Infliximab and Etanercept in Rheumatoid Arthritis: Systematic Review of Long-term Clinical Effectiveness, Safety, and Cost-Effectiveness
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APPENDIX 1: Literature Search Strategy Databases Limits Keyword/Descriptors National Library of Medicine PubMed
1. Receptors, Tumor Necrosis Factor [MeSH] 2. Etanercept [substance name] 3. 185243-69-0 [EC/RN Number] 4. (TNFR OR "TNF receptor*" OR "Cachectin receptor*" OR "tumor necrosis factor receptor*" OR "tumour necrosis factor receptor*") AND (Fc OR "fusion protein*") [Title/Abstract] 5. "tumor necrosis factors/antagonists and inhibitors" [MeSH] 6. 170277-31-3 [EC/RN Number] 7. Infliximab OR Avakine OR IFX OR Revellex OR Remicade [Title/Abstract] 8. Infliximab [Substance Name] 9. Adalimumab [Substance Name] 10. Adalimumab OR humira OR D2E7 [Title/Abstract] 11. "Anti-Tumor Necrosis Factor*" OR "Anti-Tumour Necrosis Factor*" OR "Anti Tumor Necrosis Factor*" OR "Anti Tumour Necrosis Factor*" [Title/Abstract] 12. "anti-TNF*" OR antiTNF* OR "anti TNF*" [Title/Abstract] 13. "tumor necrosis factors inhibitor*" OR "tumour necrosis factors inhibitor*" OR "tumor necrosis factors antibody" OR "tumour necrosis factors antibody" OR "tumor necrosis factors antibodies" OR "tumour necrosis factors antibodies" OR "tumor necrosis factors anti-bodies" OR "tumour necrosis factors anti-bodies" OR "tumor necrosis factors anti-body" OR "tumour necrosis factors anti-body" [Title/Abstract] 14. #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 15. Arthritis, Rheumatoid [MeSH] 16. Arthritis Rheumatoid OR rheumatoid arthritis OR RA [Title/Abstract] 17. Spondylitis Ankylosing OR Bechterew disease OR Bechterew's disease OR Marie Struempell disease OR spondylarthritis ankylopoietica [Title/Abstract] 18. "still disease" OR "stills disease" [Title/Abstract] 19. "Felty Syndrome" OR "Felty's Syndrome" [Title/Abstract] 20. (Sjogren OR sjogrens OR Sjogren’s OR Sjoegren OR sjoegrens OR Sjoegren’s OR Sicca) AND Syndrome) [Title/Abstract] 21. “caplan syndrome” OR”caplan’s syndrome” OR “caplans syndrome” [Title/Abstract] 22. #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 23. #14 AND #22 See each study type description below for search date and records returned.
National Library of Medicine PubMed
Human (not applied to “Publisher” or”In process” records)
Clinical Trials: 24. Clinical Trials OR Drug Evaluation OR epidemiologic research design OR Epidemiologic Studies [MeSH] 25. multicenter study OR randomized controlled trial OR controlled clinical trial OR clinical trial [Publication Type] 26. random OR randomized OR randomized OR randomly OR sham OR shams OR placebo OR placebos [Title/Abstract] 27. “single blind” OR “single blinded” OR “single dummy” OR “single mask” OR “single masked” [Title/Abstract] 28. RCT OR RCTS OR “double blind” OR “double blinded” OR “double dummy” OR “double mask” OR “double masked” [Title/Abstract]
Infliximab and Etanercept in Rheumatoid Arthritis: Systematic Review of Long-term Clinical Effectiveness, Safety, and Cost-Effectiveness
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29. “triple blind” OR “triple blinded” OR “triple dummy” OR “triple mask” OR “triple masked” [Title/Abstract] 30. “treble blind” OR “treble blinded” OR “treble dummy” OR “treble mask” OR “treble masked” [Title/Abstract] 31. “control study” OR “control studies” OR “controlled study” OR “controlled studies” OR “control trial” OR “control trials” OR “controlled trial” OR “controlled trials” [Title/Abstract] 32. “multicentre study” OR “multicentre studies” OR “multicentre trial” OR “multicentre trials” OR “multicenter study” OR “multicenter studies” OR “multicenter trial” OR “multicenter trials” [Title/Abstract] 33. “case-control study” OR “case-control studies” OR “case-control trial” “OR “case-control trials” [Title/Abstract] 34. case-controlled study OR case-controlled studies OR case-controlled trial OR case-controlled trials [Title/Abstract] 35. “case series” [Title/Abstract] 36. “retrospective study” OR “retrospective studies” OR “retrospective trial” OR “retrospective trials” [Title/Abstract] 37. "cohort analysis" OR "cohort analyses" OR "cohort study" OR "cohort studies" OR "cohort trial" OR "cohort trials" [Title/Abstract] 38. “prospective study” OR “prospective studies” OR “prospective trial” OR “prospective trials” [Title/Abstract] 39. “observational study” OR “observational studies” OR “observational trial” OR “observational trials” [Title/Abstract] 40. “follow-up study” OR “follow-up studies” OR “follow-up trial” OR “follow-up trials” [Title/Abstract] 41. “followup study” OR “followup studies” OR “followup trial” OR “followup trials” [Title/Abstract] 42. “open-label study” OR “open-label studies” OR “open-label trial” OR “open-label trials” [Title/Abstract] 43. drug comparison OR drug comparisons OR comparative study OR comparative studies OR comparative trials [Title/Abstract] 44. head-to-head OR crossover design OR crossover designs OR crossover study OR crossover studies OR crossover trial OR crossover trials OR cross-over study OR cross-over studies OR cross-over trial OR cross-over trials [Title/Abstract] 45. #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32 OR #33 OR #34 OR #35 OR #36 OR #37 OR #38 OR #39 OR #40 OR #41 OR #42 OR #43 OR #44 46. #23 AND #45 Date Search Performed: 16 Mar 2005 Total Records Retrieved: 822 records
National Library of Medicine PubMed
Human (not applied to “Publisher” or”In process” records)
Meta-Analyses/Systematic Reviews: 47. meta-analysis [Publication Type] 48. meta-analysis [MeSH] 49. meta-analy* OR metaanaly* OR met-analy* OR metanaly* [Title/Abstract] 50. meta-regression* OR metaregression* OR mega-regression* [Title/Abstract] 51. “systematic literature review” OR “systematic literature reviews” OR “systematic review” OR “systematic reviews” OR “systematic overview” OR “systematic overviews” [Title/Abstract] 52. “methodologic* literature review” OR “methodologic* literature reviews” OR “methodologic* review” OR “methodologic* reviews” OR “methodologic* overview” OR “methodologic* overviews” [Title/Abstract] 53. “quantitative review” OR “quantitative reviews” OR “quantitative
Infliximab and Etanercept in Rheumatoid Arthritis: Systematic Review of Long-term Clinical Effectiveness, Safety, and Cost-Effectiveness
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synthesis” OR “quantitative syntheses” OR “research integration*” OR “research overview” OR “research overviews” [Title/Abstract] 54. “integrative review” OR “integrative reviews” OR “integrative overview” OR “integrative overviews” OR “collaborative review” OR “collaborative reviews” OR “collaborative overview” OR collaborative overviews” OR “Pooled analysis” OR “pooled analyses” [Title/Abstract] 55. “data synthesis” OR “data syntheses” OR “data extraction*” OR “data abstraction*” [Title/Abstract] 56. #23 AND #55 Date Search Performed: 16 Mar 2005 Total Records Retrieved: 42 records
National Library of Medicine PubMed
Human (not applied to “Publisher” or”In process” records)
Safety/Adverse Events: 57. adverse effects OR chemically induced OR drug toxicity [MeSH] 58. adverse effect OR adverse effects OR adverse reaction OR adverse reactions OR adverse event OR adverse events OR adverse incident OR adverse incidents [Title/Abstract] 59. toxic OR toxicity [Title/Abstract] 60. (injurious OR undesirable) (effect OR effects OR reaction OR reactions OR event OR events OR incident OR incidents) [Title/Abstract] 61. “drug safety” [Title/Abstract] 62. “drug-induced” OR “chemically-induced” [Title/Abstract] 63. #57 OR #58 OR #59 OR #60 OR #61 OR #62 64. #23 AND #63
Date Search Performed: 16 Mar 2005 Total Records Retrieved: 276 records
National Library of Medicine PubMed
Economics: 65. (economics OR “costs and cost analysis” OR “value of life” OR economics, medical OR economics, hospital OR economics, nursing OR economics, pharmaceutical) [MeSH] 66. (“fees and charges” OR budgets OR models, economic OR markov chains OR monte carlo method OR decision trees OR quality of life) [MeSH] 67. (patient satisfaction OR quality-adjusted life years) [MeSH] 68. (econom* OR cost OR costly OR costing OR costed OR price OR prices OR pricing OR priced OR discount OR discounts OR discounted OR discounting) [Title/Abstract] 69. (expenditure OR expenditures OR budget* OR afford* OR pharmacoeconomic* OR pharmaco-economic*) [Title/Abstract] 70. (decision-tree OR decision-trees OR decision-analysis OR decision model OR decision models OR decision modeling) [ti,ab] 71. (QOL OR QOLY OR QOLYs OR HRQoL OR QALY OR QALYs OR “quality of life” OR “willingness to pay” OR “quality-adjusted-life” (year OR years)) [Title/Abstract] 72. #65 OR #66 OR #67 OR #68 OR #69 OR #70 OR #71 73. #23 AND #72
Date Search Performed: 16 Mar 2005 Total Records Retrieved: 145 records
DIALOG® MEDLINE® 155 ToxFile 156 EMBASE® 73
BIOSIS Previews® 5
Human 1. Receptors, Tumor Necrosis Factor/de from 155, 156 2. Tumor Necrosis Factor!(l)ai from 155,156 3. tumor necrosis factor receptor/de OR tumor necrosis factor alpha antibody/de OR tumor necrosis factor antibody/de from 73 4. etanercept/maj OR infliximab/maj OR Adalimumab/maj from 73 5. TN=enbrel OR TN=revellex OR TN=remicade OR TN=humira 6. infliximab/de from 5
Infliximab and Etanercept in Rheumatoid Arthritis: Systematic Review of Long-term Clinical Effectiveness, Safety, and Cost-Effectiveness
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7. RN=185243-69-0 OR RN=170277-31-3 OR RN=331731-18-1 8. (Etanercept OR Enbrel OR (TNFR OR TNF()receptor? OR Cachectin()receptor? OR (tumo?r()necrosis()factor()receptor?))(4n)(Fc OR fusion()protein?))/ti,ab 9. (Infliximab OR Avakine OR IFX OR Revellex OR Remicade)/ti,ab 10. (Adalimumab OR humira OR D2E7)/ti,ab 11. (Anti()Tumo?r()Necrosis)()Factor?/ti,ab 12. (anti()TNF OR antiTNF OR anti()TNF()alpha OR anti()TNFalpha OR antiTNFalpha OR antiTNF()alpha)/ti,ab 13. (tumo?r()necrosis()factor? OR TNF OR TNF-alpha OR TNFalpha)(2n)(antagonist? OR antibod? OR anti-bod? OR inhibitor?) 14. s1 OR s2 OR s3 OR s4 OR s5 OR s6 OR s7 OR s8 OR s9 OR s10 OR s11 OR s12 OR s13 15. Arthritis, Rheumatoid!/de from 155, 156 16. Rheumatoid arthritis!/de OR Ankylosing spondylitis/de OR Sjoegren syndrome/de from 73 17. (rheumatoid arthritis OR juvenile rheumatoid arthritis OR ankylosing spondylitis OR sjogren syndrome OR sjogren’s syndrome OR still’s disease)/de from 5 18. (Arthritis(1n)Rheumatoid OR RA)/ti,ab 19. (Spondylitis(1n)Ankylosing OR Bechterew?()disease OR Marie()Struempell()disease OR spondylarthritis()ankylopoietica)/ti,ab 20. (stills()disease OR still()s()disease)/ti,ab 21. (Felty()Syndrome OR Felty()s()Syndrome OR Feltys()syndrome)/ti,ab 22. (Sjogren OR sjogrens OR Sjogren()s OR Sjoegren OR sjoegrens OR Sjoegren()s OR Sicca)()Syndrome)/ti,ab 23. (caplan OR caplan()s OR caplans)()(syndrome)/ti,ab 24. s15 OR s16 OR s17 OR s18 OR s19 OR s20 OR s21 OR s22 OR s23 25. s14 AND s24
See each study type description below for search date and records returned.
