News Release

Low-dose methotrexate associated with small increase in some adverse events

Embargoed news from Annals of Internal Medicine

Peer-Reviewed Publication

American College of Physicians

Below please find summaries of new articles that will be published in the next issue of Annals of Internal Medicine. The summaries are not intended to substitute for the full articles as a source of information. This information is under strict embargo and by taking it into possession, media representatives are committing to the terms of the embargo not only on their own behalf, but also on behalf of the organization they represent.

1. Low-dose methotrexate associated with small increase in some adverse events

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A pre-specified secondary analysis of a double-blind placebo-controlled randomized trial found that low-dose methotrexate (LD-MTX) was associated with a small to modest increase in the risk for some adverse events, including skin cancer and gastrointestinal, infectious, pulmonary, and hematologic effects in patients at risk for heart disease. The risk for kidney-related side-effects was decreased. The findings are published in Annals of Internal Medicine.

LD-MTX is the most commonly used drug for systemic rheumatic diseases worldwide and the recommended first-line agent for rheumatoid arthritis. Despite decades of clinical use, few randomized controlled trials have studied adverse events associated with LD-MTX use.

Researchers from Brigham and Women's Hospital randomly assigned 4,786 patients at risk for heart disease to receive LD-MTX or placebo over a median follow-up of 23 months to objectively assess adverse event rates, risk, and risk differences in those receiving LD-MTX. All participants also received folic acid 1mg per day for six days a week. The researchers found that there was a small absolute increase in adverse events with LD-MTX compared to placebo. With the exception of an increased risk of skin cancers, there was no difference between treatment arms for the risk of other malignancies and risk for adverse events such as cirrhosis and pneumonitis in the LD-MTX group was similar to that seen in previous reports. According to the authors, this data provides new evidence to improve the monitoring guidelines and safe prescribing of LD-MTX, which is considered an efficacious and generally well-tolerated treatment for rheumatoid arthritis and other diseases.

Media contacts: For an embargoed PDF please contact Lauren Evans at To speak with the lead author, Daniel H. Solomon, MD, please contact Haley Bridger at

2. New guidelines address chronic insomnia disorders and obstructive sleep apnea in military personnel and Veterans

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The U.S. Department of Veterans Affairs (VA) and the U.S. Department of Defense (DoD) recently approved a joint clinical practice guideline for assessing and managing patients with chronic insomnia disorder and obstructive sleep apnea (OSA). Positive airway pressure therapy, or CPAP, is recommended as a first-line treatment for OSA and cognitive behavior therapy (CBT) is a key recommendation for treating insomnia. A synopsis of the key recommendations is published in Annals of Internal Medicine.

Military service is an established risk factor for sleep disorders. Accordingly, military personnel and Veterans have a higher prevalence of sleep disorders than the general population. Also, these populations have high rates of posttraumatic stress disorder (PTSD), traumatic brain injury (TBI) and other mental health disorder. When patients have insomnia and/or OSA along with PTSD, TBI or other mental health disorders, the treatment of both their sleep and other disorder is challenging. Physicians are beginning to recognize sleep disorders as an important issue to be addressed.

The guidelines recommend CPAP be used for the entirety of a patient's sleep period. For patients who do not use PAP for at least 4 hours per night, this therapy should be continued along with addressing barriers to better PAP adherence. CBT for insomnia (CBT-I) is the recommended treatment; however, brief behavioral therapy for insomnia (BBT-I) is also acceptable. Sleep hygiene is not recommended as standalone therapy for chronic insomnia disorder. Pharmacotherapy with doxepin, nonbenzodiazepine benzodiazepine receptor agonists is second-line treatment for chronic insomnia disorder and should be used for a short course of treatment. Over the counter agents to include diphenhydramine and melatonin are not indicated for the treatment of insomnia.

According to the authors, the guideline is a major step for the VA and DoD in recognizing the importance of appropriately diagnosing and treating sleep disorders in these unique populations. The guidelines highlights commitment of both organizations to adhering to evidence-based practice. The guideline was written by a joint, multi-disciplinary VA/DoD work group that utilized a standardized process to develop 41 evidence-based recommendations. The guideline is relevant to all providers who treat patients with sleep disorders. The full guideline is available at:

Media contacts: For an embargoed PDF please contact Lauren Evans at To speak with the lead author, James Sall, PhD, FNP-BC, please contact him directly at

3. Statins might be effective in treating xanthelasmas in patients with normal lipid levels

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Researchers from the Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada, observed the regression of xanthelasmas in a patient with normal lipid levels after treatment with a statin. Typical treatments for patients with xanthelasmas with normal lipid levels carry risks and high recurrence rates. The Case Report is published in Annals of Internal Medicine.

Xanthelasmas are benign, yellowish growths made up of cholesterol under the skin that appear on or around the eyelids. In about half of cases, they are associated with familial high cholesterol. In these patients, regression of xanthelasmas can occur with lipid-lowering drugs, such as statins. Many patients with xanthelasmas, however, have normal lipid levels. In these patients, xanthelasmas can be removed with liquid nitrogen, topical trichloroacetic acid, laser ablation, or surgical excision, but these therapies all carry risk for scarring or residual pigmentation and high recurrence rates (up to 40 percent).

To report the effect of statin therapy for a person with xanthelasmas with normal lipid levels, researchers prescribed 10 mg of rosuvastatin, a statin to help lower "bad" cholesterol (mainly LDL) and raise "good" cholesterol, to a 52-year-old woman with normal lipid levels who wanted her xanthelasmas removed for cosmetic reasons. Within three months of treatment, the patient's LDL cholesterol level had decreased by 50 percent, remaining steadily in that range for the next four years. Within 12 months, she reported some regression of her xanthelasmas, and after four years of rosuvastatin, they had almost completely regressed.

Media contacts: For an embargoed PDF please contact Lauren Evans at To speak with the lead author, Robert A. Hegele, MD, please contact him directly at

Also new in this issue:

Getting Incentives Right in Payment Reform: Thinking Beyond Financial Risk
Vinay K. Rathi, MD; J. Michael McWilliams, MD, PhD; Eric T. Roberts, PhD
Ideas and Opinions

Inpatient Notes: Optimizing Inpatient Nutrition--Why Hospitalists
Should Get Involved
Philipp Schuetz, MD, MPH, and Jeffrey L. Greenwald, MD
Hospitalist Commentary


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