EXHIBIT E1
`
`EXHIBIT E1
`
`ALVOGEN, Exh. 1055, p. 0211
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`ALVOGEN, Exh. 1055, p. 0211
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`

`

`Annals of the rheumatic diseases.
`DUP - General (Deflection
`W1 AN627
`
`
`
`SyntheSis and Actions‘of TNFoi
`
`— _ ln-IA‘
`[410mm 0
`
`ALVOGEN, Exh. 1055, p. 0212
`
`

`

`Advances in targeted therapies:
`TNFOL blockade in clinical practice
`
`Editors: F C Breedveld,] R Kalden,J S Smolen
`
`This su
`C
`
`pplement was made possible by unrestricted educational grants from Amgen (USA),
`ent0cor
`(rmm 1mm11111
`(USA). Knoll {Germany}: Schering—Plough (USA), and
`
`ALVOGEN, Exh. 1055, p. 0213
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`ALVOGEN, Exh. 1055, p. 0213
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`

`

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`ALVOGEN, Exh. 1055, p. 0214
`
`ALVOGEN, Exh. 1055, p. 0214
`
`

`

`SUPPLEMENT VOL 58 NO 1
`
`Annals of the Rheumatic Diseases":
`
`Advances in targeted there NA,
`TNFd blockade in clinical p,
`ii i
`
`TIONAL LIBRARY OF M
`
`EDICINE
`
`MW
`ii
`
`Preface
`
`If
`12
`
`F C Breedveld, J H Kalden, J S Smolen
`.Signai transduction by tumour necrosis factor and tumour necrosis factor related ligands and their
`receptors
`B G Darnay, B B Aggarwal
`A Kimchi
`I14 DAP kinase and DAP-3: novel positive mediators of apoptosis
`120 Tumour necrosis factor gene polymorphisms as severity markers in rheumatoid arthritis 0 L Verweij
`127 The rationale for the current boom in anti-TNFoc treatment. Is there an effective means to define therapeutic
`targets for drugs that provide all the benefits of anti-TNFoz and minimise hazards? M Feldmann,
`J Bondeson, F M Brennan, 8 M J Foxwell, F? N Maini
`132 The function of tumour necrosis factor and receptors in models of muiti-organ inflammation, rheumatoid
`arthritis, multiple sclerosis and inflammatory bowel disease G Kollias, E Douni, G Kassiotis, D Kontoyiannis
`I40 Role of tumour necrosis factor a in experimental arthritis: separate activity of interleukin 1B in chronicity
`and cartilage destruction W B van den Berg, L A B Joosten, G Kollias, FA J van de Loo
`I49 Tumour necrosis factor and other cytoklnes in murine lupus A N Theofilopou/os, B R Lawson
`156 Anti-tumour necrosis factor specific antibody (infiiximab) treatment provides insights into the
`pathophysioiogy of rheumatoid arthritis B N Maini, P C Taylor, E Paleolog, P Charles, S Ballara, F M Brennan,
`M Feldmann
`Summary of clinical trials in rheumatoid arthritis using infiiximab, an anti-TNFa treatment G Harriman, ‘
`161
`L K Harper, T F Schaib/e
`.
`165 Etanercept: therapeutic use in patients with rheumatoid arthritis
`L Garrison, N D McDonnell
`[70
`Preliminary results of early clinical trials with the fully human anti-TNFa monoclonal antibody D2E7
`J Kempeni
`I73
`PEGyiated recombinant human soluble tumour necrosis factor receptor type i (r-Hu-sTNF-Fti): novel high
`affinity TNF receptor designed for chronic inflammatory diseases 0 K Edwards, //I
`'
`182
`Pharmacoeconomic evaluation 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 6 Kreutz
`[96 Treatment of rheumatoid arthritis with interleukin 1 receptor antagonist B Bresnihan
`199
`interleukin 10 treatment for rheumatoid arthritis E W St Clair
`1103 Clinical implications of tumour necrosis factor on antagonism in patients with congestive heart failure
`G Torre-Amione, S S Stetson, J A Farmer
`L G Corral, G Kaplan
`immunomoduiation by thalidomide and thalidomide analogues
`1107
`[114 Anti-TNF antibody treatment of Crohn’s disease 8 J H van Deventer
`1121
`The role of TNFa and iymphotoxin in demyeiinating disease 0 Lock, J Oksenberg, l. Sleinman
`Consensus statement
`
`[129 Access to disease modifying treatments for rheumatoid arthritis patients
`
`This issue live and online, n,
`
`HRH
`
`é’él
`
`This material was {spied
`at. the NLM and. may the
`Subject: US Wright Laws
`
`ALVOGEN, Exh. 1055, p. 0215
`
`ALVOGEN, Exh. 1055, p. 0215
`
`

