February 22, 2018
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Staying on Top of Vaccination Schedules in Patients With Rheumatologic Diseases

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Widely regarded as one of the greatest public health achievements of the last century, vaccines have played a significant role in controlling — and in some cases eliminating — the burden of infectious diseases that were considered commonplace only a generation ago.

In addition to providing protection for vaccinated individuals, vaccination programs also foster ‘herd immunity’ in which the prevalence of immunity among a population reduces the risk for infection among unvaccinated members of the community, including patients with rheumatologic diseases. However, to remain successful in curtailing prevalence and incidence of vaccine-preventable diseases, vaccination programs require high uptake levels — a goal in continuous danger of being derailed by lax vaccination policies and resurgences of the “anti-vaccine movement.”

Patients with rheumatic diseases already bear a twofold increased risk for infection compared to healthy individuals, a risk that rises with the use of immunosuppressive drug therapies. Rheumatologists are often left in a gray area when considering vaccination for their patients: While these patients are more susceptible and therefore in greater need of the protection afforded by vaccination, the vaccines in and of themselves may carry increased risks for immunocompromised patients.

Leonard H. Calabrese, DO
Leonard H. Calabrese, DO, professor of medicine at the Cleveland Clinic, discusses the increased risk of herpes zoster, influenza and pneumococcal infections among immunocompromised patients, and how rheumatologists can address the problem.

Source: Cleveland Clinic Center for Medical Art & Photography

Two key concerns for rheumatologists include the use of certain therapies — such as methotrexate, rituximab (Rituxan, Genentech), and, in some cases, tofacitinib (Xeljanz, Pfizer) — which have been shown to reduce immune responses to some vaccines, and the novel herpes zoster vaccine Shingrix (GlaxoSmithKline) that has been approved with essentially no patient data for rheumatic or autoimmune diseases.

While Zostavax (Merck) has much more data available for clinicians to draw from, it presents clinical challenges because it is a live vaccine, thus potentially posing a threat to immunocompromised patients who theoretically could develop clinical infection from the vaccine. Regarding influenza vaccination, patients with rheumatologic diseases face the same key obstacle that individuals in the general population face: that the efficacy of the vaccine can vary greatly from year to year. Although there is no such concern for pneumococcal vaccination, the scheduling of this vaccine — one dose of pneumococcal conjugate vaccine-13 (PCV13; Prevnar 13, Pfizer) and two doses of pneumococcal polysaccharide vaccine (PPSV23; Pneumovax23, Merck) — can be confusing and difficult to monitor for both clinicians and patients.

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These complications contribute to a larger concern, which is that rates of vaccination tend to be lower in patients with rheumatic and autoimmune diseases than in other populations. Rheumatologists may be waiting for primary care providers to vaccinate their patients, and vice versa.

Leonard H. Calabrese, DO, professor of medicine at the Cleveland Clinic and Chief Medical Editor of Healio Rheumatology, laid out the two key issues underlying these clinical factors. “One issue is that many of the drugs we use impact the response to vaccines,” he said. “Our patients are particularly vulnerable.”

The second issue pertains to practice management. “We need to do a better job of vaccinating our patients,” he said. “What are we doing to protect them from downstream complications associated with herpes zoster, influenza or pneumococcal disease?”

Stephen M. Lindsey, MD, from Ochsner Health System in New Orleans, acknowledged the multifactorial and somewhat confusing interactions between rituximab, abatacept (Orencia, Bristol-Myers Squibb), disease-modifying antirheumatic drugs (DMARDs) and various vaccinations, but stressed that this should not deter rheumatologists. “You have to be on your toes,” he said. “But a culture of safety and prevention of disease is the future. Infection is the biggest risk for every biologic that hits the market. We need to think of prevention rather than treating diseases retroactively — vaccination is the most important component of this approach.”

For Lindsey, practice management is critical. “We can’t just be checking boxes or, worse, not checking boxes, during a patient visit,” he said. “We have to give some thought to the click, especially since the risks associated with flu or zoster, such as increased hospitalization, are doubled in patients with rheumatologic diseases.”

Stephen M. Lindsey, MD
Stephen M. Lindsey

Calabrese stressed that support staff, including nurses, are critical in administering vaccinations. Elizabeth Kirchner, CNP, from the department of rheumatologic and immunologic disease at Cleveland Clinic, agreed. “Nurse practitioners, physician assistants and nurses typically address health maintenance issues with patients during follow up outpatient clinic visits,” she said. “At the Cleveland Clinic Foundation, we have a prompt within our electronic medical record (EMR) to remind us when patients are due for immunizations. The vaccines can be ordered either by nurse practitioners, physician assistants or physicians and can be administered by nursing staff.”

