Key points

Introduction

Patients with rheumatoid arthritis (RA) are at greater risk of infectious complications, which is likely attributed both to medications used to treat RA, and to abnormalities in their immune systems. Because of this, vaccinations against influenza, pneumococcus, shingles, and other infections are important in the care of patients with RA. Unfortunately, vaccination rates for patients with RA in the United States remain low. Only approximately 28.5% of patients with RA in the United States are optimally vaccinated against pneumococcal pneumonia, 45.8% are optimally vaccinated against influenza, and as of 2012 only 4.0% of patients with rheumatic diseases older than 60 were vaccinated against shingles.

As the arsenal of immuno-modulatory medications used to treat RA grows, important questions arise regarding the safety and efficacy of vaccinations in the setting of these medications. Safety of vaccinations has primarily been of concern with live vaccinations, such as shingles and yellow fever (YF), due to a concern of severe infections following live vaccination of an immunosuppressed patient on a biologic drug. As we discuss in this article, trials to evaluate the true risk of these vaccines in the setting of biologic use are not yet available, although observational studies of patients treated with biologics inadvertently vaccinated with live vaccines suggest they may be safer than previously thought.

Reduced efficacy of vaccines in the setting of disease-modifying antirheumatic drug (DMARD) use is a concern across all vaccination types. The efficacy of a vaccine in preventing an infection is difficult to measure in small trials, and typically these studies evaluate immunogenicity of a vaccine as a surrogate for efficacy. We currently have studies to evaluate the impact of a number of DMARDs on vaccine immunogenicity, which are discussed in this review; however, numerous gaps in our knowledge still exist and these gaps continue to grow as more biologic agents enter the market and vaccine formulations continue to change. In this review, we summarize the current available data for each DMARD and its influence on various vaccine immunogenicity. We also discuss vaccination recommendations and schedules as they apply to patients with RA, and summarize remaining gaps in our understanding of the influence of DMARDs on vaccine safety and immunogenicity.

Introduction

Patients with rheumatoid arthritis (RA) are at greater risk of infectious complications, which is likely attributed both to medications used to treat RA, and to abnormalities in their immune systems. Because of this, vaccinations against influenza, pneumococcus, shingles, and other infections are important in the care of patients with RA. Unfortunately, vaccination rates for patients with RA in the United States remain low. Only approximately 28.5% of patients with RA in the United States are optimally vaccinated against pneumococcal pneumonia, 45.8% are optimally vaccinated against influenza, and as of 2012 only 4.0% of patients with rheumatic diseases older than 60 were vaccinated against shingles.

As the arsenal of immuno-modulatory medications used to treat RA grows, important questions arise regarding the safety and efficacy of vaccinations in the setting of these medications. Safety of vaccinations has primarily been of concern with live vaccinations, such as shingles and yellow fever (YF), due to a concern of severe infections following live vaccination of an immunosuppressed patient on a biologic drug. As we discuss in this article, trials to evaluate the true risk of these vaccines in the setting of biologic use are not yet available, although observational studies of patients treated with biologics inadvertently vaccinated with live vaccines suggest they may be safer than previously thought.

Reduced efficacy of vaccines in the setting of disease-modifying antirheumatic drug (DMARD) use is a concern across all vaccination types. The efficacy of a vaccine in preventing an infection is difficult to measure in small trials, and typically these studies evaluate immunogenicity of a vaccine as a surrogate for efficacy. We currently have studies to evaluate the impact of a number of DMARDs on vaccine immunogenicity, which are discussed in this review; however, numerous gaps in our knowledge still exist and these gaps continue to grow as more biologic agents enter the market and vaccine formulations continue to change. In this review, we summarize the current available data for each DMARD and its influence on various vaccine immunogenicity. We also discuss vaccination recommendations and schedules as they apply to patients with RA, and summarize remaining gaps in our understanding of the influence of DMARDs on vaccine safety and immunogenicity.

Recommendations for vaccination in patients with rheumatoid arthritis

Although all vaccines may be potentially important in patients with RA, in this review, we focus on influenza, pneumococcal, shingles, human papilloma virus (HPV), hepatitis B virus (HBV), and YF vaccines ( Table 1 ). The first 3 of these are important for all patients with RA, whereas the latter 3 are relevant only in select patients. The influenza vaccine is available as an intramuscular vaccine and a live intranasal vaccine, the later of which is contraindicated in the setting of immunosuppression. The intramuscular vaccine is traditionally a trivalent vaccine protecting against 2 influenza A strains and 1 influenza B strain; however, recently a quadrivalent form became available that protects against an additional B strain. All patients with RA should receive a yearly intramuscular influenza vaccine, and patients older than 65 should receive the high-dose vaccine, which has been shown to be more effective in this age group in the general population. The high-dose vaccine is available only for the trivalent vaccine, and this high-dose vaccine has not yet been evaluated specifically in patients with RA.

