Alyssa Johnsen

Mast cells contribute to initiation of autoantibody-mediated arthritis via IL-1

Mast cells are immune sentinels that participate in the defense against bacteria and parasites. Resident within the joint, mast cells become activated in human rheumatoid arthritis and are implicated in the pathogenesis of experimental murine synovitis. However, their arthritogenic role remains undefined. Using a model of autoantibody-induced arthritis, we show that mast cells contribute to the initiation of inflammation within the joint by elaboration of IL-1. Mast cells become activated to produce this cytokine via the IgG immune complex receptor FcγRIII. Interestingly, mast cells become dispensable for the perpetuation of arthritis after delivery of IL-1, highlighting the contribution of this lineage to arthritis induction. These findings illuminate a mechanism by which mast cells can participate in the pathogenesis of autoimmune inflammatory arthritis and provide insights of potential relevance to human rheumatoid arthritis.

Impact of baseline anti-cyclic citrullinated peptide-2 antibody concentration on efficacy outcomes following treatment with subcutaneous abatacept or adalimumab: 2-year results from the AMPLE trial.

Objectives To examine whether baseline anti-cyclic citrullinated peptide-2 (CCP2) antibody status and concentration correlated with clinical outcomes in patients treated with abatacept or adalimumab on background methotrexate (MTX) in the 2-year AMPLE (Abatacept versus adaliMumab comParison in bioLogic-naïvE rheumatoid arthritis subjects with background MTX) study. Methods In this exploratory analysis, anti-CCP2 antibody concentration was measured at baseline, and antibody-positive patients were divided into equal quartiles, Q1–Q4, representing increasing antibody concentrations. Clinical outcomes analysed by baseline anti-CCP2 status and quartile included change from baseline in disease activity and disability and remission rates. Results Baseline characteristics were generally comparable across quartiles and treatment groups. In both treatment groups, anti-CCP2 antibody-negative patients responded less well than antibody-positive patients. At year 2, improvements in disease activity and disability and remission rates were similar across Q1–Q3, but were numerically higher in Q4 in the abatacept group; in contrast, treatment effects were similar across all quartiles in the adalimumab group. Conclusions In AMPLE, baseline anti-CCP2 positivity was associated with a better response for abatacept and adalimumab. Patients with the highest baseline anti-CCP2 antibody concentrations had better clinical response with abatacept than patients with lower concentrations, an association that was not observed with adalimumab. Trial registration number NCT00929864.

A Broad Analysis of IL1 Polymorphism and Rheumatoid Arthritis

OBJECTIVE It has been suggested that polymorphisms in IL1 are correlated with severe and/or erosive rheumatoid arthritis (RA), but the implicated alleles have differed among studies. The aim of this study was to perform a broad and well-powered search for association between allelic polymorphism in IL1A and IL1B and the susceptibility to or severity of RA. METHODS Key coding and regulatory regions in IL1A and IL1B were sequenced in 24 patients with RA, revealing 4 novel single-nucleotide polymorphisms (SNPs) in IL1B. These and a comprehensive set of 24 SNPs tagging most of the underlying genetic diversity were genotyped in 3 independent RA case-control sample sets and 1 longitudinal RA cohort, totaling 3,561 patients and 3,062 control subjects. RESULTS No fully significant associations were observed. Analysis of the discovery case-control sample sets indicated a potential association of IL1B promoter region SNPs with susceptibility to RA (for RA3/A, odds ratio [OR] 1.27, P = 0.0021) or with the incidence of radiographic erosions (for RA4/C, OR 1.56, P = 0.036), but these findings were not replicated in independent case-control samples. No association with rheumatoid factor, anti-cyclic citrullinated peptide, or the Disease Activity Score in 28 joints was found. None of the associations previously observed in other studies were replicated here. CONCLUSION In spite of a broad and highly powered study, we observed no robust, reproducible association between IL1A/B variants and the susceptibility to or severity of RA in white individuals of European descent. Our results provide evidence that, in the majority of cases, polymorphism in IL1A and IL1B is not a major contributor to genetic susceptibility to RA.

