Clinical year in review

7 minute read

A highlight of ACR Convergence, here is a selection of the best papers published over the last year – complete with links.

The Clinical Year in Review was presented by Professor Carol Langford of the Cleveland Clinic and covers papers published since November last year.

The publications selected had a direct impact on clinical practice, explored an innovative approach or they helped weigh up risks and benefits – and some studies did all three.

Referencing mainly high impact journals, Professor Langford consulted colleagues for their opinions on which papers should make the cut. She also pointed out that there were many other papers that couldn’t be included due to time constraints.

Low dose, add-on prednisolone in patients with rheumatoid arthritis aged 65+: the pragmatic randomised, double-blind placebo-controlled GLORIA trial (Ann Rheum Dis 2022; 81:925)

The two-year GLORIA trial looked at the benefits and harms of 5mg/day prednisolone added to standard of care in RA patients aged 65 and over. The treatment resulted in a DAS28 0.37 points lower than placebo (p<0.0001) and reduction in joint damage. In terms of harms, more patients in the prednisolone group than the placebo group experienced adverse events, mainly infections, with number needed to harm of 9.5.

“This study provides insights that the practitioner can use in weighing the relative benefits and risks of low dose prednisolone individualised to each rheumatoid arthritis patient in this setting,” concluded Professor Langford.

Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis (NEJM 2022, 386:316)

The ORAL Surveillance study of cardiovascular and cancer risk in RA patients was one of the most talked about studies this year, said Professor Langford.

It found that the risk of MACE and cancers were higher with tofacitinib compared to TNF inhibitors, in terms of incidence rate as well as hazard ratio. Furthermore, it did not meet the non-inferiority criteria. As a result of the study, the FDA revised its indication in RA and added a boxed warning for tofacitinib, baricitinib and upadacitinib.

Risk of major adverse cardiovascular events with tofacitinib versus tumour necrosis factor inhibitors in patients with rheumatoid arthritis with or without a history of atherosclerotic cardiovascular disease: a post hoc analysis from ORAL Surveillance (Ann Rheum Dis 2022, online September 22)

In one of several follow-up analyses of the ORAL Surveillance data, this study looked at patients that had atherosclerotic cardiovascular disease (ASCVD). This group of patients comprised 15% of the total cohort and had a far greater increased risk of MACE (relative to TNFi) compared to patients without ASCVD.

“These results therefore inform shared decision making in that caution with tofacitinib use and rheumatoid arthritis is warranted, particularly when you get someone with a history of atherosclerotic cardiovascular disease, cardiovascular risk factors, a history of prior VTE events or in someone 65 years or older,” said Professor Langford.

A decade of JAK inhibitors: What have we learned and what may be the future? (Arthritis Rheumatol 2021; 12; 2166)

While not a clinical trial, this review paper was chosen for its overview of the evolution of JAK inhibitors and reflection on the opportunities and challenges ahead.

In light of the ORAL Surveillance data, said Professor Langford, “the question that came to mind for me is how should these findings be viewed in relationship to the other JAK inhibitors and other disease settings? There have been new indications and new mechanisms of JAK inhibition approved in the past year, and in thinking about this, I really wanted to learn more about JAK inhibitors.”

A randomized placebo-controlled study of Methotrexate to Increase Response Rates in patients with uncontrolled gOut Receiving pegloticase (MIRROR RCT): Primary efficacy and safety findings (Arthritis Rheumatol 2022, online 13 September)

This RCT examined the current administration of methotrexate to increase pegloticase response rate through the reduction of anti-drug antibodies. Patients were randomised to receive either oral methotrexate or oral placebo added to pegloticase. Patients taking MTX + pegloticase had a mean change in serum urate of -7.6 vs -5.2 for placebo + pegloticase (p<0.0001).

Benefits include improved control of gout and safer use of pegloticase by reducing infusion reactions, but there are potential methotrexate specific side effects, as well as the general effect of immunosuppression, which is not usually an issue in the treatment of gout. Based on these data, the FDA expanded the labelling of pegloticase to include co-administration with methotrexate.

Trial of intravenous immune globulin in dermatomyositis (NEJM 2022; 387:1264)

Patients were randomised to receive 2g/kg IVIG every four weeks or placebo for 16 weeks, after which time both treatment arms went on to open label extension where they received IVIG.

The primary endpoint was a composite total improvement score of 20 or greater at week 16, with no deterioration during that time. This was met in 79% of those who received IVIG, compared to 44% of placebo. However, caution is needed for people at risk of thromboembolic events.

“Based on these data, IVIG received FDA approval for adult dermatomyositis, representing the first approved agent for any form of inflammatory myopathy, and making this more available to our patients,” said Professor Langford.

Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus (Nat Med 2022; 28: 2124)

“I’d like to switch them from one of the oldest treatments in medicine to one of the newest, with a study of anti-CD 19 CAR T cell therapy for refractory systemic lupus erythematosus,” said Professor Langford.

The rationale behind this study was that the deep depletion of CD19+ B cells and tissue plasmablasts could result in an immune reset, which was supported by preclinical studies in lupus-prone mice.

The therapy was administered to five lupus patients and resulted in drug-free remission at 8 months.

However, there are risks, with cytokine release syndrome occurring in 50-90% of treated patients. There are also cost considerations.

Effect of tocilizumab on disease activity in patients with active polymyalgia rheumatica receiving glucocorticoid therapy: A randomised clinical trial (JAMA 2022; 328:1053)

In this study, glucocorticoid-dependent PMR patients, who were unable to decrease below 10mg per day after eight weeks, were administered IV tocilizumab or placebo with a standardised prednisone taper.

The primary endpoint was a composite score of CRP PMR activity scale combined with prednisone, and this was met by 67% of those on tocilizumab versus 31% of a placebo. Tocilizumab was also associated with a lower mean prednisone dose and greater ability to discontinue prednisone.

Professor Langford included two Global Rheumatology Alliance papers:

SARS-CoV-2 infection and COVID-19 outcomes in rheumatic diseases: a systematic literature review and meta-analysis (Arthritis Rheumatol 2022; 74:766)

This review found that the risk of developing infection was 52% higher in patients with RMD compared to the general population, with a higher risk of poor outcome and a 74% increased risk of death.

SARS-CoV-2 breakthrough infection among vaccinated individuals with rheumatic disease: results from the COVID-19 Global Rheumatology Alliance provider registry (RMD Open 2022; 8:e002187)

In this study, the GRA examined 197 COVID infections that occurred in partially or fully vaccinated patients. Almost all of these patients were on immunosuppressive therapy, and over half that required hospitalisation were receiving either a B cell-depleting therapy, or mycophenolate mofetil.

Intramuscular AZD7442 (tixagevimab + cilgavimab) for prevention of Covid-19 (NEJM 2022; 86: 2188)

In this original study of over 5000 adult patients who had an increased risk of an inadequate response to vaccination, or an increased risk of exposure to infection, tixagevimab + cilgavimab (Evusheld, AstraZeneca) was associated with 0.2% risk of COVID infection, compared to 1% for placebo, with a risk reduction of 77%.

“This aspect of pre-exposure prophylaxis joins our prevention measures, including non-pharmacologic and vaccination approaches. It is part of a larger strategy and optimising care, which includes risk assessment, early identification of treatment, with implementation of early treatment, and education for both the patient and the rheumatology practitioner,” said Professor Langford.

“It has been become clear during the course of the covid pandemic, and particularly over the past year, that the rheumatology practitioner has played a central role in advocating for immunocompromised rheumatic disease patients during the covid-19 era.”

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