Highlights of ACR Day 3

9 minute read

PMR, Takayasu's arteritis, GC-induced osteoporois, JAK inhibitors and cytoplasmic sensing are among today's diverse range of highlights.

Our dedicated trainee rheumatologist reporters have outdone themselves, covering a large and diverse range of topics in today’s ACR highlights!

Cytoplasmic sensing during ageing and autoimmunity – by Dr Maxine Isbel

Basic science presentations can be challenging for clinically minded rheumatologists to engage with, but remain an essential arm of medical progress.

In this session, Professor Ann Marshak-Rothstein presented work from one of her PhD students outlining the role of nucleic acid sensors in the pathogenesis of autoimmunity. Although her talk focuses on STING associated vasculopathy with onset in infancy (SAVI), it has broader applications for other disease states including systemic lupus erythematosus.

The professor painstakingly builds a case for re-evaluating the role of type II interferons and T-cell signalling in these conditions and makes a good argument for the idea that these tiny molecular mutations in nucleic acid sensors can have significant impact on the macroscopic disease phenotype. The rarity of SAVI means that this talk is unlikely to receive a wide audience, but would be of interest to those who like to understand the molecular basis of autoimmunity.

Mays Mohammed Salih, PhD candidate in California, followed with her work on the role of HnRNP-A2/B1 in rheumatoid arthritis. Antibodies to this protein – both its native type and citrullinated – are overexpressed in severe or chronic RA, but the significance is uncertain.

Ms Salih built a complex house of cards around a novel mouse model in her presentation, demonstrating that this protein moderates inflammation, complete knockout can be lethal, and macrophage selective knockout can increase inflammatory dysregulation.

Do antibodies to this protein result in tissue specific knockout causing similar dysregulation? This question remains unanswered. Instead, the leap is made into human fibroblast-like synoviocytes cultured in vitro from patients with rheumatoid arthritis, where attenuation of this protein decreases the inflammatory profile observed.

Does this mean that antibodies have an activating role? Or that the antibodies are a result of it being overexpressed and are an attempt to self-regulate? Should we be trying to attenuate this protein in RA? Or should we be trying to bolster its expression in macrophages?

The significance of this session is in the demonstration of excellent scientific exploration, which indicates that HnRNP-A2/B1 or antibodies to it may be involved in RA pathogenesis. Likely decades more work lies ahead before the exact role is established.

  • 12S104. Cytoplasmic Sensing During Aging and Autoimmunity

Dr Maxine Isbel is a Perth-based final year rheumatology trainee and is currently doing a master’s in clinical research.

PMR, Takayasu’s arteritis and glucocorticoid-induced osteoporosis: A tasting board – by Dr Bonnia Liu

Despite having major FOMO during this entire conference, virtual attendance has some pros. I can jump from room to room with the click of a button, and hence today I will be providing a tasting board of topics.

We start off the day strong with Australian representation by our very own Dr Claire Owen, taking us on a journey of imaging in polymyalgia rheumatica (PMR).

PMR has become increasingly acknowledged as a distinct disease entity owing to the recognition of unique anatomical patterns as identified on imaging (US, MRI and FDG-PET/CT). Dr Owen reports on the utility of FDG-PET/CT in identifying symmetrical peritendinous inflammation at the peri-articular shoulders, interspinous region, ischial tuberosities and posteromedial knees, which are highly specific to PMR and distinct from other inflammatory arthritides.

Imaging has also become more important due to the concomitant presence of PMR and large vessel vasculitis (LVV), and more concerningly, subclinical LVV.

An oral abstract by Dr Eugenio De Miguel suggested that 22.8% of PMR patients without symptoms were found to have LVV on imaging. Of note, isolated extracranial LVV formed the greatest proportion of subclinical LVV. These results suggest that we should move away from only thinking about PMR as a clinical diagnosis and consider confirmatory imaging for all clinically suspicious patients.

While on the topic of large vessel vasculitis, I wanted to mention the Curbside Consults session with Dr Haner Direskeneli who provided an overview of vascular imaging in the diagnosis and prognosis of Takayasu’s vasculitis. Conventional angiography is not recommended for diagnosis, instead MRI or FDG-PET/CT are the preferred modalities of choice. However, despite their initial utility, monitoring via imaging is not routine as vascular abnormalities on both MRI and FDG-PET/CT tend to persist despite disease remission.

Apart from diagnosis, what about the consequences of treatment? Now we are all aware of steroid-related side effects including osteoporosis and fracture risk, but perhaps we have underestimated the impact of even low-dose prednisolone bone health.

