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10th August 2023
Dr Laura Coates, is an NIHR clinician scientist and senior clinical research fellow specialising in psoriatic arthritis at the University of Oxford. Here, she speaks to Rod Tucker about the management of psoriatic arthritis including diagnostic challenges, unmet needs and emerging treatments.
Dr Laura Coates is a clinician and rheumatology researcher who completed her rheumatology training and PhD in the clinical management of psoriatic arthritis (PsA) at the University of Leeds in the Leeds Institute of Rheumatology and Musculoskeletal Medicine. Since 2017, she has worked at the University of Oxford where she leads the rheumatology research group, as well as the early arthritis and PsA service for the NHS.
Her main area of research is clinical, as opposed to laboratory-based, and her main focus is on PsA and the spondyloarthritides, including early diagnosis of PsA and optimal treatment pathways and strategies. She has been actively involved in clinical trials, the development of outcome measures for PsA and precision medicine.
While it is recognised that PsA affects up to 30 per cent of those with psoriasis and tends to occur around 10 years after the appearance of cutaneous symptoms, it can occur at any age. As Dr Coates explains, ‘I’ve had patients from their teens right up to their 80s who’ve developed a new psoriatic arthritis.’
Being an inflammatory-driven condition, treatment seeks to control the inflammation with immunomodulatory agents. While there is currently no known cure, PsA can often be adequately controlled with the right medication.
Unfortunately, many patients experience a delay in receiving their PsA diagnosis. Quite why this is the case is not entirely clear, but Dr Coates believes that there are several possible reasons. Perhaps the biggest, she says, is because psoriasis patients are often unfamiliar with the fact that they are at a higher risk of developing PsA. ‘It would be great if more people with psoriasis were aware of that risk because they would know to seek help earlier and not just sit on it,’ she says.
Although research shows that PsA is more common in patients whose psoriasis is accompanied by either nail or scalp involvement, and there is a definite genetic link, many clinicians may not be aware of these associations. Moreover, far less is known about potential disease triggers, but, as Dr Coates points out: ‘A lot of patients remember a traumatic event, be that physical, like an operation or an injury, or psychological, like moving house or getting a divorce, around the time they developed PsA.’
A further and confounding diagnostic problem, for both patients and their primary care practitioners, is how PsA gives rise to a wide range of symptoms. Typically, most patients experience inflammatory symptoms, Dr Coates explains, but this can literally occur in any joint. In practice, she sees patients with PsA affecting either smaller joints, such as fingers and toes, or larger joints, such as the knees.
Alongside these inflammatory symptoms, up to half of PsA patients experience pain at the point where tendons insert onto the bone – typically the Achilles tendon. Nevertheless, for some, the diagnosis is much easier, particularly where patients present with dactylitis. This is characterised by whole digit swelling and is one of the major features of PsA, although this symptom can be quite variable and even resolve in some patients.
While there are no specific biomarkers for PsA, which further hampers the diagnosis, this might be set to change soon. Dr Coates’ team are about to embark on a European-wide study to monitor those with psoriasis and determine why some of these patients develop PsA. The aim is to enable an earlier intervention.
Another option to reduce the diagnostic delay is for more primary care screening with tools such as the Psoriasis Epidemiology Screening Tool (PEST), which has been recommended in the UK by the National Institute for Health and Care Excellence. However, Dr Coates doesn’t think that this practice is widespread, despite having some merit. ‘It’s not perfect and it can pick up other conditions such as osteoarthritis,’ she says. ‘I’d expect around a third of those with PEST scores that warrant referral do actually have PsA.’
Despite this low specificity, Dr Coates does see some value in screening because it enables rheumatologists to assess patients with a possible onward referral of those with osteoarthritis for physiotherapy, and is therefore ‘not a bad use of our time’.
In fact, in Oxford, the dermatology department routinely PEST screens everyone they see with psoriasis but selectively refers patients. For instance, Dr Coates describes how patients with higher PEST scores would only be referred to her department if they are bothered by joint symptoms.
In a recent priority setting partnership, both clinicians and patients came together to collectively identify areas of unmet need in PsA. This, Dr Coates says, raised a huge number of issues that require attention. For instance, both parties wanted to better understand how to enable earlier diagnosis of the condition and to ascertain if there were subgroups of patients that were more likely to develop PsA.
A further concern was the impact of co-morbidities, such as inflammatory bowel disease, uveitis and an elevated cardiovascular risk, which serve to increase the symptom burden in those with PsA and ultimately affect how the condition is managed.