A genetic and functional relationship between T cells and cellular proliferation in the adult hippocampus.

A large correlation between variation in T cell subsets and hippocampal neurogenesis suggests that the immune system has an unexpectedly large influence on the brain.

Efficacy and safety of abatacept, a T-cell modulator, in a randomised, double-blind, placebo-controlled, phase III study in psoriatic arthritis

Objectives To assess the efficacy and safety of abatacept, a selective T-cell costimulation modulator, in a phase III study in psoriatic arthritis (PsA). Methods This study randomised patients (1:1) with active PsA (~60% with prior exposure to a tumour necrosis factor inhibitor) to blinded weekly subcutaneous abatacept 125 mg (n=213) or placebo (n=211) for 24 weeks, followed by open-label subcutaneous abatacept. Patients without ≥20% improvement in joint counts at week 16 were switched to open-label abatacept. The primary end point was the proportion of patients with ≥20% improvement in the American College of Rheumatology (ACR20) criteria at week 24. Results Abatacept significantly increased ACR20 response versus placebo at week 24 (39.4% vs 22.3%; p<0.001). Although abatacept numerically increased Health Assessment Questionnaire–Disability Index response rates (reduction from baseline ≥0.35) at week 24, this was not statistically significant (31.0% vs 23.7%; p=0.097). The benefits of abatacept were seen in ACR20 responses regardless of tumour necrosis factor inhibitor exposure and in other musculoskeletal manifestations, but significance could not be attributed due to ranking below Health Assessment Questionnaire–Disability Index response in hierarchical testing. However, the benefit on psoriasis lesions was modest. Efficacy was maintained or improved up to week 52. Abatacept was well tolerated with no new safety signals. Conclusions Abatacept treatment of PsA in this phase III study achieved its primary end point, ACR20 response, showed beneficial trends overall in musculoskeletal manifestations and was well tolerated. There was only a modest impact on psoriasis lesions. Trial registration number ClinicalTrials.gov number, NCT01860976 (funded by Bristol-Myers Squibb).

SAT0468 Presence of poor prognostic factors may predict response to abatacept in patients with active psoriatic arthritis: results from a post hoc analysis from a phase iii study

