User login
Sex-Related Differences Found in IgG4-Related Disease Epidemiology
TOPLINE:
Men with immunoglobulin G4 (IgG4)-related disease exhibit significantly lower serum lipase levels and a greater likelihood of organ involvement than women, highlighting significant sex-dependent differences in disease manifestations.
METHODOLOGY:
- Researchers conducted a retrospective study of 328 patients (69% men) diagnosed with IgG4-related disease at the Massachusetts General Hospital – Rheumatology Clinic, Boston, who met the American College of Rheumatology–European Alliance of Associations for Rheumatology (ACR-EULAR) classification criteria between January 2008 and May 2023.
- Among the 328 patients, 69% were men and 31% were women, with a significant male-to-female ratio of 2.2:1.0. Men were typically older at diagnosis (median age, 63.7 vs 58.2 years).
- Data on serum lipase levels, renal involvement, and other clinical and laboratory parameters were collected.
TAKEAWAY:
- Men had higher baseline ACR-EULAR scores, indicating more severe disease (median score of 35.0 vs 29.5; P = .0010).
- Male patients demonstrated a median baseline serum lipase concentration of 24.5 U/L, significantly lower than the 33.5 U/L observed in women.
- Pancreatic (50% vs 26%) or renal (36% vs 18%) involvement was more common in men.
- Men exhibited higher IgG4 levels (P = .0050) and active B-cell responses in the blood (P = .0095).
IN PRACTICE:
According to the authors, this work confirms “the impression of an important sex disparity among patients with IgG4-related disease, with most patients being male, and male patients demonstrating strong tendencies toward more severe disease than female patients.”
SOURCE:
The study was led by Isha Jha, MD, Massachusetts General Hospital, Boston. It was published online on May 30, 2024, in The Lancet Rheumatology.
LIMITATIONS:
The study’s retrospective design may limit the ability to establish causality between sex differences and IgG4-related disease manifestations. A relatively small percentage of patients were assessed before receiving any immunosuppressive treatment, potentially influencing the observed clinical parameters.
DISCLOSURES:
This work was supported by the National Institutes of Health/National Institute of Allergy and Infectious Diseases, the Rheumatology Research Foundation, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Some authors declared financial ties outside this work.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.
A version of this article first appeared on Medscape.com.
TOPLINE:
Men with immunoglobulin G4 (IgG4)-related disease exhibit significantly lower serum lipase levels and a greater likelihood of organ involvement than women, highlighting significant sex-dependent differences in disease manifestations.
METHODOLOGY:
- Researchers conducted a retrospective study of 328 patients (69% men) diagnosed with IgG4-related disease at the Massachusetts General Hospital – Rheumatology Clinic, Boston, who met the American College of Rheumatology–European Alliance of Associations for Rheumatology (ACR-EULAR) classification criteria between January 2008 and May 2023.
- Among the 328 patients, 69% were men and 31% were women, with a significant male-to-female ratio of 2.2:1.0. Men were typically older at diagnosis (median age, 63.7 vs 58.2 years).
- Data on serum lipase levels, renal involvement, and other clinical and laboratory parameters were collected.
TAKEAWAY:
- Men had higher baseline ACR-EULAR scores, indicating more severe disease (median score of 35.0 vs 29.5; P = .0010).
- Male patients demonstrated a median baseline serum lipase concentration of 24.5 U/L, significantly lower than the 33.5 U/L observed in women.
- Pancreatic (50% vs 26%) or renal (36% vs 18%) involvement was more common in men.
- Men exhibited higher IgG4 levels (P = .0050) and active B-cell responses in the blood (P = .0095).
IN PRACTICE:
According to the authors, this work confirms “the impression of an important sex disparity among patients with IgG4-related disease, with most patients being male, and male patients demonstrating strong tendencies toward more severe disease than female patients.”
SOURCE:
The study was led by Isha Jha, MD, Massachusetts General Hospital, Boston. It was published online on May 30, 2024, in The Lancet Rheumatology.
LIMITATIONS:
The study’s retrospective design may limit the ability to establish causality between sex differences and IgG4-related disease manifestations. A relatively small percentage of patients were assessed before receiving any immunosuppressive treatment, potentially influencing the observed clinical parameters.
DISCLOSURES:
This work was supported by the National Institutes of Health/National Institute of Allergy and Infectious Diseases, the Rheumatology Research Foundation, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Some authors declared financial ties outside this work.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.
A version of this article first appeared on Medscape.com.
TOPLINE:
Men with immunoglobulin G4 (IgG4)-related disease exhibit significantly lower serum lipase levels and a greater likelihood of organ involvement than women, highlighting significant sex-dependent differences in disease manifestations.
METHODOLOGY:
- Researchers conducted a retrospective study of 328 patients (69% men) diagnosed with IgG4-related disease at the Massachusetts General Hospital – Rheumatology Clinic, Boston, who met the American College of Rheumatology–European Alliance of Associations for Rheumatology (ACR-EULAR) classification criteria between January 2008 and May 2023.
- Among the 328 patients, 69% were men and 31% were women, with a significant male-to-female ratio of 2.2:1.0. Men were typically older at diagnosis (median age, 63.7 vs 58.2 years).
- Data on serum lipase levels, renal involvement, and other clinical and laboratory parameters were collected.
TAKEAWAY:
- Men had higher baseline ACR-EULAR scores, indicating more severe disease (median score of 35.0 vs 29.5; P = .0010).
- Male patients demonstrated a median baseline serum lipase concentration of 24.5 U/L, significantly lower than the 33.5 U/L observed in women.
- Pancreatic (50% vs 26%) or renal (36% vs 18%) involvement was more common in men.
- Men exhibited higher IgG4 levels (P = .0050) and active B-cell responses in the blood (P = .0095).
IN PRACTICE:
According to the authors, this work confirms “the impression of an important sex disparity among patients with IgG4-related disease, with most patients being male, and male patients demonstrating strong tendencies toward more severe disease than female patients.”
SOURCE:
The study was led by Isha Jha, MD, Massachusetts General Hospital, Boston. It was published online on May 30, 2024, in The Lancet Rheumatology.
LIMITATIONS:
The study’s retrospective design may limit the ability to establish causality between sex differences and IgG4-related disease manifestations. A relatively small percentage of patients were assessed before receiving any immunosuppressive treatment, potentially influencing the observed clinical parameters.
DISCLOSURES:
This work was supported by the National Institutes of Health/National Institute of Allergy and Infectious Diseases, the Rheumatology Research Foundation, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Some authors declared financial ties outside this work.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.
A version of this article first appeared on Medscape.com.
VEXAS Syndrome: Study Highlights Cutaneous Symptoms
Additionally, the most common histologic findings include leukocytoclastic vasculitis, neutrophilic dermatosis, and perivascular dermatitis; different variants in the UBA1 gene are associated with specific skin manifestations.
Those are key findings from a cohort study of 112 patients with VEXAS published online in JAMA Dermatology. The study, conducted by researchers at the National Institutes of Health (NIH) and several other institutions, aimed to define the spectrum of cutaneous manifestations in VEXAS in association with genetic, histologic, and other clinical findings.
First described in 2020, VEXAS syndrome is an adult-onset multisystem disease that can pose a diagnostic challenge to clinicians, the study’s corresponding author, Edward W. Cowen, MD, MHSc, of the dermatology branch at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), said in an interview. The disease is caused by pathogenic variants in the UBA1 gene, located on the X chromosome. Affected individuals exhibit a wide range of manifestations, including cytopenia/myelodysplasia, multiorgan systemic inflammation, and cutaneous involvement.
“Patients may present to a variety of disease specialists depending on their symptoms and providers may not immediately consider a genetic etiology in an older individual,” Dr. Cowen said in an interview. “Although skin involvement occurs in more than 80% of patients, it is pleomorphic and may resemble a variety of other conditions such as vasculitis and Sweet syndrome.”
To better understand the cutaneous manifestations of VEXAS syndrome, the researchers evaluated data from 112 patients with VEXAS-defining genetic variants in the UBA1 gene between 2019 and 2023. Of the 112 patients, 73 underwent medical record review only, and 39 were prospectively evaluated at NIH. All but one of the patients were men, 94% were White individuals, and their mean age was 64 years. Skin involvement occurred in 83% of cases and was the most common presenting feature of VEXAS in 61% of cases.
Of the 64 histopathologic reports available from 60 patients, the main skin histopathologic findings were leukocytoclastic vasculitis in 23 patients (36%), neutrophilic dermatosis in 22 patients (34%), and perivascular dermatitis in 19 patients (30%). According to Dr. Cowen, one key histologic finding was a distinct pattern of “histiocytoid” dermal neutrophilic inflammation, which was present in 13 of 15 specimens (86%) that underwent central re-review. “This pattern can occasionally also be seen in patients with Sweet syndrome, unrelated to VEXAS, but was a hallmark feature found in the majority of skin biopsies of patients with VEXAS,” he said.
“Together with another pathologic finding, leukocytoclasia, these features can be useful clues to alert the pathologist to a potential diagnosis of VEXAS. This myeloid predominant pattern of skin inflammation was also most strongly associated with the leucine pathogenic variant of the UBA1 gene.” In contrast, cutaneous vasculitis was most strongly associated with the valine pathogenic variant of UBA1. “This is important because the valine variant has been previously independently linked to decreased survival,” he said.
In findings related to pathogenic genetic variants, the researchers observed that the p.Met41Leu variant was most frequently associated with neutrophilic dermal infiltrates in 14 of 17 patients (82%) with this variant and often resembled histiocytoid Sweet syndrome. In addition, the p.Met41Val variant was associated with vasculitic lesions in 11 of 20 patients (55%) with this variant and with a mixed leukocytic infiltrate in 17 of these 20 patients (85%).
Treatment Outcomes
In the realm of therapies, skin manifestations improved in 67 of 73 patients (92%) treated with oral prednisone, while treatment with the interleukin-1 receptor antagonist anakinra improved cutaneous disease in 9 of the 16 (56%) who received it. However, 12 (75%) of those who received anakinra developed severe injection-site reactions, including ulceration in two patients and abscess formation in one patient.
Dr. Cowen noted that VEXAS is associated with high mortality (22% in this cohort), and a high degree of suspicion is required to diagnose patients with VEXAS before significant end organ damage has occurred. “This diagnosis should be considered in all older male patients who present with neutrophilic dermatosis — particularly histiocytoid Sweet syndrome, vasculitis, or leukocytoclasia without vasculitis. Patients who appear to have isolated skin involvement may have cytopenias and acute phase reactants. Therefore, complete blood count with differential and ESR and CRP should be considered to investigate for macrocytosis, cytopenias, and systemic inflammation.”
He acknowledged certain limitations of the study, including the fact that many patients were first evaluated at the NIH after having disease symptoms for many months or years. “It is possible that patients with VEXAS referred to the NIH, either for genetic testing or in person evaluation, represent a population with more aggressive disease.”
Christine Ko, MD, professor of dermatology and pathology at Yale University, New Haven, Connecticut, who was asked to comment on the study, emphasized the importance of the UBA1 mutation in the diagnosis of this complex syndrome. “Dermatologists should be aware of VEXAS syndrome as the majority of patients present with skin lesions, which can range from urticarial to Sweet syndrome–like to palpable purpura,” Dr. Ko said.
“Chondritis and periorbital edema, sometimes unilateral, are also associated. Histopathologic clues include a predominantly histiocytoid infiltrate,” she noted. In addition, “the prominent myxoid stroma around blood vessels and adnexal structures as a clue to VEXAS syndrome surprised me; I had not read that before.”
The study was supported by the Intramural Research Program of NIAMS. One of the study authors reported personal fees from Alexion, Novartis, and Sobi outside of the submitted work. No other disclosures were reported. Dr. Ko reported having no disclosures.
A version of this article appeared on Medscape.com .
Additionally, the most common histologic findings include leukocytoclastic vasculitis, neutrophilic dermatosis, and perivascular dermatitis; different variants in the UBA1 gene are associated with specific skin manifestations.
Those are key findings from a cohort study of 112 patients with VEXAS published online in JAMA Dermatology. The study, conducted by researchers at the National Institutes of Health (NIH) and several other institutions, aimed to define the spectrum of cutaneous manifestations in VEXAS in association with genetic, histologic, and other clinical findings.
First described in 2020, VEXAS syndrome is an adult-onset multisystem disease that can pose a diagnostic challenge to clinicians, the study’s corresponding author, Edward W. Cowen, MD, MHSc, of the dermatology branch at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), said in an interview. The disease is caused by pathogenic variants in the UBA1 gene, located on the X chromosome. Affected individuals exhibit a wide range of manifestations, including cytopenia/myelodysplasia, multiorgan systemic inflammation, and cutaneous involvement.
“Patients may present to a variety of disease specialists depending on their symptoms and providers may not immediately consider a genetic etiology in an older individual,” Dr. Cowen said in an interview. “Although skin involvement occurs in more than 80% of patients, it is pleomorphic and may resemble a variety of other conditions such as vasculitis and Sweet syndrome.”
To better understand the cutaneous manifestations of VEXAS syndrome, the researchers evaluated data from 112 patients with VEXAS-defining genetic variants in the UBA1 gene between 2019 and 2023. Of the 112 patients, 73 underwent medical record review only, and 39 were prospectively evaluated at NIH. All but one of the patients were men, 94% were White individuals, and their mean age was 64 years. Skin involvement occurred in 83% of cases and was the most common presenting feature of VEXAS in 61% of cases.
