The safety of etanercept for the treatment
`of plaque psoriasis
`
`R E V I E W S
`
`Kim A Papp
`University of Western Ontario, and
`K Papp Clinical Research, Waterloo,
`ON, Canada
`
`Correspondence: Kim A Papp
`University of Western Ontario, and K
`Papp Clinical Research, 135 Union Street
`East, Waterloo, ON, Canada N2J 1C4
`Tel +1 519 579 9535
`Fax +1 519 579 8312
`Email kapapp@probitymedical.com
`
`Abstract: Effective treatment with etanercept results from a congregation of immunological
`signaling and modulating roles played by tumor necrosis factor-alpha (TNF-alpha), a pervasive
`member of the TNF super-family of cytokines participating in numerous immunologic and
`metabolic functions. Macrophages, lymphocytes and other cells produce TNF as part of the
`deregulated immune response resulting in psoriasis or other chronic infl ammatory disorders.
`Tumor necrosis factor is also produced by macrophages and lymphocytes responding to foreign
`antigens as a primary response to potential infection. Interference with cytokine signaling by
`etanercept yields therapeutic response. At the same time, interference with cytokine signaling by
`etanercept exposes patients to potential adverse events. While the effi cacy of etanercept for the
`treatment of psoriasis is evident, the risks of treatment continue to be defi ned. Of the potential
`serious adverse events, response to infection is the best characterized in terms of physiology,
`incidence, and management. Rare but serious events: activation of latent tuberculosis, multiple
`sclerosis, lymphoma, and others, have been observed but have questionable or yet to be defi ned
`association with therapeutic uses of etanercept. The safe use of etanercept for the treatment of
`psoriasis requires an appreciation of potential adverse events as well as screening and monitoring
`strategies designed to manage patient risk
`Keywords: etanercept, psoriasis, demyelination, tumor necrosis factor, lymphoma, tuberculosis,
`infection, safety
`
`Characterizing the safety of a drug is rarely simple and never complete. Both short
`and long-term drug safety profi les require episodic, critical reviews of available
`information. Episodic reviews are necessary to survey case reports and put previous
`summaries into perspective. Critical evaluation is important to determine relevance,
`veracity, and adequacy of available information. Etanercept is no exception.
`The short-term safety of etanercept is well established by rigorous clinical trials in
`rheumatoid arthritis, psoriatic arthritis, and psoriasis (Leonardi et al 2003; Papp 2004;
`Keystone 2005; Kavanaugh et al 2006). Registries, now abundant in the rheumatology
`arena, are resources for assessing long-term risk and harm (Sokka 2004). Psoriasis
`registries should provide useful data over the next few years. Nonetheless, information
`extracted from registries must be put into context. The underlying disease may have
`epidemiologic characteristics different from the target disease. And, by their nature,
`registries are not as restrictive or as selective as controlled trials (Krishnan and Fries
`2004). There is a treatment bias: treatment tends to be given to a sicker population.
`There may be a confounding indication: not every enrollee fulfi lls appropriate
`diagnostic criteria. Biased patient selection, good or bad, may exaggerate effectiveness
`or safety. In addition, patients enrolled in clinical registries have few if any restriction on
`concurrent therapy thus confounding drug-drug interactions and attribution of effi cacy
`or adverse effects. On the other hand, registries are thought to be more refl ective of
`
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`real world experience. In addition, registries often provide
`larger number of patients, long periods of observation and
`data collection compared with registration trials.
`Case reports will identify unanticipated adverse events
`attributed to etanercept but are limited by the potential for
`inappropriate association of cause and effect. Etanercept is an
`effective therapy for psoriasis: effectiveness is advantageous
`to its adoption as a new therapy. This advantage is potentially
`offset by heightened scrutiny, off-label use, and sub-standard
`post marketing reports of adverse events.