Background Abatacept, a selective T-cell co-stimulation modulator, significantly increased ACR20 response and had an overall beneficial effect on musculoskeletal symptoms in patients (pts) with active psoriatic arthritis (PsA) in the Phase III Active pSoriaTic athritis RAndomizEd triAl (ASTRAEA, NCT01860976).1 Factors that may predict responses to abatacept were explored in this post hoc analysis. Objectives To evaluate the relationship between baseline characteristics and abatacept response in a post hoc analysis of ASTRAEA. Methods Pts were randomized (1:1) to SC abatacept 125 mg weekly or placebo for 24 weeks in this trial. Pts without >20% improvement in joint counts at Week 16 were switched to open-label abatacept (early escape). ACR20 response rate in pts stratified by baseline variables was investigated in a multivariate analysis and odds ratios (ORs) generated to identify differences in response. Using a cut-off of OR 1.2, indicating pt subgroups in whom abatacept appeared to have a meaningful treatment benefit, baseline variables were further investigated in a univariate analysis and estimated differences calculated. Results Of 424 pts enrolled, 213 received abatacept and 211 placebo. In abatacept-treated pts, the multivariate model showed a difference in ACR20 response (OR >1.2) for baseline CRP (>upper limit of normal [ULN] vs ≤ULN; OR 1.346 [95% CI 0.668, 2.712]), DAS28 (CRP) (>5.1 vs ≤5.1; 1.489 [0.782, 2.836]), dactylitis (>0 vs 0; 1.372 [0.708, 2.659]), and median baseline erosions (≥3 vs <3; 1.924 [1.032, 3.587]). In placebo-treated pts, the OR was >1.2 for dactylitis only (1.406 [0.619, 3.193]). These factors, which have been identified previously as indicating poor prognosis in PsA, were balanced between treatment arms at baseline. In the univariate model by poor prognostic factors, the differences in ACR20 response rates with abatacept treatment vs placebo in distinct subgroups were numerically greater in pts who were positive for these prognostic factors at baseline than in those who were not (Figure). Conclusions These findings identified subgroups of pts with PsA with certain baseline characteristics in whom abatacept is most likely to be effective. The predictive factors identified are aligned with poor prognostic factors in the EULAR and Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) guidelines,2,3 and may indicate pts with the highest unmet medical need. References Mease P, et al. Arthritis Rheumatol 2016;68(Suppl 10):[Abstract 1041]. Gossec L, et al. Ann Rheum Dis 2016;75:499–510. Coates L, et al. Arthritis Rheumatol 2016;68:1060–71. Disclosure of Interest P. Mease Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Lilly, Novartis, Pfizer, Sun, UCB, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Crescendo Biosciences, Corrona, Demira, Janssen, Lilly, Novartis, Pfizer, Sun, UCB, Zynerba, Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Crescendo Biosciences, Genentech, Janssen, Novartis, Pfizer, UCB, I. McInnes Grant/research support from: Bristol-Myers Squibb, Celgene, Janssen, UCB, Consultant for: Bristol-Myers Squibb, Celgene, Janssen, Novartis, Pfizer, AbbVie, UCB, V. Strand Consultant for: AbbVie, Amgen Corporation, AstraZeneca, Biogen Idec, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Celltrion, Corrona, Crescendo Biosciences/Myriad Genetics, EMD Serono, Genentech/Roche, GlaxoSmithKline, Janssen, Lilly, Merck, Novartis, Pfizer, Regeneron, Samsung, Sandoz, Sanofi, UCB, O. FitzGerald Grant/research support from: AbbVie, Pfizer, Bristol-Myers Squibb, Consultant for: AbbVie, Pfizer, Bristol-Myers Squibb, Celgene, Janssen, Novartis, UCB, Lilly, H. Ahmad Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, A. Johnsen Employee of: Bristol-Myers Squibb, Celgene, Janssen, Novartis, Pfizer, AbbVie, UCB, J. Ye Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, S. Banerjee Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb

AB0469 Can Anti-TNF-Induced Autoantibody Conversion be Reversed by Switching to Abatacept Therapy in Patients with RA on Background MTX?

