biologics monograph

8/8/2019 Biologics Monograph

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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

Rationale or the use o biologic therapies in rheumatologyChristopher Ritchlin, MD, MPH, Elaine Husni, MD, MPH, Carol A. Langord, MD, MHS


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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

Rationale or the use o biologic therapies in rheumatology


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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

The rationale or and clinical experience with biologic agents in gastroenterolog


8/14

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

The role o allied health proessionals in the administrationand monitoring o biologic therapies in rheumatology

Leonard Calabrese, DO, Elizabeth Kirchner, CNP, Tiany Clark, RN, Carmen Gota, MD


10/14

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.

The role o allied health proessionals in the administration and monitoring o biologic therapies in rheumatology


12/14

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

combined with low-dose weekly methotrexate in rheumatoid arthritis.


2. Maini RN, Breedveld FC, Kalden JR, et al. Sustained improvement over two

years in physical function, structural damage, and signs and symptoms among

patients with rheumatoid arthritis treated with iniximab and methotrexate.


3. Lipsky PE, van der Heijde DM, St Clair EW, et al for the Anti-Tumor

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The role o allied health proessionals in the administration and monitoring o biologic therapies in rheumatology

biologics monograph

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