Abstract
Rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis are associated with potentially sight-threatening inflammatory eye disease. Although the ocular manifestations associated with ankylosing spondylitis and psoriatic arthritis are similar, such as anterior uveitis, this differs from rheumatoid arthritis where dry eye, peripheral ulcerative keratitis and scleritis are the major ocular complications. Apart from causing sight loss, these conditions are painful, debilitating, often recurrent or chronic and may require long-term therapy. Treatments such as ocular lubricant, topical corticosteroid, systemic corticosteroid and systemic immunosuppression are often similar for the underlying systemic disease. Yet for the treatment of the ocular complications, the evidence base is weak. Close collaboration with a rheumatologist is often essential, particularly in the management of these patients.
The eye and rheumatoid arthritis
Ocular complications of rheumatoid arthritis
The ocular complications of rheumatoid arthritis (RA) more commonly affect the front (anterior segment) than the back of the eye (posterior segment) . Anterior segment disease includes dry eye, peripheral ulcerative keratitis (PUK), episcleritis and anterior scleritis . Posterior segment disease includes posterior scleritis and rarely a retinal vasculitis .
What is the most frequent ocular manifestation of RA?
The most frequent ocular manifestation in patients with RA is dry eye disease (DED, keratoconjunctivitis sicca) with up to 45% of patients having clinical features consistent with dry eye and 38% of patients being symptomatic . It is defined as a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance and tear film instability with potential damage to the ocular surface, accompanied by increased osmolarity of the tears and inflammation of the ocular surface . A vicious cycle of hyperosmolarity and chronic inflammation leads to increased friction and eventual ocular surface damage. The ocular surface is a highly intricate and specialised mucosa, with the epithelium running from the meibomian gland orifices into the meibomian glands, along the tarsal conjunctival epithelium (on the back surface of the eyelids), the forniceal conjunctiva (deep in the natural gutter between the eyelid and eye ball), the epithelium of the lacrimal gland and the bulbar conjunctival epithelium (overlying the eyeball), merging into the corneal epithelium at the limbus. Each specialised layer of the ocular surface contributes to a component of the tear film. The lacrimal and accessory glands produce the central nutritive aqueous component; the Meibomian glands, the oily outer lipid that provides tear film stability; and the conjunctival goblet cells, the inner ‘surfactant’ mucin that primarily improves the wettability of the ocular surface. The eyelids and lashes provide fundamental protection through the blink mechanism, as well as wiping away debris from the ocular surface and replenishing surface with a fresh layer of tears. All components of the ocular surface are linked functionally by the key ‘systems’ (neural, vascular, endocrinological and immunological) that are vital for ocular surface homoeostasis and defence . The ocular surface system has a unique function to maintain optical clarity of ocular tissues through provision of protective mechanisms, resisting trauma and pathogens. Deficiency of any component of the ocular surface system may lead to DED that is classically defined as aqueous deficient or evaporative. Both forms are prevalent in RA where the majority of patients have mixed disease. Risk factors include older age, female gender, reduced androgen levels, use of exogenous oestrogens, imbalance in the dietary intake of omega-3 and omega-6 fatty acids and the use of antidepressants.
What is the impact of dry eyes on a patient’s life?
DED is a significant global public health problem and there is yet no effective treatment . Symptoms are variable and include itching or burning, sensation of a foreign object in the eye, crusty material clinging to the eyelashes, light sensitivity, intermittent blurred vision and complaint of scant or broken eyelashes. Visual disturbances lead to problems associated with activities such as reading, computer use, cooking, navigating stairs, and driving a car, together with lower professional work performance, role limitations, lower vitality and poorer general health . Several studies have indicated that the health-related quality of life (HRQoL) burden increases with the severity of disease and 2 utility assessment studies have shown that utilities for severe DED are similar to those reported for renal dialysis and severe angina . The impact of DED on mental health is also apparent. In a study evaluating 7207 patients with dry eyes correcting for factors associated with systemic disease, adjusted odds ratio for DED and anxiety was found to be 2.8 (95% confidence interval [CI] 2.6–3.0) and for depression 2.9 (95% CI 2.7–3.1) . In a meta-analysis, dry eye patients with rheumatic disease were more likely to suffer from depression .
