MODELS OF COMBINATION THERAPY \VITH DISEASE-MODIFYINGANTIRHEUlVIATIC DRUGS

Early, Aggressive Therapy for Rheumatoid Arthritis:Concerns, Descriptions, and Estimate of Outcome

By William S . Wilke, Thomas J. Sweeney, and Leonard H. Calabrese

The past few years have witnessed changing per­ceptions about rheumatoid arthritis (RA); it is nowconsidered a serious systemic disease that confersnot only physical and social morbidity but alsoearlier mortality. The long-term outcome of se­quential monotherapy based on the therapeuticpyramid has been disappointing. A review ofprognostic factors, acute disease activity mea­sures, functional measures, and the results ofpreliminary trials with combination therapy sug­gests that specific goals of treatment can be es­tablished and that logical, aggressive treatment

"Basic Principles. In the management of rheu­matoidarthritis. a physician shouldkeepthefol­lowing facts ill mind:

I. III most patientsthe disease is chronic:2. Spontaneous remissions occur illalmostall

patients;3. Themajorityof'patients call continueto lead

active lives with varying degrees ofrestric­tion; and

4. Complications of'drug therapy, mostnotablyadrenocorticosteroids, call cause greatermorbidity than the underlying disease"

Textbook of Medicine, 1975.1

It may be I willgo withyou, but yet I'll pause,for I am loath to break our country's laws.Shakespeare W: King Richard1/. Act II, scene3, lines 167-168

I N 1975, the climate was different and rheu­matologistsdared not break ranks. Although

From the DepartmentofRheumaticand Immunologic Dis­ease. Cleveland Clinic Foundation, Cleveland, 011

William S. Wilke, MD.llead. Section ofSubspecialty Cltn­ics: Thomas J. Sweeney, MD: Staff, South Bend ArthritisCenter: Leonard H. Calabrese, MD: Vtce-Chairman, Depart­ment of Rheumatic and Immunologic Disease.

Address reprint requests 10 WilhamS. Wilke. .\ID, Sectionof Subspecialty Chnics, Department of Rhcumauc and lm­munologlc Disease.Cleveland Clime Foundation. Cleveland,01144/95,

Copyright © /993 by II'B SaundersCompany0049-0/72/93/2302·/o05S5.00/0

in early disease can be accomplished. These goalsshould include prompt control and continuous re­duction of the active joint count to ::,;4 and nor­malization of acute-phase reactants. The "grad­uated-step paradigm" of treatment designed withthese goals in mind is described, and a retrospec­tive series that gives an estimate of outcome withits use is reported.Copyright © 1993 by W.B. Saunders Company

INDEXWORDS: Rheumatoid arthritis; treatmentparadigms; early treatment.

slow in coming, it has become fashionable tocriticizeconservative therapy for rheumatoid ar­thritis (RA)as generally ineffective. Some authorshave graphically characterized RA as a seriousdisease. One series grabbed our attention byequating the prognosis of RA at its worst withstage IV Hodgkin's disease.i-' In another large25-year prospective series, RA wasthe proximateor contributingcause of death in 21 % of'patients."Other authors have appealed to our senseof guiltby reviewing or presenting long-term follow-upstudiesthat showworsening disease and disabilitydespite our best pyramidal efforts."? At the sametime, we have been warned that before we tip thepyramid and expose our patients to the potentialharm of aggressive therapy, we had better havea plan that shows some promise.i"?

In fact, there are strategies that show promise,and probably the most effective of these is theintroduction of sufficiently active drugs in earlydisease. The open trials with parenteral gold byCecil et al in 194211 and Luukkainen et al in197712 for patients with moderate to severe dis­ease and the recent controlled trial by Davis etal13 with hydroxychloroquine (HCQ) in mild dis­ease suggest that early therapy with so-called dis­ease-modifying agents isboth safeand efficacious.Furthermore, the abstract by Roger et al'" showlong-term benefit of aurothioglucose and low­dose triamcinolone in 100 patients followed upforapproximately3 years. Mostrecently, Meenan

26 Seminars in Arthntts and Rheumatism. Vol 23. No 2 . Suppl 1 (October). 1993 pp 26-41

EARLY. AGGRESSIVE THERAPY FOR RA

et aIlShave shown that even in the first year, dis­ease activity has a substantial impact on generalhealth and well-being and should be treated ap­propriately.

Before embarking on any long-term treatmentplan, we must be sure that what we measure re­flectsvalid, reproducible, and clinically significantdisease parameters. Certain questions must beanswered: Which measures of acute disease aremost reproducible and best reflect overall diseaseactivity? Are indices of acute disease activityclinically useful? If so, which best correlate withoverall disease activity? Which measures, mon­itored early in the course of disease, predict ag­gressive disease activity and potential debilita­tion? Which drugs should be used, in what order,and in what sequence or combination?

