DECEMBER 1999 VOL 58 SUPPL I
`
`Annals of the
`Rheumatic
`Diseases
`
`Advances in targeted therapies:
`TNhx, blockade in clinical practice
`
`Synthesis and Actions of TNFa
`
`Macrophage
`or activated
`T-cell
`
`616.993
`AN
`v.58
`supp1.3
`1999
`
`,E9TNFa
`
`4 P4
`
`TNF
`receptor
`
`• • • • • • • • \
`
`BMJ
`
`Publi hing
`Group -
`
`es."0".
`
`-0‘v
`ators
`
`Target cell
`
`

`

`Advances in targeted therapies:
`TNFa blockade in clinical practice
`
`Editors: F C Breedveld, J R Kalden, J S Smolen
`
`This supplement was made possible by unrestricted educational grants from Amgen (USA),
`Centocor (USA), Immunex (USA), Knoll (Germany), Schering-Plough (USA), and
`Wyeth-Ayerst (USA)
`
`

`

`Annals of the Rheumatic Diseases
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`

`

`!t;..~ -
`
`SUPPLEMENT VOL 58 NO 1
`SUPPLEMENT VOL 58 NO 1
`
`\ ~1~~~!,111~~~1,~n~i~11l J
`Annals of the Rheumatic Diseases
`Annals of the Rheumatic Diseases
`Advances in targeted therapies:
`Advances in targeted therapies:
`TNFa blockade in clinical practice
`TNFa blockade in clinical practice
`
`Preface
`Preface
`11
`F C Breedveld, J R Kalden, J S Smolen
`F C Breedveld, J R Ka/den, J S Smolen
`12 Signal transduction by tumour necrosis factor and tumour necrosis factor related ligands and their
`12 Signal transduction by tumour necrosis factor a.nd tumour necrosis factor related ligands and their
`receptors B G Darnay, B B Aggarwal
`receptors B G Darnay, B B Aggarwal
`'
`114 (cid:9) DAP kinase and DAP-3: novel positive mediators of apoptosis A Kimchi
`114 DAP kinase and DAP-3: novel positive mediators of apoptosis A Ktmchi
`120 (cid:9)
`Tumour necrosis factor gene polymorphisms as severity markers in rheumatoid arthritis C L Verweij
`120 Tumour necrosis factor gene polymorphisms as severity markers in rheumatoid arthritis C L Verweij
`127 (cid:9)
`The rationale for the current boom in anti-TNFa treatment. Is there an effective means to define therapeutic
`127 The rationale for the current boom in anti-TNFa treatment. Is there an effective means to define therapeutic
`targets for drugs that provide all the benefits of anti-TNFa and minimise hazards? M Feldmann,
`targets for drugs that provide all the benefits of anti-TNFa and minimise hazards? M Feldmann,
`J Bondeson, F M Brennan, B M J Foxwell, R N Maini
`J Bondeson, F M Brennan, B M J Foxwell, R N Maini
`132 (cid:9)
`The function of tumour necrosis factor and receptors in models of multi-organ inflammation, rheumatoid
`132 The function of tumour necrosis factor and receptors in models of multi-organ inflammation, rheumatoid
`arthritis, multiple sclerosis and inflammatory bowel disease G Kollias, E Douni, G Kassiotis, D Kontoyiannis
`arthritis, multiple sclerosis and inflammatory bowel disease G Kollias, E Douni, G Kassiotis, D Kontoyiannis
`140 Role of tumour necrosis factor a in experimental arthritis: separate activity of interleukin 1 f3 in chronicity
`140 (cid:9) Role of tumour necrosis factor a in experimental arthritis: separate activity of interleukin 113 in chronicity
`and cartilage destruction W B van den Berg, L A B Joosten, G Kollias, F A J van de Loo
`and cartilage destruction W B van den Berg, L A B Joosten, G Kollias, FA J van de Loo
`149 (cid:9)
`Tumour necrosis factor and other cytokines in murine lupus A N Theofilopoulos, B R Lawson
`149 Tumour necrosis factor and other cytokines ih murine lupus A N Theofilopoulos, B R Lawson
`156 Anti-tumour necrosis factor specific antibody (infliximab) treatment provides insights into the
`156 Anti-tumour necrosis factor specific antibody (infliximab) treatment provides insights into the
