Version July 2025
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) in the 1890s [1]. Three of these drugs are now primarily used due to their safety profile.
●Chloroquine phosphate (CP) and hydroxychloroquine (HCQ) are 4-aminoquinoline derivatives. They are structurally similar, differing only by replacement of an ethyl group in CP with a hydroxyethyl group in HCQ. HCQ comprises 95 percent of all rheumatic disease antimalarial prescriptions.
●Quinacrine (mepacrine) incorporates the CP 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.
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 rheumatic disorders is discussed separately under the respective management sections for specific diseases, several of which are listed here:
•RA (see "Initial treatment of rheumatoid arthritis in adults")
•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 "Antiphospholipid syndrome: Management", 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')
Hydroxychloroquine (HCQ) is also used during pregnancy for the prevention of congenital heart block in certain clinical scenarios (eg, patients who have another child with cardiac-neonatal lupus). (See "Pregnancy in women with systemic lupus erythematosus", section on 'Patients with anti-Ro/La antibodies' and "Neonatal lupus: Management and outcomes", section on 'Prevention of NL in subsequent pregnancies'.)
●Other beneficial properties – Antimalarials have also been found to have favorable metabolic and antithrombotic effects [2].
•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) [3]. High density cholesterol levels are unaffected by antimalarial use [3,4].
A small randomized trial indicated that HCQ improves glycemic control in patients with type 2 diabetes mellitus who are refractory to treatment with sulfonylureas [5]. 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 [6].
•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 [7]. It may decrease the risk of thrombotic events in patients with SLE [8-10], which may be mediated through protecting the annexin A5 anticoagulant shield [11]. 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 [12].
PHARMACOLOGY
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]).
●Metabolic differences between agents can be seen even with compounds as structurally similar as chloroquine phosphate (CP) and hydroxychloroquine (HCQ).
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 [13]. The terminal half-life for CP and HCQ is one to two months [14].
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 [15,16].
Tissue distribution is wide with accumulation in muscle, liver, spleen, kidney, lung, blood elements, adrenal and pituitary glands, and melanin-containing tissue [17]. CP binds to corneal tissue more avidly than HCQ [18].
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 CP, desethylchloroquine, can reach blood levels nearly one-half those of the parent compound [19].
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 [20,21].
Renal clearance — Excretion of these drugs is principally by direct renal clearance of the parent compound and hepatic metabolites [14,22]. Thus, the drug dose should be reduced in patients with kidney function impairment [14]. We typically reduce the dose of HCQ to 200 mg daily in patients with end-stage kidney disease. Both CP and HCQ can cause a 10 percent decrease in creatinine clearance by competitively inhibiting creatinine secretion; this does not represent a true change in kidney function. Antimalarials have been found in the urine five years after medication was stopped [23].
Drug interactions — 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 drug interactions program provided by UpToDate. Examples are provided for illustration; this is not an exhaustive list:
●Antacids – The oral bioavailability of CP is reduced when taken with antacids (eg, calcium carbonate); separate administration by four or more hours [24].
●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 [25-29]. 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 CP 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 [24,30].
●Other – HCQ and CP can increase cyclosporine and digoxin levels [31-33].
Mechanism of action — Antimalarials have a wide variety of actions, a number of which may be responsible for their immunomodulatory effects [2,34]. 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:
●Interaction with toll-like receptors – 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 [35,36]. Furthermore, antimalarials can inhibit activation of intracellular TLR-3 and TLR-7 [37]. Finally, HCQ appears to exert an inhibitor effect on TLR signaling [38]. 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 [39].
●Interference with subcellular compartment function – 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 [7]. Antimalarials antagonize immune stimulation by CpG DNA (a ligand for TLR-9), and CP 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 [23,40-42]. Immune effects include decreased lymphocyte proliferation [23], interference with natural killer cell activity [23], and, possibly, alteration of autoantibody production [43]. 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 [44].
