Key clinical point: Anti-interleukin-6 (aIL-6) receptor antibody was more effective than other biologic disease-modifying antirheumatic drugs (bDMARDs) in patients with rheumatoid arthritis (RA) with knee joint involvement but not in patients without knee joint involvement.

Major finding: At 12 weeks, treatment with aIL-6 significantly increased clinical disease activity index (CDAI) in patients with knee joint involvement compared with other bDMARDs (P = .02). In patients without swollen knee joints, aIL-6 vs. other bDMARDs showed no significant difference in CDAI improvement (P = .61).

Study details: Findings are from a retrospective analysis of 1,059 treatment courses in patients with RA from the ANSWER cohort who were treated with bDMARDs. The patients were categorized into those with (n=275; 323 bDMARDs treatment course) or without (n=561; 736 bDMARDs treatment course) joint knee involvement.

Disclosures: ANSWER Cohort was supported by grants from Abbie G.K., Asahi-Kasei Pharma, AYUMI Pharmaceutical Co., Chugai Pharmaceutical Co. Ltd., Eisai Co. Ltd., Janssen Pharmaceutical K.K., Ono Pharmaceutical Co., Sanofi, UCB Japan Co. Ltd., and Teijin Healthcare Limited. The authors including the lead author reported receiving grants, consulting fees, speaker fees, and/or honoraria from various sources.

Source: Maeda Y et al. Rheumatol Int. 2021 Apr 26. doi: 10.1007/s00296-021-04862-y.

Key clinical point: Anti-interleukin-6 (aIL-6) receptor antibody was more effective than other biologic disease-modifying antirheumatic drugs (bDMARDs) in patients with rheumatoid arthritis (RA) with knee joint involvement but not in patients without knee joint involvement.

Major finding: At 12 weeks, treatment with aIL-6 significantly increased clinical disease activity index (CDAI) in patients with knee joint involvement compared with other bDMARDs (P = .02). In patients without swollen knee joints, aIL-6 vs. other bDMARDs showed no significant difference in CDAI improvement (P = .61).

Study details: Findings are from a retrospective analysis of 1,059 treatment courses in patients with RA from the ANSWER cohort who were treated with bDMARDs. The patients were categorized into those with (n=275; 323 bDMARDs treatment course) or without (n=561; 736 bDMARDs treatment course) joint knee involvement.

Disclosures: ANSWER Cohort was supported by grants from Abbie G.K., Asahi-Kasei Pharma, AYUMI Pharmaceutical Co., Chugai Pharmaceutical Co. Ltd., Eisai Co. Ltd., Janssen Pharmaceutical K.K., Ono Pharmaceutical Co., Sanofi, UCB Japan Co. Ltd., and Teijin Healthcare Limited. The authors including the lead author reported receiving grants, consulting fees, speaker fees, and/or honoraria from various sources.

Source: Maeda Y et al. Rheumatol Int. 2021 Apr 26. doi: 10.1007/s00296-021-04862-y.

Key clinical point: Anti-interleukin-6 (aIL-6) receptor antibody was more effective than other biologic disease-modifying antirheumatic drugs (bDMARDs) in patients with rheumatoid arthritis (RA) with knee joint involvement but not in patients without knee joint involvement.

Major finding: At 12 weeks, treatment with aIL-6 significantly increased clinical disease activity index (CDAI) in patients with knee joint involvement compared with other bDMARDs (P = .02). In patients without swollen knee joints, aIL-6 vs. other bDMARDs showed no significant difference in CDAI improvement (P = .61).

Study details: Findings are from a retrospective analysis of 1,059 treatment courses in patients with RA from the ANSWER cohort who were treated with bDMARDs. The patients were categorized into those with (n=275; 323 bDMARDs treatment course) or without (n=561; 736 bDMARDs treatment course) joint knee involvement.

Disclosures: ANSWER Cohort was supported by grants from Abbie G.K., Asahi-Kasei Pharma, AYUMI Pharmaceutical Co., Chugai Pharmaceutical Co. Ltd., Eisai Co. Ltd., Janssen Pharmaceutical K.K., Ono Pharmaceutical Co., Sanofi, UCB Japan Co. Ltd., and Teijin Healthcare Limited. The authors including the lead author reported receiving grants, consulting fees, speaker fees, and/or honoraria from various sources.

Source: Maeda Y et al. Rheumatol Int. 2021 Apr 26. doi: 10.1007/s00296-021-04862-y.

Key clinical point: Combination of methotrexate (MTX) and leflunomide (LEF) had a good overall safety profile compared with MTX or LEF alone and other regimens involved in advanced therapy for rheumatoid arthritis (RA).

Major finding: The risk for serious adverse events (SAEs; adjusted hazard ratio, [aHR], 1.00; P = .984) was not higher; however, the risk for any adverse events (aHR, 1.22; P = .013) was higher with MTX+LEF vs. MTX or LEF alone. The risk for SAEs (aHR, 0.56; P = .011) and infectious SAEs (aHR, 0.48; P = .031) was lower with MTX+LEF combo vs. biologic disease-modifying antirheumatic drugs (bDMARD)/JAK inhibitor (JAKi) with MTX or LEF.

Study details: Findings are from an analysis of 1,671 patients with RA from BiobadaBrasil, a multicentric, observational study. Included patients initiated the first treatment course with a conventional synthetic-DMARD or first bDMARD/JAKi.

Disclosures: This study was funded by the Brazilian Society of Rheumatology with funds from various pharmaceutical companies marketing biological compounds. The authors declared no conflicts of interest.

Source: Bredemeier M et al. J Rheumatol. 2021 May 1. doi: 10.3899/jrheum.201248.

Key clinical point: Combination of methotrexate (MTX) and leflunomide (LEF) had a good overall safety profile compared with MTX or LEF alone and other regimens involved in advanced therapy for rheumatoid arthritis (RA).

Major finding: The risk for serious adverse events (SAEs; adjusted hazard ratio, [aHR], 1.00; P = .984) was not higher; however, the risk for any adverse events (aHR, 1.22; P = .013) was higher with MTX+LEF vs. MTX or LEF alone. The risk for SAEs (aHR, 0.56; P = .011) and infectious SAEs (aHR, 0.48; P = .031) was lower with MTX+LEF combo vs. biologic disease-modifying antirheumatic drugs (bDMARD)/JAK inhibitor (JAKi) with MTX or LEF.

Study details: Findings are from an analysis of 1,671 patients with RA from BiobadaBrasil, a multicentric, observational study. Included patients initiated the first treatment course with a conventional synthetic-DMARD or first bDMARD/JAKi.

Disclosures: This study was funded by the Brazilian Society of Rheumatology with funds from various pharmaceutical companies marketing biological compounds. The authors declared no conflicts of interest.

Source: Bredemeier M et al. J Rheumatol. 2021 May 1. doi: 10.3899/jrheum.201248.

Key clinical point: Combination of methotrexate (MTX) and leflunomide (LEF) had a good overall safety profile compared with MTX or LEF alone and other regimens involved in advanced therapy for rheumatoid arthritis (RA).

Major finding: The risk for serious adverse events (SAEs; adjusted hazard ratio, [aHR], 1.00; P = .984) was not higher; however, the risk for any adverse events (aHR, 1.22; P = .013) was higher with MTX+LEF vs. MTX or LEF alone. The risk for SAEs (aHR, 0.56; P = .011) and infectious SAEs (aHR, 0.48; P = .031) was lower with MTX+LEF combo vs. biologic disease-modifying antirheumatic drugs (bDMARD)/JAK inhibitor (JAKi) with MTX or LEF.

