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Gene ‘cut-and-paste’ treatment could offer hope for inherited immune system diseases
An “exciting” new gene-editing strategy means those born with a rare inherited disease of the immune system could be treated by repairing a fault in their cells.
CTLA-4 is a protein produced by T cells that helps to control the activity of the immune system. Most people carry two working copies of the gene responsible for producing CTLA-4, but those who have only one functional copy produce too little of the protein to sufficiently regulate the immune system.
For patients with the condition, CTLA-4 insufficiency causes regulatory T cells to function abnormally, leading to severe autoimmunity. The authors explained that the condition also affects effector T cells and thereby “hampers their immune system’s ‘memory,’ ” meaning patients can “struggle to fight off recurring infections by the same viruses and bacteria.” In some cases, it can also lead to lymphomas.
Gene editing to ‘cut’ out faulty genes and ‘paste’ in ‘corrected’ ones
The research, published in Science Translational Medicine, and led by scientists from University College London, demonstrated in human cells and in mice that the cell fault can be repaired.
The scientists used “cut-and-paste” gene-editing techniques. First, they used the CRISPR/Cas9 system to target the faulty gene in human T cells taken from patients with CTLA-4 insufficiency, and then snip the faulty CTLA-4 gene in two. Then, to repair the errors a corrected sequence of DNA – delivered to the cell using a modified virus – was pasted over the faulty part of the gene using a cellular DNA repair mechanism known as homology-directed repair.
The authors explained that this allowed them to “preserve” important sequences within the CTLA-4 gene – known as the intron – that allow it to be switched on and off by the cell only when needed.
The outcome was “restored levels of CTLA-4 in the cells to those seen in healthy T cells,” the authors said.
Claire Booth, PhD, Mahboubian professor of gene therapy and pediatric immunology, UCL Great Ormond Street Institute of Child Health, and co–senior author, said that it was “really exciting” to think about taking this treatment forward to patients. “If we can improve their symptoms and reduce their risk of getting lymphoproliferative disease this will be a major step forward.”
In addition, the researchers were also able to improve symptoms of the disease in mice with CTLA-4 insufficiency by giving them injections of gene-edited T cells.
Technique may help tackle many conditions
The current standard treatment for CTLA-4 insufficiency is a bone marrow transplant to replace the stem cells responsible for producing T cells. However, “transplants are risky” and require high doses of chemotherapy and many weeks in hospital, the authors explained. “Older patients with CTLA-4 insufficiency are typically not well enough to tolerate the transplant procedure.”
Dr. Booth highlighted that the approach has many “positive aspects”. By correcting the patient’s T cells, “we think it can improve many of the symptoms of the disease”, she said, and added that this new approach is much less toxic than a bone marrow transplant. “Collecting the T cells is easier and correcting the T cells is easier. With this approach the amount of time in hospital the patients would need would be far less.”
Emma Morris, PhD, professor of clinical cell and gene therapy and director of UCL’s division of infection and immunity, and co–senior author, said: “Genes that play critical roles in controlling immune responses are not switched on all the time and are very tightly regulated. The technique we have used allows us to leave the natural (endogenous) mechanisms controlling gene expression intact, at the same time as correcting the mistake in the gene itself.”
The researchers explained that, although CTLA-4 insufficiency is rare, the gene editing therapy could be a proof of principle of their approach that could be adapted to tackle other conditions.
“It’s a way of correcting genetic mutations that could potentially be applicable for other diseases,” suggested Dr. Morris. “The bigger picture is it allows us to correct genes that are dysregulated or overactive, but also allows us to understand much more about gene expression and gene regulation.”
The study was funded by the Wellcome Trust, the Association for Moleculary Pathology, the Medical Research Council, Alzheimer’s Research UK, and the UCLH/UCL NIHR Biomedical Research Centre. Dr. Morris is a founder sharehold of Quell Therapeutics and has received honoraria from Orchard Therapeutics, GlaxoSmithKline, and AstraZeneca. Dr. Booth has performed ad hoc consulting in the past 3 years for SOBI and Novartis and educational material production for SOBI and Chiesi. A patent on the intronic gene editing approach has been filed in the UK. The other authors declared that they have no completing interests.
A version of this article first appeared on Medscape UK.
An “exciting” new gene-editing strategy means those born with a rare inherited disease of the immune system could be treated by repairing a fault in their cells.
CTLA-4 is a protein produced by T cells that helps to control the activity of the immune system. Most people carry two working copies of the gene responsible for producing CTLA-4, but those who have only one functional copy produce too little of the protein to sufficiently regulate the immune system.
For patients with the condition, CTLA-4 insufficiency causes regulatory T cells to function abnormally, leading to severe autoimmunity. The authors explained that the condition also affects effector T cells and thereby “hampers their immune system’s ‘memory,’ ” meaning patients can “struggle to fight off recurring infections by the same viruses and bacteria.” In some cases, it can also lead to lymphomas.
Gene editing to ‘cut’ out faulty genes and ‘paste’ in ‘corrected’ ones
The research, published in Science Translational Medicine, and led by scientists from University College London, demonstrated in human cells and in mice that the cell fault can be repaired.
The scientists used “cut-and-paste” gene-editing techniques. First, they used the CRISPR/Cas9 system to target the faulty gene in human T cells taken from patients with CTLA-4 insufficiency, and then snip the faulty CTLA-4 gene in two. Then, to repair the errors a corrected sequence of DNA – delivered to the cell using a modified virus – was pasted over the faulty part of the gene using a cellular DNA repair mechanism known as homology-directed repair.
The authors explained that this allowed them to “preserve” important sequences within the CTLA-4 gene – known as the intron – that allow it to be switched on and off by the cell only when needed.
The outcome was “restored levels of CTLA-4 in the cells to those seen in healthy T cells,” the authors said.
Claire Booth, PhD, Mahboubian professor of gene therapy and pediatric immunology, UCL Great Ormond Street Institute of Child Health, and co–senior author, said that it was “really exciting” to think about taking this treatment forward to patients. “If we can improve their symptoms and reduce their risk of getting lymphoproliferative disease this will be a major step forward.”
In addition, the researchers were also able to improve symptoms of the disease in mice with CTLA-4 insufficiency by giving them injections of gene-edited T cells.
Technique may help tackle many conditions
The current standard treatment for CTLA-4 insufficiency is a bone marrow transplant to replace the stem cells responsible for producing T cells. However, “transplants are risky” and require high doses of chemotherapy and many weeks in hospital, the authors explained. “Older patients with CTLA-4 insufficiency are typically not well enough to tolerate the transplant procedure.”
Dr. Booth highlighted that the approach has many “positive aspects”. By correcting the patient’s T cells, “we think it can improve many of the symptoms of the disease”, she said, and added that this new approach is much less toxic than a bone marrow transplant. “Collecting the T cells is easier and correcting the T cells is easier. With this approach the amount of time in hospital the patients would need would be far less.”
Emma Morris, PhD, professor of clinical cell and gene therapy and director of UCL’s division of infection and immunity, and co–senior author, said: “Genes that play critical roles in controlling immune responses are not switched on all the time and are very tightly regulated. The technique we have used allows us to leave the natural (endogenous) mechanisms controlling gene expression intact, at the same time as correcting the mistake in the gene itself.”
The researchers explained that, although CTLA-4 insufficiency is rare, the gene editing therapy could be a proof of principle of their approach that could be adapted to tackle other conditions.
“It’s a way of correcting genetic mutations that could potentially be applicable for other diseases,” suggested Dr. Morris. “The bigger picture is it allows us to correct genes that are dysregulated or overactive, but also allows us to understand much more about gene expression and gene regulation.”
The study was funded by the Wellcome Trust, the Association for Moleculary Pathology, the Medical Research Council, Alzheimer’s Research UK, and the UCLH/UCL NIHR Biomedical Research Centre. Dr. Morris is a founder sharehold of Quell Therapeutics and has received honoraria from Orchard Therapeutics, GlaxoSmithKline, and AstraZeneca. Dr. Booth has performed ad hoc consulting in the past 3 years for SOBI and Novartis and educational material production for SOBI and Chiesi. A patent on the intronic gene editing approach has been filed in the UK. The other authors declared that they have no completing interests.
A version of this article first appeared on Medscape UK.
An “exciting” new gene-editing strategy means those born with a rare inherited disease of the immune system could be treated by repairing a fault in their cells.
CTLA-4 is a protein produced by T cells that helps to control the activity of the immune system. Most people carry two working copies of the gene responsible for producing CTLA-4, but those who have only one functional copy produce too little of the protein to sufficiently regulate the immune system.
For patients with the condition, CTLA-4 insufficiency causes regulatory T cells to function abnormally, leading to severe autoimmunity. The authors explained that the condition also affects effector T cells and thereby “hampers their immune system’s ‘memory,’ ” meaning patients can “struggle to fight off recurring infections by the same viruses and bacteria.” In some cases, it can also lead to lymphomas.
Gene editing to ‘cut’ out faulty genes and ‘paste’ in ‘corrected’ ones
The research, published in Science Translational Medicine, and led by scientists from University College London, demonstrated in human cells and in mice that the cell fault can be repaired.
The scientists used “cut-and-paste” gene-editing techniques. First, they used the CRISPR/Cas9 system to target the faulty gene in human T cells taken from patients with CTLA-4 insufficiency, and then snip the faulty CTLA-4 gene in two. Then, to repair the errors a corrected sequence of DNA – delivered to the cell using a modified virus – was pasted over the faulty part of the gene using a cellular DNA repair mechanism known as homology-directed repair.
The authors explained that this allowed them to “preserve” important sequences within the CTLA-4 gene – known as the intron – that allow it to be switched on and off by the cell only when needed.
The outcome was “restored levels of CTLA-4 in the cells to those seen in healthy T cells,” the authors said.
Claire Booth, PhD, Mahboubian professor of gene therapy and pediatric immunology, UCL Great Ormond Street Institute of Child Health, and co–senior author, said that it was “really exciting” to think about taking this treatment forward to patients. “If we can improve their symptoms and reduce their risk of getting lymphoproliferative disease this will be a major step forward.”
In addition, the researchers were also able to improve symptoms of the disease in mice with CTLA-4 insufficiency by giving them injections of gene-edited T cells.
Technique may help tackle many conditions
The current standard treatment for CTLA-4 insufficiency is a bone marrow transplant to replace the stem cells responsible for producing T cells. However, “transplants are risky” and require high doses of chemotherapy and many weeks in hospital, the authors explained. “Older patients with CTLA-4 insufficiency are typically not well enough to tolerate the transplant procedure.”
Dr. Booth highlighted that the approach has many “positive aspects”. By correcting the patient’s T cells, “we think it can improve many of the symptoms of the disease”, she said, and added that this new approach is much less toxic than a bone marrow transplant. “Collecting the T cells is easier and correcting the T cells is easier. With this approach the amount of time in hospital the patients would need would be far less.”
Emma Morris, PhD, professor of clinical cell and gene therapy and director of UCL’s division of infection and immunity, and co–senior author, said: “Genes that play critical roles in controlling immune responses are not switched on all the time and are very tightly regulated. The technique we have used allows us to leave the natural (endogenous) mechanisms controlling gene expression intact, at the same time as correcting the mistake in the gene itself.”
The researchers explained that, although CTLA-4 insufficiency is rare, the gene editing therapy could be a proof of principle of their approach that could be adapted to tackle other conditions.
“It’s a way of correcting genetic mutations that could potentially be applicable for other diseases,” suggested Dr. Morris. “The bigger picture is it allows us to correct genes that are dysregulated or overactive, but also allows us to understand much more about gene expression and gene regulation.”
The study was funded by the Wellcome Trust, the Association for Moleculary Pathology, the Medical Research Council, Alzheimer’s Research UK, and the UCLH/UCL NIHR Biomedical Research Centre. Dr. Morris is a founder sharehold of Quell Therapeutics and has received honoraria from Orchard Therapeutics, GlaxoSmithKline, and AstraZeneca. Dr. Booth has performed ad hoc consulting in the past 3 years for SOBI and Novartis and educational material production for SOBI and Chiesi. A patent on the intronic gene editing approach has been filed in the UK. The other authors declared that they have no completing interests.
A version of this article first appeared on Medscape UK.
FROM SCIENCE TRANSLATIONAL MEDICINE
Two biologics equally effective for extraintestinal manifestations of IBD
Vedolizumab (Entyvio) and ustekinumab (Stelara) appear to be equally effective for extraintestinal manifestation (EIM) of inflammatory bowel disease (IBD), according to results of a retrospective study published online in Digestive and Liver Disease.
Between 25% and 40% of patients with IBD experience EIM, which reduces quality of life, according to the Crohn’s & Colitis Foundation. EIM commonly involves the joints, skin, bones, eyes, kidney, and liver. Anemia is another extraintestinal complication.
Until now, it’s been unclear whether vedolizumab and ustekinumab are equally effective for treating EIM.
Vedolizumab specifically targets the gastrointestinal tract, a potential disadvantage in reducing EIM, while ustekinumab is thought to have a systemic effect, a potential treatment advantage, Moran Livne-Margolin, MD, and colleagues, Chaim Sheba Medical Center, Ramat Gan, Israel, point out.
To investigate, they included 111 adults with IBD who were treated at the medical center between 2015 and 2021 – 53 with vedolizumab and 58 with ustekinumab. Before starting treatment, all of them had active EIM, most commonly arthralgia (84%).
After 6 weeks of treatment, 66% of patients in both groups had a clinical response to their intestinal disease.
After 14 and 26 weeks of treatment, clinical response rates were 59% and 50%, respectively, with vedolizumab, and 48% and 41%, respectively, with ustekinumab.
Over 52 weeks, both biologics were equally effective against the intestinal disease, with clinical response rates of 42% with vedolizumab and 44% with ustekinumab.
A similar pattern emerged when looking at improvement in EIM.
At week 6, 44% of patients taking vedolizumab and 35% taking ustekinumab had improvement in EIM, with no significant difference between the two biologics (P = .4).
At week 14, rates of improvement in EIM were 43% for vedolizumab and 33% for ustekinumab (P = .39); at 26 weeks, rates were 39% and 33%, respectively (P = .6); and at 52 weeks, rates were 34% and 36% (P = .9).
Researchers also found a significant positive correlation between improvement of the intestinal disease and clinical improvement of EIM at each time point.
Ustekinumab is usually preferred in patients with EIM, Dr. Livne-Margolin and colleagues note. But their findings “may raise some questions whether ustekinumab is, in fact, a better choice in those specific patients.”
Limitations of the study include its retrospective design and small cohort size.
Additionally, vedolizumab is given intravenously in the clinic and mandates patients to have a routine checkup every 1-2 months, whereas ustekinumab can be given at home. As a result, data were missing on some of the patients treated with ustekinumab during the follow-up.
Another limitation is that most of the patients had articular complaints with a small presentation of other EIM.
Also, most of the patients had Crohn’s disease, with only one patient with ulcerative colitis in the ustekinumab group, compared with 12 in the vedolizumab group.
Finally, patients treated with ustekinumab had more experience with anti-TNF treatment, compared with the vedolizumab group, which might have influenced the results with a negative bias toward ustekinumab.
The study had no specific funding. Three authors have disclosed relationships with Janssen, which makes ustekinumab.
A version of this article first appeared on Medscape.com.
Vedolizumab (Entyvio) and ustekinumab (Stelara) appear to be equally effective for extraintestinal manifestation (EIM) of inflammatory bowel disease (IBD), according to results of a retrospective study published online in Digestive and Liver Disease.
Between 25% and 40% of patients with IBD experience EIM, which reduces quality of life, according to the Crohn’s & Colitis Foundation. EIM commonly involves the joints, skin, bones, eyes, kidney, and liver. Anemia is another extraintestinal complication.
Until now, it’s been unclear whether vedolizumab and ustekinumab are equally effective for treating EIM.
Vedolizumab specifically targets the gastrointestinal tract, a potential disadvantage in reducing EIM, while ustekinumab is thought to have a systemic effect, a potential treatment advantage, Moran Livne-Margolin, MD, and colleagues, Chaim Sheba Medical Center, Ramat Gan, Israel, point out.
To investigate, they included 111 adults with IBD who were treated at the medical center between 2015 and 2021 – 53 with vedolizumab and 58 with ustekinumab. Before starting treatment, all of them had active EIM, most commonly arthralgia (84%).
After 6 weeks of treatment, 66% of patients in both groups had a clinical response to their intestinal disease.
After 14 and 26 weeks of treatment, clinical response rates were 59% and 50%, respectively, with vedolizumab, and 48% and 41%, respectively, with ustekinumab.
Over 52 weeks, both biologics were equally effective against the intestinal disease, with clinical response rates of 42% with vedolizumab and 44% with ustekinumab.
A similar pattern emerged when looking at improvement in EIM.
At week 6, 44% of patients taking vedolizumab and 35% taking ustekinumab had improvement in EIM, with no significant difference between the two biologics (P = .4).
At week 14, rates of improvement in EIM were 43% for vedolizumab and 33% for ustekinumab (P = .39); at 26 weeks, rates were 39% and 33%, respectively (P = .6); and at 52 weeks, rates were 34% and 36% (P = .9).
Researchers also found a significant positive correlation between improvement of the intestinal disease and clinical improvement of EIM at each time point.
Ustekinumab is usually preferred in patients with EIM, Dr. Livne-Margolin and colleagues note. But their findings “may raise some questions whether ustekinumab is, in fact, a better choice in those specific patients.”
Limitations of the study include its retrospective design and small cohort size.
Additionally, vedolizumab is given intravenously in the clinic and mandates patients to have a routine checkup every 1-2 months, whereas ustekinumab can be given at home. As a result, data were missing on some of the patients treated with ustekinumab during the follow-up.
Another limitation is that most of the patients had articular complaints with a small presentation of other EIM.
Also, most of the patients had Crohn’s disease, with only one patient with ulcerative colitis in the ustekinumab group, compared with 12 in the vedolizumab group.
Finally, patients treated with ustekinumab had more experience with anti-TNF treatment, compared with the vedolizumab group, which might have influenced the results with a negative bias toward ustekinumab.
The study had no specific funding. Three authors have disclosed relationships with Janssen, which makes ustekinumab.
A version of this article first appeared on Medscape.com.
Vedolizumab (Entyvio) and ustekinumab (Stelara) appear to be equally effective for extraintestinal manifestation (EIM) of inflammatory bowel disease (IBD), according to results of a retrospective study published online in Digestive and Liver Disease.
Between 25% and 40% of patients with IBD experience EIM, which reduces quality of life, according to the Crohn’s & Colitis Foundation. EIM commonly involves the joints, skin, bones, eyes, kidney, and liver. Anemia is another extraintestinal complication.
Until now, it’s been unclear whether vedolizumab and ustekinumab are equally effective for treating EIM.
Vedolizumab specifically targets the gastrointestinal tract, a potential disadvantage in reducing EIM, while ustekinumab is thought to have a systemic effect, a potential treatment advantage, Moran Livne-Margolin, MD, and colleagues, Chaim Sheba Medical Center, Ramat Gan, Israel, point out.
To investigate, they included 111 adults with IBD who were treated at the medical center between 2015 and 2021 – 53 with vedolizumab and 58 with ustekinumab. Before starting treatment, all of them had active EIM, most commonly arthralgia (84%).
After 6 weeks of treatment, 66% of patients in both groups had a clinical response to their intestinal disease.
After 14 and 26 weeks of treatment, clinical response rates were 59% and 50%, respectively, with vedolizumab, and 48% and 41%, respectively, with ustekinumab.
Over 52 weeks, both biologics were equally effective against the intestinal disease, with clinical response rates of 42% with vedolizumab and 44% with ustekinumab.
A similar pattern emerged when looking at improvement in EIM.
At week 6, 44% of patients taking vedolizumab and 35% taking ustekinumab had improvement in EIM, with no significant difference between the two biologics (P = .4).
At week 14, rates of improvement in EIM were 43% for vedolizumab and 33% for ustekinumab (P = .39); at 26 weeks, rates were 39% and 33%, respectively (P = .6); and at 52 weeks, rates were 34% and 36% (P = .9).
Researchers also found a significant positive correlation between improvement of the intestinal disease and clinical improvement of EIM at each time point.
Ustekinumab is usually preferred in patients with EIM, Dr. Livne-Margolin and colleagues note. But their findings “may raise some questions whether ustekinumab is, in fact, a better choice in those specific patients.”
Limitations of the study include its retrospective design and small cohort size.
Additionally, vedolizumab is given intravenously in the clinic and mandates patients to have a routine checkup every 1-2 months, whereas ustekinumab can be given at home. As a result, data were missing on some of the patients treated with ustekinumab during the follow-up.
Another limitation is that most of the patients had articular complaints with a small presentation of other EIM.
Also, most of the patients had Crohn’s disease, with only one patient with ulcerative colitis in the ustekinumab group, compared with 12 in the vedolizumab group.
Finally, patients treated with ustekinumab had more experience with anti-TNF treatment, compared with the vedolizumab group, which might have influenced the results with a negative bias toward ustekinumab.
The study had no specific funding. Three authors have disclosed relationships with Janssen, which makes ustekinumab.
A version of this article first appeared on Medscape.com.
FROM DIGESTIVE AND LIVER DISEASE
Worse COVID outcomes seen with gout, particularly in women
People with gout, especially women, appear to be at higher risk for poor COVID-19 outcomes, including hospitalization and death, regardless of COVID-19 vaccination status, researchers suggest.
“We found that the risks of SARS-CoV-2 infection, 30-day hospitalization, and 30-day death among individuals with gout were higher than the general population irrespective of the vaccination status,” lead study author Dongxing Xie, MD, PhD, Xiangya Hospital, Central South University, Changsha, China, and his colleagues write in their large population study. “This finding informs individuals with gout, especially women, that additional measures, even after vaccination, should be considered in order to mitigate the risk of SARS-CoV-2 infection and its severe sequelae.”
People with gout, the most common inflammatory arthritis, often have other conditions that are linked to higher risk for SARS-CoV-2 infection and poor outcomes as well, including obesity, cardiovascular disease, and chronic kidney disease, the authors write. And elevated serum urate may contribute to inflammation and possible COVID-19 complications. But unlike in the case of diseases such as lupus and rheumatoid arthritis, little is known about SARS-CoV-2 infection risk among patients with gout.
As reported in Arthritis & Rheumatology, Dr. Xie and his research team used the Health Improvement Network ([THIN], now called IQVIA Medical Research Database) repository of medical conditions, demographics, and other details of around 17 million people in the United Kingdom to estimate the risk for SARS-CoV-2 infection, hospitalization, and death in people with gout. They compared those outcomes with outcomes of people without gout and compared outcomes of vaccinated vs. nonvaccinated participants.
From December 2020 through October 2021, the researchers investigated the risk for SARS-CoV-2 breakthrough infection in vaccinated people between age 18 and 90 years who had gout and were hospitalized within 30 days after the infection diagnosis or who died within 30 days after the diagnosis. They compared these outcomes with the outcomes of people in the general population without gout after COVID-19 vaccination. They also compared the risk for SARS-CoV-2 infection and its severe outcomes between individuals with gout and the general population among unvaccinated people.
They weighted these comparisons on the basis of age, sex, body mass index, socioeconomic deprivation index score, region, and number of previous COVID-19 tests in one model. A more fully adjusted model also weighted the comparisons for lifestyle factors, comorbidities, medications, and healthcare utilization.
The vaccinated cohort consisted of 54,576 people with gout and 1,336,377 without gout from the general population. The unvaccinated cohort included 61,111 individuals with gout and 1,697,168 individuals without gout from the general population.
Women more likely to be hospitalized and die
The risk for breakthrough infection in the vaccinated cohort was significantly higher among people with gout than among those without gout in the general population, particularly for men, who had hazard ratios (HRs) ranging from 1.22 with a fully adjusted exposure score to 1.30 with a partially adjusted score, but this was not seen in women. The overall incidence of breakthrough infection per 1,000 person-months for these groups was 4.68 with gout vs. 3.76 without gout.
The researchers showed a similar pattern of a higher rate of hospitalizations for people with gout vs. without (0.42/1,000 person-months vs. 0.28); in this case, women had higher risks than did men, with HRs for women ranging from 1.55 with a fully adjusted exposure score to 1.91 with a partially adjusted score, compared with 1.22 and 1.43 for men, respectively.
People with gout had significantly higher mortality than did those without (0.06/1,000 person-months vs. 0.04), but the risk for death was only higher for women, with HRs calculated to be 2.23 in fully adjusted exposure scores and 3.01 in partially adjusted scores.
These same comparisons in the unvaccinated cohort all went in the same direction as did those in the vaccinated cohort but showed higher rates for infection (8.69/1,000 person-months vs. 6.89), hospitalization (2.57/1,000 person-months vs. 1.71), and death (0.65/1,000 person-months vs. 0.53). Similar sex-specific links between gout and risks for SARS-CoV-2 infection, hospitalization, and death were seen in the unvaccinated cohort.
Patients with gout and COVID-19 need close monitoring
Four experts who were not involved in the study encourage greater attention to the needs of patients with gout.
Pamela B. Davis, MD, PhD, research professor at Case Western Reserve University, Cleveland, told this news organization, “This study brings to attention yet another potentially vulnerable group for physicians to monitor closely if they are infected with SARS-CoV-2.
“It is not clear why women with gout are more vulnerable, but fewer women than men were in the cohort with gout, and the confidence intervals for the results in women were, in general, larger,” she said.
“The authors suggest that women with gout tend to be older and have more comorbidities than men with gout,” Dr. Davis added. “The excess risk diminishes when the model is fully adjusted for comorbidities, such as obesity, hypertension, or heart disease, suggesting that already-known antecedents of infection severity account for a great deal of the excess risk.”
Kevin D. Deane, MD, PhD, associate professor of medicine and chair in rheumatology research at the University of Colorado at Denver, Aurora, advises physicians to keep in mind other conditions linked with increased risk for severe COVID-19, including advanced age; heart, lung, or kidney problems; and autoimmune diseases.
