Pınar Ç. Özdal

Moorfields Uvetis Course, Antalya, 2013

JUVENILE IDIOPATHIC ARTHRITIS

ASSOCIATED ANTERIOR UVEITIS

JUVENILE IDIOPATHIC ARTHRITIS (JIA)

The leading cause of chronic arthritis in children

Arthritis of unknown cause lasting at least 6 wks and starting < 16 years of age

Most common systemic association of childhood uveitis in USA and Europe, less common in Asia including Turkey

Heiligenhaus et al. Ocular Immunol&Inflamm 2013:21:180-91

Cumulative uveitis incidence in different JIA subgroups

Heiligenhaus et al. Prevalence and complications of uveitis in juvenile idiopathic arthritis in population-based nation-wide study in Germany: suggested modification of the current screening guidelines. Rheumatology 2007:46:1015-9.

•JIA is subdivided into seven subtypes (ILAR) •Identification of the JIA subtype is important in order to determine the risk for ocular inflammatory disease

The majority of patients develop uveitis within 4–7 years after arthritis onset

Uveitis is diagnosed before the arthritis in 10%

The highest risk for uveitis is within 2 years after the arthritis onset and declines after 8 years

Before or within the 1st year after arthritis onset: 73%

Within first 2 years: 77%

Within the first 4 years: 90%

Heiligenhaus et al. Rheumatology 2007:46:1015-9.

The average age at the time of uveitis varies (4.3 to 13 years)

A biphasic course of uveitis activity has been reported

1st active phase: early years of age (4-6 years)

A quiet period around 9 years

2nd active phase: during early teenage years (hormonal changes?)

(Hoeve et al. Br J Ophthalmol. 2012;96:852-6)

Risk factors for developing uveitis

Oligoarticular type of JIA

Female sex

Young age at onset of arthritis (4 ≤ years)

ANA positivity

RF negativity

HLA associations (HLA-DR5, HLA-DRB1*13)

Anti-histone antibodies

SCREENING OF PATIENTS

The frequency of screening is based on the risk factors for developing uveitis

Cassidy et al. Pediatrics 2006; 117:1843-1845.

Clinical characteristics of JIA associated uveitis

Asymptomatic, non-granulomatous uveitis affecting primarily the anterior segment is characteristic

Absence of ciliary injection

Fine keratic precipitates

Chronic anterior chamber cells and flare

Cellular infiltration of anterior vitreous (less than the AC)

Rare cases of granulomatous uveitis

More common in black patients (67% vs 25%)

(Keenan et al. J AAPOS 2008; 12:546-50)

Clinical characteristics of JIA associated uveitis

Bilateral in 67–89% of patients

Both eyes are simultaneously involved or within a few months

Chronic course in up to 93% of the cases

May not be realized by the patient or even the physician until chronic changes and permanent visual loss have occurred

Oligoarticular, polyarticular and psoriatic JIA

Clinical characteristics of JIA associated uveitis

Children with enthesitis-related arthritis (ERA)

Mostly boys of ≥ 10 years old

Acute symptomatic nongranulomatous anterior uveitis similar to ankylosing spondylitis associated uveitis

75% are HLA-B27 positive

Usually present with unilateral red eye, ocular pain and photophobia and may develop recurrent uveitis attacks alternating between the two eyes

Have oligoarticular involvement

May develop ankylosing spondylitis later in life

Ocular Complications

Posterior synechiae (35-75%)

Cataract (21-84%)

Band keratopathy (7-70%)

Glaucoma (8-42%)

Macular edema (7-42%)

Optic nerve edema (4%)

•Macular epiretinal membrane •Cyclitic membranes •Hypotony •Retinal detachment •Phtisis bulbi

Although the anterior segment is the major site of the inflammation;

Maculopathy has been reported in 1/3 of the patients (Dana et al. Ophthalmology 1997;104: 236–244)

Evaluation of the macula by OCT showed maculopathy in 84%

Perifoveolar thickening (74%)

Macular edema (48%)

Foveal detachment (18%)

Atrophic changes (10%) (Ducos de Lahitte et al. Br J Ophthalmol. 2008;92:64-9)

Frequency of ocular complications

Complications may be present at the time of diagnosis even in patients followed in screening programs

Ocular complication(s) were present at initial eye exam in 45-67 % of patients

(Heiligenhaus et al. Rheumatology 2007:46:1015-9)

(Woreta et al. Am J Ophthalmol 2007;143:647e55)

(Gregory et al.(SITE) Ophthalmology 2013;120: 186-92)

In patients followed for long term (mean:20.5 years) 100% of eyes had at least one ocular complication

(Ozdal et al. Ocul Immunol Inflamm 2005, 13: 33-38)

