Journal of Dermatological Treatment
`
`ISSN: 0954-6634 (Print) 1471-1753 (Online) Journal homepage: http://www.tandfonline.com/loi/ijdt20
`
`A comprehensive review and evaluation of the side
`effects of the tumor necrosis factor alpha blockers
`etanercept, infliximab and adalimumab
`
`N Scheinfeld
`
`To cite this article: N Scheinfeld (2004) A comprehensive review and evaluation of the side effects
`of the tumor necrosis factor alpha blockers etanercept, infliximab and adalimumab, Journal of
`Dermatological Treatment, 15:5, 280-294, DOI: 10.1080/09546630410017275
`To link to this article: https://doi.org/10.1080/09546630410017275
`
`Published online: 12 Jul 2009.
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`Journal of Dermatological Treatment (2004) 15, 280–294
`# 2004 Journal of Dermatological Treatment. All rights reserved. ISSN 0954-6634
`DOI: 10.1080/09546630410017275
`
`280
`
`A comprehensive review and evaluation of the side
`effects of the tumor necrosis factor alpha blockers
`etanercept, infliximab and adalimumab
`
`N Scheinfeld
`
`Department of Dermatology, St Luke’s
`Roosevelt Hospital Center, New York,
`NY, USA
`
`For more than 5 years, inflixi-
`mab and etanercept have been
`utilized to
`treat
`rheumatoid
`arthritis and Crohn’s disease.
`There is therefore much post-
`approval data on their
`side
`effects. A variety of Medline
`searches were done at the begin-
`ning of
`June 2004 using the
`terms
`‘etanercept’,
`‘infliximab’
`and
`‘adalimumab’
`and
`the
`words
`‘lymphoma’,
`‘infection’,
`‘congestive
`heart
`failure’,
`‘demyelinating disease’,
`‘lupus’,
`‘antibodies’, ‘injection site reac-
`tion’,
`‘systemic’,
`‘side effects’
`and ‘skin’. Approximately 150
`articles were so identified.
`In
`
`addition, FDA and manufac-
`turers’ data obtained by internet
`searches using Google were
`reviewed. The important
`side
`effects
`that have been most
`extensively
`related
`to
`TNFa
`blockers
`include:
`lymphoma,
`infections, congestive heart fail-
`ure, demyelinating disease, a
`lupus-like syndrome,
`induction
`of auto-antibodies, injection site
`reactions,
`and systemic
`side
`effects. The risk of these side
`effects is very low. Nevertheless,
`it is important for clinicians to
`be aware of these side effects
`when prescribing therapy. (J Der-
`matol Treat (2004) 15: 280–294)
`
`Received 25th February 2004
`Accepted 26th May 2004
`
`Keywords: Adalimumab — Congestive heart failure — Etanercept —
`Infection — Infliximab — Lymphoma — TNFa
`
`Introduction
`
`There are three approved biologic therapies that block
`the activity of tumor necrosis factor alpha (TNFa). They
`are
`etanercept
`(Enbrel), a dimeric
`fusion protein
`blocking the effect of TNFa;
`infliximab (Remicade), a
`chimeric monoclonal receptor antibody; and adalimu-
`mab (Humira), a human monoclonal TNFa antibody.
`Infliximab and etanercept have been approved and used
`respectively for more than 5 years to treat rheumatoid
`arthritis and Crohn’s disease. Therefore, there is much
`post-approval data on their side effects. This article will
`survey the side effects of TNFa blockers reported in the
`for etanercept,1
`literature and the package insert
`infliximab2 and adalimumab,3 with a particular focus
`on etanercept and infliximab.
`
`Correspondence:
`Noah Scheinfeld, MD JD , Department of Dermatology, St Luke’s Roosevelt
`Hospital Center, 1090 Amsterdam Ave, Suite 11D, New York, NY 10025,
`USA. Tel z1 212 523 3888; Fax z1 212 523 3808; E-mail:
`NSS32@columbia.edu
`
`The important side effects that have been most
`infec-
`extensively related to TNFa blockers include:
`tions,
`lymphoma, congestive heart failure, a lupus-
`like
`syndrome,
`induction of auto-antibodies and
`injection site reactions. Some aspects of these side
`effects and uses of these medications are compared in
`Table I.
