DEC 1 't 19.,
`HEALTH SCltN~t~ Llb,i.,,.
`
`VOLUME 18: NO. 11
`
`NOVEMBER 1991
`
`\
`
`Editorials
`Challenges in Designing Antirheumatic
`Drug Trials
`C.H. Goldsmith ............................................. 1643
`
`ThJ~P~~=:l~nn~~'.~ .. ~.f .. ~.~~·~·~· .~~. ~~'.'.~~~~~~ ... 1645
`
`What's Inside the Team Care Box? Is It the
`Parts, the Connections, the Attention , or
`the Gestalt? E. H. Yelin ............ .... ............. .... 1647
`Articles
`Phenotypic Abnormalities in CDS+ T
`Lymphocyte Subsets in Patients with RA
`S. Sohen, P.L. Romain, D.M. Rothstein,
`T. Yamane, S. Tanaka, P. Anderson,
`S.F. Schlossman, C. Morimoto ...................... 1649
`Prediction of Team Care Effects in
`Outpatients with RA
`M. Ah/men, A. Bjelle, M. Sullivan .................. 1655
`Prolactin Deficiency in RA
`E. Nagy, J.M. Chalmers, F.D. Baragar,
`H.G. Friesen, I. Berczi ......... ......................... 1662
`An lmmunohistochemical s1udy of the
`Collagens of Rabbit Synovilil lnterstitium
`D.E. Ashhurst, Y.S. Bland, 'J.R. Levick .......... 1669
`Metabolism of Hydralazine by Activated
`Leukocytes: Implications for Hydralazine
`Induced Lupus
`A.H. Hofstra, L.C. Matassa, J.P. Uetrecht .. .. . 1673
`Autoantibodies Against Ribosomal Proteins
`F~und with High Frequency In Patients
`with SLE with Active Disease
`T. Sato, T. Uchiumi, T. Ozawa, M. Kikuchi,
`M. Nakano, R. Kominami, M. Arakawa .......... 1681
`Sjogren's Syndrome in Patients with the
`CREST Variant of PSS A.A. Drosos,
`Y.L. Pennec, M. Elisa!, A. Lamour,
`N.C. Acritidis, J.R. Jouquan,
`H.M. Moutsopoulos, P. Youinou ........... ....... .. 1685
`
`A Reexamination of the Relationship Between
`Myositis and Malignancy
`P. Schulman, L. D. Kerr, H. Spiera ................. 1689
`MRI in the Idiopathic Inflammatory Myopathies
`D.D. Fraser, J.A. Frank, M. Dalakas,
`F. W. Miller, J.E. Hicks, P. Plotz ..................... 1693
`AS Antirheumatic Drug Trials. I. Effects of
`Standardization Procedures on Observer
`Dependent Outcome Measures
`N. Bellamy, W.W. Buchanan, J.M. Esdaile,
`A. G. Fam, W. F. Kean, J. M. Thompson,
`G.A. Wells, J. Campbell ................................ 1701
`AS Antirheumatic Drug Trials, II. Tables for
`Calculating Sample Size for Clinical Trials
`N. Bellamy, W.W. Buchanan, J.M. Esdaile,
`A.G. Fam, W. F. Kean, J.M. Thompson,
`G.A. Wells, J. Campbell ..................... .. .. ....... 1709
`AS Antirheumatic Drug Trials. Ill. Setting the
`Delta for Clinical Trials of Antirheumatic
`Drugs - Results of a Consensus Development
`(Delphi) Exercise
`N. Bellamy, W.W. Buchanan, J.M. Esdaile,
`A.G. Fam, W. F. Kean, J.M. Thompson,
`G.A. Wells, J. Campbell ............ .................... 1716
`
`Pediatric Rheumatology
`DNA Analysis of HLA-DR , DO, and DP Genes
`in Pauciarticular JRA
`K. S. Barron, A.K. Joseph, M. Macleod,
`J.C. Gonzales, D. Owerback, J. D. Reveille .... 1723
`Hypercalcemia During the Resolution of
`Calclnosis Universalis in Juvenile OM
`B.E. Ostrov, D.P. Goldsmith,
`A. H. Eichenfield, B.H. Athreya ............... .. ..... 1730
`Barrett's Esophagus In a Young Patient
`with RP
`P. Navon, A. Klar, H. Hurvitz, S.N. Adler,
`D. Branski ............................................ ........ 1735
`
`Contents continued opposite inside back cover . . .
