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Take a look at a selection of our recent media coverage:
23rd August 2023
An anti-IL17 peptide sequence has demonstrated high clinical efficacy in models of immune-mediated inflammatory conditions, warranting further clinical evaluation.
Researchers from the University of Birmingham, together with colleagues from the University of Naples Federico II, developed a novel anti-IL17 peptide sequence with greater activity and potentially fewer side effects than existing biologic therapies for immune-mediated inflammatory conditions.
Biologic therapies targeting interleukins, such as anti-IL-17, anti-IL12/23 and anti-IL23, have become established therapies in the treatment of immune-mediated inflammatory conditions such as psoriasis, rheumatoid arthritis and inflammatory bowel disease. However, these novel agents often show low therapeutic efficacy and immunogenicity in certain patient subgroups, thereby limiting their effectiveness.
Writing in the Annals of Rheumatic Disease, the researchers set out to improve the coverage and efficacy of antibodies targeting IL-17A and/or IL-17F.
Using murine and human IL-17A/F protein sequences, the researchers identified a bioactive 20-amino acid IL-17A/F-derived peptide that mimicked the pro-inflammatory actions of the full-length proteins.
Once this sequence had been determined, the team generated a novel anti-IL-17 neutralising monoclonal antibody directed against the sequence, which they named Ab-IPL-IL17™.
Using tissue and animal studies, the researchers were able to demonstrate that Ab-IPL-IL-17 was capable of effectively reversing the pro-inflammatory, pro-migratory actions of not only the 20-amino acid peptide sequence but also IL-17A/F.
In addition, when compared with secukinumab – the current gold-standard biologic – the anti-IL17 peptide gave rise to less off-target immune-related effects. There was also no reduction in platelet counts or an increase in the level of lymphocytes.
In a proof-of-concept study for rheumatoid arthritis, the anti-IL17 antibody inhibited the pro-inflammatory actions of chronically inflamed fibroblasts within the rheumatoid joint.
Similarly, using serum samples from treatment naive inflammatory bowel disease patients, their novel antibody was able to deplete plasma IL-17A, suggesting a potential to alleviate pathological pro-inflammatory changes.
The authors described how Ab-IPL-IL-17, which did not generate immunogenicity, lymphocytosis or thrombocytopenia properties, highlighted potential clinical superiority over current therapies.
They called for future clinical trials to address the varying requirements of Ab-IPL-IL17 as an alternative biological therapy for treating patients with immune-mediated inflammatory diseases.
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.
19th July 2023
A series of points to consider to help define the clinical and imaging features of people with psoriasis who transition to psoriatic arthritis (PsA) have been developed by the European Alliance of Associations for Rheumatology (EULAR) in order to identify those who might benefit from a therapeutic intervention.
The fact that psoriasis typically develops some 10 years before PsA, provides an opportunity for clinicians to investigate risk factors and predictors for PsA in those with the skin disease. Now, with the help of both dermatologists and rheumatologists, a EULAR multidisciplinary taskforce of 30 members and from 13 European countries has produced five overarching principles and a total of 10 points to consider.
Published in the Annals of the Rheumatic Diseases, these principles acknowledge that not everyone with psoriasis will go on to develop PsA, and even among those who do develop the arthritis, this can occur at different times. The taskforce also stress the importance of being able to identify specific risk factors for PsA and how these could influence the choice of treatment, which is crucial given that some systemic psoriasis treatments might reduce the risk of transitioning to PsA.
The 10 points highlight that arthralgia, together with abnormalities seen on ultrasound or magnetic resonance imaging scans, represent key elements of subclinical PsA that could serve as short-term predictors. Additionally, the more traditional risk factors for PsA – such as psoriasis severity, obesity and nail involvement – can be seen as more long-term disease predictors.
