Rheumatology News

MILAN – Results of a phase 3 trial with the investigational drug telitacicept show that patients with systemic lupus erythematosus have a significantly greater rate of response to SLE response criteria, compared with placebo, while results from a phase 2 trial of the drug in patients with primary Sjögren’s syndrome (pSS) also show significant improvements versus placebo.

“With only a limited number of treatments available for patients with lupus, this additional option is certainly an advance and the trial shows a strong efficacy result,” said Ronald van Vollenhoven, MD, PhD, who was not an investigator for either trial but presented the results for both at the annual European Congress of Rheumatology. He is professor of clinical immunology and rheumatology at Amsterdam University Medical Center and VU University Medical Center, also in Amsterdam.

Becky McCall/MDedge News

Telitacicept is a recombinant fusion protein that targets B-lymphocyte stimulator and a proliferating-inducing ligand. It is currently undergoing testing in another phase 3 trial (REMESLE-1) at sites in the United States, Europe, and Asia. The current SLE results relate to the phase 3 study conducted in China, Dr. van Vollenhoven clarified.
 

SLE trial

The double-blind, placebo-controlled trial included 335 patients with SLE who had an average age of 35 years, a body mass index of 22-23 kg/m², and a mean SELENA-SLEDAI (Safety of Estrogens in Systemic Lupus Erythematosus National Assessment–Systemic Lupus Erythematosus Disease Activity Index) score of at least 11.5, indicating high disease activity. Most patients were on glucocorticoids and immunosuppressants.

Patients were randomized 1:1 to weekly subcutaneous injections of telitacicept (160 mg; n = 167) or placebo (n = 168) in combination with standard therapy for 52 weeks. The primary endpoint was the SLE Responder Index-4 (SRI4) response rate at week 52, while key secondary endpoints included SELENA-SLEDAI, physician global assessment, and levels of immunologic biomarkers including C3, C4, IgM, IgG, IgA, and CD19+ B cells. Safety was also assessed.

At week 52, Dr. van Vollenhoven reported that significantly more patients taking telitacicept achieved a SRI4 response, compared with placebo, at 67.1% versus 32.7%, respectively (P < .001). “The difference was seen at 4-8 weeks and stabilized at around 20 weeks,” he said.

Time to first SLE flare was also reduced in patients on the trial drug at a median of 198 days (95% confidence interval, 169-254 days), compared with placebo at 115 days (95% CI, 92-140 days).

“The secondary outcomes also supported efficacy in these patients,” Dr. van Vollenhoven added, noting that there was a rapid and sustained increase of C3 and C4, the latter being significantly greater than placebo, and reduction of IgM, IgG, IgA, and CD19+ B cells observed following telitacicept treatment.

A significantly higher proportion of patients in the telitacicept group showed improvement in SELENA-SLEDAI at week 52, defined as a 4-point or greater reduction, compared with placebo (70.1% vs. 40.5%).

Telitacicept did not increase the risk of infections. Treatment-emergent adverse events occurred in 84.5% with telitacicept versus 91.6% with placebo, with infections (mostly upper respiratory) seen in 65.3% and 60.1%, respectively.
 

Sjögren’s trial

The second trial was a phase 2, randomized, placebo-controlled, 24-week study in 42 patients with pSS. Patients (18-65 years) received telitacicept at 160 mg or 240 mg subcutaneously once a week, or placebo, for a total of 24 doses. Patients had a EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) score of 5 points or more, and were anti-SSA antibody positive.

“Compared with placebo, telitacicept treatment resulted in significant improvement in ESSDAI and MFI-20 [20-item Multidimensional Fatigue Inventory],” Dr. van Vollenhoven reported, adding that, “there was a trend for improvement in salivary gland function and lacrimal gland function relative to placebo, as well as a favorable safety profile.”

ESSDAI change from baseline was 0.5, –3.8, and –2.3 in placebo, 160-mg, and 240-mg telitacicept doses, respectively. MFI-20 change from baseline was 7.0, –4.0, and –5.1, respectively. Dr. Van Vollenhoven said the difference between the doses was not statistically significant.

“If these results are confirmed, it could be the first time a biologic is proven efficacious in this disease,” Dr. Van Vollenhoven said in an interview. “It’s encouraging to know that a new treatment is showing promise in this phase 2 trial. A phase 3 trial is warranted.”
 

Studies yield promising but confusing results

In an interview, Roy Fleischmann, MD, who was not involved with either study, wondered whether the results of the SLE study could be race specific given the magnitude of response to the drug and that the trial was conducted only in China, and whether the positive results of the small Sjögren’s study will pan out in a larger trial.

“The SLE study was very interesting, but the problem is that it’s a Chinese drug in Chinese patients with Chinese doctors, so they are very dramatic results,” he said, questioning whether “these results are race specific,” and that “we will find out when they do the multinational study, but we haven’t seen this type of separation before [in response]. It’s interesting.

“The Sjögren’s was a positive study, but it was confusing because the low dose seemed to be better than the higher dose, and there were very few patients,” said Dr. Fleischmann, clinical professor of medicine at the University of Texas Southwestern Medical Center and codirector of the Metroplex Clinical Research Center, both in Dallas. The left and right eyes gave different results, which was strange, and the salivary gland test was the same [mixed results], so what can we conclude? All in all, it was a small study with a suggestion of efficacy, but we have to do the phase 3 and see what it shows.”

Both trials were sponsored by RemeGen. Dr. van Vollenhoven reported serving as a paid adviser to AbbVie, AstraZeneca, Biogen, Bristol-Myers Squibb, Galapagos, GlaxoSmithKline, Janssen, Pfizer, RemeGen, and UCB. He has received research funding from Bristol-Myers Squibb and UCB and educational support from AstraZeneca, Galapagos, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi, and UCB. Dr. Fleischmann said he had has no relevant financial relationships.

MILAN – Results of a phase 3 trial with the investigational drug telitacicept show that patients with systemic lupus erythematosus have a significantly greater rate of response to SLE response criteria, compared with placebo, while results from a phase 2 trial of the drug in patients with primary Sjögren’s syndrome (pSS) also show significant improvements versus placebo.

“With only a limited number of treatments available for patients with lupus, this additional option is certainly an advance and the trial shows a strong efficacy result,” said Ronald van Vollenhoven, MD, PhD, who was not an investigator for either trial but presented the results for both at the annual European Congress of Rheumatology. He is professor of clinical immunology and rheumatology at Amsterdam University Medical Center and VU University Medical Center, also in Amsterdam.

Becky McCall/MDedge News

Telitacicept is a recombinant fusion protein that targets B-lymphocyte stimulator and a proliferating-inducing ligand. It is currently undergoing testing in another phase 3 trial (REMESLE-1) at sites in the United States, Europe, and Asia. The current SLE results relate to the phase 3 study conducted in China, Dr. van Vollenhoven clarified.
 

SLE trial

The double-blind, placebo-controlled trial included 335 patients with SLE who had an average age of 35 years, a body mass index of 22-23 kg/m², and a mean SELENA-SLEDAI (Safety of Estrogens in Systemic Lupus Erythematosus National Assessment–Systemic Lupus Erythematosus Disease Activity Index) score of at least 11.5, indicating high disease activity. Most patients were on glucocorticoids and immunosuppressants.

Patients were randomized 1:1 to weekly subcutaneous injections of telitacicept (160 mg; n = 167) or placebo (n = 168) in combination with standard therapy for 52 weeks. The primary endpoint was the SLE Responder Index-4 (SRI4) response rate at week 52, while key secondary endpoints included SELENA-SLEDAI, physician global assessment, and levels of immunologic biomarkers including C3, C4, IgM, IgG, IgA, and CD19+ B cells. Safety was also assessed.

At week 52, Dr. van Vollenhoven reported that significantly more patients taking telitacicept achieved a SRI4 response, compared with placebo, at 67.1% versus 32.7%, respectively (P < .001). “The difference was seen at 4-8 weeks and stabilized at around 20 weeks,” he said.

Time to first SLE flare was also reduced in patients on the trial drug at a median of 198 days (95% confidence interval, 169-254 days), compared with placebo at 115 days (95% CI, 92-140 days).

“The secondary outcomes also supported efficacy in these patients,” Dr. van Vollenhoven added, noting that there was a rapid and sustained increase of C3 and C4, the latter being significantly greater than placebo, and reduction of IgM, IgG, IgA, and CD19+ B cells observed following telitacicept treatment.

A significantly higher proportion of patients in the telitacicept group showed improvement in SELENA-SLEDAI at week 52, defined as a 4-point or greater reduction, compared with placebo (70.1% vs. 40.5%).

Telitacicept did not increase the risk of infections. Treatment-emergent adverse events occurred in 84.5% with telitacicept versus 91.6% with placebo, with infections (mostly upper respiratory) seen in 65.3% and 60.1%, respectively.
 

Sjögren’s trial

The second trial was a phase 2, randomized, placebo-controlled, 24-week study in 42 patients with pSS. Patients (18-65 years) received telitacicept at 160 mg or 240 mg subcutaneously once a week, or placebo, for a total of 24 doses. Patients had a EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) score of 5 points or more, and were anti-SSA antibody positive.

“Compared with placebo, telitacicept treatment resulted in significant improvement in ESSDAI and MFI-20 [20-item Multidimensional Fatigue Inventory],” Dr. van Vollenhoven reported, adding that, “there was a trend for improvement in salivary gland function and lacrimal gland function relative to placebo, as well as a favorable safety profile.”

ESSDAI change from baseline was 0.5, –3.8, and –2.3 in placebo, 160-mg, and 240-mg telitacicept doses, respectively. MFI-20 change from baseline was 7.0, –4.0, and –5.1, respectively. Dr. Van Vollenhoven said the difference between the doses was not statistically significant.

“If these results are confirmed, it could be the first time a biologic is proven efficacious in this disease,” Dr. Van Vollenhoven said in an interview. “It’s encouraging to know that a new treatment is showing promise in this phase 2 trial. A phase 3 trial is warranted.”
 

Studies yield promising but confusing results

In an interview, Roy Fleischmann, MD, who was not involved with either study, wondered whether the results of the SLE study could be race specific given the magnitude of response to the drug and that the trial was conducted only in China, and whether the positive results of the small Sjögren’s study will pan out in a larger trial.

“The SLE study was very interesting, but the problem is that it’s a Chinese drug in Chinese patients with Chinese doctors, so they are very dramatic results,” he said, questioning whether “these results are race specific,” and that “we will find out when they do the multinational study, but we haven’t seen this type of separation before [in response]. It’s interesting.

“The Sjögren’s was a positive study, but it was confusing because the low dose seemed to be better than the higher dose, and there were very few patients,” said Dr. Fleischmann, clinical professor of medicine at the University of Texas Southwestern Medical Center and codirector of the Metroplex Clinical Research Center, both in Dallas. The left and right eyes gave different results, which was strange, and the salivary gland test was the same [mixed results], so what can we conclude? All in all, it was a small study with a suggestion of efficacy, but we have to do the phase 3 and see what it shows.”

Both trials were sponsored by RemeGen. Dr. van Vollenhoven reported serving as a paid adviser to AbbVie, AstraZeneca, Biogen, Bristol-Myers Squibb, Galapagos, GlaxoSmithKline, Janssen, Pfizer, RemeGen, and UCB. He has received research funding from Bristol-Myers Squibb and UCB and educational support from AstraZeneca, Galapagos, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi, and UCB. Dr. Fleischmann said he had has no relevant financial relationships.

MILAN – Results of a phase 3 trial with the investigational drug telitacicept show that patients with systemic lupus erythematosus have a significantly greater rate of response to SLE response criteria, compared with placebo, while results from a phase 2 trial of the drug in patients with primary Sjögren’s syndrome (pSS) also show significant improvements versus placebo.

“With only a limited number of treatments available for patients with lupus, this additional option is certainly an advance and the trial shows a strong efficacy result,” said Ronald van Vollenhoven, MD, PhD, who was not an investigator for either trial but presented the results for both at the annual European Congress of Rheumatology. He is professor of clinical immunology and rheumatology at Amsterdam University Medical Center and VU University Medical Center, also in Amsterdam.

Becky McCall/MDedge News

Telitacicept is a recombinant fusion protein that targets B-lymphocyte stimulator and a proliferating-inducing ligand. It is currently undergoing testing in another phase 3 trial (REMESLE-1) at sites in the United States, Europe, and Asia. The current SLE results relate to the phase 3 study conducted in China, Dr. van Vollenhoven clarified.
 

SLE trial

The double-blind, placebo-controlled trial included 335 patients with SLE who had an average age of 35 years, a body mass index of 22-23 kg/m², and a mean SELENA-SLEDAI (Safety of Estrogens in Systemic Lupus Erythematosus National Assessment–Systemic Lupus Erythematosus Disease Activity Index) score of at least 11.5, indicating high disease activity. Most patients were on glucocorticoids and immunosuppressants.

Patients were randomized 1:1 to weekly subcutaneous injections of telitacicept (160 mg; n = 167) or placebo (n = 168) in combination with standard therapy for 52 weeks. The primary endpoint was the SLE Responder Index-4 (SRI4) response rate at week 52, while key secondary endpoints included SELENA-SLEDAI, physician global assessment, and levels of immunologic biomarkers including C3, C4, IgM, IgG, IgA, and CD19+ B cells. Safety was also assessed.

At week 52, Dr. van Vollenhoven reported that significantly more patients taking telitacicept achieved a SRI4 response, compared with placebo, at 67.1% versus 32.7%, respectively (P < .001). “The difference was seen at 4-8 weeks and stabilized at around 20 weeks,” he said.

Time to first SLE flare was also reduced in patients on the trial drug at a median of 198 days (95% confidence interval, 169-254 days), compared with placebo at 115 days (95% CI, 92-140 days).

“The secondary outcomes also supported efficacy in these patients,” Dr. van Vollenhoven added, noting that there was a rapid and sustained increase of C3 and C4, the latter being significantly greater than placebo, and reduction of IgM, IgG, IgA, and CD19+ B cells observed following telitacicept treatment.

A significantly higher proportion of patients in the telitacicept group showed improvement in SELENA-SLEDAI at week 52, defined as a 4-point or greater reduction, compared with placebo (70.1% vs. 40.5%).

Telitacicept did not increase the risk of infections. Treatment-emergent adverse events occurred in 84.5% with telitacicept versus 91.6% with placebo, with infections (mostly upper respiratory) seen in 65.3% and 60.1%, respectively.
 

Sjögren’s trial

The second trial was a phase 2, randomized, placebo-controlled, 24-week study in 42 patients with pSS. Patients (18-65 years) received telitacicept at 160 mg or 240 mg subcutaneously once a week, or placebo, for a total of 24 doses. Patients had a EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) score of 5 points or more, and were anti-SSA antibody positive.

“Compared with placebo, telitacicept treatment resulted in significant improvement in ESSDAI and MFI-20 [20-item Multidimensional Fatigue Inventory],” Dr. van Vollenhoven reported, adding that, “there was a trend for improvement in salivary gland function and lacrimal gland function relative to placebo, as well as a favorable safety profile.”

ESSDAI change from baseline was 0.5, –3.8, and –2.3 in placebo, 160-mg, and 240-mg telitacicept doses, respectively. MFI-20 change from baseline was 7.0, –4.0, and –5.1, respectively. Dr. Van Vollenhoven said the difference between the doses was not statistically significant.

“If these results are confirmed, it could be the first time a biologic is proven efficacious in this disease,” Dr. Van Vollenhoven said in an interview. “It’s encouraging to know that a new treatment is showing promise in this phase 2 trial. A phase 3 trial is warranted.”
 

Studies yield promising but confusing results

In an interview, Roy Fleischmann, MD, who was not involved with either study, wondered whether the results of the SLE study could be race specific given the magnitude of response to the drug and that the trial was conducted only in China, and whether the positive results of the small Sjögren’s study will pan out in a larger trial.

“The SLE study was very interesting, but the problem is that it’s a Chinese drug in Chinese patients with Chinese doctors, so they are very dramatic results,” he said, questioning whether “these results are race specific,” and that “we will find out when they do the multinational study, but we haven’t seen this type of separation before [in response]. It’s interesting.

“The Sjögren’s was a positive study, but it was confusing because the low dose seemed to be better than the higher dose, and there were very few patients,” said Dr. Fleischmann, clinical professor of medicine at the University of Texas Southwestern Medical Center and codirector of the Metroplex Clinical Research Center, both in Dallas. The left and right eyes gave different results, which was strange, and the salivary gland test was the same [mixed results], so what can we conclude? All in all, it was a small study with a suggestion of efficacy, but we have to do the phase 3 and see what it shows.”

