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Study Authors: Chio Yokose, Natalie McCormick, et al.

Target Audience and Goal Statement:

Rheumatologists, internists, family medicine physicians, geriatricians, infectious disease specialists

The goal was to investigate the possible risk of gout flare in patients receiving vaccinations, other than the recombinant zoster vaccine (RZV).

Questions Addressed:

• Do gout patients who receive vaccinations other than the RZV have an increased risk of a flare within the next 2 days after vaccination?

• If so, what might be the mechanism by which the vaccines produce a gout flare?

• What is the risk/benefit ratio of vaccinating gout patients given the side effects, and what recommendation do scientists make regarding vaccinating patients with gout?

Study Synopsis and Perspective:

Patients with gout had double the risk of experiencing a flare in the days immediately following vaccination, according to a case-crossover study.

Compared with periods when no vaccines were administered, the crude odds ratio of a gout flare during the 2 days after vaccination was 2.16 (95% CI 1.14-4.12), reported Hyon Choi, MD, of Massachusetts General Hospital (MGH) and Harvard Medical School in Boston, and colleagues.

As they reported in their study online in , after the team adjusted for factors associated with gout flares, namely alcohol consumption, treatment with diuretics, and purine intake, the odds ratio for flare during the 2 days after receipt of a vaccine was 1.99 (95% CI 1.01-3.89).

had identified an association between vaccination and gout for RZV for shingles, showing a 3.6-fold increased risk of a gout flare for gout patients receiving that vaccine. A total of 27 patients who had the vaccine had a flare during the subsequent month, compared with eight patients given placebo.

In spite of an apparent increased risk for a gout flare, "the benefits of vaccinations on both individual and public health are overwhelming and cannot be emphasized enough," said the first author of the new study, Chio Yokose, MD, also of MGH. "In particular, patients with gout often are older and/or have multiple comorbidities, constituting subpopulations who stand to benefit the most from routine adult vaccinations," Yokose told MedPage Today.

Other research has suggested that the inflammatory cascade is what leads to the clinical manifestations of gout following activation of the NLRP3 inflammasome and the resultant release of interleukin-1β. RZV contains a non-aluminum adjuvant that is also thought to activate the NLRP3 inflammasome through signaling in the innate immune system. Aluminum adjuvants contained in many other adult vaccines, such as tetanus/diphtheria/pertussis and the pneumococcal and hepatitis B vaccines also have been shown to activate the inflammasome pathway.

In order to follow up on the initial evidence for an increased risk of gout flare with vaccination, Choi, Yokose, and team decided to follow gout patients who received a range of vaccines to determine whether flares resulted from other types of vaccines.

The researchers recruited 517 gout patients during 2003 to 2010. Participants completed online questionnaires every 3 months during a year of follow-up and logged onto the study website at the time of each gout flare, answering questions about exposures such as purine and alcohol consumption and medication or vaccine exposure in the 2-day hazard period prior to the flare. Control periods were the 2-day periods with no flares reported in the routine 3-month questionnaires.

"The case-crossover study design allows each participant to serve as his/her own control, thereby eliminating time-fixed confounding between participants," the authors explained.

The mean age of the patients was 55, and disease duration was 7.9 years; almost 80% of participants were men, and the majority were white.

During the 1-year follow-up, participants completed 990 hazard period questionnaires, with 28 patients reporting being vaccinated during the prior 2 days. Participants also completed 1,407 control period questionnaires, in which there were 21 vaccinations given, with logistic regression identifying a twofold higher risk of flare during the hazard periods compared with control periods.

The risks were further increased among men, whose adjusted odds ratio of gout flare following vaccination was 2.35 (95% CI 1.12-4.92). Greater risks also were seen for patients younger than 60, those with more alcohol and purine consumption, and those receiving diuretics, allopurinol, and nonsteroidal anti-inflammatory drugs, but these differences were not statistically significant, the researchers said.

"Our findings are novel because for the first time, we have identified a trigger for gout flares that presumably acts through the inflammasome pathway, as opposed to changes in serum urate," Yokose explained.

Nonetheless, the overall risk of gout flare was low. "Thus, we are not advocating that patients with gout opt out of vaccines recommended by their doctors based on the findings of our study," he cautioned. "Future studies could investigate the ability of prophylactic anti-inflammatory medication use, such as with colchicine, on mitigating the risk of gout flares associated with vaccination without compromising vaccine efficacy," Yokose concluded.

Limitations of the study, the team said, included the reliance on self-reporting for exposures and vaccinations, as well as the relatively small number of flares reported.

Source Reference: 2019: DOI:10.1136/annrheumdis-2019-215724

Study Highlights: Explanation of Findings

In two phase III studies of RZV, safety data indicated that gout patients had a 3.6-fold higher risk of having a flare following vaccination. The researchers theorized that the strong non-aluminum adjuvant used in the vaccine might be responsible for activation of the NLRP3 inflammasome.

The NLRP3 protein in cells "senses" a wide array of microbial fragments, endogenous danger signals, and environmental irritants, and forms and activates the NLRP3 inflammasome. This leads to caspase 1-dependent release of the pro-inflammatory cytokines interleukins 1β and 18. A cytosolic innate immune signaling receptor, once activated, initiates an inflammatory cell death response, and results in rodent models of a wide range of inflammatory diseases.

The new case-crossover study tested the hypothesis that other vaccines elicit an inflammatory response in gout patients, producing a gout flare response in these patients following vaccination. The team found that among 517 patients with gout, vaccines other than RZV are associated with a two-fold higher odds of a gout flare in the 2 days after vaccination (adjusted OR 1.99; 95% CI 1.10 to 3.89).

"These findings warrant further investigation into whether temporary prophylactic use of anti-inflammatory medications may mitigate the risk of gout flares with vaccination without affecting vaccine efficacy," the researchers wrote, adding, however, that "importantly," the findings "must be interpreted within the context of the overwhelming benefits of vaccines worldwide."

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