Immunosuppression and Disease-modifying Therapy

1. Introduction
2. Diseases Treated with Immunosuppression
3. Corticosteroids
4. Conventional DMARDs
   • Methotrexate
   • Sulfasalazine
   • Hydroxychloroquine
   • Leflunomide
5. Antiproliferative Agents
   • Azathioprine
   • Mycophenolate Mofetil
   • Cyclophosphamide
6. Calcineurin Inhibitors
7. Biologic Therapies
   • Anti-TNF Agents
   • Rituximab
   • Tocilizumab and Other Cytokine Inhibitors
   • Abatacept
8. JAK Inhibitors
9. General Cautions for Immunosuppressed Patients
10. Summary
11. Drug Summary Table
12. Quiz

• Immunosuppressants treat autoimmune disease, such as rheumatoid arthritis, systemic lupus erythematosus (SLE, which affects many organs), vasculitis (inflammation of blood vessels), inflammatory bowel disease (IBD), psoriasis (a scaly skin condition) and multiple sclerosis (MS). They also prevent transplant rejection and change the course of several cancers of the blood and lymph system (haematological cancers).
• The drug classes are corticosteroids, conventional DMARDs (disease-modifying antirheumatic drugs, which change the course of the disease: methotrexate, sulfasalazine, hydroxychloroquine, leflunomide), antiproliferative agents (drugs that stop cells, especially lymphocytes, dividing: azathioprine, mycophenolate, cyclophosphamide), calcineurin inhibitors (ciclosporin, tacrolimus), biologics (protein drugs aimed at one target, such as TNF, IL-6 or CD20) and JAK inhibitors (Janus kinase inhibitors). TNF is tumour necrosis factor and IL-6 is interleukin-6, two inflammatory signalling proteins. CD20 is a protein on B cells.
• The principle of "induction then maintenance" applies in most of these conditions: high-dose immunosuppression to control acute disease, then lower-dose maintenance to prevent a flare (a return of symptoms).
• Common concerns across the class are infection (especially reactivation of tuberculosis (TB), hepatitis B and varicella zoster, the virus that causes chickenpox and shingles), malignancy (cancer, mainly of the skin and of lymphoid tissue such as lymph nodes), and vaccination: live vaccines are contraindicated (should not be given) in people who are significantly immunosuppressed.

Introduction

Immunosuppressive drugs span an enormous range of indications and mechanisms. The pre-clinical curriculum focuses on the major classes, their representative drugs, and the recurring side-effect themes. This article complements the disease-specific articles in the SimpleMed pathology and rheumatology sections. It also links to the Cancer Chemotherapy article, where the two topics overlap.

Diseases Treated with Immunosuppression

The headline UK indications:

• Rheumatoid arthritis (RA): an autoimmune disease that inflames many joints at once (polyarthritis) and can affect the rest of the body. UK prevalence is around 1%. Untreated, RA causes erosive joint damage (the joint surfaces are worn away). With modern disease-modifying antirheumatic drug (DMARD) treatment, started early and adjusted to a target, the aim is remission (no sign of active disease) or, if that is not possible, low disease activity.
• Systemic lupus erythematosus (SLE): multisystem autoimmunity, predominantly affecting young women. Manifestations span skin, joints, kidneys, blood, brain, lungs and heart.
• Systemic vasculitis (inflammation of blood vessels throughout the body): ANCA-associated vasculitis (ANCA is anti-neutrophil cytoplasmic antibody, an autoantibody against proteins inside neutrophils), giant cell arteritis (inflammation of arteries, particularly at the temples), polyarteritis nodosa (a rare vasculitis that mainly affects the arteries supplying the gut, kidneys and nerves) and others. Untreated, severe forms can be fatal or lead to organ failure. Giant cell arteritis can cause stroke and blindness.
• Inflammatory bowel disease: Crohn's disease (inflammation that can affect any part of the gut) and ulcerative colitis (inflammation of the lining of the large bowel).
• Psoriasis and psoriatic arthritis: psoriasis is a scaly red skin condition, and psoriatic arthritis is joint inflammation linked to it.
• Multiple sclerosis (MS): an autoimmune disease in which the immune system damages the covering (myelin) of nerves in the brain and spinal cord. Disease-modifying therapies for relapsing-remitting MS (episodes of new symptoms followed by recovery) are chosen by how active the disease is. NICE guidance lists several options for active disease, including cladribine, ofatumumab and ocrelizumab.
• Solid-organ and stem-cell transplantation.
• Atopic dermatitis (atopic eczema, a long-term itchy skin condition) in severe forms.
• A few haematological cancers (rituximab in lymphoma, etc.).

