Ann Rheum Dis 1996;55:739-744

Effect of recombinant human erythropoietin onanaemia and disease activity in patients withrheumatoid arthritis and anaemia of chronicdisease: a randomised placebo controlled doubleblind 52 weeks clinical trial

H RM Peeters, M Jongen-Lavrencic, G Vreugdenhil, A J G Swaak

AbstractObjective-To study whether recombinanthuman erythropoietin (r-hu-Epo) im-proves anaemia and reduces diseaseactivity in patients with rheumatoidarthritis and anaemia of chronic disease(ACD).Methods-A 52 week placebo controlledrandomised double blind trial withr-hu-Epo was performed in 70 patientswith active rheumatoid arthritis andACD. Thirty four patients were treatedwith 240 U kg-l r-hu-Epo subcutaneously,initially three doses weekly, while 36patients received placebo.Results-A significant increase ofhaemo-globin from a median of 112 to 135 g litre-'occurred in the Epo group within sixweeks and could be sustained withreduced doses (median 240 U kg-' onceweekly). Sustained benefit compared toplacebo was also apparent by six weeks fordisease activity, as indicated by the Paulus20% response rate. Of patients in the Epogroup, 32% eventually showed a Paulus20% response, compared to 8% of the pla-cebo group (P = 0.016). Significant differ-ences in favour ofthe Epo group were alsoobserved in the secondary disease activitymeasures Ritchie index, number ofswollen joints, pain score, ESR, andpatients' global assessment of diseaseactivity. C reactive protein concentrationsdid not change significantly.Conclusions-Treatment ofACD in rheu-matoid arthritis with r-hu-Epo is effectivein restoring normal haemoglobin levelsand also exerts a beneficial effect ondisease activity.

(Ann Rheum Dis 1996;55:739-744)

Anaemia often occurs in patients with rheuma-toid arthritis.' Anaemia of chronic disease(ACD) is the most important cause of anaemiain this condition.2' It is characterised by lowserum iron concentrations despite normal orincreased body iron stores.5-7 The pathogenesisof ACD in rheumatoid arthritis is multifacto-rial. Iron retention by the mononuclearphagocyte system (MPS) and impaired irontransport to the erythroblast have beendescribed.8 Suppression of erythropoiesis byinflammatory cytokines, such as interleukin-1

(IL-1), tumour necrosis factor a (TNF-a), andy interferon, has been shown in vitro.'-12 Inaddition, evidence has been provided for arelatively impaired production of erythropoi-etin in response to anaemia. Serumerythropoietin concentrations in ACD arelower than in other anaemic conditions'3-'" andIL-1 and TNF-a have been shown to suppresshypoxia related erythropoietin production byHepG2 and Hep3b cell line in vitro." 1

In a number of studies treatment with r-hu-Epo resulted in improvement ofACD in rheu-matoid arthritis patients.1825 However, higherdoses of human recombinant erythropoietin(r-hu-Epo) were required to maintain the hae-matological response than in renal disease.26 Inone open pilot study with r-hu-Epo, a decreasein both pain score and swollen and painful jointcount was observed, indicating possible benefi-cial effects on disease activity as well.27 In thefive other open and two controlled clinicalstudies only slight, or no, effects on diseaseactivity were observed, although an improve-ment in general wellbeing was reported in sev-eral instances.2'-24 These studies were of shortduration (2-24 weeks) and involved only a lim-ited number of patients (2-20). We conducteda 52 week placebo controlled randomised dou-ble blind trial with r-hu-Epo as adjuvant treat-ment in patients with active rheumatoid arthri-tis and ACD to investigate the effects of longterm treatment with r-hu-Epo on haematologi-cal indices as well as on clinical and serologicalmeasures of disease activity.

MethodsPATIENTSPatients aged 18 years or older were eligible ifthey met the revised American College ofRheumatology (ACR) criteria for rheumatoidarthritis28 and were classified in functional classI, II, or III.29 Active disease was required,defined as a minimum of nine swollen jointsand a Ritchie score of 9. Treatment with thefollowing disease modifying antirheumaticdrugs was allowed, provided the dose wasstable for three months before the start of thetrial: oral gold, hydroxychloroquine,D-penicillamine, sulphasalazine, and meth-otrexate. Parenteral gold salts were allowed ifthe dose was stable for at least six months.Patients receiving azathioprine, cyclophospha-mide, or cyclosporin were excluded. Treatmentwith corticosteroids, equivalent to an average

Department ofRheumatology, DrDaniel Den HoedClinic, Rotterdam, TheNetherlandsH RM PeetersM Jongen-LavrencicA J G Swaak

Department ofInternal Medicine, StJoseph Hospital,Veldhoven, TheNetherlandsG Vreugdenhil

Correspondence to:A J G Swaak, Departnent ofRheumatology, Dr DanielDen Hoed Clinic, PO Box5201, 3008 AE Rotterdam,The Netherlands.

