Long-term management of elderly patients taking immunosuppressive medications

Elderly patients, generally defined as those aged >65 years, face a number of unique medication-related challenges. The elderly are more likely to have multiple comorbidities and are at increased risk of adverse medication reactions.¹ As the population ages, the use of immunosuppressants for the prevention of organ rejection following transplant or for the treatment of autoimmune disorders such as rheumatoid arthritis, systemic lupus erythematosus and inflammatory bowel disease is expected to increase. The average age of patients receiving solid organ transplants (SOTs) has increased over the past 20–25 years, and the majority of patients receiving SOTs are now aged >50 years.² Age is not considered an absolute contraindication to transplant if the elderly recipient has minimal comorbidities. However, frailty is associated with poorer outcomes before and after transplantation.^3,4

The management of elderly patients taking immunosuppressants is heavily dependent on close collaboration with tertiary care providers. Regular review at the tertiary institution for short- and long-term complications allows timely adjustment of treatments and early interventions. General practitioners (GPs) are often the primary source of contact for patients, and they may need to manage various aspects of the patients’ care, such as hypertension or diabetes. The GP is therefore ideally placed to recognise medication-related complications (eg adherence difficulties, medication interactions from multiple sources and medication toxicity). Coordinating care with other specialty services will ensure regular screening to recognise complications associated with immunosuppressive therapies.

Immunosenescence

Immunosenescence is a physiological part of ageing typified by an impairment of adaptive and innate immunities.⁵ Ageing in general has broad consequences for immune responses, organ function, repair mechanisms and metabolic function. Immunosenescence is linked to higher rates of diabetes, bacterial infections and malignancies.⁵ Immunosenescence may predispose elderly patients to the risks of over-immunosuppression. Theoretically, elderly transplant recipients may benefit from less immunosuppression than younger patients, but further studies are needed.⁶

Immunosuppressant regimens

The selection of immunosuppressive medication regimens in the elderly is complex as there are no specific guidelines. Specific recommendations for the elderly are difficult to ascertain as the elderly are generally excluded from studies or clinical trials.⁵ A summary of the available immunosuppressants, medication monitoring and main adverse effects is reported in Table 1. The introduction of biological agents has transformed the treatment of many autoimmune diseases. It is likely that further compounds will be introduced in the future, creating challenges for maintaining up-to-date clinical knowledge required in the monitoring of these highly effective agents.

Immunosuppression regimens and protocols are in a constant state of evolution and at present there is no universally agreed consensus to guide therapy. Immunosuppressant doses and serum target levels are individualised according to indication, disease response, side-effect profile, age and frailty of the individual patient. The frequency of monitoring may decrease over time but will reflect the individual patient’s comorbidities and complications.

Therapeutic drug monitoring (TDM) is available for the narrow therapeutic index (NTI) immunosuppressants such as tacrolimus, cyclosporin, everolimus, sirolimus and mycophenolate. However, TDM may not accurately reflect the effects of immunosenescence or the total degree of immunosuppression.⁷ As a result of immunosenescence, many clinicians may intuitively use lower immunosuppressant doses for elderly patients to minimise the risk of infection and side effects. However, there is no widespread consensus guiding specific TDM of immunosuppressants for the elderly.

Pharmacokinetics of immunosuppressants

In the elderly population, age-related physiological changes can result in clinically significant alterations in the pharmacokinetic parameters of immunosuppressants. The pharmacokinetics of medications, particularly calcineurin inhibitors (CNIs), may be altered in older patients. Initial CNI doses that are similar to those recommended for younger patients may result in higher serum concentrations. A recent study investigating the optimal dosing of CNIs in elderly kidney transplant recipients (aged ≥65 years) found that serum CNI trough levels were 50% higher in the elderly when normalised for dose and weight.⁸ The reason that elderly patients may require lower doses of CNIs to obtain the same therapeutic levels is because of a reduction in metabolism from CYP3A4 isozymes and reduced P-glycoprotein activity, resulting in improved bioavailability.⁸