`pathophysiology of rheumatoid arthritis R N Maini, P C Taylor, E Paleolog, P Charles, S Ballara, F M Brennan,
`pathophysiology of rheumatoid arthritis R N Maini, P C Taylor, E Paleolog, P Charles, S Bal/ara, F M Brennan,
`M Feldmann
`M Feldmann
`161 (cid:9)
`Summary of clinical trials in rheumatoid arthritis using infliximab, an anti-TNFa treatment G Harriman,
`161 Summary of clinical trials in rheumatoid arthritis using infliximab, an anti-TNFa treatment G Harriman,
`L K Harper, T F Schaible
`L K Harper, T F Schaible
`165 (cid:9) Etanercept: therapeutic use in patients with rheumatoid arthritis L Garrison, N D McDonnell
`165 Etanercept: therapeutic use in patients with rheumatoid arthritis L Garrison, N D McDonnell
`170 (cid:9) Preliminary results of early clinical trials with the fully human anti-TNFa monoclonal antibody D2E7
`170 Preliminary results of early clinical trials with the fully human anti-TNFa monoclonal antibody D2E7
`J Kempeni
`J Kempeni
`173 (cid:9) PEGylated recombinant human soluble tumour necrosis factor receptor type I (r-Hu-sTNF-RI): novel high
`173 PEGylated recombinant human soluble tumour necrosis factor receptor type I (r-Hu-sTNF-RI): novel high
`affinity TNF receptor designed for chronic inflammatory diseases C K Edwards, Ill
`affinity TNF receptor designed for chronic inflammatory dise"'ses C K Edwards, Ill
`182 (cid:9) Pharmacoeconomic evaluation of new treatments: efficacy versus effectiveness studies? C Bombardier,
`182 Pharmacoeconomic evaluation of new treatments: efficacy versus effectiveness studies? C Bombardier,
`A Maetzel
`A Maetzel
`186 (cid:9) Safety, cost and effectiveness issues with disease modifying anti-rheumatic drugs in rheumatoid arthritis
`186 Safety, cost and effectiveness issues with disease modifying anti-rheumatic drugs in rheumatoid arthritis
`J F Fries
`J F Fries
`190 (cid:9)
`FDA perspective on anti-TNF treatments W D Schwieterman
`190 FDA perspective on anti-TNF treatments W D Schwieterman
`192 (cid:9) European regulatory aspects on new medicines targeted at treatment of rheumatoid arthritis G Kreutz
`192 European regulatory aspects on new medicines targeted at treatment of rheumatoid arthritis G Kreutz
`Treatment of rheumatoid arthritis with interleukin 1 receptor antagonist B Bresnihan
`196 (cid:9)
`196 Treatment of .rheumatoid arthritis with interleukin 1 receptor antagonist B Bresnihan
`199 (cid:9)
`interleukin 10 treatment for rheumatoid arthritis E W St Clair
`199
`Interleukin 1 O treatment for rheumatoid arthritis E W St Clair
`1103 Clinical implications of tumour necrosis factor a antagonism in patients with congestive heart failure
`1103 Clinical implications of tumour necrosis factor a antagonism in patients with congestive heart failure
`G Torre-Amione, S S Stetson, J A Farmer
`G Torre-Amione, S S Stetson, J A Farmer ·
`1107 lmmunomodulation by thalidomide and thalidomide analogues L G Corral, G Kaplan
`lmmunomodulation by thalidomide and thalidomide analogues L G Corral, G Kaplan
`1107
`1114 Anti-TNF antibody treatment of Crohn's disease S J H van Deventer
`1114 Anti-TNF antibody treatment of Crohn's disease SJ H van Deventer
`1121 The role of TNFa and lymphotoxin in demyelinating disease C Lock, J Oksenberg, L Steinman
`1121 The role of TNFa and lymphotoxin in demyelinating disease C Lock, J Oksenberg, L Steinman
`
`Consensus statement
`Consensus statement
`1129 Access to disease modifying treatments for rheumatoid arthritis patients
`1129 Access to disease modifying treatments for rheumatoid arthritis patients
`
`\
`
`This issue live and online
`This issue live and online
`
`www.annrheumdis.com
`www .annrheumdis.com
`
`Ex. 1055 - Page 4
`
`

