TNF-Inhibition in the Treatment of Rheumatoid Arthritis

177 Pages·2004·1.69 MB·English

by  Larry W. Moreland

811_TNF Inhibition_prelims 25/09/2002 1 23 pm Page i
(cid:2)
TNF -Inhibition in the Treatment of
Rheumatoid Arthritis
811_TNF Inhibition_prelims 25/09/2002 1 23 pm Page iii
(cid:2)
TNF -Inhibition in the
Treatment of Rheumatoid
Arthritis
Edited by
Larry W Moreland MD
Professor of Medicine
Division of Clinical Immunology and Rheumatology
University of Alabama at Birmingham, Birmingham
Alabama
USA
Paul Emery MA MD FRCP
Professor of Medicine
Rheumatology and Rehabilitation Research Unit
University of Leeds School of Medicine
Leeds
UK
CRC Press
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© 2004 by Taylor & Francis Group, LLC
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Version Date: 20130325
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Contents
Contributors vii
Preface xi
1. Definition of TNF(cid:2)as a therapeutic target for rheumatoid arthritis
Marc Feldmann, Fionula M Brennan, Richard O Williams and
Ravinder N Maini 1
2. Infliximab therapy
Ravinder N Maini and Marc Feldmann 23
3. Etanercept
Sangeeta Sule and Joan M Bathon 47
4. Adalimumab (D2E7)
Leo van de Putte, Jochen Salfeld and Zehra Kaymakçalan 71
5. p55 TNF receptor therapy
John J Cush 89
6. TNF(cid:2)-inhibition in practical management of rheumatoid
arthritis: the US model
Joseph C Shanahan and Larry W Moreland 99
7. TNF(cid:2)-inhibition in practical management: the UK/European model
Paul Emery 121
8. Safety issues with anti-TNF agents: immunomodulation and
infection
Joseph C Shanahan 133
Index 163
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Contributors
Joan M Bathon MD Jack Cush
Associate Professor of Medicine Director
Johns Hopkins University, School Arthritis Center
of Medicine Presbyterian Hospital of Dallas
Director, Jackson Building
Johns Hopkins Arthritis Center 8198 Walnut Hill Lane
Bayview Medical Center Dallas, TX 75231
5501 Hopkins Bayview Circle USA
Baltimore, MD 21224
USA Paul Emery MD
Rheumatology and Rehabilitation
Fionula M Brennan Unit
Kennedy Institute of University of Leeds
Rheumatology Division 36 Clarendon Road
Faculty of Medicine Leeds LS2 9NZ
Imperial College of Science, UK
Technology and Medicine
1 Aspenlea Road
London W6 8LH
UK
811_TNF Inhibition_prelims 25/09/2002 1 23 pm Page viii
viiiContributors
Marc Feldmann MBBS, BSc, PhD, Ravinder N Maini
FRCPath, FRCP Kennedy Institute of
Head of Division Rheumatology Division
Kennedy Institute of Faculty of Medicine
Rheumatology Division Imperial College of Science,
Faculty of Medicine Technology and Medicine
Imperial College of Science, 1 Aspenlea Road
Technology and Medicine London W6 8LH
1 Aspenlea Road UK
London W6 8LH
UK Jochen Salfeld
Abbott Bioresearch Center
Zehra Kaymakcalan 100 Research Drive
Abbott Bioresearch Center Worcester, MA 01605
100 Research Drive USA
Worcester, MA 01605
USA Joseph C Shanahan MD
Assistant Professor of Medicine
Larry W Moreland MD Division of Clinical Immunology
Division of Clinical Immunology and Rheumatology
and Rheumatology University of Alabama at
University of Alabama at Birmingham Medical Center
Birmingham LHRB 412
Birmingham, AL 35294-7201 Birmingham, AL 35294
USA USA
Leo BA van de Putte Sangeeta Sule MD
Chairman, Department of Post-doctoral Fellow in
Rheumatology Rheumatology
University Medical Center Johns Hopkins Medical
Nijmegen Institutions
PO Box 9101 1830 Monument Street, Suite
6500 HB Nijmegen 7500
The Netherlands Baltimore, MD 21287
USA
811_TNF Inhibition_prelims 25/09/2002 1 23 pm Page ix
Contributors ix
Richard O Williams
Kennedy Institute of
Rheumatology Division
Faculty of Medicine
Imperial College of Science,
Technology and Medicine
1 Aspenlea Road
London W6 8LH
UK
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Preface
During the last decade, unprecedented progress has been made in our
understanding of the molecular processess involved in immune-medi-
ated inflammatory disorders such as rheumatoid arthritis (RA). In
particular, the introduction of TNF(cid:2)blocking agents has been one of the
milestones in the therapy of RA, parallel to the introduction of corticos-
teroids. These agents work very rapidly, they make patients feel well and
have considerable impact on structural damage.
The slim volume provides a handy and accessible update on the
current state of play on these new agents, with particular emphasis on
the clinical approach. In addition to discussions of the specific TNF bio-
logic response modifiers, there are reviews of current rheumatologic
practices in the USA and Europe, regarding where TNF inhibitors fit into