Renewed attention has come to the topic with the introduction of the novel zoster vaccine and with influenza data that made a splash at the American College of Rheumatology annual meeting in 2017 suggesting that temporary discontinuation of methotrexate after seasonal influenza vaccination may improve response rates.

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Discontinuing methotrexate

In their study presented at ACR, Park and colleagues investigated whether RA patients benefitted from temporary discontinuation of methotrexate following seasonal influenza vaccination. The study included 54 patients in group one who continued methotrexate, 44 patients in the second group who discontinued for 4 weeks before vaccination, 49 patients in the third group who suspended methotrexate for 2 weeks before vaccination and 2 weeks after, and 52 patients in the fourth group who suspended methotrexate for 4 weeks after vaccination.

The third group experienced a 51% response to the vaccine, compared with 31.5% for the first group (P = .044). The fold increase of antibodies against H3N2 was significantly higher among individuals in the third (12.2; P < .001) and fourth (10.0; P = .043) groups than in the first group (5.9; 95% CI, 4.3-8.1). A similar result was reported for anti-B-Yamagata antibodies, with the fold increase reaching 4.7 (P = .048) for group three and 6.1 (P < .001) for group four, compared with 2.9 (95% CI, 2.2-3.8) for group one.

Clinicians observed RA flares in 24.1% of patients in the first group, 21.2% of those in the second, 34.1% of those in the third, and 38.8% of those in the fourth (P = NS). “Temporary methotrexate discontinuation improves the immunogenicity of seasonal influenza vaccination in patients with RA,” the researchers concluded.

“Recent data strongly suggest that methotrexate should be held for 2 weeks after the flu vaccine is administered,” Kirchner said.

For Jeffrey Curtis, MD, MS, MPH, William J. Koopman endowed professor of rheumatology and immunology at the University of Alabama at Birmingham, this finding speaks to larger concerns with therapies for rheumatic diseases and vaccination. “Methotrexate will attenuate vaccine response,” he said. “However, although not statistically significant, a 10% or higher flare rate among patients that temporarily discontinue methotrexate should not be ignored —from a practical perspective, I’m not sure that it is worth it to hold methotrexate routinely. In contrast, if patients have been treated with rituximab in the last month or 2, they probably will not respond to any vaccine, and clinicians definitely need to be attentive to proper vaccination timing for these patients.”

Other therapies attenuate response to varying degrees, according to Curtis. “There is some reduced response with abatacept and steroids,” he said. “TNFs given without methotrexate do not seem to have this effect.”

Jeffrey Curtis, MD, MS, MPH
Jeffrey Curtis

Poor uptake rates

Beyond clinical response, a larger concern is that patients are simply not vaccinated as frequently as they should be. While significant research has been devoted to this problem, Curtis believes the solution can be relatively simple for vaccines given infrequently, such as the pneumonia or shingles vaccine. “When someone is diagnosed with a rheumatic or autoimmune disease, vaccinate them with everything they are supposed to receive right then,” he said.

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However, the clinical community generally does a poor job of vaccinating patients, according to Kevin L. Winthrop, MD, MPH, professor at Oregon Health & Science University. “Influenza and pneumococcal vaccination rates are not where they should be,” he said. “For shingles, the rates are also very low. We can certainly improve.”

Kirchner offered a solution. “Several institutions have tried using best practice alerts in their EMRs as well as flags on infusion ordering forms to remind providers to update vaccines before starting new medications,” she said.

But the obstacles are myriad, Winthrop reported. “Some patients don’t want to get vaccinated because they either heard something bad about it or had a bad experience themselves,” he said. “There are also communication issues between clinicians: Rheumatologists think primary care clinicians should handle it, and vice versa. I don’t know how to solve this problem other than through open communication and sharing of records. Or perhaps, a better solution is for whichever clinician thinks of it first, to just get it done.”

Winthrop also suggested that a lack of data may contribute to low vaccination rates. “While most vaccines appear safe, we often lack efficacy data within rheumatic disease patients,” he said. “We tell our patients to get it, but if we don’t know how well it works, they are less inclined to get it.”

Kevin L. Winthrop, MD, MPH
Kevin L. Winthrop

“The major issue here is developing systems to make sure our patients are vaccinated,” Calabrese said. “The [Infectious Diseases Society of America] says three-dimensional conversations need to be happening to ensure these patients don’t fall through the cracks.”

