- Related Content
- What is uveitis?
- What should you do?
- Eye Problems Caused by Ankylosing Spondylitis
- Acute anterior uveitis? Consider axial spondyloarthritis
- Inefficacy or Paradoxical Effect? Uveitis in Ankylosing Spondylitis Treated with Etanercept
- 1. Ankylosing Spondylitis: Current Definition and Extra-Articular Manifestations
- 2. Clinics, Outcomes, Pathogenesis, and Role of TNF-α in Uveitis of Spondyloarthritis
- 3. Conventional Treatment and TNFα Inhibitors in the Treatment of Uveitis
- 4. A Paradoxical Effect: Uveitis during Anti-TNFα
- 5. Case Report
- 6. Discussion
- Conflict of Interests
- Related posts:
A 23-year-old white female presented to the office after experiencing a red, painful left eye for approximately one week. Additionally, she reported photophobia and a radiating left, frontal headache. Neither artificial tears nor acetaminophen had provided significant relief. Her ocular history included bilateral myopia as well as a small-angle, constant left esotropia with mild amblyopia in that eye.
Her best-corrected visual acuity was 20/20 OD and 20/30 OS. Pupil testing, motility testing and confrontation fields were all normal. Biomicroscopy of the right eye was essentially unremarkable, but the left eye displayed 3+ injection of the bulbar conjunctiva with a notable circumlimbal flush. Additionally, the anterior chamber demonstrated grade 2+ cells and flare. Fine keratic precipitates were also evident on the corneal endothelium, most notably inferior. Intraocular pressure (IOP) was 16mm Hg OD and 12mm Hg OS. A dilated fundus examination was unremarkable.
The patient was diagnosed with acute, idiopathic anterior uveitis in her left eye. Treatment included cycloplegia (5% homatropine twice daily in each eye) and liberal use of topical corticosteroid drops (0.05% difluprednol every two hours in the left eye for the first 72 hours). The condition was brought under control in a matter of weeks; cycloplegia was discontinued and the steroid drops were slowly tapered until cells were no longer evident in the anterior chamber.
Although the patient responded well and the episode appeared singular, we discussed the implications of idiopathic anterior uveitis, as well as the potential for a systemic etiology.
We recommended she obtain a physical examination as a precautionary measure, with medical testing to follow as determined by her primary care physician. Several weeks later, she reported that serologic testing had come back positive for human leukocyte antigen-B27 (HLA-B27).
Characteristic cells and flare presentation in a patient with acute anterior uveitis.
This column reviews some of the diagnostic and management challenges associated with uveitis, as well as with HLA-B27.
Anterior uveitis is heralded by a constellation of clinically observable findings, typically including deep perilimbal injection of the conjunctiva and episclera, keratic precipitates along the corneal endothelium, variable corneal edema and “cells and flare” within the aqueous.1 “Cells” represent free-floating leukocytes, liberated from the iris vasculature in response to inflammation, while “flare” refers to plasma proteins suspended in the aqueous, giving rise to a hazy or smoky appearance. The classic presentation typically involves an individual 20 to 60 years of age, complaining of unilateral ocular pain, photophobia, and tearing.2,3
While circumstances that spark the development of uveitis vary, its resultant events stimulate a localized inflammatory state impacting the iris, ciliary body and cornea. Cytokines mediate numerous tissue changes, among them vasodilation and increased vasopermeability.4,5 As cellular debris and large molecular weight proteins accumulate in the aqueous, negative sequelae become increasingly likely, including synechiae, secondary glaucomas and neovascularization of the iris and angle.4-6 Unmanaged, the condition is potentially sight-threatening from a variety of pathogenic mechanisms.
Numerous etiologies may be implicated in anterior uveitis, ranging from trauma to widespread infection to generalized ischemic disorders.7-12 Some of the more well-known systemic etiologies include rheumatoid arthritis, systemic lupus and Lyme disease.11,12 Medical testing is generally not undertaken for isolated episodes; however, if the presentation is bilateral, severe, recalcitrant or recurrent, the patient should obtain testing to investigate for potential underlying systemic conditions (Table 1).
