CLINICAL TRIALS IN LN

02 January 2014 13:54

NIH TRIAL: compared three re !men" !n #5 pat!ent" $!th a mean "erum creat!n!ne o% appro&!mate'y 1(# to 2(0 m )d'( A'' rece!*ed ora' predn!"o'one +e !nn!n at a do"e o% 0(5 m ), per day and then taper!n o*er a per!od o% month" to a'ternate-day ma!ntenance therapy %or contro' o% e&trarena' "ymptom" .m!n!mum do"e 0(25 m ), e*ery other day/( 0arameter" at 3 Regimen A : yr" I1 C2C 3onth'y & # 20 pts Regimen B: A 4 3 month'y I* C2C %or tota' 24 month" 20 pts Lo$ 258 Lo$ Regimen C: I* methy' predn!"o'one 1 )mt "5 month'y 6 # do"e $!thout C2C 25 pts H! h 48%

7ou+'!n o% "r creat!n!ne re'pa"e

Lo$ 25 8 high

An e&tended cour"e o% pu'"e cyc'opho"pham!de !" more e%%ect!*e than # month" o% pu'"e methy'predn!"o'one !n pre"er*!n rena' %unct!on !n pat!ent" $!th "e*ere 'upu" nephr!t!"( Add!t!on o% a 5uarter'y ma!ntenance re !men to month'y pu'"e cyc'opho"pham!de reduce" the rate o% e&acer+at!on"(

pat!ent" $!th re'at!*e'y m!'d d!"ea"e ."erum creat!n!ne 91(3 m )dL :9115 m!cromo')L; and)or prote!n e&cret!on 91(0 )day/ had a %a*ora+'e pro no"!"(

2nd NIH tr!a' : <2 pt" $!th ma!n'y 7!%%u"e pro'!%erat!*e 'upu" nephr!t!"( 3ean +a"e'!ne creat!n!ne 1(1 m )d' A'' rece!*ed ora' predn!"o'one a" a+o*e= and $ere random!"ed to 3 roup" PARAMETER S STUDIED 3ed!an >? 5 yr" REGIMEN A 3onth'y I1 30 1 )m "5 6 12 month" REGIMEN B REGIMEN C I1 C2C (5-1 @)3 "5 6 30 4 I1 C2C # mth--A 3 month'y I1 C2C B 24 mth"

RC3ISSIDN : Non cen"ored 2E8 cen"ored Re'pa"e 2# 8 3#8

#28 4<8 F H! B H! H! H! H! h h 25% h h h 52%

85 % !% 0

Ad*er"e e*ent" B D"teonecro"!" In%ect!on Amenorrhea 'e"" o"teoporo"!" D*ar!an %a!'ure

H! h 52%

RC3ISSIDN de%!ned a" : G10 red +'ood ce''" per h! h po$er %!e'd= no ce''u'ar ca"t"= and prote!nur!a G1 )day

S!nce the I1 cyc'opho"pham!de re !men u"ed !" a"ooc!ated $!th "! n!%!cant to&!c!ty and "!de e%%ect"= tr!a'" $ere done to 'oo, %or e%%!cacy o% 'o$ do"e Cyc'opho"pham!de !n LN( Important "tudy !" CLNT( EUR"#UPUS NE"$RITIS TRIA# : E#NT 2002
Houssiau FA, Vasconcelos C, D'Cruz D, et al. Immunosuppressive therapy in lupus nephritis: the Euro- upus !ephritis "rial, a ran#omize# trial o$ lo%-#ose versus hi&h-#ose intravenous cyclophosphami#e. Arthritis 'heum ())(* +,:(-(-.(-/-

E0 pt" enro''ed( 3u't! centre pro"pect!*e "tudy BB 1E european centre"(( Sept !%% t& sept 2000' INC#USI"N CRITERIA: A14 yr" a e( LN c'a"" 3= 4= 5c=5d : HHD 0rote!nur!a A 500 m )d C6CL?SIDN CRITCRIA : 0re*!ou" R& $!th C2C or AIA G1yr Dn A 15 m ) d predn!"o'one( G1 month rena' T3A pre e&!"t!n CR>= pre nancy 0re*!ou" ma'! nancy: e&cept S,!n and Cer*!ca' IN 73= pre*!ou" ad*er"e e*ent" to !mmuno"upre""!on Ant!c!pated poor comp'!ance to R&

()) p(tients rece!*ed * +(i), p-)ses &. /50 mg &. I0 meth,)p1e+nis&)&ne2 %o''o$ed +y ora' 'ucocort!co!d therapy at an !n!t!a' do"a e o% 0'5 mg34g3+(, &. p1e+nis&)&ne .or e5u!*a'ent/ .&1 4 5ee4s( A do"a e o% 1 m ), )day $a" a''o$ed !n cr!t!ca''y !'' pat!ent" .tho"e $!th rena' !mpa!rment or "e*ere e&trarena' d!"ea"e/( A%ter 4 $ee,"= 'ucocort!co!d do"a e" $ere tapered by 2.5 mg of prednisolone (or equivalent) every 2 weeks( Lo$-do"e 'ucocort!co!d therapy 657/'5 mg &. p1e+nis&)&ne pe1 +(,8 5(s m(int(ine+ (t )e(st -nti) m&nth *0 (.te1 in9)-si&n'

