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GRAND ROUND Safety of B iologic T herapy in R heumatic D iseases 使用生物製劑治療風濕疾病的安全性

GRAND ROUND Safety of B iologic T herapy in R heumatic D iseases 使用生物製劑治療風濕疾病的安全性. Department of Rheumatology, Allergy and Immunology Shue-Fen Luo 羅淑芬 17/FEB/2012. Contents. Recent advances in rheumatoid arthritis treatment Case presentation Safety of biological therapy

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GRAND ROUND Safety of B iologic T herapy in R heumatic D iseases 使用生物製劑治療風濕疾病的安全性

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  1. GRAND ROUND Safety of Biologic Therapy in Rheumatic Diseases使用生物製劑治療風濕疾病的安全性 Department of Rheumatology, Allergy and Immunology Shue-Fen Luo 羅淑芬 17/FEB/2012

  2. Contents • Recentadvancesinrheumatoidarthritistreatment • Casepresentation • Safetyofbiologicaltherapy • StudiesfromCGMH

  3. Biologic Therapy in Rheumatic Diseases • Rheumatoidarthritis • Ankylosingspondylitis • Psoriais • Psoriaticarthritis • Inflammatoryboweldisease • Juvenilearthritis • others

  4. Cytokine signalling pathways involved in RA Tocilizumab IL-4 IL-10 RF IL-4 IL-6 IL-10 Th2 Macrophage Etanercept Infliximab Adalimumab Golimumab Certolizumab ThO Abatacept Plasma cell IFNg IFNg IL-12 Rituximab B cell CD4 + T cell CD11 Synovium TNF IL-1 IL-6 OPGL CD69 CD11 CD69 Osteoclast Chondrocyte Fibroblast Tocilizumab Production of metalloproteinases and other effector molecules Migration of polymorphonuclear cells Erosion of bone and cartilage Choy EH, Panayi GS. N Engl J Med 2001;344:907-916

  5. Woodrick, R. S. & Ruderman, E. M. Nat. Rev. Rheumatol. 7, 639–652 (2011)

  6. Biological Agents for Rheumatic Diseases targeting on pathways involved in inflammation • TNF Etanercept (02/NOV/1998) Adalimumab (31/DEC/2002) Golimumab (24/APR/2009) • IL-1 (anakinra, 2001) • IL-6 (tocilizumab, 2010) • T-cell co-stimulatory pathway (abatacept, 2005) • B cell (rituximab, 2006)

  7. AdvancesinRheumatoidArthritisTreatment • Treatmentarmamentarium developmentofbiologicalagents • Treatmenttargetandclinicalmonitoring T2T intensivemonitoring • Treatmentstrategy earlytreatment intensivetreatment tightcontrol

  8. Measuresofdiseaseactivityofrheumatoidarthritis DAS-28,SDAI,CDAI 1.Remission(緩解) 2.Lowdiseaseactivity(低度疾病活動度) 3.Moderatediseaseactivity(中度疾病活動度) 4.Highdiseaseactivity(重度疾病活動度)

  9. DAS-28計算公式 DAS28 = 0.56 √ (TJC28) + 0.28 √ (SJC28) + 0.70 Ln (ESR) + 0.014 (GH)

  10. Algorithm to treat RA to Target Main target Adapt therapy if state is lost Adapt therapy according to disease activity Active RA Remission Sustained Remission Use a composite measure of disease activity every 1-3 months Assess disease activity about every 3-6 months Sustained low disease activity Low disease activity Alternative target Adapt therapy according to disease activity Adapt therapy If state is lost 10 Smolen et al (submitted)

  11. TREATMENT STRATEGY • earlytreatment (Comet) • intensivetreatment (Camera) • tightcontrol (Fin-RACo,TICORA,Camera, BeSt)

  12. Need for early and effective treatment in RA Inflammation Function Severity Time Interventions Adapted from Emery P, Salmon M. Ann Rheum Dis 1995; 54: 944.

  13. Patients with early RA treated with etanercept plus MTX show more improvement 100 *P<0.0001 †P=0.0004 MTX ETN + MTX 90 * 80% 80 * 70 64% † 59% 60 * 55% * 50% 48% 50 Subjects (%) 41% 39% 40 28% 28% 30 20 10 0 DAS28 Remission (DAS28 <2.6) n=263 MTX n=265 ETN + MTX DAS28 LDA (DAS28 ≤3.2) n=263 MTX n=265 ETN + MTX ACR 70 Response n=243 MTX n=256 ETN + MTX HAQ-DI Normalised (HAQ-DI ≤0.5) n=241 MTX n=256 ETN + MTX No Radiographic Progression (Δ in mTSS ≤0.5) n=230 MTX n=246 ETN + MTX 13 Emery P et al. Lancet 2008;372:375–382.

