Slight increases in serum creatinine levels were seen in a small number of rheumatoid arthritis patients treated with tofacitinib (Xeljanz) in the phase III trials of the oral Janus kinase (JAK) inhibitor, but the clinical significance of the finding is uncertain.
The difference in least squares mean serum creatinine between patients receiving tofacitinib and those given placebo at 3 months in five trials was 0.02 mg/dL for the 5-mg twice daily dose and 0.04 mg/dL for the 10-mg twice daily dose, according to , of Newcastle University in Newcastle upon Tyne, England, and colleagues.
In addition, during the first 3 months of treatment, 1.4% of patients in the 5-mg group experienced increases of 33% or more over baseline levels, as did 1.9% of those in the 10-mg group, the researchers reported online in Arthritis Care & Research.
In most cases, the increases appeared to be early and reversible and didn't lead to progressive worsening in renal function, according to Isaacs and colleagues.
"Clinical manifestations of acute renal failure in the phase III and long-term extension studies showed no clear dose association and did not occur as a result of continuing serum creatinine increases over time, but occurred acutely, with etiologies consistent with the causes of acute renal failure in the general population (mostly pre-renal -- congestive heart failure, sepsis, or dehydration)," the authors wrote.
Further complicating matters, they said, is that while serum creatinine often is used as a surrogate for impaired kidney function in drug studies, interpretation can be difficult in patients with rheumatoid arthritis (RA) because of loss of muscle mass, reduced mobility, and inflammation.
The Clinical Significance?
To clarify the possible significance and implications of these renal findings, ľֱ spoke to , of the University of Alabama Birmingham, who writes and speaks often about drug safety in RA.
"We don't know what it means, but it's unusual," he said.
"It's clearly different and unexpected compared to most of the other drugs that we use where we don't really see this. On average, the mean magnitude of change is small, but in some patients it could lead to some concerning changes in kidney function," he said.
But there isn't a specific subgroup of patients who definitely should not be treated with tofacitinib because of this, he said.
"I think that for people who already have chronic kidney disease and have no reserve, you might look at these data and say maybe this is not the best therapy for them. Even though the likelihood of a problem is very low, they don't have any reserve, and if you've got ten other choices maybe you want to use one of the others," Curtis said.
The mechanism for this remains unknown, as does the clinical magnitude, he noted.
"It's one of those things that worries us in a somewhat vague way, but probably doesn't meaningfully result in much that we would do differently except to say that we need to keep an eye longitudinally on people's kidney function," Curtis said.
The Pattern of Events
The analysis conducted by Isaacs and colleagues included five phase III studies with 3,227 patients and two long-term extension studies.
Among patients in the 5-mg group, two patients had increases in serum creatinine above the upper limit of normal, as did four in the 10-mg group. A total of 16 patients in the phase III trials and 12 in the long-term extension studies had increases of more than 50% and discontinued treatment permanently.
Most patients who had an increase of at least 10% at the end of the phase III trial had no additional increases during the long-term extension studies.
The researchers also looked at the effects of inflammation as reflected in C-reactive protein levels at baseline, and found that high baseline levels of this marker were associated with a greater increase in serum creatinine. In one of the studies that included an adalimumab (Humira) arm, similar trends were seen for that agent, although the increase wasn't as large.
In the phase III trials, 0.3% to 0.7% of patients had adverse events that were reported as being acute renal failure, as did 2.9% and 1% of patients in the 5-mg and 10-mg groups in the long-term extension studies. Analysis of all 41 reported cases determined that 22 could be considered "clinical" acute renal failure, with 18 having a pre-renal cause such as congestive heart failure. Treatment of those underlying causes and withdrawal of the drug generally led to resolution of the renal failure, according to the researchers.
Many of the patients who developed acute renal failure were taking concomitant medications that can have effects on kidney function, including ACE inhibitors, angiotensin receptor II blockers, and nonsteroidal anti-inflammatory drugs.
A Class Effect
The researchers also pointed out that in early-phase studies of other JAK inhibitors such as baricitinib, similar changes in serum creatinine have been seen.
"I suspect it's going to be a class effect," Curtis said.
As to other safety concerns, Curtis reported at the annual meeting of the European League Against Rheumatism there was an incidence rate of 4.22 (95% CI 3.87-4.61) per 100 patient-years of herpes zoster among patients treated with the drug.
"That's the Achilles' heel of this molecule," he told ľֱ.
"But on a more positive note, there's now cancer data out past 5 years, and very reassuringly there's no safety signal that would cause any concern about increased risk. I think that's very encouraging," he added.
Disclosures
The study was sponsored by Pfizer.
Isaacs disclosed relevant relationships with Pfizer.
Several of the authors are employees of Pfizer.
One co-author is an employee of the Ann Arbor Pharmacometrics Group.
Primary Source
Arthritis Research & Therapy
Isaacs J, et al "Changes in serum creatinine in patients with active rheumatoid arthritis treated with tofacitinib: results from clinical trials" Arthritis Res Ther 2014; DOI: 10.1186/ar4673.