New Findings on Hydroxychloroquine, Denosumab

ACR Convergence 2020—At two plenary sessions, speakers highlighted key findings, including results on the QTc interval in patients on hydroxychloroquine, and data from a study on denosumab vs. alendronate for glucocorticoid-induced osteoporosis.

The QTc Interval & Hydroxychloroquine
The safety profile and optimal dosing of hydroxychloroquine has been a topic for decades because it is known to potentially result in long-term toxicities in the skin, retina and heart from long-term storage of metabolites. At the plenary session on Friday, Nov. 6, Elizabeth Park, MD, a rheumatology fellow at Columbia University Irving Medical Center, New York, discussed a study on an unresolved issue about its potential side effects: the possibility of prolonged QTc length as assessed by electrocardiogram (ECG).

Prolonged QTc length, potentially resulting from blockade of the inward cellular potassium current, has long been associated with the risk of abnormal heart rhythms that can lead to sudden cardiac death (such as torsades de pointes), although the exact length indicating true risk is a point of debate.¹ Several cohort studies have also found it a predictor of increased overall cardiovascular morbidity and mortality.² An association of increased QTc length with hydroxychloroquine use has been found in some previous medical reports, but not in others.^3–9

Dr. Park explained that interest in the topic heightened in recent months after an observational study of 90 patients hospitalized with COVID-19 found that 19% of patients who received hydroxychloroquine had a prolonged QTc of more than 500 ms, including one case of torsades de pointes. Those receiving hydroxychloroquine plus azithromycin (a drug thought to extend the QTc interval) had increased prolongation compared to those receiving only hydroxychloroquine.⁹

In their recent study, Dr. Park and colleagues examined two different rheumatoid arthritis (RA) cohorts (evaluated prospectively) and a cohort of patients with systemic lupus erythematosus (SLE, evaluated retrospectively), for a combined cohort of 530 patients. ECG information was assessed at the same time as hydroxychloroquine use, providing information from a single cross-sectional time point. They excluded potential participants with known cardiovascular disease.

Of their cohort, 93% of the patients with SLE were taking hydroxychloroquine, as were 24% of the RA patients (54% of the group as a whole).

Of the cohort, 44% had a QTc greater than or equal to 440; 7.5% demonstrated a QTc greater than or equal to 500. Dr. Park said, “This is significant, as prolonged QTc length—defined as greater than 450 in men and greater than 470 in women—independently predicts sudden cardiac death in the literature.” No cardiac arrhythmias or associated deaths occurred during the study period.

Dr. Park

In their unadjusted analysis, QTc length was significantly decreased in patients taking hydroxychloroquine compared to those not taking it. The researchers used an adjusted analysis to help account for such important confounders as age, race, steroid use, hypertension, diabetes, smoking status and aspirin use. Here, the mean adjusted QTc was comparable between the patients taking hydroxychloroquine and those not taking it. (Note: Age, current prednisone use and smoking status did predict QTc length.)

When analyzed as a categorical variable, hydroxychloroquine was also not a predictor of prolonged QTc, defined as either ≥440 ms or ≥500 ms.

The team also used stratified analysis to examine the potential interactions between hydroxychloroquine and medications known to prolong QTc, such as some antidepressants. Taken as a whole, an increase in QTc was not found in those using hydroxychloroquine in addition to one of those other medications. However, an increased QTc length was found specifically in the SLE cohort for patients taking antipsychotic medications in addition to hydroxychloroquine, compared with those taking only hydroxychloroquine.

Overall, Dr. Park says these results are in line with the results of smaller cohort studies that have not reported an association between QTc length and hydroxychloroquine use.^3-6 She noted that it is important to put in context any studies on hydroxychloroquine in COVID-19. “We must also consider the effects of COVID-19 itself on the cardiac conduction system, as well as confounding by indication, [because] sicker patients were more likely to receive hydroxychloroquine,” she said.