`
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`

`

`EDITOR
`Duncan A. Gordon
`BOOK REVIEW EDITOR
`Peter Lee
`ASSOCIATE EDITORS
`Dafna D. Gladman
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`
`MANAGING EDITOR
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`EDITORIAL ASSISTANT
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`an international journal
`founded by Metro A. Ogryzlo
`
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`
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`PHILADELPHIA, PA, USA
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`Mitsuo Homma
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`ERLANGEN, FRG
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`
`Copyright 1991.
`All rights reserved.C>
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`ii
`
`PFIZER and SAMSUNG v. GENENTECH
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`

`Case Report
`
`Humanized Monoclonal Antibody Treatment
`,n Rheumatoid Arthritis
`
`VALERIE KYLE , JANET RODDY, GEOFFREY HALE, BRIAN L . HAZ LEMAN, and HERMAN WALDMANN
`
`Abstract. A 4 1-year-old woman with active, seropositive erosive rheumatoid arthritis was treated
`with the humanized monoclonal antibody Campath IH. She had not responded or developed
`side effects to myocrisin, sulfasalazine and penicillamine, and had not responded to inpatient
`bedrest and physiotherapy. There was a rapid clinical improvement within 24 hours of infu(cid:173)
`sion , which was maintained for about 12-14 weeks after the infusion. The lymphocyte count
`was suppressed for 7 months after treatment. There were no significant side effects during
`or after treatment. No anti-Campath IH response was detected. This preliminary study sug(cid:173)
`gests humanized monoclonal antibody therapy may be of value in the treatment of rheumatoid
`arthritis. (J Rhe11ma10/ /99/; 18:1737- 8)
`
`Key Indexing Terms:
`RHEU M A TOJO ARTHRITIS
`HUMANIZED MONOCLONAL ANTIBODIES
`
`THERAPEUTICS
`
`Monoclonal antibody (Mab) therapy in rheumato id arthritis
`(RA) allo ws the targeting of speci fic cells or e ffector mechan(cid:173)
`isms believed to be important in the pathogenesis . Initial pi lot
`stud ies using rat 1•2 and mouse3 Mab have shown some
`bene fit, tho ugh there has been concern that the development
`of human ant imouse Mab may prevent retreatmentJ-s . This
`concern has been due to the risk of sens it ization, and evi(cid:173)
`dence suggests repeat infusions may be less effective. The
`development of humanized Mab6 should minimize this risk.
`We report the beneficial e ffect of Campa th I H , a humanized
`Mab , against surface antigen C DW52 in a patient with RA .
`Campath I H is the humanized fo rm of the rat Mab
`produced by fusion of the Y3 rat mye loma line with a spleen
`from a rat immun ized with human T lymphocyte . The
`hype rvariable regio ns of this rat antibody are then trans(cid:173)
`planted into no rmal human immunoglo bulin (lg) genes.
`The Campath I ant igen is present on the maj ority of, if
`not all , lymphocytes and mo nocytes7•
`
`CASE REPORT
`A 4 t-ycar-old woman wi1h ac1ivc erosive RA for 6 years was admined fo r
`1rea1me111 wi1h Campath I H. Wrinen consem and ethical approval were
`
`From the Rlrewnatology Researclr Unit and Division of Rheumatology
`Addenbrooke ·s Hospital , Cambridge, United Kingdom.