DIALOG® MEDLINE® 155 ToxFile 156 EMBASE® 73
BIOSIS Previews® 5
Human Clinical Trials 26. (Clinical Trials! OR Drug Evaluation OR epidemiologic research design! OR Epidemiologic Studies!)/de from 155, 156 27. dt=(multicenter study OR randomized controlled trial OR controlled clinical trial OR clinical trial) from 155, 156 28. (major clinical study OR multicenter study OR controlled study! OR randomized controlled trial)/de from 73 29. evidence based medicine!/de from 73 30. cohort analysis/de from 73 31. drug comparison!/de from 73 32. (multicenter study OR randomized controlled trial OR randomized clinical trial)/de from 5 33. (randomized trial OR evidence-based medicine)/de from 5 34. cohort study/de from 5 35. random?/ti,ab OR sham?/ti,ab OR placebo?/ti,ab OR singl?()(blind? OR dumm? OR mask?)/ti,ab OR doubl?()(blind? OR dumm? OR mask?)/ti,ab 36. tripl?()(blind? OR dumm? OR mask?)/ti,ab OR trebl?()(blind? OR dumm? OR mask?)/ti,ab 37. control?()(study OR studies OR trial?)/ti,ab OR RCT? ?/ti,ab 38. (multicent? OR multi()cent?)()(study OR studies OR trial?)/ti,ab 39. (case()control)()(study OR studies OR trial OR trials)/ti,ab 40. case()series/ti,ab 41. retrospective()(study OR studies OR trial OR trials)/ti,ab 42. cohort()(analysis OR analyses OR study OR studies OR trial OR
Infliximab and Etanercept in Rheumatoid Arthritis: Systematic Review of Long-term Clinical Effectiveness, Safety, and Cost-Effectiveness
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trials)/ti,ab 43. prospective()(study OR studies OR trial OR trials)/ti,ab 44. observational()(study OR studies OR trial OR trials)/ti,ab 45. (follow()up)()(study OR studies OR trial OR trials)/ti,ab 46. followup()(study OR studies OR trial OR trials)/ti,ab 47. (open()label)()(study OR studies OR trial OR trials)/ti,ab 48. (drug OR drugs)(2n)comparison?/ti,ab OR comparative()(study OR studies OR trial?)/ti,ab 49. head()to()head/ti,ab OR (crossover OR cross()over)()(design? OR study OR studies OR trial?)/ti,ab 50. s26 OR s27 OR s28 OR s29 OR s30 OR s31 OR s32 OR s33 OR s34 OR s35 OR s36 OR s37 OR s38 OR s39 OR s40 OR s41 OR s42 OR s43 OR s44 OR s45 OR s46 OR s47 OR s48 OR s49 51. s25 AND s50
Date Search Performed: 16 Mar 2005 Total Records Retrieved: 1711 Unique records MEDLINE – 625 ToxFile - 2 EMBASE - 1063 BIOSIS – 21
DIALOG® MEDLINE® 155 ToxFile 156 EMBASE® 73
BIOSIS Previews® 5
Human Meta-Analyses/Systematic Reviews: 52. dt=meta-analysis OR meta-analysis/de from 155, 156 53. mETN analysis/de from 73 54. meta-analysis/de from 5 55. meta()analy?/ti,ab OR metaanaly?/ti,ab OR met()analy?/ti,ab OR metanaly?/ti,ab 56. meta()regression?/ti,ab OR metaregression?/ti,ab OR mega()regression?/ti,ab 57. systematic?()(literature()(review OR reviews) OR review OR reviews OR overview?)/ti,ab 58. methodologic?()(literature()(review OR reviews) OR review OR reviews OR overview?)/ti,ab 59. quantitative()(review? OR overview? OR synthes?)/ti,ab OR research()(integration? OR overview?)/ti,ab 60. integrative(2w)(review OR reviews OR overview?)/ti,ab OR collaborative()(review OR reviews OR overview?)/ti,ab OR pool?()analy?/ti,ab 61. data()synthes?/ti,ab OR data()extraction?/ti,ab OR data()abstraction?/ti,ab 62. s25 AND s61
Date Search Performed: 16 Mar 2005 Total Records Retrieved: 27 unique records (Excludes overlap with clinical trials) MEDLINE – 3 ToxFile - 4 EMBASE - 19 BIOSIS – 1
DIALOG® MEDLINE® 155 ToxFile 156 EMBASE® 73
BIOSIS Previews® 5
Human Safety/Adverse Events: 63. (adverse effects! OR chemically induced OR drug toxicity!)/de from 155, 156 64. (etanercept(l)ae OR etanercept(l)ae OR infliximab(l)ae OR infliximab(l)to OR Adalimumab(l)ae OR Adalimumab(l)to)/maj from 73 64. (side effect! OR adverse drug reaction! OR drug safety OR drug toxicity and intoxication!)/de from 73 65. (adverse effects OR adverse reactions OR adverse events)/de from 5
Infliximab and Etanercept in Rheumatoid Arthritis: Systematic Review of Long-term Clinical Effectiveness, Safety, and Cost-Effectiveness
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66. (adverse drug effects OR adverse drug reactions)/de from 5 67. (side effects OR drug toxicity OR drug side effects OR drug safety)/de from 5 68. adverse(1w)(effect OR effects OR reaction OR reactions OR event OR events OR incident OR incidents)/ti,ab 69. side(w)(effect OR effects)/ti,ab 70. (toxic OR toxicity)/ti,ab 71. (injurious OR undesirable)()(effect OR effects OR reaction OR reactions OR event OR events OR incident OR incidents)/ti,ab 72. drug(2N)(safety OR toxicit? OR fatalit?)/ti,ab 73. drug()induced/ti,ab OR chemically()induced/ti,ab 74. s63 OR s64 OR s65 OR s66 OR s67 OR s68 OR s69 OR s70 OR s71 OR s72 OR s73 OR s74 75. s25 AND s74 Date Search Performed: 16 Mar 2005 Total Records Retrieved: 921 unique records (Excludes overlap with clinical trials) MEDLINE – 320 ToxFile - 0 EMBASE - 568 BIOSIS – 33
DIALOG® MEDLINE® 155 ToxFile 156 EMBASE® 73
BIOSIS Previews® 5
Economics: 76. (economics! OR “costs and cost analysis”! OR value of life OR economics, medical! OR economics, hospital! OR economics, nursing OR economics, pharmaceutical)/de from 155, 156 77. (“fees and charges”!/de OR budgets!/de OR models, economic!/de OR markov chains OR monte carlo method OR decision trees OR quality of life)/de from 155, 156 78. (Health economics! OR economic evaluation! OR pharmacoeconomics! OR economic aspect! OR quality adjusted life year OR quality of life!)/de from 73 79. (economic impact OR economic value OR pharmacoeconomics OR health care cost OR economic factors OR economics OR cost analysis OR economic analysis)/de from 5 80. (cost OR cost-effectiveness OR cost effectiveness OR costs OR quality of life OR health care cost OR cost savings OR cost-benefit analysis)/de from 5 81. (hospital costs OR medical costs OR quality-of-life)/de from 5 82. (econom? OR cost OR costly OR costing OR costed OR price OR prices OR pricing OR priced OR discount OR discounts OR discounted OR discounting)/ti,ab 83. (expenditure OR expenditures OR budget? OR afford? OR pharmacoeconomic? OR pharmaco(1n)economic?)/ti,ab 84. (decision)(1n)(tree? OR analy? OR model?)/ti,ab 85. (value OR values OR valuation)(2n)(money OR monetary OR life OR lives)/ti,ab 86. (QOL OR QOLY OR QOLYs OR HRQoL OR QALY OR QALYs OR quality(1n)life OR willingness(1n)pay OR quality(1n)adjusted()life()year?)/ti,ab 87. s76 OR s77 OR s78 OR s79 OR s80 OR s81 OR s82 OR s83 OR s84 OR s85 OR s86 OR s87 88. s25 AND s87 Date Search Performed: 16 Mar 2005
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Total Records Retrieved: 193 unique records (Excludes overlap with clinical trials) MEDLINE – 58 ToxFile - 4 EMBASE - 123 BIOSIS – 8
DIALOG® Alerts: MEDLINE® 154 EMBASE® Alert 172 BIOSIS Previews® 55
Human (for all searches except economic)
Updates performed biweekly from Mar 20, 2005 to Sep 4, 2005, inclusive Total Records Retrieved: 160 unique records
John Wiley & Sons, Inc. The Cochrane Library 2005, Issue 1
Same keywords and descriptors as PubMed, adjusting as per syntax 124 Records The Cochrane Database of Systematic Reviews = 2 complete reviews; The Database of Abstracts of Reviews of Effectiveness = 4 records; CENTRAL = 93 references; HTA database = 12 records; The NHS Economic Evaluation Database = 13 records
Regular updates performed to 2005, Issue 3, inclusive OHE-IFPMA Database Ltd. HEED: health economic evaluations database Mar 2005 Issue
All drug names Date Search Performed: 30 Mar 2005 Total Records Retrieved: 20 records
Conference proceedings
2002-2005 American College of Rheumatology (ACR), European League against Rheumatism (EULAR), Health Technology Assessment International (ISTAHC/HTAI) and International Society for Pharmacoepidemiology and Outcomes Research (ISPOR)
Websites of health technology assessment (HTA) and related agencies; clinical trial registries; other databases
e.g., AHFMR; NICE; National Research Register; University of York NHS Centre for Reviews and Dissemination – CRD databases; CMA Infobase
Infliximab and Etanercept in Rheumatoid Arthritis: Systematic Review of Long-term Clinical Effectiveness, Safety, and Cost-Effectiveness
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APPENDIX 2: Outcome Measures for Clinical Review Long-term effectiveness Measures of disease activity: SJC and TJC, pain, disability score, patient’s global assessment, physician’s global assessment, and DAS
DAS DAS28 is a validated index of RA disease activity. It consists of four measures:
• 28 TJC (TJC28) and SJC (SJC28) • ESR • patient’s general health (GH) measured on 100 mm visual analog scale (VAS)
It is calculated using the formula [0.56× (TJC28)]+[0.28× (SJC28)]+0.70× [ln(ESR)+0.014× (GH)]. The DAS28 provides a number on a scale from 0 to 10 indicating the patient’s current rheumatoid arthritis activity. A DAS28 >5.1 means high disease activity, whereas a DAS28 <3.2 indicates low disease activity. Remission is achieved when DAS28 is <2.6. ACR improvement criteria (20, 50, 70)
Definition of ACR Clinical Response Criteria ACR20 Response Must include the following:
• 20% improvement in TJC • 20% improvement in SJC • 20% improvement in three of the following criteria:
o patient pain assessment o patient global assessment o physician global assessment o patient self-assessed disability o acute phase reactant value [ESR or C-reactive protein (CRP)].
ACR50 and ACR70 calculated as ACR20 responses using 50% and 70% improvement respectively. ACR Numeric Response (ACR-N) ACR-N is defined as the smallest degree of improvement from baseline in the following three criteria:
• number of tender joints • number of swollen joints • median of the five remaining measures of disease activity.
EULAR improvement criteria
Based on the DAS, response criteria have been developed. The EULAR response criteria include not only change in disease activity but also current disease activity. To be classified as responders, patients have a significant change in DAS and low current disease activity. Three categories are defined: good, moderate, and non-responders.
Infliximab and Etanercept in Rheumatoid Arthritis: Systematic Review of Long-term Clinical Effectiveness, Safety, and Cost-Effectiveness
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Physical functional status
HAQ
Patient Label Date: We are interested in learning how your illness affects your ability to function in daily life. Please add comments at the end of this form. PLEASE TICK THE ONE RESPONSE THAT BEST DESCRIBES YOUR USUAL ABILITIES OVER THE PAST WEEK Without ANY
difficulty With SOME difficulty
With MUCH difficulty
Unable to do
Score=0 Score=1 Score=2 Score=3
1. DRESSING and GROOMING – Are you able to: dress yourself including tying shoelaces
and doing buttons? shampoo your hair?
2. RISING - Are you able to: stand up from an armless straight chair? get in and out of bed?
3. EATING - Are you able to: cut your meat? lift a cup or glass to your mouth? open a new carton of milk (or soap
powder)?
4. WALKING - Are you able to: walk outdoors on flat ground? climb up five steps?
5. HYGIENE – Are you able to: wash and dry your entire body? take a bath? get on and off the toilet?
6. REACH – Are you able to: reach and get a 5 lb object (e.g., a bag of
potatoes) from above your head)? bend down to pick up clothing from the
floor?
7. GRIP – Are you able to: open car doors? open jars that have been previously
opened? turn taps on and off?
8. ACTIVITIES – Are you able to: run errands and shop? get in and out of a car? do chores such as vacuuming, housework,
or light gardening?
PLEASE TICK ANY AIDS OR DEVICES THAT YOU USUALLY USE FOR ANY OF THESE ACTIVITIES cane devices used for dressing (button hook, zipper pull, long handled shoe horn) walking frame built-up or special utensils crutches special or built-up chair wheelchair other (specify) raised toilet seat jar opener (for jars previously opened) bath seat long handled appliances for reach bath rail other (specify) PLEASE TICK ANY CATEGORIES FOR WHICH YOU USUALLY NEED HELP FROM ANOTHER PERSON dressing and grooming eating rising walking hygiene gripping and opening things reach errands and housework
Infliximab and Etanercept in Rheumatoid Arthritis: Systematic Review of Long-term Clinical Effectiveness, Safety, and Cost-Effectiveness
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Scoring of HAQ
Add the maximum score for each of the eight sections and divide by eight to give a score between zero and three. If aid, device, or help is needed, the score for that activity=2 (unless 3 has been ticked). Normal function=0, most severely affected=3. Radiological damage
Modified Sharp method
Radiographs of hands, wrists, and feet are scored. In all, 46 joints are scored for erosions. Erosions are scored on a six-point scale. A score of 0=no new erosion and no worsening of an existing erosion. Each point increase indicates occurrence of a new erosion or 20% worsening of an existing erosion. In all, 42 joints are scored for narrowing on a five-point scale. A score of 0=no narrowing, 1=minimal narrowing, 2=loss of 50% of the joint space, and 4=complete loss of the joint space. Scores for joint-space narrowing and erosions are summed to give a total Sharp score. van der Heijde modification of Sharp method
Radiographs of hands, wrists, and feet are scored. In this case, 44 joints are scored for erosions, 32 in the hands and wrists and 12 in the feet. Each hand or wrist joint is scored on a five-point scale according to the surface involved – 0=no erosion, 5=extensive loss of bone from more than half of the articulating bone. Each foot joint is scored a maximum of 10. Maximum erosion score 160 for hands and 120 for feet. Joint-space narrowing is scored in 30 hand and wrist joints and 10 joints in the feet. A four-point scoring system is used. A score of 0=no narrowing, 1=focal or doubtful narrowing, 2=general narrowing of <50%, 3=general narrowing of >50% of the original joint space, and 4=bony ankylosis or complete luxation. The maximum scores for joint-space narrowing are 120 for hands and 48 for feet.
