articles were included
in the systematic review (Fig. 1).
Assessment of the methodological quality
The STROBE questionnaire was applied to the 5 included
articles to verify the methodological quality. Four studies
met 81% of the required criteria, and one study met 86% of
the requirements, as shown in Fig. 2.
Characteristics of the studies included in this
systematic review
The main characteristics of the five studies are presented in
Table 1. All were observational studies, including 2 to 17
subjects, with a total of 35 patients. The mean age was 58.6
years. Regarding comorbidities, none of the articles indicated
the presence of associated diseases.
The most investigated drug was RTX, followed by
infliximab (IFX), and, finally, etanercept (ETA). The mean
duration of interventions was 18.44 months. The type of vas-
culitis, the treatments prior to biological therapy, and the ad-
verse events are also detailed in Table 1.
Clin Rheumatol

Fig. 1 Flowchart of the study

selection process

IDENTIFICATION
Records identified in the Additional records identified
database search (n=4511) from other sources (n=2)

Records excluded (n=4491):

- 2071 did not cover the theme of
the systematic review
- 1472 duplicate articles
- 439 isolated case reports
- 220 published before 1988
- 146 narrative reviews
- 73 studies in children and/or
adolescents
Pre-selected studies - 23 Juvenile idiopathic arthritis
EVALUATION (n=4513) - 12 Juvenile rheumatoid arthritis
- 11 anti-TNF drugs induced
vasculitis
- 11 Meeting abstracts or Letters to
the editor
- 5 Experimental studies with
animals
- 4 in languages other than English,
Spanish or Portuguese
-3 Data from SUS (Brazil’s Health
care System)
- 1 Clinical protocol and therapeutic
guidelines
ELIGIBILITY

Whole Articles excluded (n=17)

Articles selected for reading in - 12 Review articles
full (n=22) - 2 Book chapters
- 1 in French
- 1 scientific manuscript from
meeting
- 1 Large vessel vasculitis and RA
INCLUSION

Articles included in the Systematic

Review (n=5)

In all five studies, a decrease of the mean daily dose of
prednisone was observed at the end of the biologic treat-
ment, as described in Fig. 3, as well as an improvement in
the Birmingham Vasculitis Activity Score (BVAS) or
BVAS/RA score (a modified form of the BVAS without
the criterion of arthralgia/arthritis, which was already be-
ing used in other studies with RV) (Fig. 4). Complete or
partial remission was observed in 80% of the patients, and
when analyzing only complete remission, the index was
close to 70%. The general adverse effect rate was 12/35
(34%) and the mortality of 2/35 (5.7%).
Below is presented a short description of the select studies.
Puéchal et al. (2012) evaluated the efficacy and safety of
RTX in 17 patients with systemic RV, either as a first-line
induction therapy or after previous treatment failure of another
induction therapy regimen. In these patients, the mean dura-
tion of RA was 15.31 years, and the mean duration of RV was
29.52 months, ranging from 1 month (shorter duration) to 176
months [6]. Treatment response was evaluated by BVAS/RA.
The major outcomes were complete remission (BVAS/RA
with score 0) and partial remission (improvement of BVAS/
RA by at least 50%). Complete remission occurred in 8 pa-
tients (47%) in 3 months, and in 71% of patients in a 6-month
period. Partial remission was obtained in 7 patients (41%) in 3
 Clin Rheumatol

Fig. 2 Methodological
assessment of the selected articles CHECKLIST Puéchal, Assmann, Puéchal, Josselin, Bartolucci,
using the STROBE tool STROBE 2012 6 2010 12 2008 7 2008 13 2002 14
1 Title and Abstract
Introduction
2 Background / rationale
3 Objectives
Methods
4 Study design
5 Setting
6 Participants
7 Variables
8 Data sources / measurement
9 Bias
10 Study size
11 Quantitative variables
12 Statistical methods
Results
13 Participants
14 Descriptive data
15 Outcome
16 Main results
17 Other analyses
Discussion
18 Key results
19 Limitations
20 Interpretation
21 Generalizability
Other information
22 Funding
Fulfillment of the
81% 81% 81% 86% 81%
criteria (%)

