PGMJ Online First, published on September 23, 2017 as /postgradmedj Review 1 Department of Ophthalmology, University Hospital Birmi

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1 THIS INSTRUCTION SHEET IS NOT TO BE SHOWN TO THIS INSTRUCTION SHEET IS NOT TO BE SHOWN TO, HEALTH CARE PROVIDERS, COPIED OR DISTRIBUTED COPIED FOR OR DISTRIBUTED TO EXTERNAL PARTIES Instructions for Use: Representative Education Only This material is approved for Representative Education only. This material must not be shown to, copied for, distributed to, discussed with or otherwise used with any external parties All text presented in Italics are Form Instructions that should be deleted prior to routing unique projects utilizing this Form for review and approval. Material Name: Uveitis DA Article Rep Ed Intended Sales Representative Audience (e.g., IMHC, Sales Reps, GPAEs): All Sales Reps Objective/Need for Representative Education: To educate representatives on Uveitis clinical presentation and connection with systemic disease. Clinical or Educational Rationale supporting Objective/Need: This article will provide representatives with information about the diagnosis and treatment of Uveitis. This will serve as background knowledge to provide reps with insight into the complexities of the disease. It will assist them in understanding how HUMIRA fits into the treatment landscape. Key Educational Message(s): This information in this article is for rep education only. You will receive additional specific direction on the use of promotional information and resources that can be shared with your customers. This information should not be discussed with your HCPs. Other corresponding Representative Education approved materials: This is new information that has not been provided previously. Future Plans for further Representative Education: This information will be reinforced through future training as specific needs are identified. Guardrails for Use: The accompanying information is being provided for representative education purposes only. This information must not be used with any external customer AbbVie Inc. North Chicago, IL October 2017 Printed in U.S.A. Page 1 of 1 PD02-05-F05 Version 2.0 FOR REPRESENTATIVE EDUCATION TRAINING

2 PGMJ Online First, published on September 23, 2017 as /postgradmedj Review 1 Department of Ophthalmology, University Hospital Birmingham NHS Foundation Trust, Birmingham, UK 2 Centre for Rare Diseases, Institute of Translational Medicine, Birmingham Health Partners, Birmingham, UK 3 Academic Unit of Ophthalmology, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK 4 NIHR BiomedicalResearch Centre for Ophthalmology, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, UK Correspondence to Alastair K Denniston, Academic Unit of Ophthalmology, Institute of Inflammation & Ageing, University of Birmingham, Birmingham B15 2TT, UK; a. denniston@ bham. ac. uk UK and DA contributed equally. Received 16 February 2017 Revised 31 May 2017 Accepted 20 August 2017 To cite: Krishna U, Ajanaku D, Denniston AK, et al. Postgrad Med J Published Online First: [please include Day Month Year]. doi: / postgradmedj Uveitis: a sight-threatening disease which can impact all systems Unnat Krishna, 1 Deji Ajanaku, 1 Alastair K Denniston, 1,2,3,4 Theodora Gkika 1 Abstract Uveitis describes a group of conditions characterised by intraocular inflammation. The term uveitis technically describes inflammation of the uvea which comprises the iris, ciliary body and choroid, however now encompasses inflammation of adjacent intraocular structures such as the retina, vitreous and optic nerve. Uveitis is a significant cause of blindness worldwide, but its impact is generally underappreciated due to a lack of awareness and understanding of the condition among the public and most non-ophthalmic healthcare professionals. In this review, we provide an introduction to uveitis for the non-specialist, outlining the clinical presentations that should raise the suspicion of the disease, the signs that should be looked for and a framework in which to understand the condition. We show how a logical approach to classifying uveitis by aetiology and anatomical focus of disease provides the basis for treatment strategies (drug and route of administration) and clinical presentation and prognosis. We also show why understanding uveitis is helpful to clinicians working in almost every speciality due to the wide-ranging associations with systemic disease. Introduction Uveitis describes a group of conditions characterised by intraocular inflammation. The term uveitis technically describes inflammation of the uvea which comprises the iris, ciliary body and choroid. As the intraocular inflammation can affect surrounding tissues, the clinical term uveitis may include inflammation of the retina (retinitis), optic disc (papillitis) and vitreous (vitritis) (figure 1). 