`V. Kyle, MD. MRCP. lecturer in Rheumatology: J. Roddy, MD,
`FRCP, Clinical Researc/r Fellow in Rlreumatology. R/re11111atology
`Researclr Unit; G. Hale, P/rD, Director of 771erape111ic A mibody Unit;
`B.L. Ha .. leman , MB , FRCP , Consultant Rlreumatologist , Rlreumatology
`Researclr Unit, Addenbrooke's Hospital; H. Wa/dmamr. P/rD, MRCP.
`Professor of 77terapewic /111111u110/ogy, Depar1111e111 of Patlrology.
`Address reprints requests 10 Dr. B.l . Hazle111011 , R/reumaw logy
`Researclr Unit , A dde11brooke's Hospiwl , Cambridge, United Ki11gdo111.
`S11bmi11ed December 3 / , 1990 revision accepted July /0, 1991.
`
`ob1ained. She had not responded or had developed side effec1s to sulfasala(cid:173)
`zinc, gold or penicillamine, and was laking naproxen only. Al the lime of
`1he study she had persis1en1 synovi1is affec1ing mos1 join1s, with morning
`s1iffness for 2 h, and had fa iled to improve after a period of inpa1ien1 bedres1
`and physio1herapy.
`Twelve infusions of 2 mg Campath I H in 500 ml normal saline were given
`over 4 h on Days I 1hrough 12. Pulse, blood pressure and 1emperature were
`recorded al 15-min imervals during the infusion, 1hen every 2 h for 4 h
`aflerwards. Her func1ional score was derived from 1he pain scores, sense
`of wellbeing and abilily 10 cope with daily activities. These were all meas(cid:173)
`ured using a visual analog scale, 0 being normal and JO maximal discom(cid:173)
`for1. Rilchie index, grip s1reng1h. and 1hermal index derived from themog(cid:173)
`raphy were recorded daily during infusions and every 2-4 weeks for 4 months
`aflerwards. The following labora1ory 1es1s were performed before 1reatmen1,
`daily during infusions and regularly in followup: full blood count includ(cid:173)
`ing differenlial while cell coun1, ery1hrocy1e sedimemaiion ra1e (ESR)
`(Wes1ergren), C-reactive prolein (CRP) (nephelome1ry) and rheuma1oid fac(cid:173)
`lor (RF) (nephclome1ry). Jg. CD4 and CDS levels, urea and elec1roly1es
`were measured and liver 1es1s administered before and after trealment.
`There were no significam side effec1s. There were no febrile episodes
`or cardiovascular effcc1s during !he Campalh I H infusion or over the sub(cid:173)
`sequeni 4 h. There was rapid clinical improvemenl. wi1h a fall in Ri1chie
`index from 26 10 9, a fall in funclional score from 19.5 10 5.25, and a rise
`in grip s1reng1h (Figure I). Morning s1iffncss decreased 10 30 min and the
`1hermal index fell. Func1ionally she was able 10 kni1, walk more lhan I mile
`and sleep comfortably in any posi1ion for 1he firs11ime in over a year. This
`improvemeni in fu nc1ion was main1ained for aboul 12-1 4 weeks. Her symp(cid:173)
`loms were conlrolled wi1h naproxcn alone during 1his lime. Labora1ory dala
`showed thm 1he 101al Jymphocy1e couni became unde1ec1able afler the second
`infusion. At 6 monlhs posnreatmem 1he lymphocy1e coun1 was s1ill sligh1ly
`below normal (1.05 x 109/J) and lhc suppression involved all T cell sub(cid:173)
`sels, bu1 1he B lymphocyte coum was normal. The 101al Jymphocy1e counl
`re1urned 10 normal 7 mon1hs afler 1rca1men1. During lhis lime 1here was
`no clinical evidence of immunosuppression. The monocyte coun1 had fallen
`from norn1al (0.415 x J09/J) 10 zero 2 days in10 1rca11nen1. One monlh after
`1he fi nal infu sion ii had re1urned 10 normal. RF fell wi1hin 2 days to 1/.i
`of the ini1ial value and rose afler 8 weeks 10 baseline levels. There was
`no significam change in ESR or CRP (Figures 2a and 2b).