Of the 64 histopathologic reports available from 60 patients, the main skin histopathologic findings were leukocytoclastic vasculitis in 23 patients (36%), neutrophilic dermatosis in 22 patients (34%), and perivascular dermatitis in 19 patients (30%). According to Dr. Cowen, one key histologic finding was a distinct pattern of “histiocytoid” dermal neutrophilic inflammation, which was present in 13 of 15 specimens (86%) that underwent central re-review. “This pattern can occasionally also be seen in patients with Sweet syndrome, unrelated to VEXAS, but was a hallmark feature found in the majority of skin biopsies of patients with VEXAS,” he said.
“Together with another pathologic finding, leukocytoclasia, these features can be useful clues to alert the pathologist to a potential diagnosis of VEXAS. This myeloid predominant pattern of skin inflammation was also most strongly associated with the leucine pathogenic variant of the UBA1 gene.” In contrast, cutaneous vasculitis was most strongly associated with the valine pathogenic variant of UBA1. “This is important because the valine variant has been previously independently linked to decreased survival,” he said.
In findings related to pathogenic genetic variants, the researchers observed that the p.Met41Leu variant was most frequently associated with neutrophilic dermal infiltrates in 14 of 17 patients (82%) with this variant and often resembled histiocytoid Sweet syndrome. In addition, the p.Met41Val variant was associated with vasculitic lesions in 11 of 20 patients (55%) with this variant and with a mixed leukocytic infiltrate in 17 of these 20 patients (85%).
Treatment Outcomes
In the realm of therapies, skin manifestations improved in 67 of 73 patients (92%) treated with oral prednisone, while treatment with the interleukin-1 receptor antagonist anakinra improved cutaneous disease in 9 of the 16 (56%) who received it. However, 12 (75%) of those who received anakinra developed severe injection-site reactions, including ulceration in two patients and abscess formation in one patient.
Dr. Cowen noted that VEXAS is associated with high mortality (22% in this cohort), and a high degree of suspicion is required to diagnose patients with VEXAS before significant end organ damage has occurred. “This diagnosis should be considered in all older male patients who present with neutrophilic dermatosis — particularly histiocytoid Sweet syndrome, vasculitis, or leukocytoclasia without vasculitis. Patients who appear to have isolated skin involvement may have cytopenias and acute phase reactants. Therefore, complete blood count with differential and ESR and CRP should be considered to investigate for macrocytosis, cytopenias, and systemic inflammation.”
He acknowledged certain limitations of the study, including the fact that many patients were first evaluated at the NIH after having disease symptoms for many months or years. “It is possible that patients with VEXAS referred to the NIH, either for genetic testing or in person evaluation, represent a population with more aggressive disease.”
Christine Ko, MD, professor of dermatology and pathology at Yale University, New Haven, Connecticut, who was asked to comment on the study, emphasized the importance of the UBA1 mutation in the diagnosis of this complex syndrome. “Dermatologists should be aware of VEXAS syndrome as the majority of patients present with skin lesions, which can range from urticarial to Sweet syndrome–like to palpable purpura,” Dr. Ko said.
“Chondritis and periorbital edema, sometimes unilateral, are also associated. Histopathologic clues include a predominantly histiocytoid infiltrate,” she noted. In addition, “the prominent myxoid stroma around blood vessels and adnexal structures as a clue to VEXAS syndrome surprised me; I had not read that before.”
The study was supported by the Intramural Research Program of NIAMS. One of the study authors reported personal fees from Alexion, Novartis, and Sobi outside of the submitted work. No other disclosures were reported. Dr. Ko reported having no disclosures.
A version of this article appeared on Medscape.com .
Additionally, the most common histologic findings include leukocytoclastic vasculitis, neutrophilic dermatosis, and perivascular dermatitis; different variants in the UBA1 gene are associated with specific skin manifestations.
Those are key findings from a cohort study of 112 patients with VEXAS published online in JAMA Dermatology. The study, conducted by researchers at the National Institutes of Health (NIH) and several other institutions, aimed to define the spectrum of cutaneous manifestations in VEXAS in association with genetic, histologic, and other clinical findings.
First described in 2020, VEXAS syndrome is an adult-onset multisystem disease that can pose a diagnostic challenge to clinicians, the study’s corresponding author, Edward W. Cowen, MD, MHSc, of the dermatology branch at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), said in an interview. The disease is caused by pathogenic variants in the UBA1 gene, located on the X chromosome. Affected individuals exhibit a wide range of manifestations, including cytopenia/myelodysplasia, multiorgan systemic inflammation, and cutaneous involvement.
“Patients may present to a variety of disease specialists depending on their symptoms and providers may not immediately consider a genetic etiology in an older individual,” Dr. Cowen said in an interview. “Although skin involvement occurs in more than 80% of patients, it is pleomorphic and may resemble a variety of other conditions such as vasculitis and Sweet syndrome.”
To better understand the cutaneous manifestations of VEXAS syndrome, the researchers evaluated data from 112 patients with VEXAS-defining genetic variants in the UBA1 gene between 2019 and 2023. Of the 112 patients, 73 underwent medical record review only, and 39 were prospectively evaluated at NIH. All but one of the patients were men, 94% were White individuals, and their mean age was 64 years. Skin involvement occurred in 83% of cases and was the most common presenting feature of VEXAS in 61% of cases.
Of the 64 histopathologic reports available from 60 patients, the main skin histopathologic findings were leukocytoclastic vasculitis in 23 patients (36%), neutrophilic dermatosis in 22 patients (34%), and perivascular dermatitis in 19 patients (30%). According to Dr. Cowen, one key histologic finding was a distinct pattern of “histiocytoid” dermal neutrophilic inflammation, which was present in 13 of 15 specimens (86%) that underwent central re-review. “This pattern can occasionally also be seen in patients with Sweet syndrome, unrelated to VEXAS, but was a hallmark feature found in the majority of skin biopsies of patients with VEXAS,” he said.
“Together with another pathologic finding, leukocytoclasia, these features can be useful clues to alert the pathologist to a potential diagnosis of VEXAS. This myeloid predominant pattern of skin inflammation was also most strongly associated with the leucine pathogenic variant of the UBA1 gene.” In contrast, cutaneous vasculitis was most strongly associated with the valine pathogenic variant of UBA1. “This is important because the valine variant has been previously independently linked to decreased survival,” he said.
In findings related to pathogenic genetic variants, the researchers observed that the p.Met41Leu variant was most frequently associated with neutrophilic dermal infiltrates in 14 of 17 patients (82%) with this variant and often resembled histiocytoid Sweet syndrome. In addition, the p.Met41Val variant was associated with vasculitic lesions in 11 of 20 patients (55%) with this variant and with a mixed leukocytic infiltrate in 17 of these 20 patients (85%).
Treatment Outcomes
In the realm of therapies, skin manifestations improved in 67 of 73 patients (92%) treated with oral prednisone, while treatment with the interleukin-1 receptor antagonist anakinra improved cutaneous disease in 9 of the 16 (56%) who received it. However, 12 (75%) of those who received anakinra developed severe injection-site reactions, including ulceration in two patients and abscess formation in one patient.
Dr. Cowen noted that VEXAS is associated with high mortality (22% in this cohort), and a high degree of suspicion is required to diagnose patients with VEXAS before significant end organ damage has occurred. “This diagnosis should be considered in all older male patients who present with neutrophilic dermatosis — particularly histiocytoid Sweet syndrome, vasculitis, or leukocytoclasia without vasculitis. Patients who appear to have isolated skin involvement may have cytopenias and acute phase reactants. Therefore, complete blood count with differential and ESR and CRP should be considered to investigate for macrocytosis, cytopenias, and systemic inflammation.”
He acknowledged certain limitations of the study, including the fact that many patients were first evaluated at the NIH after having disease symptoms for many months or years. “It is possible that patients with VEXAS referred to the NIH, either for genetic testing or in person evaluation, represent a population with more aggressive disease.”
Christine Ko, MD, professor of dermatology and pathology at Yale University, New Haven, Connecticut, who was asked to comment on the study, emphasized the importance of the UBA1 mutation in the diagnosis of this complex syndrome. “Dermatologists should be aware of VEXAS syndrome as the majority of patients present with skin lesions, which can range from urticarial to Sweet syndrome–like to palpable purpura,” Dr. Ko said.
“Chondritis and periorbital edema, sometimes unilateral, are also associated. Histopathologic clues include a predominantly histiocytoid infiltrate,” she noted. In addition, “the prominent myxoid stroma around blood vessels and adnexal structures as a clue to VEXAS syndrome surprised me; I had not read that before.”
The study was supported by the Intramural Research Program of NIAMS. One of the study authors reported personal fees from Alexion, Novartis, and Sobi outside of the submitted work. No other disclosures were reported. Dr. Ko reported having no disclosures.
A version of this article appeared on Medscape.com .
FROM JAMA DERMATOLOGY
Autoantibodies Nonspecific to Systemic Sclerosis May Play Role in ILD Prediction
VIENNA — Anti-Ro/SSA antibodies may help predict which patients with systemic sclerosis (SSc) are at a greater risk for interstitial lung disease (ILD) and may serve as a biomarker to guide screening, according to an analysis of data from a large European cohort.
The researchers were led by Blaž Burja, MD, PhD, a physician-scientist at the Center of Experimental Rheumatology, University Hospital Zürich, Switzerland, who reported that anti-Ro/SSA antibodies are a risk factor for ILD, with an odds ratio of 1.24, in patients with SSc.
At the annual European Congress of Rheumatology, he presented the findings of the study that aimed to find out if SSc-nonspecific antibodies might help better risk-stratify patients with SSc, focusing on lung involvement. “Among them, anti-Ro/SSA antibodies have been shown to be associated with interstitial lung disease in different connective tissue diseases,” Dr. Burja pointed out.
“A total of 15% of all patients in the SSc cohort presented with anti-Ro/SSA antibodies, and this subgroup presented with distinct clinical features: Importantly, higher prevalence of ILD and lower DLCO% [diffusing capacity of the lungs for carbon monoxide] in patients with established ILD,” reported Dr. Burja. “However, these anti-Ro/SSA antibodies do not predict ILD progression, death, or overall disease progression.”
Based on the findings, Dr. Burja suggested that these antibodies be incorporated into routine clinical practice to identify patients with SSc who have a high risk for ILD. He noted that “this has specific importance in clinical settings without availability of high-resolution computed tomography (HRCT), where anti-Ro/SSA antibodies could represent an additional biomarker to guide the screening process, in particular, in patients without SSc-specific antibodies.”
Caroline Ospelt, MD, PhD, co-moderator of the session and scientific program chair of EULAR 2024, told this news organization that the study was unique in its approach to studying ILD risk by “looking outside the box, so not just at specific antibodies but whether cross-disease antibodies may have value in stratifying patients and help predict risk of lung involvement and possibly monitor these patients.”
Dr. Ospelt, professor of experimental rheumatology at University Hospital Zürich, who was not involved in the study, noted: “It might also be the case that we could adapt this concept and use these antibodies in other rheumatic diseases, too, not just systemic sclerosis, to predict lung involvement.”
Risk-Stratifying With SSc-Nonspecific Antibodies
Dr. Burja explained that despite better stratification of patients with SSc with SSc-specific antibodies, “in clinical practice, we see large heterogeneity, and individual prognosis with regards to outcomes is still unpredictable, so we wanted to know whether by using nonspecific autoantibodies we might be better able to risk-stratify these patients.”
A study population of 4421 with at least one follow-up visit, including 3060 patients with available follow-up serologic data, was drawn from the European Scleroderma Trials and Research group database (n = 22,482). Of these 3060 patients, 461 were positive for anti-Ro/SSA antibodies and 2599 were negative. The researchers analyzed the relationships between baseline characteristics and the development or progression of ILD over 2.7 years of follow-up. Incident, de novo ILD was defined based on its presence on HRCT, and progression was defined by whether the percentage of predicted forced vital capacity (FVC%) dropped ≥ 10%, FVC% dropped 5%-9% in association with a DLCO% drop ≥ 15%, or FVC% dropped > 5%. Deaths from all causes and prognostic factors for the progression of lung fibrosis during follow-up were recorded.
High Prevalence of ILD With Anti-Ro/SSA Antibodies in SSc
At baseline, patients with anti-Ro/SSA antibodies were aged 55-56 years, 84%-87% were women, and muscular involvement was present in 18% of patients positive for anti-Ro/SSA antibodies and 12.5% of those who were negative (P < .001). According to HRCT, ILD was present in 56.2% of patients positive for anti-Ro/SSA antibodies and in 47.8% of those who were negative (P = .001). FVC% was 92.5% in patients positive for anti-Ro/SSA antibodies and 95.7% in those who were negative (P = .002). DLCO% was 66.9% in patients positive for anti-Ro/SSA antibodies and 71% in those who were negative (P < .001).
“A total of 15% of all SSc patients presented as positive for anti-Ro/SSA antibodies, and these patients all presented with higher prevalence of SSA-nonspecific antibodies, too: Of note, those with anti-La/SSB and anti-U1/RNP and rheumatoid factor,” Dr. Burja reported.
In patients with anti-U1/RNP autoantibodies, 1% were positive and 4% were negative for anti-Ro/SSA antibodies; in those with anti-La/SSB autoantibodies, 17% were positive and 1% were negative for anti-Ro/SSA antibodies; and in those with rheumatoid factor, 28% were positive and 14% were negative for anti-Ro/SSA antibodies.
Dr. Burja pointed out that the average disease duration in the study cohort at baseline was 7 years, “and at this timepoint, we expect to see some common disease manifestations. Specifically, higher muscular involvement and higher ILD based on HRCT.
