Treatment of Uveitis

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Uveitis are an important cause of impaired vision and reduced vision-related quality of life in both developed and developing countries. Understanding their etiology and clinical manifestations is important for establishing the correct anatomical diagnosis, identify underlying etiology, and defining treatment strategies. The following article summarizes the treatment strategies in uveitis.

Contents

Introduction

Appropriate management of a patient with uveitis begins with a careful clinical history collection and comprehensive ophthalmic examination, in order to determine likely etiologies, identify potential prognostic factors, and define the most appropriate therapeutic strategy. Systemic evaluation is usually indicated for bilateral acute anterior uveitis, recurrent anterior uveitis, granulomatous anterior uveitis, intermediate or posterior uveitis, or any atypical clinical presentation.

Treatment strategies for uveitis will depend on the anatomic location of inflammation (i.e., anterior vs intermediate vs posterior vs panuveitis), clinical disease severity, disease duration, and likely etiology. Uveitis-related complications also warrant specific therapeutic approaches. Finally, patient comorbidities must also be taken into account, considering possible contra-indications for different classes of drugs.

General Principles of Treatment of Uveitis – Goals of treatment

The treatment of uveitis is ultimately to achieve the following goals[1]:

  • Relief of symptoms,
  • Minimizing sequels,
  • Prevention of irreversible vision loss,
  • Prevention of recurrence,
  • Limit the side effects of drug therapies.

Acute Anterior Uveitis

General principles of treatment

Most patients with acute anterior uveitis (AAU) benefit from measures to control inflammation and to prevent sequelae from inflammation. In patients with a treatable cause of inflammation, specific treatment is either given instead or in addition to general measures.

Therapy for AAU can be divided in ocular and systemic treatments.

Ocular treatments

Topical Cycloplegics

Cycloplegic agents (e.g. tropicamide 1% q.i.d., cyclopentolate 1% t.i.d., atropine b.i.d.) are often prescribed in any case of AAU and in exacerbations of chronic anterior uveitis (CAU); they are usually given according to the severity of inflammation. In the acute stage, phenylephrine 2.5% or 10% can be used as an adjunctive drug.

The clinical usefulness of cycloplegic agents in AAU is due to[2]:

  • Symptomatic relief of pain and photophobia, by preventing ciliary muscle paralysis and pupillary muscle spasm;
  • Prevention of formation of synechiae and/or synechiolysis. In the presence of extensive posterior synechiae (PS), frequent instillation at presentation may be given to rapidly break the PS. This may be useful in order to allow more detailed assessment of the fundus by allowing more mydriasis to occur.


Shorter acting agents tend to make the pupil move more than longer acting agents; in addition, longer acting agents may result in the formation of synechiae in a dilated state, with associated risk of iris bombé.

Topical corticosteroids

Topical corticosteroids (CS) penetrate the posterior segment phakic eyes poorly, and their use is thus primarily in the setting of anterior uveitis and for the management of the anterior component of panuveitis. Posology of eye drop instillation must take into account disease severity and chronicity.

Generally, steroid therapy should be given in high doses initially and then slowly tapered according to clinical evolution[3]:

  • Mild inflammation: can be managed with a topical CS q6h (e.g. prednisolone acetate 1% or dexamethasone 0.1%);
  • Moderate to severe uveitis: topical CS q1-2h dosing initially (e.g. prednisolone acetate 1%, dexamethasone 0.1%), and a CS ophthalmic ointment can be given at night;
  • In cases of severe uveitis, a loading dose can be considered (e.g. prednisolone acetate 1% q1min for 5 minutes, then q30min-1h).


A commonly adopted regimen might consist of [2]:

  • One drop q1h for 3 days, then
  • One drop q2h for 3 days, then
  • One drop q6h for 3 days, then
  • One drop q8h for 7 days, then
  • One drop q12h for 7 days, then
  • One drop q.d. for 7 days, then stop.


Several CS exist in topical ocular formulations, and each has unique pharmacologic and pharmacokinetic properties that may provide advantages and disadvantages in specific clinical scenarios.

