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Western and proinflammatory diets are important drivers of gout risk
Diets high in red meats, saturated fats, and sugars, relative to diets dominated by fruits, vegetables, and legumes, are associated with an increased risk of gout independent of an underlying genetic risk, according to independent sets of data presented at the annual European Congress of Rheumatology.
Only one of the two retrospective analyses evaluated diet in the context of a genetic risk score, but “no evidence of an additional or multiplicative interaction” was seen when genetic risk was evaluated on top of the risk already known to be associated with a Western diet, reported Chio Yokose, MD, a researcher and clinician in the division of rheumatology, allergy, and immunology at Massachusetts General Hospital, Boston.
A parallel study presented at the EULAR Congress looked at the impact of a proinflammatory diet. Although genetic predisposition was not considered in this analysis, this diet, too, was associated with increased risk of gout independent of a long list of other variables. Each of the studies supports the potential for diet to be a target for risk reduction.
“Adhering to a diet with low inflammatory potential may mediate systemic and metabolic inflammation,” reported Natalie McCormick, PhD, a research fellow at Massachusetts General Hospital. She said the association of an inflammatory diet with gout is analogous to previous studies linking this type of diet to type 2 diabetes mellitus and cardiovascular disease because the inflammatory response is a pathogenic factor.
The two retrospective studies evaluated different but overlapping sets of data. Dr. Yokose and Dr. McCormick collaborated on both studies.
In the study of Western diet, which was restricted to women, the focus was on both diet and genes. Using food frequency questionnaires completed by 18,512 women participating in the Nurses’ Health Study (NHS), subjects were placed in quintiles for relative exposure to Western diets and for an interventional diet called DASH (Dietary Approaches to Stop Hypertension) that is high in fruits and vegetables.
A genetic risk score (GRS) was developed for participants using 114 serum urate single-nucleotide polymorphisms from a genomewide association study.
For the Western diet, there was a stepwise increased risk of gout per quintile associated with greater exposure. For the DASH diet, the same phenomenon was seen in reverse so that risk of gout was incrementally lower per quintile defining greater adherence.
When considered as a variable, GRS altered these basic relationships only for the DASH diet. After adjusting for multiple factors, such as age, menopause, use of hormone therapy, and hypertension, there was no significant interaction observed for genetic predisposition in relation to the Western diet.
For the DASH diet, there was an even greater reduction in the relative risk of gout among those with a high GRS if they were in the quintile defining greatest adherence to the DASH diet. Although this association fell just short of reaching statistical significance (P = .056), Dr. Yokose indicated that it was a strong trend.
Gout similarly associated with proinflammatory diet
The proinflammatory diet shares many food items with the Western diet, including refined carbohydrates, sweetened beverages, red meat, and fried foods. The study that evaluated its impact used dietary history collected from in 164,090 women in the NHS and 40,598 men in the Health Professionals Follow-up Study. In both, participants completed dietary questionnaires every 4 years. Patients were assigned an Empirical Dietary Index of Inflammatory Potential (EDIP) score on the basis of these questionnaires.
When the 2,874 incident gout cases were evaluated by EDIP quintile, those in the highest had a 50% greater risk of gout than did those in the lowest when adjusted for multiple potential confounders. When stratified by intake of alcohol, the impact of being in the highest quintile of inflammatory diet was even greater, producing a 2.37-fold increased risk of gout.
Impact of weight on risk for gout
The impact of proinflammatory diet was detectable even after adjusting for adiposity, a gout risk factor reconfirmed in a third study presented at EULAR by this same team of investigators. In that study, presented by Dr. Yokose, a GRS above the mean was associated with a further increased likelihood of gout among those with elevated body mass index. However, obesity remained a risk factor for gout even among those with a low GRS.
The data from this study indicate “maintaining healthy weight is an important gout prevention strategy, regardless of underlying genetic risk,” Dr. Yokose reported.
All three studies reinforce diet as a modifiable risk factor for gout. According to both Dr. Yokose and Dr. McCormick, healthy diets should be considered as a gout prevention strategy.
Annelies Boonen, MD, PhD, professor of internal medicine (rheumatology) at the University of Maastricht (the Netherlands), did not challenge these conclusions. However, she cautioned that it is “very difficult to evaluate food questionnaires.” She further noted that retrospective analyses complicate efforts to control for the many potential confounders.
Ultimately, healthy diets can be recommended for many reasons, particularly in individuals with other risk factors for gout. For this reason, Dr. Boonen indicated that it will be difficult to prove definitively that gout can be prevented by avoiding Western diets and other diets high in proinflammatory foods. However, definitive proof of this benefit might not be essential for the purpose of a general recommendation to eat healthy foods.
Dr. Yokose and Dr. McCormick reported no potential conflicts of interest.
Diets high in red meats, saturated fats, and sugars, relative to diets dominated by fruits, vegetables, and legumes, are associated with an increased risk of gout independent of an underlying genetic risk, according to independent sets of data presented at the annual European Congress of Rheumatology.
Only one of the two retrospective analyses evaluated diet in the context of a genetic risk score, but “no evidence of an additional or multiplicative interaction” was seen when genetic risk was evaluated on top of the risk already known to be associated with a Western diet, reported Chio Yokose, MD, a researcher and clinician in the division of rheumatology, allergy, and immunology at Massachusetts General Hospital, Boston.
A parallel study presented at the EULAR Congress looked at the impact of a proinflammatory diet. Although genetic predisposition was not considered in this analysis, this diet, too, was associated with increased risk of gout independent of a long list of other variables. Each of the studies supports the potential for diet to be a target for risk reduction.
“Adhering to a diet with low inflammatory potential may mediate systemic and metabolic inflammation,” reported Natalie McCormick, PhD, a research fellow at Massachusetts General Hospital. She said the association of an inflammatory diet with gout is analogous to previous studies linking this type of diet to type 2 diabetes mellitus and cardiovascular disease because the inflammatory response is a pathogenic factor.
The two retrospective studies evaluated different but overlapping sets of data. Dr. Yokose and Dr. McCormick collaborated on both studies.
In the study of Western diet, which was restricted to women, the focus was on both diet and genes. Using food frequency questionnaires completed by 18,512 women participating in the Nurses’ Health Study (NHS), subjects were placed in quintiles for relative exposure to Western diets and for an interventional diet called DASH (Dietary Approaches to Stop Hypertension) that is high in fruits and vegetables.
A genetic risk score (GRS) was developed for participants using 114 serum urate single-nucleotide polymorphisms from a genomewide association study.
For the Western diet, there was a stepwise increased risk of gout per quintile associated with greater exposure. For the DASH diet, the same phenomenon was seen in reverse so that risk of gout was incrementally lower per quintile defining greater adherence.
When considered as a variable, GRS altered these basic relationships only for the DASH diet. After adjusting for multiple factors, such as age, menopause, use of hormone therapy, and hypertension, there was no significant interaction observed for genetic predisposition in relation to the Western diet.
For the DASH diet, there was an even greater reduction in the relative risk of gout among those with a high GRS if they were in the quintile defining greatest adherence to the DASH diet. Although this association fell just short of reaching statistical significance (P = .056), Dr. Yokose indicated that it was a strong trend.
Gout similarly associated with proinflammatory diet
The proinflammatory diet shares many food items with the Western diet, including refined carbohydrates, sweetened beverages, red meat, and fried foods. The study that evaluated its impact used dietary history collected from in 164,090 women in the NHS and 40,598 men in the Health Professionals Follow-up Study. In both, participants completed dietary questionnaires every 4 years. Patients were assigned an Empirical Dietary Index of Inflammatory Potential (EDIP) score on the basis of these questionnaires.
When the 2,874 incident gout cases were evaluated by EDIP quintile, those in the highest had a 50% greater risk of gout than did those in the lowest when adjusted for multiple potential confounders. When stratified by intake of alcohol, the impact of being in the highest quintile of inflammatory diet was even greater, producing a 2.37-fold increased risk of gout.
Impact of weight on risk for gout
The impact of proinflammatory diet was detectable even after adjusting for adiposity, a gout risk factor reconfirmed in a third study presented at EULAR by this same team of investigators. In that study, presented by Dr. Yokose, a GRS above the mean was associated with a further increased likelihood of gout among those with elevated body mass index. However, obesity remained a risk factor for gout even among those with a low GRS.
The data from this study indicate “maintaining healthy weight is an important gout prevention strategy, regardless of underlying genetic risk,” Dr. Yokose reported.
All three studies reinforce diet as a modifiable risk factor for gout. According to both Dr. Yokose and Dr. McCormick, healthy diets should be considered as a gout prevention strategy.
Annelies Boonen, MD, PhD, professor of internal medicine (rheumatology) at the University of Maastricht (the Netherlands), did not challenge these conclusions. However, she cautioned that it is “very difficult to evaluate food questionnaires.” She further noted that retrospective analyses complicate efforts to control for the many potential confounders.
Ultimately, healthy diets can be recommended for many reasons, particularly in individuals with other risk factors for gout. For this reason, Dr. Boonen indicated that it will be difficult to prove definitively that gout can be prevented by avoiding Western diets and other diets high in proinflammatory foods. However, definitive proof of this benefit might not be essential for the purpose of a general recommendation to eat healthy foods.
Dr. Yokose and Dr. McCormick reported no potential conflicts of interest.
Diets high in red meats, saturated fats, and sugars, relative to diets dominated by fruits, vegetables, and legumes, are associated with an increased risk of gout independent of an underlying genetic risk, according to independent sets of data presented at the annual European Congress of Rheumatology.
Only one of the two retrospective analyses evaluated diet in the context of a genetic risk score, but “no evidence of an additional or multiplicative interaction” was seen when genetic risk was evaluated on top of the risk already known to be associated with a Western diet, reported Chio Yokose, MD, a researcher and clinician in the division of rheumatology, allergy, and immunology at Massachusetts General Hospital, Boston.
A parallel study presented at the EULAR Congress looked at the impact of a proinflammatory diet. Although genetic predisposition was not considered in this analysis, this diet, too, was associated with increased risk of gout independent of a long list of other variables. Each of the studies supports the potential for diet to be a target for risk reduction.
“Adhering to a diet with low inflammatory potential may mediate systemic and metabolic inflammation,” reported Natalie McCormick, PhD, a research fellow at Massachusetts General Hospital. She said the association of an inflammatory diet with gout is analogous to previous studies linking this type of diet to type 2 diabetes mellitus and cardiovascular disease because the inflammatory response is a pathogenic factor.
The two retrospective studies evaluated different but overlapping sets of data. Dr. Yokose and Dr. McCormick collaborated on both studies.
In the study of Western diet, which was restricted to women, the focus was on both diet and genes. Using food frequency questionnaires completed by 18,512 women participating in the Nurses’ Health Study (NHS), subjects were placed in quintiles for relative exposure to Western diets and for an interventional diet called DASH (Dietary Approaches to Stop Hypertension) that is high in fruits and vegetables.
A genetic risk score (GRS) was developed for participants using 114 serum urate single-nucleotide polymorphisms from a genomewide association study.
For the Western diet, there was a stepwise increased risk of gout per quintile associated with greater exposure. For the DASH diet, the same phenomenon was seen in reverse so that risk of gout was incrementally lower per quintile defining greater adherence.
When considered as a variable, GRS altered these basic relationships only for the DASH diet. After adjusting for multiple factors, such as age, menopause, use of hormone therapy, and hypertension, there was no significant interaction observed for genetic predisposition in relation to the Western diet.
For the DASH diet, there was an even greater reduction in the relative risk of gout among those with a high GRS if they were in the quintile defining greatest adherence to the DASH diet. Although this association fell just short of reaching statistical significance (P = .056), Dr. Yokose indicated that it was a strong trend.
Gout similarly associated with proinflammatory diet
The proinflammatory diet shares many food items with the Western diet, including refined carbohydrates, sweetened beverages, red meat, and fried foods. The study that evaluated its impact used dietary history collected from in 164,090 women in the NHS and 40,598 men in the Health Professionals Follow-up Study. In both, participants completed dietary questionnaires every 4 years. Patients were assigned an Empirical Dietary Index of Inflammatory Potential (EDIP) score on the basis of these questionnaires.
When the 2,874 incident gout cases were evaluated by EDIP quintile, those in the highest had a 50% greater risk of gout than did those in the lowest when adjusted for multiple potential confounders. When stratified by intake of alcohol, the impact of being in the highest quintile of inflammatory diet was even greater, producing a 2.37-fold increased risk of gout.
Impact of weight on risk for gout
The impact of proinflammatory diet was detectable even after adjusting for adiposity, a gout risk factor reconfirmed in a third study presented at EULAR by this same team of investigators. In that study, presented by Dr. Yokose, a GRS above the mean was associated with a further increased likelihood of gout among those with elevated body mass index. However, obesity remained a risk factor for gout even among those with a low GRS.
The data from this study indicate “maintaining healthy weight is an important gout prevention strategy, regardless of underlying genetic risk,” Dr. Yokose reported.
All three studies reinforce diet as a modifiable risk factor for gout. According to both Dr. Yokose and Dr. McCormick, healthy diets should be considered as a gout prevention strategy.
Annelies Boonen, MD, PhD, professor of internal medicine (rheumatology) at the University of Maastricht (the Netherlands), did not challenge these conclusions. However, she cautioned that it is “very difficult to evaluate food questionnaires.” She further noted that retrospective analyses complicate efforts to control for the many potential confounders.
Ultimately, healthy diets can be recommended for many reasons, particularly in individuals with other risk factors for gout. For this reason, Dr. Boonen indicated that it will be difficult to prove definitively that gout can be prevented by avoiding Western diets and other diets high in proinflammatory foods. However, definitive proof of this benefit might not be essential for the purpose of a general recommendation to eat healthy foods.
Dr. Yokose and Dr. McCormick reported no potential conflicts of interest.
FROM THE EULAR 2021 CONGRESS
Secukinumab provides clinical benefit in phase 3 juvenile arthritis trial
Favorable safety sustained at 104 weeks
Secukinumab (Cosentyx), an interleukin-17A inhibitor, is effective and reasonably well tolerated for treatment of enthesitis-related arthritis (ERA) and juvenile psoriatic arthritis (JPsA) in children and adolescents, according to a phase 3 trial presented at a late breaking abstracts session of the annual European Congress of Rheumatology.
On the primary outcome of time to flare, the curves for secukinumab and placebo separated almost immediately, with fewer than half the number of flares occurring in the experimental arm over the course of the study, according to Nicolino Ruperto, MD, senior research scientist at IRCCS Istituto Giannina Gaslini in Genoa, Italy.
The trial, called JUNIPERA, was conducted over 2 years and included an open-label treatment period (TP1) and then a randomized, placebo-controlled comparison (TP2). In TP1, 86 children were initiated on open-label secukinumab administered subcutaneously on weeks 1, 2, 3, 4, 8, and 12. The dose was 75 mg for children less than 50 kg and 150 kg for those heavier.
Average patient age was 13.1 years
Of these 86 children, 52 had ERA and 34 had JPsA. Disease duration of at least 6 months was required for entry. Patients up to the age of 18 years were permitted to enroll. The average age was 13.1 years. Most patients, two-thirds of whom were male, had received an immunomodulator prior to study entry.
At the end of TP1, 69.9% of patients had achieved 70% improvement in the Juvenile Idiopathic Arthritis American College of Rheumatology joint score (JIA ACR70). The 90.4% of patients who achieved JIA ACR30 were invited to enroll in TP2. A total of 75 patients did so.
At the end of TP2, response rates strongly favored secukinumab over placebo for JIA ACR30 (89.2% vs. 64.9%; P = .014) and JIA ACR70 (67.7% vs. 43.2%; P = .042). Higher but not statistically significant differences in response rates were seen for secukinumab over placebo for JIA ACR50 (78.4% vs. 62.2%; P = .152), JIA ACR90 (51.4% vs. 40.5%; P = .431) and JIA ACR100 (43.2% vs. 37.8%; P = .755).
During TP2, there were 10 flares in the group randomized to secukinumab versus 21 flares in the placebo group, translating by hazard ratio (HR) into a 72% risk reduction (HR, 0.28; P < .001).
Side effects similar to those in adults
The types and rates of serious adverse events were similar to those reported previously in adult patients, according to Dr. Ruperto. Although the rate of serious adverse events (14.6% vs. 10.6%) was only moderately higher in the experimental arm, more patients randomized to secukinumab than placebo discontinued therapy (13.2% vs. 6.3%) before the end of follow-up.
The side effects that occurred more commonly on secukinumab included gastrointestinal complaints, such as diarrhea (22.9% vs. 15.8%). Other adverse events occurring in more than 10% of patients included headache and nasopharyngitis, but most side effects were mild and resolved.
Although the proportion of patients with flare increased over time in both groups, Dr. Ruperto reported that protection against flares and relative improvement in clinical markers of disease activity relative to placebo “were sustained out to 2 years of follow-up.”
The submission of these data to regulatory agencies is anticipated. If secukinumab is given an indication for these forms of arthritis, it will join an indication for plaque psoriasis in children that was granted just a few days before these data were presented. The psoriasis indication is the only current use approved for children in the United States.
More biologics needed for JPsA
Additional biologics will be helpful for children with arthritis who are poorly controlled on available treatments, according to Natasha M. Ruth, MD, director of the division of pediatric rheumatology at the Medical University of South Carolina, Charleston. Dr. Ruth was senior author of a case study published 2 years ago in which secukinumab was used to control psoriatic arthritis and nail manifestations of psoriasis.
“It was a girl who had already failed to improve adequately to TNF inhibitors,” reported Dr. Ruth, who had said the child and her parent were very concerned about the nail appearance.
“The nail involvement completely resolved, so it was a very good result in a difficult situation,” Dr. Ruth explained. She said that the decision to try secukinumab was made collaboratively in a clinic in which dermatologists and rheumatologists at her institution work together on difficult cases.
“There is a need for more biologics with different mechanisms of action,” Dr. Ruth said. Based on her experience, secukinumab could be an important addition to treatment options.
Dr. Ruperto reported having financial relationships with more than 20 pharmaceutical companies, including Novartis, which provided financial support for this trial. Many coauthors had financial relationships with multiple companies, including Novartis, and some were employees of the company. Dr. Ruth reported having no potential conflicts of interest.
Favorable safety sustained at 104 weeks
Favorable safety sustained at 104 weeks
Secukinumab (Cosentyx), an interleukin-17A inhibitor, is effective and reasonably well tolerated for treatment of enthesitis-related arthritis (ERA) and juvenile psoriatic arthritis (JPsA) in children and adolescents, according to a phase 3 trial presented at a late breaking abstracts session of the annual European Congress of Rheumatology.
On the primary outcome of time to flare, the curves for secukinumab and placebo separated almost immediately, with fewer than half the number of flares occurring in the experimental arm over the course of the study, according to Nicolino Ruperto, MD, senior research scientist at IRCCS Istituto Giannina Gaslini in Genoa, Italy.
The trial, called JUNIPERA, was conducted over 2 years and included an open-label treatment period (TP1) and then a randomized, placebo-controlled comparison (TP2). In TP1, 86 children were initiated on open-label secukinumab administered subcutaneously on weeks 1, 2, 3, 4, 8, and 12. The dose was 75 mg for children less than 50 kg and 150 kg for those heavier.
Average patient age was 13.1 years
Of these 86 children, 52 had ERA and 34 had JPsA. Disease duration of at least 6 months was required for entry. Patients up to the age of 18 years were permitted to enroll. The average age was 13.1 years. Most patients, two-thirds of whom were male, had received an immunomodulator prior to study entry.
At the end of TP1, 69.9% of patients had achieved 70% improvement in the Juvenile Idiopathic Arthritis American College of Rheumatology joint score (JIA ACR70). The 90.4% of patients who achieved JIA ACR30 were invited to enroll in TP2. A total of 75 patients did so.
At the end of TP2, response rates strongly favored secukinumab over placebo for JIA ACR30 (89.2% vs. 64.9%; P = .014) and JIA ACR70 (67.7% vs. 43.2%; P = .042). Higher but not statistically significant differences in response rates were seen for secukinumab over placebo for JIA ACR50 (78.4% vs. 62.2%; P = .152), JIA ACR90 (51.4% vs. 40.5%; P = .431) and JIA ACR100 (43.2% vs. 37.8%; P = .755).
During TP2, there were 10 flares in the group randomized to secukinumab versus 21 flares in the placebo group, translating by hazard ratio (HR) into a 72% risk reduction (HR, 0.28; P < .001).
Side effects similar to those in adults
The types and rates of serious adverse events were similar to those reported previously in adult patients, according to Dr. Ruperto. Although the rate of serious adverse events (14.6% vs. 10.6%) was only moderately higher in the experimental arm, more patients randomized to secukinumab than placebo discontinued therapy (13.2% vs. 6.3%) before the end of follow-up.
The side effects that occurred more commonly on secukinumab included gastrointestinal complaints, such as diarrhea (22.9% vs. 15.8%). Other adverse events occurring in more than 10% of patients included headache and nasopharyngitis, but most side effects were mild and resolved.
Although the proportion of patients with flare increased over time in both groups, Dr. Ruperto reported that protection against flares and relative improvement in clinical markers of disease activity relative to placebo “were sustained out to 2 years of follow-up.”
The submission of these data to regulatory agencies is anticipated. If secukinumab is given an indication for these forms of arthritis, it will join an indication for plaque psoriasis in children that was granted just a few days before these data were presented. The psoriasis indication is the only current use approved for children in the United States.
