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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. REFERENCES 1. Thomas E, Symmons DP, Brewster DH, Black RJ, Macfarlane GJ. National study of cause-specific mortality in rheumatoid arthritis, juvenile chronic arthritis, and other rheumatic conditions: a 20 year followup study. J Rheumatol 2003;30(5):958-65. WHAT IS NOT KNOWN IN THIS AREA? 2. Sihvonen S, Korpela M, Laippala P, Mustonen J, Pasternack A. Death rates and causes of death in patients with rheumatoid arthritis: a population-based study [erratum in Scand J Rheumatol 2006;35(4): 332]. Scand J Rheumatol 2004;33(4):221-7. As will be clear from the above text, the use of immunisation in patients with inflammatory rheumatic diseases is largely informed by expert opinion, consensus and extrapolation from other areas of medicine, with no strong evidence base. Various areas of uncertainty can be highlighted: 3. Iliopoulos AG, Tsokos GC. Immunopathogenesis and spectrum of infections in systemic lupus erythematosus. Semin Arthritis Rheum 1996;25(5):318-36. 4. Fessler BJ. Infectious diseases in systemic lupus erythematosus: risk factors, management and prophylaxis. Best Pract Res Clin Rheumatol 2002;16(2):281-91. 5. Kang I, Park SH. Infectious complications in SLE after immunosuppressive therapies. Curr Opin Rheumatol 2003;15(5):528-34. • the need for better estimates of the morbidity and mortality due to infection in patients with rheumatic diseases, particularly those treated with modern treatment regimes. (It is also unclear whether the increased rates of infection seen in RA and SLE are seen in other inflammatory disorders such as the spondyloarthropathies) 6. Gilliland WR, Tsokos GC. Prophylactic use of antibiotics and immunisations in patients with SLE. Ann Rheum Dis 2002;61(3):191-2. 7. Sneller MC. Evaluation, treatment, and prophylaxis of infections complicating systemic vasculitis. Curr Opin Rheumatol 1998;10(1): 38-44. 8. Cacoub P, Le Thi Huong, Guillevin L, Godeau P. [Causes of death in systemic vasculitis of polyarteritis nodosa: analysis of a series of 165 patients.] Ann Med Interne (Paris) 1988;139(6):381-90. 9. Booth AD, Almond MK, Burns A et al; Pan-Thames Renal Research Group. Outcome of ANCA-associated renal vasculitis: a 5-year retrospective study. Am J Kidney Dis 2003;41(4):776-84. • the relative contribution of disease-specific and drug-related factors to the increased susceptibility to infection in patients with RA and SLE 10. Cohen J. Infection in the immunocompromised host. In: Warrell DA, Cox TM, Firth JD, Benz EJ Jr (ed). Oxford textbook of medicine. 4th edn. Oxford: Oxford University Press; 2005. Section 7.20. • the mechanisms underlying disease-specific defects in immunity 11. Cohen J, Pinching AJ, Rees AJ, Peters DK. Infection and immunosuppression: a study of the infective complications of 75 patients with immunologically-mediated disease. Q J Med 1982;51(201): 1-15. • the relationship between low-dose steroid treatment and infection, and whether these low doses impair response to immunisation 12. Boerbooms AM, Kerstens PJ, van Loenhout JW, Mulder J, van de Putte LB. Infections during low-dose methotrexate treatment in rheumatoid arthritis. Semin Arthritis Rheum 1995;24(6):411-21. 13. Franklin J, Lunt M, Bunn D, Symmons D, Silman A. Risk and predictors of infection leading to hospitalisation in a large primarycare-derived cohort of inflammatory polyarthritis. Ann Rheum Dis 2007;66(3):308-12. • the clinical- and cost-effectiveness of influenza and pneumococcal immunisation in patients with inflammatory rheumatic disease. 14. Wolfe F, Caplan L, Michaud K. Treatment for rheumatoid arthritis and the risk of hospitalization for pneumonia: associations with prednisone, disease-modifying antirheumatic drugs, and anti-tumor necrosis factor therapy. Arthritis Rheum 2006;54(2):628-34. CONCLUSIONS 15. Hernandez-Cruz B, Cardiel MH, Villa AR, Alcocer-Varela J. Development, recurrence, and severity of infections in Mexican patients with rheumatoid arthritis: a nested case-control study. J Rheumatol 1998;25(10):1900-7. Patients with inflammatory rheumatic diseases have increased morbidity and mortality from infection, par 16. Snowden N, Moran A, Booth J, Haeney MR, Swinson DR. Defective antibody production in patients with rheumatoid arthritis and bronchiectasis. Clin Rheumatol 1999;18(2):132-5. 35. Department of Health. Immunisation against infectious disease: the Green Book. London: UK Department of Health. Paper version 1996 (now outdated); web version 2006 (updated annually). www.dh.gov.uk/en/Policyandguidance/Healthandsocialcaretopics/ Greenbook/DH_4097254. 17. Snowden N, Dietch DM, Teh LS, Hilton RC, Haeney MR. Antibody 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 Transplantation. Vaccination of stem cell transplant recipients: recommendations of the Infectious Diseases Working Party of the EBMT. Bone Marrow Transplant 2005;35(8):737-46. 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: a randomised study. Br J Haematol 2005;130(1):96-8. 