Novel zoster vaccine

While there is no shortage of data on Zostavax — the long-standing live zoster vaccine — among healthy older patients in the general population, Zostavax has almost no data in this patient population. However, Winthrop and Curtis are seeking to rectify that. “Kevin and I are currently running a trial —the VERVE study —in which we have randomized more than 400 people older than 50 years to receive anti-TNF therapy with no cases of disseminated varicella, and nothing that resembles chicken pox or shingles,” he said. “The trial is ongoing, but the results so far are encouraging.

Curtis noted that “there is a new herpes zoster vaccine, Shingrix, that was recently FDA approved and will soon be available. A potential advantage of this vaccine is that it is not a live vaccine,” he said. “You cannot get varicella infection, which is at least the theoretical risk with Zostavax.”

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However, this is not to say that there are not warning flags, according to Curtis. “Because it works so well, it really revs the immune system up,” he said. “If you have an autoimmune disease like rheumatoid arthritis, psoriasis or Crohn’s disease, it has the potential to cause significant problems —we just don’t know because there is no data.”

Another factor is that Shingrix requires a two-dose schedule. “Many patients will simply not follow up for the second dose, and there are essentially no data to tell us what could happen or how long it works if a patient doesn’t receive the second dose,” Curtis said.

He also added that grade 3 systemic reactions are common with the first dose, with individuals getting sick and failing to report to work the next day. “If this vaccine makes one in six people ill, what is the likelihood that those affected individuals will get a second dose? And if they are brave enough to get the required second dose, the frequency of grade 3 reactions is even higher.”

Cost may also be an issue, said Curtis, who noted that Shingrix is likely to be somewhat more expensive than Zostavax. “There are a whole bunch of question marks and zero data on people with rheumatic diseases,” he said. “I don’t know that Shingrix will be the automatic panacea that we might have hoped for. We need to understand the flare rate and frequency of grade 3 systemic symptoms much better for people with autoimmune diseases.”

For Calabrese, a lack of warning label for patients with autoimmune diseases is a notable concern. “Some of us are concerned because we don’t know that much about it right now,” he said. “This is of particular importance because we have recently learned that zoster increases the risk for stroke and myocardial infarction. What are we doing to protect our patients from these complications?”

Elizabeth Kirchner, CNP
Elizabeth Kirchner

Shifting back to Zostavax, Lindsey suggested that the VERVE study, which is ongoing and aims to evaluate the vaccine in 1,000 patients being treated with biologic therapies, may be an important data set for assuaging lingering concerns about vaccinating these patients. “Signs indicate that we have been over-cautious and can likely vaccinate these patients much more safely than we thought,” he said. “We should be vaccinating all people who meet criteria.”

Calabrese noted that patients aged 50 years or older who have rheumatic or immunologic diseases can be safely vaccinated, even if they are being treated with glucocorticoid doses as high as 20 mg per day and standard doses of nonbiologic immunosuppressive therapies.

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Tofacitinib and zoster

In a recent study published in Arthritis and Rheumatology, Winthrop and colleagues investigated the impact of tofacitinib on immune response and safety of the live zoster vaccine (Zostavax) in a cohort of 112 patients aged 50 years or older who had active RA. The researchers measured humoral responses and cell-mediated responses at baseline, 2 weeks, 6 weeks and 14 weeks after vaccination in 55 patients who were treated with tofacitinib and 57 who received placebo. Geometric mean fold rise in varicella zoster virus-specific IgG levels served as the primary endpoint, while T cells at 6 weeks served as a secondary endpoint.

At the 6-week mark, the IgG levels were 2.11 for tofacitinib and 1.74 for placebo. Virus-specific T cell geometric mean fold rise rates were 1.5 for the active treatment group and 1.29 for placebo, which the researchers noted were similar. Three patients in the tofacitinib arm and zero patients in the placebo arm developed serious adverse events.

“Patients who began treatment with tofacitinib 2 to 3 weeks after receiving [live zoster vaccine] had [varicella zoster virus]-specific humoral and cell-mediated immune responses to [live zoster vaccine] similar to those in placebo-treated patients. Vaccination appeared to be safe in all of the patients except one patient who lacked preexisting [varicella zoster virus] immunity,” the researchers concluded.

