Current Rheumatology Reviews, 2011, 7, 77-87

77

Choice of Biologic Therapy for Patients with Rheumatoid Arthritis: The

Infection Perspective
Filip De Keyser*
Department of Rheumatology, Ghent University, Belgium
Abstract: Biologicals revolutionized the treatment of Rheumatoid Arthritis (RA). The targeted suppression of key
inflammatory pathways involved in joint inflammation and destruction allows better disease control, which, however,
comes at the price of an elevated infection risk due to relative immunosuppression. The disease-related infection risk and
the infection risk associated with the use of TNF- inhibitors (infliximab, adalimumab, etanercept, golimumab and
certolizumab pegol), rituximab, abatacept and tocilizumab are discussed. Risk factors clinicians need to take into account
when selecting the most appropriate biologic therapy for RA patients, as well as precautions and screening concerning a
number of specific infections, such as tuberculosis, intracellular bacterial infections, reactivation of chronic viral
infections and HIV are reviewed.

Keywords: Rheumatoid arthritis, infection, biologicals, targeted therapies, TNF inhibitors.

INTRODUCTION
The introduction of biological therapies targeting specific
inflammatory mediators revolutionized the treatment of
rheumatoid arthritis (RA). Targeting key components of the
immune system allows efficient suppression of the pathologic inflammation cascade that gives rise to RA symptoms
and subsequent joint destruction. As flip side of the coin,
treatment with biologicals leaves the patient more susceptible to infection by inducing a certain extent of immunosuppression.
The expanding compendium of targeted therapies for RA
includes inhibitors of TNF- (infliximab, adalimumab,
etanercept and the newer antibodies golimumab and certolizumab pegol), rituximab which targets the B-cell specific
CD 20 antigen, the T cell costimulation inhibitor abatacept
and the IL-6 receptor inhibitor tocilizumab. Although much
remains to be discovered about the precise mechanisms of
increased infection risk under biologic therapy, it is clear that
clinical differences with respect to type and frequency of
infectious complications exist between the different
compounds.
This article aims to summarize literature data on compound-related and disease-related infection risk factors that
clinicians need to take into account when selecting the most
appropriate biologic therapy for their RA patients. The risk
of serious infections associated with different biologicals is
discussed, followed by risks and precautions needed under
biological therapy with respect to a number of specific infections, such as tuberculosis, intracellular bacterial infections,
reactivation of chronic viral infections and HIV.
DISEASE-RELATED RISK OF INFECTION
RA is known to be associated with an increased risk of
infection [1,2], although it is difficult to distinguish the
*Address correspondence to this author at the Department of Rheumatology,
Ghent University Hospital 0K12, De Pintelaan 185, B-9000 Ghent,
Belgium; Tel: +32 9 332 22 30; E-mail: filip.dekeyser@ugent.be
1573-3971/11 $58.00+.00

infection risk associated with the disease per se from the

therapy-associated infection risk. Older studies suggest that
RA intrinsically entails an elevated susceptibility to infection
[3], probably through RA-associated changes in the cellular
immune response [2]. A large population-based retrospective
study comparing RA patients with matched controls reported
a nearly doubled incidence of documented infections in RA
patients [1]. RA severity indices, such as presence of rheumatoid factor, increased sedimentation rate and extraarticular involvement are predictors of serious infection
episodes in RA, in addition to corticosteroid use and the
presence of comorbidities [4]. Infection is also partly
responsible for the excess mortality rate in RA patients, with
infection-related standardised mortality rates in RA patients
ranging from 4.2 to 14.9 [5].
THERAPY-RELATED RISK OF INFECTION
General Appraisal of Serious Infection Risk
The infection risk associated with RA treatment should
always be evaluated against the background of the
intrinsically increased baseline risk of infection in RA
patients.
Corticosteroids, some disease-modifying antirheumatic
drugs (DMARDs) and targeted biologic therapies all have a
negative impact on the capacity of RA patients to mount an
adequate immune response and therefore superimpose additional infection risk to the intrinsically increased infection
susceptibility of this patient population.
Corticosteroids are well-known to increase infection risk
by inducing immunosuppression. The degree to which they
suppress immune competence increases with the dose and
duration of treatment. Treatment for longer than 2 weeks
with over 20 mg/day of prednisolone or equivalent is commonly considered to induce clinically significant immunosuppression [6], whereas a meta-analysis showed that cumulative doses below 500 mg or mean daily doses below 10 mg
do not increase the risk of infectious complications and can
be considered as not immunosuppressive [7].
2011 Bentham Science Publishers Ltd.

