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10th April 2024
Professor Paul Emery’s illustrious career has seen him influence diagnostics and treatment interventions for rheumatoid arthritis (RA) and improve patient outcomes across the globe. Here, he speaks to Helen Quinn about his career trajectory – including his recent CBE – how best practice has evolved in RA and his hopes for the future of the disease.
It is not an exaggeration to say that Professor Paul Emery has revolutionised the field of rheumatology. His pioneering research has changed not only treatment pathways and clinical outcomes but also the way clinicians think about rheumatoid arthritis (RA).
Throughout his career, Professor Emery has championed strategies for early intervention, pioneered biologic therapies for inflammatory conditions and developed the use of imaging techniques in the musculoskeletal field to prevent or slow the progression of RA. His research and clinical work have led to new treatment interventions which have been adopted worldwide, ultimately allowing patients to live without pain for much longer.
Since 1995, Professor Emery has been Versus Arthritis UK (formerly ARC) professor of rheumatology at the University of Leeds and was director of the Leeds NIHR Biomedical Research Centre from 2009-22. He has published over 1,250 peer-reviewed research articles, and in January 2024, he was appointed Commander of the British Empire (CBE) in the King’s New Year Honours for his outstanding contribution to rheumatology.
From his office in Leeds, Professor Emery says he was delighted but taken aback to be awarded the CBE – following his OBE in 2018 – which recognised his work in the UK and internationally. ‘One of the things I like is that I was given it for services to rheumatology, which is rather unusual. I’m quite proud of that. I was very surprised,’ he explains.
Professor Emery studied at the University of Cambridge, and for the first five years of his career, he practised general medicine, mainly at Guy’s Hospital and at the Royal Brompton Hospital in London. For a year he ran the intensive therapy unit at Lewisham Hospital, which he believes served him well for a career in rheumatology as it involves treating many systemic diseases.
‘I think it was a great help,’ he recollects. ‘I was lucky that I did a great deal of medicine, so I had experienced nearly all the specialties.’
Rheumatology appealed to him because of all the unanswered questions. ‘Compared to other specialties, you had so much freedom to do things because it was a relatively new speciality, and no one had devised protocols or algorithms of how to treat things. You could look at everything from afresh and first principles,’ he says.
After two years in Australia as head of rheumatology at the Walter and Eliza Hall Institute and a consultancy post at the Royal Melbourne Hospital, he returned to the UK in 1987 to become a senior lecturer at the University of Birmingham. Here, he began his research into early intervention and began to make waves in rheumatology, which would fundamentally change how the disease is treated and understood.
Professor Emery says his ‘obsession’ was to treat patients before they developed a disability. ‘Our mission statement was actually prevention of disability through research,’ he says.
To improve patients’ lives and treat early, the referral system for RA required a huge overhaul. Professor Emery set to work in Birmingham. Every three months, he would write to over one thousand GPs to convince them to refer RA patients earlier so the disease could be prevented or at least held back. Usually, patients with inflammatory arthritis would only see a specialist after suffering for years with the disease, and by this point, there was much less that could be done to help them.
‘There was this huge inertia initially. It was very difficult to convince GPs it was worth referring patients urgently to a rheumatologist because they just thought rheumatologists can’t really diagnose them. And even if they can, they can’t treat them, so what’s the point of urgent referral,’ Professor Emery recalls.
Today, clinicians around the world use a standard clinical assessment developed by Professor Emery and his team to refer RA patients at the earliest stage possible. At specialist early arthritis clinics, patients are then assessed and, where appropriate, biomarkers are used to predict how their condition will develop.
Early intervention was, in part, made possible by the development and advancement of imaging techniques. With his colleagues in Leeds, Professor Emery set out to make imaging part of the RA treatment pathway. And, despite being told by ultrasound (US) manufacturers that there was no future for musculoskeletal ultrasound, he persisted.
‘They couldn’t see what it was going to do,’ he says. ‘They hadn’t spoken to anyone who was trying to treat or cure rheumatoid arthritis.’
Professor Emery eventually persuaded an American company to give him a machine, which he brought back to the UK and began researching the use of US in RA.
As he anticipated, US and magnetic resonance imaging (MRI) proved to be much more sensitive than conventional X-rays since clinicians can non-invasively detect any swelling inside the joint, something Professor Emery notes is incredibly difficult to do without imaging at an early stage of disease. X-rays measure structural changes as a result of past inflammation, whereas US and MRI measure both structural damage and current inflammation. Thus, X-rays are historical whereas US and MRI are predictive of the future, he says.
After leading a targeted US initiative (TUI) in 43 countries, ultrasound is now routinely used in most arthritis clinics around the world to predict patient outcomes. Professor Emery and his team have also introduced MRI to examine bone abnormalities alongside ultrasound imaging for tissues.
‘These imaging modalities are diagnostic at the start of the disease,’ he says. ‘They’re used for assessment and MRI in particular can be used for understanding pathogenesis. If you find subclinical synovitis on ultrasound or MRI, you can tell which [patients] will progress.’
Early diagnosis and aggressive treatment of the disease meant that, for the first time, the disease could be put into remission with a complete suppression of synovial and systemic inflammation. This turned treatment on its head. In the past the aim had been to simply treat symptoms as they emerged to reduce or manage pain.
The Leeds-based research team led the first international trials of anti-TNF therapy using monoclonal antibodies with very early disease and showed that biologic therapy could induce remission in patients. Professor Emery’s research has resulted in remission being accepted as the outcome of choice for patients with an early diagnosis.
One of his biggest challenges today is not getting enough patients into long-term remission and not targeting the patients in most need in the early stages of RA, despite the research providing evidence of best practice.
