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A CME-CERTIFIED SUPPLEMENT TO
Rheumatology News
®
Rheumatoid Arthritis: Mechanisms
of Autoimmunity, Immunogenicity,
and Advances in Immunotherapy
The Evolving Roles of B-cells
in Autoimmune Diseases,
Including Rheumatoid Arthritis
Immunogenicity and Biologic
Therapies: Theory and Practice
Biosimilars in Rheumatology:
Present and Future
Faculty
Leonard H. Calabrese, DO, Activity Chair
Professor of Medicine
Cleveland Clinic Lerner College of Medicine
of Case Western Reserve University
R.J. Fasenmyer Chair of Clinical Immunology
Theodore F. Classen, DO, Chair of Osteopathic
Research and Education
Vice Chairman, Department of Rheumatic and
Immunologic Diseases
Cleveland, OH
Jonathan Kay, MD
Professor of Medicine
University of Massachusetts Medical School
Director of Clinical Research, Division of Rheumatology
University of Massachusetts Medical School
Worcester, MA
Gregg J. Silverman, MD
Professor of Medicine and Pathology
Director, Laboratory of B-Cell Immunology
NYU Langone Medical Center
New York, NY
Original Release Date: September 15, 2015
Expiration Date: September 15, 2016
Estimated Time to Complete Activity: 1 hour
This continuing medical education activity is provided by
Supported by an educational grant from
Bristol-Myers Squibb
A CME-CERTIFIED SUPPLEMENT TO
Rheumatology News
®
Rheumatoid Arthritis: Mechanisms
of Autoimmunity, Immunogenicity,
and Advances in Immunotherapy
Table of Contents
Page
4 Introduction
5 The Evolving Roles of B-cells in
Autoimmune Diseases, Including
Rheumatoid Arthritis
Gregg J. Silverman, MD
8 Immunogenicity and Biologic Therapies:
Theory and Practice
Leonard H. Calabrese, DO
11 Biosimilars in Rheumatology:
Present and Future
Jonathan Kay, MD
This continuing medical education (CME)
supplement was developed from the
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Faculty
Leonard H. Calabrese, DO, Activity Chair
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Professor of Medicine
Cleveland Clinic Lerner College of Medicine of Case Western Reserve University
R.J. Fasenmyer Chair of Clinical Immunology
Theodore F. Classen, DO, Chair of Osteopathic Research and Education
Vice Chairman, Department of Rheumatic and Immunologic Diseases
Cleveland, OH
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Jonathan Kay, MD
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2 Professor of Medicine
University of Massachusetts Medical School
Director of Clinical Research, Division of Rheumatology
University of Massachusetts Medical School
Worcester, MA
Gregg J. Silverman, MD
Professor of Medicine and Pathology
Director, Laboratory of B-Cell Immunology
NYU Langone Medical Center
New York, NY
Rheumatoid Arthritis: Mechanisms of Autoimmunity, Immunogenicity, and Advances in Immunotherapy
Rheumatoid Arthritis: Mechanisms of Autoimmunity,
Immunogenicity, and Advances in Immunotherapy
Activity Chair
Leonard H. Calabrese, DO
Disclosures: Consulting Fees: AbbVie, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Janssen, Pfizer, and Sanofi; Speakers Bureau: AbbVie, Bristol-Myers Squibb,
Crescendo, and Genentech
Faculty
Jonathan Kay, MD
Disclosures: Consulting Fees: AbbVie, Alexion Pharmaceuticals, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Crescendo Bioscience, Inc., Eli Lilly,
Epirus Biopharmaceuticals, Genentech, Hospira, Janssen, Merck, Nippon Kayaku, Novartis, PanGenetics, Pfizer, Samsung Bioepis, Roche, UCB; Contracted Research
(paid directly to institution): AbbVie, Ardea Biosciences, Eli Lilly, Pfizer, and Roche
Gregg J. Silverman, MD
Disclosures: Consulting Fees: Celgene, GlaxoSmithKline, Quest, and Pfizer; Speakers Bureau: Roche
External Reviewer
Kevin D. Deane, MD, PhD
Disclosures: No relevant financial relationships to disclose.
Medical Writer
Valerie Zimmerman, PhD
Disclosures: No relevant financial relationships to disclose.
Vindico Medical Education Staff
Disclosures: No relevant financial relationships to disclose. Signed disclosures are on file at Vindico Medical Education, Office of Medical Affairs and Compliance.
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Overview
Rheumatoid arthritis (RA) is an autoimmune disease characterized by a dysregulation of inflammatory processes leading to progressive joint destruction, systemic
inflammation, and extra-articular manifestations. By understanding the underlying immunologic mechanisms driving RA progression, clinicians involved in the management of patients with RA will be better equipped to evaluate the clinical and pharmacologic safety, as well as efficacy profiles of current and emerging disease modifying
antirheumatic drugs (DMARDs). This monograph integrates a discussion between the basic and clinical immunologic sciences to give learners a better understanding
of autoimmunity, treatment-associated immunogenicity, and the development of biosimilars for RA management.
Target Audience
The intended audience for this activity is rheumatologists and other health care professionals involved in the treatment of patients with rheumatoid arthritis (RA).
Learning Objectives
Upon successful completion of this educational activity, participants should be better able to:
• Assess B-cell biology and its role in immune-mediated inflammatory diseases, including rheumatoid arthritis.
• Define immunogenicity in the context of biologic therapies and appraise its role in efficacy and toxicity.
• Apply clinical advances in the use of biologic therapy to optimize the treatment of rheumatoid arthritis.
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Supported by an educational grant from
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Rheumatoid Arthritis: Mechanisms of Autoimmunity, Immunogenicity, and Advances in Immunotherapy • globalacademycme.com/rheumatology 3
Introduction
T
he treatment of rheumatoid arthritis (RA) has undergone major changes in the last 2 decades, largely
attributable to the increased understanding of the immune and inflammatory pathways involved
in RA pathogenesis. The multiple roles of B-cells and other cell types in the pathogenesis of RA
are increasingly apparent, and results of ongoing research to understand their mechanisms and identify
potential therapeutic targets are constantly emerging. The increase in biologic treatment options has been
accompanied by reports of anti-drug antibodies (ADA) that can develop in response to these immunogenic treatments, which can potentially compromise treatment effectiveness and decrease tolerability. In the
17 years since the first biologic drug for RA became available, in addition to continuing efforts to develop
more effective agents, the development of biosimilar agents has recently become a global phenomenon.
To provide an opportunity for practitioners to assure they are up-to-date on the status of and developments in these dynamic aspects of RA pathology and therapy, Vindico Medical Education provided a forum
on immunological approaches to RA management, inviting experts in the field to share their expertise on
the pathogenesis of RA, focusing on the involvement of B-cells and their interaction with other key players
that produces the sustained autoimmune environment characteristic of RA; reviewed factors associated
with the development of ADA and their consequences, focusing on treatment with tumor necrosis factor
inhibitors; and introduced the concept of biosimilars, summarizing global regulatory policies, current
research status, and concerns and considerations related to the potential inclusion of biosimilars in the RA
treatment armamentarium.
I thank the panelists for their contribution to the discussion and the preparation of this monograph.
Readers can expect to improve their understanding of these salient aspects of RA disease and its management,
and become better equipped to critically appraise new developments as they become available.
Leonard H. Calabrese, DO
Activity Chair
4 Rheumatoid Arthritis: Mechanisms of Autoimmunity, Immunogenicity, and Advances in Immunotherapy • globalacademycme.com/rheumatology
The Evolving Roles of B-cells in Autoimmune Diseases,
Including Rheumatoid Arthritis
Gregg J. Silverman, MD
T
he pathogenesis of rheumatoid arthritis (RA) is characterized
by a continuous interaction of numerous cells, molecules, and
processes. A striking pathological change is the transition of the
synovial lining from 2 to 3 layers of fibroblast-like synoviocytes (FLS) into
several layers of macrophage-like cells.1 In health, the synovial lining is a
veil-like structure, while in RA, there are hypertrophic and hyperplastic
changes of the FLS to assume a frond-like appearance. The abnormal
growth and survival of these synovial fibroblast-like cells are supported by
the neoangiogenesis promoted by ongoing inflammation. There are several
features of these cellular changes within the RA synovium that have been
likened to the cells in a metastatic tumor.
The complex processes leading to cartilage loss and synovial inflammation that occurs in RA involves, at a minimum, B-cells, T cells, as well as
cells from the innate immune system (dendritic cells, macrophages, and
mast cells), and the cytokines and chemokines that these cells express
(Figure 1).2-4 B-cells infiltrating the synovium play a number of roles in the
pathophysiology of RA, where they can differentiate into autoantibodyproducing plasma cells. B-cells are also involved with T-cell activation,
antigen presentation, and cytokine production. Activated T cells stimulate
B-cells directly and through their membrane-associated and soluble-proinflammatory mediators. The activated B-cells can then differentiate into
antibody-producing plasma cells, and produce a range of soluble-proinflammatory mediators that include IL-6, TNF-α, IFN-γ, and lymphotoxin.
