TBD Meeting (3521-23)

Milan – Clinical trial and registry data comparisons between patients with rheumatoid arthritis who take Janus kinase inhibitors (JAKi) such as tofacitinib (Xeljanz) and tumor necrosis factor inhibitors (TNFi) continue to contribute to a better understanding of their efficacy and cardiovascular safety profile, based on presentations given at the annual European Congress of Rheumatology.

Tofacitinib vs. TNFi efficacy with or without history of atherosclerotic CVD

The efficacy of tofacitinib appears to be at least as good as TNFi, regardless of the presence of atherosclerotic cardiovascular disease (ASCVD) and baseline cardiovascular risk, according to a post hoc analysis of the ORAL Surveillance study presented by Maya Buch, MD, PhD, of NIHR Manchester Biomedical Research Centre and University of Manchester, England. ORAL Surveillance was a randomized, open-label, postmarketing safety study sponsored by Pfizer. The study enrolled patients aged 50 or older, with one or more additional CV risk factors, and with active disease despite methotrexate treatment. The cohort included patients treated with the tofacitinib at two different doses (5 mg or 10 mg daily) or TNFi.

Given that a prior “post hoc analysis showed differences in the risk of major adverse CV events (MACE) with tofacitinib versus TNFi, depending on the personal history of atherosclerotic cardiovascular disease,” Dr. Buch and coauthors aimed to further characterize the benefit/risk profile of tofacitinib by evaluating its efficacy, compared with TNFi, in patients with a history of ASCVD and baseline CV risk. Out of the 4,362 patients, 640 (14.7%) had a positive history of ASCVD, while 3,722 (85.3%) did not. For the latter group, the 10-year risk of ASCVD was calculated at baseline, which was high (≥ 20%) in 22.5% and intermediate (≥ 7.5% to < 20%) in 39.4%.

The analysis demonstrated that in patients without a history of ASCVD, the odds of achieving either remission (Clinical Disease Activity Index [CDAI] ≤ 2.8) or low disease activity (CDAI ≤ 10) were greater with tofacitinib vs. TNFi. With a history of ASCVD, the likelihood of achieving remission or low disease activity (LDA) was not statistically different between tofacitinib and TNFi. Patients with high or intermediate CV risk scores tended to be more likely to reach remission or LDA with tofacitinib vs. TNFi.

Dr. Buch emphasized that selecting the right therapy for each patient requires careful consideration of potential benefits and risks by the rheumatologist, taking into account individual patient history. “Stratification by baseline risk of CV events may help ensure appropriate and effective use of tofacitinib in patients with RA,” she concluded.

Kim Lauper, MD, of the division of rheumatology at Geneva University Hospitals, who was not involved in the study, commented on the importance of this data: “These findings are important because we currently lack information on how the presence of CV comorbidities can impact the efficacy of RA drugs.”
 

A real-world perspective

MACE occurred at similar rates between JAKi and TNFi, as well as for biologic disease-modifying antirheumatic drugs (bDMARDs) with other modes of action (OMA) vs. TNFi, in the JAK-Pot study, an international collaboration of RA registries, reported Romain Aymon, of Geneva University Hospitals. But a subanalysis of JAK-Pot in patients resembling the population in the ORAL Surveillance trial found that the incidence of MACE was higher in each treatment group, compared with the overall population. However, no significant difference was found between JAKi vs. TNFi and OMA vs. TNFi.

Mr. Aymon said that the analysis is still ongoing, with additional registries being included.

Dr. Lauper, who is the principal investigator of the study presented by Mr. Aymon, noted that “the absence of a difference in MACE risk in the population resembling the ORAL Surveillance study is in contrast with the results from the ORAL Surveillance itself. This may be due to differences in the populations, with the ORAL Surveillance study having a more selected set of patients.”
 

The Dutch perspective

In line with the findings from the JAK-Pot study, a retrospective inception cohort study conducted on a Dutch RA population also revealed no difference in the incidence of cardiovascular events between JAKi starters and bDMARD starters, according to Merel Opdam, MSc, of Sint Maartenskliniek in Ubbergen, the Netherlands, who reported the findings at the meeting. Two subanalyses of the cohort study, funded by Pfizer, also did not show any difference between tofacitinib and baricitinib (Olumiant), compared with DMARDs, or in patients above 65 years of age. The analysis was conducted on 15,191 patients with RA who were initiating treatment with a JAKi or a new bDMARD, selected from IQVIA’s Dutch Real-World Data Longitudinal Prescription database, which covers approximately 63% of outpatient prescriptions in the Netherlands.

“Not all DMARDs have similar effects on cardiovascular outcomes, and observational studies can contribute to understanding the cardiovascular risks associated with JAKi,” Ms. Opdam said.

“Real-world data holds significant importance as it provides insights into a broader spectrum of patients and reflects the actual clinical practice where treatment decisions are tailored to individual patient needs,” commented Anja Strangfeld, MD, PhD, of the German Rheumatism Research Center Berlin, and Charité University Medicine Berlin. She said that registries have a pivotal role in this regard.

Dr. Buch reports serving on a speakers bureau for AbbVie; serving as a consultant to AbbVie, CESAS Medical, Eli Lilly, Galapagos, Gilead, and Pfizer; and receiving grant/research support from Gilead, Pfizer, and UCB. Mr. Aymon and Ms. Opdam report no relevant financial relationships.

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

Milan – Clinical trial and registry data comparisons between patients with rheumatoid arthritis who take Janus kinase inhibitors (JAKi) such as tofacitinib (Xeljanz) and tumor necrosis factor inhibitors (TNFi) continue to contribute to a better understanding of their efficacy and cardiovascular safety profile, based on presentations given at the annual European Congress of Rheumatology.

Tofacitinib vs. TNFi efficacy with or without history of atherosclerotic CVD

The efficacy of tofacitinib appears to be at least as good as TNFi, regardless of the presence of atherosclerotic cardiovascular disease (ASCVD) and baseline cardiovascular risk, according to a post hoc analysis of the ORAL Surveillance study presented by Maya Buch, MD, PhD, of NIHR Manchester Biomedical Research Centre and University of Manchester, England. ORAL Surveillance was a randomized, open-label, postmarketing safety study sponsored by Pfizer. The study enrolled patients aged 50 or older, with one or more additional CV risk factors, and with active disease despite methotrexate treatment. The cohort included patients treated with the tofacitinib at two different doses (5 mg or 10 mg daily) or TNFi.

Given that a prior “post hoc analysis showed differences in the risk of major adverse CV events (MACE) with tofacitinib versus TNFi, depending on the personal history of atherosclerotic cardiovascular disease,” Dr. Buch and coauthors aimed to further characterize the benefit/risk profile of tofacitinib by evaluating its efficacy, compared with TNFi, in patients with a history of ASCVD and baseline CV risk. Out of the 4,362 patients, 640 (14.7%) had a positive history of ASCVD, while 3,722 (85.3%) did not. For the latter group, the 10-year risk of ASCVD was calculated at baseline, which was high (≥ 20%) in 22.5% and intermediate (≥ 7.5% to < 20%) in 39.4%.

The analysis demonstrated that in patients without a history of ASCVD, the odds of achieving either remission (Clinical Disease Activity Index [CDAI] ≤ 2.8) or low disease activity (CDAI ≤ 10) were greater with tofacitinib vs. TNFi. With a history of ASCVD, the likelihood of achieving remission or low disease activity (LDA) was not statistically different between tofacitinib and TNFi. Patients with high or intermediate CV risk scores tended to be more likely to reach remission or LDA with tofacitinib vs. TNFi.

Dr. Buch emphasized that selecting the right therapy for each patient requires careful consideration of potential benefits and risks by the rheumatologist, taking into account individual patient history. “Stratification by baseline risk of CV events may help ensure appropriate and effective use of tofacitinib in patients with RA,” she concluded.

Kim Lauper, MD, of the division of rheumatology at Geneva University Hospitals, who was not involved in the study, commented on the importance of this data: “These findings are important because we currently lack information on how the presence of CV comorbidities can impact the efficacy of RA drugs.”
 

A real-world perspective

MACE occurred at similar rates between JAKi and TNFi, as well as for biologic disease-modifying antirheumatic drugs (bDMARDs) with other modes of action (OMA) vs. TNFi, in the JAK-Pot study, an international collaboration of RA registries, reported Romain Aymon, of Geneva University Hospitals. But a subanalysis of JAK-Pot in patients resembling the population in the ORAL Surveillance trial found that the incidence of MACE was higher in each treatment group, compared with the overall population. However, no significant difference was found between JAKi vs. TNFi and OMA vs. TNFi.

Mr. Aymon said that the analysis is still ongoing, with additional registries being included.

Dr. Lauper, who is the principal investigator of the study presented by Mr. Aymon, noted that “the absence of a difference in MACE risk in the population resembling the ORAL Surveillance study is in contrast with the results from the ORAL Surveillance itself. This may be due to differences in the populations, with the ORAL Surveillance study having a more selected set of patients.”
 

The Dutch perspective

In line with the findings from the JAK-Pot study, a retrospective inception cohort study conducted on a Dutch RA population also revealed no difference in the incidence of cardiovascular events between JAKi starters and bDMARD starters, according to Merel Opdam, MSc, of Sint Maartenskliniek in Ubbergen, the Netherlands, who reported the findings at the meeting. Two subanalyses of the cohort study, funded by Pfizer, also did not show any difference between tofacitinib and baricitinib (Olumiant), compared with DMARDs, or in patients above 65 years of age. The analysis was conducted on 15,191 patients with RA who were initiating treatment with a JAKi or a new bDMARD, selected from IQVIA’s Dutch Real-World Data Longitudinal Prescription database, which covers approximately 63% of outpatient prescriptions in the Netherlands.

“Not all DMARDs have similar effects on cardiovascular outcomes, and observational studies can contribute to understanding the cardiovascular risks associated with JAKi,” Ms. Opdam said.

“Real-world data holds significant importance as it provides insights into a broader spectrum of patients and reflects the actual clinical practice where treatment decisions are tailored to individual patient needs,” commented Anja Strangfeld, MD, PhD, of the German Rheumatism Research Center Berlin, and Charité University Medicine Berlin. She said that registries have a pivotal role in this regard.

Dr. Buch reports serving on a speakers bureau for AbbVie; serving as a consultant to AbbVie, CESAS Medical, Eli Lilly, Galapagos, Gilead, and Pfizer; and receiving grant/research support from Gilead, Pfizer, and UCB. Mr. Aymon and Ms. Opdam report no relevant financial relationships.

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

Milan – Clinical trial and registry data comparisons between patients with rheumatoid arthritis who take Janus kinase inhibitors (JAKi) such as tofacitinib (Xeljanz) and tumor necrosis factor inhibitors (TNFi) continue to contribute to a better understanding of their efficacy and cardiovascular safety profile, based on presentations given at the annual European Congress of Rheumatology.