LEGEND:
All information
Green is described
Contains
partial
Yellow information
Does not have
this
Red information

months and in 24% of patients in a 6-month period. In addi-
tion, no improvement of vasculitis was observed in 2 patients.
Three severe infections occurred with one death due to sepsis,
resulting from extensive gangrene 5 months after the initial
infusion of RTX.
Assmann et al. studied the efficacy of RTX treatment in
RV refractory to treatment with prednisolone, through a ret-
rospective analysis of 4 female patients with cutaneous vas-
culitic ulcers. The mean duration of RA in these patients was
21.75 years [12]. In their study, three of the four patients
achieved complete remission, defined by the healing of ulcers,
within 4.33 weeks after the initiation of treatment, on average.
One patient remained refractory to treatment, requiring 70 mg
prednisolone daily, and needing retreatment with IFX, which,
in turn, led to a slight improvement, without healing of le-
sions. There were no adverse events or death, related to the
use of the RTX.
Puéchal et al. (2008) assessed the effect of anti-TNFα
agents in 9 patients with RV, refractory to treatment with
cyclophosphamide and glucocorticoids, through a
retrospective study. The mean duration of RA in these patients
was 16.11 years. In turn, RV had a mean duration of 29.6
months, ranging from 5 months (shorter duration) to 102
months (longer duration) [7]. After 28.6 weeks of treatment
with anti-TNFα agents, complete remission was achieved in 5
patients, partial remission in one patient, a failure to achieve
remission was observed in one patient, and 2 stopped the
medication due to adverse effects. After a 32.6-month
follow-up period, 8 patients were alive, and 5 were being
treated with the initial anti-TNFα agent. Four adverse events
and one death occurred in this study due to multiple microor-
ganism infections.
Josselin et al. aimed to demonstrate the efficacy of IFX in
treating systemic necrotizing vasculitis, refractory to conven-
tional therapeutic regimes. Fifteen patients were selected
through a retrospective medical record review, and 3 out of
them had vasculitis associated with RA. The mean duration of
RV was 0.415 years. The outcomes obtained were as follows:
one sustained remission (> 6 months), but still required pred-
nisone 15 mg/day; one remission with early relapse which was
Table 1 Main characteristics of observational studies presented in the systematic review

Reference Country Year Sample Mean Sex Drug Dosage Mean Combination with Adverse event Type of Previous treatment
size age used duration of drugs vasculitis
Clin Rheumatol

(years) intervention

Puéchal France 2012 17 63.5 F (10)/M (7) RTX 1 g of RTX, at 2-week 33.1 months Oral 3 severe infections Active systemic Methylprednisolone,
et al. intervals (13 patients); (cutaneous) 1 death
corticosteroids,M- vasculitis high doses of
[6] 0.5 or 0.75 g RTX at TX, AZA, and IV (sepsis caused by with prednisone, CYC,
2-week intervals or 4 CYC extensive gangrene mononeuritis AZA, MTX
infusions of 0.75 or due to an uncon- multiplex leflunomide, IFX,
1 g with 1-week inter- trolled vasculitis) and/or cuta- ADA
val (4 patients) neous vascu-
litic lesions
Assmann Germany 2010 4 63.25 F (4) RTX Two infusions 1000 mg 4 months Prednisolone 70 No adverse events Vasculitis IFX, MTX, ADA,
et al. RTX at 2-week inter- mg/day or prednis- associated leflunomide
[12] val olone 20 mg/day with
and MTX 20 cutaneous
mg/day or ulcers
leflunomide 20
mg/day
Puéchal France 2008 9 57 F (4)/M (5) ETA 25 mg ETA-SC twice a 32.6 months Prednisolone, MTX, Four adverse events: Cutaneous CYC and
et al. or week (2 patients); in- AZA (1) diffuse cutane- vasculitis, glucocorticoids
[7] IF- fusions of 3 mg/kg (3 ous reaction, (2) multiple
X patients) or 5 mg/kg (4 Listeria septicemi a mononeurop-
patients) of IFX on with sepsis by athy
weeks 0, 2, and 6, and Staphylococcus and
after each 8-week in- bronchopneum onia
terval by Klebsiella,
Pneumocystis
jiroveci and Cand
ida, (3) esophageal
candidiasis (4) skin
infection by
Staphylococcus 1
death due to an un-
controlled vasculitis
Josselin England France 2008 3 58.333 F (2)/M (1) IFX 5 mg/kg IFX on days 0, 16.5 months MTX or AZA No adverse events Systemic CYC and other
et al. 15, and 45 and then necrotizing immunosuppres-
[13] followed by 4–6-week vasculitis sants
intervals depending on (peripheral
clinical response nervous
system and/or
skin)
Bartolucci England/France 2002 2 51 F (2) IFX 5 mg/kg IFX on days 1, 6 months Prednisolone 5–65 No adverse events Mononeuritis MTX, CYC, and
et al. 14, and 42 and after mg/day multiplex and cyclosporine
[14] every 8 weeks necrotizing
cutaneous
vasculitis

