The BATTS conference program will focus on these key areas:
- cutting-edge science related to meeting goals
- leveraging lessons learned from related autoimmune diseases
- strengthening partnerships between industry and academia
- improving clinical trials
BATTS Conference Schedule Summary:
- Sunday through Friday night: hotel discounts are in effect
- Monday night: BATTS conference begins at 6:00 pm with an Opening Lecture and Welcome Reception
- Tuesday & Wednesday: Invited Speaker/Abstract Presentations (oral, poster); conference dinner
- Thursday morning: Invited Speaker/Abstract Presentations; BATTS conference ends at 10:00 am
Program (as of 8/22/16)
6:00 pm – 9:00 pm
Katherine Hammitt, MA: “Sjögren’s Syndrome Foundation: The Patient Voice”
Sjögren’s Syndrome Foundation
Bethesda, MD USA
The Sjögren’s Syndrome Foundation (SSF) is the only U.S. entity focused first and foremost on the patient with an ultimate goal of creating better lives for Sjögren’s patients. The patient voice is and should be critical in determining everything those connected with Sjögren’s do from patient care to research. Patients face a high burden of illness that can deplete family finances and affect all aspects of quality of life. To improve diagnosis, enhance clinical care and pave the way for the successful development of new therapies, the SSF is engaged in numerous major national and international initiatives and brings all stakeholders together to address barriers to better care. The SSF also helps ensure patient voices around the world are heard via its role as a facilitator of the International Sjögren’s Network of patients.
Roland Jonsson, DMD, PhD: “Sjögren’s Syndrome – Time has Come for Definition of Biomarkers”
University of Bergen
The eponym Sjögren’s syndrome is named after the Swedish ophthalmologist Henrik Sjögren (1899 – 1986). He is probably the most well-known Swedish physician internationally. His early career is interesting since he nearly failed his doctoral thesis defence, omitting an academic future. Utilizing genomics, proteomics or imaging technologies, time has now come to focus on defining biomarkers applicable to the handling of Sjögren’s patients. Our recent aims have been to identify and verify disease-related biomarkers in Sjögren’s syndrome (SS) utilizing body fluids, cells and target tissues. The most obvious is autoantibody profiling, helping to identify individuals at risk many years before disease onset. A cornerstone in this field was laid by Dr. Morris Reichlin, a former scientist at the Oklahoma Medical Research Foundation. Close follow-up on disease progression and treatment outcome are highly desirable in patient care. Biomarkers may be of substantial help in early diagnosis, disease prevention, drug target identification, and drug response in SS. However, their reliability in the stratification and diagnosis of the complexity of SS deserves a number of joint efforts.
Session 1: Autoimmune Disease Mechanisms in SS
8:00 am – 12:00 pm
llias Allevizos DMD: “Alteration of the Secretory Mechanism of Salivary Glands in Sjögren’s Syndrome”
National Institutes of Health/NIDCR
Bethesda, MD USA
Salivary gland dysfunction is one of the hallmarks of Sjögren’s syndrome. Even if the majority of the salivary glands biopsies might seem intact in Sjögren’s syndrome, the functionality of these glands is compromised. In this talk, updates on key altered proteins such STIM1 and IP3R, will be presented, including the role of regulatory non-coding RNAs in the secretory dysfunction associated with this syndrome.
Steve C. Pflugfelder, MD: “Conjunctival Goblet Cell Loss – A Key Pathogenic Feature in Sjögren’s Syndrome”
Baylor College of Medicine
Houston, TX USA
Goblet cells are specialized secretory epithelia in the conjunctiva that are well recognized to produce tear-stabilizing mucins. Under cholinergic regulation, goblet cell associated antigen passages (GAPs) serve as conduits for antigen delivery to dendritic cells (DCs) and draining lymphatics. Goblet cell products condition DCs with tolerizing properties. A significant decrease in conjunctival goblet cell density has been found in Sjögren’s syndrome (SS). Evidence suggests this goblet loss results from increased exposure to IFN-g and reduced trophic support by IL-13. Using primary conjunctival goblet cell cultures, we found the Th2 cytokine IL-13 stimulated production of gel forming mucins MUC5AC and MUC2, as well as a number of immunomodulatory factors. In contrast, IFN-γ inhibited goblet cell function and induced an unfolded protein response and apoptosis in concentrations as low as 0.2ng/ml. Goblet cells were found to condition tolerogenic properties in bone marrow derived DCs. This property may be diminished in mucosa tissues in SS. These findings may explain why loss of conjunctival goblet cells is associated with severe chronic ocular surface inflammation in SS.
