Rare diseases

Hope dries up for abatacept in Sjögren’s syndrome


Despite showing promising results in Sjögren’s syndrome in open-label studies, abatacept has failed to show a significant benefit in the condition when compared with placebo in a randomised controlled trial.

A Dutch study that compared 24 weeks of treatment with abatacept with placebo in 80 adults with primary Sjögren’s syndrome found no significant difference in the primary outcome (change in EULAR Sjögren’s Syndrome Disease Activity Index, ESSDAI).

The patients had a baseline ESSDAI score of 5 or more and these were reduced by −2·4 at week 12 and −1·3 at week 24 by abatacept compared to placebo. However, no significant differences were found in proportions of patients reaching the minimally clinically important change for ESSDAI. The largest decrease in activity was seen in the articular, glandular, and constitutional ESSDAI subdomains. Improvements were seen in some secondary outcomes such as sexual function in female patients with abatacept but not in others such assalivary and tear gland function.

There was also no significant difference in patient-reported outcomes of dryness, fatigue and pain, as measured by the ESSPRI score, although abatacept-treated patients showed slightly larger improvements than placebo .

Writing in the Lancet Rheumatology, the investigators from the ASAP-III study noted that the biological DMARD did inhibit T-cell-dependent B-cell hyperactivity, which has a central role in the pathogenesis of primary Sjögren’s syndrome.

But the lack of effect on active systemic disease suggested that abatacept would not have a role in the treatment of Sjogren’s, except perhaps in subgroups of patients yet to be identified, they concluded.

This view was echoed in a commentary by Professor Benjamin Fisher of the University of Birmingham’s Rheumatology Research Group, who said the ASAP-III trial’s negative results appeared to be the end of the road for abatacept in Sjogrens syndrome.

“Unless future analyses reveal clear histological improvement or subgroups enriched for abatacept response, it is hard to see a way forward for abatacept in Sjögren’s syndrome,” he wrote.

“However, abatacept targets only one of many immune co-stimulation pathways. Given the importance of T-cell activation and B-cell-to-T-cell interactions in Sjögren’s syndrome, these alternative pathways should be actively explored.”

Professor Maureen Rischmueller, a rheumatologist at Queen Elizabeth Hospital Adelaide said the negative findings from two recent phase III trials of abatacept were very disappointing given there are currently no licensed treatments for systemic disease that is present in up to 50% of Sjögren’s syndrome patients.

“In clinical practice unproven therapies are being re-purposed from other indications, such as hydroxychloroquine, methotrexate, leflunomide, low dose steroids, and in severe cases mycophenolate, rituximab, azathioprine or cyclophosphamide,” she said.

However she noted that both studies had shown improvement in biological indices such as rheumatoid factor (RF) and IgG levels, which are independent risk factors for severe systemic disease and the develo​pment of non Hodgkin lymphoma in Sjögren’s syndrome, “implying that benefit might be derived from targeting T cell costimulation in the subset of patients with high RF and IgG.”

And exploratory investigations into the effects of abatacept on other biomarkers and immune cell subsets, including T follicular helper cells, Tregs, and plasmablasts, are being undertaken in samples from both of the phase III studies, and the publication of these results is anticipated to shed more light on this area, and on the immunopathology underlying SjS, said Prof Rischmueller.

“It has also recently been demonstrated in Dr Vanessa Bryant’s lab at WEHI in Melbourne that naive B cells from a subset of patients with Sjögren’s syndrome are hyper-responsive ​to T-independent B cell activation … thus therapies targeting B cells may be more appropriate for this group of patients than T cell costimulation inhibitors,” she added.

According to Prof Rischmueller, a number of promising novel therapies are currently under investigation for Sjögren’s syndrome, including those targeting B cells: inhibitors of Bruton tyrosine kinase, B-cell activating factor (BAFF), and CD20-targeting B cell depletors; and inhibition of T cell co-stimulation with anti-CD40.

“As for SLE, it is crucial that appropriate outcome measures are defined for clinical trials in Sjögren’s syndrome, and to this end Australia will have representation on the first OMERACT Sjogren’s interest group in Colarado Springs in April 2020,” she said.

 

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