`This article will discuss the class of agents of TNFa
`blockers generally and then each TNFa blocker
`specifically as it relates to these side effects. The data
`in this article were assembled using a variety of Medline
`searches done in June 2004 using the terms ‘etaner-
`cept’,
`‘infliximab’ and ‘adalimumab’, and the words
`‘lymphoma’,
`‘infection’,
`‘congestive heart
`failure’,
`‘demyelinating disease’,
`‘lupus’,
`‘antibodies’,
`‘injection
`site
`reaction’,
`‘systemic’,
`‘side
`effects’ and ‘skin’.
`Approximately 150 articles were
`identified
`and
`reviewed. In addition, the Food and Drug Administra-
`tion (FDA) and manufacturers’ data obtained by
`internet searches using the Google search engine were
`reviewed. (Figure 1)
`
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`N Scheinfeld
`
`The side effects of tumor necrosis factor alpha blockers
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`281
`
`Etanercept
`
`Infliximab
`
`Adalimumab
`
`PPD test required
`Worsens CHF, NYHA III–V
`Infusion can cause anaphylaxis
`Approved to treat Crohn’s disease
`Generation of clinically significant medication neutralizing antibodies
`
`No
`Minimal evidence
`No
`No
`No
`
`Yes
`Some evidence
`Yes
`Yes
`Yes
`
`No
`No evidence
`No
`No
`No
`
`PPD test=purified protein derivative test; CHF=congestive heart failure; NYHA=New York Heart Association.
`
`Table I
`Comparison of some side effects and indications of TNFa blockers1,2,3
`
`Evaluation of safety data and
`side-effect reports
`
`is
`effects of medications
`side
`evaluation of
`The
`complicated.
`In large well-designed, well-monitored,
`placebo-controlled, clinical studies, powered with a
`number of patients sufficient to detect efficacy differ-
`ences, side effects can be established with some surety in
`a population with a given disease. Such clinical studies
`are referred to as Phase III studies. After a medication is
`approved and used by the general population, its safety
`is monitored in so-called Phase IV studies
`(post-
`marketing studies). The safety assessment that goes
`on in these Phase IV studies is more amorphous than
`
`Figure 1
`Stable plaque psoriasis on the sacrum.
`
`that conducted in Phase III studies because reporting is
`more inexact. Adverse events can occur randomly in
`larger groups and thus because there is no control
`group in Phase IV studies, one cannot be sure which
`side effects are due to a medication that is used and
`which side effects are due to chance, i.e. some intrinsic
`quality of the population with a disease or some other
`uncontrolled factor(s).
`the data that were found
`This review cites all
`regarding medication side effects; however, case reports
`of side effects in one or several patients must be
`evaluated based on an understanding of their anecdotal
`nature. Additionally, it should be noted that side effects
`in one population (e.g. patients with rheumatoid
`arthritis) cannot strictly be compared with side effects
`in another population (e.g. patients with psoriasis)
`because a patient’s underlying disease state shapes the
`host response to external stimuli and may lead to
`different population side effect profiles.
`The FDA has assembled data on the side effects of
`TNFa blockers. In 2001, the FDA published the first
`such post-marketing data.4 These data will be discussed
`in this article. The FDA published additional data on
`these medications that it assembled in March of 2003,
`which are also summarized in this article.5 An excellent
`series of lectures on these medications is available from
`Medscape6 and the side effects of TNFa blockers have
`been surveyed recently by Cush.7
`
`Lymphoma
`
`immunosuppressive effects of TNFa
`The specific but
`blockers engendered a desire by the FDA to actively
`monitor their possible role in the induction of malignancy,
`in particular lymphoma.8 The FDA summarized the
`clinical trial experience data in 2003 (Table II).5 When
`considering these data it must be noted that the incidence
`of
`lymphoma is increased (approximately doubled) in
`patients with rheumatoid arthritis9 and psoriasis.10
`In 2002, scientists from the FDA further explicated
`the link between TNFa blockers and lymphoma and
`reported 26 cases of
`lymphoproliferative disorders
`following treatment with etanercept
`(18 cases) and
`infliximab (eight cases).11 In all, 81% of cases were
`
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`N Scheinfeld
`
`The side effects of tumor necrosis factor alpha blockers
`
`Treated/exposure
`patient numbers
`patient years
`Total number of lymphomas
`Hodgkin’s
`non-Hodgkin’s
`mean time to onset
`Standardized incidence ratio compared with general population
`
`Table II
`Lymphoma clinical trial experience5
`
`non-Hodgkin’s lymphomas. The interval between the
`initiation of therapy with etanercept or infliximab and
`the development of lymphoma was very short (median 8
`weeks). In two instances (one infliximab, one etaner-
`cept),
`lymphoma regression was observed following
`discontinuation of anti-TNFa treatment, in the absence
`of
`specific
`cytotoxic
`therapy directed toward the
`lymphoma.
