PROMISING NEW DEVELOPMENTS IN
SJOGREN'S SYNDROME

Although several million people suffer from Sjogren's syndrome, it's a low-profile condition, worldwide. But a host of clinical trials and research projects suggest promising new treatments may be just ahead.

In both forms of Sjogren's, sensitized lymphocytes attack and destroy exocrine glandular tissue, starting with salivary and lacrimal glands. Levels of saliva and tear production fall quickly. Scandinavian researchers consider primary Sjogren's syndrome the most common disorder among chronic systemic rheumatic diseases (1). Secondary Sjogren's sufferers also have an extraglandular connective tissue disease--often rheumatoid arthritis or systemic lupus erythematosus. 90% of Sjogren's patients are women.

THE HORMONAL FACTOR

Several studies are exploring hormonal effects on dry eyes. In an observational study of 36,995 women, subjects on Hormone Replacement Therapy were at a 70% higher risk for dry eye syndrome. Estrogen/progesterone brought a lower risk, but it was still higher than in women who had never used HRT. If HRT promotes dry eyes in a healthy population, it may well affect women with Sjogren's syndrome, observes lead investigator Debra A. Schaumberg, ScD, MPH, Division of Preventive Medicine, Brigham and Women's Hospital.

Androgen deficiency appears to be a critical factor in the pathogenesis of dry eye in Sjogren's syndrome. "Women normally make about 2/3 the amount of androgen as men, but women with Sjogren's are androgen-deficient. Given that androgens appear to be very important for optimal lacrimal and meibomian gland function, this deficiency may promote the development of dry eye," says David A. Sullivan, PhD, Senior Scientist, Schepens Eye Institute, Harvard Medical School.

His colleague, Reza Dana, MD, an ophthalmologist with many Sjogren's patients, also researches androgen's effects. "If low levels of androgen are bad, will patients get better with exogenous androgen? We've tried to develop a testosterone analog formulation of an androgen. On anti- androgen therapy, secretions of lipids in people's eyes-- associated with dry eye--change."

TREATING SJOGREN'S SYMPTOMS

Two new drugs for one major symptom are on the market. Salagen (pilocarpine HCl) from MGI Pharma, Inc. relieves the dry mouth of Sjogren's Syndrome. Among other benefits, Salagen helps users sleep without needing additional liquid.

During trials of Evoxac (celameline HCl) by Daiichi Pharmaceutical Corp., both primary and secondary Sjogren's patients reported significant improvement in salivary flow, tongue dryness, and ability to chew, swallow food, or speak without drinking. FDA-approved for dry mouth, Evoxac is now in clinical trials for its effectiveness on dry eyes.

Allergan will soon be testing in Phase II trials whether androgen eyedrops are a safe and effective therapy for the treatment of various aqueous-deficient and evaporative dry eye syndromes. "Topical androgen application may suppress the lacrimal gland inflammation and correct the meibomian gland dysfunction in Sjogren's syndrome patients," says Dr. Sullivan. Androgen eyedrops would be the first treatment for dry eye on the USA market.

Inspire Pharmaceuticals is in Phase III clinical trials of INS365, "a small molecule to stimulate specific receptors in the eye which regulate and stimulate natural secretion of tears or mucin on the inner eyelids or cornea surface," explains CEO Christy Shaffer. The topical eyedrop activates tear secretion by epithelial cells, lubricating through mucin release, without the stinging or burning of many ocular applications. Inspire expects INS365 to be available in 2003.

AFFECTING THE UNDERLYING CAUSES

Some products now in research or development target causes, rather than symptoms, of Sjogren's syndrome.

Restasis (cyclosporine) from Allergan is slated to be the first therapeutic product aimed at the underlying inflammatory process that is present in dry eye. By preventing T-cell activation, both on the ocular surface and in the lacrimal gland, Restasis maintains homeostasis in these tissues, explains David Power, Director, Global Eye Care Pharmaceutical Marketing. Allergan is now conducting a study to confirm earlier findings.

Amarillo Biosciences finished a second Phase III clinical trial for a natural interferon alpha (IFN-a) lozenge to stimulate saliva production. IFN-a patients had more than twice the placebo group's rise in unstimulated whole saliva (UWS), important for oral health and comfort. "UWS increases may result from improvement in underlying gland function and salivary pathology, suggesting IFN-a is more than a symptomatic treatment in Sjogren's syndrome; it addresses the underlying secretory dysfunction," says Joseph M. Cummins, Ph D, President, Amarillo Biosciences, Inc. (2)

Pre-clinical proof of concept studies at the National Institutes of Health show gene transfer to the salivary gland is possible. "In primary Sjogren's, the reason for secretory cell loss is unknown. Adenoviruses are not good for the long-term treatment Sjogren's requires, so we switched to adeno-associated virus. The vectors we made are effective but haven't yet been tested on a Sjogren's model. Immunomodulatory strategies are used. By injecting through a tube, we can transfer genes in and they express. It's encouraging," reports Bruce Baum, DMD, PhD, Chief, Gene Therapy branch, National Institute of Dental & Craniofacial Research (NIDCR).

