Application of genetic signatures to clinical care of lupus

Transcription

1 Application of genetic signatures to clinical care of lupus Dr Durga Prasanna Misra MD, MRCP(UK), DM Assistant Professor Department of Clinical Immunology, JIPMER, Puducherry.

2 LAYOUT Genetics of lupus Interferons Genesis of Type I Interferons in lupus How are interferons implicated in lupus Interferon signature metric Therapies directly targeting Type I interferons Therapies indirectly affecting Type I interferons Conclusion

3 LAYOUT Genetics of lupus Interferons Genesis of Type I Interferons in lupus How are interferons implicated in lupus Interferon signature metric Therapies directly targeting Type I interferons Therapies indirectly affecting Type I interferons Conclusion

4 Genetics driving pathogenesis of SLE Nat Rev Rheumatol 2010; 6:

5 LAYOUT Genetics of lupus Interferons Genesis of Type I Interferons in lupus How are interferons implicated in lupus Interferon signature metric Therapies directly targeting Type I interferons Therapies indirectly affecting Type I interferons Conclusion

6 Interferons IFN Type Name (Number of genes) Type I IFN-α (14) IFN-β (1) IFN-κ (1) IFN-ε (1) IFN-ω (1) Location in human chromosome Receptors 9 IFN-αR1 and IFNαR2 (also known as IFNAR1 and IFNAR2) Type II IFN-γ (1) 12 IFN-γR1 and IFNγR2 (also known as IFNGR1 and IFNGR2) Type III IFN-λ (3) 19 IFNλR1 (also known as IL-28RA) and IL- 10R2 Cytokine Growth Factor Rev 2015 ;26(2):

7 Type I IFN activation Arthritis Research and Therapy 2011

8 Induction of type I IFN Nat Rev Immunol 2014;14(1):36-49.

9 Canonical pathway of Type I IFN signalling Nat Rev Immunol 2014;14(1):36-49.

10 LAYOUT Genetics of lupus Interferons Genesis of Type I Interferons in lupus How are interferons implicated in lupus Interferon signature metric Therapies directly targeting Type I interferons Therapies indirectly affecting Type I interferons Conclusion

11 Apoptosis And SLE Nat Rev Rheumatol 2010; 6: 280-9

12 Arthritis Research & Therapy 2010, 12:207

13 Type I interferonopathies Current Opinion in Immunology 2015, 32:7 12

14 LAYOUT Genetics of lupus Interferons Genesis of Type I Interferons in lupus How are interferons implicated in lupus Interferon signature metric Therapies directly targeting Type I interferons Therapies indirectly affecting Type I interferons Conclusion

15 Induction of type I IFN Nat Rev Immunol 2014;14(1):36-49.

16 LAYOUT Genetics of lupus Interferons Genesis of Type I Interferons in lupus How are interferons implicated in lupus Interferon signature metric Therapies directly targeting Type I interferons Therapies indirectly affecting Type I interferons Conclusion

17 Interferon signature in lupus Peripheral blood Peripheral blood mononuclear cells (PBMC) isolated RNA isolated Microarray to identify genetic signature Heat map

18 Interferon signature in lupus J Exp Med 2003; 197(6):

19 Interferon signature in lupus J Exp Med 2003; 197(6):711-2; Arthritis Rheum 2013; 65(2):

20 Extinction of interferon signature following intravenous steroid pulses J Exp Med 2003; 197(6):

21 Interferon signature metric - ISM The ISM can be derived using any number of feasible genes. Lupus Science & Medicine 2015;2:e

22 ISM segregates patients with SLE Arthritis Rheum 2012; 64(11):

23 High Interferon Gene Signature in lupus Increased disease activity Reduced complement C3 and C4 Increased oral corticosteroid use Ranade K et al. Arthritis Rheumatol 2015; 67 (suppl 10). Serum IFNα - elevated in lupus nephritis - correlates with IFN Score Serum IFNβ - elevated in mucocutaneous disease Ducreux J et al. Arthritis Rheumatol 2014; 66 (suppl 10).

24 ISM high vs low subjects Type I IFN signature high subjects - Enrichment of B cells, plasma cells and CD40L pathways. Type I IFN signature low subjects - Enrichment for eosinophils and type II IFN (IFN-γ) specifically inducible gene signatures Liu H et al. Arthritis Rheumatol. 2016; 68 (suppl 10).