EULAR suggests standard naming to define the three distinct stages relevant to the prevention of PsA: people with psoriasis at higher risk of PsA, subclinical PsA and clinical PsA. This, the EULAR group felt, was important because in other inflammatory rheumatic musculoskeletal diseases, such as rheumatoid arthritis, the clinical onset is usually preceded by a preclinical phase encompassing arthralgia and immunological or imaging abnormalities, but without a clinical diagnosis.
A definition for early psoriatic arthritis was proposed by EULAR based on the development of joint swelling as a clinical outcome measure for trials of PsA prevention.
EULAR believes that the points to consider will help to define the clinical and imaging features of those with psoriasis that raise the index of suspicion for progression to PsA. Furthermore, these points could be used to identify people who could benefit from a therapeutic intervention to delay or prevent PsA.
An additional and important practice issue, is that clinicians inform patients with psoriasis about the risk of developing PsA and encourage them to report any joint-related symptoms to facilitate early diagnosis. Previous studies have shown that even a diagnostic delay as short as six months can lead to significantly more severe radiographic joint damage, worse physical function and decrease the changes of therapeutic success
17th July 2023
JNJ-77242113 is the first oral peptide able to directly bind to the interleukin-23 (IL-23) receptor, and appears to be effective in moderate to severe plaque psoriasis.
Data presented at the recent 25th World Congress of Dermatology (WCD) from the FRONTIER 1 trial, suggests that JNJ-77242113 (also known as JNJ-2113), a first-in-class oral IL-23 inhibitor, provides a significant improvement in Psoriasis Area Severity Index (PASI) scores compared to a placebo in a dose ranging study.
In the phase 2, randomised, placebo-controlled trial presented at WCD, patients with moderate-to-severe plaque psoriasis were randomised to six different dosing regimens taken either daily (QD) or twice a day (BID) for a total of 16 weeks: 25 mg QD, 50 mg QD, 100 mg QD, or 25 mg BID, 100 mg BID, 100 mg BID or placebo.
The primary outcome was the proportion of patients achieving a 75% improvement in PASI scores at week 16 – known as PASI75. In addition, the team also considered the proportion achieving a PASI90.
At week 16, only 9.3% of participants achieved a PASI75. In contrast, a PASI75 was achieved by 37.2% of those given 25 mg and 58.1% of those with a 50 mg daily dose. The highest proportion of patients achieving a PASI75 was for the 100 mg twice daily dose (78.6%).
In addition, while only 2.3% of placebo patients achieved a PASI90, this occurred with 25.6% of those given the 25 mg dose and 59.5% of those given 100 mg twice daily.
For both PASI75 and PASI90 all comparisons with placebo were statistically significant (nominal p < 0.02).
The proportions of patients with adverse events were similar for the different doses of JNJ-77242113 and the placebo group, mainly Covid-19 and nasopharyngitis with no dose-dependent trends.
A recent study found that 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.
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.
Topical roflumilast is being increasingly trialled for a number of skin conditions but how effective is it, and will it take centre stage in the field of dermatology? Rod Tucker investigates.
Oral roflumilast is licensed for maintenance treatment in severe chronic obstructive pulmonary disease. Its mode of action relates to the suppression of inflammation, but this benefit extends far beyond respiratory diseases.
Roflumilast inhibits the enzyme phosphodiesterase 4 (PDE4), which hydrolyses cyclic adenosine monophosphate (cAMP), a secondary messenger within cells that is involved in many biological processes in the body. With research suggesting that higher levels of cAMP supress inflammation, PDE4 inhibitors effectively suppress the production of inflammatory markers.
PDE4 inhibitors have become a promising class of drugs with a potential role in a number of therapy areas such as pulmonary, dermatological and neurological diseases. To date, there are two further PDE inhibitors available: apremilast, which is an established oral therapy for psoriasis, and crisaborole, a topical agent used to treat atopic eczema.
But how effective is topical roflumilast in the management of skin diseases?
