Statin Reverses Tofacitinib-Induced Lipid Changes in RA

LONDON – Statin therapy can reverse one of the most important side effects observed in clinical trials of the experimental oral biologic tofacitinib in rheumatoid arthritis, a study has shown.

Concomitant treatment with atorvastatin significantly lessened dyslipidemia observed in a cohort of rheumatoid arthritis patients taking tofacitinib in a phase II trial.

Of 111 rheumatoid arthritis patients enrolled in the study, tofacitinib-treated patients who took atorvastatin (Lipitor) following an open-label lead-in period had a 35% reduction in mean low-density lipoprotein cholesterol (LDL-C) compared with a 5.8% increase observed in tofacitinib-treated patients randomized to concomitant placebo. Those who took atorvastatin had improvements in other lipid measures as well, reported Dr. Iain McInnes of the University of Glasgow (Scotland).

Treatment with tofacitinib, an oral Janus kinase (JAK) inhibitor being investigated as a targeted immunomodulator, has been associated with increases in serum lipids, including LDL and HDL cholesterol and triglycerides in phase II and III rheumatoid arthritis trials, said Dr. McInnes. The same effect is seen with other JAK inhibitors. Certain proinflammatory cytokines have been shown to have an effect on serum lipid levels. Considering the synergy between inflammation and lipid metabolism, "it should be no surprise at all that an agent that modifies inflammation can also cause metabolic changes," he said at the annual European Congress of Rheumatology.

To evaluate whether use of a lipid-lowering drug could safely and effectively modulate lipid increases associated with tofacitinib treatment, Dr. McInnes and his colleagues evaluated the lipid levels of study patients who completed 6 weeks of 10-mg tofacitinib twice daily and were subsequently randomized to an additional 6 weeks of treatment with concomitant atorvastatin or placebo.

From baseline to week 6 of tofacitinib therapy, the average increases for the predominantly female study group (mean age, 52 years) were 185-230 mg/dL for total cholesterol; 109-126 mg/dL for LDL-C; 51-67 mg/dL for high-density lipoprotein cholesterol (HDL-C); 136-165 mg/dL for apolipoprotein A-1; 87-97 mg/dL for apolipoprotein B; and 100-109 mg/dL for triglycerides, Dr. McInnes reported. By week 12, total cholesterol, LDL-C, apolipoprotein B, and triglycerides were significantly decreased in the atorvastatin patients relative to placebo, "to levels below those observed at baseline," he said, while the HDL-C levels increased similarly in both the placebo and atorvastatin groups from week 6 to week 12.

With respect to clinical responses, at week 6, a minimum 20% improvement in American College of Rheumatology criteria (ACR20) was seen in 76% of the study population. "By week 12, 82.6% of the atorvastatin group exhibited an ACR20 response, compared with 65.2% of the placebo group, and 67.4% of the atorvastatin group vs. 45.7% exhibited a minimum 50% improvement in ACR criteria [ACR50)," said Dr. McInnes, who noted that, although the differences in clinical response between the atorvastatin and placebo groups were not statistically significant, the trend toward additional improvements are notable and warrant further study.

In safety analyses, the investigators observed a safety profile similar to that reported in other tofacitinib trials in rheumatoid arthritis, said Dr. McInnes. Specifically, treatment-related adverse events were experienced by 23.4% of the patients during the first 6 weeks of the study, and by 10% of the atorvastatin group and 17% of the placebo group from week 6 to week 12, said Dr. McInnes. Serious adverse events, including pneumonia, occurred in 1.8% of the patients during the open-label phase of the study, he said, noting that none of the atorvastatin patients and 2.1% of the placebo patients experienced serious adverse events between weeks 6 and 12.

"The findings of this study are important in that they demonstrate that any changes in lipids are reversible by addition of a statin," Dr. McInnes said in an interview. "It’s too early to determine how statins and tofacitinib will be used in standard of care. More data are required at this stage."

Dr. Joel Kremer agreed. The chief of medicine at Albany Medical College in New York, Dr. Kremer was the lead investigator of a phase III trial that he reported at the meeting. Data from the phase III trial demonstrated the efficacy of tofacitinib in rheumatoid arthritis patients who failed to respond to treatment with other disease-modifying antirheumatic drugs.

In an interview, Dr. Kremer noted that it’s uncertain whether concurrent lipid-lowering therapy will be considered routine standard of care with tofacitinib in rheumatoid arthritis patients, "but it probably will become quite common, as it is becoming common with Actemra [tocilizumab]."

Dr. McInnes and Dr. Kremer disclosed receiving grant and research support from and serving as consultants for Pfizer.