78 Current Rheumatology Reviews, 2011, Vol. 7, No. 1

Corticosteroids and combination therapy of corticosteroids and conventional DMARDs were shown to increase the
risk of serious infections in RA patients, but non-biological
DMARD therapy without corticosteroids was not associated
with increased incidence of infection [4,8], although some
DMARDS (methotrexate, azathioprine, leflunomide, cyclophosphamide, cyclosporine) have well-known negative
effects on the immune system. Hydroxychloroquine, sulfasalazine, and gold salts do not have immunosuppressive
effects.
Biological therapies specifically inhibiting targeted molecules of the immune system allow far better disease control,
at the expense of an increased risk of infections (reviewed in
[9]).
Most of the available data on the infection risk of
targeted therapies concern inhibitors of tumor necrosis factor
alpha (TNF-), which have been in clinical use the longest,
while information on the newer biologicals is much more
limited. Infectious complications of biological therapy include bacterial infections, such as tuberculosis, Streptococcus
pneumoniae and Listeria monocytogenes and potential
reactivation of viral infections such as hepatitis B or C,
herpes and varicella zoster.
TNF Inhibitors
TNF- is a cytokine secreted by macrophages in
response to inflammatory stimuli and is involved in immune
regulation and inflammation as well as in sepsis, apoptotic
cell death and cancer. TNF inhibitors were the first class of
biological agents on the market for the treatment of RA, with
the first agent etanercept introduced in 1998, so we can now
look back on a decade of clinical experience with these
products. Most of the data available concern the first three
products of this therapeutic class: etanercept, a recombinant
soluble decoy TNF-receptor; infliximab, a chimeric monoclonal anti-TNF antibody; and adalimumab, a fully human
anti-TNF monoclonal antibody. Studies directly comparing
the different TNF-inhibitors are lacking, but a recent network meta-analysis covering Cochrane reviews on different
biologicals for RA found a reduced therapy withdrawal rate
for adverse events under etanercept as compared with
infliximab and adalimumab [10].
Although the incidence of infections and serious infections (defined as life-threatening, requiring hospitalization or
intravenous antibiotics) in the randomized controlled registration trials of the first 3 TNF inhibitors etanercept, infliximab and adalimumab mostly did not report significant
increases in infection risk with these products in comparison
with controls [9], epidemiological studies as well as registry
data have revealed increased incidences of infection with
these compounds (reviewed in [9]).
A meta-analysis of serious infections in 9 randomized
controlled trials with the anti-TNF antibodies infliximab and
adalimumab found an odds ratio of serious infections of 2.01
(95% CI 1.31-3.09) for patients treated with anti-TNF antibodies for at least 12 weeks, in comparison with a control
population treated with placebo or placebo in combination
with DMARDs [11]. These findings contrast with a more
recent and broader (including etanercept) meta-analysis by

Filip De Keyser

Leombruno et al., who report only non-significant increases

in serious adverse event and infection rates under anti-TNF
therapy [12]. These discrepancies may be explained by
different study inclusion criteria, but also by the inclusion of
more recent trials, where increased awareness of possible
infectious complications with anti-TNF therapy led to more
stringent patient screening and selection.
In the German RABBIT registry study the relative risks
for serious infection was 2.82 (95% CI 1.45.9) in etanercept-treated patients (corresponding to 15.73 [95% CI 12.6
19.7] episodes/100 patient-years) and 2.70 (95% CI 1.35.9)
under infliximab treatment (corresponding to 20.59 [95% CI
16.226.2] episodes/100 patient-years) in comparison with
patients treated with conventional DMARDs, where the
incidence rate of serious infections was 5.08 (95% CI 3.5
7.3) per 100 patient-years [13]. In the British Society for
Rheumatology Biologics Register, overall serious infection
rates during anti-TNF therapy compared with DMARD
treatment were not increased (IRR 1.03, 95% CI 0.681.57),
but in contrast anti-TNF therapy increased the rate of serious
skin and soft tissue infections (IRR of 4.28, 95% CI 1.06
17.17) [14]. A Swedish observational study reported an
increased relative risk for hospitalisation due to infection
during the first year of anti-TNF treatment, which subsided
with increasing duration of treatment [15].
A systematic retrospective analysis in a tertiary clinical
center revealed an increased incidence of serious infections
during the first course of anti TNF-therapy (10.5 +/- 86.9 per
100 patient-years, in comparison with 3.4 +/- 38.7 before
TNF-therapy), with a number needed to harm of 14 [16]. A
recent Italian registry study reported an incidence rate of
3.59 serious infections per 100 patient-years (95% CI 2.774.41) in the first 36 months of anti-TNF therapy, without
significant differences in incidence and type of infection
between the different anti-TNF agents [17].
A recent study using data from the North American
CORRONA registry indicates that MTX and TNF inhibitor
therapy and the combination of both are all associated with a
comparable increase in the incidence of overall infections as
well as opportunistic infections [18].
Data on the infectious complication risk with the newer
TNF-inhibitors golimumab and certolizumab are still limited. Golimumab is a fully human anti-TNF monoclonal antibody, whereas certolizumab pegol consists of a humanized
Fab-fragment fused to polyethylene glycol (PEG) moiety.
Replacement of the Fc-fragment by PEG may avoid Fcmediated side effects such as complement activation, may
contribute to its preferential distribution to inflamed tissues
and increases the half-life of certolizumab pegol to 14 days.
RCTs with golimumab (reviewed in [19]) report serious
infection rates of 0.98 to 2.44 percent over 24 weeks [20-22],
with one study observing serious infections in 2.19% of
patients over a one-year period [23]. These figures are in
range with what has been reported for other anti-TNF agents.
In the FAST4WARD study, monotherapy with certolizumab
pegol yielded a serious infection incidence rate of 1.8%,
whereas combination of certolizumab with MTX induced
serious infections in 2.85 and 4.99% of treated patients
[24,25].

