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Compared to placebo treatment, there was no difference in the reduction of

 and disability for those who underwent spinal manipulation or spinal mobilization.

The findings suggested spinal manipulation and spinal mobilization were both ineffective interventions for young adults with mild to moderate chronic low back pain.

James Thomas, PhD, and colleagues conducted a single-blinded, placebo-controlled randomized clinical trial to evaluate the comparative effectiveness of spinal manipulation and spinal mobilization at reducing pain and disability compared with a placebo control group.

The team randomized patients in a 1:1: ratio into 1 of 3 groups. In group 1, patients received spinal manipulation treatment 2 times per week for 3 weeks. Patients in group 2 received spinal mobilization treatment 2 times per week for 3 weeks. Those in the placebo group received sham cold laser treatment 2 times per week for 3 weeks.

For spinal manipulation treatment, participants were placed in a side-lying position facing the clinician with the more painful side facing upward. The clinician flexed the participant’s hips and knees to induce lumbar spine flexion until they felt the spinous process of the vertebrae begin to move. The participant was then rotated to their torso opposite to the side they were lying on until they felt rotation. The clinician added thrust to the shoulder and pelvis which resulted in a rotation force. Treatment was complete if an audible pop occurred. If not, the treatment was attempted again with a maximum of 2 attempts per side.

During spinal mobilization treatment, the participant was positioned the same way as during spinal manipulation. A clinician put 1 hand on the anterior should and 1 on the posterior pelvis. The participant was told to gently push the shoulder and pelvis into the clinician’s hands. The participant held the contraction for a minimum of 7 seconds with a maximum of 60 seconds. If an audible pop occurred or the clinician noticed a release in tissue tension, treatment was considered complete.

In the placebo group, a sham laser was delivered over the painful region. An insignificant amount of light energy or heat was delivered.

The investigators randomized 162 participants with a mean age of 25 years old, a majority of whom were women (57%), with chronic low back pain (mean NPRS sore, 4.3 on a scale of 1-10; higher scores indicated more pain). Of the participants, 54 were randomized into each group. The team noted no significant group differences for sex, age, BMI, duration of low back pain symptoms, depression, fear avoidance, current pain, average pain over the last 7 days, and self-reported disability.

For the primary endpoint, there was no significant difference in change in pain scores between spinal manipulation and spinal mobilization (.24; 95% CI, -.38 to .86; 

=.45), spinal manipulation and placebo (-.03; 95% CI, -.65 to .59; 

=.92), or spinal mobilization and placebo (-.26; 95% CI, -.38 to .85; 

=.39). There was also no significant difference in change in self-reported disability scores between spinal manipulation and spinal mobilization (-1; 95% CI, -2.27 to .36; 

=.14), spinal manipulation and placebo (-.7; 95% CI, -1.43 to 1.29; 

=.92), or spinal mobilization and placebo (.93; 95% CI, -.41 to 2.29; 

“We conclude that these manipulative therapy techniques do not appear to be effective for chronic low back pain, at least among relatively young individuals with mild to moderate back pain,” Thomas and the team concluded.

Effect of Spinal Manipulative and Mobilization Therapies in Young Adults With Mild to Moderate Chronic Low Back Pain

Articles

Manipulative techniques are not effective for chronic low back pain among relatively young individuals. 

Manipulative Therapy Ineffective for Chronic Low Back Pain

A new drug targeting gut microbiota could help patients with 

A team, led by Matthew R. Henn, Seres Therapeutics, evaluated the safety and efficacy of SER-287, an oral formulation of Firmicutes spores, as well as the effects of vancomycin preconditioning on the expansion or engraftment of SER-287 species in the colon, in patients with ulcerative colitis.

Firmicutes bacteria produce metabolites that maintain the intestinal barrier and provide mucosal immunity. Firmicutes are reduced in the intestinal microbiota of patients suffering from ulcerative colitis.

In the double blind phase 1b trial, the investigators examined 58 adults with active mild-to-moderate ulcerative colitis, defined as a modified Mayo score 4-10 and endoscopic subscores of at least 1.

Each patient received 6 days of preconditioning with oral vancomycin 125 mg 4 times daily or placebo. This was followed by either placebo or SER-287 once weekly or vancomycin followed by SER-287 once weekly or SER-287 once daily. Each patient was randomized in a 2:3:3:3 ratio to the 4 groups.

The investigators sought clinical endpoints of safety and clinical remission, defined as modified Mayo score ≤ 2 and endoscopic subscores 0 or 1. They also pursued microbiome endpoints including SER-287 engraftment (dose species detected in stool after, but not before, SER-287 administration).

The team measured the engraftment of SER-287 and changes in microbiome composition and associated metabolites by analyses of stool specimens collected at baseline, after preconditioning, and during and 4 weeks after administration of the study drug or placebo.