Accepted for publication6June 1996

739

on March 31, 2020 by guest. P

rotected by copyright.http://ard.bm

j.com/

Ann R

heum D

is: first published as 10.1136/ard.55.10.739 on 1 October 1996. D

ownloaded from

Peeters, Jongen-Lavrencic, Vreugdenhil, Swaak

maximum daily dosage of 10 mg prednisone,was allowed if dosage had not been changedthe last month before entry to the trial.Anaemia of chronic disease for a minimum

duration of three months had to be present inall patients. Haemoglobin concentrationsbelow 1 17 g litre' (for both males and females)were required without signs ofvitamin and irondeficiency, blood loss, haemolysis, or otherhaematological disorder. Body iron stores wereassessed preferably by iron staining of bonemarrow smears. A semiquantitative scale wasused: 0 = no stainable iron; 0 -1 = minimal tovery small amount; 2 = slight small and patchycontent; 3 or more = increased stainable iron.Patients with a stainable iron content of 2 ormore were considered not to be irondeficient.30 When patients did not agree withbone marrow aspiration, serum ferritin levelsshould be above 50 mg litre' and serum trans-ferrin levels below 50 mmol litre-Y.3

Further exclusion criteria were: history ofthromboembolic events or epileptic fits,uncontrolled hypertension, and clinicallyrelevant impairment of kidney or liverfunction.

All patients gave their informed consent forthe trial, which was approved by theinstitutional ethics committee.

TREATMENTThe study was a 52 week randomised doubleblinded placebo controlled parallel clinicalstudy. Disease activity measures were assessedby the first observer (RP), who remainedblinded for treatment schedules and laboratoryresults. Randomisation of the patients, controlof adverse events and laboratory results, andadministration of the study medication wasdone by a second independent observer (MJ).The treatment group received r-hu-Epo(Recormon, Boehringer Mannheim) at a doseof 240 U kg-l subcutaneously (sc), initiallythree times a week. The aim of the treatmentwas a normal Hb level (female > 117 ; male >136 g litre-') and the dose was adjusted accord-ingly by changing the frequency of administra-tion. The placebo group received a visuallysimilar placebo. After randomisation, patientsin the placebo group were matched withpatients in the treatment group and followedtheir treatment regime with respect tofrequency of administration. Oral iron supple-mentation was given if serum ferritin fell below50 mg litre', and was discontinued upon ironrepletion. Adjustment of the dose of diseasemodifying antirheumatic drugs or prednisone,as well as local measures, particularlyintra-articular corticosteroid injections, wasnot allowed during the study.

ASSESSMENTSPatients were evaluated every two weeks forthree months and monthly afterwards untilweek 52.

Primary assessmentsEffects of treatment of anaemia were evaluatedusing haemoglobin (Hb). As primary diseaseactivity measure the clinical response in

individual patients was analysed using a modi-fied Paulus index.3' According to this compos-ite index, patients are considered to show a sig-nificant clinical response if at least four out ofsix variables [Ritchie index, number of swollenjoints, duration of morning stiffness, bothpatients' and observers' assessment of diseaseactivity, and erythrocyte sedimentation rate(ESR)] improve. As our secondary diseaseactivity measures did not include an observer'sglobal assessment of disease activity, the Paulusresponse was evaluated using the other fivevariables. Patients had to show simultaneousimprovement in four of these five variables inorder to fulfil the criteria for a 20% Paulusresponse. Improvement was defined by a 20%decrease in the continuous variables and a 40%decrease in the patients global assessment ofdisease activity (1-10 scale) (or 20% in case ofbaseline value below 4.0).

Secondary assessmentsAs secondary evaluation criteria a core set ofsingle measures of disease activity endorsed bythe ACR3 was used. Besides the Ritchie index,the number of swollen joints, patients' globalassessment, and Westergren ESR, this includesa pain score (1-10) and C reactive protein con-centrations. Serum ferritin was assessed onevery visit as the primary marker for iron statusand as a guideline for iron suppletion.

STATISTICAL PROCEDURESData from the patient files were transferred tosoftware packages (SPSS 5.01 and Egret) forstatistical analysis. All variables were checkedfor their suitability for standard statisticalanalysis. In case ofnon-parametric distributiona transformation towards normality was tried.At baseline, groups were compared using Stu-dent's t test, the Mann-Whitney test, and the x'test where appropriate. The repeated measure-ments of continuous outcome variables in thetwo groups were analysed by analysis ofvariance for repeated measurements (MANovA)using weeks 0 (baseline), 6, 12, 24,36, and 52as time points. The overall effect of treatmentwas tested for significance using the F test onthe interaction between the two patient groupsand the repeated measurements factor time. Incase of significance, differences between thegroups at individual time points wereinvestigated with Bonferroni correction formultiple testing. Overall treatment effects onthe Paulus 20% response rate were evaluatedusing logistic regression with random effects.Groups were compared at individual points offollow up using Fischer's exact tests.

Analysis was done on the basis of intentionto treat as well as on completers. Both methodsled to the same results except for slightdifferences in the Paulus 20% response rate.Results of the intention to treat analysis areshown and end point differences in Paulusresponse described separately.