`
`Kyle, et al: Huma11iud Mab therapy
`
`1737
`
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`

`G>
`0 100
`u
`Cf)
`ii 80
`C:
`
`.2 " 60
`
`C:
`:,
`u..
`
`40
`
`• )(
`G>
`
`G>
`
`'t, .: 20
`:c
`~ 0 0
`a:
`
`100
`
`G')
`
`80 -6'
`~
`60 ~
`:,
`cc
`40 !
`3
`3
`20 ::i::
`e
`
`0
`100
`
`.••. o-------·"°',,,,,., .. "O •····
`
`20
`
`40
`
`60
`
`80
`
`Days
`Fig. /. Clinical course in pa1ien1 receiving Campa1h IH. Infusions were
`given on Days 1-12. The Ritchie index is used 10 assess joint inflamma(cid:173)
`tion. Grip s1rcng1h R.l . L • : functional score • : Ritchie index 0.
`
`,,
`
`10
`
`0
`"
`;:
`..J
`...
`"'
`0 ...
`;;;
`w
`t;:
`O..l
`o -
`:<:o a.-
`
`~ ) (
`..J
`
`,..
`...
`...
`... m
`"' ,,
`,,. 3
`..
`..
`..
`
`3
`
`~
`
`100
`
`10
`
`20
`
`lO
`
`,o
`
`50
`
`60
`
`70
`
`10
`
`tO
`
`100
`
`DAYS
`
`20
`
`Fig. 2a. Laboratory variables in patient receiving Campa!h I H. Toial while
`blood cell count 6. lymphocytes O, ESR • .
`
`14
`
`12
`
`10
`
`·~
`
`:;:;
`~
`E
`ll.
`a:
`0
`
`lO
`
`20
`
`30
`
`40
`
`SO
`
`60
`
`70
`
`Days
`
`,,
`,,
`c
`3
`"'
`
`1500
`
`1000
`
`500
`
`IO
`
`90
`
`100
`
`:t~~-Laboratory variables in patient receiving Campath IH, CRP • .
`
`No an1i-Campa1h I H respo~se was dc1ec1~. lg levels before and afier
`treatment were unchanged, w11h a polyclonal increase in lgA and lgG but
`normal lgM .
`
`DISCUSSION
`Earlier studies using lymphopheresis or T cell irradiation
`resulted in short term benefit in patients with RA. More
`recently, studies have shown benefit from treatment with
`Mab8·9 . Campath I H infusions caused destruction or
`removal of T lymphocytes from peripheral blood and were
`followed by sustai ned clinical benefit for 3 months. The fall
`in RF probably reflects loss of T cell cooperation in stimulat(cid:173)
`ing B cell production of RF. It is interesting that neither ESR
`nor CRP fell significantly despite the marked clinical
`improvement; this may have been due to established inflam(cid:173)
`mation that was unaffected by T cell removal.
`The development of humanized Mab such as Campath 1H
`should allow repeated infusions without the risk of sensiti(cid:173)
`zation or decreasing efficacy. No antibodies to Campath IH
`were detected. There were no serious side effects following
`Campath I H in our study or reported during treatment of
`patients with lymphatic malignancies to. Although lym(cid:173)
`phopenia can predispose to viral or fungal infections, this
`was not a problem in our patient.
`Further studies of humanized Mab are warranted.
`
`REFERENCES
`I. Mathieson W, Cobbold P, Hale C , et al: Monoclonal antibody
`therapy in systemic vasculi1is. N £11gl J Med /990;323:250-4 .