Topical roflumilast 0.3% has gained gained FDA approval for use in patients with plaque psoriasis. In the two trials leading to FDA approval, disease severity was assessed by a score of ‘clear’ or ‘almost clear’ and a two-point improvement on the Investigator Global Assessment (IGA) scale. This endpoint was achieved by 41.5% and 36.7% of patient treated with topical roflumilast compared to 5.8% and 7.1% with placebo.
In addition, roflumilast has also been found to significantly improve symptoms of scalp psoriasis. But, an added bonus for the drug, is that it is also effective and approved for psoriasis affecting intertriginous sites. Management of intertriginous, or inverse, psoriasis, is a therapeutic challenge, as noted by a recent systemic review which concluded that there is a lack of good quality evidence upon which to base treatment recommendations.
Although clinically distinct from psoriasis, seborrhoeic eczema is associated with an inflammatory milieu characterised by several cytokines. In a recent phase 2a, double-blind, vehicle-controlled trial, researchers investigated the efficacy of a roflumilast 0.3% foam in patients with the condition. Participants assigned to roflumilast saw significant improvements in the IGA score (73.8%) compared the the vehicle group (40.9%), and there were also signification reductions in pruritus.
PDE4 inhibition is also a potentially valuable target in atopic eczema, as demonstrated by crisaborole, which is a proven effective treatment. However, a recent turn of events has provided the manufacturer of topical roflumilast, Arcutis Biotherapeutics, with a distinct advantage in the topical treatment of atopic eczema, particularly in Europe.
In the UK, NICE has not provided a recommendation for the use of Pfizer’s crisaborole in atopic eczema, after the manufacturer withdrew its evidence submission. Similarly, in 2022, the marketing authorisation for crisaborole in the EU was withdrawn. As a result, the drug, is not recommended in the 2022 European guidelines on the management of atopic eczema.
Nevertheless, the position adopted by the UK and EU is in sharp contrast to the US, where the most recent iteration of the American Academy of Dermatology guidelines on atopic eczema do include a recommendation to use crisaborole.
Although roflumilast now has an advantage over crisaborole in the European market, initial findings for the drug in atopic eczema were disappointing. The results of a phase 2 proof-of-concept trial using two strengths of the drug (0.15% and 0.05%) found that neither strength improved Eczema Area and Severity Index (EASI) scores compared to the vehicle cream.
In contrast, the most recent data are more encouraging. In an abstract that combined two phase 3 trials in patients with atopic eczema, those assigned to roflumilast 0.15% cream achieved a significantly higher treatment success (p < 0.0001) compared to vehicle in both trials.
Arcutis Biotherapeutics appears to have great ambitions for its drug. Some work with the PDE4 inhibitor apremilast, demonstrated an ability to control the progression of vitiligo. Moreover, given that vitiligo is mediated via oxidative stress and that roflumilast is able to reduce oxidative stress, the drug may also be of value in this condition.
In preliminary work, it was shown that roflumilast enhanced melanin synthesis when combined with forskolin, a cAMP stimulator, but only exhibited a slight influence on melanogenesis when used alone. Although this indicates a potential role in vitiligo, which is reflected on the manufacturer’s website, this is not an active area of research.
Finally, with evidence from a trial demonstrating that apremilast improved disease severity in papulopustular rosacea, a trial of roflumilast in facial papulopustular rosacea is currently recruiting patients.
There is now mounting evidence to suggest that topical roflumilast has the potential to make an important impact on the treatment landscape of psoriasis, seborrhoeic and atopic eczema and possibly rosacea. But exactly where the drug might sit in the treatment ladder for these conditions is uncertain given the absence of studies with active comparators.
Nonetheless, any effective addition to the clinician’s therapeutic armamentarium in the fight against skin diseases is to be welcomed. With Arcutis Biotherapeutics having only just begun its journey with topical roflumilast, it remains to be seen whether the drug will ultimately achieve the status of a dermatological panacea.
6th April 2023
Norwegian researchers have found that oral vitamin D supplementation given throughout the winter months to patients with psoriasis, despite increasing serum levels of the vitamin, does not lead to an improvement in disease severity.
