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Characteristics of difficult-to-treat rheumatoid arthritis: results of an international survey

EULAR 2018
Although the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR) recommendations on RA predominantly focus on early phases of the disease and on pharmacological management, a sizeable portion of patients can be characterised as difficult-to-treat (estimated prevalence around 5-20%). In order to develop adequate guidelines and recommendations for this population, a difficult-to-treat RA classification needs to be defined.

Roodenrijs et al. set out to define characteristics of difficult-to-treat RA patients via an online survey among rheumatologists. [9] This questionnaire consisted of 9 questions regarding the background of the respondents, aspects to be included in the definition of difficult-to-treat RA, and missing items on its comprehensive management in the current EULAR management recommendations.

Respondents answered questions on the necessity of incorporating the following items into the definition: disease activity level (e.g. the DAS assessing 28 joints [DAS28-ESR]), presence of fatigue, number of DMARDs that failed, and the inability to reduce oral glucocorticoid treatment. Optional open questions were used to identify additional features for the definition of difficult-to-treat RA and to collect items on its comprehensive management not covered by the current EULAR recommendations. A total of 390 rheumatologists from 31 countries, including a small number who were in training, completed the survey between July and December 2017. Half of respondents would include signs that are suggestive of active disease or a DAS28-ESR score >3.2 in the definition. Furthermore, 41% added fatigue. The most selected option for the number and category of DMARDs that had to have been used to be included in the definition was 1) failure to ≥2 conventional synthetic DMARDs, and 2) ≥2 bDMARDs or targeted sDMARDs with different mechanisms of action. Furthermore, 89% of respondents suggested including inability to taper oral glucocorticoids below 5 or 10 mg.

The main finding of this survey was that difficult-to-treat RA is seen as a heterogeneous condition. This means that next to signs of active disease, failure to DMARDs and inability to taper glucocorticoids may be included in the definition. Researchers also noted that the large number of respondents, as well as responses with regard to items not covered by the current EULAR RA management recommendations, underscore the need for recommendations on comprehensive management of difficult-to-treat RA.

Link between obesity and rheumatoid arthritis not clear yet

A longstanding issue in risk assessment of RA is the role of obesity. Especially over the last decades, which have seen an increase in the prevalence of obesity worldwide, this question has become increasingly relevant. This is even more surprising as there could well be a link between obesity and RA, as adipose tissue harbours biologic mechanisms of inflammation which in its turn may be linked to chronic systemic inflammation.

It has been shown that circulating adiponectin (a protein produced largely by adipocytes) levels are generally higher in RA patients than in the general population. It is also known that adiponectin levels drop as the weight of a subject increases, whilst they increase as a subject loses weight. There also seems to be an association between adipokines and cytokines (which are targeted in RA).

While there are several studies which have examined the potential influence of obesity on the development of RA, the results have been inconsistent. For instance, a review by Qin et al. showed that increased body mass index (BMI) can contribute to a higher risk for RA, but a Swedish study by Turesson et al. showed that there was not really such risk in obese subjects. In fact, the opposite was the case, where obesity may even have some protective effect.[10,11]

Other studies, such as individual Nurses’ Health Study, the Iowa Women’s Health Study, and the British UK General Practice Research Database have found no or only modest association between obesity and the risk of RA. Two more studies showed that obesity was related to ACPA-negative RA with an inverse association between BMI and ACPA-positive RA for male subjects. Furthermore, abdominal obesity and BMI based obesity may carry different risks for RA. It can also be argued that RA associates with altered body composition and that the WHO definition of overweightness (BMI 25 - <30 kg/m2) and obesity (BMI ≥30 kg/m2) may not be adequate for RA patients. Specific attention may be needed for fat distribution in the body. Also, the role of adipokines in RA should be investigated further, as there is an association between obesity and chronic inflammation. Obese subjects also have higher levels of oestrogens and androgens; as sex hormones play a role in RA development and could be modified by obesity, this warrants further study as well.

In conclusion, there seems to be a slightly higher risk of RA in overweight and obese subjects, probably more pronounced in those who have seronegative RA. Inconsistent results have been seen for the contribution of gender and ACPA status on the background of a modest overall risk of RA in obesity. The reported negative association between ACPA+ RA status and obesity is intriguing. The evidence so far generates more questions than it answers, which prompts for ongoing research.[12]

  1. Roodenrijs NMT, et al. Abstract OP0139. EULAR 2018.

  2. Qin B, et al. Arthritis Res Ther. 2015 Mar 29;17:86.

  3. Turesson C, et al. Rheumatology 2016 Feb;55(2):307-14.

  4. Uhlig T. Abstract SP0071. EULAR 2018.

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