More biologics needed for JPsA
Additional biologics will be helpful for children with arthritis who are poorly controlled on available treatments, according to Natasha M. Ruth, MD, director of the division of pediatric rheumatology at the Medical University of South Carolina, Charleston. Dr. Ruth was senior author of a case study published 2 years ago in which secukinumab was used to control psoriatic arthritis and nail manifestations of psoriasis.
“It was a girl who had already failed to improve adequately to TNF inhibitors,” reported Dr. Ruth, who had said the child and her parent were very concerned about the nail appearance.
“The nail involvement completely resolved, so it was a very good result in a difficult situation,” Dr. Ruth explained. She said that the decision to try secukinumab was made collaboratively in a clinic in which dermatologists and rheumatologists at her institution work together on difficult cases.
“There is a need for more biologics with different mechanisms of action,” Dr. Ruth said. Based on her experience, secukinumab could be an important addition to treatment options.
Dr. Ruperto reported having financial relationships with more than 20 pharmaceutical companies, including Novartis, which provided financial support for this trial. Many coauthors had financial relationships with multiple companies, including Novartis, and some were employees of the company. Dr. Ruth reported having no potential conflicts of interest.
Secukinumab (Cosentyx), an interleukin-17A inhibitor, is effective and reasonably well tolerated for treatment of enthesitis-related arthritis (ERA) and juvenile psoriatic arthritis (JPsA) in children and adolescents, according to a phase 3 trial presented at a late breaking abstracts session of the annual European Congress of Rheumatology.
On the primary outcome of time to flare, the curves for secukinumab and placebo separated almost immediately, with fewer than half the number of flares occurring in the experimental arm over the course of the study, according to Nicolino Ruperto, MD, senior research scientist at IRCCS Istituto Giannina Gaslini in Genoa, Italy.
The trial, called JUNIPERA, was conducted over 2 years and included an open-label treatment period (TP1) and then a randomized, placebo-controlled comparison (TP2). In TP1, 86 children were initiated on open-label secukinumab administered subcutaneously on weeks 1, 2, 3, 4, 8, and 12. The dose was 75 mg for children less than 50 kg and 150 kg for those heavier.
Average patient age was 13.1 years
Of these 86 children, 52 had ERA and 34 had JPsA. Disease duration of at least 6 months was required for entry. Patients up to the age of 18 years were permitted to enroll. The average age was 13.1 years. Most patients, two-thirds of whom were male, had received an immunomodulator prior to study entry.
At the end of TP1, 69.9% of patients had achieved 70% improvement in the Juvenile Idiopathic Arthritis American College of Rheumatology joint score (JIA ACR70). The 90.4% of patients who achieved JIA ACR30 were invited to enroll in TP2. A total of 75 patients did so.
At the end of TP2, response rates strongly favored secukinumab over placebo for JIA ACR30 (89.2% vs. 64.9%; P = .014) and JIA ACR70 (67.7% vs. 43.2%; P = .042). Higher but not statistically significant differences in response rates were seen for secukinumab over placebo for JIA ACR50 (78.4% vs. 62.2%; P = .152), JIA ACR90 (51.4% vs. 40.5%; P = .431) and JIA ACR100 (43.2% vs. 37.8%; P = .755).
During TP2, there were 10 flares in the group randomized to secukinumab versus 21 flares in the placebo group, translating by hazard ratio (HR) into a 72% risk reduction (HR, 0.28; P < .001).
Side effects similar to those in adults
The types and rates of serious adverse events were similar to those reported previously in adult patients, according to Dr. Ruperto. Although the rate of serious adverse events (14.6% vs. 10.6%) was only moderately higher in the experimental arm, more patients randomized to secukinumab than placebo discontinued therapy (13.2% vs. 6.3%) before the end of follow-up.
The side effects that occurred more commonly on secukinumab included gastrointestinal complaints, such as diarrhea (22.9% vs. 15.8%). Other adverse events occurring in more than 10% of patients included headache and nasopharyngitis, but most side effects were mild and resolved.
Although the proportion of patients with flare increased over time in both groups, Dr. Ruperto reported that protection against flares and relative improvement in clinical markers of disease activity relative to placebo “were sustained out to 2 years of follow-up.”
The submission of these data to regulatory agencies is anticipated. If secukinumab is given an indication for these forms of arthritis, it will join an indication for plaque psoriasis in children that was granted just a few days before these data were presented. The psoriasis indication is the only current use approved for children in the United States.
More biologics needed for JPsA
Additional biologics will be helpful for children with arthritis who are poorly controlled on available treatments, according to Natasha M. Ruth, MD, director of the division of pediatric rheumatology at the Medical University of South Carolina, Charleston. Dr. Ruth was senior author of a case study published 2 years ago in which secukinumab was used to control psoriatic arthritis and nail manifestations of psoriasis.
“It was a girl who had already failed to improve adequately to TNF inhibitors,” reported Dr. Ruth, who had said the child and her parent were very concerned about the nail appearance.
“The nail involvement completely resolved, so it was a very good result in a difficult situation,” Dr. Ruth explained. She said that the decision to try secukinumab was made collaboratively in a clinic in which dermatologists and rheumatologists at her institution work together on difficult cases.
“There is a need for more biologics with different mechanisms of action,” Dr. Ruth said. Based on her experience, secukinumab could be an important addition to treatment options.
Dr. Ruperto reported having financial relationships with more than 20 pharmaceutical companies, including Novartis, which provided financial support for this trial. Many coauthors had financial relationships with multiple companies, including Novartis, and some were employees of the company. Dr. Ruth reported having no potential conflicts of interest.
FROM THE EULAR 2021 CONGRESS
Risankizumab shows efficacy, tolerability in patients with PsA
Risankizumab (Skyrizi) was effective for treating psoriatic arthritis (PsA) in patients who did not respond to or who could not tolerate other biologics or standard disease-modifying antirheumatic drugs (DMARDs), according to a study presented at the annual European Congress of Rheumatology. It was also well tolerated.
“Treatment with risankizumab resulted in significantly greater improvements in signs and symptoms of psoriatic arthritis, including assessments of disease activity in joints and skin and patient-reported outcomes, compared with placebo, in patients who did not respond to or were intolerant to biologics or DMARDs,” reported Andrew Ostor, MD, of Monash University and Cabrini Hospital, both in Melbourne,. The safety profile was “consistent with that established for risankizumab in the treatment moderate to severe psoriasis,” he told attendees.
Risankizumab is approved in the United States for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. It is a humanized immunoglobulin G1 monoclonal antibody that selectively inhibits cytokine interleukin-23 by binding to its p19 subunit. IL-23 has been implicated in the development of PsA.
This was a phase 3 trial with “promising results in line with the ACR 20 response [at least 20% improvement in American College of Rheumatology response criteria] of other biologics in psoriatic arthritis,” according to Gaëlle Varkas, MD, PhD, of the Ghent (the Netherlands) University VIB Center for Inflammation Research and the department of rheumatology, Ghent University Hospital. “Especially in patients with severe and/or refractory skin disease or inadequate response at the level of the joint to other DMARDs or biologics, risankizumab is filling a void,” Dr. Varkas, who was not involved in the research, said in an interview.
There were no major safety problems, although long-term data, especially in regard to cancer and cardiovascular effects, “are always of interest, as they can be missed in randomized, controlled trials,” she said. In addition, “efficacy in concomitant axial disease, uveitis, and inflammatory bowel disease might favor one treatment over the other.” Another clinically significant takeaway was risankizumab’s “better effect on skin psoriasis while maintaining the effect on joint manifestations.”
Details of 24-week trial results
The phase 3, randomized, placebo-controlled, double-blind KEEPSAKE 2 trial involved 444 patients who had active PsA, defined as at least five swollen joints and at least five tender joints. All the patients either had an inadequate response to or were intolerant of one or two biologics or at least one conventional synthetic DMARD.
A total of 224 patients were randomly assigned to receive 150 mg of subcutaneous risankizumab at baseline and at 4 and 16 weeks after baseline; 220 participants received placebo injections. The primary endpoint was the proportion of patients who had at least 20% improvement in American College of Rheumatology response criteria at week 24.
Demographic and clinical characteristics were similar in both groups at baseline. Among the participants, the total mean number of swollen joints was 13.3, and the total mean number of tender joints was 22.6. The participants had PsA for an average of 8.2 years. The proportions of patients previously treated with biologics and DMARDs were similar in both groups, as were the proportions of patients currently taking glucocorticoids, NSAIDs, or methotrexate or another DMARD. At week 24, there remained 199 patients in the placebo group and 215 in the risankizumab group.
Just over half (51.3%) of patients who took risankizumab achieved at least 20% improvement in their ACR 20 score, compared with just over a quarter (26.5%) of those who received placebo (P < .001). All secondary endpoints also showed statistically significant improvements (P < .001 for all except P < .009 for the Fatigue Functional Assessment of Chronic Illness Therapy–Fatigue [FACIT-Fatigue] secondary endpoint).
Scores on the Health Assessment Questionnaire–Disability Index were –0.22 in the risankizumab group and –0.05 in the placebo group (P < .001). In the risankizumab group, 55% of patients achieved at least a 90% reduction in scores on the Psoriasis Area Severity Index, compared with 10.2% of patients who received placebo. Similarly, 25.6% of patients who took risankizumab and 11.4% of patients who received placebo had minimal disease activity 24 weeks after baseline.
In the 36-item Short Form Health Survey Physical Component Summary, the score change among risankizumab patients was 5.9, compared with 2 among the patients who received placebo. The change in FACIT-Fatigue score was 4.9 for patients who took risankizumab and 2.6 for patients who received placebo.
The researchers also assessed how many patients achieved higher levels of response to treatment. At least a 50% improvement in ACR response criteria occurred among 26.3% of patients taking risankizumab and 9.3% of patients taking placebo (P < .001). ACR 70 responses were seen in 12% of patients receiving risankizumab, compared with 5.9% of patients receiving placebo (P < .02). In the risankizumab group, 72.5% of patients had resolution of dactylitis and 42.9% had resolution of enthesitis, compared with 42.1% and 30.4%, respectively, in the placebo group.
Serious adverse events occurred in 4% of patients who received risankizumab and 5.5% of patients who received placebo. Serious infections occurred in 0.9% of those receiving risankizumab and 2.3% of those receiving placebo. Rates of treatment-emergent adverse events were also similar in the risankizumab (55.4%) and placebo (54.8%) groups.
In response to a question about whether it was possible to identify patients who might respond better to IL-23 inhibitors, compared with IL-17 inhibitors, Dr. Ostor acknowledged that rheumatologic practice is not yet proficient at using biomarkers to direct therapy, so the benefit from these drugs lay elsewhere.
“What I think is great is the luxury of choice these days,” Dr. Ostor told attendees. “We have these agents now, including risankizumab, that do work very effectively across the spectrum of the clinical features. It’s just lovely to have these agents available that can truly make a difference to the clinical picture of the individual.”
The trial was sponsored by AbbVie. Dr. Ostor has received research grants or speaking or consulting fees from AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, Sanofi, and UCB. Dr. Varkas has received research grants or speaker fees from AbbVie and Pfizer.
A version of this article first appeared on Medscape.com.
Risankizumab (Skyrizi) was effective for treating psoriatic arthritis (PsA) in patients who did not respond to or who could not tolerate other biologics or standard disease-modifying antirheumatic drugs (DMARDs), according to a study presented at the annual European Congress of Rheumatology. It was also well tolerated.
“Treatment with risankizumab resulted in significantly greater improvements in signs and symptoms of psoriatic arthritis, including assessments of disease activity in joints and skin and patient-reported outcomes, compared with placebo, in patients who did not respond to or were intolerant to biologics or DMARDs,” reported Andrew Ostor, MD, of Monash University and Cabrini Hospital, both in Melbourne,. The safety profile was “consistent with that established for risankizumab in the treatment moderate to severe psoriasis,” he told attendees.
Risankizumab is approved in the United States for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. It is a humanized immunoglobulin G1 monoclonal antibody that selectively inhibits cytokine interleukin-23 by binding to its p19 subunit. IL-23 has been implicated in the development of PsA.
This was a phase 3 trial with “promising results in line with the ACR 20 response [at least 20% improvement in American College of Rheumatology response criteria] of other biologics in psoriatic arthritis,” according to Gaëlle Varkas, MD, PhD, of the Ghent (the Netherlands) University VIB Center for Inflammation Research and the department of rheumatology, Ghent University Hospital. “Especially in patients with severe and/or refractory skin disease or inadequate response at the level of the joint to other DMARDs or biologics, risankizumab is filling a void,” Dr. Varkas, who was not involved in the research, said in an interview.
There were no major safety problems, although long-term data, especially in regard to cancer and cardiovascular effects, “are always of interest, as they can be missed in randomized, controlled trials,” she said. In addition, “efficacy in concomitant axial disease, uveitis, and inflammatory bowel disease might favor one treatment over the other.” Another clinically significant takeaway was risankizumab’s “better effect on skin psoriasis while maintaining the effect on joint manifestations.”
Details of 24-week trial results
The phase 3, randomized, placebo-controlled, double-blind KEEPSAKE 2 trial involved 444 patients who had active PsA, defined as at least five swollen joints and at least five tender joints. All the patients either had an inadequate response to or were intolerant of one or two biologics or at least one conventional synthetic DMARD.
A total of 224 patients were randomly assigned to receive 150 mg of subcutaneous risankizumab at baseline and at 4 and 16 weeks after baseline; 220 participants received placebo injections. The primary endpoint was the proportion of patients who had at least 20% improvement in American College of Rheumatology response criteria at week 24.
Demographic and clinical characteristics were similar in both groups at baseline. Among the participants, the total mean number of swollen joints was 13.3, and the total mean number of tender joints was 22.6. The participants had PsA for an average of 8.2 years. The proportions of patients previously treated with biologics and DMARDs were similar in both groups, as were the proportions of patients currently taking glucocorticoids, NSAIDs, or methotrexate or another DMARD. At week 24, there remained 199 patients in the placebo group and 215 in the risankizumab group.
Just over half (51.3%) of patients who took risankizumab achieved at least 20% improvement in their ACR 20 score, compared with just over a quarter (26.5%) of those who received placebo (P < .001). All secondary endpoints also showed statistically significant improvements (P < .001 for all except P < .009 for the Fatigue Functional Assessment of Chronic Illness Therapy–Fatigue [FACIT-Fatigue] secondary endpoint).
Scores on the Health Assessment Questionnaire–Disability Index were –0.22 in the risankizumab group and –0.05 in the placebo group (P < .001). In the risankizumab group, 55% of patients achieved at least a 90% reduction in scores on the Psoriasis Area Severity Index, compared with 10.2% of patients who received placebo. Similarly, 25.6% of patients who took risankizumab and 11.4% of patients who received placebo had minimal disease activity 24 weeks after baseline.
In the 36-item Short Form Health Survey Physical Component Summary, the score change among risankizumab patients was 5.9, compared with 2 among the patients who received placebo. The change in FACIT-Fatigue score was 4.9 for patients who took risankizumab and 2.6 for patients who received placebo.
The researchers also assessed how many patients achieved higher levels of response to treatment. At least a 50% improvement in ACR response criteria occurred among 26.3% of patients taking risankizumab and 9.3% of patients taking placebo (P < .001). ACR 70 responses were seen in 12% of patients receiving risankizumab, compared with 5.9% of patients receiving placebo (P < .02). In the risankizumab group, 72.5% of patients had resolution of dactylitis and 42.9% had resolution of enthesitis, compared with 42.1% and 30.4%, respectively, in the placebo group.
Serious adverse events occurred in 4% of patients who received risankizumab and 5.5% of patients who received placebo. Serious infections occurred in 0.9% of those receiving risankizumab and 2.3% of those receiving placebo. Rates of treatment-emergent adverse events were also similar in the risankizumab (55.4%) and placebo (54.8%) groups.
In response to a question about whether it was possible to identify patients who might respond better to IL-23 inhibitors, compared with IL-17 inhibitors, Dr. Ostor acknowledged that rheumatologic practice is not yet proficient at using biomarkers to direct therapy, so the benefit from these drugs lay elsewhere.
“What I think is great is the luxury of choice these days,” Dr. Ostor told attendees. “We have these agents now, including risankizumab, that do work very effectively across the spectrum of the clinical features. It’s just lovely to have these agents available that can truly make a difference to the clinical picture of the individual.”
The trial was sponsored by AbbVie. Dr. Ostor has received research grants or speaking or consulting fees from AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, Sanofi, and UCB. Dr. Varkas has received research grants or speaker fees from AbbVie and Pfizer.
A version of this article first appeared on Medscape.com.
Risankizumab (Skyrizi) was effective for treating psoriatic arthritis (PsA) in patients who did not respond to or who could not tolerate other biologics or standard disease-modifying antirheumatic drugs (DMARDs), according to a study presented at the annual European Congress of Rheumatology. It was also well tolerated.
“Treatment with risankizumab resulted in significantly greater improvements in signs and symptoms of psoriatic arthritis, including assessments of disease activity in joints and skin and patient-reported outcomes, compared with placebo, in patients who did not respond to or were intolerant to biologics or DMARDs,” reported Andrew Ostor, MD, of Monash University and Cabrini Hospital, both in Melbourne,. The safety profile was “consistent with that established for risankizumab in the treatment moderate to severe psoriasis,” he told attendees.
Risankizumab is approved in the United States for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. It is a humanized immunoglobulin G1 monoclonal antibody that selectively inhibits cytokine interleukin-23 by binding to its p19 subunit. IL-23 has been implicated in the development of PsA.
This was a phase 3 trial with “promising results in line with the ACR 20 response [at least 20% improvement in American College of Rheumatology response criteria] of other biologics in psoriatic arthritis,” according to Gaëlle Varkas, MD, PhD, of the Ghent (the Netherlands) University VIB Center for Inflammation Research and the department of rheumatology, Ghent University Hospital. “Especially in patients with severe and/or refractory skin disease or inadequate response at the level of the joint to other DMARDs or biologics, risankizumab is filling a void,” Dr. Varkas, who was not involved in the research, said in an interview.
There were no major safety problems, although long-term data, especially in regard to cancer and cardiovascular effects, “are always of interest, as they can be missed in randomized, controlled trials,” she said. In addition, “efficacy in concomitant axial disease, uveitis, and inflammatory bowel disease might favor one treatment over the other.” Another clinically significant takeaway was risankizumab’s “better effect on skin psoriasis while maintaining the effect on joint manifestations.”
Details of 24-week trial results
The phase 3, randomized, placebo-controlled, double-blind KEEPSAKE 2 trial involved 444 patients who had active PsA, defined as at least five swollen joints and at least five tender joints. All the patients either had an inadequate response to or were intolerant of one or two biologics or at least one conventional synthetic DMARD.
A total of 224 patients were randomly assigned to receive 150 mg of subcutaneous risankizumab at baseline and at 4 and 16 weeks after baseline; 220 participants received placebo injections. The primary endpoint was the proportion of patients who had at least 20% improvement in American College of Rheumatology response criteria at week 24.
Demographic and clinical characteristics were similar in both groups at baseline. Among the participants, the total mean number of swollen joints was 13.3, and the total mean number of tender joints was 22.6. The participants had PsA for an average of 8.2 years. The proportions of patients previously treated with biologics and DMARDs were similar in both groups, as were the proportions of patients currently taking glucocorticoids, NSAIDs, or methotrexate or another DMARD. At week 24, there remained 199 patients in the placebo group and 215 in the risankizumab group.
Just over half (51.3%) of patients who took risankizumab achieved at least 20% improvement in their ACR 20 score, compared with just over a quarter (26.5%) of those who received placebo (P < .001). All secondary endpoints also showed statistically significant improvements (P < .001 for all except P < .009 for the Fatigue Functional Assessment of Chronic Illness Therapy–Fatigue [FACIT-Fatigue] secondary endpoint).
Scores on the Health Assessment Questionnaire–Disability Index were –0.22 in the risankizumab group and –0.05 in the placebo group (P < .001). In the risankizumab group, 55% of patients achieved at least a 90% reduction in scores on the Psoriasis Area Severity Index, compared with 10.2% of patients who received placebo. Similarly, 25.6% of patients who took risankizumab and 11.4% of patients who received placebo had minimal disease activity 24 weeks after baseline.
In the 36-item Short Form Health Survey Physical Component Summary, the score change among risankizumab patients was 5.9, compared with 2 among the patients who received placebo. The change in FACIT-Fatigue score was 4.9 for patients who took risankizumab and 2.6 for patients who received placebo.
The researchers also assessed how many patients achieved higher levels of response to treatment. At least a 50% improvement in ACR response criteria occurred among 26.3% of patients taking risankizumab and 9.3% of patients taking placebo (P < .001). ACR 70 responses were seen in 12% of patients receiving risankizumab, compared with 5.9% of patients receiving placebo (P < .02). In the risankizumab group, 72.5% of patients had resolution of dactylitis and 42.9% had resolution of enthesitis, compared with 42.1% and 30.4%, respectively, in the placebo group.
Serious adverse events occurred in 4% of patients who received risankizumab and 5.5% of patients who received placebo. Serious infections occurred in 0.9% of those receiving risankizumab and 2.3% of those receiving placebo. Rates of treatment-emergent adverse events were also similar in the risankizumab (55.4%) and placebo (54.8%) groups.
