Lupus & Connective Tissue Diseases

ATLANTA – Rituximab (Rituxan) is superior to azathioprine (Imuran) for preventing ANCA-associated vasculitis relapses in patients with histories of previous relapses, according to a randomized trial of 170 patients presented at the annual meeting of the American College of Rheumatology.

Rituximab has been previously shown to be the superior remission maintenance option in the French MAINRITSAN trial (N Engl J Med. 2014 Nov 6;371[19]:1771-80), but mostly in newly diagnosed patients after cyclophosphamide induction. The results expand the finding to those with relapsing disease who previously had remission induced with rituximab, said lead investigator Rona Smith, MD, a clinical lecturer at Cambridge (England) University.

Subjects in the RITAZAREM trial (rituximab versus azathioprine as therapy for maintenance of remission for antineutrophil cytoplasmic antibody [ANCA]–associated vasculitis) were enrolled during a relapse of either granulomatosis with polyangiitis or microscopic polyangiitis and underwent remission induction with rituximab 375 mg/m² per week for 4 weeks coupled with prednisone, either 1 or 0.5 mg/kg per day at provider discretion.

After successful induction – defined as a Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis of 1 point or less on no more than 10 mg/day prednisone – 85 patients were randomized to rituximab 1 g every 4 months for 20 months and 85 to azathioprine 2 mg/kg per day for 20 months, followed by a taper. Prednisone was tapered per protocol to discontinuation at 20 months.

Eleven rituximab patients (13%) relapsed during the 20-month maintenance phase; two relapses were major. There were 32 relapses (38%) in the azathioprine group, 12 of them (38%) major (hazard ratio for rituximab versus azathioprine, 0.3; 95% CI, 0.15-0.60; P less than .001). ANCA type, glucocorticoid induction regimen, and severity of the enrollment relapse did not affect the outcomes.

Also, “there was an increase in the proportion of patients who became ANCA negative” in the rituximab arm, while “there was really no change” with azathioprine. In short, “rituximab is superior to azathioprine for prevention of disease relapse,” Dr. Smith said.

Her audience had a few questions about the rituximab regimen. The French MAINRITSAN trial dosed rituximab every 6 months instead of every 4, for a cumulative dose of 2.5 g, not 5 g, which an audience member said is the standard approach.

Dr. Smith explained that she and her colleagues have seen relapses with rituximab maintenance at 5 and 6 months, so they wanted to move to a shorter schedule. As for the higher dose, they wanted to “achieve complete B-cell depletion for the duration of the treatment period” to see if it translates into longer lasting remissions. “We will hopefully be able to address that question” with further analysis, she said.

There were no new safety signals; 19 rituximab patients (22%) and 31 azathioprine subjects (36%) had at least one serious adverse event; an infection requiring hospitalization occurred in 7 rituximab patients (8%) and 11 azathioprine patients (13%). Twenty-five (29%) rituximab and 21 (25%) azathioprine subjects developed hypogammaglobulinemia (IgG less than 5 g/L), and about half of each group developed an infection that required antibiotics, but not hospitalization.

There was one death in the azathioprine arm from malignancy, and three in the rituximab group, one from infection and two as of yet unclassified.

The groups were well balanced. Subjects were a median of 59 years old, with a median disease duration of 5.3 years. Refractory patients – those who had not achieved remission during a previous relapse – were excluded, as were patients who had received a B cell–depleting treatment in the previous 6 months and those with eosinophilic granulomatosis with polyangiitis or a malignancy in the past 5 years. Among patients in the study, 72% had tested positive for anti–proteinase 3 ANCA, and 28% for myeloperoxidase ANCA.

The work was funded by Versus Arthritis (formerly Arthritis Research UK), the National Institutes of Health, and the makers of rituximab, Roche/Genentech. Dr. Smith reported ties to Roche, Sanofi, and MedImmune.

[email protected]

SOURCE: Smith R et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 806.

ATLANTA – Rituximab (Rituxan) is superior to azathioprine (Imuran) for preventing ANCA-associated vasculitis relapses in patients with histories of previous relapses, according to a randomized trial of 170 patients presented at the annual meeting of the American College of Rheumatology.

Rituximab has been previously shown to be the superior remission maintenance option in the French MAINRITSAN trial (N Engl J Med. 2014 Nov 6;371[19]:1771-80), but mostly in newly diagnosed patients after cyclophosphamide induction. The results expand the finding to those with relapsing disease who previously had remission induced with rituximab, said lead investigator Rona Smith, MD, a clinical lecturer at Cambridge (England) University.

Subjects in the RITAZAREM trial (rituximab versus azathioprine as therapy for maintenance of remission for antineutrophil cytoplasmic antibody [ANCA]–associated vasculitis) were enrolled during a relapse of either granulomatosis with polyangiitis or microscopic polyangiitis and underwent remission induction with rituximab 375 mg/m² per week for 4 weeks coupled with prednisone, either 1 or 0.5 mg/kg per day at provider discretion.

After successful induction – defined as a Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis of 1 point or less on no more than 10 mg/day prednisone – 85 patients were randomized to rituximab 1 g every 4 months for 20 months and 85 to azathioprine 2 mg/kg per day for 20 months, followed by a taper. Prednisone was tapered per protocol to discontinuation at 20 months.

Eleven rituximab patients (13%) relapsed during the 20-month maintenance phase; two relapses were major. There were 32 relapses (38%) in the azathioprine group, 12 of them (38%) major (hazard ratio for rituximab versus azathioprine, 0.3; 95% CI, 0.15-0.60; P less than .001). ANCA type, glucocorticoid induction regimen, and severity of the enrollment relapse did not affect the outcomes.

Also, “there was an increase in the proportion of patients who became ANCA negative” in the rituximab arm, while “there was really no change” with azathioprine. In short, “rituximab is superior to azathioprine for prevention of disease relapse,” Dr. Smith said.

Her audience had a few questions about the rituximab regimen. The French MAINRITSAN trial dosed rituximab every 6 months instead of every 4, for a cumulative dose of 2.5 g, not 5 g, which an audience member said is the standard approach.

Dr. Smith explained that she and her colleagues have seen relapses with rituximab maintenance at 5 and 6 months, so they wanted to move to a shorter schedule. As for the higher dose, they wanted to “achieve complete B-cell depletion for the duration of the treatment period” to see if it translates into longer lasting remissions. “We will hopefully be able to address that question” with further analysis, she said.

There were no new safety signals; 19 rituximab patients (22%) and 31 azathioprine subjects (36%) had at least one serious adverse event; an infection requiring hospitalization occurred in 7 rituximab patients (8%) and 11 azathioprine patients (13%). Twenty-five (29%) rituximab and 21 (25%) azathioprine subjects developed hypogammaglobulinemia (IgG less than 5 g/L), and about half of each group developed an infection that required antibiotics, but not hospitalization.

There was one death in the azathioprine arm from malignancy, and three in the rituximab group, one from infection and two as of yet unclassified.

The groups were well balanced. Subjects were a median of 59 years old, with a median disease duration of 5.3 years. Refractory patients – those who had not achieved remission during a previous relapse – were excluded, as were patients who had received a B cell–depleting treatment in the previous 6 months and those with eosinophilic granulomatosis with polyangiitis or a malignancy in the past 5 years. Among patients in the study, 72% had tested positive for anti–proteinase 3 ANCA, and 28% for myeloperoxidase ANCA.

The work was funded by Versus Arthritis (formerly Arthritis Research UK), the National Institutes of Health, and the makers of rituximab, Roche/Genentech. Dr. Smith reported ties to Roche, Sanofi, and MedImmune.

[email protected]

SOURCE: Smith R et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 806.

ATLANTA – Rituximab (Rituxan) is superior to azathioprine (Imuran) for preventing ANCA-associated vasculitis relapses in patients with histories of previous relapses, according to a randomized trial of 170 patients presented at the annual meeting of the American College of Rheumatology.

Rituximab has been previously shown to be the superior remission maintenance option in the French MAINRITSAN trial (N Engl J Med. 2014 Nov 6;371[19]:1771-80), but mostly in newly diagnosed patients after cyclophosphamide induction. The results expand the finding to those with relapsing disease who previously had remission induced with rituximab, said lead investigator Rona Smith, MD, a clinical lecturer at Cambridge (England) University.

