Residual Symptoms in Patients with Rheumatoid Arthritis

Doctor and patient knee physical therapy
There are still significant unmet needs among these patients, many of whom continue to report significant residual symptoms, including pain, fatigue, and functional disability, according to a systematic review.

Treat-to-target (T2T) strategies aimed at achieving remission in patients with rheumatoid arthritis (RA) are widely adopted in clinical practice, but there are still significant unmet needs among these patients, many of whom continue to report significant residual symptoms, including pain, fatigue, and functional disability, according to a systematic review published in Arthritis Care and Research.1

The 2015 American College of Rheumatology (ACR) guidelines for the treatment of RA emphasized the T2T for RA, aimed at reaching a target of sustained remission or low disease activity.2 Similarly, the 2019 update of the European League Against Rheumatism (EULAR) guidelines for the management of RA recommended the T2T strategy in every patient.3

The classification criteria for RA provided by the ACR, along with the expansion of effective pharmacological options against RA, have significantly improved the management of patients with RA. However, even when remission or low disease activity target is achieved patients may still report significant troublesome symptoms.1,4

While reduction in inflammation, prevention of structural damage, and achieving remission are regarded by physicians as the main treatment goals, patients wish to be involved in the treatment plan and are frequently interested in reduction in pain, joint swelling, and general well-being. Functional disability secondary to residual fatigue, joint inflammation, and deformities, may impair work productivity and activities of daily living in patients with RA in remission or with low disease activity.4

While the management of patients with RA continue to evolve and improve, not all patients are able to attain the desirable treatment goal of remission or low disease activity.4 The presence and magnitude of residual symptoms may depend on the stringency of the remission or low disease activity measure attained as well as on the durability of this level of response.

Michaud et al. conducted a systematic review of the literature in an effort to better understand the residual symptoms in patients with RA who meet the definitions of remission or low disease activity. The researchers included prospective and retrospective studies in adults with RA who were treated according to a T2T strategy and collected data on patient symptoms (pain, fatigue, and functioning) as well as disease impact (health-related quality of life, absenteeism, or presenteeism).1

The most commonly reported symptom was functional disability which may be secondary to prior structural damage or due to advanced age. Work environment, functional requirements, and cultural expectations in the working environment may all influence the level of impairment an individual experiences related to work.5 Physical functioning is better in patients with sustained remission, compared to those with occasional remission.1,6 Of note, poorer functional status was previously reported to be associated with higher mortality rates.7

In spite of effective immunosuppressive therapies, pain was found to be another important residual symptom and was more common in patients who achieved only low disease activity, and not remission.1 Navarro-Millán et al. reported that the majority of patients in remission had low pain scores (86% with pain ≤1 on 0–10 visual analog scale).6  Altawil et al. reported that remaining pain affects almost a third of patients with early RA with a good EULAR response to treatment.8 It was previously suggested that the development of pain in RA may be in large part related to the inflammatory impact on the peripheral nerves, thus may be insufficiently controlled by anti-rheumatic drugs.8

Fatigue was also a common residual symptom in a substantial proportion of patients with RA and is a major determinant of quality of life.1,9 Navarro-Millán et al. reported that over a quarter of patients with RA in remission had significant fatigue levels.6  A previous study showed that anti-rheumatic drugs, including biologics, do not significantly impact fatigue levels in patients with RA.10 Data suggest that many patients with RA report that improving fatigue levels should serve as a key treatment goal, although fatigue-related endpoints are rarely reported in clinical trials.11

Additional potential residual symptoms include anxiety, depression, sleep disturbances, or morning stiffness.1

When the T2T strategy fails, focusing on personalized treatment goals may be more appropriate, including treatment aimed at reducing pain or fatigue, or combining pharmacological and non-pharmacological interventions that incorporate patient-centered approaches.1

The systematic review by Michaud and colleagues confirmed the currently unmet need in patients with RA, particularly with regards to improving pain, fatigue and function.1 A review of the prevalence and unmet needs in the management of RA in Africa and the Middle East suggested that additional unmet needs included limited disease awareness, delays in diagnosis and start of treatment, lack of country-specific treatment guidelines, and difficulties accessing treatment.5

“From a pragmatic perspective, these findings suggest that setting personalized goals for the individual in addition to the practice of T2T may inform individualized management as part of holistic care,” concluded the researchers.  They suggest that adding patient-reported outcomes to a T2T strategy may improve the management of these patients.


  1. Michaud K, Pope J, van M, et al. A systematic literature review of residual symptoms and unmet need in patients with rheumatoid arthritis. Arthritis Care Res (Hoboken). Published online Jul 3, 2020. doi:10.1002/acr.24369
  2. Singh JA, Saag KG, Bridges SL et al. 2015 American College of Rheumatology Guideline for the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2016;68(1):1-25. doi:10.1002/acr.22783
  3. Smolen JS, Landewé RBM, Bijlsma JWJ, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis. 2020;79(6):685-699. doi:10.1136/annrheumdis-2019-216655
  4. Taylor PC, Moore A, Vasilescu R, Alvir J, Tarallo M. A structured literature review of the burden of illness and unmet needs in patients with rheumatoid arthritis: a current perspective. Rheumatol Int. 2016;36(5):685-95. doi:10.1007/s00296-015-3415-x
  5. Almoallim H, Al Saleh J, Badsha H, et al. A Review of the prevalence and unmet needs in the management of rheumatoid arthritis in Africa and the Middle East. Rheumatol Ther. Published online Nov 23, 2020 doi:10.1007/s40744-020-00252-1
  6. Navarro-Millán I, Chen L, Greenberg JD, Pappas DA, Curtis JR. Predictors and persistence of new-onset clinical remission in rheumatoid arthritis patients. Semin Arthritis Rheum. 2013;43(2):137-43. doi:10.1016/j.semarthrit.2013.02.002
  7. Symmons D, Mathers C, Pfleger B. The global burden of rheumatoid arthritis in the year 2000 global burden of disease. World Health Organ. 2015;18(4):1–30.
  8. 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;68(8):1061-8. doi:10.1002/acr.22790
  9. Rupp I, Boshuizen HC, Jacobi CE, Dinant HJ, van den Bos GA. Impact of fatigue on health-related quality of life in rheumatoid arthritis. Arthritis Rheum. 2004;51(4):578-85. doi:10.1002/art.20539
  10. Bae SC, Gun SC, Mok CC, et al. Improved health outcomes with etanercept versus usual DMARD therapy in an Asian population with established rheumatoid arthritis. BMC Musculoskelet Disord. 2013;14:13. doi:10.1186/1471-2474-14-13
  11. Ahlmén M, Nordenskiöld U, Archenholtz B, et al. Rheumatology outcomes: the patient’s perspective. A multicentre focus group interview study of Swedish rheumatoid arthritis patients. Rheumatology (Oxford). 2005;44(1):105-10. doi:10.1093/rheumatology/keh412