In response to a question about whether it was possible to identify patients who might respond better to IL-23 inhibitors, compared with IL-17 inhibitors, Dr. Ostor acknowledged that rheumatologic practice is not yet proficient at using biomarkers to direct therapy, so the benefit from these drugs lay elsewhere.
“What I think is great is the luxury of choice these days,” Dr. Ostor told attendees. “We have these agents now, including risankizumab, that do work very effectively across the spectrum of the clinical features. It’s just lovely to have these agents available that can truly make a difference to the clinical picture of the individual.”
The trial was sponsored by AbbVie. Dr. Ostor has received research grants or speaking or consulting fees from AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, Sanofi, and UCB. Dr. Varkas has received research grants or speaker fees from AbbVie and Pfizer.
A version of this article first appeared on Medscape.com.
TNF inhibitors have delayed effect on spondyloarthritis radiographic progression
Tumor necrosis factor inhibitors reduce both spinal and sacroiliac radiographic progression in early axial spondyloarthritis (axSpA), but the effects take time.
According to data from the German Spondyloarthritis Inception Cohort (GESPIC), it could take 2-4 years after the initiation of TNF inhibitor treatment before x-rays will show any sign of a benefit in either the spine or sacroiliac joints (SIJ).
“The association between anti-TNF treatment and the retardation of radiographic spinal progression in spondyloarthritis appears to be time-shifted,” GESPIC study investigator Denis Poddubnyy, MD, said at the annual European Congress of Rheumatology.
Reporting the spinal findings, Dr. Poddubnyy, who is head of the rheumatology department at Campus Benjamin Franklin of the Charité University Hospital in Berlin noted that “at least 4 years of observation is required” to see an effect of TNF inhibitors on new bone formation. “This might be related to the intermediate and long-lasting process of bone repair that follows the resolution of inflammation and precedes the development of new bone,” he suggested.
The effect on the SIJ may precede the spinal damage, so it’s important to look at how anti-inflammatory treatment might affect the SIJ, Dr. Poddubnyy said in an interview. Results from the SIJ analysis, which were presented by Murat Torgutalp, MD, suggested that there might be a 2-year time lag between TNFi treatment and being able to see something on x-rays.
“Everybody in the past focused on the spine, considering that spinal changes are functionally more relevant than changes in the SIJ,” Dr. Poddubnyy observed.
Structural damage in the spine and SIJ in radiographic axSpA probably occur by different processes, he explained. While it’s more to do with new bone formation in the spine, it’s more to do with erosive damage followed by repair in the SIJ. “It is very likely that in the majority of patients we see that those two processes are somehow disconnected in time,” he suggested.
The GESPIC cohort provides a good base from which to examine the effects of TNF inhibitors on radiographic progression in patients with axSpA for several reasons, observed Dr. Poddubnyy. For one it was established in 2000, so “well before the introduction of TNF-alpha inhibitors.” That means that almost all patients would have been put on TNF inhibitors while enrolled in the cohort, he said, “so we could really follow up them prospectively for a few years.” In fact, just nine patients had been treated with TNF inhibitors at baseline.
Spinal findings
Although TNF inhibitors are widely accepted to be effective anti-inflammatory drugs that can relieve patients’ spinal symptoms, there were inconclusive data on whether they can also have an impact on radiographic progression.
To look at the possible immediate or later effect of TNF inhibitors on spinal radiographic progression, the GESPIC investigators looked at sets of radiographs, taken at least 2 years apart over a 10-year period, from 266 patients, 77 of whom who had been treated with a TNF inhibitor for at least 12 months or more. Overall, there were 103 2-year intervals covered by TNF inhibitor treatment of any duration, and 78 intervals in which treatment had lasted for at least 12 months.
“This cohort included patients with quite early disease, including both nonradiographic and radiographic forms,” Dr. Poddubnyy said, adding that some patients had been treated with a TNF inhibitor for up to 10 years.
While there were no significant changes in radiographic progression as measured using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) between patients who had and who had not received at least 12 months’ TNF inhibitor therapy in the first 2 years, there was a substantial difference after 4 years.
The mSASSS change in scores over 2 years in patients who were and were not treated with a TNF inhibitor for 12 months or more were a respective 0.35 and 0.81 (P = .047) considering treatment in the previous 2-year treatment period, and 0.33 and 0.77 (also P = .047) considering treatment in the prior 2-year treatment period and the current 2-year period.
“Our interpretation is that within the first 2 years we see a resolution of inflammation, a process of repair, maybe even a process of bone formation, but then if you continue this inflammation control for longer than 2 years, then we see the effect on structural damage,” Dr. Poddubnyy said.
SIJ findings
The SIJ analysis included 301 patients who had at least two sets of radiographs taken every 2 years over a 10-year follow-up period, 87 (28.9%) of whom had been treated with at least one TNF inhibitor during follow-up.
Radiographic SIJ progression was defined as the change in the sacroiliitis sum score over 2 years. Calculations considered both the current 2-year period and the previous 2-year period, as well as any use of TNF inhibitors or more than 12 months’ use.
There were no significant differences in sacroiliitis sum scores comparing people who were and were not treated with TNF inhibitors for at least 12 months in the current 2-year period. However, when the previous 2-year period was looked at there was a significant difference in the score between those who had and had not been treated for 12 or more months (0.15 vs. 0.27, respectively; P = .024).
“These data indicate that TNF inhibitors have a late effect,” Dr. Torgutalp said. “You cannot observe the effect of the TNF inhibitor on radiographic progression in the same interval, you have to wait to see this effect in the next interval,” he explained. That means that when a patient uses a TNF inhibitor, you must wait to see the effect on SIJ progression in the subsequent 2 years, he qualified.
Lessons for practice
“If we control inflammation, we might control structural damage progression,” Dr. Poddubnyy said.
If this is the case, then it is likely that other drugs that control inflammation in axSpA will have a similar effect, such as those that target interleukin-17 or Janus kinases. This is something in the future to look at in the GESPIC cohort once enough patient-years of data are available.
Early treatment is probably important, Dr. Poddubnyy suggested, “because in patients with early disease we can expect not that much structural damage at baseline.” Starting treatment early, at the inflammatory stage rather than at the stage where there was a lot of damage already there, could yield better results, he proposed.
“As a clinician, as a researcher, I would be really interested in demonstrating in a prospective, clinical trial that treating patients to target, achieving a remission, would be associated with retardation of structural damage progression. This has only been shown in observational studies so far, so this is an open question.”
Questions on adjustments made for confounding factors
Questions on the spinal presentation included whether there were any differences in NSAID use, to which Dr. Poddubnyy responded, “Patients on TNF inhibitors normally reduce NSAIDs. We adjusted, therefore, for NSAID use.”
The SIJ presentation garnered more questioning. Dr. Torgutalp qualified that both radiographic and nonradiographic patients had been included in the analysis, and “we observe the same effect.”
Asked how clinically relevant the findings were, he noted that, “to the best of our knowledge, this is the first data for sacroiliac joint progression.” The data for spinal progression seem to “reconcile the results from previous investigators,” where there had been some conflicting data on whether 2 or 4 years’ TNF-inhibitor therapy had any effect on radiographic progression.
“I don’t think you’ve adjusted for the baseline level of damage of the SIJ?” queried Pedro Machado, MD, of University College London Hospital. “As you know, in the spine, but also at the SIJ level, the baseline level of damage is usually one of the strongest predictors of further damage.”
This is not something that was adjusted for, Dr. Torgutalp conceded. “We will do it for further analysis,” he said.
Since 2010, GESPIC has been supported by grants from AbbVie. Dr. Poddubnyy reported financial relationships with AbbVie and numerous other pharmaceutical companies. Dr. Torgutalp had no relevant disclosures.
Tumor necrosis factor inhibitors reduce both spinal and sacroiliac radiographic progression in early axial spondyloarthritis (axSpA), but the effects take time.
According to data from the German Spondyloarthritis Inception Cohort (GESPIC), it could take 2-4 years after the initiation of TNF inhibitor treatment before x-rays will show any sign of a benefit in either the spine or sacroiliac joints (SIJ).
“The association between anti-TNF treatment and the retardation of radiographic spinal progression in spondyloarthritis appears to be time-shifted,” GESPIC study investigator Denis Poddubnyy, MD, said at the annual European Congress of Rheumatology.
Reporting the spinal findings, Dr. Poddubnyy, who is head of the rheumatology department at Campus Benjamin Franklin of the Charité University Hospital in Berlin noted that “at least 4 years of observation is required” to see an effect of TNF inhibitors on new bone formation. “This might be related to the intermediate and long-lasting process of bone repair that follows the resolution of inflammation and precedes the development of new bone,” he suggested.
The effect on the SIJ may precede the spinal damage, so it’s important to look at how anti-inflammatory treatment might affect the SIJ, Dr. Poddubnyy said in an interview. Results from the SIJ analysis, which were presented by Murat Torgutalp, MD, suggested that there might be a 2-year time lag between TNFi treatment and being able to see something on x-rays.
“Everybody in the past focused on the spine, considering that spinal changes are functionally more relevant than changes in the SIJ,” Dr. Poddubnyy observed.
Structural damage in the spine and SIJ in radiographic axSpA probably occur by different processes, he explained. While it’s more to do with new bone formation in the spine, it’s more to do with erosive damage followed by repair in the SIJ. “It is very likely that in the majority of patients we see that those two processes are somehow disconnected in time,” he suggested.
The GESPIC cohort provides a good base from which to examine the effects of TNF inhibitors on radiographic progression in patients with axSpA for several reasons, observed Dr. Poddubnyy. For one it was established in 2000, so “well before the introduction of TNF-alpha inhibitors.” That means that almost all patients would have been put on TNF inhibitors while enrolled in the cohort, he said, “so we could really follow up them prospectively for a few years.” In fact, just nine patients had been treated with TNF inhibitors at baseline.
Spinal findings
Although TNF inhibitors are widely accepted to be effective anti-inflammatory drugs that can relieve patients’ spinal symptoms, there were inconclusive data on whether they can also have an impact on radiographic progression.
To look at the possible immediate or later effect of TNF inhibitors on spinal radiographic progression, the GESPIC investigators looked at sets of radiographs, taken at least 2 years apart over a 10-year period, from 266 patients, 77 of whom who had been treated with a TNF inhibitor for at least 12 months or more. Overall, there were 103 2-year intervals covered by TNF inhibitor treatment of any duration, and 78 intervals in which treatment had lasted for at least 12 months.
“This cohort included patients with quite early disease, including both nonradiographic and radiographic forms,” Dr. Poddubnyy said, adding that some patients had been treated with a TNF inhibitor for up to 10 years.
While there were no significant changes in radiographic progression as measured using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) between patients who had and who had not received at least 12 months’ TNF inhibitor therapy in the first 2 years, there was a substantial difference after 4 years.
The mSASSS change in scores over 2 years in patients who were and were not treated with a TNF inhibitor for 12 months or more were a respective 0.35 and 0.81 (P = .047) considering treatment in the previous 2-year treatment period, and 0.33 and 0.77 (also P = .047) considering treatment in the prior 2-year treatment period and the current 2-year period.
“Our interpretation is that within the first 2 years we see a resolution of inflammation, a process of repair, maybe even a process of bone formation, but then if you continue this inflammation control for longer than 2 years, then we see the effect on structural damage,” Dr. Poddubnyy said.
SIJ findings
The SIJ analysis included 301 patients who had at least two sets of radiographs taken every 2 years over a 10-year follow-up period, 87 (28.9%) of whom had been treated with at least one TNF inhibitor during follow-up.
Radiographic SIJ progression was defined as the change in the sacroiliitis sum score over 2 years. Calculations considered both the current 2-year period and the previous 2-year period, as well as any use of TNF inhibitors or more than 12 months’ use.
There were no significant differences in sacroiliitis sum scores comparing people who were and were not treated with TNF inhibitors for at least 12 months in the current 2-year period. However, when the previous 2-year period was looked at there was a significant difference in the score between those who had and had not been treated for 12 or more months (0.15 vs. 0.27, respectively; P = .024).
“These data indicate that TNF inhibitors have a late effect,” Dr. Torgutalp said. “You cannot observe the effect of the TNF inhibitor on radiographic progression in the same interval, you have to wait to see this effect in the next interval,” he explained. That means that when a patient uses a TNF inhibitor, you must wait to see the effect on SIJ progression in the subsequent 2 years, he qualified.
Lessons for practice
“If we control inflammation, we might control structural damage progression,” Dr. Poddubnyy said.
If this is the case, then it is likely that other drugs that control inflammation in axSpA will have a similar effect, such as those that target interleukin-17 or Janus kinases. This is something in the future to look at in the GESPIC cohort once enough patient-years of data are available.
Early treatment is probably important, Dr. Poddubnyy suggested, “because in patients with early disease we can expect not that much structural damage at baseline.” Starting treatment early, at the inflammatory stage rather than at the stage where there was a lot of damage already there, could yield better results, he proposed.
“As a clinician, as a researcher, I would be really interested in demonstrating in a prospective, clinical trial that treating patients to target, achieving a remission, would be associated with retardation of structural damage progression. This has only been shown in observational studies so far, so this is an open question.”
Questions on adjustments made for confounding factors
Questions on the spinal presentation included whether there were any differences in NSAID use, to which Dr. Poddubnyy responded, “Patients on TNF inhibitors normally reduce NSAIDs. We adjusted, therefore, for NSAID use.”
The SIJ presentation garnered more questioning. Dr. Torgutalp qualified that both radiographic and nonradiographic patients had been included in the analysis, and “we observe the same effect.”
Asked how clinically relevant the findings were, he noted that, “to the best of our knowledge, this is the first data for sacroiliac joint progression.” The data for spinal progression seem to “reconcile the results from previous investigators,” where there had been some conflicting data on whether 2 or 4 years’ TNF-inhibitor therapy had any effect on radiographic progression.
“I don’t think you’ve adjusted for the baseline level of damage of the SIJ?” queried Pedro Machado, MD, of University College London Hospital. “As you know, in the spine, but also at the SIJ level, the baseline level of damage is usually one of the strongest predictors of further damage.”
This is not something that was adjusted for, Dr. Torgutalp conceded. “We will do it for further analysis,” he said.
Since 2010, GESPIC has been supported by grants from AbbVie. Dr. Poddubnyy reported financial relationships with AbbVie and numerous other pharmaceutical companies. Dr. Torgutalp had no relevant disclosures.
Tumor necrosis factor inhibitors reduce both spinal and sacroiliac radiographic progression in early axial spondyloarthritis (axSpA), but the effects take time.
According to data from the German Spondyloarthritis Inception Cohort (GESPIC), it could take 2-4 years after the initiation of TNF inhibitor treatment before x-rays will show any sign of a benefit in either the spine or sacroiliac joints (SIJ).
“The association between anti-TNF treatment and the retardation of radiographic spinal progression in spondyloarthritis appears to be time-shifted,” GESPIC study investigator Denis Poddubnyy, MD, said at the annual European Congress of Rheumatology.
Reporting the spinal findings, Dr. Poddubnyy, who is head of the rheumatology department at Campus Benjamin Franklin of the Charité University Hospital in Berlin noted that “at least 4 years of observation is required” to see an effect of TNF inhibitors on new bone formation. “This might be related to the intermediate and long-lasting process of bone repair that follows the resolution of inflammation and precedes the development of new bone,” he suggested.
The effect on the SIJ may precede the spinal damage, so it’s important to look at how anti-inflammatory treatment might affect the SIJ, Dr. Poddubnyy said in an interview. Results from the SIJ analysis, which were presented by Murat Torgutalp, MD, suggested that there might be a 2-year time lag between TNFi treatment and being able to see something on x-rays.
“Everybody in the past focused on the spine, considering that spinal changes are functionally more relevant than changes in the SIJ,” Dr. Poddubnyy observed.
Structural damage in the spine and SIJ in radiographic axSpA probably occur by different processes, he explained. While it’s more to do with new bone formation in the spine, it’s more to do with erosive damage followed by repair in the SIJ. “It is very likely that in the majority of patients we see that those two processes are somehow disconnected in time,” he suggested.
The GESPIC cohort provides a good base from which to examine the effects of TNF inhibitors on radiographic progression in patients with axSpA for several reasons, observed Dr. Poddubnyy. For one it was established in 2000, so “well before the introduction of TNF-alpha inhibitors.” That means that almost all patients would have been put on TNF inhibitors while enrolled in the cohort, he said, “so we could really follow up them prospectively for a few years.” In fact, just nine patients had been treated with TNF inhibitors at baseline.
Spinal findings
Although TNF inhibitors are widely accepted to be effective anti-inflammatory drugs that can relieve patients’ spinal symptoms, there were inconclusive data on whether they can also have an impact on radiographic progression.
To look at the possible immediate or later effect of TNF inhibitors on spinal radiographic progression, the GESPIC investigators looked at sets of radiographs, taken at least 2 years apart over a 10-year period, from 266 patients, 77 of whom who had been treated with a TNF inhibitor for at least 12 months or more. Overall, there were 103 2-year intervals covered by TNF inhibitor treatment of any duration, and 78 intervals in which treatment had lasted for at least 12 months.
“This cohort included patients with quite early disease, including both nonradiographic and radiographic forms,” Dr. Poddubnyy said, adding that some patients had been treated with a TNF inhibitor for up to 10 years.
While there were no significant changes in radiographic progression as measured using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) between patients who had and who had not received at least 12 months’ TNF inhibitor therapy in the first 2 years, there was a substantial difference after 4 years.
The mSASSS change in scores over 2 years in patients who were and were not treated with a TNF inhibitor for 12 months or more were a respective 0.35 and 0.81 (P = .047) considering treatment in the previous 2-year treatment period, and 0.33 and 0.77 (also P = .047) considering treatment in the prior 2-year treatment period and the current 2-year period.
“Our interpretation is that within the first 2 years we see a resolution of inflammation, a process of repair, maybe even a process of bone formation, but then if you continue this inflammation control for longer than 2 years, then we see the effect on structural damage,” Dr. Poddubnyy said.
SIJ findings
The SIJ analysis included 301 patients who had at least two sets of radiographs taken every 2 years over a 10-year follow-up period, 87 (28.9%) of whom had been treated with at least one TNF inhibitor during follow-up.
Radiographic SIJ progression was defined as the change in the sacroiliitis sum score over 2 years. Calculations considered both the current 2-year period and the previous 2-year period, as well as any use of TNF inhibitors or more than 12 months’ use.
There were no significant differences in sacroiliitis sum scores comparing people who were and were not treated with TNF inhibitors for at least 12 months in the current 2-year period. However, when the previous 2-year period was looked at there was a significant difference in the score between those who had and had not been treated for 12 or more months (0.15 vs. 0.27, respectively; P = .024).
“These data indicate that TNF inhibitors have a late effect,” Dr. Torgutalp said. “You cannot observe the effect of the TNF inhibitor on radiographic progression in the same interval, you have to wait to see this effect in the next interval,” he explained. That means that when a patient uses a TNF inhibitor, you must wait to see the effect on SIJ progression in the subsequent 2 years, he qualified.
Lessons for practice
“If we control inflammation, we might control structural damage progression,” Dr. Poddubnyy said.
If this is the case, then it is likely that other drugs that control inflammation in axSpA will have a similar effect, such as those that target interleukin-17 or Janus kinases. This is something in the future to look at in the GESPIC cohort once enough patient-years of data are available.
Early treatment is probably important, Dr. Poddubnyy suggested, “because in patients with early disease we can expect not that much structural damage at baseline.” Starting treatment early, at the inflammatory stage rather than at the stage where there was a lot of damage already there, could yield better results, he proposed.
“As a clinician, as a researcher, I would be really interested in demonstrating in a prospective, clinical trial that treating patients to target, achieving a remission, would be associated with retardation of structural damage progression. This has only been shown in observational studies so far, so this is an open question.”
Questions on adjustments made for confounding factors
Questions on the spinal presentation included whether there were any differences in NSAID use, to which Dr. Poddubnyy responded, “Patients on TNF inhibitors normally reduce NSAIDs. We adjusted, therefore, for NSAID use.”
The SIJ presentation garnered more questioning. Dr. Torgutalp qualified that both radiographic and nonradiographic patients had been included in the analysis, and “we observe the same effect.”
Asked how clinically relevant the findings were, he noted that, “to the best of our knowledge, this is the first data for sacroiliac joint progression.” The data for spinal progression seem to “reconcile the results from previous investigators,” where there had been some conflicting data on whether 2 or 4 years’ TNF-inhibitor therapy had any effect on radiographic progression.
“I don’t think you’ve adjusted for the baseline level of damage of the SIJ?” queried Pedro Machado, MD, of University College London Hospital. “As you know, in the spine, but also at the SIJ level, the baseline level of damage is usually one of the strongest predictors of further damage.”
This is not something that was adjusted for, Dr. Torgutalp conceded. “We will do it for further analysis,” he said.
Since 2010, GESPIC has been supported by grants from AbbVie. Dr. Poddubnyy reported financial relationships with AbbVie and numerous other pharmaceutical companies. Dr. Torgutalp had no relevant disclosures.
FROM THE EULAR 2021 CONGRESS
Lenabasum missed mark for systemic sclerosis but may show promise for adjunctive therapy
Although a phase 3 trial of lenabasum did not meet its primary endpoint for treatment of diffuse cutaneous systemic sclerosis (dcSSc), the drug led to more improvement in participants who were not receiving background immunosuppressant therapy during the trial than that seen in participants who received the placebo. Lenabasum also had a favorable safety profile, according to findings presented at the annual European Congress of Rheumatology.
