Immunoglobulin Deficiency a Treatable Cause of Fatigue in Patients With Multiple Sclerosis (MS)?

Multiple sclerosis (MS) is the most common cause of mental and physical disability in young adults affecting approximately 10'000-15'000 persons in Switzerland (incidence 16/100000; prevalence 190/100000). MS-fatigue affects at least 75% of the MS-patients (affected persons in Switzerland 7500-11250). MS-related fatigue has socioeconomic consequences leading to increased sick leaves and a higher probability of unemployment. Effective treatment strategies for MS-fatigue are missing, despite the appearance of more effective immunotherapies to treat autoimmune neuroinflammation and to control MS disease activity. The reason for the lack of therapeutic options is the unclear pathophysiological mechanism of fatigue with many non-MS associated influencing factors like thyroid dysfunction and anaemia.

Fatigue is also present in other inflammatory diseases, cancers and immunodeficiency syndromes. Regarding the latter patients with primary immunodeficiencies (PIDs) and common variable immunodeficiency (CVID) suffer from fatigue in 30 - 76%, which is more common than in the normal population. Studies investigating immunoglobulin replacement therapy in patients with CVID demonstrated a correlation between the frequency of infusions / s.c. applications and wear-off effect/fatigue.

Immunoglobulin deficiency seems to be much more common in people with autoimmune diseases. In MS reduced serum immunglobulin G (IgG) concentrations regardless of immunotherapy affect between 8 - 26% of the patients. Nonetheless consequences of IgG hypogammaglobulinemia in MS are partly unknown. However, based on the findings in patients with CVID, fatigue might be one of them. To close this knowledge gap prospective observational studies are needed.

Inclusion criteria

• Diagnosis of Multiple Sclerosis following McDonald 2017-Criteria
• Age 18-65 years
• Stable MS disease at inclusion (definition: no clinical relapse, no MRI activity, stable disability within the last 12 months)
• Unchanged immunotherapy within the last 12 months
• Expanded Disability Status Scale (EDSS) level <4 points indicating fully ambulatory patients.
• Capability of written informed consent

Exclusion criteria

• Severe depression (definition: Beck Depression Index-II (BDI-II) ≥29 points) or other established psychiatric diagnosis
• Immunodeficiency other than hypogammaglobulinemia
• Immunglobulin replacement therapy or indication for immunoglobulin replacement therapy
• Severe Sleepiness (definition: Epworth-Sleepiness-Scale (ESS) >16 points)
• Fatigue aggravating factors such: liver/renal/thyroid dysfunction, substance abuse, medication (tranquilizers /antiepileptics/psychopharmaceuticals), chronic infectious disease (like hepatitis/HIV).
• Other neurodegenerative/autoimmune disease.
• Patients not able to give written consent
• Vulnerable patients such as children, pregnant women and prisoners