Risk of Coccidioidomycosis Infection Among Individuals Using Biologic Response Modifiers, Corticosteroids, and Oral Small Molecules.

OBJECTIVE: The study objective was to examine associations between the use of biologic response modifiers (BRMs), corticosteroids, and oral small molecules (OSMs) and subsequent coccidioidomycosis infection risk among US Medicare beneficiaries with rheumatic or autoimmune diseases. METHODS: This retrospective cohort study used US 2011 to 2016 Medicare claims data. We identified geographic areas with endemic coccidioidomycosis (≥25 cases per 10,000 beneficiaries). Among beneficiaries having any rheumatic/autoimmune diseases, we identified those initiating BRMs, corticosteroids, and OSMs. Based on refill days supplied, we created time-varying exposure variables for BRMs, corticosteroids, and OSMs with a 90-day lag period after drug cessation. We examined BRMs, corticosteroids, and OSMs and subsequent coccidioidomycosis infection risk using multivariable Cox proportional hazard regression. RESULTS: Among 135,237 beneficiaries (mean age: 67.8 years; White race: 83.1%; Black race: 3.6%), 5,065 had rheumatic or autoimmune diseases, of which 107 individuals were diagnosed with coccidioidomycosis during the study period (6.1 per 1,000 person-years). Increased risk of coccidioidomycosis was observed among beneficiaries prescribed any BRMs (17.7 per 1,000 person-years; adjusted hazard ratio [aHR] 3.94; 95% confidence interval [CI] 1.18-13.16), followed by individuals treated with only corticosteroids (12.2 per 1,000 person-years; aHR 2.29; 95% CI 1.05-5.03) compared to those treated with only OSMs (4.2 per 1,000 person-years). The rate of those treated with only OSMs was the same as that of beneficiaries without these medications. CONCLUSION: Incidence of coccidioidomycosis was low among 2011 to 2016 Medicare beneficiaries with rheumatic or autoimmune diseases. BRM and corticosteroid users may have higher risks of coccidioidomycosis compared to nonusers, warranting consideration of screening for patients on BRMs and corticosteroids in coccidioidomycosis endemic areas.

New molecular mechanism for Ullrich congenital muscular dystrophy: a heterozygous in-frame deletion in the COL6A1 gene causes a severe phenotype.

Recessive mutations in two of the three collagen VI genes, COL6A2 and COL6A3, have recently been shown to cause Ullrich congenital muscular dystrophy (UCMD), a frequently severe disorder characterized by congenital muscle weakness with joint contractures and coexisting distal joint hyperlaxity. Dominant mutations in all three collagen VI genes had previously been associated with the considerably milder Bethlem myopathy. Here we report that a de novo heterozygous deletion of the COL6A1 gene can also result in a severe phenotype of classical UCMD precluding ambulation. The internal gene deletion occurs near a minisatellite DNA sequence in intron 8 that removes 1.1 kb of genomic DNA encompassing exons 9 and 10. The resulting mutant chain contains a 33-amino acid deletion near the amino-terminus of the triple-helical domain but preserves a unique cysteine in the triple-helical domain important for dimer formation prior to secretion. Thus, dimer formation and secretion of abnormal tetramers can occur and exert a strong dominant negative effect on microfibrillar assembly, leading to a loss of normal localization of collagen VI in the basement membrane surrounding muscle fibers. Consistent with this mechanism was our analysis of a patient with a much milder phenotype, in whom we identified a previously described Bethlem myopathy heterozygous in-frame deletion of 18 amino acids somewhat downstream in the triple-helical domain, a result of exon 14 skipping in the COL6A1 gene. This deletion removes the crucial cysteine, so that dimer formation cannot occur and the abnormal molecule is not secreted, preventing the strong dominant negative effect. Our studies provide a biochemical insight into genotype-phenotype correlations in this group of disorders and establish that UCMD can be caused by dominantly acting mutations.