Uveitis: Systemic and Ocular Approaches to Management Blair B Lonsberry, MS, OD, MEd., FAAO Diplomate, American Board of Optometry Clinic Director and Professor of Optometry Pacific University College of Optometry blonsberry@pacificu.edu

Case 1: Payne

Case 30 BF presents with eye pain in both eyes for the past several days Severe pain (8/10) Never had eye exam before PMHx: Has chronic bronchitis Rash on legs Has recently lost weight and has a fever Taking aspirin for pain

Ocular Health Assessment VA: 20/30 OD, OS PERRL FTFC EOM”s: FROM with eye pain in all quadrants SLE: 3+ injection, 3+ cells and trace flare, deposits on endo (see photo) IOP: 18, 18 mmHg DFE: see attached fundus image and fluorescein angiography.

Classification of Uveitis 4 main questions we need answered Where is the inflammation located? Is disease acute or chronic? Granulomatous or non-granulomatous? Unilateral or bilateral?

Classification of Uveitis Secondary Questions: Demographics of the patient Has this happened before? If so did it respond to treatment? Systemic questions: Lung /breathing problems? Rashes/skin problems? Joint problems or low back pain? Urination issues? Digestive problems – diarrhea? Bloody stools? Cramps? Have you been out of the country recently? Have you been in a wooded area? Ticks? Any other systemic/autoimmune diseases? Use these secondary questions to further rule in/out similar causes of uveitis

Classification Classification is the key to the proper diagnosis and management of the uveitic patient Most common classifications Anterior vs. Intermediate vs. Posterior vs. Panuveitis Acute vs. Chronic/Recurrent Granulomatous vs. Non-granulomatous Infectious vs. Autoimmune Classification makes the diagnosis much simpler. If a person has uveitis – there can literally be dozens upon dozens of diseases that could be causing it Whereas if we say that a 28 yoM has an acute, unilateral, non-granulomatous anterior uveitis that narrows down our options. We may not know what the exact diagnosis is but there are a lot of conditions that we are now more suspicious of and a lot that we are less concerned about

Anterior Uveitis Classification Acute, unilateral (or bilateral), non-granulomatous anterior uveitis Idiopathic, HLA-B27, Herpetic, Behcet’s Chronic, bilateral (or unilateral), non-granulomatous anterior uveitis JIA, Fuch’s Heterochromic, Idiopathic, Herpetic Chronic, bilateral (or unilateral), granulomatous anterior uveitis TB, Sarcoid, Syphilis, VKH

Ocular Manifestations-Uveitis Signs/symptoms include: pain, photophobia, blurred vision, ciliary flush, cells/flare, rarely posterior involvement

Ciliary Flush, Cells, Flare

Treatment of Uveitis Treat the disease properly 2 main drugs/drops Minimize complications of the disease itself Minimize complications of the treatment 2 main drugs/drops Cycloplegics Topical Corticosteroids

Treatment Cycloplegia: used for reduction of pain, break/prevent the formation of posterior synechiae also functions in the reduction of inflammation I have seen quite a number of corneal FB’s that have come into the ER here and have been in there for 2 or 3 days, even a week. A lot of the times they have a mild traumatic iritis going on, and by the time I remove the FB with the spud or the alger brush they might have a fairly decent epithelial defect and I might not want to put a steroid on it with that huge defect. If they are in a lot of pain, 1) I am going to put a bandage CL on them 2) I am going to cycloplege them, and I will probably prescribe Homatropine instead of just putting it in office. And often times that alone with take care of that mild traumatic iritis.

Cycloplegics cyclopentolate 1-2% tid for mild-to-moderate, Common cycloplegic agents include: cyclopentolate 1-2% tid for mild-to-moderate, homatropine 5% or scopolamine 0.25% or atropine 1% bid-tid for moderate-to-severe inflammation most common is the use of Homatropine 5% bid be careful using atropine as there is potential for severe systemic side effects Also makes the iris essentially immobile can increase chances of peripheral anterior synechiae and peripheral posterior synechiae In cases of chronic uveitis where there is a lot of flare and the AC has that sticky, fibrinous quality, tropicamide and cyclopentolate are the way to go since often times these patients are not in a lot of pain and we want to keep the pupil relatively mobil to prevent posterior synechiae