Choice of Biologic Therapy for Patients with Rheumatoid Arthritis

Rituximab
Rituximab is a genetically engineered chimeric monoclonal antibody that targets CD20-positive B cells. By
binding to CD20, rituximab depletes subpopulations of peripheral B cells through different mechanisms, including cellmediated and complement-dependent cytotoxicity and promotion of apoptosis. B cells can contribute to the initiation
and maintenance of the inflammatory cascade in RA by acting on antigen presentation by T cells and through production of pro-inflammatory cytokines and auto-antibodies.
The incidence of serious infections under rituximab
treatment appears to be rather limited: 1.27 to 2.27% over 24
weeks [26,27], 4.96% over 48 weeks [28]. A recent metaanalysis reported that the overall pooled odds ratio for
serious infection under rituximab treatment was not significantly increased (OR 1.45, 95% CI 0.56-3.73) [29]. All
serious infections occurred in patients treated with the
highest (2 times 1000 mg) dose of rituximab [29]. Although
the overall increase in infection risk under rituximab seems
to be limited, rituximab treatment has been associated with
rare cases of progressive multifocal leukoencephalopathy
(PML) (read further).
Abatacept
The T cell costimulation modulator abatacept is a fully
human soluble fusion protein that consists of the extracellular domain of human CTLA-4 linked to the modified Fc
portion of human IgG1. Upon antigen recognition T cells
require a costimulatory signal for full activation. Like the
natural CTLA4 molecule, abatacept interferes with the
CD80/CD86 binding to T cell CD28 with higher avidity than
CD28.
The limited data available on abatacept suggest that the
risk of serious infections with these products may be more
limited than that of the TNF inhibitors. Abatacept phase III
RCTs reported serious infection incidences of 2.33% [30]
and 2.39% [31] over 26 weeks, and 2.54% [32] to 3.13%
[33] over one year. A five year extension of a 1 year double
blind RCT reported 3.0 serious infections per 100 patientyears over the whole study period, versus 2.1/100 patientyears in the first year of the study [34]. In the ATTEST trial
which compared the efficacy and safety of infliximab and
abatacept plus MTX in patients with insufficient response to
MTX alone, considerably lower rates of serious infections
were observed under abatacept treatment (1.9 versus 8.5%)
[35] A recent meta-analysis by Salliot et al. found that
abatacept did not significantly increase the risk of serious
infections in RA patients [29].
The incidence of serious infection episodes does not
increase with prolonged abatacept treatment, as evidenced by
the open label extension studies of the AIM trial, reporting
4.3 [36] and 3.0 [34] serious infections per 100 patient-years
after 2 and 5 years of treatment, respectively, in comparison
with 4.2 serious infections per 100 patient-years observed in
the 1 year double blind phase of the study [37,38].
Combination of abatacept with etanercept yielded little
clinical benefit, but did increase the incidence of serious
infections (3.5% in the combination group versus 0% in the
etanercept group) [39]. This study confirmed earlier findings

Current Rheumatology Reviews, 2011, Vol. 7, No. 1

79

that abatacept in combination with another biological agent

increased the incidence of serious adverse events, including
serious infections [33].
Tocilizumab
Tocilizumab is a humanised monoclonal antibody targeting the interleukin-6 receptor, which can be found both on
cell surfaces and in the circulation. Tocilizumab blocks the
downstream effects of IL-6, a cytokine with pleiotropic
effects that contributes to the inflammation cascade in RA,
by affecting the function of neutrophils, T cells, B cells,
monocytes, and osteoclasts. Additionally, IL-6 is a potent
inducer of the hepatic acute phase response.
The risk of serious infections under tocilizumab
treatment reported in RCTs is relatively low, with figures
reported ranging from 2.29 to 9.98 per 100 patient-years
[40]. However, a number of these studies excluded patients
with a history of infections or increased infection risk, so
further evidence from clinical practice or registry studies is
needed in order to assess the real-life infection risk
associated with tocilizumab.
SPECIFIC INFECTIONS
THERAPY

