Ocular manifestation of rheumatoid arthritis-diff erent forms and frequency

Rheumatoid arthritis (RA) is a systemic infl ammatory disease associated with a number of extra-articular organ manifestations. Ocular manifestations involved with RA are keratoconjunctivitis sicca, episcleritis, scleritis , corneal changes, and retinal vasculitus. Th e etiopathogenesis of this autoimmune disorder is still unknown. Aim of our study was to present diff erent ocular manifestations of RA and their frequency. We have examined  patient with the diagnoses of RA. All examined patients were in I or II stage of the disease according to criteria of Th e American College of Rheumatology. Ophthalmological exam obtained: visual acuity by Snellen sings, biomicroscopy of anterior segment, Schirmer test, tear break-up time (BUT), applanation tonometry and indirect ophthalmoscopy. In all patients with retinal vasculitis fotofundus and in indicated cases fl uorescein angiography was preformed. Th e most common manifestation of ocular involvement was keratoconjunctivitis sicca. Episcleritis was diagnosed in . patients with RA, while scleritis was present in . of patients. Diff use scleritis was present in one patient, while nodular was present in  patients. Th ere were no patients with posterior or necrotizing scleritis among examined patients. Sclerosing keratitis was diagnosed in  female patients. It is characterized with peripheral thickening and opacifi cation of the stroma adjacent to the site of infl ammation. Posterior scleritis or scleromalacia of cornea was not present in our patients, because all of them were in I or II stage of disease. Retinal vasculitis was present in three patients, two male and one female patient (.). Ocular manifestation was present in . of patients. Women were more aff ected. ©  Association of Basic Medical Sciences of FBIH. All rights reserved


Introduction
Rheumatoid arthritis (RA) is a systemic infl ammatory disease, which is associated with a number of extra-articular organ manifestations, such as pericarditis, pleuritis, major cutaneous vasculitis, Felty's syndrome, neuropathy, ocular manifestations, glomerulonephritis, and other types of vasculitis [, , , , ].Th e etiopathogenesis of this autoimmune disorder is still unknown.Th ere are many diff erent theories [, , , , ].Extra-articular manifestation in RA are present in - of patients which are more frequent in seropositive patients [].Ocular manifestations involved with RA are keratoconjunctivitis sicca, episcleritis, scleritis, corneal changes, and and retinal vasculitus [, , ].Keratoconjunctivitis sicca is common in individuals with RA and is often the initial manifestation [, ].Episcleritis is an infl ammatory condition aff ecting the episcleral tissue that lies between the conjunctiva and the sclera.Episcle-ritis is usually a mild, self-limiting, recurrent disease.Most cases are idiopathic; although up to one third have an underlying systemic condition [, , ].Scleritis is a chronic, painful, and potentially blinding infl ammatory disease that is characterized by edema and cellular infiltration of the scleral and episcleral tissues.It may be classifi ed into anterior and posterior.Anterior scleritis can be diff use, nodular, necrotizing with infl ammation (necrotizing), and necrotizing without inflammation (scleromalacia perforans) [].Th e most common clinical forms are diff use scleritis and nodular scleritis.Necrotizing scleritis with or without inflammation is much less frequent, more ominous, and frequently associated with systemic autoimmune disorders.Posterior scleritis is characterized by flattening of the posterior aspect of the globe, thickening of the posterior coats of the eye (choroid and sclera), and retrobulbar oedema [, ].RA is common disorder to aff ect peripheral cornea.Corneal changes such as sclerosing keratitis, peripheral corneal thinning, acute stromal keratitis and acute corneal melting are manifestations [, ].Vasculitis aff ects patients with established RA in approximately  to  [].Retinal vasculitis is usually present on periphery of retina and involves veins and arteries peripheral branches.

Patients
During the period from -, we have examined  patients with diagnose of RA.All examined patients were in I or II stage of disease according to criteria of Th e American College of Rheumatology (Table ) [].The presence of Rheumatoid factor (RFIgM) in serum was evaluated by standard test methods based on principle of agglutination (Waaler-Rose and Latex tests) in Immunological Laboratory in Niš.All patients were seropositive.Ophthalmological exam obtained: visual acuity by Snellen sings, biomicroscopy of anterior segment, Schirmer test, tear break-up time (BUT), applanation tonometry and indirect ophthalmoscopy.In all patients with retinal vasculitis fotofundus documentation, and in indicated case fluorescein angiography was done.