Subjects in the RITAZAREM trial (rituximab versus azathioprine as therapy for maintenance of remission for antineutrophil cytoplasmic antibody [ANCA]–associated vasculitis) were enrolled during a relapse of either granulomatosis with polyangiitis or microscopic polyangiitis and underwent remission induction with rituximab 375 mg/m² per week for 4 weeks coupled with prednisone, either 1 or 0.5 mg/kg per day at provider discretion.

After successful induction – defined as a Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis of 1 point or less on no more than 10 mg/day prednisone – 85 patients were randomized to rituximab 1 g every 4 months for 20 months and 85 to azathioprine 2 mg/kg per day for 20 months, followed by a taper. Prednisone was tapered per protocol to discontinuation at 20 months.

Eleven rituximab patients (13%) relapsed during the 20-month maintenance phase; two relapses were major. There were 32 relapses (38%) in the azathioprine group, 12 of them (38%) major (hazard ratio for rituximab versus azathioprine, 0.3; 95% CI, 0.15-0.60; P less than .001). ANCA type, glucocorticoid induction regimen, and severity of the enrollment relapse did not affect the outcomes.

Also, “there was an increase in the proportion of patients who became ANCA negative” in the rituximab arm, while “there was really no change” with azathioprine. In short, “rituximab is superior to azathioprine for prevention of disease relapse,” Dr. Smith said.

Her audience had a few questions about the rituximab regimen. The French MAINRITSAN trial dosed rituximab every 6 months instead of every 4, for a cumulative dose of 2.5 g, not 5 g, which an audience member said is the standard approach.

Dr. Smith explained that she and her colleagues have seen relapses with rituximab maintenance at 5 and 6 months, so they wanted to move to a shorter schedule. As for the higher dose, they wanted to “achieve complete B-cell depletion for the duration of the treatment period” to see if it translates into longer lasting remissions. “We will hopefully be able to address that question” with further analysis, she said.

There were no new safety signals; 19 rituximab patients (22%) and 31 azathioprine subjects (36%) had at least one serious adverse event; an infection requiring hospitalization occurred in 7 rituximab patients (8%) and 11 azathioprine patients (13%). Twenty-five (29%) rituximab and 21 (25%) azathioprine subjects developed hypogammaglobulinemia (IgG less than 5 g/L), and about half of each group developed an infection that required antibiotics, but not hospitalization.

There was one death in the azathioprine arm from malignancy, and three in the rituximab group, one from infection and two as of yet unclassified.

The groups were well balanced. Subjects were a median of 59 years old, with a median disease duration of 5.3 years. Refractory patients – those who had not achieved remission during a previous relapse – were excluded, as were patients who had received a B cell–depleting treatment in the previous 6 months and those with eosinophilic granulomatosis with polyangiitis or a malignancy in the past 5 years. Among patients in the study, 72% had tested positive for anti–proteinase 3 ANCA, and 28% for myeloperoxidase ANCA.

The work was funded by Versus Arthritis (formerly Arthritis Research UK), the National Institutes of Health, and the makers of rituximab, Roche/Genentech. Dr. Smith reported ties to Roche, Sanofi, and MedImmune.

[email protected]

SOURCE: Smith R et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 806.

WASHINGTON – A novel antibody, obinutuzumab, enhances renal responses in patients with lupus nephritis, through more complete B-cell depletion, compared with standard immunotherapy, and is well tolerated, according to results from the phase 2 NOBILITY trial.

“We know from our previous trials with anti–B-cell antibodies that results were mixed and we felt that these variable results were possibly due to variability in B-cell depletion with a type 1 anti-CD20 antibody such as rituximab,” Brad Rovin, MD, director, division of nephrology, Ohio State University in Columbus, told a press briefing here at Kidney Week 2019: American Society of Nephrology annual meeting.

“So we hypothesized that if we could deplete B cells more efficiently and completely, we would achieve better results. At week 52, 35% of patients in the obinutuzumab-treated group achieved a complete renal response, compared to 23% in the standard-of-care arm.”

And by week 76, the difference between obinutuzumab and the standard of care was actually larger at 40% vs. 18%, respectively, “and this was statistically significant at a P value of .01,” added Dr. Rovin, who presented the full findings of the study at the conference.

Obinutuzumab, a highly engineered anti-CD20 antibody, is already approved under the brand name Gazyva for use in certain leukemias and lymphomas. The NOBILITY study was funded by Genentech-Roche, and Dr. Rovin reported being a consultant for the company.

Asked by Medscape Medical News to comment on the study, Duvuru Geetha, MBBS, noted that with standard-of-care mycophenolate mofetil (MMF) plus corticosteroids, “the remissions rates we achieve [for lupus nephritis] are still not great,” ranging from 30% to 50%, depending on the patient population.

“This is why there is a need for alternative agents,” added Dr. Geetha, who is an associate professor of medicine, Johns Hopkins University, Baltimore.

With obinutuzumab, “the data look very promising because there is a much more profound and sustained effect on B-cell depletion and the renal response rate is much higher [than with MMF and corticosteroids],” she noted.

Dr. Geetha added, however, that she presumes patients were all premedicated with prophylactic agents to prevent infectious events, as they are when treated with rituximab.

“I think what is definitely different about this drug is that it induces direct cell death more efficiently than rituximab and that is probably what’s accounting for the higher efficacy seen with it,” said Dr. Geetha, who disclosed having received honoraria from Genentech a number of years ago.

“So yes, I believe the results are clinically meaningful,” she concluded.

NOBILITY study design

The NOBILITY trial randomized 125 patients with Class III or IV lupus nephritis to either obinutuzumab plus MMF and corticosteroids, or to MMF plus corticosteroids alone, for a treatment interval of 104 weeks.

Patients in the obinutuzumab group received two infusions of the highly engineered anti-CD20 antibody at week 0 and week 2 and another two infusions at 6 months.

“The primary endpoint was complete renal response at week 52,” the authors wrote, “while key secondary endpoints included overall renal response and modified complete renal response.”

Both at week 52 and week 76, more patients in the obinutuzumab group achieved an overall renal response as well as a modified complete renal response, compared with those treated with immunosuppression alone.

“If you look at the complete renal response over time, you can see that the curves separate after about 6 months but the placebo group starts to decline as you go further out, whereas the obinutuzumab group continues to separate, so my prediction is that we are going to see this trend continue because of the mechanism of action of obinutuzumab,” Dr. Rovin explained.

Phase 3 trials to start early 2020

All of the serologies relevant to lupus and lupus nephritis “including C3 and C4 improved while antidoubled stranded DNA levels declined, as did the urine protein-to-creatinine ratio, although the decline was more rapid and more profound in the obinutuzumab-treated patients,” Dr. Rovin said.

Importantly as well, despite the profound B-cell depletion produced by obinutuzumab, “the adverse event profile of this drug was very similar to the placebo group,” he stressed.

As expected, rates of infusion reactions were slightly higher in the experimental group than the immunosuppression alone group, but rates of serious adverse events were the same between groups, as were adverse infectious events, he noted.

Investigators have now initiated a global phase 3 trial, scheduled to start in early 2020, to evaluate the same treatment protocol in a larger group of patients.


Kidney Week 2019. Abstract #FR-OR136. Presented Nov. 8, 2019.
 

This story first appeared on Medscape.com.

WASHINGTON – A novel antibody, obinutuzumab, enhances renal responses in patients with lupus nephritis, through more complete B-cell depletion, compared with standard immunotherapy, and is well tolerated, according to results from the phase 2 NOBILITY trial.

“We know from our previous trials with anti–B-cell antibodies that results were mixed and we felt that these variable results were possibly due to variability in B-cell depletion with a type 1 anti-CD20 antibody such as rituximab,” Brad Rovin, MD, director, division of nephrology, Ohio State University in Columbus, told a press briefing here at Kidney Week 2019: American Society of Nephrology annual meeting.

“So we hypothesized that if we could deplete B cells more efficiently and completely, we would achieve better results. At week 52, 35% of patients in the obinutuzumab-treated group achieved a complete renal response, compared to 23% in the standard-of-care arm.”

And by week 76, the difference between obinutuzumab and the standard of care was actually larger at 40% vs. 18%, respectively, “and this was statistically significant at a P value of .01,” added Dr. Rovin, who presented the full findings of the study at the conference.