Infliximab and Etanercept in Rheumatoid Arthritis: Systematic Review of Long-term Clinical Effectiveness, Safety, and Cost-Effectiveness
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APPENDIX 3: Selection Criteria Forms Step 2 – Selection form
Rater Citation Author Language (initials) ID Year Source Master ID
English
other (specify):
abstract comments: Previous Rating Excluded Included Unsure
Excluded Select ALL that apply
laboratory (only)
mostly no rheumatoids arthritis
no infliximab or etanercept
adalimumab ONLY
insufficient data
commentary, editorials, short updates, news
opinion letters
language
unable to retrieve paper
other
other (specify)
_____________________________
excluded on abstract only (no full paper available)
ongoing study
Included Unsure Select ALL that apply for inclusion reason:
economic evaluation
clinical effectiveness
If clinical effectiveness, then select all
categories that apply from below:
effectiveness – <12 months
effectiveness – at least 12 months
safety
dose escalation
sequential
switching anti TNF
included based on abstract only (specify
abstract comments)
Comments:
Study type (for included and unsure)
original data: full paper
original data: letter
original data: abstract
original data: other specify:
health technology assessment
clinical practice guidelines
review
economic evaluation
decision analysis
other specify:
Infliximab and Etanercept in Rheumatoid Arthritis: Systematic Review of Long-term Clinical Effectiveness, Safety, and Cost-Effectiveness
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Step 3 — Original data for clinical effectiveness
Etanercept Infliximab
Final Inclusion Original Inclusion
Yes No
Comments
Etanercept RCT/CCT (≥12 months) Infliximab RCT/CCT (≥12 months) Observational (ETN or IFX) /effectiveness (≥12 months)
Dose escalation (≥3 months) Sequence of administration Switching anti-TNF (≥3 months) Safety Etanercept — RCT/CCT
Inclusion Criteria (all criteria must be met)
Yes No Not specified Comments 1. Duration ≥12 months 2. Patients ≥16 years old 3. RA diagnosed by ACR criteria 4. Disease activity with at least 2 of the following: tender joints swollen joints morning stiffness ≥30 minutes increased ESR or CPR
5. ETN SC – 10 mg or 25 mg twice/week or 50 mg/week 6. Control group: placebo or other (disease modifying anti-rheumatic drug, biologic or steroid)
7. Clinical outcomes ACR outcomes (TJC, SJC, pain, patient global, physician
global, function, acute phase reactants) or DAS or ACR improvement criteria or EULAR improvement criteria or radiologic damage or QoL
8. Sufficient data reported
Infliximab and Etanercept in Rheumatoid Arthritis: Systematic Review of Long-term Clinical Effectiveness, Safety, and Cost-Effectiveness
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Infliximab — RCT/CCT
Inclusion Criteria (all criteria must be met)
Yes No Not specified Comments 1. Duration ≥12 months 2. Patients ≥16 years old 3. RA diagnosed by ACR criteria 4. Disease activity with at least 2 of the following: tender joints swollen joints morning stiffness ≥30 minutes increased ESR or CPR
5. IFX ≥1mg/kg induction, then every 8 weeks 6. Control group: placebo or other (disease modifying anti-rheumatic drug, biologic or steroid)
7. Clinical outcomes ACR outcomes (TJC, SJC, pain, patient global, physician
global, function, acute phase reactants) or DAS or ACR improvement criteria or EULAR improvement criteria or radiologic damage or QoL
8. Sufficient data reported Effectiveness or Observational — Inclusion Criteria (all criteria must be met)
Yes No Not specified Comments1. Duration ≥12 months 2. RA as specified by authors 3. Treatment with ETN or IFX 4. N ≥30 5. Clinical outcomes ≥1 of the following: SJC DAS ACR improvement criteria EULAR improvement criteria functional status QoL radiologic damage terminations AE
5. Sufficient data reported
Infliximab and Etanercept in Rheumatoid Arthritis: Systematic Review of Long-term Clinical Effectiveness, Safety, and Cost-Effectiveness
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Dose Escalation
These clinical trials or observational studies report changes in dosage (increase or decrease) in ETN or IFX, to maintain efficacy
Yes No Not specified Comments1. Duration ≥3 months 2. RA as specified by authors 3. Treatment with ETN or IFX 4. Clear denominator: dosages reported for all patients in cohort or trial – clear denominator (no case series)
5. Sufficient data reported Sequence of Administration
These clinical trials or observational studies report the effectiveness of different sequencing or time of initiation of anti-TNF therapy. For this component, all the included RCTs and observational studies included will be examined to determine the impact of disease staging or use of biologic agents at initial treatment or after failure with other drugs. In addition to the specific criteria for RCT or observational studies, the following criteria are required to be included in sequence studies.
Yes No Not specified Comments1. Selected RCT or observational study 2. Clear identification of sequence of administration 3. Sufficient data reported SWITCHING ANTI-TNF
RCTs or observational studies reporting clinical response after switching anti-TNF agents
Yes No Not specified Comments1. RCT or observational study 1. Duration ≥3 months 2. RA as specified by authors 3. Treatment with ETN or IFX, switched to other anti-TNF 5. Clinical outcomes ≥1 of the following: ACR outcomes (TJC, SJC, pain, patient global, physician
global, function, acute phase reactants) DAS ACR improvement criteria EULAR improvement criteria radiologic damage AE
5. Sufficient data reported
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Step 3 – Inclusion or Exclusion Form Clinical Effectiveness Rater Author ID Source (Initials) ETANERCEPT Master ID INFLIXIMAB *Parent study=large-scale project leading to different subset of articles.
PREVIOUS RATINGS ID Step 1 rating Step 2 rating Clinical effectiveness Economic evaluation
DESIGNS RCT/CCT ETANERCEPT RCT/CCT INFLIXIMAB OBSERVATIONAL EFFECTIVENESS ETN (N≥30) OBSERVATIONAL EFFECTIVENESS IFX (N≥30) OBSERVATIONAL EFFECTIVENESS Both (N≥30) CASE SERIES (N<30) CASE REPORTS (N=1) OTHER SPECIFY
Is this a parent study*? (check if yes) Does this article have a parent study? (check if yes)
If yes, specify parent study (author and year)
Parent study identification
Adjudicator (check if yes)
Comments:
GENERAL EXCLUSION REASONS children pharmacokinetics different therapy laboratory drug development methods gene therapy other diseases genetics RA general comments: other (no drug, no disease)
SAFETY ONLY (not otherwise included)
OF INTEREST
Specify:
FINAL INCLUSION Full paper
Abstract only, reviewed
ETANERCEPT RCT/CCT (at least 6 months) If so, was it at least 12 months?
INFLIXIMAB RCT/CCT (at least 6 months) If so, was it at least 12 months?
OBSERVATIONAL (ETN OR IFX)
EFFECTIVENESS (at least 12 months)
DOSE ESCALATION (at least 3 months) SEQUENCE OF ADMINISTRATION
SWITCHING ANTI-TNF
FINAL EXCLUSION RA patients poorly defined
(no ACR criteria)
Duration <6 months
Disease activity not specified
No clear control group
No clinical outcomes
Insufficient data reported
Duration <12 months
<30 patients
No clinical outcomes
Insufficient data reported
<3 months
RA poorly specified
Insufficient data reported
RCT <6 months / obsvervation <12 months
Insufficient data
Unclear identification of sequence of administration
Duration <3 months
RA patients poorly defined
No clinical outcomes
Insufficient data
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APPENDIX 4: Data Extraction Forms Clinical review — data extraction
Form 1 – Data sets and study quality baseline 12 months None 3 months 18 months Single Blind – patient
6 months 24 months Single Blind – observer 9 months 36 months Double blind Triple blind Reference Manager ID Title Language of publication Year published Journal title Volumes and pages Primary author Country of primary author Publication type Location of trial Review type Funding not specified Granting body Industry Other source of funding
Data set ID
Date
Data collected by
Duration of study (months)
REFERENCE MANAGER INFORMATION
GEOGRAPHY AND PUBLICATIONS
FUNDING
OUTCOMES REPORTED AT OTHER TIMEPOINTS: BLINDING
Inclusion Criteria Diagnosed with RA Appropriate doses? Relevant outcomes? Adequate data? Adequate duration? Included Original study Study related to
Excluded No OMERACT outcomes No placebo group Withdrawal study Insufficient data Follow-up study
Jadad Study Quality RCT RCT bonus RCT double blinded study? Double blind bonus Withdrawals described? Jadad score ____________
STUDY QUALITY Concealment of allocation
adequate
unclear
inadequate
not used
Attrition (losses to follow-up) Analysis of completers? <80% overall or not reported ≥80% Intention to treat explicit, clear Intention to treat statistics
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Form 2 – Outcomes
Measured? Circle one
Reported? Circle one
Measure Used
Minimum Score
Maximum Score
Improvements Circle one
Tender joint count YES NO YES NO High Low
Tender joint index YES NO YES NO High Low
Swollen joint count YES NO YES NO High Low
Swollen joint index YES NO YES NO High Low
Pain YES NO YES NO High Low
Global patient YES NO YES NO High Low
Global physician YES NO YES NO High Low
Functional status YES NO YES NO High Low
X-rays YES NO YES NO High Low
Quality of life YES NO YES NO High Low
ESR YES NO YES NO High Low
Other: ACR YES NO YES NO High Low
Other: EULAR YES NO YES NO High Low
Other: DAS YES NO YES NO High Low
Data set ID Date
Comments:
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Form 3 – Study Characteristics
INCLUDE FREQUENCY SCHEME VIA
TREATMENT AND DOSAGE
TREATMENT AND DOSAGE
TREATMENT AND DOSAGE
Intervention class
Combination?
N randomized
% females
Mean age (SD)
Median, range of age
Mean of disease duration (SD)
Median of disease ddration
Minimum, maximum of disease duration
% positive R F
Concurrent DMARD? (Yes/No)
Concurrent DMARD %
Concurrent steroids? (yes or no)
Concurrent steroids %
Previous steroids
Previous DMARD
Data set ID Date
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Form 4A – Continuous Outcome Data-Baseline
INTERVENTION INTERVENTION INTERVENTION
Tender joint count N Mean Method SD Method N Mean Method SD Method N Mean Method SD Method
Tender joint index
Swollen joint count
Swollen joint index
Pain
Global patient
Global physician
Functional status
Walking distance
Quality of life
ESR
X-ray scores
CRP
DAS
Data Set ID Date
Method for Calculating Mean and SD
1) reported 6) imputed from IQ range 2) calculated 7) imuted from other data
3) calculated from graphs 8) imputed from other papers
4) imputed from median
5) imputed from range
Comments
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*A composite index for estimating improvement in individual RA patients that requires responses in four of six selected measures: ≥20% for morning stiffness, Westergren erythrocyte sedimentation rate, joint pain/tenderness score and joint swelling score, ≥2 on 5-grade scale, or from grade 2 to grade 1 for patient’s and physician’s overall assessment of current disease severity.
INTERVENTION INTERVENTION INTERVENTION INTERVENTION Number with feature Total N Number with feature Total N Number with feature Total N Number with feature Total N
INTERVENTION INTERVENTION INTERVENTION INTERVENTION Number with feature Total N Number with feature Total N Number with feature Total N Number with feature Total N
Radiologic erosions
Comments
Data set ID Date of data
collection Date collected by
BASELINE
Comments
TIME POINT
Radiologic erosions
ACR20
ACR50
Paulus*
ACR70
Form 5 – Outcome Data (Other)
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INTERVENTION INTERVENTION INTERVENTION Withdrawals Side-Effects Comments Withdrawals Side-Effects Comments Withdrawals Side-Effects Comments
N
Total withdrawals
Lack of efficacy
Adverse effects
Concurrent disease
Other withdrawals
Gastrointestinal problems
Upper GI problems
Lower GI problems
MC problems
Renal toxicity
Liver abnormality
Hematology
Infection
Headache or dizziness
Cardiovascular
Deaths
Pulmonary
Drug termination
Serious morbidity
Hospitalization
Mortality
TIMEPOINT: Data set ID Date Form 6 – Withdrawals and Side-Effects
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APPENDIX 5: Clinical Review—Excluded Studies RCTs <12 months duration
1. Brennan FM, Browne KA, Green PA, Jaspar JM, Maini RN, Feldmann M. Reduction of serum matrix metalloproteinase 1 and matrix metalloproteinase 3 in rheumatoid arthritis patients following anti-tumour necrosis factor-alpha (cA2) therapy. Br J Rheumatol 1997;36(6):643-50.
2. Durez P, Nzeusseu TA, Lauwerys BR, Manicourt DH, Verschueren P, Westhovens R, et al. A randomised comparative study of the short term clinical and biological effects of intravenous pulse methylprednisolone and infliximab in patients with active rheumatoid arthritis despite methotrexate treatment. Ann Rheum Dis 2004;63(9):1069-74.
3. Elliott MJ, Maini RN, Feldmann M, Kalden JR, Antoni C, Smolen JS, et al. Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis. Lancet 1994;344(8930):1105-10.
4. Feldmann M, Elliott MJ, Brennan FM, Maini RN. Use of anti-tumor necrosis factor antibodies in rheumatoid arthritis. J Interferon Res 1994;14(5):299-300.
5. Genovese MC, Cohen S, Moreland L, Lium D, Robbins S, Newmark R, et al. Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis Rheum 2004;50(5):1412-9.
