Dr Avinash Jain
SGPGI, Lucknow

Prepared by

Dr Avinash Jain

SGPGI, Lucknow

Dr Rutviz Mistry

SGPGI, Lucknow

Reviewed by : Dr Liza Rajshekhar, Dr Vikas Agarwal, Dr Aman Sharma, Dr Praveen Hisaria and Dr Sapan C Pandya

Infections are the major cause of morbidity and mortality in patients with Autoimmune Rheumatic Diseases. Immune response in these patients is impaired and the “immunosuppressive” medications used to treat them add fuel to the fire. Infections are the biggest threat in the management of rheumatic conditions. Influenza, invasive pneumococcal infection, herpes zoster and hepatitis B are the major vaccine preventable infections seen in our patients.

Vaccination in rheumatic disease and its studies present with a unique set of challenges. Vaccination leads to immune response to particular antigen; however, non-specific response in this situation might lead to flare of the autoimmune disease. Ideally, studies on efficacy should use clinical endpoints to test the role of vaccines in rheumatic diseases to establish its clinical benefits. Such studies with clinical endpoints are logistically demanding and require a large sample size. Hence, most of the current studies use laboratory parameters (serologic titres of antibodies or T cell reactivity against antigen) to establish the efficacy of the vaccines. However, laboratory surrogates lack correlation with the clinical endpoints of reducing infection. Studies related to vaccination need to be interpreted with this consideration in mind.

In this write-up we will focus on the evidence of efficacy of various vaccines in rheumatic diseases and end with the current recommendations pertaining to vaccination.

Influenza virus

Influenza vaccine currently available in the market include inactivated and live attenuated. Trivalent and tetravalent vaccines containing three and four strains are available; however, the most commonly used is the trivalent inactivated vaccine. Multiple studies including a prospective1, and a retrospective large registry based Taiwanese study2 with clinical endpoints suggest reduction in pneumonitis, bronchitis, hospitalization in Rheumatoid arthritis and SLE patients vaccinated with influenza vaccine as compared to unvaccinated patients. In SLE, the serological response to the influenza subunit varied among different studies. Few studies show mild reduction in sero-protection while the others did not show any difference in seroconversionbetween vaccinated and unvaccinated patients.3,4 Serologic evidence of protection in Systemic Sclerosis5, Granulomatosis with polyangitis6 and Sjögren’s syndrome7 have been observed after influenza vaccination. Significant body of evidence exists to suggest efficacy of Influenza vaccination with concomitant use of glucocorticoids, csDMARDs and antiTNF therapy and tocilizumab. In one study, the arm on combination therapy with methotrexate and anti-TNF had lower titres of antibodies to influenza as compared to methotrexate alone, however, multiple other studies have shown good response with combination therapy as well.8 Studies with rituximab in RA however have documented significant lower seroconversion rates.9None of the studies have raised concerns regarding the safety or flare of underlying autoimmune disease.

Antigenic Drift and Shift leads to changing immunogenicity of the Influenza strains each year. Depending on the strains in circulation in a particular demographic area, the manufacturers “update” their vaccine to include the recent strains. This should be kept in mind while administering vaccine to patients. The best time to vaccinate with yearly shot is before the onset of monsoon10 (April-May) since influenza infection is particularly more common in monsoon and winter.

Thus, current body of evidence suggest influenza vaccines are well tolerated but underutilized in rheumatic diseases patients and are generally immunogenic even with immunosuppressants with the exception of rituximab.Vaccines should ideally be administered before B cell-depleting biological therapy [BCDT] is started or, when patients are on such a treatment already, at least 6 months after the start but 4 weeks before the next course.The European League Against Rheumatism (EULAR) recommend yearly vaccination with influenza of all patients with rheumatic diseases11.

Streptococcus pneumoniae

Currently two forms of pneumococcal vaccines are available. PPSV23 is derived from polysaccharide capsule while PCV13 is a conjugated vaccine with diphtheria carrier protein. PPSV23 response is T cell independent while PCV13 is T cell dependent. The immunological response is robust in PCV13 compared to PPSV23.Hence, boosters are required in PPSV23 while a single dose is sufficient in PCV13. Majority of the available literature has used PPSV23 in rheumatic diseases. Another reason for heterogeneity among the available data is lack of generally accepted serologic protection criteria for immunologic response to Pneumococcal vaccine.