“I would be very cautious about the finding that there was not a difference in outcomes in individuals with gout based on vaccination status,” he cautioned, urging clinicians to “still strongly recommend vaccines according to guidelines.”
Sarah E. Waldman, MD, associate clinical professor of infectious diseases at UC Davis Health in Sacramento, Calif., called the study interesting but not surprising.
“The reason for increased risk for COVID-19 infection among those with gout may have to do with their underlying inflammatory state. Additional research needs to be done on this topic.
“Retrospective population-based cohort studies can be difficult to interpret due to biases,” she added. Associations identified in this type of study do not determine causation.
“As the researchers noted, those with gout tend to have additional comorbidities as well as advanced age,” she said. “They may also seek medical care more often and be tested for SARS-CoV-2 more frequently.”
Dr. Waldman advises clinicians to counsel patients with gout about their potential increased infection risk and ways they can protect themselves, including COVID-19 vaccinations.
“The strong association between gout and COVID-19 infection could involve coexisting conditions such as diabetes, hypertension, cardiovascular disease, and chronic kidney disease,” Dr. Aung added.
Earlier studies show links between gout and severe COVID-19 outcomes
Lead author Kanon Jatuworapruk, MD, PhD, of Thammasat University in Pathumthani, Thailand, and his colleagues investigated characteristics and outcomes of people with gout who were hospitalized for COVID-19 between March 2020 and October 2021, using data from the COVID-19 Global Rheumatology Alliance registry.
“This cohort of people with gout and COVID-19 who were hospitalized had high frequencies of ventilatory support and death,” the authors write in ACR Open Rheumatology . “This suggests that patients with gout who were hospitalized for COVID-19 may be at risk of poor outcomes, perhaps related to known risk factors for poor outcomes, such as age and presence of comorbidity.”
In their study, the average age of the 163 patients was 63 years, and 85% were men. Most lived in the Western Pacific Region and North America, and 46% had two or more comorbidities, most commonly hypertension, cardiovascular disease, diabetes, chronic kidney disease, and obesity. The researchers found that:
- Sixty-eight percent of the cohort required supplemental oxygen or ventilatory support during hospitalization.
- Sixteen percent of deaths were related to COVID-19, with 73% of deaths occurring in people with two or more comorbidities.
Ruth K. Topless, assistant research fellow in the department of biochemistry at the University of Otago in Dunedin, New Zealand, is the lead author on a study she and her colleagues are conducting using the UK Biobank databases of 459,837 participants in the United Kingdom, including 15,871 people with gout, through April 6, 2021, to investigate whether gout is a risk factor for diagnosis of COVID-19 and COVID-19–related death.
“Gout is a risk factor for COVID-19-related death in the UK Biobank cohort, with an increased risk in women with gout, which was driven by risk factors independent of the metabolic comorbidities of gout,” the researchers conclude in The Lancet Rheumatology.
In their study, gout was linked with COVID-19 diagnosis (odds ratio, 1.20; 95% confidence interval, 1.11-1.29) but not with risk for COVID-19–related death in the group of patients with COVID-19 (OR, 1.20; 95% CI, 0.96-1.51). In the entire cohort, gout was linked with COVID-19–related death (OR, 1.29; 95% CI, 1.06-1.56); women with gout were at increased risk for COVID-19–related death (OR, 1.98; 95% CI, 1.34-2.94), but men with gout were not (OR, 1.16; 95% CI, 0.93-1.45). The risk for COVID-19 diagnosis was significant in the nonvaccinated group (OR, 1.21; 95% CI, 1.11-1.30) but not in the vaccinated group (OR, 1.09; 95% CI, 0.65-1.85).
Editorial authors join in recommending further related research
In a commentary in The Lancet Rheumatology about the UK Biobank and other related research, Christoffer B. Nissen, MD, of University Hospital of Southern Denmark in Sonderborg, and his co-authors call the Topless and colleagues study “an elegantly conducted analysis of data from the UK Biobank supporting the hypothesis that gout needs attention in patients with COVID-19.”
Further studies are needed to investigate to what degree a diagnosis of gout is a risk factor for COVID-19 and whether treatment modifies the risk of a severe disease course,” they write. “However, in the interim, the results of this study could be considered when risk stratifying patients with gout in view of vaccination recommendations and early treatment interventions.”
Each of the three studies received grant funding. Several of the authors of the studies report financial involvements with pharmaceutical companies. All outside experts commented by email and report no relevant financial involvements.
A version of this article first appeared on Medscape.com.
People with gout, especially women, appear to be at higher risk for poor COVID-19 outcomes, including hospitalization and death, regardless of COVID-19 vaccination status, researchers suggest.
“We found that the risks of SARS-CoV-2 infection, 30-day hospitalization, and 30-day death among individuals with gout were higher than the general population irrespective of the vaccination status,” lead study author Dongxing Xie, MD, PhD, Xiangya Hospital, Central South University, Changsha, China, and his colleagues write in their large population study. “This finding informs individuals with gout, especially women, that additional measures, even after vaccination, should be considered in order to mitigate the risk of SARS-CoV-2 infection and its severe sequelae.”
People with gout, the most common inflammatory arthritis, often have other conditions that are linked to higher risk for SARS-CoV-2 infection and poor outcomes as well, including obesity, cardiovascular disease, and chronic kidney disease, the authors write. And elevated serum urate may contribute to inflammation and possible COVID-19 complications. But unlike in the case of diseases such as lupus and rheumatoid arthritis, little is known about SARS-CoV-2 infection risk among patients with gout.
As reported in Arthritis & Rheumatology, Dr. Xie and his research team used the Health Improvement Network ([THIN], now called IQVIA Medical Research Database) repository of medical conditions, demographics, and other details of around 17 million people in the United Kingdom to estimate the risk for SARS-CoV-2 infection, hospitalization, and death in people with gout. They compared those outcomes with outcomes of people without gout and compared outcomes of vaccinated vs. nonvaccinated participants.
From December 2020 through October 2021, the researchers investigated the risk for SARS-CoV-2 breakthrough infection in vaccinated people between age 18 and 90 years who had gout and were hospitalized within 30 days after the infection diagnosis or who died within 30 days after the diagnosis. They compared these outcomes with the outcomes of people in the general population without gout after COVID-19 vaccination. They also compared the risk for SARS-CoV-2 infection and its severe outcomes between individuals with gout and the general population among unvaccinated people.
They weighted these comparisons on the basis of age, sex, body mass index, socioeconomic deprivation index score, region, and number of previous COVID-19 tests in one model. A more fully adjusted model also weighted the comparisons for lifestyle factors, comorbidities, medications, and healthcare utilization.
The vaccinated cohort consisted of 54,576 people with gout and 1,336,377 without gout from the general population. The unvaccinated cohort included 61,111 individuals with gout and 1,697,168 individuals without gout from the general population.
Women more likely to be hospitalized and die
The risk for breakthrough infection in the vaccinated cohort was significantly higher among people with gout than among those without gout in the general population, particularly for men, who had hazard ratios (HRs) ranging from 1.22 with a fully adjusted exposure score to 1.30 with a partially adjusted score, but this was not seen in women. The overall incidence of breakthrough infection per 1,000 person-months for these groups was 4.68 with gout vs. 3.76 without gout.
The researchers showed a similar pattern of a higher rate of hospitalizations for people with gout vs. without (0.42/1,000 person-months vs. 0.28); in this case, women had higher risks than did men, with HRs for women ranging from 1.55 with a fully adjusted exposure score to 1.91 with a partially adjusted score, compared with 1.22 and 1.43 for men, respectively.
People with gout had significantly higher mortality than did those without (0.06/1,000 person-months vs. 0.04), but the risk for death was only higher for women, with HRs calculated to be 2.23 in fully adjusted exposure scores and 3.01 in partially adjusted scores.
These same comparisons in the unvaccinated cohort all went in the same direction as did those in the vaccinated cohort but showed higher rates for infection (8.69/1,000 person-months vs. 6.89), hospitalization (2.57/1,000 person-months vs. 1.71), and death (0.65/1,000 person-months vs. 0.53). Similar sex-specific links between gout and risks for SARS-CoV-2 infection, hospitalization, and death were seen in the unvaccinated cohort.
Patients with gout and COVID-19 need close monitoring
Four experts who were not involved in the study encourage greater attention to the needs of patients with gout.
Pamela B. Davis, MD, PhD, research professor at Case Western Reserve University, Cleveland, told this news organization, “This study brings to attention yet another potentially vulnerable group for physicians to monitor closely if they are infected with SARS-CoV-2.
“It is not clear why women with gout are more vulnerable, but fewer women than men were in the cohort with gout, and the confidence intervals for the results in women were, in general, larger,” she said.
“The authors suggest that women with gout tend to be older and have more comorbidities than men with gout,” Dr. Davis added. “The excess risk diminishes when the model is fully adjusted for comorbidities, such as obesity, hypertension, or heart disease, suggesting that already-known antecedents of infection severity account for a great deal of the excess risk.”
Kevin D. Deane, MD, PhD, associate professor of medicine and chair in rheumatology research at the University of Colorado at Denver, Aurora, advises physicians to keep in mind other conditions linked with increased risk for severe COVID-19, including advanced age; heart, lung, or kidney problems; and autoimmune diseases.
“I would be very cautious about the finding that there was not a difference in outcomes in individuals with gout based on vaccination status,” he cautioned, urging clinicians to “still strongly recommend vaccines according to guidelines.”
Sarah E. Waldman, MD, associate clinical professor of infectious diseases at UC Davis Health in Sacramento, Calif., called the study interesting but not surprising.
“The reason for increased risk for COVID-19 infection among those with gout may have to do with their underlying inflammatory state. Additional research needs to be done on this topic.
“Retrospective population-based cohort studies can be difficult to interpret due to biases,” she added. Associations identified in this type of study do not determine causation.
“As the researchers noted, those with gout tend to have additional comorbidities as well as advanced age,” she said. “They may also seek medical care more often and be tested for SARS-CoV-2 more frequently.”
Dr. Waldman advises clinicians to counsel patients with gout about their potential increased infection risk and ways they can protect themselves, including COVID-19 vaccinations.
“The strong association between gout and COVID-19 infection could involve coexisting conditions such as diabetes, hypertension, cardiovascular disease, and chronic kidney disease,” Dr. Aung added.
Earlier studies show links between gout and severe COVID-19 outcomes
Lead author Kanon Jatuworapruk, MD, PhD, of Thammasat University in Pathumthani, Thailand, and his colleagues investigated characteristics and outcomes of people with gout who were hospitalized for COVID-19 between March 2020 and October 2021, using data from the COVID-19 Global Rheumatology Alliance registry.
“This cohort of people with gout and COVID-19 who were hospitalized had high frequencies of ventilatory support and death,” the authors write in ACR Open Rheumatology . “This suggests that patients with gout who were hospitalized for COVID-19 may be at risk of poor outcomes, perhaps related to known risk factors for poor outcomes, such as age and presence of comorbidity.”
In their study, the average age of the 163 patients was 63 years, and 85% were men. Most lived in the Western Pacific Region and North America, and 46% had two or more comorbidities, most commonly hypertension, cardiovascular disease, diabetes, chronic kidney disease, and obesity. The researchers found that:
- Sixty-eight percent of the cohort required supplemental oxygen or ventilatory support during hospitalization.
- Sixteen percent of deaths were related to COVID-19, with 73% of deaths occurring in people with two or more comorbidities.
Ruth K. Topless, assistant research fellow in the department of biochemistry at the University of Otago in Dunedin, New Zealand, is the lead author on a study she and her colleagues are conducting using the UK Biobank databases of 459,837 participants in the United Kingdom, including 15,871 people with gout, through April 6, 2021, to investigate whether gout is a risk factor for diagnosis of COVID-19 and COVID-19–related death.
“Gout is a risk factor for COVID-19-related death in the UK Biobank cohort, with an increased risk in women with gout, which was driven by risk factors independent of the metabolic comorbidities of gout,” the researchers conclude in The Lancet Rheumatology.
In their study, gout was linked with COVID-19 diagnosis (odds ratio, 1.20; 95% confidence interval, 1.11-1.29) but not with risk for COVID-19–related death in the group of patients with COVID-19 (OR, 1.20; 95% CI, 0.96-1.51). In the entire cohort, gout was linked with COVID-19–related death (OR, 1.29; 95% CI, 1.06-1.56); women with gout were at increased risk for COVID-19–related death (OR, 1.98; 95% CI, 1.34-2.94), but men with gout were not (OR, 1.16; 95% CI, 0.93-1.45). The risk for COVID-19 diagnosis was significant in the nonvaccinated group (OR, 1.21; 95% CI, 1.11-1.30) but not in the vaccinated group (OR, 1.09; 95% CI, 0.65-1.85).
Editorial authors join in recommending further related research
In a commentary in The Lancet Rheumatology about the UK Biobank and other related research, Christoffer B. Nissen, MD, of University Hospital of Southern Denmark in Sonderborg, and his co-authors call the Topless and colleagues study “an elegantly conducted analysis of data from the UK Biobank supporting the hypothesis that gout needs attention in patients with COVID-19.”
Further studies are needed to investigate to what degree a diagnosis of gout is a risk factor for COVID-19 and whether treatment modifies the risk of a severe disease course,” they write. “However, in the interim, the results of this study could be considered when risk stratifying patients with gout in view of vaccination recommendations and early treatment interventions.”
Each of the three studies received grant funding. Several of the authors of the studies report financial involvements with pharmaceutical companies. All outside experts commented by email and report no relevant financial involvements.
A version of this article first appeared on Medscape.com.
People with gout, especially women, appear to be at higher risk for poor COVID-19 outcomes, including hospitalization and death, regardless of COVID-19 vaccination status, researchers suggest.
“We found that the risks of SARS-CoV-2 infection, 30-day hospitalization, and 30-day death among individuals with gout were higher than the general population irrespective of the vaccination status,” lead study author Dongxing Xie, MD, PhD, Xiangya Hospital, Central South University, Changsha, China, and his colleagues write in their large population study. “This finding informs individuals with gout, especially women, that additional measures, even after vaccination, should be considered in order to mitigate the risk of SARS-CoV-2 infection and its severe sequelae.”
People with gout, the most common inflammatory arthritis, often have other conditions that are linked to higher risk for SARS-CoV-2 infection and poor outcomes as well, including obesity, cardiovascular disease, and chronic kidney disease, the authors write. And elevated serum urate may contribute to inflammation and possible COVID-19 complications. But unlike in the case of diseases such as lupus and rheumatoid arthritis, little is known about SARS-CoV-2 infection risk among patients with gout.
As reported in Arthritis & Rheumatology, Dr. Xie and his research team used the Health Improvement Network ([THIN], now called IQVIA Medical Research Database) repository of medical conditions, demographics, and other details of around 17 million people in the United Kingdom to estimate the risk for SARS-CoV-2 infection, hospitalization, and death in people with gout. They compared those outcomes with outcomes of people without gout and compared outcomes of vaccinated vs. nonvaccinated participants.
From December 2020 through October 2021, the researchers investigated the risk for SARS-CoV-2 breakthrough infection in vaccinated people between age 18 and 90 years who had gout and were hospitalized within 30 days after the infection diagnosis or who died within 30 days after the diagnosis. They compared these outcomes with the outcomes of people in the general population without gout after COVID-19 vaccination. They also compared the risk for SARS-CoV-2 infection and its severe outcomes between individuals with gout and the general population among unvaccinated people.
They weighted these comparisons on the basis of age, sex, body mass index, socioeconomic deprivation index score, region, and number of previous COVID-19 tests in one model. A more fully adjusted model also weighted the comparisons for lifestyle factors, comorbidities, medications, and healthcare utilization.
The vaccinated cohort consisted of 54,576 people with gout and 1,336,377 without gout from the general population. The unvaccinated cohort included 61,111 individuals with gout and 1,697,168 individuals without gout from the general population.
Women more likely to be hospitalized and die
The risk for breakthrough infection in the vaccinated cohort was significantly higher among people with gout than among those without gout in the general population, particularly for men, who had hazard ratios (HRs) ranging from 1.22 with a fully adjusted exposure score to 1.30 with a partially adjusted score, but this was not seen in women. The overall incidence of breakthrough infection per 1,000 person-months for these groups was 4.68 with gout vs. 3.76 without gout.
The researchers showed a similar pattern of a higher rate of hospitalizations for people with gout vs. without (0.42/1,000 person-months vs. 0.28); in this case, women had higher risks than did men, with HRs for women ranging from 1.55 with a fully adjusted exposure score to 1.91 with a partially adjusted score, compared with 1.22 and 1.43 for men, respectively.
People with gout had significantly higher mortality than did those without (0.06/1,000 person-months vs. 0.04), but the risk for death was only higher for women, with HRs calculated to be 2.23 in fully adjusted exposure scores and 3.01 in partially adjusted scores.
These same comparisons in the unvaccinated cohort all went in the same direction as did those in the vaccinated cohort but showed higher rates for infection (8.69/1,000 person-months vs. 6.89), hospitalization (2.57/1,000 person-months vs. 1.71), and death (0.65/1,000 person-months vs. 0.53). Similar sex-specific links between gout and risks for SARS-CoV-2 infection, hospitalization, and death were seen in the unvaccinated cohort.
Patients with gout and COVID-19 need close monitoring
Four experts who were not involved in the study encourage greater attention to the needs of patients with gout.
Pamela B. Davis, MD, PhD, research professor at Case Western Reserve University, Cleveland, told this news organization, “This study brings to attention yet another potentially vulnerable group for physicians to monitor closely if they are infected with SARS-CoV-2.
“It is not clear why women with gout are more vulnerable, but fewer women than men were in the cohort with gout, and the confidence intervals for the results in women were, in general, larger,” she said.
“The authors suggest that women with gout tend to be older and have more comorbidities than men with gout,” Dr. Davis added. “The excess risk diminishes when the model is fully adjusted for comorbidities, such as obesity, hypertension, or heart disease, suggesting that already-known antecedents of infection severity account for a great deal of the excess risk.”
Kevin D. Deane, MD, PhD, associate professor of medicine and chair in rheumatology research at the University of Colorado at Denver, Aurora, advises physicians to keep in mind other conditions linked with increased risk for severe COVID-19, including advanced age; heart, lung, or kidney problems; and autoimmune diseases.
“I would be very cautious about the finding that there was not a difference in outcomes in individuals with gout based on vaccination status,” he cautioned, urging clinicians to “still strongly recommend vaccines according to guidelines.”
Sarah E. Waldman, MD, associate clinical professor of infectious diseases at UC Davis Health in Sacramento, Calif., called the study interesting but not surprising.
“The reason for increased risk for COVID-19 infection among those with gout may have to do with their underlying inflammatory state. Additional research needs to be done on this topic.
“Retrospective population-based cohort studies can be difficult to interpret due to biases,” she added. Associations identified in this type of study do not determine causation.
“As the researchers noted, those with gout tend to have additional comorbidities as well as advanced age,” she said. “They may also seek medical care more often and be tested for SARS-CoV-2 more frequently.”
Dr. Waldman advises clinicians to counsel patients with gout about their potential increased infection risk and ways they can protect themselves, including COVID-19 vaccinations.
“The strong association between gout and COVID-19 infection could involve coexisting conditions such as diabetes, hypertension, cardiovascular disease, and chronic kidney disease,” Dr. Aung added.
Earlier studies show links between gout and severe COVID-19 outcomes
Lead author Kanon Jatuworapruk, MD, PhD, of Thammasat University in Pathumthani, Thailand, and his colleagues investigated characteristics and outcomes of people with gout who were hospitalized for COVID-19 between March 2020 and October 2021, using data from the COVID-19 Global Rheumatology Alliance registry.
“This cohort of people with gout and COVID-19 who were hospitalized had high frequencies of ventilatory support and death,” the authors write in ACR Open Rheumatology . “This suggests that patients with gout who were hospitalized for COVID-19 may be at risk of poor outcomes, perhaps related to known risk factors for poor outcomes, such as age and presence of comorbidity.”
In their study, the average age of the 163 patients was 63 years, and 85% were men. Most lived in the Western Pacific Region and North America, and 46% had two or more comorbidities, most commonly hypertension, cardiovascular disease, diabetes, chronic kidney disease, and obesity. The researchers found that:
- Sixty-eight percent of the cohort required supplemental oxygen or ventilatory support during hospitalization.
- Sixteen percent of deaths were related to COVID-19, with 73% of deaths occurring in people with two or more comorbidities.
Ruth K. Topless, assistant research fellow in the department of biochemistry at the University of Otago in Dunedin, New Zealand, is the lead author on a study she and her colleagues are conducting using the UK Biobank databases of 459,837 participants in the United Kingdom, including 15,871 people with gout, through April 6, 2021, to investigate whether gout is a risk factor for diagnosis of COVID-19 and COVID-19–related death.
“Gout is a risk factor for COVID-19-related death in the UK Biobank cohort, with an increased risk in women with gout, which was driven by risk factors independent of the metabolic comorbidities of gout,” the researchers conclude in The Lancet Rheumatology.
In their study, gout was linked with COVID-19 diagnosis (odds ratio, 1.20; 95% confidence interval, 1.11-1.29) but not with risk for COVID-19–related death in the group of patients with COVID-19 (OR, 1.20; 95% CI, 0.96-1.51). In the entire cohort, gout was linked with COVID-19–related death (OR, 1.29; 95% CI, 1.06-1.56); women with gout were at increased risk for COVID-19–related death (OR, 1.98; 95% CI, 1.34-2.94), but men with gout were not (OR, 1.16; 95% CI, 0.93-1.45). The risk for COVID-19 diagnosis was significant in the nonvaccinated group (OR, 1.21; 95% CI, 1.11-1.30) but not in the vaccinated group (OR, 1.09; 95% CI, 0.65-1.85).
Editorial authors join in recommending further related research
In a commentary in The Lancet Rheumatology about the UK Biobank and other related research, Christoffer B. Nissen, MD, of University Hospital of Southern Denmark in Sonderborg, and his co-authors call the Topless and colleagues study “an elegantly conducted analysis of data from the UK Biobank supporting the hypothesis that gout needs attention in patients with COVID-19.”
Further studies are needed to investigate to what degree a diagnosis of gout is a risk factor for COVID-19 and whether treatment modifies the risk of a severe disease course,” they write. “However, in the interim, the results of this study could be considered when risk stratifying patients with gout in view of vaccination recommendations and early treatment interventions.”
Each of the three studies received grant funding. Several of the authors of the studies report financial involvements with pharmaceutical companies. All outside experts commented by email and report no relevant financial involvements.
A version of this article first appeared on Medscape.com.
FDA approves upadacitinib (Rinvoq) for sixth indication
The United States Food and Drug Administration has approved the Janus kinase (JAK) inhibitor upadacitinib (Rinvoq) for adults with nonradiographic axial spondyloarthritis (nr-axSpA) who have objective signs of inflammation and who have had an inadequate response to or are intolerant of one or more tumor necrosis factor (TNF) inhibitors, according to an announcement from the manufacturer, AbbVie.
The indication is the sixth in the United States for the JAK inhibitor. Upadacitinib 15 mg once daily is already approved in the United States for adults with moderately to severely active rheumatoid arthritis, active psoriatic arthritis (PsA), and active ankylosing spondylitis (AS). All these indications are for patients who have had an inadequate response to or are intolerant of one or more TNF inhibitors.
Upadacitinib is now the only JAK inhibitor that has been approved for both nr-axSpA and AS.
“Many patients living with nr-axSpA continue to experience symptoms and are unable to control disease with current treatments. In the SELECT-AXIS 2 trials, Rinvoq demonstrated efficacy in both nr-axSpA and AS with safety that was consistent across indications,” Atul Deodhar, MD, lead investigator of the trial, said in the announcement. “Today’s FDA approval offers an important new therapeutic option for patients and their caregivers to help take control of their symptoms and disease.”
Upadacitinib is also approved at a dose of 15 mg once daily for adults and children 12 years of age and older who weigh at least 40 kg and who have refractory, moderate to severe atopic dermatitis that is not adequately controlled with other systemic drug products, including biologics, or when use of those therapies is inadvisable.
It is approved as well at 45 mg once daily for 8 weeks as an induction therapy for adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to or are intolerant of one or more TNF blockers. Following induction therapy for patients with ulcerative colitis, the recommended dose for maintenance treatment is 15 mg once daily, but a dose of 30 mg once daily may be considered for patients with refractory, severe, or extensive disease.
The FDA’s decision is supported by data from the phase 3 SELECT-AXIS 2 clinical trial, which assessed the efficacy, safety, and tolerability of upadacitinib in adults with active nr-axSpA.
Nearly half of patients treated with upadacitinib had achieved 40% improvement in Assessment of Spondyloarthritis International Society response criteria (ASAS 40), the primary endpoint, at week 14, compared with placebo (44.9% vs. 22.3%). These responses were observed as early as 2 weeks after initiation of therapy. The safety profile was consistent with what’s known in patients with RA, PsA, and AS.
Upadacitinib can lower the ability to fight infections. Serious infections, some fatal, have occurred, including tuberculosis and infections caused by bacteria, fungi, or viruses. It is associated with an increased risk of death and major cardiovascular events in people aged 50 and older who have at least one heart disease risk factor, and it is associated with an increased risk of some cancers, including lymphoma and skin cancers.
A version of this article first appeared on Medscape.com.
The United States Food and Drug Administration has approved the Janus kinase (JAK) inhibitor upadacitinib (Rinvoq) for adults with nonradiographic axial spondyloarthritis (nr-axSpA) who have objective signs of inflammation and who have had an inadequate response to or are intolerant of one or more tumor necrosis factor (TNF) inhibitors, according to an announcement from the manufacturer, AbbVie.
The indication is the sixth in the United States for the JAK inhibitor. Upadacitinib 15 mg once daily is already approved in the United States for adults with moderately to severely active rheumatoid arthritis, active psoriatic arthritis (PsA), and active ankylosing spondylitis (AS). All these indications are for patients who have had an inadequate response to or are intolerant of one or more TNF inhibitors.