6. Kalden-Nemeth D, Grebmeier J, Antoni C, Manger B, Wolf F, Kalden JR. NMR monitoring of rheumatoid arthritis patients receiving anti-TNF-alpha monoclonal antibody therapy. Rheumatol Int 1997;16(6):249-55.
7. Kavanaugh A, St Clair EW, McCune WJ, Braakman T, Lipsky P. Chimeric anti-tumor necrosis factor-alpha monoclonal antibody treatment of patients with rheumatoid arthritis receiving methotrexate therapy. J Rheumatol 2000;27(4):841-50.
8. Keystone EC, Schiff MH, Kremer JM, Kafka S, Lovy M, DeVries T, et al. Once-weekly administration of 50 mg etanercept in patients with active rheumatoid arthritis: results of a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2004;50(2):353-63.
9. Lan JL, Chou SJ, Chen DY, Chen YH, Hsieh TY, Young M. A comparative study of etanercept plus methotrexate and methotrexate alone in Taiwanese patients with active rheumatoid arthritis: a 12-week, double-blind, randomized, placebo-controlled study. J Formos Med Assoc 2004;103(8):618-23.
10. Lorenz HM, Grunke M, Hieronymus T, Antoni C, Nusslein H, Schaible TF, et al. In vivo blockade of tumor necrosis factor-alpha in patients with rheumatoid arthritis: longterm effects after repeated infusion of chimeric monoclonal antibody cA2. J Rheumatol 2000;27(2):304-10.
11. Maini R, St Clair EW, Breedveld F, Furst D, Kalden J, Weisman M, et al. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. Lancet 1999;354(9194):1932-9.
12. Maini RN, Breedveld FC, Kalden JR, Smolen JS, Davis D, Macfarlane JD, et al. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum 1998;41(9):1552-63.
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13. Mathias SD, Colwell HH, Miller DP, Moreland LW, Buatti M, Wanke L. Health-related quality of life and functional status of patients with rheumatoid arthritis randomly assigned to receive etanercept or placebo. Clin Ther 2000;22(1):128-39.
14. Maurice MM, Van der Graaff WL, Leow A, Breedveld FC, Van Lier RAW, Verweij CL. Treatment with monoclonal anti-tumor necrosis factor alpha antibody results in an accumulation of TH1 CD4+ T cells in the peripheral blood of patients with rheumatoid arthritis. Arthritis Rheum 1999;42(10):2166-73.
15. Moreland LW, Margolies G, Heck LW, Saway A, Blosch C, Hanna R, et al. Recombinant soluble tumor necrosis factor receptor (p80) fusion protein: toxicity and dose finding trial in refractory rheumatoid arthritis. J Rheumatol 1996;23(11):1849-55.
16. Moreland LW, Baumgartner SW, Schiff MH, Tindall EA, Fleischmann RM, Weaver AL, et al. Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. N Engl J Med 1997;337(3):141-7.
17. Moreland LW, Schiff MH, Baumgartner SW, Tindall EA, Fleischmann RM, Bulpitt KJ, et al. Etanercept therapy in rheumatoid arthritis: a randomized, controlled trial. Ann Intern Med 1999;130(6):478-86.
18. Paleolog EM, Hunt M, Elliott MJ, Feldmann M, Maini RN, Woody JN. Deactivation of vascular endothelium by monoclonal anti-tumor necrosis factor alpha antibody in rheumatoid arthritis. Arthritis Rheum 1996;39(7):1082-91.
19. Perkins DJ, St Clair EW, Misukonis MA, Weinberg JB. Reduction of NOS2 overexpression in rheumatoid arthritis patients treated with anti-tumor necrosis factor alpha monoclonal antibody (cA2). Arthritis Rheum 1998;41(12):2205-10.
20. Smeets TJ, Kraan MC, van Loon ME, Tak PP. Tumor necrosis factor alpha blockade reduces the synovial cell infiltrate early after initiation of treatment, but apparently not by induction of apoptosis in synovial tissue. Arthritis Rheum 2003;48(8):2155-62.
21. Weinblatt ME, Kremer JM, Bankhurst AD, Bulpitt KJ, Fleischmann RM, Fox RI, et al. A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med 1999;340(4):253-9.
RCTs subgroup analysis
1. Criswell LA, Lum RF, Turner KN, Woehl B, Zhu Y, Wang J, et al. The influence of genetic variation in the HLA-DRB1 and LTA-TNF regions on the response to treatment of early rheumatoid arthritis with methotrexate or etanercept. Arthritis Rheum 2004;50(9):2750-6.
2. Smolen JS, Han C, Bala M, Maini RN, Kalden JR, van der HD, et al. Evidence of radiographic benefit of treatment with infliximab plus methotrexate in rheumatoid arthritis patients who had no clinical improvement: a detailed subanalysis of data from the anti-tumor necrosis factor trial in rheumatoid arthritis with concomitant therapy study. Arthritis Rheum 2005;52(4):1020-30.
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RCTs laboratory study
1. Moreland LW, Bucy RP, Weinblatt ME, Mohler KM, Spencer-Green GT, Chatham WW. Immune function in patients with rheumatoid arthritis treated with etanercept. Clin Immunol 2002;103(1):13-21.
2. St Clair EW, Wagner CL, Fasanmade AA, Wang B, Schaible T, Kavanaugh A, et al. The relationship of serum infliximab concentrations to clinical improvement in rheumatoid arthritis: results from ATTRACT, a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2002;46(6):1451-9.
RCTs commentary, report on other included studies
1. Medical progress: on the trail of new arthritis treatments. Harv Health Lett 1997;23(1):7.
2. Antoni C, Kalden JR. Combination therapy of the chimeric monoclonal anti-tumor necrosis factor alpha antibody (infliximab) with methotrexate in patients with rheumatoid arthritis. Clin Exp Rheumatol 1999;17(6 Suppl 18):S73-7.
3. Bathon JM, Genovese MC. The Early Rheumatoid Arthritis (ERA) trial comparing the efficacy and safety of etanercept and methotrexate. Clin Exp Rheumatol 2003;21(5 Suppl 31):S195-7.
Observational studies or uncontrolled follow-up studies with <12 months duration or <30 subjects
1. Alessandri C, Bombardieri M, Papa N, Cinquini M, Magrini L, Tincani A, et al. Decrease of anti-cyclic citrullinated peptide antibodies and rheumatoid factor following anti-TNFalpha therapy (infliximab) in rheumatoid arthritis is associated with clinical improvement. Ann Rheum Dis 2004;63(10):1218-21.
2. Baeten D, De Keyser F, Veys EM, Theate Y, Houssiau FA, Durez P. Tumour necrosis factor alpha independent disease mechanisms in rheumatoid arthritis: a histopathological study on the effect of infliximab on rheumatoid nodules. Ann Rheum Dis 2004;63(5):489-93.
3. Balanescu A, Radu E, Nat R, Regalia T, Bojinca V, Ionescu R, et al. Early and late effect of infliximab on circulating dendritic cells phenotype in rheumatoid arthritis patients. Int J Clin Pharmacol Res 2005;25(1):9-18.
4. Bartram D, Sheeran T, Price T, Mulherin D. Anti-tumour necrosis factor therapy in the West Midlands [letter]. Rheumatology 2004;43(3):400-1.
5. Buch MH, Marzo-Ortega H, Bingham SJ, Emery P. Long-term treatment of rheumatoid arthritis with tumour necrosis factor alpha blockade: outcome of ceasing and restarting biologicals [letter]. Rheumatology (Oxford) 2004;43(2):243-4.
6. Buch MH, Seto Y, Bingham SJ, Bejarano V, Bryer D, White J, et al. C-reactive protein as a predictor of infliximab treatment outcome in patients with rheumatoid arthritis: defining subtypes of nonresponse and subsequent response to etanercept. Arthritis Rheum 2005;52(1):42-8.
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7. Capria A, De Nardo D, De Sanctis G, Simonelli AR, Kroegler B, Silvestri F, et al. Endothelial dysfunction in rheumatoid arthritis is improved by anti-tumor necrosis factoralpha treatment. Eur J Inflamm 2004;2(3):113-8.
8. Caramaschi P, Canestrini S, Biasi D, Carletto A, Scambi C, Scarperi A, et al. Infliximab in aggressive and refractory rheumatoid arthritis: a pilot study [in Italian]. Recenti Prog Med 2002;93(1):19-24.
9. Catrina AI, Lampa J, Ernestam S, af KE, Bratt J, Klareskog L, et al. Anti-tumour necrosis factor (TNF)-alpha therapy (etanercept) down-regulates serum matrix metalloproteinase (MMP)-3 and MMP-1 in rheumatoid arthritis. Rheumatology (Oxford) 2002;41(5):484-9.
10. Crnkic M, Mansson B, Larsson L, Geborek P, Heinegard D, Saxne T. Serum cartilage oligomeric matrix protein (COMP) decreases in rheumatoid arthritis patients treated with infliximab or etanercept. Arthritis Res Ther 2003;5(4):R181-5.
11. Cuchacovich M, Ferreira L, Aliste M, Soto L, Cuenca J, Cruzat A, et al. Tumour necrosis factor-alpha (TNF-alpha) levels and influence of -308 TNF-alpha promoter polymorphism on the responsiveness to infliximab in patients with rheumatoid arthritis. Scand J Rheumatol 2004;33(4):228-32.
12. Davis D, Charles PJ, Potter A, Feldmann M, Maini RN, Elliott MJ. Anaemia of chronic disease in rheumatoid arthritis: in vivo effects of tumour necrosis factor alpha blockade. Br J Rheumatol 1997;36(9):950-6.
13. De Rycke L, Verhelst X, Kruithof E, Van den BF, Hoffman IEA, Veys EM, et al. Rheumatoid factor, but not anti-cyclic citrullinated peptide antibodies, is modulated by infliximab treatment in rheumatoid arthritis. Ann Rheum Dis 2005;64(2):299-302.
14. Drynda S, Kuhne C, Kekow J. Soluble tumour necrosis factor receptor treatment does not affect raised transforming growth factor bETN levels in rheumatoid arthritis. Ann Rheum Dis 2002;61(3):254-6.
15. Elkayam O, Caspi D, Reitblatt T, Charboneau D, Rubins JB. The effect of tumor necrosis factor blockade on the response to pneumococcal vaccination in patients with rheumatoid arthritis and ankylosing spondylitis. Semin Arthritis Rheum 2004;33(4):283-8.
16. Elliott MJ, Maini RN, Feldmann M, Long-Fox A, Charles P, Katsikis P, et al. Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor alpha. Arthritis Rheum 1993;36(12):1681-90.
17. Elliott MJ, Maini RN, Feldmann M, Long-Fox A, Charles P, Bijl H, et al. Repeated therapy with monoclonal antibody to tumour necrosis factor alpha (cA2) in patients with rheumatoid arthritis. Lancet 1994;344(8930):1125-7.
18. Fabris M, Tolusso B, Di Poi E, Assaloni R, Sinigaglia L, Ferraccioli G. Tumor necrosis factor-alpha receptor II polymorphism in patients from southern Europe with mild-moderate and severe rheumatoid arthritis. J Rheumatol 2002;29(9):1847-50.
19. Familian A, Voskuyl AE, van Mierlo GJ, Heijst HA, Twisk JWR, Dijkmans BAC, et al. Infliximab treatment reduces complement activation in patients with rheumatoid arthritis. Ann Rheum Dis 2005;64(7):1003-8.
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20. Fernandez-Nebro A, Tomero E, Ortiz-Santamaria V, Castro MC, Olive A, de Haro M, et al. Treatment of rheumatic inflammatory disease in 25 patients with secondary amyloidosis using tumor necrosis factor alpha antagonists. Am J Med 2005;118(5):552-6.
21. Ferraccioli GF, Assaloni R, Di Poi E, Gremese E, De Marchi G, Fabris M. Rescue of combination therapy failures using infliximab, while maintaining the combination or monotherapy with methotrexate: results of an open trial. Rheumatology (Oxford) 2002;41(10):1109-12.
22. Fiocco U, Ferro F, Vezzu M, Cozzi L, Checchetto C, Sfriso P, et al. Rheumatoid and psoriatic knee synovitis: clinical, grey scale, and power Doppler ultrasound assessment of the response to etanercept. Ann Rheum Dis 2005;64(6):899-905.
23. Fitzcharles MA, Clayton D, Menard HA. The use of infliximab in academic rheumatology practice: an audit of early clinical experience. J Rheumatol 2002;29(12):2525-30.
24. Flendrie M, Creemers MCW, Welsing PMJ, Van Riel PLCM. The influence of previous and concomitant leflunomide on the efficacy and safety of infliximab therapy in patients with rheumatoid arthritis: a longitudinal observational study. Rheumatology 2005;44(4):472-8.
25. Garces M, Lozada CJ. Pharmacologic management of rheumatoid arthritis. J Clin Outcomes Manage 2004;11(9):585-92.
26. Godinho F, Godfrin B, El Mahou S, Navaux F, Zabraniecki L, Cantagrel A. Safety of leflunomide plus infliximab combination therapy in rheumatoid arthritis. Clin Exp Rheumatol 2004;22(3):328-30.
27. Hansen KE, Cush J, Singhal A, Cooley DA, Cohen S, Patel SR, et al. The safety and efficacy of leflunomide in combination with infliximab in rheumatoid arthritis. Arthritis Rheum 2004;51(2):228-32.
28. Heiberg MS, Nordvag B, Mikkelsen K, Rodevand E, Kaufmann C, Mowinckel P, et al. The comparative effectiveness of tumor necrosis factor-blocking agents in patients with rheumatoid arthritis and patients with ankylosing spondylitis: a six-month, longitudinal, observational, multicenter study. Arthritis Rheum 2005;52(8):2506-12.
