Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2010

Full text

Consensus statement
Ann Rheum Dis 2011;70(Suppl 1):i2–i36. doi:10.1136/ard.2010.146852i2
INTRODUCTION
As in previous years, the consensus group to con-
sider the use of biological agents in the treatment
of rheumatic diseases met during the 12th Annual
Workshop on Advances in Targeted Therapies in
April 2010. The group consisted of rheumatologists
from a number of universities among the conti-
nents of Europe, North America, South America,
Australia and Asia.
Pharmaceutical industry support was obtained
from a number of companies for the annual
workshop itself but these companies had no part
in the decisions about the specifi c programme
or about the academic participants at this con-
ference. Representatives of the supporting spon-
sors participated in the initial working groups
to supply factual information. The sponsors did
not participate in the drafting of the consensus
statement.
This consensus was prepared from the perspec-
tive of the treating physician.
In view of the new data for abatacept, B cell-
specifi c agents, interleukin 1 antagonists (IL-1),
tocilizumab and tumour necrosis factor α (TNFα)
blocking agents, an update of the previous con-
sensus statement is appropriate. To allow ease of
updating, the 2008 updates (March 2009–February
2009) have been incorporated into the body of the
manuscript, while 2010 updates (March 2009–
February 2010) are separated and highlighted. The
consensus statement is annotated to document the
credibility of the data supporting it as much as pos-
sible. This annotation is that of Shekelle et al and is
described in an appendix.1 We have modifi ed the
Shekelle annotation by designating all abstracts
as ‘category D evidence’, whether they describe
well-controlled trials or not, as details of the study
were often not available in the abstracts. Further,
the number of possible references has become so
large that reviews are sometimes included; if they
contain category A references, they will be referred
to as category A evidence.
The rheumatologists and bioscientists who
attended the consensus conference were from 23
countries and were selected for their expertise in
the use of biological agents for the treatment of
rheumatic diseases. The number of attendees and
participants was limited so that not everyone who
might have been interested could be invited. All
participants reviewed a draft document developed
by the coauthors, based on a review of all relevant
clinical published articles relating to abatacept and
rituximab (B-cell-specifi c therapy) as well as IL-1
blocking agents, tocilizumab and TNFα blocking
agents. The draft was discussed in small working
groups. The revisions suggested by each group
were discussed by all participants in a fi nal open
session and this led to a fi nal document, represent-
ing this updated consensus statement.
It is hoped that this statement, which is based
on the best evidence available at this time and
is modifi ed by expert opinion, will facilitate the
optimal use of these agents for patients with
conditions approved by the Food and Drug
Administration (FDA) or European Medicines
Agency (EMA) for clinical use. Extensive tables of
the use of these agents in non-registered uses are
included as appendices, to help experienced doc-
tors to use these drugs in exceptional (‘off-label’)
circumstances.
GENERAL STATEMENTS
The formatting of this document is arranged as
follows: general introduction and general state-
ments followed by each biological agent arranged
by generic name or general mechanism (when
appropriate). Within each biological agent, the
data are arranged by indication, the information is
arranged according to clinical use, such as dosing,
time to response, etc. Some combination of indi-
cations occurs when appropriate safety is arranged
together after clinical use, in alphabetical order.
Individual patients differ in the clinical expres-
sion and aggressiveness of their disease, its con-
comitant structural damage, the effect of their
disease on their quality of life (QoL) and the symp-
toms and signs engendered by their disease. They
also differ in their risk for, and expression of, side
effects to drugs. All these factors must be exam-
ined when considering biological treatment for a
patient, as must the toxicity of previous and/or
alternative disease-modifying antirheumatic drug
(DMARD) use.
As increasing evidence has accumulated on the
effi cacy and clinical use of biological agents for
the treatment of psoriatic arthritis (PsA) and anky-
losing spondylitis (AS), these diseases will be dis-
cussed separately from rheumatoid arthritis (RA).
Adverse reactions, unless disease specifi c, however,
will remain combined for all indications.
In general, in RA, when measuring response
to treatment or when following up patients over
For numbered affi liations see
end of article
Correspondence to
Professor D E Furst, David
Geffen School of Medicine,
UCLA – RM 32-59, 1000
Veteran Avenue, Los Angeles,
CA 90025, USA;
defurst@mednet.ucla.edu
Accepted 2 December 2010
Updated consensus statement on biological agents
for the treatment of rheumatic diseases, 2010
D E Furst,1 E C Keystone,2 J Braun,3 F C Breedveld,4 G R Burmester,5 F De Benedetti,5
T Dörner,5 P Emery,6 R Fleischmann,7 A Gibofsky,8 J R Kalden,9 A Kavanaugh,10
B Kirkham,11 P Mease,12 J Sieper,12 N G Singer,13 J S Smolen,14 P L C M Van Riel,15
M H Weisman,16 K Winthrop17
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Consensus statement
Ann Rheum Dis 2011;70(Suppl 1):i2–i36. doi:10.1136/ard.2010.146852 i3
(category C evidence12). Abatacept has been used with MTX
and other DMARDs. (category A, B evidence10 11 13–17).
Juvenile idiopathic arthritis
Abatacept is recommended for treatment of active polyarticu-
lar juvenile idiopathic arthritis (JIA) as monotherapy or with
DMARDs after an adequate trial of MTX. In the USA, it is
approved after the use of another effective DMARD as well
(category C evidence18 19).
In Europe, abatacept in combination with MTX is indicated
for the treatment of moderate to severe polyarticular JIA in
patients 6 years and older who have insuffi cient response to
other DMARDs, including at least one TNFα blocking agent.
Clinical use
Dosing
Rheumatoid arthritis
The adult dosing regimen is 750 mg or 1000 mg given at 0, 2 and
4 weeks then monthly, intravenous (FDA product label).
Time to response
Some patients respond to abatacept, using the American College
of Rheumatology response criteria, within 2–4 weeks. Most
adult patients respond within 12–16 weeks of starting treat-
ment. (It may take longer in children—see below (category A
evidence19 20.) Patients continue to improve for up to 12 months
(category A evidence7 8 21). QoL and other patient- related
outcomes, such as sleep, fatigue and activity, also improve
(category A evidence22).
Cost-effectiveness
Abatacept appears cost-effective and comparable to other bio-
logical agents (category B effective14 23–26).
Persistence
Some patients maintained response on abatacept for up to
3 (TNF-incomplete responders (TNF-IR)) to 5 years (MTX-
incomplete responders (MTX-IR)) in long-term open-label
extension studies (category C evidence24 27).
Comparison with TNFα blocking agents
In a controlled trial, the clinical effi cacy of abatacept (10 mg/kg)
was similar to low dose infl iximab (3 mg/kg); these were numeri-
cally fewer serious adverse events in the abatacept treated patients
(category A evidence28).
Structural changes
Abatacept in combination with MTX inhibits or reduces radio-
graphic progression in RA in MTX-IR patients (category A, B
and C evidence24 29–31).
In MTX naïve early RA patients, MTX plus abatacept was
superior to MTX plus Placebo (category A evidence27).
Juvenile idiopathic arthritis
Dosing
Abatacept is administered as intravenous infusions of 10 mg/kg
for weights <75 kg; 750 mg for weights of 75–100 kg and 1000 mg
for weights >100 kg. All regimens are given intravenously at
0, 2 and 4 weeks, then monthly (FDA product label)) (category
A evidence19).
Time to response
While most patients with JIA respond within 16 weeks of starting
treatment, some children may take 3–6 months or longer before
their maximal response is achieved (category A evidence19 20).
time, validated quantitative measures for clinical trials can
be used, such as Disease Activity Score, Simplifi ed Disease
Activity Index, Clinical Disease Activity Index, RAPID, Health
Assessment Questionnaire Disability Index (HAQ-DI), visual
analogue scales (VAS) or Likert scales of global response or
pain by the patient, or global response by the doctor. Other
validated measures for individual patient care, joint tenderness
and/or swelling counts and laboratory data may all be used and
may be appropriate measures for individual patients (category
A, B2– 8). The doctor should evaluate a patient’s response using
one of the above instruments to determine the patient’s status
and change.
For PsA, measures of response such as joint tenderness and
swelling, enthesitis and dactylitis, global and pain response
measures, functional indices and acute phase reactants, both as
single measures and as part of composite measures have been
used.2 4 9
For AS, measures such as the Bath Ankylosing Spondylitis
Disease Activity Index and the Bath Ankylosing Spondylitis
Functional Index are used; they have been used in clinical tri-
als but have not been validated for routine clinical practice
(category C evidence).5 In this disease, clinical measures such
as joint tenderness and swelling, spinal motion, global and pain
response measures, functional indices and acute phase reactants
have been used and are validated.
Pregnancy remains a controversial topic when using biologi-
cal agents in the rheumatic diseases. For all but the TNFα and
IL-1 blocking agents, there are too few data to draw any conclu-
sions. Since a lack of association is extremely diffi cult to prove,
no biological agent can be assumed to be safe. In the absence
of such data, this recommendation depends on the USA-FDA
designation. Abatacept and tocilizumab have a category C des-
ignation while TNFα and IL-1 blocking agents are designated as
category B (see specifi c drugs).
The appropriate use of biological agents will require doc-
tors experienced in the diagnosis, treatment and assessment of
RA, PsA, AS and other rheumatic diseases who are aware of
the data regarding long-term observations of effi cacy and toxic-
ity, including cohort studies and data from registries. Because
biological agents have adverse effects, patients or their repre-
sentatives should be provided with information about potential
risks and benefi ts so that they may give informed consent for
treatment. To enable ease of reference, the biological agents are
listed in alphabetical order: abatacept; B-cell therapy; IL-1 block-
ing agents; tocilizumab; TNF blocking agents.
ABATACEPT
One agent which modulates T-cell activation (abatacept) has
been approved in the United States and Europe.
Indications
Rheumatoid arthritis
Abatacept is recommended for treatment of active RA as
monotherapy or with DMARDs in moderate to severe adult
RA after an adequate trial of methotrexate (MTX) or another
effective DMARD (in the USA). In early RA abatacept has been
approved in North America in MTX-naïve patients in combina-
tion with MTX6 (category A evidence7 8 10 11). Abatacept had
been approved by the EMA for active RA after an inadequate
response to a non-biological DMARD and a failure of at least
one TNFα blocking agent.
Abatacept may be administered at the time when the next
dose of the TNFα blocking agent would normally be given
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Consensus statement
Ann Rheum Dis 2011;70(Suppl 1):i2–i36. doi:10.1136/ard.2010.146852i4
Based on theoretical concerns, live vaccines should not be
given while a patient is receiving abatacept or within 3 months
of using abatacept.
2010 Update:
Pregnancy—There have been too few cases of preg-
nancy when using abatacept for any defi nite conclusion to
be drawn. See general statement on page i2. According to
the US FDA, abatacept is considered category C, meaning
‘No human studies and animal studies either show risk
or are lacking. However, potential benefi ts may justify
potential risks.’
RITUXIMAB B-CELL THERAPY
Rituximab is a chimeric anti-CD20 monoclonal antibody which
was approved in 1997 for treatment of indolent CD20, B-cell
non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic
leukaemia.
A consensus statement on the use of rituximab in patients
with RA has been published (category D evidence40).
Indications
Rheumatoid arthritis
Rituximab has been approved by the FDA in the USA for the
treatment of moderate-to-severe RA, with MTX, in patients for
whom at least one TNFα blocking agent has produced an inade-
quate response (category A and D evidence41–43) (FDA and EMA
label; category C and D evidence44–49). It may also be used when
TNFα blockers are not suitable (category D evidence50–52).
A greater rate of American College of Rheumatology responses
was seen with rituximab in rheumatoid factor/anti-cyclic cit-
rullinated peptide-positive patients who were DMARD non-
responders (category C evidence44 46) and in non-responders to
TNFα blocking agents (category D evidence44 50 53 54).
Clinical use
Dosing
Rituximab is administered intravenously as two 1 g or two
500 mg rituximab infusions (given with 100 mg methylpred-
nisolone or equivalent) separated by an interval of 2 weeks.
These doses are equivalent clinically, although the higher
dose retards radiographic measures better than the lower
dose (category A evidence41 44 47–49 55 56). In RA, it may be
used alone or in combination with MTX or other DMARDs
(category A and D evidence41–43 52 53 56), although the optimal
treatment schedule remains under further investigation (cat-
egory D evidence41 46 50 53).
Time to response
In clinical trials, rituximab results in signifi cant improvement in
signs and symptoms and/or laboratory measures by 8–16 weeks
(category A, D evidence56–63).
