Wolfgang Hueber

Effects of AIN457, a Fully Human Antibody to Interleukin-17A, on Psoriasis, Rheumatoid Arthritis, and Uveitis

A human antibody to interleukin-17A is well tolerated and may be effective in the treatment of psoriasis, rheumatoid arthritis, and noninfectious uveitis. Stopping Inflammation in Its Tracks Inflammation—characterized by redness, swelling, and pain and derived from the Latin word inflammare (to set on fire)—is the body’s principal defense against infection and injury. Once the infection has been squelched by the immune system, the inflammatory response is usually switched off. Sometimes, however, immune cells activated during inflammation elude the “off switch,” resulting in tissue destruction and various diseases—including cancer, rheumatoid arthritis, and skin disorders such as psoriasis. Cytokines that activate immune cells are key drivers of inflammation. To address whether blocking one of these cytokines, interleukin-17A (IL-17A), might be a useful therapeutic strategy for treating inflammatory diseases, Hueber and colleagues used a human monoclonal antibody (AIN457) against IL-17A to treat patients in three small proof-of-concept trials for psoriasis, rheumatoid arthritis, and uveitis (eye inflammation). Their results demonstrate that IL-17A participates in these diseases and that the antibody against this cytokine may be an effective therapeutic agent. The proinflammatory cytokine IL-17A is produced by T helper 17 (TH17) cells and affects many different cell types including macrophages and dendritic cells of the immune system, as well as epithelial, endothelial, and skin cells. IL-17A has been implicated in psoriasis, rheumatoid arthritis, and uveitis, but its exact role is unclear. The etiologies and symptoms of these three diseases are very different. TH17 and TH1 cells have been implicated in both psoriasis (characterized by excessive turnover of skin cells resulting in scaly skin patches) and uveitis (intraocular inflammation that can lead to vision loss). In contrast, in the autoimmune disease rheumatoid arthritis, autoreactive T and B cells together with autoantibodies promote prolonged inflammation, ultimately resulting in the destruction of cartilage and bone. In their three proof-of-concept trials, Hueber and co-workers treated a total of 60 patients with the human monoclonal antibody AIN457 at different doses and observed no major adverse effects. Although the trials were small and the results were preliminary, improvements were seen in all three disease groups. Psoriasis patients receiving AIN457 showed reduced scaly skin patches, decreased production of inflammatory cytokines, and a reduction in T cells infiltrating the skin lesions compared with placebo-treated patients. After receiving infusions of AIN457, rheumatoid arthritis patients exhibited reduced inflammation of the synovial joints as shown by improvements in three different clinical scores compared with placebo-treated patients. Meanwhile, patients with uveitis treated with AIN457 showed improved visual acuity, reduced ocular inflammation, or a reduced need for steroid drugs after 8 weeks. These encouraging results warrant larger clinical trials to assess further the safety and efficacy of AIN457 for treating psoriasis, rheumatoid arthritis, and uveitis and perhaps other inflammatory diseases in which IL-17A has been implicated. Interleukin-17A (IL-17A) is elaborated by the T helper 17 (TH17) subset of TH cells and exhibits potent proinflammatory properties in animal models of autoimmunity, including collagen-induced arthritis, experimental autoimmune encephalomyelitis, and experimental autoimmune uveitis. To determine whether IL-17A mediates human inflammatory diseases, we investigated the efficacy and safety of AIN457, a human antibody to IL-17A, in patients with psoriasis, rheumatoid arthritis, and chronic noninfectious uveitis. Patients with chronic plaque-type psoriasis (n = 36), rheumatoid arthritis (n = 52), or chronic noninfectious uveitis (n = 16) were enrolled in clinical trials to evaluate the effects of neutralizing IL-17A by AIN457 at doses of 3 to 10 mg/kg, given intravenously. We evaluated efficacy by measuring the psoriasis area and severity index (PASI), the American College of Rheumatology 20% response (ACR20) for rheumatoid arthritis, or the number of responders for uveitis, as defined by either vision improvement or reduction in ocular inflammation or corticosteroid dose. AIN457 treatment induced clinically relevant responses of variable magnitude in patients suffering from each of these diverse immune-mediated diseases. Variable response rates may be due to heterogeneity in small patient populations, differential pathogenic roles of IL-17A in these diseases, and the different involvement or activation of IL-17A–producing cells. The rates of adverse events, including infections, were similar in the AIN457 and placebo groups. These results support a role for IL-17A in the pathophysiology of diverse inflammatory diseases including psoriasis, rheumatoid arthritis, and noninfectious uveitis.

Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial

Objective The authors tested whether the anti-interleukin (IL)-17A monoclonal antibody secukinumab was safe and effective for the treatment of active Crohns disease. Design In a double-blind, randomised, placebo-controlled proof-of-concept study, 59 patients with moderate to severe Crohns disease (Crohns Disease Activity Index (CDAI) ≥220 to ≤450) were assigned in a 2:1 ratio to 2×10 mg/kg intravenous secukinumab or placebo. The primary end point, addressed by Bayesian statistics augmented with historical placebo information, was the probability that secukinumab reduces the CDAI by ≥50 points more than placebo at week 6. Ancillary analyses explored associations of 35 candidate genetic polymorphisms and faecal calprotectin response. Results 59 patients (39 secukinumab, 20 placebo, mean baseline CDAI 307 and 301, respectively) were recruited. 18/59 (31%) patients discontinued prematurely (12/39 (31%) secukinumab, 6/20 (30%) placebo), 10/59 (17%) due to insufficient therapeutic effect (8/39 (21%) secukinumab, 2/20 (10%) placebo). Fourteen serious adverse events occurred in 10 patients (seven secukinumab, three placebo); 20 infections, including four local fungal infections, were seen on secukinumab versus none on placebo. Primary end point analysis estimated <0.1% probability (∆CDAI (SD) =33.9 (19.7), 95% credible interval −4.9 to 72.9) that secukinumab reduces CDAI by ≥50 points more than placebo. Secondary area under the curve analysis (weeks 4–10) showed a significant difference (mean ΔCDAI=49; 95% CI (2 to 96), p=0.043) in favour of placebo. Post hoc subgroup analysis showed that unfavourable responses on secukinumab were driven by patients with elevated inflammatory markers (CRP≥10 mg/l and/or faecal calprotectin≥200 ng/ml; mean ΔCDAI=62; 95% CI (−1 to 125), p=0.054 in favour of placebo). Absence of the minor allele of tumour necrosis factor-like ligand 1A was strongly associated with lack of response measured by baseline-adjusted changes in calprotectin at week 6 (p=0.00035 Bonferroni-corrected). Conclusions Blockade of IL-17A was ineffective and higher rates of adverse events were noted compared with placebo. Clinical trial registration This trial was registered at ClinicalTrial.gov with the number NCT01009281.

Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial

BACKGROUND Ankylosing spondylitis is a chronic immune-mediated inflammatory disease characterised by spinal inflammation, progressive spinal rigidity, and peripheral arthritis. Interleukin 17 (IL-17) is thought to be a key inflammatory cytokine in the development of ankylosing spondylitis, the prototypical form of spondyloarthritis. We assessed the efficacy and safety of the anti-IL-17A monoclonal antibody secukinumab in treating patients with active ankylosing spondylitis. METHODS We did a randomised double-blind proof-of-concept study at eight centres in Europe (four in Germany, two in the Netherlands, and two in the UK). Patients aged 18-65 years were randomly assigned (in a 4:1 ratio) to either intravenous secukinumab (2×10 mg/kg) or placebo, given 3 weeks apart. Randomisation was done with a computer-generated block randomisation list without a stratification process. The primary efficacy endpoint was the percentage of patients with a 20% response according to the Assessment of SpondyloArthritis international Society criteria for improvement (ASAS20) at week 6 (Bayesian analysis). Safety was assessed up to week 28. This study is registered with ClinicalTrials.gov, number NCT00809159. FINDINGS 37 patients with moderate-to-severe ankylosing spondylitis were screened, and 30 were randomly assigned to receive either intravenous secukinumab (n=24) or placebo (n=6). The final efficacy analysis included 23 patients receiving secukinumab and six patients receiving placebo, and the safety analysis included all 30 patients. At week 6, ASAS20 response estimates were 59% on secukinumab versus 24% on placebo (99·8% probability that secukinumab is superior to placebo). One serious adverse event (subcutaneous abscess caused by Staphylococcus aureus) occurred in the secukinumab-treated group. INTERPRETATION Secukinumab rapidly reduced clinical or biological signs of active ankylosing spondylitis and was well tolerated. It is the first targeted therapy that we know of that is an alternative to tumour necrosis factor inhibition to reach its primary endpoint in a phase 2 trial. FUNDING Novartis.

