`EXHIBIT E1
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`ALVOGEN, Exh. 1055,p. 0211
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`ALVOGEN, Exh. 1055, p. 0211
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`- = oe oh
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`Synthesis andActionsofT.NFOL
`
`Annals of the rheumatic diseases.
`UP - Genera} Callection
`W1 AN627
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`PROPERTY O
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`ALVOGEN, Exh. 1055, p. 0212
`
`
`
`Advancesin targeted therapies:
`T'NFa blockade in clinical practice
`
`Editors: F C Breedveld, J R Kalden, J S Smolen
`
`ae Supplement was made possible by unrestricted educational grants from Amgen (USA),
`€ntocor
`(TISA\
` Tmamnnev
`(TISA). Knoll
`(Germany), Schering-Plough (USA), and
`
`ALVOGEN, Exh. 1055, p. 0213
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`ALVOGEN, Exh. 1055, p. 0213
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`ALVOGEN, Exh. 1055, p. 0214
`
`ALVOGEN, Exh. 1055, p. 0214
`
`
`
`SUPPLEMENT VOL 58 NO 1
`
`Annals of the Rheumatic Diseases
`Advancesin targeted ther: waii |
`TNFablockadein clinical p_ [iii
`
`MEDICINE
`
`M Feldmann
`
`Preface
`It
`FC Breedveld, JR Kalden, J S Smolen
`12
`.Signal transduction by tumournecrosis factor and tumour necrosis factor related ligands and their
`receptors BG Damay, BB Aggarwal
`114 DAP kinase and DAP-3: novel Positive mediators of apoptosis
`A Kimchi
`120
`Tumournecrosis factor gene polymorphismsas severity markers in rheumatoid arthritis CL Verweij
`127
`Therationale for the current boomin anti-TNFa treatment. Is there an effective means to define therapeutic
`targets for drugs that provideall the benefits of anti-TNFa and minimise hazards?
`MM Feldmann,
`J Bondeson, F M Brennan, B M J Foxwell, R N Maini
`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
`140 Role of tumour necrosis factor a in experimentalarthritis: separate activity of interleukin 1B in chronicity
`and cartilage destruction WB van den Berg, L A B Joosten, G Kollias, FA J van de Loo
`149
`Tumournecrosis factor and other cytokines in murine lupus AN Theofilopoulos, B R Lawson
`156 Anti-tumour necrosis factor specific antibody (infliximab) treatment provides insights into the
`pathophysiology of rheumatoid arthritis FN Maini, P C Taylor, E Paleolog, P Charles, $ Ballara, F M Brennan,
`Summaryofclinicaltrials in rheumatoid arthritis usinginfliximab, an anti-TNFa treatment G Harriman, -
`161
`L K Harper, T F Schaible
`.
`165 Etanercept: therapeutic usein patients with rheumatoid arthritis
`L Garrison, N D McDonnell
`170
`Preliminary results of early clinical trials with the fully human anti-TNFo. monoclonal antibody D2E7
`J Kempeni
`173
`PEGylated recombinant human soluble tumournecrosis factor receptor typeI (r-Hu-sTNF-Rl): novel high
`affinity TNF receptor designed for chronic inflammatory diseases CK Edwards, tl
`—
`182
`Pharmacoeconomicevaluation of new treatments:efficacy versus effectiveness studies? C Bombardier,
`A Maetzel
`©
`186
`Safety, cost and effectiveness issues with disease modifying anti-rheumatic drugs In rheumatoid arthritis
`J F Fries
`”
`190
`FDA perspective on anti-TNF treatments W D Schwieterman
`192 European regulatory aspects on new medicines targeted at treatment of rheumatoid arthritis G Kreutz
`196 Treatmentof rheumatoid arthritis with interleukin 1 receptor antagonist 8 Bresnihan
`199
`Interleukin 10 treatment for rheumatoid arthritis EW St Clair
`1103 Clinical implications of tumour necrosis factor o antagonism in patients with congestive heart failure
`G Torre-Amione, S § Stetson, J A Farmer
`1107
`Immunomodulation by thalidomide and thalidomide analogues LG Corral, G Kaplan
`1114 Anti-TNF antibody treatment of Crohn’s disease SJH van Deventer
`1121
`The role of TNFo. and lymphotoxin in demyelinating disease C Lock, J Oksenberg, L Steinman
`Consensus statement
`1129 Access to disease modifying treatments for rheumatoid arthritis patients
`
`
`
` UEESICMNEIieh online|
`
`www.annf(ig AEV2
`
`8
`Bsmoe
`eet
`tel su mB IE
`
`This material was copied
`atthe NLMand maybe
`Subject US Copyright Laws
`
`ALVOGEN,Exh.1055, p. 0215
`
`ALVOGEN, Exh. 1055, p. 0215
`
`
`
`Ann Kheum Dis 19993;58:(Supp! 1) 1107-1113
`
`1107
`
`Immunomodulation by thalidomide and
`thalidomide analogues
`
`Laura G Corral, Gilla Kaplan
`
`Tumour necrosis factor a. (TNFa), a key
`cytokine involved in the host
`immune re
`sponse, also contributes to the pathogenesis of
`both infectious and autoimmunediseases. To
`ameliorate the pathology resulting from TNFa
`in theseclinical settings, strategies for the inhi-
`bition of this cytokine have been developed.