Persistence
Rituximab is effective over up to 5 years in patients with an
inadequate response to MTX for whom conventional DMARDs
have failed or who have used one or more TNF inhibitors (cat-
egory A, B evidence41 56 60 62–65).
2010 Update:
Studies have shown that repeated treatment courses
are effective in previously responsive patients with RA
(category C, D evidence61 64). Open-label extension stud-
ies of up to 6 years showed continued response (cate-
gory D evidence66). Most of the patients who received
subsequent courses did so 24 weeks or more after the
Safety
Autoimmune disease
No increased incidence of autoimmune diseases was noted in
the abatacept clinical trial database (category D evidence32).
Infections
Tuberculosis
All patients in abatacept phase III trials were screened for tubercu-
losis (TB) with a tuberculin skin test (TST) but were still included
if the screen was positive and they were treated for latent TB.
Cases of TB were observed in the clinical trial programme (cat-
egory C, D evidence23 33). The risk for reactivation of latent TB or
for developing new TB when using abatacept is unknown. Until
the risk is known, it is appropriate to screen patients considered
for abatacept therapy for TB according to local practice.
Serious infections
Patients with chronic obstructive pulmonary disease (COPD)
treated with abatacept had more serious lower respiratory tract
infections than patients treated with placebo; therefore its use
in patients with RA and COPD should be undertaken with
caution.
In comparison with placebo in clinical trials, the incidence
of serious infections with abatacept was increased in trials at
12 months but not in a meta-analysis pooling 6- and 12-month
safety data (category A evidence33 34). In a review of clinical trial
data, the incidence of hospitalisations for infections remained
stable for up to 5 years and the incidence was not signifi cantly
different in the long-term extension as compared with the
blinded phase of clinical trials (3.0 vs 2.1/100 000 patient-years).
As with the other such trials, the uncontrolled cohort design
with observed data limits the generalisability of these data (cat-
egory C evidence33).
For abatacept in combination with other biological agents,
the rate of serious infections is 4.4% (vs 1.5% in controls) (cat-
egory C evidence15). The use of abatacept with a TNFα blocking
agent is not recommended, as an increased incidence of serious
infections was noted when the combination was used (category
A evidence35 36). There are no data about the combination of
abatacept and rituximab.
Malignancies
One case of a lymphoma occurred in a double-blind trial with
abatacept versus none in the placebo group; four additional
cases occurred in the open-label extension (cumulatively
5/4134 patient-years), while an epidemiological overview
showed no increase (category B, D evidence32 37). Although
this number is consistent with that expected from large RA
cohorts, continuing surveillance is necessary. When abata-
cept clinical trial data were compared with national registries,
no increased rates of lymphoma, lung, breast, colorectal or
total malignancies were found, although the control popula-
tions were not entirely comparable (category D evidence32).
Epidemiological experience in six RA cohorts showed no
increased rate of solid malignancies compared with the RA
cohorts (category D evidence37), although continued monitor-
ing is necessary. (category C evidence37)
Vaccinations
There was a decreased response to infl uenza, tetanus and
pneumococcal vaccinations when using abatacept in healthy
volunteers (category C evidence38). Infl uenza and pneumococ-
cal vaccinations in patients with RA receiving abatacept were
reduced, comparable to previous reports in patients with RA
receiving MTX (category D evidence39).
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Consensus statement
Ann Rheum Dis 2011;70(Suppl 1):i2–i36. doi:10.1136/ard.2010.146852 i5
Severe infections
Similar to TNFα blockers and other biological agents, a small
increase in serious bacterial infections was seen in patients
receiving rituximab. There was no increase in the incidence of
serious infectious events with up to nine courses of treatment
(category A, D evidence46 66 77)
No increase in the rate of serious infections was seen in a
cohort of 259 patients who received another biological agent
after rituximab treatment compared with patients receiv-
ing rituximab treatment before a biological agent (category D
evidence78).
Baseline immunoglobulin levels were generally normal in
patients entering clinical studies, and decreased levels of IgM,
IgA and IgG have been seen with rituximab. In clinical tri-
als, no increase in serious infections has been reported in the
patients with reduced levels of IgM after rituximab treatment
compared with their previously normal IgM levels (category B
evidence47 53).
After repeated courses of rituximab, a proportion of patients
develop IgG levels below the lower limit of normal. Those
patients have demonstrated a numerical increase in infections
in open studies (category C, evidence66). This increase has not
been confi rmed by open-label extension studies for patients
with initial normal IgG levels. In contrast, patients with IgM and
IgA below the limit of normal before rituximab treatment are a
patient group at highest risk (category C evidence79).
B-cell levels have been measured in clinical trials but their
importance in routine practice has not been proved. Depletion
of the CD20+ B-cell subpopulation by routine measures was
not predictive of achieving or maintaining a clinical response in
patients with RA (category D evidence48 80–85). This suggests that
the timing of re-treatment should be based on disease activity.
2010 Update:
In a small open randomised study of rituximab in com-
bination with adalimumab or etanercept, no signifi cant
increase of serious infectious events over 6 months was
observed (category C evidence86)
Infusion reactions
The most widespread adverse events are infusion reactions,
which are most common with the fi rst infusion of the fi rst
course (up to 35%) and are reduced with the second and subse-
quent infusion (about 5–10%). Intravenous corticosteroids were
shown to reduce the incidence and severity of infusion reac-
tions by about 30% without changing effi cacy (category A, C
and D evidence41 42 44 46 51–53). Rare anaphylactoid reactions have
occurred when rituximab is used (category C evidence).
Malignancies
There is no evidence that rituximab is associated with an
increased incidence of solid tumours in RA. Nevertheless, vigi-
lance for the occurrence of solid malignancies remains warranted
during treatment with rituximab (category B evidence66).
Neurological syndromes
Cases of progressive multifocal leucoencephalopathy (PML)
have been seen in patients with systemic rheumatic diseases
with and without rituximab treatment (FDA communication).
Three cases reported to regulatory agencies of PML in patients
with RA treated with rituximab have been reported. The causal
relationship between PML and rituximab remains unclear.
2010 Update Pregnancy:
See general statement on page i2. According to the
US FDA, rituximab is considered category C, ‘no human
previous course and none received repeated courses ear-
lier than 16 weeks after the previous course (category
B, D evidence65 66). Treatment with rituximab every 6
months demonstrated better clinical effi cacy than on-
demand treatment without signifi cantly increasing
adverse events (category B evidence65). There are con-
fl icting data on the effi cacy of re-treatment of initial non-
responders (category C evidence67).
Degree of response
In a retrospective non-randomised open-label study,68 and in an
observational study comprising 2500 patients,69 70 patients for
whom one or more TNFα blocking agent had failed (owing to
ineffectiveness) switching to rituximab or another TNFα blocker
and rituximab was more effective than using another TNFα
blocking agent.
Improvement has also been demonstrated in patient-related
outcomes such as HAQ-DI, patient global VAS, fatigue, disabil-
ity and QoL (category A, evidence71 72). Data from randomised
controlled trials (RCTs) show that the combination of rituximab
with MTX yields better clinical effi cacy for RA than monother-
apy (category A evidence42 46 51 60). Preliminary data of non-inter-
ventional studies69 70 suggest that combination with lefl unomide
yields even higher responses than with MTX.
Structural changes
Rituximab inhibits radiographic progression in both MTX-naïve
patients and in those for whom one or more TNFα blocking
agent has produced an inadequate response (category A evi-
dence). In RA, at 1 year, rituximab in combination with MTX,
the 1000 mg×2, regimen, reached the primary end point of pro-
tection against radiographic progression compared with MTX
alone (category B evidence73).
Safety
Hepatitis
Rituximab treatment is normally contraindicated in hepatitis B
since fatal hepatitis B reactivation has been reported in patients
with NHL treated with rituximab. In the case of occult or of
latent hepatitis B virus, alanine aminotransferase (ALT) should
be measured regularly and if elevated hepatitis B virus DNA is
found, should be checked with sensitive assays.74 Hepatitis B
status should be assessed before treatment.
Rituximab has been used in hepatitis C virus (HCV)-associated
cryoglubulinaemic vasculitis (category A, D evidence75 76). Data
are not available in HCV-infected patients with RA who have
cryoglobulinaemia and rituximab appears effective and safe in
these case reports.
Infections (see also ‘Neurological syndromes’ below)
Tuberculosis
In general, patients who did not respond to TNF inhibitors will
also have been prescreened for the presence of active or latent
TB. In the RA clinical trials of rituximab in TNFα non-responders,
patients with active TB were excluded. Others were screened by
chest radiograph examination, but were not screened for latent
TB by purifi ed protein derivative testing. There is no evidence of
an increased incidence of TB in patients with NHL treated with
rituximab. There are insuffi cient data to make a determination
about the necessity to screen for TB before starting treatment.
Thus, the clinician should be vigilant for the occurrence of TB
during treatment.
Rituximab should not be given in the presence of serious or
opportunistic infections.
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Consensus statement
Ann Rheum Dis 2011;70(Suppl 1):i2–i36. doi:10.1136/ard.2010.146852i6
cold autoinfl ammatory syndrome/familial cold urticaria (cat-
egory A, C evidence107–109). These are all rare conditions due
to mutations in the NALP3 gene, in which a major role for IL-1
has been shown. The effi cacy of rilonacept and canakinumab
has been shown in placebo-controlled randomised clinical trials
(category A evidence97 98). Canakinumab is indicated in the USA
and Europe in adults, adolescents and children with CAPS aged
≥4 years with a body weight >15 kg. Rilonacept is indicated in
the USA and Europe in adults and adolescents with CAPS aged
≥12 years (category A, C evidence97 98 107 108).
Anti-IL-1 agents have prompt, major and sustained clinical
benefi t in CAPS.97 98 107–109 Canakinumab is administered sub-
cutaneously every 8 weeks at a dose of 150 mg for patients
with body weight >40 kg and at 2 mg/kg for patients with body
weight >15 kg and <40 kg. No dose adjustment is needed in
patients with end-stage renal disease (category C evidence110).
Rilonacept is administered subcutaneously once a week at
a dose of 160 mg for patients >18 years and at 2.2 mg/kg for
patients between 12 and 18 years of age. There is no evidence
that one agent is more effective than another in CAPS.
JIA and adult-onset Still’s disease
IL-1β signalling pathway blockade with anakinra is effective in
a proportion of patients with systemic-onset JIA and adult-onset
Still’s disease (see Table A.3 for additional references).
ANKYLOSING SPONDYLITIS AND PSA
Anakinra has been evaluated in two open-label studies of AS,
but without consistent evidence of effi cacy.582 583 Anakinra did
not demonstrate clinical effi cacy in PsA.584
CRYSTAL-ASSOCIATED ARTHROPATHIES
There are anecdotal reports of clinical effi cacy following treatment
with anakinra in patients with intractable gout585 and pseudogout.586
OTHER ARTHROPATHIES
Treatment with intra-articular anakinra was evaluated in a ran-
domised clinical trial of patients with osteoarthritis (category
A evidence587). Treatment was well tolerated but no improve-
ments were observed compared with placebo.
Anakinra has been used with effect in CAPS, familial
Mediterranean fever, the TNF receptor-associated periodic syn-
drome, defi ciency of the interleukin-1-receptor antagonist and
Schnitzler syndrome.
Clinical use
Timing of response
Anakinra can lead to signifi cant improvement in symptoms,
signs and/or laboratory parameters of RA within 16 weeks and
can inhibit or induce slowing of radiographic progression (cat-
egory A evidence99 102 103 111). If improvement is not seen by
16 weeks, discontinuation of anakinra should be considered.
Comparison with TNFα blocking agents
2010 Update:
A recent meta-analysis demonstrates that anakinra is
less effective than the TNFα inhibitors in treating RA (cat-
egory A evidence90)
Safety
These agents have largely been established in patients with
RA receiving anakinra. Use of newer drugs (canakinumab or
rilonacept) or use in non-approved indications may disclose
other safety concerns (category A, C evidence98 110).
studies and animal studies either show risk or are lacking.
However, potential benefi ts may justify potential risks.’
Because of the possible B-cell depletion in the fetus
after rituximab, it is recommended that it be discontinued
1 year before a planned pregnancy.87 88
There have been too few cases of pregnancy when
using rituximab for any conclusion about their use during
pregnancy.89 90 The antibody, as an IgG, is excreted with
milk.
Skin reactions
Rare reports of psoriasis, including severe cases and rare instances
of vasculitis,91 have been reported in patients with RA, systemic
lupus erythematosus and NHL after rituximab treatment (cat-
egory D evidence92 93). The causative role of rituximab in these
circumstance remains unknown.