`to review the
`The FDA asked an advisory panel
`evidence linking the TNFa blockers to an increased
`risk of
`lymphoma. In March 2003, summarizing the
`panel’s findings, the panel’s chairman stated,
`‘‘There
`are not enough numbers to say there’s causality, but
`there’s enough to say there may be a signal.’’12 Some
`have reviewed the data relating lymphoma and TNFa
`blockers and denied a link between TNFa blockers and
`lymphoma.13
`
`Lymphoma – etanercept
`
`The only linkage of lymphoma to etanercept appeared in
`the 2002 FDA case series mentioned above. Thus, it
`remains unclear whether there is an increased incidence
`of lymphoma in patients using etanercept.14 Informa-
`tion relating to lymphoma as a side effect of etanercept
`is not mentioned in its package insert.1
`
`Lymphoma – infliximab
`
`As stated, the 2002 FDA case series reported lymphoma
`in eight patients taking infliximab. Others postulated
`that use of infliximab in Crohn’s disease is associated
`with an increase in lymphoma risk of around fivefold
`compared with non-immunosuppressive use, and ten-
`fold compared with the general population.15 Non-
`Hodgkin’s
`lymphoma occurred in a patient with
`refractory dermatomyositis who had been treated with
`infliximab.16 The risk of lymphoma is not listed in the
`package insert of infliximab.2
`
`Lymphoma – adalimumab
`
`Adalimumab has only recently been approved and most
`data that relate its side effects come from clinical trials.
`
`Etanercept
`
`Infliximab
`
`Adalimumab
`
`3389
`8336
`9
`3
`6
`21 months
`3.47
`
`1298
`2458
`4
`1
`3
`10–19 months
`6.4
`
`8729
`7885
`13
`1
`12
`21 months
`4.35
`
`Among 2468 patients treated in clinical trials with
`adalimumab for a of 24 months, 48 malignancies of
`various types were observed, including 10 patients with
`lymphoma.3 The standardized incidence ratio (SIR)
`(ratio of observed to age-adjusted expected in the
`general population)
`for malignancies was 1.0 (95%
`CI, 0.7, 1.3) and for lymphomas was 5.4 (95% CI, 2.6,
`10.0).3 An isolated report
`linking adalimumab and
`lymphoma has been published.17
`
`Non-lymphoma cancers
`
`There does not appear to be any linkage between the
`use of TNFa blockers and the development of non-
`lymphoma malignancies. Only isolated case reports exist
`of the development of non-lymphoma cancers while
`these medications are being taken.
