Rapamycin (Sirolimus) Autoimmune Disease Considerations

Is Sirolimus Approved for Autoimmune Disease?

No. The Rapamune label, which covers sirolimus tablets and oral solution, lists two approved uses: prophylaxis of organ rejection in patients 13 years and older receiving renal transplants, and treatment of lymphangioleiomyomatosis [1]. Nothing in the labeled indications covers lupus, autoimmune lymphoproliferative syndrome, pemphigus, rheumatoid arthritis, or any other autoimmune disease, so all of these uses are off-label [1].

The label's dosing, warnings, and monitoring are built around transplant and LAM use [1]. The off-label studies described below used their own dosing and their own targets.

What Evidence Exists in ALPS?

In a small published report, four patients with autoimmune lymphoproliferative syndrome (ALPS) and autoimmune cytopenias were treated with sirolimus after failing or not tolerating other therapies; all four had a rapid complete or near-complete response [2]. Two patients treated for autoimmune arthritis and colitis showed marked improvement, three patients had complete resolution of lymphadenopathy and splenomegaly, and all patients had a reduction in the double-negative T cells that are the hallmark of the disease [2]. The authors recommended sirolimus as second-line therapy for steroid-refractory disease [2].

This is a very small series. It supports the rationale for studying sirolimus in ALPS; it does not establish how often the drug works or how long responses last.

What Evidence Exists in Lupus?

A single-arm, open-label phase 1/2 trial enrolled adults with active systemic lupus erythematosus that had not responded to, or could not be tolerated from, conventional medications [3]. Patients received oral sirolimus starting at 2 mg per day, with the dose adjusted to maintain a therapeutic range of 6 to 15 ng/mL, for 12 months [3]. The primary efficacy endpoint was change in disease activity measured by the British Isles Lupus Assessment Group index and the Systemic Lupus Erythematosus Disease Activity Index [3]. The trial excluded patients with proteinuria (a urine protein-to-creatinine ratio above 0.5), anemia, leukopenia, or thrombocytopenia [3].

The design has a real limit: with no placebo or comparator arm, the results cannot separate the effect of sirolimus from the natural course of lupus or from the other care patients received.

How Does Sirolimus Affect Immune Cells?

The label calls sirolimus an mTOR inhibitor immunosuppressant [1]. In laboratory work with mouse cells, rapamycin selectively expanded CD4+CD25+FoxP3+ regulatory T cells in vitro; the expanded cells suppressed proliferation of syngeneic T cells in vitro and prevented allograft rejection in vivo [4]. That finding comes from mouse cells and laboratory experiments, not from a human autoimmune disease trial [4].

The label warns that oversuppression of the immune system can increase susceptibility to infection, including opportunistic infections such as tuberculosis, fatal infections, and sepsis [1].

What Does the Label Warn About?

The boxed warning says increased susceptibility to infection and possible development of lymphoma and other malignancies, particularly of the skin, may result from immunosuppression [1]. It also says only physicians experienced in immunosuppressive therapy and renal transplant management should use Rapamune for transplant prophylaxis, and that patients should be managed in facilities with adequate laboratory and supportive medical resources [1]. The label says Rapamune is not recommended in liver or lung transplant patients; the boxed warning cites excess mortality, graft loss, hepatic artery thrombosis, and bronchial anastomotic dehiscence [1].

Other labeled warnings include hypersensitivity reactions, angioedema, fluid accumulation and impaired wound healing, hyperlipidemia, proteinuria, interstitial lung disease, renal function decline with long-term cyclosporine, calcineurin-inhibitor-associated HUS/TTP/TMA, embryo-fetal toxicity, male infertility (azoospermia or oligospermia), and avoidance of live vaccines [1]. These are label facts for Rapamune, not autoimmune-specific findings.

What Interactions Matter?

Sirolimus is a substrate of CYP3A4 and P-glycoprotein. Inducers of these pathways may decrease sirolimus concentrations, and inhibitors may increase them [1]. The label says to avoid strong inducers such as rifampin and rifabutin, and strong inhibitors such as ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, and clarithromycin [1]. It lists many weak or moderate modulators that require caution, including diltiazem, fluconazole, verapamil, carbamazepine, phenytoin, and St. John's wort [1]. Cannabidiol can raise sirolimus blood levels [1]. The Rapamune label says grapefruit juice must not be taken with the drug or used to dilute it, because grapefruit juice inhibits the CYP3A4-mediated metabolism of sirolimus [1]. Cyclosporine increases sirolimus concentrations, and the label says to take Rapamune 4 hours after cyclosporine [1].