Christopher Lessard, PhD: “Understanding Sjögren’s Disease Mechanisms Through Genetics and Genomics”
Oklahoma Medical Research Foundation
Oklahoma City, OK USA
The advances in technology over the last decade has led to an explosion in our understanding of the complexities of the human genome. The initial draft of the human genome completed in 2003, the identification of linkage disequilibrium (or correlation) within the genome by the HapMap project, the cataloging of non-coding DNA elements by the ENCODE project, and sequencing of diverse populations of the world all have contributed to our ability today identify disease associated loci. To date, >10 distinct genetic intervals have been established as risk factors for Sjögren’s with many more remaining to be discovered. Moreover, RNA-sequencing studies of Sjögren’s has added the role of non-coding RNAs along with the many dysgreguated proteins in the pathophysiology. These topics will be along with unpublished data will be presented.
Gunnel Nordmark, MD, PhD: “Epigenetics in Sjögren’s Syndrome: Towards Identification of Novel Therapeutic Targets”
Increasing evidence suggests an epigenetic contribution to the pathogenesis of autoimmune diseases, including primary Sjögren’s syndrome (pSS). Epigenetic modifications may serve as a dynamic link between genotype, environment and phenotype, for example by modulating gene expression. Methylation of DNA cytosine residues, mainly in the context of CpG sites, is the most commonly studied epigenetic mark, where hypomethylation of promoter regions generally permits transcription factor binding and subsequent gene expression. Epigenome-wide DNA methylation has been studied in different cell types and tissues from patients with pSS. Prominent hypomethylation in regulatory regions of interferon-induced genes has been demonstrated in all investigated tissues, with corresponding increased gene expression in B cells. Additional differentially methylated sites in genes and pathways of particular interest in the pathogenesis of pSS and certain subphenotypes, as well as the genetic control of DNA methylation will be discussed.
Monserrat Anguera, PhD: “X-Chromosome Inactivation Maintenance in Female Lymphocytes: a Novel Factor Influencing Female-biased Disease”
University of Pennsylvania
Philadelphia, PA USA
Females have a greater immunological advantage than men, yet they are more prone to autoimmune disorders. The basis for this sex bias lies in the X-chromosome, which contains many immunity-related genes. Female mammals use X-Chromosome Inactivation (XCI) to generate a transcriptionally silent inactive X chromosome (Xi) enriched with heterochromatic modifications and XIST/Xist RNA, which equalizes gene expression between the sexes. We have recently discovered that the Xi is maintained differently in female lymphocytes, where mature naïve cells lack Xist RNA and heterochromatin marks on the Xi. Following in vitro and in vivo stimulation, these marks return to the Xi in some cells. Consistent with relaxed X-silencing, some female lymphocytes exhibit biallelic expression of autoimmunity-related genes. Furthermore, we examined T and B cells from patients with systemic lupus erythematosus, an autoimmune disorder with a strong female bias, and observed mis-localized XIST RNA transcripts and evidence of biallelic expression of immunity-related genes from both X-chromosomes. We will present our recent findings investigating the molecular mechanisms of Xist RNA return to the Xi following inactivation, and how the transcription factor YY1 mediates this process. Our results support a new model for understanding the female bias of autoimmune disorders such as Sjögren’s Syndrome and Systemic Lupus Erythematosus, and reveal novel epigenetic pathways that could be targeted for future therapies.
Wan-Fai Ng, MA, PhD, FRCP: “Peripheral Blood Gene Expression Profile in Primary Sjögren’s Syndrome – What Can it Tell Us?”