29. Hermann J, Mueller T, Fahrleitner A, Dimai HP. Early onset and effective inhibition of bone resorption in patients with rheumatoid arthritis treated with the tumour necrosis factor alpha antibody infliximab. Clin Exp Rheumatol 2003;21(4):473-6.
30. Hurlimann D, Forster A, Noll G, Enseleit F, Chenevard R, Distler O, et al. Anti-tumor necrosis factor-alpha treatment improves endothelial function in patients with rheumatoid arthritis. Circulation 2002;106(17):2184-7.
31. Irace C, Mancuso G, Fiaschi E, Madia A, Sesti G, Gnasso A. Effect of anti TNFalpha therapy on arterial diameter and wall shear stress and HDL cholesterol. Atherosclerosis 2004;177(1):113-8.
32. Jacobsson Lennart TH, Turesson C, Gulfe A, Kapetanovic MC, Petersson IF, Saxne T, et al. Treatment with tumor necrosis factor blockers is associated with a lower incidence of first cardiovascular events in patients with rheumatoid arthritis. J Rheumatol 2005;32(7):1213-8.
33. Kiely PD, Johnson DM. Infliximab and leflunomide combination therapy in rheumatoid arthritis: an open-label study. Rheumatology (Oxford) 2002;41(6):631-7.
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34. Klimiuk PA, Sierakowski S, Domyslawska I, Chwiecko J. Effect of repeated infliximab therapy on serum matrix metalloproteinases and tissue inhibitors of metalloproteinases in patients with rheumatoid arthritis. J Rheumatol 2004;31(2):238-42.
35. Korczowska I, Hrycaj P, Lacki JK. Does infliximab decrease bone turnover in rheumatoid arthritis patients. Joint Bone Spine 2003;70(5):398-400.
36. Kucharz EJ, Gozdzik J, Kopec M, Kotulska A, Lewicki M, Pieczyrak R, et al. A single infusion of infliximab increases the serum endostatin level in patients with rheumatoid arthritis. Clin Exp Rheumatol 2003;21(2):273-4.
37. Labarca C, Massardo L, Garcia PI, Jacobelli S. Effectiveness of infliximab in patients with inflammatory arthritis refractory to conventional treatment [in Spanish]. Rev Med Chil 2003;131(10):1157-64.
38. Martinez A, Salido M, Bonilla G, Pascual-Salcedo D, Fernandez-Arquero M, De Miguel S, et al. Association of the major histocompatibility complex with response to infliximab therapy in rheumatoid arthritis patients. Arthritis Rheum 2004;50(4):1077-82.
39. Mugnier B, Balandraud N, Darque A, Roudier C, Roudier J, Reviron D. Polymorphism at position -308 of the tumor necrosis factor alpha gene influences outcome of infliximab therapy in rheumatoid arthritis. Arthritis Rheum 2003;48(7):1849-52.
40. Nikas SN, Temekonidis TI, Zikou AK, Argyropoulou MI, Efremidis S, Drosos AA. Treatment of resistant rheumatoid arthritis by intra-articular infliximab injections: a pilot study. Ann Rheum Dis 2004;63(1):102-3.
41. Nissinen R, Leirisalo-Repo M, Peltomaa R, Palosuo T, Vaarala O. Cytokine and chemokine receptor profile of peripheral blood mononuclear cells during treatment with infliximab in patients with active rheumatoid arthritis. Ann Rheum Dis 2004;63(6):681-7.
42. Ohshima S, Saeki Y, Mima T, Sasai M, Nishioka K, Ishida H, et al. Long-term follow-up of the changes in circulating cytokines, soluble cytokine receptors, and white blood cell subset counts in patients with rheumatoid arthritis (RA) after monoclonal anti-TNF alpha antibody therapy. J Clin Immunol 1999;19(5):305-13.
43. Padyukov L, Lampa J, Heimburger M, Ernestam S, Cederholm T, Lundkvist I, et al. Genetic markers for the efficacy of tumour necrosis factor blocking therapy in rheumatoid arthritis. Ann Rheum Dis 2003;62(6):526-9.
44. Papadaki HA, Kritikos HD, Valatas V, Boumpas DT, Eliopoulos GD. Anemia of chronic disease in rheumatoid arthritis is associated with increased apoptosis of bone marrow erythroid cells: improvement following anti-tumor necrosis factor-alpha antibody therapy. Blood 2002;100(2):474-82.
45. Pawlik A, Ostanek L, Brzosko I, Brzosko M, Masiuk M, Machalinski B, et al. Therapy with infliximab decreases the CD4+CD28- T cell compartment in peripheral blood in patients with rheumatoid arthritis. Rheumatol Int 2004;24(6):351-4.
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46. Ravindran J, Shenker N, Bhalla AK, Lachmann H, Hawkins P. Case report: response in proteinuria due to AA amyloidosis but not Felty's syndrome in a patient with rheumatoid arthritis treated with TNF-alpha blockade. Rheumatology 2004;43(5):669-72.
47. Ribbens C, Andre B, Marcelis S, Kaye O, Mathy L, Bonnet V, et al. Rheumatoid hand joint synovitis: gray-scale and power Doppler US quantifications following anti-tumor necrosis factor-alpha treatment: pilot study. Radiology 2003;229(2):562-9.
48. Schotte H, Schluter B, Willeke P, Mickholz E, Schorat MA, Domschke W, et al. Long-term treatment with etanercept significantly reduces the number of proinflammatory cytokine-secreting peripheral blood mononuclear cells in patients with rheumatoid arthritis. Rheumatology (Oxford) 2004;43(8):960-4.
49. Schotte H, Schorat MA, Willeke P, Domschke W, Gaubitz M. Etanerceptbehandlung bei rheumatoider Arthritis - monozentrische Langzeitbeobachtung uber vier Jahre [Four-year observation of etanercept therapy for rheumatoid arthritis in a single German center]. Z Rheumatol 2005;64(4):265-73.
50. Shenker N, Haigh R, Clarke A. Worse patient VAS occurs at weeks 7 and 8 after infliximab infusions. Ann Rheum Dis 2005;64(3):502-3.
51. Shergy WJ, Isern RA, Cooley DA, Harshbarger JL, Huffstutter JE, Hughes GM, et al. Open label study to assess infliximab safety and timing of onset of clinical benefit among patients with rheumatoid arthritis. J Rheumatol 2002;29(4):667-77.
52. Singh R, Cuchacovich R, Huang W, Espinoza LR. Infliximab treatment in a patient with rheumatoid arthritis on hemodialysis. J Rheumatol 2002;29(3):636-7.
53. Smith GR, Tymms KE, Falk M. Etanercept treatment of renal amyloidosis complicating rheumatoid arthritis. Intern Med J 2004;34(9-10):570-2.
54. Smith JR, Levinson RD, Holland GN, Jabs DA, Robinson MR, Whitcup SM, et al. Differential efficacy of tumor necrosis factor inhibition in the management of inflammatory eye disease and associated rheumatic disease. Arthritis Rheum 2001;45(3):252-7.
55. Sokka T, Pincus T. Contemporary disease modifying antirheumatic drugs (DMARD) in patients with recent onset rheumatoid arthritis in a US private practice: methotrexate as the anchor drug in 90% and new DMARD in 30% of patients. J Rheumatol 2002;29(12):2521-4.
56. Straub RH, Pongratz G, Scholmerich J, Kees F, Schaible TF, Antoni C, et al. Long-term anti-tumor necrosis factor antibody therapy in rheumatoid arthritis patients sensitizes the pituitary gland and favors adrenal androgen secretion. Arthritis Rheum 2003;48(6):1504-12.
57. Tak PP, Taylor PC, Breedveld FC, Smeets TJ, Daha MR, Kluin PM, et al. Decrease in cellularity and expression of adhesion molecules by anti-tumor necrosis factor alpha monoclonal antibody treatment in patients with rheumatoid arthritis. Arthritis Rheum 1996;39(7):1077-81.
58. Taylor PC, Peters AM, Glass DM, Maini RN. Effects of treatment of rheumatoid arthritis patients with an antibody against tumour necrosis factor alpha on reticuloendothelial and intrapulmonary granulocyte traffic. Clin Sci (Lond) 1999;97(1):85-9.
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59. Temekonidis TI, Georgiadis AN, Alamanos Y, Bougias DV, Voulgari PV, Drosos AA. Infliximab treatment in combination with cyclosporin A in patients with severe refractory rheumatoid arthritis. Ann Rheum Dis 2002;61(9):822-5.
60. Terslev L, Torp-Pedersen S, Qvistgaard E, Kristoffersen H, Rogind H, Danneskiold-Samsoe B, et al. Effects of treatment with etanercept (Enbrel, TNRF:Fc) on rheumatoid arthritis evaluated by Doppler ultrasonography. Ann Rheum Dis 2003;62(2):178-81.
61. Thonhofer R, Gaugg M, Kriessmayr M, Neumann HJ, Erlacher L. Spontaneous remission of marginal zone B cell lymphoma in a patient with seropositive rheumatoid arthritis after discontinuation of infliximab-methotrexate treatment. Ann Rheum Dis 2005;64(7):1098-9.
62. Ulfgren AK, Andersson U, Engstrom M, Klareskog L, Maini RN, Taylor PC. Systemic anti-tumor necrosis factor alpha therapy in rheumatoid arthritis down-regulates synovial tumor necrosis factor alpha synthesis. Arthritis Rheum 2000;43(11):2391-6.
63. Unger L, Kayser M, Nusslein HG. Successful treatment of severe rheumatoid vasculitis by infliximab. Ann Rheum Dis 2003;62(6):587-8.
64. van Oosterhout M, Levarht EWN, Sont JK, Huizinga TWJ, Toes REM, Van Laar JM. Clinical efficacy of infliximab plus methotrexate in DMARD naive and DMARD refractory rheumatoid arthritis is associated with decreased synovial expression of TNF alpha and IL18 but not CXCL12. Ann Rheum Dis 2005;64(4):537-43.
65. van Vollenhoven RF, Ernestam S, Harju A, Bratt J, Klareskog L. Etanercept versus etanercept plus methotrexate: a registry-based study suggesting that the combination is clinically more efficacious. Arthritis Res Ther 2003;5(6):R347-51.
66. Vassallo R, Matteson E, Thomas CF, Jr. Clinical response of rheumatoid arthritis-associated pulmonary fibrosis to tumor necrosis factor-alpha inhibition. Chest 2002;122(3):1093-6.
67. Vis M, Wolbink GJ, Lodder MC, Kostense PJ, Van De Stadt RJ, De Koning MHMT, et al. Early changes in bone metabolism in rheumatoid arthritis patients treated with infliximab [multiple letters]. Arthritis Rheum 2003;48(10):2996-7.
68. Vis M, Nurmohamed MT, Wolbink G, Voskuyl AE, De Koning MHMT, Van De Stadt RJ, et al. Short term effects of infliximab on the lipid profile in patients with rheumatoid arthritis. J Rheumatol 2005;32(2):252-5.
69. Wittwer H, Schattenkirchner M, Kellner H. Sichere und effiziente therapie mit infliximab in der rheumatologie: ein teilstationares modell [Safe and efficient therapy with Infliximab in rheumatology-A partly inpatient model]. Aktuelle Rheumatol 2003;28(1):49-52.
70. Wolbink GJ, Voskuyl AE, Lems WF, de Groot E, Nurmohamed MT, Tak PP, et al. Relationship between serum trough infliximab levels, pretreatment C reactive protein levels, and clinical response to infliximab treatment in patients with rheumatoid arthritis. Ann Rheum Dis 2005;64(5):704-7.
71. Zamarron C, Maceiras F, Mera A, Gomez-Reino JJ. Effect of the first infliximab infusion on sleep and alertness in patients with active rheumatoid arthritis. Ann Rheum Dis 2004;63(1):88-90.
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Observational: drugs combined in report
1. Cannon GW, Holden WL, Juhaeri J, Dai W, Scarazzini L, Stang P. Adverse events with disease modifying antirheumatic drugs (DMARD): a cohort study of leflunomide compared with other DMARD. J Rheumatol 2004;31(10):1906-11.
2. Wolfe F, Michaud K. Fatigue, rheumatoid arthritis, and anti-tumor necrosis factor therapy: an investigation in 24,831 patients. J Rheumatol 2004;31(11):2115-20.
Observational: pharmacokinetics
1. Zhou H, Mayer PR, Wajdula J, Fatenejad S. Unaltered etanercept pharmacokinetics with concurrent methotrexate in patients with rheumatoid arthritis. J Clin Pharmacol 2004;44(11):1235-43.
Observational: no clinical outcomes
1. Kaiser MJ, Bozonnat MC, Jorgensen C, Daures JP, Sany J. Effect of etanercept on tenosynovitis and nodules in rheumatoid arthritis. Arthritis Rheum 2002;46(2):559-60.
2. Wiland P, Wiela-Hojenska A, Glowska A, Chlebicki A, Hurkacz M, Orzechowska-Juzwenko K, et al. Renal function in rheumatiod arthritis patients treated with methotrexate and infliximab. Clin Exp Rheumatol 2004;22(4):469-72.
Observational: no TNF antagonists
1. Jobanputra P, Maggs F, Homer D, Bevan J. Monitoring and assessing the safety of disease-modifying antirheumatic drugs: a West Midlands experience. Drug Saf 2002;25(15):1099-105.
Observational: laboratory study
1. Garnero P, Gineyts E, Christgau S, Finck B, Delmas PD. Association of baseline levels of urinary glucosyl-galactosyl-pyridinoline and type II collagen C-telopeptide with progression of joint destruction in patients with early rheumatoid arthritis. Arthritis Rheum 2002;46(1):21-30.