Relative potencies of CS must also be taken into account, given the safety profile of these drugs and the risks of ocular and systemic complications derived from the use of CS. Relative potencies of CS are established compared to the reference of hydrocortisone; CS are presented in decreasing order of relative potency in the table below:

Relative potencies of corticosteroids
Corticosteroid Systemic Equivalent (mg) Relative Potency

Bethamethasone

0.6

33.0

Dexamethasone

0.75

26.0

Methylprednisolone

4

5.0

Triamcinolone

4

5.0

Prednisolone

4

5.0

Prednisone

5

4.0

Hydrocortisone

20

1.0

Cortisone

25

0.8

Side effects

Side effects from topical CS are the same for any ocular or systemic CS, although the risk of side effects is related to administration route and relative potency of the drugs:

  • Cataract, usually a posterior subcapsular cataract (PSC);
  • Elevation of intra-ocular pressure (IOP) and glaucoma: up to 30% of CS-treated patients may develop IOP increases, which may be transient and resolve after discontinuation of the drug, or may lead to persistent IOP elevation and development of steroid-induced glaucoma or progression of previous glaucoma. Steroid-induced glaucoma is a form of open angle glaucoma.[4][5]


Risk factors

Risk of steroid-induced glaucoma is related to both patient and drug factors[5]:

Patient factors
  • primary open-angle glaucoma,
  • high myopia,
  • post-keratoplasty,
  • post-keratorefractive surgery,
  • very young patients or elderly patients,
  • diabetes mellitus,
  • connective tissue diseases,
  • pigment dispersion syndrome,
  • traumatic angle recession,
  • endogenous hypercortisolism.
Drug factors
  • steroid potency,
  • duration of administration,
  • route of administration.
  • Secondary infection,
  • Reactivation of herpes keratitis,
  • Corneal melting/perforation,
  • Systemic side effects are rare with topical CS.

Topical aqueous humor suppressants

Most cases of anterior uveitis are characterized by low IOP secondary to ciliary body hyposecretion. However, elevated IOP can occur – hypertensive uveitis (e.g., herpetic, lens-induced, Fuchs heterochromic iridocyclitis, Posner-Schlossman syndrome). In these cases, AH suppressants (e.g., timolol eyedrops 0.5% b.i.d., brimonidine tartrate 0.2% b.i.d. to t.i.d., dorzolamide eyedrop 2% b.i.d. to t.i.d.) are indicated to reduce IOP.

Although it remains a controversial topic, prostaglandin analogues are not typically prescribed due to potential risk of exacerbating inflammation, reactivation of herpetic keratouveitis, and macular oedema. Pilocarpine should also be avoided due to miosis and increased risk of PS and cataract formation.


Periocular corticosteroids

In cases of severe uveitis, unilateral uveitis, and uveitis not responding to topical CS, periocular repository CS should be considered[3]:

  • Subconjunctival betamethasone sodium phosphate solution (4 mg in 1 mL) alone or in combination with betamethasone acetate suspention (Celestone, 6 mg in 1 mL),
  • Subtenon triamcinolone (0.5 to 1.0 mL subtenon injection of triamcinolone acetonide 40 mg/mL).


Below are shown some of the clinical scenarios where periocular steroids might be considered:

  • Severe unilateral anterior uveitis,
  • Anterior uveitis with hypopyon,
  • Anterior uveitis complicated by cystoid macular oedema (CMO),
  • Adjunctive treatment in association with topical or systemic CS,
  • Contraindications for systemic steroid treatment,
  • Poor patient compliance to topical medications posing a likely factor for unresponsiveness to topical treatment.

Subtenon steroid injection

The procedure for subtenon steroid injection can be an inferior transseptal (“orbital floor”) injection or a posterior subtenon approach[2]:

Inferior transseptal injection
  1. Topical anaesthesia (e.g., tetracaine),
  2. Disinfection of the skin of the lower eyelid and maxillary area (e.g., povidone-iodine 5%),
  3. Shake the vial containing the steroid,
  4. Draw 1 mL steroid (triamcinolone acetonide or methylprednisolone acetate 40 mg/mL) into a 2 mL syringe,
  5. Replace the drawing-up needle with a 25-gauge needle,
  6. Instruct the patient to look straight ahead,
  7. Insert the 25-gauge needle through the skin at the junction of the other third and the inner two-thirds of the lower orbital rim, entering close to the bony margin whilst clearing the margin itself (Note: some authors inject via the conjunctiva),
  8. Advance the needle slowly and tangentially to the globe,
  9. Slightly withdraw the plunger to ascertain no blood enters the syringe, and inject the full 1 mL of steroid in a slowly fashion,
  10. Withdraw the needle carefully.
Posterior Subtenon approach
  1. Topical anaesthesia,
  2. Place a small cotton pledget impregnated with an anaesthetic agent (e.g., tetracaine, lidocaine 2% gel) in the superior fornix at the site of injection for 2 minutes,
  3. Shake the vial containing the steroid,
  4. Draw 1 mL steroid (triamcinolone acetonide or methylprednisolone acetate 40 mg/mL) into a 2 mL syringe,
  5. Replace the drawing-up needle with a 25-gauge needle,
  6. Instruct the patient to look in the nasal inferior direction (i.e., the direction opposite to the superotemporal injection site),
  7. Penetrate the bulbar conjunctiva with the needle tip, bevel towards the eye globe,
  8. Slowly insert the needle posteriorly, following the contour of the globe, making side-to-side motions to prevent globe penetration,
  9. Slightly withdraw the plunger to ascertain no blood enters the syringe, and inject the full 1 mL of steroid in a slowly fashion,
  10. Withdraw the needle carefully.


