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Erythropoiesis-stimulating agents for anemia in rheumatoid arthritis

  1. Arturo J Martí-Carvajal1,*,
  2. Luis H Agreda-Pérez2,
  3. Ivan Solà3

Editorial Group: Cochrane Musculoskeletal Group

Published Online: 28 FEB 2013

DOI: 10.1002/14651858.CD000332.pub3


How to Cite

Martí-Carvajal AJ, Agreda-Pérez LH, Solà I. Erythropoiesis-stimulating agents for anemia in rheumatoid arthritis. Cochrane Database of Systematic Reviews 2013, Issue 2. Art. No.: CD000332. DOI: 10.1002/14651858.CD000332.pub3.

Author Information

  1. 1

    Iberoamerican Cochrane Network, Valencia, Venezuela

  2. 2

    Hospital "Dr. Adolfo Prince Lara", Medicina Interna, Pto. Cabello, Edo. Carabobo, Venezuela

  3. 3

    CIBER Epidemiología y Salud Pública (CIBERESP), Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Catalunya, Spain

*Arturo J Martí-Carvajal, Iberoamerican Cochrane Network, Valencia, Venezuela. arturo.marti.carvajal@gmail.com.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 28 FEB 2013

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Characteristics of included studies [ordered by study ID]

Methods1. Design: parallel-design (2 arms)

2. Country: Sweden (7 sites)

3. Intention-to-treat analysis: no

4. Follow-up period: 12 weeks

5. Unit of randomization: patient

6. Unit of analysis: patient


Participants1. Randomized: 46 (Quote "three active, one placebo") (page 68)
Erythropoietin (EPO) group: 36
Placebo group: 10

2. Patients receiving drug: 46
EPO group: 36 (78.2%)
Placebo group: 10 (21.7%)

3. Analyzed patients:
EPO group: 26 (72.2%)
Placebo group: 9 (90%)
Imbalance between groups: 17.8%

4. Age (years; mean±SD; range)
EPO group: 56.1±12.7; 25 to 76
Placebo group: 56.9±12.7; 29 to 79

5. Gender (female):
Overall: 85% (39/46)
EPO group: 80.5% (29/36)
Placebo group: 100% (10/10)

6. Inclusion criteria:

  • Clinical diagnosis of rheumatoid arthritis by American College of Rheumatology (ACR) criteria.
  • Independent of disease activity with stable disease.
  • The Disease-Modifying Anti-rheumatic Drugs (DMARDs) regimens unchanged during the treatment.
  • Hemoglobin concentrations below ≤ 100 g/L (women) and ≤ 110 g/L (men).
  • Hemoglobin concentrations during iron supplementations did not increase by more than 15 g/L.


7. Exclusion criteria:

  • Hemorrhage.
  • Hemolysis.
  • Folic acid deficiency.
  • Vitamin B12 deficiency.
  • Uncontrolled hypertension.
  • Kidney disease.
  • Liver disease.
  • High doses of corticosteroids (exceeding 10 mg of prednisone or equivalent).


Interventions
  1. Interventional group: recombinant human erythropoietin (rHuEPO; Express 10,000 U/ml, Cilag AB Sweden), 150 IU/ kg subcutaneous injected twice weekly. Duration: 12 weeks.
  2. Placebo: subcutaneous injection twice weekly for 12 weeks. Nature of placebo: not given.
  3. Co-intervention: oral iron supplementations at a median dose of 200 mg elemental iron per day.


OutcomesOutcomes were not defined explicitly as primary or secondary:

  1. An adequate response was defined as reaching an Hb≥ 120 g/L at least once after the study start (page 68).
  2. Elevation of energy level (page 70).
  3. Safety (page 71).


Notes1. Sample size calculation a priori: not reported.
2. Sponsor: Cilag AB Sweden.
3. Roll of sponsor: not specified.

4. Conflict of interest: not described.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: “Randomization was carried out in blocks of four patients (three active, one placebo) and allocation within each block was in random order” (page 68).

Insufficient information to consider 'low risk' or 'high risk'.

Comment: there is an imbalance in gender and duration of disease variables (page 69, table 1).

Allocation concealment (selection bias)Unclear riskInsufficient information to permit judgment of 'low risk' or 'high risk'.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskInsufficient information to permit judgment of 'low risk' or 'high risk'.

This trial was reported as double-blind.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information to permit judgment of 'low risk' or 'high risk'.

This trial was reported as double-blind.

Incomplete outcome data (attrition bias)
All outcomes
High risk1. Lost postrandomization: 24% (11/46).
EPO group: 38.4% (10/26).
Placebo group: 11.1% (1/9).

