There is tired, and there is fatigue. Then there is fatigue associated with a rheumatic or autoimmune disease, which is multifactorial and debilitating and has confounded physicians and patients for decades.

“Time and again, I hear my patients say that at some point in the day, they hit the wall, or they feel like they are in quicksand,” Philip J. Mease, MD, of the Swedish Medical Center in Seattle and the University of Washington, told Healio Rheumatology. “They have to stop and rest because they simply cannot function at all, period. It is a bone-crushing weariness.”

It would follow that such a pervasive and significant problem should be addressed routinely in the clinic, if not in research. But data have consistently shown that patients still feel as though their fatigue is not acknowledged sufficiently by their rheumatologist. Or, worse, many patients feel as though their fatigue is ignored or not taken seriously.

One issue is the source. “The reality is that lots of things probably drive fatigue in rheumatic diseases,” Katie Druce, PhD, MSc, BSc, of the Centre for Epidemiology Versus Arthritis at the University of Manchester in the U.K., said in an interview. “There may be differences in the things that initially cause the fatigue — such as inflammation through sickness behavior — and the things that perpetuate it, such as chronic pain and low mood.”

With so many potential etiologies, treating or even managing this comorbidity can be difficult. This could partially explain why patients have felt like their physicians have been unable or unwilling to tackle the problem for so long.

Biologic therapies have helped, regularly demonstrating the capacity to mitigate fatigue to a certain extent. But getting cytokines in order is only part of a successful management regimen. A growing body of data is showing that exercise and wellness behaviors like mindfulness and meditation can improve associated factors such as sleep, pain, anxiety and depression.

However, understanding that wellness can help and actually putting such a regimen into action are two different things, according to Patricia Katz, PhD, professor of medicine and health policy at the University of California, San Francisco. “You can’t just tell a patient they should exercise,” she said. “They need a specific exercise prescription that is tailored to their needs, and that is just not part of training for most rheumatologists.”

Exercise and wellness paradigms are, in fact, evolving. Accordingly, rheumatologists have grown more comfortable discussing them as potential mitigators of fatigue.

In addition, COVID-19 put a spotlight on how mental health comorbidities can induce that ‘bone-crushing’ weariness. When the effectiveness of biologics is factored into the equation, it is possible that patients with rheumatic diseases may finally have hope that the disease comorbidity that is so important to them may be addressed in a meaningful and structured way.

But considerable work needs to be done to iron out the details. It starts with simply understanding why fatigue happens in the first place.

Down to the Roots

While Mease would not claim to fully understand fatigue as it pertains to the specialty, he offered a starting point for rheumatologists to consider. “I often acknowledge to my patients that having a rheumatic disease is like having a full-time job,” he said, noting the endless stream of doctor visits, medication or injection schedules, lab tests and imaging analyses that can keep patients away from their work, family and support systems. All of this, of course, sits on top of and exacerbates the routine stresses of life.

But it takes more than simply acknowledging fatigue to understand it, according to Leonard H. Calabrese, DO, director of the RJ Fasenmyer Center for Clinical Immunology at the Cleveland Clinic. He offered a reason why so many rheumatologists are loath to even open the dialogue. “We as rheumatologists are so well trained to identify, sort out and treat chief complaints in our patients,” he said. “But we are not nearly as good at evaluating a patient’s chief concerns.”

Desiree Azizoddin, PsyD, of the research faculty in the department of emergency medicine at Brigham and Women’s Hospital and clinical instructor at Harvard Medical School, urged rheumatologists to keep it simple. “Sleep is a big one,” she said. “Patients need to understand sleep hygiene, and that too much sleep or too little sleep can be a signal or a cause of fatigue.”

Azizoddin, who has conducted research in systemic lupus erythematosus, also highlighted stress as a critical component of fatigue. But this is where the etiologic challenges arise. The impact of stress on individuals without a chronic rheumatic disease can be difficult enough to parse out. When a condition like SLE is involved, it can be nearly impossible to understand where the stress of life ends and the stresses associated with the disease begin.