In RA, good body of evidence exists to suggest adequate serologic response to pneumococcal vaccination independent of the DMARD used and disease activity12. However, newer studies have documented mildly reduced seroconversion with methotrexate-antiTNF combination and severely impaired humoral response with BCDT.13,14 Recent studies of PPSV23 in SLE suggest reduced immunogenicity as compared to healthy controls.15 Efficacy of pneumococcal vaccine is also established in Systemic sclerosis16 and Psoriatic arthritis.17

Center for Disease Control (CDC) recommends PCV-13 followed by PPSV-23 at least 8 weeks later for general population. For those who have already received PPSV-23, PCV-13 should be given at least 1 year later with and additional PPSV-23 booster given as usual 5 years from the first18

EULAR Guidelinesstrongly recommend pneumococcal vaccination inall patients with rheumatic diseases11.

Table 1: Immunogenicity of various vaccines in the presence of various immunosuppressants in RA and SLE

* combination – reduced immunogenicity; ± Doubtful; ↓ Reduced; + Intact immunogenicity; NA,Not available; TNFi, TNF inhibitor

Hepatitis B

Studies in RA, SLE, Ankylosing Spondylitis, Behcet’s disease suggest immunogenicity of the Hepatitis B vaccination irrespective of disease activity, steroid or DMARD use. However, the amount of the data is insufficient to draw meaningful conclusions. EULAR guidelines recommend Hepatitis B vaccination for the patients at risk including intravenous drug abuse, multiple sex partners in the previous 6 months or health care personnel11. Hepatitis B vaccination is a part of universal immunization programme in India.

Herpes Zoster

Herpes zoster infection risk is increased in Rheumatic diseases. Special concerns regarding Herpes Zoster are being raised in view of increased risk in patients of RA receiving tofacitinib.As HZV is a live attenuated vaccine, its use in immunosuppressed patients is controversial. However, evidence is accumulating from larger registry based studies suggesting its safety in immunosuppressed patients with rheumatic diseases19. American Advisory Committee on Immunization Practices(ACIP) recommends using HZV in general population ≥ 50 years, persons anticipating immunosuppressant (at least two weeks prior to administration of immunosuppressive agent), in persons taking low-dose immunosuppressive therapy (e.g., <20 mg/day of prednisone or equivalent or using inhaled or topical steroids)20. Temporary discontinuation of immunosuppressive medication before vaccination with live attenuated vaccines might also be considered, but there are no studies to support this strategy.

Live vaccination should be avoided in following scenarios

• Steroids – steroid more than 10 mg for two weeks or more
• cDMARDs- Cyclosporine>2.5 mg/kg per day, Sulfasalazine >40 mg/kg per day or 2 g/day, Azathioprine>3 mg/kg,Cyclophosphamide >2.0 mg/kg per day, Leflumomide>0.5 mg/kg per day
• Biologic except B cell depletion therapy (BCDT) – Avoid anti TNF for four weeks
• BCDT – Avoid after BCDT for 6 months and can be given 4 weeks prior to BCDT initiation

Vaccine coverage in an outpatient rheumatology clinic in Germany were 18% and 25% for pneumococcal and influenza respectively.21 Another telephone based survey reported reasons for failure to receive pneumococcal and influenza vaccine were lack of doctor recommendations (55%), safety or efficacy concern (21%) and lack of motivation (19%)22. Simple interventions shown to be useful in increasing coverage include: presentation to rheumatology providers, creation of immunization algorithm, placing reminders on clinic forms, stocking the vaccine in clinic, establishing protocols for vaccination at admission.

To summarize, Box 2 shows the EULAR recommendations for the vaccination of individuals with AIRD. Recently, updates of these guidelines were presented in EULAR Meeting, Amsterdam, 2018.