ResultsPATIENTSSeventy patients were enrolled in the study, 34receiving r-hu-Epo (Epo group) and 36 receiv-

740

on March 31, 2020 by guest. P

rotected by copyright.http://ard.bm

j.com/

Ann R

heum D

is: first published as 10.1136/ard.55.10.739 on 1 October 1996. D

ownloaded from

Recombinant human erythropoietin in rheumatoid arthritis

ing placebo (placebo group). No significantdifferences in demographic and diseasecharacteristics between the treatment groupswere found (table 1). Baseline haemoglobinconcentrations were the same in the twogroups (table 1). In 51 patients the diagnosis ofanaemia of chronic disease was made by ironstaining of bone marrow smears, while in theremaining 19 patients iron deficiency was ruledout using serum ferritin and transferrin levels.Fifty eight patients completed the study. Fivepatients withdrew from the Epo group (after a

median period of 24 weeks), in three cases

because of high disease activity and in twobecause of poor compliance. Seven patientswithdrew from the placebo group (after a

median of 16 weeks), five for reasons of highdisease activity and two because of poorcompliance. Injections of r-hu-Epo were toler-ated well. No local reactions or other seriousside effects were observed. None of thepatients, including those patients already beingtreated with antihypertensive drugs before thestart of the trial, showed a significant rise inblood pressure. No thromboembolic complica-tions were observed.

PRIMARY ASSESSMENTSThe Epo group showed significantly higherhaemoglobin concentrations during treatment(figure, panel A). A statistically significantincrease in Hb occurred within six weeks andcould be sustained during entire follow upperiod. At the end of follow up the Epo groupshowed a median Hb of 134 (range 1 10 to 158g litre-'), compared to 112 (86-128 g litre-') inthe placebo group. After a median of six weeks(range 2 to 24) the dose of r-hu-Epo could bedecreased in 90% of responders to an eventualmedian of one injection (range 0.5 to 2) of 240U kg-' weekly at the end of follow up. Of 34patients in the Epo group, 32 (94%) achieved a

normal Hb during follow up, compared toeight out of 36 (22%) of placebo treatedpatients. The first of the two non-respondersinitially showed a rise in Hb from 98 g litre'1 atbaseline to 1 18 g litre-' at week 8, butconsequently fell back to 98 g litre-' again with-out responding to an increase of the weeklydosage to four times 240 U kg-'. The other

Table 1 Baseline characteristics of the two treatmentgroups. Data are presented as median (5th to 95th centile)or number (percentage).

non-responder showed no response of Hb atall, despite increasing dosages of rh-h-Epo. Inboth patients no other causes of anaemiabesides ACD were diagnosed. The first patientused sulphasalazine, while the second patientwas treated with hydroxychloroquine.A Paulus 20% response was observed

significantly more often in patients of the Epogroup, compared to patients of the placebogroup (figure, panel B). This effect occurredwithin six weeks of treatment and could besustained throughout follow up. Of all patientstreated with rhu-Epo, 32% achieved a Paulus20% response at the end of their follow up

compared to 8% in placebo group. For thosepatients completing 52 weeks these percent-ages were respectively 38% and 8%.

SECONDARY ASSESSMENTSCompared to the placebo group, significantimprovements were observed in Ritchie articu-lar index, the number of swollen joints,patients' global assessment of disease activity,and pain score in the Epo group (table 2). Thechanges within time in these variables were

similar to those in the primary outcome meas-

ures, with sustained improvement in the Epogroup reached within six weeks (Ritchie indexand swollen joint count) or 12 weeks (patientassessment and pain). ESR showed a rapiddecline in the Epo group, reaching its lowestlevel during weeks 6-12, and then increasedagain but remained significantly lower than inthe placebo group (table 2). C reactive proteinconcentrations levels did not change signifi-cantly in either of the treatment groups (table2).An overall difference in ferritin concentra-

tions between the two treatment groups was

observed (table 2). Ferritin showed a fast andsteep decline in the Epo group during the firstphase of the trial. Iron supplementation provednecessary in 88% of Epo treated patients, pre-dominantly in the first period of r-hu-Epotreatment (after a median of four weeks). In77% of these patients it was later possibleto discontinue iron supplementation. The

duration of treatment with iron supplementswas a median of eight weeks. During the laterstage of the trial, serum ferritin concentrationsremained significantly lower in the Epo group

compared to baseline or to the placebo group.

