Joint Statement (DZK, DGRh, DDG) on the Tuberculosis Risk with Treatment Using Novel Non-TNF-Alpha Biologicals

R. Diel; T. Schaberg; A. Nienhaus; R. Otto-Knapp; C. Kneitz; A. Krause; M. Fabri; U. Mrowietz; T. Bauer; B. Häcker

doi:10.1055/a-1294-1580

Pneumologie 2021; 75(04): 293-303
DOI: 10.1055/a-1294-1580

Review

Joint Statement (DZK, DGRh, DDG) on the Tuberculosis Risk with Treatment Using Novel Non-TNF-Alpha Biologicals

Gemeinsame Stellungnahme des Deutschen Zentralkomitees zur Bekämpfung der Tuberkulose (DZK), der Deutschen Gesellschaft für Rheumatologie (DGRh) und der Deutschen Dermatologischen Gesellschaft (DDG) zum Tuberkuloserisiko unter Therapie mit neuen Biologika (Non-TNF-alpha-Inhibitoren)

R. Diel

¹Institute for Epidemiology, University Medical Hospital Schleswig-Holstein, Campus Kiel, Germany. Member of the German Center for Lung Research (ARCN)

²LungClinic Grosshansdorf, Germany. Airway Research Center North (ARCN), German Center for Lung Research (DZL)

³German Central Committee against Tuberculosis, Berlin, Germany

,

T. Schaberg

³German Central Committee against Tuberculosis, Berlin, Germany

,

A. Nienhaus

⁴Institution for Statutory Accident Insurance and Prevention in the Health and Welfare Services (BGW), Hamburg, Germany

⁵Institute for Health Service Research in Dermatology and Nursing, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

,

R. Otto-Knapp

³German Central Committee against Tuberculosis, Berlin, Germany

,

C. Kneitz

⁶Medicine, Rheumatology, rheumatological main practice Schwerin, Germany

,

A. Krause

⁷Department of Rheumatology, Clinical Immunology and Osteology, Immanuel Hospital Berlin, Germany

,

M. Fabri

⁸Department of Dermatology, University of Cologne, Germany

,

U. Mrowietz

⁹Psoriasis Center, Department of Dermatology, University Medical Center Schleswig-Holstein, Campus Kiel, Germany

,

T. Bauer

³German Central Committee against Tuberculosis, Berlin, Germany

,

B. Häcker

³German Central Committee against Tuberculosis, Berlin, Germany

› Author Affiliations

Abstract

Background While the risk of tuberculosis (TB) reactivation is adequately documented in relation to TNF-alpha inhibitors (TNFi), the question of what the tuberculosis risk is for newer, non-TNF biologics (non-TNFi) has not been thoroughly addressed.

Methods We conducted a systematic review of randomized phase 2 and phase 3 studies, and long-term extensions of same, published through March 2019. Of interest was information pertaining to screening and treating of latent tuberculosis (LTBI) in association with the use of 12 particular non-TNFi. Only rituximab was excluded. We searched MEDLINE and the ClinicalTrial.gov database for any and all candidate studies meeting these criteria.

Results 677 citations were retrieved; 127 studies comprising a total of 34,293 patients who received non-TNFi were eligible for evaluation. Only 80 out of the 127 studies, or 63 %, captured active TB (or at least opportunistic diseases) as potential outcomes and 25 TB cases were reported. More than two thirds of publications (86/127, 68 %) mentioned LTBI screening prior to inclusion of study participants in the respective trial, whereas in only 4 studies LTBI screening was explicitly considered redundant. In 21 studies, patients with LTBI were generally excluded from the trials and in 42 out of the 127 trials, or 33 %, latently infected patients were reported to receive preventive therapy (PT) at least 3 weeks prior to non-TNFi treatment.

Conclusions The lack of information in many non-TNFi studies on the number of patients with LTBI who were either excluded prior to participating or had been offered PT hampers assessment of the actual TB risk when applying the novel biologics. Therefore, in case of insufficient information about drugs or drug classes, the existing recommendations of the German Central Committee against Tuberculosis should be applied in the same way as is done prior to administering TNFi. Well designed, long-term “real world” register studies on TB progression risk in relation to individual substances for IGRA-positive cases without prior or concomitant PT may help to reduce selection bias and to achieve valid conclusions in the future.

Zusammenfassung

Hintergrund Während das Risiko einer Reaktivierung der Tuberkulose (TB) durch TNF-alpha-Inhibitoren (TNFi) hinreichend dokumentiert ist, kann das Tuberkulose-Risiko beim Einsatz neuerer Nicht-TNFi-Biologika bislang nur unzureichend eingeschätzt werden.

Methoden Wir führten ein systematisches Review zu 12 Nicht-TNFi-Biologika durch und bezogen alle randomisierten Phase-2- und Phase-3-Originalstudien sowie deren Anschlussstudien ein, die bis März 2019 veröffentlicht wurden. Nur Rituximab wurde ausgeschlossen. Im Mittepunkt des Interesses standen Informationen zum Screening auf und zur Behandlung von latenter Tuberkulose (LTBI). Durchsucht wurden die MEDLINE-Datenbank und das ClinicalTrial.gov-Register.

Ergebnisse 677 Publikationen wurden ermittelt, von denen 127 Studien mit insgesamt 34 293 Patienten, die Nicht-TNFi-Biologika erhalten hatten, evaluiert werden konnten. Nur in 80 der 127 Studien (63 %) war eine Tuberkulose (oder zumindest opportunistische Krankheiten) als potenzielle Nebenwirkung überhaupt erfasst worden; insgesamt wurden 25 TB-Fälle gemeldet. Mehr als ⅔ der Veröffentlichungen (86/127, 68 %) erwähnten ein LTBI-Screening vor Einbeziehung der Probanden in die jeweilige Studie, während ein LTBI-Screening in nur 4 Studien ausdrücklich als redundant angesehen wurde. In 21 Studien wurden Patienten mit LTBI grundsätzlich von der Studienteilnahme ausgeschlossen, und in 42 der 127 Studien (33 %) wurde berichtet, dass latent infizierte Patienten mindestens 3 Wochen vor der Nicht-TNFi-Behandlung eine präventive Therapie erhalten hatten.

