By Mary Whitman, MD
Faculty Peer Reviewed
Clinical question: What should the medical work-up be for an adult newly diagnosed with uveitis?
Uveitis, defined as intraocular inflammation of the eye, can be idiopathic and limited to the eyes, or can be a manifestation of systemic inflammatory diseases and infectious diseases.
The single most common cause of uveitis is idiopathic.[1] However, uveitis is a manifestation in spondylarthropathies, inflammatory bowel disease, Behcet’s Disease, and sarcoidosis, and may be the presenting symptom of these systemic disorders. Uveitis can also be caused by infections such as HIV, CMV, syphilis, tuberculosis (TB), toxoplasmosis, cat scratch disease, West Nile virus, Lyme disease, and herpes simplex virus. There are also some “masquerade syndromes,” such as intraocular large cell lymphoma, that can initially present as uveitis. Given the broad differential, there are a myriad of tests that could be ordered, and the work-up could be quite expensive. Based on simple classifications, however, a more tailored, efficient, and cost-effective work-up is possible.
Uveitis is classified based on anatomic location of the inflammation, laterality and clinical course. Anterior uveitis (also known as iritis) involves the iris or ciliary body; intermediate uveitis involves the vitreous, pars plana and peripheral retina; and posterior uveitis involves the choroid or retina. The term “panuveitis” is used when more than one area is involved. Clinical course is defined as acute, chronic, or recurrent. Bilateral uveitis is simultaneous involvement of both eyes.[2] These distinctions are important, as different presentations of uveitis are associated with different systemic diseases, and should guide further investigations.
The most important first step for all patients with uveitis is a complete, detailed history and full physical exam. In many patients, there will be other signs or symptoms of systemic disease, such as joint pain, diarrhea, or oral or genital ulcers, that suggest a certain diagnosis, and then the work-up should be tailored toward the suspected diagnosis. It is also important to assess risk factors for the possible infectious etiologies. Many infections have characteristic eye findings and will be diagnosed by the ophthalmologist, but syphilis, TB, and Lyme disease do not, and need to be considered in the medical work-up.[3]
For patients without signs or symptoms suggesting a systemic disease, the pattern of the uveitis guides the investigation. In a patient with no signs of systemic disease upon thorough review of systems, a simple, unilateral acute anterior uveitis that responds appropriately to topical anti-inflammatory therapy demands no investigation, except perhaps a one-year follow-up.[4] Anterior uveitis does need further investigation if it is recurrent, bilateral, severe, or has granulomatous features.[5] HLA-B27 associated uveitis often presents as acute unilateral severe anterior uveitis, which often relapses, and represents about 50% of cases of anterior uveitis.5 A significant majority of patients with HLA-B27 positive anterior uveitis develops spondylarthropathies, and over half are not diagnosed until ophthalmologic manifestations are present.[6],[7] Thus, these patients should have an HLA-B27 test, and if it is positive, further investigation or rheumatology referral.
Sarcoidosis and syphilis are the great mimickers and need to be ruled out for almost all types of uveitis. Since syphilitic uveitis occurs in the secondary or tertiary stages of the disease, when screening tests such as VDRL can be negative, both VDRL and a confirmatory test such as FTA-ABS should be ordered for all patients.5 For sarcoid, a chest x-ray is the first step, along with measurement of serum angiotensin-converting enzyme (ACE) levels. High ACE has a sensitivity of 84%, and specificity of 95% among uveitis patients for diagnosis of sarcoid.[8] Among older women with chronic uveitis, chest CT reveals sarcoidosis in a significant proportion, even with a negative chest x-ray,[9] so should be considered in the workup of that population.
TB is now a relatively rare cause of uveitis in developed countires,1 but needs to be ruled out in patients with TB risk factors and granulomatous features of uveitis. Negative PPD skin testing and chest x-ray (which is included in the sarcoidosis work-up as above) are generally sufficient to rule the disease out, but further testing is indicated if either is positive.