Tofacitinib vs. TNFi efficacy with or without history of atherosclerotic CVD

The efficacy of tofacitinib appears to be at least as good as TNFi, regardless of the presence of atherosclerotic cardiovascular disease (ASCVD) and baseline cardiovascular risk, according to a post hoc analysis of the ORAL Surveillance study presented by Maya Buch, MD, PhD, of NIHR Manchester Biomedical Research Centre and University of Manchester, England. ORAL Surveillance was a randomized, open-label, postmarketing safety study sponsored by Pfizer. The study enrolled patients aged 50 or older, with one or more additional CV risk factors, and with active disease despite methotrexate treatment. The cohort included patients treated with the tofacitinib at two different doses (5 mg or 10 mg daily) or TNFi.

Given that a prior “post hoc analysis showed differences in the risk of major adverse CV events (MACE) with tofacitinib versus TNFi, depending on the personal history of atherosclerotic cardiovascular disease,” Dr. Buch and coauthors aimed to further characterize the benefit/risk profile of tofacitinib by evaluating its efficacy, compared with TNFi, in patients with a history of ASCVD and baseline CV risk. Out of the 4,362 patients, 640 (14.7%) had a positive history of ASCVD, while 3,722 (85.3%) did not. For the latter group, the 10-year risk of ASCVD was calculated at baseline, which was high (≥ 20%) in 22.5% and intermediate (≥ 7.5% to < 20%) in 39.4%.

The analysis demonstrated that in patients without a history of ASCVD, the odds of achieving either remission (Clinical Disease Activity Index [CDAI] ≤ 2.8) or low disease activity (CDAI ≤ 10) were greater with tofacitinib vs. TNFi. With a history of ASCVD, the likelihood of achieving remission or low disease activity (LDA) was not statistically different between tofacitinib and TNFi. Patients with high or intermediate CV risk scores tended to be more likely to reach remission or LDA with tofacitinib vs. TNFi.

Dr. Buch emphasized that selecting the right therapy for each patient requires careful consideration of potential benefits and risks by the rheumatologist, taking into account individual patient history. “Stratification by baseline risk of CV events may help ensure appropriate and effective use of tofacitinib in patients with RA,” she concluded.

Kim Lauper, MD, of the division of rheumatology at Geneva University Hospitals, who was not involved in the study, commented on the importance of this data: “These findings are important because we currently lack information on how the presence of CV comorbidities can impact the efficacy of RA drugs.”
 

A real-world perspective

MACE occurred at similar rates between JAKi and TNFi, as well as for biologic disease-modifying antirheumatic drugs (bDMARDs) with other modes of action (OMA) vs. TNFi, in the JAK-Pot study, an international collaboration of RA registries, reported Romain Aymon, of Geneva University Hospitals. But a subanalysis of JAK-Pot in patients resembling the population in the ORAL Surveillance trial found that the incidence of MACE was higher in each treatment group, compared with the overall population. However, no significant difference was found between JAKi vs. TNFi and OMA vs. TNFi.

Mr. Aymon said that the analysis is still ongoing, with additional registries being included.

Dr. Lauper, who is the principal investigator of the study presented by Mr. Aymon, noted that “the absence of a difference in MACE risk in the population resembling the ORAL Surveillance study is in contrast with the results from the ORAL Surveillance itself. This may be due to differences in the populations, with the ORAL Surveillance study having a more selected set of patients.”
 

The Dutch perspective

In line with the findings from the JAK-Pot study, a retrospective inception cohort study conducted on a Dutch RA population also revealed no difference in the incidence of cardiovascular events between JAKi starters and bDMARD starters, according to Merel Opdam, MSc, of Sint Maartenskliniek in Ubbergen, the Netherlands, who reported the findings at the meeting. Two subanalyses of the cohort study, funded by Pfizer, also did not show any difference between tofacitinib and baricitinib (Olumiant), compared with DMARDs, or in patients above 65 years of age. The analysis was conducted on 15,191 patients with RA who were initiating treatment with a JAKi or a new bDMARD, selected from IQVIA’s Dutch Real-World Data Longitudinal Prescription database, which covers approximately 63% of outpatient prescriptions in the Netherlands.

“Not all DMARDs have similar effects on cardiovascular outcomes, and observational studies can contribute to understanding the cardiovascular risks associated with JAKi,” Ms. Opdam said.

“Real-world data holds significant importance as it provides insights into a broader spectrum of patients and reflects the actual clinical practice where treatment decisions are tailored to individual patient needs,” commented Anja Strangfeld, MD, PhD, of the German Rheumatism Research Center Berlin, and Charité University Medicine Berlin. She said that registries have a pivotal role in this regard.

Dr. Buch reports serving on a speakers bureau for AbbVie; serving as a consultant to AbbVie, CESAS Medical, Eli Lilly, Galapagos, Gilead, and Pfizer; and receiving grant/research support from Gilead, Pfizer, and UCB. Mr. Aymon and Ms. Opdam report no relevant financial relationships.

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

MILAN – Most people with recent-onset chronic back pain who are referred to a rheumatologist and then diagnosed with definite axial spondyloarthritis (axSpA) maintain that diagnosis over the next 2 years, but for those with residual diagnostic uncertainty for axSpA, particular characteristics may help to identify those who will or will not go on to receive a definite diagnosis, according to presentations given at the annual European Congress of Rheumatology.

Although a rheumatologist’s early axSpA diagnosis is reliable, new research also presented at the meeting reveals that the axSpA clinical phenotype presentation has great heterogeneity around the world, adding to the challenge.

These findings also dovetail with the consensus of an expert panel from the Assessment of SpondyloArthritis international Society (ASAS) that determined early axSpA should be defined by a duration of axial symptoms of less than 2 years, a move that should make research studies of early disease more consistent.
 

Diagnosis at first sight

To help in overcoming the long diagnostic delay typically encountered by patients with axSpA, researchers involved in the longitudinal Spondyloarthritis Caught Early (SPACE) cohort have sought to measure the prevalence of axSpA and the reliability of an early diagnosis in patients with chronic back pain (CBP). SPACE researcher Mary Lucy Marques, MD, a rheumatologist at Coimbra (Portugal) Hospital and University Center, and PhD student at Leiden (the Netherlands) University Medical Center, presented the main results of the study, which included patients younger than 45 years with CBP of unknown origin lasting 3 months to 2 years.

Patients referred to rheumatologists were judged at each visit for the presence or absence of axSpA, and the baseline judgment was reviewed after 2 years to assess its reliability. Baseline diagnostic judgments remained rather stable, and definite axSpA was present in one-third of the patients referred to the rheumatologist (175 out of 555 patients; 32%). After 2 years, the number of patients with definite axSpA diagnosis changed to 165, due to 5% of the definite diagnoses being refuted and 8% gaining a definite axSpA diagnosis. Among the features related to axSpA, the presence (or absence) of imaging-detected sacroiliitis at baseline was the best discriminator for a definite diagnosis at 2 years.

In commenting on these findings, Alexandre Sepriano, MD, PhD, assistant professor of rheumatology, NOVA Medical School, Lisbon, Portugal, who was not involved in the study, said: “These data show that the key is likely the referral of the ‘right patients’ to tertiary care centers. The [ASAS] has developed referral criteria that can be used for this purpose. According to these, patients with chronic low back pain starting before 45 years of age should be referred to a rheumatologist if at least one additional SpA feature is present.

“It should be acknowledged that axSpA is not a disease of males only. In fact, there is a 1:1 ratio between males and females in the full spectrum of the disease. Also, although imaging findings are important, not all patients will have these. Similarly, not all patients with imaging abnormalities will have the disease, and their sole presence without other SpA features does not suffice for diagnosis.”
 

Repeated assessment: Is it worth it?

Despite the positive findings described above, residual diagnostic uncertainty remained for 15% of patients, representing an obstacle to initiating an appropriate treatment. Therefore, it is important to understand whether and how the repeated assessment of axSpA features is of value for a definite diagnosis.

This last question was addressed in a second abstract also presented by Dr. Marques that focused on the yield of repeated assessment in CBP patients with suspected axSpA from the SPACE cohort. The main outcome of the study was the clinical diagnosis of definite axSpA at 2 years. Compared with baseline, at the 2-year evaluation 32 patients changed their diagnosis and were classified as definite axSpA: Sixteen were previously described as uncertain axSpA at baseline, 11 as uncertain no axSpA, and 5 as definite no axSpA.

On average, three axSpA features were present at baseline with one or two adjunctive features found throughout the study that led to the final diagnosis of definite axSpA. These adjunctive features were most commonly response to NSAIDs and sacroiliitis on MRI. Dr. Marques and colleagues concluded that the yield of repeated assessment in this setting was modest for a new diagnosis of definite axSpA. “Usefulness of repeating MRI in terms of diagnostic yield is low but can be considered in HLA-B27+ patients, especially if male,” Dr. Marques said, commenting on the analysis of SpA features in patients who changed their diagnosis to definite axSpA at 2 years.

“The early diagnosis of axial spondyloarthritis remains a challenge,” Dr. Sepriano said in commenting on the second SPACE study. “Probably one of the main reasons is the yet suboptimal awareness of the [full spectrum] of the disease in a primary care setting, in which most patients will first show up to get medical care. It is now well-known that patients do not always have changes in pelvic radiographs and that waiting for these to make a diagnosis of [radiographic] axSpA results in further delay and in missing many patients who will never develop these changes.

“Still, recognizing the clinical picture of early axSpA and differentiating it from other more common causes of chronic back pain (e.g., degenerative spinal disease) can sometimes be difficult. Continuous efforts in raising awareness and in education will likely result in further reducing the diagnostic delay gap and, as such, improve the prognosis of this often-debilitating rheumatic inflammatory disease.”

One epidemiologic size does not fit all

According to data from the International Map of Axial Spondyloarthritis (IMAS), axSpA clinical phenotype presentation shows great heterogeneity around the world. Marco Garrido-Cumbrera, PhD, of the University of Seville in Spain, presented the results of an analysis of an IMAS online survey (2017-2022).

The study, supported by Novartis, aimed at exploring differences in axSpA clinical phenotype presentation in a large sample of unselected patients: a total of 5,557 individuals from 27 countries across five regions. The results showed statistically significant differences among countries in almost all the analyzed characteristics, from age at onset of symptoms (the highest in Latin America) to HLA-B27 positivity frequency (lowest in Latin America and highest in Asia).

Differences also emerged in the presence of a positive family history of the disease (most common in Europe) and of physical and mental comorbidities (common in Africa). The authors also reported treatment data showing that most of the patients had used NSAIDs, and almost half of the patients had ever taken biologic disease-modifying antirheumatic drugs. Data also showed a mean delay in diagnosis of 7 years, with the longest values observed in South Africa and the lowest in Asia.
 

A consensus definition of early AxSpA

Early axSpA for the first time has been defined based on ASAS expert consensus, and the definition was presented at the meeting by Victoria Navarro-Compán, MD, PhD, of La Paz University Hospital, Madrid. An international working group came to a definition based on the symptom duration and taking solely axial symptoms into account. At the end of a five-step process, the group successfully developed the first consensus definition of early axSpA: “patients with diagnosis of axSpA with axial symptoms duration of ≤ 2 years.” Also to be noted are axial symptoms as assessed by a rheumatologist, which should include spinal/buttock pain or morning stiffness.

