INTRODUCTION — A variety of antimalarial medications have been shown to be effective for systemic rheumatic diseases since quinine was first used to treat systemic lupus erythematosus (SLE) more than 100 years ago. Three of these drugs are now primarily used due to their safety profile.
●Chloroquine and hydroxychloroquine (HCQ) are 4-aminoquinoline derivatives. They are structurally similar, differing only by replacement of an ethyl group in chloroquine with a hydroxyethyl group in HCQ. HCQ comprises 95 percent of all rheumatic disease antimalarial prescriptions.
●Quinacrine (mepacrine) incorporates the chloroquine structure but is a 9-aminoacridine compound. It causes a yellowish skin color with long-term treatment and is no longer commercially available in most settings.
Pharmacokinetics — There are several problems in analysis of the pharmacokinetics of antimalarials:
●Variation from individual to individual is wide.
●Disease states may affect metabolism (eg, increased protein binding in patients with active rheumatoid arthritis [RA]).
Despite these difficulties, it appears that absorption of antimalarial drugs averages around 70 percent and is not affected by diarrhea. The mean absorption half-life is four hours with a lag time of slightly more than 30 minutes . The terminal half-life for chloroquine and HCQ is one to two months .
The (S) enantiomer of HCQ (50 percent of the commercial product) has greater bioavailability but a shorter half-life than the (R) enantiomer and holds promise for formulation as a more potent product with less eye toxicity potential [3,4].
Tissue distribution is wide with accumulation in muscle, liver, spleen, kidney, lung, blood elements, adrenal and pituitary glands, and melanin-containing tissue . Chloroquine binds to corneal tissue more avidly than HCQ .
Steady state antimalarial blood concentrations vary greatly; 94 percent equilibrium is achieved by quinacrine in four weeks compared with 96 percent by HCQ in six months. The major metabolite of chloroquine, desethylchloroquine, can reach blood levels nearly one-half those of the parent compound .
Because of the considerable time required to reach equilibrium, higher (loading) doses have been assessed in patients with RA. Although higher daily doses (up to 1200 mg per day for six weeks) are associated with higher blood concentrations of HCQ and its metabolites and with more rapid onset of beneficial clinical effects, such high-dose regimens are also associated with more frequent adverse gastrointestinal side effects [8,9].
Renal clearance — Excretion of these drugs is principally by direct renal clearance of the parent compound and hepatic metabolites [2,10]. Thus, the drug dose should be reduced in patients with renal insufficiency . We typically reduce the dose of HCQ to 200 mg daily in patients with end-stage kidney disease. Both chloroquine and HCQ can cause a 10 percent decrease in creatinine clearance by competitively inhibiting creatinine secretion; this does not represent a true change in renal function. Antimalarials have been found in the urine five years after medication was stopped .
Drug interactions — Chloroquine phosphate (CP) is metabolized by cytochromes 2D6 and 3A4 and can prolong the QTc interval on the electrocardiogram. In contrast, HCQ is subject to fewer significant pharmacokinetic drug interactions, and most evidence suggests that it has a lower risk of prolonging the QTc interval. Before initiating or altering therapy, specific interactions with other medications should be checked by use of a drug interactions program, such as the Lexicomp drug interactions tool provided by UpToDate. Examples are provided for illustration; this is not an exhaustive list:
●Additive QTc prolongation – CP prolongs the QTc interval, which can rarely lead to a life-threatening arrhythmia, torsade de points; HCQ appears to be relatively lower risk [13-17]. Risk is additive when either is used with other drugs that prolong the QTc interval (eg, other antimalarials [artemether, halofantrine, mefloquine], intravenous [IV] haloperidol); use with drugs that prolong QTc interval (table 1) and also increase chloroquine levels via CYP interactions (eg, clarithromycin, voriconazole) are of greater concern, and such combinations should generally be avoided. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".)
●CYP interactions – CP, but not HCQ, is dependent on CYP2D6 and CYP3A4 hepatic metabolism for clearance; CP levels may be altered when taken with drugs that strongly interact with CYP2D6 or CYP3A4 metabolism; lists of such drugs are provided in the tables (table 2 and table 3).
●Hypoglycemics – HCQ and CP can increase risk of hypoglycemia with antidiabetic agents (eg, sulfonylureas, insulins, others), although this is rarely observed in clinical practice [12,18].
