Download Immunisation of immunosuppressed patients with rheumatic

REPORTS ON THE RHEUMATIC DISEASES SERIES 5
Topical Reviews
An overview of current research and practice in rheumatic disease
Medical Editor: Andrew Keat
Production Editor: Frances Mawer (arc). ISSN 1469-3097.
Published by the Arthritis Research Campaign, Copeman House,
St Mary’s Court, St Mary’s Gate, Chesterfield S41 7TD.
Registered Charity No. 207711.
June 2007
Number 12
Published 3 times a year
IMMUNISATION OF IMMUNOSUPPRESSED
PATIENTS WITH RHEUMATIC DISEASES
Neil Snowden
Consultant Rheumatologist
North Manchester General Hospital
INTRODUCTION: INFECTION IN
PATIENTS WITH INFLAMMATORY
RHEUMATIC DISEASES
•Patients with inflammatory rheumatic
diseases treated with immunosuppressive drugs are at increased risk from infection
Patients with inflammatory rheumatological diseases
have increased morbidity and mortality from infection.
In rheumatoid arthritis (RA), deaths from infection
(usually chest infection) are 2–5 times more common
than would be predicted by age and sex.1,2 In systemic
lupus erythematosus (SLE), infection kills almost as
many patients as active disease in the first 5 years of
illness and is responsible for about one-third of deaths
in this condition.3-6 Infection is also the cause of about
one-third of deaths in patients with severe vasculitis.7-9
Several factors contribute to this increased susceptibility, although the relative importance of these factors
is not well defined.
•Immunisation, particularly against influenza and pneumococci, may reduce
this risk
•Immunosuppressed patients usually
have a reasonable immunological
response to immunisation, although
aggressive immunosuppression may
reduce the response. Where possible
immunisation should take place before
immunosuppression
Treatment with immunosuppressive drugs (including
corticosteroids) is perhaps the most plausible risk factor for infection, with the risk of infection increasing
with the degree and duration of immunosuppression.
The risks of infection are clearest in patients receiving
high-intensity treatment with drugs such as cyclophosphamide for life-threatening connective tissue disease
(CTD) and vasculitis, and there is an abundant literature
on the increased risks of infection in all clinical situations associated with profound therapeutic immunosuppression, such as cancer chemotherapy and transplantation.10 It is notable that most infections occurring in
patients receiving potent immunosuppressive drugs are
with common community-acquired organisms, rather
•Live vaccines are contraindicated in the
immunosuppressed, but immunisation
poses no other major risks in the
immunosuppressed, and does not lead
to a flare in the underlying disease
•Authoritative detailed advice on
immunisation can be obtained from the
UK Department of Health Green Book
accessed on-line at www.dh.gov.uk/
immunisation
than with unusual opportunistic infections (although
opportunistic infection does occur).11
and other intracellular bacterial infections, but the risk
of many other forms of infection is unchanged.19
Although there is clear evidence of the risk of infection
associated with aggressive immunosuppressive regimes,
it has been much more difficult to determine whether
less intensively-immunosuppressant disease-modifying
anti-rheumatic drug (DMARD) treatment regimes are
associated with an increased risk of infection. There
are sporadic reports of opportunistic infection (such as
Pneumocystis carinii pneumonia) occurring in patients
on methotrexate and other DMARDs.12 However,
such infections are rare. Larger studies of infection in
patients with RA have generally shown that use of most
DMARDs is not associated with any major infection,
although leflunomide may be associated with pneumonia.13,14 Methotrexate is generally considered to be
immunosuppressive, and an increased incidence of
infection has been reported in patients on this drug.12,15
However, larger studies have not confirmed this.13,14
Many DMARDs, such as sulfasalazine, gold and antimalarials, have no conventional immunosuppressive
effect, although gold and sulfasalazine are associated
with a low risk of idiosyncratic bone marrow toxicity and
defective immunoglobulin production which may increase risk of infection in a small number of patients.16,17
Corticosteroids, however, have consistently been shown
to be associated with an increased risk of infection with
a dose-dependent effect on immune responses. There
is evidence that long-term use of even very low doses
of prednisolone (<5 mg daily) are associated with an
increased risk of infection.14,18 Immunosuppression is
not an homogeneous process: different drugs affect
different parts of the immune system (Table 1), and
hence the specific risk of infection may vary from drug to
drug. This is exemplified most clearly with anticytokine
biologicals: inhibition of tumour necrosis factor (TNF)
is associated with very specific risks of mycobacterial
Diseases such as SLE and RA may also be associated
with defective immune responses to infection: some
mechanisms underlying these defects are clear, such as
complement depletion and functional hyposplenism in
patients with SLE, but other more subtle immunological defects may also be present in RA and SLE. The relative contribution of drugs and disease in determining
susceptibility to infection is unclear. However, some
evidence suggests that, in both RA and SLE, diseaserelated susceptibility to infection may be as or more
important than the effect of immunosuppressive drug
treatment.3-5,13,14 In a large inception cohort study of
patients with inflammatory arthritis, infections severe
enough to require hospitalisation were about twice as
common as in matched controls, with smoking and a
positive test for rheumatoid factor being associated with
a particularly high risk of infection.13 Corticosteroid use
was also identified as an independent risk factor for
infection, but not use of DMARDs. In SLE, the increased
death rates from infection were first noted before the use
of immunosuppressant drugs and steroids, and the risk
seems highest in patients with active disease.3-5 Patients
with SLE treated with cyclophosphamide may have a
higher risk of infection than patients with other disorders
treated with similar treatment regimes.3-5,20,21
In addition to the specific effects of disease and treatment, non-specific factors such as frailty, poor nutrition
and organ failure (especially renal failure) may account
for some of the increase in risk, especially in patients
with severe, long-standing arthritis.