“There are neurological manifestations of lupus disease that can lead to psychiatric disorders and fatigue,” Azizoddin added. “However, they may be underlying conditions, or they may be completely unrelated or they may be genetically driven. Lupus can lead to depression and anxiety, but many patients may have had depression and anxiety before their lupus diagnosis.”

Turning to more clinical explanations, Mease noted that excessive proinflammatory cytokines in the central nervous system can affect various parts of the brain that may be related to the experience of fatigue. He said that TNF may be implicated, along with interleukin-1, IL-17 and IL-23.

Understanding the exact nature and impact of these cytokines has proven challenging, according to Druce. “We consistently see that symptoms like pain, mood and disability are important, while the relationship with inflammation and disease activity can be less clear,” she said.

Further complicating the picture is that there may be “important subtypes” of fatigue within any disease group, according to Druce. “These subtypes may highlight differing symptom etiologies,” she said. “Some patients have high levels of inflammation but good mental health, while others have high inflammation and poor mental health. While we might be comfortable recommending only immunomodulation for the first group, we might want to try a hybrid immunomodulation and cognitive behavior therapy approach in the second.”

Katz added another layer to the problem. “When a patient has high disease activity, getting that activity under control is always the first target,” she said. Treatment to the target of controlled disease with disease-modifying antirheumatic drugs and, to a greater extent, biologic therapies, often yields benefits in fatigue, as well.

But patients with severe disease are not the only ones who are chronically fatigued. “The harder nut to crack is people who have their disease under control but still experience fatigue that affects their daily lives,” Katz said.

“Fatigue does not always correlate with disease activity,” Azizoddin added.

Conventional wisdom would suggest that understanding the root causes of a comorbidity is a good place to start. After that, having a number of tools at hand to assess it would be the next step. Such tools proliferate, along with data investigating their utility, but making sense of that information has also proven challenging.

Missing the Mark

In 2019, Barbacki and colleagues conducted a database review in the Journal of Rheumatology outlining the instruments used to assess fatigue in SLE since 2007, which yielded 37 studies using eight different measures of fatigue. Results showed that the visual analog scale (VAS), Fatigue Severity Scale (FSS) and Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT) fatigue scale were most frequent. Two studies used the Multidimensional Assessment of Fatigue, while one used the Brief Fatigue Index (BFI).

“The FACIT score is a multidimensional questionnaire that gets at different qualities or aspects of fatigue,” Mease said. “It respects the fact that it is not a single item.”

In a paper published in Rheumatology Advances in Practice, Pearson and colleagues conducted a review of published articles to determine the quality and acceptability of PRO measures used to evaluate fatigue in axial spondyloarthritis. While 23 articles yielded evidence for nine fatigue-specific measures, they were unable to identify a fatigue measure specifically targeting the axial spondyloarthritis patient population. “Most measures provide a limited reflection of fatigue,” they wrote.

That said, the Multi-dimensional Assessment of Fatigue, Multi-dimensional Fatigue Inventory-20, FACIT and FSS were the “most comprehensive,” according to their findings. “The limited content and often poor quality of the reviewed measures limit any clear recommendation for fatigue assessment in this population,” they wrote.

Calabrese noted that the Cleveland Clinic uses the Patient-Reported Outcomes Measurement Information System (PROMIS) global fatigue score. “At a glance, I can see how severe fatigue is, and how much interference it is causing,” he said.

Katz acknowledged the utility of many of these parameters. However, she brought it back to basics. “If you are in a clinical setting, the best thing you can do is ask about fatigue,” she said.

A companion point is that as long as a rheumatologist is, in fact, addressing fatigue with their patients, any of these measures could have utility. “It depends on how you want to use it and what you are trying to achieve,” Katz said.

It is also important to understand the difference between measures used in a clinical setting and those used for research, according to Katz. “I understand that doctors have a small amount of time to discuss fatigue, so a simple rating scale, tracked over time from visit to visit, can be effective in learning whether a patient is feeling more or less fatigue,” she said. “In a research setting, we can use a longer questionnaire that has more precision. We can hit our targets a little better and hopefully extrapolate that information to the clinic.”

