Use of high-dose steroid therapy: addition of anakinra in the treatment of severe COVID-19.

OBJECTIVE: The aim of this study was to compare the clinical effects of the addition of anakinra to high-dose steroid therapy in COVID-19 patients with macrophage activation syndrome. METHODS: This was a single-center retrospective study conducted in Ümraniye Training and Research Hospital between March 11, 2020, and April 28, 2021. Patients receiving only high-dose steroid or anakinra+steroid were enrolled. The first day of anakinra was considered as day 0. Laboratory values and oxygen requirements were followed up for 7 days. Patients were divided into two groups: 66 patients in the high-dose steroid group and 67 patients in the anakinra+steroid group. The primary outcome was 28-day mortality. RESULTS: After treatment, a significant decrease in ferritin levels was detected only in the anakinra+steroid group (p=0.001). In both groups, there were significant changes in lymphocytes, C-reactive protein, lactate dehydrogenase, and fibrinogen levels during the 7-day follow-up. Changes in oxygen status according to the World Health Organization clinical scale on day 3 and day 7 between high-dose steroid and anakinra+steroid groups were similar (p=0.976). Complications were higher in the anakinra+steroid group than in the steroid group (26% vs. 12%, p=0.03). The rates of 28-day mortality were 57% in the anakinra+steroid group and 42% in the high-dose steroid group (p=0.48). In multivariate regression, anakinra did not affect 28-day mortality (p=0.67). CONCLUSION: The addition of anakinra to steroid treatment resulted in a significant decrease in biochemical parameters. However, no significant difference was observed in the oxygen status between the groups. The addition of anakinra to steroid treatment did not decrease mortality. Clinicians should be aware of the complications of anti-inflammatory therapies.

Efficacy of colchicine in addition to anakinra in patients with recurrent pericarditis.

AIM: Anakinra, an anti IL-1 agent targeting IL-1 alfa and beta, is available for the treatment of recurrent pericarditis in cases with corticosteroid dependence and colchicine resistance after failure of conventional therapies. However, it is unclear if the combination with colchicine, a non-specific inhibitor of the inflammasome targeting the same inflammatory pathway of IL-1, could provide additional benefit to prevent further recurrences. The aim of the present observational study is to assess whether the addition of colchicine on top of anakinra could prolong the time to first recurrence and prevent recurrences better than anakinra alone. METHODS: International, all-comers, multicentre, retrospective observational cohort study analysing all consecutive patients treated with anakinra for corticosteroid-dependent and colchicine-resistant recurrent pericarditis. The efficacy endpoint was recurrence rate and the time to the first recurrence. RESULTS: A total of 256 patients (mean age 45.0±15.4 years, 65.6% females, 80.9% with idiopathic/viral aetiology) were included. 64 (25.0%) were treated with anakinra as monotherapy while 192 (75.0%) with both anakinra and colchicine. After a follow-up of 12 months, 56 (21.9%) patients had recurrences. Patients treated with colchicine added to anakinra had a lower incidence of recurrences (respectively, 18.8% vs 31.3%; p=0.036) and a longer event-free survival (p=0.025). In multivariable analysis, colchicine use prevented recurrences (HR 0.52, 95% CI 0.29 to 0.91; p=0.021). CONCLUSIONS: The addition of colchicine on top of anakinra treatment could be helpful to reduce recurrences and prolong the recurrence-free survival.

Randomized trial of anakinra plus zinc vs. prednisone for severe alcohol-associated hepatitis.

