Rachel Lutz

Long-term ruxolitinib use was well-tolerated in a 32-year-old male patient with steroid refractory 

Investigators described the treatment of the patient, who began with 

order to provide more context on the subject, which they describe as limited. There are clinical trials underway for ruxolitinib use in treating srGVHD, but there are no existing guidelines or protocols for long-term use.

Most srGVHD treatments with immunomodulatory drugs have side effects including lymphoproliferative disorders, relapse of disease, and opportunistic infections, the authors explained. But ruxolitinib can reduce side effects from srGVHD in acute settings up to 46% and in chronic settings up to 81%, according to some of the existing literature.

The patient had been on ruxolitinib for 5 years but could not tolerate a reduction in dosage due to flare-ups. At 26, the patient was diagnosed with AML and treated with 2 rounds of induction therapy with a 7 + 3 regimen. However, the authors said, the disease continued. He had a history of mucositis, pneumonia with sepsis, and decreased ejection fraction due to previous therapy. Because of these factors, he was given a high-dose cytarabine 1500 mg/m2 with sorafenib.

He received status postmatched unrelated donor stem cell transplant (MUD SCT) in November 2013 and began displaying acute GVHD after the transplant, for which he received topical steroids. He was also given sorafenib 200 mg and azacytidine to help with continued GVHD.

In May 2014, the patient presented with severe chronic GVHD involving the skin, eyes, and lungs; more than 50% of his skin was impacted. He was treated with prednisone 2 mg/kg given his severe GVHD and his skin symptoms improved.

When the authors attempted to taper below 20 mg, his skin flared up and he experienced worsening lung function. Steroid therapy was ineffective in 2014, the study authors said, so the patient began 5 mg of ruxolitinib twice a day and responded well.

Attempting to wean to once per day worsened his symptoms, the authors said, and a total discontinuation was not possible.

There are no reported identifiable issues or side effects from the long-term ruxolitinib use, they explained. They did note that there was one hospital admission for community-acquired pneumonia in 2018. That experience resolved with standard antibiotic therapy, they added.

The investigators still have a plan in place to wean the patient off ruxolitinib. They will attempt a taper every 3-4 months with 2.5 mg every 2 months to wean off therapy as the patient tolerates it. They will then weigh if the patient is gaining a benefit from ruxolitinib therapy, and if the risk for unknown long-term use outweighs the benefit of his current stability in suppressing his GVHD.

“With no seemingly therapeutic consequences of long-term use, we argue that there may be no reason not to continue our patient on therapy and monitor closely as with other immunosuppressive therapies,” the study authors concluded. “Our experience thus far has not shown any increased overall morbidity or mortality due to long-term ruxolitinib use.”

His flare ups were controlled when the therapy was restarted at 5 mg twice per day. The study authors said that the patient “seemingly tolerates the treatment with ruxolitinib.”

Sobash PT, Guddati AK, Kota V. Long-term use of ruxolitinib in an AML patient with posttransplant steroid refractory GVHD. 

Published online April 6, 2020. doi: 10.1155/2020/4936846

Articles

Researchers discuss the case of a 32-year-old patient who is being treated with ruxolitinib over a period of years to treat steroid refractory graft-versus-host disease.

Report Describes Use of Ruxolitinib Over the Long-Term for Young Patient

 (COPD) can have similar signs and symptoms as many cardiovascular diseases (CVD), thus leading to diagnostic confusion and muddled therapeutic approaches, according to a 

Authors from Moscow and Geneva outlined various forms of CVD and what effect they each have on the health of those with COPD as well as quality of life. The authors said that CVD and COPD coexist due to shared risk factors, the mechanisms of their interactions, and influence of systemic inflammation. A typical patient with COPD suffers from an average of 4 comorbidities and a third of patients can be taking 5 to 10 different drugs, the authors said. Therefore, they added, it is extremely important to determine the significance of a particular comorbidity for the treatment of COPD.

The common shared risk factors for CVD and COPD are smoking, age, and not following a healthy lifestyle (physical activity, nutrition, etc.). Whether one smokes is the most important factors, as it has negative effects on both the lungs and the cardiovascular system, the authors said.

“Individuals susceptible to damage caused by pollutants and smoking can suffer from both heart and lung disease,” they wrote. “Just as pulmonary disease can contribute to heart disease, cardiac illness can itself contribute to pulmonary disease.”

Another factor in the relationship between COPD and CVD how lung hyperinflation and the resulting increased size of the lungs can compress the heart muscle and hinder its ability to pump blood through a patient’s body. As the authors point out, other published literature demonstrated that the severity of COPD and the appearance of emphysema are associated with the decrease in heart size during X-ray exams. 