Both trials were sponsored by RemeGen. Dr. van Vollenhoven reported serving as a paid adviser to AbbVie, AstraZeneca, Biogen, Bristol-Myers Squibb, Galapagos, GlaxoSmithKline, Janssen, Pfizer, RemeGen, and UCB. He has received research funding from Bristol-Myers Squibb and UCB and educational support from AstraZeneca, Galapagos, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi, and UCB. Dr. Fleischmann said he had has no relevant financial relationships.

A team of researchers has identified genomic variants that cause disabling pansclerotic morphea (DPM), a rare, severe inflammatory skin disorder, and report that the Janus kinase (JAK) inhibitor ruxolitinib may be a useful therapy, especially in patients who have not responded to other interventions.

DPM was first reported in 1923, and while a genetic cause has been suspected, it had not been identified until now. The disease is the most severe form of deep morphea, which affects individuals with juvenile localized scleroderma. Patients, generally children under age 14, experience rapid sclerosis of all layers of the skin, fascia, muscle, and bone. DPM is also deadly: Most patients do not live more than 10 years after diagnosis, as they contract squamous cell carcinoma, restrictive pulmonary disease, sepsis, and gangrene.

In the study, published in the New England Journal of Medicine, the researchers discovered that people with DPM have an overactive version of the protein STAT4, which regulates inflammation and wound healing. The scientists studied four patients from three unrelated families with an autosomal dominant pattern of inheritance of DPM.

“Researchers previously thought that this disorder was caused by the immune system attacking the skin,” Sarah Blackstone, a predoctoral fellow in the inflammatory disease section at the National Human Genome Research Institute and co–first author of the study, said in a statement from the National Institutes of Health describing the results. “However, we found that this is an oversimplification, and that both skin and the immune system play an active role in disabling pansclerotic morphea,” added Ms. Blackstone, also a medical student at the University of South Dakota, Sioux Falls.

The overactive STAT4 protein creates a positive feedback loop of inflammation and impaired wound-healing. By targeting JAK, the researchers were able to stop the feedback and patients’ wounds dramatically improved. After 18 months of treatment with oral ruxolitinib, one patient had discontinued all other medications, and had complete resolution of a chest rash, substantial clearing on the arms and legs, and global clinical improvement.

The authors said that oral systemic JAK inhibitor therapy is preferred over topical therapy. Their research also suggested that anti–interleukin-6 monoclonal antibodies – such as tocilizumab, approved for indications that include rheumatoid arthritis and systemic sclerosis–associated interstitial lung disease, “may be an alternative therapy or may be useful in combination with JAK inhibitors in patients with DPM,” the authors wrote.

Most current DPM therapies – including methotrexate, mycophenolate mofetil, and ultraviolet A light therapy – have been ineffective, and some have severe side effects.

“The findings of this study open doors for JAK inhibitors to be a potential treatment for other inflammatory skin disorders or disorders related to tissue scarring, whether it is scarring of the lungs, liver or bone marrow,” Dan Kastner, MD, PhD, an NIH distinguished investigator, head of the NHGRI’s inflammatory disease section, and a senior author of the paper, said in the NIH statement.

“We hope to continue studying other molecules in this pathway and how they are altered in patients with disabling pansclerotic morphea and related conditions to find clues to understanding a broader array of more common diseases,” Lori Broderick, MD, PhD, a senior author of the paper and an associate professor at University of California, San Diego, said in the statement.

The study was led by researchers at NHGRI in collaboration with researchers from UCSD and the University of Pittsburgh. Researchers from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institute of Allergy and Infectious Diseases also participated.

The study was supported by grants from the American Academy of Allergy, Asthma, and Immunology Foundation; the Ludwig Institute for Cancer Research; the University of California, San Diego, department of pediatrics; and the Novo Nordisk Foundation. Additional support and grants were given by the Deutsche Forschungsgemeinschaft, various institutes at the NIH, the California Institute for Regenerative Medicine, the Hydrocephalus Association, the Scleroderma Research Foundation, the Biowulf High-Performance Computing Cluster of the Center for Information Technology, the Undiagnosed Diseases Program of the Common Fund of the Office of the Director of the NIH, and the NIH Clinical Center.

A team of researchers has identified genomic variants that cause disabling pansclerotic morphea (DPM), a rare, severe inflammatory skin disorder, and report that the Janus kinase (JAK) inhibitor ruxolitinib may be a useful therapy, especially in patients who have not responded to other interventions.

DPM was first reported in 1923, and while a genetic cause has been suspected, it had not been identified until now. The disease is the most severe form of deep morphea, which affects individuals with juvenile localized scleroderma. Patients, generally children under age 14, experience rapid sclerosis of all layers of the skin, fascia, muscle, and bone. DPM is also deadly: Most patients do not live more than 10 years after diagnosis, as they contract squamous cell carcinoma, restrictive pulmonary disease, sepsis, and gangrene.

In the study, published in the New England Journal of Medicine, the researchers discovered that people with DPM have an overactive version of the protein STAT4, which regulates inflammation and wound healing. The scientists studied four patients from three unrelated families with an autosomal dominant pattern of inheritance of DPM.

“Researchers previously thought that this disorder was caused by the immune system attacking the skin,” Sarah Blackstone, a predoctoral fellow in the inflammatory disease section at the National Human Genome Research Institute and co–first author of the study, said in a statement from the National Institutes of Health describing the results. “However, we found that this is an oversimplification, and that both skin and the immune system play an active role in disabling pansclerotic morphea,” added Ms. Blackstone, also a medical student at the University of South Dakota, Sioux Falls.

The overactive STAT4 protein creates a positive feedback loop of inflammation and impaired wound-healing. By targeting JAK, the researchers were able to stop the feedback and patients’ wounds dramatically improved. After 18 months of treatment with oral ruxolitinib, one patient had discontinued all other medications, and had complete resolution of a chest rash, substantial clearing on the arms and legs, and global clinical improvement.

The authors said that oral systemic JAK inhibitor therapy is preferred over topical therapy. Their research also suggested that anti–interleukin-6 monoclonal antibodies – such as tocilizumab, approved for indications that include rheumatoid arthritis and systemic sclerosis–associated interstitial lung disease, “may be an alternative therapy or may be useful in combination with JAK inhibitors in patients with DPM,” the authors wrote.

Most current DPM therapies – including methotrexate, mycophenolate mofetil, and ultraviolet A light therapy – have been ineffective, and some have severe side effects.

“The findings of this study open doors for JAK inhibitors to be a potential treatment for other inflammatory skin disorders or disorders related to tissue scarring, whether it is scarring of the lungs, liver or bone marrow,” Dan Kastner, MD, PhD, an NIH distinguished investigator, head of the NHGRI’s inflammatory disease section, and a senior author of the paper, said in the NIH statement.

“We hope to continue studying other molecules in this pathway and how they are altered in patients with disabling pansclerotic morphea and related conditions to find clues to understanding a broader array of more common diseases,” Lori Broderick, MD, PhD, a senior author of the paper and an associate professor at University of California, San Diego, said in the statement.

The study was led by researchers at NHGRI in collaboration with researchers from UCSD and the University of Pittsburgh. Researchers from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institute of Allergy and Infectious Diseases also participated.

The study was supported by grants from the American Academy of Allergy, Asthma, and Immunology Foundation; the Ludwig Institute for Cancer Research; the University of California, San Diego, department of pediatrics; and the Novo Nordisk Foundation. Additional support and grants were given by the Deutsche Forschungsgemeinschaft, various institutes at the NIH, the California Institute for Regenerative Medicine, the Hydrocephalus Association, the Scleroderma Research Foundation, the Biowulf High-Performance Computing Cluster of the Center for Information Technology, the Undiagnosed Diseases Program of the Common Fund of the Office of the Director of the NIH, and the NIH Clinical Center.

A team of researchers has identified genomic variants that cause disabling pansclerotic morphea (DPM), a rare, severe inflammatory skin disorder, and report that the Janus kinase (JAK) inhibitor ruxolitinib may be a useful therapy, especially in patients who have not responded to other interventions.

DPM was first reported in 1923, and while a genetic cause has been suspected, it had not been identified until now. The disease is the most severe form of deep morphea, which affects individuals with juvenile localized scleroderma. Patients, generally children under age 14, experience rapid sclerosis of all layers of the skin, fascia, muscle, and bone. DPM is also deadly: Most patients do not live more than 10 years after diagnosis, as they contract squamous cell carcinoma, restrictive pulmonary disease, sepsis, and gangrene.

In the study, published in the New England Journal of Medicine, the researchers discovered that people with DPM have an overactive version of the protein STAT4, which regulates inflammation and wound healing. The scientists studied four patients from three unrelated families with an autosomal dominant pattern of inheritance of DPM.

“Researchers previously thought that this disorder was caused by the immune system attacking the skin,” Sarah Blackstone, a predoctoral fellow in the inflammatory disease section at the National Human Genome Research Institute and co–first author of the study, said in a statement from the National Institutes of Health describing the results. “However, we found that this is an oversimplification, and that both skin and the immune system play an active role in disabling pansclerotic morphea,” added Ms. Blackstone, also a medical student at the University of South Dakota, Sioux Falls.

The overactive STAT4 protein creates a positive feedback loop of inflammation and impaired wound-healing. By targeting JAK, the researchers were able to stop the feedback and patients’ wounds dramatically improved. After 18 months of treatment with oral ruxolitinib, one patient had discontinued all other medications, and had complete resolution of a chest rash, substantial clearing on the arms and legs, and global clinical improvement.

The authors said that oral systemic JAK inhibitor therapy is preferred over topical therapy. Their research also suggested that anti–interleukin-6 monoclonal antibodies – such as tocilizumab, approved for indications that include rheumatoid arthritis and systemic sclerosis–associated interstitial lung disease, “may be an alternative therapy or may be useful in combination with JAK inhibitors in patients with DPM,” the authors wrote.

Most current DPM therapies – including methotrexate, mycophenolate mofetil, and ultraviolet A light therapy – have been ineffective, and some have severe side effects.

“The findings of this study open doors for JAK inhibitors to be a potential treatment for other inflammatory skin disorders or disorders related to tissue scarring, whether it is scarring of the lungs, liver or bone marrow,” Dan Kastner, MD, PhD, an NIH distinguished investigator, head of the NHGRI’s inflammatory disease section, and a senior author of the paper, said in the NIH statement.

“We hope to continue studying other molecules in this pathway and how they are altered in patients with disabling pansclerotic morphea and related conditions to find clues to understanding a broader array of more common diseases,” Lori Broderick, MD, PhD, a senior author of the paper and an associate professor at University of California, San Diego, said in the statement.

The study was led by researchers at NHGRI in collaboration with researchers from UCSD and the University of Pittsburgh. Researchers from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institute of Allergy and Infectious Diseases also participated.

The study was supported by grants from the American Academy of Allergy, Asthma, and Immunology Foundation; the Ludwig Institute for Cancer Research; the University of California, San Diego, department of pediatrics; and the Novo Nordisk Foundation. Additional support and grants were given by the Deutsche Forschungsgemeinschaft, various institutes at the NIH, the California Institute for Regenerative Medicine, the Hydrocephalus Association, the Scleroderma Research Foundation, the Biowulf High-Performance Computing Cluster of the Center for Information Technology, the Undiagnosed Diseases Program of the Common Fund of the Office of the Director of the NIH, and the NIH Clinical Center.

Around 5% of patients treated with dupilumab (Dupixent) for moderate-to-severe atopic dermatitis experience musculoskeletal (MSK) symptoms, according to the results of a descriptive study.

The main MSK symptom seen in the observational cohort was enthesitis, but some patients also experienced arthritis and tenosynovitis a median of 17 weeks after starting dupilumab treatment. Together these symptoms represent a new MSK syndrome, say researchers from the United Kingdom.

“The pattern of MSK symptoms and signs is characteristic of psoriatic arthritis/peripheral spondyloarthritis,” Bruce Kirkham, MD, and collaborators report in Arthritis & Rheumatology.

“We started a few years ago and have been following the patients for quite a long time,” Dr. Kirkham, a consultant rheumatologist at Guy’s and St. Thomas’ NHS Foundation Trust, London, told this news organization.

Characterizing the MSK symptoms

Of 470 patients with atopic dermatitis who started treatment with dupilumab at Guy’s and St. Thomas’ NHS Foundation Trust between October 2018 and February 2021, 36 (7.65%) developed rheumatic symptoms and were referred to the rheumatology department. These individuals had their family history assessed and thorough MSK evaluations, which included antibody and inflammatory markers, ultrasound of the peripheral small joints, and MRI of the large joints and spine.

A total of 26 (5.5%) patients – 14 of whom were male – had inflammatory enthesitis, arthritis, and/or tenosynovitis. Of the others, seven had osteoarthritis and three had degenerative spine disease.

Enthesitis was the most common finding in those with rheumatic symptoms, occurring on its own in 11 patients, with arthritis in three patients, and tenosynovitis in two patients.  

These symptoms appeared 2-48 weeks after starting dupilumab treatment and were categorized as mild in 16 (61%) cases, moderate in six cases, and severe in four cases.

No specific predictors of the MSK symptoms seen were noted. Patient age, sex, duration of their atopic dermatitis, or how their skin condition had been previously treated did not help identify those who might develop rheumatic problems.
 

Conservative management approach

All patients had “outstanding” responses to treatment, Dr. Kirkham noted: The mean Eczema Area and Severity Index score before dupilumab treatment was 21, falling to 4.2 with treatment, indicating a mean 80% improvement.

Co-author Joseph Nathan, MBChB, of London North West Healthcare NHS Trust, who collaborated on the research while working within Dr. Kirkham’s group, said separately: “The concern that patients have is that when they start a medication and develop a side effect is that the medication is going to be stopped.”

Clinicians treating the patients took a conservative approach, prescribing NSAIDs such as cyclooxygenase-2 inhibitors or altering the frequency with which dupilumab was given.

With this approach, MSK symptoms resolved in 15 patients who remained on treatment and in seven who had to stop dupilumab. There were four patients, however, who had unresolved symptoms even once dupilumab treatment had been stopped.
 

Altering the local cytokine balance

Dupilumab is a monoclonal antibody that binds to the alpha subunit of the interleukin-4 receptor. This results in blocking the function of not only IL-4 but also IL-13.

Dr. Kirkham and colleagues think this might not only alter the balance of cytokines in the skin but also in the joints and entheses with IL-17, IL-23, or even tumor necrosis factor playing a possible role. Another thought is that many circulating T-cells in the skin move to the joints and entheses to trigger symptoms.

IL-13 inhibition does seem to be important, as another British research team, from the Centre for Epidemiology Versus Arthritis at the University of Manchester (England), has found.

At the recent annual meeting of the British Society for Rheumatology, Sizheng Steven Zhao, MBChB, PhD, and colleagues reported that among people who carried a genetic variant predisposing them to having low IL-13 function, there was a higher risk for inflammatory diseases such as psoriatic arthritis and other spondyloarthropathy-related diseases.

Sara Freeman/Frontline Medical News

Dermatology perspective

Approved by the U.S. Food and Drug Administration in 2017, dupilumab has since been hailed as a “breakthrough” in atopic dermatitis treatment. Given as a subcutaneous injection every 2 weeks, it provides a much-needed option for people who have moderate-to-severe disease and have tried other available treatments, including corticosteroids.

Dupilumab has since also been approved for asthma, chronic sinusitis with nasal polyposis, eosinophilic esophagitis, and prurigo nodularis and is used off-label for other skin conditions such as contact dermatitis, chronic spontaneous urticaria, and alopecia areata.

“Dupilumab, like a lot of medications for atopic dermatitis, is a relatively new drug, and we are still learning about its safety,” Joel M. Gelfand, MD, MSCE, of the University of Pennsylvania Perelman School of Medicine, Philadelphia, told this news organization.

“Inflammatory arthritis has been reported in patients treated with dupilumab, and this new study provides some useful estimates,” added Dr. Gelfand, who is a professor of dermatology and epidemiology and directs the Psoriasis and Phototherapy Treatment Center, Philadelphia.

“There was no control group,” Dr. Gelfand said, so “a causal relationship cannot be well established based on these data alone. The mechanism is not known but may result from a shifting of the immune system.”

Dr. Zhao observed: “We don’t know what the natural history of these adverse events is. We don’t know if stopping the drug early will prevent long-term adverse events. So, we don’t know if people will ultimately develop permanent psoriatic arthritis if we don’t intervene quick enough when we observe an adverse event.”

Being aware of the possibility of rheumatic side effects occurring with dupilumab and similar agents is key, Dr. Gelfand and Dr. Kirkham both said independently.

“I have personally seen this entity in my practice,” Dr. Gelfand said. “It is important to clinicians prescribing dupilumab to alert patients about this potential side effect and ask about joint symptoms in follow-up.”