As reported by the authors, this ASAS definition is based on expert consensus, with the limitation of a lack of scientific evidence to support it, especially with regard to the specific duration of symptoms from the time of disease onset. Nonetheless, ASAS recommends the use of this definition in studies referring to early axSpA.

Dr. Marques reports no relevant financial relationships. Dr. Navarro-Compán reports serving on the speakers bureau for AbbVie, Eli Lilly, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, and UCB; consulting for AbbVie, Eli Lilly, Galapagos, MoonLake, Merck Sharp & Dohme, Novartis, Pfizer, and UCB; and receiving grant/research support from AbbVie and Novartis. Dr. Garrido-Cumbrera reports receiving grant or research support from Novartis.
 

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

MILAN – Most people with recent-onset chronic back pain who are referred to a rheumatologist and then diagnosed with definite axial spondyloarthritis (axSpA) maintain that diagnosis over the next 2 years, but for those with residual diagnostic uncertainty for axSpA, particular characteristics may help to identify those who will or will not go on to receive a definite diagnosis, according to presentations given at the annual European Congress of Rheumatology.

Although a rheumatologist’s early axSpA diagnosis is reliable, new research also presented at the meeting reveals that the axSpA clinical phenotype presentation has great heterogeneity around the world, adding to the challenge.

These findings also dovetail with the consensus of an expert panel from the Assessment of SpondyloArthritis international Society (ASAS) that determined early axSpA should be defined by a duration of axial symptoms of less than 2 years, a move that should make research studies of early disease more consistent.
 

Diagnosis at first sight

To help in overcoming the long diagnostic delay typically encountered by patients with axSpA, researchers involved in the longitudinal Spondyloarthritis Caught Early (SPACE) cohort have sought to measure the prevalence of axSpA and the reliability of an early diagnosis in patients with chronic back pain (CBP). SPACE researcher Mary Lucy Marques, MD, a rheumatologist at Coimbra (Portugal) Hospital and University Center, and PhD student at Leiden (the Netherlands) University Medical Center, presented the main results of the study, which included patients younger than 45 years with CBP of unknown origin lasting 3 months to 2 years.

Patients referred to rheumatologists were judged at each visit for the presence or absence of axSpA, and the baseline judgment was reviewed after 2 years to assess its reliability. Baseline diagnostic judgments remained rather stable, and definite axSpA was present in one-third of the patients referred to the rheumatologist (175 out of 555 patients; 32%). After 2 years, the number of patients with definite axSpA diagnosis changed to 165, due to 5% of the definite diagnoses being refuted and 8% gaining a definite axSpA diagnosis. Among the features related to axSpA, the presence (or absence) of imaging-detected sacroiliitis at baseline was the best discriminator for a definite diagnosis at 2 years.

In commenting on these findings, Alexandre Sepriano, MD, PhD, assistant professor of rheumatology, NOVA Medical School, Lisbon, Portugal, who was not involved in the study, said: “These data show that the key is likely the referral of the ‘right patients’ to tertiary care centers. The [ASAS] has developed referral criteria that can be used for this purpose. According to these, patients with chronic low back pain starting before 45 years of age should be referred to a rheumatologist if at least one additional SpA feature is present.

“It should be acknowledged that axSpA is not a disease of males only. In fact, there is a 1:1 ratio between males and females in the full spectrum of the disease. Also, although imaging findings are important, not all patients will have these. Similarly, not all patients with imaging abnormalities will have the disease, and their sole presence without other SpA features does not suffice for diagnosis.”
 

Repeated assessment: Is it worth it?

Despite the positive findings described above, residual diagnostic uncertainty remained for 15% of patients, representing an obstacle to initiating an appropriate treatment. Therefore, it is important to understand whether and how the repeated assessment of axSpA features is of value for a definite diagnosis.

This last question was addressed in a second abstract also presented by Dr. Marques that focused on the yield of repeated assessment in CBP patients with suspected axSpA from the SPACE cohort. The main outcome of the study was the clinical diagnosis of definite axSpA at 2 years. Compared with baseline, at the 2-year evaluation 32 patients changed their diagnosis and were classified as definite axSpA: Sixteen were previously described as uncertain axSpA at baseline, 11 as uncertain no axSpA, and 5 as definite no axSpA.

On average, three axSpA features were present at baseline with one or two adjunctive features found throughout the study that led to the final diagnosis of definite axSpA. These adjunctive features were most commonly response to NSAIDs and sacroiliitis on MRI. Dr. Marques and colleagues concluded that the yield of repeated assessment in this setting was modest for a new diagnosis of definite axSpA. “Usefulness of repeating MRI in terms of diagnostic yield is low but can be considered in HLA-B27+ patients, especially if male,” Dr. Marques said, commenting on the analysis of SpA features in patients who changed their diagnosis to definite axSpA at 2 years.

“The early diagnosis of axial spondyloarthritis remains a challenge,” Dr. Sepriano said in commenting on the second SPACE study. “Probably one of the main reasons is the yet suboptimal awareness of the [full spectrum] of the disease in a primary care setting, in which most patients will first show up to get medical care. It is now well-known that patients do not always have changes in pelvic radiographs and that waiting for these to make a diagnosis of [radiographic] axSpA results in further delay and in missing many patients who will never develop these changes.

“Still, recognizing the clinical picture of early axSpA and differentiating it from other more common causes of chronic back pain (e.g., degenerative spinal disease) can sometimes be difficult. Continuous efforts in raising awareness and in education will likely result in further reducing the diagnostic delay gap and, as such, improve the prognosis of this often-debilitating rheumatic inflammatory disease.”

One epidemiologic size does not fit all

According to data from the International Map of Axial Spondyloarthritis (IMAS), axSpA clinical phenotype presentation shows great heterogeneity around the world. Marco Garrido-Cumbrera, PhD, of the University of Seville in Spain, presented the results of an analysis of an IMAS online survey (2017-2022).

The study, supported by Novartis, aimed at exploring differences in axSpA clinical phenotype presentation in a large sample of unselected patients: a total of 5,557 individuals from 27 countries across five regions. The results showed statistically significant differences among countries in almost all the analyzed characteristics, from age at onset of symptoms (the highest in Latin America) to HLA-B27 positivity frequency (lowest in Latin America and highest in Asia).

Differences also emerged in the presence of a positive family history of the disease (most common in Europe) and of physical and mental comorbidities (common in Africa). The authors also reported treatment data showing that most of the patients had used NSAIDs, and almost half of the patients had ever taken biologic disease-modifying antirheumatic drugs. Data also showed a mean delay in diagnosis of 7 years, with the longest values observed in South Africa and the lowest in Asia.
 

A consensus definition of early AxSpA

Early axSpA for the first time has been defined based on ASAS expert consensus, and the definition was presented at the meeting by Victoria Navarro-Compán, MD, PhD, of La Paz University Hospital, Madrid. An international working group came to a definition based on the symptom duration and taking solely axial symptoms into account. At the end of a five-step process, the group successfully developed the first consensus definition of early axSpA: “patients with diagnosis of axSpA with axial symptoms duration of ≤ 2 years.” Also to be noted are axial symptoms as assessed by a rheumatologist, which should include spinal/buttock pain or morning stiffness.

As reported by the authors, this ASAS definition is based on expert consensus, with the limitation of a lack of scientific evidence to support it, especially with regard to the specific duration of symptoms from the time of disease onset. Nonetheless, ASAS recommends the use of this definition in studies referring to early axSpA.

Dr. Marques reports no relevant financial relationships. Dr. Navarro-Compán reports serving on the speakers bureau for AbbVie, Eli Lilly, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, and UCB; consulting for AbbVie, Eli Lilly, Galapagos, MoonLake, Merck Sharp & Dohme, Novartis, Pfizer, and UCB; and receiving grant/research support from AbbVie and Novartis. Dr. Garrido-Cumbrera reports receiving grant or research support from Novartis.
 

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

MILAN – Most people with recent-onset chronic back pain who are referred to a rheumatologist and then diagnosed with definite axial spondyloarthritis (axSpA) maintain that diagnosis over the next 2 years, but for those with residual diagnostic uncertainty for axSpA, particular characteristics may help to identify those who will or will not go on to receive a definite diagnosis, according to presentations given at the annual European Congress of Rheumatology.

Although a rheumatologist’s early axSpA diagnosis is reliable, new research also presented at the meeting reveals that the axSpA clinical phenotype presentation has great heterogeneity around the world, adding to the challenge.

These findings also dovetail with the consensus of an expert panel from the Assessment of SpondyloArthritis international Society (ASAS) that determined early axSpA should be defined by a duration of axial symptoms of less than 2 years, a move that should make research studies of early disease more consistent.
 

Diagnosis at first sight

To help in overcoming the long diagnostic delay typically encountered by patients with axSpA, researchers involved in the longitudinal Spondyloarthritis Caught Early (SPACE) cohort have sought to measure the prevalence of axSpA and the reliability of an early diagnosis in patients with chronic back pain (CBP). SPACE researcher Mary Lucy Marques, MD, a rheumatologist at Coimbra (Portugal) Hospital and University Center, and PhD student at Leiden (the Netherlands) University Medical Center, presented the main results of the study, which included patients younger than 45 years with CBP of unknown origin lasting 3 months to 2 years.

Patients referred to rheumatologists were judged at each visit for the presence or absence of axSpA, and the baseline judgment was reviewed after 2 years to assess its reliability. Baseline diagnostic judgments remained rather stable, and definite axSpA was present in one-third of the patients referred to the rheumatologist (175 out of 555 patients; 32%). After 2 years, the number of patients with definite axSpA diagnosis changed to 165, due to 5% of the definite diagnoses being refuted and 8% gaining a definite axSpA diagnosis. Among the features related to axSpA, the presence (or absence) of imaging-detected sacroiliitis at baseline was the best discriminator for a definite diagnosis at 2 years.

In commenting on these findings, Alexandre Sepriano, MD, PhD, assistant professor of rheumatology, NOVA Medical School, Lisbon, Portugal, who was not involved in the study, said: “These data show that the key is likely the referral of the ‘right patients’ to tertiary care centers. The [ASAS] has developed referral criteria that can be used for this purpose. According to these, patients with chronic low back pain starting before 45 years of age should be referred to a rheumatologist if at least one additional SpA feature is present.

“It should be acknowledged that axSpA is not a disease of males only. In fact, there is a 1:1 ratio between males and females in the full spectrum of the disease. Also, although imaging findings are important, not all patients will have these. Similarly, not all patients with imaging abnormalities will have the disease, and their sole presence without other SpA features does not suffice for diagnosis.”
 

Repeated assessment: Is it worth it?

Despite the positive findings described above, residual diagnostic uncertainty remained for 15% of patients, representing an obstacle to initiating an appropriate treatment. Therefore, it is important to understand whether and how the repeated assessment of axSpA features is of value for a definite diagnosis.

This last question was addressed in a second abstract also presented by Dr. Marques that focused on the yield of repeated assessment in CBP patients with suspected axSpA from the SPACE cohort. The main outcome of the study was the clinical diagnosis of definite axSpA at 2 years. Compared with baseline, at the 2-year evaluation 32 patients changed their diagnosis and were classified as definite axSpA: Sixteen were previously described as uncertain axSpA at baseline, 11 as uncertain no axSpA, and 5 as definite no axSpA.