Schlussfolgerungen Der Mangel an Informationen hinsichtlich der Zahl der Patienten mit LTBI, die entweder vor der Teilnahme an einer Studie mit Nicht-TNFi-Biologika ausgeschlossen wurden oder denen eine präventive Therapie angeboten wurde, erschwert die Einschätzung des tatsächlichen TB-Risikos beim Einsatz der neuen Substanzen. Bei unzureichenden Informationen über das Studiendesign bei neuen Biologika oder Biologika-Arten sollten daher die bestehenden Empfehlungen des Deutschen Zentralkomitees gegen Tuberkulose in gleicher Weise angewendet werden wie vor der Verabreichung von TNFi. Gut konzipierte Langzeitregisterstudien zum TB-Progressionsrisiko bei IGRA-positiven Patienten ohne vorherige oder begleitende präventive Therapie könnten dazu beitragen, einen Selektionsbias zu vermeiden und valide Schlussfolgerungen zu ermöglichen.

Full Text

References

References
1 Zhang Z, Fan W, Yang G. et al. Risk of tuberculosis in patients treated with TNF-α antagonists: a systematic review and meta-analysis of randomised controlled trials. BMJ Open 2017; 7: e012567
2 Singh JA, Wells GA, Christensen R. et al. Adverse effects of biologics: a network meta-analysis and Cochrane overview. Cochrane Database Syst Rev 2011; (02) Cd008794
3 Souto A, Maneiro JR, Salgado E. et al. Risk of tuberculosis in patients with chronic immune-mediated inflammatory diseases treated with biologics and tofacitinib: a systematic review and meta-analysis of randomized controlled trials and long-term extension studies. Rheumatology (Oxford) 2014; 53: 1872-1885
4 Diel R, Hauer B, Loddenkemper R. et al. Empfehlungen für das Tuberkulosescreening vor Gabe von TNF-alpha-Inhibitoren bei rheumatischen Erkrankungen [Recommendations for tuberculosis screening before initiation of TNF-alpha-inhibitor treatment in rheumatic diseases]. Pneumologie 2009; 63: 329-334
5 Frisell T, Dehlin M, Di Giuseppe D. et al. Comparative effectiveness of abatacept, rituximab, tocilizumab and TNFi biologics in RA: results from the nationwide Swedish register. Rheumatology 2019; 58: 1367-1377
6 Buch MH, Smolen JS, Betteridge N. et al. Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis. Ann Rheum Dis 2011; 70: 909-920
7 Bathon J, Robles M, Ximenes AC. et al. Sustained disease remission and inhibition of radiographic progression in methotrexate-naive patients with rheumatoid arthritis and poor prognostic factors treated with abatacept: 2-year outcomes. Ann Rheum Dis 2011; 70: 1949-1956
8 Kremer JM, Dougados M, Emery P. et al. Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: twelve-month results of a phase iib, double-blind, randomized, placebo-controlled trial. Arthritis Rheum 2005; 52: 2263-2271
9 Kremer JM, Genant HK, Moreland LW. et al. Effects of abatacept inpatients with methotrexate-resistant active rheumatoid arthritis: a randomized trial. Ann Intern Med 2006; 144: 865-876
10 Kremer JM, Genant HK, Moreland LW. et al. Results of a two-year followup study of patients with rheumatoid arthritis who received a combination of abatacept and methotrexate. Arthritis Rheum 2008; 58: 953-963
11 Kremer JM, Russell AS, Emery P. et al. Long-term safety, efficacy and inhibition of radiographic progression with abatacept treatment in patients with rheumatoid arthritis and an inadequate response to methotrexate: 3-year results from the AIM trial. Ann Rheum Dis 2011; 70: 1826-1830
12 Lovell DJ, Ruperto N, Mouy R. et al.; Pediatric Rheumatology Collaborative Study Group and the Paediatric Rheumatology International Trials Organisation. Long-term safety, efficacy, and quality of life in patients with juvenile idiopathic arthritis treated with intravenous abatacept for up to seven years. Arthritis Rheumatol 2015; 67: 2759-2770
13 Ruperto N, Lovell DJ, Quartier P. et al.; Paediatric Rheumatology INternational Trials Organization; Pediatric Rheumatology Collaborative Study Group. Abatacept in children with juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled withdrawal trial. Lancet 2008; 372: 383-391
14 Ruperto N, Lovell DJ, Quartier P. et al. Long-term safety and efficacy of abatacept in children with juvenile idiopathic arthritis. Arthritis Rheum 2010; 62: 1792-1802
15 Schiff M, Keiserman M, Codding C. et al. Efficacy and safety of abatacept or infliximab vs placebo in ATTEST: a phase III, multi-centre, randomised, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Ann Rheum Dis 2008; 67: 1096-1103
16 Westhovens R, Robles M, Ximenes AC. et al. Clinical efficacy and safety of abatacept in methotrexate-naive patients with early rheumatoid arthritis and poor prognostic factors. Ann Rheum Dis 2009; 68: 1870-1877
17 Westhovens R, Kremer JM, Moreland LW. et al. Safety and efficacy of the selective costimulation modulator abatacept in patients with rheumatoid arthritis receiving background methotrexate: a 5-year extended phase IIB study. J Rheumatol 2009; 36: 736-742
18 Westhovens R, Kremer JM, Emery P. et al. Long-term safety and efficacy of abatacept in patients with rheumatoid arthritis and an inadequate response to methotrexate: a 7-year extended study. Clin Exp Rheumatol 2014; 32: 553-562 Epub 2014 Jul 8. PubMed PMID: 25005467