2. Imbalance between comparison groups: 27.3%

Quote: "(5 patients excluded due to entering the extension study, 5 drop-outs) patients receiving rHuEPO over 9 patients receiving placebo (one drop out)" (page 70)

3. Comment: potentially inappropriate application of simple imputation.

4. Comment: For continuous outcome data, plausible effects size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size and potentially inappropriate application of simple imputation.

Selective reporting (reporting bias)High riskQuote: "A significant rise in Hb was noted in 26 (5 patients excluded due to entering the extension study, 5 drop-outs) patients receiving rHuEPO over 9 patients receiving placebo (one drop-out) (Hb elevation from 95 g/L to 107 g/L vs 93 g/L to 97 g/L, P < 0.05), from week 10 onwards that lasted throughout the study. A significant elevation of red blood cells was noted already from 4 weeks onward (P = 0.02) and Hct levels at week 12 (P = 0.009)" (page 70)

Quote: "only 14.6% (N = 6) of the patients were considered responders according to the preset criteria of Hb level equaling or exceeding 120 g/l" (page 70).

Quote "A significant elevation of energy (NHP variable) was noted at the end of the study after week 12 (P = 0.004). Otherwise, HAQ scores, NHP scores, classification of functional class or joint score index scores did not differ significantly between the two groups". (page 70).

Comment: one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta-analysis.

Other biasHigh riskComments:

1. There is imbalance between comparison groups regarding gender, duration of disease (years) and medication for treating ARA variables (page 69).

2. There was a potential source of bias related to the specific study design used, with extreme baseline imbalance.


Methods1. Design: parallel design (2 arms)
2. Country: Netherlands

3. Multicenter study: unclear.
4. Intention-to-treat analysis: yes
5. Per protocol analysis: yes
6. Follow-up period: 52 weeks

7. Unit of randomization: patient

8.Unit of analysis: patient


Participants1. Randomized: 70
Erythropoietin (EPO) group: 34
Placebo group: 36

2. Age: years; median 5th to 95th centile
EPO group: 56; 23 to 79
Placebo group: 58; 39 to 75

3. Gender (female):

EPO group: 79% (27/34)
Placebo group: 86% (31/36)

4. Inclusion criteria:

  • Age 18 years or older.
  • Clinical diagnosis of rheumatoid arthritis by American College of Rheumatology (ACR) criteria (functional class I, II, III). Active disease defined as a minimum of nine swollen joints and a Richie score of 9.
  • Anemia of chronic disease for a minimum duration of three months.
  • Hemoglobin concentrations below 117 g/L (for both men and women), without signs of vitamin and iron deficiency, blood loss, hemolysis, or other hematological disorder.


5. Exclusion criteria:

  • Patient receiving azathioprine, cyclophosphamide or cyclosporine
  • Signs of vitamin deficiency
  • Signs of iron deficiency
  • Blood loss
  • Hemolysis
  • Hematological disorders
  • History of thromboembolic events
  • History of epileptic fits
  • Uncontrolled hypertension
  • Renal disease
  • Liver disease


Interventions1. Intervention group: recombinant human erythropoietin (rHuEPO ), 240 U per kg subcutaneous (sc) initially three times a week. Duration: 52 weeks.

2. Placebo: visually similar. Composition of placebo was not reported.

3. Co-intervention: oral iron supplementation.

Quote "Adjusment of the dose of disease modifying antirheumatic drugs or prednisone, as well as local measures, particularly intra-articular corticosteroids injections, was not allowed during the study (page 740)


Outcomes1. Primary:

  • Hemoglobin measurements
  • Primary disease activity measure assessed by modified Paulus index (See Appendix 9)


2. Secondary:

  • Ritchie index
  • The number of swollen joints
  • Patient's global assessment
  • Westergren Erythro Sedimentation Rate
  • Pain score (1 to 10)
  • C-reactive protein concentration


Notes1. Sample size calculation a priori: not reported.
2. Sponsor: Dutch League against Rheumatism (Het Nationaal Rheuma Fonds).
3. Sponsor: Boehringer Mannheim provided rHuEPO.
4. Conflict of interest: not reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote " randomisation of the patients...was done by a second independent observer" (page 740).

Insufficient information to permit judgment of 'low risk' or 'high risk'.

Allocation concealment (selection bias)Unclear riskQuote: 'Randomisation of the patients ... was done by a second independent observer.'

Insufficient information to permit judgment of 'low risk' or 'high risk'.

