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Biologic Therapies:Clinical Implications for Rheumatologists,Gastroenterologists, Allied Health Practitioners
R.J. Fasenmyer Center for Clinical Immunology
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Spondyloarthritis: TherapeuticImplications o Advances in PathogenesisThree prevalent forms of inammatory arthritis include rheu-
matoid arthritis (RA), psoriatic arthritis (PsA), and ankylosingspondylitis (AS). Although they share certain characteristics,
they are distinguished by the specic sites of joint inammation
associated with each: the synovium in RA; the bone, enthesis,
and synovium in PsA; and the bone and enthesis in AS. The
location of inammation is an important factor to consider
when making treatment decisions. For example, an agent that is
effective for peripheral synovitis may not have the same level of
therapeutic response in axial disease or enthesitis.
Osteoclast precursors as a biomarker
Osteoclast precursors are monocyte effector cells in the circulation.
An abundance of osteoclast precursors is observed in patients with
certain phenotypes of erosive immune-mediated inammatory
disorders, namely RA, PsA, and psoriasis (see Figure 1). Of note,
osteoclast precursors are strikingly high in a subset of patients
with psoriasis without musculoskeletal signs and symptoms who
later develop inammatory arthritis, which suggests that osteo-
clast precursors may be useful as a biomarker for susceptibility
to arthritis in this population.
Fig 1. Osteoclast precursors in erosiveIMID phenotypes
Control AS Crohns RA PsA Ps
OCPpermillionmonocy
tes
100 --
80 --
60 --
40 --
20 --
0 ---- -- -- -- -- -- --
IMID = immune-mediated inflammatory disorders
Therapeutic opportunityAn opportunity to arrest the development of a severely
inammatory phenotype of arthritis lies in the identication of
patients with psoriasis and subclinical joint inammation and
patients with early inammatory disease. This will enable clini-
cians to intervene with disease-modifying antirheumatic drugs
and/or biologic agents at an early stage.
T-cell pathways in spondyloarthropathies
Activation of precursor T helper cells in response to signal-
ing through transforming growth factor-beta-1 and interleu-
kin (IL)-6 is considered a promoter of the Th17 phenotype, an
especially inammatory phenotype. The activator of the Th17
response is the dendritic cell, a master cell that releases IL-23
which drives and perpetuates the Th17 phenotype. Th17 cells
are a subset of CD4+ T cells that produce IL-17. The Th17
cells release a number of cytokines that are integral to thehyperproliferation of keratinocytes that is observed in psoriasis.
In addition, Th17 cells encourage osteoclastogenesis by three
mechanisms:
1) The release of IL-17 by Th17 cells induces the expression o
receptor activator NF-B ligand (RANKL) on synovial
broblasts,
2) Th17 cells express RANKL on the cell surface which binds
to RANK on OCPS and promotes the osteoclastogenesis, and
3) Th17 produces tumor necrosis factor (TNF), a cytokine that
potentiates the formation of osteoclasts.1,2
Other evidence implicating the IL-17 subset in an inammatoryphenotype is the observed association between psoriasis, PsA
and AS with IL-23 alleles; the presence of increased levels of IL-
17 in the blood and synovial uid of patients with PsA, and the
effectiveness of anti-p40 antibodies in the treatment of psoriasis
and PsA.
Therapeutic targets
Th17 represents a therapeutic target for joint destruction asso
ciated with T cell activation. Other logical therapeutic targets
include IL-23 (a perpetuator of the Th17 phenotype), IL-17, IL
21, dendritic cells that express IL-23, and dendritic cell specic
transmembrane protein (DC-STAMP).Anti-p40 antibody was associated with an improvement in the
American College of Rheumatology (ACR) 20 response com
pared with placebo in patients with PsA, but the ACR20, ACR50
and ACR70 response achieved was somewhat inferior to that of
other biologic agents tested in randomized, placebo-controlled
trials, and typically lower than that achieved in the treatment of
plaque psoriasis.3
Dendritic cell specic transmembrane protein is a 7-transmem
brane protein that is present on monocytes. Its role in osteoclas
togenesis is as a regulator of cell to cell fusion in the formation
of a polykaryon. When a monocyte forms an osteoclast, it must
form a multinucleated cell, called a polykaryon. DC-STAMP iscritical to polykaryon formation.
DC-STAMP may therefore be a therapeutic target; DC-STAMP
antibodies added to culture have been shown to prevent polykaryon
formation. DC-STAMP is but one signaling pathway required
for osteoclast formation and activation. Osteoclast activation can
also be blocked at RANK or in accessory pathways downstream
of RANK, such as Syk. Molecules that bind to Syk have shown
impressive efcacy in the treatment of RA.
Osteoblasts and osteoclasts offer different therapeutic targets
The Wnt signaling pathway is a critical pathway responsible for
osteoblast formation and development of new bone. The Dick
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kopf (DKK) family of proteins acts as inhibitors of the Wnt path-
way and may interfere with new bone formation by interrupting
osteoblast differentiation. DKK-1 is highly elevated in patients
with RA, which may explain the relative absence of bone repara-
tive response associated with RA.
The effect of TNF inhibition on new bone formation has been a
concern, but two phase 3 clinical trials with etanercept and
adalimumab revealed no decline in radiographic progression
(when compared to progression in a historical cohort).4-6
New models of AS consider that osteoproliferation may be
uncoupled from inammation, such that new bone formation
may be inuenced by pathways that are separate from those that
regulate bone resorption. The possibility that TNF may actually
inhibit new bone formation has also been suggested, and in this
scenario, TNF blockade may actually promote the development
of a pathologic bone formation phenotype.
Biologics and Systemic VasculitisThe investigation of biologic agents to treat vasculitis is ongo-
ing. The use of biologic agents must be evaluated in the context
of standard therapies, as no biologic agent has been proven to beeffective in this patient population.
Theoretical advantages and objectives with the use of biologic
agents in vasculitis are the reduction in the toxicity of therapy,
the reduction in the incidence of disease relapse, and the induc-
tion of disease remission permitted by specic immunologic tar-
geting. Of concern, however, is that such specic targeting may
be insufcient to modulate the disease and reduce the potential
for disease-specic toxicities.
In considering the use of a biologic agent for a patient with sys-
temic vasculitis, several issues must be contemplated, including
the goals of treatment, the effectiveness of current standard thera-
py, and clinical data on biologic agents drawn from the particular
form of vasculitis being treated. For this discussion, these issues
will be examined in the settings of Wegeners granulomatosis
and giant cell arteritis.
Wegeners granulomatosis
Wegeners granulomatosis is a potentially life-threatening dis-
ease, and protection of patient survival is the first priority.
Because of the effectiveness of current treatment options, the
goals may be broadened to include the following:
1) Induction of remission, dened as the absence of disease
activity;
2) Avoidance of disease relapse, dened as the return of
disease activity after achieving remission; and
3) Minimization of therapeutic toxicity.
The current treatment approach to Wegeners granulomatosis is
based on two phases: an induction phase in which active disease
is placed into remission and a maintenance of remission phase
(see Figure 2). Wegeners granulomatosis is a disease that has a
wide spectrum of severity ranging from localized upper airway
disease to acute multisystem disease involvement. The choice
of therapy has traditionally been based on the degree of disease
severity, with cyclophosphamide induction followed by less toxic
maintenance therapy (eg, methotrexate, azathioprine, mycophe
nolate mofetil) for severe disease and methotrexate for induction
and maintenance of less severe active disease.