A number of strategies can be considered for reducing
this increased risk of infection. Firstly, improved general
health and nutrition might be expected to reduce the
risk of infection, although there is little direct evidence
TABLE 1. Drugs with potentially immunosuppressive actions used in treatment of rheumatological
disease, and their effects upon the immune system.
Drug
Severity and pattern of immunosuppression
Cyclophosphamide and other cytotoxic drugs
Severe, T- and B-cells
Azathioprine
Severe, mainly T-cells
Ciclosporin, tacrolimus, sirolimus
Severe, mainly T-cells
Mycophenolate mofetil
Severe, mainly T-cells
Leflunomide
Uncertain, probably severe, mainly T-cells
Methotrexate (at doses ≤25 mg/week)
Uncertain, probably moderate
Anti-TNF drugs
Highly selective: main risk is mycobacterial infection
Rituximab
Highly selective: likely to inhibit new antibody responses
Corticosteroids
Dose-dependent, but dose threshold for immunosuppression unclear: see Table 4
Sulfasalazine, intramuscular gold
No conventional immunosuppressive effect, but may cause impairment of antibody
production in a small proportion of patients treated
TABLE 2. Glossary.
Term
Definition
Active immunisation
Induction of host immune response by administration of vaccine derived from or with structural
similarity to infecting organism
Passive immunisation
Protection from infection using immunoglobulins (derived from immune hosts) with high titres of
antibody against infecting organism
Polysaccharide
vaccine
Purified polysaccharide, usually from bacterial cell wall, used to induce active immunity to capsulate
organism. 23-valent (contains polysaccharides from 23 strains of pneumococci) pneumococcal
vaccine and meningococcal quadrivalent ACWY vaccine are examples. Polysaccharide vaccines are less
powerfully immunogenic than protein vaccines, and produce very poor immune responses in children
under 2 years of age
Conjugate vaccine
Polysaccharide vaccine conjugated to carrier protein. This leads to an enhanced immune response
to the polysaccharide component. Examples include Haemophilus influenzae b and 12-valent
pneumococcal vaccine (contains polysaccharide from 12 strains)
that this is the case. Secondly, judicious and careful use
of immunosuppressive drugs is appropriate, although
clearly significant levels of immunosuppression are unavoidable in severe disease (and, indeed, failure to control the disease may increase the disease-specific risk of
infection – for example complement levels will remain
low in poorly controlled SLE). Refinement of treatment
regimes – for example towards smaller cumulative doses
of cyclophosphamide22 and other immunosuppressive
drugs23 – can reduce the risk of severe infection. Thirdly,
antibiotic prophylaxis may be appropriate with some
treatment regimes, and in patients at particularly high
risk of infection – for example drug prophylaxis with
low-dose co-trimoxazole is effective in the prophylaxis of
Pneumocystis carinii pneumonia. However, there is no
evidence that antibiotic prophylaxis is effective against
common bacterial infections, except pneumococcal
infection post splenectomy. Finally, immunisation may
also be used to reduce the risk of infection.24-27
firstly, that immunisation may cause flaring of the
underlying rheumatic disease, and secondly, that the
use of live, attenuated vaccines in immunosuppressed
patients may lead to productive infection.24-27
Immunisation and disease activity
Although it is immunologically plausible that immunisation might, mainly by non-specific adjuvant effects, cause flaring of autoimmune diseases, there is
no evidence that this occurs commonly. Several studies
have examined disease activity in RA and SLE following
pneumococcal and influenza immunisation, and found
this to be unchanged.28-31 Most of these studies are,
however, small and not sufficiently powerful to exclude
the possibility that immunisation may lead to flares as
a rare adverse reaction. Case reports have suggested
that hepatitis B immunisation might be particularly
associated with exacerbation of rheumatic diseases.
Surveillance studies suggest that any risk is likely to
be small, although this is an area that requires further
study.25,32,33
IMMUNISATION IN PATIENTS WITH
INFLAMMATORY RHEUMATIC
DISEASES
There are several case reports describing onset of rheumatic diseases following immunisation. Surveillance
studies of vaccination programmes suggest that there
may be a small risk of persistent rheumatological problems, including inflammatory arthritis and CTD, being
triggered by immunisation (with hepatitis B vaccine being most convincingly associated),32,33 and the Norfolk
Arthritis Register (NOAR) inception cohort study found
that patients with inflammatory arthritis were twice as
likely to have been exposed to immunisation in the
6 weeks before onset of arthritis compared to matched
controls.34 These findings do not justify any change
in immunisation policy, but continuing surveillance
is required.
