Primecuts – This week in the journals

November 12, 2021

PrimeCuts 7 min read

By Brendan Denvir, MD

Peer Reviewed

With medicine advancing at such a rapid pace, it is crucial for physicians to keep up with the medical literature. This can quickly become an overwhelming endeavor given the sheer quantity and breadth of literature released on a daily basis. Primecuts helps you stay current by taking a shallow dive into recently released articles that should be on your radar. Our goal is for you to slow down and take a few small sips from the medical literature firehose. 

Annals: Effectiveness of Belimumab After Rituximab in Systemic Lupus Erythematosus1

Rituximab is part of guideline therapy for treatment-refractory lupus. It is a monoclonal antibody that targets CD20, a receptor present on mature B cells. Despite some evidence of efficacy, many patients experience disease flares during therapy with this agent. One of the proposed mechanisms of flares in the setting of rituximab treatment is through an increase in B-cell activating factor (BAFF). In essence,  rituximab decreases one’s B-cell population, which causes a compensatory increase in BAFF, which causes increased B-cell activity upon re-population. Belimumab is a BAFF-neutralizing monoclonal antibody. In this study, Shipa et al. hypothesized that using belimumab after rituximab therapy would cause a more profound decrease in B-cell activity compared to rituximab alone and, therefore, reduce the frequency of SLE flares.

The patients enrolled in this study were 18-75 years old with a formal  diagnosis of SLE, had a positive anti-dsDNA in the past 5 years, and were eligible to receive rituximab treatment in the setting of having failed conventional therapy. 52 patients, after receiving rituximab, were randomly assigned to receive belimumab or placebo. Most patients in the trial were simultaneously on other lupus treatments — predominantly a combination of hydroxychloroquine, steroid therapy, and one additional immunosuppressant. The primary endpoint measured was anti-dsDNA level at 52 weeks. Secondary endpoints involved occurrence of SLE flares and steroid requirements.

The authors found that the treatment group had significantly reduced IgG anti-dsDNA levels compared to placebo (47 IU/mL [95% CI, 25-88 Iu/mL] versus 103IU/mL [CI, 49-213 IU/mL], respectively) and those in the belimumab group had a 70% greater reduction from baseline IgG anti-dsDNA levels (CI, 46%-84%, p< 0.00) at 52 weeks compared to placebo. Regarding secondary measures, they showed belimumab treatment reduced risk for a severe lupus flare by 73% (HR 0.27 [CI, 0.07 to 0.98]. Regarding safety measures and adverse events, there were no differences between treatment and control group. In fact, more patients in the placebo group withdrew due to increased flare activity compared to the treatment group.

This study serves an exploratory role into the efficacy of combined rituximab-belimumab therapy. It demonstrates adequate safety of the treatment as well as promising evidence of efficacy in reducing SLE flares. A more robust trial is warranted for further study — one that includes more patients, and uses measurements of clinical improvement (rather than changes in serology) as primary outcomes.

NEJM: Chlorthalidone for Hypertension in Advanced CKD2

Thiazide diuretics are well established in their role for treatment of hypertension. However, in patients with kidney disease, this role is less clear. The authors of this study set out to answer a simple question: does chlorthalidone decrease blood pressure in patients with advanced CKD?

Individuals studied were those with Stage 4 CKD and poorly controlled blood pressure. Enrolled patients were on a mean of 3.4 blood pressure medications at baseline and patients on high dose loop diuretics were excluded. 160 patients were randomized — 81 to the chlorthalidone group and 79 to the placebo group. The chlorthalidone patients received a 12.5 mg starting dose for the first 4 weeks and, if they were still hypertensive (SBP > 135 or DBP > 85) at the 4 week time mark, their chlorthalidone dose was doubled (12.5 mg to 25 mg). This procedure was repeated at the 8 week time mark (25 mg to 50 mg). The primary outcome measure was change in 24-hour ambulatory systolic blood pressure after 12 weeks. Secondary outcomes were aimed at determining mechanisms of blood pressure lowering and included changes in urine albumin/creatinine ratio, pro-BNP, plasma renin and aldosterone levels, and total body volume.

In the study, authors found a significant improvement in systolic blood pressure in the treatment group compared to placebo by 10.5 mmHg at 12 weeks [CI, -14.6 to -6.4]. Most of the blood pressure improvements occurred in the first four weeks, corresponding to initiation of the drug, rather than subsequent dose increases. In terms of secondary outcomes, the chlorthalidone group demonstrated decreased pro-BNP, decreased body weight from baseline, and decreased total body volume, suggesting the reduction in blood pressure is at least in part attributable to decreased effective intravascular volume.