These regimens have been proven to prolong survival and to
induce remission in more than 85% of patients, but relapse
occurs in 50% to 75% of patients and therapy is potentially toxic
As a result, other treatment options, particularly biologic agents
have been investigated.
Fig 2. Wegeners granulomatosis: Summary ocurrent treatment
Induction
Cyclophosphamide
Methotrexate
Maintenance
Methotrexate
Azathioprine
(Mycophenolate mofetil)
Methotrexate
prolong survivalremission in >85% of patients
high frequence of relapsepotential toxicity
}}
Severe Disease
Non-severe Disease
Interfering with the pathway leading to granulomatous inam
mation may represent a therapeutic strategy in Wegeners granu
lomatosis. Information gleaned from other human diseases and
murine models indicates that CD4+ T cells with the Th1 cytokine
pattern play an important role in the initiation and maintenance
of granuloma formation. The primacy of this cytokine pattern
in Wegeners granulomatosis has been supported by evidencegained from the laboratory.
Based on these data, therapies that interrupt TNF production gen
erated initial excitement in Wegeners granulomatosis. However
a clinical trial of 180 patients randomized to etanercept or placebo
failed to support the use of this agent for the induction or mainte
nance of remission in patients with Wegeners granulomatosis.
There were six malignancies documented in patients receiving
etanercept (none with placebo); all malignancies occurred in
patients receiving concurrent cyclophosphamide.8 Although this
occurred in a small population, it raises caution against the use of
cyclophosphamide concurrently with any anti-TNF agent.
An open-label trial of iniximab in 32 patients with Wegenersgranulomatosis or microscopic polyangiitis achieved an 88%
remission rate, but all patients were also receiving standard ther
apy concomitantly.9 The rate of relapse was 18%, the mortality
rate was 6%, and 21% of patients experienced serious infec
tions. In the absence of a sufciently powered trial, the efcacy
of other anti-TNF agents cannot be determined. Current evi
dence, however, does not support the use of any anti-TNF agen
in Wegeners granulomatosis.
Another avenue for intervention in Wegeners granulomatosis
is interference with T-cell activation. Abatacept is an agent that
acts on this pathway, although there is currently no experience
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with it in the treatment of Wegeners granulomatosis. A clinical
trial of abatacept in the treatment of mild, relapsing Wegeners
granulomatosis by the Vasculitis Clinical Research Consortium
is ongoing.
B-celldepleting therapies were rst explored based on the
rationale of interfering with the production of antineutrophil
cytoplasmic antibodies (ANCA). The role of ANCA in disease
pathogenesis remains unclear, although bodies of evidence from
the laboratory have supported a means through which ANCA-induced neutrophil-mediated vascular injury might occur. Two
open-label studies of rituximab combined with glucocorticoids
in patients with refractory ANCA-associated vasculitis resulted
in undetectable levels of B cells and induction of remission in
all patients.10,11 All patients remained in remission as long as B
lymphocytes were depleted; 10% to 20% relapsed in association
with a return of B cells and ANCA. Although ANCA produc-
tion declined in all patients, it remained positive in up to 40% of
patients, which raises the possibility that rituximab may exert its
action through other mechanisms.
In addition to its potential efcacy, important questions that
remain with B-celldepleting therapy are whether its effectsdiffer between organs and whether any disease impact occurs
through ANCA or other B-celldependent mechanisms. These
questions are being explored through the ongoing Rituximab in
ANCA-associated Vasculitis (RAVE) trial.
Giant cell arteritis
Giant cell arteritis is the most common form of vasculitis, and it
carries many phenotypes. It is most commonly associated with
cranial disease (temporal arteritis) and a risk of loss of vision, but
it also includes polymyalgia rheumatica and potential involve-
ment of large vessels of the aorta and its branch vessels.
Treatment goals for giant cell arteritis are to prevent seriousmorbidity or mortality, reduce symptoms that affect quality of
life, lessen disease relapse, and avoid therapeutic toxicity. Pred-
nisone and aspirin remain the standard treatments (see Figure 3).
Relapse, however, occurs in 75% to 90% of treated patients, and
toxicity is common.
The introduction of biologic therapies offered great potential,
particularly in the inhibition of TNF. However, Hoffman et al12
found no difference between placebo and iniximab on relapse
through week 22 in patients with newly diagnosed giant cell
arteritis, all of whom also received standard doses of pred-
nisone. More patients randomized to iniximab had infec-
tion than placebo recipients. This nding was replicated in aplacebo-controlled study of iniximab in patients with newly
diagnosed polymyalgia rheumatica, all of whom were also
treated with prednisone.13
Intervention with T-cell activation, as with abatacept, is a
potential therapeutic target in giant cell arteritis. The T cell is one
cell that appears to play a role in the pathogenesis of giant cell
arteritis. Activated T cells in the arterial wall secrete cytokines
that initiate and maintain granulomatous inammation. Granulo-
mas in the vessel wall, formed by interferon-gamma-producing
CD4+ T cells and macrophages, are a characteristic feature of
giant cell arteritis.
Figure 3. Giant cell arteritis treatment
1950
Prednisone+
Aspirin
2009
Prednisone+
Aspirin
Improves symptoms
Reduces risks of blindness
Relapse 75-90%
Toxicity 35-86%
PsA: QOL Issues and the Role o BiologicsUp to 30% of patients with psoriasis can have inammatory joint
disease or arthritis.
Features that distinguish PsA from RA are seronegativity and
associated dactylitis and enthesitis. The arthritis in a patient with
PsA can range from mild nondestructive disease to a severely
rapid and destructive arthropathy. In addition to joint involve
ment, the tendons, ligaments, and bone are affected in PsA
(see Table 1).
Table 1. Psoriatic arthritis conditions17-21
Musculoskeletal
Arthritis
Dactylitis/sausage digits
Enthesitis
Tenosynovitis
Sacroliitis/spondylitis
Cutaneous and extraarticular maniestations
Psoriasis
Nail pitting
Onycholysis
Conjunctivitis/iritis/uveitis
Radiographic characteristics
Erosions
Pencil-in-cup deformity
Ray distribution
Osteolysis
Nonmarginal asymmetric syndesmophytes
Asymmetric sacroiliitis
Novel applications are being used in various disease states
including PsA, to assess the impact of disease on QOL and to mea
sure patient preferences associated with health-related QOL.
Measuring QOL
In public health and in medicine, the concept of health-related
QOL refers to a person or groups perceived physical and men
tal health over time. Tracking health-related QOL in differen
populations can identify subgroups with poor physical or menta
health and can help guide interventions to improve their health
Quality of life has not been a standard outcome measure in the
recent past in studies of biologic therapies. However, as the bar is
being raised regarding how much treatment effect can be gained
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with biologic agents, an effort is being made to quantify more
outcomes measures for patients suffering from PsA.