Across these conditions, the approach is similar. Identify and treat early, before irreversible damage. Use the lowest effective dose for maintenance. Combine drugs so that each can be used at a dose below the level that causes toxicity (a sub-toxic dose).

Corticosteroids

Prednisolone, methylprednisolone, hydrocortisone and dexamethasone are the principal therapeutic glucocorticoids (drugs that act like cortisol, the steroid hormone made by the adrenal glands). They bind glucocorticoid receptors in the cytoplasm (the fluid inside the cell). The bound receptor moves into the nucleus and changes the transcription (copying into RNA) of hundreds of genes. The overall effect is anti-inflammatory and immunosuppressive. The main actions are:

• Inhibition of phospholipase A₂ (an enzyme that frees arachidonic acid from cell membranes) → reduced arachidonic acid (a fatty acid) → reduced prostaglandins and leukotrienes (inflammatory chemical messengers made from it).
• Reduced production of cytokines (small proteins that carry signals between immune cells) such as interleukin-1 (IL-1), IL-2, IL-6 and tumour necrosis factor (TNF), by macrophages and T cells (white blood cells that direct and carry out immune responses).
• Suppression of T-cell activation and proliferation (multiplication).
• Inhibition of leucocyte (white blood cell) trafficking, which is the movement of white blood cells out of the bloodstream into tissues.

Indications are too numerous to list in full. They include flares of all the autoimmune diseases above and transplant rejection. They also include asthma, flare-ups of chronic obstructive pulmonary disease (COPD, a long-term lung disease with airflow limitation) and croup (a viral infection of the upper airway in young children that causes a barking cough). Other uses are septic shock with relative adrenal insufficiency (the adrenal glands cannot meet the extra demand of severe illness), malignant lymphomas, and adrenal replacement (giving steroid when the body does not make enough). In anaphylaxis, steroids are not part of routine first-line treatment. The UK Resuscitation Council algorithm makes intramuscular adrenaline the priority. Steroids such as hydrocortisone are no longer recommended for the routine treatment of anaphylaxis.

Side effects: they follow from the drugs acting like cortisol. They are a common topic in pre-clinical exams:

• Cushingoid features: central obesity, moon face, buffalo hump, striae (purple stretch marks), thinning skin, easy bruising.
• Osteoporosis (thinning and weakening of the bones): rapid bone loss, particularly in the first 6 months. The National Osteoporosis Guideline Group (NOGG) advises starting bone protection at the same time as the steroid, without waiting for a bone density scan, in three groups. They are anyone with a previous fragility fracture (a fracture from a minor fall or knock), women aged 70 or over, and postmenopausal women and men aged 50 or over taking prednisolone 7.5 mg a day or more (or equivalent) over 3 months. Other postmenopausal women and men aged 50 or over are treated if their FRAX (Fracture Risk Assessment Tool) estimate of fracture probability is above the intervention threshold. The first-line drugs are an oral bisphosphonate (alendronate or risedronate) or intravenous zoledronate. Bisphosphonates are drugs that slow bone loss.
• Cataracts and glaucoma: clouding of the lens of the eye, and raised pressure inside the eye that can damage the optic nerve.
• Avascular necrosis (death of bone from a poor blood supply), typically of the femoral head, the ball of the hip joint.
• Hyperglycaemia (high blood sugar): can unmask or worsen diabetes ("steroid-induced diabetes").
• Hypertension and fluid retention.
• Mood disturbance: insomnia, irritability and frank psychosis (a clear loss of touch with reality, such as hallucinations or delusions).
• Increased infection risk, particularly fungal infections and reactivation of latent (dormant) tuberculosis (TB) and herpes viruses.
• Suppression of the hypothalamic-pituitary-adrenal (HPA) axis (the system by which the brain controls the adrenal glands' cortisol output): abrupt withdrawal after a prolonged course can lead to acute adrenal insufficiency (an adrenal crisis), low blood pressure or death. Steroids can usually be stopped without tapering (a gradual dose reduction) after a course of 3 weeks or less, if the disease is unlikely to relapse. The exceptions are more than 40 mg prednisolone a day for more than 1 week, repeated recent courses, or other risk factors for adrenal suppression. After longer courses, withdraw gradually.
• Peptic ulceration (ulcers in the stomach or duodenum), particularly in combination with NSAIDs (non-steroidal anti-inflammatory drugs, such as ibuprofen).
• Weight gain, growth retardation in children.