Uveitis: Treatment “Classical treatment”: Newer treatment option: Pred forte: every 1-2 hours, ensure taper Pred forte: prednisolone acetate formulation which allows penetration through cornea to anterior chamber Newer treatment option: Durezol

Treatment Steroids: necessary for the treatment of active inflammation Most common is the use of prednisolone acetate 1% (e.g. Pred Forte 1%) Phosphate form -> does not penetrate cornea well Steroid medication that is felt to have less IOP response and report to not need as long of a taper is loteprednol etabonate (Lotemax)

Treatment options Durezol: Difluprednate Steroid emulsion BAK free only difluorinated steroid Steroid emulsion BAK free Increased “potency” so dosing needs to be less than “classical treatment” with Pred Forte rough recommendation is 1/2 dosing of Pred Forte

Treatment Topical administration is most common though periocular injections and systemic meds are useful for posterior uveitis and difficult cases Dosing is dependent upon severity of the inflammation typically you want to hit the uveitis hard and fast! E.g 1 gtt q 2hrs until the inflammation is gone! If you have a minimal anterior chamber reaction then steroid may not be necessary at all Periocular route – intermediate uveitis, posterior uveitis, CME, severe anterior uveitis unresponsive to topical meds given every month until the desired effect is achieved Systemic meds – severe posterior uveitis/panuveitis or anterior uveitis unresponsive to topical/periocular therapy

Treatment NOTE: it is crucial to taper your steroid treatment! You will have a rebound inflammation if you simply remove your patient from their steroids… The taper will be dependent upon how long you have had them on the steroid to get rid of the inflammation! Typically, a slow taper is better in order to prevent rebound inflammation If the patient has been on the steroid for less than a week a faster taper can be considered. And if you get rebound inflammation now you are setting yourself up for second guessing yourself. Did I miss something more serious, is the uveitis back and its now a recurrent uveitis for which I might send the patient for expensive lab-work? We taper based on the patients symptoms, some patients you may have to taper for months or even years. Every time the uvea is inflamed and opened up it is more susceptible to recurrent inflammation. So if a patient has had a recurrent inflammation 4-5 times you are going to have to taper them much more slowly. To prevent a low-grade smoldering iritis, you must treat beyond the cell and flare. In other words, if you taper corticosteroids too quickly in any case of iritis, especially a case associated with a systemic condition, such as Crohn's disease, sarcoidosis or ankylosing spondylitis, low-grade anterior chamber inflammation could linger dormant or even "reignite." By maintaining prolonged steroid dosing, even as conservatively as q.d. for one week after cell and flare are no longer evident in the anterior chamber, you can help prevent a rebound iritis.

Treatment NSAIDs: do not play an important role in the treatment of an acute uveitis may be used in the treatment of a chronic uveitis such as in a JRA patient who is using NSAIDs for the treatment of systemic pain. May be used as an adjunct to allow lower doses of corticosteroid

Treatment: Additional Therapies Immunosuppressive agents (cytotoxic) reserved for sight-threatening uveitis that have not responded to conventional treatment e.g. cyclophosphamide Antimetabolites (e.g. methotrexate) have been found useful in JRA related iridocyclitis and scleromalacia Cyclosporin has a very specific effect on the immune system and has been found useful in posterior and intermediate uveitis

Follow-up Every 1-7 days in acute phase depending upon severity and every 1-6 months when stable. On each f/u visit the AC reaction and IOP should be evaluated DFE should be performed for flare-ups, when VA affected, or every 3-6 months.

Follow Up If AC reaction improving, then steroid drops can be slowly tapered. cycloplegia can also be tapered as the AC reaction improves. slow taper recommended for chronic granulomatous uveitis.