A!m m!n!m!Je SC o% C2C( Random!Jed pt" to 'o$ do"e C2C .B 500 m C2C +!$ee,'y 6 # month"/ *" NIH protoco'( A'' pt" rece!*ed predn!"o'one and AIA %or ma!nta!nance( 2 $, a%ter 'a"t cyc do"e( 7o"e 2 m ), )d NI$ p1&t&9&) : # motnh'y pu'"e 4 2 5uarter'y 7o"e adKu"ted to ma!nta!n nad!r TLC In!t!a' do"e 0(5 )m2= then !ncrea"e +y 250 m to ach!e*e nad!r TLC 3A6 1500 m ) pu'"e 3e"na : +a"ed on R& phy"!c!an dec!"!on( Len! n rena' %'are" .!(e(= tho"e not meet!n the de%!n!t!on o% "e*ere %'are" :"ee +e'o$;/ $ere treated $!th 'o$-do"e 'ucocort!co!d" .915 m o% predn!"o'one per day/ %or a 2-$ee, per!od= hydro&ych'oro5u!ne .# m ), )day/= and)or non"tero!da' ant!!n%'ammatory dru " .NSAI7"/( A "e*ere rena' %'are $a" de%!ned a" 1 o% the %o''o$!n 3 %eature": 1en() imp(i1ment2 in91e(se in p1&tein-1i(2 &1 se:e1e s,stemi9 +ise(se' Ren() imp(i1ment $a" de%!ned a" an SLC-re'ated !ncrea"e o% A338 !n the "erum creat!n!ne 'e*e' $!th!n a 1-month per!od( An in91e(se in p1&tein-1i( $a" de%!ned a" the recurrence or appearance o% nephrot!c "yndrome .a'+um!nem!a G3(5 m)d' and prote!nur!a M3 m !n a 24-hour "amp'e/( In pat!ent" $!th 'o$- rade prote!nur!a at +a"e'!ne .M0(5 m +ut G1 m !n 24 hour"/= a 3-%o'd !ncrea"e !n 24-hour ur!nary prote!n 'e*e'" $!th!n a 3-month per!od $a" a'"o con"!dered a "e*ere %'are= p1&:i+e+ th(t it 5(s (99&mp(nie+ ;, mi91&s9&pi9 hem(t-1i( (n+ ( <**% 1e+-9ti&n &. se1-m C* )e:e)s 5ithin ( *=m&nth pe1i&+' Se:e1e s,stemi9 +ise(se $a" de%!ned a" any o% the %o''o$!n e*ent": centra' ner*ou" "y"tem d!"ea"e= throm+ocytopen!a .G100=000 p'ate'et")N'/= hemo'yt!c anem!a= 'upu" pneumon!t!"= 'upu" myocard!t!"= e&ten"!*e ",!n *a"cu'!t!"= or "ero"!t!" not re"pond!n to 'o$do"e 'ucocort!co!d and)or NSAI7 treatment( A se:e1e .)(1e 5(s ()5(,s t1e(te+ ;, an !ncrea"e !n the 'ucocort!co!d do"a e .0(5O1(0 m ), )day o% predn!"o'one/ %or 1 month= and then prompt'y tapered to the pat!entP" pre%'are do"a e( ?p to 2 I1 pu'"e" o% methy'predn!"o'one .F50 m / $ere a''o$ed $!th!n a 1-$ee, per!od( Hyperten"!on .d!a"to'!c +'ood pre""ure ME0 mm H / $a" treated !n!t!a''y $!th an !oten"!ncon*ert!n enJyme !nh!+!tor"= un'e"" contra!nd!cated( 0at!ent" $ere e*a'uated month'y $!th!n the %!r"t year a%ter "tudy !nc'u"!on and 5uarter'y therea%ter( 3ed!an %o''o$up $a" 41 month" .ran e <O#2 month"/( In add!t!on to the pr!mary end po!nt= 3 "econdary end po!nt" $ere e&am!ned( The p1im(1, en+ p&int 5(s treatment %a!'ure= $h!ch $a" de%!ned a" 1 o% the %o''o$!n 3 %eature": a+"ence o% a pr!mary re"pon"e a%ter # month" o% therapy= occurrence o% a 'ucocort!co!d-re"!"tant %'are= or a dou+'!n o% the "erum creat!n!ne 'e*e

The * se9&n+(1, en+ p&ints $ere a" %o''o$": 1/ the 4ineti9s &. the 1esp&nse t& the1(p, in the .i1st ,e(1= +a"ed on "er!a' mea"urement" o% "erum creat!n!ne= "erum a'+um!n= 24-hour ur!nary prote!n= and "erum C3 'e*e'"= a" $e'' a" the CCLA3 "coreQ 2/ the 1(te &. 1en() 1emissi&n= de%!ned a" G10 red +'ood ce''")h! h-po$er %!e'd and a 24-hour ur!nary prote!n 'e*e' G1 m= !n the a+"ence o% a dou+'!n o% the "erum creat!n!ne 'e*e'Q and 3 the n-m;e1 &. se:e1e .)(1e"= a" de%!ned a+o*e(

>U 4! m&nths R? .(i)-1e ND pr!mary re"pon"e Stero!d re"!"tant %'a!r Cr 62 Cumu'at!*e do"e

