Primecuts – This Week in the Journals

July 23, 2018

PrimeCuts 7 min read

By Nihar Shah, MD

Peer Reviewed

Amidst the backdrop of an ever-tumultuous political landscape, this week has seen global heatwave warnings issued as beachgoers and sun-tanners seek respite with summer nearing its midpoint — notable warnings include those in the UK and Japan [1,2].

The sports world is still reeling from France’s victory over Croatia in the FIFA World Cup, as well as the events of this year’s Wimbledon Championships at the All England Lawn Tennis and Croquet Club. 23-time Grand Slam Champion, new mother, and arguably the greatest female tennis player of all time, Serena Williams, began her meteoric rise back to the top of the sport, making an impressive run to the women’s final at Wimbledon, where she fell in straight sets to Germany’s Angelique Kerber [3]. Serbia’s Novak Djokovic’s also began to consolidate his return to tennis dominance as the 2018 Wimbledon Men’s Singles Champion, with a run to the title highlighted by a marathon 5-set match spanning two days with old rival Rafael Nadal and a straight sets victory over Kevin Anderson in the final [4].

And now, we turn to emerging clinical research from the medical literature.

Association of human immunodeficiency virus (HIV) infection and risk of peripheral artery disease (Circulation)

The association between HIV infection and an increased risk of atherosclerosis, myocardial infarction and ischemic stroke has been previously documented [5]. However, the association between HIV infection and peripheral artery disease (PAD) is not well understood. Using data from the Veterans Aging Cohort Study over a 12 year period, investigators studied the incidence of PAD events in veterans living with HIV, comparing them with matched control participants who were HIV negative. Primary outcomes included new incidence of PAD and secondary outcomes included mortality and limb amputation. Statistical analyses adjusted for demographics, atherosclerotic risk factors, and other covariate risk factors such as anemia and COPD. Investigators found newly incident PAD events occurred more commonly in the HIV+ veterans at a rate of 11.9% (95% confidence interval 11.5-12.4) compared to a rate of 9.9% for HIV- veterans (95% confidence interval 9.6-10.1), with a hazard ratio (HR) of 1.19 (95% confidence interval 1.71-2.13). This increase in risk was even higher in those veterans with CD4+ cell count <200cells/mm3 (HR 1.51) and those with HIV viral loads >500copies/mL (HR = 1.91). Notably, those with CD4+ cell count >500cells/mm3 were at no increased risk for PAD compared to HIV- controls. Overall, there was no difference with respect to mortality or limb amputation between groups [6].

The Bottom Line: There is a 19% increase in risk of PAD in veterans living with HIV, with risk modulation according to how well the infection is controlled, as indicated by CD4+ cell count and HIV viral load. After development of PAD, there is no difference with regards to mortality or limb amputation. The data suggests that HIV infection in itself is a risk factor for PAD independent of other atherosclerotic risk factors, and treatment with both antiretroviral and anti-atherosclerotic therapy is paramount in this patient population.

Trimethoprim-sulfamethoxazole prophylaxis prevents severe/life-threatening infections following rituximab in antineutrophil cytoplasm antibody-associated vasculitis (Annals of the Rheumatic Diseases)

Antineutrophil cytoplasm antibody-associated (ANCA) vasculitis spans three disease entities: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (eGPA). Rituximab is a chimeric monoclonal antibody targeting CD20+ B cells used in the treatment of these conditions, however this drug leaves patients immunocompromised and susceptible to adverse events, notably severe infection (defined by a grade > 3 according to the Common Terminology Criteria for Adverse Events V4.0) [7]. This retrospective cohort analysis sought to delineate the presence of identifiable risk factors in these patients predisposing them to infection. Participants were originally identified on the basis of rituximab referral between 2004-2014 from tertiary care centers in the UK and Austria, and chart data was retrospectively analyzed for development of severe infection in these patients over a 2-year period after initiation of rituximab. Respiratory tract infection was most common (n=63), followed by urinary tract infection (n=12); some participants developed gastrointestinal and skin infection. Overall, 49/192 patients (25.52%) experienced severe infection, and univariate analyses revealed prophylactic trimethoprim-sulfamethoxazole (TMP-SMX) to be correlated with decreased risk of severe infection (HR 0.30, confidence interval 1.01-1.05). Several risk factors were found to be associated with an elevated risk of severe infection, including older age (HR 1.03), endobronchial involvement (HR 4.27), and COPD (HR 6.30) [8].

The Bottom Line: Prophylactic TMP-SMX in patients with ANCA vasculitis on rituximab is associated with a decreased risk of developing severe infection compared to patients who do not receive prophylaxis.

