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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.
22nd June 2023
The use of biologics in women with psoriasis who are either pregnant or planning to conceive is not associated with an increased risk of miscarriage, abortion or congenital malformations, according to the findings of a recent study.
The available literature suggests that psoriasis improves during pregnancy although there is a slight risk of a disease flare following delivery. Although biologics are used for patients with moderate to severe psoriasis, the continued use of biologic therapy in pregnancy is a difficult decision to make because of the lack of safety data. Moreover, these decisions are further hampered by the fact that pregnant women are invariably excluded from clinical trials using biologics.
With uncertainty over the safety of biologics in pregnancy, in the current study, published in Journal of the European Academy of Dermatology and Venereology, Spanish researchers conducted a systematic review and meta-analysis to examine examine pregnancy outcomes in women with psoriasis exposed to biologics within three months before or during pregnancy. The team also included studies where women were planning to conceive and who were exposed to biologics.
A total of 51 observational studies in women with a mean age of 30.3 years and with 739 pregnancies exposed to approved biologics were included in the analysis. In most cases (70.4%) the biologics were administered during the first trimester, with the most common agent being ustekinumab (36.0%), followed by etanercept (19.3%). However, there were no studies with newer agents such as brodalumab, risankizumab or bimekizumab.
The estimated prevalence of miscarriage was 15.3% (95% CI 12.7 – 18.0) and elective abortions, 10.8% (95% CI 7.7 – 14.3). Congenital malformations occurred in about 3.0% (95% CI 1.6 – 4.8) of live births. These estimates were similar to those reported in the general population.
The researchers concluded that biologics used in psoriasis are safe and pose an acceptable risk to foetuses and neonates.
24th August 2021
Psoriasis is best described as a complex, chronic, multifactorial and inflammatory disease characterised by increased proliferation of keratinocyte cells in the skin giving rise to silvery/white plaques. The disease typically presents on extensor surfaces such as the elbows, knees and lower back and there if often involvement of the scalp. The incidence of psoriasis appears to vary across the world, with a recent study noting a wide variation. For instance, the incidence was 30.3 per 100,000 person years in Taiwan but 321 per 100,000 person years in Italy.
Among those with psoriasis, one study of over 9,000 patients, found that just over half (51.8%) had mild disease, with 35.8% and 12.4% having moderate and severe disease respectively. Patients with mild to moderate disease are normally managed with topical therapies, whereas those with moderate to severe disease are increasing treated with biological agents, in particular, monoclonal antibodies. Although the precise cause of psoriasis remains to be determined, several interleukins appear to be important disease drivers, especially the interleukin-17 (IL-17) pathway which includes six similar agents, IL-17A – IL-17F.
Research suggests that two members of the IL-17 family, IL-17A and IL-17F are implicated in autoimmunity and IL17F appears to regulate pro-inflammatory gene expression and which requires the IL-17A receptor, suggesting that both are involved in the pathology of psoriasis. Bimekizumab is the first monoclonal antibody which selectively inhibits both IL-17A and IL-17F and is therefore a potentially important advancement in the management of patients with moderate to severe psoriasis.
Clinical efficacy
The EU approval of bimekizumab was supported by the results of three phase 3 clinical trials, all undertaken in patients with moderate to severe psoriasis. The first, BE READY, randomised 435 patients (4:1) to bimekizumab 320 mg every 4 weeks or placebo. The co-primary endpoint was a PASI90 (i.e., 90% improvement in disease severity compared to baseline) and the proportion of patients achieving a score of 0 (i.e., clear skin) or 1 (almost clear), based on a 5-point investigator global assessment (IGA) score after 16 weeks of treatment.
The results showed that a staggering 91% of those assigned to bimekizumab achieved a PASI90 compared to only 1% in the placebo group. In the BE VIVID trial, 567 patients were randomised to bimekizumab (at the same dosage as the BE READY trial) or this time, ustekinumab 45 or 90 mg every 12 weeks and which is an active comparator or placebo. Once again at week 16 there was a high response in the bimekizumab group with 85% achieving a PASI90 compared to 50% in the ustekinumab. The third trial, BE SURE, enrolled 478 patients who were randomised to either bimekizumab (same dosage as in the other trials) or adalimumab (another active comparator) at a dose of 40 mg every 2 weeks. At week 16, a PASI90 was achieved 85.3% of those using bimekizumab and 57.2% of those given adalimumab.
The most common adverse effects from bimekizumab are upper respiratory tract infections (14.5%) and patients are advised to seek medical advice if they display symptoms suggestive of an infection.
The EU approval applies to all 27 member states as well as Iceland, Liechtenstein and Norway at a dose of 320 mg administered by subcutaneous injections every 4 weeks for week 16 and every 8 weeks thereafter. The drug is currently under review by the US Food and Drug administration.
10th August 2021
Atopic eczema (AE) is a common, chronic, relapsing-remitting skin condition, characterised by inflammation and intense pruritus and which has a substantial impact on quality of life. It affects up to 22.6% of children, whereas the prevalence in adults varies between 1.2 to 17.1%. While the precise cause of AE remains to be clarified, it is driven by pro-inflammatory interleukins (IL) including IL-4 and IL-13. Evidence that these two cytokines have an important role in the pathophysiology comes from studies with the monoclonal antibody dupilumab.