`Our previous work has shown that the drug
`thalidomideis a partial inhibitor ofTNFe pro-
`duction in vivo. For example, when leprosy
`patients suffering from erythema nodosum
`leprosum (ENL)are treated with thalidomide,
`the increased serum TNFa concentrations
`characteristic of this syndrome are reduced,
`with a concomitant improvement in clinical
`symptoms. Similarly, we have found that in
`patients with tuberculosis, with or without HIV
`infection, short-term thalidomide treatment
`reduces plasma TNFu levels in association
`with an accelerated weight gain. In vitro, we
`have also shown that
`thalidomide partially
`inhibits TNFa produced by human peripheral
`blood mononuclearcells (PBMC) responding
`to stimulation with lipopolysaccharide (LPS),
`Recently, we found that thalidomide can also
`act
`as
`a costimulatory signal
`for T cell
`activation in vitro resulting in increased
`production of interleukin 2 (IL2) and inter-
`feron y
`(IFNy). We also observed a bi-
`directional effect on IL12 production: IL12
`production is inhibited by thalidomide when
`PBMCare stimulated with LPS, however,
`IL12 productionis increased in the presenceof
`the drug whencells are stimulated via the T cell
`receptor. The latter effect is associated with
`upregulation of T cell CD40 ligand (CD40L)
`expression. Thus, in addition to its monocyte
`inhibitory activity,
`thalidomide exerts a co-
`stimulatory or adjuvant effect on T cell
`responses. This combination of effects may
`contribute to the immunomodulating proper-
`ties of the drug.
`To obtain drugs with increased anti-TNFa
`activity that have reduced or absent toxicities,
`novel TNFo inhibitors were designed using
`thalidomide as template. These thalidomide
`analogues were found to be up to 50 000 times
`moreactive than thalidomide. The compounds
`comprise two different types of TNFa inhibi-
`tors. One class of compounds, shown to be
`potent phosphodiesterase 4 (PDE4) inhibitors,
`are selective TNFa inhibitors in LPS stimu-
`lated PBMC andhaveeither noeffect or a sup-
`pressive effect on T cell activation. The other
`class of compoundsalso inhibit TNFa produc-
`tion, but do not inhibit PDE4 enzyme. These
`eamnoannas are alen natent inhihitare af cavaral
`
`stimulate the anti-inflammatory cytokine IL10.
`Similarly to thalidomide, these drugs that do
`not inhibit PDE4 act as costimulators of T cells
`but are much more potent than the parent
`drug. The distinct immunomodulatoryactivity
`of these new TNFainhibitors may potentially
`allow them to be used in the clinic for the
`treatment of a wide variety of immunopatho-
`logical disorders of different aetiologies.
`
`TNFis a key player in the immune
`response
`a pleiotropic cytokine produced
`TNFa is
`primarily by monocytes and macrophages, but
`also by lymphocytes and NKcells. TNFaplays
`a central part in the host immuneresponseto
`viral, parasitic, fungal and bacterial infections.