Lo$ do"e 44 1#8 2 2 3

NIH protoco' 4# 0TS 208 4 2 3

<(5

Remissi&n RENA# >#ARE Ad*er"e e*ent"

30 .F18/ 12 .2F8/ 11 dur!n AIA R& B

22 . 548/ 13 .2E8/ F dur!n I1 C2C R& B +ut numer!ca''y h! her !n%ect!on" 10 pt" . 1F ep!"ode"/

In%ect!on" . SC1CRC/ 5 pt" . F ep!"ode"/ 7eath

2 0 A : 14 yr $!h SRI 4 nephrot!c prote!nur!a 4 CH>( 2< th day o% R& : 3D> L: 51 yr dropped o "tudy S 121 "t $ee, : Lrea"t cancer--A "udden death $ee, 1E4 : cau"e TT 1 .$, 20</ 2 .$, : 104 U 1E3/

CSR7 7ou+'!n o% "erum creat!n!ne : @onada' to&!c!ty

LDN@ TCR3 B10 yr >? o% C?RDL?0?S Hou""!au >A= 1a"conce'o" C= 7PCruJ 7= et a'( The 10-year %o''o$up data o% the Curo-Lupu" Nephr!t!" Tr!a' compar!n 'o$-do"e and h! h-do"e !ntra*enou" cyc'opho"pham!de( Ann Rheum 7!" 2010Q #E: #1O#4 #imit(ti&ns &. the E#NT st-+,: 3a!n'y done !n Cauca"!an popu'at!on= 3aKor!ty . B F<8 / o% pat!ent" had pre"er*ed rena' %unct!on .creat!n!ne G1(3 m )d'/= the "ma'' num+er o% pat!ent" treated= and that care $a" de'!*ered at "pec!a'!Jed re%erra' center"( S!nce C2C !" a""oc!ated $!th onadoto&!c!ty= r!", o% !n%ect!on" and 'ater ma'! nancy= A'ternate a ent" $ere "tud!ed a" !nduct!on a ent( 33> !" e"ta+'!"hed a" a a'ternate to I1 C2C= due to %o''o$!n "tud!e": MM> (s in+-9ti&n : $&5 @ 5h, 5(s it -se+A V Sa%ety and e%%!cacy !n rena' T& pt"( V An!ma' "tud!e" 1( Corna D, Morigi M, Facchinetti D, et al. Mycophenolate mofetil limits renal damage and prolongs life in murine lupus autoimmune disease. Kidney Int 1997; 1!1 "#$1 "9. %. &an 'ruggen MC, (algreen ', )i*+e ,-, et al. .ttenuation of murine lupus nephritis /y mycophenolate mofetil. 0 .m 1oc 2ephrol 199"; 9!1347$ 131 5 V Tr!a'" !n ch!na :

3( Chan T3= L! >R= Tan CS= et a'( C%%!cacy o% mycopheno'ate mo%et!' !n pat!ent" $!th d!%%u"e pro'!%erat!*e 'upu" nephr!t!"( Hon Ron -@uan Jhou Nephro'o y Study @roup( N Cn ' J 3ed 2000Q 343:115#O11#2( 44 pt" = non !n%er!or!ty(!n%ect!on" B 4( Chan T3= T"e RC= Tan CS= et a'( Lon -term "tudy o% mycopheno'ate mo%et!' a" cont!nuou" !nduct!on and ma!ntenance treatment %or d!%%u"e pro'!%erat!*e 'upu" nephr!t!"( J Am Soc Nephro' 2005Q 1#:10F#O10<4 !st RCT 9&mp(1ing MM> t& CBC : 42 pat!ent" random!"ed to 33> or C2C: Loth rece!*ed "tero!d"( 42 pt" 7DSC 33> 2 )d 6 # 3th" AIA 1(5 m ), )d 6 # mth" B B B C2C 1 )d 6 # mth" Dra' 2(5 m ), )d 6 # mth" B B B more

CR U 0R Re'pa"e CR7)CSR7 In%ect!on"

RCTs COMPARING MMF TO IV CYC. Ginzler EM, Dooley MA, Aranow C, et al. Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. N Engl Med !""#$ %#%&!!'() !!!*.

a mu't!center= open-'a+e'= non!n%er!or!ty tr!a'( DEC !%%% = "CT 200* E?9)-si&n 91ite1i( $ere creat!n!ne c'earance o% 'e"" than 30 m' per m!nute= "erum creat!n!ne on repeated te"t!n reater than 3(0 m per dec!'!ter .2#5(2 Nmo' per '!ter/= "e*ere coe&!"t!n cond!t!on" prec'ud!n !mmuno"uppre""!*e therapy or cond!t!on" re5u!r!n !ntra*enou" ant!+!ot!c therapy= pr!or treatment $!th mycopheno'ate mo%et!'= treatment $!th !ntra*enou" cyc'opho"pham!de $!th!n the pa"t 12 month"= monoc'ona' ant!+ody therapy $!th!n the pa"t 30 day"= or pre nancy or 'actat!on( MM> : 3ycopheno'ate mo%et!' $a" !n!t!ated at a do"e o. 500 mg t5i9e +(i),= and the do"e $a" !ncrea"ed to /50 mg t5i9e +(i), (t 5ee4 2 and ad*anced $ee,'y to ( m(?im-m +&se &. !000 mg th1ee times +(i), un'e"" the $h!te-ce'' count %e'' +e'o$ 3000 per cu+!c m!''!meter( I: 9,9 : NI$ 1egimen= nad!r TLC 2500 S 10 day"( 0at!ent" rece!*ed p1e+nis&ne (t ( +&se &. ! mg pe1 4i)&g1(m o% +ody $e! ht per day= $!th taper!n +y 10 to 20 percent at one-$ee, or t$o-$ee, !nter*a'"= on the +a"!" o% c'!n!ca' !mpro*ement( C'!n!ca' deter!ort!on R&ed $!th !ncrea"!n "tero!d(