The proinflammatory mediators from both T cells and B-cells activate
macrophages, which produce IL-6, TNF-α, IL-1, and IFN-γ, and secrete
metalloproteinases and other proteolytic enzymes that damage synovial
tissue. TNF-α, IL-1, and IL-6 produced by dendritic cells attract additional
cells to the inflammatory infiltrate in the synovium. Mast cells, also derived
from monocytes, may be part of the triggering process that initiates the
inflammatory response leading to self-perpetuating synovitis.
Targeting these cytokines is a therapeutic objective for treating RA.
Anakinra, a recombinant human IL-1 receptor antagonist, was approved
in 2001, and tocilizumab, a recombinant humanized anti-IL-6 receptor
monoclonal antibody, received FDA approval in 2010.5 In addition, antiTNF-α agents have been used for the treatment of RA for over a decade
now, with the first agent (etanercept) gaining FDA approval in 1998.6
Figure 1.Integrated Immune Response During
the Pathogenesis of Rheumatoid Arthritis
An array of cell types are drawn into the downstream effector mechanism, including synoviocytes and endothelial cells, which are induced
to undergo morphologic changes. The process results in an inflamed,
hyperplastic synovium and leads to joint damage and destruction. These
damaged chondrocytes are unable to repair the injured matrix and cartilage is lost. Osteoclasts are multi-nucleated myeloid cells that acquire the
ability to resorb cortical bone, and due to imbalances with osteoblasts, are
major contributors to joint destruction. Following a chemokine trail into
the joint, osteoclasts fuse to become multicellular structures that promote
progressive bone erosion.
On a functional level, the inflammatory cytokine mediators facilitate cell
interactions through 2 major pathways.2-4 Cell membrane-associated receptors may react with a ligand on another cell, or they may produce autocrine
effects on the same cell. T-cell activation cannot be completed without a
second signal involving other costimulatory molecules. For example, when
a T cell encounters an antigen in the context of a major histocompatibility
complex (MHC) protein on an antigen presenting cell (APC), costimulatory molecules, such as CD28 on the T cell, with its CD80 and CD86
ligands, allows the T cell to become fully activated. Accordingly, abatacept,
a CTLA-4 fusion protein, was approved in 2005 for the treatment of RA,
as this agent mediates interruption of T-cell stimulation during the pathogenesis of this autoimmune disease.5
Activated T cells proliferate and secrete other cytokines that induce
further proliferation. When cytokines, such as TNF, are locally produced
in excess levels, enzymatic cleavage from the cell membrane releases them to
enter the circulation, where they can cause remote effects, including stimulatory effects on bone marrow cells. Hence, the effects of cytokine blockade
extend beyond cells in the synovium.
The autoantibodies that characterize RA include rheumatoid factors (RF)
and anti-citrullinated peptide antibodies (ACPA). Both RF and ACPA antibodies form immune complexes that can activate complement and attract
other inflammatory cells to the synovium. Levels of these autoantibodies
may be reduced following treatment with CTLA4-Ig and TNF blockade.7
B-cell Involvement in Rheumatoid Arthritis
In adults, B-cells are continuously generated from bone marrow, with
sequential stages of differentiation, including stem cells that produce
Pro-B and Pre-B precursor cells from which mature B-cells will later arise.
Each cell stage has different surface receptors and follows different activation pathways in vivo, nurtured by local signals that can lead to the next
differentiation stage.8 Differentiation of immature B-cells continues in
peripheral lymphoid tissues, with entry of naïve cells into a germinal center
where, with cooperation of CD4+ T-follicular cells (TFH), selected B-cells
acquire antigen specificity, and are banked in memory.
In the autoimmune disease setting, these normal physiologic functions
can become distorted, and the adaptive immune system, that evolved to
defend from infections, instead can attack the body itself. Several B-cell
functions can contribute to the pathogenesis of autoimmune disorder, and
these may all contribute to the pathogenesis of RA.
Lymphoid Organogenesis
Adapted from: Smolen JS, et al. Nat Rev Drug Discov. 2003;2:473-488; Choy EH, et al. N Eng J Med.
2001;344:907-916; Silverman GJ, et al. Arthritis Res Ther. 2003;5(suppl 4):S1-S6.
When activated inappropriately at sites of a lesion, B-cells can be a source
of chemokines, such as lymphotoxin-β, that recruit other cells to the site
of inflammatory disease. Ectopic lymphoid results, for example, can have
many of the features of a lymph node. This can occur in joints such as the
knee in RA, or in the salivary and lacrimal glands in Sjögren’s Syndrome.
Rheumatoid Arthritis: Mechanisms of Autoimmunity, Immunogenicity, and Advances in Immunotherapy • globalacademycme.com/rheumatology 5
The Evolving Roles of B-cells in Autoimmune Diseases, Including Rheumatoid Arthritis
Antigen Presentation and Costimulation
In this pathological setting, immune tolerance is bypassed and expansion
of damaging autoreactive clones can occur. When an antigen triggers the
antigen-receptor of a B cell, a complex is formed which becomes internalized and this is directed to a lysosomal compartment where enzymes
degrade B-cell antigen complexes into their constituent peptides. Some of
these antigenic peptides can potentially become loaded onto MHC Class II
molecules that enable self-peptide presentation to autoreactive follicular
helper T cells (TFH). B-cells can thereby present antigen to T-cell receptors (TCRs), and also provide costimulatory signals to T cells.3,9 The
activated T cells may produce proinflammatory cytokines that contribute
to activation of other local cells including macrophages.9-11
Inflammatory Cytokines
Inflammatory cytokines produced by activated B-cells, including IL-6,
TNF-α, IFN-γ, and lymphotoxin can also directly affect T cells and other
cells downstream. Although each B cell may not produce as much of the
inflammatory cytokines as other innate cells, such as macrophages, by
initiating the production of these factors B-cells may start a process with
downstream amplification. For this reason, the potential role of B-cells as
cytokine producers may be very important in autoimmune pathogenesis.
B-cells can polarize into separate types, expressing either Th1- or Th2-like
cytokines, and there are recent reports that some B-cells may also be
producers of IL-17 that may be an important driver of autoimmune injury.
Autoantibodies
Many autoantibodies have been identified in patients with RA, including
rheumatoid factors (RF) and anti-citrullinated protein antibodies (ACPA),
as well as anti-glucose-g-phosphate isomerase (anti-GPI), and antiRA33.3,12,13 These autoantibodies may act as stimuli for immune complex
formation that are further contributors to the self-perpetuation phase of
this chronic condition.11,14 In fact, autoantibodies are not always directly
pathogenic through their binding activity. In clinical practice, these autoantibodies may be sufficiently specific that they aid diagnosis as they serve
as disease markers. There are probably only a handful of cases in which
the autoantibodies themselves are directly toxic. For example, antibodies
produced in Graves’ disease can stimulate the excessive release of thyroid
hormone, and antibodies in myasthenia gravis can have pathological effects
by directly interacting with the neuromuscular junction. In addition, autoantibodies produced in pemphigus vulgaris interact with desmoglein 1 and 3,
desmosomal adherens proteins in the skin, producing a blistering disease
that can result in skin loss over major portions of the body.
Immune Complexes
As mentioned, most of the antibodies that contribute to disease diagnosis are
not destructive in themselves. Rather, they form immune complexes that can
change the properties of the IgG constant region, acquiring the capacity to
trigger Fc receptors inducing an inflammatory response. These autoantibody
immune complexes also can contribute to RA pathogenesis through activation
of the complement cascade. Therefore, there are several roles for B-cells that are
very relevant in the pathogenesis of RA. Rituximab, a chimeric murine-human
monoclonal antibody that binds to and depletes CD20-positive B-cells, was
the first monoclonal antibody approved for cancer treatment (non-Hodgkin’s
lymphoma), and in 2006 this B-cell depleting agent was FDA-approved for RA
patients with inadequate response to TNF blockers.5,15
Fundamental Roles of BLyS/BAFF in B-cell Survival
The B-lymphocyte stimulator/B-cell activating factor of the TNF family
(BLyS/BAFF) is potentially expressed by multiple immune cells and levels
are often increased in response to inflammation.16,17 BLyS (TNFSF13B)
exists in membrane-bound and soluble forms, and is genetically and structurally related to another TNF family member called the A Proliferation
Inducing Ligand (APRIL, TNFSF13). Three molecules bind together to
form the trimeric soluble protein.16,18 BLyS participates in ensuring that
new B-cells mature, survive, and differentiate. BLyS/BAFF is expressed by
TFH to select germinal center B-cells.
6 RA Pathogenesis: Putting It All Together
The RA pathogenesis often extends beyond the local synovitis; rather, this
chronic condition requires the continuous trafficking of cells and molecules
into and out of the disease site.19 We believe that disease initiation is triggered
by breaches in immunologic tolerance with antigen presentation to selfreactive T cells. Affected joints are then subjected to the interactions of
diverse cell types. A consequence of disease is the local release of inflammatory cytokines, such as TNF-α, that then enters the circulation to enter
other sites, such as the bone marrow where it can cause the premature release
of activated neutrophils and B-cell precursors. These cells may then home
to inflamed joints in response to the local release of chemotactic factors.
Inflammatory factors in the joints also cause synoviocytes and leukocytes,
such as neutrophils and dendritic cells, to release additional factors that
include the B cell survival factors, such as BAFF and APRIL, and also IL-6
and stromal cell-derived factor 1 (SDF-1). There are similar pathways for
T cells, and similar differentiation factors for monocytes to become macrophages or osteoclasts. Together these contribute to the active synovitis of
this common autoimmune disease.
