PPMS had lower seroprevalence of EBV IgG (81.0%) than RRMS (93.5%) and SPMS (100%) ( < 0.001 for both). SPMS (36.4%) and RRMS (15.2%) showed more anti-EBV-IgM reactivation than PPMS (0%)
US Army and Navy Physical Disability Agency and the Department of Defense Serum Repository
Department of Defense Serum Repository
148/74
Epstein-Barr virus (EBV)
Incident
Risk of developing RRMS increased with a 4-fold increase in average anti-EBNA-1 IgG titers (RR: 2.3, 1.7–3.2) and anti-EBNA complex titers (RR: 3.3, 2.3–4.7)
Epstein-Barr virus (EBV) Human herpesvirus-6 (HHV-6) Chlamydia pneumoniae (CP)
Prevalent (mean disease duration = 1.8 years RRMS; 15.9 years SPMS)
RRMS patients had higher levels of anti-HHV-6 IgM antibody titers than healthy controls (15.02 versus 10.19, = 0.002). No statistically significant difference between RRMS, SPMS, and healthy controls for anti-EBV EBNA IgG or anti-CP antibodies
Higher proportion of RRMS patients were seropositive for remote EBV infection (19/22) compared to healthy age and sex-matched controls (35/77, = 0.008)
Clinic-based; healthy controls (34) and other neurological disease (3)
11/25
Human herpesvirus-6 (HHV-6)
Prevalent (disease duration not reported)
24% (6/24) of RRMS patients, 40% (2/5) of SPMS patients, and 24.2% (8/33) of controls were HHV-6 positive. No statistically significant difference in the presence of HHV-6 viral DNA between any of the groups ( > 0.05)
36/66 (controls: 14 healthy controls, 31 OND, and 21 OID)
RRMS (22)
PPMS (14)
Clinic-based
Clinic-based; healthy controls and OND or OID
NR
Human herpesvirus-6 (HHV-6)
Prevalent (disease duration not reported)
Increased IgM response to early antigen of HHV-6 in RRMS compared to healthy controls ( < 0.001). No differences in IgG response among any groups tested
No differences in IgG or IgM response in PPMS versus controls ( = 0.06) or RRMS ( > 0.05)
Army RRMS () SPMS ( Unknown ( KPMCP RRMS () SPMS OR PPMS ( Unknown (13
Army PPMS (15) Unknown (18 KPMCP SPMS OR PPMS (26 Unknown (13
US Army Physical Disability Agency Database and the Kaiser Permanente Northern California Health Plan (KPMCP)
US Army Physical Disability Agency Database and the Kaiser Permanente Northern California Health Plan (KPMCP); healthy controls
60/69
Chlamydia pneumoniae (CP)
Incident
CP seropositivity did not predict risk of RRMS (OR: 0.8; 0.4–1.7). Fourfold difference in titer levels of anti-CP IgG antibodies did not increase risk for RR course at onset (OR: 0.9; 0.6–1.3)
CP seropositivity did not predict risk of PPMS (OR: 1.0; 0.3–3.7). Fourfold difference in titer levels of anti-CP IgG antibodies did not increase risk for PPMS course at onset (OR: 1.1; 0.6–2.0)
Of the ever smokers starting before the age of 15 ( = 29); 11 (38%) had a progressive onset versus 6 of the 46 never smokers (13%) ( = 0.012). note: only a subgroup were included in the analysis: 17 progressive onsets and 58 relapsing onsets.
14,799 MS cases 13,783 unaffected siblings 13675451 population controls
RRMS/SPMS (11,465)
PPMS (3334)
Canadian Collaborative Project on Genetic Susceptibility to MS
Unaffected siblings and Canadian population controls
Not reported
Month of birth
Prevalent (disease duration not reported)
Birth ratio (May/November) was higher for RRMS compared to controls (1.43 versus 1.18, = 0.000032)
Birth ratio (May/November) was not significantly different for PPMS compared to controls (1.15 versus 1.18, > 0.05)
18
CIS = clinically isolated syndrome. NA = not applicable. NR = not reported. OID = other inflammatory disease. OND = other neurological disease. PPMS = primary progressive multiple sclerosis. RRMS = relapsing-remitting multiple sclerosis. SPMS = secondary progressive multiple sclerosis. These individuals did not contribute to the main findings/statistics reported in the final columns. CIS patients not included, unless otherwise stated. 22 PPMS patients were included in the analysis (Table 2 from original paper) despite =20 PPMS patients reportedly included in the overall study. †Quality assessment was based on the Modified Downs and Black criteria for observational studies [37]. The assigned score could range from 0 to 20; a higher score implies better quality.