Imaging studies are also part of the medical workup. X-rays of the sacroiliac joint are useful in diagnosing ankylosing spondylitis, while a chest radiograph helps identify tuberculosis or sarcoidosis infiltration into the pulmonary system.14 Unfortunately, these tests are time-consuming and expensive. Rather than taking a “scatter-shot” approach, we prefer to comanage patients with an internist or rheumatologist who can choose the most appropriate tests.
Table 1. Systemic Tests
Refer a patient for testing when the history or associated symptoms are suggestive of a particular disease.13 Tests to consider include:14
- Complete blood count with differential and platelets.
- Erythrocyte sedimentation rate.
- Antinuclear antibody.
- Human leukocyte antigen typing.
- Rheumatoid factor.
- Angiotensin-converting enzyme.
- Purified protein derivative with anergy panel.
- Fluorescent treponemal antibody absorption.
- Rapid plasma reagin.
- Lyme immunoassay.
Human Leukocyte Antigen-B27
HLA proteins, often found on white blood cells, are encoded by genes of the major histocompatibility complex.15-17 While their specific functions are diverse, they are principally implicated in the immune response and inflammatory pathways.16 Researchers classify HLAs into different types (e.g., HLA-A, HLA-B, HLA-C), and those types into further, numbered versions, or alleles (e.g., HLA-A24, HLA-B13). The HLA-B27 serotype is strongly linked with the seronegative spondyloarthropathies group of autoimmune diseases.15-18 In these conditions, blood tests may reveal a positive HLA-B27 result. However, rheumatoid factor and antinuclear antibody are characteristically negative. The most prevalent of these conditions is ankylosing spondylitis; other known disorders include reactive arthritis, spondylitis associated with inflammatory bowel disease (including Crohn’s disease and ulcerative colitis), psoriatic arthritis and juvenile idiopathic arthritis. Additionally, HLA-B27+ individuals may manifest inflammation localized solely to the uveal tract, known clinically as isolated acute anterior uveitis.17,19
For our patient, identification of the HLA-B27 serotype resulted in mixed emotions. While we were somewhat relieved at having discovered an underlying cause, we were greatly concerned about her future. Would she be likely to suffer additional recurrences of uveitis? Could she potentially develop any of the systemic illnesses mentioned? What steps can she take now to help prevent potential complications later on? While these questions are difficult to answer with absolute certainty, the reality is that individuals who are HLA-B27+ have a high tendency toward recurrent anterior uveitis; of even greater concern is the fact that about 50% will develop an associated spondyloarthropathy during their lifetime.20 Unfortunately, the only known prophylactic measure that can lessen the severity of complications associated with HLA-B27+ disorders is diligence. Proactive care with the PCP or managing rheumatologist, as well as regular evaluations by the eye care provider, are all that we can presently recommend for individuals like our patient.
1. Agrawal R, Murthy S, Sangwan V, Biswas J. Current approach in diagnosis and management of anterior uveitis. Indian J Ophthalmol. 2010;58(1):11-9.
2. Wakefield D, Chang J. Epidemiology of uveitis. Int Ophthalmol Clin. 2005;45(2):1-13.
3. Miserocchi E, Fogliato G, Modorati G, Bandello F. Review on the worldwide epidemiology of uveitis. Eur J Ophthalmol. 2013;23(5):705-17.
4. Casey R, Li WW. Factors controlling ocular angiogenesis. Am J Ophthalmol. 1997;124(4):521-9.
5. Kuo IC, Cunningham ET Jr. Ocular neovascularization in patients with uveitis. Int Ophthalmol Clin. 2000;40(2):111-26.
6. Sng C, Barton K. Mechanism and management of angle closure in uveitis. Curr Opin Ophthalmol. 2015;26(2):121-7.
7. Zeboulon N, Dougados M, Gossec L. Prevalence and characteristics of uveitis in the spondyloarthropathies: a systematic literature review. Ann Rheum Dis. 2008;67(7):955-9.
8. Hooper C, McCluskey P. Intraocular inflammation: its causes and investigations. Curr Allergy Asthma Rep. 2008;8(4):331-8.
9. Liberman P, Gauro F, Berger O, Urzua CA. Causes of uveitis in a tertiary center in Chile: A cross-sectional retrospective review. Ocul Immunol Inflamm. 2014;Dec 1:1-7.