Objective symptomatology is graded according to a range of patient reported outcome utility instruments specific for ocular surface disease, dry eye diagnosis, epidemiological studies and clinical trials. The questionnaires interrogate disease in different ways; for example, diagnosis alone, to identify precipitating factors or to quantify the impact on quality of life. The time taken to administer a questionnaire and mode of administration (self, interviewer and phone) influence the choice of questionnaire. The most commonly used in an ophthalmology setting is the Ocular Surface Disease Index measuring the severity of DED in the form of a 12-item questionnaire subdivided into 3 domains (visual function (6), ocular symptoms (3), environmental triggers (3)) providing a scoring algorithm ranging from 100 for complete disability to 0 for no disability ( Table 1 ). By contrast, The National Eye Institute Visual Functioning Questionnaire-25 is a generic tool that compares vision-targeted HRQoL applicable to multiple ocular conditions, offering 25 items that examine the frequency and severity of a symptom and how this affects activities of daily living within multiple domains (near vision, general health, social problems, distance vision). Ocular symptomatology scoring is also integrated into rheumatology scoring systems most commonly for primary Sjögren’s syndrome (SS) such as Profile of Fatigue and Discomfort, Sicca Symptoms Inventory and European League Against Rheumatism Sjögren’s Syndrome Patient Reported Index, correlating with disease activity or damage scores (SS Disease Activity Index, SS Clinical Activity Index, EULAR SS Disease Activity Index). There are no RA activity and damage instruments that incorporate ocular symptoms or vision-related quality of life.
| Circle the number in the box that best represents each answer | ||||||
|---|---|---|---|---|---|---|
| Have you experienced any of the following during the last week ? | All of the time | Most of the time | Half of the time | Some of the time | None of the time | |
| 1. Eyes that are sensitive to light? | 4 | 3 | 2 | 1 | 0 | |
| 2. Eyes that feel gritty? | 4 | 3 | 2 | 1 | 0 | |
| 3. Painful or sore eyes? | 4 | 3 | 2 | 1 | 0 | |
| 4. Blurred vision? | 4 | 3 | 2 | 1 | 0 | |
| 5. Poor vision? | 4 | 3 | 2 | 1 | 0 | |
| Subtotal score for answers 1 to 5. A= | ||||||
| Have problems with your eyes limited you in performing any of the following during the last week ? | All of the time | Most of the time | Half of the time | Some of the time | None of the time | N/A |
| 6. Reading? | 4 | 3 | 2 | 1 | 0 | N/A |
| 7. Driving at night? | 4 | 3 | 2 | 1 | 0 | N/A |
| 8. Working with a computer or bank machine (ATM) | 4 | 3 | 2 | 1 | 0 | N/A |
| 10. Watching TV? | 4 | 3 | 2 | 1 | 0 | N/A |
| Subtotal score for answers 6 to 10. B= | ||||||
| Have your eyes felt uncomfortable in any of the following situations during the last week ? | All of the time | Most of the time | Half of the time | Some of the time | None of the time | N/A |
| 10. Windy conditions? | 4 | 3 | 2 | 1 | 0 | N/A |
| 11. Places or areas with low humidity (very dry)? | 4 | 3 | 2 | 1 | 0 | N/A |
| 12. Areas that are air conditioned | 4 | 3 | 2 | 1 | 0 | N/A |
| Subtotal score for answers 10 to 12. C= | ||||||
| Add subtotals A, B and C to obtain D . | ||||||
| Total number of questions answered (do not include questions answered N/A) | ||||||
| OSDI = [(sum of scores (D)) × 25]/(number of questions answered) | ||||||
What are the signs of DED?