Though dupilumab was the first biologic agent to be used in patients with moderate-to-severe atopic eczema, only just over a third of patients in two of the largest trials achieved the primary endpoint of clear or almost clear skin. Thus, other pathways are likely to be involved in AE and recent work has implicated the Janus Kinase pathway (JAK) in the signalling of several interleukins including IL-4 and IL-13. Upadacitinib is an oral JAK inhibitor which is currently licensed for use in rheumatoid arthritis.
Nevertheless, a recent phase 3 trial in patients with moderate-to-severe AE found that when combined with topical steroids, oral upadacitinib at a dose of either 15 or 30 mg, led to a significant improvement in disease severity in over 60% of patients. While such data highlights that upadacitinib is an effective treatment, what is less clear, is its position in the eczema treatment pathway.
This led a team from Oregon Medical Research Centre, Portland, US, to undertake a randomised trial, comparing upadacitinib with dupilumab. Eligible patients were adults aged 18 to 75 years, diagnosed with AE and who were candidates for systemic treatment, after a failure of topical therapy. All were randomised 1:1 to 30mg of upadacitinib given once daily until week 24 or 300mg dupilumab subcutaneously every 2 weeks (after a 600mg loading dose). The primary outcome was an EASI75, which represents a 75% improvement in disease severity at week 16.
Findings
A total of 348 participants with a mean age of 36.6 years (52.6% male) were randomised to upadacitinib and 344 with the same mean age (56.4% male) to dupilumab. After 16 weeks, 71% using upadacitinib and 61.1% given dupilumab achieved an EASI75 (p = 0.006). In addition, 27.9% using upadacitinib and 7.6% using dupilumab, achieved an EASI100 (p < 0.001), i.e., were completely clear of their eczema. There were also significantly better improvements in measure of itch severity using upadacitinib compared to dupilumab.
Based on these findings, the authors concluded that upadacitinib was well tolerated and provided superior efficacy to dupilumab.
Citation
Blauvelt A et al. Efficacy and Safety of Upadacitinib vs Dupilumab in Adults with Moderate-to-Severe Atopic Dermatitis. A Randomised Clinical Trial. JAMA Dermatol 2021
22nd July 2021
Systemic juvenile idiopathic arthritis (SJIA) is a rare and serious auto-inflammatory disease characterised by joint pain or stiffness, tiredness and blurry vision and which affects 10 – 20% of children with juvenile arthritis. The cause of the condition remains largely unknown and the treatment of SJIA has historically involved the use of large doses of systemic corticosteroids, delivered as mini-pulses and which serves to achieve disease control. Nevertheless, while effective, long-term use of corticosteroids can cause serious side-effects in children including osteoporosis, slowed growth and a greater risk of infections. Studies have shown that in children with SJIA there are elevated levels of interleukins, in particular, interleukin-1 and interleukin-6. Furthermore, in 2012, two studies emerged supporting the use of the biologics canakinumab, which is an anti-interleukin-1 agent and tocilizumab, an anti-interleukin-6, in the management of SJIA. Management guidelines from the American College of Rheumatology in 2013, advocated the use of biologics as a first-line treatment for SJIA and it has been shown that biologic monotherapy is effective, avoiding the need for corticosteroids. However, what is less clear is whether the early introduction of a biologic will reduce the need for corticosteroids among children hospitalised with systemic juvenile idiopathic arthritis. Using a retrospective analysis, a team from the Children’s Hospital of Philadelphia, Division of Rheumatology, Philadelphia, US, sought to determine whether the early use of a biologic would reduce the need for corticosteroids children with SJIA. The team used electronic patient records to extract demographic and treatment data and set the primary outcome as the initiation of corticosteroids during the initial hospital stay for children with SJIA. Participants were then divided into two groups as either biologic initiators or non-initiators.
Findings
A total of 468 children with SJIA were included, of whom 71 were initiated on a biologic, with a mean age of 7 years (57.7% male). The most common agent was an interleukin-1 inhibitor although one received an anti-interleukin-6 agent (tocilizumab). A lower proportion of those given a biologic subsequently received a corticosteroid (36.8% vs 56.9%, biologic initiators vs non-initiators, p = 0.09). There was a non-significant trend towards a reduced odds of receiving a corticosteroid in the biological initiator arm (odds ratio, OR = 0.39, 95% CI 0.13–1.15).
Commenting on these findings, the authors felt that early use of a biologic appeared to reduce the need for concomitant corticosteroid therapy in children with new onset systemic juvenile idiopathic arthritis. They concluded by calling for future studies to provide an evidence base for the use of corticosteroids in children with this condition, given the problems associated with the long-term use of these drugs.
Citation
Peterson RG et al. Effect of first-line biologic initiation on glucocorticoid exposure in children hospitalized with new-onset systemic juvenile idiopathic arthritis: emulation of a pragmatic trial using observational data. Pediatr Rheumatol Online J 2021
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