BACKGROUND & AIMS: Severe alcohol-associated hepatitis (SAH) is associated with high 90-day mortality. Glucocorticoid therapy for 28 days improves 30- but not 90-day survival. We assessed the efficacy and safety of a combination of anakinra, an IL-1 antagonist, plus zinc (A+Z) compared to prednisone using the Day-7 Lille score as a stopping rule in patients with SAH. METHODS: In this phase IIb double-blind randomized trial in adults with SAH and MELD scores of 20-35, participants were randomized to receive either daily anakinra 100 mg subcutaneously for 14 days plus daily zinc sulfate 220 mg orally for 90 days, or daily prednisone 40 mg orally for 30 days. Prednisone or prednisone placebo was stopped if Day-7 Lille score was >0.45. All study drugs were stopped for uncontrolled infection or ≥5 point increase in MELD score. The primary endpoint was overall survival at 90 days. RESULTS: Seventy-three participants were randomized to prednisone and 74 to A+Z. The trial was stopped early after a prespecified interim analysis showed prednisone was associated with higher 90-day overall survival (90% vs. 70%; hazard ratio for death = 0.34, 95% CI 0.14-0.83, p = 0.018) and transplant-free survival (88% vs. 64%; hazard ratio for transplant or death = 0.30, 95% CI 0.13-0.69, p = 0.004) than A+Z. Acute kidney injury was more frequent with A+Z (45%) than prednisone (22%) (p = 0.001), but rates of infection were similar (31% in A+Z vs. 27% in prednisone, p = 0.389). CONCLUSIONS: Participants with SAH treated with prednisone using the Day-7 Lille score as a stopping rule had significantly higher overall and transplant-free 90-day survival and lower incidence of acute kidney injury than those treated with A+Z. IMPACT AND IMPLICATIONS: There is no approved treatment for severe alcohol-associated hepatitis (SAH). In this double-blind randomized trial, patients with SAH treated with prednisone using the Lille stopping rule on Day 7 had higher 90-day overall and transplant-free survival and lower rates of acute kidney injury compared to patients treated with a combination of anakinra and zinc. The data support continued use of glucocorticoids for patients with SAH, with treatment discontinuation for those with a Lille score >0.45 on Day 7. TRIAL REGISTRATION: NCT04072822.

Using Machine Learning to Determine a Suitable Patient Population for Anakinra for the Treatment of COVID-19 Under the Emergency Use Authorization.

A randomized, double-blind, placebo-controlled study (SAVEMORE trial) provided data to support an Emergency Use Authorization (EUA) of anakinra in hospitalized adults with positive results of direct severe acute respiratory syndrome-coronavirus 2 viral testing with pneumonia requiring supplemental oxygen (low- or high-flow oxygen) who are at risk of progressing to severe respiratory failure and likely to have an elevated plasma soluble urokinase plasminogen activator receptor (suPAR). Currently, the suPAR assay is not commercially available in the United States. An alternative method was needed to identify patients that best reflect the population in the clinical trial selected based on suPAR level ≥ 6 ng/mL at baseline. A machine learning approach based on data from the SAVEMORE trial was used to develop a scoring rule to identify patients who are likely to have a suPAR level ≥ 6 ng/mL at baseline. External validation of the scoring rule was conducted with data from a different trial (SAVE). This clinical scoring rule with high positive predictive value, high specificity, reasonable sensitivity, and biological relevance is expected to identify patients who are likely to have an elevated suPAR level ≥ 6 ng/mL at baseline. As such, it is included in the EUA to identify patients that fall within the authorized population for whom the known and potential benefits outweigh the known and potential risks of anakinra.

The efficacy and safety of interleukin-1 receptor antagonist in stroke patients: A systematic review.

Stroke is the leading cause of disability worldwide, yet there is currently no effective treatment available to mitigate its negative consequences. Pro-inflammatory cytokines, such as interleukin-1 (IL-1), are known to play a crucial role in exacerbating the aftermath of stroke. Thus, it is hypothesized that blocking inflammation and administering anti-inflammatory drugs at an optimal time and dosage may improve the long-term quality of life for stroke patients. This systematic review examines the effectiveness and safety of IL-1 receptor antagonist (IL-1Ra), commercially known as "anakinra," in clinical studies involving the treatment of stroke patients. A comprehensive literature search was conducted until October 2023 to identify relevant studies. The search yielded 1403 articles, out of which 598 were removed due to duplication. After a thorough review of 805 titles and abstracts, 797 articles were further excluded, resulting in 8 studies being included in this systematic review. The findings from all the included studies demonstrate that IL-1Ra is safe for use in acute ischemic and hemorrhagic stroke patients, with no significant adverse events reported. Additionally, biomarkers, clinical assessments, serious adverse events (AEs), and non-serious AEs consistently showed more favorable outcomes in IL-1Ra receiving patients. Stroke elevates the levels of several inflammatory cytokines, however, administration of IL-1RA directly or indirectly modulates these markers and improves some clinical outcomes, suggesting a potential therapeutic benefit of this intervention.

Evaluation of clinical outcomes in systemic juvenile idiopathic arthritis patients treated with biological agents in Turkey: the TURSIS study.