“We decided to focus on patients with established ILD at baseline,” said Dr. Burja. “Anti-Ro/SSA-positive patients with established ILD at baseline presented with lower DLCO values at 59% in patients positive for anti-Ro/SSA antibodies and 61% for those who were negative.”
After conducting a multivariable analysis of 14,066 healthcare visits and adjusting for known risk factors for ILD, the researchers concluded that anti-Ro/SSA antibodies are an independent risk factor for ILD, with an odds ratio of 1.24 (95% CI, 1.07-1.44; P = .006). They also determined that anti-Ro/SSA antibodies are a risk factor for lower DLCO values in patients with ILD, with a regression coefficient of −1.93.
The researchers then explored the progression of ILD and overall disease progression and survival during the follow-up period in a longitudinal analysis. “However, anti-Ro/SSA antibodies were not found to predict the progression of ILD,” reported Dr. Burja, adding that this was true regardless of the definition of ILD progression used. “Nor did anti-Ro/SSA antibodies do not predict survival or overall disease progression.”
Dr. Burja pointed out the limitations in his study, including the lack of standardized criteria for all centers to assess anti-Ro/SSA positivity; there was a lack of discrimination between anti-Ro52 and anti-Ro60 subtypes, and there were no standardized applicable criteria to study lung progression in SSc.
Dr. Burja and Dr. Ospelt had no relevant financial disclosures.
A version of this article appeared on Medscape.com.
VIENNA — Anti-Ro/SSA antibodies may help predict which patients with systemic sclerosis (SSc) are at a greater risk for interstitial lung disease (ILD) and may serve as a biomarker to guide screening, according to an analysis of data from a large European cohort.
The researchers were led by Blaž Burja, MD, PhD, a physician-scientist at the Center of Experimental Rheumatology, University Hospital Zürich, Switzerland, who reported that anti-Ro/SSA antibodies are a risk factor for ILD, with an odds ratio of 1.24, in patients with SSc.
At the annual European Congress of Rheumatology, he presented the findings of the study that aimed to find out if SSc-nonspecific antibodies might help better risk-stratify patients with SSc, focusing on lung involvement. “Among them, anti-Ro/SSA antibodies have been shown to be associated with interstitial lung disease in different connective tissue diseases,” Dr. Burja pointed out.
“A total of 15% of all patients in the SSc cohort presented with anti-Ro/SSA antibodies, and this subgroup presented with distinct clinical features: Importantly, higher prevalence of ILD and lower DLCO% [diffusing capacity of the lungs for carbon monoxide] in patients with established ILD,” reported Dr. Burja. “However, these anti-Ro/SSA antibodies do not predict ILD progression, death, or overall disease progression.”
Based on the findings, Dr. Burja suggested that these antibodies be incorporated into routine clinical practice to identify patients with SSc who have a high risk for ILD. He noted that “this has specific importance in clinical settings without availability of high-resolution computed tomography (HRCT), where anti-Ro/SSA antibodies could represent an additional biomarker to guide the screening process, in particular, in patients without SSc-specific antibodies.”
Caroline Ospelt, MD, PhD, co-moderator of the session and scientific program chair of EULAR 2024, told this news organization that the study was unique in its approach to studying ILD risk by “looking outside the box, so not just at specific antibodies but whether cross-disease antibodies may have value in stratifying patients and help predict risk of lung involvement and possibly monitor these patients.”
Dr. Ospelt, professor of experimental rheumatology at University Hospital Zürich, who was not involved in the study, noted: “It might also be the case that we could adapt this concept and use these antibodies in other rheumatic diseases, too, not just systemic sclerosis, to predict lung involvement.”
Risk-Stratifying With SSc-Nonspecific Antibodies
Dr. Burja explained that despite better stratification of patients with SSc with SSc-specific antibodies, “in clinical practice, we see large heterogeneity, and individual prognosis with regards to outcomes is still unpredictable, so we wanted to know whether by using nonspecific autoantibodies we might be better able to risk-stratify these patients.”
A study population of 4421 with at least one follow-up visit, including 3060 patients with available follow-up serologic data, was drawn from the European Scleroderma Trials and Research group database (n = 22,482). Of these 3060 patients, 461 were positive for anti-Ro/SSA antibodies and 2599 were negative. The researchers analyzed the relationships between baseline characteristics and the development or progression of ILD over 2.7 years of follow-up. Incident, de novo ILD was defined based on its presence on HRCT, and progression was defined by whether the percentage of predicted forced vital capacity (FVC%) dropped ≥ 10%, FVC% dropped 5%-9% in association with a DLCO% drop ≥ 15%, or FVC% dropped > 5%. Deaths from all causes and prognostic factors for the progression of lung fibrosis during follow-up were recorded.
High Prevalence of ILD With Anti-Ro/SSA Antibodies in SSc
At baseline, patients with anti-Ro/SSA antibodies were aged 55-56 years, 84%-87% were women, and muscular involvement was present in 18% of patients positive for anti-Ro/SSA antibodies and 12.5% of those who were negative (P < .001). According to HRCT, ILD was present in 56.2% of patients positive for anti-Ro/SSA antibodies and in 47.8% of those who were negative (P = .001). FVC% was 92.5% in patients positive for anti-Ro/SSA antibodies and 95.7% in those who were negative (P = .002). DLCO% was 66.9% in patients positive for anti-Ro/SSA antibodies and 71% in those who were negative (P < .001).
“A total of 15% of all SSc patients presented as positive for anti-Ro/SSA antibodies, and these patients all presented with higher prevalence of SSA-nonspecific antibodies, too: Of note, those with anti-La/SSB and anti-U1/RNP and rheumatoid factor,” Dr. Burja reported.
In patients with anti-U1/RNP autoantibodies, 1% were positive and 4% were negative for anti-Ro/SSA antibodies; in those with anti-La/SSB autoantibodies, 17% were positive and 1% were negative for anti-Ro/SSA antibodies; and in those with rheumatoid factor, 28% were positive and 14% were negative for anti-Ro/SSA antibodies.
Dr. Burja pointed out that the average disease duration in the study cohort at baseline was 7 years, “and at this timepoint, we expect to see some common disease manifestations. Specifically, higher muscular involvement and higher ILD based on HRCT.
“We decided to focus on patients with established ILD at baseline,” said Dr. Burja. “Anti-Ro/SSA-positive patients with established ILD at baseline presented with lower DLCO values at 59% in patients positive for anti-Ro/SSA antibodies and 61% for those who were negative.”
After conducting a multivariable analysis of 14,066 healthcare visits and adjusting for known risk factors for ILD, the researchers concluded that anti-Ro/SSA antibodies are an independent risk factor for ILD, with an odds ratio of 1.24 (95% CI, 1.07-1.44; P = .006). They also determined that anti-Ro/SSA antibodies are a risk factor for lower DLCO values in patients with ILD, with a regression coefficient of −1.93.
The researchers then explored the progression of ILD and overall disease progression and survival during the follow-up period in a longitudinal analysis. “However, anti-Ro/SSA antibodies were not found to predict the progression of ILD,” reported Dr. Burja, adding that this was true regardless of the definition of ILD progression used. “Nor did anti-Ro/SSA antibodies do not predict survival or overall disease progression.”
Dr. Burja pointed out the limitations in his study, including the lack of standardized criteria for all centers to assess anti-Ro/SSA positivity; there was a lack of discrimination between anti-Ro52 and anti-Ro60 subtypes, and there were no standardized applicable criteria to study lung progression in SSc.
Dr. Burja and Dr. Ospelt had no relevant financial disclosures.
A version of this article appeared on Medscape.com.
VIENNA — Anti-Ro/SSA antibodies may help predict which patients with systemic sclerosis (SSc) are at a greater risk for interstitial lung disease (ILD) and may serve as a biomarker to guide screening, according to an analysis of data from a large European cohort.
The researchers were led by Blaž Burja, MD, PhD, a physician-scientist at the Center of Experimental Rheumatology, University Hospital Zürich, Switzerland, who reported that anti-Ro/SSA antibodies are a risk factor for ILD, with an odds ratio of 1.24, in patients with SSc.
At the annual European Congress of Rheumatology, he presented the findings of the study that aimed to find out if SSc-nonspecific antibodies might help better risk-stratify patients with SSc, focusing on lung involvement. “Among them, anti-Ro/SSA antibodies have been shown to be associated with interstitial lung disease in different connective tissue diseases,” Dr. Burja pointed out.
“A total of 15% of all patients in the SSc cohort presented with anti-Ro/SSA antibodies, and this subgroup presented with distinct clinical features: Importantly, higher prevalence of ILD and lower DLCO% [diffusing capacity of the lungs for carbon monoxide] in patients with established ILD,” reported Dr. Burja. “However, these anti-Ro/SSA antibodies do not predict ILD progression, death, or overall disease progression.”
Based on the findings, Dr. Burja suggested that these antibodies be incorporated into routine clinical practice to identify patients with SSc who have a high risk for ILD. He noted that “this has specific importance in clinical settings without availability of high-resolution computed tomography (HRCT), where anti-Ro/SSA antibodies could represent an additional biomarker to guide the screening process, in particular, in patients without SSc-specific antibodies.”
Caroline Ospelt, MD, PhD, co-moderator of the session and scientific program chair of EULAR 2024, told this news organization that the study was unique in its approach to studying ILD risk by “looking outside the box, so not just at specific antibodies but whether cross-disease antibodies may have value in stratifying patients and help predict risk of lung involvement and possibly monitor these patients.”
Dr. Ospelt, professor of experimental rheumatology at University Hospital Zürich, who was not involved in the study, noted: “It might also be the case that we could adapt this concept and use these antibodies in other rheumatic diseases, too, not just systemic sclerosis, to predict lung involvement.”
Risk-Stratifying With SSc-Nonspecific Antibodies
Dr. Burja explained that despite better stratification of patients with SSc with SSc-specific antibodies, “in clinical practice, we see large heterogeneity, and individual prognosis with regards to outcomes is still unpredictable, so we wanted to know whether by using nonspecific autoantibodies we might be better able to risk-stratify these patients.”
A study population of 4421 with at least one follow-up visit, including 3060 patients with available follow-up serologic data, was drawn from the European Scleroderma Trials and Research group database (n = 22,482). Of these 3060 patients, 461 were positive for anti-Ro/SSA antibodies and 2599 were negative. The researchers analyzed the relationships between baseline characteristics and the development or progression of ILD over 2.7 years of follow-up. Incident, de novo ILD was defined based on its presence on HRCT, and progression was defined by whether the percentage of predicted forced vital capacity (FVC%) dropped ≥ 10%, FVC% dropped 5%-9% in association with a DLCO% drop ≥ 15%, or FVC% dropped > 5%. Deaths from all causes and prognostic factors for the progression of lung fibrosis during follow-up were recorded.
High Prevalence of ILD With Anti-Ro/SSA Antibodies in SSc
At baseline, patients with anti-Ro/SSA antibodies were aged 55-56 years, 84%-87% were women, and muscular involvement was present in 18% of patients positive for anti-Ro/SSA antibodies and 12.5% of those who were negative (P < .001). According to HRCT, ILD was present in 56.2% of patients positive for anti-Ro/SSA antibodies and in 47.8% of those who were negative (P = .001). FVC% was 92.5% in patients positive for anti-Ro/SSA antibodies and 95.7% in those who were negative (P = .002). DLCO% was 66.9% in patients positive for anti-Ro/SSA antibodies and 71% in those who were negative (P < .001).
“A total of 15% of all SSc patients presented as positive for anti-Ro/SSA antibodies, and these patients all presented with higher prevalence of SSA-nonspecific antibodies, too: Of note, those with anti-La/SSB and anti-U1/RNP and rheumatoid factor,” Dr. Burja reported.
In patients with anti-U1/RNP autoantibodies, 1% were positive and 4% were negative for anti-Ro/SSA antibodies; in those with anti-La/SSB autoantibodies, 17% were positive and 1% were negative for anti-Ro/SSA antibodies; and in those with rheumatoid factor, 28% were positive and 14% were negative for anti-Ro/SSA antibodies.
Dr. Burja pointed out that the average disease duration in the study cohort at baseline was 7 years, “and at this timepoint, we expect to see some common disease manifestations. Specifically, higher muscular involvement and higher ILD based on HRCT.
“We decided to focus on patients with established ILD at baseline,” said Dr. Burja. “Anti-Ro/SSA-positive patients with established ILD at baseline presented with lower DLCO values at 59% in patients positive for anti-Ro/SSA antibodies and 61% for those who were negative.”
After conducting a multivariable analysis of 14,066 healthcare visits and adjusting for known risk factors for ILD, the researchers concluded that anti-Ro/SSA antibodies are an independent risk factor for ILD, with an odds ratio of 1.24 (95% CI, 1.07-1.44; P = .006). They also determined that anti-Ro/SSA antibodies are a risk factor for lower DLCO values in patients with ILD, with a regression coefficient of −1.93.
The researchers then explored the progression of ILD and overall disease progression and survival during the follow-up period in a longitudinal analysis. “However, anti-Ro/SSA antibodies were not found to predict the progression of ILD,” reported Dr. Burja, adding that this was true regardless of the definition of ILD progression used. “Nor did anti-Ro/SSA antibodies do not predict survival or overall disease progression.”
Dr. Burja pointed out the limitations in his study, including the lack of standardized criteria for all centers to assess anti-Ro/SSA positivity; there was a lack of discrimination between anti-Ro52 and anti-Ro60 subtypes, and there were no standardized applicable criteria to study lung progression in SSc.