140 pt" !nc'uded Dra' 33> . 3 )d/ *" I1 C2C L'ac, and h!"pan!c" repre"ented . race $!th "e*ere d!"ea"e/ 0r!mary endpo!nt CR S 24 $ee," ( CR CC +e.ine+ a" the return to $!th!n 10 percent o% norma' *a'ue" o% "erum creat!n!ne 'e*e'"= prote!nur!a= and ur!ne "ed!ment( "econdary endpo!nt PR' CC +e.ine+ a" !mpro*ement o% 50 percent !n a'' a+norma' rena' mea"urement"= $!thout $or"en!n .$!th!n 10 percent/ o% any mea"urement( A++iti&n() se9&n+(1, en+ p&ints !nc'uded chan e" !n rena' %unct!on= comp'ement component"= ant!Odou+'e-"tranded 7NA .d"7NA/ ant!+ody t!ter"= and "erum a'+um!n 'e*e'"( CARL2 RCS0DNSC: de%!ned a" an !mpro*ement o% 30 percent !n at 'ea"t t$o mea"ure" o% rena' %unct!on ."erum creat!n!ne= prote!nur!a= or ur!ne "ed!ment/ !% a'' three mea"ure" $ere a+norma' at entry !nto the "tudy= or an !mpro*ement o% 30 percent !n one mea"ure !% one or t$o

other" $ere a+norma'= pro*!ded no mea"ure" that $ere norma' at +a"e'!ne +ecame a+norma'( R6 >AIL?RC: a cond!t!on re5u!r!n h! her do"e" o% cort!co"tero!d" %or d!"ea"e contro'= %a!'ure to eet the cr!ter!a %or an ear'y re"pon"e= or %a!'ure to reach comp'ete or part!a' rem!""!on at 24 $ee,"(

D m&nths CR 0R

MM> 22(58 2E(#8

I0 CBC 5(<8 24(#8 B 3DRC

RCLA0SC DN B >? IN>CCTIDNS @I SC ?pper Lo$er 7eath

B 3ore( 0

B +ut re5u!red adm!""!on !n F pt" 2

a: cere+ra' +'eed= on'y 1 do"e!* cyc +: "ep"!"4act!*e LN= 2 do"e !* cyc

BBA 33> non!n%er!or e*en "a%er( #IMITATI"NS: Not +'!nded( I1 C2C do"e $a" adKu"ted +a"ed on @I SC= "o 'e"" CR rate TT Short durat!on Not "tud!ed the %'are rate $!th 33> !nduct!on= and appropr!ate ma!nata!nance re !men(

Second RCT compar!n 33> $!th I1 C2C : ALMS !"#$% &! %' AL : Appe' @L= Contrera" @= 7oo'ey 3A= et a'( 3ycopheno'ate mo%et!' *er"u" cyc'opho"pham!de %or !nduct!on treatment o% 'upu" nephr!t!"( J Am Soc Nephro' 200EQ 20:1103O1112( JASN A+o*e "tud!e" $ere !n CHINA U ?S( Hence the %o''o$!n "tudy $a" done 'o+a''y( A'"o 2 pha"e tr!a' : Induct!on and ma!ntenance

Random!"ed 3F0 pt"( << centre= 20 countr!e"( 12-F5 yr a e( Ju'y 2005 - oct 200# enro''ment per!od( 3u't!nat!ona' 33> : 0(5 L7B 1 $,Q --A 1 L7 $, 2Q --A 1(5 L7 $, 3 on$ard"( Tho"e $!th SC= do"e decrea"ed to 2 )d I1 C2C : NIH protoco' Loth : 0redn!"o'one ora' #0 m )d "tart!n do"e( Induct!on pha"e : t!'' 24 $ee,"( 0at!ent" $ere $!thdra$n at $ee, 12 $hen the!r "erum creat!n!ne $a"308 a+o*e +a"e'!ne on t$o "ucce""!*e mea"urement" "eparated +y at 'ea"t 4 $, or $hen they re5u!red other !mmuno"uppre""!*e treatment( 0at!ent" cou'd +e $!thdra$n !% the 33> do"a e %e'' +e'o$ 2 )d %or 14 d or $a" "topped %or F d( AI3 : to "ee !" 33> "uper!or to I1 C2CT

MM> Cumu'at!*e rem!""!on 5#8

I0 CBC 538 B

Dutcome" S #mth" B 7eath"