MEASURES OF ACUTE DISEASE ACTIVITY

Measures of acute disease activity are not per­fect. Time-honored indicators such as joint ten­derness count and grip strength vary considerablyduring as short a period as 1 week in stable pa­tients, and the duration of morning stiffness mayvary by as much as 100%}6.17 In addition, earlymorning stiffness is imprecise' S' ? or correlatesbest with "fibrositic" a-o sleep'? and not neces­sarily with disease activity. Changes from the timeofarising until the onset ofafternoon fatigue alsomay be a result of sleep fragmentation and not apure measure of disease activity." Furthermore,grip strength, early morning stiffness, and generalfunctional abilities are governed by circadianrhythm and show diurnal variation.22•23 To berecorded accurately, pain severity must be mea­sured precisely with a horizontal, unmarked, 10­em visual analogue scale, only after patients areshown their previous marks.2-l.28

Because joint inflammation is the cardinal signand produces the compelling symptom in RA, itis unarguably the key manifestation ofactive dis­ease. However, the best way to measure it is de­batable. The number ofjoints to be measured29.30

and the reproducibility ofjoint tenderness grad­ing among different rheumatologists examiningthe same patient have been questioned." In fact,simple might be best. When four articular indiceswere compared among four rheumatologists, thesystem in which only the presence or absence ofjoint swelling or joint tenderness was assessedproduced the least observer variation.V

27

Among the objective signs of disease activity,the Westergren sedimentation rate (WSR) hasbeen the most thoroughly studied. In an evalu­ation of315 consecutive RA patients with a meandisease duration of 12 months, early bony ero­sions were significantly more frequent in patientswith WSR greater than 25 mrn/h than in patientswith lower values.P This corroborates previousreports in 64 and 67 patients, respectively, thatshowed trends of decreasing joint destructionwith lower chronic WSR values.3-l.3s A prospec­tive study of 150 consecutive patients by Daweset al36 showed that continuous control of acute­phase reactants for 1 year significantly decreasedradiological progression. Another series hasshown that tight control ofacute-phase reactantswith sulfasalazine (SSZ) could best be achie vedin younger patients with shorter duration of dis­ease." Extrapolating from the previously citedstudies with parenteral gold"·12 and the con­trolled study with HCQ,13 this may be true ofmany disease-modifying antirheumatic drugs(DMARDs).

Many other objective laboratory measures ofdisease activity have been reported. High-titerimmunoglobin A (lgA) rheumatoid factor,"rheumatoid factor that simultaneously binds hu­man IgG and sheep IgG,39 immune complexesthat bind complernent/" C-reactive protein,36.41plasma viscosity," thrombocytosis." eosino­philia;" and serum levels of soluble CD4 45 alsomay be reliable, sensitive, objective tests but havenot been scrutinized as closely.

TOWARD AN INDEX OF ACUTE

DISEASE ACTIVITY

Although rheumatologists implicitly aggregateclinical findings in the setting ofclinical practice,a formal index that provides a numerical valuefor overall disease activity can be useful as a wayto evaluate the outcome of therapy in an "objec­tive" manner. An index also lends itself to drugefficacy studies by reducing the number of pa­tients needed in each trial group. Many indices ,both judgmental and statistical, have been de­scribed . Two separate indices, both using statis­tical methods that included regression analysis toanalyze previously treated patients, showed thatthe WSR and some measure of joint inflamma­tion are very valuable and explain a high per­centage of the variance between drug-treated and

28 WILKE. SW EENEY . AND CALABRESE

Table 1: Disease Features of RA and Other Factors in RAThat Predict Poor Outcome in Selected Series

Follow-up Pat ient s

Reference (yr) (n) (FC APR AJC RF Other

Duth ie et a l. (196 4)58 9 20 0 x x X X

McKonkey e t al. (1972) 57 0 .5-6 187 X

J acoby e t a l (1973 )58 8-14 100 X X

Flemln9 et a l. (1976 )59 4 .5 10 2 X X X X [G np st rength

Feigenbaum e t al. > 5 50 X X [Gn p streng th.

(1979) 80 psycho logical

st ress

Sjoblom e t al (1984) 81 2 103 X X ~Hgb

conce ntrat ion

Raskar et a l (1984) 82 15 100 X X X ~Hgb

conc entr ation,

presence of

rheumatoid

nodu les

Kaarela e t al ( 198 5)63 8 200 X X Wo rsen ing

radi og raphic

grade .

s ym m etric

swelli ng, EMS >

1 h

Sh errer e t a l (1986) 84 11.9 681 X Wors ening

radiog raphic

grade, [ aqe,

fe male ge nder

Sco tt e t a l. (198 7 )85 20 112 X X tAge.late

pr esentation

Mottonen (1988 )88 2 5 8 X X X "Disease ac tivit y"

Erhardt e t a l. (1989) 67 8 64 Ext ra articu lar

Involvement,

tcryo globulin s.

