Immunosuppression in gastroenterology and hepatology

Abstract

In recent years, the clinician has a more diverse approach to immunosuppression. Now, for many conditions, such as solid organ transplantation or treatment of some autoimmune diseases, the consequences of immunosuppression becomes a greater risk than organ failure from immune-mediated disease. Some of the consequences of immunosuppression can be prevented by prophylaxis, immunisation, surveillance and pharmacological intervention. Infections and malignancy are major causes of morbidity and mortality in the immunosuppressed. Screening for evidence of latent infection and immunisation prior to introduction of immunosuppression (where possible and appropriate) will help reduce the risk of infection. Surveillance for those cancers that are increased in association with immunosuppression (especially skin cancers, melanoma, anal canal, Kaposi, post-transplant lymphoproliferative disease) will allow early detection and intervention and, where appropriate, alteration of agent.

Introduction

The drugs available to allow effective immunosuppression have greatly increased both in mode of action and in number. Optimal management of the patient prescribed immunosuppressive drugs requires a clear understanding of not only the selection and timing of drugs, the need for therapeutic drug monitoring in selected cases, avoidance of interactions with other drugs, but recognition not only of the manifestations of drug toxicity but the potential impact of the immunosuppression on the risk of infection, cancer and other morbidities. It is important for the clinician to be aware of these risks as mitigation is often possible; early recognition is likely to lead to better outcomes, either by reducing or switching immunosuppressive agents or early treatment. The decision whether to reduce immunosuppression is often challenging: for example, the immunosuppressive burden may be reduced in a transplant recipient with active cytomegalovirus disease: but this may lead to rejection and loss of the graft. While for a kidney recipient this mean a return to dialysis, for a heart recipient this may mean death. This dilemma is summarised by the aphorism ‘with rejection you lose the graft but with infection you lose the patient’.

In this Introduction, some of the interventions that may help reduce the general consequences of immunosuppression are described. It should be noted that several audits have shown that compliance with guidance on prophylaxis is far from as good as it could be.

Immunosuppressive drugs are used primarily to reduce the effectiveness or efficiency of the immune system. Immunosuppressive drugs can be classified in a variety of ways, but one classification is shown below:

• Corticosteroids (such as prednisone, budesonide, methylprednisolone, and dexamethasone)

• Antimetabolite/antiproliferative agents (azathioprine, cyclophosphamide, methotrexate, mycophenolate, mercaptopurine, leflunomide)

• Calcineurin inhibitors (cyclosporine, tacrolimus)

• Mammalian target of rapamycin (mTOR) inhibitors (sirolimus and everolimus)

• Antibodies to T lymphocyte cell surface antigens (monoclonal or polyclonal)

• Kinase inhibitors (such as Sotrastaurin, tofacitinib)

• Other drugs such as small biological agents as Fingolomid

• B cell inhibitors (such as belimumab, rituximab)

• Interleukin inhibitors (such as anakinra, tocilizumab, cankinumab, sarilumab)

• Selective co-stimulation modulators (such as belatacept)

• Tumour-necrosis factors inhibitors (such as adalimumab, etanercept, infliximab, crolizumab)

As with any medication, the benefits of immunosuppression need to be balanced against the risks. With very few exceptions, solid organ transplant recipients need long term, if not life-long immunosuppression (see Fig. 1) and, for many of those with inflammatory bowel disease, immunosuppressive treatments have greatly reduced the need for surgery. Tolerance is a goal that may be achievable in the near future, at least for some solid organ recipients. For those with autoimmune diseases, such as autoimmune hepatitis, long-term treatment may be needed lifelong. Newer technologies such as stem cell transplants and other forms of immunotherapy are likely radically to alter the treatment of these patients in the future.

The risks and side-effects of immunosuppression are largely well recognised and may be classified as.

Agent-specific (such as corticosteroid- [1] induced osteoporosis or tacrolimus associated diabetes).

Class-specific (such calcineurin-associated renal impairment).

Immunosuppression-specific (such as increased risk of some infections and cancers).

Sometimes it may be difficult to distinguish the side-effects of drugs from the initial disease process (such as distinguishing liver dysfunction from calcineurin hepatoxicity from liver allograft rejection or flare-up of colitis from treatment-induced CMV colitis).