OBJECTIVES: Biological drugs are one of the most effective treatment methods for systemic juvenile idiopathic arthritis (SJIA) and can significantly prevent morbidity and mortality. This study aimed to evaluate the efficacy and safety of biologics in patients with SJIA and provide real-life data that might help improve the outcomes. METHODS: TURSIS was a retrospective multicentre study carried out in patients with SJIA for whom a biological treatment had been initiated between 1st March 2013 and 30th December 2018. Data include patients' characteristics, laboratory-clinical results, outcomes, and safety-related variables. The 24-month follow-up data of the patients and the efficacy and safety of biological drugs were evaluated. RESULTS: 147 patients were enrolled. The clinical course of the disease was as follows; it was monocyclic in 38.1%, polycyclic in 49%, and persistent in 12.9% of patients. First-choice biologics were interleukin (IL)-1 blockers in the majority of patients (56.5%), followed by the anti-IL-6 (25.2%) and anti-TNF-alpha drugs (18.4%). Anakinra was the most preferred biologic agent in patients with macrophage activation syndrome (MAS), and tocilizumab was used more frequently in patients with persistent type (p=0.000 and p=0.003). The most frequent switch rate was seen in patients receiving anakinra (n=40/68, 58.8%), and it was most frequently switched to canakinumab (n=32/40, 80%). Better physician's global assessment scores were achieved in patients treated with anakinra in Month 3, compared to other treatments (p=0.04). CONCLUSIONS: The results of our study support the efficacy of biological drugs in particular anti-IL-1 and anti-IL-6 drugs, in the treatment of SJIA. These treatments resulted in improvement in activity of disease and provide a considerable decrease in the frequency of MAS.

Anakinra in cerebral haemorrhage to target secondary injury resulting from neuroinflammation (ACTION): Study protocol of a phase II randomised clinical trial.

BACKGROUND: Inflammation plays a vital role in the development of secondary brain injury after spontaneous intracerebral haemorrhage (ICH). Interleukin-1 beta is an early pro-inflammatory cytokine and a potential therapeutic target. AIM: To determine the effect of treatment with recombinant human interleukin-1 receptor antagonist anakinra on perihematomal oedema (PHO) formation in patients with spontaneous ICH compared to standard medical management, and investigate whether this effect is dose-dependent. METHODS: ACTION is a phase-II, prospective, randomised, three-armed (1:1:1) trial with open-label treatment and blinded end-point assessment (PROBE) at three hospitals in The Netherlands. We will include 75 patients with a supratentorial spontaneous ICH admitted within 8 h after symptom onset. Participants will receive anakinra in a high dose (loading dose 500 mg intravenously, followed by infusion with 2 mg/kg/h over 72 h; n = 25) or in a low dose (loading dose 100 mg subcutaneously, followed by 100 mg subcutaneous twice daily for 72 h; n = 25), plus standard care. The control group (n = 25) will receive standard medical management. OUTCOMES: Primary outcome is PHO, measured as oedema extension distance on MRI at day 7 ± 1. Secondary outcomes include the safety profile of anakinra, the effect of anakinra on serum inflammation markers, MRI measures of blood brain barrier integrity, and functional outcome at 90 ± 7 days. DISCUSSION: The ACTION trial will provide insight into whether targeting interleukin-1 beta in the early time window after ICH onset could ameliorate secondary brain injury. This may contribute to the development of new treatment options to improve clinical outcome after ICH.

Effectiveness and safety of IL1 inhibition with anakinra in chronic refractory idiopathic myocarditis.

AIM: The aim of this study was to evaluate the effectiveness and safety of the anti-IL-1 receptor anakinra in patients with chronic active myocarditis refractory to standard therapy. METHODS AND RESULTS: In this retrospective, observational study, we enrolled 6 patients with chronically active myocarditis treated with anakinra on-top-of standard treatment. Response to treatment was evaluated at different time points [disease onset (T0), anakinra beginning (T1), three months from anakinra beginning (T2), last available follow-up (T3)], and was assessed by variations in New York Heart Association (NYHA) functional class, laboratory tests [C-reactive protein (CRP), a high-sensitivity cardiac troponin T (cTnT), and Nt-proBNP], left ventricular ejection fraction (LVEF), and cardiac magnetic resonance (CMR) edema or late gadolinium enhancement. The number of premature ventricular complexes (PVCs) at 24-h EKG-recordings was considered in patients with arrhythmic manifestations. No differences were found between T0 and T1 in terms of CRP, Nt-ProBNP, and LVEF. Before anakinra beginning, all patients were still symptomatic. At T2, all patients were symptom-free, in NYHA class I. A significant decrease in CRP (p = 0.03) and a significant improvement in LVEF (p = 0.03) were observed. Sustained arrhythmic manifestations were found in 4 out of 6 patients. In this subgroup, anakinra showed effectiveness in reducing the arrhythmic burden. At T3, the improvement in laboratory values and cardiac function persisted. The arrhythmic burden remained abated. CONCLUSIONS: All patients had a rapid improvement in systemic inflammation, cardiac function, and arrhythmic burden with anti-IL1 therapy, indicating that anakinra may be an effective treatment in chronic active idiopathic myocarditis, refractory to standard treatment.