Blinding of participants and personnel (performance bias)
All outcomes
Low riskQuote: "The placebo group received a visually similar placebo. After randomisation, patients in the placebo group were matched with patients in the treatment group and followed their treatment regime with respect to frequency of administration".

Blinding of outcome assessment (detection bias)
All outcomes
Low riskQuote: "Disease activity measures were assessed by the first observer, who remained blinded for treatment schedules and laboratory results" (page 740).

Incomplete outcome data (attrition bias)
All outcomes
High risk1. Overall: 82.8% (58/70)
2. EPO group: 85% (29/34)
3. Placebo group: 80% (29/36)

4. Imbalance between groups: 5%

Comment: Missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups. However, this was a small trial.

Selective reporting (reporting bias)Low riskThis trial reported outcomes of clinical interest.

Other biasLow riskQuote: "At baseline, groups were compared using Student's t test, the Mann-Whitney test, and the x' test where appropriate."

There was no significant baseline imbalance.


Methods1. Design: parallel design (2 arms).
2. Multicenter study: USA (5 sites).
3. Intention-to-treat analysis: yes.
4. Follow-up period: 8 weeks.
5. Follow-up period: 24 weeks open label.

6.- Unit of randomization: patients

7.- Unit of analysis: patient.


Participants1. Randomized: 17
Erythropoietin (EPO) group: 13
Placebo group:  4

2. Receiving EPO and placebo: 17
EPO group:13
Placebo group: 4

3. Age: years; mean range

Both groups: 52; 25 to 73
By comparison group: not reported

4. Gender (female):
Both group: 94.1% (16/17)

By comparison group: not reported

5. Inclusion criteria: These were not reported explicitly.

Quote: " All met the 1958 American Rheumatism Association criteria for rheumatoid arthritis... were being treated only with nonsteroidal anti-inflammatory drugs and no patient was taking gold, methotrexate, azathioprine, penicillamine, or prednisone, or had taken any second-line agents for 6 months prior to, or during, erythropoietin administration" (page 162).

6. Exclusion criteria:

  • Renal disease
  • History of seizure
  • Uncontrolled hypertension
  • Severe allergic reactions
  • Asthma
  • Active hepatitis
  • Other inflammatory conditions
  • Malignancy
  • Ischemic heart disease
  • Active peptic ulcer within one month of the study
  • Neutropenia
  • Hemolytic anemia
  • Thrombocytopenia


Interventions1. Intervention group: recombinant human erythropoietin rHuEPO (50, 100, 150 U per kg three times a week, intravenous bolus given over a 5 minute period for up to 8 weeks).

2. Placebo: schedule identical to intervention. Placebo composition was not reported.

3. Co-intervention: oral ferrous sulphate (325 mg three times daily).


OutcomesThis trial did not explicitly address this domain.

1. Change in hematocrit, and leucocyte and platelet counts (page 163)

2. Safety (page 163)

3. Rheumatologic clinical status changes (page 165)


Notes1. Sample size calculation a priori: not reported.

2. Sponsor: Ortho Biotech Corporation, National Institutes of Health (grants DK-1555, RR-95, and T32-07186), Jack C Massey Foundation, and Veterans Administration Medical Research Funds.

3. Role of sponsor: Ortho Biotech Corporation provided the intervention.

4.- This study had two phases:

First phase: 8 weeks randomized double blind study.

Second Phase: 24 week-open-label-study "involved an open-label protocol in which all patients received erythropoietin three times weekly" (page 163). Quote: "Following the 8 week randomized study, the 17 patients were offered the possibility of participations in a 24 week open-label extension study" (page 162).

5. Conflict of interest: not described.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information to consider 'low risk' or 'high risk'.
Comment: there is imbalance between comparison groups regarding treated number of patients (13 treated with EPO and 4 with placebo).

Allocation concealment (selection bias)Unclear riskInsufficient information to consider 'low risk' or 'high risk'.

Blinding of participants and personnel (performance bias)
All outcomes
Low riskQuote: "identically appearing placebo" (page 162)

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information to consider 'low risk' or 'high risk'.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data.

Selective reporting (reporting bias)High riskOne or more outcomes of interest in the review are reported incompletely, so that they cannot be entered in a meta-analysis.

Comment: this trial reported only activities of daily living score and visual analog pain scale score data for intervention group. (page162).

