REVIEW URRENT C OPINION
Ocular manifestations of seronegative spondyloarthropathies Sophia L. Zagora a,b and Peter McCluskey a,b
Purpose of review This article reviews recent advances in the understanding of the ocular manifestations of seronegative spondyloarthropathies. Recent findings Ocular inflammatory disorders are common and important disease manifestations in patients with seronegative spondyloarthropathy, with anterior uveitis being the most common. There is a strong association between affected patients and the human leukocyte antigen B27. Local corticosteroid treatment is usually effective, but chronic or refractory uveitis responds well to immunosuppressive drugs that are effective for arthritis. Recent studies have highlighted the possible benefits of a number of biologic agents, including tumor necrosis factor-alpha inhibitors in such patients. Summary Uveitis is the most common ocular manifestation in patients affected by seronegative spondyloarthropathies. Both genetic and environmental factors play a role in its pathogenesis. As it tends to affect the young adult population, it carries a significant personal and population burden. Immunomodulatory therapy that also acts as a corticosteroid sparing therapy can be effective in controlling chronic uveitis in patients with spondyloarthropathy. Keywords human leukocyte antigen B27, seronegative spondyloarthropathies, uveitis
INTRODUCTION The development and use of novel biological therapies for rheumatic disease has renewed interest in the seronegative spondyloarthropathies (SSpAs) [1]. The SSpAs are a group of chronic inflammatory diseases characterized by an absence of serum rheumatoid factor and are strongly associated with the human leukocyte antigen B27 (HLA-B27). They include ankylosing spondylitis (AS), reactive arthritis (formerly Reiter’s syndrome), psoriatic arthritis, arthritis associated with inflammatory bowel disease (Crohn’s disease, ulcerative colitis) and juvenile onset spondyloarthropathy [2]. Uveitis is estimated to have a prevalence of 1/4500 in the general population and occurs typically in the 20–60-year range with both sexes being affected equally. Acute anterior uveitis is by far the most common form of uveitis and accounts for 75–90% of patients with uveitis in Western countries, but only 25–50% in Asian populations [3]. Uveitis is the most common extra-articular manifestation of seronegative spondyloarthritis,
developing in up to 25% of patients with AS and up to 10% with early psoriatic arthritis [3]. As it tends to affect the young adult population, it carries a significant personal and population quality-oflife burden [4 ]. Patients with HLA-B27-associated recurrent acute anterior uveitis, on average, have one attack per year, lasting approximately 6 weeks, which usually responds to topical corticosteroids [4 ]. Therapy for seronegative spondyloarthropathy associated acute anterior uveitis consists usually of short courses of corticosteroids administered topically, periocularly, or systemically. Seronegative &&
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a
Save Sight Institute, Discipline of Ophthalmology, Sydney Medical School, University of Sydney and bSydney Eye Hospital, Sydney, Australia Correspondence to Professor Peter McCluskey, Save Sight Institute, Campus of Sydney Eye Hospital, 8 Macquarie St., Sydney, NSW 2000, Australia. Tel: +61 2 93827111; e-mail: [email protected] Curr Opin Ophthalmol 2014, 25:495–501 DOI:10.1097/ICU.0000000000000098
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Ocular manifestations of systemic disease
KEY POINTS SSpAs – group of chronic inflammatory diseases characterized by absence serum rheumatoid factor and are strongly associated HLA-B27 antigen.
AS is related to Crohn’s disease. About 60% of patients with AS have histological evidence of Crohn’s-like changes in the large intestine, although they are usually asymptomatic. AS is also similarly related to reactive arthritis [7 ]. A definite diagnosis of Reactive Arthritis is based on the fulfillment of both major criteria and a relevant minor criterion, whereas a probable diagnosis is characterized by both major criteria but no relevant minor criterion or one or more of the minor criteria and one of the major criteria (Table 2) [8 ]. The identification of the triggering infection is also required (Table 3). Inflammatory bowel disease includes Crohn’s disease and ulcerative colitis, in which diagnosis is made by endoscopy and biopsy with histopathological confirmation. Uveitis is less frequent in patients with inflammatory bowel diseases (IBD), but it involves the posterior segment more frequently than other SSpAs. There are a number of different patterns of arthritis seen in patients with psoriasis, occurring in up to 10% of individuals. One of the patterns is an SSpA, and this type is associated with HLA-B27 and anterior uveitis [9 ]. &&
Uveitis is most common extra-articular manifestation of seronegative spondyloarthritis, developing in up to 25% of patients with AS and in up to 10% with early psoriatic arthritis. Therapy for seronegative spondyloarthropathy associated acute anterior uveitis, usually short courses of corticosteroids administered topically, periocularly, or systemically. Chronic or refractory uveitis responds well to immunosuppressive drugs that are effective for arthritis. Recent studies have highlighted possible benefits of a number of biologic agents, including TNF-a inhibitors in such patients.
spondyloarthropathy associated acute anterior uveitis is typically recurrent and alternates from eye to eye. Small numbers of patients, usually those with recurrent or chronic uveitis, require ongoing systemic therapy and may require steroid sparing agents, including the newer biologic agents including tumor necrosis factor (TNF) inhibitors which have been shown to be effective in improving both rheumatological and uveitic signs and symptoms in SSpA [2].
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Table 1. New Assessment of Spondyloarthritis International Society classification criteria for axial spondyloarthritis [6] In patients with 3 months back pain and age at onset < 45 years Sacroiliitis on imaging
THE SPONDYLOARTHROPATHIES With the new advances in treatment and subsequent outcomes, it is now more important than ever to diagnose and treat SSpA early. The modified New York criteria, the European Spondyloarthropathy Study Group criteria, and the Amor criteria are often used to guide the diagnosis of the spondyloarthropathies [5]. Spondyloarthropathies have been classified with the Amor criteria since 1990. AS is the prototype spondyloarthritis as it affects the axial skeleton. The modified New York criteria for classification of AS were developed 30 years ago; however, AS diagnosis is often missed or markedly delayed, as the modified New York criteria depend on the presence of definite sacroiliitis (grade 2 bilateral, or grade 3 or 4 unilateral). It is estimated that it takes between 6 and 10 years for radiographic sacroiliitis to develop after developing the early symptoms of axial inflammation. To address this issue the new Assessment of Spondyloarthritis International Society Classification Criteria have been developed with a newly coined term ‘axial spondyloarthritis’ (Table 1) [6]. 496
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plus
HLA-B27 OR
plus
1 SpA feature# #
2 other SpA feature#
SpA features
Sacroiliitis on imaging
Inflammatory back pain
Active (acute) inflammation on MRI highly suggestive of sacroiliitis associated with SpA
Arthritis
Definite radiographic sacroiliitis according to modified NY criteria
Enthesitis (heel) Uveitis Dactylitis Psoriasis Crohn’s/colitis Good response to NSAIDs Family history for spa HLA-B27 Elevated CRP CRP, C reactive protein; HLA, human leukocyte antigen; MRI, magnetic resonance imaging; NSAID, non-steroid anti-inflammatory drug; NY, New York; OR, odds ratio; SpA, spondyloarthropathy.