It should be noted that periocular use of triamcinolone is off-label, and thus should be discussed with patients[3]. Periocular steroids may be associated with the highest risk for development of steroid-induced glaucoma.

Complications

Complications of periocular steroids are related to the procedure itself or related to the drug, and include:

  • Subconjunctival or retrobulbar hemorrhage,
  • Eye globe perforation,
  • Optic nerve injury,
  • Cutaneous changes,
  • Orbital fat atrophy,
  • Cataract,
  • Steroid-induced glaucoma,
  • Scleral melting, particularly in patients with scleritis,
  • Retinal vascular occlusive disease.

Intracameral tissue plasminogen activator (tPA)

In severe fibrinous anterior uveitis, intracameral tPA may be administered intracamerally (12.5-25 μg t-PA in 0.1 mL) to dissolve dense fibrinous exudate, and to break down freshly formed PS[2].

Intravitreal steroids (IVS)

In cases of anterior uveitis complicated by CMO, intravitreal steroids may be used, including triamcinolone acetonide (IVTA) and slow-release intravitreal implants. However, the main use of IVS for uveitis has been in the treatment of non-infectious posterior uveitis, as discussed below.

Systemic therapy

Non-steroidal anti-inflammatory drugs (NSAIDs)

As a primary treatment modality for ocular inflammatory diseases, NSAIDSs are generally ineffective in both local and systemic formulations; an exception might be some cases of non-necrotizing anterior scleritis[1]. In addition, NSAIDs might provide some utility as an adjunct to other forms of therapy, such as the topical formulation the treatment of macular oedema, as discussed below.

Oral NSAIDs should not be used concurrently with oral CS due to increased risk of gastric ulceration.

Systemic corticosteroids

Systemic CS therapy is usually not necessary in AAU, but may be necessary in some clinical scenarios[3]:

  • Failure of local treatment on maximal topical and repository steroids,
  • Bilateral, severe anterior uveitis,
  • CAU,
  • Panuveitis.


Treatment should consist of high dosage initially and then tapering according to clinical effects. Initial dosing can be 1.0 to 1.5 mg/kg body weight/day of prednisolone, and maintenance doses may be 10-20mg/day or as low a dose as possible.

When the duration of CS therapy exceeds two weeks, then a gradual taper is instructed because of adrenal suppression. Too rapid tapering or early discontinuation of systemic CS may lead to disease recurrence[1].

Systemic CS are associated with several side effects, including:

  • Ocular side effects: cataract, hypertension/glaucoma,
  • Systemic side effects:
    • Hydroelectrolytic imbalances (fluid retention),
    • Gastrointestinal (peptic ulcer disease),
    • Dermatologic (pigmentary skin changes),
    • Neurologic,
    • Musculo-skeletal (myopathy, osteoporosis),
    • Cushing syndrome,
    • Diabetes,
    • Thromboembolic risk.


Patients on long-term steroid treatment should receive calcium and vitamin D supplementation to prevent osteoporosis, and usually proton-pump inhibitors are also prescribed to reduce the risk of peptic ulcer disease.

Immunomodulation drugs

Although the majority of cases of anterior uveitis do not generally require the use of immunosuppressants, some cases may need treatment with these type of drugs, which will be discussed later in further detail:

  • Steroid-dependent patients with CAU: steroid-dependence may be defined as the continuous need for systemic steroid treatment to prevent disease recurrence,
  • Steroid-resistant patients: patients who require large doses of CS to prevent disease recurrence or who are clinically unresponsive to CS therapy,
  • Patients with contraindications to oral CS,
  • Specific causes of anterior uveitis (e.g. juvenile idiopathic arthritis associated uveitis, inflammatory bowel disease associated uveitis).


Intermediate and Posterior Uveitis

Treatment of intermediate (IU) and posterior uveitis should be directed at the cause, if one is detected. Malignancy and infection must be ruled out before initiating nonspecific anti-inflammatory therapy.

Patients must also undergo screening for comorbidities that may preclude use of certain drugs, including evaluation of liver function, haematological status, and renal function.

It must be noted that not all IU patients require treatment: some 25% to 35% of patients with pars planitis have mild disease, no macular edema or other complications, and good vision, and do not need treatment, as these patients may maintain good vision with up to 10 years of follow-up [6]. However, when treatment is needed, the goal is complete suppression of the inflammation (i.e., to “grade 0” inflammation).