10. Slemp SN, Martin SE, Burgett RA, Hattab EM. Giant cell arteritis presenting with uveitis. Ocul Immunol Inflamm. 2014;22(5):391-3.
11. Pan J, Kapur M, McCallum R. Noninfectious immune-mediated uveitis and ocular inflammation. Curr Allergy Asthma Rep. 2014;14(1):409.
12. Barisani-Asenbauer T, Maca S, Mejdoubi L, et al. Uveitis- a rare disease often associated with systemic diseases and infections- a systematic review of 2619 patients. Orphanet J Rare Dis. 2012;7:57.
13. Jabs DA, Busingye J. Approach to the diagnosis of the uveitides. Am J Ophthalmol. 2013;156(2):228-36.
14. Kabat AG. Uveitis. In: Bartlett JD, Jaanus SD, eds. Clinical Ocular Pharmacology, 5th Edition. Boston:Butterworth-Heinemann, 2007. 587-600.
15. Chang J, McCluskey P, Wakefield D. Acute anterior uveitis and HLA-B27. Surv Ophthalmol. 2005;50(4):364-88.
16. Chang J, McCluskey P, Wakefield D. Acute anterior uveitis and HLA-B27: what’s new? In: Pleyer U, Forrester, JV (Eds). Uveitis and Immunological Disorders: Progress III. Berlin and Heidelberg: Springer-Verlag; 2009. pp. 9–18.
17. Gouveia EB, Elmann D, Morales MS. Ankylosing spondylitis and uveitis: overview. Rev Bras Reumatol. 2012;52(5):742-56.
18. Smith WM. Gender and spondyloarthropathy-associated uveitis. J Ophthalmol. 2013:928264.
19. Monnet D, Moachon L, Dougados M, Brézin AP. Severe uveitis in an HLA-B27-positive patient with ankylosing spondylitis. Nat Clin Pract Rheumatol. 2006;2(7):393-7.
20. Wakefield D, Chang JH, Amjadi S, et al. What is new HLA-B27 acute anterior uveitis? Ocul Immunol Inflamm. 2011;19(2):139-44.
Ask the experts
How does ankylosing spondylitis affect the eye, and how is it treated?
Patients with ankylosing spondylitis can develop inflammations of the iris of the eye. This is referred to as iritis. Recurrent attacks of iritis can affect either eye and is characterized by eye pain and redness with increased pain when looking at bright lights. In addition to the iris, the ciliary body and choroid of the eye can be inflamed and this is referred to as uveitis.
Iritis and uveitis can be serious complications of ankylosing spondylitis that can damage the eye and impair vision. Urgent consultation with an ophthalmologist may be required. Treatment can involve cortisone eye drops (such as pred forte) and other drops to rest the muscles of the iris. Additionally, high doses of cortisone medication by mouth and/or injected directly into the involved eye can be required.
Finally, it should be noted that iritis and inflammation of the spine can occur in other forms of arthritis, such as reactive arthritis (formerly Reiter Syndrome), psoriatic arthritis, and the arthritis of inflammatory bowel disease.
CONTINUE SCROLLING OR FOR RELATED SLIDESHOW
This information is for anyone with axial spondyloarthritis (axial SpA) including people with ankylosing spondylitis (AS)
What is uveitis?
About a quarter of people with axial SpA (AS) will have an attack of uveitis (sometimes known as iritis) at some time in their life.
This is an eye condition caused by inflammation in the front part of the eye between the cornea (the clear window at the front of the eye) and the lens.
What are the signs and symptoms of uveitis
- Pain in the eye
- Sensitivity to light. The brighter the light the more pain in the eye as the pupil gets smaller causing pain
- Redness and soreness of the eye
- Blurred vision
Uveitis usually comes on suddenly and is likely to recur
Each single attack usually lasts a few weeks and should last no more than 3 months. The inflammation can range from mild to severe and each attack may be different, even in the same person.
What should you do?
If you think you have symptoms of uveitis you should see an eye doctor (ophthalmologist) as soon as possible, ideally within 24 hours, to confirm it and start you on treatment. Early treatment reduces the risk of long term damage to the eye which can affect your vision.
You can find an ophthalmologist by asking your GP to make an urgent referral to the local ophthalmology team or you can go to your local hospital A&E department who will contact the ophthalmologist to arrange an urgent review.