Vaccination
In a controlled trial, rituximab signifi cantly decreased the
immune response to neoantigen, (keyhole limpet haemocya-
nin) and pneumococcus, whereas delayed-type hypersensitivity
responses and responses to tetanus were unchanged (category
A evidence94).
2010 Update:
Humoral responses to infl uenza vaccination in patients
with RA were severely reduced shortly after rituximab
administration but modestly restored at 6–10 months.
Importantly, patients with a previous annual infl uenza
vaccination were more likely to develop protective titres
to vaccination, suggesting that all patients should receive
yearly vaccination (category B evidence95). No data are
available on the success of vaccination against infl uenza
after several courses of rituximab.
Since rituximab causes B-cell depletion, it is recommended
that any vaccinations required by the patient, such as those to
prevent pneumonia and infl uenza, should be given before start-
ing treatment. (category A evidence96). Until further data are
available, the use of live attenuated vaccines should only be
given before the use of rituximab.
IL-1 BLOCKING AGENTS
One IL-1-blocking agent, anakinra (IL-1 receptor antagonist),
has been approved for use in RA. Two IL-1 inhibitors, rilonacept
(IL-1 Trap) and canakinumab (anti-IL-1β monoclonal) have been
approved for use in cryopyrin-associated periodic syndromes
(CAPS) (category A evidence97–101).
Indications
Rheumatoid arthritis
Anakinra may be used for the treatment of active RA, alone or
in combination with MTX, at a dose of 100 mg/day subcutane-
ously (category A evidence102–104). In Europe, the anakinra label
requires prescription in combination with MTX. Anakinra is rec-
ommended for the treatment of active RA after an adequate trial
of non-biological DMARDs or with other DMARDs (category A
evidence,99 100 105 category C evidence106). No trials of anakinra as
the fi rst DMARD for patients with early RA have been published.
Cryopyrin-associated periodic syndromes
Rilonacept and canakinumab have major clinical benefi t in
children and adults with CAPS, including severe familial cold
autoinfl ammatory syndrome, Muckle–Wells syndrome and
neonatal-onset multisystem infl ammatory disease/chronic
infantile neurological cutaneous, articular syndrome, familial
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Consensus statement
Ann Rheum Dis 2011;70(Suppl 1):i2–i36. doi:10.1136/ard.2010.146852 i7
lack of response) to DMARDs or TNFα inhibitors (category A,
D evidence120–125 132–138). The FDA has approved tocilizumab
for use in patients with moderate to severe RA who are
incomplete responders to TNF-antagonist agents (category D
evidence135–138). In Japan tocilizumab is approved in patients
with RA for whom one or more DMARDs produces insuf-
fi cient response (category A, D122 138).
JIA and other indications
In Japan and India, tocilizumab has also been approved for sys-
temic JIA based on a small open 19-patient study of systemic-
onset JIA and multicentric Castleman’s disease (category A evi-
dence132 139 140).
Clinical use
Tocilizumab reduces signs and symptoms of active RA in
incomplete responders to DMARDs or TNFα blocking agents
(category A evidence120–124). In many countries tocilizumab can
be used as monotherapy in DMARD/MTX-naïve patients (cat-
egory A, D evidence124 136 141) or DMARD inadequate respond-
ers (category A, D122 138).
Dosing
The dosing regimens recommended vary by indication and
country so they are shown in Table 1. Tocilizumab is admin-
istered intravenously monthly in a dose of 4 or 8 mg/kg. In
general, 8 mg/kg has been found to be more effective than 4
mg/kg (see table below). In combination with MTX or other
DMARDs, it can be used at 4 or 8 mg/kg although 4 mg/
kg monotherapy was less effective in DMARD incomplete
responders (category A evidence120–125 132). Tocilizumab use
and dosing have not yet been approved for use in children by
the FDA or EMA.
2010 Update:
The 2010 update is shown in Table 1.
Tocilizumab has been used in JIA-associated arthritis
(class A evidence134).
Timing of response
Onset of response can occur as early 2–4 weeks in some
patients but it may take ≥24 weeks in other patients (cat-
egory A, D evidence122 123). Biomarkers (IL-6) have been
used as a predictor of response (category D evidence142 143).
Tocilizumab can be restarted after long-term withdrawal
(category D evidence144)
Comparison with TNFα blocking agents
Tocilizumab has not been compared directly with TNFα block-
ing agents. It can be used after failure of one or more TNFα
inhibitor (category A, D evidence123 137).
Structural changes
Tocilizumab inhibits or reduces radiographic progression in
patients for whom MTX or other DMARDs have produced an
inadequate response (category A125 145 146) and it also inhibits or
Infections
Tuberculosis
To date, there is no indication that use of anakinra is associated
with an increased incidence of TB (category D evidence77).
Bacterial infections
The incidence of serious bacterial infections was increased
in patients receiving anakinra and the incidence was higher
than in patients with RA using non-biological DMARDs. The
increased incidence of infection was greatest in patients who
were also receiving corticosteroids or >100 mg/day anakinra
(category A evidence104 112). Patients should not start or con-
tinue anakinra if a serious infection is present (category A
evidence104 112 113). Treatment with anakinra in such patients
should only be resumed if the infection has been adequately
treated.114– 117 Anakinra has been used to treat macrophage
activation syndrome, which may be triggered by JIA or by
infection (category D evidence118)
When anakinra was used in combination with etanercept,
there was no increase in effi cacy. However, an increase in the
incidence of serious infection was observed in comparison with
either compound used as monotherapy. Therefore, the combi-
nation of anakinra and etanercept should not be prescribed (cat-
egory A evidence114).
Injection site reactions
A dose-related incidence of injection site reactions, affecting
up to 70% of patients, has been reported with the use of anak-
inra. These reactions often do not require treatment and seem
to moderate with continued use in most patients (category A
evidence99 102 119).
Pregnancy
See general statement on page i2. According to the USA FDA,
anakinra is considered category B—that is, no evidence of risk
in humans. If no adequate human studies are done; no animal
studies have been done; or animal studies show risk but human
studies do not.
Vaccinations
In one controlled trial, anakinra did not inhibit antitetanus anti-
body response (category D evidence111).
TOCILIZUMAB
Tocilizumab is a humanised anti-IL-6 receptor monoclonal anti-
body (category A, D evidence120–126).
Indications
Rheumatoid arthritis
Tocilizumab has been approved in the European Union and
a number of other countries in combination with MTX (cat-
egory A, B, C evidence127–131). It is approved as monotherapy
for the treatment of moderate to severe active RA in adults
who are incomplete responders (owing to adverse events or
Table 1 Tocilizumab: Dosing regimens and 2010 update
EMA area* FDA area Japan*
RA 8 mg/kg every 4 weeks 4 mg/kg every 4 weeks initially, with
an increase to 8 mg/kg every 4 weeks
if clinically indicated
8 mg/kg every 4 weeks
Polyarticular JIA139 – – 8 mg/kg every 4 weeks
Systemic onset JIA – – 8 mg/kg every 2 weeks (interval may be decreased to weekly)
Multicentric Castleman’s disease140 – – 8 mg/kg every 2 weeks (interval may be decreased to weekly)
* In the EMA area and Japan, it can also be used as monotherapy in patients with contraindications to, or intolerant of methotrexate.
EMA, European Medicines Agency; FDA, Food and Drug Administration; JIA, juvenile idiopathic arthritis.
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Consensus statement
Ann Rheum Dis 2011;70(Suppl 1):i2–i36. doi:10.1136/ard.2010.146852i8
Infections
Bacterial infections
In a 6-month controlled clinical study, the rate of serious infec-
tions in the 4 and 8 mg/kg arms were numerically higher in
the tocilizumab then placebo+DMARD arms (4.4 and 5.3/100
patient-years compared with 3.9/100 patient-years) The rates
were stable over time in open-label extensions of controlled tri-
als (category D evidence126 148 155 163 172). Tocilizumab should not
be given when serious or opportunistic infections are present
(category D evidence132). As with other biological agents, care-
ful observation for bacterial infections is necessary (category B,
D evidence148 154 155 163 164).
2010 Update:
In a 24-week randomised clinical trial involving 678 patients,
serious infections were twice as common with tocilizumab
(1.4%) as MTX alone (0.7%) (category B evidence175).
The downregulatory effect of tocilizumab on the
acute-phase reactant, C-reactive protein (CRP), may
limit the usefulness of CRP as a diagnostic indicator for
infections.
TB and opportunistic infections
Cases of TB and opportunistic infections have been observed in
patients taking tocilizumab (EMA; category A, D evidence164 176 177).
Patients should be screened for (latent) TB before treatment. See
‘TNF antagonist’ section for details of TB screening.
Viral infections
Cases of localised H zoster infection have occurred in clinical tri-
als, but it is not clear whether H zoster is increased in association
with tocilizumab (category D evidence164 169).
2010 Update:
No instances of active hepatitis B or C were found, but
patients were excluded from trials if they had positive
hepatitis B or C serologies.
Infusion-related events
Serious infusion reactions during/after treatment with tocili-
zumab are uncommon (category A, D178)
Malignancies
There is no evidence that tocilizumab therapy is associated with
an increased incidence of malignancies in patients with RA (cat-
egory A, D evidence120–125 141 148). Systematic safety surveillance
should be performed during tocilizumab treatment similar to
requirements for other biological agents.
2010 Update (pregnancy):
There have been too few cases of pregnancy when using
tocilizumab for any conclusions to be drawn (category C89).
See general statement on page i2. According to the US
FDA, this drug is considered category C, meaning ‘no
human studies and animal studies either show risk or are
lacking. However, potential benefi ts may justify potential
risks.’
Skin
Erythroderma has been ascribed to tocilizumab (category D
evidence179).
TNFΑ BLOCKING AGENTS
TNFα blockers differ in composition, precise mechanism of
action, pharmacokinetics and biopharmaceutical properties, but
this document emphasises areas of commonality. Studies that
have clearly differentiated between compounds will be dis-
cussed, where appropriate.
reduces radiographic progression as monotherapy (category A
evidence133 145).
Safety
Cardiovascular end points and lipid levels
The overall long-term effect of tocilizumab on cardiovascular
outcomes is at present not known. In a follow-up for up to 5
years (category D evidence141 147–153), there was no apparent
increase in cardiac event rates. Hypertension and cerebrovascular
accidents (CVAs) have been seen (category A, D evidence132 141
148 154–157). In a follow-up with a median of 1.5 years, no increase
in the rate of CVAs was found (category D evidence158)
Increases in mean fasting plasma lipid levels, including total
cholesterol, low-density lipoprotein, triglycerides and high-den-
sity lipoprotein, were seen in 20–30% of tocilizumab-treated
patients (category A, D evidence148 154 155 159 160). Lipid levels
should be monitored 1–2 months after initiation of treatment
and then every 6 months. It should be managed according to
local recommendations.
Initiation of statin therapy after receiving tocilizumab is effec-
tive in reducing lipids (category D evidence161).
Gastrointestinal
In 6-month controlled clinical trials, generalised peritonitis,
lower gastrointestinal perforation, fi stulae and intra-abdominal
abscesses have been reported (overall rate 0.26/100 patient-years
compared with no events in the control arm). The concomitant
use of corticosteroids and non-steroidal anti-infl ammatory drugs
may increase the risk of these events. Tocilizumab should be
used with caution in patients with a history of intestinal ulcer-
ation or diverticulitis (category D evidence162).
Haematological
Neutropenia A higher proportion of patients treated with tocili-
zumab had a decrease in the absolute neutrophil count compared
with placebo. A few patients had a decrease of polymorpho-
nuclear cells to <1000 cells/mm3 and, rarely, <500 cells/mm3.
This change usually occurs early after a dose and is transient.
Complete blood counts should be monitored regularly accord-
ing to local labels (usually every 4–8 weeks). In one study, there
was an accompanying increase in infections but this was not
seen in most studies (category A, D evidence163–168).
Vaccination
Safety and response to vaccinations were evaluated in patients
with RA receiving tocilizumab. Most patients could be effec-
tively immunised with infl uenza and pneumococcal vaccine
(category D evidence169). As for the other biological agents, live
vaccines should not be given while patients are receiving tocili-
zumab (category A, D evidence132 148 164 170 171).
Hepatic aminotransferase and bilirubin elevations
ALT and aspartate aminotransferase (AST) elevations occurred
with similar frequency with tocilizumab monotherapy compared
with MTX alone (category A evidence172–174). For tocilizumab
in combination with DMARDs, including MTX, elevations are
more common than with tocilizumab alone. Elevations of bili-
rubin, mostly indirect and sometimes associated with Gilbert’s
syndrome, occur separately and are not associated with hepatic
dysfunction. Liver function should be monitored regularly.
