Pain Reduction With Oral Methotrexate in Knee Osteoarthritis: A Randomized, Placebo-Controlled Clinical Trial: Annals of Internal Medicine: Vol 177, No 9

Background: Treatments for osteoarthritis (OA) are limited. Previous small studies suggest that the antirheumatic drug methotrexate may be a potential treatment for OA pain. Objective: To assess symptomatic benefits of methotrexate in knee OA (KOA). Design: A multicenter, randomized, double-blind, placebo-controlled trial done between 13 June 2014 and 13 October 2017. (ISRCTN77854383; EudraCT: 2013-001689-41) Setting: 15 secondary care musculoskeletal clinics in the United Kingdom. Participants: A total of 207 participants with symptomatic, radiographic KOA and knee pain (severity ≥4 out of 10) on most days in the past 3 months with inadequate response to current medication were approached for inclusion. Intervention: Participants were randomly assigned 1:1 to oral methotrexate once weekly (6-week escalation 10 to 25 mg) or matched placebo over 12 months and continued usual analgesia. Measurements: The primary end point was average knee pain (numerical rating scale [NRS] 0 to 10) at 6 months, with 12-month follow-up to assess longer-term response. Secondary end points included knee stiffness and function outcomes and adverse events (AEs). Results: A total of 155 participants (64% women; mean age, 60.9 years; 50% Kellgren–Lawrence grade 3 to 4) were randomly assigned to methotrexate (n = 77) or placebo (n = 78). Follow-up was 86% (n = 134; methotrexate: 66, placebo: 68) at 6 months. Mean knee pain decreased from 6.4 (SD, 1.80) at baseline to 5.1 (SD, 2.32) at 6 months in the methotrexate group and from 6.8 (SD, 1.62) to 6.2 (SD, 2.30) in the placebo group. The primary intention-to-treat analysis showed a statistically significant pain reduction of 0.79 NRS points in favor of methotrexate (95% CI, 0.08 to 1.51; P = 0.030). There were also statistically significant treatment group differences in favor of methotrexate at 6 months for Western Ontario and McMaster Universities Osteoarthritis Index stiffness (0.60 points [CI, 0.01 to 1.18]; P = 0.045) and function (5.01 points [CI, 1.29 to 8.74]; P = 0.008). Treatment adherence analysis supported a dose-response effect. Four unrelated serious AEs were reported (methotrexate: 2, placebo: 2). Limitation: Not permitting oral methotrexate to be changed to subcutaneous delivery for intolerance. Conclusion: Oral methotrexate added to usual medications demonstrated statistically significant reduction in KOA pain, stiffness, and function at 6 months. Primary Funding Source: Versus Arthritis.

Accurate Measurements of Gastric Emptying and Gastrointestinal Symptoms in the Evaluation of Glucagon-like Peptide-1 Receptor Agonists

Brief Commentary: Treating Pain—The Cannabis Conundrum

Tumor Necrosis Factor Inhibitors and Cancer Recurrence in Swedish Patients With Rheumatoid Arthritis: A Nationwide Population-Based Cohort Study: Annals of Internal Medicine: Vol 169, No 5

Background: Use of tumor necrosis factor inhibitors (TNFi) in patients with a history of cancer remains a clinical dilemma. Objective: To investigate whether TNFi treatment in rheumatoid arthritis (RA) is associated with increased risk for cancer recurrence. Design: Population-based cohort study based on linkage of nationwide registers. Setting: Sweden. Participants: Patients with RA who started TNFi treatment between 2001 and 2015, after being diagnosed with cancer, and matched patients with RA and a history of the same cancer who had never received biologics. Measurements: The primary outcome was the first recurrence of cancer. Adjusted Cox proportional hazards models were used to estimate hazard ratios (HRs), taking into account time, cancer type, and whether the cancer was invasive or in situ (or tumor, node, metastasis [TNM] classification system stage in a subset of patients). Results: Among 467 patients who started TNFi treatment (mean time after cancer diagnosis, 7.9 years), 42 had cancer recurrences (9.0%; mean follow-up, 5.3 years); among 2164 matched patients with the same cancer history, 155 had recurrences (7.2%; mean follow-up, 4.3 years) (HR, 1.06 [95% CI, 0.73 to 1.54). Hazard ratios were close to 1 in analyses of patient subsets matched on cancer stage or with similar time from index cancer diagnosis to the start of TNFi treatment, as well as in unmatched analyses. Several CIs had upper limits close to 2. Limitation: The outcome algorithm was partly nonvalidated, and channeling bias was possible if patients with a better index cancer prognosis were more likely to receive TNFi. Conclusion: The findings suggest that TNFi treatment is not associated with increased risk for cancer recurrence in patients with RA, although meaningful risk increases could not be ruled out completely. Primary Funding Source: ALF (an agreement in Stockholm County Council concerning medical education and research in health and medical care), the Swedish Cancer Society, the Swedish Foundation for Strategic Research, and the Swedish Research Council.