Mechanism of action — Antimalarials have a wide variety of actions, a number of which may be responsible for their immunomodulatory effects [22,23]. The most important mechanisms of action that affect the inflammatory diseases include their effects on the innate immune system and their lysosomotropic actions. Potential mechanisms of action include the following:
●One of the most important actions deals with its actions related to toll-like receptors (TLRs). Cytosine phosphate diester-guanine (CpG) deoxyribonucleic acid (DNA) stimulates cells through TLR-9, which is found in lysosomes. Chloroquines may block costimulation of the B cell antigen receptor and TLR-9 pathways and, thus, may act as an antiinflammatory agent [24,25]. Furthermore, antimalarials can inhibit activation of intracellular TLR-3 and TLR-7 . Finally, HCQ appears to exert an inhibitor effect on TLR signaling . Nucleic acid-sensing TLRs are located intracellularly and are activated by foreign nucleic acids that are presented to them by intermediate molecules, such as Fc-gamma receptors. TLRs are processed by endosomes before becoming active; thus, antimalarial inhibition of endosomal activation inhibits TLR activation. In addition, the binding of nucleic acids to TLR through nucleic acid-binding epitopes is also mechanically inhibited by antimalarial binding that masks these epitopes .
●Another important mechanism appears to be interference with normal physiologic function of subcellular compartments that depend upon an acidic milieu. This effect is termed a "lysosomotropic action" because it was first demonstrated in lysosomes. Antimalarials are weak bases that enter not just lysosomes but all acidic compartments in which they are protonated, that raise the pH, and that interfere with functions dependent upon an acidic pH . Antimalarials antagonize immune stimulation by CpG DNA (a ligand for TLR-9), and chloroquine inhibits immune stimulation by small nuclear ribonucleic acid (RNA; a ligand for TLR-7) and subsequent production of interferon alpha. TLRs require an acidic pH; thus, an increase in lysosomal pH caused by antimalarials may prevent functional transformation of intracellular TLRs and may inhibit their activation.
This mode of action has many secondary effects. It interferes with receptor recycling, intracellular processing, and the secretion of proteins, which leads to a decreased production of cytokines and other inflammatory mediators [11,30-32]. Immune effects include decreased lymphocyte proliferation , interference with natural killer cell activity , and, possibly, alteration of autoantibody production . In addition, antimalarials may influence the binding of autoantigenic peptides to major histocompatibility complex (MHC) class II molecules, thereby interfering with antigen processing and ultimately with the immune response to autoantigens .
●It has also been suggested that decreased secretion of monocyte-derived proinflammatory cytokines may be due to nonlysosomotropic effects of antimalarials. These include a decrease in secretion of tumor necrosis factor (TNF)-alpha by stimulated human peripheral blood-derived mononuclear cells in response to chloroquine, which was associated with decreased amounts of TNF-messenger RNA .
●Other actions may play a role in the antirheumatic activity of antimalarials. Antiinflammatory effects may include inhibiting phospholipases, antagonizing prostaglandin, stabilizing lysosomal membranes, inhibiting T- and B-cell receptor calcium signaling, decreasing fibronectin release by macrophages, blocking superoxide release, and decreasing metalloproteinase production by synoviocytes [34,36-38]. These drugs also block ultraviolet light absorption, an effect that may protect against lupus skin lesions .
ADMINISTRATION, DOSING, AND MONITORING
Preparations — Hydroxychloroquine (HCQ) sulfate is available as a 200 mg tablet. Chloroquine phosphate (CP) is available in 250 mg and 500 mg tablets. Doses in this topic are expressed as hydroxychloroquine sulfate salt and chloroquine phosphate salt, following labeling conventions of North America [12,18]. In some countries outside of North America, chloroquine (and less frequently HCQ) strengths are expressed as base or as another salt form (eg, chloroquine sulfate or hydrochloride), and different tablet strengths may be available.
To avoid a dosing error, locally available product information should be consulted to confirm strength and equivalence for the specific preparation. The following equivalences may be useful:
Some generic preparations of both HCQ and CP come as scored tablets and can be split or cut in one-half. Additional information is available in the Lexicomp drug monographs included within UpToDate for hydroxychloroquine and chloroquine. Quinacrine (mepacrine) is no longer commercially available in most settings [40,41].
