Monitor lupus patients for toxic maculopathy

Because there is no cure for systemic lupus erythematosus, these patients are often on therapy for long periods of time.

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A 49-year-old white female presented for a follow-up eye examination in December 2011. She had a history of lupus erythematosus, for which she was being treated with Plaquenil 400 mg (hydroxychloroquine, Sanofi-Aventis) once daily for 10 years.

Other medications included 0.075 mg of Levoxyl (levothyroxine sodium, King Pharmaceuticals) for hypothyroidism. She was taking a generic multivitamin supplement once daily in addition to a calcium mineral supplement and vitamin D pill, dosage unknown.

Her entering visual acuity was 20/30+2 OD and 20/40 OS; it was best corrected to 20/20 OD and 20/20+ OS with a high compound myopic astigmatic correction. However, she preferred undercorrection to enable reading without bifocals. The prescription worn was: -7.75 D -1.00 D X 80 OD and -8.00 D -0.75 D X 85 OS; the autorefraction was: -9.25 D -0.50 D X 66 OD 20/20, -9.50 D -0.50 D X 66 OS 20/20.

The patient reported increased glare at night for the last few years, which prompted a careful analysis.

External examination including slit lamp examination was normal in both eyes. Amsler grid revealed no scotoma or metamorphopsia. Color vision testing was normal in both eyes.

Dilated fundus examination showed cup-to-disc ratio of 0.4 OU with large peripapillary atrophy and thinning temporally, consistent with high myopia. The macular area exhibited retinal pigment epithelium (RPE) mottling nasal to fovea with good foveal reflex present. Humphrey visual field (Carl Zeiss Meditec) showed central scotomas. A referral to a retinal specialist was deemed appropriate.

Images: Hallak J

Multifocal electroretinogram (mfERG) test was ordered using 61 hexagon stimulus pattern with 14 m-sequence bits examining the central 30 degree field. Both eyes demonstrated subnormal waveforms, more so in the paracentral areas; the subnormal findings were more prominent in the left eye than the right. MfERG and pattern ERG may help locate specific pathological anatomy, including the macula and optic nerve. Some recent studies have shown that the longitudinal decline in retinal function correlates with the macular visual field mean deviation values.

Spectral domain optical coherence tomography with the Heidelberg Spectralis showed a mild irregularity of the RPE complex centrally with central thickness of 276 and 271 microns OD/OS.

The macular OCT takes on an ovoid appearance with an interruption of the perifoveal photoreceptors integrity line. Chen and colleagues studied a few cases of confirmed hydroxychloroquine (HCQ) toxicity and described the “loss of the perifoveal photoreceptor inner segment/outer segment junction with intact outer retina directly under the fovea.” He called this feature the “flying saucer” sign and stated that it is pathognomonic for retinal toxicity.

The patient’s high myopia is not contributory. Data are being collected to correlate OCT findings to the retinopathy progression on follow-up visits.

The diagnosis was toxic maculopathy secondary to Plaquenil use for about 10 years, based on RPE mottling, subnormal ERG waveforms and central relative scotomas in both eyes despite good corrected visual acuity. The only subjective complaint was the glare at night that could have been overlooked if not for the subtle RPE mottling and subsequent macular field subtle defects.

Systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with a broad spectrum manifestation in association with antinuclear antibody (ANA) production. It affects the skin (butterfly rash in 50% of cases over the cheeks and bridge of nose). It causes Raynaud’s phenomenon (pain and swelling of the joints) and causes swollen lymph nodes, fatigue, general discomfort, mouth sores, nonspecific fever and light sensitivity (glare).

It affects major organs at a later stage: the kidney, as nephritis; the brain and nervous system; vision problems; the heart, as arrhythmias (endocarditis and myocarditis); the lung, as difficulty breathing and pleurisy; the digestive tract, as pain and nausea; and anemia. The prevalence is 15 to 50 out of every 100,000 people. It is 10 times more common in women; it is four times more common in African Americans and in Asians, and it occurs at any age, but most often between the ages of 10 and 50. SLE tends to be more active the first years after diagnosis and when it manifests in people younger than 40 years.