Newcastle Upon Tyne, UK
Although the key target organs in primary Sjögren’s syndrome (PSS) are the salivary and lacrimal glands, these organs are vascularized tissues and therefore blood may provide “sample” of the pathological processes in these organs. Furthermore, many extra-glandular manifestations of PSS correlate with glandular pathology poorly. In addition, the accessibility of peripheral blood samples makes blood potentially a convenient and useful source for disease monitoring in the clinic. This seminar will summarize the current data on gene expression using peripheral blood samples from patients with PSS. It will also discuss how the gene expression data may help to better understand the pathogenesis of PSS, patient stratification, inform novel therapeutic developments and their potential as biomarkers.
Marie Wahren-Herlenius, MD, PhD: “Dysregulation of the Humoral Immune Response in Sjögren’s Syndrome”
The B cell compartment in Sjögren’s syndrome is deranged. The amounts of circulating memory B cells is decreased, ectopic germinal centers form in the salivary glands with local somatic hypermutation, clonal expansion and accumulation of plasma cells and memory B cells. Serologically, hypergammaglobulineimia and autoantibodies to the Ro/SSA and La/SSB antigens reflect the B cell disturbances and notably present long before clincial symptoms are manifest. The presentation will focus on signaling pathways that promote the plasma cell differentiation in Sjögren’s syndrome, and the role of the autoantibodies in disease pathogenesis.
Session 2: Biomarkers for Patient Diagnosis and Stratification
1:00 pm – 5:30 pm
Gabor Illei, MD: “Development of Biomarkers for Clinical Trials”
Gaithersburg, MD, USA
A biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathologic processes, or biological responses to a therapeutic intervention. Although important during all stages of drug development, the requirements for biomarkers in the clinical stages are different from the preclinical studies. There are several categories of biomarkers addressing specific aspects of the disease or treatment. These include susceptibility or risk biomarkers, diagnostic biomarkers, predictive biomarkers (to identify individuals who are more likely than similar patients without the biomarker to experience a favorable or unfavorable effect from a specific intervention or exposure), prognostic biomarkers (to identify likelihood of a clinical event, disease recurrence or progression), monitoring biomarker (measured serially and used to detect a change in the degree or extent of disease or to indicate toxicity or assess safety), pharmacodynamics response (to show that a biological response has occurred in an individual who has received an intervention or exposure) or safety (to indicate the presence or extent of toxicity related to an intervention or exposure). To be considered as clinical endpoints, biomarkers have to go through a rigorous evaluation process including analytical validation, qualification (assessment of evidence on associations between the biomarker and disease states) and utilization (contextual analysis based on the specific use proposed for the biomarker).
Athanasios Tzioufas, MD, PhD: “Biomarkers for Diagnosis and Treatment of Primary Sjögren’s Syndrome”
University of Athens
Primary Sjögren’s syndrome (pSS) is a chronic systemic autoimmune disease with a diverse clinical picture, extending from organ-specific involvement of exocrine glands to systemic disease and lymphoma development. In the current presentation, the following items will be discussed:
- The clinical phenotypes of the disease.
- Clinical, serological, pathological and molecular indices that may predict the poor outcome of patients with pSS, and
- The extraction of biomarkers from existing data and the development of new ones.
Alan Baer, MD: “Can Serum Autoantibodies Define Sjögren Disease Activity?”
Johns Hopkins University School of Medicine
Baltimore, MD USA
Disease severity in Sjögren’s syndrome can be defined by various measures, including patient symptoms, systemic disease activity, salivary and lacrimal gland function, salivary gland histopathology, lymphoma risk factors, and mortality. In contrast to most other systemic rheumatic diseases where measures of disease severity correlate closely with each other, this is often not the case in Sjögren’s syndrome. What defines “severe” Sjögren’s syndrome thus remains a point of contention, reflecting the disease’s phenotypic heterogeneity and relatively stable course with low mortality. Conventional autoantibody markers of disease severity include La and Ro52 antibodies, as well as the simple number of definable autoantibodies. Serum cryoglobulins and IgMκ rheumatoid factor are robust markers of lymphoma risk. Anti-centromere antibodies define a disease subset with more severe lacrimal and salivary gland dysfunction and lymphoma risk. Novel autoantibodies, including anti-IFI16 and TRIM38, have also been correlated with more severe disease.
