|Year : 2020 | Volume
| Issue : 5 | Page : 40-44
Uveitis in spondyloarthropathies: Current concepts
Division of Rheumatology, Southern Illinois University School of Medicine, Springfield, Illinois, USA
|Date of Web Publication||23-May-2020|
Dr. Krati Chauhan
801 N Rutledge St. Suite 1201, Springfield, Illinois 62702
Source of Support: None, Conflict of Interest: None
Uveitis is the inflammation of the middle layer of the eye, the Uvea. Spondyloarthropathies are systemic disorders with common clinical and pathological features. Uveitis is an important and frequent extraarticular manifestation of spondyloarthropathies. Recently, there has been a remarkable enhancement in the management of uveitis with the approval of biologics. This review discusses epidemiology, clinical features and management of uveitis associated with spondyloarthropathies.
Keywords: Immunosuppressive therapy, spondyloarthropathies, Uveitis
|How to cite this article:|
Chauhan K. Uveitis in spondyloarthropathies: Current concepts. Indian J Rheumatol 2020;15, Suppl S1:40-4
| Introduction|| |
Eyes are the windows to the soul, and in spondyloarthropathies, uveitis becomes our gateway to these systemic conditions. Uveitis is inflammation of the uvea, the middle layer of the eye, present between the outer layer (sclera) and the inner layer (retina). Uvea comprises iris anteriorly, ciliary body in the middle, and choroid posteriorly. According to the Standardization of Uveitis Nomenclature criteria, uveitis is classified based on the anatomical location into anterior, intermediate, posterior, and panuveitis. The primary site of inflammation for the anterior uveitis is the anterior chamber (iritis, iridocyclitis, and anterior cyclitis), intermediate is the vitreous (pars planitis and posterior cyclitis), posterior is the choroid or retina (choroiditis, chorioretinitis, retinochoroiditis, retinitis, or neuroretinitis), and panuveitis is the inflammation of the anterior chamber, vitreous, and choroid or retina. Uveitis is termed acute when an episode is sudden in onset and lasts <3 months. Repeated episodes, with periods of no disease activity without treatment, lasting >3 months are termed recurrent. Moreover, uveitis which relapses in <3 months after discontinuing treatment is termed chronic. When no cells are present in the anterior chamber, the disease is considered inactive.
| Epidemiology and Etiology|| |
The incidence of uveitis is 17–52/10,000, and the prevalence is 100–150 cases/100,000 in the developed countries, affects around two million people worldwide, and is associated with 10% of all cases of blindness. Etiologically, it is generally classified into infectious and noninfectious causes, although it is often considered a simplified way of classifying a complex disease like uveitis. Noninfectious uveitis is more common in the Western world, and around 40% are associated with systemic autoimmune diseases such as spondyloarthropathies, Behcet's disease, and sarcoidosis. About one-third of noninfectious uveitis are termed idiopathic, as these do not have an associated systemic disease. Infectious uveitis is common in developing countries, associated with tuberculosis, toxoplasmosis, syphilis, and onchocerciasis.
| Clinical Features and Diagnosis|| |
Anterior uveitis presents with pain, redness of the eye, and photophobia, whereas intermediate and posterior uveitis may be clinically silent initially or present with floaters, blind spots, and vision loss. Complications of uveitis include cataract, glaucoma, synechia formation, and macular edema. Inflammation in the eye is clinically recognized with the use of split lamp (these may show the presence of cells in the anterior chamber and in the vitreous) and indirect ophthalmoscope, and it may be further supplemented with the use of fluorescein angiography and optical coherence tomography. Diagnostic workup is guided by the history, physical examination, and anatomical location of the uveitis. It is recommended that all patients suspected of having uveitis get a complete blood count, erythrocyte sedimentation rate, C-reactive protein, tuberculin skin test or interferon-gamma release assay, syphilis serology, and chest X-ray (to evaluate the presence of tuberculosis and sarcoidosis). Human leukocyte antigen (HLA)-B27, Cytomegalovirus, and varicella-zoster virus serology may be obtained in patients presenting with acute anterior uveitis. HLA-B27 is particularly useful in patients with recurring anterior uveitis. Intraocular specimens obtained through anterior chamber tap, vitrectomy, or retinochoroidal biopsy may be obtained, depending on the individual patient, when the initial diagnostic tests are nonconclusive.