Upadacitinib is now the only JAK inhibitor that has been approved for both nr-axSpA and AS.
“Many patients living with nr-axSpA continue to experience symptoms and are unable to control disease with current treatments. In the SELECT-AXIS 2 trials, Rinvoq demonstrated efficacy in both nr-axSpA and AS with safety that was consistent across indications,” Atul Deodhar, MD, lead investigator of the trial, said in the announcement. “Today’s FDA approval offers an important new therapeutic option for patients and their caregivers to help take control of their symptoms and disease.”
Upadacitinib is also approved at a dose of 15 mg once daily for adults and children 12 years of age and older who weigh at least 40 kg and who have refractory, moderate to severe atopic dermatitis that is not adequately controlled with other systemic drug products, including biologics, or when use of those therapies is inadvisable.
It is approved as well at 45 mg once daily for 8 weeks as an induction therapy for adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to or are intolerant of one or more TNF blockers. Following induction therapy for patients with ulcerative colitis, the recommended dose for maintenance treatment is 15 mg once daily, but a dose of 30 mg once daily may be considered for patients with refractory, severe, or extensive disease.
The FDA’s decision is supported by data from the phase 3 SELECT-AXIS 2 clinical trial, which assessed the efficacy, safety, and tolerability of upadacitinib in adults with active nr-axSpA.
Nearly half of patients treated with upadacitinib had achieved 40% improvement in Assessment of Spondyloarthritis International Society response criteria (ASAS 40), the primary endpoint, at week 14, compared with placebo (44.9% vs. 22.3%). These responses were observed as early as 2 weeks after initiation of therapy. The safety profile was consistent with what’s known in patients with RA, PsA, and AS.
Upadacitinib can lower the ability to fight infections. Serious infections, some fatal, have occurred, including tuberculosis and infections caused by bacteria, fungi, or viruses. It is associated with an increased risk of death and major cardiovascular events in people aged 50 and older who have at least one heart disease risk factor, and it is associated with an increased risk of some cancers, including lymphoma and skin cancers.
A version of this article first appeared on Medscape.com.
The United States Food and Drug Administration has approved the Janus kinase (JAK) inhibitor upadacitinib (Rinvoq) for adults with nonradiographic axial spondyloarthritis (nr-axSpA) who have objective signs of inflammation and who have had an inadequate response to or are intolerant of one or more tumor necrosis factor (TNF) inhibitors, according to an announcement from the manufacturer, AbbVie.
The indication is the sixth in the United States for the JAK inhibitor. Upadacitinib 15 mg once daily is already approved in the United States for adults with moderately to severely active rheumatoid arthritis, active psoriatic arthritis (PsA), and active ankylosing spondylitis (AS). All these indications are for patients who have had an inadequate response to or are intolerant of one or more TNF inhibitors.
Upadacitinib is now the only JAK inhibitor that has been approved for both nr-axSpA and AS.
“Many patients living with nr-axSpA continue to experience symptoms and are unable to control disease with current treatments. In the SELECT-AXIS 2 trials, Rinvoq demonstrated efficacy in both nr-axSpA and AS with safety that was consistent across indications,” Atul Deodhar, MD, lead investigator of the trial, said in the announcement. “Today’s FDA approval offers an important new therapeutic option for patients and their caregivers to help take control of their symptoms and disease.”
Upadacitinib is also approved at a dose of 15 mg once daily for adults and children 12 years of age and older who weigh at least 40 kg and who have refractory, moderate to severe atopic dermatitis that is not adequately controlled with other systemic drug products, including biologics, or when use of those therapies is inadvisable.
It is approved as well at 45 mg once daily for 8 weeks as an induction therapy for adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to or are intolerant of one or more TNF blockers. Following induction therapy for patients with ulcerative colitis, the recommended dose for maintenance treatment is 15 mg once daily, but a dose of 30 mg once daily may be considered for patients with refractory, severe, or extensive disease.
The FDA’s decision is supported by data from the phase 3 SELECT-AXIS 2 clinical trial, which assessed the efficacy, safety, and tolerability of upadacitinib in adults with active nr-axSpA.
Nearly half of patients treated with upadacitinib had achieved 40% improvement in Assessment of Spondyloarthritis International Society response criteria (ASAS 40), the primary endpoint, at week 14, compared with placebo (44.9% vs. 22.3%). These responses were observed as early as 2 weeks after initiation of therapy. The safety profile was consistent with what’s known in patients with RA, PsA, and AS.
Upadacitinib can lower the ability to fight infections. Serious infections, some fatal, have occurred, including tuberculosis and infections caused by bacteria, fungi, or viruses. It is associated with an increased risk of death and major cardiovascular events in people aged 50 and older who have at least one heart disease risk factor, and it is associated with an increased risk of some cancers, including lymphoma and skin cancers.
A version of this article first appeared on Medscape.com.
Psoriatic arthritis has greater impact on women than men
Women with psoriatic arthritis (PsA) experience a higher disease burden than that of men with regard to pain, disability, and quality of life, based on data from a cross-sectional survey of more than 2,000 individuals and their rheumatologists and dermatologists.
Although PsA affects men and women in equal numbers, previous research suggests differences in clinical manifestations based on gender that may manifest in many ways, including quality of life, but data on sex differences in PsA are limited, wrote Laure Gossec, MD, of the Pitié-Salpêtrière Hospital and Sorbonne University, Paris, and colleagues.
In a study published in The Journal of Rheumatology, the researchers conducted a cross-sectional survey of rheumatologists and dermatologists and their patients with PsA during June-August 2018. The study population included 2,270 adults from France, Germany, Italy, Spain, the United Kingdom, and the United States. The mean age of the patients was 48.6 years, the mean duration of disease was 4.9 years, and 46% (1,047 patients) were women.
The survey data included information on demographics, treatment, and clinical characteristics, such as tender and swollen joint counts and body surface area affected by psoriasis. The researchers assessed quality of life on the survey using the EuroQoL 5-Dimension questionnaire (EQ-5D) and the impact of disease using the 12-item Psoriatic Arthritis Impact of Disease (PsAID12). They assessed patients’ disability and work productivity using the Health Assessment Questionnaire–Disability Index (HAQ-DI) and Work Productivity and Impairment questionnaire (WPAI).
Overall disease presentation, duration, and use of biologics were similar between men and women. However, women reported significantly worse quality of life compared with men, with a mean EQ-5D score of 0.80 vs. 0.82 (P = .02).
Women also scored higher than men on measures of disability and work impairment, with mean HAQ-DI scores of 0.56 vs. 0.41 and mean WPAI scores of 27.9% vs. 24.6%, respectively (P < .01).
Disease burden was significantly higher in women vs. men based on PsAID12 scores (2.66 vs. 2.27, respectively) and women reported significantly higher levels of fatigue and pain (P < .01 for all).
More men than women reported working full-time (68.6% vs. 49.4%) but no gender differences emerged for work time missed because of PsA, the researchers noted.
However, women had significantly fewer comorbidities compared with men, based on the Charlson Comorbidity Index (1.10 vs. 1.15, P < .01).
“Other factors not assessed in the study are likely to be contributing to disease burden, and these unmeasured factors may affect men and women differently,” the researchers wrote in their discussion. These factors may include hormone levels and treatment outcomes, as well as sleep disturbance, anxiety, and joint erosion, they said.
The study findings were limited by several factors, including the possible overrepresentation of patients who visited physicians more often, the use of self-reports, and potential recall bias, as well as the lack of data on fibromyalgia prevalence using a validated score, the researchers noted. However, the results were strengthened by the large and geographically diverse study population and highlight the need for more research to examine the additional disease burden of PsA in women, and the potential of alternative treatment regimens to improve management of PsA in women, they concluded.
Mechanisms driving sex differences remain unclear
“In the past few decades, there has been increasing interest in the effect of sex on the manifestations and impact of PsA as well as on the response to therapy,” Dafna D. Gladman, MD, of the University of Toronto and the Krembil Research Institute at Toronto Western Hospital, wrote in an accompanying editorial.
The current study findings support previous research showing differences in disease expression in PsA between men and women, Dr. Gladman said. Several studies have shown more axial disease and joint damage in men than in women, while women reported greater functional disability and worse quality of life than men. The reasons for gender differences remain unclear, and genetics may play a role as well, she said.
Dr. Gladman emphasized the need for more research on the impact of fibromyalgia (FM) in particular. “As was shown in a previous study, the presence of FM affects the clinical assessment of patients with PsA,” she wrote. Fibromyalgia and pain reporting also may affect clinical trials of patients with PsA; however, the effect of fibromyalgia on sex differences is uncertain, she said. “In a disease that affects men and women equally, recognizing sex effect is important,” and more research is needed to explore the mechanisms behind this effect, she concluded.
The study was supported by Janssen Research & Development. Dr. Gossec disclosed receiving research grants and/or consulting fees from Janssen and 13 other pharmaceutical companies. Several study coauthors disclosed relationships with multiple companies, and several coauthors are employees and stockholders of Janssen. Dr. Gladman had no financial conflicts to disclose.
Women with psoriatic arthritis (PsA) experience a higher disease burden than that of men with regard to pain, disability, and quality of life, based on data from a cross-sectional survey of more than 2,000 individuals and their rheumatologists and dermatologists.
Although PsA affects men and women in equal numbers, previous research suggests differences in clinical manifestations based on gender that may manifest in many ways, including quality of life, but data on sex differences in PsA are limited, wrote Laure Gossec, MD, of the Pitié-Salpêtrière Hospital and Sorbonne University, Paris, and colleagues.
In a study published in The Journal of Rheumatology, the researchers conducted a cross-sectional survey of rheumatologists and dermatologists and their patients with PsA during June-August 2018. The study population included 2,270 adults from France, Germany, Italy, Spain, the United Kingdom, and the United States. The mean age of the patients was 48.6 years, the mean duration of disease was 4.9 years, and 46% (1,047 patients) were women.
The survey data included information on demographics, treatment, and clinical characteristics, such as tender and swollen joint counts and body surface area affected by psoriasis. The researchers assessed quality of life on the survey using the EuroQoL 5-Dimension questionnaire (EQ-5D) and the impact of disease using the 12-item Psoriatic Arthritis Impact of Disease (PsAID12). They assessed patients’ disability and work productivity using the Health Assessment Questionnaire–Disability Index (HAQ-DI) and Work Productivity and Impairment questionnaire (WPAI).
Overall disease presentation, duration, and use of biologics were similar between men and women. However, women reported significantly worse quality of life compared with men, with a mean EQ-5D score of 0.80 vs. 0.82 (P = .02).
Women also scored higher than men on measures of disability and work impairment, with mean HAQ-DI scores of 0.56 vs. 0.41 and mean WPAI scores of 27.9% vs. 24.6%, respectively (P < .01).
Disease burden was significantly higher in women vs. men based on PsAID12 scores (2.66 vs. 2.27, respectively) and women reported significantly higher levels of fatigue and pain (P < .01 for all).
More men than women reported working full-time (68.6% vs. 49.4%) but no gender differences emerged for work time missed because of PsA, the researchers noted.
However, women had significantly fewer comorbidities compared with men, based on the Charlson Comorbidity Index (1.10 vs. 1.15, P < .01).
“Other factors not assessed in the study are likely to be contributing to disease burden, and these unmeasured factors may affect men and women differently,” the researchers wrote in their discussion. These factors may include hormone levels and treatment outcomes, as well as sleep disturbance, anxiety, and joint erosion, they said.
The study findings were limited by several factors, including the possible overrepresentation of patients who visited physicians more often, the use of self-reports, and potential recall bias, as well as the lack of data on fibromyalgia prevalence using a validated score, the researchers noted. However, the results were strengthened by the large and geographically diverse study population and highlight the need for more research to examine the additional disease burden of PsA in women, and the potential of alternative treatment regimens to improve management of PsA in women, they concluded.
Mechanisms driving sex differences remain unclear
“In the past few decades, there has been increasing interest in the effect of sex on the manifestations and impact of PsA as well as on the response to therapy,” Dafna D. Gladman, MD, of the University of Toronto and the Krembil Research Institute at Toronto Western Hospital, wrote in an accompanying editorial.
The current study findings support previous research showing differences in disease expression in PsA between men and women, Dr. Gladman said. Several studies have shown more axial disease and joint damage in men than in women, while women reported greater functional disability and worse quality of life than men. The reasons for gender differences remain unclear, and genetics may play a role as well, she said.
Dr. Gladman emphasized the need for more research on the impact of fibromyalgia (FM) in particular. “As was shown in a previous study, the presence of FM affects the clinical assessment of patients with PsA,” she wrote. Fibromyalgia and pain reporting also may affect clinical trials of patients with PsA; however, the effect of fibromyalgia on sex differences is uncertain, she said. “In a disease that affects men and women equally, recognizing sex effect is important,” and more research is needed to explore the mechanisms behind this effect, she concluded.
The study was supported by Janssen Research & Development. Dr. Gossec disclosed receiving research grants and/or consulting fees from Janssen and 13 other pharmaceutical companies. Several study coauthors disclosed relationships with multiple companies, and several coauthors are employees and stockholders of Janssen. Dr. Gladman had no financial conflicts to disclose.
Women with psoriatic arthritis (PsA) experience a higher disease burden than that of men with regard to pain, disability, and quality of life, based on data from a cross-sectional survey of more than 2,000 individuals and their rheumatologists and dermatologists.
Although PsA affects men and women in equal numbers, previous research suggests differences in clinical manifestations based on gender that may manifest in many ways, including quality of life, but data on sex differences in PsA are limited, wrote Laure Gossec, MD, of the Pitié-Salpêtrière Hospital and Sorbonne University, Paris, and colleagues.
In a study published in The Journal of Rheumatology, the researchers conducted a cross-sectional survey of rheumatologists and dermatologists and their patients with PsA during June-August 2018. The study population included 2,270 adults from France, Germany, Italy, Spain, the United Kingdom, and the United States. The mean age of the patients was 48.6 years, the mean duration of disease was 4.9 years, and 46% (1,047 patients) were women.
The survey data included information on demographics, treatment, and clinical characteristics, such as tender and swollen joint counts and body surface area affected by psoriasis. The researchers assessed quality of life on the survey using the EuroQoL 5-Dimension questionnaire (EQ-5D) and the impact of disease using the 12-item Psoriatic Arthritis Impact of Disease (PsAID12). They assessed patients’ disability and work productivity using the Health Assessment Questionnaire–Disability Index (HAQ-DI) and Work Productivity and Impairment questionnaire (WPAI).
Overall disease presentation, duration, and use of biologics were similar between men and women. However, women reported significantly worse quality of life compared with men, with a mean EQ-5D score of 0.80 vs. 0.82 (P = .02).
Women also scored higher than men on measures of disability and work impairment, with mean HAQ-DI scores of 0.56 vs. 0.41 and mean WPAI scores of 27.9% vs. 24.6%, respectively (P < .01).
Disease burden was significantly higher in women vs. men based on PsAID12 scores (2.66 vs. 2.27, respectively) and women reported significantly higher levels of fatigue and pain (P < .01 for all).
More men than women reported working full-time (68.6% vs. 49.4%) but no gender differences emerged for work time missed because of PsA, the researchers noted.
However, women had significantly fewer comorbidities compared with men, based on the Charlson Comorbidity Index (1.10 vs. 1.15, P < .01).
“Other factors not assessed in the study are likely to be contributing to disease burden, and these unmeasured factors may affect men and women differently,” the researchers wrote in their discussion. These factors may include hormone levels and treatment outcomes, as well as sleep disturbance, anxiety, and joint erosion, they said.
The study findings were limited by several factors, including the possible overrepresentation of patients who visited physicians more often, the use of self-reports, and potential recall bias, as well as the lack of data on fibromyalgia prevalence using a validated score, the researchers noted. However, the results were strengthened by the large and geographically diverse study population and highlight the need for more research to examine the additional disease burden of PsA in women, and the potential of alternative treatment regimens to improve management of PsA in women, they concluded.
Mechanisms driving sex differences remain unclear
“In the past few decades, there has been increasing interest in the effect of sex on the manifestations and impact of PsA as well as on the response to therapy,” Dafna D. Gladman, MD, of the University of Toronto and the Krembil Research Institute at Toronto Western Hospital, wrote in an accompanying editorial.
The current study findings support previous research showing differences in disease expression in PsA between men and women, Dr. Gladman said. Several studies have shown more axial disease and joint damage in men than in women, while women reported greater functional disability and worse quality of life than men. The reasons for gender differences remain unclear, and genetics may play a role as well, she said.
Dr. Gladman emphasized the need for more research on the impact of fibromyalgia (FM) in particular. “As was shown in a previous study, the presence of FM affects the clinical assessment of patients with PsA,” she wrote. Fibromyalgia and pain reporting also may affect clinical trials of patients with PsA; however, the effect of fibromyalgia on sex differences is uncertain, she said. “In a disease that affects men and women equally, recognizing sex effect is important,” and more research is needed to explore the mechanisms behind this effect, she concluded.
The study was supported by Janssen Research & Development. Dr. Gossec disclosed receiving research grants and/or consulting fees from Janssen and 13 other pharmaceutical companies. Several study coauthors disclosed relationships with multiple companies, and several coauthors are employees and stockholders of Janssen. Dr. Gladman had no financial conflicts to disclose.
FROM THE JOURNAL OF RHEUMATOLOGY
Ten-day methotrexate pause after COVID vaccine booster enhances immunity against Omicron variant
People taking methotrexate for immunomodulatory diseases can skip one or two scheduled doses after they get an mRNA-based vaccine booster for COVID-19 and achieve a level of immunity against Omicron variants that’s comparable to people who aren’t immunosuppressed, a small observational cohort study from Germany reported.
“In general, the data suggest that pausing methotrexate is feasible, and it’s sufficient if the last dose occurs 1-3 days before the vaccination,” study coauthor Gerd Burmester, MD, a senior professor of rheumatology and immunology at the University of Medicine Berlin, told this news organization. “In pragmatic terms: pausing the methotrexate injection just twice after the vaccine is finished and, interestingly, not prior to the vaccination.”
The study, published online in RMD Open, included a statistical analysis that determined that a 10-day pause after the vaccination would be optimal, Dr. Burmester said.
Dr. Burmester and coauthors claimed this is the first study to evaluate the antibody response in patients on methotrexate against Omicron variants – in this study, variants BA.1 and BA.2 – after getting a COVID-19 mRNA booster. The study compared neutralizing serum activity of 50 patients taking methotrexate – 24 of whom continued treatments uninterrupted and 26 of whom paused treatments after getting a second booster – with 25 nonimmunosuppressed patients who served as controls. A total of 24% of the patients taking methotrexate received the mRNA-1273 vaccine while the entire control group received the Pfizer/BioNTech BNT162b2 vaccine.
The researchers used SARS-CoV-2 pseudovirus neutralization assays to evaluate post-vaccination antibody levels.
The U.S. Centers for Disease Control and Prevention and other government health agencies have recommended that immunocompromised patients get a fourth COVID-19 vaccination. But these vaccines can be problematic in patients taking methotrexate, which was linked to a reduced response after the second and third doses of the COVID-19 vaccine.
Previous studies reported that pausing methotrexate for 10 or 14 days after the first two vaccinations improved the production of neutralizing antibodies. A 2022 study found that a 2-week pause after a booster increased antibody response against S1 RBD (receptor binding domain) of the SARS-CoV-2 spike protein about twofold. Another recently published study of mRNA vaccines found that taking methotrexate with either a biologic or targeted synthetic disease-modifying antirheumatic drug reduces the efficacy of a third (booster) shot of SARS-CoV-2 mRNA vaccine in older adults but not younger patients with RA.
“Our study and also the other studies suggested that you can pause methotrexate treatment safely from a point of view of disease activity of rheumatoid arthritis,” Dr. Burmester said. “If you do the pause just twice or once only, it doesn’t lead to significant flares.”
Study results
The study found that serum neutralizing activity against the Omicron BA.1 variant, measured as geometric mean 50% inhibitory serum dilution (ID50s), wasn’t significantly different between the methotrexate and the nonimmunosuppressed groups before getting their mRNA booster (P = .657). However, 4 weeks after getting the booster, the nonimmunosuppressed group had a 68-fold increase in antibody activity versus a 20-fold increase in the methotrexate patients. After 12 weeks, ID50s in both groups decreased by about half (P = .001).
The methotrexate patients who continued therapy after the booster had significantly lower neutralization against Omicron BA.1 at both 4 weeks and 12 weeks than did their counterparts who paused therapy, as well as control patients.
The results were very similar in the same group comparisons of the serum neutralizing activity against the Omicron BA.2 variant at 4 and 12 weeks after booster vaccination.
Expert commentary
This study is noteworthy because it used SARS-CoV-2 pseudovirus neutralization assays to evaluate antibody levels, Kevin Winthrop, MD, MPH, professor of infectious disease and public health at Oregon Health & Science University, Portland, who was not involved in the study, said. “A lot of studies don’t look at neutralizing antibody titers, and that’s really what we care about,” Dr. Winthrop said. “What we want are functional antibodies that are doing something, and the only way to do that is to test them.”
The study is “confirmatory” of other studies that call for pausing methotrexate after vaccination, Dr. Winthrop said, including a study he coauthored, and which the German researchers cited, that found pausing methotrexate for a week or so after the influenza vaccination in RA patients improved vaccine immunogenicity. He added that the findings with the early Omicron variants are important because the newest boosters target the later Omicron variants, BA.4 and BA.5.
“The bottom line is that when someone comes in for a COVID-19 vaccination, tell them to be off of methotrexate for 7-10 days,” Dr. Winthrop said. “This is for the booster, but it raises the question: If you go out to three, four, or five vaccinations, does this matter anymore? With the flu vaccine, most people are out to 10 or 15 boosters, and we haven’t seen any significant increase in disease flares.”
The study received funding from Medac, Gilead/Galapagos, and Friends and Sponsors of Berlin Charity. Dr. Burmester reported no relevant disclosures. Dr. Winthrop is a research consultant to Pfizer.
A version of this article first appeared on Medscape.com.
People taking methotrexate for immunomodulatory diseases can skip one or two scheduled doses after they get an mRNA-based vaccine booster for COVID-19 and achieve a level of immunity against Omicron variants that’s comparable to people who aren’t immunosuppressed, a small observational cohort study from Germany reported.
“In general, the data suggest that pausing methotrexate is feasible, and it’s sufficient if the last dose occurs 1-3 days before the vaccination,” study coauthor Gerd Burmester, MD, a senior professor of rheumatology and immunology at the University of Medicine Berlin, told this news organization. “In pragmatic terms: pausing the methotrexate injection just twice after the vaccine is finished and, interestingly, not prior to the vaccination.”
The study, published online in RMD Open, included a statistical analysis that determined that a 10-day pause after the vaccination would be optimal, Dr. Burmester said.
Dr. Burmester and coauthors claimed this is the first study to evaluate the antibody response in patients on methotrexate against Omicron variants – in this study, variants BA.1 and BA.2 – after getting a COVID-19 mRNA booster. The study compared neutralizing serum activity of 50 patients taking methotrexate – 24 of whom continued treatments uninterrupted and 26 of whom paused treatments after getting a second booster – with 25 nonimmunosuppressed patients who served as controls. A total of 24% of the patients taking methotrexate received the mRNA-1273 vaccine while the entire control group received the Pfizer/BioNTech BNT162b2 vaccine.
The researchers used SARS-CoV-2 pseudovirus neutralization assays to evaluate post-vaccination antibody levels.
The U.S. Centers for Disease Control and Prevention and other government health agencies have recommended that immunocompromised patients get a fourth COVID-19 vaccination. But these vaccines can be problematic in patients taking methotrexate, which was linked to a reduced response after the second and third doses of the COVID-19 vaccine.
Previous studies reported that pausing methotrexate for 10 or 14 days after the first two vaccinations improved the production of neutralizing antibodies. A 2022 study found that a 2-week pause after a booster increased antibody response against S1 RBD (receptor binding domain) of the SARS-CoV-2 spike protein about twofold. Another recently published study of mRNA vaccines found that taking methotrexate with either a biologic or targeted synthetic disease-modifying antirheumatic drug reduces the efficacy of a third (booster) shot of SARS-CoV-2 mRNA vaccine in older adults but not younger patients with RA.
“Our study and also the other studies suggested that you can pause methotrexate treatment safely from a point of view of disease activity of rheumatoid arthritis,” Dr. Burmester said. “If you do the pause just twice or once only, it doesn’t lead to significant flares.”
Study results
The study found that serum neutralizing activity against the Omicron BA.1 variant, measured as geometric mean 50% inhibitory serum dilution (ID50s), wasn’t significantly different between the methotrexate and the nonimmunosuppressed groups before getting their mRNA booster (P = .657). However, 4 weeks after getting the booster, the nonimmunosuppressed group had a 68-fold increase in antibody activity versus a 20-fold increase in the methotrexate patients. After 12 weeks, ID50s in both groups decreased by about half (P = .001).
The methotrexate patients who continued therapy after the booster had significantly lower neutralization against Omicron BA.1 at both 4 weeks and 12 weeks than did their counterparts who paused therapy, as well as control patients.
The results were very similar in the same group comparisons of the serum neutralizing activity against the Omicron BA.2 variant at 4 and 12 weeks after booster vaccination.
Expert commentary
This study is noteworthy because it used SARS-CoV-2 pseudovirus neutralization assays to evaluate antibody levels, Kevin Winthrop, MD, MPH, professor of infectious disease and public health at Oregon Health & Science University, Portland, who was not involved in the study, said. “A lot of studies don’t look at neutralizing antibody titers, and that’s really what we care about,” Dr. Winthrop said. “What we want are functional antibodies that are doing something, and the only way to do that is to test them.”
The study is “confirmatory” of other studies that call for pausing methotrexate after vaccination, Dr. Winthrop said, including a study he coauthored, and which the German researchers cited, that found pausing methotrexate for a week or so after the influenza vaccination in RA patients improved vaccine immunogenicity. He added that the findings with the early Omicron variants are important because the newest boosters target the later Omicron variants, BA.4 and BA.5.
