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

Indeed, one can also note that some CS-resistant noninfectious uveitis may be responsive to immunomodulatory therapy alone. The absence of response to CS treatment does not preclude the response to immunomodulation. This can justify why, in certain disease entities, the immunomodulatory therapy must be started very early during the course of the uveitis. It is the case in severe noninfectious uveitis associated with extraocular manifestation such as Behçet’s disease, or in severe isolated intractable noninfectious uveitis (without systemic inflammatory manifestations) such as birdshot chorioretinopathy.

Alternate-Day Therapy. Alternate-day therapy in which a single dose is administered every other morning is the dosage regimen of choice for long-term oral CS treatment of most conditions. This regimen provides relief of symptoms while minimizing adrenal suppression, protein catabolism, and other adverse effects such as growth retardation. Although an alternate-day dosage regimen is generally insufficient to control long-standing noninfectious uveitis, it can be tempted and proposed in childhood uveitis in order to minimize the incidence of adverse effects, particularly growth retardation. Most authorities consider only a ‘short-acting’ glucocorticoid that suppresses the hypothalamic-pituitary-adrenal axis less than 1.5 days after a single oral dose (e.g. prednisone, prednisolone, methylprednisolone) to be suitable.

Practical Therapeutic Utilization

General Considerations

CS-intensive induction treatment permits to overcome a difficult threatening phase during the course of the disease. A prolonged maintenance treatment with lower doses is often needed.

As for significant intraocular inflammation, one must always initiate an intensive treatment from the onset of the disease instead of beginning with moderate doses and increase them progressively. Indeed, it is important to control as rapidly as possible the inflammation to avoid irreversible tissue alteration secondary to inflammation and to prevent devastating tissue destruction and scarring. This approach will also shorten the duration of the treatment and decrease the cumulative doses of drug and therefore the risk of developing severe side effects. Moreover, this strategy is clinically valid for infectious (anti-infectious drugs) as well as for noninfectious/autoimmune inflammatory diseases (CS).

Evidently, an aggressive CS therapy cannot be initiated without excluding an infectious etiology. If a doubt still persists on the noninfectious nature of the disease, one should not start CS therapy before administering (several days before beginning the CS treatment) an anti-infectious treatment presumed to cover the suspected infectious etiology. This is the case in self-evolving inflammatory processes following/ accompanying an initial infectious trigger in which disease activity can be exacerbated

Posterior uveitis/intermediate uveitis

Bilateral: disease

activity score?

Unilateral

Fig. 2. Corticosteroids: therapeutic strategies (2).

or reactivated by systemic CS alone (toxoplasmosis, Lyme disease, hypersensitivity to

Mycobacterium tuberculosis proteins for example).

Therapeutic Strategies

Therapeutic strategies are summarized in figures 1–5. The therapeutic decision depends upon the type, the uni-/bilaterality and the course of the uveitis.

It is difficult to standardize the management of uveitis in general because of the lack of a validated ‘disease activity score’ particularly for posterior uveitis. Most of the therapeutic regimens are given according to the physician’s clinical judgment. There is no standard treatment because of the heterogeneity of clinical responses for the ‘same’ apparent disease. However, it is still important to base the therapeutic adjustment on objective criteria. We used a combination of factors: clinical examination, laser flare photometry, OCT, fundus angiograms (fluorescein and indocyanine green), visual fields. Obviously, the visual acuity must not be the only criteria.

In most of the cases, a unilateral anterior uveitis can be treated locally by drops and subconjunctival CS injections which induce higher aqueous humor CS concentrations than peribulbar/parabulbar CS injections. Although it can induce significant CS serum levels on a short-term, the local treatment causes much less side effects than a systemic CS administration. When the uveitis is unilateral, it is very important to exclude an infectious etiology before any CS application (fig. 1, 2). The physician may decide to give a systemic treatment if she/he considers that the intraocular inflammation is not efficiently controlled by the local treatment and in the case of accompanying extraocular manifestations of a systemic disease. In severe bilateral anterior

Fig. 3. Corticosteroids: therapeutic strategies (3). FA = Fluorescein angiography; ICG-A = indocyanine green angiography; IMT = immunomodulatory treatment; MTX = methotrexate; AZA = azathioprine; MMF = mycophenolate mofetil; CSA = cyclosporine; IFN = interferon; IvIg = intravenous immunoglobulins.

Chronic ant./posterior uveitis/retinitis/choroiditis

Resistance to CS

Anterior chamber tap/diagnostic vitrectomy

PCR and LAP

Culture and PCR

(viruses, parasites)

(bacteria)

Fig. 4. Corticosteroids: therapeutic strategies (4). LAP = Local Antibody Production.

