Anakinra for the treatment of acute severe gout in critically ill patients

doi:10.1016/j.semarthrit.2015.02.006

Seminars in Arthritis and Rheumatism

Volume 45, Issue 1, August 2015, Pages 81-85

https://doi.org/10.1016/j.semarthrit.2015.02.006 Get rights and content

Abstract

Objectives

To report on the efficacy and safety of anakinra for treatment of acute gouty arthritis in medically complex, critically ill patients.

Methods

Retrospective chart review of 13 critically ill hospitalized patients treated with anakinra for 20 episodes of acute gouty arthritis between 2009 and 2014 at a single health plan and institution (HealthPartners Medical Group and Regions Hospital) in Saint Paul, Minnesota. Data was obtained on baseline characteristics, medical comorbidities, reason for hospitalization, prior gout treatment, reason for choosing anakinra over standard therapy, anakinra dosing, response to treatment, and adverse outcomes.

Results

A total of 10 patients were in the Intensive Care Unit, 1 was in the Burn Unit for extensive 3rd degree burns, 1 was critically ill with a new diagnosis of hemophagocytic lymphohistiocytosis, and 1 was critically ill in isolation with active disseminated multidrug-resistant tuberculosis. Of these patients, 85% had active infections and 92% had renal insufficiency. All patients had a significant response to anakinra treatment: 50% (10/20 episodes) within 24 h, an additional 40% (8/20 episodes) by 48 h, and the remaining 10% (2/20 episodes) by 72 h. Anakinra was well tolerated with only 1 case of leukopenia and 1 possible infectious complication.

Conclusions

Anakinra is a safe and efficacious treatment for acute gouty arthritis in medically complex, critically ill patients when standard treatment modalities cannot be used.

Introduction

Gout is a chronic, episodic inflammatory disease characterized by intra-articular deposition of monosodium urate crystals resulting in monoarticular or polyarticular arthritis. Acute gouty flares are not uncommon in hospitalized patients. Treatment with traditional anti-inflammatory therapies—non-steroidal anti-inflammatory drugs (NSAID), colchicine, and systemic or intra-articular corticosteroids—can be limited by relative and absolute contraindications in the acutely ill patient, especially in the case of elderly patients. NSAID have well established renal and bleeding complications. Systemic steroid therapy may cause impairment in wound healing (which is of particular concern in surgical patients), immunosuppression, hyperglycemia, mood disturbance, myopathy, and insomnia. Colchicine frequently causes gastrointestinal adverse reactions, especially in the setting of renal impairment.

The inflammatory mechanism of gout begins with formation and deposition of monosodium urate crystals into the intra-articular space. This crystal deposition activates the NALP3 inflammasome, which is responsible for binding and activation of caspase I. This enzyme catalyzes the cleavage of pro-IL-1β to the mature IL-1β [1]. IL-1β is a pro-inflammatory cytokine which is involved in multiple inflammatory pathways that ultimately lead to the production of Tumor Necrosis Factor, IL-6, prostaglandin E2, nitric oxide, and adhesion molecules that are involved in articular inflammation [2]. This inflammatory cascade is counterbalanced by a naturally occurring IL-1β receptor antagonist, produced by macrophages, which competitively binds to the IL-1β receptor.

Several studies have described the use of IL-1 receptor antagonism with anakinra in cases of acute gout flares. These studies have been fairly small in size but have shown a significant improvement in acute gout symptoms after treatment with anakinra, a recombinant IL-1 receptor antagonist, as well as good tolerability [3], [4], [5], [6]. One study has reported on the use of anakinra in hospitalized patients with comorbid medical conditions [3], but there are no reports of its use specifically in critically ill patients. We describe the efficacy and tolerability of anakinra in 13 critically ill patients with acute gout flares.