Dr Giovanni Adami presented a longitudinal cohort study of 884 women with autoimmune disease on prednisolone and the effects on BMD and fractures. Doses as low as prednisolone 2.5mg/day was associated with reduction in BMD and more importantly, increased fractures in patients not on anti-osteoporotic treatment.  For patients on prednisolone doses ≥ 5mg/day, patients still experienced a reduction in BMD despite treatment.  Based on this, I wonder where it is considered “safe” to leave patients on chronic low-dose prednisolone 5mg/day.

Thank you all for your reading, and I hope you can watch some of these excellent sessions online or read the linked abstracts.

Dr Bonnia Liu is a rheumatology fellow and nuclear medicine advanced trainee at Austin Health in Melbourne.

The jury on JAKi and ACR glucocorticoid-induced osteoporosis guidelines – by Dr Sadia Islam

It has been a rollercoaster ride with JAK inhibitors and Dr Jon Giles began his session with the disclaimer that the jury is still not out. Though the evidence is limited and there are few head-to-head trials, the efficacy of JAK inhibitors is established. But what about safety?

The ORAL surveillance safety trial was a phase 4 randomised, open-label non-inferiority trial comparing tofacitinib with TNFi (+ methotrexate) with regard to MACE and malignancy. Patients were over 50 years and had at least one CVD risk factor and no history of malignancy. Following an excellent statistic lesson, Dr Giles summarised the findings. Tofacitinib was not non-inferior to TNFi for both MACE and cancer. Age, higher baseline CVD risk and smoking were all risk factors.

In post-hoc analyses, CVD risk and differential effect versus TNFi was concentrated in those with a history of CAD and aggregate CVD risk, with no differential observed in those without history of CAD. So, when considering whether to treat or not treat with JAK inhibitors, perhaps there is a risk group to focus on.

Real world data was presented in the STAR-RA study which found no difference in hospitalised myocardial infarction/stroke between tofacitinib and TNFi initiated patients. In a subgroup of patients who met criteria for ORAL, the HR was 1.24 for tofacitinib versus TNFi, and met non-inferiority criteria in this significantly larger cohort.

It remains unclear whether these findings apply to other JAK inhibitors and diseases other than RA though studies are underway for baricitinib (RA-BRIDGE and RA-BRANCH).

Incidence of malignancy in ORAL was 1.13 for tofacitinib versus 0.77 for TNFi, with the differential effect primarily for lung and non-melanoma skin cancer. Notably, ORAL excluded those with prior malignancy, so it is unknown whether this carries an additional risk.

With all this data, how do we practically communicate this to our patients so they can be involved in making an informed decision? Dr Giles recommended the NNH as an effective tool to convey risk: NNH for tofacitinib versus TNF inhibitor over 5 years for MACE was 113 and for malignancy was 55. Discussions should be tailored to patients’ demographics and specific risk factors, balanced with anticipated benefits and considerations for screening and risk mitigation.

Next was the updated American College of Rheumatology Guidelines for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis, a stimulating discussion on glucocorticoid-induced osteoporosis from start through to question time.

We were reminded of the significant morbidity and mortality associated with fractures, with a one-year mortality of greater than 20% following a hip fracture, and 80% being unable to perform at least one ADL. The impact of even low dose prednisone <2.5mg daily was highlighted with an RR of 1.55 for vertebral fracture compared to control, increasing to an RR of 5.18 in prednisone >7.5mg daily.

Dr Mary Beth Humphrey gave a succinct summary of the guidelines, first highlighting the recommendation to use the FRAX tool for risk assessment and importantly to adjust according to glucocorticoid dose, particularly for prednisone >7.5mg. This involves multiplying the major osteoporotic fracture risk by 1.15 and the hip fracture risk by 1.2, which can often mean a change in risk categories for patients.

Initial risk assessment included a recommendation for no further assessment in adults aged < 40 years at low risk, which raised the question of why no baseline is recommended if serial BMDs are to be performed.

When switching therapy following a new fracture after 12 months of treatment, it was not recommended to switch from denosumab to a PTH/PTHrP due to transient decrease in hip BMD. Interestingly, both oral or IV bisphosphonates were recommended following denosumab, however we know that data regarding the efficacy and appropriate timing and duration of therapy remains unclear.

Dr Linda Russell provided a case-based discussion for application of the guidelines. A recurring recommendation was against the use of romosozumab/SERMs in people aged < 40 years due to risk of thrombosis, cardiovascular events and death. However, this was a contentious point given the uncertainty in the literature regarding these risks.

Treatment of women of child-bearing potential with oral bisphosphonates or teriparatide was also highlighted, with risedronate having the shortest half-life.

This is a continually evolving field and guidelines provide only guidance. Remaining up to date with emerging literature is one of the most important roles for a clinician in providing optimal care.

Dr Sadia Islam is a final year rheumatology advanced trainee at Royal Prince Alfred Hospital in Sydney.

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