Elderly patients require higher doses of mycophenolic acid (MPA) when compared with younger patients. The reason may be that MPA is strongly bound to serum albumin, and lower albumin levels in elderly patients result in increased clearance of unbound MPA. A pharmacokinetic study comparing MPA exposure in elderly (63 ± 1 years) versus younger (41 ± 5 years) transplant patients showed lower overall exposure and trough concentrations in the elderly.⁹ Data from liver and renal transplant recipients showed that mycophenolate doses were significantly higher in patients with lower serum albumin when compared with patients who had normal serum albumin.^10,11

The metabolism and excretion of methotrexate is affected by age. Elderly patients in particular require close monitoring, as high rates of discontinuation as a result of toxicity have been observed in this cohort of patients.¹² Accumulation of methotrexate is likely to lead to side effects such as nausea and vomiting, myelosuppression and liver enzyme elevations.¹³ Many pharmacokinetic studies of mammalian target of rapamycin (mTOR) inhibitors in the elderly showed no difference with excretion and ageing.¹⁴ The effects of ageing on the pharmacokinetics of prednisolone are unknown.¹⁵

Generics

Generic substitution of NTI immunosuppressants remains a contentious issue within the transplant community. Bioequivalence studies are performed in healthy young volunteers and do not take into account chronic disease, repeated dosing or medication interactions.^16,17 In a prospective single-centre study evaluating a generic formulation of tacrolimus in elderly patients following kidney transplant, the generic product did not meet the bioequivalent standards when compared with the innovator version. The generic formulation had higher trough concentrations and higher exposure.¹⁸

Elderly patients receiving CNIs or mycophenolate should consistently receive the same brand of immunosuppressant once they are stabilised. Interchanging brands is likely to result in variability of immunosuppressant levels, potentially exposing the patient to an increased risk of adverse effects.

The introduction of biologics has transformed the treatment of many autoimmune diseases. However, the prohibitive high cost has limited the use of and access to these agents. The lower cost biosimilars are required to be highly similar to the reference product with regard to their clinical efficacy, safety and pharmacokinetics.¹⁹ Concerns about immunogenicity when switching from the reference product have limited their widespread uptake. However, clinical trials to date have not shown significant changes in immunogenicity.²⁰

Comorbidities in patients receiving immunosuppressants

Immunosuppressants can cause or exacerbate comorbidities such as hypertension, renal dysfunction, diabetes and hyperlipidaemia.²¹ Table 2 has a suggested frequency of monitoring for comorbidities or side effects exacerbated by long-term immunosuppression. Even in the absence of immunosuppression, older patients have an increased risk of cardiovascular-related disease or death. Mortality related to cardiovascular disease ranges from 40% after cardiac and renal transplantation, to 20% after liver transplantation, to 5% after lung transplantation.²¹

The most clinically significant change in the elderly is the decline in renal function, with age-related decline in renal function at approximately 10% per decade of increasing age.²² Close monitoring of renal function in the elderly is essential during methotrexate therapy, as many methotrexate-related adverse effects can be related to impaired renal function.^12,23 Elderly recipients of lung transplants have higher rates of severe renal dysfunction over long-term follow up than younger receipients of lung transplants.²⁴ CNI minimisation strategies with mTOR inhibitors to preserve renal function may provide benefits in the elderly transplant population.^25,26

The risk of developing new-onset diabetes mellitus after transplantation (NODAT) increases 1.5-fold for every decade increase in age following kidney transplant.²⁷ The incidence of NODAT varies across SOT: 4–25% in renal transplant recipients, 2–38% in liver transplant recipients, 7–26% in heart transplant recipients and 32–57% in lung transplant recipients.^28–30 Immunosuppressants such as corticosteroids, CNIs and mTOR inhibitors have diabetogenic potential.²⁸ Corticosteroids have the strongest diabetogenic potential, which is dose dependent.