The major consequences from immunosuppression include an increased risk of some de novo malignancies, increased risk of some infections and cardiovascular disease. This triad, coupled with drug-specific side-effects, may have a significant adverse impact on both the quality and quantity of life of the recipient. It is difficult to distinguish the impact of immunosuppression from other factors, such as pre-existing disease, co-morbidities and organ failure. The impact of these consequences will depend on the duration, type and dose of the agent used. Despite the use of immunosuppressive agents, graft loss from rejection is not invariably prevented; compliance is an issue in some groups and may be exacerbated by the drug side-effects (such as the skin changes associated with corticosteroids may precipitate non-compliance and lead to graft loss). However, it must be stressed that the benefits of immunosuppression, in both prevention of graft rejection and suppression of inflammation, outweighs the side-effects. Death with a functioning graft is a more common cause of late death after liver transplant than death associated with graft rejection.

Clinicians must be more effective in using a personalised approach. Patterns of immunosuppression vary and the variation in regimens in liver transplant programmes in the United States is shown in Fig. 1.

Orlicka [1] have identified the most common infections associated with immunosuppression: these may be bacteria, mycobacterial, viral, protozoal, fungal infections (see Table 1).

Several groups have advised on the management of patients receiving immunosuppression during the Covid pandemic and lessons learned from these advisory bodies may be extrapolated to some other situations. Prevention is probably the most important factor is reducing the impact of Covid on those who are scheduled or currently taking immunosuppressive agents. Data comparing the outcomes of those on IMS are conflicting, in large part because of the lack of suitable control of other co-morbidities, other risk factors and case selection, and the information available is increasing, although it seems probable that those solid organ recipients are at increased risk of death from the infection.

Thus, for patients with inflammatory bowel disease, the British Society of Gastroenterology [2] has suggested the highest risk group includes those receiving intravenous or oral steroids ≥20 mg prednisolone or equivalent per day or within 6 weeks of starting biologic plus immunomodulator or systemic corticosteroids whereas those at moderate risk include those on Anti-TNF monotherapy, biologic plus immunomodulator, in stable patients on Ustekinumab, Vedolizumab, Thiopurines (azathioprine, mercaptopurine, thioguanine), methotrexate, calcineurin inhibitors, Janus kinase (JAK) inhibitors, mycophenolate, thalidomide or prednisolone <20 mg or equivalent per day.

For recipients of solid organ transplant, the optimal approach is not clear. One survey in the United States, reported that for kidney transplant recipients, antimetabolites were reported to have been stopped by 90% and CNI) reduced by 27% of respondents, although the numbers were lower for liver recipients [3].

Administration of immunosuppression may result in reactivation of quiescent infection; in some instances, monitoring may be adequate, and treatment reserved when infection becomes symptomatic; in other cases, prophylactic treatment is indicated. Infections that may be reactivated include viral infections (such as papillomavirus, Hepatitis B virus, JC virus, BK polyoma virus and CMV), bacteria, parasites (such as Toxoplasmosis and Leishmaniasis), fungi and mycobacteria.

Herpes infections may reactivate during immunosuppression and the risk may be lessened by vaccination. Since the vaccines for these infections are live, they should be offered before administration of the immunosuppression and not if the patient is taking antiviral medication. For varicella-zoster and other Herpes virus infections, some advocate a long course of antiviral therapy with acyclovir, valganciclovir or ganciclovir.

Immunosuppression can lead to reactivation of Hepatitis B. Pawlowska and colleagues [3] have classified the risk of HBV reactivation in those who are HBsAg positive as shown in Table 2.

The risk of reactivation in HBsAg-negative, anti-HBc-positive patients taking these medications is lower, with the exception of those taking B-cell depletion therapies, where the risk is as high as in HBsAg-positive patients.

Patients with an established diagnosis of HBV infection and receiving nucleos(t)ide analogues (NA) should continue treatment and remain monitored by a hepatologist or infectious disease clinician [4]. Those who are HBsAg-positive with detectable HBV-DNA should receive NA prophylaxis regardless of the level of HBV reactivation risk. NAs should be started before the start of immunosuppressive therapy; where possible, immunosuppression should be delayed until HBV-DNA levels are below the limit of detection. NA prophylaxis should continue until 18 months after completion of immunosuppression and monitored for a further year.