UNDER

BIOLOGICAL

The most common sites of infections associated with

biological therapy are respiratory tract infections - including
pneumonia - septic arthritis, skin and soft tissue infections,
and urinary tract infections [9]. As TNF plays an important
role in the host defense mechanism against intracellular
pathogens [41,42], anti-TNF therapy is associated with
increased risk of infection with intracellular micro-organisms, such as Mycobacterium tuberculosis, Listeria monocytogenes and Legionella pneumophila.
Intracellular Bacterial Infections
Biological therapies for RA are associated with an
increased risk of tuberculosis, mainly by reactivation of a
latent Mycobacterium tuberculosis infection. The impact of
biological therapies on tuberculosis risk must, however, be
evaluated against the background of increased incidence of
tuberculosis (TB) due to RA itself and regional differences
in exposure to Mycobacterium tuberculosis [43-46]. Conventional DMARDs and corticosteroids are also associated
with an increased risk of tuberculosis [47].
A Swedish study over the period 2000-2001 reported a 4fold increase in TB risk for RA patients treated with TNF
antagonists [48], whereas a Korean study observed a relative
risk of TB of 8.9 for RA patients and 30.1 for RA patients
treated with infliximab in comparison with the general
population [49]. In the Spanish biologicals register
BIOBADASER, annual TB incidence rates of 1893 and
1113 per 100 000 were reported in the year 2000 and 2001
respectively, in anti-TNF treated RA patients, in comparison
with 95/100 000 in RA patients not treated with TNF
inhibitors and 20/100 000 in the general population [50,51].
Reactivation of latent tuberculosis emerged as an adverse
event from early clinical experience with the first generation
TNF antagonists (reviewed in [52,53]), concurrent with the
important role of TNF in the immune response to myco-

80 Current Rheumatology Reviews, 2011, Vol. 7, No. 1

bacteria [54,55]: TNF stimulates phagocytosis of mycobacteria by macrophages and enhances mycobacterial killing in
concert with IFN-, is crucial in recruitment of inflammatory
cells and stimulates chemokine production [59,60]. TNF
further plays a key role in confining mycobacteria to
granulomas and achieving a latent state of the disease, which
may explain both the timing of disease reactivation,usually
observed within the first months of treatment, and the
difference between the different TNF antagonist, which
display different kinetics leading to different TNF bioavailability in granulomatous tissue [56,57].
Later trials with newer biologicals have used TB screening and prophylaxis or excluded patients with evidence of
previous TB exposure and hence reported much lower TB
incidence rates. The impact and importance of TB screening
and prophylaxis is further illustrated by the drastic decrease
in TB cases after implementation of TB screening and
prophylaxis guidelines [50,58]. The majority of TB cases in
anti-TNF treated patients afterwards were due to incorrect
implementation of TB screening and prophylaxis guidelines
[42,50]. TB risk with the anti-TNF antibodies infliximab and
adalimumab is higher than with the fusion protein etanercept
[42]. A recent study presenting long-term follow-up data on
patients with TB as a complication of TNF blocker therapy
shows that biological therapy can be safely resumed after
adequate treatment of TB [41].
The tuberculosis risk associated with rituximab is currently unknown. No tuberculosis was reported in rituximab
RCTs [26-28]. The consensus statement on the use of
biologicals in RA warns against the use of rituximab in the
presence of serious or opportunistic infections [59], but some
case reports described the use of rituximab without adverse
consequences in patients with a history of active TB [60,61].
The risk for TB reactivation associated with abatacept
therapy currently remains unknown, but one case of
tuberculosis has been observed in phase III trials with this
drug [32]. Although the B7/CD28 T cell costimulation
pathway plays a role in the granulomatous response to
mycobacterium infection [62], abatacept did not exacerbate
mycobacterium tuberculosis infection in mice, in contrast
with anti-TNF treatment [63]. The clinical significance of
these experimental findings remains to be investigated,
however. Therefore, TB screening prior to abatacept therapy
is recommended until the TB reactivation risk is known [59].
For the recently introduced IL-6 receptor antagonist
tocilizumab the risk of tuberculosis reactivation appears to
be low. No cases of tuberculosis reactivation under tocilizumab treatment were reported up to now [40,64-69], despite
the fact that most clinical trials with tocilizumab did not
perform tuberculosis screening or prophylaxis and tuberculosis was an exclusion criterion in only two trials [68,69].
In view of the well-established role of IFN- production in
the antituberculosis immune response [70], in vitro findings
that tocilizumab, in contrast with infliximab and etanercept,
does not impair IFN- production in response to mycobacterial antigen exposure [71], and Mycobacterium tuberculosis-induced interleukin 6 inhibits the responsiveness of
macrophages towards IFN- [72], may suggest a low risk for
TB reactivation during tocilizumab therapy. The clinical
significance of these experimental findings remains to be
investigated, however. As available clinical data on

