Sporadic inclusion body myositis: variability in prevalence and phenotype and influence of the MHC

Abstract

Sporadic inclusion body myositis (sIBM) is the most common myopathy presenting over the age of 40 years but its prevalence varies considerably in different populations. Genetic factors play a part in the pathogenesis of sIBM and in Caucasians susceptibility has been linked to the HLA-DR3 allele and the 8.1 MHC ancestral haplotype (AH) which is also associated with other autoimmune diseases. The variable prevalence of sIBM in different populations may be related to differences in the population frequency of this haplotype. Our recent observations indicate that the clinical phenotype at presentation is also quite variable and that the influence of the MHC is more complex than previously appreciated with HLA alleles also having modifying effects on the age-at-onset, severity and rate of progression of the disease. Recent recombinant mapping studies of polymorphisms in the Class II/III regions of the MHC by our group have further refined the susceptibility region and have identified a number of candidate genes warranting further investigation. The significance of these findings for the pathogenesis of the disease is discussed.

Figure 1

Distribution of age of onset of symptoms in a cohort of 56 Australian sIBM patients. (Reproduced from Needham et al., Journal of Neurology, Neurosurgery and Psychiatry, 2008;79:1056-1060 with permission from the BMJ Publishing Group).

Figure 2

Presenting symptoms in a cohort of 56 Australian sIBM patients. (Reproduced from Needham et al., Journal of Neurology, Neurosurgery and Psychiatry, 2008;79:1056-1060 with permission from the BMJ Publishing Group).

Figure 3

A and D: Asymmetric weakness of the finger flexors in two sIBM patients with more severe weakness of the non-dominant hand in each case. C and D: Atrophy of the quadriceps femoris muscles in two patients with longstanding sIBM.

Figure 4

Muscle biopsy findings in a 61 year old man with a 20 year history of untreated IBM. A and B: From a vastus lateralis biopsy showing chronic changes with interstitial fibrosis, myofibre atrophy and a fibre with rimmed vacuoles (arrow), and sparse inflammation (A); invasion of a non-necrotic muscle fibre by mononuclear cells (arrow) (B). C and D: From a deltoid biopsy showing a ragged-red fibre (C) and multiple blue-staining COX-negative fibres (D).

Figure 5

Biopsies from deltoid (A and B) and biceps muscles (C and D) in a 35 year old male with a 3 year history of sIBM showing endomysial mononuclear inflammatory infiltrates and myofibre invasion (A); diffuse MHC-1 upregulation (C); and multiple blue-staining COX-negative fibres in both muscles, which are more atrophic in the biceps muscle (B and D). Fibres with rimmed vacuoles were present but were sparse in both muscles.

Figure 6

Schematic outline of the pathogenesis of sporadic inclusion body myositis.

Figure 7

Kaplan-Meier plots of quadriceps muscle strength adjusted for disease duration and treatment in DR3 carriers and non-carriers.

Figure 8

Family tree showing a mother and son who suffered from inclusion body myositis. The mother was a carrier of HLA-B8, DR3 and the 8.1 ancestral haplotype (AH) whereas the son carried HLA-B5, DR15 and the 52.1 ancestral haplotype.

Figure 9

Differential rate of decline in Functional Assessment Score (FAS) in the mother and son from Figure 8 showing a more rapid progression in the son.