Dr. Burja and Dr. Ospelt had no relevant financial disclosures.
A version of this article appeared on Medscape.com.
FROM EULAR 2024
Upadacitinib Proves Successful in First JAK Inhibitor Trial for Giant Cell Arteritis
VIENNA — Results from the phase 3 SELECT-GCA study showed that the Janus kinase (JAK) inhibitor upadacitinib (Rinvoq) induces significant and sustained remission in people with new-onset or relapsing giant cell arteritis (GCA).
The primary endpoint of sustained remission — the absence of GCA signs or symptoms from weeks 12 to 52 together with adherence to a steroid-tapering regimen — occurred in 46% of 210 individuals randomly assigned to treatment treated with a once-daily 15-mg dose of upadacitinib and 29% of 105 randomly assigned to placebo (P = .0019).
Nine of the 11 secondary endpoints were also positive for upadacitinib 15 mg vs placebo, and no new safety concerns were identified in a late-breaking abstract presented at the at the annual European Congress of Rheumatology.
First JAK Trial in GCA
This is the first trial to look at the use of a JAK inhibitor for the treatment of GCA, and it is addressing a real unmet need, the presenting study investigator Daniel Blockmans, MD, PhD, of University Hospitals Leuven in Belgium, told this news organization.
Glucocorticoids remain the mainstay of treatment, and tocilizumab has been licensed for use, but people don’t always get better or can relapse, he explained.
“I have the impression that these only suppress the disease but do not cure it,” Dr. Blockmans said, adding that “patients get very well soon after these treatments are started, but there are more and more reports that there is a kind of smoldering vasculitis that exists, and this can lead to dilatation of the aorta.”
Upadacitinib inhibits two JAK-dependent cytokines, interleukin 6 and interferon gamma, which have been implicated in the pathogenesis of GCA. The latter could be particularly important, Dr. Blockmans suggested.
Study Details
SELECT-GCA is an ongoing multicenter, randomized, double-blind, placebo-controlled study designed to evaluate the safety and efficacy of upadacitinib vs placebo in patients with GCA.
A total of 428 patients have been included: 210 were randomly allocated to treatment with upadacitinib 15 mg, 105 to upadacitinib 7.5 mg, and 105 to placebo. The inclusion of the lower “minimally effective” upadacitinib dose was a requirement of the regulatory authorities, Dr. Blockmans said; the licensed dose in rheumatoid arthritis (RA) is 15 mg.
Dr. Blockmans reported data from the first 52 weeks of the trial during which all patients underwent glucocorticoid tapering — 26 weeks for upadacitinib and 52 weeks for placebo.
No imaging was done in this trial, which Dr. Blockmans said should be considered for future studies.
Secondary Endpoints
One of the key secondary endpoints was sustained complete remission, defined as sustained remission plus a normalized erythrocyte sedimentation rate to ≤ 30 mm/h and reducing high-sensitivity C-reactive protein to < 1 mg/dL.
Sustained complete remission occurred in 37% and 16% of patients treated with upadacitinib 15 mg and placebo, respectively (P < .0001).
Additionally, a significantly lower proportion of upadacitinib 15 mg- than placebo-treated patients experienced at least one disease flare through week 52 (34% vs 56%, P = .0014).
Other positive secondary endpoints for upadacitinib 15 mg vs placebo out to week 52 were the number of disease flares per patient, cumulative glucocorticoid exposure, and complete remission (also at week 24).
And significant changes in SF-36 and FACIT-Fatigue from baseline to week 52 were seen for upadacitinib 15 mg.
The only secondary endpoints not showing a clear benefit for upadacitinib 15 mg were the changes in the Treatment Satisfaction Questionnaire for Medication at 52 weeks and the rate of glucocorticoid-related adverse events through week 52.
As for the 7.5-mg dose of upadacitinib, neither the primary nor secondary endpoints were significantly better vs placebo.
‘Life-Changing’
The study’s findings could be “really life-changing” for patients with this type of vasculitis if upadacitinib gets approval for use in this indication, Milena Bond, MD, PhD, of Brunico Hospital in Italy, told this news organization at the meeting.
“Unfortunately, nowadays, we still have only a few options for treating these patients,” she said. “So, this drug could be really, really important.”
Dr. Bond added: “The data ... also shows there is a very good safety profile, which was a main concern given the class of the drug. So, I’m very positive about this treatment and very excited to see the preliminary results.”
After his presentation, Dr. Blockmans said, “Of course, if we already had an ideal treatment for GCA, there would be no need for a JAK inhibitor, but I don’t think that steroid treatment or tocilizumab treatment is the ideal treatment.”
Judicious Use Still Warranted
Upadacitinib still needs to be used cautiously, following appropriate guidance from the European Medicines Agency (EMA) and the US Food and Drug Administration.
Dr. Bond said: “It is not advised to use to the drug when people are older than 65 years old,” according to the EMA, for example, and “given the rules that we have, I would not use this drug as a first-line treatment. We do not do that for rheumatoid arthritis.”
But, she added, “As for arthritis, when you fail treating patients with the other alternatives, you could use this drug, and you have to discuss risks with the patients.”
Dr. Blockmans reported there had been no increased risk for major adverse cardiovascular events or venous thromboembolism associated with upadacitinib relative to placebo in the population of patients studied, and he pointed out that they had a much higher risk for these events than perhaps an RA population.
He said: “It’s effective, and it’s apparently safe in these older people, despite what we heard about tofacitinib in the ORAL [Surveillance] study; we didn’t see these problems here in this elderly population.”
The SELECT-GCA trial was funded by AbbVie, and the company participated in all aspects of the study, including its design, conduct, interpretation of data, and reporting. Dr. Blockmans received no funding or other honoraria from the company but reported a research grant from Roche and consulting fees from GlaxoSmithKline. Most of his coauthors reported financial relationships with AbbVie, and some are employees of the company. Dr. Bond reported no relevant financial relationships.
A version of this article appeared on Medscape.com.
VIENNA — Results from the phase 3 SELECT-GCA study showed that the Janus kinase (JAK) inhibitor upadacitinib (Rinvoq) induces significant and sustained remission in people with new-onset or relapsing giant cell arteritis (GCA).
The primary endpoint of sustained remission — the absence of GCA signs or symptoms from weeks 12 to 52 together with adherence to a steroid-tapering regimen — occurred in 46% of 210 individuals randomly assigned to treatment treated with a once-daily 15-mg dose of upadacitinib and 29% of 105 randomly assigned to placebo (P = .0019).
Nine of the 11 secondary endpoints were also positive for upadacitinib 15 mg vs placebo, and no new safety concerns were identified in a late-breaking abstract presented at the at the annual European Congress of Rheumatology.
First JAK Trial in GCA
This is the first trial to look at the use of a JAK inhibitor for the treatment of GCA, and it is addressing a real unmet need, the presenting study investigator Daniel Blockmans, MD, PhD, of University Hospitals Leuven in Belgium, told this news organization.
Glucocorticoids remain the mainstay of treatment, and tocilizumab has been licensed for use, but people don’t always get better or can relapse, he explained.
“I have the impression that these only suppress the disease but do not cure it,” Dr. Blockmans said, adding that “patients get very well soon after these treatments are started, but there are more and more reports that there is a kind of smoldering vasculitis that exists, and this can lead to dilatation of the aorta.”
Upadacitinib inhibits two JAK-dependent cytokines, interleukin 6 and interferon gamma, which have been implicated in the pathogenesis of GCA. The latter could be particularly important, Dr. Blockmans suggested.
Study Details
SELECT-GCA is an ongoing multicenter, randomized, double-blind, placebo-controlled study designed to evaluate the safety and efficacy of upadacitinib vs placebo in patients with GCA.
A total of 428 patients have been included: 210 were randomly allocated to treatment with upadacitinib 15 mg, 105 to upadacitinib 7.5 mg, and 105 to placebo. The inclusion of the lower “minimally effective” upadacitinib dose was a requirement of the regulatory authorities, Dr. Blockmans said; the licensed dose in rheumatoid arthritis (RA) is 15 mg.
Dr. Blockmans reported data from the first 52 weeks of the trial during which all patients underwent glucocorticoid tapering — 26 weeks for upadacitinib and 52 weeks for placebo.
No imaging was done in this trial, which Dr. Blockmans said should be considered for future studies.
Secondary Endpoints
One of the key secondary endpoints was sustained complete remission, defined as sustained remission plus a normalized erythrocyte sedimentation rate to ≤ 30 mm/h and reducing high-sensitivity C-reactive protein to < 1 mg/dL.
Sustained complete remission occurred in 37% and 16% of patients treated with upadacitinib 15 mg and placebo, respectively (P < .0001).
Additionally, a significantly lower proportion of upadacitinib 15 mg- than placebo-treated patients experienced at least one disease flare through week 52 (34% vs 56%, P = .0014).
Other positive secondary endpoints for upadacitinib 15 mg vs placebo out to week 52 were the number of disease flares per patient, cumulative glucocorticoid exposure, and complete remission (also at week 24).
And significant changes in SF-36 and FACIT-Fatigue from baseline to week 52 were seen for upadacitinib 15 mg.
The only secondary endpoints not showing a clear benefit for upadacitinib 15 mg were the changes in the Treatment Satisfaction Questionnaire for Medication at 52 weeks and the rate of glucocorticoid-related adverse events through week 52.
As for the 7.5-mg dose of upadacitinib, neither the primary nor secondary endpoints were significantly better vs placebo.
‘Life-Changing’
The study’s findings could be “really life-changing” for patients with this type of vasculitis if upadacitinib gets approval for use in this indication, Milena Bond, MD, PhD, of Brunico Hospital in Italy, told this news organization at the meeting.
“Unfortunately, nowadays, we still have only a few options for treating these patients,” she said. “So, this drug could be really, really important.”
Dr. Bond added: “The data ... also shows there is a very good safety profile, which was a main concern given the class of the drug. So, I’m very positive about this treatment and very excited to see the preliminary results.”
After his presentation, Dr. Blockmans said, “Of course, if we already had an ideal treatment for GCA, there would be no need for a JAK inhibitor, but I don’t think that steroid treatment or tocilizumab treatment is the ideal treatment.”
Judicious Use Still Warranted
Upadacitinib still needs to be used cautiously, following appropriate guidance from the European Medicines Agency (EMA) and the US Food and Drug Administration.
Dr. Bond said: “It is not advised to use to the drug when people are older than 65 years old,” according to the EMA, for example, and “given the rules that we have, I would not use this drug as a first-line treatment. We do not do that for rheumatoid arthritis.”
But, she added, “As for arthritis, when you fail treating patients with the other alternatives, you could use this drug, and you have to discuss risks with the patients.”
Dr. Blockmans reported there had been no increased risk for major adverse cardiovascular events or venous thromboembolism associated with upadacitinib relative to placebo in the population of patients studied, and he pointed out that they had a much higher risk for these events than perhaps an RA population.
He said: “It’s effective, and it’s apparently safe in these older people, despite what we heard about tofacitinib in the ORAL [Surveillance] study; we didn’t see these problems here in this elderly population.”
The SELECT-GCA trial was funded by AbbVie, and the company participated in all aspects of the study, including its design, conduct, interpretation of data, and reporting. Dr. Blockmans received no funding or other honoraria from the company but reported a research grant from Roche and consulting fees from GlaxoSmithKline. Most of his coauthors reported financial relationships with AbbVie, and some are employees of the company. Dr. Bond reported no relevant financial relationships.
A version of this article appeared on Medscape.com.
VIENNA — Results from the phase 3 SELECT-GCA study showed that the Janus kinase (JAK) inhibitor upadacitinib (Rinvoq) induces significant and sustained remission in people with new-onset or relapsing giant cell arteritis (GCA).
The primary endpoint of sustained remission — the absence of GCA signs or symptoms from weeks 12 to 52 together with adherence to a steroid-tapering regimen — occurred in 46% of 210 individuals randomly assigned to treatment treated with a once-daily 15-mg dose of upadacitinib and 29% of 105 randomly assigned to placebo (P = .0019).
Nine of the 11 secondary endpoints were also positive for upadacitinib 15 mg vs placebo, and no new safety concerns were identified in a late-breaking abstract presented at the at the annual European Congress of Rheumatology.
First JAK Trial in GCA
This is the first trial to look at the use of a JAK inhibitor for the treatment of GCA, and it is addressing a real unmet need, the presenting study investigator Daniel Blockmans, MD, PhD, of University Hospitals Leuven in Belgium, told this news organization.
Glucocorticoids remain the mainstay of treatment, and tocilizumab has been licensed for use, but people don’t always get better or can relapse, he explained.
“I have the impression that these only suppress the disease but do not cure it,” Dr. Blockmans said, adding that “patients get very well soon after these treatments are started, but there are more and more reports that there is a kind of smoldering vasculitis that exists, and this can lead to dilatation of the aorta.”
Upadacitinib inhibits two JAK-dependent cytokines, interleukin 6 and interferon gamma, which have been implicated in the pathogenesis of GCA. The latter could be particularly important, Dr. Blockmans suggested.
Study Details
SELECT-GCA is an ongoing multicenter, randomized, double-blind, placebo-controlled study designed to evaluate the safety and efficacy of upadacitinib vs placebo in patients with GCA.
A total of 428 patients have been included: 210 were randomly allocated to treatment with upadacitinib 15 mg, 105 to upadacitinib 7.5 mg, and 105 to placebo. The inclusion of the lower “minimally effective” upadacitinib dose was a requirement of the regulatory authorities, Dr. Blockmans said; the licensed dose in rheumatoid arthritis (RA) is 15 mg.