  14. BakkerMF,JacobsJW,VerstappenSM,BiilsmaJW: Tightcontrolinthetreatmentofrheumatoidarthritis:efficacyandfeasibility. AnnRheumDis.2007(11);66suppl3:iii56-60

  15. Tight control resulted in greater improvement and a higher percentageof patients meeting the preset aim of low disease activity or remission when compared to the control intervention. • In the FIN-RACo trial, analysing the subset of patients completing the study, 68% in the tight control group achieved remission (DAS28<2.6) verus41% in the contrast group. • In the TICORA study, 65% of patients in the tight control group versus 16% of the contrast group achieved remission, based on DAS<1.6 (p<0.0001). • In the CAMERA study, 50% of patients in the tight control group using a computer decision model achieved remission, versus 37% in the contrast group (p = 0.029). • The BeSt study consisted of only tight control groups aimed at a DAS<1.6; remission was achieved in 38-46% of patients. This is higher than the range of remission in earlier trials of 13-36%. BakkerMF,JacobsJW,VerstappenSM,BiilsmaJW: Tightcontrolinthetreatmentofrheumatoidarthritis:efficacyandfeasibility. AnnRheumDis.2007(11);66suppl3:iii56-60

  16. Major Side Effects • Infections Bacterial infections Atypical and opportunistic infections Viral complications • Malignancies non-lymphoma lymphoma • Autoimmune syndromes • Drug administration reactions infusion reactions injection site reactions

  17. Infections • Bacterial infections • Atypical and opportunistic infections TB Fungus Pneumocystis 3. Viral complications Varicella Zoster virus Hepatitis B Hepatitis C JC virus

  18. RA and infections • A large population-based retrospective study comparing RA patients with matched controls reported a nearly doubled incidence of documented infections in RA patients. • RA severity indices, such as presence of rheumatoid factor, increased sedimentation rate and extra-articular involvement are predictors of serious infection episodes in RA, in addition to corticosteroid use and the presence of comorbidities. • Infection is also partly responsible for the excess mortality rate in RA patients, with infection-related standardised mortality rates(SMR) in RA patients ranging from 4.2 to 14.9.

  19. Nat. Rev. Rheumatol. 7, 639–652 (2011)

  20. Pros and cons of registries • Advantages • Usually much larger than clinical trials • Greater power than RCTs to detect rare events • Enrolment reflects clinical practice • Potential for studying numerous outcomes • Suited to long-term follow-up • Can examine complex situations not suited to RCTs • Results can usually be generalised • Disadvantages • Non-randomised • Confounding by indication • Missing data • Potential for confounding factors • Channelling bias • Choice of reference group *Prescription to patients with more aggressive disease or previous DMARDs failure *More drop-outs in poor prognosis patients conducts to a better average prognosis RCTsare better for efficacy; Registersgive more information for safety Zink A, et al. Ann Rheum Dis 2009;68: 1240-1246.

  21. European registries 1. Askling J, et al. Ann Rheum Dis 2006;65:707–12. 2. Hyrich KL, et al. Rheumatology 2008;47:1441–3. 3. Listing J, et al. Arthritis Res Ther 2006;8:R66. 4. Tubach F, et al. Joint Bone Spine 2005;72:456–60. 5. Gomez-Reino JJ, et al. Arthritis Rheum 2003;48:2122–7. 6. Kvien TK, Clin Exp Rheumatol 2005;23(5 Suppl 39):S188–94. 7. Hetland ML. Clin Exp Rheumatol 2005;23(5 Suppl 39):S205-7. 8. Tegzova D, et al. Ann Rheum Dis 2006;65(Suppl II):505. 9. Kievit W, et al. Ann Rheum Dis 2007;66:1473–8.10. Mancarella L, J Rheumatol 2007;34:1670–3. 11. Iannone F, et al. Ann Rheum Dis 2007;66:249–52. 12. Marchesoni A, et al. Ann N Y Acad Sci 2009;1173:837-46. 13. du Pan SM, et al. Arthritis Rheum 2009;61:560–8. 14. Flouri I, et al. Ann Rheum Dis 2009;68(Suppl3):430. 1

  22. Woodrick, R. S. & Ruderman, E. M. Nat. Rev. Rheumatol. 7, 639–652 (2011)

  23. Anti-TNF BSRBR: Site specific infections and TNFi in RA 10 *Adjusted for age, gender, disease severity, co-morbidity, extra-articular manifestations, steroid use and smoking 6 4.28 4 2 1.70 Incidence Rate Ratio* (95% CI) 1.12 Skin & soft tissue 1.03 1.0 0.77 0.6 All sites 0.4 LRTI* Bone & joint Urinary tract 0.2 DMARD (Referent) * p = not significant Dixon W, et al. Arthritis Rheum 2006;54:2368-76.