In the UK, patients on long-term steroids are given a "steroid card". The Steroid Treatment Card records the risks of treatment and the prescriber, drug, dose and duration. A separate Steroid Emergency Card goes to patients with adrenal insufficiency or steroid dependence who are at risk of an adrenal crisis if they miss doses or have an illness or surgery. These patients may need stress-dose cover, which means extra steroid during illness or surgery.

Conventional DMARDs

Disease-modifying antirheumatic drugs (DMARDs) are slow-acting drugs that change the natural history of rheumatoid arthritis (the course the disease would otherwise follow). They differ from NSAIDs (non-steroidal anti-inflammatory drugs, such as ibuprofen), which relieve symptoms. They also differ from short-term steroids, which are used to relieve symptoms while a DMARD takes effect, or to treat flares. The conventional ("synthetic, non-targeted") DMARDs are inexpensive and effective. They remain the backbone of therapy.

Methotrexate

Methotrexate is a first-line DMARD for rheumatoid arthritis and one of the most commonly prescribed. NICE recommends offering a conventional DMARD (methotrexate, leflunomide or sulfasalazine) as first-line monotherapy (a single drug, used first) as soon as possible. NICE does not specify which one to use. In low-dose autoimmune use, the mechanism is incompletely understood but involves adenosine release (adenosine is a signalling molecule that dampens inflammation) and consequent anti-inflammatory effects. (At the much higher cancer doses it inhibits dihydrofolate reductase, an enzyme that makes the active form of folate, which cells need to build DNA. This is covered in Cancer Chemotherapy.)

Critical practical points:

• Once-weekly dosing: daily prescribing has caused fatalities and is a "never event" in the UK (a serious, entirely preventable patient-safety incident that should not happen when safeguards are followed).
• Always co-prescribe folic acid (typically 5 mg weekly, on a different day to the methotrexate) to reduce side effects without losing efficacy.
• The half-life (the time taken for the blood level to fall by half) is about 3 to 10 hours at low doses. Methotrexate is cleared mainly by the kidneys, so levels in the blood and tissues can rise rapidly in renal impairment.

Side effects: gastrointestinal (GI) upset, mucositis (a sore, inflamed lining of the mouth and gut), bone marrow suppression, hepatotoxicity (liver damage, so regular liver function tests (LFTs) are required), and pulmonary toxicity. The classic lung problem is methotrexate pneumonitis, inflammation of the lung tissue. It is an idiosyncratic (unpredictable) hypersensitivity reaction, an over-reaction of the immune system, and it can occur at any point in treatment. Chronic pulmonary fibrosis (scarring of the lungs) is much rarer.

Methotrexate is highly teratogenic (it causes birth defects) and an abortifacient (it can cause miscarriage), so it is absolutely contraindicated in pregnancy. The British National Formulary (BNF, the UK prescribing reference) advises effective contraception during treatment and for at least 6 months afterwards for women of childbearing potential. For men whose partner could become pregnant, it advises at least 3 months. The British Society for Rheumatology (BSR) 2022 guideline allows a shorter gap: it says methotrexate should be stopped at least one month before planned conception, and switched to another pregnancy-compatible drug. It also says paternal exposure to low-dose methotrexate (25 mg a week or less) is compatible with pregnancy. Plan any change with the specialist team.