F female, M male, TCZ tocilizumab, IV intravenous, SC subcutaneous, IFX infliximab, MTX methotrexate, ETA etanercept, AZA azathioprine, ADA adalimumab, CYC cyclophosphamide
 Clin Rheumatol

Fig. 3 Mean daily dose of

prednisone used in the studies
included in the review 70 10
60
50
40
8.1 11.2
60 10.1
30
9.8
20 29.6 26 23
10 19.2

0
Puéchal et al., Assmann et al., Puéchal et al., Josselin et al., Bartolucci et al.,
2012 2010 2008 2008 2002

Mean daily dose at the beginning of treatment (mg/day) Mean daily dose at the end of treatment (mg/day)

retreated with IFX; and one patient had no symptoms remis-
sion. No adverse events or deaths were reported for the use of
IFX in the RV treatment of these patients [13].
The study conducted by Bartolucci et al. evaluated the
short-term effect of anti-TNFα therapy in systemic vasculitis
patients, refractory to steroids and immunosuppressive agents.
The study included 10 patients with systemic vasculitis, two
of them with RV. The durations of vasculitis in patients with
RA were 3 and 7 months, respectively. In these patients, the
durations of RA were 4 and 39 years, respectively. These two
patients presented an improvement in the vasculitis; one of
them had the ulcer healed. There were no reports of adverse
effects related to the medication in neither patient [14].
Discussion
RV affects mainly men with RA (2- to 4-fold higher rate than
women) and usually occurs in people with at least a 10-year
history of RA [15]. However, rarely, RV may appear earlier,
as demonstrated in the Puéchal et al.’s study in 2012, which
reported the occurrence of this condition in a patient with 0.4
years of initiation of the disease [6]. Typically, RV affects
small- and medium-sized arteries, overlapping with
polyarteritis nodosa characteristics, and manifests mainly by
cutaneous lesions and peripheral neuropathy [15].
Classically, the treatment of RV, especially those cases
with several systemic manifestations, is accomplished with
the use of high doses of corticosteroids and cyclophospha-
mide. Although effective, this regimen is associated with sev-
eral adverse events, mainly the risk of infection. This risk is
greater in patients with RV, who have ulcerated cutaneous
lesions. Thus, other therapeutic options have been attempted,
such as biological drugs.
As reported in this systematic review, there were only five
studies including more than one patient with RV treated with
biological drugs and that provided sufficient information on
their efficacy and safety. From these retrieved studies, only
three biologicals were used: RTX, IFX, and ETA. Isolated
case reports (which was an exclusion criterion for this system-
atic review) have described the use of these and other biolog-
icals, such as abatacept, adalimumab, and tocilizumab in the
treatment of RV [16–18].
The fact that no clinical trial was included in this review is
expected as RV is a rare and serious condition and requires
immediate therapeutic intervention, precluding the individual

Fig. 4 Birmingham Vasculitis 12

Activity Score (BVAS) and its
modified version BVAS/RA of
10
three studies included in the 10.3
review
8
8
7.2
6