This review will examine several aspects of immunisation
in patients with chronic rheumatic disease:
1. Is it safe?
2. Does it work?
3. How does immunosuppression influence
the use of immunisation protocols in adults, children and travellers?
Immunisation can be active or passive (Table 2). The
main subject of this review is active immunisation,
although passive immunisation still has a role in postexposure prophylaxis, particularly against herpes zoster
and measles infections.
Use of live vaccines
Immunisation using live, attenuated organisms (Table 3)
is a powerful way of inducing a sustained and highly protective immune response. However, if the host immune
Safety
Two concerns have limited the use of vaccination in
immunosuppressed patients with rheumatic diseases:
response is reduced, the attenuated organism may induce active infection. The degree of immunosuppression required to permit vaccine-related productive infection with any individual vaccine is hard to define, since
only small numbers of cases have been reported for
any vaccine, usually across a spectrum of immune deficiency. Historically, the advice has usually therefore
been to avoid all live vaccines in any patients who have
recently received immunosuppressive drugs (Table 1)
and/or immunosuppressive doses of corticosteroids
(Table 4).35,36 More specific guidance is possible for
patients with human immunodeficiency virus (HIV) infection, where the CD4 T-cell count can be used as a surrogate marker of severity of immunosuppression. HIV
guidelines suggest that some live vaccines (for example
measles, mumps and rubella (MMR) and Varicella zoster
vaccines) can be given safely in patients with minor degrees of immunosuppression (safe until the CD4 cell
count falls below 200 mm-3), but others (such as oral
polio vaccine and BCG) need to be avoided in all infected patients.37 It is not clear how this guidance might
extrapolate to other forms of immunosuppression, but
it may usefully provide advice about the consequences
if patients receiving therapeutic immunosuppression
are inadvertently given live vaccines.
(Table 4) for more than 3 months, and has not had
other immunosuppressive treatments for more than
6 months.35,36
Efficacy
The true efficacy of a vaccine lies in its ability to protect
against infection, and incidence of infection is the best
end-point for clinical trials of vaccine use. These studies
need to be very large to have adequate power, and
hence much work on vaccine ‘efficacy’ – particularly
in the context of immunosuppression – relies upon
examination of antibody responses, often comparing
responses with levels of antibody in larger studies.
Immunosuppressed patients may mount defective immune responses. Immunisation may therefore be less
effective in the immunosuppressed, with lower levels of
T-cell and antibody response and consequently poorer
protection against disease. It would also seem intuitively obvious that vaccines would be progressively less
effective as the intensity of immunosuppression increases, although clearly this is when the risk of infection
is highest. Evidence from patients undergoing therapeutic immunosuppression and with immunodeficiency
disorders suggests that this is the case, although, perhaps surprisingly, even profoundly immunosuppressed
patients may mount some response to immunisation.36
These responses differ from vaccine to vaccine (some vaccines are more powerfully immunogenic than others)
and will also be affected by other factors such as age,
nutrition and general health: it is therefore difficult to
give a simple picture of the degree of impairment in
immune responsiveness produced by any particular
drug or disease.
Some live vaccines, such as oral polio vaccine, induce
productive non-harmful infection in healthy people,
who then excrete the live vaccine, potentially transmitting to others. Oral polio vaccine therefore needs to be
avoided in close family contacts of immunosuppressed
patients. Other live vaccines, such as MMR, do not
seem to be transmitted between family members, and
therefore can be given to close contacts of the immunosuppressed.35,36
In patients treated with very aggressive bone marrowablating chemotherapy followed by stem cell rescue
(used in rare cases of systemic autoimmune disease),
there is loss not only of new responses to immunisation
but also of pre-existing immunity in the majority. Reimmunisation following treatment is required in these
patients.38 Patients receiving aggressive chemotherapy
If there is an opportunity to give live vaccines before
the instigation of immunosuppression, then this may
be safe, although this depends upon the persistence
of the attenuated organism within the host. In general,
live vaccines may be given once the patient has not
had steroid treatment at immunosuppressive doses
TABLE 3. Live vaccines currently in use in the UK. All should be avoided in immunosuppressed
patients with rheumatic diseases. (See Table 4 for definition of immunosuppression with regard to corticosteroid treatment.)
Live vaccine
Comment
Oral polio
No longer recommended for routine use in the UK
Measles, mumps,
rubella
Passive immunisation indicated with pooled normal immunoglobulin in non-immune subjects after
exposure to measles
Yellow fever
Immunosuppressed patients should be advised against travel to endemic areas
Typhoid
Killed vaccine available but less protective
Varicella zoster
Passive immunisation indicated with zoster-immune globulin in non-immune subjects after exposure
BCG
Recommended for use in the UK only in selected groups at increased risk of tuberculosis: see Green
Book35
TABLE 4. Corticosteroid use and contraindications to use of live vaccines.