19 Fleischmann RM, Schechtman J, Bennett R. et al. Anakinra, a recombinant human interleukin-1 receptor antagonist (r-metHuIL-1ra), in patients with rheumatoid arthritis: A large, international, multicenter, placebo-controlled trial. Arthritis Rheum 2003; 48: 927-934
20 Ilowite N, Porras O, Reiff A. et al. Anakinra in the treatment of polyarticular-course juvenile rheumatoid arthritis: safety and preliminary efficacy results of a randomized multicenter study. Clin Rheumatol 2009; 28: 129-137
21 Fleischmann RM, Tesser J, Schiff MH. et al. Safety of extended treatment with anakinra in patients with rheumatoid arthritis. Ann Rheum Dis 2006; 65: 1006-1012
22 Tzanetakou V, Kanni T, Giatrakou S. et al. Safety and Efficacy of Anakinra in Severe Hidradenitis Suppurativa: A Randomized Clinical Trial. JAMA Dermatol 2016; 152: 52-59
23 Crowley J, Thaçi D, Joly P. et al. Long-term safety and tolerability of apremilast in patients with psoriasis: Pooled safety analysis for ≥ 156 weeks from 2 phase 3, randomized, controlled trials (ESTEEM 1 and 2). J Am Acad Dermatol 2017; 77: 310-317.e1
24 Cutolo M, Myerson GE, Fleischmann RM. et al. A Phase III, Randomized, Controlled Trial of Apremilast in Patients with Psoriatic Arthritis: Results of the PALACE 2 Trial. J Rheumatol 2016; 43: 1724-1734
25 Edwards CJ, Blanco FJ, Crowley J. et al. Apremilast, an oral phosphodiesterase 4 inhibitor, in patients with psoriatic arthritis and current skin involvement: a phase III, randomised, controlled trial (PALACE 3). Ann Rheum Dis 2016; 75: 1065-1073
26 Kavanaugh A, Mease PJ, Gomez-Reino JJ. et al. Treatment of psoriatic arthritis in a phase 3 randomised, placebo-controlled trial with apremilast, an oral phosphodiesterase 4 inhibitor. Ann Rheum Dis 2014; 73: 1020-1026
27 Kavanaugh A, Mease PJ, Gomez-Reino JJ. et al. Longterm (52-week) results of a phase III randomized, controlled trial of apremilast in patients with psoriatic arthritis. J Rheumatol 2015; 42: 479-488
28 Ohtsuki M, Okubo Y, Komine M. et al. Apremilast, an oral phosphodiesterase 4 inhibitor, in the treatment of Japanese patients with moderate to severe plaque psoriasis: Efficacy, safety and tolerability results from a phase 2b randomized controlled trial. J Dermatol 2017; 44: 873-884
29 Papp K, Cather JC, Rosoph L. et al. Efficacy of apremilast in the treatment of moderate to severe psoriasis: a randomised controlled trial. Lancet 2012; 380: 738-746
30 Papp KA, Kaufmann R, Thaçi D. et al. Efficacy and safety of apremilast in subjects with moderate to severe plaque psoriasis: results from a phase II, multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison study. J Eur Acad Dermatol Venereol 2013; 27: e376-e383
31 Papp K, Reich K, Leonardi CL. et al. Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, in patients with moderate to severe plaque psoriasis: Results of a phase III, randomized, controlled trial (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM] 1). J Am Acad Dermatol 2015; 73: 37-49
32 Paul C, Cather J, Gooderham M. et al. Efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate-to-severe plaque psoriasis over 52 weeks: a phase III, randomized controlled trial (ESTEEM 2). Br J Dermatol 2015; 173: 1387-1399
33 Reich K, Gooderham M, Green L. et al. The efficacy and safety of apremilast, etanercept and placebo in patients with moderate-to-severe plaque psoriasis: 52-week results from a phase IIIb, randomized, placebo-controlled trial (LIBERATE). J Eur Acad Dermatol Venereol 2017; 31: 507-517
34 Schett G, Wollenhaupt J, Papp K. et al. Oral apremilast in the treatment of active psoriatic arthritis: results of a multicenter, randomized, double-blind, placebo-controlledstudy. Arthritis Rheum 2012; 64: 3156-3167
35 Simpson EL, Imafuku S, Poulin Y. et al. A Phase 2 Randomized Trial of Apremilast in Patients with Atopic Dermatitis. J Invest Dermatol 2019; 139: 1036-1072
36 Dougados M, van der Heijde D, Chen YC. et al. Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA-BUILD study. Ann Rheum Dis 2017; 76: 88-95
37 Guttman-Yassky E, Silverberg JI, Nemoto O. et al. Baricitinib in adult patients with moderate-to-severe atopic dermatitis: a phase 2 parallel, double-blinded, randomized placebo-controlled multiple-dose study. J Am Acad Dermatol 2019; 80: 913-921.e9
38 Keystone EC, Genovese MC, Schlichting DE. et al. Safety and Efficacy of Baricitinib Through 128 Weeks in an Open-label, Longterm Extension Study in Patients with Rheumatoid Arthritis. J Rheumatol 2018; 45: 14-21
39 Keystone EC, Taylor PC, Drescher E. et al. Safety and efficacy of baricitinib at 24 weeks in patients with rheumatoid arthritis who have had an inadequate response to methotrexate. Ann Rheum Dis 2015; 74: 333-340
40 Papp KA, Menter MA, Raman M. et al. A randomized phase 2b trial of baricitinib, an oral Janus kinase (JAK) 1/JAK2 inhibitor, in patients with moderate-to-severe psoriasis. Br J Dermatol 2016; 174: 1266-1276
