Since the corona pandemic, the number of publications on fatigue symptomatology has increased exponentially, reflecting the current very high interest in this topic. As an accompanying symptom of cancer, but also of other chronic diseases such as autoimmune diseases, fatigue symptoms have been known to physicians for some time.
Since the corona pandemic, the number of publications on fatigue symptomatology has increased exponentially, reflecting the current very high interest in this topic. As an accompanying symptom of cancer, but also of other chronic diseases such as autoimmune diseases, fatigue symptoms have been known to physicians for some time. This article will focus exclusively on fatigue as an accompanying symptom of autoimmune diseases, especially inflammatory rheumatic diseases. To be distinguished from this is chronic fatigue syndrome (CFS) (myalgic encephalomyelitis ME), which is not discussed in this article.
Definition of fatigue
Fatigue is not the same as the common understanding of tiredness and/or fatigue. Patients with fatigue complain of an insurmountable, often very long-lasting feeling of tiredness, exhaustion and listlessness. They usually feel without any energy for a long period of time. Even physically easy activities such as cooking, telephone calls or other everyday activities are perceived as hardly feasible and are not improved by sufficient rest periods (such as sleep and/or vacation). Typically, exhaustion is not directly related to any preceding physical/mental exertion or strain. Fatigue is not only noticeable physically, but also mentally and spiritually. In the case of pronounced fatigue, social withdrawal, restriction of many private and professional activities and ultimately a considerable decrease in health-related quality of life can therefore also be the consequences.
Fatigue in rheumatism
Despite breakthrough advances in the treatment of rheumatic systemic diseases, 50-70% of patients with rheumatoid arthritis (RA) and 67-90% of patients with systemic lupus erythematosus (SLE) continue to complain of fatigue symptoms during the course of the disease, with one-third of patients with SLE reporting marked fatigue symptoms [1,2]. Women are affected more often than men. Fatigue symptoms are also of great socio-medical importance and are, among other things, a predictor of high (mainly indirect) medical costs, frequent visits to the doctor, long periods of sick leave and early retirement [3].
Although the symptom fatigue has been known for a long time, it was first identified as an important patient-reported outcome (PRO) parameter for clinical trials in rheumatology in 2002 and has been regularly assessed in clinical trials since 2005 [4].
In daily practice, the symptom should also be routinely inquired about and a nonspecific fatigue should be differentiated anamnestically from a typical fatigue symptomatology. Unfortunately, to date there is no biomarker that can be used to unambiguously and objectively measure fatigue symptoms. Notably, CRP at diagnosis also does not play a role as a predictor of the 2- and 5-year course of fatigue symptomatology, but mental factors (such as depressiveness, etc.) do. Since it is a subjective symptomatology, different generic but also disease-specific fatigue questionnaires are primarily used in clinical studies, which also allow the differentiation of different dimensions of fatigue (e.g. physical, cognitive, emotional fatigue). In clinical practice, a Likert or fatigue VAS scale may work well due to time constraints. Their use is particularly recommended for monitoring the course of the disease (e.g. during therapy).
Pathophysiology
The pathophysiology of fatigue is very complex and not yet clarified in detail. In acute disease, the association of inflammation and fatigue was an evolutionary advantage. The sick person rested, stayed at home (thus minimizing his psychomotor activity), ate little food and used his energy exclusively to fight off infections. We also speak here of “sickness behavior”, an adaptive withdrawal and sparing behavior that promoted the recovery process and therefore represented an evolutionary advantage.
The biological background lies in effects of proinflammatory cytokines (TNF-alpha, interkeukin-1 and interleukin-6) released in the course of the disease on the brain. These effects have been extensively studied in animal models. Receptors for interleukin-1 beta are found in various regions of the brain, and interleukin-1 beta injections into the ventricles can trigger “sickness behavior.”
In chronic diseases such as autoimmune diseases, a correlation of fatigue symptoms with disease activity is also undisputed. Again, the peripheral effects of proinflammatory cytokines such as interleukin-1 beta, interleukin-6, TNF-alpha, and others, but also their proinflammatory effects in the CNS with induction of central inflammation and “sickness behavior” (fatigue, depressiveness, anxiety, loss of appetite, cognitive decline) play an important role. The complex relationships between inflammation, cerebral metabolites (ATP, NADH, hexokinase, etc.), neurovascular factors, and the action of distinct neurotransmitters in specific brain areas and the occurrence of fatigue are becoming increasingly well understood [5].
Thus, as expected, rapid and effective therapy of the underlying disease (e.g., with TNF antagonists) usually also leads to an improvement in fatigue. However, the association between fatigue and disease activity in rheumatic diseases is usually weak [6]. A not insignificant proportion of patients continue to suffer from fatigue despite existing remission/low disease activity. This often applies to patients who already had low objective disease activity (e.g., no inflammatory constellation, no joint swelling, etc.) at disease onset and a high global score by patients, e.g., in the SDAI [7].