“The bottom line is that when someone comes in for a COVID-19 vaccination, tell them to be off of methotrexate for 7-10 days,” Dr. Winthrop said. “This is for the booster, but it raises the question: If you go out to three, four, or five vaccinations, does this matter anymore? With the flu vaccine, most people are out to 10 or 15 boosters, and we haven’t seen any significant increase in disease flares.”
The study received funding from Medac, Gilead/Galapagos, and Friends and Sponsors of Berlin Charity. Dr. Burmester reported no relevant disclosures. Dr. Winthrop is a research consultant to Pfizer.
A version of this article first appeared on Medscape.com.
People taking methotrexate for immunomodulatory diseases can skip one or two scheduled doses after they get an mRNA-based vaccine booster for COVID-19 and achieve a level of immunity against Omicron variants that’s comparable to people who aren’t immunosuppressed, a small observational cohort study from Germany reported.
“In general, the data suggest that pausing methotrexate is feasible, and it’s sufficient if the last dose occurs 1-3 days before the vaccination,” study coauthor Gerd Burmester, MD, a senior professor of rheumatology and immunology at the University of Medicine Berlin, told this news organization. “In pragmatic terms: pausing the methotrexate injection just twice after the vaccine is finished and, interestingly, not prior to the vaccination.”
The study, published online in RMD Open, included a statistical analysis that determined that a 10-day pause after the vaccination would be optimal, Dr. Burmester said.
Dr. Burmester and coauthors claimed this is the first study to evaluate the antibody response in patients on methotrexate against Omicron variants – in this study, variants BA.1 and BA.2 – after getting a COVID-19 mRNA booster. The study compared neutralizing serum activity of 50 patients taking methotrexate – 24 of whom continued treatments uninterrupted and 26 of whom paused treatments after getting a second booster – with 25 nonimmunosuppressed patients who served as controls. A total of 24% of the patients taking methotrexate received the mRNA-1273 vaccine while the entire control group received the Pfizer/BioNTech BNT162b2 vaccine.
The researchers used SARS-CoV-2 pseudovirus neutralization assays to evaluate post-vaccination antibody levels.
The U.S. Centers for Disease Control and Prevention and other government health agencies have recommended that immunocompromised patients get a fourth COVID-19 vaccination. But these vaccines can be problematic in patients taking methotrexate, which was linked to a reduced response after the second and third doses of the COVID-19 vaccine.
Previous studies reported that pausing methotrexate for 10 or 14 days after the first two vaccinations improved the production of neutralizing antibodies. A 2022 study found that a 2-week pause after a booster increased antibody response against S1 RBD (receptor binding domain) of the SARS-CoV-2 spike protein about twofold. Another recently published study of mRNA vaccines found that taking methotrexate with either a biologic or targeted synthetic disease-modifying antirheumatic drug reduces the efficacy of a third (booster) shot of SARS-CoV-2 mRNA vaccine in older adults but not younger patients with RA.
“Our study and also the other studies suggested that you can pause methotrexate treatment safely from a point of view of disease activity of rheumatoid arthritis,” Dr. Burmester said. “If you do the pause just twice or once only, it doesn’t lead to significant flares.”
Study results
The study found that serum neutralizing activity against the Omicron BA.1 variant, measured as geometric mean 50% inhibitory serum dilution (ID50s), wasn’t significantly different between the methotrexate and the nonimmunosuppressed groups before getting their mRNA booster (P = .657). However, 4 weeks after getting the booster, the nonimmunosuppressed group had a 68-fold increase in antibody activity versus a 20-fold increase in the methotrexate patients. After 12 weeks, ID50s in both groups decreased by about half (P = .001).
The methotrexate patients who continued therapy after the booster had significantly lower neutralization against Omicron BA.1 at both 4 weeks and 12 weeks than did their counterparts who paused therapy, as well as control patients.
The results were very similar in the same group comparisons of the serum neutralizing activity against the Omicron BA.2 variant at 4 and 12 weeks after booster vaccination.
Expert commentary
This study is noteworthy because it used SARS-CoV-2 pseudovirus neutralization assays to evaluate antibody levels, Kevin Winthrop, MD, MPH, professor of infectious disease and public health at Oregon Health & Science University, Portland, who was not involved in the study, said. “A lot of studies don’t look at neutralizing antibody titers, and that’s really what we care about,” Dr. Winthrop said. “What we want are functional antibodies that are doing something, and the only way to do that is to test them.”
The study is “confirmatory” of other studies that call for pausing methotrexate after vaccination, Dr. Winthrop said, including a study he coauthored, and which the German researchers cited, that found pausing methotrexate for a week or so after the influenza vaccination in RA patients improved vaccine immunogenicity. He added that the findings with the early Omicron variants are important because the newest boosters target the later Omicron variants, BA.4 and BA.5.
“The bottom line is that when someone comes in for a COVID-19 vaccination, tell them to be off of methotrexate for 7-10 days,” Dr. Winthrop said. “This is for the booster, but it raises the question: If you go out to three, four, or five vaccinations, does this matter anymore? With the flu vaccine, most people are out to 10 or 15 boosters, and we haven’t seen any significant increase in disease flares.”
The study received funding from Medac, Gilead/Galapagos, and Friends and Sponsors of Berlin Charity. Dr. Burmester reported no relevant disclosures. Dr. Winthrop is a research consultant to Pfizer.
A version of this article first appeared on Medscape.com.
FROM RMD OPEN
JAK inhibitors show no excess cardiovascular safety signal in French nationwide cohort
Janus kinase inhibitors tofacitinib (Xeljanz) and baricitinib (Olumiant) may pose no greater risk than does adalimumab (Humira and biosimilars) for major adverse cardiovascular events (MACEs) or venous thromboembolism (VTE) on the basis of a nationwide cohort study.
The French data, which included almost 16,000 patients with rheumatoid arthritis, revealed similar safety across subgroups, including older patients with at least one preexisting cardiovascular risk factor, reported lead author Léa Hoisnard, MD, of Henri Mondor Hospital, Paris, and colleagues.
These findings arrive 1 year after the U.S. Food and Drug Administration imposed class-wide boxed warnings on three Janus kinase (JAK) inhibitors, citing increased risks for both cancer and serious cardiac events detected by the open-label, randomized ORAL Surveillance postmarketing trial, which compared tofacitinib against adalimumab and etanercept.
More recently, the observational STAR-RA study, relying upon private insurance and Medicare claims in the United States, found no significant increase in cardiovascular events among patients taking tofacitinib, adding some uncertainty to the conversation.
“In this context, observational studies of unselected populations outside of North America are still needed to assess other JAK inhibitor agents,” Dr. Hoisnard and colleagues write in Annals of the Rheumatic Diseases.
Their retrospective study included 8,481 patients who received baricitinib or tofacitinib, and 7,354 patients who received adalimumab. Almost all patients in the tofacitinib group received 5 mg twice daily instead of 10 mg twice daily (99.4% vs. 0.6%), so cardiovascular safety was assessed only for the 5-mg dose. Baricitinib was prescribed at 4-mg and 2-mg doses (79.5% vs. 20.5%), allowing inclusion of both dose levels. The investigators accounted for a range of covariates, including concurrent therapy, comorbidities, and other patient characteristics.
Median follow-up durations were 440 days in the JAK inhibitor group and 344 days in the adalimumab group. The JAK inhibitor group had numerically more MACEs than did the adalimumab group, but the difference in risk was not statistically significant (54 vs. 35 MACEs; weighted hazard ratio, 1.0; 95% confidence interval, 0.7-1.5; P = .99). Similarly, more patients taking JAK inhibitors had VTEs, but relative risk was, again, not significant (75 vs. 32 VTEs; HRw, 1.1; 95% CI, 0.7-1.6; P = .63).
These findings were consistent for all subgroups, including patients aged 50 years or older and patients aged 65 years or older, although the investigators noted that statistical power was lacking for subgroup analyses.
Findings from Echo ORAL Surveillance
“I think the baricitinib data are important,” Kevin Winthrop, MD, MPH, professor of infectious diseases and epidemiology at Oregon Health & Science University, Portland, told this news organization. “There’s no difference between 2 mg and 4 mg [dose levels] in this analysis. And there doesn’t really seem to be a difference between baricitinib and tofacitinib. Most of the results are pretty consistent with ORAL Surveillance, which was a randomized, controlled trial.”
Dr. Winthrop, who has been active in JAK inhibitor clinical trials, recently coauthored an article in Nature Reviews Rheumatology encouraging clinicians to remember that the cardiovascular risks of JAK inhibitors are relative to adalimumab, and safety should be framed within the context of risk-to-benefit ratios.
He and his coauthor also called into question the FDA’s “better to be safe than sorry” approach, which resulted in boxed warnings across all JAK inhibitors, despite differences in target specificity.
“There are pros and cons of taking that approach,” Dr. Winthrop said in an interview. “The FDA might ultimately be right. Certainly, these drugs appear similar for some types of events, like herpes zoster, for example. But whether they’re similar with regard to malignancy or cardiovascular events, I don’t think we know.”
Dr. Winthrop noted that deucravacitinib was recently approved for psoriasis sans boxed warning, suggesting inconsistency in the FDA’s approach. The agent headlines as a “TYK2 inhibitor,” but TYK2 is a member of the JAK family.
“I don’t know why the FDA decided to treat them differently,” Dr. Winthrop said.
Boxed warnings encourage caution, lock treatment sequence
Michael Thakor, MD, of Arthritis & Rheumatology Clinic of Northern Colorado, Fort Collins, supports the boxed warnings because they encourage caution and transparency.
“It forces you to have that discussion with your patient, which may take some time, but it’s actually a very good thing,” Dr. Thakor said in an interview. “Some patients will say, ‘Oh my gosh, I don’t want to take that drug.’ But most patients, considering the level of risk that you’re talking about, are actually okay going ahead with the medication.”
If these risks aren’t discussed, he noted, patient trust may falter.
“They’re going to go online, and they’re going to be reading about it,” Dr. Thakor said. “And then they tend to get more spooked. They also may question your advice from then on, if you’re not telling them the possible risk.”
Reflecting on the present study, Dr. Thakor said that the findings initially appeared reassuring, but he became concerned about the lack of power and how adverse events trended higher in the JAK inhibitor group, particularly for VTEs, most of which occurred with baricitinib. This latter finding is challenging to interpret, however, because the 4-mg dose is not used in the United States, he added.
Dr. Thakor described how JAK inhibitors once seemed poised to assume a frontline role in RA until the boxed warnings came out. These safety concerns don’t take JAK inhibitors off the table, he said, but they do keep the class further down the treatment sequence, and the present data don’t alter this picture in daily practice.
“If I had a patient who was over the age of 50 with at least one cardiovascular risk factor, I might have a little bit of concern, but if they need their RA treated, I would definitely discuss the possibility of using a JAK inhibitor,” Dr. Thakor said. “If the patient is comfortable with it, then I would feel comfortable going ahead.”
The investigators disclosed no outside funding or conflicts of interest. Dr. Winthrop disclosed relationships with AbbVie, AstraZeneca, Bristol-Myers Squibb, and others. Dr. Thakor disclosed no conflicts of interest.
A version of this article first appeared on Medscape.com.
Janus kinase inhibitors tofacitinib (Xeljanz) and baricitinib (Olumiant) may pose no greater risk than does adalimumab (Humira and biosimilars) for major adverse cardiovascular events (MACEs) or venous thromboembolism (VTE) on the basis of a nationwide cohort study.
The French data, which included almost 16,000 patients with rheumatoid arthritis, revealed similar safety across subgroups, including older patients with at least one preexisting cardiovascular risk factor, reported lead author Léa Hoisnard, MD, of Henri Mondor Hospital, Paris, and colleagues.
These findings arrive 1 year after the U.S. Food and Drug Administration imposed class-wide boxed warnings on three Janus kinase (JAK) inhibitors, citing increased risks for both cancer and serious cardiac events detected by the open-label, randomized ORAL Surveillance postmarketing trial, which compared tofacitinib against adalimumab and etanercept.
More recently, the observational STAR-RA study, relying upon private insurance and Medicare claims in the United States, found no significant increase in cardiovascular events among patients taking tofacitinib, adding some uncertainty to the conversation.
“In this context, observational studies of unselected populations outside of North America are still needed to assess other JAK inhibitor agents,” Dr. Hoisnard and colleagues write in Annals of the Rheumatic Diseases.
Their retrospective study included 8,481 patients who received baricitinib or tofacitinib, and 7,354 patients who received adalimumab. Almost all patients in the tofacitinib group received 5 mg twice daily instead of 10 mg twice daily (99.4% vs. 0.6%), so cardiovascular safety was assessed only for the 5-mg dose. Baricitinib was prescribed at 4-mg and 2-mg doses (79.5% vs. 20.5%), allowing inclusion of both dose levels. The investigators accounted for a range of covariates, including concurrent therapy, comorbidities, and other patient characteristics.
Median follow-up durations were 440 days in the JAK inhibitor group and 344 days in the adalimumab group. The JAK inhibitor group had numerically more MACEs than did the adalimumab group, but the difference in risk was not statistically significant (54 vs. 35 MACEs; weighted hazard ratio, 1.0; 95% confidence interval, 0.7-1.5; P = .99). Similarly, more patients taking JAK inhibitors had VTEs, but relative risk was, again, not significant (75 vs. 32 VTEs; HRw, 1.1; 95% CI, 0.7-1.6; P = .63).
These findings were consistent for all subgroups, including patients aged 50 years or older and patients aged 65 years or older, although the investigators noted that statistical power was lacking for subgroup analyses.
Findings from Echo ORAL Surveillance
“I think the baricitinib data are important,” Kevin Winthrop, MD, MPH, professor of infectious diseases and epidemiology at Oregon Health & Science University, Portland, told this news organization. “There’s no difference between 2 mg and 4 mg [dose levels] in this analysis. And there doesn’t really seem to be a difference between baricitinib and tofacitinib. Most of the results are pretty consistent with ORAL Surveillance, which was a randomized, controlled trial.”
Dr. Winthrop, who has been active in JAK inhibitor clinical trials, recently coauthored an article in Nature Reviews Rheumatology encouraging clinicians to remember that the cardiovascular risks of JAK inhibitors are relative to adalimumab, and safety should be framed within the context of risk-to-benefit ratios.
He and his coauthor also called into question the FDA’s “better to be safe than sorry” approach, which resulted in boxed warnings across all JAK inhibitors, despite differences in target specificity.
“There are pros and cons of taking that approach,” Dr. Winthrop said in an interview. “The FDA might ultimately be right. Certainly, these drugs appear similar for some types of events, like herpes zoster, for example. But whether they’re similar with regard to malignancy or cardiovascular events, I don’t think we know.”
Dr. Winthrop noted that deucravacitinib was recently approved for psoriasis sans boxed warning, suggesting inconsistency in the FDA’s approach. The agent headlines as a “TYK2 inhibitor,” but TYK2 is a member of the JAK family.
“I don’t know why the FDA decided to treat them differently,” Dr. Winthrop said.
Boxed warnings encourage caution, lock treatment sequence
Michael Thakor, MD, of Arthritis & Rheumatology Clinic of Northern Colorado, Fort Collins, supports the boxed warnings because they encourage caution and transparency.
“It forces you to have that discussion with your patient, which may take some time, but it’s actually a very good thing,” Dr. Thakor said in an interview. “Some patients will say, ‘Oh my gosh, I don’t want to take that drug.’ But most patients, considering the level of risk that you’re talking about, are actually okay going ahead with the medication.”
If these risks aren’t discussed, he noted, patient trust may falter.
“They’re going to go online, and they’re going to be reading about it,” Dr. Thakor said. “And then they tend to get more spooked. They also may question your advice from then on, if you’re not telling them the possible risk.”
Reflecting on the present study, Dr. Thakor said that the findings initially appeared reassuring, but he became concerned about the lack of power and how adverse events trended higher in the JAK inhibitor group, particularly for VTEs, most of which occurred with baricitinib. This latter finding is challenging to interpret, however, because the 4-mg dose is not used in the United States, he added.
Dr. Thakor described how JAK inhibitors once seemed poised to assume a frontline role in RA until the boxed warnings came out. These safety concerns don’t take JAK inhibitors off the table, he said, but they do keep the class further down the treatment sequence, and the present data don’t alter this picture in daily practice.
“If I had a patient who was over the age of 50 with at least one cardiovascular risk factor, I might have a little bit of concern, but if they need their RA treated, I would definitely discuss the possibility of using a JAK inhibitor,” Dr. Thakor said. “If the patient is comfortable with it, then I would feel comfortable going ahead.”
The investigators disclosed no outside funding or conflicts of interest. Dr. Winthrop disclosed relationships with AbbVie, AstraZeneca, Bristol-Myers Squibb, and others. Dr. Thakor disclosed no conflicts of interest.
A version of this article first appeared on Medscape.com.
Janus kinase inhibitors tofacitinib (Xeljanz) and baricitinib (Olumiant) may pose no greater risk than does adalimumab (Humira and biosimilars) for major adverse cardiovascular events (MACEs) or venous thromboembolism (VTE) on the basis of a nationwide cohort study.
The French data, which included almost 16,000 patients with rheumatoid arthritis, revealed similar safety across subgroups, including older patients with at least one preexisting cardiovascular risk factor, reported lead author Léa Hoisnard, MD, of Henri Mondor Hospital, Paris, and colleagues.
These findings arrive 1 year after the U.S. Food and Drug Administration imposed class-wide boxed warnings on three Janus kinase (JAK) inhibitors, citing increased risks for both cancer and serious cardiac events detected by the open-label, randomized ORAL Surveillance postmarketing trial, which compared tofacitinib against adalimumab and etanercept.
More recently, the observational STAR-RA study, relying upon private insurance and Medicare claims in the United States, found no significant increase in cardiovascular events among patients taking tofacitinib, adding some uncertainty to the conversation.
“In this context, observational studies of unselected populations outside of North America are still needed to assess other JAK inhibitor agents,” Dr. Hoisnard and colleagues write in Annals of the Rheumatic Diseases.
Their retrospective study included 8,481 patients who received baricitinib or tofacitinib, and 7,354 patients who received adalimumab. Almost all patients in the tofacitinib group received 5 mg twice daily instead of 10 mg twice daily (99.4% vs. 0.6%), so cardiovascular safety was assessed only for the 5-mg dose. Baricitinib was prescribed at 4-mg and 2-mg doses (79.5% vs. 20.5%), allowing inclusion of both dose levels. The investigators accounted for a range of covariates, including concurrent therapy, comorbidities, and other patient characteristics.
Median follow-up durations were 440 days in the JAK inhibitor group and 344 days in the adalimumab group. The JAK inhibitor group had numerically more MACEs than did the adalimumab group, but the difference in risk was not statistically significant (54 vs. 35 MACEs; weighted hazard ratio, 1.0; 95% confidence interval, 0.7-1.5; P = .99). Similarly, more patients taking JAK inhibitors had VTEs, but relative risk was, again, not significant (75 vs. 32 VTEs; HRw, 1.1; 95% CI, 0.7-1.6; P = .63).
These findings were consistent for all subgroups, including patients aged 50 years or older and patients aged 65 years or older, although the investigators noted that statistical power was lacking for subgroup analyses.
Findings from Echo ORAL Surveillance
“I think the baricitinib data are important,” Kevin Winthrop, MD, MPH, professor of infectious diseases and epidemiology at Oregon Health & Science University, Portland, told this news organization. “There’s no difference between 2 mg and 4 mg [dose levels] in this analysis. And there doesn’t really seem to be a difference between baricitinib and tofacitinib. Most of the results are pretty consistent with ORAL Surveillance, which was a randomized, controlled trial.”
Dr. Winthrop, who has been active in JAK inhibitor clinical trials, recently coauthored an article in Nature Reviews Rheumatology encouraging clinicians to remember that the cardiovascular risks of JAK inhibitors are relative to adalimumab, and safety should be framed within the context of risk-to-benefit ratios.
He and his coauthor also called into question the FDA’s “better to be safe than sorry” approach, which resulted in boxed warnings across all JAK inhibitors, despite differences in target specificity.
“There are pros and cons of taking that approach,” Dr. Winthrop said in an interview. “The FDA might ultimately be right. Certainly, these drugs appear similar for some types of events, like herpes zoster, for example. But whether they’re similar with regard to malignancy or cardiovascular events, I don’t think we know.”
Dr. Winthrop noted that deucravacitinib was recently approved for psoriasis sans boxed warning, suggesting inconsistency in the FDA’s approach. The agent headlines as a “TYK2 inhibitor,” but TYK2 is a member of the JAK family.
“I don’t know why the FDA decided to treat them differently,” Dr. Winthrop said.
Boxed warnings encourage caution, lock treatment sequence
Michael Thakor, MD, of Arthritis & Rheumatology Clinic of Northern Colorado, Fort Collins, supports the boxed warnings because they encourage caution and transparency.
“It forces you to have that discussion with your patient, which may take some time, but it’s actually a very good thing,” Dr. Thakor said in an interview. “Some patients will say, ‘Oh my gosh, I don’t want to take that drug.’ But most patients, considering the level of risk that you’re talking about, are actually okay going ahead with the medication.”
If these risks aren’t discussed, he noted, patient trust may falter.
“They’re going to go online, and they’re going to be reading about it,” Dr. Thakor said. “And then they tend to get more spooked. They also may question your advice from then on, if you’re not telling them the possible risk.”
Reflecting on the present study, Dr. Thakor said that the findings initially appeared reassuring, but he became concerned about the lack of power and how adverse events trended higher in the JAK inhibitor group, particularly for VTEs, most of which occurred with baricitinib. This latter finding is challenging to interpret, however, because the 4-mg dose is not used in the United States, he added.
Dr. Thakor described how JAK inhibitors once seemed poised to assume a frontline role in RA until the boxed warnings came out. These safety concerns don’t take JAK inhibitors off the table, he said, but they do keep the class further down the treatment sequence, and the present data don’t alter this picture in daily practice.
“If I had a patient who was over the age of 50 with at least one cardiovascular risk factor, I might have a little bit of concern, but if they need their RA treated, I would definitely discuss the possibility of using a JAK inhibitor,” Dr. Thakor said. “If the patient is comfortable with it, then I would feel comfortable going ahead.”
The investigators disclosed no outside funding or conflicts of interest. Dr. Winthrop disclosed relationships with AbbVie, AstraZeneca, Bristol-Myers Squibb, and others. Dr. Thakor disclosed no conflicts of interest.
A version of this article first appeared on Medscape.com.
FROM ANNALS OF THE RHEUMATIC DISEASES
Hard-rock mining and other mining work raise RA risk
Workers in the hard rock and other mining industries were significantly more likely to develop rheumatoid arthritis than were controls in the general population, based on data from nearly 2,000 individuals.
Although respirable silica exposure has been consistently linked to rheumatoid arthritis (RA) in a variety of occupations including foundry work, construction, and stone crushing and drilling, the association between RA risk and hard rock mining has not been investigated, lead author Paul D. Blanc, MD, of the University of California, San Francisco, and colleagues wrote in a study published in JAMA Network Open.
“Many clinical rheumatologists and most generalists are unaware that what a person does for a living can be a risk factor for rheumatoid arthritis,” Dr. Blanc said in an interview. “This study makes an important contribution to showing that work exposures can more than double the risk of RA,” he said.
“We were surprised by the widespread nature of the work-related risk within and beyond the mining sector,” Dr. Blanc noted. Given the range of potential occupational exposures, his take-home message to rheumatologists is to ask each and every patient about their work history.
The researchers conducted random telephone surveys of 1,988 men aged 50 years and older living in the Four Corners region of the United States (Colorado, New Mexico, and Utah) in counties selected for high levels of pneumoconiosis mortality. The surveys were conducted between Jan. 12, 2021, and May 4, 2021. The mean age of the study population was 68.6 years, and 82.6% were non-Hispanic White. Approximately half reported being former or current smokers.
RA was defined as having a clinician diagnosis, and was further defined by treatment with corticosteroids or disease-modifying antirheumatic drugs (DMARDs).
A total of 262 respondents (13.1%) reported work in surface mining or ore processing, with no underground exposure; 118 respondents (5.9%) reported work in underground hard rock mining; and 62 (3.1%) reported work in underground mining of other type, primarily coal mining.
Overall, after adjusting for age, smoking, and nonmining silica exposure, any mining work was associated with a three- to fourfold increased risk of RA for individuals with a RA diagnosis who were treated with corticosteroids and those treated with DMARDs (odds ratios, 4.12 and 3.30, respectively).
The risk was approximately nine times and six times higher for individuals with a history of underground soft rock mining (mainly coal, no hard rock mining), with odds ratios of 9.74 and 6.42, for those with RA treated with corticosteroids and DMARDs, respectively.
The odds of RA were higher with coal and other underground fossil hydrocarbon mining, compared with underground hard rock mining, the researchers wrote in their discussion. Reasons for this difference could include the longer employment duration for underground coal mining, but also the possibility that “in coal mining, silica inhalation may not be the sole cause, but rather that carbonaceous materials may also be involved etiologically in RA risk in that occupation,” they wrote. No association was found between increased risk of RA and current or former smoking, they noted, in contrast to the researchers’ previous studies of Appalachian coal miners.
The study findings were limited by several factors including the potential for recall bias and misclassified exposure and diagnoses, the researchers noted. Other limitations include the focus on individuals aged 50 years and older in a limited geographic region of the United States and the relatively short time of employment in mining, they said.
However, the results support previous studies showing an increased RA risk with respirable silica exposure, and suggest that clinicians consider mining among other work exposures that could increase the risk for developing RA, the researchers concluded.
Looking ahead, Dr. Blanc said that additional research is needed to tease out disease progression and severity in the face of past occupational exposures.
The study was supported by the Alpha Foundation and the Russell/Engleman Rheumatology Research Center through grants to the researchers. The researchers had no other financial conflicts to disclose.
