Boy presents with bilateral eye pain, photophobia
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A 12-year-old boy was referred to the uveitis clinic at the New England Eye Center for evaluation of pain and photophobia in both eyes beginning 3 months prior. His symptoms were associated with daily headaches.
At the time of his exam at NEEC, he denied photophobia, pain, redness or decreased vision in either eye.
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He was initially diagnosed with conjunctivitis in the right eye by his primary care physician. When symptoms did not remit, he saw an outside ophthalmologist who treated him for iritis in the right eye with prednisolone acetate 1% every hour, cyclopentolate three times a day and tobramycin-dexamethasone ointment at nighttime. His subjective symptoms resolved at this dosing frequency.
One month later, his symptoms began in the left eye and recurred in the right eye while attempting a steroid taper. He was restarted on hourly prednisolone acetate 1% and cyclopentolate three times a day in both eyes. Over the course of the ensuing 4 weeks, he was gradually weaned from topical steroid; he was asymptomatic with no anterior chamber cells as of 2 weeks before presentation at NEEC.
The patient was otherwise healthy with no known medical history. On review of systems, he and his mother reported daily headaches during recent weeks, occasional back pain, occasional skin rash, and recent intermittent diarrhea with abdominal pain. He denied fevers, night sweats, weight loss, oral/mucosal ulcers, shortness of breath, coughing, chest pains, dysphagia, dysuria, arthralgias, morning stiffness, muscle weakness and alopecia. Other than the topical eye drops, he did not take any medications.
He had allergies to certain laundry detergents and soaps but no known drug allergies. Family history was notable for a strong history of autoimmunity including Crohn’s disease (maternal grandmother), rheumatoid arthritis (maternal great-aunt), thyroid disease (maternal grandmother) and miscarriages (maternal aunt). Family history also included lymphoma and uterine cancer on the maternal side.
He lives at home with his parents and two siblings without any pets and attends middle school.
Examination
On exam, the patient’s uncorrected visual acuity was 20/20 in both eyes. External exam was unremarkable. Extraocular movements and confrontation visual fields were normal. Pupils were reactive to light without afferent pupillary defect. IOPs were 12 mm Hg and 10 mm Hg by Goldmann applanation tonometry. Conjunctivae were white and without injection in both eyes. Corneal exam was significant for endothelial pigment dusting in both eyes, 2+ anterior chamber cells and posterior synechiae in both eyes. The lenses were clear.
Dilated fundus exam revealed moderate optic disc edema in both eyes. The vitreous was clear, the macula and peripheral retina were normal without signs of inflammatory retinitis, and the vessels were normal without evidence of vasculitis.
What is your diagnosis?
See answer below.
Bilateral anterior uveitis
This patient had bilateral acute simultaneous onset (within weeks) anterior uveitis with secondary optic disc swelling. The differential diagnosis necessitates consideration of infectious, inflammatory and drug-related etiologies. In many instances, workup is nonrevealing, and patients are followed for idiopathic disease.
Careful medication history is important as drug-induced reaction is a leading cause of bilateral simultaneous onset anterior uveitis. Oral antibiotics, such as moxifloxacin, and cancer medications are most frequently implicated. Other potential instigators include rifampin, cidofovir, sulfonamides and bisphosphonates. Topical brimonidine for treatment of elevated IOP may precipitate a mimicker reaction.
Inflammatory causes include spondyloarthropathies (such as HLA-B27), juvenile idiopathic arthritis, sarcoid, tubulointerstitial nephritis and uveitis, and inflammatory bowel disease.
Postinfectious bilateral anterior uveitis has been described; some practitioners may choose to investigate for post-streptococcal infection antibodies. Syphilis and tuberculosis should be ruled out.
