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