Health-related QOL is a measure of the effects of chronic ill-
ness with the goal of obtaining a better understanding of how an
illness interferes with a persons day-to-day life. Patients with
arthritis have signicantly worse QOL than those without
arthritis; they report twice the number of unhealthy days and
three times as many days with limitations in activity monthly.14
Scores on health-related QOL and life satisfaction question-naires are similar between patients with RA and PsA despite
greater peripheral joint damage, inammation, and physical
disability associated with RA.15 This suggests that the QOL
impact of skin disease in patients with PsA is more profound
than previously believed.
The Patient Reported Outcomes Measurement Information Sys-
tem (PROMIS) is a cooperative network of seven institutions and
the National Institutions of Health that was designed to quantify
patient-reported symptoms (eg, pain, fatigue, aspects of health-
related QOL) in clinical practice across several disease states.
Perceived changes in such symptoms is often the best way that
patients can judge the effectiveness of treatments.
Instruments that measure health-related QOL must be valid,
reliable, and responsive to change. Patient-recorded QOL
outcomes scales can be general or disease-specic. Examples
of general health measures are the SF-36, the Euro-QOL,
the Nottingham Health Prole, and the Health Assessment
Questionnaire (HAQ), which is a measure of disease activity
and long-term disability. Instruments specic to PsA include
the PsA QOL, the expanded HAQ (HAQ-SK), and the Psoriatic
Arthritis Response Criteria (PsARC).
Willingness to pay as a measure o impact
A novel technique to further extrapolate on the QOL issues isthe concept of willingness to pay. This is a method to measure
the value of stated preferences in terms of dollars, with a higher
willingness to pay associated with stronger preference. It is being
used increasingly in health care to gauge the impact of a chronic
disease on health-related QOL. Willingness to pay is able to have
the patient take all the possible factors (education, severity of ill-
ness, income, beliefs) that are important to them and balance this
in their ultimate decision for a health benet or risk.
A recent study was done to validate this in a cohort of psori -
atic arthritis patients. The impact of psoriasis on health-related
QOL was measured in 59 patients with PsA using eight QOL
domains: intimacy, physical comfort, social comfort, self-care,ability to work, ability to concentrate, ability to sleep, and emo -
tional health.16 Nearly 90% of patients were willing to pay to
fully restore physical function. Also, the emotional, sleep, and
work domains were considered important to cure by a majority.
References
1. Sato K, Suematsu A, Okamoto K, et al. Th17 functions as an osteoclastogenic
helper T cell subset that links T cell activation and bone destruction.J Exp Med
2006;203:2673-82.
2. Jandus C, Bioley G, Rivals JP, et al. Increased numbers of circulating poly-
functional Th17 memory cells in patients with seronegative spondylarthritides.
Arthritis Rheum 2008;58:2307-17.
3. Gottlieb A, Menter A, Mendelsohn A, et al. Ustekinumab, a human interleukin
12/23 monoclonal antibody, for psoriatic arthritis: a randomised, double-blind,
placebo-controlled, crossover trial.Lancet2009;373:633-40.
4. van der Heijde D, Pangan AL, Schiff MH, et al. Adalimumab effectively
reduces the signs and symptoms of active ankylosing spondylitis in patients with
total spinal ankylosis.Ann Rheum Dis 2008;67:1218-21.
5. Kavanaugh A, Klareskog L, van der Heijde D et al. Improvements in clinical
response between 12 and 24 weeks in patients with rheumatoid arthritis on etaner-
cept therapy with or without methotrexate.Ann Rheum Dis 2008;67:1444-7.
6. Mease, PJ, Gladman DD, Ritchline CT, et al, for the Adalimumab Effective-
ness in Psoriatic Arthritis Trial Study Group. Adalimumab for the treatment ofpatients with moderately to severely active psoriatic arthritis.Arthritis Rheum
2005;52:3279-89.
7. Wegeners Granulomatosis Etanercept Trial (WGET) Research Group.
Etanercept plus standard therapy for Wegeners granulomatosis.N Engl J Med
2005;352:351-61.
8. Stone JH, Holbrook JT, Marriott MA, et al. Solid malignancies among patients in
the Wegeners Granulomatosis Etanercept Trial.Arthritis Rheum 2006;54:1608-18.
9. Booth A, Harper L, Hammad T, et al. Prospective study of TNF-alpha blockade
with iniximab in anti-neutrophil cytoplasmic antibody-associated systemic
vasculitis.J Am Soc Nephrol2004;15:717-21.
10. Keogh KA, Wylam ME, Stone JH, Specks U. Induction of remission by B
lymphocyte depletion in eleven patients with refractory antineutrophil cytoplas-
mic antibody-associated vasculitis.Arthritis Rheum 2005;52:262-8.
11. Keogh KA, Ytterberg SR, Fervenza FC, Carlson KA, Schroeder DR, SpecksU. Rituximab for refractory Wegeners granulomatosis: report of a prospective,
open-label pilot trial.Am J Resp Crit Care Med2006;173:180-7.
12. Hoffman GS, Cid MC, Rendt-Zagar KE, et al. Iniximab for maintenance of
glucocorticosteroid-induced remission of giant cell arteritis: a randomized trial.
Ann Intern Med2007;146:621-30.
13. Salvarani C, Macchioni P, Manzini C, et al. Iniximab plus prednisone or
placebo plus prednisone for the initial treatment of polymyalgia rheumatica:
a randomized trial.Ann Intern Med2007;146:631-9.
14. Mili F, Helmick CG, Moriarty DG. Health related quality of life among adults
reporting arthritis: analysis of data from the Behavioral Risk Factor Surveillance
System, US, 1996-99.J Rheumatol2003;30:160-6.
15. Borman P, Toy GG, Babaoglu S, et al. A comparative evaluation of quality of
life and life satisfaction in patients with psoriatic and rheumatoid arthritis.
Clin Rheumatol2007;26:330-4.
16. Hu SW, Holt EW, Husni ME, Qureshi AA. Willingness-to-pay stated
preferences for 8 health-related quality-of-life domains in psoriatic arthritis:
a pilot study. Semin Arthritis Rheum 2008;Dec 16 [Epub ahead of print].
17. Mease P, Goffe BS. Diagnosis and treatment of psoriatic arthritis.
J Am Acad Dermatol2005;52:1-19.
18. Brockbank JE, Stein M, Schentag CT, Gladman DD. Dactylitis in psoriatic
arthritis: a marker for disease severity?Ann Rheum Dis 2005;64:188-90
[Epub ahead of print].
19. Taylor WJ. Epidemiology of psoriatic arthritis. Curr Opin Rheumatol
2002;14:98-103.
20. Gladman D. Psoriatic arthritis.Rheum Dis Clin North Am 1998;24:829-44.
21. Brockbank J, Gladman D. Diagnosis and management of psoriatic arthritis.
Drugs 2002;62:2447-57.
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Benets and Risks o Biologics inInfammatory Bowel Disease:
Critical Management DecisionsThe treatment goals in inammatory bowel disease (IBD) are
to manage symptoms, which entails induction of remission
(rapid control of symptoms) and maintenance of remission.
Other goals are to change the natural history of the disease
through endoscopic remission, thereby improving long-term out-
comes; minimize complications from treatment; and reduce the
need for surgeries and hospitalizations.
Prior to the era of biologic therapies, less than 40% of treated
patients with Crohns disease achieved remission, and approxi-
mately one-third had high disease activity. Furthermore, toxicities
associated with several classes of nonbiologic agents (eg, cortico-
steroids, methotrexate) preclude their long-term use.