Study details: Findings are from an analysis of 1,671 patients with RA from BiobadaBrasil, a multicentric, observational study. Included patients initiated the first treatment course with a conventional synthetic-DMARD or first bDMARD/JAKi.

Disclosures: This study was funded by the Brazilian Society of Rheumatology with funds from various pharmaceutical companies marketing biological compounds. The authors declared no conflicts of interest.

Source: Bredemeier M et al. J Rheumatol. 2021 May 1. doi: 10.3899/jrheum.201248.

Key clinical point: Rheumatoid meningitis should be considered in adult patients with or without a diagnosis of rheumatoid arthritis (RA). This would help in timely diagnosis and treatment, thus improving its outcomes.

Major finding: Common clinical manifestations of rheumatoid meningitis were transient focal neurologic signs (64.28%), systemic symptoms (51.78%), episodic headaches (50.00%), and neuropsychiatric changes (47.32%). Brain imaging indicated frontal (82.69%) and parietal (77.88%) lobes as the most common lesion location. Laboratory findings included high levels of rheumatoid factor (89.71%), anticyclic citrulline peptide (89.47%), C-reactive protein (82.54%), and erythrocyte deposition rate (81.81%).

Study details: Findings are from a meta-analysis of 103 studies involving 130 cases of rheumatoid meningitis. RA was diagnosed previously in 83% of cases, whereas the remaining 17% of patients were diagnosed with RA during or after the first diagnosis of rheumatoid meningitis.

Disclosures: No outside funding was provided for this study. The authors did not report any conflicts of interest.

Source: Villa E et al. Eur J Neurol. 2021 May 9. doi: 10.1111/ene.14904.

Key clinical point: Rheumatoid meningitis should be considered in adult patients with or without a diagnosis of rheumatoid arthritis (RA). This would help in timely diagnosis and treatment, thus improving its outcomes.

Major finding: Common clinical manifestations of rheumatoid meningitis were transient focal neurologic signs (64.28%), systemic symptoms (51.78%), episodic headaches (50.00%), and neuropsychiatric changes (47.32%). Brain imaging indicated frontal (82.69%) and parietal (77.88%) lobes as the most common lesion location. Laboratory findings included high levels of rheumatoid factor (89.71%), anticyclic citrulline peptide (89.47%), C-reactive protein (82.54%), and erythrocyte deposition rate (81.81%).

Study details: Findings are from a meta-analysis of 103 studies involving 130 cases of rheumatoid meningitis. RA was diagnosed previously in 83% of cases, whereas the remaining 17% of patients were diagnosed with RA during or after the first diagnosis of rheumatoid meningitis.

Disclosures: No outside funding was provided for this study. The authors did not report any conflicts of interest.

Source: Villa E et al. Eur J Neurol. 2021 May 9. doi: 10.1111/ene.14904.

Key clinical point: Rheumatoid meningitis should be considered in adult patients with or without a diagnosis of rheumatoid arthritis (RA). This would help in timely diagnosis and treatment, thus improving its outcomes.

Major finding: Common clinical manifestations of rheumatoid meningitis were transient focal neurologic signs (64.28%), systemic symptoms (51.78%), episodic headaches (50.00%), and neuropsychiatric changes (47.32%). Brain imaging indicated frontal (82.69%) and parietal (77.88%) lobes as the most common lesion location. Laboratory findings included high levels of rheumatoid factor (89.71%), anticyclic citrulline peptide (89.47%), C-reactive protein (82.54%), and erythrocyte deposition rate (81.81%).

Study details: Findings are from a meta-analysis of 103 studies involving 130 cases of rheumatoid meningitis. RA was diagnosed previously in 83% of cases, whereas the remaining 17% of patients were diagnosed with RA during or after the first diagnosis of rheumatoid meningitis.

Disclosures: No outside funding was provided for this study. The authors did not report any conflicts of interest.

Source: Villa E et al. Eur J Neurol. 2021 May 9. doi: 10.1111/ene.14904.

Key clinical point: A recent large cohort of patients with early rheumatoid arthritis (RA) revealed favorable 10-year outcomes, significantly better than the outcomes observed in a previous cohort of patients studied in 1993.

Major finding: At 10 years, disease activity score in 28 joints (DAS28)-erythrocyte sedimentation rate remission, DAS28 sustained remission, and drug-free remission were achieved by 52.4%, 40.1%, and 14.1% of patients, respectively. Half of the patients did not have a serious functional disability. Mortality rates were lower than that in the 1993 cohort (4.5% vs. 11.0%) and similar to that in the general population.

Study details: The data come from an analysis of 521 patients from the ESPOIR cohort who were diagnosed with early arthritis between 2003 and 2005 with a probable or certain diagnosis of RA and had never been prescribed disease-modifying antirheumatic drugs or glucocorticoids.

Disclosures: This work was supported by the Merck Sharp and Dohme, INSERM, French Society of Rheumatology, AbbVie, Pfizer, Lilly, Fresenius, and Galapagos. The authors including the lead author reported receiving grants, consulting fees, speaker fees, and/or honoraria from various sources.

Source: Combe B et al. Rheumatology (Oxford). 2021 May 7. doi: 10.1093/rheumatology/keab398.

Key clinical point: A recent large cohort of patients with early rheumatoid arthritis (RA) revealed favorable 10-year outcomes, significantly better than the outcomes observed in a previous cohort of patients studied in 1993.

Major finding: At 10 years, disease activity score in 28 joints (DAS28)-erythrocyte sedimentation rate remission, DAS28 sustained remission, and drug-free remission were achieved by 52.4%, 40.1%, and 14.1% of patients, respectively. Half of the patients did not have a serious functional disability. Mortality rates were lower than that in the 1993 cohort (4.5% vs. 11.0%) and similar to that in the general population.

Study details: The data come from an analysis of 521 patients from the ESPOIR cohort who were diagnosed with early arthritis between 2003 and 2005 with a probable or certain diagnosis of RA and had never been prescribed disease-modifying antirheumatic drugs or glucocorticoids.

Disclosures: This work was supported by the Merck Sharp and Dohme, INSERM, French Society of Rheumatology, AbbVie, Pfizer, Lilly, Fresenius, and Galapagos. The authors including the lead author reported receiving grants, consulting fees, speaker fees, and/or honoraria from various sources.

Source: Combe B et al. Rheumatology (Oxford). 2021 May 7. doi: 10.1093/rheumatology/keab398.

Key clinical point: A recent large cohort of patients with early rheumatoid arthritis (RA) revealed favorable 10-year outcomes, significantly better than the outcomes observed in a previous cohort of patients studied in 1993.

Major finding: At 10 years, disease activity score in 28 joints (DAS28)-erythrocyte sedimentation rate remission, DAS28 sustained remission, and drug-free remission were achieved by 52.4%, 40.1%, and 14.1% of patients, respectively. Half of the patients did not have a serious functional disability. Mortality rates were lower than that in the 1993 cohort (4.5% vs. 11.0%) and similar to that in the general population.

Study details: The data come from an analysis of 521 patients from the ESPOIR cohort who were diagnosed with early arthritis between 2003 and 2005 with a probable or certain diagnosis of RA and had never been prescribed disease-modifying antirheumatic drugs or glucocorticoids.

Disclosures: This work was supported by the Merck Sharp and Dohme, INSERM, French Society of Rheumatology, AbbVie, Pfizer, Lilly, Fresenius, and Galapagos. The authors including the lead author reported receiving grants, consulting fees, speaker fees, and/or honoraria from various sources.

Source: Combe B et al. Rheumatology (Oxford). 2021 May 7. doi: 10.1093/rheumatology/keab398.