Genetic Susceptibility and Risk of RA
The participation and interaction of genetic and environmental factors that
result in RA is not clearly understood; however, despite an uncertain initiation mechanism, there are now an increasing number of genetic factors that
have been reported to have a role in RA development through a complex
mode of inheritance. There are also variants of several candidate genes
that have been reported to be associated with an increased risk of RA.20,21
The best documented genetic susceptibility factor for RA is with Class II
MHC human leukocyte antigen-(HLA)-DRB1 alleles, including *0401
and *0404.22 This subset of MHC II alleles is called the “shared epitope”
subset because of its similar amino acid sequence in the third hypervariable
region that are directly involved in presentation of peptide epitopes to T
cells. While the shared epitope hypothesis was first published in 1987, a
genome-wide association study (GWAS) more recently confirmed that the
strongest association with RA was with the MHC region of chromosome 6.21
Carriers of 1 or 2 of these specific shared epitope alleles have a 3- to 10-fold
increased risk of developing RA. SNPs at the TRAF1-C5 locus on chromosome 9 were also significantly associated with a diagnosis of RA, as was a
variant of the regulatory cell signaling phosphatase, PTPN22.
Citrullinated Antigens
New clues regarding the nature of the causative autoantigens in RA have
been linked to the discovery that enzymes released by an inflammatory cell
can modify proteins to have a neutral citrulline amino acid molecule in
place of a positively charged arginine in the peptide chain of a protein.23,24
When processed by antigen presenting cells (APCs), some citrullinated
peptides bind with high affinity to the RA associated MHC II alleles
expressed by a APC. A common belief is that these citrullinated autoantigens thereby cause APC-induced T cell activation and clonal expansion of
autoreactive T cells against the citrullinated antigens. Autoreactive B-cells
may then be activated by these T cells to produce ACPA autoantibodies in
a self-perpetuating cycle of lymphocyte co-stimulation (Figure 2).
In support of this postulated disease associated pathways, certain citrullinated peptides were shown to have a 20- to 100-fold higher binding affinity
for certain RA associated HLA-DRB1 alleles on APCs.25 In surveys of
patient populations, the presence of serum ACPA have greater diagnostic
specificity for RA than RFs, which are also produced in several unrelated
conditions associated with chronic antigen exposure. In addition, patients
who are seropositive for ACPA autoantibodies are more likely to have
radiographic progression and a worse long-term prognosis compared with
seronegative RA patients (ie, those without RF or ACPA).
There remain many aspects about early RA pathogenesis that are poorly
understood. Serum samples taken before and after disease manifestation
were analyzed for ACPA autoantibodies to investigate the development
of recognition to citrullinated antigens in relation to symptomatic disease
development.26 The number of recognized antigens was shown to increase
in the years before synovitis developed, which has suggested that the initial
breach of immune tolerance, and start of the ACPA-associated autoimmune
Rheumatoid Arthritis: Mechanisms of Autoimmunity, Immunogenicity, and Advances in Immunotherapy • globalacademycme.com/rheumatology
Gregg J. Silverman, MD
state, in many patients may start long before the disease is detectable from
a clinical perspective. Therefore, it may be difficult to turn off the central
drivers of this autoimmune disease.
ACPA: RA Classification Criteria
Better clinical outcomes require earlier treatment before there is substantial
joint damage. Towards this goal the 2010 ACR/EULAR RA classification
criteria were developed, which incorporate 4 scored domains. A definite diagnosis of RA requires a total score of ≥6 in a clinical setting in
which there is also: (1) ≥1 specified joint with synovitis; and (2) absence
of an alternative diagnosis that better explains the synovitis (Table 1).27
Autoantibody serology results contribute 1 of the 4 domains, and can
provide up to one-half of the required diagnostic score, which illustrates
the importance of clinical RF and ACPA results.
B-cell and T-cell Infiltrates
Studies of synovial biopsies have shown that patients with RA may have
predominance of either B-cell or T-cell infiltrates, or both,28 but it has
been unclear whether the nature of these infiltrates can influence prognosis or response to therapeutic intervention. In a recent report, data from
immunohistology, synovial transcripts, and potential serum biomarkers
were examined. The authors proposed that RA could be divided into
4 major molecular phenotypes: lymphoid, myeloid, low inflammatory, and
fibroid.29 However, these findings will require independent validation as it
is currently uncertain if these different phenotypes are related to different
disease stages or represent specific forms of the disease; however, treatment data suggested different therapeutic effectiveness among phenotypes.
Specifically, patients with the lymphoid pattern were more responsive to
the IL-6 receptor blocker tocilizumab, while the myeloid pattern was more
responsive to a TNF blockade. Serologic biomarkers were also postulated
to correlate with these different synovial patterns, and this topic is currently
being examined in a number of laboratories.
Emerging Approaches to Eliminate B-cells
in Autoimmunity
In RA, the immune-mediated pathogenesis involves the complex contributions of many different lymphoid and innate immune cell types.28 As
the disease progresses, the rheumatoid synovitis can assume an organization that emulates features of lymph nodes, with evidence of coordinated
activities of the cells and cytokines that are involved in driving RA pathogenesis.30 However, the detection of a cell type and/or a particular soluble
inflammatory factor at the site of disease is insufficient to prove there is a
critical role in the disease process. Like firemen at the site of a crime, correlation does not prove causation, and some of these cells and factors may
even be working to resolve the insult. With the advent of targeted biologic
Figure 2. Potential Pathogenic Roles of ACPAs in RA
therapy, which typically removes only one cell or cytokine from the process,
we can now test for the central disease drivers, as we can unmask whether
removal of a candidate cell/factor may cause disintegration of the synovitis
and significant clinical improvement.
We are also gradually learning about the greater biologic implications of
effective treatments. In RA, there is now evidence that the clinical benefits
observed with the approved biologics abatacept, anakinra, tocilizumab,
and rituximab may also be accompanied by down-modulation of pathologic autoimmune memory B-cell responses.30 In contrast, the targeting
BAFF/BLyS by agents, such as belimumab and TACI-Ig (atacicept), failed
to provide significant clinical benefits in RA trials. These findings therefore indicate that some B-cell associated targets do not necessarily provide
relevant therapeutic approaches for the treatment of RA.
Summary
Rheumatoid arthritis is a complex inflammatory autoimmune process.
Emerging research has suggested there may be major histopathologic
subsets that could be driven by the interactions of different cell types and
pathways; however, in patients with ACPA seropositive disease, it is clear
that B-cells play dominant roles in the pathologic autoimmunity.
Targeted B-cell therapy with an anti-CD20 antibody can have dramatic
effects on pathogenesis, which can lead to amelioration of synovitis through
secondary effects on many other cells and factors. Effective clinical treatment with biological agents with several other mechanisms of action can
also correlate with normalization of B-cell abnormalities and reduced autoantibody production. Future investigations are needed to develop practical
biomarkers to identify subsets of patients with RA that are more amenable
to treatment with individual biologic agents. The ultimate goal should be to
find effective and safe approaches to reset the adaptive immune system and
wipe out all remnants of the pathogenic autoimmune state.
continued on page 14
Table 1. ACR/EULAR 2010 Rheumatoid Arthritis
Classification Criteria
Domain
Swollen/Tender Joints
1 large
0
2-10 large
1
1-3 small
2
4-10 small
3
>10
5
Serology
(0-3)
Negative RF and ACPA
0
Low-positive RF or ACPA
2
High-positive RF or ACPA
3
Symptom Duration
(0-1)
<6 weeks
0
≥6 weeks
1
Acute Phase Reactants
Image used with permission.
Source: Catrina AI, et al. Nat Rev Rheumatol. 2014. Doi:10.1038/nrrheum.2014.115.
(0-5)
(0-1)
Normal CRP and ESR
0
Abnormal CRP or ESR
1
Key: ACPA=anti-citrullinated protein autoantibodies, CRP=C-reactive protein, ESR=erythrocyte
sedimentation rate, RF=rheumatoid factor.
Source: Aletaha D, et al. Arthritis Rheum. 2010;62:2569-2581.
Rheumatoid Arthritis: Mechanisms of Autoimmunity, Immunogenicity, and Advances in Immunotherapy • globalacademycme.com/rheumatology 7
Immunogenicity and Biologic Therapies:
Theory and Practice
Leonard H. Calabrese, DO
B
iotherapeutic products indicated for rheumatoid arthritis (RA) have
targets that are associated with a wide variety of diseases. Agents
targeting T and B lymphocytes, IL-1, IL-6, and tumor necrosis
factor (TNF) are now available, which started with FDA approval of the
TNF inhibitor (TNFi) etanercept in 1998.1 The 5 TNFi currently available
represent a variety of bioengineering approaches (Table 1).1-6
These protein biologics are themselves immunogenic, inducing the
production of antidrug antibodies (ADA) in many patients. ADAs associated with TNFi often occur early during treatment. Although low-level
ADA are of little significance, high ADA levels can reduce treatment
effectiveness and enhance toxicity. ADA are seen with all TNFi, and rates
ranging from 1% to >80% have been reported.7 Variation among reports
is contributed to by study heterogeneity including treatment interval,
concomitant medications, disease details, and ADA assessment assays.