Four biologic agents have been approved for the treatment of
Crohns disease:
Iniximab, a chimeric mouse (25%)-human (75%) IgG1
monoclonal antibody;
Adalimumab, a fully human IgG1 monoclonal antibody;
Certolizumab pegol, a humanized Fab fragment of the
anti-TNF antibody that is linked to two polyethylene
glycol molecules;
Natalizumab, a humanized antibody to alpha 4 beta 7 integrins.
Randomized controlled trials have shown that anti-TNF therapy
is effective in patients for moderate to severe Crohns disease.
In several trials, remission and maintenance of remission was
achieved signicantly more often in patients assigned to anti-TNF
therapy (iniximab, adalimumab, and certolizumab) than in pla-
cebo recipients.1-5 The trials also showed signicant improvement
in maintenance of remission with biologic agents as well as lower
rates of Crohns disease-related hospitalizations, consistent with
an improvement in the natural history of the disease.
The potential mechanisms for secondary loss of response to
anti-TNF therapy are the formation of neutralizing antibodies,
increased clearance of biologic agents, and noninammatory
complications of the bowel.
About one-third of patients with Crohns disease treated with
iniximab will require dose escalation.2 In patients with sec-
ondary failure to iniximab, response rates of about 80% are
obtained with dose escalation, a rate similar to that with placebo.
About one-third of patients who do not achieve remission with
adalimumab at week 4 will need escalation from every other
week to weekly therapy to achieve and maintain remission.6
In patients who initially responded to iniximab therapy but lost
responsiveness, switching them to adalimumab achieved signi-
cant clinical response and remission rates compared with placebo.7
However, the absolute likelihood of response to a second anti-TNF
agent is lower than the response in treatment-naive patients.3,5
Loss of response to anti-TNF therapy should prompt an investiga
tion to conrm ongoing active inammation, as not all recurrent
symptoms are caused by disease activity. If the presence of inam
mation is documented, measurement of antibodies is warranted
Switching treatments within the anti-TNF class is reasonable if
antibodies are present. Dose escalation is reasonable if antibodies
and serum drug levels are absent. Switching to natalizumab is rea
sonable if antibodies are absent and serum drug levels are adequate
Factors involved in the choice o therapy
Choosing between biologic therapies is complicated because
different trial designs, patient populations, and denitions of
response and remission prevent valid comparisons of results
Taking into consideration the heterogeneity in the denition of
response, all clinical trials of TNF inhibitors have resulted in a
fairly uniform response rate of approximately 60% at week 4.With efcacy established for the biologic agents in the treatmen
of Crohns disease, attention shifts to selecting the best treatmen
and improving outcomes.
Risk o immunogenicity
Immunogenicity is a concern with the use of biologics. Factors
that contribute to immunogenicity are the molecular sequence and
structure of the agent, the treatment regimen (ongoing or episodic)
and concomitant therapy. Episodic therapy with long intervals
between iniximab infusions is associated with the formation o
anti-iniximab antibodies (ATIs). The development of ATIs corre
lates with an increased risk of infusion reactions, lower serum con
centrations of iniximab, and a shorter duration of response.1,8-1The formation of ATIs is approximately halved by concomitant
use of immunosuppressive agents.1,8-11 Therefore, it is now clear
that azathioprine, methotrexate, or 6-mercaptopurine should be
used concomitantly with iniximab, and that administering inix
imab on a scheduled basis with the recommended induction regi
men will reduce formation of ATIs.
Antibody formation is not unique to iniximab. In the treatment
of patients with rheumatoid arthritis, anti-adalimumab antibodies
developed in 1% of patients on methotrexate and 12% of patients
not on methotrexate. In another trial, 8% of patients developed
antibodies to certolizumab pegol and a similar proportion o
patients form antibodies when treated with fontolizumab.Step up or top down strategies
Two competing strategies for the treatment of Crohns disease are
the step up and top down strategies. The step up strategy is the
traditional practice in which steroids are used for induction of dis
ease remission; thiopurine or methotrexate is added for maintenance
of remission. Once steroid dependence or failure is encountered, a
biologic agent is added. The top down strategy starts with a combi
nation of a thiopurine, methotrexate, and a biologic agent, with use
of corticosteroids if loss of response occurs (see Figure 1).
A top down strategy starting with iniximab and azathioprine was
superior to a step up strategy at inducing remission without corti
The rationale or and clinicalexperience with biologic agents in gastroenterology
Aaron Brzezinski, MD, Bret Lashner, MD, Arthur McCullough, MD, Nizar Zein, MD
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costeroids and without bowel surgery in patients with Crohns dis-
ease diagnosed in the previous 4 years.12 Relapse happened later for
patients who started with iniximab and azathioprine than in those
who started on steroids. Serious adverse events were similar in each
treatment group. The rate of pancreatitis was not signicantly differ-
ent between groups, and all cases of pancreatitis occurred in patients
on azathioprine. The top down strategy was associated with a non-
signicant trend toward more eczema and rash.
Figure 1. Top down vs step up strategies12
Steroids
Steroids Steroids
+ AZAMTX
+ IFX IFX + AZA
+ (episodic) IFX
Step up Top down
Selecting therapy
The choice of biologic agent accounts for efcacy and toxicity as well
as patient preference and the willingness to cooperate with treatment.
Although efcacy in achieving and maintaining remission betweenTNF inhibitors appears similar in controlled clinical trials, deci-
phering toxicity in IBD is complicated by the use of concomitant
medications, side effects that may be related to the disease itself,
the under-recognition of adverse events during controlled trials and
clinical practice, and the uncertain reliability of the information.
Three biologic agents iniximab, natalizumab, and certoli-zumab are infusion therapies. Adalimumab, in contrast, can
be self-administered, and although it offers greater convenience,
it also requires the patient to ll the prescription.
The patients willingness to accept the potential adverse events
in exchange for clinical benets must also be considered in the
choice of treatment. In a survey of patients with chronic activedisease, greater risk acceptance correlated with greater symptom
improvement (see Figure 2).13
Figure 2. Risks vs benets: Patient acceptance
1.0 --
0.9 --
0.8 --
0.7 --
0.6 --
0.5 --
0.4 --
0.3 --
0.2 --
0.1 --
0 --Moderate
to MildModerate toRemission
Severe toModerate
Severeto Mild
Severe toRemission
Observedrisk
MAR
(Annual%R
isk)
PML
Serious infection
Lymphoma
The Role and Risks o Natalizumab inthe Treatment o IBD
Natalizumab may be considered for difcult-to-treat patients with
Crohns disease. It is approved for treating moderately to severely
active Crohns disease. The benet-to-risk ratio of natalizumab
appears favorable in appropriately selected patients. Contraindica-
tions include hypersensitivity (if severe), active infection, and a his
tory of progressive multifocal leukoencephalopathy.
Natalizumab has been shown effective for induction and main
tenance of remission, and it is steroid sparing.14 In patients in
whom anti-TNF agents had failed, the remission rate was 17%
with natalizumab versus 5% with placebo (P < 0.05). In twolarge clinical studies,15 the incidence of all-cause and Crohns
disease-related hospitalizations was reduced signicantly in the
natalizumab group in treatment-naive patients and anti-TNF failures.