The double-blind, randomized, placebo-controlled trial involved 363 adults who had had dcSSc for up to 6 years. One third of the participants received 5 mg of oral lenabasum, one third received 20 mg, and one third received a placebo. Patients already receiving immunosuppressant therapy could continue to receive it during the trial if the dose had been stable for at least 8 weeks before screening and corticosteroid therapy did not exceed 10 mg prednisone per day or the equivalent.
“The decision to allow background immunosuppressant therapies was made to reflect real-world clinical practice,” coprincipal investigator Robert Dr. Spiera, MD, director of the Vasculitis and Scleroderma Program at the Hospital for Special Surgery, New York, told attendees.
“It is surprising that we do not see any added efficacy of lenabasum in this trial, given the fact that the previous phase 2 trial in 42 patients did show a clear benefit of lenabasum over placebo in the same population,” Jeska K. de Vries-Bouwstra, MD, PhD, a rheumatologist at Leiden (the Netherlands) University Medical Center told this news organization. “Even more, the clinical response in the phase 2 study was supported by a greater change in gene expression in skin tissue of pathways involved in inflammation and fibrosis with lenabasum as compared to placebo.”
Background immunosuppressants contribute to unprecedented placebo responses
The researchers compared the ACR CRISS (Combined Response Index in Diffuse Cutaneous Systemic Sclerosis) score and several secondary endpoints at 52 weeks between the 123 participants who received the placebo and the 120 participants who received 20 mg of lenabasum. A total of 60% of the lenabasum group and 66% of the placebo group had a disease duration of 3 or fewer years, and the modified Rodnan skin score (mRSS) was 22 in the lenabasum group and 23.3 in the placebo group at baseline.
A large majority of participants in both groups – 89% in the lenabasum group and 84% in the placebo group – were receiving background immunosuppressant therapy during the trial. Specifically, 53% of each group was taking mycophenolate, and 23% of the lenabasum group and 32% of the placebo group were taking corticosteroids. In addition, 22% of the lenabasum group and 12% of the placebo group were on methotrexate, and 27% of the lenabasum group and 22% of the placebo group were on another immunosuppressant therapy.
Half of the placebo group and 58% of the lenabasum group were taking only one immunosuppressive therapy. About one-third of the lenabasum (32%) and placebo (34%) groups were taking two or more immunosuppressive therapies.
The primary endpoint at 52 weeks was not significantly different between the two groups: a CRISS score of 0.888 in the lenabasum group and 0.887 in the placebo group. A CRISS score of 0.6 or higher indicates likelihood that a patient improved on treatment. Patients with significant worsening of renal or cardiopulmonary involvement are classified as not improved (score of 0), regardless of improvements in other core items.
“We had very high CRISS scores in all three groups, and they were comparable in all three groups,” Dr. Spiera reported. Because improvement in placebo group far exceeded expectations, the researchers were unable to discern the treatment effect of lenabasum on top of the placebo effect.
The placebo group had better outcomes than expected because of the background immunosuppressant therapy, particularly the use of mycophenolate. When the researchers looked only at placebo participants, the CRISS score was 0.936 in the 97 patients receiving background immunosuppressant therapy of any kind and 0.935 in the 29 patients taking only mycophenolate with no other immunosuppressant therapy, compared with 0.417 in the 16 patients not receiving any background therapy.
In a prespecified analysis, the researchers investigated background immunosuppressive therapy as a mediator. The CRISS score for the 10 lenabasum participants not receiving background therapy was 0.811, compared with 0.417 seen in the placebo group patients not on background therapy.
Among the 173 participants taking mycophenolate in particular, the mycophenolate “had a statistically significant improvement on CRISS score that increased with each visit,” Dr. Spiera reported. The duration of mycophenolate therapy also affected efficacy results.
Patients who had been taking mycophenolate longer saw less improvement in their CRISS score over time. Those taking it more than 2 years at baseline had a CRISS score of 0.86, compared with 0.96 for those taking it for 1-2 years at baseline and 0.98 for those taking it from 6 months to 1 year at baseline. Those who had only been taking mycophenolate for up to 6 months at baseline had a CRISS score of 0.99. Meanwhile, patients not taking any background immunosuppressant therapies only had a CRISS score of about 0.35.
Changes in secondary endpoints followed same pattern as CRISS
The secondary endpoints similarly showed no statistically significant difference when comparing the lenabasum and placebo groups overall. These endpoints included change in mRSS score, change in forced vital capacity (FVC) percentage and volume, and change in the Health Assessment Questionnaire Disability Index (HAQ-DI) score.
However, the researchers again found that duration of background therapy affected FVC.
“You were more likely to have declined [in FVC] if you were on placebo and more likely to have improved or stayed stable if you were on lenabasum if you were a patient on more than 2 years of immunomodulatory therapy at baseline,” Dr. Spiera reported. “There was evidence for an effect of lenabasum on FVC suggested by post-hoc analyses that considered the effect of background immunosuppressive therapies on outcomes, but those results would require confirmation in additional studies to determine the potential of lenabasum for treating patients with diffuse cutaneous systemic sclerosis,” Dr. Spiera noted in his conclusions.
Serious adverse events occurred in 9.2% of the lenabasum group and 5.8% of the placebo group. Rates of severe adverse events were similar between the lenabasum (14.6%) and placebo (13%) groups.
Is there a subgroup for whom lenabasum would be efficacious?
Although De Vries-Bouwstra of Leiden University Medical Center acknowledged the role of mycophenolate in the trial, she does not think background therapy can totally explain the observation and speculated on other possibilities.
“For example, there were fewer males in the placebo group as compared to the phase 2 study. From previous cohort studies we know that males have higher risk of worsening of skin disease,” she said. “In addition, it could be worthwhile to evaluate antibody profiles of the population under study; some subpopulations defined by autoantibody have higher risk for skin progression, while others can show spontaneous improvement.”
Dr. De Vries-Bouwstra said that, although it’s not currently appropriate to advocate for lenabasum to treat dcSSc, it may eventually become an additional treatment in those who still show active skin or lung disease after 2 years of mycophenolate treatment if future research identifies a benefit from that application. She would also like to see an evaluation of lenabasum’s possible benefits in patients with very early and active inflammatory disease. “Ideally, one could stratify patients based on biomarkers reflecting activation in relevant pathways, for example by using gene expression analysis from skin tissue to stratify,” she said.
Jacob M. van Laar, MD, PhD, professor of rheumatology at University Medical Center Utrecht (the Netherlands), also commented on the potential differences in using the drug in early versus later disease.
“Based on ex vivo analyses of skin samples from systemic sclerosis patients, one would expect such a mechanism of action to be particularly relevant in very early disease, so the observation that it might also be effective at a later disease stage is interesting,” Dr. van Laar told this news organization. “We still have a lot to learn about this complex disease.”
Given that safety does not appear to be a major concern and that there may be a benefit in a subgroup of patients, Dr. van Laar also said he hoped “the company is not deterred by the seemingly negative result of the primary endpoint.”
Dr. Spiera expressed optimism about what this trial’s findings have revealed about management of dcSSc.
“Independent of what lenabasum did or didn’t do in this trial, I think there’s going to be a lot that we’re going to learn from this trial and that we’re already learning and analyzing right now about treating scleroderma,” he said in an interview.
He reiterated the value of allowing background therapy in the trial to ensure it better replicated real-world clinical practice.
“You’re not withholding therapies that we think are probably active from patients with active disease that, once you incur organ damage, is probably not going to be reversible,” Dr. Spiera said. “The downside is that it makes it harder to see an effect of a drug on top of the background therapy if that background therapy is effective. So what we saw in terms of this absence of benefit from lenabasum really may have been a ceiling effect.”
Nevertheless, Dr. Spiera said the findings still strongly suggest that lenabasum is an active compound.
“It’s not an enormously powerful effect, but it probably has a role as an adjunctive therapy in people on stable background therapy who have either plateaued or are getting worse,” he said. “The thing we have to keep in mind also is this was an incredibly safe therapy. It’s not immunosuppressive.”
The trial was funded by Corbus. Dr. Spiera has received grant support or consulting fees from Roche-Genentech, GlaxoSmithKline, Boehringer Ingelheim, Chemocentryx, Corbus, Formation Biologics, Inflarx, Kadmon, AstraZeneca, AbbVie, CSL Behring, Sanofi, and Janssen. Dr. De Vries-Bouwstra has received consulting fees from AbbVie and Boehringer Ingelheim and research grants from Galapagos and Janssen. Dr. Van Laar has received grant funding or personal fees from Arthrogen, Arxx Therapeutics, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Gesynta, Leadiant, Merck Sharp & Dohme, Roche, Sanofi, and Thermofisher.
A version of this article first appeared on Medscape.com.
Although a phase 3 trial of lenabasum did not meet its primary endpoint for treatment of diffuse cutaneous systemic sclerosis (dcSSc), the drug led to more improvement in participants who were not receiving background immunosuppressant therapy during the trial than that seen in participants who received the placebo. Lenabasum also had a favorable safety profile, according to findings presented at the annual European Congress of Rheumatology.
The double-blind, randomized, placebo-controlled trial involved 363 adults who had had dcSSc for up to 6 years. One third of the participants received 5 mg of oral lenabasum, one third received 20 mg, and one third received a placebo. Patients already receiving immunosuppressant therapy could continue to receive it during the trial if the dose had been stable for at least 8 weeks before screening and corticosteroid therapy did not exceed 10 mg prednisone per day or the equivalent.
“The decision to allow background immunosuppressant therapies was made to reflect real-world clinical practice,” coprincipal investigator Robert Dr. Spiera, MD, director of the Vasculitis and Scleroderma Program at the Hospital for Special Surgery, New York, told attendees.
“It is surprising that we do not see any added efficacy of lenabasum in this trial, given the fact that the previous phase 2 trial in 42 patients did show a clear benefit of lenabasum over placebo in the same population,” Jeska K. de Vries-Bouwstra, MD, PhD, a rheumatologist at Leiden (the Netherlands) University Medical Center told this news organization. “Even more, the clinical response in the phase 2 study was supported by a greater change in gene expression in skin tissue of pathways involved in inflammation and fibrosis with lenabasum as compared to placebo.”
Background immunosuppressants contribute to unprecedented placebo responses
The researchers compared the ACR CRISS (Combined Response Index in Diffuse Cutaneous Systemic Sclerosis) score and several secondary endpoints at 52 weeks between the 123 participants who received the placebo and the 120 participants who received 20 mg of lenabasum. A total of 60% of the lenabasum group and 66% of the placebo group had a disease duration of 3 or fewer years, and the modified Rodnan skin score (mRSS) was 22 in the lenabasum group and 23.3 in the placebo group at baseline.
A large majority of participants in both groups – 89% in the lenabasum group and 84% in the placebo group – were receiving background immunosuppressant therapy during the trial. Specifically, 53% of each group was taking mycophenolate, and 23% of the lenabasum group and 32% of the placebo group were taking corticosteroids. In addition, 22% of the lenabasum group and 12% of the placebo group were on methotrexate, and 27% of the lenabasum group and 22% of the placebo group were on another immunosuppressant therapy.
Half of the placebo group and 58% of the lenabasum group were taking only one immunosuppressive therapy. About one-third of the lenabasum (32%) and placebo (34%) groups were taking two or more immunosuppressive therapies.
The primary endpoint at 52 weeks was not significantly different between the two groups: a CRISS score of 0.888 in the lenabasum group and 0.887 in the placebo group. A CRISS score of 0.6 or higher indicates likelihood that a patient improved on treatment. Patients with significant worsening of renal or cardiopulmonary involvement are classified as not improved (score of 0), regardless of improvements in other core items.
“We had very high CRISS scores in all three groups, and they were comparable in all three groups,” Dr. Spiera reported. Because improvement in placebo group far exceeded expectations, the researchers were unable to discern the treatment effect of lenabasum on top of the placebo effect.
The placebo group had better outcomes than expected because of the background immunosuppressant therapy, particularly the use of mycophenolate. When the researchers looked only at placebo participants, the CRISS score was 0.936 in the 97 patients receiving background immunosuppressant therapy of any kind and 0.935 in the 29 patients taking only mycophenolate with no other immunosuppressant therapy, compared with 0.417 in the 16 patients not receiving any background therapy.
In a prespecified analysis, the researchers investigated background immunosuppressive therapy as a mediator. The CRISS score for the 10 lenabasum participants not receiving background therapy was 0.811, compared with 0.417 seen in the placebo group patients not on background therapy.
Among the 173 participants taking mycophenolate in particular, the mycophenolate “had a statistically significant improvement on CRISS score that increased with each visit,” Dr. Spiera reported. The duration of mycophenolate therapy also affected efficacy results.
Patients who had been taking mycophenolate longer saw less improvement in their CRISS score over time. Those taking it more than 2 years at baseline had a CRISS score of 0.86, compared with 0.96 for those taking it for 1-2 years at baseline and 0.98 for those taking it from 6 months to 1 year at baseline. Those who had only been taking mycophenolate for up to 6 months at baseline had a CRISS score of 0.99. Meanwhile, patients not taking any background immunosuppressant therapies only had a CRISS score of about 0.35.
Changes in secondary endpoints followed same pattern as CRISS
The secondary endpoints similarly showed no statistically significant difference when comparing the lenabasum and placebo groups overall. These endpoints included change in mRSS score, change in forced vital capacity (FVC) percentage and volume, and change in the Health Assessment Questionnaire Disability Index (HAQ-DI) score.
However, the researchers again found that duration of background therapy affected FVC.
“You were more likely to have declined [in FVC] if you were on placebo and more likely to have improved or stayed stable if you were on lenabasum if you were a patient on more than 2 years of immunomodulatory therapy at baseline,” Dr. Spiera reported. “There was evidence for an effect of lenabasum on FVC suggested by post-hoc analyses that considered the effect of background immunosuppressive therapies on outcomes, but those results would require confirmation in additional studies to determine the potential of lenabasum for treating patients with diffuse cutaneous systemic sclerosis,” Dr. Spiera noted in his conclusions.
Serious adverse events occurred in 9.2% of the lenabasum group and 5.8% of the placebo group. Rates of severe adverse events were similar between the lenabasum (14.6%) and placebo (13%) groups.
Is there a subgroup for whom lenabasum would be efficacious?
Although De Vries-Bouwstra of Leiden University Medical Center acknowledged the role of mycophenolate in the trial, she does not think background therapy can totally explain the observation and speculated on other possibilities.
“For example, there were fewer males in the placebo group as compared to the phase 2 study. From previous cohort studies we know that males have higher risk of worsening of skin disease,” she said. “In addition, it could be worthwhile to evaluate antibody profiles of the population under study; some subpopulations defined by autoantibody have higher risk for skin progression, while others can show spontaneous improvement.”
Dr. De Vries-Bouwstra said that, although it’s not currently appropriate to advocate for lenabasum to treat dcSSc, it may eventually become an additional treatment in those who still show active skin or lung disease after 2 years of mycophenolate treatment if future research identifies a benefit from that application. She would also like to see an evaluation of lenabasum’s possible benefits in patients with very early and active inflammatory disease. “Ideally, one could stratify patients based on biomarkers reflecting activation in relevant pathways, for example by using gene expression analysis from skin tissue to stratify,” she said.
Jacob M. van Laar, MD, PhD, professor of rheumatology at University Medical Center Utrecht (the Netherlands), also commented on the potential differences in using the drug in early versus later disease.
“Based on ex vivo analyses of skin samples from systemic sclerosis patients, one would expect such a mechanism of action to be particularly relevant in very early disease, so the observation that it might also be effective at a later disease stage is interesting,” Dr. van Laar told this news organization. “We still have a lot to learn about this complex disease.”
Given that safety does not appear to be a major concern and that there may be a benefit in a subgroup of patients, Dr. van Laar also said he hoped “the company is not deterred by the seemingly negative result of the primary endpoint.”
Dr. Spiera expressed optimism about what this trial’s findings have revealed about management of dcSSc.
“Independent of what lenabasum did or didn’t do in this trial, I think there’s going to be a lot that we’re going to learn from this trial and that we’re already learning and analyzing right now about treating scleroderma,” he said in an interview.
He reiterated the value of allowing background therapy in the trial to ensure it better replicated real-world clinical practice.
“You’re not withholding therapies that we think are probably active from patients with active disease that, once you incur organ damage, is probably not going to be reversible,” Dr. Spiera said. “The downside is that it makes it harder to see an effect of a drug on top of the background therapy if that background therapy is effective. So what we saw in terms of this absence of benefit from lenabasum really may have been a ceiling effect.”
Nevertheless, Dr. Spiera said the findings still strongly suggest that lenabasum is an active compound.
“It’s not an enormously powerful effect, but it probably has a role as an adjunctive therapy in people on stable background therapy who have either plateaued or are getting worse,” he said. “The thing we have to keep in mind also is this was an incredibly safe therapy. It’s not immunosuppressive.”
The trial was funded by Corbus. Dr. Spiera has received grant support or consulting fees from Roche-Genentech, GlaxoSmithKline, Boehringer Ingelheim, Chemocentryx, Corbus, Formation Biologics, Inflarx, Kadmon, AstraZeneca, AbbVie, CSL Behring, Sanofi, and Janssen. Dr. De Vries-Bouwstra has received consulting fees from AbbVie and Boehringer Ingelheim and research grants from Galapagos and Janssen. Dr. Van Laar has received grant funding or personal fees from Arthrogen, Arxx Therapeutics, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Gesynta, Leadiant, Merck Sharp & Dohme, Roche, Sanofi, and Thermofisher.
A version of this article first appeared on Medscape.com.
Although a phase 3 trial of lenabasum did not meet its primary endpoint for treatment of diffuse cutaneous systemic sclerosis (dcSSc), the drug led to more improvement in participants who were not receiving background immunosuppressant therapy during the trial than that seen in participants who received the placebo. Lenabasum also had a favorable safety profile, according to findings presented at the annual European Congress of Rheumatology.
The double-blind, randomized, placebo-controlled trial involved 363 adults who had had dcSSc for up to 6 years. One third of the participants received 5 mg of oral lenabasum, one third received 20 mg, and one third received a placebo. Patients already receiving immunosuppressant therapy could continue to receive it during the trial if the dose had been stable for at least 8 weeks before screening and corticosteroid therapy did not exceed 10 mg prednisone per day or the equivalent.
“The decision to allow background immunosuppressant therapies was made to reflect real-world clinical practice,” coprincipal investigator Robert Dr. Spiera, MD, director of the Vasculitis and Scleroderma Program at the Hospital for Special Surgery, New York, told attendees.
“It is surprising that we do not see any added efficacy of lenabasum in this trial, given the fact that the previous phase 2 trial in 42 patients did show a clear benefit of lenabasum over placebo in the same population,” Jeska K. de Vries-Bouwstra, MD, PhD, a rheumatologist at Leiden (the Netherlands) University Medical Center told this news organization. “Even more, the clinical response in the phase 2 study was supported by a greater change in gene expression in skin tissue of pathways involved in inflammation and fibrosis with lenabasum as compared to placebo.”
Background immunosuppressants contribute to unprecedented placebo responses
The researchers compared the ACR CRISS (Combined Response Index in Diffuse Cutaneous Systemic Sclerosis) score and several secondary endpoints at 52 weeks between the 123 participants who received the placebo and the 120 participants who received 20 mg of lenabasum. A total of 60% of the lenabasum group and 66% of the placebo group had a disease duration of 3 or fewer years, and the modified Rodnan skin score (mRSS) was 22 in the lenabasum group and 23.3 in the placebo group at baseline.
A large majority of participants in both groups – 89% in the lenabasum group and 84% in the placebo group – were receiving background immunosuppressant therapy during the trial. Specifically, 53% of each group was taking mycophenolate, and 23% of the lenabasum group and 32% of the placebo group were taking corticosteroids. In addition, 22% of the lenabasum group and 12% of the placebo group were on methotrexate, and 27% of the lenabasum group and 22% of the placebo group were on another immunosuppressant therapy.
Half of the placebo group and 58% of the lenabasum group were taking only one immunosuppressive therapy. About one-third of the lenabasum (32%) and placebo (34%) groups were taking two or more immunosuppressive therapies.
The primary endpoint at 52 weeks was not significantly different between the two groups: a CRISS score of 0.888 in the lenabasum group and 0.887 in the placebo group. A CRISS score of 0.6 or higher indicates likelihood that a patient improved on treatment. Patients with significant worsening of renal or cardiopulmonary involvement are classified as not improved (score of 0), regardless of improvements in other core items.
“We had very high CRISS scores in all three groups, and they were comparable in all three groups,” Dr. Spiera reported. Because improvement in placebo group far exceeded expectations, the researchers were unable to discern the treatment effect of lenabasum on top of the placebo effect.
The placebo group had better outcomes than expected because of the background immunosuppressant therapy, particularly the use of mycophenolate. When the researchers looked only at placebo participants, the CRISS score was 0.936 in the 97 patients receiving background immunosuppressant therapy of any kind and 0.935 in the 29 patients taking only mycophenolate with no other immunosuppressant therapy, compared with 0.417 in the 16 patients not receiving any background therapy.