Rules For Managing Uveitis Remember the classifications. Determine if there is corneal involvement & check IOP. Determine the severity. Is this a chronic problem? Treat strongly. Remember the classifications. Remember what are the most likely causes. Remember which systemic ?’s to ask (joint/back aches, rashes, urination problems, gut problems, breathing problems). Rule out a keratouveitis. Look for infiltrates. Are they a CL wearer? Apply NaFl & rose bengal to look for other corneal findings (epithelial defects, dendrites). Have to rule out a bacterial keratitis/ulcer, fungal keratitis, herpetic keratouveitis. Because the typically treatment for an idiopathic or even systemically caused uveitis is steroids & cycloplegic. Steroids would make all 3 causes above much worse.** Determine the severity. Is it unilateral or bilateral? Is this a recurrent condition? Are KP’s present? Are synechiae present? Is a severe anterior chamber reaction present? If 3 or more of these major findings are present, then this is likely a systemic/severe presentation and a medical workup is probably appropriate. Chronic problems. Much more likely to develop IOP spike/glaucoma, cataracts, CME, etc. To help alleviate #4, Rx strong steroids!!! For Pred Forte or Lotemax, dosing should be q2h or q1h only. (This even applies to low-grade uveitis cases, because you can taper the dose once improvement is noted.) The use of a generic steroid, however, is cautioned against, unless the patient is well educated about shaking the bottle vigorously.

Case 23 WM POHx: PMHx: Meds: Eye pain OD Severe, started 2 days ago Photophobia and redness POHx: Had similar problem and was given drops and felt better PMHx: Told to get back into shape and to reduce stress Meds: Ibuprofen for lower back pain

Assessment VA: 20/20-, 20/20+ Entrance skills unremarkable SLE: OD: 2+ injection, 2+ cell, Mild flare, Fine deposits IOP: 18, 14 mm HG DFE: unremarkable

HLA-B27 Conditions

Ankylosing Spondylitis Ankylosing spondylitis is a type of arthritis that affects the spine: symptoms include pain and stiffness from the neck down to the lower back. The vertebrae may grow or fuse together, resulting in a rigid spine. these changes may be mild or severe, and may lead to a stooped-over posture.

Ankylosing Spondylitis Ankylosing spondylitis affects about 0.1% to 0.5% of the adult population. Although it can occur at any age, spondylitis most often affects men in their 20s and 30s. It is less common and generally milder in women and most common in Native Americans. Early diagnosis and treatment helps control pain and stiffness and may reduce or prevent significant deformity.

Ankylosing Spondylitis Physical Exam: The overall points taken into account when making an AS diagnosis are: Onset is usually under 35 years of age. Pain persists for more than 3 months (i.e. it is chronic). The back pain and stiffness worsen with immobility, especially at night and early morning. The back pain and stiffness tend to ease with physical activity and exercise. Positive response to NSAIDs (nonsteroidal anti-inflammatory drugs).

Ankylosing Spondylitis X-rays: The hallmark of AS is involvement of the sacroiliac (SI) joint show erosion typical of sacroiliitis (inflammation of the sacroiliac joints). can take 7 to 10 years of disease progression for the changes in the SI joints to be serious enough to show up in conventional x-rays. Pre-Surgery Post-Surgery

Ankylosing Spondylitis HLA-B27 testing: Generally speaking, no more than 2% of people born with this gene will eventually get spondylitis it is important to note that the HLA-B27 test is not a diagnostic test for AS the association between AS and HLA-B27 varies in different ethnic and racial groups. over 95% of people in the caucasion population who have AS test HLA-B27 positive. only 50% of African American patients with AS possess HLA-B27 close to 80% among AS patients from Mediterranean countries.

Ankylosing Spondylitis Treatment: A common treatment regimen involves: Medication (NSAIDs, Methotrexate, Anti-TNF), exercise and possibly physical therapy, good posture practices, applying heat/cold to help relax muscles and reduce joint pain. In severe cases surgery may also be an option.

Psoriatic Arthritis Psoriasis is a scaly rash that occurs most frequently on the elbows, knees and scalp, but can cover much of the body. It is a chronic, inflammatory disease of the skin, scalp, nails and joints. A normal skin cell matures and falls off the body's surface in 28 to 30 days, but a psoriatic skin cell takes only three to four days to mature and gathers at the surface, thus forming lesions.