`2. Kyle V. Coughlan RJ , Tighe H. Waldmann H, Hazleman BL:
`Beneficial effect of monoclonal antibody 10 interleukin 2
`receptors on activated T cell~ m rheumatoid arthritis. A1111
`Rhe11111 Dis /989;48:428-9 .
`3. Strand V, Fi~hwild D: XOMA Rheumatoid arthritis
`invcs1iga1ors group. Treatment of rheumatoid arthritis with anti(cid:173)
`CDS immunoconjuga1e: clinical and immunologic findings and
`preliminary results of re-treatment (abstr). Arthritis R/,e11111
`/990;(suppl)33:S25 .
`4. Horneff G. Winkler T, Kalden J. Emmrich F. Bermester GR:
`Human anti-mouse antibody response induced by anti-CD4
`monoclonal antibody therapy m patients with rheumatoid
`arthritis. C/imcal /111111111wl /1111111111opmhol /99/ ;59:89- 103.
`5. Wa5smer P. eidhart M. Hintermann U. et al: Therapy of
`rheumatoid arthriw, w11h CD4 monoclonal antibodies (abstr).
`Arthritis Rhe11111 / 990:(,uppl)33:S 153.
`6. Reichmann L, Clark M, Waldmann H. Wimer G: Reshaping
`human antibodies for therapy. Nature /988:332:323- 7.
`7. Hale G. Xia M-Q. Tighe HP. Dyer MJS. Waldman H: The
`Campath-1 antigen (CDW52) . Tissue A111ige11s 1990:35: 118-27.
`8. Kingsley G: Monoclonal antibody treatment of rheumatoid
`arthritis. Br J R/re11111awl / 99/;(suppl 2)30:33-5.
`9. Horneff G. Burmester G. Emmrich F. Kalden J: Treatment of
`rheumatoid arthritis with an anti-CD4 monoclonal antibody.
`Arthritis Rhe11111 1991 ;34: 129- 40.
`10. Hale G. Cobbold S. Waldmann H: T cell depletion with
`Campaih- 1 H in allogenic bone marrow 1ransplantation.
`Tra11pla111atio11 1988;45:153- 9.
`
`1738
`
`I
`n,e Jo11ma/ of Rhe11mato ogy
`
`/ 991 · /8:/1
`,
`
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`

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`• Key Indexing Terms-a list of no more than 6 terms;
`• Name of department(s) and institution(s) to which the
`work should be attributed;
`• The source(s) of support in the form of grants or
`industrial support;
`• Initials, surnames, appointments and highest academic
`degrees of all authors;
`• Name and address of author to whom requests for
`reprints should be made;
`• Name and address of author responsible for correspon(cid:173)
`dence about the manuscript;
`• A short running head or footline of no more than 4
`words;
`Acknowledgment, if applicable, should be added at the end
`of the discussion of the paper and before the references. It
`should not contain grant or industrial support for fellowship
`awards, all of which should appear on the title page.
`Tables. Type each table on a separate sheet , double-spaced.
`Number tables consecutively and supply a brief title for each.
`References cited only in tables should be numbered in the
`sequence established by identification in the text.
`Figures. These should be numbered with the author's name
`on the back and the top clearly marked. Legends should be
`listed on a separate sheet. Figures should be professionally
`drawn and photographed and the critical area of radiographs
`or photomicrographs should be indicated. Freehand or type(cid:173)
`written lettering is unacceptable. Send sharp glossy black and
`white photographic prints no larger than 12 .8 x 18 cm (5"
`X 7 "). Cite each figure in the text in consecutive order. The
`contributor must bear all the costs of colour printing.
`References. Number references consecutively in the order
`in which they are mentioned in the text. Identify references
`
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`Os TEO ARTHRITIS
`THERAPY THAT
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`STATEMENT ...
`
`SEE PAGE ix
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`ran on last page of this ad.
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`Please see brief summary of prescribing in orma 1
`
`PFIZER and SAMSUNG v. GENENTECH
`IPR2017-01488
`PFIZER EX. 1209, Page 5
`
`