Damian Sendler: Autoimmune diseases are becoming more common worldwide. As a result, ocular complications associated with autoimmune diseases, from minor symptoms to potentially life-threatening scenarios, have also increased. These ocular manifestations may be caused by the disease itself or the treatments used to treat the primary autoimmune disease. ‘ Several autoimmune disorders are linked to an increase in the incidence of ocular complication.
Damian Jacob Sendler: There are two types of autoimmune diseases, organ-specific and systemic, which are both caused by the body’s immune system attacking its own self-antigens. Over 80 autoimmune diseases have been identified, but the exact cause of many of these illnesses remains a mystery. The cellular immune system plays an important role in determining disease susceptibility, prevalence, and severity.
Dr. Sendler: Some of the many eye symptoms associated with autoimmune diseases are frequently overlooked and undervalued. Minor annoyances to potentially life-threatening situations necessitate medical attention right away. Systemic changes in the body can affect the eye’s microenvironment, which can be a first sign of an underlying autoimmune disease (2, 3). When the disease is active or years after diagnosis, ocular manifestations can appear. Patients’ quality of life and even their vision may be jeopardized if treatment for these symptoms is postponed.
Every part of the eye is at risk for autoimmune-related problems. Routine ophthalmic examinations are necessary to diagnose, investigate, and treat any ocular symptoms that may arise during the course of treatment. Acute, sight-threatening ocular complications have been observed with several of the autoimmune diseases discussed in this review, making regular screening important even for those who are asymptomatic.
Between 1965 and 1995, the prevalence of autoimmune diseases was estimated to be 3.2 percent, rising to 19.1 – 43.1 percent in 2018. (4, 5). Autoimmune disease diagnosis market size is expected to grow from $4.1 billion in 2015 to $6.3 billion by 2026. (6). Genetic predisposition in an aging population, as well as improved diagnostic techniques, may be to blame for this rise. Environmental factors have played a larger role in the rise of these issues, suggesting that they can be reduced.
It is not uncommon for a single patient to have multiple autoimmunity syndromes, such as rheumatoid arthritis, thyroiditis and type 1 diabetes (7). Systemic manifestations, including those affecting the eye, can occur as a result of these conditions.
We can only speculate that the prevalence of ocular manifestations of autoimmune diseases will increase as the global population ages and the prevalence of autoimmune diseases increases. An epidemiological and recent literature review of the prevalence of ocular manifestations of various autoimmune disorders is highly desired (8–11), despite the existence of numerous reviews. Ocular complications associated with autoimmune diseases and those at greatest risk will be highlighted in this review so that proper screening and diagnosis can be taken.
Rhumatic diseases (ARDs) are an umbrella term for many conditions that affect joints, bones and muscles, with rheumatology the most common.
Chronic rheumatoid arthritis causes systemic polyarthritis, usually bilateral, with synovial tissue inflammation. According to recent estimates, 1% to 2% of the global population suffers from the disease (12, 13).
Approximately 10% to 35% of rheumatoid arthritis patients have keratoconjunctivitis sicca, or dry eye disease. Episcleritis, scleritis, peripheral ulcerative keratitis (PUK), and retinal vasculitis are other common symptoms. Keratoconjunctivitis sicca (KCS) is the most common ocular condition in rheumatoid arthritis patients, accounting for 85% of all ocular conditions in this study (14). The lacrimal gland is damaged by attacks on B and T lymphocytes, which cause dry eye disease. However, lubricating eye drops can be used to help alleviate and manage the symptoms that sufferers of itchiness, redness, and the sensation of a foreign object in their eyes. Tarsorrhaphy or occlusion of lacrimal drainage puncta may be necessary in more severe cases. In rheumatoid arthritis patients, there is no correlation between disease severity and the severity of the dry eye disease. Longer disease duration was linked to more severe dry eye (15). Relative to healthy control subjects, corneal thickness in patients with rheumatoid arthritis decreased as corneal curvature increased (16).
In up to 10% of patients with rheumatoid arthritis, the suprachoroidal layer is inflamed, resulting in episcleritis. There are topical eye drops that can be used to restrict blood vessels, but because they do not target vessels deep in the sclera, they are ineffective for treating eye diseases. However, there was no correlation between the severity of the disease and the thickness of the choroid layer, indicating the risk of potentially severe ocular manifestations in well-managed patients with rheumatoid arthritis (17).
