New Onset of Uveitis During Anti-Tumor Necrosis Factor Treatment for Rheumatic Diseases

Wendling, Daniel; Paccou, Julien; Berthelot, Jean‐Marie; Flipo, René‐Marc; Guillaume-Czitrom, S.; Prati, Clément; Dernis, Emmanuelle; Direz, Guillaume; Ferrazzi, V; Ristori, Jean‐Michel

doi:10.1016/j.semarthrit.2011.05.005

Cited by 123 publications

(91 citation statements)

References 34 publications

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“…[19][20][21][22] These effects include downregulation of macrophage proliferation and activation [23][24][25] as well as inhibition of DC maturation. 26 Most importantly, IL-6R blockade in humans has also been reported to cause inflammatory eye disease, 27 psoriasis, 28 as well as crescentic immune complex GN. 29 Generally, the antiinflammatory actions of IL-6 still remain very ill defined.…”

mentioning

confidence: 99%

Inflammation-Induced IL-6 Functions as a Natural Brake on Macrophages and Limits GN

Luig¹,

Kluger²,

Goerke³

et al. 2015

Journal of the American Society of Nephrology

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IL-6 can mediate proinflammatory effects, and IL-6 receptor (IL-6R) blockade as a treatment for inflammatory diseases has entered clinical practice. However, opposing effects of IL-6 have been observed in models of GN. Although IL-6 is proinflammatory in murine lupus nephritis, protective effects have been observed for IL-6 in the nephrotoxic nephritis (NTN) model of acute crescentic GN. In light of the potential dangers of IL-6-directed treatment, we studied the mechanisms underlying the contradictory findings in GN. IL-6 can signal through the membrane-bound IL-6R, which is expressed only on hepatocytes and certain leukocytes (classic), or through the soluble IL-6R, which binds the ubiquitously expressed gp130 (alternative). Preemptive treatment of mice with anti-IL-6R or anti-IL-6 worsened NTN, whereas selective blockade of alternative IL-6 signaling by the fusion protein sgp130Fc did not. FACS analysis of mouse spleen cells revealed proinflammatory macrophages express the highest levels of IL-6Ra, and in vitro treatment with IL-6 blocked macrophage proliferation. Furthermore, proinflammatory macrophages were expanded during inflammation in IL-6 2/2 mice. Late application of anti-IL-6 after establishment of adaptive nephritogenic immunity was sufficient to aggravate NTN within 2.5 days, a period when macrophages are active. Finally, NTN was aggravated in mice with macrophage-specific impairment of IL-6 classic signaling, coincident with enhanced macrophage proliferation and accumulation in the kidney. Our data thus reveal a novel mechanism in which IL-6-mediated dampening of macrophage activation protects tissues from overshooting immune responses. This finding has important implications for potential IL-6-directed therapies and supports the careful choice of recipient patients and timing.

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mentioning

confidence: 99%

Inflammation-Induced IL-6 Functions as a Natural Brake on Macrophages and Limits GN

Luig¹,

Kluger²,

Goerke³

et al. 2015

Journal of the American Society of Nephrology

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“…They both developed AAU with etanercept therapy, whereas rheumatic symptoms were under control, similarly to many cases reported. 4 AAU resolved rapidly with local therapy without etanercept discontinuation in both patients. However, AAU relapsed and the decision was taken to switch etanercept to another TNF blocker: infliximab for the first case (who had been treated by adalimumab before) and adalimumab for the second case, with no AAU relapse to date.…”

Section: Impact Of Genetic Predisposition Of De Novo Uveitis With Etamentioning

confidence: 86%

“…New onset of AAU occurred mainly in AxSpA (19 cases) compared with other rheumatic conditions (12 cases) according to data from the French nationwide network. 4 The real mechanism of this type of AAU is not yet elucidated. We would like to suggest a potential genetic predisposition for this type of event by reporting cases in two related patients, both followed for AxSpA in the Department of Rheumatology at University Hospital of Saint-Etienne.…”