Anakinra or tocilizumab in patients admitted to hospital with severe covid-19 at high risk of deterioration (IMMCoVA): A randomized, controlled, open-label trial.

BACKGROUND: Anakinra and tocilizumab are used for severe Covid-19, but only one previous randomized controlled trial (RCT) has studied both. We performed a multi-center RCT comparing anakinra or tocilizumab versus usual care (UC) for adults at high risk of deterioration. METHODS: The study was conducted June 2020 to March 2021. Eligibility required ≥ 5 liters/minute of Oxygen to maintain peripheral oxygen saturation at ≥ 93%, CRP > 70 mg/L, ferritin > 500 µg/L and at least two points where one point was awarded for lymphocytes < 1x 109/L; D-dimer ≥ 0.5 mg/L and; lactate dehydrogenase ≥ 8 microkatal/L. Patients were randomly assigned 1:1:1 to receive either a single dose of tocilizumab (8 mg/kg) or anakinra 100 mg IV QID for seven days or UC alone. The primary outcome was time to recovery. RESULTS: Recruitment was ended prematurely when tocilizumab became part of usual care. Out of a planned 195 patients, 77 had been randomized, 27 to UC, 28 to anakinra and 22 to tocilizumab. Median time to recovery was 15, 15 and 11 days. Rate ratio for recovery for UC vs anakinra was 0.91, 0.47 to 1.78, 95% [CI], p = 0.8 and for UC vs tocilizumab 1.13, 0.55 to 2.30; p = 0.7. There were non-significant trends favoring tocilizumab (and to limited degree anakinra) vs UC for some secondary outcomes. Safety profiles did not differ significantly. CONCLUSION: Premature closure of trial precludes firm conclusions. Anakinra or tocilizumab did not significantly shorten time to clinical recovery compared to usual care. (IMMCoVA, NCT04412291, EudraCT: 2020-00174824).

PAPA Syndrome: Challenges in Achieving Long-Term Remission.