Obinutuzumab, a highly engineered anti-CD20 antibody, is already approved under the brand name Gazyva for use in certain leukemias and lymphomas. The NOBILITY study was funded by Genentech-Roche, and Dr. Rovin reported being a consultant for the company.

Asked by Medscape Medical News to comment on the study, Duvuru Geetha, MBBS, noted that with standard-of-care mycophenolate mofetil (MMF) plus corticosteroids, “the remissions rates we achieve [for lupus nephritis] are still not great,” ranging from 30% to 50%, depending on the patient population.

“This is why there is a need for alternative agents,” added Dr. Geetha, who is an associate professor of medicine, Johns Hopkins University, Baltimore.

With obinutuzumab, “the data look very promising because there is a much more profound and sustained effect on B-cell depletion and the renal response rate is much higher [than with MMF and corticosteroids],” she noted.

Dr. Geetha added, however, that she presumes patients were all premedicated with prophylactic agents to prevent infectious events, as they are when treated with rituximab.

“I think what is definitely different about this drug is that it induces direct cell death more efficiently than rituximab and that is probably what’s accounting for the higher efficacy seen with it,” said Dr. Geetha, who disclosed having received honoraria from Genentech a number of years ago.

“So yes, I believe the results are clinically meaningful,” she concluded.

NOBILITY study design

The NOBILITY trial randomized 125 patients with Class III or IV lupus nephritis to either obinutuzumab plus MMF and corticosteroids, or to MMF plus corticosteroids alone, for a treatment interval of 104 weeks.

Patients in the obinutuzumab group received two infusions of the highly engineered anti-CD20 antibody at week 0 and week 2 and another two infusions at 6 months.

“The primary endpoint was complete renal response at week 52,” the authors wrote, “while key secondary endpoints included overall renal response and modified complete renal response.”

Both at week 52 and week 76, more patients in the obinutuzumab group achieved an overall renal response as well as a modified complete renal response, compared with those treated with immunosuppression alone.

“If you look at the complete renal response over time, you can see that the curves separate after about 6 months but the placebo group starts to decline as you go further out, whereas the obinutuzumab group continues to separate, so my prediction is that we are going to see this trend continue because of the mechanism of action of obinutuzumab,” Dr. Rovin explained.

Phase 3 trials to start early 2020

All of the serologies relevant to lupus and lupus nephritis “including C3 and C4 improved while antidoubled stranded DNA levels declined, as did the urine protein-to-creatinine ratio, although the decline was more rapid and more profound in the obinutuzumab-treated patients,” Dr. Rovin said.

Importantly as well, despite the profound B-cell depletion produced by obinutuzumab, “the adverse event profile of this drug was very similar to the placebo group,” he stressed.

As expected, rates of infusion reactions were slightly higher in the experimental group than the immunosuppression alone group, but rates of serious adverse events were the same between groups, as were adverse infectious events, he noted.

Investigators have now initiated a global phase 3 trial, scheduled to start in early 2020, to evaluate the same treatment protocol in a larger group of patients.


Kidney Week 2019. Abstract #FR-OR136. Presented Nov. 8, 2019.
 

This story first appeared on Medscape.com.

WASHINGTON – A novel antibody, obinutuzumab, enhances renal responses in patients with lupus nephritis, through more complete B-cell depletion, compared with standard immunotherapy, and is well tolerated, according to results from the phase 2 NOBILITY trial.

“We know from our previous trials with anti–B-cell antibodies that results were mixed and we felt that these variable results were possibly due to variability in B-cell depletion with a type 1 anti-CD20 antibody such as rituximab,” Brad Rovin, MD, director, division of nephrology, Ohio State University in Columbus, told a press briefing here at Kidney Week 2019: American Society of Nephrology annual meeting.

“So we hypothesized that if we could deplete B cells more efficiently and completely, we would achieve better results. At week 52, 35% of patients in the obinutuzumab-treated group achieved a complete renal response, compared to 23% in the standard-of-care arm.”

And by week 76, the difference between obinutuzumab and the standard of care was actually larger at 40% vs. 18%, respectively, “and this was statistically significant at a P value of .01,” added Dr. Rovin, who presented the full findings of the study at the conference.

Obinutuzumab, a highly engineered anti-CD20 antibody, is already approved under the brand name Gazyva for use in certain leukemias and lymphomas. The NOBILITY study was funded by Genentech-Roche, and Dr. Rovin reported being a consultant for the company.

Asked by Medscape Medical News to comment on the study, Duvuru Geetha, MBBS, noted that with standard-of-care mycophenolate mofetil (MMF) plus corticosteroids, “the remissions rates we achieve [for lupus nephritis] are still not great,” ranging from 30% to 50%, depending on the patient population.

“This is why there is a need for alternative agents,” added Dr. Geetha, who is an associate professor of medicine, Johns Hopkins University, Baltimore.

With obinutuzumab, “the data look very promising because there is a much more profound and sustained effect on B-cell depletion and the renal response rate is much higher [than with MMF and corticosteroids],” she noted.

Dr. Geetha added, however, that she presumes patients were all premedicated with prophylactic agents to prevent infectious events, as they are when treated with rituximab.

“I think what is definitely different about this drug is that it induces direct cell death more efficiently than rituximab and that is probably what’s accounting for the higher efficacy seen with it,” said Dr. Geetha, who disclosed having received honoraria from Genentech a number of years ago.

“So yes, I believe the results are clinically meaningful,” she concluded.

NOBILITY study design

The NOBILITY trial randomized 125 patients with Class III or IV lupus nephritis to either obinutuzumab plus MMF and corticosteroids, or to MMF plus corticosteroids alone, for a treatment interval of 104 weeks.

Patients in the obinutuzumab group received two infusions of the highly engineered anti-CD20 antibody at week 0 and week 2 and another two infusions at 6 months.

“The primary endpoint was complete renal response at week 52,” the authors wrote, “while key secondary endpoints included overall renal response and modified complete renal response.”

Both at week 52 and week 76, more patients in the obinutuzumab group achieved an overall renal response as well as a modified complete renal response, compared with those treated with immunosuppression alone.

“If you look at the complete renal response over time, you can see that the curves separate after about 6 months but the placebo group starts to decline as you go further out, whereas the obinutuzumab group continues to separate, so my prediction is that we are going to see this trend continue because of the mechanism of action of obinutuzumab,” Dr. Rovin explained.

Phase 3 trials to start early 2020

All of the serologies relevant to lupus and lupus nephritis “including C3 and C4 improved while antidoubled stranded DNA levels declined, as did the urine protein-to-creatinine ratio, although the decline was more rapid and more profound in the obinutuzumab-treated patients,” Dr. Rovin said.

Importantly as well, despite the profound B-cell depletion produced by obinutuzumab, “the adverse event profile of this drug was very similar to the placebo group,” he stressed.

As expected, rates of infusion reactions were slightly higher in the experimental group than the immunosuppression alone group, but rates of serious adverse events were the same between groups, as were adverse infectious events, he noted.

Investigators have now initiated a global phase 3 trial, scheduled to start in early 2020, to evaluate the same treatment protocol in a larger group of patients.


Kidney Week 2019. Abstract #FR-OR136. Presented Nov. 8, 2019.
 

This story first appeared on Medscape.com.

BOSTON – Exposure to heavy metals from natural and man-made sources may contribute to development of autoimmune liver disease, according to a recent U.K. study involving more than 3,500 patients.

Will Pass/MDedge News

Coal mines were particularly implicated, as they accounted for 39% of the risk of developing primary biliary cholangitis (PBC), reported lead author Jessica Dyson, MBBS, of Newcastle (England) University, and colleagues.

“We know that the etiology of autoimmune liver disease remains unclear, but we’re increasingly coming to understand that it’s likely to be a complex interplay between genetic and environmental factors,” Dr. Dyson said during a presentation at the annual meeting of the American Association for the Study of Liver Diseases. Showing a map of England, she pointed out how three autoimmune liver diseases – PBC, primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH) – each have unique clusters of distribution. “This implies that environmental exposure may have a role in disease pathogenesis.”

To investigate this possibility, Dr. Dyson and colleagues used structural equation modeling to look for associations between the above three autoimmune liver diseases, socioeconomic status, and environmental factors. Specific environmental factors included soil concentrations of heavy metals (cadmium, arsenic, lead, manganese, and iron), coal mines, lead mines, quarries, urban areas, traffic, stream pH, and landfills.