`
`Non-lymphoma cancers – etanercept
`
`the
`increases
`that entanercept does not
`seems
`It
`incidence of non-lymphoma malignancy. The package
`insert notes that in 3 years during clinical trials the
`incidence of non-lymphoma malignancies has not
`increased with extended exposure to etanercept1 and
`is similar to that expected when projected from the
`National Cancer Institute’s Surveillance, Epidemiology
`and End Results database.18
`rapid onset of
`One
`initial
`report
`linked the
`cutaneous squamous cell carcinoma in patients with
`rheumatoid arthritis treated with etanercept.19 How-
`ever, a larger series did not support
`the linkage
`between etanercept and the development of cutaneous
`squamous cell cancer.20 A case of acute myelogenous
`leukemia following etanercept
`therapy has been
`reported.21
`
`Non-lymphoma cancers – infliximab
`
`There is no clear linkage between the use of infliximab
`and the development of non-lymphoma skin cancer. In
`trials, cancers did occur, including non-Hodgkin’s B-cell
`lymphoma, breast cancer, melanoma, squamous, rectal
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`
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`
`adenocarcinoma and basal cell carcinoma, but at a rate
`no higher than in the general population.2 Acute
`leukemia has occurred after infliximab therapy.22 The
`acute development of multiple squamous cell carcino-
`mas and keratoacanthomas
`in a patient
`receiving
`infliximab for rheumatoid arthritis has been reported.23
`
`Non-lymphoma cancers – adalimumab
`
`In clinical trials, non-lymphoma malignancies observed
`during the use of adalimumab were breast, colon–
`rectum, uterine–cervical, prostate, melanoma, gallbladder–
`bile ducts, and other carcinomas. These cancers did not
`occur at a rate higher than in the general population.3
`
`Infections
`
`Infections occur at a higher rate among those who use
`TNFa blockers. The most common kind of infection that
`occurs is the upper respiratory infection but more serious
`infections can also occur, which will be considered in the
`next section. The FDA summarized data relating to
`significant infections, systemic side effects and etanercept
`and infliximab in 2001 (Table III).4
`
`Infections – etanercept
`
`The most common side effects linked to etanercept use
`in clinical trials are non-upper respiratory tract infec-
`tions followed by upper respiratory infections. The
`
`infection rate
`maker of etanercept puts the general
`with etanercept over an entire course of therapy at 35%
`in placebo-controlled trials.1
`Etanercept is associated with serious bacterial infec-
`tions. Multifocal septic arthritis and osteomyelitis caused
`by group A streptococcus has occurred in a child
`receiving etanercept.24 In addition, orbital myositis in a
`rheumatoid arthritis patient during etanercept treat-
`ment has been reported.25 Etanercept can also facilitate
`viral infections and has been linked to a case of viral
`pneumonia.26
`It has also been linked to fungal
`infections in particular histoplasmosis27 and toxoplas-
`mosis.28 There has been a report of a case of
`disseminated sporotrichosis in a 49-year-old man who
`was treated with multiple immunosuppressants, includ-
`ing etanercept and infliximab for arthritis.29 Pulmonary
`aspergillosis in a patient with rheumatoid arthritis
`treated by etanercept has been noted.30 Finally, a case
`of recurrent Mycobacterium xenopi infection presenting
`as Pott’s disease in a patient receiving etanercept for
`severe rheumatoid arthritis has been described.31
`
`Infections – infliximab
`
`Physicians, when examining patients who have used
`infliximab,
`should have a high index of clinical
`suspicion for the occurrence of infections.2 Pre-existing
`deep fungal and mycobacterial
`infections are contra-
`indications to the use of
`infliximab and residence in
`areas where these infections are endemic should
`engender cautious use of these agents.2
`
`Infectious agent or
`adverse event
`
`Infliximab
`(n ,170 000 worldwide)
`
`Etanercept
`(n ,104 000 worldwide)
`
`Mean age (years)
`Mycobacterium tuberculosis
`M. avium intracellulare
`M. marinum
`M. kansasii
`Histoplasmosis
`Listeria monocytogenes
`Pneumocystis carinii
`Aspergillosis
`Candidiasis
`Cryptococcosis
`Coccidioidomycosis
`Pancytopenia
`Aplastic anemia
`Multiple sclerosis: total
`Multiple sclerosis: new diagnosis
`Optic neuritis
`Seizures
`Lupus-like disease
`Colonic perforations
`Lymphoma
`
`53
`84
`0
`0
`0
`9
`11
`12
`6
`7
`2
`2
`15
`0
