Denise Cecil (dcecil@vapop.ucsd.edu)

Graduate Program:  Molecular Pathology
Lab PI: Robert Terkeltaub, MD
Undergraduate Education: Michigan State University
Med-into-Grad clinical training area: Inflammatory, allergic, autoimmune disease
Clinical mentor: Gary Firestein, MD, gfirestein@ucsd.edu

 

Quote: “MIG exposed me to life threatening conditions associated with lupus such as nephritis, pneumonitis, cerebritis and vasculitis.  I was astonished at how many times these young patients had been admitted to the hospital with these recurring conditions. I gained a new-found compassion toward sufferers of rheumatic diseases. MIG’s invaluable training has put a face to my research, changed my perspective and focused my research goals to the development of new therapies”.

Rationale for Med-into-Grad training:
Medical training and identification of medically-relevant research issues:
Training in diagnostics & therapeutics, and identification of unmet diagnostic & therapeutic needs:
Diagnostic, therapeutic, and research collaborations:
Student-specific experiences:
Long term impact.:
Advice for new trainees--autumn preparatory quarter:
Advice for new trainees--winter clinical training quarter:
Take home perspective on Med-into-Grad at UCSD:

Rational for Med-into-Grad training:  Changes within the synovium and cartilage associated with low-grade inflammation modulate the pathogenesis of osteoarthritis (OA), and many studies have shown that inflammatory cytokines contribute to disease progression.   There is strong evidence implicating the Receptor for Advanced Glycation Endproducts (RAGE) in chronic low-grade tissue inflammation and expression is upregulated in OA cartilage. My thesis research is analyzing the role of the non-traditional inflammatory cytokine S100A11 in cartilage.  This cytokine signals through RAGE to stimulate chondrocyte hypertrophic differentiation and dysregulated cartilage matrix catabolism, two characteristics of OA.  Additionally, the role of RAGE is being assessed in a murine OA model.
My research is disease specific and I always thought of the experiments in relation to a disease.  However I believed that the clinical exposure of the Med-into-Grad training would give me a greater understanding of how the disease really affects the patient.

Medical training and identification of medically-relevant research issues:  The clinical training provided through the division of Allergy, Immunology and Rheumatology involved inpatient consults and outpatient clinics.  Additionally, I also attended weekly Rheumatology Grand Rounds that followed different formats.  One week a faculty member would present a clinical seminar, the next week would be a journal club, where a topical publication would be discussed, and maybe the next week the fellows would present an interesting patient case.  I found the case conferences particularly interesting as we were presented with the entire medical history of the patient. The attending physicians as well as the presenting fellows would then discuss the differential diagnoses, and if I had previously seen this patient with the fellow I felt a remarkable connection.  In addition, the weekly clinical immunology seminars connected the basic science with the clinical medicine.
            In the outpatient clinics we saw patients with various rheumatologic diseases including rheumatoid arthritis (RA), spondyloarthropathies, OA, gout, scleroderma and lupus. For example, we would examine radiographs of RA joints in the hands and feet to determine if the patient had significant erosions and observed the synovitis characteristic in these patients. Some patients had gone into remission but most patients still had some active disease with occasional flares despite being treated with the latest and greatest medications.   
            I was surprised at the lack of disease modifying treatment for some notable rheumatologic conditions like OA, scleroderma, fibromyalgia and ankylosing spondylitis (AS).  The aggressive nature of both erosive OA and scleroderma (as well as the young age of the patients) were the most extraordinary, since many other rheumatologic conditions are slow to progress to destruction.
            The inpatient consult service exposed me to life threatening conditions associated with lupus such as nephritis, pneumonitis, cerebritis and vasculitis.  Again, I was astonished at how many times these young patients had been admitted to the hospital with these recurring conditions. Remarkably, a patient diagnosed with lupus at age 20 has a 1 in 6 chance of dying by age 35.

Long term impact:  The Med-into-Grad training definitely focused my attention on disease modification.  As I think about my career after graduate school I take this knowledge with me. I am now more aware of how the immune system can be affected by therapies. For example, I was reading a publication from a group involved in T-cell modulation for tumor immunotherapy.  They ablated the T-cell regulatory system and I immediately thought about the various rheumatologic conditions that could develop.  I think this approach for cancer treatment is fascinating but I am also concerned of the immunological ramifications if left unchecked.