In a prespecified analysis, the researchers investigated background immunosuppressive therapy as a mediator. The CRISS score for the 10 lenabasum participants not receiving background therapy was 0.811, compared with 0.417 seen in the placebo group patients not on background therapy.
Among the 173 participants taking mycophenolate in particular, the mycophenolate “had a statistically significant improvement on CRISS score that increased with each visit,” Dr. Spiera reported. The duration of mycophenolate therapy also affected efficacy results.
Patients who had been taking mycophenolate longer saw less improvement in their CRISS score over time. Those taking it more than 2 years at baseline had a CRISS score of 0.86, compared with 0.96 for those taking it for 1-2 years at baseline and 0.98 for those taking it from 6 months to 1 year at baseline. Those who had only been taking mycophenolate for up to 6 months at baseline had a CRISS score of 0.99. Meanwhile, patients not taking any background immunosuppressant therapies only had a CRISS score of about 0.35.
Changes in secondary endpoints followed same pattern as CRISS
The secondary endpoints similarly showed no statistically significant difference when comparing the lenabasum and placebo groups overall. These endpoints included change in mRSS score, change in forced vital capacity (FVC) percentage and volume, and change in the Health Assessment Questionnaire Disability Index (HAQ-DI) score.
However, the researchers again found that duration of background therapy affected FVC.
“You were more likely to have declined [in FVC] if you were on placebo and more likely to have improved or stayed stable if you were on lenabasum if you were a patient on more than 2 years of immunomodulatory therapy at baseline,” Dr. Spiera reported. “There was evidence for an effect of lenabasum on FVC suggested by post-hoc analyses that considered the effect of background immunosuppressive therapies on outcomes, but those results would require confirmation in additional studies to determine the potential of lenabasum for treating patients with diffuse cutaneous systemic sclerosis,” Dr. Spiera noted in his conclusions.
Serious adverse events occurred in 9.2% of the lenabasum group and 5.8% of the placebo group. Rates of severe adverse events were similar between the lenabasum (14.6%) and placebo (13%) groups.
Is there a subgroup for whom lenabasum would be efficacious?
Although De Vries-Bouwstra of Leiden University Medical Center acknowledged the role of mycophenolate in the trial, she does not think background therapy can totally explain the observation and speculated on other possibilities.
“For example, there were fewer males in the placebo group as compared to the phase 2 study. From previous cohort studies we know that males have higher risk of worsening of skin disease,” she said. “In addition, it could be worthwhile to evaluate antibody profiles of the population under study; some subpopulations defined by autoantibody have higher risk for skin progression, while others can show spontaneous improvement.”
Dr. De Vries-Bouwstra said that, although it’s not currently appropriate to advocate for lenabasum to treat dcSSc, it may eventually become an additional treatment in those who still show active skin or lung disease after 2 years of mycophenolate treatment if future research identifies a benefit from that application. She would also like to see an evaluation of lenabasum’s possible benefits in patients with very early and active inflammatory disease. “Ideally, one could stratify patients based on biomarkers reflecting activation in relevant pathways, for example by using gene expression analysis from skin tissue to stratify,” she said.
Jacob M. van Laar, MD, PhD, professor of rheumatology at University Medical Center Utrecht (the Netherlands), also commented on the potential differences in using the drug in early versus later disease.
“Based on ex vivo analyses of skin samples from systemic sclerosis patients, one would expect such a mechanism of action to be particularly relevant in very early disease, so the observation that it might also be effective at a later disease stage is interesting,” Dr. van Laar told this news organization. “We still have a lot to learn about this complex disease.”
Given that safety does not appear to be a major concern and that there may be a benefit in a subgroup of patients, Dr. van Laar also said he hoped “the company is not deterred by the seemingly negative result of the primary endpoint.”
Dr. Spiera expressed optimism about what this trial’s findings have revealed about management of dcSSc.
“Independent of what lenabasum did or didn’t do in this trial, I think there’s going to be a lot that we’re going to learn from this trial and that we’re already learning and analyzing right now about treating scleroderma,” he said in an interview.
He reiterated the value of allowing background therapy in the trial to ensure it better replicated real-world clinical practice.
“You’re not withholding therapies that we think are probably active from patients with active disease that, once you incur organ damage, is probably not going to be reversible,” Dr. Spiera said. “The downside is that it makes it harder to see an effect of a drug on top of the background therapy if that background therapy is effective. So what we saw in terms of this absence of benefit from lenabasum really may have been a ceiling effect.”
Nevertheless, Dr. Spiera said the findings still strongly suggest that lenabasum is an active compound.
“It’s not an enormously powerful effect, but it probably has a role as an adjunctive therapy in people on stable background therapy who have either plateaued or are getting worse,” he said. “The thing we have to keep in mind also is this was an incredibly safe therapy. It’s not immunosuppressive.”
The trial was funded by Corbus. Dr. Spiera has received grant support or consulting fees from Roche-Genentech, GlaxoSmithKline, Boehringer Ingelheim, Chemocentryx, Corbus, Formation Biologics, Inflarx, Kadmon, AstraZeneca, AbbVie, CSL Behring, Sanofi, and Janssen. Dr. De Vries-Bouwstra has received consulting fees from AbbVie and Boehringer Ingelheim and research grants from Galapagos and Janssen. Dr. Van Laar has received grant funding or personal fees from Arthrogen, Arxx Therapeutics, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Gesynta, Leadiant, Merck Sharp & Dohme, Roche, Sanofi, and Thermofisher.
A version of this article first appeared on Medscape.com.
Mavrilimumab may aid severe COVID-19 recovery
Inhibiting granulocyte/macrophage–colony stimulating factor (GM-CSF) with mavrilimumab prevented some patients with severe COVID-19 pneumonia and hyperinflammation from needing mechanical ventilation and reduced their risk of dying versus placebo in a phase 2 study.
There was no difference in outcomes between the two doses of mavrilimumab used in the trial (6 mg/kg or 10 mg/kg) and combined data showed a higher percentage of patients achieving the primary endpoint of being alive and free of mechanical ventilation at 29 days, at 87%, versus placebo, at 74%.
The P value was 0.12, “which achieved the prespecified evidentiary standard of 0.2,” according to Lara Pupim, MD, vice president of clinical research and development at Kiniksa Pharmaceuticals in Lexington, Mass.
Importantly, there was a 61% reduction in the risk of dying if patients had received mavrilimumab rather than placebo, she reported at the annual European Congress of Rheumatology. Mortality at day 29 was 21% in the placebo arm but just 8% in the combined mavrilimumab arms (P = .07).
Hendrik Schulze-Koops, MD, called it a “surprising study” and that “the outcome is very spectacular” in his short appraisal of the study during the Clinical Highlights session on the final day of the congress.
Mavrilimumab was “a compound that we would not have thought that would have such an impact on the outcome of COVID-19 infected patients,” Dr. Schulze-Koops of Ludwig Maximilian University of Munich added.
In this small study, “there was a consistent suggestion of a biological effect across key endpoints,” Richard Conway, MBChB, PhD, a consultant rheumatologist at St. James’s Hospital in Dublin, pointed out in an interview.
“Similar to tocilizumab, the benefits with mavrilimumab appear to be in addition to those seen with glucocorticoids, as 96% of patients received dexamethasone,” Dr. Conway observed. Furthermore, nearly one-third received antiviral or remdesivir treatment.
“This study was likely underpowered to assess a clinically meaningful benefit,” he said, adding that “there is insufficient evidence at present to begin using mavrilimumab as an alternative to currently available agents.” That said, “these results are promising for future studies.”
Rationale for GM-CSF inhibition with mavrilimumab in COVID-19 pneumonia
“The cytokine GM-CSF is vital to both lung homeostasis and regulation of inflammation in autoimmunity,” Dr. Pupim explained.
She added that “GM-CSF is implicated in the mechanism of aberrant immune cell infiltration and activation in the lungs, and it may contribute to respiratory failure and death in patients with severe COVID-19 pneumonia and systemic hyperinflammation.”
The efficacy and safety of blocking GM-CSF with mavrilimumab have been shown previously in phase 2 studies in other diseases, Dr. Pupim noted. This includes patients with rheumatoid arthritis and those with giant cell arteritis.
“It was hypothesized that GM-CSF receptor–alpha blockade may reduce infiltration of pathogenic cells into the lung and may suppress inflammation in COVID-19 pneumonia in hyperinflammation,” she explained.
Study details and other outcome results
The study presented by Dr. Pupim was a phase 2/3 double-blind, placebo-controlled trial predominantly conducted in Brazil, the United States, and South Africa, with some participation in Peru and Chile.
Patients were eligible for inclusion if they had had a positive COVID-19 test within 14 days of randomization and had been hospitalized but not ventilated. Evidence of bilateral pneumonia on chest x-ray or CT scan and clinical laboratory evidence indicative of hyperinflammation were also prerequisites for study enrollment.
The ongoing study comprised two cohorts, Dr. Pupim explained: patients who have not been ventilated and those who have recently been ventilated. Dr. Pupim presented the data on the nonventilated cohort, noting that there was a total of 116 patients aged a mean of 57 years.
Patients were randomized to one of three treatment arms: two groups received a single intravenous infusion of mavrilimumab, either 6 mg/kg or 10 mg/kg, and the third group got a placebo.
“Using a time-to-event approach, looking at mechanical ventilation-free survival, mavrilimumab recipients experienced a 65% reduction in the risk of mechanical ventilation or death,” Dr. Pupim said (P = .0175).
“Separation in the Kaplan-Meier curves was evident very early after study drug administration,” she added.
There were trends toward a faster benefit with mavrilimumab than placebo in two other key secondary endpoints: the median time to achieving a two-point clinical improvement (7 vs. 11 days) and the median time to room air (7 vs. 9 days).
Timing of mavrilimumab administration and safety
Study coauthor and chief clinical development officer at Kiniksa, Arian Pano, MD, answered questions on the presentation. When asked about the timing of giving mavrilimumab, he said: “Based on these data it is before they go to ventilation, as soon as you have symptoms of hyperinflammation and a need for oxygen.”
Mavrilimumab is given as a single infusion “and has been well tolerated; virtually no interruptions occurred in this study.”
No serious adverse events related to mavrilimumab were seen, and adverse events, including secondary infections, which are known complications of COVID-19, occurred less frequently in mavrilimumab recipients, compared with placebo.
Dr. Pupim reported that there was a case of tuberculosis in one patient treated with mavrilimumab (10 mg/kg). That case had occurred in an “endemic area for tuberculosis,” and the patient had been screened before entry but only via a sputum sample.
“Prior to these events, the patient received high-dose corticosteroids, a known risk factor for reactivation of TB, and thus the potential additive contribution of mavrilimumab, if any, is uncertain.” Dr. Pupim said.
“Thrombotic events, another known complication of COVID-19, occurred in the placebo arm only,” she added.
Dr. Pano commented that the study has now “seamlessly continued to phase 3. So, basically, we did not stop the study. At the end of phase 2, we just locked the database and collected the data.” Both the 6 mg/kg and 10 mg/kg are being studied, but it’s “very likely [that] 6 mg/kg could be the dose that we may bring forward to the clinic in terms of registration, but that’s at this point in time. We will need to wait for the phase 3 data,” he observed. Those findings will hopefully be available later this year.
Kiniksa funded the study. Dr. Pupim, Dr. Pano, and multiple study coinvestigators are employees of the company.
Dr. Schulze-Koops was not involved in the study and had no specific disclosures. Dr. Conway had no financial disclosures to make in relation to his comments.
Inhibiting granulocyte/macrophage–colony stimulating factor (GM-CSF) with mavrilimumab prevented some patients with severe COVID-19 pneumonia and hyperinflammation from needing mechanical ventilation and reduced their risk of dying versus placebo in a phase 2 study.
There was no difference in outcomes between the two doses of mavrilimumab used in the trial (6 mg/kg or 10 mg/kg) and combined data showed a higher percentage of patients achieving the primary endpoint of being alive and free of mechanical ventilation at 29 days, at 87%, versus placebo, at 74%.
The P value was 0.12, “which achieved the prespecified evidentiary standard of 0.2,” according to Lara Pupim, MD, vice president of clinical research and development at Kiniksa Pharmaceuticals in Lexington, Mass.
Importantly, there was a 61% reduction in the risk of dying if patients had received mavrilimumab rather than placebo, she reported at the annual European Congress of Rheumatology. Mortality at day 29 was 21% in the placebo arm but just 8% in the combined mavrilimumab arms (P = .07).
Hendrik Schulze-Koops, MD, called it a “surprising study” and that “the outcome is very spectacular” in his short appraisal of the study during the Clinical Highlights session on the final day of the congress.
Mavrilimumab was “a compound that we would not have thought that would have such an impact on the outcome of COVID-19 infected patients,” Dr. Schulze-Koops of Ludwig Maximilian University of Munich added.
In this small study, “there was a consistent suggestion of a biological effect across key endpoints,” Richard Conway, MBChB, PhD, a consultant rheumatologist at St. James’s Hospital in Dublin, pointed out in an interview.
“Similar to tocilizumab, the benefits with mavrilimumab appear to be in addition to those seen with glucocorticoids, as 96% of patients received dexamethasone,” Dr. Conway observed. Furthermore, nearly one-third received antiviral or remdesivir treatment.
“This study was likely underpowered to assess a clinically meaningful benefit,” he said, adding that “there is insufficient evidence at present to begin using mavrilimumab as an alternative to currently available agents.” That said, “these results are promising for future studies.”
Rationale for GM-CSF inhibition with mavrilimumab in COVID-19 pneumonia
“The cytokine GM-CSF is vital to both lung homeostasis and regulation of inflammation in autoimmunity,” Dr. Pupim explained.
She added that “GM-CSF is implicated in the mechanism of aberrant immune cell infiltration and activation in the lungs, and it may contribute to respiratory failure and death in patients with severe COVID-19 pneumonia and systemic hyperinflammation.”
The efficacy and safety of blocking GM-CSF with mavrilimumab have been shown previously in phase 2 studies in other diseases, Dr. Pupim noted. This includes patients with rheumatoid arthritis and those with giant cell arteritis.
“It was hypothesized that GM-CSF receptor–alpha blockade may reduce infiltration of pathogenic cells into the lung and may suppress inflammation in COVID-19 pneumonia in hyperinflammation,” she explained.
Study details and other outcome results
The study presented by Dr. Pupim was a phase 2/3 double-blind, placebo-controlled trial predominantly conducted in Brazil, the United States, and South Africa, with some participation in Peru and Chile.
Patients were eligible for inclusion if they had had a positive COVID-19 test within 14 days of randomization and had been hospitalized but not ventilated. Evidence of bilateral pneumonia on chest x-ray or CT scan and clinical laboratory evidence indicative of hyperinflammation were also prerequisites for study enrollment.
The ongoing study comprised two cohorts, Dr. Pupim explained: patients who have not been ventilated and those who have recently been ventilated. Dr. Pupim presented the data on the nonventilated cohort, noting that there was a total of 116 patients aged a mean of 57 years.
Patients were randomized to one of three treatment arms: two groups received a single intravenous infusion of mavrilimumab, either 6 mg/kg or 10 mg/kg, and the third group got a placebo.
“Using a time-to-event approach, looking at mechanical ventilation-free survival, mavrilimumab recipients experienced a 65% reduction in the risk of mechanical ventilation or death,” Dr. Pupim said (P = .0175).
“Separation in the Kaplan-Meier curves was evident very early after study drug administration,” she added.
There were trends toward a faster benefit with mavrilimumab than placebo in two other key secondary endpoints: the median time to achieving a two-point clinical improvement (7 vs. 11 days) and the median time to room air (7 vs. 9 days).
Timing of mavrilimumab administration and safety
Study coauthor and chief clinical development officer at Kiniksa, Arian Pano, MD, answered questions on the presentation. When asked about the timing of giving mavrilimumab, he said: “Based on these data it is before they go to ventilation, as soon as you have symptoms of hyperinflammation and a need for oxygen.”
Mavrilimumab is given as a single infusion “and has been well tolerated; virtually no interruptions occurred in this study.”
No serious adverse events related to mavrilimumab were seen, and adverse events, including secondary infections, which are known complications of COVID-19, occurred less frequently in mavrilimumab recipients, compared with placebo.
Dr. Pupim reported that there was a case of tuberculosis in one patient treated with mavrilimumab (10 mg/kg). That case had occurred in an “endemic area for tuberculosis,” and the patient had been screened before entry but only via a sputum sample.
“Prior to these events, the patient received high-dose corticosteroids, a known risk factor for reactivation of TB, and thus the potential additive contribution of mavrilimumab, if any, is uncertain.” Dr. Pupim said.
“Thrombotic events, another known complication of COVID-19, occurred in the placebo arm only,” she added.
Dr. Pano commented that the study has now “seamlessly continued to phase 3. So, basically, we did not stop the study. At the end of phase 2, we just locked the database and collected the data.” Both the 6 mg/kg and 10 mg/kg are being studied, but it’s “very likely [that] 6 mg/kg could be the dose that we may bring forward to the clinic in terms of registration, but that’s at this point in time. We will need to wait for the phase 3 data,” he observed. Those findings will hopefully be available later this year.
Kiniksa funded the study. Dr. Pupim, Dr. Pano, and multiple study coinvestigators are employees of the company.
Dr. Schulze-Koops was not involved in the study and had no specific disclosures. Dr. Conway had no financial disclosures to make in relation to his comments.
Inhibiting granulocyte/macrophage–colony stimulating factor (GM-CSF) with mavrilimumab prevented some patients with severe COVID-19 pneumonia and hyperinflammation from needing mechanical ventilation and reduced their risk of dying versus placebo in a phase 2 study.
There was no difference in outcomes between the two doses of mavrilimumab used in the trial (6 mg/kg or 10 mg/kg) and combined data showed a higher percentage of patients achieving the primary endpoint of being alive and free of mechanical ventilation at 29 days, at 87%, versus placebo, at 74%.
The P value was 0.12, “which achieved the prespecified evidentiary standard of 0.2,” according to Lara Pupim, MD, vice president of clinical research and development at Kiniksa Pharmaceuticals in Lexington, Mass.
Importantly, there was a 61% reduction in the risk of dying if patients had received mavrilimumab rather than placebo, she reported at the annual European Congress of Rheumatology. Mortality at day 29 was 21% in the placebo arm but just 8% in the combined mavrilimumab arms (P = .07).
Hendrik Schulze-Koops, MD, called it a “surprising study” and that “the outcome is very spectacular” in his short appraisal of the study during the Clinical Highlights session on the final day of the congress.
Mavrilimumab was “a compound that we would not have thought that would have such an impact on the outcome of COVID-19 infected patients,” Dr. Schulze-Koops of Ludwig Maximilian University of Munich added.
In this small study, “there was a consistent suggestion of a biological effect across key endpoints,” Richard Conway, MBChB, PhD, a consultant rheumatologist at St. James’s Hospital in Dublin, pointed out in an interview.
“Similar to tocilizumab, the benefits with mavrilimumab appear to be in addition to those seen with glucocorticoids, as 96% of patients received dexamethasone,” Dr. Conway observed. Furthermore, nearly one-third received antiviral or remdesivir treatment.
“This study was likely underpowered to assess a clinically meaningful benefit,” he said, adding that “there is insufficient evidence at present to begin using mavrilimumab as an alternative to currently available agents.” That said, “these results are promising for future studies.”
Rationale for GM-CSF inhibition with mavrilimumab in COVID-19 pneumonia
“The cytokine GM-CSF is vital to both lung homeostasis and regulation of inflammation in autoimmunity,” Dr. Pupim explained.
She added that “GM-CSF is implicated in the mechanism of aberrant immune cell infiltration and activation in the lungs, and it may contribute to respiratory failure and death in patients with severe COVID-19 pneumonia and systemic hyperinflammation.”
The efficacy and safety of blocking GM-CSF with mavrilimumab have been shown previously in phase 2 studies in other diseases, Dr. Pupim noted. This includes patients with rheumatoid arthritis and those with giant cell arteritis.
“It was hypothesized that GM-CSF receptor–alpha blockade may reduce infiltration of pathogenic cells into the lung and may suppress inflammation in COVID-19 pneumonia in hyperinflammation,” she explained.
Study details and other outcome results
The study presented by Dr. Pupim was a phase 2/3 double-blind, placebo-controlled trial predominantly conducted in Brazil, the United States, and South Africa, with some participation in Peru and Chile.
Patients were eligible for inclusion if they had had a positive COVID-19 test within 14 days of randomization and had been hospitalized but not ventilated. Evidence of bilateral pneumonia on chest x-ray or CT scan and clinical laboratory evidence indicative of hyperinflammation were also prerequisites for study enrollment.
The ongoing study comprised two cohorts, Dr. Pupim explained: patients who have not been ventilated and those who have recently been ventilated. Dr. Pupim presented the data on the nonventilated cohort, noting that there was a total of 116 patients aged a mean of 57 years.
Patients were randomized to one of three treatment arms: two groups received a single intravenous infusion of mavrilimumab, either 6 mg/kg or 10 mg/kg, and the third group got a placebo.
“Using a time-to-event approach, looking at mechanical ventilation-free survival, mavrilimumab recipients experienced a 65% reduction in the risk of mechanical ventilation or death,” Dr. Pupim said (P = .0175).
“Separation in the Kaplan-Meier curves was evident very early after study drug administration,” she added.