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Seronegative spondyloarthropathies Zagora and McCluskey Table 2. Diagnostic criteria for reactive arthritis [8 ] &&
Major criteria
Arthritis with two of three of the following findings: asymmetric mono-or oligoarthritis lower limb involvement Preceding symptomatic infection with one or two of the following findings: enteritis (defined as diarrhea for at least 1 day, and 3 days to 6 weeks before the onset of arthritis) urethritis (dysuria or discharge for at least 1 day, 3 days to 6 weeks before the onset of arthritis
Minor criteria
At least one of the following: evidence of triggering infection: positive urine ligase reaction or urethral/cervical swab for Chlamydia trachomatis positive stool culture for enteric pathogens associated with reactive arthritis evidence of persistent synovial infection (positive immunohistology or PCR for Chlamydia)
SPONDYLOARTHROPATHIES AND THE EYE The hallmark ocular manifestation of SSpA is anterior uveitis and occurs in up to 40% of patients with a SSpA. Infrequently, posterior or panuveitis develops most commonly in patients with IBD. Occasionally, patients develop scleritis and episcleritis [10]. There is a high association with HLA-B27 antigen. This is strongest in patients with AS and reactive arthritis [7 ]. Up to 40% of patients with AS will develop acute anterior uveitis (AAU) during the course of the disease. AAU associated with AS is typically of sudden onset and limited duration. Attacks are typically unilateral and alternate between eyes. The attacks respond well to topical, periocular, or systemic corticosteroids. Other types of uveitis occur infrequently in patients with AS. Reactive arthritis may be associated with conjunctivitis or uveitis. Major ocular manifestations include mild, symmetric, bilateral conjunctivitis with a mucopurulent discharge and a papillary or follicular reaction. Conjunctivitis occurs in up to 50% of patients and can be easily overlooked. Nongranulomatous anterior uveitis with fine-sized to medium-sized pale keratic precipitates is also common and typically has a protracted, persistent course. Scleritis, episcleritis and keratitis have also been reported [11]. Rarely reactive arthritis is &&
accompanied by permanent visual loss from posterior segment involvement such as optic neuropathy, macular edema and retinal vasculitis [11]. Extraintestinal manifestations occur in about 25–35% of patients with IBD. Joints, skin, eyes, liver and biliary systems are most commonly affected. Extraintestinal manifestations of IBD are divided into two groups: reactive manifestations which depend on activity of IBD including peripheral arthritis, erythema nodosum, aphthous stomatitis, episcleritis, and other manifestations which are independent of activity of IBD, such as pyoderma gangrenosum, uveitis, axial arthropathy, primary sclerosing cholangitis. Ocular involvement occurs in 2–10% of patients with IBD and may range from mild conjunctivitis to uveitis, episcleritis and scleritis [12]. The most frequent manifestation is anterior uveitis (more common in women), but vision-threatening posterior uveitis with retinal vasculitis, maculopathy, choroiditis and optic neuropathy may occur. The inflammation in the eye and the gut run independent clinical courses. Ocular disease usually responds to topical, periocular or systemic corticosteroids but may require immunomodulatory therapy [13]. Only a small proportion of patients with juvenile idiopathic arthritis has sudden-onset symptomatic anterior uveitis attacks. These are typically associated with enthesitis-related arthritis and the HLA-B27 antigen. Anterior uveitis associated with juvenile idiopathic arthritis presents insidiously as an asymptomatic chronic, bilateral, nongranulomatous uveitis often between 6 months and 4 years of age [14]. A detailed review of juvenile idiopathic arthritis associated uveitis is outside the scope of this review.
Table 3. Known infectious triggers of B27-associated disease [8 ] &&
Gastrointestinal tract
Yersinia Salmonella Shigella Campylobacter jejuni
Urogenital tract
Chlamydia trachomatis Neisseria gonorrhea Mycoplasma genitalium Ureaplasma urealyticum
Less frequent agents
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Clostridium difficile Campylobacter lari Chlamydia psittaci Chlamydia pneumoniae
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Ocular manifestations of systemic disease
EPIDEMIOLOGIC STUDIES The association between the human major histocompatibility complex (MHC), human leukocyte antigen HLA-B27 and the diseases now recognized as the HLA-B27-associated systemic inflammatory diseases and AAU is one of the strongest HLA disease associations. HLA-B27 is the strongest known genetic risk factor for the development of AAU, with at least half of White patients with AAU being HLAB27-positive compared with only 8–10% of the general White population [15]. The unexplained paradox is why only 1–2% of HLA-B27-positive individuals develop a B27-associated disease. Evidence implicates several other genetic factors and environmental triggers that characterize such individuals [9 ]. In a survey conducted by the Spondylitis Association of America investigating the relationship between uveitis and SSpA, 168 of 863 of patients with SSpA (19.5%) reported a diagnosis of uveitis. Baseline demographics were similar between the uveitis and no-uveitis groups. The presence of uveitis was significantly associated with Infliximab treatment [adjusted odds ratio (ORadj) ¼ 1.66, P ¼ 0.044], ‘lower jaw’ involvement (ORadj ¼ 1.60, P ¼ 0.015), heel involvement (ORadj ¼ 1.51, P ¼ 0.023) and a diagnosis of arthritis associated with inflammatory bowel disease (ORadj ¼ 1.92, P ¼ 0.005). The presence of uveitis was negatively associated with the use of Etanercept (ORadj ¼ 0.49, P ¼ 0.011) and a coexisting diagnosis of diabetes (ORadj ¼ 0.02, P ¼ 0.020) [10]. In the study by Karaconji et al. [15], SSpA was the systemic disease most commonly associated with uveitis, with AS being the most common. The diagnosis of AS was known at the time of presentation in 6.3% and was newly diagnosed in 4.2% (p. 0.2) as a result of their evaluation for AAU. In two of these patients, the diagnosis of AS was made on their first presentation of AAU. Undifferentiated SSpA was newly diagnosed in one HLA-B27-positive patient on their initial presentation with AAU. The diagnosis of reactive, psoriatic and inflammatory bowel disease arthropathy was known at the time of presentation with AAU in each of the other patients [15]. The study also found that men were affected 2.2 times more frequently than women, with 40–44 years being the mean age of presentation with HLA-B27-associated AAU. Globally, the relative frequency of HLA-B27positive AAU is significantly lower in Japan (6–13% of AAU), Korea (6–29% of AAU), India (2% of AAU) and the genetically distinct population of the Australian Aborigines (0–10%) than in Western countries (6–29%). Similarly, the frequency of both AS and AAU is lower in Japan, Korea &
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and India compared with Western countries. The clinical associations of AAU are similar among the Australian, American and European populations, with the frequency of systemic associations in AAU being 26% [15]. Karaconji et al. [15] also found that although patients with HLA-B27-positive AAU tended to have more severe disease activity on presentation, patients with HLA-B27-negative AAU tended to have more ocular complications [15,16].