Dose adjustment for weight — For patients who require HCQ for the chronic treatment of systemic rheumatic diseases or related conditions, we suggest a maximum daily dose of 5 mg/kg/day of actual body weight. Dosing may be once daily, if tolerated.
Patients who weigh more than 80 kg can receive the standard daily dose of HCQ of 400 mg daily. Tablets may be split or variable dosing (eg, alternating or skipping doses on certain days) may be required to meet the recommended dose limits. Similar demographic data for chloroquine are lacking, but dose comparisons have led to a suggested maximum daily dose of 2.3 mg/kg. These dosing recommendations are in agreement with the revised screening guidelines from the American Academy of Ophthalmology (AAO) and other professional societies [42,43]. Occasionally, there are instances in which short-term use (never exceeding two to three months) of higher doses may be required for better disease control. As an example, a higher dose of HCQ of 7 mg/kg daily (up to 600 mg daily) for several weeks may be helpful for treatment of an acute flare of discoid lesions.
The maximum dose limits for HCQ and chloroquine described above are based on data from a large healthcare organization database in which 2361 HCQ users were identified, all of whom had undergone more sensitive screening methods (ie, central visual field examination or spectral domain optical coherence imaging) for retinopathy . This case-control study found an overall prevalence of HCQ retinopathy of 7.5 percent, which was much higher than the risk of less than 2 percent that had been previously reported, but may be related to more sensitive measurement techniques [45-48]. The risk of retinopathy increased with higher doses of HCQ and longer duration of therapy. In patients treated with 4 to 5 mg/kg, the prevalence of retinal toxicity was less than 2 percent during the first 10 years of therapy, but the risk increased to nearly 20 percent after 20 years of use. The annual risk after an examination showing no evidence of toxicity in patients using no more than 5 mg/kg was less than 1 percent during the first 10 years of use, but rose to almost 4 percent per year after 20 years. The risk of retinopathy was also increased in patients with kidney disease (odds ratio [OR] 2.08, 95% CI 1.44-3.01) and those concurrently taking tamoxifen (OR 4.59, 95% CI 2.05-10.27), which is also retinotoxic. In addition, this study found that dose calculation by real body weight was a better predictor of risk than ideal body weight. It was this study that prompted a renewed concern regarding the appropriate dosing of HCQ, which had been previously recommended by major guideline organizations as being 6.5 mg/kg of ideal body weight (up to a maximum of 400 mg daily) .
Another study of 3325 HCQ users who underwent routine retinal scans found that the overall cumulative incidence of moderate to severe retinopathy at 15 years was 1.1 percent among patients taking 5 mg/kg/day but increased to 5.9 percent among patients taking more than 6 mg/kg/day . The risk of retinopathy was higher among patients who were at least 55 years old or had at least chronic kidney disease (CKD) stage 3 at the time of HCQ initiation.
Monitoring for toxicity — With the exception of routine eye examinations for retinopathy, monitoring for other adverse effects is typically clinical. Otherwise, the relative safety of antimalarials is reflected by the fact that no regular laboratory tests are needed to monitor for other toxicities .
Routine eye examinations — Monitoring patients with routine eye exams is necessary to avoid permanent vision loss, although the incidence of retinal toxicity is reduced through the use of lower doses of medication (see 'Dose adjustment for weight' above). The purpose of screening is to detect retinal toxicity, if it develops, before the vision is affected. The primary screening tests are automated visual fields and spectral domain optical coherence tomography (SD-OCT). Early OCT changes are almost always asymptomatic and may remain so if HCQ is discontinued. Asian and Asian American patients tend to show early damage outside the central macula and can develop serious toxicity before it would be recognized by tests that focus only on the parafovea; thus, imaging studies in this population should examine beyond the central macula [42,52].
We advise assessment of ocular health within a year of starting long-term antimalarial drug therapy. The baseline examination should include a fundus examination of the macula to rule out any underlying disease that may interfere with the interpretation of screening tests. The frequency of subsequent screening during the first five years of treatment may be individualized based upon assessment of risk. We prefer annual screening exams for all patients, but the AAO has suggested that for patients with a normal baseline exam who do not have major risk factors for toxic retinopathy, follow-up examinations may be deferred until there have been five years of exposure . Major risk factors for toxic retinopathy include a daily dose of HCQ greater than 5 mg/kg real body weight or a daily dose of chloroquine greater than 2.3 mg/kg real body weight, antimalarial use for greater than five years, the presence of renal disease, concomitant tamoxifen use, and/or the presence of macular disease. Patients should be alert for any change in visual acuity and should seek medical attention promptly if any visual loss is noted. Antimalarials should be discontinued immediately if there is any suspicion of retinopathy. Additional details regarding the potential adverse ocular effects associated with antimalarials are discussed further below. (See 'Ocular effects' below.)
