1. Vaccination in autoimmune diseases
Presented by: Medha Soowamber MD, FRCPC
February

2. Table of contents Risk factors for infection in autoimmune diseases
Live versus Inactivated vaccines
Timing of vaccination
Vaccines:
Influenza, Pneumococcal, Hepatitis B, Herpes Zoster,
HPV

3. Infection Risk
Infections are a major cause of morbidity and mortality in patients with autoimmune rheumatic diseases (AIRD).
Factors contributing to the increased risk for infection include:
Immune system dysfunction (underlying disease)
Premature “ageing” of the immune system
Comorbidities
Frequent hospitalizations /surgical procedures
Use of immunosuppressive medications
Factors contributing to the increased risk for infection include:
Westra, J et al. Nat Rev Rheumatol Mar;11(3):
Papadopoulou, D et al. Rheumatol Int Feb;34(2):

4. A few facts ...
In RA patients: Incidence of severe infections is ~2x > the general population.
TNFα antagonists 2‐fold increased risk of infection compared with patients receiving DMARD therapy.
4-fold increase in infection in the first 6 months after receiving TNFα antagonists.
In SLE patients, infection is responsible for as many as 25% of all deaths.
Curtis JR et al. Arthritis Rheum Apr;56(4):

5. A few facts...
The most effective way to prevent infectious diseases is immunization.
Patients with an autoimmune disease are NOT at risk of exacerbation after administration of any of the available vaccines.
Several vaccine-preventable infections are known to negatively affect the course of autoimmune diseases.
Wraith et al. Lancet Nov 15;362(9396):

6. Live versus Inactivated vaccines
Live attenuated
Whole living bacteria or virus
Inactivated
Killed virus or bacteria
Bombardier et al. J Rheumatol Aug;39(8):

7. Live versus Inactivated vaccines
Vaccines can either be live attenuated or inactivated: Live attenuated vaccines contain whole, living bacteria or
viruses, which induce immunity by actively replicating within the host. Patients receiving immunosuppressive therapy may be at increased risk for disseminated infection if live
attenuated vaccines are given. Inactivated vaccines contain killed bacteria or viruses. These vaccines may induce broad
immunity because multiple antigens are present and pose no
increased risk to immunocompromised persons. However,
because the response may be weaker than that induced by live
organisms, multiple doses are usually needed
; Shingrix
Bombardier et al. J Rheumatol Aug;39(8):

8. When to administer vaccines?
Ideally:
During stable disease
Before initiating immunosuppressive therapy
Inactivated vaccines:
Can administer at any time before (14 days), during or after immunosuppression.
Wherever feasible, persons with RA should be immunized at times when a maximum immune response can be anticipated (i.e., before initiating immunosuppressive therapy)
inactivated vaccines should be administered at least 14 days before initiation of immunosuppressive therapy to optimize immunogenicity (2 weeks are required for the development of an immune response.)
Although inactivated vaccines can be safely administered at any time before, during or after immunosuppression, inactivated vaccines should be administered at least 14 days before initiation of immunosuppressive therapy to optimize immunogenicity.
From the Canadian Immunization Guide: Part 3 - Vaccination of Specific Populations

9. When to administer vaccines?
Live vaccines:
Avoid live vaccines during high level immunosuppressive therapy
Varicella + live herpes zoster vaccines (Zostavax) can be considered if on low dose methotrexate (≤ 0.4 mg/kg/week); azathioprine (≤ 3 mg/kg/day).
Administer at least 4 weeks before starting biologic DMARDs
****IN CONSULTATION WITH INFECTIOUS DISEASE
Live attenuated vaccines might lead to (severe) infections in immunosuppressed patients. It is not known what level of immunosuppression renders patients to be at risk for infections
caused by these vaccines, and this risk should be balanced to the risk of (severe) infection the vaccine aims to prevent.
Tanrıöver MD et al. Eur J Rheumatol. 2015;3(1):29-35.
From the Canadian Immunization Guide: Part 3 - Vaccination of Specific Populations

10. When to administer vaccines?
Live vaccines:
Delay for at least 2 years after leflunomide (unless washout done).
Administer at least 4 weeks before starting biologic DMARDs.
Safe time intervals for the administration of live vaccines after cessation of immunosuppressive vary.
****IN CONSULTATION WITH INFECTIOUS DISEASE
depending on the pharmacodynamics features of the drugs.
What if a patient is on ….
Tanrıöver MD et al. Eur J Rheumatol. 2015;3(1):29-35.
From the Canadian Immunization Guide: Part 3 - Vaccination of Specific Populations

