Literature review

There are four components to be discussed in the literature review. Thyroid eye disease and idiopathic myositis are included in the disease of orbital myositis.

Furthermore, the anti-inflammation cytokine, IL-1 Ra, and vector, recombinant adeno-associated virus, are also discussed in details.

Session I Introduction of thyroid eye disease

Orbital myositis occurs in various diseases, like including thyroid eye

disease, and idiopathic myositis. Severe myositis could result in strabismus and

proptosis even under current treatment. The detailed pathophysiology and management of either idiopathic or thyroidal orbital myositis is not very clear.

Moreover, there is no very effective therapy or preventive method in this field for these diseases. Generally, anti-hyperthyroidism medication, oral steroid and pulse therapy are given; radiotherapy is also performed in some hospitals.

However, severe and persistent proptosis and strabismus can only be corrected by orbital decompression and muscle surgery.

There are many different names you might find for the autoimmune eye condition that is often seen with thyroid disease, including:

• Thyroid Eye Disease (TED)

• Graves' Opthamolopathy (GO)

Thyroid Eye Disease is an autoimmune eye condition that, while separate

from thyroid disease, is often seen in conjunction with Graves' Disease. The

condition, however, is seen in people with no other evidence of thyroid

dysfunction, and occasionally in patients who have Hashimoto's Disease. Most

thyroid patients, however, will not develop thyroid eye disease, and if so, only mildly so.

Graves’ ophthalmopathy continues to be a challenge for the ophthalmologist.

The lymphocytic infiltration of orbital tissues are highly suggestive of an autoimmune pathogenesis. The majority of the symptoms can be explained by the increase in volume of the orbital contents due to hyperplasia of the adipose

tissue and enlargement of the extraocular muscles following fibroblast

stimulation to proliferate and secrete glycosaminoglycan. The cytokines

stimulate the espression in orbital fibroblasts of immunomodulatory proteins, but the nature of the autoantigen responsible for the lymphocytic homing and the link with the thyroid gland remain controversial.

Thyroid eye disease is characterised by a period of inflammation and engorgement of these tissues, followed by a healing response. Among patinets with thyroid eye disease in the incidence cohort, approximately 90% had Graves hyperthyroidesm, 1% had primaty hypothyroidism, 3% had Hashimoto

thyroiditis, and 6% were euthyroid. There was a close temporal relationship between the development of hyperthyroidism and Graves ophthalmolopathy: in about 20% of patinets the diagnoses are made at the same time whereas in approximately 60% of patinets the eye disease occurred within 1 year of onset the thyroid disease.

Cytokines are key regulators and mediators of normal and pathologic immune responses. The main cytokines are interferon-gamma, which is the product of activated T cells, and interleukin-1 and tumor necrosis factor-alpha, which are mainly secreted by macrophages. In addition, human fibroblasts

express a number of regulatory molecules that influence immune mechanisms, and treatment with the proinflammatory cytokine interleukin-1 can lead to their upregulation.

The cytokine interleukin-1 stimulates cell proliferation,

glycosaminoglycans synthesis, and prostaglandin production, along with induction of adhesion molecules, immunomodulatory proteins, and

metalloproteinases in orbital fibroblasts. Interleukin-1 receptor antagonist is

a naturally occurring inhibitor of interleukin-1 that inhibits interleukin-1-induced stimulation of orbital fibroblast GAG synthesis in vitro. In vitro expression of interleukin-1 receptor antagonist mRNA and protein has been shown to be significantly lower in thyroid eye disease when compared with normal orbital fibroblasts. This suggests an imbalance between interleukin-1 receptor agonist and antagonist, which may facilitate interleukin-1 receptor–mediated

proinflammatory and fibrogenic actions in GO. GO patients who respond well to orbital radiotherapy have increased serum interleukin-1 receptor antagonist, leading the authors to hypothesize that glucocorticoid and radiotherapy may influence agonist stimulation of the interleukin-1 receptor by altering

interleukin-1 receptor antagonist expression in human orbital fibroblasts. Low doses of ultraviolet and ionizing irradiation, but not dexamethasone, were shown to stimulate interleukin-1 receptor antagonist RNA and protein expression in Graves and normal orbital fibroblasts.