Peter Schulz-Knappe, MD: “Discovery of Novel Autoantigens in Sjögrens Syndrome with Potential for Subgrouping of Disease”
The autoantibody burden in Sjögren’s Syndrome is not well understood for the importance of disease progression, for its role in patient segmentation, or for response to treatments. The discovery of autoantigens may provide a deeper understanding of mechanisms of actions for pSS drugs, and may be useful to stratify patients. Current diagnostic criteria for pSS utilize autoantibodies directed to nuclear antigens (ANA), especially to SS-A/Ro (TRIM21, TROVE2) and La (SSB), but those are not specific, and can be identified as well in SLE and even in healthy volunteers. Several studies have shown that not all patients with pSS are tested positive for Ro and La autoantibodies, but suggested the existence of additional autoantibodies in pSS. In this presentation we describe a set of novel autoantigens for diagnosis and subgroup definition in Sjögrens syndrome which was discovered by high content screening on Luminex. Validation in additional, large patient cohorts is ongoing.
David Wong, DMD, DMSc: “Saliva as a Biomarker Source for Point-of-Care Applications”
University of California Los Angeles
Los Angeles, CA USA
Advances in the science of saliva have led to identification of disease signatures of biomarkers and/or confirmation of genetic susceptibility for systemic conditions, particularly in molecular oncology. With the development of the salivary proteome, extracellular RNA (exRNA), micro-RNA, metabolome and microbiome as diagnostics alphabets (salivaomics) fully enable saliva to be translated for personalized individual medicine applications. Salivary biomarkers panels have been developed for Sjögren’s syndrome, oral cancer, lung cancer and pancreatic cancer. A recent development is saliva liquid biopsy, saliva detection of actionable oncogenic mutations in human cancers (e.g. EGFR mutations in NSCLC patients). Coupled with the development of point-of-care technologies and the emerging trend of chairside screening for medical conditions, the clinical impact of scientifically credentialed salivary biomarkers for clinical applications will include the improvement of access to care, reducing health disparities and impacting global health.
Andy Keys: “Beyond the Gene: Large-scale Proteomics for the Discovery of New Diagnostics and Therapeutics”
Boulder, CO USA
The focus on genetics and genomics for understanding diseases of all types is understandable, given the technology advances, but has proven limited. For many diseases, even knowing the genetic underpinnings has yet to lead to new and effective therapeutic interventions. It is far more likely that understanding the proteomic changes that occur before, during, and after the onset of disease could prove more immediately useful for diagnosis, prognosis and treatment selection. For example, the genetic cause of Duchenne Muscular Dystrophy (DMD) — a range of mutations in the dystrophin gene — has been known for 30 years, but little progress in new treatments, diagnostics or prognostics has been made in that time. We chose to ignore the genomic basis, undertaking instead an unbiased study of changes in protein expression in the blood of young DMD patients at different time points through the course of this devastating disease (2015, Hathout et al., PNAS USA, 112:7153-7158). Using a new proteomics technology to to measure 1,125 proteins in in the serum of 93 DMD patients and 45 controls, we discovered 44 protein biomarkers that differed significantly between patients and controls. Some of these markers have been seen before, and are generally related to muscle degeneration (as expected, although it happens far earlier than believed). Other markers, including some that are growth factors, suggest not only new diagnostic and prognostic approaches, but also new therapeutic approaches that could “bypass” the compromised dystrophin proteins. Many additional studies at different laboratories around the world are now underway based on these initial findings. We believe that the DMD “proof-of-concept” work demonstrates that this technology could provide critical new insights for many different diseases, including Sjögren’s syndrome.
