Immunosuppression and Disease-modifying Therapy

Core

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, with cross-links throughout.

Diseases Treated with Immunosuppression

The headline UK indications:

• Rheumatoid arthritis (RA): an autoimmune polyarthritis with systemic features. UK prevalence around 1%. Untreated, RA causes erosive joint damage; with modern DMARD therapy, the course is much milder.
• Systemic lupus erythematosus (SLE): multisystem autoimmunity, predominantly affecting young women. Manifestations span skin, joints, kidneys, blood, brain, lungs and heart.
• Systemic vasculitis: ANCA-associated vasculitis, giant cell arteritis, polyarteritis nodosa and others. Untreated, often fatal.
• Inflammatory bowel disease: Crohn's and ulcerative colitis.
• Psoriasis and psoriatic arthritis.
• Multiple sclerosis.
• Solid-organ and stem-cell transplantation.
• Atopic dermatitis in severe forms.
• A few haematological cancers (rituximab in lymphoma, etc.).

Across these conditions, the philosophy is similar: identify and treat early before irreversible damage; use the lowest effective dose for maintenance; combine drugs to allow each to be used at sub-toxic doses.

Corticosteroids

Prednisolone, methylprednisolone, hydrocortisone and dexamethasone are the principal therapeutic glucocorticoids. They bind cytoplasmic glucocorticoid receptors, translocate to the nucleus, and modify the transcription of hundreds of genes, with broadly anti-inflammatory and immunosuppressive effects:

• Inhibition of phospholipase A₂ → reduced arachidonic acid → reduced prostaglandins and leukotrienes.
• Reduced production of cytokines (IL-1, IL-2, IL-6, TNF) by macrophages and T cells.
• Suppression of T-cell activation and proliferation.
• Inhibition of leucocyte trafficking out of the bloodstream.

Indications are too numerous to list comprehensively but include flares of all the autoimmune diseases above, transplant rejection, asthma, COPD exacerbation, croup, septic shock with relative adrenal insufficiency, malignant lymphomas, and as adrenal replacement. Steroids are an adjunct in anaphylaxis, not first-line: the UK Resuscitation Council algorithm makes intramuscular adrenaline the priority, with steroids no longer routinely recommended.

Side effects: predictable from the cortisol mimicry, and the dominant pre-clinical exam topic:

• Cushingoid features: central obesity, moon face, buffalo hump, striae, thinning skin, easy bruising.
• Osteoporosis: rapid bone loss, particularly in the first 6 months. Bisphosphonate cover is standard if expected duration ≥ 3 months.
• Cataracts and glaucoma.
• Avascular necrosis (femoral head).
• Hyperglycaemia: can unmask or worsen diabetes ("steroid-induced diabetes").
• Hypertension and fluid retention.
• Mood disturbance: insomnia, irritability, frank psychosis.
• Increased infection risk, particularly fungal and reactivation of latent TB and herpes.
• Suppression of the hypothalamic-pituitary-adrenal (HPA) axis: the reason long-term steroids must always be tapered, never stopped abruptly. Sudden withdrawal precipitates an Addisonian crisis.
• Peptic ulceration, particularly in combination with NSAIDs.
• Weight gain, growth retardation in children.

The standard "steroid card" is given to patients on long-term steroids in the UK, advising healthcare workers of the need for stress-dose cover during illness or surgery.

Conventional DMARDs

Disease-modifying antirheumatic drugs (DMARDs) are slow-acting drugs that genuinely change the natural history of rheumatoid arthritis; in contrast to symptomatic NSAIDs and steroids. The conventional ("synthetic, non-targeted") DMARDs are inexpensive and effective; they remain the backbone of therapy.

Methotrexate

The gold standard for rheumatoid arthritis. Mechanism in low-dose autoimmune use is incompletely understood but involves adenosine release and consequent anti-inflammatory effects. (At the much higher cancer doses it inhibits dihydrofolate reductase; covered in Cancer Chemotherapy.)

Critical practical points:

• Once-weekly dosing: daily prescribing has caused fatalities and is a "never event" in the UK.
• Always co-prescribe folic acid (typically 5 mg weekly, on a different day to the methotrexate) to reduce side effects without losing efficacy.
• Long half-life and significant accumulation in renal impairment.

Side effects: GI upset, mucositis, bone marrow suppression, hepatotoxicity (regular LFTs required), and pulmonary toxicity; classically methotrexate pneumonitis, an idiosyncratic hypersensitivity reaction that can occur at any point in treatment; chronic pulmonary fibrosis is much rarer. Highly teratogenic and an abortifacient: absolute contraindication in pregnancy and a 3- to 6-month wash-out before conception is recommended.