On average, three axSpA features were present at baseline with one or two adjunctive features found throughout the study that led to the final diagnosis of definite axSpA. These adjunctive features were most commonly response to NSAIDs and sacroiliitis on MRI. Dr. Marques and colleagues concluded that the yield of repeated assessment in this setting was modest for a new diagnosis of definite axSpA. “Usefulness of repeating MRI in terms of diagnostic yield is low but can be considered in HLA-B27+ patients, especially if male,” Dr. Marques said, commenting on the analysis of SpA features in patients who changed their diagnosis to definite axSpA at 2 years.

“The early diagnosis of axial spondyloarthritis remains a challenge,” Dr. Sepriano said in commenting on the second SPACE study. “Probably one of the main reasons is the yet suboptimal awareness of the [full spectrum] of the disease in a primary care setting, in which most patients will first show up to get medical care. It is now well-known that patients do not always have changes in pelvic radiographs and that waiting for these to make a diagnosis of [radiographic] axSpA results in further delay and in missing many patients who will never develop these changes.

“Still, recognizing the clinical picture of early axSpA and differentiating it from other more common causes of chronic back pain (e.g., degenerative spinal disease) can sometimes be difficult. Continuous efforts in raising awareness and in education will likely result in further reducing the diagnostic delay gap and, as such, improve the prognosis of this often-debilitating rheumatic inflammatory disease.”

One epidemiologic size does not fit all

According to data from the International Map of Axial Spondyloarthritis (IMAS), axSpA clinical phenotype presentation shows great heterogeneity around the world. Marco Garrido-Cumbrera, PhD, of the University of Seville in Spain, presented the results of an analysis of an IMAS online survey (2017-2022).

The study, supported by Novartis, aimed at exploring differences in axSpA clinical phenotype presentation in a large sample of unselected patients: a total of 5,557 individuals from 27 countries across five regions. The results showed statistically significant differences among countries in almost all the analyzed characteristics, from age at onset of symptoms (the highest in Latin America) to HLA-B27 positivity frequency (lowest in Latin America and highest in Asia).

Differences also emerged in the presence of a positive family history of the disease (most common in Europe) and of physical and mental comorbidities (common in Africa). The authors also reported treatment data showing that most of the patients had used NSAIDs, and almost half of the patients had ever taken biologic disease-modifying antirheumatic drugs. Data also showed a mean delay in diagnosis of 7 years, with the longest values observed in South Africa and the lowest in Asia.
 

A consensus definition of early AxSpA

Early axSpA for the first time has been defined based on ASAS expert consensus, and the definition was presented at the meeting by Victoria Navarro-Compán, MD, PhD, of La Paz University Hospital, Madrid. An international working group came to a definition based on the symptom duration and taking solely axial symptoms into account. At the end of a five-step process, the group successfully developed the first consensus definition of early axSpA: “patients with diagnosis of axSpA with axial symptoms duration of ≤ 2 years.” Also to be noted are axial symptoms as assessed by a rheumatologist, which should include spinal/buttock pain or morning stiffness.

As reported by the authors, this ASAS definition is based on expert consensus, with the limitation of a lack of scientific evidence to support it, especially with regard to the specific duration of symptoms from the time of disease onset. Nonetheless, ASAS recommends the use of this definition in studies referring to early axSpA.

Dr. Marques reports no relevant financial relationships. Dr. Navarro-Compán reports serving on the speakers bureau for AbbVie, Eli Lilly, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, and UCB; consulting for AbbVie, Eli Lilly, Galapagos, MoonLake, Merck Sharp & Dohme, Novartis, Pfizer, and UCB; and receiving grant/research support from AbbVie and Novartis. Dr. Garrido-Cumbrera reports receiving grant or research support from Novartis.
 

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

MILAN – Serum uric acid of less than 6 mg/dL was achieved and maintained for a substantial period of time with a once-monthly infusion of SEL-212 in patients with refractory gout, according to results of the two phase 3 DISSOLVE I and II trials.

Both trials met their primary endpoints. In DISSOLVE I – the U.S. study – 56% of patients on SEL-212 at 0.15 mg/kg (high dose) achieved a response, defined as achievement and maintenance of a reduction in serum urate to less than 6 mg/dL for at least 80% of the time during month 6 of treatment. In DISSOLVE II – the global study – 46% of patients on SEL-212 on the 0.15-mg/kg dose achieved response.

In participants aged 50 years or older, there was a statistically significant higher response rate at the high dose of SEL-212 in both DISSOLVE I and II of 65% and 47%, respectively, compared with placebo.

Herbert S.B. Baraf, MD, clinical professor of medicine at George Washington University, Washington, and principal investigator of the DISSOLVE program, presented results of the two phase 3 trials during a late-breaking session at the annual European Congress of Rheumatology.

Arthritis Foundation

“The top-line data from the two SEL-212 phase 3 studies are encouraging. They show that induction of immunotolerance with an infusion of a rapamycin-containing nanoparticle (SEL-110), followed immediately by an infusion of pegadricase, a potent but immunogenic uricase, allows for a strong and sustained uric acid–lowering effect without the development of anti-drug antibodies,” Dr. Baraf said in an interview.

SEL-212 is a monthly two-part infusion therapy – a combination of Selecta Biosciences’s ImmTOR immune tolerance platform, and a therapeutic uricase enzyme (pegadricase), designed to treat refractory gout. SEL-110 (ImmTOR) is an immune-tolerizing, nanoencapsulated rapamycin administered 30 minutes before pegadricase and inhibits anti-pegadricase antibodies. SEL-37 is a pegylated uricase (pegadricase) that converts uric acid to excretable allantoin.

SEL-212 was originally developed by Selecta. Swedish Orphan Biovitrum (Sobi) licensed SEL-212 from Selecta in June 2020 and is responsible for development, regulatory, and commercial activities in all markets outside of China. Selecta is responsible for ImmTOR manufacturing. The phase 3 program for SEL-212 was run by Selecta and funded by Sobi.

It is understood that a biologic license application will be submitted to the Food and Drug Administration, most likely next year, and if approved, “the SEL-212 two-component infusion treatment would provide a monthly alternative to twice-monthly pegloticase, for patients with refractory gout,” Dr. Baraf added.
 

Details of the trials

The two DISSOLVE studies replicate double-blind, placebo-controlled trials in patients with chronic refractory gout. DISSOLVE I was carried out in 112 patients across 29 sites in the United States, and DISSOLVE II tested the two-part treatment in 153 patients across 37 sites in the United States, Russia, Ukraine, Georgia, and Serbia.

Both studies randomized patients 1:1:1 to a high dose (SEL-110 of 0.15 mg/kg plus SEL-037 of 0.2 mg/kg), low dose (SEL-110 of 0.1 mg/kg plus SEL-037 of 0.2 mg/kg), or placebo (saline) infused every 28 days for 6 months. Prophylaxis against infusion reactions and gout flares were given to all participants.

Adult patients had a 10- to 14-year history of symptomatic gout, with three or more flares over the 18 months prior to screening, or one or more tophus, or a diagnosis of gouty arthritis. They were also required to have chronic refractory gout with a failure to normalize serum uric acid with any xanthine oxidase inhibitor (for example, allopurinol) and to have not been previously exposed to uricase-based therapy. Serum uric acid had to be at least 7 mg/dL. Participants were balanced for age, body mass index, and sex across treatment groups. Gout severity was greater in DISSOLVE II, Dr. Baraf reported.

Both studies treated patients for 6 months, but DISSOLVE 1 continued with a 6-month, blinded safety extension. The primary endpoint in both studies was serum urate control during month 6, and secondary endpoints included tender and swollen joint counts, tophus burden, patient-reported outcomes of activity limitation, quality of life, and gout flare incidence.

In DISSOLVE I, patients on SEL-212 had a statistically significant higher response rate during month 6 of 56% with the high dose (P < .0001) and 48% with the low dose (P < .0001), compared with 4% of patients randomized to receive placebo. In DISSOLVE II, participants on SEL-212 had a statistically significant higher response rate during month 6 of 46% with the high dose (P = .0002) and 40% with the low dose (P = .0008), compared with 11% of patients randomized to receive placebo.

“We also saw significant reductions in serum uric acid for all treatment groups, compared with placebo,” Dr. Baraf reported. Mean percentage change was –62.3% and –58.3% in the high- and low-dose groups, respectively, in DISSOLVE I, and –58.1% and –52.2% in DISSOLVE II, respectively.

SEL-212 had a favorable safety profile with adverse events as expected across both doses, including mild to moderate stomatitis (3.4% in the low-dose group and 9.2% in the high-dose group versus 0% in the placebo group), and a greater number of infusion reactions at 24 hours and 1 hour after drug administration in both treatment groups versus placebo. Six patients had treatment-related serious adverse events, including two cases of anaphylaxis and one gout flare in both the high- and low-dose treatment groups. The 6-month extension period in the DISSOLVE I trial showed that the majority (75%) of patients who completed 6 months of SEL-212 treatment as a responder continued to be successfully treated through 12 months with no infusion reactions or safety signals.

“I expect more data will be forthcoming on the important clinical secondary endpoints targeted by SEL-212 therapy,” Dr. Baraf noted.
 

Need control arm taking allopurinol?

Roy Fleischmann, MD, clinical professor of medicine at the University of Texas Southwestern Medical Center and codirector of the Metroplex Clinical Research Center, both in Dallas, commented on the study methods after the presentation. “The major problem with this study is that they say the patients had had insufficient response to allopurinol, and my guess is most had received 100-200 mg of allopurinol but were not titrated up to the maximum tolerated dose,” he said, adding: “they should have had a control arm of patients on allopurinol and titrated to the maximum tolerated dose. So, I don’t know what this is really telling us with respect to allopurinol, which is a relatively cheap drug.”

Dr. Baraf reported consulting with Horizon, Sobi, and Selecta; serving on Horizon’s speakers bureau, and receiving grant/research support from Horizon and Sobi. Dr. Fleischmann reported no financial relationship of relevance to this study.

MILAN – Serum uric acid of less than 6 mg/dL was achieved and maintained for a substantial period of time with a once-monthly infusion of SEL-212 in patients with refractory gout, according to results of the two phase 3 DISSOLVE I and II trials.

Both trials met their primary endpoints. In DISSOLVE I – the U.S. study – 56% of patients on SEL-212 at 0.15 mg/kg (high dose) achieved a response, defined as achievement and maintenance of a reduction in serum urate to less than 6 mg/dL for at least 80% of the time during month 6 of treatment. In DISSOLVE II – the global study – 46% of patients on SEL-212 on the 0.15-mg/kg dose achieved response.

In participants aged 50 years or older, there was a statistically significant higher response rate at the high dose of SEL-212 in both DISSOLVE I and II of 65% and 47%, respectively, compared with placebo.