Additional workup
Laboratory investigation for systemic infectious and inflammatory etiologies included complete blood count, complete metabolic panel, urinalysis with protein-to-creatinine ratio, urine beta-2-microglobulin, treponema pallidum antibody, antistreptolysin O (ASO) antibodies, ANA, rheumatoid factor, HLA-B27, ACE, and QuantiFERON Gold.
The patient was found to have elevated erythrocyte sedimentation rate (ESR) of 26, positive ASO titer, elevated DNase B antibody of 434, ANA 1:80, and elevated urine beta-2-microglobulin of 480.77. Other laboratory investigations were normal.
Discussion
Based on ophthalmic presentation and significantly elevated urine beta-2-microglobulin, the patient was diagnosed with presumed tubulointerstitial nephritis and uveitis (TINU) syndrome. A renal biopsy was not pursued in his case; clinical diagnostic criteria are described below.
TINU is a rare entity, representing less than 2% of patients who present to uveitis clinics in tertiary care settings, and has an estimated prevalence of 3.5 per 1 million people. It should, however, remain on the provider’s differential, as it accounts for one-third of acute onset bilateral anterior uveitis cases in the pediatric population and 10% of the acute bilateral anterior uveitis cases overall; it has been reported in older adults. HLA-DQA*01, HLA-DQB1*05 and HLA-DRB*01 have been identified as high-risk alleles, but no inheritance pattern has been described, and there is no known predilection based on sex or ethnicity.
Nephritis more commonly precedes uveitis in 65% of cases, while in 15% of cases, onset of nephritis and uveitis is simultaneous. Patients with nephritis experience systemic symptoms such as fevers, weight loss and fatigue, while those with primary ocular symptoms report pain, photophobia, decreased vision or no symptoms. In 20% to 25% of cases, uveitis is the presenting sign, and patients will present with acute onset bilateral nongranulomatous anterior uveitis. On exam, sequelae of inflammation may also be identified, including cystoid macular edema, optic disc edema, elevated IOP and posterior synechiae.
The pathologic mechanism underlying TINU remains unknown, although there are theories described in the literature. One such study describes loss of T-cell tolerance and identifies a link between TINU and HLA class II subtypes. Dysregulation of humoral immunity may also be implicated, with autoreactive antibodies directed against renal and ocular antigens. One study found elevated titers of anti-monomeric C-reactive protein (anti-mCRP) antibodies in the serum of nine patients with active TINU. mCRP, a dissociated monomer of CRP involved in the regulation of the complement pathway, is increased in nephritic kidneys and also found in the iris and ciliary body.
Laboratory testing is key to diagnosis; particularly helpful is urine beta-2-microglobulin testing. Urine beta-2-microglobulin is a component of MHC class I molecules, which are present on all nucleated cells. This protein is excreted by glomeruli and resorbed by normally functioning tubular epithelium. Resorption of this protein is impaired in interstitial nephritis and can remain impaired even after renal function normalizes. If beta-2-microglobulin is elevated in the urine, this is 87.5% sensitive and 70% specific for TINU in patients who are younger than 22 years. Presence of normal urine beta-2-microglobulin can rule out the disease. Of note, urine beta-2-microglobulin can be abnormal in other disease processes that affect the kidneys, such as diabetes.
Diagnosis is classified as “definite,” “probable” and “possible” based on certain clinical criteria for interstitial nephritis in addition to the presence of typical or atypical uveitis. These criteria include abnormal renal function tests; abnormal urinalysis (elevated beta-2-microglobulin, low-grade hematuria, pyuria, urinary eosinophils, hematuria, glycosuria or white blood cell casts); and systemic illness lasting longer than 2 weeks (any combination of signs and symptoms such as fever, fatigue, weight loss and lab abnormalities including anemia, abnormal liver function tests, eosinophilia or elevated ESR). “Typical” uveitis is defined as bilateral anterior uveitis with or without posterior uveitis onset less than 2 months before or 12 months after nephritis. “Definite” cases exhibit typical uveitis and biopsy-proven interstitial nephritis or complete clinical criteria. “Probable” cases include atypical uveitis with positive renal biopsy or typical uveitis and incomplete interstitial nephritis clinical criteria. “Possible” cases are those in which there is atypical uveitis and incomplete interstitial nephritis criteria.