Intermediate Uveitis

Traditionally, a stepladder approach has been the most widely adopted strategy in the treatment of non-infectious IU, with CS therapy being the mainstay of treatment.[7][8] A four-step approach was firstly described by Kaplan in 1984 and consisted of: 1. Periocular corticosteroid (CS) injections followed by oral prednisone if considered ineffective, 2. cryotherapy or LASER photocoagulation, 3. pars plana vitrectomy and 4. immunosuppressive treatment. However, this approach is no longer recommended, as ophthalmologists have more experience with the use of immunosuppressive agents and new biological treatments. Currently preferred strategy places steroids as the mainstay of initial treatment, as follows:

  1. Corticosteroids:
    • Periocular CS (e.g., subtenon injection of 0.5-1.0 mL of triamcinolone acetonide 40 mg/mL) are beneficial in patients with unilateral or asymmetric involvement and in the presence of macular edema. Injections can be repeated every 6 to 8 weeks until the vision and macular oedema have stabilized [3]; at least 2 or 3 injections are suggested before considering this modality ineffective;
    • Intravitreal steroids (intravitreal triamcinolone acetonide, slow-release dexamethasone implant, sustained-release fluocinolone acetonide implant);
    • Systemic CS: patients with bilateral disease, severe ocular inflammation, or unilateral disease unresponsive to periocular steroids should be treated systemically (e.g., prednisone 1.0-1.5 mg/ kq body weight/day per os for 4-6 weeks, with gradual tapering according to the patient’s response;
  2. Immunosuppressive therapy: Immunosuppressants are considered a second step in patients for long-term treatment;
  3. Anti-tumor necrosis factor- α (Anti-TNF-α) agents: Anti-TNF-α agents may be used successfully as the third step in patients not responding to conventional immunosuppressive agents, although no study exists directly addressing the use of these drugs in non-infectious IU;
  4. Pars plana vitrectomy (PPV).


Intermediate and Posterior Uveitis Treatment: Drug Classes in the Management of Noninfectious Uveitis (NIU)

Systemic therapy

Systemic therapy for control of inflammation in noninfectious uveitis (NIU) has shown benefits both clinically and in clinical trials. The Multicenter Uveitis Steroid Treatment (MUST) Trial and the Follow-up Study [9] demonstrated that systemic therapy (including CS-supplemented immunomodulatory therapy and biologic agents) improved visual outcomes, controlled inflammation, and reduced macular oedema similarly to local treatment using sustained-release intravitreous fluocinolone acetonide implant in patients with IU, posterior uveitis, or panuveitis. The implant was slightly better for the first 5 years, after which they were similar with uveitis control in 87% of patients at 7 years. Data from the MUST studies suggest that oral corticosteroids and immunosuppression can be administered relatively safely for at least 7 years.

Interestingly, a Cochrane systematic review was unable to conclude that the implants are superior to traditional systemic therapy for the treatment of non-infectious uveitis, and findings regarding safety outcomes suggest increased risks of post-implant surgery for cataract and high intraocular pressure compared with standard-of-care systemic therapy including CS.[10]

The long-term safety of immunosuppression was addressed by the SITE Cohort Study, which evaluated 9250 patients with ocular inflammation with up to 30 years of follow-up. Alkylating agents did not have a significantly increased risk of overall mortality but had a borderline significant increased risk of cancer-related mortality. They found no increased malignancy risk with antimetabolites or calcineurin inhibitors in patients without an inherent increased risk, nor increased risk of mortality or cancer mortality.[6]


Corticosteroids

Systemic CS have long been regarded as a mainstay of therapy for noninfectious uveitis (NIU).

Treatment should consist of high dosage initially and then tapering according to clinical effects. Initial dosing can be 1.0 to 1.5 mg/kg body weight/day of prednisolone, and maintenance doses may be 10-20mg/day or as low a dose as possible; for chronic diseases, the target dose is < 7.5 mg/day.[6]

A typically adopted steroid tapering schedule is as follows[6]:

Prednisone dose (mg/day) Decrement (mg/day) Taper Interval
RAPID STANDARD
60-30 10 2 DAYS WEEKLY
30-15 5 2 DAYS WEEKLY
15-7.5 2.5 2 DAYS WEEKLY
< 7.5 2.5-1 2-7 DAYS WEEKLY-MONTHLY

Although systemic CS play a major role in treatment of NIU, their long term use is limited by their predictable and serious side effect profile. As mentioned above, side effects from oral CS include: ocular side effects (cataract, hypertension/glaucoma) and systemic (hydroelectrolytic, gastrointestinal, dermatological, neurological, musculo-skeletal, endocrinological, cardiovascular).

Contraindications to CS therapy include behavioural patterns (associated with risk of noncompliance), health-related factors, and reproductive status.