the treatment strategies for RA. Finally, the complexities of the immune
system regarding TNF inhibition are examined with regard to infection
complications in both animal and human models. Although uncom-
mon, serious infections can complicate the therapy of patients with
rheumatoid arthritis. The introduction of TNF inhibitors adds another
level of complexity to the balance of efficacy and safety of antirheumatic
therapies.
The editors wish to thank the authors of these chapters. Their hard
work and excellent writing is very much appreciated.
Larry W Moreland
Paul Emery
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chapter 1
(cid:2)
Definition of TNF as a
therapeutic target for
rheumatoid arthritis
Marc Feldmann, Fionula M Brennan, Richard O Williams and
Ravinder N Maini
Introduction – cytokines: a mini-primer
There are three major extracellular signalling systems that integrate the
cells of multicellular organisms and enable organ systems to function in
a coordinated fashion and to respond rapidly to environmental changes.
The nervous system brings neurotransmitters along prefixed paths to
target cells bearing the appropriate receptors. In contrast, the endocrine
system utilizes the bloodstream to deliver hormones long distances in
the blood from specialized producing cells to target cells. Communica-
tion involving the nervous and endocrine systems and their target
organs tends to be relatively long-range. In contrast, communication
between cells of the immune and inflammatory systems involves a series
of short-range protein mediators, known as cytokines, that are produced
by most cells of the body and most abundantly by blood cells and
diffuse within a few cell diameters from the producing cell to their
targets. The first cytokines were molecularly defined in the early 1980s
and by now over 150 cytokines are known, with probably 150 yet to be
identified.1
The definition of a cytokine now encompasses some cell surface mol-
ecules closely homologous to the classically secreted cytokines (e.g.
membrane trimeric LT(cid:2)(cid:3), related to secreted trimeric LT(cid:2)), and also
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2TNF(cid:2)-Inhibition in the Treatment of Rheumatoid Arthritis
includes molecules previously known as interleukins, interferons,
monokines, lymphokines and colony stimulating and growth factors.1
There are multiple types of cytokines, described according to their func-
tions. For example, major pro-inflammatorycytokines include interleukin-1
(abbreviated IL-1),2 tumour necrosis factor (cid:2) (TNF(cid:2)),3 interferon (cid:4) (IFN(cid:4))4
and IL-6.5 Important anti-inflammatory cytokines include IL-4,6 IL-107 and
transforming growth factor (cid:3)(TGF(cid:3)).8Important colony stimulating factors,
involved in haemopoiesis, include granulocyte-macrophage colony stimu-
lating factor (GM-CSF) and macrophage colony stimulating factor (M-
CSF).9 These latter two molecules are also important pro-inflammatory
cytokines, illustrating a property of cytokines, that they have multiple
diverse actions on different cell types. Chemokines, the largest family of
cytokines, are small ((cid:2)10kDa) proteins, which are important in recruiting
leukocytes to various inflammatory and immune sites.10
Unlike hormones and growth factors, one of the key features of pro-
inflammatory cytokines is that they are not constitutively produced, but
are generated in response to multiple stresses, such as bacterial or viral
infection and UV light. Pro-inflammatory cytokines are rapidly gener-
ated over a few hours, in an orderly sequence, with TNF(cid:2) being pro-
duced most rapidly within about 1 hour, and IL-1 and IL-6 within a few
hours.11 In response to lipopolysaccharide (LPS) in mice, it was found
that blocking TNF(cid:2)reduced the serum levels of IL-1 and IL-6, suggesting
the presence of a cytokine ‘cascade’, with TNF(cid:2)involved in inducing the
production of other cytokines.12
The high potency of cytokines (optimal activity at pg or ng/ml) is due
to the expression of very high affinity cytokine receptors. In general,
cytokine receptors are multi-chain complexes, which transmit intracellu-
lar signals upon cytokine binding.13 The cytokine binding chains of
many receptors (e.g. TNF receptor, IL-6 receptor, IFN(cid:4) receptor) can also
act as soluble cytokine inhibitors, after cleavage from the cell surface, to
release the extracellular binding domain.14 Triggering of cytokine recep-
tors usually involves ligand-induced receptor cross-linking, and then
cleavage of the receptor from the cell surface; it also has the effect of
reducing receptor density and, hence, the capacity of the cells to be trig-
gered.13