PATHOLOGY AND PATHOGENESIS Since the original observations by Brewerton in 1973, that first linked HLA-B27 to SSpAs, there have been multiple hypotheses including molecular mimicry, HLA misfolding, persistence of microbial antigens in involved tissue and breakdown of immune privilege to explain the strong association between the HLA-B27 and SSpAs [9 ,17]. There have been several reviews of the pathogenesis of SSpA that highlight the role of innate immunity, as well as other components of the immune system in autoimmune disease and challenge the conventional view that immune-mediated disease is due to abnormalities in the adaptive immune response. The review by Rosenbaum and Kim [7 ] provides an excellent overview of current thinking on the roles of innate and adaptive immune mechanisms in disease and highlights several important observations that support a critical role for autoinflammatory mechanisms in SSpAs, its ocular manifestations and other diseases that cause uveitis. The genetic basis of a number of rare autoinflammatory diseases, such as Blau syndrome and familial cold urticaria, is due to mutations in NOD2 and NLRP3 genes, respectively. Mutations in these genes, mutations in other immune response component genes, such as deletion of the TLR4 receptor that greatly reduces susceptibility to EIU in murine models of EIU and other mutations that exaggerate disease expression, clearly point to a strong contribution by innate immunity to disease previously thought to be autoimmune in nature. Other important observations relate to the triggering role of infection in many immune-mediated diseases. For example, in the well characterized transgenic B27 model of SSpA, the presence of normal microbial gut flora is required to induce disease. Animals raised in germ-free conditions do not develop disease in this model. There is evidence, some longstanding and some recent, that also links gastrointestinal tract infective and inflammatory abnormalities to extraintestinal manifestations of SSpA such as uveitis and arthritis [9 ]. &
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Seronegative spondyloarthropathies Zagora and McCluskey Table 4. Characteristics, route of administration, dosage and potential side-effects for selected biologic agents [19] Generic names
Trade names
Specific target
Route
Dosage
Potential side-effects
Infliximab
Remicade
TNF-a
IV
3–5 mg/kg loading at weeks 0, 2 and 6 then maintenance 3–10 mg/kg every 4–8 weeks; maximal does 20 mg/kg in children
a
Adalimumab
Humira
TNF-a
SQ
40 mg every 1 to 2 weeks (if bodyweight < 30 kg; 20 mg every 2 weeks: loading doses of 80–160 mg are recommended for CD and PsO
Etanercept
Enbrel
TNF-al-b
SQ
Adults 50 mg weekly (may be given 50 mg twice weekly for first 3 months for PsO); children 0.8 mg/kg/week (max 50 mg/week)
Golimumab
Simponi
TNF-a
SQ
50 mg SQ monthly; except for UC 200 mg at week 0, 100 mg at week 2, then 100 mg every 4 weeks
Certolizumab
Cimzia
TNF-a
SQ
400 mg SQ at weeks 0, 2 and 4, then 200 mg every 2 weeks or 400 mg every 4 weeks
Daclizumab
Zenapax
T-cells (IL-2Ra)
IV, SQ
1 to 2 mg/kg every 2 or 4 weeks
Hypersensitivity reactions, headache, and gastrointestinal disturbance
Rituximab
Rituxan
B-cells (CD20)
IV
500 or 1000 mg at week 0 and 2; may repeat at 6–12 months thereafter (different regimen for hematologic malignancies)
Susceptibility to infections, infusion reactions, gastrointestinal disturbance, cardiovascular events, muscle spasm, and headache
Abatacept
Orencia
T-cells (CTLA-4)
IV, SQ
Adult RA 500–1000 mg IV loading, then 125 mg SQ weekly; JIA 10 mg/kg, max 1000 mg IV at weeks 0, 2 and 4, then every 4 weeks
Susceptibility to infections, allergic reactions, headache, nausea, and malignancy
Basiliximab
Simulect
T-cells (IL-2Ra; CD25)
IV
40 mg IV at weeks 0, 2, 4, 8 and 12
Gastrointestinal disturbance, headache, susceptibility to infections, and hypersensitivity reactions
TNF inhibitors Susceptibility to infections, including reactivation of tuberculosis, histoplasmosis, hepatitis B, and fungal infection; hypersensitivity reactions; demyelinating disease; lupus-like syndrome; malignancy; thromboembolic events; congestive heart failure
Lymphocyte inhibitors
Specific receptor antagonists Anakinra
Kineret
IL-1 receptor
SQ
100 mg SQ daily; children, starting 1–2 mg/kg to max 8 mg/kg daily (dose adjustment for renal insufficiency)
Injection-site reaction, infections, headache, gastrointestinal disturbance, and fever
Canakinumab
Ilaris
IL-1b
IV, SQ
Systemic JIA: 4 mg/kg (max 300 mg) SQ every 4 weeks; CAPS, 2 to 3 mg/kg SQ every 8 weeks (see text)
Susceptibility to infections, headache, nausea, and abdominal pain
Gevokizumab
(XOMA 052)
IL-1b
IV, SQ
In experiment
Susceptibility to infections and hypersensitivity reactions
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Ocular manifestations of systemic disease Table 4 (Continued) Generic names
Trade names
Specific target
Route
Dosage
Potential side-effects
Tocilizumab
Actemra
IL-6 receptor
IV
Initial 4 mg/kg IV every 4 weeks, then increase to 8–12 mg/kg every 2–4 weeks
Serious infections, hypersensitivity reactions, and gastrointestinal perforation
Alemtuzumab
Campath
CD52
IV
30 mg IV, 3 days per week for 12 weeks
Cytopenias, infusion reactions, infections, gastrointestinal disturbance, and insomnia
Efalizumab
Raptiva
CD11a
SQ
0.7 mg/kg first does then 1 mg/kg weekly (max 200 mg/ dose)
Infections, progressive multifocal leukoencephalopathy, malignancy, arthritis and thrombocytopenia
Roferon-A
Nonspecific
SQ
3–6 million units SQ daily, tapering over 6 months
Injection-site reactions, flu-like symptoms and bone marrow suppression
Interferons Interferon a-2a
CAPS, cryopyrin-associated periodic syndromes; CD, Crohn’s disease; IL, interleukin; IV, intravenously; JIA, juvenile idiopathic arthritis; PsO, plaque psoriasis; RA, rheumatoid arthritis; SQ, subcutaneously; TNF, tumor necrosis factor; UC, ulcerative colitis. a Listed side-effects apply to all TNF inhibitors shown in this table.
