Bernard Ng

A retrospective cohort study: 10-year trend of disease-modifying antirheumatic drugs and biological agents use in patients with rheumatoid arthritis at Veteran Affairs Medical Centers

Objectives To evaluate the trends in patterns of disease-modifying antirheumatic drugs (DMARDs) and biological agents use from 1999 to 2009 and to identify patient characteristics associated with different patterns of their use in a national sample of Veterans with rheumatoid arthritis (RA). Design A retrospective cohort study. Settings Administrative databases of the USA Department of Veterans Affairs. Participants An incident cohort of 13 254 patients with newly diagnosed RA was identified. Primary outcome measures Trends and choice of DMARDs and biological agents’ usage, and time intervals between RA diagnosis and treatment Results Methotrexate use as first-line agent increased from 39.9% to 57.2% over the study period (p<0.001). Although biological dispensations increased over other DMARDs and biological agents, from 3.4% to 25% from 1999 to 2009, the percentage of RA patients diagnosed between 1999 and 2007 who had biologics dispensations remained steady at 23.3–26.7%. Compared with Caucasian, African Americans were less likely to receive biologics (HR 0.71, 95% CI 0.63 to 0.81). Patients aged 75 and older were less likely to receive biologics than those younger than 45 (HR 0.29, 95% CI 0.23 to 0.36). The time interval between RA diagnosis and treatment with DMARDs and biological agents decreased significantly over time (median: 51 days in 1999–2001 to 28 days in 2006–2007). Conclusions Methotrexate use increased as it became the preferred first-line agent, while other traditional agents declined. Dispensation of biologics increased significantly, but the proportion of RA patients eventually given biologics stabilised below 30%. A significant shorter time between RA diagnosis and DMARD or biological agent initiation in recent years suggests improvements in quality of care. There were disproportionately lower use of biologics in certain age and ethnic groups, and further studies will be needed to elucidate these observations.

Bcl-xL inhibits T-cell apoptosis induced by expression of SARS coronavirus E protein in the absence of growth factors

One of the hallmark findings in patients suffering from SARS (severe acute respiratory syndrome) is lymphopenia, which is the result of massive lymphocyte death. SARS-CoV (SARS coronavirus), a novel coronavirus that has been etiologically associated with SARS cases, is homologous with MHV (murine hepatitis coronavirus), and MHV small envelope E protein is capable of inducing apoptosis. We hypothesized that SARS-CoV encodes a small envelope E protein that is homologous with MHV E protein, thus inducing T-cell apoptosis. To test this hypothesis, a cDNA encoding SARS-CoV E protein was created using whole gene synthesis. Our results showed that SARS-CoV E protein induced apoptosis in the transfected Jurkat T-cells, which was amplified to higher apoptosis rates in the absence of growth factors. However, apoptosis was inhibited by overexpressed antiapoptotic protein Bcl-xL. Moreover, we found that SARS-CoV E protein interacted with Bcl-xL in vitro and endogenous Bcl-xL in vivo and that Bcl-xL interaction with SARS-CoV E protein was mediated by BH3 (Bcl-2 homology domain 3) of Bcl-xL. Finally, we identified a novel BH3-like region located in the C-terminal cytosolic domain of SARS-CoV E protein, which mediates its binding to Bcl-xL. These results demonstrate, for the first time, a novel molecular mechanism of T-cell apoptosis that contributes to the SARS-CoV-induced lymphopenia observed in most SARS patients.

Identification of rheumatoid arthritis patients using an administrative database: A Veterans Affairs study†

The accuracy of the diagnosis is vital when administrative databases are used for pharmacoepidemiologic and outcome studies. Data pertaining to the utility of databases for rheumatoid arthritis (RA) are sparse and variable. We assessed the utility of various diagnostic algorithms to identify RA patients within the Veterans Health Administration (VHA) databases.