Indirect evidence from limited observational data suggest that early screening for HCQ toxicity can reduce the risk of losing visual acuity. A study of 22 patients with different degrees of HCQ retinopathy reported a range of changes during follow-up after cessation of HCQ whose magnitude correlated with retinopathy severity at the time of cessation . The eyes with the least severe retinopathy at the time of drug cessation demonstrated a low likelihood of progression and there was even some functional and structural improvement in some cases. Eyes with more severe retinopathy, however, demonstrated progressive deterioration of retinal structures and a decline in function even years after cessation of the drug. Another small study with 11 patients with different degrees of HCQ retinopathy also detected a similar pattern in which less severe retinopathy demonstrated little progression during the follow-up period, in contrast with more severe retinopathy that continued to progress during the three-year follow-up period .
Our approach to monitoring for retinal toxicity is generally consistent with that of major professional societies .
Limited role of blood level testing — There are available laboratory tests to check levels of HCQ and its metabolites, but the role of routine testing in clinical care is somewhat uncertain.
Adherence monitoring — There has been an increased interest in blood level testing to identify patients who are nonadherent. An undetectable serum HCQ level indicates that the patient is not taking the drug. Nonadherence is a known challenge following patients with systemic rheumatic diseases. Adherence in systemic lupus erythematosus (SLE) has been estimated to be as low as 20 percent in some studies [55,56]. The impact of blood HCQ concentrations on efficacy was evaluated in a prospective six-month study of 143 patients who received 400 mg per day . Patients with active disease were found to have lower blood levels. These results were supported by additional reports in which low blood concentrations of HCQ were markers for and predictors of disease flares in patients with SLE [57-61]. In one study, in which adherence was defined as the presence of a therapeutic drug level (at least 500 ng/mL), the measurement of the HCQ blood level, together with counseling regarding dosing and repeated testing, resulted in an increase in adherence from 56 percent (at baseline) to 80 percent (after three or more visits at which levels were assessed) .
Dose adjustment — In the future, monitoring of whole blood HCQ levels may be used to adjust HCQ dosing. The same dose of HCQ may lead to different serum HCQ levels due to variations in how the drug is metabolized. One study of 537 patients with SLE indicated that both the mean and maximum whole blood HCQ levels correlate with the risk of developing HCQ retinopathy . In this cohort, 6.7 percent of patients with a HCQ level greater than 1753 ng/mL developed HCQ retinopathy. However, only 1.2 percent of patients with a HCQ level less than 1182 ng/mL developed HCQ retinopathy. A meta-analysis representing 1233 patients indicated that a HCQ level greater than 750 ng/mL was associated with a 58 percent lower risk of active disease . Taken together, these studies imply HCQ dosing may be individualized to minimize the risk of HCQ toxicity while retaining the therapeutic benefits of this drug.
NONINFECTIOUS INDICATIONS FOR ANTIMALARIALS
●Treatment of specific systemic rheumatic diseases – The immunoregulatory and antiinflammatory properties of antimalarials have been effective in the treatment of various systemic rheumatic disease. As an example, antimalarials are used to treat certain non-life-threatening manifestations of systemic lupus erythematosus (SLE) and patients with mild or moderately active rheumatoid arthritis (RA). Information regarding the effectiveness and safety of these agents in the treatment of other rheumatic disorders and of musculoskeletal and cutaneous manifestations is discussed in the management sections that deal with treatment of the specific diseases, several of which are listed here:
•Sjögren's disease (see "Treatment of dry mouth and other non-ocular sicca symptoms in Sjögren’s disease", section on 'Systemic antiinflammatory and immunosuppressive therapy' and "Treatment of Sjögren’s disease: Constitutional and non-sicca organ-based manifestations", section on 'Conventional immunosuppressive drugs and nonbiologic DMARDs')
•Antiphospholipid syndrome (see "Management of antiphospholipid syndrome", section on 'Other treatment considerations')
•Cutaneous dermatomyositis (see "Cutaneous dermatomyositis in adults: Overview and initial management", section on 'Hydroxychloroquine')
•Palindromic rheumatism (see "Clinical manifestations of rheumatoid arthritis", section on 'Palindromic rheumatism')
●Other beneficial properties – Antimalarials have also been found to have favorable metabolic and antithrombotic effects .