This evidence is succinctly summarized in the review by Rosenbaum et al. [7 ], in which observations including those cited above have resulted ‘in viewing inflammatory diseases as a spectrum in which innate immunity is critical to diseases in which the role of the adaptive immune response might appear to predominate. At one of end of the spectrum myasthenia gravis and Graves’ thyroiditis are diseases characterized by autoantibodies in which one can relate the specific autoantibody to the symptoms of the disease. Adaptive immunity might be primarily responsible for these diseases, in which as Blau syndrome, which is caused by an autosomal, dominantly inherited mutation in a component of the innate immune system may be on the other end of the spectrum. There are many of the systemic diseases associated with uveitis, such as sarcoidosis, AS and Behcet’s disease in between’ [7 ]. We are at an intriguing time in our understanding of the pathogenesis of SSpAs and their ocular manifestations. There is increasing evidence linking multiple genetic and environmental factors to the pathogenesis of these diseases; however, the compelling association between HLA-B27 and the SSpAs remains largely unexplained [7 ,9 ,18]. &&
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MEDICAL TREATMENT OF EYE DISEASE ASSOCIATED WITH SERONEGATIVE SPONDYLOARTHROPATHY Conventional therapy with corticosteroids and immunomodulatory agents may not be able to control ocular inflammation or prevent nonophthalmic 500
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complications in some patients with severe uveitis [4 ]. Biologic agents such as infliximab and adalimumab can control uveitis and scleritis in such patients and there is evidence from studies in a number of autoimmune disorders including IBD [12]. Biologic agents are recombinant proteins or antibodies directed at specific protein targets such as cytokines or cell surface receptors [19]. They target either specific cell types in the immune system such as B cells or individual molecules in the inflammatory cascade, resulting in suppression of immune responses that can cause severe ocular damage. There are many different classes of biologic agents, including anti-TNF agents, anti-interleukin agents, anti B-cell agents, interferons, antivascular endothelial growth factor agents and antibodies against specific receptors (Table 4) [4 ]. They are increasingly useful when conventional immunosuppressive therapy has failed, has been poorly tolerated or to treat concomitant ocular and systemic inflammation. Biologic therapy with infliximab, and adalimumab, may be a rapidly effective treatment for uveitis refractory to other therapies. There is now increasing experience using biologics to treat uveitis associated with juvenile idiopathic arthritis as well as uveitis associated with AS and IBD [14]. Other agents, such as golimumab, abatacept, canakinumab, gevokizumab, tocilizumab and alemtuzumab, have great promise for the treatment of uveitis; however, there is very limited clinical experience using these drugs to treat patients with uveitis. &&
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Seronegative spondyloarthropathies Zagora and McCluskey &&
Levy-Clarke et al. [4 ] conducted a systematic review of the published studies regarding antitumor necrosis factor alpha (TNF-a) biologic agents in patients with ocular inflammatory disorders. They concluded that infliximab and adalimumab can be considered second-line immunomodulatory agents for the treatment of uveitis associated with juvenile arthritis [14]. Infliximab and adalimumab can also be considered potential second-line immunomodulatory agents for the treatment of severe ocular inflammatory conditions, including posterior uveitis, panuveitis, severe uveitis associated with seronegative spondyloarthropathy and scleritis in patients requiring immunomodulation in patients who have failed or are not candidates for antimetabolite or calcineurin inhibitor immunomodulation. They also concluded that infliximab and adalimumab can also be considered in these patients in preference to etanercept, which seems to be associated with lower rates of treatment success [4 ]. &&
CONCLUSION Ocular inflammatory disorders are common and important disease manifestations in patients with seronegative spondyloarthropathy with anterior uveitis occurring most commonly. There is a strong association between affected patients and the HLAB27 antigen. Acute anterior uveitis is the commonest ocular disorder and usually responds well to treatment with local corticosteroids. Chronic or refractory uveitis responds well to immunosuppressive drugs that are effective for arthritis. Recent studies highlight the possible benefits of a number of biologic agents, including tumor necrosis factoralpha inhibitors in such patients. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Nash P, Mease PJ, Braun J, van der Heijde D. Seronegative spondylarthropathies: to lump or split? Ann Rheum Dis 2005; 64:ii9–ii13. 2. Ali A, Samson MC. Seronegative spondyloarthropathies and the eye. Curr Opin Ophthalmol 2007; 18:476–480. 3. Selmi C. Diagnosis and classification of autoimmune uveitis. Autoimmun Rev 2014; 13:591–594. 4. Levy-Clarke G, Jabs DA, Read RW, et al. Expert panel recommendations for && the use of antitumor necrosis factor biologic agents in patients with ocular inflammatory disorders. Ophthalmology 2014; 121:785–796. This article is a systematic review of published studies to provide recommendations for the use of anti-TNF-a biologic agents in patients with ocular inflammatory disorders. Recommendations were generated using the Grading of Recommendations Assessment, Development, and Evaluation group criteria. 5. Akgul O, Ozgocmen S. Classification criteria for spondyloarthropathies. World J Orthop 2011; 2:107–115. 6. Deodhar A. Axial spondyloarthritis criteria and modified NY criteria: issues and controversies. Clin Rheumatol 2014; 33:741–747. 7. Rosenbaum JT, Kim HW. Innate immune signals in autoimmune and auto&& inflammatory uveitis. Int Rev Immunol 2013; 32:68–75. This article discusses the increasing role of the innate immune system with the adaptive immune system which has previously been viewed as the essential contributor to autoimmune diseases. In this line, they argue that several multisystem inflammatory diseases affecting the uvea occur as a result of a mutation in a gene coding for a component of the innate immune system. The hypothesis that some diseases associated with uveitis have both a microbial infection and innate immunity as contributing factors is also discussed. 8. Selmia C, Gershwinc MC. Diagnosis and classification of reactive arthritis. && Autoimmun Rev 2014; 13:546–549. This article provides a broad and updated review of the current and in-development systemic biologic agents for the treatment of noninfectious uveitis. 9. Wakefield D, Chang JH, Amjadi S, et al. What is new HLA-B27 acute anterior & uveitis? Ocul Immunol Inflamm 2011; 19:139–144. This article provides a good clinical overview of HLA-B27-associated anterior uveitis. 10. Keck KM, Choi D, Savage LM, Rosenbaum JT. Insights into uveitis in association with spondyloarthritis from a large patient survey. J Clin Rheumatol 2014; 20:141–145. 11. Mansour AM, Jaroudi MO, Medawar WA, Tabbarah ZA. Bilateral multifocal posterior pole lesions in Reiter syndrome. BMJ Case Rep 2013; bcr 2013009253. doi: 10.1136/bcr-2013-009253. 12. Kujundzic´ M. The role of biologic therapy in the treatment of extraintestinal manifestations and complications of inflammatory bowel disease. Acta Med Croatica 2013; 67:195–201. 13. Calvo P, Pablo L. Managing IBD outside the gut: ocular manifestations. Dig Dis 2013; 31:229–232. 14. Faez S, Lobo AM, Sobrin L, Papaliodis GN. Treatment of seronegative spondyloarthropathy-associated uveitis with golimumab: retrospective case series. Clin Experiment Ophthalmol 2014; 42:392–395. 15. Karaconji T, Maconochie Z, McCluskey P. Acute anterior uveitis in Sydney. Ocul Immunol Inflamm 2013; 21:108–114. 16. Bawazeer AM, Joharjy HI. The association of human leukocyte antigen B27 with anterior uveitis in patients from the western region of Saudi Arabia: a retrospective study. Clin Ophthalmol 2013; 7:2107–2111. 17. Brewerton DA, Hart FD, Nicholls A, et al. Ankylosing spondylitis and HL-A 27. Lancet 1973; 301:904–907. 18. Dougados M, Baeten D. Spondyloarthritis. Lancet 2011; 377:2127–2137. 19. Pasadhika S, Rosenbaum JT. Update on the use of systemic biologic agents in the treatment of noninfectious uveitis. Biologics 2014; 15:67–81.