Psoriatic Arthritis In 5-10% of those with psoriasis, arthritis also appears. In most cases the psoriasis will precede the arthritis, sometimes by many years. When arthritis symptoms occur with psoriasis, it is called psoriatic arthritis (PsA). the joints at the end of the fingers are most commonly affected causing inflammation and pain, but other joints like the wrists, knees and ankles can also become involved. usually accompanied by symptoms of the fingernails and toes, ranging from small pits in the nails to nearly complete destruction and crumbling as seen in reactive arthritis or fungal infections.

Psoriatic Arthritis About 20% of people who develop PsA will eventually have spinal involvement, which is called psoriatic spondylitis. The inflammation in the spine can lead to complete fusion - as in ankylosing spondylitis - or skip areas where, for example, only the lower back and neck are involved. Those with spinal involvement are most likely to test positive for the HLA-B27 genetic marker. Up to 40% of people with PsA have a close relative with the disease, and if an identical twin has it, there is a 75% chance that the other twin will have PsA as well.

Psoriatic Arthritis Treatment for psoriasis remains suppressive, rather than curative. Treatment of articular manifestations generally begins with non-steroidal anti-inflammatory agents (NSAIDs). In patients with aggressive and potentially destructive disease, disease-modifying anti-rheumatic drugs (DMARDs) should be added early on in the course (Methotrexate, TNF-blockers, anti-malarials).

Reactive Arthritis Reactive Arthritis (also known as Reiter's Syndrome) is a form of arthritis that can cause inflammation and pain in the: joints, the skin, the eyes, the bladder, the genitals and the mucus membranes. Reactive arthritis is thought to occur as a "reaction" to an infection that started elsewhere in the body, generally in the genitourinary or gastrointestinal tract.

Reactive Arthritis Reactive arthritis occurs after exposure / infection caused by certain types of bacteria. These include: Chlamydia, a bacterium contracted during sexually activity, which causes either burning urination or watery discharge from the penis or vagina. Bacteria such as Salmonella, Shigella, Yersinia or Campylobacter, which cause dysentery (diarrhea, abdominal pain, vomiting, fever). Exposure to these bacteria occurs after eating spoiled or contaminated food. Not everyone exposed to these bacteria will contract ReA. Those who go on to develop ReA tend to test positive for the HLA-B27 genetic marker, although other genetic factors may be involved. Thus, it is an interaction between an individual's genetic make-up and the initial infection that causes Reactive Arthritis.

Reactive Arthritis ReA usually develops 2-4 weeks after the infection. A tendency exists for more severe and long-term disease in patients who do test positive for HLA-B27 as well as those who have a family history of the disease. Reactive Arthritis typically follows a limited course, where symptoms subsiding in 3-12 months. However, the condition has a tendency to recur. About 15-20% of people with ReA develop a chronic, and sometimes severe, arthritis or spondylitis.

Reactive Arthritis Treatment of reactive arthritis is based on where it has become manifest in the body. For joint inflammation, patients are generally initially treated with NSAIDs. prednisone is used in the short-term treatment of inflammation in reactive arthritis for the aggressive inflammation of chronic joint inflammation medications that suppress the immune system such as methotrexate

ReA Conjunctivitis Eye involvement occurs in about 50% of men with urogenital reactive arthritis and about 75% of men with enteric reactive arthritis. Conjunctivitis and uveitis can include redness of the eyes, eye pain and irritation, or blurred vision. Eye involvement typically occurs early in the course of reactive arthritis, and symptoms may come and go Treatment includes NSAIDs and/or steroids

Enteropathic Arthritis Enteropathic arthritis is a form of chronic, inflammatory arthritis associated with the occurrence of an inflammatory bowel disease (IBD): the two best-known types of which are ulcerative colitis and Crohn's disease. About one in five people with Crohn's or ulcerative colitis will develop enteropathic arthritis. The most common areas affected by enteropathic arthritis are inflammation of the peripheral (limb) joints, as well as the abdominal pain and possibly bloody diarrhea associated with the IBD component of the disease. In some cases, the entire spine can become involved as well.

Enteropathic Arthritis The course and severity of enteropathic arthritis varies from person to person. The disease "flares" - the times when the disease is most active and inflammation is occurring - tend to be self-limiting, often subsiding after 6 weeks, but reoccurrences are common. In some cases the arthritis may become chronic and destructive.

