AUTHOR AND EDITOR INFORMATION

Section 1 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

INTRODUCTION

Section 2 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Background

Approximately 6% of all cases of uveitis arise in children.¹ The most frequent cause of chronic intraocular inflammation among children is juvenile idiopathic arthritis (JIA)-associated uveitis.² A unifying classification, juvenile idiopathic arthritis (JIA), encompassing juvenile chronic arthritis and juvenile rheumatoid arthritis (JRA), has been developed by consensus.

Chronic iridocyclitis occurs in 10-20% of all patients with JIA.^{3, 4, 5, 6} Chronic uveitis characteristically is asymptomatic in children with JIA, leading to insidious but progressive morbidity and possible blindness. The involved eyes often are white and quiet appearing, yet 30-40% of patients with JIA-associated uveitis experience severe loss of vision as a consequence of their condition.

JIA, as defined by the American Rheumatism Association (ARA), is the presence of arthritis (chronic, seronegative, and peripheral) before age 16 years, of at least 3 months duration, when other causes have been excluded. It is classified by 1 of 3 types of onset.⁷

Oligoarticular (pauciarticular) onset JIA (40-60%) is common in girls (5:1). Peak age of onset is at age 2 years. Four or fewer joints are involved during the first 6 months of the disease (often asymmetric). Oligoarticular onset commonly involves the knees and, less frequently, the ankles and wrists. The arthritis may be evanescent, rarely destructive, and radiologically insignificant. Approximately 75% of these patients test positive for antinuclear antibody (ANA). This mode of onset rarely is associated with systemic signs. A high risk for uveitis exists.⁸

Polyarticular onset JIA (20-40%) is common in girls (3:1). Peak age of onset is at age 3 years. It involves 5 or more joints during the first 6 months of the disease. Polyarticular onset JIA commonly involves the small joints of the hand and, less frequently, the larger joints of the knee, ankle, or wrist. Asymmetric arthritis may be acute or chronic and may be destructive in 15% of patients. Immunoglobulin M (IgM) rheumatoid factor (RF) is present in 10% of children with this JIA subgroup. It is associated with subcutaneous nodules, erosions, and a poor prognosis. Approximately 40% of these patients test positive for ANA. Systemic symptoms, including anorexia, anemia, and growth retardation, are moderate. An intermediate risk for uveitis exists.

Systemic onset JIA (10-20%) is equal frequency in boys and girls and can appear at any age. Symmetric polyarthritis is present and may be destructive in 25% of patients. Hands, wrists, feet, ankles, elbows, knees, hips, shoulders, cervical spine, and jaw may be involved. ANA is positive in only 10% of the patients. Systemic onset is associated with fever (high in evening and normal in morning), macular rash, leukocytosis, lymphadenopathy, and hepatomegaly. Pericarditis, pleuritis, splenomegaly, and abdominal pain less commonly are observed. A low risk for uveitis exists. 

See related CME at Updates on Pediatric Rheumatoid Arthritis. 

Pathophysiology

The cause of uveitis and arthritis in JIA remains unknown.⁹ Akin to many other autoimmune diseases, the target antigen is unidentified. Immune reactions to ocular antigens (S antigen or iris antigen) have been studied; however, their actual role (active or passive) is unknown. The course of the disease may be short and limited or progressive and severe.

Frequency

United States

JIA has an estimated prevalence of about 113 cases per 100,000 children. It is estimated that JIA afflicts 60,000-70,000 children, but only a minority develop eye disease. Incidence of eye disease in the JIA population is uncertain, but it is believed to be around 10%.⁷

Mortality/Morbidity

Morbidity in JIA-associated uveitis may result either from lack of treatment or from overzealous treatment. Mortality may result from the latter.

Race

No known racial predilection exists.

Sex

A strong predilection exists for girls. The girl-to-boy ratio is 4:1.

Age

JIA is a childhood disease.

• By definition, JIA occurs in children younger than age 16 years.
• In view of the fact that the ocular disease can follow the systemic disease by numerous years, a lot of patients are well beyond their teens when they are examined and treated for uveitis.¹⁰

CLINICAL

Section 3 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

History

Always complete a thorough history of new patients. The ocular immunology and uveitis survey form, developed by Dr. C Stephen Foster, provides a complete checklist (present illness, past medical history, family history, and review of systems) and may assist the physician in the history. The patient questionnaire may be downloaded from the Massachusetts Eye and Ear Infirmary Immunology and Uveitis Service.