(+) PASCA

Reilly et al (1990)4 25 100 X X ~Hgb

co nc entr ation

Kazis e t a l. (1990) 88 5 279 tAge. poor

general health

p erception

Leigh e t al. (1991 )69 9 263 Age . work stat us.

general heal th,

pre dnison e

dos e. HAQ

scor e

Wolfe e t al. (1991)' 0 12 127 4 X Pain, d epress ion

Abbrev iat ions : RA, rheumato id arthn tis, IFC, Imp aired trunal functional capacity or wo rsemngfun ctional cap acitv, APR , chr onic elevationof acute -phase reac tants; AJC, acti ve JO int count Inv ersely related t o pro qnosis: RF, increasinq or high-lit er rheumatoid factor; Hgb,hemoglobin ; EMS. dura tion of ea rly morning st iffness; P ASCA. POSi tive tes ts for precipitating antibod ies t o so luble cellular a ntigens ,HAQ. health assessm ent quest ionna ire.Adapted a nd repnn ted wit h permiss ion 73

EARLY. AGGRESSIVE THERAPY FOR RA

Table 2: Group Characteristics at Initial Evaluation

29

< 2 yr > 2 yr Combined

Disease Disease «2 yr/>2 yr)

Age (yr) 504 535 51.9

WSR(mm/h) 462 506 484

Hgb (g/dL) 12.7 13 .1 12.9

Active [omt count" 16.6 21 188

Grip(mm Hg) 89 123 106

FC 1.9 2.2 2 .1

Abbreviations: WSR. Westergren s edimentation rate; Hqb, h emoglobin; Fe . function al class" A simple count of the pre sence or absence of swelling and/or tenderness for a tot al of 32 drarthrcdrel JOIOts (metatarsophal angealJOInts aggregated to 1 jo int for each foot)

placebo-treated patients.46•47 A consensus meeting

in the United Kingdom resulted in ajudgmentalresponse index, which consists of four measures:clinical pain , swollen/tenderjoint count, durationof early morning stiffness, and change in acute­phase reactants." This index was later tested inpatients treated with either D-penicillamine(DPN) (145 patients) or SSZ (99 patients) andshowed high sensiti vity to appropriate change."

Although grip strength was found to be usefulin one statistical study," this measure changesslowly over time, may be difficult to change in pa­tients with severe hand deformities, and is subjectto other disease influences such as median nerveentrapment distal to the wrist. Another series wasunable to show that the WSR was a sensitive mea­sure." That the WSR did not decrease with modestdisease improvement in this trial of nonsteroidalantiinflammatory drugs (NSAIOs) probably reflectsthe negligible biological effects of NSAIDs ratherthan any intrinsic shortcoming of the test.

FUNCTIONAL TESTING

The primary goal of therapy is to improve orat least maintain function in patients with RA.

Disease activity measures do not necessarilymeasure function. Some tests of function includesimple measures such as grip strength. Others aremore complex such as the Keitel Hand FunctionTestSI or the McMaster Toronto Patient Prefer­ence Questionnaire.P'P The functional tests mostoften used and best studied are the Arthritis Im­pact Measurement Scale, which is best for mea­suring mobility and pain, and the Health As­sessment Questionnaire (HAQ) , which bestmeasures social , functional, and global health.54

These functional tests allow validation ofdiseaseactivity measures and indices by the strength ofcorrelation between function and disease activity.They also focus therapy; if functional tests arcconsistently favorable, then outcome, at least withregard to function, must be favorable.

LONG-TERM PROGNOSIS

Although many series comment about the in­fluence ofacute disease activity and other factorson the final outcome in RA, data collections arevariable. In an excellent review, van der Heijdeet al55 have observed that no study fulfills opt i-

Table 3: Patients Receiving Medications at Time of Follow-Up

Presentation 1 yr 3 yr 5 yr 10 yr > 10 yr

Drug (n = 34) (n = 34) (n = 34) (n = 24) (n = 12) (n = 10)

MTX 2% 44% 64 % 50 % 75 % 90 %

HCQ 26 % 94 % 85% 95% 85 % 100 %

Predn isone 29 % 47% 55 % 12% 75 % 50 %

NSAID 47 % 76% 70 % 83% 58 % 100 %

Aspinn 17 % 14 % 5 % 8 % 8 % 20 %

Gold 0 % 5% 8 % 8 % 0 % 10 %

No therapy 20 % 0 % 0 % 0 % 0 % 0 %

Medications/pat ient 1.2 2 .8 2.9 2 .6 2 .9 3 .9

Abbreviations : MTX. methotrexate ; HCQ.hvdro xychlcroqume, NSAID.nonstero idal antunflarnmatorv drug .

30 WILKE. SWEENEY, AND CALABRESE

-"'-- ~2YRS.

