Role of monoclonal antibody drugs in the treatment of COVID-19

Currently clinicians all around the world are experiencing a pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The clinical presentation of this pathology includes fever, dry cough, fatigue and acute respiratory distress syndrome that can lead to death infected patients. Current studies on coronavirus disease 2019 (COVID-19) continue to highlight the urgent need for an effective therapy. Numerous therapeutic strategies have been used until now but, to date, there is no specific effective treatment for SARS-CoV-2 infection. Elevated inflammatory cytokines have been reported in patients with COVID-19. Evidence suggests that elevated cytokine levels, reflecting a hyperinflammatory response secondary to SARS-CoV-2 infection, are responsible for multi-organ damage in patients with COVID-19. For these reason, numerous randomized clinical trials are currently underway to explore the effectiveness of biopharmaceutical drugs, such as, interleukin-1 blockers, interleukin-6 inhibitors, Janus kinase inhibitors, in COVID-19. The aim of the present paper is to briefly summarize the pathogenetic rationale and the state of the art of therapeutic strategy blocking hyperinflammation.     

The effect of non–TNF-targeted biologics and small molecules on insulin resistance in inflammatory arthritis

Inflammatory arthritides are chronic diseases characterised by an increase in cardiovascular risk, largely attributable to the synergy between high-grade systemic inflammation and an elevated prevalence of traditional cardiovascular risk factors. Amongst the latter, insulin resistance and type 2 diabetes (T2D) play a key position. Previous studies demonstrated a potential insulin-sensitizing effect of anti-TNF biologic medications. For converse, less is known about the role of newer biologics or small molecules. For this reason, we performed a systematic review of the literature in order to identify the available data on the effect on insulin resistance of non-TNF targeting biologics and small molecules approved for the treatment of inflammatory arthritides. The search strategy initially retrieved 486 records of which only 10 articles were selected for inclusion in the final review. According to the available evidence, some of the newest molecules, in particular tocilizumab and abatacept, may have a role in improving insulin sensitivity; for converse, anakinra-mediated effect on glucose metabolism may exploit different facets of T2D pathophysiology, such as the preservation of beta-cell function. However, the data available on this issue are largely inconsistent and future, adequately designed studies are still needed to clarify the differential impact of novel therapeutics on individual pathophysiological features of T2D and other emerging cardiovascular risk factors.     

New antirheumatic drugs: any real added value? A critical overview of regulatory criteria for their marketing approval

Objective

Rheumatoid arthritis (RA) is a systemic autoimmune disorder causing chronic polyarticular synovial inflammation and progressive joint damage. New anti-rheumatic drugs, such as leflunomide, infliximab, etanercept, adalimumab and anakinra, have recently become available. The aim of this paper is to summarize and critically evaluate the type of studies and clinical endpoints accepted by the European Medicines Agency (EMEA) to approve these new drugs.

Materials and methods

Information regarding the approval of antirheumatic drugs was obtained from European Public Assessment Reports (EPARs) and published pivotal studies.

Results

Leflunomide is the only non-biological disease-modifying anti-rheumatic drug (DMARD) to receive recent approval for RA treatment, but strong evidence of its superiority over conventional therapies is lacking. Anakinra in combination with methotrexate received approval as a DMARD for RA on the basis of two pivotal trials in which American College of Rheumatology response criteria (ACR 20 response) were used as the sole primary endpoint. For easier demonstration of efficacy, studies leading to first approval of etanercept, infliximab and adalimumab were carried out on non-responders to DMARDs. Once on the market, these drugs gained an extension of the indication to methotrexate-naïve patients. Studies that provided the basis for approval were not adequately designed, given the lack of an active control and the choice of ACR response as the only clinical endpoint. Consequently, only a weak proof of efficacy emerged for the treatment of signs and symptoms of RA, and these drugs failed to show real benefit in slowing radiographic progression. Serious infections, changes in blood cell counts, severe skin and hepatic infections were the main adverse events that emerged from the clinical studies. Therefore, the unconvincing benefit of the new antirheumatic drugs can scarcely outweigh the risk associated with their use. Moreover, the monthly costs in Italy of the new biological preparations are several fold higher than those of the reference drugs.