Key clinical point: Tofacitinib vs. tocilizumab was more likely to induce and maintain improvement in clinical disease activity index (CDAI) and remission during the first 12 months of therapy in biological disease-modifying antirheumatic drugs (bDMARD)-naïve patients with methotrexate-refractory rheumatoid arthritis (RA).

Major finding: Likelihood of achieving and maintaining 85% or more (adjusted odds ratio [aOR], 3.88; P less than .001), 70% or more (aOR, 2.89; P = .003) improvement in CDAI, and remission (aOR, 3.31; P less than .001) in the first 12 months was higher with tofacitinib vs. tocilizumab in bDMARD-naïve patients but not in patients with previous bDMARD failure.

Study details: This was a multicenter cohort study of 464 patients with methotrexate-refractory RA who had high to moderate CDAI and initiated treatment with tofacitinib (n=247) or tocilizumab (n=217).

Disclosures: This study was supported by research funds from the National Hospital Organization, Japan. The authors including the leading author reported receiving lecture fees from various sources.

Source: Mori S et al. RMD Open. 2021 May 6. doi: 10.1136/rmdopen-2021-001601.

Key clinical point: Tofacitinib vs. tocilizumab was more likely to induce and maintain improvement in clinical disease activity index (CDAI) and remission during the first 12 months of therapy in biological disease-modifying antirheumatic drugs (bDMARD)-naïve patients with methotrexate-refractory rheumatoid arthritis (RA).

Major finding: Likelihood of achieving and maintaining 85% or more (adjusted odds ratio [aOR], 3.88; P less than .001), 70% or more (aOR, 2.89; P = .003) improvement in CDAI, and remission (aOR, 3.31; P less than .001) in the first 12 months was higher with tofacitinib vs. tocilizumab in bDMARD-naïve patients but not in patients with previous bDMARD failure.

Study details: This was a multicenter cohort study of 464 patients with methotrexate-refractory RA who had high to moderate CDAI and initiated treatment with tofacitinib (n=247) or tocilizumab (n=217).

Disclosures: This study was supported by research funds from the National Hospital Organization, Japan. The authors including the leading author reported receiving lecture fees from various sources.

Source: Mori S et al. RMD Open. 2021 May 6. doi: 10.1136/rmdopen-2021-001601.

Key clinical point: Tofacitinib vs. tocilizumab was more likely to induce and maintain improvement in clinical disease activity index (CDAI) and remission during the first 12 months of therapy in biological disease-modifying antirheumatic drugs (bDMARD)-naïve patients with methotrexate-refractory rheumatoid arthritis (RA).

Major finding: Likelihood of achieving and maintaining 85% or more (adjusted odds ratio [aOR], 3.88; P less than .001), 70% or more (aOR, 2.89; P = .003) improvement in CDAI, and remission (aOR, 3.31; P less than .001) in the first 12 months was higher with tofacitinib vs. tocilizumab in bDMARD-naïve patients but not in patients with previous bDMARD failure.

Study details: This was a multicenter cohort study of 464 patients with methotrexate-refractory RA who had high to moderate CDAI and initiated treatment with tofacitinib (n=247) or tocilizumab (n=217).

Disclosures: This study was supported by research funds from the National Hospital Organization, Japan. The authors including the leading author reported receiving lecture fees from various sources.

Source: Mori S et al. RMD Open. 2021 May 6. doi: 10.1136/rmdopen-2021-001601.

Key clinical point: A 3-dose regimen of intravenous tranexamic acid (IV-TXA) was more effective than a single dose in reducing postoperative blood loss in patients with rheumatoid arthritis (RA) who underwent primary unilateral total knee arthroplasty (TKA).

Major finding: Decrease in total blood loss (P = .038), hidden blood loss (P = .036), and maximum hemoglobin drop (P less than .001) was significantly lower with 3 vs. a single dose of postoperative IV-TXA. Additionally, levels of D-dimer on postoperative day 1 were significantly lower with 3 vs. a single dose of IV-TXA (P less than .001). Incidences of thromboembolic events were similar between groups.

Study details: This was a single-center, randomized controlled trial of 104 patients who underwent primary unilateral TKA for RA and were randomly allocated to receive either a single dose of IV-TXA (1 g; n=52) 3 hours postoperatively or 3 doses of IV-TXA (1 g; n=52) 3, 6, and 12 hours postoperatively.

Disclosures: This study was supported by the Foundation of Health and Family planning Commission of Shanghai, China. The authors declared no conflicts of interest.

Source: Kang BX et al. BMC Musculoskelet Disord. 2021 May 7. doi: 10.1186/s12891-021-04307-4.

Key clinical point: A 3-dose regimen of intravenous tranexamic acid (IV-TXA) was more effective than a single dose in reducing postoperative blood loss in patients with rheumatoid arthritis (RA) who underwent primary unilateral total knee arthroplasty (TKA).

Major finding: Decrease in total blood loss (P = .038), hidden blood loss (P = .036), and maximum hemoglobin drop (P less than .001) was significantly lower with 3 vs. a single dose of postoperative IV-TXA. Additionally, levels of D-dimer on postoperative day 1 were significantly lower with 3 vs. a single dose of IV-TXA (P less than .001). Incidences of thromboembolic events were similar between groups.

Study details: This was a single-center, randomized controlled trial of 104 patients who underwent primary unilateral TKA for RA and were randomly allocated to receive either a single dose of IV-TXA (1 g; n=52) 3 hours postoperatively or 3 doses of IV-TXA (1 g; n=52) 3, 6, and 12 hours postoperatively.

Disclosures: This study was supported by the Foundation of Health and Family planning Commission of Shanghai, China. The authors declared no conflicts of interest.

Source: Kang BX et al. BMC Musculoskelet Disord. 2021 May 7. doi: 10.1186/s12891-021-04307-4.

Key clinical point: A 3-dose regimen of intravenous tranexamic acid (IV-TXA) was more effective than a single dose in reducing postoperative blood loss in patients with rheumatoid arthritis (RA) who underwent primary unilateral total knee arthroplasty (TKA).

Major finding: Decrease in total blood loss (P = .038), hidden blood loss (P = .036), and maximum hemoglobin drop (P less than .001) was significantly lower with 3 vs. a single dose of postoperative IV-TXA. Additionally, levels of D-dimer on postoperative day 1 were significantly lower with 3 vs. a single dose of IV-TXA (P less than .001). Incidences of thromboembolic events were similar between groups.

Study details: This was a single-center, randomized controlled trial of 104 patients who underwent primary unilateral TKA for RA and were randomly allocated to receive either a single dose of IV-TXA (1 g; n=52) 3 hours postoperatively or 3 doses of IV-TXA (1 g; n=52) 3, 6, and 12 hours postoperatively.

Disclosures: This study was supported by the Foundation of Health and Family planning Commission of Shanghai, China. The authors declared no conflicts of interest.

Source: Kang BX et al. BMC Musculoskelet Disord. 2021 May 7. doi: 10.1186/s12891-021-04307-4.

Key clinical point: Treatment with the half dose vs. stable dose of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) was associated with increased rates of flares over 12 months in patients with rheumatoid arthritis (RA) in remission.

Major finding: At 12 months, the proportion of patients with at least 1 flare was significantly higher with half-dose vs. stable-dose csDMARDs (25% vs. 6%; risk difference, 18%; P = .003), thereby not meeting the noninferiority criterion of a 20% difference. There were 54 vs. 75 adverse events in the half-dose vs. stable-dose group.

Study details: Findings are from ARCTIC REWIND, a 36-month noninferiority trial of 160 patients with RA in remission for 12 months who were receiving stable csDMARDs. Patients were randomly allocated to either half-dose (n=80) or stable-dose (n=80) csDMARDs.