Recommendations for the management of tocilizumab-
related laboratory abnormalities have been included in the
EMA and FDA package which are consistent with those
for MTX. No instances of tocilizumab-induced hepatic fail-
ure or liver damage have been documented (category A, D
evidence120–125 132–134 141 148 154–156 163 164 169 172–174).
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Consensus statement
Ann Rheum Dis 2011;70(Suppl 1):i2–i36. doi:10.1136/ard.2010.146852 i9
level (category A, B evidence197 232 240–243). The addition or substi-
tution of other DMARDs may increase effi cacy in some patients.
Timing of response
TNFα blocking agents, when administered up to the maximum
approved dosing regimens for RA and polyarticular JIA, may elicit
response in 2–4 weeks in some patients. They usually lead to
signifi cant, documentable improvement in symptoms, signs and/
or laboratory parameters within 12–24 weeks (category A and
B evidence90 113 115 116 180–196 199 201 205 223–225 231 232 239 242 244–253).
Clinically signifi cant important responses, including patient-
oriented measures (eg, HAQ-DI, patient’s global VAS, Medical
Outcome Survey Short Form 36) and physical measures (eg, joint
counts), should be demonstrated within 12–24 weeks for RA
(category A evidence90 113 115 116 181–190 192 194 195 196 199 201 203 223–225
228 244 245–247 250 251). For patients in remission or with low disease
activity, anecdotal studies indicate that lowering the dose may be
successful without loss of effect (category C evidence113 115 183 184
188 197–202 254).
If improvement occurs, treatment should be continued. If
patients show no response to these agents, their continued use
should be re-evaluated. Etanercept weekly dosing in children
(0.8 mg/kg up to 50 mg weekly) also improves health-related
QoL and reduces disease activity.255
Comparison of TNF
α
blocking agents
There is no evidence that any one TNFα blocking
agent should be used before another can be tried. There
is also no evidence that any TNFα blocking agent is
more effective than any other in RA (category A and B
evidence25 26 30 38 49 113 176 181 191 239 243 248 252 256 257).
2010 Update:
A recent meta-analysis contended that etanercept was
safer than anakinra, adalimumab or infl iximab (category
A evidence243).
Persistence
In long-term observational studies, some patients continue to
respond for up to 10 years. (category C evidence176).
Loss of response to a TNFα blocking agent can occur. Failure
to respond to one TNFα blocking agent does not preclude
response to another (category B, D evidence239 248 252 256 257).
Patients have been switched successfully from one TNFα block-
ing agent to another. Several retrospective and observational
studies suggest the effi cacy of such switches. One recent RCT
supports this regimen (category B, D evidence24 258 259 260).
Information from observational data suggests that primary
non-responding patients are less likely to respond to a sec-
ond TNFα blocking agent. Patients who have not tolerated
one TNFα blocking agent may respond to a second but are
also more likely to have less tolerance of it (category B and D
evidence248 261 262 263). Patients who have responded to a TNFα
blocking agent but have lost response may respond to a second
TNFα blocking agent . The optimal treatment of patients not
responding to TNFα blockers remains to be determined (cat-
egory C evidence141 181 184 189 199 224 232 264).
Patients with high or moderate disease activity at base-
line can respond well to TNFα blocking agents (category C
evidence264 265).
Structural changes
TNFα blocking agents inhibit or reduce radiographic progres-
sion in RA, even in some patients without a clinical response
(category A evidence113 115 117 181 185 187 190 211 247 251 266–269). Better
clinical and radiological outcomes are achieved when TNFα
Indications
Rheumatoid arthritis
In most patients, anti-TNFα agents are used in conjunction
with another DMARD, usually MTX. TNFα blockers have also
been used successfully with other DMARDs, including sulfa-
salazine and lefl unomide. TNFα blocking agents are effective
for the treatment of RA in MTX-naive patients (category A, D
evidence90 113 115 116 180–193). A TNFα blocker can be used as the fi rst
DMARD in some patients (category A evidence90 113 117 180–189 194;
category A, B evidence35 116 117 123 186 190 195–197). Adalimumab, cer-
tolizumab, etanercept and golimumab are approved as mono-
therapy for RA. Infl iximab is only approved for use with MTX
in RA. However, observational data indicate that infl iximab, too,
is sometimes used as monotherapy (category C evidence198–200).
The combination of a TNFα blocking agent and MTX yields bet-
ter results for RA than monotherapy, particularly with respect to
excellent clinical responses and radiological outcomes (category
A evidence90 113 115 180–192 194 195 198–203).
Preliminary data indicate that a triple combination of tradi-
tional DMARDs is clinically as effective as a combination of
MTX plus etanercept (category A evidence158).
Psoriatic arthritis
Based on the demonstration of control of signs and symptoms of
joint and skin disease, improvement of function, QoL and inhi-
bition of structural damage, the available TNFα blocking agents
(adalimumab, etanercept, golimumab and infl iximab) have been
widely approved for the treatment of patients with PsA for whom
conventional treatments have produced an inadequate response.
Effi cacy has been demonstrated both as monotherapy and with
background MTX. (category A, B evidence147 170 171 204–222).
Ankylosing spondylitis
Adalimumab, etanercept, golimumab and infl iximab have been
widely approved for the treatment of active AS that is refractory
to conventional treatments. In clinical trials, the effi cacy of these
TNFα blocking agents improved signs and symptoms, function
and QoL as monotherapy as well as with concomitant second-
line agents, including sulfasalazine or MTX (category A, B evi-
dence196 223–231). There is no evidence that combination therapy
with conventional DMARDs is better than monotherapy.
A recent randomised controlled trial demonstrated no superi-
ority of a combination of MTX with infl iximab versus infl ix-
imab alone in the treatment of active AS over 1 year (category
B evidence771).
Juvenile idiopathic arthritis
Etanercept and adalimumab have been approved for JIA with
a polyarticular course (FDA: ≥2 years for etanercept; ≥4 years
for adalimumab; EMA: age 13–17 years for both) (category
A, B evidence232–239) FDA and EMA approvals) Infl iximab
was benefi cial at 6 mg/kg in polyarticular JIA (category A
evidence232 233 238 239).
2010 Update
A recent meta-analysis of RCTs demonstrated that
etanercept, infl iximab and adalimumab were more effec-
tive than anakinra in RA (category A evidence122).
Clinical use
Rheumatoid arthritis
Dosing
Increasing the dose or reducing the dosing intervals of infl iximab
may provide additional benefi t in RA, whereas increased doses of
etanercept or certolizumab have no increased benefi t at a group
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Consensus statement
Ann Rheum Dis 2011;70(Suppl 1):i2–i36. doi:10.1136/ard.2010.146852i10
for PsA based on a systematic evidence-based review of the effi -
cacy of TNFα blocking agents.216
In addition to effi cacy in joints and skin, effi cacy has been
demonstrated with TNFα blocking agent therapy for enthesi-
tis, dactylitis, function, QoL fatigue, productivity, work dis-
ability and inhibition of structural damage (category A, B, D
evidence170 171 204 206 210 211 213 215 217–222 234 287 288 289–293).
Dose and timing of response
Improvement of signs and symptoms, function and QoL occurs
within 12 weeks. Some patients continue to improve up to
week 24. For etanercept, 100 mg a week for 12 weeks, fol-
lowed by 50 mg a week, was more effective than 50 mg a week
for skin but not arthritis, enthesitis or dactylitis (category D
evidence294).
2010 Update:
In children with PsA, maximal response to etanercept
may take longer than 3 months (category C evidence235).
Comparison of TNFα blocking agents in PsA
A recent meta-analysis of randomised controlled trials suggests
that the effi cacy of TNFα antibodies may be better than that of
soluble receptor with respect to skin manifestations (category A
evidence292).
Switching between TNFα blocking agents in PsA
Preliminary data suggest that one can sometimes achieve
benefi t for PsA-related joint and skin signs and symptoms by
switching to a different TNFα blocking agent, even if effi cacy
from a previous TNFα blocker was never achieved (category C
evidence293).
Persistence
Durability of clinical effi cacy and radiographic data up to 2 years
in PsA has been demonstrated with etanercept, infl iximab and
adalimumab (category A, B, C evidence220 221).
2010 Update
Golimumab 50 and 100 mg given once monthly shows
similar clinical effi cacy for up to 104 weeks.
The golimumab and certolizumab safety profi le is simi-
lar to that seen for other anti-TNF agents (category B
evidence290 295 296).
Ankylosing spondylitis
In clinical trials in patients fulfi lling the modifi ed New York crite-
ria for AS, improvement in signs and symptoms were seen after
treatment with TNFα blocking agents using patient- reported
outcomes (Bath Ankylosing Spondylitis Disease Activity Index,
Bath Ankylosing Spondylitis Functional Index, patient global
VAS, Short Form 36)), spinal mobility measures, peripheral
arthritis, enthesitis and acute phase reactants (category A, B,
D evidence196 223–227 231 297–308). Two recent placebo-controlled
trials have shown signifi cant effi cacy in signs and symptoms in
patients with non-radiographic axial spondyloarthritis (category
A, D evidence299 302) according to the Assessment of Spondylo-
Arthritis International Society criteria for axial spondyloarthritis
(category A evidence298).
Clinical use
Two RCTs failed to demonstrate superiority of a combination
of MTX with infl iximab over infl iximab alone in the treatment
of active AS over 1 year (category B evidence72 196 223). Regular
treatment with infl iximab was more effective than ‘on-demand’
treatment for AS (category A evidence309 310).
Observational studies indicate that switching to a second TNFα
blocking agent may be effective (category B, C evidence306 311).
blockers are used in combination with a traditional DMARD
(category A evidence270).
Pharmacoeconomic data
TNFα blocking agents may be cost effective from a societal per-
spective, although this is highly dependent upon the specifi c cir-
cumstances of the analysis and the society in which the analysis
is done (category B evidence120 182 271–281).
2010 Update in RA:
Golimumab and certolizumab pegol have been recently
approved for the treatment of RA and demonstrated effi -
cacy in clinical trials similar to that of other TNFα block-
ing agents in improving signs and symptoms, physical
function, health-related QoL and reducing252 256 257 the
radiographic progression of patients with RA (category
A evidence282–285). The adverse event profi le is consistent
with that of other TNFα blockers.
Recent data on absenteeism or presenteeism as well
as work productivity have supported the effectiveness of
TNFα blocking agents.7 13 15 22
Juvenile idiopathic arthritis
Dose
TNFα blocking agents, when given up to the maximum approved
dosing regimens for polyarticular JIA, usually lead to an early sig-
nifi cant, documentable improvement in symptoms, signs and/
or laboratory parameters. Etanercept weekly dosing in children
(0.8 mg/kg up to 50 mg weekly) also improves health-related
QoL and reduces disease activity (category B evidence255).
Comparison of TNFα blocking agents in JIA
Etanercept appears less effective in patients with systemic-onset JIA
than in patients with other forms of JIA (category C evidence234–237).
There are now ongoing prospective studies in children aged <4 years;
however, some observational registry data suggest comparable effi -
cacy and safety in JIA not of the systemic-onset subtype, Except for
systemic-onset JIA, there is no evidence that any one TNFα blocking
agent should be used before another one can be tried for the other
JIA subtypes (category D evidence234). In JIA-associated uveitis,
adalimumab and infl iximab appear to be effective more often than
etanercept (category C, D evidence286 287).
2010 Update:
Some observational registry data suggest comparable
effi cacy and safety in polyarticular JIA as in the systemic-
onset subtype (category C evidence235 236).
Switching TNFα blocking agent
Anecdotal studies indicate that TNFα blocking agents may be
successfully switched in JIA (category D evidence237 238).
Persistence
In one small open study, remission occurred in 24% of patients
with systemic JIA but 45% fl ared when the TNFα blocking
agent was stopped (category C evidence234).
Structural changes
TNFα blocking agents contribute to restoration of growth veloc-
ity in children whose JIA-associated infl ammation is controlled.
Bone density improves after treatment with a TNFα blocking
agent even in patients who have incomplete disease control (cat-
egory C, D evidence234–238).
Psoriatic arthritis
The Group for Research and Assessment of Psoriasis and
Psoriatic Arthritis has developed treatment recommendations
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Consensus statement
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Antibodies directed against adalimumab or infl iximab
have been correlated with decreased clinical response in
some patients with AS. This was not found for etanercept
(category C evidence311 318–321). Acute phase reactions
correlate with response (category B evidence313 314).
The importance of adding regular physical therapy to
TNFα blocking agents has been highlighted in a recent
observational trial (category C evidence322).