• Chief complaint and history of present illness
• • Many patients are referred first by a pediatrician or rheumatologist and often are asymptomatic. Typically, patients have no pain or photophobia and the eye appears white.
  • Asymptomatic patients may recall previous insignificant symptoms that may be useful in determining the duration of the ocular disease. Therefore, ask specific questions regarding past ocular history, such as previous episodes of pink eye or conjunctivitis, blurry vision, ocular pain, or abnormal pupil size/shape.
• Past medical history
• • Crucial to establish chronicity and to determine the subtype of JIA
  • Age at onset
  • Specific joints involved and number of joints
  • Other systemic manifestations are as follows:
  • • Fever, rash, lymphadenopathy, fatigue, weight loss, hepatosplenomegaly, pericardial effusion, pleural effusion
    • Anemia
    • Growth retardation, delay of secondary sexual characteristics
    • Chronic low back pain, diarrhea, psoriasis
  • Current systemic medications for JIA
• Past ocular history
• • Previous episodes and treatment
  • Previous surgeries
  • Previous complications
  • • Cataract
    • Glaucoma
    • Band keratopathy
    • Cystoid macular edema (CME)
• Review of systems
• • General - Weight loss, fatigue, fever
  • Skin - Rash, nodules, changes in nails
  • Neck - Lymphadenopathy
  • Respiratory - Cough, wheezing
  • Cardiac - Chest pain/discomfort, dyspnea
  • Gastrointestinal - Hepatomegaly, diarrhea, frequent bowel movements
  • Genitourinary - Delayed secondary sexual characteristics
  • Musculoskeletal - Muscle or joint pain, arthritis, back pain, limitation of motion

Physical

• Ocular manifestations - Perform a complete ophthalmic examination.
• • Vision - Best-corrected visual acuity, including near acuity
  • Anterior uveitis
  • • Cells and flare; chronic flare (very common)
    • Nongranulomatous uveitis (>90%)
    • Bilateral (70-80%)
    • Iridocyclitis in approximately 90% of patients; rarely panuveitis or vitritis
    • Chronic smoldering or recurrent disease in greater than 90%; rarely acute monophasic course (<5%)
  • Conjunctiva and sclera - Most patients have no conjunctival injection even during acute exacerbations.
  • Cornea
  • • Band keratopathy - Corneal degeneration that derives its name from the distinctive appearance of calcium deposition in a band across the central cornea
    • Keratic precipitates - Small-medium, rarely mutton fat
  • Iris - Posterior synechiae; pupillary membrane; rarely may develop Koeppe nodules
  • Pupil examination
  • Lens - Posterior subcapsular cataracts
  • Posterior uveitis
  • • Dilated fundus examination - Vitritis, CME, hypotony maculopathy
    • Anterior vitreous (anterior vitreous cells not uncommon)
  • Others - Intraocular pressure, secondary glaucoma (open angle or pupillary block), hypotony
• Articular manifestations
• • Assessment must consist of a quick evaluation of the skin and joints (warmth, redness, effusion, and deformity). Identify the particular joint and number involved.
  • The ophthalmologist evaluating the patient may perform this; however, the pediatrician or rheumatologist is expected to execute a complete musculoskeletal examination.

Causes

The cause of uveitis and arthritis in JIA remains unknown. Akin to many other autoimmune diseases, the target antigen is unidentified. Associated factors may include the possibility of infectious triggers, a genetic predisposition, an autoimmune response, psychological stress, female sex, and hormone interaction.^{11, 9}

DIFFERENTIALS

Section 4 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Other Problems to be Considered

Trauma
Idiopathic uveitis
Arthritis
Sympathetic ophthalmia
Keratouveitis
Chronic iridocyclitis in girls
Heterochromic cyclitis
Pars planitis
Masquerade syndromes (leukemia)
Lupus erythematosus
Infantile multisystem inflammatory disease
Juvenile rheumatoid arthritis