•Metabolic effects – Limited data have shown that antimalarial agents favorably affect serum lipid concentrations as well as blood glucose. As an example, when fasting lipid profiles were assessed in 123 patients with SLE (nearly one-half of whom were taking antimalarials), the mean serum concentrations of total, low density, and very low density cholesterol were significantly lower in those taking antimalarials (12, 16, and 22 percent less than patients not taking these agents, respectively) . High density cholesterol levels are unaffected by antimalarial use [64,65].
A small randomized trial indicated that hydroxychloroquine (HCQ) improves glycemic control in patients with type 2 diabetes mellitus who are refractory to treatment with sulfonylureas . These data were supported by a large observational study from the Arthritis, Rheumatism, and Aging Medical Information System (ARAMIS) database that reported a reduced risk of diabetes mellitus among patients who received HCQ for RA compared with those who did not .
•Antithrombotic effects – HCQ is also a mild anticoagulant. It inhibits platelet aggregation and adhesion without altering the bleeding time, and its use is not associated with increased bleeding . It may decrease the risk of thrombotic events in patients with SLE [68-70], which may be mediated through protecting the annexin A5 anticoagulant shield . It also has a weak inhibitory effect on acetylcholinesterase; a resulting increase in synaptic transmission at neuroglandular sites may contribute to stimulation of salivary flow in Sjögren's disease .
ADVERSE EFFECTS — Antimalarials are among the safest medications used for the treatment of systemic rheumatic diseases . Serious side effects are extremely rare. The most common adverse reactions are related to the gastrointestinal tract, skin, and central nervous system (CNS). The fear of vision-threatening toxic retinopathy remains a major concern, although this can be avoided when using the appropriate doses along with routine ocular monitoring.
Gastrointestinal involvement — Gastrointestinal upset is the most common side effect necessitating discontinuation of antimalarials . It is more common with chloroquine than with hydroxychloroquine (HCQ), even at doses of relatively equal efficacy (eg, 250 mg and 400 mg, respectively) . Nausea is most common; it may be so severe that the patient does not wish to eat. Vomiting and diarrhea may also occur.
The gastrointestinal side effects are, in part, related to muscular effects that cause abdominal cramps. The antimalarials do not cause ulcer formation or life-threatening gastrointestinal complications. It may be possible to lessen these problems by taking the medication at bedtime. Alternatively, decreasing the dose to one half-pill daily or every other day, and then gradually increasing the dose every one to two weeks as tolerated, may result in improved patient tolerance. Some clinicians routinely start at one pill of HCQ daily (200 mg) and raise the dose after a week or two if it is well tolerated, as a way to minimize gastrointestinal side effects. Hepatotoxicity due to antimalarial agents is rare .
Skin changes — A dermatologic reaction occurs in approximately 10 percent of patients treated with chloroquine or HCQ. The lesions may be of almost any type and are allergic in nature. They most frequently appear as pruritic maculopapular lesions. It may be feasible to reintroduce antimalarial therapy to patients with drug hypersensitivity reactions using a slow oral desensitization regimen .
Patients receiving long-term therapy with chloroquine or HCQ may develop hyperpigmentation, usually involving the oral mucosa, shins, nails, and forearms . They can also develop hyper- or hypopigmentation of the hair and oral mucosa. The development of pigmented lesions appears to be more frequent in patients with conditions associated with easy bruising (eg, use of anticoagulants or antiplatelet agents) and usually preceded by local ecchymotic changes [78,79]. As noted above, quinacrine causes a reversible yellowing of the skin in most patients. In addition, some patients develop black and blue marks on the palate .
There have been conflicting reports regarding the safety of HCQ among patients with psoriatic skin lesions. While some case reports have suggested that HCQ is associated with exacerbations of psoriatic skin lesions, subsequent reports have found HCQ to be well-tolerated in patients with psoriasis .
