Research

Yale Rheumatology Clinical & Translational Research Laboratory (YR-CTRL) supports multidisciplinary research focused on rheumatic diseases (systemic lupus erythematosus, rheumatoid arthritis, seronegative spondyloarthropathies, and systemic sclerosis). Providing study design advice, assistance with biospecimen attainment, tracking and storage, analytical assistance, and help with grant submission and manuscript preparation are a few of the ways in which YR-CTRL members propel rheumatic and immunologic disease patient-focused research forward.

Current Research Projects:

Understand the role of aberrant Wnt-beta catenin signaling in macrophages and other cells obtained from the lungs of murine models of scleroderma as well as patients with systemic sclerosis-related lung fibrosis.
Identify novel phenotypes of heart disease in patients with systemic sclerosis based upon echocardiographic data.
Determine how seronegative spondyloarthropathies impact patient-reported health-related quality of life in order to permit assessment of treatment response.
Apply computer vision to tissues from patients with systemic sclerosis to measure disease activity, severity and treatment response.
Apply machine learning to big data from patients with systemic sclerosis in order to identify relevant disease subsets and biomarkers.
Participate in clinical trials to test novel therapies for patients with systemic sclerosis.

Our research has the following keywords: Wnt signaling, systemic sclerosis, scleroderma, Interstitial Lung Disease (ILD), spondyloarthropathies, cardiac dysfunction, computerized adaptive tests, patient-reported outcomes, systemic lupus erythematosus, computer vision, machine learning

Patient-Reported Outcome Instrument Questionnaires in Rheumatic Diseases

Dr. Abhijeet Danve MBBS, MD, FACP, and Dr. Monique Hinchcliff are implementing a rheumatology clinic workflow that will permit digital collection of patient-reported outcome (PRO) instrument, or health questionnaire, data for inclusion in the electronic health record to facilitate shared medical decision making between the patient and his/her physician. Obtaining the patient’s perspective regarding symptoms, the value of healthcare, and treatment goals is vitally important for optimal patient care and satisfaction. Moreover, novel medical treatments must improve how a patient feels, functions or survives prior to FDA approval. Administration of validated PRO instruments is an integral part of the management of all diseases especially rheumatic diseases. Widespread use of electronic health records and the availability of digital data provide tremendous opportunity to improve patient outcomes, drive quality improvement, prevent adverse events and perform innovative clinical research. The short-term project goal is to pioneer a system that permits patients to complete PRO instruments using an iPad, and enable automatic scoring for real-time use in medical decisions. The long-term goal is to use these data for quality improvement and patient-focused clinical research studies to improve health outcomes for patients with rheumatic diseases.

The Role of the EGFR pathway in Systemic Sclerosis

Figure 1. The hands of a patient with SSc demonstrating tight skin on the fingers (sclerodactyly). Sclerodactyly is the cardinal clinical feature of SSc.

Dr. Miruna Carnaru MD, PGY-5, is working with Dr. Monique Hinchcliff and Dr. Ian Odell MD PhD, assistant professor dermatology, to elucidate the role of the epidermal growth factor (EGFR) pathway, including downstream PI3K inhibition, on skin fibrosis in systemic sclerosis (SSc). Skin fibrosis is the SSc clinical hallmark (Figure 1). This will be accomplished by immunostaining and quantifying the expression of EGFR and PI3K in skin biopsies of patients with SSc compared to healthy volunteers. Expression will also be correlated with clinical patient information including serum autoantibodies and disease features. Dr. Carnaru will complete a systematic review of PI3K inhibitors currently used as chemotherapeutic agents and assess their viability as repurposed anti-fibrotic agents in SSc.

Cardiac Involvement in Rheumatic Diseases

Figure 2: A patient is prepared for a cardiac PET scan in the Cardiovascular Imaging Center at Yale. This exam takes approximately 40 minutes and involves administration of a radiotracer through an intravenous line. Yale is one of the leading cardiac PET centers in the country, with over 15 years of experience with this technique.