2. Gonzalez-Juanatey C, Testa A, Garcia-Castelo A, Garcia-Porrua C, Llorca J, Gonzalez-Gay MA. Active but transient improvement of endothelial function in rheumatoid arthritis patients undergoing long-term treatment with anti-tumor necrosis factor alpha antibody. Arthritis Rheum 2004;51(3):447-50.
3. Gonzalez-Juanatey C, Gonzalez-Gay MA. Long-term rheumatoid arthritis and endothelial dysfunction. Atherosclerosis 2004;176(1):197-8.
4. Ostanek L, Pawlik A, Brzosko I, Brzosko M, Sterna R, Drozdzik M, et al. The urinary excretion of pyridinoline and deoxypyridinoline during rheumatoid arthritis therapy with infliximab. Clin Rheumatol 2004;23(3):214-7.
5. Paleolog EM, Young S, Stark AC, McCloskey RV, Feldmann M, Maini RN. Modulation of angiogenic vascular endothelial growth factor by tumor necrosis factor alpha and interleukin-1 in rheumatoid arthritis. Arthritis Rheum 1998;41(7):1258-65.
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Observational: different therapy
1. Pavletic SZ, Klassen LW, Pope R, O'Dell JR, Traynor AE, Haire CE, et al. Treatment of relapse after autologous blood stem cell transplantation for severe rheumatoid arthritis. J Rheumatol Suppl 2001;64:28-31.
Observational: descriptive, no follow-up
1. Sokka T, Willoughby J, Yazici Y, Pincus T. Databases of patients with early rheumatoid arthritis in the USA. Clin Exp Rheumatol 2003;21(5 Suppl 31):S146-53.
2. Sokka T, Pincus T. Eligibility of patients in routine care for major clinical trials of anti-tumor necrosis factor alpha agents in rheumatoid arthritis. Arthritis Rheum 2003;48(2):313-8.
Observational: addition of MTX to anti-TNF
1. Cohen JD, Zaltni S, Kaiser MJ, Bozonnat MC, Jorgensen C, Daures JP, et al. Secondary addition of methotrexate to partial responders to etanercept alone is effective in severe rheumatoid arthritis. Ann Rheum Dis 2004;63(2):209-10.
Observational: other diseases
1. Mealy NE, Bayes M. Infliximab. Drugs Future 2004;29(4):416-8.
Observational: commentary
1. Schmutz JL, Barbaud A, Trechot P. Effects secondaires des anti-TNFalpha [Side-effects of anti-TNFalpha agents]. Ann Dermatol Venereol 2004;131(2):226.
2. Winthrop KL, Siegel JN, Jereb J, Taylor Z, Iademarco MF. Tuberculosis associated with therapy against tumor necrosis factor alpha. Arthritis Rheum 2005;52(10):2968-74.
Observational: combined diseases
1. Cairns AP, Taggart AJ. Anti-tumour necrosis factors therapy for severe inflammatory arthritis: two years of experience in Northern Ireland. Ulster Med J 2002;71(2):101-5.
2. Geborek P, Saxne T, Emery P, Panayi G, Sturrock RD, Williams BD. Clinical protocol for monitoring of targeted therapies in rheumatoid arthritis [multiple letters]. Rheumatology 2000;39(10):1159-61.
Observational: dose escalation, insufficient data
1. Bingham SJ, Buch MH, Tennant A, Emery P. The impact of escalating conventional therapy in rheumatoid arthritis patients referred for anti-tumour necrosis factor-alpha therapy. Rheumatology 2004;43(3):364-8.
2. Buch MH, Conaghan PG, Quinn MA, Bingham SJ, Veale D, Emery P. True infliximab resistance in rheumatoid arthritis: a role for lymphotoxin alpha? Ann Rheum Dis 2004;63(10):1344-6.
3. Clunie G, Voules S, Watts R. Dose reduction of etanercept: can we treat more patients using a fixed budget? Rheumatology (Oxford) 2003;42(4):600-1.
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APPENDIX 6: Clinical Review — Study Characteristics
Table 1: Study characteristics — IFX RCTs
Study Lipsky ATTRACT33
Maini Continuation of
ATTRACT34 St Clair
ASPIRE35 Taylor36 Quinn37
Country multi-centre: UK; US; The Netherlands; Germany; Austria
as in ATTRACT multi-centre: UK; US; The Netherlands; Germany;
Austria; Canada
single centre: UK single centre: UK
Funding Centocor Centocor Centocor Centocor; Arthritis Research Campaign
Arthritis Research Campaign
Number of participants 428 as in ATTRACT 1,049 24 20 Participant characteristics mean age: 52.6+11.8 years
DD: 10.6+8.4 years RF(+): 77% to 84%
as in ATTRACT mean age: 50.4+12.6 years DD: 0.8 to 0.9 years RF(+): 71% to 73%
mean age: 51 to 55 years
DD: 1.33 to 1.64 years RF(+): NR
mean age: 51 to 53 years DD: 6 to 7.4 months RF(+): 60% to 70%
Previous treatment criterion failure to MTX 12.5 mg/week as in ATTRACT no previous DMARDs failure to MTX 12.5 mg/week
no previous DMARDs
Intervention [N=number of patients per group]
IFX 3 mg/kg q8wk+MTX, N=86 IFX 3 mg/kg q4wk+MTX, N=86 IFX 10 mg/kg q8wk+MTX, N=87 IFX 10 mg/kg q4wk+MTX, N=81
N=55 N=57 N=64 N=55
IFX 3 mg/kg/q8wk+MTX, N=373
IFX 6 mg/kg/q8wk+MTX, N=378
IFX 5 mg/kg/q8wk+MTX
N=12
IFX 3mg/kg/q8wk+MTX N=10
Comparators N= number of patients per group
MTX 12.5 mg/week to 35 mg/week, N=88
N=28 MTX 7.5 mg/week to 20 mg/week, N=298
MTX 12.5 mg/week to 17.5 mg/week, N=12
MTX 7.5 mg/week up to 25 mg/week, N=10
Follow-up number of weeks 54 102 54 54 104 Primary outcomes efficacy ACR20, ACR50, ACR70, VAS,
HAQ, SF-36 HAQ, SF-36, vdH-S
score, ACR-N, HAQ, SF-36, DAS28 vdH-S score, ultrasound
assessment MRI-measured synovitis
Secondary outcomes efficacy SJC, TJC, CRP, vdH-S score ACR20, ACR50, ACR70, ANA, anti-
dsDNA
ACR20, ACR50, ACR70, ACR 90, vdH-S score, ANA,
anti-dsDNA
ACR20, ACR50, DAS28, ESR
ACR20, ACR50, ACR70, DAS28, HAQ, vdH-S,
RAQoL Outcomes assessment number of weeks
0, 10, 30, 42, 54 62, 70, 78, 86, 94, 102
0, 24, 54 0, 4, 18, 54 0, 14, 30, 46, 54, 62, 78, 104
Allocation concealment adequate as in ATTRACT adequate adequate adequate
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Table 1: Study characteristics — IFX RCTs
Study Lipsky ATTRACT33
Maini Continuation of ATTRACT34
St Clair ASPIRE35 Taylor36 Quinn37
Jadad score 5 3 4 3 4 Blinding yes yes (X-rays), no
(clinical outcomes) yes yes yes (clinical outcomes up to 54
weeks), no (clinical outcomes >54 weeks)
Intention to treat yes yes or unclear for some outcomes (X-rays)
no (completers) unclear yes
ACR=American College of Rheumatology; ANA=antinuclear auto antibodies; anti-dsDNA=anti-double-stranded deoxyribonucleic acid; ASPIRE=Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset; ATTRACT=Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group; CRP=C-reactive protein; DAS=disease activity score; DD=disease duration; DMARDs=disease-modifying anti-rheumatic drugs; HAQ=Health Assessment Questionnaire; IFX=infliximab; MRI=magnetic resonance imaging; MTX=methotrexate; NR=not reported; RF=rheumatoid factor; SJC=swollen-joint count; TJC=tender-joint count; UK=United Kingdom; US=United States; vdH-S=van der Heijde-Sharp score; wk=weeks; y=years.
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Table 2: Study characteristics — ETN RCTs
Study Bathon ERA38
Kosinski Subanalysis of
ERA41
Genovese Continuation of
ERA39
Klareskog TEMPO40
Population origin multi-centre: US; Canada as in ERA as in ERA multi-centre: Sweden; Netherlands; Spain; Czech Republic; Australia; UK;
Belgium; France; Greece; US Funding Immunex Wyeth-Ayerst,
Immunex Immunex Wyeth
Number of participants 632 424 as in RA 682 Participant characteristics, N=number of patients per group
mean age: 49 to 51 years, DD: mean 11 to 12 months 74% <18 months,
RF(+): 87% to 89%
as in ERA as in ERA mean age: 52.5 to 53 years DD: 6.3 to 6.8
RF(+): 71% to 76% Previous treatment criterion DMARDs discontinued at least 4 weeks before study
began, patients MTX-naïve as in ERA as in ERA failure to at least one DMARD; no
MTX within 6 months of enrolment Intervention, N=number of patients per group
ETN 10 mg SC biw, N=208 ETN 25 mg SC biw, N=207
ETN 25 mg SC biw,N=207
N=166 N=177
ETN 25 mg SC biw alone, N=223 ETN 25 mg SC biw+MTX, N=231
Comparator MTX 7.5 mg/week to 20 mg/week, N=217 as in ERA N=169 MTX 7.5 mg/week to 20 mg/week, N=228
Follow-up number of weeks 52 52 2 years 52
Primary outcomes ACR20, ACR50, ACR70, ACR-N SF-36 ACR20, ACR50, ACR70
ACR-N (AUC); ACR20, ACR50, ACR70, DAS28, HAQ,
Secondary outcomes vdH-S score HAQ vdH-S score, HAQ vdH-S score
Outcomes assessment 2 weeks, 2, 4, 6, 8, 10, 12 months as per ERA 15, 18, 21, 24 months
0, 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, 52 weeks
Allocation concealment unclear unclear as in ERA Adequate Jadad score 2 NR as in ERA 4
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Table 2: Study characteristics — ETN RCTs
Study Bathon ERA38
Kosinski Subanalysis of
ERA41
Genovese Continuation of
ERA39
Klareskog TEMPO40
Blinding yes yes no (clinical outcomes), yes (X-
rays)
yes
Intention to treat yes yes unclear* yes (clinical outcomes), X-rays for most patients
(some unavailable)
*Authors used last observation carried forward (LOCF) from y1 to y2; apparently not from baseline; vdH-S=van der Heijde-Sharp score; MRI=magnetic resonance imaging; DD=disease duration; y=years; MTX=methotrexate; HAQ=Health Assessment Questionnaire; NR=not reported; DMARDs=disease modified anti-rheumatic drugs; ACR=American College of Rheumatology; DAS=disease activity score; ANA=antinuclear auto antibodies; anti-dsDNA=anti-double-stranded deoxyribonucleic acid; ERA=Etanercept and/versus Methotrexate in Patients with Early Rheumatoid Arthritis; TEMPO=Trial of Etanercept and Methotrexate with Radiographic Patients Outcomes; UK=United Kingdom; US=United States of America; RF=rheumatoid factor; ETN=etanercept; biw=biweekly; SC=subcutaneous; SJC=swollen-joint count; TJC=tender-joint count; CRP=C-reactive protein; mo=months; wk=weeks; mg=milligrams; y=year
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Table 3: Study characteristics — observational studies on effectiveness
Study Study Type Country Conflict of Interest
Sample Size
Intervention (number of patients)
Duration of Follow-up Outcomes NOS
Score Abarca48 controlled
retrospective cohort US Wyeth
Pharma 244 ETN (128), IFX (89),
ETN+IFX (27) >2 years discontinuation,
dosage 6
Baumgartner42 controlled prospective cohort
US Immunex 671 recent onset RA: ETN (207) established RA: ETN (464)
3 years clinical (SJC, ACR, HAQ), discontinuation, timing
7
Breedveld63 controlled prospective cohort (open follow-up to trial)
UK, US, Germany, Austria, The Netherlands
Centocor 428 MTX, IFX 3 mg/kg q8wk, IFX 3 mg/kg q4wk, IFX 10 mg/kg q8wk, IFX 10 mg/kg q4wk
102 weeks clinical (radiologic)
7
Carreno64 uncontrolled prospective cohort
Spain none disclosed
62 IFX+MTX (62) 18 months clinical (ACR, HAQ), discontinuation
5
Chevillotte-Maillard65
controlled prospective cohort
France none disclosed
83 IFX (83) 1 year (median)
discontinuation 5
Durez51 controlled prospective cohort
Belgium Schering-Plough
511 stable dose: IFX (405) increased dose: IFX (106)
62 weeks clinical (ACR) 6
Feltelius66 uncontrolled prospective cohort
Sweden Wyeth Research
1,073 1st year ETN (820), 2nd to 4th year ETN (253)
4 years clinical (DAS), discontinuation, safety
5
Fleischmann67 controlled retrospective cohort
US Immunex 1,128 <65 years old, ETN (931); >65 years old, ETN (197)
1 year clinical (SJC, ACR), age
2
Flendrie68 controlled prospective cohort
The Netherlands none disclosed
230 ADM (94), ETN (16), IFX (120)
>30 months discontinuation, safety
7
Flendrie69 controlled prospective cohort
The Netherlands none disclosed
162 IFX (105), LEF+IFX (57) 3 years discontinuation, clinical (DAS)
8
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Table 3: Study characteristics — observational studies on effectiveness
Study Study Type Country Conflict of Interest
Sample Size Intervention Duration of
Follow-up Outcomes NOS Score
Geborek22 controlled prospective cohort
Sweden none disclosed
404 ETN (166), IFX (135), LEF (103)
1 year clinical (ACR), discontinuation, safety
7
Genovese70 controlled prospective cohort (open follow-up to trial)
US Immunex 468 MTX followed by ETN (143), low ETN followed by high ETN (163), high ETN followed by high ETN (162)
3 years clinical (SJC, ACR, DAS, HAQ, radiologic)
9
Kremer71 uncontrolled prospective cohort (open follow-up to trial)
US Immunex 79 ETN+MTX (79) 3 years clinical (SJC, ACR, HAQ), safety, discontinuation
5
Moreland72 uncontrolled prospective cohort
US Immunex 628 ETN (628) 30 months clinical (SJC, ACR, HAQ), discontinuation
5
Ortiz-Garcia73 controlled retrospective cohort
Spain none disclosed
45 IFX+LEF (45) 20 months discontinuation 4
Sfriso74 uncontrolled prospective cohort (open follow-up to trial)
Italy none disclosed
63 IFX (63) 1 year clinical (SJC, ACR)
not applicable
Sidiropoulos20 uncontrolled prospective cohort
Greece Schering-Plough
68 IFX (68) 12 infusions discontinuation 4
Stern49 uncontrolled retrospective cohort, uncontrolled prospective cohort
US Centocor 1,718 study 1 IFX (394), study 2 IFX (1,324)
3 years discontinuation 5
5
Voulgari75 uncontrolled prospective cohort
Greece none disclosed
84 IFX (84) 3 years clinical (ACR), discontinuation
5
Yazici76 uncontrolled prospective cohort (biologics registry, single centre)
US none disclosed
88 ETN (88) 1 year discontinuation, safety
8
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Table 3: Study characteristics — observational studies on effectiveness
Study Study Type Country Conflict of Interest
Sample Size Intervention Duration of
Follow-up Outcomes NOS Score
Zink77 controlled retrospective cohort
Germany Essex Pharma, Wyeth Pharma, Amgen, Abbott
1,523 ETN (511), IFX (343), ANAK (70), DMARDs (599)
1 year discontinuation 7
ACR=American College of Rheumatology improvement criteria; ANAK=Anakinra; DAS=disease activity score; ETN=etanercept; HAQ=Health Assessment Questionnaire; IFX=infliximab; LEF=leflunamide; ND=none disclosed; RA=rheumatoid arthritis; SJC=swollen joint count; US=United States.