One aspect of treatment for psoriasis involves the use of topical vitamin D although whether oral vitamin D is also an effective form of therapy remains to be clarified. One randomised trial concluded that oral vitamin D2 increased both serum vitamin D levels and disease severity.
Nevertheless, in a systematic review of 7 studies (only three of which were quantitative), the authors concluded that a favourable effect of oral vitamin D supplementation in patients with psoriasis could not be verified but called for more randomised trials to address this issue. However, the available studies did not consider a seasonal effect since vitamin D is produced in the skin by the action of UVB radiation.
In the present trial, researchers focused on trying to establish whether oral vitamin D provided during the winter months, given to psoriasis patients with low serum levels of the vitamin, would have a beneficial effect on disease severity.
The study recruited adult patients with active plaque psoriasis and 25-hydroxyvitamin D (25[OH]D) levels of less than 24 ng/mL. Cholecalciferol (oral vitamin D) was given at a loading dose of 100 000 IU, followed by 20 000 IU/week or matching placebo, for a period of 4 months.
The primary outcome was the change in the Psoriasis Area Severity Index (PASI) score, which is a measure of disease severity. The researchers also looked at the change in Dermatology Life Quality Index scores.
Oral vitamin D supplementation and psoriasis disease severity
A total of 122 participants with a mean age of 53.6 years (37.7% female) were randomised to either oral supplementation (60) or placebo. The mean baseline PASI score was 3.1.
After 4 months, the mean 25(OH)D level was 29.7 ng/mL and 12.0 in the placebo group. However, while serum levels of vitamin D had increased among participants in the intervention arm, there was no significant difference in the PASI score between the groups (adjusted difference, AD = 0.11, 95% CI -0.23 to 0.45, p = 0.52). In addition, there was no significant difference in DLQI scores between the groups (AD = -0.86, 95% CI -1.9 to 0.19, p = 0.11).
The authors concluded that oral vitamin D supplementation did not affect psoriasis severity and suggested that low baseline severity scores might have accounted for lack of measurable effect.
They also added that since less than half of the intervention group achieved a serum 25(OH)D level of 30 ng/ml, this may have affected the results.
Citation
Jenssen M et al. Effect of Vitamin D Supplementation on Psoriasis Severity in Patients With Lower-Range Serum 25-Hydroxyvitamin D Levels: A Randomized Clinical Trial. JAMA Dermatol 2023
6th January 2023
Philip Mease is a rheumatologist based in Seattle, Washington, and has been in practice since 1982. He spoke to Hospital Healthcare Europe about the management of psoriatic arthritis and findings from the DISCOVER-2 trial.
Philip Mease has an interest in psoriatic arthritis (PsA), which arose after working alongside a dermatology department in Seattle where he treated many patients referred by dermatologists for the treatment of their arthritic component. His work on PsA took off after undertaking a clinical trial with etanercept in 2000.
Since then, he has continued to play an active role in clinical research on PsA, as well as mentoring clinicians and was involved in the establishment of GRAPPA, a multidisciplinary, non-profit, organisation that promotes and disseminates information on PsA.
As Dr Mease explained, ‘psoriatic arthritis is a condition that occurs in people with psoriasis’ and that in the US and Western Europe, psoriasis occurs in around three out of 100 individuals and, of those, ‘one out of the three will have manifestations of PsA.’ He described how PsA is a unique presentation in that any joint in the body can become inflamed. A key feature of PsA Dr Mease added, was how patients can get inflammation where tendons or ligaments insert into bone. For many, the Achilles tendon is affected and this is referred to as enthesitis and which, he says, ‘can be quite disabling for patients, especially low extremity enthesitis.’ A further hallmark presentation, dactylitis, occurs on fingers or toes in which the whole digit swells, becoming sausage-like, reflecting inflammation in both the synovium and bone. Another area of the bone affected in 40-50% of patients he said, was the spine and whilst quite disabling, he finds this is often missed because of the belief that back pain invariably occurs due to degenerative arthritis of the spine as opposed to an immunologic inflammation.