The cardinal signs of DED are ocular surface (conjunctiva and cornea) staining, reduced Schirmer’s test score, increased tear film instability, accumulation of tear film debris or mucus clumping with or without filamentary keratitis, conjunctival hyperaemia, increased osmolarity and features of ocular surface failure (meibomian gland dysfunction, trichiasis, ulceration, conjunctival scarring) . Grading and staging of disease facilitate therapeutic targeting. Nevertheless, there are a significant number of patients who have disproportionate symptomatology to the clinical signs that is thought to occur secondary to nociceptive sensory receptor hypersensitivity .
Schirmer’s test
Schirmer’s test I without anaesthetic is the rheumatology ‘Gold Standard’ for quantitative measurement of tear production. Filter paper strips (5 × 35 mm Whatman grade No 1) bent at the notch are hooked over the lower eyelid midway between the middle and outer third of the lower lid margin with the patient asked to gently close their eyes throughout the duration of the test in an unanesthetised eye. The strips are read at 5 min with a cut-off of ≤5.5 mm considered to be abnormal. Schirmer’s test II with anaesthetic is conducted in the same way but after the instillation of anaesthetic eye drops and estimates basal secretion of tears. Schirmer’s test II involves induction and measurement of ‘reflex’ secretion by anaesthetising the eye with topical anaesthetic and irritating the nasal mucosa with a cotton tipped applicator or smelling an irritant substance. Neither are routinely used for DED assessment.
Ocular surface staining
Several scoring systems have been proposed to quantify ocular surface staining in DED. The most commonly used partition the exposed ocular surface into 3 components: nasal and temporal conjunctiva and the cornea. The clinically used vital dyes that grade ocular surface damage are lissamine green and fluorescein. Lissamine green identifies devitalised epithelial cells present on an intact ocular surface, whereas fluorescein stains epithelial defects. In the Oxford staining schema, the clinician is provided with a series of panels labelled A–E, in order of increasing staining severity, reproducing the staining patterns encountered in DED. Each ocular surface component is scored of 5 giving a total maximal score of 15. The van Bijsterveld (VB) schema is commonly used in grading ocular surface dryness in rheumatic disorders. This system evaluates the intensity of lissamine green in the 2 exposed conjunctival zones and cornea scored to a maximum of 3 for each zone with a cumulative maximal score of 9. The ocular staining score (OSS) is a more elaborate system gaining acceptance for scoring severity of ocular dryness in SS and uses both lissamine and fluorescein vital dyes. Lissamine green is reserved for evaluating the conjunctival staining score and fluorescein for corneal staining with each of the 3 zones scored between 0 and 3. Confluent and pupillary area fluorescein staining together with the presence of filaments add weight to the corneal score resulting in a maximal OSS of 12 for each eye .
Tear film instability
The tear film breakup time (TFBUT) measures the stability of the tear film and how quickly this evaporates. It is defined as the interval between the last complete blink and the first appearance of a dry spot or disruption in the tear film. It is performed after instillation of a drop of 2% sodium fluorescein onto the bulbar conjunctiva and using a Wratten 12 yellow filter on a standard slit-lamp magnification (×10); the duration of the tear film integrity over the cornea is observed. A TFBUT ≥10 s is considered to be normal, and ≤5 s is reduced.
Hyperosmolarity
Osmolarity tear analysis is determined by lab-on-a-chip technology using a nanolitre collecting tool providing an absolute numerical measurement with a mean average of >308 mOsm/L generally indicative of DED. Because of the large overlap between the normal distribution curves between those with and without dry eye, longitudinal follow-up of patients is essential to monitor changes. There are many patients who fall in the normal range but have significant symptomatology and staining pattern and there are those with severe DED when it is not consistently possible to obtain an osmolarity reading with the current technologies available.
Which treatments are used for DED and when?