Noncorticosteroid immunomodulatory therapy (NCSIT)

Although few treatments have been approved for the indication of uveitis treatment, treatment with systemic noncorticosteroid immunomodulatory therapy (NCSIT) and biologic agents has become increasingly widespread in cases of uveitis not controlled with CS therapy alone.

The Fundamentals of Care for Uveitis (FOCUS) global Initiative group[11] organized a consensus through evidence synthesis on the optimal systemic treatment of patients with NIU. This uveitis expert panel produced the following statements and concepts:

  • NCSIT may be introduced for the management of NIU to control persistent or severe inflammation, or to prevent ocular structural complications that present a risk to visual function;
  • Indications for introducing NCSIT also include contra-indications or intolerance to other medications, or a need for CS-sparing effect to maintain disease remission;
  • Biologic agents are generally considered for patients whose disease is inadequately controlled by CS and NCSIT drug therapy.
Indications for NCSIT in NIU

Indications for the introduction of NCSIT in NIU are based on the type and severity of uveitis, and therapeutic needs[11]:

Ocular factors:

  • Acute, sight-threatening disease,
  • Chronic, persistent inflammation,
  • Exudative retinal detachment,
  • Macular involvement,
  • Binocular sight-threatening disease.


Therapeutic needs:

  • Failure of local therapy,
  • Failure of systemic CS therapy,
  • CS intolerance,
  • Need for CS-sparing effect.


The FOCUS consensus group considered the following indicators of NIU severity in adults[11]:

  • Visual acuity < 20/100,
  • Increase of vitreous haze of grade 2 or higher,
  • Relapse of CMO,
  • Disease that impacts quality of life.


Significant heterogeneity exists regarding the criteria used to judge disease activity in NIU, as well as in defining clinical criteria supporting the adjustment of systemic therapy. Currently, clinical criteria with the strongest evidence level to support their usefulness in adjusting systemic therapy have been visual acuity and level of ocular inflammation as defined by the SUN group criteria. A recent Uveitis Disease Activity Index has been produced to assess global ocular inflammatory activity in patients with uveitis, but has not yet been validated as a method to assess need for treatment adjustment.


Classes of NCSIT and biologic agents

Immunomodulatory drugs for the treatment on NIU may be classified as follows [6]:

  1. Intracellular:
    1. Antimetabolites
      1. Purine synthesis inhibitors: Azathioprine; Mycophenolic acid
      2. Antifolate: Methotrexate
    2. Alkylating agents: Chlorambucil
    3. Calcineurin inhibitors: Tacrolimus; Cyclosporine
    4. mTOR inhibitors: Sirolimus; Everolimus; Temsirolimus
  2. Extracelullar
    1. Monoclonal antibodies
      1. Anti-TNF-α: Adalimumab; Infliximab; Etanercept
      2. Anti-CD20: Rituximab
      3. Anti-IL2R/CD25: Daclizumab
      4. Anti-IL6R: Tocilizumab
      5. Anti-IL1R: Anakinra
      6. Anti-IL1β: Gevokizumab
      7. Anti-CD52: Alemtuzumab
    2. Interferon
      1. Interferon α
      2. Interferon β


The FOCUS Initiative Group has provided insight on the level of evidence for each NCSIT available for the treatment of intermediate and posterior NIU, excluding biologics [11]. An adapted version is showed below:

Evidence Levels of NCSIT drugs in the treatment of noninfectious uveitis

 SYSTEMIC NCSITs

LEVEL OF EVIDENCE FOR NIU

RECOMMENDATION LEVEL

CLINICAL EFFECTS

MYCOPHENOLATE MOFETIL

2B

B

Control of inflammation, steroid-sparing, improved VA

AZATHIOPRINE

2B

C

Control of inflammation, steroid-sparing

METHOTREXATE

2B

B

Control of inflammation, steroid-sparing, improved VA

CYCLOSPORINE

2B

B

Control of inflammation, steroid-sparing, improved VA

TACROLIMUS

2B

B

Control of inflammation, steroid-sparing, improved VA

CYCLOPHOSPHAMIDE

4

C

Control of inflammation, steroid-sparing

CHLORAMBUCIL

4 (for panuveitis in sympathetic ophthalmia)

C

Control of inflammation, steroid-sparing, improved VA

In addition, the FOCUS Initiative group has provided information regarding the level of evidence supporting the use of biologics in uveitis [11]. A simplified version is presented below:

Evidence Levels of biologic agents in the treatment of noninfectious uveitis

BIOLOGIC AGENTS

LEVEL OF EVIDENCE FOR NIU

RECOMMENDATION LEVEL

CLINICAL EFFECTS

ADALIMUMAB

1B

A

Control of inflammation, steroid-sparing, improved VA

INFLIXIMAB

2B

B-C

Control of inflammation, steroid-sparing, improved VA

ETANERCEPT

4

C

Not recommended (EL2B)