I. -t- >2YRS.

.~

\ \~ • • I -H• • •

r--..a. .....

so

50

40

30

20

10

p 10

YEAR OF FOLLOW·UP

>10

Fig 1: WSR per year offollow-up. Mean WSR inearly patients (therapy ini­tiated 52 years after dis­ease onset; n = 22) andlate patients (therapy ini­tiated >2 years after dis­ease onset; n = 12). P,Presentation.

mum criteria, which should include regular pro­spective observations of patients starting in earlydisease, use of identical clinical protocols forevaluation performed by the same individual, andstandardized laboratory and radiological pararn­eters." Still, many prospective and retrospectiveseries have been published and contain usefulinformation4.56-7o (Table 1). Predictive factorsmost often cited include poor initial functionalcapacity, continued elevation of acute-phase reac­tants, continued high active joint count, and initialhigh-titer rheumatoid factor. Other factors includeinsidious onset of disease and the presence or ab­sence ofclass II antigens such as HLA-DR4.71

•72

NEW PHILOSOPHIES OF THERAPY

Pyramidal therapy consists ofinitiating single­drug therapy with a sequence ofpresumably saferbut lesseffective agents, which may fail over time,before "more dangerous" but possibly more ef­fective drugs and combinations of drugs are ad­ministered. This is a cookbook approach that, byits design, introduces effective therapy too late inthe course of disease for 60% to 80% of pa­tients.37,73.74 Two principal assumptions about thetreatment of RA form the foundation of pyra­midal therapy-( 1), that more effective drugs areintrinsically more dangerous, and (2) that therapyrarely if ever interferes with the inexorable march

16

14

12

10

HEMOGLOBIN 8g/dL

6

4

>10103 5

YEARS FOLLOW-UP

1P

, ......~~

.,....

-I- > 2 YRS. DZ

-+- .s: 2 YRS. DZ

I I

2

o

Fig 2: Mean hemoglobinconcentration in early pa­tients (therapy initiated5 2 years after disease on-set; n = 22) and late pa-tients (therapy initiated >2years after disease onset; n= 22). P. Presentation.

EARLY. AGGRESSIVE THERAPY FOR RA 31

25-r----,r--...,....--.-.-------..-+- > 2 YAS. OZ

-+- ~ 2 YRS. OZ2°-r-\1-1-1t...=~=.:.:==_l

>101053

YEARS FOLLOW·UP

P0+----!----+-.--+--.--.,:----__1f_-__l

5-+----!-~_±_."..~~_h:_i:----__1f_-__l

1O-+---ft---i~-_+-__,A__--_h_-~

15-;--""t-T-t---:------r---+----i~_+_-__1

JOINTCOUNTFig 3: Mean number of

joints judged to be tenderand/or swollen in early pa­tients (therapy initiatedinitiated ~2 years afterdisease onset; n = 22) andlate patients (therapy ini­tiated >2 years after dis­ease onset; n = 12).

of disease toward disability-are now at least de­batable.13.'4.37.75.76 Untested but logical innovativenew treatment philosophies have been proposed.They all imply that effective drugs are at our dis­posal and can be made more effective by properapplication.

The "step-down bridge" strategy ofWilske andHealy is the most radical." Patients who expe­rience an incomplete response to low-dose pred­nisone administered for I month are assigned toa regimen ofcombined oral gold, parenteral gold,methotrexate (MTX), and HCQ. As the diseaseresponds, the more dangerous drugs are serially

discontinued and response is maintained by theleast toxic agent(s) (ie, HCQ, oral gold). Despitethe absence of NSAIDs, this treatment programis apt to expose some patients with moderate dis­ease to unnecessary potential toxicity. In addi­tion, disease control previously achieved bycombination therapy has been shown to be dif­ficult if not impossible to achieve with mono­therapy."

The "saw-tooth" strategy ofFries" dictates thatdisease be sufficiently controlled that patients aremaintained at or below a preset ceiling of dis­ability. Unfortunately, the specific drugs to be

250-r---r---r--.,---.----r---,

200+----!---+-+_t--:--1---.--.,r,..c-__l

O+---+--~-~.......===+====+===~

Fig 4 : Handgrip strength.Mean averaged gripstrength in early patients(therapy initiated ~2 yearsafter disease onset; n= 22) and late patients(therapy initiated >2 yearsafter disease onset; n= 12).

10 >10

-J- ~ 2 YAS. DZ

-+- > 2 YAS. DZ

53

YEAAS FOLLOW-UP

1P

50-l---+---+---~

150+---rf-+~--+---r1----i---i

GAIP STRENGTH

(MM/HG) 1OO-+--:r'-i~--+---4-.£.....+----+---l-----i

32

P ERC ENT

8

4

2

1 23 4 1 2 3

WILKE. SWEENEY. AND CALABRESE

1 2 34 1 2 3 4 1 2 3 4

p 1 3 5 1 0 > 1 0

FU CTIONA L CLASS P ERYEAR OF FO LLOW-U P

Fig 5: Percent of patients in each functional class (Steinbrocker criteria) overtime among those firsttreated for RA of >2 years duration. P. Presentation.

used either singly or in combination arc not dis­cussed.