For over two decades, the acronym PAPA syndrome has been used to describe an autoinflammatory condition caused by missense mutations in the PSTPIP1 (proline-serine-threonine phosphatase interacting protein 1) gene and clinically characterized by the presence of pyogenic arthritis, pyoderma gangrenosum (PG), and acne (1,2). Due to the involvement of the PSTPIP1 gene in the regulation of innate immunity, mutations of this gene cause abnormal activation of inflammasomes, complexes of NLRP3/ASC/caspase-1 proteins. As a result, production of interleukin-1ß, a key molecule that triggers synthesis of cytokines necessary for the recruitment of neutrophils, is significantly increased (2,3). Additionally, the levels of other pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interferon-γ (INF-γ) and interleukin 17 (IL-7) are also elevated, which further disrupts inflammatory mechanisms in the microenvironment (4). Since hyperproduction of IL-1 and other involved cytokines is the predominant event in the pathogenesis, these molecules are promising targets in the treatment of PAPA syndrome. Corticosteroids and biologics are currently the most commonly used agents for inducing and hastening remission of symptoms (5). A substantial step forward in the treatment of PAPA syndrome has been the introduction of medications blocking the cytokines crucial in the pathogenesis of this disorder, with TNF-α and IL-1 inhibitors being the most frequent choice of such biological therapy (6). We report the case of a 22-year-old male patient with PAPA syndrome who was referred to our department 18 months ago due to exacerbation of skin changes. Initial presentation and subsequent evolution of disease in this patient matched the typical clinical pattern of PAPA syndrome. The first symptoms occurred at the age of two in the form of unspecific joint disease that was diagnosed as juvenile idiopathic arthritis. Subsequently, in the early adolescence the patient presented with new skin changes manifesting as severe acne and persistent pyoderma gangrenosum-like ulcers. At the same time, severity of joint involvement gradually decreased. After the characteristic phenotype of the disease had fully developed, suspicion of possible syndromic origin of symptoms arose. For this reason, genetic analysis was performed as requested by attending pediatricians at the University Clinical Center in Sarajevo, and E250Q mutation of the PSTPIP1 gene was detected. Thus, the diagnosis of PAPA syndrome was confirmed. Throughout the duration of the disease, several types of medication had been introduced in the treatment with varying success. Earliest joint symptoms were alleviated with non-steroidal anti-inflammatory drugs, while repeated courses of corticosteroids were the mainstay of the therapy during a decade-long period. As a consequence of prolonged steroid therapy, growth disorder, among various other side-effects, had been especially pronounced. Acting as a classic steroid-sparing immunosuppressive agent, methotrexate had also been part of the patient's treatment regimen. Lastly, biologics, including both TNF-α and IL-a inhibitors, had been separately administered as the remaining treatment options. However, adalimumab expressed a predominant effect on joint symptoms, whereas re-activation of previously undetected Hepatitis-B infection occurred during the subsequent therapy with anakinra. Due to this adverse reaction, anakinra treatment was discontinued. At the initial examination, the patient presented with multiple erythematous, partially excoriated papules and nodules, along with residual post-inflammatory hyperpigmented patches and scars on the skin of the whole back, chest, shoulders, and upper arms (Figure 1, Figure 2). The presence of postoperative scars on the elbows, resulting from previously performed surgical procedures of persistently affected joints with the goal of achieving pain relief and functional improvement, was also observed. Several smaller ulcers with undermined edges (Figure 3), as well as residual hyperpigmentation and cicatrices (Figure 4) were visible on the lower extremities. Additionally, the patient reported appearance of pustules and non-healing ulcers after minor trauma, which corresponds to the pathergy phenomenon, a common feature of PAPA syndrome. In contrast to the severity of cutaneous changes, the joint symptoms were mild. After thorough assessment of the patient's medical history and current condition, a multi-agent regimen was initiated, consisting of adalimumab, isotretinoin, and prednisone. Regular check-ups during the 12 months of treatment showed that the applied agents stabilized the patient's condition, alleviated more severe and acute skin changes, and slowed down further exacerbation of symptoms. Due to the rarity of PAPA syndrome, data on its treatment is scarce. Official guidelines are non-existing, and available information is based on case reports, case series, and a few smaller retrospective studies (5,7). In general, response to therapy remains inconsistent between patients, despite introduction of novel drugs. Furthermore, single treatment regimens are often not equally effective for all manifestations of the disease, which in a number of cases results in the administration of multi-agent treatment (2). As described in our case report, we opted for a multi-agent regimen not only due to specific individual role of each drug in the treatment of PAPA syndrome but also because of the possible augmented effect of combined therapy. Initially, a short course of systemic corticosteroid (prednisone 30 mg/day for 3 weeks) was introduced in order to alleviate acute symptoms until other agents started showing their effects. The initial dose of administered corticosteroid was gradually tapered by 5 mg every week and soon discontinued. Adalimumab (40 mg every 2 weeks for 12 months) was chosen since its previous administration was without significant adverse effects and with more acceptable end results, unlike therapy with anakinra (8). In addition, TNF-α inhibitors, such as adalimumab, etanercept, and infliximab, have been generally regarded as a more effective treatment option for cutaneous changes, while anakinra, an anti-IL-1 agent, has been more beneficial in alleviating joint symptoms (9-11). Since the skin of our patient was significantly more affected than the joints, adalimumab was a preferred option for biological treatment. Finally, isotretinoin (0.5 mg/kg/day for 6 months) also found a place in our multi-agent therapy plan as a specific, supportive treatment agent for acne (12). Due to the fact that our national health insurance system covered the costs of treatment with TNF-α inhibitors for only 12 months, adalimumab had to be discontinued after the end of this period. Episodes of acute exacerbation that the patient experienced after the cessation of multi-agent regimen were addressed with systemic corticosteroids and symptomatic therapy. Based on case reports, corticosteroids are usually one of the first agents to be administered in patients diagnosed with PAPA syndrome. They are frequently effective in alleviating joint symptoms, but, on the other hand, high doses of corticosteroids can worsen acne lesions (6). Moreover, due to the multiple side-effects of corticosteroids, such as electrolyte abnormalities, hypertension, hyperglycemia, osteoporosis, growth suppression, and adrenal insufficiency (13), a steroid-sparing agent is typically introduced into treatment together with or after corticosteroid therapy. A substantial step forward in the treatment of PAPA syndrome has been achieved with the introduction of medications targeting cytokines crucial in the pathogenesis of this disorder. The two most commonly used groups of such biological drugs have been those that block TNF-α and IL-1. A longer lasting improvement of symptoms has been achieved in a number of cases with both types of agents. Since other medications have often failed to establish long-term control of PAPA syndrome, such effects can be seen as a valuable accomplishment (6,14). Regardless of this observation, the response to treatment still differs between patients. More variable effects have been documented for IL-1 inhibitors, such as anakinra, while TNF-α inhibitors, such as adalimumab, infliximab, and etanercept, have been associated with more steady responses (4,6,10). The inconsistent effect of biologic therapies could be explained by the fact that PSTPIP1 protein is involved in various biochemical processes in different cells of the immune system. Thuse, none of the medications has an adequate spectrum of activity to control all involved immunological pathways (5,15). Overall, due to scarcity of valid information and guidelines, there is an increasing need for multicentric randomized controlled trials that would provide evidence-based data on effective treatment options for PAPA syndrome. Despite the rarity of this disorder, extensive research should be performed in order to discover therapies that could successfully manage all different manifestations of PAPA syndrome. Consequently, such efforts and breakthroughs would lead to decreased mortality and improved quality of life for patients suffering from this debilitating disease. The case described herein shows that PAPA syndrome can remain undiagnosed for longer periods of time, resulting in delayed treatment. Furthermore, the available therapeutic options are not sufficient to achieve long-term remission in many patients. Thus, continuous and comprehensive research is vital for ensuring adequate care of patients with PAPA syndrome.