• Vaccination status should be assessed in the initial work-up of patients
• Vaccine should ideally be administered to patients with an AIRD during stable disease
• Live attenuated vaccines should be avoided whenever possible.
• Vaccine can be administered to patients being treated with DMARDs and TNF inhibitors, but vaccine should be administered before starting B-cell-depleting biologic therapy
• Influenza vaccination should be strongly considered
• PPV23 should be considered
• Patients with an AIRD should have TT vaccination in accordance with the recommendations for the general population; in case of major or contaminated wounds in patients who received rituximab within 24 weeks, tetanus immunoglobulin instead of TT vaccine should be administered
• Herpes zoster vaccination “can” be considered
• For hyposplenic or asplenic patients, influenza, pneumococcal and H. influenzae type b and meningococcal C vaccinations are recommended
• HepatitisA and hepatitis B vaccination are only recommended for patients with an AIRD who are ‘at risk’ (i.e., intravenous drug abuse, multiple sex partners in the previous 6 months, or health care personnel)
• Patients who plan to travel are recommended to have vaccinations according to general rules, except for live-attenuated vaccines, which should be avoided whenever possible by immunosuppressed patients
• BCG vaccination is not recommended

It is under the process of publication. Newer recommendations include: immunocompetent household members of patients with AIIRD should be encouraged to receive vaccines according to national guidelines with the exception of oral poliomyelitis vaccine and live attenuated vaccine should be avoided for the first 6 months in newborn whose mother received biologics in second half of pregnancy.

bDMARDS and Vaccination

• Ideally, vaccination should be given (live or killed) four weeks before starting B cell depletion therapy. However, partial efficacy has been noted when given at least two weeks before Rituximab.
• Killed vaccine can be given during treatment with anti TNF, tocilizumab.
• JAK inhibitor predispose to Herpes Zoster reactivation. Herpes Zoster vaccine should be given at least two weeks before starting JAK inhibitor.
• Live attenuated vaccines should be avoided whenever possible.

Table 2 summarises immunogenicity of vaccines in various CTDs, disease flare and recommendations.

Table2: Efficacy of Vaccine in autoimmune rheumatic disease *with methotrexate; **more data needed; #see text for B cell depletion therapy; $BCG vaccine, oral poliomyelitis vaccine, oral typhoid fever vaccine and yellow fever vaccine csDMARDs, Conventional DMARDs; bDMARDs, biologics; E, Effective;RTX, Rituximab