Patients with rheumatoid arthritis (12) are more likely to develop scleritis, which accounts for 10% of ocular complications. In rheumatoid arthritis, PUK is a rare complication that is mostly reported in case studies. In one case, the rapid progression from generalized symptoms to severe bilateral PUK involving vision loss was documented (18). Without treatment, retinal vasculitis, which can cause vision loss, can develop from scleritis and PUK (19). Retinal vasculitis can be asymptomatic in some cases, reinforcing the importance of regular screening for all patients.
Lacrimal and salivary gland inflammation is a prominent feature of Sjogren’s syndrome. Due to the inflammation of the lacrimal and salivary exocrine glands, patients with Sjogren’s syndrome will experience sicca symptoms. One percent of the world’s people may be infected with HIV/AIDS, according to recent estimates (20).
One in three Sjogren’s syndrome patients exhibits ocular manifestations, and 13 percent of these are so severe that they threaten the patient’s vision (21). Dry eye disease is the most common ocular manifestation of rheumatoid arthritis and other autoimmune diseases. In the United States, one out of every ten people over 50 who are diagnosed with dry eye disease has Sjogren’s syndrome as a precursor (22). Sjogren’s syndrome diagnosis can take up to ten years for those who are diagnosed, indicating a lack of awareness of the importance of ocular manifestations in Sjogren’s syndrome.
Ocular manifestations of primary Sjogren’s syndrome include episcleritis, scleritis, retinal vaculitis, and corneal melt or perforation. Some research suggests that males are more likely to develop these ocular manifestations (23), although this finding can be challenged by other studies (24).
Chronic vasculitis of various organs, such as the eyes and nervous system, characterizes Bechet’s Disease. 70 percent of patients with Bechet’s disease have been found to have some form of ocular disorder, making it a common occurrence (25). Bechet’s disease is characterized by a gradual onset of ocular symptoms, but their importance cannot be overstated.
About two-thirds of patients with Bechet’s disease have recurrent bilateral uveitis (26), and 25 percent of them are at risk of going blind as a result (27). Bechet’s disease-associated uveitis can have serious side effects even in the early stages, including retinal lesions (75-80% of cases), cataracts (39.5 percent of cases), and secondary glaucoma (17.1 percent of cases). These complications can all lead to vision loss.
Corticosteroids, immunosuppressants, and a dexamethasone intravitreal implant were given to a male patient who had decreased vision and intraretinal haemorrhages, as well as macular oedema and disc oedema. It was clear that Bechet’s disease-associated uveitis had left an indelible mark on the patient’s vision even after the macular oedema had cleared (25). More than half of the patients in one study had macular oedema, according to research. Peripheral necrosis was the most common form of retinopathy (29).
In gastrointestinal autoimmune diseases, the immune system attacks the digestive tract’s organs. Literature case studies show that there is currently a lack of awareness about these diseases. For example, little is known about how IBD patients’ corneas are affected. Crohn’s disease patients with no symptoms of ocular involvement, however, were found to have decreased corneal thickness and decreased tear production in recent studies (30).
Chronic inflammation in the gastrointestinal tract can lead to scarring and ulceration as a result of Crohn’s disease. Crohn’s disease can strike anyone at any age, but it seems to strike most frequently in late adolescence. According to recent research, the prevalence of (31).
Episcleritis is the most common ocular manifestation of Crohn’s disease, followed by scleritis and uveitis, in that order (32). Crohn’s disease patients have a reported incidence of 5.6 people per 100,000 people with posterior uveitis (33). Before the diagnosis of Crohn’s disease, oral prednisolone has been shown to alleviate ocular lesions, mild vitritis, and intraretinal hemorrhages in a patient, with no reports of long-term ocular damage (34).
Most often seen in the early stages (36), ocular manifestations may also appear during active disease or remission. In Crohn’s disease, for example, orbital myositis has been reported more frequently than in ulcerative colitis, despite its rarity. Prednisolone and Adalimumab were used to quickly treat an acute onset of orbital myositis in a patient who had previously been disease free (37).