| Management|| |
The management of noninfectious uveitis is guided by the anatomic site. Anterior uveitis is generally treated with topical corticosteroids, intermediate uveitis with regional corticosteroid injections (periocular or intravitreal), or oral corticosteroids if required with immunosuppressive medications. Posterior and panuveitis are treated with oral corticosteroids and immunosuppressive medications. Topical steroids include prednisone acetate 1% and difluprednate. If a patient consistently requires 1–2 drops/day of topical steroids, it is considered an indication for either regional corticosteroid injections or systemic medications. Immunosuppressive systemic medications include antimetabolites (azathioprine, mycophenolate mofetil, and methotrexate), calcineurin inhibitors (tacrolimus and cyclosporine), alkylating agents (cyclophosphamide and chlorambucil), and biologics. The management of noninfectious uveitis has been significantly enhanced with multiple studies addressing the systemic mediations and the side effects associated with these medications. The Systemic Immunosuppressive Therapy for Eye Diseases (SITE) was a retrospective cohort study. The primary outcome of the SITE was overall and malignancy-related mortality in patients using systemic immunosuppressive therapy. Patients taking oral steroids, methotrexate, mycophenolate mofetil, azathioprine, or cyclosporine had similar overall and cancer-related mortality rates as compared with patients not taking systemic immunosuppressive therapy. Patients taking cyclophosphamide had higher cancer-related mortality rates which were not statistically significant.
The Multicenter Uveitis Steroid Treatment Trial compared the efficacy of systemic treatment to fluocinolone acetonide implant for the treatment of noninfectious intermediate uveitis, posterior uveitis, or panuveitis. Seven-year follow-up of this trial demonstrated that systemic therapy (corticosteroid along with immunosuppressive therapy) improved visual outcomes and reduced macular edema compared to fluocinolone acetonide implant. First-line antimetabolites as steroid-sparing treatment uveitis trial, a randomized study, compared methotrexate and mycophenolate for achieving corticosteroid-sparing control of noninfectious intermediate uveitis, posterior uveitis, and panuveitis. This study concluded that mycophenolate mofetil was not superior to methotrexate as a first-line corticosteroid-sparing treatment in control of inflammation. Moreover, it suggested the need for further research to determine if mycophenolate mofetil or methotrexate is more effective based on the anatomical subtype of noninfectious uveitis.
In 2016, tumor necrosis factor (TNF)-alpha inhibitor, adalimumab, became the first biologic to be approved for the treatment of noninfectious uveitis, following the VISUAL I and II trials., Etanercept, a fusion protein of the TNF-α receptor, has not been efficacious in managing noninfectious uveitis. Secukinumab, a human antibody against interleukin-17A (IL-17A), was tested in three Phase III trials (INSURE, ENDURE, and SHIELD) and was found not be efficacious. Ustekinumab, a human monoclonal antibody against IL-23 and IL-12, is being studied in two Phase II trials STELARA (NCT0291116) and STELABEC (NCT02648581).