1 It is a condition which is completely unknown to most of the population, poorly understood by most non-specialists and undervalued by most policymakers. Uveitis is, however, a condition with global impact and with direct relevance to health professionals working across many sectors and specialities. First, it is a major cause of sight loss worldwide, particularly among the working-age population. Second, it may be the first presentation of serious systemic disease and be a vital warning sign that allows early diagnosis and medical intervention. Finally, the combination of effects on sight, ocular discomfort, systemic disease and treatment-related side effects often have a profound impact on people s quality of life, and deserve due consideration. Epidemiology Estimates from Europe and the USA suggest that the incidence of uveitis is around 20 50/ / year, and prevalence estimates being in the order of / population. 2 3 There is however significant worldwide variation, with tropical and less developed countries exhibiting higher incidence and prevalence largely due to a much higher burden of infectious causes. 4 It is estimated that more that 2 million people worldwide have uveitis, 5 and is thought to be responsible for 10% of worldwide blindness. Some studies suggest that it is increasing in incidence. 3 Uveitis onset tends to most commonly occur in the working age population. 6 7 A study of 3000 consecutive patients with uveitis in the UK noted that 78% were in the age group, 13% were under 16 years of age and 9% were over 65 years of age. 6 Similarly, Çakar Özdal et al reported that the mean age of presentation with uveitis was 36 years of age. 7 With regard to gender, most but not all studies report a slight female preponderance The correlation between ethnicity and uveitis largely depends on the underlying subtype. For example, sarcoid uveitis is more common in African-Caribbean patients, herpetic uveitis is more common in Caucasian patients and tuberculous uveitis is more common in Asian patients. 6 8 Classification of uveitis Uveitis can be classified according to: 1. the anatomical parts of the eye affected by the disease, or 2. the underlying aetiological cause (box 1). Broadly, the anatomical categories refer to the regions of the uveal tract affected. This system was devised by the Standardization of Uveitis Nomenclature working group. 14 It includes anterior, intermediate, posterior and panuveitis. Anterior uveitis may involve the iris (iritis) and/or the ciliary body. 12 Intermediate uveitis is primarily characterised by inflammation of the vitreous humour (vitritis). Posterior uveitis involves the choroid (choroiditis), the overlying retina (retinitis) or both (chorioretinitis). More widespread inflammation across anatomical regions is referred to as panuveitis. 13 A number of additional descriptors are commonly used to help identify the pattern of disease, help diagnosis and guide treatment. Descriptors of the course of uveitis comprise acute (ie, sudden onset and limited duration), recurrent (repeated episodes separated by periods of inactivity off treatment of greater than 3 months in duration) and chronic (persists and relapses in less than 3 months after discontinuing treatment). Aetiologically, uveitis may be the result of infectious, non-infectious or masquerade causes as described by the International Uveitis Study Group (figure 2). 12 In Europe and the USA, uveitis is more Krishna U, et al. Postgrad Med J 2017;0:1 8. doi: /postgradmedj Copyright Article author (or their employer) Produced by BMJ Publishing Group Ltd under licence.

3 Review Figure 1 Anatomical classification of uveitis. (A) is a schematic cross-sectional diagram of the eye, with emboldened labels referring to structures that may typically be inflamed during uveitis. (B) is a flow diagram which categorises different types of uveitis (anterior, intermediate, posterior and panuveitis), according to the structures inflamed. Panuveitis refers to inflammation of the entire uveal tract. commonly due to non-infectious aetiology, with one systematic review that estimated this at around 81%. 15 Most non-infectious causes appear to be autoimmune or autoinflammatory in nature, and may be associated with systemic conditions characterised by dysregulation of the immune system or inflammasome (a multiprotein sensor that activates innate immunity after detecting pathogens). Associations include ankylosing spondylitis (AS), for whom uveitis is the most common extra-articular complication, arising in up to 50% of patients Similarly, uveitis is a Box 1 Key points on classification Classification by aetiology Infectious uveitis such as due to tuberculosis, syphilis or toxoplasma; requires treatment of the underlying infection with antimicrobials, sometimes accompanied by corticosteroids to help reduce severity of inflammation. Non-infectious uveitis which is thought to be autoimmune (or at least autoinflammatory); most treatments are forms of corticosteroid or other immunosuppressant. Masquerade uveitis in which the primary disease is not inflammatory, such as seen in intraocular lymphoma. The treatment of masquerade uveitis is specific to the cause, for example, chemotherapy for lymphoma. Classification by anatomy Anatomically, uveitis is classified according to the primary site of inflammation as seen clinically into: anterior where the primary site is the anterior chamber; intermediate where the primary site is the vitreous; posterior where the primary site is retina or choroid; and panuveitis where the inflammation is distributed between all the above. 