Workers in the hard rock and other mining industries were significantly more likely to develop rheumatoid arthritis than were controls in the general population, based on data from nearly 2,000 individuals.
Although respirable silica exposure has been consistently linked to rheumatoid arthritis (RA) in a variety of occupations including foundry work, construction, and stone crushing and drilling, the association between RA risk and hard rock mining has not been investigated, lead author Paul D. Blanc, MD, of the University of California, San Francisco, and colleagues wrote in a study published in JAMA Network Open.
“Many clinical rheumatologists and most generalists are unaware that what a person does for a living can be a risk factor for rheumatoid arthritis,” Dr. Blanc said in an interview. “This study makes an important contribution to showing that work exposures can more than double the risk of RA,” he said.
“We were surprised by the widespread nature of the work-related risk within and beyond the mining sector,” Dr. Blanc noted. Given the range of potential occupational exposures, his take-home message to rheumatologists is to ask each and every patient about their work history.
The researchers conducted random telephone surveys of 1,988 men aged 50 years and older living in the Four Corners region of the United States (Colorado, New Mexico, and Utah) in counties selected for high levels of pneumoconiosis mortality. The surveys were conducted between Jan. 12, 2021, and May 4, 2021. The mean age of the study population was 68.6 years, and 82.6% were non-Hispanic White. Approximately half reported being former or current smokers.
RA was defined as having a clinician diagnosis, and was further defined by treatment with corticosteroids or disease-modifying antirheumatic drugs (DMARDs).
A total of 262 respondents (13.1%) reported work in surface mining or ore processing, with no underground exposure; 118 respondents (5.9%) reported work in underground hard rock mining; and 62 (3.1%) reported work in underground mining of other type, primarily coal mining.
Overall, after adjusting for age, smoking, and nonmining silica exposure, any mining work was associated with a three- to fourfold increased risk of RA for individuals with a RA diagnosis who were treated with corticosteroids and those treated with DMARDs (odds ratios, 4.12 and 3.30, respectively).
The risk was approximately nine times and six times higher for individuals with a history of underground soft rock mining (mainly coal, no hard rock mining), with odds ratios of 9.74 and 6.42, for those with RA treated with corticosteroids and DMARDs, respectively.
The odds of RA were higher with coal and other underground fossil hydrocarbon mining, compared with underground hard rock mining, the researchers wrote in their discussion. Reasons for this difference could include the longer employment duration for underground coal mining, but also the possibility that “in coal mining, silica inhalation may not be the sole cause, but rather that carbonaceous materials may also be involved etiologically in RA risk in that occupation,” they wrote. No association was found between increased risk of RA and current or former smoking, they noted, in contrast to the researchers’ previous studies of Appalachian coal miners.
The study findings were limited by several factors including the potential for recall bias and misclassified exposure and diagnoses, the researchers noted. Other limitations include the focus on individuals aged 50 years and older in a limited geographic region of the United States and the relatively short time of employment in mining, they said.
However, the results support previous studies showing an increased RA risk with respirable silica exposure, and suggest that clinicians consider mining among other work exposures that could increase the risk for developing RA, the researchers concluded.
Looking ahead, Dr. Blanc said that additional research is needed to tease out disease progression and severity in the face of past occupational exposures.
The study was supported by the Alpha Foundation and the Russell/Engleman Rheumatology Research Center through grants to the researchers. The researchers had no other financial conflicts to disclose.
Workers in the hard rock and other mining industries were significantly more likely to develop rheumatoid arthritis than were controls in the general population, based on data from nearly 2,000 individuals.
Although respirable silica exposure has been consistently linked to rheumatoid arthritis (RA) in a variety of occupations including foundry work, construction, and stone crushing and drilling, the association between RA risk and hard rock mining has not been investigated, lead author Paul D. Blanc, MD, of the University of California, San Francisco, and colleagues wrote in a study published in JAMA Network Open.
“Many clinical rheumatologists and most generalists are unaware that what a person does for a living can be a risk factor for rheumatoid arthritis,” Dr. Blanc said in an interview. “This study makes an important contribution to showing that work exposures can more than double the risk of RA,” he said.
“We were surprised by the widespread nature of the work-related risk within and beyond the mining sector,” Dr. Blanc noted. Given the range of potential occupational exposures, his take-home message to rheumatologists is to ask each and every patient about their work history.
The researchers conducted random telephone surveys of 1,988 men aged 50 years and older living in the Four Corners region of the United States (Colorado, New Mexico, and Utah) in counties selected for high levels of pneumoconiosis mortality. The surveys were conducted between Jan. 12, 2021, and May 4, 2021. The mean age of the study population was 68.6 years, and 82.6% were non-Hispanic White. Approximately half reported being former or current smokers.
RA was defined as having a clinician diagnosis, and was further defined by treatment with corticosteroids or disease-modifying antirheumatic drugs (DMARDs).
A total of 262 respondents (13.1%) reported work in surface mining or ore processing, with no underground exposure; 118 respondents (5.9%) reported work in underground hard rock mining; and 62 (3.1%) reported work in underground mining of other type, primarily coal mining.
Overall, after adjusting for age, smoking, and nonmining silica exposure, any mining work was associated with a three- to fourfold increased risk of RA for individuals with a RA diagnosis who were treated with corticosteroids and those treated with DMARDs (odds ratios, 4.12 and 3.30, respectively).
The risk was approximately nine times and six times higher for individuals with a history of underground soft rock mining (mainly coal, no hard rock mining), with odds ratios of 9.74 and 6.42, for those with RA treated with corticosteroids and DMARDs, respectively.
The odds of RA were higher with coal and other underground fossil hydrocarbon mining, compared with underground hard rock mining, the researchers wrote in their discussion. Reasons for this difference could include the longer employment duration for underground coal mining, but also the possibility that “in coal mining, silica inhalation may not be the sole cause, but rather that carbonaceous materials may also be involved etiologically in RA risk in that occupation,” they wrote. No association was found between increased risk of RA and current or former smoking, they noted, in contrast to the researchers’ previous studies of Appalachian coal miners.
The study findings were limited by several factors including the potential for recall bias and misclassified exposure and diagnoses, the researchers noted. Other limitations include the focus on individuals aged 50 years and older in a limited geographic region of the United States and the relatively short time of employment in mining, they said.
However, the results support previous studies showing an increased RA risk with respirable silica exposure, and suggest that clinicians consider mining among other work exposures that could increase the risk for developing RA, the researchers concluded.
Looking ahead, Dr. Blanc said that additional research is needed to tease out disease progression and severity in the face of past occupational exposures.
The study was supported by the Alpha Foundation and the Russell/Engleman Rheumatology Research Center through grants to the researchers. The researchers had no other financial conflicts to disclose.
FROM JAMA NETWORK OPEN
Previous endemic coronavirus encounters linked with long COVID
People who develop long COVID may be responding more strongly to a non–SARS-CoV-2 virus they encountered in the past than to SARS-CoV-2, a study by researchers at Harvard Medical School suggests.
Long COVID, also called postacute sequelae of COVID-19 (PASC), causes various symptoms that persist at least 4 weeks after the initial SARS-CoV-2 infection, they write in the preprint server medRxiv. Four authors explained their research into possible mechanisms of long COVID in an interview.
“Immunity to non-COVID endemic coronaviruses may play a role in who develops PASC,” co–lead author Jonathan D. Herman, MD, PhD, said. “There’s still so much more we need to understand, but it is striking that back-boosting of immune responses to coronavirus OC43 was uniquely enriched in individuals with PASC.”
“In the study, individuals with PASC preferentially generated stronger responses to previously encountered cold-causing coronaviruses,” co–senior author Galit Alter, PhD, said.
“Instead of generating strong SARS-CoV-2 immunity, they bolstered a response to a different coronavirus, potentially making their response less effective in clearing SARS-CoV-2. Surprisingly, most of the individuals had been vaccinated – and they still maintained this unusual antibody response – pointing to new therapeutic pathways to treat PASC,” Dr. Alter said.
Humoral immunity offers a clue to long-COVID origins
One-fifth of COVID-19 patients progress to long COVID, but which patients develop PASC and why are not well understood, the authors write.
“Antibodies represent powerful biomarkers that have been used for decades to diagnose disease. However, antibodies also provide a powerful source of information on previous infections. The use of antibody profiling, here, pointed to the presence of incomplete antibody responses to SARS-CoV-2 in individuals with PASC,” Dr. Alter said.
The researchers reviewed the medical records of patients in the Mass General Brigham health care system in Boston, including referrals from rheumatologists of participants diagnosed with COVID-19 outside the MGB system, starting on March 1, 2020.
They focused on patients with systemic autoimmune rheumatic diseases (SARDs) because their tendency toward inflammation and autoantibody production may make them more susceptible to PASC and enrich for specific inflammatory-driven endotypes.
All 43 participants had COVID-19 without hospital admission and SARDs. Patients treated only for fibromyalgia, osteoarthritis, mechanical back pain, gout, or pseudogout without a SARD were excluded from the study.
Overall, 79% of participants were female, 35% had rheumatoid arthritis, 19% had psoriatic arthritis, and 95% had received a COVID-19 vaccine.
The researchers used systems serology to perform comprehensive antibody profiling against SARS-CoV-2 and a panel of endemic pathogens or routine vaccine antigens.
Long-COVID patients had a distinct immune response
Overall, 17 patients developed PASC and 26 did not, and in those with PASC, they found a distinct humoral immune response. Patients with PASC:
- harbored less inflamed and weaker Fc-gamma receptor–binding anti–SARS-CoV-2 antibodies;
- showed a significantly expanded and more inflamed antibody response against endemic coronavirus OC43; and
- mounted more avid IgM responses and developed expanded inflammatory OC43 S2–specific Fc-receptor–binding responses, which were linked to cross reactivity across SARS-CoV-2 and common coronaviruses.
“Strengths of the study include the detailed phenotypes of cases after COVID-19, particularly to classify PASC presence or absence, as well as the depth and breadth of antibody profiling. This allowed us to identify a humoral immune signature of PASC,” said co–senior author Jeffrey A. Sparks, MD, MMSc.
“However, the study was limited in its size to investigate different types of PASC, such as fatigue or lung symptoms, that may have biologic differences. Also, all patients in the study had a preexisting rheumatic disease,” he acknowledged.
“A substantial portion of patients with COVID-19 will develop PASC, which can have substantial impact on health and quality of life,” said co–senior author Zachary S. Wallace, MD, MS. “Given the higher risk of COVID-19 in many patients with rheumatic disease, it is important to understand the etiology of PASC in this vulnerable population, to enable future diagnostic and therapeutic advances.”
Davey Smith, MD, professor of medicine and head of infectious diseases and global public health at the University of California, San Diego, in La Jolla, who was not involved in the study, called the findings interesting even though the results will not immediately affect patient care.
“There may be a link between previous non–SARS-CoV-2 coronavirus infection and PASC,” he added. “Perhaps, by understanding why some people do and do not get PASC, we can develop treatments for the condition.
“This paper is a preprint and will need to go through peer review,” Dr. Smith said. “There are many elements that need to be scrutinized. For example, there is no definition of PASC that is universally accepted, so how did that play into this study?”
Mark Cameron, PhD, associate professor in the department of population and quantitative health sciences at Case Western Reserve University, Cleveland, called this a strong study from a strong group, although it is a preprint prior to peer review.
“In this initial study, the scientists focused on people who had rheumatic disease before getting COVID-19, knowing they are at higher risk for lasting complications and hopefully are more immunologically similar when diagnosed with long COVID – a single ‘endotype’ or group of patients with similar clinical symptoms and background,” he noted.
“Our immune system’s memory sometimes fails to effectively fight a new virus that looks too much like a virus it saw before. This ineffective immune response can set up various problems, including the poor recoveries we see in people with long COVID,” he said.
“OC43 probably emerged in the late 1800s and probably caused a pandemic of severe respiratory illness between 1889 and 1890, previously thought to be a flu,” Dr. Cameron recalled. “OC43 is still around as an endemic coronavirus, usually causing mild or moderate upper-respiratory infections.”
COVID-19 immunity is complex, and previous SARS-CoV-2 infection doesn’t guarantee we won't get COVID-19 again, especially as new variants emerge, added Dr. Cameron, who also was not involved in the study.
“This study may help us better understand the risks and possible mechanisms associated with COVID-19 and long COVID in the face of previous coronavirus infections,” he said. “It may also help guide future COVID-19 therapies and vaccines.”
The authors plan further related research.
The study received grant support and an anonymous donation. Dr. Alter, Dr. Sparks, and Dr. Wallace report financial relationships with the pharmaceutical industry. All other authors, and Dr. Davey and Dr. Cameron, report no conflicts of interest with the study. All experts commented by email.
* This story was updated 10/12/2022.
People who develop long COVID may be responding more strongly to a non–SARS-CoV-2 virus they encountered in the past than to SARS-CoV-2, a study by researchers at Harvard Medical School suggests.
Long COVID, also called postacute sequelae of COVID-19 (PASC), causes various symptoms that persist at least 4 weeks after the initial SARS-CoV-2 infection, they write in the preprint server medRxiv. Four authors explained their research into possible mechanisms of long COVID in an interview.
“Immunity to non-COVID endemic coronaviruses may play a role in who develops PASC,” co–lead author Jonathan D. Herman, MD, PhD, said. “There’s still so much more we need to understand, but it is striking that back-boosting of immune responses to coronavirus OC43 was uniquely enriched in individuals with PASC.”
“In the study, individuals with PASC preferentially generated stronger responses to previously encountered cold-causing coronaviruses,” co–senior author Galit Alter, PhD, said.
“Instead of generating strong SARS-CoV-2 immunity, they bolstered a response to a different coronavirus, potentially making their response less effective in clearing SARS-CoV-2. Surprisingly, most of the individuals had been vaccinated – and they still maintained this unusual antibody response – pointing to new therapeutic pathways to treat PASC,” Dr. Alter said.
Humoral immunity offers a clue to long-COVID origins
One-fifth of COVID-19 patients progress to long COVID, but which patients develop PASC and why are not well understood, the authors write.
“Antibodies represent powerful biomarkers that have been used for decades to diagnose disease. However, antibodies also provide a powerful source of information on previous infections. The use of antibody profiling, here, pointed to the presence of incomplete antibody responses to SARS-CoV-2 in individuals with PASC,” Dr. Alter said.
The researchers reviewed the medical records of patients in the Mass General Brigham health care system in Boston, including referrals from rheumatologists of participants diagnosed with COVID-19 outside the MGB system, starting on March 1, 2020.
They focused on patients with systemic autoimmune rheumatic diseases (SARDs) because their tendency toward inflammation and autoantibody production may make them more susceptible to PASC and enrich for specific inflammatory-driven endotypes.
All 43 participants had COVID-19 without hospital admission and SARDs. Patients treated only for fibromyalgia, osteoarthritis, mechanical back pain, gout, or pseudogout without a SARD were excluded from the study.
Overall, 79% of participants were female, 35% had rheumatoid arthritis, 19% had psoriatic arthritis, and 95% had received a COVID-19 vaccine.
The researchers used systems serology to perform comprehensive antibody profiling against SARS-CoV-2 and a panel of endemic pathogens or routine vaccine antigens.
Long-COVID patients had a distinct immune response
Overall, 17 patients developed PASC and 26 did not, and in those with PASC, they found a distinct humoral immune response. Patients with PASC:
- harbored less inflamed and weaker Fc-gamma receptor–binding anti–SARS-CoV-2 antibodies;
- showed a significantly expanded and more inflamed antibody response against endemic coronavirus OC43; and
- mounted more avid IgM responses and developed expanded inflammatory OC43 S2–specific Fc-receptor–binding responses, which were linked to cross reactivity across SARS-CoV-2 and common coronaviruses.
“Strengths of the study include the detailed phenotypes of cases after COVID-19, particularly to classify PASC presence or absence, as well as the depth and breadth of antibody profiling. This allowed us to identify a humoral immune signature of PASC,” said co–senior author Jeffrey A. Sparks, MD, MMSc.
“However, the study was limited in its size to investigate different types of PASC, such as fatigue or lung symptoms, that may have biologic differences. Also, all patients in the study had a preexisting rheumatic disease,” he acknowledged.
“A substantial portion of patients with COVID-19 will develop PASC, which can have substantial impact on health and quality of life,” said co–senior author Zachary S. Wallace, MD, MS. “Given the higher risk of COVID-19 in many patients with rheumatic disease, it is important to understand the etiology of PASC in this vulnerable population, to enable future diagnostic and therapeutic advances.”
Davey Smith, MD, professor of medicine and head of infectious diseases and global public health at the University of California, San Diego, in La Jolla, who was not involved in the study, called the findings interesting even though the results will not immediately affect patient care.
“There may be a link between previous non–SARS-CoV-2 coronavirus infection and PASC,” he added. “Perhaps, by understanding why some people do and do not get PASC, we can develop treatments for the condition.
“This paper is a preprint and will need to go through peer review,” Dr. Smith said. “There are many elements that need to be scrutinized. For example, there is no definition of PASC that is universally accepted, so how did that play into this study?”
Mark Cameron, PhD, associate professor in the department of population and quantitative health sciences at Case Western Reserve University, Cleveland, called this a strong study from a strong group, although it is a preprint prior to peer review.
“In this initial study, the scientists focused on people who had rheumatic disease before getting COVID-19, knowing they are at higher risk for lasting complications and hopefully are more immunologically similar when diagnosed with long COVID – a single ‘endotype’ or group of patients with similar clinical symptoms and background,” he noted.
“Our immune system’s memory sometimes fails to effectively fight a new virus that looks too much like a virus it saw before. This ineffective immune response can set up various problems, including the poor recoveries we see in people with long COVID,” he said.
“OC43 probably emerged in the late 1800s and probably caused a pandemic of severe respiratory illness between 1889 and 1890, previously thought to be a flu,” Dr. Cameron recalled. “OC43 is still around as an endemic coronavirus, usually causing mild or moderate upper-respiratory infections.”
COVID-19 immunity is complex, and previous SARS-CoV-2 infection doesn’t guarantee we won't get COVID-19 again, especially as new variants emerge, added Dr. Cameron, who also was not involved in the study.
“This study may help us better understand the risks and possible mechanisms associated with COVID-19 and long COVID in the face of previous coronavirus infections,” he said. “It may also help guide future COVID-19 therapies and vaccines.”
The authors plan further related research.
The study received grant support and an anonymous donation. Dr. Alter, Dr. Sparks, and Dr. Wallace report financial relationships with the pharmaceutical industry. All other authors, and Dr. Davey and Dr. Cameron, report no conflicts of interest with the study. All experts commented by email.
* This story was updated 10/12/2022.
People who develop long COVID may be responding more strongly to a non–SARS-CoV-2 virus they encountered in the past than to SARS-CoV-2, a study by researchers at Harvard Medical School suggests.
Long COVID, also called postacute sequelae of COVID-19 (PASC), causes various symptoms that persist at least 4 weeks after the initial SARS-CoV-2 infection, they write in the preprint server medRxiv. Four authors explained their research into possible mechanisms of long COVID in an interview.
“Immunity to non-COVID endemic coronaviruses may play a role in who develops PASC,” co–lead author Jonathan D. Herman, MD, PhD, said. “There’s still so much more we need to understand, but it is striking that back-boosting of immune responses to coronavirus OC43 was uniquely enriched in individuals with PASC.”
“In the study, individuals with PASC preferentially generated stronger responses to previously encountered cold-causing coronaviruses,” co–senior author Galit Alter, PhD, said.
“Instead of generating strong SARS-CoV-2 immunity, they bolstered a response to a different coronavirus, potentially making their response less effective in clearing SARS-CoV-2. Surprisingly, most of the individuals had been vaccinated – and they still maintained this unusual antibody response – pointing to new therapeutic pathways to treat PASC,” Dr. Alter said.
Humoral immunity offers a clue to long-COVID origins
One-fifth of COVID-19 patients progress to long COVID, but which patients develop PASC and why are not well understood, the authors write.
“Antibodies represent powerful biomarkers that have been used for decades to diagnose disease. However, antibodies also provide a powerful source of information on previous infections. The use of antibody profiling, here, pointed to the presence of incomplete antibody responses to SARS-CoV-2 in individuals with PASC,” Dr. Alter said.
The researchers reviewed the medical records of patients in the Mass General Brigham health care system in Boston, including referrals from rheumatologists of participants diagnosed with COVID-19 outside the MGB system, starting on March 1, 2020.
They focused on patients with systemic autoimmune rheumatic diseases (SARDs) because their tendency toward inflammation and autoantibody production may make them more susceptible to PASC and enrich for specific inflammatory-driven endotypes.
All 43 participants had COVID-19 without hospital admission and SARDs. Patients treated only for fibromyalgia, osteoarthritis, mechanical back pain, gout, or pseudogout without a SARD were excluded from the study.
Overall, 79% of participants were female, 35% had rheumatoid arthritis, 19% had psoriatic arthritis, and 95% had received a COVID-19 vaccine.
The researchers used systems serology to perform comprehensive antibody profiling against SARS-CoV-2 and a panel of endemic pathogens or routine vaccine antigens.
Long-COVID patients had a distinct immune response
Overall, 17 patients developed PASC and 26 did not, and in those with PASC, they found a distinct humoral immune response. Patients with PASC:
- harbored less inflamed and weaker Fc-gamma receptor–binding anti–SARS-CoV-2 antibodies;
- showed a significantly expanded and more inflamed antibody response against endemic coronavirus OC43; and
- mounted more avid IgM responses and developed expanded inflammatory OC43 S2–specific Fc-receptor–binding responses, which were linked to cross reactivity across SARS-CoV-2 and common coronaviruses.
“Strengths of the study include the detailed phenotypes of cases after COVID-19, particularly to classify PASC presence or absence, as well as the depth and breadth of antibody profiling. This allowed us to identify a humoral immune signature of PASC,” said co–senior author Jeffrey A. Sparks, MD, MMSc.
“However, the study was limited in its size to investigate different types of PASC, such as fatigue or lung symptoms, that may have biologic differences. Also, all patients in the study had a preexisting rheumatic disease,” he acknowledged.
“A substantial portion of patients with COVID-19 will develop PASC, which can have substantial impact on health and quality of life,” said co–senior author Zachary S. Wallace, MD, MS. “Given the higher risk of COVID-19 in many patients with rheumatic disease, it is important to understand the etiology of PASC in this vulnerable population, to enable future diagnostic and therapeutic advances.”
Davey Smith, MD, professor of medicine and head of infectious diseases and global public health at the University of California, San Diego, in La Jolla, who was not involved in the study, called the findings interesting even though the results will not immediately affect patient care.
“There may be a link between previous non–SARS-CoV-2 coronavirus infection and PASC,” he added. “Perhaps, by understanding why some people do and do not get PASC, we can develop treatments for the condition.
“This paper is a preprint and will need to go through peer review,” Dr. Smith said. “There are many elements that need to be scrutinized. For example, there is no definition of PASC that is universally accepted, so how did that play into this study?”
Mark Cameron, PhD, associate professor in the department of population and quantitative health sciences at Case Western Reserve University, Cleveland, called this a strong study from a strong group, although it is a preprint prior to peer review.
“In this initial study, the scientists focused on people who had rheumatic disease before getting COVID-19, knowing they are at higher risk for lasting complications and hopefully are more immunologically similar when diagnosed with long COVID – a single ‘endotype’ or group of patients with similar clinical symptoms and background,” he noted.
“Our immune system’s memory sometimes fails to effectively fight a new virus that looks too much like a virus it saw before. This ineffective immune response can set up various problems, including the poor recoveries we see in people with long COVID,” he said.
“OC43 probably emerged in the late 1800s and probably caused a pandemic of severe respiratory illness between 1889 and 1890, previously thought to be a flu,” Dr. Cameron recalled. “OC43 is still around as an endemic coronavirus, usually causing mild or moderate upper-respiratory infections.”
COVID-19 immunity is complex, and previous SARS-CoV-2 infection doesn’t guarantee we won't get COVID-19 again, especially as new variants emerge, added Dr. Cameron, who also was not involved in the study.
“This study may help us better understand the risks and possible mechanisms associated with COVID-19 and long COVID in the face of previous coronavirus infections,” he said. “It may also help guide future COVID-19 therapies and vaccines.”
The authors plan further related research.
The study received grant support and an anonymous donation. Dr. Alter, Dr. Sparks, and Dr. Wallace report financial relationships with the pharmaceutical industry. All other authors, and Dr. Davey and Dr. Cameron, report no conflicts of interest with the study. All experts commented by email.
* This story was updated 10/12/2022.
FROM MEDRXIV
Would your patient benefit from a monoclonal antibody?
Small-molecule drugs such as aspirin, albuterol, atorvastatin, and lisinopril are the backbone of disease management in family medicine.1 However, large-molecule biological drugs such as monoclonal antibodies (MAbs) are increasingly prescribed to treat common conditions. In the past decade, MAbs comprised 20% of all drug approvals by the US Food and Drug Administration (FDA), and today they represent more than half of drugs currently in development.2 Fifteen MAbs have been approved by the FDA over the past decade for asthma, atopic dermatitis (AD), hyperlipidemia, osteoporosis, and migraine prevention.3 This review details what makes MAbs unique and what you should know about them.
The uniqueness of monoclonal antibodies
MAbs are biologics, but not all biologics are MAbs—eg, adalimumab (Humira) is a MAb, but etanercept (Enbrel) is not. MAbs are therapeutic proteins made possible by hybridoma technology used to create an antibody with single specificity.4-6 Monoclonal antibodies differ from small-molecule drugs in structure, dosing, route of administration, manufacturing, metabolism, drug interactions, and elimination (TABLE 17-9).