Background Anti-TNF therapy is associated with the induction of antinuclear antibodies (ANAs) and anti-double-stranded DNA (anti-dsDNA) antibodies in patients (pts) with RA.1,2 The effect of subsequent biologic therapy on such pts has not been explored. Objectives To compare the development of ANA and anti-dsDNA antibodies during treatment with abatacept (ABA) and anti-TNFs in the ATTEST and AMPLE trials, and to evaluate the effect of switching to ABA in pts with RA who developed anti-TNF-induced ANA/anti-dsDNA antibodies in the ATTEST trial. Methods In the 1-year double-blind (DB) ATTEST trial, pts were randomized to IV ABA (∼10 mg/kg every 4 weeks), infliximab (IFX; 3 mg/kg every 8 weeks) or placebo, all on background MTX. At Mth 6, placebo-treated pts were reallocated to ABA (blinding maintained); pts initially randomized to ABA or IFX continued treatment. Pts completing the 1-year DB period were eligible to receive ABA in an open-label long-term extension (OLE). In the head-to-head AMPLE trial, pts were randomized to SC ABA (125 mg weekly) or SC adalimumab (ADA; 40 mg biweekly), on background MTX for 2 years. Pts in both trials were biologic naïve, with an inadequate response to prior MTX and active RA. Blood samples were collected for the measurement of ANA and anti-dsDNA at baseline, Mth 6, Year 1 (end of DB period) and Year 2 (OLE) in the ATTEST trial, and at baseline, Year 1 and Year 2 in the AMPLE trial. Results In the ATTEST DB period, 156 pts received IV ABA and 165 received IFX; 132 ABA- and 136 IFX-treated pts continued into the OLE and received IV ABA. In AMPLE, 318 pts received SC ABA and 328 received ADA. At baseline in the ATTEST trial, 69 pts on active treatment (32 IV ABA, 37 IFX) were ANA positive and 26 pts (11 IV ABA, 15 IFX) were anti-dsDNA positive. In the AMPLE study, the respective numbers at baseline were: 166 ANA-positive pts (72 SC ABA, 94 ADA) and 6 anti-dsDNA-positive pts (1 SC ABA, 5 ADA). The % of pts with seroconversion for ANA or anti-dsDNA in the active treatment arms of each trial are shown in the Table. In both ATTEST and AMPLE, a higher % of pts receiving anti-TNF therapy seroconverted from baseline negative to positive during Year 1 of treatment, compared with those receiving ABA. This difference in autoantibody induction for anti-TNF versus ABA continued during the second year of AMPLE. In ATTEST, 48.5% (ANA) and 48.3% (anti-dsDNA) of IFX-treated pts who entered the OLE seroconverted from baseline ANA or anti-dsDNA negative to positive at Year 1; this dropped to 22.4% and 13.3%, respectively, at Year 2 after switching to ABA. The % of pts who converted from baseline positive to negative status increased from 12.1% in the IFX group to 20.6% on switching to ABA (Table). Conclusions In the ATTEST trial, switching from infliximab to abatacept seemed to reverse the autoantibody induction observed with anti-TNF treatment. Anti-TNF therapy was associated with greater autoantibody (ANA and anti-dsDNA) induction than abatacept in the ATTEST and AMPLE trials. These data provide additional insights into differences in the mechanism of action of anti-TNFs and abatacept, and imply an effect of T-cell co-stimulation blockade on B-cell function and autoantibody production. References Charles PJ, et al. Arthritis Rheum 2000;43:2383–90. Eriksson C, et al. Ann Rheum Dis 2005;64:403–7. Disclosure of Interest M. H. Buch Grant/research support from: Pfizer, Bristol-Myers Squibb, Speakers bureau: AbbVie, Bristol-Myers Squibb, Roche-Chugai, Pfizer, A. Johnsen Employee of: Bristol-Myers Squibb, D. A. Wong Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, M. Schiff Grant/research support from: UCB, Consultant for: AbbVie, Amgen, Antares, Bristol-Myers Squibb, Eli Lilly, Horizon, Johnson and Johnson, Novartis, Novo Nordisk, Pfizer, Roche, UCB, Speakers bureau: AbbVie

Development of a Molecular Signature to Monitor Pharmacodynamic Responses Mediated by In Vivo Administration of Glucocorticoids

To develop an objective, readily measurable pharmacodynamic biomarker of glucocorticoid (GC) activity.

AB0248 The impact of therapy on anti-carbamylated protein antibody isotypes and serostatus in patients with early ra treated with abatacept and methotrexate

