Dr. David Pisetsky, professor of immunology at Duke University, Durham, N.C., discussed the implications of HCQ’s anti-TLR activity at the congress. "This relatively benign drug has powerful immunological effects, even though we don’t really think of it that way," he said. "When we’re talking about strategies to block TLR, we’ve already been probably doing it unbeknownst to us rather effectively."
Dr. David Pisetsky
Dr. Buyon, who was moderating Dr. Pisetsky’s talk, noted: "Maybe we’re really underselling ourselves [with HCQ]. Most of us confine ourselves to 6.5 mg/kg," she said, referring to the well-known risk of ocular toxicity and retinal changes associated with long-term HCQ treatment, requiring patients on HCQ to get eye exams yearly. Dr. Pisetsky agreed: "To me it would seem very worthwhile to push the dose to get more out of it."
Dr. Pisetsky and Dr. Buyon both expressed hope that manufacturers would seek to create an HCQ-like compound without the ocular risk, allowing the administration of higher doses with presumably more clinical effect. "But so far there’s been a very limited effort," Dr. Pisetsky said.
Another lupus researcher, rheumatologist and epidemiologist Dr. Sasha Bernatsky of McGill University, Montreal, expressed cautious optimism about some of the recent findings. Like Dr. Urowitz, Dr. Inanc, Dr. Buyon, Dr. Ruiz-Irastorz, and many other international scientists, Dr. Bernatsky is a member of the Systemic Lupus International Collaborating Clinics research group, which studies long-term outcomes in SLE.
"The exact possibilities, in terms of disease modification, remain a matter for further study," Dr. Bernatsky said in an interview, adding that while she strongly endorses HCQ for its many benefits, and recommends the drug in almost all SLE patients, she doesn’t fully understand the extremely strong effects that recent studies have suggested, related to nephritis, central nervous system manifestations, cancer, and overall survival.
Dr. Bernatsky struggles with the findings of a study that found HCQ associated with a 70% reduction in renal damage in lupus patients (Arthritis Rheum. 2009;61:830-9; Arthritis Rheum. 2009;61:1614-5). "I am amazed by that degree of disease-modifying effect in terms of active kidney disease, with [HCQ]," she said.
The recent finding of reduced seizures in lupus patients taking HCQ also surprised her. "A hazards ratio of 0.07 suggests that antimalarials reduce 93% of the risk of seizures, which is an incredibly large effect size."
One area of particular debate in HCQ and lupus concerns cancer risk. While Dr. Ruiz-Irastorza and his colleagues found a protective effect associated with HCQ in a cohort study of 235 patients (Ann. Rheum. Dis. 2007;66:815-7), "I did not believe the results at first," Dr. Ruiz-Irastorza said. "However, after discovering several papers showing biological plausibility for such an effect, I changed my mind. It seems to work by a number of different mechanisms, including inhibition of autophagy and sensitization of tumor cells to chemotherapy."
Dr. Bernatsky and SLICC investigators have studied malignancy risk and medication exposures in a large cohort (n = 16,409) of SLE patients (J. Autoimmun. 2013;42:130-5) without finding a protective effect associated with HCQ. "While I would not rule out some beneficial effects for cancer risk in the rheumatic diseases, I think the jury is still out," she said.
Nonetheless, Dr. Bernatsky said, "At our clinic, we keep most of our patients on antimalarials for years, and I hope it is similar in the United States and Europe. I’m happy for almost all SLE patients to be on HCQ because I think it’s a great drug."
None of the investigators mentioned have financial disclosures related to HCQ.