In contrast, interleukin-1 beta induced transcription of two of the three hyaluronan synthase genes in GO orbital fibroblasts, and this could be attenuated by dexamethasone. Hyaluronan is one of the three main glycoaminoglycans found in GO. An increase in chondroitin sulfate in GO orbits in vivo and in

particular a shift to more highly sulfated, negatively charged compounds, with an increased water binding capacity, has been reported.

(1) Epidemiology of Thyroid Eye Disease

GO affected women approximately six times more frequently than men. The peak incidence rates occurred in the age groups 40-44 years and 60-64 years in women and 45-49 years and 65-69 years in men. The median age at the time of diagnosis of GO was 43 years. Although GO typically is associated with

hyperthyroidism, and some cases arise in the setting of primary hypothyroidism, a small portion of patients with GOare euthyroid. Previous studies estimated the prevalence of euthyroid GO to be 6 to 21% in patients with GO. A recent study, however, indicates that more sensitive assays for thyroid hormone concentrations may be able to detect hyperthyroidism in the vast majority of patients with GO.

Only 0.7% of patients in this study of 1020 Asian patients with GO were found to be euthyroid. In contrast to the low level of euthyroidism detected in this Asian study, a European group reported a 12.9% prevalence of euthyroid GO in patients with myasthenia gravis, compared with a 3.1% prevalence of euthyroid GO in patients without myasthenia. Although the results obtained in this

university clinic-based study may have been influenced in part by referral bias, they may prompt future population-based studies to address more rigorously whether euthyroidism is more prevalent in myasthenic patients with GO than in patients with GO who do not have myasthenia gravis.

The prevalence of open-angle glaucoma in patients with hyperthyroidism or GO recently was reported to be higher than previously considered. Clinicians should consider GO a possible risk factor for ocular hypertension and open

angle glaucoma, and should monitor patients' intraocular pressure, optic nerve

appearance, and visual fields accordingly.

(2) Clinical Features of Thyroid Eye Disease

Signs and symptoms include:

Pain in the eyes, pain when looking up, down or sideways

•

Dryness, itching, dry eyes, difficulty wearing contact lenses

•

Inflammation and swelling of the eye, and its surrounding tissues

•

Swelling in the orbital tissues which causes the eye to be pushed forward

-- referred to as exophthalmos -- which can make Thyroid Eye Disease sufferers appear to have a wide-eyed or bulging stare.

• Bloodshot appearance to eyes

• diplopia

• Impaired vision

Thyroid Eye Disease is known to go through varying degrees of severity, and can go into periods of remission as well. When it has been inactive for a period of around a half a year, it's less likely to recur.

(3)Treatment of Thyroid Eye Disease

1. Medical treatment

Although corticosteroids commonly are prescribed for clinically active GO, their many side effects limit their long-term usefulness. Patients with mild

symptoms can often be successfully treated with frequent application of

lubricating eye drops and eye covers at night. Humidification of room air can

prevent drying of the eyes, and wrap-around polarizing sunglasses can also help relieve glare. Diplopia can be alleviated with prism lenses while awaiting either spontaneous improvement or surgical correction. Temporary plastic prisms are available which are applied to glasses and changed as needed. Prednisone, a steroid medication, may be taken orally to provide temporary relief from pain, swelling and redness, although side effects of the medication may limit the use of prednisone and related drugs. Overall, it is important to keep in mind that eye disease associated with Graves' disease will only improve gradually.

2. Radiation treatment

Orbital radiation is used to treat the compressive optic neuropathy and the orbital inflammatory signs associated with GO. Radiotherapy decreased orbital congestion by interrupting the immunologic processes that promote

inflammation in the retrobulbar tissue. A recent study confirms prior case series data by reporting good efficacy of orbital radiation in treating compressive optic neuropathy. In this retrospective, uncontrolled case series with four months of follow-up, the authors report that 8 of 10 GO patients treated with 2000 cGy showed improved optic nerve function after radiation therapy. Although the authors did not provide statistical analysis, their descriptive data indicate that mean visual acuity improved modestly from 20/30 before treatment to 20/20 after treatment. Color vision and peripheral visual field measures also improved.

The efficacy of orbital radiation in treating GO-associated orbital edema, myopathy, and proptosis was evaluated in two retrospective case series, with conflicting results.