Willkens suggests staging the disease much asoncologists stage malignancies, based on physi­ologic events that result in joint destruction.P'!'Once staged, patients arc matched to logical butempiric treatment. The philosophy of this strat­egy is sound, but the specifics of implementation,such as HLA typing, may be expensive and in­convenient. In addition, guidelines for continuingcare arc not given.

The "graduated-step" paradigm advocated bythese authors combines initial staging techniqueswith a preset ceiling of disease activity that dic­tates therapy over time to maintain disease con-

trol. 73 Drug choices arc provided at each level oftherapy based on revised information about rel­ative efficacy and toxicity.82.86 Numerical valuesarc assigned for prognostic features , disease se­verity, and disease activity, lending this systemto prospective and retrospective analysis.

Briefly, with this paradigm patients arc enteredinto the treatment protocol at or near the timeof diagnosis based on "disease severity," whichis the sum of arbitrarily derived prognostic fea­tures and a "disease activity index" modifiedfrom a response index described and tested byScott et al:~8A9 Further treatment depends on thedisease activity index alone. Decisions about thetreatment of patients with subacute disease arc

EARLY. AGGRESSIVE THERAPY FOR RA 33

?ERCENT

8

4

2

1 2 34 1 23 4 1 2 34 1 2 3 4 1 2 3 4

p 1 3 5 , 0 :> 1 0

FU CT IONA L CLASS P ERYEAR OF FOLLO W-UP

Fig 6: Percent of patients in each functional class (Steinbrocker criteria) over time among those firsttreated for RA of 52 years' duration. P. Presentation.

made only after considering factors that may beunique to each patient or treatment regimen . Thisallows fine tuning of the system by taking intoaccount important "subjective" features of dis­ease management. At pivotal times , after inter­ruption oftherapy because ofsignificant toxicity,pregnancy, or surgery, for instance, the diseaseseverity score may be recalculated and the processreinitiated.

Data other than those included in the diseaseactivity index also are recorded, including timeto afternoon fatigue and global assessments. Inaddition, grip strength is recorded at each visitand the HAQ is completed at least twice yearly.These measures offunction have been kept apartfrom the treatment indices so that they might be

used to measure the system's validity. (For furtherinformation, see Appendix.)

SOME OBSERVATIONS ABOUT AGGRESSIVELY

TREATED PATIENTS

Although we have only recently formally de­scribed the "graduated-step paradigm," it is basedon the style of treatment of RA used in the De­partment of Rheumatic and Immunologic Dis­ease since the late 1970s. To provide some esti­mate of results that might be expected using thisparadigm, the medical records of 50 consecutivepatients returning for follow-up visits with thefirst author during December 1991 through lateFebruary 1992 were reviewed retrospectively.Thirty-four of 50 medical records were judged to

34 WILKE, SWEENEY . AND CALABRESE

contain sufficient documentation of relativelyuninterrupted care of at least 3 years ' duration.Only efficacy information from the initial visitand visits at I, 3, 5, and 10 years, or the last visitif more than 10 years, was recorded. This infor­mation included grip strength, a simple count ofthe presence or absence of tenderness or swellingin 32 diarthrodial joints, WSR, rheumatoid fac­tor, hemoglobin concentration, functional class,and medications. The entire record was analyzedfor adverse effects. The patient population con­sisted of 20 (59%) women and 14 (41%) men.The mean age of patients at the initial visit was54 years for men and 44 years for women. At theinitial visit, rheumatoid factor was positive in 8of 14 men (57%) and 16 of20 women (80%).

All patients satisfied current American Collegeof Rheumatology criteria for the diagnosis ofRA.87 Therapy was initiated within 2 years ofdisease onset in 22 of 34 (65%) patients. Thesepatients arc designated "early patients." The re­maining 12, in whom treatment was started after

Table 4: Side-Effect Profile

Dyspepsia

Alopecia

Tongue swelling/soreness

Mouth ulcer

Diarrhea

Peptic ulcer

Rash/hives

Headaches

Osteomyelit is

No side effects

32%

18%

14%

9%

11%

9%

8%

2%

2%

38 %

Table 5: Combinations of Slow-ActingRheumatic Drugs

Effective or Probably Effective

HCQ + parenteral gold

HCQ + MTX

HCQ + MTX + AZA

MTX + DPN

MTX + oral gold

parenteral gold + DPN

parenteral gold + AZA

parenteral gold + MTX

parenteral gold + SSZ

CSA + HCQ

No Data

HCQ + oral gold

HCQ + SSZ

SSZ + oral gold

AZA + HCQ

AZA + oral gold

Abbreviations: HCQ. hydroxvchloroqume : MTX, methotrexat e;ASA, asp inn; DPN,n-p enlclllarrune: SSZ. sulfasalaz ine; CSA, cy­closponnData from references 73. 89 -91 .102

2 or more years of disease duration, arc desig­nated "late patients."