41 Tanaka Y, Emoto K, Cai Z. et al. Efficacy and Safety of Baricitinib in Japanese Patients with Active Rheumatoid Arthritis Receiving Background Methotrexate Therapy: A 12-week, Double-blind, Randomized Placebo-controlled Study. J Rheumatol 2016; 43: 504-511
42 Wallace DJ, Furie RA, Tanaka Y. et al. Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet 2018; 392: 222-231
43 Banham GD, Flint SM, Torpey N. et al. Belimumab in kidney transplantation: an experimental medicine, randomised, placebo-controlled phase 2 trial. Lancet. 2018 2018; 391: 2619-2630
44 Furie R, Petri M, Zamani O. et al.; BLISS-76 Study Group. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum 2011; 63: 3918-3930
45 Furie RA, Wallace DJ, Aranow C. et al. Long-Term Safety and Efficacy of Belimumab in Patients With Systemic Lupus Erythematosus: A Continuation of a Seventy-Six-Week Phase III Parent Study in the United States. Arthritis Rheumatol 2018; 70: 868-877
46 Gordon JK, Martyanov V, Franks JM. et al. Belimumab for the Treatment of Early Diffuse Systemic Sclerosis: Results of a Randomized, Double-Blind, Placebo-Controlled, Pilot Trial. Arthritis Rheumatol 2018; 70: 308-316
47 Merrill JT, Ginzler EM, Wallace DJ. et al. Long-term safety profile of belimumab plus standard therapy in patients with systemic lupus erythematosus. Arthritis Rheum 2012; 64: 3364-3373
48 Navarra SV, Guzmán RM, Gallacher AE. et al.; BLISS-52 Study Group. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet 2011; 377: 721-731
49 Stohl W, Schwarting A, Okada M. et al. Efficacy and Safety of Subcutaneous Belimumab in Systemic Lupus Erythematosus: A Fifty-Two-Week Randomized, Double-Blind, Placebo-Controlled Study. Arthritis Rheumatol 2017; 69: 1016-1027
50 Krause K, Tsianakas A, Wagner N. et al. Efficacy and safety of canakinumab in Schnitzler syndrome: A multicenter randomized placebo-controlled study. J Allergy Clin Immunol 2017; 139: 1311-1320
51 Rissanen A, Howard CP, Botha J. et al. for the Global Investigators. Effect of anti-IL-1beta antibody (canakinumab) on insulin secretion rates in impaired glucose or type 2 diabetes: results of a randomized, placebo-controlled trial. Diabetes Obes Metab 2012; 14: 1088-1096
52 Ruperto N, Brunner HI, Quartier P. et al. Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. N Engl J Med 2012; 367: 2396-2406
53 Hensen J, Howard CP, Walter V. et al. Impact of interleukin-1β antibody (canakinumab) on glycaemic indicators in patients with type 2 diabetes mellitus: results of secondary endpoints from a randomized,placebo-controlled trial. Diabetes Metab 2013; 39: 524-531
54 Deodhar A, Poddubnyy D, Pacheco-Tena C. et al. Efficacy and Safety of Ixekizumab in the Treatment of Radiographic Axial Spondyloarthritis: Sixteen-Week Results From a Phase III Randomized, Double-Blind, Placebo-Controlled Trial in Patients With Prior Inadequate Response to or Intolerance of Tumor Necrosis Factor Inhibitors. Arthritis Rheumatol 2019; 71: 599-611
55 Gordon KB, Leonardi CL, Lebwohl M. et al. A 52-week, open-label study of the efficacy and safety of ixekizumab, an anti-interleukin-17A monoclonal antibody, in patients with chronic plaque psoriasis. J Am Acad Dermatol 2014; 71: 1176-1182
56 Gordon KB, Blauvelt A, Papp KA. et al. Phase 3 Trials of Ixekizumab in Moderate-to-Severe Plaque Psoriasis. N Engl J Med 2016; 375: 345-356
57 Griffiths CEM, Reich K, Lebwohl M. et al. Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials. Lancet 2015; 386: 541-551
58 Leonardi C, Matheson R, Zachariae C. et al. Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. N Engl J Med 2012; 366: 1190-1199
59 Mease PJ, van der Heijde D, Ritchlin CT. et al. Ixekizumab, an interleukin-17A specific monoclonal antibody, for the treatment of biologic-naive patients with active psoriatic arthritis: results from the 24-week randomised, double-blind, placebo-controlled and active (adalimumab)-controlled period of the phase III trial SPIRIT-P1. Ann Rheum Dis 2017; 76: 79-87
60 Nash P, Kikham B, Okada M. et al. Ixekizumab for the treatment of patients with active psoriatic arthritis and an inadequate response to tumour necrosis factor inhibitors: results from the 24-week randomised, double-blind, placebo-controlled period of the SPIRIT-P2 phase 3 trial. Lancet 2017; 389: 2317-2327
61 van der Heijde D, Gladman DD, Kishimoto M. et al. Efficacy and Safety of Ixekizumab in Patients with Active Psoriatic Arthritis: 52-week Results from a Phase III Study (SPIRIT-P1). J Rheumatol 2018; 45: 367-377
62 Zachariae C, Gordon K, Kimball AB. et al. Efficacy and Safety of Ixekizumab Over 4 Years of Open-Label Treatment in a Phase 2 Study in Chronic Plaque Psoriasis. J Am Acad Dermatol 2018; 79: 294-301.e6
63 Baeten D, Sieper J, Braun J. et al. Secukinumab, an interleukin-17A inhibitor, in ankylosing spondylitis. N Engl J Med 2015; 373: 2534-2548
64 Baraliakos X, Kivitz AJ, Deodhar AA. et al. Long-term effects of interleukin-17A inhibition with secukinumab in active ankylosing spondylitis: 3-year efficacy and safety results from an extension of the Phase 3 MEASURE 1 trial. Clin Exp Rheumatol 2018; 36: 50-55