Factors contributing to ADA include drug structure; genetics, disease and
patient characteristics; treatment route; and concomitant medications.
Bioengineering of the Drug
Antibodies are comprised of 2 heavy and 2 light chains connected by disulfide bonds, each with constant and variable regions. The variable amino acid
sequences of the antibody Fab portions define the antigen binding site.8
The Fc portion that defines the immunoglobulin isotype and subclass can
bind to the Fc receptor on effector cells and activate immune mediators
including complement.
In 1975, the production of monoclonal antibodies that bind to the same
epitope was described,9 which led to their becoming an important research
tool and novel class of biotherapeutic agents. The initial mouse antibodies
were highly immunogenic in humans, which can affect treatment tolerance as well as efficacy.10 Subsequently, chimeric antibodies were made
that substituted the variable regions of human antibodies with the relevant
mouse sequences. Reducing the foreign component of the antibody further
by grafting murine hypervariable, or complementarity-determining, regions
to a human antibody framework resulted in a humanized antibody. Further
advancements in genetic engineering allowed removing all xenogenic components, or use of a transgenic mouse model to produce human antibodies.11-13
Each antibody binds with idiotypic specificity. Within the antigenbinding pocket, the specific hypervariable portion of light and heavy
chains, known as the paratope, is a unique set of amino acids that binds
directly to the epitope, its cognate ligand on the antigen. Anti-idiotypic
antibodies can be produced in response to monoclonal antibodies that
contain foreign idiotypes. Aggregated therapeutic antibodies can also
induce ADAs, as can nonhuman glucosylation or pegylation. In addition,
patients with alternative allotypes compared with the single polymorphic
IgG allotype comprising the treatment biologic may generate ADAs against
these allotypes.
Among the 5 available TNFi, infliximab, adalimumab, and golimumab
are full-length monoclonal antibodies (Figure 1).14 Infliximab contains
approximately 25% of mouse-derived amino acids in its variable domains,
while adalimumab and golimumab have framework regions that are approximately 98% human.12,14 Certolizumab is a humanized protein, containing
murine complementarity-determining regions from a mouse TNF monoclonal antibody inserted into the variable domains on a humanized antibody
Fab’ fragment that is conjugated to polyethylene glycol. Etanercept is the
only TNFi that is not a TNF monoclonal antibody or fragment. Etanercept
comprises a genetically engineered dimeric fusion protein from the ligand
binding extracellular portions of human TNF receptor 2, which is fused to
the Fc portion of human IgG.
These structural differences can be related to the immunogenicity of
the TNFi(s), although other factors can contribute to varying immunogenicity among agents. ADAs can be induced against mouse epitopes on
the variable regions of chimeric antibody constructs; theoretically, therefore, they would be the most immunogenic, which is usually the case.11-14
Approximately one-half of patients with an initial response to the chimeric
Table 1. Currently Available TNF Inhibitors for Treating Rheumatoid Arthritis
Biologic
Structure
RA Treatment
Other Indications
FDA Approval
Etanercept
Recombinant human dimeric
fusion protein linked to Fc portion
of human IgG1
First-line monotherapy or
in combination with MTX
JIA, PsA, AS, Ps
1998
Infliximab
Chimeric murine-human IgG1
monoclonal Ab
First-line only in combination
with MTX
PsA, AS, A/P CD,
A/P UC, Ps, PsA
1999
Adalimumab
Fully human IgG monoclonal Ab
First-line monotherapy or
in combination with MTX
JIA, PsA, AS,
A/P CD, UC, Ps
2002
Golimumab
Fully human IgG monoclonal Ab
First-line only in combination
with MTX
PsA, AS, UC
2009
Certolizumab pegol
Fc-free humanized pegylated
anti-TNF Fab fragment
First-line monotherapy or
in combination with MTX
AS, CD, PsA
2009
Key: Ab=antibody, A/P=adult/pediatric, AS=ankylosing spondylitis, CD=Crohn’s disease, IgG=immunoglobulin G, JIA=juvenile idiopathic arthritis, MTX=methotrexate, Ps=plaque psoriasis, PsA=psoriatic arthritis,
RA=rheumatoid arthritis, TNF=tumor necrosis factor, UC=ulcerative colitis.
Source: Meier FMP, et al. Immunotherapy. 2013;5:955-974; see prescribing information for each biologic.
8 Rheumatoid Arthritis: Mechanisms of Autoimmunity, Immunogenicity, and Advances in Immunotherapy • globalacademycme.com/rheumatology
Leonard H. Calabrese, DO
Figure 1. Molecular Structures of TNF Antagonists
Effects of Immunosuppressants on Antidrug Antibodies
Concomitant treatment with methotrexate (MTX) and other immunosuppressive disease-modifying treatments has been shown to reduce the
immunogenicity of TNFi. Among the available TNFi, infliximab and golimumab are indicated for treatment of RA in combination with MTX.
The development of ADA has been reported to be inversely associated
with MTX use and dosage for infliximab, adalimumab, and golimumab.7,21
An early study reported 53%, 21%, and 7% ADA after 26 weeks in patients
with RA treated with 1, 3, or 10 mg/kg infliximab.22 Patients receiving
concomitant MTX had 15%, 7%, and 0% ADA at the 3 infliximab dose
levels. Studies have also reported an MTX dose-dependent decrease in
ADAs during adalimumab treatment. In 4 patient subgroups based on
receiving no MTX to high-dose MTX, ADAs were less frequent with
MTX compared with patients without MTX (odds ratio [OR] 0.20; 95%
confidence interval [CI]: 0.12, 0.34; P<0.001), with ADA development
inversely proportional with increasing MTX.23 In addition, the incidence
of adverse events was not increased when immunosuppressants were added
to the TNFi treatment.
Detection of Antidrug Antibodies
Source: Tracey D, et al. Pharmacol Ther. 2008;117:244-279.
antibody infliximab experience disease flare after several months, with TNFi
antibodies associated with the secondary response failure.12 Immunogenic
epitopes remain in human and humanized monoclonal antibodies,
primarily in the hypervariable regions of the binding site. Exemplifying the
contribution to immunogenicity of other than a xenogenic origin of antibody components, ADAs were observed within 28 weeks of treatment in
over half of patients with RA who were treated with the fully human monoclonal antibody adalimumab.15 Almost all of the antibody response was
specific for the adalimumab idiotype, and resulted in functional neutralization of the drug.
The dimeric fusion protein etanercept is the least immunogenic of the
TNFi. When ADAs were detected they were nonneutralizing, and not
associated with a loss of treatment effectiveness.16
Patient-related Factors
Not all patients develop ADA. Genetic susceptibility may have a role,
as patients who developed ADAs against infliximab were more likely to
develop ADAs against adalimumab, and were less likely to respond.13
Conversely, treatment response assessed in switchers from infliximab or
adalimumab to etanercept in 1 study revealed that the response to etanercept was similar between switchers who had ADAs and TNFi-naïve
patients (P=0.74); while switchers without ADA had a reduced response
to etanercept compared with TNFi-naïve patients (P=0.001) and switchers
with ADAs (P=0.017).17
A possible association between IL-10 polymorphisms and anti-adalimumab antibody development has been reported.18 Higher baseline disease
has also been reported to be associated with ADA development, suggesting
a role of inflammation in the ADA response.16 Similarly, infections that
trigger the immune response may increase the likelihood of ADA development. Patients with RA are more likely to produce antibodies to TNFi
compared to patients with ankylosing spondylitis who are being treated
following the same regimen.19
Treatment-related Factors
Drug dose, route, frequency, and duration are often associated with sensitization risk. Lower doses administered intermittently are generally considered
to be more immunogenic compared with larger bolus doses.16 Although
increased immunogenicity is typically associated with subcutaneous
compared with intravenous administration, subcutaneous tocilizumab used
to treat RA was not more immunogenic than intravenous tocilizumab.20
Interpretation of ADA development data must consider the assay that
was used, as ADA detection results very widely among assays, and with
TNFi and ADA levels. 12,15 This variation complicates making valid
comparisons among studies. Many assays do not distinguish between
functionally active and inactive antidrug antibodies. ELISA, antigenbinding test (ABT), and PIA (pH-shift anti-idiotype antigen binding)
test detect free ADA but not free TNFi; accordingly, a pharmacokinetic
(PK) assay is necessary to determine the amount of functional drug ;
however, a PK assay will not detect free ADA. Results are less predictable
in the presence of ADA-drug complexes, and separating them for assay
purposes is laborious, reassociation may occur, and the process itself may
introduce artifacts.
Clinical Consequences of Antidrug Antibodies
Increasing ADA are associated with decreased levels of drug, and may
correlate with decreased treatment effectiveness.23-25 Immune complexes
may form that are also immunogenic. Data are emerging that support an
association between ADA and toxicity, including hypersensitivity and infusion reactions.
Variability of Response to Anti-TNF Agents
From 30% to 40% of patients with RA, inflammatory bowel disease (IBD),
juvenile idiopathic arthritis, and spondyloarthritis (SpA) treated with a
TNFi fail to derive a significant benefit.26 In addition, some patients experience a relapse, or secondary failure, after an initial response. Failure may
also occur due to toxicity. The mechanism of treatment failure is incompletely understood, and may be related to several factors including the drug
mechanism of action, pharmacokinetics, toxicity, host factors such as a nonTNF-driven disease, and immunogenicity.
