Ординатура / Офтальмология / Английские материалы / New Treatments in Noninfectious Uveitis_Miserocchi, Modorati, Foster_2012

Fig. 1. Corticosteroids: therapeutic strategies (1). Rx = Treatment; TNF = tumor necrosis factor.

Pharmacology

The term CS refers to both glucocorticoids and mineralocorticoids, but is often used as a synonym for glucocorticoids. They are naturally produced by the adrenal cortex. Glucocorticoids can control or prevent inflammation by suppressing the migration of polymorphonuclear leukocytes and fibroblasts and by reversing capillary permeability. They have potent anti-inflammatory and immunosuppressive properties. As a consequence, glucocorticoids are widely used as drugs to treat inflammatory conditions such as arthritis, dermatitis, and noninfectious uveitis and as an adjunct therapy for autoimmune diseases.

Nowadays, only synthetic molecules are used in clinical practice. All CS have 21 carbon atoms, forming a molecule with four rings. Modifications of the basic structure result in compounds with various biologic properties. Thus, their respective anti-inflammatory activity, sodium-retaining activity, duration of action, intraocular pressure (IOP) increase, transcorneal penetration can vary from one molecule to another. The glucocorticoid molecule enters passively the target cell. It then binds to a specific cytoplasmic receptor (glucocorticoid receptor). The cytoplasmic steroidreceptor complex becomes activated, crosses the nuclear membrane and binds to specific sites of the DNA called glucocorticoid response elements. This binding controls the transcription of specific genes promoting or inhibiting the production of certain mRNAs. The rate of protein synthesis of the target cell is thereby modified, activated for some, inhibited for others. These mechanisms explain the rapidity and the multiplicity of action of a single hormone binding to a single receptor. Cells involved in inflammatory reactions are the main targets: lymphocytes, monocytes, local resident cells such as endothelial cells, fibroblasts, hepatocytes. Nuclear translocation of

Table 1. Relative anti-inflammatory activity of glucocorticoids

cytoplasmic glucocorticoid receptors has been shown in the iris-ciliary body and the adjacent corneoscleral structure in rabbits. The relative anti-inflammatory activity of glucocorticoids is summarized in table 1 [1].

Preparations and Administration

Topical Preparations and Administration Route

Different CS preparations of variable anti-inflammatory potencies are available for ophthalmic topical use (table 2) [2–4]. The more potent the preparations are, the more ocular side effects are observed (elevated IOP, cataract). Most of them are listed in table 3 in decreasing order of anti-inflammatory potency. Dexamethasone is theoretically the most potent topical steroid. However, the better transcorneal penetration and the higher molar aqueous humor concentration of prednisolone acetate make it theoretically relatively more potent than dexamethasone alcohol/sodium phosphate drops. In rabbits, there are controversial results concerning the corneal and anterior chamber penetration of various CS preparations depending on whether the corneal epithelium is intact or not. Besides the drug concentrations, numerous metabolic parameters can influence the therapeutic effectiveness of different CS preparations: glucocorticoid receptor binding affinity, local enzyme-induced inactivation, intraocular clearance, inherent anti-inflammatory potency. In clinical practice, other factors influencing the effectiveness of topical CS administration should not be overlooked such as the dosage frequency or compliance problems, among which the need for shaking a suspension.

Table 2. Relative anti-inflammatory effects and peak aqueous concentration of topical CS preparations (drops)

Table 3. Topical CS preparations: in descending order of intraocular anti-inflammatory potency

Although some animal studies showed corneal penetration differences between prednisolone acetate and sodium phosphate drops, we have not noticed any clinical relevance in everyday practice.

Ophthalmic CS ointments induce lower corneal and anterior chamber drug concentrations than the solutions because the petrolatum vehicle retains the active molecules that are released very slowly. Nevertheless, CS ophthalmic ointments can be an

acceptable alternative at night when they remain in the conjunctival fornix in closed eyes with a subsequent prolonged contact time with the ocular surface.

Topical CS administration as a sole therapy usually represents an effective treatment for anterior uveitis but not for intermediate or posterior uveitides except as an adjunct to other therapeutic regimens in case of accompanying anterior segment inflammation such as in panuveitis.

Topical CS route is the treatment of choice for acute (idiopathic or HLA-B27- associated), subacute or chronic (juvenile idiopathic arthritis) anterior uveitis without posterior segment involvement; they can also be indicated for sclerouveitis and some keratouveitis combined with an adequate anti-infectious treatment if there is any doubt on the origin of the corneal involvement.