2 Krishna U, et al. Postgrad Med J 2017;0:1 8. doi: /postgradmedj Figure 2 Aetiological classification of uveitis. This flow diagram categorises uveitis according to its various causes. Broadly, these being infectious, non-infectious and masquerade syndrome, for which selected examples are shown. Most non-infectious uveitis appears to be autoimmune (or auto-inflammatory ). *This is a phenomenon observed where patients with HIV develop uveitis, shortly after initiating highly active antiretroviral therapy (HAART). **This refers to diseases which resemble uveitis but are secondary to non-inflammatory disease, such as lymphoma and other cancers. CMV, cytomegalovirus; HSV, herpes simplex virus; VZV, varicella zoster virus significant extra-articular manifestation of inflammatory bowel disease (IBD) and reactive arthritis, although less commonly than in AS. 18 A retrospective study of 4911 patients with uveitis found that 7% were associated with sarcoidosis, 5% with spondyloarthropathies (eg, AS) and 2.4% due to IBD. 19 In around one-third of uveitis, no associated systemic disease or other precipitant is identified. Such uveitis is termed idiopathic, although there is good evidence for it having an autoimmune/autoinflammatory aetiology In a small proportion, some other precipitant is identified: trauma (including ocular surgery) or, rarely, lens induced or drugs (eg, cidofovir or rifabutin). Infectious causes of uveitis are much more common in tropical and/or developing countries. 24 Whereas in Europe and the USA, infectious uveitis only accounts for 13% 21% (commonly herpes simplex, varicella zoster or toxoplasma), in some developing countries infectious cases are responsible for over 50% of uveitis cases (commonly toxoplasmosis, tuberculosis (TB), onchocerciasis; less commonly cysticercosis, leprosy and leptospirosis) Of all anatomical categories, posterior uveitis is the most likely to have an infectious aetiology. 20 Infectious uveitis may be particularly problematic in the context of immunosuppression. For example, cytomegalovirus (CMV) retinitis is an important cause of sight loss in patients with profound immunosuppression due to HIV or immunosuppressant drugs. Pathogenesis Although aetiology may lead to differences in the early stages in the pathogenesis of uveitis (particularly the distinction between infectious and non-infectious aetiologies), this is rapidly followed by shared inflammatory pathways that lead to the various common clinical presentations. Infectious uveitis may arise from local infection, 21 or more commonly due to haematogenous transport of pathogens from distant sites in the body to the uvea (figure 3A). 28 The pathogenic

4 Figure 3 Potential pathogenic mechanisms for uveitis through (A) an appropriate and (B C) inappropriate immune response. (A C) all initially show antigen presentation with a specific peptide. This is followed by activation of T cells, which subsequently cause damage by attacking antigens within the uveal tract. (A) Here, a pathogenic antigen is the target for activated T cells. In the process of attacking the antigen, collateral damage and inflammation are caused at the respective part of the uveal tract. (B) The fundamental derangement in autoimmune disease is that the immune system attacks a self-antigen (eg, from a retinal melanocyte). (C) A key mechanism by which this may be triggered is molecular mimicry where an appropriate immune response to a pathogenic antigen is followed by an inappropriate immune response to self-antigen due to the structural similarity between the two antigens. antigens are presented to leucocytes within the eye, which are activated against the infectious agent. Therefore, the disease occurs as collateral damage from what is an otherwise appropriate immune response. However, for non-infective uveitis, the autoimmune causes result from an inappropriate immune response, mediated by T cells. 21 Such antiself T cells may arise due to a breakdown in tolerance to previously unseen self-antigens found within retinal tissue (figure 3B), 29 or may arise due to cross-reactivity between their target antigen (an appropriate non-self target) and a self-antigen with structural similarity (figure 3C). 30 Some forms of uveitis may also be characterised by autoinflammatory mechanisms mediated by the innate immune system. 31 A common feature of both infectious and non-infectious forms of uveitis is a breach of the blood retinal barrier due to the inflammatory cascade, leading to influx of fluid to the site of inflammation; upregulation of adhesion molecules on local endothelium and release of chemokines attract leukocytes to the site of inflammation. Genetic background may contribute to a number of forms of uveitis, although the mechanism is generally unclear. The most common example is the association of acute anterior uveitis (AAU) with HLA-B27, an association which also leads to the strong association of AAU with AS. 33 A less common but profound example is the association of HLA-A29 with birdshot chorioretinopathy (BCR), where over 99% of patients with BCR Krishna U, et al. Postgrad Med J 2017;0:1 8. doi: /postgradmedj Review carry the HLA-A29 gene. A weaker HLA association is present in Behcet s disease which is associated with HLA-B51. Clinical assessment As with other branches of medicine, a detailed history is vital, including ocular, systemic, family and social. This will substantially inform the detailed examination and direct subsequent investigations. 