Disorders9 SECTIONTissue Connective •
common agent considered is methotrexate. Randomized clinical trials have shown no real benefit in using methotrexate as a steroid sparing agent or to control GCA.
Overall, management of GCA is taxing and laborious, for both the patient and the physician, and it requires the trust and cooperation of all, including the patient’s local physician, because of the systemic side-effects of the prolonged steroid therapy.
Hunder GG, Sheps SG, Allen GL, Joyce JW: Daily and alternate-day corticosteroid regimens in treatment of giant cell arteritis: comparison in a prospective study. Ann Intern Med 82:613–618, 1975.
Spiera RF, Mitnick HJ, Kupersmith M, et al: A prospective, double-blind, randomized, placebo controlled trial of methotrexate in the treatment of giant cell arteritis (GCA). Clin Exp Rheumatol 19:495–501, 2001.
OCULAR OR PERIOCULAR
MANIFESTATIONS
Optic nerve
Anterior ischemic optic neuropathy, posterior ischemic optic neuropathy.
Retina
Central retinal artery occlusion, cilioretinal artery occlusions, cotton wool spots.
Choroid
Infracts.
Extraocular muscles
Ischemic paresis or paralysis.
Pupil
Pupillary abnormalities.
Eye
Ocular ischemia.
Brain
Cortical blindness, internuclear ophthalmoplegia.
REFERENCES
Costello F, Zimmerman MB, Podhajsky PA, Hayreh SS: Role of thrombocytosis in diagnosis of giant cell arteritis and differentiation of arteritic from non-arteritic anterior ischemic optic neuropathy. Eur J Ophthalmol 14:245–257, 2004.
Hayreh SS: Steroid therapy for visual loss in patients with giant-cell arteritis. Lancet 355:1572–1573; 356:434, 2000.
Hayreh SS, Podhajsky PA, Raman R, Zimmerman B: Giant cell arteritis: validity and reliability of various diagnostic criteria. Am J Ophthalmol 123:285–296, 1997.
Hayreh SS, Podhajsky PA, Zimmerman B: Ocular manifestations of giant cell arteritis. Am J Ophthalmol 125:509–520, 1998.
Hayreh SS, Podhajsky PA, Zimmerman B: Occult giant cell arteritis: ocular manifestations. Am J Ophthalmol 125:521–526, 893, 1998.
Hayreh SS, Zimmerman B: Visual deterioration in giant cell arteritis patients while on high doses of corticosteroid therapy. Ophthalmology 110:1204–1215, 2003.
Hayreh SS, Zimmerman B: Management of giant cell arteritis. Ophthalmologica 217:239–259, 2003.
Hayreh SS, Zimmerman B, Kardon RH: Visual improvement with corticosteroid therapy in giant cell arteritis. Acta Ophthalmol Scand 80:355–367, 2002.
Hoffman GS, Cid MC, Hellmann DB, et al: International Network for the Study of Systemic Vasculitides: a multicenter, randomized, doubleblind, placebo-controlled trial of adjuvant methotrexate treatment for giant cell arteritis. Arthritis Rheum 46:1309–1318, 2002.
Hunder GG, Bloch DA, Michel BA, et al: The American College of Rheumatology 1990 criteria for the classification of giant cell arteritis. Arthritis Rheum 33:1122–1128, 1990.
99 UVEITIS ASSOCIATED WITH JUVENILE IDIOPATHIC ARTHRITIS
714.30
Quan Dong Nguyen, MD, MSc
Baltimore, Maryland
Diana V. Do, MD
Baltimore, Maryland
ETIOLOGY/INCIDENCE
Juvenile idiopathic arthritis (JIA) is the currently most widely accepted term to describe the formerly designated term of juvenile rheumatoid arthritis (JRA) or juvenile chronic arthritis. Therefore, in this chapter, the term JIA will be applied in lieu of JRA. Uveitis associated with JIA is the most common cause of chronic intraocular inflammation among children.