The pneumococcal vaccine is available in the United States as a 13-valent conjugate vaccine (PCV-13), and a 23-valent polysaccharide vaccine (PPSV-23). Conjugate vaccines are generally more immunogenic than polysaccharide vaccines, although in patients with RA the previous 7-valent conjugate vaccine (PCV-7) was found to be no more immunogenic than the PPSV-23 vaccine. The newer PCV-13 vaccine has not yet been extensively evaluated for immunogenicity in the setting of DMARD therapy, although 1 study so far has found lower yet adequate antibody levels in 22 patients with RA taking etanercept and methotrexate (MTX) compared with controls without RA. For all immunosuppressed adults naive to pneumococcal vaccinations, the Centers for Disease Control and Prevention (CDC) recommends vaccination with PCV-13 followed by PPSV-23 ≥8 weeks to 1 year later. If patients have already received PPSV-23, PCV-13 should be given ≥1 year after PPSV-23. PCV-13 is a once in a lifetime vaccine. PPSV-23 given before the age of 65 is followed by a single booster after 5 years, and then a final dose after the age of 65; doses of PPSV-23 should be separated by at least 5 years. This vaccination schedule, however, has not been specifically evaluated in the setting of patients with RA or DMARD therapy.

The herpes zoster or shingles vaccine is a live vaccine and is contraindicated in the setting of biologic therapy or high-dose corticosteroids. There are nonlive shingles vaccines in development that might eventually be a good option for this patient population; however, at this time only the live vaccine is commercially available in the United States. This vaccine is approved for adults older than 50; however, citing differences in cost-effectiveness and concerns of decreased efficacy over time, the CDC recommends the vaccines only after the age of 60 in the general population. These cost-effectiveness analyses were not done specifically for RA, however, and because of the high risk of shingles infection in these patients, the American College of Rheumatology (ACR) guidelines recommend vaccinating immunocompetent patients with RA who are older than 50. Data are not available regarding safe levels of immunosuppressant medications at which the shingles vaccine can be given; however, based on expert opinion guidelines, the CDC advises that the shingles vaccine can be used safely with MTX (<0.4 mg/kg per week; eg, 25 mg/wk); low to moderate doses of glucocorticoids (<20 mg/d prednisone or equivalent); intra-articular, bursal, or tendon corticosteroid injections; and azathioprine (<3.0 mg/kg per day). If patients on biologic therapy are to be vaccinated for shingles, it is recommended to wait at least 1 month after discontinuation of biologics before giving the vaccine, or vaccinating 2 to 4 weeks before starting a biologic. These wait times are recommended broadly for all immunosuppressant medications, but because the duration of immuno-modulatory effect varies greatly among biologics, this recommendation should be considered carefully in patients taking biologics with longer effect duration.

Several other vaccinations, such as YF, HPV, and HBV, become important for select patients with RA such as those living in or traveling to a YF-endemic country, those in a younger age group, and those at risk of HBV. The YF vaccine is a live vaccine and similarly to shingles is contraindicated in all patients on immunosuppression.

The HPV vaccine is available as a bivalent, quadrivalent, and more a recently 9-valent vaccine; the 9-valent vaccine covers strains 6, 11, 16, 18, 31, 33, 45, 52, and 58, and is now the preferred vaccine. All male and female children should be vaccinated at age 11 or 12. Female patients who were not previously vaccinated should receive the vaccine between ages 13 and 26. Male patients typically are recommended to be vaccinated only through age 21; however, immunosuppressed men should be vaccinated through age 26. The HPV vaccine should be given to any patient with RA if it would normally be indicated regardless of immunosuppression.

HBV vaccination is of particular importance in patients with RA, as biologic therapy can increase the risk of reactivation in those infected. Before initiating biologic therapy, HBV serology should be checked in all patients. Patients are considered to be immune if they have positive hepatitis B surface antibody (either by natural infection if they are hepatitis B core antibody positive, or by vaccination if they are hepatitis B core antibody negative). All those who are hepatitis B surface antibody negative are considered nonimmune, and vaccination is recommended for all nonimmune patients with RA with risk factors for acquiring HBV. Risk factors include having a household contact or sexual partner who is hepatitis B surface antigen (HBsAg) positive; having more than 1 sexual partner in the previous 6 months; seeking evaluation for treatment of a sexually transmitted disease; men who have sex with men; current or recent intravenous (IV) drug use; residing or working in a facility for the developmentally disabled; working in health care; traveling to endemic areas; having diabetes, human immunodeficiency virus, end-stage renal disease, or chronic liver disease; and using glucometers for diabetes.