Background Maturation of autoantibody responses has been suggested to be a proxy for disease maturation. Autoantibody responses against post-translationally modified antigens are present in autoimmune diseases and antibodies directed against carbamylated proteins (anti-CarP antibodies) are a marker of RA. Anti-CarP antibody analysis in patients with early RA offers the opportunity to estimate whether specific intervention during such early stages of autoantibody development may have an impact on the maturation of the anti-CarP antibody response. Objectives We assessed the relationship between changes in anti-CarP isotypes and rates of seroconverson to negative in patients with early RA. Methods In the Assessing Very Early Rheumatoid arthritis Treatment study (AVERT; NCT01142726), patients with early RA were treated with abatacept (ABA)+MTX, ABA monotherapy or MTX alone.1 Patients in AVERT were anti-cyclic citrullinated peptide-2 positive at baseline for study entry.1 In this post hoc analysis, concentrations of anti-CarP isotypes were measured using custom ELISAs. Anti-CarP ELISAs for immunoglobulin (Ig)G, IgM or IgA isotypes were performed in patient serum at baseline, and at Days 85 and 365 on treatment. Baseline levels of each anti-CarP antibody isotype and % seropositivity were comparable across the three treatment arms. Adjusted mean change from baseline was calculated using a longitudinal repeated measures model. Results At baseline, 51.3, 42.5 and 29.3% of all patients with serum available in AVERT were positive for IgG, IgM (indicative of an ongoing immunoresponse) and IgA anti-CarP isotypes, respectively. Overall, approximatly 65% of patients were positive for at least one anti-CarP antibody isotype. Median % change from baseline (25%, 75%) for anti-CarP isotypes levels from baseline to Days 85 and 365 are shown (Table). Analysing patients who were positive at baseline for each of the isotypes, we observed that 19/48 (40%), 16/43 (37%) and 11/48 (23%) of the patients positive for the IgG isotype became negative on ABA+MTX, ABA and MTX, respectively, at 1 year. For the IgM isotype, 26/48 (54%), 14/36 (39%) and 15/38 (39%) became negative on ABA+MTX, ABA and MTX, respectively. For the IgA isotype, 12/26 (46%), 10/23 (43%) and 13/31 (42%) became negative on ABA+MTX, ABA and MTX, respectively.Table 1. Median % change from baseline (25%, 75%) for anti-CarP isotypes Day 85 Day 365 IgG IgM IgA IgG IgM IgA ABA −17.3 (−55.7, 0.0) −26.3 (−57.9, 0.0) −6.8 (−35.1, 0.0) −31.2 (−67.4, 0.0) 26.0 (-81.2, 0.0) −26.7 (−72.9, 13.0) MTX −19.3 (−53.6, 0.0) −35.7 (−54.4, −6.9) −27.2 (−42.4, −3.9) −17.7 (−65.1, 0.0) −38.3 (−63.7, 0.0) −21.9 (−50.3, 0.0) ABA+ MTX −38.8 (−62.3, 0.0) −44.2 (−59.5, −13.8) −41.3 (−54.9, −28.3) −55.7 (−76.7, 0.0) −45.7 (−72.5, −0.2) −46.4 (−66.7, 0.0) Conclusions Concentrations of all anti-CarP isotypes (IgM, IgA, IgG) were numerically reduced by abatacept+MTX therapy compared with MTX or abatacept alone. Abatacept+MTX trended towards higher rates of seroconversion to negative for all isotypes over 1 year of treatment. These results indicate that the extent of the anti-CarP antibody response can be modulated by intervention with abatacept on background MTX in anti-citrullinated protein antibody-positive patients with early RA. References Emery P, et al. Ann Rheum Dis 2015;74:19–26. Disclosure of Interest L. Trouw: None declared, S. Connolly Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, A. Johnsen Employee of: Bristol-Myers Squibb, J. Ye Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, M. Maldonado Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, R. Toes: None declared, T. Huizinga Grant/research support from: EU & Dutch Arthritis Foundation, Consultant for: Abbott Laboratories, Biotest AG, Bristol-Myers Squibb, Crescendo Bioscience, Inc, Novartis Pharmaceuticals Corporation, Pfizer Inc, Roche, sanofi-aventis, Schering-Plough, UCB, Inc., Eli Lilly, Speakers bureau: Abbott Laboratories, Biotest AG, Bristol-Myers Squibb, Novartis Pharmaceuticals Corporation, Pfizer Inc, Roche, sanofi-aventis, Schering-Plough

THU0114 Effect of Anti-Cyclic Citrullinated Peptide 2 Immunoglobulin M Serostatus on Efficacy Outcomes Following Treatment with Abatacept Plus Methotrexate in the Avert Trial