There were trends toward a faster benefit with mavrilimumab than placebo in two other key secondary endpoints: the median time to achieving a two-point clinical improvement (7 vs. 11 days) and the median time to room air (7 vs. 9 days).
Timing of mavrilimumab administration and safety
Study coauthor and chief clinical development officer at Kiniksa, Arian Pano, MD, answered questions on the presentation. When asked about the timing of giving mavrilimumab, he said: “Based on these data it is before they go to ventilation, as soon as you have symptoms of hyperinflammation and a need for oxygen.”
Mavrilimumab is given as a single infusion “and has been well tolerated; virtually no interruptions occurred in this study.”
No serious adverse events related to mavrilimumab were seen, and adverse events, including secondary infections, which are known complications of COVID-19, occurred less frequently in mavrilimumab recipients, compared with placebo.
Dr. Pupim reported that there was a case of tuberculosis in one patient treated with mavrilimumab (10 mg/kg). That case had occurred in an “endemic area for tuberculosis,” and the patient had been screened before entry but only via a sputum sample.
“Prior to these events, the patient received high-dose corticosteroids, a known risk factor for reactivation of TB, and thus the potential additive contribution of mavrilimumab, if any, is uncertain.” Dr. Pupim said.
“Thrombotic events, another known complication of COVID-19, occurred in the placebo arm only,” she added.
Dr. Pano commented that the study has now “seamlessly continued to phase 3. So, basically, we did not stop the study. At the end of phase 2, we just locked the database and collected the data.” Both the 6 mg/kg and 10 mg/kg are being studied, but it’s “very likely [that] 6 mg/kg could be the dose that we may bring forward to the clinic in terms of registration, but that’s at this point in time. We will need to wait for the phase 3 data,” he observed. Those findings will hopefully be available later this year.
Kiniksa funded the study. Dr. Pupim, Dr. Pano, and multiple study coinvestigators are employees of the company.
Dr. Schulze-Koops was not involved in the study and had no specific disclosures. Dr. Conway had no financial disclosures to make in relation to his comments.
FROM EULAR 2021 CONGRESS
Novel study links air pollution to increased risk of rheumatoid arthritis flares
Pollution appears to trigger inflammation
In patients with rheumatoid arthritis, exposure to air pollution is associated with both elevated levels of C-reactive protein (CRP) and increased risk of arthritis flares, according to a novel longitudinal study presented at the annual European Congress of Rheumatology.
The data revealed “a striking association between air pollution and increased CRP levels and risk of an arthritis flare,” reported first author Giovanni Adami, MD, DSc, of the rheumatology unit at the University of Verona (Italy).
The excess risk of elevated CRP and flares began “at very low levels of exposure, even those below commonly used thresholds for risk to human health,” he added.
Study details
Researchers collected data on 888 patients with RA from numerous patient visits in the context of more than 13,000 air pollution records. The CRP levels and RA flares were evaluated in the context of air pollution monitoring that is performed on a daily basis at several sites in the city of Verona where the study was conducted. Verona is an industrial city in northern Italy that has high but variable levels of air pollution based on factory activity and weather conditions.
Patients with RA who provided clinical data for this study were matched by their proximity to specific air pollution monitoring sites. By linking CRP levels and disease activity to air pollution levels over multiple follow-up visits, the design allowed the RA study participants “to serve as their own controls,” Dr. Adami explained.
At each patient visit during the study, CRP levels were measured and disease activity assessed. Patients were considered to have elevated CRP when levels were 5 mg/L or higher. The presence of an RA flare was defined by a 1.2-point increase or more in 28-joint Disease Activity Score using CRP (DAS28-CRP).
Both the CRP level and the presence or absence of a flare were evaluated in relationship to the patient’s specific local air pollution levels in the prior 60 days.
Increased levels of CRP, a surrogate for inflammatory activity, and increased disease activity, were both associated with elevated exposure to air pollutants prior to an office visit. These associations remained statistically significant when evaluated by specific air pollutants such as carbon monoxide (CO), nitrogen oxides (NO2, NO), small particulate matter (PM10; particles ≤ 10 mcm), and ozone (O3).
The relationship between increased exposure to air pollution contaminants and elevated CRP was supported by a dose effect. In the case of PM10, for example, the odds ratio of having elevated CRP was increased by only about 25% (OR, 1.25) when mean levels were 30 mcg/m3 or lower in the period prior to the office visit. This rose incrementally for higher mean levels of PM10, reaching 70% (OR, 1.70) for levels > 50 mcg/m3.
The researchers detected statistically significant differences in mean and area-under-the curve (AUC) values of most air pollutants in the 60 days prior to office visits when patients had a flare versus when disease activity was low. For example, the difference in mean and AUC levels in the period prior to a flare relative to a period with low disease activity was significant for CO (P = .001 for both) and NO and NO2 (P = .003 for both), and O3 (P = .002 and P = .001, respectively). For PM10, P values were .011 and .005, respectively.
“Remarkably, we found that the cumulative exposure to NO2 in the 60 days preceding a flare was approximately 500 mcg/m3 higher than the low disease activity visit, an exposure that equates to approximately 200 passively smoked cigarettes,” Dr. Adami reported.
Trying to confirm causality of association
Dr. Adami’s study is not the first study to link air pollution to risk of RA. Several have suggested that air pollution is a risk factor for developing joint disease, but a recently published study conducted in Kuwait associated greater disease activity with NO2 and another air pollutant, sulfur dioxide (SO2), although not CO, PM10, or O3.
A coauthor of that study, which evaluated pollution in regard to disease activity on DAS score, Adeeba Al-Herz, MD, a rheumatology consultant at Al-Amiri Hospital, Kuwait City, said in an interview, “We proved the correlation between them but not the causality.”
However, she believes that this is an important area of inquiry.
“We are working now on another paper in which we studied a causal relationship between the two, meaning that we are evaluating whether SO2 and NO2 trigger RA activity,” Dr. Al-Herz said. That study is now complete, and the manuscript is being written.
The magnitude of the association in these two studies suggest that there might be a clinical message if causality can be confirmed, according to Dr. Adami. Although there are many reasons to seek to reduce and avoid air pollution, these data suggest risk of a proinflammatory state might be one of them.
Dr. Adami believes that the evidence of an adverse effect on patients with RA is strong.
“In order to reduce the burden of RA, public and environmental health policy makers should aim to diminish gaseous and particulate matter emissions to a larger extent than currently recommended,” he said.
In an interview after his presentation, Dr. Adami suggested that the risk of an inflammatory response and increases in arthritis flares from air pollution is not surprising. Previous studies have linked cigarette smoking to both.
“The mechanisms underlying the development of inflammation are very similar. Indeed, the toxic components contained in cigarette smoking are largely shared with diesel exhaust and fossil fuel combustion,” he said.
Although causality between air pollution and arthritis flares cannot be confirmed in these data, a basis for suspecting a causal relationship is supported by “plenty of in vitro and animal studies,” according to Dr. Adami.
On the basis of these studies, several mechanisms have been postulated.
“As an example, exposure to air pollution can promote the activation of the bronchus-associated lymphoid tissue (BALT), which can trigger the activation of the transcription factor nuclear factor-kappaB,” he said. This, in turn, can “lead to the secretion of proinflammatory cytokines, such as tumor necrosis factor–alpha and interleukin-1.”
Another theory is that posttranslational modification of proteins in the lung, a process called citrullination, “can lead to production of autoantibodies known to have a pathogenic role in RA,” he added.
Proving a causal relationship, however, is difficult.
“We certainly cannot conduct a randomized clinical trial on that and voluntarily expose some patients to pollution. Thus, we need to rely on observational data,” Dr. Adami said.
Of strategies being considered to generate evidence of a causal relationship between pollution and the exacerbation of RA, “we certainly will try to study those patients that move from a highly polluted area to a greener zone and vice versa,” he said. This will allow us “to explore what happens when the exposure to pollution changes dramatically in a short period of time.”
In the meantime, “given what is known to date, I would certainly advise my RA patients to avoid exposure to air pollution,” Dr. Adami said. He acknowledged there is no proof that this will help patients to reduce the risk of flares, but there are already many good reasons to minimize exposure to air pollution.
Dr. Adami and Dr. Al-Herz report no potential conflicts of interest.
Pollution appears to trigger inflammation
Pollution appears to trigger inflammation
In patients with rheumatoid arthritis, exposure to air pollution is associated with both elevated levels of C-reactive protein (CRP) and increased risk of arthritis flares, according to a novel longitudinal study presented at the annual European Congress of Rheumatology.
The data revealed “a striking association between air pollution and increased CRP levels and risk of an arthritis flare,” reported first author Giovanni Adami, MD, DSc, of the rheumatology unit at the University of Verona (Italy).
The excess risk of elevated CRP and flares began “at very low levels of exposure, even those below commonly used thresholds for risk to human health,” he added.
Study details
Researchers collected data on 888 patients with RA from numerous patient visits in the context of more than 13,000 air pollution records. The CRP levels and RA flares were evaluated in the context of air pollution monitoring that is performed on a daily basis at several sites in the city of Verona where the study was conducted. Verona is an industrial city in northern Italy that has high but variable levels of air pollution based on factory activity and weather conditions.
Patients with RA who provided clinical data for this study were matched by their proximity to specific air pollution monitoring sites. By linking CRP levels and disease activity to air pollution levels over multiple follow-up visits, the design allowed the RA study participants “to serve as their own controls,” Dr. Adami explained.
At each patient visit during the study, CRP levels were measured and disease activity assessed. Patients were considered to have elevated CRP when levels were 5 mg/L or higher. The presence of an RA flare was defined by a 1.2-point increase or more in 28-joint Disease Activity Score using CRP (DAS28-CRP).
Both the CRP level and the presence or absence of a flare were evaluated in relationship to the patient’s specific local air pollution levels in the prior 60 days.
Increased levels of CRP, a surrogate for inflammatory activity, and increased disease activity, were both associated with elevated exposure to air pollutants prior to an office visit. These associations remained statistically significant when evaluated by specific air pollutants such as carbon monoxide (CO), nitrogen oxides (NO2, NO), small particulate matter (PM10; particles ≤ 10 mcm), and ozone (O3).
The relationship between increased exposure to air pollution contaminants and elevated CRP was supported by a dose effect. In the case of PM10, for example, the odds ratio of having elevated CRP was increased by only about 25% (OR, 1.25) when mean levels were 30 mcg/m3 or lower in the period prior to the office visit. This rose incrementally for higher mean levels of PM10, reaching 70% (OR, 1.70) for levels > 50 mcg/m3.
The researchers detected statistically significant differences in mean and area-under-the curve (AUC) values of most air pollutants in the 60 days prior to office visits when patients had a flare versus when disease activity was low. For example, the difference in mean and AUC levels in the period prior to a flare relative to a period with low disease activity was significant for CO (P = .001 for both) and NO and NO2 (P = .003 for both), and O3 (P = .002 and P = .001, respectively). For PM10, P values were .011 and .005, respectively.
“Remarkably, we found that the cumulative exposure to NO2 in the 60 days preceding a flare was approximately 500 mcg/m3 higher than the low disease activity visit, an exposure that equates to approximately 200 passively smoked cigarettes,” Dr. Adami reported.
Trying to confirm causality of association
Dr. Adami’s study is not the first study to link air pollution to risk of RA. Several have suggested that air pollution is a risk factor for developing joint disease, but a recently published study conducted in Kuwait associated greater disease activity with NO2 and another air pollutant, sulfur dioxide (SO2), although not CO, PM10, or O3.
A coauthor of that study, which evaluated pollution in regard to disease activity on DAS score, Adeeba Al-Herz, MD, a rheumatology consultant at Al-Amiri Hospital, Kuwait City, said in an interview, “We proved the correlation between them but not the causality.”
However, she believes that this is an important area of inquiry.
“We are working now on another paper in which we studied a causal relationship between the two, meaning that we are evaluating whether SO2 and NO2 trigger RA activity,” Dr. Al-Herz said. That study is now complete, and the manuscript is being written.
The magnitude of the association in these two studies suggest that there might be a clinical message if causality can be confirmed, according to Dr. Adami. Although there are many reasons to seek to reduce and avoid air pollution, these data suggest risk of a proinflammatory state might be one of them.
Dr. Adami believes that the evidence of an adverse effect on patients with RA is strong.
“In order to reduce the burden of RA, public and environmental health policy makers should aim to diminish gaseous and particulate matter emissions to a larger extent than currently recommended,” he said.
In an interview after his presentation, Dr. Adami suggested that the risk of an inflammatory response and increases in arthritis flares from air pollution is not surprising. Previous studies have linked cigarette smoking to both.
“The mechanisms underlying the development of inflammation are very similar. Indeed, the toxic components contained in cigarette smoking are largely shared with diesel exhaust and fossil fuel combustion,” he said.
Although causality between air pollution and arthritis flares cannot be confirmed in these data, a basis for suspecting a causal relationship is supported by “plenty of in vitro and animal studies,” according to Dr. Adami.
On the basis of these studies, several mechanisms have been postulated.
“As an example, exposure to air pollution can promote the activation of the bronchus-associated lymphoid tissue (BALT), which can trigger the activation of the transcription factor nuclear factor-kappaB,” he said. This, in turn, can “lead to the secretion of proinflammatory cytokines, such as tumor necrosis factor–alpha and interleukin-1.”
Another theory is that posttranslational modification of proteins in the lung, a process called citrullination, “can lead to production of autoantibodies known to have a pathogenic role in RA,” he added.
Proving a causal relationship, however, is difficult.
“We certainly cannot conduct a randomized clinical trial on that and voluntarily expose some patients to pollution. Thus, we need to rely on observational data,” Dr. Adami said.
Of strategies being considered to generate evidence of a causal relationship between pollution and the exacerbation of RA, “we certainly will try to study those patients that move from a highly polluted area to a greener zone and vice versa,” he said. This will allow us “to explore what happens when the exposure to pollution changes dramatically in a short period of time.”
In the meantime, “given what is known to date, I would certainly advise my RA patients to avoid exposure to air pollution,” Dr. Adami said. He acknowledged there is no proof that this will help patients to reduce the risk of flares, but there are already many good reasons to minimize exposure to air pollution.
Dr. Adami and Dr. Al-Herz report no potential conflicts of interest.
In patients with rheumatoid arthritis, exposure to air pollution is associated with both elevated levels of C-reactive protein (CRP) and increased risk of arthritis flares, according to a novel longitudinal study presented at the annual European Congress of Rheumatology.
The data revealed “a striking association between air pollution and increased CRP levels and risk of an arthritis flare,” reported first author Giovanni Adami, MD, DSc, of the rheumatology unit at the University of Verona (Italy).
The excess risk of elevated CRP and flares began “at very low levels of exposure, even those below commonly used thresholds for risk to human health,” he added.
Study details
Researchers collected data on 888 patients with RA from numerous patient visits in the context of more than 13,000 air pollution records. The CRP levels and RA flares were evaluated in the context of air pollution monitoring that is performed on a daily basis at several sites in the city of Verona where the study was conducted. Verona is an industrial city in northern Italy that has high but variable levels of air pollution based on factory activity and weather conditions.
Patients with RA who provided clinical data for this study were matched by their proximity to specific air pollution monitoring sites. By linking CRP levels and disease activity to air pollution levels over multiple follow-up visits, the design allowed the RA study participants “to serve as their own controls,” Dr. Adami explained.
At each patient visit during the study, CRP levels were measured and disease activity assessed. Patients were considered to have elevated CRP when levels were 5 mg/L or higher. The presence of an RA flare was defined by a 1.2-point increase or more in 28-joint Disease Activity Score using CRP (DAS28-CRP).
Both the CRP level and the presence or absence of a flare were evaluated in relationship to the patient’s specific local air pollution levels in the prior 60 days.
Increased levels of CRP, a surrogate for inflammatory activity, and increased disease activity, were both associated with elevated exposure to air pollutants prior to an office visit. These associations remained statistically significant when evaluated by specific air pollutants such as carbon monoxide (CO), nitrogen oxides (NO2, NO), small particulate matter (PM10; particles ≤ 10 mcm), and ozone (O3).
The relationship between increased exposure to air pollution contaminants and elevated CRP was supported by a dose effect. In the case of PM10, for example, the odds ratio of having elevated CRP was increased by only about 25% (OR, 1.25) when mean levels were 30 mcg/m3 or lower in the period prior to the office visit. This rose incrementally for higher mean levels of PM10, reaching 70% (OR, 1.70) for levels > 50 mcg/m3.
The researchers detected statistically significant differences in mean and area-under-the curve (AUC) values of most air pollutants in the 60 days prior to office visits when patients had a flare versus when disease activity was low. For example, the difference in mean and AUC levels in the period prior to a flare relative to a period with low disease activity was significant for CO (P = .001 for both) and NO and NO2 (P = .003 for both), and O3 (P = .002 and P = .001, respectively). For PM10, P values were .011 and .005, respectively.
“Remarkably, we found that the cumulative exposure to NO2 in the 60 days preceding a flare was approximately 500 mcg/m3 higher than the low disease activity visit, an exposure that equates to approximately 200 passively smoked cigarettes,” Dr. Adami reported.
Trying to confirm causality of association
Dr. Adami’s study is not the first study to link air pollution to risk of RA. Several have suggested that air pollution is a risk factor for developing joint disease, but a recently published study conducted in Kuwait associated greater disease activity with NO2 and another air pollutant, sulfur dioxide (SO2), although not CO, PM10, or O3.
A coauthor of that study, which evaluated pollution in regard to disease activity on DAS score, Adeeba Al-Herz, MD, a rheumatology consultant at Al-Amiri Hospital, Kuwait City, said in an interview, “We proved the correlation between them but not the causality.”
However, she believes that this is an important area of inquiry.
“We are working now on another paper in which we studied a causal relationship between the two, meaning that we are evaluating whether SO2 and NO2 trigger RA activity,” Dr. Al-Herz said. That study is now complete, and the manuscript is being written.
The magnitude of the association in these two studies suggest that there might be a clinical message if causality can be confirmed, according to Dr. Adami. Although there are many reasons to seek to reduce and avoid air pollution, these data suggest risk of a proinflammatory state might be one of them.
Dr. Adami believes that the evidence of an adverse effect on patients with RA is strong.
“In order to reduce the burden of RA, public and environmental health policy makers should aim to diminish gaseous and particulate matter emissions to a larger extent than currently recommended,” he said.
In an interview after his presentation, Dr. Adami suggested that the risk of an inflammatory response and increases in arthritis flares from air pollution is not surprising. Previous studies have linked cigarette smoking to both.
“The mechanisms underlying the development of inflammation are very similar. Indeed, the toxic components contained in cigarette smoking are largely shared with diesel exhaust and fossil fuel combustion,” he said.
Although causality between air pollution and arthritis flares cannot be confirmed in these data, a basis for suspecting a causal relationship is supported by “plenty of in vitro and animal studies,” according to Dr. Adami.
On the basis of these studies, several mechanisms have been postulated.
“As an example, exposure to air pollution can promote the activation of the bronchus-associated lymphoid tissue (BALT), which can trigger the activation of the transcription factor nuclear factor-kappaB,” he said. This, in turn, can “lead to the secretion of proinflammatory cytokines, such as tumor necrosis factor–alpha and interleukin-1.”
Another theory is that posttranslational modification of proteins in the lung, a process called citrullination, “can lead to production of autoantibodies known to have a pathogenic role in RA,” he added.
Proving a causal relationship, however, is difficult.
“We certainly cannot conduct a randomized clinical trial on that and voluntarily expose some patients to pollution. Thus, we need to rely on observational data,” Dr. Adami said.
Of strategies being considered to generate evidence of a causal relationship between pollution and the exacerbation of RA, “we certainly will try to study those patients that move from a highly polluted area to a greener zone and vice versa,” he said. This will allow us “to explore what happens when the exposure to pollution changes dramatically in a short period of time.”
In the meantime, “given what is known to date, I would certainly advise my RA patients to avoid exposure to air pollution,” Dr. Adami said. He acknowledged there is no proof that this will help patients to reduce the risk of flares, but there are already many good reasons to minimize exposure to air pollution.
Dr. Adami and Dr. Al-Herz report no potential conflicts of interest.
FROM THE EULAR 2021 CONGRESS
Patients with RA on rituximab at risk for worse COVID-19 outcomes
Patients with rheumatoid arthritis who were using rituximab at the time of COVID-19 onset had a fourfold higher risk of being hospitalized, needing mechanical ventilation, or dying, compared with patients taking a tumor necrosis factor inhibitor (TNFi), according to a report given at the annual European Congress of Rheumatology.
The use of Janus kinase inhibitors (JAKi) also was associated with a twofold higher risk for these COVID-19 outcomes, said Jeffrey A. Sparks, MD, of Brigham and Women’s Hospital and Harvard Medical School, Boston, in presenting the analysis from the COVID-19 Global Rheumatology Alliance (GRA) Physician Registry.
“The strong association of rituximab and JAK inhibitor use with poor COVID-19 outcomes highlights the prioritization of risk mitigation strategies for these patients,” Dr. Sparks said at the meeting.
The full findings have now been published in Annals of the Rheumatic Diseases.
JAKi association questioned
These findings provide “an important understanding for the risk of our patients in times before vaccination,” said Hendrik Schulze-Koops, MD, of Ludwig Maximilian University of Munich, who chaired the session in which the study was presented.
However, “recently, baricitinib was licensed to prevent particular aspects of severe COVID. What’s the explanation for this discrepancy?” he asked.