E 5 F due to !n%ect!on 2 !n%ect!on None due to SLC 2 SLC

In%ect!on" @I SC H!thdra$a' due to SC

#<(5 #1(4 138

#1(F ##(F F(28

C"NC#USI"N: 33> no "uper!or!ty o*er I1 C2C( H! h r!", popu'at!on re"ponded +etter $!th 33>( LLACR RACC= LATINS= h!"pan!c": re"ponded poor'y to I1 C2C( Comp'ete rem!""!on rate" $ere 'o$ %or +oth treatment" !n compar!"on $!th other "tud!e"( 0er"!"tent ur!ne prote!n !" common a%ter #mo o% treatment %or "e*ere LN= re ard'e"" o% treatment re !men= and u"ua''y decrea"e" %urther $!th cont!nued %o''o$-up So !" Induct!on o% # month" enou hTT IS MM> e..e9ti:e in : a! D-62 7 M2 : Radha,r!"hnan J= 3outJour!" 7A= @!nJ'er C3= et a'( 3ycopheno'ate mo%et!' and !ntra*enou" cyc'opho"pham!de are "!m!'ar a" !nduct!on therapy %or c'a"" 1 'upu" nephr!t!"( R!dney Int 2010Q FF:152O1#0( Rar!m 32= 0!"on! CN= >erro L= et a'( Reduct!on o% prote!nur!a $!th mycopheno'ate mo%et!' !n predom!nant'y mem+ranou" 'upu" nephropathy( Rheumato'o y .D&%ord/ 2005Q 44:131FO 1321( Spet!e 7N= Tan 2= Ro*!n LH= et a'( 3ycopheno'ate therapy o% SLC mem+ranou" nephropathy( R!dney Int 2004Q ##:2411O2415( /! crescentic 82 ! Tan I= 2an @= 2u C= et al. C%%ect" o% mycopheno'ate mo%et!' %or pat!ent" $!th cre"cent!c 'upu" nephr!t!"( c! /lac+ 7 hispanics : I"en+er 7= Appe' @L= Contrera" @= et a'( In%'uence o% race)ethn!c!ty on re"pon"e to 'upu" nephr!t!" treatment: the AL3S "tudy( Rheumato'o y .D&%ord/ 2010Q 4E:12<O140( 3ohan S= Radha,r!"hnan J( @eo raph!ca' *ar!at!on !n the re"pon"e o% 'upu" nephr!t!" to mycopheno'ate mo%et!' !nduct!on therapy( C'!n Nephro' 2011Q F5:233O241( W Th!" "tudy ana'yJed the 'upu" nephr!t!" outcome" %or 33> *"( other !nduct!on therap!e" !n the conte&t o% eo raph!c %actor"= and %ound that 33> 'ed to more comp'ete rem!""!on" !n pat!ent" out"!de o% A"!a ST?7ICS DN CNI a" !nduct!on a ent: C,9)&sp&1ine in #N : 3 RCT"( 1"t : >u LH= 2an L2= Chen H0= et a'( C'!n!ca' e%%!cacy o% cyc'o"por!n A neora' !n the treatment o% paed!atr!c 'upu" nephr!t!" $!th hea*y prote!nur!a( Lr J Rheumato' 1EE<Q 3F:21FO 221( 40 ch!'dren $!th SR pro'!%erat!*e LN( Random!"ed to rece!*e cyc'o"por!ne .5 m ), )day/ or ora' cyc'opho"pham!de .2 m ), )day/ and predn!"one .2 m ), )day/( At 1 year= +oth roup" ach!e*ed "!m!'ar reduct!on" !n prote!nur!a

2nd : NIH !n 3N
Austin HA 3rd, Illei GG, Braun MJ, et al. Randomized, controlled trial of prednisone, cyclophosphamide, and cyclosporine in lupus membranous nephropathy. J Am oc !ephrol "##$% "#&$#'($''.

42 pt" : 3 roup" C"A 4 0red 11 I1 cyc # do"e a'ternate mth month 4 0red 1 yr cumu'at!*e rem!""!on rate <38 h! he"t Xu!c,e"t rem!""!on 3rd : 2010
)a*ada J, +esic,o*a , Rysa*a R, et al. -yclosporine A or intra*enous cyclophosphamide for lupus nephritis& the Cyclofa-Lune study. Lupus 2010% '$&'".'('".$.

A'ernate day predn!"o'one a'one 2F 8 'o$e"t

#08 >e$ re'ap"e

Jan 2002 - 7ec 200#( CJech R 4 S'o*a,!a

C2C I1 10 m ), C"a !nduct!on E month" < +o'u"e" !n E month" 4-5 m ), )d !n d!*!ded do"e >o''o$ed +y ora' C2C 10 m )d # 3a!nta!nence: radua' taper to 3(F5-< $ee," !nter*a' 1(25 m (, (d E month CR !n prote!nur!a Sta+'e ) !mpro*ed creat!n!ne 3<8 3ore <#8 3ore #E8 4F8 Increa"e L0= decra"e @>r