Herbert S.B. Baraf, MD, clinical professor of medicine at George Washington University, Washington, and principal investigator of the DISSOLVE program, presented results of the two phase 3 trials during a late-breaking session at the annual European Congress of Rheumatology.

Arthritis Foundation

“The top-line data from the two SEL-212 phase 3 studies are encouraging. They show that induction of immunotolerance with an infusion of a rapamycin-containing nanoparticle (SEL-110), followed immediately by an infusion of pegadricase, a potent but immunogenic uricase, allows for a strong and sustained uric acid–lowering effect without the development of anti-drug antibodies,” Dr. Baraf said in an interview.

SEL-212 is a monthly two-part infusion therapy – a combination of Selecta Biosciences’s ImmTOR immune tolerance platform, and a therapeutic uricase enzyme (pegadricase), designed to treat refractory gout. SEL-110 (ImmTOR) is an immune-tolerizing, nanoencapsulated rapamycin administered 30 minutes before pegadricase and inhibits anti-pegadricase antibodies. SEL-37 is a pegylated uricase (pegadricase) that converts uric acid to excretable allantoin.

SEL-212 was originally developed by Selecta. Swedish Orphan Biovitrum (Sobi) licensed SEL-212 from Selecta in June 2020 and is responsible for development, regulatory, and commercial activities in all markets outside of China. Selecta is responsible for ImmTOR manufacturing. The phase 3 program for SEL-212 was run by Selecta and funded by Sobi.

It is understood that a biologic license application will be submitted to the Food and Drug Administration, most likely next year, and if approved, “the SEL-212 two-component infusion treatment would provide a monthly alternative to twice-monthly pegloticase, for patients with refractory gout,” Dr. Baraf added.
 

Details of the trials

The two DISSOLVE studies replicate double-blind, placebo-controlled trials in patients with chronic refractory gout. DISSOLVE I was carried out in 112 patients across 29 sites in the United States, and DISSOLVE II tested the two-part treatment in 153 patients across 37 sites in the United States, Russia, Ukraine, Georgia, and Serbia.

Both studies randomized patients 1:1:1 to a high dose (SEL-110 of 0.15 mg/kg plus SEL-037 of 0.2 mg/kg), low dose (SEL-110 of 0.1 mg/kg plus SEL-037 of 0.2 mg/kg), or placebo (saline) infused every 28 days for 6 months. Prophylaxis against infusion reactions and gout flares were given to all participants.

Adult patients had a 10- to 14-year history of symptomatic gout, with three or more flares over the 18 months prior to screening, or one or more tophus, or a diagnosis of gouty arthritis. They were also required to have chronic refractory gout with a failure to normalize serum uric acid with any xanthine oxidase inhibitor (for example, allopurinol) and to have not been previously exposed to uricase-based therapy. Serum uric acid had to be at least 7 mg/dL. Participants were balanced for age, body mass index, and sex across treatment groups. Gout severity was greater in DISSOLVE II, Dr. Baraf reported.

Both studies treated patients for 6 months, but DISSOLVE 1 continued with a 6-month, blinded safety extension. The primary endpoint in both studies was serum urate control during month 6, and secondary endpoints included tender and swollen joint counts, tophus burden, patient-reported outcomes of activity limitation, quality of life, and gout flare incidence.

In DISSOLVE I, patients on SEL-212 had a statistically significant higher response rate during month 6 of 56% with the high dose (P < .0001) and 48% with the low dose (P < .0001), compared with 4% of patients randomized to receive placebo. In DISSOLVE II, participants on SEL-212 had a statistically significant higher response rate during month 6 of 46% with the high dose (P = .0002) and 40% with the low dose (P = .0008), compared with 11% of patients randomized to receive placebo.

“We also saw significant reductions in serum uric acid for all treatment groups, compared with placebo,” Dr. Baraf reported. Mean percentage change was –62.3% and –58.3% in the high- and low-dose groups, respectively, in DISSOLVE I, and –58.1% and –52.2% in DISSOLVE II, respectively.

SEL-212 had a favorable safety profile with adverse events as expected across both doses, including mild to moderate stomatitis (3.4% in the low-dose group and 9.2% in the high-dose group versus 0% in the placebo group), and a greater number of infusion reactions at 24 hours and 1 hour after drug administration in both treatment groups versus placebo. Six patients had treatment-related serious adverse events, including two cases of anaphylaxis and one gout flare in both the high- and low-dose treatment groups. The 6-month extension period in the DISSOLVE I trial showed that the majority (75%) of patients who completed 6 months of SEL-212 treatment as a responder continued to be successfully treated through 12 months with no infusion reactions or safety signals.

“I expect more data will be forthcoming on the important clinical secondary endpoints targeted by SEL-212 therapy,” Dr. Baraf noted.
 

Need control arm taking allopurinol?

Roy Fleischmann, MD, clinical professor of medicine at the University of Texas Southwestern Medical Center and codirector of the Metroplex Clinical Research Center, both in Dallas, commented on the study methods after the presentation. “The major problem with this study is that they say the patients had had insufficient response to allopurinol, and my guess is most had received 100-200 mg of allopurinol but were not titrated up to the maximum tolerated dose,” he said, adding: “they should have had a control arm of patients on allopurinol and titrated to the maximum tolerated dose. So, I don’t know what this is really telling us with respect to allopurinol, which is a relatively cheap drug.”

Dr. Baraf reported consulting with Horizon, Sobi, and Selecta; serving on Horizon’s speakers bureau, and receiving grant/research support from Horizon and Sobi. Dr. Fleischmann reported no financial relationship of relevance to this study.

MILAN – Serum uric acid of less than 6 mg/dL was achieved and maintained for a substantial period of time with a once-monthly infusion of SEL-212 in patients with refractory gout, according to results of the two phase 3 DISSOLVE I and II trials.

Both trials met their primary endpoints. In DISSOLVE I – the U.S. study – 56% of patients on SEL-212 at 0.15 mg/kg (high dose) achieved a response, defined as achievement and maintenance of a reduction in serum urate to less than 6 mg/dL for at least 80% of the time during month 6 of treatment. In DISSOLVE II – the global study – 46% of patients on SEL-212 on the 0.15-mg/kg dose achieved response.

In participants aged 50 years or older, there was a statistically significant higher response rate at the high dose of SEL-212 in both DISSOLVE I and II of 65% and 47%, respectively, compared with placebo.

Herbert S.B. Baraf, MD, clinical professor of medicine at George Washington University, Washington, and principal investigator of the DISSOLVE program, presented results of the two phase 3 trials during a late-breaking session at the annual European Congress of Rheumatology.

Arthritis Foundation

“The top-line data from the two SEL-212 phase 3 studies are encouraging. They show that induction of immunotolerance with an infusion of a rapamycin-containing nanoparticle (SEL-110), followed immediately by an infusion of pegadricase, a potent but immunogenic uricase, allows for a strong and sustained uric acid–lowering effect without the development of anti-drug antibodies,” Dr. Baraf said in an interview.

SEL-212 is a monthly two-part infusion therapy – a combination of Selecta Biosciences’s ImmTOR immune tolerance platform, and a therapeutic uricase enzyme (pegadricase), designed to treat refractory gout. SEL-110 (ImmTOR) is an immune-tolerizing, nanoencapsulated rapamycin administered 30 minutes before pegadricase and inhibits anti-pegadricase antibodies. SEL-37 is a pegylated uricase (pegadricase) that converts uric acid to excretable allantoin.

SEL-212 was originally developed by Selecta. Swedish Orphan Biovitrum (Sobi) licensed SEL-212 from Selecta in June 2020 and is responsible for development, regulatory, and commercial activities in all markets outside of China. Selecta is responsible for ImmTOR manufacturing. The phase 3 program for SEL-212 was run by Selecta and funded by Sobi.

It is understood that a biologic license application will be submitted to the Food and Drug Administration, most likely next year, and if approved, “the SEL-212 two-component infusion treatment would provide a monthly alternative to twice-monthly pegloticase, for patients with refractory gout,” Dr. Baraf added.
 

Details of the trials

The two DISSOLVE studies replicate double-blind, placebo-controlled trials in patients with chronic refractory gout. DISSOLVE I was carried out in 112 patients across 29 sites in the United States, and DISSOLVE II tested the two-part treatment in 153 patients across 37 sites in the United States, Russia, Ukraine, Georgia, and Serbia.

Both studies randomized patients 1:1:1 to a high dose (SEL-110 of 0.15 mg/kg plus SEL-037 of 0.2 mg/kg), low dose (SEL-110 of 0.1 mg/kg plus SEL-037 of 0.2 mg/kg), or placebo (saline) infused every 28 days for 6 months. Prophylaxis against infusion reactions and gout flares were given to all participants.

Adult patients had a 10- to 14-year history of symptomatic gout, with three or more flares over the 18 months prior to screening, or one or more tophus, or a diagnosis of gouty arthritis. They were also required to have chronic refractory gout with a failure to normalize serum uric acid with any xanthine oxidase inhibitor (for example, allopurinol) and to have not been previously exposed to uricase-based therapy. Serum uric acid had to be at least 7 mg/dL. Participants were balanced for age, body mass index, and sex across treatment groups. Gout severity was greater in DISSOLVE II, Dr. Baraf reported.

Both studies treated patients for 6 months, but DISSOLVE 1 continued with a 6-month, blinded safety extension. The primary endpoint in both studies was serum urate control during month 6, and secondary endpoints included tender and swollen joint counts, tophus burden, patient-reported outcomes of activity limitation, quality of life, and gout flare incidence.

In DISSOLVE I, patients on SEL-212 had a statistically significant higher response rate during month 6 of 56% with the high dose (P < .0001) and 48% with the low dose (P < .0001), compared with 4% of patients randomized to receive placebo. In DISSOLVE II, participants on SEL-212 had a statistically significant higher response rate during month 6 of 46% with the high dose (P = .0002) and 40% with the low dose (P = .0008), compared with 11% of patients randomized to receive placebo.

“We also saw significant reductions in serum uric acid for all treatment groups, compared with placebo,” Dr. Baraf reported. Mean percentage change was –62.3% and –58.3% in the high- and low-dose groups, respectively, in DISSOLVE I, and –58.1% and –52.2% in DISSOLVE II, respectively.

SEL-212 had a favorable safety profile with adverse events as expected across both doses, including mild to moderate stomatitis (3.4% in the low-dose group and 9.2% in the high-dose group versus 0% in the placebo group), and a greater number of infusion reactions at 24 hours and 1 hour after drug administration in both treatment groups versus placebo. Six patients had treatment-related serious adverse events, including two cases of anaphylaxis and one gout flare in both the high- and low-dose treatment groups. The 6-month extension period in the DISSOLVE I trial showed that the majority (75%) of patients who completed 6 months of SEL-212 treatment as a responder continued to be successfully treated through 12 months with no infusion reactions or safety signals.

“I expect more data will be forthcoming on the important clinical secondary endpoints targeted by SEL-212 therapy,” Dr. Baraf noted.
 

Need control arm taking allopurinol?