Rheumatologists have been hitting their targets with greater frequency in recent years, thanks to an evolving therapeutic armamentarium. But truly life-altering improvements in fatigue have continued to be elusive.

Treating to Target

“It is important to give credit where it is due by saying that rheumatologists were, rightly, for a very long time focused on targeting the aspects of rheumatic diseases which were most destructive, such as joint erosions, or most likely to lead to mortality,” Druce said. “It is only now that biologics, biosimilars and treat-to-target paradigms have revolutionized the impact and progression of many rheumatic diseases that there is space to consider some of the previously less urgent symptoms experienced by patients, like fatigue.”

Mease has hope for the capacity of biologics and other DMARDs to play a key role in helping patients combat their fatigue. “We are starting to see that fatigue may even improve before pain relief comes or joint swelling improves,” he said. “We know there is likely a centrally acting mechanism by which various drugs will do this. It is one of the things we are very interested in, how the drugs we use may impact central nervous system function.”

That said, it is still unclear how those mechanisms work. In the meantime, it is important for rheumatologists to manage expectations, according to Mease. “When I speak to patients about reaching targets for improvement in any clinical domain, including fatigue, I tell them that if we get 50% or 70% improvement, we have accomplished something,” he said.

While it can be difficult, Mease also tries to impress upon his patients the limits of therapeutic interventions. “We may not be able to remove the stress from your work or your family, but we can improve inflammation or certain parameters of immune-mediated fatigue,” he said.

If there is one other reason for optimism in hitting fatigue-based targets, it is that the FDA is finally beginning to recognize this comorbidity as a relevant entity, according to Mease. “Over the years, even though fatigue is always measured in trials, it did not make it to the label of our drugs,” he said. “This resistance was not bullheadedness on the part of the FDA; they were not ignoring the phenomenon. They wanted to be careful and note that fatigue can be present for many reasons.”

That changed recently when treatment of fatigue was added as a component to the label of guselkumab (Tremfya, Janssen). Several other drugs are applying to include fatigue on their labels, as well. This may allow clinicians to address the subject in a more structured way and induce a broader conversation about multipronged efforts to deal with fatigue. All of this may help achieve a goal that is so important to patients: breaking the cycle of disease activity, pain, depression and exhaustion that can lead to the most significant fatigue.

Breaking the Cycles

In a review published in Current Opinions in Rheumatology, Katz noted that while disease activity such as inflammation, pain and joint symptoms can yield greater fatigue in patients, this type of disease activity only accounts for “a small portion” of what patients actually feel.

“Instead, factors outside the direct effects of rheumatoid arthritis, such as obesity, physical inactivity, sleep disturbance and depression explain the majority of variation in fatigue,” she wrote.

A growing body of data is validating this conclusion. In a paper published in Lupus, Azizoddin and colleagues reported on a cohort of 116 patients with SLE. Multivariate analysis and stepwise regression analysis results showed significant and independent effects of depression, stress and pain on fatigue.

“Investigators are shooting themselves in the foot when including fatigue as an outcome but not including stress and depression in their models,” Azizoddin said. “We know they are related. This is why fatigue continues to be unsolved.”

In a paper published in the Pakistan Journal of Medical Sciences, Fertelli and colleagues investigated associations between fatigue and sleep quality, pain and depression in 151 patients with knee osteoarthritis and 147 healthy controls. Results showed that the knee OA group showed significantly higher fatigue scores and higher Pittsburgh Sleep Quality Index (PSQI) and Beck Depression Inventory (BDI) total scores compared with controls (P < .05). Moreover, a positive correlation was observed for fatigue score and PSQI, VAS and BDI scores (P < .05). “This fatigue suffered by them affected their sleep quality, pain and depression negatively,” the researchers concluded.

“Fatigue and depression are intertwined so closely that, sometimes, it may be difficult to disentangle them,” Katz said. “The descriptions are pretty similar across diseases.”

