r.j. fasenmyer center for clinical immunology biologic therapies

Biologic Therapies: Clinical Implications for Rheumatologists, Gastroenterologists, Allied Health Practitioners

R.J. Fasenmyer Center for Clinical Immunology

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Spondyloarthritis: Therapeutic Implications of Advances in PathogenesisThree prevalent forms of inflammatory arthritis include rheu-matoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS). Although they share certain characteristics, they are distinguished by the specific sites of joint inflammation associated with each: the synovium in RA; the bone, enthesis, and synovium in PsA; and the bone and enthesis in AS. The location of inflammation 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 biomarkerOsteoclast precursors are monocyte effector cells in the circulation. An abundance of osteoclast precursors is observed in patients with certain phenotypes of erosive immune-mediated inflammatory 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 inflammatory 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 erosive IMID phenotypes

Control AS Crohn’s RA PsA Ps

OCP

per

milli

on m

onoc

ytes 100 --

80 --

60 --

40 --

20 --

0 -- -- -- -- -- -- -- --

IMID = immune-mediated inflammatory disorders

Therapeutic opportunityAn opportunity to arrest the development of a severely inflammatory phenotype of arthritis lies in the identification of patients with psoriasis and subclinical joint inflammation and patients with early inflammatory 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 spondyloarthropathiesActivation 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 inflammatory 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 the hyperproliferation 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 of receptor activator NF-κB ligand (RANKL) on synovial fibroblasts, 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 inflammatory phenotype 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 fluid of patients with PsA, and the effectiveness of anti-p40 antibodies in the treatment of psoriasis and PsA.

Therapeutic targetsTh17 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 specific 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 specific 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 is critical 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 efficacy 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 for the use of biologic therapies in rheumatologyChristopher Ritchlin, MD, MPH, Elaine Husni, MD, MPH, Carol A. Langford, 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 inflammation, such that new bone formation may be influenced 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 be effective 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 specific immunologic tar-geting. Of concern, however, is that such specific targeting may be insufficient to modulate the disease and reduce the potential for disease-specific 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 Wegener’s granulomatosis and giant cell arteritis.

Wegener’s granulomatosisWegener’s 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, defined as the absence of disease activity; 2) Avoidance of disease relapse, defined as the return of disease activity after achieving remission; and 3) Minimization of therapeutic toxicity.

The current treatment approach to Wegener’s 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). Wegener’s 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. Wegener’s granulomatosis: Summary of current 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 inflam-mation may represent a therapeutic strategy in Wegener’s 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 Wegener’s granulomatosis has been supported by evidence gained from the laboratory.Based on these data, therapies that interrupt TNF production gen-erated initial excitement in Wegener’s 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 Wegener’s granulomatosis.7 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 infliximab in 32 patients with Wegener’s granulomatosis 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 sufficiently powered trial, the efficacy of other anti-TNF agents cannot be determined. Current evi-dence, however, does not support the use of any anti-TNF agent in Wegener’s granulomatosis.Another avenue for intervention in Wegener’s 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 Wegener’s granulomatosis. A clinical trial of abatacept in the treatment of mild, relapsing Wegener’s granulomatosis by the Vasculitis Clinical Research Consortium is ongoing.B-cell–depleting therapies were first 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 efficacy, important questions that remain with B-cell–depleting therapy are whether its effects differ between organs and whether any disease impact occurs through ANCA or other B-cell–dependent mechanisms. These questions are being explored through the ongoing Rituximab in ANCA-associated Vasculitis (RAVE) trial.

Giant cell arteritisGiant 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 serious morbidity 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 infliximab 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 infliximab had infec-tion than placebo recipients. This finding was replicated in a placebo-controlled study of infliximab 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 inflammation. 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 symptomsReduces risks of blindness

Relapse 75-90% Toxicity 35-86%

PsA: QOL Issues and the Role of BiologicsUp to 30% of patients with psoriasis can have inflammatory 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 manifestations

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 QOLIn public health and in medicine, the concept of health-related QOL refers to a person or group’s perceived physical and men-tal health over time. Tracking health-related QOL in different populations can identify subgroups with poor physical or mental 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 person’s day-to-day life. Patients with arthritis have significantly 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, inflammation, 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-specific. Examples of general health measures are the SF-36, the Euro-QOL, the Nottingham Health Profile, and the Health Assessment Questionnaire (HAQ), which is a measure of disease activity and long-term disability. Instruments specific to PsA include the PsA QOL, the expanded HAQ (HAQ-SK), and the Psoriatic Arthritis Response Criteria (PsARC).

