Tofacitinib not associated with higher rates of malignancies than TNF inhibitors

Mark E. Pearson, MD, FACR

The JAK inhibitors have become a welcome addition to the treatment options available for patients with RA. Starting with tofacitinib in 2012, these oral medications have been extremely helpful, with or without methotrexate, in controlling disease progression among those who have failed older biologics such as TNF inhibitors. However, results from post-marketing in the Oral Surveillance safety trial have demonstrated a significant increase in malignancies in direct comparison to TNF agents. The HR of 1.48 (1.04-2.09) resulted in the placement of a black box warning on the entire class of drugs by the FDA.

JAK inhibitors have become too important of an option in treating RA not to do similar studies to confirm or disagree with the warnings. This recent attempt from Khosrow-Khavar and associates at Harvard is by far the best and most important to date. They used a large insurance-based population, including Medicare, for evaluation. In addition to using similar restrictive  parameters to the Oral Surveillance trial (age greater than 50 years, cardiovascular risk factors) as a study cohort, they also created a “real world evidence” (RWE) cohort without these restrictions.  

To summarize the data, this RWE cohort included more than 83,000 patients and demonstrated an HR of 1.01 (0.83-1.22) compared with TNF inhibitors. The comparison cohort to the original Oral Surveillance data revealed an HR of 1.17 (0.85-1.62), which was not significant and not in agreement with the original HR that led to the black box warning.

This leads to the obvious question of what we, as practicing rheumatologists, should do with all of the data and warnings with regard to important treatment decisions?

My thoughts:

• The conflicting data are unsettling but not enough so to remove this important class of medications from our formulary.
• At this stage, “older” modalities such as TNF inhibitors should be used before considering the JAK inhibitors, assuming there are no contraindications. We have more than 20 years of real-world evidence compared to the more recent JAK inhibitors. I also feel the same with T-cell and IL-6 inhibitors. We all have become quite comfortable using these agents with regard to safety and efficacy.
• B-cell inhibitors such as rituximab (Rituxan, Genentech) may take more thought in this age of COVID-19.

Lastly, thanks to this Harvard team, I will be discussing  all of the new data with my patients who I feel may benefit from a JAK inhibitor trial. They need to know that these are newer agents that unfortunately do not benefit from the 20-plus years of data obtained from the “early” biologics.

David A. McLain, MD, MACR, FACP, FRCP

Rheumatologists are always concerned with the safety of immunosuppressive medications in our patients. The risk for malignancy has been a concern for a number of years starting with the use of azathioprine and cyclophosphamide in the 1970s. There are many studies on the incidence of cancer in rheumatoid arthritis with and without treatment. The risk for some cancers appears to be different in patients with RA compared with the general population.

RA has an increased risk for lymphoma, renal cancer and lung cancer. Patients with persistently active disease are at increased risk for lymphoma and, to confound the situation, more severe disease is correlated with more aggressive immunosuppression. RA patients in the top 20% of disease activity have a markedly increased risk for lymphoma.   Cancer in RA is also associated with male sex and increased age. In spite of the association with increased age, the higher cancer incidence in RA patients occurs in the first 5 years after diagnosis.

There is a double-edged sword in RA treatment: Immunosuppressive treatment itself may cause some lymphomas, but better disease control appears to negate this increased risk. The selection of control groups in assessing iatrogenic cancer risk is a major concern. The FDA uses the general population as a control group to assess risk despite the fact that RA itself, without treatment, increases cancer risk. Even using patients with less severe RA as a control group can be a source of misinformation as to risk if the treated group had more severe RA.

The early biologic randomized controlled trials in RA, for example, often enrolled patients with severe disease not adequately controlled with available therapy and were thus at an increased risk for cancer from the RA alone.

It is reassuring that this big data, real world evidence study arm consisting of 83,295 patients did not show an increased risk for cancer comparing tofacitinib-treated patients with those initiating a TNF inhibitor. About 80% of the patients in this analysis were female, which is higher than the expected female-to-male ratio of 3:1. As noted above, cancer risk in RA is higher in males and the excess of females may have skewed the results.

The follow-up was a minimum of 2 years, which may not be long enough to see the development of cancer. In both arms of the study, treatment discontinuation rates were more than 50% in all the groups at 2 years. This statistic alone is sobering as to the state of the art of RA treatment.