Corneal ulcers, blepharitis, cataracts, conjunctivitis, macular haemorrhage, subepithelial infiltrates, perivascular sheathing, and retinal vasculitis are less common manifestations, but they can also occur (36). It is more common in Crohn’s disease than ulcerative colitis to have dry eye disease (30, 38). It took five years before gastrointestinal symptoms made it possible to diagnose Crohn’s disease that retinal vasculitis was discovered (2).
The incidence of ocular manifestations in ulcerative colitis patients ranges from 4% to 12%, but uveitis and iritis are more frequently associated with ulcerative colitis than Crohn’s disease (32). Ocular manifestations were found in 83% of patients in one study; cataracts and conjunctivitis were the most common (38). Some studies have found a link between ulcerative colitis and an increased risk of ocular manifestations (39, 40), while another found a link between Crohn’s disease and an increased risk of ocular manifestations (41, 42). (41).
Vasculitis, central serous chorioretinopathy, peripheral corneal ulcers, corneal infiltrates, central retinal vein occlusion, and retinal detachment are all uncommon manifestations. Vitamin A deficiency can also cause keratopathy and night blindness (42). Ocular side effects such as vitritis, uveal effusion, choroidal neovascularization, cranial nerve palsy, and optic neuritis are less frequently encountered. A few cases of orbital myositis arising from ulcerative colitis have been documented (43, 44). It is worth noting that CRVO can cause permanent vision loss in some patients with ulcerative colitis (2, 45). ulcerative colitis and IgG4-ROD have been linked for the first time, resulting in orbital swelling (46).
Celiac disease is a long-term condition of the small intestine that affects 1–2 percent of the world’s population (47). Up to 15 percent of celiac patients are also at risk for developing Sjogren’s syndrome (48), which can lead to ocular complications.
Damian Sendler
Vitamin D deficiency can lead to cataract formation in 20 to 60 percent of celiac patients (47). Because of factors such as oxidative stress and dehydration caused by chronic diarrhoea in celiac patients, they are at greater risk of developing cataracts than the general population. Nyctalopia, dry eye disease, and corneal ulcers can all result from vitamin A deficiency in up to a third of patients (49).
For those with celiac disease but no symptoms, ocular manifestations, such as filamentary and keratomalacia, as well as corneal ulcers, can be a sign. Women are more likely to suffer from diplopia than men, so they should be tested for orbital myositis. Patients with celiac disease are also more likely to have abnormalities in the corneal epithelium (51). When celiac disease is linked to type 1 diabetes mellitus, retinopathy has been linked to the disease (52). Celiac disease has been linked to anterior scleritis (53), in which gastrointestinal and ocular symptoms were both alleviated when a gluten-free diet was resumed following gluten consumption.
Most cases of celiac disease go unnoticed because of a lack of awareness and a lack of symptoms, which can have devastating effects on the eye. Findings from the Dogan et al. study show that celiac patients who were diagnosed after 60 months had thinner subfoveal choroid layers, indicating the need for more efficient diagnosis and awareness to avoid eye complications (54).
Multiple sclerosis is a debilitating disease of the central nervous system that worsens over time. To put it another way, nerve fibers are demyelinated by the autoimmune reaction, resulting in a reduced or completely blocked transmission of signals along the nerves. In 70% of MS cases, ocular movement is affected, according to research (55). There are currently 2 million people worldwide with multiple sclerosis (56).
Optic neuritis is a common complication of multiple sclerosis, affecting 7 out of 10 patients (57) and is more common in women than men. Acute vision loss and ocular pain are the most common symptoms of optic neuritis, but the condition can also have more serious side effects. To avoid vision loss or chronic optic neuritis, patients with atypical optical neuritis must receive aggressive treatment to address the retinal haemorrhages, optic atrophy, and swelling of the optic nerve.
More than 60 percent of multiple sclerosis patients have been found to have abnormalities in their pupils (58). Internuclear ophthalmoplegia, caused by lesions on the medial longitudinal fasciculus, occurs in 30% of people with multiple sclerosis and limits eye movement (59). The most common form of nystagmus in MS patients is acquired pendular nystagmus (APN) (60). Despite the fact that APN can lead to severe visual impairment, this can be reversed with timely and appropriate treatment (61).