Guidance on noncorticosteroid systemic immunomodulatory therapy in noninfectious uveitis: Fundamentals of Care of Uveitis (FOCUS) initiative” provides clinicians evidence based and practical information on systemic therapy for managing non-infectious uveitis. These guidelines provide recommendations, when to start noncorticosteroid systemic immunomodulatory treatment and which medication to choose. Any information which is slight threatening presence of macular involvement or if the inflammation persists despite topical treatment; are indications for initiating systemic therapy. The choice of the medication is best, when it is individualized to the patient, depending on the patients' other medical comorbidities, ability of a patient to tolerate side effects associated with the medication, and the cost of the medication. Biologics are generally added after the patient has tried one of the nonbiologic medications. Managing patients with uveitis requires close collaboration among specialists, as ophthalmologists assess uveitis activity and ocular complications and usually provide topical medications, and rheumatologists in majority of the cases manage systemic medications.
| Spondyloarthropathies|| |
Spondyloarthropathies are a group of inflammatory disorders which share clinical, pathological, radiological, immunological, and genetic features. These include ankylosing spondylitis, reactive arthritis, psoriatic arthritis, inflammatory bowel disease (IBD), and undifferentiated spondyloarthropathies. Uveitis is the most common extra-articular manifestation of spondyloarthropathies. It is common in patients with the diagnosis of spondyloarthropathy for 10 years or more, who are HLA-B27 positive and have sacroiliitis.
| Ankylosing Spondylitis and Uveitis|| |
Ankylosing spondylitis is a chronic inflammatory disease that primarily affects the spine and the sacroiliac joints. It commonly presents during the second and third decades. Patients are generally males, who are HLA-B27 positive. Gradual onset back pain, relieved with activity, increased with rest and at night, and associated with morning stiffness, lasting for greater than an hour is the classic clinical presentation of ankylosing spondylitis. Acute anterior uveitis is the most common extra-articular presentation, occurring in 20%–30% of the patients. There is no correlation of uveitis with joint disease severity and exacerbation. It is characterized as unilateral, sudden onset, and recurrent in nature. The patient presents with eye pain, redness, and photophobia. Slit-lamp examination shows cells in the anterior chamber and keratic precipitates on the cornea. Anterior uveitis responds well to topical corticosteroids, which controls the inflammation and a mydriatic agent which decreases ciliary muscle spasm and reduces eye pain. Acute anterior uveitis associated with ankylosing spondylitis has an excellent prognosis. Only patients who have a high recurrence of uveitis benefit from oral steroids or immunosuppressive drugs. It has been reported that ankylosing spondylitis patients treated with anti-TNF-alpha agents show a significant decrease in the number of uveitis flares.
| Inflammatory Bowel Diseases and Uveitis|| |
IBD is a chronic inflammatory disorder of the gastrointestinal tract of unknown etiology. These include ulcerative colitis (UC) and Crohn's disease (CD). CD may affect any part of the gastrointestinal tract, whereas UC affects the colon and rectum. Lesions in UC are continuous and involve submucosa and mucosa. While CD is characterized by skip lesions and involvement of all the layers of the bowel wall. Extraintestinal involvement in IBD may involve the joints, eye, skin, and liver. Ocular involvement is more common in CD, and it occurs in about 4%–10% of the patients. It may occur before or after the diagnosis of IBD, and it is more common in patients with colitis, ileocolitis, and those with other extraintestinal involvements.
The hypothesis for ocular involvement includes autoantibody production against cellular antigens shared by the colon and other organs. Inflammation disrupts the mucosal lining, allowing proteins, or microorganisms to pass through the intestinal barrier and cause a reactive lymphoid tissue response. It results in the production of circulating antibodies or antigen–antibody complexes, causing ocular inflammation. These patients also have a higher prevalence of HLA-B27, indicating genetic involvement.
Acute anterior uveitis is the most common uveitis associated with IBD, and posterior and panuveitis are less common. It may precede the diagnosis of IBD and may occur when IBD is active or quiescent. It is commonly associated with erythema nodosum and joint involvement and the presence of HLA-B27. Anterior uveitis is managed with topical steroid drops or subtenon steroid injection and cycloplegics. Posterior and panuveitis are managed with the systemic steroids and use of immunosuppressive therapy such as azathioprine or biologics such as infliximab or adalimumab.