Anakinra and hepatotoxicity in pediatric rheumatology: a case series.

BACKGROUND: Anakinra is a recombinant interleukin-1 (IL-1) receptor antagonist used in systemic juvenile idiopathic arthritis (sJIA), refractory Kawasaki disease (KD) and cryopyrin-associated autoinflammatory syndrome (CAPS). Anakinra associated hepatotoxicity, while rare, has been described in several cases in daily practice. ​In this case series the authors describe three pediatric patients with this side effect in the setting of severe macrophage activation syndrome (MAS) in KD and sJIA. CASE PRESENTATION: The first patient was a 12-year-old boy who presented with fever, maculo-papular exanthema and polyarthralgia. Tonsillitis, distal limb induration and tender cervical lymph nodes were observed. Erythrocyte-sedimentation rate (ESR), C-reactive protein (CRP), ferritin (11,975 ng/mL), D-dimers (5,98 mg/L FEU) and soluble CD25 (3645 pg/mL) levels were elevated. Exclusion of sepsis / toxic shock syndrome warranted introduction of IV methylprednisolone and immunoglobulin (IG IV), with partial response. A MAS secondary to KD was assumed, and anakinra 2 mg/kg/day was introduced. Twenty days later he developed new-onset nausea and severe cyto-cholestasis, normalizing after 2 months of drug discontinuation. Posterior onset of polyarthritis and evanescent lead to a final diagnosis of sJIA. The second patient was a 2-year-old boy with a 10-day history of fevers, generalized rash, hepatosplenomegaly and strawberry tongue. Leucocytosis with neutrophilia and elevated CRP were observed. Initial treatment with IVIG in the setting of incomplete KD was ineffective. Mild anaemia, leukopenia and very high serum ferritin (maximum 26,128 ng/mL) ensued. Presumptive sJIA associated MAS was treated with IV methylprednisolone and anakinra 2 mg/kg/day, with prompt response. Four weeks later transaminitis was detected, and temporary anakinra suspension led to normalisation of laboratorial values. The third case related to a 4-year-old boy presenting with fever, maculopapular rash and cervical lymphadenopathy. CRP and ESR were elevated, and KD was diagnosed. IVIG and methylprednisolone were initiated with clinical worsening, warranting for anakinra introduction at 2 mg/kg/day. After three weeks, liver enzymes progressively elevated, resolving on 2 weeks of anakinra discontinuation. CONCLUSIONS: To the best of our knowledge, this is the first case series describing anakinra associated hepatotoxicity in pediatric patients with rheumatic diseases other than sJIA, bringing additional insight to therapeutic monitoring in patients undergoing this treatment.

Relapse of colchicine-intolerant, corticosteroid-dependent recurrent idiopathic pericarditis after perigestational discontinuation of anakinra: uncertain safety of anakinra in pregnancy and the need for shared decision-making.