Willingness to pay as a measure of impactA novel technique to further extrapolate on the QOL issues is the 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 benefit 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.References1. 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. Lancet 2009;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 of patients with moderately to severely active psoriatic arthritis. Arthritis Rheum 2005;52:3279-89.

7. Wegener’s Granulomatosis Etanercept Trial (WGET) Research Group. Etanercept plus standard therapy for Wegener’s granulomatosis. N Engl J Med 2005;352:351-61.

8. Stone JH, Holbrook JT, Marriott MA, et al. Solid malignancies among patients in the Wegener’s 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 infliximab in anti-neutrophil cytoplasmic antibody-associated systemic vasculitis. J Am Soc Nephrol 2004;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, Specks U. Rituximab for refractory Wegener’s granulomatosis: report of a prospective, open-label pilot trial. Am J Resp Crit Care Med 2006;173:180-7.

12. Hoffman GS, Cid MC, Rendt-Zagar KE, et al. Infliximab for maintenance of glucocorticosteroid-induced remission of giant cell arteritis: a randomized trial. Ann Intern Med 2007;146:621-30.

13. Salvarani C, Macchioni P, Manzini C, et al. Infliximab plus prednisone or placebo plus prednisone for the initial treatment of polymyalgia rheumatica: a randomized trial. Ann Intern Med 2007;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 Rheumatol 2003;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 Rheumatol 2007;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 Dermatol 2005;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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Benefits and Risks of Biologics in Inflammatory Bowel Disease: Critical Management DecisionsThe treatment goals in inflammatory 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 Crohn’s 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 Crohn’s disease: • Infliximab, 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 Crohn’s disease. In several trials, remission and maintenance of remission was achieved significantly more often in patients assigned to anti-TNF therapy (infliximab, adalimumab, and certolizumab) than in pla-cebo recipients.1-5 The trials also showed significant improvement in maintenance of remission with biologic agents as well as lower rates of Crohn’s 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 noninflammatory complications of the bowel.About one-third of patients with Crohn’s disease treated with infliximab will require dose escalation.2 In patients with sec-ondary failure to infliximab, 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 infliximab therapy but lost responsiveness, switching them to adalimumab achieved signifi-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 confirm ongoing active inflammation, as not all recurrent symptoms are caused by disease activity. If the presence of inflam-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 of therapyChoosing between biologic therapies is complicated because different trial designs, patient populations, and definitions of response and remission prevent valid comparisons of results. Taking into consideration the heterogeneity in the definition of response, all clinical trials of TNF inhibitors have resulted in a fairly uniform response rate of approximately 60% at week 4.With efficacy established for the biologic agents in the treatment of Crohn’s disease, attention shifts to selecting the best treatment and improving outcomes.

Risk of immunogenicityImmunogenicity 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 infliximab infusions is associated with the formation of anti-infliximab antibodies (ATIs). The development of ATIs corre-lates with an increased risk of infusion reactions, lower serum con-centrations of infliximab, and a shorter duration of response.1,8-10 The 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 infliximab, and that administering inflix-imab on a scheduled basis with the recommended induction regi-men will reduce formation of ATIs. Antibody formation is not unique to infliximab. 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 of patients form antibodies when treated with fontolizumab.

“Step up” or “top down” strategies Two competing strategies for the treatment of Crohn’s 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 infliximab and azathioprine was superior to a step up strategy at inducing remission without corti-

The rationale for and clinical experience 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 Crohn’s dis-ease diagnosed in the previous 4 years.12 Relapse happened later for patients who started with infliximab and azathioprine than in those who started on steroids. Serious adverse events were similar in each treatment group. The rate of pancreatitis was not significantly differ-ent between groups, and all cases of pancreatitis occurred in patients on azathioprine. The top down strategy was associated with a non-significant 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 therapyThe choice of biologic agent accounts for efficacy and toxicity as well as patient preference and the willingness to cooperate with treatment. Although efficacy in achieving and maintaining remission between TNF 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 — infliximab, 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 fill the prescription.The patient’s willingness to accept the potential adverse events in exchange for clinical benefits must also be considered in the choice of treatment. In a survey of patients with chronic active disease, greater risk acceptance correlated with greater symptom improvement (see Figure 2).13

