|Year : 2017 | Volume
| Issue : 2 | Page : 57-62
Ocular involvement and its manifestations in rheumatoid arthritis patients
Safaa A Aboud MD 1, Mohamed O Abd Elkhalek1, Nagla H Aly2, Enas A Abd Elaleem3
1 Department of Ophthalmology, Beni Suef University, Beni Suef, Egypt
2 Memorial Institute for Ophthalmic Research, Giza, Egypt
3 Department of Rheumatology and Rehabilitation, Beni Suef University, Beni Suef, Egypt
|Date of Submission||02-Feb-2017|
|Date of Acceptance||06-Mar-2017|
|Date of Web Publication||20-Jun-2017|
Safaa A Aboud
23 Namek street, Moold Elnaby Square, Beni Suef
Source of Support: None, Conflict of Interest: None
Rheumatoid arthritis (RA) is a systemic inflammatory disease associated with a number of extra-articular organ manifestations. Ocular manifestations involved with RA are keratoconjunctivitis sicca (KCS), episcleritis, scleritis, keratitis, and retinal vasculitis. The etiopathogenesis of this autoimmune disorder is still debated. The aim of the current study was to present different ocular manifestations of RA and their frequency.
Patients and methods
A total of 180 patients with RA participated in this cross-sectional survey. All patients were subjected to general and specific examinations, ophthalmological examinations, and rheumatologic examinations in addition to blood investigations for rheumatoid factor and anti-cyclic citrullinated peptide.
Of the 180 examined patients, 61 (33.9%) patients had ocular manifestations. There were 52 (85.3%) patients with KCS, three (4.9%) patients with episcleritis, three (4.9%) patients with scleritis, and three (4.9%) patients with keratitis. Patients with longer disease duration were much more likely to have ocular manifestations (odds ratio=7.13, P<0.001). In addition, patients with positive history of steroid intake were more likely to have ocular manifestations (odds ratio=1.88, P<0.001).
Ocular manifestations involved with RA are significant. The most common manifestation of ocular involvement was KCS. Ocular manifestations were more common among patients with longer disease duration.
Keywords: episcleritis, keratoconjunctivitis sicca, rheumatoid arthritis, scleritis
|How to cite this article:|
Aboud SA, Abd Elkhalek MO, Aly NH, Abd Elaleem EA. Ocular involvement and its manifestations in rheumatoid arthritis patients. Delta J Ophthalmol 2017;18:57-62
|How to cite this URL:|
Aboud SA, Abd Elkhalek MO, Aly NH, Abd Elaleem EA. Ocular involvement and its manifestations in rheumatoid arthritis patients. Delta J Ophthalmol [serial online] 2017 [cited 2023 Jun 1];18:57-62. Available from: http://www.djo.eg.net/text.asp?2017/18/2/57/208532
| Introduction|| |
Rheumatoid arthritis (RA) is a systemic inflammatory 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 ,,,,. Extra-articular manifestations in RA are present in 10–40% of patients and are more frequently seen in seropositive patients . Ocular manifestations involved with RA are mainly keratoconjunctivitis sicca (KCS), episcleritis, scleritis, corneal changes, and retinal vasculitis ,,.
KCS is common in individuals with RA and is often the initial manifestation. KCS appears as a result of the decreased secretion of tears from the main and accessory lacrimal glands. The interruption of lacrimal secretion is caused by the atrophic and cirrhotic changes in the lacrimal glands and leads to the reduction of the middle layer of the precorneal lacrimal film, which becomes viscous in later stages. In KCS, conjunctival goblet cells are stimulated to increase the secretion of the mucus. Very often, fibrous coverings of mucin tied down to the cornea or laid in the lower fornix are seen. It rarely appears as a form of filamentous keratitis − for example, twisted filaments tied up to the cornea by one part. This is a particularly painful condition, because blinking moves the filaments, tugging the epithelial attachments and tending to strip off further epithelium ,.
Episcleritis is an inflammatory condition affecting the episcleral tissue that lies between the conjunctiva and the sclera. Usually, episcleritis is a mild, self-limiting, recurrent disease; although most cases are of unknown etiology, up to one-third of patients have an underlying systemic condition ,,.
Scleritis is a chronic, painful, and potentially blinding inflammatory disease that is characterized by edema and cellular infiltration of the scleral and episcleral tissues. It may be classified into anterior and posterior. Anterior scleritis can be diffuse, nodular, necrotizing with inflammation (necrotizing), and necrotizing without inflammation (scleromalacia perforans) . The most common clinical forms are diffuse 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 edema; however, it is rarely seen in patients with RA ,,.