SLE may also be caused by certain drugs. Drug-induced lupus erythematosus (DILE) manifests as arthritis and serositis. It is reversible 4 to 6 weeks after stopping medications. The culprits are procainamide HCl, hydralazine, penicillamine, minocycline (anti-acne agent), isoniazid (anti-tuberculosis agent), methyldopa, quinidine, chlorpromazine, diltiazem (considered to be the drug of choice for vasospastic angina and used to control ventricular rate in atrial fibrillation as well as atrial flutter) and anti-TNF (tumor necrosis factor).

SLE: An auto-immune disease

The underlying cause of autoimmune diseases is not fully known. Periods of flare-up and remissions are common. SLE remains a chronic, long-term inflammatory disease. It starts with autoantibodies recruiting the immune system to attack itself. This is termed as a “loss of self-tolerance,” leading ultimately to vasculitis and subsequent organ damage.

According to the American College of Rheumatology, the causes of SLE could be a mix of genetic tendencies and environmental triggers. These include viruses, sunlight and drug allergies. People with lupus may also have an impaired process for clearing old and damaged cells from the body, which causes an abnormal immune response that is chronic in nature. The malar rash is considered pathognomonic. Discoid rash (red, raised) raises suspicion for SLE.

It is believed that SLE has genetic and environmental components that remain chronic long term. According to Hahn and colleagues, the process involves:

• activation of innate immunity (dendritic cells, monocyte/macrophages) by CpG DNA, DNA in immune complexes, viral RNA and RNA in RNA/protein self-antigens;
• lowered activation thresholds and abnormal activation pathways in adaptive immunity cells (T and B lymphocytes);
• ineffective regulatory CD4+ and CD8+ T cells; and
• reduced clearance of immune complexes and of apoptotic cells.

In SLE patients their own antigens are picked up by their immune system constantly, which leads to chronic inflammation and progression of the disease; in essence it is coined as a “loss of self tolerance” process.

Munroe and colleagues evaluated changes in plasma concentrations of soluble mediators (cytokines, chemokines and soluble receptors) preceding clinically defined disease flares. They concluded that pro–inflammatory adaptive cytokines and shed TNF receptors are elevated prior to disease flare, while regulatory mediators are elevated during periods of stable disease. The authors said that alterations in the balance between inflammatory and regulatory mediators may help identify patients at risk of disease flare and help decipher SLE pathogenic mechanisms.

Exams, tests

According to the American College of Rheumatology, any four of the following problems would lead to the diagnosis of SLE, prompting a rheumatologist referral:

• characteristic rashes on skin with exposure to sun are pathognomonic;
• sores in the mouth or nose lasting from a few days to more than a month;
• arthritis: tenderness and swelling lasting for a few weeks in two or more joints;

• lung or heart inflammation: swelling of the tissue lining the lungs (referred to as pleurisy or pleuritis) or the heart (pericarditis), which can cause chest pain when breathing deeply;
• kidney problem: blood or protein in the urine, or tests that suggest poor kidney function (lupus nephritis);
• neurologic problem: seizures, strokes or psychosis (a mental health problem); and
• abnormal blood tests.

Abnormal blood tests may include:

• low blood cell counts: anemia, low white blood cells or low platelets;
• positive antinuclear antibody: referred to as ANA and present in nearly all patients with lupus. However, some patients show false positive values – next tests are then necessary;
• certain antibodies that show an immune system problem: anti-double-strand DNA (called anti-dsDNA), anti-Smith (referred to as anti-Sm) or antiphospholipid antibodies, or a false-positive blood test for syphilis in the absence of the disease; and
• the presence of antiphospholipid antibodies can help doctors detect lupus. These antibodies signal a raised risk of certain complications such as miscarriage, difficulties with memory or blood clots that may lead to stroke or lung injury.

Other tests include CBC, ESR, rheumatoid factor, anticardiolipin, liver function and X-ray. The complement proteins in the blood (C3/C4) are part of the immune system in the blood and help detect and follow up the progress of the disease.

According to Hahn, ANA is the most important autoantibody to detect because the test is positive in more than 95% of patients with SLE, usually at the onset of symptoms. A few patients develop positive ANA within 1 year of symptom onset; repeated testing may, thus, be useful. ANA-negative lupus exists but is rare in adults and is usually associated with other autoantibodies (anti-Ro or anti-DNA). High-titer IgG antibodies to double-stranded DNA (dsDNA), but not to single-stranded DNA, are specific for SLE.