Dr. Kirkham said: “Prescribers need to be aware of it, because up until now it’s been just very vaguely discussed as sort of aches and pains, arthralgias, and it’s a much more specific of a kind of syndrome of enthesitis, arthritis, tenosynovitis – a little like psoriatic arthritis.”

Not everyone has come across these side effects, however, as Steven Daveluy, MD, associate professor and dermatology program director at Wayne State University, Detroit, said in an interview.

“This article and the other case series both noted the musculoskeletal symptoms occurred in about 5% of patients, which surprised me since I haven’t seen it in my practice and have enough patients being treated with dupilumab that I would expect to see a case at that rate,” Dr. Daveluy said.

“The majority of cases are mild and respond to treatment with anti-inflammatories like naproxen, which is available over the counter. It’s likely that patients with a mild case could simply treat their pain with naproxen that’s already in their medicine cabinet until it resolves, never bringing it to the doctor’s attention,” he suggested.

“Dupilumab is still a safe and effective medication that can change the lives of patients suffering from atopic dermatitis,” he said.

“Awareness of this potential side effect can help dermatologists recognize it early and work together with patients to determine the best course of action.”

All research mentioned in this article was independently supported. Dr. Kirkham, Mr. Nathan, Dr. Zhao, and Dr. Daveluy report no relevant financial relationships. Dr. Gelfand has served as a consultant for numerous pharmaceutical companies and receives research grants from Amgen, Boehringer Ingelheim, and Pfizer. He is a co-patent holder of resiquimod for treatment of cutaneous T-cell lymphoma.

A version of this article first appeared on Medscape.com.

Around 5% of patients treated with dupilumab (Dupixent) for moderate-to-severe atopic dermatitis experience musculoskeletal (MSK) symptoms, according to the results of a descriptive study.

The main MSK symptom seen in the observational cohort was enthesitis, but some patients also experienced arthritis and tenosynovitis a median of 17 weeks after starting dupilumab treatment. Together these symptoms represent a new MSK syndrome, say researchers from the United Kingdom.

“The pattern of MSK symptoms and signs is characteristic of psoriatic arthritis/peripheral spondyloarthritis,” Bruce Kirkham, MD, and collaborators report in Arthritis & Rheumatology.

“We started a few years ago and have been following the patients for quite a long time,” Dr. Kirkham, a consultant rheumatologist at Guy’s and St. Thomas’ NHS Foundation Trust, London, told this news organization.

Characterizing the MSK symptoms

Of 470 patients with atopic dermatitis who started treatment with dupilumab at Guy’s and St. Thomas’ NHS Foundation Trust between October 2018 and February 2021, 36 (7.65%) developed rheumatic symptoms and were referred to the rheumatology department. These individuals had their family history assessed and thorough MSK evaluations, which included antibody and inflammatory markers, ultrasound of the peripheral small joints, and MRI of the large joints and spine.

A total of 26 (5.5%) patients – 14 of whom were male – had inflammatory enthesitis, arthritis, and/or tenosynovitis. Of the others, seven had osteoarthritis and three had degenerative spine disease.

Enthesitis was the most common finding in those with rheumatic symptoms, occurring on its own in 11 patients, with arthritis in three patients, and tenosynovitis in two patients.  

These symptoms appeared 2-48 weeks after starting dupilumab treatment and were categorized as mild in 16 (61%) cases, moderate in six cases, and severe in four cases.

No specific predictors of the MSK symptoms seen were noted. Patient age, sex, duration of their atopic dermatitis, or how their skin condition had been previously treated did not help identify those who might develop rheumatic problems.
 

Conservative management approach

All patients had “outstanding” responses to treatment, Dr. Kirkham noted: The mean Eczema Area and Severity Index score before dupilumab treatment was 21, falling to 4.2 with treatment, indicating a mean 80% improvement.

Co-author Joseph Nathan, MBChB, of London North West Healthcare NHS Trust, who collaborated on the research while working within Dr. Kirkham’s group, said separately: “The concern that patients have is that when they start a medication and develop a side effect is that the medication is going to be stopped.”

Clinicians treating the patients took a conservative approach, prescribing NSAIDs such as cyclooxygenase-2 inhibitors or altering the frequency with which dupilumab was given.

With this approach, MSK symptoms resolved in 15 patients who remained on treatment and in seven who had to stop dupilumab. There were four patients, however, who had unresolved symptoms even once dupilumab treatment had been stopped.
 

Altering the local cytokine balance

Dupilumab is a monoclonal antibody that binds to the alpha subunit of the interleukin-4 receptor. This results in blocking the function of not only IL-4 but also IL-13.

Dr. Kirkham and colleagues think this might not only alter the balance of cytokines in the skin but also in the joints and entheses with IL-17, IL-23, or even tumor necrosis factor playing a possible role. Another thought is that many circulating T-cells in the skin move to the joints and entheses to trigger symptoms.

IL-13 inhibition does seem to be important, as another British research team, from the Centre for Epidemiology Versus Arthritis at the University of Manchester (England), has found.

At the recent annual meeting of the British Society for Rheumatology, Sizheng Steven Zhao, MBChB, PhD, and colleagues reported that among people who carried a genetic variant predisposing them to having low IL-13 function, there was a higher risk for inflammatory diseases such as psoriatic arthritis and other spondyloarthropathy-related diseases.

Sara Freeman/Frontline Medical News

Dermatology perspective

Approved by the U.S. Food and Drug Administration in 2017, dupilumab has since been hailed as a “breakthrough” in atopic dermatitis treatment. Given as a subcutaneous injection every 2 weeks, it provides a much-needed option for people who have moderate-to-severe disease and have tried other available treatments, including corticosteroids.

Dupilumab has since also been approved for asthma, chronic sinusitis with nasal polyposis, eosinophilic esophagitis, and prurigo nodularis and is used off-label for other skin conditions such as contact dermatitis, chronic spontaneous urticaria, and alopecia areata.

“Dupilumab, like a lot of medications for atopic dermatitis, is a relatively new drug, and we are still learning about its safety,” Joel M. Gelfand, MD, MSCE, of the University of Pennsylvania Perelman School of Medicine, Philadelphia, told this news organization.

“Inflammatory arthritis has been reported in patients treated with dupilumab, and this new study provides some useful estimates,” added Dr. Gelfand, who is a professor of dermatology and epidemiology and directs the Psoriasis and Phototherapy Treatment Center, Philadelphia.

“There was no control group,” Dr. Gelfand said, so “a causal relationship cannot be well established based on these data alone. The mechanism is not known but may result from a shifting of the immune system.”

Dr. Zhao observed: “We don’t know what the natural history of these adverse events is. We don’t know if stopping the drug early will prevent long-term adverse events. So, we don’t know if people will ultimately develop permanent psoriatic arthritis if we don’t intervene quick enough when we observe an adverse event.”

Being aware of the possibility of rheumatic side effects occurring with dupilumab and similar agents is key, Dr. Gelfand and Dr. Kirkham both said independently.

“I have personally seen this entity in my practice,” Dr. Gelfand said. “It is important to clinicians prescribing dupilumab to alert patients about this potential side effect and ask about joint symptoms in follow-up.”

Dr. Kirkham said: “Prescribers need to be aware of it, because up until now it’s been just very vaguely discussed as sort of aches and pains, arthralgias, and it’s a much more specific of a kind of syndrome of enthesitis, arthritis, tenosynovitis – a little like psoriatic arthritis.”

Not everyone has come across these side effects, however, as Steven Daveluy, MD, associate professor and dermatology program director at Wayne State University, Detroit, said in an interview.

“This article and the other case series both noted the musculoskeletal symptoms occurred in about 5% of patients, which surprised me since I haven’t seen it in my practice and have enough patients being treated with dupilumab that I would expect to see a case at that rate,” Dr. Daveluy said.

“The majority of cases are mild and respond to treatment with anti-inflammatories like naproxen, which is available over the counter. It’s likely that patients with a mild case could simply treat their pain with naproxen that’s already in their medicine cabinet until it resolves, never bringing it to the doctor’s attention,” he suggested.

“Dupilumab is still a safe and effective medication that can change the lives of patients suffering from atopic dermatitis,” he said.

“Awareness of this potential side effect can help dermatologists recognize it early and work together with patients to determine the best course of action.”

All research mentioned in this article was independently supported. Dr. Kirkham, Mr. Nathan, Dr. Zhao, and Dr. Daveluy report no relevant financial relationships. Dr. Gelfand has served as a consultant for numerous pharmaceutical companies and receives research grants from Amgen, Boehringer Ingelheim, and Pfizer. He is a co-patent holder of resiquimod for treatment of cutaneous T-cell lymphoma.

A version of this article first appeared on Medscape.com.

Around 5% of patients treated with dupilumab (Dupixent) for moderate-to-severe atopic dermatitis experience musculoskeletal (MSK) symptoms, according to the results of a descriptive study.

The main MSK symptom seen in the observational cohort was enthesitis, but some patients also experienced arthritis and tenosynovitis a median of 17 weeks after starting dupilumab treatment. Together these symptoms represent a new MSK syndrome, say researchers from the United Kingdom.

“The pattern of MSK symptoms and signs is characteristic of psoriatic arthritis/peripheral spondyloarthritis,” Bruce Kirkham, MD, and collaborators report in Arthritis & Rheumatology.

“We started a few years ago and have been following the patients for quite a long time,” Dr. Kirkham, a consultant rheumatologist at Guy’s and St. Thomas’ NHS Foundation Trust, London, told this news organization.

Characterizing the MSK symptoms

Of 470 patients with atopic dermatitis who started treatment with dupilumab at Guy’s and St. Thomas’ NHS Foundation Trust between October 2018 and February 2021, 36 (7.65%) developed rheumatic symptoms and were referred to the rheumatology department. These individuals had their family history assessed and thorough MSK evaluations, which included antibody and inflammatory markers, ultrasound of the peripheral small joints, and MRI of the large joints and spine.

A total of 26 (5.5%) patients – 14 of whom were male – had inflammatory enthesitis, arthritis, and/or tenosynovitis. Of the others, seven had osteoarthritis and three had degenerative spine disease.

Enthesitis was the most common finding in those with rheumatic symptoms, occurring on its own in 11 patients, with arthritis in three patients, and tenosynovitis in two patients.  

These symptoms appeared 2-48 weeks after starting dupilumab treatment and were categorized as mild in 16 (61%) cases, moderate in six cases, and severe in four cases.

No specific predictors of the MSK symptoms seen were noted. Patient age, sex, duration of their atopic dermatitis, or how their skin condition had been previously treated did not help identify those who might develop rheumatic problems.
 

Conservative management approach

All patients had “outstanding” responses to treatment, Dr. Kirkham noted: The mean Eczema Area and Severity Index score before dupilumab treatment was 21, falling to 4.2 with treatment, indicating a mean 80% improvement.

Co-author Joseph Nathan, MBChB, of London North West Healthcare NHS Trust, who collaborated on the research while working within Dr. Kirkham’s group, said separately: “The concern that patients have is that when they start a medication and develop a side effect is that the medication is going to be stopped.”

Clinicians treating the patients took a conservative approach, prescribing NSAIDs such as cyclooxygenase-2 inhibitors or altering the frequency with which dupilumab was given.

With this approach, MSK symptoms resolved in 15 patients who remained on treatment and in seven who had to stop dupilumab. There were four patients, however, who had unresolved symptoms even once dupilumab treatment had been stopped.
 

Altering the local cytokine balance

Dupilumab is a monoclonal antibody that binds to the alpha subunit of the interleukin-4 receptor. This results in blocking the function of not only IL-4 but also IL-13.

Dr. Kirkham and colleagues think this might not only alter the balance of cytokines in the skin but also in the joints and entheses with IL-17, IL-23, or even tumor necrosis factor playing a possible role. Another thought is that many circulating T-cells in the skin move to the joints and entheses to trigger symptoms.

IL-13 inhibition does seem to be important, as another British research team, from the Centre for Epidemiology Versus Arthritis at the University of Manchester (England), has found.

At the recent annual meeting of the British Society for Rheumatology, Sizheng Steven Zhao, MBChB, PhD, and colleagues reported that among people who carried a genetic variant predisposing them to having low IL-13 function, there was a higher risk for inflammatory diseases such as psoriatic arthritis and other spondyloarthropathy-related diseases.

Sara Freeman/Frontline Medical News

Dermatology perspective

Approved by the U.S. Food and Drug Administration in 2017, dupilumab has since been hailed as a “breakthrough” in atopic dermatitis treatment. Given as a subcutaneous injection every 2 weeks, it provides a much-needed option for people who have moderate-to-severe disease and have tried other available treatments, including corticosteroids.

Dupilumab has since also been approved for asthma, chronic sinusitis with nasal polyposis, eosinophilic esophagitis, and prurigo nodularis and is used off-label for other skin conditions such as contact dermatitis, chronic spontaneous urticaria, and alopecia areata.

“Dupilumab, like a lot of medications for atopic dermatitis, is a relatively new drug, and we are still learning about its safety,” Joel M. Gelfand, MD, MSCE, of the University of Pennsylvania Perelman School of Medicine, Philadelphia, told this news organization.

“Inflammatory arthritis has been reported in patients treated with dupilumab, and this new study provides some useful estimates,” added Dr. Gelfand, who is a professor of dermatology and epidemiology and directs the Psoriasis and Phototherapy Treatment Center, Philadelphia.

“There was no control group,” Dr. Gelfand said, so “a causal relationship cannot be well established based on these data alone. The mechanism is not known but may result from a shifting of the immune system.”

Dr. Zhao observed: “We don’t know what the natural history of these adverse events is. We don’t know if stopping the drug early will prevent long-term adverse events. So, we don’t know if people will ultimately develop permanent psoriatic arthritis if we don’t intervene quick enough when we observe an adverse event.”

Being aware of the possibility of rheumatic side effects occurring with dupilumab and similar agents is key, Dr. Gelfand and Dr. Kirkham both said independently.

“I have personally seen this entity in my practice,” Dr. Gelfand said. “It is important to clinicians prescribing dupilumab to alert patients about this potential side effect and ask about joint symptoms in follow-up.”

Dr. Kirkham said: “Prescribers need to be aware of it, because up until now it’s been just very vaguely discussed as sort of aches and pains, arthralgias, and it’s a much more specific of a kind of syndrome of enthesitis, arthritis, tenosynovitis – a little like psoriatic arthritis.”

Not everyone has come across these side effects, however, as Steven Daveluy, MD, associate professor and dermatology program director at Wayne State University, Detroit, said in an interview.

“This article and the other case series both noted the musculoskeletal symptoms occurred in about 5% of patients, which surprised me since I haven’t seen it in my practice and have enough patients being treated with dupilumab that I would expect to see a case at that rate,” Dr. Daveluy said.

“The majority of cases are mild and respond to treatment with anti-inflammatories like naproxen, which is available over the counter. It’s likely that patients with a mild case could simply treat their pain with naproxen that’s already in their medicine cabinet until it resolves, never bringing it to the doctor’s attention,” he suggested.

“Dupilumab is still a safe and effective medication that can change the lives of patients suffering from atopic dermatitis,” he said.

“Awareness of this potential side effect can help dermatologists recognize it early and work together with patients to determine the best course of action.”

All research mentioned in this article was independently supported. Dr. Kirkham, Mr. Nathan, Dr. Zhao, and Dr. Daveluy report no relevant financial relationships. Dr. Gelfand has served as a consultant for numerous pharmaceutical companies and receives research grants from Amgen, Boehringer Ingelheim, and Pfizer. He is a co-patent holder of resiquimod for treatment of cutaneous T-cell lymphoma.

A version of this article first appeared on Medscape.com.

MILAN – Secukinumab (Cosentyx) and biosimilar adalimumab-adaz (Hyrimoz) injection proved to have similar efficacy for limiting spinal radiographic progression over a 2-year period in patients with radiographic axial spondyloarthritis (r-axSpA) in the SURPASS study, a phase 3b, randomized controlled trial.

The study, presented at the annual European Congress of Rheumatology, represents the first head-to-head trial comparing the effects of two biologic disease-modifying antirheumatic drugs (bDMARDs) in axSpA. Notably, secukinumab and adalimumab-adaz target different pathways as an interleukin-17A inhibitor and a tumor necrosis factor (TNF) inhibitor, respectively.

Both TNF and IL-17A have been implicated in the pathogenesis of axSpA. Anti-TNF agents and the IL-17A inhibitor secukinumab have demonstrated effectiveness in improving symptoms, signs, and physical function in patients with axSpA and are approved therapies for the disease. However, limited data exist regarding the effect of bDMARDs in slowing radiographic progression, which is a key therapeutic goal in axSpA to prevent irreversible structural damage.