Based on the above case stratification, the patient presented here is within the “probable” category with typical uveitis plus normal renal function and abnormal urinalysis, with signs of systemic illness including increased ESR and gastrointestinal symptoms.
No large randomized controlled trials have been conducted to establish treatment guidelines for patients with TINU. As in other uveitic disease processes, the typical patient begins with topical steroid therapy and graduates to systemic steroid or immunomodulatory therapy (IMT) based on the severity of disease and risk for vision-threatening ocular sequelae. IMT is indicated in cases when symptoms recur with discontinuation or tapering of steroids, and it has the benefit of reducing steroid-related side effects. IMT can mitigate ocular complications of recurrent inflammation, such as posterior synechiae, secondary glaucoma and secondary cataract (from prolonged steroid therapy), macular edema and band keratopathy. Consideration and early initiation of IMT in pediatric patients is crucial, as steroids can delay or impair pubertal growth, which may be irreversible.
The use of biologics has been described in a small group of patients with TINU. A 2005 study features 13 patients who had clinical deterioration despite IMT (such as corticosteroids, cyclosporine, methotrexate and interferon-alpha) or had a serious side effect due to treatment. These patients received a series of one to 12 infusions of anti-TNF-alpha therapy with infliximab. All patients showed an improvement in inflammation and visual acuity, and the majority could then be controlled on IMT alone thereafter. In a study from 2018, long-term outcomes for patients with uveitis treated with biologic therapy were favorable; recurrences were fewer, and remission was achieved in six of nine p atients.
The ocular prognosis is typically favorable, although two-thirds of patients will require systemic therapy, often driven by eye disease rather than nephritis. One-third of patients will respond to topical therapy alone. Chronic uveitis is more common in pediatric patients. A subset of patients with renal disease will have permanent kidney damage secondary to inflammation, while some patients will have restoration of normal kidney function. Prompt initiation of systemic treatment may improve renal outcomes. Rarely, TINU may lead to end-stage renal disease requiring dialysis and transplant. The presence or absence of uveitis has not been shown to correlate with severity of renal disease.
TINU is one of several inflammatory and infectious diseases that can cause concomitant uveitis with nephritis. In patients presenting with a history of or simultaneous onset of uveitis and interstitial nephritis, sarcoid, lupus, granulomatosis with polyangiitis, Behçet’s disease, tuberculosis and syphilis should be considered. It is essential to keep a broad differential in mind, investigate all possible etiologies, and work with an interdisciplinary team to manage multisystem disease.
Case resolution
The patient was started on prednisolone acetate six times daily and tropicamide two times daily in both eyes with close ophthalmology follow-up. He was managed by pediatric nephrology and rheumatology concurrently and began injectable methotrexate 20 mg weekly. He improved, and the steroid was tapered over the course of 8 weeks. His symptoms recurred within 1 month after completion of steroid taper; treatment was reinitiated, and he remained at twice-daily dosing for 10 months. His methotrexate dose was increased to 25 mg weekly. Due to his persistent inflammation not well controlled by methotrexate alone, he was started on injectable adalimumab 40 mg/0.4 mL every 2 weeks. He was then able to decrease topical steroid to once daily and ultimately discontinue it.
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- For more information:
- Erin Lanzo, MD, and Lana Rifkin, MD, can be reached at New England Eye Center, Tufts University School of Medicine, 800 Washington St., Box 450, Boston, MA 02111; website: www.neec.com.
- Edited by Yi Ling Dai, MD, and Teresa P. Horan, MD. They can be reached at New England Eye Center, Tufts University School of Medicine, 800 Washington St., Box 450, Boston, MA 02111; website: www.neec.com.