HBsAg-positive patients without detectable HBV-DNA, and HBsAg-negative and anti-HBc-positive patients should start HBV-prophylaxis for HBV reactivation before treatment with agents associated with high or moderate risk or reactivation.

HBsAg-positive individuals without detectable HBV-DNA, and HBsAg-negative/anti-HBc-positive patients treated with agents associated with a low risk of reactivation) should be offered HBV vaccination and monitored at least every 3 months and if ALT levels increase, then they should be tested for HBV-DNA and, if levels are positive, treatment with NA offered.

In the UK, the National Institute for Health Care and Excellence [5] recommends that in adults who are anticipated to be or are currently receiving immunosuppression, there should be a risk-assessment to establish whether testing should be offered, taking into account the risk of progression to active TB based on the degree, type and duration of immunosuppression and any risk factors for TB infection, such as country of birth or any recent contact with an index case with suspected infectious or confirmed pulmonary or laryngeal TB. For most, a Mantoux test is adequate although an interferon-gamma release assay may help. Treatment options include a 3-month course of isoniazid (with pyridoxine) and rifampicin to people younger than 35 years or a 6 month course of isoniazid (with pyridoxine) but specialist advice should be sought.

EBV reactivation is of particular concern in the solid organ transplant recipient and where T-cell depletion therapy is given where the outcome if post-transplant lymphoproliferative disorder (PTLD). EBV monitoring of high-risk patients (such as younger patients or those following intestinal transplants) may allow pre-emptive use of rituximab or reducing the degree of immunosuppression, although there is often a difficult balance between preventing graft loss form rejection and patient death from PTLD. Antiviral agents, such as acyclovir, ganciclovir, and valganciclovir are not widely used for prevention of PTLD, although they may be used for treatment even though data are limited.

Although CMV remains a challenge in solid organ transplant recipients, the condition may cause problems in those with gastroenterological diseases. In the transplant patient, CMV infection may be donor-derived, primary or reactivation. It is important to differentiate CMV infection from CMV disease:

CMV infection: evidence of CMV replication regardless of symptoms. Replication may be defined as virus isolation, detection of viral proteins or nucleic acid in any body fluid or tissue specimen.

CMV disease: evidence of CMV infection with attributable symptoms. CMV disease can be further categorized as a viral syndrome (characterised by fever, malaise, leukopenia, and/or thrombocytopenia), or as tissue invasive disease (such as hepatitis, pneumonitis, colitis).

CMV infection is best diagnosed by demonstrating circulating viral DNA or using immunocytology on histology [6]. Recent guidelines emphasise the lack of universal standards for the measurement of CMV DNA. Ideally, testing should be done with quantitative nucleic acid technology testing on whole blood or plasma. CMV-cellular specific immune monitoring, (such as using ELIspot testing) may be of help in monitoring those at risk of disease activation or reactivation.

For those transplant recipients at risk of developing CMV infection from the donor (D+/R-), there remains uncertainty universal prophylaxis or pre-emptive therapy in preferable for the prevention of CMV disease. Prophylaxis is given for between 3 and 12 months, depending on the transplanted organ. For initial and recurrent episodes of CMV disease, valganciclovir or intravenous ganciclovir is recommended, with the dose adjusted according to renal function. Foscarnet is a second line option and drug resistance may occur. It is likely that a vaccine may become available.

Pneumonia due to Pneumocytis juroveci (PJP) may develop via airborne transmission or following reactivation of prior infection. Solid organ transplant and haematological recipients are usually offered prophylaxis with trimethoprim-sulfamethoxazole for the first 3–6 months or during enhanced immunosuppression (for example, in association with treatment for rejection).

Whether those with inflammatory bowel disease undergoing immunosuppressive therapy should also receive PJP prophylaxis remains uncertain; certainly, a recent report suggested there was a very low risk, but, in line with other guidelines, it was suggested that prophylaxis should be considered especially in those treated with high dose corticosteroids [7].

Individuals with immunosuppression may not make a full immune response to vaccination. Those who are immunosuppressed should not receive a live or attenuated vaccine.

Guidance in the UK from the Joint Committee on Vaccination (JCVI) suggests that those who are receiving or have recently received high doses of some immunosuppressive agents and biological therapies (see list below) should not be given live vaccines because of the risk of severe or fatal infections. The Committee [8] recommends avoidance of vaccine for those adults:

Who are receiving, or have received in the past 6 months, immunosuppressive therapy for a solid organ transplant (with some exceptions).

