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Take a look at a selection of our recent media coverage:

Anti-IL17 peptide shows high clinical efficacy for immune-related inflammatory diseases

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.

Anti-IL17 peptide

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.

Do JAK inhibitors increase the risk of MACE in atopic eczema?

17th August 2023

JAK inhibitors are known to increase the risk of major adverse cardiovascular events when used in rheumatoid arthritis, but does this elevated risk also apply when this class of drugs is used in atopic eczema? Clinical writer Rod Tucker investigates.

Since the 1990s, the treatment of severe rheumatoid arthritis (RA) has centred on biologics such as tumour necrosis factor (TNF) inhibitors. However, a better understanding of cell signalling pathways and, in particular, intracellular signal transduction, led to the development of alternative therapies, one of which being oral Janus kinase (JAK) inhibitors. Several of these have been approved for use in RA since 2011.

What’s more, as JAK inhibitors disrupt intracellular signalling through a variety of cytokine and haematopoietic growth factor receptors, this mode of action suggests the drug class may have a much wider role in a number of immune-mediated inflammatory diseases. As such, approvals for JAK inhibitors in Crohn‘s disease, psoriasis and atopic eczema have been seen in recent years.

JAK inhibitors and MACE in context

Despite their apparent effectiveness in RA, a recent post-marketing study has raised safety concerns over JAK inhibitors compared to TNF inhibitors. The Oral Rheumatoid Arthritis Trial (ORAL) was a randomised, post-authorisation, non-inferiority trial designed to evaluate the safety and efficacy of the JAK inhibitor tofacitinib compared to a TNF inhibitor such as etanercept or adalimumab. It focused on patients with RA who were aged 50 or older and had at least one additional cardiovascular risk factor.

The findings were somewhat disturbing. JAK inhibitor use led to a significantly higher incidence of both major adverse cardiovascular events (MACE) and cancers compared to a TNF inhibitor, even though the efficacies were broadly similar.

The ORAL trial served to highlight how JAK inhibitors may increase the risk of MACE when used in patients with RA who are already at an elevated risk due to their condition. Indeed, a meta-analysis of 24 studies with over 111,000 RA patients estimated a 50% higher risk of cardiovascular mortality.

So, with three JAK inhibitors (upadacitinib, baricitinib and abrocitinib) approved for atopic eczema, and representing an important and promising development for its treatment, should dermatologists be concerned over the risk of MACE when using this class of drugs?

Atopic eczema and the risk of MACE

Before considering whether JAK inhibitors might increase the risk of adverse cardiovascular sequelae in those with atopic eczema, its worth exploring whether atopic eczema, itself an inflammatory condition, is linked to a higher risk of MACE. After all, such a risk is theoretically possible, given the emerging evidence of the pivotal role of inflammation in the development and progression of both cardiac and vascular diseases.

The current evidence of an association between atopic eczema and MACE is equivocal. Some work, for instance, clearly demonstrates that atopic eczema is associated with increased risk of myocardial infarction compared to the general population. In contrast, another study found no such independent association in women.

Nevertheless, pooling data from several studies does suggest a positive relationship. For example, a 2018 meta-analysis of 15 studies, which included over 3.5 million participants, did show that atopic eczema was independently associated with an increased risk of stroke and myocardial infarction, especially in male subjects and those with more severe disease.

In addition, a recent Danish study, looked at what happened to patients over time following a diagnosis of atopic eczema. It included over 40,000 atopic eczema patients and an equal number of matched controls and found that adults were at a significantly higher risk of experiencing a subsequent cardiovascular disease.

Finally, a UK prospective study including 387,439 patients with atopic eczema followed for over five years, concluded that severe active atopic eczema was associated with an increased risk of cardiovascular outcomes.

While prospective studies are subject to confounding, Mendelian randomisation studies, are able to provide an estimate causality without the influence of confounders. One such study showed that asthma and atopic eczema were causal risk factors for heart failure and suggested that the underlying inflammatory nature of both diseases was a major contributory factor.

As ever, things are never that straightforward. In a recent bidirectional Mendelian randomisation study, it was found that there was no robust association between cardiovascular disease and atopic eczema.