A nulligravid woman in her mid-20s with colchicine-intolerant, steroid-dependent recurrent idiopathic pericarditis was in remission for 2 years on anakinra monotherapy when she had an unplanned pregnancy. Due to very limited and conflicting data, European Alliance of Associations for Rheumatology and American College of Rheumatology guidelines are equivocal on the use of anakinra in pregnancy, emphasising an individualised approach. Anakinra was discontinued but a month later, in the second month of gestation, the patient had an acute pericarditis flare. A multidisciplinary, patient-centred discussion about the competing risks of infection, obstetric complications and fetal malformations with anakinra versus suboptimally managed recurrent acute pericarditis guided the patient to choosing improved symptom control. Chest pain resolved and CRP normalised after daily anakinra injections were resumed. In the second trimester, the patient had mild COVID-19 infection and streptococcal pharyngitis on anakinra. At 34 weeks gestation, the patient went into preterm labour and had a spontaneous vaginal delivery of a healthy neonate.

Efficacy and safety of anti-interleukin-1 in children with colchicine-resistant familial Mediterranean fever.

BACKGROUND: The aim of this study was to evaluate the efficacy and safety of anti-interleukin-1 (IL-1) therapies in colchicine-resistant pediatric patients with familial Mediterranean fever (FMF). METHODS: In this study, we retrospectively evaluated 656 children with FMF and 27 patients who had been treated with anti-IL-1 therapies (anakinra/canakinumab) . Clinical and laboratory features, MEFV gene mutations, treatment responses were investigated. RESULTS: Twenty of the patients were treated with anakinra (the treatment of 6 patients who initially used anakinra was switched to canakinumab in the follow-up period), and 13 patients were treated with canakinumab. Clinical symptom and severity scores decreased in all patients A decrease in acute phase reactants was also observed in patients. A total of 18 (66%) patients had a M694V homozygous mutation, while 24 (89%) patients had a M694V mutation, at least in one allele. CONCLUSIONS: FMF patients with colchicine resistance may progress to amyloidosis. IL-1 antagonist treatment could be used safely with a favorable outcome in pediatric patients with FMF resistance to colchicine therapy and/or who have renal amyloidosis.

Clinical outcomes and safety of anakinra in the treatment of multisystem inflammatory syndrome in children: a single center observational study.

BACKGROUND AND OBJECTIVE: Evidence for the treatment of multisystem inflammatory syndrome in children (MIS-C) is lacking. Anakinra, which targets IL-1-mediated inflammation, is reserved for refractory cases of MIS-C; however, its use in the treatment of MIS-C is not clearly established. PATIENTS AND METHODS: To examine a role for anakinra in MIS-C, we performed a single center observational cohort study of all MIS-C patients diagnosed at our children's hospital from May 15 to November 15, 2020. Demographics, clinical features, diagnostic testing, and cardiac function parameters were compared between MIS-C patients treated with intravenous immunoglobulin (IVIG) monotherapy and IVIG with anakinra (IVIG + anakinra). RESULTS: Among 46 patients with confirmed MIS-C, 32 (70%) were in the IVIG + anakinra group, of which 9 (28%) were also given corticosteroids (CS). No patients were treated with anakinra alone. MIS-C patients in the IVIG + anakinra group were enriched in a CV shock phenotype (p = 0.02), and those with CV shock were treated with higher doses of anakinra for a longer duration. Furthermore, MIS-C patients in the IVIG + anakinra group exhibited improvements in fever and cardiac function with or without CS. No significant adverse events were observed, and no differences in IL-1ß levels were found among MIS-C patients in the IVIG + anakinra group. CONCLUSIONS: Anakinra treatment, which was co-administered with IVIG primarily in patients with severe MIS-C, was associated with improvements in fever and cardiac function, and demonstrated a favorable side-effect profile. These findings suggest a role for adjunctive anakinra in the treatment of severe MIS-C.

CD19 CAR T-cell therapy and prophylactic anakinra in relapsed or refractory lymphoma: phase 2 trial interim results.