Michael Mingueneau, PhD: “CyTOF Deep Phenotyping of Sjögren’s Patients: Toward New Biomarkers and Targets”
Cambridge, MA USA
Mass cytometry has recently emerged as a promising tool for clinical research. However, few studies have demonstrated its benefit for patient stratification and biomarker identification. Primary Sjögren’s syndrome (pSS) is a prototype of chronic autoimmune disease, the pathogenesis of which remains unclear and for which treatment does not exist. We will present an observational case-control study, which was designed to discover new cellular biomarkers and therapeutic targets in patients with pSS. This first application of mass cytometry to a well-stratified clinical cohort and small biopsy tissues establishes the benefits of such an approach for the discovery of new biomarkers and therapeutic targets. Similar high-dimensional immunophenotyping strategies could be implemented in longitudinal and interventional clinical settings in this and other disease areas.
Session 3: Emerging Biologic Therapeutic Targets in SS
8:00 am – 10:50 am
Roald Omdal, MD, PhD: “A Biological Basis for Chronic Fatigue”
Stavanger University Hospital
Chronic fatigue is a prevalent phenomenon in chronic inflammatory diseases, as well as in cancer and neurodegenerative disorders. Fatigue is influenced by pain and depression, but more and more data show that there is an evolutionary and genetic basis for fatigue, and that fatigue is signaled through specific molecular pathways. Down-regulation of inflammation and cellular stresses are important generators for fatigue, and may explain the lack off association between severity of fatigue and disease activity. New knowledge of fatigue mechanisms provide basis for treatment of this difficult problem.
Xavier Mariette, MD, PhD: “Mechanisms of Lymphoma in Sjögren’s Syndrome”
Primary Sjögren’s Syndrome (pSS) is the auto-immune disease associated with the higher risk of lymphoma. Lymphomas complicating pSS have specific features. They are mostly low grade B cell non-Hodgkin lymphomas, with predominance of marginal zone histological type. Mucosal localization is predominant and notably MALT lymphomas. Lymphomas often develop in organs where pSS is active such as salivary glands. Germinal center (GC) like structures, high BAFF and high Flt3-ligand levels and genetic impairment of TNFAIP3 are new predictors of lymphoma development. These new findings allow a better understanding of the pathogenic mechanisms leading to lymphoma. We propose the following scenario: auto-immune B cells with rheumatoid factor (RF) activity are continuously stimulated by immune complexes containing antibodies against more specific auto-antigens like SSA/Ro, SSB/La or others. Germline abnormality of TNFAIP3 leads to a decreased control of the NF-kB pathway and thus promotes survival of B cells and oncogenic mutations especially in GC structure. Moreover, B cells are stimulated by BAFF, increased in pSS, and acquire the capacity of autocrine BAFF production leading to a positive loop of activation. Thus, lymphomagenesis associated with pSS exemplifies the development of antigen driven B-cell lymphoma. The control of disease activity by a well-targeted immunosuppressor is the primary objective of the management of the patient in order to repress chronic B cell stimulation.
Hal Scofield, MD: “A New Pathogenic Mechanism for Raynaud’s”
University of Oklahoma Health Sciences Center
Oklahoma City, OK USA
Raynaud’s phenomenon is clinical manifestations resulting from episodic, intense vasoconstriction in digital arteries, but the pathogenesis of Raynaud’s phenomenon is unknown. The association of Raynaud’s with autoimmune rheumatic illnesses and its predilection for young women is unexplained. The physiology of normal cold-induced vasoconstriction has recently been elucidated. The α2C adrenergic receptor (α2C-AR) mediates this normal physiological response to cold exposure in human digital arteries. Under normal physiological ambient temperature, α2C-AR accumulates in the endoplasmic reticulum, and is not found at the cell surface. With cold exposure, α2C-AR is rapidly transported to the cell surface, where the receptor is bound by circulating catecholamines, which induces vasoconstriction. Autoimmunity directed against other members of this class of receptors, in the form of activating or blocking antibodies, is well described. We are testing the hypothesis that activating antibodies binding α2C-AR after cold-induced translocation are the causative agent in some humans with Raynaud’s phenomenon. In fact, our initial results demonstrate binding and activation of α2C-AR by circulating antibody as well as recombinant human monoclonal antibodies produced by purification of antibody-secreting cells from minor salivary gland biopsies.