Approximately 6% of all cases of uveitis occur in children, and up to 80% of all cases of anterior uveitis in childhood are associated with JIA. Chronic uveitis is a serious complication of JIA: up to12% of children with uveitis associated with pauciarticular JIA develop permanent blindness as a result of lowgrade chronic intraocular inflammation.
The prevalence of JIA in the United States has been estimated at 60,000 to 70,000 cases. JIA is more common in girls, with a female-to-male ratio of 3 : 2. There are 3 modes of JIA onset: systemic; polyarticular (5 or more joints); and pauciarticular (less than 5 joints). The peak age at onset of JIA is between 2 and 4 years. The incidence of iridocyclitis in patients with JIA ranges from 8% to 24%, and varies among subgroups of JIA. The uveitis is diagnosed an average of 18 months after the arthritis, although ocular manifestation may be the first sign of JIA in a child who has not yet begun to manifest evidence of systemic arthritis.
As with many other autoimmune conditions, where the targeted antigen is unknown.
The etiology for JIA or its associated uveitis is not known.
DISEASE COURSE/PROGNOSIS
Vision-threatening morbidities in JIA are mainly due to intraocular inflammation. The duration of the inflammation often correlates with the complications that cause vision impairment. The prognosis is dependent on the incidence and severity of the inflammatory disease, as well as the proper management of the patients. Overall, once the eye is affected with JIA uveitis, the prognosis is poor. Acute uveitis is often associated with persistent arthritis.
●Only one third of affected eyes retain visual acuity of >20/40 long-term.
●Approximately one third develop severe visual disability of <20/200.
180
Poor prognosticators include:
●Female sex;
●Young age of disease onset;
●Pauciarticular arthritis;
●Antinuclear antibody (ANA)-positivity;
●Posterior synechiae;
●Glaucomatous optic neuropathy.
DIAGNOSIS
Clinical signs and symptoms
JIA is not a precisely defined entity, but its presence is based on a clinical diagnosis.
●American Rheumatism Association defines JIA as clinical evidence of chronic arthritis (with duration of at least 3 months) of unknown cause in a child younger than 16 years.
●Patients with arthritis associated with a known etiology (see Differential diagnosis) are not classified to have JIA.
●ANA seropositivity is the chief laboratory risk factor for eye disease.
●Vast majority of JRA patients who develop eye disease are rheumatoid factor-negative.
●Three main subtypes of JIA:
●Chronic smoldering or recurrent course (>90%); rarely (<5%) acute monophasic.
●Mostly iridocyclitis (90%); rarely panuveitis or vitritis.
Differential diagnosis
●JIA.
●Juvenile arthropathies associated with HLA-B27.
●Juvenile spondyloarthropathy;
●Juvenile psoriatic arthritis;
●Juvenile Reiter syndrome;
●Juvenile enteritis (Crohn disease or ulcerative colitis).
●Juvenile sarcoidosis.
●Familial juvenile systemic granulomatosis.
●Infectious diseases (e.g. syphilis, herpetic keratouveitis, Lyme disease, tuberculosis).
●Masquerade syndromes:
●Leukemia;
●Retinoblastoma;
●Other malignancies.
TREATMENT
JIA-associated uveitis may be silent; thus, the child may be asymptomatic and the eye may be normal in appearance until
●Systemic 11% to 20%. Associated with fever, hepatleukocoria secondary to cataract is detected or when the child
osplenomegaly, lymphadenopathy, leukocytosis. Very |
fails a visual screening examination. Therefore, it is of signifi- |
low risk for eye disease; |
cant importance that guidelines for ophthalmologic examina- |
●Polyarticular 20% to 40%. Symmetric arthritis. Intertions, including slit-lamp biomicroscopy, be followed in all
mediate risk for eye disease: approximately 5% of patients with polyarticular-onset JIA develop uveitis;
●Pauciarticular 40% to 70%. Four or fewer joints involved; often asymmetrically. High risk of developing uveitis: approximately 20% of patients with polyarticular-onset JIA develop uveitis.
