Patients with MPNs and retinal drusen show signs of complement system dysregulation and a high degree of chronic low-grade inflammation

Liisborg, Charlotte; Skov, Vibe; Kjær, Lasse; Hasselbalch, Hans Carl; Sørensen, Torben Lykke

doi:10.1016/j.eclinm.2021.101248

Cited by 11 publications

(16 citation statements)

References 86 publications

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“…In the CD8 compartment, patients with PMF had a significantly higher percentage of terminally differentiated EMRA cells compared to both ET and near significant compared to PV, indicating an increasing senescent profile over the continuum. This fits well with our previous finding of increasing CLI over the continuum [ 9 ]. We also observed a tendency to lose costimulatory markers and increased CD56 expression over the continuum, but the results were not statistically significant.…”

Section: Discussionsupporting

confidence: 93%

“…The result was 119 included patients: 29 nAMD, 28 iAMD, 35 MPNd, and 27 MPNn. The patients are the same as in our previous work, and patient characteristics ( Table 1 ) are therefore identical [ 9 ].…”

Section: Resultsmentioning

confidence: 99%

“…We have published several differences between MPN patients with and without drusen. The MPNd have a higher level of CLI and signs of a dysregulated complement system [ 9 ]. In this study, we investigated immunosenescence markers, and the results suggest that MPNd have accelerated T cell differentiation with more effector T cells than MPNn and a similar differentiation profile to AMD and iAMD patients.…”

Section: Discussionmentioning

confidence: 99%

“…The participants in this cross-sectional study consisted of the same participants as in our recent work, and the description of the methods in this study will be very similar [ 9 ]. We included 29 patients with nAMD, 28 with intermediate AMD (iAMD) [ 57 ], and 65 patients with MPNs [ 58 ] between July 2018 and November 2020.…”

Section: Methodsmentioning

confidence: 99%

“…Our recent work investigated AMD in patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) [ 9 ]. The MPNs are a group of closely related hematological cancers named essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF).…”

Section: Introductionmentioning

confidence: 99%

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Retinal drusen in patients with chronic myeloproliferative blood cancers are associated with an increased proportion of senescent T cells and signs of an aging immune system

Liisborg

Skov

Kjær

et al. 2021

Aging

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The cause of age-related macular degeneration (AMD) is unknown, but evidence indicates that both innate and adaptive immunity play a role in the pathogenesis. Our recent work has investigated AMD in patients with myeloproliferative neoplasms (MPNs) since they have increased drusen and AMD prevalence. We have previously found increased levels of chronic low-grade inflammation (CLI) in MPN patients with drusen (MPNd) compared to MPN patients with normal retinas (MPNn). CLI and AMD are both associated with aging, and we, therefore, wanted to study immunosenescence markers in MPNd, MPNn, and AMD. The purpose was to identify differences between MPNd and MPNn, which might reveal novel information relevant to drusen pathophysiology and thereby the AMD pathogenesis. Our results suggest that MPNd have a T cell differentiation profile resembling AMD and more effector memory T cells than MPNn. The senescence-associated-secretory-phenotype (SASP) is associated with effector T cells. SASP is thought to play a role in driving CLI seen with advancing age. Senescent cells with SASP may damage healthy tissue, including the eye tissues affected in AMD. The finding of increased effector cells in MPNd could implicate a role for adaptive immunity and senescent T cells together with increased CLI in drusen pathophysiology.

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Section: Discussionsupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Retinal drusen in patients with chronic myeloproliferative blood cancers are associated with an increased proportion of senescent T cells and signs of an aging immune system

Liisborg

Skov

Kjær

et al. 2021

Aging

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Janus Kinase Inhibitor Therapy and Risk of Age-Related Macular Degeneration in Autoimmune Disease

