Colchicine suppresses neutrophil superoxide production in a murine model of gouty arthritis: a rationale for use of low-dose colchicine

Background:Gouty arthritis is a common, potentially disabling and increasingly prevalent disease [1]. The main goals of treatment are to treat acute arthritis, decrease uric acid (UA) levels and prevent occurrence of further attacks. According to 2016 updated EULAR evidence-based recommendations for the management of gout, the most common and efficient options include prescription of colchicine (up to 6 mg during the first day) and intra-articular injections of glucocorticoids (GC) [2]. First option often causes diarrhea, the latter is extremely traumatic and painful in this group of patients.Objectives:The aim of this study was to determine the efficacy of sustainability of anti-inflammatory effect of combination of low dose colchicine with sporadic intramuscular injections of betamethasone in the treatment of acute gouty arthritis.Methods:41 treatment naïve patients with acute gouty arthritis (27 male /65,9 %/, 14 female /34,1 %/, mean age 55,9 ± 13,7 years, mean disease duration 5,9 ± 4,4 years) were recruited in the study. On the first visit all the patients were prescribed 1.5 mg of colchicine per day and 2 intramuscular injections of betamethasone preparation (7mg-1ml) with an interval of 4 days. On the second visit (30thday) daily dose of colchicine was decreased to 1.0 mg, urate-lowering therapy (ULT) was begun. 21 patients (51,2%) received febuxostat 80 mg/day, 20 patients (48,8%) – allopurinol 100-150 mg/day.Routine investigation included accurate collection of disease history, objective examination with determining the disease activity (Gout Activity Score /GAS/) and visual analogue scale (VAS patient), CBC, CRP, measurement of serum UA and creatinine level, urinalysis and other examinations [4]. GAS, VAS, CRP and uric acid were measured 3 times: at baseline, on 30thand 60thday of follow-up period.Results:Investigation had shown the following results at baseline: sUA1- 9,2 ± 1,5 mg/dl, CRP1- 24,3 ± 21,5 mg/L, VAS1- 8,3 ± 1,3 cm, GAS16,3 ± 0,7. All enrolled patients completed 60 days of treatment. Preparations were well tolerated, no serious adverse events occurred: mild dyspepsia was observed in 4 (9,8%) patients, mild hypertension – in 7 (17,1%), 10 (24,4%) patients had transient diarrhea. Only in 14 out of 41 patients (34,1 %) there was a necessity to add NSAIDs to the main scheme of treatment.On the second visit (30thday) all investigated measures with exception for UA (sUA2- 8,8 ± 1,9 mg/dl, p>0.05) had shown significantly lower results: CRP2- 4,9±3,5 mg/dl, VAS2– 4,2±1,2 cm, GAS2- 4,9 ± 0,7 (p<0.001).On the third visit (60thday) the following results were obtained: sUA3- 4,7 ± 1,3 mg/dl, CRP3- 3,5±2,0 mg/L, VAS3- 3,3±2,1 cm, GAS3- 3,7±0,9. All the measures were significantly lower than at baseline (p<0,001).During all the follow-up period recurrent attacks of arthritis were observed in 6 patients (14,6%), particularly, only 2 patients experienced arthritis after the prescription of ULT.Conclusion:Low dose colchicine in combination with sporadic (1-2) intramuscular injections of betamethasone can present as an efficient, non-traumatic, safe and cost-effective option for the treatment of acute gouty arthritis. Moreover, according to results of our study, anti-inflammatory effect was stable even after the prescription of ULT.References:[1]Kuo C-F, Grainge MJ, Zhang W, et al. Global epidemiology of gout: prevalence, incidence and risk factors. Nat Rev Rheumatol 2015;11:649–62. doi:10.1038/nrrheum.2015.91[2]Richette P, et al. 2016 updated EULAR evidence-based recommendations for the management of gout Ann Rheum Dis 2017;76:29–42. doi:10.1136/annrheumdis-2016-209707[3]Scirè, Carlo A et al. “Development and First Validation of a Disease Activity Score for Gout.” Arthritis care & research vol. 68,10 (2016): 1530-7. doi:10.1002/acr.22844Disclosure of Interests: :None declared

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Inhibition of neutrophil superoxide production by fanetizole