65 Braun J, Baraliakos X, Deodhar A. et al.; MEASURE 1 Study Group. Effect of secukinumab on clinical and radiographic outcomes in ankylosing spondylitis: 2-year results from the randomised phase III MEASURE 1 study. Ann Rheum Dis 2017; 76: 1070-1077
66 Genovese MC, Durez P, Richards HB. et al. One-year efficacy and safety results of secukinumab in patients with rheumatoid arthritis: phase II, dose-finding, double-blind, randomized, placebo-controlled study. J Rheumatol 2014; 41: 414-421
67 Gottlieb AB, Blauvelt A, Prinz JC. et al. Secukinumab Self-Administration by Prefilled Syringe Maintains Reduction of Plaque Psoriasis Severity Over 52 Weeks: Results of the FEATURE Trial. J Drugs Dermatol 2016; 15: 1226-1234
68 Kammüller M, Tsai T-F, Griffiths C. Inhibition of IL-17A by secukinumab shows no evidence of increased Mycobacterium tuberculosis infections. Clinical & Translational Immunology 2017; 6: e152
69 Kavanaugh A, Mease PJ, Reimold AM. et al.; FUTURE-1 Study Group. Secukinumab for Long-Term Treatment of Psoriatic Arthritis: A Two-Year Followup From a Phase III, Randomized, Double-Blind Placebo-Controlled Study. Arthritis Care Res (Hoboken) 2017; 69: 347-355
70 Lacour JP, Paul C, Jazayeri S. et al. Secukinumab administration by autoinjector maintains reduction of plaque psoriasis severity over 52 weeks: results of the randomized controlled JUNCTURE trial. J Eur Acad Dermatol Venereol 2017; 31: 847-856
71 Langley RG, Elewski BE, Lebwohl M. et al.; ERASURE Study Group; FIXTURE Study Group. Secukinumab in plaque psoriasis -- results of two phase 3 trials. N Engl J Med 2014; 371: 326-338
72 Marzo-Ortega H, Sieper J, Kivitz A. et al.; MEASURE 2 Study Group. Secukinumab and Sustained Improvement in Signs and Symptoms of Patients With Active Ankylosing Spondylitis Through Two Years: Results From a Phase III Study. Arthritis Care Res (Hoboken) 2017; 69: 1020-1029
73 McInnes IB, Mease PJ, Ritchlin CT. et al. Secukinumab sustains improvement in signs and symptoms of psoriatic arthritis: 2 year results from the phase 3 FUTURE 2 study. Rheumatology (Oxford) 2017; 56: 1993-2003
74 Mease PJ, McInnes IB, Kirkham B. et al.; FUTURE 1 Study Group. Secukinumab Inhibition of Interleukin-17A in Patients with Psoriatic Arthritis. N Engl J Med 2015; 373: 1329-1339
75 Pavelka K, Kivitz A, Dokoupilova E. et al. Efficacy, safety, and tolerability of secukinumab in patients with active ankylosing spondylitis: a randomized, double-blind phase 3 study, MEASURE 3. Arthritis Res Ther 2017; 19: 285
76 Rich P, Sigurgeirsson B, Thaci D. et al. Secukinumab induction and maintenance therapy in moderate-to-severe plaque psoriasis: a randomized, double-blind, placebo-controlled, phase II regimen-finding study. Br J Dermatol 2013; 168: 402-411
77 Tlustochowicz W, Rahman P, Seriolo B. et al. Efficacy and Safety of Subcutaneous and Intravenous Loading Dose Regimens of Secukinumab in Patients with Active Rheumatoid Arthritis: Results from a Randomized Phase II Study. J Rheumatol 2016; 43: 495-503
78 De Benedetti F, Brunner HI, Ruperto N. et al.; PRINTO; PRCSG. Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. N Engl J Med 2012; 367: 2385-2395 Erratum in: N Engl J Med 2015; 372 (9): 887
79 Emery P, Keystone E, Tony HP. et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis 2008; 67: 1516-1523
80 Kremer JM, Blanco R, Brzosko M. et al. Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate responses to methotrexate: results from the double-blind treatment phase of a randomized placebo-controlled trial of tocilizumab safety and prevention of structural joint damage at one year. Arthritis Rheum 2011; 63: 609-621
81 Kivitz A, Wallace T, Olech E. et al. Long-Term Safety and Efficacy of Subcutaneously Administered Tocilizumab for Adult Rheumatoid Arthritis: A Multicenter Phase 3b Long-term Extension Study. Rheumatol Ther 2016; 3: 291-304
82 Kaneko Y, Kameda H, Ikeda K. et al. Tocilizumab in patients with adult-onset still's disease refractory to glucocorticoid treatment: a randomised, double-blind, placebo-controlled phase III trial. Ann Rheum Dis 2018; 77: 1720-1729
83 Kivitz A, Olech E, Borofsky M. et al. Subcutaneous tocilizumab versus placebo in combination with disease-modifying antirheumatic drugs in patients with rheumatoid arthritis. Arthritis Care Res (Hoboken) 2014; 66: 1653-1661
84 Sieper J, Porter-Brown B, Thompson L. et al. Assessment of short-term symptomatic efficacy of tocilizumab in ankylosing spondylitis: results of randomised, placebo-controlled trials. Ann Rheum Dis 2014; 73: 95-100
85 Stone JH, Tuckwell K, Dimonaco S. et al. Trial of Tocilizumab in Giant-Cell Arteritis. N Engl J Med 2017; 377: 317-328
86 Yokota S, Imagawa T, Mori M. et al. Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial. Lancet 2008; 371: 998-1006
87 Villiger PM, Adler S, Kuchen S. et al. Tocilizumab for induction and maintenance of remission in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet 2016; 387: 1921-1927