Further, RA commonly affects the peripheral cornea. Corneal changes such as sclerosing keratitis, peripheral corneal thinning, acute stromal keratitis, and acute corneal melting are the frequent manifestations ,.
Retinal vasculitis usually affects patients with established RA in ∼1–5% and is usually present in the periphery of the retina and involves veins, arteries, and peripheral branches .
The aim of this study was to present different ocular manifestations of RA and their frequencies.
| Patients and methods|| |
A total of 180 patients with RA attending the Rheumatology Outpatient Clinics at Beni Suef University Hospital were randomly selected to participate in this cross-sectional study during the period between October 2014 and August 2015. Patients were selected according to strict eligibility criteria.
- Patients with RA diagnosed according to the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria were included in the study .
- Other types of retinopathy due to other reasons such as diabetic retinopathy, retinitis pigmentosa, and retinopathy due to blood disorders.
- Other autoimmune diseases (e.g. Behcet’s disease).
All patients were subjected to the following:
- Full history taking with special attention to disease duration. To study the type, occurrence, and nature of ocular manifestations among patients with RA, patients were carefully questioned about history of xerostomia and associated oral and pharyngeal symptoms of Sjogren’s disease.
- General and specific rheumatologic examinations.
- Disease Activity Score 28 (DAS 28) calculation and categorization according to this activity into mild, moderate, and severe.
- Full ophthalmological examination including the following: visual acuity, slit-lamp biomicroscopy, intraocular pressure measurement, and fundus examination.
- Special ophthalmological tests including the following: tear film break-up time, Schirmer’s test, and fluorescein staining test.
- Laboratory investigations including the following: erythrocyte sedimentation rate, latex agglutination slide test for the detection of rheumatoid factor (RF), and enzyme-linked immunosorbent assay to detect antibodies to cyclic citrullinated peptide (anti-CCP).
The study was approved by the Ethical Committee of the Faculty of Medicine, Beni Suef University. The participants were informed about the purpose of the study and its consequences, and confidentiality of data was assured. Informed consent was obtained from all participants.
Data were analyzed using the software statistical package for the social science (SPSS version 20; SPSS Inc., Chicago, Illinois, USA), and then processed and tabulated. Frequency distribution with its percentage and descriptive statistics with mean and SD were calculated. Chi-square, t-test ,and correlations were done whenever needed. P values of less than 0.05 were considered significant.
| Results|| |
Of the 180 patients who were recruited for the study, 150 (83.3%) were female and 30 (16.7%) were male. The age of the patients ranged between 20 and 72 years with a mean of 44.97±11.75 years. The duration of RA since it was diagnosed for the first time ranged between 1 and 18 years with a mean of 5.73±4.13 years; 81 (45%) patients had a history of RA more than 5 years and 99 (55%) patients had a duration less than 5 years. The mean erythrocyte sedimentation rate of the patients was 45.13±12.05 mm.
Throughout the study, 101 (56.1%) patients were on monotherapy, and the rest of the patients were taking more than one medication, with 165 (91.7%) patients being on methotrexate, 75 (41.7%) patients on steroids, and 48 (26.7%) patients on antimalarial drugs.
Totally, 61 (33.9%) patients had ocular manifestations (three male and 58 female): 52 patients (85.3% of patients with ocular symptoms and 28.9% of all RA patients) had KCS (two male and 50 female); three patients (4.9% of patients with ocular symptoms and 1.7% of all RA patients) had episcleritis (all were female); three patients (4.9% of patients with ocular symptoms and 1.7% of all RA patients) had scleritis (all were female); and three patients (4.9% of patients with ocular symptoms and 1.7% of all RA patients) had keratitis (one male and two female). There was no statistically significant difference between the two sexes as regards the form of ocular manifestations (P>0.05) ([Table 1]). The three patients with scleritis were found to have anterior diffuse scleritis.