In a meta-analysis of 17 qualifying studies of infliximab, adalimumab,
and etanercept in patients with RA, SpA, psoriasis, and IBD, ADA was
compared with drug response.27 Anti-etanercept antibodies were not
detected. In the presence of ADA against infliximab or adalimumab,
drug response was reduced 68%, which was attenuated by concomitant
MTX treatment. Concomitant MTX or azathioprine/mercaptopurine
reduced ADA frequency by 37% when assessed by ELISA, and 64%
when assessed by RIA.
One etanercept study in patients with RA that failed to observe ADA
reported that low circulating etanercept levels were a nonresponse predictor.28
Another study reported 6% ADA positive patients, and the nonneutralizing
antibodies did not have an effect on clinical response or tolerance; however,
patients with concomitant MTX had a better clinical response.
Rheumatoid Arthritis: Mechanisms of Autoimmunity, Immunogenicity, and Advances in Immunotherapy • globalacademycme.com/rheumatology 9
Immunogenicity and Biologic Therapies: Theory and Practice
Therefore, the variability in response to TNFi can be partly explained
by ADAs; however, there may be alternative causes of relapse that are
not yet clearly defined. For example, there may be an immunopathogenic breach, where the disease transitions from a TNF mechanism to
an IL-17 mechanism.
ADA and Drug Safety
Many studies show a correlation between ADA and specific acute adverse
events (AEs). A meta-analysis with 60 qualifying studies in chronic
immune-mediated inflammatory conditions reported ADA seropositive
patients had a significantly higher risk of hypersensitivity reactions (OR
3.75; 95% CI: 2.36, 6.67; P<0.001) compared with seronegative patients.29
When 3 patients who developed severe venous and arterial thromboembolic events during treatment with adalimumab were shown to have ADA,
data from 272 adalimumab-treated RA patients were reviewed for presence of ADA and thromboembolic events.30 Over one-fourth (28%) of
patients had anti-adalimumab antibodies. Eight thromboembolic events
were observed, with an increased incidence rate in seropositive (26.9/1000
person-years) compared with seronegative (8.4/1000 person-years) patients
that approached significance by univariate analysis (hazard ratio [HR] 3.8;
95% CI: 0.9-15.3; P=0.064). After adjusting for duration of follow-up, age,
BMI, ESR, and prior thromboembolic events, seropositive patients had a
significant 7.6-fold increased risk of a thromboembolic event compared
with seronegative patients (HR 7.6; 95% CI: 1.3, 45.1; P=0.025).
Therapeutic Drug Monitoring
Therapeutic drug monitoring may assist with patient management and
contribute to understanding of individual variability of immune responses.31
Robust, standardized assays are necessary for this to be feasible. Therapeutic
drug monitoring has traditionally been used for small drug molecules, such
as seizure medications and antimicrobials. Therapeutic drug monitoring
can be beneficial when used for agents with the following characteristics:
• Clinically difficult to assess efficacy or toxicity
• Established therapeutic window
• Narrow therapeutic range
• No active metabolites
An algorithm for monitoring serum TNFi levels and ADAs in patients
with TNFi failure has been proposed to provide a predictive tool for
choosing biologics (Figure 2).7 In the proposed model, when a patient is
not responding to a TNFi, drug concentration and ADA are measured,
which can yield 1 of 4 results based on TNFi concentration (optimal/
suboptimal) and ADA seropositivity status (positive/negative).
Patients with low TNFi without ADA may be hypermetabolizing, or
this situation may represent a sink effect. Increasing the injection dose
or frequency can be appropriate for these patients. A switch to another
TNFi, or to another drug class, may be warranted for ADA positive
patients with suboptimal TNFi levels, and for ADA negative patients
Figure 2. Patients With Failure of TNF Therapy
Non-responder to TNF Inhibitor
Drug Concentration and ADAb Measurement
Suboptimal TNF Inhibitor
ADAb –
Suboptimal TNF Inhibitor
ADAb +
Increase dose or
injection frequency
Switch to another
TNF inhibitor
Key: ADAb=antidrug antibody
Source: Vincent F, et al. Ann Rheum Dis. 2012;0:1-14.
10 Optimal TNF Inhibitor
ADAb –
Optimal TNF Inhibitor
ADAb +
Switch to biologic with
another mechanism of action
with optimal TNFi levels. If patients are seropositive and have optimal
TNFi levels, a switch to a biologic with another mechanism of action may
be the best treatment strategy.
Summary
Biologics are important tools in the therapy of immune-mediated inflammatory diseases. Although factors leading to both failure and toxicity
remain poorly understood, ADAs are reported to contribute to drug failure
and increased toxicity, primarily infusion hypersensitivity reactions. ADAs
have been observed with all TNFi in RA and non-RA disorders. There
is variability in ADA development among the TNFi, which is low with
etanercept treatment, and higher with infliximab; however, ADAs are also
observed following treatment with totally human antibodies.
Several studies have shown a correlation between ADAs and reductions
in serum drug concentrations and clinical responses. High-dose tolerance
has been suggested as a possible explanation for decreased immunogenicity at higher treatment doses,14,32 and the decrease in immunogenicity
observed in the setting of concomitant MTX use is most likely related to
the immunosuppressive activity of MTX.14
ADA and therapeutic monitoring may be able to improve clinical
decision-making. However, assays for treatment monitoring lack uniformity and robust predictive power to justify routine use. Strategies to reduce
the development of ADA and its associated undesirable effects are an
important research objective.
References
1. Enbrel [Package insert]. Thousand Oaks, CA: Amgen; 2015.
2. Meier F, Frerix M, Hermann W, Muller-Ladner U. Current Immunotherapy in rheumatoid arthritis.
Immunotherapy. 2013;5:955-974.
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4. HUMIRA [Package insert]. North Chicago, IL: AbbVie Inc.; 2014.
5. REMICADE [Package insert]. Horsham, PA: Janssen Biotech, Inc.; 2015.
6. SIMPONI [Package insert]. Horsham, PA: Janssen Biotech, Inc.; 2013.
7. Vincent F, Morand E, Murphy K, Mackay F, Mariette X, Marcelli C. Antidrug antibodies (ADAb) to
tumour necrosis factor (TNF)-specific neutralising agents in chronic inflammatory diseases: a real issue, a
clinical perspective. Ann Rheum Dis. 2013;72:165-178.
8. Schroeder Jr H, Cavacini L. Structure and function of immunoglobulins. J Allergy Clin Immunol.
2010;125:S41-S52.
9. Kohler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature.
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10. Brekke O, Sandlie I. Therapeutic antibodies for human diseases at the dawn of the twenty-first century.
Nat Rev Drug Discov. 2003;2:52-62.
11. Bendtzen K, Ainsworth M, Steenholdt C, Thomsen O, Brynskov J. Individual medicine in inflammatory
bowel disease: monitoring bioavailability, pharmacokinetics and immunogenicity of anti-tumour necrosis
factor-alpha antibodies. Scand J Gastroenterol. 2009;44:774-781.
12. Bendtzen K. Anti-TNF-alpha biotherapies. Perspectives for evidence-based personal medicine.
Immunotherapy. 2012;4:1167-1179.
13. Jani M, Barton A, Warren R, Griffiths C, Chinoy H. The role of DMARDs in reducing the immunogenicity
of TNF inhibitors in chronic inflammatory disease. Rheumatology. 2014;53:213-222.
14. Tracey D, Klareskog L, Sasso E, Salfeld J, Tak P. Tumor necrosis factor antagonist mechanisms of action:
A comprehensive review. Pharmacol Ther. 2008;117:244-279.
15. van Schouwenburg P, van de Stadt L, de Jong R, et al. Adalimumab elicits a restricted anti-idiotypic antibody
response in autoimmune patients resulting in functional neutralisation. Ann Rheum Dis. 2013;72:104-109.
16. Jullien D, Prinz J, Nestle F. Immunogenicity of biotherapy used in psoriasis: The science behind the success.
J Invest Dermatol. 2015;135:31-38.
17. Jamnitski A, Bartelds G, Nurmohamed M, et al. The presence or absence of antibodies to infliximab or
adalimumab determines the outcome of switching to etanercept. Ann Rheum Dis. 2011;70:284-288.
18. Bartelds G, Wijbrandts C, Nurmohamed M, et al. Anti-adalimumab antibodies in rheumatoid arthritis
patients are associated with interleukin-10 gene polymorphisms. Arthritis Rheum. 2009;60:2541-2542.
19. Kang JH, Park DJ, Lee JW, et al. Drug survival rates of tumor necrosis factor inhibitors in patients with
rheumatoid arthritis and ankylosing spondylitis. J Korean Med Sci. 2014;29(9):1205-1211.
20. Ogata A, Tanimura K, Sugimoto T, et al. Phase III study of the efficacy and safety of subcutaneous versus
intravenous tocilizumab monotherapy in patients with rheumatoid arthritis. Arthritis Care Res (Hoboken).
2014;66(3):344-354.
21. Vermeire S, Noman M, Assche G, Baert F, D’Haens G, Rutgeerts P. Effectiveness of concomitant immunosuppressive therapy in suppressing the formation of antibodies to infliximab in Crohn’s disease. Gut.