Corticosteroids produce dose-dependent immunosuppression, but there is no clear evidence or consensus as to the dose required
(and this may vary between individuals). For prednisolone (or equivalent doses of other steroids):
• In adults ≤10 mg/day is unlikely to be immunosuppressive.
• In adults a full immunosuppressive dose may be as little as 20 mg/day although the Green Book regards doses <40 mg
as safe.
• In children, significant immunosuppression is usually considered to occur with doses of 2 mg/kg/day for >1 week, or
1 mg/kg/day for >1 month.
There are no contraindications to using live vaccines if steroid treatment is:
•
•
•
•
•
for <1 week
with alternate-day short-acting steroid (e.g. prednisolone)
by topical, intra-articular or soft-tissue route
physiological replacement in adrenal insufficiency
with long-term, low-dose steroids (although note that low-dose treatment may be associated with infection in rheumatic diseases).
for haematological malignancy have severely impaired
responses to immunisation, with only about one-fifth
responding to influenza immunisation, a vaccine which
produces protective antibody responses in 80–100%
of healthy controls.39 Patients receiving immunosuppression for solid organ transplants in general show
higher responses, with around 50–90% of patients producing protective responses.40,41 Perhaps the clearest correlations between response to immunisation and level
of immunosuppression have been defined in patients
with HIV infection where the response can be correlated
with CD4 count.37
there are no data from patients with rheumatic diseases
to confirm or refute this.
Poorer responses to immunisation seem likely to occur in patients receiving powerful immunosuppressive
treatment. There is, however, very little evidence in this
area, with reports of reasonable responses to pneumococcal immunisation in patients with SLE treated with
cyclophosphamide.25,29 A reasonable estimate might be
that patients treated with cyclophosphamide, azathioprine and similar immunosuppressants might display
similar modest defects in response to immunisation to
those seen in solid organ transplants.40,44 Anti-B-cell treatment with rituximab surprisingly does not reduce levels
of protective antibodies when exposure has occurred
pre-treatment, but responses to immunisation following treatment are likely to be severely impaired.45
There are some clinical scenarios requiring immunosuppression, such as transplantation, where it is practical
to immunise before immunosuppression commences.
This is often not practical in patients with rheumatic
diseases, particularly in those with aggressive disease,
but should be attempted if possible.
Evidence is also limited as to the effects of corticosteroids
on response to immunisation: studies in chronic lung
disease suggest no major impairment. Since even lowdose corticosteroid use is identified as a major risk factor
for infection in RA, this may be a particularly important
group of patients to target for immunisation.13,14,18
Studies of response to immunisation in patients receiving DMARDs for RA have given conflicting results.24-27
Some studies suggest a normal response, although most
report modest reductions in antibody production, with
5–30% fewer subjects failing to achieve protective levels
of antibody compared to controls of comparable age
and sex.28-30,42,43 It is clear, however, that the profound
suppression in antibody response seen in some patients
receiving aggressive chemotherapy does not occur. Not
all anti-rheumatic drugs have equal effects on response
to immunisation: methotrexate does seem to modestly
impair the response to the polysaccharide pneumococcal vaccine43 and anti-TNF drugs may modestly impair
the response to influenza immunisation (a protein antigen).42 Reduced antibody responses to immunisation
also occur in a minority of patients receiving DMARDs
which are not usually considered to be immunosuppressive, such as gold and sulfasalazine.16 Impaired responses to immunisation suggest that the clinical efficacy of the vaccine in protecting against infection would
be reduced, but while this is a reasonable assumption,
If there are disease-specific defects in immunity in diseases such as RA and SLE, it is reasonable to hypothesise that there might be defects in response to immunisation which are intrinsic to the disease. No large
studies have been performed to systematically examine
this possibility, although several small studies suggest
that in SLE there may be modest impairment in response to immunisation with both polysaccharide and
protein vaccines (usually pneumococcal and influenza
vaccines).25,29,30 In these studies it is often very difficult
to disentangle the effects of disease, treatment and other
factors known to influence response to immunisation
such as age and sex. It does, however, seem reasonably
clear that major defects in response to immunisation
do not occur in the great majority of patients with
rheumatic diseases. The reasonable levels of response
seen in the majority of patients support the continued
use of immunisation in these patients. Even a partial
response to immunisation may reduce morbidity and
mortality from infection, particularly where the risk of
infection is high. Whether minor defects in response
to immunisation are clinically significant remains to
be established.
TABLE 5. UK Department of Health recommended
schedule for childhood immunisation (2006).35
MMR is the only live vaccine in this schedule.