WORKUP

Section 5 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Lab Studies

• The different subtypes of JIA have individual serologic characteristics. Specific laboratory studies may be helpful to gauge the risk for developing uveitis and to rule out other possible diagnoses.^{8, 3, 7, 12}
• Antinuclear antibody
• • The term ANA encompasses all the antibodies that can be demonstrated to react with nuclei in tissue sections by the classic indirect immunofluorescence test (IFA).
  • ANA-positivity is present in most children with oligoarticular onset JIA and uveitis; however, it is present in up to 80% of those without uveitis. For that reason, ANA negativity may be some help in predicting that a child will not develop uveitis, but their positivity does not assist in the prediction of the development of uveitis.
  • ANA-positivity in young girls with pauciarticular JIA presents the highest risk of developing uveitis.
• Rheumatoid factor
• • RF classically is defined as an IgM antibody to the Fc portion of human immunoglobulin G (IgG) antibody; it often is present in serum in a complex with IgG antibody.
  • Many patients with JIA who develop uveitis are RF negative. A few adolescent girls who are RF positive have juvenile variant idiopathic arthritis, and they are not at significant risk for developing ocular disease.
• Human leukocyte antigen B27
• • The only HLA antigen with a disease association strong enough to be useful in differential diagnosis is human leukocyte antigen B27 (HLA-B27).
  • A subgroup of older boys having pauciarticular arthritis with high risk for developing uveitis often is positive for HLA-B27 and negative for both RF and ANA.
  • A significant percentage of patients with JIA with spinal involvement are HLA-B27 positive.
  • HLA-B27 determination also is useful in ruling out seronegative spondyloarthropathies.

Imaging Studies

• X-ray imaging of joints: Radiographic studies of affected joints typically reveal nondestructive but chronic articular changes.

Other Tests

• Additional serologic tests: After undergoing a complete history, a detailed review of systems, and a comprehensive examination, additional serologic tests may be requested based on the findings (differentials). These tests may include the following:
• • Syphilis serologies (treponemal and nontreponemal)
  • Lyme titers
  • Angiotensin-converting enzyme (ACE)
  • Serum lysozyme
• Serologic prognosticators presently under study¹³
• • Recent investigations are concentrated on determining which specific subsets of ANA and human leukocyte antigen D (human leukocyte antigen DR, human leukocyte antigen DP, and human leukocyte antigen DQ) have significant associations with early onset pauciarticular (EOPA) JIA uveitis.
  • Human leukocyte antigen DR5 is associated with uveitis in children with oligoarticular JIA. On the other hand, human leukocyte antigen DR1 and human leukocyte antigen DR4 are associated negatively with uveitis.

Histologic Findings

Pathologic results demonstrate that the synovium becomes hyperplastic, with subsynovial lymphocytic infiltration, vascular endothelial hyperplasia, and edema. A comparable histologic picture is observed in the eyes of patients with JIA-associated uveitis where lymphocytes, plasma cells, and scattered giant cells infiltrate the iris and ciliary body.

TREATMENT

Section 6 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Medical Care

The management of patients with JIA-associated uveitis should be approached in a stepladder manner.^{14, 15, 16, 17}

• Treatment initially should begin with topical corticosteroids. Most patients would respond to this initial treatment. Around 20% of patients with JIA-associated uveitis have little or no response.
• The presence of vitreous cells, severe disease, or chronic inflammation increases the risk for CME. These patients may be given additional nonsteroidal anti-inflammatory drugs (NSAIDs).
• The decision to use regional corticosteroids depends on the patient's response to topical therapy and/or the presence of posterior segment involvement. Monocular involvement also weighs in more toward regional corticosteroid use. Bilaterality may favor the use of systemic corticosteroids.
• Systemic immunomodulatory agents may be useful for patients with limited or no response to systemic corticosteroids or those who develop unacceptable adverse effects.^{9, 18, 19, 20, 21, 22, 23, 24, 25, 26}