Results
Age of life and sex of patients with ocular manifestations of RA are presented in Table .The frequency of RA increases with age and peaks in persons aged - years.RA is more common in females than in males.
Ocular manifestations among examined  patients were present in  patients or in . (Table ).Scleritis as manifestation of RA may have different forms such as diff use, nodular and necrotizing.Th e frequency of these forms of scleritis in our patients is given in Table .
Keratoconjunctivitis sicca (Figure ) was present in  patients or .  of all patients.Episcleritis (Figure ) was diagnosed in (.)patients with RA, while scleritis was present in  (.) of patients.Diffuse scleritis was present in one patient while nodular was present in  patients.There were no patients with posterior or necrotizing scleritis among examined patients.Sclerosing keratitis was diagnosed in  female patients.Peripheral thickening and opacifi cation of the stroma adjacent to the site of infl ammation characterize it (Figure ).Retinal vasculitis was present in three patients, two male and one female patient (.).In all patients diagnose of RA was established from one to three years before the retinal vas-     ] and is present in - of patients, more frequent in seropositive patients [].Th e most common manifestation of ocular involvement was keratoconjunctivitis sicca in ..Th e incidence keratoconjunctivitis sicca is between ,  to , in literature [, , ].Th e keratoconjunctivitis in RA is classically described as an aqueous tear defi ciency.Th ose patients with this disorder need supplementation of artificial tears for lifetime.Hori, Maeda and Sakamoto proved that in patients with due to an altered ocular environment or chronic topical medication use demonstrate a disruption of the natural flora with a marked increase in antibioticresistant organisms [].Sometimes disease-modifying anti rheumatic drugs (DMARDs) systemic immunosuppressive agents may be necessary to improve tear production and to resolve severe sucu as keratoconjunctivitis like Cyclosporin A, or a monoclonal antibody to TNF-alpha such as infl iximab [,, , -].Episcleritis was diagnosed in  patients.In the most of the cases, treatment was not necessary.Th e infl ammatory response is localized to the superfi cial episcleral vascular network, and histopathology shows nongranulomatous infl ammation with vascular dilatation and perivascular infi ltration [].Th e  clinical types are simple and nodular [].Th e most common type is simple episcleritis, in which there are intermittent bouts of moderate-tosevere infl ammation that often recur at -to -month intervals.Th e episodes usually last - days and most resolve after - weeks.Prolonged episodes may be more common in patients with associated systemic conditions.Some patients note that episodes are more common in the spring or fall.Patients with nodular episcleritis have prolonged attacks of infl ammation that are typically more painful than simple episcleritis [].However, some patients with mild symptoms demand treatment and may benefit from the use of artifi cial tears.Nodular episcleritis have an associ- ated systemic disease.Simple episcleritis often requires no treatment.Artifi cial tears are useful for patients with mildto-moderate symptoms.Patients with severe or prolonged episodes may require artifi cial tears and/or topical corticosteroids.Nodular episcleritis is more indolent and may require local corticosteroid drops or anti-infl ammatory agents.Topical ophthalmic . prednisolone, . dexamethasone or . betamethasone daily may be used.If nodular episcleritis is unresponsive to topical therapy, systemic antiinfl ammatory agents may be useful.Flurbiprofen ( mg tid) is usually eff ective until infl ammation is suppressed.If there is no response to fl urbiprofen, indomethacin should be used;  mg daily and decreased to  mg when there is a response.Many patients who do not respond to one nonsteroidal anti-infl ammatory agent (NSAID) may respond to another NSAID [].Scleritis may be the initial or only presenting clinical manifestation of these potentially lethal disorders.Th e correct and rapid diagnosis and the appropriate systemic therapy can halt the relentless progression of both ocular and systemic processes, thus preventing destruction of the globe and prolonging survival [].Scleritis may be classifi ed into anterior and posterior.Anterior scleritis can be diffuse, nodular, necrotizing with inflammation (necrotizing), and necrotizing without inflammation (scleromalacia perforans).Th e most common clinical forms are diff use scleritis and nodular scleritis.Necrotizing scleritis with or without infl ammation is much less frequent, more ominous, and frequently associated with systemic autoimmune disorders.Posterior scleritis is characterized by fl attening of the posterior aspect of the globe, thickening of the posterior coats of the eye (choroid and sclera), and retrobulbar edema [, , ].Ocular complications of scleritis, which cause vision loss and eye destruction, appear as a result of the extending scleral infl ammation.Peripheral ulcerative keratitis (-), uveitis (about ), glaucoma (-), cataract (-), and fundus abnormalities (about .).Th ese complications are most common in necrotizing scleritis, the most destructive type of scleritis [].Scleritis was present in . of all patients that is according to similar literature studies.Anterior scleritis was diagnosed in all patients.Th e primary sign was redness.It may be localized in one sector or involve the whole sclera; most frequently, it is in the interpalpebral area.[].In our patients with retinal vasculitis diagnose of RA was established one to three years before diagnosed vasculitis.All of them had seropositive RA.Retinal vasculitis is usually present on periphery of retina and involves veins and arteries peripheral branches.Th erapy includes topical corticosteroid, NSAID's, systemic corticosteroid and therapy known as biological therapy [, ].Th ere are new data that new bio-tech therapies, such as Rituximab provide signifi cant effi ciacy and safety [].