A hierarchy of symptoms and clinical features provide dry eye severity scales that inform potential therapeutic strategies based on recommendations from the Dry Eye Workshop and Meibomian Gland Dysfunction Workshop ( Table 2 ) . Interventions can broadly be classified into environmental optimisation, treatment of meibomian gland dysfunction, tear supplementation, retention and stimulation, use of anti-inflammatories and specialised interventions. Treatments should be tailored to patient’s needs, severity of dry eye and symptoms, and frequently, the optimal regime is based on patient’s preference and tolerability.
| Level 1: mild dry eye | Level 2: moderate dry eye | Level 3/4: severe dry eye (ophthalmology only) |
|---|---|---|
| Features TFBUT: >9 s Staining: VB score = 0 to 3, OSS = 0 | Features TFBUT: 5–9 s Staining: VB score = 4 to 5, OSS = 1–6 | Features TFBUT: <5 s Staining: VB score = 7–12, OSS = 5–12 |
Management
| As for mild plus :
| As for moderate plus :
|
a Adapted from The British Society for Rheumatology (BSR) and British Health Professionals in Rheumatology (BHPR) Guideline for the Management of Adults with Primary Sjögren’s Syndrome 2016 (in press).
Strategies for removing desiccating stress are cardinal to the management of DED. Avoidance of irritating substances including cigarette smoke, pollution or peri-ocular cosmetics and low humidity atmospheres such as central heated houses, aeroplanes and windy locations is vital. Drugs that precipitate dryness should be avoided (antihistamines, antidepressants) as well as limiting activities that promote tear film instability (prolonged reading or computer work). Increasing humidity with a cool mist humidifier is recommended and the wearing of moisture chamber glasses created by using a soft, compressible eye cup or gasket affixed to the frame. Dietary modifications by increasing omega-3 fatty acids (eicosapentaenoic acid (EPA)) or linoleic acid and gamma-linolenic acid (flaxseed oil, that is, metabolised to EPA before entering the anti-inflammatory cascade) has been shown to have clinical benefit by inhibiting proinflammatory lipid mediators (prostaglandin E2 and leukotriene B4) and blocking the production of IL-1 and anti-tumour necrosis factor-α (TNF-α). The benefit of omega 7 (sea buckthorn oil) supplementation has also been observed.
Stagnated meibum oils, hypercolonisation of the lid margin by staphylococcal species, chronic inflammation, lid margin hyperkeratinisation, cicatrisation and irreversible blockage of meibomian glands may be controlled by, warm glandular expression, lid margin hygiene, topical emollient lubrication, oral low dose tetracyclines (used as anti-inflammatories) and antitopical lubricant and inflammatory therapy. Effective lid margin hygiene is essential requiring warm compresses for up to 30 min twice daily (using warm flannel or proprietary devices) to increase the fluidity of the stagnant oils within the glands easing expression when the lids are massaged by a firm stroking motion towards the lid margins. Expressed matter should be cleansed lightly with a cotton tipped applicator moistened with boiled cooled water or with proprietary lid wipes. In the presence of extensive glandular and duct atrophy associated with thickened and indurated lids, cicatrisation and negligible excreta, response may only be partial or even refractory.
Tear supplementation is designed primarily to reduce biomechanical trauma caused by dry eye states and dilute toxic mediators on the surface of the eye. The supplements do not replace the intricate composition of the tear film and therefore have limited patient satisfaction. For mild DED, preserved eye drops may be used but dosing is critical. If dosing is more than 4–6 drops per day of the total number of eye drops, non-preserved tear supplementation and those not containing benzalkonium chloride (BAK) should be administered into the eye . BAK damages the ocular surface epithelium causing chronic ocular surface inflammation and paradoxical aggravation of disease. Carboxymethylcellulose containing compounds have higher ocular surface retention and facilitate epithelial proliferation and those with sodium hyaluronate glycosaminoglycans (CD44 ligand) facilitate wound healing, reduce inflammation and have longer lasting lubrication. Tear retention can be achieved not only by wearing moisture chamber spectacles conserving the tear film meniscus on the ocular surface, but also by punctal occlusion with either punctal plugs or punctal cautery. Punctal occlusion can increase proinflammatory cytokine expression so timing of occlusion is critical . Secretagogues have been used with variable success in DED. Oral cholinergic agonists, pilocarpine, reportedly improve symptoms and possibly increase goblet cell density in the conjunctiva . Use is frequently limited by intolerable systemic cholinergic symptoms. Alternative use of topical pilocarpine 4% eye drops administered orally has been used with variable effect. Approximately 3 drops provide an equivalent dose of 5 mg ( Table 2 ).