`The importance of TNFu and TNFusignal-
`ling through its receptors in the host immune
`response to disease has become clearer as a
`result of a number of seminal studies. For
`example, mice genetically deficient in TNFa
`have a significantly reduced humoral immune
`response to adenovirus infection.’ In Leishma-
`nia major infection, TNFa signalling is impor-
`tant for protection as mice lacking TNFa p35
`receptor (TNFR-p55) show delayed elimina-
`tion of the parasites compared with controls
`and thelesions formed failed to resolve.” Mice
`deficient in TNFR-p55 are also significantly
`impaired in their ability to clear infection with
`Candida albicans and readily succumb to the
`infection. TNFu signalling is also crucial
`in
`resisting Streptococcus pneumoniae infections in
`mice.’
`In addition, TNFa is essential
`for
`protection
`against murine
`tuberculosis.
`TNFR-p55 deficient mice have been shown to
`be more susceptible to tuberculosis infection.
`When TNFzwasneutralised in vivo by mono-
`clonal antibodies impaired protection against
`mycobacterial infection was observed.'’ The
`data from both models also established that
`TNFa and the TNFR- p55 are essential for
`production of reactive nitrogen intermediates
`by macrophagesearly in infection.
`
`TNFa contributes to disease pathogenesis
`Although TNFa is crucial
`to the protective
`immuneresponse, it also plays a part in the
`pathogenesis of both infectious and autoim-
`mune diseases. Increased concentrations of
`TNFu have been shown to trigger the lethal
`effects of septic shock syndrome.” TNF« has
`also been implicated in the development of
`cachexia, the state of malnutrition that compli-
`cates the course of chronic infections and many
`eancere ’ In rheumatoid arthritis, TNFa is a
`
`ALVOGEN, Exh. 1055, p. 0216
`
`Celgene Corporation,
`Warren, NJ, USA
`LG Corral
`
`Laboratoryof Cellular
`Physiology and
`Immunology, The
`Rockefeller University,
`New York, NY, USA
`G Kaplan
`
`Correspondenceto:
`Dr L. G Corral, The
`
`ALVOGEN, Exh. 1055, p. 0216
`
`
`
`1108
`
`Corral, Kaplan
`
`Recently, it has been shownthattreatment of
`patients with neutralising anti-TNFa. antibod-
`ies produces a dramatic reduction in disease
`activity in this condition.® Similarly, it has been
`shown that
`in inflammatory bowel disease,
`neutralisation of TNFa results in a profound
`amelioration of clinical symptoms.’ !° Reduc-
`tions in TNFulevels havealso been linked with
`a significant reductionofclinical symptomsin
`leprosy patients with ENL,
`including fever,
`malaise, and arthritic and neuritic pain." In
`tuberculosis patients, reduction of TNFa levels
`was associated with accelerated weightgain.”
`
`Thalidomide inhibits TNFa production
`by monocytes
`The pathology associated with TNFu produc-
`tion is profound and in manydiseases leads to
`significant morbidity and mortality. This has
`led to a concerted effort to discover drugs that
`will down regulate the production of this
`cytokine. Agents conventionally used in these
`diseases may inhibit TNFa production, but are
`also often broadly immunosuppressive (for
`example, cyclosporin A and corticosteroids)
`and therefore associated with extensive side
`effects." Drugs
`that are potentially more
`specific in inhibiting TNFu are under active
`investigation and development. Our previous
`work has shown that
`the drug thalidomide
`(u-N-phthalimidiglutarimide)
`is
`a
`relatively
`selective inhibitor of TNFa production by
`human monocytes in vivo. This property of
`thalidomide was
`first described in leprosy
`patients with ENL, an acute inflammatory
`complication of lepromatous leprosy that
`is
`accompanied by increased serum TNFalevels.