88 van der Heijde D, Strand V, Tanaka Y. et al. Tofacitinib in Combination with Methotrexate in Patients with Rheumatoid Arthritis: Clinical Efficacy, Radiographic and Safety Outcomes from the 24-Month Phase 3 ORAL Scan Study. Arthritis Rheumatol 2019; 71: 878-891
89 Bissonnette R, Papp KA, Poulin Y. et al. Topical tofacitinib for atopic dermatitis: a phase IIa randomized trial. Br J Dermatol 2016; 175: 902-911
90 Boyle DL, Soma K, Hodge J. et al. The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid arthritis. Ann Rheum Dis 2015; 74: 1311-1316
91 Conaghan PG, Østergaard M, Bowes MA. et al. Comparing the effects of tofacitinib, methotrexate and the combination, on bone marrow oedema, synovitis and bone erosion in methotrexate-naive, early active rheumatoid arthritis: results of an exploratory randomised MRI study incorporating semiquantitative and quantitative techniques. Ann Rheum Dis 2016; 75: 1024-1033
92 Fleischmann R, Cutolo M, Genovese MC. et al. Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs. Arthritis Rheum 2012; 64: 617-629
93 Fleischmann R, Mysler E, Hall S. et al. Efficacy and safety of tofacitinib monotherapy, tofacitinib with methotrexate, and adalimumab with methotrexate in patients with rheumatoid arthritis (ORAL Strategy): a phase 3b/4, double-blind, head-to-head, randomised controlled trial. Lancet 2017; 390: 457-468
94 Genovese MC, van Vollenhoven RF, Wilkinson B. et al. Switching from adalimumab to tofacitinib in the treatment of patients with rheumatoid arthritis. Arthritis Res Ther 2016; 18: 145
95 Kremer JM, Bloom BJ, Breedveld FC. et al. The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo. Arthritis Rheum 2009; 60: 1895-1905 Erratum in: Arthritis Rheum 2012 May; 64 (5): 1487
96 Kremer J, Li ZG, Hall S. et al. Tofacitinib in combination with nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis: a randomized trial. Ann Intern Med 2013; 159: 253-261
97 Kremer JM, Cohen S, Wilkinson BE. et al. A phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) versus placebo in combination with background methotrexate in patients with active rheumatoid arthritis and an inadequate response to methotrexate alone. Arthritis Rheum 2012; 64: 970-981
98 Merola JF, Elewski B, Tatulych S. et al. Efficacy of tofacitinib for the treatment of nail psoriasis: Two 52-week, randomized, controlled phase 3 studies in patients with moderate-to-severe plaque psoriasis. J Am Acad Dermatol 2017; 77: 79-87
99 Papp KA, Krueger JG, Feldman SR. et al. Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: Long-term efficacy and safety results from 2 randomized phase-III studies and 1 open-label long-term extension study. J Am Acad Dermatol 2016; 74: 841-850
100 Papp KA, Bissonnette R, Gooderham M. et al. Treatment of plaque psoriasis with an ointment formulation of the Janus kinase inhibitor, tofacitinib: a Phase 2b randomized clinical trial. BMC Dermatol 2016; 16: 15
101 Papp KA, Menter A, Strober B. et al. Efficacy and safety of tofacitinib, an oral Janus kinase inhibitor, in the treatment of psoriasis: a Phase 2b randomized placebo-controlled dose-ranging study. Br J Dermatol 2012; 167: 668-677
102 Strand V, Burmester GR, Zerbini CA. et al. Tofacitinib with methotrexate in third-line treatment of patients with active rheumatoid arthritis: patient-reported outcomes from a phase III trial. Arthritis Care Res (Hoboken) 2015; 67: 475-483
103 Tanaka Y, Takeuchi T, Yamanaka H. et al. Efficacy and safety of tofacitinib as monotherapy in Japanese patients with active rheumatoid arthritis: a 12-week, randomized, phase 2 study. Mod Rheumatol 2015; 25: 514-521
104 Valenzuela F, Korman NJ, Bissonnette R. et al. Tofacitinib in patients with moderate to severe chronic plaque psoriasis: long-term safety and efficacy in an open-label extension study. Br J Dermatol 2018; 179: 853-862
105 van der Heijde D, Deodhar A, Wei JC. et al. Tofacitinib in patients with ankylosing spondylitis: a phase II, 16-week, randomised, placebo-controlled, dose-ranging study. Ann Rheum Dis 2017; 76: 1340-1347
106 van Vollenhoven RF, Fleischmann R, Cohen S. et al.; ORAL Standard Investigators. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med 2012; 367: 508-519 Erratum in: N Engl J Med 2013 Jul 18; 369 (3): 293
107 Wallenstein GV, Kanik KS, Wilkinson B. et al. Effects of the oral Janus kinase inhibitor tofacitinib on patient-reported outcomes in patients with active rheumatoid arthritis: results of two Phase 2 randomised controlled trials. Clin Exp Rheumatol 2016; 34: 430-442
108 Winthrop KL, Wouters AG, Choy EH. et al. The Safety and Immunogenicity of Live Zoster Vaccination in Patients With Rheumatoid Arthritis Before Starting Tofacitinib: A Randomized Phase II Trial. Arthritis Rheumatol 2017; 69: 1969-1977
109 Yamanaka H, Tanaka Y, Takeuchi T. et al. Tofacitinib, an oral Janus kinase inhibitor, as monotherapy or with background methotrexate, in Japanese patients with rheumatoid arthritis: an open-label, long-term extension study. Arthritis Res Ther 2016; 18: 34