The SURPASS trial, funded by Novartis, enrolled 859 biologic-naive adult patients with moderate to severe r-axSpA. Participants were randomly assigned (1:1:1) to receive secukinumab 150 mg (n = 287), secukinumab 300 mg (n = 286), or adalimumab-adaz 40 mg (n = 286). The primary endpoint was the proportion of patients with no radiographic progression at the 2-year mark (week 104). Radiographic progression was defined as a change from baseline in modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS; range, 0-72) of 0.5 or less. The radiographic assessments were conducted by three independent evaluators who were blinded to treatment and the chronology of images.

Baseline characteristics indicated that the study population (78.5% male; mean age, 42.1 years) had a high risk of radiographic progression. The proportion of patients with no radiographic progression at week 104 was 66.1% in the secukinumab 150-mg arm, 66.9% in the secukinumab 300-mg arm, and 65.6% in the adalimumab-adaz arm. The mean change from baseline in mSASSS was 0.54, 0.55, and 0.72, respectively.

Notably, more than half of the patients (56.9%, 53.8%, and 53.3%, respectively) with at least one syndesmophyte at baseline did not develop new syndesmophytes over the 2-year period. The observed reductions in sacroiliac joint and spinal edema were comparable across all treatment groups. The safety profile of secukinumab and adalimumab-adaz was consistent with their well-established profiles.

No significant differences were observed between the treatment groups in terms of the primary and secondary endpoints. Study presenter and lead author Xenofon Baraliakos, MD, PhD, medical director of the Rheumatism Centre and professor of internal medicine and rheumatology at Ruhr University Bochum (Germany), stated: “Anti-TNF therapy has been considered the gold-standard treatment for axial spondyloarthritis in terms of slowing or halting radiographic progression. Our aim was to investigate whether other modes of action, such as IL-17 inhibition, achieve the same results. The primary hypothesis was that IL-17 inhibition could be even more effective than TNF blockade. However, our data indicate that secukinumab is at least as good as TNF blockers.

“Several risk factors, including high C-reactive protein [CRP] levels, male gender, high disease activity, and baseline radiographic damage (e.g., presence of syndesmophytes), are associated with structural progression,” Dr. Baraliakos explained. “We performed subgroup analyses and found no differences. This is a positive outcome as it suggests that there is no need to select patients based on either secukinumab or anti-TNF agents.”

When making treatment decisions, other factors must be taken into consideration. “Our study specifically examined radiographic progression. The clinical outcomes, indications, and contraindications for anti-TNF agents and secukinumab differ,” Dr. Baraliakos explained. “For instance, secukinumab may be preferred for patients with psoriasis, while adalimumab is more suitable for those with inflammatory bowel disease. Although these bDMARDs are not interchangeable, they have the same positive effect on radiographic progression.”
 

Not a definitive answer about structural progression

An open question remains. Alexandre Sepriano, MD, PhD, a rheumatologist at Hospital Egas Moniz and researcher at NOVA Medical School, both in Lisbon, commented: “The study was designed to maximize the chances of detecting a difference, if any, in spinal radiographic progression between secukinumab 150 mg and 300 mg and adalimumab. The included patients had a high risk of progression at baseline; in addition to back pain, they either had elevated CRP or at least one syndesmophyte on spine radiographs. Consequently, baseline structural damage was high [mean mSASSS, 17].”

“After 2 years, no difference was observed in the percentage of patients with no progression across the study arms. This finding does not definitively answer whether bDMARDs can modify structural progression or if secukinumab and adalimumab are equally effective in this regard,” explained Dr. Sepriano, who was not involved in the study. “However, there is good news for patients. Both secukinumab and adalimumab are potent anti-inflammatory drugs that effectively alleviate axial inflammation caused by the disease. This was demonstrated by the reduction in inflammatory scores on MRI in the SURPASS study. It aligns with robust evidence that both IL-17 inhibitors and TNF inhibitors are effective in improving symptoms in individuals with axSpA.

“Researchers continue to make significant efforts to understand how axial inflammation contributes to pathological new bone formation in axSpA,” Dr. Sepriano continued. “Understanding these mechanisms can guide future research aimed at interfering with disease progression. Furthermore, the use of new methods to quantify structural progression in axSpA, such as low-dose CT, which has shown greater sensitivity to change than traditional methods, can pave the way for new studies with fewer patients and shorter follow-up periods, thereby increasing the likelihood of detecting treatment effects.”

Dr. Baraliakos has received speaking and consulting fees and grant/research support from AbbVie, Bristol-Myers Squibb, Celgene, Chugai, Merck Sharp & Dohme, Novartis, Pfizer, and UCB. Dr. Sepriano has received speaking and/or consulting fees from AbbVie, Novartis, UCB, and Lilly. The trial was sponsored by Novartis.

A version of this article first appeared on Medscape.com.

MILAN – Secukinumab (Cosentyx) and biosimilar adalimumab-adaz (Hyrimoz) injection proved to have similar efficacy for limiting spinal radiographic progression over a 2-year period in patients with radiographic axial spondyloarthritis (r-axSpA) in the SURPASS study, a phase 3b, randomized controlled trial.

The study, presented at the annual European Congress of Rheumatology, represents the first head-to-head trial comparing the effects of two biologic disease-modifying antirheumatic drugs (bDMARDs) in axSpA. Notably, secukinumab and adalimumab-adaz target different pathways as an interleukin-17A inhibitor and a tumor necrosis factor (TNF) inhibitor, respectively.

Both TNF and IL-17A have been implicated in the pathogenesis of axSpA. Anti-TNF agents and the IL-17A inhibitor secukinumab have demonstrated effectiveness in improving symptoms, signs, and physical function in patients with axSpA and are approved therapies for the disease. However, limited data exist regarding the effect of bDMARDs in slowing radiographic progression, which is a key therapeutic goal in axSpA to prevent irreversible structural damage.

The SURPASS trial, funded by Novartis, enrolled 859 biologic-naive adult patients with moderate to severe r-axSpA. Participants were randomly assigned (1:1:1) to receive secukinumab 150 mg (n = 287), secukinumab 300 mg (n = 286), or adalimumab-adaz 40 mg (n = 286). The primary endpoint was the proportion of patients with no radiographic progression at the 2-year mark (week 104). Radiographic progression was defined as a change from baseline in modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS; range, 0-72) of 0.5 or less. The radiographic assessments were conducted by three independent evaluators who were blinded to treatment and the chronology of images.

Baseline characteristics indicated that the study population (78.5% male; mean age, 42.1 years) had a high risk of radiographic progression. The proportion of patients with no radiographic progression at week 104 was 66.1% in the secukinumab 150-mg arm, 66.9% in the secukinumab 300-mg arm, and 65.6% in the adalimumab-adaz arm. The mean change from baseline in mSASSS was 0.54, 0.55, and 0.72, respectively.

Notably, more than half of the patients (56.9%, 53.8%, and 53.3%, respectively) with at least one syndesmophyte at baseline did not develop new syndesmophytes over the 2-year period. The observed reductions in sacroiliac joint and spinal edema were comparable across all treatment groups. The safety profile of secukinumab and adalimumab-adaz was consistent with their well-established profiles.

No significant differences were observed between the treatment groups in terms of the primary and secondary endpoints. Study presenter and lead author Xenofon Baraliakos, MD, PhD, medical director of the Rheumatism Centre and professor of internal medicine and rheumatology at Ruhr University Bochum (Germany), stated: “Anti-TNF therapy has been considered the gold-standard treatment for axial spondyloarthritis in terms of slowing or halting radiographic progression. Our aim was to investigate whether other modes of action, such as IL-17 inhibition, achieve the same results. The primary hypothesis was that IL-17 inhibition could be even more effective than TNF blockade. However, our data indicate that secukinumab is at least as good as TNF blockers.

“Several risk factors, including high C-reactive protein [CRP] levels, male gender, high disease activity, and baseline radiographic damage (e.g., presence of syndesmophytes), are associated with structural progression,” Dr. Baraliakos explained. “We performed subgroup analyses and found no differences. This is a positive outcome as it suggests that there is no need to select patients based on either secukinumab or anti-TNF agents.”

When making treatment decisions, other factors must be taken into consideration. “Our study specifically examined radiographic progression. The clinical outcomes, indications, and contraindications for anti-TNF agents and secukinumab differ,” Dr. Baraliakos explained. “For instance, secukinumab may be preferred for patients with psoriasis, while adalimumab is more suitable for those with inflammatory bowel disease. Although these bDMARDs are not interchangeable, they have the same positive effect on radiographic progression.”
 

Not a definitive answer about structural progression

An open question remains. Alexandre Sepriano, MD, PhD, a rheumatologist at Hospital Egas Moniz and researcher at NOVA Medical School, both in Lisbon, commented: “The study was designed to maximize the chances of detecting a difference, if any, in spinal radiographic progression between secukinumab 150 mg and 300 mg and adalimumab. The included patients had a high risk of progression at baseline; in addition to back pain, they either had elevated CRP or at least one syndesmophyte on spine radiographs. Consequently, baseline structural damage was high [mean mSASSS, 17].”

“After 2 years, no difference was observed in the percentage of patients with no progression across the study arms. This finding does not definitively answer whether bDMARDs can modify structural progression or if secukinumab and adalimumab are equally effective in this regard,” explained Dr. Sepriano, who was not involved in the study. “However, there is good news for patients. Both secukinumab and adalimumab are potent anti-inflammatory drugs that effectively alleviate axial inflammation caused by the disease. This was demonstrated by the reduction in inflammatory scores on MRI in the SURPASS study. It aligns with robust evidence that both IL-17 inhibitors and TNF inhibitors are effective in improving symptoms in individuals with axSpA.

“Researchers continue to make significant efforts to understand how axial inflammation contributes to pathological new bone formation in axSpA,” Dr. Sepriano continued. “Understanding these mechanisms can guide future research aimed at interfering with disease progression. Furthermore, the use of new methods to quantify structural progression in axSpA, such as low-dose CT, which has shown greater sensitivity to change than traditional methods, can pave the way for new studies with fewer patients and shorter follow-up periods, thereby increasing the likelihood of detecting treatment effects.”

Dr. Baraliakos has received speaking and consulting fees and grant/research support from AbbVie, Bristol-Myers Squibb, Celgene, Chugai, Merck Sharp & Dohme, Novartis, Pfizer, and UCB. Dr. Sepriano has received speaking and/or consulting fees from AbbVie, Novartis, UCB, and Lilly. The trial was sponsored by Novartis.

A version of this article first appeared on Medscape.com.

MILAN – Secukinumab (Cosentyx) and biosimilar adalimumab-adaz (Hyrimoz) injection proved to have similar efficacy for limiting spinal radiographic progression over a 2-year period in patients with radiographic axial spondyloarthritis (r-axSpA) in the SURPASS study, a phase 3b, randomized controlled trial.

The study, presented at the annual European Congress of Rheumatology, represents the first head-to-head trial comparing the effects of two biologic disease-modifying antirheumatic drugs (bDMARDs) in axSpA. Notably, secukinumab and adalimumab-adaz target different pathways as an interleukin-17A inhibitor and a tumor necrosis factor (TNF) inhibitor, respectively.

Both TNF and IL-17A have been implicated in the pathogenesis of axSpA. Anti-TNF agents and the IL-17A inhibitor secukinumab have demonstrated effectiveness in improving symptoms, signs, and physical function in patients with axSpA and are approved therapies for the disease. However, limited data exist regarding the effect of bDMARDs in slowing radiographic progression, which is a key therapeutic goal in axSpA to prevent irreversible structural damage.

The SURPASS trial, funded by Novartis, enrolled 859 biologic-naive adult patients with moderate to severe r-axSpA. Participants were randomly assigned (1:1:1) to receive secukinumab 150 mg (n = 287), secukinumab 300 mg (n = 286), or adalimumab-adaz 40 mg (n = 286). The primary endpoint was the proportion of patients with no radiographic progression at the 2-year mark (week 104). Radiographic progression was defined as a change from baseline in modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS; range, 0-72) of 0.5 or less. The radiographic assessments were conducted by three independent evaluators who were blinded to treatment and the chronology of images.

Baseline characteristics indicated that the study population (78.5% male; mean age, 42.1 years) had a high risk of radiographic progression. The proportion of patients with no radiographic progression at week 104 was 66.1% in the secukinumab 150-mg arm, 66.9% in the secukinumab 300-mg arm, and 65.6% in the adalimumab-adaz arm. The mean change from baseline in mSASSS was 0.54, 0.55, and 0.72, respectively.

Notably, more than half of the patients (56.9%, 53.8%, and 53.3%, respectively) with at least one syndesmophyte at baseline did not develop new syndesmophytes over the 2-year period. The observed reductions in sacroiliac joint and spinal edema were comparable across all treatment groups. The safety profile of secukinumab and adalimumab-adaz was consistent with their well-established profiles.

No significant differences were observed between the treatment groups in terms of the primary and secondary endpoints. Study presenter and lead author Xenofon Baraliakos, MD, PhD, medical director of the Rheumatism Centre and professor of internal medicine and rheumatology at Ruhr University Bochum (Germany), stated: “Anti-TNF therapy has been considered the gold-standard treatment for axial spondyloarthritis in terms of slowing or halting radiographic progression. Our aim was to investigate whether other modes of action, such as IL-17 inhibition, achieve the same results. The primary hypothesis was that IL-17 inhibition could be even more effective than TNF blockade. However, our data indicate that secukinumab is at least as good as TNF blockers.

“Several risk factors, including high C-reactive protein [CRP] levels, male gender, high disease activity, and baseline radiographic damage (e.g., presence of syndesmophytes), are associated with structural progression,” Dr. Baraliakos explained. “We performed subgroup analyses and found no differences. This is a positive outcome as it suggests that there is no need to select patients based on either secukinumab or anti-TNF agents.”

When making treatment decisions, other factors must be taken into consideration. “Our study specifically examined radiographic progression. The clinical outcomes, indications, and contraindications for anti-TNF agents and secukinumab differ,” Dr. Baraliakos explained. “For instance, secukinumab may be preferred for patients with psoriasis, while adalimumab is more suitable for those with inflammatory bowel disease. Although these bDMARDs are not interchangeable, they have the same positive effect on radiographic progression.”
 

Not a definitive answer about structural progression

An open question remains. Alexandre Sepriano, MD, PhD, a rheumatologist at Hospital Egas Moniz and researcher at NOVA Medical School, both in Lisbon, commented: “The study was designed to maximize the chances of detecting a difference, if any, in spinal radiographic progression between secukinumab 150 mg and 300 mg and adalimumab. The included patients had a high risk of progression at baseline; in addition to back pain, they either had elevated CRP or at least one syndesmophyte on spine radiographs. Consequently, baseline structural damage was high [mean mSASSS, 17].”

“After 2 years, no difference was observed in the percentage of patients with no progression across the study arms. This finding does not definitively answer whether bDMARDs can modify structural progression or if secukinumab and adalimumab are equally effective in this regard,” explained Dr. Sepriano, who was not involved in the study. “However, there is good news for patients. Both secukinumab and adalimumab are potent anti-inflammatory drugs that effectively alleviate axial inflammation caused by the disease. This was demonstrated by the reduction in inflammatory scores on MRI in the SURPASS study. It aligns with robust evidence that both IL-17 inhibitors and TNF inhibitors are effective in improving symptoms in individuals with axSpA.

“Researchers continue to make significant efforts to understand how axial inflammation contributes to pathological new bone formation in axSpA,” Dr. Sepriano continued. “Understanding these mechanisms can guide future research aimed at interfering with disease progression. Furthermore, the use of new methods to quantify structural progression in axSpA, such as low-dose CT, which has shown greater sensitivity to change than traditional methods, can pave the way for new studies with fewer patients and shorter follow-up periods, thereby increasing the likelihood of detecting treatment effects.”

Dr. Baraliakos has received speaking and consulting fees and grant/research support from AbbVie, Bristol-Myers Squibb, Celgene, Chugai, Merck Sharp & Dohme, Novartis, Pfizer, and UCB. Dr. Sepriano has received speaking and/or consulting fees from AbbVie, Novartis, UCB, and Lilly. The trial was sponsored by Novartis.

A version of this article first appeared on Medscape.com.

MILAN – The oral Janus kinase (JAK) 1/2 inhibitor baricitinib (Olumiant) demonstrated significantly better efficacy than cyclophosphamide infusions in the treatment of lupus nephritis in a small, independently funded, phase 3, double-blind clinical trial, Manal Hassanien, MD, reported at the annual European Congress of Rheumatology.