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confidence: 99%

Impact of genetic predisposition of de novo uveitis with etanercept in ankylosing spondylitis

et al. 2014

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We read with interest the paper by Sieper et al 1 reporting acute anterior uveitis (AAU) during etanercept or sulfasalazine therapies for axial spondyloarthritis (AxSpA). AAU is a well-known symptom in AxSpA without therapy and is itself a good indication for tumour necrosis factor (TNF) blockers.2 However during the last years, new onsets of AAU were reported with TNF blockers, 3 as a paradoxical effect of this therapy, similarly to paradoxical psoriasis. New onset of AAU occurred mainly in AxSpA (19 cases) compared with other rheumatic conditions (12 cases) according to data from the French nationwide network. 4 The real mechanism of this type of AAU is not yet elucidated. We would like to suggest a potential genetic predisposition for this type of event by reporting cases in two related patients, both followed for AxSpA in the Department of Rheumatology at University Hospital of Saint-Etienne. They both developed AAU with etanercept therapy, whereas rheumatic symptoms were under control, similarly to many cases reported.4 AAU resolved rapidly with local therapy without etanercept discontinuation in both patients. However, AAU relapsed and the decision was taken to switch etanercept to another TNF blocker: infliximab for the first case (who had been treated by adalimumab before) and adalimumab for the second case, with no AAU relapse to date. AAU was more frequently reported with etanercept, the soluble receptor p55, than with monoclonal antibody TNF blockers. This discrepancy between TNF blockers may be due to the specific structure of etanercept, which is a fusion protein combining two extracellular ligand-binding portions of the human soluble TNF receptor p75 with the end Fc fragment of human immunoglobulin G1. 5Since de novo uveitis is a rare event with approximately 1 case for 100 patient-years exposed to TNF blockers, 1 4 occurrence in two cousins from the same family, both treated for AxSpA by etanercept, suggested a genetic predisposition to this paradoxical side effect with TNF blockers. Since the microsatellite, D9S157, on chromosome 9p was identified by genomewide scan to be associated with AAU in AxSpA, 6 we analysed this region using several microsatellites in these two patients. Both patients shared an identical allele at three contiguous polymorphic markers, located at 9p21.3-p22.2: D9S157, D9S1684 and D9S162, but are different for D9S156 and D9S171. This locus covers approximately a 6 Mb interval and contains some 37 genes. This identity might be an additional indication for a genetic predisposition to uveitis at this locus, and along these lines, it is noteworthy that the cluster of interferon type 1 genes is present in this region between markers D9S162 and D9S171.Conversely, in our family, there is a probability of 1/16 that this haplotype identity occurred by chance. Further experiments are required to determine the specific gene from this area related to AAU.According to our experience and the findings of this genetic analysis, we would suggest avoiding etanercept among TNF blockers when p...

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“…This could explain the differences observed between classes of TNF blockers in Crohn disease, in which only monoclonal antibodies (adalimumab or infliximab) are effective. Moreover, occurrence of a disease for which a treatment is known to be effective, called a paradoxical effect, has been reported for TNF blockers in psoriasis, inflammatory bowel diseases, sarcoidosis, episcleritis or uveitis, and vasculitis 6,7,8,9,10,11,12 .…”

Section: Casementioning

confidence: 99%

Retroperitoneal Fibrosis During Etanercept Therapy for Rheumatoid Arthritis

et al. 2013

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New Onset of Uveitis During Anti-Tumor Necrosis Factor Treatment for Rheumatic Diseases

Cited by 123 publications

References 34 publications

Inflammation-Induced IL-6 Functions as a Natural Brake on Macrophages and Limits GN

Inflammation-Induced IL-6 Functions as a Natural Brake on Macrophages and Limits GN

Impact of genetic predisposition of de novo uveitis with etanercept in ankylosing spondylitis

Retroperitoneal Fibrosis During Etanercept Therapy for Rheumatoid Arthritis

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