VariableNo of patientsFemale (%)Age (years)Haemoglobin (g 11):

Disease duration (yePositive rheumatoidErosive joint damageNo of patients using

(%)

No of patients usingmethotrexate

No of patients using(%)

Epo3427 (79%)56 (23/79)

:All 111

(93-116)Female 109

(93-116)Male 114

(107-116)ars) 3.5 (0.3/21)factor (%) 18 (53%)e (%) 29 (85%);DMARD 23 (68%)

prednisone

3 (9%)

3 (9%)

DiscussionPlacebo Our results suggest that in patients with active

36

31 (86%) rheumatoid arthritis and well classified ACD,58 (39/75) r-hu-Epo is effective in restoring normal Hb1(-106) concentrations as well as reducing rheumatic113 disease activity. Sustained benefit compared to(101-106) placebo was apparent by six weeks for both Hb

(113-116) concentrations and the primary measures of4.7 (0.3/32) disease activity. Normalisation of Hb was21 (58%) achieved in 94% of treated patients. At the end28 (78%) of follow up 32% of the patients in the Epo

group fulfilled the criteria for a Paulus 20%4 (11%) response, compared to 8% of the placebo

6 (17%) treated patients. Significant differences infavour of the treatment group were alsoobserved in the secondary outcome measures:

Ritchie index, number of swollen joints, painEpo, erythropoietin; DMARD, disease modifyingantirheumatic drugs

741

on March 31, 2020 by guest. P

rotected by copyright.http://ard.bm

j.com/

Ann R

heum D

is: first published as 10.1136/ard.55.10.739 on 1 October 1996. D

ownloaded from

Peeters,Jongen-Lavrencic, Vreugdenhil, Swaak

Overall interaction: P < 0.001en

Erythropoietin c,cx~~~~~~~~~~~~~~~~~C

/ * * * <1> 250l

160Placebo X3a-

0 6 12 24 36Time (weeks)

50

52 0 6 12 24 36Time (weeks)

Primary outcome measures. (A): median Hb (interquartile range) in the two treatment groups. (B): percentage ofpatientsfulfilling the criteria for a Paulus 20% response. Statistical analysis: P values for overall interaction between groups andtime calculated with analysis of variance for repeated measurements (uANoVA) for Hb, and logistic regression with randomeffects for Paulus 20% response. Between group comparisons at individual time points: *P < 0.001, fP < 0. 01.

score, ESR, and patients' global assessment ofdisease activity. C reactive protein concentra-tions did not change significantly. Normal lev-els of Hb could be sustained with reduced dos-age of r-hu-Epo in most patients, andconcomitant iron suppletion proved only tem-porarily necessary during the induction of thehaematological response.The observed response of Hb during

r-hu-Epo treatment was comparable withprevious clinical studies with r-hu-Epo inrheumatoid arthritis and ACD.'022 23-25 in the

present study, dosage of r-hu-Epo could bereduced in responders, although the mainte-nance dosage of r-hu-Epo varied considerablybetween patients. 2 23 24 Although an initiallyhigher dosage of r-hu-Epo was used in thepresent study than in previous clinical trials,the eventual maintenance dosage did not differsignificantly.22-24A modified Paulus index was used as a

primary measure of disease activity. Theobserved frequency of a Paulus 20% responsein 8% of all controls is comparable with the

observed responses in 3-12% of controlpatients in previous trials.'1 Significant bias dueto the modification of the Paulus criteriumseems unlikely. The occurrence of a Paulus20% response in 32% of all r-hu-Epo treatedpatients is comparable with results ofcontrolled studies with several of the now

widely used disease modifying antirheumaticdrugs.31 The fall of ESR in the Epo treatedpatients may reflect correction of anaemia.However, one cannot exclude the possibilitythat the changes in ESR are partially related tochanges in disease activity as well. In the laterstage of the trial a rise in ESR was observedwithout significant concomitant changes in Hblevels, suggesting the possible role of other fac-tors involved in the ESR. The other secondarydisease activity measures used in the Paulusindex are not clearly influenced by correctionof anaemia and all show significantimprovement in the Epo treated patients.Therefore the differences in 20% Paulusresponse between the two treatment groupsshould be considered to reflect the

Table 2 Course of secondary disease activity measures and serum ferritin

Follow upVariable Group Overall

Baseline Week 6 Week 12 Week 24 Week 36 Week 52

Ritchie articular index Epo 26 (10 to 43) 19 (4 to 37) 17 (4 to 37) 15 (2 to 35) 14 (2 to 37) 15 (3 to 32) P = 0.002(0-81) Placebo 31 (17 to 44) 30 (10 to 43) 29 (10 to 54) 28 (9 to 48) 26 (6 to 48) 26 (3 to 48)

95% CI to4 2to 51 1 to4t 1 to4* 1 to4*Swollen joints Epo 28 (13 to 34) 18 (7 to 31) 19 (5 to 33) 17 (5 to 32) 17 (5 to 35) 19 (5 to 34) P = 0.003(number 0-52) Placebo 29 (17 to 37) 28 (17 to 37) 26 (15 to 40) 26 (13 to 38) 27 (14 to 39) 27 (15 to 39)

95% CI I to 4t I to 3t I to 4t I to 3t I to 3tPatients' global Epo 4.4 (2.5 to 6.0) 3.8 (1.0 to 6.0) 3.5 (1.5 to 3.7 (1.5 to 6.0) 4.0 (1.5 to 6.0) 3.5 (1.0 to 6.0) P = 0.027

assessment 5.5)(VAS score 0-10) Placebo 4.3 (2.0 to 7.0) 4.2 (1.0 to 7.5) 4.0 (1.0 to 4.5 (1.0 to 7.0) 4.7 (1.0 to 7.5) 4.5 (2.0 to 7.5)