‘We still don’t see patients early enough, and we’re not allowed by NICE to necessarily use the best drugs at the earliest moment,’ he says. He believes 70-90% of RA patients could be put into long-term remission from the current research findings. A RCT of personalised medicine with biologiscs has just been completed at Leeds, which hopefully influence this issue, he says.
Working collaboratively with different specialties has been essential in both Professor Emery’s research and clinical work. In his clinics, he works with neurologists, immunologists, respiratory physicians, renal pysicians, cardiologists and dermatologists and he’s the first to admit that this multidisciplinary approach has enhanced his practice. ‘I’ve learned more from other specialties than I do from my own speciality, and I think they do as well,’ he says.
Professor Emery hopes his continued research will move the field even further, and he’s keen to work with colleagues in other specialities to support this. He finds running research ideas by them particularly beneficial.
In the last decade it has been realised that RA is the end point of a continuum. RA patients go through a ‘pre-clinical’ phase characterised by autoimmunity, with or without subclinical joint and systemic inflammation, and thus, RA is initially a systemic disease. Furthermore, the first musculoskeletal involvement frequently is not the joint but the tendon and, specifically, peritendon of the interossei.
For the last 17 years Leeds has run a national study of individuals at risk of RA. ‘We’ve developed, probably, the most definitive risk score, so we can very accurately tell GPs which at-risk patients to refer,’ Professor Emery explains. ‘We’ve got very accurate predictors now of not only who will get rheumatoid arthritis, but when.’
The Leeds team is currently involved in a prevention study examining how a patient’s gene expression affects the efficacy of medications. The next steps, Professor Emery says, will be to identify those with gene expression abnormalities and tie them to a specific drug, identifying individual groups of patients for particular treatment regimens.
Prevention of RA is the ultimate goal. ‘We don’t cure the patients, we don’t prevent it – or we haven’t until now,’ he says. ‘I never thought we’d get to prevention. That’s what I wanted to do the first day I saw a rheumatoid patient, to try and prevent it, and that was a long, long time ago. It’s only now that people are waking up to the fact that this is possible, and I think in the next few years it’ll become a routine process.’
25th March 2024
Abatacept can reduce the risk of rheumatoid arthritis (RA) onset in high-risk patients, as well as alleviating clinical symptoms where the condition is more developed, according to a new clinical trial.
Conducted at 14 hospitals across Europe, the trial showed that abatacept, which modulates the activation of T-cells, can prevent the development of the disease in patients with preclinical rheumatoid arthritis.
After six months of treatment, half of patients with clinical signs of rheumatoid arthritis showed a significant improvement in joint inflammation assessed by magnetic resonance imaging (MRI).
The effects of the interventions in both preclinical and clinical rheumatoid arthritis continued throughout a year-long observation phase.
The findings are published in The Lancet and could help establish early pre-clinical interventions in rheumatoid arthritis.
Individuals with anti-citrullinated protein antibodies (ACPAs) and subclinical inflammatory changes in joints are at high risk of developing rheumatoid arthritis, but treatment strategies to intercept this pre-stage clinical disease remain to be developed.
The researchers conducted a randomised, double-blind, placebo-controlled trial at 14 hospitals and community centres across Europe: 11 in Germany, two in Spain, and one in the Czech Republic. Between 6 November 2014 and 15 June 2021, a total of 139 adults with rheumatoid arthritis aged 18 years or over were screened. They all had ACPA positivity; joint pain but no swelling; and signs of osteitis, synovitis or tenosynovitis in their hand which showed up on MRI.
Of these, 100 participants (78% female) were assigned to two cohorts, and 98 participants completed the trial.
Over a period of six months, the first cohort (n=49) was given a weekly subcutaneous dose of 125mg abatacept, and the second cohort (n=49) was given a placebo.
MRI was used to determine any reductions in inflammatory lesions at six months. All participants were followed up for 12 months after the drug intervention in a double-blind, drug-free observation phase.
After six months, 26% fewer cases of rheumatoid arthritis were diagnosed in people treated with abatacept, and over half of the patients who received the drug showed a significant improvement in joint inflammation when assessed by MRI.
Of those treated with abatacept, 8% of participants (n= 4/49) developed rheumatoid arthritis, compared to 35% (n=17/49) in the placebo group. Reduced inflammation was seen in 57% (n=28/49) of participants in the abatacept group, compared with 31% (n=15/49) in the placebo group.
Improvements in MRI inflammation remained significantly different between the two groups 12 months after the end of the intervention, with 51% of participants in the abatacept group showing improvements compared to 24% in the placebo group.
Progression to rheumatoid arthritis was seen in 35% of participants in the abatacept cohort compared to 57% of participants in the placebo group.
The researchers reported 12 serious adverse events across the trial (n=4/48 in the abatacept group and n=7/49 in the placebo group) and no deaths.
Commenting on the trial, Juan D. Cañete, a clinical rheumatologist at the Hospital Clínic de Barcelona and senior researcher at FRCB-IDIBAPS in Barcelona, said: ‘These results indicate that if we could establish therapeutic interventions in the previous phase of the disease, there could be a window of opportunity to prevent rheumatoid arthritis from developing.’
He added: ‘We believe that this approach could help many people at risk of suffering from the disease.’
In 2023, it was found that patients with rheumatic and musculoskeletal conditions were particularly vulnerable to long-term opioid use with one in three of those with rheumatoid arthritis or fibromyalgia having received long-term prescriptions for these potentially addictive drugs to manage their pain.
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.
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.
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?
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.
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.
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.
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.
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.
26th July 2021
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
28th May 2021
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
9th October 2020
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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