`

`Aim Rheum Dis 1999;58:(Suppl I) 1107—11 13
`
`l107
`
`Immunomodulation by thalidomide and
`thalidomide analogues
`
`Laura G Corral, Gilla Kaplan
`
`Tumour necrosis factor a . (TNFu), a key
`cytokine involved in the host
`immune re—
`sponse, also contributes to the pathogenesis of
`both infectious and autoimmune diseases. To
`ameliorate the pathology resulting from TNFa
`in these clinical settings, strategies for the inhi-
`bition of this cytokine have been developed.
`Our previous work has shown that the drug
`thalidomide is a partial inhibitor of TNFOL 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 TNFQ levels in association
`with an accelerated weight gain. In vitro, we
`have also shown that
`thalidomide partially
`inhibits TNFd produced by human peripheral
`blood mononuclear cells (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 (1L2) and inter-
`feron y
`(IFNy). We also observed a
`bi—
`directional effect on, IL12 production: ILlZ
`production is inhibited byithalidomide when
`PBMC are stimulated with LPS, however,
`1L1 2 production is increased in the presence of
`the drug when cells are stimulated via the T cell
`receptor. The latter effect is associated with
`upregulation of T cell CD40 ligand (CD40L)
`expressxon. 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 TNFu. inhibitors were designed using
`thalidomide as template. These thalidomide
`analogues were found to be up to 50 000 times
`more active than thalidomide. The compounds
`comprise two different types of TNFu inhibi—
`tors. One class of compounds, shown to be
`potent phosphodiesterase 4 (PDE4) inhibitors,
`are selective TNFu inhibitors in LPS stimu-
`lated PBMC and have either no effect or a sup—
`pressive effect on T cell activation. The other
`class of compounds also inhibit TNFtt produc—
`tion, but do not inhibit PDE4 enzyme. These
`nnmnnnnrlc m-n nlcn nan-nr inhikirnre n? cpunrnl
`
`stimulate the anti-inflammatory cytokine ILl 0.
`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 immunomodulatory activity
`of these new TNFa inhibitors may potentially
`allow them to be used in the clinic for the
`
`treatment of a wide variety of immunopatho—
`logical disorders of different aetiologies.
`
`TNFu is a key player in the immune
`response
`a pleiotropic cytokine produced
`TNFa is
`primarily by monocytes and macrophages, but
`also by lymphocytes and NK cells. TNFa plays
`a central part in the host immune response to
`viral, parasitic, fungal and bacterial infections.
`The importance of TNR: and TNFu signal—
`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—
`m'a major infection, TNFo signalling is impor—
`tant for protection as mice lacking TNFu p55
`receptor (TNFR—pSS) show delayed elimina-
`tion of the parasites compared with controls
`and the lesions formed failed to resolve.2 Mice
`deficient in TNFR—pSS are also significantly
`impaired in their ability to clear infection with
`Candida albz‘cans and readily succumb to the
`infection. TNFu signalling is also crucial
`in
`resisting Streptococcus pnczrmom‘ae infections in
`mice.3 In addition, TNFa is essential
`for
`protection
`against murine
`tuberculosis.
`TNFR—pSS deficient mice have been shown to
`be more susceptible to tuberculosis infection.
`When TNFu was neutralised in vivo by mono—
`clonal antibodies impaired protection against
`mycobacterial infecuon was observed.“ 5 The
`data from both models also established that
`TNFtt and the TNFR- p55 are essential for
`production of reactive nitrogen intermediates
`by macrophages early in infection.
`
`TNFa contributes to disease pathogenesis
`Although TNFu is crucial
`to the protective
`immune response, it also plays a part in the
`pathogenesis of both infectious and autoim-
`mune diseases. Increased concentrations of
`TNFa have been shown to trigger the lethal
`effects of septic shock syndrome." TNFu has
`also been implicated in the development of
`cachexia, the state of malnutrition that compli-
`cates the course of chronic infections and many
`mnmre 7 ln rheumatoid arthritis, TNFu is a
`
`ALVOGEN, Exh. 1055, p. 0216
`
`Celgcne Corporation,
`Warren, NJ, USA
`L G Corral
`
`Laboratory of Cellular
`Physiology and
`Immunology, The
`Rockefeller University,
`New York, NY, USA
`G Kaplan
`
`Correspondence to:
`Dr I. G Corral. The
`
`ALVOGEN, Exh. 1055, p. 0216
`
`

