sirolimus and Graves-Ophthalmopathy

To offer an update on advances and controversies in the assessment, investigation and treatment of thyroid eye disease (TED), a disfiguring orbital autoimmune disease, which can manifest with diplopia and threaten not only sight - but also life.. Developments in biomarkers and imaging are helping to tailor the management of patients. Emerging therapies target different pathways in the disease and are informed by studies into TED pathogenesis: the last 2 years has, for example, seen the culmination of a two-decade long bench-to-bedside story in which an original focus on the IGF1 receptor has translated into an effective treatment for proptosis in thyroid eye disease. Whether this will result in a real-world reduction in TED-related morbidity will depend on access; commercial pricing decisions may preclude widespread adoption of novel therapies.. Thyroid eye disease research is enjoying a renaissance with advances in both monitoring and treatment coupled with a renewed emphasis on a holisitic approach, which includes aesthetic care for patients; this is perhaps the most exciting time to be part of the international thyroid eye disease community in decades - for physicians, surgeons and patients. The commercial window for break-through drugs are narrowing with an array of new therapeutic agents in the pipeline over the coming decade.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Decompression, Surgical; Graves Ophthalmopathy; Humans; Immunosuppressive Agents; Methotrexate; Mycophenolic Acid; Sirolimus

CD4+ cytotoxic T lymphocytes (CTLs) were recently implicated in immune-mediated inflammation and fibrosis progression of Graves' orbitopathy (GO). However, little is known about therapeutic targeting of CD4+ CTLs. Herein, we studied the effect of rapamycin, an approved mTOR complex 1 (mTORC1) inhibitor, in a GO mouse model, in vitro, and in patients with refractory GO. In the adenovirus-induced model, rapamycin significantly decreased the incidence of GO. This was accompanied by the reduction of both CD4+ CTLs and the reduction of orbital inflammation, adipogenesis, and fibrosis. CD4+ CTLs from patients with active GO showed upregulation of the mTOR pathway, while rapamycin decreased their proportions and cytotoxic function. Low-dose rapamycin treatment substantially improved diplopia and the clinical activity score in steroid-refractory patients with GO. Single-cell RNA-Seq revealed that eye motility improvement was closely related to suppression of inflammation and chemotaxis in CD4+ CTLs. In conclusion, rapamycin is a promising treatment for CD4+ CTL-mediated inflammation and fibrosis in GO.

Topics: Animals; CD4-Positive T-Lymphocytes; Fibrosis; Graves Ophthalmopathy; Inflammation; Mice; Sirolimus; T-Lymphocytes, Cytotoxic; TOR Serine-Threonine Kinases

Topics: Diplopia; Drug Therapy, Combination; Graft Rejection; Graves Ophthalmopathy; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Mycophenolic Acid; Prospective Studies; Sirolimus

A beneficial effect of sirolimus in Graves' orbitopathy (GO) was reported, suggesting a possible use in clinical practice. We conducted an observational, single-centre, no-profit, clinical study to investigate the efficacy of sirolimus as a second-line treatment for moderate-to-severe, active GO compared with methylprednisolone.. Data from consecutive patients given sirolimus (2 mg orally on first day, followed by 0.5 mg/day for 12 weeks) or methylprednisolone [500 mg iv/weekly (6 weeks), 250 mg/weekly (6 weeks)] as a second-line treatment were collected and compared.. overall GO outcome at 24 weeks, based on a composite evaluation. Secondary objectives at 24 weeks: (1) improvement in quality of life, evaluated using a specific uestionnaire (GO-QoL); (2) reduction in proptosis; (3) reduction in the clinical activity score (CAS); (4) improvement of eye ductions; and (5) reduction in eyelid aperture.. Data from 30 patients (15 per group) treated between January 15, 2020, and June 15, 2021, were analysed. Proportion of GO responders (primary outcome) at 24 weeks was significantly greater in sirolimus group compared with methylprednisolone group (86.6% vs 26.6%; OR: 17.8; 95% CI from 2.7 to 116.8; P = 0.0026). GO-quality of life (GO-QoL) score was greater in sirolimus group. Proportion of proptosis responders was greater in sirolimus group, as well as proportion of clinical activity score (CAS) responders. No serious adverse events were observed, with no differences between groups.. Sirolimus seems to be an effective second-line treatment for GO. Further randomized clinical trials are needed to confirm our observations.

Topics: Exophthalmos; Graves Ophthalmopathy; Humans; Methylprednisolone; Quality of Life; Sirolimus; Treatment Outcome

Rapamycin (alternatively known as sirolimus) is a macrolide immunosuppressant commonly used for organ transplantation. It acts both on lymphocytes through the mechanistic target of rapamycin (mTOR) pathway to reduce their sensitivity to interleukin-2 (IL-2) and, importantly, also has anti-fibrotic properties by acting on myofibroblasts. The latter have been implicated in the pathogenesis of thyroid eye disease (TED).. To describe successful treatment and reversal of extraocular muscle fibrosis in TED with sirolimus.. Case report and literature review with clinic-pathological correlation.. A patient with Graves' orbitopathy (GO) developed significant ocular motility restriction, which was unresponsive to steroids and conventional immunosuppression. Unlike these prior treatments, rapamycin therapy improved the diplopia and fields of binocular single vision over a period of months. There were no adverse effects directly attributable to the treatment.. With its low renal toxicity and ability to specifically target the underlying fibrotic pathways in GO, rapamycin may prove a useful adjunct to standard immunosuppressive regimes. We encourage further reporting of case series or the instigation of controlled trial.

Topics: Adult; Graves Ophthalmopathy; Humans; Immunosuppressive Agents; Male; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

To investigate the effects of rapamycin on the TNF-α-induced secretion of interleukin-6 (IL-6) and IL-8 in orbital fibroblasts and its possible mechanism.. Orbital fibroblasts were obtained from patients with thyroid-associated ophthalmopathy. IL-6 and IL-8 levels were measured by enzyme-linked immunosorbent assays. The down-regulation of PDCD4 was performed by PDCD4 siRNA transfection.. Rapamycin significantly enhanced TNF-α-induced IL-6 and IL-8 secretion from orbital fibroblasts. Down-regulation of PDCD4 by PDCD4 siRNA transfection reduced TNF-α-induced IL-6 and IL-8 secretion from orbital fibroblasts. In addition, TNF-α was found to promote the mTOR-dependent proteasome-mediated degradation of PDCD4. Rapamycin increased PDCD4 expression via the inhibition of TNF-α-induced PDCD4 degradation in orbital fibroblasts.. Rapamycin enhances the TNF-α-induced secretion of IL-6 and IL-8 by suppressing PDCD4 degradation in orbital fibroblasts.

Topics: Adipose Tissue; Adult; Apoptosis Regulatory Proteins; Female; Fibroblasts; Graves Ophthalmopathy; Humans; Immunosuppressive Agents; Interleukin-6; Interleukin-8; Male; Orbit; RNA-Binding Proteins; RNA, Small Interfering; Sirolimus; Tumor Necrosis Factor-alpha