2007;56:1226-1231.
22. Maini R, Beedveld F, Kalden J, 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.
23. Krieckaert C, Nurmohamed M, Wolbink G. Methotrexate reduces immunogenicity in adalimumab treated
rheumatoid arthritis patients in a dose dependent manner. Ann Rheum Dis. 2012;71:1914-1915.
24. Aikawa E, deCarvalho J, Silva C, Bonfa E. Immunogenicity of anti-TNF-alpha agents in autoimmune
diseases. Clin Rev Allergy Immunol. 2010;38:82-89.
25. Rutgeerts P, Vermeire S, Van Assche G. Predicting the response to infliximab from trough serum levels. Gut.
2010;59:7-8.
26. Moots R, Naisbett-Groet B. The efficacy of biologic agents in patients with rheumatoid arthritis
and an inadequate response to tumour necrosis factor inhibitors: a systematic review. Rheumatology.
2012;51:2252-2261.
continued on page 14
Rheumatoid Arthritis: Mechanisms of Autoimmunity, Immunogenicity, and Advances in Immunotherapy • globalacademycme.com/rheumatology
Biosimilars in Rheumatology:
Present and Future
Jonathan Kay, MD
T
he term “biosimilar” implies the same general meaning worldwide;
however, its regulatory definition varies among global markets
(Table 1). Terminology also varies across countries and agencies, including “subsequent entry biologic” (Canada), “similar biologic”
(India), and the World Health Organization (WHO) term “similar
biotherapeutic product.”1 The European Union (EU) was the first to
develop a distinct regulatory pathway for biosimilar product approval, and
similar guidelines became adopted standards in several other countries.
In the EU, a biosimilar is defined as “a biologic medicinal product that
contains a version of the active substance of an already authorized original
biologic medicinal product (reference medicinal product). A biosimilar
demonstrates similarity to the reference medicinal product in terms of
quality characteristics, biologic activity, safety, and efficacy based on a
comprehensive comparability exercise.”2 In some countries, such as India,
the approval process for biosimilars is less rigorous than it is in the EU,
United States, and other highly regulated countries.
In the United States, an abbreviated licensure pathway for biosimilars
was implemented through the Biologics Price Competition and Innovation
Act (BPCIA) of 2009.1 Although modeled on the Hatch-Waxman generic
act, the BPCIA additionally describes requirements for establishing
“similarity” between biological products, made necessary because biological
drugs are never exact copies of the reference biopharmaceutical. According
to the FDA, biosimilarity means “that the biologic product is highly similar
to the reference product notwithstanding minor differences in clinically
inactive components” and that “there are no clinically meaningful differences between the biologic product and the reference product in terms of
the safety, purity, and potency of the product.”3
Biosimilars are not second-generation biopharmaceuticals, which are
structurally different from the originally licensed biopharmaceutical.4
Second-generation biopharmaceuticals are intended to improve performance while preserving the mechanism of action of the first-generation
biologic. For example, adalimumab was intended to be an improvement on
infliximab, because it is humanized. Accordingly, adalimumab is a second
generation TNF-inhibition biotherapeutic.
Biosimilars also are not biomimics, or intended copies, as biomimics are
not developed, assessed, or approved according to a regulatory pathway for
biosimilars.4 Similarity with the reference biopharmaceutical has not been
demonstrated by a stepwise and comprehensive comparability exercise.
Table 1. Terminology by Country/Organization for Biosimilar
Biomimics may differ from the reference product in primary structure, as
well as in formulation, dose/dosing regimen, efficacy, safety, and immunogenicity. Biomimics of rituximab and etanercept have been developed
and manufactured in India, Mexico, and China.5 These are not biosimilars,
as they have not been reviewed following a stringent regulatory pathway.
CT-P13: Biosimilar Infliximab
In 2013, CT-P13 was the first biosimilar monoclonal antibody approved
by the European Medicines Agency (EMA).6 Approvals in other countries
followed, and it is now available in more than 70 countries worldwide as an
approved biosimilar. Approved indications include those for which infliximab was approved: rheumatoid arthritis (RA), ankylosing spondylitis
(AS), psoriatic arthritis (PsA), Crohn’s disease (CD; adult and juvenile),
and ulcerative colitis (UC; adult and juvenile).7 Canada and Japan did not
extrapolate approval to all of these disease indications. CT-P13 is currently
under FDA review in the United States. Other agents have been approved
as biosimilars in South Korea and India (Table 2).7,8
Several additional biosimilars are in clinical trials (Table 3; see
Clinicaltrials.gov), while others are in preclinical development.
In March 2015 the FDA approved the leukocyte growth factor biosimilar filgrastim-sndz, marking its first approval of a biosimilar product.9
The EU allows biosimilars to use the same international nonproprietary
name as their reference products; however, the United States policy has
not yet been established.10 As an interim measure, the FDA required the
biosimilar manufacturer to add the “-sndz” suffix to facilitate differentiation
between the originator and biosimilar products. Applications have been
filed with the FDA for 4 other biosimilar products, including CT-P13,
between August 2014 and February 2015; however, the CT-P13 advisory
committee meeting was postponed pending receipt of additional information requested from the sponsor.11
All biopharmaceuticals, including biosimilars and the reference products (originators), are subject to variability over time, as posttranslational
modifications of a protein change coincident with modifications in the
manufacturing process.12 These differences can be due to physical changes
that include protein-folding variants, misfolding, aggregation, enzymatic
cleavage, and degradation. Biochemical changes, including glycosylation,
disulfide bond formation, phosphorylation, deamidation, oxidation, and
amino acid substitution may also contribute to variation. Any of these
changes can affect the function of the biopharmaceutical. However, subtle
changes that occur over time do not make a product a biosimilar of itself,
because these versions of the reference product never undergo comparative
evaluation according to a regulatory pathway for biosimilars.
Biosimilar data are submitted for approval to the FDA through an
Abbreviated Biological License Application.13 The process requires
evaluation of the biosimilar against a single reference biological product.
Country/Organization
Terminology
WHO
Similar biotherapeutic product (SBP)
EU
Similar biological medicinal product
US
Biosimilar
Australia
Biosimilar
Mexico
Biocomparable
Brazil
Biologic product
BOW015
Canada
Subsequent-entry biological
HD203
India
Similar biologic
ZRC-3197
Adalimumab
Table 2. Global Biosimilar Approvals
Product
Active Substance
Country
Approval Date
Infliximab
India
September 15, 2014
Etanercept
Korea
November 11, 2014
India
December 9, 2014
Rheumatoid Arthritis: Mechanisms of Autoimmunity, Immunogenicity, and Advances in Immunotherapy • globalacademycme.com/rheumatology 11
Biosimilars in Rheumatology: Present and Future
Table 3. Biosimilar Agents in Development to Treat
Rheumatologic Diseases
Drug
Manufacturer Location
Figure 1. Comparative Pathways to Regulatory Submission
Clinical Trial Status
Originator Pathway
[§351(a)]
Clinical Studies
Biosimilar Pathway
[§351(a)]
Adalimumab biosimilar
ABP 501
United States
Phase 3
BI695501
Germany
Phase 3
SB5
South Korea
Phase 3
PF-06410293
United States
Phase 1
South Korea
Phase 3
Taiwan
Phase 3
CHS-0214
United States
Phase 3
LBEC0101
South Korea
Phase 3
Daewoong Pharmaceutical Co.
Ltd. (South Korea)
Phase I
Clinical
Studies
Clinical Pharmacology
PK/PD
Clinical
Pharmacology
PK/PD
Preclinical
Preclinical
Etanercept biosimilar
SB4
TuNEX (ENIA11)
DWP422
CT-P13
South Korea
US: FDA Review
SB2
South Korea
Phase 3
PF-06438179
United States
Phase 3
GS-071
South Korea
Phase 1
Russian Federation
Phase 3
Rituximab biosimilar
BI695500
Germany
Phase 3
CT‑P10
South Korea
Phase 3
SAIT101
South Korea
Development halted
in 2012
Israel
Development halted
in 2012
TL011
PF-05280586
United States
Phase 1/2 completed
GP2013
Switzerland
Phase 1/2
MK-8808
United States
Phase 1 completed
The biosimilar and reference product must have the same presumed mechanism of action, route of administration, dosage form, and potency. The
reference product must have been reviewed and approved by the FDA for
the indications applied for by the biosimilar.
Data demonstrating that the biosimilar is highly similar to its reference product must be submitted. These must be obtained from analytical
studies, toxicology studies, pharmacokinetic (PK) and pharmacodynamic
(PD) studies, and at least one clinical trial performed in patients who
have a disease for which the reference product has an existing license. The
“totality of evidence” from these studies must demonstrate safety, purity,
and potency of the biosimilar. There also must be an assessment which
establishes that the biosimilar is not more immunogenic than the reference
product. If there is a Risk and Evaluation Mitigation Strategy (REMS) for
the reference product, the same REMS must be applied to the biosimilar.
The biosimilar pathway represents a paradigm shift from the standard
regulatory pathway for originator biopharmaceuticals (Figure 1).14-18
12 Analytical
Source: Macdonald J. 2013 APEC Harmonization Center Biotherapeutics Workshop; Seoul; September 25, 2013.