But a particularly important area for both patients and clinicians was drug therapy, for which there are still many unknowns. As Dr Coates says: ‘We haven’t got a lot of evidence that tells us how to use them. We’ve got a lot of “drug A works better than placebo”, but not had a lot of comparative studies or strategies trials.’
A further uncertainty surrounds the prognosis of PsA, which can be highly variable. In those with significant disease, ‘about a quarter to half of patients will have radiographic damage despite treatment’, after two years, she explains. In contrast, for others with milder disease, PsA waxes and wanes and might only flare if, for example, they become stressed. As a result, while initiating therapy is those with troublesome disease is straightforward, it becomes much more difficult for those with less severe disease and those who only experience intermittent flares.
Among patients at the milder end of the disease spectrum, non-steroidal anti-inflammatory drugs and occasional intra-joint corticosteroids will often suffice. But where the disease becomes more bothersome, disease-modifying antirheumatic drug (DMARD) therapy, with drugs such as methotrexate, will be initiated. As it progresses further, and DMARDs fail to provide satisfactory control, rheumatologists can initiate biologic treatment. But whether or not conventional DMARDs, despite their widespread use, are effective in preventing radiographic damage is unclear.
‘There is limited data for conventional DMARDs on radiographic progression, hence proving that they prevent joint damage is harder,’ notes Dr Coates. In contrast, she describes how there is efficacy data showing that methotrexate reduces swelling and tender joint counts, and patient-reported outcomes, though the quality of the data isn’t particularly strong. But, for other DMARDs, the evidence base is much greater, and she mentions how the best trial data for conventional DMARDs is for newer agents such as leflunomide.
There is a general consensus that interleukin-23 (IL-23) has an important pathophysiological role in PsA. This, combined with good data on the value of the IL-23 inhibitor guselkumab in patients with psoriasis, it seems reasonable to examine the drug in PsA. Research, such as the COSMOS trial, clearly shows that guselkumab is effective in PsA, and Dr Coates was recently involved in a post hoc analysis of trial data, which focused on minimal disease activity. In her analysis, Dr Coates looked at patient responses across different domains – skin, joints, enthesitis, pain, et cetera – and found that guselkumab gave rise to an ‘overall’ treatment response.
While PsA affects peripheral joints, the condition can also affect the spine, which is referred to as axial disease. Whether guselkumab is also effective for this form of the disease is still uncertain. Dr Coates says current evidence shows IL-23 inhibitors are ineffective for this phenotype, but, curiously, when patients were specifically asked about their spinal symptoms, they reported an improvement.
Dr Coates thinks there is a plausible explanation to account for this apparent discrepancy. It’s possible, she explains, that because the back pain questionnaires used are reasonably non-specific, the observed improvements in other domains, such as skin and joints, might have led patients to report an overall positive effect. In other words, a patient’s subjective response to the back pain questions is influenced by the other peripheral disease questions.
To better understand if guselkumab is effective in axial PsA, there is a specific trial in axial PsA underway that will involve magnetic resonance imaging scans. Using the imaging modality, researchers can obtain more definitive evidence of joint inflammation rather than damage, and this data can be used alongside the self-reported patient outcomes.
With preliminary evidence showing that a combination of biologics may be more effective in hard-to-treat cases, this is an active line of current research, although as Dr Coates pointed out, there are potentially higher risks of infection. Consequently, clinicians need to be careful in the selection of which biologics to combine. There are more IL-17 inhibitors – another cytokine with a role in PsA – in the pipeline, with purported benefits such as greater albumin binding. However, Dr Coates is unsure if these purported differences will translate to a difference in clinical practice. Currently, the GRAPPA treatment recommendations consider drugs to be similar within class until there is evidence to the contrary.
Other agents on the horizon include TYK2 inhibitors as well as JAK inhibitors, and there are even nanobody IL-17 inhibitors in development, which may enable greater tissue and tendon penetration. Again, until there is evidence that this modification improves patient outcomes, there is no strong data to choose one drug over another within the same class.
There is little doubt that more treatments will become available for the treatment of PsA in the near future. Although Dr Coates agrees that a wider range of therapeutic options is invaluable for clinicians, gazing into the future, she would prefer to see more studies that focus on how best to use existing therapies and head-to-head trials with active comparators.
Moreover, she sees precision medicine as an equally important goal in PsA. If it becomes possible to utilise serum or tissue biomarkers, this will enable clinicians to tailor treatment and ultimately provide the best possible outcomes for the individual patient.