Disclosures: ARCTIC REWIND study was funded by the Research Council of Norway and South-Eastern Norway Regional Health Authority. The authors including the lead author reported receiving grants, personal fees, and nonfinancial support from various sources.

Source: Lillegraven S et al. JAMA. 2021 May 4. doi: 10.1001/jama.2021.4542.

Key clinical point: Treatment with the half dose vs. stable dose of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) was associated with increased rates of flares over 12 months in patients with rheumatoid arthritis (RA) in remission.

Major finding: At 12 months, the proportion of patients with at least 1 flare was significantly higher with half-dose vs. stable-dose csDMARDs (25% vs. 6%; risk difference, 18%; P = .003), thereby not meeting the noninferiority criterion of a 20% difference. There were 54 vs. 75 adverse events in the half-dose vs. stable-dose group.

Study details: Findings are from ARCTIC REWIND, a 36-month noninferiority trial of 160 patients with RA in remission for 12 months who were receiving stable csDMARDs. Patients were randomly allocated to either half-dose (n=80) or stable-dose (n=80) csDMARDs.

Disclosures: ARCTIC REWIND study was funded by the Research Council of Norway and South-Eastern Norway Regional Health Authority. The authors including the lead author reported receiving grants, personal fees, and nonfinancial support from various sources.

Source: Lillegraven S et al. JAMA. 2021 May 4. doi: 10.1001/jama.2021.4542.

Key clinical point: Treatment with the half dose vs. stable dose of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) was associated with increased rates of flares over 12 months in patients with rheumatoid arthritis (RA) in remission.

Major finding: At 12 months, the proportion of patients with at least 1 flare was significantly higher with half-dose vs. stable-dose csDMARDs (25% vs. 6%; risk difference, 18%; P = .003), thereby not meeting the noninferiority criterion of a 20% difference. There were 54 vs. 75 adverse events in the half-dose vs. stable-dose group.

Study details: Findings are from ARCTIC REWIND, a 36-month noninferiority trial of 160 patients with RA in remission for 12 months who were receiving stable csDMARDs. Patients were randomly allocated to either half-dose (n=80) or stable-dose (n=80) csDMARDs.

Disclosures: ARCTIC REWIND study was funded by the Research Council of Norway and South-Eastern Norway Regional Health Authority. The authors including the lead author reported receiving grants, personal fees, and nonfinancial support from various sources.

Source: Lillegraven S et al. JAMA. 2021 May 4. doi: 10.1001/jama.2021.4542.

Veterans with chronic headaches had a greater risk of a suicide attempt than that of veterans suffering from chronic neck or back pain, according to findings presented at the American Headache Society’s 2021 annual meeting. Risk rose even more in those with chronic headache pain and a comorbid traumatic brain injury (TBI).

“In addition, as expected, veterans with psychiatric conditions have increased risk of suicide attempt with the exception of anxiety in men and dependent personality in women,” said X. Michelle Androulakis, MD, associate professor of neurology at the University of South Carolina, Columbia.
 

‘Surprising’ findings

“These findings are eye-opening but not surprising since we know that veterans in general and people with chronic pain are at higher risk for suicidal behaviors compared with their civilian counterparts,” said Amy. S Grinberg, PhD, a clinical health psychologist who practices in New Rochelle, N.Y. Dr. Grinberg, who also works at VA Connecticut Healthcare System, was not involved in the study.

“It is, however, very interesting that suicidal attempts are higher in veterans with chronic headache compared with other chronic pain disorders, such as chronic neck and back pain,” Dr Grinberg said. “This really highlights the impact of living with a chronic headache disorder, and emphasizes the continued efforts that should be put into place to support veterans with chronic headache, including improved access to a range of treatment options and continued funding for future research.”
 

Veterans with chronic pain

The researchers retrospectively analyzed Veterans Health Administration electronic health records of 3,252,704 veterans, predominantly male and White, who had been diagnosed with any type of chronic pain from 2000 to 2010.

The researchers looked at overall headache diagnoses instead of specific diagnoses, such as migraine, cluster headache, or posttraumatic headache, since specific headache disorders are frequently underdiagnosed.

The population included 14.7% of patients with chronic headache, 14.9% with chronic neck pain, 59.2% with chronic back pain, and 60.2% with other types of chronic pain, including arthritis, fibromyalgia, joint pain, and reflex sympathetic dystrophy.

Traumatic brain injury occurred in 11.2% of those with chronic headaches, compared with 6.8% of those with chronic back pain, 8.5% of those with chronic neck pain, and 5.9% of those with other chronic pain.

More than half (56.4%) of those with chronic headache had depression, the most common comorbidity in the group, followed by 31.5% who had posttraumatic stress disorder (PTSD), and 21.8% who had adjustment disorder. Other rates of psychiatric disorders were all below 10%. Prevalence of depression occurred in 44.5% of those with back pain, 52.4% of those with neck pain, and 39% of those with other chronic pain. PTSD rates were also lower in those with back (22%), neck (27.2%), or other chronic pain (18.6%).

“Interestingly, this study found that those veterans with a history of traumatic brain injury and psychiatric comorbidities, such as depression, are at greater risk for suicide attempts,” said Dr. Grinberg. “The good news is that these are modifiable risk factors, and evidence-based treatments for depression, PTSD, and headache, for example, are widely disseminated within the VA.”

The majority of headache diagnoses were not otherwise specified (80.1%). Half (50.2%) were migraine headaches while rates were much lower for tension-type headache (8.8%), trigeminal neuralgia (5%), cluster headache (0.8%), and posttraumatic headache (0.7%).

The highest incidence of suicide attempts occurred among those with chronic headaches, ranging from 329 to 396 per 100,000, aside from a peak of 482 per 100,000 in 2005. Suicide attempts peaked among all patients with chronic pain in 2005, “likely related to the deployment and policy changes in the Veterans Health Administration,” Dr. Androulakis said.

Those with neck pain had the next highest rate of suicide attempts, ranging from 263 to 314 per 100,000, excluding the peak of 398 per 100,000 in 2005.

Male veterans with chronic headaches had a 1.5 times greater likelihood of a suicide attempt than did those with back or neck pain (relative risk [RR] = 1.5), which increased to a relative risk of 2.8 greater for those with concurrent TBI. Among female veterans, chronic headache was associated with a 1.6 times greater risk of a suicide attempt, which rose to 2.15 times greater with concurrent TBI.

“Knowing that veterans with chronic headache disorders have an elevated rate of suicide, it is imperative that doctors and other clinical providers continue to conduct in-depth risk assessments and implement strategies to support those veterans who are at risk,” said Dr. Grinberg. “Clinical providers should continue in their efforts to reduce stigma associated with headache disorders and mental health treatment in order to effectively engage veterans in evidence-based treatments that are likely a step towards reducing symptoms and suicidal attempts.”

No external funding was noted. Dr. Androulakis and Dr. Grinberg had no disclosures.

Veterans with chronic headaches had a greater risk of a suicide attempt than that of veterans suffering from chronic neck or back pain, according to findings presented at the American Headache Society’s 2021 annual meeting. Risk rose even more in those with chronic headache pain and a comorbid traumatic brain injury (TBI).

“In addition, as expected, veterans with psychiatric conditions have increased risk of suicide attempt with the exception of anxiety in men and dependent personality in women,” said X. Michelle Androulakis, MD, associate professor of neurology at the University of South Carolina, Columbia.
 

