Thyroid Eye Disease: Current and Emerging Therapies Clinical Update

Clinical Update
OCU LOPL A STICS
Thyroid Eye Disease:
Current and Emerging Therapies
by denny smith, contributing writer
interviewing kimberly p. cockerham, md, and raymond s. douglas, md, phd
E
r ay m o n d s . d o u g l a s , m d , p h d
xcept perhaps for diabetic
retinopathy, thyroid eye
disease, or TED, may be the
most multifaceted medical
challenge that ophthalmologists face. The characteristic exophthalmos, eyelid retraction, strabismus
and diplopia familiar to ophthalmologists are just a few of the many symptoms of hyperthyroidism, a systemic
autoimmune disorder also known as
Graves disease.
The systemic symptoms of hyperthyroidism include arrhythmias,
myopathy, hyperhidrosis, menstrual
irregularities, insomnia, anxiety,
weight loss, mood disorders, fatigue
and shortness of breath. But the ocular manifestations may have a greater
psychosocial impact and may call for
a more customized approach than the
systemic problems. “Without intervention, the disfigurement and dysfunction of TED can lead to job loss,
quality-of-life issues and divorce,” said
Kimberly P. Cockerham, MD, who has
cared for many TED patients in her oculoplastic and neuro-ophthalmology
practice in Los Altos, Calif.
Control of Systemic Disease
Is No Cure for TED
Medical management of systemic
thyroid disease is well established
with radioactive iodine or antithyroid
medications. If these treatments fail,
thyroidectomy is a possible next step.
Fortunately, in at least nine out of
10 patients, the disease resolves with
treatment. Moreover, “the active phase
O r bi t al D e c o mp r e s si o n
Patient who had exposure keratopathy as a result of exophthalmos is shown before (left) and two months after (right) orbital decompression surgery.
of disease lasts for 18 to 36 months in
most patients and will evolve into an
inactive state even without any intervention,” said Dr. Cockerham.
However, systemic therapy does not
address the exophthalmos caused by
TED, for which corticosteroids have
long been the main treatment. But because the side effects of corticosteroids
have made clinicians hesitant to use
them for extended periods, steroidsparing immunosuppressive agents
such as azathioprine, cyclosporine and
methotrexate, along with biologics like
adalimumab and rituximab, have been
tried for TED.
A stepwise approach to TED. Nevertheless, Dr. Cockerham has found
that her patients generally respond
to a course of steroids that is limited
enough in dose and duration to avoid
serious side effects. “My average TED
patient is not going to be treated with
immunosuppressants. If the patient
has moderate to severe TED, IV steroids, such as 250 mg of methylprednisolone given weekly for six weeks,
can be effective and will avoid the side
effects of oral steroids,” she said. She
also wants her patients to be comfortable during this period. “In mild active
disease, Nasonex [mometasone nasal
inhalation], which is lipophilic, can
enter the orbit through the thin medial
wall. This, used along with preservative-free artificial tears, can improve
patient comfort.”
For her patients who don’t respond
to that six-week steroid course, Dr.
Cockerham offers surgical decompression of the orbit; and, if that fails, her
next step is x-ray therapy. Only when
the results of XRT are inadequate does
she try immunosuppressive therapy.
“Immunosuppressants are usually
reserved for patients whose condition
defies steroids, radiation and surgical
decompression.”
Customization is key. Raymond S.
Douglas, MD, PhD, associate professor of ophthalmology and director
of the TED center at the University
of Michigan in Ann Arbor, uses the
same therapies but varies their order
and emphasis. Dr. Douglas said that
corticosteroids are indeed the first-line
therapy for most Canadian and European ophthalmologists. “But in the
e y e n e t
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Oculoplastics
United States, we try to use them sparingly, often as a bridge between therapies. The effects of steroids are transient, and studies have demonstrated
minimal long-term improvement with
their use. I probably take more patients
off steroids than I put on. My treatment rationale is customized based
upon the severity of the disease and
the likelihood of double vision or optic
neuropathy threatening the patient’s
vision. So my preferred initial therapy
is patience, possibly with short-term
steroids, followed by decompression
surgery. XRT is way down on my list,
since controlled studies have uniformly shown it to be ineffectual.”
Rituximab to the rescue. However,
Dr. Douglas is optimistic about one
agent now being tried for TED treatment: the biologic agent rituximab.