`

`132 (cid:9)
`
`Ann Rheum Dis 1999;58:(Suppl I) I32-i3,p,
`
`The function of tumour necrosis factor and
`receptors in models of multi-organ inflammation,
`rheumatoid arthritis, multiple sclerosis and
`inflammatory bowel disease
`
`George Kollias, Eleni Douni, George Kassiotis, Dimitris Kontoyiannis
`
`Abstract
`There is now good evidence to demon-
`strate that aberrations in tumour necrosis
`factor (TNF) production in vivo may be
`either pathogenic or protective and sev-
`eral plausible mechanisms may explain
`these contrasting activities. According to
`the classic pro-inflammatory scenario,
`failure to regulate the production of TNF
`at a site of immunological injury may lead
`to chronic activation of innate immune
`cells and to chronic inflammatory re-
`sponses, which may consequently lead to
`organ specific inflammatory pathology
`and tissue damage. However, more cryptic
`functions of this molecule may be consid-
`ered to play a significant part in the devel-
`opment of TNF mediated pathologies.
`Direct interference of TNF with the
`differentiation, proliferation or death of
`specific pathogenic cell targets may be an
`alternative mechanism for disease initia-
`tion or progression. In addition to these
`activities, there is now considerable evi-
`dence to suggest that TNF may also
`directly promote or down regulate the
`adaptive immune response. A more com-
`plete understanding of the temporal and
`spatial context of TNF/TNF receptor
`(TNF-R) function and of the molecular
`and cellular pathways leading to the
`development of TNF/TNF-R mediated
`pathologies is necessary to fully compre-
`hend relevant mechanisms of disease
`induction and progression in humans. In
`this paper, the potential pathogenic
`mechanisms exerted by TNF and recep-
`tors in models of multi-organ inflamma-
`tion, rheumatoid arthritis, multiple
`sclerosis and inflammatory bowel disease
`are discussed. Elucidating the nature and
`level of contribution of these mechanisms
`in chronic inflammation and autoimmu-
`nity may lead to better regulatory and
`therapeutic applications.
`(Ann Rheum Dis 1999;58:(Suppl I) 132-139)
`
`differential bioactivities of its soluble and
`transmembrane form' and the differential
`functioning of its two tumour necrosis factor
`receptors (TNF-Rs).2 TNF has been for many
`years at the apex of factors showing dominant
`contribution to disease pathogenesis, especially
`chronic inflammation and autoimmunity. Its in
`vitro activities are now well understood and the
`signals transduced by the two TNF-Rs have
`been sufficiently detailed both at the molecular
`and the cellular level. However, the specific role
`of TNF and receptors in disease pathogenesis
`remains still poorly defined. Data discussed in
`this review, point towards multiple in vivo
`activities for this molecule. Firstly, the potent
`innate inflammatory activities of TNF seem
`central to disease induction and progression,
`particularly when sustained TNF expression is
`provoked. Evidence for direct effects of TNF
`on non-immune stromal cell types, which are
`important for the function of a given tissue or
`organ, is also available, and may offer alterna-
`tive mechanisms for pathogenic contribution.
`Lastly, more recent data indicating direct
`modulation by TNF of the adaptive immune
`response may also be taken into consideration,
`to explain the beneficial or at times detrimental
`role of TNF in spontaneous models of autoim-
`munity. It is evident that no unique scenario is
`available to explain the role of TNF in inflam-
`matory or autoimmune pathology. Rather, a
`diverse range of activities is expected to
`function in each model case, and most
`probably also in human disease. In figure 1, we
`have summarised the factors affecting TNF/
`TNF-R function in disease. Obviously, the
`diverse in vivo functions of TNF may signifi-
`cantly depend on the duration, quantity and
`quality of TNF signals. In addition, genetic
`background, locality and timing of TNF
`expression may also modulate the function of
`this molecule and diversify the end result of the
`immune response, either to the benefit or
`distress of the host. Experimental modification
`of these parameters in transgenic and knockout
`animal models of TNF mediated disease has
`been revealing.
`
`Laboratory of
`Molecular Genetics,
`Hellenic Pasteur
`Institute, 127 Vas
`Sofias Avenue, Athens
`115 21, Greece
`
`Correspondence to:
`Dr G Kollias.
`
`Tumour necrosis factor (TNF) is produced in
`response to infection or immunological injury
`and effects multiple responses, which extend
`beyond its well characterised proinflammatory
`properties' to include diverse signals for cellu-
`lar differentiation, proliferation and death.'
`Part of the complexity of TNF mediated
`responses may be related to the apparent
`
`Role of TNF in models of rheumatoid
`arthritis (RA)
`The majority of the joint inflammatory disor-
`ders, typified by the manifestations of RA, are
`characterised by the hyper-proliferation of
`synovial tissue and the infiltration of blood
`derived cells resulting in the progressive
`erosion of the cartilage and bone. Genetic sus-
`
`