Filip De Keyser

tuberculosis risk under tocilizumab treatment are too limited

to estimate the TB risk for this compound, screening for TB
according to local practice before initiating tocilizumab
therapy is recommended [59].
In addition to the risk of TB reactivation, biological
therapy is also believed to increase the risk of nontuberculous or atypical mycobacterial infections, including M.
avium complex, M. chelonae, M. marinum and M. abscessus.
Nontuberculous mycobacteria are ubiquitously found in
water and soil and known to cause lung infections in patients
with underlying lung disease, skin and soft tissue infections
and disseminated disease in severely immunocompromised
patients [73]. Published data on atypical mycobacterial
infections under biological therapy are scarce, with the FDA
surveillance system reporting an incidence lower than TB
under anti-TNF therapy [74,75], whereas the Emerging
Infections Network of the Infectious Disease Society of
America suggested a higher incidence than that of TB in
patients receiving TNF inhibitors. A possible explanation for
this difference may be that TB incidence is declining due to
screening and prophylaxis for TB, which has no effect on
atypical mycobacteriosis [73]. Most cases of nontuberculous
mycobacteriosis were observed in patients treated with
infliximab and more than half of the cases presented with
pulmonary disease [73].
Tubach et al. reported a series of pneumonia cases by
infection with the intracellular bacteria Legionella
pneumophila in patients treated with TNF inhibitors. 5 out
of 11 cases developed acute respiratory distress syndrome,
but all recovered with appropriate antibiotic therapy. The
relative risk of legionella infection in RA patients treated
with anti-TNF compounds was calculated to be between 16.5
to 21.0 in comparison with the overall risk in France [76].
Cases of infection with the gram-positive intracellular
pathogen Listeria monocytogenes have been reported for all
three first generation TNF antagonists [77-79]. Listeriosis in
patients treated with TNF inhibitors can present as septic
arthritis [77,80,81], meningitis [82,83] or sepsis [79,84].
Slifman et al. report 15 cases of Listeria infection associated
with anti-TNF treatment in the FDA postmarketing
surveillance system, 6 of them fatal, mainly in association
with infliximab treatment (14/15 cases). They estimated the
US annual incidence of Listeria infection to be 43 per
million in anti-TNF treated patients, versus 13 per million in
the general population aged over 60 [85]. Experimental
evidence indicates that TNF signaling plays a central role in
the complex host resistance to listeria infection [86,87]. To
date there are no reports linking the newer biologicals
golimumab, certolizumab or abatacept with listeria infection.
A single case reports describes listeriosis and hepatitis B
reactivation in a leukemia patient treated with chemotherapy
and rituximab [88].
In view of the serious course of listeria infections in
immunocompromised patients, Slifman recommends physicians to advise patients receiving immunosuppressant therapy, including anti-TNF compounds, to avoid or adequately
heat foods that are potential sources of L. monocytogenes
[85]. Visceral leishmaniasis represents a rare complication
of biological treatments, which should be suspected in
patients with fluctuant fever, pancytopenia and splenomegaly, especially if coming from endemic areas.

Choice of Biologic Therapy for Patients with Rheumatoid Arthritis

Salmonella Infection
A number of case reports indicate that treatment with
TNF inhibitors may lead to an increased susceptibility for
infection with different salmonella species [89-91]. A
Spanish cohort study found the risk of non-typhi salmonellosis in RA patients treated with biologicals at 0.73/1000
patient-years not significantly increased in comparison with
either RA patients not treated with biologicals or controls
from the same region without RA. However, the fact that
9/17 reported cases of salmonella infection in patients under
biological therapy had severe systemic infection, suggests
that biological therapy may predispose RA patients to a more
serious course of disease in case of Salmonella infection
[92].
Viral Infections
The immunosuppressive effects of biological therapies
have also been associated with increased risk for reactivation
of chronic viral infections, such as hepatitis B and C, herpes
zoster and even PML.
TNF- plays an important role in the host antiviral response, so anti-TNF treatments may theoretically increase the
reactivation risk of chronic viral infections. Polymorphisms
in the TNF- promoter, leading to inadequate TNF secretion,
have been shown to adversely influence the outcome of
hepatitis B infection [93]. Moreover, imbalance between
TNF- and IFN- impairs viral clearance and promotes
evolution towards chronic infection [93,94]. A recent metaanalysis reported no such association of TNF gene
polymorphisms and the susceptibility to hepatitis C infection
[95], although TNF production was shown to be activated in
hepatitis C infection [96].
In spite of the intrinsic underlying risk of hepatitis
reactivation, biological agents represent an attractive therapeutic answer to the therapeutic challenges posed by RA
patients with concurrent hepatitis, in view of the well-known
hepatotoxic side effects of a number of conventional
DMARDs, such as MTX and leflunomide.
A number of case reports alerted clinicians to the
potential danger of reactivation of hepatitis B under antiTNF therapy, with sometimes serious consequences, like
death or liver transplantation [97-99]. Available data on
reactivation of hepatitis B under anti-TNF therapy mainly
come from case reports and retrospective studies with a
limited number of patients [99]. Chung et al. reported
hepatitis B reactivation in 1 out of 8 HBsAg carriers with
normal liver function and undetectable viral load [100].
Roux et al. found no increase in viral load in 3 patients with
chronic antiHBc positive hepatitis B concurrently treated
with anti-TNF and lamivudine [101]. None of the three
patients with hepatitis B (treated with etanercept or
adalimumab without antiviral prophylaxis) in the case series
of Li et al. experienced rises in serum transaminases or
hepatitis B viral load [102]. Kaur et al. reported no negative
effects on liver histology after 4 months of adalimumab
therapy in a patient with a transient rise in hepatitis viral load
[103]. Hepatic side effects and reactivation of viral hepatitis
have been more frequently reported for infliximab than for
either adalimumab or etanercept. This may be due to the
structural differences between these compounds [99].