Uveitis is usually treated with a combination of eye drops.
- Steroid eye drops such as dexamethasone and prednisolone reduce the inflammation
- Dilating drops dilate the pupil which reduces the risk of the iris sticking to the lens and break any attachments that have already formed
Rheumatic diseases don’t just affect the joints; they can attack many different body parts, including the eyes. Save your vision by bringing any of the following symptoms to your doctor’s attention.
Eyes that burn, itch or feel gritty could point to Sjögren’s syndrome, an autoimmune attack on the body’s moisture- producing glands. About half of people living with Sjögren’s also have another autoimmune disease, such as rheumatoid arthritis (RA) or lupus.
Bloodshot eyes that are accompanied by pain, light sensitivity or blurred vision may be a sign of uveitis, inflammation of the middle layer of the eye. Though it is linked to many kinds of infections and rheumatic diseases, uveitis is most closely associated with ankylosing spondylitis, reactive arthritis and juvenile arthritis, and it may cause vision loss if left untreated.
Pain that is accompanied by tearing, sensitivity to light or redness that doesn’t go away with the use of over-the counter drops like tetrahydrozoline (Visine) could signal scleritis, inflammation of the eye’s whitish outer layer. This condition, which is associated with RA, is most commonly seen in adults ages 40 to 70.
Eye Problems Caused by Ankylosing Spondylitis
How Is Anterior Uveitis Treated?
An ophthalmologist (a medical doctor who specializes in eye care and surgery) examining a person with anterior uveitis will obtain a medical history that includes specific questions about the presence of low back pain. In fact, an ophthalmologist may be the first doctor to make the diagnosis of ankylosing spondylitis.
An ophthalmologist also performs a complete eye exam on a person with anterior uveitis. The exam includes a visual acuity test, a pupil examination, a slit-lamp examination, an intraocular pressure measurement, and a careful inspection of the back of the eye after dilating the pupils.
Treatment of anterior uveitis usually consists of dilating eyedrops called cycloplegics. Cycloplegic eyedrops dilate the pupil and relieve the pain caused by the spasm of the iris. Cycloplegic eyedrops also temporarily paralyze the focusing mechanism of the eye. Cycloplegic eyedrops include the following:
- Tropicamide (Mydriacyl, Opticyl, Tropicacyl)
- Cyclopentolate (Cyclogyl)
- Homatropine (Isopto Homatropine)
- Scopolamine ophthalmic (Isopto Hyoscine)
- Atropine (Isopto Atropine)
Additional medications that may be used include one or more of the following:
In certain cases, oral nonsteroidal anti-inflammatory drugs such as ibuprofen and oral corticosteroids such as prednisone may be used. See the article Understanding Ankylosing Spondylitis Medications for more information.
Occasionally, the severity of inflammation may require treatment with corticosteroid injections around the eye. If the intraocular pressure (pressure within the eye) is elevated, additional eyedrops may be required to decrease the pressure.
The person’s primary-care doctor may recommend other oral immunosuppressive drugs to be taken in conjunction with the eye drops prescribed by the ophthalmologist. In recalcitrant cases, injections of immunomodulating drugs such as infliximab, etanercept or adalimumab may be considered.
Complications of repeated episodes of anterior uveitis caused by ankylosing spondylitis may include adhesions of the iris to the lens (meaning that the iris sticks to the lens), cataract formation, glaucoma, and macular edema. Macular edema is a swelling of the center of the retina and can cause decreased vision. To minimize the occurrence of these complications, the ophthalmologist closely observes the person and promptly treats any episodes of anterior uveitis.
Some people who have recurrent anterior uveitis may require continual treatment with eyedrops to prevent these recurrences. People with ankylosing spondylitis must understand that any eye redness or eye pain requires prompt attention by their ophthalmologist.
The ophthalmologist usually consults with the person’s primary-care doctor, the rheumatologist (a medical doctor who specializes in diseases of the joints, muscles, and bones), or both, and together, they will use a team approach to manage the care of the person with ankylosing spondylitis and anterior uveitis. Ankylosing spondylitis is a chronic condition that requires a person to be aware of and understand the disease process as well as to be an active participant in the treatment process. Careful attention to this condition results most often in successful control and preservation of function.