`

`TNF in RA, MS and IBD (cid:9)
`
`Duration
`Quantity
`Quality
`
`Genetic background
`Developmental timing
`Locality
`
`133
`
`Non-specific inflammation
`
`Direct cell effects
`Immune activation
`Immune suppression
`Figure 1 The diverse in vivo functions of TNF may significantly depend on the duration, quantity and quality of TNF
`signals. In addition, genetic background, locality and timing of TNF expression may also modulate the function of this
`molecule and diversify the end result of the immune response, either to the benefit or distress of the host.
`
`ceptibility, physical stress, infectious agents and
`aberrant immune responses have all been
`implicated in the pathogenesis of RA.' The
`increased genetic linkage of specific HLA-DR
`haplotypes with RA' and the presence of
`experimental models of RA, induced in geneti-
`cally susceptible animals after immunisation
`with collagen, led to the original assumption of
`autoimmune mechanisms playing a dominant
`part in both the induction and maintenance of
`the disease. However, the contribution of
`adaptive mechanisms in the pathogenesis of
`RA could not be confirmed at the clinical level,
`as both anti-CD4 and anti-CD5 clinical trials
`failed to induce a beneficial outcome."
`The role of lymphocytes in driving the
`arthritogenic response in the popular animal
`model of collagen induced arthritis (CIA) has
`also recently been challenged. Although T cell
`transfers and antibody depleting studies" had
`previously established the pathogenic potential
`of specific antigen reactive cells in this model,
`administration of collagen type II in CD4- and
`CD8-deficient mice resulted in the appearance
`(albeit with lower incidence) of the typical CIA
`profile, failing to provide evidence for an
`essential role in disease induction." In view of
`the conflicting evidence on the role of an adap-
`tive pathogenic immune response in CIA, we
`recently backcrossed Rag-1 deficient mice
`lacking mature lymphocytes into the CIA sus-
`ceptible DBA/1 genetic background.' Colla-
`gen type II immunisation of these mice resulted
`in the development of arthritic lesions in their
`joints characterised by synovial hyperplasia
`with occasional inflammation as well as carti-
`lage and bone destruction. The observed
`delayed onset and reduced severity of disease
`suggests that lymphocytes do play a significant,
`yet secondary part in disease induction.
`Evidence of synoviocyte proliferation in the
`absence of inflammation, after collagen admin-
`istration in the DBA/1-immunodeficient mice,
`indicated an immediate responsiveness of this
`cell type to collagen. It may therefore be
`suggested that in susceptible genetic back-
`grounds, sequestration of collagen resulting
`from insults affecting joint integrity may
`activate the synoviocyte and cause pathology.
`These, non-antigenic properties of collagen
`may offer new clues as to the mechanisms
`operating in the pathogenesis of RA.
`Early detection of a broad range of pro-
`inflammatory cytokines in RA biopsy speci-
`mens and explant cultures, established their