As we are going to discuss later, in the matter of intraocular inflammation, one must always initiate an intensive treatment from the beginning of the disease. It is recommended for the patient to occlude the lacrimal ducts with the thumb and the forefinger during the 30 s following the instillation of the CS drop in the lower conjunctival fornix in order to avoid systemic absorption particularly in high-frequency application regimen.

In a typical presentation of unilateral idiopathic acute anterior uveitis, the treatment schedule can be as follows (depending on the severity of the intraocular inflammation):

−mydriatics/cycloplegics.

−analgesics, rest.

−topical CS drops (well shaken bottle of 1% prednisolone acetate for example): one drop every 10 min for 1–2 h, then one drop every hour for 1–2 days, then decrease progressively the dosage frequency from one drop 8 times/day to 3 times/day

at various time intervals depending upon the clinical response which is unique to each patient. Some patients need to be treated with 1 or 2 drops/day during

several weeks or even months. However, one should avoid prolonging such topical treatment more than 3 months; an alternative treatment must be then proposed because of increased risks of adverse effects (glaucoma, cataract). The tapering

of topical CS administration can be assisted by repeated Laser Flare Photometry measurements. Progressive tapering can be done initially by decreasing the drops instillation frequency and afterwards by using less and less potent molecules switching from prednisolone acetate to rimexolone and then to lodeprednol.

−during the acute phase, one can concomitantly prescribe a corticosteroids ophthalmic ointment (0.05% dexamethasone sodium phosphate ointment) 3 times/day or only during the night-time.

−If there is no or poor clinical improvement after a relatively short period of topical treatment (2–3 days), one should consider adding a regional and possibly

a systemic CS therapy even if the ocular inflammation remains unilateral. Despite a frequent dosing schedule, the dexamethasone concentration in the aque-

ous humor is far lower than after a subconjunctival injection with dexamethasone sodium phosphate.

Table 4. Corticosteroids preparations for regional injections (subconjunctival/tenon or transseptal injections)

Topical CS administration is inefficient for posterior segment inflammatory disorders. The penetration of topical dexamethasone into the vitreous after repeated drop instillations is negligible compared with other administration routes (subconjunctival injection, peribulbar injection or oral administration).

Iontophoresis Technology

It is an active noninvasive method of drug delivery achieving higher drug level inside the eye. A low electric current creates an electrical field promoting the movement of charged substances (drug molecules such as dexamethasone phosphate) across biological membranes (cornea, conjunctiva, episclera). It is currently under investigation for noninfectious anterior uveitis and anterior scleritis.

Regional Preparations and Administration Routes

The most common preparations for periocular injections are listed in table 4. Periocular steroid injections represent an effective mode of treating uveitis,

mostly without inducing steroid systemic side effects. They are particularly indicated in unilateral diseases, in the absence of extraocular inflammatory manifestations, in case of insufficient response to topical CS for the treatment of anterior uveitis.

The advantages of periocular steroids are (1) a high local concentration; (2) a longer duration of action – compared with the topical route – determined by the solubility of the steroid and the location of the injection, and (3) their effectiveness against inflammatory disorders of the posterior segment. The duration and severity of IOP rise is inversely related to the solubility of the injected steroid. Triamcinolone acetonide is a very high-risk agent as it is the least soluble and a long-acting repository steroid. Repeated periocular injections may increase the risk of developing glaucoma.

Periocular injections consist in placing the CS preparation periocularly after topical anesthesia (proparacaine 0.5%, oxybuprocaine 0.4%, tetracaine 0.5–1.0%). Besides repeated topical instillations of anesthetic drops, it is often useful to add in the syringe a local anesthetic (0.1 ml of lidocaine 1%) to the CS preparation. Note that the terms ‘peribulbar, periocular or parabulbar injections’ are often misused to signify posterior sub-Tenon injections.

The different techniques of periocular injections comprise subconjunctival, peribulbar and retrobulbar injections. They have theoretically different goals:

The subconjunctival and anterior sub-Tenon injections (both are commonly improperly referred to as ‘subconjunctival injections’) are supposedly aimed to treat anterior segment inflammation and are at higher risk of raised IOP than more posterior injections. In fact, a subconjunctival injection of 2.5 mg of dexamethasone results in a vitreous dexamethasone peak concentration 3 times higher than after a peribulbar injection of 5 mg of dexamethasone and 12 times higher than after an oral dose of 7.5 mg of dexamethasone. The dexamethasone concentration is 11.8 times higher in the aqueous humor than in the vitreous. Thus, a subconjunctival injection is the most effective method for delivering dexamethasone into both the anterior and posterior segments of the eye. Systemic drug absorption following a subconjunctival injection is very high and is similar to the one observed after peribulbar injection.

