Table 5.

Overview of risk factors related to MS onset symptom classes.

	Involved latent classes	Findings	First line interpretation(s)	Alternative or specific interpretation(s)
Infectious mononucleosis (IM)/Epstein Barr virus (EBV)	LC6 and LC3 with increased proportions LC4 and LC2 with decreased proportions	• IM is indicative of an EBV infection • EBV seropositive status is highly prevalent (>90% of population); hoever, persons with a seronegative status do not develop MS (40–42) • IM is more frequent when the EBV infection occurs later than in childhood, i.e., in adolescence and adulthood (43) • EBV the most securely established risk factor in MS (41, 44) • IM is per se an additional risk factor for MS (43)	• Higher proportions of IM hint at delayed EBV infections • A delayed EBV infection with (and without) IM increases the MS risk	• Subjects with a “resilient,” i.e., well-trained and well-regulated immune system less frequently experience manifest outcomes of common infections (30, 45), thus report also lower rates of mononucleosis (e.g., LC4 and LC2 members)
Angina/Tonsillitis	LC3 with increased proportion	• Tonsillitis is a risk factor of MS (46) • Tonsillectomy is a risk factor of MS (47–50)	• Upper respiratory tract inflammation (URTI) increases MS risk	• URTI (as a comprehensive category) does not predict RRMS (51) • The comorbidity of tonsillectomy with other autoimmune diseases [e.g., Crohn's disease (52, 53) and others (50)] indicates a more generalized deficiency of the immune system
Smoking	LC1 and LC3 with increased proportions	• Established risk factor of MS (54) • Also a risk factor regarding disease progression (55), including axonal desintegration (56) and a predictor of the number of functional domains involved (5) • Even passive smoking increases the risk of MS (57–59) • Snuff does not increase the risk of MS (60)	• Smoking contributes to URTI	• The comorbidity of smoking with many other autoimmune and chronical inflammatory diseases indicates a more generalized deficiency of the immune system
Migraine	LC3 with increased proportion	• Migraine increases the risk of MS and, vice versa, MS increases the risk of migraine (61)	• Migraine (in particular migraine with aura) could lead to an increase of the BBB permeability (61)	• Migraine could emerge in a pre-symptomatic MS phase (61)
Skin diseases	LC3 with increased proportion	• Reported associations between MS and skin diseases relate to psoriasis (62–64) • Onset of psoriasis preceding MS onset yields a severity-response relationship (63)	• Increased levels of TNF-α and IL17 in both diseases (63)
Autoimmune diseases	LC1 with increased proportion	• Increased comorbidity with autoimmune diseases typically includes inflammatory bowel disease, thyroid disease, psoriasis (65–68) • Comorbidity between RA and MS may be reduced (69)	• The comorbidity with other autoimmune and chronical inflammatory diseases indicates a more generalized deficiency of the immune system