Uveitis

Fig. 5. Corticosteroids: therapeutic strategies (5).

uveitis, a bilateral intensive local treatment is rapidly efficient most of the time, but a combination of local and systemic CS treatment is often used in order to shorten the duration of such a disabling condition.

Unlike bilateral anterior uveitis, one tends to use more often a systemic therapeutic approach for bilateral posterior uveitis rather than a bilateral local treatment (fig. 2). In posterior uveitis, which are more often chronic and long-standing than anterior uveitis (there are exceptions such as in juvenile idiopathic arthritis for example, even though the anterior uveitis can be controlled with topical CS and rarely needs periocular CS injections), it is difficult to repeat bilateral periocular injections for a prolonged period of time. The systemic treatment has also the advantage of modifying the immune and inflammatory response upstream of the eye itself by a direct action on the general immune system. Local treatments are acting only at the end of the chain, although, as already said, a periocular CS injection can induce CS serum levels equivalent to an oral systemic administration.

If the intraocular inflammation is resistant to a proper CS treatment, one must again rule out an underlying infection or a masquerade syndrome before proceeding with immunomodulation (fig. 3, 4). Ocular fluid analysis is very helpful for excluding an infection (local antibody production, PCR, culture).

The therapeutic approach is different according to the course of the disease (fig. 5). During a sight-threatening acute attack, we tend to use the intravenous route (pulse i.v. methylprednisolone or i.v. anti-TNF agents), although there is no evidence that pulse i.v. CS give a better outcome than high-dose oral CS. However, the clinical impression is that the intraocular inflammation seems to subside more rapidly after i.v. pulse than oral CS.

During the chronic stage of a long-standing non-infectious uveitis, the minimum CS treatment must be administered. The goal is to determine the CS threshold needed to control the intraocular inflammation. If the threshold is too high, above 7 mg/day of prednisone, an immunomodulatory therapy must be added. For unilateral uveitis, a repeated local treatment should be favored knowing that the adjunction of a lowdose systemic therapy can sometimes decrease the frequency and the dosing of the local treatment.

New therapeutic approaches [corticosteroid intravitreal devices and implants; see the chapter by de Smet, pp. 122–133] are now available for treating noninfectious uveitis locally, avoiding the severe adverse effects of a systemic treatment. Those novel methods are particularly interesting in unilateral cases without extraocular manifestations.

Adverse Effects of Corticosteroid Therapy

CS associated adverse effects are dependent on both the average dose and the duration of therapy. Even low-dose CS therapy could lead to serious adverse effects [6].

Ocular Side Effects of Corticosteroid Treatment

General Considerations

Ocular side effects following systemic administration include [7]: posterior subcapsular cataract (cataracts 15%, and fractures 12% were among the most serious adverse effects of long-term CS therapy), increased IOP/glaucoma, increased susceptibility to infection, reactivation of viral diseases (i.e. herpes group), impaired corneal wound healing, corneal/scleral thinning, subconjunctival hemorrhage, myopia, proptosis, diplopia, extraocular muscle paresis, ptosis, eyelid edema, visual hallucinations, abnormal electroretinogram/visual evoked potential, optic disc edema, central serous chorioretinopathy, iris/ciliary body microcysts.

The threshold for the increase in IOP was observed at dosages of over 7.5 mg/ day of prednisone. A very low threshold was observed for eye cataract (<5 mg/day of prednisone).

Ocular side effects following topical or periocular administration are: cataract, increased IOP/glaucoma (a patient’s negative response to topical steroids does not predict the response to periocular steroids), increased susceptibility to infection, impaired corneal/scleral wound healing, corneal/scleral thinning, subconjunctival hemorrhage/ hematoma, superficial punctate keratitis, corneal deposits, paresis of accommodation, extraocular muscle paresis, ptosis, strabismus, accidental intraocular injection.

Ocular side effects following intravitreal injections include [for more details, see the chapter by de Smet, pp. 122–133]: pain, impaired visual acuity/floaters, elevated

IOP/glaucoma is frequent (>50%), retinal/vitreous hemorrhage, retinal tear/detachment, endophthalmitis, elevated risk of infectious retinitis.

Whatever the route of CS administration is, the two main frequent issues are the rise in IOP and the development of cataract.

Intraocular Pressure Elevation

CS have been shown to cause an elevation in IOP through all modes of administration. The rise in IOP usually occurs over a period of 4–7 weeks if used topically and months or years if used systemically. There have been some reports of an elevation of IOP within hours of initiating intensive topical steroid use.