Avoid trimethoprim with methotrexate, because the combination raises the risk of blood problems that are sometimes fatal. Co-trimoxazole is trimethoprim combined with sulfamethoxazole. It is predicted to raise methotrexate levels, so it should also be avoided where possible. NSAIDs (such as ibuprofen) are predicted to raise methotrexate toxicity, so if one is used, monitor the patient.

Sulfasalazine

Sulfasalazine is a pro-drug (an inactive form that the body converts into the active drug). It consists of 5-aminosalicylate (5-ASA, an anti-inflammatory) linked to sulfapyridine (a carrier molecule from the sulfonamide family of antibiotics). Bacteria in the colon cleave the link and release both parts. It is used in:

• Rheumatoid arthritis. Sulfasalazine is one of several DMARDs that are compatible with pregnancy, along with hydroxychloroquine, azathioprine, ciclosporin and tacrolimus. Folic acid 5 mg a day is recommended around conception and during the first trimester.
• Ulcerative colitis (the 5-ASA component acts locally).

Side effects relate mainly to the sulfapyridine moiety (the sulfapyridine part of the molecule): rash, nausea, headache, reversible male infertility, and occasionally myelosuppression (reduced blood cell production by the bone marrow) and hepatitis (liver inflammation).

Hydroxychloroquine

An antimalarial with immunomodulatory action (it adjusts the immune response rather than switching it off). The mechanism is incompletely understood. It involves raising the pH of lysosomes (the acid-filled compartments inside cells) and changing signalling through Toll-like receptors (receptors on immune cells that detect germs and damaged cells). Hydroxychloroquine is used in mild RA and SLE, particularly for skin and joint manifestations.

The key adverse effect is retinopathy (damage to the retina at the back of the eye). It is more common than once thought. In one large US study of people who had taken hydroxychloroquine for at least 5 years, about 7.5% had retinopathy, and the risk rose with higher daily doses and longer use. The changes are largely irreversible. Annual monitoring, including retinal imaging, is recommended for everyone who has taken hydroxychloroquine for more than 5 years. Monitoring may start sooner if there are extra risk factors: a dose above 5 mg/kg/day, tamoxifen use (a breast cancer drug), or reduced kidney function (an eGFR, a measure of kidney function, below 60).

Leflunomide

Leflunomide inhibits dihydroorotate dehydrogenase (an enzyme needed to make pyrimidines, which are building blocks of DNA and RNA), so it blocks pyrimidine synthesis in T cells. It is used as an alternative to methotrexate in RA. The active metabolite has a long half-life (weeks to months). A "wash-out" is therefore needed before pregnancy or further immunosuppression. This means giving cholestyramine or activated charcoal to speed removal of the drug.

Antiproliferative Agents

Azathioprine

A pro-drug converted to 6-mercaptopurine, then to active metabolites that inhibit DNA and RNA synthesis, particularly in proliferating lymphocytes. Used in IBD, SLE and vasculitis maintenance, atopic dermatitis, and as transplant immunosuppression.

Two points about how the body handles azathioprine:

• TPMT (thiopurine methyltransferase) testing is advised before starting (the BNF says to consider measuring TPMT activity): patients with low or absent TPMT activity accumulate active drug and develop life-threatening myelosuppression.
• Allopurinol blocks xanthine oxidase, an enzyme that inactivates 6-mercaptopurine (the product of azathioprine) by an alternative route. Blocking it makes active drug build up. Combined use produces severe myelosuppression and is generally avoided. If it is unavoidable, the azathioprine dose must be reduced to about a quarter.

Other side effects: hepatotoxicity, GI upset, infection, increased non-melanoma skin cancer and lymphoma risk with prolonged use.