In another data set from Winthrop and colleagues investigating tofacitinib and the risk of zoster, the researchers aimed to determine if concomitant treatment with DMARDs or glucocorticoids increased risk for disease. The meta-analysis included 16,839 patient-years from 6,192 patients. Results showed herpes zoster was reported in 636 patients treated with tofacitinib (incidence rate = 4; 95% CI 3.7-4.4). Non-serious disease accounted for 93% of these cases, while 94% had disease that involved just one dermatome.

Findings from the phase-3 studies showed that incidence ratios for tofacitinib use, background DMARD use, and baseline use of glucocorticoids varied. Patients treated with tofacitinib at a dose of 5 mg twice daily without glucocorticoids carried the lowest incidence rate, at 0.56 (95% CI, 0.07-2.01) per 100 patient years, while 10 mg twice daily with DMARDs and glucocorticoids carried a rate of 5.44 (95% CI, 3.72-7.68) per 100 patient years.

“Age, [glucocorticoid] use, tofacitinib dose, and enrollment within Asia were independent risk factors for [herpes zoster],” the researchers wrote. “Patients receiving treatment with tofacitinib and [glucocorticoids] appear to have a greater risk of developing [herpes zoster] compared with patients receiving tofacitinib monotherapy without [glucocorticoids].”

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“Zoster gained a lot of interest in the rheumatology field when tofacitinib came out,” Curtis said. “It doubles or triples the rate of zoster reactivation compared to other arthritis therapies. This is probably a class effect for the JAK family, and it’s been similarly seen with baricitinib. The reason that infection gets our attention is that it’s preventable through zoster vaccination.”

Issues with influenza

Hua and colleagues conducted a literature review to investigate RA therapies on the humoral response to pneumococcal and influenza vaccines. Data from 12 studies showed a reduced response to H1N1 influenza vaccination associated with rituximab (pooled OR = 0.44; 95% CI, 0.17-1.12), H3N2 (OR = 0.11; 95% CI, 0.04-0.31), and B (OR = 0.29; 95% CI, 0.1-0.81). However, no such effect was observed for patients treated with TNF inhibitors (OR = 0.93; 95% CI, 0.36-2.37) with H1N1, H3N2 (OR = 0.79; 95% CI, 0.34-1.83), or B (OR = 0.79; 95% CI, 0.37-1.7). Data were unclear for methotrexate and depended on the method of analysis, according to the researchers.

Among 139 patients treated with methotrexate who received pneumococcal vaccination, response was lower compared with controls for serotype 6B (OR = 0.33; 95% CI 0.2-0.54) and 23F (OR = 0.58; 95% CI, 0.36-0.94). However, patients treated with TNF inhibitors who received pneumococcal vaccination did not have a reduced response for 6B (OR = 0.96; 95% CI 0.57-1.59) or 23F (OR = 1.20; 95% CI 0.57-2.54). Rituximab also reduced pneumococcal vaccine response (OR = 0.25; 95% CI, 0.11-0.58) for 6B and 23F (OR = 0.21; 95% CI, 0.04-1.05).

“Methotrexate decreases humoral response to pneumococcal vaccination and may impair response to influenza vaccination,” the researchers concluded. “The immune response to both vaccines is reduced with [rituximab] but not with anti-TNF alpha therapy in RA patients.”

“Other than findings for methotrexate, the flu vaccine generally holds up well with biologics,” Winthrop said. “Of course, however, rituximab is going to annihilate response, and there is not much data for abatacept.”

Kirchner zeroed in on rituximab as a key area of concern. “As far as treatment decisions, it is an issue for live vaccines and all biologics as well as all vaccines with rituximab,” she said. “The best you can do is try to vaccinate as far away from rituximab as possible, but sometimes that is just not possible.”

An important issue is the variation in vaccine efficacy from year to year, according to Calabrese. “Even though it is a lousy vaccine this year, our patients are vulnerable to influenza,” he said.

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Lindsey noted an age component to influenza vaccination. “People hear that influenza is dangerous for people younger than 2 years and older than 60,” he said, adding that uptake can also be an issue. “When patients are up to about 60 years old, the vaccination rates are around 60% or 70%, but when you get down to 20-year-olds, it is about 20%. We vaccinate about 90% of our patients, and that is what we should expect. We are never going to reach 100%, but we can do better.”