Infectious diseases

Infections are an important cause of morbidity and mortality in elderly patients taking immunosuppressants. Immunocompetence decreases with age, and older patients are more likely to die from bacterial infections than younger transplant recipients. The risk and severity of infection increases with the level of immunosuppression and is usually higher within the first six months after organ transplant.³¹ SOT recipients aged >50 years have a 2-fold increase in the risk of developing bacteraemia with septic shock.³²

The incidence of opportunistic infections – such as Pneumocystis jirovecii (PJP), herpes zoster and tuberculosis – has risen with the increased prescribing of biologics.³³ A prospective analysis examined the risk factors for opportunistic infections in patients with inflammatory bowel disease. An increased rate of opportunistic infections was seen in patients aged ≥50 years and with the use of steroids, thiopurines and combination immunosuppressant therapy.³⁴

Immunosuppressive regimens prescribed may predispose to specific infections. For example, corticosteroids predispose to PJP, hepatitis B, bacterial and fungal infections, while T-lymphocyte depletion may activate latent Cytomegalovirus (CMV) reactivation.^35,36 Azathioprine has been associated with papillomavirus, and mycophenolate has been associated with late CMV.³⁵

The GP will often be involved in the first-line management of infections in the elderly. The decision to withhold or alter the doses of immunosuppressive therapy should only be undertaken in close consultation with the transplant physician. Although most infectious complications related to immunosuppression are preventable, they can become life threatening in a matter of hours, as infection progresses rapidly in the immunocompromised host. Urgent referral for hospital management is sometimes necessary.

Treatment of infections can be problematic as it may destabilise immunosuppressant regimens as a result of medication interactions and toxicities (eg nephrotoxicity, leukopenias and hepatotoxicity). Table 3 provides a summary of some of the clinically significant medication interactions between immunosuppressants and other frequently prescribed medications in the elderly patient.

Vaccinations

GPs play a crucial part in ensuring that immunisation is up to date. Vaccinating immunocompromised patients can be challenging as they may have a reduced response to vaccines, as well as reduced protection from previous vaccinations. Immunocompromised patients may need extra doses of inactivated vaccines to optimise protection against specific diseases. Vaccination should ideally be undertaken prior to immunosuppressive therapy to improve the immune response.³⁷

Administration of live vaccines – such as measles, mumps and rubella (MMR); varicella and zoster vaccines – to immunocompromised hosts is generally contraindicated. Mildly immunosuppressed patients, such as those taking conventional disease-modifying antirheumatic medications (eg low-dose methotrexate, azathioprine or corticosteroids), can receive live vaccines, but only under rheumatologist advice.³⁷ Otherwise, patients should ideally wait four weeks before starting immunosuppression after receiving a live vaccine.

Table 4 provides an overview of the recommended vaccines for an elderly patient receiving immunosuppressants, and Table 5 provides a list of vaccines that require case-by-case consideration. As recommendations are in a constant state of flux, practitioners are advised to refer to the The Australian immunisation handbook for complete and up-to-date information.

Malignancy

Immunosenescence may contribute to an increased risk of malignancy in the elderly because of decreased immunosurveillance.⁵ Cancer incidence and mortality increase after the age of 65 years, levelling off at the age of approximately 85–90 years. The risk for malignancy in transplant recipients is approximately two or three times that seen in the non-transplant population, with the risk related to the intensity and duration of immunosuppression.³⁸

Advanced age has shown to be an important predictor of malignancy in kidney transplant recipients.³⁹ One study reported a five-fold increase in the risk of cancers in kidney transplant recipients aged >60 years when compared with recipients aged <45 years.⁴⁰ Forty per cent of lung transplant recipients had at least one malignancy at 10 years post-transplantation. The most common cancers are skin related, followed by lymphoproliferative disorders. Recipients aged >65 years had higher rates of skin cancers than younger recipients.²⁴

mTOR inhibitors may have a role in minimising the risk of malignancy because of their dual antiproliferative and anti-cancer activity. mTOR inhibitors can be prescribed for renal cell and breast cancers.⁴¹ Although early clinical trials have been promising, evidence to date has not been compelling.³⁸

Conclusion

Age broadly affects the immune response as well as the pharmacokinetics of immunosuppressants. In general, elderly patients are more likely to experience over-immunosuppression, manifesting in infectious complications and malignancy. More studies with older patients are required, as clinical trials have generally excluded the elderly. Close surveillance and collaboration is necessary by all practitioners involved in their care.