Acute anterior uveitis? Consider axial spondyloarthritis
SNOWMASS, COLO. – Ankylosing spondylitis, far and away, is the most common systemic disease in North America associated with uveitis, Dr. James T. Rosenbaum said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
The uveitis associated with ankylosing spondylitis and other HLA-B27-positive axial spondyloarthropathies is highly distinctive: It’s an anterior uveitis, meaning it occurs in front of the lens. It is sudden in onset, unilateral, often recurs in the opposite eye, and it resolves completely between attacks within several months. Also, it is associated with reduced intraocular pressure, according to Dr. Rosenbaum, professor of inflammatory diseases and chief of the division of arthritis and rheumatic diseases at Oregon Health & Science University and chief of ophthalmology at the Devers Eye Institute in Portland, Ore.
Dr. James T. Rosenbaum
The differential diagnosis for a red eye is extensive. It includes conjunctivitis, scleritis, episcleritis, keratitis, and acute closed angle glaucoma, as well as anterior uveitis. But the only cause of a red eye that results in a constricted pupil is a sudden-onset acute anterior uveitis, he noted.
A patient with acute anterior uveitis has a 50% likelihood of being HLA-B27-positive. And a B27-positive patient with acute anterior uveitis and inflammatory back pain has nearly a 90% chance of having a spondyloarthropathy. Roughly half of these individuals meet diagnostic criteria for ankylosing spondylitis, and another 40% fulfill the Assessment of Spondyloarthritis International Society definition of spondyloarthritis, which doesn’t require definite evidence of inflammation of the sacroiliac joints on plain x-rays. An analysis of National Health and Nutrition Examination Survey data showed that 1% of U.S. adults have axial spondyloarthritis (Arthritis Care Res. 2012;64:905-10).
Yet in Dr. Rosenbaum’s experience, two-thirds of patients who present with HLA-B27-positive, unilateral, sudden-onset acute anterior uveitis have no idea that their inflammatory low back pain is a manifestation of ankylosing spondylitis or axial spondyloarthritis.
“Back pain is so endemic in our society that it’s rarely realized that the chronic back inflammation is related to the eye disease,” he observed.
Dr. Rosenbaum said that for most nonophthalmologists, uveitis flies under the radar.
“Most people don’t know what it is, but uveitis actually accounts for about 10% of all cases of blindness. And it’s a disease that often occurs in the prime of life, unlike macular degeneration or blindness due to diabetes,” he continued.
His uveitis treatment ladder starts with topical corticosteroids, which are often quite effective for anterior uveitis. Second-line therapy consists of periocular or intravitreal steroid injections, “just like you’d inject a shoulder or knee.” Oral corticosteroids are effective, but their long-term use is problematic, so Dr. Rosenbaum will quickly switch to an antimetabolite, with methotrexate his top choice.
“I would never use a TNF inhibitor to treat spondyloarthropathy-associated acute anterior uveitis per se, because this type of uveitis is typically short lived. As a practical matter, by the time I got approval from the third-party payer the uveitis would be gone. But if a patient is having recurrent severe episodes of uveitis, a TNF inhibitor will reduce the intensity and frequency of those flares. So will sulfasalazine. Methotrexate will, too, but it doesn’t affect the spondyloarthropathy,” he said.
Dr. Rosenbaum reported receiving consulting fees from a dozen pharmaceutical companies and research grants from AbbVie, Eyegate, Genentech, and Psivida.
Inefficacy or Paradoxical Effect? Uveitis in Ankylosing Spondylitis Treated with Etanercept
Ankylosing spondylitis (AS) is presented with axial and peripheral articular involvement. Uveitis is a severe and rather specific manifestation of AS. Biologics targeting tumor necrosis factor (TNF) α are effective on both articular and ocular manifestations of disease. The occurrence of uveitis in patients that never had eye involvement or the relapse of uveitis is described during anti-TNFα treatment. The frequency of these events is slightly higher during therapy with etanercept. The available TNFα blockers show different pharmacokinetics and pharmacodynamics yielding different biological effects. There is an ongoing debate whether uveitis during anti-TNFα has to be considered as paradoxical effect or an inadequate response to therapy. Here, we present a case report and review what the evidences for the two hypotheses are.