Treatment A common treatment regimen for all the spondyloarthropathies (ankylosing spondylitis, reactive arthritis, psoriatic arthritis, enteropathic arthritis, and undifferentiated spondyloarthropathy) involves medication, exercise and possibly physical therapy, good posture practices, and other treatment options such as applying heat/cold to help relax muscles and reduce joint pain. In severe cases of ankylosing spondylitis, surgery may also be an option.

Treatment Medication NSAIDs (nonsteroidal anti-inflammatory drugs) are still the cornerstone of treatment and the first stage of medication in treating the pain and stiffness associated with spondylitis. However, NSAIDs can cause significant side effects, in particular, damage to the gastrointestinal tract. When NSAIDs are not enough, the next stage of medications, (also known as second line medications), are sometimes called disease modifying anti-rheumatic drugs (DMARDS). This group of medications include: Sulfasalazine, Methotrexate and Corticosteroids.

Treatment Medication The most recent and most promising medications for treating ankylosing spondylitis are the biologics, or TNF Blockers. These drugs have been shown to be highly effective in treating not only the arthritis of the joints, but also the spinal arthritis. Included in this group are Enbrel, Remicade, Humira and Simponi

References Spondylitis Association of America http://www.spondylitis.org/main.aspx

Juvenile Idiopathic Arthritis

Juvenile Rheumatoid Idiopathic Arthritis (JRA/JIA) “Rheumatoid like” disease with onset before age 17 Group of arthritides responsible for significant functional loss in children Most common chronic disease with genetic predisposition in children. 2:1 female:male, with peak incidence b/w 2-4 and then 10-12

Natural History Pathogenesis unknown Immune-mediated activity directed towards Type II collagen RF mediated responses rarely found 1o involves weight bearing joints of lower extremities (knees/ankles) as well as joints of elbows/hands Little associated pain/tenderness observed

Diagnosis Synovitis that persists for at least 6 weeks is the essential criterion for diagnosis. Hematologic and radiographic studies are beneficial in diagnosis and classification. Fewer than 20% of patients have positive RF Radiographic evaluation of inflamed joints reveal soft tissue swelling and peri-articular osteoporosis with possible new bone formation. Loss of the cartilaginous space with erosions occur after long duration.

Treatment and Management-Systemic Primary goal is to control pathologic changes in articular tissues Typically runs self limiting course medical therapy needed only when persistent arthritis warrants Tx. ASA plays significant role in Tx in conjunction with exercise. NSAIDs have gained popularity and a few are approved for JIA. Dose dependent on body mass (e.g. indomethacin 1-3mg/kg/day TID)

Treatment and Management-Systemic Antimalarial not used as frequently as in RA efficacy is good but toxicity a concern when used they are limited to a 2 year course at 5-7 mg/kg/day. Use of gold salts common when arthritis not responding to ASA or NSAIDs. Immunosuppressive reserved for life threatening cases or cases unresponsive to other conservative therapies. Proper DX and TX results in recovery in about 85% cases

Ocular Manifestations Classic triad of iridocyclitis, cataract and band keratopathy Overall incidence of iridocyclitis is apprx 20%. Cataract, glaucoma, and band keratopathy are seen in 50% of patients who develop persistent iridocyclitis.

Ciliary Flush, Cells, Flare

Ocular Manifestations Severe vision loss results primarily from cataract formation and less frequently from band keratopathy. Insidious onset of ocular involvement, with the iridocyclitis commonly following the arthritis symptoms (though occasionally preceding) Patients are often asymptomatic and therefore require ocular evaluation for detection

Ocular Manifestations Evidence of chronic iridocyclitis may be presenting sign leading to Dx of JIA Posterior segment involvement is not commonly seen Band keratopathy in children <16 is pathognomonic for JIA results from aggressive/chronic ocular inflammation (not abnormal calcium metabolism). JIA patients do not present with the dry eye and K sicca manifestations that are so prevalent in RA.

Treatment and Management-Ocular Systemic medical therapy has minimal effect on ocular inflammation Topical steroids and short acting cycloplegics remain primary treatment Decreased VA 2o to cataract requiring extraction Band keratopathy develops in eyes with chronic iridocyclitis and require treatment with chelating agents Patients who develop glaucoma need to be treated aggressively