Associations between SLE and spontaneous IFN-g release. Jenna Thomason, MD, MPH Grant Hughes, MD April 29, 2017

Transcription

1 Associations between SLE and spontaneous IFN-g release Jenna Thomason, MD, MPH Grant Hughes, MD April 29, 2017

2 None Disclosures

3 Outline Background Methods Preliminary results Conclusions

4 March, 1980

5 IFN-g and SLE pathogenesis MICE Accelerates disease, NZB/NZW (Jacob et al. 1987) Promotes lymphadenopathy, anti-dsdna Abs and glomerulonephritis, MRL/lpr (Balomenos et al. 1998) HUMANS IFN-γ mrna increased in PBMCs of SLE patients (Csiszar et al., 2000; Harigai et al., 2008) Serum IFN-γ positive correlates with disease activity (Funauchi et al., 1991) Increased IFN-γ/IL-4 ratios in patients with glomerulonephritis (Akahoshi et al., 1999; Masutani et al., 2001) Phase I anti-ifn-g trial, AMG811 (Welcher et al. 2015)

6 Interferon-g release assay (IGRA) Estimates probability of TB infection (LTBI) based on IFN-γ release: Whole blood after 18 hours of exposure to 1. TB antigen 2. Mitogen 3. No stimulation (negative control, NC or QFTBNL)

7 Distribution of QFTBNL values, Number of Results Uche Obih, MD IFN-g (IU/mL) Distribution of IGRA nil test results and percentiles from the median, (n = 19,456). High interferon-γproduction defined as > 5 SD above median nil test result ( 3 IU/mL) and shown in box.

8 Spontaneous IFN-g release associated with SLE, TB, HIV and HLH diagnosis codes QFTBNL <3 vs. 3 IU/mL Diagnosis Odds Ratio (CI) P-value HIV 2.16 ( ) SLE 3.79 ( ) LTBI 3.88 ( ) < Active TB 4.11 ( ) Any evidence of TB 4.03 ( ) < HLH ( ) <0.001 Uche Obih, MD and Christian Lood, PhD

9 Spontaneous IFN-g release in SLE patients Observation: HIGH QFTBNL appears to be associated with subset of SLE patients Question: Are QFTBNL values associated with disease activity and/or select disease manifestations? Hypothesis: 1. QFTBNL positively associated with SLEDAI 2. High QFTBNL associated with select disease manifestations (nephritis, CNS)

10 Study Design Retrospective cohort analysis, UWMC, HMC, UW neighborhood clinics 99 individuals meeting SLICC criteria with subsequent/concurrent QFTBNL result SLEDAI calculated at time of QFTBNL (n = 50)

11 SLE Cohort (select features) N = 97 Age 39 (18 84) Sex (female) 85% White 29.9% Black 22.7% Asian 15.5% Mexican/Mexican- American 15.5% N = 97 Anti-dsDNA 76.3% Anti-Sm 37.1% APLA/LAC 61.9% DAT/Coombs 18.6% SLEDAI (avg) 12 SLEDAI (range) 0 30 Leukopenia 89.7% Arthralgia/Arthritis 79.4% Acute cutaneous (ever) 47.4% Renal 36.1 Serositis 33% NPSLE 19.6%

12 QFTBNL correlates with SLEDAI QFTBNL by quartiles (n = 50) SLEDAI * Kruskal-Wallis test p = st 2nd 3rd QFTBNL (IU/mL) 4th

13 QFTBNL correlates with SLEDAI 40 QFTBNL x SLEDAI (n = 50) SLEDAI Spearman correlation r = p = QFTBNL (IU/mL)

14 High QFTBNL associated with current renal and acute skin disease Lowest quartile (n = 27) Highest quartile (n = 24) Odds Ratio (95% CI) P value Ever (SLICC) Renal 10/27 12/ ( ) Neuropsychiatric 3/27 7/ ( ) Acute cutaneous 12/27 13/ ( ) Low complement 22/27 20/ ( ) Current (SLEDAI) Renal 5/16 9/ ( ) Neuropsychiatric 1/19 3/ ( ) New rash 0/19 8/ ( ) Low complement 11/15 9/ ( ) 0.157

15 QFTBNL detects active disease with high specificity SLEDAI > 6 SENS SPEC p Yes No Anti-dsDNA (> 75th percentile) Yes 13 3 No QFTBNL (> 75th percentile) dsdna + QFTBNL Yes 12 1 No Yes 8 0 No Fisher s exact test, one-sided

16 Conclusions - I A subgroup of SLE patients exhibit increased spontaneous interferon-g release (high QFTBNL). QFTBNL correlates positively with SLEDAI with about same r and p values as anti-dsdna levels. High QFTBNL appears to associate with renal and acute skin disease.