The research laboratory of Dr. Edward Miller, MD PhD, Associate Professor of Medicine and Radiology, focuses on optimizing the evaluation and management strategies for patients with infiltrative cardiac diseases including sarcoidosis and amyloidosis. Dr. Miller uses nuclear imaging techniques including Positron Emission Tomography (PET) scanning to identify areas of active cardiac inflammation as well as decreased coronary blood flow (Figure 2). Currently, Dr. Miller is developing standardized and validated protocols for accurate quantification of cardiac disease burden by using Rubidium 82 (Rb 82 ) and 18 F-fluorodeoxyglucose (FDG) PET imaging. Rb 82 PET imaging permits identification of myocardial areas with decreased myocardial blood flow such as those affected by ischemia or scar. Fluorodeoxyglucose (FDG) PET imaging permits visualization and quantification of inflammed myocardium. Based on the acquired information, a color-coded map of the heart, representing different slices of the heart at different angles at rest and during stress, can be generated (Figure 3, left panel). The obtained information can be used to quantify the blood flow supplying the myocardium at rest and during stress (Figure 3, right panel). The signal can be depicted by multiple color-coded images with different colors representing areas of the heart that have normal or reduced blood supply.

Dr. Hinchcliff has partnered with Dr. Miller and members of his research team in order to determine the utility of Rb 82 /F 18 -FDG-PET imaging in patients with systemic sclerosis (SSc) . Heart dysfunction is a leading cause of SSc-related deaths, and Rb 82 /F 18 -FDG -PET imaging can help to detect heart problems safely, quickly, and with low radiation exposure. The ability to measure the extent and degree of cardiac inflammation, scar tissue formation and microvascular dysfunction by using Rb 82 /F 18 -FDG PET will enable the development of SSc cardiac disease screening protocols as well as provide a method for assessing response to treatment. There are currently no SSc-cardiac disease specific treatments although electrocardiograms, echocardiography, cardiac magnetic resonance imaging (MRI) and single photon emission tomography (SPECT) studies in SSc patients demonstrate that the heart is commonly affected in SSc patients. The benefit of Rb 82 /F 18 -FDG -PET is that the examiner can distinguish scar formation from active inflammation that may warrant active treatment.

Rb82 Positron Emission Tomography

Figure 3. An example of a Rb82 Positron Emission Tomography (PET) scan which is a useful test for evaluating for heart artery blockages, including the small vessels in the heart that can be impacted by scleroderma (so called ‘microvascular disease). Heart dysfunction is a leading cause of death in patients with scleroderma, and Rb82 PET imaging can help detect problems with the heart safely, quickly, and with low radiation exposure. The left panel shows an example of a normal study (stress and rest) and the right panel shows abnormal myocardial blood flow, indicative of microvascular disease like that seen in scleroderma.

Novel Discovery of Autoantibodies in Rheumatic Diseases

Dr. Mei Xue Dong, MD PhD, Assistant Professor of Medicine, Section of Rheumatology Allergy and Immunology, is interested in cardiac disease in connective tissue disorders, specifically systemic sclerosis (SSc). Systemic sclerosis cardiac involvement is a leading cause of SSc-related death, but there is currently no methodology for identification of patients at high risk for this outcome. To date, no serum autoantibodies have been found to be associated with SSc heart disease. We hypothesize that there are unique serum protein signatures in patients with SSc cardiac disease compared to patients with cardiac involvement due to other autoimmune diseases including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) and to healthy persons. We have partnered with members of the laboratory of Dr. Aaron Ring, Assistant Professor, Immunobiology Department, to apply their cutting-edge Rapid Exoproteome Antibody Profiling (REAP) technology to serum samples from patients with various autoimmune diseases. REAP technology works by re-purposing a protein engineering technology—yeast surface display—to rapidly query a large library of extracellular proteins for IgG binding in a highly parallelized fashion. Identifiation of novel serum autoantibody signatures may provide useful insights into SSc cardiac disease pathogenesis and potential therapeutic targets.

In other preliminary studies, we have partnered with members of Dr. Aaron Ring’s laboratory, to apply their cutting-edge Rapid Exoproteome Antibody Profiling (REAP) technology to serum samples from patients with various autoimmune diseases. REAP technology works by re-purposing a protein engineering technology—yeast surface display—to rapidly query a large library of extracellular proteins for IgG binding in a high throughput fashion. Identification of novel serum autoantibody signatures may provide useful insights into SSc cardiac disease pathogenesis and potential therapeutic targets.