Given the combination of a painful arthritis and an unsightly skin and nail disease, Dr Mease is unsurprised that such patients experience a significant detriment in their quality of life, characterised by a higher incidence of depression and suicidal ideation than for most other chronic disease.
As Dr Mease explained, rheumatoid arthritis tends to be more common in women and is predominately restricted to inflammation of the synovial lining tissue of the joints and without some of the defining features (e.g. enthesis) of PsA. In contrast, PsA is equigender – occurring equally in males and females – and tends to present in fewer joints. He also noted that PsA rarely occurs in the absence of the cutaneous manifestation of psoriasis that sometimes the arthritis precedes the development of skin-related symptoms. On average, he says, ‘people will develop psoriasis about 10 years before they develop the arthritis manifestations.’
Unfortunately, and unlike rheumatoid arthritis, Dr Mease revealed how there are no specific clinical biomarkers indicative of PsA. Consequently, the diagnosis is a clinical one and rests on the presence of specific symptoms and the presence of concomitant psoriasis.
While there are some biomarkers that are elevated in PsA, none of these are particularly informative. For instance, inflammatory markers such as C-reactive protein are sometimes elevated, but as he says, ‘this only happens in around 40% of the time, even in patients with very active disease.’ Occasionally, he added, a gene marker, HLA b27 is measured when investigating the presence of spinal involvement but again, ‘maybe about 30% of patients with spinal involvement will have the presence of this particular gene marker.’
While disabling, as Dr Mease explained, the symptoms of PsA such as joint pain, stiffness and swelling can vary considerably among sufferers. For some patients, these symptoms can be particularly burdensome, occurring daily, whereas for others, symptoms may persist for several weeks at a time before quiescence. A further complication is PsA is degenerative, resulting in the destruction of bones and joints, leading to constant, debilitating pain.
He believes that PsA can be diagnosed by both dermatologists and rheumatologists although recognises how many dermatologists freely admit to being unable to differentiate between PsA and osteoarthritis or sometimes, might not even enquire about the presence of musculoskeletal symptoms in their psoriasis patients.
With a cosmetically disfiguring skin disease and associated painful joints, the burden upon PsA sufferers is huge, severely impacting on social and occupational activities and ultimately their quality-of-life. Dr Mease discussed how in practice patients become overburdened by heightened levels of pain and fatigue together with social embarrassment due to the visible nature of their skin condition.
Although untreated, PsA becomes degenerative over a period of several years, Dr Mease mentioned how in a patient who first presents with dactylitic digit, ‘we can see within a year the destruction of the joint within that finger or toe.’
Although the presence of psoriasis, particularly severe disease, is known to be linked with a higher risk of cardiovascular disease, the association with PsA is less well defined. Nevertheless, as Dr Mease noted, ‘we know that the deeper the inflammatory burden that the patient has, the greater likelihood of associated cardiovascular risk.’ Moreover, given how there is already a genetically predisposed risk for cardiovascular risk in both PsA and psoriasis patients, he sees it as vital to educate both patients and clinicians about this potential higher cardiovascular risk.
According to Dr Mease, ‘psoriatic arthritis is considered to be an auto-immune disease due to the activation of predominately T lymphocytes but also to some extent, B lymphocyte as well as other immune cells such as natural killer cells.’ Each of these different cells have the capacity to over-produce key pro-inflammatory cytokines including tumour necrosis factor (TNF) and interleukins 17, 23 and, to a lesser extent, interleukin-6. These inflammatory molecules migrate to areas of inflammation and stimulate cells to become overactive. Consequently, these molecules have become a key target for treatment.
While initial management for a psoriasis patient who complains of joint aches and pains might be over-the-counter or prescribed non-steroidal anti-inflammatory agents, by the time they reach a rheumatologist, many will no longer find these drugs to be effective.