RESULTS

The mean period of follow-up for the entirepopulation was 8 years (range, 3 to 17 years).Mean follow-up for the early patients was 8 years(range, 3 to 17 years) and for the late patientswas 9 years (range , 3 to 17 years). The mean ageand disease characteristics at initial presentationfor each group are given in Table 2.

DEPENDENT DISEASEVARIABLES

INDEPENDENT DISEASEVARIABLES

Acute Phase Reactants

Active Joint Count

~-------~

Grip Strength

HAQ Score

FunctIonalCZlpaclt)'

RadiographicDamage

Fig 7: Classification ofdisease variables. Pro­posed relationship of in­dependent disease vari­ables (primary diseaseeffects) to dependent dis­ease variables (secondarydisease effects. the con­sequences of active dis­ease) suggesting a thera­peutic goal. HAQ. Healthassessment question­naire .

EARLY, AGGRESSIVE THERAPY FOR RA

Table 6: Disease Activity

Inactive Subacute

Disease Marked Response Partial

Activity or Remission Score Response Score

Pain None 0 Interm ittent

EMS (min) <15 0 15-30

ST [omts 0-2 0 3 -5

WSR (mm/h) or < 30 0 30-45

CRP (mg/dL) < 2 0 2.0-2 6Total 0 4

35

Active

Poor

Response Score

Constant 2

> 30 2> 5 2

> 4 5 2>2 .6

8

Abbreviations : EMS, duration of early morning stiffness ; ST JOints, total count of swollen and/or tender JO ints, (a JO int that IS swo llen

and/or tend er IS given a v alue of 1); WSR, Westergren sedimentation r ate; CRP, C-reactive proteinNOTE. Disease activity index has b een adapted from a drug response Index conceived and tested by Scott e t al.48 4 9 One numencal

value IS ass igned to each efficacy measure . Gnp strength was not included because of d iurnal vanauon and the inh erent problems ofinterpretation because of s imultaneous median neuropathy in some patients and fi xed d eformities and d egenerative changes at the

carpal/metacarpal [omt of th e thumb In others .

Data from Wilke and Clough ."

MedicationsAt presentation, 34 patients were receiving 42

medications, a mean of 1.2 drugs per patient.Thereafter, the mean medication per patientranged from 2.6 to 3.9, with a mean during theentire time of follow-up of 3.0 drugs per patient.At 10 years the mean number of drugs was 3.9.

Drugs given and the frequency of their use aredetailed in Table 3. The combination of MTX(mean, 9.1 mg/wk) with HCQ (200 mg/d) withor without aspirin or another NSAID, prednisone(range,S to 10 mg/d), or parenteral gold was pre­scribed for 24 of 34 (70%) patients.

Changes ill Laboratory ParametersThe mean WSR decreased from 48.5 mm/h

(range, 2 to 139 mrn/h) to 25.6 mm/h (range, 3

Abbreviations: WSR, Westergren sedirn entauon rate; RF,rh eu­rnato id factor •• Includes worsen ing function al class and/or change i n employ­

ment capacity .t Includes rh eumatoid nodul es, i nflammatory eye disease, s icca

comp lex, vasculit is, and pleural or pulmonary Involvem entData from Wilke and Clough 72

Table 7: Prognostic Factors

Factor

Deteriorating function capacity '

Susta ined (;;,:6 mol e levated WSR

RF uter z 1:640 latex

Extraarncular diseaset

Rad iologic joint damage

Total

Score

1

1

1

115

to 114 mrn/h) at I year for the entire populationof patients. The mean WSR was maintained be­low 30 mm/h for both the early and late patients(Fig 1). Hemoglobin concentration improvedfrom 12.7 g/dl, to 13.5 g/dl, after 1 year of treat­ment in the early patients. Only minimal changefrom 13.1 g/dl, to 13.3 g/dl, was noted in the.late patients. Hemoglobin values remained stablein both groups after I year (Fig 2).

Joint COl/lit

The number of tender/swollen joints decreasedfrom a mean of 17 to 5 joints after I year oftreatment in early patients. Late patients alsoshowed marked improvement, with a decreasefrom 21 to 3 active joints after 1 year of therapy.However, the mean number of active joints forthe entire period of follow-up after I year was3.45 joints in the early patients and 8.35 jointsin the late patients (Fig 3).

Grip Strength

Grip strength improved to a greater degree inthe early patients. At presentation, the mean gripstrength was 89 mm Hg, which improved to lSImm Hg after I year. This measure of functioncontinued to improve over time in the early pa­tients, with a mean of 193 mm Hg for the rest ofthe observation period. The mean grip strengthat initiation was 123 mm Hg, and 185 mm Hgat I year, with a mean of 143 mm Hg thereafterin the late patients (Fig 4).

