The recently defined COPA mutation is responsible for the development of a syndrome characterized by rheumatoid factor positive RA, interstitial lung disease with pulmonary hemorrhage and ANCA-positive vasculitis. This autosomal-dominant transmitted mutation, a 14-residue region of the WD40 domain of the ubiquitously expressed gene for COPA, encodes a resident chaperone protein in the endoplasmic reticulum. An aberration in the structure of this protein results in the development of a rheumatologic disorder that is virtually identical to RA with lung disease and in some patients, a systemic vasculitis.
A dear patient of mine was recently identified as having this mutation in her genome. She is a member of one of the five families with multiple individuals afflicted by pulmonary hemorrhage who were studied in the original report.8 Her physical exam, imaging studies and lab tests were all consistent with a classical presentation of RA. Her episode of acute pulmonary hemorrhage displayed all the appearances of a systemic vasculitis, including a positive ANCA antibody along with an active urinary sediment with a rising serum creatinine. She responded to treatment with intravenous cyclophosphamide, and over the ensuing years, her “RA” has been adequately controlled with a combination of drugs, although her pulmonary function continues to slowly decline.
Undoubtedly, the identification of these subsets of patients carrying unique genetic features will alter our understanding of what drives autoimmunity, and we can get even more precise in creating targeted therapies.
Another example of moving the bench to the clinic is the emerging use of various forms of molecular diagnostics in establishing diagnoses of rare or hard-to-diagnose conditions. You can’t call yourself a rheumatologist if you haven’t experienced the situation in which a patient has an array of abnormal findings yet a conclusive diagnosis remains elusive. Now, there are ways to move beyond this diagnostic roadblock. Consider the use of metagenomics deep sequencing (MDS) that was recently described in these pages.
MDS is an unbiased, hypothesis-free approach toward infectious disease diagnosis that leverages the remarkable efficiency of massively parallel sequencing technologies paired with concomitant advances in computational algorithms and processing speed that is required for the resulting large volumes of sequence data. It’s now possible to sequence all the nucleic acid in a patient sample, filter out all the human sequences and then rapidly query large public databases to identify the source of the nonhuman sequences present in the sample. It’s akin to searching massive databases for one exact phrase—the ultimate needle in a haystack.