7.0)95% CI -0.1 to 0.6 0.0 to 0.6 0.1 to 0.7* 0.0 to 0.6 0.2 to 0.8*

Pain Epo 5.0 (2.0 to 8.0) 4.5 (1.0 to 7.5) 4.2 (1.0 to 4.0 (0.5 to 9.0) 4.0 (1.0 to 8.5) 3.5 (2.0 to 7.0) P 0.0027.0)

(VAS score 0-10) Placebo 5.0 (2.5 to 8.0) 5.1 (1.5 to 9.0) 5.2 (1.5 to 5.8 (2.0 to 9.8) 5.8 (2.0 to 9.8) 5.6 (2.0 to 9.8)9.5)

95% CI -0.1 to 0.7 0.1 to 0.9* 0.3 to 1.2t 0.3 to 1.2t 0.4 to 1.21ESR Epo 56 (25 to 110) 23 (6 to 102) 28 (9 to 94) 39 (14 to 107) 39 (11 to 97) 35 (9 to 97) P 0.035(mmh-1) Placebo 44(15tollO) 45(17tollO) 45(13tollO) 52(12tollO) 50(12tollO) 48(11tollO)

95% CI lOto 191 9to 19 2to 12t 4to 13t 5to 141CRP Epo 28 (2 to 101) 23 (2 to 91) 30 (2 to 115) 31 (2 to 123) 29 (2 to 144) 37 (3 to 113) P 0.122(mg l) Placebo 19 (2 to 66) 23 (2 to 84) 22 (2 to 91) 11 (2 to 93) 14 (2 to 96) 21 (2 to 94)

95%CI -4to8 -5to7 -12to 1 -8to4 -4to8Serumferritin Epo 93 (28 to 402) 29 (10 to 215) 52 (10to 221) 75 (13 to 133) 67 (13 to 227) 51 (14 to 213) P < 0.001(pgl-) Placebo 79 (25 to 241) 67 (22 to 230) 68 (21 to 148) 67 (23 to 191) 70 (57) 67 (24 to 181)

95% CI 25 to 551 9 to 39t -13 to 28 -3 to 28 4 to 35*

Data presented as median (5th to 95th centile). No significant differences between groups were found at baseline. CI, confidence interval. Statistics: Overall effectof treatment (P value on the interaction between groups and time) and between-group comparison at individual time points (95% CI and P values : *P < 0.05, tP< 0.01, ¶ P < 0.001) calculated with analysis of variance for repeated measurements (MANovA).

A

140 -

Ia) 120-

.o 100-

I

52

III~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

742

on March 31, 2020 by guest. P

rotected by copyright.http://ard.bm

j.com/

Ann R

heum D

is: first published as 10.1136/ard.55.10.739 on 1 October 1996. D

ownloaded from

Recombinant human erythropoietin in rheumatoid arthritis

improvement of disease activity in Epo treatedpatients. It is not clear why C reactive proteinconcentrations did not change despite theobserved clinical response. However, therelation between disease activity and the acutephase response is not fully understood yet. Asubset of rheumatoid arthritis patients hasbeen described in whom disease progressesclinically without an increase in C reactive pro-tein and ESR." Non-steroidal antiinflamma-tory drugs fail to lower C reactive protein,although they reduce inflammatory activity.34Recently oral corticosteroids were reported todecrease rheumatoid disease activity and theprogression of joint destruction without effecton acute phase response."5 Independent devel-opment of erosions, clinical symptoms, and theacute phase response was observed, though theseparate control mechanisms have not yet beenidentified."5 One should consider thepossibility that r-hu-Epo may exert beneficialeffects on disease activity without decreasing Creactive protein levels. However, the mecha-nisms for this action still remain unclear.Comparison of the observed clinical effects

with previous trials with r-hu-Epo inrheumatoid arthritis is more difficult, since asimilar measure of disease activity was notused. Two studies were placebo controlleddouble blind studies,20"2 but comprised consid-erably fewer patients (17 and 20 respectively).Pincus and coworkers measured pain score anda health assessment questionnaire (HAQ) andfound no differences between r-hu-Epo treatedpatients and controls. Patients receivingdisease modifying antirheumatic drugs wereexcluded and r-hu-Epo was given intrave-nously (three times a week at 50-150 U kg-').20Murphy et al evaluated pain score, Ritchieindex, duration of morning stiffness, HAQscore, and C reactive protein and observed atrend towards improvement in pain score andC reactive protein but not the other variables.24Three of the open label studies examined