Avoid combination with co-trimoxazole, trimethoprim or NSAIDs (the last because of competition for renal clearance) where possible.

Sulfasalazine

Sulfasalazine is a pro-drug consisting of 5-aminosalicylate (5-ASA, an anti-inflammatory) linked to sulfapyridine (a sulfonamide carrier). Cleaved by colonic bacteria. Used in:

• Rheumatoid arthritis (especially in pregnancy: one of the few safe DMARDs).
• Ulcerative colitis (the 5-ASA component acts locally).

Side effects relate mainly to the sulfapyridine moiety: rash, nausea, headache, reversible male infertility, occasional myelosuppression and hepatitis.

Hydroxychloroquine

An antimalarial with immunomodulatory action, mechanism incompletely understood (involves lysosomal pH and Toll-like receptor signalling). Used in mild RA and SLE, particularly for skin and joint manifestations.

The key adverse effect is retinopathy: rare but irreversible; annual ophthalmology review is recommended after 5 years of use.

Leflunomide

Inhibits dihydroorotate dehydrogenase, blocking pyrimidine synthesis in T cells. Used as alternative to methotrexate in RA. Long half-life of the active metabolite (weeks to months), so a "wash-out" with cholestyramine is needed before pregnancy or further immunosuppression.

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 pharmacogenetic points:

• TPMT (thiopurine methyltransferase) testing is mandatory before starting: patients with low or absent TPMT activity accumulate active drug and develop life-threatening myelosuppression.
• Allopurinol blocks xanthine oxidase, the alternative inactivation pathway. Combined use produces severe myelosuppression and is generally avoided; if 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

Inhibits inosine monophosphate dehydrogenase, the rate-limiting enzyme of de novo purine synthesis. Lymphocytes uniquely depend on de novo purine synthesis (other cells use the salvage pathway), so mycophenolate selectively suppresses lymphocyte proliferation.

Indications: solid-organ transplantation, lupus nephritis (induction and maintenance), vasculitis maintenance. Increasingly preferred over cyclophosphamide for lupus nephritis because of lower toxicity.

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.

The signature toxicities (haemorrhagic cystitis from acrolein, infertility, increased bladder cancer and haematological malignancy risk) all apply at autoimmune as well as cancer doses. Mesna co-prescribed with the higher doses to bind acrolein.

Calcineurin Inhibitors

Ciclosporin (binds cyclophilin) and tacrolimus (binds FKBP-12) inhibit calcineurin, a phosphatase that normally activates the transcription factor NFAT. Without NFAT, T cells cannot transcribe IL-2, the central T-cell growth factor, and clonal expansion is blocked.

Indications: solid-organ transplantation (the backbone of most modern regimens), severe atopic dermatitis, psoriasis, refractory autoimmune disease.

Side effects are extensive and predictable:

• Nephrotoxicity: the dose-limiting toxicity; chronic interstitial fibrosis and acute renal vasoconstriction.
• Hypertension.
• Diabetes mellitus (more with tacrolimus).
• Gum hypertrophy and hirsutism (more with ciclosporin): classic exam findings.
• Tremor and headache.
• Hyperlipidaemia, hyperkalaemia, hypomagnesaemia.
• Drug interactions via CYP3A4: ciclosporin and tacrolimus are both CYP3A4 substrates; inhibitors (macrolides, azoles, grapefruit juice) raise levels and inducers (rifampicin, anticonvulsants) lower them.

Both are narrow-therapeutic-index drugs requiring routine plasma level monitoring.

Biologic Therapies

Biologic DMARDs are protein-based drugs (almost all monoclonal antibodies or fusion proteins) targeting specific cytokines, surface markers, or signalling pathways. They have transformed the management of RA, IBD, psoriasis, ankylosing spondylitis and several other conditions.

Suffix conventions:

• "-mab": monoclonal antibody.
• "-cept": fusion protein.

Anti-TNF Agents

Infliximab, adalimumab, golimumab, etanercept and certolizumab all target tumour necrosis factor α (TNFα), reducing inflammation and joint destruction.

Used in: rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, severe psoriasis.

The defining safety concern is reactivation of latent infection:

• Tuberculosis: TNF is essential for granuloma maintenance. Always screen for latent TB before starting.
• Hepatitis B and C: serology before starting; treat or co-prescribe antiviral cover.
• Increased risk of serious bacterial infection generally.
• Demyelinating disease (rare).
• Drug-induced lupus.
• Immunogenicity: antibodies can develop against the drug, especially with intermittent dosing of infliximab.

Rituximab

Rituximab is an anti-CD20 monoclonal antibody that depletes circulating B cells (CD20 is not expressed on plasma cells or stem cells, so antibody production is partially preserved and the marrow regenerates).