Efficacy and safety of secukinumab, a fully human anti-interleukin-17A monoclonal antibody, in patients with moderate-to-severe psoriatic arthritis: a 24-week, randomised, double-blind, placebo-controlled, phase II proof-of-concept trial

Objective To evaluate the efficacy and safety of secukinumab, a fully human, anti-interleukin (IL)-17A monoclonal antibody, in patients with psoriatic arthritis (PsA). Methods 42 patients with active PsA fulfilling ClASsification for Psoriatic ARthritis (CASPAR) criteria were randomly assigned (2:1) to receive two intravenous secukinumab doses (10 mg/kg; n=28) or placebo (n=14) 3 weeks apart. The primary endpoint was the proportion of American College of Rheumatology (ACR) 20 responses at week 6 for secukinumab versus placebo (one-sided p<0.1). Results Primary endpoint: ACR20 responses at week 6 were 39% (9/23) for secukinumab versus 23% (3/13) for placebo (p=0.27). ACR20 responses were greater with secukinumab versus placebo at week 12 (39% (9/23) vs 15% (2/13), p=0.13) and week 24 (43% (10/23) vs 18% (2/11), p= 0.14). At week 6, ‘good’ European League Against Rheumatism response was seen in 21.7% (5/23) secukinumab versus 9.1% (1/11) placebo patients. Compared with placebo at week 6, significant reductions were observed among secukinumab recipients for C reactive protein (p=0.039), erythrocyte sedimentation rate (p=0.038), Health Assessment Questionnaire Disability Index (p=0.002) and Short Form Health Survey (SF-36; p=0.030) scores. The overall adverse event (AE) frequency was comparable between secukinumab (26 (93%)) and placebo (11 (79%)) recipients. Six serious AEs (SAEs) were reported in four secukinumab patients and one SAE in one placebo patient. Conclusions Although the primary endpoint was not met, clinical responses, acute-phase reactant and quality of life improvements were greater with secukinumab versus placebo, suggesting some clinical benefit. Secukinumab exhibited satisfactory safety. Larger clinical trials of secukinumab in PsA are warranted.

The number of elevated cytokines and chemokines in preclinical seropositive rheumatoid arthritis predicts time to diagnosis in an age-dependent manner.