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81

Reactivation of viral hepatitis B has also been described

in association with B cell depletion by rituximab treatment,
mainly in an oncological setting [88,104].
Information on tocilizumab and hepatitis is limited to a
case report describing long-term (6.5 years) tocilizumab
therapy without adverse consequences in a patient who was
later discovered to be a hepatitis B carrier [105]. The effect
of inhibition of IL-6 signalling on the course of viral
hepatitis remains to be elucidated, since IL-6 has been
implicated in both hepatitis B related hepatocellular injury,
as well as in hepatitis B viral clearance [105].
The risk of hepatitis reactivation of the newer TNF
inhibitors, golimumab and certolizumab pegol, are still
unknown, as is the hepatitis B risk under abatacept
treatment.
Hepatitis C reactivation under biological therapy has
been described. Several retrospective studies reported no
hepatitis C reactivation in a series of patients treated with
infliximab or etanercept [106-110]. Li reports one patient
with an increased viral load after switching from etanercept
to infliximab [102], whereas the study of Cansu et al.
describes reactivation in 2 out of 4 patients [111]. In a
prospective study with 31 patients, one patient experienced
drastic increase in ALT, 4 showed an increase in viral load
and 19 patients were still on TNF therapy with good clinical
response and stable liver enzymes and viral load after 2211
months of follow-up [112].
Marotte reported a good safety profile of 3-months of
treatment with etanercept in RA patients with concomitant
hepatitis C [113]. Beneficial effects of etanercept in RA
patients treated for hepatitis C with ribavirin and interferon
alpha have also been reported [114,115].
Stable liver enzymes and hepatitis viral load were
reported for a treatment regimen consisting of anti-TNF therapy in combination with cyclosporine A [116,117]. Besides
its well-known immunosuppressive effects, cyclosporine
also inhibits replication of the hepatitis virus [118,119] and
may therefore be a good choice for patients with chronic
hepatitis C infection.
Herpes zoster is a neurocutaneous disease resulting from
reactivation of the varicella zoster virus and is characterized
by a painful dermatomal rash. Complications of herpes
zoster include bacterial superinfection and more importantly
postherpetic neuralgia, which can cause prolonged and
substantial morbidity. A condition of reduced cellular immunity increases the risk of developing an herpes zoster
episode. Herpes zoster is one of the more commonly
occurring infectious complications reported in RCTs of
biological agents for the treatment of RA [65-67,120], but
this fact must be evaluated taking into account the increased
incidence of herpes zoster in RA patients in comparison with
the general population. Odds ratios for herpes zoster in RA
patients treated with biologicals in a US health plan database
population were modestly increased (OR 1.52, 95% CI 1.032.23), whereas combination of biologicals with corticosteroids (OR 2.51, 95% CI 2.11-3.00) or triple therapy with
biologicals, steroids and conventional DMARDs (OR 1.96,
95% CI 1.02-3.80) yielded much higher herpes zoster risks
[121]. A German RA registry study reported herpes zoster
incidence rates of 11.1 (95% CI 7.9-15.1) per 1000 patient-

