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2 Weeks Off Methotrexate OK for Flu Vaccine

Stopping methotrexate for 2 weeks after the administration of flu vaccine led to improved immunogenicity without increasing disease activity among patients with rheumatoid arthritis (RA), a prospective Korean study showed.

Among patients in whom methotrexate was withheld for 2 weeks, a satisfactory vaccine response was seen in 75.5% compared with 54.5% of those who continued on the drug, according to Eun Bong Lee, MD, of Seoul National University College of Medicine, and colleagues. A satisfactory response was an increase of at least four-fold in the hemagglutination inhibition antibody titer from baseline 4 weeks after the vaccination against two or more of four of the current vaccine strains.

The difference between the group with temporary methotrexate discontinuation and those who continued was 21% (95% CI 10.6%-31.7%, P<0.001), the researchers reported online in Annals of the Rheumatic Diseases.  (Citation source: http://bit.ly/2uuMKvI)

RA patients are more susceptible to infections than the general population because of the underlying immune dysfunction and the immune suppression associated with treatments, so vaccines are strongly recommended for these patients by groups such as the American College of Rheumatology and the European League Against Rheumatism. 

Methotrexate remains the anchor drug for the treatment of RA, but it can interfere significantly with the response to influenza and pneumococcal vaccines. The researchers previously conducted a pilot study of methotrexate discontinuation for 4 weeks after the seasonal flu vaccine, finding increased immunogenicity but also a 1.4-fold risk of disease flare. 

They conducted a randomized, parallel-group study comparing a 2-week methotrexate discontinuation versus continuation in 316 patients with RA.

Participants were recruited from October 2016 to January 2017. That year's seasonal quadrivalent vaccine included the H1N1, H3N2, B-Yamagata, and B-Victoria strains. Serum was collected before the vaccine was administered and again at week 4.

During the discontinuation period, patients who experienced flares could take acetaminophen, nonsteroidal anti-inflammatory drugs, and prednisone in dosages up to 10 mg/day.

More than 80% of patients were women, mean age was 53, and mean disease duration was 6.9 years. Baseline Disease Activity Score in 28 joints (DAS28) was 2.3 in the discontinuation group and 2.2 in the continuation group. About half were taking glucocorticoids, with mean doses of 1.8 mg/day. Mean methotrexate dose was 13.2 mg/week.

The proportion of patients who achieved at least a four-fold increase in antibody titer in more than one of the four strains was 89.4% in the discontinuation group versus 75.6% in the continuation group, for a difference of 13.8% (95% CI 5.4-22.1, P=0.001). The proportions having a response to three of the four strains were 61.9% versus 36.5%, for a difference of 25.4% (95% CI 14.3-36.4, P<0.001), and for all four strains, the proportions were 45.6% versus 21.8%, for a difference of 23.8% (95% CI 13.4-34.3, P<0.001).

For the specific influenza antigens, the discontinuation group had a higher frequency of response, with differences of 11.9% (95% CI 0.9%-22.8%, P=0.033) for H1N1, 16.8% (95% CI 6.1%-27.4%, P=0.002) for H3N2, 22.7% (95% CI 11.7%-33.7%, P<0.001) for B-Yamagata, and 32.8% (95% CI 21.8%-43.6%, P<0.001) for B-Victoria.

Baseline seroprotection against the four antigens was similar between the discontinuation and continuation groups, but postvaccination seroprotection rates were higher in the discontinuation group, with differences of 10.7%, 15.9%, 13.7%, and 14.7%, respectively.

No differences in vaccine response was seen for patients whose methotrexate dosage was 7.5 mg/week or less, but significant differences were observed for those on 15 mg/week or more.

No serious adverse events were reported.

For disease activity, the change in DAS28 was only 0.1 point in both groups. Flares occurred in the 4 weeks after vaccination in 5.1% of the continuation group and in 10.6% of the discontinuation group, which was not a significant difference (P=0.07). Rescue medications for joint pain were used during that follow-up period by 4.5% of the continuation group and in 6.3% of the discontinuation group (P=0.487). For all patients who experienced a flare, disease activity declined to baseline when methotrexate was restarted.

The researchers noted that the vaccine response was more prominent for the type B strains of the virus, to which fewer individuals have had prior exposure. For the more common H1N1 and H3N2, response rates increased by 11.9% and 16.8%, respectively, whereas for the B-Yamagata and B-Victoria strains, the increases in response were 22.7% and 32.8%.

"These results suggest that this methotrexate discontinuation strategy might be more crucial for response to influenza viruses relatively new to humans," they observed.

A study limitation was its inclusion of only Korean patients who had stable disease. "Further studies testing the generalizability of our results to patients with moderate to high disease activity or other ethnicities are warranted," the authors concluded.

The study was sponsored by GC Pharma, formerly known as Green Cross Corporation.

Lee disclosed no relevant relationships with industry. One co-author reported financial relationships with Green Cross, Hanmi Pharm, and Pfizer.

Disclosures: 
The author has no conflicts of interest to disclose related to this subject

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