Central nervous system involvement — CNS side effects are usually not severe. Headaches are most common, followed by lightheadedness . Both of these effects may disappear spontaneously within several weeks, although a temporary daily dose reduction may be needed.
Other problems include tinnitus, insomnia, and increased nervousness. Rare complications include psychosis and convulsions [11,82].
Neuromuscular toxicity — Antimalarial drugs used in the treatment of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) have been reported to cause a toxic neuropathy, drug-induced skeletal myopathy, cardiomyopathy, and rarely, cardiac arrhythmias [83-88]. Myopathy is a rare complication of these drugs; one study estimated the incidence to be 1 in 100 patient-years, although this has not been confirmed by others . Most of the case reports of myopathy have involved CP, but HCQ has also been implicated . A more detailed discussion of the myopathy associated with antimalarials is presented elsewhere. (See "Drug-induced myopathies", section on 'Chloroquine/hydroxychloroquine'.)
Cardiotoxicity — Cardiac conduction abnormalities, cardiomyopathy resulting in heart failure, and sudden cardiac arrest have occurred rarely in patients receiving long-term oral therapy with chloroquine phosphate (CP) and hydroxychloroquine (HCQ) for rheumatic diseases [91-93]. Long-term use of CP or HCQ has been recognized as a potential cause of direct myocardial injury and/or worsening clinical status in patients with pre-existing heart disease . Depending upon the severity of the underlying cardiac disease, we generally avoid or use these agents with caution in patients with underlying heart disease and monitor all patients on long-term therapy for signs and symptoms of cardiac compromise. The risk of cardiomyopathy associated with the use of antimalarials is discussed in more detail separately. (See "Drug-induced myopathies", section on 'Chloroquine/hydroxychloroquine'.)
As discussed above, both CP and HCQ have been associated with QTc interval prolongation, torsades de pointes, and ventricular arrhythmias. The risk of QTc prolongation appears to be greater with CP compared with HCQ [16,94,95], particularly if CP is administered at high doses or in patients taking other QT-prolonging medications (table 1) or drugs that may elevate CP levels. Fatal cases have been reported. Thus, CP and HCQ should be avoided in patients with congenital long QT syndrome, persistent corrected QT measurements >500 milliseconds, bradycardia, a history of ventricular arrhythmias, uncorrected hypokalemia and/or hypomagnesemia, recent myocardial infarction, or uncompensated heart failure; for patients taking other drugs that prolong the QT interval or elevate CP levels, consideration should be given to discontinuing these other drugs, as well as the benefit of adding CP or HCQ versus the risk of toxicity, prior to initiating therapy. (See 'Drug interactions' above and "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management", section on 'Precautions for any patient starting QT-prolonging drugs'.)
Ocular effects — Serious ophthalmologic toxicity is relatively rare if the patient is periodically monitored but remains the most feared adverse effect of antimalarial drugs since it can result in loss of vision. The two main ocular toxicities of antimalarials relate to the cornea (always reversible) and retinopathy (irreversible).
Retinopathy — As mentioned above, vision-threatening toxic retinopathy is the most important ophthalmologic complication of antimalarial therapy . The exact mechanism in which HCQ and chloroquine can lead to retinopathy is not entirely clear . It had been hypothesized that antimalarials bind to melanin in the retinal pigment epithelium (RPE), an effect that may damage the overlying photoreceptors and may lead to permanent vision loss. It is still a matter of debate as to whether the primary effect of the antimalarials occurs at the level of the RPE or the photoreceptors.
Estimates of risk are higher than previously thought due to the availability of more sensitive screening methods. The risk of retinopathy also appears to increase with higher doses and a longer duration of therapy [44,45]. This is discussed in detail above. (See 'Dose adjustment for weight' above.)
The earliest retinal abnormalities are asymptomatic and can only be detected by ophthalmologic examination. These "premaculopathy" changes consist of macular edema, increased pigmentation, increased granularity, and loss of the foveal reflex. Subtle functional loss in the paracentral retina can occur before biomicroscopic changes in the RPE [98-100]. Detection of changes at this stage, using techniques such as spectral domain optical coherence tomography (SD-OCT) and multifocal electroretinography, is desirable since such changes are likely to stabilize without loss of visual acuity and, in some cases, retinopathy may be completely reversible upon discontinuation of the medication [54,101]. With the advanced electrophysiological screening methods, up to 7 percent of patients taking HCQ have retinal changes after five years of use . These are rarely symptomatic but may require alterations in the dosing regimen and drug discontinuation.