Patients were categorized according to DAS 28 into mild, moderate, and severe RA. Among the 36 (20%) patients having mild RA, there were six patients with KCS and one with episcleritis, whereas among patients with moderate RA (90, 50%), 27 patients were suffering from KCS and two from episcleritis. Among severe RA patients (54, 30%), 19 patients had KCS, three patients had scleritis, and three patients had keratitis. There were no statistically significant differences between the three categories as regards the presence of ocular manifestations or the form of manifestations (P>0.05) ([Table 2]).
|Table 2 Distribution of ocular manifestations according to Disease Activity Score 28 category|
Click here to view
Patients were categorized according to duration of disease as follows: patients with disease duration less than 5 years (81, 45%) (48 with KCS, one with scleritis, one with episcleritis, and two with keratitis); and patients with disease duration lower to 5 years (99, 55%) (four with KCS, two with episcleritis, two with scleritis, and one with keratitis). Patients with longer disease duration were much more likely to have ocular manifestations (odds ratio=7.13, P<0.001) ([Table 3]).
|Table 3 Distribution of ocular manifestations according to duration of disease|
Click here to view
The results show that 168 (93.3%) patients had positive anti-CCP and 159 (88.3%) patients were RF positive. Patients were distributed as follows: 156 (86.7%) patients were positive for both anti-CCP and RF; 12 (6.7%) patients were positive for anti-CCP and negative for RF; three (1.6%) patients were positive for RF and negative for anti-CCP; and nine (5%) patients were negative for both. No statistically significant differences were seen between the four groups as regards the distribution of ocular manifestations (P>0.05) ([Table 4]).
|Table 4 Distribution of ocular manifestations according to anti-cyclic citrullinated peptide and rheumatoid factor|
Click here to view
Patients were categorized according to steroid intake as follows: those with a positive history of steroid intake (75, 41.7%) (28 with KCS, one with scleritis, one with episcleritis, and two with keratitis) and those with a negative history of steroid intake (105, 58.3%) (24 with KCS, two with episcleritis, two with scleritis, and one with keratitis). Patients with a positive history of steroid intake were more likely to have ocular manifestations (odds ratio=1.88, P<0.001) ([Table 5]).
|Table 5 Distribution of ocular manifestations according to steroid intake|
Click here to view
| Discussion|| |
RA is a chronic systemic inflammatory disease of unknown cause that primarily affects the peripheral joints in a symmetric pattern. There are many theories of pathogenesis of RA ,. The majority of scientists support the immunology-based theory on discovery of RF. RF is an anti-immunoglobulin with a course against fragment Fc of immunoglobulin G molecule. Probably, CD4+ T cells, mononuclear phagocytes, fibroblasts, osteoclasts, and neutrophils play major cellular roles in the pathophysiology of RA, whereas B lymphocytes produce autoantibodies (i.e. RF). Abnormal production of numerous cytokines, chemokines, and other inflammatory mediators has been demonstrated in patients with RA. However, RF may be present in other inflammatory disorders and in healthy individuals and hence cannot be a pathognomonic sign of RA. Persistently increased RF is a more predisposing factor for developing RA .
The other leading theory is genetic. RA has a significant genetic component, and the shared epitope of the human leukocyte antigen-DR4/DR1 cluster is present in up to 90% of patients with RA. Genetic factors and immune system abnormalities contribute to disease development and propagation. Inflammation 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 significant ,,,,,.
In the present study, the prevalence of KCS was 28.7% of total patients with RA. This finding coincides with many previous studies that reported this prevalence between 11.6 and 50% ,,,. In addition, KCS was the most common ocular manifestation to be diagnosed in the current study, which is in agreement with previous studies ,.
Reddy et al.  studied one hundred RA patients, irrespective of their age and sex, to detect various ocular manifestations. They estimated the prevalence of ocular manifestations to be 39%. The prevalence of ocular manifestations was as follows: KCS, 29%; scleritis, 1%; episcleritis, 1%; and retinal vasculitis, 1% .
Zlatanovic et al.  examined 690 RA Bosnian patients and found ocular manifestations in 182 (27.2%) patients. KCS was detected in 17.65% of the patients, episcleritis in 5.06%, and scleritis in 2.06% of the patients. There were no patients with posterior or necrotizing scleritis among the examined patients. Keratitis was diagnosed in 1.5% of the patients and retinal vasculitis in 0.45% of the patients .
Vignesh and Srinivasan  examined 392 eyes of the 196 RA patients. A total of 77 (39%) patients had ocular manifestations. KCS was the most common ocular manifestation (28%) of patients, 3% had episcleritis and 2% had scleritis. Peripheral ulcerative keratitis and sclerosing keratitis were detected in 1% of the patients .
KCS in RA is classically described as an aqueous tear deficiency. Those patients with this disorder need supplementation of artificial tears for lifetime. Hori and colleagues proved that in patients with an altered ocular environment or chronic topical medication use there is a disruption of the natural flora with a marked increase in antibiotic-resistant organisms ,,.