3. Surgical treatment

Ophthalmopathy may contimue to progress even after a euthyroid state has been achieved. In most patients, the eye disease tends to stabilize over a course of weeks to monthes. If the eye condition does not improve or deteriorates despite treatment, surgery may be required.

The enlargement of tissue behind the eye may sometimes cause significant exophthalmos, which produces the disfigurement, worsens the symptoms, and causes ocular exposure. Swelling in the orbit may actually contribute to vision loss as pressure increases on the optic nerve. Surgical procedures to relieve pressure on the optic nerve improve vision and allow the eye to settle back to a more normal position. Orbital decompression, although typically indicated to treat optic neuropathy, severe orbital congestion, or advanced proptosis, has been used increasingly in recent years as an elective procedure to enhance cosmesis in patients without sight-threatening ophthalmopathy.

If intractable diplopia in primary gaze or in the teading position persistd, then strabismus surery may be helpful in restoring single vision. This surgery entails detaching and repositioning the eye movement muscles on the eyeball to improve ocular alignment and minimize double-vision.

Retracted and puffy eyelids can alter a person's appearance and increase the risk of cornea drying. Similarly, procedures to correct eyelid retraction may improve ocular comfort and help to restore a more normal appearance.

Corrective eyelid surgery can alleviate the problem through adjustable loosening of the eyelid muscles, as well as removal of scar tissue, excessive fatty tissue and

skin to place the eyelids into a more normal position. Elective orbital

decompression, strabismus surgery and eyelid retraction repair ususlly are not considered until a euthroid state has been maintained for several months and the ophthalmic signs have been confirmed to be stable.

Patients with eye disease who have had their hyperthyroidism treated previously should also be examined at regular intervals to make certain that thyroid function remains normal since recurrence of hyperthyroidism, or development of hypothyroidism, may cause the eye disease to flare up.

Session II Introduction of Idiopathic orbital myositis

Both children and adults may be afflicated by idiopathic inflammation of the orbital tissue. Idiopathic orbital inflammation is often subclassified on the basis of the anatomic target area within the orbit. Idiopathic orbital myositis is a subtype of nonspecific orbital inflammation primarily involving the extraocular muscles. It occurs most frequently in young to middle-aged adults with a 2 to 1 female predominance.

Typically, patients present with acute onset of orbital pain, restreicted eye movement, and proptosis. Conjunctival vascular injection and chemosis are common, as are eyelid erythema and soft-tissue swelling. The classic patient presents with an abrupt onset of edema, erythema, chemosis, and pain and shows exquisite sensitivity to oral corticosteroids, often reporting subjective improvement within one or two days. In the ideal case, there is no flare-up as steroids are tapered. Myositis may affect one or multiple extraocular muscles.

IOI may be unilateral or bilateral, and both sides may be involved either

simultaneously or at varied intervals

(1.) Pathogenesis

In recent studies, increased expression of proinflammatory cytokines particularly interleukin-1 alpha and interleukin-1 beta, tumor necrosis

factor-alpha and macrophage inflammatory protein-1 alpha, was observed in

muscle of idiopathic inflammatory myopathies. The cytokine interleukin-1 stimulates cell proliferation, glycoaminoglycan synthesis, and prostaglandin production in orbital fibroblasts. There were no difference in cytokine and chemokine patterns between polymyositis, dermatomyositis, and inclusion body myositis, which could indicate that similar pathogenetic mechanisms are

involved in these subsets of myositis.

(2.) Histopathlogy

Histopathologically, the extaocular myositis ic characterized by a pleomorphic cellular infiltrate consisting of lymphocytes, plasma cells, and histiocytes within the edematous with variable degrees of reactive fibrosis, but preserved architecture of affected tissue. There may be extensive destruction of the background extraocular muscle fibers (Figure 2-1), or other affected tissues.

Granulomas, including giant cells, require exclusion of mycobacterial and fungal infections, sarcoidosis and Wegener granulomatosis.

Source: Ophthalmic Plastic and Reconstructive Surgery, Inc. Volume 22(2), March/April 2006, pp 79-86

FIG. 2-1. Idiopathic orbital myositis with severe muscle destruction

(hematoxylin and eosin stain, original magnification ×40). Inset, Dense mixed inflammatory cell infiltrate among swollen, degenerating muscle fibers (arrows) (hematoxylin and eosin stain, original magnification ×400).