OBJECTIVE To evaluate levels of biomarkers in preclinical rheumatoid arthritis (RA) and to use elevated biomarkers to develop a model for the prediction of time to future diagnosis of seropositive RA. METHODS Stored samples obtained from 73 military cases with seropositive RA prior to RA diagnosis and from controls (mean 2.9 samples per case; samples collected a mean of 6.6 years prior to diagnosis) were tested for rheumatoid factor (RF) isotypes, anti-cyclic citrullinated peptide (anti-CCP) antibodies, 14 cytokines and chemokines (by bead-based assay), and C-reactive protein (CRP). RESULTS Preclinical positivity for anti-CCP and/or ≥2 RF isotypes was >96% specific for future RA. In preclinical RA, levels of the following were positive in a significantly greater proportion of RA cases versus controls: interleukin-1α (IL-1α), IL-1β, IL-6, IL-10, IL-12p40, IL-12p70, IL-15, fibroblast growth factor 2, flt-3 ligand, tumor necrosis factor α, interferon-γ-inducible 10-kd protein, granulocyte-macrophage colony-stimulating factor, and CRP. Also, increasing numbers of elevated cytokines/chemokines were present in cases nearer to the time of diagnosis. RA patients who were ≥40 years old at diagnosis had a higher proportion of samples positive for cytokines/chemokines 5-10 years prior to diagnosis than did patients who were <40 years old at diagnosis (P < 0.01). In regression modeling using only case samples positive for autoantibodies highly specific for future RA, increasing numbers of cytokines/chemokines were predictive of decreased time to diagnosis, and the predicted time to diagnosis based on cytokines/chemokines was longer in older compared with younger cases. CONCLUSION Levels of autoantibodies, cytokines/chemokines, and CRP are elevated in the preclinical period of RA development. In preclinical autoantibody-positive cases, the number of elevated cytokines/chemokines is predictive of the time of diagnosis of future RA in an age-dependent manner.

Evidence that a neutrophil–keratinocyte crosstalk is an early target of IL-17A inhibition in psoriasis

The response of psoriasis to antibodies targeting the interleukin (IL)‐23/IL‐17A pathway suggests a prominent role of T‐helper type‐17 (Th17) cells in this disease. We examined the clinical and immunological response patterns of 100 subjects with moderate‐to‐severe psoriasis receiving 3 different intravenous dosing regimens of the anti‐IL‐17A antibody secukinumab (1 × 3 mg/kg or 1 × 10 mg/kg on Day 1, or 3 × 10 mg/kg on Days 1, 15 and 29) or placebo in a phase 2 trial. Baseline biopsies revealed typical features of active psoriasis, including epidermal accumulation of neutrophils and formation of microabscesses in >60% of cases. Neutrophils were the numerically largest fraction of infiltrating cells containing IL‐17 and may store the cytokine preformed, as IL‐17A mRNA was not detectable in neutrophils isolated from active plaques. Significant clinical responses to secukinumab were observed 2 weeks after a single infusion, associated with extensive clearance of cutaneous neutrophils parallel to the normalization of keratinocyte abnormalities and reduction of IL‐17‐inducible neutrophil chemoattractants (e.g. CXCL1, CXCL8); effects on numbers of T cells and CD11c‐positive dendritic cells were more delayed. Histological and immunological improvements were generally dose dependent and not observed in the placebo group. In the lowest‐dose group, a recurrence of neutrophils was seen in some subjects at Week 12; these subjects relapsed faster than those without microabscesses. Our findings are indicative of a neutrophil–keratinocyte axis in psoriasis that may involve neutrophil‐derived IL‐17 and is an early target of IL‐17A‐directed therapies such as secukinumab.

Long-term effects of secukinumab on MRI findings in relation to clinical efficacy in subjects with active ankylosing spondylitis: an observational study

Introduction A 28-week study suggested efficacy of the anti-interleukin-17A monoclonal antibody secukinumab in active ankylosing spondylitis (AS). MRI-assessed inflammation was reduced at weeks 6, 28. Objective To analyse the longer-term effects of secukinumab on MRI inflammatory and non-inflammatory spinal lesions in relation to its clinical efficacy in subjects with active AS. Methods Spinal MRI results (baseline, week 94) for 13 subjects with AS initially treated with secukinumab 2×10 mg/kg intravenously (n=10) or placebo (n=3) and receiving a secukinumab maintenance dose of 3 mg/kg IV every 4 weeks up to week 94 were evaluated by the Berlin score; inflammatory/non-inflammatory (fatty) changes were assessed at vertebral edges (VEs). Results were compared with clinical outcomes. Results Most of the 13 subjects assessed at week 94 had sustained clinical responses: 8 (62%) achieved Assessment of SpondyloArthritis international Society 20% (ASAS20), including 6 (46%) achieving ASAS40 responses, corresponding to 75% and 83% reductions in the Berlin score, respectively. In the 10 subjects treated with secukinumab throughout the study period, 79/91 (87%) inflammatory VEs at baseline resolved by week 94; new fatty lesions occurred in 39/796 (4.9%) of VEs; 87/124 (70%) VEs with fatty lesions at baseline remained unchanged; 30% were no longer visible. Conclusions In this pilot study, secukinumab treatment up to 2 years yielded sustained clinical improvement accompanied by regression of spinal inflammation. The impact of secukinumab on the development of fatty changes and bone formation in AS will be assessed in larger trials. Trial registration number This study is registered with ClinicalTrials.gov, number NCT00809159.

