PROMISING NEW DEVELOPMENTS IN
by Carol Milano
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
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
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,
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
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."
- "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
- from a statement released by Amarillo Biosciences, Inc. on
- from an internal memo for review at NIH (provided by Dr.
Bruce Baum on 1/8/2001)
Bruce Baum (301)496-1363 email@example.com
Reza Dana (617)912-7401
Philip Fox (301)320-8200 firstname.lastname@example.org
Inspire Pharmaceuticals (919)287-1236
Stewart Kassan (303)534-2107 email@example.com
Stanley Pillemer (301)496-4072 firstname.lastname@example.org
David Power email@example.com
Debra Schaumberg (617)278-0849
David Sullivan (617)912-0287
Carol Milano, a member of the National Association of Science
Writers, is based in New York City.
Many of these articles
appear on the publication's website, which are often password-protected
or members-only. For your convenience, I've gathered them on my own