(3.) Treatment Strategy

Initial therapy consists of systemic corticosteroids in doses adjusted to the individual patinet’s need in typical cases. Atypical clinical or imaging findings should prompt biopsy (Figure 2-2A). The threshold for biopsy should be lower for lacrimal gland lesions, since aggressive malignancies can present with inflammatory signs. If the biopsy reveals nonspecific inflammation, or if there are specific patterns of inflammation and systemic disease is excluded, treatment with steroids can begin.

Source: Idiopathic Orbital Inflammation: A Pathogenetic Construct and Treatment Strategy:

The 2005 ASOPRS Foundation Lecture

FIG. 2-2. Treatment strategy for idiopathic orbital inflammation. A, For atypical cases. B, For cases with the abrupt onset of inflammatory signs and symptoms, and with imaging compatible with a topographical variant of IOI.

If the findings are typical, systemic corticosteroids should be beginned (Figure 2-2B). Acute cases generally responde rapidly. With a rapid response that is sustained and well-tolerated, dosage should be slowly tapered. Because many other orbital pathologic processes may be masked by steroids, incomplete therapeutic response suggests the need for orbial biopsy for histopathlogic

confirmation after 1 to 2 weeks at the higher doses, biopsy should then be

performed. If the results are consistent with idiopathic inflammation, alternative therapy will be needed, and a rheumatologist should be enlisted at that point.

(4.) Therapeutic Options

Therapeutic approaches to idiopathic extraocular myositis have included observation, nonsteroidal antiinflammatory drugs, radiation therapy,

“therapeutic” surgery, intravenous immunoglobulin, plasmapheresis,

corticosteroids, immunosuppressants, and immunobiologic agents. In very mild cases, simple observation or nonsteroidal agents may suffice. Radiation may be effective in some patients who are steroid-responsive but steroid-intolerant.

Rarely, orbital decompression or surgical debulking may have value for large sclerotic masses.

Corticosteroids remain the first-line treatment in most cases. Depending on

severity and response, beginning dose with oral prednisolone at 1.0 to 1.5

mg/kg/d (60-80 mg/d) for 1 to 2 weeks and then taper dosage very slowly below about 40 mg per day, generally over a period of several months. If a biopsy is performed prior to treatment, intraoperative corticosteroids (intravenous methylprednisolone, 125 to 250 mg) can be administered after frozen-section confirmation of the diagnosis. Intravenous corticosteroids at higher doses (methylprednisolone, 1.0 g/d for 1 to 3 days) can be given to patients with atypical involvement and vision loss. Intraorbital triamcinolone (40 mg/ml) is useful during surgery, especially in sclerosing inflammation, and can be

considered for outpatients with steroid-responsive but steroid-intolerant disease.

Immunosuppressants have been used for patients who do not fully respond

to corticosteroids, or cannot tolerate side effect. Orbital radiation, antimetabolites, T-cell inhibitors and alkylating agents (e.g., cyclophosphamide) may be useful in controlling the disease.

Session III Interleukin-I Receptor Antagonist

Interleukin-1 receptor antagonist (IL-1 Ra) is a naturally occurring protein that binds to IL-1 receptor and blocks the binding of both IL-1α and IL-1β without inducing a signal of its own and thus is a very effective inhibitor of inflammation. The balance between IL-1 and IL-1Ra in local tissues plays an important role in the susceptibility to and severity of many diseases. In 1990 IL-1Ra was cloned and later on, a large numbers of studies led to disclosure of the crucial importance of the imbalance between IL-1 and IL-1Ra in the pathogenesis of rheumatoid arthritis. Due to the short half life of protein, long term oral medication or repeat injection was used in former experiment.

1.) Endogenous Interleukin-I Receptor Antagonist

IL-1Ra, discovered in the 1980s, inhibits the proinflammatory effects of IL-1 by functioning as a competitive inhibitor for receptor binding of IL-1. Restoring the balance between IL-1Ra and IL-1 with the administration of exogenous recombinant IL-lra is one therapeutic approach that has been investigated in recent years.