Association of HLA-DRB1 alleles with clinical responses to the anti-interleukin-17A monoclonal antibody secukinumab in active rheumatoid arthritis

OBJECTIVE To assess whether preliminary findings of associations between the HLA-DRB1*04 and HLA-DRB1* shared epitope (SE) allelic groups and response to the anti-IL-17A mAb secukinumab in RA were reproducible in an independent RA cohort. METHODS Biologic-naïve subjects (n = 100) with RA by 2010 criteria with tender/swollen joint counts (each ≥6) and high-sensitivity CRP (hsCRP) >10 mg/l were randomized 2:1 to secukinumab 10 mg/kg i.v. or placebo every 2 weeks until week 10. Potential associations with treatment response to secukinumab at week 12 (DAS28-CRP change from baseline by analysis of covariance, ACR20 response rate by logistic regression) were assessed for HLA-DRB1*04 (primary end point), HLA-DRB1*SE and HLA-DRB1 position 11 V/L (HLA-DRB1*pos11 V/L) allelic groups, and baseline levels of hsCRP, RF and anti-CCP. RESULTS Secukinumab was significantly more effective than placebo in reducing DAS28-CRP (-2.41 vs -0.71; P < 0.0001) and producing ACR20 responses (87.1% vs 25.0%; P < 0.0001) at week 12. The HLA-DRB1*04 allelic group was not significantly related to secukinumab response vs placebo. For change from baseline in DAS28-CRP, HLA-DRB1*SE (P = 0.003) and HLA-DRB1*pos11 V/L (P = 0.002) allelic groups were associated with positive treatment response. Higher RF levels, but not anti-CCP positivity, were significantly associated with DAS28-CRP reductions (P = 0.015) and ACR20 (P = 0.008) responses. Secukinumab was well tolerated. CONCLUSION Secukinumab significantly reduced signs and symptoms of RA vs placebo. As the HLA-DRB1*SE and HLA-DRB1*pos11 V/L results were driven by lack of placebo response in carriers, the hypothesis of clinical utility for HLA-DRB1* allelic groups in RA anti-IL-17A short-term response prediction could not be corroborated. TRIAL REGISTRATION ClinicalTrials.gov; https://clinicaltrials.gov/; NCT01426789.

LONG TERM INHIBITION OF IL-17A WITH SECUKINUMAB REDUCES SPINAL INFLAMMATION BUT HAS NO INFLUENCE ON FATTY LESIONS AS ASSESSED BY MAGNETIC RESONANCE IMAGING IN PATIENTS WITH ANKYLOSING SPONDYLITIS