Figure 2. Risks vs benefits: 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

Severe to Mild

Severe toRemission

Observed risk

MAR

(Ann

ual %

Ris

k)

PMLSerious infectionLymphoma

The Role and Risks of Natalizumab in the Treatment of IBDNatalizumab may be considered for difficult-to-treat patients with Crohn’s disease. It is approved for treating moderately to severely active Crohn’s disease. The benefit-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 two large clinical studies,15 the incidence of all-cause and Crohn’s disease-related hospitalizations was reduced significantly 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 confirmed among the 39,000 patients worldwide who have been treated with natalizumab, only one of whom was being treated for Crohn’s 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 certified through the monitoring program developed in accordance with the US Food and Drug Administration. Figure 3 shows 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 US FDA and approved

by European Medicines Agency

January 2008: Approved by US FDA

for moderately to severely active Crohn’s Disease

Current Use: 35,500patients worldwide

September 2006: Approved by Health 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 for Biologic Agents in the Management of Nonalcoholic and Alcoholic Fatty Liver DiseaseNonalcoholic fatty liver disease represents a wide spectrum of 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, inflammation of the liver, necrosis of liver cells, and possibly fibrosis), but the progression from alcoholic liver disease to hepatitis and cirrho-sis is much greater. Whereas about 1% of patients with nonalcoholic

The rationale for and clinical experience with biologic agents in gastroenterology

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steatosis will progress over their lifetime to cirrhosis and liver-related death, alcoholic hepatitis will progress to cirrhosis and one-fifth will die from liver-related injury. However, the prevalence of nonalco-holic steatohepatitis is much higher than that for alcoholic hepatitis.

Alcoholic fatty liver: The rationale for biologicsThe 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 through the administration of gadolinium chloride, ethanol-induced increases in AST can be blunted.16 Fatty liver, inflammation, and fibrosis have been prevented by knocking out TNF-R1 and by administration of TNF-alpha antibodies.

Clinical data with biologics in alcoholic fatty liverEtanercept and infliximab have been studied in alcoholic liver disease. A standard dose of infliximab results in reductions in ALT and total bilirubin, but mortality in severe alcoholic hep-atitis was increased with the addition of infliximab 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 significantly 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 significant 40% reduction in mortality compared with placebo.19 The difference in mortality occurred after 2 to 3 weeks of therapy and was due to a reduction in the development of hepatorenal syndrome.

Nonalcoholic fatty liver disease: The rationale for 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 deficient diet, anti-TNF therapy produced significant reductions in the percentage of steatotic cells, inflammation, necrotic focus, fibro-sis, and activated stellate cells compared with placebo. In experimental nonalcoholic fatty liver disease, infliximab decreased total liver fat and levels of TNF, IL-8, and other

cytokines. Inhibition of TNF-alpha using pentoxyfylline reduced ALT significantly with a reduction in insulin resistance in patients with nonalcoholic steatohepatitis.20