`In this review, every effort is made to provide a balanced
`appraisal of risk. Pathophysiology and likelihood of
`association are considered as complements to incident reports
`when evaluating safety (Mulrow et al 1997; Ioannidis et al
`2006). Where assessment of risk is hampered by insuffi cient
`epidemiologic data, provisional estimates or cautionary
`comments are inserted.
`
`Background
`TNF-alpha, often referred to as tumor necrosis factor (TNF),
`is one member of the TNF superfamily of cytokines (Zhou
`et al 2002). TNF was initially described as a hemorrhagic
`necrosis factor produced by lipopolysaccharide-stimulated
`tumours. We now appreciated that TNF is a ubiquitous
`cytokine expressed by many cell types and having activity
`in innate and adaptive immune pathways (Zhou et al 2002).
`As a consequence of its important immunological function,
`TNF plays a central role in acute and chronic infl ammation
`(Liz-Grana and Carnota 2001; Pfeffer, 2003). The variety
`of immunological and metabolic processes affected by
`TNF-alpha, the functions of soluble and membrane bound
`TNF-alpha, and interactions between members of the TNF
`superfamily are impacted by the molecular activity of TNF-
`inhibitors such as etanercept. Both unanticipated risks and
`unanticipated benefi ts may arise through long-term high
`frequency exposure to a TNF-inhibitor. Given the unique
`molecular characteristics of each TNF-inhibitor, we expect
`common risk-benefi t profi les and differences.
`Etanercept is a dimeric fusion protein produced using
`recombinant genetic programming of Chinese hamster ovary
`cells. The protein has a molecular weight of 150 kDa and
`consists of two 75 kDa TNF-alpha receptors linked to the Fc
`portion of human immunoglobulin G1 (Dembic et al 1990;
`Mohler et al 1993).
`Clinical study reports are suffi ciently detailed to provide
`short term safety data, but none are powered to identify rare
`events. The National Data Bank for Rheumatic Diseases
`
`and the publicly available BIOBADASER are examples of
`registries that provide excellent longitudinal information
`on patients with rheumatologic diseases treated with TNF-
`antagonists.
`The structure of this review is as follows: Broad
`categories of adverse events are identifi ed. Within each
`category there may be specifi c, noteworthy concerns. Inciting
`observations and scientifi c rationale preface each general and
`specifi c category. Data relevant to the category are presented
`accompanied by brief commentary. Comparative data for
`TNF-antagonists as a group are avoided where possible to
`limit the scope of the review.
`
`Mechanisms of action
`Tumor necrosis factor-alpha engages in many aspect of
`immunological function. By its activity on TNF-alpha,
`etanercept will impact immunological and infl ammatory
`processes ranging from innate and extrinsic immunological
`response, cellular traffi cking, acute and chronic infl ammation,
`fever, and neuroendocrine regulation (Gruss and Dower
`1995). TNF interacts with glucocorticoids to regulate Toll-
`like receptor 2 gene expression (Hermoso et al 2004).
`The precise mechanisms of action of TNF-antagonists
`are not known. Certainly etanercept binds to free, soluble,
`or non-membrane-bound TNF-alpha but etanercept also
`has activity against the p55 receptor TNF-beta, also called
`lymphotoxin (Williams and Griffi ths 2002; Keystone and
`Dinarello 2005). Contrary to the effects on TNF-alpha, the
`activity of etanercept against p55 may stimulate immuno-
`reactivity (Han et al 2005) in addition to having effects on B-,
`T-, NK-cells and lymphoid architecture (Spahn et al 2005).
`Moreover, there is evidence that both etanercept and infl iximab
`induce apoptosis in macrophages, but not lymphocytes within
`rheumatoid arthritis (RA) joints (Catrina et al 2005). In general,
`the effects of etanercept are mediated by its binding of soluble
`TNF-alpha, but other TNF-antagonist activities are recognized.
`The implications of accessory TNF-antagonist activities are
`not known. Etanercept has peak absorption at 51 hours and a
`mean half-life of 68 hours (Korth-Bradley et al 2000).