13 Taking a history in the patient with uveitis The presenting complaint (current symptoms) of the patient will immediately provide a clue to the presence of uveitis and its type. Anterior uveitis, if acute, is typically associated with ocular redness and pain, with prominent photophobia; vision is usually minimally affected. 34 In contrast, chronic anterior uveitis (CAU) is commonly asymptomatic and may only picked up due to a screening examination or a routine optometric review, or when sight-threatening complications have developed. Intermediate uveitis typically presents with floaters and may lead to variable reduction in vision, but may also be asymptomatic in mild cases. Posterior uveitis may also be associated with floaters and the presence of scotomata ( blind spots ), which depending on location may affect the central vision. Panuveitis may exhibit all the above symptoms. All forms of uveitis may develop sight-threatening complications over time, noticeably cataract, glaucoma and macular oedema, which may themselves cause symptomatic reduction in vision. The age of the patient at the onset of the first episode of uveitis is important. Some forms of uveitis have a predilection for a certain age. In children, for example, uveitis is most commonly of the CAU form, and is frequently seen in the context of juvenile idiopathic arthritis. In terms of infectious uveitis, ocular toxocara may be seen in children, whereas this is rare in adults. Conditions such as HLA-B27-associated AAU and Behcet s disease typically present for the first time in young adults, whereas BCR and serpiginous choroiditis usually present in the age group. First presentation of uveitis over the age of 60 years is uncommon, and should prompt consideration of a masquerade syndrome, notably intraocular lymphoma. Ethnicity is also relevant due to the influence of genetic and environmental factors. Behcet s syndrome is most common in patients from the Mediterranean, Middle East and Asia; sarcoidosis is most common in the African-Caribbean population; Vogt-Koyanagi-Harada syndrome is most common in patients from Asia, and is very rare in white Caucasians. Country of origin and travel history are important since certain forms of infectious uveitis are endemic in specific areas. Ocular history can provide important diagnostic clues. For example, recurrent episodes of anterior uveitis which is acute and intermittently affects either eye are typically HLA-B27 associated (or idiopathic), whereas a recurrent unilateral anterior uveitis which only ever affects one eye is commonly viral in origin (usually herpes simplex or herpes zoster). Previous ocular trauma or surgery may raise the possibility that inflammation is due to a rare condition such as sympathetic ophthalmia or lens-induced uveitis. Prior medical history may immediately reveal the presence of an underlying systemic cause of inflammation (such as AS, sarcoidosis, Behcet s disease or TB), but it is important to recognise that the uveitis may be the first presentation of such pathology or that the patient may not reveal the diagnosis (eg, a recent diagnosis of syphilis or HIV). 3

5 Review Figure 4 Anterior uveitis. Slit lamp examination of the left eye of a patient with acute anterior uveitis revealing keratic precipitates and posterior synechiae. Drug history is relevant as a number of drugs such as rifabutin, cidofovir and zoledronic acid may trigger uveitis. Additionally, it may reveal the presence of systemic disease that the patients have overlooked, and is relevant to identifying any potentially harmful interactions between ocular and other drugs. Systemic review will detect the presence of associated features that may identify an underlying systemic pathology such as the presence of lower back pain and stiffness in AS; mouth and/ or genital ulcers in Behcet s disease; neurological symptoms in multiple sclerosis; or shortness of breath in sarcoidosis. Social history is an important part of the holistic care of the patient but is also relevant to disease type. For example, dietary habits may affect risk of a number of infectious uveitides including toxocariasis (pica), toxoplasmosis (consumption of raw meat or water in rural areas) and cysticercosis (consumption of pork in endemic areas). The sexual behaviour of the patient may increase risk of syphilis and HIV. Intravenous drug abuse is a risk factor for HIV and endogenous endophthalmitis. Pets may increase risk of toxocariasis (puppies) and toxoplasmosis (cats). Examining the patient with uveitis The patient with anterior uveitis (figure 4) The