Section snippets

Materials and methods

We performed a retrospective chart review of a total of 13 hospitalized patients treated with anakinra for acute gouty arthritis at a single health plan and institution (HealthPartners Medical Group and Regions Hospital) between 2009 and 2014. Patients were identified by searching the electronic medical record for the term anakinra. Patients treated with anakinra for diagnoses other than acute gouty arthritis were excluded from the study. The diagnosis of acute gouty arthritis was confirmed by

Results

A total of 13 patients were treated with anakinra for 20 episodes of acute gouty arthritis—12 males and 1 female with a mean age of 58 years (range: 41–70). All patients were critically ill with multiple comorbidities. Of the patients, 10 (77%) were in the Medical Intensive Care Unit, 1 was in the Burn Unit for extensive 3rd degree burns requiring multiple surgeries, 1 was critically ill with a new diagnosis of hemophagocytic lymphohistiocytosis (HLH), and 1 was critically ill in isolation with

Discussion

Treatment of severe gout in critically ill patients with serious comorbid conditions such as sepsis and renal failure can be challenging. Routinely used medications such as non-steroidal anti-inflammatory drugs, colchicine, and corticosteroids may be totally or relatively contraindicated. We present our experience that anakinra can be a safe and efficacious treatment for acute gouty arthritis in critically ill patients with multiple comorbidities who have contraindications or incomplete

Conclusion

While this was a non-randomized, observational, retrospective review of our experience with anakinra at a single large institution, our experience suggests that anakinra is a therapeutic option for acute gout in medically complex, critically ill patients even with serious infections and renal insufficiency where other treatment modalities cannot be used.