`6
`3
`4
`29
`4
`NA
`10
`
`Table III
`Infections, systemic side effects and TNFa blockers — 2001 data4
`
`56
`11
`6
`1
`1
`1
`1
`5
`2
`3
`3
`0
`12
`4
`14
`6
`3
`26
`4
`13
`18
`
`Historic population:
`incidence rate
`(historic)
`
`–
`USA 8.2/100 000 patient years
`NA
`NA
`NA
`NA
`NA
`NA
`NA
`NA
`NA
`NA
`NA
`RA 5.7–8.2/100 000 patient years
`NA
`4/100 000 patient years
`5/100 000 patient years
`35/100 000 patient years
`NA
`NA
`NA
`
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`The side effects of tumor necrosis factor alpha blockers
`
`infections that
`Infliximab has been related to viral
`include: Kaposi’s sarcoma (HHV8),32 fulminant hepatitis
`B,33 herpes zoster,34,35 and disseminated cytomegalo-
`virus.36 A patient manifested with molluscum on the
`eyelids while using methotrexate and infliximab.37 It
`does not seem to increase the viral
`load in patients
`infected with the Epstein Barr virus.38
`Infliximab has been related to bacterial infections that
`include: Legionella,39Moraxella catarrhalis septic arthri-
`tis,40 and listeria.41,42 Severe pneumococcal pneumonia
`has followed treatment with infliximab for Crohn’s
`disease.43 Infliximab was linked to severe septicemia in
`a patient with polychondritis and Sweet’s syndrome
`after initiation of treatment.44
`Infliximab has been related to fungal infections that
`include: disseminated sporotrichosis,45 pulmonary cryp-
`tococcosis,46Pneumocystis
`pneumonia,47
`carinii
`and
`invasive pulmonary aspergillosis.48 The combined use
`of methotrexate and infliximab has been associated with
`disseminated cryptococcal infection.49 Pneumonia in a
`patient receiving infliximab due to a possible zoonotic
`transmission from a pet cockatiel has been noted.50
`Of particular concern in patients taking infliximab is the
`development of histoplasmosis.2 Reports have linked it to
`histoplasmosis infection51 and reactivation of histoplas-
`mosis infections.52 Data reported to the FDA noted:
`
`9 cases of histoplasmosis infection in patients treated
`with infliximab, the patients (5 with RA and 4 with
`CD) presented typically with fever, malaise, cough,
`dyspnea, and interstitial pneumonitis on chest X-ray
`(CXR) within 1 week to 6 months of receiving the first
`(or only) infliximab dose. All patients had preexisting
`immunosuppressive risk factors, typically the con-
`comitant use of prednisone and/or methotrexate. The
`9 patients resided in endemic histoplasmosis areas:
`Ohio (2 patients), Tennessee (2 patients), Alabama,
`Iowa, Kentucky, Louisiana, or Wisconsin. Eight
`patients required aggressive treatment in the inten-
`sive care unit; one patient was successfully managed
`
`as an outpatient. Definitive diagnosis of histoplasmo-
`sis was made by blood cultures or tissue biopsies of
`lung, liver, and/or bone marrow. Antifungal therapy
`(typically intravenous amphotericin B) resulted in
`recovery in 8 patients; one patient died. In all 9
`patients, the primary disease (RA or CD) improved
`significantly with infliximab therapy.53
`
`Infections – adalimumab
`
`The package insert of adalimumab lists adalimumab’s
`most frequent adverse event versus placebo as upper
`respiratory infection 17% versus 13% for placebo; sinusitis
`11% versus 9%, flu syndrome 7% versus 6%, and urinary
`infection 8% versus 5%.3 In placebo-controlled trials, the
`of was one per year in the adalimumab-treated patients
`and 0.9 year in the placebo-treated patients.3 The
`infections consisted primarily of upper respiratory infec-
`tions, and infections. Most patients continued to take
`adalimumab after the resolved without recurrence of
`infection.3 The incidence of serious infections was 0.04
`year in adalimumab-treated patients and 0.02 year in
`placebo-treated patients. Serious
`infections observed
`included pneumonia, arthritis, prosthetic and post-surgi-
`cal infections, erysipelas, cellulitis, diverticulitis, and . In
`sum, the rates for acquiring common infections such as
`lower tract infections or upper track infection are very low.
`Six cases of opportunistic infections caused by histo-
`plasma, aspergillus, and nocardia were also reported in
`trials of adalimumab.3
`
`Tuberculosis and TNFa blockers
`
`There is a link between TNFa blockers and tuberculosis
`(TB). The FDA has summarized the data on this linkage
`(Table IV).5 Diabetes mellitus and the concomitant use
`of corticosteroids increase a patient’s susceptibility to
`tuberculosis. Specific case reports exist regarding these
`agents and tuberculosis.