Dr. Blockmans reported data from the first 52 weeks of the trial during which all patients underwent glucocorticoid tapering — 26 weeks for upadacitinib and 52 weeks for placebo.
No imaging was done in this trial, which Dr. Blockmans said should be considered for future studies.
Secondary Endpoints
One of the key secondary endpoints was sustained complete remission, defined as sustained remission plus a normalized erythrocyte sedimentation rate to ≤ 30 mm/h and reducing high-sensitivity C-reactive protein to < 1 mg/dL.
Sustained complete remission occurred in 37% and 16% of patients treated with upadacitinib 15 mg and placebo, respectively (P < .0001).
Additionally, a significantly lower proportion of upadacitinib 15 mg- than placebo-treated patients experienced at least one disease flare through week 52 (34% vs 56%, P = .0014).
Other positive secondary endpoints for upadacitinib 15 mg vs placebo out to week 52 were the number of disease flares per patient, cumulative glucocorticoid exposure, and complete remission (also at week 24).
And significant changes in SF-36 and FACIT-Fatigue from baseline to week 52 were seen for upadacitinib 15 mg.
The only secondary endpoints not showing a clear benefit for upadacitinib 15 mg were the changes in the Treatment Satisfaction Questionnaire for Medication at 52 weeks and the rate of glucocorticoid-related adverse events through week 52.
As for the 7.5-mg dose of upadacitinib, neither the primary nor secondary endpoints were significantly better vs placebo.
‘Life-Changing’
The study’s findings could be “really life-changing” for patients with this type of vasculitis if upadacitinib gets approval for use in this indication, Milena Bond, MD, PhD, of Brunico Hospital in Italy, told this news organization at the meeting.
“Unfortunately, nowadays, we still have only a few options for treating these patients,” she said. “So, this drug could be really, really important.”
Dr. Bond added: “The data ... also shows there is a very good safety profile, which was a main concern given the class of the drug. So, I’m very positive about this treatment and very excited to see the preliminary results.”
After his presentation, Dr. Blockmans said, “Of course, if we already had an ideal treatment for GCA, there would be no need for a JAK inhibitor, but I don’t think that steroid treatment or tocilizumab treatment is the ideal treatment.”
Judicious Use Still Warranted
Upadacitinib still needs to be used cautiously, following appropriate guidance from the European Medicines Agency (EMA) and the US Food and Drug Administration.
Dr. Bond said: “It is not advised to use to the drug when people are older than 65 years old,” according to the EMA, for example, and “given the rules that we have, I would not use this drug as a first-line treatment. We do not do that for rheumatoid arthritis.”
But, she added, “As for arthritis, when you fail treating patients with the other alternatives, you could use this drug, and you have to discuss risks with the patients.”
Dr. Blockmans reported there had been no increased risk for major adverse cardiovascular events or venous thromboembolism associated with upadacitinib relative to placebo in the population of patients studied, and he pointed out that they had a much higher risk for these events than perhaps an RA population.
He said: “It’s effective, and it’s apparently safe in these older people, despite what we heard about tofacitinib in the ORAL [Surveillance] study; we didn’t see these problems here in this elderly population.”
The SELECT-GCA trial was funded by AbbVie, and the company participated in all aspects of the study, including its design, conduct, interpretation of data, and reporting. Dr. Blockmans received no funding or other honoraria from the company but reported a research grant from Roche and consulting fees from GlaxoSmithKline. Most of his coauthors reported financial relationships with AbbVie, and some are employees of the company. Dr. Bond reported no relevant financial relationships.
A version of this article appeared on Medscape.com.
FROM EULAR 2024
FDA Approves Polyarticular JIA Indication for Sarilumab
The US Food and Drug Administration (FDA) has approved sarilumab (Kevzara) for the treatment of polyarticular juvenile idiopathic arthritis (pJIA) for patients weighing ≥ 63 kg (139 lb).
“Polyarticular juvenile idiopathic arthritis (JIA) can be a painful disease for children where multiple joints are impacted by this chronic inflammation,” said George D. Yancopoulos, MD, PhD, president and chief scientific officer at Regeneron in a press release.
It is estimated that nearly 300,000 children in the United States have JIA, and 1 in 4 of them have pJIA, according to the Arthritis Foundation. 
“Not only are their daily lives impacted, but their futures can be disrupted without adequate treatment,” Dr. Yancopoulos continued. “The approval of Kevzara in polyarticular juvenile idiopathic arthritis provides these vulnerable patients and their families a new FDA-approved treatment option to help navigate this disease.”
Sarilumab, jointly developed by Sanofi and Regeneron, is an interleukin 6 receptor blocker. It was first approved in 2017 for the treatment of moderate to severely active rheumatoid arthritis (RA) in adults who had inadequate response or intolerance to at least one other disease-modifying antirheumatic drug (DMARD).
In 2023, the FDA approved sarilumab as the first biologic treatment for polymyalgia rheumatica in adults who had inadequate response to corticosteroids and could not tolerate a corticosteroid taper.
For pJIA, sarilumab is administered subcutaneously using a 200-mg/1.14-mL prefilled syringe once every 2 weeks. The medication can be used alone or in combination with other conventional DMARDs.
“Use of KEVZARA in pediatric patients with pJIA is supported by evidence from adequate and well-controlled studies of KEVZARA in adults with RA, pharmacokinetic data from adult patients with RA,” and pharmacokinetic comparability in 101 pediatric patients aged 2-17 years treated with sarilumab, according to the prescribing information. Sarilumab is not approved for pediatric patients < 63 kg “because of a lack of an appropriate dosage form.”
The most common reported adverse reactions for sarilumab in pJIA are nasopharyngitis, neutropenia, upper respiratory tract infection, and injection site erythema. The pJIA trial recorded no new adverse reactions or safety concerns, compared with patients with RA.
A version of this article appeared on Medscape.com.
The US Food and Drug Administration (FDA) has approved sarilumab (Kevzara) for the treatment of polyarticular juvenile idiopathic arthritis (pJIA) for patients weighing ≥ 63 kg (139 lb).
“Polyarticular juvenile idiopathic arthritis (JIA) can be a painful disease for children where multiple joints are impacted by this chronic inflammation,” said George D. Yancopoulos, MD, PhD, president and chief scientific officer at Regeneron in a press release.
It is estimated that nearly 300,000 children in the United States have JIA, and 1 in 4 of them have pJIA, according to the Arthritis Foundation.
“Not only are their daily lives impacted, but their futures can be disrupted without adequate treatment,” Dr. Yancopoulos continued. “The approval of Kevzara in polyarticular juvenile idiopathic arthritis provides these vulnerable patients and their families a new FDA-approved treatment option to help navigate this disease.”
Sarilumab, jointly developed by Sanofi and Regeneron, is an interleukin 6 receptor blocker. It was first approved in 2017 for the treatment of moderate to severely active rheumatoid arthritis (RA) in adults who had inadequate response or intolerance to at least one other disease-modifying antirheumatic drug (DMARD).
In 2023, the FDA approved sarilumab as the first biologic treatment for polymyalgia rheumatica in adults who had inadequate response to corticosteroids and could not tolerate a corticosteroid taper.
For pJIA, sarilumab is administered subcutaneously using a 200-mg/1.14-mL prefilled syringe once every 2 weeks. The medication can be used alone or in combination with other conventional DMARDs.
“Use of KEVZARA in pediatric patients with pJIA is supported by evidence from adequate and well-controlled studies of KEVZARA in adults with RA, pharmacokinetic data from adult patients with RA,” and pharmacokinetic comparability in 101 pediatric patients aged 2-17 years treated with sarilumab, according to the prescribing information. Sarilumab is not approved for pediatric patients < 63 kg “because of a lack of an appropriate dosage form.”
The most common reported adverse reactions for sarilumab in pJIA are nasopharyngitis, neutropenia, upper respiratory tract infection, and injection site erythema. The pJIA trial recorded no new adverse reactions or safety concerns, compared with patients with RA.
A version of this article appeared on Medscape.com.
The US Food and Drug Administration (FDA) has approved sarilumab (Kevzara) for the treatment of polyarticular juvenile idiopathic arthritis (pJIA) for patients weighing ≥ 63 kg (139 lb).
“Polyarticular juvenile idiopathic arthritis (JIA) can be a painful disease for children where multiple joints are impacted by this chronic inflammation,” said George D. Yancopoulos, MD, PhD, president and chief scientific officer at Regeneron in a press release.
It is estimated that nearly 300,000 children in the United States have JIA, and 1 in 4 of them have pJIA, according to the Arthritis Foundation.
“Not only are their daily lives impacted, but their futures can be disrupted without adequate treatment,” Dr. Yancopoulos continued. “The approval of Kevzara in polyarticular juvenile idiopathic arthritis provides these vulnerable patients and their families a new FDA-approved treatment option to help navigate this disease.”
Sarilumab, jointly developed by Sanofi and Regeneron, is an interleukin 6 receptor blocker. It was first approved in 2017 for the treatment of moderate to severely active rheumatoid arthritis (RA) in adults who had inadequate response or intolerance to at least one other disease-modifying antirheumatic drug (DMARD).
In 2023, the FDA approved sarilumab as the first biologic treatment for polymyalgia rheumatica in adults who had inadequate response to corticosteroids and could not tolerate a corticosteroid taper.
For pJIA, sarilumab is administered subcutaneously using a 200-mg/1.14-mL prefilled syringe once every 2 weeks. The medication can be used alone or in combination with other conventional DMARDs.
“Use of KEVZARA in pediatric patients with pJIA is supported by evidence from adequate and well-controlled studies of KEVZARA in adults with RA, pharmacokinetic data from adult patients with RA,” and pharmacokinetic comparability in 101 pediatric patients aged 2-17 years treated with sarilumab, according to the prescribing information. Sarilumab is not approved for pediatric patients < 63 kg “because of a lack of an appropriate dosage form.”
The most common reported adverse reactions for sarilumab in pJIA are nasopharyngitis, neutropenia, upper respiratory tract infection, and injection site erythema. The pJIA trial recorded no new adverse reactions or safety concerns, compared with patients with RA.
A version of this article appeared on Medscape.com.
Knowing My Limits
The records came in by fax. A patient who’d recently moved here and needed to connect with a local neurologist.
When I had time, I flipped through the records. He needed ongoing treatment for a rare neurological disease that I’d heard of, but wasn’t otherwise familiar with. It didn’t even exist in the textbooks or conferences when I was in residency. I’d never seen a case of it, just read about it here and there in journals.
I looked it up, reviewed current treatment options, monitoring, and other knowledge about it, then stared at the notes for a minute. Finally, after thinking it over, I attached a sticky note for my secretary that, if the person called, to redirect them to one of the local subspecialty neurology centers.
I have nothing against this patient, but realistically he would be better served seeing someone with time to keep up on advancements in esoteric disorders, not a general neurologist like myself.
Isn’t that why we have subspecialty centers?
Some of it is also me. There was a time in my career when keeping up on newly discovered disorders and their treatments was, well, cool. But after 25 years in practice, that changes.
It’s important to be at least somewhat aware of new developments (such as in this case) as you may encounter them, and need to know when it’s something you can handle and when to send it elsewhere.
Driving home that afternoon I thought, “I’m an old dog. I don’t want to learn new tricks.” Maybe that’s all it is. There are other neurologists my age and older who thrive on the challenge of learning about and treating new and rare disorders that were unknown when they started out. There’s nothing wrong with that.
But I’ve never pretended to be an academic or sub-sub-specialist. My patients depend on me to stay up to date on the large number of commonly seen neurological disorders, and I do my best to do that.
It ain’t easy being an old dog.
Dr. Block has a solo neurology practice in Scottsdale, Arizona.
The records came in by fax. A patient who’d recently moved here and needed to connect with a local neurologist.
When I had time, I flipped through the records. He needed ongoing treatment for a rare neurological disease that I’d heard of, but wasn’t otherwise familiar with. It didn’t even exist in the textbooks or conferences when I was in residency. I’d never seen a case of it, just read about it here and there in journals.
I looked it up, reviewed current treatment options, monitoring, and other knowledge about it, then stared at the notes for a minute. Finally, after thinking it over, I attached a sticky note for my secretary that, if the person called, to redirect them to one of the local subspecialty neurology centers.
I have nothing against this patient, but realistically he would be better served seeing someone with time to keep up on advancements in esoteric disorders, not a general neurologist like myself.
Isn’t that why we have subspecialty centers?
Some of it is also me. There was a time in my career when keeping up on newly discovered disorders and their treatments was, well, cool. But after 25 years in practice, that changes.
It’s important to be at least somewhat aware of new developments (such as in this case) as you may encounter them, and need to know when it’s something you can handle and when to send it elsewhere.
Driving home that afternoon I thought, “I’m an old dog. I don’t want to learn new tricks.” Maybe that’s all it is. There are other neurologists my age and older who thrive on the challenge of learning about and treating new and rare disorders that were unknown when they started out. There’s nothing wrong with that.
But I’ve never pretended to be an academic or sub-sub-specialist. My patients depend on me to stay up to date on the large number of commonly seen neurological disorders, and I do my best to do that.
It ain’t easy being an old dog.
Dr. Block has a solo neurology practice in Scottsdale, Arizona.
The records came in by fax. A patient who’d recently moved here and needed to connect with a local neurologist.
When I had time, I flipped through the records. He needed ongoing treatment for a rare neurological disease that I’d heard of, but wasn’t otherwise familiar with. It didn’t even exist in the textbooks or conferences when I was in residency. I’d never seen a case of it, just read about it here and there in journals.
