Is Hydroxychloroquine an Immunosuppressant?
Hydroxychloroquine is classified as an immunomodulatory agent rather than a true immunosuppressant, with mild immunosuppressive effects that are significantly weaker than conventional immunosuppressants like azathioprine, mycophenolate, or calcineurin inhibitors. 1
Classification and Mechanism
Hydroxychloroquine is a 4-aminoquinoline agent that exerts immunomodulatory effects by interfering with cytokine production, antigen processing, and antigen presentation, rather than causing broad immunosuppression 1
The American College of Rheumatology explicitly distinguishes hydroxychloroquine from immunosuppressants in their COVID-19 guidance, recommending continuation of hydroxychloroquine during SARS-CoV-2 exposure while temporarily stopping true immunosuppressants (tacrolimus, cyclosporine, mycophenolate, azathioprine) 1
In vitro studies demonstrate that hydroxychloroquine requires concentrations exceeding 100 ng/mL to achieve immunosuppressive effects, but conventional clinical dosing produces plasma concentrations of only 75-200 ng/mL, suggesting limited systemic immunosuppression at therapeutic doses 2
Clinical Evidence Supporting Immunomodulatory Rather Than Immunosuppressive Classification
KDIGO guidelines for lupus nephritis recommend hydroxychloroquine for all patients with lupus nephritis unless contraindicated, while separately listing true immunosuppressants (cyclophosphamide, mycophenolate, azathioprine, calcineurin inhibitors) as distinct therapeutic categories 1
The American College of Rheumatology guidelines for lupus nephritis recommend hydroxychloroquine as background therapy for all SLE patients with nephritis, while treating it as adjunctive rather than primary immunosuppressive therapy 1
During the COVID-19 pandemic, rheumatology guidelines recommended continuing hydroxychloroquine due to its immunomodulatory rather than immunosuppressive profile, noting its antiviral efficacy and lower infection risk compared to true immunosuppressants 1
Practical Clinical Implications
Hydroxychloroquine can be safely continued during active infections when true immunosuppressants must be held - the American College of Rheumatology recommends continuing hydroxychloroquine following SARS-CoV-2 exposure while temporarily stopping immunosuppressants 1
In kidney transplant recipients, hydroxychloroquine can be added to maintenance immunosuppression (tacrolimus + mycophenolate + prednisone) without significantly increasing infection risk, though cardiac monitoring for QT prolongation and arrhythmias is warranted 3
The European League Against Rheumatism classifies hydroxychloroquine as a conventional synthetic DMARD with mild immunomodulatory effects compared to other immunosuppressants 4
Important Caveats
While systemic immunosuppression is limited at therapeutic doses, tissue drug concentrations may be substantially higher due to hydroxychloroquine's physicochemical properties, potentially resulting in significant local immunosuppression 2
The ECCO guidelines on infections in IBD classify immunosuppressive therapy as conferring high risk for certain infections (Legionella, Salmonella, Listeria), but do not include hydroxychloroquine in this category 1
Common pitfall: Assuming hydroxychloroquine carries the same infection risk as true immunosuppressants like mycophenolate or calcineurin inhibitors - this leads to unnecessary drug discontinuation during minor infections 1