International Delphi Consensus on the Management of AQP4-IgG+ NMOSD: Recommendations for Eculizumab, Inebilizumab, and Satralizumab.

BACKGROUND AND OBJECTIVES: Neuromyelitis optica spectrum disorder (NMOSD) is a rare debilitating autoimmune disease of the CNS. Three monoclonal antibodies were recently approved as maintenance therapies for aquaporin-4 immunoglobulin G (AQP4-IgG)-seropositive NMOSD (eculizumab, inebilizumab, and satralizumab), prompting the need to consider best practice therapeutic decision-making for this indication. Our objective was to develop validated statements for the management of AQP4-IgG-seropositive NMOSD, through an evidence-based Delphi consensus process, with a focus on recommendations for eculizumab, inebilizumab, and satralizumab. METHODS: We recruited an international panel of clinical experts in NMOSD and asked them to complete a questionnaire on NMOSD management. Panel members received a summary of evidence identified through a targeted literature review and provided free-text responses to the questionnaire based on both the data provided and their clinical experience. Responses were used to generate draft statements on NMOSD-related themes. Statements were voted on over a maximum of 3 rounds; participation in at least 1 of the first 2 rounds was mandatory. Panel members anonymously provided their level of agreement (6-point Likert scale) on each statement. Statements that failed to reach a predefined consensus threshold (≥67%) were revised based on feedback and then voted on in the next round. Final statements were those that met the consensus threshold (≥67%). RESULTS: The Delphi panel comprised 24 experts, who completed the Delphi process in November 2021 after 2 voting rounds. In round 1, 23/25 statements reached consensus and were accepted as final. The 2 statements that failed to reach consensus were revised. In round 2, both revised statements reached consensus. Twenty-five statements were agreed in total: 11 on initiation of or switching between eculizumab, inebilizumab, and satralizumab; 3 on monotherapy/combination therapy; 7 on safety and patient population considerations; 3 on biomarkers/patient-reported outcomes; and 1 on research gaps. DISCUSSION: An established consensus method was used to develop statements relevant to the management of AQP4-IgG-seropositive NMOSD. These international statements will be valuable for informing individualized therapeutic decision-making and could form the basis for standardized practice guidelines.

Multiple vaccine and pyridostigmine bromide interactions in the common marmoset Callithrix jacchus: immunological and endocrinological effects.

Following active service during the 1990/1991 Gulf Conflict, a number of UK and US veterans presented with a diverse range of symptoms, collectively known as Gulf Veterans Illnesses (GVI). The administration of vaccines and/or the pretreatment against possible nerve agent poisoning, pyridostigmine bromide (PB), given to Armed Forces personnel during the Gulf Conflict has been implicated as a possible factor in the aetiology of these illnesses. The possibility that adverse health effects may result from the administration of these vaccines (anthrax, pertussis, plague, yellow fever, polio, typhoid, tetanus, hepatitis B, meningococcal meningitis and cholera) and/or PB, have been investigated over an eighteen month period, in a non-human primate model, the common marmoset. This study reports immunological indices, including leukocyte phenotypes, intracellular cytokines IFN-gamma and IL-4 and antibody responses against vaccine antigens. Using human isotyping reagents previously shown to cross react with marmoset immunoglobulins (ibid) it was shown that marmosets responded strongly against anthrax PA and pertussis and weakly against killed whole cell plague, cholera and typhoid. At the end of the study the immune response to a previously unseen T-cell dependent antigen, keyhole limpet haemocyanin (KLH), was examined in order to determine whether immune function had been compromised by the compounds administered. Statistically equivalent, robust antibody responses were measured against KLH in all treatment groups indicating that the immune system had not been compromised by any of the treatments. In addition, urinary cortisol was measured at key points throughout the study as an index of physiological stress which may have been induced by the treatments. There were no effects of treatment on urinary cortisol secretion. With respect to the other immunological indices measured, there were no statistical differences between the treatment groups during the period of the study.

Development of methods to measure humoral immune responses against selected antigens in the common marmoset (Callithrix jacchus) and the effect of pyridostigmine bromide administration.

This methodological study was carried out in preparation for a major long term study, also reported in this volume, which was designed to investigate whether the combination of vaccines and pyridostigmine bromide (PB) could have been responsible for adverse signs and symptoms reported by a number of veterans of the 1990/1991 Gulf conflict. In this context, the marmoset has been used to model aspects of the human immune system. The purposes of this methodological study were to select appropriate immunochemical reagents to measure humoral responses induced in marmosets in response to selected health and hygiene and biological warfare vaccines and to initially assess the effects of PB on the responses recorded. Vaccines were administered at 1/5th of a human dose, and also investigated in combination with the nerve agent pretreatment compound PB. PB dosing was selected to induce an inhibition of erythrocyte acetylcholinesterase by 30%. In order to assess the functionality of the immune system, antibody responses to a neo-antigen (keyhole limpet haemocyanin--KLH), administered some 2 months following the completion of the vaccination schedule, were measured. The present study identified appropriate isotyping reporter reagents which cross-reacted with equivalent marmoset immunoglobulins. Robust antibody responses were identified against anthrax protective antigen (PA), whole cell pertussis vaccine and KLH, while weaker responses were measured against cholera and typhoid vaccines. The killed whole cell plague vaccine induced a response which was at the limit of detection of the assay. Coadministered PB had no discernable effect on immunological responses in this study.

Development of a model of hookworm infection exhibiting salient characteristics of human infection.

Patent and pathologic infections of the human hookworm Necator americanus were established in the common marmoset (Callithrix jacchus). In a pilot study, a laboratory strain of N. americanus was compared with a fresh field isolate. Pathology was more severe in animals infected with a fresh isolate. In all animals, infection was associated with increased total plasma IgE and production of IgG specific to adult worm excretory/secretory (ES) products. Histamine was released by basophils in response to IgE, ES products, and a recombinant hookworm allergen, calreticulin. The pilot study indicated the potential of this animal model of hookworm infection and led us to investigate the consequences of infecting a further cohort with the fresh field isolate. This second study confirmed our initial findings, that it is possible to investigate the human hookworm N. americanus in a model exhibiting many of the characteristics of the immunology of hookworm infection in its definitive host.

Immune response to two different dosing schedules of the anthrax vaccine precipitated (AVP) vaccine.

A pilot study compared the immune response of regular (0, 3, 6, 32 weeks) and extended (0, 10, 13, 32 weeks) schedules of the UK anthrax vaccine (anthrax vaccine precipitated, AVP). Concentrations of antibodies to protective antigen (PA) were higher (p<0.05) among recipients of the extended (n=7) versus regular schedule (n=6) at week 32, and 2 weeks after the second and third vaccinations. Toxin neutralisation assay levels and anti-lethal factor antibodies followed patterns similar to anti-PA antibodies. Extending the interval between the first two AVP vaccinations may produce a stronger immune response, but persistence of this effect needs further study.