1. Ankylosing Spondylitis: Current Definition and Extra-Articular Manifestations
Ankylosing spondylitis (AS) is the most important among spondyloarthritis (SpA), a family of chronic inflammatory conditions with common epidemiology, immunogenetics, clinics, and radiological features. The group of SpA includes AS, reactive arthritis, psoriatic arthritis, arthritis associated to colitis, and undifferentiated SpA . AS is a chronic progressive inflammatory disease predominantly affecting the axial skeleton and the sacroiliac joints. Enthesitis is the key pathogenetic component of AS and all SpA. Enthesitis is the inflammation of the enthesis, that is, where tendons, ligaments, and joint capsule are attached to the bone. The progressive ossification of enthesis resulting from the chronic inflammation leads to irreversible loss of function . The trigger for the inflammation at this site could be a bacterial antigen and/or other environmental factors that prompt an abnormal immunological activation. In subjects with a predisposing genetic background, this may result in the perpetuation of the immunological response. Interleukine-12 (IL-12), IL-17, and TNFα are overexpressed in these patients.
The disease debut is usually around 20 and 40 years, more frequently in male subjects. HLA-B27 gene is often present, while no specific antibodies are found. Signs of systemic inflammation are seldom evident. Diagnosis requires one clinical criterion among chronic inflammatory pain, limited lumbar spine excursion, and limited thoracic expansion and one radiographic criterion, that could be either a bilateral grade II sacroiliitis or a grade III-IV sacroiliitis on one side (according to the 1984 modified New York criteria). In the early stages, magnetic resonance imaging (MRI) has proven to be more sensitive in detecting sacroiliitis, preceding changes on conventional radiography even for many years. In fact, new Assessment of SpA International Society (ASAS) criteria for axial SpA allow the diagnosis of a preradiographic axial SpA in case there is a sacroiliitis on MRI along with one other SpA feature, or HLA-B27 positivity along with two SpA features. In any case, progression to AS is not definite .
First line therapy for SpA is physical exercise together with nonsteroidal anti-inflammatory drugs (NSAIDs). Corticosteroids, immunosuppressants, and biologics can be then considered.
SpA present mostly with peripheral arthritis, dactylitis, enthesitis, and, nonetheless, extra-articular manifestations. The burden of these manifestations includes uveitis, psoriasis, inflammation of the pulmonary parenchyma and of the pleura, neuropathies, gastrointestinal inflammation, urogenital involvement, cardiac valvular pathologies, myocardium and conduction tissue dysfunction, renal involvement with microhematuria, IgA-associated glomerulonephritis, and secondary, amyloidosis, generalized, and periarticular osteoporosis .
2. Clinics, Outcomes, Pathogenesis, and Role of TNF-α in Uveitis of Spondyloarthritis
The most frequent nonarticular manifestation in AS is the inflammatory eye disease. Ninety percent of uveitis is anterior uveitis and is monolateral. Anterior uveitis can be found in up to 30% of AS cases . Anterior uveitis comprehends iritis (i.e., the inflammation of the iris and of the anterior chamber of the eye), iridocyclitis (i.e., inflammation of the iris and of the ciliary body, with inflammatory cells in the aqueous humor), and cyclitis (i.e., inflammation of the ciliary body and of the aqueous humor). In 9.1% of the cases, uveitis is bilateral. Other structures of the eye are seldom involved (3.5%): posterior uveitis (choroiditis or retinochoroiditis), intermediate uveitis (vitritis, peripheral retinitis, and pars planitis), or panuveitis, in case that more than one segment of the eye is involved.
Uveitis is typically acute, with red and painful eye, photophobia, hyperlacrimation, and blurred vision. It resolves in 2 or 3 months and usually has no sequelae. In SpA patients, relapses are frequent (50.6%) often in the other eye. If treatment is not proper, it can cause hypopyon, cataract, glaucoma, synechiae (39.5%), and macular edema (19.7%). Visual loss is therefore a possible outcome (8.3% of uveitis).
Association between uveitis and HLA-B27 positivity is well known. The HLA-B27 positivity correlates with a worse prognosis and frequent relapses. Uveitis incidence correlates linearly with the disease duration up to 20 years and then reaches a plateau. It is also significantly associated with cervical pain, prior diagnosis of inflammatory bowel disease, Short Form-36 (SF36), physical impairment, and disease debut after an infection. Moreover, AS patients with uveitis have worse BASDAI and BASFI scores.