The study was conducted in the northeast of England, where migration rates are low, Dr. Dyson said. From this region, the investigators identified patients with PBC (n = 2,150), AIH (n = 963), and PSC (n = 472). Conceptual models were used to examine relationships between covariates and prevalence of disease, with good models exhibiting a root-mean-square error of association less than 0.05 and a 95% covariate significance. After adjusting for population density, comparative fit was used to measure variation within each model.

The best model for PBC revealed the aforementioned link with coal mines, proximity to which accounted for 39% of the pathogenesis of PBC. High levels of cadmium in soil had an interactive role with coal mines, and itself directly contributed 22% of the risk of PBC; however, Dr. Dyson noted that, while many cadmium-rich areas had high rates of PBC, not all did.

“This demonstrates the complexity of causality of disease, and we certainly can’t say that cadmium, in its own right, is a direct cause and effect,” Dr. Dyson said. “But I think [cadmium] certainly potentially is one of the factors at play.”

For AIH, coal mines contributed less (6%), although cadmium still accounted for 22% of variation of disease, as did alkaline areas. Finally, a significant link was found between PSC and regions with high arsenic levels.

“To conclude, our data suggest that heavy metals may be risk factors for autoimmune liver disease,” Dr. Dyson said. “There are a number of exposure routes that may be pertinent to patients, from heavy metals occurring via natural sources, and also via virtue of human activity, such as burning of fossil fuels, heavy-metal production, and pesticides.” Dr. Dyson emphasized this latter route, as some rural areas, where pesticide use is common, had high prevalence rates of autoimmune liver disease.

Dr. Dyson went on to put her findings in context. “Heavy metals are a well-recognized cause of immune dysregulation and epithelial injury and are actually actively transported into the bile, and that may be particularly relevant in terms of cholangiopathies. And this leads us to the possibility of interventions to reduce toxic exposure that may modify risk of disease.”

Looking to the future, Dr. Dyson described plans to build on this research with measurements of heavy metals in tissues, serum, and urine.

The investigators reported no relevant disclosures.

SOURCE: Dyson J et al. The Liver Meeting 2019, Abstract 48.

BOSTON – Exposure to heavy metals from natural and man-made sources may contribute to development of autoimmune liver disease, according to a recent U.K. study involving more than 3,500 patients.

Will Pass/MDedge News

Coal mines were particularly implicated, as they accounted for 39% of the risk of developing primary biliary cholangitis (PBC), reported lead author Jessica Dyson, MBBS, of Newcastle (England) University, and colleagues.

“We know that the etiology of autoimmune liver disease remains unclear, but we’re increasingly coming to understand that it’s likely to be a complex interplay between genetic and environmental factors,” Dr. Dyson said during a presentation at the annual meeting of the American Association for the Study of Liver Diseases. Showing a map of England, she pointed out how three autoimmune liver diseases – PBC, primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH) – each have unique clusters of distribution. “This implies that environmental exposure may have a role in disease pathogenesis.”

To investigate this possibility, Dr. Dyson and colleagues used structural equation modeling to look for associations between the above three autoimmune liver diseases, socioeconomic status, and environmental factors. Specific environmental factors included soil concentrations of heavy metals (cadmium, arsenic, lead, manganese, and iron), coal mines, lead mines, quarries, urban areas, traffic, stream pH, and landfills.

The study was conducted in the northeast of England, where migration rates are low, Dr. Dyson said. From this region, the investigators identified patients with PBC (n = 2,150), AIH (n = 963), and PSC (n = 472). Conceptual models were used to examine relationships between covariates and prevalence of disease, with good models exhibiting a root-mean-square error of association less than 0.05 and a 95% covariate significance. After adjusting for population density, comparative fit was used to measure variation within each model.

The best model for PBC revealed the aforementioned link with coal mines, proximity to which accounted for 39% of the pathogenesis of PBC. High levels of cadmium in soil had an interactive role with coal mines, and itself directly contributed 22% of the risk of PBC; however, Dr. Dyson noted that, while many cadmium-rich areas had high rates of PBC, not all did.

“This demonstrates the complexity of causality of disease, and we certainly can’t say that cadmium, in its own right, is a direct cause and effect,” Dr. Dyson said. “But I think [cadmium] certainly potentially is one of the factors at play.”

For AIH, coal mines contributed less (6%), although cadmium still accounted for 22% of variation of disease, as did alkaline areas. Finally, a significant link was found between PSC and regions with high arsenic levels.

“To conclude, our data suggest that heavy metals may be risk factors for autoimmune liver disease,” Dr. Dyson said. “There are a number of exposure routes that may be pertinent to patients, from heavy metals occurring via natural sources, and also via virtue of human activity, such as burning of fossil fuels, heavy-metal production, and pesticides.” Dr. Dyson emphasized this latter route, as some rural areas, where pesticide use is common, had high prevalence rates of autoimmune liver disease.

Dr. Dyson went on to put her findings in context. “Heavy metals are a well-recognized cause of immune dysregulation and epithelial injury and are actually actively transported into the bile, and that may be particularly relevant in terms of cholangiopathies. And this leads us to the possibility of interventions to reduce toxic exposure that may modify risk of disease.”

Looking to the future, Dr. Dyson described plans to build on this research with measurements of heavy metals in tissues, serum, and urine.

The investigators reported no relevant disclosures.

SOURCE: Dyson J et al. The Liver Meeting 2019, Abstract 48.

BOSTON – Exposure to heavy metals from natural and man-made sources may contribute to development of autoimmune liver disease, according to a recent U.K. study involving more than 3,500 patients.

Will Pass/MDedge News

Coal mines were particularly implicated, as they accounted for 39% of the risk of developing primary biliary cholangitis (PBC), reported lead author Jessica Dyson, MBBS, of Newcastle (England) University, and colleagues.

“We know that the etiology of autoimmune liver disease remains unclear, but we’re increasingly coming to understand that it’s likely to be a complex interplay between genetic and environmental factors,” Dr. Dyson said during a presentation at the annual meeting of the American Association for the Study of Liver Diseases. Showing a map of England, she pointed out how three autoimmune liver diseases – PBC, primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH) – each have unique clusters of distribution. “This implies that environmental exposure may have a role in disease pathogenesis.”

To investigate this possibility, Dr. Dyson and colleagues used structural equation modeling to look for associations between the above three autoimmune liver diseases, socioeconomic status, and environmental factors. Specific environmental factors included soil concentrations of heavy metals (cadmium, arsenic, lead, manganese, and iron), coal mines, lead mines, quarries, urban areas, traffic, stream pH, and landfills.

The study was conducted in the northeast of England, where migration rates are low, Dr. Dyson said. From this region, the investigators identified patients with PBC (n = 2,150), AIH (n = 963), and PSC (n = 472). Conceptual models were used to examine relationships between covariates and prevalence of disease, with good models exhibiting a root-mean-square error of association less than 0.05 and a 95% covariate significance. After adjusting for population density, comparative fit was used to measure variation within each model.

The best model for PBC revealed the aforementioned link with coal mines, proximity to which accounted for 39% of the pathogenesis of PBC. High levels of cadmium in soil had an interactive role with coal mines, and itself directly contributed 22% of the risk of PBC; however, Dr. Dyson noted that, while many cadmium-rich areas had high rates of PBC, not all did.

“This demonstrates the complexity of causality of disease, and we certainly can’t say that cadmium, in its own right, is a direct cause and effect,” Dr. Dyson said. “But I think [cadmium] certainly potentially is one of the factors at play.”

For AIH, coal mines contributed less (6%), although cadmium still accounted for 22% of variation of disease, as did alkaline areas. Finally, a significant link was found between PSC and regions with high arsenic levels.

“To conclude, our data suggest that heavy metals may be risk factors for autoimmune liver disease,” Dr. Dyson said. “There are a number of exposure routes that may be pertinent to patients, from heavy metals occurring via natural sources, and also via virtue of human activity, such as burning of fossil fuels, heavy-metal production, and pesticides.” Dr. Dyson emphasized this latter route, as some rural areas, where pesticide use is common, had high prevalence rates of autoimmune liver disease.