`

`I108
`
`Corral, [Cap/cm
`
`Recently, it has been shown that treatment of
`patients with neutralising anti-TNFu antibod-
`ies produces a dramatic reduction in disease
`activity in this condition" Similarly, it has been
`shown that
`in inflammatory bowel disease,
`neutralisation of TNFu results in a profound
`amelioration of clinical symptoms.9 ‘0 Reduc-
`tions in TNFu levels have also been linked with
`a significant reduction of clinical symptoms in
`leprosy patients with ENL,
`including fever,
`malaise, and arthritic and neuritic pain.” In
`tuberculosis patients, reduction of TNFOL levels
`was associated with accelerated weight gain.”
`
`ALVOGEN, EXh. 1055, p. 0217
`
`Thalidomide has T cell costimulatory
`properties
`Recently, we reported that thalidomide also has
`a hitherto unappreciated immunomodulatory
`efiect:
`the drug was shown to costimulate
`human T cells in vitro, synergising with stimu-
`lation via the T cell
`receptor complex to
`increase 1L2 mediated T cell proliferation and
`T cell IFNy production.23 Optimal T cell acti—
`vation requires two signals.21 The first signal or
`signal 1
`is delivered by clustering of the T cell
`antigen-receptor—CD3 complex through en—
`gagement of specific 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 eytokines 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 1L2, which ultimately drive T cell
`clonal expansion. As antigenic stimulation in
`the absence of costimulatory signals leads to T
`cell anergy or apoptosis, costimulation is 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.23 In our experiments in vitro, stimulation
`of purified T cells with anti-CD3 antibodies, in
`the absence of signal 2, induced only minimal
`T cell proliferation. However, the addition of
`thalidomide to this cell culture system resulted
`in a concentration dependent
`increase in
`proliferative responses.“ 2" The thalidomide
`mediated costimulation of T cell proliferation
`was accompanied by increases in 1L2 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 TNFu production
`by purified T cells stimulated by anti~CD3
`antibodies. This is in contrast with the effects
`ofthe 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.23
`
`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.25 2“ CD40UCD4O interaction occurs
`early in the sequence of signalling events
`between T cells and antigen presenting cells
`(APC). Signalling through CD40 has been
`shown to activate APC and to induce expres—
`sion of costimulatory molecules such as B7, as
`well as stimulating production of IL]2.37 3“
`Thus, CD40 signalling results in a stimulatory
`
`Thalidomide inhibits TNFa production
`by monocytes
`The pathology associated with TNFu produc—
`tion is profound and in many diseases leads to
`significant morbidity and mortality. This has
`led to a concerted effort to discover drugs that
`will down regulate the production of this
`cytokinc. Agents conventionally used in these
`diseases may inhibit TNFu 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 TNFa are under active
`investigation and development. Our previous
`work has shown that
`the drug thalidomide
`(u-N—phthalimidiglutarimide)
`is
`a
`relatively
`selective inhibitor of TNFu 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 TNFa levels.
`Thalidomide treatment of patients with ENL
`was shown to induce a prompt reduction of
`TNFa serum levels with a concomitant abro—
`gation of clinical symptoms.” Furthermore, in
`patients with tuberculosis, with or without
`concomitant HIV infection, thalidomide treat—
`ment was found to both decrease plasma
`TNFu protein levels as well as monocytc
`TNFu mRNA levels. This decrease was associ—
`ated with an accelerated weight gain.12 In a
`rabbit model of mycobacterial meningitis, tha—
`lidomide treatment combined with antibiotics
`produced a marked reduction in TNFct levels,
`leucocytosis, and brain disease.H In addition,
`thalidomide inhibited TNFo serum levels in
`mice
`challenged with LPS thus partially
`protecting the animals from septic shock.15
`In vitro, we have found that
`thalidomide
`selectively reduces the production of TNFa by
`human monocytes cultured in the presence of
`both LPS and mycobacterial products.” How-
`ever, this inhibition was only partial (50% to
`70%) possibly because of the instability of the
`drug in aqueous solutions.I7 The mechanism
`by which thalidomide reduces TNFtt produc-
`tion is still unclear. The drug seems to inhibit
`TNFa production by human monocytes in
`vitro in association with enhanced degradation
`of TNFu mRNA.” It also inhibits the activa-
`
`ALVOGEN, Exh. 1055, p. 0217
`
`