36 WILKE. SWEENEY. AND CALABRESE

Other combinationsor CSAor Biologicalsor Apheresisor Tidal Lavage

1M Gold or DPNor MIX or AZA ±

Consider: Consider: Consider:Increase dose ofprevious drugs + +

Oral Gold or SSZor MTX ± ±

AI Level 1 AI Level 1 or 2 +

HCQ + + +NSAID + ± (analgesic?) ± (analgesic?)OT/PT/Pt. Ed. + + +

Mild (0-4) Moderate (5-7) Severe (8-13) Reserved

Fig 8: Disease severity classification. The initial level of therapy is based on the sum of the diseaseactivity index (Table 6) and the prognostic factor score (Table 7). Subsequent therapy decisions dependonly on the disease activity index. Therapies enclosed in the "consider" block may be used but are notmandatory. This allows individual flexibility while maintaining the spirit of the paradigm. The "reserved"step should not be used as initial therapy and is used only if patients step 3 fails ("severe" disease).Acute intervention (AI) level 1: joint aspiration. corticosteroid joint injection. intramuscular administrationof corticosteroids and/or corticotropin. and oral corticosteroid (0.1 mg/kg prednisone equivalent). AI level2: "induction therapies" with intramuscular or joint injection of chemotherapeutic agents. intravenouschemotherapeutic agents such as nitrogen mustard. and intravenous high-dose " pulsed" corticosteroids.HCn. hydroxychloroquine; NSAlDs. nonsteroidal antiinflammatory drugs; QT. occupational therapy; PT.physical therapy; Pt. Ed.• patient education; SSZ. sulfasalazine; MTX. methotrexate; 1M gold. intramus­cular or other parenteral gold; DPN. D·penicillamine; AZA. azathioprine; CSA. cyclosporine A. (Reprintedwith permlsslon.P]

Functional Capacity Class

The functional class improved from a meanvalue of 1.9 to 1.4 in the early patients and from2.25 to 1.5 in the late patients after I year oftreatment. The mean functional class after I yearwas 1.34 for the early patients and 2.05 for thelate patients. Eight (24%) patients were judgedfunctional class 1 and 1 (3%) functional class 4at initiation. After 1 year, 19 (56%) were func­tional class 1 and none were functional class 4.This I-year pattern was maintained throughoutthe rest of the observation period (Figs 5 and 6).A confusing finding. the reversal of the 10- and> 1O-yearlate patients is attributable to inconsis-

tent data points that occur in retrospective seriesand to the relatively small numbers of patientsin this series.

Medication Side E.DeclsDyspepsia was the most common ad verse

effect, noted in 11 (32%) patients. In 3 (9%)patients, peptic ulcer disease was confirmed byeith er endoscopy or upper gastrointestinal ra­diography. MTX was discontinued in 3 (9%)patients because of rash, dyspepsia, or alopecia.MTX therapy was interrupted temporarily in 3(9%) oth er patients because of oral ulcerations.Rash resulted in the discontinuation ofHCQ in1 (3%) patient (Table 4).

EARLY, AGGRESSIVE THERAPY FOR RA

Table 8: Other Factors That InfluenceTreatment Decisions

Drug allergy or intolerance

Age

Patient expectat ions

Coexisting disease

Peptic ulcer disease

Diabetes mel litus

Malignancy

Macular degeneration

Active infection

Impa ired renal function

Liver disease

Drug interact ion

Anticoagulants

Anuconvulsants

Alcohol

Allopurinol

Antibiotics

Additron

Noncompliance

Drug failure and need for surgery

Data from Wil ke and Clough."

DISCUSSION

Our data show that moderately aggressivecombination therapy given early in the course ofRA and then continued may control the diseaseprocess and improve and maintain function asmeasured by grip strength and functional class.In contrast, patients treated later in the course ofdisease experienced control of disease activity ,measured as WSR and active joint count, butshowed only limited functional improvement,presumably because of prior joint damage. Ourdata also suggest that after a drug is initiated, itis either continued or (due to side effects or lackofefficacy)replaced, but generally not discontin­ued without substitution. Patients were receivinga mean of2.8 arthritis medications at 1 year and3.9 medications at 10 years. The data also suggestthat gradual weaning to a single agent after theapparent arrest ofdisease progression may be dif­ficult to achieve. An impressive series of studiesby Wolfe et al6 suggests that despite treatment,functional status measured by grip strength andthe HAQ deteriorate over time. In our small , ret­rospective series, when therapy is begun in earlydisease, grip strength improves and is maintainedover time. If therapy is started in patients withmore than 2 years' disease duration, function

37

measured as grip strength does not improve ordeteriorate. Guillemin et al88 have shown thatfunctional disability in early disease depends pri­marily on the biological activity of the disease,which transl ates into number of active joints andWSR . These variables , which are signs ofinflam­mation, can be directly influenced by therapy.We might conveniently divide the measures ofrheumatoid disease into independent (primarydisease effects) and dependent (secondary diseaseeffects, the consequences of active disease) vari­ables (Fig 7). The independent variables are theacute-phase reactants and the number ofaffectedjoints. The dependent variables include morningstiffness, fatigue, fragmented sleep, grip strength,progression of erosions, and HAQ scores. Controlof the independent variables early in disease con­trols the dependent variables. In later disease,disease duration, Larson score, and extraarticularlesions most influence disability." These featuresof established disease are at best difficult to con­trol or reverse. This conclusion is supported bythe 25-year prospective data ofReillyet al,"whichindicate that a favorable long-term prognosis wasassociated with a lower WSR, higher hemoglobin,and ajoint score of 4 or less at 1 year. The "grad­uated-step" paradigm is designed to control theindependent variables ofdisease activity early andmaintain that control.