No current role for biologicsBiologic 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 therapy that interrupts the natural history of NAFLD is bariatric surgery.References1. Hanauer S, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 2002;359:1541-9.2. Rutgeerts P, Feagan BG, Lichtenstein GR, et al. Comparison of scheduled and episodic treatment strategies of infliximab in Crohn’s disease. Gastroenterology 2004;126:402-13.3. Colombel JF, Sandborn WJ, Rutgeerts P, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial. Gastroenterology 2007;132:52-65.4. Feagan BG, Panaccione R, Sandborn WJ, et al. Effects of adalimumab therapy on incidence of hospitalization and surgery in Crohn’s disease: results from the CHARM study. Gastroenterology 2008;135:1493-9.5. Schreiber S, Khalig-Kareemi M, Lawrence IC, et al. Maintenance therapy with certolizumab pegol for Crohn’s disease. N Engl J Med 2007;357:239-50.6. Sandborn WJ, Hanauer SB, Rutgeerts P, et al. Adalimumab for maintenance treatment of Crohn’s disease: results of the CLASSIC II trial. Gut 2007;56:1232-9.7. Sandborn WJ, Rutgeerts P, Enns R, et al. Adalimumab induction therapy for Crohn’s disease previously treated with infliximab: a randomized trial. Ann Intern Med 2007;146:829-38.8. Baert F, Noman M, Vermeire S, et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn’s disease. N Engl J Med 2003;348:601-8.9. Sands BE, Anderson FH, Bernstein CN, et al. Infliximab maintenance therapy for fistulizing Crohn’s disease. N Engl J Med 2004;350:876-85.10. Kugathasan S, Levy MB, Saeian K, et al. Infliximab retreatment in adults and children with Crohn’s disease: risk factors for the development of delayed severe systemic reaction. Am J Gastroenterol 2002;97:1408-14.11. Farrell RJ, Alsahli M, Jeen YT, et al. Intravenous hydrocortisone premedication reduces antibodies to infliximab in Crohn’s disease: a randomized controlled trial. Gastroenterology 2003;124:917-24.12. D’Haens G, Baert F, van Assche G et al. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn’s disease: an open randomised trial Lancet 2008;371:660-7.13. Sands B, Siegel C, Hass S, et al. Crohn’s disease patients’ willingness to accept the risks of serious adverse events in exchange for clinical benefit. Presentation at Digestive 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 active Crohn’s disease: results of the ENCORE Trial. Gastroenterology 2007;132:1672-83.15. Sands BE, Siegel CA, Spencer M, Hass S. Natalizumab reduces the hospitalization rate in moderate to severe Crohn’s disease patients: A pooled analysis of the ENACT-1 and 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 early alcohol-induced liver injury. Hepatology 1994;20:453-60.17. Naveau S, Chollet-Martin S, Dharancy S, et al. A double-blind randomized controlled trial of infliximab 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 tolerability of etanercept in patients with alcoholic hepatitis. Am J Gastroenterol 2004;99:255-60.19. Akriviadis E, Botla R, Briggs W, et al. Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled trial. Gastroenterology 2000;119:1637-48.20. Satapathy SK, Garg S, Chauhan R, et al. Beneficial 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 of Biologic Agents for 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 defined 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-inflicted toxins), and physical damage (eg, tissue injury, cell death).In the case of an insult that punctures the skin, the first 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 inflammatory cells by upregulating the

endothelium’s adhesion molecules (selectins and integrins). They further upregulate the microbicidal activity of the resident phagocytic cells to allow them to kill the invader bacteria. This cytokine response occurs within a matter of hours, producing inflammation and erythema. If the innate immune system fails, it must recruit additional 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 fibrinogen, 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-cific antigen, demonstrating the features of specificity 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 different type of antigen. When an antigen enters a cell, transport mole-cules called major histocompatibility complex (MHC) molecules within the cell attach themselves to the cell’s 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 essential 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

(late: >96 hours)

Infection

Infection

Infection

Recognition bypreformed,

nonspeci�c effectors

Recruitment ofeffector cells

Transport ofantigen to

lymphiod organs

Removal ofinfectious agent

Recognition,activation ofeffector cells

Recognitionby naive

B and T cells


Clonal expansionand differentiationto effector cells


The role of allied health professionals in the administration and monitoring of biologic therapies in rheumatology

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

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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 final 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 that have 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 inflammation and joint destruction in the patient with rheu-matoid arthritis (RA). An important pathogenic inflammatory 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 B cells. It is active in many tissues including those of the liver, bone, immune cells, fat, muscle, and kidney.

Role of the Allied Health Professional in use of Biologic Therapies for RAEach limb of the immune system is a potential target for immune-based therapies. The infusible biologic agents with indications in rheumatology are infliximab, abatacept, and rituximab (see Table 1).

Table 1. Indications for TNF inhibitors

Disease Etanercept Infliximab Adalimumab

Rheumatoid arthritis Yes Yes Yes

Psoriatic arthritis Yes Yes Yes

Ankylosing spondylitis Yes Yes Yes

Juvenile idiopathic arthritis

Yes In trials Yes

Crohn’s disease No Yes Yes

Ulcerative colitis No Yes In trials

InfliximabInfliximab 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.

AbataceptAbatacept 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 cell’s CD28 protein to the B7 protein on the APC.

Abatacept, which contains a high-affinity binding site for B7, works by binding to the B7 protein on antigen-presenting cells and preventing them from delivering the costimulatory signal to T cells, thus preventing the full activation of T cells.

RituximabRituximab 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 of biologic disease-modifying antirheumatic drugsActive 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 significant 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 infliximab).

