Juvenile Idiopathic Arthritis Uveitis

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.

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.

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]

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[11, 12] :

• Female sex

• Early onset pauciarticular arthritis–JIA, as follows:

  • Young age at disease onset

  • Pauciarticular arthritis

• ANA - Positive

• Others, as follows:

  • Posterior synechiae

  • Secondary glaucoma

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, see eMedicineHealth's patient education articles Juvenile Rheumatoid Arthritis and Rheumatoid Arthritis Medications.

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.

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 may include the following:

• 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 may include the following:

• Previous episodes and treatment

• Previous surgeries

• Previous complications, as follows:

  • Cataract

  • Glaucoma

  • Band keratopathy

  • Cystoid macular edema (CME)

Review of systems may reveal the following:

• 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

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 (shown in the image below) - Corneal degeneration that derives its name from the distinctive appearance of calcium deposition in a band across the central cornea

    Juvenile idiopathic arthritis uveitis. Band keratopathy. Courtesy of Manolette Roque, MD, Roque Eye Clinic.

  • 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.

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.[13, 9]

Ocular complications may be sight threatening and include glaucoma, cataract, cyclitic membrane and hypotony, and band keratopathy.[14, 15, 8, 5]

Although uveitis in JIA usually is anterior, vitritis, CME, and optic nerve edema may be present.

Complications from lack of treatment[16]  may include the following:

• 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.[17, 18]

Complications from treatment[12, 16]  may include the following:

• 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)

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, 19]

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.

Radiography of joints: Radiographic studies of affected joints typically reveal nondestructive but chronic articular changes.

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 study

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.[20]

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.

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.

The management of patients with JIA-associated uveitis is difficult primarily because children rarely complain about their vision and are generally difficult to examine. Therefore, the authors of this article advocate a top-down approach in treatment, contrary to the stepladder manner frequently reported.[21, 11, 22, 23] Based on the top-down approach, systemic management is started as soon as possible and at the highest systemically tolerated level to eliminate intraocular inflammation in order to preserve vision potential.

The authors of this article advocate zero tolerance to ocular inflammation. If slit-lamp biomicroscopy examination reveals cells and flare or keratic precipitates, medical management is necessary, regardless of the absence of ocular complaints by the child.

Biologics, anti–tumor necrosis factor (TNF)–alpha agents in particular, are now accepted as the mainstream therapy for JIA-associated uveitis.

Systemic immunomodulatory agents may be useful for patients with limited or no response to systemic corticosteroids or those who develop unacceptable adverse effects.[9, 24, 25, 26, 27, 28, 29, 30, 31, 32]

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.

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).

During the period of quiescence, some cells and flare may be noted, despite previous control with systemic or regional management. Topical corticosteroid treatment may be sufficient in managing the residual or recurrent inflammation. Most patients respond to this initial treatment. Around 20% of patients with JIA-associated uveitis have little or no response and may need systemic or regional management.

Ethylenediaminetetraacetic acid (EDTA) chelation for band keratopathy may be performed. The procedural technique for EDTA chelation is as follows:

• 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.[33, 34, 35]

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 (see the images below).

With proper selection of patients and appropriate surgical technique and follow-up, the implantation of an intraocular lens simultaneous with cataract extraction has been shown to yield better visual results than cataract extraction alone. The risk of ocular hypertension, cystoid macular edema, and optic disc swelling was not higher with lens implantation with control of perioperative inflammation.[36]

Whenever the implantation of an intraocular lens is performed simultaneously with cataract extraction, posterior capsulotomy, anterior vitrectomy, and posterior steroid injection (or implantation) appear to improve the prognosis after surgery.[37, 38]

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

• Ocular immunology and uveitis specialist

• Pediatric rheumatologist

• Child psychiatrist

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.

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.

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.

Class Summary

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.

Prednisolone acetate (Pred Mild, Pred Forte, Econopred)

Strongest steroid of its group and best choice for uveitis. Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability.

Triamcinolone (Kenalog)

Periocular injections of corticosteroids reserved for patients with more severe disease, or those with posterior segment (eg, vitreous) inflammation. Also used in patients at high risk for CME.

Prednisone (Deltasone)

May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

Dexamethasone intravitreal implant (OZURDEX)

Dexamethasone is a potent corticosteroid that suppresses inflammation by inhibiting multiple inflammatory cytokines. This inhibition results in decreased edema, fibrin deposition, capillary leakage, and migration of inflammatory cells. Its FDA-approved indications include treatment of macular edema following branch retinal vein occlusion or central retinal vein occlusion, and treatment of noninfectious uveitis affecting the posterior segment of the eye.