Azizoddin believes that rheumatologists can play a critical role in mitigating the synergistic effects of these disease comorbidities. “What physicians say carries weight,” she said. “So, when a physician says, ‘Your sleep and your stress are going to impact your disease and cause you to have more fatigue,’ they are inclined to listen.”

At that point, the physician may have more leverage in motivating the patient to engage in some sort of self-management regimen, whether it is exercise, meditation or a dedicated sleep hygiene routine.

Azizoddin added: “It can be helpful to remind patients that they can and should practice stress-relieving behavioral techniques, such as relaxation, breathing, yoga, and exercise, that can make a big difference.”

Get Well Soon

It does not take a physician with years of training and experience to understand that exercise is beneficial for healthy individuals and those with chronic diseases alike. Nor is it a significant logical leap to assume that wellness behaviors such as meditation or mindfulness can help with the stress, depression or anxiety that come with a chronic disease and may be driving fatigue.

The issue, for many rheumatologists, is that understanding these basic principles of general health and actually prescribing programs to target the specific fatigue experienced by an individual patient are two different animals altogether. In a paper published in Rheumatic and Musculoskeletal Diseases Open, Pope wrote that “specific programs for exercise and behavioral interventions are not standardized.”

But attempts are being made to figure out how to design such interventions to target fatigue.

Sveaas and colleagues wrote a paper in Physical Therapy investigating exercise as a treatment for axSpA. They noted that most programs for this patient population target flexibility rather than high-intensity exercise.

The study included 50 patients assigned a 3-month high-intensity exercise regimen and 50 controls. Results showed that 38 participants in the exercise group followed at least 80% of the program. Initial results showed a significant benefit of exercise on fatigue (mean group differences = –0.4; 95% CI, –0.7 – –0.1), vitality (5.0; 95% CI, 1.1-10.5), mood (–2; 95% CI, –3.7 – –0.04) and general health (9.0; 95% CI, 3.3-14.7).

“When we have completed needs assessments among rheumatologists and patients, we see that rheumatologists are very interested in wellness interventions,” Calabrese said. “The issue is that they do not have the time, expertise or confidence to engage with this kind of therapy.”

Calabrese added that many DOs and MDs are loath to refer their patients to “alternative therapies,” for fear that they may default on immune-based treatment. “We believe that wellness behavioral modification must complement targeted and aggressive therapy,” he said. “We believe it can provide an empowering message to improve not only self-efficacy among patients, but, ultimately, medication adherence.”

This message is starting to gain validation. Further conclusions from the Katz paper showed that the most effective approaches to reducing RA fatigue appear to be behavioral — such as increasing physical activity — or cognitive — such as cognitive behavioral interventions.

Katz suggested that the simple approach may be the best approach. “People just need to move more and sit less,” she said.

Until the mechanism of fatigue is completely understood — and, admittedly, it is entirely possible that it will never be understood — Calabrese encouraged rheumatologists to continue to talk to their patients about it. If they lack the confidence or know-how to follow-up on a wellness regimen, he noted that a wealth of materials is available online, including from the Cleveland Clinic.

But Calabrese believes that the current moment is a “new era in wellness,” with robust data being reported in “high impact” publications. This is not to mention the notion that COVID-19 “taught us that wellness behavior is critical to survival,” he said. “This is all incredibly validating for those of us who have been interested in fatigue for a long time.”

• References:
• Azizoddin DR, et al. Lupus. 2019;doi:10.1177/0961203318817826.
• Barbacki A, et al. J Rheumatol. 2019;doi:10.3899/jrheum.180831.
• Fertelli TK, et al. Pak J Med Sci. 2019;doi:10.12669/pjms.35.4.383.
• Katz PE. Curr Opin Rheumatol. 2017;doi: 10.1097/BOR.0000000000000376.
• Pearson NA, et al. Rheumatol Adv Prac. 2018;doi:10.1093/rap/rky017.
• Pope JE. RMD Open. 2020;doi: doi: 10.1136/rmdopen-2019-001084.
• Sveaas SH, et al. Phys Ther. 2020;doi:10.1093/ptj/pzaa086.