While the next step in the UK is the use of immunosuppressants such as methotrexate, Dr Mease described that in the US, recent guidance suggested earlier use of an anti-TNF agent. This he says, is because anti-TNF agents are known to be more effective than immunosuppressants such as methotrexate and help to delay both disease progression and ultimately destruction of joints, making them more cost-effective.
However, Dr Mease depicted how there is a reluctance to use biologics before drugs like methotrexate due to the higher cost of the former agents. Nonetheless, he thinks that this stance may well change in the future after more widespread adoption of biosimilars, which while still expensive, are considerably cheaper than their original reference products and therefore serve to increase patient access to treatment.
Dr Mease described how the overarching aim of the DISCOVER-2 trial was to investigate the ‘safety and efficacy of guselkumab, an IL-23 inhibitor, in treating the various clinical domains of PsA including the ability to inhibit structural damage progression or not.’ The trial itself included over 700 patients with psoriatic arthritis and enabled researchers to document safety and efficacy for the drug and which would form part of the submission required for regulatory approval.
The main efficacy and safety outcomes were assessed after 24 weeks but further assessments were made at 52 and 100 weeks. He stated that an important part of the analysis was the use of non-responder imputation. Using this approach, participants who discontinued therapy for any number of different reasons would be counted as a non-responder.
This was a more stringent test and, as Dr Mease explained, given that ‘three-quarters of the patients had an ACR20 [a composite efficacy measure] response, it was a comment about the efficacy and longevity of the effect of the medication.’
The trial also found how patients responded quickly, with responses seen as early as one month after starting treatment. In addition, Dr Mease described how there was also a climbing response over time, ‘so that an ACR20 response was achieved by about two-thirds of patients at the 24-week mark and by about 50% of patients at the 16-week mark’ and continued to climb as the study continued and were even higher at the 100-week mark.
Dr Mease thinks that the trial showed how treatment with guselkumab not only provides a relatively fast onset of action but also that the response continues to increase over time and probably becomes maximal after 52 weeks. As well as clinical efficacy, Dr Mease described how guselkumab produced a statistically superior response to placebo for all the quality-of-life measures assessed in the trial.
While clearly the response to treatment wanes over time, he noted how biologic registry data, which include thousands of patients, suggests that for this class of drugs, the persistency of response is between 1.5 and 3 years. A further and reassuring point he added was that the emerging registry data tend to mirror the safety profile of agents observed in clinical trials.
Dr Mease also said that there are currently several other drugs being considered for the management of PsA, including interleukin (IL)-17 and -23 inhibitors and TNF inhibitors. Nevertheless, he thinks that IL-23 is a somewhat attractive target for PsA given how blockage of this cytokine is effective against both cutaneous and arthritic symptoms. He mentioned how it was also effective in a subgroup of patients with psoriatic spondylitis in their spine.
Dr Mease described the emergence of therapies with different molecular targets. One intracellular pathway target is tyrosine kinase 2, which is part of the Janus kinase (JAK) family. The use of an inhibitor of this pathway, deucravacitinib, has been shown to be well tolerated and improves disease severity. In addition, two oral JAK inhibitors, tofacitinib and upadacitinib, have already received FDA approval for PsA. Finally, although not currently available, neurokinin 2 inhibitors are under development for the treatment of not only PsA, but also rheumatoid arthritis and lupus.
Dr Mease believes that the last 25 years has witnessed a significant improvement in both the understanding and treatment of PsA and that today, is what he described as a ‘terrific time to treat people with the condition because we can actually often get them into remission or low disease activity.’
17th March 2022
Psoriasis patients report using more analgesics than members of the general public without the disease and this is largely because of an increased level of joint pain. This was the finding of a study by researchers from the Department of Dermatology and Allergy, Copenhagen University Hospitale-Herlev and Gentofte Hospital, Copenhagen, Denmark.