Inflammation ◽

10.1007/bf00916274 ◽

1985 ◽

Vol 9 (3) ◽

pp. 233-244 ◽

Cited By ~ 6

Author(s):

Barbara Styrt ◽

Ross E. Rocklin ◽

Mark S. Klempner

Keyword(s):

Superoxide Production ◽

Neutrophil Superoxide

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Digestion of C1q collagen-like domain with MMPs-1, -2, -3, and -9 further defines the sequence involved in the stimulation of neutrophil superoxide production

Journal of Leukocyte Biology ◽

10.1002/jlb.66.3.416 ◽

1999 ◽

Vol 66 (3) ◽

pp. 416-422 ◽

Cited By ~ 22

Author(s):

S. Ruiz ◽

A. H. Henschen-Edman ◽

H. Nagase ◽

A. J. Tenner

Keyword(s):

Superoxide Production ◽

Neutrophil Superoxide ◽

Stimulation Of

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724 Evaluation of an anti-human IL-1β antibody in monosodium urate crystals-induced peritonitis model in hIL-1β HuGEMM™ mice

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.724 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A753-A753

Author(s):

Xiaoyu An ◽

Kaixia Lian ◽

Jia Zheng ◽

Fei Jian ◽

Henry Li ◽

...

Keyword(s):

Treatment Group ◽

Murine Model ◽

Gouty Arthritis ◽

Chronic Inflammatory Disease ◽

Vehicle Group ◽

Inflammasome Activation ◽

Monosodium Urate ◽

Vehicle Treatment ◽

Peritonitis Model ◽

Msu Crystals

BackgroundGout is a chronic inflammatory disease featuring the deposition of monosodium urate (MSU) crystals in the synovial fluid of patients, followed by NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome activation and bioactive IL-1β release, which recruits neutrophils to the local inflammation sites. Blocking IL-1β function is becoming a a potent therapeutic approach for gout and gouty arthritis. Conventional MSU-induced peritonitis in C57BL/6 mice provides a simple and rapid evaluation of therapeutics targeting inflammasome activation. However, this murine model has limitations when it comes to the evaluation of human-specific antibodies, for example, anti-human IL-1β (anti-hIL-1β) monoclonal antibodies (mAb). Thus, a murine model to assess the efficacy of anti-hIL-1β mAb is needed. We have developed a hIL-1β knock-in mouse model (hIL-1β HuGEMM™), which is able to facilitate the pre-clinical evaluation of drugs targeting specific human biological molecules especially when mouse ortholog is not available. Therefore, an MSU crystals induced peritonitis model using hIL-1β HuGEMM™ mice provides a robust model to evaluate therapies targeting hIL-1β.MethodsMSU crystals were injected intraperitoneally into human IL-1β (hIL-1β) knock-in mice, where the coding sequence of mouse IL-1β was replaced by hIL-1β. Prior to MSU crystal administration, mice received treatment of either vehicle or anti-hIL-1β antibody. Six hours facilitate post MSU crystal injection, serum and lavage flushed with PBS were collected. Subsequently, cytokine protein levels in the serum were determined by MSD, and the population of polymorphonuclear leukocytes (PMNs) (live CD11b+ Ly-6GHi cells) in the lavage was analysed by flow cytometry.ResultsThe vehicle treatment group showed a dramatic increase in hIL-1β secretion and PMN leukocytes, in comparison to the group that did not receive MSU, which suggests a successful induction of acute inflammatory response in the peritoneal cavity. In contrast, mice that received a single administration of anti-hIL-1β antibody 24 hours prior to MSU injection exhibited a significantly lower level of hIL-1β when compared to the vehicle treatment group, which implies that the anti-hIL-1β mAb efficaciously neutralized hIL-1β secretion. In addition, TNF-α and IL-6, two further cytokines downstream of IL-1β, were significantly reduced in the anti-hIL-1β mAb treatment group. However, the PMN leukocyte infiltration in the anti-hIL-1β mAb treatment group did not change in comparison to the vehicle group.ConclusionsIn this study, an MSU crystals-induced peritonitis model was successfully established in hIL-1β HuGEMM mice, which has the potential to evaluate immune therapeutics with anti-hIL-1β blockades.

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