PRACTICAL STRATEGIES FOR IMMUNISATION IN IMMUNOSUPPRESSED
PATIENTS
It is beyond the scope of this review to provide comprehensive advice on indications, contraindications,
schedules for immunisation, or doses and preparations
of vaccine. These can be rapidly accessed on-line in the
UK Department of Health Green Book (www.dh.gov.uk/
immunisation) which is regularly updated (latest edition
2006) and which should be consulted before immunisation is performed.35 This guidance is summarised in the
British National Formulary (BNF).46 The Royal College of
Paediatrics and Child Health has also developed detailed
guidance36 on immunisation in immunosuppressed
children, although this guidance was produced in 2002
and needs to be read alongside the latest version of
the Green Book.
Age
Vaccine
2 months
Diphtheria, tetanus, pertussis
(whooping cough), inactivated polio
and Hib
PCV
3 months
Diphtheria, tetanus, pertussis
(whooping cough), inactivated polio
and Hib
MenC
4 months
Diphtheria, tetanus, pertussis
(whooping cough), inactivated polio
and Hib
MenC
PCV
12 months
Hib and MenC
13 months
MMR
PCV
3 years 4 months–
5 years
Diphtheria, tetanus, pertussis and
inactivated polio
MMR
13–18 years
Tetanus, diphtheria and inactivated
polio
Hib Haemophilus influenzae b; MenC meningococcal C conjugate
vaccine; MMR measles, mumps and rubella; PCV pneumococcal
conjugate vaccine
Immunisation for overseas travel
As noted above, non-live vaccines are generally safe
in immunosuppressed patients and induce antibody
responses in most patients who are not profoundly immunosuppressed. Live vaccines are in general contraindicated in patients on immunosuppressive drugs. This
has a number of implications for use of immunisation in
both children and adults, with modification of ‘routine’
immunisation schedules and use of some immunisation specifically because of immunosuppression.
Yellow fever, oral polio and live typhoid vaccination are
contraindicated. All other immunisations, viz hepatitis
A, cholera, rabies, quadrivalent (ACW135Y) meningococcal polysaccharide and typhoid Vi polysaccharide, can
proceed as normal. For immunosuppressed travellers,
the increased risk of infection makes adequate pre-travel
immunisation particularly important.35
Immunisations recommended specifically
in the immunosuppressed
Effects on routine childhood immunisation
schedules
Influenza and pneumococcal infection account for a
substantial proportion of the morbidity and mortality
from acute respiratory tract infection in all ages and
across the world, and these are the only common
causes that can be prevented by immunisation.47 A
major observational study involving 250,000 subjects
suggested that the combined impact of immunisation
against pneumococci and influenza might reduce overall
mortality in the over 65s by as much as 50%.48
This should proceed as advised in the Green Book35
(Table 5), except that live vaccines cannot be used. If it
is possible to defer treatment with immunosuppressive
drugs then live vaccines can be given up to a minimum of
2 (but preferably 4) weeks before immunosuppression.
Live (oral) polio vaccine is no longer used routinely in
the UK, and inactivated polio vaccine is advised instead.
In countries where oral polio vaccine is still used, this
should be avoided in both the immunosuppressed
patient and their close family contacts as person-toperson transmission can occur. MMR vaccine should
not be given to the immunosuppressed, but it can be
safely administered to other family members as productive infection following person-to-person transmission
has not been recorded.
The immunocompromised are particularly vulnerable
to these infections. Response to pneumococcal and
influenza vaccines may be reduced in this group, but
because the risks are greater, even a modest reduction
in severity of infection may make immunisation worthwhile, at least until data to the contrary become available. These vaccines are therefore recommended by the
UK Department of Health for all who are immunosuppressed, whether by disease or by treatment. The other
indications for pneumococcal and influenza immunisation are summarised in Table 6. It will be apparent
that many patients with chronic rheumatic diseases will
have multiple indications for immunosuppression (and
hence, also, multiple reasons for susceptibility to infection). ‘Immunosuppression’ is not precisely defined by
the Department of Health, other than for corticosteroids,
but it seems reasonable to offer immunisation to any
patient receiving any of the drugs detailed in Table 1.
A case can be made for immunising patients with
rheumatic diseases on any dose of long-term corticosteroids, since treatment with these drugs, even at
doses below 5 mg daily, is clearly identified as a
major risk factor for infection.13,14,18 If at all possible,
immunisation should be performed 2 weeks or more
before any immunosuppressive drug is introduced,
but immunisation after treatment is started is still likely
to produce a significant response in most patients.
should also receive a second booster immunisation if
they have not been immunised previously – see the
Green Book for details), as soon as the current year’s
production of vaccine becomes available, and ideally
before November, before the incidence of influenza
cases increases. There is some evidence that patients
who are immunised in successive years develop a higher
cumulative level of protection than those receiving
their first annual immunisation.47
Pneumococcus
Polysaccharide and conjugate pneumococcal vaccines
are currently available for use in the UK (see Table 2).