Roy Fleischmann, MD, clinical professor of medicine at the University of Texas Southwestern Medical Center and codirector of the Metroplex Clinical Research Center, both in Dallas, commented on the study methods after the presentation. “The major problem with this study is that they say the patients had had insufficient response to allopurinol, and my guess is most had received 100-200 mg of allopurinol but were not titrated up to the maximum tolerated dose,” he said, adding: “they should have had a control arm of patients on allopurinol and titrated to the maximum tolerated dose. So, I don’t know what this is really telling us with respect to allopurinol, which is a relatively cheap drug.”

Dr. Baraf reported consulting with Horizon, Sobi, and Selecta; serving on Horizon’s speakers bureau, and receiving grant/research support from Horizon and Sobi. Dr. Fleischmann reported no financial relationship of relevance to this study.

MILAN – Targeted synthetic and biologic therapies are recommended as disease-modifying agents for key fibrotic manifestations of systemic sclerosis for the first time in the 2023 update of European Alliance of Associations for Rheumatology recommendations for the treatment of systemic sclerosis.

Reflecting important advances over the past 8 years, mostly relating to the use of new treatments being made available to patients, the recommendations provide an update on the 2017 recommendations, which relied on evidence published through 2014. Of note, these include the use of immunosuppressive agents, for example, the monoclonal antibody rituximab (Rituxan) for skin and lung fibrosis.

“For the first time, synthetic and targeted treatments are recommended for the treatment of systemic sclerosis–interstitial lung disease, including mycophenolate mofetil [Cellcept], nintedanib [Ofev], rituximab, and tocilizumab [Actemra]. None of these were present in 2017. Mycophenolate mofetil is also recommended for the treatment of skin fibrosis, and this was not present in 2017,” Francesco Del Galdo, MD, rheumatology consultant at Leeds Teaching Hospital NHS Trust, Leeds, England, and member of the 2023 recommendations task force, said in an interview. He gave an overview of the preliminary recommendations at the annual European Congress of Rheumatology.

“Phosphodiesterase-5 [PDE-5] inhibitors and endothelin receptor antagonist [ERA] monotherapy are also recommended for up-front combination use for digital ulcers and pulmonary hypertension, and this is new for 2023 and was not present in the 2017 recommendations,” Dr. Del Galdo added.

The new recommendations also note that iloprost is categorized as having grade A evidence for use in Raynaud’s phenomenon and digital ulcers, while it has grade B evidence for pulmonary hypertension.

“We are not allowed to share the final table [of recommendations] today because the wording has only very recently been agreed” upon, Dr. Del Galdo said, but he provided a summary representation and reflected on some changes, noting that the task force is aiming to publish the 2023 recommendations by the end of the year.

Consideration and discussion of both established and new evidence highlighted a need for more evidence on the use of immunosuppressive agents in vascular manifestations of systemic sclerosis, as well as for gastrointestinal and musculoskeletal ones.

In this update to the 2017 recommendations, high-grade evidence was identified for use of immunosuppressants in skin and lung fibrosis. Grade A evidence has been accepted for the use of rituximab in skin fibrosis; for interstitial lung disease, rituximab, cyclophosphamide, and nintedanib also have grade A evidence, which is a change from the 2017 recommendations.

A total of 20 updated recommendations were agreed on, an increase from 16 in 2017. These were grouped into eight disease domains: Raynaud’s phenomenon, digital ulcers, pulmonary arterial hypertension, skin fibrosis, interstitial lung disease, musculoskeletal and gastrointestinal manifestations, and renal crisis. Interventions were then graded A-D based on the evidence reviewed.

“This approach allowed us to see clearly that there were patterns of similar recommendations in different organ manifestations, reflecting an understanding of common pathogenic pathways,” said Dr. Del Galdo.

He also noted that the development of the recommendations highlighted certain gaps in research that limit treatment options. “By grouping the recommendations in blocks – for example, skin fibrosis or vascular [manifestations] – we show that immunosuppressive treatments have only been studied in skin and lung, while vascular manifestations have very little evidence for immunosuppression. They might be effective but there’s no evidence yet [hence no recommendation in vascular manifestations].”

“Also, there’s no grade A evidence at all for musculoskeletal and gastrointestinal manifestations, and this should help to define the research agenda going forward,” Dr. Del Galdo said.

The 2023 recommendations task force comprised 28 members from 14 countries, including 18 rheumatologists, 1 EULAR methodologist, 1 health professional representative, 5 rheumatology fellows, 1 librarian, and 2 patient representatives. They used a consensual approach incorporating the views of 101 European Scleroderma Trials and Research group (EUSTAR) centers, sourced via a survey in which questions were advanced to an extensive systematic review if there was 70% or greater agreement.

Eventually, 31 questions on interventions were chosen, and the task force reviewed 12,500 abstracts (up to December 2022) related to interventions and outcomes that were either included in the 2017 recommendations or were totally new.

Dr. Del Galdo said that the three vascular manifestations of scleroderma – Raynaud’s, pulmonary arterial hypertension, and digital ulcers – were treated with the same drugs, all with a similar grade of evidence. “This suggests two things – firstly there’s a vascular disease continuum in the disease, and secondly, we’ve borrowed these drugs from vascular community, but we have not yet tested synthetic and biologic targeted treatments in these manifestations, and we should.

“Treating one manifestation may benefit the other, and this is important time wise because pulmonary hypertension usually comes around 10 years after the first phenomena so by treating digital ulcers and Raynaud’s phenomena, we may prevent pulmonary hypertension, but a study is needed,” added Dr. Del Galdo, who is also president of EUSTAR.

Finally, he pointed out that research remains particularly open for nonpharmacologic treatments for digital ulcers and severe gastrointestinal involvement. “Patients can now ask for studies into this because of the current lack of evidence.”

Moderator Ariane Herrick, PhD, professor of rheumatology at the University of Manchester (England), shared her thoughts on the guidelines. “These recommendations have been long awaited by the scleroderma community because there has been some exciting progress in recent years, and the new recommendations reflect these new developments.”

Commenting on the paucity of evidence in some areas, she added that “there do remain some huge areas of unmet need that are difficult to address, and these are musculoskeletal, gastrointestinal, and calcinosis, for which there have been no trials at all.”

Dr. Del Galdo declared disclosures relating to AstraZeneca, Janssen, Boehringer Ingelheim, Capella, Chemomab, GlaxoSmithKline, and Mitsubishi-Tanabe. Dr. Herrick disclosed serving as a consultant for Boehringer Ingelheim and Janssen.

MILAN – Targeted synthetic and biologic therapies are recommended as disease-modifying agents for key fibrotic manifestations of systemic sclerosis for the first time in the 2023 update of European Alliance of Associations for Rheumatology recommendations for the treatment of systemic sclerosis.

Reflecting important advances over the past 8 years, mostly relating to the use of new treatments being made available to patients, the recommendations provide an update on the 2017 recommendations, which relied on evidence published through 2014. Of note, these include the use of immunosuppressive agents, for example, the monoclonal antibody rituximab (Rituxan) for skin and lung fibrosis.

“For the first time, synthetic and targeted treatments are recommended for the treatment of systemic sclerosis–interstitial lung disease, including mycophenolate mofetil [Cellcept], nintedanib [Ofev], rituximab, and tocilizumab [Actemra]. None of these were present in 2017. Mycophenolate mofetil is also recommended for the treatment of skin fibrosis, and this was not present in 2017,” Francesco Del Galdo, MD, rheumatology consultant at Leeds Teaching Hospital NHS Trust, Leeds, England, and member of the 2023 recommendations task force, said in an interview. He gave an overview of the preliminary recommendations at the annual European Congress of Rheumatology.

“Phosphodiesterase-5 [PDE-5] inhibitors and endothelin receptor antagonist [ERA] monotherapy are also recommended for up-front combination use for digital ulcers and pulmonary hypertension, and this is new for 2023 and was not present in the 2017 recommendations,” Dr. Del Galdo added.

The new recommendations also note that iloprost is categorized as having grade A evidence for use in Raynaud’s phenomenon and digital ulcers, while it has grade B evidence for pulmonary hypertension.

“We are not allowed to share the final table [of recommendations] today because the wording has only very recently been agreed” upon, Dr. Del Galdo said, but he provided a summary representation and reflected on some changes, noting that the task force is aiming to publish the 2023 recommendations by the end of the year.

Consideration and discussion of both established and new evidence highlighted a need for more evidence on the use of immunosuppressive agents in vascular manifestations of systemic sclerosis, as well as for gastrointestinal and musculoskeletal ones.

In this update to the 2017 recommendations, high-grade evidence was identified for use of immunosuppressants in skin and lung fibrosis. Grade A evidence has been accepted for the use of rituximab in skin fibrosis; for interstitial lung disease, rituximab, cyclophosphamide, and nintedanib also have grade A evidence, which is a change from the 2017 recommendations.

A total of 20 updated recommendations were agreed on, an increase from 16 in 2017. These were grouped into eight disease domains: Raynaud’s phenomenon, digital ulcers, pulmonary arterial hypertension, skin fibrosis, interstitial lung disease, musculoskeletal and gastrointestinal manifestations, and renal crisis. Interventions were then graded A-D based on the evidence reviewed.

“This approach allowed us to see clearly that there were patterns of similar recommendations in different organ manifestations, reflecting an understanding of common pathogenic pathways,” said Dr. Del Galdo.

He also noted that the development of the recommendations highlighted certain gaps in research that limit treatment options. “By grouping the recommendations in blocks – for example, skin fibrosis or vascular [manifestations] – we show that immunosuppressive treatments have only been studied in skin and lung, while vascular manifestations have very little evidence for immunosuppression. They might be effective but there’s no evidence yet [hence no recommendation in vascular manifestations].”

“Also, there’s no grade A evidence at all for musculoskeletal and gastrointestinal manifestations, and this should help to define the research agenda going forward,” Dr. Del Galdo said.

The 2023 recommendations task force comprised 28 members from 14 countries, including 18 rheumatologists, 1 EULAR methodologist, 1 health professional representative, 5 rheumatology fellows, 1 librarian, and 2 patient representatives. They used a consensual approach incorporating the views of 101 European Scleroderma Trials and Research group (EUSTAR) centers, sourced via a survey in which questions were advanced to an extensive systematic review if there was 70% or greater agreement.

Eventually, 31 questions on interventions were chosen, and the task force reviewed 12,500 abstracts (up to December 2022) related to interventions and outcomes that were either included in the 2017 recommendations or were totally new.

Dr. Del Galdo said that the three vascular manifestations of scleroderma – Raynaud’s, pulmonary arterial hypertension, and digital ulcers – were treated with the same drugs, all with a similar grade of evidence. “This suggests two things – firstly there’s a vascular disease continuum in the disease, and secondly, we’ve borrowed these drugs from vascular community, but we have not yet tested synthetic and biologic targeted treatments in these manifestations, and we should.

“Treating one manifestation may benefit the other, and this is important time wise because pulmonary hypertension usually comes around 10 years after the first phenomena so by treating digital ulcers and Raynaud’s phenomena, we may prevent pulmonary hypertension, but a study is needed,” added Dr. Del Galdo, who is also president of EUSTAR.

Finally, he pointed out that research remains particularly open for nonpharmacologic treatments for digital ulcers and severe gastrointestinal involvement. “Patients can now ask for studies into this because of the current lack of evidence.”