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Table 4: Study characteristics — dose escalation
Study Study Type Country Conflict of Interest
Sample Size (n) Biologic Agent (n)
Duration of Follow-
up Outcomes
Administrative Databases Harley19 database study of Medicare and health
plan claims US Centocor 2,662 IFX (141), ETN (853),
[MTX (1,668)] 1 year dosage, costs
Gilbert43 database study of pharmacy and medical claims data from 61 US health plans
US Abbott 1,548 IFX (598), ETN (950) 1 year dosage, frequency, costs
Stockl44 database and medical chart study of pharmacy claims
US Centocor 369 IFX (164), ETN (205) unclear dosage, frequency, costs
George45 database study of managed health care plans
US Amgen 201 IFX (201) 8 infusions dosage, costs
Etemad46* database study of large health-plan claims
US Amgen 1,114* IFX (424), ETN (690) mean 14.8 months
dosage, costs
Ollendorf47 database study of large health-plan claims
US Bristol-Myers Squibb
1,236 IFX (1,236) mean 15 months
dosage, frequency, costs
Observational Studies Geborek22† prospective multi-centre cohort study Sweden none disclosed 404 IFX (135), ETN (166),
[LEF (103)] >4 months dosage,
frequency (IFX only)
Abarca48 retrospective multi-centre review of medical records
US Amgen 244 IFX (89), ETN (128), [Both (27)]
mean IFX 15 months, ETN 29 months
dosage
Sidiropoulos20 prospective single-centre cohort study Greece Schering-Plough
68 IFX (68) 12 infusions dosage, frequency, clinical
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*8% of patients had psoriatic arthritis; †clinical study that does not report clinical outcomes in relation to dose escalation; ETN=etanercept; IFX=infliximab; LEF=leflunamide; MTX=methotrexate; US=United States.
Table 4: Study characteristics — dose escalation
Study Study Type Country Conflict of Interest
Sample Size (n)
Biologic Agent (n)
Duration of Follow-up Outcomes
Stern49 Study 1 retrospective cohort study of 2 clinical practices
US Centocor 394 IFX (394) ≥4 infusions dosage, frequency
Stern49 Study 2 cross-sectional self-report survey of patients enrolled in National Data Bank for Rheumatic Diseases
US Centocor 1,324 IFX (1,324) mean 1.4 years dosage, clinical
Van Vollenhoven50
retrospective nested case-control in population-based research registry: IFX at 5 mg/kg to 7 mg/kg compared to IFX at 3 mg/kg and ETN
Sweden none disclosed 124 IFX cases (44), IFX controls (44), ETN controls (36)
unclear, ongoing follow-up
clinical
Durez51 prospective open study where patients without improvement at 30 weeks increased their IFX dose by 100 mg
Belgium Schering-Plough Centocor
511 IFX (511) 1 year dosage, clinical
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Table 5: Study characteristics — switching between IFX and ETN
Study Study Type Country Conflict of Interest Sample Size Type of
Switch: n Duration
Follow-up Outcomes
Ang52 retrospective review of medical records
single centre: US ND total 142, switching 29
ETN to IFX 24, IFX to ETN 5
ETN 8.2 months, IFX 10 months (unclear if before or after switch)
joint counts: patients with 20% improvement, ESR, CRP
Brocq53 retrospective review (possibly chart review)
single centre: France
ND total 131; 67 IFX; 64 ETN; switching 14
ETN to IFX 6; IFX to ETN 8
ETN to IFX 3 to 8 months, IFX to ETN 4 to 12 months
response undefined
Brocq53 retrospective review; update of previous study, focus is on switch to ADM
single centre: France
ND total 275; 120 IFX; 155 ETN; switching 46 (of these, 18 switched to ADM)
NR NR for IFX to ETN switch
response undefined, NR for IFX to ETN switch
Van Vollenhoven55*
case series from database registry of biologic agents (STURE) (prospective data collection)
multi-centre: Sweden
ND switching 31 (25 RA)
ETN to IFX 18 (14 RA); IFX to ETN 13 (11 RA)
best result for ETN to IFX 6 months, IFX to ETN 7 months
SJC, DAS28, ACR-N
Van Vollenhoven21*
similar data as previous study plus review of literature (8 studies)
multi-centre: Sweden
ND same
Favalli56* prospective open-label series
single centre: Italy ND switching 15 (8 RA, 7 JRA)
ETN to IFX 1 IFX to ETN 14
6 months TJC, SJC, DAS28, HAQ, global VAS, pain, CRP, ESR
Gomez-Puerta57 case series (retrospective)
single centre: Spain ND switching 12 IFX to ETN 12 6 months DAS28, EULAR response
Sanmartí58 case series (retrospective)
single centre: Spain
ND switching 14 IFX to ETN 12
Haraoui59 prospective open-label series
multi-centre: Canada
Amgen Wyeth
switching 25 (only 22 reported)
IFX to ETN 22 12 weeks ACR responses (and individual measures)
Hansen60 retrospective chart review: comparison of patients switching with naïve patients
multi-centre: US Aventis total 93; switching 20; initiating IFX 73
ETN to IFX 20; mean dose 3.2 mg/kg; controls 73 (anti-TNF-naïve starting IFX)
ETN to IFX: mean 5.7 infusions; controls mean 5.5 infusions
TJC, SJC, global, CRP, ESR, discontinuations
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Table 5: Study characteristics — switching between IFX and ETN
Study Study Type Country Conflict of Interest Sample Size Type of
Switch: n Duration
Follow-up Outcomes
initiating therapy Mean dose 4.4 mg/kg All pts in both groups also received LEF
Yazici61
IFX registry, comparison of patients switching with naïve patients initiating therapy (prospective data collection)
single centre: US ND total 88 (only 62 included in final analysis); switching 37 (21); initiating IFX 51 (41)
ETN to IFX 21 reported
mean 6.7 months mHAQ, pain scores, morning stiffness, discontinuations
*Includes other inflammatory arthritis; ND=none disclosed; AEs=adverse events; ADM=adalimumab; NR=not reported.
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APPENDIX 7: Clinical Review Results — Therapeutic Timing, RCTs
Table 1: Therapeutic timing — relative risk (benefit) according to DD at 54 weeks IFX+MTX versus MTX
DD >2 DD <2 Study ACR50 ACR70 Study ACR50 ACR70
ATTRACT 54 weeks33 ASPIRE 54 weeks35 Taylor 54 weeks36 Quinn 54 weeks37
4.14 (2.00, 8.57)* no data no data no data
7.89 (1.97, 31.66)* no data no data no data
ATTRACT 54 weeks32 ASPIRE Study 54 weeks34 Taylor 54 weeks35 Quinn 54 weeks36
no data 1.50 (1.24, 1.81)*
7.00 (0.40, 122.44) 2.00 (0.88, 4.54)
no data 1.63 (1.27, 2.09)*
no data 2.33 (0.83, 6.54)
POOLED POOLED 1.53 (1.27, 1.84)* 1.65 (1.29, 211)* ETN+MTX versus MTX TEMPO 52 weeks40 1.60 (1.35, 1.90)* 2.27 (1.67, 3.04)* no data no data no data ETN versus MTX ERA 52 weeks38 TEMPO 52 weeks40
no data 1.12 (0.91, 1.37)
no data 1.28 (0.90, 1.83)
ERA 52 weeks37 TEMPO 52 weeks39
1.14 (0.93, 1.40) no data
1.14 (0.81, 1.60) no data
*statistically significant
Table 2: Therapeutic timing — RD (benefit) and NNT according to DD at 54 week IFX+MTX versus MTX
DD >2 DD < 2 Study ACR50 NNT ACR70 NNT Study ACR50 NNT ACR70 NNT
ATTRACT 54 weeks33 ASPIRE 54 weeks35 Taylor 54 weeks36 Quinn 54 weeks37
25% (17%, 33%)* no data no data no data
4.0* no datano datano data
16% (11%, 21%)*no data no data no data
6.2* no data no data no data
ATTRACT 54 weeks32 ASPIRE study 54 weeks34 Taylor 54 weeks35 Quinn 54 weeks36
no data 16% (9%, 23%)* 25% (−1%, 51%) 40% (1%, 79%)*
no data 6.2* 4.0
2.5*
no data 13% (7%, 19%)*
no data 40% (0%, 80%)
no data 7.6*
no data 2.5*
POOLED no data no data no data no data POOLED 17% (10%, 23%)* 5.8* 14% (8%, 20%)* 7.1* ETN+MTX versus MTX
TEMPO 52 weeks40 24% (16%, 32%)*
4.2* 24% (16%, 32%)*
4.2* TEMPO 52 weeks39 no data no data no data no data
ETN versus MTX ERA 52 weeks38 TEMPO 52 weeks40
no data 5% (−4%, 14%)
no data 20.0
no data 5% (−2%, 13%)
no data 20.0
ERA 52 weeks37 TEMPO 52 weeks39
6% (−4%, 15%) no data
16.7 no data
3% (−5%, 11%) no data
33.3 no data
*statistically significant
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Table 3: Therapeutic timing — RR (benefit) according to previous treatment with MTX at 54 weeks IFX+MTX versus MTX
Previous MTX MTX-Naïve Study ACR50 ACR70 Study ACR50 ACR70
ATTRACT 54 weeks33 ASPIRE 54 weeks35 Taylor 54 weeks36 Quinn 54 weeks37
4.14 (2.00, 8.57)* no data
7.00 (0.40, 122.44) no data
7.89 (1.97, 31.66)* no data no data no data
ATTRACT 54 weeks32 ASPIRE Study 54 weeks34 Taylor 54 weeks35 Quinn 54 weeks36
no data 1.50 (1.24, 1.81)*
no data 2.00 (0.88, 4.54)
no data 1.63 (1.27, 2.09)*
no data 2.33 (0.83, 6.54)
POOLED 4.26 (2.11, 8.62)* no data POOLED 1.51 (1.26, 1.82)* 1.65 (1.29, 2.11)* ETN+MTX versus MTX TEMPO 52 weeks40 1.60 (1.35, 1.90)* 2.27 (1.67, 3.04)* TEMPO 52 weeks39 no data no data
ETN versus MTX ERA 52 weeks38 TEMPO 52 weeks40
no data 1.12 (0.91, 1.37)
no data 1.28 (0.90, 1.83)
ERA 52 weeks37 TEMPO 52 weeks39
1.14 (0.93, 1.40) no data
1.14 (0.81, 1.60) no data
*statistically significant.
Table 4: Therapeutic timing — RD (benefit) and NNT according to previous treatment with MTX at 54 weeks IFX+MTX versus MTX
Previous MTX MTX-naive Study ACR50 NNT ACR70 NNT Study ACR50 NNT ACR70 NNT
ATTRACT 54 weeks33 ASPIRE 54 weeks35 Taylor 54 weeks36 Quinn 54 weeks37
25% (17%, 33%)* no data no data
25% (−1%, 51%)
4.0* no datano data
4.0
16% (11%, 21%)*no data no data no data
6.2* no data no data no data
ATTRACT 54 weeks32 ASPIRE 54 weeks34 Taylor 54 weeks35 Quinn 54 weeks36
no data 16% (9%, 23%)*
no data 40% (1%, 79%)*
no data 6.2*
no data 2.5*
no data 13% (7%, 19%)*
no data 40% (0%, 80%)
no data 7.6
no data 2.5
POOLED 25% (18%, 32%)* 4.0* no data no data POOLED 16% (10%, 23%)* 6.2* 14% (8%, 20%)*
7.1*
ETN+MTX versus MTX TEMPO 52 weeks40 24% (16%, 32%)* 4.2* 24% (16%, 32%)* 4.2* TEMPO 52 weeks39 no data no data
ETN versus MTX ERA 52 weeks38 TEMPO 52 weeks40
no data 5% (−4%, 14%)
no data 20.0
no data 5% (−2%, 13%)
no data 20.0
ERA 52 weeks37 TEMPO 52 weeks39
6% (−4%, 15%) no data
16.7 no data
3% (−5%, 11%) no data
33.3 no data
*statistically significant.