Background Secukinumab (fully human IgG1k anti-IL17A monoclonal antibody) significantly improved clinical signs and symptoms of active ankylosing spondylitis (AS) patients enrolled in a recent proof-of-concept (PoC) study. Magnetic resonance images (MRI) of these patients (pts) showed reduction of spinal inflammation at week (W) 6 and W28 after initiation of treatment. Objectives To evaluate a subgroup of pts (N=13) in the open label extension study, who had MRI assessments at baseline (BL), W28 and W94. Methods In the 28W PoC study, 27/30 pts had sequential MRI studies, 22 had received secukinumab 2x10 mg/kg administered intravenously 3 Ws apart, and 5 pts had been randomised to placebo. 20 patients entered the extension study, 13 having MRI data at W94. Of these 13, ten were treated with secukinumab and 3 with placebo in the core study. In the extension study, all received secukinumab 14x3 mg/kg administered 4 Ws apart. MRIs (T1 and STIR) were rescored for this study. ASspiMRI-a scores and the occurrence of vertebral edges (VE) inflammatory and fatty lesions were evaluated by an independent blinded reader. Results All 13 pts completed this exploratory MRI substudy. In pts receiving 2x10 mg/kg secukinumab followed by 14x3 mg/kg (n=10) secukinumab, spinal inflammation was reduced compared to BL at W28 –similar to the results of the core study– and this reduction was sustained up to W94 (Fig 1). Also in 3 pts who had initially received placebo switching to secukinumab at W28, MRI inflammation at W94 was reduced. Of the 920 VEs evaluated, the proportion of VEs with inflammatory lesions was reduced from 9.9% (n=91) at BL to 3.7% (n=34) at W28 and 3.6% (n=33) at W94. In contrast, the proportion of fatty lesions at BL (13.5%, n=124) remained largely unchanged at W28 (14.3%, n=132) and W94 (13.7%, n=126). Image/graph Conclusions MRI analysis suggests that the IL-17 inhibitor secukinumab may reduce spinal inflammation and this effect may be sustained for up to 2 years, using a lower maintenance dose compared to the induction regimen. Notably, secukinumab appeared not to have any influence on fatty lesions. This observation contrasts recent reports of AS pts treated with TNF-blockers. The potential impact of these preliminary findings on radiographic progression under secukinumab therapy will be studied in larger trials. Disclosure of Interest X. Baraliakos: None Declared, J. Braun Grant/research support from: Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, EBEWE Pharma, Medac, MSD (Schering-Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi-Aventis, UCB, Consultant for: Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, EBEWE Pharma, Medac, MSD (Schering-Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi-Aventis, UCB, Speakers bureau: Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, EBEWE Pharma, Medac, MSD (Schering-Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi-Aventis and UCB, D. Laurent Shareholder of: Novartis, Employee of: Novartis, D. Baeten Grant/research support from: Abbott, MSD, Pfizer, Centocor, Jansen, Novartis, UCB, Eli Lilly, Boehringer, Roche, BMS., Consultant for: Abbott, MSD, Pfizer, Centocor, Jansen, Novartis, UCB, Eli Lilly, Boehringer, Roche, BMS., D. van der Heijde Grant/research support from: AbbVie, Amgen, AstraZeneca, BMS, Centocor, Chugai, Daiichi, Eli-Lilly, GSK, Janssen Biologics, Merck, Novartis, Novo-Nordisk, Otsuka, Pfizer, Roche, Sanofi-Aventis, Schering-Plough, UCB, Vertex, Consultant for: AbbVie, Amgen, AstraZeneca, BMS, Centocor, Chugai, Daiichi, Eli-Lilly, GSK, Janssen Biologics, Merck, Novartis, Novo-Nordisk, Otsuka, Pfizer, Roche, Sanofi-Aventis, Schering-Plough, UCB, Vertex, Employee of: Director of Imaging Rheumatology bv, J. Sieper Consultant for: Novartis, P. Emery: None Declared, I. McInnes Consultant for: Novartis, J. van Laar: None Declared, R. Landewe Grant/research support from: Abbott, Amgen, Centocor, Novartis, Pfizer, Rhoche, Schering-Plough, UCB, Wyeth, Consultant for: Abbott, Ablynx, Amgen, Astra-Zeneca, Bristol Myers Squibb, Centocor, Glaxo-Smith-Kline, Novartis, Merck, Pfizer, Rhoche, Schering-Plough, UCB, Wyeth, Employee of: director of Rheumatology Consultancy BV, Speakers bureau: Abbott, Amgen, Bristol Myers Squibb, Centocor, Merck, Pfizer, Rhoche, Schering-Plough, UCB, Wyeth, P. Wordsworth: None Declared, J. Wollenhaupt: None Declared, H. Kellner: None Declared, A. Wright Shareholder of: Novartis, Employee of: Novartis, F. Vandenhende: None Declared, K. Radford Employee of: Novartis contractor, B. Borah Employee of: Novartis, W. Hueber Shareholder of: Novartis, Employee of: Novartis