`Thalidomide treatment of patients with ENL
`was shown to induce a prompt reduction of
`TNFa serum levels with a concomitant abro-
`gation ofclinical symptoms."! Furthermore, in
`patients with tuberculosis, with or without
`concomitant HIV infection, thalidomidetreat-
`ment was found to both decrease plasma
`TNF« protein levels as well as monocyte
`TNFa mRNAlevels. This decrease was associ-
`ated with an accelerated weight gain.” In a
`rabbit model of mycobacterial meningitis, tha-
`lidomide treatment combined with antibiotics
`produced a marked reduction in TNFalevels,
`leucocytosis, and brain disease." In addition,
`thalidomide inhibited TNFa serum levels in
`mice
`challenged with LPS thus partially
`protecting the animals from septic shock.'®
`In vitro, we have found that
`thalidomide
`selectively reduces the production of TNFu by
`human monocytescultured in the presence of
`both LPS and mycobacterial products,'* How-
`ever, this inhibition was only partial (50% to
`70%) possibly because ofthe instability of the
`drug in aqueous solutions."” The mechanism
`by which thalidomide reduces TNFa produc-
`tion is still unclear. The drug seemsto inhibit
`TNFu production by human monocytes in
`vitro in association with enhanced degradation
`of TNFu mRNA." It also inhibits the activa-
`
`Thalidomide has T cell costimulatory
`properties
`Recently, we reported that thalidomidealso has
`a hitherto unappreciated immunomodulatory
`effect:
`the drug was shown to costimulate
`humanTcells in vitro, synergising with stimu-
`lation via the T cell
`receptor complex to
`increase IL2 mediated T cell proliferation and
`T cell IFNy production.” Optimal T cell acti-
`vation requires two signals.”' Thefirst signal or
`signal |
`is delivered by clustering of the T cell
`antigen-receptor-CD3 complex through en-
`gagementofspecific foreign peptides bound to
`MHC molecules on the surface of an antigen
`presenting cell
`(APC). Signal
`1
`can be
`mimicked by crosslinking the T cell receptor
`(TCR) complexes with anti-CD3 antibodies.
`Signal 2 (or costimulation) is antigen inde-
`pendent and may be provided by cytokines or
`by surface ligands on the APC that interact
`with their receptors on the T cell. Costimula-
`tory signals are essential to induce maximal T
`cell proliferation and secretion of cytokines,
`including IL2, which ultimately drive T cell
`clonal expansion. As antigenic stimulation in
`the absence of costimulatory signals leads to T
`cell anergy or apoptosis, costimulationis criti-
`cally important in the induction and regulation
`of cellular immunity.
`Thalidomide appears to act as a costimulator
`to T cells that have received signal
`1 via the
`TCR.”In our experimentsin vitro, stimulation
`ofpurified T cells with anti-CD3 antibodies, in
`the absence ofsignal 2, induced only minimal
`T cell proliferation. However, the addition of
`thalidomideto this cell culture system resulted
`in a concentration dependent
`increase in
`proliferative responses.”The thalidomide
`mediated costimulation of T cell proliferation
`was accompanied byincreases in IL2 and IFNy
`production, It is noteworthy that in the absence
`of anti-CD3, there was no T cell proliferative
`response to thalidomide,
`indicating that the
`drug is not mitogenic in itself.
`It
`is also
`interesting to note that in these experiments,
`thalidomide did not inhibit TNFa production
`by purified T cells stimulated by anti-CD3
`antibodies. This is in contrast with the effects
`of the drug on TNFu produced by monocytes.
`As already described above, thalidomide inhib-
`its monocyte TNFu production. The costimu-
`latory effect of thalidomide was greater on the
`CD8+ T cells than on the CD4+ T cell
`subset.”
`In addition to its effects on T cell prolifera-
`tion and T cell cytokine production, we
`observed that
`thalidomide induced the up-
`regulation of CD40L expression on activated T
`cells.” °° CD40L/CD40 interaction occurs
`early in the sequence of signalling events
`between T cells and antigen presenting cells
`(APC). Signalling through CD40 has been
`shownto activate APC and to induce expres-
`sion of costimulatory molecules such as B7, as
`well as stimulating production of IL12.2">
`Thus, CD40signalling results in a stimulatory ALVOGEN,Exh. 1055,p. 0217
`
`ALVOGEN, Exh. 1055, p. 0217
`
`
`
`Inununomodulation by thalidomide andthalidomide analogues
`
`1109
`
`a
`
`pr
`
`-.
`
`concentrations.
`
`-
`
`birth defects.” In addition, thalidomide treat-
`tial for the survival of CD8+ T cells and thatin
`its absence these cells die or become anergic.” mentis often accompanied by a numberofside
`
`These studies show that in addition to its_effects, including peripheral neuropathy.”
