Strategies for optimal suppression of rheumatoid arthritis Kooij, S.M. van der

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(1)Strategies for optimal suppression of rheumatoid arthritis Kooij, S.M. van der. Citation Kooij, S. M. van der. (2009, January 22). Strategies for optimal suppression of rheumatoid arthritis. Retrieved from https://hdl.handle.net/1887/13425 Version:. Corrected Publisher’s Version. License:. Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden. Downloaded from:. https://hdl.handle.net/1887/13425. Note: To cite this publication please use the final published version (if applicable)..

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patients randomized. 126 assigned to sequential monotherapy (group 1). 121 assigned to step-up combination therapy (group 2). 133 assigned to initial combination therapy incl. prednisone (group 3). 128 assigned to initial combination therapy with MTX + IFX (group 4). 40 patients on delayed IFX. 10 patients on delayed IFX. 19 patients on delayed IFX. 120 patients on initial MTX + IFX. 1 patient missing data. 1 patient missing data. 67 patients started delayed MTX + IFX. 3 patients missing data. 117 patients started initial MTX + IFX. 3 patients dropped out. 67 patients completed 3-year follow-up. 114 patients completed 3-year follow-up. Figure 1. Flowchart of the study. Reasons for dropout were: deceased due to disseminated tuberculosis (n=1), deceased due to myocardial infarction (n=1), and patient refusal (n=1). IFX = inlfiximab, MIX = methothrexate.. .

(28) Table 1. Demographic and disease characteristics at the time of inclusion in the BeSt study of patients treated with initial IFX and delayed IFX. Initial IFX (n=117) Female sex (%) Age at diagnosis, mean ± SD RF positive (%). Delayed IFX (n=67). P value. 68. 81. 0.057. 53.8 ± 14.1. 49.8 ± 12.4. 0.054. 64. 75. 0.141. 23 (13-45). 29 (17-56). 0.175. Disease duration (weeks), median (IQR). 3 (1-5). 2 (1-5). 0.069. Tender joints (no.), mean ± SD. 13 ± 6. 16 ± 7. <0.001 0.049. Symptom duration (weeks), median (IQR). Swollen joints (no.), mean ± SD. 14 ± 7. 16 ± 6. ESR, median (IQR). 35 (19-56). 40 (22-68). 0.157. DAS, mean ± SD. 4.29 ± 0.8. 4.73 ± 0.8. 0.001. HAQ, mean ± SD. 1.36 ± 0.7. 1.49 ± 0.5. 0.159. Erosion score, median (IQR). 2.0 (0.5-5.0). 1.5 (0.5-3.5). 0.294. Narrowing score, median (IQR). 1.5 (0.0-3.8). 1.5 (0.0-4.0). 0.953. Total Sharp score, median (IQR). 4.0 (1.5-9.0). 3.0 (1.0-7.5). 0.568. IFX, infliximab; SD, standard deviation; RF, rheumatoid factor; IQR, interquartile range; ESR, erythrocyte sedimentation rate; DAS, disease activity score; HAQ, health assessment questionnaire.. *KHI>GLBMRFH=>E .A>IKHI>GLBMRFH=>EA:=:GHO>K:EE:<<NK:<RH?:G=BG<EN=>=MA>?HEEHPBG@ ;:L>. EBG> <HO:KB:M>L @>G=>K :@> :M BG<ENLBHG LRFIMHF =NK:MBHG =BL>:L> =NK:MBHG A>B@AM P>B@AM;H=RF:LLBG=>Q'#:E<HAHE<HGLNFIMBHGLFHDBG@KA>NF:MHB=?:<MHK, LM:MNL:GMB <R<EB<<BMKNEEBG:M>=I>IMB=>:GMB *LM:MNLIK>OBHNL:GMBF:E:KB:EMA>K:IR AHKFHG:E K>IE:<>F>GM MA>K:IR - - BG <:M>@HKB>L ≤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