Moderator Ariane Herrick, PhD, professor of rheumatology at the University of Manchester (England), shared her thoughts on the guidelines. “These recommendations have been long awaited by the scleroderma community because there has been some exciting progress in recent years, and the new recommendations reflect these new developments.”

Commenting on the paucity of evidence in some areas, she added that “there do remain some huge areas of unmet need that are difficult to address, and these are musculoskeletal, gastrointestinal, and calcinosis, for which there have been no trials at all.”

Dr. Del Galdo declared disclosures relating to AstraZeneca, Janssen, Boehringer Ingelheim, Capella, Chemomab, GlaxoSmithKline, and Mitsubishi-Tanabe. Dr. Herrick disclosed serving as a consultant for Boehringer Ingelheim and Janssen.

MILAN – Targeted synthetic and biologic therapies are recommended as disease-modifying agents for key fibrotic manifestations of systemic sclerosis for the first time in the 2023 update of European Alliance of Associations for Rheumatology recommendations for the treatment of systemic sclerosis.

Reflecting important advances over the past 8 years, mostly relating to the use of new treatments being made available to patients, the recommendations provide an update on the 2017 recommendations, which relied on evidence published through 2014. Of note, these include the use of immunosuppressive agents, for example, the monoclonal antibody rituximab (Rituxan) for skin and lung fibrosis.

“For the first time, synthetic and targeted treatments are recommended for the treatment of systemic sclerosis–interstitial lung disease, including mycophenolate mofetil [Cellcept], nintedanib [Ofev], rituximab, and tocilizumab [Actemra]. None of these were present in 2017. Mycophenolate mofetil is also recommended for the treatment of skin fibrosis, and this was not present in 2017,” Francesco Del Galdo, MD, rheumatology consultant at Leeds Teaching Hospital NHS Trust, Leeds, England, and member of the 2023 recommendations task force, said in an interview. He gave an overview of the preliminary recommendations at the annual European Congress of Rheumatology.

“Phosphodiesterase-5 [PDE-5] inhibitors and endothelin receptor antagonist [ERA] monotherapy are also recommended for up-front combination use for digital ulcers and pulmonary hypertension, and this is new for 2023 and was not present in the 2017 recommendations,” Dr. Del Galdo added.

The new recommendations also note that iloprost is categorized as having grade A evidence for use in Raynaud’s phenomenon and digital ulcers, while it has grade B evidence for pulmonary hypertension.

“We are not allowed to share the final table [of recommendations] today because the wording has only very recently been agreed” upon, Dr. Del Galdo said, but he provided a summary representation and reflected on some changes, noting that the task force is aiming to publish the 2023 recommendations by the end of the year.

Consideration and discussion of both established and new evidence highlighted a need for more evidence on the use of immunosuppressive agents in vascular manifestations of systemic sclerosis, as well as for gastrointestinal and musculoskeletal ones.

In this update to the 2017 recommendations, high-grade evidence was identified for use of immunosuppressants in skin and lung fibrosis. Grade A evidence has been accepted for the use of rituximab in skin fibrosis; for interstitial lung disease, rituximab, cyclophosphamide, and nintedanib also have grade A evidence, which is a change from the 2017 recommendations.

A total of 20 updated recommendations were agreed on, an increase from 16 in 2017. These were grouped into eight disease domains: Raynaud’s phenomenon, digital ulcers, pulmonary arterial hypertension, skin fibrosis, interstitial lung disease, musculoskeletal and gastrointestinal manifestations, and renal crisis. Interventions were then graded A-D based on the evidence reviewed.

“This approach allowed us to see clearly that there were patterns of similar recommendations in different organ manifestations, reflecting an understanding of common pathogenic pathways,” said Dr. Del Galdo.

He also noted that the development of the recommendations highlighted certain gaps in research that limit treatment options. “By grouping the recommendations in blocks – for example, skin fibrosis or vascular [manifestations] – we show that immunosuppressive treatments have only been studied in skin and lung, while vascular manifestations have very little evidence for immunosuppression. They might be effective but there’s no evidence yet [hence no recommendation in vascular manifestations].”

“Also, there’s no grade A evidence at all for musculoskeletal and gastrointestinal manifestations, and this should help to define the research agenda going forward,” Dr. Del Galdo said.

The 2023 recommendations task force comprised 28 members from 14 countries, including 18 rheumatologists, 1 EULAR methodologist, 1 health professional representative, 5 rheumatology fellows, 1 librarian, and 2 patient representatives. They used a consensual approach incorporating the views of 101 European Scleroderma Trials and Research group (EUSTAR) centers, sourced via a survey in which questions were advanced to an extensive systematic review if there was 70% or greater agreement.

Eventually, 31 questions on interventions were chosen, and the task force reviewed 12,500 abstracts (up to December 2022) related to interventions and outcomes that were either included in the 2017 recommendations or were totally new.

Dr. Del Galdo said that the three vascular manifestations of scleroderma – Raynaud’s, pulmonary arterial hypertension, and digital ulcers – were treated with the same drugs, all with a similar grade of evidence. “This suggests two things – firstly there’s a vascular disease continuum in the disease, and secondly, we’ve borrowed these drugs from vascular community, but we have not yet tested synthetic and biologic targeted treatments in these manifestations, and we should.

“Treating one manifestation may benefit the other, and this is important time wise because pulmonary hypertension usually comes around 10 years after the first phenomena so by treating digital ulcers and Raynaud’s phenomena, we may prevent pulmonary hypertension, but a study is needed,” added Dr. Del Galdo, who is also president of EUSTAR.

Finally, he pointed out that research remains particularly open for nonpharmacologic treatments for digital ulcers and severe gastrointestinal involvement. “Patients can now ask for studies into this because of the current lack of evidence.”

Moderator Ariane Herrick, PhD, professor of rheumatology at the University of Manchester (England), shared her thoughts on the guidelines. “These recommendations have been long awaited by the scleroderma community because there has been some exciting progress in recent years, and the new recommendations reflect these new developments.”

Commenting on the paucity of evidence in some areas, she added that “there do remain some huge areas of unmet need that are difficult to address, and these are musculoskeletal, gastrointestinal, and calcinosis, for which there have been no trials at all.”

Dr. Del Galdo declared disclosures relating to AstraZeneca, Janssen, Boehringer Ingelheim, Capella, Chemomab, GlaxoSmithKline, and Mitsubishi-Tanabe. Dr. Herrick disclosed serving as a consultant for Boehringer Ingelheim and Janssen.

MILAN – About 80% of patients with gout who took the investigational selective uric acid transporter 1 (URAT1) inhibitor AR882 over 3 months reduced their serum uric acid levels to below recommended thresholds (below 5 or 4 mg/dL) for better flare and tophi reduction in a phase 2b study.

The drug was well tolerated, and patients with comorbidities did not require any adjustments in disease management.

At 75 mg, the highest tested dose of AR882, 73% of patients had serum uric acid levels < 5 mg/dL and 55% had < 4 mg/dL by week 12 of therapy in the intent-to-treat population, whereas in the per-protocol analysis, 82% had serum uric acid levels < 5 mg/dL and 63% < 4 mg/dL.

Becky McCall/MDedge News

“These efficacy results are not typically what you see with a once-daily oral medication, so it is really exciting,” Robert Keenan, MD, chief medical officer of Arthrosi Therapeutics, San Diego, said in presenting the results at the annual European Congress of Rheumatology.

“Regardless of whether you’re treating subclinical, hidden crystal deposition, versus clinically visible tophi, versus chronic, debilitating gout, we believe that AR882 has the potential to treat the entire gout spectrum with a once-daily monotherapy,” Dr. Keenan asserted.

“Currently, most gout patients around the world do not have a safe, effective, and easy to use alternative to allopurinol or febuxostat, which decrease the production of uric acid,” he said. “AR882 is a URAT1 inhibitor that goes to the root of the problem in over 90% of gout patients, helping the kidneys eliminate uric acid to levels similar to all those without hyperuricemia and gout.”

Abhishek Abhishek, MD, professor of rheumatology at the University of Nottingham (England), welcomed the study. “It’s a promising study and the reduction in uric acid was substantial. It was a small study and a larger phase 3 study is needed, but it does offer real hope for patients with gout as a third treatment option because we only have allopurinol and febuxostat, so if it is shown efficacious and safe and gets approved, then it’ll help more patients with gout.”

Anne-Kathrin Tausche, MD, a rheumatologist from University Clinic Dresden (Germany), said: “These results are really impressive. We’ve lost lesinurad now because Grünenthal no longer produces it, so this might be a good alternative for patients with severe gout.

“It is favorable with [few] side effects. With allopurinol, we have to titrate it in patients with poor renal function, but it doesn’t seem to be the case with this drug. I really hope they start phase 3 soon,” she added.
 

Phase 2 study, but promising results

Results of the global phase 2b, randomized, double-blind trial compared the safety, tolerability, and efficacy of AR882 against placebo in patients with gout.

A total of 140 patients with gout, aged 18-75 years with an estimated glomerular filtration rate (eGFR) > 30 mL/min, were recruited across the United States, Australia, and Taiwan. Patients received either once-daily AR882 50 mg (n = 46) for 12 weeks, AR882 50 mg for 2 weeks and then AR882 75 mg (n = 47) for 10 weeks, or matching placebo for 12 weeks (n = 47). Flare prophylaxis with daily colchicine started 10 days prior to the first dose and continued throughout the study.

“Patient characteristics were typical for gout trials except for having a very diverse population,” he said. The trial included 57.9% White, 27.9% Asian, and 15% Black patients. They had a mean age of 55 years, body mass index 31-32 kg/m². There was a range of comorbidities including hypertension, hyperlipidemia, diabetes, and cardiovascular disease, evenly distributed across placebo and AR882 treatment groups.

The efficacy endpoints were the proportion of patients who reached serum uric acid below 6, 5, 4, and 3 mg/dL, at 6 weeks of therapy, while safety was also monitored throughout the study. Reductions in serum uric acid at weeks 2, 4, 6, 12 were exploratory endpoints.

The primary endpoint of the percentage of patients below < 6 mg/dL at 6 weeks in the intent-to-treat population was met by 66% with AR882 at the lower dose (50 mg) and 84% at the higher dose (75 mg).

With the 50-mg dose, serum uric acid was reduced at week 6 to < 5mg/dL by 41%, < 4mg/dL by 12%, and < 3mg/dL by 2%, whereas these percentages were 68%, 52%, and 23%, respectively, with the 75-mg dose.

Exploratory endpoints showed that by week 12, serum uric acid levels dropped from baseline 8.6 mg/dL to about 5.0 mg/dL with AR882 50 mg and from baseline 8.6 mg/dL to about 3.5 mg/dL with AR882 75 mg. Also at week 12, 55% and 23% reached serum uric acid levels of < 4mg/dL and < 3mg/dL in the intent-to-treat population. No change was observed in the placebo group.