Differential Diagnosis

Sarcoidosis

Pars planitis

Lyme disease

Ankylosing spondylitis

Chronic anterior uveitis without any systemic disease association

Behcet’s Disease

Reiter’s syndrome

Inflammatory bowel disease

VKH

Hereditary autoinflammatory syndromes

TINU

Treatment of JIA associated uveitis

High rate of ocular complications

Poor visual prognosis

An earlier institution of immunosuppressive therapy

When complications have started to develop, may be too late for improving the long-term visual prognosis

No tolerance for even a low-grade intraocular inflammation !! is recommended

An aggressive treatment as soon as the diagnosis has been made

The goal of treating JIA-associated uveitis

“no cells in the anterior chamber”

Treatment being initiated when > 0.5+ cells are present

A stepladder approach using steroid-sparing therapy

1. Topical corticosteroids (CS) & short acting mydriatics

2. Systemic CS 3. Immunosuppressives 4. Biologic agents

• Anti-TNF treatment • New biologics

1-Topical Corticosteroids (CS) & Mydriatics

Still the mainstay of treatment in anterior uveitis attacks

Frequency of instillation depends on inflammatory activity

High-potency drops (prednisolone acetate 1% ,

dexamethasone) should be preferred

Should be tapered slowly

Monitorization for possible systemic adverse effects

This risk increases in children < 4 years using high-potency topical CS bilaterally and frequently

(Kotaniemi et al.Surv Ophthalmol 2003, Heiligenhaus et al. Rheumatol Int 2012)

Monitorization for cataract and IOP rise

≤ 3 drops/day risk of cataract development 87% (Thorne JE et al. Ophthalmology 2010)

SYSTEMIC TREATMENT

Treatment effective for both arthritis and uveitis

Corticosteroids

Immunosuppressives

Biologics

Systemic NSAID are not effective in the treatment of uveitis (less efficacious than high-potency topical CS)

Indications for treatment intensification

Presence of worse prognostic factors (Heiligenhaus et al. 2012)

High laser flare photometry values (Herbort CP. 2009)

Indications for systemic treatment

An initial visual acuity of ≤ 20/60

High inflammatory activity at time of diagnosis

An interval 6 months between the onset of arthritis and uveitis

An early onset of uveitis

Long duration of uveitis

Macular edema, vitreous condensation, ocular hypotony and secondary glaucoma

(Heiligenhaus et al. Rheumatol Int 2012)

2-Systemic Corticosteroids

Short-term systemic CS therapy Treatment of exacerbations Controlling the disease until the onset of action of

immunosuppressive

Oral prednisolone 1-2 mg/kg I.V. pulse 30 mg/kg methylprednisolone The main limitations are their adverse effects Growth retardation Cataract Intraocular pressure rise Weight increase Hypertension

The use of CS should be limited to 3 months and the dose be tapered to prednisolone 0.15 mg/kg equivalent within 4 wks

(Heiligenhaus et al. Rheumatol Int 2012)

3-Immunosuppressive Therapy

• Continuing activity with topical CS ≤ 3 drops and a maintenance CS dose of 0.15 mg/kg within 3 months

• Adverse effects of CS

• Occurrence of new ocular complications

• Addition of immunosuppressive therapy decreases the risk of ocular complications and improves the visual prognosis

(Petty et al. Am J Ophthalmol 2003; 135:879–884)

Systemic immunosuppressive treatment

(Heiligenhaus et al. Rheumatol Int 2012)

Immunosuppressive Therapy Collaboration of uveitis specialists & pediatric

rheumatologists!

The choice and the dosage of immunosuppressive agents should be based on;

Physician’s experience

Current treatment guidelines

Individual factors of the patient

Agents of choice

Methotrexate (MTX) (10–15 mg/m2 /wk ) 1st CHOICE

Azathioprine (AZT)

Mycophenolate mofetil (MMF)

Cyclosporine-A (CSA) Preferred for

combination therapy

BIOLOGIC AGENTS 4-Anti-TNF Therapy

Patients not responding to conventional immunosuppressives and who have a high risk of visual loss should be treated with biologics

Uveitis persisting or recurring with < 3 drops/daily of topical CS or a systemic CS of > 0.15 mg/ kg

Development of new complications while under immunosuppressive treatment

The treatment should be intensified!! An Anti-TNF- agent should be added to treatment

(Heiligenhaus et al. Rheumatol Int 2012)

Anti-TNF Therapy

Infliksimab 5mg-10/kg IV (at wks 0, 2, 6, then every 4–8 wks ) A chimeric mouse-human monoclonal antibody Powerful and rapid anti-inflammatory effect

Adalimumab 24mg/m2 SC, every other wks Fully humanized monoclonal antibody An effective inflammation control and steroid-sparing effect

Etanercept was not found to be better than the placebo in patients with JIA-associated uveitis

(Smith et al. Arthritis Rheum 2005)

Infliximab vs Adalimumab

Similar effect for obtaining a remission of the inflammation

Adalimumab is more efficacious in preventing the uveitis attacks and maintaining the remission

(Simonini et al. Arthritis Care Res 2011; 63:612-8)