‘Surprising’ findings

“These findings are eye-opening but not surprising since we know that veterans in general and people with chronic pain are at higher risk for suicidal behaviors compared with their civilian counterparts,” said Amy. S Grinberg, PhD, a clinical health psychologist who practices in New Rochelle, N.Y. Dr. Grinberg, who also works at VA Connecticut Healthcare System, was not involved in the study.

“It is, however, very interesting that suicidal attempts are higher in veterans with chronic headache compared with other chronic pain disorders, such as chronic neck and back pain,” Dr Grinberg said. “This really highlights the impact of living with a chronic headache disorder, and emphasizes the continued efforts that should be put into place to support veterans with chronic headache, including improved access to a range of treatment options and continued funding for future research.”
 

Veterans with chronic pain

The researchers retrospectively analyzed Veterans Health Administration electronic health records of 3,252,704 veterans, predominantly male and White, who had been diagnosed with any type of chronic pain from 2000 to 2010.

The researchers looked at overall headache diagnoses instead of specific diagnoses, such as migraine, cluster headache, or posttraumatic headache, since specific headache disorders are frequently underdiagnosed.

The population included 14.7% of patients with chronic headache, 14.9% with chronic neck pain, 59.2% with chronic back pain, and 60.2% with other types of chronic pain, including arthritis, fibromyalgia, joint pain, and reflex sympathetic dystrophy.

Traumatic brain injury occurred in 11.2% of those with chronic headaches, compared with 6.8% of those with chronic back pain, 8.5% of those with chronic neck pain, and 5.9% of those with other chronic pain.

More than half (56.4%) of those with chronic headache had depression, the most common comorbidity in the group, followed by 31.5% who had posttraumatic stress disorder (PTSD), and 21.8% who had adjustment disorder. Other rates of psychiatric disorders were all below 10%. Prevalence of depression occurred in 44.5% of those with back pain, 52.4% of those with neck pain, and 39% of those with other chronic pain. PTSD rates were also lower in those with back (22%), neck (27.2%), or other chronic pain (18.6%).

“Interestingly, this study found that those veterans with a history of traumatic brain injury and psychiatric comorbidities, such as depression, are at greater risk for suicide attempts,” said Dr. Grinberg. “The good news is that these are modifiable risk factors, and evidence-based treatments for depression, PTSD, and headache, for example, are widely disseminated within the VA.”

The majority of headache diagnoses were not otherwise specified (80.1%). Half (50.2%) were migraine headaches while rates were much lower for tension-type headache (8.8%), trigeminal neuralgia (5%), cluster headache (0.8%), and posttraumatic headache (0.7%).

The highest incidence of suicide attempts occurred among those with chronic headaches, ranging from 329 to 396 per 100,000, aside from a peak of 482 per 100,000 in 2005. Suicide attempts peaked among all patients with chronic pain in 2005, “likely related to the deployment and policy changes in the Veterans Health Administration,” Dr. Androulakis said.

Those with neck pain had the next highest rate of suicide attempts, ranging from 263 to 314 per 100,000, excluding the peak of 398 per 100,000 in 2005.

Male veterans with chronic headaches had a 1.5 times greater likelihood of a suicide attempt than did those with back or neck pain (relative risk [RR] = 1.5), which increased to a relative risk of 2.8 greater for those with concurrent TBI. Among female veterans, chronic headache was associated with a 1.6 times greater risk of a suicide attempt, which rose to 2.15 times greater with concurrent TBI.

“Knowing that veterans with chronic headache disorders have an elevated rate of suicide, it is imperative that doctors and other clinical providers continue to conduct in-depth risk assessments and implement strategies to support those veterans who are at risk,” said Dr. Grinberg. “Clinical providers should continue in their efforts to reduce stigma associated with headache disorders and mental health treatment in order to effectively engage veterans in evidence-based treatments that are likely a step towards reducing symptoms and suicidal attempts.”

No external funding was noted. Dr. Androulakis and Dr. Grinberg had no disclosures.

Veterans with chronic headaches had a greater risk of a suicide attempt than that of veterans suffering from chronic neck or back pain, according to findings presented at the American Headache Society’s 2021 annual meeting. Risk rose even more in those with chronic headache pain and a comorbid traumatic brain injury (TBI).

“In addition, as expected, veterans with psychiatric conditions have increased risk of suicide attempt with the exception of anxiety in men and dependent personality in women,” said X. Michelle Androulakis, MD, associate professor of neurology at the University of South Carolina, Columbia.
 

‘Surprising’ findings

“These findings are eye-opening but not surprising since we know that veterans in general and people with chronic pain are at higher risk for suicidal behaviors compared with their civilian counterparts,” said Amy. S Grinberg, PhD, a clinical health psychologist who practices in New Rochelle, N.Y. Dr. Grinberg, who also works at VA Connecticut Healthcare System, was not involved in the study.

“It is, however, very interesting that suicidal attempts are higher in veterans with chronic headache compared with other chronic pain disorders, such as chronic neck and back pain,” Dr Grinberg said. “This really highlights the impact of living with a chronic headache disorder, and emphasizes the continued efforts that should be put into place to support veterans with chronic headache, including improved access to a range of treatment options and continued funding for future research.”
 

Veterans with chronic pain

The researchers retrospectively analyzed Veterans Health Administration electronic health records of 3,252,704 veterans, predominantly male and White, who had been diagnosed with any type of chronic pain from 2000 to 2010.

The researchers looked at overall headache diagnoses instead of specific diagnoses, such as migraine, cluster headache, or posttraumatic headache, since specific headache disorders are frequently underdiagnosed.

The population included 14.7% of patients with chronic headache, 14.9% with chronic neck pain, 59.2% with chronic back pain, and 60.2% with other types of chronic pain, including arthritis, fibromyalgia, joint pain, and reflex sympathetic dystrophy.

Traumatic brain injury occurred in 11.2% of those with chronic headaches, compared with 6.8% of those with chronic back pain, 8.5% of those with chronic neck pain, and 5.9% of those with other chronic pain.

More than half (56.4%) of those with chronic headache had depression, the most common comorbidity in the group, followed by 31.5% who had posttraumatic stress disorder (PTSD), and 21.8% who had adjustment disorder. Other rates of psychiatric disorders were all below 10%. Prevalence of depression occurred in 44.5% of those with back pain, 52.4% of those with neck pain, and 39% of those with other chronic pain. PTSD rates were also lower in those with back (22%), neck (27.2%), or other chronic pain (18.6%).

“Interestingly, this study found that those veterans with a history of traumatic brain injury and psychiatric comorbidities, such as depression, are at greater risk for suicide attempts,” said Dr. Grinberg. “The good news is that these are modifiable risk factors, and evidence-based treatments for depression, PTSD, and headache, for example, are widely disseminated within the VA.”

The majority of headache diagnoses were not otherwise specified (80.1%). Half (50.2%) were migraine headaches while rates were much lower for tension-type headache (8.8%), trigeminal neuralgia (5%), cluster headache (0.8%), and posttraumatic headache (0.7%).

The highest incidence of suicide attempts occurred among those with chronic headaches, ranging from 329 to 396 per 100,000, aside from a peak of 482 per 100,000 in 2005. Suicide attempts peaked among all patients with chronic pain in 2005, “likely related to the deployment and policy changes in the Veterans Health Administration,” Dr. Androulakis said.

Those with neck pain had the next highest rate of suicide attempts, ranging from 263 to 314 per 100,000, excluding the peak of 398 per 100,000 in 2005.

Male veterans with chronic headaches had a 1.5 times greater likelihood of a suicide attempt than did those with back or neck pain (relative risk [RR] = 1.5), which increased to a relative risk of 2.8 greater for those with concurrent TBI. Among female veterans, chronic headache was associated with a 1.6 times greater risk of a suicide attempt, which rose to 2.15 times greater with concurrent TBI.