Ocular
●Bilateral in 70% to 80%.
●Nongranulomatous uveitis (>90%).
children diagnosed with JIA (Table 99.1).
Uveitis associated with JIA is often the most stubborn and most difficult to bring into durable remission. Leading authorities in the field of ocular immunology and uveitis have emphasized the need for ophthalmologist/ocular immunologist to ‘stay in the hunt,’ not quitting on the children with stubborn JIA-associated uveitis simply because the first NSAID or immunomodulatory agent that is tried does not successfully induce a durable remission. Rather, physicians should continue to search for a medication or combination of medications that will
TABLE 99.1 – American Academy of Pediatrics guidelines for ophthalmologic examination in children with JIA
Risk |
Type |
ANA |
Age at |
Duration |
|
|
|
Onset |
of Disease |
|
|
|
|
|
High |
Pauci or poly |
+ |
≤7 |
≤4 years |
Moderate |
Pauci or poly |
+ |
≤7 |
>4 years |
|
|
|
|
|
|
Pauci or poly |
− |
Any |
≤4 years |
|
|
|
|
|
|
Pauci or poly |
+ |
>7 |
>4 years |
Low |
Systemic |
− |
Any |
Any |
|
|
|
|
|
|
Pauci or poly |
(Rarely +) |
≤7 |
After 7 years |
|
|
|
|
|
|
Pauci or poly |
+ or − |
>7 |
After 4 years |
|
|
|
|
|
*American Academy of Pediatrics. Guidelines for examinations in children with Juvenile rheumatoid arthritis (RE9320). Pediatrics 92:295–296, 1993.
High risk: ophthalmologic exam Q 3–4 months
Moderate risk: ophthalmologic exam Q 6 months
Low risk: ophthalmologic exam Q 12 months
Recommendations for low-risk follow-up continue into adulthood.
Arthritis Idiopathic Juvenile with Associated Uveitis • 99 CHAPTER
181
Disorders9 SECTIONTissue Connective •
allow the patients to be completely free of all recurrences of inflammation, while at the same time being free of all steroid use at all times.
Systemic
●Systemic NSAIDs (e.g. naproxen at 10 to 15 mg/kg/day in divided doses) are used either as adjunctive therapy to help the steroid taper or as the sole systemic agent to supplement topical therapeutic measures.
●Long-term systemic treatment with corticosteroids is discouraged. A short course of systemic steroid therapy is occasionally used to supplement topical therapy in patients with significant inflammation. Systemic corticosteroid therapy retards linear growth in children, and most importantly, this effect can persist even after cessation of the corticosteroid therapy.
● Systemic steroid treatment (usually started at 0.5 to 1.0 mg/kg/day prednisone PO) is reserved for:
●Severe uveitis;
●Uveitis that is resistant to local treatment;
●Uveitis that involves posterior segment.
●Systemic chemotherapy is reserved for very severe cases that prove steroid-resistant and is used to limit complications resulting from prolonged use of systemic corticosteroids.
●The immunomodulatory drug of choice is methotrexate, which is often administered weekly. A second immunosuppressive medication is used when the chronic or recurrent uveitis not controlled with methotrexate as monotherapy. An alkylating agent such as chlorambucil has been shown to be effective and safe in patients with JIA-associated uveitis. Biological agents (infliximab, daclizumab) may have a role in the management of JIA-associated uveitis. Studies suggest that cyclosporine A, either as monotherapy or as an add-on agent to methotrexate immunomodulatory therapy program, is not the ideal agent for induction of durable remission of JIA-associated uveitis. Etanercept, which has been found to be efficacious in managing rheumatoid arthritis, has not been shown to be effective in managing uveitis such as that associated with JIA.