A decrease in inforced expiratory volume in 1 second (FEV

) is linked with an increased risk of cardiovascular mortality, the authors said. For patients with COPD, the risk of CVD is about 2 to 3 times higher than comparable persons, the authors said. Other studies have shown that about 2 in 5 patients with mild to moderate COPD died due to CVD. That represents about 8 to 10 times more risk than deaths in the same group due to respiratory insufficiency, the authors said.

Coronary heart disease (CHD) has a strong relationship with COPD in terms of epidemiology and shared inflammation factors, the authors said. The prevalence of COPD patients with CHD is high, but there is a high level of underdiagnosis. That is also the case for congestive heart failure (CHF). When the authors compared patients with and without CHD, they found that those with CHD were characterized by older age, male sex, higher smoking index, lower quality of life, tolerance of physical activity, increased intensity of shortness of breath, and a longer recovery period after exacerbations, they said.

Arrhythmias (AF) are prevalent in between about 5% and 15% of patients with COPD, but that prevalence increases with very severe COPD, the authors said. In patients with AF, the prevalence of COPD can also reach 65% in patients older than 65 years. The frequency of AF is related to FEV

. In published studies, AF was a negative prognostic factor in patients with COPD  in terms of their quality of life and health status, risk of hospitalizations, and mortality from all causes, the authors said.

Heart failure (HF) is also significantly more prevalent among patients with COPD (10% to 30%) compared with the general population (1% to 2%). One meta-analysis they pointed to determined that COPD increased the risk of mortality in patients with HF. Patients with both COPD and HF skewed slightly older than patients with COPD but not HF and also were a higher percentage of men, had more apparent symptoms and had more concomitant diseases, the authors said added. HF and COPD have different triggers that cause exacerbations, leading to difficulty in diagnoses, the authors said.

“It should be emphasized that COPD patients today are a heterogeneous group of subjects with a complex multimorbidity, requiring a differentiated approach,” the authors concluded. “Current available data cannot answer all the questions faced by doctors of different specialties, who encounter such patients in their daily practice. At the same time, it becomes obvious that only an integrated holistic multidisciplinary approach will achieve success in the understanding and management of this group of patients.”

Aisanov Z, Khaltaev N. Management of cardiovascular comorbidities in chronic obstructive pulmonary disease patients. 

 2020;12(5):2791-2802. doi: 10.21037/jtd.2020.03.60

A recent review discussed how to manage comorbid cardiovascular disease in patients with chronic obstructive pulmonary disease (COPD).

Understanding Clinical Considerations for Patients With Both COPD, Cardiovascular Disease

 (COPD) may be used to predict clinically important deterioration (CID) by including more than just the airflow limitation captured by the forced expiratory volume in 1 second (FEV

Investigators from Germany used the previously reported UPLIFT study and conducted a post hoc analysis in order to test the idea that using a composite endpoint could give a fuller assessment of CID in patients enrolled in COPD clinical trials. The international UPLIFT study included patients with moderate-to-very severe COPD, according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines.

The authors noted that most investigators measure the impact of interventions by the annual rate of decline of FEV

 over years. However, manifestation of COPD progression can vary over time and among individuals; some patients may end their involvement in a trial early, “underestimating the true mean rate of decline in the control arm,” the authors said.

CID attempts to measure factors at the individual patient level in order to better capture what might matter more to those with the disease. CID includes trough FEV

, St. George’s Respiratory Questionnaire (SGRQ) score, and moderate/severe exacerbation. Besides being clinically relevant, these factors are important to a patient’s well-being and predict future outcomes, the researchers said.

Researchers sought to test the validity of CID when only FEV

and SGRQ events were confirmed at a later visit by these patients in order to show that CID predicts future outcomes. Their analysis measured time to first CID, defined as time to the first occurrence of at least either a decrease in trough FEV

, increase in SGRQ total score, or moderate/severe exacerbation.

To exclude short-term changes in disease, the researchers only included confirmed FEV

 or SGRQ deteriorations that were present in at least 2 consecutive  visits that took place about 5 to 6 months apart.

The analysis included 5652 patients who had both measurements at baseline for FEV

 and SGRQ; of the total, 2811 received tiotropium and 2841 received placebo.

More than 4 in 5 patients included in the study experienced at least 1 CID during the study period, and exacerbations were more frequent than declines in either FEV1 or SGRQ.

About half of the patients experienced at least 2 of the 3 events qualifying as CID, but fewer patients experienced all 3 events, the investigators found.

A similar proportion of patients in each GOLD group (stage 2, 3, or 4) experienced at least 2 CID events. While a similar proportion of patients classified as GOLD 2 and 3 had a similar rate for experiencing all 3 CID events, only a few patients classified as GOLD 4, or more severe disease, experienced all 3 CID events, the authors said.

 decline was sustained between 12 and 48 months after the initial event in a majority of patients, the authors found. SGRQ decline was sustained between 12 and 42 months after the initial event, also in most patients. This was true for the GOLD subgroups, they added.