`

`I'mmImomndnlan’on by titalidorrzrlie and thalidomide analogues
`
`Il09
`
`tial for the survival of CD8+ T cells and that in
`its absence these cells die or become anergic.30
`These studies show that in addition to its
`inhibitory effect on the production of mono—
`cyte cytol<ines, thalidomide exerts a costimula—
`tory or adiuvant effect on T cell responses. The
`immune modulating effects of the drug in
`patients may thus be attributable to a balance
`between the inhibition of production of mono—
`cyte cytokines,
`including TNFa, and the
`costimulation of T cell activity. The effects of
`thalidomide in vivo in HIV infected patients
`seem to reflect the costimulatory activity of the
`drug?0 In a placebo controlled study to evalu—
`ate the effects of in vivo immunomodulation
`with thalidomide, the drug was administered
`for
`four weeks
`to HIV infected patients.
`Thalidomide treatment did not affect TNFa
`levels in these patients. In contrast, thalidomide
`treatment
`resulted in significant
`immune
`stimulation. This was reflected by increases in
`DTH responses and increased plasma levels of
`T cell activation markers such as soluble IL2
`receptor (SILZR) and soluble CD8 antigen. An
`earlier study of tuberculosis patients treated
`with thalidomide showed increased plasma
`levels of IFNy suggesting an immunostimula—
`tory effect of the drug.12 Recently, patients suf-
`fering from sarcoidosis have shown consistent
`increases in sILZR plasma levels after thalido—
`mide treatment (Oliver er a], manuscript in
`preparation). In the same study, thalidomide
`treatment increased the proliferation of sarcoid
`patient T cells in response to concanavalin A in
`Vitro. These results
`strongly suggest
`that
`thalidomide directly stimulates T cells in vivo
`in patients, corresponding to the T cell
`costimulatory properties of the drug observed
`in Vitro in T cells from normal donors,23 5 as
`well as in the T cells of HIV infected patients?“
`
`Thalidomide analogues are improved
`TNFa inhibitors
`In addition to being the drug of choice for the
`treatment of ENL,
`thalidomide has been
`shown to be useful in a number of clinical situ—
`ations
`including rheumatoid arthritis, HIV
`assoc1ated aphthous ulcers and chronic graft
`versus host disease.”‘” However, thalidomide
`is a potent teratogen and ingestion of the drug
`by a pregnant woman can lead to catastrophic
`Thalidomide
`
`IMiDs
`
`0o
`
`N
`
`0
`
`(Kill)?
`
`o
`
`SelCiDs
`
`birth defects.35 In addition, thalidomide treat-
`ment is often accompanied by a number of side
`effects,
`including peripheral
`neuropathy.3b
`Therefore,
`the use of thalidomide requires
`strict monitoring of all patients.37 Thus, there is
`a pressing need to develop drugs with increased
`TNFa inhibitory activity and reduced or
`absent toxicities. Towards this end, structural
`analogues of thalidomide have been designed
`and synthesised at Celgene Corporation (War—
`ren, New Jersey) and screened for inhibition of
`TNFa production. A large number of potent
`novel TNFu inhibitors were thus identified.
`Recently, some of these compounds were
`described.” "”0 On a molar basis, the more
`potent of these thalidomide analogues were
`found to be up to 50 OOO—fold more potent
`than thalidomide at inhibiting TNFa produc-
`tion by human PBMC stimulated by LPS in
`vitro. Furthermore, we have shown that some
`of these compounds retain high activity in LPS
`stimulated human whole blood;‘0 In vivo,
`several of
`these new compounds
`showed
`improved activity in reducing LPS induced
`TNFd levels in mice17 and in inhibiting the
`development of adjuvant arthritis in rats.‘”“
`
`Thalidomide analogues comprise two
`distinct classes of molecules
`
`A group of thalidomide analogues, selected for
`their capacity to potently inhibit TNFu pro—
`duction by LPS stimulated PBMC, was further
`investigated (fig 1). When tested for their effect
`in vitro on LPS induced cytokines, different
`patterns of cytokine modulation were shown.25
`One class of compounds, class I or ImiDs
`(Immunomodulatory Imide Drugs)
`showed
`not only potent inhibition of TNFQ but also
`marked inhibition of LPS induced monocyte
`ILlB and IL12 production. LPS induced 1L6
`was also inhibited by these drugs, albeit
`partially. These drugs were potent stimulators
`of LPS induced ILl 0, increasing ILlO levels by
`ZOO—300%. In contrast, the other class of com—
`pounds, class II or SelCiDs (Selective Cytokine
`Inhibitory Drugs), while still potently inhibit—
`ing TNFtt production, had a more modest
`inhibitory effect on LPS induced ILlli and
`IL1 2, and did not inhibit 1L6 even at high drug
`concentrations. In addition, SelCiDs produced
`a more modest ILlO stimulation (20—50%
`increases). In all of these characteristics, SelC—
`iDs were more similar to thalidomide than
`ImiDs.”‘ ’7
`Further characterisation of the SelCiDs
`showed that they are potent PDE4 inhibitors.”
`PDE4 is one of the major phosphodiesterase
`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
`CAMP levels leading to the modulation of LPS
`induced cytokines
`including inhibition of
`TNFu.” Increasing intracellular CAMP levels
`have been shown to inhibit TNFa production
`
`00
`
`N
`
`O
`
`O 0 N
`
`@3ij edoo
`
`NH2 0
`
`““2
`
`o
`
`o
`
`N
`
`N
`HZC
`
`
`o
`
`orCl-l3
`
`O’CHJ
`
`o
`N
`
`: :0
`
`o—CH,
`O
`
`NH2
`
`0,
`
`o
`N
`
`o-ca,
`O
`
`NH2
`
`0
`
`CW
`
`HeN
`
`ALVOGEN, EXh. 1055, p. 0218
`
`ALVOGEN, Exh. 1055, p. 0218
`
`