The conjugate vaccine is more immunogenic, especially
in children under the age of 2 years, but only provides
protection against 7 common strains whereas the polysaccharide vaccine contains pneumococcal capsular
polysaccharide from 23 common serotypes. These
23 serotypes account for about 95% of cases of pneumococcal infection in the UK.35,47
The efficacy of pneumococcal vaccine is uncertain:
some observational studies in older adults suggest an
approximately 40% reduction in pneumococcal pneumonia, but a recent large study suggests no protection
against pneumonia in this age group.49 There is more
consistent evidence that immunisation protects against
pneumococcal bacteraemia.49 There are no adequate
studies of rates of infection following pneumococcal
immunisation in the immunosuppressed, although
subgroup analysis from a large observational study
showed no protective effect in the immunosuppressed
(with no clear definition of immunosuppression).49
Influenza
Immunisation against influenza A and B is highly effective in protection against these infections.35,47 The surface
proteins of prevalent strains of influenza change gradually
year-on-year (known as antigenic drift), and occasionally
more major changes occur (known as antigenic shift).
Currently available vaccines are trivalent: they contain
surface proteins from two strains of influenza A (the
major pathogen) and one strain of influenza B. Influenza
vaccines offered by the UK Department of Health are
modified annually to give maximal protection against
the strains prevalent in the community that year. This
gives the vaccine the potential to reduce the number of
incident cases by 70–80% in most years, with protection
lasting for about a year. Immunisation should be offered to all immunosuppressed patients over the age of
6 months. Patients should receive influenza vaccine
annually (and children between 6 months and 12 years
In immunosuppressed adults, a single dose of pneumococcal polysaccharide vaccine should be offered. In
children, a more intensive immunisation schedule than
that shown in Table 5 should be used:
• In children between 2 and 12 months, give 3 doses
of conjugate vaccine as in the routine immunisation
TABLE 6. UK Department of Health recommended patient groups for immunisation against pneumococcal and influenza infection.35
Age >65, or those in the following high-risk groups (age >2 months for pneumococcus and >6 months for
influenza):
• Chronic respiratory disease
• Chronic heart disease
• Chronic liver disease
• Diabetes
• Immunosuppression due to disease or treatment. The only therapeutic definition of immunosuppression offered by the Green Book is corticosteroids for >1 month at equivalent prednisolone ≥20 mg daily (≥1 mg/kg for children weighing <20 kg) – but note that much lower doses may be associated with increased risks of infection in patients with rheumatic diseases
• People in long-term residential care (influenza only)
• People with cerebrospinal fluid leaks or cochlear implants (pneumococcal only)
Close contacts of the immunosuppressed
schedule, followed by 1 additional dose of polysaccharide vaccine at 2 years of age.
Close contacts of the severely immunosuppressed
should be strongly encouraged to be fully immunised
according to the UK schedule. Influenza and Varicella
zoster immunisation should also be considered.
• In children between 1 and 5 years (not previously immunised), give 2 doses of conjugate vaccine spaced
by 2 months, followed by 1 dose of polysaccharide
vaccine at least 2 months later and not before the
second birthday.
Disease-specific recommendations
Autoimmune rheumatic diseases
As discussed above, the susceptibility to infection found
in patients with inflammatory rheumatic diseases is
not just due to immunosuppressive treatment, but
seems also to reflect altered immunity as part of the
autoimmune disease process. In both RA and SLE, this
disease-specific immunosuppression may possibly be
more important than any effect due to treatment. A case
can therefore be made for immunising patients with
rheumatic diseases with pneumococcal and influenza
vaccine, even if they are not currently being treated
with immunosuppressive drugs. This argument can
be made most strongly in patients with severe disease,
who are by definition already likely to be treated with
immunosuppressants (or to receive such treatment in
the near future). It is the opinion of the author that
pneumococcal and influenza immunisation should be
offered to patients with severe active inflammatory arthritis or SLE who, for whatever reason, are not currently
being treated. It may be helpful to consider immunisation
at the time of the initial diagnosis prior to commencing
immunosuppression, although treatment should not
be delayed for this reason. Immunisation should also
be offered to patients with severe end-organ damage
and/or high levels of disability, even if their disease is
inactive, since organ damage and disability seem to
predict a higher risk of infection, with the infection
having more severe consequences when it occurs. Many
of these patients will also justify immunisation on the
basis of age or cardiorespiratory disease.
Pneumococcal vaccine is usually only given once in
adults. Repeat doses are recommended at 5 years in
subjects with hyposplenism or the nephrotic syndrome,
since antibody levels are known to decline more rapidly
in these conditions.35,36 Since responses to polysaccharide vaccines may be reduced in rheumatic diseases
and by immunosuppressive drug treatment, and are
possibly poorly sustained,28 some have advocated the
use of reimmunisation at shorter intervals with the
measurement of post-immunisation antibody titres.
While this strategy seems logical and appealing, its
safety, clinical- and cost-effectiveness are uncertain,
and therefore it cannot be generally recommended.
Clinical immunologists may be able to offer advice on
individual patients who are felt to be at particularly
high risk from infection.