REFERENCES

• 1. Stojanovich, L. Influenza vaccination of patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Clin. Dev. Immunol.13, 373–375 (2006).
• 2. Chang, C.-C., Chang, Y.-S., Chen, W.-S., Chen, Y.-H. & Chen, J.-H. Effects of annual influenza vaccination on morbidity and mortality in patients with Systemic Lupus Erythematosus: A Nationwide Cohort Study. Sci. Rep.6, 37817 (2016)..
• 3. Louie, J. S. et al. Clinical and antibody responses after influenza immunization in systemic lupus erythematosus. Ann. Intern. Med.88, 790–2 (1978).
• 4. Holvast, A. et al. Safety and efficacy of influenza vaccination in systemic lupus erythematosus patients with quiescent disease. Ann. Rheum. Dis.65, 913–918 (2005).
• 5. Setti, M. et al. Flu vaccination with a virosomal vaccine does not affect clinical course and immunological parameters in scleroderma patients. Vaccine27, 3367–3372 (2009).
• 6. Holvast, A. et al. Wegener’s granulomatosis patients show an adequate antibody response to influenza vaccination. Ann. Rheum. Dis.68, 873–878 (2009).
• 7. Pasoto, S. G. et al. Short and long-term effects of pandemic unadjuvanted influenza A(H1N1)pdm09 vaccine on clinical manifestations and autoantibody profile in primary Sjögren’s syndrome. Vaccine31, 1793–1798 (2013).
• 8. Westra, J., Rondaan, C., Van Assen, S. & Bijl, M. Vaccination of patients with autoimmune inflammatory rheumatic diseases. Nat. Rev. Rheumatol.11, 135–145 (2015).
• 9. Kapetanovic, M. C. et al. Impact of anti-rheumatic treatment on immunogenicity of pandemic H1N1 influenza vaccine in patients with arthritis. Arthritis Res. Ther.16, R2 (2014).
• 10. Kumar, S., Rath, P. & Malaviya, A. A practical guide to adult vaccination for patients with autoimmune inflammatory rheumatic diseases in India. Indian J. Rheumatol.12, 160 (2017).
• 11. van Assen, S. et al. EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases. Ann. Rheum. Dis.70, 414–422 (2011).
• 12. Friedman, M. A. & Winthrop, K. Vaccinations for rheumatoid arthritis. Curr. Opin. Rheumatol.28, 330–336 (2016).
• 13. Bingham, C. O. et al. Immunization responses in rheumatoid arthritis patients treated with rituximab: Results from a controlled clinical trial. Arthritis Rheum.62, 64–74 (2010).
• 14. Kapetanovic, M. C. et al. Influence of methotrexate, TNF blockers and prednisolone on antibody responses to pneumococcal polysaccharide vaccine in patients with rheumatoid arthritis. Rheumatology45, 106–111 (2006).
• 15. Mathian, A., Pha, M. & Amoura, Z. Lupus and vaccinations. Curr. Opin. Rheumatol. 1 (2018). doi:10.1097/BOR.0000000000000525
• 16. MERCADO, U., ACOSTA, H. & DIAZ-MOLINA, R. Antibody Response to Pneumococcal Polysaccharide Vaccine in Systemic Sclerosis. J. Rheumatol.36, 1549–1550 (2009).
• 17. Mease, P. J. et al. Pneumococcal vaccine response in psoriatic arthritis patients during treatment with etanercept. J. Rheumatol.31, 1356–61 (2004).
• 18. Kobayashi, M. et al. Intervals Between PCV13 and PPSV23 Vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. Morb. Mortal. Wkly. Rep.64, 944–947 (2015).
• 19. Yun, H. et al. Risk of Herpes Zoster in Autoimmune and Inflammatory Diseases: Implications for Vaccination. Arthritis Rheumatol.68, 2328–2337 (2016).
• 20. Dooling, K. L. et al. Recommendations of the Advisory Committee on Immunization Practices for Use of Herpes Zoster Vaccines. MMWR. Morb. Mortal. Wkly. Rep.67, 103–108 (2018).
• 21. Krasselt, M., Baerwald, C. & Seifert, O. Insufficient vaccination rates in patients with systemic lupus erythematosus in a German outpatient clinic. Z. Rheumatol.77, 727–734 (2018).
• 22. Lawson, E. F., Trupin, L., Yelin, E. H. & Yazdany, J. Reasons for failure to receive pneumococcal and influenza vaccinations among immunosuppressed patients with systemic lupus erythematosus. Semin. Arthritis Rheum.44, 666–71 (2015).

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Authors

Dr Sakir Ahmed

KIMS, Bhubaneshwar

Ipsita Mohanty

Bhubaneshwar

Reviewed by : Dr Liza Rajshekhar, Dr Vikas Agarwal, Dr Aman Sharma

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Authors

Dr Sakir Ahmed

KIMS, Bhubaneshwar

Ipsita Mohanty

Bhubaneshwar

Reviewed by : Dr Liza Rajshekhar, Dr Vikas Agarwal, Dr Aman Sharma

Reviewed and Edited by : Dr Avinash Jain

This document is a summary of guidelines of EULAR, ACR and BSR along with the inputs from a literature search. It is designed to be brief and in simple language understandable both to the patient and the specialist. However patients are strongly advised not to interpret the drug advisory on their own without consulting their treating physicians.

A. A successful pregnancy is possible in almost all rheumatic diseases provided disease is well-controlled, and there is no permanent organ damage.

• 1. Pregnancies are more likely to be successful when they are planned, with adequate discussion among the patient, the rheumatologist and the obstetrician.
• 2. Successful, however, does not mean uneventful. Doctors and patients must be prepared to deal with possible complications for both mother and child.
• 3. Diseases with the potential to affect the kidneys, or lung (including increasing pressure of the pulmonary arteries) like lupus, antiphospholipid syndrome, inflammatory myositis, systemic sclerosis and overlap syndromes are more likely to affect pregnancy outcome than others.
• 4. Persistently raised creatinine (end-stage renal disease) or high pulmonary arterial pressures may hinder successful pregnancies. In fact in these conditions, pregnancy may worsen the health condition of the mother.
• 5. Any rheumatic diseasemust be under optimal control for 6 months before pregnancy is planned.

