Tofacitinib (XELJANZ): The Wrong Choice for Rheumatoid Arthritis

Tofacitinib (XELJANZ) is one of the newer members of the disease-modifying antirheumatic drug (DMARD) family. It was approved by the Food and Drug Administration (FDA) in November 2012 for the treatment of moderate-to-severe rheumatoid arthritis in adults who have had an inadequate response to methotrexate (TREXALL, XATMEP).[1] Tofacitinib is taken orally and works by inhibiting an enzyme that plays a key role in joint inflammation and damage.[2]

Public Citizen’s Health Research Group has designated this drug as Do Not Use because it can cause serious adverse effects including fatal infections and cancer, and it has not been shown to be as effective as adalimumab (AMJEVITA, HUMIRA), an older biologic DMARD. In addition, the long-term cardiovascular safety of tofacitinib is not known.

FDA approval of tofacitinib was based on evidence from five clinical trials that demonstrated that it reduced joint tenderness and swelling and improved physical function in rheumatoid arthritis patients.[3]

Data from one trial indicated that tofacitinib is no more effective than adalimumab in relieving these symptoms.[4]

In contrast to tofacitinib, however, adalimumab is proven effective in reducing disease progression and preventing joint damage in rheumatoid arthritis patients.[5]

Infection risk

Similar to all DMARDs, tofacitinib suppresses the body’s immune system and increases the risk of serious bacterial, viral and fungal infections. This risk, however, is greater in patients who are treated with tofacitinib. For example, during clinical trials, use of tofacitinib was associated with nearly double the rate of serious infections when compared with use of either adalimumab or placebo.[6]

During the trials, 15 subjects died due to serious infections, including 12 from pneumonia. All but one of these 15 deaths occurred in tofacitinib-treated subjects.[7] Moreover, opportunistic infections — which typically develop in patients with weakened immune systems — only occurred in subjects taking tofacitinib.[8]

Cancer risk

Tofacitinib increases the risk of lymphoma and lymphoproliferative disorders (LPD). During clinical trials, seven cases of lymphoma or LPD occurred in tofacitinib-treated subjects, whereas no such cases occurred in those receiving a placebo or adalimumab.[9]

Tofacitinib also increases the risk of various other types of cancer. In fact, during clinical trials lasting only 12 months, tofacitinib-treated subjects were substantially more likely to be diagnosed with non-lymphoma cancer (12 cases) than subjects taking adalimumab (one case) or a placebo (none).[10] The most frequent types of cancer were breast and lung cancer.

FDA reviewers were particularly concerned about this cancer risk because it increased over time, which has “not been observed with other approved [rheumatoid arthritis] treatments.”[11]

Cardiovascular risk

Tofacitinib also has an adverse effect on important risk factors for cardiovascular disease.

The product label mentions that during clinical trials, tofacitinibtreated subjects were more likely to develop hypertension (high blood pressure) than those receiving a placebo.[12] The product label fails to mention, however, that seven cases of hypertension crisis – a quick and severe increase in blood pressure that can lead to stroke and require hospitalization — occurred in subjects receiving tofacitinib.[13] Four such crises occurred during the first three months of using the drug. No hypertension crises occurred in subjects receiving adalimumab or a placebo.

Tofacitinib also causes elevations in both “bad” cholesterol — low-density lipoprotein (LDL) — and “good” cholesterol — high-density lipoprotein (HDL) — levels. High levels of LDL are a known risk factor for cardiovascular disease, including heart attacks and stroke. During clinical trials, LDL cholesterol increased on average by 15% in tofacitinibtreated patients during just the first month of treatment — a change not seen in subjects receiving a placebo.[14]

Other risks

Tofacitinib causes decreased white blood cell counts, which can contribute to the development of serious infections. The drug also can cause anemia (low red blood cell counts), which can lead to fatigue.[15]

Evidence from the clinical trials also indicates that the drug can cause decreased kidney function and may be associated with an increased risk of liver damage.

Finally, during clinical trials of tofacitinib, some subjects taking the drug had gastrointestinal perforations (tears), which can be life-threatening.