more than 10 patients. Swaak et al described astatistically significant reduction in number ofswollen joint, Ritchie index, pain score, andduration of morning stiffness in 10 patientstreated for nine weeks.27 Giidbj6rnson et alrequired patients to have active disease andobserved a reduction of the Ritchie index inseven of 10 patients within six weeks, althoughthe mean Ritchie index of the entire group didnot improve significantly.22 Functional capac-ity, duration of morning stiffness, and jointpain did not change. Pettersson et al evaluatedjoint pain, morning stiffness and a joint scorein 11 patients without finding any effect.2'However, an improvement in general wellbeingwas described by most workers even in theabsence of clinical improvement.2 -24 As in thepresent study, a decrease of ESR, but not of Creactive protein was observed in most studies.22 2324 Thus indications for a possible effect ofr-hu-Epo on disease activity were found in pre-vious studies. A similar improvement of diseaseactivity-as observed in the present study-hasnot been described before. Considerabledifferences in number and selection ofpatients, dosage of r-hu-Epo, duration of treat-

ment, and concomitant iron supplementation,as well as disease activity measures used, couldperhaps account for these differences inobserved clinical responses to r-hu-Epo.

Several mechanisms can explain thebeneficial effects of r-hu-Epo. Treatment withr-hu-Epo increases iron turnover, which ismobilised from storage elsewhere in the bodyand transferred to the bone marrow to fulfil theenhanced requirements of stimulated erythro-poiesis.'6 Deposition of iron in synovial tissuewas found to be increased in rheumatoid

37 38arthritis. This has been associated with per-sistent joint inflammation in rheumatoidarthritis'9 since iron catalyses the generation oftoxic oxygen radicals,24 stimulates DNAsynthesis in synovial cells, and has an additiveeffect on the activity of human cytokines forproliferation of synovial cells.' Iron suppletionhas been associated with exacerbation of syno-vial inflammation in rheumatoid arthritispatients,4' whereas iron chelators caused arapid decrease in body iron storage and animprovement in clinical disease activity.'5 42 Inthe present study an equally rapid decrease inbody iron stores and rheumatic disease activitywas observed. Reduction of the iron availabilityin synovial tissue could account for theobserved improvement in disease activityduring r-hu-Epo treatment.

In addition to effects on iron deposition,modulating effects of r-hu-Epo on the immunesystem cannot be ruled out entirely.Erythropoietin has been found to regulate IgEproduction in vitro by T cell and monocytedependent mechanisms.4' In renal patientstreated with r-huEpo, an improvement in Tcell function has been described.44 To whatextent these observations are associated withthe beneficial clinical effects of r-hu-Epo inrheumatoid arthritis in the present studyremains to be established. A randomised studyof the effects of rhu-Epo and blood transfusionon both the immune system and clinicaldisease activity might be helpful in elucidatingthe way of action of r-hu-Epo.The clinical use of r-hu-Epo may be limited

by its expense. Furthermore, one can arguewhether ACD should be treated in rheumatoidarthritis patients, as it is usually mild.4 5However, ACD is a frequent manifestation inrheumatoid arthritis,' 4 and in our studytreatment of this typically mild anaemia withr-hu-Epo had a beneficial effect. Furthermore,no side effects were observed. This might resultin an important improvement of the quality oflife of rheumatoid arthritis patients, which isconsidered to be a major aim of treatment.Therefore further research on the effects ofr-hu-Epo on quality of life in relation to itscosts-as compared to standard regimens-isrequired to elucidate the value of r-hu-Epo inthe treatment of rheumatoid arthritis andACD. Other patient groups, like anaemicpatients undergoing surgery or anaemicpatients starting with slow acting second linedrugs, should be studied in this way as well.

In summary, our study is the firstrandomised placebo controlled long termstudy with r-huEpo in which effects on

743

on March 31, 2020 by guest. P

rotected by copyright.http://ard.bm

j.com/

Ann R

heum D

is: first published as 10.1136/ard.55.10.739 on 1 October 1996. D

ownloaded from

Peeters, Jongen-Lavrencic, Vreugdenhil, Swaak

anaemia as well as on disease activity werestudied extensively and adequately in a largenumber of patients with active rheumaticdisease and anaemia of chronic disease. Rapidnormalisation of Hb occurred in the majorityof patients. Parallel to the response of Hb, arapid and sustained improvement in diseaseactivity was observed. The results of this trialsuggest that r-hu-Epo might serve as a usefuladdition to the therapeutic armamentarium inrheumatoid arthritis patients with activedisease and ACD.

We would like to express our gratitude to Prof F C Breedveld(Department of Rheumatology, University Hospital Leiden,The Netherlands) for critically revising this manuscript, toBoehringer-Mannheim for providing r-hu-Epo (Recormon), toH M Markusse, A C M Romme, and J H LM van Groenendael(Department of Rheumatology, Daniel den Hoed Clinic,Rotterdam) for their help in recruiting the patients and to LBaggerman for his help in processing the laboratory data. Thisstudy was made possible by a grant from the Dutch Leagueagainst Rheumatism ("Het Nationaal Rheuma Fonds").