Hallak,

Abbasi,

Goldberg

et al. 2024

JAMA Ophthalmol

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ImportanceThe involvement of chronic inflammation in the pathogenesis of age-related macular degeneration (AMD) opens therapeutic possibilities to AMD management.ObjectiveTo determine whether Janus kinase inhibitors (JAKis) are associated with a reduced risk of AMD development in patients with autoimmune diseases.Design, Setting, and ParticipantsThis retrospective observational cohort study used administrative claims data from Merative MarketScan research databases (Commercial and Medicare Supplemental) and Optum Clinformatics Data Mart databases between January 1, 2010, and January 31, 2022. Patients with autoimmune diseases satisfying study eligibility criteria and who received JAKi treatment (9126 in MarketScan and 5667 in Optum) were propensity score matched (1:1) to identical numbers of study-eligible patients who received non–JAKi-based immunotherapy.ExposureTreatment duration of 6 months or longer.Main Outcomes and MeasuresIncidence rates of AMD (exudative and nonexudative) over the first 6 to 18 months of treatment were determined, and bayesian Poisson regression models were used to estimate incidence rate ratios, 95% CIs, and posterior probabilities of AMD.ResultsAfter matching, female sex represented the majority of the patient population in both MarketScan and Optum (14 019/18 252 [76.6%] and 8563/3364 [75.2%], respectively in the JAKi patient population). More than 60% of the patient population was older than 55 years of age in both cohorts. Over the specified treatment period, a 49% relative reduction in incidence of AMD was observed among patients who received JAKi therapy (10/9126 events; adjusted incidence rate ratio [AIRR], 0.51; 95% CI, 0.19-0.90) vs those who received non-JAKi therapy (43/9126 events; AIRR, 1 [reference]) in MarketScan, and a 73% relative reduction in incidence of AMD was observed among patients who received JAKi therapy (3/5667 events; AIRR, 0.27; 95% CI, 0.03-0.74) vs those who received non-JAKi therapy (21/5667 events; AIRR, 1 [reference]) in Optum. The absolute percentage reductions were 0.36% (MarketScan) and 0.32% (Optum), favoring patients who received JAKi therapy. Posterior probabilities of the adjusted risk being less than unity were 97.6% (MarketScan) and 98.9% (Optum) for those who received JAKi therapy vs those who received non-JAKi therapy in MarketScan and Optum, respectively.Conclusions and RelevanceJAKi use may be associated with a reduced risk of incident AMD in US adults with major autoimmune diseases. The absolute percentage reduction is consistent with a potential role for JAKi in this population. Future studies with long-term follow-up are recommended to investigate the association between JAKi use and incident AMD in other disease indications. Investigation into the role of systemic inflammation and JAK–signal transducers and activators of transcription signaling in AMD may improve understanding of the pathophysiology of AMD and lead to new treatment options.

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Serum levels of IL-4, IL-13 and IL-33 in patients with age-related macular degeneration and myeloproliferative neoplasms

Gotfredsen

Liisborg

Skov

et al. 2023

Sci Rep

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Immune responses play a key role in the pathogenesis and progression of myeloproliferative neoplasms (MPN) and age-related macular degeneration (AMD). Recent studies suggested using MPNs as a “Human Inflammation Model” of drusen development and previous results showed interleukin-4 (IL-4) dysregulation in MPN and AMD. IL-4, IL-13 and IL-33 are all cytokines involved in the type 2 inflammatory response. This study investigated the cytokine levels of IL-4, IL-13 and IL-33 in serum of MPN and AMD patients. This cross-sectional study included 35 patients with MPN with drusen (MPNd) and 27 with MPN and normal retinas (MPNn), 28 patients with intermediate AMD (iAMD) and 29 with neovascular AMD (nAMD). With immunoassays, we quantified and compared levels of IL-4, IL-13 and IL-33 in serum between the groups. The study was conducted at Zealand University Hospital, Roskilde, Denmark, between July 2018 and November 2020. The serum levels of IL-4 were significantly higher in the MPNd group than in the MPNn group (p = 0.003). In regard to IL-33, the difference between MPNd and MPNn was not significant (p = 0.069), however, when subdivided into subgroups, a significant difference was found between polycythemia vera patients with drusen and those without drusen (p = 0.005). We found no IL-13 difference between the MPNd and MPNn groups. Our data didn’t show any significant IL-4 or IL-13 serum level difference between the MPNd and iAMD groups but in regard to IL-33, data recorded a significant serum level difference between the two groups. There was no statistically significant difference between the MPNn, iAMD and nAMD groups in levels of IL-4, IL-13 and IL-33. These findings suggested that the serum levels of IL-4 and IL-33 might play a role in drusen development in MPN patients. The results might represent the type 2 inflammatory arm of the disease. The findings support the association between chronic inflammation and drusen.

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Patients with MPNs and retinal drusen show signs of complement system dysregulation and a high degree of chronic low-grade inflammation

Cited by 11 publications

References 86 publications

Retinal drusen in patients with chronic myeloproliferative blood cancers are associated with an increased proportion of senescent T cells and signs of an aging immune system

Retinal drusen in patients with chronic myeloproliferative blood cancers are associated with an increased proportion of senescent T cells and signs of an aging immune system

Janus Kinase Inhibitor Therapy and Risk of Age-Related Macular Degeneration in Autoimmune Disease

Serum levels of IL-4, IL-13 and IL-33 in patients with age-related macular degeneration and myeloproliferative neoplasms

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