Rheumatology

COPENHAGEN – Use of the dual interleukin (IL)–17 inhibitor bimekizumab (Bimzelx) was associated with rapid reductions in signs and symptoms of radiographic axial spondyloarthritis, reported investigators in the BE MOBILE 2 phase 3 trial.

At least half of all patients achieved an Ankylosing Spondylitis Disease Activity Score (ASDAS) of less than 2.1 by week 24 of treatment with bimekizumab, and there were marked reductions in objective signs of inflammation, reported Désiréé van der Heijde, MD, PhD, of Leiden (Netherlands) University Medical Center.

“The safety we have seen in this trial was consistent with what we have seen [with bimekizumab] in other trials and other diseases,” she said at the annual European Congress of Rheumatology.
 

IL-17 inhibitor times 2

Bimekizumab is a monoclonal immunoglobulin 1 antibody that selectively inhibits IL-17A and IL-17F. It is approved in the European Union for treating adults with moderate to severe plaque psoriasis.

In the BE MOBILE 2 trial, investigators enrolled patients aged 18 years and older who had ankylosing spondylitis, who met modified New York criteria, who had active disease at screening and at baseline, as defined by having a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of 4 or more and spinal pain of 4 or more on a scale of 0-10, and whose disease failed to respond to two different NSAIDs or who were either intolerant of or had contraindications to NSAIDs.

The patients were randomly assigned on a 2:1 basis to receive either bimekizumab 160 mg every 4 weeks (221 patients) or placebo (111 patients) for 16 weeks. All patients were switched over at 16 weeks to bimekizumab maintenance for up to 1 year of total treatment.

Dr. Van der Heijde reported 24-week data from the trial, including data from 8 weeks of additional follow-up.
 

All endpoints met

The trial met its primary endpoint of 40% improvement in Assessment of Spondyloarthritis International Society response criteria (ASAS 40) at week 16. There was a 44.8% improvement with bimekizumab, compared with 22.6% with placebo (P < .001).

All secondary endpoints also favored the bimekizumab arm, including ASAS 40 among patients who had not previously received a tumor necrosis factor (TNF)–alpha inhibitor, ASAS 20, BASDAI functional index, ankylosing spondylitis quality-of-life index, and others.

Responses to bimekizumab were consistent across subpopulations of patients with or without prior TNF-alpha inhibitor exposure, Dr. van der Heidje said.

In addition, use of bimekizumab was associated with a significant improvement from baseline, compared with placebo, in objective measures of inflammation, including MRI spine Berlin score at week 16 (mean, –2.3 vs. 0; P < .001), Spondylitis Research Consortium of Canada (SPARCC) MRI sacroiliac joint score at week 16 (mean, –5.6 vs. 1.1), and high-sensitivity C-reactive protein at week 16 (mean, 2.4 vs. 6.3 mg/L; P < .001).

The most frequent treatment-related adverse events were nasopharyngitis, diarrhea, and oral candidiasis, all of which were more common in the bimekizumab arm, as well as headache, the incidence of which was similar between the arms.

Overall, 6.4% of patients taking bimekizumab had fungal infections, compared with none in the placebo group. The infections were mild or moderate, localized, and mucocutaneous in nature. Only two patients discontinued the drug because of fungal infections: one for oral candidiasis, and one for esophageal candidiasis.

‘Promising results’

Fabian Proft, MD, head of the clinical trials unit at Charité University Hospital in Berlin, who was not involved in the study, told this news organization that the data looked very good.

“These are the first phase 3 data on dual inhibition of IL-17A and F with bimekizumab in axial spondyloarthritis, and the data are really promising,” he said. “For nonradiographic disease, the data also look very promising, and when we’re looking into the future, it might be a therapeutic option for us as treating rheumatologists.”

The study was funded by UCB Pharma. Dr. van der Heijde has received consulting fees from the company and others. Dr. Proft has consulted for and has been on the speaker’s bureau for UCB and other pharmaceutical companies.

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

COPENHAGEN – Use of the dual interleukin (IL)–17 inhibitor bimekizumab (Bimzelx) was associated with rapid reductions in signs and symptoms of radiographic axial spondyloarthritis, reported investigators in the BE MOBILE 2 phase 3 trial.

At least half of all patients achieved an Ankylosing Spondylitis Disease Activity Score (ASDAS) of less than 2.1 by week 24 of treatment with bimekizumab, and there were marked reductions in objective signs of inflammation, reported Désiréé van der Heijde, MD, PhD, of Leiden (Netherlands) University Medical Center.

“The safety we have seen in this trial was consistent with what we have seen [with bimekizumab] in other trials and other diseases,” she said at the annual European Congress of Rheumatology.
 

IL-17 inhibitor times 2

Bimekizumab is a monoclonal immunoglobulin 1 antibody that selectively inhibits IL-17A and IL-17F. It is approved in the European Union for treating adults with moderate to severe plaque psoriasis.

In the BE MOBILE 2 trial, investigators enrolled patients aged 18 years and older who had ankylosing spondylitis, who met modified New York criteria, who had active disease at screening and at baseline, as defined by having a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of 4 or more and spinal pain of 4 or more on a scale of 0-10, and whose disease failed to respond to two different NSAIDs or who were either intolerant of or had contraindications to NSAIDs.

The patients were randomly assigned on a 2:1 basis to receive either bimekizumab 160 mg every 4 weeks (221 patients) or placebo (111 patients) for 16 weeks. All patients were switched over at 16 weeks to bimekizumab maintenance for up to 1 year of total treatment.

Dr. Van der Heijde reported 24-week data from the trial, including data from 8 weeks of additional follow-up.
 

All endpoints met

The trial met its primary endpoint of 40% improvement in Assessment of Spondyloarthritis International Society response criteria (ASAS 40) at week 16. There was a 44.8% improvement with bimekizumab, compared with 22.6% with placebo (P < .001).

All secondary endpoints also favored the bimekizumab arm, including ASAS 40 among patients who had not previously received a tumor necrosis factor (TNF)–alpha inhibitor, ASAS 20, BASDAI functional index, ankylosing spondylitis quality-of-life index, and others.

Responses to bimekizumab were consistent across subpopulations of patients with or without prior TNF-alpha inhibitor exposure, Dr. van der Heidje said.

In addition, use of bimekizumab was associated with a significant improvement from baseline, compared with placebo, in objective measures of inflammation, including MRI spine Berlin score at week 16 (mean, –2.3 vs. 0; P < .001), Spondylitis Research Consortium of Canada (SPARCC) MRI sacroiliac joint score at week 16 (mean, –5.6 vs. 1.1), and high-sensitivity C-reactive protein at week 16 (mean, 2.4 vs. 6.3 mg/L; P < .001).

The most frequent treatment-related adverse events were nasopharyngitis, diarrhea, and oral candidiasis, all of which were more common in the bimekizumab arm, as well as headache, the incidence of which was similar between the arms.

Overall, 6.4% of patients taking bimekizumab had fungal infections, compared with none in the placebo group. The infections were mild or moderate, localized, and mucocutaneous in nature. Only two patients discontinued the drug because of fungal infections: one for oral candidiasis, and one for esophageal candidiasis.

‘Promising results’

Fabian Proft, MD, head of the clinical trials unit at Charité University Hospital in Berlin, who was not involved in the study, told this news organization that the data looked very good.

“These are the first phase 3 data on dual inhibition of IL-17A and F with bimekizumab in axial spondyloarthritis, and the data are really promising,” he said. “For nonradiographic disease, the data also look very promising, and when we’re looking into the future, it might be a therapeutic option for us as treating rheumatologists.”

The study was funded by UCB Pharma. Dr. van der Heijde has received consulting fees from the company and others. Dr. Proft has consulted for and has been on the speaker’s bureau for UCB and other pharmaceutical companies.

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

COPENHAGEN – Use of the dual interleukin (IL)–17 inhibitor bimekizumab (Bimzelx) was associated with rapid reductions in signs and symptoms of radiographic axial spondyloarthritis, reported investigators in the BE MOBILE 2 phase 3 trial.

At least half of all patients achieved an Ankylosing Spondylitis Disease Activity Score (ASDAS) of less than 2.1 by week 24 of treatment with bimekizumab, and there were marked reductions in objective signs of inflammation, reported Désiréé van der Heijde, MD, PhD, of Leiden (Netherlands) University Medical Center.

“The safety we have seen in this trial was consistent with what we have seen [with bimekizumab] in other trials and other diseases,” she said at the annual European Congress of Rheumatology.
 

IL-17 inhibitor times 2

Bimekizumab is a monoclonal immunoglobulin 1 antibody that selectively inhibits IL-17A and IL-17F. It is approved in the European Union for treating adults with moderate to severe plaque psoriasis.

In the BE MOBILE 2 trial, investigators enrolled patients aged 18 years and older who had ankylosing spondylitis, who met modified New York criteria, who had active disease at screening and at baseline, as defined by having a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of 4 or more and spinal pain of 4 or more on a scale of 0-10, and whose disease failed to respond to two different NSAIDs or who were either intolerant of or had contraindications to NSAIDs.

The patients were randomly assigned on a 2:1 basis to receive either bimekizumab 160 mg every 4 weeks (221 patients) or placebo (111 patients) for 16 weeks. All patients were switched over at 16 weeks to bimekizumab maintenance for up to 1 year of total treatment.

Dr. Van der Heijde reported 24-week data from the trial, including data from 8 weeks of additional follow-up.
 

All endpoints met

The trial met its primary endpoint of 40% improvement in Assessment of Spondyloarthritis International Society response criteria (ASAS 40) at week 16. There was a 44.8% improvement with bimekizumab, compared with 22.6% with placebo (P < .001).

All secondary endpoints also favored the bimekizumab arm, including ASAS 40 among patients who had not previously received a tumor necrosis factor (TNF)–alpha inhibitor, ASAS 20, BASDAI functional index, ankylosing spondylitis quality-of-life index, and others.

Responses to bimekizumab were consistent across subpopulations of patients with or without prior TNF-alpha inhibitor exposure, Dr. van der Heidje said.

In addition, use of bimekizumab was associated with a significant improvement from baseline, compared with placebo, in objective measures of inflammation, including MRI spine Berlin score at week 16 (mean, –2.3 vs. 0; P < .001), Spondylitis Research Consortium of Canada (SPARCC) MRI sacroiliac joint score at week 16 (mean, –5.6 vs. 1.1), and high-sensitivity C-reactive protein at week 16 (mean, 2.4 vs. 6.3 mg/L; P < .001).

The most frequent treatment-related adverse events were nasopharyngitis, diarrhea, and oral candidiasis, all of which were more common in the bimekizumab arm, as well as headache, the incidence of which was similar between the arms.

Overall, 6.4% of patients taking bimekizumab had fungal infections, compared with none in the placebo group. The infections were mild or moderate, localized, and mucocutaneous in nature. Only two patients discontinued the drug because of fungal infections: one for oral candidiasis, and one for esophageal candidiasis.

‘Promising results’

Fabian Proft, MD, head of the clinical trials unit at Charité University Hospital in Berlin, who was not involved in the study, told this news organization that the data looked very good.

“These are the first phase 3 data on dual inhibition of IL-17A and F with bimekizumab in axial spondyloarthritis, and the data are really promising,” he said. “For nonradiographic disease, the data also look very promising, and when we’re looking into the future, it might be a therapeutic option for us as treating rheumatologists.”

The study was funded by UCB Pharma. Dr. van der Heijde has received consulting fees from the company and others. Dr. Proft has consulted for and has been on the speaker’s bureau for UCB and other pharmaceutical companies.

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

COPENHAGEN – Discontinuing maintenance immunosuppressive therapy (IST) in patients with proliferative lupus nephritis in remission proved less effective than continuing it in terms of the rates of renal relapse and severe systemic lupus erythematosus (SLE) flare, results from the WIN-Lupus trial show.

Lead researcher Noemie Jourde-Chiche, MD, assistant professor at Aix-Marseille (France) University, presented the results at the annual European Congress of Rheumatology.

The randomized, controlled trial aimed to determine the optimal duration of maintenance IST for proliferative lupus nephritis, by asking whether discontinuation of such therapy after 2-3 years was noninferior to IST continuation for 2 more years.

“This is the first randomized IST trial in proliferative lupus nephritis,” Dr. Jourde-Chiche reported. “We found that noninferiority of IST discontinuation was not demonstrated, and those who discontinued had a higher risk of SLE flares, but the majority of patients who discontinued did not experience flare.”

Regarding the incidence of renal relapse, no statistically significant difference was found between patients who continued versus those who discontinued IST.

Rheumatologist Christophe Richez, MD, of the Groupe Hospitalier Pellegrin-CHU de Bordeaux (France) welcomed the trial. “The work does not find a significant difference but suggests that with more power, the difference would have been significant,” he said in an interview.

He added that a significant number of patients refused to enter the study for several reasons, including scheduling a pregnancy and fear of relapse after stopping the treatment. “This in itself shows that we need this type of study to know if we can stop the treatment to plan a pregnancy or if a relay treatment is necessary. These data also mean we can now better inform our patients about the benefit-risk [profile] of continuing treatment or not.”

Dr. Richez, who was not involved in the trial, noted that the data provide information that strongly suggest more research is needed to better determine which patients are at risk of relapse, and consequently, for which patients is discontinuation possible. “There’s also a need for further analysis of tolerance to the immunosuppressive drugs according to the strategy.”

Finally, he referred to the issue around therapeutic adherence that is often faced with management of lupus. “The data from this study will allow us to better explain to patients the need to continue or discontinue their treatments, including hydroxychloroquine, and also the possibility of decreasing the immunosuppressive drugs to half-dose.”

Maintenance therapy in lupus nephritis: To continue or not?

Conducted in 28 French centers, participants had class III or IV lupus nephritis with active lesions and had previously received induction IST of cyclophosphamide or mycophenolate mofetil with hydroxychloroquine and glucocorticoids. Maintenance IST was azathioprine or mycophenolate mofetil, hydroxychloroquine, and possibly low-dose glucocorticoids (below 10 mg/day).

A total of 96 patients were randomized into two groups: continuation of maintenance therapy (azathioprine or mycophenolate mofetil for 2-3 more years, hydroxychloroquine, and possibly low-dose glucocorticoids (below 10 mg/day), or discontinuation of maintenance therapy (azathioprine or mycophenolate mofetil) over 3 months.

Both study arms were similar with a mean age of 36-37 years, and 82%-86% of patients were female, 59%-67% were White. They had a mean disease duration of 7-9 years, and 72%-80% had experienced their first flare of proliferative nephritis. A total of 54%-65% had received cyclophosphamide induction therapy, and 75%-81% were on mycophenolate mofetil maintenance therapy that had been ongoing for a mean of 2.8 years. Tests of patients’ kidney function revealed a mean serum creatinine of 67-72 micromol/L and estimated glomerular filtration rate (eGFR) of 94-101 mL/min per 1.73 m². The mean SLE Disease Activity Index score was around 2.

Follow-up visits were conducted every 3 months for 2 years, and the trial had a primary end point of renal relapse rate at 24 months (confirmed by kidney biopsy), while secondary endpoints included rate of severe SLE flares, survival without renal relapse, or severe flare and adverse events, among others.

Patients were excluded if they were not taking hydroxychloroquine, had extrarenal SLE, an eGFR less than 30 mL/min per 1.73 m² or stage VI disease. After some participants did not finish the trial because of pregnancy, wish for pregnancy, or adverse events, data from a total of 40 in the IST continuation group and 44 in the discontinuation group were analyzed.
 

Noninferiority of discontinuation versus continuation not shown

A total of 12.5% in the continuation arm experienced renal relapse over 24 months, compared with 27.3% in the discontinuation arm (P = .079).

“The endpoint of noninferiority of discontinuation of immunosuppressive therapy was not shown, but no statistically significant difference was found between groups for renal relapse,” Dr. Jourde-Chiche said.

Severe SLE flares (renal or extrarenal) occurred significantly less often over 24 months in the continuation arm at 12.5% versus 31.8% in the discontinuation arm (P = .034).

However, Dr. Jourde-Chiche pointed out that “the majority of patients who discontinued treatment did not experience a flare.”

No differences were seen between groups with respect to any secondary endpoints. “Fortunately, no patients died or reached end-stage renal disease, and overall, the adverse events did not differ between groups,” she reported.

The study identified several risk factors for renal relapse, among which were low complement component 3 and higher baseline urinary protein to creatinine ratio.
 

Longer immunosuppressive therapy prediscontinuation leads to better results

Gabriella Moroni, MD, of the nephrology unit at Ospedale Maggiore Policlinico, Milan, authored a review of studies that attempted to interrupt glucocorticoids and other immunosuppressive agents in lupus nephritis and in SLE. Her review concluded that “the available data suggest that therapy withdrawal is feasible at least in patients enjoying a complete clinical remission after a prolonged therapy.”

Asked to comment on the French study, Dr. Moroni said the trial was very welcome. “In our long-term experience, we have stopped IST in 73 patients with lupus nephritis, followed for a mean of 23 years. Of these, 32 never reassumed therapy and 20 had at least one flare.”

Dr. Moroni noted that those participants who did not experience flares had significantly longer IST and longer remission before discontinuation and took hydroxychloroquine more frequently.

“We feel that, to prevent severe flares, firstly, lupus nephritis should be in complete remission for at least 3 years, and secondly, patients should have received IST for at least 5 years before discontinuation; immunosuppressive drugs should be tapered off very slowly and after strict clinical surveillance, and finally, hydroxychloroquine can prevent extrarenal flares.

Dr. Jourde-Chiche reported serving on a speakers bureau for Vifor Pharma and receiving grant/research support from Fresenius Medical Care. Some coauthors reported financial ties to many pharmaceutical companies. Dr. Richez said he has received fees for lectures or boards from GlaxoSmithKline, AstraZeneca, and Novartis. Dr. Moroni had no relevant disclosures.

COPENHAGEN – Discontinuing maintenance immunosuppressive therapy (IST) in patients with proliferative lupus nephritis in remission proved less effective than continuing it in terms of the rates of renal relapse and severe systemic lupus erythematosus (SLE) flare, results from the WIN-Lupus trial show.

Lead researcher Noemie Jourde-Chiche, MD, assistant professor at Aix-Marseille (France) University, presented the results at the annual European Congress of Rheumatology.

The randomized, controlled trial aimed to determine the optimal duration of maintenance IST for proliferative lupus nephritis, by asking whether discontinuation of such therapy after 2-3 years was noninferior to IST continuation for 2 more years.

“This is the first randomized IST trial in proliferative lupus nephritis,” Dr. Jourde-Chiche reported. “We found that noninferiority of IST discontinuation was not demonstrated, and those who discontinued had a higher risk of SLE flares, but the majority of patients who discontinued did not experience flare.”

Regarding the incidence of renal relapse, no statistically significant difference was found between patients who continued versus those who discontinued IST.

Rheumatologist Christophe Richez, MD, of the Groupe Hospitalier Pellegrin-CHU de Bordeaux (France) welcomed the trial. “The work does not find a significant difference but suggests that with more power, the difference would have been significant,” he said in an interview.

He added that a significant number of patients refused to enter the study for several reasons, including scheduling a pregnancy and fear of relapse after stopping the treatment. “This in itself shows that we need this type of study to know if we can stop the treatment to plan a pregnancy or if a relay treatment is necessary. These data also mean we can now better inform our patients about the benefit-risk [profile] of continuing treatment or not.”

Dr. Richez, who was not involved in the trial, noted that the data provide information that strongly suggest more research is needed to better determine which patients are at risk of relapse, and consequently, for which patients is discontinuation possible. “There’s also a need for further analysis of tolerance to the immunosuppressive drugs according to the strategy.”

Finally, he referred to the issue around therapeutic adherence that is often faced with management of lupus. “The data from this study will allow us to better explain to patients the need to continue or discontinue their treatments, including hydroxychloroquine, and also the possibility of decreasing the immunosuppressive drugs to half-dose.”

Maintenance therapy in lupus nephritis: To continue or not?

Conducted in 28 French centers, participants had class III or IV lupus nephritis with active lesions and had previously received induction IST of cyclophosphamide or mycophenolate mofetil with hydroxychloroquine and glucocorticoids. Maintenance IST was azathioprine or mycophenolate mofetil, hydroxychloroquine, and possibly low-dose glucocorticoids (below 10 mg/day).

A total of 96 patients were randomized into two groups: continuation of maintenance therapy (azathioprine or mycophenolate mofetil for 2-3 more years, hydroxychloroquine, and possibly low-dose glucocorticoids (below 10 mg/day), or discontinuation of maintenance therapy (azathioprine or mycophenolate mofetil) over 3 months.

Both study arms were similar with a mean age of 36-37 years, and 82%-86% of patients were female, 59%-67% were White. They had a mean disease duration of 7-9 years, and 72%-80% had experienced their first flare of proliferative nephritis. A total of 54%-65% had received cyclophosphamide induction therapy, and 75%-81% were on mycophenolate mofetil maintenance therapy that had been ongoing for a mean of 2.8 years. Tests of patients’ kidney function revealed a mean serum creatinine of 67-72 micromol/L and estimated glomerular filtration rate (eGFR) of 94-101 mL/min per 1.73 m². The mean SLE Disease Activity Index score was around 2.

Follow-up visits were conducted every 3 months for 2 years, and the trial had a primary end point of renal relapse rate at 24 months (confirmed by kidney biopsy), while secondary endpoints included rate of severe SLE flares, survival without renal relapse, or severe flare and adverse events, among others.

Patients were excluded if they were not taking hydroxychloroquine, had extrarenal SLE, an eGFR less than 30 mL/min per 1.73 m² or stage VI disease. After some participants did not finish the trial because of pregnancy, wish for pregnancy, or adverse events, data from a total of 40 in the IST continuation group and 44 in the discontinuation group were analyzed.
 

Noninferiority of discontinuation versus continuation not shown

A total of 12.5% in the continuation arm experienced renal relapse over 24 months, compared with 27.3% in the discontinuation arm (P = .079).

“The endpoint of noninferiority of discontinuation of immunosuppressive therapy was not shown, but no statistically significant difference was found between groups for renal relapse,” Dr. Jourde-Chiche said.

Severe SLE flares (renal or extrarenal) occurred significantly less often over 24 months in the continuation arm at 12.5% versus 31.8% in the discontinuation arm (P = .034).

However, Dr. Jourde-Chiche pointed out that “the majority of patients who discontinued treatment did not experience a flare.”

No differences were seen between groups with respect to any secondary endpoints. “Fortunately, no patients died or reached end-stage renal disease, and overall, the adverse events did not differ between groups,” she reported.

The study identified several risk factors for renal relapse, among which were low complement component 3 and higher baseline urinary protein to creatinine ratio.
 

Longer immunosuppressive therapy prediscontinuation leads to better results

Gabriella Moroni, MD, of the nephrology unit at Ospedale Maggiore Policlinico, Milan, authored a review of studies that attempted to interrupt glucocorticoids and other immunosuppressive agents in lupus nephritis and in SLE. Her review concluded that “the available data suggest that therapy withdrawal is feasible at least in patients enjoying a complete clinical remission after a prolonged therapy.”

Asked to comment on the French study, Dr. Moroni said the trial was very welcome. “In our long-term experience, we have stopped IST in 73 patients with lupus nephritis, followed for a mean of 23 years. Of these, 32 never reassumed therapy and 20 had at least one flare.”

Dr. Moroni noted that those participants who did not experience flares had significantly longer IST and longer remission before discontinuation and took hydroxychloroquine more frequently.

“We feel that, to prevent severe flares, firstly, lupus nephritis should be in complete remission for at least 3 years, and secondly, patients should have received IST for at least 5 years before discontinuation; immunosuppressive drugs should be tapered off very slowly and after strict clinical surveillance, and finally, hydroxychloroquine can prevent extrarenal flares.

Dr. Jourde-Chiche reported serving on a speakers bureau for Vifor Pharma and receiving grant/research support from Fresenius Medical Care. Some coauthors reported financial ties to many pharmaceutical companies. Dr. Richez said he has received fees for lectures or boards from GlaxoSmithKline, AstraZeneca, and Novartis. Dr. Moroni had no relevant disclosures.

COPENHAGEN – Discontinuing maintenance immunosuppressive therapy (IST) in patients with proliferative lupus nephritis in remission proved less effective than continuing it in terms of the rates of renal relapse and severe systemic lupus erythematosus (SLE) flare, results from the WIN-Lupus trial show.

Lead researcher Noemie Jourde-Chiche, MD, assistant professor at Aix-Marseille (France) University, presented the results at the annual European Congress of Rheumatology.

The randomized, controlled trial aimed to determine the optimal duration of maintenance IST for proliferative lupus nephritis, by asking whether discontinuation of such therapy after 2-3 years was noninferior to IST continuation for 2 more years.

“This is the first randomized IST trial in proliferative lupus nephritis,” Dr. Jourde-Chiche reported. “We found that noninferiority of IST discontinuation was not demonstrated, and those who discontinued had a higher risk of SLE flares, but the majority of patients who discontinued did not experience flare.”

Regarding the incidence of renal relapse, no statistically significant difference was found between patients who continued versus those who discontinued IST.

Rheumatologist Christophe Richez, MD, of the Groupe Hospitalier Pellegrin-CHU de Bordeaux (France) welcomed the trial. “The work does not find a significant difference but suggests that with more power, the difference would have been significant,” he said in an interview.

He added that a significant number of patients refused to enter the study for several reasons, including scheduling a pregnancy and fear of relapse after stopping the treatment. “This in itself shows that we need this type of study to know if we can stop the treatment to plan a pregnancy or if a relay treatment is necessary. These data also mean we can now better inform our patients about the benefit-risk [profile] of continuing treatment or not.”

Dr. Richez, who was not involved in the trial, noted that the data provide information that strongly suggest more research is needed to better determine which patients are at risk of relapse, and consequently, for which patients is discontinuation possible. “There’s also a need for further analysis of tolerance to the immunosuppressive drugs according to the strategy.”

Finally, he referred to the issue around therapeutic adherence that is often faced with management of lupus. “The data from this study will allow us to better explain to patients the need to continue or discontinue their treatments, including hydroxychloroquine, and also the possibility of decreasing the immunosuppressive drugs to half-dose.”

Maintenance therapy in lupus nephritis: To continue or not?

Conducted in 28 French centers, participants had class III or IV lupus nephritis with active lesions and had previously received induction IST of cyclophosphamide or mycophenolate mofetil with hydroxychloroquine and glucocorticoids. Maintenance IST was azathioprine or mycophenolate mofetil, hydroxychloroquine, and possibly low-dose glucocorticoids (below 10 mg/day).

A total of 96 patients were randomized into two groups: continuation of maintenance therapy (azathioprine or mycophenolate mofetil for 2-3 more years, hydroxychloroquine, and possibly low-dose glucocorticoids (below 10 mg/day), or discontinuation of maintenance therapy (azathioprine or mycophenolate mofetil) over 3 months.

Both study arms were similar with a mean age of 36-37 years, and 82%-86% of patients were female, 59%-67% were White. They had a mean disease duration of 7-9 years, and 72%-80% had experienced their first flare of proliferative nephritis. A total of 54%-65% had received cyclophosphamide induction therapy, and 75%-81% were on mycophenolate mofetil maintenance therapy that had been ongoing for a mean of 2.8 years. Tests of patients’ kidney function revealed a mean serum creatinine of 67-72 micromol/L and estimated glomerular filtration rate (eGFR) of 94-101 mL/min per 1.73 m². The mean SLE Disease Activity Index score was around 2.

Follow-up visits were conducted every 3 months for 2 years, and the trial had a primary end point of renal relapse rate at 24 months (confirmed by kidney biopsy), while secondary endpoints included rate of severe SLE flares, survival without renal relapse, or severe flare and adverse events, among others.

Patients were excluded if they were not taking hydroxychloroquine, had extrarenal SLE, an eGFR less than 30 mL/min per 1.73 m² or stage VI disease. After some participants did not finish the trial because of pregnancy, wish for pregnancy, or adverse events, data from a total of 40 in the IST continuation group and 44 in the discontinuation group were analyzed.
 

Noninferiority of discontinuation versus continuation not shown

A total of 12.5% in the continuation arm experienced renal relapse over 24 months, compared with 27.3% in the discontinuation arm (P = .079).

“The endpoint of noninferiority of discontinuation of immunosuppressive therapy was not shown, but no statistically significant difference was found between groups for renal relapse,” Dr. Jourde-Chiche said.

Severe SLE flares (renal or extrarenal) occurred significantly less often over 24 months in the continuation arm at 12.5% versus 31.8% in the discontinuation arm (P = .034).

However, Dr. Jourde-Chiche pointed out that “the majority of patients who discontinued treatment did not experience a flare.”

No differences were seen between groups with respect to any secondary endpoints. “Fortunately, no patients died or reached end-stage renal disease, and overall, the adverse events did not differ between groups,” she reported.

The study identified several risk factors for renal relapse, among which were low complement component 3 and higher baseline urinary protein to creatinine ratio.
 

Longer immunosuppressive therapy prediscontinuation leads to better results

Gabriella Moroni, MD, of the nephrology unit at Ospedale Maggiore Policlinico, Milan, authored a review of studies that attempted to interrupt glucocorticoids and other immunosuppressive agents in lupus nephritis and in SLE. Her review concluded that “the available data suggest that therapy withdrawal is feasible at least in patients enjoying a complete clinical remission after a prolonged therapy.”

Asked to comment on the French study, Dr. Moroni said the trial was very welcome. “In our long-term experience, we have stopped IST in 73 patients with lupus nephritis, followed for a mean of 23 years. Of these, 32 never reassumed therapy and 20 had at least one flare.”

Dr. Moroni noted that those participants who did not experience flares had significantly longer IST and longer remission before discontinuation and took hydroxychloroquine more frequently.

“We feel that, to prevent severe flares, firstly, lupus nephritis should be in complete remission for at least 3 years, and secondly, patients should have received IST for at least 5 years before discontinuation; immunosuppressive drugs should be tapered off very slowly and after strict clinical surveillance, and finally, hydroxychloroquine can prevent extrarenal flares.

Dr. Jourde-Chiche reported serving on a speakers bureau for Vifor Pharma and receiving grant/research support from Fresenius Medical Care. Some coauthors reported financial ties to many pharmaceutical companies. Dr. Richez said he has received fees for lectures or boards from GlaxoSmithKline, AstraZeneca, and Novartis. Dr. Moroni had no relevant disclosures.

The Food and Drug Administration has approved adding adult patients with rheumatoid arthritis to the list of indications for the rituximab biosimilar Riabni (rituximab-arrx) on the basis of results of a randomized, double-blind, comparative clinical study with the CD20-directed cytolytic antibody reference product, Rituxan, the biosimilar’s manufacturer, Amgen, announced June 6.

The RA indication is specifically for adults with moderate to severely active disease who have had an inadequate response to one or more tumor necrosis factor inhibitors. Riabni was approved in December 2020 for the treatment of adult patients with non-Hodgkin lymphoma, chronic lymphocytic leukemia, granulomatosis with polyangiitis, and microscopic polyangiitis.

The clinical study testing Riabni against Rituxan involved 311 patients with moderate to severe RA who received Riabni, Rituxan manufactured in the United States, and Rituxan manufactured in the European Union. The patients who received the U.S.-manufactured Rituxan were transitioned to receive Riabni for their second dose of rituximab, whereas patients in other groups stayed with the same treatment. The trial’s primary efficacy endpoint of the change in Disease Activity Score in 28 joints using C-reactive protein from baseline to week 24 was within the predefined equivalence margin for clinical efficacy between Riabni and Rituxan. The two products also had similar safety, pharmacokinetics, and immunogenicity profiles, according to Amgen.

Currently, Riabni and Ruxience (rituximab-pvvr) are the only two approved rituximab biosimilars in the United States. Ruxience is approved for the same indications. Rituxan alone has protected orphan drug status for the indication of adult patients with moderate to severe pemphigus vulgaris.

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

The Food and Drug Administration has approved adding adult patients with rheumatoid arthritis to the list of indications for the rituximab biosimilar Riabni (rituximab-arrx) on the basis of results of a randomized, double-blind, comparative clinical study with the CD20-directed cytolytic antibody reference product, Rituxan, the biosimilar’s manufacturer, Amgen, announced June 6.

The RA indication is specifically for adults with moderate to severely active disease who have had an inadequate response to one or more tumor necrosis factor inhibitors. Riabni was approved in December 2020 for the treatment of adult patients with non-Hodgkin lymphoma, chronic lymphocytic leukemia, granulomatosis with polyangiitis, and microscopic polyangiitis.

The clinical study testing Riabni against Rituxan involved 311 patients with moderate to severe RA who received Riabni, Rituxan manufactured in the United States, and Rituxan manufactured in the European Union. The patients who received the U.S.-manufactured Rituxan were transitioned to receive Riabni for their second dose of rituximab, whereas patients in other groups stayed with the same treatment. The trial’s primary efficacy endpoint of the change in Disease Activity Score in 28 joints using C-reactive protein from baseline to week 24 was within the predefined equivalence margin for clinical efficacy between Riabni and Rituxan. The two products also had similar safety, pharmacokinetics, and immunogenicity profiles, according to Amgen.

Currently, Riabni and Ruxience (rituximab-pvvr) are the only two approved rituximab biosimilars in the United States. Ruxience is approved for the same indications. Rituxan alone has protected orphan drug status for the indication of adult patients with moderate to severe pemphigus vulgaris.

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

The Food and Drug Administration has approved adding adult patients with rheumatoid arthritis to the list of indications for the rituximab biosimilar Riabni (rituximab-arrx) on the basis of results of a randomized, double-blind, comparative clinical study with the CD20-directed cytolytic antibody reference product, Rituxan, the biosimilar’s manufacturer, Amgen, announced June 6.

The RA indication is specifically for adults with moderate to severely active disease who have had an inadequate response to one or more tumor necrosis factor inhibitors. Riabni was approved in December 2020 for the treatment of adult patients with non-Hodgkin lymphoma, chronic lymphocytic leukemia, granulomatosis with polyangiitis, and microscopic polyangiitis.

The clinical study testing Riabni against Rituxan involved 311 patients with moderate to severe RA who received Riabni, Rituxan manufactured in the United States, and Rituxan manufactured in the European Union. The patients who received the U.S.-manufactured Rituxan were transitioned to receive Riabni for their second dose of rituximab, whereas patients in other groups stayed with the same treatment. The trial’s primary efficacy endpoint of the change in Disease Activity Score in 28 joints using C-reactive protein from baseline to week 24 was within the predefined equivalence margin for clinical efficacy between Riabni and Rituxan. The two products also had similar safety, pharmacokinetics, and immunogenicity profiles, according to Amgen.

Currently, Riabni and Ruxience (rituximab-pvvr) are the only two approved rituximab biosimilars in the United States. Ruxience is approved for the same indications. Rituxan alone has protected orphan drug status for the indication of adult patients with moderate to severe pemphigus vulgaris.

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

COPENHAGEN – Most patients with immune-mediated inflammatory diseases (IMID) should not be considered at high risk for severe COVID-19 breakthrough infections, but those on anti-CD20 therapy are the exception, data from a large prospective, cohort study show.

“Overall, the data are reassuring, with conventional risk factors, such as age, and comorbidities seeming to be more important regarding risk of severe COVID-19 breakthrough infections than rheumatic disease or immunosuppressant medication,” said Laura Boekel, MD, from Amsterdam UMC, who presented the study at the annual European Congress of Rheumatology.

peterschreiber_media/iStock/Getty Images

But, she added, there was an exception for anti-CD20 therapy. “This is especially relevant for patients with conventional risk factors that might accumulate, and rheumatologists might want to consider alternative treatment options if possible. It is important to inform patients about the risks of anti-CD20.”

Another study, presented during the same session at the congress by Rebecca Hasseli, MD, from the University of Giessen (Germany) saw no deaths and no COVID-19 related complications in a cohort of triple-vaccinated patients with inflammatory rheumatic diseases, despite a higher median age and a higher rate of comorbidities compared to double-vaccinated and unvaccinated cohorts.

Ingrid Jyssum, MD, from Diakonhjemmet Hospital, Oslo, who presented results of the Nor-vaC study investigating the impact of different DMARDs on the immunogenicity of a third COVID-19 vaccine dose, welcomed the research by Dr. Boekel and Dr. Hasseli.

“The findings of Hasseli are interesting in the light of our data on serological response after the third dose, with a lack of breakthrough infections after three doses corresponding well to the robust antibody response that we found in our cohort,” she remarked. “This is very reassuring for our patients. Our own work together with the findings of Hasseli and Boekel demonstrate that additional vaccine doses are important to keep this population well protected against severe COVID-19 infections.”

The Nor-vaC study was conducted with a cohort of 1,100 patients with inflammatory joint and bowel diseases. “These patients had attenuated antibody responses after two vaccine doses; however, we found that a third vaccine dose brought the humoral response in patients up to the antibody levels that healthy controls had after two doses,” said Dr. Jyssum. “In addition, we found that the decline in antibodies after the third dose was less than the decline seen after the second dose. Importantly, the third dose was safe in our patients, with no new safety issues.”
 

Breakthrough infections and immunosuppressants

“Like the rest of the world, we were wondering if our patients were at increased risk of COVID-19, and if the immunosuppressants used by these patients influenced their risk,” said Dr. Boekel.

The researchers compared both the incidence and severity of COVID-19 breakthrough infections with the SARS-CoV-2 Delta variant in a population of fully vaccinated IMID patients taking immunosuppressants and controls (IMID patients not taking immunosuppressants and healthy controls).

Two large ongoing, prospective, multicenter cohort studies provided pooled data collected between February and December 2021 using digital questionnaires, standardized electronic case record forms, and medical files.

Finger-prick tests were used to collect blood samples that were analyzed after vaccination against SARS-CoV-2 for anti–receptor-binding domain (RBD) antibodies, and antinucleocapsid antibodies to identify asymptomatic breakthrough infections. Any associations between antibodies and the incidence of breakthrough infections were generated, and results were adjusted for sex, cardiovascular disease, chronic pulmonary disease, obesity, and vaccine type.

The analysis included 3,207 IMID patients taking immunosuppressants, and 1,810 controls (985 IMID patients not on immunosuppressants and 825 healthy controls).

Initially, Dr. Boekel and her colleagues looked at incidence of infections and hospitalizations prior to vaccination, and then after vaccination, which was the main aim of the study.

Prior to vaccination, hospitalization risk for COVID-19 was somewhat higher for IMID patients overall compared with controls, reported Dr. Boekel. “But those treated with anti-CD20 therapy, demonstrated much greater risk for severe disease.”

After the SARS-CoV-2 vaccination campaign began, the researchers then looked at how immunosuppressants influenced humoral response to SARS-CoV-2 vaccination.

“Anti-CD20 therapy showed the greatest impact on humoral immune response after SARS-CoV-2 vaccination,” said Dr. Boekel. Other immunosuppressant drugs had variable effects on humoral and cellular immunity. 

Once they had established that immunosuppressant drugs impaired immune responses to SARS-CoV-2 vaccination, the researchers wanted to determine if this affected clinical outcomes. Blood samples taken 28 days after the second vaccination enabled Dr. Boekel and her colleagues to see if antibody production was associated with breakthrough infections.   

Breakthrough infections were seen in 5% of patients on immunosuppressants, 5% of patients not on immunosuppressants, and 4% of healthy controls. Also, asymptomatic COVID-19 breakthrough cases were comparable between IMID patients taking immunosuppressants and controls, at 10% in each group.

“We saw that the incidence [of getting COVID-19] was comparable between groups, independent of whether they were receiving immunosuppressants or not, or healthy controls. However, if they developed antibodies against the two vaccinations the chance of getting infected was lower,” reported Dr. Boekel.

Hospitalization (severe disease) rates were also comparable between groups. “Patients with rheumatic diseases, even when treated with immunosuppressants were not at increased risk of severe disease from Delta breakthrough infections,” added the researcher. “Cases that were hospitalized were mainly elderly and those with comorbidities, for example cardiovascular disease and cardiopulmonary disease.”

Hospital admissions were 5.4% in patients on immunosuppressants, 5.7% in those not on immunosuppressants, and 6% in health controls.

However, once again, there was one exception, Dr. Boekel stressed. “Patients treated with anti-CD20 therapy were at increased risk of severe disease and hospitalization.”

Omicron variant has a different transmissibility than Delta, so the researchers continued the study looking at the Omicron variant. The data “were mostly reassuring,” said Dr. Boekel. “As expected, hospitalization rates decreased overall, with the exception of patients on anti-CD20 therapy where, despite overall reduced pathogenicity, patients remain at increased risk.”

She said that they were awaiting long-term data so the data reflect only short-term immunity against Omicron. “However, we included many elderly and patients with comorbidities, so this made the analysis very sensitive to detect severe cases,” she added.

Breakthrough infection among double- and triple-vaccinated patients

A lower rate of COVID-19 related complications and deaths were seen in patients who were triple-vaccinated against SARS-CoV-2, than in double-vaccinated or unvaccinated patients, despite the former having more comorbidities and use of rituximab (Rituxan), said Dr. Hasseli.

“These data support the recommendation of booster vaccination to reduce COVID-19-related mortality in patients with inflammatory rheumatic diseases [IRDs],” she said.

“A small number of COVID-19 cases were seen in patients with IRD after vaccinations, and in a few cases, hospitalizations were required. Breakthrough infections were mostly seen in patients on B-cell depletion therapy,” she added.

Dr. Hasseli and her colleagues looked at the characteristics and outcomes of SARS-CoV-2 breakthrough infections among double- and triple-vaccinated patients with IRD.

“We wanted to understand if patients with IRD are protected in the same way as the general population following vaccination, given that these patients receive drugs that might impair the immune response,” she explained.

Data for analysis were drawn from the German COVID-19-IRD registry covering February 2021 and January 2022, and patients who were double- or triple- vaccinated against COVID-19 either 14 days or more prior to a SARS-CoV-2 infection were included. Type of IRD, vaccine, immunomodulation, comorbidities, and outcome of the infection were compared with 737 unvaccinated IRD patients with COVID-19. Those with prior COVID-19 were excluded.

Cases were stratified by vaccinations status: unvaccinated (1,388 patients, median age 57 years); double vaccinated (462, 56 years) and triple vaccinated (301, 53 years). Body mass index was similar across groups (25-26 kg/m²), and time between SARS-CoV-2 infection and last vaccination was 156 days in double-vaccinated patients, and 62 days in triple-vaccinated patients.

Patients had rheumatoid arthritis in 44.7% and 44.4% of unvaccinated and double-vaccinated patients respectively, but fewer triple-vaccinated patients had RA (37.2%). Triple vaccination was seen in 32.2% of patients with spondyloarthritis, 16.6% connective tissue diseases, 5.3% other vasculitis, and 3.3% ANCA-associated vasculitis. Of triple-vaccinated patients, 26.2% were treated with tumor necrosis factor-alpha (TNF-alpha) inhibitors, and 6.3% with rituximab, while 5.3% were not on immunomodulation. At least 25% were treated with glucocorticoids, reported Dr. Hasseli.

“Arterial hypertension and diabetes, that might be risk factors for COVID-19, were less frequently reported in triple-vaccinated patients. More patients in the double-vaccinated group [42.9%] than the triple-vaccinated [23.8%] reported absence of relevant comorbidities,” she said.

COVID-19 related complications were less often reported in double- and triple-vaccinated groups with hospitalizations at 9.5% and 4.3% in double and triple-vaccinated people respectively.

Dr. Boekel and Dr. Hasseli report no relevant conflicts of interest.

COPENHAGEN – Most patients with immune-mediated inflammatory diseases (IMID) should not be considered at high risk for severe COVID-19 breakthrough infections, but those on anti-CD20 therapy are the exception, data from a large prospective, cohort study show.

“Overall, the data are reassuring, with conventional risk factors, such as age, and comorbidities seeming to be more important regarding risk of severe COVID-19 breakthrough infections than rheumatic disease or immunosuppressant medication,” said Laura Boekel, MD, from Amsterdam UMC, who presented the study at the annual European Congress of Rheumatology.

peterschreiber_media/iStock/Getty Images

But, she added, there was an exception for anti-CD20 therapy. “This is especially relevant for patients with conventional risk factors that might accumulate, and rheumatologists might want to consider alternative treatment options if possible. It is important to inform patients about the risks of anti-CD20.”

Another study, presented during the same session at the congress by Rebecca Hasseli, MD, from the University of Giessen (Germany) saw no deaths and no COVID-19 related complications in a cohort of triple-vaccinated patients with inflammatory rheumatic diseases, despite a higher median age and a higher rate of comorbidities compared to double-vaccinated and unvaccinated cohorts.

Ingrid Jyssum, MD, from Diakonhjemmet Hospital, Oslo, who presented results of the Nor-vaC study investigating the impact of different DMARDs on the immunogenicity of a third COVID-19 vaccine dose, welcomed the research by Dr. Boekel and Dr. Hasseli.

“The findings of Hasseli are interesting in the light of our data on serological response after the third dose, with a lack of breakthrough infections after three doses corresponding well to the robust antibody response that we found in our cohort,” she remarked. “This is very reassuring for our patients. Our own work together with the findings of Hasseli and Boekel demonstrate that additional vaccine doses are important to keep this population well protected against severe COVID-19 infections.”

The Nor-vaC study was conducted with a cohort of 1,100 patients with inflammatory joint and bowel diseases. “These patients had attenuated antibody responses after two vaccine doses; however, we found that a third vaccine dose brought the humoral response in patients up to the antibody levels that healthy controls had after two doses,” said Dr. Jyssum. “In addition, we found that the decline in antibodies after the third dose was less than the decline seen after the second dose. Importantly, the third dose was safe in our patients, with no new safety issues.”
 

Breakthrough infections and immunosuppressants

“Like the rest of the world, we were wondering if our patients were at increased risk of COVID-19, and if the immunosuppressants used by these patients influenced their risk,” said Dr. Boekel.

The researchers compared both the incidence and severity of COVID-19 breakthrough infections with the SARS-CoV-2 Delta variant in a population of fully vaccinated IMID patients taking immunosuppressants and controls (IMID patients not taking immunosuppressants and healthy controls).

Two large ongoing, prospective, multicenter cohort studies provided pooled data collected between February and December 2021 using digital questionnaires, standardized electronic case record forms, and medical files.

Finger-prick tests were used to collect blood samples that were analyzed after vaccination against SARS-CoV-2 for anti–receptor-binding domain (RBD) antibodies, and antinucleocapsid antibodies to identify asymptomatic breakthrough infections. Any associations between antibodies and the incidence of breakthrough infections were generated, and results were adjusted for sex, cardiovascular disease, chronic pulmonary disease, obesity, and vaccine type.

The analysis included 3,207 IMID patients taking immunosuppressants, and 1,810 controls (985 IMID patients not on immunosuppressants and 825 healthy controls).

Initially, Dr. Boekel and her colleagues looked at incidence of infections and hospitalizations prior to vaccination, and then after vaccination, which was the main aim of the study.

Prior to vaccination, hospitalization risk for COVID-19 was somewhat higher for IMID patients overall compared with controls, reported Dr. Boekel. “But those treated with anti-CD20 therapy, demonstrated much greater risk for severe disease.”

After the SARS-CoV-2 vaccination campaign began, the researchers then looked at how immunosuppressants influenced humoral response to SARS-CoV-2 vaccination.

“Anti-CD20 therapy showed the greatest impact on humoral immune response after SARS-CoV-2 vaccination,” said Dr. Boekel. Other immunosuppressant drugs had variable effects on humoral and cellular immunity. 

Once they had established that immunosuppressant drugs impaired immune responses to SARS-CoV-2 vaccination, the researchers wanted to determine if this affected clinical outcomes. Blood samples taken 28 days after the second vaccination enabled Dr. Boekel and her colleagues to see if antibody production was associated with breakthrough infections.   

Breakthrough infections were seen in 5% of patients on immunosuppressants, 5% of patients not on immunosuppressants, and 4% of healthy controls. Also, asymptomatic COVID-19 breakthrough cases were comparable between IMID patients taking immunosuppressants and controls, at 10% in each group.

“We saw that the incidence [of getting COVID-19] was comparable between groups, independent of whether they were receiving immunosuppressants or not, or healthy controls. However, if they developed antibodies against the two vaccinations the chance of getting infected was lower,” reported Dr. Boekel.

Hospitalization (severe disease) rates were also comparable between groups. “Patients with rheumatic diseases, even when treated with immunosuppressants were not at increased risk of severe disease from Delta breakthrough infections,” added the researcher. “Cases that were hospitalized were mainly elderly and those with comorbidities, for example cardiovascular disease and cardiopulmonary disease.”

Hospital admissions were 5.4% in patients on immunosuppressants, 5.7% in those not on immunosuppressants, and 6% in health controls.

However, once again, there was one exception, Dr. Boekel stressed. “Patients treated with anti-CD20 therapy were at increased risk of severe disease and hospitalization.”

Omicron variant has a different transmissibility than Delta, so the researchers continued the study looking at the Omicron variant. The data “were mostly reassuring,” said Dr. Boekel. “As expected, hospitalization rates decreased overall, with the exception of patients on anti-CD20 therapy where, despite overall reduced pathogenicity, patients remain at increased risk.”

She said that they were awaiting long-term data so the data reflect only short-term immunity against Omicron. “However, we included many elderly and patients with comorbidities, so this made the analysis very sensitive to detect severe cases,” she added.

Breakthrough infection among double- and triple-vaccinated patients

A lower rate of COVID-19 related complications and deaths were seen in patients who were triple-vaccinated against SARS-CoV-2, than in double-vaccinated or unvaccinated patients, despite the former having more comorbidities and use of rituximab (Rituxan), said Dr. Hasseli.

“These data support the recommendation of booster vaccination to reduce COVID-19-related mortality in patients with inflammatory rheumatic diseases [IRDs],” she said.

“A small number of COVID-19 cases were seen in patients with IRD after vaccinations, and in a few cases, hospitalizations were required. Breakthrough infections were mostly seen in patients on B-cell depletion therapy,” she added.

Dr. Hasseli and her colleagues looked at the characteristics and outcomes of SARS-CoV-2 breakthrough infections among double- and triple-vaccinated patients with IRD.

“We wanted to understand if patients with IRD are protected in the same way as the general population following vaccination, given that these patients receive drugs that might impair the immune response,” she explained.

Data for analysis were drawn from the German COVID-19-IRD registry covering February 2021 and January 2022, and patients who were double- or triple- vaccinated against COVID-19 either 14 days or more prior to a SARS-CoV-2 infection were included. Type of IRD, vaccine, immunomodulation, comorbidities, and outcome of the infection were compared with 737 unvaccinated IRD patients with COVID-19. Those with prior COVID-19 were excluded.

Cases were stratified by vaccinations status: unvaccinated (1,388 patients, median age 57 years); double vaccinated (462, 56 years) and triple vaccinated (301, 53 years). Body mass index was similar across groups (25-26 kg/m²), and time between SARS-CoV-2 infection and last vaccination was 156 days in double-vaccinated patients, and 62 days in triple-vaccinated patients.

Patients had rheumatoid arthritis in 44.7% and 44.4% of unvaccinated and double-vaccinated patients respectively, but fewer triple-vaccinated patients had RA (37.2%). Triple vaccination was seen in 32.2% of patients with spondyloarthritis, 16.6% connective tissue diseases, 5.3% other vasculitis, and 3.3% ANCA-associated vasculitis. Of triple-vaccinated patients, 26.2% were treated with tumor necrosis factor-alpha (TNF-alpha) inhibitors, and 6.3% with rituximab, while 5.3% were not on immunomodulation. At least 25% were treated with glucocorticoids, reported Dr. Hasseli.

“Arterial hypertension and diabetes, that might be risk factors for COVID-19, were less frequently reported in triple-vaccinated patients. More patients in the double-vaccinated group [42.9%] than the triple-vaccinated [23.8%] reported absence of relevant comorbidities,” she said.

COVID-19 related complications were less often reported in double- and triple-vaccinated groups with hospitalizations at 9.5% and 4.3% in double and triple-vaccinated people respectively.

Dr. Boekel and Dr. Hasseli report no relevant conflicts of interest.

COPENHAGEN – Most patients with immune-mediated inflammatory diseases (IMID) should not be considered at high risk for severe COVID-19 breakthrough infections, but those on anti-CD20 therapy are the exception, data from a large prospective, cohort study show.

“Overall, the data are reassuring, with conventional risk factors, such as age, and comorbidities seeming to be more important regarding risk of severe COVID-19 breakthrough infections than rheumatic disease or immunosuppressant medication,” said Laura Boekel, MD, from Amsterdam UMC, who presented the study at the annual European Congress of Rheumatology.

peterschreiber_media/iStock/Getty Images

But, she added, there was an exception for anti-CD20 therapy. “This is especially relevant for patients with conventional risk factors that might accumulate, and rheumatologists might want to consider alternative treatment options if possible. It is important to inform patients about the risks of anti-CD20.”

Another study, presented during the same session at the congress by Rebecca Hasseli, MD, from the University of Giessen (Germany) saw no deaths and no COVID-19 related complications in a cohort of triple-vaccinated patients with inflammatory rheumatic diseases, despite a higher median age and a higher rate of comorbidities compared to double-vaccinated and unvaccinated cohorts.

Ingrid Jyssum, MD, from Diakonhjemmet Hospital, Oslo, who presented results of the Nor-vaC study investigating the impact of different DMARDs on the immunogenicity of a third COVID-19 vaccine dose, welcomed the research by Dr. Boekel and Dr. Hasseli.

“The findings of Hasseli are interesting in the light of our data on serological response after the third dose, with a lack of breakthrough infections after three doses corresponding well to the robust antibody response that we found in our cohort,” she remarked. “This is very reassuring for our patients. Our own work together with the findings of Hasseli and Boekel demonstrate that additional vaccine doses are important to keep this population well protected against severe COVID-19 infections.”

The Nor-vaC study was conducted with a cohort of 1,100 patients with inflammatory joint and bowel diseases. “These patients had attenuated antibody responses after two vaccine doses; however, we found that a third vaccine dose brought the humoral response in patients up to the antibody levels that healthy controls had after two doses,” said Dr. Jyssum. “In addition, we found that the decline in antibodies after the third dose was less than the decline seen after the second dose. Importantly, the third dose was safe in our patients, with no new safety issues.”
 

Breakthrough infections and immunosuppressants

“Like the rest of the world, we were wondering if our patients were at increased risk of COVID-19, and if the immunosuppressants used by these patients influenced their risk,” said Dr. Boekel.

The researchers compared both the incidence and severity of COVID-19 breakthrough infections with the SARS-CoV-2 Delta variant in a population of fully vaccinated IMID patients taking immunosuppressants and controls (IMID patients not taking immunosuppressants and healthy controls).

Two large ongoing, prospective, multicenter cohort studies provided pooled data collected between February and December 2021 using digital questionnaires, standardized electronic case record forms, and medical files.

Finger-prick tests were used to collect blood samples that were analyzed after vaccination against SARS-CoV-2 for anti–receptor-binding domain (RBD) antibodies, and antinucleocapsid antibodies to identify asymptomatic breakthrough infections. Any associations between antibodies and the incidence of breakthrough infections were generated, and results were adjusted for sex, cardiovascular disease, chronic pulmonary disease, obesity, and vaccine type.

The analysis included 3,207 IMID patients taking immunosuppressants, and 1,810 controls (985 IMID patients not on immunosuppressants and 825 healthy controls).

Initially, Dr. Boekel and her colleagues looked at incidence of infections and hospitalizations prior to vaccination, and then after vaccination, which was the main aim of the study.

Prior to vaccination, hospitalization risk for COVID-19 was somewhat higher for IMID patients overall compared with controls, reported Dr. Boekel. “But those treated with anti-CD20 therapy, demonstrated much greater risk for severe disease.”

After the SARS-CoV-2 vaccination campaign began, the researchers then looked at how immunosuppressants influenced humoral response to SARS-CoV-2 vaccination.

“Anti-CD20 therapy showed the greatest impact on humoral immune response after SARS-CoV-2 vaccination,” said Dr. Boekel. Other immunosuppressant drugs had variable effects on humoral and cellular immunity. 

Once they had established that immunosuppressant drugs impaired immune responses to SARS-CoV-2 vaccination, the researchers wanted to determine if this affected clinical outcomes. Blood samples taken 28 days after the second vaccination enabled Dr. Boekel and her colleagues to see if antibody production was associated with breakthrough infections.   

Breakthrough infections were seen in 5% of patients on immunosuppressants, 5% of patients not on immunosuppressants, and 4% of healthy controls. Also, asymptomatic COVID-19 breakthrough cases were comparable between IMID patients taking immunosuppressants and controls, at 10% in each group.

“We saw that the incidence [of getting COVID-19] was comparable between groups, independent of whether they were receiving immunosuppressants or not, or healthy controls. However, if they developed antibodies against the two vaccinations the chance of getting infected was lower,” reported Dr. Boekel.

Hospitalization (severe disease) rates were also comparable between groups. “Patients with rheumatic diseases, even when treated with immunosuppressants were not at increased risk of severe disease from Delta breakthrough infections,” added the researcher. “Cases that were hospitalized were mainly elderly and those with comorbidities, for example cardiovascular disease and cardiopulmonary disease.”

Hospital admissions were 5.4% in patients on immunosuppressants, 5.7% in those not on immunosuppressants, and 6% in health controls.

However, once again, there was one exception, Dr. Boekel stressed. “Patients treated with anti-CD20 therapy were at increased risk of severe disease and hospitalization.”

Omicron variant has a different transmissibility than Delta, so the researchers continued the study looking at the Omicron variant. The data “were mostly reassuring,” said Dr. Boekel. “As expected, hospitalization rates decreased overall, with the exception of patients on anti-CD20 therapy where, despite overall reduced pathogenicity, patients remain at increased risk.”

She said that they were awaiting long-term data so the data reflect only short-term immunity against Omicron. “However, we included many elderly and patients with comorbidities, so this made the analysis very sensitive to detect severe cases,” she added.

Breakthrough infection among double- and triple-vaccinated patients

A lower rate of COVID-19 related complications and deaths were seen in patients who were triple-vaccinated against SARS-CoV-2, than in double-vaccinated or unvaccinated patients, despite the former having more comorbidities and use of rituximab (Rituxan), said Dr. Hasseli.

“These data support the recommendation of booster vaccination to reduce COVID-19-related mortality in patients with inflammatory rheumatic diseases [IRDs],” she said.

“A small number of COVID-19 cases were seen in patients with IRD after vaccinations, and in a few cases, hospitalizations were required. Breakthrough infections were mostly seen in patients on B-cell depletion therapy,” she added.

Dr. Hasseli and her colleagues looked at the characteristics and outcomes of SARS-CoV-2 breakthrough infections among double- and triple-vaccinated patients with IRD.

“We wanted to understand if patients with IRD are protected in the same way as the general population following vaccination, given that these patients receive drugs that might impair the immune response,” she explained.

Data for analysis were drawn from the German COVID-19-IRD registry covering February 2021 and January 2022, and patients who were double- or triple- vaccinated against COVID-19 either 14 days or more prior to a SARS-CoV-2 infection were included. Type of IRD, vaccine, immunomodulation, comorbidities, and outcome of the infection were compared with 737 unvaccinated IRD patients with COVID-19. Those with prior COVID-19 were excluded.

Cases were stratified by vaccinations status: unvaccinated (1,388 patients, median age 57 years); double vaccinated (462, 56 years) and triple vaccinated (301, 53 years). Body mass index was similar across groups (25-26 kg/m²), and time between SARS-CoV-2 infection and last vaccination was 156 days in double-vaccinated patients, and 62 days in triple-vaccinated patients.

Patients had rheumatoid arthritis in 44.7% and 44.4% of unvaccinated and double-vaccinated patients respectively, but fewer triple-vaccinated patients had RA (37.2%). Triple vaccination was seen in 32.2% of patients with spondyloarthritis, 16.6% connective tissue diseases, 5.3% other vasculitis, and 3.3% ANCA-associated vasculitis. Of triple-vaccinated patients, 26.2% were treated with tumor necrosis factor-alpha (TNF-alpha) inhibitors, and 6.3% with rituximab, while 5.3% were not on immunomodulation. At least 25% were treated with glucocorticoids, reported Dr. Hasseli.

“Arterial hypertension and diabetes, that might be risk factors for COVID-19, were less frequently reported in triple-vaccinated patients. More patients in the double-vaccinated group [42.9%] than the triple-vaccinated [23.8%] reported absence of relevant comorbidities,” she said.

COVID-19 related complications were less often reported in double- and triple-vaccinated groups with hospitalizations at 9.5% and 4.3% in double and triple-vaccinated people respectively.

Dr. Boekel and Dr. Hasseli report no relevant conflicts of interest.

In patients with uncontrolled gout, response rates were increased by 32% when methotrexate was used in conjunction with pegloticase versus pegloticase plus a placebo, it was reported at the annual European Congress of Rheumatology.

In the phase 4 MIRROR trial, 71% of patients who received pretreatment with methotrexate and then the combination of methotrexate and pegloticase achieved uric-acid levels lower than 6 mg/dL for more than 80% of the time during weeks 20-24 of the 52-week study. By comparison, only 39% of those treated with pegloticase plus a placebo achieved this primary endpoint (P < .0001).

This is good news for patients, suggested two rheumatologists who were not involved in the study. The combination appears “useful for a select group of gout patients,” observed Christian Ammitzbøll, MD, PhD, from Aarhus University Hospital, Denmark.

“Very promising in refractory gout,” agreed Emre Bilgin, MD, from Ankara, Turkey.
 

Rationale for using methotrexate

“Oral urate lowering agents are the mainstay of treatment of gout, but there are patients that just don’t respond to oral agents,” said Dr. Botson, a rheumatologist in private practice from Anchorage, Alaska.

“These patients are very difficult to treat,” he added. “They have a lot of physical disabilities, they have high medical comorbidities, and they have a low quality of life. Their treatment options are extremely limited.”

One of the few options they have is pegloticase, a pegylated uric acid specific enzyme sold under the brand name Krystexxa for the past 12 years. It lowers serum uric acid by converting it to allantoin, which is more water soluble and thus is easier to excrete from the body.

However, one of the problems of using the drug is that anti-drug antibodies frequently develop, meaning that discontinuation rates can be as high as 50%, with around a quarter of patients at high risk of experiencing an infusion reaction.

“Methotrexate is a medication we’re very familiar with for other rheumatologic conditions that use biologic medications, and we use this to prevent anti-drug antibodies. So, the MIRROR RCT was a study we performed to examine the pegloticase therapy in combination with methotrexate co therapy,” explained Dr. Botson.

In fact, co-administration of methotrexate and pegloticase was associated with fewer infusion reactions than using pegloticase alone (3% vs. 31%).
 

Study design and results

A total of 152 patients were included in the trial and were treated with methotrexate at a weekly dose of 15 mg for 2 weeks before being randomized, 2:1, to either continue methotrexate and then receive intravenous pegloticase or receive the latter with a placebo. Pegloticase was given at a dose of 8 mg every 2 weeks. Treatment was for 52 weeks, with the primary endpoint of serum uric acid response tested at 6 months.

The reason for the 2-week run-in period with methotrexate was to check that patients would be able to tolerate it, Dr. Botson explained.

The mean age of patients was around 54 years, the majority (> 84%) were male and were White (69%). The average duration of gout was about 14 years, with over 74% having tophi present at screening and experiencing 10-11 flares in the previous year. Baseline serum uric acid averaged at about 9 mg/dL.

Almost three-quarters of the 100 patients (73%) who were treated with the combination completed treatment to week 24 while the corresponding percentage in the placebo arm (n = 52) was 39%. The main reason for stopping was due to lack of efficacy (27% and 61% of cases, respectively), defined as having serum uric acid levels above 6 mg/dL on two consecutive measurements.

The median time to discontinuation was 69 days for those in the placebo arm; “it was non-estimable” in the methotrexate arm, Dr. Botson reported.

The mean change in serum uric acid through to week 24 was higher in the methotrexate than placebo arm, at a respective 7.66 and 5.23 mg/dL, giving a significant mean difference of 2.43 mg/dL.

There was a “dramatic resolution of tophaceous deposits,” Dr. Botson said. Complete resolution of tophi was seen in 34.6% of methotrexate-treated patients versus 13.8% of pegloticase-placebo–treated patients (P = .043).

One of the most common adverse events associated with pegloticase treatment is gout flare, which occurred in about 70% of participants in both study arms. Overall, the addition of methotrexate did not increase the risk for adverse events in general, and of the two deaths seen in the study – both in methotrexate-treated patients – one was because of a heart attack and another due COVID-19, so they were unrelated to study treatment.

In patients with renal insufficiency

Concern was raised during the discussion, however, on how to handle methotrexate use in patients with renal insufficiency.

“That’s been a debate that we’ve had in this study and others,” said Dr. Botson, acknowledging that “methotrexate is often a concern for the nephrologist that we’re co-treating these patients with.” However, no dose adjustments were needed in the study.

“There are some other studies with other immunomodulators that do suggest that other agents could be used that may be a little less potentially renal toxic, but we didn’t see any toxicity in the patients that we had, even in those that had a reduced [glomerular filtration rate],” he added.

Dr. Botson has received research support from Horizon and Radius Health. He also acknowledged receiving speakers fees from AbbVie, Amgen, Aurinia, ChemoCentryx*, Horizon, Eli Lilly, and Novartis.
 

Correction, 6/7/22: The name of the company ChemoCentryx was misstated.

In patients with uncontrolled gout, response rates were increased by 32% when methotrexate was used in conjunction with pegloticase versus pegloticase plus a placebo, it was reported at the annual European Congress of Rheumatology.

In the phase 4 MIRROR trial, 71% of patients who received pretreatment with methotrexate and then the combination of methotrexate and pegloticase achieved uric-acid levels lower than 6 mg/dL for more than 80% of the time during weeks 20-24 of the 52-week study. By comparison, only 39% of those treated with pegloticase plus a placebo achieved this primary endpoint (P < .0001).

This is good news for patients, suggested two rheumatologists who were not involved in the study. The combination appears “useful for a select group of gout patients,” observed Christian Ammitzbøll, MD, PhD, from Aarhus University Hospital, Denmark.

“Very promising in refractory gout,” agreed Emre Bilgin, MD, from Ankara, Turkey.
 

Rationale for using methotrexate

“Oral urate lowering agents are the mainstay of treatment of gout, but there are patients that just don’t respond to oral agents,” said Dr. Botson, a rheumatologist in private practice from Anchorage, Alaska.

“These patients are very difficult to treat,” he added. “They have a lot of physical disabilities, they have high medical comorbidities, and they have a low quality of life. Their treatment options are extremely limited.”

One of the few options they have is pegloticase, a pegylated uric acid specific enzyme sold under the brand name Krystexxa for the past 12 years. It lowers serum uric acid by converting it to allantoin, which is more water soluble and thus is easier to excrete from the body.

However, one of the problems of using the drug is that anti-drug antibodies frequently develop, meaning that discontinuation rates can be as high as 50%, with around a quarter of patients at high risk of experiencing an infusion reaction.

“Methotrexate is a medication we’re very familiar with for other rheumatologic conditions that use biologic medications, and we use this to prevent anti-drug antibodies. So, the MIRROR RCT was a study we performed to examine the pegloticase therapy in combination with methotrexate co therapy,” explained Dr. Botson.

In fact, co-administration of methotrexate and pegloticase was associated with fewer infusion reactions than using pegloticase alone (3% vs. 31%).
 

Study design and results

A total of 152 patients were included in the trial and were treated with methotrexate at a weekly dose of 15 mg for 2 weeks before being randomized, 2:1, to either continue methotrexate and then receive intravenous pegloticase or receive the latter with a placebo. Pegloticase was given at a dose of 8 mg every 2 weeks. Treatment was for 52 weeks, with the primary endpoint of serum uric acid response tested at 6 months.

The reason for the 2-week run-in period with methotrexate was to check that patients would be able to tolerate it, Dr. Botson explained.

The mean age of patients was around 54 years, the majority (> 84%) were male and were White (69%). The average duration of gout was about 14 years, with over 74% having tophi present at screening and experiencing 10-11 flares in the previous year. Baseline serum uric acid averaged at about 9 mg/dL.

Almost three-quarters of the 100 patients (73%) who were treated with the combination completed treatment to week 24 while the corresponding percentage in the placebo arm (n = 52) was 39%. The main reason for stopping was due to lack of efficacy (27% and 61% of cases, respectively), defined as having serum uric acid levels above 6 mg/dL on two consecutive measurements.

The median time to discontinuation was 69 days for those in the placebo arm; “it was non-estimable” in the methotrexate arm, Dr. Botson reported.

The mean change in serum uric acid through to week 24 was higher in the methotrexate than placebo arm, at a respective 7.66 and 5.23 mg/dL, giving a significant mean difference of 2.43 mg/dL.

There was a “dramatic resolution of tophaceous deposits,” Dr. Botson said. Complete resolution of tophi was seen in 34.6% of methotrexate-treated patients versus 13.8% of pegloticase-placebo–treated patients (P = .043).

One of the most common adverse events associated with pegloticase treatment is gout flare, which occurred in about 70% of participants in both study arms. Overall, the addition of methotrexate did not increase the risk for adverse events in general, and of the two deaths seen in the study – both in methotrexate-treated patients – one was because of a heart attack and another due COVID-19, so they were unrelated to study treatment.

In patients with renal insufficiency

Concern was raised during the discussion, however, on how to handle methotrexate use in patients with renal insufficiency.

“That’s been a debate that we’ve had in this study and others,” said Dr. Botson, acknowledging that “methotrexate is often a concern for the nephrologist that we’re co-treating these patients with.” However, no dose adjustments were needed in the study.

“There are some other studies with other immunomodulators that do suggest that other agents could be used that may be a little less potentially renal toxic, but we didn’t see any toxicity in the patients that we had, even in those that had a reduced [glomerular filtration rate],” he added.

Dr. Botson has received research support from Horizon and Radius Health. He also acknowledged receiving speakers fees from AbbVie, Amgen, Aurinia, ChemoCentryx*, Horizon, Eli Lilly, and Novartis.
 

Correction, 6/7/22: The name of the company ChemoCentryx was misstated.

In patients with uncontrolled gout, response rates were increased by 32% when methotrexate was used in conjunction with pegloticase versus pegloticase plus a placebo, it was reported at the annual European Congress of Rheumatology.

In the phase 4 MIRROR trial, 71% of patients who received pretreatment with methotrexate and then the combination of methotrexate and pegloticase achieved uric-acid levels lower than 6 mg/dL for more than 80% of the time during weeks 20-24 of the 52-week study. By comparison, only 39% of those treated with pegloticase plus a placebo achieved this primary endpoint (P < .0001).

This is good news for patients, suggested two rheumatologists who were not involved in the study. The combination appears “useful for a select group of gout patients,” observed Christian Ammitzbøll, MD, PhD, from Aarhus University Hospital, Denmark.

“Very promising in refractory gout,” agreed Emre Bilgin, MD, from Ankara, Turkey.
 

Rationale for using methotrexate

“Oral urate lowering agents are the mainstay of treatment of gout, but there are patients that just don’t respond to oral agents,” said Dr. Botson, a rheumatologist in private practice from Anchorage, Alaska.

“These patients are very difficult to treat,” he added. “They have a lot of physical disabilities, they have high medical comorbidities, and they have a low quality of life. Their treatment options are extremely limited.”

One of the few options they have is pegloticase, a pegylated uric acid specific enzyme sold under the brand name Krystexxa for the past 12 years. It lowers serum uric acid by converting it to allantoin, which is more water soluble and thus is easier to excrete from the body.

However, one of the problems of using the drug is that anti-drug antibodies frequently develop, meaning that discontinuation rates can be as high as 50%, with around a quarter of patients at high risk of experiencing an infusion reaction.

“Methotrexate is a medication we’re very familiar with for other rheumatologic conditions that use biologic medications, and we use this to prevent anti-drug antibodies. So, the MIRROR RCT was a study we performed to examine the pegloticase therapy in combination with methotrexate co therapy,” explained Dr. Botson.

In fact, co-administration of methotrexate and pegloticase was associated with fewer infusion reactions than using pegloticase alone (3% vs. 31%).
 

Study design and results

A total of 152 patients were included in the trial and were treated with methotrexate at a weekly dose of 15 mg for 2 weeks before being randomized, 2:1, to either continue methotrexate and then receive intravenous pegloticase or receive the latter with a placebo. Pegloticase was given at a dose of 8 mg every 2 weeks. Treatment was for 52 weeks, with the primary endpoint of serum uric acid response tested at 6 months.

The reason for the 2-week run-in period with methotrexate was to check that patients would be able to tolerate it, Dr. Botson explained.

The mean age of patients was around 54 years, the majority (> 84%) were male and were White (69%). The average duration of gout was about 14 years, with over 74% having tophi present at screening and experiencing 10-11 flares in the previous year. Baseline serum uric acid averaged at about 9 mg/dL.

Almost three-quarters of the 100 patients (73%) who were treated with the combination completed treatment to week 24 while the corresponding percentage in the placebo arm (n = 52) was 39%. The main reason for stopping was due to lack of efficacy (27% and 61% of cases, respectively), defined as having serum uric acid levels above 6 mg/dL on two consecutive measurements.

The median time to discontinuation was 69 days for those in the placebo arm; “it was non-estimable” in the methotrexate arm, Dr. Botson reported.

The mean change in serum uric acid through to week 24 was higher in the methotrexate than placebo arm, at a respective 7.66 and 5.23 mg/dL, giving a significant mean difference of 2.43 mg/dL.

There was a “dramatic resolution of tophaceous deposits,” Dr. Botson said. Complete resolution of tophi was seen in 34.6% of methotrexate-treated patients versus 13.8% of pegloticase-placebo–treated patients (P = .043).

One of the most common adverse events associated with pegloticase treatment is gout flare, which occurred in about 70% of participants in both study arms. Overall, the addition of methotrexate did not increase the risk for adverse events in general, and of the two deaths seen in the study – both in methotrexate-treated patients – one was because of a heart attack and another due COVID-19, so they were unrelated to study treatment.

In patients with renal insufficiency

Concern was raised during the discussion, however, on how to handle methotrexate use in patients with renal insufficiency.

“That’s been a debate that we’ve had in this study and others,” said Dr. Botson, acknowledging that “methotrexate is often a concern for the nephrologist that we’re co-treating these patients with.” However, no dose adjustments were needed in the study.

“There are some other studies with other immunomodulators that do suggest that other agents could be used that may be a little less potentially renal toxic, but we didn’t see any toxicity in the patients that we had, even in those that had a reduced [glomerular filtration rate],” he added.

Dr. Botson has received research support from Horizon and Radius Health. He also acknowledged receiving speakers fees from AbbVie, Amgen, Aurinia, ChemoCentryx*, Horizon, Eli Lilly, and Novartis.
 

Correction, 6/7/22: The name of the company ChemoCentryx was misstated.

COPENHAGEN – European recommendations and overarching principles for the management of patients with axial spondyloarthritis (axSpA) have remained largely unchanged since 2016 – with a few notable but very important exceptions.

The 2022 updated recommendations include a new point regarding which biologic agents to use for patients with recurrent uveitis, active inflammatory bowel disease (IBD), or significant psoriasis, as well as new advice to reevaluate the diagnosis and consider the presence of comorbidities if the disease doesn’t respond to current therapies, reported Sofia Ramiro, MD, PhD, from Leiden (Netherlands) University Medical Center.

She summarized the 2022 updates at the annual European Congress of Rheumatology on behalf of colleagues in the ASAS (Assessment of SpondyloArthritis International Society)/EULAR committee.

Among other significant updates are a recommendation for managing patients with persistently high disease activity despite conventional therapy, and a recommendation as to what to do when a first biologic or targeted synthetic disease-modifying antirheumatic drug (DMARD) fails, Dr. Ramiro said at the meeting.

“Although we have more changes in the pharmacological part, I would like to emphasize the importance of nonpharmacological treatment in axial SpA,” she said.

Overarching principles

The members of the committee that created the recommendations were in complete agreement that axSpA, as they state in the overarching principles, “is a potentially severe disease with diverse manifestations, usually requiring multidisciplinary management coordinated by the rheumatologist.”

They also universally acknowledged that “the primary goal of treating the patient with axSpA is to maximize health-related quality of life through control of symptoms and inflammation, prevention of progressive structural damage, preservation/normalization of function, and social participation.”

The overarching principles include the aforementioned emphasis on both pharmacologic and nonpharmacologic management, shared decision-making between patients and rheumatologists, and awareness of the potential financial toxicities and societal problems that patients face.

A closer look: New recommendations

As noted before, there are two new recommendations since the 2016 iteration.

Recommendation No. 10 states, “If there is a history of recurrent uveitis or active IBD, preference should be given to a monoclonal antibody against TNF-alpha [tumor necrosis factor–alpha]. For patients with significant psoriasis, an IL-17 [interleukin-17] inhibitor may be preferred.”

This recommendation stipulates that it refers only to IL-17A inhibitors.

The other new recommendation, No. 11, seems like plain common sense. It states, “Absence of response to treatment should trigger reevaluation of the diagnosis and consideration of the presence of comorbidities.”

Revised recommendations

The two significantly revised recommendations deal with drug therapy.

Recommendation No. 9 holds that for patients with persistently high disease activity despite conventional therapy, a TNF inhibitor, including the pegylated humanized antigen-binding fragment certolizumab pegol (Cimzia), an IL-17 inhibitor, or Janus kinase (JAK) inhibitor, should be considered.

Recommendation No. 12 states that if the first biologic or targeted synthetic DMARD fails, switching to another biologic DMARD (TNF inhibitor or IL-17 inhibitor) or JAK inhibitor should be considered.

Transatlantic similarities, differences

Lianne Gensler, MD, a rheumatologist and professor of medicine at the University of California, San Francisco, who served on the committee that developed the 2019 American College of Rheumatology guidelines for the treatment of ankylosing spondylitis and nonradiographic axSpA, said that, while there are similarities between some of the recommendations promulgated on each side of the Atlantic, there are significant differences and even opposing viewpoints.

A primary difference between the two is the methodology used to arrive at the recommendations in the first place, she said in an interview with this news organization.

“ACR uses a very robust approach to guideline development, where each question is addressed by a ‘PICO’ ” population, intervention, control, and outcomes – and that’s good if you have good evidence, but sometimes – often, in fact – we don’t have strong evidence that would lead everyone to choose the same approach every time, and that’s true especially in inflammatory arthritis, where there’s a lot of shared decision-making, so many of the recommendations out of ACR are conditional,” she said.

In contrast, the ASAS/EULAR recommendations are based largely on broader levels of evidence and on consensus. In developing the European recommendations, the authors were able to take into account drugs that were newly approved since the 2019 ACR guidelines were issued, she noted.

Although many of the broader recommendations are similar, they diverge when it comes to specific issues, such as whether to treat to target.

“ACR guidelines say, ‘Do not treat to target.’ EULAR guidelines say it’s okay to treat to target. ACR guidelines made that decision because at that time, there was no treat-to-target data,” Dr, Gensler said.

“I think, as rheumatologists, we always want to aim for a goal in a patient, so it’s not unreasonable, but I think we shouldn’t attach too much to a number,” she said.

Another difference is that the ACR guidelines recommend against switching to a biosimilar agent when a patient’s condition is stable with the originator biologic.

Dr. Gensler said that she particularly appreciated the new EULAR recommendation (No. 11) to reconsider the diagnosis for patients for whom therapies have failed.

“The sense that nonresponse means ongoing disease activity and therefore drug escalation or change needs to happen is not always the right answer,” she said.

The process for developing the recommendations was supported by EULAR. Dr. Ramiro has received research grants and consulting and/or speaking fees from AbbVie, Eli Lilly, Galapagos, Merck Sharp and Dohme, Novartis, Pfizer, Sanofi, and UCB. Dr. Gensler has received research grant support from Novartis, Pfizer, and UCB and has consulting relationships with AbbVie, Gilead, Janssen, MoonLake, Novartis, and Pfizer.

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

COPENHAGEN – European recommendations and overarching principles for the management of patients with axial spondyloarthritis (axSpA) have remained largely unchanged since 2016 – with a few notable but very important exceptions.

The 2022 updated recommendations include a new point regarding which biologic agents to use for patients with recurrent uveitis, active inflammatory bowel disease (IBD), or significant psoriasis, as well as new advice to reevaluate the diagnosis and consider the presence of comorbidities if the disease doesn’t respond to current therapies, reported Sofia Ramiro, MD, PhD, from Leiden (Netherlands) University Medical Center.

She summarized the 2022 updates at the annual European Congress of Rheumatology on behalf of colleagues in the ASAS (Assessment of SpondyloArthritis International Society)/EULAR committee.

Among other significant updates are a recommendation for managing patients with persistently high disease activity despite conventional therapy, and a recommendation as to what to do when a first biologic or targeted synthetic disease-modifying antirheumatic drug (DMARD) fails, Dr. Ramiro said at the meeting.

“Although we have more changes in the pharmacological part, I would like to emphasize the importance of nonpharmacological treatment in axial SpA,” she said.

Overarching principles

The members of the committee that created the recommendations were in complete agreement that axSpA, as they state in the overarching principles, “is a potentially severe disease with diverse manifestations, usually requiring multidisciplinary management coordinated by the rheumatologist.”

They also universally acknowledged that “the primary goal of treating the patient with axSpA is to maximize health-related quality of life through control of symptoms and inflammation, prevention of progressive structural damage, preservation/normalization of function, and social participation.”

The overarching principles include the aforementioned emphasis on both pharmacologic and nonpharmacologic management, shared decision-making between patients and rheumatologists, and awareness of the potential financial toxicities and societal problems that patients face.

A closer look: New recommendations

As noted before, there are two new recommendations since the 2016 iteration.

Recommendation No. 10 states, “If there is a history of recurrent uveitis or active IBD, preference should be given to a monoclonal antibody against TNF-alpha [tumor necrosis factor–alpha]. For patients with significant psoriasis, an IL-17 [interleukin-17] inhibitor may be preferred.”

This recommendation stipulates that it refers only to IL-17A inhibitors.

The other new recommendation, No. 11, seems like plain common sense. It states, “Absence of response to treatment should trigger reevaluation of the diagnosis and consideration of the presence of comorbidities.”

Revised recommendations

The two significantly revised recommendations deal with drug therapy.

Recommendation No. 9 holds that for patients with persistently high disease activity despite conventional therapy, a TNF inhibitor, including the pegylated humanized antigen-binding fragment certolizumab pegol (Cimzia), an IL-17 inhibitor, or Janus kinase (JAK) inhibitor, should be considered.

Recommendation No. 12 states that if the first biologic or targeted synthetic DMARD fails, switching to another biologic DMARD (TNF inhibitor or IL-17 inhibitor) or JAK inhibitor should be considered.

Transatlantic similarities, differences

Lianne Gensler, MD, a rheumatologist and professor of medicine at the University of California, San Francisco, who served on the committee that developed the 2019 American College of Rheumatology guidelines for the treatment of ankylosing spondylitis and nonradiographic axSpA, said that, while there are similarities between some of the recommendations promulgated on each side of the Atlantic, there are significant differences and even opposing viewpoints.

A primary difference between the two is the methodology used to arrive at the recommendations in the first place, she said in an interview with this news organization.

“ACR uses a very robust approach to guideline development, where each question is addressed by a ‘PICO’ ” population, intervention, control, and outcomes – and that’s good if you have good evidence, but sometimes – often, in fact – we don’t have strong evidence that would lead everyone to choose the same approach every time, and that’s true especially in inflammatory arthritis, where there’s a lot of shared decision-making, so many of the recommendations out of ACR are conditional,” she said.

In contrast, the ASAS/EULAR recommendations are based largely on broader levels of evidence and on consensus. In developing the European recommendations, the authors were able to take into account drugs that were newly approved since the 2019 ACR guidelines were issued, she noted.

Although many of the broader recommendations are similar, they diverge when it comes to specific issues, such as whether to treat to target.

“ACR guidelines say, ‘Do not treat to target.’ EULAR guidelines say it’s okay to treat to target. ACR guidelines made that decision because at that time, there was no treat-to-target data,” Dr, Gensler said.

“I think, as rheumatologists, we always want to aim for a goal in a patient, so it’s not unreasonable, but I think we shouldn’t attach too much to a number,” she said.

Another difference is that the ACR guidelines recommend against switching to a biosimilar agent when a patient’s condition is stable with the originator biologic.

Dr. Gensler said that she particularly appreciated the new EULAR recommendation (No. 11) to reconsider the diagnosis for patients for whom therapies have failed.

“The sense that nonresponse means ongoing disease activity and therefore drug escalation or change needs to happen is not always the right answer,” she said.

The process for developing the recommendations was supported by EULAR. Dr. Ramiro has received research grants and consulting and/or speaking fees from AbbVie, Eli Lilly, Galapagos, Merck Sharp and Dohme, Novartis, Pfizer, Sanofi, and UCB. Dr. Gensler has received research grant support from Novartis, Pfizer, and UCB and has consulting relationships with AbbVie, Gilead, Janssen, MoonLake, Novartis, and Pfizer.

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

COPENHAGEN – European recommendations and overarching principles for the management of patients with axial spondyloarthritis (axSpA) have remained largely unchanged since 2016 – with a few notable but very important exceptions.

The 2022 updated recommendations include a new point regarding which biologic agents to use for patients with recurrent uveitis, active inflammatory bowel disease (IBD), or significant psoriasis, as well as new advice to reevaluate the diagnosis and consider the presence of comorbidities if the disease doesn’t respond to current therapies, reported Sofia Ramiro, MD, PhD, from Leiden (Netherlands) University Medical Center.

She summarized the 2022 updates at the annual European Congress of Rheumatology on behalf of colleagues in the ASAS (Assessment of SpondyloArthritis International Society)/EULAR committee.

Among other significant updates are a recommendation for managing patients with persistently high disease activity despite conventional therapy, and a recommendation as to what to do when a first biologic or targeted synthetic disease-modifying antirheumatic drug (DMARD) fails, Dr. Ramiro said at the meeting.

“Although we have more changes in the pharmacological part, I would like to emphasize the importance of nonpharmacological treatment in axial SpA,” she said.

Overarching principles

The members of the committee that created the recommendations were in complete agreement that axSpA, as they state in the overarching principles, “is a potentially severe disease with diverse manifestations, usually requiring multidisciplinary management coordinated by the rheumatologist.”

They also universally acknowledged that “the primary goal of treating the patient with axSpA is to maximize health-related quality of life through control of symptoms and inflammation, prevention of progressive structural damage, preservation/normalization of function, and social participation.”

The overarching principles include the aforementioned emphasis on both pharmacologic and nonpharmacologic management, shared decision-making between patients and rheumatologists, and awareness of the potential financial toxicities and societal problems that patients face.

A closer look: New recommendations

As noted before, there are two new recommendations since the 2016 iteration.

Recommendation No. 10 states, “If there is a history of recurrent uveitis or active IBD, preference should be given to a monoclonal antibody against TNF-alpha [tumor necrosis factor–alpha]. For patients with significant psoriasis, an IL-17 [interleukin-17] inhibitor may be preferred.”

This recommendation stipulates that it refers only to IL-17A inhibitors.

The other new recommendation, No. 11, seems like plain common sense. It states, “Absence of response to treatment should trigger reevaluation of the diagnosis and consideration of the presence of comorbidities.”

Revised recommendations

The two significantly revised recommendations deal with drug therapy.

Recommendation No. 9 holds that for patients with persistently high disease activity despite conventional therapy, a TNF inhibitor, including the pegylated humanized antigen-binding fragment certolizumab pegol (Cimzia), an IL-17 inhibitor, or Janus kinase (JAK) inhibitor, should be considered.

Recommendation No. 12 states that if the first biologic or targeted synthetic DMARD fails, switching to another biologic DMARD (TNF inhibitor or IL-17 inhibitor) or JAK inhibitor should be considered.

Transatlantic similarities, differences

Lianne Gensler, MD, a rheumatologist and professor of medicine at the University of California, San Francisco, who served on the committee that developed the 2019 American College of Rheumatology guidelines for the treatment of ankylosing spondylitis and nonradiographic axSpA, said that, while there are similarities between some of the recommendations promulgated on each side of the Atlantic, there are significant differences and even opposing viewpoints.

A primary difference between the two is the methodology used to arrive at the recommendations in the first place, she said in an interview with this news organization.

“ACR uses a very robust approach to guideline development, where each question is addressed by a ‘PICO’ ” population, intervention, control, and outcomes – and that’s good if you have good evidence, but sometimes – often, in fact – we don’t have strong evidence that would lead everyone to choose the same approach every time, and that’s true especially in inflammatory arthritis, where there’s a lot of shared decision-making, so many of the recommendations out of ACR are conditional,” she said.

In contrast, the ASAS/EULAR recommendations are based largely on broader levels of evidence and on consensus. In developing the European recommendations, the authors were able to take into account drugs that were newly approved since the 2019 ACR guidelines were issued, she noted.

Although many of the broader recommendations are similar, they diverge when it comes to specific issues, such as whether to treat to target.

“ACR guidelines say, ‘Do not treat to target.’ EULAR guidelines say it’s okay to treat to target. ACR guidelines made that decision because at that time, there was no treat-to-target data,” Dr, Gensler said.

“I think, as rheumatologists, we always want to aim for a goal in a patient, so it’s not unreasonable, but I think we shouldn’t attach too much to a number,” she said.

Another difference is that the ACR guidelines recommend against switching to a biosimilar agent when a patient’s condition is stable with the originator biologic.

Dr. Gensler said that she particularly appreciated the new EULAR recommendation (No. 11) to reconsider the diagnosis for patients for whom therapies have failed.

“The sense that nonresponse means ongoing disease activity and therefore drug escalation or change needs to happen is not always the right answer,” she said.

The process for developing the recommendations was supported by EULAR. Dr. Ramiro has received research grants and consulting and/or speaking fees from AbbVie, Eli Lilly, Galapagos, Merck Sharp and Dohme, Novartis, Pfizer, Sanofi, and UCB. Dr. Gensler has received research grant support from Novartis, Pfizer, and UCB and has consulting relationships with AbbVie, Gilead, Janssen, MoonLake, Novartis, and Pfizer.

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

A host of psoriatic arthritis symptoms can be improved by the investigational interleukin (IL)-17 blocker izokibep, according to the results of a phase 2 trial presented at the annual European Congress of Rheumatology.

Around half of all participants in the trial who were treated with izokibep achieved a 50% or higher improvement in American College of Rheumatology response criteria (ACR50) at week 16, the trial’s primary endpoint. This was highly significant (P = .0003) when compared to the control group, where only 13% of patients given a placebo achieved an ACR50.

There was also a significant improvement in skin symptoms, as assessed by the Psoriasis Area and Severity Index (PASI) and resolution of enthesitis in 88% of patients given the highest dose of izokibep.

Aurelie Najm, MD, PhD, of the Institute of Infection, Immunity and Inflammation at the University of Glasgow, who tweeted about the main results, said that the data also looked “promising for the enthesitis domain” with a “safety profile similar to that observed in PsO [psoriasis].”Peter Taylor, MA, PhD, FRCP, FRCPE, of the University of Oxford in England, said: “The improvements demonstrated in arthritis, psoriasis, and enthesitis are exciting relative to responses reported for the current standard of care.”

He continued, in a statement issued jointly by Affibody, Acelyrin, and Immagene Biopharmaceuticals – the three companies assessing izokibep’s therapeutic potential – that the drug “seems promising” and that he was “eager to see its continued development for patients.”

Small and potent, a novel IL-17 inhibitor

Izokibep is an antibody mimetic that inhibits IL-17A designed to “overcome the limitations of monoclonal antibodies,” according to its developers.

Due to its small molecular size – reportedly about one-tenth of the size of a monoclonal antibody – they say that levels of high drug exposure can be achieved from a single, subcutaneous injection rather than an intravenous infusion, which is needed for monoclonal antibodies.

Moreover, izokibep’s small size means it could potentially reach target tissues “that may otherwise be inaccessible to the much larger monoclonal antibodies.” 

So far more than 300 patients have been treated with izokibep, some for up to 3 years, but not all have had psoriatic arthritis. Indeed, the drug has been tested in patients with psoriasis, and there are a few actively recruiting trials including one in ankylosing spondylitis, another in noninfective uveitis, and one in the rare and painful skin condition hidradenitis suppurativa.

Testing two doses of izokibep in psoriatic arthritis

The trial presented at the EULAR 2022 Congress tested two doses of izokibep – 40 mg and 80 mg – given by subcutaneous injection every 2 weeks – against placebo in 135 adult patients with active psoriatic arthritis. For inclusion in the trial patients had to have at least three swollen and at least three tender joints and have had an inadequate response to prior therapy including nonsteroidal anti-inflammatory drugs, conventional synthetic disease-modifying antirheumatic drugs, or tumor necrosis factor inhibitors.

Principle investigator Frank Behrens, MD, of Goethe University Frankfurt, Germany, reported that it was a multicenter effort conducted at 22 European sites with the primary endpoint being an ACR50 response at 16 weeks. This was met by 52% of patients given the 80-mg dose of izokibep, 48% of patients given the 40-mg dose of izokibep, and just 13% of patients who had been randomized to placebo.

ACR20 and ACR70 response were one of several key secondary endpoints tested, again at 16 weeks, with a respective 75%, 60%, and 20% of patients in each group achieving the lower response target and 20%, 32%, and 5%, achieving the more stringent response target.

“Izokibep demonstrated a robust efficacy in the musculoskeletal arthritic domains, but also in the extra-articular musculoskeletal domain,” Dr. Behrens said.

Not only that, but the values were “at the top end” of what’s been demonstrated for drugs currently regarded as the standard of care.

More than 80% of patients achieved a PASI75 response and 57% a PASI50 response with the two doses of izokibep, and 63%-88% achieved a resolution of enthesitis. The latter was measured using the Leeds Enthesitis Index.

There was also improvement in quality of life, measured using the Psoriatic Impact of Disease questionnaire, with a percentage increase beyond the MCID of 31%-41% with izokibep versus 12% for placebo.

“These are the first data of the phase 2 study in psoriatic arthritis,” Dr. Behrens reported.

“The safety profile was consistent with placebo,” with the only “standout aspect” being a higher number of injection-site reactions with izokibep versus placebo; but there were no serious infections, no serious adverse events,” he added.

“The interesting thing is from the preclinical research there was no dose-limiting toxicity with izokibep, therefore, I think the plan in the future is maybe to increase the dose to optimize treatment outcome based on the really robust effectiveness we see here in the first study in this clinical trial,” he said.

As a small study, stratifying results by gender wasn’t an option, Dr. Behrens noted in answering a question during the discussion period, but might be something that will be included in future and larger trials based on the post-hoc findings of other IL-17 trials.

Moving forward, the next step will involve a phase 2b/3 pivotal study which will likely include a higher dosing regimen of 160 mg once weekly alongside the twice-weekly dosing used in this trial.

Izokibep is an investigational treatment being developed by Affibody AB, Sweden, and ACELYRIN, USA. All three companies funded the phase 2 trial and were involved in the study design, conduct and reporting of results.

Dr. Behrens and Dr. Taylor were investigators in the study.

Dr. Behrens disclosed he was a shareholder of Pfizer, Sanofi, GlaxoSmithKline, Gilead Sciences, Inc. and Novartis; part of the speakers’ bureau for Amgen, Horizon, Lilly, Novartis, Pfizer, Sanofi, Genzyme, Flexion and AbbVie; a consultant of AbbVie, Boehringer Ingelheim, Flexion, Janssen, Pfizer, Sanofi, Regeneron, SUN Pharma Advanced Research, Gilead Sciences, Inc.; and had received grant or research support from Pfizer, Janssen, Chugai, Celgene and Roche

Dr. Taylor acknowledged grant or research support from: Celgene and Galapagos, and acted as a consultant for AbbVie, Biogen, Bristol Myers Squibb, Fresenius, Galapagos, Gilead, GlaxoSmithKline, Janssen, Lilly, Nordic Pharma, Pfizer, Roche, Sanofi and UCB.
 

A host of psoriatic arthritis symptoms can be improved by the investigational interleukin (IL)-17 blocker izokibep, according to the results of a phase 2 trial presented at the annual European Congress of Rheumatology.

Around half of all participants in the trial who were treated with izokibep achieved a 50% or higher improvement in American College of Rheumatology response criteria (ACR50) at week 16, the trial’s primary endpoint. This was highly significant (P = .0003) when compared to the control group, where only 13% of patients given a placebo achieved an ACR50.

There was also a significant improvement in skin symptoms, as assessed by the Psoriasis Area and Severity Index (PASI) and resolution of enthesitis in 88% of patients given the highest dose of izokibep.

Aurelie Najm, MD, PhD, of the Institute of Infection, Immunity and Inflammation at the University of Glasgow, who tweeted about the main results, said that the data also looked “promising for the enthesitis domain” with a “safety profile similar to that observed in PsO [psoriasis].”Peter Taylor, MA, PhD, FRCP, FRCPE, of the University of Oxford in England, said: “The improvements demonstrated in arthritis, psoriasis, and enthesitis are exciting relative to responses reported for the current standard of care.”

He continued, in a statement issued jointly by Affibody, Acelyrin, and Immagene Biopharmaceuticals – the three companies assessing izokibep’s therapeutic potential – that the drug “seems promising” and that he was “eager to see its continued development for patients.”

Small and potent, a novel IL-17 inhibitor

Izokibep is an antibody mimetic that inhibits IL-17A designed to “overcome the limitations of monoclonal antibodies,” according to its developers.

Due to its small molecular size – reportedly about one-tenth of the size of a monoclonal antibody – they say that levels of high drug exposure can be achieved from a single, subcutaneous injection rather than an intravenous infusion, which is needed for monoclonal antibodies.

Moreover, izokibep’s small size means it could potentially reach target tissues “that may otherwise be inaccessible to the much larger monoclonal antibodies.” 

So far more than 300 patients have been treated with izokibep, some for up to 3 years, but not all have had psoriatic arthritis. Indeed, the drug has been tested in patients with psoriasis, and there are a few actively recruiting trials including one in ankylosing spondylitis, another in noninfective uveitis, and one in the rare and painful skin condition hidradenitis suppurativa.

Testing two doses of izokibep in psoriatic arthritis

The trial presented at the EULAR 2022 Congress tested two doses of izokibep – 40 mg and 80 mg – given by subcutaneous injection every 2 weeks – against placebo in 135 adult patients with active psoriatic arthritis. For inclusion in the trial patients had to have at least three swollen and at least three tender joints and have had an inadequate response to prior therapy including nonsteroidal anti-inflammatory drugs, conventional synthetic disease-modifying antirheumatic drugs, or tumor necrosis factor inhibitors.

Principle investigator Frank Behrens, MD, of Goethe University Frankfurt, Germany, reported that it was a multicenter effort conducted at 22 European sites with the primary endpoint being an ACR50 response at 16 weeks. This was met by 52% of patients given the 80-mg dose of izokibep, 48% of patients given the 40-mg dose of izokibep, and just 13% of patients who had been randomized to placebo.

ACR20 and ACR70 response were one of several key secondary endpoints tested, again at 16 weeks, with a respective 75%, 60%, and 20% of patients in each group achieving the lower response target and 20%, 32%, and 5%, achieving the more stringent response target.

“Izokibep demonstrated a robust efficacy in the musculoskeletal arthritic domains, but also in the extra-articular musculoskeletal domain,” Dr. Behrens said.

Not only that, but the values were “at the top end” of what’s been demonstrated for drugs currently regarded as the standard of care.

More than 80% of patients achieved a PASI75 response and 57% a PASI50 response with the two doses of izokibep, and 63%-88% achieved a resolution of enthesitis. The latter was measured using the Leeds Enthesitis Index.

There was also improvement in quality of life, measured using the Psoriatic Impact of Disease questionnaire, with a percentage increase beyond the MCID of 31%-41% with izokibep versus 12% for placebo.

“These are the first data of the phase 2 study in psoriatic arthritis,” Dr. Behrens reported.

“The safety profile was consistent with placebo,” with the only “standout aspect” being a higher number of injection-site reactions with izokibep versus placebo; but there were no serious infections, no serious adverse events,” he added.

“The interesting thing is from the preclinical research there was no dose-limiting toxicity with izokibep, therefore, I think the plan in the future is maybe to increase the dose to optimize treatment outcome based on the really robust effectiveness we see here in the first study in this clinical trial,” he said.

As a small study, stratifying results by gender wasn’t an option, Dr. Behrens noted in answering a question during the discussion period, but might be something that will be included in future and larger trials based on the post-hoc findings of other IL-17 trials.

Moving forward, the next step will involve a phase 2b/3 pivotal study which will likely include a higher dosing regimen of 160 mg once weekly alongside the twice-weekly dosing used in this trial.

Izokibep is an investigational treatment being developed by Affibody AB, Sweden, and ACELYRIN, USA. All three companies funded the phase 2 trial and were involved in the study design, conduct and reporting of results.

Dr. Behrens and Dr. Taylor were investigators in the study.

Dr. Behrens disclosed he was a shareholder of Pfizer, Sanofi, GlaxoSmithKline, Gilead Sciences, Inc. and Novartis; part of the speakers’ bureau for Amgen, Horizon, Lilly, Novartis, Pfizer, Sanofi, Genzyme, Flexion and AbbVie; a consultant of AbbVie, Boehringer Ingelheim, Flexion, Janssen, Pfizer, Sanofi, Regeneron, SUN Pharma Advanced Research, Gilead Sciences, Inc.; and had received grant or research support from Pfizer, Janssen, Chugai, Celgene and Roche

Dr. Taylor acknowledged grant or research support from: Celgene and Galapagos, and acted as a consultant for AbbVie, Biogen, Bristol Myers Squibb, Fresenius, Galapagos, Gilead, GlaxoSmithKline, Janssen, Lilly, Nordic Pharma, Pfizer, Roche, Sanofi and UCB.
 

A host of psoriatic arthritis symptoms can be improved by the investigational interleukin (IL)-17 blocker izokibep, according to the results of a phase 2 trial presented at the annual European Congress of Rheumatology.

Around half of all participants in the trial who were treated with izokibep achieved a 50% or higher improvement in American College of Rheumatology response criteria (ACR50) at week 16, the trial’s primary endpoint. This was highly significant (P = .0003) when compared to the control group, where only 13% of patients given a placebo achieved an ACR50.

There was also a significant improvement in skin symptoms, as assessed by the Psoriasis Area and Severity Index (PASI) and resolution of enthesitis in 88% of patients given the highest dose of izokibep.

Aurelie Najm, MD, PhD, of the Institute of Infection, Immunity and Inflammation at the University of Glasgow, who tweeted about the main results, said that the data also looked “promising for the enthesitis domain” with a “safety profile similar to that observed in PsO [psoriasis].”Peter Taylor, MA, PhD, FRCP, FRCPE, of the University of Oxford in England, said: “The improvements demonstrated in arthritis, psoriasis, and enthesitis are exciting relative to responses reported for the current standard of care.”

He continued, in a statement issued jointly by Affibody, Acelyrin, and Immagene Biopharmaceuticals – the three companies assessing izokibep’s therapeutic potential – that the drug “seems promising” and that he was “eager to see its continued development for patients.”

Small and potent, a novel IL-17 inhibitor

Izokibep is an antibody mimetic that inhibits IL-17A designed to “overcome the limitations of monoclonal antibodies,” according to its developers.

Due to its small molecular size – reportedly about one-tenth of the size of a monoclonal antibody – they say that levels of high drug exposure can be achieved from a single, subcutaneous injection rather than an intravenous infusion, which is needed for monoclonal antibodies.

Moreover, izokibep’s small size means it could potentially reach target tissues “that may otherwise be inaccessible to the much larger monoclonal antibodies.” 

So far more than 300 patients have been treated with izokibep, some for up to 3 years, but not all have had psoriatic arthritis. Indeed, the drug has been tested in patients with psoriasis, and there are a few actively recruiting trials including one in ankylosing spondylitis, another in noninfective uveitis, and one in the rare and painful skin condition hidradenitis suppurativa.

Testing two doses of izokibep in psoriatic arthritis

The trial presented at the EULAR 2022 Congress tested two doses of izokibep – 40 mg and 80 mg – given by subcutaneous injection every 2 weeks – against placebo in 135 adult patients with active psoriatic arthritis. For inclusion in the trial patients had to have at least three swollen and at least three tender joints and have had an inadequate response to prior therapy including nonsteroidal anti-inflammatory drugs, conventional synthetic disease-modifying antirheumatic drugs, or tumor necrosis factor inhibitors.

Principle investigator Frank Behrens, MD, of Goethe University Frankfurt, Germany, reported that it was a multicenter effort conducted at 22 European sites with the primary endpoint being an ACR50 response at 16 weeks. This was met by 52% of patients given the 80-mg dose of izokibep, 48% of patients given the 40-mg dose of izokibep, and just 13% of patients who had been randomized to placebo.

ACR20 and ACR70 response were one of several key secondary endpoints tested, again at 16 weeks, with a respective 75%, 60%, and 20% of patients in each group achieving the lower response target and 20%, 32%, and 5%, achieving the more stringent response target.

“Izokibep demonstrated a robust efficacy in the musculoskeletal arthritic domains, but also in the extra-articular musculoskeletal domain,” Dr. Behrens said.

Not only that, but the values were “at the top end” of what’s been demonstrated for drugs currently regarded as the standard of care.

More than 80% of patients achieved a PASI75 response and 57% a PASI50 response with the two doses of izokibep, and 63%-88% achieved a resolution of enthesitis. The latter was measured using the Leeds Enthesitis Index.

There was also improvement in quality of life, measured using the Psoriatic Impact of Disease questionnaire, with a percentage increase beyond the MCID of 31%-41% with izokibep versus 12% for placebo.

“These are the first data of the phase 2 study in psoriatic arthritis,” Dr. Behrens reported.

“The safety profile was consistent with placebo,” with the only “standout aspect” being a higher number of injection-site reactions with izokibep versus placebo; but there were no serious infections, no serious adverse events,” he added.

“The interesting thing is from the preclinical research there was no dose-limiting toxicity with izokibep, therefore, I think the plan in the future is maybe to increase the dose to optimize treatment outcome based on the really robust effectiveness we see here in the first study in this clinical trial,” he said.

As a small study, stratifying results by gender wasn’t an option, Dr. Behrens noted in answering a question during the discussion period, but might be something that will be included in future and larger trials based on the post-hoc findings of other IL-17 trials.

Moving forward, the next step will involve a phase 2b/3 pivotal study which will likely include a higher dosing regimen of 160 mg once weekly alongside the twice-weekly dosing used in this trial.

Izokibep is an investigational treatment being developed by Affibody AB, Sweden, and ACELYRIN, USA. All three companies funded the phase 2 trial and were involved in the study design, conduct and reporting of results.

Dr. Behrens and Dr. Taylor were investigators in the study.

Dr. Behrens disclosed he was a shareholder of Pfizer, Sanofi, GlaxoSmithKline, Gilead Sciences, Inc. and Novartis; part of the speakers’ bureau for Amgen, Horizon, Lilly, Novartis, Pfizer, Sanofi, Genzyme, Flexion and AbbVie; a consultant of AbbVie, Boehringer Ingelheim, Flexion, Janssen, Pfizer, Sanofi, Regeneron, SUN Pharma Advanced Research, Gilead Sciences, Inc.; and had received grant or research support from Pfizer, Janssen, Chugai, Celgene and Roche

Dr. Taylor acknowledged grant or research support from: Celgene and Galapagos, and acted as a consultant for AbbVie, Biogen, Bristol Myers Squibb, Fresenius, Galapagos, Gilead, GlaxoSmithKline, Janssen, Lilly, Nordic Pharma, Pfizer, Roche, Sanofi and UCB.
 

COPENHAGEN – Temporary methotrexate in clinically suspected arthralgia delays but does not prevent clinical arthritis development; however, it does lead to sustained reduction of disease burden and MRI-detected inflammation in all at-risk groups, shows the 2-year Treat Earlier study.

“These data provide the first evidence for disease modification when intervening in ‘pre-RA [rheumatoid arthritis]’ or arthralgia,” said Doortje Krijbolder, MD, of Leiden (the Netherlands) University Medical Center, who presented her study at the annual European Congress of Rheumatology.  

The randomized, double-blind, study aimed to find out if giving methotrexate in the pre-arthritis phase of arthralgia (with subclinical joint inflammation) prevents the development of clinical arthritis or reduces the burden of disease.  

“This is the first trial that aims to reduce the burden of disease, and as such, in pre-RA, it is important that disease modification is sustained after temporary treatment otherwise patients will start regressing with disease activity,” said Dr. Krijbolder.

She explained that methotrexate is usually initiated as first-line treatment when arthritis becomes clinically apparent with joint swelling, but “disease processes begin long before this, and only become clinically recognizable when patients develop symptoms.” 

 

Clinically detectable arthritis development

All 236 patients included in the study had arthralgia of the small joints that, because of the character of the symptoms, was found clinically suspect for progression to RA over time.

“Importantly, these participants had not yet developed clinical arthritis that could be detected on physical joint examination, and were clinically suspected of progressing to RA. They had all undergone an MRI and subclinical joint-inflammation had been detected that was more than prevalent in symptom-free controls,” said Dr. Krijbolder.

Patients were randomized (1:1) to either a single intramuscular glucocorticoid injection (120 mg methylprednisolone [Depo Medrol]) and a 1-year course of oral methotrexate (up to 25 mg/week), or to placebo injection and placebo tablets, and were then followed for a further year without medication to see whether disease progressed.  

Treatment and placebo groups were matched with an average age of 46-47 years, 62%-68% were women, they had had symptoms (joint pain) for 27-28 weeks, C-reactive protein was increased in 27%-30%, and 20%-26% were anti-citrullinated protein autoantibody (ACPA) positive.  

The primary endpoint was the development of clinically detectable arthritis (fulfilling the 2010 RA-criteria or involving ≥ 2 joints) that persisted for at least 2 weeks. The main secondary endpoints were related to disease burden, including patient-reported physical functioning, along with symptoms and workability (presenteeism at work – the percentage of productivity lost caused by the joint complaints), and measured every 4 months, said Dr. Krijbolder.

She and her colleagues also followed the course of MRI-detected inflammation, which comprised the sum of tenosynovitis, synovitis, and osteitis scored with the RA-MRI Scoring (RAMRIS) method.  

Analysis was carried out on an intention-to-treat basis, and two prespecified subgroup analyses were also performed to obtain a better understanding of the effect of methotrexate and glucocorticoids in participants with high risk of clinical arthritis development (positive predictive value (PPV) ≥ 70%), and in patients stratified for ACPA status.  

 

Delays but does not prevent

There was no difference between treatment and placebo groups in the development of persistent clinical arthritis over 2 years (80% vs. 82%, hazard ratio [HR] 0.81; 95% confidence interval [CI], 0.45, 1.48]); however, in the high-risk group subanalysis, 67% in the placebo group developed persistent clinical arthritis. For the treatment group, 7%developed persistent clinical arthritis at 6 months, 27% at 12 months, 40% at 18 months, and 67% at 24 months. For the placebo group: 56% developed persistent clinical arthritis at 6 months, and 67% at 12 months, 18 months, and 24 months. 

“Strikingly, in the treatment group there was a statistically significant difference between 6 and 12 months, but in year 2, this difference disappeared, suggesting a delayed arthritis development but no prevention,” said Dr. Krijbolder. 

Persistent clinical arthritis became similar at 24 months, at 67% in both groups. A similar, but less pronounced, delaying effect was seen with the ACPA-positive patients, with 48% and 52% developing persistent clinical arthritis at 24 months.  

In joint pain, there was a decline in the treatment group compared with the placebo group and this persisted over 2 years (–9 on scale of 0 to 100: (95%CI, –12,–4; P < .001), and a similar effect was seen in high-risk and ACPA subgroups, reported Dr. Krijbolder.  

Physical functioning improved more in the treatment-group compared with the placebo group during the first months and remained better (mean between-group difference over 2 years HAQ [health assessment questionnaire] –0.1 [–0.2, –0.03; P = .004]), and morning stiffness (–12 [95%CI, –16, –8; P < .001]), and presenteeism (–8% [95%CI, –13%, –3%; P = .001]) also showed improvement over time compared with placebo.  

MRI-detected joint-inflammation was also persistently improved with a mean difference over 2 years –1.4 points (95%CI, –2.0, –0.9; P < .001). “As we know that symptoms and functional impairments are associated with MRI-detected joint inflammation, it was not surprising that treatment induced a decline in joint inflammation that persisted over time, also after the stop of the treatment in the second year,” explained Dr. Krijbolder.  

In the high-risk subgroup, as well as in both ACPA-positive and ACPA-negative participants, a comparable statistically significant decline in MRI-detected inflammation was found.

“It may seem counterintuitive that on the one hand we found a delaying effect of treatment on persistent clinical arthritis but no prevention, while on the other, we saw a sustained treatment effect on MRI-detected joint-inflammation and related symptoms and functional impairments,” added Dr. Krijbolder.

To help understand this, the researchers performed a post hoc analysis in high-risk participants, comparing those who did not progress with those who did progress to arthritis. “Both progressors and nonprogressors showed a sustained treatment effect for pain and MRI-detected joint-inflammation, and in nonprogressors, there was almost a complete relief of pain and they nearly returned to the normal range of MRI-detected joint-inflammation as seen in symptom-free controls,” reported Dr. Krijbolder. 

“In those who progressed to arthritis, there was less pain and less MRI-detected joint inflammation in the treatment group, but also at the time when they developed clinical arthritis. So both progressors and nonprogressors benefit from treatment,” she noted.  

The number of serious adverse events was the same between the groups and adverse events were as expected from methotrexate.  

Dr. Krijbolder said, “the results are encouraging and will open up a new treatment landscape in pre-RA at the future, but at the moment it is too early to give recommendations for clinical practice; we definitely do not want to advocate the start of treatment in all at-risk individuals from now on.”

More research should unravel the mechanisms within the joint that contribute to the development of clinical arthritis and disease chronicity, she said. “If we understand these, we may be able to use more targeted interventions in the future and prevent the development of clinical arthritis all together.

“We are also looking forward to learning more about the long-term beneficial effects of this early treatment in our ongoing observational extension of the trial.” 

Hendrik Schulze-Koops, MD, of Ludwig-Maximilians-University of Munich, who moderated the session, asked Dr. Krijbolder, “As well as giving methotrexate to the participants in the treatment group, you also gave a single glucocorticoid injection at baseline, and a placebo injection in the placebo group, can you comment on that?”

EULAR

COPENHAGEN – Temporary methotrexate in clinically suspected arthralgia delays but does not prevent clinical arthritis development; however, it does lead to sustained reduction of disease burden and MRI-detected inflammation in all at-risk groups, shows the 2-year Treat Earlier study.

“These data provide the first evidence for disease modification when intervening in ‘pre-RA [rheumatoid arthritis]’ or arthralgia,” said Doortje Krijbolder, MD, of Leiden (the Netherlands) University Medical Center, who presented her study at the annual European Congress of Rheumatology.  

The randomized, double-blind, study aimed to find out if giving methotrexate in the pre-arthritis phase of arthralgia (with subclinical joint inflammation) prevents the development of clinical arthritis or reduces the burden of disease.  

“This is the first trial that aims to reduce the burden of disease, and as such, in pre-RA, it is important that disease modification is sustained after temporary treatment otherwise patients will start regressing with disease activity,” said Dr. Krijbolder.

She explained that methotrexate is usually initiated as first-line treatment when arthritis becomes clinically apparent with joint swelling, but “disease processes begin long before this, and only become clinically recognizable when patients develop symptoms.” 

 

Clinically detectable arthritis development

All 236 patients included in the study had arthralgia of the small joints that, because of the character of the symptoms, was found clinically suspect for progression to RA over time.

“Importantly, these participants had not yet developed clinical arthritis that could be detected on physical joint examination, and were clinically suspected of progressing to RA. They had all undergone an MRI and subclinical joint-inflammation had been detected that was more than prevalent in symptom-free controls,” said Dr. Krijbolder.

Patients were randomized (1:1) to either a single intramuscular glucocorticoid injection (120 mg methylprednisolone [Depo Medrol]) and a 1-year course of oral methotrexate (up to 25 mg/week), or to placebo injection and placebo tablets, and were then followed for a further year without medication to see whether disease progressed.  

Treatment and placebo groups were matched with an average age of 46-47 years, 62%-68% were women, they had had symptoms (joint pain) for 27-28 weeks, C-reactive protein was increased in 27%-30%, and 20%-26% were anti-citrullinated protein autoantibody (ACPA) positive.  

The primary endpoint was the development of clinically detectable arthritis (fulfilling the 2010 RA-criteria or involving ≥ 2 joints) that persisted for at least 2 weeks. The main secondary endpoints were related to disease burden, including patient-reported physical functioning, along with symptoms and workability (presenteeism at work – the percentage of productivity lost caused by the joint complaints), and measured every 4 months, said Dr. Krijbolder.

She and her colleagues also followed the course of MRI-detected inflammation, which comprised the sum of tenosynovitis, synovitis, and osteitis scored with the RA-MRI Scoring (RAMRIS) method.  

Analysis was carried out on an intention-to-treat basis, and two prespecified subgroup analyses were also performed to obtain a better understanding of the effect of methotrexate and glucocorticoids in participants with high risk of clinical arthritis development (positive predictive value (PPV) ≥ 70%), and in patients stratified for ACPA status.  

 

Delays but does not prevent

There was no difference between treatment and placebo groups in the development of persistent clinical arthritis over 2 years (80% vs. 82%, hazard ratio [HR] 0.81; 95% confidence interval [CI], 0.45, 1.48]); however, in the high-risk group subanalysis, 67% in the placebo group developed persistent clinical arthritis. For the treatment group, 7%developed persistent clinical arthritis at 6 months, 27% at 12 months, 40% at 18 months, and 67% at 24 months. For the placebo group: 56% developed persistent clinical arthritis at 6 months, and 67% at 12 months, 18 months, and 24 months. 

“Strikingly, in the treatment group there was a statistically significant difference between 6 and 12 months, but in year 2, this difference disappeared, suggesting a delayed arthritis development but no prevention,” said Dr. Krijbolder. 

Persistent clinical arthritis became similar at 24 months, at 67% in both groups. A similar, but less pronounced, delaying effect was seen with the ACPA-positive patients, with 48% and 52% developing persistent clinical arthritis at 24 months.  

In joint pain, there was a decline in the treatment group compared with the placebo group and this persisted over 2 years (–9 on scale of 0 to 100: (95%CI, –12,–4; P < .001), and a similar effect was seen in high-risk and ACPA subgroups, reported Dr. Krijbolder.  

Physical functioning improved more in the treatment-group compared with the placebo group during the first months and remained better (mean between-group difference over 2 years HAQ [health assessment questionnaire] –0.1 [–0.2, –0.03; P = .004]), and morning stiffness (–12 [95%CI, –16, –8; P < .001]), and presenteeism (–8% [95%CI, –13%, –3%; P = .001]) also showed improvement over time compared with placebo.  

MRI-detected joint-inflammation was also persistently improved with a mean difference over 2 years –1.4 points (95%CI, –2.0, –0.9; P < .001). “As we know that symptoms and functional impairments are associated with MRI-detected joint inflammation, it was not surprising that treatment induced a decline in joint inflammation that persisted over time, also after the stop of the treatment in the second year,” explained Dr. Krijbolder.  

In the high-risk subgroup, as well as in both ACPA-positive and ACPA-negative participants, a comparable statistically significant decline in MRI-detected inflammation was found.

“It may seem counterintuitive that on the one hand we found a delaying effect of treatment on persistent clinical arthritis but no prevention, while on the other, we saw a sustained treatment effect on MRI-detected joint-inflammation and related symptoms and functional impairments,” added Dr. Krijbolder.

To help understand this, the researchers performed a post hoc analysis in high-risk participants, comparing those who did not progress with those who did progress to arthritis. “Both progressors and nonprogressors showed a sustained treatment effect for pain and MRI-detected joint-inflammation, and in nonprogressors, there was almost a complete relief of pain and they nearly returned to the normal range of MRI-detected joint-inflammation as seen in symptom-free controls,” reported Dr. Krijbolder. 

“In those who progressed to arthritis, there was less pain and less MRI-detected joint inflammation in the treatment group, but also at the time when they developed clinical arthritis. So both progressors and nonprogressors benefit from treatment,” she noted.  

The number of serious adverse events was the same between the groups and adverse events were as expected from methotrexate.  

Dr. Krijbolder said, “the results are encouraging and will open up a new treatment landscape in pre-RA at the future, but at the moment it is too early to give recommendations for clinical practice; we definitely do not want to advocate the start of treatment in all at-risk individuals from now on.”

More research should unravel the mechanisms within the joint that contribute to the development of clinical arthritis and disease chronicity, she said. “If we understand these, we may be able to use more targeted interventions in the future and prevent the development of clinical arthritis all together.

“We are also looking forward to learning more about the long-term beneficial effects of this early treatment in our ongoing observational extension of the trial.” 

Hendrik Schulze-Koops, MD, of Ludwig-Maximilians-University of Munich, who moderated the session, asked Dr. Krijbolder, “As well as giving methotrexate to the participants in the treatment group, you also gave a single glucocorticoid injection at baseline, and a placebo injection in the placebo group, can you comment on that?”

EULAR

COPENHAGEN – Temporary methotrexate in clinically suspected arthralgia delays but does not prevent clinical arthritis development; however, it does lead to sustained reduction of disease burden and MRI-detected inflammation in all at-risk groups, shows the 2-year Treat Earlier study.

“These data provide the first evidence for disease modification when intervening in ‘pre-RA [rheumatoid arthritis]’ or arthralgia,” said Doortje Krijbolder, MD, of Leiden (the Netherlands) University Medical Center, who presented her study at the annual European Congress of Rheumatology.  

The randomized, double-blind, study aimed to find out if giving methotrexate in the pre-arthritis phase of arthralgia (with subclinical joint inflammation) prevents the development of clinical arthritis or reduces the burden of disease.  

“This is the first trial that aims to reduce the burden of disease, and as such, in pre-RA, it is important that disease modification is sustained after temporary treatment otherwise patients will start regressing with disease activity,” said Dr. Krijbolder.

She explained that methotrexate is usually initiated as first-line treatment when arthritis becomes clinically apparent with joint swelling, but “disease processes begin long before this, and only become clinically recognizable when patients develop symptoms.” 

 

Clinically detectable arthritis development

All 236 patients included in the study had arthralgia of the small joints that, because of the character of the symptoms, was found clinically suspect for progression to RA over time.

“Importantly, these participants had not yet developed clinical arthritis that could be detected on physical joint examination, and were clinically suspected of progressing to RA. They had all undergone an MRI and subclinical joint-inflammation had been detected that was more than prevalent in symptom-free controls,” said Dr. Krijbolder.

Patients were randomized (1:1) to either a single intramuscular glucocorticoid injection (120 mg methylprednisolone [Depo Medrol]) and a 1-year course of oral methotrexate (up to 25 mg/week), or to placebo injection and placebo tablets, and were then followed for a further year without medication to see whether disease progressed.  

Treatment and placebo groups were matched with an average age of 46-47 years, 62%-68% were women, they had had symptoms (joint pain) for 27-28 weeks, C-reactive protein was increased in 27%-30%, and 20%-26% were anti-citrullinated protein autoantibody (ACPA) positive.  

The primary endpoint was the development of clinically detectable arthritis (fulfilling the 2010 RA-criteria or involving ≥ 2 joints) that persisted for at least 2 weeks. The main secondary endpoints were related to disease burden, including patient-reported physical functioning, along with symptoms and workability (presenteeism at work – the percentage of productivity lost caused by the joint complaints), and measured every 4 months, said Dr. Krijbolder.

She and her colleagues also followed the course of MRI-detected inflammation, which comprised the sum of tenosynovitis, synovitis, and osteitis scored with the RA-MRI Scoring (RAMRIS) method.  

Analysis was carried out on an intention-to-treat basis, and two prespecified subgroup analyses were also performed to obtain a better understanding of the effect of methotrexate and glucocorticoids in participants with high risk of clinical arthritis development (positive predictive value (PPV) ≥ 70%), and in patients stratified for ACPA status.  

 

Delays but does not prevent

There was no difference between treatment and placebo groups in the development of persistent clinical arthritis over 2 years (80% vs. 82%, hazard ratio [HR] 0.81; 95% confidence interval [CI], 0.45, 1.48]); however, in the high-risk group subanalysis, 67% in the placebo group developed persistent clinical arthritis. For the treatment group, 7%developed persistent clinical arthritis at 6 months, 27% at 12 months, 40% at 18 months, and 67% at 24 months. For the placebo group: 56% developed persistent clinical arthritis at 6 months, and 67% at 12 months, 18 months, and 24 months. 

“Strikingly, in the treatment group there was a statistically significant difference between 6 and 12 months, but in year 2, this difference disappeared, suggesting a delayed arthritis development but no prevention,” said Dr. Krijbolder. 

Persistent clinical arthritis became similar at 24 months, at 67% in both groups. A similar, but less pronounced, delaying effect was seen with the ACPA-positive patients, with 48% and 52% developing persistent clinical arthritis at 24 months.  

In joint pain, there was a decline in the treatment group compared with the placebo group and this persisted over 2 years (–9 on scale of 0 to 100: (95%CI, –12,–4; P < .001), and a similar effect was seen in high-risk and ACPA subgroups, reported Dr. Krijbolder.  

Physical functioning improved more in the treatment-group compared with the placebo group during the first months and remained better (mean between-group difference over 2 years HAQ [health assessment questionnaire] –0.1 [–0.2, –0.03; P = .004]), and morning stiffness (–12 [95%CI, –16, –8; P < .001]), and presenteeism (–8% [95%CI, –13%, –3%; P = .001]) also showed improvement over time compared with placebo.  

MRI-detected joint-inflammation was also persistently improved with a mean difference over 2 years –1.4 points (95%CI, –2.0, –0.9; P < .001). “As we know that symptoms and functional impairments are associated with MRI-detected joint inflammation, it was not surprising that treatment induced a decline in joint inflammation that persisted over time, also after the stop of the treatment in the second year,” explained Dr. Krijbolder.  

In the high-risk subgroup, as well as in both ACPA-positive and ACPA-negative participants, a comparable statistically significant decline in MRI-detected inflammation was found.

“It may seem counterintuitive that on the one hand we found a delaying effect of treatment on persistent clinical arthritis but no prevention, while on the other, we saw a sustained treatment effect on MRI-detected joint-inflammation and related symptoms and functional impairments,” added Dr. Krijbolder.

To help understand this, the researchers performed a post hoc analysis in high-risk participants, comparing those who did not progress with those who did progress to arthritis. “Both progressors and nonprogressors showed a sustained treatment effect for pain and MRI-detected joint-inflammation, and in nonprogressors, there was almost a complete relief of pain and they nearly returned to the normal range of MRI-detected joint-inflammation as seen in symptom-free controls,” reported Dr. Krijbolder. 

“In those who progressed to arthritis, there was less pain and less MRI-detected joint inflammation in the treatment group, but also at the time when they developed clinical arthritis. So both progressors and nonprogressors benefit from treatment,” she noted.  

The number of serious adverse events was the same between the groups and adverse events were as expected from methotrexate.  

Dr. Krijbolder said, “the results are encouraging and will open up a new treatment landscape in pre-RA at the future, but at the moment it is too early to give recommendations for clinical practice; we definitely do not want to advocate the start of treatment in all at-risk individuals from now on.”

More research should unravel the mechanisms within the joint that contribute to the development of clinical arthritis and disease chronicity, she said. “If we understand these, we may be able to use more targeted interventions in the future and prevent the development of clinical arthritis all together.

“We are also looking forward to learning more about the long-term beneficial effects of this early treatment in our ongoing observational extension of the trial.” 

Hendrik Schulze-Koops, MD, of Ludwig-Maximilians-University of Munich, who moderated the session, asked Dr. Krijbolder, “As well as giving methotrexate to the participants in the treatment group, you also gave a single glucocorticoid injection at baseline, and a placebo injection in the placebo group, can you comment on that?”

EULAR

Scientists have confirmed that a receptor long suspected to be linked to lupus is, in fact, a major driver of the autoimmune disease for at least some subset of patients, according to a study recently published in Nature. Researchers discovered the crucial role of toll-like receptor 7 (TLR7) because of a rare mutation in a pediatric patient with systemic lupus erythematosus (SLE) who had a particularly severe presentation.

“Sometimes it’s valuable to find these very severe cases where there is one mutation that has a strong effect because if we understand how those mutations work, the lessons we learn can generally tell us about disease mechanisms,” explained senior author Carola G. Vinuesa, MD, PhD, of the Centre for Personalised Immunology at Australian National University in Canberra and The Francis Crick Institute in London.

courtesy Michael Bowles

“It’s quite difficult to find one mutation that can alone cause the entire disease,” Dr. Vinuesa added, but what it reveals about how the disease develops may lead to more effective targeted therapies than the immune suppressants most often used to treat lupus currently.

The mutation they found was in the TLR7 gene that encodes the TLR7 protein. TLR7 is a receptor used by immune cells to identify viral RNA so they can fight off viral infections, including COVID-19. But if the body’s own genetic material binds to TLR7 in susceptible individuals, it can lead to an overproduction of type 1 interferons, which are cytokines that trigger or exacerbate the immune reactions that lead to lupus symptoms. The TLR7 gene occurs on the X chromosome, which may explain men’s greater susceptibility to COVID-19 and the greater incidence of lupus in women, who have two X chromosomes instead of the one that men have, Dr. Vinuesa said.

Previous research had shown an association between TLR7 and lupus, but this new study is the first to provide definitive proof that a TLR7 mutation by itself can directly cause human lupus. After discovering the variant in the patient, Dr. Vinuesa’s team used CRISPR to edit the genome of a mouse model and introduce the same mutation the patient had. “And they developed full-blown disease, just with this one single base-pair substitution – 1 letter in the 3 billion letters of the genome,” Dr. Vinuesa said. “It tells us that these receptors are not just there to recognize viral RNA, that in some circumstances, they could be triggered by our own nucleic acids.”
 

One pathway among many?

The finding does not mean that every lupus patient has this mutation, which remains rare, but suggests that overactivity in this receptor already reported in many lupus patients may be causally related to disease, Dr. Vinuesa said.

Noa Schwartz, MD, an assistant professor of medicine at Albert Einstein College of Medicine, New York, and director of the Montefiore-Einstein Institute for Lupus Care and Research, said in an interview that lupus is thought of as a syndrome, a collection of different but similar diseases that don’t necessarily have a single cause. But finding a single gene mutation that could potentially lead to lupus is an important piece of the puzzle, said Dr. Schwartz, who was not involved in the study. Based on past research in mice models, “we’ve hypothesized that TLR7 is important in humans as well, but this is the last nail in the coffin.”

One of the key questions this finding has prompted is how many patients’ disease results from TLR7 activity. “Because of the evidence from Ignacio Sanz’s group demonstrating TLR7 overactivity in a significant fraction of SLE patients, we believe that it is probably going to be pretty important,” Dr. Vinuesa said. “My feeling is that it is going to be quite a central pathway in lupus pathogenesis, if not the central pathway.”

Dr. Schwartz was more cautious, noting that it is probably important for a subset of patients but may “have a limited effect on the general lupus population.” While it’s not yet clear how large that subset is, it is possible it will include people with cutaneous lupus, those with primarily dermatologic symptoms.

“Hydroxychloroquine works particularly well for cutaneous manifestations of lupus, and one of the ways that works is by inhibiting TLR7 and TLR9, so this [finding] potentially matters for skin disease and lupus, but it’s very early,” Dr. Schwartz said. If it does turn out that TLR7 activity is particularly associated with cutaneous lupus, it may mean therapies with fewer side effects, she said. “Specifically for cutaneous lupus, the concept of suppressing the entire immune system for skin illness sometimes feels, especially to patients, very extreme, so they are [patients] who directed therapy could be so especially relevant for.”

Laura Lewandowski, MD, an assistant clinical investigator and head of the lupus genomics and global health disparities unit at the National Institute of Arthritis and Musculoskeletal and Skin Disease, described this study as particularly remarkable in the way it revealed the mechanism leading to lupus symptoms.

“As whole genome sequencing becomes faster and less expensive, more and more people are employing them in their studies,” most of which report changes in certain genes, Dr. Lewandowski said. “One of the most striking findings about this paper was that they took it to the next step and did a really elegant study on the exact way this gain-of-function TLR7 mutation leads to the autoimmunity that we see in lupus. The detail of mechanism in this paper is really unique.”
 

A step toward personalized medicine

Dr. Lewandowski is part of a team that recently presented a poster related to genomic sequencing in lupus patients at the annual meeting of the Childhood Arthritis and Rheumatology Research Alliance. Her study reported on the whole genome sequencing of patients with childhood-onset SLE who were already enrolled in the CARRA Lupus Registry. Children with lupus may be more likely than adults to have rare genetic variants, so a registry of childhood-onset SLE patients with fully sequenced genomes provides an opportunity to look for single-gene mutations specifically linked to lupus, said Dr. Lewandowski, who has recently begun a research collaboration with Dr. Vinuesa.

“As we move forward and more and more patients are included in these studies, we will understand a little bit more about the genetic architecture of patients who have rare variations leading to disease, or even common variations,” Dr. Lewandowski said about the intersection between her research and Dr. Vinuesa’s study. The more data they gather, the more they can explore the possible interactions of rare and common variants that play a role in SLE as well as what environmental triggers, such as viral infection or pollution exposure, might tip someone into having an autoimmune disease. “We’re just starting to peek under the hood,” Dr. Lewandowski said.

If further research can reveal the relative contribution of genetics to the disease and what those genetic drivers are, it may allow for greater precision in therapies and “ultimately improve the quality of life for our patients, the ultimate goal of all of these studies,” Dr. Lewandowski said.

Drugs that target TLR7 already exist for other indications, and clinical trials have already begun to see if these TLR7 inhibitors benefit lupus patients.

“If the clinical trials work, this will be quite a nice, targeted therapy with potentially much less side effects than other therapies on the market at the moment,” Dr. Vinuesa said. She is cautiously hopeful, saying it’s likely to make an impact on lupus treatment, but it’s too early to say precisely how much.

“It allows us to understand the disease mechanisms a little bit better and to try and assess what percentage of patients’ disease can be explained by overactivity in this receptor,” Dr. Vinuesa said. She thinks it’s possible that TLR7 over activation may be relevant to other systemic autoimmune diseases as well, such as Sjögren’s syndrome, rheumatoid arthritis, or juvenile dermatomyositis, but it will take more studies to find out.

“Right now, we have medicines that broadly inhibit the immune system and aren’t as targeted, but we have a lot more clinical and scientific work to do before we move this field forward for lupus patients,” Dr. Lewandowski said. “This is one case where they were able to find the exact molecular defect, and it’s not the end of the path of precision medicine — it’s the beginning.”

Dr. Vinuesa, Dr. Schwartz, and Dr. Lewandowski reported no disclosures.

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

Scientists have confirmed that a receptor long suspected to be linked to lupus is, in fact, a major driver of the autoimmune disease for at least some subset of patients, according to a study recently published in Nature. Researchers discovered the crucial role of toll-like receptor 7 (TLR7) because of a rare mutation in a pediatric patient with systemic lupus erythematosus (SLE) who had a particularly severe presentation.

“Sometimes it’s valuable to find these very severe cases where there is one mutation that has a strong effect because if we understand how those mutations work, the lessons we learn can generally tell us about disease mechanisms,” explained senior author Carola G. Vinuesa, MD, PhD, of the Centre for Personalised Immunology at Australian National University in Canberra and The Francis Crick Institute in London.

courtesy Michael Bowles

“It’s quite difficult to find one mutation that can alone cause the entire disease,” Dr. Vinuesa added, but what it reveals about how the disease develops may lead to more effective targeted therapies than the immune suppressants most often used to treat lupus currently.

The mutation they found was in the TLR7 gene that encodes the TLR7 protein. TLR7 is a receptor used by immune cells to identify viral RNA so they can fight off viral infections, including COVID-19. But if the body’s own genetic material binds to TLR7 in susceptible individuals, it can lead to an overproduction of type 1 interferons, which are cytokines that trigger or exacerbate the immune reactions that lead to lupus symptoms. The TLR7 gene occurs on the X chromosome, which may explain men’s greater susceptibility to COVID-19 and the greater incidence of lupus in women, who have two X chromosomes instead of the one that men have, Dr. Vinuesa said.

Previous research had shown an association between TLR7 and lupus, but this new study is the first to provide definitive proof that a TLR7 mutation by itself can directly cause human lupus. After discovering the variant in the patient, Dr. Vinuesa’s team used CRISPR to edit the genome of a mouse model and introduce the same mutation the patient had. “And they developed full-blown disease, just with this one single base-pair substitution – 1 letter in the 3 billion letters of the genome,” Dr. Vinuesa said. “It tells us that these receptors are not just there to recognize viral RNA, that in some circumstances, they could be triggered by our own nucleic acids.”
 

One pathway among many?

The finding does not mean that every lupus patient has this mutation, which remains rare, but suggests that overactivity in this receptor already reported in many lupus patients may be causally related to disease, Dr. Vinuesa said.

Noa Schwartz, MD, an assistant professor of medicine at Albert Einstein College of Medicine, New York, and director of the Montefiore-Einstein Institute for Lupus Care and Research, said in an interview that lupus is thought of as a syndrome, a collection of different but similar diseases that don’t necessarily have a single cause. But finding a single gene mutation that could potentially lead to lupus is an important piece of the puzzle, said Dr. Schwartz, who was not involved in the study. Based on past research in mice models, “we’ve hypothesized that TLR7 is important in humans as well, but this is the last nail in the coffin.”

One of the key questions this finding has prompted is how many patients’ disease results from TLR7 activity. “Because of the evidence from Ignacio Sanz’s group demonstrating TLR7 overactivity in a significant fraction of SLE patients, we believe that it is probably going to be pretty important,” Dr. Vinuesa said. “My feeling is that it is going to be quite a central pathway in lupus pathogenesis, if not the central pathway.”

Dr. Schwartz was more cautious, noting that it is probably important for a subset of patients but may “have a limited effect on the general lupus population.” While it’s not yet clear how large that subset is, it is possible it will include people with cutaneous lupus, those with primarily dermatologic symptoms.

“Hydroxychloroquine works particularly well for cutaneous manifestations of lupus, and one of the ways that works is by inhibiting TLR7 and TLR9, so this [finding] potentially matters for skin disease and lupus, but it’s very early,” Dr. Schwartz said. If it does turn out that TLR7 activity is particularly associated with cutaneous lupus, it may mean therapies with fewer side effects, she said. “Specifically for cutaneous lupus, the concept of suppressing the entire immune system for skin illness sometimes feels, especially to patients, very extreme, so they are [patients] who directed therapy could be so especially relevant for.”

Laura Lewandowski, MD, an assistant clinical investigator and head of the lupus genomics and global health disparities unit at the National Institute of Arthritis and Musculoskeletal and Skin Disease, described this study as particularly remarkable in the way it revealed the mechanism leading to lupus symptoms.

“As whole genome sequencing becomes faster and less expensive, more and more people are employing them in their studies,” most of which report changes in certain genes, Dr. Lewandowski said. “One of the most striking findings about this paper was that they took it to the next step and did a really elegant study on the exact way this gain-of-function TLR7 mutation leads to the autoimmunity that we see in lupus. The detail of mechanism in this paper is really unique.”
 

A step toward personalized medicine

Dr. Lewandowski is part of a team that recently presented a poster related to genomic sequencing in lupus patients at the annual meeting of the Childhood Arthritis and Rheumatology Research Alliance. Her study reported on the whole genome sequencing of patients with childhood-onset SLE who were already enrolled in the CARRA Lupus Registry. Children with lupus may be more likely than adults to have rare genetic variants, so a registry of childhood-onset SLE patients with fully sequenced genomes provides an opportunity to look for single-gene mutations specifically linked to lupus, said Dr. Lewandowski, who has recently begun a research collaboration with Dr. Vinuesa.

“As we move forward and more and more patients are included in these studies, we will understand a little bit more about the genetic architecture of patients who have rare variations leading to disease, or even common variations,” Dr. Lewandowski said about the intersection between her research and Dr. Vinuesa’s study. The more data they gather, the more they can explore the possible interactions of rare and common variants that play a role in SLE as well as what environmental triggers, such as viral infection or pollution exposure, might tip someone into having an autoimmune disease. “We’re just starting to peek under the hood,” Dr. Lewandowski said.

If further research can reveal the relative contribution of genetics to the disease and what those genetic drivers are, it may allow for greater precision in therapies and “ultimately improve the quality of life for our patients, the ultimate goal of all of these studies,” Dr. Lewandowski said.

Drugs that target TLR7 already exist for other indications, and clinical trials have already begun to see if these TLR7 inhibitors benefit lupus patients.

“If the clinical trials work, this will be quite a nice, targeted therapy with potentially much less side effects than other therapies on the market at the moment,” Dr. Vinuesa said. She is cautiously hopeful, saying it’s likely to make an impact on lupus treatment, but it’s too early to say precisely how much.

“It allows us to understand the disease mechanisms a little bit better and to try and assess what percentage of patients’ disease can be explained by overactivity in this receptor,” Dr. Vinuesa said. She thinks it’s possible that TLR7 over activation may be relevant to other systemic autoimmune diseases as well, such as Sjögren’s syndrome, rheumatoid arthritis, or juvenile dermatomyositis, but it will take more studies to find out.

“Right now, we have medicines that broadly inhibit the immune system and aren’t as targeted, but we have a lot more clinical and scientific work to do before we move this field forward for lupus patients,” Dr. Lewandowski said. “This is one case where they were able to find the exact molecular defect, and it’s not the end of the path of precision medicine — it’s the beginning.”

Dr. Vinuesa, Dr. Schwartz, and Dr. Lewandowski reported no disclosures.

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

Scientists have confirmed that a receptor long suspected to be linked to lupus is, in fact, a major driver of the autoimmune disease for at least some subset of patients, according to a study recently published in Nature. Researchers discovered the crucial role of toll-like receptor 7 (TLR7) because of a rare mutation in a pediatric patient with systemic lupus erythematosus (SLE) who had a particularly severe presentation.

“Sometimes it’s valuable to find these very severe cases where there is one mutation that has a strong effect because if we understand how those mutations work, the lessons we learn can generally tell us about disease mechanisms,” explained senior author Carola G. Vinuesa, MD, PhD, of the Centre for Personalised Immunology at Australian National University in Canberra and The Francis Crick Institute in London.

courtesy Michael Bowles

“It’s quite difficult to find one mutation that can alone cause the entire disease,” Dr. Vinuesa added, but what it reveals about how the disease develops may lead to more effective targeted therapies than the immune suppressants most often used to treat lupus currently.

The mutation they found was in the TLR7 gene that encodes the TLR7 protein. TLR7 is a receptor used by immune cells to identify viral RNA so they can fight off viral infections, including COVID-19. But if the body’s own genetic material binds to TLR7 in susceptible individuals, it can lead to an overproduction of type 1 interferons, which are cytokines that trigger or exacerbate the immune reactions that lead to lupus symptoms. The TLR7 gene occurs on the X chromosome, which may explain men’s greater susceptibility to COVID-19 and the greater incidence of lupus in women, who have two X chromosomes instead of the one that men have, Dr. Vinuesa said.

Previous research had shown an association between TLR7 and lupus, but this new study is the first to provide definitive proof that a TLR7 mutation by itself can directly cause human lupus. After discovering the variant in the patient, Dr. Vinuesa’s team used CRISPR to edit the genome of a mouse model and introduce the same mutation the patient had. “And they developed full-blown disease, just with this one single base-pair substitution – 1 letter in the 3 billion letters of the genome,” Dr. Vinuesa said. “It tells us that these receptors are not just there to recognize viral RNA, that in some circumstances, they could be triggered by our own nucleic acids.”
 

One pathway among many?

The finding does not mean that every lupus patient has this mutation, which remains rare, but suggests that overactivity in this receptor already reported in many lupus patients may be causally related to disease, Dr. Vinuesa said.

Noa Schwartz, MD, an assistant professor of medicine at Albert Einstein College of Medicine, New York, and director of the Montefiore-Einstein Institute for Lupus Care and Research, said in an interview that lupus is thought of as a syndrome, a collection of different but similar diseases that don’t necessarily have a single cause. But finding a single gene mutation that could potentially lead to lupus is an important piece of the puzzle, said Dr. Schwartz, who was not involved in the study. Based on past research in mice models, “we’ve hypothesized that TLR7 is important in humans as well, but this is the last nail in the coffin.”

One of the key questions this finding has prompted is how many patients’ disease results from TLR7 activity. “Because of the evidence from Ignacio Sanz’s group demonstrating TLR7 overactivity in a significant fraction of SLE patients, we believe that it is probably going to be pretty important,” Dr. Vinuesa said. “My feeling is that it is going to be quite a central pathway in lupus pathogenesis, if not the central pathway.”

Dr. Schwartz was more cautious, noting that it is probably important for a subset of patients but may “have a limited effect on the general lupus population.” While it’s not yet clear how large that subset is, it is possible it will include people with cutaneous lupus, those with primarily dermatologic symptoms.

“Hydroxychloroquine works particularly well for cutaneous manifestations of lupus, and one of the ways that works is by inhibiting TLR7 and TLR9, so this [finding] potentially matters for skin disease and lupus, but it’s very early,” Dr. Schwartz said. If it does turn out that TLR7 activity is particularly associated with cutaneous lupus, it may mean therapies with fewer side effects, she said. “Specifically for cutaneous lupus, the concept of suppressing the entire immune system for skin illness sometimes feels, especially to patients, very extreme, so they are [patients] who directed therapy could be so especially relevant for.”

Laura Lewandowski, MD, an assistant clinical investigator and head of the lupus genomics and global health disparities unit at the National Institute of Arthritis and Musculoskeletal and Skin Disease, described this study as particularly remarkable in the way it revealed the mechanism leading to lupus symptoms.

“As whole genome sequencing becomes faster and less expensive, more and more people are employing them in their studies,” most of which report changes in certain genes, Dr. Lewandowski said. “One of the most striking findings about this paper was that they took it to the next step and did a really elegant study on the exact way this gain-of-function TLR7 mutation leads to the autoimmunity that we see in lupus. The detail of mechanism in this paper is really unique.”
 

A step toward personalized medicine

Dr. Lewandowski is part of a team that recently presented a poster related to genomic sequencing in lupus patients at the annual meeting of the Childhood Arthritis and Rheumatology Research Alliance. Her study reported on the whole genome sequencing of patients with childhood-onset SLE who were already enrolled in the CARRA Lupus Registry. Children with lupus may be more likely than adults to have rare genetic variants, so a registry of childhood-onset SLE patients with fully sequenced genomes provides an opportunity to look for single-gene mutations specifically linked to lupus, said Dr. Lewandowski, who has recently begun a research collaboration with Dr. Vinuesa.

“As we move forward and more and more patients are included in these studies, we will understand a little bit more about the genetic architecture of patients who have rare variations leading to disease, or even common variations,” Dr. Lewandowski said about the intersection between her research and Dr. Vinuesa’s study. The more data they gather, the more they can explore the possible interactions of rare and common variants that play a role in SLE as well as what environmental triggers, such as viral infection or pollution exposure, might tip someone into having an autoimmune disease. “We’re just starting to peek under the hood,” Dr. Lewandowski said.

If further research can reveal the relative contribution of genetics to the disease and what those genetic drivers are, it may allow for greater precision in therapies and “ultimately improve the quality of life for our patients, the ultimate goal of all of these studies,” Dr. Lewandowski said.

Drugs that target TLR7 already exist for other indications, and clinical trials have already begun to see if these TLR7 inhibitors benefit lupus patients.

“If the clinical trials work, this will be quite a nice, targeted therapy with potentially much less side effects than other therapies on the market at the moment,” Dr. Vinuesa said. She is cautiously hopeful, saying it’s likely to make an impact on lupus treatment, but it’s too early to say precisely how much.

“It allows us to understand the disease mechanisms a little bit better and to try and assess what percentage of patients’ disease can be explained by overactivity in this receptor,” Dr. Vinuesa said. She thinks it’s possible that TLR7 over activation may be relevant to other systemic autoimmune diseases as well, such as Sjögren’s syndrome, rheumatoid arthritis, or juvenile dermatomyositis, but it will take more studies to find out.

“Right now, we have medicines that broadly inhibit the immune system and aren’t as targeted, but we have a lot more clinical and scientific work to do before we move this field forward for lupus patients,” Dr. Lewandowski said. “This is one case where they were able to find the exact molecular defect, and it’s not the end of the path of precision medicine — it’s the beginning.”

Dr. Vinuesa, Dr. Schwartz, and Dr. Lewandowski reported no disclosures.

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

COPENHAGEN – Pregnant women with systemic lupus erythematosus (SLE) are at significantly higher risk of requiring transfusion, developing a cerebrovascular disorder, or developing acute renal failure than pregnant women without SLE, a review of data from an American national sample indicates.

Pregnant women with SLE also have a twofold-higher risk for premature delivery, and a threefold risk of having a fetus with intrauterine growth restriction than their pregnant counterparts without SLE, reported Bella Mehta, MBBS, MS, MD, a rheumatologist at the Hospital for Special Surgery in New York.

“Severe maternal morbidity and fetal morbidity still remain high, but this work can help inform physicians and counsel patients for pregnancy planning and management,” she said at the annual European Congress of Rheumatology.

Although in-hospital maternal and fetal mortality rates for women with SLE have declined over the past 2 decades, the same cannot be said for morbidities, prompting the investigators to conduct a study to determine the proportion of fetal and maternal morbidity in SLE deliveries, compared with non-SLE deliveries over a decade.

Inpatient Sample

Dr. Mehta and colleagues studied retrospective data on 40 million delivery-related admissions from the National Inpatient Sample database. Of these patients, 51,161 had a diagnosis of SLE.

They identified all delivery-related hospital admissions for patients with and without SLE from 2008 through 2017 using diagnostic codes.

The researchers looked at fetal morbidity indicators, including preterm delivery and intrauterine growth restriction, and used the Centers for Disease Control and Prevention standard definition of severe maternal morbidity as “unexpected outcomes of labor and delivery that result in significant short- or long- term consequences to a woman’s health.”

They identified 21 severe maternal morbidity outcomes, including blood transfusion requirements, acute renal failure, eclampsia and disseminated intravascular coagulation, cardiovascular and peripheral vascular disorders, and general medical issues (hysterectomy, shock, sepsis, adult respiratory distress syndrome, severe anesthesia complications, temporary tracheostomy, and ventilation).

Study results

Women with SLE were slightly older at the time of delivery (mean age, 30.05 vs. 29.19 years) and had more comorbidities, according to the Elixhauser Comorbidity Scale, with 97.84% of women in this group having one to four comorbidities, compared with 19.4% of women without SLE.

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

COPENHAGEN – Pregnant women with systemic lupus erythematosus (SLE) are at significantly higher risk of requiring transfusion, developing a cerebrovascular disorder, or developing acute renal failure than pregnant women without SLE, a review of data from an American national sample indicates.

Pregnant women with SLE also have a twofold-higher risk for premature delivery, and a threefold risk of having a fetus with intrauterine growth restriction than their pregnant counterparts without SLE, reported Bella Mehta, MBBS, MS, MD, a rheumatologist at the Hospital for Special Surgery in New York.

“Severe maternal morbidity and fetal morbidity still remain high, but this work can help inform physicians and counsel patients for pregnancy planning and management,” she said at the annual European Congress of Rheumatology.

Although in-hospital maternal and fetal mortality rates for women with SLE have declined over the past 2 decades, the same cannot be said for morbidities, prompting the investigators to conduct a study to determine the proportion of fetal and maternal morbidity in SLE deliveries, compared with non-SLE deliveries over a decade.

Inpatient Sample

Dr. Mehta and colleagues studied retrospective data on 40 million delivery-related admissions from the National Inpatient Sample database. Of these patients, 51,161 had a diagnosis of SLE.

They identified all delivery-related hospital admissions for patients with and without SLE from 2008 through 2017 using diagnostic codes.

The researchers looked at fetal morbidity indicators, including preterm delivery and intrauterine growth restriction, and used the Centers for Disease Control and Prevention standard definition of severe maternal morbidity as “unexpected outcomes of labor and delivery that result in significant short- or long- term consequences to a woman’s health.”

They identified 21 severe maternal morbidity outcomes, including blood transfusion requirements, acute renal failure, eclampsia and disseminated intravascular coagulation, cardiovascular and peripheral vascular disorders, and general medical issues (hysterectomy, shock, sepsis, adult respiratory distress syndrome, severe anesthesia complications, temporary tracheostomy, and ventilation).

Study results

Women with SLE were slightly older at the time of delivery (mean age, 30.05 vs. 29.19 years) and had more comorbidities, according to the Elixhauser Comorbidity Scale, with 97.84% of women in this group having one to four comorbidities, compared with 19.4% of women without SLE.

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

COPENHAGEN – Pregnant women with systemic lupus erythematosus (SLE) are at significantly higher risk of requiring transfusion, developing a cerebrovascular disorder, or developing acute renal failure than pregnant women without SLE, a review of data from an American national sample indicates.

Pregnant women with SLE also have a twofold-higher risk for premature delivery, and a threefold risk of having a fetus with intrauterine growth restriction than their pregnant counterparts without SLE, reported Bella Mehta, MBBS, MS, MD, a rheumatologist at the Hospital for Special Surgery in New York.

“Severe maternal morbidity and fetal morbidity still remain high, but this work can help inform physicians and counsel patients for pregnancy planning and management,” she said at the annual European Congress of Rheumatology.

Although in-hospital maternal and fetal mortality rates for women with SLE have declined over the past 2 decades, the same cannot be said for morbidities, prompting the investigators to conduct a study to determine the proportion of fetal and maternal morbidity in SLE deliveries, compared with non-SLE deliveries over a decade.

Inpatient Sample

Dr. Mehta and colleagues studied retrospective data on 40 million delivery-related admissions from the National Inpatient Sample database. Of these patients, 51,161 had a diagnosis of SLE.

They identified all delivery-related hospital admissions for patients with and without SLE from 2008 through 2017 using diagnostic codes.

The researchers looked at fetal morbidity indicators, including preterm delivery and intrauterine growth restriction, and used the Centers for Disease Control and Prevention standard definition of severe maternal morbidity as “unexpected outcomes of labor and delivery that result in significant short- or long- term consequences to a woman’s health.”

They identified 21 severe maternal morbidity outcomes, including blood transfusion requirements, acute renal failure, eclampsia and disseminated intravascular coagulation, cardiovascular and peripheral vascular disorders, and general medical issues (hysterectomy, shock, sepsis, adult respiratory distress syndrome, severe anesthesia complications, temporary tracheostomy, and ventilation).

Study results

Women with SLE were slightly older at the time of delivery (mean age, 30.05 vs. 29.19 years) and had more comorbidities, according to the Elixhauser Comorbidity Scale, with 97.84% of women in this group having one to four comorbidities, compared with 19.4% of women without SLE.

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