ANAKINRA

4 (for Behçet’s disease)

C

Control of inflammation

GEVOKIZUMAB

2B (for Behçet’s disease)

C

Control of inflammation

DACLIZUMAB

2B

B

Control of inflammation, steroid-sparing, improved VA

TOCILIZUMAB

4

C

Control of inflammation, improved VA

RITUXIMAB

2B (for Behçet’s disease)

C

Control of inflammation

ALEMTUZUMAB

2B (for Behçet’s disease)

C

Control of inflammation, steroid-sparing

INTERFERON-ALFA

2B

B

Control of inflammation, steroid-sparing, improved VA

INTERFERON-BETA

2B (IU or MS-related uveitis)

C

Control of inflammation, improved VA

Adalimumab is the biologic agent with the highest-quality evidence for the treatment of nonanterior NIU in adults (grade A recommendation). It is approved in the United States for the treatment of NIU, IU, posterior uveitis, and panuveitis; in Europe indications are for adults with inadequate response to CS, patients in need for steroid-sparing therapy, or in whom CS treatment is inappropriate. More recently, evidence from the randomized clinical trial SYCAMORE has shown that combining adalimumab with methotrexate in children with juvenile idiopathic arthritis-associated anterior uveitis has a beneficial effect over methotrexate alone[11].

Failure of NCSIT therapy

The SUN group has defined failure of NCSIT therapy as:

  • Either a 2-step increase in the level of inflammation, or
  • Lack of 2-step decrease in the level of inflammation and inability to decrease to inactive disease despite therapy.


Before considering treatment failure/lack of benefit, the diagnosis should be reconsidered, with particular attention to possible infection, masquerade syndrome, or patient noncompliance.

The choice of therapy for patients with NIU refractory to NCSIT must be individualized taking into account the patients’s history, cause of uveitis, and comorbidities. The following strategies can be considered when a NCSIT is not adequately effective or tolerated[11]:

  • Dose escalation of the drug to the maximum tolerated therapeutic dose;
  • Switch to another NCSIT;
  • Add-on therapy with introduction of a novel NCSIT;
  • Withdrawal of NCSIT: the decision to stop a NCSIT must be made on an individual basis, and involves a risk-benefit assessment that considers the risk of disease recurrence or aggravation against the benefits derived from not being subjected to systemic immunosuppression (e.g., systemic side effects).

Treatment of selected Uveitis-related complications

Cataract

Cataract surgery in patients with uveitic cataract should only be performed after inflammation has cleared, ideally with no inflammation for at least 3 months. Some authors advocate starting oral prednisone 1 mg/kg body weight/day for 5 days before surgery, with tapering over the following month.[3]

An adequate preoperative control of inflammation, a meticulous surgical technique, a foldable hydrophobic acrylic intraocular lens (IOL) implanted in the capsular bag and good postoperative inflammation control are crucial for successful cataract surgery in pars planitis patients. A combined pars plana vitrectomy may be considered in cases with significant vitreous opacity.

Although most ophthalmologists consider hydrophobic, acrylic IOLs are associated with better outcomes post-cataract surgery in patients with uveitis, this remains unsettled. A recent Cochrane systematic review [12] considered there is uncertainty as to which type of IOL provides the best visual and clinical outcomes in people with uveitis undergoing cataract surgery. The authors state that the studies were small, not all lens materials were compared in all studies, and not all lens materials were available in all study sites. Evidence of a superior effect of hydrophobic acrylic lenses over silicone lenses, specifically for posterior synechiae outcomes comes from a single study at a high risk of performance and detection bias. They concluded that they had found “insufficient information to assess these and other types of IOL materials for cataract surgery for eyes with uveitis”.

Studies have shown good visual outcomes after cataract surgery in patients with IU, with a high number of patients obtaining at least some improvement in vision.


Hypertensive Uveitis/ Uveitic Glaucoma

The treatment of hypertensive uveitis requires prompt, aggressive control of inflammation. Treatment can be medical or surgical, as follows.

Medical treatment

Treatment of hypertensive uveitis / uveitic glaucoma must include treatment of the underlying cause and systemic anti-inflammatory treatment, and local treatment.[13]


Ocular treatment

  • Local steroids in cases of anterior uveitis, as discussed above;
  • Topical aqueous suppressants, as discussed above;

Surgical management of uveitic glaucoma

LASER Trabeculoplasty (LTP)

LTP should not be performed, in light of the risk of peripheral anterior synechiae formation using the Argon LASER Trabeculoplasty (ALT);


LASER Iridotomy (LPI) or Surgical Iridectomy

LPI or surgical iridectomy with synechiolysis are indicated in cases of uveitic glaucoma with angle closure and pupillary block;