●Other proposed mechanisms – 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 CP, which was associated with decreased amounts of TNF-messenger RNA [45].
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 [44,46-48]. These drugs also block ultraviolet light absorption, an effect that may protect against lupus skin lesions [49].
ADMINISTRATION, DOSING, AND MONITORING
Preparations — Hydroxychloroquine (HCQ) sulfate is available in 100, 200, 300, and 400 mg tablets. Chloroquine phosphate (CP) is available in 250 and 500 mg tablets. Doses in this topic are expressed as HCQ sulfate salt and CP salt, following labeling conventions of North America [24,30]. In some countries outside of North America, CP (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:
●HCQ sulfate 200 mg salt contains 155 mg of HCQ base [30]
●CP 500 mg salt contains 300 mg chloroquine base [24]
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 drug monographs included within UpToDate for HCQ and CP. Quinacrine (mepacrine) is no longer commercially available in most settings [50,51].
Dosing — Typical dosing of HCQ and CP is outlined below, as well as recommended dosing adjustment based on weight and HCQ blood levels. While serious adverse effects are rare, dose adjustment can help minimize the risk of complications (eg, retinopathy).
●Hydroxychloroquine – Typical daily dosing of HCQ for treatment of rheumatic diseases is between 200 and 400 mg. Dosing may be once daily, if tolerated, or in two divided doses to minimize adverse effects such as stomach upset. When dosing HCQ, we adjust the daily dose based on actual body weight (maximum daily dose of 5 mg/kg/day, up to 400 mg) and/or HCQ blood levels (within therapeutic range) when available to minimize the risk of toxicity.
•Dose adjustment for weight – The daily dose of HCQ should be adjusted based on the patient's actual body weight. Most patients should not receive a daily dose >5 mg/kg/day using actual body weight or 400 mg, whichever is lower, due to the low but serious risk of retinal toxicity. To meet the recommended weight-based dose limit, tablets may be split or given with variable dosing (eg, alternating or skipping doses on certain days so the average daily dose over the week is ≤5 mg/kg/day). The weight-based dosing recommendations are in agreement with the revised screening guidelines from the American Academy of Ophthalmology (AAO) and other professional societies [52,53].
Occasionally, there are instances in which short-term use (never exceeding two to three months) of higher doses of HCQ may be required for better disease control. As an example, a higher dose of HCQ of up to 600 mg daily (7 mg/kg/day) for several weeks may be helpful for treatment of an acute flare of discoid lupus erythematosus lesions.
The maximum weight-based dose limits for HCQ are based on an analysis of 2361 HCQ users from a large health care organization database, all of whom had undergone sensitive screening methods (ie, central visual field examination or spectral domain optical coherence imaging) for retinopathy [54]. The overall prevalence of HCQ retinopathy was 7.5 percent. The risk of retinopathy increased with higher daily doses of HCQ (odds ratio [OR] 5.67, 95% CI 4.14-7.79 for >5 mg/kg/day) and longer duration of therapy (OR 3.22, 95% CI 2.20-4.70 for >10 years). Using actual body weight to adjust the dose of HCQ was a better predictor of risk than ideal body weight. The risk of retinopathy was further increased for patients with comorbid kidney disease or concurrent tamoxifen use (OR 2.08, 95% CI 1.44-3.01 and OR 4.59, 95% CI 2.05-10.27, respectively).
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 [55]. The risk of retinopathy was higher among female patients and among those who were at least 55 years old or had at least chronic kidney disease stage 3 at the time of HCQ initiation [55,56].
•Dose adjustment based on blood level testing – If available, monitoring of whole blood HCQ levels may be used to adjust HCQ dosing to ensure that the blood level within the therapeutic range; the range may vary by assay but is generally between 500 and 2000 ng/mL [57]. Dose adjustment based on blood level testing may be more accurate than weight-based dosing in certain clinical situations, such as in patients with body mass indices >30 mg/m2 or those with nephrotic syndrome [58]. Blood levels of HCQ are most accurate when patients have been taking HCQ daily for three to six months. They can be checked once or twice a year or more frequently for large fluctuations in weight (eg, >10 kg).