110 Zhang J, Tsai T-F, Lee M-G. et al. The efficacy and safety of tofacitinib in Asian patients with moderate to severe chronic plaque psoriasis: A Phase 3, randomized, double-blind, placebo-controlled study. J Dermatol Sci 2017; 88: 36-45
111 Feagan BG, Sandborn WJ, Gasink C. et al.; UNITI-IM-UNITi Study Group. Ustekinumab as Induction and Maintenance Therapy for Crohnʼs Disease. N Engl J Med 2016; 375: 1946-1960
112 Gottlieb A, Menter A, Mendelsohn A. et al. Ustekinumab, a human interleukin 12/23 monoclonal antibody, for psoriatic arthritis: randomised, double-blind, placebo-controlled, crossover trial. Lancet 2009; 373: 633-640
113 Igarashi A, Kato T, Kato M. et al. Efficacy and safety of ustekinumab in Japanese patients with moderate-to-severe plaque-type psoriasis: long-term results from a phase 2/3 clinical trial. J Dermatol 2012; 39: 242-252
114 Judson MA, Baughman RP, Costabel U. et al. Safety and efficacy of ustekinumab or golimumab in patients with chronic sarcoidosis. Eur Respir J 2014; 44: 1296-1307
115 Kavanaugh A, Puig L, Gottlieb AB. et al.; PSUMMIT 1 Study Group. Maintenance of Clinical Efficacy and Radiographic Benefit Through Two Years of Ustekinumab Therapy in Patients With Active Psoriatic Arthritis: Results From a Randomized, Placebo-Controlled Phase III Trial. Arthritis Care Res (Hoboken) 2015; 67: 1739-1749
116 Khattri S, Brunner PM, Garcet S. et al. Efficacy and safety of ustekinumab treatment in adults with moderate-to-severe atopic dermatitis. Exp Dermatol 2017; 26: 28-35
117 Kimball AB, Papp KA, Wasfi Y. et al.; PHOENIX 1 Investigators. Long-term efficacy of ustekinumab in patients with moderate-to-severe psoriasis treated for up to 5 years in the PHOENIX 1 study. J Eur Acad Dermatol Venereol 2013; 27: 1535-1545
118 Leonardi CL, Kimball AB, Papp KA. et al.; PHOENIX 1 study investigators. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet 2008; 371: 1665-1674 Erratum in: Lancet 2008 May 31; 371 (9627): 1838
119 McInnes IB, Kavanaugh A, Gottlieb AB. et al.; PSUMMIT 1 Study Group. Efficacy and safety of ustekinumab in patients with active psoriatic arthritis: 1 year results of the phase 3, multicentre, double-blind, placebo-controlled PSUMMIT 1 trial. Lancet 2013; 382: 780-789
120 Papp KA, Langley RG, Lebwohl M. et al.; PHOENIX 2 study investigators. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet 2008; 371: 1675-1684
121 Papp KA, Gordon KB, Langley RG. et al. Impact of previous biologic use on the efficacy and safety of brodalumab and ustekinumab in patients with moderate-to-severe plaque psoriasis: integrated analysis of the randomized controlled trials AMAGINE-2 and AMAGINE-3. Br J Dermatol 2018; 179: 320-328 Epub 2018 May 23. PubMed PMID: 29488226
122 Ritchlin C, Rahman P, Kavanaugh A. et al.; PSUMMIT 2 Study Group. Efficacy and safety of the anti-IL-12/23 p40 monoclonal antibody, ustekinumab, in patients with active psoriatic arthritis despite conventional non-biological and biological anti-tumour necrosis factor therapy: 6-month and 1-year results of the phase 3, multicentre, double-blind, placebo-controlled, randomised PSUMMIT 2 trial. Ann Rheum Dis 2014; 73: 990-999
123 Lebwohl M, Strober B, Menter A. et al. Phase 3 Studies Comparing Brodalumab with Ustekinumab in Psoriasis. N Engl J Med 2015; 373: 1318-1328
124 Saeki H, Kabashima K, Tokura Y. et al. Efficacy and safety of ustekinumab in Japanese patients with severe atopic dermatitis: a randomized, double-blind, placebo-controlled, phase II study. Br J Dermatol 2017; 177: 419-427
125 Sandborn WJ, Rutgeerts P, Gasink C. et al. Long-term efficacy and safety of ustekinumab for Crohn's disease through the second year of therapy. Aliment Pharmacol Ther 2018; 48: 65-77
126 Tsai TF, Ho JC, Song M. et al.; PEARL Investigators. Efficacy and safety of ustekinumab for the treatment of moderate-to-severe psoriasis: a phase III, randomized, placebo-controlled trial in Taiwanese and Korean patients (PEARL). J Dermatol Sci 2011; 63: 154-163
127 van Vollenhoven RF, Hahn BH, Tsokos GC. et al. Efficacy and safety of ustekinumab, an IL-12 and IL-23 inhibitor, in patients with active systemic lupus erythematosus: results of a multicentre, double-blind, phase 2,randomised, controlled study. Lancet 2018; 392: 1330-1339
128 Zhu X, Zheng M, Song M. et al. Efficacy and safety of ustekinumab in Chinese patients with moderate to severe plaque-type psoriasis: results from a phase 3 clinical trial (LOTUS). J Drugs Dermatol 2013; 12: 166-174
129 Colombel JF, Sands BE. et al. The safety of vedolizumab for ulcerative colitis and Crohnʼs disease. Gut 2017; 66: 839-851
130 Feagan BG, Rutgeerts P, Sands BE. et al.; GEMINI 1 Study Group. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2013; 369: 699-710
131 Motoya S, Watanabe K, Ogata H. et al. Vedolizumab in Japanese patients with ulcerative colitis: A Phase 3, randomized, double-blind, placebo-controlled study. PLoS One 2019; 14: e0212989