●All systemic immunosuppressive agents should be used in consultation with experts in the use of these agents in the pediatric population. It is strongly recommended that management of patients with JIA-associated uveitis be conducted by ocular immunologists/uveitis specialists whenever possible.
formation, maintain blood-aqueous barrier, and minimize visual disability from posterior subcapsular cataracts.
●Topical nonsteroidal anti-inflammatory drugs (NSAIDs) are employed as adjunctive therapy in patients at high risk for CME.
●Antiglaucoma therapy is necessary for patients with secondary ocular hypertension or glaucoma.
Surgical
●Cataract surgery.
●Glaucoma surgery.
●Ethylenediaminetetraacetic acid (EDTA) chelation for band keratopathy.
●Core vitrectomy for clearing inflammatory debris.
●Pars plana vitrectomy and membrane peeling for cyclitic and epiretinal membranes.
COMPLICATIONS
●Cataracts: 40% to 80%.
●Band keratopathy: 30% to 80%.
●Macular edema or epiretinal membrane formation: 30% to 50% in chronic cases.
●Vitreous haze/debris: 25%.
●Glaucoma: 15% to 30%.
●Chronic hypotony (ciliary body atrophy) and phthisis: 5% to 17%.
●Other posterior pole complications (disk neovascularization, ischemic optic neuropathy, macular hole): rare but can occur in chronic cases.
●Complications of treatments:
●Ocular hypertension caused by steroids;
●Growth stunting caused by oral corticosteroids;
●Infectious disease and organ toxicity in patients receiving immunosuppressive chemotherapy.
SUMMARY
JIA-associated uveitis — the most common type of pediatric ocular inflammation — is, ironically, often asymptomatic in children with JIA, leading to insidious but progressive morbidity in a significant number of children with this serious disease:
Local
●Corticosteroids (e.g. prednisolone acetate 1%) are the mainstay of therapy for patients with mild to moderate disease. Once disease activity is controlled, the frequency and potency of the regimen is reduced (e.g. to fluoromethalone 0.1%).
●About 20% of patients show little to no response to topical steroidal therapy.
●Periocular injections of corticosteroids (e.g. triamcinolone given as anterior sub-Tenon’s injections) or intravitreal injections are reserved for:
●More severe inflammation;
●Patients with more posterior inflammation;
●Patients with or at high risk for cystoid macular edema (CME).
●Prolonged therapy with steroids is associated with cataracts
and glaucoma. |
FIGURE 99.1. Chronic JIA-associated uveitis, with low grade inflam- |
●Mydriatics (cycloplegics; e.g. scopolamine 0.25%) are used mation and synnechiae, often presented as a ‘white, quiet-appearing’ as adjunctive therapy to minimize posterior synechiae eye.
182
FIGURE 99.2. Improper management of JIA-associated uveitis may lead to formation of cataract, development of glaucoma, band keratopathy, among others, and eventual phthisis.
JIA-associated uveitis still blinds children. It is imperative that JIA patients with a high risk of developing eye disease (ANApositive girls with pauciarticular disease) be identified, screened, and followed closely. Similarly, once the diagnosis of JIA uveitis is made, every attempt should be made to eradicate the inflammation so as to minimize the chance of irreversible loss of vision (Figures 99.1 and 99.2).
REFERENCES
Brewer EJ, Bass J, Baum J, et al: Current proposed revision of JRA criteria. Arthritis Rheum 20:195–199, 1977.
Chen CS, Roberton D, Hammerton ME: Juvenile arthritis-associated uveitis: visual outcomes and prognosis. Can J Ophthalmol 39:614–620, 2004.
Dana MR, Merayo-Lloves J, Schaumberg DA, Foster CS: Visual outcomes prognosticators in juvenile rheumatoid arthritis-associated uveitis. Ophthalmology 104:236–244, 1997.
Efthimiou P, Markenson JA: Role of biological agents in immune-mediated inflammatory diseases. South Med J 98:192–204, 2005.
Foster CS: Diagnosis and treatment of juvenile idiopathic arthritis-associ- ated uveitis. Current Opinion in Ophthalmology 14:395–398, 2003.