Episcleritis was diagnosed in three patients in the present study. In the three cases, treatment was not necessary. In agreement with such finding, a previous study by Ferry considered scleritis as one of the manifestations of low prevalence among patients with RA .
The inflammatory response is usually localized to the superficial episcleral vascular network, and histopathology shows nongranulomatous inflammation with vascular dilatation and perivascular infiltration. The main clinical types are simple and nodular. The most common type is simple episcleritis, in which there are intermittent bouts of moderate-to-severe inflammation that often recur at 1–3 month intervals. The episodes usually last 7–10 days and most resolve after 2–3 weeks. Prolonged episodes may be more common in patients with associated systemic conditions. Some patients note that episodes are more common during the spring or fall. Patients with nodular episcleritis have prolonged attacks of inflammation that are typically more painful compared with simple episcleritis. However, some patients with mild symptoms demand treatment and may benefit from the use of artificial tears ,,.
Ocular complications of scleritis, which cause vision loss and eye destruction, appear as a result of the extending scleral inflammation. In the current study only three patients were diagnosed with diffuse scleritis. Anterior scleritis was diagnosed in all patients. The primary sign was redness. This redness was localized in one sector in one patient, involved the whole sclera in another patient, and was in the interpalpebral area in the third patient. Other symptoms of scleritis were pain, tearing or photophobia, and tenderness. On biomicroscopy examination of the anterior segment in scleritis, maximum congestion was noticed in the deep episcleral network with some congestion in the superficial episcleral network. The present study coincided with previous literature ,,,. Treatment of scleritis requires systemic therapy such as NSAID’s, corticosteroids, or disease-modifying antirheumatic drugs . Posterior scleritis or scleromalacia were not detected in the current study, may be because of the limited sample size.
Besides, patients were categorized according to duration of the disease as follows: patients with disease duration less than 5 years (81, 45%) and patients with disease duration lower to 5 years (99, 55%). Patients with longer disease duration were much more likely to have ocular manifestations. This finding coincides with many previous studies ,,. However, Markovitz et al.  did not find any association between age of patients and prevalence of ocular manifestations.
In the present study, patients were categorized according to DAS 28 into mild RA (36, 20%), moderate RA (90, 50%), and severe RA (54, 30%). There were no statistically significant differences between the three categories as regards the presence of ocular manifestations or the form of these manifestations. Similarly, Markovitz et al.  and Zakeri et al.  did not find any association between DAS 28 and prevalence of ocular manifestations.
The current study showed that 168 (93.3%) patients had positive anti-CCP and 159 (88.3%) patients were RF positive. Patients were distributed as follows: 156 (86.7%) were positive for both anti-CCP and RF, 12 (6.7%) were positive for anti-CCP and negative for RF, three (1.6%) were positive for RF and negative for anti-CCP, and nine (5%) were negative for both. No statistically significant differences were seen between the four groups as regards the distribution of ocular findings. These findings are consistent with that of Markovitz and colleagues, who could not find a relation between RF and anti-CCP positivity with the ocular manifestations. However, many previous studies did not agree with the current study ,,,.
| Conclusion|| |
Ocular manifestations involved with RA are significant, especially KCS, episcleritis, scleritis, and keratitis. The most common manifestation of ocular involvement was KCS. Posterior scleritis or scleromalacia were not detected in the current study. Ocular manifestations were more common among patients with longer disease duration.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Felson DT, Anderson JJ, Boers M. American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 1995; 38:727–735.
Turesson C, O’Fallon WM, Crowson CS, Gabriel SE, Matteson EL. Extra-articular disease manifestations in rheumatoid arthritis: incidence trends and risk factors over 46 years. Ann Rheum Dis 2003; 62:722–727.
Sahatçiu-Meka V, Rexhepi S, Manxhuka-Kërliu S, Rexhepi M. Extraaricular manifestation of seronegative and seropositive rheumatoid arthritis. Bosn J Basic Med Sci 2010; 10:27–31.
Lilleby V, Gran JT. Systemic rheumatoid arthritis. Tidsskr Nor Laegeforen 1997; 117:4223–4225.
Goronzy JJ, Weyand CM. Developments in the scientific understanding of rheumatoid arthritis. Arthritis Res Ther 2009; 11:249.
Cimmino MA, Salvarani C, Macchioni P, Montecucco C, Fossaluzza V, Mascia MT et al.
Extra-articular manifestations in 587 Italian patients with rheumatoid arthritis. Rheumatol Int 2000; 19:213–217.