Thus, other factors must also be important in the development of fatigue symptoms. For example, pain and depressiveness correlate very well with fatigue symptoms. Fatigue is therefore a multidimensional phenomenon in patients with an underlying inflammatory rheumatic disease. In addition to the actual underlying rheumatic disease, numerous other factors such as comorbidities, lifestyle, psychosocial factors, as well as secondary fibromyalgia syndrome, which is common in rheumatic diseases, may also be causative. The latter manifests itself not only with pain, but usually also with sleep disturbances, which can further aggravate fatigue (Fig. 1).
Diagnosis
If a patient complains of fatigue, other (possibly easily treatable) causes should always be excluded first. Thus, fatigue symptomatology may also be due to drug therapy with antihypertensives (β-blockers, diuretics), antihistamines, benzodiazepines, etc. Anemia can also lead to fatigue and can be well treated by therapy (e.g., iron deficiency, vitamin B12 deficiency). Even very commonly used rheumatism drugs such as MTX can trigger fatigue as a side effect in the patient, which can recede after discontinuation of the drug. Vitamin D deficiency, more commonly observed in patients with rheumatic diseases, has also been associated with fatigue, although the data in this regard are controversial. In a small observational study of 80 patients with vitamin D deficiency, associated fatigue was improved by vitamin D supplementation [8]. Other causes of fatigue symptomatology that are not related to the underlying disease (e.g., metabolic disorders) are listed in Table 1.
Therapy
If an active rheumatic disease is present, effective guideline-based therapy should be initiated early. The therapeutic spectrum has expanded considerably in recent decades. In addition to the classic csDMARDs (conventional synthetic disease-modifying antirheumatic drugs) such as methotrexate, leflunomide in RA or hydroxychloroquine in SLE, bDMARDs (so-called biologics, “biological DMARDS”) such as tumor necrosis factor-alpha (TNF-alpha) antagonists, interleukin-6 receptor antagonists and many others are now being used at an early stage. In addition, a new group of substances, the tsDMARDS (targeted synthetic DMARDs), to which, for example, the Janus kinase (JAK) inhibitors belong, has been available for a few years.
The goal of therapy for rheumatic diseases is remission or the lowest possible disease activity. This applies to all inflammatory rheumatic diseases. To achieve this, close monitoring and, if necessary, rapid adjustment of therapy is required. In most cases, fatigue will improve with improvement in disease activity [9], although the association between disease activity and fatigue is not very strong. A Cochrane analysis demonstrated only small to moderate improvements in fatigue in active RA with biologics therapy [10]. The authors found no difference between TNF antagonists and other biologics with regard to improvement in fatigue. The good analgesic effect of JAK inhibitors could possibly explain that they had a better effect on fatigue symptoms in patients with RA compared with a TNF antagonist (adalimumab) in one study [11]. Accompanying the specific rheumatism therapy with medication, a detailed medication history should always be taken in order to discontinue fatigue-inducing/enhancing medications if possible. Comorbidities (e.g. renal insufficiency, COPD, etc.) must also be recorded and, ideally, treated consistently on an interdisciplinary basis.
Since factors such as pain, depression, and sleep disturbances may also be of pathophysiological relevance, only multimodal therapy is likely to be successful in the long term. Physical activity and psychological interventions can favorably influence fatigue symptoms. For example, a Cochrane analysis published back in 2013 included 6 studies with a total of 388 patients with RA. Physical activity improved fatigue by 14 points on a VAS scale 0-100 compared with control group. The number needed to treat (NNT) to achieve a beneficial effect was [12].
Recently, another prospective randomized three-arm study was published that examined the efficacy of cognitive behavioral therapy and personalized exercise programs using telecommunicative guidance. Two hundred and seventy-four women and 92 men with various inflammatory rheumatic diseases were included. After one year, compared with usual care, both cognitive behavioral therapy and the personalized exercise program improved fatigue symptoms [13]. Overall, however, studies on the efficacy of physical activity on fatigue in inflammatory rheumatic diseases are still limited.