Who are receiving or have received in the past 12 months immunosuppressive biological therapy (such as anti-TNF therapy such as alemtuzumab, ofatumumab, rituximab).

Those who are receiving or have received in the past 3 months immunosuppressive therapy including high-dose corticosteroids (>40 mg prednisolone per day or equivalent) for >1 week

Those on lower dose corticosteroids (>20 mg prednisolone per day) for more than 14 days

Adults on non-biological oral immune modulating drugs such as methotrexate >25 mg per

Week, azathioprine >3.0 mg/kg/day or 6-mercaptopurine >1.5 mg/kg/day.

For Covid vaccination, the JCVI recommends that all individual who are immunosuppressed should be offered vaccination. Some vaccines, such as the AstraZeneca COVID-19 vaccine, contain a live adenovirus vector, but as the virus is not replicating, it is considered safe in this group. There remain some safety concerns about thrombosis, so the vaccine is not suitable for all. Where possible, the 2-dose schedule to be completed prior to commencing immunosuppression, with the second dose at least 3–4 weeks after the first.

Where possible, live vaccinations should be offered so that the last dose of vaccine is given at least 4 weeks before the start of immunosuppression. It must be stressed that the decision to offer or withhold vaccination should be made on an individual basis, with specialist advice if needed, balancing risks and benefits. Because the response to immunisation is often less strong in the immunosuppressed, where possible and where appropriate, transplant patients should be offered immunisation for Hepatitis B and A virus prior to transplantation (although transplant should not be delayed solely to ensure a good response. Other vaccines that should be considered prior to transplant in the non-immune patient include DPT (diphtheria-pertussis-tetanus), HiB (haemophilus influenza B), 9vHPV (9-valent human papillomavirus vaccine), IPV (inactivated Polio), Influenza, Men-(Meningococcal B or quadrivalent conjugate vaccine), MMR (measles, mumps, rubella), Pneumococcal vaccine, Varicella vaccine. Annual flu vaccination is recommended if immunosuppression is ongoing.

Malignancy in the transplanted individual may be donor derived, donor transmitted or de novo. Malignancy may be increased by immunosuppression by one or more of the mechanisms.

• A direct pro-oncogenic properties of select immunosuppressive drugs;

• Oncogenic virus reactivation;

• Impaired immunosurveillance of tumour cells

The viruses implicated in cancers associated with immunosuppression include:

• Human Papilloma virus (HPV): non-melanoma skin cancers

• Epstein-Barr Virus (EBV): post-transplant lymphoproliferative disease

• Human Herpes virus-8: Kaposi sarcoma

• Merkel cell polyomavirus (MCV): Merkel call carcinoma

There have been many studies evaluating the risk of malignancy in immunosuppressed patients and the findings must be treated with some caution: Transplant recipients are a selected group and those with known, active malignancy are usually excluded from transplantation as sometimes are those who are actively smoking or taking excess alcohol. Furthermore, transplant recipients and others receiving long-term immunosuppression are generally followed up more closely than the general population, so surveillance might be anticipated to detect more cancers, including those which have no impact on survival. To determine which cancers may be increased by immunosuppression, comparison with an age and sex matched population is probably the most helpful approach.

Our own study in England and Wales [9] found the 10-year incidence of de novo cancer in transplant recipients is twice that of the general population, with the incidence of nonmelanoma skin cancer being 13 times greater. Non-melanoma skin cancer, cancer of the lip, post-transplant lymphoproliferative disease and anal cancer have the largest standardized incidence ratios, but the incidence of different types of malignancy differs according to the organ transplanted. Patterns in standardized incidence ratios over time since transplantation are different for different types of transplant recipient, as well as for different malignancies. Of note, there was no significant increase in cancer of the breast or uterus, suggesting enhanced surveillance is not indicated.

Different classes of immunosuppressive agents are associated with different levels of risk; indeed, the mTORi are effective in the treatment of some malignancies, such as skin cancers and Kaposi's sarcoma.