11. When to administer vaccines?
Delay live vaccines 5 half-lives after the administration of biological agents
Wait for at least 4 weeks before starting immunosuppressive therapy, after the administration of the live vaccination.
****IN CONSULTATION WITH INFECTIOUS DISEASE
Tanrıöver MD et al. Eur J Rheumatol. 2015;3(1):29-35.
Bombardier et al. J Rheumatol Aug;39(8):

12. Special considerations
Live vaccines:
Prednisone:
Can be given immediately on discontinuation of high dose steroid therapy if duration <14 days.
Can be given on low-to-moderate dose (<20 mg/day of Prednisone) or physiologic replacement therapy (5-7.5 mg/day)
Rituximab:
Can be given 6 months POST Rituximab infusion
From the Canadian Immunization Guide: Part 3 - Vaccination of Specific Populations

13. Which vaccines? Before starting a cDMARD or a biologic DMARD*:
Influenza**
Pneumococcal**
Hepatitis B (in high risk patients)
Herpes Zoster vaccine***
Human Papilloma Virus (HPV) vaccine****
*ACR guidelines
**Strongly recommended
***CRA guidelines: if >60 years old
****Routine schedule: up to age 26
Singh JA, et al. Arthritis Care Res (Hoboken). 2012;64(5):
From Canadian Immunization Guide: Part 1 - Key Immunization Information
Westra J, et al. Nat Rev Rheumatol Mar;11(3):

14. Which vaccines?
Westra J, et al. Nat Rev Rheumatol Mar;11(3):

15. Influenza
Influenza vaccination is strongly recommended for patients with rheumatological diseases. EVERY PATIENT EVERY YEAR

16. Influenza
46,000 patients with rheumatoid arthritis and matched controls.
RA is associated with increased incidence of seasonal influenza.
Presence or absence of DMARDs or biologics had no significant effect.
2.75-fold increase in incidence of influenza complications in RA.
A study involving 46,000 patients with rheumatoid arthritis and matched controls reported that the complications of influenza were increased 2.75 folds in patients with rheumatoid arthritis than in those without the condition and this risk has been reported to be independent of the drug used.
Blumentals WA et al. BMC Musculoskelet Disord. 2012;13:158

17. June 6, 2018 Flu Vaccine Cuts Mortality in Patients With Rheumatoid Arthritis
Receiving influenza vaccine was associated with reduced risk of hospitalization for septicemia, bacteremia or viremia and lower risk of mortality.
The effectiveness was particularly significant in elderly patients (>65).
In this retrospective nationwide study, we included 3748 RA patients who received influenza vaccinations in 2008, 2009 and 2010, and 3748 matched RA patients who did not receive influenza vaccinations. We followed the patients from 4 weeks after influenza vaccination to the end of the influenza season in each year.
Chen CM, et al. Int J Rheum Dis Jun;21(6):

18. Influenza vaccine: Increasing effectiveness
MTX discontinuation (>15mg/week) for 2 weeks after vaccination significantly increases the immunogenicity of a seasonal influenza vaccine in patients with stable RA.
Jin Kyun Park et al. Ann Rheum Dis 2018;77:

19. Satisfactory vaccine response at 4 weeks after vaccination in
Frequency of vaccination responses to the influenza antigens.
Satisfactory vaccine response at 4 weeks after vaccination in
MTX hold group
Frequency of vaccination responses to the influenza antigens. Satisfactory vaccine response, defined as greater than or equal to four fold increase of haemagglutination inhibition antibody titre at 4 weeks after vaccination against ≥2 of 4 vaccine strains (A) and against ≥1 of 4, ≥3 of 4 and 4 of 4 vaccine strains (B). Numbers in the bars indicate the percentage of satisfactory responders. Error bar represents 95% CI. P values were generated by Χ2 test. MTX, methotrexate.
Jin Kyun Park et al. Ann Rheum Dis 2018;77:
©2018 by BMJ Publishing Group Ltd and European League Against Rheumatism

20. Pneumococcal vaccine
The pneumococcal vaccine is recommended for patients with rheumatic diseases before or during treatment with traditional and biologic DMARD.
Van Assen S et al. Ann Rheum Dis Mar;70(3):

21. Invasive Pneumococcal disease (IPD)
Serious illness caused by the bacterium Streptococcus pneumoniae.
Occurs when the bacterium invades normally sterile sites, such as the bloodstream and central nervous system leading to several syndromes including bacteremia, meningitis, and/or pneumonia with bacteremia.
Can be spread from an infected person by droplets from the nose or mouth, by sneezing or coughing.
From NACI statement: Conjugate Pneumococcal Vaccine – 13 Valent in Adults