Giannini EH, Brower EJ, Kuzmind N, et al: Methotrexate in resistant juvenile rheumatoid arthritis: results of the U.S.A.-U.S.S.R. doubleblind, placebo-controlled trial. N Engl J Med 326:1043–1049, 1992.
Kanski JJ, Shun-Shin A: Systemic uveitis syndromes in childhood: an analysis of 340 cases. Ophthalmology 91:1247–1252, 1984.
Kanski JJ: Uveitis in juvenile chronic arthritis: incidence, clinical features and prognosis. Eye 2:641–645, 1988.
Kanski JJ: Juvenile arthritis and uveitis. Surv Ophthalmol 34:253–267, 1990.
Kimura SJ, Hogan MJ, Thygeson P: Uveitis in children. Arch Ophthalmol 51:80–88, 1954.
Nguyen QD, Foster CS: Saving the vision of children with juvenile rheumatoid arthritis-associated uveitis. JAMA 280:1133–1134, 1998.
Olson NY, Lindsley CB, Godfrey WA: Nonsteroidal anti-inflammatory drug therapy in chronic childhood iridocyclitis. Am J Dis Child 142:1289– 1292, 1988.
Rosenberg AM: Uveitis associated with juvenile rheumatoid arthritis. Semin Arthritis Rheum 16:158–173, 1987.
Smith JA, Thompson DJ, Whitcup SM, et al: A randomized, placebo-con- trolled, double-masked clinical trial of etanercept for the treatment of uveitis associated with juvenile idiopathic arthritis. Arthritis Rheum 53:18–23, 2005.
Wolf MD, Lichter PR, Ragsdale CG: Prognostic factors in the uveitis of juvenile rheumatoid arthritis. Ophthalmology 94:1242–1247, 1987.
100 WEGENER GRANULOMATOSIS
446.4
James L. Kinyoun, MD
Seattle, Washington
ETIOLOGY/INCIDENCE
Wegener granulomatosis is a necrotizing, granulomatous vasculitis of the sinuses (upper respiratory tract), lungs (lower respiratory tract), and kidneys. A limited form of the disease exists in which renal lesions are not present. All age groups can be affected, and symptoms include rhinorrhea, sinus pain, cough, malaise and weight loss. There is no gender predilection; almost all affected patients are white. Although the etiology remains unknown, available evidence (deposition of immune complexes) indicates that immunopathogenic mechanisms are responsible.
COURSE/PROGNOSIS
Most patients with Wegener granulomatosis initially have signs of upper respiratory tract inflammation that do not respond to treatment for commonly diagnosed conditions such as infection. Once the diagnosis has been established by biopsy, most affected patients have a relatively good prognosis with treatment; however, even with successful treatment, the disease is chronic, relapses occur and treatment complications are common.
DIAGNOSIS
Clinical signs and symptoms
Because eye symptoms can be the initial manifestation of Wegener granulomatosis, ophthalmologists should be aware of this disorder. Ophthalmic manifestations include proptosis due to orbital involvement usually via extension from adjacent sinuses; dry eyes; conjunctivitis; superficial corneal infection and ulceration (secondary to proptosis) Figure 100.1; scleritis or episcleritis; and uveitis. Other reported eye or periocular abnormalities include obstruction of the nasolacrimal duct, optic neuritis, papilledema, central retinal artery occlusion, retinal vasculitis and choriocapillariitis.
Laboratory findings
●Clinical findings: sinus and lung inflammation with or without renal involvement (e.g. proteinuria, hematuria, urinary casts).
●Histopathology: necrotizing, granulomatous vasculitis with infiltrative neutrophils, lymphocytes, plasma cells, histiocytes and giant cells.
●Antineutrophil cytoplasmic antibody (cANCA).
Differential diagnosis
●Upper respiratory infection (e.g. pulmonary infiltrates, sinusitis).
100GranulomatosisCHAPTER Wegener •
183