Progressive multifocal leukoencephalopathy (PML) is an infec
tious disease caused by the JC virus. The infection is asymptomatic
occurs in childhood, and remains latent; however, immunosuppres
sive medications have been associated with reactivation of the virus
If not recognized early, PML is almost uniformly fatal.
Seven cases of PML have been conrmed among the 39,000
patients worldwide who have been treated with natalizumab, onlyone of whom was being treated for Crohns disease. This patient
received eight doses of natalizumab, was taking azathioprine con
comitantly, and had a history of reduced white blood cell counts.
Natalizumab distribution is restricted to pharmacies and infusion
centers certied through the monitoring program developed in
accordance with the US Food and Drug Administration. Figure 3shows the timeline for natalizumab marketing approvals.
Figure 3. Natalizumab approval dates
2004 2005 2006 2007 2008 2009| | | | | |
November 2004:Approval by US FDA
February 2005:Voluntarily withdrawn by
manufacturer due to PML
June 2006:Re-approved by USFDA and approved
by EuropeanMedicines Agency
January 2008:Approved by US FDA
for moderately to
severely activeCrohns Disease
Current Use: 35,500patients worldwide
September 2006:Approved byHealth Canada
US Approval:- Monotherapy- Relapsing forms of MS to delay disability
and reduce frequence of relapses- Mandatory registryto receive natalizumab
EU Approval:- Monotherapy, relapsing
remitting MS- No required registry
The Potential Role or Biologic Agents
in the Management o Nonalcoholic andAlcoholic Fatty Liver DiseaseNonalcoholic fatty liver disease represents a wide spectrum o
liver disease, ranging from steatosis (relatively benign fatty liv
er) to nonalcoholic steatohepatitis (NASH) and cirrhosis. Only
a minority with nonalcoholic fatty liver progress to NASH, and
few of those progress to cirrhosis.
The histologic picture of alcoholic fatty liver disease is much the same
as nonalcoholic fatty liver disease (accumulation of fat in liver cells
inammation of the liver, necrosis of liver cells, and possibly brosis),
but the progression from alcoholic liver disease to hepatitis and cirrho
sis is much greater. Whereas about 1% of patients with nonalcoholic
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steatosis will progress over their lifetime to cirrhosis and liver-related
death, alcoholic hepatitis will progress to cirrhosis and one-fth will
die from liver-related injury. However, the prevalence of nonalco-
holic steatohepatitis is much higher than that for alcoholic hepatitis.
Alcoholic atty liver: The rationale or biologics
The basis for the use of biologic agents in alcoholic fatty liver
disease lies in the histology of liver injury. The Kupffer cell is
the resident macrophage in the liver. These cells are the critical
controllers of the stellate cell, which can cause scarring and cir-rhosis when activated. Alcohol abuse increases the production of
reactive oxygen species and endotoxemia, upregulating nuclear
factor kappa beta to increase the production of TNF, leading to
bacterial translocation and oxidative tissue injury.
Tumor necrosis factor signaling through activation of Kupffer cells
is crucial to the development of hepatotoxicity. The liver is normally
resistant to TNF, but Kupffer cells undergo priming and activation
during alcoholic steatohepatitis to increase production of TNF and
sensitization to TNF. Nearly all experimental models of liver disease
are associated with elevated levels of plasma or tissue TNF.
The Kupffer cell is critical in activating the cytokine response
in alcoholic liver disease. By inactivating Kupffer cells throughthe administration of gadolinium chloride, ethanol-induced
increases in AST can be blunted.16 Fatty liver, inammation, and
brosis have been prevented by knocking out TNF-R1 and by
administration of TNF-alpha antibodies.
Clinical data with biologics in alcoholic atty liver
Etanercept and iniximab have been studied in alcoholic liver
disease. A standard dose of iniximab results in reductions in
ALT and total bilirubin, but mortality in severe alcoholic hep-
atitis was increased with the addition of iniximab to steroids
compared with steroids alone.17
In a placebo-controlled study of etanercept in patients with alcoholic
hepatitis, six doses of etanercept over 30 days increased mortality
signicantly at 30 days but not at 60 days relative to placebo.18
Pentoxyfylline, an inhibitor of TNF synthesis, appears to be the
most promising of the biologic agents in the treatment of alcoholic
fatty liver disease. In addition to inhibiting cytokine synthesis, it
decreases blood viscosity and improves renal microcirculation.
In severe alcoholic hepatitis, pentoxyfylline was associated with a
signicant 40% reduction in mortality compared with placebo.19The
difference in mortality occurred after 2 to 3 weeks of therapy and
was due to a reduction in the development of hepatorenal syndrome.
Nonalcoholic atty liver disease:
The rationale or biologicsThe basis for the use of biologic agents in nonalcoholic fatty liver
disease lies in adipocyte production and release of cytokines as
fat mass increases. In addition to TNF, the release of non-TNF
cytokines, such as transdermal growth factor-beta and IL-8, has
an important role in the genesis of nonalcoholic fatty liver disease.
When administered to animals on a methionine-choline decient
diet, anti-TNF therapy produced signicant reductions in the
percentage of steatotic cells, inammation, necrotic focus, bro-
sis, and activated stellate cells compared with placebo.
In experimental nonalcoholic fatty liver disease, iniximab
decreased total liver fat and levels of TNF, IL-8, and other
cytokines. Inhibition of TNF-alpha using pentoxyfylline
reduced ALT signicantly with a reduction in insulin resistance in
patients with nonalcoholic steatohepatitis.20
No current role or biologics
Biologic agents have no proven value in alcoholic fatty liver dis
ease, at least in the doses studied, and the safety data are concern
ing. In nonalcoholic fatty liver disease (NAFLD), their role is mut
ed since lifelong therapy would be required unless patients lose a
substantial amount of weight. Although invasive, the only therapythat interrupts the natural history of NAFLD is bariatric surgery.
References
1. Hanauer S, Feagan BG, Lichtenstein GR, et al. Maintenance iniximab for Crohnsdisease: the ACCENT I randomised trial.Lancet2002;359:1541-9.
2. Rutgeerts P, Feagan BG, Lichtenstein GR, et al. Comparison of scheduled andepisodic treatment strategies of iniximab in Crohns disease.Gastroenterology 2004;126:402-13.
3. Colombel JF, Sandborn WJ, Rutgeerts P, et al. Adalimumab for maintenance ofclinical response and remission in patients with Crohns disease: the CHARM trial.Gastroenterology 2007;132:52-65.
4. Feagan BG, Panaccione R, Sandborn WJ, et al. Effects of adalimumab therapy onincidence of hospitalization and surgery in Crohns disease: results from the CHARMstudy. Gastroenterology 2008;135:1493-9.
5. Schreiber S, Khalig-Kareemi M, Lawrence IC, et al. Maintenance therapy withcertolizumab pegol for Crohns disease.N Engl J Med2007;357:239-50.
6. Sandborn WJ, Hanauer SB, Rutgeerts P, et al. Adalimumab for maintenancetreatment of Crohns disease: results of the CLASSIC II trial. Gut2007;56:1232-9.