22. Invasive Pneumococcal disease (IPD)
Population-based surveillance for IPD conducted in Metropolitan Toronto and Peel Region from 1995 to 2012
IPD incidence was 12-fold higher in immunocompromised compared to immunocompetent persons.
Use of immunosuppressive medications is associated with a 2.1–2.7 fold increase in the risk of IPD.
Immunocompromised individuals comprised 28% of IPD.
Shigayeva et al. Clin Infect Dis Jan 15;62(2):

23. 2 forms of pneumococcal vaccine Polysaccharide vaccines
Conjugated vaccines
Polysaccharide vaccines
Longer lasting
Coming to our rescue is
There are two types of pneumococcal vaccine, both of which are inactivated:
Pneumococci bacteria is surrounded by a wall the wall, which is magnified, is called the polysaccharide capsule.(wall of the bacteria).
A polysaccharide vaccine, which is made using a piece of the polysaccharide capsule that surrounds pneumococcal bacteria.
A conjugate vaccine is not only made by a piece of the wall of the bacteria but added to it is a protein carrier.
With the addition of the protein, PCV13 produces a T-cell dependent immune response with antibody production and the potential for immune memory
Conjugated vaccines elicits a T‐cell dependent response with establishment of B‐cell memory and long‐term immunisation
Conjugated vaccine administered first augments the immune response to unconjugated vaccines, as opposed to administration of unconjugated vaccines first
Image from:
From NACI statement: Conjugate Pneumococcal Vaccine – 13 Valent in Adults

24. Polysaccharide vaccines
Pneumococcal vaccine
~90 serotypes
E.g.
Prevnar 13
Conjugated vaccines
Effective against 13 serotypes
PNEUMOVAX®23
Polysaccharide vaccines
Effective against 23 serotypes
Prevnar13 ®, a conjugated pneumococcal vaccine, is a sterile solution of polysaccharide capsular antigen of 13 serotypes of Streptococcus pneumoniae
In Ontario, PPV23 was authorized for use in 1978 and has been recommended for adults over 65 years of age and persons aged 2–64 years with underlying illness predisposing to IPD
From NACI statement: Conjugate Pneumococcal Vaccine – 13 Valent in Adults

25. Pneumococcal vaccine schedule
1 dose of Prevnar 13 followed 8 weeks later by one dose of PNEU-P-23.
Prevnar 13 at least 1 year after any previous dose of PNEU-P-23.
1 lifetime booster dose of PNEU-P-23 vaccine at least 5 years or more after the most recent dose of PNEU-P-23.
If ≥ 65 years, one-time revaccination is recommended if vaccinated ≥5 years previously.
In Ontario, PPV23 was authorized for use in 1978 and has been recommended for adults over 65 years of age and persons aged 2–64 years with underlying illness predisposing to IPD
Prevnar13 ®, a conjugated pneumococcal vaccine, is a sterile solution of polysaccharide capsular antigen of 13 serotypes of Streptococcus pneumoniae
No evidence that a PNEU-C-13 booster dose adds any benefit.
given the potential for decrease in antibody titers following PNEU-P-23, severity of IPD in immunocompromised individuals, and benefits from PNEU-C-13 in this patient population, NACI recommends to administer PNEU-C-13 at least one year after any previous dose of PNEU-P-23.
From NACI statement: Conjugate Pneumococcal Vaccine – 13 Valent in Adults

26. Hepatitis B
Screen all patients receiving immunosuppressive therapy including Prednisone >7.5mg per day.

27. Hepatitis B serologies
HBsAg
Anti-HBs
Anti-HBc
Immune from vaccination - +
Immune from infection
Infected
Anti-HBs: Hep B surface Antibody
Anti-HBc: HepB core Antibody
HBsAg: Hep B surface Antigen
>9.9 IU/L

28. Hepatitis B
Immunosuppressive medications can cause hepatitis B reactivation.
B cell–depleting agents such as Rituximab  high risk of HBV reactivation
25-40% risk of HBsAg seroeversion in patients who are anti-HBc positive.
profound effect on antibody production, and the loss of antiHBs during rituximab therapy in patients with evidence for past infection has been relatively well described.
25-40% risk of HBsAg seroeversion in patients who are anti-HBc positive
Perrillo et al. Gastroenterology Jan;148(1):

29. Hepatitis B
Corticosteroids have been most often implicated in HBV reactivation.
After being on Prednisone 10mg for 3.5 year, death rates were overall higher in HBsAg+ patients.
Screen all patients receiving Prednisone >7.5mg per day.
Of all the traditional immunosuppressive medications, Corticosteroids have been most often implicated in the induction of HBV reactivation.
Lam, K et al. N Engl J Med Feb 12;304(7):380-6.