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Treatment of acute gouty arthritis in complex hospitalized patients with anakinra
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Caspase-1 is a critical mediator of the inflammatory process by activating various pro-inflammatory cytokines such as pro-IL-1β, IL-18 and IL-33. Uncontrolled activation of caspase-1 leads to various cytokines-mediated diseases. Thus, inhibition of Caspase-1 is considered therapeutically beneficial to halt the progression of such diseases. Currently, rilonacept, canakinumab and anakinra are in use for caspase-1-mediated autoinflammatory diseases. However, the poor pharmacokinetic profile of these peptides limits their use as therapeutic agents. Therefore, several peptidomimetic inhibitors have been developed, but only a few compounds (VX-740, VX-765) have advanced to clinical trials; because of their toxic profile. Several small molecule inhibitors have also been progressing based on the three-dimensional structure of caspase-1. However there is no successful candidate available clinically. In this perspective, we highlight the mechanism of caspase-1 activation, its therapeutic potential as a disease target and potential therapeutic strategies targeting caspase-1 with their limitations.
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Currently, multiple biologic agents targeting IL-1β are being used to prevent NLRP3-associated diseases. The IL-1R antagonist Anakinra has been demonstrated to effectively treat cryopyrin-associated periodic syndrome, an autoinflammatory syndrome [9], and acute gout flares [10,11]. Therapy with the human IL-1β antibody canakinumab resulted in remarkably lower rates of cardiovascular disease, arthritis, and gout in clinical trials [12].
Tanshinones, the active ingredients derived from the roots of Salvia miltiorrhiza, have been widely used as traditional medicinal herbs for treating human diseases. Although tanshinones showed anti-inflammatory effects in many studies, large knowledge gaps remain regarding their underlying mechanisms. Here, we identified 15 tanshinones that suppressed the activation of NLRP3 inflammasome and studied their structure–activity relationships. Three tanshinones (tanshinone IIA, isocryptotanshinone, and dihydrotanshinone I) reduced mitochondrial reactive-oxygen species production in lipopolysaccharide (LPS)/nigericin-stimulated macrophages and correlated with altered mitochondrial membrane potentials, mitochondria complexes activities, and adenosine triphosphate and protonated-nicotinamide adenine dinucleotide production. The tanshinones may confer mitochondrial protection by promoting autophagy and the AMP-activated protein kinase pathway. Importantly, our findings demonstrate that dihydrotanshinone I improved the survival of mice with LPS shock and ameliorated inflammatory responses in septic and gouty animals. Our results suggest a potential pharmacological mechanism whereby tanshinones can effectively treat inflammatory diseases, such as septic and gouty inflammation.
Effectiveness and safety of anakinra in gout patients with stage 4-5 chronic kidney disease or kidney transplantation: A multicentre, retrospective study
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Les inhibiteurs de l’interleukine (IL)-1β, efficaces dans les crises de goutte, sont recommandés en cas de contre-indications à la prise en charge standard, notamment insuffisance rénale chronique (IRC) de stade 4 ou 5. Or, il existe peu de données disponibles sur l’efficacité et la sécurité de ces agents dans cette population de patients. Nous avons souhaité explorer l’efficacité et la sécurité de l’anakinra utilisé pour traiter les crises de goutte chez des patients présentant une IRC de stade 4 ou 5 ou ayant subi une transplantation rénale.
Cette étude rétrospective menée dans trois centres universitaires a inclus des patients consécutifs présentant une IRC de stade 4 ou 5 ou ayant subi une transplantation rénale qui prenaient de l’anakinra en traitement d’une arthrite goutteuse aiguë et avaient effectué au moins une visite de suivi. L’efficacité, la survenue d’infections et les variations de la fonction rénale ont été consignées.
Sur les 31 patients inclus (24 hommes, âge moyen 72 ± 11 ans), 25 n’avaient pas subi de transplantation et présentaient une IRC de stade 4 ou 5 (estimation du débit de filtration glomérulaire moyen [eDFG] selon la formule MDRD 22,7 ± 6,5 mL/min/1,73 m²) et 6 avaient subi une transplantation rénale (eDFG moyen 41,5 ± 22,8 mL/min/1,73 m²). La durée médiane de la goutte était de 3,5 ans et le taux moyen d’uricémie de 8,7 mg/dL. Vingt-et-un patients (68 %) présentaient des tophi et 21, une arthropathie goutteuse. L’anakinra a été efficace chez tous les patients (EVA final 10 et CRP finale 10 mg/L). Dix patients (32 %) étaient dépendants de l’anakinra (c.-à-d. qu’un traitement prolongé d’anakinra était nécessaire). Une infection grave a été enregistrée chez une seule patiente, trois mois après l’instauration de l’anakinra. Aucune variation significative de la fonction rénale n’a été observée.
L’anakinra peut constituer une option thérapeutique sûre chez les patients goutteux présentant une IRC à un stade avancé. Des études comparatives randomisées supplémentaires sont nécessaires pour confirmer nos résultats.
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No serious AEs occurred, and her renal function remained stable, even with an initial AKN regimen of 200 mg/day. For the gout indication, a single case series reported a good safety profile for AKN in cases of renal insufficiency of various severity [29]; moreover, AKN did not appear to worsen pre-existing infections or affect the response to antibiotics. The management of acute gout remains challenging in patients with stage 4–5 CKD.
Interleukin (IL)-1β blocking is effective for the treatment of gout flares and is recommended in patients with contraindications to the standard of care, such as stage 4–5 chronic kidney disease (CKD) patients. However, efficacy and safety data regarding these agents are lacking in this population. We aimed to investigate the efficacy and safety of anakinra for the treatment of gout flares in patients with stage 4–5 CKD or renal transplantation.
This retrospective study encompassing 3 academic centres included consecutive patients with stage 4–5 CKD or kidney transplantation who received anakinra for the treatment of acute gouty arthritis and completed at least one follow-up visit. Efficacy, occurrence of infection, and renal function variations were recorded.
Of the 31 included patients (24 men, mean age 72 ± 11 years), 25 were non-transplant subjects with stage 4–5 CKD (mean estimated glomerular filtration rate, MDRD formula (eGFR) 22.7 ± 6.5 mL/min/1.73 m²), and six had undergone kidney transplantation (mean eGFR 41.5 ± 22.8 mL/min/1.73 m²). Median gout duration was 3.5 years, and the mean serum urate (SUA) level was 8.7 mg/dL. Twenty-one (68%) patients had tophi, and 21 had gout arthropathy. Anakinra was efficacious in all patients (final VAS 10 and CRP level 10 mg/L). Ten patients (32%) were anakinra dependent (i.e., required prolonged treatment with anakinra). A serious infection was recorded in only one patient, occurring 3 months after starting anakinra. No significant variation in renal function was observed.
Anakinra may be a safe therapeutic option for gout patients with advanced CKD. Further randomized controlled studies are required to confirm our results.

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: This study was performed without financial support.

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Anakinra for the treatment of acute severe gout in critically ill patients

Abstract

Objectives

Methods

Results

Conclusions

Introduction

Section snippets

Materials and methods

Results

Discussion

Conclusion

Vitam Horm

Semin Arthritis Rheum

Gout-associated uric acid crystals activate the NALP3 inflammasome

Nature

Treatment of acute gouty arthritis in complex hospitalized patients with anakinra

Arthritis Care Res

A pilot study of IL-1 inhibition by anakinra in acute gout

Arthritis Res Ther