Tofacitinib for induction and maintenance therapy of Crohn’s disease: results of two phase IIb randomised placebo-controlled trials (British Medical Journal)

Crohn’s disease (CD) is a type of inflammatory bowel disease (IBD) characterized by disparate areas of inflammation along the digestive tract, strictures, fistulae, and extra-intestinal complications (i.e. rash, arthritis, fatigue). The goal of therapy is remission, nowadays achieved with the advent of novel biologic therapies. In this multi-center phase IIb trial, patients were randomized to receive either placebo, 5mg, or 10mg induction therapy with tofacitinib, an oral Janus Kinase (JAK) inhibitor, twice daily as part of an 8-week induction treatment course. Patients achieving a “clinical response-100”, defined as a >100 point decrease from their baseline Crohn’s Disease activity index (CDAI) or clinical remission (CDAI <150 at 8 weeks) were re-randomized to placebo, 5mg, and 10mg maintenance therapy with tofacitinib for 26 weeks, and outcomes were again assessed using the same criteria. Rates of remission were found to be 43.5% and 43.0% with 5 and 10mg tofacitinib induction therapy versus 36.7% with placebo (p=0.325 and 0.392, respectively), and 55.8% with 10mg tofacitinib maintenance therapy versus. 38.1% with placebo (p=0.130) [9].

The Bottom Line: Despite a mild increase in remission rates with maintenance therapy using 10mg tofacitinib twice daily, there was no statistically significant difference in the proportion of participants achieving clinical remission rates between groups. However, the safety of tofacitnib between all groups suggests further investigation into JAK inhibitor therapy for Crohn’s disease.

Effect of Acute Exacerbation of Idiopathic Pulmonary Fibrosis on Lung Transplantation Outcome (Chest)

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease with a median survival of 3 to 5 years [10]. However an acute exacerbation of IPF (AE-IPF), defined as IPF with new ground-glass opacity or consolidation on high resolution chest CT and/or new or worsening dyspnea within the past month not otherwise explained by cardiac failure or fluid overload, is correlated with hospitalization and premature death [11]. Definitive treatment of IPF consists of lung transplantation of the fibrotic lung, however data regarding transplantation outcomes and survival rates are limited to few studies, and to date have not separately studied AE-IPF in regards to transplantation. In this study, investigators compared survival rates after lung transplantation in patients with stable IPF versus those experiencing AE-IPF at the time of transplantation. The AE-IPF group had a 50% mortality rate at a mean follow-up time of 1.6 years (SD +/- 1.2 years), compared to the stable IPF group which had a 12% mortality at a mean follow-up time of 2.6 years (SD +/- 1.2 years) [12].

The Bottom Line: Short and long term survival are reduced in patients undergoing lung transplantation for AE-IPF compared to those undergoing lung transplantation with stable IPF.

Mini-Cuts:

Spoken words are processed during dexmedetomidine-induced unconsciousness (British Journal of Anaesthesia)

Investigators contend that even under anesthesia mediated by the heavy sedation of dexmedetomidine, word processing and liminal states of consciousness continue unfettered [13].

Effects of walnut consumption on blood lipids and other cardiovascular disease risk factors (American Journal of Clinical Nutrition) 

Investigators contend that eating walnuts favorably modulates cardiovascular risk factor [14].

Modulation of anti-tumor immunity by the brain’s reward system (Nature)

Investigators contend that your emotions may directly modulate tumor size and growth [15].

Dr. Nihar Shah is a first year internal medicine resident at NYU Langone Health

Peer reviewed by Dana Zalkin MD, Associate Editor, Clinical Correlations

Image courtesy of Wikimedia Commons

References:

  1. BBC News; “Japan heatwave: Warnings issued amid scorching temperatures”. https://www.bbc.com/news/world-asia-44910435
  2. BBC News; “UK heatwave: Wales on track for driest summer on record”. https://www.bbc.co.uk/news/uk-wales-44872858
  3. ESPN News Services; “Angelique Kerber wins Wimbledon, keeps Serena Williams from tying all time mark”. ESPN. http://www.espn.com/tennis/story/_/id/24096564/wimbledon-2018-angelique-kerber-beats-serena-williams-3rd-grand-slam-title
  4. Bodo, Peter; “Wimbledon win could spark another era of Djokovic dominance”. ESPN. http://www.espn.com/tennis/story/_/id/24106728/wimbledon-2018-novak-djokovic-wins-wimbledon-crown-another-slam-run
  5. Sico JJ, Chang CC, So-Armah K, Justice AC, Hylek E, Skanderson M, Mc- Ginnis K, Kuller LH, Kraemer KL, Rimland D, Bidwell Goetz M, Butt AA, Rodriguez-Barradas MC, Gibert C, Leaf D, Brown ST, Samet J, Kazis L, Bryant K, Freiberg MS; Veterans Aging Cohort Study. HIV status and the risk of ischemic stroke among men. Neurology. 2015;84:1933–1940. doi: 10.1212/WNL.0000000000001560.
  6. Beckman JA, Duncan MS, Alcorn CW, So-Armah K, Butt AA, Goetz MB, Tindle HA, Sico JJ, Tracy RP, Justice AC, Freiberg MS. Association of Human Immunodeficiency Virus Infection and Risk of Peripheral Artery Disease. 2018 Jul 17;138(3):255-265. doi: 10.1161/CIRCULATIONAHA.117.032647. Epub 2018 Mar 13. PubMed PMID: 29535090; PubMed Central PMCID: PMC6050082.
  7. National Cancer Institute, “Common Terminology Criteria fo Adverse Events (CTCAE)”. https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40
  8. Kronbichler A, Kerschbaum J, Gopaluni S, Tieu J, Alberici F, Jones RB, Smith RM, Jayne DRW.Trimethoprim-sulfamethoxazole prophylaxis prevents severe/life-threatening infections following rituximab in antineutrophil cytoplasm antibody-associated vasculitis. Ann Rheum Dis. 2018 Jun 27. pii: annrheumdis-2017-212861. doi: 10.1136/annrheumdis-2017-212861. [Epub ahead of print] PubMed PMID: 29950327.
  9. Panés J, Sandborn WJ, Schreiber S, Sands BE, Vermeire S, D’Haens G, Panaccione R, Higgins PDR, Colombel JF, Feagan BG, Chan G, Moscariello M, Wang W, Niezychowski W, Marren A, Healey P, Maller E.Tofacitinib for induction and maintenance therapy of Crohn’s disease: results of two phase IIb randomised placebo-controlled trials.  2017 Jun;66(6):1049-1059. doi: 10.1136/gutjnl-2016-312735. Epub 2017 Feb 16. PubMed PMID: 28209624; PubMed Central PMCID: PMC5532457.
  10. Natsuizaka M, Chiba H, Kuronuma K, et al. Epidemiologic survey of Japanese patients with idiopathic pulmonary fibrosis and investigation of ethnic differences. Am J Respir Crit Care Med 2014;190:773–779.
  11. Collard HR, Ryerson CJ, Corte TJ, et al. Acute exacerbation of idiopathic pulmonary fibrosis: an international working group report. Am J Respir Crit Care Med 2016;194:265–275.
  12. Dotan Y, Vaidy A, Shapiro W, Zhao H, Dass C, Toyoda Y, Marchetti N, Shenoy K, Cordova F, Criner GJ, Mamary AJ.Effect of Acute Exacerbation of Idiopathic Pulmonary Fibrosis on Lung Transplantation Outcome. 2018 Jun 29. pii: S0012-3692(18)30979-6. doi: 10.1016/j.chest.2018.06.027. [Epub ahead of print] PubMed PMID: 29966665.
  13. Kallionpää RE, Scheinin A, Kallionpää RA, Sandman N, Kallioinen M, Laitio R, Laitio T, Kaskinoro K, Kuusela T, Revonsuo A, Scheinin H, Valli K. Spoken words are processed during dexmedetomidine-induced unresponsiveness.Br J Anaesth. 2018 Jul;121(1):270-280. doi: 10.1016/j.bja.2018.04.032. Epub 2018 May 23. PubMed PMID: 29935582.
  14. Guasch-Ferré M, Li J, Hu FB, Salas-Salvadó J, Tobias DK.Effects of walnut consumption on blood lipids and other cardiovascular risk factors: an updated meta-analysis and systematic review of controlled trials. Am J Clin Nutr. 2018 Jul 1;108(1):174-187. doi: 10.1093/ajcn/nqy091. PubMed PMID: 29931130.
  15. Ben-Shaanan TL, Schiller M, Azulay-Debby H, Korin B, Boshnak N, Koren T, Krot M, Shakya J, Rahat MA, Hakim F, Rolls A. Modulation of anti-tumor immunity by the brain’s reward system. Nat Commun. 2018 Jul 13;9(1):2723. doi: 10.1038/s41467-018-05283-5. PubMed PMID: 30006573; PubMed Ce