The authors said that time to first CID event and time to the first occurrence of any of the separate factors was affected by the intervention, with patients receiving tiotropium taking longer to reach the first CID or any number of events compared with those receiving placebo. This held for patients in GOLD 2 and 3 groups but ot as often in the GOLD 4 group.

If patients experienced CID events by month 6, they were more likely to experience a moderate or severe exacerbation, severe exacerbation, or death, and this risk was similar for all GOLD subgroups.

“A composite endpoint of CID is a promising endpoint to assess disease activity in COPD clinical trials and may be a useful outcome that helps clinicians interpret the implications of trial results for individual patient management,” the authors concluded.

Identifying patients based on time to CID may make it possible to predict which ones may need earlier treatment, the authors wrote. In addition, using a composite endpoint may allow for reduced number of patients in clinical trials, as well as reduced length of such trials, they said.

Rabe, K.F., Halpin, D.M.G., Han, M.K. et al. Composite endpoints in COPD: clinically important deterioration in the UPLIFT trial. 

. Published online July 9, 2020. doi:10.1186/s12931-020-01431-y

Using composite endpoints to predict clinically important deterioration in chronic obstructive pulmonary disease (COPD) could help investigators assess disease activity in clinical trials and better manage individual patients, according to a recent study.

Researchers Explore Benefits of Using Composite End Points in COPD Trials

Adhering to a healthy diet was associated with a lower prevalence of chronic obstructive pulmonary disease (COPD), according to a 

Investigators from McMaster University in Hamilton, Ontario, Canada, conducted a meta-analysis of relevant publications in order to determine the strength of the association between dietary patterns and the prevalence and incidence of COPD. The study authors said current efforts to curb COPD prevalence and incidence focus on smoking cessation, which is a major risk factor, but COPD is still present in nonsmokers—this led researchers to focus on other risk factors, like diet.

Investigations into the relationship between diet and COPD have shown that high fatty acid content or high dietary fiber consumption may lead to reduced risk for COPD, in addition to consumption of high levels of fruits, vegetables, and antioxidants, the study authors summarized.

Ultimately, the investigators discovered 8 observational studies between January 1980 and November 2019 that were relevant for their analysis. Of those, 3 reported on unhealthy eating patterns, but all 8 evaluated healthy dietary patterns. None of the studies examined quality of life or mortality.

Each of the studies included adult patients (aged 20 to 75 years) and collected dietary information from patients via food frequency questionnaires, the study authors explained.

The study authors said that the papers that focused on patients adhering to a healthy diet pattern demonstrated a lower risk of COPD. But the study authors also said that these cross-sectional papers, taken together, had minimal heterogeneity. There was heterogeneity present in the cohort studies, though, they said. One other limitation of this finding was that one study only examined males, while another only examined females, the study authors noted.

The studies that reported on unhealthy diet patterns and development of COPD showed what the study authors described as a “nonsignificant increase in the prevalence of COPD.” They did add that there was significant heterogeneity among the studies, but there were insufficient study numbers to continue conducting subgroup analysis.

The investigators said they planned to do a meta-analysis of longitudinal studies looking at the relationship between unhealthy diet and COPD development, but there were only 2 studies they identified with available data.

Additionally, there was 1 study that examined the mean percent of predicted spirometric values for COPD patients and controls adhering to a DASH diet. In that study, the investigators said, there was no significant association between DASH diet adherence and spirometric outcomes with COPD. That paper did note that there was a significant decrease in the FEV1/FVC ratio in those adhering to a DASH diet compared to controls.

“Overall, adherence to a healthy dietary pattern was associated with a lower prevalence of COPD, whereas adhering to an unhealthy dietary pattern was associated with a higher prevalence of COPD (statistically not significant),” the study authors wrote.

While it is still unknown how a person’s diet may affect their risk of COPD, the study authors said it remains an important area for ongoing research.

“Additional research looking at other important outcomes in COPD (i.e. exacerbations, spirometry, quality of life, and mortality) and the cumulative effects of confounding exposures associated with COPD (i.e. pollution, sex, physical activity, occupational exposures and socioeconomic status) is also needed and will be useful in translating current research into future clinical practice,” the authors concluded.

Parvizian MK, Dhaliwal M, Li J, Satia I, Kurmi OP. Relationship between dietary patterns and COPD: a systematic review and meta-analysis. 

. 2020;6(2):00168-2019. doi:10.1183/23120541.00168-2019

The focus on curbing COPD prevalence has largely focused on smoking cessation, but there are other factors, including diet, that can contribute to the risk of developing COPD.

Author | Rachel Lutz

Articles

Report Describes Use of Ruxolitinib Over the Long-Term for Young Patient

Understanding Clinical Considerations for Patients With Both COPD, Cardiovascular Disease

Researchers Explore Benefits of Using Composite End Points in COPD Trials

Does Diet Have an Effect on COPD Prevalence and Incidence?