MAbs can be classified as naked, “without any drug or radioactive material attached to them,” or conjugated, “joined to a chemotherapy drug, radioactive isotope, or toxin.”10 MAbs work in several ways, including competitively inhibiting ligand-receptor binding, receptor blockade, or cell elimination from indirect immune system activities such as antibody-dependent cell-mediated cytotoxicity.11,12
Monoclonal antibody uses in family medicine
Asthma
Several MAbs have been approved for use in severe asthma, including but not limited to: omalizumab (Xolair),13 mepolizumab (Nucala),9,14 and dupilumab (Dupixent).15
Omalizumab is a humanized MAb that prevents IgE antibodies from binding to mast cells and basophils, thereby reducing inflammatory mediators.13 A systematic review found that, compared with placebo, omalizumab used in patients with inadequately controlled moderate-to-severe asthma led to significantly fewer asthma exacerbations (absolute risk reduction [ARR], 16% vs 26%; odds ratio [OR] = 0.55; 95% CI, 0.42-0.60; number needed to treat [NNT] = 10) and fewer hospitalizations (ARR, 0.5% vs 3%; OR = 0.16; 95% CI, 0.06-0.42; NNT = 40).13
Significantly more patients in the omalizumab group were able to withdraw from, or reduce, the dose of ICS. GINA recommends omalizumab for patients with positive skin sensitization, total serum IgE ≥ 30 IU/mL, weight within 30 kg to 150 kg, history of childhood asthma and recent exacerbations, and blood eosinophils ≥ 260/mcL.16 Omalizumab is also approved for use in chronic spontaneous urticaria and nasal polyps.
Mepolizumab
Continue to: Another trial found that...
Another trial found that mepolizumab reduced total OCS doses in patients with severe asthma by 50% without increasing exacerbations or worsening asthma control.18 All 3 anti-IL-5 drugs—including not only mepolizumab, but also benralizumab (Fasenra) and reslizumab (Cinqair)—appear to yield similar improvements. A 2017 systematic review found all anti-IL-5 treatments reduced rates of clinically significant asthma exacerbations (treatment with OCS for ≥ 3 days) by roughly 50% in patients with severe eosinophilic asthma and a history of ≥ 2 exacerbations in the past year.
Dupilumab is a humanized MAb that inhibits IL-4 and IL-13, which influence multiple cell types involved in inflammation (eg, mast cells, eosinophils) and inflammatory mediators (histamine, leukotrienes, cytokines).15 In a recent study of patients with uncontrolled asthma, dupilumab 200 mg every 2 weeks compared with placebo showed a modest reduction in the annualized rate of severe asthma exacerbations (0.46 exacerbations vs 0.87, respectively). Dupilumab was effective in patients with blood eosinophil counts ≥ 150/μL but was ineffective in patients with eosinophil counts < 150/μL.15
For patients ≥ 12 years old with severe eosinophilic asthma, GINA recommends using dupilumab as add-on therapy for an initial trial of 4 months at doses of 200 or 300 mg SC every 2 weeks, with preference for 300 mg SC every 2 weeks for OCS-dependent asthma. Dupilumab is approved for use in AD and chronic rhinosinusitis with nasal polyposis. If a biologic agent is not successful after a 4-month trial, consider a 6- to 12-month trial. If efficacy is still minimal, consider switching to an alternative biologic therapy approved for asthma.16
❯ Asthma: Test your skills
Subjective findings: A 19-year-old man presents to your clinic. He has a history of nasal polyps and allergic asthma. At age 18, he was given a diagnosis of severe persistent asthma. He has shortness of breath during waking hours 4 times per week, and treats each of these episodes with albuterol. He also wakes up about twice a week with shortness of breath and has some limitations in normal activities. He reports missing his prescribed fluticasone/salmeterol 500/50 μg, 1 inhalation bid, only once each month. In the last year, he has had 2 exacerbations requiring oral steroids.
Medications: Albuterol 90 μg, 1-2 inhalations, q6h prn; fluticasone/salmeterol 500/50 μg, 1 inhalation bid; tiotropium 1.25 μg, 2 puffs/d; montelukast 10 mg every morning; prednisone 10 mg/d.
Continue to: Objective data
Objective data: Patient is in no apparent distress and afebrile, and oxygen saturation on room air is 97%. Ht, 70 inches; wt, 75 kg. Labs: IgE, 15 IU/mL; serum eosinophils, 315/μL.
Which MAb would be appropriate for this patient? Given that the patient has a blood eosinophil level ≥ 300/μL and severe exacerbations, adult-onset asthma, nasal polyposis, and maintenance OCS at baseline, it would be reasonable to initiate mepolizumab 100 mg SC every 4 weeks, or dupilumab 600 mg once, then 300 mg SC every 2 weeks. Both agents can be self-administered.
Atopic dermatitis
Two MAbs—dupilumab and tralokinumab (Adbry; inhibits IL-13)—are approved for treatment of AD in adults that is uncontrolled with conventional therapy.15,19 Dupilumab is also approved for children ≥ 6 months old.20 Both MAbs are dosed at 600 mg SC, followed by 300 mg every 2 weeks. Dupilumab was compared with placebo in adult patients who had moderate-to-severe AD inadequately controlled on topical corticosteroids (TCSs), to determine the proportion of patients in each group achieving improvement of either 0 or 1 points or ≥ 2 points in the 5-point Investigator Global Assessment (IGA) score from baseline to 16 weeks.21 Thirty-seven percent of patients receiving dupilumab 300 mg SC weekly and 38% of patients receiving dupilumab 300 mg SC every 2 weeks achieved the primary outcome, compared with 10% of those receiving placebo (P < .001).21 Similar IGA scores were reported when dupilumab was combined with TCS, compared with placebo.22
It would be reasonable to consider dupilumab or tralokinumab in patients with: cutaneous atrophy or hypothalamic-pituitary-adrenal axis suppression with TCS, concerns of malignancy with topical calcineurin inhibitors, or problems with the alternative systemic therapies (cyclosporine-induced hypertension, nephrotoxicity, or immunosuppression; azathioprine-induced malignancy; or methotrexate-induced bone marrow suppression, renal impairment, hepatotoxicity, pneumonitis, or gastrointestinal toxicity).23
A distinct advantage of MAbs over other systemic agents in the management of AD is that MAbs do not require frequent monitoring of blood pressure, renal or liver function, complete blood count with differential, electrolytes, or uric acid. Additionally, MAbs have fewer black box warnings and adverse reactions when compared with other systemic agents.
Continue to: Hyperlipidemia
Hyperlipidemia
Three MAbs are approved for use in hyperlipidemia: the angiopoietin-like protein 3 (ANGPTL3) inhibitor evinacumab (Evkeeza)24 and 2 proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, evolocumab (Repatha)25 and alirocumab (Praluent).26
ANGPTL3 inhibitors block ANGPTL3 and reduce endothelial lipase and lipoprotein lipase activity, which in turn decreases low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride formation. PCSK9 inhibitors prevent PCSK9 from binding to LDL receptors, thereby maintaining the number of active LDL receptors and increasing LDL-C removal.
Evinacumab is indicated for homozygous familial hypercholesterolemia and is administered intravenously every 4 weeks. Evinacumab has not been evaluated for effects on cardiovascular morbidity and mortality.
Evolocumab 140 mg SC every 2 weeks or 420 mg SC monthly has been studied in patients on statin therapy with LDL-C ≥ 70 mg/dL. Patients on evolocumab experienced significantly less of the composite endpoint of cardiovascular death, myocardial infarction (MI), stroke, hospitalization for unstable angina, or coronary revascularization compared with placebo (9.8% vs 11.3%; hazard ratio [HR] = 0.85; 95% CI, 0.79-0.92; NNT = 67.27
Alirocumab 75 mg SC every 2 weeks has also been studied in patients receiving statin therapy with LDL-C ≥ 70 mg/dL. Patients taking alirocumab experienced significantly less of the composite endpoint of death from coronary heart disease, nonfatal MI, ischemic stroke, or hospitalization for unstable angina compared with placebo (9.5% vs 11.1%; HR = 0.85; 95% CI, 0.78-0.93; NNT = 63).
Continue to: According to the 2018...
According to the 2018 AHA Cholesterol Guidelines, PCSK9 inhibitors are indicated for patients receiving maximally tolerated LDL-C-lowering therapy (statin and ezetimibe) with LDL-C ≥ 70 mg/dL, if they have had multiple atherosclerotic cardiovascular disease (ASCVD) events or 1 major ASCVD event with multiple high-risk conditions (eg, heterozygous familial hypercholesterolemia, history of coronary artery bypass grafting or percutaneous coronary intervention, hypertension, estimated glomerular filtration rate of 15 to 59 mL/min/1.73m2).29 For patients without prior ASCVD events or high-risk conditions who are receiving maximally tolerated LDL-C-lowering therapy (statin and ezetimibe), PCSK9 inhibitors are indicated if the LDL-C remains ≥ 100 mg/dL.
Osteoporosis
The 2 MAbs approved for use in osteoporosis are the receptor activator of nuclear factor kB ligand (RANKL) inhibitor denosumab (Prolia)30 and the sclerostin inhibitor romosozumab (Evenity).31
Denosumab prevents RANKL from binding to the RANK receptor, thereby inhibiting osteoclast formation and decreasing bone resorption. Denosumab is approved for use in women and men who are at high risk of osteoporotic fracture, including those taking OCSs, men receiving androgen deprivation therapy for prostate cancer, and women receiving adjuvant aromatase inhibitor therapy for breast cancer.
In a 3-year randomized trial, denosumab 60 mg SC every 6 months was compared with placebo in postmenopausal women with T-scores < –2.5, but not < –4.0 at the lumbar spine or total hip. Denosumab significantly reduced new radiographic vertebral fractures (2.3% vs 7.2%; risk ratio [RR] = 0.32; 95% CI, 0.26-0.41; NNT = 21), hip fracture (0.7% vs 1.2%), and nonvertebral fracture (6.5% vs 8.0%).32 Denosumab carries an increased risk of multiple vertebral fractures following discontinuation, skin infections, dermatologic reactions, and severe bone, joint, and muscle pain.
Romosozumab inhibits sclerostin, thereby increasing bone formation and, to a lesser degree, decreasing bone resorption. Romosozumab is approved for use in postmenopausal women at high risk for fracture (ie, those with a history of osteoporotic fracture or multiple risk factors for fracture) or in patients who have not benefited from or are intolerant of other therapies. In one study, postmenopausal women with a T-score of –2.5 to –3.5 at the total hip or femoral neck were randomly assigned to receive either romosozumab 210 mg SC or placebo for 12 months, then each group was switched to denosumab 60 mg SC for 12 months. After the first year, prior to initiating denosumab, patients taking romosozumab experienced significantly fewer new vertebral fractures than patients taking placebo (0.5% vs 1.8%; RR = 0.27; 95% CI, 0.16-0.47; NNT = 77); however, there was no significant difference between the 2 groups with nonvertebral fractures (HR = 0.75; 95% CI, 0.53-1.05).33
Continue to: In another study...
In another study, romosozumab 210 mg SC was compared with alendronate 70 mg weekly, followed by alendronate 70 mg weekly in both groups. Over the first 12 months, patients treated with romosozumab saw a significant reduction in the incidence of new vertebral fractures (4% vs 6.3%; RR = 0.63, P < .003; NNT = 44). Patients treated with romosozumab with alendronate added for another 12 months also saw a significant reduction in new incidence of vertebral fractures (6.2% vs 11.9%; RR = 0.52; P < .001; NNT = 18).34 There was a higher risk of cardiovascular events among patients receiving romosozumab compared with those treated with alendronate, so romosozumab should not be used in individuals who have had an MI or stroke within the previous year.34 Denosumab and romosozumab offer an advantage over some bisphosphonates in that they require less frequent dosing and can be used in patients with renal impairment (creatinine clearance < 35 mL/min, in which zoledronic acid is contraindicated and alendronate is not recommended; < 30 mL/min, in which risedronate and ibandronate are not recommended).
Migraine prevention
Four
Erenumab, fremanezumab, and galcanezumab are all available in subcutaneous autoinjectors (or syringe with fremanezumab). Eptinezumab is an intravenous (IV) infusion given every 3 months.
Erenumab is available in both 70-mg and 140-mg dosing options. Fremanezumab can be given as 225 mg monthly or 675 mg quarterly. Galcanezumab has an initial loading dose of 240 mg followed by 120 mg given monthly. Erenumab targets the CGRP receptor; the others target the CGRP ligand. Eptinezumab has 100% bioavailability and reaches maximum serum concentration sooner than the other antagonists (due to its route of administration), but it must be given in an infusion center. Few insurers approve the use of eptinezumab unless a trial of least 1 of the monthly injectables has failed.
There are no head-to-head studies of the medications in this class. Additionally, differing study designs, definitions, statistical analyses, endpoints, and responder-rate calculations make it challenging to compare them directly against one another. At the very least, all of the CGRP MAbs have efficacy comparable to conventional preventive migraine medications such as propranolol, amitriptyline, and topiramate.40
Continue to: The most commonly reported adverse...
The most commonly reported adverse effect for all 4 CGRPs is injection site reaction, which was highest with the quarterly fremanezumab dose (45%).37 Constipation was most notable with the 140-mg dose of erenumab (3%)35; with the other CGRP MAbs it is comparable to that seen with placebo (< 1%).
Erenumab-induced hypertension has been identified in 61 cases reported through the FDA Adverse Event Reporting System (FAERS) as of 2021.41 This was not reported during MAb development programs, nor was it noted during clinical trials. Blood pressure elevation was seen within 1 week of injection in nearly 50% of the cases, and nearly one-third had pre-existing hypertension.41 Due to these findings, the erenumab prescribing information was updated to include hypertension in its warnings and precautions. It is possible that hypertension could be a class effect, although trial data and posthoc studies have yet to bear that out. Since erenumab was the first CGRP antagonist brought to market (May 2018 vs September 2018 for fremanezumab and galcanezumab), it may have accumulated more FAERS reports. Nearly all studies exclude patients with older age, uncontrolled hypertension, and unstable cardiovascular disease, which could impact data.41
Overall, this class of medications is very well tolerated, easy to use (again, excluding eptinezumab), and maintains a low adverse effect profile, giving added value compared with conventional preventive migraine medications.
The American Headache Society recommends a preventive oral therapy for at least 3 months before trying an alternative medication. After treatment failure with at least 2 oral agents, CGRP MAbs are recommended.42 CGRP antagonists offer convenient dosing, bypass gastrointestinal metabolism (which is useful in patients with nausea/vomiting), and have fewer adverse effects than traditional oral medications.
Worth noting. Several newer oral agents have been recently approved for migraine prevention, including atogepant (Qulipta) and rimegepant (Nurtec), which are also CGRP antagonists. Rimegepant is approved for both acute migraine treatment and prevention.
Continue to: Migraine
❯ Migraine: Test your skills
Subjective findings: A 25-year-old woman presents to your clinic for management of episodic migraines with aura. Her baseline average migraine frequency is 9 headache days/month. Her migraines are becoming more frequent despite treatment. She fears IV medication use and avoids hospitals.
History: Hypertension, irritable bowel syndrome with constipation (IBS-C), and depression. The patient is not pregnant or trying to get pregnant.
Medications: Current medications (for previous 4 months) include propranolol 40 mg at bedtime, linaclotide 145 μg/d, citalopram 20 mg/d, and sumatriptan 50 mg prn. Past medications include venlafaxine 150 mg po bid for 5 months.
What would be appropriate for this patient? This patient meets the criteria for using a CGRP antagonist because she has tried 2 preventive treatments for more than 60 to 90 days. Erenumab is not the best option, given the patient’s history of hypertension and IBS-C. The patient fears hospitals and IV medications, making eptinezumab a less-than-ideal choice. Depending on her insurance, fremanezumab or galcanezumab would be good options at this time.
CGRP antagonists have not been studied or evaluated in pregnancy, but if this patient becomes pregnant, a first-line agent for prevention would be propranolol, and a second-line agent would be a tricyclic antidepressant, memantine, or verapamil. Avoid ergotamines and antiepileptics (topiramate or valproate) in pregnancy.43,44
Continue to: The challenges associated with MAbs
The challenges associated with MAbs
MAbs can be expensive (TABLE 2),45 some prohibitively so. On a population scale, biologics account for around 40% of prescription drug spending and may cost 22 times more than small-molecule drugs.46 Estimates in 2016 showed that MAbs comprise $90.2 billion (43%) of the biologic market.46
MAbs also require prior authorization forms to be submitted. Prior authorization criteria vary by state and by insurance plan. In my (ES) experience, submitting letters of medical necessity justifying the need for therapy or expertise in the disease states for which the MAb is being prescribed help your patient get the medication they need.
Expect to see additional MAbs approved in the future. If the costs come down, adoption of these agents into practice will likely increase.
CORRESPONDENCE
Evelyn Sbar, MD, Texas Tech University Health Sciences Center, 1400 South Coulter Street, Suite 5100, Amarillo, TX 79106; [email protected]
1. Rui P, Okeyode T. National Ambulatory Medical Care Survey: 2016 national summary tables. National Center for Health Statistics. Accessed June 15, 2022. www.cdc.gov/nchs/data/ahcd/namcs_summary/2016_namcs_web_tables.pdf
2. IDBS. The future of biologics drug development is today. June 27, 2018. Accessed June 15, 2022. www.idbs.com/blog/2018/06/the-future-of-biologics-drug-development-is-today/
3. Antibody therapeutics approved or in regulatory review in the EU or US. Antibody Society. Accessed June 15, 2022. www.antibodysociety.org/resources/approved-antibodies/
4. FDA. Code of Federal Regulations, Title 21, Chapter I, Subchapter F biologics. March 29, 2022. Accessed June 15, 2022. www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=600.3
5. Köhler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975;256:495-497. doi: 10.1038/256495a0
6. Raejewsky K. The advent and rise of monoclonal antibodies. Nature. November 4, 2019. Accessed June 15, 2022. www.nature.com/articles/d41586-019-02840-w
7. Flovent. Prescribing information. GlaxoSmithKline; 2010. Accessed June 15, 2022. www.accessdata.fda.gov/drugsatfda_docs/label/2010/021433s015lbl.pdf
8. NLM. National Center for Biotechnology Information. PubChem. Method for the preparation of fluticasone and related 17beta-carbothioic esters using a novel carbothioic acid synthesis and novel purification methods. Accessed June 15, 2022. pubchem.ncbi.nlm.nih.gov/patent/WO-0162722-A2
9. Nucala. Prescribing information. GlaxoSmithKline; 2019. Accessed June 15, 2022. www.accessdata.fda.gov/drugsatfda_docs/label/2019/761122s000lbl.pdf
10. Argyriou AA, Kalofonos HP. Recent advances relating to the clinical application of naked monoclonal antibodies in solid tumors. Mol Med. 2009;15:183-191. doi: 10.2119/molmed.2009.00007
11. Wang W, Wang EQ, Balthasar JP. Monoclonal antibody pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther. 2008;84:548-558. doi: 10.1038/clpt.2008.170
12. Zahavi D, AlDeghaither D, O’Connell A, et al. Enhancing antibody-dependent cell-mediated cytotoxicity: a strategy for improving antibody-based immunotherapy. Antib Ther. 2018;1:7-12. doi: 10.1093/abt/tby002
13. Normansell R, Walker S, Milan SJ, et al. Omalizumab for asthma in adults and children. Cochrane Database Syst Rev. 2014:CD003559. doi: 10.1002/14651858.CD003559.pub4
14. Farne HA, Wilson A, Powell C, et al. Anti-IL5 therapies for asthma. Cochrane Database Syst Rev. 2017;9:CD010834. doi: 10.1002/14651858.CD010834.pub3
15. Castro M, Corren J, Pavord ID, et al. Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma. N Engl J Med. 2018;378:2486-2496. doi: 10.1056/NEJMoa1804092
16. GINA. Global strategy for asthma management and prevention. 2022 Difficult-to-treat and severe asthma guide—slide set. Accessed June 23, 2022. https://ginasthma.org/severeasthma/
17. Ortega HG, Liu MC, Pavord ID, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014;371:1198-1207. doi: 10.1056/NEJMoa1403290
18. Bel EH, Wenzel SE, Thompson PJ, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014;371:1189-1197. doi: 10.1056/NEJMoa1403291
19. Adbry. Prescribing information. Leo Pharma Inc; 2021. Accessed June 24, 2022. www.accessdata.fda.gov/drugsatfda_docs/nda/2022/761180Orig1s000lbl.pdf
20. Dupixent. Prescribing information. Regeneron Pharmaceuticals; 2022. Accessed October 5, 2022. https://www.regeneron.com/downloads/dupixent_fpi.pdf
21. Simpson EL, Bieber T, Guttman-Yassky E, et al. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2016;375:2335-2348. doi: 10.1056/NEJMoa1610020
22. Blauvelt A, de Bruin-Weller M, Gooderham M, et al. Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomised, double-blinded, placebo-controlled, phase 3 trial. Lancet. 2017;389:2287-2303. doi: 10.1016/s0140-6736(17)31191-1
23. Sidbury R, Davis DM, Cohen DE, et al. Guidelines of care for the management of atopic dermatitis: section 3. Management and treatment with phototherapy and systemic agents. J Am Acad Dermatol. 2014;71:327-349. doi: 10.1016/j.jaad.2014.03.030
24. Evkeeza. Prescribing information. Regeneron Pharmaceuticals; 2021. Accessed June 24, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761181s000lbl.pdf
25. Repatha. Prescribing information. Amgen; 2015. Accessed June 24, 2022. www.accessdata.fda.gov/drugsatfda_docs/label/2017/125522s014lbl.pdf
26. Praluent. Prescribing information. Sanofi Aventis and Regeneron Pharmaceuticals. 2015. Accessed June 24, 2022. www.accessdata.fda.gov/drugsatfda_docs/label/2017/125559s002lbl.pdf
27. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376:1713-1722. doi: 10.1056/NEJMoa1615664
28. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018;379:2097-2107. doi:10.1056/NEJMoa1801174
29. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. J Am Coll Cardiol. 2019;73:e285-e350. doi: 10.1016/j.jacc.2018.11.003
30. Prolia. Prescribing information. Amgen; 2010. Accessed June 24, 2022. www.accessdata.fda.gov/drugsatfda_docs/label/2013/125320s094lbl.pdf
31. Evenity. Prescribing information. Amgen; 2019. Accessed June 24, 2022. www.accessdata.fda.gov/drugsatfda_docs/label/2019/761062s000lbl.pdf
32. Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361:756-765. doi: 10.1056/NEJMoa0809493
33. Cosman F, Crittenden DB, Adachi JD, et al. Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med. 2016;375:1532-1543. doi: 10.1056/NEJMoa1607948
34. Saag KG, Petersen J, Brandi ML, et al. Romosozumab or alendronate for fracture prevention in women with osteoporosis. N Engl J Med. 2017;377:1417-1427. doi: 10.1056/NEJMoa1708322
35. Aimovig. Prescribing information. Amgen; 2018. Accessed June 24, 2022. www.accessdata.fda.gov/drugsatfda_docs/label/2018/761077s000lbl.pdf
36. Vyepti. Prescribing information. Lundbeck Seattle BioPharmaceuticals; 2020. Accessed June 24, 2022. www.accessdata.fda.gov/drugsatfda_docs/label/2020/761119s000lbl.pdf
37. Ajovy. Prescribing information. Teva Pharmaceuticals; 2018. Accessed June 24, 2022. www.accessdata.fda.gov/drugsatfda_docs/label/2018/761089s000lbl.pdf
38. Emgality. Prescribing information. Eli Lilly and Co.; 2018. Accessed June 24, 2022. www.accessdata.fda.gov/drugsatfda_docs/label/2018/761063s000lbl.pdf
39. Edvinsson L, Haanes KA, Warfvinge K, et al. CGRP as the target of new migraine therapies - successful translation from bench to clinic. Nat Rev Neurol. 2018;14:338-350. doi: 10.1038/s41582-018-0003-1
40. Vandervorst F. Van Deun L, Van Dycke A, et al. CGRP monoclonal antibodies in migraine: an efficacy and tolerability comparison with standard prophylactic drugs. J Headache Pain. 2021;22:128. doi: 10.1186/s10194-021-01335-2
41. Saely S, Croteau D, Jawidzik L, et al. Hypertension: a new safety risk for patients treated with erenumab. Headache. 2021;61:202-208. doi: 10.1111/head.14051
42. American Headache Society. The American Headache Society position statement on integrating new migraine treatments into clinical practice. Headache. 2019;59:1-18. doi: 10.1111/head.13456
43. Burch R. Headache in pregnancy and the puerperium. Neurol Clin. 2019;37:31-51. doi: 10.1016/j.ncl.2018.09.004
44. Burch R. Epidemiology and treatment of menstrual migraine and migraine during pregnancy and lactation: a narrative review. Headache. 2020;60:200-216. doi: 10.1111/head.13665
45. Lexi-Comp. Lexi-drug database. Accessed April 4, 2022. https://online.lexi.com/lco/action/login
46. Walker N. Biologics: driving force in pharma. Pharma’s Almanac. June 5, 2017. Accessed June 15, 2020. www.pharmasalmanac.com/articles/biologics-driving-force-in-pharma
Small-molecule drugs such as aspirin, albuterol, atorvastatin, and lisinopril are the backbone of disease management in family medicine.1 However, large-molecule biological drugs such as monoclonal antibodies (MAbs) are increasingly prescribed to treat common conditions. In the past decade, MAbs comprised 20% of all drug approvals by the US Food and Drug Administration (FDA), and today they represent more than half of drugs currently in development.2 Fifteen MAbs have been approved by the FDA over the past decade for asthma, atopic dermatitis (AD), hyperlipidemia, osteoporosis, and migraine prevention.3 This review details what makes MAbs unique and what you should know about them.
The uniqueness of monoclonal antibodies
MAbs are biologics, but not all biologics are MAbs—eg, adalimumab (Humira) is a MAb, but etanercept (Enbrel) is not. MAbs are therapeutic proteins made possible by hybridoma technology used to create an antibody with single specificity.4-6 Monoclonal antibodies differ from small-molecule drugs in structure, dosing, route of administration, manufacturing, metabolism, drug interactions, and elimination (TABLE 17-9).
