APPENDIX 1: Literature Search Strategy...Infliximab and Etanercept in Rheumatoid Arthritis: Systematic Review of Long-term Clinical Effectiveness, Safety, and Cost-Effectiveness A-5

Infliximab and Etanercept in Rheumatoid Arthritis: Systematic Review of Long-term Clinical Effectiveness, Safety, and Cost-Effectiveness

A-1

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]


A-2

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



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


A-3

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



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


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


A-4

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.


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


A-5

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


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


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


A-6

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


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


A-7

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


A-8

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.


A-9

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


A-10

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.


A-11

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:


A-12

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


A-13

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



A-14

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



A-15

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



<3 months

RA poorly specified


RCT <6 months / obsvervation <12 months

Insufficient data

Unclear identification of sequence of administration

Duration <3 months

RA patients poorly defined


Insufficient data


A-16

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


A-17

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:


A-18

Form 3 – Study Characteristics

INCLUDE FREQUENCY SCHEME VIA

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


A-19

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


A-20

*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)


A-21

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


A-22

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.


A-23

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.


A-24

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.


A-25

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.


A-26

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.


A-27

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.


A-28

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.


A-29

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.


A-30

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.


A-31

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.


A-32

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


A-33

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.


A-34

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


A-35

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


A-36

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


A-37



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


A-38



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.


A-39

Table 4: Study characteristics — dose escalation


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


A-40

*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


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


A-41

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


A-42

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.


A-43

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


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


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


6% (−4%, 15%) no data

16.7 no data

3% (−5%, 11%) no data

33.3 no data

*statistically significant


A-44

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


4.14 (2.00, 8.57)* no data

7.00 (0.40, 122.44) 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


no data 1.12 (0.91, 1.37)

no data 1.28 (0.90, 1.83)


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


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


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


no data 5% (−4%, 14%)

no data 20.0

no data 5% (−2%, 13%)

no data 20.0


6% (−4%, 15%) no data

16.7 no data

3% (−5%, 11%) no data

33.3 no data

*statistically significant.


A-45

*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


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)*


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


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


no data 212

no data −2.28 (−4.11, −0.45)*

no data −0.24 (−0.43, −0.05)*


207 no data

−0.59 (−3.42, 2.24) no data

−0.04 (−0.23, 0.15) no data


A-46

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.


A-47

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%)


A-48

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


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


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


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


NR=not reported; I=initial dose


A-49

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


A-50

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

Documents

APPENDIX 1: Literature Search Strategy...Infliximab and Etanercept in Rheumatoid Arthritis: Systematic Review of Long-term Clinical Effectiveness, Safety, and Cost-Effectiveness A-5