Other immunosuppressants

Overview

“Other immunosuppressants” is a pharmacological category that encompasses a diverse group of agents used to suppress or modulate the immune system that do not fall under traditional immunosuppressive classes like corticosteroids, calcineurin inhibitors (e.g., cyclosporine, tacrolimus), antimetabolites (e.g., azathioprine, mycophenolate), or mTOR inhibitors (e.g., sirolimus). These agents are employed in the prevention of organ transplant rejection, treatment of autoimmune diseases, and management of certain inflammatory or dermatologic disorders. Their mechanisms of action vary widely, and they often target specific cellular pathways, cytokines, or immune cell subtypes.

This class includes small molecules, biologics, and monoclonal antibodies that work through novel or specialized immunosuppressive mechanisms.

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1. Mechanism of Action

Due to the heterogeneity of this class, the mechanisms vary, but generally fall under:

• T-cell inhibition: Blocking T-cell activation or cytokine production

• Cytokine blockade: Inhibiting pro-inflammatory cytokines such as IL-1, IL-6, TNF-α

• B-cell suppression: Inhibiting B-cell proliferation or antibody production

• JAK-STAT pathway inhibition: Blocking intracellular signaling downstream of cytokines

• Selective adhesion molecule inhibition: Preventing immune cell migration to inflammatory sites

• Fusion proteins or monoclonal antibodies: Targeting specific immune receptors or ligands

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2. Therapeutic Uses

Indication	Examples of Application
Organ transplantation (kidney, liver, heart)	Belatacept (selective T-cell costimulation blocker)
Rheumatoid arthritis	Tofacitinib, Baricitinib, Abatacept
Psoriasis and psoriatic arthritis	Apremilast, Brodalumab
Inflammatory bowel disease (IBD)	Ustekinumab, Vedolizumab
Multiple sclerosis (MS)	Teriflunomide, Dimethyl fumarate
Systemic lupus erythematosus (SLE)	Anifrolumab, Belimumab
Myasthenia gravis	Eculizumab
Dermatomyositis and autoimmune skin diseases	IVIG, Rituximab

3. Representative Agents

Below is a breakdown of selected immunosuppressants within this class:

A. Biologics and Monoclonal Antibodies

Generic Name	Target/Mechanism	Indications
Belatacept	CTLA-4-Ig fusion protein inhibiting CD80/CD86	Kidney transplant
Abatacept	CTLA-4 agonist inhibiting T-cell activation	RA, juvenile idiopathic arthritis
Ustekinumab	IL-12/IL-23 inhibitor	Psoriasis, Crohn’s disease
Anifrolumab	Type I interferon receptor antagonist	Systemic lupus erythematosus
Belimumab	Inhibits BLyS (B-lymphocyte stimulator)	SLE
Vedolizumab	α4β7 integrin blocker (gut-specific)	Ulcerative colitis, Crohn’s disease
Eculizumab	Complement C5 inhibitor	PNH, aHUS, generalized myasthenia gravis

B. Small Molecule Inhibitors

Generic Name	Mechanism of Action	Indications
Tofacitinib	JAK1/JAK3 inhibitor	RA, PsA, UC
Baricitinib	JAK1/JAK2 inhibitor	RA
Upadacitinib	JAK1 selective inhibitor	RA, PsA, UC
Apremilast	PDE4 inhibitor	Psoriasis, PsA
Teriflunomide	Pyrimidine synthesis inhibitor	Relapsing MS
Dimethyl fumarate	Nrf2 activator; anti-inflammatory	MS

C. Miscellaneous / Other Agents

Generic Name	Notes	Indications
Thalidomide	TNF-α inhibitor; anti-angiogenic	Multiple myeloma, erythema nodosum leprosum
Lenalidomide	Immunomodulatory derivative of thalidomide	Myeloma, MDS
Pomalidomide	Next-generation IMiD	Refractory myeloma
Hydroxychloroquine	Inhibits antigen presentation	SLE, RA
IVIG	Pooled immunoglobulin with immunomodulatory effects	CIDP, ITP, Kawasaki, dermatomyositis

4. Dosage Examples (Selected Agents)

Drug	Typical Adult Dose
Tofacitinib	5 mg PO BID or 11 mg XR QD (RA, UC)
Belatacept	IV infusion 5 mg/kg at 2-week intervals post-transplant
Ustekinumab	45–90 mg SC q12 weeks (depending on weight and condition)
Apremilast	30 mg PO BID after titration
Abatacept	125 mg SC weekly or IV infusion monthly
Anifrolumab	300 mg IV every 4 weeks

5. Pharmacokinetics and Dynamics

Parameter	Details
Absorption	Small molecules: good oral bioavailability Biologics: parenteral only
Onset of action	Varies: from days (JAK inhibitors) to weeks/months (biologics)
Half-life	Short (e.g., Apremilast ~6–9 hrs) to long (e.g., Ustekinumab ~3 weeks)
Metabolism	Hepatic (CYP enzymes for small molecules), proteolytic (mAbs)
Excretion	Renal for many small molecules; minimal renal excretion for biologics

6. Adverse Effects

Category	Common Reactions
Infections	Upper respiratory infections, opportunistic infections, reactivation of TB
Hematologic	Neutropenia, anemia, thrombocytopenia (e.g., with JAK inhibitors)
GI	Diarrhea, nausea (notably with Apremilast, Dimethyl fumarate)
Dermatologic	Rash, injection site reactions
Serious	Malignancies (e.g., lymphoma), thromboembolism, hepatotoxicity
Neurologic	Headache, PML (with natalizumab – not covered here, but related class)

7. Contraindications

• Active serious infections (e.g., TB, hepatitis B/C)

• Severe hepatic impairment (some agents)

• History of malignancy (caution with JAK inhibitors)

• Hypersensitivity to monoclonal antibodies (biologic agents)

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8. Precautions and Monitoring

Monitoring Parameter	Recommendation
CBC, LFTs, renal function	Baseline and periodically (JAK inhibitors, thalidomide derivatives)
TB screening (PPD/IGRA)	Before biologic or JAK inhibitor therapy
Hepatitis B/C status	Prior to immunosuppressive therapy
Vaccination status	Live vaccines contraindicated during therapy
Pregnancy status	Teratogenicity with some agents (e.g., thalidomide, JAK inhibitors)

9. Drug Interactions

Agent	Interaction Considerations
Tofacitinib	CYP3A4 and CYP2C19 substrates – avoid strong inhibitors/inducers
Apremilast	Induced by CYP3A4 inducers (e.g., rifampin, carbamazepine)
Thalidomide	Additive sedative/CNS depressant effects
Biologics	Risk of enhanced immunosuppression with other DMARDs or corticosteroids

Avoid combining two biologic immunosuppressants due to risk of serious infection.

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10. Clinical Pearls

• JAK inhibitors offer oral immunosuppressive therapy but carry black box warnings for thromboembolism, malignancy, and infections.

• Belatacept is preferred over cyclosporine in renal transplant recipients due to less nephrotoxicity.

• Apremilast is not immunosuppressive in the traditional sense and has a favorable safety profile but less efficacy than biologics.

• Anifrolumab and Belimumab are targeted therapies for SLE and mark a shift toward precision immunosuppression.

• Teriflunomide has a long half-life (weeks) and requires accelerated elimination if pregnancy is desired.