TACR"#IMUS in #N: 5 "tud!e"( A: compar!"!on to I1 C2C --A Ch!ne"e "tudy -- <1 pt" TAC 4 Stero!d" *" h! h do"e I1 C2C 4 Stero!d" BBA rate o% CR= cumu'at!*e rem!""!on and ad*er"e e%%ect( 2nd tr!a' : #0 pt": TAC4"tero!d *" 33>4 "tero!d" *" h! h do"e I1 C2C 4 "tero!d"( S!m!'ar CR and cumu'at!*e rem!""!on rate( Rap!d !mpro*ement !n Sr a'+um!n and prote!nur!a !n a+o*e tr!a' $!th TAC( ST?7ICS 3AINL2 IN CHINCSC( C%%!cacy !n more d!*er"e cohort" not ,no$n( 3?LTITAR@CT THCRA02 : TAC4 33> Lao H= L!u IH= 6!e HL= et a'( Succe""%u' treatment o% c'a"" 1 Y I1 'upu" nephr!t!" $!th mu't!tar et therapy( J Am Soc Nephro' 200<Q 1E:2001O2010(

Corte"-HernandeJ J= Torre"-Sa'!do 3T= 3edrano AS= et a'( Lon -term outcome" O mycopheno'ate mo%et!' treatment %or 'upu" nephr!t!" $!th add!t!on o% tacro'!mu" %or re"!"tant ca"e"( Nephro' 7!a' Tran"p'ant 2010Q 25:3E3EO 3E4<( Lanata C3= 3ahmood T= >!ne 73= et a'( Com+!nat!on therapy o% mycopheno'ate mo%et!' and tacro'!mu" !n 'upu" nephr!t!"( Lupu" 2010Q 1E:E35OE40( RITUEIMAB IN #N: D%% 'a+e' u"e( ()at *+ 'ad)akris)nan ,. ( lymp)o-ytes and lupus nep)ritis. new insig)ts into pat)ogenesis and targeted t)erapies. /idney nt 20012 34.2567251.889 role of ( lymp)o-ytes in L!( 0(1i&-s St-+ies h(:e sh&5n th(t in Resist(nt #N : ?SC o% RIT?6I3AL 4 I1 C2C 4 predn!"o'one !n re%ractory LN BB r!tu&!ma+ 4 "tero!d( So= $hether add!n R!tu&!ma+ to pr!mary Induct!on a ent !" u"e%u'T Th!" $a" "tud!ed !n L?NAR( L?NAR( The #-p-s Neph1itis Assessment Fith Rit-?im(; St-+, T1i() BBA 'ar e"t ( 144 pt"( "BGECTI0E : To e*a'uate the e%%!cacy and "a%ety o% r!tu&!ma+ !n a random!Jed= dou+'e+'!nd= p'ace+o contro''ed pha"e III tr!a' !n pat!ent" $!th 'upu" nephr!t!" treated concom!tant'y $!th mycopheno'ate mo%et!' .33>/ and cort!co"tero!d"( 33>4"tero!d 4 R!tu&!ma+ or p'ace+o( -rimary end point : rena' re"pon"e at 52 $ee,"( R!tu&!ma+ !*en at do"e o% 1 on day 1= 15= 1#< and 1<2 33> : 500 m T7S --A +y 4 $ee, 3 )d(--A 9&ntin-e+ .&1 52 5ee4s' MP I1 1000 m 71 F 73 Dra' predn!"o'one : 0(F5 m ), ma& #0 m %or 1# day"= tapered to G 10 m )d +y 1# $ee,( Any pt re5u!r!n re"cue therapy --A 'a+e''ed a" non re"ponder and $!thdra$n(

D*era'' re"pon"e 5F *" 4#8(

The pr!mary end po!nt ."uper!or re"pon"e rate $!th r!tu&!ma+/ $a" not ach!e*ed( C! ht p'ace+o-treated pat!ent" and no r!tu&!ma+-treated pat!ent" re5u!red cyc'opho"pham!de re"cue therapy throu h $ee, 52( Stat!"t!ca''y "! n!%!cant !mpro*ement" !n "erum comp'ement C3= C4= and ant!O dou+'e-"tranded 7NA .ant!-d"7NA/ 'e*e'" $ere o+"er*ed amon pat!ent" treated $!th r!tu&!ma+( In +oth treatment roup"= a reduct!on !n ant!-d"7NA 'e*e'" reater than the med!an reduct!on $a" a""oc!ated $!th reduced prote!nur!a(

Ad*er"e e*ent" $ere e5ua'= +ut RT6 a""oc!ated $!th more neutropen!a= 'eucopen!a and hypoten"!on( 8IMI,.I92! 2ot included refractory cases. 8:2.) sho;ed )itu<ima/ addon ;as of no /enefit, /ut fe; small studies had sho;n it to /e /enficial in reistant 82, so a metaanalysis of these studies ;ere done and pu/lished in 2D, ! Be,&n+ the #UNAR t1i()' E..i9(9, &. 1it-?im(; in 1e.1(9t&1, )-p-s neph1itis : N7T 2012 A "y"temat!c re*!e$ o% u"e o% R!tu&!ma+ !n re%ractory LN(

M(inten(n9e the1(p, t1i()s: NI$ Stud!e" !n 1E<0" and 1EE0" "ho$ed that a%ter Induct!on therapy= ma!nta!nence !mmuno"uppre""!on $a" +ene%!c!a' !n pre*ent!n re'ap"e"( >!r"t a ent "tud!e" $a" 5uarter'y pu'"e I1 C2C( S!nce !t !" a""oc!ated $!th "! n!%!cant to&!c!ty= a'ternate a ent" $ere "tud!ed( >!r"t $a" AIA= %o''o$ed +y 33>( AIA $a" "tud!ed !n NIH= and $a" e5u!*a'ent to Xuarter'y pu'"e I1 C2C( So AIA had +ecome "tandard ma!nta!nence a ent t!'' 33> $a" a*a!'a+'e( H!th e"ta+'!"hed "a%ety and e%%!cacy o% 33>= !t $a" "tud!ed a" ma!nta!nence a ent( >i1st RCT &n MM>:

Contrera" @= 0ardo 1= Lec'erc5 L= et a'( Se5uent!a' therap!e" %or pro'!%erat!*e 'upu" nephr!t!"( N Cn ' J 3ed 2004Q 350:EF1OE<0( 5E pt"( Induct!on $!th h! h do"e I1 C2C4 0redn!"o'one 3a!nta!nance $!th : e!ther 33> or AIA or Xuarter'y I1 C2C( 0r!mary endpo!nt $a" death ) CR>( RCS?LT: 33> U AIA A to C2C 33> $!th %e$ re'ap"e( Lo$er !n%ect!on $!th 33> U AIA( SD I1 C2C ma!nat!nence $a" d!"carded TRIA#S 9&mp(1ing MM> 5ith AHA: MAINTAIN NEP$RITIS TRIA# :
Houssiau 2A, 34-ruz 3, an5le , et al. Azathioprine *ersus mycophenolate mofetil for lon56term immunosuppression in lupus nephritis& results from the MAI!7AI! !ephritis 7rial. Ann Rheum Dis 2010; 8$&"#.3("#.$. 9:R;+9A! +;+:<A7I;!, =uly "##" 6 march "##8, '#> pts I!3:-7I;! ?A 9<!7.

3AINTAINANCC $!th 33> DR AIA : The pr!mary end po!nt o% the tr!a' $a" t!me to rena' %' are RCS?LT--A no d!%%erence !n rena' %'are o*er 4 yr per!od !n +oth roup( Res-)t Ren() .)(1e MM> 10 o% 53 1E8 AHA 13 o% 52 258 # 4 3

Nephrot!c < Increa"e creat 2 Increa"e prote!nur!a AD0ERSE E0ENTS Cr 62 7CATH

3 4 0TS 2 .In%ect!onQ d!"ea"e act!*!ty/ --

Cytopen!a more !n AIA roup( BBA 33> BB AIA= non "uper!or #imit(ti&n: Cauca"!an Sma'' "amp'e "!Je Non L'!nd 3a!nta!nence R& "tarted pr!or to ach!e*ement o% "! n!%!cant ren5' re"pon"e( A#MS MAINTAINENCE TRIA#: 22F pt"( Induct!on 6 # mth" : I1 C2C or 33>( Tho"e $ho had atta!ned rena' re"pon"e $ere nc'uded(

11# : 33% 2 )d ma!nata!nence 111 AIA 2 m ), )d ma!nta!nence( The p1im(1, e..i9(9, en+ p&int $a" the t!me to treatment %a!'ure= $h!ch $a" de%!ned a" death= end-"ta e rena' d!"ea"e= dou+'!n o% the "erum creat!n!ne 'e*e'= rena' %'are= or re"cue therapy %or 'upu" nephr!t!"( Se9&n+(1, (ssessments !nc'uded the t!me to the !nd!*!dua' component" o% treatment %a!'ure and ad*er"e e*ent"( * ,1 .&))&5 -p 3m% : 'e"" treatment %a!'ure= and 'on er t!me to re'ap"e( Ad*er"e e*ent" "!m!'ar !n +oth Ser!ou" ad*er"e e*ent" more !n AIA roup( H!thdra$a' due to SC more !n AIA roup( CC< .(:&1 MM> (s m(in(tin(n9e RE &. 9h&i9e i11espe9ti:e &. in+-9ti&n R?2 1(9e2 se?2 ge&g1(ph,' 7oo'ey 3A= Jayne 7= @!nJ'er C3= et a'( 3ycopheno'ate *er"u" aJath!opr!ne a" ma!ntenance therapy %or 'upu" nephr!t!"( N Cn ' J 3ed 2011Q 3#5:1<<#O 1<E5( WW The AL3S ma!ntenance tr!a' !" the 'ar e"t RCT conducted !n the ma!ntenance treatment o% 'upu" nephr!t!"= and the re"u't" %a*ored 33> u"e o*er AIA(