Topical corticosteroids remain the mainstay to targeting the inflammatory component DED (prednisolone 0.5%, dexamethasone 0.1%) but ophthalmological surveillance is mandatory because of the risk of steroid-induced raised intraocular pressure (IOP) causing permanent optic neuropathy or cataract formation. The anti-metalloproteinase properties of long-term oral tetracyclines (such as doxycycline 50 mg once daily for a minimum of 3 months or longer term maintenance) provide anti-inflammatory (anti-TNF-α, IL-1) treatment. Tetracyclines are additionally antibacterial and antiangiogenic thus conducive to promoting an optimal ocular surface microenvironment in DED states. The introduction of topical calcineurin inhibitors (cyclosporin A—Restasis, Ikervis) has also been found to improve the clinical signs of dry eye together with subjective improvement in symptoms in patients who are refractory to ocular lubricants alone. These agents can only be initiated by an ophthalmologist and are reported to increase goblet cell density and reduce lymphocyte activation markers, while sparing the local adverse effects of topical corticosteroids. Other specialist interventions include the use of contact lenses that protect and hydrate the ocular surface but introduce a risk of corneal neovascularisation or sight-threatening corneal infection. The contact lens material enables high oxygen permeability, extended overnight wear and/or continuous use (maximum 3 months). Rigid gas permeable scleral-supported contact lenses with no corneal touch create a corneal reservoir behind the lens to enable capture of tears and therapeutically applied agents to be retained within reservoir.
In severe cases or those with exposure, resistant filamentary keratitis taping the lids or surgical tarsorrhaphy may be required or amniotic membrane transplant to the corneal surface. Salivary gland autotransplantation is reserved only for severe clinical states where the mouth is not excessively dry. The only true biological tear substitutes are serum eye drops (either autologous or allogeneic). The epitheliotrophic potential of serum drops has been shown to be beneficial because of the similarities of the large number of biological substances that are present in tears .
Patients whose symptoms disproportionate to clinical signs may benefit from pain management strategies including tramadol, gabapentin and pregabalin .
How common is PUK in patients with RA?
PUK is a rare manifestation of RA with a reported frequency of 3 per million population per year . It is characterised by a progressive thinning of the peripheral cornea secondary to immune complex disease accompanied by complement activation, release of collagenases and proteases in the region of the limbal vasculature and avascular cornea . This leads to keratolysis that may be with or without ulceration. The triggers for PUK are largely unknown but are broadly categorised as infectious or non-infectious, the latter due mainly to underlying systemic disease or trauma (such as surgical intervention) with the progression of disease compounded by the presence of DED. Patients may clinically have quiescent eyes and present incidentally with gradual reduction of vision secondary to circumcorneal keratolysis with subsequent corneal distortion or more rarely with a painful eye, severe inflammation and/or corneal perforation. This is frequently independent of systemic disease marker activity although a single study has indicated that ocular manifestations in RA may correlate with anti-cyclic citrullinated peptide antibodies but only 4 of a total 77 patients had PUK . An underlying infective cause or secondary infection must be excluded and treated before instituting immunosuppressive therapy and the classical features (red eye, corneal abscess) masked because of concomitant immunosuppression for the systemic component of disease. Mortality after the diagnosis of PUK in 34 patients has been reported as high as 53% compared with patients with PUK on immunosuppression (5%) . In a more recent study evaluating a 10-year single centre review of 70 patients with PUK , subgroup comparison of 46 patients with RA was made with a historic published cohort from the same centre 10 years earlier , showing mortality rates of 15% and 28%, respectively. In addition, there was significant improvement in visual outcomes (VA vs than 6/60, 3.4% vs 34%), fewer perforations (14% vs 65%) and fewer enucleations (0% vs 10%).
