Long-term Risk of Malignancy Among Patients Treated With Immunosuppressive Agents for Ocular Inflammation: A Critical Assessment of the Evidence

Kempen, John H.; Gangaputra, Sapna; Daniel, Ebenezer; Levy-Clarke, Grace A.; Nussenblatt, Robert B.; Rosenbaum, James T.; Suhler, Eric B.; Thorne, Jennifer E.; Foster, C. Stephen; Jabs, Douglas A.; Helzlsouer, Kathy J.

doi:10.1016/j.ajo.2008.04.035

Cited by 128 publications

(105 citation statements)

References 89 publications

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“…15 These repeated administrations are associated with severe side effects including an increased risk of opportunistic infections and malignancies. [16][17][18][19] It was also observed that a constant level of drug is needed to avoid reactivation of the inflammatory processes. 15,19 Thus, when uveitis is the main (or sole) manifestation of inflammation, sustained levels of local intraocular anti-TNF therapy may allow for the control of the intraocular inflammatory processes with little (or no) unwarranted systemic effects.…”

Section: Introductionmentioning

confidence: 99%

Effects of ciliary muscle plasmid electrotransfer of TNF-α soluble receptor variants in experimental uveitis

et al. 2009

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Intraocular inflammation has been recognized as a major factor leading to blindness. Because tumor necrosis factor-a (TNF-a) enhances intraocular cytotoxic events, systemic anti-TNF therapies have been introduced in the treatment of severe intraocular inflammation, but frequent re-injections are needed and are associated with severe side effects. We have devised a local intraocular nonviral gene therapy to deliver effective and sustained anti-TNF therapy in inflamed eyes. In this study, we show that transfection of the ciliary muscle by plasmids encoding for three different variants of the p55 TNF-a soluble receptor, using electrotransfer, resulted in sustained intraocular secretion of the encoded proteins, without any detection in the serum. In the eye, even the shorter monomeric variant resulted in efficient neutralization of TNF-a in a rat experimental model of endotoxininduced uveitis, as long as 3 months after transfection. A subsequent downregulation of interleukin (IL)-6 and iNOS and upregulation of IL-10 expression was observed together with a decreased rolling of inflammatory cells in anterior segment vessels and reduced infiltration within the ocular tissues. Our results indicate that using a nonviral gene therapy strategy, the local self-production of monomeric TNF-a soluble receptors induces a local immunomodulation enabling the control of intraocular inflammation.

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Section: Introductionmentioning

confidence: 99%

Effects of ciliary muscle plasmid electrotransfer of TNF-α soluble receptor variants in experimental uveitis

et al. 2009

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“…Despite frequently expressed reservations, these drugs are associated with a low rate of adverse effects if used adequately and monitored [48][49][50]. By using immunosuppressive treatment, visual prognosis and rate of complications could be improved in JIA-associated uveitis [13,51].…”

Section: Treatment With Immunosuppressives and Biologicalsmentioning

confidence: 99%

Evidence-based, interdisciplinary guidelines for anti-inflammatory treatment of uveitis associated with juvenile idiopathic arthritis

et al. 2011

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Uveitis in juvenile idiopathic arthritis (JIA) is frequently associated with the development of complications and visual loss. Topical corticosteroids are the first-choice therapy, and immunosuppression is commonly used. However, treatment has not been standardized. Representatives from the German Ophthalmological Society, Society for Childhood and Adolescent Rheumatology, and the German Society for Rheumatology reached consensus on a standardized treatment strategy according to disease severity in the individual patient. The recommendations were based on a systematic literature analysis in MEDLINE and consensus expert meetings. Evidence and recommendations were graded, and an algorithm for anti-inflammatory treatment and final statements confirmed in a Delphi method. An interdisciplinary, evidence-based treatment guideline for JIA uveitis is presented.

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“…In a cohort study looking at over 66 802 person years of treatment it was noted that for the most commonly used immunosuppressive drugs there was no increase in overall or cancer mortality. 63,64 However, whether that is true for the biologics, which are in increasing use, will require longer follow-up and improved clinical outcome surveillance. Since the early reports of CAMPATH-1H, 65,66 most evidence for the success of biologics has accumulated using anti-TNF therapies, which have followed an iterative process of evidence for their efficacy in animal models, through to early phase studies, small RCTs and are now undergoing more definitive assessment in commercially-led RCTs.…”

Section: Recent and Future Treatmentsmentioning

confidence: 99%

Current concepts and future directions in the pathogenesis and treatment of non-infectious intraocular inflammation

Lee

Dick

2011

Eye

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The blockbuster drug paradigm is under increasing scrutiny across the biopharmaceutical industry. Intraocular inflammation poses particular challenges to this, given the heterogeneity of conditions in the uveitis spectrum, and the increasing acknowledgement of individual patient and disease variance in underlying immune responses. This need has triggered a drive towards personalised and stratified medicine, supported and enabled as a result of continued development of both experimental models and molecular biological techniques and improved clinical classification. As such we have the ability now to systematically appraise at a genomic, transcriptomic, and proteomic level individual immunophenotype, and the promise that in the eye this can be augmented by in vivo immune imaging to identify individual immunopathology. With such advances all running in parallel, we are entering an era of experimental medicine that will facilitate early diagnosis, generate biomarkers for accurate prognostication, and enable the development of individualised and targeted therapies, which can progress rapidly into clinical practice.

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Long-term Risk of Malignancy Among Patients Treated With Immunosuppressive Agents for Ocular Inflammation: A Critical Assessment of the Evidence

Cited by 128 publications

References 89 publications

Effects of ciliary muscle plasmid electrotransfer of TNF-α soluble receptor variants in experimental uveitis

Effects of ciliary muscle plasmid electrotransfer of TNF-α soluble receptor variants in experimental uveitis

Evidence-based, interdisciplinary guidelines for anti-inflammatory treatment of uveitis associated with juvenile idiopathic arthritis

Current concepts and future directions in the pathogenesis and treatment of non-infectious intraocular inflammation

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