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Ocular manifestations of seronegative spondyloarthropathies Sophia L. Zagora a,b and Peter McCluskey a,b
Purpose of review This article reviews recent advances in the understanding of the ocular manifestations of seronegative spondyloarthropathies. Recent findings Ocular inflammatory disorders are common and important disease manifestations in patients with seronegative spondyloarthropathy, with anterior uveitis being the most common. There is a strong association between affected patients and the human leukocyte antigen B27. Local corticosteroid treatment is usually effective, but chronic or refractory uveitis responds well to immunosuppressive drugs that are effective for arthritis. Recent studies have highlighted the possible benefits of a number of biologic agents, including tumor necrosis factor-alpha inhibitors in such patients. Summary Uveitis is the most common ocular manifestation in patients affected by seronegative spondyloarthropathies. Both genetic and environmental factors play a role in its pathogenesis. As it tends to affect the young adult population, it carries a significant personal and population burden. Immunomodulatory therapy that also acts as a corticosteroid sparing therapy can be effective in controlling chronic uveitis in patients with spondyloarthropathy. Keywords human leukocyte antigen B27, seronegative spondyloarthropathies, uveitis
INTRODUCTION The development and use of novel biological therapies for rheumatic disease has renewed interest in the seronegative spondyloarthropathies (SSpAs) [1]. The SSpAs are a group of chronic inflammatory diseases characterized by an absence of serum rheumatoid factor and are strongly associated with the human leukocyte antigen B27 (HLA-B27). They include ankylosing spondylitis (AS), reactive arthritis (formerly Reiter’s syndrome), psoriatic arthritis, arthritis associated with inflammatory bowel disease (Crohn’s disease, ulcerative colitis) and juvenile onset spondyloarthropathy [2]. Uveitis is estimated to have a prevalence of 1/4500 in the general population and occurs typically in the 20–60-year range with both sexes being affected equally. Acute anterior uveitis is by far the most common form of uveitis and accounts for 75–90% of patients with uveitis in Western countries, but only 25–50% in Asian populations [3]. Uveitis is the most common extra-articular manifestation of seronegative spondyloarthritis,
developing in up to 25% of patients with AS and up to 10% with early psoriatic arthritis [3]. As it tends to affect the young adult population, it carries a significant personal and population quality-oflife burden [4 ]. Patients with HLA-B27-associated recurrent acute anterior uveitis, on average, have one attack per year, lasting approximately 6 weeks, which usually responds to topical corticosteroids [4 ]. Therapy for seronegative spondyloarthropathy associated acute anterior uveitis consists usually of short courses of corticosteroids administered topically, periocularly, or systemically. Seronegative &&
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a
Save Sight Institute, Discipline of Ophthalmology, Sydney Medical School, University of Sydney and bSydney Eye Hospital, Sydney, Australia Correspondence to Professor Peter McCluskey, Save Sight Institute, Campus of Sydney Eye Hospital, 8 Macquarie St., Sydney, NSW 2000, Australia. Tel: +61 2 93827111; e-mail: [email protected] Curr Opin Ophthalmol 2014, 25:495–501 DOI:10.1097/ICU.0000000000000098
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Ocular manifestations of systemic disease
KEY POINTS SSpAs – group of chronic inflammatory diseases characterized by absence serum rheumatoid factor and are strongly associated HLA-B27 antigen.
AS is related to Crohn’s disease. About 60% of patients with AS have histological evidence of Crohn’s-like changes in the large intestine, although they are usually asymptomatic. AS is also similarly related to reactive arthritis [7 ]. A definite diagnosis of Reactive Arthritis is based on the fulfillment of both major criteria and a relevant minor criterion, whereas a probable diagnosis is characterized by both major criteria but no relevant minor criterion or one or more of the minor criteria and one of the major criteria (Table 2) [8 ]. The identification of the triggering infection is also required (Table 3). Inflammatory bowel disease includes Crohn’s disease and ulcerative colitis, in which diagnosis is made by endoscopy and biopsy with histopathological confirmation. Uveitis is less frequent in patients with inflammatory bowel diseases (IBD), but it involves the posterior segment more frequently than other SSpAs. There are a number of different patterns of arthritis seen in patients with psoriasis, occurring in up to 10% of individuals. One of the patterns is an SSpA, and this type is associated with HLA-B27 and anterior uveitis [9 ]. &&
Uveitis is most common extra-articular manifestation of seronegative spondyloarthritis, developing in up to 25% of patients with AS and in up to 10% with early psoriatic arthritis. Therapy for seronegative spondyloarthropathy associated acute anterior uveitis, usually short courses of corticosteroids administered topically, periocularly, or systemically. Chronic or refractory uveitis responds well to immunosuppressive drugs that are effective for arthritis. Recent studies have highlighted possible benefits of a number of biologic agents, including TNF-a inhibitors in such patients.
spondyloarthropathy associated acute anterior uveitis is typically recurrent and alternates from eye to eye. Small numbers of patients, usually those with recurrent or chronic uveitis, require ongoing systemic therapy and may require steroid sparing agents, including the newer biologic agents including tumor necrosis factor (TNF) inhibitors which have been shown to be effective in improving both rheumatological and uveitic signs and symptoms in SSpA [2].
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Table 1. New Assessment of Spondyloarthritis International Society classification criteria for axial spondyloarthritis [6] In patients with 3 months back pain and age at onset < 45 years Sacroiliitis on imaging
THE SPONDYLOARTHROPATHIES With the new advances in treatment and subsequent outcomes, it is now more important than ever to diagnose and treat SSpA early. The modified New York criteria, the European Spondyloarthropathy Study Group criteria, and the Amor criteria are often used to guide the diagnosis of the spondyloarthropathies [5]. Spondyloarthropathies have been classified with the Amor criteria since 1990. AS is the prototype spondyloarthritis as it affects the axial skeleton. The modified New York criteria for classification of AS were developed 30 years ago; however, AS diagnosis is often missed or markedly delayed, as the modified New York criteria depend on the presence of definite sacroiliitis (grade 2 bilateral, or grade 3 or 4 unilateral). It is estimated that it takes between 6 and 10 years for radiographic sacroiliitis to develop after developing the early symptoms of axial inflammation. To address this issue the new Assessment of Spondyloarthritis International Society Classification Criteria have been developed with a newly coined term ‘axial spondyloarthritis’ (Table 1) [6]. 496
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plus
HLA-B27 OR
plus
1 SpA feature# #
2 other SpA feature#
SpA features
Sacroiliitis on imaging
Inflammatory back pain
Active (acute) inflammation on MRI highly suggestive of sacroiliitis associated with SpA
Arthritis
Definite radiographic sacroiliitis according to modified NY criteria
Enthesitis (heel) Uveitis Dactylitis Psoriasis Crohn’s/colitis Good response to NSAIDs Family history for spa HLA-B27 Elevated CRP CRP, C reactive protein; HLA, human leukocyte antigen; MRI, magnetic resonance imaging; NSAID, non-steroid anti-inflammatory drug; NY, New York; OR, odds ratio; SpA, spondyloarthropathy.