7. Sandborn WJ, Rutgeerts P, Enns R, et al. Adalimumab induction therapy forCrohns disease previously treated with iniximab: a randomized trial.
Ann Intern Med2007;146:829-38.
8. Baert F, Noman M, Vermeire S, et al. Inuence of immunogenicity on the long-termefcacy of iniximab in Crohns disease.N Engl J Med2003;348:601-8.
9. Sands BE, Anderson FH, Bernstein CN, et al. Iniximab maintenance therapy forstulizing Crohns disease.N Engl J Med2004;350:876-85.
10. Kugathasan S, Levy MB, Saeian K, et al. Iniximab retreatment in adults andchildren with Crohns disease: risk factors for the development of delayed severesystemic reaction.Am J Gastroenterol2002;97:1408-14.
11. Farrell RJ, Alsahli M, Jeen YT, et al. Intravenous hydrocortisone premedicationreduces antibodies to iniximab in Crohns disease: a randomized controlled trial.Gastroenterology 2003;124:917-24.
12. DHaens G, Baert F, van Assche G et al. Early combined immunosuppression orconventional management in patients with newly diagnosed Crohns disease:an open randomised trialLancet2008;371:660-7.
13. Sands B, Siegel C, Hass S, et al. Crohns disease patients willingness to accept therisks of serious adverse events in exchange for clinical benet. Presentation atDigestive Disease Week; Los Angeles, CA; May 20-25, 2006:Abstract W1200.
14. Targan SR, Feagan BG, Fedorak RN, et al. Natalizumab for the treatment of activeCrohns disease: results of the ENCORE Trial. Gastroenterology2007;132:1672-83.
15. Sands BE, Siegel CA, Spencer M, Hass S. Natalizumab reduces the hospitalizationrate in moderate to severe Crohns disease patients: A pooled analysis of the ENACT-1and ENCORE studies. Presentation at Digestive Disease Week; San Diego, CA;May 17-22, 2008:Abstract 1039.
16. Adachi Y, Bradford BU, Gao W, et al. Inactivation of Kupffer cells prevents earlyalcohol-induced liver injury.Hepatology 1994;20:453-60.
17. Naveau S, Chollet-Martin S, Dharancy S, et al. A double-blind randomizedcontrolled trial of iniximab associated with prednisolone in acute alcoholic hepatitis.
Hepatology 2004;39:1390-7.
18. Menon KV, Stadheim L, Kamath PS, et al. A pilot study of the safety and tolerabilityof etanercept in patients with alcoholic hepatitis.Am J Gastroenterol2004;99:255-60.
19. Akriviadis E, Botla R, Briggs W, et al. Pentoxifylline improves short-term survivalin severe acute alcoholic hepatitis: a double-blind, placebo-controlled trial.Gastroenterology2000;119:1637-48.
20. Satapathy SK, Garg S, Chauhan R, et al. Benecial effects of tumor necrosis factor-alpha inhibition by pentoxifylline on clinical, biochemical, and metabolic parameters of
patients with nonalcoholic steatohepatitis.Am J Gastroenterology 2004;99:1946-52.
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Immunology o Biologic Agents or
NonimmunologistsThe immune system is an integrated system composed of the
innate immune system and the adaptive immune system. Even
though they are distinct systems, they are intimately linked.
The innate immune response can be dened by several principles:
It has no memory, so when assaulted, it responds as it did to
previous assaults.
The response occurs early and rapidly through quick
mobilization of its cellular elements macrophages,
polymorphonuclear leukocytes, dendritic cells, and the
soluble components that complement acute-phase proteins.
It operates by expressing the germ-line encoded receptors. It does not recognize every antigen; instead, it recognizes
highly conserved structures.
The role of the immune system is to protect against outside
invasion. It does this by detecting danger in the form of infection,
chemical insults (eg, environmental and self-inicted toxins),
and physical damage (eg, tissue injury, cell death).
In the case of an insult that punctures the skin, the rst layer
of defense is the epithelium, which contains molecules (eg, beta
defensins) that have antibacterial properties. Bacteria also reside
in the subcutaneous space for insults that penetrate the epithelium.
Dendritic cells in the epithelium (Langerhans cells in the epi -dermis) have a system of pattern recognition receptors, such
as pathogen-associated molecular pattern (PAMP) receptors.
When stimulated, dendritic cells secrete cytokines (eg, tumor
necrosis factor, IL-1, IL-6). These cytokines serve as an early
warning signal to the immune system. Resident tissue macro-
phages respond to this danger signal by accumulating at the
injury site. The cytokines prepare the endothelium to allow
the invasion of more inammatory cells by upregulating the
endotheliums adhesion molecules (selectins and integrins)
They further upregulate the microbicidal activity of the residen
phagocytic cells to allow them to kill the invader bacteria. Thiscytokine response occurs within a matter of hours, producing
inammation and erythema.
If the innate immune system fails, it must recruit additiona
defenses, such as natural killer cells (see Figure 1). The acute
phase response is an innate defense that involves increases in
the production of acute-phase proteins in the serum, one being
C-reactive proteins, which have the ability to bind to certain
bacterial recognition agents and activate brinogen, hapto
globin, and serum amyloid A, among others.
If infection persists despite the efforts of the innate immune
system, elements of the adaptive immune system are recruited
Remaining bacteria migrate to the regional lymph nodes, where
they interact with the adaptive immune system.
The adaptive immune response is a delayed response to a spe
cic antigen, demonstrating the features of specicity and
memory, two elements lacking in innate immunity. The two
types of adaptive immune response are cell-mediated and
humoral. Whenever adaptive immunity is elicited, it creates
cells that have immunologic memory to react quickly should
the invader attack again. Antigens are taken up by macrophages
and presented to helper T cells.
Both antibodies and T cells have unique surface receptors. Each
cell bears its own type of receptor that responds to a differenttype of antigen. When an antigen enters a cell, transport mole
cules called major histocompatibility complex (MHC) molecules
within the cell attach themselves to the cells surface, where they
present the antigen to helper T cells so that the T cell can bind to
the presented antigen. A second costimulatory signal is essentia
to activate the T cell. These costimulatory signals are members
of the B7 family and are expressed constitutively by T cells and
react to ligands on antigen-presenting cells.
Figure 1. Immune response stages
Innate Immunity(immediate:0-4 hours)
Early inducedresponse
(early:4-96 hours)
Adaptive immuneresponse
Infection
Infection
Infection
Recognition bypreformed,
nonspecic effectors
Recruitment ofeffector cells
Transport ofantigen to
Removal ofinfectious agent
Recognition,activation ofeffector cells
Recognitionby naive
Removal ofinfectious agent
Clonal expansionand differentiation
Removal of
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After the antigen has migrated to the regional lymph nodes and
has found the appropriate helper T cells, which have become
activated, the nal step in the adaptive response is deployment.
One limb of the activated T cell forms active effector cells, which
recognize cytokines and chemokines emanating from the area
of infection, and another limb of the activated T cells turns into
memory cells, which recognize the infection should it recur.
At the same time, B cells that have differentiated in the bone mar-
row migrate to the lymph nodes and search for the antigens thathave migrated from the skin. On the surface of every B cell are
Y-shaped antibodies called immunoglobulins (IgG, IgM, IgD, IgA,
and IgE) that have the capacity to recognize larger pieces of the
antigen. This is part of the humoral immune response. The anti-
body binds to the antigen at the arms of the Y.