Although we believe this report supports theuse of early, aggressive therapy in RA, the evi­dence is not yet conclusive. First, the role of pa­tient selection bias confounds some of our con­clusions. Most patients in this study populationwere responders who returned, over many yearsin some instances, because they perceived thattreatment was successful and had not experiencedserious or limiting adverse reactions from ther­apy. To provide some control, we limited oursample to consecutive patients. Still, the bias fa­vors response. In addition, this series is retro­spective and cannot provide complete informa­tion about the magnitude of toxicity associatedwith early aggressive therapy. Currently, a pro­spective trial using the formal paradigm is underway and will provide that information. Despiteits shortcomings, this report documents that asubset of patients with moderate to severe RAtolerate an early, aggressive approach and do notappear to lose function over 5 to 10 years of fol­low-up.

38

Use of the graduated-step strategy requiressome familiarity with the literature of combina­tion therapy. The subject has been reviewed else­where.73.89-91 A brief overview of combinationtherapy is given in Table 5. In general, combi­nations that include the frequent use ofalkylatingagents should be avoided because ofpotential fu­ture oncogenesis with these drugs." The com­binations that in our experience showed the mostpromise are MTX and HCQ; MTX, azathio­prine, and HCQ; and MTX and oral gold. Fromthe literature, HCQ and parenteral gold93.94SSZand DPN9s;SSZ and parenteral gold'"; MTX andSSZ97; MTX and DPN98; MTX and parenteralgold'"; and MTX and oral gold78 have been usedwith some success. Sufficient studies are availableto discourage the use of antimalarials andDPN.1oo.IOI An in vitro system using mitogen­stimulated human peripheral blood mononuclearcells shows antagonism with the combination ofchloroquine and DPN, confirming the previoustwo clinical studies.l'" In addition, this systemshowed synergy when chloroquine and cyclo­sporine were combined. Clinical correlation islacking and should be sought.

Although it is difficult to show the effectivenessofcombinations compared with single drugs, theproblem may attributable in part to study de­sign.I03 When the outcome of our patient pop­ulation is compared with long-term prospectivedescriptions ofmonotherapy from the perspectiveof the number of affected, active joints and thelevel ofacute-phase reactants, our patients appearto have faired better.I04.lo6

CONCLUSION

The controlled, double-blind trial that allowsfew variables to test a new modality against pla­cebo still has a place in rheumatology, especiallyin the study of new biological agents. However,

WILKE. SWEENEY. AND CALABRESE

this scientific endeavor, conceived to answer ashort-term physiological question, is not a tem­plate for clinical practice. Long-term (5 to 10years) careful, prospective comparative clinicalobservations pitting one philosophy or paradigmof treatment against another may be of equal orgreater importance. Each approach, with itsmyriad of variables, must be designed to provideconsistent, structured therapy but allow moderateindividual variation in treatment to "fit" mostpatients. These strategies must also be computerfriendly to allow for prospective and retrospectiveanalysis.

The causes of RA elude us. Specific, safe, ef­fective therapy awaits discovery and seems un­likely in the near future. Unfortunately, RA pa­tients urgently need treatment today. Relativelysafe and effective drugs do exist. We believe theyshould be applied early and wisely and that thereasonable goal of treatment is near remission,defined here as four or fewer active joints andnormal acute-phase reactants."

APPENDIX: "GRADUATED-STEP" PARADIGM

Immediately after the diagnosis of RA isestablished, diseaseactiv ityisdeterminedbysummingthe variables given in Table6. Disease severity iscomputedbyaddingthe prognostic factorscore(Table 7) to the disease acnvity score, Patientsarc thenentered into the appropriate level or therapy in the paradigmcorresponding to mild. moderate,or severe disease. At regularperiods (3 to 6 months), patients arc reevaluated. Only thedisease activityindex isdetermined. A scoreof0 to 3 suggestsgood response and inactivedisease. These patients should becontinued at their present treatment level, or thc treatmentlev el should be reduced. Patients with a poor response andactivedisease (scores of 6 to 8) deserve treatment escalation.Patientswith intermediateactiv ity(scores of 4 or 5) havesub­acute disease. The level of treatment (Fig 8) may be main­tained, or treatment may bc escalated depending on otherefficacy measuressuch as thc time from arising to the onsetofafternoon fatigue, changes ingripstrength, changes in globalassessment, or any changes in prognostic factorssuch as newonsetor worseningof extraarticular manifestations. Treatmentdecisions also are based on "subjective"factors(Table 8).

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