clinical signs of uveitis vary according to the type of disease. In anterior uveitis, the visual acuity (VA) is usually near normal; a significant reduction in VA suggests that there may be significant posterior inflammation. The eye appears red with the hyperaemia seen circumferentially just behind the cornea where the tissues overlie the ciliary body; this is often confused with conjunctivitis by the non-specialist, but should be easily differentiated since in conjunctivitis the redness is more pink and diffuse, and is associated with discharge (not seen in uveitis). Other signs that may be seen macroscopically with the naked eye include a hypopyon and posterior synechiae (discussed below), but more detailed assessment requires a biomicroscope (commonly known as a slit-lamp ). All patients with uveitis of any form should be referred urgently for ophthalmic assessment; in general, same-day assessment by a specialist such as in an eye casualty is recommended for all patients with suspected uveitis (box 2). With the benefit of a biomicroscope, the intraocular inflammation can be more fully appreciated. Cells and inflammatory 4 Krishna U, et al. Postgrad Med J 2017;0:1 8. doi: /postgradmedj Box 2 Key points for anterior uveitis Acute anterior uveitis Symptoms of pain, redness, photophobia. Most important clinical signs are anterior chamber cells and flare; usually unilateral. Other signs include keratic precipitates, posterior synechiae, iris nodules. Associations include: HLA-B27, ankylosing spondylitis, but idiopathic in 50%. Treatment: topical corticosteroids and topical mydriatics. Chronic anterior uveitis Often asymptomatic; may present with reduced vision due to complications. Most important clinical signs are anterior chamber cells and flare; often bilateral. Other signs include keratic precipitates, posterior synechiae, cataract. Associations include: juvenile idiopathic arthritis, but commonly idiopathic. Treatment: topical corticosteroids, topical mydriatics but may require systemic immunosuppression. aggregates (keratic precipitates; KPs) may accumulate on the endothelium of the cornea (see figure 4), with different patterns being attributed to different forms of uveitis. Specific forms of KPs include the large mutton fat KPs seen in granulomatous diseases such as tuberculous uveitis or sarcoid uveitis and fine stellate KPs seen in the uncommon idiopathic uveitis, Fuchs heterochromic cyclitis (FHC). The pupil may be small (miotic) due to spasm of the iris sphincter, and abnormal adhesions of the iris to the lens (posterior synechiae; figure 4) may occur. Granulomatous lesions may appear as nodules on the iris (Busacca nodules) or at the pupillary margin (Koeppe nodules). The major signs by which anterior uveitis is scored are AC cells and AC flare. If the AC cells are extremely numerous they may settle to form a visible level within the AC (hypopyon). Hypopyon in uveitis is classically seen with HLA-B27 disease and Behcet s syndrome. In HLA-B27 disease, the presence of fibrin means that the hypopyon is relatively immobile and slow to resorb; in Behcet s syndrome, the lack of fibrin means that the hypopyon easily shifts position, and resorbs quickly. It should be noted that a hypopyon may also occur in severe ocular infection (eg, endophthalmitis, severe microbial keratitis). AC flare relates to the positive Tyndall effect in which light shone through the AC is scattered by the presence of protein arising due to the breakdown of the blood aqueous barrier. The presence of fibrin in the aqueous humour is most commonly seen in HLA-B27 positive AAU. Intraocular pressure (IOP) in uveitis may be low, normal or high. Low IOP may occur due to reduced production of aqueous humour through the ciliary body; high IOP during acute inflammation is commonly seen in herpetic uveitis, FHC and Posner- Schlossman syndrome, but may occur in almost any form of uveitis over time. Whereas AAU is usually unilateral, CAU is commonly bilateral. As noted earlier, it is usually asymptomatic, and so may present with signs of chronicity including visually significant complications. One sign of persistent inflammation is calcium deposition on the cornea (band keratopathy), affecting vision and causing significant discomfort. Cataract and glaucoma are

6 Box 3 Key points for intermediate uveitis Intermediate uveitis Symptoms of floaters and reduced vision. Most important clinical signs are vitreous cells and vitreous haze. Other signs which may be present include snowbanks, the hallmark of the pars planitis form of intermediate uveitis. Associations include: multiple sclerosis, sarcoidosis; but commonly idiopathic. Treatment: may require systemic immunosuppression. common features in chronic uveitis, and are the major causes of loss of vision. The patient with intermediate uveitis In intermediate uveitis, the inflammation appears to be focused on the vitreous. Two main forms are recognised: pars planitis and non-pars planitis intermediate uveitis. The hallmark of pars planitis is the presence of snowbanks of grey-white fibrovascular plaques usually located inferiorly, and which may have areas