JAK inhibitors and MACE in atopic eczema

In trying to establish if there was a higher risk of MACE in patients with atopic eczema prescribed a JAK inhibitor, researchers recently undertook a systematic review and meta-analysis. The findings were published in July 2023 in the British Journal of Dermatology and included phase 2b or 3 randomised controlled trials and controlled cohort studies.

The primary outcome was the occurrence of MACE, which the researchers defined as a composite of acute coronary syndrome (ACS), ischaemic stroke and CV death.

A total of 23 studies were included in the analysis. Very few cases of MACE were found, leading the researchers to suggest that JAK inhibitors may have little-to-no effect on the occurrence of MACE in patients with atopic eczema compared to placebo. However, they did add the caveat that the evidence was uncertain.

In addition, MACE generally occurred in patients at a high cardiovascular risk and not in the younger, healthy patients typically seen in routine clinical practice.

Further and reassuring evidence of the absence of a possible association with MACE comes from real-world studies on the use of JAK inhibitors in atopic eczema. There have been at least four such studies, none of which have identified any cases of MACE, even though some have been conducted in patients with more severe disease.

EMA safety advice

Although patients with atopic eczema may have a higher risk of MACE, this is more likely to occur either in those with severe disease or for patients at a greater risk of cardiovascular disease. Over time, pharmacovigilance data will no doubt shed further light on the level of risk associated with JAK inhibitors.

For now, the European Medicines Agency (EMA) issued advice in January 2023 on the use of JAK inhibitors in all chronic inflammatory disorders, including atopic eczema. This recommended avoiding against the use of a JAK inhibitor in those aged 65 years or above, in patients at an increased risk of major cardiovascular problems, smokers and individuals at a higher risk of cancer, unless there are no suitable alternatives.

For most patients with atopic eczema, JAK inhibitors represent a potentially game-changing addition to a dermatologist’s armamentarium for their treatment. Provided that clinicians heed the current safety guidance, those prescribed a JAK inhibitor for atopic eczema have much to gain but without the attendant risk of MACE.

Long-term opioid use risk in one in three patients with rheumatic and MSK conditions

19th May 2023

Patients with rheumatic and musculoskeletal conditions are particularly vulnerable to long-term opioid use, new research has found.

A study of GP research database between 2006 and 2021 found one in three of those with rheumatoid arthritis or fibromyalgia had received long-term prescriptions for the potentially addictive drugs to manage their pain.

Overall, the team analysed more than 840,000 patient records and looked at different patterns of opioid use depending on frequency and number of prescriptions.

There were 1,081,216 new episodes of opioid use among all patients with just under 17% transitioning to ‘standard’ long-term use, defined as three or more prescriptions within a 90-day period, or more than 90 days supply in the first year.

Another 11% were categorised as having ‘stringent’ opioid prescribing with 10 or more prescriptions over more than 90 days, or 120 plus days of supply in the first year.

The research also found that 22% moved onto ‘broad’ opioid prescriptions which was classed as more than three opioid prescriptions at monthly intervals in the first year.

Reporting the findings in the Annals of Rheumatic Diseases, the team said the highest proportion of long-term users were patients with fibromyalgia—27.5%, 21%, and 34% for standard, stringent and broad prescribing categories.

This was followed by those with rheumatoid arthritis (26%, 18.5%, and 32% respectively) and those with axial spondyloarthritis at 24%, 17%, and 30%.

The results also showed an increasing proportion of patients with systemic lupus erythematosus and fibromyalgia who moved from one opioid prescription to long-term prescribing between 2006 and 2019.

But the converse pattern was true in rheumatoid arthritis with a decreasing trend over the time period, although the researchers noted the overall proportion remained high at 24.5% in 2020.

Calls for opioid use optimisation

A 2019 review by Public Health England, found one in four adults were prescribed medications associated with dependence, including opioids, benzodiazepines and antidepressants.

NICE has since issued guidance on safe prescribing and withdrawal management for addictive drugs.

Dr Joyce Huang, study author and research associate in the Division of Musculoskeletal and Dermatological sciences at the University of Manchester, said: ‘Our study does not intend to stigmatise patients who use opioids.