82 Current Rheumatology Reviews, 2011, Vol. 7, No. 1

years for the monoclonal anti-TNF antibodies infliximab and

adalimumab, and 8.9 (95% CI, 5.6-13.3) for etanercept, in
comparison with 5.6 (95% CI, 3.6-8.3) for conventional
DMARDs [120]. Studies investigating the differences in
herpes zoster risk among the different TNF inhibitors yield
conflicting results [120,122,123].
In patients under biological therapy, herpes zoster may
present with atypical [124] or disseminated symptomatology
[125,126].
In view of their immunosuppressive effects, the use of
biologicals in HIV positive patients remains controversial.
Although the role of TNF in HIV infection is not fully
elucidated yet, it appears to contribute to HIV pathogenesis
rather than to its defense [127]. A number of reports indicate
that TNF inhibitors can safely be used for HIV positive RA
patients refractory to conventional therapies [127,128]. One
of eight HAART-treated patients with stable CD4 counts in
the case series of Cepeda et al. experienced an infectious
episode under anti-TNF treatment [128]. In a case of a
psoriasis HIV-patient with low CD4 counts, etanercept treatment was stopped due to severe polymicrobial infection [129]. No studies on the use of other biologicals in HIV
positive RA patients are available up to now.
Progressive multifocal leukoencephalopathy or PML
is a rare, progressive, usually fatal demyelinating brain
disease, caused by reactivation of latent JC virus, a polyoma
virus. Although most cases of PML occur in settings with
severe immunosuppression, such as AIDS, malignancies or
overly immunosuppressed transplant patients, the disease has
occasionally been described in rheumatic diseases, mostly in
systemic lupus erythematosus [130]. Recently, an increasing
number of PML cases in association with biological therapy
with antibodies targeting immune mediators have been
described [131,132]. Of relevance to RA, cases of PML have
been described after treatment with rituximab [130,131,
133,134] and recently also with tocilizumab [135].
PML is a rare complication with an infaust prognosis.
Since the diagnosis of PML is difficult and the most
important therapeutic measure consists of relieving the
immunosuppressed state, it is important for clinicians to be
aware of its existence.
PRECAUTIONS AND SCREENING BEFORE SELECTING AND STARTING BIOLOGICAL THERAPY
Screening and Prophylaxis for Latent Tuberculosis
In view of the risk of TB reactivation under biological
therapy, it is advisable to assess a patients TB history and
exposure. Screening for latent TB is recommended for all
biological agents, except rituximab, where clinical vigilance
would suffice in view of the paucity of arguments pointing
towards an elevated tuberculosis risk with this drug [59].
Latent tuberculosis is sometimes operationally defined as
the combination of absence of TB signs or symptoms in the
presence of one or more risk factors for TB (TB exposure or
underlying disease), together with a positive PPD (purified
protein derivative) skin test [58].
However, direct diagnosis of latent tuberculosis infection
is not possible. The diagnostic tests used to identify indivi-

Filip De Keyser

duals latently infected with M. tuberculosis, the in vivo

tuberculin skin test and the ex vivo interferon-release assays
(IGRAs), are designed to identify an adaptive immune
response against the bacterium, and do not directly diagnose
the presence of latent mycobacteria. Furthermore, it is
currently unknown what the proportion of individuals with
positive TB screening tests is that truly remains infected with
mycobacteria or whether and how long the adaptive immune
responses responsible for a positive test persist [136].
The tuberculin skin test is the classic in vivo TB screening test in which tuberculin PPD is injected intradermally. In
the presence of a TB immune response, PPD injection is
followed by appearance of an induration at the injection site.
The diameter of the induration considered positive depends
upon the underlying risk status of the patient. In TB screening of RA patients before the start of biological therapy
indurations above 5 mm are usually considered positive. In
the follow-up of patients under biological therapy an increase in induration diameter by 6mm or more would be
indicative of TB reactivation [137]. Tuberculin skin testing
is not very reliable in immunocompromised populations. The
PPD response was shown to be subdued in RA patients
[138], and influenced by previous BCG vaccination
[136,139].
The tuberculosis-specific interferon-gamma release assay
(IGRA) as an alternative screening for latent TB has been
adopted so eagerly by the clinical community, as to interfere
with the proper investigation of its predictive value [136].
Although a number of studies report better results in RA
patients with IGRA in comparison with tuberculin skin
testing [140] and good agreement between results of
different IGRAs [141], IGRA testing suffers from a certain
percentage of indeterminate results, necessitating the
combination of both screening tests [142-145].
Patients with a positive TB screening test should be
assessed for active disease with a chest X-ray and treated
with appropriate prophylactic TB therapy. Chemoprophylaxis for latent TB usually consists of isoniazid single
therapy for 9 months, or alternatively, rifampicin for 4
months [58]. In regions with TB drug resistance of >10%
combination drug therapy must be considered. Liver function
tests should be monitored every two to four weeks during TB
treatment, especially in patients concurrently taking
potentially hepatotoxic medications [146].
A Greek retrospective study observed 11 cases of active
TB among 45/613 patients fulfilling the criteria for TB
chemoprophylaxis, with 3 cases occurring in a subset of 9
patients not complying with the chemoprophylaxis scheme
used. However, failure of TB prophylaxis in 8/36 compliant
patients indicates that the TB prophylaxis schemes used in
this study (6 months of isoniazid or isoniazid in combination
with rifampicin for 3 months) were inadequate [147].
In view of the evidence pointing towards a lower risk for
tuberculosis reactivation with etanercept in comparison with
infliximab and adalimumab [42,148] one might at this
moment consider etanercept as the treatment of choice for
patients with elevated TB risk (increased TB exposure due to
socioeconomic factors, proven contact with a TB case,
positive tuberculin skin test), in combination with adequate
TB chemoprophylaxis if necessary. However, the evidence at