  24. Tocilizumab • A Japanese 5‑year extension study that followed patients in the STREAM trial reported a rate of 5.7 infections per 100 patient-years. • A safety and efficacy analysis of data pooled from five phase III trials reported that infection rates remained stable over time. • The rates of serious infection in patients treated with tocilizumabwere not significantly higher than in placebo groups. (Cochrane review ) • Nevertheless, Japanese data have suggested an increased risk of serious respiratory infection in patients with RA treated with tocilizumab, when compared with a control cohort treated in separate studies.

  25. Abatacept • The increase in serious infections was not statistically significant.(Cochranereview) • Patients with COPD had higher rates of pulmonary complications, including infections.(productlabel) • patients in the abatacept plus biologic DMARD arm had a higher risk of serious infections.(Assure) • no increase in the rate of infection or serious infection in patients switching directly to abatacept from a TNF inhibitor.(ARRIVE)

  26. Rituximab • Rituximabcauseslong duration of peripheral Bcell depletion and the likelihood for chronic therapyinRA. • Similar overall and serious infection rates between rituximab and placebo groups. • The rates of infection were stable throughout the follow-up time period and after each consecutive course. • Rituximab is similar to other biologic agents with respect to infection risk.

  27. 臺灣仍是結核病中度流行區 結核病例報告率為西元2004年之每十萬人74例至2007每十萬人85例; 在2010年則降為每十萬人57例 Hong Kong 77 N. Korea 178 China 102 S. Korea 87 Taiwan 66.7 Singapore 41 Japan 31 Australia 5.7 Phillipines 296 USA 4.6 Canada 5.5 Malaysia 106 UK 12 S. Africa 536 Indonesia 285 Guam 60 Every 100,000 people Data From WHO: World TB Report 2005 Vietnam 178 Thailand 142

  28. 結核病十年減半全民動員計畫 行政院95年7月7日院臺衛字第0950031290號函核定 行政院衛生署 中華民國95年7月 National TB ProgramMobilization Plan to Halve Tuberculosis Incidence in Ten Years • Goal: To halve TB incidence/cases in 10 years • ♦ 67 per 100,000 → 34 per 100,000 • ♦ 15,000 per year → 7,500 per year • Trend: 5% average decrease per year Duration of implementation: 2006 – 2015 Approved by the Executive Yuan on 7 July 2006

  29. Action Plans ● Plan 1－ Case finding campaign　(July 2007) ● Plan 2－ Laboratory capacity improvement ● Plan 3－ Direct Observe Treatment (DOTs)　(April 2006) ● Plan 4－ Hospital Care Enhancement & infection control ● Plan 5－ MDR-TB project (DOTS-Plus)　(May 2007) ● Plan 6－ Air Travel control　(Sept 2007) ● Plan 7－ Surveillance and database ● Plan 8－ National Health Insurance related issues ● Plan 9－ Local government evaluation ● Plan 10－ LTBI treatment pilot program (April 2008) ● Plan 11－ New immigrant program ● Plan 12－ BCG evaluation ● Plan 13－ IC and R&D ● Plan 14－ Mandatory isolation implementation

  30. 肺結核的自然史 傳播 初次感染 潛伏性感染 再活化發病 約有30%的親密接觸者受到感染,且初次感染並沒有明顯的症狀 感染後約有10% 的人終其一生會發病, 但誰會發病？ Management of tuberculosis in the United States, NEJM 2001/07/19

  31. Risk Factors for Active TB Following Infection Reider HL. Epidemiol Rev 1989;11:79-98.

  32. Ann Rheum Dis 2005 Ann Rheum Dis 2005;64:iv24–iv28

  33. Anti-TNFandTB • FDA found an increase in TB shortly after initiation of infliximab therapy, suggesting reactivation of latent disease. • A broader study of granulomatous infections reported to the FDA Adverse Events Reporting System between January 1998 and September 2002 concluded that infliximab use was associated with a much (2–17-fold) higher risk of TB and of the fungal infections than use of etanercept.