There is evidence that patients with blood levels of HCQ above the therapeutic range have an increased risk of toxicity, while patients with levels within the therapeutic range have better disease control [59-61]. One study of 537 patients with systemic lupus erythematosus (SLE) indicated that both the mean and maximum whole blood HCQ levels correlate with the risk of developing HCQ retinopathy [59]. In this cohort, 6.7 percent of patients with a HCQ level greater than 1753 ng/mL developed HCQ retinopathy, while only 1.2 percent of patients with a HCQ level less than 1182 ng/mL did. For patients who are in the therapeutic range, 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 [60]. 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.
●Chloroquine phosphate – We adjust the dose of CP to be less than 2.3 mg/kg/day. This threshold is extrapolated from studies of HCQ discussed above and is consistent with recommendations issued by the AAO [52]. Blood levels are not typically available for CP.
Monitoring for toxicity — Antimalarials are among the safest medications used for the treatment of systemic rheumatic diseases but do still require monitoring for the development of various toxicities. Monitoring for adverse effects is typically done clinically through routine assessment of patient symptoms and physical examination. In addition, routine eye examinations are performed in all patients to screen for retinopathy, and electrocardiograms are obtained in selected patients to evaluate for QTc prolongation. Laboratory tests are typically not needed to monitor for other toxicities [62] but are often indicated to monitor the condition being treated.
Routine eye examinations for all patients — Monitoring patients with routine eye examinations is necessary to avoid permanent vision loss, although the incidence of retinal toxicity is reduced when medication doses are appropriately adjusted (see 'Dosing' above). The purpose of screening is to detect potential retinal toxicity before it affects vision. Early spectral domain optical coherence tomography (SD-OCT) changes are almost always asymptomatic and may remain so if HCQ is discontinued.
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 primary screening tests are automated visual fields and SD-OCT. Imaging studies for patients identifying as Asian or Asian American should examine beyond the central macula, as early damage outside the central macula has been reported in this population and would be missed by tests that focus only on the parafovea [52,63].
The frequency of subsequent screening during the first five years of treatment may be individualized based upon assessment of risk. We prefer annual screening examinations for all patients, but the AAO has suggested that for patients with a normal baseline examination who do not have major risk factors for toxic retinopathy, follow-up examinations may be deferred until there have been five years of exposure [52]. Major risk factors for toxic retinopathy include a daily dose of HCQ greater than 5 mg/kg actual body weight or a daily dose of CP greater than 2.3 mg/kg actual body weight, antimalarial use for greater than five years, the presence of kidney 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; the magnitude of changes correlated with the severity of retinopathy at the time of cessation [64]. 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. However, eyes with more severe retinopathy 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 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 [65].
Our approach to monitoring for retinal toxicity is generally consistent with that of major professional societies [53].
Electrocardiograms in selected patients — Cardiac conduction abnormalities, including acquired long QT syndrome, have been reported in patients taking CP and HCQ [66]. This issue was highlighted when QTc prolongation was reported in patients who received higher doses of HCQ (eg, 600 to 800 mg/day) as a potential treatment for coronavirus disease 2019 (COVID-19); HCQ was subsequently shown to be ineffective for the treatment of COVID-19 [67]. However, these potential toxicities are rare among patients with rheumatic disease taking typical doses of HCQ who do not have concomitant cardiac disease. In patients with certain preexisting cardiac conditions (eg, congenital long QT syndrome, recent myocardial infarction), CP and HCQ should be avoided. (See 'Contraindications' below.)