Pars planitis, a specific form of intermediate uveitis, is associated with multiple sclerosis, so those patients should receive neurological evaluation.[10] ,[11]
Other systemic illnesses associated with uveitis include IBD, psoriatic arthritis, tubulointerstitial nephritis and uveitis (TINU), and Vogt-Koyanagi-Harada disease. Specific testing for these disorders in the absence of signs or symptoms is not warranted, but it is important to recognize the symptoms and test appropriately. It is also important to reassess patients at regular intervals, as extraocular manifestations of these disorders can develop later in the disease course, and if they do, then the patient deserves further investigation.
TINU, which is rare and associated with HLA-DRB1*01, presents with a sudden onset of acute bilateral anterior uveitis. Patients generally have constitutional symptoms that might suggest renal disease, and the initial workup should include CBC, chemistries and urinalysis. [12]
Behcet’s disease is common in Japan and the Mediterranean, and is typically associated with an anterior or posterior uveitis that is chronic and bilateral. Uveitis can be the presenting symptom in up to 25% of cases. Diagnosis is clinical, based on the presence of uveitis, oral ulcers, genital ulcers, and skin lesions.[13]
Vogt-Koyanagi-Harada disease is an autoimmune disorder against melanocyte-associated antigens. It is an uncommon cause of uveitis in the United States, but more common in Japan. The uveitis is bilateral, sudden onset and may be anterior, posterior or pan-uveitis. Audiology testing is suggested, as up to 50% of patients show sensory hearing loss.[14]
Although many inflammatory disorders are associated with specific HLA types, a recent review shows that routine HLA typing is of limited usefulness, with a positive predictive value <0.5 in most disorders. The exception is HLA-B27 testing in patients with recurrent acute anterior uveitis.[15]
In summary, the initial approach to the adult with uveitis begins with a thorough history and physical. When signs of a specific disorder are present, that disorder should be investigated. In an otherwise asymptomatic patient, a simple mild case of anterior uveitis that responds to therapy only needs follow-up. Severe, bilateral, chronic or recurrent anterior uveitis in an otherwise asymptomatic patient warrants HLA-B27 testing, chest x-ray, ACE, VDRL and FTA-ABS, PPD and possibly chest CT. Other tests routinely ordered, such as CBC, ANA, ESR, rheumatoid factor, chemistries, and UA, are of low yield in achieving a specific diagnosis, and significantly increase costs.[16] All patients need to be reevaluated periodically for the development of symptoms that would suggest a systemic disorder.
Dr. Whitman is a former NYU resident and is now a 1st year ophthalmology resident at Columbia university
Peer reviewed by Peter Izmirly, MD, Assistant Professor, Department of Medicine (Rheumatology), NYU Langone Medical Center
Image courtesy of Wikimedia Commons
References:
[1] Rodriguez A, Calonge M, Pedroza-SeresM, Akova YA, Messmer EM D’Amico DJ, Foster CS. Referral patterns of uveitis in a tertiary eye care center. Arch Ophthalmol. 1996 May;114(5):593-9. http://archopht.ama-assn.org/cgi/content/abstract/114/5/593
[2] Standardization of Uveitis Nomenclature (SUN) Working Group: Standardization of uveitis nomenclature for reporting clinical data. Results of the fi rst international workshop. Am J Ophthalmol 2005, 140: 509– 516. http://www.ajo.com/article/S0002-9394(05)00407-1/abstract
[3] Rosenbaum JT. An algorithm for the systemic evaluation of patients with uveitis: guidelines for the consultant. Semin Arthitis Rheum. 1990. Feb;19(4):248-57. http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WWX-4C0MJNN-7W&_user=10&_coverDate=02%2F28%2F1990&_alid=1353218893&_rdoc=1&_fmt=high&_orig=search&_cdi=7142&_sort=r&_docanchor=&view=c&_ct=1&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=fc7e030be7638c94886d77039471114c
[4] Wade NK. Diagnostic testing in patients with ocular inflammation. Int Ophthalmol Clin. 2000. 40(2):37-54. http://journals.lww.com/internat-ophthalmology/Citation/2000/04000/Diagnostic_Testing_in_Patients_With_Ocular.5.aspx
[5] Forooghian F, Gupta R, Wong DT, Derzko-Dzulynsky L. Anterior uveitis investigation by Canadian ophthalmologists: insights from the Canadian National Uveitis Survey. Can J Ophthalmol. 2006. 41:576-83. http://pubservices.nrc-cnrc.ca/rp-ps/absres.jsp?jcode=cjo&ftl=i06-048&lang=eng
[6] Linssen A, Meenken C. Outcomes of HLA-B27-positive and HLA-B27-negative acute anterior uveitis. Am J Ophthalmol. 1995. 120(3):351-61.