“Certainly, the JAK inhibitor finding deserves further study,” Dr. Sparks acknowledged, adding that the data were analyzed by class rather than for individual drugs.
“One possible explanation could be when JAK inhibitors are used,” he suggested. “It might be different for patients who [have been] just infected – that might have different biologic effects – as opposed to choosing to treat patients right when there’s a hyperinflammatory cascade, or there’s oxygen need.”
Regarding the JAK inhibitor finding, Ronald van Vollenhoven, MD, PhD, of the University of Amsterdam, pointed out during the online Q&A that “JAKi have a very short half-life compared to biologics.”
Dr. van Vollenhoven asked: “Could the practice of stopping these drugs upon COVID infection have a negative impact on the course?” To which Dr. Sparks responded: “The different half-life of drugs would be a promising avenue to look at, to see whether increases in disease activity might have imparted some of the effects we saw.”
Performing the analysis
As of April 12, 2021, the GRA Physician Registry contained the records of more than 15,000 patients. Dr. Sparks, collaborator Zachary Wallace, MD, of Massachusetts General Hospital, Boston, and associates limited their analysis to 2,869 patients with RA who had been treated with either a biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD) at the time they were diagnosed with COVID-19.
“We wanted to limit it to a single disease and also limit it to drugs that are considered for that disease,” Dr. Sparks explained in an interview.
“Because patients with rheumatoid arthritis are often treated sequentially, we wanted to further limit the analysis to patients who were on advanced therapies so that they were at a similar disease state, and also had the opportunity to receive advanced therapies.”
This approach hopefully minimizes the possibility of confounding by indication, Dr. Sparks said.
Most of the patients included in the analysis had received a TNFi (n = 1,388), and they were used as the control arm of the analysis. Outcomes associated with treatment with the other b/tsDMARDs, which included abatacept (n = 237), rituximab (n = 364), interleukin-6 inhibitors (IL-6i; n = 317), and JAKi (n = 563), were then compared with TNFi.
Baseline characteristics of patients were broadly similar across the groups. The mean age was 56.7 years and 80.8% of the study population was female. There were a few expected differences among users of rituximab versus TNFi, notably a higher percentage of patients with interstitial lung disease (11% vs. 1.4% of TNFi users) or cancer (7.4% vs. 0.9%) among patients treated with rituximab since it is commonly used in these patients, Dr. Sparks said.
“We did perform a sensitivity analysis where we restricted the population to not having ILD or cancer and we actually found really similar findings,” he added.
Four COVID-19 outcomes assessed
The researchers used a four-point ordinal scale modeled after one set by the World Health Organization to assess four COVID-19 outcomes: not hospitalized, hospitalized without oxygenation, hospitalized with oxygenation or ventilation, and death.
Odds ratios (ORs) comparing rituximab to TNFi for these four COVID-19 outcomes were a respective 4.53, 2.87, 4.05, and 4.57. The ORs for JAKi versus TNFi were a respective 2.4, 1.55, 2.03, and 2.04.
“We found no consistent associations of abatacept or interleukin-6 inhibitors with COVID-19 severity, compared to TNF inhibitors,” which is reassuring, Dr. Sparks said.
ORs for the four COVID-19 outcomes with abatacept were a respective 1.18, 1.12, 1.41, and 1.46, and for IL-6i were 0.84, 0.72, 0.75, and 1.13.
Rituximab use in patients with RA who develop COVID-19
So, should rituximab be stopped in patients with RA if they develop COVID-19? “This is an important question and one that would be decided on a case-by-case basis,” Dr. Sparks said. “Of course, the drug has a very long half-life, so risk mitigation strategies are still of utmost importance,” he added.
“I think everyone’s a bit reticent to want to start rituximab in this environment, but it might also make me pause about starting a JAK inhibitor,” Dr. Sparks added. “Given that this is a first finding, I’m not sure I would necessarily change patients who are doing well on these medications. I think what it really makes me want to do is to try to obviously vaccinate the patients on JAK inhibitors as they do have a short half-life.”
More observational studies would be helpful, Dr. Sparks said, adding that “the most pressing need is to try to figure out how to protect our patients with rituximab.”
The COVID-19 Global Rheumatology Alliance Physician Registry is supported by the American College of Rheumatology and the European Alliance of Associations for Rheumatology. Dr. Sparks disclosed serving as a consultant for Bristol Myers Squibb, Gilead, Inova, Optum, and Pfizer for work unrelated to this study. Dr. Wallace disclosed receiving grant support from Bristol Myers Squibb and Principia/Sanofi and serving as a consultant for Viela Bio and Medpace for work unrelated to this study.
Patients with rheumatoid arthritis who were using rituximab at the time of COVID-19 onset had a fourfold higher risk of being hospitalized, needing mechanical ventilation, or dying, compared with patients taking a tumor necrosis factor inhibitor (TNFi), according to a report given at the annual European Congress of Rheumatology.
The use of Janus kinase inhibitors (JAKi) also was associated with a twofold higher risk for these COVID-19 outcomes, said Jeffrey A. Sparks, MD, of Brigham and Women’s Hospital and Harvard Medical School, Boston, in presenting the analysis from the COVID-19 Global Rheumatology Alliance (GRA) Physician Registry.
“The strong association of rituximab and JAK inhibitor use with poor COVID-19 outcomes highlights the prioritization of risk mitigation strategies for these patients,” Dr. Sparks said at the meeting.
The full findings have now been published in Annals of the Rheumatic Diseases.
JAKi association questioned
These findings provide “an important understanding for the risk of our patients in times before vaccination,” said Hendrik Schulze-Koops, MD, of Ludwig Maximilian University of Munich, who chaired the session in which the study was presented.
However, “recently, baricitinib was licensed to prevent particular aspects of severe COVID. What’s the explanation for this discrepancy?” he asked.
“Certainly, the JAK inhibitor finding deserves further study,” Dr. Sparks acknowledged, adding that the data were analyzed by class rather than for individual drugs.
“One possible explanation could be when JAK inhibitors are used,” he suggested. “It might be different for patients who [have been] just infected – that might have different biologic effects – as opposed to choosing to treat patients right when there’s a hyperinflammatory cascade, or there’s oxygen need.”
Regarding the JAK inhibitor finding, Ronald van Vollenhoven, MD, PhD, of the University of Amsterdam, pointed out during the online Q&A that “JAKi have a very short half-life compared to biologics.”
Dr. van Vollenhoven asked: “Could the practice of stopping these drugs upon COVID infection have a negative impact on the course?” To which Dr. Sparks responded: “The different half-life of drugs would be a promising avenue to look at, to see whether increases in disease activity might have imparted some of the effects we saw.”
Performing the analysis
As of April 12, 2021, the GRA Physician Registry contained the records of more than 15,000 patients. Dr. Sparks, collaborator Zachary Wallace, MD, of Massachusetts General Hospital, Boston, and associates limited their analysis to 2,869 patients with RA who had been treated with either a biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD) at the time they were diagnosed with COVID-19.
“We wanted to limit it to a single disease and also limit it to drugs that are considered for that disease,” Dr. Sparks explained in an interview.
“Because patients with rheumatoid arthritis are often treated sequentially, we wanted to further limit the analysis to patients who were on advanced therapies so that they were at a similar disease state, and also had the opportunity to receive advanced therapies.”
This approach hopefully minimizes the possibility of confounding by indication, Dr. Sparks said.
Most of the patients included in the analysis had received a TNFi (n = 1,388), and they were used as the control arm of the analysis. Outcomes associated with treatment with the other b/tsDMARDs, which included abatacept (n = 237), rituximab (n = 364), interleukin-6 inhibitors (IL-6i; n = 317), and JAKi (n = 563), were then compared with TNFi.
Baseline characteristics of patients were broadly similar across the groups. The mean age was 56.7 years and 80.8% of the study population was female. There were a few expected differences among users of rituximab versus TNFi, notably a higher percentage of patients with interstitial lung disease (11% vs. 1.4% of TNFi users) or cancer (7.4% vs. 0.9%) among patients treated with rituximab since it is commonly used in these patients, Dr. Sparks said.
“We did perform a sensitivity analysis where we restricted the population to not having ILD or cancer and we actually found really similar findings,” he added.
Four COVID-19 outcomes assessed
The researchers used a four-point ordinal scale modeled after one set by the World Health Organization to assess four COVID-19 outcomes: not hospitalized, hospitalized without oxygenation, hospitalized with oxygenation or ventilation, and death.
Odds ratios (ORs) comparing rituximab to TNFi for these four COVID-19 outcomes were a respective 4.53, 2.87, 4.05, and 4.57. The ORs for JAKi versus TNFi were a respective 2.4, 1.55, 2.03, and 2.04.
“We found no consistent associations of abatacept or interleukin-6 inhibitors with COVID-19 severity, compared to TNF inhibitors,” which is reassuring, Dr. Sparks said.
ORs for the four COVID-19 outcomes with abatacept were a respective 1.18, 1.12, 1.41, and 1.46, and for IL-6i were 0.84, 0.72, 0.75, and 1.13.
Rituximab use in patients with RA who develop COVID-19
So, should rituximab be stopped in patients with RA if they develop COVID-19? “This is an important question and one that would be decided on a case-by-case basis,” Dr. Sparks said. “Of course, the drug has a very long half-life, so risk mitigation strategies are still of utmost importance,” he added.
“I think everyone’s a bit reticent to want to start rituximab in this environment, but it might also make me pause about starting a JAK inhibitor,” Dr. Sparks added. “Given that this is a first finding, I’m not sure I would necessarily change patients who are doing well on these medications. I think what it really makes me want to do is to try to obviously vaccinate the patients on JAK inhibitors as they do have a short half-life.”
More observational studies would be helpful, Dr. Sparks said, adding that “the most pressing need is to try to figure out how to protect our patients with rituximab.”
The COVID-19 Global Rheumatology Alliance Physician Registry is supported by the American College of Rheumatology and the European Alliance of Associations for Rheumatology. Dr. Sparks disclosed serving as a consultant for Bristol Myers Squibb, Gilead, Inova, Optum, and Pfizer for work unrelated to this study. Dr. Wallace disclosed receiving grant support from Bristol Myers Squibb and Principia/Sanofi and serving as a consultant for Viela Bio and Medpace for work unrelated to this study.
Patients with rheumatoid arthritis who were using rituximab at the time of COVID-19 onset had a fourfold higher risk of being hospitalized, needing mechanical ventilation, or dying, compared with patients taking a tumor necrosis factor inhibitor (TNFi), according to a report given at the annual European Congress of Rheumatology.
The use of Janus kinase inhibitors (JAKi) also was associated with a twofold higher risk for these COVID-19 outcomes, said Jeffrey A. Sparks, MD, of Brigham and Women’s Hospital and Harvard Medical School, Boston, in presenting the analysis from the COVID-19 Global Rheumatology Alliance (GRA) Physician Registry.
“The strong association of rituximab and JAK inhibitor use with poor COVID-19 outcomes highlights the prioritization of risk mitigation strategies for these patients,” Dr. Sparks said at the meeting.
The full findings have now been published in Annals of the Rheumatic Diseases.
JAKi association questioned
These findings provide “an important understanding for the risk of our patients in times before vaccination,” said Hendrik Schulze-Koops, MD, of Ludwig Maximilian University of Munich, who chaired the session in which the study was presented.
However, “recently, baricitinib was licensed to prevent particular aspects of severe COVID. What’s the explanation for this discrepancy?” he asked.
“Certainly, the JAK inhibitor finding deserves further study,” Dr. Sparks acknowledged, adding that the data were analyzed by class rather than for individual drugs.
“One possible explanation could be when JAK inhibitors are used,” he suggested. “It might be different for patients who [have been] just infected – that might have different biologic effects – as opposed to choosing to treat patients right when there’s a hyperinflammatory cascade, or there’s oxygen need.”
Regarding the JAK inhibitor finding, Ronald van Vollenhoven, MD, PhD, of the University of Amsterdam, pointed out during the online Q&A that “JAKi have a very short half-life compared to biologics.”
Dr. van Vollenhoven asked: “Could the practice of stopping these drugs upon COVID infection have a negative impact on the course?” To which Dr. Sparks responded: “The different half-life of drugs would be a promising avenue to look at, to see whether increases in disease activity might have imparted some of the effects we saw.”
Performing the analysis
As of April 12, 2021, the GRA Physician Registry contained the records of more than 15,000 patients. Dr. Sparks, collaborator Zachary Wallace, MD, of Massachusetts General Hospital, Boston, and associates limited their analysis to 2,869 patients with RA who had been treated with either a biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD) at the time they were diagnosed with COVID-19.
“We wanted to limit it to a single disease and also limit it to drugs that are considered for that disease,” Dr. Sparks explained in an interview.
“Because patients with rheumatoid arthritis are often treated sequentially, we wanted to further limit the analysis to patients who were on advanced therapies so that they were at a similar disease state, and also had the opportunity to receive advanced therapies.”
This approach hopefully minimizes the possibility of confounding by indication, Dr. Sparks said.
Most of the patients included in the analysis had received a TNFi (n = 1,388), and they were used as the control arm of the analysis. Outcomes associated with treatment with the other b/tsDMARDs, which included abatacept (n = 237), rituximab (n = 364), interleukin-6 inhibitors (IL-6i; n = 317), and JAKi (n = 563), were then compared with TNFi.
Baseline characteristics of patients were broadly similar across the groups. The mean age was 56.7 years and 80.8% of the study population was female. There were a few expected differences among users of rituximab versus TNFi, notably a higher percentage of patients with interstitial lung disease (11% vs. 1.4% of TNFi users) or cancer (7.4% vs. 0.9%) among patients treated with rituximab since it is commonly used in these patients, Dr. Sparks said.
“We did perform a sensitivity analysis where we restricted the population to not having ILD or cancer and we actually found really similar findings,” he added.
Four COVID-19 outcomes assessed
The researchers used a four-point ordinal scale modeled after one set by the World Health Organization to assess four COVID-19 outcomes: not hospitalized, hospitalized without oxygenation, hospitalized with oxygenation or ventilation, and death.
Odds ratios (ORs) comparing rituximab to TNFi for these four COVID-19 outcomes were a respective 4.53, 2.87, 4.05, and 4.57. The ORs for JAKi versus TNFi were a respective 2.4, 1.55, 2.03, and 2.04.
“We found no consistent associations of abatacept or interleukin-6 inhibitors with COVID-19 severity, compared to TNF inhibitors,” which is reassuring, Dr. Sparks said.
ORs for the four COVID-19 outcomes with abatacept were a respective 1.18, 1.12, 1.41, and 1.46, and for IL-6i were 0.84, 0.72, 0.75, and 1.13.
Rituximab use in patients with RA who develop COVID-19
So, should rituximab be stopped in patients with RA if they develop COVID-19? “This is an important question and one that would be decided on a case-by-case basis,” Dr. Sparks said. “Of course, the drug has a very long half-life, so risk mitigation strategies are still of utmost importance,” he added.
“I think everyone’s a bit reticent to want to start rituximab in this environment, but it might also make me pause about starting a JAK inhibitor,” Dr. Sparks added. “Given that this is a first finding, I’m not sure I would necessarily change patients who are doing well on these medications. I think what it really makes me want to do is to try to obviously vaccinate the patients on JAK inhibitors as they do have a short half-life.”
More observational studies would be helpful, Dr. Sparks said, adding that “the most pressing need is to try to figure out how to protect our patients with rituximab.”
The COVID-19 Global Rheumatology Alliance Physician Registry is supported by the American College of Rheumatology and the European Alliance of Associations for Rheumatology. Dr. Sparks disclosed serving as a consultant for Bristol Myers Squibb, Gilead, Inova, Optum, and Pfizer for work unrelated to this study. Dr. Wallace disclosed receiving grant support from Bristol Myers Squibb and Principia/Sanofi and serving as a consultant for Viela Bio and Medpace for work unrelated to this study.
FROM THE EULAR 2021 CONGRESS
GRAPPA refines recommendations on psoriatic disease treatment
The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) has included more drugs and data and is moving toward a slightly more stepped approach to treating some forms of psoriatic disease in the latest iteration of their recommendations.
“There’s been an explosion over the last few years in terms of the number of medications,” available to treat psoriasis and psoriatic arthritis, Laura C. Coates, MBChB, PhD, said in an interview ahead of presenting the draft recommendations at the annual European Congress of Rheumatology.
“The good thing about having more drugs is you’ve got more choice, but actually it makes these recommendations even more important because it becomes more complicated to choose optimal treatment for individuals,” added Dr. Coates, a senior clinical research fellow at the University of Oxford (England).
“We’ve been waiting for a while now for the new GRAPPA recommendations,” Laure Gossec, MD, PhD, of Sorbonne University and Pitié-Salpêtrière Hospital in Paris, said in a separate interview.
The last version of the guidelines was developed in 2015 and published in 2016, and since then there have been new data on Janus kinase inhibitors and interleukin-23 inhibitors, for example, which have now been incorporated into the updated recommendations alongside the old stalwarts of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and tumor necrosis factor inhibitors.
“I think that we can see some similarities but also differences compared to the previous version of the recommendations,” Dr. Gossec said.
One similarity is that the recommendations retain their modular or domain-oriented approach, keeping the core way that clinicians can use the recommendations based on their patients’ presentations. So, they still cover the management of peripheral arthritis, axial disease, enthesitis, dactylitis, and skin and nail disease individually.
What’s different, however, is that the domain on comorbidities has been split into two to cover general comorbidities and to give more specific guidance on managing inflammatory bowel disease (IBD) and uveitis, “both of which may not ‘strictly speaking’ be treated by rheumatologists or dermatologists, but are manifestations which can appear in psoriatic disease,” Dr. Gossec noted.
IBD and uveitis “are part of the whole spondyloarthritis syndrome and are genetically related,” Dr. Coates said in her interview. “A lot of the drugs have licenses in those particular areas. The evidence is much stronger for which medication you should choose if somebody has psoriatic arthritis and Crohn’s disease or psoriatic arthritis and uveitis,” she noted.
When it comes to the rest of the comorbidities, think “cardiovascular disease, liver disease, infections – all the ‘normal’ comorbidities,” she added, noting “that’s usually where there’s a lot less data” on which drug to use.
New overarching principle and position statements
The goal of the recommendations hasn’t really changed since the first iteration of the guidelines in 2009, Dr. Coates noted in her presentation. They are intended to provide clinicians with recommendations “based on the best available evidence” for the management of patients with psoriatic disease.
To that end, a through process was followed, starting with the setting of PICO (Patient/population/problem; intervention; comparison; outcome) questions followed by systematic literature searches, data extraction, and review that assess the quality of evidence and then grade it accordingly before using it to inform the recommendation statements.
There is a new overarching principle that says: “These recommendations, which include the most current data concerning the optimal assessment of and therapeutic approached to psoriatic arthritis, present contextual considerations to empower shared decision making.”
The other overarching principles remain the same as in the 2015 version, with “minor wording changes particularly around the comorbidities overarching principle,” Dr. Coates said.
Also new are two position statements. “One of them is specifically around biosimilars, because that’s been a big shift since 2015,” Dr. Coates said. “It has basic rules about what evidence there should be, what we should consider when we’re using them, and patient involvement and decision making.”
The second statement covers “similar advice on tapering or discontinuing therapy – what we do when people are doing really well, how we should stop or taper, and which drugs we should choose to stop along with shared decision making with patients.”
GRAPPA intentionally gives clinicians more freedom
While there may be data to show differences in efficacy and side effects between the various drugs cited in the recommendations, “GRAPPA makes the choice to not prioritize one drug over another,” Dr. Gossec said. This decision gives “a lot of freedom then to the physician to make the decision.”
One important change according to Dr. Gossec is that oral “NSAIDs have clearly been put back as first-line treatment, before going on to disease-modifying drugs for most of the musculoskeletal manifestations. She added that for skin manifestations, topical NSAIDs were recommended, but that NSAIDs were more recommended for IBD and uveitis of course.
“I feel that’s a big step towards more of a step-up approach,” Dr. Gossec said. “The old recommendations were not clear that you would precede an NSAID before moving on to a disease-modifying drug. So, I think that makes it a little bit more similar to the 2019 EULAR recommendations.” The use of csDMARDs such as methotrexate has also been “pushed up a notch” in peripheral arthritis, she said.
What’s next?
There are a few fine tunings still to be made before the final recommendations are published. They also have to be discussed at the meeting of the GRAPPA task force, which consists of rheumatologists, dermatologists, and patient representatives.
Besides the recommendations manuscript, there will be individual papers detailing the evidence underpinning the recommendations in each of the eight domains, Dr. Coates noted. Those “will look at relative efficacy in detail,” she said. “There will be a lot more discussion/evidence summary included” to help with drug selection.
“We also plan to have some case studies to illustrate how the recommendations can be used, similar to that included in the 2015 recommendations,” she added.
Paul Studenic, MD, PhD, of the Karolinska Institute in Stockholm and Medical University of Vienna, tweeted that the GRAPPA recommendations showed treatment “needs to be tailored to the patient” taking “comorbidities as well as the heterogeneity of features of the clinical presentation into account.”
He said in an interview: “The third edition of the GRAPPA is a huge collaborative effort.” The new overarching principle put the recommendations in the context of shared decision making and, he added, they emphasize an “integrated management plan taking not only ‘classical’-related manifestations like uveitis into account but [also] a spectrum of comorbidities and reproductive health.”
