Fatigue in primary Sjögren’s syndrome: A proteomic pilot study of cerebrospinal fluid | 24 June 2019

June 24, 2019

Dr Charles Shepherd, Hon. Medical Adviser, ME Association.

This is a recent and very interesting approach to the investigation of central (brain) fatigue in Sjogren’s Syndrome (SS) – an autoimmune condition that has some important clinical and pathological overlaps with ME/CFS.

Nerve Cells Concept Source: 123RF/Ralwel

In addition to the very debilitating chronic fatigue that is often found in people with SS, other core symptoms include joint pains and dry eyes/mouth (which is why SS should always be considered in someone with ME/CFS who also has a significant problem with dry eyes) and neurological sensory and autonomic dysfunction symptoms.

The neurological sensory symptoms in SS may also be related to the presence of what is called dorsal root ganglionitis – inflammation in bundles of nerves that lie just outside the spinal cord.

The same pathological finding has been discovered in some of the post-mortem examinations that we have been involved with in people with ME/CFS.

The new SS research involves the collection of cerebrospinal fluid through a lumbar puncture and then looking for changes in specific proteins (proteomics) that have important roles in the regulation of innate immunity, cellular stress defence, and other regulatory functions in the central nervous system.

This is not a straightforward piece of research to arrange, however, it is something worth considering in ME/CFS and I will be discussing these recent findings with my research colleagues later in the week.

More information:

  1. Information on the overlap between ME/CFS and SS can be found in the clinical assessment section of the ME Association clinical and research guide (The ‘Purple Book’).
  2. General information on symptoms, diagnosis and management of Sjogren’s Syndrome from NHS Choices.

Fatigue in primary Sjögren’s syndrome: A proteomic pilot study of cerebrospinal fluid

First Published: May 2019

Eivind Larssen et al. Research Department, Stavanger University Hospital, Stavanger, Norway


Fatigue is a frequent and often disabling phenomenon that occurs in patients with chronic inflammatory and immunological diseases, and the underlying biological mechanisms are largely unknown. Because fatigue is generated in the brain, we aimed to investigate cerebrospinal fluid and search for molecules that participate in the pathophysiology of fatigue processes.

A label-free shotgun proteomics approach was applied to analyze the cerebrospinal fluid proteome of 20 patients with primary Sjögren’s syndrome. Fatigue was measured with the fatigue visual analog scale.

A total of 828 proteins were identified and the 15 top discriminatory proteins between patients with high and low fatigue were selected. Among these were apolipoprotein A4, hemopexin, pigment epithelium-derived factor, secretogranin-1, secretogranin-3, selenium-binding protein 1, and complement factor B.

Most of the discriminatory proteins have important roles in regulation of innate immunity, cellular stress defense, and/or functions in the central nervous system. These proteins and their interacting protein networks may therefore have central roles in the generation and regulation of fatigue, and the findings contribute with evidence to the concept of fatigue as a biological phenomenon signaled through specific molecular pathways.

Extracts from the full paper:


Fatigue can be defined as an overwhelming sense of tiredness, lack of energy, and a feeling of exhaustion.1

It is a frequent and often disabling phenomenon that occurs in patients with chronic immunological diseases, cancer, neurological diseases, and several other conditions in which inflammation and/or cellular stress occurs.2 Nevertheless, chronic fatigue has a substantial impact on the patient’s quality of life and is a major cause of sick leave and disability.

It is a common view that inflammation and disease activity directly influence the severity of fatigue, and several studies have reported associations between fatigue and inflammatory markers such as C-reactive protein, pro-inflammatory cytokines, and other variables.3,4 

However, some authors question these observations and argue that studies using fatigue instruments that do not capture elements of disease activity (generic fatigue instruments) do not confirm these associations.5,6 

Another seemingly contradictory observation is that instead of experiencing relief, fatigue worsens during chemotherapy or radiation treatment in cancer patients.7 

In chronic fatigue syndrome (CFS)—a much-debated condition in which no specific underlying disease can be revealed—several inconsistent disturbances in genetic, immunological, and molecular markers have been described over the years, so far with no definite and uniform overarching theory and conclusion reached.8,9

The biological mechanisms that cause fatigue are largely unknown, the hypotheses are conflicting, and it is important to uncover the pathophysiology and identify signaling pathways that generate and regulate this important phenomenon.2,10,11


In this study, a CSF protein pattern associated with the level of fatigue in pSS patients was identified, with many novel protein candidates detected. Several of these proteins have important functions in the central nervous system and add evidence to the concept of fatigue as a cerebral phenomenon.

Of special interest is that some of the proteins are associated with severe depression (hemopexin, apolipoprotein A4, pigment epithelium-derived factor, and secretogranin-3) and/or loss of appetite (apolipoprotein A4, selenium-binding protein 1, and secretogranin-3), which are cardinal findings of sickness behavior, in which fatigue constitutes a major element.

In addition, three of the 15 proteins have previously been identified in the CSF of patients with CFS (hemopexin, pigment epithelium-derived factor, and secretogranin-3) …

In general, our findings correspond to an increasing understanding of fatigue as part of the “sickness behavior response” observed during damage, cellular stress, infection, or chronic inflammation.2,12 

Sickness behavior is characterized by fatigue, sleepiness, depression, social withdrawal and loss of appetite, thirst and grooming, and is hypothesized to be an automated and non-conscious survival enhancing strategy that is deeply conserved during evolution.27 

In the individual, the protective molecular processes of cellular life are complemented by an element of survival behavior. In states of chronic inflammation and autoimmunity, these mechanisms are constantly active, and fatigue is chronic.

The significance of our findings is strengthened by the associations with other highly relevant proteins in the pathway analysis (Figure 3), which illustrates the interplay between pro-inflammatory signals, downregulation of inflammation, and cellular protection against oxidative stress and other cellular stressors.

In line with this, we recently showed that heat shock protein 90 in blood is strongly associated with increased fatigue in patients with pSS.26 

Only a few previous studies have investigated the CSF proteome in states with chronic fatigue, such as post-treatment Lyme disease,28 multiple sclerosis,29 Persian Gulf War syndrome, fibromyalgia, and CFS.30

[30. Baraniuk, et al. A chronic fatigue syndrome—related proteome in human cerebrospinal fluid. BMC Neurol 2005; 5: 22.]

It is necessary to validate the present findings in CSF of other diseases characterized by fatigue, as well as in blood, a much more easily accessible fluid than CSF. Whether some of the proteins may represent consistent biomarkers of fatigue for future research and routine diagnostics, therefore, remains to be seen.

In conclusion, the present findings give further support to the concept of fatigue as a sickness behavior phenomenon that has been strongly conserved during evolution, generated and regulated through a redundancy of molecular signaling pathways to the brain.

The findings also support the hypothesis that fatigue signaling is in part associated with cellular stress defense mechanisms, wound healing, and both up- and downregulation of innate immunity. This can explain the frequent finding of lack of association between severity of fatigue and disease activity in several studies.

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