Uveitis associated with multiple sclerosis has a wide range of prevalence estimates in the literature, with the highest being 36 percent (62). A retinal detachment or cataract may result if the uveitis associated with multiple sclerosis is ignored.
Gullain-Barre syndrome, which causes demyelination and axonal degeneration, is estimated to affect 1 person in every 100,000 people (63). It is usually preceded by an infection of the digestive or respiratory tracts. Gullain-Barre syndrome is characterized by weakening of facial and limb muscles, as well as decreased nerve conduction. The disease worsens rapidly, sometimes in just a few weeks’ time.
In the absence of ophthalmoplegia, accommodation insufficiency and ptosis can indicate an underlying Gullain-Barre syndrome (64). It has also been documented that papillophlebitis is an initial disease manifestation that can lead to serious complications such as optic nerve haemorrhage, macular oedema, and cotton wool spots (65).
Ophthalmoparesis is a common ocular manifestation of Gullain-Barre syndrome, which affects up to 50% of patients (64). Dry eye disease and other eye symptoms can be caused by palsies of cranial nerves three, six, or twelve, which can cause esotropia, eye pain, ocular muscle paresis, corneal sensitivity, lagophthalmos, and ectropion, as well as decreased eyelid movement (66). Increased cerebral fluid and oedema in some Gullain-Barre patients can cause papilloedema (67).
Damian Jacob Sendler
Miller Fisher Syndrome (MFS) can be misdiagnosed as ocular myasthenia gravis (68) because of its similar clinical symptoms, such as lid abnormalities and pupillary dysfunction. External ophthalmoplegia causes diplopia, which is normally absent in Gullain-Barre patients. MFS accounts for 5 to 10 percent of all Gullain-Barre cases (69). Up to 25% of Gullain-Barre cases in Japan are caused by MFS (70). Gullain-Barre syndrome can also cause blepharoptosis, blurred vision, photophobia, vertical gaze palsy, internal ophthalmoplegia and abnormal lid function, mydriasis, anisocoria, ptosis and upper lid jerks. These include color-blindness, decreased visual acuity and pupillary abnormalities as well as supranuclear gaze palsy.
Receptor cells at nerve junctions are destroyed in myasthenia gravis, resulting in reduced signal transmission in skeletal muscles. There is an increased risk of thyroid eye disease for people with myasthenia gravis because of this vulnerability (71).
Myasthenia gravis is on the rise, with a global prevalence of 20 people per 100,000 people estimated at this time (72). Interestingly, a study found that ocular weakness was the first symptom in 82% of patients (73).
If you notice diplopia and symmetrical extraocular involvement (74, 75), you may be suffering from ocular myasthenia gravis, which is the most common symptom of myasthenia gravis (OMG). About 10% to 40% of myasthenia gravis sufferers have OMG (76). Pupil sparing ophthalmoplegia (PSOP), internuclear ophthalmoplegia (IOP), and thyroid eye disease (THD) are among the symptoms these patients will experience. All of the extraocular muscles can experience ophthalmoparesis, resulting in severely restricted movement of the eyeball. A study by Tang et al. found that 70 percent and 25 percent of the participants had diplopia and ptosis on their first evaluation, respectively. The lateral rectus muscle, which controls eye movement, was found in all 40 patients (73).
Blepharitis, lagophthalmos, and orbicularis weakness have all been linked to dry eye disease in 21% of OMG patients (77). (74). OMG is more common in myasthenia gravis, but nystagmus and pseudo-intranuclear ophthalmoplegia have been documented in rare cases (78). Adduction will be minimal in these patients.
It is the destruction of insulin-producing beta-pancreatic cells that causes type 1 diabetes mellitus because insulin signals cells to take in glucose. Type 1 diabetes mellitus is a systemic disease that has the potential to cause serious health issues. As a result, early detection is essential for avoiding damage to various organs, such as the eye. Type 1 diabetes, in contrast to type 2, is more commonly discovered in childhood.
9.5 percent of the world’s population will have type 1 diabetes by 2020, according to current estimates. When it comes to type 1 diabetes cases, only about 10 percent of these cases occurred in the United Kingdom between 1980 and 2014. (79).