`inhibitory effect on the production of mono- Therefore,
`the use of thalidomide requires
`cyte cytokines, thalidomideexerts a costimula-
`strict monitoringofall patients.” Thus, there is
`tory or adjuvanteffect on T cell responses. The
`a pressing need to develop drugs with increased
`immune modulating effects of the drug in TNFa inhibitory activity and reduced or
`patients may thus beattributable to a balance_absenttoxicities. Towards this end, structural
`between the inhibition of production of mono-
`analogues of thalidomide have been designed
`cyte cytokines,
`including TNFa, and the
`and synthesised at Celgene Corporation (War-
`costimulation of T cell activity. The effects of
`ren, New Jersey) and screenedfor inhibition of
`thalidomide in vivo in HIV infected patients TNFa production. A large number of potent
`seem to reflect the costimulatory activity of the
`novel TNFa inhibitors were thus identified.
`drug.” In a placebo controlled study to evalu- Recently, some of these compounds were
`ate the effects of in vivo immunomodulation
` described.2” *“° On a molar basis, the more
`with thalidomide, the drug was administered
`potent of these thalidomide analogues were
`for
`four weeks
`to HIV infected patients.
`found to be up to 50 000-fold more potent
`Thalidomide treatment did not affect TNFa
`than thalidomide at inhibiting TNFa produc-
`levels in these patients. In contrast, thalidomide
`tion by human PBMCstimulated by LPS in
`treatment
`resulted in significant
`immune
`vitro. Furthermore, we have shown that some
`stimulation. This was reflected by increases in_of these compoundsretain high activity in LPS
`DTHresponses and increased plasma levels of
`stimulated human whole blood.In vivo,
`T cell activation markers such as soluble IL2
`several of
`these new compounds
`showed
`receptor (sIL2R) and soluble CD8antigen. An
`improved activity in reducing LPS induced
`earlier study of tuberculosis patients treated TNFa levels in mice” and in inhibiting the
`with thalidomide showed increased plasma
`developmentofadjuvantarthritis in rats."
`levels of IFNy suggesting an immunostimula-
`tory effect of the drug.” Recently, patients suf-
`fering from sarcoidosis have shown consistent Thalidomide analogues comprise two
`increases in sIL2R plasmalevels after thalido-
`distinct classes of molecules
`mide treatment (Oliver ez al, manuscript in A group of thalidomide analogues, selected for
`Preparation). In the same study, thalidomide_their capacity to potently inhibit TNFa pro-
`treatment increased theproliferation of sarcoid
`duction by LPS stimulated PBMC,wasfurther
`patient T cells in response to concanavalin Ain
`investigated (fig 1). When tested for their effect
`vitro. These results Strongly suggest
`that
`in vitro on LPS induced cytokines, different
`thalidomide directly stimulates T cells in vivo
`patterns of cytokine modulation were shown.”
`in patients, corresponding to the T cell
`Oneclass of compounds, class I or ImiDs
`costimulatory properties of the drug observed
`(mmunomodulatory Imide Drugs)
`showed
`in vitro in T cells from normal donors,”as not only potent inhibition of TNFa but also
`well as in the T cells of HIV infected patients.” marked inhibition of LPS induced monocyte
`,
`ILIB and IL12 production. LPS induced IL6
`Thalidomide analogues are improved
`was also inhibited by these drugs, albeit
`TNFainhibitors
`partially. These drugs were potent stimulators
`In addition to being the drug of choice for the
`Of LPSinduced IL10,increasing IL10 levels by
`treatment of ENL,
`thalidomide has been
`2090-300%. In contrast,the other class of com-
`shownto be useful in a numberofclinical situ-
`pounds, class II or SelCiDs (Selective Cytokine
`ations
`including rheumatoid arthritis, HIV Inhibitory Drugs), while still potently inhibit-
`associated aphthous ulcers and chronic graft
`ing ‘TNFa production, had a more modest
`versus host disease.However, thalidomide
`inhibitory effect on LPS induced ILIB and
`i 4 potent teratogen andingestion of the drug
`1112; anddid eeeieee mean
`re catastrophic
`a more modest ILIO stimulation (20-50%
`Thalidomide
`increases). In all of these characteristics, SelC-
`iDs were more similar to thalidomide than
`ImiDs.'*
`Further characterisation of the SelCiDs
`
`PDE4is one of the major phosphodiesterase
`
`*
`
`onCh,
`o-cy,
`i
`NH
`
`2
`
`showed that they are potent PDE4inhibitors.”
`isoenzymes found in human myeloid and lym-
`phoid lineage cells.“ The enzyme plays a
`.
`.
`.
`.