Baricitinib, licensed by Eli Lilly, has been recognized as a potential therapeutic option in systemic lupus, and is approved in the United States to treat RA, alopecia areata, and COVID-19 in certain hospitalized adults. It is also approved to treat atopic dermatitis in Europe. However, it previously yielded disappointing results in phase 3 clinical trials SLE-BRAVE-I and SLE-BRAVE-II for systemic lupus erythematosus. The trial results presented at EULAR suggest that baricitinib could be beneficial in the treatment of lupus nephritis, further establishing the role of JAK inhibitors in autoimmune disease therapy.

“Lupus nephritis typically develops within 5 years of initial lupus symptoms,” said Dr. Hassanien, of the rheumatology research and advanced therapeutics department at Assiut (Egypt) University. “Research has shown that up to 60% of lupus patients will eventually develop lupus nephritis. The management of proliferative lupus nephritis usually involves an initial phase focused on preventing the development of irreversible damage, followed by a maintenance phase to control lupus activity. Despite significant progress, lupus nephritis still carries an increased risk of end-stage renal disease and mortality.”

The study’s primary endpoint of 24-hour proteinuria response rate (≥ 50% reduction from baseline) at week 12 was significantly greater with baricitinib 4 mg daily, compared with monthly cyclophosphamide infusions at 0.7 mg/m² (70% vs. 43%; P < .0001). At week 24, 76.6% of the baricitinib group met the primary endpoint, compared with 50% in the cyclophosphamide group. Two multiplicity-controlled secondary endpoints, C3 serum level and the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), also showed statistical significance at 12 weeks (P < .01).

The 6-month trial included 60 adult patients (age 18 years and older) with a clinical diagnosis of lupus nephritis fulfilling classification criteria for LN grade III and IV. Patients needed to demonstrate objective signs of active nephritis consistent with persistent proteinuria greater than 0.5 g/day and/or cellular casts at screening to be included. Additional inclusion criteria were SLEDAI-2K greater than 4 and assessment of anti–double-stranded DNA and C3 serum levels at study entry. The patients were randomly assigned to two equal-sized groups, with one group receiving baricitinib 4 mg daily and a monthly placebo saline infusion, and the other group receiving monthly cyclophosphamide infusions and oral placebo tablets.

The incidence of adverse events was comparable between the two treatment groups, with 48% of patients in the baricitinib group and 46% in the cyclophosphamide group experiencing adverse events. Only three serious adverse events, specifically serious infection or herpes zoster, were recorded, leading to treatment discontinuation.

Two patients (6.6%) in the baricitinib group and one patient (3.3%) in the cyclophosphamide group were affected. The researchers recorded no major adverse cardiovascular or venous thromboembolic events, which are known to occur at higher rates among some users of baricitinib and other JAK inhibitors. The safety profile of baricitinib was consistent with observations made in other inflammatory musculoskeletal diseases, and no new risks were identified.

However, there were some concerns expressed by audience members during the presentation.

“The primary endpoint is limited at proteinuria, while biopsy is considered the gold standard for measuring efficacy,” said Eric F. Morand, MD, head of the Monash Health rheumatology unit, Melbourne. This was not the only critical comment regarding the study that emerged during the discussion. The use of a 4-mg dosage regimen throughout the entire study duration (despite official recommendations suggesting a 2-mg dosage in the long run) and the positive outcomes observed in the control group treated with cyclophosphamide were also mentioned.

Dr. Hassanien acknowledged that this is a small and relatively short study and disclosed plans to extend the follow-up period to 1 year and conduct a renal biopsy.

Dr. Hassanien reported no relevant financial relationships. Assiut University funded the trial.

A version of this article first appeared on Medscape.com.

MILAN – The oral Janus kinase (JAK) 1/2 inhibitor baricitinib (Olumiant) demonstrated significantly better efficacy than cyclophosphamide infusions in the treatment of lupus nephritis in a small, independently funded, phase 3, double-blind clinical trial, Manal Hassanien, MD, reported at the annual European Congress of Rheumatology.

Baricitinib, licensed by Eli Lilly, has been recognized as a potential therapeutic option in systemic lupus, and is approved in the United States to treat RA, alopecia areata, and COVID-19 in certain hospitalized adults. It is also approved to treat atopic dermatitis in Europe. However, it previously yielded disappointing results in phase 3 clinical trials SLE-BRAVE-I and SLE-BRAVE-II for systemic lupus erythematosus. The trial results presented at EULAR suggest that baricitinib could be beneficial in the treatment of lupus nephritis, further establishing the role of JAK inhibitors in autoimmune disease therapy.

“Lupus nephritis typically develops within 5 years of initial lupus symptoms,” said Dr. Hassanien, of the rheumatology research and advanced therapeutics department at Assiut (Egypt) University. “Research has shown that up to 60% of lupus patients will eventually develop lupus nephritis. The management of proliferative lupus nephritis usually involves an initial phase focused on preventing the development of irreversible damage, followed by a maintenance phase to control lupus activity. Despite significant progress, lupus nephritis still carries an increased risk of end-stage renal disease and mortality.”

The study’s primary endpoint of 24-hour proteinuria response rate (≥ 50% reduction from baseline) at week 12 was significantly greater with baricitinib 4 mg daily, compared with monthly cyclophosphamide infusions at 0.7 mg/m² (70% vs. 43%; P < .0001). At week 24, 76.6% of the baricitinib group met the primary endpoint, compared with 50% in the cyclophosphamide group. Two multiplicity-controlled secondary endpoints, C3 serum level and the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), also showed statistical significance at 12 weeks (P < .01).

The 6-month trial included 60 adult patients (age 18 years and older) with a clinical diagnosis of lupus nephritis fulfilling classification criteria for LN grade III and IV. Patients needed to demonstrate objective signs of active nephritis consistent with persistent proteinuria greater than 0.5 g/day and/or cellular casts at screening to be included. Additional inclusion criteria were SLEDAI-2K greater than 4 and assessment of anti–double-stranded DNA and C3 serum levels at study entry. The patients were randomly assigned to two equal-sized groups, with one group receiving baricitinib 4 mg daily and a monthly placebo saline infusion, and the other group receiving monthly cyclophosphamide infusions and oral placebo tablets.

The incidence of adverse events was comparable between the two treatment groups, with 48% of patients in the baricitinib group and 46% in the cyclophosphamide group experiencing adverse events. Only three serious adverse events, specifically serious infection or herpes zoster, were recorded, leading to treatment discontinuation.

Two patients (6.6%) in the baricitinib group and one patient (3.3%) in the cyclophosphamide group were affected. The researchers recorded no major adverse cardiovascular or venous thromboembolic events, which are known to occur at higher rates among some users of baricitinib and other JAK inhibitors. The safety profile of baricitinib was consistent with observations made in other inflammatory musculoskeletal diseases, and no new risks were identified.

However, there were some concerns expressed by audience members during the presentation.

“The primary endpoint is limited at proteinuria, while biopsy is considered the gold standard for measuring efficacy,” said Eric F. Morand, MD, head of the Monash Health rheumatology unit, Melbourne. This was not the only critical comment regarding the study that emerged during the discussion. The use of a 4-mg dosage regimen throughout the entire study duration (despite official recommendations suggesting a 2-mg dosage in the long run) and the positive outcomes observed in the control group treated with cyclophosphamide were also mentioned.

Dr. Hassanien acknowledged that this is a small and relatively short study and disclosed plans to extend the follow-up period to 1 year and conduct a renal biopsy.

Dr. Hassanien reported no relevant financial relationships. Assiut University funded the trial.

A version of this article first appeared on Medscape.com.

MILAN – The oral Janus kinase (JAK) 1/2 inhibitor baricitinib (Olumiant) demonstrated significantly better efficacy than cyclophosphamide infusions in the treatment of lupus nephritis in a small, independently funded, phase 3, double-blind clinical trial, Manal Hassanien, MD, reported at the annual European Congress of Rheumatology.

Baricitinib, licensed by Eli Lilly, has been recognized as a potential therapeutic option in systemic lupus, and is approved in the United States to treat RA, alopecia areata, and COVID-19 in certain hospitalized adults. It is also approved to treat atopic dermatitis in Europe. However, it previously yielded disappointing results in phase 3 clinical trials SLE-BRAVE-I and SLE-BRAVE-II for systemic lupus erythematosus. The trial results presented at EULAR suggest that baricitinib could be beneficial in the treatment of lupus nephritis, further establishing the role of JAK inhibitors in autoimmune disease therapy.

“Lupus nephritis typically develops within 5 years of initial lupus symptoms,” said Dr. Hassanien, of the rheumatology research and advanced therapeutics department at Assiut (Egypt) University. “Research has shown that up to 60% of lupus patients will eventually develop lupus nephritis. The management of proliferative lupus nephritis usually involves an initial phase focused on preventing the development of irreversible damage, followed by a maintenance phase to control lupus activity. Despite significant progress, lupus nephritis still carries an increased risk of end-stage renal disease and mortality.”

The study’s primary endpoint of 24-hour proteinuria response rate (≥ 50% reduction from baseline) at week 12 was significantly greater with baricitinib 4 mg daily, compared with monthly cyclophosphamide infusions at 0.7 mg/m² (70% vs. 43%; P < .0001). At week 24, 76.6% of the baricitinib group met the primary endpoint, compared with 50% in the cyclophosphamide group. Two multiplicity-controlled secondary endpoints, C3 serum level and the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), also showed statistical significance at 12 weeks (P < .01).

The 6-month trial included 60 adult patients (age 18 years and older) with a clinical diagnosis of lupus nephritis fulfilling classification criteria for LN grade III and IV. Patients needed to demonstrate objective signs of active nephritis consistent with persistent proteinuria greater than 0.5 g/day and/or cellular casts at screening to be included. Additional inclusion criteria were SLEDAI-2K greater than 4 and assessment of anti–double-stranded DNA and C3 serum levels at study entry. The patients were randomly assigned to two equal-sized groups, with one group receiving baricitinib 4 mg daily and a monthly placebo saline infusion, and the other group receiving monthly cyclophosphamide infusions and oral placebo tablets.

The incidence of adverse events was comparable between the two treatment groups, with 48% of patients in the baricitinib group and 46% in the cyclophosphamide group experiencing adverse events. Only three serious adverse events, specifically serious infection or herpes zoster, were recorded, leading to treatment discontinuation.

Two patients (6.6%) in the baricitinib group and one patient (3.3%) in the cyclophosphamide group were affected. The researchers recorded no major adverse cardiovascular or venous thromboembolic events, which are known to occur at higher rates among some users of baricitinib and other JAK inhibitors. The safety profile of baricitinib was consistent with observations made in other inflammatory musculoskeletal diseases, and no new risks were identified.

However, there were some concerns expressed by audience members during the presentation.

“The primary endpoint is limited at proteinuria, while biopsy is considered the gold standard for measuring efficacy,” said Eric F. Morand, MD, head of the Monash Health rheumatology unit, Melbourne. This was not the only critical comment regarding the study that emerged during the discussion. The use of a 4-mg dosage regimen throughout the entire study duration (despite official recommendations suggesting a 2-mg dosage in the long run) and the positive outcomes observed in the control group treated with cyclophosphamide were also mentioned.

Dr. Hassanien acknowledged that this is a small and relatively short study and disclosed plans to extend the follow-up period to 1 year and conduct a renal biopsy.

Dr. Hassanien reported no relevant financial relationships. Assiut University funded the trial.

A version of this article first appeared on Medscape.com.

MILAN – Patients with psoriatic arthritis (PsA) who are using biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) have fivefold higher risk for interstitial lung disease (ILD) than does the general population, according to the first study to explore risk of ILD in this particular patient group.

The study also found 10-fold higher risk of ILD in patients with RA who were starting a b/tsDMARD, compared with the general population, while the addition of methotrexate did not appear to be associated with increased risk for ILD in either RA nor PsA.

Becky McCall/MDedge News

Sella Aarrestad Provan, MD, of the Center for Treatment of Rheumatic and Musculoskeletal Diseases at Diakonhjemmet Hospital, Oslo, presented the results at the annual European Congress of Rheumatology.

Explaining the motivation for the study, Dr. Aarrestad Provan said that, in RA, methotrexate’s role in ILD development remained unclear, while some small studies linked b/tsDMARDs with risk for ILD. “In PsA, very few studies have explored the risk of ILD, and no systematic studies have looked at ILD risk factors in this disease.”

The researchers analyzed patient data from hospital and death registries across five Nordic countries (Denmark, Norway, Finland, Iceland, and Sweden) and compared them with general population controls. They calculated risk ratios for people who developed ILD within 5 years of starting a b/tsDMARD (with or without methotrexate).

A total of 37,010 patients with RA, 12,341 with PsA, and 569,451 members of the general population were included in the analysis, with respective disease durations of 10 and 8.9 years. Methotrexate was used along with b/tsDMARDs in 49% of patients with RA and 41% with PsA, and most patients were already on methotrexate when b/tsDMARDs were started. The tumor necrosis factor inhibitor etanercept (Enbrel) was the most commonly used b/tsDMARD in both RA and PsA, followed by infliximab (Remicade and biosimilars) and adalimumab (Humira and biosimilars).

The incidence of ILD within 5 years of starting a b/tsDMARD was 0.8% in patients with RA, 0.2% with PsA, and 0.1% in the general population, and these findings generated hazard ratios of 10.1 (95% confidence interval, 8.6-11.9) for RA and 5.0 (95% CI, 3.4-7.4) for PsA, compared with the general population as reference.

When the risk for ILD was explored according to methotrexate use in RA patients, “there was no signal of increased risk across patients using methotrexate,” Dr. Aarrestad Provan reported. When risk of ILD was explored according to b/tsDMARD use in RA patients, a signal of increased risk was observed with rituximab, she noted, “but upon adjusting for age, sex, and comorbidities, this association was no longer significant, but was still numerically increased.”

Iain McInnes, MD, PhD, vice principal, professor of rheumatology, and head of the College of Medical, Veterinary and Life Sciences at the University of Glasgow, remarked that he “loves results that are unexpected” and thanked the researcher for such an “important study.”

“For years, we’ve been interested in the potential for DMARDs to impact interstitial lung disease, with potential that drugs could make it worse, or better,” he said. “This study is wonderful and novel because first of all, there hasn’t, until now, been a direct comparison between RA and PsA in quite this way, and secondly, we haven’t really assessed whether there is a drug-related risk in PsA. Note that drug related does not necessarily imply causality.”

Regarding mechanisms, Dr. McInnes added that “epidemiologic studies suggest that PsA often coexists with the presence of cardiometabolic syndrome and obesity, which has a higher prevalence in PsA than in RA. Obesity is also related to ILD. As such, it begs the question of whether cardiometabolic, diabetes, or obesity-related features may give us a clue as to what is going on in these PsA patients.”

The research was supported by NordForsk and FOREUM. Dr. Aarrestad Provan reported serving as a consultant to Boehringer Ingelheim and Novartis and receiving grant/research support from Boehringer Ingelheim. Dr. McInnes declared no disclosures relevant to this study.

MILAN – Patients with psoriatic arthritis (PsA) who are using biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) have fivefold higher risk for interstitial lung disease (ILD) than does the general population, according to the first study to explore risk of ILD in this particular patient group.

The study also found 10-fold higher risk of ILD in patients with RA who were starting a b/tsDMARD, compared with the general population, while the addition of methotrexate did not appear to be associated with increased risk for ILD in either RA nor PsA.

Becky McCall/MDedge News

Sella Aarrestad Provan, MD, of the Center for Treatment of Rheumatic and Musculoskeletal Diseases at Diakonhjemmet Hospital, Oslo, presented the results at the annual European Congress of Rheumatology.

Explaining the motivation for the study, Dr. Aarrestad Provan said that, in RA, methotrexate’s role in ILD development remained unclear, while some small studies linked b/tsDMARDs with risk for ILD. “In PsA, very few studies have explored the risk of ILD, and no systematic studies have looked at ILD risk factors in this disease.”

The researchers analyzed patient data from hospital and death registries across five Nordic countries (Denmark, Norway, Finland, Iceland, and Sweden) and compared them with general population controls. They calculated risk ratios for people who developed ILD within 5 years of starting a b/tsDMARD (with or without methotrexate).

A total of 37,010 patients with RA, 12,341 with PsA, and 569,451 members of the general population were included in the analysis, with respective disease durations of 10 and 8.9 years. Methotrexate was used along with b/tsDMARDs in 49% of patients with RA and 41% with PsA, and most patients were already on methotrexate when b/tsDMARDs were started. The tumor necrosis factor inhibitor etanercept (Enbrel) was the most commonly used b/tsDMARD in both RA and PsA, followed by infliximab (Remicade and biosimilars) and adalimumab (Humira and biosimilars).