LONDON – Statin therapy can reverse one of the most important side effects observed in clinical trials of the experimental oral biologic tofacitinib in rheumatoid arthritis, a study has shown.

Concomitant treatment with atorvastatin significantly lessened dyslipidemia observed in a cohort of rheumatoid arthritis patients taking tofacitinib in a phase II trial.

Of 111 rheumatoid arthritis patients enrolled in the study, tofacitinib-treated patients who took atorvastatin (Lipitor) following an open-label lead-in period had a 35% reduction in mean low-density lipoprotein cholesterol (LDL-C) compared with a 5.8% increase observed in tofacitinib-treated patients randomized to concomitant placebo. Those who took atorvastatin had improvements in other lipid measures as well, reported Dr. Iain McInnes of the University of Glasgow (Scotland).

Treatment with tofacitinib, an oral Janus kinase (JAK) inhibitor being investigated as a targeted immunomodulator, has been associated with increases in serum lipids, including LDL and HDL cholesterol and triglycerides in phase II and III rheumatoid arthritis trials, said Dr. McInnes. The same effect is seen with other JAK inhibitors. Certain proinflammatory cytokines have been shown to have an effect on serum lipid levels. Considering the synergy between inflammation and lipid metabolism, "it should be no surprise at all that an agent that modifies inflammation can also cause metabolic changes," he said at the annual European Congress of Rheumatology.

To evaluate whether use of a lipid-lowering drug could safely and effectively modulate lipid increases associated with tofacitinib treatment, Dr. McInnes and his colleagues evaluated the lipid levels of study patients who completed 6 weeks of 10-mg tofacitinib twice daily and were subsequently randomized to an additional 6 weeks of treatment with concomitant atorvastatin or placebo.

From baseline to week 6 of tofacitinib therapy, the average increases for the predominantly female study group (mean age, 52 years) were 185-230 mg/dL for total cholesterol; 109-126 mg/dL for LDL-C; 51-67 mg/dL for high-density lipoprotein cholesterol (HDL-C); 136-165 mg/dL for apolipoprotein A-1; 87-97 mg/dL for apolipoprotein B; and 100-109 mg/dL for triglycerides, Dr. McInnes reported. By week 12, total cholesterol, LDL-C, apolipoprotein B, and triglycerides were significantly decreased in the atorvastatin patients relative to placebo, "to levels below those observed at baseline," he said, while the HDL-C levels increased similarly in both the placebo and atorvastatin groups from week 6 to week 12.

With respect to clinical responses, at week 6, a minimum 20% improvement in American College of Rheumatology criteria (ACR20) was seen in 76% of the study population. "By week 12, 82.6% of the atorvastatin group exhibited an ACR20 response, compared with 65.2% of the placebo group, and 67.4% of the atorvastatin group vs. 45.7% exhibited a minimum 50% improvement in ACR criteria [ACR50)," said Dr. McInnes, who noted that, although the differences in clinical response between the atorvastatin and placebo groups were not statistically significant, the trend toward additional improvements are notable and warrant further study.

In safety analyses, the investigators observed a safety profile similar to that reported in other tofacitinib trials in rheumatoid arthritis, said Dr. McInnes. Specifically, treatment-related adverse events were experienced by 23.4% of the patients during the first 6 weeks of the study, and by 10% of the atorvastatin group and 17% of the placebo group from week 6 to week 12, said Dr. McInnes. Serious adverse events, including pneumonia, occurred in 1.8% of the patients during the open-label phase of the study, he said, noting that none of the atorvastatin patients and 2.1% of the placebo patients experienced serious adverse events between weeks 6 and 12.

"The findings of this study are important in that they demonstrate that any changes in lipids are reversible by addition of a statin," Dr. McInnes said in an interview. "It’s too early to determine how statins and tofacitinib will be used in standard of care. More data are required at this stage."

Dr. Joel Kremer agreed. The chief of medicine at Albany Medical College in New York, Dr. Kremer was the lead investigator of a phase III trial that he reported at the meeting. Data from the phase III trial demonstrated the efficacy of tofacitinib in rheumatoid arthritis patients who failed to respond to treatment with other disease-modifying antirheumatic drugs.

In an interview, Dr. Kremer noted that it’s uncertain whether concurrent lipid-lowering therapy will be considered routine standard of care with tofacitinib in rheumatoid arthritis patients, "but it probably will become quite common, as it is becoming common with Actemra [tocilizumab]."

Dr. McInnes and Dr. Kremer disclosed receiving grant and research support from and serving as consultants for Pfizer.