`
`Number treated
`Patient years exposure
`Country of use
`USA
`Europe/Norway
`TB cases
`Geography
`USA
`Other countries
`Time to onset
`
`Extrapulmonary
`Miliary
`
`Table IV
`Tuberculosis and TNFa blockers5
`
`Etanercept
`
`w150 000
`w230 000
`
`90%
`10%
`38
`
`20
`18
`Median 11.2 months
`
`34%
`16%
`
`Infliximab
`
`198 235
`227 559
`
`64%
`36%
`172
`
`55
`117
`By six infusions: 75%
`By 7 months: 97%
`30–45%
`NA
`
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`
`Tuberculosis – infliximab
`
`Infliximab is the TNFa agent most closely linked to the
`development of tuberculosis. Testing for tuberculosis
`with the PPD (purified protein derivative) test should
`occur prior to initiation of therapy with infliximab.54 In
`those not so tested, there is a clustering of reports
`shortly after initiation of
`treatment with infliximab,
`which is consistent with reactivation of latent infection
`rather than new infection.55 Despite prophylaxis with
`isoniazid, a 58-year-old patient with mild rheumatoid
`arthritis developed disseminated tuberculosis, pulmon-
`ary aspergillosis and cutaneous herpes simplex infection
`during treatment with infliximab and methotrexate.56
`Development of tuberculosis in a patient treated with
`infliximab alone occurred despite chemoprophylaxis
`with isoniazid.57 In one case there has been noted an
`exacerbation of Mycobacterium tuberculosis
`enteritis
`masquerading as Crohn’s disease after treatment with
`infliximab.58 Tuberculosis following therapy with inflix-
`imab may be refractory to antibiotic therapy.59 Extra-
`pulmonary presentation has been seen in 30–50% of
`cases reported and included fever of unknown origin
`(FUO), miliary tuberculosis, or tuberculosis-associated
`lymphadenopathy, peritonitis, meningitis, vertebral and
`bladder disease.60 Miliary tuberculosis after infliximab
`therapy has been reported in a patient in Lebanon.61
`
`Tuberculosis – etanercept and adalimumab
`
`Etanercept and adalimumab can promote the reactiva-
`tion of
`tuberculous, albeit
`to a lesser extent of
`infliximab. Scattered cases of the reactivation and/or
`development of
`tuberculous occurred in the clinical
`tonsillitis62 and
`trials
`for
`etanercept. Tuberculous
`Mycobacteria tuberculosis peritonitis63 have been noted
`in patients receiving etanercept
`treatment. Thirteen
`cases of TB occurred in early adalimumab trials;
`these patients were thought
`to have pre-existing
`disease.64 Once PPD tests were performed to exclude
`quiescent TB before enrolling patients in clinical trials,
`no cases of TB occurred.65 Through 2003, pre- and
`post-screening TB rates in clinical trials of adalimumab
`were 1.3 per 100 patient years and 0.08 (North
`America) and 0.13 (EU) respectively.
`
`suggestion that they worsened CHF and this will be
`discussed below. The mechanism for this effect is poorly
`understood.
`In rheumatoid arthritis clinical trials of TNF antago-
`nists, new-onset and worsening CHF were not observed;
`however, a recent review of post-marketing data with
`etanercept and infliximab documented 51 cases of CHF
`as of February 2002: 30 in patients who received
`etanercept and 21 in patients who received inflix-
`imab.5,67 Forty-two of these cases were of new-onset
`disease, half of which had no identifiable risk factors,
`such as previous myocardial infarction, coronary heart
`disease, or hypertension. Median time to onset was 3.5
`months, and 20% of patients were younger than 50
`years old.5
`Other evidence exists that TNFa blockers do not just
`prevent CHF. They enanced cardiac function in one
`study in patients with rheumatoid arthritis.
`In this
`study,
`rheumatoid arthritis
`(n=13 171) and osteo-
`arthritis (n=2568) patients were studied during a 2-
`year period ending in June 2002;
`the diagnosis
`of heart
`failure was based on self-report or review
`of medical records.68 Heart
`failure was significantly
`(p,0.05) less common in anti-TNFa-treated patients
`(3.1% [180/5832])
`than in the remaining patients
`(3.8% [281/7339]), even after adjusting for baseline
`differences. In the absence of pre-existing cardiovascular
`disease, the risk of heart failure was low (0.4% [24/
`6251]) and was not related to anti-TNFa therapy.