“Thus far, studies of rituximab are
limited; but, in our anecdotal experience, we have had fantastic results with
it. The effect of rituximab in patients
with severe disease that has failed to
respond to steroids has been dramatic,
and I will consider its use in patients
who are not candidates for surgery. At
500 mg, administered intravenously by
slow infusion twice, two weeks apart,
rituximab stops the progression of
TED virtually immediately. Within
two to four weeks, the disease became
quiescent in more than 20 patients we
have followed.”
Collaborate with endocrinologists.
Dr. Douglas also customizes TED
treatment by collaborating closely with
endocrinologists who are managing
his patients’ systemic thyroid disorder.
“We like to have the thyroid controlled
medically, surgically or with radioactive iodine prior to orbital management if possible.”
C o ul d Ri t u x imab B e a G am e Chang e r?
Every once in a while, a drug appears to have so many uses that it generates the
claims—and the concerns—of a “miracle” product. Rituximab, one of the newest
agents being studied in the treatment of TED, could be one of those drugs. This
monoclonal antibody, which targets the CD20 antigen on B cells, is currently marketed as Rituxan in the United States and MabThera elsewhere. Administered by
slow IV infusion, it costs $5,000 to $10,000 per dose. Originally approved in the
1990s to treat relapsed or refractory B-cell non-Hodgkin lymphoma, its approved
indications have since expanded to encompass chronic lymphocytic leukemia as
well as rheumatoid arthritis, Wegener granulomatosis and microscopic polyangiitis.
It is also being used off label in the treatment of uveitis, diabetes, systemic lupus
erythematosus, hemolytic anemia, idiopathic thrombocytopenic purpura and Sjögren
syndrome. It is even being studied in organ transplant rejection and chronic fatigue
syndrome.
Dr. Douglas was one of the principal investigators in a trial that looked at rituximab in treating TED. In this case series, all six patients with corticosteroid-refractory disease experienced rapid and sustained resolution of orbital inflammation and
optic neuropathy following treatment with rituximab.1 Another recent study of 12
patients also achieved promising results,2 and a randomized, double-blind trial is
currently under way at the Mayo Clinic.
However, Dr. Douglas said that drugs that modulate the immune cascade pose
a threat of opportunistic infection, and some patients taking rituximab run the risk
of a devastating reactivation of previously quiescent infections, including progressive multifocal leukoencephalopathy (PML), the subject of a black box warning.
“Although I am very optimistic about rituximab, we currently cannot treat with it
because it is not covered by insurance; and the manufacturer, Genentech, is not interested in additional clinical trials in nonmalignant disease due to the risk of PML.” 1 Khanna, D. et al. Ophthalmology 2010;117(1):133–139.e2.
2 Silkiss, R. Z. et al. Ophthal Plast Reconstr Surg 2010;26(5):310–314.
generally remains quiescent after it has
been controlled. “Once hyperthyroidism is inactive, it is unusual to see it
reactivate,” Dr. Cockerham said. “I
have had only two patients reactivate
over 23 years.”
Good News on TED Prognosis
Dr. Douglas noted that, despite the
sometimes severe cosmetic problems
associated with exophthalmos, less
than 5 percent of patients suffer visual loss, most commonly from optic
neuropathy secondary to optic nerve
compression.
In addition, unlike other autoimmune disorders, hyperthyroidism
Future Therapies
Even though treatment success rates
are high, Dr. Cockerham would like a
more reliable and safer protocol for her
TED patients. “Ideally, there would be
a minimally invasive treatment that
would prevent the complications of
TED.”
Drug-eluting devices. Dr. Cockerham is pursuing the possibility of
using ocular implant technology for
treating exophthalmos in TED. “The
best bet would be an orbital implant
that elutes immunomodulators.
Eluting technology has evolved, but
because orbital disease is a relatively
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n o v e m b e r / d e c e m b e r
infrequent diagnosis, financial backing
is tough to get. I am currently funded
by the U.S. Department of Defense to
optimize an episcleral implant, and I
hope to translate that into orbital applications.”
IGF-I blockers. Dr. Douglas noted
another novel therapeutic approach in
TED: “The insulinlike growth factor I
receptor has been implicated in TED,
and a drug blocking the interaction of
the IGF-I receptor with the immune
system may be highly beneficial. So
while specific, potent immunomodulators such as rituximab remain interesting for the treatment of TED, I am
even more excited about the prospect
of a new class of treatment that will
block recognition and activation of autoantigens in this disease.”
Drs. Cockerham and Douglas report no financial disclosures.