Dr. Park and colleagues did not have data to stratify by hydroxychloroquine dose or by length of time taking the drug, which might be a factor in potential QTc prolongation. It will also be important to get a sense of whether these data apply to patients who do have underlying cardiovascular disease (unlike study participants), because they may be the most vulnerable if QTc prolongation is ultimately found to be a risk.

Denosumab vs. Alendronate for Osteoporosis
Although glucocorticoids are a critical treatment in managing many autoimmune inflammatory diseases, they are also the leading cause of secondary osteoporosis. First-line osteoporosis treatment is oral bisphosphonate therapy, but these drugs have poor adherence rates, partly due to side effects such as esophageal irritation.¹⁰ The human monoclonal antibody denosumab (targeting RANKL ligand) is another, albeit much more expensive, option.

Several head-to-head, randomized controlled trials in postmenopausal women have suggested denosumab is more effective than oral bisphosphonates at raising bone mineral density with 12 months of treatment. However, relatively little data has been available to compare the efficacy of these approaches in long-term users of glucocorticoids. Chi Chiu Mok, MD, chief of the Division of Rheumatology of Tuen Mun Hospital, Hong Kong, discussed the contributions of his team to this topic during the third plenary session on Sunday, Nov. 8.

We must also consider the effects of COVID-19 itself on the cardiac conduction system. —Dr. Park

In a previous randomized controlled trial of 42 women taking long-term corticosteroids and bisphosphonate therapy, Dr. Mok and colleagues demonstrated that the spinal bone mineral density was significantly higher in a treatment arm that switched to denosumab.¹¹ Another key, recent study, sponsored by Amgen, of 795 patients either continuing or starting glucocorticoids found that denosumab was superior to risedronate in improving bone mineral density of the lumbar spine at 12 months.¹²

In its current study, Dr. Mok’s group contrasted the efficacy of denosumab and oral alendronate in 139 long-term glucocorticoid users. The participants received either subcutaneous denosumab (60 mg every six months) or 70 mg alendronate weekly. The study group contained a high proportion of individuals with SLE (81%), with RA being the next most common subset (9%). The mean dose at treatment entry was 5.1 mg/day prednisolone (or equivalent), although doses as low as 2.5 mg/day were permitted for inclusion.

For patients in both treatment arms, bone mineral density was significantly higher in the spine, hip and femoral neck compared with their pre-study value. But the denosumab group showed a statistically significant greater improvement in bone mineral density after adjusting for the baseline density, age, sex, other osteoporotic risk factors and the cumulative doses of steroids in 12 months.

However, no statistically significant difference was found at the hip and femoral neck after adjusting for those same covariates. Dr. Mok noted the period of treatment of their study was relatively short, and a longer treatment duration might have yielded a clearer difference.

The researchers also analyzed bone markers, such as CTX (i.e., C-terminal telopeptide of type 1 collagen), and adjusted for these same covariates. They found a statistically significant difference between the two groups at 12 months, with the denosumab group more effectively suppressing bone turnover as shown by these indicators.

Dr. Mok pointed out that in contrast to the Amgen study, theirs was not sponsored by any commercial sources.¹² He said, “We showed that the magnitude of the increase in spinal [bone mineral density] was comparable with the Amgen study in a subgroup of patients continuing glucocorticoids at 12 months. In general, our results in Asian patients are largely confirmatory.”

It is important to note that neither study provided direct evidence that denosumab is more effective at reducing fracture risk than alendronate. These data may not capture the true extent of the difference between the groups in a real-world setting, in which compliance with bisphosphonates might be decreased. Oral bisphosphonates are known to have poor patient adherence, likely related to their side effect profile. Some studies have indicated higher patient preference and greater adherence with denosumab compared to oral bisphosphonates.¹⁰ These new data may help further inform decisions about treatment for prevention of osteoporosis in patients on chronic steroids.

Ruth Jessen Hickman, MD, is a graduate of the Indiana University School of Medicine. She is a freelance medical and science writer living in Bloomington, Ind.

References

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