(29) Table 2. Distribution of characteristics at study inclusion within propensity quintiles. Quintile. 1. 2. 3. 4. 5. Initial IFX (n=117). 28. 29. 13. 22. 25. Delayed IFX (n=67). 2. 6. 9. 18. 32. 0.03. 0.08. 0.14. 0.23. 0.44. 47. 54. 73. 80. 91 45.3. Propensity score, median Female sex (%) Age at diagnosis, mean. 60.3. 55.4. 55.0. 52.3. RF positive (%). 50. 63. 82. 63. 79. Symptom duration (weeks), median. 28. 27. 24. 22. 24. Tender joints (no.), mean. 10. 11. 14. 15. 17. Swollen joints (no.), mean. 10. 13. 14. 17. 17. ESR, median. 23. 31. 31. 41. 45. DAS, mean. 3.69. 4.11. 4.36. 4.76. 4.88. HAQ, median. 1.25. 1.25. 1.44. 1.50. 1.38. IFX, infliximab; RF, rheumatoid factor; ESR, erythrocyte sedimentation rate; DAS, disease activity score; HAQ, health assessment questionnaire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able 3. Radiographic progression greater than the smallest detectable change (SDC) after 3 years, and IFX discontinuation 2 years after the start of MTX + IFX in the initial and delayed MTX + IFX groups, adjusted for propensity score. Initial IFX. Delayed IFX. OR (95% CI). P-value. Patients with progression SHS > SDC, %. 26. 50 0.47 (0.24-0.95). 0.034. Patients who discontinued IFX due to a sustained DAS ≤2.4, %. 56. 29. 0.008. 2.56 (1.27-5.16). IFX, infliximab; OR, odds ratio; SHS, modified Sharp/van der Heijde Score; SDC, smallest detectable change; DAS, disease activity score.. .

(30) Table 4. Treatment outcome and required IFX doses 2 years after starting initial or delayed MTX + IFX. Initial IFX (n=117). Delayed IFX (n=67). P-value <0.001. Stopped IFX and still DAS ≤2.4, no. (%). 66 (56). 19 (29). max dose IFX 3mg/kg, no.. 38. 10. max dose IFX 6mg/kg, no.. 21. 8. max dose IFX 7.5mg/kg, no.. 4. 1. 3. . 22 (19). 27 (40). max dose IFX 3mg/kg, no.. 7. 5. max dose IFX 6mg /kg, no.. 4. 4. max dose IFX 7.5mg/kg, no.. 6. 5. max dose IFX 10mg/kg, no.. 5. 13. Failed on MTX + IFX, no. (%). 29 (25). 21 (31). max dose IFX 10mg/kg, no. Remained on MTX + IFX, no. (%). Due to toxicity, no.. 8. 6. Due to inefficacy, no.. 21. 13. Due to other reasons, no.. . 2. 0.002. 0.336. MTX, methotrexate; IFX, infliximab; DAS, disease activity score.. # 2=HL>:G=MK>:MF>GM=BL<HGMBGN:MBHG ?M>K:=CNLMF>GM?HKIKHI>GLBMRL<HK> I:MB>GMLMK>:M>=PBMABGBMB:E'.2# 2P>K>LB@GB. <:GMERFHK>EBD>ERMHA:O>=BL<HGMBGN>=# 2=N>MH:LNLM:BG>=-≤ ),# * M:;E> #GH?I:MB>GMLBGMA>BGBMB:E@KHNI :G=BGH?I:MB>GML BGMA>=>E:R>=@KHNI LN<<>LL?NE# 2=BL<HGMBGN:MBHGP:L:<AB>O>=HGER:?M>K:G# 2 =HL>BG<K>:L> .A>I>K<>GM:@>LH?I:MB>GML?:BEBG@HG'.2# 2 :LP>EE:LMA>K>:LHGL?HK ?:BENK>BGMA>@KHNILP>K><HFI:K:;E>.:;E> .AKHN@AHNMR>:KL I:MB>GMLMK>:M>=PBMA BGBMB:E'.2# 2K><>BO>=HG:O>K:@># 2BG?NLBHGL<HKK>LIHG=BG@MH:F>=B:G<NFNE:. MBO># 2=HL>H? F@

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(32) D@. delayed MTX+IFX 1.5. initial MTX+IFX. HAQ. 1.0. 0.5. 0.0 0. 3. 6. 9. 12. 15. 18. 21. 24. 27. 30. 33. 36. Figure 2. Functioning as measured by the Health Assessment Questionnaire (HAQ) during 3 years follow-up in the initial and delayed IFX groups, corrected for propensity score. To obtain corrected HAQ values, means adjusted for propensity quintile were estimated by repeated measures models. The grey rectangle represents the period (median 13 months, interquartile range, 12 to 17 months) during which patients in the delayed group started MTX + IFX.. time (months). >??B<:<RH?BGBMB:EO>KLNL=>E:R>=MK>:MF>GMPBMAFMQ:G=?MQ. .

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