[7] Monnet D, Breban M, Hudry C, Dougados M, Brezin AP. Ophthalmic findings and frequency of extraocular manifestations in patients with HLA-B27 uveitis: a study of 175 cases. Ophthalmology. 2004. 111(4):802-9. http://www.ophsource.org/periodicals/ophtha/article/S0161-6420(03)01529-X/abstract
[8] Baarsma GS, La Hey E, Glasius E: The predictive value of serum angiotensin converting enzyme and lysozyme for the diagnosis of ocular sarcoidosis. Am J Ophthalmol 1987, 104: 211– 217.
[9] Kaiser PK, Lowder CY, Sullivan P, Sanislo SR, Kosmorsky GS, Meziane MA, Rice TW, Smith SD, Meisler DM. Chest Computerized Tomography in the evaluation of uveitis in elderly women. Am J Ophthalmol. 2002. 133(4):499-505. http://www.ajo.com/article/S0002-9394(02)01333-8/abstract
[10] Zein G, Berta A, Foster CS. Multiple sclerosis-associated uveitis. Ocul Immunol Inflamm. 2004; 12:137-42. http://www.informaworld.com/smpp/content~db=all~content=a714018221~frm=abslink
[11] Malinowski SM, Pulido JS, Folk JC. Long-term visual outcome and complications associated with pars planitis. Ophthalmology. 1993. 100:818-24. http://www.ophsource.org/periodicals/ophtha/article/S0161-6420(93)31567-8/abstract
[12] Mackensen F, Billing H. Tubulointerstitial nephritis and uveitis syndrome. Curr Opin Ophthalmol 2009. Nov, 20(6):525-31. http://journals.lww.com/co-ophthalmology/Abstract/2009/11000/Tubulointerstitial_nephritis_and_uveitis_syndrome.17.aspx
[13] Hooper C, McCluskey P. Intraocular Inflammation: Its Causes and Investigations. Curr Allergy and Asthma Reports. 2008: 8:331-338. http://www.current-reports.com/article_frame.cfm?PubID=AL08-4-2-02&Type=Abstract
[14] Mantovani A, Resta A, Herbort C, et al. : Work-up, diagnosis and management of acute Vogt-Koyanagi-Harada disease. Int Ophthalmol 2007, 27: 105– 115. http://www.springerlink.com/content/c335mr637v837782/?p=e7a80f6ede3944a48cd2a281b06d3b54&pi=5
[15] Zamecki KJ, Jabs DA. HLA typing in uveitis: use and misuse. Am J Ophthalmol. 2010 Feb;149(2):189-193.e2 http://www.ajo.com/article/S0002-9394(09)00731-4/abstract
[16] Noble J, Hollands H, Forooghian F, Yazdani A, Sharma S, Wong DT, Derzko-Dzulynsky L. Evaluating the cost-effectiveness of anterior uveitis investigation by Canadian ophthalmologists. Can J Ophthalmol. 2008. 43(6):652-57. http://pubservices.nrc-cnrc.ca/rp-ps/absres.jsp?jcode=cjo&ftl=i08-147&lang=eng
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