Cataracts, glaucoma, diabetic retinopathy, and diplopia have all been observed in patients with type 1 diabetes, and the latter is more common in its early stages (80). In diabetics, age-related changes to the lens are more pronounced, as well as lower accommodation reflexes (81). In the absence of regular ophthalmic screening, vascular damage may go undetected during the prediabetic period, allowing eye disease to develop and progress before it is even discovered.
Early detection of DR is critical for the preservation of vision, as early intervention has been shown to reduce the risk of developing DR disease and the ability to prevent a decrease in visual acuity (83). Implementing early and routine ophthalmic screening could save millions of people’s vision, as DR develops in one-third of diabetes patients over 40 (84). Retinopathy was found in 27.4% of a T1DM cohort, with 8% of those cases being severe. According to 40-year follow-up estimates, 84.1% of patients had retinopathy, with 50.2% having a severe form, demonstrating the potential consequences of patients’ lack of knowledge, lack of screening, and untimely treatment (85). Srinivasan et al. also found that 43 percent of the studied cohort had worsening DR after follow-up (86).
Damien Sendler: The degree of capillary loss in patients with DR is strongly associated with decreased visual acuity; however, these changes may be asymptomatic at the time. As Duet and colleagues found, approximately 30 percent of patients who underwent OCT-A and OCT imaging showed vascular density reductions in the deep capillary plexus, even though they had no symptoms of DDR (87). For all patients, early screening is critical.
A higher incidence of glaucoma and cataracts among African American populations is seen in patients with type 1 diabetes mellitus (80). (88). Additionally, women are more susceptible to developing cataracts as a result of type 1 diabetes (89, 90). As many as 0.7 – 3.5 percent of children with type 1 diabetes (91), often within the first six months of diagnosis (92) have cataracts, which can result in permanent loss of sight. As a result, even those with no obvious cataract symptoms should have their eyes examined on a regular basis. There is, however, a paucity of data on ocular screening in type 1 diabetic children.
Hashimoto’s thyroiditis is the most common cause of hypothyroidism in developed countries because immune cells attack the thyroid (101). Rheumatoid arthritis and type 1 diabetes are two other autoimmune diseases with which it’s been linked (102). Hashimoto’s thyroiditis has been linked to eye problems, but large-scale studies are needed before these findings can be made generalizable.
In Hashimoto’s thyroiditis patients, thyroid-associated ophthalmopathy (TAO) has been reported in 6% of cases, but it is more common in Graves’ disease patients (70%). TAO risks include old age, illness, and smoking (103). Research into Graves’ disease has largely ignored the association between TAO and Hashimoto’s thyroiditis because TAO is more common in Graves’ disease. Several studies (104, 105) describe cases of severe TAO, in which the ocular muscles become enlarged. Despite its rarity, thyroid-associated optic neuropathy (TAO) can occur in patients who are not hypothyroid, highlighting the importance of conducting thorough screenings in order to avoid optic nerve compression and subsequent vision loss.
Patients with Hashimoto’s disease have also been observed to have abnormalities or differences in their corneas. A Hashimoto’s thyroiditis cohort had significantly reduced corneal hysteresis and a higher corneal compensated IOP compared to the control group, according to Kirgiz and colleagues. Reduced corneal hysteresis leads to increased pressure on the optic nerve, which can lead to glaucoma and other vision-threatening conditions (106).
Damian Jacob Markiewicz Sendler: Case studies have also shown that Hashimoto’s patients can suffer from long-term diplopia and vision loss (107). Over the course of a year, a patient previously misdiagnosed with double elevator palsy developed severe diplopia. Hashimoto’s thyroiditis was not discovered until a positive forced duction test, blood tests, and ultrasounds revealed hypothyroidism. Prednisolone was ineffective in resolving the patient’s diplopia. Patients with both typical and atypical TAO symptoms should be screened on a regular basis, according to this study. If more timely and thorough screening had been implemented, would this have prevented misdiagnosis and led to better treatment outcomes? inevitably arises.