1 Mowat AG. Hematologic abnormalities in rheumatoidarthritis. Semin Arthitis Rheum 197 1;1:383-90.

2 Hansen NE. The anaemia of chronic disorders: a bag ofunsolved questions. ScandJ Haematol 1983;31:397-402.

3 Vreugdenhil G, Wognum AW, Van Eijk HG, Swaak AJ.Anaemia in rheumatoid arthritis: the role of iron, vitaminB12, and folic acid deficiency, and erythropoietin respon-siveness. Ann Rheum Dis 1990;49:93-8.

4 Peeters HRM, Jongen-Lavrencic M, Raja AN, Ramdin HS,Vreugdenhil G, Breedveld FC, et al. Course andcharacteristics of anaemia in patients with rheumatoidarthritis of recent onset. Ann Rheum Dis 1996;55:162-8.

5 Cartwright GE, Lee GR. The anaemia of chronic disorders.BrJ Haematol 1971;21:147-52.

6 Krantz SB. Pathogenesis and treatment of the anemia ofchronic disease. AmJ Med Sci 1994;307:353-9.

7 Smith RJ, Davis P, Thomson ABR, Wadsworth LD, FackreP. Serum ferritin levels in the anaemia of rheumatoidarthritis. J Rheumatol 1977;4:389-92.

8 Roester HP. Iron metabolism in inflammation and malig-nant disease. In: Jacobs A, Worwood M, eds. Iron inbiochemistry and medicine II. London: Academic Press,1980:605-40.

9 Maury CJP, Anderson LC, Teppo AM, Partanen S, JuvonenE. Mechanism of the anaemia in rheumatoid arthritis:demonstration of raised interleukin lbeta concentrationsin anaemic patients and of interleulin 1 mediatedsuppression of normal erythropoiesis and proliferation ofhuman erythroleukemia (HEL). Ann Rheum Dis 1988;47:972-87.

10 Roodman GD, Bird A, Hutzer D, Montgomery W. Tumornecrosis factor-alpha and haematopoietic progenitorsCFU-E and BFU-E and the haematopoietic cell linesK562, HL60 and HEL cells. Exp Hematol 1987;15:928-35.

11 Means RT, Krantz SB. Inhibition of human erythroidcolony-forming units by gamma interferon can becorrected by recombinant human erythropoietin [seecomments]. Blood 1991;78:2564-7.

12 Jongen-Lavrencic M, Peeters HRM, Wognum AW,Vreugdenhil G, Swaak AJG. Erythropoietin receptorexpression on bone marrow cells from rheumatoid arthri-tis patients with anaemia of chronic disease and controlpatients. Clin Rheumatol 1994;13:176.

13 Baer AN, Dessypries EN, Goldwasser E, Krantz SB.Blunted erythropoietin response to anaemia in rheumatoidarthritis. BrJ'Haematol 1987;66:559-64.

14 Hochberg MC, Arnold CM, Hogans BB, Spivak JL. Serumimmunoreactive erythropoietin in rheumatoid arthritis:impaired response to anemia. Arthritis Rheum 1988;31:1318-21.

15 Vreugdenhil G, Kontoghiorghes GJ, Van Eijk HG, SwaakAJG. Impaired erythropoietin responsivenes to the anemiain rheumatoid arthritis. A possible inverse relationshipwith iron stores and effects of the oral chelator1,2-dimethyl-3-hydroxypyrid-4-one. Clin Exp Rheumatol199 1;9:35-40.

16 Jelkman W, Pagel H, WolffM, Fandrey J. Monokines inhibiterythropoietin production in human hepatoma culturesand isolated perfused rat kidneys. Life Sci 1991;50:301-8.

17 Faquin WC, Schneider TJ, Goldberg MA. Effect of inflam-matory cytokines on hypoxia-induced erythropoietin pro-duction. Blood 1992;79:1987-94.

18 Means RT, Olsen NJ, Krantz ST, Dessypris EN, Graber SE,Stone WJ, et al. Treatment of the anemia of rheumatoidarthritis with recombinant erythropoietin:clinical and invivo studies. Arthritis Rheum 1989;32:638-42.

19 Takashina N, Kondo H, Kashiwazaki S. Suppressed serumerythropoietin response to anaemia and the efficacy ofrecombinant erythropoietin in the anaemia ofrheumatoidarthritis. J Rheumatol 1990;17:885-7.

20 Pincus T, Olsen NJ, Russel J, Wolfe F, Harris ER, BoccagnoJA, et al. Multicenter study of recombinant humanerythropoietin in correction of anemia in rheumatoidarthritis. Am _J Med 1990;89:161-8.

21 Salvarani C, Lasagni D, Casali B, Macchioni P, Boiardi L,Rossi F, et al. Recombinant human erythropoietin therapyin patients with rheumatoid arthritis with the anemia ofchronic disease. Jf Rheumatol 199 1;18: 1168-71.

22 Gudbjornsson B, Hallgren R, Wide L, Birgegard G.Response of anaemia in rheumatoid erthritis to treatmentwith subcutaneous recombinant human erythropoietin.Ann Rheum Dis 1992;51:747-52.