Training in diagnostics & therapeutics, and identification of unmet diagnostic & therapeutic needs: The field of rheumatology covers both autoimmune and inflammatory conditions.  Though the etiologies of the diseases are unknown, some inflammatory mediators have been identified, i.e. RA is particularly modulated by TNF. In that context, various TNF blockade therapies, referred to as “biologics”, have been used to treat RA (Remicade, Enbrel, Humira). Other immune regulation therapies have been used in the treatment of RA, i.e. T-cell (Orencia) and B-cell (Rituxan) modulation. These biologics are used in conjunction with non-steroidal anti-inflammatories (NSAIDS) and/or Methotrexate (the “gold standard” disease modifying anti-rheumatic drug or DMARD). However, none of these current medications is uniformly effective and toxicity is variable. Currently, there are no means of predicting an individual patient's response to a given treatment and 5-10% of RA patients fail to respond to any treatments.  Studies have shown that complete remission is possible if TNF inhibition is administered within the first year after diagnosis. One possible method to predict both efficacy and toxicity of various therapies would be to use a pharmacogenomic approach. This method would identify genetic markers (a genotype or haplotype) which correspond to a patient’s response to a given drug. This diagnostic tool would facilitate a successful therapy regimen for each individual RA patient.  But this approach is highly complicated considering the varied pathogenesis and the genetic heterogeneity in this disease.  
Some of the biologic therapies have proven effective in other rheumatic diseases, such as lupus.  Since lupus is characterized by autoimmunity to various cytoplasmic and nuclear antigens, complete ablation of antibody-producing B-cells (Rituxan) along with the modulation of T-cell activation is beneficial.  Additionally, TNF inhibition has been approved to treat the symptoms of AS.  Though particularly helpful for preventing the destructive cartilage erosions in patients with RA, biologic therapy does not prevent the boney fusion associated with AS. 
Incomplete knowledge of the etiology and pathogenesis in many of the rheumatologic diseases has prevented better therapy development.  For example, current OA treatment only reduces pain and partially improves function, but has no impact on the disease incidence or progression.  Many treatments have been speculated upon including inhibitors of enzymatic cartilage destruction, cytokine and growth factor modulation and stem cell therapies.  One major problem in therapeutic development is identifying early stages of disease where therapy could inhibit the irreversible cartilage destruction characteristic to OA.

Diagnostic & therapeutic collaborations: Scleroderma is characterized by excessive and pathologic deposition of collagen in the skin as well as heart, lungs, and kidneys. Though the pathogenesis of the disease is poorly understood, autoantibody production and release of inflammatory cytokines have been described. Notably, stimulatory autoantibodies targeting the PDGF receptor have been detected in serum of patients with scleroderma. Therefore, I would propose that a soluble PDGF receptor (sPDGFR) could potentially sequester the autoantibodies, inhibiting the excessive production of collagen.  This therapy could be developed in the same manner as Enbrel (soluble TNF receptor fusion to the Fc portion of IgG).   Since scleroderma patient serum induces the scleroderma phenotype in normal human fibroblasts, the inhibition of the excessive collagen production could be tested in vitro with the addition of sPDGFR/Fc.  A potential murine model of PDGFR autoantibody-induced fibrosis could be developed by injecting the serum of human patients into mice.  If this model is successful at mimicking the human scleroderma phenotype, then treatment with sPDGFR/Fc could prevent the fibrosis.

Student-specific experiences:  I did not realize how affected I would become by the conditions of the patients. I am reminded of one particular interaction with a patient who was recently diagnosed with scleroderma. The look of helplessness on her face when the physician told her there was no treatment for her condition made me want to go back to my lab and start researching therapies for scleroderma.  But I was pleased to know that there is an active Scleroderma Support Group for these individuals in San Diego.
            After I had been going to the clinic for over one month we started to see the follow-up patients.  I found this extremely helpful in determining the efficacy of the treatments and how adjusting the therapy, even a little, could be enough to reduce the inflammation and pain.  However, it was distressing to see a patient fail to respond to any of the therapies.
            When an attending physician asked if my experience at the clinic had prompted me to go to medical school, my first thought was no, I enjoyed the research side of improving human health.  But after going to the clinic everyday and seeing how a treatment actually did improve their pain, stiffness and overall outlook on life, I could understand why one would want to do both. 

Advice for new trainees--autumn preparatory quarter:  I would recommend attending a general lecture on arthritis/rheumatology sponsored by the medical school.  Also the lecture Dr. Firestein presented in the “From Bedside to Bench” course offered in the autumn quarter was beneficial.  Lastly I would highly recommend taking a basic immunology course as I believe if you are familiar with the basic science you are able to more easily apply it to treatments.

Advice for new trainees—winter clinical training quarter:  The fellows and attending physicians in the rheumatology clinics are all very helpful, accommodating and knowledgeable.  They will take the time to answer any questions you have, all you have to do is ask them. The unfamiliar atmosphere of the clinic might seem intimidating, but the physicians understand you do not have extensive medical training. Therefore, I would recommend an assertive approach to the outpatient clinic, inpatient consults and case conference presentations.  The more you immerse yourself in the field, the more comprehensive are your research and therapeutic ideas. 

Take home perspective on Med-into-Grad at UCSD:  I would highly recommend this program to any student interested in disease pathogenesis. My overall experience of the UCSD Med-into-Grad program has been very positive and I feel I have gained a new found compassion toward sufferers of rheumatic diseases. This invaluable training has put a face to my research, changed my perspective and focused my research goals to the development of new therapies so that I might not have to see that helpless look on any patient’s face again.