How is PUK treated?
Exclude and treat infection
An underlying infective cause or secondary infection must be excluded and treated before instituting immunosuppressive therapy and the classical features (red eye, corneal abscess) may be masked due to concomitant immunosuppression for the systemic component of disease or topical corticosteroids or cyclosporin for dry eye. Corneal scraping for microscopy, culture and antibiotic sensitivity of cultured organisms is essential. Corneal scrapes have the added advantage of debriding necrotic tissue and enhancing topical therapy penetration. Because of the small inoculum size, ocular specimens are inoculated directly onto the culture media to reduce false negatives. Some of the pathogens isolated from ocular infections particularly in patients who are immunosuppressed are considered to be normal flora by non-ocular microbiologists, so it is important for ophthalmologists to liaise closely with the laboratory. The clinical course is broadly categorised into sterilisation, healing and remodelling phases. This is a continuum with cut-offs being dependent on factors related to virulence of underlying organisms (if present) and patient factors (immunosuppression, severity of DED, etc.).
Control inflammation and promote healing
Generally, sterilisation is achieved with intensive (day and night, hourly) broad spectrum antibiotics together with ‘healing’ strategies to optimise the ocular surface including doxycycline (a metallomatrix proteinase inhibitor), ascorbate (a free radical scavenger) and lubricants to promote epithelial wound closure. Ancillary anti-inflammatory/antiscarring treatment in the form of topical glucocorticoids is usually commenced around 2–3 days when sterilisation is likely to be complete. With pending perforations of the cornea or actual perforations, rapid control of inflammation is achieved through implementing rescue therapy with pulsed intravenous glucocorticoid given early (usually at 24 h) followed by high dose oral glucocorticoids in conjunction with steroid-sparing antiproliferative agents (e.g., mycophenolate mofetil, methotrexate and azathioprine) or T-cell inhibitors (e.g., cyclosporin, tacrolimus) if the patient is not already on these Disease-modifying antirheumatic drugs (DMARDs). If patients are on existing immunosuppression, a step-up in dose or a switch to more potent therapy should be considered. For severely active necrotising disease associated with scleritis, pulsed oral or pulsed intravenous cyclophosphamide therapy should be considered . More recently, biological therapies (e.g., TNF-α family, anti CD-20 (rituximab)) have been introduced for both induction of remission and maintenance but there are no randomised controlled trials to support use (see scleritis).
How are corneal perforations sealed?
Corneal perforation is an ophthalmic surgical emergency. The primary aim is to seal the perforation and prevent an endophthalmitis that may lead to loss of eye. In the presence of a corneal perforation, holes less than 2 mm in diameter, tissue adhesives using higher cyanoacryalate esters (enbucrilate, N-Butyl-2 cyanoacrylate C 8 H 11 NO 2 ) that polymerise on contact with moisture on the ocular surface, together with a 4-mm polythene patch and a therapeutic contact lens (applied to reduce the discomfort associated with the irregular surface of the polymerised glue) are used. A series of glue patches are frequently required for more arcuate lesions. Larger holes are sealed with layered amniotic membrane glued with fibrin and sutured to the cornea ( Fig. 1 ). If glue or amniotic membrane fails to seal a perforation in an acute situation, ocular surface reconstructive surgery with lamellar or full thickness keratoplasty (allogeneic corneal transplantation) with amniotic membrane overlay with or without a tarsorraphy is undertaken combined with supplementary intravenous steroids to reduce surgically induced aggravation of disease with remission induced with pulsed cyclophosphamide.
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