Timing of Pegfilgrastim Administration and Pegfilgrastim-Induced Bone Pain: A Prospective, Randomized, Phase 3 Trial: Annals of Internal Medicine: Vol 179, No 5

Background: Pegfilgrastim-induced bone pain (PIBP) is common and lacks effective treatment. Objective: To determine whether there is an association between the timing of pegfilgrastim administration and PIBP. Design: Three-arm randomized controlled trial. (ClinicalTrials.gov: NCT05841186) Setting: A tertiary A-level hospital. Patients: Patients with I to III stage breast cancer who were naive to chemotherapy. Intervention: Patients were randomly allocated in a 1:1:1 ratio to the 24-hour, 48-hour, or 72-hour group based on the timing of pegfilgrastim administration postchemotherapy. Measurements: The primary end point was the area under the curve (AUC) of the daily worst bone pain score (assessed using the “worst pain” question from the Brief Pain Inventory, a 0 to 10 numerical rating scale [NRS]) for 5 consecutive days in the first chemotherapy cycle. Secondary end points included the incidence of severe bone pain (>5 on the NRS), neutropenia, and febrile neutropenia (FN). Results: The intention-to-treat analyses included 159 patients, with 53 in each group. For the first cycle, in the 72-hour group, the mean AUC exhibited a statistically significant reduction from 12.74 in the 24-hour group and 14.20 in the 48-hour group to 6.05 (all P < 0.001). Furthermore, the incidence of severe bone pain also declined significantly from 58.5% in the 24-hour group and 66.0% in the 48-hour group to 22.6% in the 72-hour group (all P < 0.001). There was no substantial difference in the incidence of neutropenia among groups, and no patients developed FN. Limitation: Open label, single center, and relatively small sample size. Conclusion: Administration of pegfilgrastim 72 hours postchemotherapy reduced PIBP compared with 24- and 48-hour administration and did not seem to be associated with higher rates of neutropenia or FN. Primary Funding Source: National Natural Science Foundation of China.

Bariatric surgery improved HbA1c at 5 y more than intensive medical care alone in obese patients with T2DM

Source Citation Schauer PR, Bhatt DL, Kirwan JP, et al; STAMPEDE Investigators. Bariatric surgery versus intensive medical therapy for diabetes—5-year outcomes. N Engl J Med. 2017;376:641-51. 28199805

Kneeling Was the First Step for Sickle Cell Disease

Pharmacotherapy for the Treatment of Cannabis Use Disorder: A Systematic Review: Annals of Internal Medicine: Vol 172, No 6

Background: Cannabis use disorder (CUD) is a growing concern, and evidence-based data are needed to inform treatment options. Purpose: To review the benefits and risks of pharmacotherapies for the treatment of CUD. Data Sources: MEDLINE, PsycINFO, Cochrane Database of Systematic Reviews, and clinical trial registries from inception through September 2019. Study Selection: Pharmacotherapy trials of adults or adolescents with CUD that targeted cannabis abstinence or reduction, treatment retention, withdrawal symptoms, and other outcomes. Data Extraction: Data were abstracted by 1 investigator and confirmed by a second. Study quality was dually assessed, and strength of evidence (SOE) was determined by consensus according to standard criteria. Data Synthesis: Across 26 trials, the evidence was largely insufficient. Low-strength evidence was found that selective serotonin reuptake inhibitors (SSRIs) do not reduce cannabis use or improve treatment retention. Low- to moderate-strength evidence was found that buspirone does not improve outcomes and that cannabinoids do not increase abstinence rates (moderate SOE), reduce cannabis use (low SOE), or increase treatment retention (low SOE). Across all drug studies, no consistent evidence of increased harm was found. Limitations: Few methodologically rigorous trials have been done. Existing trials are hampered by small sample sizes, high attrition rates, and heterogeneity of concurrent interventions and outcomes assessment. Conclusion: Although data on pharmacologic interventions for CUD are scarce, evidence exists that several drug classes, including cannabinoids and SSRIs, are ineffective. Because of increasing access to and use of cannabis in the general population, along with a high prevalence of CUD among current cannabis users, an urgent need exists for more research to identify effective pharmacologic treatments. Primary Funding Source: U.S. Department of Veterans Affairs. (PROSPERO: CRD42018108064)

In high-risk adults, individualized vs. routine BP management during major abdominal surgery did not improve outcomes at 7 d

Clinical Impact Ratings GIM/FP/GP: 5 out of 7

National Institutes of Health COVID-19 Treatment Guidelines Panel: Perspectives and Lessons Learned

Description: In March 2020, the White House Coronavirus Task Force determined that clinicians in the United States needed expert treatment guidelines to optimally manage patients with COVID-19, a potentially life-threatening disease caused by a new pathogen for which no specific treatments were known to be effective. Methods: The U.S. Department of Health and Human Services requested that the National Institutes of Health (NIH) take the lead in expeditiously convening a panel of experts to create “living” guidelines that would be widely accessible and capable of frequent updating as important new information became available. Recommendations: The purpose of this article is to expand on the experiences of the NIH COVID-19 Treatment Guidelines Panel (the Panel) over the past 4 years, summarize the Panel’s final recommendations for COVID-19, highlight some challenges and unanswered questions about COVID-19 management, and inform future responses to public health emergencies. The Panel was formed in March 2020, and the first iteration of the guidelines was released in April 2020. Now that the public health emergency has ended, the NIH COVID-19 Treatment Guidelines have sunsetted. This role will now fall to professional societies and organizations, such as the American College of Physicians, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the World Health Organization, all of which have been active in this area.