of neovascularisation (box 3). Other features which may be present in both forms of uveitis include the presence of cells suspended in the vitreous, vitreous haze (due to proteins from blood ocular barrier breakdown) and inflammatory aggregates within the vitreous known as snowballs. Cystoid macular oedema may be present and is a major cause of visual loss in intermediate uveitis. Peripheral retinal vasculitis may also be seen. Although there may be some signs of inflammation in the anterior chamber of the eye (AC cells and KPs), these tend to be mild. Intermediate uveitis is usually bilateral but can be markedly asymmetric. For the non-specialist, examination with an ophthalmoscope may detect that the vitreous is cloudier than normal but the elucidation of other clinical signs would usually require specialist examination with a biomicroscope. Pars planitis usually affects children and adolescents and is idiopathic; non-pars planitis intermediate uveitis tends to affect older patients (25 35 years old), and may be associated with systemic diseases such as multiple sclerosis and sarcoidosis. Overall, intermediate uveitis represents 15% of all uveitis cases. Box 4 Key points for posterior uveitis The patient with posterior uveitis Posterior uveitis described forms of uveitis in which the inflammation is primarily focused on the retina or choroid and commonly involves both these layers (box 4). These lesions may be unifocal, or multifocal, and can vary greatly in size. They are generally white, with blurred margins when active, becoming Posterior uveitis Symptoms of floaters, reduced vision and may be aware of blind spots. Most important clinical signs are visible lesions within the retina or choroid, which are commonly seen as white spots and may be associated with oedema. Associations include: tuberculosis, sarcoidosis; but commonly idiopathic. Treatment: usually requires systemic immunosuppression or antimicrobials according to underlying cause. Krishna U, et al. Postgrad Med J 2017;0:1 8. doi: /postgradmedj Figure 5 Posterior uveitis. Posterior uveitis due to ocular toxoplasmosis; an active white lesion can be seen to be bordering an old pigmented scar indicative that this is a reactivation. Box 5 Key points for panuveitis Review more sharply defined as active inflammation resolves. Choroidal lesions may cause visible elevation of the overlying retina. Posterior uveitis may be associated with retinal vasculitis. In some cases, this will be restricted to the vicinity of the inflammatory lesions, but in other cases it will be widespread. Inflammation of the veins is the more common form of retinal vasculitis; inflammation of the retinal arteries is commonly seen in infectious posterior uveitis such as acute retinal necrosis (a rare very severe retinitis caused by herpes simplex or herpes zoster) and ocular toxoplasmosis (figure 5). For the non-specialist, examination with an ophthalmoscope may detect that the vitreous is cloudier than normal and detect abnormal fundal features such as haemorrhages and pale areas, but the elucidation of other clinical signs would usually require specialist examination with a biomicroscope. The patient with panuveitis In panuveitis, the inflammation is distributed through the AC, vitreous and retina or choroid (box 5). The clinical signs reflect the distribution of the disease and so almost any aspect of anterior, intermediate or posterior uveitis may be seen. Panuveitis may be idiopathic, but may also occur with a number of systemic conditions such as Behcet s syndrome, sarcoidosis and TB. Investigations Some uveitis can be diagnosed with confidence on purely clinical grounds based on history and biomicroscopic examination. For example, in AAU, HLA-B27 testing is not routine, unless it will be helpful to support a rheumatological diagnosis, since it will Panuveitis Variable symptoms reflecting the wide distribution of inflammation which may include redness, photophobia, floaters, reduced vision and blind spots. Clinical signs include any features seen in anterior, intermediate or posterior uveitis. Associations include: Behcet s syndrome, sarcoidosis and tuberculosis but may be idiopathic. Treatment: usually requires systemic immunosuppression or antimicrobials according to underlying cause. 5

7 Review not affect management. 13 In general, the most important investigations are to confirm or rule out infectious aetiologies, as this will radically change the approach to treatment Diagnostic investigations The following would be a common approach to investigation in uveitis: AAU: none Atypical clinical features or features suggestive of a particular systemic disease on systemic review may prompt specific investigations. All other uveitis: Venereal Disease Research Laboratory test or treponemal serology (for syphilis) Chest X-ray (may show features of sarcoidosis or TB) ACE (may be elevated in sarcoidosis, although the diagnostic value of this test is limited) Baseline blood tests including full blood count, glucose, urea and electrolytes (U+E), calcium, and liver function tests are commonly done. These are primarily done as a vital baseline