Calcineurin Inhibitors & Biologic Therapy

Calcineurin Inhibitor Drug Class

Cyclosporine and tacrolimus both belong to the calcineurin inhibitor drug class. Despite binding different intracellular proteins, both ultimately inhibit calcineurin phosphatase, blocking T-cell activation and cytokine production — specifically, blocking dephosphorylation of NFAT (nuclear factor of activated T-cells), which is required for interleukin-2 gene transcription. Without IL-2, T-cell proliferation and activation are suppressed. This gives calcineurin inhibitors a faster, more targeted onset than antimetabolites, which act on the broader pool of dividing cells rather than specifically on T-cell signaling.

Cyclosporine

Cyclosporine binds the intracellular protein cyclophilin, and this cyclosporine–cyclophilin complex is what inhibits calcineurin phosphatase, preventing NFAT dephosphorylation and subsequent IL-2 gene transcription.

A patient started on cyclosporine for sight-threatening uveitis needs regular monitoring of serum creatinine and blood pressure, since cyclosporine causes nephrotoxicity and hypertension. Dose reduction is indicated if creatinine rises significantly above baseline — this monitoring pair is the practical counterpart to methotrexate's liver function tests and azathioprine's TPMT testing: every steroid-sparing agent has its own specific thing to watch.

Tacrolimus

Tacrolimus achieves the same downstream calcineurin inhibition as cyclosporine but through a different intracellular target: it binds FK-binding protein 12 (FKBP-12), and this complex inhibits calcineurin phosphatase activity, blocking NFAT-mediated IL-2 gene transcription. The cyclophilin-vs-FKBP-12 distinction between cyclosporine and tacrolimus is a classic pairing worth keeping straight, since both drugs converge on the same final pathway despite starting from different binding proteins.

Alkylating Agents

For more aggressive, sight-threatening or refractory disease, alkylating agents represent a step up in intensity. Cyclophosphamide, the classic example, cross-links DNA strands to prevent replication, inducing apoptosis in rapidly dividing lymphocytes. This mechanism is more cytotoxic and less selective than the antimetabolite or calcineurin-inhibitor pathways above, which is why alkylating agents are generally reserved for severe cases rather than used as first-line steroid-sparing therapy.

Biologic Therapy

Anti-TNF Therapy: Adalimumab

Adalimumab is a fully human monoclonal antibody that binds soluble and membrane-bound tumor necrosis factor-alpha (TNF-α), preventing it from interacting with its receptors and reducing downstream inflammatory signaling. Anti-TNF therapy is a mainstay for refractory non-infectious uveitis, particularly in disease associated with systemic inflammatory conditions.

Anti-TNF agents also carry a distinct, noninfectious caution: they should be avoided or used with extreme care in anyone with a personal or family history of a demyelinating disorder such as multiple sclerosis, since case reports and pharmacovigilance data link the class to new or worsening central nervous system demyelination. A brief neurologic history is a reasonable part of the pre-treatment workup for this reason, separate from the infection screening covered below.

Rituximab

Rituximab is a monoclonal antibody that targets the CD20 antigen on the surface of B lymphocytes, leading to their depletion via complement- and antibody-dependent cytotoxicity. It's useful in refractory autoimmune uveitis where B-cell-driven autoimmunity is a significant contributor.

Tocilizumab

Tocilizumab is a monoclonal antibody against the interleukin-6 (IL-6) receptor, blocking IL-6-mediated inflammatory signaling implicated in chronic uveitis that hasn't responded to other agents.

Infection Risk & Pre-Treatment Screening

Every agent on this page shares a common downside: meaningful immunosuppression brings real infection risk, and several specific infections need to be actively screened for or prevented before — not after — starting treatment.

• Tuberculosis reactivation: corticosteroid- and immunosuppressant-induced immunosuppression can reactivate latent TB, so screening with a tuberculin skin test or interferon-gamma release assay is recommended before starting long-term immunosuppressive therapy of any kind, including anti-TNF biologics.
• Pneumocystis jirovecii pneumonia (PJP): patients on chronic high-dose immunosuppression, particularly high-dose corticosteroids, are often given trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis, since prolonged impairment of cell-mediated immunity increases PJP risk.
• Strongyloides hyperinfection: patients from endemic regions should be screened for Strongyloides before starting immunosuppressive therapy, since suppressing the eosinophilic immune response that normally controls larval autoinfection can trigger fatal hyperinfection syndrome.
• Live attenuated vaccines: these are generally contraindicated in patients on high-dose systemic immunosuppression, because impaired control of vaccine-strain replication risks disseminated, potentially life-threatening infection.

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