Pneumococcal immunisation may be particularly important in SLE: there is a particularly strong risk of
severe, invasive pneumococcal infection in patients
with severe SLE, especially in those with renal disease
and/or complement depletion.25,50
Varicella zoster: passive immunisation
Immunosuppressed patients without prior immunity
to Varicella zoster virus (VZV) are at risk of severe disseminated disease if exposed to infection. VZV vaccine is
live, and is contraindicated in the immunosuppressed,
but if possible can be given at least 4 weeks before
immunosuppression is initiated. The vaccine can also
be offered to non-immune family members at this
stage. If a non-immune immunosuppressed patient
is exposed to VZV, then passive immunisation with an
immunoglobulin preparation containing high titres of
VZV (VZIG) can reduce the risk of developing infection.
The recommended procedure for use of VZIG is summarised in the Green Book.35
If severe rheumatological diseases cause immunosuppression as part of the disease process, then the question
arises as to whether live vaccines should be avoided in
these diseases. There is no evidence that this precaution
is necessary.
Hyposplenism and splenectomy
Patients with rheumatic diseases may undergo therapeutic splenectomy (for example for refractory thrombocytopenia). Functional hyposplenism may also occur
as a consequence of the disease process: patients with
severe, active SLE are especially likely to have splenic
dysfunction, which may contribute to the increased susceptibility to severe pneumococcal disease in patients
with SLE. Patients with an absent spleen, for whatever
reason, should be immunised against infection with common capsulate microorganisms: pneumococci, men-
Measles: passive immunisation
Because of press and public concern about use of the
MMR vaccine, significant numbers of children do not
have protective immunity against measles, and the disease is becoming more common. Immunosuppressed
patients coming into contact with measles can reduce
their chances of infection by passive immunisation with
human normal immunoglobulin (which contains high
titres of anti-measles antibody). This should be given
in the event of any significant contact, regardless of
antibody status.
ingococci type C and Haemophilus influenzae type B.
Antibiotic prophylaxis is also required, usually with penicillin V. These immunisations should be given before
splenectomy if possible. It is the opinion of the author
that patients with severe, active SLE (especially those
with class III or IV nephritis and hypocomplementaemia)
should also be offered pneumococcal immunisation,
and immunisation with the other capsulate vaccines
should be considered.
ticularly respiratory tract infection. This increased susceptibility probably reflects an interaction between
disease- and drug-related immunosuppression. Immunisation with non-live vaccines is safe and probably
reasonably effective in these patients. Influenza and
pneumococci are two of the major causes of respiratory
tract infection, and immunisation is probably effective in reducing the impact of these infections. All
patients on immunosuppressive drugs, including corticosteroids, should be offered these immunisations:
annually for influenza and as a single dose of pneumococcal vaccine. They should also be offered to patients
with severe disease even in the absence of immunosuppressive drugs.
WHAT HAPPENS IN PRACTICE?
There are no systematically collected data on uptake of
immunisation with rheumatic disease, but audit data51
suggest that many who justify pneumococcal and influenza immunisation do not receive it, particularly in
the under-65 age group (perhaps because these patients
are not easily identified in primary care registers). A
survey of immunisation practice among paediatric
rheumatologists in the UK suggested that there is wide
variation in both knowledge and practice.52
ACKNOWLEDGEMENTS
I thank my colleagues Will Dixon, Beverley Harrison, Ariane Herrick
and Gail Thomson for their helpful comments on this review.
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As will be clear from the above text, the use of immunisation in patients with inflammatory rheumatic diseases
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CONCLUSIONS
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www.dh.gov.uk/en/Policyandguidance/Healthandsocialcaretopics/
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deficiency associated with gold treatment: natural history and management in 22 patients. Ann Rheum Dis 1996;55(9):616-21.
36. Royal College of Paediatrics and Child Health. Immunisation of
the immunocompromised child. Best Practice Statement. London:
RCPCH; 2002. www.rcpch.ac.uk/publications/publications-list-bytitle#1.
18. Sihvonen S, Korpela M, Mustonen J, Huhtala H, Karstila K,
Pasternack A. Mortality in patients with rheumatoid arthritis treated
with low-dose oral glucocorticoids: a population-based cohort study.
J Rheumatol 2006 Sep;33(9):1740-6.
37. British HIV Association Immunisation Subcommittee. Immunisation guidelines for HIV-infected adults (2006). www.bhiva.org.
19. Dixon WG, Watson K, Lunt M, Hyrich KL, Silman AJ, Symmons DP;
British Society for Rheumatology Biologics Register. Rates of serious
infection, including site-specific and bacterial intracellular infection,
in rheumatoid arthritis patients receiving anti-tumor necrosis factor
therapy: results from the British Society for Rheumatology Biologics
Register. Arthritis Rheum 2006;54(8):2368-76.
38. Ljungman P, Engelhard D, de la Camara R et al; Infectious
Diseases Working Party of the European Group for Blood and Marrow
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20. Pryor BD, Bologna SG, Kahl LE. Risk factors for serious infection
during treatment with cyclophosphamide and high-dose corticosteroids for systemic lupus erythematosus [erratum in Arthritis
Rheum 1997;40(9):1711]. Arthritis Rheum 1996;39(9):1475-82.
