Elizabeth Kirchner

Immunologic Failure Despite Suppressive Antiretroviral Therapy Is Related to Activation and Turnover of Memory CD4 Cells

BACKGROUND Failure to normalize CD4(+) T-cell numbers despite effective antiretroviral therapy is an important problem in human immunodeficiency virus (HIV) infection. METHODS To evaluate potential determinants of immune failure in this setting, we performed a comprehensive immunophenotypic characterization of patients with immune failure despite HIV suppression, persons who experienced CD4(+) T-cell restoration with therapy, and healthy controls. RESULTS Profound depletion of all CD4(+) T-cell maturation subsets and depletion of naive CD8(+) T cells was found in immune failure, implying failure of T-cell production/expansion. In immune failure, both CD4(+) and CD8(+) cells were activated but only memory CD4(+) cells were cycling at increased frequency. This may be the consequence of inflammation induced by in vivo exposure to microbial products, as soluble levels of the endotoxin receptor CD14(+) and interleukin 6 were elevated in immune failure. In multivariate analyses, naive T-cell depletion, phenotypic activation (CD38(+) and HLA-DR expression), cycling of memory CD4(+) T cells, and levels of soluble CD14 (sCD14) distinguished immune failure from immune success, even when adjusted for CD4(+) T-cell nadir, age at treatment initiation, and other clinical indices. CONCLUSIONS Immune activation that appears related to exposure to microbial elements distinguishes immune failure from immune success in treated HIV infection.

Rheumatic immune-related adverse events of checkpoint therapy for cancer: case series of a new nosological entity

Immunotherapy of cancer with checkpoint inhibitors has been associated with a spectrum of autoimmune and systemic inflammatory reactions known as immune-related adverse events (irAEs). Rheumatic irAEs are infrequently reported and extensively described. Here, we report our experience over an 18-month period with 15 patients evaluated in the rheumatology department for rheumatic irAEs. We identified 13 patients without pre-existing autoimmune disease (AID) who subsequently developed rheumatic irAEs, and two with established AID referred pre-emptively. irAEs encountered included: inflammatory arthritis, sicca syndrome, polymyalgia rheumatica-like symptoms and myositis. All cases required glucocorticoids, and three required a biological agent. Rheumatic irAEs led to temporary or permanent cessation of immunotherapy in all but five patients. One patient with pre-existing AID experienced a flare after starting immunotherapy. Our findings underscore that rheumatic irAEs are complex, at times require additional immunosuppressive therapy, and may influence ongoing immunotherapy regimens for the primary disease. Similar irAEs will be increasingly seen as checkpoint inhibitors adopted as standard of care in the community.

The 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis Should Include New Standards for Hepatitis B Screening: Comment on the Article by Singh et al.

We read with interest the recent article by Singh et al in which they presented updated American College of Rheumatology (ACR) treatment guidelines for rheumatoid arthritis (RA) (1). We congratulate the authors for their hard work and appreciate the rigor of the Grading of Recommendations Assessment, Development, and Evaluation methodology, which they used to develop these guidelines. The section on management of high-risk comorbidities includes strong recommendations for managing hepatitis B virus (HBV) and HCV infection and endorses the use of immunosuppressive therapy when prophylactic antiviral therapy is administered. Although we wholeheartedly agree with those recommendations, we were disappointed that no changes from the 2008 American College of Rheumatology (ACR) recommendations (2) were put forth regarding screening for HBV (and accordingly HCV). We suggest that because the standards of screening and preventing HBV reactivation have changed dramatically, the ACR guidelines are accordingly overdue for changes. The 2008 ACR guidelines (2) suggested screening for HBV when administering methotrexate and leflunomide and in patients at high risk of acquiring HBV infection (e.g., engaging in parenteral drug use or high-risk sexual activity). In 2010, we proposed that it was time to change these guidelines to include a more liberal policy that, at the minimum, would include screening prior to initiation of biologic therapy (3). Since that time, a Boxed Warning regarding HBV reactivation has been added to the prescribing information for the biologic agent rituximab (4). Screening for HBV infection prior to initiating treatment with rituximab is now mandatory, which serves as evidence of the veracity of screening before beginning treatment with a biologic agent. It also should be noted that the ACR guidelines have been out of step with the 2008 Centers for Disease Control and Prevention Guidelines (5), which recommended screening of all patients scheduled to receive immunosuppressive medications. Finally, we draw attention to a key meeting in early 2014 that was sponsored by the American Association for the Study of Liver Diseases (AASLD) with support from the American Academy of Dermatology, the American Society of Clinical Oncology, and the ACR at which one of the authors (LHC) presented the concerns of the rheumatology community. An article synthesizing the recommendations from this workshop, enhanced by a systematic review of the literature and crafted by an expert panel of world-renowned hepatologists, was published online in January 2015 and in print in February 2015 (6). In this article, the authors again assert that there is “good evidence to support routine screening of all patients prior to undergoing chemotherapy or immunosuppressive therapy.” Gone are caveats regarding high-risk behavior, the geographic origin of patients (e.g., areas with a high prevalence of infection), and the precise immunosuppressive agent. The authors simply state that when immunosuppressive therapy is being contemplated, screening should be performed. In an elegant editorial published in 2012, Lok and colleagues summarized the challenges posed and solutions needed in the title, “Reactivation of hepatitis B during immunosuppressive therapy: potentially fatal yet preventable” (7). The opinion piece was a call to arms to increase screening and prevention, and we strongly believe it is time for the ACR to align itself with these changes. Although we understand the rigor of the process that has gone into developing the ACR guidelines, we must also question whether such a process is adequate to keep pace with important treatment issues especially in terms of safety, where the publishing of even a few instances of a rare complication (e.g., progressive multifocal leukoencephalopathy) can generate letters from regulatory agencies to health care providers. Perhaps we should take note of other organizations similarly generating guidelines in fast-changing fields. We would like to draw attention in particular to the HCV treatment guidelines published by the AASLD and the Infectious Disease Society of America (8). These organizations now use a web-based process for the rapid formulation and dissemination of evidence-based, expert-developed recommendations and in fact explicitly state that “static versions” (i.e., printouts, slides, etc.) may be outdated and urge practitioners to review the evidence provided on the web site. Guidelines are being increasingly scrutinized and need to be assessed for their efficacy and cost effectiveness (9). It has been suggested that increased efficiency in guideline utilization (e.g., HBV/HCV screening) may be enhanced by attempts to construct common themes across guidelines. This could be achieved if all organizations involved in the treatment of patients with immunosuppression or receiving immunosuppressive therapy could actually agree on and disseminate a cohesive front.

Barriers to Immunizations and Strategies to Enhance Immunization Rates in Adults with Autoimmune Inflammatory Diseases

For as long as there have been immunizations, there have been barriers to them. Immunization rates in the United States are below target. Rheumatologists and rheumatology practitioners need to understand the issues of immunizations in patients with autoimmune inflammatory disease to identify and overcome barriers to immunization. Several strategies for overcoming these barriers are discussed.