William Rees, PhD: “Exploring the role of the Type I interferon pathway in autoimmune diseases”
Gaithersburg, MD, USA
Angus MacDonald, PhD: “Potential Therapeutic Targets in SS – Examples from Ultrasensitive Assays”
Eli Lilly and Co.
Indianapolis, IN USA
Eli Lilly & Company is pursuing several different pathways to alleviate signs and symptoms in patients with various autoimmune diseases. Autoreactive B cells have been implicated in the pathogenesis of primary Sjögren’s Syndrome (pSS). The Th17 axis is also strongly associated with pSS disease progression, e.g. by a marked increase of IL-17A-secreting Th17 cells in salivary glands. In proximal (saliva) and peripheral (plasma) biofluids, we measured biomarkers associated with B cell and Th17 cell pathways in pSS by analyzing BAFF and IL-17A with ultrasensitive immunoassays and correlating their concentrations with clinical traits.
Stephen Oliver, MD: “Targeting the Germinal Center in pSS”
Novartis Pharma AG
Evidence in primary Sjögren’s syndrome (pSS) patients for B cell hyperactivity with autoantibody production and an increased risk for lymphoma development support a pathogenic role for this lymphocyte subset in the disease process. However, inconsistent clinical benefits of B cell targeting with rituximab (anti-CD20 mAb) suggest that more effective means of eliminating the pathogenic B cell clones within disease tissues may be necessary to improve outcomes for patients. In this presentation we will discuss the rationales for targeting the receptor for B cell activating factor of the TNF-a family (BAFF-R), for CD40 and for PI3 kinase delta in pSS and report our findings from a randomized, blinded proof-of-concept trial with an antibody-mediated, cellular cytotoxicity, (ADCC)-enhanced monoclonal antibody targeting the BAFF-R.
John Throup, PhD: “A Novel Head to Head Study of Investigational Agents in Sjögren’s Syndrome”
Princeton, NJ USA
The molecular pathology of primary Sjögren’s syndrome is complex with defects reported in B cell activity, effector T cell cytotoxicity, antigen presentation and abnormalities in cytokines/complement pathways. It remains to be determined which of these pathways may yield the most promising therapeutic targets for Sjögren’s disease and animal models generally offer limited predictive value. BMS has a diverse early clinical stage portfolio comprised of agents designed to selectively inhibit a variety of targets that are implicated in autoimmune disease. With the advent of new measures of disease activity for Sjögren’s we may now have the ability to assess the relative safety and efficacy of potential therapeutic agents in humans in a cost effective manner. As first step in this approach BMS is initiating a novel Phase 2 clinical trial in Sjögren’s syndrome, which directly compares the safety and efficacy of two investigational agents targeting disparate immunological pathways. As well as providing real world prioritization data for future development, the study may provide a platform for future molecules and insights into the underlying causes of Sjögren’s disease.
Session 4: Challenges and Successes in Clinical Trials
2:30 pm – 5:00 pm
Stanley Pillemer, MD: “Clinical Development of New Treatments for SS: The Path Ahead”
American Biopharma Corporation
Gaithersburg, MD, USA
Recent advances in Sjögren’s syndrome and allied fields raise many opportunities for development of new treatments. Biomarkers can refine the diagnosis and classification of patients and could provide early signals of responses to treatment. Among the autoimmune diseases, Sjögren’s syndrome allows for not only blood samples, but also for accessible tissue samples. This is helpful in mechanistic and pharmacodynamic studies in early phase trials. During clinical development, at the transition from early to late phase trials, it is important to balance mechanistic, pharmacodynamic, and other data together with clinical signals to make go/no go decisions. Sjögren’s syndrome-specific clinical outcome measures and patient reported outcomes have been developed and used in trials, and considerable progress has been made. However, more work is needed to refine clinical outcome measures to focus on the domains that are most sensitive to change in clinical trials. Formal guidance documents from regulatory authorities would greatly assist and encourage those striving to develop new treatments for Sjögren’s syndrome. Optimizing selection of appropriate patients, biomarkers, clinical outcome measures and patient reported outcomes together with a clear regulatory pathway can more rapidly bring new treatments to fruition.