Proptosis and hypothyroidism are risk factors for dry eye disease in up to 85% of TAO patients (108,109), but there are few studies on the disease’s manifestation. However, euthyroid patients’ dry eye disease has no relation to the severity of Hashimoto’s thyroiditis, which is milder (109). Compared to healthy controls, Hashimoto’s patients have significantly lower mean tear production and tear stability, making dry eye disease more common. Additionally, lid retraction, soft tissue swelling, proptosis and extraocular involvement have been reported (110). Dry eye disease, decreased tear production and stability, Meibomian gland dysfunction, proptosis, and decreased goblet cell density were found in this study.. Average meibomian gland area loss was 25%, but one patient experienced a 50% loss.
Scleroderma, a form of systemic sclerosis that affects multiple organs, affects up to 2.5 million people worldwide (124). Scleroderma can affect the skin or it can affect multiple organs. Swelling and joint pain are common symptoms of systemic sclerosis, which is marked by an increase in collagen production. Sjogren’s syndrome and rheumatoid arthritis have been linked to scleroderma, as have other autoimmune diseases (125). Only 20,000 people in the UK have systemic sclerosis, and that number is expected to rise by 26% in the next decade, according to the National Institutes of Health (NIH) (126).
In systemic sclerosis, there are numerous ocular manifestations of varying severity, such as abnormalities in the retina and cataracts, blepharitis, telangiectasia, scleral pits, and keratoconus (127, 128). Following dry eye disease (64.71 percent), skin alterations of the eyes (56.86 percent) and retinal abnormalities (56.86 percent) were the most common findings in one study (50.98 percent ). Patients may experience choroidal atrophy as a result of a lack of blood supply (129). Grennan et al. conducted a small-scale study and found that choroidal abnormalities were present in 50% of the patients, even though dry eye disease and retinal abnormalities were not common in these patients (130). There was corneal steeping, severe dry eye disease, and decreased tear stability in one keratoconus patient (131). When scleroderma interferes with iris pigments, transillumination occurs (132). Patients with scleroderma have been found to have subfoveal choroid layers that are less dense.
Nearly all patients with systemic sclerosis have dry eye disease (133). Despite the fact that only a third of their study participants reported dry eye symptoms, almost half reported decreased tear secretion, which suggests that dry eye disease may be on the horizon (134). Dry eye disease can be caused by lacrimal gland fibrosis, chronic blepharitis, and meibomian gland dysfunction. Patients with scleroderma have reported experiencing eyelid stiffness in up to 65 percent of the patients studied (125). It can lead to a condition known as lagophthalmos, which puts patients at risk of infection or damage (132).
The limited disease type has ocular manifestations as well. Ptosis, uveitis, dry eye, episcleritis, orbital myositis (135), and decreased size of the globe and ocular muscles are just a few of the many ocular symptoms of En Coup de Sabre (ECS) (136). 26 percent of ECS patients reported experiencing ocular symptoms. Diagnosis of keratopathy, retinal detachment, restricted eye movement, diplopia, cataracts, and corneal astigmatism (136). Adie pupil has been reported as an early disease indicator of ECS, despite its rarity (135). Ocular symptoms are more common in the ESC subtype in children (137), but linear scleroderma is more common in children (138). As well as retinal detachment and uveitis associated with linear ECS scleroderma, it has been linked to retinal telangiectasia (138).
All of the autoimmune diseases examined in this review have ocular complications, ranging from minor symptoms to sight-threatening scenarios, despite the fact that they are frequently underestimated and ignored. Misdiagnosis, delayed treatment, and a lack of awareness about the disease can all have long-term consequences on a patient’s vision. Epidemiology studies and market reports show that autoimmune diseases are becoming more common around the world. Environmental factors, such as the increasing westernization of lifestyles in Eastern countries, are expected to contribute to the current increase in population. Many autoimmune diseases are predisposed to be more severe in women due to gender-specific genetic factors. Even in patients who are asymptomatic or only show subtle ocular symptoms, clinicians can better diagnose, screen for, and treat autoimmune diseases and their associated ocular manifestations by identifying those most at risk. In many cases, the eye can serve as a warning sign of an underlying illness. As a result, doctors should make use of this useful tool and not ignore any minor ocular symptoms that occur in the absence of more obvious signs of disease.