Indications:

• Non-Hodgkin B-cell lymphomas (with chemotherapy).
• Rheumatoid arthritis refractory to anti-TNF.
• ANCA vasculitis (alternative to cyclophosphamide).
• Lupus and other refractory autoimmune disease.
• Multiple sclerosis (off-label in some forms).

Side effects: infusion reactions, infection (especially reactivation of hepatitis B), late progressive multifocal leukoencephalopathy (rare).

Tocilizumab and Other Cytokine Inhibitors

• Tocilizumab: anti-IL-6 receptor; RA, giant cell arteritis, cytokine release syndrome, severe COVID-19 (added to the UK regimen during the pandemic).
• Secukinumab, ixekizumab: anti-IL-17; psoriasis, ankylosing spondylitis.
• Ustekinumab, guselkumab: anti-IL-12/23 or anti-IL-23; psoriasis, IBD.
• Anakinra: IL-1 receptor antagonist; some autoinflammatory conditions, rare RA use.

Abatacept

Abatacept is a CTLA-4-Ig fusion protein that blocks T-cell costimulation by binding CD80/CD86 on antigen-presenting cells, preventing their interaction with CD28 on the T cell. Used in RA after methotrexate failure.

JAK Inhibitors

Targeted synthetic DMARDs: tofacitinib, baricitinib, upadacitinib: are oral small molecules that inhibit Janus kinases (JAK 1, 2, 3 to varying extents). JAKs are downstream of many cytokine receptors, so JAK inhibition produces a broad cytokine blockade.

Indications: rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, atopic dermatitis, alopecia areata.

The MHRA has issued safety warnings about increased risk of major adverse cardiovascular events, malignancy and venous thromboembolism in older patients with cardiovascular risk factors, and JAK inhibitors are now generally reserved for second-line use after biologics in this population.

General Cautions for Immunosuppressed Patients

Several themes recur across all immunosuppressive drugs:

• Infection: bacterial, viral and fungal. Patients should know to seek medical attention promptly with fever or new symptoms; vaccination history must be checked and updated before immunosuppression starts.
• Latent TB screening before biologics (particularly anti-TNF).
• Hepatitis B and C serology before any major immunosuppression; antiviral cover for hepatitis B carriers.
• Vaccination: live vaccines (MMR, BCG, yellow fever, varicella, oral typhoid, rotavirus, live attenuated intranasal influenza) are contraindicated in significant immunosuppression. Inactivated vaccines (injected influenza, pneumococcal, COVID-19) are encouraged but may be of reduced efficacy.
• Skin cancer, particularly squamous cell carcinoma; encourage sun protection.
• Pregnancy planning: methotrexate, leflunomide, mycophenolate and cyclophosphamide are teratogenic; sulfasalazine, hydroxychloroquine and azathioprine are generally considered acceptable; biologics are increasingly used in pregnancy with growing evidence of safety.
• Bone protection with long-term steroids: bisphosphonates plus calcium and vitamin D.
• Stress-dose steroid cover for surgery or serious illness in patients on long-term oral steroids.
• Drug monitoring: LFTs, FBC, U&Es as appropriate (e.g. methotrexate FBC and LFTs every 2 weeks then 3-monthly; ciclosporin/tacrolimus levels).

Summary

• Corticosteroids (prednisolone) are powerful broad-spectrum anti-inflammatories; the long-term side effects (Cushingoid features, osteoporosis, diabetes, hypertension, infection, HPA suppression) make minimal-effective-dose use the rule.
• Conventional DMARDs: methotrexate (gold standard for RA, weekly dosing, with folic acid), sulfasalazine, hydroxychloroquine (annual eye check), leflunomide.
• Antiproliferative: azathioprine (TPMT testing first, beware allopurinol), mycophenolate (better tolerated than cyclophosphamide for lupus nephritis), cyclophosphamide (severe disease, mesna for cystitis prophylaxis).
• Calcineurin inhibitors: ciclosporin and tacrolimus: nephrotoxic, hypertensive, gum hypertrophy, narrow therapeutic index, CYP3A4 substrates.
• Biologics: anti-TNF (infliximab, adalimumab, etanercept; screen for TB), rituximab (anti-CD20), tocilizumab (anti-IL-6), anti-IL-17/23, abatacept.
• JAK inhibitors (tofacitinib, baricitinib): oral, broad cytokine blockade; MHRA cautions in older cardiovascular-risk patients.
• Cross-cutting concerns: infection, latent TB and hepatitis screening, live vaccine avoidance, malignancy risk, pregnancy planning, drug monitoring, stress-dose steroid cover.

Drug Summary Table

Reviewed by: Dr. Marcus Judge

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