Cardiovascular and cerebrovascular disease is a major cause of death in solid organ transplant recipients with a functioning graft [10]. These recipients have multiple risk factors for vascular disease but immunosuppressive agents may play a role. Immunosuppressive agents increase the risk of weight gain and obesity, new onset post-transplant diabetes, hypertension, renal impairment and hyperlipidemia and these factors may all play a role in the increased cardiovascular and cerebrovascular morbidity and mortality. The extent to which immunosuppression contributes to mortality in those with inflammatory bowel disease is less certain but may contribute to the excess morbidity and mortality seen in those with inflammatory bowel disease [11].

For solid organ transplant recipients, guidelines recommend the routine use of HMG-CoA reductase inhibitors. For example, the ALERT trial [12], which showed fluvastatin in those with kidney transplants not only lowered LDL-cholesterol by one third but also reduced the risk of cardiac death and non-fatal MI by a similar degree. The impact was greatest if the statin was introduced within two years of transplant. However, several audits have shown that compliance is variable.

If statins are to be prescribed, clinicians should be aware of the pharmacokinetic differences between cyclosporine and tacrolimus. In contrast to cyclosporin, tacrolimus does not affect P-glycoprotein and organic anion transporting polypeptide (OATP) and so does not increase the risk of statin-related toxicity.

There are several guidelines for those who are immunosuppressed, whether because of medication or the disease process. For example, the recommendations from the Government of Canada [13] list some of the foods and drinks that patients are advised to avoid. These include.

• Raw or unpasteurized dairy products (such as milk).

• Unpasteurized and pasteurized soft and semi-soft cheeses.

• All unpasteurized and pasteurized blue-veined cheeses.

• Raw or unpasteurized fruit drinks

• Raw or lightly cooked eggs

• Raw or undercooked meat or poultry

• Refrigerated pates and meat spreads

• Raw or undercooked seafood

• Raw seafood, such as sushi, raw oysters, clams and mussels.

• Smoked seafood

• Raw sprouts

Other organisations have given similar advice. The evidence base for some of these recommendations is not always strong.

In general, solid organ transplant recipients are advised to wait 1 year after transplant before consideration of pregnancy and until good graft function is established. Some immunosuppressive drugs are teratogenic and should be avoided in those who may or wish to become pregnant. These include mycophenolate and mTORi agents. Registry data [14] suggest women with solid-organ transplants are at risk for premature birth, low birth weight, higher risk of Caesarean delivery, and hypertensive disorders of pregnancy. Most immunosuppressive regimens are safe. Although some drugs may be excreted in breast milk, breast feeding by those on with tacrolimus, cyclosporine, azathioprine, and prednisone appears safe. Long-acting reversible contraceptive methods are safe and effective for transplant recipients. There have been some concerns about the use of intra-uterine contraceptive devices because of the risk of infection, but the extent of risk is not clear and their use must be considered in light of the risks and benefits of other methods of contraception.

In those with IBD, a recent meta-analysis [15] concluded that biologic therapy was associated with comparable rates of early pregnancy loss, preterm birth, stillbirth, low birth weight, and congenital malformations. The prevalence of early pregnancy loss and preterm birth was higher in vedolizumab treated women compared with those on anti-TNF. There was no association between disease activity or concomitant thiopurine on adverse outcomes. Continued TNF inhibitor use during the third trimester was not associated with risk of preterm birth, low birth weight or congenital malformations.

The development of understanding of the immune response and newer agents to modify the immune response has resulted in a greater choice for the clinician and patient and improved approaches to management of immune-mediated disease with much better outcomes for patients.

Key areas for development include agents that have greater specificity so that the generic impact of these drugs can be reduced without reducing efficacy and more responsive technologies that will allow the immunosuppressive burden to be more accurately assessed. Tolerance is a goal that remains elusive but its time is approaching.

Current approaches which control the immune response may be replaced in time by those that correct any immune abnormalities rather than modify them.

While immunosuppression has greatly improved the management of patients in the fields of hepatology and gastroenterology, toxicity of these drugs remains a challenge.

The increasing diversity of immunosuppression means that it is both more feasible and challenging for clinicals to tailor immunosuppression to the individual.

Clinicians and patients must be alert to both the drug specific and class specific side-effects of drugs. Major issues include increased risk of some malignancies, some infections and cardiovascular disease.

Vaccination or medication may prevent primary infection or reactivation of infections.

Furthermore, it may be difficult sometimes to distinguish side-effects of drugs from the disease itself.