The proportions of patients with adverse events ultimately did not differ significantly among the different treatment groups.

However, there were a higher proportion of patients in the daily treatment groups of vancomycin/SER-287 (40%) that achieved clinical remission at week 8 than patients in the placebo/placebo group (0), placebo/SER-287 weekly group (13.3%), or vancomycin/SER-287 weekly group (17.7%) (

= 0.024 for vancomycin/SER-287 daily vs placebo/placebo).

By day 7, there were higher numbers of SER-287 dose species detected in stool samples from all of the SER-287 groups compared with the placebo group (

<0.05). However, this difference was not maintained beyond day 7 in the placebo/SER-287 weekly group.

In the vancomycin groups, there was a greater number of dose species detected in stool collected on day 10, as well as all subsequent time points, through 4 weeks post-dosing, compared with the placebo group (

Changes in fecal microbiome composition and metabolites were associated with both vancomycin/SER-287 groups.

“In this small phase 1b trial of limited duration, the safety and tolerability of SER-287 were similar to placebo,” the authors wrote. “SER-287 following vancomycin was significantly more effective than placebo for induction of remission in patients with active mild-to-moderate UC. Engraftment of dose species was facilitated by vancomycin preconditioning and daily dosing of SER-287.”

A Phase 1b safety study of SER-287, a spore-based microbiome therapeutic, for active mild to moderate ulcerative colitis

Firmicutes bacteria can help produce metabolites that maintain intestinal barriers and mucosal immunity. 

SER-287 Shows Efficacy in Treating Ulcerative Colitis in Early Phase Trial

Findings of a recent study demonstrated patients who started dipeptidyl peptidase-4 (DPP-4) inhibitor therapy had a higher risk of 

 than those who initiated second-generation sulfonylurea therapy.

The findings suggested clinicians should be aware of the rare adverse effect in subgroups with higher risk.

Hemin Lee, MD, MPH, and colleagues characterized the incidence rate of bullous pemphigoid associated with DPP-4 inhibitor use compared with second-generation sulfonylureas. The team used data from 3 large US healthcare databases, Optum Clinformatics Data Mart, IBM MarketScan Research Database, and Medicare Parts A, B, and D. The Optum and MarketScan databases included longitudinal medical and pharmacy claims of the commercially insured population in the US.

The investigators created a new-user cohort of patients with a prescription claim for a DPP-4 inhibitor or a second-generation sulfonylurea from the date of the first approval for DPP-4 inhibitors, October 17, 2006, to the end of available data in each database. They applied a washout period of 180 days for both drugs. The date of the first prescription corresponded to the date of cohort entry.

Patients were included if they had at least 180 days of continuous enrollment in commercial insurance and fee-for-service Medicare and at least 1 diagnosis of 

. The team excluded patients younger than 40 years old because bullous pemphigoid is typically seen in older individuals.

The primary outcome was the occurrence of bullous pemphigoid, defined based on ICD-9 or ICD-10 diagnosis codes. Follow-up started 1 day after cohort entry and continued until either the occurrence of bullous pemphigoid, the end of healthcare or pharmacy eligibility, the end of the study period, the switch to a comparator drug, and discontinuation of the index drug.

Overall, the cohort consisted of 870,709 new users of DPP-4 inhibitors, a majority of whom were female (51%) with a mean age of 63.7 years old. There were more than 1.9 million new users of second-generation sulfonylureas, with more than half (51.8%) being male and a mean age of 64.8 years old.

Before matching propensity scores, sulfonylurea users were older than DPP-4 inhibitor users (mean age, 64.8 years old vs 63.7 years old) and had a higher number of antidiabetic drugs prescribed at the index date (mean, 1.26 vs 1.16). After score matching, there were 199,780 pairs of DPP-4 inhibitor or second-generation sulfonylurea users in Optum, 354,759 pairs in MarketScan, and 277,901 pairs in Medicare.

The incidence rates (IRs) per 1000 person-years of bullous pemphigoid for DPP-4 inhibitor versus sulfonylurea groups in each database were .36 vs .27 cases (HR, 1.34; 95% CI, .88-2.04) in Optum; .19 vs .19 cases (HR, 1; 95% CI, .68-1.49) in MarketScan; and .81 vs .48 cases (HR, 1.68; 95% CI, 1.3-2.17) in Medicare. The pooled number in the 3 databases was 247 cases (IR, .42 per 1000 person-years) in the DPP-4 inhibitor group and 184 cases (IR, .31 per 1000 person-years) in the sulfonylurea group. The pooled HR was 1.42 (95% CI, 1.17-1.72).

