Can a patient with a history of rheumatoid arthritis or lupus experience hydroxychloroquine (Plaquenil) withdrawal?

Hydroxychloroquine Withdrawal: Disease Flare Risk, Not True Withdrawal Syndrome

Patients do not experience a true pharmacologic withdrawal syndrome from hydroxychloroquine discontinuation, but they face a significant risk of disease flare—particularly in lupus where the risk increases 1.5 to 3-fold compared to continued therapy. 1, 2

Key Distinction: Disease Flare vs. Withdrawal

Hydroxychloroquine discontinuation does not cause a physiologic withdrawal syndrome with symptoms like those seen with opioids, benzodiazepines, or corticosteroids. Instead, the concern is loss of disease control leading to flare of the underlying rheumatic condition. 1

Risk of Flare After Discontinuation

In Systemic Lupus Erythematosus (SLE)

• Discontinuing hydroxychloroquine in SLE patients increases flare risk substantially, with hazard ratios ranging from 1.56 to 2.30 in large observational cohorts. 1

• Even in patients with SLE in remission for at least one year, hydroxychloroquine withdrawal increases flare risk 3-fold (31.3% vs 12.5% over 36 months; OR 3.1,95% CI 1.2-8.2). 2

• Severe flares occurred in 25% of patients who discontinued versus 11.5% who continued hydroxychloroquine. 2

• Elevated anti-dsDNA antibodies identify patients at highest risk for flare after discontinuation (HR 5.4,95% CI 1.5-18.7). 2

• Pooled flare incidence after glucocorticoid withdrawal is 24% for any flare and 13% for major flares, while hydroxychloroquine discontinuation shows similar or higher rates. 1

In Rheumatoid Arthritis (RA)

• The 2021 ACR guidelines conditionally recommend gradual discontinuation over abrupt discontinuation for all DMARDs, including hydroxychloroquine, in patients at target for at least 6 months. 1

• When tapering triple therapy (methotrexate + sulfasalazine + hydroxychloroquine), gradual discontinuation of sulfasalazine is preferred over hydroxychloroquine due to sulfasalazine's poorer tolerability profile. 1

• Long-term continuation rates are significantly lower in RA than SLE (54% discontinued by 24 months in RA vs 24% in SLE), primarily due to inadequate disease control rather than toxicity. 3

Safer Approaches to Discontinuation

Gradual Tapering Strategy

• Tapering hydroxychloroquine to a lower dose reduces flare risk compared to abrupt discontinuation (45.9% vs 72.6% flare rate; p=0.01). 1

• Gradual dose reduction before complete withdrawal is conditionally recommended over abrupt cessation in both RA and SLE. 1

Patient Selection for Discontinuation

• Only consider discontinuation in patients who have been at target (low disease activity or remission) for at least 6 months. 1

• Avoid discontinuation in patients with serologically active disease (elevated anti-dsDNA, low complement), as they have increased flare risk (OR 1.78,95% CI 1.00-3.15). 1

• In older stable SLE patients (mean age >60 years) with quiescent disease, withdrawal may be safer, though one retrospective study showed non-significant trends toward earlier flares. 4

Common Reasons for Discontinuation

• Retinal toxicity is the most common reason for hydroxychloroquine withdrawal (42.3% of cases), followed by patient preference (34.6%) and other adverse effects (15.4%). 4

• **Retinopathy risk is <2% in the first 10 years with proper dosing (≤5 mg/kg actual body weight)**, but increases to >20% after 20 years of use. 1, 5

Critical Pitfalls to Avoid

• Never abruptly discontinue hydroxychloroquine without a plan for alternative disease control, especially in SLE where it reduces mortality and prevents thrombotic events. 6

• Do not stop hydroxychloroquine for borderline or questionable ophthalmologic findings without definitive evidence of retinopathy confirmed by repeat testing and retinal consultation. 1

• Ensure patients maintain at least one DMARD when discontinuing hydroxychloroquine to prevent complete loss of disease control. 1

• Monitor closely for 6-12 months after discontinuation, as most flares occur within this timeframe. 2

Management After Discontinuation

• Intensify other immunosuppressive therapy (azathioprine, methotrexate, mycophenolate) to maintain disease control when hydroxychloroquine must be stopped. 6

• Consider alternative antimalarials like quinacrine for cutaneous manifestations if hydroxychloroquine cannot be continued. 6

• Shared decision-making between patient, rheumatologist/dermatologist, and ophthalmologist is essential when weighing retinal toxicity risk against disease flare risk. 1