`Whether or not TNF is an intrinsic pyrogen remains
`controversial (Stefferl et al 1996; Luheshi et al 1997;
`Dinarello 2005). In the mouse model, TNF does not appear
`to have pyrogen activity (Dinarello 2005). Nonetheless,
`resolving the question for humans is signifi cant as fever is a
`common, early, ubiquitous sign of infection and infections
`remain the most prominent safety concern during treatment
`with TNF-antagonists.
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`A more complex role is refl ected in the effects TNF may have
`on neuroendocrine response. Pituitary and hypothalamic response
`are potentiated when TNF is present in high levels (Turnbull
`and Rivier 1999). The neuroendocrine effects of TNF may be
`refl ected in the psychological state of patients experiencing
`chronic infl ammatory disease (Tyring et al 2006).
`
`Adverse events
`Injection site reactions
`Mechanical processes such as poor injection technique,
`irritation, or immunologically mediated inflammatory
`processes associated with either drug or excipients cause
`injection site reactions. Foreign proteins may cause direct
`or indirect infl ammatory response (Shepherd 2003). It is not
`surprising that injection site reactions are by far the most
`common side effect associated with etanercept.
`Studies evaluating etanercept for the treatment of RA
`report a high incidence of injection site reactions with
`34%–37% of etanercept-treated patients compared with
`7%–10% of controls reporting reactions (Lebwohl 2002;
`Fleischmann and Yocum 2004). The high incidence in the
`RA population contrasts with a much lower incidence seen
`in psoriasis studies: 14%–20% (Leonardi et al 2003; Papp
`2004; Papp et al 2005). Why there are stark differences in
`the incidence of injection site reactions between RA and
`psoriasis populations is not known.
`Injection site reactions with 25 mg doses of etanercept
`are mild, well tolerated, self-limiting, and tend to occur early
`in the course of therapy (Zeltser et al 2001; Papp 2004).
`Irritation during and briefl y following injection is very
`common with the 50 mg single dose compared with the 25
`mg dosing formulation. Occasionally, persistent reactions
`of moderate severity are noted. Persistent reactions are
`characterized by erythematous, indurated, and urticarial like
`plaques (Edwards et al 2003). The histology of etanercept
`injection site reactions is consistent with a delayed-type
`hypersensitivity reaction (Werth and Levinson 2001; Zeltser
`et al 2001). Delayed and recall injection site reactions are
`infrequent but tend to be somewhat more severe than typical
`etanercept-associated injection site reactions (Zeltser et al
`2001; Rajakulendran and Deighton 2004). Signifi cant
`and severe injection site reactions are rare with etanercept
`regardless of dose (Papp 2004).
`
`Infection
`Clinical trials and post-marketing experience suggest that
`infection is the most common signifi cant category of adverse
`
`Safety of etanercept for the treatment of plaque psoriasis
`
`events experienced by patients treated with etanercept. Less
`common infections including tuberculosis and opportunistic
`infections, specifi cally histoplasmosis and listeriosis, are
`considered separately.
`TNF is involved in the immune response to bacterial
`and viral infections (Imanishi 2000; Herbein and O’Brien
`2000). More specifi cally, TNF plays an essential role in
`host response to intracellular pathogens (Choy and Panayi
`2001). The important role of TNF in immune response to
`intracellular organisms is further supported by TNF-defi cient
`animal models (Marino et al 1997). For Gram-positive and
`Gram-negative infections, clearance of organisms may
`be impeded by TNF-suppression (Takashima et al 1997;
`O’Brien et al 1999; Rijneveld et al 2003; Moore et al 2003,
`2005). Clinical studies, registries, and case reports confi rm
`that host response to infection is the most common signifi cant
`safety concern in patients treated with etanercept.