17 Conclusions - II QFTBNL may have value as a readily available biomarker. Supports a pathogenic role for IFN-g in renal and skin disease. High QFTBNL may identify a subset of SLE patients that will response to IFN-g blockade.

18 Thank you and Acknowledgements Uche Obih, MD Christian Lood, PhD Grant Hughes, MD David Koelle, MD UW DOM Pilot Grant Award

19 Extra slides

20 Disease duration Number of Subjects Disease duration (years)

21 Duration x QFTBNL QFTBNL (IU/mL) Spearman correlation r = p = Disease duration (years)

22 Interferons critical anti-viral cytokines Proteins Cellular sources Receptor Functions Type 1 IFN-a IFN-b IFN-e IFN-k IFN-t IFN-w Dendritic cells Fibroblasts Endometrium Keratinocytes - - IFNAR1/2 Anti-viral host defense Anti-viral immunity Anti-protozoal defense Type 2 IFN-g T cells NK cells IFNGR1/2 Anti-viral host defense Anti-viral immunity Macrophage activation Type 3 IFN-l DCs/Mϕ IL28Ra/IL- 10R2 (epithelial cells) Anti-viral host defense Gonzales-Navajas et al. Nat Rev Immunol 2012:12:125 Laidlaw and Dustin Frontiers in Immunology 2014;5:545 Oon et al. Clin Transl Immunol 2016;5:e79

23 Distribution of QFTBNL values in HIV+ and SLE patients, QFTBNL values <0.5 in HIV population, QFTBNL values <0.5 in SLE population, Fraction All (N = 15,405) HIV (n = 2,600) Fraction All (N = 15,405) SLE (n = 334) IFN-g (IU/mL) 0.00 IFN-g (IU/mL)

24 Cohort Identification DCDR 3/21/1999 8/1/ or M32 ANA+ 1 QFTBNL value SLICC criteria At least one QFTBNL result within 7 days before or anytime after the patient met SLICC criteria Initial cohort n = 167 Met SLICC Criteria n = 99 Two patients removed due to positive TB quantiferon SLEDAI completed n = 50 Study cohort n = 97

25 SLE cohort Age at the time of IGRA testing. All subjects (n=97) Mean/n Range/% Mean age (years)* 39 (18 84) Sex (female) 82 (84.5) Race/ethnicity White 29 (29.9) Black 22 (22.7) Asian 15 (15.5) Mexican/Mexican-American 15 (15.5) Filipino, Pacific Islander, Samoan or Native Hawaiian Native American 6 (6.2) 2 (2.1) Hispanic (not Mexican) 0 (0) Unknown 5 (5.2) Other 3 (3.1)

26 Demographics: SLICC Clinical Criteria All patients (n=97) Patients with SLEDAI (n=50) n % n % Leukopenia or lymphopenia 87 (89.7) 45 (90) Joint disease 77 (79.4) 40 (80) Acute cutaneous lupus 46 (47.4) 27 (54) Renal disease 35 (36.1) 14 (28) Serositis 32 (33) 18 (36) Nonscarring alopecia 29 (29.9) 16 (32) Oral/nasal ulcerations 28 (28.9) 15 (30) Thrombocytopenia (<100k) 24 (24.7) 17 (34) Neurologic 19 (19.6) 14 (28) Chronic cutaneous lupus 13 (13.4) 5 (10) Hemolytic anemia 12 (12.4) 8 (16)

27 Demographics: SLICC Immunologic Criteria All patients (n=97) Patients with SLEDAI (n=50) n % n % ANA 97 (100) 50 (100) Low complement 76 (78.4) 42 (84) Anti-dsDNA 74 (76.3) 39 (78) Antiphospholipids/LAC 60 (61.9) 35 (70) Anti-Smith 36 (37.1) 16 (32) Direct Coombs positive 18 (18.6) 12 (24)

28 Demographics: Renal disease All patients (n=35) n % n % Class 1 0 (0) 0 (0) Patients with SLEDAI (n=14) Class 2 2 (5.7) 1 (7.1) Class 3 or 4 12 (34.3) 4 (28.6) Class 5 3 (8.6) 3 (21.4) Class 5 + 2, 3, or 4 9 (25.7) 3 (21.4) Clinical diagnosis only 8 (22.9) 1 (7.1) Unknown type 1 (2.9) 0 (0)

29 SLEDAI scores Minimum: 0 Mean: 12 Maximum: 30

30 QFTBNL values Minimum: % Percentile: Median: % Percentile: Maximum: 10.00

31 dsdna x SLEDAI (n = 49) SLEDAI Spearman correlation r = p = anti-dsdna (U/mL)

32 dsdna-hs x SLEDAI (n = 33) SLEDAI Spearman correlation r = p = anti-dsdna-hs (U/mL)

33 QFTBNL x anti-dsdna (n = 68) QFTBNL (IU/mL) Spearman correlation r = p = anti-dsdna (U/mL)