if systemic corticosteroids or other immunosuppression is being considered, but may also occasionally reveal diagnostic clues: for example, undiagnosed diabetes or tubulointerstitial nephritis may rarely be the cause of the uveitis. Examples of specific scenarios which may require additional investigations: Intermediate uveitis with neurological symptoms suggestive of multiple sclerosis: neurological referral for consideration of investigations which may include MRI brain/ spinal cord and cerebrospinal fluid analysis Posterior uveitis with bilateral scattered pale flecks suggestive of BCR: HLA-A29 (present in more than 99% of patients with this disease) Posterior uveitis with retinal necrosis ( Acute Retinal Necrosis (ARN) ): AC tap and vitreous biopsy for PCR analysis to detect herpes simplex, varicella zoster, CMV and toxoplasmosis Any uveitis with suspected systemic disease: Additional investigations according to features of concern. Common example would be the use of interferon gamma release assay and/or Mantoux test where there is concern over possible TB, and high-resolution CT thorax in suspected sarcoidosis. Monitoring investigations Non-invasive high-resolution imaging of the eye has become standard through the advent of optical coherence tomography (OCT). This light-based technology allows visualisation of many structures in the eye to a resolution of a few microns. This is used to monitor the macula (particularly to detect macular oedema; figure 6) and optic nerve (to detect and monitor progression of retinal nerve fibre loss associated with disc cupping suggestive of glaucoma). Since macular oedema and glaucoma are two of the leading causes of sight loss in uveitis, OCT is now an extremely valuable tool. 35 Over the next few years, it is likely that OCT will be able to provide similar objective monitoring for other aspects of uveitis activity including vitritis, chorioretinitis and AC cells. If there is concern that secondary glaucoma may be developing, it is important to undertake regular perimetry (visual field testing) to monitor any functional changes. 6 Krishna U, et al. Postgrad Med J 2017;0:1 8. doi: /postgradmedj Figure 6 Optical coherence tomography (OCT) of macular oedema. OCT images of the left eye of a patient with severe macular oedema secondary to intermediate uveitis before (A) and after (B) treatment with systemic corticosteroids. Angiography of the retinal and choroidal vasculature can be achieved using two separate intravenous dyes, fluorescein and indocyanine green, respectively. Fluorescein angiography is valuable in detecting and monitoring the presence of retinal vasculitis, ischaemia and macular oedema. Indocyanine green angiography is helpful in detecting a choroidal vasculitis, ischaemia and other lesions. Treatments The main aims of treatment 12 are to: control and prevent ocular inflammation treat sight-threatening complications (eg, cataract, cystoid macular oedema, glaucoma) preserve and restore vision improve quality of life. While individual therapies are discussed below, it is worth mentioning some basic principles at this point. Crucially, for the non-specialist, suspected cases of uveitis should be referred urgently to an ophthalmologist within 24 hours; this is to allow a full slit lamp investigation including dilation in order to confirm the presence of uveitis and diagnose its type. 38 Whereas anterior uveitis often responds to topical therapy alone, intermediate, posterior and panuveitis usually require local and/or systemic therapy. 1 If uveitis is secondary to systemic disease, then treating the latter is likely to improve the uveitis, emphasising the need for coordination between ophthalmologists and other specialities A detailed discussion about the range of current and emerging therapies for uveitis is beyond the scope of this review but has recently been reviewed. 21 The following points are however important for the non-specialist to be aware of, although all such treatments should be directed by a specialist. Treatment of non-infectious anterior uveitis Frequent topical corticosteroids such as dexamethasone 0.1% or prednisolone acetate 1% (initially may be hourly),

8 reducing over weeks or even months according to clinical signs. Mydriatics such as cyclopentolate 1% three times a day to reduce risk of posterior synechiae. If severe, consider subconjunctival injection of corticosteroid or a short course of oral corticosteroid. Treatment of non-infectious intermediate, posterior or panuveitis Systemic treatment is common, with corticosteroids as first-line therapy. In severe inflammation, this may be with pulsed intravenous methylprednisolone or with high-dose oral prednisolone. The numerous side effects of systemic corticosteroids, particularly at high doses, can be reduced through a maintenance dose of less than 7.5 mg/day. A failure to achieve this indicates the need for some alternative or additional treatment such as the introduction of a secondline immunosuppressant (commonly mycophenolate mofetil, methotrexate, ciclosporin or tacrolimus) or additional local therapies. The use of biological therapies (commonly