Safety (arranged alphabetically) across indications
General reviews of the safety of TNFα blocking agents have
been published (category A, B evidence86 90 113 181 184 189 243 251
305 306 323).
Autoimmune-like syndromes
Antiphospholipid and lupus-like syndromes have occurred in
both adult and paediatric patients during treatment with TNFα
blocking agents. Autoantibody formation is common after
TNFα blocker therapy (eg, antinuclear antibodies), but clinical
syndromes associated with these antibodies are rare (category C
evidence282 283).
Cardiovascular
Treatment of non-RA patients with advanced chronic heart fail-
ure with TNFα blockers was associated with greater morbidity/
mortality (infl iximab) or lack of effi cacy (etanercept). Studies that
examined the risk of heart failure in patients with RA treated
with TNFα blockers have shown inconsistent results (category
B evidence261 262 323).
On the other hand, several studies showed decreased cardio-
vascular events (myocardial infarction, stroke or transient
ischaemic attack) (category D evidence261 324 325). Results of
studies evaluating the effect of TNFα blocking agents on lipids
are confl icting (category D evidence318–320 326–329).
2010 Update
A review (category C evidence262 330) and multiple open
studies of TNFα blocking agents have been published
(category C, D evidence329–333). Infl iximab, etanercept
and golimumab are reported to improve lipid and arthro-
genic profi les, reduce arterial stiffness and decrease insu-
lin resistance in comparison with controls. No long-term
studies regarding CVA or death have appeared (category
C, D evidence261 262 318 319 324 326–328 330–336). One long-term
study demonstrated that a reduction in myocardial infarc-
tions was found (category C evidence324 336). To date these
profi les seem to refl ect the degree to which infl ammation
is controlled. Better disease control was refl ected in either
unchanged or improved lipid profi les, whereas incom-
plete control was associated with worsening profi les. The
clinical signifi cance of these changes on cardiovascular
symptoms is unknown.
Haematological
Rare instances of pancytopenia and aplastic anaemia have been
reported (category C evidence262 323). If haematological adverse
events occur, TNFα blocking agents should be stopped and
patients evaluated for evidence of other underlying diseases or
association with concomitant drugs.
Transaminase elevation
Elevated liver function tests have been observed in patients
treated with adalimumab and infl iximab, with ALT/AST
increased in 3.5–17.6% and increased more than twice the upper
limit of normal in up to 2.1 % (category B, D evidence263 337). The
use of concomitant drugs and other clinical conditions confound
2010 Update:
In a head-to-head comparison trial of a conventional
DMARD (sulfasalazine) with a TNFα blocking agent
(etanercept), the latter was more effective (category A
evidence246 312).
There is evidence that the incidence of uveitis fl ares is
reduced when patients are treated with TNFα blocking
agents. There is a trend for TNFα antibodies to reduce
the frequency of uveitis episodes more than etanercept
(category A evidence286 287).
Young patients with active AS and raised CRP levels
responded better to TNFα blocking agents than older patients
without such markers (category A evidence196 301 303 313 314).
However, even in patients with advanced and severe AS, there
is evidence that TNFα blocking agents can be effi cacious (cat-
egory D evidence303 315).
Dosing
The approved doses of TNFα blocking agents for treatment of
AS are 5 mg/kg infl iximab intravenously every 6–8 weeks after
induction; subcutaneous etanercept, 25 mg twice a week or 50
mg once a week; 50 mg subcutaneous golimumab monthly
and 40 mg adalimumab subcutaneously every other week
(category A and B evidence223 224 225 299 316). No dose-ranging
studies have been done with most of these drugs, except for
golimumab, where no major differences in effi cacy and safety
between 50 mg and 100 mg doses were seen (category B
evidence217).
Time to response
Although improvement may be seen more rapidly, a reduc-
tion in signs and symptoms and improvement in function
and QoL will usually be seen by 6–12 weeks in response
to treatment with a TNFα blocking agent (category A
evidence231 309 312).
Comparison of TNF
α
blocking agents in AS
There is no evidence that any TNFα blocking agent is more
effective for musculoskeletal symptoms in AS than any other
(category A, B, D evidence196 223–227 231 297–308).
Persistence
TNFα blocking agents (adalimumab, etanercept, infl iximab)
maintained effi cacy for 2–7 years in open-label studies. The dis-
ease usually fl ares after discontinuation of the blocking agent
(category C evidence298 301–304). When TNFα blocking agents are
restarted, treatment response reoccurs in over 70% (category C
evidence303).
Imaging changes
Several studies have shown that active infl ammation of the
sacroiliac joints and spine, as shown by MRI, is signifi cantly
reduced for up to 3 years by adalimumab, etanercept, infl iximab
and golimumab (category A, B, C evidence302 304 311 316).
Patients with AS who received TNFα blocking agents showed
signifi cant increases in bone mineral density scores (category C
evidence297 298).
Pharmacoeconomic data in AS
The use of TNFα blocking agents may be cost effective in
patients with active AS (category B evidence317).
2010 Update in patients with AS:
The Assessment of Spondylo-Arthritis International
Society has updated its recommendations for the use of
TNFα blocking agents in AS (category C evidence231 297 298).
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Consensus statement
Ann Rheum Dis 2011;70(Suppl 1):i2–i36. doi:10.1136/ard.2010.146852i12
recommendations (category B, C and D evidence). In areas of
high TB prevalence (ie, high-risk populations or in the event of
potential TB exposure) repeat screening should be considered.
(category C evidence349 364 365).
The TST is a diagnostic aid and false-negative results can occur
in the setting of immune suppression (eg, HIV, renal dialysis,
corticosteroid use and RA) (category C evidence276). The TST
can also be falsely positive due to previous BCG vaccination.
New blood-based diagnostic assays (interferon γ release assays)
have been developed using TB-specifi c antigens. These tests
(Quantiferon-Gold In-tube and T-Spot TB) have greater specifi c-
ity for latent TB infection than the TST and therefore might pro-
vide a useful tool in evaluating people for latent TB (particularly
those with history of BCG vaccination). It should be noted that
false-negative results and indeterminate results also occur with
the interferon γ release assays (category C evidence366 367). The
background rate of TB in the population should be considered in
the interpretation of these tests.
The precise role of these tests in diagnosing latent TB in
patients with rheumatoid disease remains under study (category
C evidence361).
Repeat screening should be performed in the event of TB
exposure and should be considered in patients who are at ongo-
ing risk for TB exposure (eg, living or extended travel to endemic
areas (category C evidence349). Local screening guidelines should
be followed. Continued vigilance is required to detect reactiva-
tion of latent TB or acquisition of new cases.
In treating latent TB, the optimal time frame between starting
preventive treatment for latent TB infection and starting TNFα
blocking agents is unknown. Given the low numbers of bacilli
present in latent TB infection, it is likely that long time periods
between initiating preventive treatment and TNF blockade is
unnecessary. Although there are no prospective trials assessing
this question, observational data from Spain suggest that initi-
ating isoniazid therapy 1 month before TNF blockade substan-
tially decreases the risk of latent TB reactivation. (category C
evidence276 362 363). Before starting preventive anti-TB treatment
in accordance with local guidelines, consultation with an infec-
tious disease specialist should be considered.
2010 Update:
There are case reports of reinitiation of TNFα blocking
agents after successful completion of a full course anti-TB
therapy (category C evidence368).
Other opportunistic infections
Other opportunistic infections have been reported in patients treated
with TNFα blocking agents (category C evidence90 113 265 369 370–373).
Particular vigilance is needed when considering patients with infec-
tions whose containment is macrophage/granuloma dependent, such
as those with listeriosis, non-tuberculous mycobacteria (category D
evidence361 372), coccidiomycosis or histoplasmosis (including reacti-
vation of latent histoplasmosis) (category C and D evidence90 113 370
371 373).
A British registry study found that the rate of intracellular
infections among patients with RA treated with TNFα blocking
agents was 200/100 000 and signifi cantly higher than in similar
patients treated with DMARDs or corticosteroids (category C
and D evidence357 369).
Bacterial infections
Serious bacterial infections (usually defi ned as bacterial infec-
tions requiring intravenous antibiotics or hospitalisation) have
also been seen in patients receiving TNFα blocking agents at
rates between 0.07 and 0.09/patient-year compared with 0.01–
0.06/patient-year in controls using other DMARDs (category C
the interpretation of this observation (FDA; category B and C evi-
dence289 337 338–342). The follow-up and monitoring for increases in
liver function test should be governed by the patient’s concomi-
tant drugs, conditions and patient-related risk factors. Worsening
of alcoholic hepatitis has been seen in patients receiving TNFα
blocking agents (category C evidence337).
2010 Update:
Golimumab and certolizumab, like the other TNFα
blocking agents, are subject to liver function test eleva-
tions (category A, C, D evidence295 343–348).
Infections
Tuberculosis
An increased susceptibility for TB or reactivation of latent TB
has been reported for all TNFα blocking agents (category A,B,C
evidence275 276 295 349–368). The risk of TB is also increased by the
use of corticosteroids. There appears to be a higher incidence
of TB in patients using the monoclonal antibodies, infl iximab
and adalimumab, as compared with etanercept (category B, C,
D evidence350 352–354). Although this difference may be due, in
part, to differences in mechanism of action, biology or kinet-
ics as compared with the soluble receptor (category C, D evi-
dence295 350–365), it may also be, in part, due to the fact that
populations treated with the various TNFα blocking agents
differ (eg, higher background rates of TB in some countries)
and the data come from registries and voluntary reporting
systems.
The clinical manifestations of active TB may be atypical in
patients treated with TNFα blocking agents (eg, miliary or extra
pulmonary presentations) as has been seen with other immuno-
compromised patients (category C evidence358 359 360).
2010 Update:
Two recent, large observational studies from the United
Kingdom and France have reported the rates of TB reac-
tivation in patients using adalimumab or infl iximab to be
signifi cantly higher than in patients using etanercept (cat-
egory C evidence353 354).
TB risk data for golimumab and certolizumab are lim-
ited. Trials of golimumab exclude patients with active or
latent TB and cases of TB were uncommon (category B evi-
dence295). In trials of certolizumab there was an increased
incidence of TB relative to controls, but TB screening pro-
cedures were not standardised among sites (category C
evidence176).
In the United States, an area with low TB prevalence, the
majority of mycobacterial infections among TNFα blocker
users were caused by non-tuberculous mycobacteria, with only
35% mycobacterium TB. M avium was as frequently found as
M tuberculosis, and multiple other non-tuberculous mycobacte-
rial infections accounted for the rest of the mycobacterial infec-
tions (category C evidence361).
Screening of patients about to start TNFα blocking agents has
reduced the risk of reactivating latent TB for patients treated
with these agents (category B evidence362 363). Every patient
should be evaluated for the possibility of latent TB, including
a history that should comprise seeking a history of prior expo-
sure, prior drug addiction or active drug addiction, HIV infec-
tion, birth or extended living in a region of high TB prevalence
and a history of working or living in TB high-risk settings such
as jails, homeless shelters and drug rehabilitation centres (cat-
egory B evidence275 358).
In addition, physical examination and screening tests such as
TSTs and chest radiographs should be carried out before treat-
ment with TNFα blocking agents is started, according to local
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Consensus statement
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A recent observational study reported a small increase
risk of herpes zoster with monoclonal antibodies, while
another observational study found no increase in risk
with anti-TNF therapy as a whole and reported signifi -
cantly lower risks for etanercept and adalimumab than for
infl iximab (category D and B evidence277 377).
Injection site/infusion reactions
In placebo-controlled trials, injection site reactions, most of
which were mild to moderate (but some of which resulted in
drug discontinuation) were more common with subcutaneously
administered TNFα blocking agents than with placebo (category
A, B evidence90 113 117 181 265 305 323). One study indicated that
human antichimeric antibodies against infl iximab were associ-
ated with decreased response and increased infusion reactions
(category C evidence285).
Acute reactions after adalimumab, golimumab administra-
tion are uncommon and are usually mild to moderate, but may,
rarely, be serious (category A, B evidence113 180 188 226 347 378). In
most instances, infusion reactions can be treated by the use of
corticosteroids or antihistamines, or by slowing the infusion rate
(category B and C evidence278 285 379).
2010 Update:
Golimumab and certolizumab are associated with a
very low incidence of injection site reactions (category B,
C evidence295 348).
Malignancies
The incidence of lymphoma is increased in chronic infl amma-
tory diseases such as RA. This increase is associated with high
disease activity (category C evidence315 380). In most studies the
risk for lymphoma (especially non-Hodgkin’s lymphoma) is
increased two- to fi vefold in patients with RA as compared with
the general population (category B evidence381–386). A similar
risk is seen in patients with RA who have received TNFα block-
ing therapy (category A, B, C evidence315 323 380–387). It is unclear
if the risk of lymphoma is increased.