Conclusion
Extra-articular involvement of organs in RA is signifi cant.Ocular manifestations involved with RA are keratoconjunctivitis sicca, episcleritis, scleritis corneal changes, and retinal vasculitis.They were present in , of patients.
Women were more affected.The most common manifestation of ocular involvement was keratoconjunctivitis sicca.Posterior scleritis or scleromalacia of cornea was not present in patients with I or II stage of disease.The new bio-tech therapies provide significant efficiacy and safety.The evaluative disease activity requires intensive treatment with DMARDs including biological therapy for rheumatoid arthritis and its ocular manifestations such as keratoconjunctivitis sicca and retinal vasculitis.

Declaration of interest
Authors declare no confl ict of interest.
culitis was diagnosed.Retinal vasculitis is usually present on periphery of retina and involves veins and arteries peripheral branches (Figure).DiscussionRheumatoid arthritis (RA) is a chronic systemic infl ammatory disease of unknown cause that primarily aff ects the peripheral joints in a symmetric pattern.Th ere are many theories of pathogenesis of RA[, , , , ].Th e majority of scientists support the immunology based theory on discovery of RF.RF is an antiimunglobuline with a course against fragment Fc of IgG human molecule.Probably, CD  T cells, mononuclear phagocytes, fi broblasts, osteoclasts, and neutrophils play major cellular roles in the pathophysiology of RA, while B lymphocytes produce autoantibodies (ie, [RF's]).Abnormal production of numerous cytokines, chemokines, and other infl ammatory mediators (has been demonstrated in patients with RA.RF may be present in other inflammatory disorders and be present in healthy person and can't be pathognomonic sign of RA.Persistently increased RF is more predisposing factor to developing RA[].Other leading theory is genetic.RA has a signifi cant genetic component, and the shared epitope of the HLA-DR / DR  cluster is present in up to  of patients with RA.Genetic factors and immune system abnormalities contribute to disease development and propagation.Infl ammation and exuberant proliferation of synovium leads to destruction of various tissues, including cartilage, bone, tendons, ligaments, and blood vessels.Extra-articular involvement of organs such as the skin, heart, lungs, and eyes is signifi cant[, , ,

TABLE 1 .
The American College of Rheumatology criteria in determining the progression, remission, and functional status of patients with RA.

TABLE 2 .
Age of life and sex of patients with ocular manifestations of RA Class I -Completely able to perform usual activities of daily living Class II -Able to perform usual self-care and vocational activities but limited in avocational activities Class III -Able to perform usual self-care activities but limited in vocational and avocational activities Class IV -Limited in ability to perform usual self-care, vocational, and avocational activities

TABLE 3 .
Ocular manifestation in patients with RA

TABLE 4 .
Diff erent forms of scleritis among examined patients with RA NSAID's), corticosteroids, or DMARDs are indicated[, ].Posterior scleritis or scleromalacia of cornea was not present in our patients, because all of them were in I or II stage of disease.Retinal vasculitis is one of the ocular manifestations of RA.It aff ects patients with established RA in approximately  to  .).Other symptoms of scleritis were pain, tearing or photophobia, tenderness.By biomicroscopy examination of anterior segment in scleritis, maximum congestion is in the deep episcleral network with some congestion in the superfi cial episcleral network.Treatment of scleritis requires systemic therapy such as nonsteroidal anti-infl ammatory drugs (