Regulatory agencies’ concerns

In 2013, the European Medicines Agency initially rejected approval for tofacitinib because the agency “had major concerns about the overall safety profile” and was “of the opinion that the benefits did not outweigh its risks.”[16]

One FDA clinical reviewer shared some of these concerns, stating “it is not possible to make definitive conclusions about the treatment effect of tofacitinib on [joint] damage progression. This is particularly important in determining the overall benefit-risk profile of tofacitinib, which is associated with serious safety concerns.”[17]

Although the FDA also recognized a “significant numerical imbalance in the number of deaths between tofacitinib and control groups,”[18] it still approved tofacitinib but required the manufacturer to conduct a postapproval clinical trial to evaluate the drug’s cardiovascular, cancer and infection risks.[19] Results of this trial are not expected until 2020 at the earliest.

What You Can Do

You should avoid taking tofacitinib if you are not currently taking it. If you are taking this drug, you should consult your doctor about switching to an alternative treatment. Do not stop taking any medication without consulting your doctor. Regardless of the treatment chosen by you and your doctor, you should consider engaging in an exercise program and physical therapy designed within the limits of pain. This will help to strengthen muscles and maintain or improve range of motion in the joints.

References

[1] Pfizer. Label: tofacitinib tablet (XELJANZ). February 2016. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=cf74ba2f-afc5-4baa-8594-979c889a5831&type=pdf&name=cf74ba2f-afc5-4baa-8594-979c889a5831. Accessed July 12, 2017.

[2] Tofacitinib (Xeljanz) for rheumatoid arthritis. Med Lett Drugs Ther. 2013 Jan 7;55(1407):1-3.

[3] Pfizer. Label: tofacitinib tablet (XELJANZ). February 2016. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=cf74ba2f-afc5-4baa-8594-979c889a5831&type=pdf&name=cf74ba2f-afc5-4baa-8594-979c889a5831. Accessed July 12, 2017.

[4] Van Vollenhoven RF, Fleischmann R, Cohen S, et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med. 2012;367(6):508-19.

[5] Abbvie. Label: adalimumab (HUMIRA). April 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125057s402lbl.pdf. Accessed July 12, 2017.

[6] Food and Drug Administration. Arthritis Advisory Committee meeting briefing package, NDA 203214 . May 9, 2012. https://wayback.archive-it.org/7993/20170405205859/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM302958.pdf. Accessed July 12, 2017.

[7] Food and Drug Administration. Summary review, NDA 203214. November 6, 2012. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000SumR.pdf. Accessed July 12, 2017.

[8] Ibid.

[9] Ibid.

[10] Food and Drug Administration. Summary review, NDA 203214. November 6, 2012. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000SumR.pdf. Accessed July 12, 2017.

[11] Food and Drug Administration. Cross Discipline team leader review, NDA 203214. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000CrossR.pdf. Accessed July 12, 2017.

[12] Pfizer. Label: tofacitinib tablet (XELJANZ). February 2016. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=cf74ba2f-afc5-4baa-8594-979c889a5831&type=pdf&name=cf74ba2f-afc5-4baa-8594-979c889a5831. Accessed July 12, 2017.

[13] Charles-Schoeman C, Wicker P, Gonzalez-Gay MA, et al. Cardiovascular safety findings in patients with rheumatoid arthritis treated with tofacitinib, an oral Janus kinase inhibitor. Semin Arthritis Rheum. 2016;46(3):261-271.

[14] Pfizer. Label: tofacitinib tablet (XELJANZ). February 2016. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=cf74ba2f-afc5-4baa-8594-979c889a5831&type=pdf&name=cf74ba2f-afc5-4baa-8594-979c889a5831. Accessed July 12, 2017.

[15] Pfizer. Label: tofacitinib tablet (XELJANZ). February 2016. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=cf74ba2f-afc5-4baa-8594-979c889a5831&type=pdf&name=cf74ba2f-afc5-4baa-8594-979c889a5831. Accessed July 12, 2017.

[16] European Medicines Agency. Refusal of the marketing authorisation for Xeljanz (tofacitinib). July 26, 2013. http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/002542/WC500146629.pdf. Accessed July 13, 2017.

[17] Food and Drug Administration. Cross Discipline team leader review, NDA 203214. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000CrossR.pdf. Accessed July 12, 2017.

[18] Food and Drug Administration. Arthritis Advisory Committee meeting briefing package, NDA 203214 . May 9, 2012. https://wayback.archive-it.org/7993/20170405205859/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM302958.pdf. Accessed July 12, 2017

[19] Food and Drug Administration. Approval letter, NDA 203214. November 6, 2012. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2012/203214Orig1s000ltr.pdf. Accessed July 13, 2017.