2 2.5 2.6

1
0
Bartolucci et al., 2002 Josselin et al., 2008 Puéchal et al., 2008

BVAS at the beginning of the treatment. BVAS at the end of treatment

Clin Rheumatol
participation in randomized placebo-controlled double-blind
clinical studies. Other significant obstacles to the implemen-
tation of clinical trials in RV are the lack of validated classifi-
cation criteria and the heterogeneity of the clinical
presentations.
Of the five articles included, two evaluated the use of RTX
for the treatment of RV with similar results in terms of effica-
cy, analyzing 21 patients, representing 60% of the total pa-
tients included in this systematic review. In another study, not
included in this systematic review due to lack of relevant
information, two patients with severe refractory cutaneous
RV were treated with RTX with improvement of the vasculitic
lesions, together with a reduction of the disease activity score
28 (DAS-28) and the mean dose of corticosteroids. Of note,
one patient had been treated previously with ETA, which was
stopped due to lack of efficacy [19].
The rationale for using RTX in RV is its proven efficacy in
other types of small vessel vasculitis. Furthermore, the preva-
lence of high titers of autoantibodies and circulating immune
complexes in RV is a reason for using B cell depletion in this
condition [5].
The three remaining studies included in this review
assessed the use of anti-TNFα (1 IFX and 2 ETA) in RV,
analyzing a total of 14 patients. Regarding efficacy, all of
them reported improvement of symptoms, BVAS/RA score,
and the reduction of the daily prednisone dose. However, im-
portant side effects (infections) were observed in one of these
studies, with an adverse event rate of 44% [7].
Makol et al. conducted a retrospective study which includ-
ed 86 patients with RV, who met the Scott and Bacon criteria.
Histopathological confirmation was available in 58% of these
patients. The median age at the time of diagnosis of RV was
63 years, with a median duration of RA of 10.8 years. In this
study, 21 patients used biological therapy to treat RV: anti-
TNFα agents (12 patients), RTX (6 patients), anakinra (2
patients), and abatacept (1 patient). Although many RV pa-
tients were enrolled, this study was not included in this review
because it did not present details of the clinical outcomes after
the use of biological therapy [20].
The main limitations of our systematic review are as fol-
lows: (1) the small number of patient samples with RV, found
in selected studies; (2) the evaluated studies’ design, as there
were only descriptive retrospective studies and no randomized
clinical trials controlled by placebo; (3) the absence of pub-
lished studies, comparing biological drugs with each other so
that a better general assessment could be made of these drugs’
effect in treating RV; (4) the studies that did not evaluate other
risk factors, besides seropositive RA, and did not specify the
comorbidities of these patients.
Another possible bias observed in the evaluated studies
was the fact that some patients with RA who developed RV
had already been treated with other biological drugs, such as
IFX and adalimumab [6, 12]. It is known that the anti-TNFα
drugs can also lead to cutaneous vasculitis, and in these cases
the medication should be interrupted and replaced by an alter-
native regimen to control the disease. Thus, the development
of vasculitis can be either due to the use of biological drugs or
due to the progression of RA, and therefore histologic evalu-
ation and extensive investigation for other organs involvement
must be pursued [21].
After performing this systematic review, as a way of stan-
dardizing future studies on this topic, we recommend some
points: Whenever possible, provide histopathological data
confirming the presence of vasculitis and clearly describe
the presence of comorbidities such as diabetes mellitus and
peripheral vascular disease (other causes of skin ulcers in
these patients) and, finally, the need for using scores such as
BVAS, BVAS/AR, and DAS-28 to evaluate the treatment
response. Other important parameters to be evaluated are the
time of remission and the decrease of the daily dose of
corticosteroids.
In conclusion, despite the advances in treatment strategies
for RA, management of RV remains undefined, mainly rely-
ing on high doses of corticosteroids and cyclophosphamide.
Based on the results of the present review, we believe that the
use of biological therapy such as RTX and anti-TNFα can be
beneficial in treating this complication.
Acknowledgments M.B.S is currently receiving a scholarship from
Conselho Nacional de Desenvolvimento Científico e Tecnológico
(CNPq).
Compliance with ethical standards
Disclosures None.
Ethical approval This article does not contain any studies with human
participants performed by any of the authors.
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