The posterior sub-Tenon, transseptal (both of them are often commonly referred as ‘perior parabulbar injections’) and retrobulbar injections are thought to be more effective for posterior segment inflammation particularly for macular edema. All three have the same potential to place the drug in the intraand extraconal spaces. Computed tomography studies have demonstrated the existence of multiple communications between these two compartments, allowing the injected drug to diffuse from one to the other. It is therefore pointless and more dangerous to perform a retrobulbar injection instead of a sub-Tenon injection also known as parabulbar injection.

Generally speaking, the posterior sub-Tenon injection (commonly referred as a ‘sub-Tenon injection’ as opposed to a ‘subconjunctival injection’) is performed with a 25or 27-g, 5/8˝ (16-mm) long needle with the bevel towards the globe in the superotemporal quadrant with a side-to-side circumferential motion of the needle in order to verify not entering the sclera while the patient is looking down and nasally; the

parabulbar injection usually refers to the deposition of the drug preparation posteriorly, in contact with the sclera, with a gently curved blunt cannula through a small conjunctival/Tenon capsule incision 3–5 mm posterior to the corneoscleral limbus.

Another peribulbar injection technique is called the transseptal injection; it is done through the lower lid at the lateral third of the orbital margin; this technique is comparable to the orbital floor injection.

Summary

Subconjunctival dexamethasone injections (2.5 mg dexamethasone) induce 3 times higher vitreous drug concentrations than peribulbar injections (5.0 mg dexamethasone) [5].

Subconjunctival dexamethasone injections (2.5 mg dexamethasone) induce 12 times higher vitreous drug concentrations than oral administration (7.5 mg dexamethasone).

After a subconjunctival injection, the dexamethasone concentration is 11.8 times higher in the aqueous humor than in the vitreous

Periocular injections (either subconjunctival or peribulbar) are not just a local treatment but can result in significant serum levels comparable to those achieved by a single high oral dose.

The choice of the drug to be injected is dictated by the presentation of the uveitis and the risk factors taking into account the anti-inflammatory potency and the duration of action of the CS preparation. A short-acting CS preparation can be injected once a day for 1–5 days because it disappears in less than 24 h. A long-acting CS preparation can be injected several times over a 1- to 3-month interval; it shows a clinical effect in 2–3 days.

Technique, Indications and Contraindications of Intravitreal Corticosteroids

The technique, indications and contraindications of intravitreal CS injections are described in the chapter by Modorati and Miserocchi [pp. 110–121].

Systemic Preparations

Commonly used preparations for systemic CS therapy are presented in order of increasing anti-inflammatory activity in table 5.

Adjunctive therapy

Adjunctive therapy can prevent some adverse effects particularly during prolonged CS treatments. We tend to give it in all patients on CS treatment whatever the duration or the dosage is. It comprises oral potassium and calcium supplementation, oral vitamin D3,

Table 5. Systemic CS preparations

proton pump inhibitors (omeprazole, pantoprazole) or histamine H2-receptor antagonist (ranitidine, cimetidine), antiacids, gastric mucosal coating. One must be aware that bisphosphonates can cause uveitis or episcleritis/scleritis in 0.05–0.08% of the patients.

Systemic CS administration

Systemic CS administration can be considered in noninfectious sight-threatening uveitis, particularly when the disease is bilateral and resistant to local therapy.

Induction Therapy. The induction treatment must be aggressive with high doses. The CS administration can be done either by oral or by intravenous route depending on the severity of the inflammation.

In acute sight-threatening inflammation, intravenous pulse CS are usually administered at a dose of 1 g of methylprednisolone per day for 3 consecutive days followed

by 0.5–1 mg/kg/day oral prednisone depending upon the severity and the vision threat.

In severe subacute or chronic uveitis, one can treat readily the patient with 1.0–1.2 mg/kg/day of oral prednisone without any previous intravenous pulse CS therapy.

The calculation of the dose according to the weight of the patient is not based on scientific randomized studies. It represents a mean to avoid excessive or insufficient dosage in patients of various weight and size. It also facilitates the adjustment of the treatment along the course of the disease. Thus, one should avoid administering the same average dose of 40 mg/day of oral prednisone to every patient whatever their weight and size are.

Discontinuation and Tapering of Therapy. When the maximum improvement of the inflammation is obtained, one can start to decrease the doses progressively. Sometimes, the intolerance to CS requires discontinuing the treatment. The more the period of CS treatment has been prolonged, the slower the tapering should be. If the patient was treated for only brief periods (less than one month), the treatment may be discontinued rapidly within 1–2 weeks. For certain acute exacerbations of chronic uveitis, glucocorticoids may be administered for a shortterm (e.g. for 10–30 days). Administer an initial high dose during the first days of therapy, and then withdraw therapy by tapering the dose over several days.