Considerations before starting anti-TNF therapy

Hepatitis screeningRare 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 screeningConfirm 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 defined. An increased risk of lymphoma has been not-ed in clinical trials.

TuberculosisData 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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InfectionsSerious and potentially fatal infections have been reported including bacterial sepsis and tuberculosis. Patients should be assessed for active infection prior to every infusion.

Vaccination updateAll vaccines should be brought up to date before starting anti-TNF therapy. Immunosuppressed patients should not receive live vaccines.

Pregnancy testAnti-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 inflammation 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 failure (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 considerationsSpecific 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 screening should be up to date.

Monitoring therapy with biologic agents

AbataceptSix 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 efficacy without the need for a blood draw. Because patients must present to the office every 4 weeks for abatacept treatments, it provides an opportunity 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.

RituximabMonitoring patients on rituximab is unlike monitoring patients on other biologics. Following rituximab infusion, 90% of the patient’s 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 efficacy as 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 of Infusion-Related IssuesThe ability to generate an adverse reaction to infusible biolog-ic 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 classified in three categories (see Figure 2).

FIgure 2. Adverse effects of biologics

Adverse effects to drugs

Related directly to the mechanism 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 classified 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 Hg, flushing, 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. Without these symptoms, the reaction is probably not allergic.

InfliximabIn five studies of patients with RA, infusion reactions to inflix-imab occurred in 15% to 20% of patients and in 3% of infusions.1-5 Most reactions were mild with only 0.5% severe. Approximately 0.4% of reactions were delayed.2 Reactions were similar for trials in patients with Crohn’s disease (Table 2).6-10

Management of acute infusion reactionsThe severity of the reaction guides the management strategies for acute infliximab 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 infliximab 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 infliximab infusion reactions.11

Table 2. Infusion reactions with infliximabStudy, disease Pts Infusions Infusion reactions

Infliximab Placebo

Rheumatoid Arthritis

Maini1 340 20% pts 10%

Maini2 259 3% 2%

St Clair4 751 15%-20% pts 0

Westhovens5 721 7592 2.6%

Crohn’s 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 for and againstPreinfusion treatment with antihistamines or acetaminophen to reduce the likelihood of infusion reactions is controversial. Diphenhydramine pretreatment provided no benefit to patients with previous infliximab 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 pretreatmentGlucocorticoid pretreatment may be reasonable in RA patients with prior moderate to severe infliximab 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 infliximab 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 infliximab but should not be used solely for this purpose.15 Pre-

infusion treatment with IV betamethasone, however, was not found to reduce the risk of infliximab infusion reactions.16

Anti-infliximab antibodiesInfliximab infusion reactions are often attributed to anti-inflix-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 efficacy of infliximab.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-infliximab antibodies can develop at any time but are more likely to occur with sporadic infusions. Maser et al19 found that compared with scheduled infusions of infliximab, 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-fifth lose response.

RituximabRituximab infusion reactions are easily managed medically with acetaminophen and diphenhydramine before the first admin-istered dose of rituximab. Additional doses of acetaminophen, hydrocortisone, 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 significantly reduced both the incidence and severity of acute infusion reactions in rituximab recipients.

Mechanism is multifactorialAntichimeric 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-Hodgkin’s lymphoma and chronic lymphocytic leukemia who have been treated with rituximab.25 Hypersensitivity reactions are also possible. In patients with Hodgkin’s lymphoma, some patients have developed tumor lysis syndrome.

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AbataceptAbatacept is a human fusion protein that has the ability to pre-vent the costimulation of T cells. The FDA classifies abatacept infusion reactions as peri-infusional (within 24 hours) and acute infusion events (within the first 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 are dizziness, headaches, and nausea.

Uncertain mechanismThe 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.References1. Maini RN, Breedveld FC, Kalden JR, et al. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum 1998;41:1552-63.

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 infliximab and methotrexate. Arthritis Rheum 2004;50:1051-65.

3. Lipsky PE, van der Heijde DM, St Clair EW, et al for the Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. Infliximab and methotrexate in the treatment of rheumatoid arthritis. N Engl J Med 2000;343:1594-602.

4. St Clair W, van der Heijde DM, Smolen JS, et al. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial. Arthritis Rheum 2004;50:3432-43.

5. Westhovens R, Yocum D, Han J, et al. The safety of infliximab, combined with background treatments, among patients with rheumatoid arthritis and various comorbidities: a large, randomized, placebo-controlled trial. Arthritis Rheum 2006;54:1075-86.