`Serious infection is defi ned within studies and for safety
`monitoring as one requiring intravenous antibiotics or
`hospitalization (Keystone 2004). The incidence of serious
`infections in patients treated with etanercept varies according
`to the population treated, severity of disease, concomitant
`medication, and adherence to a defi nition of serious infection.
`Some report serious infections as those requiring systemic
`therapy.
`During the clinical trial development of etanercept, the
`observed serious infection rate in the RA population was
`0.03–0.04 serious infectious events per patient-year (SIE/
`pt-yr), equal to rates seen in placebo controls (Cush 2004a
`2004b). Post-marketing surveillance across all indicated
`diseases has shown the rates of SIE with etanercept and
`infl iximab to be 0.007 SIE/pt-yr (confi dence interval [CI]
`0.03–0.09/pt-yr). Signifi cant under-reporting with post-
`marketing surveillance is expected but confounding effects
`include a less well defi ned treated population, inclusion of
`indications other than those reported in the clinical studies,
`and thus these rates may be substantially more common in
`the RA population (Cush 2004a, 2004b).
`Within the RA population, an increased risk of
`serious infection is seen in patients having extra-articular
`manifestations of RA, presence of comorbid diseases, and
`immunosuppressive therapy (Doran et al 2002a). These
`infections tend to be upper respiratory, skin, and urinary
`tract infections.
`Tumor necrosis factor-antagonist therapy may increase
`the risk of infection in the RA population. Reports of
`the number of infection-related adverse events per 100
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`patient-years during an 18 month period show that etanercept
`had a rate of 22.6 (18.7–27.2) events per hundred years
`compared with controls (those receiving disease modifying
`and remitting drugs [DMARDs]) with a rate of 6.8 (5.0–9.4)
`per hundred patient years (Listing et al 2005). The rates
`for serious infections were 6.4 (4.5–9.1) and 2.3 (1.3–3.9)
`for etanercept and control groups respectively. Adjusting for
`case-patient mix, the rates of serious infection were similar
`for etanercept and infl iximab. These results suggest there
`is an increased risk of infection in those treated with TNF-
`antagonists. This study is limited by small numbers, a short
`observation period, and bias in populations: those on anti-
`TNF cannot be the same population as those on DMARDs
`since general patients with more severe disease are treated
`with TNF-antagonists, which introduces potential bias in the
`study populations.
`It is certain that TNF-antagonists exacerbate septicemia
`with increase in mortality among septic patients on etanercept
`(Fisher et al 1996; Baghai et al 2001).
`Patients developing new infections while on etanercept
`should be closely monitored and discontinued in those with
`serious infections or sepsis. Etanercept should not be initiated
`in patients with active infections including chronic or local-
`ized infections. Caution should be exercised when initiating
`etanercept in patients with a history of or predisposition to
`frequent recurrent infections.
`
`Mycobacterium tuberculosis
`Susceptibility to mycobacterium tuberculosis (TB) impacted
`by multiple factors including age, environment, immune
`status, and microbial virulence (Mitsos et al 2003) and
`genetic susceptibility (Abel and Casanova 2000; Casanova
`and Abel 2002). Latent tuberculosis remains a signifi cant
`global health concern with nearly 30% of the world
`population infected (Jasmer et al 2002). TNF is necessary
`for cell recruitment, granuloma formation, and clearance of
`mycobacterial infection (Roach et al 2002). Recent clinical
`results demonstrating reactivation of latent TB in patients
`receiving anti-TNF monoclonal antibody therapy solidifi es
`the importance of TNF in host response to TB (Keane et al
`2001; Keane 2004, 2005).