  34. RATIO: TB risk is lowest with etanercept 69 TB. No correct previous prophylaxis in any case Adapted from Tubach F, et al. Arthritis Rheum 2009;60:1884–94.

  35. In clinical trials and US post-marketing surveillance of RA patients receiving anti-TNF therapy The incidence of active TB markedly decreasedafter TB screening by history, TST and CXR Pre-screening* 1.5 1.3 1.3 1.1 0.9 Events per 100 PYs Post-screening* 0.7 0.5 0.33 0.08 0.3 0.1 0 Europe 7 cases Europe 23 cases North America 4 cases Ann Rheum Dis 2006;65:889-894

  36. IRR vs. popul. IRR vs. RA cohort BIOBADASER: Risk and incidence of TB reduced with screening compliance Before screening recommendation After screening recommendation* 1.0 5.0 10.0 15.0 20.0 25.0 OR *Most of new TB cases associated to non compliance of screening recommendations Carmona L, et al. Arthritis Rheum 2005;52:1766-72

  37. Tuberculosis screening for TNF antagonistsin Spain PPD test + chest X-Ray +ve past TB treatment < 5 mm >= 5 mm = POSITIVE 1 week Booster 9 months ISONIAZIDE (5 mg/kg/d) < 5 mm >= 5 mm = POSITIVE Treatment without TB treatment 40 Emilio Martin-Mola.

  38. In vitroIFN-γ release assays (QFT, T-spot) 利用結核分枝桿菌特有抗原ESAT-6 ,CFP-10, TB7.7 (BCG沒有此抗原)刺激病患全血細胞，以ELISA測量血漿IFN-γ 若病患曾感染結核菌，免疫細胞應分泌較大量IFN-γ

  39. A recent meta-analysis: QFT assay has high specificity (96%), whereas TST has low specificity in BCG-vaccinated people (Ann Intern Med 2008;149:177-84 ) Sensitivity Specificity TST QFT

  40. 潛伏結核感染篩檢與防治之初步建議(2011) Baseline IGRAs結果為Indeterminate時，1個月後再做一次IGRAs *考量個別病患之TB風險，依臨床狀況做最適之防治措施 Close monitor:注意是否有結核病變，每六個月追蹤CXR及IGRAs

  41. 若確定有潛伏結核感染，則須於生物製劑治療之前1-2個月給予預防性藥物治療: 考慮以下三種處方 (1). INAH（首選） 服用1-2M再生物製劑治療 持續服用9個月(2). INAH+ Rifampin （次之） 持續服用共3-4個月(3). Rifampin （若對INAH過敏） 持續服用共4個月

  42. BiologicalsandTB • Despite the generally rare reports of TB with abataceptandtocilizumab, both agents carry warnings in their labeling—on the basis of precautionary procedures in place during clinical trials with these agents, which became the established approach—to screen for latent TB before use. • Only anakinra and rituximab do not require routine screening for TB. • Although there are no formal guidelines for TB testing once biologic therapy is underway, periodic monitoring should be considered in situations in which the risk of exposure remains high.

  43. Fungal infections • A case series from Southwestern USA reported 13 cases of coccidioidomycosis infection in patients treated with TNF inhibitors; 12 were treated with infliximab, 1 with etanercept. • Cases of disseminated histoplasmosis have also been associated with TNF inhibitors; again, cases have been most frequently associated with infliximab use.

  44. Pneumocystis • Pneumocystisjeroveciiinfection has also been reported with infliximab, adalimumab and etancercept. • Although this organism might be a consequential infection, and a Japanese study reported a high carrier rate in the elderly population. • no guidelines on P. jeroveciiprophylaxis in patients treated with TNF inhibitors have been established.

  45. 《杜鵑花》 　　本無淩厲風 　　更少衝天志 　　春喚青峰峭 　　紫發漫山枝 　　鵑聲藏翠綠 　　澗響聞空靈 　　和風雨飄搖 　　長虹為晨曦

  46. RABBIT: Incidence of Herpes zoster is higher with mAb treatment vs etanercept 49 Strangfeld A, et al. JAMA 2009;301:737-44

  47. Prevalence of chronic HBV carriers in different countries HBsAg Endemicity 8% and above – High 2% - 8% - Intermediate Below 2% - Low From: World Health Organization. Introduction of hepatitis B vaccine into childhood immunization services, 2001, Geneva, WHO, WHO/v&B/01.31

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