At 6 months, patients receiving 10 mg of tofacitinib twice daily had a change from baseline in radiographic scores of 0.06 units, compared with 0.47 units for those given placebo, according to Désirée van der Heijde, MD, PhD, of Leiden University in the Netherlands, and colleagues.
However, treatment with 5 mg twice daily resulted in a change of 0.12 units on the modified total Sharp/van der Heijde radiographic scores, which was not a statistically significant difference compared with placebo, the investigators reported in the March Arthritis & Rheumatism.
The nonsignificant difference for the lower dose may reflect the fact that patients randomized to placebo who failed to respond by 3 months were switched to the active treatment for ethical reasons, which "makes the demonstration of a structural benefit more challenging," the researchers observed.
In fact, the published literature suggested that patients in the placebo group would experience an increase of 1.4 units in their radiographic scores by 6 months, the investigators pointed out.
Previous phase II studies showed "sustained efficacy and manageable safety" for tofacitinib, a JAK inhibitor, during 2 years of treatment either with or without methotrexate, but effects on structural disease progression have not previously been demonstrated.
This uncertainty about whether tofacitinib would inhibit RA joint damage had been a source of concern to FDA reviewers when the drug was being considered for approval. The agency eventually approved the drug in November 2012, on the condition that a postmarketing study be performed to monitor adverse events.
The current study was designed to examine the effects of 2 years of treatment on joint preservation, RA disease activity, and physical function in 797 patients with active disease and at least three joint erosions or serologic evidence of rheumatoid factor or antibodies to cyclic citrullinated peptide.
This report looked at safety and efficacy outcomes at 12 months.
Approximately 10 percent to 20 percent of patients had previously received a tumor necrosis factor inhibitor, and up to 5% had received another type of biologic therapy.
Throughout the trial, all patients were on stable doses of methotrexate.
Patients' mean age was 53, mean disease duration was 9 years, and 85 percent were women.
Along with improvements in radiographic and clinical parameters, patients also reported "clinically meaningful" benefits for pain and fatigue.
The most common adverse events during the first 12 months of the trial were infections, gastrointestinal disturbances, and laboratory abnormalities. Serious infections were seen at rates of 3.68 per 100 patient-years for placebo, compared with 4.17 and 2.32 per 100 patient-years for the 5-mg and 10-mg doses.
Seven opportunistic infections developed in patients receiving tofacitinib, and there were six deaths, five of which were in the active treatment groups.
Causes of death included pneumonia, lung cancer, and renal failure.
In addition, six patients receiving tofacitinib had nonfatal cardiovascular events such as angina pectoris and cerebral infarction, and nine developed malignancies such as non-Hodgkin's lymphoma, basal cell carcinoma, and stomach adenocarcinoma.
Laboratory abnormalities included changes in LDL cholesterol, neutrophil counts, and serum creatinine levels, but there were no withdrawals for leukopenia and no cases of renal failure.
"Overall, the results of this 12-month analysis from a 24-month phase III study confirm findings seen previously in phase II and phase III studies in patients with active RA treated with tofacitinib and, for the first time, provide evidence of the potential to inhibit progression of structural damage," concluded van der Heijde and colleagues.
Source: Oral JAK Drug Stops Arthritis Joint Damage
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