Hendrika Bootsma, MD, PhD: “Primary Sjögren’s Syndrome Clinical Trials – Progress to Date”
University of Groningen
Groningen, the Netherlands
The last years, significant progress has been made in the evaluation and treatment of primary Sjögren’s syndrome (pSS). 40-50% of the pSS patients will develop extraglandular manifestations like purpura, polyneuropathy and arthritis. Lymphomas develop in about 7.5% of pSS patients, mostly marginal zone B-cell lymphomas. Furthermore, pSS has a very substantial impact on the patients’ quality of life and their daily activities. Not only systemic features are disabling, also sicca symptoms and fatigue are disabling for pSS patients. Many biological DMARDs are currently available and in development to target various molecules involved in the cascade of hyperactive B-cells and plasma cells including biologicals that can interfere with a large number of relevant cytokines and chemokines. Besides the efficacy and safety of different biologicals used in several trials, insight in pathogenetic mechanism learned from these trials will be discussed. Finally the possibilities of developing personalized medicine in pSS are part of this lecture.
Daniel Wallace, MD, FACP, MACR: “Lessons Learned From Autoimmune Clinical Trials: Getting More Out of SS studies”
Cedars-Sinai Medical Center
Los Angeles, CA USA
In 1999, OMERACT (Outcome Measures for Rheumatology) proposed that clinical trials for disorders such as Sjögren’s syndrome should improve disease activity, decrease damage, benefit health related quality of life and have a satisfactory safety profile. Unlike lupus or rheumatoid arthritis, no FDA guidelines for conducting these studies exist. This void was filled by a EULAR committee that devised the ESSDAI and ESSPRI as measures of disease activity and patient reported outcomes. When combined with established indices of salivary and tear function, several clinical trials have been conducted since 2011. Although some parameters have demonstrated clinical improvements, neither belimumab, rituximab, nor hydroxychloroquine met their primary outcome measures. Several flaws in the process, mostly relating to the ultility of ESSDAI being limited to the 10% of Sjögren’s patients with extraglandular disease and lack of disease specific accuracy for the ESSPRI, have hampered clinical these studies. Constructive suggestions related to how to improve the rigor of the Sjögren’s trial process will be presented.
Xavier Mariette, MD, PhD: “ESSDAI and ESSPRI: Refinement for use in future trials”
The ESSDAI (Eular Sjögren Syndrome Disease Activity index) and ESSPRI (Eular Sjögren Syndrome Patient Reported index) are clinical indexes designed to measure disease activity and severity of patients’ symptoms in primary Sjögren’s Syndrome. They are now consensually and widely used in clinical trials. Preliminary data from recent trials have shown that both indexes are sensitive to change. For both ESSDAI and ESSPRI definition of minimal clinically relevant improvement has been defined. Uncertainty remained on the best way to use these criteria in clinical trials, as outcome measure as well as entry criteria. Work on previous and ongoing trials will help the Sjögren community at designing composite response criteria using the better combination of these existing tools that could be used in future clinical trials.
Theresa Lawrence-Ford, MD: “SSF Clinical Trials Consortium: Improving Success for Clinical Trials”
North Georgia Rheumatology Group, PC
Duluth, GA USA
The Sjögren’s Syndrome Foundation (SSF) Clinical Trials Consortium is an international initiative whose mission is to increase the availability and accessibility of therapies for treating Sjögren’s by 1) supporting and promoting objectives that facilitate the design of clinical trials (biomarkers, novel diagnostics, and internationally-accepted classification criteria and outcome measures); 2) increasing industry partnerships; and 3) engaging in a dialogue with government agencies that oversee therapy approval. The Consortium currently is identifying key barriers to successful clinical trials, facilitating resolutions, and engaging in discussions with the FDA.