39. Ljungman P, Nahi H, Linde A. Vaccination of patients with haematological malignancies with one or two doses of influenza vaccine:
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21. Noel V, Lortholary O, Casassus P et al. Risk factors and prognostic
influence of infection in a single cohort of 87 adults with systemic
lupus erythematosus. Ann Rheum Dis 2001;60(12):1141-4.
40. Duchini A, Goss JA, Karpen S, Pockros PJ. Vaccinations for adult
solid-organ transplant recipients: current recommendations and
protocols. Clin Microbiol Rev 2003;16(3):357-64.
22. Houssiau FA, Vasconcelos C, D’Cruz D et al. Immunosuppressive
therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide. Arthritis Rheum 2002;46(8):2121-31.
41. Huang KL, Armstrong JA, Ho M. Antibody response after influenza
immunization in renal transplant patients receiving cyclosporin A
or azathioprine. Infect Immun 1983;40(1):421-4.
42. Kapetanovic MC, Saxne T, Nilsson JA, Geborek P. Influenza
vaccination as model for testing immune modulation induced by
anti-TNF and methotrexate therapy in rheumatoid arthritis patients.
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44. Dengler TJ, Strnad N, Buhring I et al. Differential immune response to influenza and pneumococcal vaccination in immunosuppressed patients after heart transplantation. Transplantation 1998;
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29. Holvast A, Huckriede A, Wilschut J et al. Safety and efficacy of
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47. Horwood F, MacFarlane J. Pneumococcal and influenza vaccination: current situation and future prospects. Thorax 2002;57 Suppl
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30. Elkayam O, Paran D, Caspi D et al. Immunogenicity and safety of
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48. Christenson B, Lundbergh P, Hedlund J, Ortqvist A. Effects of a
large-scale intervention with influenza and 23-valent pneumococcal
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31. Chalmers A, Scheifele D, Patterson C et al. Immunization of patients
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49. Jackson LA, Neuzil KM, Yu O et al; Vaccine Safety Datalink.
Effectiveness of pneumococcal polysaccharide vaccine in older adults.
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32. Geier MR, Geier DA. A case-series of adverse events, positive
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50. Naveau C, Houssiau FA. Pneumococcal sepsis in patients with
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33. Geier DA, Geier MR. A case-control study of serious autoimmune
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Pneumococcal and influenza vaccination in patients with rheumatic
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10
KEY POINTS FOR CLINICIANS
Immunosuppression is assumed to occur:
• in those on immunosuppressive drugs – cyclophosphamide, azathioprine, mycophenolate,
leflunomide, methotrexate, ciclosporin, biological agents at any dose
• in those receiving corticosteroids for more than 1 week at doses >20 mg/day (adults), >2 mg/kg/day
(children), or >1 mg/kg/day for more than 1 month (children). Corticosteroids are associated with a
dose-dependent risk of infection – but even very low doses (e.g. 5 mg prednisolone daily) are
associated with infection
• in patients with severe autoimmune rheumatic diseases irrespective of treatment.
Practical tips
• Immunisation is generally safe provided live vaccines are avoided.
– There is no convincing evidence that immunisation causes flaring of the underlying rheumatic
disease.
• Live vaccines should be avoided during treatment and for 6 months after immunosuppressive drug
treatment and 3 months after corticosteroids.
– Live vaccines in common use in the UK include BCG, MMR, yellow fever, Varicella zoster, oral
typhoid. Oral polio vaccine is not now routinely used (inactivated vaccine used instead).
• Killed/inactivated vaccines can be used as normal.
• The immune response to immunisation varies with the strength of immunosuppression but is generally
good, although not as good as in healthy subjects. The true clinical effectiveness of immunisation
in protecting immunosuppressed patients is not known, but is assumed to be beneficial.
• Where possible immunisation should be performed before immunosuppressive drug treatment is
started.
• Normal childhood immunisation schedules should be followed except:
– live vaccines (e.g. MMR, BCG) should be avoided
– a more intensive schedule for pneumococcal immunisation should be used (see Green Book).
• Travel immunisation should proceed as normal except for avoidance of live vaccines.
• Influenza and pneumococcal immunisation are specifically recommended in:
– all those on immunosuppressive drug treatment and long-term corticosteroids
– all patients with severe inflammatory rheumatic disease even if not currently on immunosuppressive
drugs or DMARDs.
• Influenza immunisation should be given annually.
• Pneumococcal vaccine should be given once. Repeat immunisation cannot be routinely recommended
but specialist advice may be useful if there are concerns about adequacy of cover.
• Ascertaining immune status to Varicella zoster is recommended. Varicella zoster-specific immunoglobulin
may be indicated post exposure in non-immune subjects.
Detailed advice on immunisation is available from the UK Department of Health Green Book,
accessible on-line at www.dh.gov.uk/immunisation, and from the BNF.
Specialist advice on individual patients should be sought from an infectious disease physician/
paediatrician, clinical immunologist or public health physician.
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