`
`Cardiovascular disease – etanercept
`
`Two large clinical trials assessing etanercept in the
`treatment of heart failure were terminated early due to
`failure to show positive effect.69 While these studies did
`not demonstrate substantive complications, there was
`a suggestion of worse heart
`failure outcomes with
`the two trials.70
`etanercept
`treatment
`in one of
`Physicians have filed post-marketing reports of worsen-
`ing of CHF, with and without identifiable precipitating
`factors, in patients taking etanercept. Most patients will
`experience an improvement or disappearance of the CHF
`after therapy is stopped but rarely patients can die.71
`Therefore, etanercept should be avoided in patients with
`severe CHF and used with caution in patients with
`milder CHF.
`
`Cardiovascular disease
`
`Cardiovascular disease – infliximab
`
`Tumor necrosis factor exerts negative inotropic effects
`and can promote fibrosis, hypertrophy, and cardiomyo-
`pathy in animal models. Moreover, cardiac specific TNF
`levels are regulated by pressure and volume load in
`animals and in humans. Because of these effects, trials
`were conducted evaluating the use of etanercept and
`infliximab for congestive heart failure (CHF). These trials
`show benefit.66 In fact,
`did not
`there was
`some
`
`There is evidence that treatment with infliximab can
`worsen heart failure.72 In a study of 150 patients with
`moderate-to-severe CHF (New York Heart Association
`[NYHA] class III–V), patients were treated with three
`infusions of infliximab 5 mg, 10 mg or placebo over 6
`weeks. Those treated with infliximab, especially at
`10 mg/kg doses, had worse outcomes. When published,
`the report noted 7/101 infliximab-treated patients had
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`The side effects of tumor necrosis factor alpha blockers
`
`the 49 patients treated with
`died versus none of
`placebo.73 The package insert of
`infliximab has been
`altered to reflect this and it should not generally be used
`in patients with moderate-to-severe CHF. Some have
`suggested that infliximab should be used with caution in
`patients with mild CHF (NYHA class I/II).74
`
`Cardiovascular disease – adalimumab
`
`No trial assessing adalimumab has been performed
`assessing its utility in the treatment of CHF. However,
`due to the results of trials with other TNFa blockers it
`should be avoided in those with severe CHF. Adalimu-
`mab is contraindicated in patients with moderate-to-
`severe CHF (NYHA class
`III–IV)
`in the European
`Union.75
`
`Demyelinating disease
`
`Preliminary evidence suggested that blocking the effects
`of TNFa may result in an amelioration of multiple
`sclerosis (MS). To this end, a TNFa blocker named
`lenercept, a recombinant TNF receptor p55-immuno-
`globulin fusion protein (sTNFR-IgG p55), was developed
`and studied for the treatment of patients with MS.76
`Lenercept was studied in a clinical trial of 168 patients
`with MS. These patients received 10, 50, or 100 mg of
`lenercept, or placebo intravenously (IV) every 4 weeks
`for up to 48 weeks. Although in animals, lenercept had
`previously demonstrated some protection against experi-
`mental allergic
`encephalomyelitis,
`the
`trial
`failed.
`Patients with MS who were treated with lenercept
`demonstrated more frequent and severe exacerbations of
`MS and more severe neurologic deficits than did the
`patients taking placebo. It was notable, however, that in
`the two treatment groups the number of magnetic
`resonance imaging (MRI) lesions was similar.
`Limited evidence suggests that etanercept, infliximab
`and adalimumab should be avoided in patients with
`or a history of multiple sclerosis.1–3 The FDA has
`summarized this data (Table V).5 Mohan et al77 noted
`that 19 patients with similar neurological events
`were identified from the FDA database: 17 following
`etanercept administration and two following infliximab
`
`All events
`Multiple sclerosis — new onset and relapse
`Optic neuritis
`Neuropathy
`Paresthesias
`Myelitis
`Guillain—Barre´/chronic inflammatory demyelinating disorder
`
`Table V
`Demyelinating disorder linked to etanercept and infliximab5
`
`administration for inflammatory arthritis. All neurolo-
`gical events were temporally related to use of anti-TNFa
`blocker therapy, with partial or complete resolution on
`discontinuation. One patient exhibited a positive re-
`challenge phenomenon; that is, the patient developed
`neurological problems with therapy, which resolved
`when therapy was stopped and symptoms returned
`when therapy was tried again.