Dr. Dyson went on to put her findings in context. “Heavy metals are a well-recognized cause of immune dysregulation and epithelial injury and are actually actively transported into the bile, and that may be particularly relevant in terms of cholangiopathies. And this leads us to the possibility of interventions to reduce toxic exposure that may modify risk of disease.”

Looking to the future, Dr. Dyson described plans to build on this research with measurements of heavy metals in tissues, serum, and urine.

The investigators reported no relevant disclosures.

SOURCE: Dyson J et al. The Liver Meeting 2019, Abstract 48.

MADRID – Oral apremilast’s beneficial effects on Behçet’s disease oral ulcer disease severity and patient quality of life were sustained through week 64 of the long-term extension phase of the pivotal RELIEF trial, Alfred Mahr, MD, PhD, reported at the annual congress of the European Academy of Dermatology and Venereology.

Bruce Jancin/MDedge News

“We now have strong evidence that apremilast is an effective and safe therapy to treat oral ulcers in patients with Behçet’s syndrome. I think this is a major advance in the field,” declared Dr. Mahr, a rheumatologist at St. Gallen (Switzerland) Cantonal Hospital.

Based largely upon the results of the 12-week, double-blind portion of the phase 3 RELIEF trial, the Food and Drug Administration approved apremilast (Otezla) for the treatment of oral ulcers in patients with Behçet’s disease in the summer of 2019.

The safety profile of the oral phosphodiesterase-4 inhibitor was as seen in other studies, including in patients with psoriatic arthritis, an FDA-approved indication for the drug since 2014. The main side effects in the long-term extension of RELIEF were diarrhea and nausea, typically mild or moderate in nature and roughly twice as frequent as in placebo-treated controls in the double-blind study phase.

“At the end of the day, at week 64, only 12% of patients treated with apremilast during the entire 64 weeks discontinued the drug due to a treatment-emergent adverse event, which I believe is a good indicator of the safety of this medication,” the rheumatologist said. “The overall feeling is that the benefit-to-risk ratio is very good and it’s a safe drug to prescribe.”

At the close of the initial 12-week, double-blind phase of RELIEF, 178 of the original 207 participants elected to enter the long-term extension, either staying on apremilast at 30 mg twice a day for an additional 52 weeks or switching to that regimen from placebo.

The focus of the long-term extension was on disease activity and quality of life outcomes. The results in patients who had switched from placebo to apremilast after 12 weeks proved to be reassuringly similar to outcomes in patients on the drug for the full duration. For example, the mean improvement on the patient-reported Behçet’s Syndrome Activity Scale was 18.6 points after 12 weeks of double-blind apremilast, 16.9 points after 64 weeks of continuous apremilast, and 16.8 points with 12 weeks of placebo followed by 52 weeks of active therapy.

After 12 weeks of double-blind apremilast, patients averaged a 3.4-point improvement on the Behçet’s Disease Quality of Life measure. After 64 weeks on the drug, the improvement over baseline was 3.6 points, while in the switch group it was 3.4 points. Similarly, on all three components of the SF-36 quality of life metric, the continuous apremilast group showed maintenance of effect from week 12 to week 64, while the placebo-to-apremilast group caught up. The same was true with regards to the Behçet’s Disease Current Activity Index, which encompasses measures of both the patient’s and clinician’s perception of disease activity.

At the outset of the RELIEF trial, participants averaged four oral ulcers. At week 64, the continuous apremilast group averaged 1.4 and the switch group 0.8, a nonsignificant difference.

Asked if apremilast had a favorable impact upon other manifestations of Behçet’s disease besides the oral ulcers, Dr. Mahr replied, “This is a very good question. People often wonder about it. We do, too. But this trial was not designed to capture less common manifestations of Behçet’s syndrome, such as genital ulcers. There have been some analyses done, but the number of patients who had genital ulcers at 12 weeks were very few. The same was true for eye manifestations. There was sort of a signal that it works, but we can’t prove it in a placebo-controlled trial.”

Dr. Mahr reported receiving research funding from and serving as a consultant to Celgene, the study sponsor.

[email protected]

MADRID – Oral apremilast’s beneficial effects on Behçet’s disease oral ulcer disease severity and patient quality of life were sustained through week 64 of the long-term extension phase of the pivotal RELIEF trial, Alfred Mahr, MD, PhD, reported at the annual congress of the European Academy of Dermatology and Venereology.

Bruce Jancin/MDedge News

“We now have strong evidence that apremilast is an effective and safe therapy to treat oral ulcers in patients with Behçet’s syndrome. I think this is a major advance in the field,” declared Dr. Mahr, a rheumatologist at St. Gallen (Switzerland) Cantonal Hospital.

Based largely upon the results of the 12-week, double-blind portion of the phase 3 RELIEF trial, the Food and Drug Administration approved apremilast (Otezla) for the treatment of oral ulcers in patients with Behçet’s disease in the summer of 2019.

The safety profile of the oral phosphodiesterase-4 inhibitor was as seen in other studies, including in patients with psoriatic arthritis, an FDA-approved indication for the drug since 2014. The main side effects in the long-term extension of RELIEF were diarrhea and nausea, typically mild or moderate in nature and roughly twice as frequent as in placebo-treated controls in the double-blind study phase.

“At the end of the day, at week 64, only 12% of patients treated with apremilast during the entire 64 weeks discontinued the drug due to a treatment-emergent adverse event, which I believe is a good indicator of the safety of this medication,” the rheumatologist said. “The overall feeling is that the benefit-to-risk ratio is very good and it’s a safe drug to prescribe.”

At the close of the initial 12-week, double-blind phase of RELIEF, 178 of the original 207 participants elected to enter the long-term extension, either staying on apremilast at 30 mg twice a day for an additional 52 weeks or switching to that regimen from placebo.

The focus of the long-term extension was on disease activity and quality of life outcomes. The results in patients who had switched from placebo to apremilast after 12 weeks proved to be reassuringly similar to outcomes in patients on the drug for the full duration. For example, the mean improvement on the patient-reported Behçet’s Syndrome Activity Scale was 18.6 points after 12 weeks of double-blind apremilast, 16.9 points after 64 weeks of continuous apremilast, and 16.8 points with 12 weeks of placebo followed by 52 weeks of active therapy.

After 12 weeks of double-blind apremilast, patients averaged a 3.4-point improvement on the Behçet’s Disease Quality of Life measure. After 64 weeks on the drug, the improvement over baseline was 3.6 points, while in the switch group it was 3.4 points. Similarly, on all three components of the SF-36 quality of life metric, the continuous apremilast group showed maintenance of effect from week 12 to week 64, while the placebo-to-apremilast group caught up. The same was true with regards to the Behçet’s Disease Current Activity Index, which encompasses measures of both the patient’s and clinician’s perception of disease activity.

At the outset of the RELIEF trial, participants averaged four oral ulcers. At week 64, the continuous apremilast group averaged 1.4 and the switch group 0.8, a nonsignificant difference.

Asked if apremilast had a favorable impact upon other manifestations of Behçet’s disease besides the oral ulcers, Dr. Mahr replied, “This is a very good question. People often wonder about it. We do, too. But this trial was not designed to capture less common manifestations of Behçet’s syndrome, such as genital ulcers. There have been some analyses done, but the number of patients who had genital ulcers at 12 weeks were very few. The same was true for eye manifestations. There was sort of a signal that it works, but we can’t prove it in a placebo-controlled trial.”

Dr. Mahr reported receiving research funding from and serving as a consultant to Celgene, the study sponsor.

[email protected]

MADRID – Oral apremilast’s beneficial effects on Behçet’s disease oral ulcer disease severity and patient quality of life were sustained through week 64 of the long-term extension phase of the pivotal RELIEF trial, Alfred Mahr, MD, PhD, reported at the annual congress of the European Academy of Dermatology and Venereology.

Bruce Jancin/MDedge News

“We now have strong evidence that apremilast is an effective and safe therapy to treat oral ulcers in patients with Behçet’s syndrome. I think this is a major advance in the field,” declared Dr. Mahr, a rheumatologist at St. Gallen (Switzerland) Cantonal Hospital.

Based largely upon the results of the 12-week, double-blind portion of the phase 3 RELIEF trial, the Food and Drug Administration approved apremilast (Otezla) for the treatment of oral ulcers in patients with Behçet’s disease in the summer of 2019.