We do not routinely obtain electrocardiograms to screen for QTc prolongation in most patients. For patients who are taking other medications that may prolong the QTc interval (table 1) or who have positive anti-Ro (SSA) antibody [68,69], we obtain a baseline electrocardiogram prior to initiating therapy with CP or HCQ. We also check a repeat electrocardiogram after three to six months of therapy and with any subsequent clinical changes that may impact the QTc interval (eg, changing the dose of a QTc-prolonging medication). In addition, we clinically monitor all patients on long-term therapy for signs and symptoms of cardiac compromise. This approach can also be used for patients starting CP who are on a medication that can elevate CP levels. (See 'Drug interactions' above.)
Monitoring adherence — When patients who are taking HCQ have persistent disease activity, it is important to assess adherence. Checking blood levels of HCQ can be helpful in this process, since an undetectable serum HCQ level indicates that the patient is not taking the drug. Adherence is a common challenge for patients with rheumatic disease [70,71]. A general approach to assessing adherence to therapy for patients with SLE is discussed in detail elsewhere. (See "Lupus nephritis: Treatment of focal or diffuse lupus nephritis resistant to initial therapy", section on 'Assess patient adherence to therapy'.)
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 [72]. 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, new-onset lupus nephritis, and/or disease damage in patients with SLE [72-77]. 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) [74].
CONTRAINDICATIONS —
Antimalarial medications should be avoided or used with caution in patients with the following preexisting conditions:
●Retinopathy – We avoid hydroxychloroquine (HCQ) and chloroquine phosphate (CP) in patients with preexisting retinopathy due to the rare but serious risk of retinal toxicity and difficulty monitoring for superimposed retinopathy due to HCQ or CP. (See 'Retinopathy' below.)
●Patients with underlying heart disease – We avoid using CP and HCQ or use them with caution in patients with underlying heart disease, depending on the disease severity, due to the rare risk of cardiotoxicity. (See 'Cardiotoxicity' below.)
●Patients with or who are at high risk of developing QTc prolongation – We avoid using CP and HCQ in patients with congenital long QT syndrome, persistent corrected QT measurements >500 milliseconds, bradycardia, a history of clinically significant ventricular arrhythmias, uncorrected hypokalemia and/or hypomagnesemia, recent myocardial infarction (ie, within the past six months), and/or uncompensated heart failure. This is due to the risk of QTc prolongation when taking antimalarials. Notably, when patients taking HCQ or CP develop such conditions, drug concentrations will persist for up to several months even if the medication is discontinued. (See 'Drug interactions' above and "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management", section on 'Precautions for any patient starting QT-prolonging drugs'.)
ADVERSE EFFECTS —
Antimalarials are among the safest medications used for the treatment of systemic rheumatic diseases [78]. 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 concern, although the risk of this complication can be minimized by appropriately adjusting the dose and performing routine ocular monitoring. (See 'Dosing' above and 'Routine eye examinations for all patients' above.)
Gastrointestinal involvement — Gastrointestinal upset related to antimalarials most commonly includes nausea, which may be severe, and less commonly vomiting and/or diarrhea. This type of adverse effect is more common with chloroquine phosphate (CP) than with hydroxychloroquine (HCQ), even at doses of relatively equal efficacy (eg, 250 mg and 400 mg, respectively) [79]. Gastrointestinal adverse effects are the most common side effect necessitating discontinuation of antimalarials [80]; as an example, in a retrospective study of 156 patients with systemic lupus erythematosus (SLE) who had received HCQ, 7 percent discontinued therapy due to adverse gastrointestinal effects [81].
The gastrointestinal side effects are partially 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 [82].
Skin changes — A dermatologic reaction occurs in approximately 10 percent of patients treated with CP or HCQ. The lesions may be of almost any type and are allergic in nature. They most frequently appear as pruritic maculopapular lesions, although patients may also experience pruritus without visible skin lesions. It may be feasible to reintroduce antimalarial therapy to patients with drug hypersensitivity reactions using a slow oral desensitization regimen [83].