Trabeculectomy

Trabeculectomy failure rates are higher in patients with uveitic glaucoma. To increase the success rates of the surgery, most ophthalmic surgeons use adjunctive antimetabolite drugs (e.g., mytomicin C) following the Moorfields Safer Surgery System defined by Khaw;


Glaucoma Drainage Devices (GDD)

GDD have shown higher efficacy than trabeculectomy for uveitic glaucoma. Success rates may be as high as 57% even in patients in uncontrolled uveitis, and higher success rates have been reported after control of inflammation with systemic therapy. Longer term success rates have been reported, including a 94% success rate 4 years after Ahmed Glaucoma Valve implantation and 76% at 20-year follow-up post-Molteno implant surgery.[13]

Cyclodestructive procedures

Cycloablation has been used in advanced glaucomas with intractable IOP or blind painful eyes with high IOP. However, given their risk of hypotony, phtisis bulbi, retinal detachment, and vision loss, these procedures are usually reserved for eyes with low visual potential.



Uveitic Macular Oedema (UMO)

Macular oedema (MO), including CMO, is a frequent complication and a major cause of vision loss in uveitis patients. Aggressive treatment is recommended to rapidly restore the macular anatomy and thus increase the potential for visual gain.

The treatment of UMO includes both systemic control of inflammation and ocular treatments.[14][15]

Systemic Treatment

The importance of systemic treatment in the improvement of UMO has been highlighted in the Multicenter Uveitis Steroid Treatment Trial (MUST trial ) and the 7-year follow-up study, as discussed above.[9]


Systemic therapies for UMO include:

Systemic CS

Oral prednisone is often used to treat patients with significant vision-threatening uveitis bilateral UMO and MO refractory to topical treatment.[14]

Relatively high dose “induction” therapy is generally recommended to achieve an anatomical recovery of the macula and they are typically continued until optimal visual acuity is achieved. When this stage is reached, steroid-sparing medications are started and the corticosteroids are tapered slowly. OCT studies have documented a more rapid decrease of ME with oral than with periocular corticosteroid treatment, making oral therapy the preferred route for some clinicians, especially if rapid recovery is essential.

Immunomodulatory drugs and biologic agents

Acetazolamide: randomized studies showed no significant effect on visual acuity, but younger adults may derive more benefit than older patients

Octreotide: this somatostatin-analogue is under study for treatment of CMO.

Ocular treatments

Local therapies for treatment of UMO include topical NSAIDs, periocular CS, intravitreal steroids, intravitreal anti-VEGF agents, and vitrectomy.[15]

Topical NSAIDs

Topical NSAID’s (e.g., nepafenac 0.1% b.i.d., bromfenac 0.09% b.i.d.

Bromfenac may have better ocular penetration and longer duration of anti-inflammatory activity than nepafenac. However, topical NSAID therapy seems to be ineffective for uveitic MO, by it may have synergistic effect with IVS.

Periocular steroids

Randomized clinical trials shown that posterior subtenon injections of triamcinolone acetonide improved visual acuity ad macular thickness in patients with CMO secondary to IU.[16]


Intravitreal injection of triamcinolone acetonide (IVTA)

Positive responses to IVTA have been reported in patients with UMO, with improvement in visual acuity, reduction of macular thicnkness, and prevention/delay of recurrence.[17][18] A randomized trial comparing intravitreal bevacizumab to IVTA[18] showed that both treatments had similar efficacy regarding improvement in visual acuity; however, when the effects of cataract induction by IVTA were removed, the IVTA group had more improvement in vision than the bevacizumab group.

IVTA appears to have similar results as periocular triamcinolone with improvement in VA and CME lasting 1.5 to 5 months after a single injection and the need for reinjection in some patients due to CME recurrence.


Sustained-release steroid intravitreal implants

Dexamethasone intravitreal implant (Ozurdex)

Dexamethasone 0.7 ug slow-release intravitreal implants have shown in case series to significantly improve retinal thickness and visual acuity and to delay and reduce recurrence of UMO [19], including patients with vitrectomized eyes and UMO.[20] A study comparing outcomes of Ozurdex in non-vitrectomized eyes and vitrectomized eyes with UMO showed similar long-term clinical outcomes and safety profiles, with good results in terms of retinal thickness reduction, visual acuity, and vitreous haze improvement.[21]

Fluocinolone acetonide intravitreal implants (Iluvien, Retisert)

Although the MUST trial suggested that 0.59 mg implants provided no significantly increased efficacy compared to systemic treatment, a few studies have shown implanted eyes have improved UMO [22],[23]. Interestingly, a longitudinal evaluation of vision-related quality of life of patients enrolled in the MUST trial showed that, although both the implant group and the systemic treatment group improved NEI-VFQ-25 scores improved, results from the intravitreal implant were immediately seen and stabilized at 6 months, whereas in the systemic treatment group the effect was gradual. In addition, only in the implant group was noted visual improvement in the subgroups of patients with worst vision at baseline.[24]

Overall, fluocinolone implants have long-lasting effects of up to 3 years in decreasing UMO, and may allow for decreased requirements of systemic immunosuppressive drugs, including a steroid-sparing effect. However, the use of fluocinolone implants has been limited by the high rate of complications, incluiding cataract formation, ocular hypertension, and hypotony, as well as costs.