The pathogenesis of the eye disease in AS has not yet been cleared: specific genetical susceptibility, both innate and adaptive immunological systems, and, in the end, an environmental trigger are implicated .
The major genetic predisposing factor is HLA-B27, especially the B2704 allele and, to a lesser extent, the polymorphisms of LMP2 and HLA-DR8 genes. HLA-B27 positivity is associated with higher TNFα levels in active uveitis . Patients who also have A allele in −238 and −308 nucleotides of the TNFα gene promoter are more prone to uveitis. Estrogens are proved to inhibit IL-1, IL-6, and TNFα expression through nitroxide production. Toll-like receptors (TLR) genes recently appeared to be implicated in the eye disease of AS, together with the killer cell immunoglobulin-like receptors (KIR) and the vitamin-D binding protein. Th17 lymphocytes are implicated in uveitis through the production of IL-17 and IL-23. In animal models deficiency of either interferon-γ or IL-1 receptor antagonist leads to higher ocular inflammation. Notwithstanding these evidences, the most important effects are likely due to HLA-B27 positivity and TNFα expression.
3. Conventional Treatment and TNFα Inhibitors in the Treatment of Uveitis
Uveitis has to be regarded as an ophthalmological emergency in order to prevent irreversible outcomes. The choice of treatment must be driven by severity of inflammation and by response to therapy. Topical treatment with corticosteroids is usually effective. Mydriatics and cycloplegics reduce the spasms of the ciliary muscle and thus the pain and, importantly, avoid development of posterior synechiae. About 13–19% of patients do not respond to the topical treatment and inflammation becomes chronic. In these cases, intraocular steroid injections should be preferred to systemic corticosteroids.
Immunosuppressants are sometimes needed in case of involvement of posterior eye structures or in case of frequent relapses and chronic disease.
Sulfasalazine (SSZ) has been shown to reduce frequency and severity of uveitis in case of more than 3 relapses a year . Methotrexate (MTX) lowers significantly the number of uveitis relapses: 0.89 episodes a year with MTX compared to 3.4 episodes without MTX . NSAIDs have a positive effect on recurrence (0.53 episodes a year compared to 2.84); besides, they can be used to control the articular manifestations of AS .
In cases of uveitis refractory to immunosuppressants and in case of involvement of posterior eye structures, anti-TNFα are recommended and effective . A meta-analysis proved that both infliximab (IFX, monoclonal antibody against TNFα) and etanercept (ETA, the soluble receptor of TNFα) significantly reduce uveitis recurrences (3.4 and 7.9 per 100 patient-years, respectively, compared to 15.6 of placebo). Adalimumab (ADA, monoclonal antibody against TNFα) reduced the number of recurrences by 50% . A retrospective study found that the anti-TNFα antibodies, IFX and ADA, were more effective in preventing relapses than the placebo (9.0 versus 47.4 episodes per 100 patients-years for IFX and 0 versus 60.5 for ADA). ETA was not superior to placebo (54.6 versus 58.5 per 100 patients-years) in one study . Further studies proved that ETA is more effective than placebo (8.6 versus 19.3 per 100 patients-years) or at least as effective as SSZ (10.7 versus 14.7 per 100 patient-years) . All anti-TNFα improved the treatment of SpA uveitis, particularly, the antibodies, IFX and ADA.
4. A Paradoxical Effect: Uveitis during Anti-TNFα
Several cases of new onset uveitis or uveitis relapses have been reported during anti-TNFα treatment, while the other articular manifestations where controlled by the therapy . Contradictory effects of anti-TNFα are also psoriasis-like cutaneous lesions and inflammatory bowel manifestations. A French national surveillance and numerous English case reports highlighted the association between TNFα inhibitors and uveitis, with 31 and 121 cases, respectively. ETA was mostly associated with uveitis: 23 of the 31 French uveitis cases and 103 of the 121 English cases had been treated with ETA . There is a difference in the mechanism of action between antibodies and the receptor: besides TNFα, ETA inhibits also TNFβ. In an animal model of uveitis, higher TNFβ was found, and therefore ETA is expected to be even more effective . Nevertheless, uveitis seems to be specifically associated with ETA and not with all anti-TNFα .
