What are the potential side effects of hydroxychloroquine in patients with rheumatoid arthritis or lupus, and how can they be monitored and managed?

Hydroxychloroquine Side Effects and Management

Hydroxychloroquine is generally well-tolerated with a relatively low rate of drug-related adverse effects, but requires vigilant monitoring for retinopathy (the most serious long-term toxicity), cardiotoxicity, and less common neuromuscular complications. 1

Most Common Side Effects

Gastrointestinal Effects

• Nausea, vomiting, and diarrhea are the most frequently reported side effects, typically occurring within days to weeks of treatment initiation 2
• These account for most treatment intolerances and are usually mild and reversible 1
• Taking hydroxychloroquine with food or milk reduces gastrointestinal symptoms 3

Dermatologic Reactions

• Drug eruptions or rashes may develop within days to weeks of exposure 2
• Cutaneous hyperpigmentation, pruritus, and lichenoid skin eruptions can occur with prolonged use 1
• Bleaching of hair and discoloration of nail beds and mucous membranes may develop 1
• Rare but serious: Stevens-Johnson syndrome and toxic epidermal necrolysis 2
• Most dermatologic effects resolve with drug discontinuation 1

Neuropsychiatric Effects

• Headache, confusion, disorientation, and hallucinations may occur within 24-48 hours of drug initiation 2
• If hallucinations develop, immediately discontinue hydroxychloroquine and obtain neurology/psychiatric consultation to exclude other causes 4

Serious Long-Term Toxicities

Retinopathy (Most Important Dose-Limiting Toxicity)

Risk stratification by duration:

• <1% risk during first 5 years when dosed at ≤5 mg/kg actual body weight daily 5
• <2% risk at 5-10 years with appropriate dosing 5
• 0.5% after 6 years, increasing to 7.5% in long-term users, and >20% after 20 years of treatment 1, 6, 5

Critical monitoring algorithm:

• No baseline ophthalmologic examination required before initiating treatment 1
• Begin annual screening after 1 year in high-risk patients (concomitant tamoxifen use, eGFR <60 ml/min/1.73 m², dose >5 mg/kg/d, or chloroquine use) 1
• Begin annual screening after 5 years in standard-risk patients 1, 5, 4
• Screening must include 10-2 visual field testing, spectral-domain OCT, and fundus autofluorescence 5
• Retinopathy may progress even after drug cessation if detected late, making early detection crucial 5

Cardiotoxicity

Acute/Short-term cardiac effects:

• QT/QTc prolongation, particularly when combined with azithromycin 2
• Conduction abnormalities including heart block 1
• Some clinicians perform yearly ECGs in asymptomatic patients, especially with chloroquine 1

Long-term cardiac effects (with high cumulative exposure):

• Cardiomyopathy manifesting as heart failure 1, 7
• Conduction abnormalities including Mobitz II A-V block 7
• Valvular disorders 2
• Cardiotoxicity may be reversible with early detection and prompt discontinuation 7
• Patients on long-term therapy (>20-30 years) presenting with shortness of breath, reduced ejection fraction, or conduction abnormalities should be evaluated for HCQ cardiotoxicity 7

Neuromuscular Toxicity (Rare)

• Insidious onset proximal myopathy, potentially associated with peripheral neuropathy 8
• Toxic myopathy with muscle weakness and extremity weakness 1
• Pseudoparkinsonism (rare) 1
• Muscle biopsy reveals curvilinear bodies and vacuolar changes 8
• Resolution is slow after discontinuation and may be incomplete 8
• Possible predisposing factors: Caucasian race and concomitant renal failure 8

Less Common but Important Side Effects

Hematologic

• Risk of hemolysis in patients with G6PD deficiency 1
• Measure G6PD levels before starting hydroxychloroquine in men, especially those of African, Asian, or Middle Eastern origin 1
• Anemia may occur in G6PD-deficient patients 2

Metabolic

• Hypoglycemia (rare with standard therapeutic use) 2
• Hypokalemia secondary to intracellular shift in severe toxicity/overdose 3

Other Rare Effects

• Ototoxicity (irreversible) when doses exceed 250 mg/day 1
• Urinary incontinence (extremely rare, first case reported in 2013) 9
• Interference with selected vaccines 1

Overdose Manifestations

Symptoms manifest rapidly (within 1-3 hours): 3, 2

• Life-threatening cardiovascular toxicity: QRS/QTc prolongation, ventricular arrhythmias, torsade de pointes, cardiac arrest 3, 2
• Severe hypotension is common 3
• CNS depression, seizures, visual disturbances, transient blindness, coma 3, 2
• Deaths most often result from cardiovascular collapse 2

Dosing Adjustments to Minimize Toxicity

• Daily dose should not exceed 5 mg/kg actual body weight to minimize retinopathy risk 1, 6, 4
• Doses of 2-3 mg/kg/day may not achieve adequate blood levels and are associated with higher flare rates 1
• In patients with eGFR <30 ml/min/1.73 m², reduce dose by 25% 1, 6
• Target blood hydroxychloroquine level >0.6 mg/L for optimal disease control 1

Special Populations

Pregnancy

• Hydroxychloroquine is safe during pregnancy (Pregnancy Class C) 1, 6
• Associated with decreased lupus activity without harm to the fetus 1, 6
• 133 pregnancies resulted in 117 live births with no difference in complications compared to untreated patients 1

Geriatric Patients

• Start with lowest recommended dose due to greater frequency of decreased renal, hepatic, or cardiac function 3
• Hydroxychloroquine is substantially excreted by the kidney; risk of toxic reactions is greater with impaired renal function 3

Hepatic or Renal Disease

• Dose reduction necessary in patients with hepatic or renal disease 3

Key Clinical Pitfalls to Avoid

• Do not use chloroquine as a substitute unless cost is prohibitive, as it has higher toxicity risk than hydroxychloroquine 1, 6
• Do not delay ophthalmologic screening beyond recommended timeframes, as retinopathy detected late may be irreversible 5
• Do not ignore cardiac symptoms in long-term users (>20 years), as cardiotoxicity is potentially reversible if caught early 7
• Do not combine with drugs that prolong QT interval without careful monitoring 2
• Monitor for drug interactions with D-penicillamine and cimetidine, which lead to higher drug levels 1