6. Kugathasan S, Levy MB, Saeian K, et al. Infliximab retreatment in adults and children with Crohn’s disease: risk factors for the development of delayed severe systemic reaction. Am J Gastroenterol 2002;97:1408-14.

7. Baert F, Noman M, Vermeire S, et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn’s disease. N Engl J Med 2003;348:601-8.

8. Cheifetz A, Smedley M, Martin S, et al. The incidence and management of infusion reactions to infliximab: a large center experience. Am J Gastroenterol 2003;98:1315-24.

9. Farrell RJ, Alsahli M, Jeen YT, et al. Intravenous hydrocortisone premedication reduces antibodies to infliximab in Crohn’s disease: a randomized controlled trial. Gastroenterology 20003;124:917-24.

10. Hanauer SB, Feagan BG, Lichtenstein GR, et al, for the ACCENT I Study Group. Maintenance infliximab for Crohn’s disease: the ACCENT I randomized trial. Lancet 2002;359:1541-9.

11. Lequerré T, Vittecoq O, Klemmer N, et al. Management of infusion reactions to infliximab in patients with rheumatoid arthritis or spondyloarthritis: experience from an immunotherapy unit of rheumatology. J Rheumatol 2006;33:1301-14.

12. Wasserman MJ, Weber DA, Guthrie JA, et al. Infusion-related reactions to infliximab in patients with rheumatoid arthritis in a clinical practice setting: relationship to dose, antihistamine pretreatment, and infusion number. J Rheumatol 2004;31:1912-7.

13. Cheifetz A, Smedley M, Martin S, et al. The incidence and management of infusion reactions to infliximab: a large center experience. Am J Gastroenterol 2003;98:1315-24.

14. Farrell RJ, Alsahli M, Jeen YT, et al. Intravenous hydrocortisone pre-medication reduces antibodies to infliximab in Crohn’s disease: a randomized controlled trial. Gastroenterology 2003;124:917-24.

15. Augustsson J, Eksborg S, Ernestam S, et al. Low-dose glucocorticoid therapy decreases risk for treatment-limiting infusion reaction to infliximab in patients with rheumatoid arthritis. Ann Rheum Dis 2007;44:1462-6.

16. Sany J, Kaiser MJ, Jorgensen C, Trape G. Study of the tolerance of inflix-imab infusions with or without betamethasone premedication in patients with active rheumatoid arthritis. Ann Rheum Dis 2005;64:1647-9.

17. Baert F, Noman M, Vermeire S, et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn’s disease. N Engl J Med 2003;348:601-8.

18. Hanauer SB, Feagan BJ, Lichtenstein GR, et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 2002;359:1541-9.

19. Maser EA, Villela R, Silverberg MS, Greenberg GR. Association of trough serum infliximab to clinical outcome after scheduled maintenance treatment for Crohn’s disease. Clin Gastroenterol Hepatol 2006;4:1248-54.

20. Braun J, Kästner P, Flaxenberg P, et al. Comparison of the clinical efficacy and safety of subcutaneous versus oral administration of methotrexate in patients with active rheumatoid arthritis: results of a six-month, multicenter, randomized, double-blind, controlled, phase IV trial. Arthritis Rheum 2008;58:73-81.

21. Maini RN, Breedveld FC, Kalden JR, et al. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum 1998;41:1552-63.

22. Vermeire S, Noman M, Van Assche G, et al. Effectiveness of concomitant immunosuppressive therapy in suppressing the formation of antibodies to infliximab in Crohn’s disease. Gut 2007;56:1226-31.

23. Hanauer SB, Wagner CL, Bala M, et al. Incidence and importance of antibody responses to infliximab after maintenance or episodic treatment in Crohn’s disease. Clin Gastroenterol Hepatol 2004;2:542-53.

24. Emery P, Fleischmann R, Filipowicz-Sosnowska A, et al. The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial. Arthritis Rheum 2006;54:1390-400.

25. Winkler U, Jensen M, Manzke O, et al. Cytokine-release syndrome in patients with B-cell chronic lymphocytic leukemia and high lymphocyte counts after treatment with an anti-CD20 monoclonal antibody (rituximab, IDEC-C2B8). Blood 1999;94:2217-24.


r.j. fasenmyer center for clinical immunology biologic therapies

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