Conclusions

Recently approved anti-RA products should be a therapeutic option only for patients refractory to conventional drugs.

     

A variant Muckle-Wells syndrome with a novel mutation in<Emphasis Type="Italic"> CIAS1</Emphasis> gene responding to anakinra

Muckle-Wells syndrome (MWS) is a subset of autoinflammatory diseases. It is characterized by recurrent inflammatory crises associated with fever, abdominal pain, persistent urticaria, arthralgia, sensorineural deafness, and possible development of multiorgan amyloid A protein (AA)-type amyloidosis. Mutations in the CIAS1 gene have been reported in MWS. Interleukin 1B (IL-1B) probably plays a major role in the pathophysiology of the disease, and IL-1B blockade may be therapeutic for this syndrome. We report here a Turkish child with MWS treated with anakinra. A novel mutation (I480F) was identified in exon 3 of the CIAS1 gene in this patient. The resolution of inflammatory symptoms, normalization of serological values, and improvement in hearing was noted with anakinra treatment.     

Anakinra in the treatment of polyarticular-course juvenile rheumatoid arthritis: safety and preliminary efficacy results of a randomized multicenter study

This study assessed the safety and preliminary efficacy of the interleukin-1 receptor antagonist anakinra in patients with polyarticular-course juvenile rheumatoid arthritis (JRA). Eighty-six patients entered a 12-week open-label run-in phase (1 mg/kg anakinra daily, ≤100 mg/day). Fifty responders were randomized to anakinra or placebo in a 16-week blinded phase, followed by a 12-month open-label extension (N = 44). Due to low enrollment, the primary endpoint was changed from efficacy to safety. The incidence and nature of adverse events were similar across all study phases, with the exception of injection site reactions, which were mild to moderate and decreased with time. Anakinra produced a nonsignificant (P = 0.11) reduction in disease flares compared with placebo. When normalized to 1 mg/kg dose, anakinra plasma concentrations were similar to values in adult patients with rheumatoid arthritis. These results indicate that anakinra 1 mg/kg once daily (≤100 mg/day) is safe and well tolerated in patients with JRA.     

Hydrocephalus in CINCA syndrome treated with anakinra

Introduction Chronic infantile neurologic, cutaneous, articular (CINCA) syndrome is a rare congenital autoinflammatory disease characterized by neonatal-onset chronic meningitis, hydrocephalus, sensorineural hearing loss, persistent urticarial rash, deforming arthritis, and recurrent fever. This clinical entity is believed to result from dysregulation of cytokine production. No recommended treatment protocol exists so far for CINCA syndrome.Case report We report a 7-year-old child affected with CINCA syndrome in whom no therapy had resulted effective. Anakinra, an interleukin-1-receptor antagonist, was administered in a 1-year period with complete inflammatory symptom remission and dramatically ameliorated laboratory tests. This optimal response has been supported by the demonstration of a stabilized hydrocephalus upon magnetic resonance imaging and by an overall improvement of the neurodevelopmental issues.Discussion This paper emphasizes and discusses the medical approach with anakinra in CINCA syndrome presenting with hydrocephalus in which a consistent control of the neurological picture can be obtained.     

Approach to the patients with inadequate response to colchicine in familial Mediterranean fever

Familial Mediterranean fever (FMF) is the most common form of monogenic autoinflammatory conditions, and response to colchicine has been considered as one of its distinctive features among other hereditary periodic fever disorders. Prophylactic colchicine has been shown to be effective in the prevention of inflammatory attacks and development of amyloidosis. However, the highest tolerable doses of colchicine may not be adequate enough to manage these goals in approximately 5% of FMF patients. Inadequate response to colchicine in fully compliant FMF patients may be associated with genetic and/or environmental factors affecting disease severity and colchicine bioavailability. Clarification of the molecular pathogenic mechanisms of FMF has revealed that interleukin-1 beta (IL-1β) cytokine is the most likely target to attack, and several case reports and case series have already documented the efficacy and safety of available anti-IL-1 agents, such as anakinra, rilonacept, and canakinumab in those patients inadequately responding to colchicine. Characterization and early identification of those FMF patients with uncontrolled inflammatory activity have become more important after the availability of new treatment options for the prevention of disease-associated complications and permanent damages.