Clinical, ocular manifestations

Clinical manifestations include cutaneous (81% of the cases), musculoskeletal (85% to 95%), cardiopulmonary (33%), renal (77%), gastrointestinal (30%) and neurologic (54%), according to Dall’Era and colleagues. The more severe cases involve multi-organs.

Ocular manifestations include sicca syndrome, conjunctivitis or episcleritis, and Raynaud’s syndrome in 20%.

Anterior segment manifestations are common but not sight threatening, according to Peponis and colleagues. Keratoconjunctivitis sicca (KSC) tops the list, being seen in 25% to 35% of patients.

El-Shereef and colleagues reported a 35% prevalence of ocular lesions in their small sample, with only 25% of patients being symptomatic. Here, too, the most common ocular lesion is sicca syndrome. All lesions correlate well with the severity of the disease activity index. Retinal and optic nerve involvement scored next highest after KSC.

KSC is attributed to the presence of HLA-DRW52 antigen and anti-Ro (SSA) and anti-La (SSB) antibodies. KSC is not necessarily Sjögren’s syndrome although it could present in 8.3% of patients, according to Peponis and colleagues. Lid involvement is seen with discoid lupus erythomatosus. The outer third of the lower lids are involved in 6% of patients, with injection, scarring and loss of pigmentation and eyelashes (madarosis).

Recurrent episcleritis is found in up to 28% of cases, according to Pringle and colleagues, so SLE should be considered in the diagnostic work-up.

Prevalence of retinal involvement is second after KSC (3.3% to 28.1%), according to Peponis and colleagues. It is considered as an immune complex-mediated vasculopathy, but not necessarily vasculitis. It manifests as cotton-wool spots, ischemia of the retinal nerve fiber layer, exudates and hemorrhage, all of which can be seen with other systemic disorders (hypertension, diabetes, etc.). They tend to resolve once the systemic disease is treated.

Retinal disease primarily occurs when the disease is active and manifests as cotton-wool spots in 9.6% of cases (El-Shereef et al.). However, vasculitis and vaso-occlusive phenomena as part of the antiphospholipid antibodies syndrome are harbingers of poor prognosis and survival by affecting the central nervous system (CNS); the optic nerve is not spared in these cases.

According to Tolentino and colleagues, retinal vasculitis is an extremely uncommon manifestation of the classical systemic vasculitides.

Antiphospholipid antibodies are thrombogenic and have been reported with higher incidence in SLE patients with retinal vascular disease, 77% vs. 29%, according to Peponis and colleagues.

SLE can mimic rheumatoid arthritis (RA). The first symptom usually is joint pain in about 90% of SLE patients.

RA is a systemic, chronic inflammatory disease that affects the synovium of the joints as well as the cartilage and bone. Similarly, RA usually presents between the ages of 20 to 40 years old and is more common in women. The etiology of the disease is unknown, but there is some genetic factor here, too.

The likelihood that a first-degree relative of a patient will share the diagnosis of RA is two to 10 times greater than in the general population, according to Shah and colleagues. They also mentioned that even though twin studies imply that these factors can explain about 60% of occurrence of RA, the more common range is 10% to 25%. Variation of the HLA-DRB1 gene located on the major histocompatibility complex was the allele that was most associated with the risk of RA.

Graham and colleagues and Smith and colleagues stated that keratoconjunctivitis sicca is present in 15% of rheumatoid arthritis cases, and that peripheral corneal melting may occur in more severe cases. Some of the more common problems are pleural effusion, rheumatoid nodules (25% with Rh positive), as well as secondary Sjögren’s syndrome. Sicca syndrome and nonspecific conjunctivitis are common in SLE and rarely threaten vision. In contrast, retinal vasculitis and optic neuritis are serious manifestations. It is important to note that HCQ is also used to treat RA.

Treatment for SLE

There is no cure for SLE.

Mild forms of the disease may be treated, in increasing order, with:

• nonsteroidal anti-inflammatory drugs, such as ibuprofen, for joint symptoms such as arthralgia or myalgia and pleurisy;
• corticosteroid creams for skin rashes and avoidance of sun exposure; and
• the antimalarial drug HCQ and low-dose corticosteroids for skin, arthritis symptoms and mild cardiopulmonary manifestation.