Patients receiving long-term therapy with CP or HCQ may develop hyperpigmentation, usually involving the oral mucosa, shins, nails, and forearms [84]. 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 [84,85]. 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 [86].
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 [87].
Central nervous system involvement — CNS side effects are usually not severe. Headaches are most common, followed by lightheadedness [79]. 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 [23,88].
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 [89-94]. 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 [95]. Most of the case reports of myopathy have involved CP, but there is also a case report of HCQ myopathy [96]. A more detailed discussion of the myopathy associated with antimalarials is presented elsewhere. (See "Drug-induced myopathies", section on 'Chloroquine/hydroxychloroquine'.)
Cardiotoxicity — Rarely, cardiac conduction abnormalities, cardiomyopathy resulting in heart failure, and sudden cardiac arrest have occurred in patients receiving long-term oral therapy with CP and HCQ for rheumatic diseases [97-99]. Conduction abnormalities include QTc interval prolongation, torsades de pointes, and ventricular arrhythmias. The risk of QTc prolongation appears to be greater with CP compared with HCQ [28,100,101], particularly if CP is administered at high doses or with other medications that prolong the QTc interval (table 1) or elevate CP levels. Fatal cases have been reported. 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 preexisting heart disease [99]. The risk of cardiomyopathy associated with the use of antimalarials is discussed in more detail separately. (See "Drug-induced myopathies", section on 'Chloroquine/hydroxychloroquine'.)
We avoid using HCQ and CP in patients with certain preexisting cardiac conditions, as outlined above. (See 'Contraindications' above.)
For patients taking antimalarial drugs with 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. These patients may also benefit from additional monitoring if CP or HCQ are used. (See 'Electrocardiograms in selected patients' above.)
Ocular effects — While serious ophthalmologic toxicity related to CP and HCQ can result in vision loss, this complication is relatively rare and the risk can be minimized with appropriate dose adjustment and routine ocular monitoring. The two main ocular toxicities of antimalarials relate to the cornea (always reversible) and retinopathy (irreversible).
Retinopathy — As mentioned above, irreversible, vision-threatening toxic retinopathy is the most important ophthalmologic complication of antimalarial therapy [102]. 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 [54,103], which is discussed in detail above. (See 'Dosing' above.)
Typical symptoms and progression of retinopathy depend on the stage at which it is diagnosed:
●Early retinal changes – The earliest retinal abnormalities are asymptomatic and can only be detected by ophthalmologic examination by using techniques such as spectral domain optical coherence tomography (SD-OCT) and multifocal electroretinography. Up to 7 percent of patients taking HCQ have retinal changes after five years of use when using these screening techniques [54]. Importantly, early retinal changes are rarely symptomatic, are likely to stabilize without loss of visual acuity, and may be completely reversible in some cases upon discontinuation of the medication [65,104]. Subtle functional loss in the paracentral retina can occur before biomicroscopic changes in the RPE [105-107].
●Retinopathy – 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 (ie, 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 [46,108]. Severe retinopathy, including RPE damage, has been shown on SD-OCT to progress for at least three years following drug discontinuation [65]; depigmentation and functional loss may continue for one year or more after the drug has been stopped [109]. Potential risk factors for the development of retinopathy include a higher dose of HCQ, older age at initiation of HCQ, female sex, tamoxifen use, and chronic kidney disease (stage 3 or greater) [56].
In addition to the typical parafoveal (bull's eye) changes, many patients with HCQ toxicity have a mixed pattern that also includes pericentral (arcade region) changes [110]. Some patients only exhibit a pericentral pattern of damage, with changes limited to the periphery of the field examined by usual screening techniques [110]. A mixed pattern of damage or changes in the pericentral pattern alone are especially common among those of Asian ancestry [63,110], and the pericentral pattern is also more common in patients identifying as Black compared with those identifying as White [56].