In preclinical models, anakinra, an IL-1 receptor antagonist (IL-1Ra), reduced immune effector cell-associated neurotoxicity syndrome (ICANS) without compromising anti-CD19 chimeric antigen receptor (CAR) T-cell efficacy. We initiated a phase 2 clinical trial of anakinra in patients with relapsed/refractory large B-cell lymphoma and mantle cell lymphoma treated with commercial anti-CD19 CAR T-cell therapy. Here we report a non-prespecified interim analysis reporting the final results from cohort 1 in which patients received subcutaneous anakinra from day 2 until at least day 10 post-CAR T-cell infusion. The primary endpoint was the rate of severe (grade ≥3) ICANS. Key secondary endpoints included the rates of all-grade cytokine release syndrome (CRS) and ICANS and overall disease response. Among 31 treated patients, 74% received axicabtagene ciloleucel, 13% received brexucabtagene ciloleucel and 4% received tisagenlecleucel. All-grade ICANS occurred in 19%, and severe ICANS occurred in 9.7% of patients. There were no grade 4 or 5 ICANS events. All-grade CRS occurred in 74%, and severe CRS occurred in 6.4% of patients. The overall disease response rate was 77% with 65% complete response rate. These initial results show that prophylactic anakinra resulted in a low incidence of ICANS in patients with lymphoma receiving anti-CD19 CAR T-cell therapy and support further study of anakinra in immune-related neurotoxicity syndromes.

Phase II randomised, placebo-controlled, clinical trial of interleukin-1 receptor antagonist in intracerebral haemorrhage: BLOcking the Cytokine IL-1 in ICH (BLOC-ICH).

PURPOSE: Recombinant human interleukin-1 receptor antagonist (anakinra) is an anti-inflammatory with efficacy in animal models of stroke. We tested the effect of anakinra on perihaematomal oedema in acute intracerebral haemorrhage (ICH) and explored effects on inflammatory markers. METHODS: We conducted a multicentre, randomised, double-blind, placebo-controlled trial in patients with acute, spontaneous, supratentorial ICH between May 2019 and February 2021. Patients were randomised to 100 mg subcutaneous anakinra within 8 h of onset, followed by five, 12-hourly, 100 mg subcutaneous injections, or matched placebo. Primary outcome was oedema extension distance (OED) on a 72 h CT scan. Secondary outcomes included plasma C-reactive protein (CRP) and interleukin-6 (IL-6). FINDINGS: 25 patients (target = 80) were recruited, 14 randomised to anakinra, 11 to placebo. Mean age was 67 and 52% were male. The anakinra group had higher median baseline ICH volume (12.6 ml, interquartile range[IQR]:4.8-17.9) versus placebo (5.5 ml, IQR:2.1-10.9). Adjusting for baseline, 72 h OED was not significantly different between groups (mean difference OED anakinra vs placebo -0.05 cm, 95% confidence interval [CI]: -0.17-0.06, p = 0.336). There was no significant difference in area-under-the-curve to Day 4 for IL-6 and CRP, but a post-hoc analysis demonstrated IL-6 was 56% (95% CI: 2%-80%) lower at Day 2 with anakinra. There were 10 and 2 serious adverse events in anakinra and placebo groups, respectively, none attributed to anakinra. CONCLUSION: We describe feasibility for delivering anakinra in acute ICH and provide preliminary safety data. We lacked power to test for effects on oedema thus further trials will be required.

Anakinra versus etoposide-based therapy added to high-dose steroids for the treatment of secondary hemophagocytic lymphohistiocytosis.

OBJECTIVE: Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening, hyperinflammatory syndrome usually treated with high-dose steroids (HDS), often complemented with adjunct therapies, such as etoposide (HLH-94 protocol). Anakinra has been reported to effectively treat HLH; however, has not been comparatively examined with etoposide-based therapies. We sought to evaluate the effectiveness and durability of these treatment approaches. METHODS: We performed a retrospective analysis of all adult patients diagnosed with secondary HLH between January 2011 and November 2022 who received anakinra and HDS, the HLH-94 protocol, HDS alone, or supportive care. RESULTS: Thirty adult patients with secondary HLH were included. Cumulative incidence (CI) of response at 30 days was 83.3%, 60%, and 36.4% for patients treated with anakinra, the HLH-94 protocol, and HDS alone, respectively. CI of relapse at 1 year was 50%, 33.3%, and 0% with the HLH-94 protocol, HDS, and anakinra and HDS, respectively. Overall survival at 1 year was higher with anakinra and HDS compared to the HLH-94 protocol, yet was not statistically significant (77.8% vs. 33.3%; hazard ratio: 0.29; p = .25). CONCLUSION: Treatment with anakinra and HDS in adults with secondary HLH was associated with higher response rates with longer survival compared with alternative therapies and should be further investigated in this setting.