Class Summary

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

Cyclopentolate 0.5-2% (Cyclogyl)

Induces cycloplegia in 25-75 min and mydriasis in 30-60 min. These effects last up to 1 d; however, the duration may be less in the setting of a severe anterior chamber reaction. For this reason, cyclopentolate is less attractive for treating uveitis than homatropine.

Homatropine (Isopto)

Induces cycloplegia in 30-90 min and mydriasis in 10-30 min. Useful in treating pain from ciliary spasm and decreasing formation of synechiae. These effects last 10-48 h for cycloplegia and 6 h to 4 d for mydriasis, but the duration may be less in the setting of a severe anterior chamber reaction. Homatropine is the preferred agent of choice for uveitis.

Class Summary

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.

Indomethacin (Indocin)

For relief of mild to moderate pain; inhibits inflammatory reactions and pain by decreasing activity of cyclooxygenase, which is responsible for prostaglandin synthesis.

Naproxen (Anaprox, Naprelan, Naprosyn)

For relief of mild to moderate pain; inhibits inflammatory reactions and pain by decreasing activity of cyclooxygenase, which is responsible for prostaglandin synthesis.

Ibuprofen (Ibuprin, Advil, Motrin)

For relief of mild to moderate pain. Inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.

Ketorolac ophthalmic (Acular)

Inhibits prostaglandin synthesis by decreasing the activity of the enzyme, cyclooxygenase, which results in decreased formation of prostaglandin precursors.

Diclofenac ophthalmic (Voltaren)

Inhibits prostaglandin synthesis by decreasing activity of enzyme cyclooxygenase, which, in turn, decreases formation of prostaglandin precursors. May facilitate outflow of aqueous humor and decreases vascular permeability.

Class Summary

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.

Etanercept (Enbrel)

Binds specifically to tumor necrosis factor (TNF) and blocks its interaction with cell-surface TNF receptor. TNF is a naturally occurring cytokine that is involved in normal inflammatory and immune responses.

Methotrexate (Folex PFS)

Folic acid analog, decreases inflammation, and has steroid-sparing effect. Useful in JIA-associated uveitis, where may reduce inflammation in patients who do not respond adequately to steroid treatment.

Cyclosporine (Sandimmune)

Potent immunosuppressive agent with narrow therapeutic range. Cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions (eg, delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft-vs-host disease) for a variety of organs.

Cyclophosphamide (Cytoxan, Neosar)

Chemically related to nitrogen mustards. As alkylating agent, mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.

Chlorambucil (Leukeran)

Aromatic nitrogen mustard derivative that acts as bifunctional alkylating agent. Alkylation takes place through formation of highly reactive ethylenimonium radical. Probable mode of action involves cross-linkage of the ethylenimonium derivative between 2 strands of helical DNA and subsequent interference with replication.

Class Summary

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.

Adalimumab (Humira)

Recombinant human IgG1 monoclonal antibody specific for human tumor necrosis factor (TNF). Indicated to reduce inflammation and inhibit progression of structural damage in moderate-to-severe rheumatoid arthritis. Reserved for those who experience inadequate response to one or more disease-modifying antirheumatic drugs (DMARDs). Can be used alone or in combination with methotrexate (MTX) or other DMARDs. Binds specifically to TNF-alpha and blocks interaction with p55 and p75 cell-surface TNF receptors. In 2008, adalimumab was approved by the FDA for juvenile idiopathic arthritis.

Infliximab (Remicade)

Chimeric IgG1k monoclonal antibody that neutralizes cytokine TNF-alpha and inhibits its binding to TNF-alpha receptor. Reduces infiltration of inflammatory cells and TNF-alpha production in inflamed areas. Used with methotrexate in patients who have had inadequate response to methotrexate monotherapy.

Class Summary

Abatacept decreases inflammation by blocking T-cell activation.

Abatacept (Orencia)

Selective co-stimulation modulator that inhibits T-cell activation by binding to CD80 and CED86, thereby blocking CD28 interaction. CD28 interaction provides a signal needed for full T-cell activation that is implicated in RA pathogenesis. Indicated for reducing signs and symptoms of RA, slowing progression of structural damage and improving physical function in adults with moderate-to-severe RA who have inadequate response to DMARDs, methotrexate, or TNF antagonists. May be used as monotherapy or with DMARDs (other than TNF antagonists, because of increased risk of serious infections [4.4% vs 0.8%]). Not recommended for concomitant use with anakinra (insufficient experience).