Both were found to be effective and safe in refractory JIA-associated uveitis

Adalimumab had a higher remission rate (67.4% vs 42.8%; p = 0.025)

(Zannin et al. J Rheumatol. 2013; 40:74-9)

5-New Biologic Agents

Daclizumab (anti-IL2R)

Abatacept (CTLA4 fusion protein)

Rituximab (anti-CD20)

Anakinra (recombinant IL1R antagonist)

Canakinumab (anti-IL1beta)

Tocilizumab (anti-IL6)

Golimumab (humanize anti-TNF-)

Treatment of Ocular Complications CATARACT SURGERY Prognosis of cataract surgery in children with JIA-

associated uveitis has been improved Advances in microsurgical techniques Improvement in IOL materials Better control of inflammation

Different techniques have been suggested Phacoemulsification ± IOL implantation ± posterior

capsulorhexis Pars plana lensectomy + anterior vitrectomy

Relative contraindications for IOL implantation in Age < 4 years Hypotony IOL-related complication in fellow eye Shallow anterior chamber

(Sijssens et al. Br J Ophthalmol 2010; 94:1145-9)

Cataract surgery in JIA patients

The success of cataract surgery is closely related with an adequate control of preoperative inflammation (at least 3 months)

If effective and sustained control of inflammation could not be achieved, IOL implantation should be avoided

Treatment of Ocular Complications

Secondary glaucoma refractory to medical treatment

Glaucoma surgery Conventional filtering surgery with or without

antimetabolites Implantation of glaucoma implant devices

Band keratopathy

Chelating agents

Excimer laser Lesion tends to recur A good control of inflammation prevents the progress of

band keratopathy

Treatment of Ocular Complications

All intraocular surgical procedures are safer than previously reported in JIA patients

Newer immunosuppressive drugs and biologic agents

Inflammation control for at least 3 months is the gold standard for planning any surgery in these children

This period of time may need to be compromised when weighed against the risks of amblyopia in younger children

MONITORING THE TREATMENT EFFICACY

Grading the anterior chamber (AC) cells

Subjective and needs experience

Significant prognostic differences between the absence and the presence of even a small number of cells AC inflammation of at least 0.5+

during follow-up was associated with a three-fold increased risk of blindness

(Thorne et al. Am J Ophthalmol 2007)

MONITORING THE TREATMENT EFFICACY

AC flare Represents the blood-aqueous barrier disruption

May be present in the absence of AC cells

May be detected clinically May differ between observers and visits

Laser flare photometry Provides an objective and reliable measurement

(Kempen et al. Am J Ophthalmol 2008)

Higher values of AC flare

(> 20ph/ms)

increased risk of complications

and poor visual prognosis

Aggressive treatment

OTHER PARAMETERS IN MONITORING THE TREATMENT EFFICACY

The number of visits with active uveitis

Visual acuity levels

Documentation of structural complications

Anterior segment pictures (p.synechia, band keratopathy…)

Fundus pictures, OCT (maculopathy)

When to stop the medical treatment??

Using the follow-up parameters, we should be sure that uveitis is inactive

The general opinion is to taper the systemic treatment after 12–24 months of uveitis’ quiescence

An inactivity of at least 2 years is recommended

Relapse-free survival after withdrawal of MTX was significantly longer in those

treated for 3 years

with an inactivity of at least 2 years

who were 8 years at the time of withdrawal (Kalinina Ayuso V et al. Am J Ophthalmol 2011)

OCULAR PROGNOSIS

JIA has a blinding potential which is often underappreciated

Author Year % of blind eyes

(VA<20/200)

Kanski 1988 25

Dana 1997 25

Edelsten 2001 6

Kump 2006 12

Rosenberg 2002 10

Özdal 2005 10

Ayuso 2010 13

Gregory 2013 18

Conditions associated with poor visual prognosis

Younger age at disease onset

Short duration between the onset of arthritis and uveitis

Uveitis onset prior to arthritis

Ocular complications at presentation (p.synechia)

Previous intraocular surgery

Long period of chronic inflammation

0.5+ ≤ anterior chamber cells, high flare (> 20ph/ms)

Development of glaucoma, cataract requiring surgery, macular edema and chronic hypotony

Delay in presentation to a uveitis subspecialist

Male sex

ANA (??), HLAB15/w62, antibodies to retinal-S ag, elevated α2 – globulin

CONCLUSIONS

JIA-associated uveitis is a serious disease with a poor visual prognosis

Because of asymptomatic uveitis and inadequate screening programs, most cases present with complication(s)

Routine eye examinations in pre-school children and ocular screenings in children diagnosed with JIA are very important in detecting ocular involvement

The frequency of ophthalmologic examinations should be determined depending on the severity of uveitis, presence of complications and the medications used

CONCLUSIONS

Crucial factors to improve the prognosis

Early diagnosis

Increased awareness of poor prognostic factors

A prompt and aggressive treatment

Early referral to subspecialists before the development of permanent ocular damage

Collaboration with pediatric rheumatologists