The incidence of ILD within 5 years of starting a b/tsDMARD was 0.8% in patients with RA, 0.2% with PsA, and 0.1% in the general population, and these findings generated hazard ratios of 10.1 (95% confidence interval, 8.6-11.9) for RA and 5.0 (95% CI, 3.4-7.4) for PsA, compared with the general population as reference.

When the risk for ILD was explored according to methotrexate use in RA patients, “there was no signal of increased risk across patients using methotrexate,” Dr. Aarrestad Provan reported. When risk of ILD was explored according to b/tsDMARD use in RA patients, a signal of increased risk was observed with rituximab, she noted, “but upon adjusting for age, sex, and comorbidities, this association was no longer significant, but was still numerically increased.”

Iain McInnes, MD, PhD, vice principal, professor of rheumatology, and head of the College of Medical, Veterinary and Life Sciences at the University of Glasgow, remarked that he “loves results that are unexpected” and thanked the researcher for such an “important study.”

“For years, we’ve been interested in the potential for DMARDs to impact interstitial lung disease, with potential that drugs could make it worse, or better,” he said. “This study is wonderful and novel because first of all, there hasn’t, until now, been a direct comparison between RA and PsA in quite this way, and secondly, we haven’t really assessed whether there is a drug-related risk in PsA. Note that drug related does not necessarily imply causality.”

Regarding mechanisms, Dr. McInnes added that “epidemiologic studies suggest that PsA often coexists with the presence of cardiometabolic syndrome and obesity, which has a higher prevalence in PsA than in RA. Obesity is also related to ILD. As such, it begs the question of whether cardiometabolic, diabetes, or obesity-related features may give us a clue as to what is going on in these PsA patients.”

The research was supported by NordForsk and FOREUM. Dr. Aarrestad Provan reported serving as a consultant to Boehringer Ingelheim and Novartis and receiving grant/research support from Boehringer Ingelheim. Dr. McInnes declared no disclosures relevant to this study.

MILAN – Patients with psoriatic arthritis (PsA) who are using biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) have fivefold higher risk for interstitial lung disease (ILD) than does the general population, according to the first study to explore risk of ILD in this particular patient group.

The study also found 10-fold higher risk of ILD in patients with RA who were starting a b/tsDMARD, compared with the general population, while the addition of methotrexate did not appear to be associated with increased risk for ILD in either RA nor PsA.

Becky McCall/MDedge News

Sella Aarrestad Provan, MD, of the Center for Treatment of Rheumatic and Musculoskeletal Diseases at Diakonhjemmet Hospital, Oslo, presented the results at the annual European Congress of Rheumatology.

Explaining the motivation for the study, Dr. Aarrestad Provan said that, in RA, methotrexate’s role in ILD development remained unclear, while some small studies linked b/tsDMARDs with risk for ILD. “In PsA, very few studies have explored the risk of ILD, and no systematic studies have looked at ILD risk factors in this disease.”

The researchers analyzed patient data from hospital and death registries across five Nordic countries (Denmark, Norway, Finland, Iceland, and Sweden) and compared them with general population controls. They calculated risk ratios for people who developed ILD within 5 years of starting a b/tsDMARD (with or without methotrexate).

A total of 37,010 patients with RA, 12,341 with PsA, and 569,451 members of the general population were included in the analysis, with respective disease durations of 10 and 8.9 years. Methotrexate was used along with b/tsDMARDs in 49% of patients with RA and 41% with PsA, and most patients were already on methotrexate when b/tsDMARDs were started. The tumor necrosis factor inhibitor etanercept (Enbrel) was the most commonly used b/tsDMARD in both RA and PsA, followed by infliximab (Remicade and biosimilars) and adalimumab (Humira and biosimilars).

The incidence of ILD within 5 years of starting a b/tsDMARD was 0.8% in patients with RA, 0.2% with PsA, and 0.1% in the general population, and these findings generated hazard ratios of 10.1 (95% confidence interval, 8.6-11.9) for RA and 5.0 (95% CI, 3.4-7.4) for PsA, compared with the general population as reference.

When the risk for ILD was explored according to methotrexate use in RA patients, “there was no signal of increased risk across patients using methotrexate,” Dr. Aarrestad Provan reported. When risk of ILD was explored according to b/tsDMARD use in RA patients, a signal of increased risk was observed with rituximab, she noted, “but upon adjusting for age, sex, and comorbidities, this association was no longer significant, but was still numerically increased.”

Iain McInnes, MD, PhD, vice principal, professor of rheumatology, and head of the College of Medical, Veterinary and Life Sciences at the University of Glasgow, remarked that he “loves results that are unexpected” and thanked the researcher for such an “important study.”

“For years, we’ve been interested in the potential for DMARDs to impact interstitial lung disease, with potential that drugs could make it worse, or better,” he said. “This study is wonderful and novel because first of all, there hasn’t, until now, been a direct comparison between RA and PsA in quite this way, and secondly, we haven’t really assessed whether there is a drug-related risk in PsA. Note that drug related does not necessarily imply causality.”

Regarding mechanisms, Dr. McInnes added that “epidemiologic studies suggest that PsA often coexists with the presence of cardiometabolic syndrome and obesity, which has a higher prevalence in PsA than in RA. Obesity is also related to ILD. As such, it begs the question of whether cardiometabolic, diabetes, or obesity-related features may give us a clue as to what is going on in these PsA patients.”

The research was supported by NordForsk and FOREUM. Dr. Aarrestad Provan reported serving as a consultant to Boehringer Ingelheim and Novartis and receiving grant/research support from Boehringer Ingelheim. Dr. McInnes declared no disclosures relevant to this study.

Even the plague wanted to visit Stonehenge

We’re about to blow your mind: The history you learned in school was often inaccurate. Shocking, we know, so we’ll give you a minute to process this incredible news.

Better? Good. Now, let’s look back at high school European history. The Black Death, specifically. The common narrative is that the Mongols, while besieging a Crimean city belonging to the Genoese, catapulted dead bodies infected with some mystery disease that turned out to be the plague. The Genoese then brought the plague back to Italy, and from there, we all know the rest of the story.

Ian Hodkinson, [email protected]

The Black Death was certainly extremely important to the development of modern Europe as we know it, but the history books gloss over the much longer history of the plague. Yersinia pestis did not suddenly appear unbidden in a Mongol war camp in 1347. The Black Death wasn’t even the first horrific, continent-wide pandemic caused by the plague; the Plague of Justinian 800 years earlier crippled the Byzantine Empire during an expansionist phase and killed anywhere between 15 million and 100 million.

Today, though, LOTME looks even deeper into history, nearly beyond even history itself, back into the depths of early Bronze Age northern Europe. Specifically, to two ancient burial sites in England, where researchers have identified three 4,000-year-old cases of Y. pestis, the first recorded incidence of the disease in Britain.

Two of the individuals, identified through analysis of dental pulp, were young children buried at a mass grave in Somerset, while the third, a middle-aged woman, was found in a ring cairn in Cumbria. These sites are hundreds of miles apart, yet carbon dating suggests all three people lived and died at roughly the same time. The strain found is very similar to other samples of plague found across central and western Europe starting around 3,000 BCE, suggesting a single, easily spread disease affecting a large area in a relatively small period of time. In other words, a pandemic. Even in these ancient times, the world was connected. Not even the island of Britain could escape.

Beyond that though, the research helps confirm the cyclical nature of the plague; over time, it loses its effectiveness and goes into hiding, only to mutate and come roaring back. This is a story with absolutely no relevance at all to the modern world. Nope, no plagues or pandemics going around right now, no viruses fading into the background in any way. What a ridiculous inference to make.
 

Uncovering the invisible with artificial intelligence

This week in “What Else Can AI Do?” new research shows that a computer program can reveal brain injury that couldn’t be seen before with typical MRI.

The hot new AI, birthed by researchers at New York University, could potentially be a game changer by linking repeated head impacts with tiny, structural changes in the brains of athletes who have not been diagnosed with a concussion. By using machine learning to train the AI, the researchers were, for the first time, able to distinguish the brain of athletes who played contact sports (football, soccer, lacrosse) from those participating in noncontact sports such as baseball, basketball, and cross-country.

Andrea Danti/Thinkstock

How did they do it? The investigators “designed statistical techniques that gave their computer program the ability to ‘learn’ how to predict exposure to repeated head impacts using mathematical models,” they explained in a written statement. Adding in data from the MRI scans of 81 male athletes with no known concussion diagnosis and the ability to identify unusual brain features between athletes with and without head trauma allowed the AI to predict results with accuracy even Miss Cleo would envy.

“This method may provide an important diagnostic tool not only for concussion, but also for detecting the damage that stems from subtler and more frequent head impacts,” said lead author Junbo Chen, an engineering doctoral candidate at NYU. That could make this new AI a valuable asset to science and medicine.

There are many things the human brain can do that AI can’t, and delegation could be one of them. Examining the data that represent the human brain in minute detail? Maybe we leave that to the machine.
 

Talk about your field promotions

If you’re a surgeon doing an amputation, the list of possible assistants pretty much starts and ends in only one place: Not the closest available janitor.

That may seem like an oddly obvious thing for us to say, but there’s at least one former Mainz (Germany) University Hospital physician who really needed to get this bit of advice before he attempted an unassisted toe amputation back in October of 2020. Yes, that does seem like kind of a long time ago for us to be reporting it now, but the details of the incident only just came to light a few days ago, thanks to German public broadcaster SWR.

Ente75/Wikipedia

Since it was just a toe, the surgeon thought he could perform the operation without any help. The toe, unfortunately, had other plans. The partially anesthetized patient got restless in the operating room, but with no actual trained nurse in the vicinity, the surgeon asked the closest available person – that would be the janitor – to lend a hand.

The surgical manager heard about these goings-on and got to the operating room too late to stop the procedure but soon enough to see the cleaning staffer “at the operating table with a bloody suction cup and a bloody compress in their hands,” SWR recently reported.

The incident was reported to the hospital’s medical director and the surgeon was fired, but since the patient experienced no complications not much fuss was made about it at the time.

Well, guess what? It’s toe-tally our job to make a fuss about these kinds of things. Or could it be that our job, much like the surgeon’s employment and the patient’s digit, is here toe-day and gone toe-morrow?

Even the plague wanted to visit Stonehenge

We’re about to blow your mind: The history you learned in school was often inaccurate. Shocking, we know, so we’ll give you a minute to process this incredible news.

Better? Good. Now, let’s look back at high school European history. The Black Death, specifically. The common narrative is that the Mongols, while besieging a Crimean city belonging to the Genoese, catapulted dead bodies infected with some mystery disease that turned out to be the plague. The Genoese then brought the plague back to Italy, and from there, we all know the rest of the story.

Ian Hodkinson, [email protected]

The Black Death was certainly extremely important to the development of modern Europe as we know it, but the history books gloss over the much longer history of the plague. Yersinia pestis did not suddenly appear unbidden in a Mongol war camp in 1347. The Black Death wasn’t even the first horrific, continent-wide pandemic caused by the plague; the Plague of Justinian 800 years earlier crippled the Byzantine Empire during an expansionist phase and killed anywhere between 15 million and 100 million.

Today, though, LOTME looks even deeper into history, nearly beyond even history itself, back into the depths of early Bronze Age northern Europe. Specifically, to two ancient burial sites in England, where researchers have identified three 4,000-year-old cases of Y. pestis, the first recorded incidence of the disease in Britain.

Two of the individuals, identified through analysis of dental pulp, were young children buried at a mass grave in Somerset, while the third, a middle-aged woman, was found in a ring cairn in Cumbria. These sites are hundreds of miles apart, yet carbon dating suggests all three people lived and died at roughly the same time. The strain found is very similar to other samples of plague found across central and western Europe starting around 3,000 BCE, suggesting a single, easily spread disease affecting a large area in a relatively small period of time. In other words, a pandemic. Even in these ancient times, the world was connected. Not even the island of Britain could escape.

Beyond that though, the research helps confirm the cyclical nature of the plague; over time, it loses its effectiveness and goes into hiding, only to mutate and come roaring back. This is a story with absolutely no relevance at all to the modern world. Nope, no plagues or pandemics going around right now, no viruses fading into the background in any way. What a ridiculous inference to make.
 

Uncovering the invisible with artificial intelligence

This week in “What Else Can AI Do?” new research shows that a computer program can reveal brain injury that couldn’t be seen before with typical MRI.

The hot new AI, birthed by researchers at New York University, could potentially be a game changer by linking repeated head impacts with tiny, structural changes in the brains of athletes who have not been diagnosed with a concussion. By using machine learning to train the AI, the researchers were, for the first time, able to distinguish the brain of athletes who played contact sports (football, soccer, lacrosse) from those participating in noncontact sports such as baseball, basketball, and cross-country.

Andrea Danti/Thinkstock

How did they do it? The investigators “designed statistical techniques that gave their computer program the ability to ‘learn’ how to predict exposure to repeated head impacts using mathematical models,” they explained in a written statement. Adding in data from the MRI scans of 81 male athletes with no known concussion diagnosis and the ability to identify unusual brain features between athletes with and without head trauma allowed the AI to predict results with accuracy even Miss Cleo would envy.

“This method may provide an important diagnostic tool not only for concussion, but also for detecting the damage that stems from subtler and more frequent head impacts,” said lead author Junbo Chen, an engineering doctoral candidate at NYU. That could make this new AI a valuable asset to science and medicine.

There are many things the human brain can do that AI can’t, and delegation could be one of them. Examining the data that represent the human brain in minute detail? Maybe we leave that to the machine.
 

Talk about your field promotions

If you’re a surgeon doing an amputation, the list of possible assistants pretty much starts and ends in only one place: Not the closest available janitor.

That may seem like an oddly obvious thing for us to say, but there’s at least one former Mainz (Germany) University Hospital physician who really needed to get this bit of advice before he attempted an unassisted toe amputation back in October of 2020. Yes, that does seem like kind of a long time ago for us to be reporting it now, but the details of the incident only just came to light a few days ago, thanks to German public broadcaster SWR.

Ente75/Wikipedia

Since it was just a toe, the surgeon thought he could perform the operation without any help. The toe, unfortunately, had other plans. The partially anesthetized patient got restless in the operating room, but with no actual trained nurse in the vicinity, the surgeon asked the closest available person – that would be the janitor – to lend a hand.

The surgical manager heard about these goings-on and got to the operating room too late to stop the procedure but soon enough to see the cleaning staffer “at the operating table with a bloody suction cup and a bloody compress in their hands,” SWR recently reported.

The incident was reported to the hospital’s medical director and the surgeon was fired, but since the patient experienced no complications not much fuss was made about it at the time.

Well, guess what? It’s toe-tally our job to make a fuss about these kinds of things. Or could it be that our job, much like the surgeon’s employment and the patient’s digit, is here toe-day and gone toe-morrow?

Even the plague wanted to visit Stonehenge

We’re about to blow your mind: The history you learned in school was often inaccurate. Shocking, we know, so we’ll give you a minute to process this incredible news.

Better? Good. Now, let’s look back at high school European history. The Black Death, specifically. The common narrative is that the Mongols, while besieging a Crimean city belonging to the Genoese, catapulted dead bodies infected with some mystery disease that turned out to be the plague. The Genoese then brought the plague back to Italy, and from there, we all know the rest of the story.

Ian Hodkinson, [email protected]

The Black Death was certainly extremely important to the development of modern Europe as we know it, but the history books gloss over the much longer history of the plague. Yersinia pestis did not suddenly appear unbidden in a Mongol war camp in 1347. The Black Death wasn’t even the first horrific, continent-wide pandemic caused by the plague; the Plague of Justinian 800 years earlier crippled the Byzantine Empire during an expansionist phase and killed anywhere between 15 million and 100 million.

Today, though, LOTME looks even deeper into history, nearly beyond even history itself, back into the depths of early Bronze Age northern Europe. Specifically, to two ancient burial sites in England, where researchers have identified three 4,000-year-old cases of Y. pestis, the first recorded incidence of the disease in Britain.

Two of the individuals, identified through analysis of dental pulp, were young children buried at a mass grave in Somerset, while the third, a middle-aged woman, was found in a ring cairn in Cumbria. These sites are hundreds of miles apart, yet carbon dating suggests all three people lived and died at roughly the same time. The strain found is very similar to other samples of plague found across central and western Europe starting around 3,000 BCE, suggesting a single, easily spread disease affecting a large area in a relatively small period of time. In other words, a pandemic. Even in these ancient times, the world was connected. Not even the island of Britain could escape.

Beyond that though, the research helps confirm the cyclical nature of the plague; over time, it loses its effectiveness and goes into hiding, only to mutate and come roaring back. This is a story with absolutely no relevance at all to the modern world. Nope, no plagues or pandemics going around right now, no viruses fading into the background in any way. What a ridiculous inference to make.
 

