Can a patient with seronegative arthritis, specifically an adult with a history of chronic inflammation and joint pain, on hydroxychloroquine (HCQ) experience more frequent flares of herpes simplex virus (HSV) due to their immunosuppressed state?

Hydroxychloroquine Does Not Increase HSV Flares in Seronegative Arthritis

Hydroxychloroquine is not considered an immunosuppressant and does not increase the risk of HSV reactivation in patients with seronegative arthritis. In fact, HCQ may provide antiviral benefits while controlling inflammatory disease activity.

Hydroxychloroquine's Immunologic Profile

• HCQ is classified as a conventional synthetic disease-modifying antirheumatic drug (csDMARD), not an immunosuppressant 1
• The risk of serious infections with HCQ is relatively small, particularly when given as monotherapy 1
• HCQ has demonstrated antiviral properties in clinical studies, including a 1-log decrease in recoverable HIV-1 RNA in patients with inflammatory arthritis 2
• The mechanism involves immunomodulation rather than immunosuppression, with improved mitogen- and antigen-specific immune responses observed during HCQ therapy 2

Evidence Regarding Viral Infections and HCQ

• Continuing HCQ during acute viral infections is recommended because discontinuation increases the risk of disease flares without providing infection-related benefits 3
• In patients with systemic lupus erythematosus, HCQ use trended toward decreased risk of disease flare (OR 0.50,95% CI 0.23 to 1.07), though not statistically significant 1
• There is no documented association between HCQ monotherapy and increased herpes simplex virus reactivation in the rheumatologic literature 1

Actual Risk Factors for HSV Reactivation in Rheumatic Disease

The medications that DO increase viral infection risk include:

• High-dose corticosteroids (≥10 mg/day prednisone) are associated with increased herpes zoster risk (aOR=2.30,95% CI 1.25 to 4.22) 4
• Biologic agents (anti-TNF therapies) significantly increase herpes zoster risk (aOR=2.07,95% CI 1.34 to 3.19) and are associated with shorter time-to-diagnosis and more severe presentations 4
• JAK inhibitors have documented increased risk of herpes zoster reactivation through dampening of innate antiviral effects of type I and type II interferons 1
• True immunosuppressants like methotrexate (aOR=1.98), azathioprine, mycophenolate, and cyclosporine carry infection risks 1, 4

Clinical Management Recommendations

• Continue HCQ in patients with seronegative arthritis regardless of HSV history 1, 3
• Standard HCQ dosing is 200-400 mg daily (maximum 5 mg/kg actual body weight) 3
• If the patient is on additional immunosuppressive medications (corticosteroids, biologics, or other DMARDs), those agents—not the HCQ—would be the concern for HSV reactivation 4
• Consider prophylactic antiviral therapy (acyclovir 200-400 mg daily) only if the patient is on biologics or high-dose corticosteroids with recurrent HSV 5

Important Caveats

• The case report of disseminated HSV-1 occurred with infliximab (a biologic), not with HCQ 5
• In that case, the patient successfully continued on adalimumab with low-dose acyclovir prophylaxis (200 mg alternate days) without HSV recurrence 5
• HCQ was successfully used in patients with HIV and inflammatory arthritis, demonstrating both antiinflammatory and antiviral effects simultaneously 2
• The increased herpes zoster risk associated with HCQ in one Asian study (aOR=1.95) likely reflects confounding by indication—patients with more active disease requiring HCQ had higher baseline infection risk 4