`
`Demyelinating disease – etanercept
`
`The package insert for etanercept notes that it has
`‘‘been associated with rare cases of new onset or
`exacerbation of central nervous system demyelinating
`disorders, some presenting with mental status changes
`and some associated with permanent disability’’, and
`‘‘with cases of
`transverse myelitis, optic neuritis,
`multiple sclerosis, and new-onset or exacerbation of
`seizure disorders.’’1 Rare reports have linked etanercept
`with the development of multiple sclerosis.78 A case
`report has noted paraplegia in a patient with rheuma-
`toid arthritis treated with etanercept who had repeated
`neurological evaluations revealing no abnormalities and
`who had experienced painful paresthesias in both legs
`for 1 year prior to treatment with etanercept.79
`
`Demyelinating disease – infliximab
`infliximab2 states it has been
`The package insert of
`associated in rare cases with neuritis, and new onset or
`of
`symptoms and/or
`radiographic of demyelinating
`disorders,80 including sclerosis, and that it should be
`used with caution in patients with pre-existing or recent
`onset of or disorders. Several reports note that it can
`cause optic neuritis.81,82 Additional cases of optic
`neuritis have been reported.83,84 The role of
`re-
`challenge with infliximab after development of neuro-
`logical complications is unclear. Cisternas et al85 have
`reported the case of a 34-year-old man with a history of
`Guillain-Barre´ syndrome with severe psoriatic arthritis
`and very extensive skin involvement who experienced
`a resolution of his psoriasis but who developed a
`recurrence of Guillain-Barre´ syndrome after infliximab
`treatment. The Guillain-Barre´ syndrome was treated
`successfully with intravenous immunoglobulin, which
`
`Etanercept
`
`Infliximab
`
`29
`19
`5
`5
`0
`0
`0
`
`68
`21
`0
`37
`0
`1
`9
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`was administered (2 g/kg in 5 days). Subsequent
`treatment with infliximab 100 mg resulted in no
`recurrence of Guillain-Barre´ syndrome.
`
`Demyelinating disease – adalimumab
`
`The package insert of adalimumab notes the risk of
`neurological disease with adalimumab treatment and
`explains that it should not be used in patients with such
`disease and should be discontinued if such diseases
`occur.3
`
`Lupus
`
`the TNFa blockers have been associated the
`All
`development of drug-induced lupus. The mechanism
`for this is unclear but may be linked to the rise of
`autoimmune antibody titers that
`these medications
`induce, which will be discussed later in this article.
`This lupus resolves with a discontinuation of the anti-
`lupus
`TNFa therapy. The risk of the development of
`with such therapy is extremely low.
`
`Lupus – etanercept
`
`treatment of
`Lupus has occurred in the context of
`rheumatoid arthritis with etanercept.86–88 Reports have
`linked etanercept with increased auto-antibody titers
`and lupus in a variety of contexts.89 Etanercept has
`induced subacute cutaneous lupus erythematosus.90
`One patient was noted to have a patch of erythema with
`follicular hyperkeratosis at the injection site of etaner-
`cept and other similar lesions at non-injection sites
`whose histology revealed discoid lupus.91 Drug-induced
`systemic lupus erythematosus associated with etaner-
`cept
`therapy has occurred in a child with juvenile
`idiopathic arthritis92 and in other contexts.93
`
`Lupus – infliximab
`
`Infliximab has been reported to induce systemic lupus
`erythematosus.94 It can induce a lupus-like syndrome
`that resolves with its discontinuation.95,96 One report
`noted that this lupus-like syndrome was associated with
`inflammatory arthritis and an urticarial and papulos-
`quamous rash and was accompanied by high titers of
`antinuclear, double-stranded DNA, glomerular-binding,
`and histone antibodies and by reduced levels of the C4
`component of complement.97 In clinical studies,
`four
`patients developed clinical symptoms consistent with a
`lupus-like syndrome, three with rheumatoid arthritis
`and one with Crohn’s disease. All
`four patients
`improved following discontinuation of
`therapy and
`appropriate medical treatment. No patients had lupus
`that manifested in the central nervous system or
`kidneys.2
`
`Lupus – adalimumab
`
`Of 2334 patients who received adalimumab, one patient
`developed signs consistent with new-onset lupus-like
`syndrome; these signs improved following discontinua-
`tion of the drug.3 There were no instances l