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.

A meta-analysis of biologic therapies on risk of new or recurrent cancer in patients with rheumatoid arthritis and a prior malignancy.

OBJECTIVES: To explore the risk of new and recurrent cancer in adult RA patients with prior malignancy and subsequently exposed to biologic therapies. METHODS: Separate searches were performed of PubMed, EMBASE and Cochrane Library and conference proceedings for observational studies reporting cancer incidence or recurrence in patients with RA and prior malignancy treated with biologics and conventional synthetic DMARDs (csDMARDs). Mantel-Haenszel fixed-effects method was conducted to calculate relative risk and 95% CI. RESULTS: A total of 12 studies involving 13 598 patients and 32 473 patient-years of follow-up were included (10, 3 and 1 studies for TNF inhibitors [TNFi], rituximab and anakinra, respectively). The crude incidence of new and recurrent cancer per 1000 patient-years were 34.4 for TNFi, 32.3 for rituximab, 32.3 for anakinra and 31.8 for csDMARDs. In the quantitative meta-analysis, biologics were not associated with an increased risk of new or recurrent cancer compared with csDMARDs in patients with RA and prior cancer (TNFi: relative risk = 0.95, 95% CI = 0.83, 1.09; rituximab: relative risk = 0.89, 95% CI = 0.52, 1.53). Secondary analyses of stratification of cancer types, the interval between initiation of TNFi and prior cancer diagnosis, and duration of TNFi exposure, found similar results. CONCLUSION: Compared with csDMARDs, there is no increased risk of developing cancer overall or some specific subtypes in RA patients with a prior cancer receiving biologics. More investigations are warranted to explore the risk of cancer development in individual cancer as well as to determine optimal time to initiate biologic therapy after the diagnosis of cancer or completion of cancer treatment.

Long-term surveillance of biologic therapies in systemic-onset juvenile idiopathic arthritis: data from the German BIKER registry.

OBJECTIVE: Using data from the German Biologics JIA Registry (BIKER), long-term safety of biologics for systemic-onset JIA with regard to adverse events of special interest was assessed. METHODS: Safety assessments were based on adverse event reports after first dose through 90 days after last dose. Rates of adverse event, serious adverse event and 25 predefined adverse events of special interest were analysed. Incidence rates were compared for each biologic against all other biologics combined applying a mixed-effect Poisson model. RESULTS: Of 260 systemic-onset JIA patients in this analysis, 151 patients received etanercept, 109 tocilizumab, 71 anakinra and 51 canakinumab. Patients with etanercept had higher clinical Juvenile Arthritis Disease Activity Score 10 scores, active joint counts and steroid use at therapy start. Serious adverse events were reported with higher frequency in patients receiving canakinumab [20/100 patient years (PY)] and tocilizumab (21/100 PY). Cytopenia and hepatic events occurred with a higher frequency with tocilizumab and canakinumab. Medically important infections were seen more often in patients with IL-6 or IL-1 inhibition. Macrophage activation syndrome occurred in all cohorts with a higher frequency in patients with canakinumab (3.2/100 PY) and tocilizumab (2.5/100 PY) vs anakinra (0.83/100 PY) and etanercept (0.5/100 PY). After adjustment only an elevated risk for infections in anakinra-treated patients remained significant. Three definite malignancies were reported in patients ever exposed to biologics. Two deaths occurred in patients treated with etanercept. CONCLUSION: Surveillance of pharmacotherapy as provided by BIKER is an import approach especially for patients on long-term treatment. Overall, tolerance was acceptable. Differences between several biologics were noted and should be considered in daily patient care.

Interventions for reducing inflammation in familial Mediterranean fever.