`importance in joint inflammation.' Among
`them, the significance of TNF in mediating the
`arthritogenic response, has been demonstrated
`by the amelioration of arthritic lesions in anti-
`TNF treated animal models of arthritis' 14 and
`most importantly in human disease.' Perhaps,
`
`the most informative animal model, as to the
`TNF mediated mechanisms operating in ar-
`thritis, has been produced by the introduction
`of modified human TNF transgene in mice.'
`Based on the possible role of TNF 3'UTR on
`the translational repression of TNF mRNA,
`this region was replaced by that of the I3-globin
`gene. The resulting transgenic mice developed
`a form of erosive arthritis with similar histo-
`logical characteristics to RA. A similar form of
`arthritis appeared also in targeted mutant mice
`lacking the 3'AU—rich elements (TNF'
`mutant mice), confirming the role of these ele-
`ments in the maintenance of a physiological
`TNF response in the joint.' In addition,
`neutralisation of arthritis by treatment of the
`hTNF transgenic mice with antibodies against
`TNF or the type I ILl receptor established the
`idea that a functional hierarchy exists, in which
`the IL1R acts in series and downstream of
`TNF to effect TNF mediated arthritogenic
`responses."
`Absence of the 3'ARE elements from the
`mRNA of TNF results in chronic polyarthritis.
`A proposed mechanism that may affect the
`pathogenic outcome in arthritis, may be the
`inability of natural anti-inflammatory signals to
`suppress the destructive TNF expression in the
`arthritic joint. Anti-inflammatory mediators
`such as ILI 0, IL4 and TGF-I3 are abundant in
`rheumatoid joints, supporting the hypothesis of
`a counter-reaction compensating for the in-
`creased proinflammatory load.1819 However,
`this equilibrating response is apparently not
`sufficient to block disease progression. The
`inability of IL10 to efficiently suppress macro-
`phage and/or synoviocyte TNF production
`because of the absence of the natural TNF
`3'UTR (our unpublished observations), postu-
`late a possible involvement of mutations affect-
`ing the expression of TNF (for example, func-
`tional mutations in TNF's ARE sequences) as
`aetiopathogenic factors in disease initiation or
`progression. This is further suggested by the
`fact that treatment of hTNF3'globin trans-
`genic mice with cellular vectors producing IL4,
`IL10 and IL13 did not significantly affect
`development of arthritis in this model." The
`minimal, if any, role of adaptive immunity in
`the development of arthritis in these models
`has been confirmed in studies demonstrating
`that the course of disease in hTNF transgenic
`and TNF' mutant mice is not affected by the
`absence of mature T and B cells.1"1 This is in
`agreement with transplantation studies show-
`ing destruction of human cartilage by RA
`derived synoviocytes engrafted in the kidney
`capsule of SCID mice." 23
`Perhaps most importantly, the ARE deletion
`results in a profound spontaneous capacity of
`synoviocyte fibroblasts to produce TNF.16 21
`
`