23 Pettersson T, Rosenl6f K, Friman C, Mickos A, TeppoA-M, Fyhrquist F. Succesful treatment of the anaemia ofrheumatoid arthritis with subcutaneously administeredrecombinant human erythropietin. Scand J Rheumatol1993;22: 188-93.

24 Murphy EA, Bell AL, Wojtulewski J, Brzeski M, Madhok R,Capell HA. Study of erythropoietin in treatment ofanaemia in patients with rheumatoid arthritis. BMJ 1994;309:1337-8.

25 Vreugdenhil G, Manger B, Nieuwenhuizen C, Feelders RA,Van Eijk HG, Swaak AJG. Iron stores and serum transfer-rin receptor levels during recombinant human erythropoi-etin treatment of anemia in rheumatoid arthritis. AnnHematol 1992;65:265-8.

26 Eschbach JW. Erythropoietin 1991 - an overview. Am J Kid-ney Dis 1991;18(suppl 1):3-9.

27 Swaak AJG, Nieuwenhuizen C, Vreugdenhil G. Recom-binant human erythropoietin (r-hu-EPO) treatment inpatients with rheumatoid arthritis and anaemia of chronicdisease (ACD). Clin Exp Rheumatol 1995;12:577.

28 Arnett FC, Edworthy SM, Bloch DA, McShane DJ, FriesJF, Cooper NS, et al. The American RheumatismAssociation 1987 revised criteria for the classification ofrheumatoid arthritis. Arthritis Rheum 1988;31:315-24.

29 Hochberg MC, Chang RW, Dwosh I, Lindsey S, Pincus T,Wolfe F. The Americam College of Rheumatology 1991revised criteria for the classification of global functionalstatus in rheumatoid arthritis. Arthritis Rheum 1992;35:498-502.

30 Lundin P, Persson E, Weinfeld A. Comparison of hemosi-derin estimation in bone marrow sections and bonemarrow smears. Acta Med Scand 1964;175:383-90.

31 Paulus HE, Egger MJ, Ward JR, Williams HJ. Cooperativesystemic studies of rheumatic diseases group. Analysis ofimprovement in individual rheumatoid arthritis patientstreated with disease-modifying antirheumatic drugs, basedon the findings in patients treated with placebo. ArthritisRheum 1990;33:477-84.

32 Felson DT, Anderson JJ, Boers M, Bombardier C, ChernoffM, Fried B, et al. The American College of Rheumatologypreliminary core set of disease activity measures for rheu-matoid arthritis clinical trials. Arthritis Rheum 1993;36:729-40.

33 McConkey B. Clinical conundrum. Br J Rheumatol1990;29:88.

34 Dixon JS, Bird HA, Sitton NG, Pickup ME, Wright V.C-reactive protein in the serial assessment of disease activ-ity in rheumatoid arthritis. ScandJfRheumatol 1984;13:39-44.

35 Kirwan JR. The Arthritis and Rheumatism CouncilLow-dose Glucorticoid Study Group. The effect of gluco-corticosteroids on joint destruction in rheumatoid arthri-tis. N EnglJ_7Med 1995;333:142-6.

36 Kooistra MP, van Es A, Struyvenberg A, Marx JJM. Ironmetabolism in patients with the anaemia of end-stage renaldisease during treatment with recombinant human eryth-ropoietin. BrJ Haematol 199 1;79:634-9.

37 Muirden KD, Senator GB. Iron in the synovial membrane inrheumatoid arthritis and other joint diseases. Ann RheumDis 1968;27:38-48.

38 Biemond P, Swaak AJG, Van Eijk HG, Koster JF.Intraarticular ferritin-bound iron in rheumatoid arthritis.Arthritis Rheum 1986;29:1187-93.

39 Blake DR, Gallagher PJ, Potter AR, Bell MJ, Bacon PA. Theeffect of synovial iron on the progression of rheumatoiddisease. Arthritis Rheum 1984;27:495-501.

40 Nishiya K. Stimulation ofhuman synovial cell DNA synthe-sis by iron.J Rheumatol 1994;21:1802-7.

41 Reddy PS, Lewis M. The adverse effects of intravenous irondextran in rheumatoid arthritis. Arthritis Rheum 1969;12:454-7.

42 Magaro M, Zoli A, Altomonte L, Mirone L, Corvino G,Storti S. Iron chelation in rheumatoid arthritis: clinicaland laboratory evaluation. Ann Rheum Dis 1990;49:268-9.

43 Kimata H, Yoshida A, Ishioka C, Mikawa H. Effect ofrecombinant human erythropoietin on human IgE pro-duction in vitro. Clin Exp Immunol 1991;83:483-7.

44 Singh AB, Singh M, Palekar S, Levy S, Nunn C, Mann RA.The effects of recombinant human erythropoietin on thecell mediated immune response of renal failure patients. JMed Clin Exp Theoret 1992;23:289-302.

744

on March 31, 2020 by guest. P

rotected by copyright.http://ard.bm

j.com/

Ann R

heum D

is: first published as 10.1136/ard.55.10.739 on 1 October 1996. D

ownloaded from