MAbs can be classified as naked, “without any drug or radioactive material attached to them,” or conjugated, “joined to a chemotherapy drug, radioactive isotope, or toxin.”10 MAbs work in several ways, including competitively inhibiting ligand-receptor binding, receptor blockade, or cell elimination from indirect immune system activities such as antibody-dependent cell-mediated cytotoxicity.11,12
Monoclonal antibody uses in family medicine
Asthma
Several MAbs have been approved for use in severe asthma, including but not limited to: omalizumab (Xolair),13 mepolizumab (Nucala),9,14 and dupilumab (Dupixent).15
Omalizumab is a humanized MAb that prevents IgE antibodies from binding to mast cells and basophils, thereby reducing inflammatory mediators.13 A systematic review found that, compared with placebo, omalizumab used in patients with inadequately controlled moderate-to-severe asthma led to significantly fewer asthma exacerbations (absolute risk reduction [ARR], 16% vs 26%; odds ratio [OR] = 0.55; 95% CI, 0.42-0.60; number needed to treat [NNT] = 10) and fewer hospitalizations (ARR, 0.5% vs 3%; OR = 0.16; 95% CI, 0.06-0.42; NNT = 40).13
Significantly more patients in the omalizumab group were able to withdraw from, or reduce, the dose of ICS. GINA recommends omalizumab for patients with positive skin sensitization, total serum IgE ≥ 30 IU/mL, weight within 30 kg to 150 kg, history of childhood asthma and recent exacerbations, and blood eosinophils ≥ 260/mcL.16 Omalizumab is also approved for use in chronic spontaneous urticaria and nasal polyps.
Mepolizumab
Continue to: Another trial found that...
Another trial found that mepolizumab reduced total OCS doses in patients with severe asthma by 50% without increasing exacerbations or worsening asthma control.18 All 3 anti-IL-5 drugs—including not only mepolizumab, but also benralizumab (Fasenra) and reslizumab (Cinqair)—appear to yield similar improvements. A 2017 systematic review found all anti-IL-5 treatments reduced rates of clinically significant asthma exacerbations (treatment with OCS for ≥ 3 days) by roughly 50% in patients with severe eosinophilic asthma and a history of ≥ 2 exacerbations in the past year.
Dupilumab is a humanized MAb that inhibits IL-4 and IL-13, which influence multiple cell types involved in inflammation (eg, mast cells, eosinophils) and inflammatory mediators (histamine, leukotrienes, cytokines).15 In a recent study of patients with uncontrolled asthma, dupilumab 200 mg every 2 weeks compared with placebo showed a modest reduction in the annualized rate of severe asthma exacerbations (0.46 exacerbations vs 0.87, respectively). Dupilumab was effective in patients with blood eosinophil counts ≥ 150/μL but was ineffective in patients with eosinophil counts < 150/μL.15
For patients ≥ 12 years old with severe eosinophilic asthma, GINA recommends using dupilumab as add-on therapy for an initial trial of 4 months at doses of 200 or 300 mg SC every 2 weeks, with preference for 300 mg SC every 2 weeks for OCS-dependent asthma. Dupilumab is approved for use in AD and chronic rhinosinusitis with nasal polyposis. If a biologic agent is not successful after a 4-month trial, consider a 6- to 12-month trial. If efficacy is still minimal, consider switching to an alternative biologic therapy approved for asthma.16
❯ Asthma: Test your skills
Subjective findings: A 19-year-old man presents to your clinic. He has a history of nasal polyps and allergic asthma. At age 18, he was given a diagnosis of severe persistent asthma. He has shortness of breath during waking hours 4 times per week, and treats each of these episodes with albuterol. He also wakes up about twice a week with shortness of breath and has some limitations in normal activities. He reports missing his prescribed fluticasone/salmeterol 500/50 μg, 1 inhalation bid, only once each month. In the last year, he has had 2 exacerbations requiring oral steroids.
Medications: Albuterol 90 μg, 1-2 inhalations, q6h prn; fluticasone/salmeterol 500/50 μg, 1 inhalation bid; tiotropium 1.25 μg, 2 puffs/d; montelukast 10 mg every morning; prednisone 10 mg/d.
Continue to: Objective data
Objective data: Patient is in no apparent distress and afebrile, and oxygen saturation on room air is 97%. Ht, 70 inches; wt, 75 kg. Labs: IgE, 15 IU/mL; serum eosinophils, 315/μL.
Which MAb would be appropriate for this patient? Given that the patient has a blood eosinophil level ≥ 300/μL and severe exacerbations, adult-onset asthma, nasal polyposis, and maintenance OCS at baseline, it would be reasonable to initiate mepolizumab 100 mg SC every 4 weeks, or dupilumab 600 mg once, then 300 mg SC every 2 weeks. Both agents can be self-administered.
Atopic dermatitis
Two MAbs—dupilumab and tralokinumab (Adbry; inhibits IL-13)—are approved for treatment of AD in adults that is uncontrolled with conventional therapy.15,19 Dupilumab is also approved for children ≥ 6 months old.20 Both MAbs are dosed at 600 mg SC, followed by 300 mg every 2 weeks. Dupilumab was compared with placebo in adult patients who had moderate-to-severe AD inadequately controlled on topical corticosteroids (TCSs), to determine the proportion of patients in each group achieving improvement of either 0 or 1 points or ≥ 2 points in the 5-point Investigator Global Assessment (IGA) score from baseline to 16 weeks.21 Thirty-seven percent of patients receiving dupilumab 300 mg SC weekly and 38% of patients receiving dupilumab 300 mg SC every 2 weeks achieved the primary outcome, compared with 10% of those receiving placebo (P < .001).21 Similar IGA scores were reported when dupilumab was combined with TCS, compared with placebo.22
It would be reasonable to consider dupilumab or tralokinumab in patients with: cutaneous atrophy or hypothalamic-pituitary-adrenal axis suppression with TCS, concerns of malignancy with topical calcineurin inhibitors, or problems with the alternative systemic therapies (cyclosporine-induced hypertension, nephrotoxicity, or immunosuppression; azathioprine-induced malignancy; or methotrexate-induced bone marrow suppression, renal impairment, hepatotoxicity, pneumonitis, or gastrointestinal toxicity).23
A distinct advantage of MAbs over other systemic agents in the management of AD is that MAbs do not require frequent monitoring of blood pressure, renal or liver function, complete blood count with differential, electrolytes, or uric acid. Additionally, MAbs have fewer black box warnings and adverse reactions when compared with other systemic agents.
Continue to: Hyperlipidemia
Hyperlipidemia
Three MAbs are approved for use in hyperlipidemia: the angiopoietin-like protein 3 (ANGPTL3) inhibitor evinacumab (Evkeeza)24 and 2 proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, evolocumab (Repatha)25 and alirocumab (Praluent).26
ANGPTL3 inhibitors block ANGPTL3 and reduce endothelial lipase and lipoprotein lipase activity, which in turn decreases low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride formation. PCSK9 inhibitors prevent PCSK9 from binding to LDL receptors, thereby maintaining the number of active LDL receptors and increasing LDL-C removal.
Evinacumab is indicated for homozygous familial hypercholesterolemia and is administered intravenously every 4 weeks. Evinacumab has not been evaluated for effects on cardiovascular morbidity and mortality.
Evolocumab 140 mg SC every 2 weeks or 420 mg SC monthly has been studied in patients on statin therapy with LDL-C ≥ 70 mg/dL. Patients on evolocumab experienced significantly less of the composite endpoint of cardiovascular death, myocardial infarction (MI), stroke, hospitalization for unstable angina, or coronary revascularization compared with placebo (9.8% vs 11.3%; hazard ratio [HR] = 0.85; 95% CI, 0.79-0.92; NNT = 67.27
Alirocumab 75 mg SC every 2 weeks has also been studied in patients receiving statin therapy with LDL-C ≥ 70 mg/dL. Patients taking alirocumab experienced significantly less of the composite endpoint of death from coronary heart disease, nonfatal MI, ischemic stroke, or hospitalization for unstable angina compared with placebo (9.5% vs 11.1%; HR = 0.85; 95% CI, 0.78-0.93; NNT = 63).
Continue to: According to the 2018...
According to the 2018 AHA Cholesterol Guidelines, PCSK9 inhibitors are indicated for patients receiving maximally tolerated LDL-C-lowering therapy (statin and ezetimibe) with LDL-C ≥ 70 mg/dL, if they have had multiple atherosclerotic cardiovascular disease (ASCVD) events or 1 major ASCVD event with multiple high-risk conditions (eg, heterozygous familial hypercholesterolemia, history of coronary artery bypass grafting or percutaneous coronary intervention, hypertension, estimated glomerular filtration rate of 15 to 59 mL/min/1.73m2).29 For patients without prior ASCVD events or high-risk conditions who are receiving maximally tolerated LDL-C-lowering therapy (statin and ezetimibe), PCSK9 inhibitors are indicated if the LDL-C remains ≥ 100 mg/dL.
Osteoporosis
The 2 MAbs approved for use in osteoporosis are the receptor activator of nuclear factor kB ligand (RANKL) inhibitor denosumab (Prolia)30 and the sclerostin inhibitor romosozumab (Evenity).31
Denosumab prevents RANKL from binding to the RANK receptor, thereby inhibiting osteoclast formation and decreasing bone resorption. Denosumab is approved for use in women and men who are at high risk of osteoporotic fracture, including those taking OCSs, men receiving androgen deprivation therapy for prostate cancer, and women receiving adjuvant aromatase inhibitor therapy for breast cancer.
In a 3-year randomized trial, denosumab 60 mg SC every 6 months was compared with placebo in postmenopausal women with T-scores < –2.5, but not < –4.0 at the lumbar spine or total hip. Denosumab significantly reduced new radiographic vertebral fractures (2.3% vs 7.2%; risk ratio [RR] = 0.32; 95% CI, 0.26-0.41; NNT = 21), hip fracture (0.7% vs 1.2%), and nonvertebral fracture (6.5% vs 8.0%).32 Denosumab carries an increased risk of multiple vertebral fractures following discontinuation, skin infections, dermatologic reactions, and severe bone, joint, and muscle pain.
Romosozumab inhibits sclerostin, thereby increasing bone formation and, to a lesser degree, decreasing bone resorption. Romosozumab is approved for use in postmenopausal women at high risk for fracture (ie, those with a history of osteoporotic fracture or multiple risk factors for fracture) or in patients who have not benefited from or are intolerant of other therapies. In one study, postmenopausal women with a T-score of –2.5 to –3.5 at the total hip or femoral neck were randomly assigned to receive either romosozumab 210 mg SC or placebo for 12 months, then each group was switched to denosumab 60 mg SC for 12 months. After the first year, prior to initiating denosumab, patients taking romosozumab experienced significantly fewer new vertebral fractures than patients taking placebo (0.5% vs 1.8%; RR = 0.27; 95% CI, 0.16-0.47; NNT = 77); however, there was no significant difference between the 2 groups with nonvertebral fractures (HR = 0.75; 95% CI, 0.53-1.05).33
Continue to: In another study...
In another study, romosozumab 210 mg SC was compared with alendronate 70 mg weekly, followed by alendronate 70 mg weekly in both groups. Over the first 12 months, patients treated with romosozumab saw a significant reduction in the incidence of new vertebral fractures (4% vs 6.3%; RR = 0.63, P < .003; NNT = 44). Patients treated with romosozumab with alendronate added for another 12 months also saw a significant reduction in new incidence of vertebral fractures (6.2% vs 11.9%; RR = 0.52; P < .001; NNT = 18).34 There was a higher risk of cardiovascular events among patients receiving romosozumab compared with those treated with alendronate, so romosozumab should not be used in individuals who have had an MI or stroke within the previous year.34 Denosumab and romosozumab offer an advantage over some bisphosphonates in that they require less frequent dosing and can be used in patients with renal impairment (creatinine clearance < 35 mL/min, in which zoledronic acid is contraindicated and alendronate is not recommended; < 30 mL/min, in which risedronate and ibandronate are not recommended).
Migraine prevention
Four
Erenumab, fremanezumab, and galcanezumab are all available in subcutaneous autoinjectors (or syringe with fremanezumab). Eptinezumab is an intravenous (IV) infusion given every 3 months.
Erenumab is available in both 70-mg and 140-mg dosing options. Fremanezumab can be given as 225 mg monthly or 675 mg quarterly. Galcanezumab has an initial loading dose of 240 mg followed by 120 mg given monthly. Erenumab targets the CGRP receptor; the others target the CGRP ligand. Eptinezumab has 100% bioavailability and reaches maximum serum concentration sooner than the other antagonists (due to its route of administration), but it must be given in an infusion center. Few insurers approve the use of eptinezumab unless a trial of least 1 of the monthly injectables has failed.
There are no head-to-head studies of the medications in this class. Additionally, differing study designs, definitions, statistical analyses, endpoints, and responder-rate calculations make it challenging to compare them directly against one another. At the very least, all of the CGRP MAbs have efficacy comparable to conventional preventive migraine medications such as propranolol, amitriptyline, and topiramate.40
Continue to: The most commonly reported adverse...
The most commonly reported adverse effect for all 4 CGRPs is injection site reaction, which was highest with the quarterly fremanezumab dose (45%).37 Constipation was most notable with the 140-mg dose of erenumab (3%)35; with the other CGRP MAbs it is comparable to that seen with placebo (< 1%).
Erenumab-induced hypertension has been identified in 61 cases reported through the FDA Adverse Event Reporting System (FAERS) as of 2021.41 This was not reported during MAb development programs, nor was it noted during clinical trials. Blood pressure elevation was seen within 1 week of injection in nearly 50% of the cases, and nearly one-third had pre-existing hypertension.41 Due to these findings, the erenumab prescribing information was updated to include hypertension in its warnings and precautions. It is possible that hypertension could be a class effect, although trial data and posthoc studies have yet to bear that out. Since erenumab was the first CGRP antagonist brought to market (May 2018 vs September 2018 for fremanezumab and galcanezumab), it may have accumulated more FAERS reports. Nearly all studies exclude patients with older age, uncontrolled hypertension, and unstable cardiovascular disease, which could impact data.41
Overall, this class of medications is very well tolerated, easy to use (again, excluding eptinezumab), and maintains a low adverse effect profile, giving added value compared with conventional preventive migraine medications.
The American Headache Society recommends a preventive oral therapy for at least 3 months before trying an alternative medication. After treatment failure with at least 2 oral agents, CGRP MAbs are recommended.42 CGRP antagonists offer convenient dosing, bypass gastrointestinal metabolism (which is useful in patients with nausea/vomiting), and have fewer adverse effects than traditional oral medications.
Worth noting. Several newer oral agents have been recently approved for migraine prevention, including atogepant (Qulipta) and rimegepant (Nurtec), which are also CGRP antagonists. Rimegepant is approved for both acute migraine treatment and prevention.
Continue to: Migraine
❯ Migraine: Test your skills
Subjective findings: A 25-year-old woman presents to your clinic for management of episodic migraines with aura. Her baseline average migraine frequency is 9 headache days/month. Her migraines are becoming more frequent despite treatment. She fears IV medication use and avoids hospitals.
History: Hypertension, irritable bowel syndrome with constipation (IBS-C), and depression. The patient is not pregnant or trying to get pregnant.
Medications: Current medications (for previous 4 months) include propranolol 40 mg at bedtime, linaclotide 145 μg/d, citalopram 20 mg/d, and sumatriptan 50 mg prn. Past medications include venlafaxine 150 mg po bid for 5 months.
What would be appropriate for this patient? This patient meets the criteria for using a CGRP antagonist because she has tried 2 preventive treatments for more than 60 to 90 days. Erenumab is not the best option, given the patient’s history of hypertension and IBS-C. The patient fears hospitals and IV medications, making eptinezumab a less-than-ideal choice. Depending on her insurance, fremanezumab or galcanezumab would be good options at this time.
CGRP antagonists have not been studied or evaluated in pregnancy, but if this patient becomes pregnant, a first-line agent for prevention would be propranolol, and a second-line agent would be a tricyclic antidepressant, memantine, or verapamil. Avoid ergotamines and antiepileptics (topiramate or valproate) in pregnancy.43,44
Continue to: The challenges associated with MAbs
The challenges associated with MAbs
MAbs can be expensive (TABLE 2),45 some prohibitively so. On a population scale, biologics account for around 40% of prescription drug spending and may cost 22 times more than small-molecule drugs.46 Estimates in 2016 showed that MAbs comprise $90.2 billion (43%) of the biologic market.46
MAbs also require prior authorization forms to be submitted. Prior authorization criteria vary by state and by insurance plan. In my (ES) experience, submitting letters of medical necessity justifying the need for therapy or expertise in the disease states for which the MAb is being prescribed help your patient get the medication they need.
Expect to see additional MAbs approved in the future. If the costs come down, adoption of these agents into practice will likely increase.
CORRESPONDENCE
Evelyn Sbar, MD, Texas Tech University Health Sciences Center, 1400 South Coulter Street, Suite 5100, Amarillo, TX 79106; [email protected]
Small-molecule drugs such as aspirin, albuterol, atorvastatin, and lisinopril are the backbone of disease management in family medicine.1 However, large-molecule biological drugs such as monoclonal antibodies (MAbs) are increasingly prescribed to treat common conditions. In the past decade, MAbs comprised 20% of all drug approvals by the US Food and Drug Administration (FDA), and today they represent more than half of drugs currently in development.2 Fifteen MAbs have been approved by the FDA over the past decade for asthma, atopic dermatitis (AD), hyperlipidemia, osteoporosis, and migraine prevention.3 This review details what makes MAbs unique and what you should know about them.
The uniqueness of monoclonal antibodies
MAbs are biologics, but not all biologics are MAbs—eg, adalimumab (Humira) is a MAb, but etanercept (Enbrel) is not. MAbs are therapeutic proteins made possible by hybridoma technology used to create an antibody with single specificity.4-6 Monoclonal antibodies differ from small-molecule drugs in structure, dosing, route of administration, manufacturing, metabolism, drug interactions, and elimination (TABLE 17-9).
MAbs can be classified as naked, “without any drug or radioactive material attached to them,” or conjugated, “joined to a chemotherapy drug, radioactive isotope, or toxin.”10 MAbs work in several ways, including competitively inhibiting ligand-receptor binding, receptor blockade, or cell elimination from indirect immune system activities such as antibody-dependent cell-mediated cytotoxicity.11,12
Monoclonal antibody uses in family medicine
Asthma
Several MAbs have been approved for use in severe asthma, including but not limited to: omalizumab (Xolair),13 mepolizumab (Nucala),9,14 and dupilumab (Dupixent).15
Omalizumab is a humanized MAb that prevents IgE antibodies from binding to mast cells and basophils, thereby reducing inflammatory mediators.13 A systematic review found that, compared with placebo, omalizumab used in patients with inadequately controlled moderate-to-severe asthma led to significantly fewer asthma exacerbations (absolute risk reduction [ARR], 16% vs 26%; odds ratio [OR] = 0.55; 95% CI, 0.42-0.60; number needed to treat [NNT] = 10) and fewer hospitalizations (ARR, 0.5% vs 3%; OR = 0.16; 95% CI, 0.06-0.42; NNT = 40).13
Significantly more patients in the omalizumab group were able to withdraw from, or reduce, the dose of ICS. GINA recommends omalizumab for patients with positive skin sensitization, total serum IgE ≥ 30 IU/mL, weight within 30 kg to 150 kg, history of childhood asthma and recent exacerbations, and blood eosinophils ≥ 260/mcL.16 Omalizumab is also approved for use in chronic spontaneous urticaria and nasal polyps.
Mepolizumab
Continue to: Another trial found that...
Another trial found that mepolizumab reduced total OCS doses in patients with severe asthma by 50% without increasing exacerbations or worsening asthma control.18 All 3 anti-IL-5 drugs—including not only mepolizumab, but also benralizumab (Fasenra) and reslizumab (Cinqair)—appear to yield similar improvements. A 2017 systematic review found all anti-IL-5 treatments reduced rates of clinically significant asthma exacerbations (treatment with OCS for ≥ 3 days) by roughly 50% in patients with severe eosinophilic asthma and a history of ≥ 2 exacerbations in the past year.
Dupilumab is a humanized MAb that inhibits IL-4 and IL-13, which influence multiple cell types involved in inflammation (eg, mast cells, eosinophils) and inflammatory mediators (histamine, leukotrienes, cytokines).15 In a recent study of patients with uncontrolled asthma, dupilumab 200 mg every 2 weeks compared with placebo showed a modest reduction in the annualized rate of severe asthma exacerbations (0.46 exacerbations vs 0.87, respectively). Dupilumab was effective in patients with blood eosinophil counts ≥ 150/μL but was ineffective in patients with eosinophil counts < 150/μL.15
For patients ≥ 12 years old with severe eosinophilic asthma, GINA recommends using dupilumab as add-on therapy for an initial trial of 4 months at doses of 200 or 300 mg SC every 2 weeks, with preference for 300 mg SC every 2 weeks for OCS-dependent asthma. Dupilumab is approved for use in AD and chronic rhinosinusitis with nasal polyposis. If a biologic agent is not successful after a 4-month trial, consider a 6- to 12-month trial. If efficacy is still minimal, consider switching to an alternative biologic therapy approved for asthma.16
❯ Asthma: Test your skills
Subjective findings: A 19-year-old man presents to your clinic. He has a history of nasal polyps and allergic asthma. At age 18, he was given a diagnosis of severe persistent asthma. He has shortness of breath during waking hours 4 times per week, and treats each of these episodes with albuterol. He also wakes up about twice a week with shortness of breath and has some limitations in normal activities. He reports missing his prescribed fluticasone/salmeterol 500/50 μg, 1 inhalation bid, only once each month. In the last year, he has had 2 exacerbations requiring oral steroids.
Medications: Albuterol 90 μg, 1-2 inhalations, q6h prn; fluticasone/salmeterol 500/50 μg, 1 inhalation bid; tiotropium 1.25 μg, 2 puffs/d; montelukast 10 mg every morning; prednisone 10 mg/d.
Continue to: Objective data
Objective data: Patient is in no apparent distress and afebrile, and oxygen saturation on room air is 97%. Ht, 70 inches; wt, 75 kg. Labs: IgE, 15 IU/mL; serum eosinophils, 315/μL.
Which MAb would be appropriate for this patient? Given that the patient has a blood eosinophil level ≥ 300/μL and severe exacerbations, adult-onset asthma, nasal polyposis, and maintenance OCS at baseline, it would be reasonable to initiate mepolizumab 100 mg SC every 4 weeks, or dupilumab 600 mg once, then 300 mg SC every 2 weeks. Both agents can be self-administered.
Atopic dermatitis
Two MAbs—dupilumab and tralokinumab (Adbry; inhibits IL-13)—are approved for treatment of AD in adults that is uncontrolled with conventional therapy.15,19 Dupilumab is also approved for children ≥ 6 months old.20 Both MAbs are dosed at 600 mg SC, followed by 300 mg every 2 weeks. Dupilumab was compared with placebo in adult patients who had moderate-to-severe AD inadequately controlled on topical corticosteroids (TCSs), to determine the proportion of patients in each group achieving improvement of either 0 or 1 points or ≥ 2 points in the 5-point Investigator Global Assessment (IGA) score from baseline to 16 weeks.21 Thirty-seven percent of patients receiving dupilumab 300 mg SC weekly and 38% of patients receiving dupilumab 300 mg SC every 2 weeks achieved the primary outcome, compared with 10% of those receiving placebo (P < .001).21 Similar IGA scores were reported when dupilumab was combined with TCS, compared with placebo.22
It would be reasonable to consider dupilumab or tralokinumab in patients with: cutaneous atrophy or hypothalamic-pituitary-adrenal axis suppression with TCS, concerns of malignancy with topical calcineurin inhibitors, or problems with the alternative systemic therapies (cyclosporine-induced hypertension, nephrotoxicity, or immunosuppression; azathioprine-induced malignancy; or methotrexate-induced bone marrow suppression, renal impairment, hepatotoxicity, pneumonitis, or gastrointestinal toxicity).23
A distinct advantage of MAbs over other systemic agents in the management of AD is that MAbs do not require frequent monitoring of blood pressure, renal or liver function, complete blood count with differential, electrolytes, or uric acid. Additionally, MAbs have fewer black box warnings and adverse reactions when compared with other systemic agents.
Continue to: Hyperlipidemia
Hyperlipidemia
Three MAbs are approved for use in hyperlipidemia: the angiopoietin-like protein 3 (ANGPTL3) inhibitor evinacumab (Evkeeza)24 and 2 proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, evolocumab (Repatha)25 and alirocumab (Praluent).26
ANGPTL3 inhibitors block ANGPTL3 and reduce endothelial lipase and lipoprotein lipase activity, which in turn decreases low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride formation. PCSK9 inhibitors prevent PCSK9 from binding to LDL receptors, thereby maintaining the number of active LDL receptors and increasing LDL-C removal.
Evinacumab is indicated for homozygous familial hypercholesterolemia and is administered intravenously every 4 weeks. Evinacumab has not been evaluated for effects on cardiovascular morbidity and mortality.
Evolocumab 140 mg SC every 2 weeks or 420 mg SC monthly has been studied in patients on statin therapy with LDL-C ≥ 70 mg/dL. Patients on evolocumab experienced significantly less of the composite endpoint of cardiovascular death, myocardial infarction (MI), stroke, hospitalization for unstable angina, or coronary revascularization compared with placebo (9.8% vs 11.3%; hazard ratio [HR] = 0.85; 95% CI, 0.79-0.92; NNT = 67.27
Alirocumab 75 mg SC every 2 weeks has also been studied in patients receiving statin therapy with LDL-C ≥ 70 mg/dL. Patients taking alirocumab experienced significantly less of the composite endpoint of death from coronary heart disease, nonfatal MI, ischemic stroke, or hospitalization for unstable angina compared with placebo (9.5% vs 11.1%; HR = 0.85; 95% CI, 0.78-0.93; NNT = 63).
Continue to: According to the 2018...