The safety profile of the oral phosphodiesterase-4 inhibitor was as seen in other studies, including in patients with psoriatic arthritis, an FDA-approved indication for the drug since 2014. The main side effects in the long-term extension of RELIEF were diarrhea and nausea, typically mild or moderate in nature and roughly twice as frequent as in placebo-treated controls in the double-blind study phase.

“At the end of the day, at week 64, only 12% of patients treated with apremilast during the entire 64 weeks discontinued the drug due to a treatment-emergent adverse event, which I believe is a good indicator of the safety of this medication,” the rheumatologist said. “The overall feeling is that the benefit-to-risk ratio is very good and it’s a safe drug to prescribe.”

At the close of the initial 12-week, double-blind phase of RELIEF, 178 of the original 207 participants elected to enter the long-term extension, either staying on apremilast at 30 mg twice a day for an additional 52 weeks or switching to that regimen from placebo.

The focus of the long-term extension was on disease activity and quality of life outcomes. The results in patients who had switched from placebo to apremilast after 12 weeks proved to be reassuringly similar to outcomes in patients on the drug for the full duration. For example, the mean improvement on the patient-reported Behçet’s Syndrome Activity Scale was 18.6 points after 12 weeks of double-blind apremilast, 16.9 points after 64 weeks of continuous apremilast, and 16.8 points with 12 weeks of placebo followed by 52 weeks of active therapy.

After 12 weeks of double-blind apremilast, patients averaged a 3.4-point improvement on the Behçet’s Disease Quality of Life measure. After 64 weeks on the drug, the improvement over baseline was 3.6 points, while in the switch group it was 3.4 points. Similarly, on all three components of the SF-36 quality of life metric, the continuous apremilast group showed maintenance of effect from week 12 to week 64, while the placebo-to-apremilast group caught up. The same was true with regards to the Behçet’s Disease Current Activity Index, which encompasses measures of both the patient’s and clinician’s perception of disease activity.

At the outset of the RELIEF trial, participants averaged four oral ulcers. At week 64, the continuous apremilast group averaged 1.4 and the switch group 0.8, a nonsignificant difference.

Asked if apremilast had a favorable impact upon other manifestations of Behçet’s disease besides the oral ulcers, Dr. Mahr replied, “This is a very good question. People often wonder about it. We do, too. But this trial was not designed to capture less common manifestations of Behçet’s syndrome, such as genital ulcers. There have been some analyses done, but the number of patients who had genital ulcers at 12 weeks were very few. The same was true for eye manifestations. There was sort of a signal that it works, but we can’t prove it in a placebo-controlled trial.”

Dr. Mahr reported receiving research funding from and serving as a consultant to Celgene, the study sponsor.

[email protected]

ATLANTA – The benefits of tocilizumab for giant cell arteritis (GCA), as demonstrated in the pivotal phase 3 GiACTA trial, proved durable in nearly half of the patients treated weekly during the trial, according to findings from a 2-year long-term extension period.

Of 250 patients treated in the double-blind portion of the trial, 215 entered the extension period (part 2 of the trial), and 197 (92%) completed all 3 years of the trial. A total of 38 of 81 (47%) extension participants in clinical remission (CR) at week 52 after receiving tocilizumab (Actemra) weekly maintained it throughout the extension, and 13 of 36 (36%) treated every other week maintained it, John Stone, MD, reported at the annual meeting of the American College of Rheumatology.

Notably, more of those 51 patients treated with tocilizumab who maintained CR throughout the extension were treatment free at the end of the extension, compared with those originally assigned to the placebo groups (65% vs. 45%), and their median time to first flare after stopping treatment was longer, said Dr. Stone, director of clinical rheumatology at Massachusetts General Hospital and associate professor of medicine in the division of rheumatology at Harvard Medical School, both in Boston.

For example, times to first flare were 575 and 428 days for the weekly and biweekly tocilizumab dosing groups – which each had 26-week prednisone tapering – but they were only 162 days in a placebo group with 26-week prednisone tapering and 295 days for patients in another placebo group with 52-week prednisone tapering, Dr. Stone explained. Retreatment with tocilizumab restored CR in patients who experienced flares after discontinuing treatment, he added.

Importantly, cumulative glucocorticoid doses over the 3 years were also lower in the tocilizumab groups (2,647 and 3,782 mg/day with weekly and biweekly tocilizumab and 5,248, and 5,323 mg/day in the placebo groups, respectively), Dr. Stone said.

No new safety signals were observed during the extension. Rates of serious adverse events (SAEs) and serious infections per 100 patient-years during the entire 3 years of the study were comparable among those who never received tocilizumab and those who received at least 1 dose (23.2 and 25.4 for SAEs and 4.6 and 3.5 for serious infections).
 

Detailed results of the extension period

GiACTA enrolled patients with GCA and randomized them to receive weekly or biweekly treatment with the interleukin-6 receptor–alpha inhibitor tocilizumab at doses of 162 mg delivered subcutaneously with a 26-week prednisone taper, or to the placebo groups with a 26- or 52-week prednisone taper. The results, reported in 2017, demonstrated the superiority of tocilizumab over placebo for providing sustained glucocorticoid-free remission and ultimately led to approval from Food and Drug Administration of the biologic agent for the treatment of GCA.

The current analysis was carried out to determine long-term safety, to explore maintenance of efficacy after discontinuation, and to “gain insight into the long-term glucocorticoid-sparing effects of tocilizumab,” Dr. Stone said.

He noted that the extension period was not randomized because of the way that patients in the “original four randomized groups had sorted themselves out into very different groups by virtue of their response in part 1 [of the trial],” which made randomization impossible because of the varying categories of patients.

Patients in the extension were also treated at investigators’ discretion to prevent “catastrophic GCA flares, vision loss, and other problems” that could potentially occur with discontinuation of the blinded injections in part 1, he said.

Nevertheless, the analysis “provides some incredibly important information about the management of GCA now,” he said, adding that the dramatic effect of the original randomization was still profound at 3 years “despite the fact that investigators could treat the patients as they wished.”

“Even at 3 years there was still a profound difference in the cumulative glucocorticoid [use], compared to those patients who were randomized to one of the placebo versus prednisone groups,” he explained.

However, the most important question from this study relates to what happened when weekly tocilizumab was stopped: Of the 81 patients in part 2 who were in CR on tocilizumab after part 1 of the study, 59 (73%) were not started on any treatment by their investigator, and of those, 25 (42%) maintained treatment-free remission for 2 full years following discontinuation of tocilizumab, he said.
 

What happened when prednisone was stopped?

In the absence of a direct comparison group (since the extension wasn’t a randomized, controlled part of the trial), the best comparison to that is what happens when prednisone is stopped, he noted.

“And we did that experiment in part 1” of the trial, he said. Overall, 68% of patients in the prednisone/placebo groups flared in 1-year of follow-up, and most of those did so even before they stopped prednisone. In the group that received placebo plus a 52-week prednisone taper, 49% of patients flared and “every single one of those patients flared before they got off prednisone,” he said.

“So in that context, 2 years of treatment-free remission following weekly tocilizumab discontinuation seems very good,” he added.

Of the patients who flared in part 2 of the trial, 11 whose investigator elected to treat them with only tocilizumab reentered remission in a median of 15.8 days, 13 treated with tocilizumab and glucocorticoids reentered remission in a median of 8.5 days (1 didn’t reenter remission at all), and 15 treated with only glucocorticoids reentered remission in a median of 38 days.

“There are a number of biases in these data, but they do point out the fact that some patients can be treated with tocilizumab alone,” Dr. Stone said. “I would be very careful doing that.”

The trial was not powered for the comparison of weekly versus biweekly dosing, he said. However, “multiple lines of investigation and analysis support the idea that weekly tocilizumab is more effective at controlling disease,” he added. But “if you want to be assured that you are doing everything you can to control the disease, weekly tocilizumab would be better than every-other-week tocilizumab,” he said.

GiACTA was funded by Roche. Dr. Stone reported research grants from Roche/Genentech and consulting fees from Chugal, Roche/Genentech, and Xencor.

[email protected]

SOURCE: Stone J et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 808.

ATLANTA – The benefits of tocilizumab for giant cell arteritis (GCA), as demonstrated in the pivotal phase 3 GiACTA trial, proved durable in nearly half of the patients treated weekly during the trial, according to findings from a 2-year long-term extension period.

