Recent research revealed complex mechanisms underlying persistent pain in rheumatoid arthritis, even when inflammation appeared well-controlled.
In a comprehensive review, published in Nature Reviews Rheumatology, investigators highlighted emerging evidence implicating autoantibodies, mesenchymal cells, and abnormal neuron-immune cell interactions as key drivers of chronic pain in rheumatoid arthritis (RA). They emphasized that pain may remain a significant unmet clinical need in RA, with up to 40% of patients experiencing persistent pain despite advances in disease-modifying therapies. This pain can often become uncoupled from observable joint inflammation, challenging traditional views of RA pathophysiology.
Among the key findings from the review were:
- Autoantibodies, particularly anti-citrullinated protein antibodies (ACPAs), directly induced pain-like behaviors in animal models, independent of inflammation. However, clinical evidence linking ACPAs to pain levels in patients with RA remained inconclusive.
- Large-scale single-cell RNA sequencing studies revealed heterogeneous cellular profiles in RA synovial tissue. Analysis of a cohort of 70 patients with RA identified at least six different cell-type abundance profiles based on predominant cell types in synovial tissue.
- Mesenchymal cells, especially fibroblasts, emerged as potential key players in driving peripheral neuron hyperactivity. Synovial fibroblasts produced known proalgesic mediators and may promote sensory nerve sprouting in RA joints.
- Recent transcriptomic analyses of human dorsal root ganglia identified potential differences in pain-related gene expression between humans and rodents, highlighting the need for caution in translating animal model findings.
- Janus kinase (JAK) inhibitors showed promising results in reducing pain in RA clinical trials. Two phase III trials indicated that JAK inhibitors (baricitinib and upadacitinib) outperformed the anti-TNF antibody adalimumab in terms of pain measurements, though differences were subtle.
The review emphasized the need for interdisciplinary collaboration between rheumatologists, immunologists, and pain biologists to advance the understanding of RA pain mechanisms. The investigators called for several key improvements in pain research:
- Larger, well-powered preclinical studies with improved experimental design and reporting to enhance reproducibility and translation.
- Development of better tools to assess diverse pathophysiologic processes driving chronic pain in patients, including standardized quantitative sensory testing protocols.
- Establishment of universally accepted definitions of inflammation and its resolution in RA, accounting for both macroscopic and microscopic changes.
- Recognition of pain as a distinct and essential clinical outcome in RA trials, beyond traditional measures of disease activity and tissue damage.
- Patient stratification based on mechanistic pain phenotyping to improve the likelihood of success in analgesic drug trials.
The review provided evidence of inadequate pain management in RA. A survey of over 2,700 patients with RA across the United States and Europe found that 60% to 65% of them were dissatisfied with their pain levels. One study examining three large cohorts (n = 683–7,090) found persistent pain in 59% to 79% of patients over 3 years, with no marked difference between patients treated with biologic drugs compared with other medications (79% vs 73%, respectively).
The investigators discussed current treatment approaches, including DMARDs, biologic drugs, and JAK inhibitors. They noted that if administered early in the disease course, 50% to 60% of patients have an initial response rate to methotrexate, but few (~20%) achieve complete remission, often requiring addition of biologic drugs.
The review highlighted recent technical advances in RA research, such as three-dimensional synovial tissue organoid systems and microfluidic setups for neuronal cultures, which could facilitate more sophisticated in vitro models of RA pain mechanisms.
Conflict of interest disclosures can be found in the study.