Granulocyte-macrophage colony-stimulating factor neutralisation in patients with axial spondyloarthritis in the UK (NAMASTE): a randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a proinflammatory cytokine overproduced in several inflammatory and autoimmune diseases, including axial spondyloarthritis. Namilumab is a human IgG1 monoclonal anti-GM-CSF antibody that potently neutralises human GM-CSF. We aimed to assess the efficacy of namilumab in participants with moderate-to-severe active axial spondyloarthritis. METHODS: This proof-of-concept, randomised, double-blind, placebo-controlled, phase 2, Bayesian (NAMASTE) trial was done at nine hospitals in the UK. Participants aged 18-75 years with axial spondyloarthritis, meeting the Assessment in SpondyloArthritis international Society (ASAS) criteria and the ASAS-defined MRI criteria, with active disease as defined by a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), were eligible. Those who had inadequately responded or had intolerance to previous treatment with an anti-TNF agent were included. Participants were randomly assigned (6:1) to receive subcutaneous namilumab 150 mg or placebo at weeks 0, 2, 6, and 10. Participants, site staff (except pharmacy staff), and central study staff were masked to treatment assignment. The primary endpoint was the proportion of participants who had an ASAS ≥20% improvement (ASAS20) clinical response at week 12 in the full analysis set (all randomly assigned participants). This trial is registered with ClinicalTrials.gov (NCT03622658). FINDINGS: From Sept 6, 2018, to July 25, 2019, 60 patients with moderate-to-severe active axial spondyloarthritis were assessed for eligibility and 42 were randomly assigned to receive namilumab (n=36) or placebo (n=six). The mean age of participants was 39·5 years (SD 13·3), 17 were women, 25 were men, 39 were White, and seven had previously received anti-TNF therapy. The primary endpoint was not met. At week 12, the proportion of patients who had an ASAS20 clinical response was lower in the namilumab group (14 of 36) than in the placebo group (three of six; estimated between-group difference 6·8%). The Bayesian posterior probability η was 0·72 (>0·927 suggests high clinical significance). The rates of any treatment-emergent adverse events in the namilumab group were similar to those in the placebo group (31 vs five). INTERPRETATION: Namilumab did not show efficacy compared with placebo in patients with active axial spondyloarthritis, but the treatment was generally well tolerated. FUNDING: Izana Bioscience, NIHR Oxford Biomedical Research Centre (BRC), NIHR Birmingham BRC, and Clinical Research Facility.

Humoral immune response after COVID-19 infection or BNT162b2 vaccine among older adults: evolution over time and protective thresholds.

The objectives of this study were to assess the dynamics of the SARS-CoV-2 anti-RBD-IgG response over time among older people after COVID-19 infection or vaccination and its comparison with indicative levels of protection. Geriatric patients with SARS-CoV-2 serological test results were included and divided into three groups. A vaccine group (n = 34), a group of natural COVID-19 infection (n = 32), and a group who contracted COVID-19 less than 15 days after the first injection (n = 17). Eighty-three patients were included; the median age with IQR was 87 (81-91) years. In the vaccine group at 1 month since the first vaccination, the median titer of anti-RBD-IgG was 620 (217-1874) BAU/ml with 87% of patients above the theoretical protective threshold of 141 BAU/ml according to Dimeglio et al. (J Infec. 84(2):248-88, [7]). Seven months after the first vaccination, this titer decreased to 30 (19-58) BAU/ml with 9.5% of patients > 141 BAU/ml. In the natural COVID-19 infection group, at 1 month since the date of first symptom onset, the median titer was 798 (325-1320) BAU/ml with 86.7% of patients > 141 BAU/ml and fell to 88 (37-385) with 42.9% of patients > 141 BAU/ml at 2 months. The natural infection group was vaccinated 3 months after the infection. Five months after the vaccination cycle, the median titer was 2048 (471-4386) BAU/ml with 83.3% of patients > 141 BAU/ml. This supports the clinical results describing the decrease in vaccine protection over time and suggests that vaccination after infection can maintain significantly higher antibody titer levels for a prolonged period of time.

Novel Therapeutic Targets in Axial Spondyloarthritis.

PURPOSE OF REVIEW: Axial spondyloarthritis remains an area of significant unmet clinical need with only two immune pathways currently targeted by licenced therapies compared to other immune-mediated inflammatory joint disorders such as rheumatoid arthritis where a multitude of therapeutic options are available. This review will look at emerging therapeutic targets in axial spondyloarthritis beyond the neutralisation of IL-17A and TNF by monoclonal antibodies. RECENT FINDINGS: Several promising targets are in various stages of pre-clinical and clinical development in axial spondyloarthritis. These include small molecule approaches to target transcription factors, epigenetic modification and intracellular modulation of cytokine signalling by kinase inhibition. GM-CSF has also emerged as a potential driver of inflammation. SUMMARY: A number of novel and promising therapeutic options are in various stages of development in axial spondyloarthritis. The Janus kinase inhibitors have shown great promise in other immune-mediated inflammatory disorders and will be an exciting addition to the axial spondyloarthritis field as the first oral disease-modifying agents. GM-CSF blockade also shows great promise since antibodies for neutralising this cytokine are safe in patients and have shown efficacy in other immune-mediated inflammatory diseases.

An audit of the use of hydroxychloroquine in rheumatology clinics.

OBJECTIVE: The aim was to audit the use, indications, complications and patient information regarding HCQ treatment in rheumatology clinics in a tertiary referral centre. METHODS: During a 9-month period, we identified all patients prescribed HCQ and attending rheumatology clinics in one hospital. We established: (i) the indication for HCQ; (ii) the prevalence of HCQ overdosing based on absolute body weight (ABW); (iii) documentation of warning of risk of retinal toxicity; (iv) systemic and ocular co-morbidities; (v) ocular symptoms during treatment; and (vi) reasons for stopping HCQ. RESULTS: We identified 427 patients (104 male and 323 female). The cumulative dose of HCQ was lower in RA (median 365 g; range 6-1752 g) compared with SLE (450 g; 66-1788 g) (P = 0.105). The median duration of HCQ therapy was 4 years (range 0.1-13 years); 28% of patients with RA and 29% with SLE continued HCQ beyond 5 years. After adjusting for ABW and renal function, 10% (31/312) had been prescribed doses exceeding recommendations. Formal documentation of counselling on ocular complications was found in only one-third of patients. Three cases of HCQ retinopathy were identified (all of whom had RA). CONCLUSION: HCQ therapy is being used for >5 years in 29% of patients with rheumatic diseases, with higher than recommended doses in ∼10% of patients. We recommend more rigorous scrutiny of the use of HCQ to reduce the risk of retinopathy.