132 Parikh A, Leach T, Wyant T. et al. Vedolizumab for the treatment of active ulcerative colitis: a randomized controlled phase 2 dose-ranging study. Inflamm Bowel Dis 2012; 18: 1470-1479
133 Parikh A, Fox I, Leach T. et al. Long-term clinical experience with vedolizumab in patients with inflammatory bowel disease. Inflamm Bowel Dis 2013; 19: 1691-1699
134 Sandborn WJ, Feagan BG, Rutgeerts P. et al.; GEMINI 2 Study Group. Vedolizumab as induction and maintenance therapy for Crohn's disease. N Engl J Med 2013; 369: 711-721
135 Sands BE, Sandborn WJ, Van Assche G. et al. Vedolizumab as Induction and Maintenance Therapy for Crohnʼs Disease in Patients Naïve to or Who Have Failed Tumor Necrosis Factor Antagonist Therapy. Inflamm Bowel Dis 2017; 23: 97-106
136 Park HJ, Choi BY, Sohn M. et al. Effects of Tumor Necrosis Factor-alpha Inhibitors on the Incidence of Tuberculosis. Korean J Clin Pharm 2018; 28: 333-341
137 Solovic I, Sester M, Gomez-Reino JJ. et al. The risk of tuberculosis related to tumour necrosis factor antagonist therapies: a TBNET consensus statement. Eur Respir J 2010; 36: 1185-1206
138 Smolen JS, Genovese MC, Takeuchi T. et al. Safety profile of baricitinib in patients with active rheumatoid arthritis with over 2 years median time in treatment. J Rheumatol 2019; 46: 7-18
139 Cantini F, Nannini C, Niccoli L. et al. Risk of Tuberculosis Reactivation in Patients with Rheumatoid Arthritis, Ankylosing Spondylitis, and Psoriatic Arthritis Receiving Non-Anti-TNF-Targeted Biologics. Mediators Inflamm 2017; 2017: 8909834
140 Cantini F, Blandizzi C, Niccoli L. et al. Systematic review on tuberculosis risk in patients with rheumatoid arthritis receiving inhibitors of Janus Kinases. Expert Opin Drug Saf 2020; 19: 861-872
141 Mariette X, Gottenberg JE, Ravaud P. et al. Registries in rheumatoid arthritis and autoimmune diseases:data from the French registries. Rheumatology (Oxford) 2011; 50: 222-229
142 Takahashi N, Kojima T, Kaneko A. et al. Longterm eﬃcacy and safety of abatacept in patients with rheumatoid arthritis treated in routine clinical practice: eﬀect of concomitant methotrexate after 24 weeks. J Rheumatol 2015; 42: 786-793
143 Kalb RE, Fiorentino DF, Lebwohl MG. et al. Risk of serious infection with biologic and systemic treatment of psoriasis: results from the Psoriasis Longitudinal Assessment and Registry (PSOLAR). JAMA Dermatology 2015; 151: 961-969
144 Redelman-Sidi G, Michielin O, Cervera C. et al. ESCMID Study Group for Infections in Compromised Hosts (ESGICH) consensus document on the safety of targeted and biological therapies: an infectious diseases perspective (immune checkpoint inhibitors, celladhesion inhibitors, sphingosine-1-phosphate receptor modulators and pro-teasome inhibitors). Clin Microbiol Infect 2018; 24 (Suppl. 95) e107
145 Winthrop KL, Mariette X, Silva JT. et al. ESCMID Study Group for Infections in CompromisedHosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: anInfectious Diseases perspective (Soluble immune effector molecules [II]: agents targeting interleukins,immunoglobulins and complement factors). Clin Microbiol Infect 2018; 24 (Suppl. 02) S21-S40
146 Reinwald M, Silva JT, Mueller NJ. et al. ESCMID Study Group for Infections in Compromised Hosts (ESGICH)consensus document on the safety of targeted and biological therapies: aninfectious diseases perspective (Intracellular signaling pathways). ClinMicrobiol Infect 2018; 24: S53e70
147 Winthrop KL, Yamashita S, Beekmann SE. et al. Mycobacterial and other serious infections in patients receiving anti-tumor necrosis factor and other newly approved biologic therapies: Case finding through the emerging infections network. Clin Infect Dis 2008; 46: 1738-1740
148 Fowler E, Ghamrawi RI, Ghiam N. et al. Risk of tuberculosis reactivation during interleukin-17 inhibitor therapy for psoriasis: a systematic review. J Eur Acad Dermatol Venereol 2020; 34: 1449-1456
149 https://www.dgrh.de/Start/Publikationen/Empfehlungen/Medikation/
150 Menzies D, Adjobimey M, Ruslami R. et al. Four Months of Rifampin or Nine Months of Isoniazid for Latent Tuberculosis in Adults. N Engl J Med 2018; 379: 440-453
151 Khanna U, Ellis A, Galadari A. et al. Utility of Repeat Latent Tuberculosis Testing in Patients Taking Biologics [abstract]. Arthritis Rheumatol; 2019 71. Available at (Accessed August 1, 2020): https://acrabstracts.org/abstract/utility-of-repeat-latent-tuberculosis-testing-in-patients-taking-biologics/
152 Ya J, Khanna U, Havele S. et al. Utility of repeat latent tuberculosis testing with QuantiFERON‐TB Gold test in psoriasis patients treated with TNF‐α inhibitors at a single U. S. institution. Br J Dermatol 2020; 182: 800-802
153 Mrowietz U, Riedl E, Winkler S. et al. No reactivation of tuberculosis in patients with latent tuberculosis infection receiving ixekizumab: A report from 16 clinical studies of patients with psoriasis or psoriatic arthritis. J Am Acad Dermatol 2020; 83: 1436-1439 [Epub 2020 Jun 8]

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