Of 250 patients treated in the double-blind portion of the trial, 215 entered the extension period (part 2 of the trial), and 197 (92%) completed all 3 years of the trial. A total of 38 of 81 (47%) extension participants in clinical remission (CR) at week 52 after receiving tocilizumab (Actemra) weekly maintained it throughout the extension, and 13 of 36 (36%) treated every other week maintained it, John Stone, MD, reported at the annual meeting of the American College of Rheumatology.

Notably, more of those 51 patients treated with tocilizumab who maintained CR throughout the extension were treatment free at the end of the extension, compared with those originally assigned to the placebo groups (65% vs. 45%), and their median time to first flare after stopping treatment was longer, said Dr. Stone, director of clinical rheumatology at Massachusetts General Hospital and associate professor of medicine in the division of rheumatology at Harvard Medical School, both in Boston.

For example, times to first flare were 575 and 428 days for the weekly and biweekly tocilizumab dosing groups – which each had 26-week prednisone tapering – but they were only 162 days in a placebo group with 26-week prednisone tapering and 295 days for patients in another placebo group with 52-week prednisone tapering, Dr. Stone explained. Retreatment with tocilizumab restored CR in patients who experienced flares after discontinuing treatment, he added.

Importantly, cumulative glucocorticoid doses over the 3 years were also lower in the tocilizumab groups (2,647 and 3,782 mg/day with weekly and biweekly tocilizumab and 5,248, and 5,323 mg/day in the placebo groups, respectively), Dr. Stone said.

No new safety signals were observed during the extension. Rates of serious adverse events (SAEs) and serious infections per 100 patient-years during the entire 3 years of the study were comparable among those who never received tocilizumab and those who received at least 1 dose (23.2 and 25.4 for SAEs and 4.6 and 3.5 for serious infections).
 

Detailed results of the extension period

GiACTA enrolled patients with GCA and randomized them to receive weekly or biweekly treatment with the interleukin-6 receptor–alpha inhibitor tocilizumab at doses of 162 mg delivered subcutaneously with a 26-week prednisone taper, or to the placebo groups with a 26- or 52-week prednisone taper. The results, reported in 2017, demonstrated the superiority of tocilizumab over placebo for providing sustained glucocorticoid-free remission and ultimately led to approval from Food and Drug Administration of the biologic agent for the treatment of GCA.

The current analysis was carried out to determine long-term safety, to explore maintenance of efficacy after discontinuation, and to “gain insight into the long-term glucocorticoid-sparing effects of tocilizumab,” Dr. Stone said.

He noted that the extension period was not randomized because of the way that patients in the “original four randomized groups had sorted themselves out into very different groups by virtue of their response in part 1 [of the trial],” which made randomization impossible because of the varying categories of patients.

Patients in the extension were also treated at investigators’ discretion to prevent “catastrophic GCA flares, vision loss, and other problems” that could potentially occur with discontinuation of the blinded injections in part 1, he said.

Nevertheless, the analysis “provides some incredibly important information about the management of GCA now,” he said, adding that the dramatic effect of the original randomization was still profound at 3 years “despite the fact that investigators could treat the patients as they wished.”

“Even at 3 years there was still a profound difference in the cumulative glucocorticoid [use], compared to those patients who were randomized to one of the placebo versus prednisone groups,” he explained.

However, the most important question from this study relates to what happened when weekly tocilizumab was stopped: Of the 81 patients in part 2 who were in CR on tocilizumab after part 1 of the study, 59 (73%) were not started on any treatment by their investigator, and of those, 25 (42%) maintained treatment-free remission for 2 full years following discontinuation of tocilizumab, he said.
 

What happened when prednisone was stopped?

In the absence of a direct comparison group (since the extension wasn’t a randomized, controlled part of the trial), the best comparison to that is what happens when prednisone is stopped, he noted.

“And we did that experiment in part 1” of the trial, he said. Overall, 68% of patients in the prednisone/placebo groups flared in 1-year of follow-up, and most of those did so even before they stopped prednisone. In the group that received placebo plus a 52-week prednisone taper, 49% of patients flared and “every single one of those patients flared before they got off prednisone,” he said.

“So in that context, 2 years of treatment-free remission following weekly tocilizumab discontinuation seems very good,” he added.

Of the patients who flared in part 2 of the trial, 11 whose investigator elected to treat them with only tocilizumab reentered remission in a median of 15.8 days, 13 treated with tocilizumab and glucocorticoids reentered remission in a median of 8.5 days (1 didn’t reenter remission at all), and 15 treated with only glucocorticoids reentered remission in a median of 38 days.

“There are a number of biases in these data, but they do point out the fact that some patients can be treated with tocilizumab alone,” Dr. Stone said. “I would be very careful doing that.”

The trial was not powered for the comparison of weekly versus biweekly dosing, he said. However, “multiple lines of investigation and analysis support the idea that weekly tocilizumab is more effective at controlling disease,” he added. But “if you want to be assured that you are doing everything you can to control the disease, weekly tocilizumab would be better than every-other-week tocilizumab,” he said.

GiACTA was funded by Roche. Dr. Stone reported research grants from Roche/Genentech and consulting fees from Chugal, Roche/Genentech, and Xencor.

[email protected]

SOURCE: Stone J et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 808.

ATLANTA – The benefits of tocilizumab for giant cell arteritis (GCA), as demonstrated in the pivotal phase 3 GiACTA trial, proved durable in nearly half of the patients treated weekly during the trial, according to findings from a 2-year long-term extension period.

Of 250 patients treated in the double-blind portion of the trial, 215 entered the extension period (part 2 of the trial), and 197 (92%) completed all 3 years of the trial. A total of 38 of 81 (47%) extension participants in clinical remission (CR) at week 52 after receiving tocilizumab (Actemra) weekly maintained it throughout the extension, and 13 of 36 (36%) treated every other week maintained it, John Stone, MD, reported at the annual meeting of the American College of Rheumatology.

Notably, more of those 51 patients treated with tocilizumab who maintained CR throughout the extension were treatment free at the end of the extension, compared with those originally assigned to the placebo groups (65% vs. 45%), and their median time to first flare after stopping treatment was longer, said Dr. Stone, director of clinical rheumatology at Massachusetts General Hospital and associate professor of medicine in the division of rheumatology at Harvard Medical School, both in Boston.

For example, times to first flare were 575 and 428 days for the weekly and biweekly tocilizumab dosing groups – which each had 26-week prednisone tapering – but they were only 162 days in a placebo group with 26-week prednisone tapering and 295 days for patients in another placebo group with 52-week prednisone tapering, Dr. Stone explained. Retreatment with tocilizumab restored CR in patients who experienced flares after discontinuing treatment, he added.

Importantly, cumulative glucocorticoid doses over the 3 years were also lower in the tocilizumab groups (2,647 and 3,782 mg/day with weekly and biweekly tocilizumab and 5,248, and 5,323 mg/day in the placebo groups, respectively), Dr. Stone said.

No new safety signals were observed during the extension. Rates of serious adverse events (SAEs) and serious infections per 100 patient-years during the entire 3 years of the study were comparable among those who never received tocilizumab and those who received at least 1 dose (23.2 and 25.4 for SAEs and 4.6 and 3.5 for serious infections).
 

Detailed results of the extension period

GiACTA enrolled patients with GCA and randomized them to receive weekly or biweekly treatment with the interleukin-6 receptor–alpha inhibitor tocilizumab at doses of 162 mg delivered subcutaneously with a 26-week prednisone taper, or to the placebo groups with a 26- or 52-week prednisone taper. The results, reported in 2017, demonstrated the superiority of tocilizumab over placebo for providing sustained glucocorticoid-free remission and ultimately led to approval from Food and Drug Administration of the biologic agent for the treatment of GCA.

The current analysis was carried out to determine long-term safety, to explore maintenance of efficacy after discontinuation, and to “gain insight into the long-term glucocorticoid-sparing effects of tocilizumab,” Dr. Stone said.

He noted that the extension period was not randomized because of the way that patients in the “original four randomized groups had sorted themselves out into very different groups by virtue of their response in part 1 [of the trial],” which made randomization impossible because of the varying categories of patients.