CNIs In m(int(in the1(p,: Cyc'o"por!ne ha" +een e&p'ored !n t$o RCT" a" ma!ntenance therapy( The %!r"t tr!a' compared cyc'o"por!ne p'u" "tero!d" to AIA p'u" "tero!d" a%ter 3 month" o% !nduct!on therapy $!th ora' cyc'opho"pham!de and "tero!d"( The SLC re'ap"e rate" $ere the "ame !n +oth roup"= there $a" no d!%%erence !n rena' %unct!on= and more pat!ent" !n the cyc'o"por!ne roup ach!e*ed cont!nued undetecta+'e prote!nur!a at 4 year" o% %o''o$-up( The "econd "tudy pre"cr!+ed E month" o% !nduct!on therapy $!th cyc'o"por!ne or !ntra*enou" cyc'opho"pham!de ."ee a+o*e/= then ma!ntenance therapy $!th cyc'o"por!ne or ora' cyc'opho"pham!de(At E month" o% ma!ntenance therapy .1< month" tota' therapy/= rem!""!on rate" $ere "!m!'ar= +ut more pat!ent" !n the cyc'o"por!ne roup had comp'ete rem!""!on !n prote!nur!a( Tacro'!mu" ha" +een "tud!ed a" ma!ntenance therapy !n one p!'ot "tudy !n Japane"e pat!ent":44; and one recent RCT !n Ch!ne"e pat!ent"( The RCT $a" an e&ten"!on o% the tacro'!mu" !nduct!on therapy RCT de"cr!+ed a+o*e and random!Jed pat!ent" $ho ach!e*ed comp'ete or part!a' rem!""!on to ma!ntenance therapy $!th 'o$-do"e "tero!d" p'u" e!ther tacro'!mu" or AIA( At # month"= re'ap"e" occurred !n 0 o% 33 pat!ent" !n the tacro'!mu" roup and 2 o% 30 .F8/ pat!ent" !n the AIA roup= and 'eucopen!a $a" more common !n the AIA roup( >am!'!ar!ty $!th the 'on -term u"e o% the CNI" !n tran"p'ant pat!ent" ma,e" the!r u"e a" ma!ntenance therapy !n 'upu" nephr!t!" an attract!*e opt!on( Ho$e*er= the '!m!ted data and concern %or nephroto&!c!ty $!th pro'on ed u"e pre*ent the!r de"! nat!on a" the %!r"t-'!ne ma!ntenance therap!e" !n 'upu" nephr!t!" A++iti&n() the1(p, -se+ in #N: HCXS :

The C(n(+i(n $,+1&?,9h)&1&I-ine St-+, G1&-p demon"trated *!a a "ma'' random!Jed $!thdra$a' tr!a' that "ta+'e SLC pat!ent" $ho cont!nued HCX e&per!enced 'e"" d!"ea"e %'are" o*er a 24-$ee, per!od compared $!th tho"e $ho too, p'ace+o(@/8A At 3 year" o% %o''o$-up= there $a" a non"! n!%!cant trend to$ard 'e"" rena' %'are" .re'at!*e r!", 0(2#= E58 con%!dence !nter*a' 0(03O2(54= P B 0(25/ $!th cont!nu!n HCX( #8 pt" ret!nopathy B--A there%ore re u'ar optha'mo'o !ca' e&am!nat!on mu"t( RAAS +'oc,ade : The Lupu" !n 3!nor!t!e": Nature *"( Nurture "tudy demon"trated an a""oc!at!on +et$een ACCI u"e and 'e"" de*e'opment o% 'upu" nephr!t!" !n tho"e $ho d!d not ha*e rena' d!"ea"e= and an !mpro*ement !n prote!nur!a and decrea"ed r!", o% d!"ea"e act!*!ty !n tho"e $!th e"ta+'!"hed 'upu" nephr!t!"( Spe9i() C)ini9() C&nsi+e1(ti&ns Homen $!th SLC are 5O< t!me" more '!,e'y to ha*e coronary heart d!"ea"e than tho"e !n the enera' popu'at!on(:5<=5E; A'thou h opt!mum cho'e"tero' 'e*e'" !n 'upu" nephr!t!" pat!ent" ha*e not +een e"ta+'!"hed= !t !" appropr!ate to u"e "tat!n" !n 'upu" nephr!t!" "!m!'ar'y to other cau"e" o% chron!c ,!dney d!"ea"e( D"teopen!a and o"teoporo"!" are common !n SLC= perhap" '!n,ed to e&ce"" 'ucocort!co!d u"e= and 'ead to a %!*e-%o'd !ncrea"ed r!", o% "ymptomat!c %racture !n SLC pat!ent" compared $!th the enera' popu'at!on(:#0; 3ana ement o% +one d!"ea"e $!th ca'c!um and *!tam!n 7 "upp'ementat!on "hou'd +e con"!dered !n a'' pat!ent" $!th 'upu" nephr!t!"( >!na''y= appro&!mate'y 308 o% pat!ent" $!th SLC $!'' a'"o de*e'op the ant!pho"pho'!p!d ant!+ody "yndrome .A0LS/ and are at r!", %or throm+oem+o'!c e*ent"= rena' throm+ot!c m!croan !o raphy= and cata"troph!c A0LS(

RCCD33CN7ATIDN IN L?0?S NC0HRITIS : 1( Lert"!a" @R= Te,ton!dou 3= Amoura I= et a'( Jo!nt Curopean Lea ue A a!n"t Rheumat!"m and Curopean Rena' A""oc!at!on-Curopean 7!a'y"!" and Tran"p'ant A""oc!at!on .C?LAR)CRA-C7TA/ recommendat!on" %or the mana ement o% adu't and paed!atr!c 'upu" nephr!t!"( Ann Rheum 7!" 2012Q F1:1FF1O1F<2( 2( Hahn LH= 3c3ahon 3A= H!',!n"on A= et a'( Amer!can Co''e e o% Rheumato'o y u!de'!ne" %or "creen!n = treatment= and mana ement o% 'upu" nephr!t!"( Arthr!t!" Care Re" .Ho+o,en/ 2012Q #4:FEFO<0<