The exact mechanism in which HCQ and CP can lead to retinopathy is not entirely clear [111]. It had been hypothesized that antimalarials bind to melanin in the retinal pigment epithelium, an effect that may damage the overlying photoreceptors and may lead to permanent vision loss.
Routine screening for retinopathy and avoidance of antimalarials in patients with preexisting retinopathy are discussed above. (See 'Routine eye examinations for all patients' above and 'Contraindications' above.)
Corneal deposits — Deposits of the drug or metabolites on the cornea are related to high daily doses. The deposits do not affect vision but can create transient halos or heightened light sensitivity, and they are reversible upon discontinuation of the medication. Corneal deposits are more common with CP, although the incidence per daily dose is not known [112], and are rare with typical doses of HCQ.
Other — Other potential adverse effects that have been described include the following:
●Cytopenias – Rare toxicities include agranulocytosis and aplastic anemia with CP and quinacrine; however, there has never been a report of this occurring with HCQ in doses less than 7 mg/kg/day. 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 [113].
●Overdose – Fatal accidental overdose has occurred in children under age six who ingested one or two tablets of CP; doses of >10 mg/kg of CP require medical attention [114].
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'.)
INFORMATION FOR PATIENTS —
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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●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
●Noninfectious indications for antimalarials – The immunoregulatory and antiinflammatory properties of the antimalarials hydroxychloroquine (HCQ) and chloroquine phosphate (CP) have been effective in the treatment of various systemic rheumatic disease and related conditions. (See 'Noninfectious indications for antimalarials' above.)
●Pharmacology – Antimalarial drugs are administered orally, are relatively well-absorbed, and have a very long half-life; for HCQ and CP, it is one to two months. (See 'Pharmacology' above.)
•Renal clearance – Excretion of the parent compound and hepatic metabolites is principally by direct renal clearance; dose reduction is appropriate for patients with impaired kidney function. (See 'Renal clearance' above.)
•Mechanism of action – 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.)
●Dosing
•Hydroxychloroquine – Typical daily dosing of HCQ for treatment of rheumatic diseases is between 200 and 400 mg. When dosing HCQ, we adjust the daily dose based on actual body weight (maximum daily dose of 5 mg/kg/day, up to 400 mg) and/or HCQ blood levels (within therapeutic range) when available to minimize the risk of toxicity. HCQ blood levels are most accurate when patients have been taking HCQ daily for three to six months and may be more precise than weight-based adjustments in certain clinical scenarios (eg, patients with body mass indices of >30 mg/m2 and/or nephrotic syndrome).
•Chloroquine phosphate – We adjust the dose of CP to be less than 2.3 mg/kg/day based on dose comparisons to HCQ. Blood levels are not typically available for CP.
●Monitoring for toxicity
•Routine eye examinations – 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 for all patients' above.)
•Electrocardiograms in select patients – We do not routinely obtain electrocardiograms to screen for QTc prolongation in most patients. For patients who are taking other medications that may prolong the QTc interval (table 1) or who have positive anti-Ro (SSA) antibody [68,69], we obtain a baseline electrocardiogram prior to initiating therapy with CP or HCQ. We also check a repeat electrocardiogram after three to six months of therapy and with any subsequent clinical changes that may impact the QTc interval (eg, changing the dose of a QTc-prolonging medication). In addition, we clinically monitor all patients on long-term therapy for signs and symptoms of cardiac compromise. (See 'Electrocardiograms in selected patients' above.)
●Contraindications – We avoid using antimalarial medications in patients with preexisting retinopathy, QTc prolongation (eg, congenital long QT syndrome, persistent corrected QT measurements >500 milliseconds), and/or significant risk factors for QTc prolongation (eg, bradycardia, a history of ventricular arrhythmias, uncorrected hypokalemia and/or hypomagnesemia, recent myocardial infarction, and/or uncompensated heart failure). We also avoid use or use antimalarials with caution in patients with preexisting heart disease, depending on disease severity. (See 'Contraindications' above.)
●Adverse effects – 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.)