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Seronegative spondyloarthropathies Zagora and McCluskey Table 2. Diagnostic criteria for reactive arthritis [8 ] &&
Major criteria
Arthritis with two of three of the following findings: asymmetric mono-or oligoarthritis lower limb involvement Preceding symptomatic infection with one or two of the following findings: enteritis (defined as diarrhea for at least 1 day, and 3 days to 6 weeks before the onset of arthritis) urethritis (dysuria or discharge for at least 1 day, 3 days to 6 weeks before the onset of arthritis
Minor criteria
At least one of the following: evidence of triggering infection: positive urine ligase reaction or urethral/cervical swab for Chlamydia trachomatis positive stool culture for enteric pathogens associated with reactive arthritis evidence of persistent synovial infection (positive immunohistology or PCR for Chlamydia)
SPONDYLOARTHROPATHIES AND THE EYE The hallmark ocular manifestation of SSpA is anterior uveitis and occurs in up to 40% of patients with a SSpA. Infrequently, posterior or panuveitis develops most commonly in patients with IBD. Occasionally, patients develop scleritis and episcleritis [10]. There is a high association with HLA-B27 antigen. This is strongest in patients with AS and reactive arthritis [7 ]. Up to 40% of patients with AS will develop acute anterior uveitis (AAU) during the course of the disease. AAU associated with AS is typically of sudden onset and limited duration. Attacks are typically unilateral and alternate between eyes. The attacks respond well to topical, periocular, or systemic corticosteroids. Other types of uveitis occur infrequently in patients with AS. Reactive arthritis may be associated with conjunctivitis or uveitis. Major ocular manifestations include mild, symmetric, bilateral conjunctivitis with a mucopurulent discharge and a papillary or follicular reaction. Conjunctivitis occurs in up to 50% of patients and can be easily overlooked. Nongranulomatous anterior uveitis with fine-sized to medium-sized pale keratic precipitates is also common and typically has a protracted, persistent course. Scleritis, episcleritis and keratitis have also been reported [11]. Rarely reactive arthritis is &&
accompanied by permanent visual loss from posterior segment involvement such as optic neuropathy, macular edema and retinal vasculitis [11]. Extraintestinal manifestations occur in about 25–35% of patients with IBD. Joints, skin, eyes, liver and biliary systems are most commonly affected. Extraintestinal manifestations of IBD are divided into two groups: reactive manifestations which depend on activity of IBD including peripheral arthritis, erythema nodosum, aphthous stomatitis, episcleritis, and other manifestations which are independent of activity of IBD, such as pyoderma gangrenosum, uveitis, axial arthropathy, primary sclerosing cholangitis. Ocular involvement occurs in 2–10% of patients with IBD and may range from mild conjunctivitis to uveitis, episcleritis and scleritis [12]. The most frequent manifestation is anterior uveitis (more common in women), but vision-threatening posterior uveitis with retinal vasculitis, maculopathy, choroiditis and optic neuropathy may occur. The inflammation in the eye and the gut run independent clinical courses. Ocular disease usually responds to topical, periocular or systemic corticosteroids but may require immunomodulatory therapy [13]. Only a small proportion of patients with juvenile idiopathic arthritis has sudden-onset symptomatic anterior uveitis attacks. These are typically associated with enthesitis-related arthritis and the HLA-B27 antigen. Anterior uveitis associated with juvenile idiopathic arthritis presents insidiously as an asymptomatic chronic, bilateral, nongranulomatous uveitis often between 6 months and 4 years of age [14]. A detailed review of juvenile idiopathic arthritis associated uveitis is outside the scope of this review.
Table 3. Known infectious triggers of B27-associated disease [8 ] &&
Gastrointestinal tract
Yersinia Salmonella Shigella Campylobacter jejuni
Urogenital tract
Chlamydia trachomatis Neisseria gonorrhea Mycoplasma genitalium Ureaplasma urealyticum
Less frequent agents
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Clostridium difficile Campylobacter lari Chlamydia psittaci Chlamydia pneumoniae
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Ocular manifestations of systemic disease
EPIDEMIOLOGIC STUDIES The association between the human major histocompatibility complex (MHC), human leukocyte antigen HLA-B27 and the diseases now recognized as the HLA-B27-associated systemic inflammatory diseases and AAU is one of the strongest HLA disease associations. HLA-B27 is the strongest known genetic risk factor for the development of AAU, with at least half of White patients with AAU being HLAB27-positive compared with only 8–10% of the general White population [15]. The unexplained paradox is why only 1–2% of HLA-B27-positive individuals develop a B27-associated disease. Evidence implicates several other genetic factors and environmental triggers that characterize such individuals [9 ]. In a survey conducted by the Spondylitis Association of America investigating the relationship between uveitis and SSpA, 168 of 863 of patients with SSpA (19.5%) reported a diagnosis of uveitis. Baseline demographics were similar between the uveitis and no-uveitis groups. The presence of uveitis was significantly associated with Infliximab treatment [adjusted odds ratio (ORadj) ¼ 1.66, P ¼ 0.044], ‘lower jaw’ involvement (ORadj ¼ 1.60, P ¼ 0.015), heel involvement (ORadj ¼ 1.51, P ¼ 0.023) and a diagnosis of arthritis associated with inflammatory bowel disease (ORadj ¼ 1.92, P ¼ 0.005). The presence of uveitis was negatively associated with the use of Etanercept (ORadj ¼ 0.49, P ¼ 0.011) and a coexisting diagnosis of diabetes (ORadj ¼ 0.02, P ¼ 0.020) [10]. In the study by Karaconji et al. [15], SSpA was the systemic disease most commonly associated with uveitis, with AS being the most common. The diagnosis of AS was known at the time of presentation in 6.3% and was newly diagnosed in 4.2% (p. 0.2) as a result of their evaluation for AAU. In two of these patients, the diagnosis of AS was made on their first presentation of AAU. Undifferentiated SSpA was newly diagnosed in one HLA-B27-positive patient on their initial presentation with AAU. The diagnosis of reactive, psoriatic and inflammatory bowel disease arthropathy was known at the time of presentation with AAU in each of the other patients [15]. The study also found that men were affected 2.2 times more frequently than women, with 40–44 years being the mean age of presentation with HLA-B27-associated AAU. Globally, the relative frequency of HLA-B27positive AAU is significantly lower in Japan (6–13% of AAU), Korea (6–29% of AAU), India (2% of AAU) and the genetically distinct population of the Australian Aborigines (0–10%) than in Western countries (6–29%). Similarly, the frequency of both AS and AAU is lower in Japan, Korea &
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and India compared with Western countries. The clinical associations of AAU are similar among the Australian, American and European populations, with the frequency of systemic associations in AAU being 26% [15]. Karaconji et al. [15] also found that although patients with HLA-B27-positive AAU tended to have more severe disease activity on presentation, patients with HLA-B27-negative AAU tended to have more ocular complications [15,16].
