To successfully address rheumatoid arthritis (RA), strategies need to be developed to target the underlying disease mechanisms and enable a sustained interruption of disease progression, according to a review published in Nature Reviews Rheumatology. According to the report, factors that may prevent successful treatment of RA include smoking, gut leakiness, and alterations to the central nervous system.
Remission vs Cure
The review defines “cure” as the principle absence of disease, and the term “remission” is used to indicate that disease is still present but is sufficiently controlled by therapy.
“Little research has been carried out on how to cure RA, and the term ‘cure’ still requires definition for this disease,” the review authors explained. “Even now, achieving a cure seems to be a rare occurrence among individuals with RA.”
Studies of patients with early RA have found that reaching sustained drug-free remission is rare, achieved only by 9% to 15% of all patients. Patients who attain sustained drug-free remission appear to have no relevant progression of joint damage, the researchers noted.
Drivers of RA and Potential Therapeutic Strategies
Smoking is considered a remote, non-joint based factor that prevents cure of RA and worsens response to treatment. In addition, gut leakiness may be a further driver of immune cell influx into the joints, subsequently promoting disease relapse.
Likewise, central nervous systems changes may also affect the possibility of curing RA. Certain patients with RA experience hypersensitivity to pain; a process that likely involves alterations to the central nervous system.1
Psychological stress is also a well-known trigger for disease flares in patients with RA, the investigators reported. However, the association between stress and RA remains unclear. According to the review, “One potential explanation is that, in patients with RA, the stress response is considered to be defective, leading to inadequate immune-regulatory sympathetic signals in the joints, as well as a dysfunctional hypothalamic–pituitary axis, which results in robust, prolonged cytokine release.”
The researchers suggest that smoking cessation and moderate alcohol consumption may play a protective role against RA. Investigators suggest ethanol applies a potent inhibitory function on TFH cells via its metabolite acetate, which blocks IL-21 secretion, thereby resulting in a decrease of auto-antibody production and selectively interfering with adaptive immune system activation. Further research is needed to investigate whether regular moderate alcohol consumption, they acknowledge, in conjunction with conventional anti-inflammatory treatment could potentially serve as a cure for RA.1
In patients with type 1 diabetes mellitus, another chronic autoimmune disease, therapies such as anti-CD3 antibodies in the late stages of pre-disease may delay or even prevent RA. Fiber-rich diets may also potentially relieve symptoms associated with the disease.1
Research points out that physical and occupation therapy may be beneficial in patients with RA. It is recommended that these patients perform exercise routinely to preserve joint mobility and strengthen muscles around the joints. Calcium and vitamin D supplements are also recommended to prevent osteoporosis.2
The research team recommends efficient treatment of early RA or even treating individuals at elevated risk of developing RA. Ultimately, the treatment of RA should always be focused on swiftly controlling the signs and symptoms of the disease, the investigators say.
Remission is an important factor in RA, however, it may require lifelong therapy if a cure is not achieved, according to the researchers.
“More work is required to define the factors that determine the crossroads between remission and cure in RA; however, we should now start to embrace the potential for cure as we better understand the pathophysiology of RA,” the reviewers stated.
“Targeting the underlying drivers of RA, which are different from the pro-inflammatory effectors, is likely to become a central approach in attempts to attain cure in RA, not least because there is a certain saturation effect of anti-inflammatory drugs in RA and because most of the underlying drivers are not tackled by current therapeutics,” the review authors write. “Using such approaches, abolishing disease rather than suppressing symptoms could become the principle aim of RA treatment.”
1. Schett G, Tanaka Y, Isaacs JD. Why remission is not enough: underlying disease mechanisms in RA that prevent cure. Nat Rev Rheumatol. Published online December 10, 2020. doi.org/10.1038/s41584-020-00543-5
2. Bullock J, Rizvi SAA, Saleh AM, et al. Rheumatoid Arthritis: A Brief Overview of the Treatment. Med Princ Pract. Published online September 2, 2018. doi:10.1159/000493390