Treatments for more severe lupus may include high-dose corticosteroids or medications to decrease the immune system response when active or, once renal, neurologic and hematologic problems manifest. The side effects are multiple: facial swelling, fat redistribution, muscle weakness, hyperglycemia, glucose intolerance (contraindicated in diabetes), hypertension and osteoporosis. Increased intraocular pressure and posterior subcapsular cataract are potential risk factors. Elevated IOP and subsequent glaucoma are related to decreased aqueous outflow secondary to accumulation of mucopolysaccharide extracellularly in the trabecular meshwork. Patients with established glaucoma show a much greater increase in IOP. It is important to note that the side effects of systemic medications usually take longer to manifest than those of topical steroids. Cytotoxic drugs (drugs that block cell growth) can also be used to treat more severe lupus when corticosteroids stop working or when symptoms get worse.

The quinolone family of drugs has long been used as antimalarials. Chloroquine was discovered in 1934 and used as an antimalarial in 1946. Ruiz-Irastorza and colleagues reviewed various randomized controlled studies on treatment with antimalarial drugs between 1982 and 2007. The beneficial and safety profile of HCQ vs. chloroquine was overwhelming. They concluded that HCQ should be given to most patients with SLE during the entire disease course regardless of severity, including during pregnancy. Accordingly, HCQ reduced corticosteroid treatment significantly and reduced flare-ups and nephritis complications, although to a limited extent. In addition, HCQ taken early in the course of the disease might protect against thrombotic events.

HCQ has some beneficial effect against irreversible multi-organ damage and survival rate. Johnson and colleagues, as reported by Ruiz-Irastorza and colleagues, found patients with fine granularity of the macular pigment epithelium in 30% of a small group of patients on high doses of HCQ (over 1 G) for 14.2 years. The previous authors recommend treatment with HCQ as soon as the diagnosis of SLE is made. They considered a maintenance dose of 400 mg/day or less to be safe, given regular ophthalmological examination as recommended by the American Academy of Ophthalmology. To date, there are an estimated 150,000 patients on HCQ.

Concurrently, Wolfe and colleagues said Plaquenil toxicity increases by 2% for every 10 to 15 years of continued use, which makes it safe in the long run. But any damage is irreversible and continues even after drug discontinuation.

Ophthalmic perspectives – more cautions and revisions

Chloroquine was first recognized in 1959 as inducing retinal toxicity. HCQ side effects followed in 1967. The retinal damage with few exceptions is irreversible and bilateral. Peponis and colleagues cited a prevalence of 6.8 out of every thousand people, according to a study of 4,000 patients. A safe dose is accepted to be at 6.5 mg/kg ideal body weight up to a cumulative dose of more than 1,000 G, which is attained in 5 to 7 years. However obese or short stature patients are at risk for overdosing. Therefore, for women, the ideal weight is 100 lb. for 5 feet, plus 5 lb. per extra inch of height. For men, the ideal weight is 110 lb. for 5 feet, plus 5 lb. per extra inch of height.

Risk factors that increase the chance of HCQ retinopathy include daily dosage, cumulative dose, renal or liver disease, age and previous retinal disease.

By contrast and unrelated to the retinal toxicity are deposits of salts in the corneal epithelium (verticillata); they are asymptomatic and wane after stopping the treatment.

Metabolism, mechanism of ocular toxicity

HCQ is cleared by both the kidney and liver, and, therefore, any renal and hepatic impairment can increase the risk for retinal toxicity. Older patients (older than 60 years) may be at increased risk for retinal toxicity. Lastly, previous retinal and macular disease are risk factors, possibly due to slow clearance from the retina and body.

The mechanism of HCQ retinal toxicity has yet to be fully elucidated. Studies have shown that the drug affects the metabolism of retinal cells and also binds to melanin in the RPE, which could explain the persistent toxicity after discontinuation of the medication. However, these findings do not explain the clinical pigmentary changes causing a bull’s-eye maculopathy.