PATHOLOGY AND PATHOGENESIS Since the original observations by Brewerton in 1973, that first linked HLA-B27 to SSpAs, there have been multiple hypotheses including molecular mimicry, HLA misfolding, persistence of microbial antigens in involved tissue and breakdown of immune privilege to explain the strong association between the HLA-B27 and SSpAs [9 ,17]. There have been several reviews of the pathogenesis of SSpA that highlight the role of innate immunity, as well as other components of the immune system in autoimmune disease and challenge the conventional view that immune-mediated disease is due to abnormalities in the adaptive immune response. The review by Rosenbaum and Kim [7 ] provides an excellent overview of current thinking on the roles of innate and adaptive immune mechanisms in disease and highlights several important observations that support a critical role for autoinflammatory mechanisms in SSpAs, its ocular manifestations and other diseases that cause uveitis. The genetic basis of a number of rare autoinflammatory diseases, such as Blau syndrome and familial cold urticaria, is due to mutations in NOD2 and NLRP3 genes, respectively. Mutations in these genes, mutations in other immune response component genes, such as deletion of the TLR4 receptor that greatly reduces susceptibility to EIU in murine models of EIU and other mutations that exaggerate disease expression, clearly point to a strong contribution by innate immunity to disease previously thought to be autoimmune in nature. Other important observations relate to the triggering role of infection in many immune-mediated diseases. For example, in the well characterized transgenic B27 model of SSpA, the presence of normal microbial gut flora is required to induce disease. Animals raised in germ-free conditions do not develop disease in this model. There is evidence, some longstanding and some recent, that also links gastrointestinal tract infective and inflammatory abnormalities to extraintestinal manifestations of SSpA such as uveitis and arthritis [9 ]. &
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Seronegative spondyloarthropathies Zagora and McCluskey Table 4. Characteristics, route of administration, dosage and potential side-effects for selected biologic agents [19] Generic names
Trade names
Specific target
Route
Dosage
Potential side-effects
Infliximab
Remicade
TNF-a
IV
3–5 mg/kg loading at weeks 0, 2 and 6 then maintenance 3–10 mg/kg every 4–8 weeks; maximal does 20 mg/kg in children
a
Adalimumab
Humira
TNF-a
SQ
40 mg every 1 to 2 weeks (if bodyweight < 30 kg; 20 mg every 2 weeks: loading doses of 80–160 mg are recommended for CD and PsO
Etanercept
Enbrel
TNF-al-b
SQ
Adults 50 mg weekly (may be given 50 mg twice weekly for first 3 months for PsO); children 0.8 mg/kg/week (max 50 mg/week)
Golimumab
Simponi
TNF-a
SQ
50 mg SQ monthly; except for UC 200 mg at week 0, 100 mg at week 2, then 100 mg every 4 weeks
Certolizumab
Cimzia
TNF-a
SQ
400 mg SQ at weeks 0, 2 and 4, then 200 mg every 2 weeks or 400 mg every 4 weeks
Daclizumab
Zenapax
T-cells (IL-2Ra)
IV, SQ
1 to 2 mg/kg every 2 or 4 weeks
Hypersensitivity reactions, headache, and gastrointestinal disturbance
Rituximab
Rituxan
B-cells (CD20)
IV
500 or 1000 mg at week 0 and 2; may repeat at 6–12 months thereafter (different regimen for hematologic malignancies)
Susceptibility to infections, infusion reactions, gastrointestinal disturbance, cardiovascular events, muscle spasm, and headache
Abatacept
Orencia
T-cells (CTLA-4)
IV, SQ
Adult RA 500–1000 mg IV loading, then 125 mg SQ weekly; JIA 10 mg/kg, max 1000 mg IV at weeks 0, 2 and 4, then every 4 weeks
Susceptibility to infections, allergic reactions, headache, nausea, and malignancy
Basiliximab
Simulect
T-cells (IL-2Ra; CD25)
IV
40 mg IV at weeks 0, 2, 4, 8 and 12
Gastrointestinal disturbance, headache, susceptibility to infections, and hypersensitivity reactions
TNF inhibitors Susceptibility to infections, including reactivation of tuberculosis, histoplasmosis, hepatitis B, and fungal infection; hypersensitivity reactions; demyelinating disease; lupus-like syndrome; malignancy; thromboembolic events; congestive heart failure
Lymphocyte inhibitors
Specific receptor antagonists Anakinra
Kineret
IL-1 receptor
SQ
100 mg SQ daily; children, starting 1–2 mg/kg to max 8 mg/kg daily (dose adjustment for renal insufficiency)
Injection-site reaction, infections, headache, gastrointestinal disturbance, and fever
Canakinumab
Ilaris
IL-1b
IV, SQ
Systemic JIA: 4 mg/kg (max 300 mg) SQ every 4 weeks; CAPS, 2 to 3 mg/kg SQ every 8 weeks (see text)
Susceptibility to infections, headache, nausea, and abdominal pain
Gevokizumab
(XOMA 052)
IL-1b
IV, SQ
In experiment
Susceptibility to infections and hypersensitivity reactions
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Ocular manifestations of systemic disease Table 4 (Continued) Generic names
Trade names
Specific target
Route
Dosage
Potential side-effects
Tocilizumab
Actemra
IL-6 receptor
IV
Initial 4 mg/kg IV every 4 weeks, then increase to 8–12 mg/kg every 2–4 weeks
Serious infections, hypersensitivity reactions, and gastrointestinal perforation
Alemtuzumab
Campath
CD52
IV
30 mg IV, 3 days per week for 12 weeks
Cytopenias, infusion reactions, infections, gastrointestinal disturbance, and insomnia
Efalizumab
Raptiva
CD11a
SQ
0.7 mg/kg first does then 1 mg/kg weekly (max 200 mg/ dose)
Infections, progressive multifocal leukoencephalopathy, malignancy, arthritis and thrombocytopenia
Roferon-A
Nonspecific
SQ
3–6 million units SQ daily, tapering over 6 months
Injection-site reactions, flu-like symptoms and bone marrow suppression
Interferons Interferon a-2a
CAPS, cryopyrin-associated periodic syndromes; CD, Crohn’s disease; IL, interleukin; IV, intravenously; JIA, juvenile idiopathic arthritis; PsO, plaque psoriasis; RA, rheumatoid arthritis; SQ, subcutaneously; TNF, tumor necrosis factor; UC, ulcerative colitis. a Listed side-effects apply to all TNF inhibitors shown in this table.