‘We want to highlight the high frequency of long-term opioid use needs to be optimised and prevent people living with [rheumatic and musculoskeletal disorders] from opioid-related harm.’

Study lead Dr Meghna Jani, senior lecturer at the Centre for Epidemiology Versus Arthritis, said the results show that a ‘considerable proportion of patients’ with these conditions starting opioids for the first time, transition to long-term use that is much higher than people who are starting an opioid for non-cancer pain in general which is around one in seven people.

‘Because long-term opioid therapy is associated with poor health outcomes, these findings warrant vigilance when prescribing these drugs.

‘Long term use is particularly pronounced in fibromyalgia patients, who suffer chronic widespread pain for which there are no disease modifying treatment options. This is also more common than we initially thought, in rheumatoid arthritis and axial spondyloarthritis.’

A version of this story was originally published by our sister publication Pulse.

Inception cohort study revealed that a third of RA patients experienced long-term pain

26th July 2021

Following patients with rheumatoid arthritis (RA) over a 5-year period revealed that over a third continued to experience unacceptable pain.

Rheumatoid arthritis (RA) is an autoimmune disease that causes joint inflammation, pain, stiffness and destruction of articulator bone and cartilage that affects around 51/10,000 people. Treatment involves the use disease-modifying anti-rheumatic agents (DMARDs) but despite this, evidence suggests that patients continue to experience activity limitations and pain, despite reduced levels of inflammation. The persistence of pain has a negative impact on quality of life and leads to fatigue. In fact, it has been suggested that the extent of pain identified by patients at the point of diagnosis can predict the level of fatigue subsequently reported. Hence, a better understanding of the potential predictors of pain early in the disease course, could enable better targeting of pain interventions. In trying to identify the predictors of pain, a team from the Department of Clinical Sciences, Malmo, Lund University, Sweden, turned to data on an inception cohort of patients with RA, recruited between 1995 and 2005, who had been diagnosed with the condition for less than 12 months. A structured examination and data collection programme occurred at inception and then after 6 months, 1, 2 and 5 years. There was no specific treatment protocol and patients were all managed according to standard care. Patient reported outcomes and disease activity measures were collected at each follow-up visit and pain was assessed using a visual analogue scale (VAS), ranging from 0 to 100, with higher scores indicating more severe pain. In addition, a patient global assessment of disease activity (PGA) was included as were measures of swollen joint counts and various biological measures e.g., anti-CCP antibodies. For the purposes of the study, unacceptable pain was defined as a VAS scores > 40.

Findings
In total, 232 patients with early rheumatoid arthritis with a mean age of 60.5 years (70.3% female) were included in the analysis but only 179 attended the 5-year follow-up appointment. At inception, the mean VAS pain score was 41.2 and reduced to 32.3 at the first 6-month appointment but remained unchanged during the next five years. The proportion of patients with unacceptable pain scores at inception was 49.1% although this decreased to 30.1% during the first year. However, as with mean VAS scores, the proportion of patients with unacceptable pain did not alter over time. At the two-year follow-up, significant predictors of unacceptable pain included female sex (odds ratio, OR = 2.57, 95% CI 1.27–5.33) and VAS pain scores (OR = 1.56). After 5 years, 34.1% of patients still had unacceptable pain and significant predictors included lower swollen joint counts (OR = 0.71) and anti-CCP antibodies (OR = 0.50).

The authors noted that while RA patients had low inflammatory activity, a third continued to experience pain 5 years later. They concluded that future studies should focus on how to optimise pain management at an early disease stage because this was associated with a great burden over time.

Citation
Eberhard A et al. Predictors of unacceptable pain with and without low inflammation over 5 years in early rheumatoid arthritis — an inception cohort study. Arthritis Res Ther 2021

Cannabinoids likely to be of limited value in rheumatoid arthritis

28th May 2021

Cannabinoids are widely used for the management of pain but whether the treatments help the pain associated with rheumatoid arthritis is uncertain.

