The Biological Basis of Sjogren’s Fatigue

Fatigue- Part 4

To get the most out of this post, be sure to read Parts 1-3 of the Fatigue series. Part 1- Fatigue: The Top Unmet Need Part 2- The Major Categories of Fatigue Part 3- The Causes of Fatigue

Why Isn’t Sjogren’s Fatigue Taken Seriously? Have you ever tried to get help for fatigue, only to be dismissed?  Sjogren’s patients are often told that Sjogren’s fatigue "isn't that bad," that it must be caused by something else, or that nothing can be done. Despite its devastating impact on daily function and quality of life, fatigue gets little attention.

This happens in part because doctors are rarely taught the biological basis of Sjogren's fatigue. As a result, they may fail to take it seriously, default to psychological or lifestyle explanations, or conclude that it is not their job to evaluate and treat it.

The purpose of this post is to highlight the specific biological mechanisms driving Sjogren’s fatigue. This information, along with the “laundry list” on Fatigue Part 3, will give you tools to advocate for proper medical evaluation and management. An upcoming post will provide more strategies to help you communicate effectively with your doctors about fatigue.

The Web of Biological Pathways   Sjogren’s fatigue does not have a single, specific cause. Instead, it is driven by a highly complex web of interconnected biological processes (283). It is not a simple, linear progression where immune and cellular changes cause inflammation, and more inflammation automatically equals more fatigue. Here are the biological processes that researchers have identified to date:

1.Immune System Dysregulation and Inflammation Inflammation and Immune dysfunction are thought to be the core drivers of fatigue as well as the many other systemic features of the disease. Although inflammation plays an important role, it may not be what you expect.  

The Fatigue-Inflammation Paradox: While it seems logical to assume that higher inflammation equals more severe fatigue, research suggests the opposite may be true. The downregulation (or suppression) of inflammation appears to be a central mechanism driving Sjogren’s fatigue (204).  It’s like driving a car with the brakes on.  

Standard blood tests for inflammation and systemic disease activity (CRP, ESR, and ESSDAI) do not correlate with fatigue in Sjogren’s. Nearly all Sjogren's pateints experience life-altering fatigue, but it is more severe, on average, in SSA-negative patients.

Treatment Implications Fortunately, new therapies currently in clinical trials target specific immune system abnormalities, and a handful of potential new drugs look promising for reducing fatigue. Hydroxychloroquine (HCQ), an immunomodulator is already widely used, and many patients find it helpful for managing their fatigue symptoms.

2. Mitochondria dysfunction and damage Mitochondria produce the energy our cells need to function. Recent research has demonstrated abnormal mitochondrial function in Sjogren’s (284). When mitochondria cannot keep up with daily energy needs, it causes severe fatigue and functional loss. It is like running on a low battery that never fully recharges. Malfunctioning mitochondria can damage tissues and trigger even more inflammation.  3. Autonomic disorders (dysautonomia) Autonomic disorders Autonomic disorders are common neurological conditions caused directly by Sjogren’s. Although they are a leading cause of severe fatigue and work disability, these treatable conditions are frequently overlooked. Furthermore, despite being distinct physical manifestations of the disease, they are often mistaken for anxiety or functional neurological disorder (FND). 4. Genetics Studies show a genetic susceptibility to fatigue in Sjogren’s patients (283).

5. Systemic (non-sicca) involvement:  Below are examples of how systemic manifestations can contribute to Sjogren’s fatigue. (Not a complete list):

• Lungs: Lung involvement can lead to inadequate oxygen delivery to the bloodstream.

• Kidneys: Kidney disease can cause electrolyte abnormalities, leading to muscle weakness and fatigue.

• Brain: Inflammation can cause demyelinating disease (resembling Multiple Sclerosis). Central nervous system involvement may also be the origin of the high rates of migraines, severe headaches, cognitive dysfunction ("brain fog"), and sleep disturbances seen in patients. All these conditions can cause physical fatigue.

Emerging Research

The following factors (items 6-8) may play a significant role in Sjogren’s fatigue, but more research is needed to fully understand their impact.

6. Neuroinflammation/ neuroimmune dysfunction Sjogren’s is likely, in part, a neuroimmune axis disorder. A dysregulated immune system activation and inflammation can cause damage or dysfunction of the peripheral and central nervous system. In turn, the stressed nervous system signals back to the immune system, fueling more inflammation.

7.  Gut dysbiosis Due to lack of research, there is no direct evidence that altered gut microbiome contributes to Sjogren’s fatigue, although this is certainly possible or even likely. At a minimum, dysbiosis (abnormal gut microbiome) can contribute to nutritional deficiencies, which are known to cause or worsen fatigue.

8. Mast cell activation syndrome (MCAS) Mast cells are white blood cells crucial to the immune system. Scientists are increasingly studying their potential role in driving both dysautonomia and systemic autoimmune diseases.

The Takeaway Fatigue is a biologically based, core systemic feature of Sjogren’s. While science cannot yet pinpoint exactly how different biological processes causes interact or why they vary from person to person, this complexity explains why patients respond differently to the same treatments.

Although more research is needed, current evidence can help you counter misconceptions, communicate more effectively with your clinicians, and pursue an individualized treatment plan tailored to your unique situation.

Looking Ahead:  An upcoming post in this series will provide specific tips and strategies for communicating with your medical team about fatigue.