I looked it up, reviewed current treatment options, monitoring, and other knowledge about it, then stared at the notes for a minute. Finally, after thinking it over, I attached a sticky note for my secretary that, if the person called, to redirect them to one of the local subspecialty neurology centers.
I have nothing against this patient, but realistically he would be better served seeing someone with time to keep up on advancements in esoteric disorders, not a general neurologist like myself.
Isn’t that why we have subspecialty centers?
Some of it is also me. There was a time in my career when keeping up on newly discovered disorders and their treatments was, well, cool. But after 25 years in practice, that changes.
It’s important to be at least somewhat aware of new developments (such as in this case) as you may encounter them, and need to know when it’s something you can handle and when to send it elsewhere.
Driving home that afternoon I thought, “I’m an old dog. I don’t want to learn new tricks.” Maybe that’s all it is. There are other neurologists my age and older who thrive on the challenge of learning about and treating new and rare disorders that were unknown when they started out. There’s nothing wrong with that.
But I’ve never pretended to be an academic or sub-sub-specialist. My patients depend on me to stay up to date on the large number of commonly seen neurological disorders, and I do my best to do that.
It ain’t easy being an old dog.
Dr. Block has a solo neurology practice in Scottsdale, Arizona.
FDA Grants New Pediatric Arthritis Indications for Upadacitinib
Upadacitinib (Rinvoq) is now indicated for patients aged 2 years or older with active polyarticular juvenile idiopathic arthritis (pJIA) and psoriatic arthritis (PsA) who cannot tolerate or achieve adequate disease response with one or more tumor necrosis factor (TNF) blockers, according to a press release from manufacturer AbbVie.
For the youngest patients, upadacitinib is also available as a weight-based oral solution (Rinvoq LQ) in addition to the previously available tablets, according to the company. JIA, which includes pJIA and juvenile PsA, affects nearly 300,000 children and adolescents in the United States, and alternatives to TNF inhibitor (TNFi) therapy are limited, according to the company. 
“Pediatric patients with pJIA and PsA can be severely limited in their ability to complete daily physical tasks and participate in everyday activities. Understanding their needs today and knowing the likelihood of disease in adulthood underscores the need for additional treatment options,” Aarat Patel, MD, a pediatric rheumatologist at Bon Secours Rheumatology Center, Richmond, Virginia, said in the press release. “Having a treatment option available for patients who do not respond well to a TNFi addresses a need for the healthcare community, patients, and their families,” he said.
Upadacitinib, a Janus kinase (JAK) inhibitor, is being studied for multiple immune-mediated inflammatory diseases. The new indication was supported by data from adults with rheumatoid arthritis (RA) and PsA, 51 pediatric patients with pJIA and active polyarthritis, and safety data from 83 pediatric patients aged 2 years to younger than 18 years with pJIA and active polyarthritis.
In the studies, the drug’s safety in pediatric patients was similar to the known safety profile in adults, which includes increased risk for serious infections such as tuberculosis, cancer, immune system problems, blood clots, and serious allergic reactions to components of the drug, according to the press release. However, the safety and effectiveness of upadacitinib for pJIA and PsA in patients younger than 2 years are unknown.
“Upadacitinib plasma exposures in pediatric patients with pJIA and PsA at the recommended dosage are predicted to be comparable to those observed in adults with RA and PsA based on population pharmacokinetic modeling and simulation,” according to the press release.
Currently, upadacitinib’s only other pediatric indication is for moderate to severe atopic dermatitis in children aged 12 years or older. Upadacitinib also is indicated for treatment of adults with moderate to severe RA, active PsA, active ankylosing spondylitis, active nonradiographic axial spondyloarthritis, and moderate to severe ulcerative colitis and Crohn’s disease, but safety and efficacy for its use in treatment of these conditions in children and adolescents is unknown.
Upadacitinib also is being studied in phase 3 trials for treatment of conditions including alopecia areata, ankylosing spondylitis, atopic dermatitis, axial spondyloarthritis, Crohn’s disease, giant cell arteritis, hidradenitis suppurativa, psoriatic arthritis, RA, systemic lupus erythematosus, Takayasu arteritis, ulcerative colitis, and vitiligo, according to the press release.
Full prescribing information and safety data for upadacitinib are available here.
A version of this article appeared on Medscape.com.
Upadacitinib (Rinvoq) is now indicated for patients aged 2 years or older with active polyarticular juvenile idiopathic arthritis (pJIA) and psoriatic arthritis (PsA) who cannot tolerate or achieve adequate disease response with one or more tumor necrosis factor (TNF) blockers, according to a press release from manufacturer AbbVie.
For the youngest patients, upadacitinib is also available as a weight-based oral solution (Rinvoq LQ) in addition to the previously available tablets, according to the company. JIA, which includes pJIA and juvenile PsA, affects nearly 300,000 children and adolescents in the United States, and alternatives to TNF inhibitor (TNFi) therapy are limited, according to the company.
“Pediatric patients with pJIA and PsA can be severely limited in their ability to complete daily physical tasks and participate in everyday activities. Understanding their needs today and knowing the likelihood of disease in adulthood underscores the need for additional treatment options,” Aarat Patel, MD, a pediatric rheumatologist at Bon Secours Rheumatology Center, Richmond, Virginia, said in the press release. “Having a treatment option available for patients who do not respond well to a TNFi addresses a need for the healthcare community, patients, and their families,” he said.
Upadacitinib, a Janus kinase (JAK) inhibitor, is being studied for multiple immune-mediated inflammatory diseases. The new indication was supported by data from adults with rheumatoid arthritis (RA) and PsA, 51 pediatric patients with pJIA and active polyarthritis, and safety data from 83 pediatric patients aged 2 years to younger than 18 years with pJIA and active polyarthritis.
In the studies, the drug’s safety in pediatric patients was similar to the known safety profile in adults, which includes increased risk for serious infections such as tuberculosis, cancer, immune system problems, blood clots, and serious allergic reactions to components of the drug, according to the press release. However, the safety and effectiveness of upadacitinib for pJIA and PsA in patients younger than 2 years are unknown.
“Upadacitinib plasma exposures in pediatric patients with pJIA and PsA at the recommended dosage are predicted to be comparable to those observed in adults with RA and PsA based on population pharmacokinetic modeling and simulation,” according to the press release.
Currently, upadacitinib’s only other pediatric indication is for moderate to severe atopic dermatitis in children aged 12 years or older. Upadacitinib also is indicated for treatment of adults with moderate to severe RA, active PsA, active ankylosing spondylitis, active nonradiographic axial spondyloarthritis, and moderate to severe ulcerative colitis and Crohn’s disease, but safety and efficacy for its use in treatment of these conditions in children and adolescents is unknown.
Upadacitinib also is being studied in phase 3 trials for treatment of conditions including alopecia areata, ankylosing spondylitis, atopic dermatitis, axial spondyloarthritis, Crohn’s disease, giant cell arteritis, hidradenitis suppurativa, psoriatic arthritis, RA, systemic lupus erythematosus, Takayasu arteritis, ulcerative colitis, and vitiligo, according to the press release.
Full prescribing information and safety data for upadacitinib are available here.
A version of this article appeared on Medscape.com.
Upadacitinib (Rinvoq) is now indicated for patients aged 2 years or older with active polyarticular juvenile idiopathic arthritis (pJIA) and psoriatic arthritis (PsA) who cannot tolerate or achieve adequate disease response with one or more tumor necrosis factor (TNF) blockers, according to a press release from manufacturer AbbVie.
For the youngest patients, upadacitinib is also available as a weight-based oral solution (Rinvoq LQ) in addition to the previously available tablets, according to the company. JIA, which includes pJIA and juvenile PsA, affects nearly 300,000 children and adolescents in the United States, and alternatives to TNF inhibitor (TNFi) therapy are limited, according to the company.
“Pediatric patients with pJIA and PsA can be severely limited in their ability to complete daily physical tasks and participate in everyday activities. Understanding their needs today and knowing the likelihood of disease in adulthood underscores the need for additional treatment options,” Aarat Patel, MD, a pediatric rheumatologist at Bon Secours Rheumatology Center, Richmond, Virginia, said in the press release. “Having a treatment option available for patients who do not respond well to a TNFi addresses a need for the healthcare community, patients, and their families,” he said.
Upadacitinib, a Janus kinase (JAK) inhibitor, is being studied for multiple immune-mediated inflammatory diseases. The new indication was supported by data from adults with rheumatoid arthritis (RA) and PsA, 51 pediatric patients with pJIA and active polyarthritis, and safety data from 83 pediatric patients aged 2 years to younger than 18 years with pJIA and active polyarthritis.
In the studies, the drug’s safety in pediatric patients was similar to the known safety profile in adults, which includes increased risk for serious infections such as tuberculosis, cancer, immune system problems, blood clots, and serious allergic reactions to components of the drug, according to the press release. However, the safety and effectiveness of upadacitinib for pJIA and PsA in patients younger than 2 years are unknown.
“Upadacitinib plasma exposures in pediatric patients with pJIA and PsA at the recommended dosage are predicted to be comparable to those observed in adults with RA and PsA based on population pharmacokinetic modeling and simulation,” according to the press release.
Currently, upadacitinib’s only other pediatric indication is for moderate to severe atopic dermatitis in children aged 12 years or older. Upadacitinib also is indicated for treatment of adults with moderate to severe RA, active PsA, active ankylosing spondylitis, active nonradiographic axial spondyloarthritis, and moderate to severe ulcerative colitis and Crohn’s disease, but safety and efficacy for its use in treatment of these conditions in children and adolescents is unknown.
Upadacitinib also is being studied in phase 3 trials for treatment of conditions including alopecia areata, ankylosing spondylitis, atopic dermatitis, axial spondyloarthritis, Crohn’s disease, giant cell arteritis, hidradenitis suppurativa, psoriatic arthritis, RA, systemic lupus erythematosus, Takayasu arteritis, ulcerative colitis, and vitiligo, according to the press release.
Full prescribing information and safety data for upadacitinib are available here.
A version of this article appeared on Medscape.com.
Inebilizumab ‘MITIGATES’ Flare Risk in IgG4-Related Disease
TOPLINE:
Inebilizumab-cdon, a monoclonal antibody that depletes B cells, reduces the risk for flares without showing any new safety signals in patients with immunoglobulin G4-related disease (IgG4-RD) who have multiorgan disease and are on glucocorticoid therapy.
METHODOLOGY:
- IgG4-RD is an immune-mediated, fibroinflammatory condition that affects multiple organs, causing irreversible organ damage. MITIGATE is the first multinational, placebo-controlled trial involving patients with IgG4-RD.
- Researchers evaluated the efficacy and safety of inebilizumab in 135 adult patients at risk for flares due to a history of multiorgan disease and active disease requiring treatment with glucocorticoids.
- The patients were randomly assigned to receive 300-mg intravenous inebilizumab or placebo on day 1, day 15, and week 26.
- The primary endpoint was the time to the first treated and adjudicated IgG4-RD flare within 52 weeks.
- The secondary endpoints included the annualized flare rate, flare-free and treatment-free complete remission, and flare-free and corticosteroid-free complete remission.
TAKEAWAY:
- Compared with the placebo, inebilizumab reduced the risk for IgG4-RD flares by 87% during the 52-week trial period (hazard ratio, 0.13; P < .0001).
- All the secondary endpoints showed improvement following treatment with inebilizumab.
- The most common adverse reactions with inebilizumab, as observed in a previous trial for neuromyelitis optica spectrum disorder, were urinary tract infection and arthralgia.
- There were no new safety signals in the MITIGATE trial.
IN PRACTICE:
“These data mark a major milestone for the IgG4-RD community and provide substantial insight into not only how inebilizumab can help manage IgG4-RD but also key insights into the nature of this condition,” John Stone, MD, MPH, principal investigator, said in a news release.
SOURCE:
Dr. Stone, a professor of medicine at the Harvard Medical School and the Edward A. Fox Chair in Medicine at the Massachusetts General Hospital, Boston, led this study.
LIMITATIONS:
This press release did not discuss any limitations of the current study.
DISCLOSURES:
This study was funded by Mitsubishi Tanabe Pharma and Hansoh Pharma and sponsored by Amgen. The author disclosures were not available.
A version of this article appeared on Medscape.com.
TOPLINE:
Inebilizumab-cdon, a monoclonal antibody that depletes B cells, reduces the risk for flares without showing any new safety signals in patients with immunoglobulin G4-related disease (IgG4-RD) who have multiorgan disease and are on glucocorticoid therapy.
METHODOLOGY:
- IgG4-RD is an immune-mediated, fibroinflammatory condition that affects multiple organs, causing irreversible organ damage. MITIGATE is the first multinational, placebo-controlled trial involving patients with IgG4-RD.
- Researchers evaluated the efficacy and safety of inebilizumab in 135 adult patients at risk for flares due to a history of multiorgan disease and active disease requiring treatment with glucocorticoids.
- The patients were randomly assigned to receive 300-mg intravenous inebilizumab or placebo on day 1, day 15, and week 26.
- The primary endpoint was the time to the first treated and adjudicated IgG4-RD flare within 52 weeks.
- The secondary endpoints included the annualized flare rate, flare-free and treatment-free complete remission, and flare-free and corticosteroid-free complete remission.
TAKEAWAY:
- Compared with the placebo, inebilizumab reduced the risk for IgG4-RD flares by 87% during the 52-week trial period (hazard ratio, 0.13; P < .0001).
- All the secondary endpoints showed improvement following treatment with inebilizumab.