However, there are already a large number of studies in oncology patients that have shown improvement in fatigue by increasing physical activity. Increasing physical activity not only increases cardiopulmonary exercise capacity, but also results in numerous positive psychosocial effects such as lower depression, less anxiety, more social contact, and ultimately better sleep. Sleep disorders should be regularly discussed with those affected and measures for sleep hygiene and, if necessary, extended sleep diagnostics should be pointed out. Stress should also be addressed with those affected. Here, a recently published study of 650 predominantly female (92%) SLE patients showed that stress is a significant predictor of the occurrence of fatigue during the course of the disease and is thus also a potentially important therapeutic target [14]. As far as psychosocial interventions are concerned (mind-body medicine, mindfulness interventions, yoga, psychoeducation, etc.), there are only few studies for rheumatism patients, which may also be due to the low level of financial support. However, in oncological diseases, there is now sufficient evidence that fatigue can be improved by physical activity and psychosocial measures [15]. In this context, a multimodal complex rehabilitation measure can also lead to a significant improvement in fatigue and quality of life, as we have been able to show in our own studies [16,17]. Unfortunately, such studies are still largely lacking for rheumatism patients.
Take-Home Messages
- Fatigue is a common symptom in inflammatory rheumatic diseases and should be regularly recorded anamnestically.
- Fatigue is associated with disease activity, especially pain and mental factors such as depressiveness.
- Therapy includes consistent drug therapy for the underlying disease, but also non-drug measures.
Literature:
- Hewlett S, Cockshott Z, Byron M, et al: Patients’ perceptions of fatigue in rheumatoid arthritis: overwhelming, uncontrollable, ignored. Arth Rheum 2005; 53: 697-702.
- Pollard LC, Choy HE, Gonzalez J, et al: Fatigue in rheumatoid arthritis reflects pain, not disease activity. Rheumatology 2006; 45: 885-889.
- Baker K, Pope J: Employment and work disability in systemic lupus erythematosus: a systematic review. Rheumatology 2014; 48: 281-284.
- Kirwan JR, Ahlen M, DeWit M, et al: Progress since OMERACT 6 on including patients perspective in rheumatoid arthritis outcome assessment. J Rheumatol 2005; 32(11): 2246-2249.
- Zielinski MR, Systrom DM, Rose NR: Fatigue, Sleep, and Autoimmune and related Disorders. Front Immunol 2019; doi: 10.3389/fimmu.2019.01827.
- Madsen SG, Danneskiold-Samsoe B, Stockmarr A, et al: Correlations between fatigue and disease duration, disease activity, and pain in patients with rheumatoid arthritis: a systematic review. Scand J Rheumatol 2016; 45: 255-261.
- Holten K, et al: Fatigue in patients with early rheumatoid arthritis undergoing treat-to-target therapy: predictors and response to treatment. Ann Rheum Dis 2022; 81: 344-350.
- Ruiz-Irastorza G, Gordo S, Olicares N, et al: Changes in vitamin D levels in patients with systemic lupus erythematosus: effects on fatigue, disease activity and damage. Arthritis Care Res 2010; 62: 1160-1165.
- 9 Holdren M, Schieir O, Bartlett SJ, et al: Achieving a low disease state within 3 months in early rheumatoid arthritis results in lower fatigue over 5 years. Ann Rheum Dis 2019; 78: A240.
- Almeida C, Choy EH, Hewlett S, et al: Biologic interventions for fatigue in rheumatoid arthritis. Cochrane Database Syst Rev 2016; 6: CD008334; doi: 10.1002/14651858.CD008334.pub2.
- Fautrel B, Krikham B, Pope JE, et al: Effect of baricitinib and adalimumab in reducing pain and improving function in patients with rheumatoid arthritis in low disease activity: exploratory analyses from RA-BEAM. J Clin Med 2019; 8: E1394.
- Cramp F, Hewlett S, Almeida C, et al: Nonpharmacological interventions for fatigue in rheumatoid arthritis. Cochrane Database Syst Rev 2013; CD008322.
- Bachmair EM, Martin K, Aucott L, et al: Remotely delivered cognitive behavioural and personalised exercise interventions for fatigue severity and impact in inflammatory rheumatic diseases (LIFT): a multicentre, randomised, controlled, open-label, parallel-group trial. Lancet Rheumatol 2022; 4: e534-e545.
- Azzizoddin DR, Jolly M, Arora S, et al: Longitudinal Study of Fatigue, Stress and Depression: Role of Reduction in Stress toward Improvement in Fatigue. Arthritis Care Res 2021: 72(10): 1440-1448.
- Fabi A, Bhargava R, Fatigoni S, et al: Cancer-related fatigue: ESMO Clinical Practice Guidelines for diagnosis and treatment. Ann Oncol 2020; 31: 713-723; doi: 10.1016/j.annonc.2020.02.016.
- Hartmann U, Ring C, Reuss-Borst M: Improvement of health-related quality of life in breast cancer patients by inpatient rehabilitation. Med Clin 2004; 99(8): 422-429.
- Peters E, Mendoza-Schulz L, Reuss-Borst M: Quality of life after cancer – how the extent of impairment is influenced by patient characteristics. BMC Cancer 2016; 16(1): 787.
HAUSARZT PRAXIS 2023; 18(8): 14-17