While two meta-analyses (with infl iximab and adalimumab)
report a higher rate of solid malignancies, including skin (cat-
egory A evidence388 389), several other large observational data-
bases and a case–control study did not demonstrate an increased
incidence of solid tumours in patients receiving TNFα blocking
agents compared with matched controls (category B, C evi-
dence315 382–386 390–396).
Further studies found no increased risk of solid tumours in
analyses of the same data, in which positive associations were
previously found. (category A, B, C evidence394 395). Neither the
duration of treatment nor the duration of follow-up were associ-
ated with an increased risk of cancer during the fi rst 5 years of
treatment (category B evidence392).
The evidence regarding an increased incidence of non-melan-
otic skin cancers associated with TNFα blocking agents is con-
fl icting (category B evidence381).
In patients with COPD, there may be an increased risk of lung
cancers when treated with TNFα blocking agents. In a trial of
patients with COPD assigned to infl iximab versus placebo, nine
developed lung cancers during the trial and another four lung can-
cers were found during an open-label follow-up (category A evi-
dence396 397). Lung cancer appears to be increased in RA, although
whether this is owing to disease activity or confounding factors
is not known (category C evidence396 397). In a study of Wegener’s
granulomatosis, the use of etanercept with cyclophosphamide
was associated with six solid malignancies versus none in the
cyclophosphamide placebo group (category A evidence393).
evidence112 258 259 260 268). Risk ratios of 1–3 were documented
(category B, C268 269). TNFα blocking agents should not be
administered in the presence of active serious infections and/
or opportunistic infections, including septic arthritis, infected
prostheses, acute abscess, osteomyelitis, sepsis, systemic fungal
infections and listeriosis (category C evidence112 268 270).
Treatment with TNFα blocking agents in such patients may
be resumed if the infections have been treated adequately (cat-
egory D evidence; FDA90 112 113 258–260 268).
Other studies indicate that serious infections in certain sites,
such as the skin, soft tissues and joints, are more common when
using TNFα blocking agents and the risk may be highest during
the fi rst 6 months of treatment. It may be increased further in
elderly patients (category D evidence,270 category C evidence260).
Biological agents and high-dose corticosteroids affect acute
phase reactions (eg, erythrocyte sedimentation rate, CRP)
irrespective of the cause of the infl ammation. Therefore care
needs to be exercised when these measures are used to help
diagnose infection in the presence of these agents (category C
evidence,277 278 category B evidence259 260 374).
The incidence of other bacterial infections (not designated as
serious) may be increased when using TNFα blocking agents
(RR=2.3–3.0, 95% CI 1.4 to 5.1) (category C evidence112 258–260 268).
The incidence of serious infections is approximately doubled
when IL-1 receptor antagonist or abatacept is used with any of
the TNFα blocking agents in combination (category A evidence,
FDA35 36 198 306).
The use of TNFα plus IL-1 blocking agents or abatacept in
combination is not recommended.
2010 Update:
Among patients with JIA in an open study, the rate of
serious infections was not different among MTX, etan-
ercept and etanercept plus MTX groups (category C
evidence20).
Viral infections
Hepatitis
Patients should be screened for viral hepatitis before initiation of
TNFα blocking agents, as the long-term safety of these agents in
patients with chronic viral hepatitis (hepatitis B and C) is not known.
In patients with hepatitis C and RA, several observational studies in
infected patients have shown no increased incidence of toxicity (eg,
raised liver function tests or viral load) associated with TNFα block-
ing agents (category C, D evidence279 289 309 339 340 341 375). Interestingly,
one reported controlled trial of etanercept given adjunctively to stan-
dard anti-HCV therapy was associated with signifi cant improvement
in liver enzymes, viral load and symptoms (category C evidence376).
In hepatitis B, patients treated with adalimumab, etanercept and inf-
liximab have experienced increased symptoms, worsening of viral
load and in some cases hepatic failure (especially after stopping the
TNFα blocking agents ) (category C, D evidence289 339 340 342 375).
Specifi c warnings about hepatitis B reactivation have been
added to the US label by the FDA. Thus TNFα blocking agents
should generally not be used in patients with known persistent
hepatitis B infection. If hepatitis B infection is discovered during
use of TNFα blocking agents, prophylactic antiviral treatment
can be employed (category C evidence376).
2010 Update:
Small cases series have been reported in which
TNFα blocking agents were used in patients with evi-
dence of previous hepatitis B (HBsAb positive, HBsAg
and DNA negative) with only transient elevations in
transaminases and no change in viral load (category D
evidence340).
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Consensus statement
Ann Rheum Dis 2011;70(Suppl 1):i2–i36. doi:10.1136/ard.2010.146852i14
and no transfer of etanercept in breast milk (category D evi-
dence411). These data, if corroborated will help guide advice
to mothers treated with TNFα blocking agents.
Male sexual function
In limited data, sperm volume and function were not different
from normal. Men using TNFα blocking agents can father nor-
mal children, and sexual function seems either unaffected or
improved (category C evidence412).
Pulmonary
Rare instances of acute, severe and sometimes fatal interstitial
lung disease have been reported in patients using TNFα blocking
agents (category C evidence413).
Skin disease
Cases of psoriasis, psoriaform lesions or exacerbation of pso-
riasis have been reported when using all TNFα blocking agents.
In some cases, switching TNFα blocker allowed continuation
of treatment without recrudescence of skin lesions (category D
evidence414–418). Additionally, rare cases of Stevens–Johnson
syndrome, digital vasculitis, erythema multiforme, toxic epider-
mal necrolysis granulomatous reactions in skin and lungs have
been noted (category D evidence379 398 419–423). Hypersensitivity
reactions to TNFα blocking agents were not associated with the
atopic status of the patients, in one small study.
Vaccinations
Appropriate vaccinations should be carried out before initi-
ating treatment with TNFα blockers, according to national
guidelines.
TNFα blocking agents do not usually adversely effect the
development of protective antibodies after vaccination with
infl uenza or polysaccharide pneumococcal vaccine, although
there is a small decrease in the prevalence of adequate protec-
tion and a decrease in the titre of response, especially in combi-
nation with MTX (category A, B evidence280 281 284). Vaccination
with live attenuated vaccines (eg, nasal fl u vaccine, BCG, yel-
low fever, herpes zoster) is not recommended, though vaccina-
tion with MMR with appropriate memory vaccine response has
been reported in patients with JIA treated with etanercept and
MTX (category D424).
OTHER BIOLOGICAL AGENTS
Alefacept is approved in the USA for psoriasis but not PsA.
Alefacept is a fully human fusion protein that blocks interac-
tion between LFA-3 on antigen-presenting cells and CD2 on T
cells, leading to decreased T-cell activation and deletion of cer-
tain T-cell clones. A phase II trial in PsA demonstrated modest
effi cacy in joints and skin at 24 weeks (category B evidence425). A
second course (each course is 12 weekly intramuscular injections
followed by 12 weeks off) during an open-label extension dem-
onstrated sustained articular effi cacy (category A evidence425)
Efalizumab is a humanised monoclonal antibody to the CD11
subunit of LFA-1. It has been removed from the market after
cases of progressive multifocal leucoencephalopathy.
Ustekinumab is an inhibitor of IL-12 and IL-23 which acts
in both the TH17 and TH1 pathways of infl ammation and is
approved for the treatment of psoriasis, given at 0, 4 and then
every 12 weeks subcutaneously (category B evidence426).
CONCLUSION
The treatment of RA and other rheumatic diseases and condi-
tions of altered immunoreactivity has changed dramatically for
The concomitant use of azathioprine with infl iximab in ado-
lescents has been associated with the occurrence of rare hepato-
splenic lymphomas (category C evidence, FDA). It is not currently
known if TNF blockade worsens an underlying malignancy or
increase the risk of recurrence (category B evidence384 394).
Vigilance for the occurrence of lymphomas and other malig-
nancies (including recurrence of solid tumours) remains appro-
priate in patients treated with TNFα blocking agents.
2010 Update:
In JIA, malignancies have been reported in patients
treated with TNFα blocking agents but it is unknown if
the rate of malignancy is increased compared with JIA
itself. Malignancies were seen in a long-term follow up
study of etanercept in JIA (category C and D evidence
FDA letter and Giannini et al236).
After starting TNFα blocking agents, the risk of can-
cer does not increase with time (category B, evidence392).
One study has shown that monoclonal antibodies are
associated with a higher risk of lymphoma than soluble
receptors, but additional confounding factors need to be
examined (category C evidence385).
Certolizumab was not associated with solid malig-
nancies but was associated with lymphoma (category B
evidence296).
Neurological diseases
Rare instances of central and peripheral demyelinating syn-
dromes, including multiple sclerosis, optic neuritis and Guillain–
Barré syndrome, have been reported in patients using TNFα
blocking agents (category C evidence398–407). In some cases, but
not all, these syndromes improved after withdrawal of TNFα
blockers and steroids were given. Accordingly, TNFα blocking
agents should not be given to patients with a history of demy-
elinating disease, multiple sclerosis or optic neuritis (category C,
D, evidence398–407).
2010 Update:
The demyelinating events tend to occur within the fi rst
5–8 months of use (category C evidence400 406).
Risks during pregnancy
The safety of anti-TNF therapy during pregnancy is unknown.
Experts disagree about whether TNFα blocking agents should be
stopped when pregnancy is being considered or whether they
can be continued throughout pregnancy. Some studies found no
increased fetal loss or miscarriages when using TNFα blockers,
while one recent study found an increased rate of spontaneous
abortions (category C, D evidence408–411).
A rare combination of congenital abnormalities (vertebral
abnormalities, anal atresia, cardiac defect, tracheo-oesophageal,
renal and limb abnormalities (VACTERL)) and partial VACTERL
defect have been reported rarely, although the risk and causality
are unclear (category C evidence410).
2010 Update (pregnancy)
See general statement on page i2. According to the US
FDA, this drug class is considered category B, meaning no
evidence of risk in humans. If no adequate human stud-
ies are done, no animal studies have been done or animal
studies show risk but human studies do not.
A systematic review of 667 pregnancies came to the
conclusion that, to date, no defi nite harm to pregnancy
can be ascribed to TNFα blocking agents (FDA category
B evidence89).
A single patient study examined maternal serum, placenta,
breast milk and infant etanercept levels, fi nding an approxi-
mately 3% transfer of etanercept from serum to placenta
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Ann Rheum Dis 2011;70(Suppl 1):i2–i36. doi:10.1136/ard.2010.146852 i15
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the better since the introduction of biological agents into the
armamentarium of the treating physician. It is hoped that this
consensus statement will provide guidance to the clinician in
his/her efforts to improve the QoL of patients with these con-
ditions. In addition, this consensus statement should provide
evidence-based support for the selection of agents and justifi ca-
tion for their use
APPENDICES: CATEGORIES OF EVIDENCE
Category A evidence: based on evidence from at least one
randomised controlled trial or meta-analyses of randomised
controlled trials. Also includes reviews if these contain cat-
egory A references.
Category B evidence: based on evidence from at least one
controlled trial without randomisation or at least one other
type of experimental study, or on extrapolated recommen-
dations from randomised controlled trials or meta-analyses.
Category C evidence: based on non-experimental descriptive
studies such as comparative studies, correlational studies
and case–control studies which are extrapolated from ran-
domised controlled trials, non-randomised controlled stud-
ies or other experimental studies.
Category D evidence: based on expert committee reports or
opinions or clinical experience of respected authorities or
both, or extrapolated recommendations from randomised
controlled trials, meta-analyses, non-randomised controlled
trials, experimental studies or non-experimental descriptive
studies. Also includes all abstracts.
Author affi liations 1University of California at Los Angeles, Los Angeles, California,
USA
2University of Toronto, Toronto, Canada
3Rheumazentrum Ruhrgebiet, Herne, Germany
4Leiden University Medical Centre, Leiden, The Netherlands
5Laboratorio di Reumatologia, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy
6Academic Unit of Musculoskeletal Disease, Chapel Allerton Hospital, Leeds, UK
7University of Texas Southwestern Medical Center, Dallas, Texas, USA
8Rheumatology/Medicine Hospital for Special Surgery, New York, New York, USA
9University of Erlangen-Nuremberg, Erlangen, Germany
10Rheumatology/Allergy Immunology, University of California, San Diego, San Diego,
California, USA
11Rheumatology Department/Guys Hospital, London, UK
12Swedish Medical Center and University of Washington, Seattle, Washington, USA
13Division of Rheumatology, MetroHealth Medical Center/Case Western Reserve
Society, Cleveland, Ohio, USA
142nd Department of Medicine, Krankenhaus Lainz and Department of Rheumatology,
Internal Medicine III, Medical University of Vienna, Vienna, Austria
15Radboud University, Nijmegen Medical Centre, Nijmegen, The Netherlands
16Cedars Sinai Medical Center, Los Angeles, California, USA
17Oregon Health and Science University, Portland, Oregon, USA
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.