PCV13 and PPSV23

In a recent study published in Joint Bone Spine, Rákóczi and colleagues investigated the immunogenicity of PCV13 in a cohort of 15 RA patients receiving treatment with etanercept and methotrexate and seven patients receiving etanercept monotherapy, while 24 individuals with osteoarthritis not receiving either of these therapies served as a control arm. Both study arms demonstrated similar anti-pneumococcal antibodies at 4 weeks after vaccination, according to the findings. This trend held through week 8, with a slight drop in antibody levels reported. However, mean protective antibody levels were higher in the control arm than in the study arm at 4 weeks (P = .016) and 8 weeks (P = .039) compared with levels post-vaccination.

“There were no clinically significant side effects or reactions after administration of vaccine observed in any of these patients after the 2-month follow-up period, all patients’ medical conditions were stable,” the researchers wrote. “In RA patients treated with [etanercept], vaccination with PCV13 is effective and safe, resulting in [protective antibody response] one and two months after vaccination. The vaccine is safe in RA patients on [etanercept].”

To further assess the impact of pneumococcal vaccines, Kapetanovic and colleagues studied antibody responses among 253 immunosuppressed RA patients who received the heptavalent pneumococcal conjugate vaccine (PCV7), along with another 149 RA patients and 47 healthy controls who received PPSV23. RA patients were receiving methotrexate, anti-TNF therapy, or a combination of those two treatments. Similar antibody response ratios and positive antibody responses were reported for both serotypes that was not contingent upon the vaccine used, according to the findings.

Reduced positive antibody response for both serotypes as observed in patients who were older at vaccination and among those treated with methotrexate. However, vaccine type failed to demonstrate a significant impact on positive antibody response. “PCV7 elicits similar antibody response as PPSV23 in patients with RA receiving immunosuppressive treatment,” the researchers concluded.

Winthrop summed up the drug-drug interaction story for pneumococcal vaccines. “It is largely the same story as other vaccines, where rituximab is going to annihilate the response, and methotrexate and tofacitinib will decrease PPSV23 response,” he said. “For the new conjugate vaccine, PCV-13, there is still not enough data.”

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In another study, Winthrop and colleagues investigated a cohort of 60 patients with psoriasis being treated with 10 mg tofacitinib twice daily who received T cell-dependent vaccines, including the monovalent tetanus toxoid and PCV13. The researchers assessed patients for humoral responses to the tetanus vaccination and for serotype-specific opsonophagocytic antibody responses for PCV13. Results at 4 weeks showed a mean fold increase from baseline ranging from 8.3 for serotype 3 to 101.9 for serotype 6A.

An increase of twofold or greater of antibody concentration was reported among 88% of patients receiving the tetanus toxoid vaccine, while 60% of patients receiving this vaccine experienced an increase of fourfold or greater. “The majority of psoriasis patients who receive tofacitinib can mount satisfactory T cell-dependent responses to PCV-13 and tetanus vaccines,” the researchers concluded.

Lindsey acknowledged the confusing nature of pneumococcal vaccination. “There are two different vaccines on two different schedules,” he said. “If a patient has already had PPSV23, they have to wait a year to get PCV13. If you get PCV13, you are supposed to wait 8 weeks for immunocompromised patients.”

For Lindsey, the difficulty is that patients are often responsible for remembering which dose of which vaccine they have received. “It’s not that complicated for a clinician to document,” he said. “For patients, it is a different story, because — especially for our patients — this is just one part of a complicated medical history. This leads to a fragmentation of care.”

Lindsey noted that giving the vaccines out of sequence is not necessarily dangerous, but it is still not ideal. He also voiced another concern. “Direct-to-consumer advertising doesn’t help,” he said. “The messaging for Prevnar is that it’s one and done; however, you need Pneumovax as a booster, which is two doses for a total of three. Patients may not realize that.”

Calabrese summed up many of these challenges rheumatologists face. “There are a number of barriers to immunization,” he said. “The more we can discuss them, and discuss strategies for overcoming them, the better off our patients will be.” – by Rob Volansky

Disclosures: Calabrese reports consulting, teaching and speaking for AbbVie, Bristol-Myers Squibb, Genentech/Roche and Janssen; consulting for GlaxoSmithKline, Pfizer and UCB; and teaching and speaking for Crescendo. Curtis reports support from AbbVie, Roche/Genentech, BMS, UCB, Myraid, Eli Lilly, Amgen, Janssen, Pfizer, Corrona and Crescendo. Kirchner and Lindsey report no relevant financial disclosures. Winthrop reports he consults for and receives a research grant from Bristol-Myers Squibb; is a consultant for AbbVie, Galapagos, Genentech/Roche, Eli Lilly, Pfizer and UCB.