`The role of TNF in initial host response and subsequent
`confi nement of TB organisms is complex and not completely
`elucidated. TNF regulates chemokine induction that in turn
`orchestrates cell recruitment, granuloma formation, and
`clearance of mycobacterial infection (Roach et al 2002;
`Stenger 2005). Mice lacking TNF mount delayed chemokine
`
`response and cellular infi ltrate. Subsequent high chemokine
`production produced disorganized T-cell and macrophage
`responses capable of producing high levels of interferon-
`gamma but unable to protect against fatal TB infections 28
`days post inoculation. Wild mouse strains survived 16 weeks
`or longer. The response of TNF-defi cient mice exposed to
`mycobacteria anticipates the prominent role TNF plays in the
`initial response to infection and subsequent maintenance of
`granulomas. In large part, mortality results from unchecked
`type-1 infl ammatory response producing tissue necrosis
`(Zganiacz et al 2004). Animal models also suggest there
`are differences in the activity of membrane-bound and -free
`TNF in acute and chronic response to TB (Olleros et al 2005;
`Saunders et al 2005). TNF is also required to maintain latency
`of TB (Botha and Ryffel 2003). Thus, the role of TNF in
`immune response to TB is poly-modal: initiate infl ammatory
`response, regulate and suppress the infl ammatory response,
`and maintain chronic immunological response.
`RA patients on etanercept showed a linear incidence
`of TB infection (Wallis et al 2004a, 2004b) suggesting
`that acquisition of TB was related to exposure and not
`re-activation of latent infection. Infl iximab-treated patients
`demonstrated an accelerated incidence of TB infection in
`keeping with activation of latent disease (Wallis et al 2004a,
`2004b). While the incidence of TB in patients on etanercept
`may not be signifi cantly greater than the background rate,
`treatment with etanercept does alter the clinical presentation
`of TB (Arend et al 2003; Gardam et al 2003). Approximately
`half of patients treated with etanercept who develop clinical
`TB present with extra-pulmonary manifestations including
`disseminated TB. The expected rate of extra-pulmonary
`TB in immunocompetent hosts is less than 15% (Dye et al
`1999).
`In summary, there is no scientifi c data in support of
`screening for latent TB prior to initiating therapy with
`etanercept. However, patients treated with etanercept who
`acquire infection with TB are more likely to have atypical
`presenting signs and symptoms. Etanercept-treated patients
`developing TB may be at increased risk of severe and
`potentially fatal infection. Screening for active TB with a
`chest X-ray is medically prudent. A more cautious approach
`is to screen for latent and active TB by chest X-ray (CXR)
`and tuberculin (PPD) testing prior to initiating etanercept
`in patients at high risk. Based upon minimal data, but
`highlighting the need for extreme safety, some suggest a
`CXR and PPD prior to introducing any immunosuppressive
`treatment (CDC 2004; Keane 2005).
`
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`Opportunistic infections
`Opportunistic infections occur in patients on TNF-blocking
`agents (Jarvis and Faulds 1999; Garrison and McDonnell
`1999; Mease et al 2000; Doran et al 2002a, 2002b; Netea
`et al 2003; Elkayam et al 2004), but these are rare (Keystone
`2004).
`Histoplasmosis is an uncommon opportunistic infection
`endemic to many regions of the world (Cano and Hajjeh
`2001). Normal host defense to infection is dependent upon
`TNF expression (Smith et al 1990; Zhou et al 1998). Infection
`with histoplasmosis may be exacerbated in patients on therapy
`with TNF-antagonists, but lack of control comparators and
`cases occurring in histoplasmosis-endemic regions of the
`US make any conclusions tentative (Lee et al 2002). Less
`certain is the question of risk of reactivation of latent infection
`with histoplasmosis. This uncertainty is highlighted by
`reports of disseminated histoplasmosis occurring in patients
`on low-dose methotrexate (Berry 1969; Witty et al 1992;
`LeMense and Sahn 1994; Voloshin et al 1995; Roy and
`Hammerschmidt 2000; Arunkumar et al 2004).