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Ann Rheum Dis 2011;70(Suppl 1):i2–i36. doi:10.1136/ard.2010.146852 i29
764. Guignard S, Gossec L, Salliot C, et al. Effi cacy of tumour necrosis factor blockers in
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Table A2 Anecdotal studies using rituximab
Rituximab synopsis
Disease Author, ref no. N: Outcome
ANCA-associated vasculitis
WG Keogh et al435 10: Effective
WG/MPA Stasi et al436 10: 8WG/2MPA: Effective
WG/MPA Eriksson et al437 9: 7WG/2MPA: Effective
WG/MPA Keogh et al438 11: 10WG/1MPA: Effective
WG/MPA/CSS Smith et al439 11: 5WG/5MPA/1CSS: Effective
WG Aries et al440 8: Granulomatous manifestations: Effective
in 3; no response in 3; ineffective in 2
WG Brihaye et al441 8: Refractory/relapsing: Effective
WG Henes et al442 6: Refractory: Effective
WG Golbin et al443 28: Refractory: Effective
WG Sailler et al444 37: WG (3); autoimmune cytopenia19;
autoimmune coagulation disorder5;
cryoglobulinaemia7; pemphigus2; SLE (1)
Effective: Increased incidence of SAE
ANCA vasculitis Lovric et al445 15: Refractory ANCA-associated vasculitis:
Effective
WG Seo et al446 8: Effective
ANCA associated Roccatello et al447 448 7: Effective
WG Martinez et al449 34: Effective
WG Guillevin et al450 21: As effective as infl iximab
WG Ramos-Casals et al451 8: Effective
WG Palm et al452 9: Effective: suppressing infl ammation not
airway stenosis
Refractory WG Cohen et al453 22: As effective as infl iximab
Refractory WG – meningitis Sharma et al454 1: Effective
CSS Dønvik and Omdal455 2: Effective
WG Martinez DelPero M et al456 34: Effective
ANCA vasculitis (children) Eleftheriou D et al457 17: Effective
WG Taylor SR et al458 10: Effective
ANCA vasculitis Brito-Zeron et al459 19: Effective
Stone et al460 197: Effective (similar to Cytoxan)
Hepatitis C-related vasculitis Terrier et al461 32: Effective
Cryoglobulinaemia
Type II HCV-associated Sene et al462 6: Ineffective
Type II and III Sansonno et al463 20: Effective
Continued
774. Sato H, Sakai T, Sugaya T, et al. Tocilizumab dramatically ameliorated life-threatening
diarrhea due to secondary amyloidosis associated with rheumatoid arthritis.
Clin Rheumatol 2009;28:1113–16.
775. Hirao M, Hashimoto J, Tsuboi H, et al. Laboratory and febrile features after joint surgery in
patients with rheumatoid arthritis treated with tocilizumab. Ann Rheum Dis 2009;68:654–7.
APPENDIX 1 ABATACEPT
JIA-associated uveitis may improve with abatacept treat-
ment (category C evidence427).
Table A1 Anecdotal studies using abatacept
Disease Authors Patients (n) Outcome
Ankylosing spondylitis Olivieri et al428 1 Positive
Berner et al429 3 1 Positive
2 Negative
Autoimmune thrombocyotopenia Kloepfer et al430 1 Positive
Gout Puszczewicz et al431 1 Positive
PsA Mease et al432 1 Positive
SLE Merrill et al433 2 1 Negative
1 Positive
Uveitis JIA Zulian et al434 6 Positive
JIA, juvenile idiopathic arthritis; PsA, psoriatic arthritis; SLE, systemic lupus
erythematosus.
APPENDIX 2 RITUXIMAB
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Consensus statement
Ann Rheum Dis 2011;70(Suppl 1):i2–i36. doi:10.1136/ard.2010.146852i30
Table A2 Continued
Rituximab synopsis
Disease Author, ref no. N: Outcome
Type II Zaja et al464 15: 12 HCV: Effective
Type II HCV-associated Quartuccio et al465 5: Effective
Type III Basse et al466 7 : Renal transplant patients : 5 HCV:
Effective
Type II Bryce et al467 8: Essential 1; HCV/SS/LPD 7: Effective
Type II HCV-associated Saadoun et al468 16: Effective
Type II Cavallo et al469 13: Effective
Type II HCV-associated Ramos-Casals et al470 8: Effective
Type II HCV-associated Roccatello et al447 12: Effective
Type II HCV-associated Visentini et al471 6: Effective
Type II HCV-associated Roccatello et al472 6 HCV: 5 had GN: Effective
Type II Brito-Zeron et al459 9: Effective
Mixed Saadoun et al473 38: Effective
Henoch–Schönlein purpura
Donnithorne et al474 3: Effective
Sjögren’s syndrome
Voulgarelis et al475 6: Effective
Dass et al476 17: Effective for fatigue
Pijpe et al477 15: 8 SS and 7 SS/MALT: Effective
Devauchelle-Pensec et al478 16: SS: Effective
Seror et al479 16: SS/NHL: Effective
Gottenberg et al480 6: 4 SS and 2 SS/MALT: Effective
Galarza et al481 8: Effective
Meijer et al482 8: SS/7 MALT: Effective
St Clair et al483 12: SS: Effective
Ramos-Casals et al451 10:Effective
Meijer et al484 30: Effective
Vivino et al485 6: Effective
Ramos-Casals et al470 24: Effective
Tsirogianni et al486 11: Effective
Vasilyev et al487 11: Effective
Pijpe et al488 5: Effective
Brito-Zeron459 15: Effective
Gottenberg et al489 43: Effective
Juvenile idiopathic arthritis
Juvenile autoimmune disease El-Hallak et al490 10: Effective
Juvenile idiopathic arthritis Alexeeva et al491 50: Effective
Systemic lupus erythematosus
SLE Merrill et al433 257: Ineffective
Refractory SLE Tanaka et al492 15: Partially effective
SLE haemolytic anaemia Gomard-Mennesson et al493 26:Effective
Paediatric SLE/LN Haddad et al494 11: Effective
Paediatric SLE MacDermott and Lehman495 ;
Marks and Tullus496
7: Effective
Paediatric SLE/LN Marks and Tullus496 7:Effective
SLE Ng et al497 7: Refractory: Effective 4/7
Refractory SLE Tokunaga et al498 7: Effective
SLE Leandro et al499 6: Effective
SLE Leandro et al500 24: Effective
SLE Looney et al501 17: Effective
SLE Tokunga et al502 5: Effective
SLE Ng et al503 41: Effective
SLE Tanaka et al504 19: Effective
SLE Amoura et al505 22: Effective
SLE Welin-Henriksson et al506 20: Effective
SLE Cambridge et al55 25: Effective
SLE Gillis et al507 6: Effective
SLE Nwobi et al508 18: Effective
SLE Albert et al509 18: Effective
SLE Boletis et al510 10: Effective
SLE Jónsdóttir et al511 512 16: Effective
SLE Lindholm et al513 31: Effective
SLE: thrombocytopenia and haemolytic
anaemia
Lindholm et al514 19: Effective
SLE Melander et al515 20: Effective
SLE Reynolds et al516 11: Effective
SLE Tanaka et al517 15: Effective
Continued
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Consensus statement
Ann Rheum Dis 2011;70(Suppl 1):i2–i36. doi:10.1136/ard.2010.146852 i31
Rituximab synopsis
Disease Author, ref no. N: Outcome
SLE Podolskaya et al518 19: Effective
SLE Ramos-Casals et al451 27: Effective
SLE Ramos-Casals et al451 27: Effective
SLE Lu et al519 45: 19 achieved remission; 21 achieved
partial remission
Paediatric SLE with autoimmune thrombocytopenia
and/or haemolytic anaemia
Kumar et al520 9: Effective
SLE Garcia-Carrasco et al521 52: Effective
SLE Brito-Zeron459 107: Effective
Refractory SLE Gilboe et al522 16: Effective
SLE Terrier et al523 86: Effective
Karpouzas et al524 30: Effective
Refractory SLE Garcia-Carrasco et al521 52: Effective
SLE Karpouzas et al525 35: Effective
SLE + Sjögren’s syndrome Logvinenko et al526 48: Effective
Lupus nephritis
LN Guzman et al527 35: Effective
LN Sangle et al528 16: Effective except in rapidly progressive
crescentic LN
LN Sfi kakis et al529 7: Effective
LN Jónsdóttir et al512 18: Effective
Refractory LN Arce-Salinas et al530 8: Effective
LN Pepper et al531 18: Effective
LUNAR Furie et al532 144: Ineffective
Refractory juvenile-onset Olmos et al533 12: Effective
LN Jónsdóttir et al534 58: Effective
Idiopathic and infl ammatory myopathy/myositis
DM Levine535 6: Effective
DM Chung et al536 8: (partial response)
PM Ramos-Casals et al451 3: Effective
Idiopathic infl ammatory myopathy Sultan537 8: Effective in DM only
DM Rios Fernandez et al538 4: Effective
PM Majmudar et al539 3: Effective
PM Frikha et al540 2: Effective
DM Sánchez-Ramón et al541 1: Effective
Brito-Zeron459 20: Effective
Antisignal recognition particle (Anti-SRP)
myopathy
Valiyil et al542 8: Effective
Behçet disease
Retinal vasculitis Sadreddini et al543 1: Effective
Severe ocular lesions Davatchi et al544 10: Effective
Ocular infl ammatory disease Kurz et al545 4: Effective
Polyneuropathy
IgM antibody associated polyneuropathy Pestronk et al546 21: Effective
Anti-MAG antibodies associated with
polyneuropathy
Renaud et al547 9: Effective
IgM antibody associated with polyneuropathy Levine et al548 5: Effective
Anti-MAG antibodies associated with
polyneuropathy
Benedetti et al549 13: Effective
Anti-MAG antibodies associated with
polyneuropathy
Benedetti et al550 10: Effective
Anti-MAG antibodies associated with
polyneuropathy
Dalakas et al551 13: Effective in 4
Demyelinating diseases of the CNS
Neuromyelitis optica Cree et al552 8: Effective
Relapsing-remitting MS Hauser et al553 69: Effective
Relapsing-remitting MS Bar-Or et al554 26: Effective
Neuromyelitis optica Genain et al555 9: Effective
Neuromyelitis optica Jacob et al556 25: Effective
Multiple sclerosis (primary progressive) Hawker et al557 439: Ineffective
Pemphigus, pemphigoid, epidermolysis bullosa
and other dermatological
BP, PV Schmidt et al558 7: Effective
PV Goh et al559 5: Partially effective
PV Cianchini et al560 12: Effective
Pemphigus Joly et al561 21: Effective
Pemphigus Marzano et al562 6: Effective
Table A2 Continued
Continued
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Consensus statement
Ann Rheum Dis 2011;70(Suppl 1):i2–i36. doi:10.1136/ard.2010.146852i32
APPENDIX 3 IL-1 BLOCKING AGENTS
Rituximab synopsis
Disease Author, ref no. N: Outcome
PV Allen et al563 42: Effective
PV Antonucci et al564 5: Effective
Atopic eczema Simon et al565 6: Effective
Pemphigus Shimanovich et al566 7: Effective
Pemphigus (ocular) Foster et al567 12: Effective
Pemphigus Schmidt E et al568 136: Effective
Pemphigus Pfütze M et al569 5: Effective
Scleroderma
Scleroderma ILD McGonagle et al570 1: Effective
Scleroderma Lafyatis et al571 15: Not effective
Scleroderma skin Smith et al572 8: Effective
Scleroderma pulmonary/skin Daoussis et al573 14: Effective
Antiphospholipid syndrome
Relapsing catastrophic antiphospholipid
syndrome
Asherson et al574 3: Effective
Relapsing catastrophic antiphospholipid
syndrome
Manner et al575 1: Effective
Paediatric CAPS Nageswara Rao et al576 1: Effective
Brito-Zeron459 5: Effective
Autoimmune pulmonary alveolar proteinosis
Borie et al577 1: Effective
Relapsing polychondritis
Leroux et al578 9: Ineffective
Mixed connective tissue disease
Abdelghani et al579 5: Effective
Ankylosing spondylitis
Nocturne et al580 8: Ineffective
Song et al581 20: Effective
ANCA, antineutrophil cytoplasmic antibodies; BP, bullous pemphigoid; CAPS, cryopyrin-associated periodic syndrome; CNS,
central nervous system; CSS, Churg–Strauss syndrome; DM, dermatomyositis; GN, glomerulonephritis; HCV, hepatitis C
virus; ILD, ILD, interstitial lung disease; LN, lupus nephritis; LPD, lymphoproliferative disease; MALT, mucosa-associated
lymphoid tissue; MAG, myelin-associated glycoprotein; MPA, microscopic polyangiitis; MS, multiple sclerosis; NHL,
non-Hodgkin’s lymphoma; PM, polymyositis; PV, pemphigus vulgaris; SAE, serious adverse event; SLE, systemic lupus
erythematous; SS, Sjögren’s syndrome; WG, Wegener’s granulomatosis.