One theory for ETA-associated uveitis is that, when the soluble receptor ETA binds with TNFα, it prevents the clearance of TNFα and prolongs its half-life and thus the presence within the eye structures. As is well known, anti-TNFα antibodies are effective in Chrohn’s disease when compared to ETA. In Chrohn’s disease, a defect in T lymphocyte apoptosis is present. ETA does not induce apoptosis and it increases lymphocyte stimulating cytokines, whereas IFX decreases them . The lymphocyte inhibition could explain also the increased frequency of tuberculosis reactivation especially during the therapy with antibodies.
In any case, uveitis is described also during therapy with the anti-TNFα antibodies and has also been successfully treated with ETA. Still, uveitis is a manifestation of SpA: assuming uveitis is an adverse event triggered by anti-TNFα inhibitors might be an awkward statement . Uveitis can occur long time after the start of anti-TNFα therapy, usually after 12–27 months. Some cases had benefit with the switch to another TNF blocker, but in most reported cases uveitis was solved without anti-TNFα interruption. Further, in some cases, the reintroduction of the same anti-TNFα did not cause disease relapse.
5. Case Report
A 19-year-old patient suffering from inflammatory back pain was treated with NSAIDs on demand by her general practitioner. Three years afterwards, she developed polyarthritis and tenosynovitis in the hands, knees, and feet. She was referred to a rheumatologist and she was found to be HLA-B27 positive, systemic inflammation was present, and pelvic radiographs showed bilateral grade 2 sacroiliitis. A diagnosis of AS was then made. The patient was treated successfully with methyl-prednisone 4 mg and SSZ 2000 mg daily. After two years, disease relapsed. MTX at the dose of 15 mg a week did not improve arthritis or inflammation after 6 months of treatment. At the age of 25 years, she started IFX, 200 mg every 6 weeks, in combination with MTX and achieved complete remission (BASDAI score 0 and normal blood exams). After two years, she experienced a severe infusion reaction to IFX with hypotension and dyspnea. She was switched to ETA, 25 mg twice weekly. The patient maintained complete remission for 2 years, and then ETA was tapered to 25 mg weekly. Three years afterwards, she presented with blurred vision, photophobia, hyperemia of the conjunctiva, and pain in the left eye. The ophthalmologist diagnosed an anterior uveitis of the left eye and suggested treatment with topical steroids. As she had no improvement, after one week she was switched to ADA, 40 mg every two weeks and the uveitis recovered promptly. Indeed, the patient started complaining about back pain and peripheral arthritis after a few weeks. Following discussion with the patient and the ophthalmologist, ETA was started at 25 mg twice a week. The patient achieved disease remission shortly after the start of ETA and to date, after 5 years, no other relapses of uveitis or articular disease have been reported.
Inhibitors of TNFα are very effective in all SpA and AS manifestations. Monoclonal antibodies appear to be more effective in controlling uveitis compared to the soluble TNF receptor ETA. However, successfully treated uveitis is described with all anti-TNFα therapies. Uveitis during TNFα inhibitors could be regarded as a paradoxical effect. Likewise, psoriasis is induced by TNFα blockers, although these therapies are very effective in the treatment of the skin disease. Presumably TNFα blocking may create an imbalance in cellular and cytokine networks disturbing the immunoregulatory function of TNFα on autoreactive T-cells, Th17 and T-reg cells .
This statement might not be appropriate in our case, as the reintroduction of ETA led to no recurrence of uveitis. Uveitis during TNFα inhibitors could rather be the sign of an insufficient control of the disease. Our case proves that IFX adequately blocked the disease manifestation until probably antidrug neutralizing antibodies hampered its efficacy and induced an allergic reaction. ETA then adequately controlled the disease, but, when the dose was lowered, uveitis occurred. Another monoclonal antibody, ADA, had no efficacy on articular manifestations of the disease. In the end, full dose ETA achieved and maintained remission of all disease manifestations for a long time.
Thus, ETA should be deemed as an effective treatment choice in patients with SpA and uveitis, especially in view of the fact that all other therapeutic pathways targeted by newer biologicals seem to be ineffective .
Conflict of Interests
No conflict of interests is present.