`

`134 (cid:9)
`
`Kollias, Douni, Kassiotis, et al
`
`Synoviocytes have been considered pivotal for
`the development of the arthritic reaction as
`they proliferate in response to TNF" and pro-
`duce extracellular matrix-degradative enzymes
`and chemokines.' 26 Their capacity to also
`produce TNF as a result of an ARE deletion,
`underscores their central role as both target
`and effector cells capable of initiating and
`maintaining the arthritogenic response. In an
`effort to assess if the TNF expressing synovial
`fibroblast is sufficient to induce disease, we
`have recently transferred clones of hTNF
`expressing synovial fibroblasts into the knee
`joint of histocompatible normal recipients.
`Migration of such fibroblasts from the injection
`site into other joints and different organs of the
`mouse could be demonstrated. Furthermore,
`four weeks after engraftment, a percentage of
`the mice developed polyarthritis with all the
`basic characteristics described for the donor
`(David Plows, Sylva Haralambous and George
`Kollias, unpublished observations). Interest-
`ingly, synoviocytes are seen to behave like
`tumour cells and can readily invade and
`destroy the environment that they home into."
`In this context, the migration and homing of
`transferred TNF transgenic synoviocytes into
`multiple joints of recipient mice can be viewed
`as a metastatic process and the capacity to form
`a tumour mass may also rely on the angiogenic
`activities of TNF.
`In conclusion, in models of TNF mediated
`arthritis, conceivably also in RA, the most
`critical phenomenon for both the initiation and
`perpetuation of disease seems to be the capac-
`ity of TNF to transform the nature of the syno-
`vial fibroblast, a cell with immense potential for
`unrestricted proliferation and autonomous
`invasion into the cartilage or bone. In this con-
`text, the contribution of non-specific inflam-
`mation and adaptive immunity seems to be in
`the regulation rather than initiation of disease.
`Understanding further the biology of the syno-
`vial fibroblast may offer new clues on addi-
`tional molecules and mechanisms playing criti-
`cal parts in the pathogenesis of arthritic
`disease.
`
`Role of TNF in models of inflammatory
`bowel disease (IBD)
`Pathogenesis of idiopathic IBD has been
`closely associated with the altered production
`of several pro-inflammatory cytokines. More
`specifically, the correlation between increased
`TNF production and IBD development has
`been exemplified in several animal models for
`this disease via the use of specific neutralising
`antibodies or cytokine gene knockouts.'"
`Most convincing, the central role of TNF in
`the pathophysiology of human Crohn's disease
`(CD) has been overtly confirmed in clinical
`trials using a single dose of anti-TNF mono-
`clonal antibody in patients with treatment
`refractory CD.' Furthermore, a similar to the
`human form of IBD appeared also in targeted
`mutant mice lacking the 3'AU—rich elements,'
`further substantiating the role of TNF in the
`development of diseases affecting the gut. The
`gut histopathological characteristics of the
`TNF' mice, including transmural inflamma-
`
`tion, granuloma formation and ileal confine-
`ment, most closely resemble the human condi-
`tion of CD32 providing, for the first time
`positive evidence for TNF in inducing this
`form of IBD.16
`TNF action in IBD has been considered
`mainly inflammatory through the activation of
`endothelial cells, induction of chemokines, and
`recruitment of neutrophils in the gut mucosa.'
`TNF has been shown to influence intestinal
`epithelial cell growth," permeability,' and
`integrity via matrix metalloproteinase (MMP)
`production" and to induce epithelial cell
`apoptosis.37 In addition, TNF has been impli-
`cated in the formation of bacterial induced
`granulomas through the induction of MCP-1
`production by endothelial cells.' Intestinal
`epithelial damage is considered an early
`histopathological manifestation in CD39 sup-
`porting the assumption that TNF plays a cen-
`tral part in initiating mucosal events in IBD.
`However, the action of TNF in the TNF'
`model of CD does not seem to be solely of an
`innate pro-inflammatory character. Intestinal
`pathology in these mice is heavily dependent
`on the presence of mediators or cells of the
`adaptive immune response, because in the
`absence of mature lymphocytes (for example,
`in backcrosses to Rag-1 deficient mice) intesti-
`nal inflammation is neutralised.' It is therefore
`possible that the chronic TNF production
`resulting from the ARE deletion shapes up a
`pathogenic lymphocytic response. TNF pro-
`duction has been numerously suggested to
`drive pathogenic Thl -like responses in concert
`with both IL12 and IFNy.' Interestingly,
`activated mucosal T cells from CD patients
`demonstrate a characteristic Thl cytokine pro-
`file associated with active disease.' Further-
`more, a significant reduction of Th 1 -like
`lamina propria mononuclear cells has been
`reported in CD patients treated with the cA2
`anti-TNF