Activated B cells secrete cytokines such as macrophages, T
cells, and dendritic cells. These cytokines and proteins cause
inammation and joint destruction in the patient with rheu-
matoid arthritis (RA). An important pathogenic inammatory
cytokine produced directly by activated B cells is IL-6, which
has a number of biological activities. Interleukin-6 is found
in the highest concentration of all the cytokines released by Bcells. It is active in many tissues including those of the liver,
bone, immune cells, fat, muscle, and kidney.
Role o the Allied Health Proessionalin use o Biologic Therapies or RAEach limb of the immune system is a potential target for
immune-based therapies. The infusible biologic agents with
indications in rheumatology are iniximab, abatacept, and
rituximab (see Table 1).
Table 1. Indications or TNF inhibitors
Disease Etanercept Infiximab Adalimumab
Rheumatoid arthritis Yes Yes Yes
Psoriatic arthritis Yes Yes Yes
Ankylosing spondylitis Yes Yes Yes
Juvenile idiopathic
arthritis
Yes In trials Yes
Crohns disease No Yes Yes
Ulcerative colitis No Yes In trials
Infiximab
Iniximab is an antibody that neutralizes the biological activ-
ity of TNF-alpha by binding to its soluble and transmembrane
forms and inhibiting TNF-alpha binding.
Abatacept
Abatacept is a fusion protein composed of an immunoglobulin
fused to the extracellular domain of CTLA-4, a molecule
capable of binding B7. Abatacept is a selective costimulation
modulator as it inhibits the costimulation of T cells.
Ordinarily, full T cell activation requires the following:
1) Binding of the T-cell receptor to the antigen-MHC
complex on the APC, and
2) A costimulatory signal provided by the binding of the
T cells CD28 protein to the B7 protein on the APC.
Abatacept, which contains a high-afnity binding site for B7
works by binding to the B7 protein on antigen-presenting cells
and preventing them from delivering the costimulatory signato T cells, thus preventing the full activation of T cells.
Rituximab
Rituximab is a chimeric monoclonal antibody against the
protein CD20, which is widely expressed on B cells, from
early pre-B cells to later in differentiation. Rituximab destroys
B lymphocytes, and thus, it is used to treat diseases that are
characterized by having too many B cells, overactive B cells
or dysfunctional B cells.
Contraindications to the use o biologicdisease-modiying antirheumatic drugs
Active infection and pneumonitis are contraindications to the
use of biologics. Others are prior lymphoproliferative disease
diagnosed and/or treated in the past 5 years, moderate to severe
heart failure (New York Heart Association Class III-IV), acute
hepatitis B virus (HBV) or hepatitis C virus (HCV) infection
(or chronic HBV or HCV infection for those with signican
liver injury), and multiple sclerosis or demyelinating disorders.
In patients scheduled for surgery, the American College of
Rheumatology recommends holding the medication for 1
week before and after surgery. An attempt should be made
to schedule the surgery in the middle of the infusion cycle
(eg, week 4 for those on iniximab).
Considerations beore starting anti-TNF therapy
Hepatitis screening
Rare reactivation of hepatitis B has occurred in chronic carriers
of the virus; evaluate all patients prior to initiation and during
treatment in patients at risk for hepatitis B infection.
Malignancy screening
Conrm that appropriate cancer screening is complete. Use of
anti-TNF therapies may affect defenses against malignancies
the impact on the development and course of malignancies is
not fully dened. An increased risk of lymphoma has been not
ed in clinical trials.
Tuberculosis
Data have associated TNF inhibitors with tuberculosis (TB)
reactivation, so patients should be evaluated for latent TB
infection with a tuberculin skin test before starting therapy
If results are positive, TB therapy should be initiated before
administering TNF inhibitors. Some patients who test negative
prior to therapy will develop active TB infection; therefore, it is
imperative to monitor for TB infection in all patients.
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Inections
Serious and potentially fatal infections have been reported
including bacterial sepsis and tuberculosis. Patients should be
assessed for active infection prior to every infusion.
Vaccination update
All vaccines should be brought up to date before starting anti-TNF
therapy. Immunosuppressed patients should not receive live vaccines.
Pregnancy test
Anti-TNF therapy has not been studied in pregnancy, so use of
these therapies during pregnancy should be avoided.
Nervous system disorders (demyelinating disease)
Demyelinating disease, such as multiple sclerosis, seizures, or
inammation of the nerves, have occurred in rare cases. Symp-
toms include numbness or tingling, problems with vision, weak-
ness in arms and legs, and dizziness. Patients should be screened
for these types of symptoms prior to beginning therapy.
Congestive heart ailure (CHF)
An echocardiogram or examination to rule out signs and symp-toms of CHF should be performed prior to initiating anti-TNF
therapy. Administration of anti-TNF agents has been linked to
worsening or new onset CHF.
Additional considerations
Specic TNF inhibitors have additional factors to consider
before starting therapy:
Abatacept should not be used in combination with anakinra
or TNF-blocking agents.
Baseline measures of immunoglobulins are recommended
because rituximab can deplete IgM and sometimes IgG.
Although evidence does not indicated an increased frequency
of TB in patients with lymphoma treated with rituximab, it
is often used concomitantly with methotrexate, so TB screen-
ing should be up to date.
Monitoring therapy with biologic agents
Abatacept
Six infusions of abatacept (5 months of treatment) may be re-
quired before its full effect is observed. A joint count and health
assessment questionnaire can help measure efcacy without the
need for a blood draw. Because patients must present to the
ofce every 4 weeks for abatacept treatments, it provides anopportunity to assess for new or subtle symptoms.
Monitoring is recommended approximately every 3 months.
This frequency allows clinicians to obtain a disease activity
score with three variables (DAS28-3), which requires a sedi-
mentation rate evaluation.
Rituximab
Monitoring patients on rituximab is unlike monitoring patients
on other biologics. Following rituximab infusion, 90% of the
patients B cells are depleted, although patients may not report
an improvement in RA symptoms for 6 weeks.
Our practice (Clark/Kirchner) checks patients 2 to 4 weeks
after they complete their second dose of rituximab, at which
point patients are evaluated for signs of clinical efcacy a
well as new symptoms or adverse events. Laboratory values
are monitored, including a complete blood count, B cell count
metabolic panel, and acute phase reactants. A 28-joint count
(DAS28) is advised.
Management o Inusion-Related IssuesThe ability to generate an adverse reaction to infusible biologic agents depends in part on the amount of antihuman protein
contained. The immune system reacts to these antibodies as a
foreign antigen and creates its own antibodies. Adverse effects
are classied in three categories (see Figure 2).
FIgure 2. Adverse eects o biologics
Adverse effects to drugs
Related directly to themechanism of action
allergicidiosyncratic
Infusion reactions to biologics can be either acute (occurring
within 24 hours, most commonly 10 minutes to 4 hours) or
delayed (occurring after 24 hours, most commonly 5 to 7 days)
Acute reactions are classied based on their severity (mild to mod
erate or severe). Mild to moderate reactions can consist of a change
in systolic blood pressure (SBP) of less than 20 mm Hg, headache
dizziness, pruritus, nausea, and palpitations. Severe reactions are
those causing a change in systolic BP of more than 40 mm Hgushing, fever, and shortness of breath with wheezing.