Surgical Care

• Ethylenediaminetetraacetic acid (EDTA) chelation for band keratopathy may be performed. The procedural technique for EDTA chelation is outlined below.
• • This procedure is ideally performed in a minor operating room setting using an operating microscope as well as topical (proparacaine or tetracaine) anesthesia.
  • Apply a self-retaining lid speculum to keep the eyelids open.
  • Perform epithelial debridement using an ophthalmic surgical blade (blade 15) or a sharp spatula to expose the underlying calcium.
  • Apply Weck-cel sponges, soaked with 0.05 mol, 1.5% neutral disodium EDTA, to the corneal surface. A corneal well, similar to a corneal trephine, may be used to soak the exposed calcium to EDTA.
  • Using a blunt (Paton) spatula, firmly scrape the corneal surface to remove calcium deposits.
  • Repeat the procedure of soaking and scraping as often as necessary to clear up the central visual axis. Usually, thin calcium deposits are dissolved in 5 minutes. Sometimes, it may take as long as 30-45 minutes to remove thick plaques.
  • Place topical antibiotic and nonsteroidal agents on the cornea. Use the topical medications until the bandage contact lenses are in place.
  • Place a bandage contact lens over the cornea. Maintain the bandage contact lens for 1-2 weeks until the cornea is completely reepithelialized.
  • Cataract surgery is reserved for those patients with poor visual acuity or in cases where the vitreous and retina cannot be visualized. The decision to perform cataract surgery should be weighed against the risks and benefits. Routine placement of an intraocular lens is contraindicated in most patients with JIA.^{27, 28, 29}
  • Glaucoma surgery is reserved for patients in whom medical therapy has failed and evidence exists of progressive optic nerve damage.
  • If vitreous debris prevents optimal vision or examination of the fundus, core vitrectomy for clearing inflammatory debris is a good adjunct to cataract surgery.
  • Membranectomy/vitrectomy for cyclitic membranes may be performed to prevent phthisis resulting from prolonged hypotony.

Consultations

A team approach to management of patients with severe, chronic disease requiring systemic immunomodulatory treatment is recommended.

• Ocular immunology and uveitis specialist
• Pediatric rheumatologist
• Child psychiatrist

MEDICATION

Section 7 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

The treatment of JIA-associated uveitis is a step-wise progression beginning with topical steroids and mydriatics, progressing to regional steroids, systemic NSAIDs, systemic steroids, immunosuppressive agents, and biologics.

Drug Category: Corticosteroids

These agents decrease inflammation. When considered, corticosteroid treatment often is initiated only after consultation with an ophthalmologist. However, long-term systemic therapy results in an unfavorable visual prognosis.

Drug Category: Cycloplegics

These agents block nerve impulses to the pupillary sphincter and ciliary muscles, easing pain and photophobia.

Drug Category: Nonsteroidal anti-inflammatory drugs

NSAIDs reduce pain and inflammation and allow for improvements in mobility and function. Used to reduce effect of diffusing prostaglandins on retinal microvasculature and, hence, used in patients at high risk for the development of CME. There are several NSAIDs; however, no single agent exists that is superior to another. Naproxen is used commonly in children.

Drug Category: Immunosuppressives (systemic)

These are second-line agents that ameliorate the disease process. Most frequently they are used in combination with first-line agents. They include methotrexate, cyclosporin A, cyclophosphamide, and chlorambucil.

Drug Category: Tumor necrosis factor (TNF) inhibitors

TNF is a cytokine of which 2 forms have been identified with similar biological properties. TNF-alpha or cachectin is produced predominantly by macrophages, and TNF-beta or lymphotoxin is produced by lymphocytes. TNF is but one of many cytokines involved in the inflammatory cascade that may contribute to symptoms.

Drug Category: Immunomodulator

Abatacept decreases inflammation by blocking T-cell activation.

FOLLOW-UP

Section 8 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Further Outpatient Care

• Patients with JIA-associated uveitis need to be seen by an ophthalmologist regularly, every 3 or 4 months (more often if with active uveitis). It is easy to miss flare-ups due to the white and quiet presentation of this type of uveitis. Moreover, children often do not complain of visual problems, precluding the possibility of early detection.
• Children with JIA-associated uveitis on systemic medications require meticulous monitoring (CBC, LFTs, BUN, creatinine) for drug toxicity (bone marrow, liver, kidney), disease complications (eg, glaucoma, cataract, band keratopathy), disease exacerbations, or breakthrough inflammation.

In/Out Patient Meds

• The mainstay of therapy of the ocular inflammation in these patients consists of topical corticosteroids and cycloplegics.

Deterrence/Prevention

• The cause of JIA-associated uveitis is unknown. Therefore, the prevention of the disease has not been established.
• Evaluate children who are at risk for JIA-related ocular complications on a frequent regular basis and monitor closely for the development of ocular inflammation.