Uncovering the invisible with artificial intelligence

This week in “What Else Can AI Do?” new research shows that a computer program can reveal brain injury that couldn’t be seen before with typical MRI.

The hot new AI, birthed by researchers at New York University, could potentially be a game changer by linking repeated head impacts with tiny, structural changes in the brains of athletes who have not been diagnosed with a concussion. By using machine learning to train the AI, the researchers were, for the first time, able to distinguish the brain of athletes who played contact sports (football, soccer, lacrosse) from those participating in noncontact sports such as baseball, basketball, and cross-country.

Andrea Danti/Thinkstock

How did they do it? The investigators “designed statistical techniques that gave their computer program the ability to ‘learn’ how to predict exposure to repeated head impacts using mathematical models,” they explained in a written statement. Adding in data from the MRI scans of 81 male athletes with no known concussion diagnosis and the ability to identify unusual brain features between athletes with and without head trauma allowed the AI to predict results with accuracy even Miss Cleo would envy.

“This method may provide an important diagnostic tool not only for concussion, but also for detecting the damage that stems from subtler and more frequent head impacts,” said lead author Junbo Chen, an engineering doctoral candidate at NYU. That could make this new AI a valuable asset to science and medicine.

There are many things the human brain can do that AI can’t, and delegation could be one of them. Examining the data that represent the human brain in minute detail? Maybe we leave that to the machine.
 

Talk about your field promotions

If you’re a surgeon doing an amputation, the list of possible assistants pretty much starts and ends in only one place: Not the closest available janitor.

That may seem like an oddly obvious thing for us to say, but there’s at least one former Mainz (Germany) University Hospital physician who really needed to get this bit of advice before he attempted an unassisted toe amputation back in October of 2020. Yes, that does seem like kind of a long time ago for us to be reporting it now, but the details of the incident only just came to light a few days ago, thanks to German public broadcaster SWR.

Ente75/Wikipedia

Since it was just a toe, the surgeon thought he could perform the operation without any help. The toe, unfortunately, had other plans. The partially anesthetized patient got restless in the operating room, but with no actual trained nurse in the vicinity, the surgeon asked the closest available person – that would be the janitor – to lend a hand.

The surgical manager heard about these goings-on and got to the operating room too late to stop the procedure but soon enough to see the cleaning staffer “at the operating table with a bloody suction cup and a bloody compress in their hands,” SWR recently reported.

The incident was reported to the hospital’s medical director and the surgeon was fired, but since the patient experienced no complications not much fuss was made about it at the time.

Well, guess what? It’s toe-tally our job to make a fuss about these kinds of things. Or could it be that our job, much like the surgeon’s employment and the patient’s digit, is here toe-day and gone toe-morrow?

Treatment of chronic back pain remains a challenge for primary care physicians, and a new Cochrane Review confirms previous studies suggesting that analgesics and antidepressants fall short in terms of relief.

Data from another Cochrane Review support the value of exercise for chronic low back pain, although it is often underused, and the Food and Drug Administration’s recent approval of a spinal cord stimulation device for chronic back pain opens the door for another alternative.

Regardless of treatment type, however, patients report that empathy and clear communication from their doctors go a long way in their satisfaction with pain management, according to another recent study.
 

Exercise helps when patients adhere

The objective of the Cochrane Review on “Exercise therapy for chronic low back pain” was to determine whether exercise improves pain and functioning for people with chronic low back pain, compared with no treatment, usual care, or other common treatments, corresponding author Jill Hayden, PhD, of Dalhousie University, Halifax, N.S., said in an interview.

When back pain is chronic, it is expensive in terms of health care costs and lost work hours, said Dr. Hayden. “Exercise is promoted in many guidelines and is often recommended for, and used by, people with chronic low back pain.” However, “systematic reviews have found only small treatment effects, with considerable variation across individual trials.”

The 2021 review is one of the largest in the Cochrane Library, and included 249 trials and 24,486 study participants. However, Dr. Hayden said she had been disappointed by the methodological limitations of many of the trials. “The field is saturated with small exercise trials, many of which suffer from poor planning, conduct, and reporting due to limited resources.”

In the current review, “we found that exercise is likely to be effective for chronic low back pain. Overall, 3 months after the start of treatment, people receiving exercise treatment rated their pain an average of 15 points better on a scale of 0-100, and functional limitations were 7 points better, compared to people who had no treatment or usual care,” said Dr. Hayden.

Barriers to the use of exercise to treat pain may include fear of movement on the part of patients, she noted.

“Although our related network meta-analysis found some differences between specific types of exercise, we found all exercise types are more effective than minimal treatment,” she said. “People with chronic low back pain should be encouraged to do exercises that they enjoy and will do consistently to promote adherence.”
 

Limitations of medications

Both the safety and effectiveness of analgesics and antidepressants for pain in general and back pain in particular have come under scrutiny in recent research. A study published online in the British Medical Journal of patients with acute low back pain found that, although some medications were associated with large reductions in pain intensity, compared with placebo, the quality of the studies was “low or very low confidence,” according to a Medscape report on the findings.

This conclusion was supported in a large-scale analysis of the safety and effectiveness of antidepressants in chronic pain conditions, including back pain.

A new Cochrane Review led by a team of researchers in the United Kingdom found inadequate evidence to support the effectiveness of most antidepressants used for chronic pain, including amitriptyline, fluoxetine, citalopram, paroxetine, sertraline, and duloxetine.

“While chronic pain remains one of the top causes of daily disability worldwide, clinicians’ choices at offering interventions are getting fewer, especially if they tend toward a medical model and want a pharmacological solution,” corresponding author Tamar Pincus, PhD, of the University of Southampton (England), said in an interview. “We now know that opioids harm patients, and the evidence for common analgesics such as paracetamol and ibuprofen, for some conditions such as back pain, suggest they are not effective and might cause harm. This leaves clinicians with few options, and the most common prescription, supported by guidelines, is antidepressants.”

The study found moderate evidence that duloxetine can reduce pain in the short term and improve physical activity and some evidence that milnacipran might also be effective, Dr. Pincus said. “For all other antidepressants, including the commonly prescribed amitriptyline, the evidence was poor. Of importance, the average length of trials was 10 weeks, so long-term effects for all antidepressants remain unknown, and side effects and adverse events were reported poorly, so we also don’t know if any antidepressants are harmful.”

The takeaway message for the management of back pain in particular? “If a clinician and a patient decide together that it would be a good idea to try an antidepressant to reduce pain, they should consider starting with duloxetine, the drug with supporting evidence,” she said.
 

Physician attitude matters

Antidepressants may not have much impact on chronic pain, but a physician’s empathy and support do, according to data from a registry study of more than 1,300 individuals.

Despite efforts and guidelines from multiple medical organizations to promote optimal pain management, “much remains unknown regarding how the patient-physician interaction affects the process of delivering medical care for chronic low back pain and, ultimately, patient satisfaction,” John C. Licciardone, DO, of the University of North Texas Health Science Center, Fort Worth, and colleagues wrote in Annals of Family Medicine.

Previous studies have examined the relationship between clinical outcomes and patient satisfaction, but data on patient satisfaction with medical care for chronic low back pain specifically are limited, they said.

The researchers reviewed data from a national pain registry of adults aged 21-79 years that included self-reported measures of physician communication and empathy, prescribing data for opioids, and outcomes data for pain intensity, physical function, and health-related quality of life.

In a multivariate analysis, physician empathy and physician communication showed the strongest associations with patient satisfaction (P < .001).

The researchers found a negligible correlation between opioid prescription and perceived physician empathy and communication, “although current physician prescribing of opioids was also associated with patient satisfaction,” they wrote.

“Our findings pertaining to physician empathy are intriguing because they do not necessarily involve a therapeutic alliance with the patient based on collaborative communication or the expectation of a therapeutic effect via pharmacotherapy,” the researchers wrote .

The findings were limited by several factors including the cross-sectional design that prevented conclusions about cause and effect, the researchers noted. “It is possible that prior improvements in pain intensity, physical function, or [health-related quality of life] might have prompted participants to report more favorable ratings for physician empathy, physician communication, or patient satisfaction at registry enrollment.” However, the study supports the view that patients with low back pain in particular value physicians who validate their concerns and symptoms, and who make an effort to communicate treatment plans clearly.
 

Back pain patients continue to challenge primary care

“Back pain is a major issue in U.S. health care, in part because too many people have tough physical jobs or longstanding injuries that become chronic,” William Golden, MD, professor of medicine and public health at the University of Arkansas for Medical Sciences, Little Rock, said in an interview.

“There are no magic bullets for a lot of back pain patients, so empathy and support are key drivers,” he noted. “Helping patients maximize functionality as opposed to seeking mythical cures is the stronger line of visit discussions, but that takes a bit of time and skill in interviewing.

“It is fairly well established that duloxetine is useful in pain management, especially when present with mood disorders, either primary or secondary to the back-related disability,” said Dr. Golden. “Greater dissemination of its utility is probably useful, as is the side effect profile of the drug as well,” given the “nasty discontinuation syndrome when the treatment is reduced or stopped.”

Looking ahead, “more research is needed about microsurgery, namely for whom and for what anatomic presentations,” said Dr. Golden. Other topics for further research include a better understanding about medical marijuana and pain management and its interactions and side effects with other opioids and muscle relaxants. “Polypharmacy is still an issue in this class of patient,” and many of these patients are frustrated and angry “so the psychosocial skills of the PCP can be greatly tested as well,” he said.
 

Empathy promotes patient adherence to treatment

The new opioid prescription guidelines have increased interest among clinicians in how to improve patient satisfaction with the care for back pain provided, Noel Deep, MD, said in an interview. “These studies address this concern and bring forth an important aspect of the physician-patient relationship, namely the human touch and empathy.”

“I have been a strong proponent of the trust and relationship between a physician and patient; displaying empathy and increased and transparent communication between the physician and the patient has always resulted in better relationships and better outcomes for patients, especially those dealing with chronic health concerns,” said Dr. Deep, who is a general internist in a multispecialty group practice with Aspirus Antigo (Wisc.) Clinic and the chief medical officer and a staff physician at Aspirus Langlade Hospital, also in Antigo.

Potential barriers to effective pain management include beliefs and attitudes on the part of patients, Dr. Deep noted. “Physicians lacking adequate time to communicate effectively with the patient and describe nonopioid and nonsurgical interventions would be another potential barrier.” Other issues include the time and effort, as well as cost, associated with interventions such as physical therapy and other nondrug and nonsurgical interventions. Issues with family and social support and health literacy are also potential barriers to pain management.
 

Clinical takeaways

Low back pain is one of the most common reasons for a visit in primary care and can be “chronic and debilitating,” Grace Lin, MD, an internal medicine physician and primary care provider at the University of California, San Francisco, said in an interview.

“One issue with the Cochrane Review on exercise is that the studies on exercise were heterogeneous, so it’s difficult to know whether there is a particular kind of exercise that would be most effective and should be recommended to patients,” she said.

Furthermore, she said, “there is a physical therapist shortage in the U.S. I practice in a major city with a large health care system, and it can still take months to get an appointment with a physical therapist.” Also, insurance coverage may limit which therapists a patient can see and how many visits they can have.

“On the clinician side, I think physicians need to be better informed about the evidence base for back pain treatment, namely that exercise is effective and that, long term, analgesics are not,” Dr. Lin said. “This might decrease overprescription of ineffective analgesics and encourage more education about and referrals to physical therapy.”

“Physicians should continue to educate patients that physical therapy is the first-line treatment for back pain and that pain medications are secondary,” she said. “I think that analgesics can be effective for the short term to get people to a point where they feel well enough to do physical therapy. Duloxetine also appears to be moderately effective for chronic low back pain, in part because it may also help address coexisting depression and anxiety,” but these options should be reserved for adjuncts to physical therapy for back pain.

The findings from the study on empathy and communication suggest that the main challenges to these behaviors are systemic, said Dr. Lin.

“Our health care system is not conducive to treating chronic back pain,” she said. Primary care visits that last for 15 or 20 minutes are not long enough to diagnose and counsel patients on such a complex problem as chronic low back pain. Since back pain is usually not the only issue the primary care physician is dealing with during that visit, this can lead to patients feeling like their doctor isn’t listening to them and doesn’t care about their pain.

“We need to better understand the mechanisms by which people develop chronic, debilitating back pain,” Dr. Lin said. “I think if we understood this better, more effective and targeted treatments, both pharmacological and nonpharmacological, could be developed.”

The Annals of Family Medicine study received no outside funding, and the researchers had no financial conflicts to disclose. The Cochrane Reviews was supported by the National Institute for Health and Care Research’s Health Technology Assessment program, and the authors had no financial conflicts to disclose. Dr. Golden and Dr. Deep had no financial conflicts to disclose and serve on the editorial advisory board of Internal Medicine News. Dr. Lin disclosed receiving research funding from the Institute for Clinical and Economic Review and the National Institutes of Health.

Treatment of chronic back pain remains a challenge for primary care physicians, and a new Cochrane Review confirms previous studies suggesting that analgesics and antidepressants fall short in terms of relief.

Data from another Cochrane Review support the value of exercise for chronic low back pain, although it is often underused, and the Food and Drug Administration’s recent approval of a spinal cord stimulation device for chronic back pain opens the door for another alternative.

Regardless of treatment type, however, patients report that empathy and clear communication from their doctors go a long way in their satisfaction with pain management, according to another recent study.
 

Exercise helps when patients adhere

The objective of the Cochrane Review on “Exercise therapy for chronic low back pain” was to determine whether exercise improves pain and functioning for people with chronic low back pain, compared with no treatment, usual care, or other common treatments, corresponding author Jill Hayden, PhD, of Dalhousie University, Halifax, N.S., said in an interview.

When back pain is chronic, it is expensive in terms of health care costs and lost work hours, said Dr. Hayden. “Exercise is promoted in many guidelines and is often recommended for, and used by, people with chronic low back pain.” However, “systematic reviews have found only small treatment effects, with considerable variation across individual trials.”

The 2021 review is one of the largest in the Cochrane Library, and included 249 trials and 24,486 study participants. However, Dr. Hayden said she had been disappointed by the methodological limitations of many of the trials. “The field is saturated with small exercise trials, many of which suffer from poor planning, conduct, and reporting due to limited resources.”

In the current review, “we found that exercise is likely to be effective for chronic low back pain. Overall, 3 months after the start of treatment, people receiving exercise treatment rated their pain an average of 15 points better on a scale of 0-100, and functional limitations were 7 points better, compared to people who had no treatment or usual care,” said Dr. Hayden.

Barriers to the use of exercise to treat pain may include fear of movement on the part of patients, she noted.

“Although our related network meta-analysis found some differences between specific types of exercise, we found all exercise types are more effective than minimal treatment,” she said. “People with chronic low back pain should be encouraged to do exercises that they enjoy and will do consistently to promote adherence.”
 

Limitations of medications

Both the safety and effectiveness of analgesics and antidepressants for pain in general and back pain in particular have come under scrutiny in recent research. A study published online in the British Medical Journal of patients with acute low back pain found that, although some medications were associated with large reductions in pain intensity, compared with placebo, the quality of the studies was “low or very low confidence,” according to a Medscape report on the findings.

This conclusion was supported in a large-scale analysis of the safety and effectiveness of antidepressants in chronic pain conditions, including back pain.

A new Cochrane Review led by a team of researchers in the United Kingdom found inadequate evidence to support the effectiveness of most antidepressants used for chronic pain, including amitriptyline, fluoxetine, citalopram, paroxetine, sertraline, and duloxetine.

“While chronic pain remains one of the top causes of daily disability worldwide, clinicians’ choices at offering interventions are getting fewer, especially if they tend toward a medical model and want a pharmacological solution,” corresponding author Tamar Pincus, PhD, of the University of Southampton (England), said in an interview. “We now know that opioids harm patients, and the evidence for common analgesics such as paracetamol and ibuprofen, for some conditions such as back pain, suggest they are not effective and might cause harm. This leaves clinicians with few options, and the most common prescription, supported by guidelines, is antidepressants.”

The study found moderate evidence that duloxetine can reduce pain in the short term and improve physical activity and some evidence that milnacipran might also be effective, Dr. Pincus said. “For all other antidepressants, including the commonly prescribed amitriptyline, the evidence was poor. Of importance, the average length of trials was 10 weeks, so long-term effects for all antidepressants remain unknown, and side effects and adverse events were reported poorly, so we also don’t know if any antidepressants are harmful.”

The takeaway message for the management of back pain in particular? “If a clinician and a patient decide together that it would be a good idea to try an antidepressant to reduce pain, they should consider starting with duloxetine, the drug with supporting evidence,” she said.
 