Some modes of administration can be discontinued easily, thereby reducing or reversing any untoward effects on IOP. Other modes of administration, however, such as sub-Tenon’s, or intravitreal injections, are not as easily reversed if problems arise.

‘Steroid responder’ patients represent 5–6% of the normal population; they develop a marked increase of IOP of more than 16 mm Hg after 4–6 weeks of topical steroid administration, while 30% of the population have a rise of 6–15 mm Hg. Monitoring IOP in all patients receiving steroids is necessary. Once the steroids have been stopped, the IOP almost always returns to baseline within 4 weeks [8–10].

A sub-Tenon injection of a CS preparation with depot effect induces much more frequently an elevation of the IOP than when using a non-depot CS preparation. A rise in IOP ≥5 mm Hg was found in 46% of the eyes, and an IOP >21 mm Hg was found in 30% of the eyes after a single injection of triamcinolone. The IOP increased within 3 months in 81% of the eyes and after 4 months in 19% of the eyes. The IOP began to increase significantly from 2 weeks up to 5 months and returned to the baseline IOP in 10 months. The incidence of IOP elevation ≥5 mm Hg or an IOP of >21 mm Hg after multiple sub-Tenon injections of triamcinolone was significantly higher than after a single injection (62 and 47%, respectively) [11]. IOP elevation occurs in 21% of the patients after sub-Tenon triamcinolone injections for noninfectious uveitis with a clinical improvement in 52% of the cases [12].

CS-induced glaucoma is more frequent in some patients: children, elderly, patients with higher baseline IOP, patient or family history of primary open angle glaucoma, high myopia, diabetes mellitus, connective tissue disease, traumatic angle recession glaucoma, Cushing’s syndrome, high doses of subtenon CS injection [13, 14].

Management consists of discontinuation of steroids, medical therapy and/or surgical intervention. Recent studies showed that prostaglandin analogs may be used in uveitic glaucoma patients [15].

IOP elevation is related to steroid type, potency, dose, duration and route of administration. The steroid types inducing glaucoma are in ascending order: medrysone, hydrocortisone, fluorometholone, rimexolone, prednisolone/prednisone, dexamethasone/betamethasone. The routes of administration inducing glaucoma are in

ascending order: systemic, topical, subtenon (depot preparation), subconjunctival (depot preparation), intravitreal (depot preparation).

Corticosteroid-Induced Cataract Formation

The incidence of posterior subcapsular cataract is related to the duration and the dose of CS therapy. If the patient was treated less than one year, there was no CSinduced cataract whatever the dose of CS treatment was (even for doses as high as 60 mg/day of prednisone). During CS treatment lasting between 1 and 4 years, doses below 10 mg/day of prednisone did not induce cataract formation. The incidence of cataract formation increased to 11% for doses between 10 and 15 mg/day of prednisone and to 78% for doses above 16 mg/day of prednisone. If low-dose CS treatment ≥3 mg/day is prolonged more than 4 years, the incidence of cataract is 83% [16].

The incidence of cataract formation after one subtenon triamcinolone injection varies from 2.1 to 18% within 12 months following the injection depending on different series [17, 18].

In children with juvenile idiopathic arthritis-related uveitis, the chronic use of topical CS dosed at ≤3 drops daily was associated with an 87% lower risk of cataract formation compared with eyes treated with >3 drops daily independently of uveitis activity [19].

Nonocular Side Effects of Corticosteroid Treatment

The nonocular adverse effects of CS therapy are as outlined below.

Fluid and electrolyte disturbances: Sodium retention, fluid retention, congestive heart failure in susceptible patients, potassium loss, hypokalemic alkalosis, hyperosmolar coma, hypertension. We recommend a salt-free diet above 10 mg/day of oral prednisone.

Musculoskeletal: Muscle weakness, steroid myopathy, loss of muscle mass, osteoporosis, vertebral compression fractures, aseptic necrosis of femoral and humeral heads, pathologic fracture of long bones, tendon rupture. Risk of osteoporosis on long-term CS is as follows: prednisone 1–5 mg: relative risk 1.9×; prednisone 5–10 mg: relative risk 4.5×; prednisone >10 mg: relative risk 32×.

Recommended lifestyle measures from day 1 of CS treatment: smoking cessation, weight-bearing and strength-building exercises, calcium intake of 1,000–1,500 mg per day, vitamin D 800–1,000 IU/day.

Bisphosphonates are effective and recommended, but one must be aware that they can induce anterior uveitis and episcleritis/scleritis in rare cases.