“Knowing that veterans with chronic headache disorders have an elevated rate of suicide, it is imperative that doctors and other clinical providers continue to conduct in-depth risk assessments and implement strategies to support those veterans who are at risk,” said Dr. Grinberg. “Clinical providers should continue in their efforts to reduce stigma associated with headache disorders and mental health treatment in order to effectively engage veterans in evidence-based treatments that are likely a step towards reducing symptoms and suicidal attempts.”

No external funding was noted. Dr. Androulakis and Dr. Grinberg had no disclosures.

Granularly mixed laterally spreading colorectal tumors (GM-LSTs) that are located in the rectum or are larger than 4 cm should be considered to be at high risk of developing into covert submucosal invasive cancer (SMIC), and should be treated by en bloc resection, according to a retrospective analysis of patients from seven Italian centers.

GM-LSTs are 1-cm or larger nonpolypoid lesions with lateral growth. They make up 1%-6% of colorectal lesions, and are important clinically because of the possibility that they are SMICs that aren’t visibly apparent.

On the one hand, homogeneous granular-type LSTs have been found to have a very low SMIC risk (0.5%) and are candidates for piecemeal removal, while non-granular LSTs present higher risk, suggesting that en bloc resection would be an appropriate strategy. Piecemeal attempts that discover a SMIC can lead to follow-up surgery because it may not be possible to evaluate submucosal invasion at pathology. Further surgery can be particularly onerous in rectal lesions, where it can reduce quality of life.

On the other hand, granularly mixed LSTs present a conundrum: SMIC risk falls somewhere between the granular and nongranular LSTs, and they make up about 25% of laterally spreading tumors.
 

A deeper look

To better characterize GM-LSTs and predict which might be covert SMICs, Ferdinando D’Amico at Humanitas University in Milan and colleagues analyzed data from 693 patients with colorectal GM-LSTs at seven Italian centers, between 2016 and 2019. The results appeared in Clinical Gastroenterology and Hepatology. Median age was 69 years, and 50.6% of patients were men.

Of patients in the study, 9.5% were found to have SMICs at histology. Of these, 62.1% occurred in lesions 4 cm or larger, and none in lesions smaller than 2 cm, and 63.6% occurred in the rectum. Overall, 24.2% of patients underwent en bloc resection.

A multivariate analysis found that lesion size was associated with risk of covert SMIC (odds ratio per mm, 1.02; 95% confidence interval, 1.0-1.03). A cutoff of 4.0 cm yielded the optimal discrimination for SMIC risk, with a 6.0% risk below that size and 14.8% above (OR, 2.32; P = .002). The researchers also considered GM-LST location in this multivariate analysis, and found a greater risk of SMIC in those located in the rectum than for those in other colonic segments (15.1% vs. 5.8%; OR, 3.08; P = .004). A logistic regression model combining size and location yielded a sensitivity of 47.0%, specificity 82.6%, and area under the curve of 0.69.

When lesions of 4 cm or greater in the rectal area were compared with nonrectal lesions less than 4 cm, the number needed to treat (NNT) to detect one covert SMIC dropped from 20 to 5.

“The 22% risk of covert SMIC for ≥4-cm rectal GM-LSTs equals the 21.4% previously reported as the highest risk for nongranular LSTs, justifying the need for an aggressive treatment, especially when considering that the unexpected finding of a covert SMIC after piecemeal resection of a rectal lesion may result in an unnecessary surgery, with major consequences for the patient. Thus, referral of these patients to a center with adequate competence in advanced resection, including [endoscopic submucosal dissection], should be recommended,” the authors wrote.

They noted that the NNT of 5 is low enough to compensate for the risk of conducting ESD instead of piecemeal endoscopic mucosal resection. Meanwhile, the NNT of 20 for smaller, nonrectal tumors puts them close to the risk category of homogeneous granular LSTs, which wouldn’t justify a more complex procedure and could instead be resected piecemeal.

For rectal lesions less than 4 cm or nonrectal lesions 4 cm or larger, SMIC risk is below 10%. In deciding which approach to take, endoscopists must weigh the low risk of surgery after discovery of an unexpected SMIC. The authors suggest use of dye or virtual chromoendoscopy for lesion characterization, along with optical magnification if available.

The study had some limitations. One is that the authors did not assess how frequently the SMIC was limited to the dominant nodule, which might affect resection strategies. Another is that the actual SMIC rate in GM-LSTs may have been underestimated: Not only were signs of overt invasion an exclusion criterion, but also patients with difficult-to-treat SMIC lesions might have been referred elsewhere.

The authors disclosed no funding source and declared that they had no relevant financial disclosures.

Granularly mixed laterally spreading colorectal tumors (GM-LSTs) that are located in the rectum or are larger than 4 cm should be considered to be at high risk of developing into covert submucosal invasive cancer (SMIC), and should be treated by en bloc resection, according to a retrospective analysis of patients from seven Italian centers.

GM-LSTs are 1-cm or larger nonpolypoid lesions with lateral growth. They make up 1%-6% of colorectal lesions, and are important clinically because of the possibility that they are SMICs that aren’t visibly apparent.

On the one hand, homogeneous granular-type LSTs have been found to have a very low SMIC risk (0.5%) and are candidates for piecemeal removal, while non-granular LSTs present higher risk, suggesting that en bloc resection would be an appropriate strategy. Piecemeal attempts that discover a SMIC can lead to follow-up surgery because it may not be possible to evaluate submucosal invasion at pathology. Further surgery can be particularly onerous in rectal lesions, where it can reduce quality of life.

On the other hand, granularly mixed LSTs present a conundrum: SMIC risk falls somewhere between the granular and nongranular LSTs, and they make up about 25% of laterally spreading tumors.
 

A deeper look

To better characterize GM-LSTs and predict which might be covert SMICs, Ferdinando D’Amico at Humanitas University in Milan and colleagues analyzed data from 693 patients with colorectal GM-LSTs at seven Italian centers, between 2016 and 2019. The results appeared in Clinical Gastroenterology and Hepatology. Median age was 69 years, and 50.6% of patients were men.

Of patients in the study, 9.5% were found to have SMICs at histology. Of these, 62.1% occurred in lesions 4 cm or larger, and none in lesions smaller than 2 cm, and 63.6% occurred in the rectum. Overall, 24.2% of patients underwent en bloc resection.

A multivariate analysis found that lesion size was associated with risk of covert SMIC (odds ratio per mm, 1.02; 95% confidence interval, 1.0-1.03). A cutoff of 4.0 cm yielded the optimal discrimination for SMIC risk, with a 6.0% risk below that size and 14.8% above (OR, 2.32; P = .002). The researchers also considered GM-LST location in this multivariate analysis, and found a greater risk of SMIC in those located in the rectum than for those in other colonic segments (15.1% vs. 5.8%; OR, 3.08; P = .004). A logistic regression model combining size and location yielded a sensitivity of 47.0%, specificity 82.6%, and area under the curve of 0.69.

When lesions of 4 cm or greater in the rectal area were compared with nonrectal lesions less than 4 cm, the number needed to treat (NNT) to detect one covert SMIC dropped from 20 to 5.

“The 22% risk of covert SMIC for ≥4-cm rectal GM-LSTs equals the 21.4% previously reported as the highest risk for nongranular LSTs, justifying the need for an aggressive treatment, especially when considering that the unexpected finding of a covert SMIC after piecemeal resection of a rectal lesion may result in an unnecessary surgery, with major consequences for the patient. Thus, referral of these patients to a center with adequate competence in advanced resection, including [endoscopic submucosal dissection], should be recommended,” the authors wrote.