2.) Human Recombinant Interleukin-1 Receptor Antagonist (ANAKINRA)

Endogenous IL-1Ra has been purified, sequenced, cloned as a cDNA, and expressed in Escherichia coli. Anakinra has a molecular weight of 17 kDa and binds to IL-1 receptors with an affinity nearly equal to that of IL-1. The

mechanism is required of a second cell membrane molecule termed IL-1

accessory protein (IL-1AcP). When IL-1 binds to the IL-1RI, IL-1AcP interacts with the receptor-ligand complex and initiates cell stimulation. Anakinra, when bound to the IL-1RI, prevents IL-1AcP from interacting with the receptor, resulting in no response. Figure 2-3 illustrates the mechanism of action of endogenous IL-1Ra, which operates in the same manner as anakinra. The

antagonistic effects of anakinra on IL-1- induced PGE 2 secretion, production of metalloproteinases, and proteoglycan degradation have been demonstrated in vitro. Anakinra blocked IL-1-induced T-cell proliferation and PGE 2 as well as collagenase production in cultured synovial cells.

Source: Clinical Therapeutics. 2004;26:1960-1975)

Session IV Recombinant Adeno-asssociated Virus Vector

With the recent advances in gene therapy, the IL-1Ra gene has been delivered by retrovirus-based, adenovirus-based, and adeno-associated virus vectors into synoviocytes to achieve antiinflammatory effects both in vivo and in vitro with varying success. Adenovirus-associated virus vector with a

microdystrophin gene was inserted in the muscle tissue and the protein

synthesized successfully in a mouse of Duchenne muscular dystrophy. In this study, to establish potential of rAAV in myositis gene therapy, rAAV-delivered IL-1Ra gene was introduced into extraocular muscles.

(1.) AAV and Recombinatn AAV Vectors

AAV is one of a relatively small group of viruses that have been

successfully modified for use as gene transfer agents in human trials. AAV is a 20-nm diameter replication-deficient parvovirus native to humans and nonhuman primates and exists in nature in over 100 distinct variants, including both those defined serologically as serotypes and those defined by DNA sequence as

genomovars. There is no consistent indication of AAV infection being associated with human disease.

The life cycle of AAV has been studied in detail. Cells infected with AAV require a helper virus, such as an adenovirus, herpesvirus, or vaccinia virus, to replicate efficiently in cell culture.

Recombinant adeno-associated virus (rAAV) has proven to be a promising

gene delivery vector for human gene therapy.Recombinant AAV vectors based

on the most frequently studied serotype, AAV2, were produced in the mid-1980s by creating ITR-deleted helper plasmids to supply rep and cap functionsm.

Recombinant AAV2 vector plasmids were also constructed in which

ITR-sequences flanked the therapeutic gene of interest, along with an appropriate promoter and polyadenylation signal. When helper plasmids and vector plasmids were co-transfected into permissive cells (usually human embryonic kidney 293 cells) that were also infected with a helper adenovirus, those cells packaged rAAV2 virions containing only the therapeutic vector genomes. Vector particles, thus produced, could be purified using CsCl density gradient ultacentrifugation.

Over time, rAAV2 packaging and purification technology has improved, and helper plasmids now most frequenly encode both adenovirus and AAV helper genes. Recombinant vector particles are often purified using column

chromatography methods and/or nonionic gradient media, resulting in a higher level of infectivity of recombinant virus as well as higher overall titers.

Preclinical studies demonstrated that rAAV vectors were capable of

long-term gene transfer and expression in the bronchial epithelium of rabbits and nonhuman primates. Importantly, studies also demonstrated no increase in

inflammatory cells, or pro-inflammatory cytokines after rAAV delivery to the lower airways of nonhuman primates. Likewise, there were no adverse changes in chest x-rays, arterial blood gases, or pulmonary function tests in these animals after rAAV delivery. Based on this information, a number or phase I and phase II clinical trials of rAAV2-CFTR were performed.

(2.) Future Directions

rAAV is characterized by excellent safety profiles, wide host range, and the ability to transduce differentiated cells. Numerous rAAV-based vectors providing efficient and sustained expression of transgenes in target tissues have been

rAAV is characterized by excellent safety profiles, wide host range, and the ability to transduce differentiated cells. Numerous rAAV-based vectors providing efficient and sustained expression of transgenes in target tissues have been

在文檔中 腺相關病毒傳送第一介白質接受器拮抗蛋白基因應用於預防眼外肌炎; Prevention of Extraocular Myositis by Recombinant Adeno-asssociated Virus Vector With Delivary Of Interleukin-1 Receptor Antagonist (頁 11-0)