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease affecting the small joints of the hands and feet. Clinically, the condition presents with swelling, heat, stiffness and pain in affected joints, warranting the use of analgesics to relieve symptoms. Cannabis and related cannabinoids are used for the management of range of painful conditions although there is uncertainty over the value of cannabis-related medicines for chronic pain. Despite this uncertainty, analysis of a US rheumatic disease registry found that nearly two-thirds of patients who used cannabis felt that it was helpful in relieving symptoms. But what is the evidence to support the use of cannabinoids in RA was the question posed by a team from the Department of Clinical Immunology and Rheumatology, Pontificia University, Chile.

Findings
A literature search identified 26 systematic reviews but within these reviews, there was only one randomised, controlled trial that specifically addressed the role of cannabinoids in RA. The study included 58 patients (79.3% female) with active RA that was inadequately controlled with standard medication including disease modifying anti-rheumatic drugs (DMARDS) and which had been used at the same dose for 3 months prior to enrolment. The trial involved the use of an oromucosal spray (nabiximols) containing 2.7mg tetrahydrocannabinol (THC) and 2.5mg of cannabidiol (CBD) and compared this with a placebo spray. A single dose was administered once daily and up-titrated every two days to a maximum of 6 doses per day for a period of 21 days. Outcomes reported included various pain measures, e.g., morning pain, pain at rest, present pain and a disease activity score.

The overall reported pain score was 3.3 vs 2.6 (nabiximols vs placebo) and disease activity score was 5.9 vs 5.0 (nabiximols vs placebo). However, there was a higher incidence of serious adverse events (74 vs 13, nabiximols vs placebo).

Commenting on the results of this single study, the authors noted that it was not possible to extrapolate the findings to other cannabis containing products or different routes of administration. The authors conclude that cannabis-related compounds may slightly reduce disease activity but that there appeared to be little, if any, effect on pain scores. Nevertheless, they did identify three ongoing, randomised clinical trials and indicated that these should provide more relevant information on the potential value of cannabinoids once published.

Citation
Schulze-Schiappacasse C et al. Are cannabis, cannabis-derived products and synthetic cannabinoids a therapeutic tool for rheumatoid arthritis? A friendly summary of the body of evidence. J Clin Rheumatol 2021

Large placebo response in subjective and objective measures in RA trials

9th October 2020

It is largely expected that in a randomised, double-blind clinical trial, individuals assigned to placebo will experience some level of improvement in relevant outcomes and this can lead to an underestimation of the effectiveness of the therapy being tested.

Consequently, researchers often use a combination of objective and subjective measures when assessing the response to treatment. For instance, it is known that subjective measures, for example, pain scores can be high, hence the need for independent, objective measures. However, in a new analysis of the placebo response among patients in trials for rheumatoid arthritis therapies, a team from the Brigham and Women’s Hospital, Boston, USA, found significant improvements in both measures. The team examined the placebo arm responses for five double-blind trials conducted internationally of at least 24 weeks duration between 2005 and 2009 among patients with rheumatoid arthritis. They extracted the individual level patient data from trials and focused on pain scores (subjective) and C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) values, both of which are objective measures. Pain scores were assessed using a standardised measure, namely a 0 to 100 mm visual analogue scale (VAS) and CPR and ESR were measured by blood testing. As some patients in the trials crossed-over to the active treatment, the researchers pre-selected 12 weeks from baseline to assess responses. Study medications included methotrexate and other disease-modifying antirheumatics.

Findings
The data set included 788 patients (82% women) with a mean age of 51 years. There was a statistically significant reduction in pain intensity (-14mm, 95% CI – 12 to 16 mm), CRP levels (-0.51mg/dl 95% CI -0.47 to -0.56) and ESR (-11mm/h, 95% CI -10 to -12), all with p values less than 0.001. Commenting on their findings, the authors were surprised by the clinically meaningful reductions in subjective and objective measures observed in placebo participants, indicating that it was more than a psychological placebo effect.

Furthermore, the cautioned that simply using objective rather than subjective measures in future trials would not necessarily lead to clearer results and that there was a need to further understand the effect of confounding factors and baseline covariates in placebo responders.

Reference
Vollett J et al. Assessment of placebo response in objective and subjective outcome measures in rheumatoid arthritis clinical trials. JAMA Netw Open 2020;3(9):e2013196. doi:10.1001/jamanetworkopen.2020.13196

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