The team analyzed subgroups of patients in both groups and found there was an increased risk in those who were at least 65 years old (pooled HR, 1.62; 95% CI, 1.32-1.99) and while (pooled HR, 1.7; 95% CI, 1.3-2.24). For DPP-4 inhibitor agents, linagliptin showed the highest risk (pooled HR, 1.68; 95% CI, 1.16-2.43). The risk was less obvious in sitagliptin and saxagliptin compared with sulfonylurea use. Higher risk of bullous pemphigoid in the DPP-4 inhibitor groups was similar between men (pooled HR, 1.38; 95% CI, 1.06-1.79) and women (pooled HR, 1.34; 95% CI, 1.03-1.75).

The results of the study were consistent with other previous studies in reporting a positive association between DPP-4 inhibitors and bullous pemphigoid. Although there was an increased risk of bullous pemphigoid among DPP-4 inhibitor users compared with second-generation sulfonylurea users, the condition is rare and not all cases are associated with morbidity or mortality.

“Therefore, although clinicians should not avoid DPP-4 inhibitors entirely in patients with type 2 diabetes who may be otherwise good candidates for the therapy, they should be aware of the potential risk of bullous pemphigoid in DPP-4 inhibitor use, especially in subgroups of older and white patients and linagliptin users,” Lee and the investigators concluded.

Evaluation of Risk of Bullous Pemphigoid With Initiation of Dipeptidyl Peptidase-4 Inhibitor vs Second-generation Sulfonylurea

Older, white patients and those who use linagliptin are at a higher risk of bullous pemphigoid.

DDP-4 Inhibitors Increase Risk of Bullous Pemphigoid

A pre-print article from a team of investigators at Brigham and Women’s Hospital and Harvard Medical School highlight the important of distinguishing 

 from chronic pulmonary conditions in interpreting patient risks due to 

The findings, which show evidence for risk in asthma-coronavirus overlap, also highlight the continued burden clinicians face in interpreting symptoms between asthma and other chronic respiratory diseases.

The team, led by Liqin Wang, PhD, of the Division of General Internal Medicine and Primary Care, noted respiratory viral illnesses are often associated with asthma exacerbations in both children and adults. And indeed, research from COVID-affected regions of China have suggested chronic pulmonary disease is a risk factor for COVID-19 severity and mortality.

Currently, the US reports approximately 7-9% of hospitalized COVID-19 patients have chronic lung disease—with asthma being more prevalent than 

chronic obstructive pulmonary disease (COPD).

“Recent analyses of COVID-19 cohorts suggest that chronic respiratory disease may unexpectedly be less of a risk factor for COVID-19 infection and severity than non-respiratory diseases,” they wrote. “However, most studies to date do not distinguish asthma from COPD within chronic respiratory disease, limiting identification of asthma-specific risk factors.”

Wang and colleagues used data from March 3 to June 8 from the Massachusetts-based health system’s electronic health record (EHR) to establish their case series. Patients who were COVID-19 positive, aged ≥18 years old at diagnosis, with previously diagnosed asthma and a history of care in the health system were included in assessment.

The team sought associations of demographic and clinical characteristics with hospitalization and intensive care unit (ICU) admissions among asthmatic patients hospitalized for COVID-19, as well as those who died from it. Their assessment included both univariable and multivariable adjustments via age-stratified logistic regression.

Their eligible patient population included 1827 patients, with a median age of 54 years (IQR, 37-66), and two-thirds (67.4%) being female.

Most patients were triaged to outpatient care; 30.9% were hospitalized, and of that group, 41.8 (n = 236) were admitted to the ICU. Nearly all hospitalized patients were admitted to inpatient (99.3%) or ICU (97.9%) care within 2 weeks of COVID-19 diagnosis.

Among patients with asthma, mortality rate was 5.4% among both outpatient and hospitalized patients—with greater rates being reported among asthmatic patients who were hospitalized (15.6%) and/or admitted to the ICU (23.3%). More than 71% of patients who died did so within 14 days of their diagnosis.

Versus the outpatient group, hospitalized patients were observed to have greater baseline use of inhaled corticosteroid (ICS) and long acting-beta agonist (LABA) combination use, as well as more anti-cholinergic controller therapy. Fewer hospitalized patients had just a short-acting beta agonist (SABA) prescription in the past year (

Wang and colleagues also observed significantly increased hospitalization risk associated with older age versus outpatient care (unadjusted OR, 1.46; 95% CI, 1.38-1.55; 

 <.001 for every 10 years). Males were also 75% more likely to be hospitalized versus outpatient care (aOR, 1.75, 95% CI, 1.36-2.24; 

 <.001), while Black (aOR, 1.65) and Asian patients (aOR, 3.19) were observed to be at greater hospitalization risk, as well.

Comorbid conditions associated with significantly greater hospitalization risk versus outpatient care included diabetes mellitus (aOR, 1.33); COPD (aOR, 1.92); or cardiovascular disease (aOR, 1.52). Investigators also observed significantly associations with obesity and chronic kidney disease; however, the findings were not robust.