`Listeria monocytogenes is an uncommon but ubiquitous,
`opportunistic, intracellular pathogen causing gastroenteritis,
`meningitis, encephalitis, and septicemia (Hamon et al
`2006). TNF is essential to effect normal host response to
`listeria (Havell, 1989, Rothe et al 1993; Kanaly et al 1999;
`Dinarello 2003; Torres et al 2005) and treatment with
`etanercept may predispose patients to infection (Schett et al
`2005). Infection with listeria is reported in patients treated
`with TNF-antagonists and particularly etanercept (Slifman
`et al 2003; Ehlers 2005; La Montagna and Valentini 2005;
`Nadarajah and Pritchard 2005; Rachapalli and O’Daunt 2005;
`Schett et al 2005). What is not evident is whether there is a
`real increased risk of infection or a modifi cation of clinical
`presentation and host response (Pagliano et al 2004). Given
`that etanercept does affect lymphotoxin (Williams and
`Griffi ths 2002) and that lymphotoxin is essential in providing
`normal immune response to listeria (Ehlers et al 2003), the
`possible increased susceptibility to infection with listeria
`must be considered.
`Rare cases of disseminated sporotrichosis further stress
`the importance of TNF in maintaining normal host response
`to infections (Gottlieb et al 2003).
`
`Vaccination
`TNF plays a signifi cant role in immune response to pathogens
`(Herbein and O’Brien 2000) and may therefore modulate
`host response to vaccination. A number of studies have
`
`Safety of etanercept for the treatment of plaque psoriasis
`
`evaluated response to infl uenza vaccine in RA patients treated
`with etanercept. In general, response to infl uenza vaccine is
`blunted but not completely suppressed (Fomin et al 2006).
`The addition of methotrexate further suppresses the response
`to vaccination (Kapetanovic et al 2006).
`
`Malignancy exclusive of lymphoma
`The role of TNF in carcinogenicity and tumor surveillance
`has not been established. Early cell culture studies indicated
`that TNF is cytotoxic for certain tumor cell lines (Old 1985;
`Creasey et al 1986; Palladino, Patton, et al 1987; Palladino,
`Srivastava, et al 1987). Subsequent studies revealed that, for
`certain types of malignancies, TNF may act as a growth factor
`(Freedman et al 1992; Warzocha et al 1995; Filella et al 1996;
`Warzocha and Salles 1998; Warzocha, Bienvenu, et al 1998;
`Warzocha, Ribero, et al 1998; Renard et al 1999; Moore
`et al 1999) and may even enhance the metastatic potential of
`certain tumors (Balkwill et al 1990; Malik et al 1990).
`Review of the clinical studies and registries for TNF-
`antagonists shows no increase in the incidence of solid tumors
`in the RA population (Keystone 2003, 2005). Likewise, in
`the clinical studies evaluating etanercept for the treatment of
`psoriasis, there is no evidence of increased risk of malignancy
`(Leonardi et al 2003; Papp 2004; Papp et al 2005). The
`potential for increased risk of solid tumors in patients
`receiving concurrent etanercept and alkylating agents must
`be considered (Mukhtyar and Luqmani 2005; WGET 2005;
`Hellmich et al 2006; Stone et al 2006). There are cases of
`rapidly developing squamous cell carcinomas in RA patients
`initiating therapy with etanercept (Smith and Skelton 2001).
`To the contrary, TNF-alpha defi cient mice are resistant to
`cutaneous carcinogenesis (Arnott et al 2002).
`
`Lymphoma
`There is a strong association of non-Hodgkin’s lymphoma with
`Epstein-Barr virus (EBV) infection and immunosuppression
`(Liebowitz 1998; Meyer et al 2004; Poppema 2005).
`Approximately 95% of adults are infected with EBV. Many
`develop subclinical reactivation (Rickinson and Kieff 1996).
`Members of the TNF superfamily of receptors play a role
`in pathogenesis of EBV-positive lymphomas arising in
`immunosupressed patients, but the role of TNF-alpha is not
`established (Liebowitz 1998; Herbein and O’Brien 2000).