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*statistically significant; WMD=weighted mean difference; SMD=standardized mean difference.
*statistically significant; WMD=weighted mean difference; SMD=standardized mean difference.
Table 5: Therapeutic timing — radiographic outcomes (total scores); WMD and SMD according to DD at 54 weeks DD >2 DD <2 Study N
WMD SMD Study N
WMD SMD
IFX+MTX versus MTX
ATTRACT 54 weeks33 ASPIRE 54 weeks35 Taylor 54 weeks36 Quinn 54 weeks37
285 722 12 10
−6.40 (−9.00, −3.8)* no data no data no data
−0.97 (−1.25, −0.69)* no data no data no data
ATTRACT 54 weeks32
ASPIRE 54 weeks34 Taylor 54 weeks35 Quinn 54 weeks36
285 722 12 10
no data −3.30 (−4.49, −2.11)* −8.90 (−14.97, −2.83)*
no data
no data −0.48 (−0.62, −0.34)* −1.13 (−2.01, −0.26)*
no data POOLED no data no data no data −3.51 (−4.68, −2.34)* −0.49 (−0.63, −0.36)* ETN+MTX versus MTX TEMPO 52 weeks40 218 −3.34 (−5.12, −1.56)* −0.36 (−0.55, −0.17)* TEMPO 52 weeks39 no data no data no data ETN versus MTX ERA 52 weeks38 TEMPO 52 weeks40
no data 212
no data −2.28 (−4.11, −0.45)*
no data −0.24 (−0.43, −0.05)*
ERA 52 weeks37 TEMPO 52 weeks39
207 no data
−0.59 (−3.42, 2.24) no data
−0.04 (−0.23, 0.15) no data
Table 6: Therapeutic timing — radiographic outcomes (total scores); WMD and SMD according to previous treatment with MTX at 54 weeks Previous MTX MTX-Naive Study N
WMD SMD Study N
WMD SMD IFX+MTX versus MTX ATTRACT 54 weeks33 ASPIRE 54 weeks35 Taylor 54 weeks36 Quinn 54 weeks37
285 722 12 10
−6.40 (−9.00, −3.8)* no data
−8.90 (−14.97, −2.83)* no data
−0.97 (−1.25, −0.69)* no data
−1.13 (−2.01, −0.26)* no data
ATTRACT 54 weeks32 ASPIRE 54 weeks34 Taylor 54 weeks35 Quinn 54 weeks36
285 722 12 10
no data −3.30 (−4.49, −2.11)*
no data no data
no data −0.48 (−0.62, −0.34)*
no data no data
POOLED −6.79 (−9.18, −4.40)* −0.99 (−1.25, −0.72)* no data no data no data ETN+MTX versus MTX TEMPO 52 weeks40 218 −3.34 (−5.12, −1.56)* −0.36 (−0.55, −0.17)* TEMPO 52 weeks39 no data no data
ETN versus MTX ERA 52 weeks38 TEMPO 52 weeks40
no data 212
no data −2.28 (−4.11, −0.45)*
no data −0.24 (−0.43, −0.05)*
ERA 52 weeks37 TEMPO 52 weeks39
207 no data
−0.59 (−3.42, 2.24) no data
−0.04 (−0.23, 0.15) no data
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APPENDIX 8: Clinical Review Results — Therapeutic Timing, Observational Study
Table 1: Therapeutic timing (observational study) discontinuation rates, SJC, ACR responses and HAQ Follow-up Outcome RA Status N Baseline
1 year 2 years 3 years recent RA 207 NR NR NR 59 (29%) Discontinuation, all
causes, n/N (%) established RA 464 NR NR NR 176 (38%) recent RA 207 NR NR NR 11 (5%) Discontinuation, lack
of efficacy, n/N (%) established RA 464 NR NR NR 42 (9%)
recent RA 207 23.5 (207) 9.0 (207) 7.0 (207) 6.0 (207) SJC mean (n) established RA 464 25.1 (464) 9.8 (464) 7.5 (464) 7.5 (464)
recent RA 207 NR NR NR 157/207 (76%) ACR20 n/N (%)
established RA 464 NR NR NR 357/464 (77%) recent RA 207 NR NR NR 116/207 (56%) ACR50 n/N (%)
established RA 464 NR NR NR 232/464 (50%) recent RA 207 NR NR NR 68/207 (33%) ACR70 n/N (%)
established RA 464 NR NR NR 130/464 (28%)
recent RA 207 NR NR NR 92/148 (62%) HAQ <1 n/N (%) established RA 464 NR NR NR 150/288 (52%)
recent RA 207 NR NR NR 39/148 (26%) HAQ=0 n/N (%) established RA 464 NR NR NR 40/288 (14%)
Source: Baumgartner et al.;42 NR=not reported.
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APPENDIX 9: Clinical Review Results — Dose Escalation
Table 1: Dose escalation in administrative database studies Study IFX ETN Comments
N Dose (mg) Initial (I) Final (F)
(% increase)
Dose interval Costs (US$) N Dose (mg), Initial (I), Final
(F) (% increase)
Dose interval Costs (US$)
Harley19 141 I=276, F=328 (19%)
annual costs of administration,
I=$10,446, F=$12,363 (18%)
853 I=59, F=54 (−8%)
NR
Gilbert43 598 Escalation in 58% (number
of vials; increase in
dose or frequency)
see dose annual costs total=$19,144, patients
with no escalation=$16,713;
patients with escalation=$20,915
(25%)
950 escalation in 18% (mean daily dose;
increase in dose or frequency)
see dose annual costs administration
stable, total=$13,977
Stockl44 164 I=3.5 mg/kg, F=4.2 mg/kg
(20%)
documented in 45% follow-up: 60% received q8wk (no information about other 40%)
drug costs, I=$13,936, F=$15,734 (13%)
205 I=27.9, F=25.7 (−8%)
documented in 70% follow-up: 84% received biweekly (no
information about other 16%)
drug costs stable $17,105
for 67% of administered IFX infusions, ≤expected number of vials used
George45 201 I=307 F=434 (41%)
billed charges per infusion, I=$3,388,
F=$4,916 (45%)
no data
no data no data no data dose escalation similar for ≥65 years and <65 years old
Etemad46 424 I=282 F=383 (29%)
annual costs of administration,
variation per dosing $17,799 to $23,332
(31%)
690 I=51.3, F=49.8 (−3%)
annual costs of administration stable, $17,818
Ollendorf47 1,236 I increased in 55%
increased in 22% patients with no escalation=$14,425;
patients with escalation=$22,283
(54%)
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Table 2: Dose escalation in clinical studies Study IFX ETN
N Dose (mg) Initial (I) Final (F)
(% increase)
Dose interval Clinical N Dose (mg) Initial (I), Final
(F) (% increase)
Dose interval
Clinical
Geborek22 135 dose increase or shortened interval in 57% of patients
see dose no data 166 NR NR no data
Abarca48 89 I=3.4 mg/kg, F=4.5 mg/kg (32%)
no data no data 128 I=25.0, F=25.8 (3%)
no data no data
Sidiropoulos20 68 dose increase in MTX or IFX in 79% of patients
increased to every 6 weeks in 73% of patients by the time of 12th infusion
mean point of adjustment week 8; with increase, 26% improved, 61% remained same, 13% worsened
no data
no data no data no data
Stern49 Study 1 394 I=3.6 mg/kg, 1 year= 4.9 mg/kg, F 2 years= 5.1 mg/kg (41%); dose increase in 61% of patients
no increase in frequency
median time to escalation 7 months
no data
no data no data no data
Stern49 Study 2 1,324 mean dose after 1.5 years= 5.0 mg/kg; if vial is charged for, mean dose after 1.5 years=5.5 mg/kg; dose increase in 56% of patients
no data
higher doses more frequent in patients with more severe disease, comorbidities, and fibromyalgia
no data
no data no data no data
van Vollenhoven50
44 dose increased from 3 mg/kg, to 5 to 7 mg/kg per infusion in cases
no increase in frequency
median decrease in DAS after 3 infusions 0.6, relative improvement similar to that observed in controls without dose increase (did not achieve same level as controls)
no data
no data no data no data
Durez51 511 dose increase in 22% of patients
no data patients requiring increase had worse baseline disease; with dose increase, ACR50 responses went from 12% to 25%; without increase, ACR50 responses went from 37% to 50%
no data
no data no data no data
NR=not reported; I=initial dose
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APPENDIX 10: Clinical Review Results — Switching between IFX and ETN
Table 1: Switching between IFX and ETN Study N
Switch/Total (%) Reason for
Switching (n) Method of Analysis Effectiveness Recurrence of AEs
Ang52 29/142 (20%) lack of efficacy, toxicity, other
cross-tabulation of all 29 patients for responses to IFX and ETN
no significant association with use of either drug in 20% improvement responses; 5/12 (42%) who did not respond to IFX responded to ETN; 7/14 (50%) who did not respond to ETN responded to IFX
no significant association with use of either drug for infections, hypersensitivity; significant association for anemia
Brocq53 14/131 (11%), ETN to IFX 6/64 (9%), IFX to ETN 8/67 (12%)
lack of efficacy, toxicity
number of respondents in each switch group
beneficial response: ETN to IFX 3/6 (50%); IFX to ETN 5/8 (62%)
1/4 (25%) patients experiencing hypersensitivity with 1st agent had hypersensitivity with 2nd; 1 patient developed neutropenia with both
Brocq54 46/275 (17%) lack of efficacy, toxicity
number of respondents for all IFX and/or ETN switches combined, study focus on switch to ADM
10/46 (22%) did not respond to IFX and/or ETN switch, and were switched to ADM (50% responded); additional 8 who received ETN only switched to ADM
NR for IFX or ETN switch
Van Vollenhoven55*
31 (no denominator), ETN to IFX n=18 (14 RA), IFX to ETN n=13 (11 RA)
ETN to IFX, lack of efficacy; IFX to ETN, toxicity and miscellaneous
best DAS28, ACR-N, and ACR20 before and after switch
ETN to IFX, n=18; DAS28, 4.8 to 3.6 (p<0.05); ACR-N, 17% to 40% (p=0.08); ACR20, 33% to 67% (p NR); IFX to ETN, n=13; DAS28, 4.1 to 3.6 (p<0.05); ACR-N, NS (data NR); ACR20, NS (data NR)
toxicity with IFX did not recur after switching to ETN
Van Vollenhoven21*
same as previous54 same as previous
Favalli56* 15 (no denominator) (8 RA, 7 JRA), ETN to IFX n=1, IFX to ETN n=14
ETN to IFX, lack of efficacy (1); IFX to ETN, lack of efficacy (8), toxicity (6)
mean change in outcomes 6 months after switch
results for RA subgroup (n=8), all switches pooled (p values NR); DAS28, 6.0 to 4.6; SJC, 12 to 7; ESR, 50 to 34
1 recurrence of angioedema
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ND=none disclosed; AEs=adverse events; ADM=adalimumab; NS=not significant; *included patients with other inflammatory arthritis; NR=not reported.
Table 1: Switching between IFX and ETN Study N Switch/total (%) Reason for switching (n) Method of
analysis Effectiveness Recurrence of AEs
Gomez-Puerta57 12 (no denominator), IFX to ETN n=12
lack of efficacy (12) mean change in DAS28 6 months after switch; proportion with good or moderate EULAR response
IFX to ETN, n=12; DAS28, 5.6 to 4.3 (p=0.02); EULAR response: good 2/12 (16%), moderate 8/12 (66%)
Sanmartí58 14 (no denominator), IFX to ETN n=14
lack of efficacy (12), toxicity (2)
same as previous57 no AEs with ETN
Haraoui59 25 (no denominator), IFX to ETN n=22 (only 22 reported)
lack of efficacy (19), toxicity (3)
number of respondents with ACR criteria
IFX to ETN, n=22; ACR20, 14/22 (64%); ACR50, 5/22 (23%); ACR70 1/22 (5%)
no serious AEs with ETN
Hansen60 20 (no denominator), ETN to IFX n=20, naïve controls starting IFX n=73
lack of efficacy (17), thrombocytopenia (1), miscellaneous (2)
comparison of mean outcome changes between patients switching and controls
swollen joint count, ETN to IFX, 14 to 5; controls, 13 to 5 (NS) erythrocyte sedimentation rate, ETN to IFX, 13 to 26; controls, 45 to 28 (p=0.04) patient global assessment, good to very good; ETN to IFX, 5/20 (25%); controls, 16/73 (21%) (NS) physician GL, good to very good (NS); ETN to IFX, 6/20 (30%); controls 16/73 (26%) (NS) discontinuations (lack of efficacy) ETN to IFX, 2/20 (10%); controls, 2/73 (2%)
patient with thrombocytopenia: persistence after switching
Yazici61 37/88 (42%), report on 62, ETN to IFX n=21, naïve controls starting IFX n=41
lack of efficacy (21) comparison of mean outcome changes between patients switching and controls (data not shown, only overall statements)
MHAQ, pain, morning stiffness ETN to IFX, no improvement; controls, significant improvement; discontinuations ETN to IFX, 6/21 (28%); controls 7/41 (17%)
no differences in AEs between groups