“Several hospitalization risk factors for patients with asthma and COVID-19 reflect those identified in general populations of COVID-19 patients, including male sex, race, older age, and non-respiratory comorbidities,” investigators wrote. “Notably, male sex was a risk factor despite female predominance in COVID-19 testing and in positive diagnosis among asthma patients.”

Comorbid COPD was observed a strong risk factor for hospitalization—in fact, it was the only comorbidity that remained statistically significant after multiple comparison corrections. Asthma-specific variables were not predictive of neither ICU care nor mortality, and differences between risk for inpatient hospitalization and ICU admission were marked as a future avenue of assessment.

Investigators concluded that individuals with asthma-COPD overlap may be at particularly raised COVID-19 severity and mortality risk—though there is significant importance in distinguishing asthma from chronic pulmonary disease in COVID-positive patients to interpret individual risks.

“Further research examining the course of hospitalized patients is necessary to elucidate predictors of disease progression and clinical outcomes,” they wrote.

The pre-proof analysis, “Risk factors for hospitalization, intensive care and mortality among patients with asthma and COVID-19,” will be published in 

The Journal of Allergy and Clinical Immunology

New findings suggest differing chronic lung diseases are associated with varying risk factors among COVID-19 patients.

Older, Male Asthmatics at Greater COVID-19 Severity Risk

Delayed administration of subsequent denosumab doses by more than 16 weeks is associated with increased risk of 

 compared with on-time administration in patients with 

Still, the evidence was insufficient to conclude risk for fracture was increased at other anatomical sites with long delay.

Houchen Lyu, MD, PhD, and colleagues estimated the risk for fracture among denosumab users who delayed subsequent doses compared with those who received doses on time. The team used an electronic database of medical records from primary care physicians in the UK. The database contained health information on nearly 17 million patients from 790 general practices. The investigators extracted data on demographic characteristics, diagnosis, and medications from 2010-2019.

Lyu and the team compared 3 dosing intervals for subsequent denosumab injections: on time, short delay, and long delay.

The investigators included injection data from patients at least 45 years old who initiated denosumab therapy for the management of osteoporosis. They identified denosumab dosages of 60 mg subcutaneously every 6 months. Patients were excluded if they had only 1 denosumab prescription record, received the subsequent injection within 150 days after the prior dose, or used any other antiosteoporosis drugs.

The recommended date of a subsequent dose of denosumab was set at 6 months after a prior dose. The team compared the effect of various delays of the subsequent dose on time (within 4 weeks after the recommended date), short delay (between 4 and 16 weeks after the recommended date), and long delay (more than 16 weeks after the recommended date but not beyond 6 months.

Lyu and the investigative team compared fracture risk among the 3 groups during the six-month follow-up. The main outcome was composite fracture, while additional outcomes included major osteoporotic fracture, vertebral fracture, hip fracture, and nonvertebral fracture.

Overall, 3964 patients who initiated denosumab treatment for osteoporosis were included in the study. The team excluded 1370 patients who did not complete the run-in period, resulting in the final cohort of 2594 patients. Patients included contributed a total of 6144 qualified denosumab injections.

Participants had a low burden of comorbid conditions but had a very high risk for fracture, with a mean 10-year risk for major osteoporotic fracture of 22%. More than half of the patients (53%) had a history of major osteoporotic fracture, while 19% had a history of hip fracture and 15% had a vertebral fracture.

Over 6 months, the risk for composite fracture was 27.3 in 1000 for on-time dosing, 32.2 in 1000 for short delay, and 42.4 in 1000 for long delay. In a comparison with on-time injections, short delay had a hazard ratio (HR) for composite fracture of 1.03 (95% CI, .63-1.69) and long delay had an HR of 1.44 (95% CI, .96-2.17) both with 

=.093). The team noted for vertebral fractures, short delay had an HR of 1.48 (95% CI, .58-3.79) and long delay had an HR of 3.91 (95% CI, 1.62-9.45).

“…Findings are consistent with known denosumab pharmacokinetics and prior studies of fracture incidence after denosumab treatment discontinuation,” Kristine Ensrud, MD, MPH, and John Schousboe, MD, PhD, both of University of Minnesota, wrote in an 

. “Therefore, it is of utmost importance that clinicians considering denosumab treatment carefully counsel patients before its initiation on the importance of not delaying or abruptly discontinuing injections.”

Delayed Denosumab Injections and Fracture Risk Among Patients With Osteoporosis

,” was published online in the journal 

It is important for clinicians considering prescribing denosumab treatment to counsel patients before its initiation on the importance of not delaying or discontinuing injections.

Denosumab Doses Must Be Delivered On Time for Patients With Osteoporosis

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