`Chronic infl ammation produces elevated TNF levels, which
`in turn produce indirect alterations in immunological function
`(Khan 2006; Weyand et al 2006) and modulatory effects
`of TNF on T-cell surveillance (Baran-Marszak et al 2006).
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`Confounding the role of TNF in the develoment of lymphoma
`is the association of chronic infl ammatory processes and
`lymphoma (Kato et al 2003; Chang et al 2005). The potential
`association of TNF, TNF-antagonism, and the development
`of lymphomas is confounded by epidemiologic surveys
`showing a strong trend in risk in patients with psoriasis
`(Hannuksela-Svahn et al 2000; Gelfand et al 2003, 2006)
`though these fi ndings are not substantiated by larger surveys
`(Smedby et al 2006). The association of lymphoma and
`rheumatoid arthritis appear more certain (Baecklund et al
`1998, 2003, 2004, 2006; Ekstrom et al 2003).
`There are case reports of lymphoma developing in
`patients receiving TNF-antagonists (Brown et al 2002). Of
`the 26 cases reported, 18 developed in patients on etanercept.
`The mean time to onset of lesions after commencing therapy
`was 8 weeks. Data from an RA registry suggests an increased
`risk of lymphoma in patients treated with TNF-antagonists
`or methotrexate compared with those who are not (Wolfe
`and Michaud 2004b). There is; however, a strong selection
`bias in that those receiving anti-TNF therapy tend to be the
`most severely affected patients, a cohort already known to
`have a greater risk of lymphoma (Baecklund et al 1998)
`and that the strongest association is not with therapy but the
`underlying RA itself (Baecklund et al 2006). In addition, two
`cases of cutaneous and systemic T-cell lymphoma progressed
`rapidly after initiating TNF-blockade: one with etanercept
`and one with infl iximab (Adams et al 2004). Both cases
`were described as rapid in onset with fulminate courses:
`extensive cutaneous, and systemic involvement resulting in
`death within months of diagnosis.
`While there are numerous case reports of lymphoma
`developing in patients treated with etanercept, the relative
`risk of lymphoma remains constant for RA patients regardless
`of therapy with TNF-antagonists (Keystone 2005). The high
`incidence of lymphoma in RA patients makes risk assessment
`complex. The lower incidence of lymphoma in the psoriasis
`population may be instrumental in the assessment of risk
`associated with long-term treatment with etanercept.
`Central nervous system
`demyelination events
`We have some understanding of the incidence of multiple
`sclerosis (MS) in the general population: women more com-
`monly affected, there are regional variations in incidence
`and prevalence (Ebers and Sadovnick, 1993, Magnano et al
`2004). Incidence in the general population is approximately 6
`per 100 000 per year with a prevalence of nearly 85/100 000.
`
`An increased in risk of MS is reported in individuals with
`affected fi rst degree relatives (Sadovnick et al 1993).
`MS is uncommon. Furthermore, assessments may be
`complicated as not all instances of magnetic resonance
`imaging (MRI) fi ndings consistent with demyelination are
`MS (Koller et al 2005a). Instances of chronic, infl ammatory,
`demyelinating polyneuropathy are usually peripheral,
`but may include cortical and optic nerve demyelination.
`Interestingly, MS appears to be a Th1 disorder mediated by
`cytokines including TNF and evinces many of the pathogenic
`pathways active in psoriasis (Koller et al 2005b).
`The putative relationships between TNF, TNF-antagonism,
`and MS are not obvious. Many theoretical reasons support
`TNF-antagonist activity induces demyelization (Magnano
`et al 2004). Equally supportive arguments support the
`contrary: TNF-antagonism does not increase the risk of MS
`and may potentially be of therapeutic value (Magnano et al
`2004). Reporting bias of case reports (Magnano et al 2004)
`and potential association with other autoimmune diseases
`(Midgard et al 1996) confound the role of TNF-antagonist
`therapy in the onset or exacerbation of MS.
