ISSS Wrap-Up of Conference: Lessons Learned, Future Directions Robert I. Fox, M.D., Ph.D. Scripps Memorial Hospital-Ximed La Jolla, California USA robertfoxmd@icloud.com

Many thanks to: Alan Baer and the organizing committee Our 35 international expert speakers Our 30 oral abstract presentations Our 188 poster presentations Our Hands-On course for salivary gland ultrasound Our 400 attendees—who renewed old friendships and made new ones.

Different participants have traveled: From distant countries and many time zones. From different disciplines—often a journey greater than time zones. To be “energized” about a subject (Sjogren’s) that most of our colleagues find difficult to pronounce.

Compared to our original SS meetings … Pleased to see a younger audience with energy and new ideas. Many women --both as presenters and co-authors.

An independent and unappreciated benefit: Avoiding Physician Burn-Out The editorials of journals and newspapers frequently warn that the new “most dangerous disease in medicine” is physician “burn-out.” This meeting provides the opportunity to return to the goals of comradery and joy of health care that led most of us into Medicine… and Re-kindles the excitement of our individual goals and lets us know that there is more than “frustration” of the newly mandated Electronic Medical Record (EMR) systems and profit-driven administrators.

We heard about the early and current leaders in the field of Sjogren’s Sjogren, Block, Talal and his disciples over 30 years-- we remember. To the younger researchers and clinicians who are attending the meeting — Welcome to this club of Old Timers– We will protect and encourage you. You are compassionate (take the time to listen and care) and you will be the inheritors of the research that will improve your patients’ lives.

Did we learn the answers to the big questions? What is the “cure” for Sjogren’s? How do improve symptomatic treatment? How do we improve systemic manifestations?

What we heard about in clinical trials Exciting data about the Novartis “anti-CD40L” therapy. Actually 3 studies had data presented—the 10mg/kg IV (ACR), and subsequently, the lower dose and now higher dose subcutaneous routes of administration. Efficacy in achieving ESSDAI >3.5 units at the higher doses. Modest improvement in “benign” symptoms even when ESSDAI improved and looked like the low ESSDAI patients had the least improvement in benign symptoms. Problem is -- that only about 10% of our patients have a high enough ESSDAI to qualify for this study.

Other drugs in trial now (or pending) Abatacept (CTLA-4) P3I Inhibitors Anti-Baff-R antibody Anti-IL 6 antibody Expect them to work in high ESSDAI patients but.. same problem that caused failure of the prior 20 drugs in trials: The majority of patients have ”benign” symptoms— dry eyes, dry mouth, fatigue and vague cognitive impairment.

New Directions Perhaps think of Sjogren’s more like Multiple Sclerosis (relapsing/remitting) than continuous in the RA or psoriasis model. Extend our search for biomarkers to predict the extra-glandular manifestations and treat that subset early.

Symptomatic Eye - 1 Listen to our Ophthalmologists (and patients). It is not the Schirmer’s Test, but the difficulty in “blurring,” contrast that make it difficult for SS patients to use computers, read a book or drive. We saw dramatic demonstrations of how measurement of “best corrected vision chart” does NOT predict real life functions.

Ocular Symptoms - 2 In addition to dry eye (aqueous), we need to be more aware of tear film stability and Meibomian Gland Dysfunction (MGD). The frequency of blepharitis in SS patients is over 90%. Tears and lubricants may be helpful for aqueous, but be aware of preservatives and exacerbating MGD.

Be Aware… Recognize and include ”functional” measurements of dry eye in our evaluations when recording history. Use of doxycycline, azithromycin, and lid scrubs may help, and will need to get guidelines from Ophthalmology. Also heated moisturizing masks to help clear clear the plugging of Meibomian ducts (available on Amazon).

The Truth about Oral Symptoms Salivary aqueous flow does NOT correlate well with patient’s sensation of dry mouth or functions such as swallowing. Mucins that provide ”flexibility” (decreased viscosity) that are a key players we have ignored and attributed to dryness. Inner and outer layers of mucin are part of innate immune system.

Future Directions- Oral In addition to saliva biomarkers— we need to understand more about mucins that may play a key role in patient discomfort. Gastric reflux is ubiquitous-- especially at night when diurnal rhythms decreases saliva and needs to be treated. Artificial saliva with mucin need to be developed that are tolerable. For now-- olive oil diluted in baking soda, and calcium citrate rinses may help delay costly dental restorations.

Specific Areas of Presentations Pathogenesis— Genetic, epigenetic, and environmental Ultrasound— will it replace minor salivary gland biopsy? Guidance from FDA for future drug development. Talk from FDA about our trial design and the “bar” for approval. Reports on clinical trials now and in future

The Answers to Pathogenesis? What causes Sjogren’s—we still have not discovered the answer. HOWEVER --- We are identifying the genes and epigenetic factors- and know that different regions of world have different genetics. Epigenetic studies on hypo methylation are in progress

New directions in Pathogenesis Only 18% of SS-A patients get SS—so what is the co-factor that converts these patients to disease? SS-A is a hYRNA that accompanies many viral RNA’s as a chaperone. Endogenous miRNA’s may bind to SS-A by folding like hYRNA members and trigger Toll receptors

Pathogenesis-2 Endogenous miRNA’s may bind to SS-A by folding like hYRNA members and triggering Toll receptors. Almost 20% of our genomic DNA may be remnants of old viral infections -- and the salivary glands are ideal sites to “break tolerance.”

Emerging Precision Medicine - 1 We have embarked on the developmental era of “personalized” medicine, where we hope that: genomics, proteomics, and immune markers will direct “individualized treatment” by computer algorithm—much like markers on a breast cancer cell (Her2, BRACA).

Emerging Precision Medicine - 2 Individualized treatment protocols need to be developed to address: Complex problems of fatigue and cognitive dysfunction. Neurologic manifestations-- peripheral and central manifestations Autonomic neuropathies and some other neuropathies that often seem closer to diabetes than mono-neuritis multiplex.

Future Direction Needs Outside a few academic centers in U.S., salivary gland biopsies are not read according to the rigid guidelines used in Europe. We need to request special stains to detect germinal centers and follow specific protocols. Current ultrasound (hypo-echoic areas) correlate poorly with parotid biopsies— so we need better biomarkers for prognosis—similar to breast CA biopsies (Her2, ER, etc.).

Future Direction Considerations The FDA will demand a higher bar for drug approval since benign symptoms of SS not “life threatening.” We need more input from neuro-chemists who are tackling the same problems in the field of Multiple Sclerosis.

The UBER driverless car suspended The “brain” of the self driving car

The point is that: Current therapy will allow: The headlights and windshield for clear vision The gas tank and tail lights are intact for continued fueling. The paint job and doors are working The engine, carburetor and fuel lines are “tuned”

More time will be required to get the artificial intelligence optimized We need to be able to treat different parts of the car in our existing repair shop Our goal in next decade is to understand the neuro-immune axis that connects the parts

Therapeutically We need to let the FDA separate the treatment of benign symptoms and extra-glandular symptoms Over 20 failed therapeutic trials and many disappointed patients require that we address these distinct pathways individually

We need to move to a “holistic analysis” The consumer wants an “energetic and responsive” car that is roaring to go, and we are offering: new headlights (ophthalmology) and a better way to fill the gas tank (oral medicine).

Extra-glandular Improvements But the car also needs “body work” including touch-up paint, wheels, and interior improvements as well as a dashboard “danger warning light” and we are not “FDA-approved for emerging biological tools” in our clinical “Body Shop.”

Thank you for inviting me to the 2018 ISSS San Diego skyline (where it is WARM in Spring)