Adverse events were more likely to occur in the chlorthalidone group and included increases in serum creatinine and electrolyte derangements, as well as demonstrable decline in renal function (change from baseline in estimated GFR -2.7 ml/min per 1.73m2 in the chlorthalidone group versus no change in the placebo group, CI -3.9 to -1.6), This was most notable in patients on loop diuretics. However, these effects were largely reversible after discontinuation of the drug.

The findings in this study suggest that there is a role for thiazide diuretics in blood pressure lowering in advanced CKD patients with treatment-refractory hypertension. Despite this, they should be used with caution in patients already on loop diuretics, as these patients have a higher risk of worsening renal function on this therapy. Phase 3 trials with larger sample sizes are warranted for further investigation.

Nature Medicine: IL-1-driven stromal–neutrophil interactions define a subset of patients with inflammatory bowel disease that does not respond to therapies3 

Despite development of new medications in recent years to treat IBD, many patients are non-responders to currently available therapies. Friedrich et al. aimed to identify cellular and genomic characteristics of inflamed tissue in patients who are unresponsive to anti-TNF and anti-integrin therapies.

Tissue samples in the study were derived from resected bowel of patients with poorly controlled IBD. These samples were compared to non-tumor tissue of patients with CRC who also had undergone bowel resection. By comparing inflamed and uninflamed tissue within individual subjects, several patterns of gene expression, or “modules”, were identified as being associated with inflammation. These modules were sought out in the inflamed tissue of known anti-TNF non-responders in 3 prospective cohorts. Among the identified gene expression modules, two (M4 and M5) stood out as being consistently present among non-responders. Upon further exploration of what these modules represent, it was elucidated that M4 signifies the presence of inflammatory fibroblasts.

On further analysis, the inflammatory fibroblasts identified in the tissue of non-responders had little expression of TNF and integrin receptors — likely explaining their poor response to treatment with these receptors as therapeutic targets. However, these cells did show high levels of expression IL-1B receptor. Additional investigation showed that these activated fibroblasts used IL-1 signaling to attract neutrophils in generating a characteristic neutrophil-rich pattern of ulceration.

The authors suggest that these previously unidentified characteristics of inflammation have clinical implications. They argue it serves as a proof-of-concept for targeting IL-1 or IL-1R in treatment-refractory IBD patients. A large, randomized trial of anakinra (an IL-1 receptor antagonist) in treatment of IBD is currently ongoing.4

JAMA: Effect of Antithrombotic Therapy on Clinical Outcomes in Outpatients With Clinically Stable Symptomatic COVID-195

In September 2020, the ACTIV-4B trial set out to explore the role of anticoagulation and/or antiplatelet therapy in patients with COVID-19. The population studied were individuals with symptomatic COVID who did not require hospitalization. Over nine months, 657 patients were randomized into one of 4 groups: receiving aspirin 81 mg daily, apixaban 2.5 mg twice daily, apixaban 5 mg twice daily, and placebo, respectively. After nine months, the trial was stopped prematurely due to lower than anticipated event rates in the control group. No difference in hospitalization and/or all-cause mortality was seen between groups. 

NEJM: Empagliflozin in Heart Failure with a Preserved Ejection Fraction6 

SGLT-2 inhibitors are all the rage in heart failure with reduced EF, but do they improve outcomes in patients with HFpEF? This randomized controlled trial found that in patients with Class II – IV chronic heart failure and EF > 40%, 10 mg of daily empagliflozin significantly reduced primary outcomes (composite of cardiovascular death or hospitalization for heart failure) compared to placebo at 26 months. These findings suggest a role for SGLT-2 inhibitors as part of therapy for HFpEF.

Annals: Midodrine for the Prevention of Vasovagal Syncope7 

Midodrine has a known role in preventing syncope from orthostatic hypotension. In this randomized controlled trial, Sheldon et al. studied relatively young and healthy patients that suffered from recurrent vasovagal syncope. They found that midodrine reduced likelihood of syncope recurrence with a NNT of 5.3.