`Much of the current concern over TNF-antagonism
`and MS results from a single study evaluating lenercept; a
`p55, recombinant, soluble TNFR1 receptor protein, for the
`treatment of relapsing-remitting and secondarily progressive
`MS (LMS-UBC 1999). The study found no increase in new
`or active lesions as demonstrated on MRI. However, there
`was a signifi cant dose-related increase of attack frequency
`though not attack severity nor attack duration. The contrary
`response of MS patients treated with lenercept underscores
`the diffi culty in extrapolating results from animal models.
`Antibodies to lenercept did not affect clinical response but
`did increase rate of drug clearance (Wiendl and Hohlfeld
`2002). Two cases of MS patients treated with infl iximab
`demonstrated increased MRI activity but no clinical
`worsening (van Oosten et al 1996).
`The rarity of MS in psoriasis patients treated with
`etanercept is highlighted by the rarity of case reports (Sukal
`et al 2006). From the rheumatology literature, there are
`cases temporally related to TNF-suppression, some of which
`resolved upon withdrawal of treatment (Mohan et al 2001).
`MS remains rare and of uncertain causal association with
`anti-TNF therapy (Mohan et al 2001; Magnano et al 2004).
`Many but not all patients develop recurrent symptoms on
`re-challenge (Mohan et al 2001; Cisternas et al 2002).
`There is growing concern among some groups of
`neurologists who suggest pretreatment MRI scans for all
`
`250
`
`Therapeutics and Cl nical Risk Management 2007:3(2)
`
`Biogen Exhibit 2119
`Mylan v. Biogen
`IPR 2018-01403
`
`Page 6 of 14
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`

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`patients about to receive a TNF-antagonists (Bellesi et al
`2006). Currently, etanercept should be avoided in patients
`with a personal history of any central nervous system
`demyelinating disorder and used with caution in patients
`with a family history of these disorders. Pretreatment MRI
`may be considered in patients with equivocal histories of
`neuropathy or signs or symptoms of demyelination and fi rst
`degree family histories of MS.
`
`Hematological events
`Rare cases of pancytopenia and aplastic anemia are reported
`in association with etanercept (Lebwohl 2002). A fatal
`outcome is reported in some cases (Jarvis and Faulds 1999;
`Khanna et al 2004). Nonetheless, it is important to review
`drug and medical history to exclude other potential causes
`of myelosuppression (Baumelou et al 1993; Marshall et al
`2006).
`
`Hepatitis
`TNF plays a role in host response to hepatitis B and C (Herbein
`and O’Brien 2000). With 1.8% of the world population
`infected with hepatitis C virus and 5% infected with hepatitis
`B, the potential for exacerbation of viral hepatitis associated
`with TNF-antagonist therapy is noteworthy. While TNF does
`play a role in viral hepatic infection, the importance of TNF
`in maintaining suppression of viral replication is not clear
`(Calabrese et al 2004).
`Mixed reports on response of patients with hepatitis B
`treated with anti-TNF agents correlates with the natural,
`variable history of the infection (Khanna et al 2003;
`Calabrese et al 2004; Khanna et al 2004; Lok and McMahon
`2004). Nonetheless, TNF plays a primary role in sustaining a
`normal response to infection with hepatitis B (Schlaak et al
`1999; Michel et al 2003; Ostuni et al 2003). Recently, Health
`Canada issued an advisory related to possible reactivation
`of hepatitis B in patients receiving anti-TNF therapy. The
`advisory is based upon a single case report (HPB Canada
`2006).
`The mechanisms relating to reactivation of hepatitis B
`are uncertain. Equally uncertain is the association between
`treatment with TNF-antagonists or other immunosuppressant
`and hepatitis B reactivation. More likely is reaction upon drug
`discontinuation or rebound with replication of hepatitis B
`in hepatocytes upon discontinuation of immunosuppressive
`therapy (Herbein and