Background Anti-citrullinated protein antibodies (ACPA) are a marker of RA, and the presence of the immunoglobulin M (IgM) isotype indicates an ongoing immune response involving the recruitment of naïve B cells.1 Abatacept (ABA) modulates T-cell co-stimulation and has been shown to impact ACPA maturation, including seroconversion of IgM, in the AVERT (Assessing Very Early Rheumatoid arthritis Treatment) trial.2 Objectives To assess the efficacy of treatment with ABA+MTX, ABA monotherapy or MTX alone in patients (pts) from the AVERT trial based on their anti-cyclic citrullinated peptide 2 (CCP2; a surrogate for ACPA) IgM serostatus at baseline (BL), and seroconversion (anti-CCP2 IgM positive to negative) through 1 year. Methods The AVERT trial has been described previously.3 In this post hoc analysis, pt samples were analysed by ELISA to determine anti-CCP2 IgM serostatus. Efficacy outcomes analysed by BL anti-CCP2 IgM serostatus included remission rate at 12 mths (CDAI, SDAI, Boolean and DAS28 [CRP] <2.6-defined remission), and adjusted mean change in DAS28 (CRP) and HAQ-DI over time (samples taken every 28 days up to Mth 12 and analysed with a longitudinal repeated-measures model). Boolean remission was analysed in pts who seroconverted. Results In the ABA+MTX treatment arm, a higher proportion of pts who were anti-CCP2 IgM positive at BL achieved remission by all indices compared with pts who were BL IgM negative (Figure). This trend was most clearly observed in the stringent indices of CDAI, SDAI and Boolean remission, compared with DAS28 (CRP)-defined remission. This trend was not observed in either the ABA monotherapy or MTX alone arms. Mean improvement in DAS28 (CRP) and HAQ-DI over time was also greatest in BL anti-CCP2 IgM-positive pts treated with ABA+MTX. A numerically higher proportion of pts who seroconverted from anti-CCP2 IgM positive at BL to negative at Mth 12 achieved Boolean remission versus pts who remained seropositive in the ABA+MTX and ABA monotherapy arms (Table). Conclusions Abatacept in combination with MTX had greater clinical efficacy in pts who were anti-CCP2 IgM positive at BL than in those who were anti-CCP2 IgM negative at BL, and in those who seroconverted over time than those who did not, suggesting that the impact on ACPA is associated with clinical benefit. References Verpoort KN, et al. Arthritis Rheum 2006;54:3799–808. Huizinga TWJ, et al. Arthritis Rheum 2014;66:S666. Poster 1515. Emery P, et al. Ann Rheum Dis 2015:74:19–26. Disclosure of Interest T. W. J. Huizinga Grant/research support from: EU & Dutch Arthritis Foundation, Consultant for: Abbott Laboratories, Biotest AG, Bristol-Myers Squibb, Crescendo Bioscience, Inc, Novartis Pharmaceuticals Corporation, Pfizer Inc, Roche, sanofi-aventis, Schering-Plough, UCB, Inc., Eli Lilly, Meteor Board, Speakers bureau: Abbott Laboratories, Biotest AG, Bristol-Myers Squibb, Novartis Pharmaceuticals Corporation, Pfizer Inc, Roche, sanofi-aventis, Schering-Plough, S. E. Connolly Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, A. Johnsen Employee of: Bristol-Myers Squibb, J. Zhu Employee of: Bristol-Myers Squibb, D. E. Furst Grant/research support from: AbbVie, Actelion, Amgen, Bristol-Myers Squibb, Gilead, GSK, NIH, Novartis, Pfizer, Roche/Genentech, UCB, Consultant for: AbbVie, Actelion, Amgen, Bristol-Myers Squibb, Cytori, Janssen, Gilead, GSK, NIH, Novartis, Pfizer, Roche/Genentech, UCB, Speakers bureau: (CME only) AbbVie, Actelion, UCB, V. P. Bykerk Grant/research support from: Amgen, Pfizer, Bristol-Myers Squibb, Janssen, UCB, Roche/Genentech, Consultant for: Amgen, Pfizer, Bristol-Myers Squibb, UCB, Roche, G. R. Burmester Grant/research support from: Bristol-Myers Squibb, AbbVie, Pfizer, Medimmune, Novartis, Roche, UCB, Lilly, Consultant for: Bristol-Myers Squibb, AbbVie, Pfizer, MSD, Medimmune, Roche, UCB, Speakers bureau: Bristol-Myers Squibb, AbbVie, Pfizer, MSD, Roche, UCB, B. G. Combe Grant/research support from: Pfizer, Roche-Chugai, Speakers bureau: Bristol-Myers Squibb, Merck, Pfizer, Roche-Chugai, UCB, D. A. Wong Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, L. A. Trouw: None declared, R. E. M. Toes: None declared, P. Emery Grant/research support from: Abbvie, Merck, Pfizer, Roche, Consultant for: Abbvie, Bristol-Myers Squibb, Merck, Pfizer, Roche, Lilly, Novartis