AB0632 Essdai domain evaluation of primary sjÖgren’s syndrome (PSS) patients enrolled in two independent poc studies indicates differential utility of domains for trial inclusion and composite endpoints in pss trials

Background According to international consensus, disease activity in primary Sjögren’s syndrome (pSS) patients shall be scored across 12 different domains according to the European Sjögren Syndrome Disease Activity Index (ESSDAI1). Two separate phase 2 proof-of-concept (PoC) studies using either BAFF receptor inhibitor (VAY736; ianalumab) or CD40 inhibitor (CFZ533) have recently been completed in comparable pSS cohorts with ESSDAI as the primary endpoint. Objectives To evaluate contribution of individual domains to composite ESSDAI scores at baseline and after interventional treatment with either VAY736 or CFZ533, or placebo. Aggregate efficacy and safety results were presented at previous meetings. 2 3 Methods Key inclusion criteria for both studies were fulfilling revised European US consensus criteria for pSS,4 autoantibody positivity, exclusion of secondary SS and ESSDAI ≥6. Permitted background medications in both trials included stable doses of hydroxychloroquine, methotrexate and prednisone ≤10 mg/d and also azathioprine in the CFZ533 trial. The primary endpoint was change in ESSDAI at week 12. Descriptive and principal component analysis were done with the goal to identify distinct subgroups of patients based on ESSDAI involvement at baseline (BL), and the relative importance of single domain contribution to overall ESSDAI responses were explored. Results 27 patients received single i.v. dose VAY736 10 mg/kg (n=12) or 3 mg/kg (n=6) or placebo, and 44 patients received multiple doses of CFZ533 10 mg/kg i.v. (n=21) or 3 mg/kg s.c. (n=8) or placebo. ESSDAI breakdown at BL showed a predominance of the articular, glandular, biological, constitutional and lymphadenopathy domains in both trials. Activity in more than 3 domains was recorded for 12/27 (44%) and 12/44 (27%) of patients in the VAY736 and CFZ533 studies, respectively. Principal component analysis identified the articular domain as the key component describing the difference between patients in their ESSDAI domains at BL. Two other domains that explained the variability between patients were the biological and glandular domains. Treatment effects in domains with low BL scores were more difficult to assess using ESSDAI. The majority of ESSDAI domains were not amenable to quantitative analysis, due to absence or low incidence at baseline. Conclusions The most frequently observed ESSDAI domain was articular involvement. Our results provide insights into ESSDAI domain frequency and distribution in the randomised controlled trial setting that may have implication for future trial design in pSS. Reference [1] Seror R, et al. (2016)Ann Rheum Dis75:382–389. [2] Dörner Th, et al. (2016)Arthritis Rheumatol68 Suppl 10; [3] Fisher B, et al. (2017) Arthritis Rheumatol69; Suppl 10; [4] Vitali C, et al. (2002) Ann Rheum Dis61:554–558. Disclosure of Interest T. Dörner Grant/research support from: Novartis, Charite CRO, Consultant for: Novartis, B. Fisher Consultant for: Novartis, Roche, BMS and AstraZeneca/MedImmune., X. Ren Employee of: Novartis Pharmaceuticals, P. Faerber Employee of: Novartis Pharmaceuticals, P. Gergely Shareholder of: Novartis Pharmaceuticals, Employee of: Novartis Pharmaceuticals, L. Mooney Employee of: Novartis Pharmaceuticals, Y. Li Shareholder of: Novartis Pharmaceuticals, Employee of: Novartis Pharmaceuticals, S. Oliver Shareholder of: Novartis Pharmaceuticals, Employee of: Novartis Pharmaceuticals, W. Hueber Shareholder of: Novartis Pharmaceuticals, Employee of: Novartis Pharmaceuticals, A. Wright Shareholder of: Novartis Pharmaceuticals, Employee of: Novartis Pharmaceuticals