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. Rheumatology (Oxford) 2007;46(4):608-11. 23. Vanrenterghem Y, van Hooff JP, Squifflet JP et al; European Tacrolimus/MMF Renal Transplantation Study Group. Minimization of immunosuppressive therapy after renal transplantation: results of a randomized controlled trial. Am J Transplant 2005;5(1):87-95. 43. Kapetanovic MC, Saxne T, Sjoholm A, Truedsson L, Jonsson G, Geborek P. Influence of methotrexate, TNF-blockers and prednisolone on antibody responses to pneumococcal polysaccharide vaccine in patients with rheumatoid arthritis. Rheumatology (Oxford) 2006;45(1):106-11. 24. Turner-Stokes L, Isenberg DA. Immunisation of patients with rheumatoid arthritis and systemic lupus erythematosus. Ann Rheum Dis 1988;47(7):529-31. 25. O’Neill SG, Isenberg DA. Immunizing patients with systemic lupus erythematosus: a review of effectiveness and safety. Lupus 2006;15(11):778-83. 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; 66(10):1340–7. 26. Mercado U. Why have rheumatologists been reluctant to vaccinate patients with systemic lupus erythematosus? J Rheumatol 2006; 33(8):1469-71. 45. Cambridge G, Leandro MJ, Teodorescu M et al. B cell depletion therapy in systemic lupus erythematosus: effect on autoantibody and antimicrobial antibody profiles. Arthritis Rheum 2006;54(11):361222. 27. Gluck T. Vaccinate your immunocompromised patients! Rheumatology (Oxford) 2006;45(1):9-10. 28. Lipnick RN, Karsh J, Stahl NI, Blackwelder WC, Schiffman G, Klippel JH. Pneumococcal immunization in patients with systemic lupus erythematosus treated with immunosuppressives. J Rheumatol 1985;12(6):1118-21. 46. British National Formulary 53. 2007 March. Section 14: Immunological products and vaccines. www.bnf.org/bnf. 29. Holvast A, Huckriede A, Wilschut J et al. Safety and efficacy of influenza vaccination in systemic lupus erythematosus patients with quiescent disease. Ann Rheum Dis 2006;65(7):913-8. 47. Horwood F, MacFarlane J. Pneumococcal and influenza vaccination: current situation and future prospects. Thorax 2002;57 Suppl 2:ii24-ii30. 30. Elkayam O, Paran D, Caspi D et al. Immunogenicity and safety of pneumococcal vaccination in patients with rheumatoid arthritis or systemic lupus erythematosus. Clin Infect Dis 2002;34(2):147-53. 48. Christenson B, Lundbergh P, Hedlund J, Ortqvist A. Effects of a large-scale intervention with influenza and 23-valent pneumococcal vaccines in adults aged 65 or older: a prospective study. Lancet 2001;357(9261):1008-11. 31. Chalmers A, Scheifele D, Patterson C et al. Immunization of patients with rheumatoid arthritis against influenza: a study of vaccine safety and immunogenicity. J Rheumatol 1994;21(7):1203-6. 49. Jackson LA, Neuzil KM, Yu O et al; Vaccine Safety Datalink. Effectiveness of pneumococcal polysaccharide vaccine in older adults. N Engl J Med 2003;348(18):1747-55. 32. Geier MR, Geier DA. A case-series of adverse events, positive re-challenge of symptoms, and events in identical twins following hepatitis B vaccination: analysis of the Vaccine Adverse Event Reporting System (VAERS) database and literature review. Clin Exp Rheumatol 2004;22(6):749-55. 50. Naveau C, Houssiau FA. Pneumococcal sepsis in patients with systemic lupus erythematosus. Lupus 2005;14(11):903-6. 33. Geier DA, Geier MR. A case-control study of serious autoimmune adverse events following hepatitis B immunization. Autoimmunity 2005;38(4):295-301. 51. Fahy WA, Farnworth E, Yeldrem KP, Melling GS, Grennan DM. Pneumococcal and influenza vaccination in patients with rheumatic conditions and receiving DMARD therapy. Rheumatology (Oxford) 2006;45(7):912-3. 34. Harrison BJ, Thomson W, Pepper L et al. Patients who develop inflammatory polyarthritis (IP) after immunization are clinically indistinguishable from other patients with IP. Br J Rheumatol 1997; 36(3):366-9. 52. Davies K, Woo P. Immunization in rheumatic diseases of childhood: an audit of the clinical practice of British Paediatric Rheumatology Group members and a review of the evidence. Rheumatology (Oxford) 2002;41(8):937-41. 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. 11 NEW PUBLICATIONS Drug Information Two new information sheets in the arc ‘Drug Information’ series have been published this year: • Iloprost (Code 6272) • Intravenous Immunoglobulin (Code 6273) An information sheet on drugs for osteoporosis is currently in preparation. As part of arc’s educational work these resources are provided free of charge within the UK. See below for ordering instructions. This issue of ‘Topical Reviews’ can be downloaded as html or a PDF file from the Arthritis (www.arc.org.uk/arthinfo/rdr.asp and follow the links). Research Campaign website (www.arc.org.uk/about_arth/rdr5.htm and follow the links). Hard copies of this and all other arc publications are obtainable via the on-line ordering by email ([email protected]), or from:Link, arc Trading system (www.arc.org.uk/orders), (at www.arc.org.uk/orders) or from: arc Trading Ltd, James Nicolson Clifton Ltd, James Link, Clifton Moor, York YO30 4XX. Moor, York Nicolson YO30 4XX. 12