`«
`crucial part in regulating cellular activity by
`degrading the ubiquitous second messenger
`cAMP and maintaining it at low intracellular
`levels. Inhibition of PDE4 results in increased
`cAMPlevels leading to the modulation of LPS
`TNFu.” Increasing intracellular cAMPlevels
`induced cytokines
`including inhibition of
`
`have been shownto inhibit TNFu production
`:
`tas
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`O
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`mes
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`vt
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`o
`
`9
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`
`2
`
`N
`
`9 Q
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`0
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`=
`ALVOGEN, Exh. 1055, p. 0218
`
`ALVOGEN, Exh. 1055, p. 0218
`
`
`
`1110
`
`Corral, Kaplan
`
`regulated. Interestingly, the IMiDs and tha-
`induced primarily by the interaction of CD40
`lidomide were found notto inhibit PDE4.”
`on the surface of the APC with CD40L onthe
`In addition to the differential modulation of
`surface of activated T cells.” When Tcells
`LPS induced monocyte cytokines,
`the two
`were stimulated by anti-CD3, thalidomide and
`classes of compounds showed distinct effects
`IMiDs treatment causedasignificant stimula-
`on T cell activation. SelCiDs,
`the PDE4
`tion of IL12 production.” Thalidomide and
`inhibitors, hadlittle effect on T cell activation
`IMiDs
`also induced an up-regulation of
`causing onlyaslight inhibition of T cell prolif.
`CD40L onthe surface of T cells.” ° Blockade
`eration. This effect was not unexpected asit is
`of this pathway inhibits the production of IL12
`well established that increasing cAMPlevels in
`and
`abolishes
`the
`stimulatory
`effect of
`T cells during the early phase of mitogen or
`thalidomide.” Interestingly,
`in HIV infected
`antigen activation results in a decrease in
`patients,
`the consistent
`increases in plasma
`proliferative potential.’ On the other hand,
`IL12 levels induced by thalidomide treatment
`IMiDs, the non-PDE4 inhibitors, were potent
`lagged behindtheincreases in T cell activation
`costimulators of T cells and increased cell pro-
`markers.** This observation suggested that
`liferation dramatically in a dose dependent
`IL12 production was augmented as a conse-
`manner.” Similarly to thalidomide, these com-
`quence of drug inducedTcell activation.
`poundshada greater costimulatory effect on
`The dichotomous nature of thalidomide
`the CD8+ T cell subset than on the CD4+ T
`cytokine modulation may explain the seem-
`cell subset (Corral e¢ al, unpublished observa-
`ingly opposite effects observed in different
`tion). IMiDs, when added to anti-CD3 stimu-
`clinical situations. When patients with Behcet’s
`lated T cells, also caused marked increases in
`syndromearetreated with thalidomide, healing
`the secretion of IL2 and IFNy and induced the
`of inflammatory aphthousulcers occurs, butis
`up-regulation of CD40L expression on T
`sometimes accompanied by exacerbation of
`cells.” These findings show thatin addition to
`erythema nodosum.” Similarly, the paradoxi-
`their
`strong anti-inflammatory properties,
`cal worseningofgraft versus host disease" and
`IMiDsefficiently costimulate T cells with 100
`toxic epidermalnecrolysis”reported in clinical
`to 1000 times the potency ofthe parent drug.
`trials of thalidomide may be a manifestation of
`The molecular target of these co-stimulatory
`the unsuspected immune stimulatory effect of
`cytokine modulating drugsis as yet unknown.
`this drug.
`
`Potential clinical applications of
`thalidomide and thalidomide analogues
`The thalidomide analogues discussed here
`seem to have retained different properties of
`the parent drug (table
`1). The distinct
`immunomodulatory activities of
`these two
`classes of drugs suggest they may haveapplica-
`tions in different immunopathological disor-
`ders. SelCiDs, which inhibit PDE4, may be
`used in clinical situations in which PDE4inhi-
`bition and selective TNFu inhibition are
`beneficial. Therapeutic increase ofintracellular
`cAMP levels by PDE4 inhibitors has anti-
`inflammatoryeffects, which may afford conse-
`quent benefits in a variety of discases such as
`asthma,” atopic dermatitis’ and rheumatoid
`arthritis.” Indeed, in an animal model of adju-
`vant
`arthritis,
`thalidomide derived PDE4
`inhibitors have shown efficacy in suppressing
`the development of disease as measured by
`ankle swelling, hind limb radiographic changes
`and weight gain."*