`

`1110
`
`Corral, Kaplan
`
`regulated. Interestingly, the IMiDs and tha—
`lidomide were found not to inhibit PDE4.“°
`In addition to the differential modulation of
`LPS induced monocyte cytokines,
`the two
`classes of compounds showed distinct effects
`on T cell activation. SelCiDs,
`the PDE4
`inhibitors, had little effect on T cell activation
`causing only a slight inhibition of T cell prolif-
`eration. This effect was not unexpected as it is
`well established that increasing CAMP levels in
`T cells during the early phase of mitogen or
`antigen activation results in a decrease in
`proliferative potential.“ On the other hand,
`IMiDs, the non-PDE4 inhibitors, were potent
`costimulators of T cells and increased cell pro—
`liferation dramatically in a dose dependent
`manner.25 Similarly to thalidomide, these com-
`pounds had a greater costimulatory effect on
`the CD8+ T cell subset than on the CD4+ T
`cell subset (Corral er al, unpublished observa-
`tion). IMiDs, when added to anti-CD3 stimu-
`lated T cells, also caused marked increases in
`the secretion of 1L2 and IFN“{ and induced the
`up—regulation of CD40L expression on T
`cells.25 These findings show that in addition to
`their
`strong anti-inflammatory properties,
`IMiDs efficiently costimulate T cells with 100
`to 1000 times the potency of the parent drug.
`The molecular target of these co-stimulatory
`cytokine modulating drugs is as yet unknown.
`
`induced primarily by the interaction of CD40
`on the surface of the APC with CD40L on the
`surface of activated T cells.2H "" When T cells
`were stimulated by anti-CD3, thalidomide and
`IMiDs treatment caused a significant stimula—
`tion of IL12 production.” Thalidomide and
`IMiDs
`also induced an up—regulation of
`CD40L on the surface of T cells.” 3“ Blockade
`of this pathway inhibits the production of IL12
`and
`abolishes
`the
`stimulatory
`effect of
`thalidomide.” Interestingly,
`in HIV infected
`patients,
`the consistent
`increases in plasma
`IL12 levels induced by thalidomide treatment
`lagged behind the increases in T cell activation
`markers?" This observation suggested that
`IL12 production was augmented as a conse-
`quence of drug induced T cell activation.
`The dichotomous nature of thalidomide
`cytokine modulation may explain the seem—
`ingly opposite effects observed in different
`clinical situations. When patients with Behcet’s
`syndrome are treated with thalidomide, healing
`of inflammatory aphthous ulcers occurs, but is
`sometimes accompanied by exacerbation of
`erythema nodosum."7 Similarly, the paradoxi-
`cal worsening ofgraft versus host disease“ and
`toxic epidermal necrolysis” reported in clinical
`trials of thalidomide may be a manifestation of
`the unsuspected immune stimulatory effect of
`this drug.
`
`Thalidomide and IMiDs modulate
`cytokines differently according to cell
`type and stimulation pathway
`As described above,
`thalidomide has been
`shown to inhibit IL12 production by LPS
`stimulated monocytes in vitro.2545 In vivo,
`however,
`thalidomide
`treatment of HIV
`infected” and M tuberculosis infected patients
`induced increases
`in plasma
`IL12 levels
`(Bekker er al, submitted data). Thalidomide
`treatment also resulted in increases in plasma
`IL12 levels in patients with scleroderma and
`sarcoidosis (Oliver er a1, manuscripts in prepa-
`ration). These dual and opposite effects of