| Psoriatic Arthritis and Uveitis|| |
Psoriasis is an inflammatory skin condition, presenting as scaly erythematous plaques, involving the extensor surface of elbows and knees, affecting 2%–4% of the Western population. 20%–30% of the patients with psoriasis develop an inflammatory arthritis called psoriatic arthritis. Uveitis occurs in about 6%–9% of the patients with psoriatic arthritis. It is more common in patients with axial joint involvement and who are HLA-B27 positive. Cytokines IL-17 and IL-23 are thought to play an important role in the pathogenesis of uveitis in psoriatic arthritis. It also been proposed that inflammation in psoriasis and psoriatic arthritis may result in a breakdown of the barrier between the blood and the aqueous humor. This breakdown allows inflammatory cells such as activated neutrophils to reach the aqueous humor and begin intraocular inflammation. As compared to ankylosing spondylitis, uveitis associated with psoriatic arthritis is insidious in onset, continuous as compared to episodic, bilateral as compared to unilateral, and more common to be posterior, and it resembles uveitis seen in patients with IBD. Management depends on the anatomical location, and anterior uveitis is managed with topical steroids and mydriatic agents. Posterior and panuveitis are managed with oral steroids and immunosuppressive therapy.
| Reactive Arthritis and Uveitis|| |
Reactive arthritis is an inflammatory condition which occurs as a result of bacterial infection of the gastrointestinal tract or the genitourinary system. The frequency of reactive arthritis after enteric infection is around 1%–4%. Common pathogens are Campylobacter, Salmonella More Details, Shigella, and Yersinia More Details. 1%–3% of the patients with genitourinary system infections may develop reactive arthritis, though this percentage may be higher as genitourinary infections may not be recognized. Reactive arthritis usually presents 1–4 weeks following the gastrointestinal tract or the genitourinary infection, which presents as asymmetric oligoarthritis localized to the large joints of the lower extremities. In general, the symptoms last for 4–5 months; sometimes, symptoms may persist for more than a year. Acute anterior uveitis presenting as pain, photophobia, and redness may be seen in 5% of the patients, who are HLA-B27 positive, and some studies report a higher percentage of uveitis. Uveitis in reactive arthritis is managed with topical steroids and cyloplegic agents, as detailed earlier in previous spondyloarthropathies.
| Uveitis in Pediatric Population|| |
Uveitis is the most common extra-articular manifestation of juvenile idiopathic arthritis (JIA). Uveitis in JIA is chronic and is present in 10%–20% of the patients. It is rarely symptomatic and may not be detected till late in the course of the disease, hence the need for routine ophthalmologic screening for JIA patients. Undetected or untreated or undertreated chronic uveitis in JIA patients results in cataracts, glaucoma in 25%–50%, and vision loss in 10%–20%.
In the year 2019, the American College of Rheumatology and Arthritis Foundation released new screening, monitoring, and treatment guidelines for JIA patients with uveitis. JIA patients with oligoarthritis, antinuclear antibody positive, younger than 7 years at the time of JIA onset, JIA of <4 years, polyarthritis (rheumatoid factor negative), psoriatic arthritis, and undifferentiated arthritis should undergo ophthalmologic screening every 3 months. Guidelines recommend using prednisone acetate 1% over difluprednate, adding or increasing the dose of topical steroids over starting oral steroids for short-term control of uveitis. In patients who require systemic therapy, subcutaneous methotrexate is recommended over oral methotrexate as the first line therapy. Monoclonal antibody against TNF-alpha antibody may be started along with methotrexate for severe disease. Like adults, children with spondyloarthropathies most commonly present with acute anterior uveitis which usually responds to topical steroids.
| Conclusion|| |
Uveitis is an important part of the clinical spectrum of spondyloarthropathies. It is a common extra-articular manifestation and may be the presenting symptom of spondyloarthropathies. It is best managed with close collaboration between ophthalmology and rheumatology. There has been advancement in the management, especially with the use of biologics. Novel research continuously adds to our understanding and management of uveitis.
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