Physician attitude matters

Antidepressants may not have much impact on chronic pain, but a physician’s empathy and support do, according to data from a registry study of more than 1,300 individuals.

Despite efforts and guidelines from multiple medical organizations to promote optimal pain management, “much remains unknown regarding how the patient-physician interaction affects the process of delivering medical care for chronic low back pain and, ultimately, patient satisfaction,” John C. Licciardone, DO, of the University of North Texas Health Science Center, Fort Worth, and colleagues wrote in Annals of Family Medicine.

Previous studies have examined the relationship between clinical outcomes and patient satisfaction, but data on patient satisfaction with medical care for chronic low back pain specifically are limited, they said.

The researchers reviewed data from a national pain registry of adults aged 21-79 years that included self-reported measures of physician communication and empathy, prescribing data for opioids, and outcomes data for pain intensity, physical function, and health-related quality of life.

In a multivariate analysis, physician empathy and physician communication showed the strongest associations with patient satisfaction (P < .001).

The researchers found a negligible correlation between opioid prescription and perceived physician empathy and communication, “although current physician prescribing of opioids was also associated with patient satisfaction,” they wrote.

“Our findings pertaining to physician empathy are intriguing because they do not necessarily involve a therapeutic alliance with the patient based on collaborative communication or the expectation of a therapeutic effect via pharmacotherapy,” the researchers wrote .

The findings were limited by several factors including the cross-sectional design that prevented conclusions about cause and effect, the researchers noted. “It is possible that prior improvements in pain intensity, physical function, or [health-related quality of life] might have prompted participants to report more favorable ratings for physician empathy, physician communication, or patient satisfaction at registry enrollment.” However, the study supports the view that patients with low back pain in particular value physicians who validate their concerns and symptoms, and who make an effort to communicate treatment plans clearly.
 

Back pain patients continue to challenge primary care

“Back pain is a major issue in U.S. health care, in part because too many people have tough physical jobs or longstanding injuries that become chronic,” William Golden, MD, professor of medicine and public health at the University of Arkansas for Medical Sciences, Little Rock, said in an interview.

“There are no magic bullets for a lot of back pain patients, so empathy and support are key drivers,” he noted. “Helping patients maximize functionality as opposed to seeking mythical cures is the stronger line of visit discussions, but that takes a bit of time and skill in interviewing.

“It is fairly well established that duloxetine is useful in pain management, especially when present with mood disorders, either primary or secondary to the back-related disability,” said Dr. Golden. “Greater dissemination of its utility is probably useful, as is the side effect profile of the drug as well,” given the “nasty discontinuation syndrome when the treatment is reduced or stopped.”

Looking ahead, “more research is needed about microsurgery, namely for whom and for what anatomic presentations,” said Dr. Golden. Other topics for further research include a better understanding about medical marijuana and pain management and its interactions and side effects with other opioids and muscle relaxants. “Polypharmacy is still an issue in this class of patient,” and many of these patients are frustrated and angry “so the psychosocial skills of the PCP can be greatly tested as well,” he said.
 

Empathy promotes patient adherence to treatment

The new opioid prescription guidelines have increased interest among clinicians in how to improve patient satisfaction with the care for back pain provided, Noel Deep, MD, said in an interview. “These studies address this concern and bring forth an important aspect of the physician-patient relationship, namely the human touch and empathy.”

“I have been a strong proponent of the trust and relationship between a physician and patient; displaying empathy and increased and transparent communication between the physician and the patient has always resulted in better relationships and better outcomes for patients, especially those dealing with chronic health concerns,” said Dr. Deep, who is a general internist in a multispecialty group practice with Aspirus Antigo (Wisc.) Clinic and the chief medical officer and a staff physician at Aspirus Langlade Hospital, also in Antigo.

Potential barriers to effective pain management include beliefs and attitudes on the part of patients, Dr. Deep noted. “Physicians lacking adequate time to communicate effectively with the patient and describe nonopioid and nonsurgical interventions would be another potential barrier.” Other issues include the time and effort, as well as cost, associated with interventions such as physical therapy and other nondrug and nonsurgical interventions. Issues with family and social support and health literacy are also potential barriers to pain management.
 

Clinical takeaways

Low back pain is one of the most common reasons for a visit in primary care and can be “chronic and debilitating,” Grace Lin, MD, an internal medicine physician and primary care provider at the University of California, San Francisco, said in an interview.

“One issue with the Cochrane Review on exercise is that the studies on exercise were heterogeneous, so it’s difficult to know whether there is a particular kind of exercise that would be most effective and should be recommended to patients,” she said.

Furthermore, she said, “there is a physical therapist shortage in the U.S. I practice in a major city with a large health care system, and it can still take months to get an appointment with a physical therapist.” Also, insurance coverage may limit which therapists a patient can see and how many visits they can have.

“On the clinician side, I think physicians need to be better informed about the evidence base for back pain treatment, namely that exercise is effective and that, long term, analgesics are not,” Dr. Lin said. “This might decrease overprescription of ineffective analgesics and encourage more education about and referrals to physical therapy.”

“Physicians should continue to educate patients that physical therapy is the first-line treatment for back pain and that pain medications are secondary,” she said. “I think that analgesics can be effective for the short term to get people to a point where they feel well enough to do physical therapy. Duloxetine also appears to be moderately effective for chronic low back pain, in part because it may also help address coexisting depression and anxiety,” but these options should be reserved for adjuncts to physical therapy for back pain.

The findings from the study on empathy and communication suggest that the main challenges to these behaviors are systemic, said Dr. Lin.

“Our health care system is not conducive to treating chronic back pain,” she said. Primary care visits that last for 15 or 20 minutes are not long enough to diagnose and counsel patients on such a complex problem as chronic low back pain. Since back pain is usually not the only issue the primary care physician is dealing with during that visit, this can lead to patients feeling like their doctor isn’t listening to them and doesn’t care about their pain.

“We need to better understand the mechanisms by which people develop chronic, debilitating back pain,” Dr. Lin said. “I think if we understood this better, more effective and targeted treatments, both pharmacological and nonpharmacological, could be developed.”

The Annals of Family Medicine study received no outside funding, and the researchers had no financial conflicts to disclose. The Cochrane Reviews was supported by the National Institute for Health and Care Research’s Health Technology Assessment program, and the authors had no financial conflicts to disclose. Dr. Golden and Dr. Deep had no financial conflicts to disclose and serve on the editorial advisory board of Internal Medicine News. Dr. Lin disclosed receiving research funding from the Institute for Clinical and Economic Review and the National Institutes of Health.

Treatment of chronic back pain remains a challenge for primary care physicians, and a new Cochrane Review confirms previous studies suggesting that analgesics and antidepressants fall short in terms of relief.

Data from another Cochrane Review support the value of exercise for chronic low back pain, although it is often underused, and the Food and Drug Administration’s recent approval of a spinal cord stimulation device for chronic back pain opens the door for another alternative.

Regardless of treatment type, however, patients report that empathy and clear communication from their doctors go a long way in their satisfaction with pain management, according to another recent study.
 

Exercise helps when patients adhere

The objective of the Cochrane Review on “Exercise therapy for chronic low back pain” was to determine whether exercise improves pain and functioning for people with chronic low back pain, compared with no treatment, usual care, or other common treatments, corresponding author Jill Hayden, PhD, of Dalhousie University, Halifax, N.S., said in an interview.

When back pain is chronic, it is expensive in terms of health care costs and lost work hours, said Dr. Hayden. “Exercise is promoted in many guidelines and is often recommended for, and used by, people with chronic low back pain.” However, “systematic reviews have found only small treatment effects, with considerable variation across individual trials.”

The 2021 review is one of the largest in the Cochrane Library, and included 249 trials and 24,486 study participants. However, Dr. Hayden said she had been disappointed by the methodological limitations of many of the trials. “The field is saturated with small exercise trials, many of which suffer from poor planning, conduct, and reporting due to limited resources.”

In the current review, “we found that exercise is likely to be effective for chronic low back pain. Overall, 3 months after the start of treatment, people receiving exercise treatment rated their pain an average of 15 points better on a scale of 0-100, and functional limitations were 7 points better, compared to people who had no treatment or usual care,” said Dr. Hayden.

Barriers to the use of exercise to treat pain may include fear of movement on the part of patients, she noted.

“Although our related network meta-analysis found some differences between specific types of exercise, we found all exercise types are more effective than minimal treatment,” she said. “People with chronic low back pain should be encouraged to do exercises that they enjoy and will do consistently to promote adherence.”
 

Limitations of medications

Both the safety and effectiveness of analgesics and antidepressants for pain in general and back pain in particular have come under scrutiny in recent research. A study published online in the British Medical Journal of patients with acute low back pain found that, although some medications were associated with large reductions in pain intensity, compared with placebo, the quality of the studies was “low or very low confidence,” according to a Medscape report on the findings.

This conclusion was supported in a large-scale analysis of the safety and effectiveness of antidepressants in chronic pain conditions, including back pain.

A new Cochrane Review led by a team of researchers in the United Kingdom found inadequate evidence to support the effectiveness of most antidepressants used for chronic pain, including amitriptyline, fluoxetine, citalopram, paroxetine, sertraline, and duloxetine.

“While chronic pain remains one of the top causes of daily disability worldwide, clinicians’ choices at offering interventions are getting fewer, especially if they tend toward a medical model and want a pharmacological solution,” corresponding author Tamar Pincus, PhD, of the University of Southampton (England), said in an interview. “We now know that opioids harm patients, and the evidence for common analgesics such as paracetamol and ibuprofen, for some conditions such as back pain, suggest they are not effective and might cause harm. This leaves clinicians with few options, and the most common prescription, supported by guidelines, is antidepressants.”

The study found moderate evidence that duloxetine can reduce pain in the short term and improve physical activity and some evidence that milnacipran might also be effective, Dr. Pincus said. “For all other antidepressants, including the commonly prescribed amitriptyline, the evidence was poor. Of importance, the average length of trials was 10 weeks, so long-term effects for all antidepressants remain unknown, and side effects and adverse events were reported poorly, so we also don’t know if any antidepressants are harmful.”

The takeaway message for the management of back pain in particular? “If a clinician and a patient decide together that it would be a good idea to try an antidepressant to reduce pain, they should consider starting with duloxetine, the drug with supporting evidence,” she said.
 

Physician attitude matters

Antidepressants may not have much impact on chronic pain, but a physician’s empathy and support do, according to data from a registry study of more than 1,300 individuals.

Despite efforts and guidelines from multiple medical organizations to promote optimal pain management, “much remains unknown regarding how the patient-physician interaction affects the process of delivering medical care for chronic low back pain and, ultimately, patient satisfaction,” John C. Licciardone, DO, of the University of North Texas Health Science Center, Fort Worth, and colleagues wrote in Annals of Family Medicine.

Previous studies have examined the relationship between clinical outcomes and patient satisfaction, but data on patient satisfaction with medical care for chronic low back pain specifically are limited, they said.

The researchers reviewed data from a national pain registry of adults aged 21-79 years that included self-reported measures of physician communication and empathy, prescribing data for opioids, and outcomes data for pain intensity, physical function, and health-related quality of life.

In a multivariate analysis, physician empathy and physician communication showed the strongest associations with patient satisfaction (P < .001).

The researchers found a negligible correlation between opioid prescription and perceived physician empathy and communication, “although current physician prescribing of opioids was also associated with patient satisfaction,” they wrote.

“Our findings pertaining to physician empathy are intriguing because they do not necessarily involve a therapeutic alliance with the patient based on collaborative communication or the expectation of a therapeutic effect via pharmacotherapy,” the researchers wrote .

The findings were limited by several factors including the cross-sectional design that prevented conclusions about cause and effect, the researchers noted. “It is possible that prior improvements in pain intensity, physical function, or [health-related quality of life] might have prompted participants to report more favorable ratings for physician empathy, physician communication, or patient satisfaction at registry enrollment.” However, the study supports the view that patients with low back pain in particular value physicians who validate their concerns and symptoms, and who make an effort to communicate treatment plans clearly.
 

Back pain patients continue to challenge primary care

“Back pain is a major issue in U.S. health care, in part because too many people have tough physical jobs or longstanding injuries that become chronic,” William Golden, MD, professor of medicine and public health at the University of Arkansas for Medical Sciences, Little Rock, said in an interview.

“There are no magic bullets for a lot of back pain patients, so empathy and support are key drivers,” he noted. “Helping patients maximize functionality as opposed to seeking mythical cures is the stronger line of visit discussions, but that takes a bit of time and skill in interviewing.

“It is fairly well established that duloxetine is useful in pain management, especially when present with mood disorders, either primary or secondary to the back-related disability,” said Dr. Golden. “Greater dissemination of its utility is probably useful, as is the side effect profile of the drug as well,” given the “nasty discontinuation syndrome when the treatment is reduced or stopped.”

Looking ahead, “more research is needed about microsurgery, namely for whom and for what anatomic presentations,” said Dr. Golden. Other topics for further research include a better understanding about medical marijuana and pain management and its interactions and side effects with other opioids and muscle relaxants. “Polypharmacy is still an issue in this class of patient,” and many of these patients are frustrated and angry “so the psychosocial skills of the PCP can be greatly tested as well,” he said.
 

Empathy promotes patient adherence to treatment

The new opioid prescription guidelines have increased interest among clinicians in how to improve patient satisfaction with the care for back pain provided, Noel Deep, MD, said in an interview. “These studies address this concern and bring forth an important aspect of the physician-patient relationship, namely the human touch and empathy.”

“I have been a strong proponent of the trust and relationship between a physician and patient; displaying empathy and increased and transparent communication between the physician and the patient has always resulted in better relationships and better outcomes for patients, especially those dealing with chronic health concerns,” said Dr. Deep, who is a general internist in a multispecialty group practice with Aspirus Antigo (Wisc.) Clinic and the chief medical officer and a staff physician at Aspirus Langlade Hospital, also in Antigo.

Potential barriers to effective pain management include beliefs and attitudes on the part of patients, Dr. Deep noted. “Physicians lacking adequate time to communicate effectively with the patient and describe nonopioid and nonsurgical interventions would be another potential barrier.” Other issues include the time and effort, as well as cost, associated with interventions such as physical therapy and other nondrug and nonsurgical interventions. Issues with family and social support and health literacy are also potential barriers to pain management.
 

Clinical takeaways

Low back pain is one of the most common reasons for a visit in primary care and can be “chronic and debilitating,” Grace Lin, MD, an internal medicine physician and primary care provider at the University of California, San Francisco, said in an interview.

“One issue with the Cochrane Review on exercise is that the studies on exercise were heterogeneous, so it’s difficult to know whether there is a particular kind of exercise that would be most effective and should be recommended to patients,” she said.

Furthermore, she said, “there is a physical therapist shortage in the U.S. I practice in a major city with a large health care system, and it can still take months to get an appointment with a physical therapist.” Also, insurance coverage may limit which therapists a patient can see and how many visits they can have.

“On the clinician side, I think physicians need to be better informed about the evidence base for back pain treatment, namely that exercise is effective and that, long term, analgesics are not,” Dr. Lin said. “This might decrease overprescription of ineffective analgesics and encourage more education about and referrals to physical therapy.”

“Physicians should continue to educate patients that physical therapy is the first-line treatment for back pain and that pain medications are secondary,” she said. “I think that analgesics can be effective for the short term to get people to a point where they feel well enough to do physical therapy. Duloxetine also appears to be moderately effective for chronic low back pain, in part because it may also help address coexisting depression and anxiety,” but these options should be reserved for adjuncts to physical therapy for back pain.

The findings from the study on empathy and communication suggest that the main challenges to these behaviors are systemic, said Dr. Lin.

“Our health care system is not conducive to treating chronic back pain,” she said. Primary care visits that last for 15 or 20 minutes are not long enough to diagnose and counsel patients on such a complex problem as chronic low back pain. Since back pain is usually not the only issue the primary care physician is dealing with during that visit, this can lead to patients feeling like their doctor isn’t listening to them and doesn’t care about their pain.

“We need to better understand the mechanisms by which people develop chronic, debilitating back pain,” Dr. Lin said. “I think if we understood this better, more effective and targeted treatments, both pharmacological and nonpharmacological, could be developed.”

The Annals of Family Medicine study received no outside funding, and the researchers had no financial conflicts to disclose. The Cochrane Reviews was supported by the National Institute for Health and Care Research’s Health Technology Assessment program, and the authors had no financial conflicts to disclose. Dr. Golden and Dr. Deep had no financial conflicts to disclose and serve on the editorial advisory board of Internal Medicine News. Dr. Lin disclosed receiving research funding from the Institute for Clinical and Economic Review and the National Institutes of Health.