Tofacitinib for refractory uveitis and scleritis

Paley, Michael; Karacal, Hümeyra; Rao, P. Kumar; Margolis, Todd P.; Miner, Jonathan J.

doi:10.1016/j.ajoc.2018.12.001

Cited by 93 publications

(52 citation statements)

References 28 publications

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“…In line with this finding, a reduction in gene expression of IL-17A is found after treatment with Ruxolitinib in the iris and ciliary body. Furthermore, a recent report has demonstrated a case of using another JAK inhibitor, Tofacitinib, in the treatment of refractory uveitis and scleritis (33), supporting the potential application of JAK inhibitors in the treatment of ocular inflammation.…”

Section: Discussionmentioning

confidence: 90%

Signaling mechanisms of growth hormone-releasing hormone receptor in LPS-induced acute ocular inflammation

Liang

Ren

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Ocular inflammation is a major cause of visual impairment attributed to dysregulation of the immune system. Previously, we have shown that the receptor for growth-hormone–releasing hormone (GHRH-R) affects multiple inflammatory processes. To clarify the pathological roles of GHRH-R in acute ocular inflammation, we investigated the inflammatory cascades mediated by this receptor. In human ciliary epithelial cells, the NF-κB subunit p65 was phosphorylated in response to stimulation with lipopolysaccharide (LPS), resulting in transcriptional up-regulation of GHRH-R. Bioinformatics analysis and coimmunoprecipitation showed that GHRH-R had a direct interaction with JAK2. JAK2, but not JAK1, JAK3, and TYK2, was elevated in ciliary body and iris after treatment with LPS in a rat model of endotoxin-induced uveitis. This elevation augmented the phosphorylation of STAT3 and production of proinflammatory factors, including IL-6, IL-17A, COX2, and iNOS. In explants of iris and ciliary body, the GHRH-R antagonist, MIA-602, suppressed phosphorylation of STAT3 and attenuated expression of downstream proinflammatory factors after LPS treatment. A similar suppression of STAT3 phosphorylation was observed in human ciliary epithelial cells. In vivo studies showed that blocking of the GHRH-R/JAK2/STAT3 axis with the JAK inhibitor Ruxolitinib alleviated partially the LPS-induced acute ocular inflammation by reducing inflammatory cells and protein leakage in the aqueous humor and by repressing expression of STAT3 target genes in rat ciliary body and iris and in human ciliary epithelial cells. Our findings indicate a functional role of the GHRH-R/JAK2/STAT3–signaling axis in acute anterior uveitis and suggest a therapeutic strategy based on treatment with antagonists targeting this signaling pathway.

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Section: Discussionmentioning

confidence: 90%

Signaling mechanisms of growth hormone-releasing hormone receptor in LPS-induced acute ocular inflammation

Liang

Ren

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…While IL-17 inhibition seems to be not effective in AAU, 133 a case report of a patient with anterior and intermediate uveitis described a favorable outcome under tofacitinib, a pan-JAK-inhibitor. 139 A phase II trial of tofacitinib in non-infectious uveitis is currently underway [ ClinicalTrials.gov identifier: NCT03580343]. Another phase II trial is investigating the effect of filgotinib, a selective JAK-1 inhibitor, in uveitis [ ClinicalTrials.gov identifier: NCT03207815].…”

Section: Treatment Optionsmentioning

confidence: 99%

Uveitis in spondyloarthritis

Rademacher

Poddubnyy

Pleyer

2020

Therapeutic Advances in Musculoskeletal

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Uveitis is the most frequent extra-articular manifestation of axial spondyloarthritis (SpA), occurring in up to one-third of the patients. In the majority of patients, uveitis is acute, anterior and unilateral and presents with photosensitivity, sudden onset of pain and blurred vision. Topical steroids are an effective treatment; however, recurrent or refractory cases may need conventional disease-modifying antirheumatic drugs or biological treatment with monoclonal tumor necrosis factor (TNF) inhibitors, thus also influencing treatment strategy of the underlying SpA. Though the exact pathogenesis of SpA and uveitis remains unknown, both seem to result from the interaction of a specific, mostly shared genetical background (among other HLA-B27 positivity), external influences such as microbiome, bacterial infection or mechanical stress and activation of the immune system resulting in inflammation. Up to 40% of patients presenting with acute anterior uveitis (AAU) have an undiagnosed SpA. Therefore, an effective referral strategy for AAU patients is needed to shorten the diagnostic delay of SpA and enable an early effective treatment. Further, the risk for ophthalmological manifestations increases with the disease duration in SpA; and patients presenting with ocular symptoms should be referred to an ophthalmologist. Thus, a close collaboration between patient, rheumatologist and ophthalmologist is needed to optimally manage ocular inflammation in SpA.

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“…[150][151][152][153] Paley et al described two patients with refractory anterior uveitis or scleritis, who could not tolerate immunosuppressants or ADA, and whose ocular disease improved upon tofacitinib treatment. 154 Nevertheless, both were treated with concurrent MTX and the specific effect of tofacitinib remains difficult to establish. Bauermann et al reported a 22-year-old woman suffering from bilateral JIA-associated anterior uveitis responding only to intraocular dexamethasone implants in the past, while several disease-modifying antirheumatic drug (DMARDs; including biological) failed to control disease activity and macular edema.…”

Section: Anti-tnf-α Treatmentmentioning

confidence: 99%

Ocular Sarcoidosis

Sève

Jamilloux

Tilikete

et al. 2020

Semin Respir Crit Care Med

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Sarcoidosis is one of the leading causes of inflammatory eye disease. Any part of the eye and its adnexal tissues can be involved. Uveitis and optic neuropathy are the main manifestations, which may require systemic treatment. Two groups of patients with sarcoid uveitis can be distinguished: one of either sex and any ethnicity in which ophthalmological findings are various and another group of elderly Caucasian women with mostly chronic posterior uveitis. Clinically isolated uveitis revealing sarcoidosis remains a strictly ocular condition in a large majority of cases. Although it can be a serious condition involving functional prognosis, early recognition in addition to a growing therapeutic arsenal (including intravitreal implant) has improved the visual prognosis of the disease in recent years. Systemic corticosteroids are indicated when uveitis does not respond to topical corticosteroids or when there is bilateral posterior involvement, especially macular edema. In up to 30% of the cases that require an unacceptable dosage of corticosteroids to maintain remission, additional immunosuppression is used, especially methotrexate. As with other forms of severe noninfectious uveitis, monoclonal antibodies against tumor necrosis factor-α have been used. However, only very rarely does sarcoid uveitis fail to respond to combined corticosteroids and methotrexate therapy, a situation that should suggest either poor adherence or another granulomatous disease. Optic neuropathy often affects women of African and Caribbean origins. Some authors recommend that patients should be treated with high-dose of corticosteroids and concurrent immunosuppression from the onset of this manifestation, which is associated with a poorer outcome.

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Tofacitinib for refractory uveitis and scleritis

Cited by 93 publications

References 28 publications

Signaling mechanisms of growth hormone-releasing hormone receptor in LPS-induced acute ocular inflammation

Signaling mechanisms of growth hormone-releasing hormone receptor in LPS-induced acute ocular inflammation

Uveitis in spondyloarthritis

Ocular Sarcoidosis

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