Psoriasis is best defined as a chronic, immune-mediated inflammatory disease and which varies in prevalence around the world ranging from 30.3 per 100 000 person years to 321.0 per 100 000 person years.
Although psoriasis presents clinically as an inflammatory skin condition, it has become recognised that 1 in 4 patients with psoriasis also have an associated and painful inflammatory joint condition, termed psoriatic arthritis.
While the dry, flaky skin elevated psoriatic plaques are often highly pruritic, over recent years, it has become more apparent that skin pain is a frequently reported and bothersome symptom among people with psoriasis.
Indeed, one retrospective analysis of over 4,500 psoriasis patients clearly showed how patients experience pain, finding that two-thirds were co-prescribed non-steroidal anti-inflammatory drugs, 59.5% other analgesics and 45.9% opioids.
What remains unclear however, is why people with psoriasis take analgesics and so for the present study, the Danish team turned to data contained within the Danish Skin Cohort to assess disease burden and the use of analgesics among psoriasis patients with and without psoriatic arthritis (PsA) and for comparative purposes, included a control group without either condition.
Psoriasis patients and use of analgesics
A total of 3169 patients with psoriasis only and a mean age of 59 years (55.8% female) were included along side, 3490 controls and 847 individuals with both psoriasis and PsA.
The median skin and joint pain in the general population was 0 and 2 respectively. In contrast, moderate-to-severe skin pain was reported by 30% of those with PsA and 21% with psoriasis alone (p < 0.0001). In addition, moderate-to-severe joint pain was reported by 69% of those with PsA and 45% of those with only psoriasis (p < 0.0001).
The use of opioid analgesics in the last 12 months was reported by 9% of the control group, 14.2% of those with psoriasis alone but 22.7% of those with both psoriasis and PsA. Using multivariable regression, the authors calculated that only joint pain was significantly associated with the use of analgesics (odds ratio, OR = 3.72, 95% CI 2.69 – 5.14, p < 0.001).
The authors concluded that physicians should pay increased attention to those with psoriasis who report any joint pain in order to further improve their clinical management.
Citation
Loft N et al. Disease burden, symptoms, and use of analgesics in patients with psoriasis with or without psoriatic arthritis: A cross-sectional study J Am Acad Dermatol 2022
7th September 2021
The National Institute for Health and Care Excellence (NICE) has approved the use of the monoclonal antibody Cosentyx (secukinumab) as an option for the treatment of plaque psoriasis in children and young people aged six to 17 years of age. It is only recommended where the psoriasis area and severity index (PASI), which is a measure of disease severity, is greater than 10 (meaning moderate to severe disease) and where other systemic therapies have been unsuccessful. The systemic therapies mentioned in the guidance are ciclosporin, methotrexate, as well as phototherapy, although Cosentyx can also be used in cases where any of these treatments are contra-indicated. In addition, NICE has recommended use of Cosentyx only where the manufacturer provides the drug in line with an agreed commercial arrangement.
The outcome of interest when using Cosentyx is the achievement of a PASI75, i.e., a 75% improvement in disease severity, after 12 weeks of treatment. If such an improvement has not occurred, then NICE recommends stopping Cosentyx. A further point in the guideline is that where a clinician considers that secukinumab is the most appropriate therapy, the least expensive option should be used and it has been increasing recognised that there are huge potential and achievable savings for the NHS through the use of biosimilars,
In making its decision, NICE received information on the comparative clinical efficacy of other biologics used in psoriasis including etanercept, adalimumab and ustekinumab. The committee noted from studies that secukinumab was more effective than etanercept, based on a higher proportion of participants achieving a PASI75 and that the efficacy was comparable with ustekinumab. Although there were no direct comparisons of Cosentyx with adalimumab in the paediatric population, a network meta-analysis submitted by the manufacturer, showed that adalimumab was as effective as ustekinumab. Furthermore, there were no differences in safety outcomes for Cosentyx compared with other similar biologics.
Source. NICE 2021
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