Mycophenolate Mofetil

Mycophenolate inhibits inosine monophosphate dehydrogenase, the rate-limiting enzyme (the slowest step, which sets the speed of the pathway) of de novo purine synthesis. De novo means making purines from scratch, and purines are building blocks of DNA and RNA. Lymphocytes uniquely depend on de novo purine synthesis (other cells can use the salvage pathway, which recycles existing purines). So mycophenolate selectively suppresses lymphocyte proliferation (multiplication).

Indications: solid-organ transplantation and lupus nephritis (inflammation of the kidneys caused by lupus), for both induction and maintenance. The European Alliance of Associations for Rheumatology (EULAR) 2023 guidance recommends glucocorticoids with either mycophenolate or low-dose intravenous cyclophosphamide as the core ("anchor") treatment for active lupus nephritis. It also says that add-on belimumab (a biologic drug) or a calcineurin inhibitor (voclosporin or tacrolimus; see Calcineurin Inhibitors below) should be considered. Mycophenolate is not a first choice for maintaining remission in ANCA-associated vasculitis. In the IMPROVE trial it was less effective than azathioprine. EULAR 2022 guidance recommends rituximab for maintenance in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), two types of ANCA-associated vasculitis, with azathioprine or methotrexate as alternatives.

Side effects: GI symptoms (especially diarrhoea), bone marrow suppression, infection. Teratogenic.

Cyclophosphamide

Already covered in Cancer Chemotherapy. Used at lower doses in:

• Severe lupus (especially lupus nephritis or CNS disease).
• ANCA-associated vasculitis (induction).
• Some refractory autoimmune conditions (those that have not responded to other treatment).

The signature toxicities all apply at autoimmune as well as cancer doses. They are haemorrhagic cystitis (bleeding and inflammation of the bladder) from acrolein (a toxic breakdown product of cyclophosphamide that irritates the bladder lining), infertility, and an increased risk of bladder cancer and haematological malignancy. Mesna is co-prescribed with the higher doses to bind acrolein.

Calcineurin Inhibitors

Ciclosporin (binds cyclophilin, a protein inside cells) and tacrolimus (binds FKBP-12, a different protein inside cells) inhibit calcineurin. Calcineurin is a phosphatase, an enzyme that removes phosphate groups from other proteins. It normally activates the transcription factor NFAT (nuclear factor of activated T cells), a protein that switches genes on. Without NFAT, T cells cannot transcribe IL-2, the central T-cell growth factor (interleukin-2). Clonal expansion, the multiplication of T cells that recognise the antigen, is then blocked.

Indications: solid-organ transplantation (the backbone of most modern regimens) and refractory autoimmune disease. Ciclosporin is also used, on expert advice, for severe atopic dermatitis and severe psoriasis when conventional treatment has not worked or is unsuitable. Tacrolimus is used as an ointment on the skin for moderate to severe atopic eczema when conventional treatment has not worked or is not tolerated.

Side effects are extensive and predictable:

• Nephrotoxicity (toxicity to the kidneys): the dose-limiting toxicity, meaning the effect that limits how much can be given. It includes chronic interstitial fibrosis (scarring of the kidney tissue) and acute renal vasoconstriction (narrowing of the blood vessels in the kidney).
• Hypertension.
• Diabetes mellitus (more with tacrolimus).
• Gum hypertrophy and hirsutism (overgrown gums and excess body and facial hair; more with ciclosporin): classic exam findings.
• Tremor and headache.
• Hyperlipidaemia, hyperkalaemia, hypomagnesaemia: high blood fats, high blood potassium and low blood magnesium.
• Drug interactions via CYP3A4 (a liver enzyme that breaks down many drugs): ciclosporin and tacrolimus are both CYP3A4 substrates, which means the enzyme breaks them down. Inhibitors of the enzyme (macrolide antibiotics, azole antifungals, grapefruit juice) raise their levels. Inducers, which speed the enzyme up (rifampicin, anticonvulsants), lower them.

Both are narrow-therapeutic-index drugs (the dose that works is close to the dose that causes toxicity), so they need routine plasma level monitoring (blood tests to measure the drug level).

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