Alex Nowbar’s journal reviews—26 February 2021

Alex Nowbar reviews the latest research from the top medical journals

Immune checkpoint inhibitors in autoimmune disease

Immune checkpoint inhibitors are used to treat advanced melanoma. People with autoimmune disease have historically been excluded from trials of these medications for fear of immune related adverse events, so this Dutch cohort study provides some much needed evidence on the safety of these drugs in people with autoimmune disease. Van der Kooij and colleagues studied 228 people with advanced melanoma and autoimmune disease treated with an immune checkpoint inhibitor compared with 2546 people with advanced melanoma but no autoimmune disease. There was no difference in the incidence of immune related adverse events. There was also no difference in survival with and without an autoimmune disease. This evidence supports the use of immune checkpoint inhibitors in people with autoimmune disease, although we don’t know how bad the autoimmune disease was in the individuals studied. Perhaps people with more severe autoimmune disease were not given the medication, so we still don’t really know how safe this is.

Ann Intern Med doi:10.7326/M20-3419

Vitamin D for covid-19

I am not an expert in vitamin D nor in covid-19, but the connection isn’t intuitive. But when in doubt, do a randomised controlled trial. Murai and colleagues randomised 240 hospital inpatients in Brazil with moderate to severe covid-19 to a one-off dose of 200 000 units of vitamin D in a double-blind fashion. There was no difference in length of hospital stay (the primary endpoint) between groups. This is not to say that vitamin D isn’t vital in immune function or indeed other bodily functions. It just means supplementation in this way was not helpful. One can hypothesise that vitamin D needs to be replaced earlier in the disease course, or even before the infection, but I doubt it.

JAMA doi:10.1001/jama.2020.26848

Moderna’s covid vaccine and variants

Whether covid-19 variants will be resistant to vaccines is the big question of the moment, as the answer determines the world’s short term future. In some senses, only time will tell, but this can be evaluated. Wu and colleagues tested serum from participants who received the Moderna vaccine in the phase I trial. They assessed the neutralising activity of the serum against a number of mutations using a pseudovirus (safer than using real virus). Here, the pseudovirus is recombinant vesicular stomatitis virus—this isn’t an important detail, more cool to know. Serum neutralising activity was not altered with the B.1.1.7 variant (the Kent variant) but may have been reduced with the B.1.351 variant (the South African variant). The conclusion was that further work is needed investigating the South African variant.

N Engl J Med doi:10.1056/NEJMc2102179

What about the Pfizer vaccine?

Lui and colleagues tested serum from 15 participants in the efficacy trial for Pfizer’s vaccine. The neutralising power of the serum was reduced by two thirds against B.1.351 (the South African variant) compared with other forms of the virus. This type of assessment may make immunological sense but is not the same as testing whether recipients of the vaccine are protected from the variant compared with those who got a placebo. This is because the vaccine does more than just generate neutralising antibodies—other immune mechanisms would come into play that weren’t measured in this study. Additionally, it would be valuable to know if the vaccine prevents severe disease from variants as opposed to infections. Perhaps challenge trials will be able to test vaccine efficacy against variants. While challenge trials carry risk, I am proud that the UK is the first country to ethically approve such a trial.

N Engl J Med doi:10.1056/NEJMc2102017

Efficacy for bleeding fibroids?

The LIBERTY trials randomised women with fibroid-associated heavy menstrual bleeding to relugolix combination therapy for six months in a double-blind fashion. Response was defined as volume of menstrual blood loss <80 mL and a ≥50% reduction in volume from baseline. The response rate (which was the primary endpoint) was over 70% with the treatment and less than 20% with placebo, with preservation of bone mineral density and without concerning adverse events. The secondary endpoints also favoured the treatment, including a greater improvement in the Bleeding and Pelvic Discomfort scale score. Relugolix is an oral gonadotropin-releasing hormone receptor antagonist, and it was combined with estradiol and norethindrone acetate (that is, oestrogen and progesterone). Overtly, this is a success for the therapy, but the study design does seem weighted in its favour—the control was placebo rather than other medications that might be considered standard care.

N Engl J Med doi:10.1056/NEJMoa2008283

Alex Nowbar is a clinical research fellow at Imperial College London. Twitter @AlexNowbar