Infliximab biosimilar
BCD-020
Analytical
The objective of a biosimilar development program is to establish biosimilarity based upon the “totality of evidence,” not to re-establish benefit.
Research and development activities for an originator begin with analytical studies to characterize the biopharmaceutical, followed by preclinical
studies, including in vitro assays and animal studies to characterize the
mechanism of action and toxicology of the drug. After appropriate preclinical studies have been conducted, PK and PD studies are undertaken in
human subjects. For an originator biopharmaceutical, at least 2 large
randomized, placebo-controlled trials are required to provide efficacy and
safety data in each disease for which approval is being sought.
In contrast, the biosimilar approval pathway is based upon an extensive
and robust analytical data package, which compares the biosimilar to its
reference product. Comparative preclinical in vitro assays are performed,
followed by clinical pharmacology to demonstrate that the biosimilar has
the same PK and PD characteristics as the reference product. Finally, at
least one clinical trial comparing the biosimilar to its reference product is
conducted in patients with the disease that is most responsive to treatment
with that biopharmaceutical, as a bioassay to confirm safety and efficacy
of the biosimilar. Since the biosimilar must be highly similar to the reference biopharmaceutical, comparative efficacy must be shown to be within
a prespecified equivalence margin. If the biosimilar were to be superior to
its reference biopharmaceutical, it would not be biosimilar. Thus, a noninferiority trial design is not adequate to assess biosimilarity. The biosimilar
must be studied at the same does that is licensed for the reference biopharmaceutical; accordingly, dose-ranging Phase 2 trials are not needed.19,20
Dose-ranging (Phase 2) studies are not necessary, since the biosimilar must
have the same potency and dosage form as the reference product. FDA
scientists integrate the submitted data to formulate an overall assessment
that a biologic is biosimilar to its approved reference product.15
Data from a clinical trial of a biosimilar in one disease can be extrapolated
to support other indications for which the reference product is licensed.13
The sponsor of the biosimilar must choose which inflammatory disease to
study for the obligatory clinical trial, expecting to acquire adequate information for extrapolation to other indications. In the case of CT-P13, data
from a Phase 1 study in patients with ankylosing spondylitis and a Phase 3
study in patients with rheumatoid arthritis were extrapolated by regulatory
agencies in several countries to include those other disease states for which
infliximab is approved. Health Canada, however, did not grant approval for
CD and UC, citing in vitro differences between CT-P13 and infliximab,
potential differences in the mechanism of action of infliximab in these
conditions, and the absence of clinical studies.21
Rheumatoid Arthritis: Mechanisms of Autoimmunity, Immunogenicity, and Advances in Immunotherapy • globalacademycme.com/rheumatology
Jonathan Kay, MD
Immunogenicity
Antidrug antibodies (ADA) can develop in patients treated with either
the reference product or the biosimilar. Small differences between the
biosimilar and reference biologic may result in increased immunogenicity,
if patients are switched repeatedly between the two. Therefore, both animal
and clinical studies of the biosimilar should include assessments of immunogenicity.14 In the clinical study, evaluation of immunogenicity should
assess the incidence and nature of the immune response (eg, anaphylaxis,
induction of neutralizing antibodies) and its severity and clinical relevance
(eg, loss of efficacy, adverse events) in the population studied. If the biosimilar manufacturer aims to extrapolate immunogenicity findings from one
indication to others, the population chosen for study should be adequately
sensitive to predict a difference in immune responses across indications.
Because AS and RA patients may have a lower incidence of ADAs to
infliximab than patients with PS, CD, or UC, these may not be the ideal
populations from which to extrapolate immunogenicity data.21
CT-P13 Immunogenicity
The development of ADAs is complicated and can vary among conditions and treatment doses. The Phase 1 PLANETAS study randomized
patients with active ankylosing spondylitis (AS) to receive 5 mg/kg CT-P13
(n=125) or infliximab (INX; n=125) without concomitant MTX.22 The
Phase 3 PLANETRA study randomized patients with active RA that was
inadequately responsive to MTX to receive 3 mg/kg CT-P13 (n=302) or
INX (n=304), in combination with MTX and folic acid.23 ADA were
assessed by an electrochemiluminescent immunoassay.
Follow-up data through 60 weeks revealed that approximately 25% of
patients with AS receiving 5 mg/kg CT-P13 (22.9%) or INX (26.7%)
as monotherapy developed ADA, compared with approximately 50% of
patients with RA taking 3 mg/kg CT-P13 (52.3%) or INX (49.5%) in
combination with MTX (Figure 2). The reason for this discrepancy is not
clear.24 Patients with AS are not predisposed to form clinically detectable
autoantibodies, whereas many with RA have circulating autoantibodies.
However, this difference may be affected more by the dose administered,
with the higher dose inducing immunologic tolerance, than by concomitant treatment with MTX.
Interchangeability
Switching and substitution may be similar. Switching occurs when a patient
is transitioned to a biosimilar after initial treatment with the reference
product. The consequences of such transitioning can be investigated in a
single-switch study, such as takes place in the open-label extension phases
of most biosimilar trials when subjects treated initially with the reference
product are switch to receive the biosimilar while those treated initially with
the biosimilar continue to receive that product. Substitution occurs when a
different product is substituted for that initially prescribed. This may result
in a single switch or in repeated switches, which constitute “interchange.”
The BPCIA indicates that the FDA can judge a biologic product to
be interchangeable. This additional standard can be met if the product is
biosimilar to the reference product and it is expected to produce the same
clinical outcomes as the reference product in any given patient.25 In addition, if it is given more than once, the risk in terms of safety or decreased
efficacy of alternating between the reference product and the biosimilar
must not be greater than the risk of using the reference product without
such repeated switching. By definition in the Act, the designation of
interchangeability would allow the biosimilar product to be substituted
for the reference product without involving the health care provider who
prescribed the reference product. Accordingly, to support this designation,
a study design with repeated switching would be appropriate; however, a
single switch study could fulfill the current statutory requirement.
The BPCIA offers 1 year of exclusive marketing rights to the first biosimilar shown to be interchangeable with its reference product. However, the
FDA has not yet provided specific guidance as to the trial design necessary to achieve the designation of “interchangeability,” and the logistics of
conducting such a trial are cumbersome which may be prohibitive to its
successful conduct.
Biosimilars: Looking Forward
The justification for biosimilars assumes that the potential risk to the individual patient of switching to a lower cost biosimilar is outweighed by the
potential benefit to society of expanding access to care. Currently marketed
biosimilars are priced considerably lower than their reference products.
If a biosimilar is approved according to a regulatory pathway designated
for biosimilar products, approval will be based on the biosimilar being as
effective and safe as the reference product. The designation of “interchangeability” is unlikely to be granted in the near future because a clinical trial
adequate to support such a designation is unlikely to be accomplished.
However, in the United States, insurance carriers and pharmacy benefit
management companies will likely dictate switching between the originator
and a biosimilar or between 2 biosimilars.
Figure 2. CT-P13: Immunogenicity
60
60
PLANETAS
Ankylosing
Spondylitis
50
PLANETRA
Rheumatoid
Arthritis
52.3%
49.5%
48.4%
50
% Subjects With ADA
48.2%
40
40
27.4%
30
30
25.8%
26.7%
22.9%
20
25.4%
20
22.5%
11.0%
10
10
CT-P13 5 mg/kg (n=128)
INX 5 mg/kg (n=122)
9.1%
0
0
10
20
30
Week
40
50
Key: ADA=anti-drug antibodies, INX=infliximab, MTX=methotrexate.
Source: Park W, et al. Ann Rheum Dis. 2013;72:1605-1612; Yoo DH, et al. Ann Rheum Dis. 2013;72:1613-1620.
60
MTX + CT-P13 3 mg/kg (n=302)
MTX + INX 3 mg/kg (n=304)
0
0
10
20
30
40
50
60
Week
Rheumatoid Arthritis: Mechanisms of Autoimmunity, Immunogenicity, and Advances in Immunotherapy • globalacademycme.com/rheumatology 13
Biosimilars in Rheumatology: Present and Future
The lack of standardization among regulatory approval pathways for
biosimilars makes regulatory submissions to multiple national regulatory
agencies challenging.1 This may inhibit biosimilar manufacturers that are
targeting international markets. In addition, the unified International
Committee on Harmonization authorized reference standard could facilitate the development of effective and safe biosimilars.
Conclusions
Biosimilars are highly similar to their reference products. The objective
of biosimilar development programs is to establish biosimilarity, not to
reestablish benefit. A stepwise and comprehensive comparative approach to
claim biosimilarity must demonstrate highly similar physiochemical characteristics, biologic activity, pharmacokinetics, and clinical safety and efficacy.
The biological license application submitted for approval of a biosimilar
is abbreviated, compared with applications submitted for approval of an
originator biopharmaceutical. However, in the EU, United States, and
several other countries, biosimilars undergo a rigorous regulatory approval
process in which regulators assess the “totality of evidence.” Many biopharmaceuticals will be going off-patent in the near future; accordingly, the
opportunity exists to expand patient access through the availability of
lower-cost biosimilars.
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16. Macdonald J. Biosimilar regulatory frameworks with room for convergence-what more is needed? 2013
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19. Chamberlain P. Assessing immunogenicity of biosimilar therapeutic monoclonal antibodies: regulatory and
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23. Yoo D, Hrycaj P, Miranda P, et al. A randomised, double-blind, parallel-group study to demonstrate
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2013;72:1613-1620.