Table A2 Continued
Table A3 Anecdotal studies using interleukin 1 inhibitors
Disease Author, ref no. Patients (n)
Acute stroke Emsley et al588 34
Adult-onset Still’s disease Rudinskaya et al589 1
Lequerré et al590 15
Aelion et al591 2
Haraoui et al592 3
Kalliolias et al593 5
Nordstrom et al594 3
Fitzgerald et al595 4
Vasques Godinho et al596 1
Behçet disease Botsios et al597 1
Continued
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Ann Rheum Dis 2011;70(Suppl 1):i2–i36. doi:10.1136/ard.2010.146852 i33
APPENDIX 4 TNFα BLOCKING AGENTS
Disease Author, ref no. Patients (n)
Tan et al583 1
Consider intra-articular use of anakinra Birmingham et al598 7
Cytophagic histiocytic panniculitis Behrens et al599 1
Diabetes type 2 Larsen et al600 70
Larsen et al601 67
Familial Mediterranean fever Bilginer et al602 1
Mitroulis et al603 1
Moser C et al604 1
Roldan R et al605 1
Gattringer et al606 2
Kuijk et al607 1
Calligaris et al608 1
Belkhir et al609 1
Gout So et al610 10
Gratton et al611 1
McGonagle585 1
Singh et al612 1
GVHD Antin et al613 186
Hyper-IgD syndrome Bodar et al614 3
Rigante et al615
Cailliez et al616 1
Macrophage activation syndrome Kelly et al617 1
Psoriatic arthritis Jung et al618 20
Gibbs et al619 12
Recurrent pericarditis Picco et al620 3
Relapsing polychondritis Vounotrypidis et al621 1
Wendling et al622 1
Buonuomo et al623 1
Schnitzler’s syndrome Besada et al624 24
Systemic lupus erythematosus Moosig et al625 3
Ostendorf et al626 4
TNF receptor-associated periodic
syndrome (TRAPS)
Gattorno et al627 4
Sacré et al628 1
Simon et al629 1
GVHD, graft-versus-host disease; TNF, tumour necrosis factor.
Table A3 Continued
Continued
Table A4 Anecdotal studies of antitumour necrosis factor agents
Disease Author, ref no. Drugs Patients (n)
Adult Still’s disease Huffstutter and Sienknechet630 Infl iximab 2
Kraetsch et al631 Infl iximab 6
Weinblatt et al632 Etanercept 12
Fernández-Nebro633 Etanercept 3
Amyloidosis Elkayam et al634 Infl iximab 1
Gottenberg et al635 Etanercept/infl iximab 15
Ortiz-Santamaria et al636 Infl iximab 6
Tomero et al637 Infl iximab 12
Smith et al638 Etanercept 1
Aphthous stomatitis Robinson and Guitart639 Etanercept 1
Vujevich and Zirwas640 Adalimumab
Atzeni et al641 Etanercept 1
Back pain (including sciatica) Sakellariou et al642 lnfl iximab 1
Genevay et al643 Etanercept 10
Behçet disease Estrach et al644 Infl iximab/adalimumab 7
Gulli et al645 Infl iximab 1
Hassard et al646 Infl iximab 1
Licata et al647 Infl iximab 1
Magliocco and Gottlieb648 Etanercept 20
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Consensus statement
Ann Rheum Dis 2011;70(Suppl 1):i2–i36. doi:10.1136/ard.2010.146852i34
Table A4 Continued
Disease Author, ref no. Drugs Patients (n)
Morillas-Arques et al649 Adalimumab/etanercept
Rozenbaum et al650 Anti-TNF
Saulsbury and Mann651 Infl iximab
Sangle et al652 Infl iximab 1
Sfi kakis et al653 Infl iximab 16
Ribi et al654 Infl iximab 1
Sweiss et al655 Infl iximab 3
van Laar et al656 Adalimumab 6
Bronchiolitis Cortot et al657 Etanercept 1
Cirrhosis and alcoholic hepatitis Naveau et al658 Infl iximab 36
Spahr et al659 Infl iximab 20
Wendling et al342 Infl iximab 1
Menon et al660 Etanercept 13
Cutaneous T-cell lymphoma Tsimberidou et al661 Etanercept 13
Dermatitis, hidradenitis, miscellaneous Bongartz et al388 Infl iximab
Cortis et al662 Etanercept
Cummins et al663 Etanercept
Zeichner et al664 Adalimumab 1
Cusack and Buckley665 Etanercept 6
Dermatomyositis Hengstman et al666 Infl iximab 2
Miller et al667 Etanercept 10
Sprott et al668 Etanercept 1
Nzeusseu et al669 Infl iximab 1
Saadeyh670 Etanercept 4
Norman et al671 Etanercept 2
Erythema nodosum Ortego-Centeno et al672 Adalimumab 1
Familial Mediterranean fever Takada et al673 Etanercept 2
Ozgocmen et al674 Etanercept 1
Felty’s syndrome Ghavami et al675 Etanercept 1
Giant cell arteritis Andonopoulos et al676 Infl iximab 2
Cantini et al677 Infl iximab 4
Tan et al678 Etanercept 1
Ahmed et al679 1
Graft vs host disease (acute) Wolff et al680 Etanercept 21
Uberti et al681 Etanercept 20
Kennedy et al682 Etanercept 20
Chiang et al683 Etanercept 8
Pavletic et al684 Etanercept 4
Andolina et al685 Etanercept 1
Graves ophthalmopathy Paridaens et al686 Etanercept 10
Hepatitis C Cacoub et al687 Interferon 27
McMinn et al688 Etanercept 3
Peterson et al689 Infl iximab/etanercept 24
Pritchard690 Etanercept 1
Ince et al691 Etanercept 12
Moreno et al692 Etanercept 5
Allen and Wolverton563 Etanercept 2
Marotte et al693 Etanercept 9
Rokhsar et al694 Etanercept 1
Magliocco and Gottlieb648 Etanercept 3
HIV immunodefi ciency (common variable) Wallis et al695 Etanercept 16
Smith and Skelton696 Etanercept 1
Lin et al697 Etanercept 1
Cepeda et al698 Etanercept 7
Inclusion body myositis Barohn et al699 Etanercept 9 (ineffective)
Singh et al700 Etanercept 1
Juvenile-onset HLA-B27-associated severe
and refractory heal enthesitis
Olivieri et al701 Adalimumab 1
Kawasaki’s disease Weiss et al702 Infl iximab 1
Burns et al703 Infl iximab 16
Multicentric histiocytosis Lovelace et al704 Etanercept 1
Matejicka et al705 Etanercept 1
Kovach et al706 Etanercept 1
Myelodysplasia Birnbaum and Gentile707 Etanercept 1
Deeg et al708 Etanercept 14
Rosenfeld and Bedell709 Etanercept 19 (ineffective)
Raza et al710 Etanercept 26
Continued
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Consensus statement
Ann Rheum Dis 2011;70(Suppl 1):i2–i36. doi:10.1136/ard.2010.146852 i35
Disease Author, ref no. Drugs Patients (n)
Maciejewski et al711 Etanercept 16
Osteoarthritis (erosive) Magnano et al712 Adalimumab 12
Periodic fever (children) Athreya et al713 Etanercept 3
Pigmented villonodular synovitis Kroot et al714 TNF blocking agent
Polychondritis Carter716 Infl iximab 1
Ehresman717 Etanercept 5
Polymyositis Hengstman et al666 Infl iximab 2
Sprott et al668 Etanercept 1
Adams et al715 Adalimumab 2
Pyoderma gangrenosum Fonder et al718 Adalimumab 1
Sacroiliitis ankylosing spondylitis Heffernan et al719 Adalimumab 1
SAPHO syndrome Anker and Coats720 lnfl iximab/etanercept 150
Sweiss et al721 Infl iximab 3
Callejas-Rubio et al722 Adalimumab 1
Korhonen et al723 Infl iximab 12
Korhonen et al724 Infl iximab 40
Lam et al725 Infl iximab 18
Pasternack et al726 Etanercept 4
Tobinick and Davoodifar727 Etanercept 43
Khanna et al728 Etanercept 1
Utz et al729 Etanercept 17
Wagner et al730 Etanercept 2
Moul and Korman731 Adalimumab 1
Sarcoidosis Khanna et al728 Etanercept 1
Utz et al729 Etanercept 1
Heffernan and Smith732 Adalimumab 1
Callejas-Rubio722 Adalimumab 1
Querfeld733 Etanercept 1
Sweiss et al655 Etanercept 1
Hobbs734 Etanercept 1
Scleroderma Ellman et al735 Etanercept 8
Bosello et al736 Etanercept
Silicone granulomas Pasternack et al726 Etanercept 4
Sjögren’s syndrome Zandbelt et al737 Etanercept 15 (ineffective)
Sankar et al738 Etanercept 14(ineffective)
Pessler et al739 Etanercept 1
Still’s disease (includes adult onset) Fautrel et al740 Etanercept 20 (ineffective)
Stern et al741 Etanercept 1 (worsening)
Asherson et al742 Etanercept 1
Kumari and Uppal743 Etanercept 1
Sweet’s syndrome Gindi et al744 Etanercept 1
Yamauchi et al745 Etanercept 24
Systemic lupus erythematosus Aringer et al746 Infl iximab 6
Fautrel et al740 Etanercept 1 (SCLE)
Lurati et al747 Etanercept 1
Norman et al671 Etanercept 1 (SCLE)
Hernandez-Ibarra et al748 N/A –
Principi et al749 Infl iximab 1
Takayasu’s arteritis Hoffman et al750 Anti-TNF 15
Della Rossa et al751 Infl iximab 2
Tato et al752 Adalimumab 1
TRAPS Hull et al753 Etanercept >50
Lamprecht et al754 Etanercept 2
Drewe et al755 Etanercept 1
Estrach et al644 Infl iximab/adalimumab 7
Joseph et al756 Infl iximab 5
Smith et al757 Etanercept 7
Braun et al758 Etanercept/infl iximab 717(uveitis in AS)
Foster et al759 Etanercept 20 (ineffective)
Biester et al760 Adalimumab 18
Foeldvari et al286 Anti-TNF 47
Vazquez-Cobian et al761 Adalimumab 14
Reiff et al762 Etanercept 10
Schmeling and Horneff763 Etanercept 20 (ineffective)
Guignard et al764 Adalimumab 8
Table A4 Continued
Continued
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Consensus statement
Ann Rheum Dis 2011;70(Suppl 1):i2–i36. doi:10.1136/ard.2010.146852i36
Disease Author, ref no. Drugs Patients (n)
Vasculitis* Booth et al765 Infl iximab 32
Feinstein and Arroyo766 Etanercept 1
van der Bijl et al767 Infl iximab 11
Saji and Kemmotsu768 Infl iximab 1 (Kawasaki’s
disease)
Sangle et al652 Infl iximab 1 (Churg–Strauss)
Arbach et al769 Etanercept/infl iximab 3
Wegener’s granulomatosis Gause et al770 Infl iximab 10
Sangle et al652 Infl iximab 3
Table A5
Disease Authors Patients (n) Outcome
Reactive arthritis Tanaka et al772 1 Positive
Amyloidosis Nishida et al773 1 Positive
Sato et al774 1 Positive
After joint surgery Hirao et al775 ?
Table A4 Continued
APPENDIX 5 ANECDOTAL STUDIES USING TOCILIZUMAB
Tocilizumab to include iritis (JIA) in a dose of 8 mg/kg every
2 weeks (category A evidence134) and in polyarticular JIA (cat-
egory A, D evidence132).
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doi: 10.1136/ard.2010.146852
2011 70: i2-i36Ann Rheum Dis
D E Furst, E C Keystone, J Braun, et al.
diseases, 2010
agents for the treatment of rheumatic
Updated consensus statement on biological
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