Dr. Baum's team is developing "an orally implantable fluid secretory device: an artificial salivary gland. The blind-end tube prototype design has a monolayer of allogeneic graft cells grown on a suitable bio-compatible substratum coated with matrix proteins." Potentially clinic-ready in seven to ten years, the device would help any patient who has lost acinar cells and parenchymal tissue in the glands, leading to severe salivary gland hypofunction. (3)

NIDCR is completing a two-year Phase II clinical trial of DHEA, a mild androgen, on 28 primary Sjogren's patients. "Some animal models suggest DHEA ameliorates inflammation that causes dry eyes," says Stanley Pillemer, MD, Senior Staff Physician, Gene Therapy branch. The rheumatologist notes that researchers have shown DHEA is lower in rheumatoid arthritis victims, and helps systemic lupus patients. "DHEA is sold over the counter, so people can get it easily," he cautions. (Classified as a food supplement, DHEA won't be FDA-regulated as a drug; purity of compounds may become an issue.)

Dr. Pillemer's group is studying thalidomide's immunomodulatory actions. "Sjogren's syndrome patients have an increase of Tumor Necrosis Factor alpha (TNFa) in salivary and lacrimal glands," he explains. "Evidence shows higher TNFa is produced primarily by epithelial cells. TNFa is considered a powerful pro-inflammatory cytokine." Possibly by inhibiting TNFa action, thalidomide has helped in other auto-immune diseases, especially Bechet's syndrome and lupus. Another NIH trial explores a TNF antagonist, etancercept (Enbrel), for Sjogren's patients; the drug has been successful in treating rheumatoid arthritis.

TOOLS FOR DIAGNOSIS AND MONITORING

Diagnosing Sjogren's is not simple. Like many auto- immune diseases, its symptoms mimic other conditions.

"Ophthalmologists may mistake serious dry eye for infectious conjunctivitis," says Dr. Dana. "Rheumatologists, often cognizant of primary Sjogren's, frequently overlook secondary Sjogren's, with its other manifestations diverting the doctor's attention." He recommends asking patients very specifically if they have dry or red eyes, ocular irritation, occasional pain, difficulty chewing, or problems swallowing dry food (like a cracker).

Levels of cytokines which may increase in Sjogren's syndrome can be tracked. "We believe interleukin 6 is elevated in Sjogren's, indicating an actual gland inflammation," notes Philip Fox, DDS, a board member of the Sjogren's Syndrome Foundation. In cases with possible Sjogren's symptoms, the interleukin 6 level may be useful for diagnosis. Otherwise, Dr. Fox believes, it's helpful for monitoring a patient.

Stewart Kassan, MD, heads a large Sjogren's Syndrome Foundation committee working on a set of standard international criteria for Sjogren's. Eager to define the specific patient population, the rheumatologist says, "This may not absolutely change how the disease is diagnosed, but it raises awareness of Sjogren's syndrome and gives insight into specificity and sensitivity of each criterion for diagnosis: not just dry eyes/dry mouth but other significant clinical features, such as use of a lip biopsy."

What can international standards bring? "Research will be more productive because we can define the patient population more consistently. Secondarily, pharmaceutical firms want specific criteria to allow them to develop new drugs for this patient population." Hoping his committee's work builds awareness among rheumatologists, other MDs, and the lay public, Dr. Kassan declares, "This should make it very clear that Sjogren's syndrome is not uncommon, and it is not a rare disease."

NOTES:

1. "Primary Sjogren's Syndrome: Diagnostic Criteria, Clinical Features, and Disease Activity." Rolf Manthorpe, MD, Karsten Asmussen, MD, Peter Oxholm, MD. Journal of Rheumatology 1997, Vol. 24, Supplement 50
2. from a statement released by Amarillo Biosciences, Inc. on 1/5/2001
3. from an internal memo for review at NIH (provided by Dr. Bruce Baum on 1/8/2001)

SOURCES

Bruce Baum (301)496-1363 bbaum@dir.nidcr.nih.gov
Reza Dana (617)912-7401
dana@bics.bwh.harvard.edu
Philip Fox (301)320-8200 pcfox@erols.com
Inspire Pharmaceuticals (919)287-1236
gmossing@inspirepharm.com
Stewart Kassan (303)534-2107 s.kassan@juno.com
Stanley Pillemer (301)496-4072 pillemer@nih.gov
David Power power_david@allergan.com
Debra Schaumberg (617)278-0849
dschaumberg@rics.bwh.harvard.edu
David Sullivan (617)912-0287
sullivan@vision.eri.harvard.edu

Carol Milano, a member of the National Association of Science Writers, is based in New York City.

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