30. Herpes Zoster (HZ)
>130,000 Canadians are diagnosed with shingles each year.
Post-herpetic neuralgia (PHN), which can be debilitating, is the most frequent complication of HZ.
From rheumatologyadvisor.com
More than 130,000 Canadians are diagnosed with shingles each year
Characterized by neuropathic pain and dermatomal vesicular rash.
From: Herpes Zoster (Shingles) Vaccine: Canadian Immunization Guide

31. Herpes Zoster (HZ)
RA patients have a nearly 2-fold increase in the risk of HZ compared with individuals without RA.
Elevated risk of HZ was observed in patients treated with biologics (esp non-TNFs), cDMARDs and corticosteroids.
Increased HZ risk of 21-61% with JAK inhibitors such as tofacitinib:
HZ occurred early in the treatment course.
Higher doses of tofacitinib posed an increased risk of HZ.
2007: Two retrospective cohort studies were conducted
2016: first review to systematically examine the risks of HZ associated with immunosuppressants across various autoimmune disease states while including evidence from RCTs
systematic literature search from January 1946 to February 2016
Smitten et al Arthritis Rheum Dec 15;57(8):
Fawziah et al. Open Forum Infect Dis Oct; 3(4)

32. Herpes Zoster (HZ) vaccine
burden of disease due to HZ among people >60 years of age by ~60 %
incidence of postherpetic neuralgia (PHN) by ~66.5%
PHN HZ
enrolled 38,546 adults 60 years of age or older in a randomized, double-blind, placebo-controlled trial of an investigational live attenuated Oka/Merck VZV vaccine (“zoster vaccine”)
- but no studies have been performed in patients with AIIRD.
Oxman et al. N Engl J Med Jun 2;352(22):

33. Herpes Zoster vaccine
2 different Herpes Zoster vaccines currently authorized for use in Canada:
Zostavax II (Live Zoster Vaccine)
Shingrix (Recombinant Zoster Vaccine)
For individuals
≥50 years of age

34. Date of authorization in Canada
Herpes Zoster vaccine
Zostavax
Shingrix
Date of authorization in Canada
2011
2017
Type of vaccine
Live
Recombinant
Schedule
1 dose
2 doses, 2-6 months apart
Route
Subcutaneous
Intramuscular
A recombinant vaccine is a vaccine produced through recombinant DNA technology. This involves inserting the DNA encoding an antigen (such as a bacterial surface protein) that stimulates an immune response
From Herpes Zoster (Shingles) Vaccine: Canadian Immunization Guide

35. Herpes Zoster Vaccination
CRA guidelines: Before cDMARDs or bDMARDs in patients >60 years old
ACR guidelines:
Before starting cDMARDs or bDMARDs
ONLY Shingrix: Can be given before or while on cDMARDs or bDMARDs
If you’re between 65 and 70 years old, you can get vaccinated against shingles free of charge in Ontario - Zostavax
But Shingrix is relatively pricey – a $244 list price,
Zostavax, has a list price of $177
Interval for RZV following LZV immunization: at least 1 year.
Interval for RZV following HZ episode: at least 1 year.

36. HPV Infection
Women with rheumatic diseases such as SLE and RA are vulnerable to HPV infection and the progression of cervical disease.
An increased risk of cervical pre-malignant and malignant lesions has been reported in SLE women.
Individuals with immunosuppression are at risk for cervical cancer:
Immunosuppressed individuals  HPV persistence  necessary for malignant transformation.
Immunization as per Canadian guidelines.
Kim SC et al. Rheumatology (Oxford) Jul 1;57
Garcia-Carrasco, M et al. Autoimmun Rev Feb;18(2):

37. Re-Cap
Influenza, Pneumococcal, Hepatitis B, HPV and Herpes Zoster vaccinations should be undertaken before starting a DMARD or a biologic.
The influenza vaccine is strongly recommended to every patient, every year.
Consider holding MTX for 2 weeks after the influenza vaccine to increase efficacy in stable RA patents.
Both types of pneumococcal vaccines (Prevnar 13 and Pneumovax 23) should be given to patients.