Pain, mechanisms of fatigue and autonomic function in rheumatoid arthritis

Rheumatoid arthritis (RA) is a disabling chronic autoimmune disease characterized by joint pain, and potentially leading to a serious decay of life quality. Pain remains the most important problem for patients with RA, and there is an obvious need to increase the knowledge of pain patterns in early disease and relation to anti-rheumatic treatment. The first three papers of this thesis are based on the population-based early RA cohort (EIRA study), linked to the Swedish Rheumatology Register (SRQ). The main focus was to investigate pain patterns in early RA and the relation to other clinical factors.

First we studied the frequency of remaining pain after three months’ treatment with the first-line agent methotrexate, and found this outcome in a majority of the patients. Moreover, remaining pain was found in almost a third of patients with good clinical response, and predicted by high disability and low inflammatory activity at diagnosis. Further, we found that despite satisfactory inflammation control one year after diagnosis, strongly predicts development of outcome, unacceptable pain, and studied the pain course during the first five years after remaining pain widespread pain and fatigue three years after diagnosis. Next, we used a more severe pain diagnosis. We found that almost a third of the patients still have unacceptable pain after one year of adequate anti-rheumatic treatment, and there is minor further decrease of the proportion with this outcome after five years, suggesting that optimization of immune suppressive treatment can not decrease pain levels further at this stage. Women were more likely than men to develop unacceptable pain and the strongest predictors at diagnosis for this outcome were disability, patients global assessment (PGA) of disease, high number of tender joint count (TJC) and low number of swollen joint count (SJC). At diagnosis, pain correlated to disease activity and SJC/TJC, and this correlation increased after three months to stable levels that remained throughout the first five years of disease. TJC was higher correlated to pain than SJC during the whole early RA disease course. Pain mechanisms are closely linked to the autonomic nervous system (ANS), and dysfunction of autonomic activity is well documented in pain conditions such as fibromyalgia (FM).

Our investigation of ANS function in RA and FM revealed different autonomic patterns that could also be coupled to differences in neuroinflammation. Thus, central nervous system (CNS) mechanisms in RA were characterized by an IL-1β dominated intrathecal immune activation, which, unlike in FM, was coupled to reduced parasympathetic activity. These data indicate an earlier unknown interaction between CNS mediators and autonomic activity, which may be of interest to further identify treatment targets in neuro-immune regulation. Conversely in FM, there was an increase of central IL-8, known to associate with pain regulation, and FM also displayed an upregulation of sympathetic activity, which was independent of neuroinflammation.

Altogether, our data imply that remaining pain after anti-rheumatic treatment is not uncommon. The frequency of remaining pain stabilizes during the first years of disease and is a strong risk factor for subsequent generalized pain. Furthermore, we have shown that neuroinflammatory patterns in RA are coupled to autonomic dysfunction, and also clearly differ from FM, indicating different mechanisms behind RA pain and dysfunctional pain. The findings of this thesis have illustrated the pain problem in early RA, and hopefully this knowledge may contribute to early identification and treatment of patients at risk of developing pain conditions in connection to their rheumatic disease.

List of scientific papers

I. Altawil R, Saevarsdottir S, Wedrén S, Alfredsson L, Klareskog L, Lampa J. Remaining pain in early rheumatoid arthritis patients treated with methotrexate. Arthritis Care Res (Hoboken). 2016 Aug: 68(8):1061–1068.
https://doi.org/10.1002/acr.22790

II. Schelin MEC, Saevarsdottir S, Altawil R, Klareskog L, Alfredsson L and Lampa J. Remaining pain despite inflammation control in rheumatoid arthritis – long-term increased risk for widespread pain and fatigue. [Manuscript]

III. Altawil R, Westerlind H, Schelin M, Klareskog L, Alfredsson L, Lampa J. Repeated pain assessments and the cumulative frequency of unacceptable pain during the first five years after diagnosis in Swedish rheumatoid arthritis patients. [Manuscript]

IV. Kosek E, Altawil R, Kadetoff D, Finn A, Westman M, Le Maître E, Andersson M, Jensen-Urstad M and Lampa J. Evidence of different mediators of central inflammation in dysfunctional and inflammatory pain - interleukin-8 in fibromyalgia and interleukin-1β in rheumatoid arthritis. J Neuroimmunol. 2015 Mar; 15;280:49-55.
https://doi.org/10.1016/j.jneuroim.2015.02.002