LONDON – Statin therapy can reverse one of the most important side effects observed in clinical trials of the experimental oral biologic tofacitinib in rheumatoid arthritis, a study has shown.

Concomitant treatment with atorvastatin significantly lessened dyslipidemia observed in a cohort of rheumatoid arthritis patients taking tofacitinib in a phase II trial.

Of 111 rheumatoid arthritis patients enrolled in the study, tofacitinib-treated patients who took atorvastatin (Lipitor) following an open-label lead-in period had a 35% reduction in mean low-density lipoprotein cholesterol (LDL-C) compared with a 5.8% increase observed in tofacitinib-treated patients randomized to concomitant placebo. Those who took atorvastatin had improvements in other lipid measures as well, reported Dr. Iain McInnes of the University of Glasgow (Scotland).

Treatment with tofacitinib, an oral Janus kinase (JAK) inhibitor being investigated as a targeted immunomodulator, has been associated with increases in serum lipids, including LDL and HDL cholesterol and triglycerides in phase II and III rheumatoid arthritis trials, said Dr. McInnes. The same effect is seen with other JAK inhibitors. Certain proinflammatory cytokines have been shown to have an effect on serum lipid levels. Considering the synergy between inflammation and lipid metabolism, "it should be no surprise at all that an agent that modifies inflammation can also cause metabolic changes," he said at the annual European Congress of Rheumatology.

To evaluate whether use of a lipid-lowering drug could safely and effectively modulate lipid increases associated with tofacitinib treatment, Dr. McInnes and his colleagues evaluated the lipid levels of study patients who completed 6 weeks of 10-mg tofacitinib twice daily and were subsequently randomized to an additional 6 weeks of treatment with concomitant atorvastatin or placebo.

From baseline to week 6 of tofacitinib therapy, the average increases for the predominantly female study group (mean age, 52 years) were 185-230 mg/dL for total cholesterol; 109-126 mg/dL for LDL-C; 51-67 mg/dL for high-density lipoprotein cholesterol (HDL-C); 136-165 mg/dL for apolipoprotein A-1; 87-97 mg/dL for apolipoprotein B; and 100-109 mg/dL for triglycerides, Dr. McInnes reported. By week 12, total cholesterol, LDL-C, apolipoprotein B, and triglycerides were significantly decreased in the atorvastatin patients relative to placebo, "to levels below those observed at baseline," he said, while the HDL-C levels increased similarly in both the placebo and atorvastatin groups from week 6 to week 12.

With respect to clinical responses, at week 6, a minimum 20% improvement in American College of Rheumatology criteria (ACR20) was seen in 76% of the study population. "By week 12, 82.6% of the atorvastatin group exhibited an ACR20 response, compared with 65.2% of the placebo group, and 67.4% of the atorvastatin group vs. 45.7% exhibited a minimum 50% improvement in ACR criteria [ACR50)," said Dr. McInnes, who noted that, although the differences in clinical response between the atorvastatin and placebo groups were not statistically significant, the trend toward additional improvements are notable and warrant further study.

In safety analyses, the investigators observed a safety profile similar to that reported in other tofacitinib trials in rheumatoid arthritis, said Dr. McInnes. Specifically, treatment-related adverse events were experienced by 23.4% of the patients during the first 6 weeks of the study, and by 10% of the atorvastatin group and 17% of the placebo group from week 6 to week 12, said Dr. McInnes. Serious adverse events, including pneumonia, occurred in 1.8% of the patients during the open-label phase of the study, he said, noting that none of the atorvastatin patients and 2.1% of the placebo patients experienced serious adverse events between weeks 6 and 12.

"The findings of this study are important in that they demonstrate that any changes in lipids are reversible by addition of a statin," Dr. McInnes said in an interview. "It’s too early to determine how statins and tofacitinib will be used in standard of care. More data are required at this stage."

Dr. Joel Kremer agreed. The chief of medicine at Albany Medical College in New York, Dr. Kremer was the lead investigator of a phase III trial that he reported at the meeting. Data from the phase III trial demonstrated the efficacy of tofacitinib in rheumatoid arthritis patients who failed to respond to treatment with other disease-modifying antirheumatic drugs.

In an interview, Dr. Kremer noted that it’s uncertain whether concurrent lipid-lowering therapy will be considered routine standard of care with tofacitinib in rheumatoid arthritis patients, "but it probably will become quite common, as it is becoming common with Actemra [tocilizumab]."

Dr. McInnes and Dr. Kremer disclosed receiving grant and research support from and serving as consultants for Pfizer.