Complications

• Ocular complications may be sight threatening and include glaucoma, cataract, cyclitic membrane and hypotony, and band keratopathy.^{30, 31, 8, 5}
• Although uveitis in JIA usually is anterior, vitritis, CME, and optic nerve edema may be present.
• Complications from lack of treatment³²
• • Cataracts (40-80%)
  • Band keratopathy (30-80%)
  • Macular edema or epiretinal membrane formation (30-50% in chronic cases)
  • Vitreous haze/debris (20-30%)
  • Glaucoma (10-30%)
  • Chronic hypotony and phthisis (5-20%)
  • Other posterior pole complications (eg, disc neovascularization, macular hole) are rare.^{33, 34}
• Complications from treatment^{35, 32}
• • Cataracts, keratitis, and steroid-induced glaucoma from topical steroids
  • Lid abnormalities, orbital socket contraction, and globe perforation from regional corticosteroids
  • Gastrointestinal bleeding from nonsteroidal NSAIDs
  • Growth retardation, weight gain, acne, mood swings, and infections from systemic corticosteroids
  • Bone marrow suppression and pancytopenia from immunosuppressive therapy (methotrexate, cyclosporine-A, cyclophosphamide, chlorambucil)

Prognosis

• Most vision-threatening morbidities in JIA are secondary to intraocular inflammation (eg, severity, chronicity). The development of JIA-associated uveitis heralds a poor prognosis.
• Of affected eyes, 30-40% maintain long-term acuity greater than 20/40. Conversely, approximately 30-40% develop severe visual disability with acuity less than 20/200.
• Poor prognosticators (higher risk for chronic iridocyclitis) include the following^{15, 35}:
• • Female sex
  • Early onset pauciarticular arthritis–JIA
  • • Young age at disease onset
    • Pauciarticular arthritis
  • ANA - Positive
  • Others
  • • Posterior synechiae
    • Secondary glaucoma

Patient Education

• Patients (and relatives) with JIA-associated uveitis require a significant amount of education regarding the signs and symptoms of disease exacerbation. Emphasize the need for lifestyle changes to prevent exacerbations, to preserve vision, and for appropriate pain control.
• The need to maintain regular eye visits to check for ocular activity cannot be overemphasized, if one is to preserve the patients remaining useful vision.
• For excellent patient education resources, visit eMedicine's Arthritis Center. Also, see eMedicine's patient education articles Juvenile Rheumatoid Arthritis and Understanding Rheumatoid Arthritis Medications.

MISCELLANEOUS

Section 9 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Medical/Legal Pitfalls

• Missed diagnosis of JIA-associated uveitis may lead to litigation. The inability to ascribe the diagnosis to a particular patient may result in chronic uncontrolled subclinical activity leading to permanent loss of useful vision.
• Prolonged aggressive treatment with NSAIDs may result in GI hemorrhage.
• Prolonged treatment with oral corticosteroids may result in numerous adverse effects (eg, weight gain, stunted growth, mood swings).
• Failure to arrange for close follow-up may complicate JIA-associated uveitis.
• Inadequate systemic monitoring for use of immunosuppressive agents may lead to significant bone marrow suppression and pancytopenia.

Special Concerns

• A young patient with systemic and ocular problems necessitating multiple and/or prolonged medications, and visits to the hospital is subjected to an enormously abnormal amount of stress. The physician and the family should be extremely sensitive to the emotional needs of the patient. Address the child's mental health accordingly if the need arises. Appropriate referral to a child psychiatrist may be necessary in these situations.

ACKNOWLEDGMENTS

Section 10 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

The authors and editors of eMedicine gratefully acknowledge the assistance of Ryan I Huffman, MD, with the literature review and referencing for this article.

MULTIMEDIA

Section 11 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Media file 1:  Acute anterior uveitis with hypopyon in a child. Courtesy of Manolette Roque, MD, Ophthalmic Consultants Philippines Co, EYE REPUBLIC Ophthalmology Clinic.
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Media file 2:  Juvenile idiopathic arthritis uveitis. Band keratopathy. Courtesy of Manolette Roque, MD, Ophthalmic Consultants Philippines Co, EYE REPUBLIC Ophthalmology Clinic.
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Media file 3:  Juvenile idiopathic arthritis uveitis. Pseudophakia with posterior chamber intraocular lens with anterior membrane and posterior capsular opacification with cyclitic membrane formation. Courtesy of Manolette Roque, MD, Ophthalmic Consultants Philippines Co, EYE REPUBLIC Ophthalmology Clinic.
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Media type:  Photo