A small study compared the efficacy of the dexamethasone intravitreal implant with the fluocinolone implant. Whilst the two implants were equivalent in preventing disease recurrence of NIU and improving visual acuity, the dexamethasone implant showed a superior safety profile.[25]

Intravitreal anti-VEGF agent injections (IVI)

Bevacizumab (Avastin)

Several retrospective studies have examined the impact of bevacizumab IVI. Repeat bevacizumab injections appear to improve visual acuity and reduce macular thickness in refractory UMO.[16][18]


Ranibizumab (Lucentis)

Ranibizumab has been used to treat diabetic macular oedema (DMO) neovascular age-related macular degeneration (nvAMD), and MO related to retinal vein occlusion (RVO). Its use in UMO has been studied in several case series.

More recently, results of a randomized trial with ranibizumab have been published. The PROMETHEUS trial[26] was a 12-month randomized study designed to evaluate the efficacy and safety of ranibizumab 0.5 mg in adult patients with MO from causes other than DMO, nvAMD or RVO; this included inflammatory, post-surgical, idiopathic, miscellaneous). At 12 months, ranibizumab showed superiority in visual acuity gain over sham, reaching a + 5.45 letters of visual acuity treatment effect in the inflammatory/post-uveitis MO subgroup.


Aflibercept (Eylea)

To date, no large studies have been conducted to evaluate the clinical results of intravitreal aflibercept in UMO, and very little evidence available in the literature is derived from anecdotal case reports.[27]


Pars plana vitrectomy (PPV)

Vitrectomy might be indicated in cases of MO in which traction is contributing to oedema, or in cases associated with ERM development. There is lack of sufficient quality data on PPV for this indication, and clinical results in the literature are confliciting.


Uveitic choroidal neovascularization (uvCNV) and retinal neovascularization (RNV)

Posterior segment uveitis can be complicated by choroidal neovascularization (uvCNV) and/or retinal neovascularization (RNV). Treatment should be prompt and aggressive to prevent CNV-related complications.

Treatment modalities for uvCNV involve systemic anti-inflammatory treatment and treatment of the underlying cause, and local therapy to promote neovascular membrane regression and reduction of leakage.

Anti-VEGF therapy has gained popularity for the treatment of CNV from other causes, mainly nvAMD and myopic CNV. Multiple reports have been published on the use of anti-VEGF IVI for the management of uvCNV.[28] Most studies involved bevacizumab, and few involved ranibizumab. Bevacizumab has shown in many studies to improve visual acuity and reduce macular thickness in there patients, usually requiring multiple injections. Evidence supporting the use of aflibercept for uvCNV is scarce, with only one small case series suggesting clinical benefit from a switch strategy from ranibizumab to aflibercept in refractory uvCNV.[29]

The MINERVA study[30] was a 12-month randomized clinical trial designed to evaluate the efficacy and safety of ranibizumab 0.5 mg in adult patients with CNV from uncommon causes, including inflammatory disease. Patients required a mean number of 5.8 injections. At 12 months, ranibizumab showed clinically significant treatment effect versus sham in all CNV subgroups. In the post-inflammatory CNV subgroup, 12-month visual acuity treatment effect was + 6.53 letters compared to sham. Results from the MINERVA study led to approval of ranibizumab by the European Union for the treatment of visual impairment due to CNV from uncommon causes, including inflammatory CNV.

Long-term data is lacking concerning the efficacy of anti-VEGF IVI for uveitic RNV.

Conclusions

Uveitis may account for up to 10-15% of total blindness in the developed world; these data reinforce the important of prompt and aggressive treatment of uveitis.

The treatment and follow-up of the uveitis patient represents a challenge for both the patient and the clinician. Referral to uveitis specialists should be considered early in the course of the disease in cases of anterior uveitis refractory to initial topical treatment, in any complicated uveitis case, and in nonanterior uveitis.

The ultimate goals of treatment of uveitis are to preserve vision, prevent significant vision-related morbidity, and to prevent the iatrogenic effects of local and systemic therapies. Finally, treatment of the uveitis patient must always consider the underlying systemic disease. Thus, close collaboration with autoimmune disease specialists, infectious disease specialists, and other medical specialties dedicated to these diseases is of utmost importance.

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