They noted that the NNT of 5 is low enough to compensate for the risk of conducting ESD instead of piecemeal endoscopic mucosal resection. Meanwhile, the NNT of 20 for smaller, nonrectal tumors puts them close to the risk category of homogeneous granular LSTs, which wouldn’t justify a more complex procedure and could instead be resected piecemeal.

For rectal lesions less than 4 cm or nonrectal lesions 4 cm or larger, SMIC risk is below 10%. In deciding which approach to take, endoscopists must weigh the low risk of surgery after discovery of an unexpected SMIC. The authors suggest use of dye or virtual chromoendoscopy for lesion characterization, along with optical magnification if available.

The study had some limitations. One is that the authors did not assess how frequently the SMIC was limited to the dominant nodule, which might affect resection strategies. Another is that the actual SMIC rate in GM-LSTs may have been underestimated: Not only were signs of overt invasion an exclusion criterion, but also patients with difficult-to-treat SMIC lesions might have been referred elsewhere.

The authors disclosed no funding source and declared that they had no relevant financial disclosures.

Granularly mixed laterally spreading colorectal tumors (GM-LSTs) that are located in the rectum or are larger than 4 cm should be considered to be at high risk of developing into covert submucosal invasive cancer (SMIC), and should be treated by en bloc resection, according to a retrospective analysis of patients from seven Italian centers.

GM-LSTs are 1-cm or larger nonpolypoid lesions with lateral growth. They make up 1%-6% of colorectal lesions, and are important clinically because of the possibility that they are SMICs that aren’t visibly apparent.

On the one hand, homogeneous granular-type LSTs have been found to have a very low SMIC risk (0.5%) and are candidates for piecemeal removal, while non-granular LSTs present higher risk, suggesting that en bloc resection would be an appropriate strategy. Piecemeal attempts that discover a SMIC can lead to follow-up surgery because it may not be possible to evaluate submucosal invasion at pathology. Further surgery can be particularly onerous in rectal lesions, where it can reduce quality of life.

On the other hand, granularly mixed LSTs present a conundrum: SMIC risk falls somewhere between the granular and nongranular LSTs, and they make up about 25% of laterally spreading tumors.
 

A deeper look

To better characterize GM-LSTs and predict which might be covert SMICs, Ferdinando D’Amico at Humanitas University in Milan and colleagues analyzed data from 693 patients with colorectal GM-LSTs at seven Italian centers, between 2016 and 2019. The results appeared in Clinical Gastroenterology and Hepatology. Median age was 69 years, and 50.6% of patients were men.

Of patients in the study, 9.5% were found to have SMICs at histology. Of these, 62.1% occurred in lesions 4 cm or larger, and none in lesions smaller than 2 cm, and 63.6% occurred in the rectum. Overall, 24.2% of patients underwent en bloc resection.

A multivariate analysis found that lesion size was associated with risk of covert SMIC (odds ratio per mm, 1.02; 95% confidence interval, 1.0-1.03). A cutoff of 4.0 cm yielded the optimal discrimination for SMIC risk, with a 6.0% risk below that size and 14.8% above (OR, 2.32; P = .002). The researchers also considered GM-LST location in this multivariate analysis, and found a greater risk of SMIC in those located in the rectum than for those in other colonic segments (15.1% vs. 5.8%; OR, 3.08; P = .004). A logistic regression model combining size and location yielded a sensitivity of 47.0%, specificity 82.6%, and area under the curve of 0.69.

When lesions of 4 cm or greater in the rectal area were compared with nonrectal lesions less than 4 cm, the number needed to treat (NNT) to detect one covert SMIC dropped from 20 to 5.

“The 22% risk of covert SMIC for ≥4-cm rectal GM-LSTs equals the 21.4% previously reported as the highest risk for nongranular LSTs, justifying the need for an aggressive treatment, especially when considering that the unexpected finding of a covert SMIC after piecemeal resection of a rectal lesion may result in an unnecessary surgery, with major consequences for the patient. Thus, referral of these patients to a center with adequate competence in advanced resection, including [endoscopic submucosal dissection], should be recommended,” the authors wrote.

They noted that the NNT of 5 is low enough to compensate for the risk of conducting ESD instead of piecemeal endoscopic mucosal resection. Meanwhile, the NNT of 20 for smaller, nonrectal tumors puts them close to the risk category of homogeneous granular LSTs, which wouldn’t justify a more complex procedure and could instead be resected piecemeal.

For rectal lesions less than 4 cm or nonrectal lesions 4 cm or larger, SMIC risk is below 10%. In deciding which approach to take, endoscopists must weigh the low risk of surgery after discovery of an unexpected SMIC. The authors suggest use of dye or virtual chromoendoscopy for lesion characterization, along with optical magnification if available.

The study had some limitations. One is that the authors did not assess how frequently the SMIC was limited to the dominant nodule, which might affect resection strategies. Another is that the actual SMIC rate in GM-LSTs may have been underestimated: Not only were signs of overt invasion an exclusion criterion, but also patients with difficult-to-treat SMIC lesions might have been referred elsewhere.

The authors disclosed no funding source and declared that they had no relevant financial disclosures.

A novel oncogene may be a key driver in hepatoblastoma, according to a new study. Hepatoblastoma is the most common form of pediatric cancer, and many tumors harbor beta-catenin mutations and alterations to the Hippo tumor suppression pathway.

In mice, cells can be turned cancerous by coexpressing beta-catenin mutants and the Hippo effector YAP. Some hepatoblastomas have mutations in NFE2L2/NRF2 (NFE2L2), which is a transcription factor that can either promote or suppress tumorigenesis.

In a report in Cellular and Molecular Gastroenterology and Hepatology, researchers led by Huabo Wang, PhD, of the UPMC Children’s Hospital of Pittsburgh investigated the potential role of NFE2L2 by expressing all combinations of mutant beta-catenin, YAP^S127A, and two NFE2L2 mutants previously discovered in patients (L30P and R34P).

The researchers found that both the L30P and R34P mutations led to an increase in cellular growth and to both necrosis and cyst formation, which are both clinically uncommon. Any two of beta-catenin, YAP^S127A, and L30P/R34P caused tumor formation, indicating that NFE2L2 is an oncogene, according to the authors.

Among tumors with changes in all three regions, unbiased RNA sequencing across all combinations of mutations revealed 22 RNA transcripts common to all of them. These are probably the most important contributors to cell transformation and may also be related to increased growth, cystogenesis, and necrosis found in these tumors. Of those transcripts, 10 were highly correlated with survival in human hepatoblastomas, and 17 correlated with survival in more than one adult cancer.

Although hepatoblastomas have fewer mutations than most tumors, around 5%-10% have mutations in NFE2L2. About half have an increase in the copy number of NFE2L2.

The results suggest that wild-type NFE2L2 plays a role in suppressing cell proliferation in response to oxidative, metabolic, and electrophilic stresses. But the picture is more complex than that because NFE2L2’s pathway can have opposite effects, depending on the timing and context. Early in the oncogenesis pathway, it may protect against the damaging effects of reactive oxygen species (ROS). Later, it can make cells more tolerant to the effects of oncoproteins and promote tumor evolution, expansion, and even resistance to therapy.

Previous in vitro and tumor xenograft studies had suggested that NFE2L2 targets might play a role in apoptosis, metabolism, angiogenesis, and chemotherapeutic drug detoxification. The new results show that the L30P/R34P mutations can accelerate tumorigenesis caused by beta-catenin mutations and can promote transformation when co-expressed with either beta-catenin or YAP^S127A. That suggests that some hepatoblastomas may be driven at least in part by changes to NFE2L2. The researchers speculate that it may also be involved in combination with other oncoproteins in other types of tumors.