Steven Taylor: “Patient Engagement in Clinical Trial Design”
Sjögren’s Syndrome Foundation
Bethesda, MD USA
During this session, Steven Taylor will review the Sjögren’s Syndrome Foundation’s work on involving patients in clinical trial design. From the moment a compound is identified and throughout the stages of planning and execution of a clinical trial, patients can be a wealth of knowledge to pharmaceuticals companies on the burden of living with Sjögren’s, suggestions about how to design patient-friendly protocols as well as how best to recruit patients to join a clinical trial.
James Witter, MD, PhD, FACR: “Patient-Reported Outcomes (PROs) and Treat To Target (TTT) in Sjögren’s Syndrome”
National Institute of Arthritis and Musculoskeletal Diseases/NIH
PROMIS® (Patient-Reported Outcomes Measurement Information System) offers a new, improved approach to the assessment of Patient-Reported Outcomes (PROs) for either adults or children. PROMIS is a universally applicable assessment tool for symptoms and health related quality of life for the life course from children to adults. Due to its agnostic nature to disease or setting, PROMIS offers a unique opportunity for within and between disease comparisons, whether in a clinical trial or care. This presentation will also discuss new/emerging NIH initiatives to advance the science of pediatric PROs as well as a brief look at the NIH Toolbox, which includes performance-based assessments.
Panel Discussion: “Integrating Biomarkers and Clinical Measures to Improve and Find New Treatments”
Session 5: Future Directions in Improving Clinical Care
8:50 am – 10:00 am
Michael Passineau, PhD: “A Paradigm for Clinical Genetic Intervention in the Salivary Gland to Disrupt Sjögren’s Syndrome Pathobiology”
Drexel University College of Medicine
Pittsburgh, PA, USA
Gene transfer presents a novel therapeutic modality that allows temporary reprogramming of cells and target tissues, potentially allowing an approach to Sjögren’s syndrome pathophysiology that is not achievable with conventional pharmaceuticals or biopharmaceuticals. Successful gene transfer to the salivary gland of a mammal was first reported in 1994, and careful and determined efforts spearheaded by the NIDCR Gene Therapeutics Branch culminated in the first-in-man human salivary gland gene therapy clinical trial NCT00372320. This “AdAQP1” clinical trial demonstrated both the safety and efficacy of viral vector-mediated gene therapy in the human salivary gland. However, concerns remain regarding the applicability of this technology to treatment of the salivary gland in SS, principally due to the highly immunogenic vector used (Adenovirus). This talk will give a synthesis of a 5-year clinical translational pathway beginning with the proof-of-concept that ultrasound-mediated sonoporation can accomplish gene transfer in the salivary gland of the mouse and culminating with therapeutic proof-of-principle in a large animal model as a precursor to a Phase I clinical trial. It is our hope that this technology platform, by obviating the need for a viral vector, will allow immunologically occur molecular reprogramming of the salivary gland as a new approach to treating SS-related xerostomia.
Judith James, MD, PhD: “Preclinical Evaluation and Prevention Studies in Sjögren’s: Lessons from RA and Lupus”
Oklahoma Medical Research Foundation
Oklahoma City, OK USA
By the time that Sjögren’s patients present to the clinician for symptoms, aggressive inflammation and potentially fibrosis with irreversible damage has already occurred. Unfortunately, very little is known about the pre-clinical period of Sjögren’s development, although autoantibodies are known to be present for years and sometimes decades before clinical diagnosis and classification. Investigation within type 1 diabetes, rheumatoid arthritis and systemic lupus erythematosus have uncovered serologic biomarkers and predictors of disease transition. This information has led to prevention trials being conducted, launched or planned for these disorders. Lessons learned from these other autoimmune diseases will be summarized and the unique challenges with planning and implementing natural history and prevention trials in Sjögren’s syndrome will be discussed.
Optional Post-BATTS Conference Activities at OMRF
11:00 am – ?
Salivary Gland Ultrasound Workshop
This workshop will include discussions about current efforts to develop ultrasonography as a tool for assessing parotid gland changes relevant to Sjögren’s Syndrome diagnosis and disease activity. Demonstrations and opportunities for hands-on training will be included. RSVP is required.
Tours of OMRF labs and facilities may be arranged. RSVP is required.
Individual or small group meetings with OMRF faculty may be arranged. RSVP is required.