BACKGROUND: Familial Mediterranean fever, a hereditary auto-inflammatory disease, mainly affects ethnic groups living in the Mediterranean region. Early studies reported colchicine as a potential drug for preventing attacks of familial Mediterranean fever. For those people who are colchicine-resistant or intolerant, drugs such as rilonacept, anakinra, canakinumab, etanercept, infliximab, thalidomide and interferon-alpha might be beneficial. This is an updated version of the review. OBJECTIVES: To evaluate the efficacy and safety of interventions for reducing inflammation in people with familial Mediterranean fever. SEARCH METHODS: We used detailed search strategies to search the following databases: CENTRAL; MEDLINE; Embase; Chinese Biomedical Literature Database (CBM); China National Knowledge Infrastructure Database (CNKI); Wan Fang; and VIP. In addition, we also searched the clinical trials registries including ClinicalTrials.gov, the International Standard Randomized Controlled Trial Number Register, the WHO International Clinical Trials Registry Platform and the Chinese Clinical Trial Registry, as well as references listed in relevant reports.Date of last search: 21 August 2018. SELECTION CRITERIA: Randomized controlled studies (RCTs) of people diagnosed with familial Mediterranean fever, comparing active interventions (including colchicine, anakinra, rilonacept, canakinumab, etanercept, infliximab, thalidomide, interferon-alpha, ImmunoGuard™ (a herbal dietary supplement) and non-steroidal anti-inflammatory drugs) with placebo or no treatment, or comparing active drugs to each other. DATA COLLECTION AND ANALYSIS: The authors independently selected studies, extracted data and assessed risk of bias. We pooled data to present the risk ratio or mean difference with their 95% confidence intervals. We assessed overall evidence quality according to the GRADE approach. MAIN RESULTS: We included nine RCTs with a total of 249 participants (aged three to 53 years); five were of cross-over and four of parallel design. Six studies used oral colchicine, one used oral ImmunoGuard™ and the remaining two used rilonacept or anakinra as a subcutaneous injection. The duration of each study arm ranged from one to eight months.The three studies of ImmunoGuard™, rilonacept and anakinra were generally well-designed, except for an unclear risk of detection bias in one of these. However, some inadequacy existed in the four older studies on colchicine, which had an unclear risk of selection bias, detection bias and reporting bias, and also a high risk of attrition bias and other potential bias. Neither of the two studies comparing a single to a divided dose of colchicine were adequately blinded, furthermore one study had an unclear risk of selection bias and reporting bias, a high risk of attrition bias and other potential bias.We aimed to report on the number of participants experiencing an attack, the timing of attacks, the prevention of amyloid A amyloidosis, any adverse drug reactions and the response of a number of biochemical markers from the acute phase of an attack, but data were not available for all outcomes across all comparisons.One study (15 participants) reported a significant reduction in the number of people experiencing attacks at three months with 0.6 mg colchicine three times daily (14% versus 100%), risk ratio 0.21 (95% confidence interval 0.05 to 0.95) (low-quality evidence). A further study (22 participants) of 0.5 mg colchicine twice daily showed no significant reduction in the number of participants experiencing attacks at two months (low-quality evidence). A study of rilonacept in individuals who were colchicine-resistant or intolerant (14 participants) also showed no reduction at three months (moderate-quality evidence). Likewise, a study of anakinra given to colchicine-resistant people (25 participants) showed no reduction in the number of participants experiencing an attack at four months (moderate-quality evidence).Three studies reported no significant differences in duration of attacks: one comparing colchicine to placebo (15 participants) (very low-quality evidence); one comparing single-dose colchicine to divided-dose colchicine (90 participants) (moderate-quality evidence); and one comparing rilonacept to placebo (14 participants) (low-quality evidence). Three studies reported no significant differences in the number of days between attacks: two comparing colchicine to placebo (24 participants in total) (very low-quality evidence); and one comparing rilonacept to placebo (14 participants) (low-quality evidence).No study reported on the prevention of amyloid A amyloidosis.One study of colchicine reported loose stools and frequent bowel movements (very low-quality evidence) and a second reported diarrhoea (very low-quality evidence). The rilonacept study reported no significant differences in gastrointestinal symptoms, hypertension, headache, respiratory tract infections, injection site reactions and herpes, compared to placebo (low-quality evidence). The ImmunoGuard study observed no side effects (moderate-quality evidence). The anakinra study reported no significant differences between intervention and placebo, including injection site reaction, headache, presyncope, dyspnea and itching (moderate-quality evidence). When comparing single and divided doses of colchicine, one study reported no difference in adverse events (including anorexia, nausea, diarrhoea, abdominal pain, vomiting and elevated liver enzymes) between groups (moderate-quality evidence) and the second study reported no adverse effects were detected.The rilonacept study reported no significant reduction in acute phase response indicators after three months (low-quality evidence). In the ImmunoGuard™ study, these indicators were not reduced after one month of treatment (moderate-quality evidence). The anakinra study, reported that C-reactive protein was significantly reduced after four months (moderate-quality evidence). One of the single dose versus divided dose colchicine studies reported no significant reduction in acute phase response indicators after eight months (low-quality evidence), while the second study reported no significant reduction in serum amyloid A concentration after six months (moderate-quality evidence). AUTHORS' CONCLUSIONS: There were limited RCTs assessing interventions for people with familial Mediterranean fever. Based on the evidence, three times daily colchicine appears to reduce the number of people experiencing attacks, colchicine single dose and divided dose might not be different for children with familial Mediterranean fever and anakinra might reduce C-reactive protein in colchicine-resistant participants; however, only a few RCTs contributed data for analysis. Further RCTs examining active interventions, not only colchicine, are necessary before a comprehensive conclusion regarding the efficacy and safety of interventions for reducing inflammation in familial Mediterranean fever can be drawn.