Dr. Brendan Denvir is a 2nd year internal medicine resident at NYU Langone Health

Reviewed by Alexandria Imperato, MD, chief resident, medicine, NYU Langone Health

Image courtesy of Wikimedia Commons, source: U.S. Air Force photo by airman 1st Class Joshua Magbanua, 86th Airlift Wing Public Affairs

References

  1. Shipa M, Embleton-Thirsk A, Parvaz M, Santos LR, Muller P, Chowdhury K, Isenberg DA, Doré CJ, Gordon C, Ehrenstein MR; BEAT-LUPUS Investigators*. Effectiveness of Belimumab After Rituximab in Systemic Lupus Erythematosus : A Randomized Controlled Trial. Ann Intern Med. 2021 Oct 26. doi: 10.7326/M21-2078. Epub ahead of print. PMID: 34698499.  https://www.acpjournals.org/doi/10.7326/M21-2078
  2. Agarwal R, Sinha AD, Cramer AE, Balmes-Fenwick M, Dickinson JH, Ouyang F, Tu W. Chlorthalidone for Hypertension in Advanced Chronic Kidney Disease. N Engl J Med. 2021 Nov 5. doi: 10.1056/NEJMoa2110730. Epub ahead of print. PMID: 34739197. https://pubmed.ncbi.nlm.nih.gov/34739197/
  3. Friedrich M, Pohin M, Jackson MA, Korsunsky I, Bullers SJ, Rue-Albrecht K, Christoforidou Z, Sathananthan D, Thomas T, Ravindran R, Tandon R, Peres RS, Sharpe H, Wei K, Watts GFM, Mann EH, Geremia A, Attar M; Oxford IBD Cohort Investigators; Roche Fibroblast Network Consortium, McCuaig S, Thomas L, Collantes E, Uhlig HH, Sansom SN, Easton A, Raychaudhuri S, Travis SP, Powrie FM. IL-1-driven stromal-neutrophil interactions define a subset of patients with inflammatory bowel disease that does not respond to therapies. Nat Med. 2021 Oct 21. doi: 10.1038/s41591-021-01520-5. Epub ahead of print. PMID: 34675383. https://www.biolifesolutions.com/bio-preservation-evidence/cryopreservation/il-1-driven-stromal-neutrophil-interactions-define-a-subset-of-patients-with-inflammatory-bowel-disease-that-does-not-respond-to-therapies/
  4. Cader MZ, Kaser A. Finding the right target for drug-resistant inflammatory bowel disease. Nat Med. 2021 Nov 8. doi: 10.1038/s41591-021-01551-y. Epub ahead of print. PMID: 34750554.
  5. Connors JM, Brooks MM, Sciurba FC, Krishnan JA, Bledsoe JR, Kindzelski A, Baucom AL, Kirwan BA, Eng H, Martin D, Zaharris E, Everett B, Castro L, Shapiro NL, Lin JY, Hou PC, Pepine CJ, Handberg E, Haight DO, Wilson JW, Majercik S, Fu Z, Zhong Y, Venugopal V, Beach S, Wisniewski S, Ridker PM; ACTIV-4B Investigators. Effect of Antithrombotic Therapy on Clinical Outcomes in Outpatients With Clinically Stable Symptomatic COVID-19: The ACTIV-4B Randomized Clinical Trial. JAMA. 2021 Nov 2;326(17):1703-1712. doi: 10.1001/jama.2021.17272. PMID: 34633405; PMCID: PMC8506296.
  6. Anker SD, Butler J, Filippatos G, Ferreira JP, Bocchi E, Böhm M, Brunner-La Rocca HP, Choi DJ, Chopra V, Chuquiure-Valenzuela E, Giannetti N, Gomez-Mesa JE, Janssens S, Januzzi JL, Gonzalez-Juanatey JR, Merkely B, Nicholls SJ, Perrone SV, Piña IL, Ponikowski P, Senni M, Sim D, Spinar J, Squire I, Taddei S, Tsutsui H, Verma S, Vinereanu D, Zhang J, Carson P, Lam CSP, Marx N, Zeller C, Sattar N, Jamal W, Schnaidt S, Schnee JM, Brueckmann M, Pocock SJ, Zannad F, Packer M; EMPEROR-Preserved Trial Investigators. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. N Engl J Med. 2021 Oct 14;385(16):1451-1461. doi: 10.1056/NEJMoa2107038. Epub 2021 Aug 27. PMID: 34449189. https://pubmed.ncbi.nlm.nih.gov/34449189/
  7. Sheldon R, Faris P, Tang A, Ayala-Paredes F, Guzman J, Marquez M, Morillo CA, Krahn AD, Kus T, Ritchie D, Safdar S, Maxey C, Raj SR; POST 4 investigators. Midodrine for the Prevention of Vasovagal Syncope : A Randomized Clinical Trial. Ann Intern Med. 2021 Oct;174(10):1349-1356. doi: 10.7326/M20-5415. Epub 2021 Aug 3. PMID: 34339231.  https://pubmed.ncbi.nlm.nih.gov/34339231/