All adverse events were mild to moderate, with the most prevalent being gout flares. There was little difference between doses. There were no clinically significant changes in a total of 778 post-dose measurements of alanine transaminase (ALT) and aspartate transaminase (AST) and 723 post-dose triplicated electrocardiogram (ECG) measurements.

Dr. Keenan is chief medical officer of Arthrosi Therapeutics. Dr. Tausche and Dr. Abhishek have no relevant financial relationships to disclose.

MILAN – About 80% of patients with gout who took the investigational selective uric acid transporter 1 (URAT1) inhibitor AR882 over 3 months reduced their serum uric acid levels to below recommended thresholds (below 5 or 4 mg/dL) for better flare and tophi reduction in a phase 2b study.

The drug was well tolerated, and patients with comorbidities did not require any adjustments in disease management.

At 75 mg, the highest tested dose of AR882, 73% of patients had serum uric acid levels < 5 mg/dL and 55% had < 4 mg/dL by week 12 of therapy in the intent-to-treat population, whereas in the per-protocol analysis, 82% had serum uric acid levels < 5 mg/dL and 63% < 4 mg/dL.

Becky McCall/MDedge News

“These efficacy results are not typically what you see with a once-daily oral medication, so it is really exciting,” Robert Keenan, MD, chief medical officer of Arthrosi Therapeutics, San Diego, said in presenting the results at the annual European Congress of Rheumatology.

“Regardless of whether you’re treating subclinical, hidden crystal deposition, versus clinically visible tophi, versus chronic, debilitating gout, we believe that AR882 has the potential to treat the entire gout spectrum with a once-daily monotherapy,” Dr. Keenan asserted.

“Currently, most gout patients around the world do not have a safe, effective, and easy to use alternative to allopurinol or febuxostat, which decrease the production of uric acid,” he said. “AR882 is a URAT1 inhibitor that goes to the root of the problem in over 90% of gout patients, helping the kidneys eliminate uric acid to levels similar to all those without hyperuricemia and gout.”

Abhishek Abhishek, MD, professor of rheumatology at the University of Nottingham (England), welcomed the study. “It’s a promising study and the reduction in uric acid was substantial. It was a small study and a larger phase 3 study is needed, but it does offer real hope for patients with gout as a third treatment option because we only have allopurinol and febuxostat, so if it is shown efficacious and safe and gets approved, then it’ll help more patients with gout.”

Anne-Kathrin Tausche, MD, a rheumatologist from University Clinic Dresden (Germany), said: “These results are really impressive. We’ve lost lesinurad now because Grünenthal no longer produces it, so this might be a good alternative for patients with severe gout.

“It is favorable with [few] side effects. With allopurinol, we have to titrate it in patients with poor renal function, but it doesn’t seem to be the case with this drug. I really hope they start phase 3 soon,” she added.
 

Phase 2 study, but promising results

Results of the global phase 2b, randomized, double-blind trial compared the safety, tolerability, and efficacy of AR882 against placebo in patients with gout.

A total of 140 patients with gout, aged 18-75 years with an estimated glomerular filtration rate (eGFR) > 30 mL/min, were recruited across the United States, Australia, and Taiwan. Patients received either once-daily AR882 50 mg (n = 46) for 12 weeks, AR882 50 mg for 2 weeks and then AR882 75 mg (n = 47) for 10 weeks, or matching placebo for 12 weeks (n = 47). Flare prophylaxis with daily colchicine started 10 days prior to the first dose and continued throughout the study.

“Patient characteristics were typical for gout trials except for having a very diverse population,” he said. The trial included 57.9% White, 27.9% Asian, and 15% Black patients. They had a mean age of 55 years, body mass index 31-32 kg/m². There was a range of comorbidities including hypertension, hyperlipidemia, diabetes, and cardiovascular disease, evenly distributed across placebo and AR882 treatment groups.

The efficacy endpoints were the proportion of patients who reached serum uric acid below 6, 5, 4, and 3 mg/dL, at 6 weeks of therapy, while safety was also monitored throughout the study. Reductions in serum uric acid at weeks 2, 4, 6, 12 were exploratory endpoints.

The primary endpoint of the percentage of patients below < 6 mg/dL at 6 weeks in the intent-to-treat population was met by 66% with AR882 at the lower dose (50 mg) and 84% at the higher dose (75 mg).

With the 50-mg dose, serum uric acid was reduced at week 6 to < 5mg/dL by 41%, < 4mg/dL by 12%, and < 3mg/dL by 2%, whereas these percentages were 68%, 52%, and 23%, respectively, with the 75-mg dose.

Exploratory endpoints showed that by week 12, serum uric acid levels dropped from baseline 8.6 mg/dL to about 5.0 mg/dL with AR882 50 mg and from baseline 8.6 mg/dL to about 3.5 mg/dL with AR882 75 mg. Also at week 12, 55% and 23% reached serum uric acid levels of < 4mg/dL and < 3mg/dL in the intent-to-treat population. No change was observed in the placebo group.

All adverse events were mild to moderate, with the most prevalent being gout flares. There was little difference between doses. There were no clinically significant changes in a total of 778 post-dose measurements of alanine transaminase (ALT) and aspartate transaminase (AST) and 723 post-dose triplicated electrocardiogram (ECG) measurements.

Dr. Keenan is chief medical officer of Arthrosi Therapeutics. Dr. Tausche and Dr. Abhishek have no relevant financial relationships to disclose.

MILAN – About 80% of patients with gout who took the investigational selective uric acid transporter 1 (URAT1) inhibitor AR882 over 3 months reduced their serum uric acid levels to below recommended thresholds (below 5 or 4 mg/dL) for better flare and tophi reduction in a phase 2b study.

The drug was well tolerated, and patients with comorbidities did not require any adjustments in disease management.

At 75 mg, the highest tested dose of AR882, 73% of patients had serum uric acid levels < 5 mg/dL and 55% had < 4 mg/dL by week 12 of therapy in the intent-to-treat population, whereas in the per-protocol analysis, 82% had serum uric acid levels < 5 mg/dL and 63% < 4 mg/dL.

Becky McCall/MDedge News

“These efficacy results are not typically what you see with a once-daily oral medication, so it is really exciting,” Robert Keenan, MD, chief medical officer of Arthrosi Therapeutics, San Diego, said in presenting the results at the annual European Congress of Rheumatology.

“Regardless of whether you’re treating subclinical, hidden crystal deposition, versus clinically visible tophi, versus chronic, debilitating gout, we believe that AR882 has the potential to treat the entire gout spectrum with a once-daily monotherapy,” Dr. Keenan asserted.

“Currently, most gout patients around the world do not have a safe, effective, and easy to use alternative to allopurinol or febuxostat, which decrease the production of uric acid,” he said. “AR882 is a URAT1 inhibitor that goes to the root of the problem in over 90% of gout patients, helping the kidneys eliminate uric acid to levels similar to all those without hyperuricemia and gout.”

Abhishek Abhishek, MD, professor of rheumatology at the University of Nottingham (England), welcomed the study. “It’s a promising study and the reduction in uric acid was substantial. It was a small study and a larger phase 3 study is needed, but it does offer real hope for patients with gout as a third treatment option because we only have allopurinol and febuxostat, so if it is shown efficacious and safe and gets approved, then it’ll help more patients with gout.”

Anne-Kathrin Tausche, MD, a rheumatologist from University Clinic Dresden (Germany), said: “These results are really impressive. We’ve lost lesinurad now because Grünenthal no longer produces it, so this might be a good alternative for patients with severe gout.

“It is favorable with [few] side effects. With allopurinol, we have to titrate it in patients with poor renal function, but it doesn’t seem to be the case with this drug. I really hope they start phase 3 soon,” she added.
 

Phase 2 study, but promising results

Results of the global phase 2b, randomized, double-blind trial compared the safety, tolerability, and efficacy of AR882 against placebo in patients with gout.

A total of 140 patients with gout, aged 18-75 years with an estimated glomerular filtration rate (eGFR) > 30 mL/min, were recruited across the United States, Australia, and Taiwan. Patients received either once-daily AR882 50 mg (n = 46) for 12 weeks, AR882 50 mg for 2 weeks and then AR882 75 mg (n = 47) for 10 weeks, or matching placebo for 12 weeks (n = 47). Flare prophylaxis with daily colchicine started 10 days prior to the first dose and continued throughout the study.

“Patient characteristics were typical for gout trials except for having a very diverse population,” he said. The trial included 57.9% White, 27.9% Asian, and 15% Black patients. They had a mean age of 55 years, body mass index 31-32 kg/m². There was a range of comorbidities including hypertension, hyperlipidemia, diabetes, and cardiovascular disease, evenly distributed across placebo and AR882 treatment groups.

The efficacy endpoints were the proportion of patients who reached serum uric acid below 6, 5, 4, and 3 mg/dL, at 6 weeks of therapy, while safety was also monitored throughout the study. Reductions in serum uric acid at weeks 2, 4, 6, 12 were exploratory endpoints.

The primary endpoint of the percentage of patients below < 6 mg/dL at 6 weeks in the intent-to-treat population was met by 66% with AR882 at the lower dose (50 mg) and 84% at the higher dose (75 mg).

With the 50-mg dose, serum uric acid was reduced at week 6 to < 5mg/dL by 41%, < 4mg/dL by 12%, and < 3mg/dL by 2%, whereas these percentages were 68%, 52%, and 23%, respectively, with the 75-mg dose.

Exploratory endpoints showed that by week 12, serum uric acid levels dropped from baseline 8.6 mg/dL to about 5.0 mg/dL with AR882 50 mg and from baseline 8.6 mg/dL to about 3.5 mg/dL with AR882 75 mg. Also at week 12, 55% and 23% reached serum uric acid levels of < 4mg/dL and < 3mg/dL in the intent-to-treat population. No change was observed in the placebo group.

All adverse events were mild to moderate, with the most prevalent being gout flares. There was little difference between doses. There were no clinically significant changes in a total of 778 post-dose measurements of alanine transaminase (ALT) and aspartate transaminase (AST) and 723 post-dose triplicated electrocardiogram (ECG) measurements.

Dr. Keenan is chief medical officer of Arthrosi Therapeutics. Dr. Tausche and Dr. Abhishek have no relevant financial relationships to disclose.

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

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

Becky McCall/MDedge News

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

SLE trial

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

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

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

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

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

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

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

Sjögren’s trial

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

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

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

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

Studies yield promising but confusing results

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

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

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

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

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

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

Becky McCall/MDedge News

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

SLE trial

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

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

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

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

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

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

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

Sjögren’s trial

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

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

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

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

Studies yield promising but confusing results

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

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

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

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

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

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

Becky McCall/MDedge News

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

SLE trial

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

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

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

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

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

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

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

Sjögren’s trial

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

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

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

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

Studies yield promising but confusing results

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

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

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

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

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

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

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

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

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

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

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

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

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

Not a definitive answer about structural progression

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Not a definitive answer about structural progression

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Not a definitive answer about structural progression

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Becky McCall/MDedge News

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

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

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

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

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

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

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

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

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

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

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

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

Becky McCall/MDedge News

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

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

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

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

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

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

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

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

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

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

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

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

Becky McCall/MDedge News

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

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

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

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

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

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

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

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

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

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