The Role of Aberrant Wnt Signaling in SSc lung cells

Dr. Monique Hinchcliff, MD MS, and colleagues are obtaining cells directly from the lungs of animal models of scleroderma as well as from patients with SSc using bronchoalveolar lavage (application and retrieval of saline from the lungs). The role of deregulated Wnt signaling in inflammatory cells is under investigation. Dr. Hinchcliff was recently awarded a grant from the National Institutes of Health to study the role of deregulated gene expression in lung cells. Lung fibrosis is currently the leading cause of death in patients with SSc. Although treatments benefit some patients, the effects are modest. Thus, there is a large unmet clinical need to better understand the pathogenesis of SSc lung disease in order to identify more effective treatments.

Accurate Quantification of Calcinosis Cutis in SSc

Figure 4. Dual energy computed tomography (DECT) of a patient with SSc and calcinosis cutis. A calcinosis cutis lesion at the fingertip (left panel) is measured by segmenting the three finger bones (middle panel) permitting the computer “to see” and quantify image pixels that contain calcium

Dr. Anita Chandrasekaran, MD MPH, PGY-5 and Dr. Monique Hinchcliff lead a multidisciplinary team that includes Drs. Imran Omar and Annie Wang (musculoskeletal radiologists at Northwestern University and Yale School of Medicine, respectively), and Drs. Shangping Ren, PhD and Zhicheng Fu, PhD (computer scientists at San Diego State University). The team works to optimize a deep learning computer algorithm, applied to dual-energy CT scans, to allow for accurate, precise, and rapid quantification of calcinosis cutis (painful and disfiguring calcium deposits in the skin that can become secondarily infected) burden in patients with SSc. Dual energy CT (DECT), an imaging modality established for the detection of coronary calcifications and monosodium urate deposits in gout is a useful approach for differentiating calcinosis cutis lesions from adjacent healthy bone (Figure 5), but radiologists must manually quantify the area of calcification, which is time imprecise, time consuming, and costly. This project aims to improve the accuracy and consistency of calcinosis cutis diagnosis and to permit valid clinical trials to be conducted to evaluate the efficacy of potential calcinosis cutis therapies. The long term project goal is to create a de-identified dataset of DECT images, made publicly available, to facilitate future research in calcinosis cutis, and to apply the deep learning approach to other diseases that result in dystrophic calcification, such as chronic kidney disease and malignancy.

Shared Medical Decision-Making in Rheumatoid Arthritis

Dr. Betty Hsiao MD, and her mentor, Dr. Liana Fraenkel MD, MPH, are investigating shared medical decision-making between patients with rheumatoid arthritis (RA) and their doctors. Fortunately, there are many useful drugs for RA treatment. How patients with RA and their doctors choose the appropriate treatment is under investigation. Dr. Hsiao has developed an electronic and interactive brochure that patients with RA complete during routine office visits when a decision regarding treatment escalation must be made. This brochure was vetted using an iterative process, based upon feedback from clinicians and patients. Dr. Hsiao is testing the performance of the brochure in the clinic setting.

Evaluation of pregnancy and birth outcomes of DMARD and non-DMARD utilization patterns in SLE patients

Pregnancy is a vulnerable time for patients with systemic lupus erythematosus (SLE). Use of Disease Modifying Anti-Rheumatic Drugs (DMARDs) and non-DMARDs such as antidepressants are crucial to control disease activity, yet studies of medication use in pregnant patients with SLE are few. Dr. Eugenia Chock, MD MPH, Instructor within the Section of Rheumatology, is collaborating with Dr. Zeyan Liew, PhD MPH, Assistant Professor at the Yale Center for Perinatal, Pediatric and Environmental Epidemiology (CPPEE) to assess DMARD and non-DMARD utilization patterns before and during pregnancy in SLE patients and to evaluate pregnancy and birth outcomes. Subsequently, Drs. Chock and Liew will examine predictors of hydroxychloroquine use, a mainstay of SLE treatment in this population. They will analyze longitudinal data from the Danish National Patient Registry (DNPR) and the Danish National Prescription Register (NPR), that includes information for ~800 pregnant women with SLE from 1995-2018. They will link DNPR and NPR information to fetal ultrasound data to evaluate the potential impact of medications on fetal growth trajectories.