Delayed reactions mimic serum sickness and are often associated
with joint pain, mild fever, headache, myalgia, and skin rash.
Infusion reactions may have a hypersensitivity basis, but these
are rare. The clinical manifestations of anaphylactic acute
infusion reactions include bronchospasm and urticaria. Withou
these symptoms, the reaction is probably not allergic.
Infiximab
In ve studies of patients with RA, infusion reactions to inix
imab occurred in 15% to 20% of patients and in 3% of infusions.1-
Most reactions were mild with only 0.5% severe. Approximately0.4% of reactions were delayed.2 Reactions were similar for trials
in patients with Crohns disease (Table 2).6-10
Management o acute inusion reactions
The severity of the reaction guides the management strategie
for acute iniximab infusion reactions. Slowing the rate of infu
sion decreases the opportunity for immune complexes to form
With hemodynamic changes (eg, hypotension), stopping the
infusion may be necessary. Medications such as acetaminophen
(for fever) and diphenhydramine (for pruritus or mild allergy)
can be used on a symptomatic basis.
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For more severe reactions, methylprednisolone or hydrocorti-
sone have been recommended. For anaphylactic reactions, epi-
nephrine is advised.
Monitoring vital signs is important. The frequency of monitor-
ing depends on the severity of the reaction, which can range
from every 10 minutes with mild reactions to every 2 minutes
with very severe reactions.
Once the reaction is stable, the infusion can be reattempted at
a lower rate, following treatment with IV or oral diphenhydr-amine, 25 to 50 mg, and oral acetaminophen, 650 mg. Start
with an iniximab test dose of 10 mL/hr for 15 minutes then
gradually increase it to 125 mL/hr over 3 hours. A protocol has
been developed for effectively managing iniximab infusion
reactions.11
Table 2. Inusion reactions with infiximab
Study, disease Pts Inusions Inusion reactions
Infiximab Placebo
Rheumatoid Arthritis
Maini1 340 20% pts 10%
Maini2 259 3% 2%
St Clair4 751 15%-20% pts 0
Westhovens5 721 7592 2.6%
Crohns Disease
Kugathasan6 86 304 24% pts
Baert7 125 487 27% pts
Cheifetz8 165 479 6.1%
Farrell9 53 199 28% pts
Hanauer10 573 2863 3%-6%
Premedication: Evidence or and against
Preinfusion treatment with antihistamines or acetaminophen
to reduce the likelihood of infusion reactions is controversial.
Diphenhydramine pretreatment provided no benet to patients
with previous iniximab infusion reactions.12
Investigators developed a protocol for patients with prior
severe infusion reactions in which patients were treated with
oral diphenhydramine and oral acetaminophen 90 minutes
before the infusion, in addition to oral prednisone (or alterna-
tively IV hydrocortisone or IV methylprednisolone) 20 minutes
before the infusion.13 This protocol allowed successful retreat-
ment of three of four patients with severe acute reactions and
all patients with prior mild or moderate acute reactions.
Glucocorticoid pretreatment
Glucocorticoid pretreatment may be reasonable in RA patients
with prior moderate to severe iniximab infusion reactions or
comorbidities, or when changing to another infusible biologic
is not an option.
Preinfusion treatment with IV hydrocortisone has been shown
to reduce the development of antibodies to iniximab and the
incidence of subsequent infusion reactions.14 Use of daily low-
dose glucocorticoids has been found by some to be associated
with fewer treatment-limiting immediate infusion reactions to
iniximab but should not be used solely for this purpose.15 Pre-
infusion treatment with IV betamethasone, however, was no
found to reduce the risk of iniximab infusion reactions.16
Anti-infiximab antibodies
Iniximab infusion reactions are often attributed to anti-inix
imab antibodies (ATIs). Their true incidence is unknown be
cause measurement of ATIs depends on analytical technique
timing of sampling, dosing regimen, circulating drug, and con
comitant therapy.
Development of ATIs has been associated with a greater risk
of infusion reactions and tends to limit the long-term efcacy
of iniximab.17 Hanauer et al18 showed that infusion reactions
occurred in 16% of patients who were positive for ATIs compared
with 8% who were negative. Higher titers of ATIs have also been
associated with a greater frequency of infusion reactions.
Anti-iniximab antibodies can develop at any time but are more
likely to occur with sporadic infusions. Maser et al19 found tha
compared with scheduled infusions of iniximab, episodic infu
sions were associated with a greater rate of ATIs (39% vs 16%
P= 0.036) and infusion reactions (50% vs 21%; P= 0.018)
The development of ATIs was reduced only by scheduled
maintenance treatment. Patients receiving other immunosup
pressive therapy (eg, methotrexate) are much less likely to
develop ATIs.19-23
Even when treatment is optimized to avoid ATIs through
scheduled maintenance or by concomitant immunomodulator
therapy, approximately one-half of patients still need dose
adjustment to treat recurrent symptoms and about one-fth lose
response.
Rituximab
Rituximab infusion reactions are easily managed medically with
acetaminophen and diphenhydramine before the rst admin
istered dose of rituximab. Additional doses of acetaminophenhydrocortisone, and diphenhydramine can be used if fever or any
type of bronchospastic symptom occurs. If rigors occur, they can
be managed with meperidine. Most symptoms such as broncho
spasm, rigor, fever, and hypotension will resolve if treatment is
delayed for 30 minutes after additional medications.
If a side effect occurs, recommendations are to stop the infusion
for approximately 30 minutes, add IV saline, then resume the
infusion at a rate one step slower than the rate at the time of the
reaction. If the reaction abates, slowly increase the rate.
Emery et al24 showed that premedication with IV glucocorti
coids signicantly reduced both the incidence and severity of
acute infusion reactions in rituximab recipients.
Mechanism is multiactorial
Antichimeric antibodies are very rarely encountered in ritux
imab recipients. Rather, the mechanism of rituximab infusion
reactions appears to be multifactorial. A cytokine release syn
drome has been described in which increases in IL-6 and TNF-
alpha have been documented in patients with non-Hodgkins
lymphoma and chronic lymphocytic leukemia who have been
treated with rituximab.25 Hypersensitivity reactions are also
possible. In patients with Hodgkins lymphoma, some patients
have developed tumor lysis syndrome.
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Abatacept
Abatacept is a human fusion protein that has the ability to pre-
vent the costimulation of T cells. The FDA classies abatacept
infusion reactions as peri-infusional (within 24 hours) and
acute infusion events (within the rst hour). The incidence of
peri-infusional reactions is 22.8% and the incidence of acute
infusion reactions is 8.9%. Treatment discontinuation due to
infusion reactions is 0.6%. Most abatacept infusion reactions
are mild to moderate in severity. The most common effects aredizziness, headaches, and nausea.
Uncertain mechanism
The mechanism of abatacept infusion reactions is uncertain. The
immunogenicity potential is very low: antiabatacept antibodies
have been observed in only 1.7% of infusions, with antibody
titers being slightly higher with missed doses or long intervals
between infusions.
References
1. Maini RN, Breedveld FC, Kalden JR, et al. Therapeutic efcacy of multiple
intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody
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