According to the 2018 AHA Cholesterol Guidelines, PCSK9 inhibitors are indicated for patients receiving maximally tolerated LDL-C-lowering therapy (statin and ezetimibe) with LDL-C ≥ 70 mg/dL, if they have had multiple atherosclerotic cardiovascular disease (ASCVD) events or 1 major ASCVD event with multiple high-risk conditions (eg, heterozygous familial hypercholesterolemia, history of coronary artery bypass grafting or percutaneous coronary intervention, hypertension, estimated glomerular filtration rate of 15 to 59 mL/min/1.73m2).29 For patients without prior ASCVD events or high-risk conditions who are receiving maximally tolerated LDL-C-lowering therapy (statin and ezetimibe), PCSK9 inhibitors are indicated if the LDL-C remains ≥ 100 mg/dL.
Osteoporosis
The 2 MAbs approved for use in osteoporosis are the receptor activator of nuclear factor kB ligand (RANKL) inhibitor denosumab (Prolia)30 and the sclerostin inhibitor romosozumab (Evenity).31
Denosumab prevents RANKL from binding to the RANK receptor, thereby inhibiting osteoclast formation and decreasing bone resorption. Denosumab is approved for use in women and men who are at high risk of osteoporotic fracture, including those taking OCSs, men receiving androgen deprivation therapy for prostate cancer, and women receiving adjuvant aromatase inhibitor therapy for breast cancer.
In a 3-year randomized trial, denosumab 60 mg SC every 6 months was compared with placebo in postmenopausal women with T-scores < –2.5, but not < –4.0 at the lumbar spine or total hip. Denosumab significantly reduced new radiographic vertebral fractures (2.3% vs 7.2%; risk ratio [RR] = 0.32; 95% CI, 0.26-0.41; NNT = 21), hip fracture (0.7% vs 1.2%), and nonvertebral fracture (6.5% vs 8.0%).32 Denosumab carries an increased risk of multiple vertebral fractures following discontinuation, skin infections, dermatologic reactions, and severe bone, joint, and muscle pain.
Romosozumab inhibits sclerostin, thereby increasing bone formation and, to a lesser degree, decreasing bone resorption. Romosozumab is approved for use in postmenopausal women at high risk for fracture (ie, those with a history of osteoporotic fracture or multiple risk factors for fracture) or in patients who have not benefited from or are intolerant of other therapies. In one study, postmenopausal women with a T-score of –2.5 to –3.5 at the total hip or femoral neck were randomly assigned to receive either romosozumab 210 mg SC or placebo for 12 months, then each group was switched to denosumab 60 mg SC for 12 months. After the first year, prior to initiating denosumab, patients taking romosozumab experienced significantly fewer new vertebral fractures than patients taking placebo (0.5% vs 1.8%; RR = 0.27; 95% CI, 0.16-0.47; NNT = 77); however, there was no significant difference between the 2 groups with nonvertebral fractures (HR = 0.75; 95% CI, 0.53-1.05).33
Continue to: In another study...
In another study, romosozumab 210 mg SC was compared with alendronate 70 mg weekly, followed by alendronate 70 mg weekly in both groups. Over the first 12 months, patients treated with romosozumab saw a significant reduction in the incidence of new vertebral fractures (4% vs 6.3%; RR = 0.63, P < .003; NNT = 44). Patients treated with romosozumab with alendronate added for another 12 months also saw a significant reduction in new incidence of vertebral fractures (6.2% vs 11.9%; RR = 0.52; P < .001; NNT = 18).34 There was a higher risk of cardiovascular events among patients receiving romosozumab compared with those treated with alendronate, so romosozumab should not be used in individuals who have had an MI or stroke within the previous year.34 Denosumab and romosozumab offer an advantage over some bisphosphonates in that they require less frequent dosing and can be used in patients with renal impairment (creatinine clearance < 35 mL/min, in which zoledronic acid is contraindicated and alendronate is not recommended; < 30 mL/min, in which risedronate and ibandronate are not recommended).
Migraine prevention
Four
Erenumab, fremanezumab, and galcanezumab are all available in subcutaneous autoinjectors (or syringe with fremanezumab). Eptinezumab is an intravenous (IV) infusion given every 3 months.
Erenumab is available in both 70-mg and 140-mg dosing options. Fremanezumab can be given as 225 mg monthly or 675 mg quarterly. Galcanezumab has an initial loading dose of 240 mg followed by 120 mg given monthly. Erenumab targets the CGRP receptor; the others target the CGRP ligand. Eptinezumab has 100% bioavailability and reaches maximum serum concentration sooner than the other antagonists (due to its route of administration), but it must be given in an infusion center. Few insurers approve the use of eptinezumab unless a trial of least 1 of the monthly injectables has failed.
There are no head-to-head studies of the medications in this class. Additionally, differing study designs, definitions, statistical analyses, endpoints, and responder-rate calculations make it challenging to compare them directly against one another. At the very least, all of the CGRP MAbs have efficacy comparable to conventional preventive migraine medications such as propranolol, amitriptyline, and topiramate.40
Continue to: The most commonly reported adverse...
The most commonly reported adverse effect for all 4 CGRPs is injection site reaction, which was highest with the quarterly fremanezumab dose (45%).37 Constipation was most notable with the 140-mg dose of erenumab (3%)35; with the other CGRP MAbs it is comparable to that seen with placebo (< 1%).
Erenumab-induced hypertension has been identified in 61 cases reported through the FDA Adverse Event Reporting System (FAERS) as of 2021.41 This was not reported during MAb development programs, nor was it noted during clinical trials. Blood pressure elevation was seen within 1 week of injection in nearly 50% of the cases, and nearly one-third had pre-existing hypertension.41 Due to these findings, the erenumab prescribing information was updated to include hypertension in its warnings and precautions. It is possible that hypertension could be a class effect, although trial data and posthoc studies have yet to bear that out. Since erenumab was the first CGRP antagonist brought to market (May 2018 vs September 2018 for fremanezumab and galcanezumab), it may have accumulated more FAERS reports. Nearly all studies exclude patients with older age, uncontrolled hypertension, and unstable cardiovascular disease, which could impact data.41
Overall, this class of medications is very well tolerated, easy to use (again, excluding eptinezumab), and maintains a low adverse effect profile, giving added value compared with conventional preventive migraine medications.
The American Headache Society recommends a preventive oral therapy for at least 3 months before trying an alternative medication. After treatment failure with at least 2 oral agents, CGRP MAbs are recommended.42 CGRP antagonists offer convenient dosing, bypass gastrointestinal metabolism (which is useful in patients with nausea/vomiting), and have fewer adverse effects than traditional oral medications.
Worth noting. Several newer oral agents have been recently approved for migraine prevention, including atogepant (Qulipta) and rimegepant (Nurtec), which are also CGRP antagonists. Rimegepant is approved for both acute migraine treatment and prevention.
Continue to: Migraine
❯ Migraine: Test your skills
Subjective findings: A 25-year-old woman presents to your clinic for management of episodic migraines with aura. Her baseline average migraine frequency is 9 headache days/month. Her migraines are becoming more frequent despite treatment. She fears IV medication use and avoids hospitals.
History: Hypertension, irritable bowel syndrome with constipation (IBS-C), and depression. The patient is not pregnant or trying to get pregnant.
Medications: Current medications (for previous 4 months) include propranolol 40 mg at bedtime, linaclotide 145 μg/d, citalopram 20 mg/d, and sumatriptan 50 mg prn. Past medications include venlafaxine 150 mg po bid for 5 months.
What would be appropriate for this patient? This patient meets the criteria for using a CGRP antagonist because she has tried 2 preventive treatments for more than 60 to 90 days. Erenumab is not the best option, given the patient’s history of hypertension and IBS-C. The patient fears hospitals and IV medications, making eptinezumab a less-than-ideal choice. Depending on her insurance, fremanezumab or galcanezumab would be good options at this time.
CGRP antagonists have not been studied or evaluated in pregnancy, but if this patient becomes pregnant, a first-line agent for prevention would be propranolol, and a second-line agent would be a tricyclic antidepressant, memantine, or verapamil. Avoid ergotamines and antiepileptics (topiramate or valproate) in pregnancy.43,44
Continue to: The challenges associated with MAbs
The challenges associated with MAbs
MAbs can be expensive (TABLE 2),45 some prohibitively so. On a population scale, biologics account for around 40% of prescription drug spending and may cost 22 times more than small-molecule drugs.46 Estimates in 2016 showed that MAbs comprise $90.2 billion (43%) of the biologic market.46
MAbs also require prior authorization forms to be submitted. Prior authorization criteria vary by state and by insurance plan. In my (ES) experience, submitting letters of medical necessity justifying the need for therapy or expertise in the disease states for which the MAb is being prescribed help your patient get the medication they need.
Expect to see additional MAbs approved in the future. If the costs come down, adoption of these agents into practice will likely increase.
CORRESPONDENCE
Evelyn Sbar, MD, Texas Tech University Health Sciences Center, 1400 South Coulter Street, Suite 5100, Amarillo, TX 79106; [email protected]
1. Rui P, Okeyode T. National Ambulatory Medical Care Survey: 2016 national summary tables. National Center for Health Statistics. Accessed June 15, 2022. www.cdc.gov/nchs/data/ahcd/namcs_summary/2016_namcs_web_tables.pdf
2. IDBS. The future of biologics drug development is today. June 27, 2018. Accessed June 15, 2022. www.idbs.com/blog/2018/06/the-future-of-biologics-drug-development-is-today/
3. Antibody therapeutics approved or in regulatory review in the EU or US. Antibody Society. Accessed June 15, 2022. www.antibodysociety.org/resources/approved-antibodies/
4. FDA. Code of Federal Regulations, Title 21, Chapter I, Subchapter F biologics. March 29, 2022. Accessed June 15, 2022. www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=600.3
5. Köhler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975;256:495-497. doi: 10.1038/256495a0
6. Raejewsky K. The advent and rise of monoclonal antibodies. Nature. November 4, 2019. Accessed June 15, 2022. www.nature.com/articles/d41586-019-02840-w
7. Flovent. Prescribing information. GlaxoSmithKline; 2010. Accessed June 15, 2022. www.accessdata.fda.gov/drugsatfda_docs/label/2010/021433s015lbl.pdf
8. NLM. National Center for Biotechnology Information. PubChem. Method for the preparation of fluticasone and related 17beta-carbothioic esters using a novel carbothioic acid synthesis and novel purification methods. Accessed June 15, 2022. pubchem.ncbi.nlm.nih.gov/patent/WO-0162722-A2
9. Nucala. Prescribing information. GlaxoSmithKline; 2019. Accessed June 15, 2022. www.accessdata.fda.gov/drugsatfda_docs/label/2019/761122s000lbl.pdf
10. Argyriou AA, Kalofonos HP. Recent advances relating to the clinical application of naked monoclonal antibodies in solid tumors. Mol Med. 2009;15:183-191. doi: 10.2119/molmed.2009.00007
11. Wang W, Wang EQ, Balthasar JP. Monoclonal antibody pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther. 2008;84:548-558. doi: 10.1038/clpt.2008.170
12. Zahavi D, AlDeghaither D, O’Connell A, et al. Enhancing antibody-dependent cell-mediated cytotoxicity: a strategy for improving antibody-based immunotherapy. Antib Ther. 2018;1:7-12. doi: 10.1093/abt/tby002
13. Normansell R, Walker S, Milan SJ, et al. Omalizumab for asthma in adults and children. Cochrane Database Syst Rev. 2014:CD003559. doi: 10.1002/14651858.CD003559.pub4
14. Farne HA, Wilson A, Powell C, et al. Anti-IL5 therapies for asthma. Cochrane Database Syst Rev. 2017;9:CD010834. doi: 10.1002/14651858.CD010834.pub3
15. Castro M, Corren J, Pavord ID, et al. Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma. N Engl J Med. 2018;378:2486-2496. doi: 10.1056/NEJMoa1804092
16. GINA. Global strategy for asthma management and prevention. 2022 Difficult-to-treat and severe asthma guide—slide set. Accessed June 23, 2022. https://ginasthma.org/severeasthma/
17. Ortega HG, Liu MC, Pavord ID, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014;371:1198-1207. doi: 10.1056/NEJMoa1403290
18. Bel EH, Wenzel SE, Thompson PJ, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014;371:1189-1197. doi: 10.1056/NEJMoa1403291
19. Adbry. Prescribing information. Leo Pharma Inc; 2021. Accessed June 24, 2022. www.accessdata.fda.gov/drugsatfda_docs/nda/2022/761180Orig1s000lbl.pdf
20. Dupixent. Prescribing information. Regeneron Pharmaceuticals; 2022. Accessed October 5, 2022. https://www.regeneron.com/downloads/dupixent_fpi.pdf
21. Simpson EL, Bieber T, Guttman-Yassky E, et al. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2016;375:2335-2348. doi: 10.1056/NEJMoa1610020
22. Blauvelt A, de Bruin-Weller M, Gooderham M, et al. Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomised, double-blinded, placebo-controlled, phase 3 trial. Lancet. 2017;389:2287-2303. doi: 10.1016/s0140-6736(17)31191-1
23. Sidbury R, Davis DM, Cohen DE, et al. Guidelines of care for the management of atopic dermatitis: section 3. Management and treatment with phototherapy and systemic agents. J Am Acad Dermatol. 2014;71:327-349. doi: 10.1016/j.jaad.2014.03.030
24. Evkeeza. Prescribing information. Regeneron Pharmaceuticals; 2021. Accessed June 24, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761181s000lbl.pdf
25. Repatha. Prescribing information. Amgen; 2015. Accessed June 24, 2022. www.accessdata.fda.gov/drugsatfda_docs/label/2017/125522s014lbl.pdf
26. Praluent. Prescribing information. Sanofi Aventis and Regeneron Pharmaceuticals. 2015. Accessed June 24, 2022. www.accessdata.fda.gov/drugsatfda_docs/label/2017/125559s002lbl.pdf
27. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376:1713-1722. doi: 10.1056/NEJMoa1615664
28. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018;379:2097-2107. doi:10.1056/NEJMoa1801174
29. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. J Am Coll Cardiol. 2019;73:e285-e350. doi: 10.1016/j.jacc.2018.11.003
30. Prolia. Prescribing information. Amgen; 2010. Accessed June 24, 2022. www.accessdata.fda.gov/drugsatfda_docs/label/2013/125320s094lbl.pdf
31. Evenity. Prescribing information. Amgen; 2019. Accessed June 24, 2022. www.accessdata.fda.gov/drugsatfda_docs/label/2019/761062s000lbl.pdf
32. Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361:756-765. doi: 10.1056/NEJMoa0809493
33. Cosman F, Crittenden DB, Adachi JD, et al. Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med. 2016;375:1532-1543. doi: 10.1056/NEJMoa1607948
34. Saag KG, Petersen J, Brandi ML, et al. Romosozumab or alendronate for fracture prevention in women with osteoporosis. N Engl J Med. 2017;377:1417-1427. doi: 10.1056/NEJMoa1708322
35. Aimovig. Prescribing information. Amgen; 2018. Accessed June 24, 2022. www.accessdata.fda.gov/drugsatfda_docs/label/2018/761077s000lbl.pdf
36. Vyepti. Prescribing information. Lundbeck Seattle BioPharmaceuticals; 2020. Accessed June 24, 2022. www.accessdata.fda.gov/drugsatfda_docs/label/2020/761119s000lbl.pdf
37. Ajovy. Prescribing information. Teva Pharmaceuticals; 2018. Accessed June 24, 2022. www.accessdata.fda.gov/drugsatfda_docs/label/2018/761089s000lbl.pdf
38. Emgality. Prescribing information. Eli Lilly and Co.; 2018. Accessed June 24, 2022. www.accessdata.fda.gov/drugsatfda_docs/label/2018/761063s000lbl.pdf
39. Edvinsson L, Haanes KA, Warfvinge K, et al. CGRP as the target of new migraine therapies - successful translation from bench to clinic. Nat Rev Neurol. 2018;14:338-350. doi: 10.1038/s41582-018-0003-1
40. Vandervorst F. Van Deun L, Van Dycke A, et al. CGRP monoclonal antibodies in migraine: an efficacy and tolerability comparison with standard prophylactic drugs. J Headache Pain. 2021;22:128. doi: 10.1186/s10194-021-01335-2
41. Saely S, Croteau D, Jawidzik L, et al. Hypertension: a new safety risk for patients treated with erenumab. Headache. 2021;61:202-208. doi: 10.1111/head.14051
42. American Headache Society. The American Headache Society position statement on integrating new migraine treatments into clinical practice. Headache. 2019;59:1-18. doi: 10.1111/head.13456
43. Burch R. Headache in pregnancy and the puerperium. Neurol Clin. 2019;37:31-51. doi: 10.1016/j.ncl.2018.09.004
44. Burch R. Epidemiology and treatment of menstrual migraine and migraine during pregnancy and lactation: a narrative review. Headache. 2020;60:200-216. doi: 10.1111/head.13665
45. Lexi-Comp. Lexi-drug database. Accessed April 4, 2022. https://online.lexi.com/lco/action/login
46. Walker N. Biologics: driving force in pharma. Pharma’s Almanac. June 5, 2017. Accessed June 15, 2020. www.pharmasalmanac.com/articles/biologics-driving-force-in-pharma
1. Rui P, Okeyode T. National Ambulatory Medical Care Survey: 2016 national summary tables. National Center for Health Statistics. Accessed June 15, 2022. www.cdc.gov/nchs/data/ahcd/namcs_summary/2016_namcs_web_tables.pdf
2. IDBS. The future of biologics drug development is today. June 27, 2018. Accessed June 15, 2022. www.idbs.com/blog/2018/06/the-future-of-biologics-drug-development-is-today/
3. Antibody therapeutics approved or in regulatory review in the EU or US. Antibody Society. Accessed June 15, 2022. www.antibodysociety.org/resources/approved-antibodies/
4. FDA. Code of Federal Regulations, Title 21, Chapter I, Subchapter F biologics. March 29, 2022. Accessed June 15, 2022. www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=600.3
5. Köhler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975;256:495-497. doi: 10.1038/256495a0
6. Raejewsky K. The advent and rise of monoclonal antibodies. Nature. November 4, 2019. Accessed June 15, 2022. www.nature.com/articles/d41586-019-02840-w
7. Flovent. Prescribing information. GlaxoSmithKline; 2010. Accessed June 15, 2022. www.accessdata.fda.gov/drugsatfda_docs/label/2010/021433s015lbl.pdf
8. NLM. National Center for Biotechnology Information. PubChem. Method for the preparation of fluticasone and related 17beta-carbothioic esters using a novel carbothioic acid synthesis and novel purification methods. Accessed June 15, 2022. pubchem.ncbi.nlm.nih.gov/patent/WO-0162722-A2
9. Nucala. Prescribing information. GlaxoSmithKline; 2019. Accessed June 15, 2022. www.accessdata.fda.gov/drugsatfda_docs/label/2019/761122s000lbl.pdf
10. Argyriou AA, Kalofonos HP. Recent advances relating to the clinical application of naked monoclonal antibodies in solid tumors. Mol Med. 2009;15:183-191. doi: 10.2119/molmed.2009.00007
11. Wang W, Wang EQ, Balthasar JP. Monoclonal antibody pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther. 2008;84:548-558. doi: 10.1038/clpt.2008.170
12. Zahavi D, AlDeghaither D, O’Connell A, et al. Enhancing antibody-dependent cell-mediated cytotoxicity: a strategy for improving antibody-based immunotherapy. Antib Ther. 2018;1:7-12. doi: 10.1093/abt/tby002
13. Normansell R, Walker S, Milan SJ, et al. Omalizumab for asthma in adults and children. Cochrane Database Syst Rev. 2014:CD003559. doi: 10.1002/14651858.CD003559.pub4
14. Farne HA, Wilson A, Powell C, et al. Anti-IL5 therapies for asthma. Cochrane Database Syst Rev. 2017;9:CD010834. doi: 10.1002/14651858.CD010834.pub3
15. Castro M, Corren J, Pavord ID, et al. Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma. N Engl J Med. 2018;378:2486-2496. doi: 10.1056/NEJMoa1804092
16. GINA. Global strategy for asthma management and prevention. 2022 Difficult-to-treat and severe asthma guide—slide set. Accessed June 23, 2022. https://ginasthma.org/severeasthma/
17. Ortega HG, Liu MC, Pavord ID, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014;371:1198-1207. doi: 10.1056/NEJMoa1403290
18. Bel EH, Wenzel SE, Thompson PJ, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014;371:1189-1197. doi: 10.1056/NEJMoa1403291
19. Adbry. Prescribing information. Leo Pharma Inc; 2021. Accessed June 24, 2022. www.accessdata.fda.gov/drugsatfda_docs/nda/2022/761180Orig1s000lbl.pdf
20. Dupixent. Prescribing information. Regeneron Pharmaceuticals; 2022. Accessed October 5, 2022. https://www.regeneron.com/downloads/dupixent_fpi.pdf
21. Simpson EL, Bieber T, Guttman-Yassky E, et al. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2016;375:2335-2348. doi: 10.1056/NEJMoa1610020
22. Blauvelt A, de Bruin-Weller M, Gooderham M, et al. Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomised, double-blinded, placebo-controlled, phase 3 trial. Lancet. 2017;389:2287-2303. doi: 10.1016/s0140-6736(17)31191-1
23. Sidbury R, Davis DM, Cohen DE, et al. Guidelines of care for the management of atopic dermatitis: section 3. Management and treatment with phototherapy and systemic agents. J Am Acad Dermatol. 2014;71:327-349. doi: 10.1016/j.jaad.2014.03.030
24. Evkeeza. Prescribing information. Regeneron Pharmaceuticals; 2021. Accessed June 24, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761181s000lbl.pdf
25. Repatha. Prescribing information. Amgen; 2015. Accessed June 24, 2022. www.accessdata.fda.gov/drugsatfda_docs/label/2017/125522s014lbl.pdf
26. Praluent. Prescribing information. Sanofi Aventis and Regeneron Pharmaceuticals. 2015. Accessed June 24, 2022. www.accessdata.fda.gov/drugsatfda_docs/label/2017/125559s002lbl.pdf
27. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376:1713-1722. doi: 10.1056/NEJMoa1615664
28. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018;379:2097-2107. doi:10.1056/NEJMoa1801174
29. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. J Am Coll Cardiol. 2019;73:e285-e350. doi: 10.1016/j.jacc.2018.11.003
30. Prolia. Prescribing information. Amgen; 2010. Accessed June 24, 2022. www.accessdata.fda.gov/drugsatfda_docs/label/2013/125320s094lbl.pdf
31. Evenity. Prescribing information. Amgen; 2019. Accessed June 24, 2022. www.accessdata.fda.gov/drugsatfda_docs/label/2019/761062s000lbl.pdf
32. Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361:756-765. doi: 10.1056/NEJMoa0809493
33. Cosman F, Crittenden DB, Adachi JD, et al. Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med. 2016;375:1532-1543. doi: 10.1056/NEJMoa1607948
34. Saag KG, Petersen J, Brandi ML, et al. Romosozumab or alendronate for fracture prevention in women with osteoporosis. N Engl J Med. 2017;377:1417-1427. doi: 10.1056/NEJMoa1708322
35. Aimovig. Prescribing information. Amgen; 2018. Accessed June 24, 2022. www.accessdata.fda.gov/drugsatfda_docs/label/2018/761077s000lbl.pdf
36. Vyepti. Prescribing information. Lundbeck Seattle BioPharmaceuticals; 2020. Accessed June 24, 2022. www.accessdata.fda.gov/drugsatfda_docs/label/2020/761119s000lbl.pdf
37. Ajovy. Prescribing information. Teva Pharmaceuticals; 2018. Accessed June 24, 2022. www.accessdata.fda.gov/drugsatfda_docs/label/2018/761089s000lbl.pdf
38. Emgality. Prescribing information. Eli Lilly and Co.; 2018. Accessed June 24, 2022. www.accessdata.fda.gov/drugsatfda_docs/label/2018/761063s000lbl.pdf
39. Edvinsson L, Haanes KA, Warfvinge K, et al. CGRP as the target of new migraine therapies - successful translation from bench to clinic. Nat Rev Neurol. 2018;14:338-350. doi: 10.1038/s41582-018-0003-1
40. Vandervorst F. Van Deun L, Van Dycke A, et al. CGRP monoclonal antibodies in migraine: an efficacy and tolerability comparison with standard prophylactic drugs. J Headache Pain. 2021;22:128. doi: 10.1186/s10194-021-01335-2
41. Saely S, Croteau D, Jawidzik L, et al. Hypertension: a new safety risk for patients treated with erenumab. Headache. 2021;61:202-208. doi: 10.1111/head.14051
42. American Headache Society. The American Headache Society position statement on integrating new migraine treatments into clinical practice. Headache. 2019;59:1-18. doi: 10.1111/head.13456
43. Burch R. Headache in pregnancy and the puerperium. Neurol Clin. 2019;37:31-51. doi: 10.1016/j.ncl.2018.09.004
44. Burch R. Epidemiology and treatment of menstrual migraine and migraine during pregnancy and lactation: a narrative review. Headache. 2020;60:200-216. doi: 10.1111/head.13665
45. Lexi-Comp. Lexi-drug database. Accessed April 4, 2022. https://online.lexi.com/lco/action/login
46. Walker N. Biologics: driving force in pharma. Pharma’s Almanac. June 5, 2017. Accessed June 15, 2020. www.pharmasalmanac.com/articles/biologics-driving-force-in-pharma
PRACTICE RECOMMENDATIONS
› Consider anti-immunoglobulin E, anti-interleukin 5, or anti-interleukin 4/interleukin 13 for patients with moderate-to-severe asthma and type 2 airway inflammation. B
› Consider dupilumab for patients with moderate-to-severe atopic dermatitis (with or without topical corticosteroids), or when traditional oral therapies are inadequate or contraindicated. B
› Consider proprotein convertase subtilisin/kexin type 9 inhibitors for patients with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease when maximally tolerated statins or ezetimibe have not lowered low-density lipoprotein cholesterol levels far enough. A
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