Kanski JJ. In: Clinical Ophthalmology. Chapter 24, Systemic disease. 6th ed. London: Elsevier; 2010: pp. 870–871.
Whitson WE, Krachmer JH. Adult rheumatoid arthritis. In: Gold DH, Weingeist TA. The eye in systemic disease. Philadelphia: JB Lippincott; 1990. pp. 127–208.
Hakin KN, Ham J, Lightman SL. Use of orbital floor steroids in the management of patients with uniocular non-necrotizing scleritis. Br J Ophthalmol 1991; 75:337–339.
Galor A, Jabs DA, Leder HA, Kedhar SR, Dunn JP, Peters GB. Comparison of antimetabolite drugs as corticosteroid-sparing therapy for noninfectious ocular inflammation. Ophthalmology 2008; 115:1826–1832.
Baldassano VF. Ocular manifestations of reumatic diseases. Curr Opin Ophthalmol 1998; 9:85–88.
Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO et al.
Rheumatoid arthritis classification criteria. Arthritis Rheum 2010; 62:2569–2581.
Reddy SC, Gupta SD, Jain IS, Deodhar SD. Ocular manifestations of rheumatoid arthritis. Indian J Ophthalmol 1977; 25:20–26.
] [Full text]
Zlatanovic G, Veselinović D, Cekić S, Zivković M, Dorđević-Jocić J, Zlatanović M. Ocular manifestation of rheumatoid arthritis-different forms and frequency. Bosn J Basic Med Sci 2010; 10:324–327.
Vignesh AP, Srinivasan R. Ocular manifestations of rheumatoid arthritis and their correlation with anti-cyclic citrullinated peptide antibodies. Clin Ophthalmol 2015; 9:393–397.
Hori Y, Maeda N, Sakamoto M, Koh S, Inoue T, Tano Y. Bacteriologic profile of the conjunctiva in the patients with dry eye. Am J Ophthalmol 2008; 146:729–734.
Sobrin L, Kim EC, Christen W, Papadaki T, Letko E, Foster CS. Infliximab therapy for the treatment of refractory ocular inflammatory disease. Arch Ophthalmol 2007; 125:895–900.
Markovitz E, Perry ZH, Tsumi E. Ocular involvement and its manifestations in rheumatoid arthritis patients. Harefuah 2011; 150:713–718.
Zakeri Z, Parsa M, Zanjani H, Ansarimoghaddam A, Sandoughi M, Aminifard M et al.
Relationship between severity of RA and dry eye. Health Scope 2012; 1:186–188.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
|This article has been cited by|
||Prevalence and spectrum of eye disorders among patients with rheumatoid arthritis and systemic lupus erythematosus in a tertiary hospital in Northern Nigeria
| ||MaryamH Abdullahi, Victoria Pam, KehindeKabir Oladigbolu, AbdulAziz Umar, RilwanChiroma Muhammad |
| ||Journal of West African College of Surgeons. 2022; 12(1): 48 |
|[Pubmed] | [DOI]|
||Ocular Manifestations in Colombian Patients with Systemic Rheumatologic Diseases
| ||Pilar Uribe-Reina,Juliana Muñoz-Ortiz,Carlos Cifuentes-Gonzalez,Juliana Reyes-Guanes,Juan Pablo Terreros-Dorado,William Zambrano-Romero,Carolina Lopez-Rojas,Fabien Mantilla-Sylvain,Ruben Dario Mantilla-Hernandez,Alejandra de-la-Torre |
| ||Clinical Ophthalmology. 2021; Volume 15: 2787 |
|[Pubmed] | [DOI]|
||Epidemiology of Ocular Manifestations in Autoimmune Disease
| ||Katie Glover, Deepakkumar Mishra, Thakur Raghu Raj Singh |
| ||Frontiers in Immunology. 2021; 12 |
|[Pubmed] | [DOI]|
||Evaluation of tear film in cases of rheumatoid arthritis
| ||Kruti Shah,Vedant Murkey,Swapnagandha Halikar |
| ||Indian Journal of Clinical and Experimental Ophthalmology. 2020; 6(3): 348 |
|[Pubmed] | [DOI]|
||Ocular surface involvement in patients with rheumatoid arthritis: Relation with disease activity and duration
| ||Zeiad H. Eldaly,Sahar A. Saad,Nevin Hammam |
| ||The Egyptian Rheumatologist. 2019; |
|[Pubmed] | [DOI]|