25 LAYOUT Genetics of lupus Interferons Genesis of Type I Interferons in lupus How are interferons implicated in lupus Interferon signature metric Therapies directly targeting Type I interferons Therapies indirectly affecting Type I interferons Conclusion

26 Sifalimumab Phase I 2011 LISA study - Phase I study - one iv dose of sifalimumab(0.3, 1, 3, 10 or 30 mg/kg) vs placebo. Similar adverse effect profile to placebo. Ann Rheum Dis 2011;70:

27 Sifalimumab Phase I 2011 Ann Rheum Dis 2011;70:

28 Sifalimumab Phase I received sifalimumab ( mg/kg; mg/kg; mg/kg; and mg/kg) and 40 received placebo. Similar safety profile. ISM 21 genes 75% had high ISM Arthritis Rheum 2013 ;65(4):

29 Sifalimumab Phase II patients stratified to receive iv placebo (108) or sifalimumab 200 mg (108), 600 mg (108) or 1200 mg (107) on days 1, 15 and 29, and every 28 days. Primary outcome measure - proportion attaining SLE Responder Index (SRI) - Secondary outcome measures - % with decreased oral pred doses - 4-point reduction in CLASI - >3-point improvement in FACIT Ann Rheum Dis 2016;75:

30 Sifalimumab Phase II 2016 ISM 4 genes Subgroup analyses - SRI(4), msri(8) and BICLA by IFN status : substantial improvements observed for IFN-high patients versus placebo (small numbers of IFN-low patients - 19% - prevented meaningful statistical comparison) Ann Rheum Dis 2016;75:

31 Rontalizumab Phase I 2012 Similar safety profile to placebo Arthritis Rheum ;64(11):

32 Rontalizumab Phase II 2015 ROSE trial Paradoxically more effective in IFN low lupus reduction in flares on active treatment, reduction in dose of oral prednisolone Further drug development halted as of now Ann Rheum Dis 2016;75:

33 Endogenous production of antibodies to IFN IFN α kinoid(ifn-k)-inactive IFNα2b conjugated to KLH Delays onset of proteinuria and improves survival in NZB/W F1 mice. Proc Natl Acad Sci U S A ;106(13): ; Rheumatology 2014; 53:

34 IFN-K Phase I/II study 2013 Arthritis Rheum 2013 ;65(2):

35 Anifrolumab phase II Improved rash, alopecia, arthritis in ISM high patients. Merrill J et al. Arthritis Rheumatol. 2016; 68 (suppl 10). Neutralized ISG. Brohawn P et al. Arthritis Rheumatol. 2015; 67 (suppl 10). Significantly reduced disease activity compared with placebo across multiple clinical endpoints, especially in ISM-high patients with lupus. Furie R et al. Arthritis Rheumatol. 2015; 67 (suppl 10).

36 Direct targeting of IFNs Nat Rev Rheumatol 2016; 12:

37 LAYOUT Genetics of lupus Interferons Genesis of Type I Interferons in lupus How are interferons implicated in lupus Interferon signature metric Therapies directly targeting Type I interferons Therapies indirectly affecting Type I interferons Conclusion

38 HCQ impairs production of IFN from SLE pdcs Arthritis Research & Therapy 2012, 14:R155

39 Proteasome Is IFN-α from SLE PBMC Arthritis Rheum 2012; 64(2) :

40 BORTEZOMIB Macrophag e and other APCs Plasma cell Apoptotic nuclear debris Apoptosis Autoantibodies Drive further autoantibody production by plasma cells IFN targeted therapies SIFALIMUMAB RONTALIZUMAB MEDI-546 AIA122 IFN α KINOID Anifrolumab Secondary necrotic debris Endosomal TLRs HCQ Btk antagonists DIhydroartemisinin S1PR agonist Inhibitory ODNs Upregulation of genes related to Type I IFN INTERFERON SIGNATURE METRIC Type I interferons Immune complex formation Bcl-2 antagonists TISSUE INJURY Plasmacytoid dendritic cells Durga Prasanna Misra

41 LAYOUT Genetics of lupus Interferons Genesis of Type I Interferons in lupus How are interferons implicated in lupus Interferon signature metric Therapies directly targeting Type I interferons Therapies indirectly affecting Type I interferons Conclusion

42 CONCLUSION Type I IFNs promote lupus pathogenesis. Approximately ¾ patients with SLE display an IFN signature in peripheral blood (quantified by ISM). ISM is extinguished following high dose steroid therapy. Newer therapies directly targeting Type I IFN are under development.

43 Please select the correct responses I. Which is NOT an interferon-targeted therapy? II. The interferon signature metric comprises 1. Sifalimumab 1. Rontalizumab 2. Gevokizumab 1. Anifrolumab 1. Three genes 2. Seven genes genes 1. Any number of genes

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