- The most common adverse reactions with inebilizumab, as observed in a previous trial for neuromyelitis optica spectrum disorder, were urinary tract infection and arthralgia.
- There were no new safety signals in the MITIGATE trial.
IN PRACTICE:
“These data mark a major milestone for the IgG4-RD community and provide substantial insight into not only how inebilizumab can help manage IgG4-RD but also key insights into the nature of this condition,” John Stone, MD, MPH, principal investigator, said in a news release.
SOURCE:
Dr. Stone, a professor of medicine at the Harvard Medical School and the Edward A. Fox Chair in Medicine at the Massachusetts General Hospital, Boston, led this study.
LIMITATIONS:
This press release did not discuss any limitations of the current study.
DISCLOSURES:
This study was funded by Mitsubishi Tanabe Pharma and Hansoh Pharma and sponsored by Amgen. The author disclosures were not available.
A version of this article appeared on Medscape.com.
TOPLINE:
Inebilizumab-cdon, a monoclonal antibody that depletes B cells, reduces the risk for flares without showing any new safety signals in patients with immunoglobulin G4-related disease (IgG4-RD) who have multiorgan disease and are on glucocorticoid therapy.
METHODOLOGY:
- IgG4-RD is an immune-mediated, fibroinflammatory condition that affects multiple organs, causing irreversible organ damage. MITIGATE is the first multinational, placebo-controlled trial involving patients with IgG4-RD.
- Researchers evaluated the efficacy and safety of inebilizumab in 135 adult patients at risk for flares due to a history of multiorgan disease and active disease requiring treatment with glucocorticoids.
- The patients were randomly assigned to receive 300-mg intravenous inebilizumab or placebo on day 1, day 15, and week 26.
- The primary endpoint was the time to the first treated and adjudicated IgG4-RD flare within 52 weeks.
- The secondary endpoints included the annualized flare rate, flare-free and treatment-free complete remission, and flare-free and corticosteroid-free complete remission.
TAKEAWAY:
- Compared with the placebo, inebilizumab reduced the risk for IgG4-RD flares by 87% during the 52-week trial period (hazard ratio, 0.13; P < .0001).
- All the secondary endpoints showed improvement following treatment with inebilizumab.
- The most common adverse reactions with inebilizumab, as observed in a previous trial for neuromyelitis optica spectrum disorder, were urinary tract infection and arthralgia.
- There were no new safety signals in the MITIGATE trial.
IN PRACTICE:
“These data mark a major milestone for the IgG4-RD community and provide substantial insight into not only how inebilizumab can help manage IgG4-RD but also key insights into the nature of this condition,” John Stone, MD, MPH, principal investigator, said in a news release.
SOURCE:
Dr. Stone, a professor of medicine at the Harvard Medical School and the Edward A. Fox Chair in Medicine at the Massachusetts General Hospital, Boston, led this study.
LIMITATIONS:
This press release did not discuss any limitations of the current study.
DISCLOSURES:
This study was funded by Mitsubishi Tanabe Pharma and Hansoh Pharma and sponsored by Amgen. The author disclosures were not available.
A version of this article appeared on Medscape.com.
Belimumab Autoinjector Approved for Pediatric Lupus
The US Food and Drug Administration (FDA) has approved Benlysta (belimumab) autoinjector for patients aged 5 years or older with active systemic lupus erythematosus (SLE) on standard therapy. This is the first time that children with SLE can receive this treatment at home, according to a GSK press release.
Prior to this approval, pediatric patients aged 5 years or older could receive belimumab only intravenously via a 1-hour infusion in a hospital or clinic setting.
“Going to the doctor’s office once every 4 weeks can be a logistical hurdle for some children and their caregivers, so having the option to administer Benlysta in the comfort of their home provides much-needed flexibility,” Mary Crimmings, the interim CEO and senior vice president for marketing and communications at the Lupus Foundation of America, said in a statement.
An estimated 5000-10,000 children in the United States are living with SLE.
Belimumab is a B-lymphocyte stimulator–specific inhibitor approved for the treatment of active SLE and active lupus nephritis in patients aged 5 years or older receiving standard therapy. This approval of the subcutaneous administration of belimumab applies only to pediatric patients with SLE.
The 200-mg injection can be administered once every week for children who weigh ≥ 40 kg and should be given once every 2 weeks for children weighing between 15 and 40 kg.
The autoinjector “will be available immediately” for caregivers, the company announcement said.
“Patients are our top priority, and we are always working to innovate solutions that can improve lives and address unmet needs,” Court Horncastle, senior vice president and head of US specialty at GSK, said in the press release. “This approval for an at-home treatment is the first and only of its kind for children with lupus and is a testament to our continued commitment to the lupus community.”
A version of this article appeared on Medscape.com.
The US Food and Drug Administration (FDA) has approved Benlysta (belimumab) autoinjector for patients aged 5 years or older with active systemic lupus erythematosus (SLE) on standard therapy. This is the first time that children with SLE can receive this treatment at home, according to a GSK press release.
Prior to this approval, pediatric patients aged 5 years or older could receive belimumab only intravenously via a 1-hour infusion in a hospital or clinic setting.
“Going to the doctor’s office once every 4 weeks can be a logistical hurdle for some children and their caregivers, so having the option to administer Benlysta in the comfort of their home provides much-needed flexibility,” Mary Crimmings, the interim CEO and senior vice president for marketing and communications at the Lupus Foundation of America, said in a statement.
An estimated 5000-10,000 children in the United States are living with SLE.
Belimumab is a B-lymphocyte stimulator–specific inhibitor approved for the treatment of active SLE and active lupus nephritis in patients aged 5 years or older receiving standard therapy. This approval of the subcutaneous administration of belimumab applies only to pediatric patients with SLE.
The 200-mg injection can be administered once every week for children who weigh ≥ 40 kg and should be given once every 2 weeks for children weighing between 15 and 40 kg.
The autoinjector “will be available immediately” for caregivers, the company announcement said.
“Patients are our top priority, and we are always working to innovate solutions that can improve lives and address unmet needs,” Court Horncastle, senior vice president and head of US specialty at GSK, said in the press release. “This approval for an at-home treatment is the first and only of its kind for children with lupus and is a testament to our continued commitment to the lupus community.”
A version of this article appeared on Medscape.com.
The US Food and Drug Administration (FDA) has approved Benlysta (belimumab) autoinjector for patients aged 5 years or older with active systemic lupus erythematosus (SLE) on standard therapy. This is the first time that children with SLE can receive this treatment at home, according to a GSK press release.
Prior to this approval, pediatric patients aged 5 years or older could receive belimumab only intravenously via a 1-hour infusion in a hospital or clinic setting.
“Going to the doctor’s office once every 4 weeks can be a logistical hurdle for some children and their caregivers, so having the option to administer Benlysta in the comfort of their home provides much-needed flexibility,” Mary Crimmings, the interim CEO and senior vice president for marketing and communications at the Lupus Foundation of America, said in a statement.
An estimated 5000-10,000 children in the United States are living with SLE.
Belimumab is a B-lymphocyte stimulator–specific inhibitor approved for the treatment of active SLE and active lupus nephritis in patients aged 5 years or older receiving standard therapy. This approval of the subcutaneous administration of belimumab applies only to pediatric patients with SLE.
The 200-mg injection can be administered once every week for children who weigh ≥ 40 kg and should be given once every 2 weeks for children weighing between 15 and 40 kg.
The autoinjector “will be available immediately” for caregivers, the company announcement said.
“Patients are our top priority, and we are always working to innovate solutions that can improve lives and address unmet needs,” Court Horncastle, senior vice president and head of US specialty at GSK, said in the press release. “This approval for an at-home treatment is the first and only of its kind for children with lupus and is a testament to our continued commitment to the lupus community.”
A version of this article appeared on Medscape.com.
Don’t Miss the Dx: A 24-Year-Old Man With Sudden-Onset Hematuria, Proteinuria, Edema, and Hypertension
Presentation
A 24-year-old man with no significant past medical history presents to urgent care with a 1-week history of sudden-onset dark urine, leg swelling, and unusually high blood pressure readings, with recent values around 160/100 mm Hg. Physical examination reveals pitting edema up to the mid-shins and mild periorbital edema, with an elevated blood pressure of 158/98 mm Hg. Past medical history was significant for frequent upper respiratory tract infections over the past year. Laboratory findings include hematuria, proteinuria, and a raised serum creatinine level at 1.8 mg/dL, indicating a reduced estimated glomerular filtration rate (eGFR) of 45 mL/min/1.73 m2. Other tests such as a complete blood count and comprehensive metabolic panel (except for creatinine and albumin) are within normal limits. Given these findings, the patient is referred to nephrology for further evaluation to determine the underlying cause of his renal symptoms.
Differential Diagnosis
A glomerular disease can be assumed to be present if the patient manifests glomerular hematuria, glomerular proteinuria, or both, such as in this patient.
Glomerulonephritis occurs due to inflammation in the glomeruli, which leads to blood in urine, variable degrees of protein in urine (sometimes in the nephrotic range), and white blood cells in urine without any urinary tract infection. Patients may also experience hypertension and kidney function impairment. Diagnoses to consider include:
- Postinfectious glomerulonephritis
- Crescentic glomerulonephritis
- Diffuse proliferative glomerulonephritis
- Glomerulonephritis associated with nonstreptococcal infection
- Membranoproliferative glomerulonephritis
- Membranous glomerulonephritis
- Poststreptococcal glomerulonephritis
- Rapidly Progressive glomerulonephritis
All patients presenting with proteinuria and hematuria should undergo a thorough evaluation for glomerular disease, which generally involves laboratory testing and, in most patients, a kidney biopsy to obtain a definitive diagnosis.
Diagnosis
This patient underwent a renal biopsy, which showed C3-dominant deposition by immunofluorescence; electron microscopy (EM) showed discontinuous, ill-defined intramembranous deposits; and mass spectrometry showed terminal complement components in C3 deposits. The patient was diagnosed with C3 glomerulonephritis (C3G).
The diagnosis of C3G is established by kidney biopsy demonstrating the characteristic findings on immunofluorescence microscopy or EM in a patient with suspected glomerulonephritis. In patients with biopsy-confirmed C3G, additional testing should be performed to help identify the underlying etiology of the glomerulopathy to help determine therapy.
For all patients diagnosed with C3G, especially those who are older than 50 years, it is important to rule out monoclonal gammopathy which can be done through various tests such as serum protein electrophoresis and immunofixation, serum free light chains, and urine protein electrophoresis and immunofixation. The presence of a paraprotein, including a monoclonal light chain, can activate the alternative complement cascade and may be responsible for the condition.
Expert opinion recommends a comprehensive complement evaluation for all C3 glomerulopathy patients, including overall complement activity assessment, serum levels measurement of complement proteins and their split products, and autoantibodies screening.
Complement evaluation may include:
- Serum C3 and C4
- Soluble C5b-9 (soluble membrane attack complex)
- Serum factor H
- Serum factor B, factor I, and membrane cofactor protein (MCP; CD46)
All patients with C3G should also undergo screening for autoantibodies:
- C3 nephritic factor (C3NeF)
- C5 nephritic factor (C5NeF)
- C4 nephritic factor (C4NeF)
- Other autoantibodies against factor H, factor B, and/or C3b
It is recommended that genetic testing be considered for patients with C3 glomerulopathy to screen for complement genes including C3, CFB, CFH, CFHR5, and CFI and copy number variations and rearrangements of the CFH-CFHR gene cluster. The value of genetic testing in the clinical setting is still being defined; however, it has been observed that patients with mutations in complement genes generally respond less favorably to mycophenolate mofetil (MMF) compared with those who are positive for nephritic factors.
Management
The patient was managed with an angiotensin-converting enzyme (ACE) inhibitor to treat proteinuria and hypertension and MMF for immunosuppression. Enrollment in a clinical trial of an investigational complement inhibitor was discussed with the patient.
Currently, there are no therapeutic agents specifically designed to target the underlying complement dysregulation that occurs in individuals with C3G, and an optimal treatment for C3 glomerulopathy has not been established.
Various nonspecific therapies have been used to treat C3G, including plasmapheresis, steroids, rituximab, cyclophosphamide, and MMF and have shown positive results. For patients with C3G who have a known genetic variant (eg, CFH mutation) or who have acute kidney injury, plasmapheresis and plasma exchange may be helpful. Using these agents judiciously and in conjunction with optimal blood pressure control is important for maximum benefit in treating C3G. When someone with end-stage renal disease (ESRD) caused by C3G chooses to have a kidney transplant, it is important to know that C3G is likely to return in almost all cases and is the leading cause of transplant failure in 50%-90% of recipients.
Prognosis
The prognosis of C3G varies and is affected by various clinical and histological factors. While some patients may have consistently low levels of protein in their urine and maintain stable kidney function over time, others may experience severe nephrotic syndrome or rapidly progressive glomerulonephritis, which often leads to a poor prognosis.
Progression to ESRD is a major complication of C3G, with approximately 70% of affected children and 30%-50% of adults reaching this stage. In addition, disease recurrence is common after kidney transplantation, with about 50% of patients experiencing allograft loss within 10 years. Predictive factors for disease progression, although not robustly established, include initial eGFR at diagnosis, percentage of tubular atrophy, and extent of interstitial fibrosis in the cortical area as observed on kidney biopsies.
Clinical Takeaways
For patients exhibiting symptoms like proteinuria and hematuria indicative of glomerulonephritis, a comprehensive evaluation including laboratory tests and a kidney biopsy is essential to confirm a C3G diagnosis through characteristic findings on immunofluorescence microscopy or electron microscopy.
Additional tests to rule out associated conditions like monoclonal gammopathy and comprehensive complement evaluation are also recommended to understand the underlying etiology and guide therapy.
Though there are no treatments specifically targeting the underlying complement dysregulation unique to C3G, nonspecific therapies like ACE inhibitors, immunosuppressants (eg, MMF), and plasmapheresis are commonly used.
Some anticomplement therapies are available or under investigation, which might offer more targeted intervention options.
The prognosis for patients with C3G can vary widely and factors such as initial eGFR, the extent of tubular atrophy, and interstitial fibrosis are important predictors of disease progression.
Dr. Alper is an associate professor, Nephrology, Tulane University School of Medicine, New Orleans, Louisiana. He has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Presentation
A 24-year-old man with no significant past medical history presents to urgent care with a 1-week history of sudden-onset dark urine, leg swelling, and unusually high blood pressure readings, with recent values around 160/100 mm Hg. Physical examination reveals pitting edema up to the mid-shins and mild periorbital edema, with an elevated blood pressure of 158/98 mm Hg. Past medical history was significant for frequent upper respiratory tract infections over the past year. Laboratory findings include hematuria, proteinuria, and a raised serum creatinine level at 1.8 mg/dL, indicating a reduced estimated glomerular filtration rate (eGFR) of 45 mL/min/1.73 m2. Other tests such as a complete blood count and comprehensive metabolic panel (except for creatinine and albumin) are within normal limits. Given these findings, the patient is referred to nephrology for further evaluation to determine the underlying cause of his renal symptoms.
Differential Diagnosis
A glomerular disease can be assumed to be present if the patient manifests glomerular hematuria, glomerular proteinuria, or both, such as in this patient.
Glomerulonephritis occurs due to inflammation in the glomeruli, which leads to blood in urine, variable degrees of protein in urine (sometimes in the nephrotic range), and white blood cells in urine without any urinary tract infection. Patients may also experience hypertension and kidney function impairment. Diagnoses to consider include:
- Postinfectious glomerulonephritis
- Crescentic glomerulonephritis
- Diffuse proliferative glomerulonephritis
- Glomerulonephritis associated with nonstreptococcal infection
- Membranoproliferative glomerulonephritis
- Membranous glomerulonephritis
- Poststreptococcal glomerulonephritis
- Rapidly Progressive glomerulonephritis
All patients presenting with proteinuria and hematuria should undergo a thorough evaluation for glomerular disease, which generally involves laboratory testing and, in most patients, a kidney biopsy to obtain a definitive diagnosis.
Diagnosis
This patient underwent a renal biopsy, which showed C3-dominant deposition by immunofluorescence; electron microscopy (EM) showed discontinuous, ill-defined intramembranous deposits; and mass spectrometry showed terminal complement components in C3 deposits. The patient was diagnosed with C3 glomerulonephritis (C3G).
The diagnosis of C3G is established by kidney biopsy demonstrating the characteristic findings on immunofluorescence microscopy or EM in a patient with suspected glomerulonephritis. In patients with biopsy-confirmed C3G, additional testing should be performed to help identify the underlying etiology of the glomerulopathy to help determine therapy.
For all patients diagnosed with C3G, especially those who are older than 50 years, it is important to rule out monoclonal gammopathy which can be done through various tests such as serum protein electrophoresis and immunofixation, serum free light chains, and urine protein electrophoresis and immunofixation. The presence of a paraprotein, including a monoclonal light chain, can activate the alternative complement cascade and may be responsible for the condition.
Expert opinion recommends a comprehensive complement evaluation for all C3 glomerulopathy patients, including overall complement activity assessment, serum levels measurement of complement proteins and their split products, and autoantibodies screening.
Complement evaluation may include:
- Serum C3 and C4
- Soluble C5b-9 (soluble membrane attack complex)
- Serum factor H
- Serum factor B, factor I, and membrane cofactor protein (MCP; CD46)
All patients with C3G should also undergo screening for autoantibodies:
- C3 nephritic factor (C3NeF)
- C5 nephritic factor (C5NeF)
- C4 nephritic factor (C4NeF)
- Other autoantibodies against factor H, factor B, and/or C3b
It is recommended that genetic testing be considered for patients with C3 glomerulopathy to screen for complement genes including C3, CFB, CFH, CFHR5, and CFI and copy number variations and rearrangements of the CFH-CFHR gene cluster. The value of genetic testing in the clinical setting is still being defined; however, it has been observed that patients with mutations in complement genes generally respond less favorably to mycophenolate mofetil (MMF) compared with those who are positive for nephritic factors.
Management
The patient was managed with an angiotensin-converting enzyme (ACE) inhibitor to treat proteinuria and hypertension and MMF for immunosuppression. Enrollment in a clinical trial of an investigational complement inhibitor was discussed with the patient.
Currently, there are no therapeutic agents specifically designed to target the underlying complement dysregulation that occurs in individuals with C3G, and an optimal treatment for C3 glomerulopathy has not been established.
Various nonspecific therapies have been used to treat C3G, including plasmapheresis, steroids, rituximab, cyclophosphamide, and MMF and have shown positive results. For patients with C3G who have a known genetic variant (eg, CFH mutation) or who have acute kidney injury, plasmapheresis and plasma exchange may be helpful. Using these agents judiciously and in conjunction with optimal blood pressure control is important for maximum benefit in treating C3G. When someone with end-stage renal disease (ESRD) caused by C3G chooses to have a kidney transplant, it is important to know that C3G is likely to return in almost all cases and is the leading cause of transplant failure in 50%-90% of recipients.
Prognosis
The prognosis of C3G varies and is affected by various clinical and histological factors. While some patients may have consistently low levels of protein in their urine and maintain stable kidney function over time, others may experience severe nephrotic syndrome or rapidly progressive glomerulonephritis, which often leads to a poor prognosis.
Progression to ESRD is a major complication of C3G, with approximately 70% of affected children and 30%-50% of adults reaching this stage. In addition, disease recurrence is common after kidney transplantation, with about 50% of patients experiencing allograft loss within 10 years. Predictive factors for disease progression, although not robustly established, include initial eGFR at diagnosis, percentage of tubular atrophy, and extent of interstitial fibrosis in the cortical area as observed on kidney biopsies.
Clinical Takeaways
For patients exhibiting symptoms like proteinuria and hematuria indicative of glomerulonephritis, a comprehensive evaluation including laboratory tests and a kidney biopsy is essential to confirm a C3G diagnosis through characteristic findings on immunofluorescence microscopy or electron microscopy.
Additional tests to rule out associated conditions like monoclonal gammopathy and comprehensive complement evaluation are also recommended to understand the underlying etiology and guide therapy.
Though there are no treatments specifically targeting the underlying complement dysregulation unique to C3G, nonspecific therapies like ACE inhibitors, immunosuppressants (eg, MMF), and plasmapheresis are commonly used.
Some anticomplement therapies are available or under investigation, which might offer more targeted intervention options.
The prognosis for patients with C3G can vary widely and factors such as initial eGFR, the extent of tubular atrophy, and interstitial fibrosis are important predictors of disease progression.
Dr. Alper is an associate professor, Nephrology, Tulane University School of Medicine, New Orleans, Louisiana. He has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Presentation
A 24-year-old man with no significant past medical history presents to urgent care with a 1-week history of sudden-onset dark urine, leg swelling, and unusually high blood pressure readings, with recent values around 160/100 mm Hg. Physical examination reveals pitting edema up to the mid-shins and mild periorbital edema, with an elevated blood pressure of 158/98 mm Hg. Past medical history was significant for frequent upper respiratory tract infections over the past year. Laboratory findings include hematuria, proteinuria, and a raised serum creatinine level at 1.8 mg/dL, indicating a reduced estimated glomerular filtration rate (eGFR) of 45 mL/min/1.73 m2. Other tests such as a complete blood count and comprehensive metabolic panel (except for creatinine and albumin) are within normal limits. Given these findings, the patient is referred to nephrology for further evaluation to determine the underlying cause of his renal symptoms.
Differential Diagnosis
A glomerular disease can be assumed to be present if the patient manifests glomerular hematuria, glomerular proteinuria, or both, such as in this patient.
Glomerulonephritis occurs due to inflammation in the glomeruli, which leads to blood in urine, variable degrees of protein in urine (sometimes in the nephrotic range), and white blood cells in urine without any urinary tract infection. Patients may also experience hypertension and kidney function impairment. Diagnoses to consider include:
- Postinfectious glomerulonephritis
- Crescentic glomerulonephritis
- Diffuse proliferative glomerulonephritis
- Glomerulonephritis associated with nonstreptococcal infection
- Membranoproliferative glomerulonephritis
- Membranous glomerulonephritis
- Poststreptococcal glomerulonephritis
- Rapidly Progressive glomerulonephritis
All patients presenting with proteinuria and hematuria should undergo a thorough evaluation for glomerular disease, which generally involves laboratory testing and, in most patients, a kidney biopsy to obtain a definitive diagnosis.
Diagnosis
This patient underwent a renal biopsy, which showed C3-dominant deposition by immunofluorescence; electron microscopy (EM) showed discontinuous, ill-defined intramembranous deposits; and mass spectrometry showed terminal complement components in C3 deposits. The patient was diagnosed with C3 glomerulonephritis (C3G).
The diagnosis of C3G is established by kidney biopsy demonstrating the characteristic findings on immunofluorescence microscopy or EM in a patient with suspected glomerulonephritis. In patients with biopsy-confirmed C3G, additional testing should be performed to help identify the underlying etiology of the glomerulopathy to help determine therapy.
For all patients diagnosed with C3G, especially those who are older than 50 years, it is important to rule out monoclonal gammopathy which can be done through various tests such as serum protein electrophoresis and immunofixation, serum free light chains, and urine protein electrophoresis and immunofixation. The presence of a paraprotein, including a monoclonal light chain, can activate the alternative complement cascade and may be responsible for the condition.
Expert opinion recommends a comprehensive complement evaluation for all C3 glomerulopathy patients, including overall complement activity assessment, serum levels measurement of complement proteins and their split products, and autoantibodies screening.
Complement evaluation may include:
- Serum C3 and C4
- Soluble C5b-9 (soluble membrane attack complex)
- Serum factor H
- Serum factor B, factor I, and membrane cofactor protein (MCP; CD46)
All patients with C3G should also undergo screening for autoantibodies:
- C3 nephritic factor (C3NeF)
- C5 nephritic factor (C5NeF)
- C4 nephritic factor (C4NeF)
- Other autoantibodies against factor H, factor B, and/or C3b
It is recommended that genetic testing be considered for patients with C3 glomerulopathy to screen for complement genes including C3, CFB, CFH, CFHR5, and CFI and copy number variations and rearrangements of the CFH-CFHR gene cluster. The value of genetic testing in the clinical setting is still being defined; however, it has been observed that patients with mutations in complement genes generally respond less favorably to mycophenolate mofetil (MMF) compared with those who are positive for nephritic factors.
Management
The patient was managed with an angiotensin-converting enzyme (ACE) inhibitor to treat proteinuria and hypertension and MMF for immunosuppression. Enrollment in a clinical trial of an investigational complement inhibitor was discussed with the patient.
Currently, there are no therapeutic agents specifically designed to target the underlying complement dysregulation that occurs in individuals with C3G, and an optimal treatment for C3 glomerulopathy has not been established.
Various nonspecific therapies have been used to treat C3G, including plasmapheresis, steroids, rituximab, cyclophosphamide, and MMF and have shown positive results. For patients with C3G who have a known genetic variant (eg, CFH mutation) or who have acute kidney injury, plasmapheresis and plasma exchange may be helpful. Using these agents judiciously and in conjunction with optimal blood pressure control is important for maximum benefit in treating C3G. When someone with end-stage renal disease (ESRD) caused by C3G chooses to have a kidney transplant, it is important to know that C3G is likely to return in almost all cases and is the leading cause of transplant failure in 50%-90% of recipients.
Prognosis
The prognosis of C3G varies and is affected by various clinical and histological factors. While some patients may have consistently low levels of protein in their urine and maintain stable kidney function over time, others may experience severe nephrotic syndrome or rapidly progressive glomerulonephritis, which often leads to a poor prognosis.
Progression to ESRD is a major complication of C3G, with approximately 70% of affected children and 30%-50% of adults reaching this stage. In addition, disease recurrence is common after kidney transplantation, with about 50% of patients experiencing allograft loss within 10 years. Predictive factors for disease progression, although not robustly established, include initial eGFR at diagnosis, percentage of tubular atrophy, and extent of interstitial fibrosis in the cortical area as observed on kidney biopsies.
Clinical Takeaways
For patients exhibiting symptoms like proteinuria and hematuria indicative of glomerulonephritis, a comprehensive evaluation including laboratory tests and a kidney biopsy is essential to confirm a C3G diagnosis through characteristic findings on immunofluorescence microscopy or electron microscopy.
Additional tests to rule out associated conditions like monoclonal gammopathy and comprehensive complement evaluation are also recommended to understand the underlying etiology and guide therapy.
Though there are no treatments specifically targeting the underlying complement dysregulation unique to C3G, nonspecific therapies like ACE inhibitors, immunosuppressants (eg, MMF), and plasmapheresis are commonly used.
Some anticomplement therapies are available or under investigation, which might offer more targeted intervention options.
The prognosis for patients with C3G can vary widely and factors such as initial eGFR, the extent of tubular atrophy, and interstitial fibrosis are important predictors of disease progression.
Dr. Alper is an associate professor, Nephrology, Tulane University School of Medicine, New Orleans, Louisiana. He has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.