GRAPPA is a not-for-profit organization and receives funding from multiple pharmaceutical companies. Currently this includes AbbVie, Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Janssen, Eli Lilly, Novartis, Pfizer, UCB, and Sun Pharma with Galapagos and Nordic Bioscience as Innovation Partners. Dr. Coates acknowledged receiving research funding, honoraria, speaker fees or all of these from most of the aforementioned companies.
Dr. Gossec has received research funding or other support from numerous pharmaceutical companies and is a member of GRAPPA and the task force that developed the EULAR guidelines on the pharmacological management of psoriatic arthritis.
Dr. Studenic had nothing to disclose.
The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) has included more drugs and data and is moving toward a slightly more stepped approach to treating some forms of psoriatic disease in the latest iteration of their recommendations.
“There’s been an explosion over the last few years in terms of the number of medications,” available to treat psoriasis and psoriatic arthritis, Laura C. Coates, MBChB, PhD, said in an interview ahead of presenting the draft recommendations at the annual European Congress of Rheumatology.
“The good thing about having more drugs is you’ve got more choice, but actually it makes these recommendations even more important because it becomes more complicated to choose optimal treatment for individuals,” added Dr. Coates, a senior clinical research fellow at the University of Oxford (England).
“We’ve been waiting for a while now for the new GRAPPA recommendations,” Laure Gossec, MD, PhD, of Sorbonne University and Pitié-Salpêtrière Hospital in Paris, said in a separate interview.
The last version of the guidelines was developed in 2015 and published in 2016, and since then there have been new data on Janus kinase inhibitors and interleukin-23 inhibitors, for example, which have now been incorporated into the updated recommendations alongside the old stalwarts of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and tumor necrosis factor inhibitors.
“I think that we can see some similarities but also differences compared to the previous version of the recommendations,” Dr. Gossec said.
One similarity is that the recommendations retain their modular or domain-oriented approach, keeping the core way that clinicians can use the recommendations based on their patients’ presentations. So, they still cover the management of peripheral arthritis, axial disease, enthesitis, dactylitis, and skin and nail disease individually.
What’s different, however, is that the domain on comorbidities has been split into two to cover general comorbidities and to give more specific guidance on managing inflammatory bowel disease (IBD) and uveitis, “both of which may not ‘strictly speaking’ be treated by rheumatologists or dermatologists, but are manifestations which can appear in psoriatic disease,” Dr. Gossec noted.
IBD and uveitis “are part of the whole spondyloarthritis syndrome and are genetically related,” Dr. Coates said in her interview. “A lot of the drugs have licenses in those particular areas. The evidence is much stronger for which medication you should choose if somebody has psoriatic arthritis and Crohn’s disease or psoriatic arthritis and uveitis,” she noted.
When it comes to the rest of the comorbidities, think “cardiovascular disease, liver disease, infections – all the ‘normal’ comorbidities,” she added, noting “that’s usually where there’s a lot less data” on which drug to use.
New overarching principle and position statements
The goal of the recommendations hasn’t really changed since the first iteration of the guidelines in 2009, Dr. Coates noted in her presentation. They are intended to provide clinicians with recommendations “based on the best available evidence” for the management of patients with psoriatic disease.
To that end, a through process was followed, starting with the setting of PICO (Patient/population/problem; intervention; comparison; outcome) questions followed by systematic literature searches, data extraction, and review that assess the quality of evidence and then grade it accordingly before using it to inform the recommendation statements.
There is a new overarching principle that says: “These recommendations, which include the most current data concerning the optimal assessment of and therapeutic approached to psoriatic arthritis, present contextual considerations to empower shared decision making.”
The other overarching principles remain the same as in the 2015 version, with “minor wording changes particularly around the comorbidities overarching principle,” Dr. Coates said.
Also new are two position statements. “One of them is specifically around biosimilars, because that’s been a big shift since 2015,” Dr. Coates said. “It has basic rules about what evidence there should be, what we should consider when we’re using them, and patient involvement and decision making.”
The second statement covers “similar advice on tapering or discontinuing therapy – what we do when people are doing really well, how we should stop or taper, and which drugs we should choose to stop along with shared decision making with patients.”
GRAPPA intentionally gives clinicians more freedom
While there may be data to show differences in efficacy and side effects between the various drugs cited in the recommendations, “GRAPPA makes the choice to not prioritize one drug over another,” Dr. Gossec said. This decision gives “a lot of freedom then to the physician to make the decision.”
One important change according to Dr. Gossec is that oral “NSAIDs have clearly been put back as first-line treatment, before going on to disease-modifying drugs for most of the musculoskeletal manifestations. She added that for skin manifestations, topical NSAIDs were recommended, but that NSAIDs were more recommended for IBD and uveitis of course.
“I feel that’s a big step towards more of a step-up approach,” Dr. Gossec said. “The old recommendations were not clear that you would precede an NSAID before moving on to a disease-modifying drug. So, I think that makes it a little bit more similar to the 2019 EULAR recommendations.” The use of csDMARDs such as methotrexate has also been “pushed up a notch” in peripheral arthritis, she said.
What’s next?
There are a few fine tunings still to be made before the final recommendations are published. They also have to be discussed at the meeting of the GRAPPA task force, which consists of rheumatologists, dermatologists, and patient representatives.
Besides the recommendations manuscript, there will be individual papers detailing the evidence underpinning the recommendations in each of the eight domains, Dr. Coates noted. Those “will look at relative efficacy in detail,” she said. “There will be a lot more discussion/evidence summary included” to help with drug selection.
“We also plan to have some case studies to illustrate how the recommendations can be used, similar to that included in the 2015 recommendations,” she added.
Paul Studenic, MD, PhD, of the Karolinska Institute in Stockholm and Medical University of Vienna, tweeted that the GRAPPA recommendations showed treatment “needs to be tailored to the patient” taking “comorbidities as well as the heterogeneity of features of the clinical presentation into account.”
He said in an interview: “The third edition of the GRAPPA is a huge collaborative effort.” The new overarching principle put the recommendations in the context of shared decision making and, he added, they emphasize an “integrated management plan taking not only ‘classical’-related manifestations like uveitis into account but [also] a spectrum of comorbidities and reproductive health.”
GRAPPA is a not-for-profit organization and receives funding from multiple pharmaceutical companies. Currently this includes AbbVie, Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Janssen, Eli Lilly, Novartis, Pfizer, UCB, and Sun Pharma with Galapagos and Nordic Bioscience as Innovation Partners. Dr. Coates acknowledged receiving research funding, honoraria, speaker fees or all of these from most of the aforementioned companies.
Dr. Gossec has received research funding or other support from numerous pharmaceutical companies and is a member of GRAPPA and the task force that developed the EULAR guidelines on the pharmacological management of psoriatic arthritis.
Dr. Studenic had nothing to disclose.
The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) has included more drugs and data and is moving toward a slightly more stepped approach to treating some forms of psoriatic disease in the latest iteration of their recommendations.
“There’s been an explosion over the last few years in terms of the number of medications,” available to treat psoriasis and psoriatic arthritis, Laura C. Coates, MBChB, PhD, said in an interview ahead of presenting the draft recommendations at the annual European Congress of Rheumatology.
“The good thing about having more drugs is you’ve got more choice, but actually it makes these recommendations even more important because it becomes more complicated to choose optimal treatment for individuals,” added Dr. Coates, a senior clinical research fellow at the University of Oxford (England).
“We’ve been waiting for a while now for the new GRAPPA recommendations,” Laure Gossec, MD, PhD, of Sorbonne University and Pitié-Salpêtrière Hospital in Paris, said in a separate interview.
The last version of the guidelines was developed in 2015 and published in 2016, and since then there have been new data on Janus kinase inhibitors and interleukin-23 inhibitors, for example, which have now been incorporated into the updated recommendations alongside the old stalwarts of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and tumor necrosis factor inhibitors.
“I think that we can see some similarities but also differences compared to the previous version of the recommendations,” Dr. Gossec said.
One similarity is that the recommendations retain their modular or domain-oriented approach, keeping the core way that clinicians can use the recommendations based on their patients’ presentations. So, they still cover the management of peripheral arthritis, axial disease, enthesitis, dactylitis, and skin and nail disease individually.
What’s different, however, is that the domain on comorbidities has been split into two to cover general comorbidities and to give more specific guidance on managing inflammatory bowel disease (IBD) and uveitis, “both of which may not ‘strictly speaking’ be treated by rheumatologists or dermatologists, but are manifestations which can appear in psoriatic disease,” Dr. Gossec noted.
IBD and uveitis “are part of the whole spondyloarthritis syndrome and are genetically related,” Dr. Coates said in her interview. “A lot of the drugs have licenses in those particular areas. The evidence is much stronger for which medication you should choose if somebody has psoriatic arthritis and Crohn’s disease or psoriatic arthritis and uveitis,” she noted.
When it comes to the rest of the comorbidities, think “cardiovascular disease, liver disease, infections – all the ‘normal’ comorbidities,” she added, noting “that’s usually where there’s a lot less data” on which drug to use.
New overarching principle and position statements
The goal of the recommendations hasn’t really changed since the first iteration of the guidelines in 2009, Dr. Coates noted in her presentation. They are intended to provide clinicians with recommendations “based on the best available evidence” for the management of patients with psoriatic disease.
To that end, a through process was followed, starting with the setting of PICO (Patient/population/problem; intervention; comparison; outcome) questions followed by systematic literature searches, data extraction, and review that assess the quality of evidence and then grade it accordingly before using it to inform the recommendation statements.
There is a new overarching principle that says: “These recommendations, which include the most current data concerning the optimal assessment of and therapeutic approached to psoriatic arthritis, present contextual considerations to empower shared decision making.”
The other overarching principles remain the same as in the 2015 version, with “minor wording changes particularly around the comorbidities overarching principle,” Dr. Coates said.
Also new are two position statements. “One of them is specifically around biosimilars, because that’s been a big shift since 2015,” Dr. Coates said. “It has basic rules about what evidence there should be, what we should consider when we’re using them, and patient involvement and decision making.”
The second statement covers “similar advice on tapering or discontinuing therapy – what we do when people are doing really well, how we should stop or taper, and which drugs we should choose to stop along with shared decision making with patients.”
GRAPPA intentionally gives clinicians more freedom
While there may be data to show differences in efficacy and side effects between the various drugs cited in the recommendations, “GRAPPA makes the choice to not prioritize one drug over another,” Dr. Gossec said. This decision gives “a lot of freedom then to the physician to make the decision.”
One important change according to Dr. Gossec is that oral “NSAIDs have clearly been put back as first-line treatment, before going on to disease-modifying drugs for most of the musculoskeletal manifestations. She added that for skin manifestations, topical NSAIDs were recommended, but that NSAIDs were more recommended for IBD and uveitis of course.
“I feel that’s a big step towards more of a step-up approach,” Dr. Gossec said. “The old recommendations were not clear that you would precede an NSAID before moving on to a disease-modifying drug. So, I think that makes it a little bit more similar to the 2019 EULAR recommendations.” The use of csDMARDs such as methotrexate has also been “pushed up a notch” in peripheral arthritis, she said.
What’s next?
There are a few fine tunings still to be made before the final recommendations are published. They also have to be discussed at the meeting of the GRAPPA task force, which consists of rheumatologists, dermatologists, and patient representatives.
Besides the recommendations manuscript, there will be individual papers detailing the evidence underpinning the recommendations in each of the eight domains, Dr. Coates noted. Those “will look at relative efficacy in detail,” she said. “There will be a lot more discussion/evidence summary included” to help with drug selection.
“We also plan to have some case studies to illustrate how the recommendations can be used, similar to that included in the 2015 recommendations,” she added.
Paul Studenic, MD, PhD, of the Karolinska Institute in Stockholm and Medical University of Vienna, tweeted that the GRAPPA recommendations showed treatment “needs to be tailored to the patient” taking “comorbidities as well as the heterogeneity of features of the clinical presentation into account.”
He said in an interview: “The third edition of the GRAPPA is a huge collaborative effort.” The new overarching principle put the recommendations in the context of shared decision making and, he added, they emphasize an “integrated management plan taking not only ‘classical’-related manifestations like uveitis into account but [also] a spectrum of comorbidities and reproductive health.”
GRAPPA is a not-for-profit organization and receives funding from multiple pharmaceutical companies. Currently this includes AbbVie, Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Janssen, Eli Lilly, Novartis, Pfizer, UCB, and Sun Pharma with Galapagos and Nordic Bioscience as Innovation Partners. Dr. Coates acknowledged receiving research funding, honoraria, speaker fees or all of these from most of the aforementioned companies.
Dr. Gossec has received research funding or other support from numerous pharmaceutical companies and is a member of GRAPPA and the task force that developed the EULAR guidelines on the pharmacological management of psoriatic arthritis.
Dr. Studenic had nothing to disclose.
FROM THE EULAR 2021 CONGRESS
Secondhand smoke in childhood and adulthood linked to increased risk of rheumatoid arthritis
Secondhand smoke exposure in both childhood and adulthood is associated with an increased risk of rheumatoid arthritis in women, according to a study presented at the annual European Congress of Rheumatology.
“These results suggest that smoking by-products, whether actively or passively inhaled or absorbed, could generate autoimmunity, at least towards antigens involved in rheumatoid arthritis pathogenesis,” said Yann Nguyen, MD, MPH, of the center for research in epidemiology and population health at the University of Paris-Saclay in Villejuif and of Beaujon Hospital at the University of Paris in Clichy, France.
Previous research has already repeatedly implicated smoking as a risk factor for rheumatoid arthritis positive for anticitrullinated protein antibodies (ACPA), especially in those who have the HLA-DRB1-shared epitope (SE) alleles, Dr. Nguyen explained to attendees. This study looked at whether exposure to others’ smoke had any similar associations.
The researchers relied on the French prospective cohort study known as E3N-EPIC (Etude Epidémiologique auprès de femmes de la Mutuelle Générale de l’Education Nationale), which is designed to examine potential associations between environmental factors and chronic disease. Of the 98,995 healthy French women the longitudinal study has tracked since 1990, this study included 79,806 participants with an average age of 49 years. A total of 698 women developed rheumatoid arthritis during the study an average of 11.7 years after baseline.
Exposure to secondhand smoke, or passive smoking, in childhood was defined as spending several hours a day in a smoky room as a child, based on participants’ self-report. Adult exposure to passive smoking referred to women’s self-report of spending at least 1 hour a day around actively smoking adults. Researchers further stratified participants according to whether they currently smoke, have never smoked, or used to smoke. Additional covariates in the fully adjusted models included body mass index and educational level.
About one in seven of the women (13.5%) reported exposure to childhood passive smoking, and just over half (53.6%) reported passive smoking exposure as adults. Overall, 58.9% of participants had secondhand exposure in adulthood or childhood, and 8.25% had both.
A positive association existed between childhood exposure and rheumatoid arthritis in the unadjusted and adjusted models. In the fully adjusted model, the risk of rheumatoid arthritis was 1.24 times greater overall for those exposed to secondhand smoke in childhood compared with those who had no exposure. The risk was even greater, however, among women who had never smoked (hazard ratio, 1.42), and the association was not statistically significant in women who had ever smoked.
Similarly, risk of rheumatoid arthritis was greater among those women reporting exposure to passive smoking in adulthood in the unadjusted and adjusted models (HR, 1.19 after adjustment). Once again, women who had never smoked had a modestly higher increased risk (HR, 1.27) if they had secondhand smoke exposure in adulthood, but no statistically significant association existed for women who were current or former smokers.
Although research had previously shown the association between active smoking and rheumatoid arthritis, these new findings suggest clinicians need to emphasize to their patients this additional negative effect from smoking.
Dr. Nguyen, Dr. Carmona, and Dr. Schulze-Koops have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Secondhand smoke exposure in both childhood and adulthood is associated with an increased risk of rheumatoid arthritis in women, according to a study presented at the annual European Congress of Rheumatology.
“These results suggest that smoking by-products, whether actively or passively inhaled or absorbed, could generate autoimmunity, at least towards antigens involved in rheumatoid arthritis pathogenesis,” said Yann Nguyen, MD, MPH, of the center for research in epidemiology and population health at the University of Paris-Saclay in Villejuif and of Beaujon Hospital at the University of Paris in Clichy, France.
Previous research has already repeatedly implicated smoking as a risk factor for rheumatoid arthritis positive for anticitrullinated protein antibodies (ACPA), especially in those who have the HLA-DRB1-shared epitope (SE) alleles, Dr. Nguyen explained to attendees. This study looked at whether exposure to others’ smoke had any similar associations.
The researchers relied on the French prospective cohort study known as E3N-EPIC (Etude Epidémiologique auprès de femmes de la Mutuelle Générale de l’Education Nationale), which is designed to examine potential associations between environmental factors and chronic disease. Of the 98,995 healthy French women the longitudinal study has tracked since 1990, this study included 79,806 participants with an average age of 49 years. A total of 698 women developed rheumatoid arthritis during the study an average of 11.7 years after baseline.
Exposure to secondhand smoke, or passive smoking, in childhood was defined as spending several hours a day in a smoky room as a child, based on participants’ self-report. Adult exposure to passive smoking referred to women’s self-report of spending at least 1 hour a day around actively smoking adults. Researchers further stratified participants according to whether they currently smoke, have never smoked, or used to smoke. Additional covariates in the fully adjusted models included body mass index and educational level.
About one in seven of the women (13.5%) reported exposure to childhood passive smoking, and just over half (53.6%) reported passive smoking exposure as adults. Overall, 58.9% of participants had secondhand exposure in adulthood or childhood, and 8.25% had both.
A positive association existed between childhood exposure and rheumatoid arthritis in the unadjusted and adjusted models. In the fully adjusted model, the risk of rheumatoid arthritis was 1.24 times greater overall for those exposed to secondhand smoke in childhood compared with those who had no exposure. The risk was even greater, however, among women who had never smoked (hazard ratio, 1.42), and the association was not statistically significant in women who had ever smoked.
Similarly, risk of rheumatoid arthritis was greater among those women reporting exposure to passive smoking in adulthood in the unadjusted and adjusted models (HR, 1.19 after adjustment). Once again, women who had never smoked had a modestly higher increased risk (HR, 1.27) if they had secondhand smoke exposure in adulthood, but no statistically significant association existed for women who were current or former smokers.
Although research had previously shown the association between active smoking and rheumatoid arthritis, these new findings suggest clinicians need to emphasize to their patients this additional negative effect from smoking.
Dr. Nguyen, Dr. Carmona, and Dr. Schulze-Koops have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Secondhand smoke exposure in both childhood and adulthood is associated with an increased risk of rheumatoid arthritis in women, according to a study presented at the annual European Congress of Rheumatology.
“These results suggest that smoking by-products, whether actively or passively inhaled or absorbed, could generate autoimmunity, at least towards antigens involved in rheumatoid arthritis pathogenesis,” said Yann Nguyen, MD, MPH, of the center for research in epidemiology and population health at the University of Paris-Saclay in Villejuif and of Beaujon Hospital at the University of Paris in Clichy, France.
Previous research has already repeatedly implicated smoking as a risk factor for rheumatoid arthritis positive for anticitrullinated protein antibodies (ACPA), especially in those who have the HLA-DRB1-shared epitope (SE) alleles, Dr. Nguyen explained to attendees. This study looked at whether exposure to others’ smoke had any similar associations.
The researchers relied on the French prospective cohort study known as E3N-EPIC (Etude Epidémiologique auprès de femmes de la Mutuelle Générale de l’Education Nationale), which is designed to examine potential associations between environmental factors and chronic disease. Of the 98,995 healthy French women the longitudinal study has tracked since 1990, this study included 79,806 participants with an average age of 49 years. A total of 698 women developed rheumatoid arthritis during the study an average of 11.7 years after baseline.
Exposure to secondhand smoke, or passive smoking, in childhood was defined as spending several hours a day in a smoky room as a child, based on participants’ self-report. Adult exposure to passive smoking referred to women’s self-report of spending at least 1 hour a day around actively smoking adults. Researchers further stratified participants according to whether they currently smoke, have never smoked, or used to smoke. Additional covariates in the fully adjusted models included body mass index and educational level.
About one in seven of the women (13.5%) reported exposure to childhood passive smoking, and just over half (53.6%) reported passive smoking exposure as adults. Overall, 58.9% of participants had secondhand exposure in adulthood or childhood, and 8.25% had both.
A positive association existed between childhood exposure and rheumatoid arthritis in the unadjusted and adjusted models. In the fully adjusted model, the risk of rheumatoid arthritis was 1.24 times greater overall for those exposed to secondhand smoke in childhood compared with those who had no exposure. The risk was even greater, however, among women who had never smoked (hazard ratio, 1.42), and the association was not statistically significant in women who had ever smoked.
Similarly, risk of rheumatoid arthritis was greater among those women reporting exposure to passive smoking in adulthood in the unadjusted and adjusted models (HR, 1.19 after adjustment). Once again, women who had never smoked had a modestly higher increased risk (HR, 1.27) if they had secondhand smoke exposure in adulthood, but no statistically significant association existed for women who were current or former smokers.
Although research had previously shown the association between active smoking and rheumatoid arthritis, these new findings suggest clinicians need to emphasize to their patients this additional negative effect from smoking.
Dr. Nguyen, Dr. Carmona, and Dr. Schulze-Koops have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM THE EULAR 2021 CONGRESS