A Novel Mechanism of Alternative Promoter and Splicing Regulates the Epitope Generation of Tumor Antigen CML66-L

This report describes the difference in the epitope generation of two isoforms of self-tumor Ag CML66 and the regulation mechanism. We identified a new CML66 short isoform, termed CML66-S. The previously identified long CML66 is referred to as CML66-L. CML66-S shares the C terminus with CML66-L but has its unique N terminus. CML66-S is predominantly expressed in testis, but is also expressed in very low levels in tumor cells, whereas CML66-L is expressed in tumor cells and testis. Differential expression of CML66-L and CML66-S in tumor cells resulted from regulation at transcription, although alternative splicing also participated in the generation of the isoforms. In addition, Ab titers to a CML66-L peptide were significantly higher than that to CML66-S peptide in the sera from patients with tumors. Finally, the Abs to full-length CML66-L in the sera from patients with tumors were correlated with the Abs in the sera from these patients to CML66-L-38, which is a fusion protein with a CML66-L-specific N terminus. This suggests that the CML66-L isoform is mainly responsible for the epitope generation. Our studies have identified the alternative promoter in combination with alternative splicing as a novel mechanism for regulation of the epitope generation of a self-tumor Ag.

“You never asked doc., I do fish”

Joint pains and swellings are routine complaints in rheumatology clinics. Infectious diseases may mimic common rheumatic conditions and thus need to be ruled out before initiating any immunosuppressive treatment. Mycobacterium marinum is an organism that can present with a typical arthritis picture. A 60-year-old gentleman with a complicated medical history presented with a right wrist swelling which was initially managed as a case of remitting seronegative arthritis. He eventually required tenolysis and the biopsy showed M. marinum. On inquiry, he was found to be an avid fisherman. This report discusses typical diagnostic pitfalls, literature review on the reported cases and treatment strategies. The most important point is to ask for occupational and hobby history in such cases.

Reply: To PMID 22623324.

Medicare, Medicare Advantage, or commercial insurance plans (2). Excluding patients with encounters billed to a non-VA source would increase the probability that patients were receiving care within the VA health care system and increase the validity of the results. Second, the reported positive predictive values (PPVs) may be inaccurate because they were not weighted for the total population. The authors selected a sample (543 patients) from the 1,779 patients entering the study for medical record review stratified on each classification group of interest (those with or without prolonged diseasemodifying antirheumatic drug [DMARD] therapy, at least 1 rheumatologist visit, etc.). In the summary of PPVs in Table 2 of the article, the estimates were not weighted to take into account the distribution of these classification groups in the total population of 1,779 patients. Without knowledge of the proportion of patients from the 1,779 patients in each classification group listed, it is not possible to generate an estimate of the number of patients with RA. This may have resulted in a significant underor overestimation of the PPVs in the total population. For example, the authors selected 100 patients receiving DMARDs for 180 days who had at least 1 rheumatologist visit and no RA code made at any rheumatologist visit for chart review, accounting for 18% of their sample (100/ 543); none of the patients met the gold standard criteria for RA. If only 200 of the 1,779 patients fell into this category, then the overall PPV would have been underestimated by up to 9%. Third, the gold standard definition for RA may be overly restrictive. The authors performed chart reviews to document 4 of 7 1987 American College of Rheumatology (ACR) RA criteria (3), a positive anti–cyclic citrullinated peptide (anti-CCP) antibody test, or mention of an outside rheumatologist managing RA. Patients with longstanding disease may not have had ACR criteria described in the visits reviewed by chart abstractors and may have been diagnosed prior to the widespread use of an anti-CCP antibody test. Furthermore, to our knowledge, there is no structured field for designating the presence of an outside rheumatologist, so this may have been difficult to detect through chart review or missed altogether. Given the size of the population potentially obtaining rheumatologic care outside of the VA system, this could result in a substantial underestimation of the number of patients with real RA. Details of the chart review procedure, including which notes were reviewed during which time periods and how they were searched, would be valuable information for the reader. Finally, the studies of RA patients using administrative data and performance measures applied to RA patients often use 2 face-to-face physician encounters as the definition for RA, not just 2 diagnostic codes. This is a meaningful difference in definition that makes this study less generalizable. As the authors note, administrative data sets are increasingly being used for comparative effectiveness studies and an accurate algorithm for detecting RA patients with high specificity is essential. However, studies of resource underuse and access to care, especially in vulnerable populations, would benefit from an algorithm that is both sensitive and specific. We believe that a revised (potentially higher) PPV estimate taking our comments into account could highlight the reliability of an administrative algorithm that does not rely on DMARDs or specialty visits. Supported by the University of California, San Francisco Clinical and Translational Science Institute (grant 8-KL2-TR00014307), the Rosalind Russell Medical Research Center for Arthritis, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant 1K23-AR060259-01).