Choice of Biologic Therapy for Patients with Rheumatoid Arthritis

hand presently does not allow turning this cautious consideration into a true recommendation, in line with the recently
published EULAR recommendations which do not mention
any preference of one drug over another, nor take infection
risk into consideration in any of the 15 recommendations
[149].
Hepatitis B and C Screening and Antiviral Prophylaxis
A screening and prophylaxis workup for hepatitis B in
RA patients has been described by Calabrese et al. [150].
Prior to initiation of biological therapy hepatitis B serology
should be assessed by HBsAg, anti-HBs and anti-HBc tests.
Negative patients should be considered for hepatitis B
vaccination. Patients positive for hepatitis B core antibodies
have gone through active hepatitis infection and should be
monitored closely for reactivation. Addition of antiviral
prophylaxis should be considered on an individual patient
basis. Periodical follow-up of liver enzymes and hepatitis B
viral load is advised when no prophylaxis is given. Patients
with HBsAg positivity should receive prophylaxis with
antiviral drugs before starting immunosuppressive therapy.
Antiviral prophylaxis with lamivudine (100 mg/day) has
been used with good short-term results, while its long-term
use may be involved in the development of resistant HBV
strains. Little information is available on alternative antiviral
therapies in RA [150].
Screening for hepatitis C virus prior to biological therapy
is appropriate [127]. In view of the role of TNF in hepatitis
C infection and the relative safety of TNF blockers in
patients with hepatitis C infection, no change of antiviral
therapy is needed, provided there is adequate monitoring of
liver enzymes and viral load [112].
HIV
HIV screening prior to biological therapy is recommended in patients with risk behavior. Biological therapy
should be reserved for stable HIV positive patients with
adequate (>200/ml) CD4 cell counts [127].

Current Rheumatology Reviews, 2011, Vol. 7, No. 1

83

therapy discontinuation depends on the type, dose and

duration of the therapy [153]. As a rule of thumb, a period of
3 months is estimated to be sufficient for restoration of the
immune response. For rituximab, B cell repletion and
adequate restoration of the immune response may require a
longer period of 6 to 10 months [154].
Inactivated vaccines can be safely administered during
biological therapy. Although the influenza, pneumococcal
and hepatitis B vaccines have been demonstrated to be safe
and effective in RA patients treated with biologicals, a
number of studies indicate that the quality of the vaccineelicited immune response in these patients is lower, with
either reduced seroconversion rates after vaccination
leaving a subset of patients unprotected - or reduced quantity
or quality of the antibody response to the vaccine, which in
turn may have a negative effect on the duration of
protection [155].
CONCLUSIONS
Clinicians considering starting biological therapy for an
RA patient should be aware that biological therapy further
increases the already moderately increased infection risk of
the RA patient. Precautions needed before the start of biological therapy include checking and updating the patients
vaccination status and screening for latent tuberculosis.
Current evidence includes insufficient data from comparative studies to make recommendations concerning the
choice of biological from an infection risk perspective.
However, the lower risk for tuberculosis reactivation
reported for etanercept in comparison with infliximab and
adalimumab may cautiously prompt the consideration of
etanercept as the product of choice for patients with elevated
TB risk.
ACKNOWLEDGEMENT
The authors acknowledge the contribution of Veerle
Persy, MD, PhD as an independent medical writer.

Vaccination
RA patients treated with biological therapy must be
regarded as immunocompromised individuals and are as
such at increased risk of infection and complications for
some vaccine-preventable diseases. The benefits of vaccination in this population are even greater than in the general
population, but vaccination coverage is surprisingly low
[151,152].
Like in all immunocompromised individuals, live vaccines (measles-mumps-rubella, varicella and zoster vaccine,
yellow fever, oral poliomyelitis) are contraindicated in RA
patients under biological therapy. For inactivated vaccines,
biological therapy may have a negative impact on the quality
of the vaccine-induced immune response. Therefore, vaccination status should be checked and updated as appropriate
before the start of biological therapy.
Live vaccines need to be given 3 to 4 weeks prior to the
start of therapy to ensure clearance of the vaccine virus
before the immune response is impaired. The waiting period
needed before administering live vaccines after biological

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Accepted: November 10, 2010