24. Braun J, Baraliakos X, Kudrin A, Kim H, Lee S. Striking discrepancy in the development of anti-drug antibodies (ADA) in patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS) in response to
infliximab (INF) and its biosimilar CT-P13. Arthritis Rheum. 2014;66:Suppl 11; Abstr L21.
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Competition and Innovation Act of 2009. Revision 1. May 2015. DRAFT GUIDANCE.
The Evolving Roles of B-cells in Autoimmune Diseases, Including Rheumatoid Arthritis
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2. Choy E, Panayi G. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Eng J Med.
2001;344:907-916.
3. Silverman G, Carson D. Roles of B-cells in rheumatoid arthritis. Arthritis Res Ther. 2003;5:S1-S6.
4. Smolen J, Steiner G. Therapeutic strategies for rheumatoid arthritis. Nat Rev Drug Discov. 2003;2:473-488.
5. Meier F, Frerix M, Hermann W, Muller-Ladner U. Current Immunotherapy in rheumatoid arthritis.
Immunotherapy. 2013;5:955-974.
6. Etanercept [package insert]. Thousand Oaks, CA: Immunex Corp; 2013.
7. Silverman GJ, Pelzek A. Rheumatoid arthritis clinical benefits from abatacept, cytokine blockers, and rituximab are all linked to modulation of memory B cell responses. J Rheumatol. 2014;41(5):825-828.
8. Martin F, Chan A. B cell immunobiology in disease: evolving concepts from the clinic. Annu Rev Immunol.
2006;24:467-496.
9. Lund F, Garvy B, Randall T, Harris D. Regulatory roles for cytokine-producing B-cells in infection and
autoimmune disease. Curr Dir Autoimmun. 2005;8:25-54.
10. Duddy M, Alter A, Bar-Or A. Distinct profiles of human B cell effector cytokines: a role in immune regulation?
J Immunol. 2004;172:3422-3427.
11. Klippel J, Stone J, Crofford L, White P, eds. Primer on the Rheumatic Diseases. 13th ed. 2007.
12. Hirano T. Revival of the autoantibody model in rheumatoid arthritis. Nat Immunol. 2002;3:342-344.
13. Steiner G, Smolen J. Autoantibodies in rheumatoid arthritis and their clinical significance. Arthritis Res.
2002;4:S1-S5.
14. Roosnek E, Lanzavecchia A. Efficient and selective presentation of antigen-antibody complexes by
rheumatoid factor B-cells. J Exp Med. 1991;173:487-489.
15. RITUXAN [Package insert]. South San Francisco, CA: Genentech, Inc.; 2014.
16. Cancro M, D’Cruz D, Khamashta M. The role of B lymphocyte stimulator (BLyS) in systemic lupus
erythematosus. J Clin Invest. 2009;119:1066-1073.
17. Chu V, Enghard P, Schurer S, et al. Systemic activation of the immune system induces aberrant BAFF
and APRIL expression in B-cells in patients with systemic lupus erythematosus. Arthritis Rheum.
2009;60:2083-2093.
18. Miller J, Stadanlick J, Cancro M. Space, selection, and surveillance: Setting boundaries with BLyS.
J Immunol. 2006;176:6405-6410.
19. Silverman G. Therapeutic B cell depletion and regeneration in rheumatoid arthritis. Arthritis Rheum.
2006;54:2356-2367.
20. Newton J, Harney S, Wordsworth B, Brown M. A review of the MHC genetics of rheumatoid arthritis.
Genes Immunity. 2004;5:151-157.
21. Plenge R, Seielstad M, Padyukov L, et al. TRAF1-C5 as a risk locus for rheumatoid arthritis--a genomewide
study. N Eng J Med. 2007;357:1199-1209.
22. Holoshitz J. The rheumatoid arthritis HLA-DRF1 shared epitope. Curr Opin Rheumatol. 2010;22:293-298.
23. Niewold T, Harrison M, Paget S. Anti-CCP antibody testing as a diagnostic and prognostic tool in rheumatoid arthritis. QJ Med. 2007;100:193-201.
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26. van der Woude D, Rantapaa-Dahlqvist S, Ioan-Facsinay A, et al. Epitope spreading of the anti-citrullinated
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27. Aletaha D, Neogi T, Silman A, et al. 2010 rheumatoid arthritis classification criteria. Arthritis Rheum.
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29. Dennis Jr G, Holweg C, Kummerfeld S, et al. Synovial phenotypes in rheumatoid arthritis correlate with
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30. Silverman G, Pelzec A. Rheumatoid arthritis clinical benefits from abatacept, cytokine blockers, and
rituximab are all linked to modulation of memory B cell responses. J Rheumatol. 2014;41:825-828.
Immunogenicity and Biologic Therapies: Theory and Practice
27. Garces S, Demengeot J, Benito-Garcia E. The immunogenicity of anti-TNF therapy in immunemediated inflammatory diseases: a systematic review of the literature with a meta-analysis. Ann Rheum Dis.
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29. Maneiro J, Salgado E, Gomez-Reino J. Immunogenicity of monoclonal antibodies against tumor necrosis
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14 continued from page 7
continued from page 10
30. Korswagen L, Bartelds G, Krieckaert C, et al. Venous and arterial thromboembolic events in adalimumabtreated patients with antiadalimumab antibodies. Arthritis Rheum. 2011;63:877-883.
31. Deehan M, Garces S, Kramer D, et al. Managing unwanted immunogenicity of biologicals. Autoimmunity
Rev. 2015;14:569-574.
32. Braun J, Baraliakos X, Kudrin A, Kim H, Lee S. Striking discrepancy in the development of anti-drug
antibodies (ADA) in patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS) in response
to infliximab (INF) and its biosimilar CT-P13. Arthritis Rheum. 2014;66:Suppl 11; Abstr L21.
Rheumatoid Arthritis: Mechanisms of Autoimmunity, Immunogenicity, and Advances in Immunotherapy • globalacademycme.com/rheumatology
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CME Posttest
1. Which of the following best describes the mechanism
of action for anakinra?
A. IL-1 recombinant human IL-1 receptor antagonist
B. Recombinant humanized anti-human IL-6 receptor
monoclonal antibody
C. CTLA-4 fusion protein
D. CD28 antibody
2. Which of the following best describes the mechanism
of action for tocilizumab?
A. IL-1 recombinant human IL-1 receptor antagonist
B. Recombinant humanized anti-human IL-6 receptor
monoclonal antibody
C. CTLA-4 fusion protein
D. CD28 antibody
3. Which of the following best describes the mechanism
of action for abatacept?
A. IL-1 recombinant human IL-1 receptor antagonist
B. Recombinant humanized anti-human IL-6 receptor
monoclonal antibody
C. CTLA-4 fusion protein
D. CD28 antibody
4. Which of the following drugs is a chimeric murinehuman monoclonal antibody that binds to and depletes
CD20-positive B-cells?
A. Etanercept
B. Rituximab
C. Golimumab
D. Infliximab
5. Which of the following drugs is a fully human IgG
monoclonal Ab?
A. Etanercept
B. Certolizumab
C. Methotrexate
D. Golimumab
6. Among the available TNF inhibitors, which one is
indicated for treatment of RA only when used in
combination with MTX?
A. Adalimumab
B. Etanercept
C. Golimumab
D. Certolizumab
7. According to the FDA, biosimilarity means that:
A. The biologic medicinal product contains a version of
the inactive substance of an already authorized original
biologic medicinal product.
B. The biologic medicinal product is slightly similar to the
reference product notwithstanding minor differences in
clinically active components.
C. The biologic medicinal product is highly similar to the
reference product notwithstanding minor differences
in clinically inactive components.
D. The biologic medicinal product is identical to the
reference product notwithstanding minor differences in
clinically active components.
8. Which of the following statements is true concerning
biosimilars?
A. Biosimilars are biomimics.
B. Biosimilars are intended copies.
C. Biosimilars are developed, assessed, or
approved according to the same regulatory
guidelines as biomimics.
D. Biosimilars are not second-generation
biopharmaceuticals.
9. Which of the following statements is true concerning
biomimics?
A. Biomimics may have differences in primary structure
compared with the reference product.
B. Biomimics never differ from the reference product in
formulation or doses/dosing regimen.
C. Biomimics never differ from the reference product
in efficacy.
D. Biomimics never differ from the reference product in
safety and immunogenicity.
10.You are treating a 45-year-old male with rheumatoid
arthritis with a TNF inhibitor. He continues to
experience painful flares that impair his quality of life.
Blood tests reveal low levels of the TNF inhibitor with
no antidrug antibodies. Which of the following would
be the best recommended approach to treatment?
A. Stop the TNF inhibitor and begin the patient on
high-dose prednisone
B. Switch to another TNF inhibitor
C. Increase the dose or frequency of the TNF inhibitor
D. Switch to a biologic with a different mechanism of action
Rheumatoid Arthritis: Mechanisms of Autoimmunity, Immunogenicity, and Advances in Immunotherapy • globalacademycme.com/rheumatology 15
Rheumatoid Arthritis: Mechanisms of Autoimmunity,
Immunogenicity, and Advances in Immunotherapy
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