HCQ warnings

In brief, the recommendations advanced by Marmor and sanctioned by the American Academy of Ophthalmology include:

• a baseline examination when the drug is initiated (slit lamp, 10-2 Humphrey field, possibly SD-OCT and mfERG;
• annual screening starting after 5 years of use barring any additional risk factors, including all of the above and possibly autofluorescence within the parafoveal and perifoveal regions (autofluorescence usually indicates accumulation of lipofuscin, and the black area afterwards denotes dead cells at a later stage); and
• by 5 years or a cumulative dose of Plaquenil more than 1,000 G, closer and detailed follow-up and testing are critical because of the irreversible nature of the side effects.

Tests now suggested as inadequate for screening include biomicroscopy alone, fundus photography, time-domain OCT, fluorescein angiography, full-field electroretinogram, Amsler grid, color vision testing and electro-oculogram. Early RPE changes on biomicroscopy are flag points ushering referral and more specific testing.

Complementary, alternative medicine

Cases of refractory cutaneous lupus may respond to a variety of other systemic agents including Dapsone (diaminodiphenylsulfone, Jacobus Pharmaceutical) in limited cases. Trials with thalidomide are fraught with toxicities. Azathioprine and intravenous immune globulin may be beneficial for severe cutaneous disease.

Faced with dire course of the disease and side effects of medications, many people turn to complementary and alternative medicine (CAM). Homeopathy, chiropractic, traditional Chinese medicine (such as acupuncture and tai chi), Ayurveda, naturopathy, massage therapy, meditation, biofeedback, and herbs or other supplements are examples of CAM.

Studies have shown that acupuncture provides relief of acute pain, but there is no scientific evidence that it is effective for chronic pain, such as in SLE (Marcus et al.). Meditation and biofeedback techniques can offer relief from stress and help with pain management. However CAM, in general, lacks scientific testing and clinical research to validate it.

Tai chi in RA has yet to be researched extensively but may have a positive outlook in terms of disability index, vitality and depression index.

A number of herbs and natural supplements also are being studied because they show promise in helping lupus, particularly the herbs that may address inflammation. Based on studies showing the positive effects of a Chinese herb known as thunder god vine (Tripterygium wilfordii), the NIH is studying it.

Patient follow-up

Back to our patient: It was suggested to hold Plaquenil treatment for 3 months and reevaluate. Progression of maculopathy is possible despite cessation of oral medication. However, if the re-testing is stable, Plaquenil can be restarted at a lower dose. The recommended dose should not exceed 6.5 mg of medication/kg of body weight/day, or 390 mg for this patient. Typically, hydroxychloroquine is dosed at 200 mg or 400 mg per day.

Our patient refused to stop hydroxychloroquine use; it seems to have been for good reasons. Hydroxychloroquine is the drug of choice, with life-saving effect. The treatment dose was within the accepted safe range. The maculopathy changes are irreversible and the hope is that they will not progress. There is also a risk of major or minor flare-up of the disease with discontinuation of HCQ treatment. In addition, she is well controlled without having to resort to corticosteroid therapy, which carries its own devastating side effects. Maculopathy is usually rare – not so much if you are the patient that is affected – if the recommended dose of HCQ is used. Objective and subjective methods in OCT, macular visual field and ERG are available today to monitor the patient closely and comanage with the treating rheumatologist.

• References:
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• Dall’Era M et al. Treatment of systemic lupus erythematosus. In: Longo DL, et al., eds. Harrison’s Principles of Internal Medicine. 18th ed. New York, NY: McGraw Hill; 2012.
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• Pringle et al. Ocular disorders associated with systemic diseases. In: Riordan-Eva P, et al., eds. Vaughan & Asbury’s General Ophthalmology, 18th ed. New York, NY: McGraw Hill; 2011.
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• Tolentino M, et al. Retinal vasculitis associated with systemic disorders and infections. http://www.uptodate.com/contents/retinal-vasculitis-associated-with-systemic-disorders-and-infections. Updated Oct. 2, 2014. Accessed June 3, 2015.
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• For more information:
• Joseph Hallak, OD, PhD, is in private practice in Syosset, N.Y. He can be reached at drjhallak@aol.com.
• Guy-Philippe Beauzile, PA-C, can be reached at guybeauzile@gmail.com.

Disclosures: Hallak and Beauzile report no financial disclosures.

Acknowledgment: Our thanks and deep gratitude to retina specialist Rodney Coe, MD, for comanaging our patient and providing pertinent illustrations.