The researchers noted that the cysts seen in tumors with NFE2L2 mutations are bloodless, and resembled cysts that are sometimes seen in human hepatoblastomas. They were unrelated to tumor growth rate.

“Our findings demonstrate that NFE2L2 mutants alter redox balance in beta-catenin/YAP^S127A HBs and increase growth, cystogenesis, and necrosis. The unanticipated oncogenicity of L30P/R34P when coexpressed with beta-catenin or YAP^S127A also demonstrated their direct role in transformation in vivo and unequivocally established NFE2L2 as an oncoprotein that can be activated by mutation, overexpression, or other factors that perturb the normal NFE2L2:KEAP1 balance,” the authors wrote.

The study received funding from various nonindustry sources. The study authors disclosed no conflicts of interest.

A novel oncogene may be a key driver in hepatoblastoma, according to a new study. Hepatoblastoma is the most common form of pediatric cancer, and many tumors harbor beta-catenin mutations and alterations to the Hippo tumor suppression pathway.

In mice, cells can be turned cancerous by coexpressing beta-catenin mutants and the Hippo effector YAP. Some hepatoblastomas have mutations in NFE2L2/NRF2 (NFE2L2), which is a transcription factor that can either promote or suppress tumorigenesis.

In a report in Cellular and Molecular Gastroenterology and Hepatology, researchers led by Huabo Wang, PhD, of the UPMC Children’s Hospital of Pittsburgh investigated the potential role of NFE2L2 by expressing all combinations of mutant beta-catenin, YAP^S127A, and two NFE2L2 mutants previously discovered in patients (L30P and R34P).

The researchers found that both the L30P and R34P mutations led to an increase in cellular growth and to both necrosis and cyst formation, which are both clinically uncommon. Any two of beta-catenin, YAP^S127A, and L30P/R34P caused tumor formation, indicating that NFE2L2 is an oncogene, according to the authors.

Among tumors with changes in all three regions, unbiased RNA sequencing across all combinations of mutations revealed 22 RNA transcripts common to all of them. These are probably the most important contributors to cell transformation and may also be related to increased growth, cystogenesis, and necrosis found in these tumors. Of those transcripts, 10 were highly correlated with survival in human hepatoblastomas, and 17 correlated with survival in more than one adult cancer.

Although hepatoblastomas have fewer mutations than most tumors, around 5%-10% have mutations in NFE2L2. About half have an increase in the copy number of NFE2L2.

The results suggest that wild-type NFE2L2 plays a role in suppressing cell proliferation in response to oxidative, metabolic, and electrophilic stresses. But the picture is more complex than that because NFE2L2’s pathway can have opposite effects, depending on the timing and context. Early in the oncogenesis pathway, it may protect against the damaging effects of reactive oxygen species (ROS). Later, it can make cells more tolerant to the effects of oncoproteins and promote tumor evolution, expansion, and even resistance to therapy.

Previous in vitro and tumor xenograft studies had suggested that NFE2L2 targets might play a role in apoptosis, metabolism, angiogenesis, and chemotherapeutic drug detoxification. The new results show that the L30P/R34P mutations can accelerate tumorigenesis caused by beta-catenin mutations and can promote transformation when co-expressed with either beta-catenin or YAP^S127A. That suggests that some hepatoblastomas may be driven at least in part by changes to NFE2L2. The researchers speculate that it may also be involved in combination with other oncoproteins in other types of tumors.

The researchers noted that the cysts seen in tumors with NFE2L2 mutations are bloodless, and resembled cysts that are sometimes seen in human hepatoblastomas. They were unrelated to tumor growth rate.

“Our findings demonstrate that NFE2L2 mutants alter redox balance in beta-catenin/YAP^S127A HBs and increase growth, cystogenesis, and necrosis. The unanticipated oncogenicity of L30P/R34P when coexpressed with beta-catenin or YAP^S127A also demonstrated their direct role in transformation in vivo and unequivocally established NFE2L2 as an oncoprotein that can be activated by mutation, overexpression, or other factors that perturb the normal NFE2L2:KEAP1 balance,” the authors wrote.

The study received funding from various nonindustry sources. The study authors disclosed no conflicts of interest.

A novel oncogene may be a key driver in hepatoblastoma, according to a new study. Hepatoblastoma is the most common form of pediatric cancer, and many tumors harbor beta-catenin mutations and alterations to the Hippo tumor suppression pathway.

In mice, cells can be turned cancerous by coexpressing beta-catenin mutants and the Hippo effector YAP. Some hepatoblastomas have mutations in NFE2L2/NRF2 (NFE2L2), which is a transcription factor that can either promote or suppress tumorigenesis.

In a report in Cellular and Molecular Gastroenterology and Hepatology, researchers led by Huabo Wang, PhD, of the UPMC Children’s Hospital of Pittsburgh investigated the potential role of NFE2L2 by expressing all combinations of mutant beta-catenin, YAP^S127A, and two NFE2L2 mutants previously discovered in patients (L30P and R34P).

The researchers found that both the L30P and R34P mutations led to an increase in cellular growth and to both necrosis and cyst formation, which are both clinically uncommon. Any two of beta-catenin, YAP^S127A, and L30P/R34P caused tumor formation, indicating that NFE2L2 is an oncogene, according to the authors.

Among tumors with changes in all three regions, unbiased RNA sequencing across all combinations of mutations revealed 22 RNA transcripts common to all of them. These are probably the most important contributors to cell transformation and may also be related to increased growth, cystogenesis, and necrosis found in these tumors. Of those transcripts, 10 were highly correlated with survival in human hepatoblastomas, and 17 correlated with survival in more than one adult cancer.

Although hepatoblastomas have fewer mutations than most tumors, around 5%-10% have mutations in NFE2L2. About half have an increase in the copy number of NFE2L2.

The results suggest that wild-type NFE2L2 plays a role in suppressing cell proliferation in response to oxidative, metabolic, and electrophilic stresses. But the picture is more complex than that because NFE2L2’s pathway can have opposite effects, depending on the timing and context. Early in the oncogenesis pathway, it may protect against the damaging effects of reactive oxygen species (ROS). Later, it can make cells more tolerant to the effects of oncoproteins and promote tumor evolution, expansion, and even resistance to therapy.

Previous in vitro and tumor xenograft studies had suggested that NFE2L2 targets might play a role in apoptosis, metabolism, angiogenesis, and chemotherapeutic drug detoxification. The new results show that the L30P/R34P mutations can accelerate tumorigenesis caused by beta-catenin mutations and can promote transformation when co-expressed with either beta-catenin or YAP^S127A. That suggests that some hepatoblastomas may be driven at least in part by changes to NFE2L2. The researchers speculate that it may also be involved in combination with other oncoproteins in other types of tumors.

The researchers noted that the cysts seen in tumors with NFE2L2 mutations are bloodless, and resembled cysts that are sometimes seen in human hepatoblastomas. They were unrelated to tumor growth rate.

“Our findings demonstrate that NFE2L2 mutants alter redox balance in beta-catenin/YAP^S127A HBs and increase growth, cystogenesis, and necrosis. The unanticipated oncogenicity of L30P/R34P when coexpressed with beta-catenin or YAP^S127A also demonstrated their direct role in transformation in vivo and unequivocally established NFE2L2 as an oncoprotein that can be activated by mutation, overexpression, or other factors that perturb the normal NFE2L2:KEAP1 balance,” the authors wrote.

The study received funding from various nonindustry sources. The study authors disclosed no conflicts of interest.