B. Effects of rheumatic diseases on pregnancies:

• 1. In the absence of permanent organ damage, the fertility of patients is not altered due to rheumatic diseases. Diseases like systemic sclerosis or sjogrensyndrome may lead to dyspareunia.
• 2. Uncontrolled rheumatic diseases have a lot of inflammation and may lead to pregnancy loss especially in the 1st
• 3. In the later phase there are more chances of pregnancy induced hypertension and foetal growth retardation. Patients who have or have had kidney disease, due to vasculitis, scleroderma, or lupus, generally have an increased risk of severe hypertension and pre-eclampsia.
• 4. Pulmonary arterial hypertension worsens in the post-partumperiod.Patients with high pulmonary artery pressures are advised not to get pregnant.
• 5. APS probably has the greatest impact on pregnancy. It causes both early and late miscarriage.Other complications include premature birth, low-weight babies, athrombosis (condition where blood clots form in the blood vessels) and pre-eclampsia. Thus, pregnancy with APS should always be considered as high risk and require close medical and obstetric monitoring. Treatment is based on low-dose aspirin and heparin.
• 6. Babies of mothers having anti-Ro antibodies (in Sjogren or lupus) are at higher risk of developing congenital heart blocks. The anti-Ro antibodies may interfere with the development of the electric conduction system of the heart. Thus mother with anti-Ro antibodies needsfoetal heart monitoring with foetal echocardiography (ultrasound of foetalheart) during 2nd
• 7. It is important to discuss the possible effects of various anti-rheumatic drugs on pregnancy. There should be expert assessment of risk-benefit to determine the drugs to be continued during pregnancy starting from the pre-conception stage.

C. Effect of pregnancies on rheumatic diseases:

• The earlier paradigm was that diseases like rheumatoid arthritis tend to go into quiescence (2/3rd of RA) while diseases like lupus would invariably flare (50% of SLE flare with 20% being major organ flares) during pregnancy.
• With newer treatment strategies and better disease control, studies have shown that only a minority (~10%) of RA have improved disease activity while lupus patients (in remission for at least 6 months, and on hydroxychloroquine) do not have increased flare rates.
• It is very important to report any new symptoms and any worsening to both your rheumatologist and obstetrician.

D. Drugs permissible in pregnancy:

• Previously drugs were prescribed followingUSFDA pregnancy categories: A, B, C, D, and X. However these are not water-tight compartments and this has lead the FDA to abandonthis approach. Thus, risk-benefit of each drugs should be discussed in context of the patient, the disease and the age of gestation.
• As overarching guidelines, we endorse the ACR recommendation that currently stand as: (please also see the BSR guidelines: table 2)

• There is strong evidence that hydroxychloroquine must be continued in lupus and APS during pregnancy and it is our personal opinion that it should be continued in RA during pregnancy as well.
• Captopril and enalapril are to be avoided in pregnancy but are safe drugs during breastfeeding.
• Other drugs:

Tocilizumab

• Tocilizumab (TCZ) should be stopped at least 3 months before conception, but unintentional exposure early in the first trimester is unlikely to be harmful
• There are no data upon TCZ use in breastfeeding

Abatacept

• There are insufficient data to recommend abatacept (ABA) in pregnancy. Unintentional exposure early in the first trimester is unlikely to be harmful
• There are no data upon ABA use in breastfeeding

Secukinumab

• There are insufficient data to recommend Secukinumab(SEK) in pregnancy.
• There are no data upon SEK use in breastfeeding

Preconception planning for males:

• Limited data is available but it has shown that Methotrexate is unlikely to affect male fertility (table 2). Currently there are no recommendations to stop it during pre-conception stage.
• For sulfasalazine, conception rates may be enhanced by stopping sulfasalazine for 3 months prior to conception
• Thalidomide should be stopped at least 3 months in advance prior to planned conception (as it is present in spermatozoa).

Summary::

• The likelihood of a successful and healthy pregnancy is highest if kidney and heart function, and blood pressure are normal.
• The disease is inactive for at least 6 months prior to conception.
• Drugs should be used after patient tailored risk-benefit assessment.

Table 2: BSR guideline for drugs used in rheumatology during pregnancy:

Table 3 The impact of rheumatic disease on pregnancy and vice-versa.

T2T: treat to target strategy; PAH: pulmonary arterial hypertension; HCQ: hydroxychloroquine; ANCA: anti-neutrophil cytoplasmic antibodies; CHB: complete heart block

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