adalimumab or infliximab) is effective and is commonly used as a third-line treatment. Local treatment is increasingly common, and is usually corticosteroid based, although non-steroid drugs are under evaluation. Ozurdex, a dexamethasone implant, may last for up to 6 months and is licensed for the treatment of non-infectious uveitis affecting the posterior segment of the eye. These drugs are effective, but have significant rates of elevated IOP and cataract formation. Despite these limitations, they are very useful particularly in the treatment of unilateral or asymmetric disease where they can mitigate the level of systemic immunosuppression required. Treatment of infectious uveitis The identification of an infectious cause of a particular uveitis will direct appropriate antimicrobial treatment. This may vary according to local guidelines and should be done in consultation with a microbiologist. It is worth noting that additional corticosteroid treatment may sometimes be necessary to control the level of inflammation and reduce secondary damage. Conclusions Patients with uveitis may suffer from the impact of the disease on their sight, their systemic health and their quality of life. An appreciation of its range of presentations will help the non-ophthalmologist suspect the condition early, and refer for appropriate urgent assessment and intervention. Similarly, ophthalmologists, other hospital physicians and primary care physicians need to recognise the interdependencies of ocular and systemic disease and their treatments, to ensure that ocular and systemic complications of the disease and drugs are kept to a minimum. Advances in imaging and in local and systemic therapies have radically improved the care of the patient with uveitis, but uveitis is still a sight-threatening disease. The challenge remains for the whole healthcare team to have sufficient knowledge of the condition, to be alert to its presentations and to coordinate their care so that the sight and health of the patient may be preserved. Contributors AKD conceived the review and supervised the project. DA, UK and TG performed the literature search and drafted the manuscript. All authors reviewed and approved the final manuscript. UK and DA share the role of the first author. Competing interests None declared. Krishna U, et al. Postgrad Med J 2017;0:1 8. doi: /postgradmedj Main messages Uveitis is a significant cause of blindness worldwide but is often poorly understood and underestimated. Classification of uveitis by aetiology and anatomical focus of disease provides a basis for both diagnosis and treatment strategy. Understanding uveitis is helpful to clinicians in almost every specialty due to wide-ranging associations with systemic disease. Current research questions What causes non-infectious uveitis? How should we measure disease activity in uveitis? What are the most effective treatments for sight-threatening uveitis? Key references 1. Guly CM, Forrester JV. Investigation and management of uveitis. BMJ 2010;341:c Durrani OM, Meads CA, Murray PI. Uveitis: a potentially blinding disease. Ophthalmologica : Denniston A, Murray P. Chapter 11 Uveitis. In: Oxford Handbook of Ophthalmology. 3rd edn. Oxford University Press; Jabs DA, Nussenblatt RB, Rosenbaum JY. Standardization of uveitis nomenclature for reporting clinical data. Results of the first international workshop. Am J Ophthalmol 2005;140: Barry RJ, Nguyen QD, Lee RW, et al. Pharmacotherapy for uveitis: current management and emerging therapy. Clin Ophthalmol 2014;8: Self assessment questions Review Provenance and peer review Not commissioned; externally peer reviewed. Article author(s) (or their employer(s) unless otherwise stated in the text of the article) All rights reserved. No commercial use is permitted unless otherwise expressly granted. References 1 Guly CM, Forrester JV. Investigation and management of uveitis. BMJ 2010;341:c4976. Please answer true or false to the below statements. 1. Typically, uveitis affects those over the age of A 32-year-old woman complains of a painful, red left eye. She finds it uncomfortable looking at bright lights, but has not noticed any significant change to her vision. You suspect she may have uveitis. Therefore, this warrants an urgent, sameday referral for ophthalmic assessment. 3. Posterior uveitis typically presents with pain. 4. In typical cases of acute anterior uveitis no investigations are usually required. 5. Topical therapies are usually effective for treating posterior uveitis. 7

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10 References alerting service Notes Uveitis: a sight-threatening disease which can impact all systems Unnat Krishna, Deji Ajanaku, Alastair K Denniston and Theodora Gkika Postgrad Med J published online September 23, 2017 Updated information and services can be found at: These include: This article cites 37 articles, 4 of which you can access for free at: 891#BIBL Receive free alerts when new articles cite this article. Sign up in the box at the top right corner of the online article. To request permissions go to: To order reprints go to: To subscribe to BMJ go to: