Interaction between HLA-DR2 and abnormal brain MRI in optic neuritis and early MS

Methods.

The design of the ONTT has been described in prior publications.6 In brief, the study enrolled 457 patients between 1988 and 1991 subject to the following criteria: diagnosis of acute unilateral ON with visual symptoms of 8 days or less, age between 18 and 46 years, no previous history of ON or ophthalmoscopic signs of optic atrophy in the affected eye, no evidence of a systemic disease other than MS that might be associated with ON, and no previous treatment with corticosteroids for ON in the fellow eye or for MS. Patients were assigned randomly to receive oral placebo, oral prednisone, or IV methylprednisolone followed by oral prednisone, and were followed to assess visual recovery and development of MS. The study protocol was approved by the institutional review board at each clinical center. Written informed consent was obtained from each patient.

Participation in the human leukocyte antigen (HLA) typing study was optional for both clinical centers and patients. Thirteen of the 15 clinical centers and 178 (45%) of the 392 patients enrolled at these centers agreed to participate. Collection of samples took place between March 1995 and October 1996, which corresponded to follow-up years 4 to 7 depending on patient start date.

Results.

Of the 178 patients, 80% were women and 92% were white; the mean age was 33 ± 7 years. Compared with the 279 ONTT patients who did not participate in the HLA study, the participants had a similar gender distribution (80% women versus 75%, p = 0.26), were more likely to be white (92% versus 81%, p = 0.002), and were slightly older at study entry (33 ± 7 years versus 31 ± 6 years, p = 0.003). It is unlikely that these differences were sufficient to produce any meaningful bias.

At study entry, CDMS was present in 19 patients (11%) and probable MS was present in 11 patients (6%). After 5 years, CDMS was the diagnosis of 75 patients (42%) and probable MS was the diagnosis of 21 patients (12%). Among the 103 patients without CDMS at 5 years, the 5-year follow-up was complete for all but one patient.

HLA haplotype DR2 was present in 85 (48%) of the 178 patients, and was more prevalent when there was clinical evidence of MS at 5 years (p = 0.04; table 1). With only two exceptions—both African-Americans, who were DRB1*1503 positive—all DR2 alleles were typed as DRB*1501. HLA-DR2 was associated with an increased odds of MS at 5 years (OR for CDMS, 1.77; exact 95% CI, 0.93 to 3.39; p = 0.08; OR for probable or definite MS, 1.92; exact 95% CI, 1.01 to 3.67; p = 0.04). Adjusting for baseline MRI results did not change this association appreciably (table 2). However, the association between HLA-DR2 and MS was most apparent among patients with abnormal baseline brain MRI (see table 2).

Discussion.

A high prevalence of DR2 was present in this cohort of patients with acute unilateral ON. This finding is consistent with earlier studies of HLA genes in which the DR2 association was nearly as strong for ON as for MS.5 We also confirm that DR2 is associated with evolution of ON to MS, as reported in some, but not other, earlier reports.5 The predictive power of HLA typing in ON was weak compared with an abnormal MR image, an expected observation considering the relatively high prevalence of DR2 in healthy white people, and the specificity of MRI abnormalities for MS. Unexpected was the strong association observed between DR2 and MS among ON patients with abnormal baseline MRI, and the absence of this association in patients whose MRI results were normal. Although derived from a relatively small number of observations, which limits the statistical power, this nevertheless suggests that multifocal disease at onset may be influenced by the HLA status of the individual, specifically by DR2 itself or by another gene in linkage disequilibrium with DR2.

Disease heterogeneity is an important emerging concept in MS. Neuropathologic studies support the concept that more than one form of MS exists, defined by whether the oligodendrocyte or the myelin sheath is the initial target of injury, and by whether evidence of antibody-mediated tissue damage is present.8,9 One clinical example of a restricted variant of MS is primary progressive MS, which in whites is characterized by common occurrence in men, little inflammation, few cerebral lesions, frequent spinal cord disease, and a prominent axonal pathology.10 In another example, two clinical forms of MS have been described in Japan.2 The first, a disseminated disorder with widespread brain lesions detected by MRI, resembles MS in white people and is associated with DR2. The second, a relapsing–remitting or progressive disorder with predominant spinal cord and optic nerve involvement is not DR2 associated. Thus, at least in some situations, DR2-negative individuals may have a propensity to develop topographically restricted forms of demyelinating disease.