Gastrointestinal: Peptic ulcer with possible subsequent perforation and hemorrhage of small and large bowel; pancreatitis; abdominal distention; ulcerative esophagitis; nausea; increased appetite.

Dermatologic: Impaired wound healing, thin fragile skin; petechiae and ecchymoses; facial erythema; increased sweating; may suppress reactions to skin tests.

Neurological: Convulsions; increased intracranial pressure with papilledema (pseudotumor cerebri) usually after treatment; vertigo; headaches; insomnia.

Psychiatric effects: Patients and/or carers should be warned that potentially severe psychiatric reactions may occur. Symptoms typically emerge within a few days or weeks of starting treatment. Most reactions recover after either dose reduction or withdrawal, although specific treatment may be necessary. Patients and/or carers should be encouraged to seek medical advice if worrying psychological symptoms develop, especially if depressed mood or suicidal ideation is suspected. Particular care is required when considering the use of CS in patients with existing or previous history of severe affective disorders. Psychic derangements range from euphoria, insomnia, mood swings, hyperexcitability, personality changes and severe depression to frank psychotic manifestations.

Endocrine: Menstrual irregularities; development of cushingoid state; suppression of growth in children; secondary adrenocortical and pituitary unresponsiveness, particularly in times of stress, as in trauma, surgery, or illness; decreased carbohydrate tolerance; hirsutism; manifestations of latent diabetes mellitus; increased requirements for insulin or oral hypoglycemic agents in diabetics. We recommend a diet without quick-burning sugars.

Metabolic: Negative nitrogen balance due to protein catabolism; centripetal obesity. Immunologic: Impaired inflammatory response.

Other: Weight gain; hypertension; thromboembolism.

The following additional adverse reactions are related to parenteral and intralesional corticosteroid therapy: rare instances of blindness associated with intralesional therapy around the face and head; hyperpigmentation or hypopigmentation; subcutaneous and cutaneous atrophy; sterile abscess; anaphylactoid reactions have been rarely reported.

High-Risk Group of Patients

Pregnancy

CS have been shown to be teratogenic in many species when given in doses equivalent to the human dose. Animal studies in which CS have been given to pregnant mice, rats, and rabbits have yielded an increased incidence of cleft palate in the offspring. There are no adequate and well-controlled studies in pregnant women. CS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Infants born to mothers who have received CS during pregnancy should be carefully observed for signs of hypoadrenalism. The final decision depends on the benefit/risk ratio and should be discussed with the patient’s gynecologist.

Use in Lactation

CS appear in breast milk and could suppress growth, interfere with endogenous CS production or cause other unwanted effects in breastfed infants. Women taking CS should be advised not to breastfeed.

Use in Children

CS cause growth retardation in infancy, childhood and adolescence, which may be irreversible and therefore long-term administration of pharmacological doses should be avoided. If prolonged therapy is necessary, treatment should be limited to the minimum suppression of the hypothalamo-pituitary adrenal axis and growth retardation, the growth and development of infants and children should be closely monitored. Treatment should be administered when possible as a single dose on alternate days. Children are at special risk from raised intracranial pressure.

Use in the Elderly

Long-term use in the elderly should be planned bearing in mind the more serious consequences of the common side effects of CS in old age, especially osteoporosis, diabetes, hypertension, hypokalemia, susceptibility to infection and thinning of the skin. Close medical supervision is required to avoid life-threatening reactions.

Conclusion

CS are considered to be the mainstay of therapy in noninfectious uveitis. Their indications depend upon numerous factors, among them the type (involving or not the posterior segment), the severity, the uni-/bilaterality, the chronicity of the intraocular inflammation. CS should not be used at high doses as a sole treatment in the long-term because of severe adverse effects. The goal is to find, for each individual patient, the minimum CS dose necessary for controlling the intraocular inflammation. If the threshold of CS dependence is too high, an infectious origin has to be considered and must be excluded again by a novel complete workup. The exclusion of an infection and of a masquerade syndrome is mandatory before starting an immunomodulating treatment for sparing the CS dosage. Although CS administration by various routes is the first line of therapy for noninfectious uveitis, it cannot remain the sole prolonged treatment in long-standing diseases in the majority of the cases.

Combining immunomodulating agents with low-dose CS is the preferred regimen for controlling intraocular inflammation with a minimum of side effects when longterm therapy is needed.

Phuc LeHoang

Department of Ophthalmology University of Paris VI Pitié-Salpêtrière Hospital

83 Boulevard de L’Hôpital FR–75013 Paris (France)

E-Mail phuc.lehoang@psl.ap-hop-paris.fr