This evidence is succinctly summarized in the review by Rosenbaum et al. [7 ], in which observations including those cited above have resulted ‘in viewing inflammatory diseases as a spectrum in which innate immunity is critical to diseases in which the role of the adaptive immune response might appear to predominate. At one of end of the spectrum myasthenia gravis and Graves’ thyroiditis are diseases characterized by autoantibodies in which one can relate the specific autoantibody to the symptoms of the disease. Adaptive immunity might be primarily responsible for these diseases, in which as Blau syndrome, which is caused by an autosomal, dominantly inherited mutation in a component of the innate immune system may be on the other end of the spectrum. There are many of the systemic diseases associated with uveitis, such as sarcoidosis, AS and Behcet’s disease in between’ [7 ]. We are at an intriguing time in our understanding of the pathogenesis of SSpAs and their ocular manifestations. There is increasing evidence linking multiple genetic and environmental factors to the pathogenesis of these diseases; however, the compelling association between HLA-B27 and the SSpAs remains largely unexplained [7 ,9 ,18]. &&
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MEDICAL TREATMENT OF EYE DISEASE ASSOCIATED WITH SERONEGATIVE SPONDYLOARTHROPATHY Conventional therapy with corticosteroids and immunomodulatory agents may not be able to control ocular inflammation or prevent nonophthalmic 500
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complications in some patients with severe uveitis [4 ]. Biologic agents such as infliximab and adalimumab can control uveitis and scleritis in such patients and there is evidence from studies in a number of autoimmune disorders including IBD [12]. Biologic agents are recombinant proteins or antibodies directed at specific protein targets such as cytokines or cell surface receptors [19]. They target either specific cell types in the immune system such as B cells or individual molecules in the inflammatory cascade, resulting in suppression of immune responses that can cause severe ocular damage. There are many different classes of biologic agents, including anti-TNF agents, anti-interleukin agents, anti B-cell agents, interferons, antivascular endothelial growth factor agents and antibodies against specific receptors (Table 4) [4 ]. They are increasingly useful when conventional immunosuppressive therapy has failed, has been poorly tolerated or to treat concomitant ocular and systemic inflammation. Biologic therapy with infliximab, and adalimumab, may be a rapidly effective treatment for uveitis refractory to other therapies. There is now increasing experience using biologics to treat uveitis associated with juvenile idiopathic arthritis as well as uveitis associated with AS and IBD [14]. Other agents, such as golimumab, abatacept, canakinumab, gevokizumab, tocilizumab and alemtuzumab, have great promise for the treatment of uveitis; however, there is very limited clinical experience using these drugs to treat patients with uveitis. &&
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Seronegative spondyloarthropathies Zagora and McCluskey &&
Levy-Clarke et al. [4 ] conducted a systematic review of the published studies regarding antitumor necrosis factor alpha (TNF-a) biologic agents in patients with ocular inflammatory disorders. They concluded that infliximab and adalimumab can be considered second-line immunomodulatory agents for the treatment of uveitis associated with juvenile arthritis [14]. Infliximab and adalimumab can also be considered potential second-line immunomodulatory agents for the treatment of severe ocular inflammatory conditions, including posterior uveitis, panuveitis, severe uveitis associated with seronegative spondyloarthropathy and scleritis in patients requiring immunomodulation in patients who have failed or are not candidates for antimetabolite or calcineurin inhibitor immunomodulation. They also concluded that infliximab and adalimumab can also be considered in these patients in preference to etanercept, which seems to be associated with lower rates of treatment success [4 ]. &&
CONCLUSION Ocular inflammatory disorders are common and important disease manifestations in patients with seronegative spondyloarthropathy with anterior uveitis occurring most commonly. There is a strong association between affected patients and the HLAB27 antigen. Acute anterior uveitis is the commonest ocular disorder and usually responds well to treatment with local corticosteroids. Chronic or refractory uveitis responds well to immunosuppressive drugs that are effective for arthritis. Recent studies highlight the possible benefits of a number of biologic agents, including tumor necrosis factoralpha inhibitors in such patients. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Nash P, Mease PJ, Braun J, van der Heijde D. Seronegative spondylarthropathies: to lump or split? Ann Rheum Dis 2005; 64:ii9–ii13. 2. Ali A, Samson MC. Seronegative spondyloarthropathies and the eye. Curr Opin Ophthalmol 2007; 18:476–480. 3. Selmi C. Diagnosis and classification of autoimmune uveitis. Autoimmun Rev 2014; 13:591–594. 4. Levy-Clarke G, Jabs DA, Read RW, et al. Expert panel recommendations for && the use of antitumor necrosis factor biologic agents in patients with ocular inflammatory disorders. Ophthalmology 2014; 121:785–796. This article is a systematic review of published studies to provide recommendations for the use of anti-TNF-a biologic agents in patients with ocular inflammatory disorders. Recommendations were generated using the Grading of Recommendations Assessment, Development, and Evaluation group criteria. 5. Akgul O, Ozgocmen S. Classification criteria for spondyloarthropathies. World J Orthop 2011; 2:107–115. 6. Deodhar A. Axial spondyloarthritis criteria and modified NY criteria: issues and controversies. Clin Rheumatol 2014; 33:741–747. 7. Rosenbaum JT, Kim HW. Innate immune signals in autoimmune and auto&& inflammatory uveitis. Int Rev Immunol 2013; 32:68–75. This article discusses the increasing role of the innate immune system with the adaptive immune system which has previously been viewed as the essential contributor to autoimmune diseases. In this line, they argue that several multisystem inflammatory diseases affecting the uvea occur as a result of a mutation in a gene coding for a component of the innate immune system. The hypothesis that some diseases associated with uveitis have both a microbial infection and innate immunity as contributing factors is also discussed. 8. Selmia C, Gershwinc MC. Diagnosis and classification of reactive arthritis. && Autoimmun Rev 2014; 13:546–549. This article provides a broad and updated review of the current and in-development systemic biologic agents for the treatment of noninfectious uveitis. 9. Wakefield D, Chang JH, Amjadi S, et al. What is new HLA-B27 acute anterior & uveitis? Ocul Immunol Inflamm 2011; 19:139–144. This article provides a good clinical overview of HLA-B27-associated anterior uveitis. 10. Keck KM, Choi D, Savage LM, Rosenbaum JT. Insights into uveitis in association with spondyloarthritis from a large patient survey. J Clin Rheumatol 2014; 20:141–145. 11. Mansour AM, Jaroudi MO, Medawar WA, Tabbarah ZA. Bilateral multifocal posterior pole lesions in Reiter syndrome. BMJ Case Rep 2013; bcr 2013009253. doi: 10.1136/bcr-2013-009253. 12. Kujundzic´ M. The role of biologic therapy in the treatment of extraintestinal manifestations and complications of inflammatory bowel disease. Acta Med Croatica 2013; 67:195–201. 13. Calvo P, Pablo L. Managing IBD outside the gut: ocular manifestations. Dig Dis 2013; 31:229–232. 14. Faez S, Lobo AM, Sobrin L, Papaliodis GN. Treatment of seronegative spondyloarthropathy-associated uveitis with golimumab: retrospective case series. Clin Experiment Ophthalmol 2014; 42:392–395. 15. Karaconji T, Maconochie Z, McCluskey P. Acute anterior uveitis in Sydney. Ocul Immunol Inflamm 2013; 21:108–114. 16. Bawazeer AM, Joharjy HI. The association of human leukocyte antigen B27 with anterior uveitis in patients from the western region of Saudi Arabia: a retrospective study. Clin Ophthalmol 2013; 7:2107–2111. 17. Brewerton DA, Hart FD, Nicholls A, et al. Ankylosing spondylitis and HL-A 27. Lancet 1973; 301:904–907. 18. Dougados M, Baeten D. Spondyloarthritis. Lancet 2011; 377:2127–2137. 19. Pasadhika S, Rosenbaum JT. Update on the use of systemic biologic agents in the treatment of noninfectious uveitis. Biologics 2014; 15:67–81.
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