Treatment of hidradenitis suppurativa with biologic medications.

Given the absence of significant improvement in the treatment of hidradenitis suppurativa (HS) with traditional medical and surgical therapies, biologics have piqued the interest of research investigators. The efficacy of biologics in the treatment of inflammatory conditions like psoriasis and rheumatoid arthritis is well-documented. More recently, success with biologics has been demonstrated in atopic dermatitis, another dermatological condition associated with inflammatory states. Researchers have begun to probe the utility of biologic agents in less prevalent conditions that feature inflammation as a key characteristic, namely, hidradenitis suppurativa. Five agents in particular adalimumab, anakinra, etanercept, infliximab, and ustekinumab, have been explored in the setting of HS. Results to date put forward adalimumab and infliximab as biologic treatments that can safely be initiated with some expectant efficacy. Other biologic agents require more rigorous examination before they are worthy of addition to the treatment armamentarium.

New therapeutic options in rheumatoid arthritis: a focus on interleukin-6 blockade.

Rheumatoid arthritis (RA), a chronic and incurable autoimmune disease characterized by synovial joint damage and systemic inflammation, often leads to substantial disability and reduced quality of life. Biologics, a class of medication that targets key pathways in the RA inflammatory response, have increased therapeutic options in the past decade. Because several biologics are administered intravenously, specialized training in administration and updates on RA management are increasingly needed. This article reviews the pathogenesis of RA and the biologics newly approved by the US Food and Drug Administration, such as the interleukin-6 inhibitor tocilizumab, including their targets in the inflammatory cascade.

Effect of anakinra on functional status in patients with active rheumatoid arthritis receiving concomitant therapy with traditional disease modifying antirheumatic drugs: evidence from the OMEGA Trial.

OBJECTIVE: To assess changes in functional status in patients with rheumatoid arthritis (RA) receiving the interleukin-1 receptor antagonist anakinra in addition to a disease modifying antirheumatic drug (DMARD). METHODS: In this large, multicenter, open-label, single-arm study, adult patients with RA receiving methotrexate, sulfasalazine, or hydroxychloroquine for > or = 3 months were given anakinra 100 mg once daily for up to 36 weeks. The primary objective was to evaluate changes from baseline to week 36 in the Health Assessment Questionnaire (HAQ) disability index and subscales. Changes in the 28-joint Disease Activity Score (DAS28), proportion of patients meeting European League Against Rheumatism (EULAR) response criteria, and the safety of each combination regimen were also assessed. RESULTS: A total of 1207 patients were enrolled, received > or = 1 dose of anakinra, and were included in the efficacy and safety analyses. A statistically significant change in the HAQ disability index was observed (p = 0.0001); no significant differences were seen among the 3 DMARD groups. A clinically meaningful improvement in HAQ (> 0.22) was observed in 51% of patients. Mean improvement in DAS28 was 1.5 (p < 0.0001), and 64% of patients achieved a good or moderate EULAR response score. Injection site reaction was the most frequently (62%) reported adverse event. The incidence of infections (24%), most commonly respiratory infection, was similar across treatment groups. No notable changes were observed in laboratory findings and vital signs. CONCLUSION: These findings indicate that anakinra 100 mg/day in combination with DMARD therapy safely improved functional status in patients with active RA.

[Rheumatoid arthritis: current status of therapy]. / Actualités thérapeutiques de la polyarthrite rhumatoïde.

Rheumatoid Arthritis (RA) is a frequent chronic inflammatory disease characterized by distal, bilateral and symmetrical lesions, leading to joint distortions and articular destructions. RA can also cause severe extra-articular manifestations associated with a poor prognosis. Recent advances in the field of immunopathology of RA have oriented treatment targeting the pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF alpha), interleukin (IL) and IL6. These biotherapies are considered as an important therapeutic progress in the treatment of RA acting at the level of cellular processes responsible for rheumatoid disease. These new therapies are active not only in controlling the disease inflammatory processes but also to stop the radiological course of RA. These new therapies are however efficient as long as prescribed, their interruption being rapidly followed by a flare-up of RA. Multiple adverse events attributed to anti-TNF-alpha have been described especially severe opportunistic infections and tuberculosis. B cells playing a critical role in sustaining the chronic inflammatory process in RA, targeted depleting B cells therapies have been developed in refractory forms of RA giving promising results. However, before any biotherapy prescription especially of anti-TNF-alpha, an initial screening should be achieved to exclude patients with history of untreated tuberculosis, solid cancers, malignant hemopathies or demyelinating disorders. It is also essential to assure a strict follow-up in patients under biotherapy to detect adverse events that can be sometimes severe. Thus, the ratio benefit/risk must be evaluated before any biotherapy prescription.