Other biasUnclear riskComment: this trial did not report baseline characteristics of the patients assigned to placebo group.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Arndt 2005Clinical trial but not an RCT

Birgegard 1991Case report

Dyjas 2005Controlled clinical trial but not an RCT

Fantini 1992Case report

Goodnough 1997Narrative review of the responses to erythropoietin in patients with rheumatoid arthritis

Kaltwasser 2001Clinical trial but not an RCT

Kato 1994Trial was conducted using historical controls

Krantz 1995Narrative review of erythropoietin and the anemia of chronic disease

Matsuda 2001Trial included patients without anemia

Means 1989Case report

Mercuriali 1996Narrative review of erythropoietin alpha for autologous blood donations in patients with rheumatoid arthritis and concomitant anemia

Mercuriali 1997Trial was conducted using historical controls

Murphy 1994This study is shown as RCT involving 20 participants (10 assigned to EPO versus 10 randomized to placebo).

Quote "Intervention group: recombinant human erythropoietin (rHuEPO) "starting at 40 IU per kg (patients 1-10) and 100 U/Kg (patients 11-20)" (page 1337), subcutaneous (sc), twice a week by 20 weeks".

Therefore, it must be considered as non-randomized.

Pettersson 1993aCase report

Saikawa 1994Study including anemic and non-anemic with rheumatoid arthritis. All participants received erythropoietin.

Salvarani 1991Case report

Swaak 1994Case report

Takashina 1990Case report

Tauchi 1990Case report

Vreugdenhil 1990Case report

Vreugdenhil 1992Case report

 
Summary of findings for the main comparison. Erythropoietin (subcutaneous or intravenous at varying dosages) compared to placebo for anemia in patients with rheumatoid arthritis

Erythropoietin (subcutaneous or intravenous at varying dosages) compared to placebo for anemia in patients with rheumatoid arthritis

Patient or population: anemia in patients with rheumatoid arthritis
Settings: outpatient
Intervention: erythropoietin (subcutaneous or intravenous at varying dosages)
Comparison: placebo

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

PlaceboErythropoietin (subcutaneous or intravenous at varying dosages)

Health-related quality of life
Follow-up: 8 to 52 weeks
See commentSee comment136
(3 studies1)
⊕⊝⊝⊝
very low2,3
Peeters 1996, with 70 participants followed up during 52 weeks reporting patients' global assessment (VAS score 0 to 10), found statistically significant differences comparing EPO versus placebo (median and interquartile range at 52 weeks: 3.5 (1.0 to 6.0) and 4.5 (2.0 to 7.5) P = 0.027, respectively.

Pincus 1990, with 17 participants followed up during 8 weeks, reported no significant differences between groups of patient satisfaction in activities of daily living using the mHAQ5 but data were not provided.

Nordström 1997, with 46 participants followed up at 12 weeks, reported no significant difference between groups in Stanford Health Assessment Questionnaire scores, Nottingham Health Profile scores, classification of functional class or joint score index scores.

Hemoglobin (Hb) level at the end of the study
Follow-up: 12 to 52 weeks4
See comment116
(2 studies4)
⊕⊕⊝⊝
low2
Nordström 1997 (46 participants) reported a statistically significant increase in hemoglobin level at 12 weeks in the EPO group compared with placebo group (MD 8.00, 95% CI 7.43 to 8.57 g/l; P = 0.00001)

Peeters 1996 (70 participants) reported a statistically significant increase in hemoglobin level at 52 weeks in the EPO group (median 134; interquartile range 110 to 158 g/L) compared with placebo group (median 112; interquartile range 86 to 128 g/L) (P = 0.001).

Fatigue

Not reported
See commentSee commentNot estimable-See commentThis outcome was not assessed by any of the trials.

Safety (Adverse events including adverse drug reaction)

Follow-up: 8 to 52 weeks
See commentSee commentNot estimable(3 studies1)⊕⊝⊝⊝
very low2,3
Nordström 1997 found no significant alterations in pulse, blood pressure, platelet counts, albumin, creatinine, alanine aminotransferase, or aspartate aminotransferase values .

Peeters 1996 assessed adverse events and found no significant rise in blood pressure and thromboembolic complications.

Pincus 1990 found no adverse reactions.

Withdrawals due to adverse eventsSee commentSee commentNot estimable-See commentNordström 1997 reported no serious adverse events causing premature discontinuation. This outcome was not reported by the other two trials (Peeters 1996; Pincus 1990).

Withdrawals due to lack of efficacySee commentSee commentNot estimable-See commentThis outcome was not assessed by any of the trials.

Withdrawals due to high blood pressureSee commentSee commentNot estimable-See commentThis outcome was not assessed by any of the trials.

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1. Nordström 1997, Peeters 1996, Pincus 1990
2. Almost all domains had a high or unclear risk of bias.
3. Small sample size
4. Nordström 1997, Peeters 1996
5. mHAQ: modified Stanford Health Assessment Questionnaire