More advanced macular disease, a true retinopathy, is characterized by a central patchy area of depigmentation of the macula surrounded by a concentric ring of pigmentation, a "bull's eye" lesion. Symptoms at this stage are generally not reversible and may include a dropout of letters from words when reading, photophobia, blurred distance vision, reduced night vision, visual field defects, and flashing lights [36,102]. Severe retinopathy, including RPE damage, has been shown on SD-OCT to progress for at least three years following drug discontinuation ; depigmentation and functional loss may continue for one year or more after the drug has been stopped .
In addition to the typical parafoveal (bulls-eye) changes, many patients with HCQ toxicity have a mixed pattern that also includes pericentral (arcade region) changes, and some patients only exhibit a pericentral pattern of damage, with changes limited to the periphery of the field examined by usual screening techniques . A mixed pattern of damage or changes in the pericentral pattern alone are especially common among those of Asian ancestry [52,103].
Corneal deposits — Deposits of the drug or metabolites on the cornea are related to high daily doses. This effect is more common with chloroquine, although the incidence per daily dose is not known . Corneal deposits are rare with HCQ at a dose of 400 mg/day. The deposits do not affect vision but can create transient halos or heightened light sensitivity, and they are reversible upon discontinuation of the medication.
Other — Rare toxicities include agranulocytosis and aplastic anemia with chloroquine and quinacrine; there has never been a report of this occurring with HCQ in doses less than 7 mg/kg/day. Fatal accidental overdose has occurred in children under age six who ingested one or two tablets of chloroquine; doses of >10 mg/kg of chloroquine require medical attention . Despite older reports suggesting otherwise, most experts consider the use of HCQ at usual therapeutic doses to be safe in patients with Class II and III glucose-6-phosphate dehydrogenase (G6PD) deficiency based on available data .
PREGNANCY AND LACTATION — The safety of antimalarials when used during pregnancy and lactation in women with rheumatic disease is discussed in detail separately. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Hydroxychloroquine'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Side effects of anti-inflammatory and anti-rheumatic drugs".)
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●Beyond the Basics topics (see "Patient education: Rheumatoid arthritis symptoms and diagnosis (Beyond the Basics)" and "Patient education: Rheumatoid arthritis treatment (Beyond the Basics)" and "Patient education: Disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●The immunoregulatory and antiinflammatory properties of the antimalarials hydroxychloroquine (HCQ) and chloroquine have been effective in the treatment of various systemic rheumatic disease and related conditions. (See 'Noninfectious indications for antimalarials' above.)
●Excretion of the parent compound and hepatic metabolites is principally by direct renal clearance; dose reduction is appropriate for patients with impaired renal function. (See 'Renal clearance' above.)
●Many effects of antimalarial drugs have been documented. While it is unclear which is most important, blocking proinflammatory pathways is a common theme. (See 'Mechanism of action' above.)
●For patients who require HCQ for the treatment of systemic rheumatic diseases or related conditions, we suggest a daily dose of 5 mg/kg/day of actual body weight (maximum 400 mg/day) (Grade 2C). Tablets may be split or variable dosing (eg, alternating or skipping doses on certain days) may be required to meet the recommended dose limits. Patients who weigh more than 80 kg can receive the standard daily dose of HCQ of 400 mg daily. Although comparable data for chloroquine are lacking, dose comparisons have led to a suggested maximum daily dose of 2.3 mg/kg. (See 'Dose adjustment for weight' above.)
●We advise assessment of ocular health within one year of starting long-term antimalarial drug therapy. The baseline examination should include a fundus examination of the macula to rule out any underlying disease that may interfere with the interpretation of screening tests. The frequency of screening during the first five years of treatment should be individualized based upon assessment of risk. At least annual screening should be performed for patients receiving treatment for more than five years. Patients should be alert for any change in visual acuity and should seek medical attention promptly if any visual loss is noted. (See 'Routine eye examinations' above.)
●Antimalarials are among the safest medications used for the treatment of systemic rheumatic diseases. Serious side effects are rare. The most common adverse reactions are related to the gastrointestinal tract, skin, and central nervous system (CNS). The fear of vision-threatening toxic retinopathy remains the most serious concern. (See 'Adverse effects' above.)
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