In contrast, if the CS treatment was administered for a prolonged period of time (more than 1–3 months), one should be very cautious and decrease slowly the doses until complete discontinuation of the CS. This approach will avoid a steroid withdrawal syndrome (of lethargy, fever, myalgia) and a recurrence of the intraocular inflammation with a rebound effect. Many methods of slow withdrawal or ‘tapering’ have been described.

In one suggested regimen, one can decrease by 2–4 mg prednisone equivalent every 3–7 days until the physiologic dose (4–5 mg of prednisone equivalent) is reached.

Other recommendations state that decrements usually should not exceed 2 mg every 1–2 weeks. Generally, the high initial doses of 1 mg/kg/day of prednisone are decreased relatively rapidly by 5–10 mg/day every 10 days until reaching the dose of 20 mg/day of prednisone. Starting from the dose of 20 mg/day of prednisone, we decrease only by 10% the dose of CS at various time intervals (1, 2 weeks or 1 month or more) until the dose of 10 mg/day of prednisone is reached. Thereafter, we taper the dose by only 1 mg per day every 10–30 days depending on the monitoring of the uveitis. In our institution, we tend to take into account the laser flare photometry for the monitoring of anterior uveitis. For posterior uveitis, we consider primarily the visual function (visual acuity, visual fields), the optical coherence tomography (OCT) and the fundus angiogram results. Indeed, OCT is very informative for the macula area but cannot explore the possible resurgence of chorioretinal inflammation at the periphery during the tapering period.

When a physiologic dosage has been reached, a single oral morning dose of 20 mg of hydrocortisone can be substituted for whatever CS the patient has been receiving. It is recommended to previously check the plasma cortisol levels (at 8.00 a.m. and at 4.00 p.m.), although they are not constantly a reliable indicator of the hypothalamic- pituitary-adrenal axis function. After 2–4 weeks, you may decrease hydrocortisone dosage by 2.5 mg every week until a single morning dosage of 10 mg daily is reached.

In fact, the rate of tapering is dependent upon the disease activity. As there is no validated ‘disease activity scoring’ system, one should monitor very closely the patient and rely on a set of criteria based on clinical examination and ancillary tests (see further on). The importance of each criterion varies according to the type and severity of the uveitis.

Corticosteroid Dependence. If the intraocular inflammation recurs during the progressively slow tapering of the CS treatment before the complete discontinuation of the CS treatment, particularly if the patient has experienced the same event in the past, one must consider the uveitis as CS dependent. If the threshold needed for controlling the uveitis is above 10 mg/day of prednisone, a CS-sparing agent must be proposed in order to avoid the toxicity of a prolonged CS therapy. If the threshold is below 9–10 mg/day of prednisone, one can consider administering sustained lowdose CS for a prolonged period of time if the treatment is indispensable to maintain a good visual function and to control the intraocular inflammation. This approach must be reevaluated every 6 months with a novel attempt to lower the doses. One can maintain tolerable very low dose CS therapy for several years only if the patient needs less than 7 mg/day of CS. If the uveitis necessitates more than 7 mg/day of prednisone after one year of treatment, one should definitely add a CS-sparing agent.

It must be remembered that one should not wait too long before proposing a combined therapy with a CS-sparing agent. This should be done before the development of CS-induced side effects. Different types of immunomodulatory drugs can be administered in combination with CS. Their choice will depend on the association with extraocular manifestations, the type, the course and the severity of the uveitis.

Corticosteroid Resistance. The uveitis can be ‘CS resistant’. High doses of CS cannot control the intraocular inflammation either during the induction treatment or during the tapering of the CS doses. If the inflammation does not respond to the initial intense CS doses (1–1.2 mg/kg/day of prednisone or pulse i.v. methylprednisolone) or to less than 0.5 mg/kg/day during the tapering phase, the uveitis is considered as resistant to CS therapy. A novel workup must be performed, and may be repeated several times in order to exclude an infection or a masquerade syndrome. If a primary intraocular lymphoma is suspected, the CS treatment must be discontinued several weeks before ocular fluid analysis (IL-10 levels in the aqueous humor and in the vitreous, identification of malignant lymphoma cells in the vitreous, gene rearrangement analysis). The exclusion of an infection or a masquerade syndrome is mandatory before starting any immunomodulating treatment.