Patients in the extension were also treated at investigators’ discretion to prevent “catastrophic GCA flares, vision loss, and other problems” that could potentially occur with discontinuation of the blinded injections in part 1, he said.

Nevertheless, the analysis “provides some incredibly important information about the management of GCA now,” he said, adding that the dramatic effect of the original randomization was still profound at 3 years “despite the fact that investigators could treat the patients as they wished.”

“Even at 3 years there was still a profound difference in the cumulative glucocorticoid [use], compared to those patients who were randomized to one of the placebo versus prednisone groups,” he explained.

However, the most important question from this study relates to what happened when weekly tocilizumab was stopped: Of the 81 patients in part 2 who were in CR on tocilizumab after part 1 of the study, 59 (73%) were not started on any treatment by their investigator, and of those, 25 (42%) maintained treatment-free remission for 2 full years following discontinuation of tocilizumab, he said.
 

What happened when prednisone was stopped?

In the absence of a direct comparison group (since the extension wasn’t a randomized, controlled part of the trial), the best comparison to that is what happens when prednisone is stopped, he noted.

“And we did that experiment in part 1” of the trial, he said. Overall, 68% of patients in the prednisone/placebo groups flared in 1-year of follow-up, and most of those did so even before they stopped prednisone. In the group that received placebo plus a 52-week prednisone taper, 49% of patients flared and “every single one of those patients flared before they got off prednisone,” he said.

“So in that context, 2 years of treatment-free remission following weekly tocilizumab discontinuation seems very good,” he added.

Of the patients who flared in part 2 of the trial, 11 whose investigator elected to treat them with only tocilizumab reentered remission in a median of 15.8 days, 13 treated with tocilizumab and glucocorticoids reentered remission in a median of 8.5 days (1 didn’t reenter remission at all), and 15 treated with only glucocorticoids reentered remission in a median of 38 days.

“There are a number of biases in these data, but they do point out the fact that some patients can be treated with tocilizumab alone,” Dr. Stone said. “I would be very careful doing that.”

The trial was not powered for the comparison of weekly versus biweekly dosing, he said. However, “multiple lines of investigation and analysis support the idea that weekly tocilizumab is more effective at controlling disease,” he added. But “if you want to be assured that you are doing everything you can to control the disease, weekly tocilizumab would be better than every-other-week tocilizumab,” he said.

GiACTA was funded by Roche. Dr. Stone reported research grants from Roche/Genentech and consulting fees from Chugal, Roche/Genentech, and Xencor.

[email protected]

SOURCE: Stone J et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 808.

ATLANTA – Black race was the single greatest predictor of cardiovascular disease (CVD) events in systemic lupus erythematosus, with black patients having an 18-fold higher risk than white patients from 2 years before to 8 years after diagnosis, according to a review of 336 patients in the Georgia Lupus Registry that was presented at the annual meeting of the American College of Rheumatology.

The greatest risk was in the first 2 years after diagnosis, which has been reported before in white patients, but not before in a mostly (75%) black cohort.

Lupus is known to strike earlier and be more aggressive in black patients, so “we were expecting racial disparities in incident CVD, but” the magnitude of the increased risk “was very surprising. This study [identifies] a population that needs more attention, more targeted CVD prevention. We have to intervene early and be on top of everything,” especially for black patients, said lead investigator Shivani Garg, MD, an assistant professor of rheumatology at the University of Wisconsin–Madison.

Lipids, blood pressure, and the other usual CVD risk factors, as well as lupus itself, have to be optimally controlled; glucocorticoid use limited as much as possible; and there needs to be improved adherence to hydroxychloroquine, which has been shown to reduce CVD events in lupus patients, she said in an interview.

The 336 patients, mostly women (87%) from the Atlanta area, were diagnosed during 2002-2004 at a mean age of 40 years. Dr. Garg and associates reviewed CVD events – ischemic heart disease, stroke, transient ischemic attack, and peripheral vascular disease – and death over 16 years, beginning 2 years before diagnosis.

About 22% of subjects had a CVD event, most commonly within 2 years after diagnosis. The risk was 500% higher in black patients overall (adjusted hazard ratio, 6.4; 95% confidence interval, 2.4-17.5; P = .0003), and markedly higher in the first 10 years (aHR, 18; 95% CI, 2.2-141; P less than .0001). The findings were not adjusted for socioeconomic factors.

In the first 12 years of the study, the mean age at lupus diagnosis was 46 years and the first CVD event occurred at an average of 48 years. From 12 to 16 years follow-up, the mean age of diagnosis was 38 years, and the first CVD event occurred at 52 years.

Age older than 65 years (aHR, 7.9; 95% CI, 2.2-29) and the presence of disease-associated antibodies (aHR, 2.1; 95% CI, 1.01-4.4) increased CVD risk, which wasn’t surprising, but another predictor – discoid lupus – was unexpected (aHR, 3.2; 95% CI, 1.5-6.8). “A lot of times, we’ve considered discoid rash to be a milder form, but these patients have some kind of chronic, smoldering inflammation that is leading to atherosclerosis,” Dr. Garg said.

At diagnosis, 84% of the subjects had lupus hematologic disorders, 69% immunologic disorders, and 14% a discoid rash. CVD risk factor data were not collected.

There was no external funding, and the investigators reported no disclosures.

[email protected]

SOURCE: Garg S et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 805.

ATLANTA – Black race was the single greatest predictor of cardiovascular disease (CVD) events in systemic lupus erythematosus, with black patients having an 18-fold higher risk than white patients from 2 years before to 8 years after diagnosis, according to a review of 336 patients in the Georgia Lupus Registry that was presented at the annual meeting of the American College of Rheumatology.

The greatest risk was in the first 2 years after diagnosis, which has been reported before in white patients, but not before in a mostly (75%) black cohort.

Lupus is known to strike earlier and be more aggressive in black patients, so “we were expecting racial disparities in incident CVD, but” the magnitude of the increased risk “was very surprising. This study [identifies] a population that needs more attention, more targeted CVD prevention. We have to intervene early and be on top of everything,” especially for black patients, said lead investigator Shivani Garg, MD, an assistant professor of rheumatology at the University of Wisconsin–Madison.

Lipids, blood pressure, and the other usual CVD risk factors, as well as lupus itself, have to be optimally controlled; glucocorticoid use limited as much as possible; and there needs to be improved adherence to hydroxychloroquine, which has been shown to reduce CVD events in lupus patients, she said in an interview.

The 336 patients, mostly women (87%) from the Atlanta area, were diagnosed during 2002-2004 at a mean age of 40 years. Dr. Garg and associates reviewed CVD events – ischemic heart disease, stroke, transient ischemic attack, and peripheral vascular disease – and death over 16 years, beginning 2 years before diagnosis.

About 22% of subjects had a CVD event, most commonly within 2 years after diagnosis. The risk was 500% higher in black patients overall (adjusted hazard ratio, 6.4; 95% confidence interval, 2.4-17.5; P = .0003), and markedly higher in the first 10 years (aHR, 18; 95% CI, 2.2-141; P less than .0001). The findings were not adjusted for socioeconomic factors.

In the first 12 years of the study, the mean age at lupus diagnosis was 46 years and the first CVD event occurred at an average of 48 years. From 12 to 16 years follow-up, the mean age of diagnosis was 38 years, and the first CVD event occurred at 52 years.

Age older than 65 years (aHR, 7.9; 95% CI, 2.2-29) and the presence of disease-associated antibodies (aHR, 2.1; 95% CI, 1.01-4.4) increased CVD risk, which wasn’t surprising, but another predictor – discoid lupus – was unexpected (aHR, 3.2; 95% CI, 1.5-6.8). “A lot of times, we’ve considered discoid rash to be a milder form, but these patients have some kind of chronic, smoldering inflammation that is leading to atherosclerosis,” Dr. Garg said.

At diagnosis, 84% of the subjects had lupus hematologic disorders, 69% immunologic disorders, and 14% a discoid rash. CVD risk factor data were not collected.

There was no external funding, and the investigators reported no disclosures.

[email protected]

SOURCE: Garg S et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 805.

ATLANTA – Black race was the single greatest predictor of cardiovascular disease (CVD) events in systemic lupus erythematosus, with black patients having an 18-fold higher risk than white patients from 2 years before to 8 years after diagnosis, according to a review of 336 patients in the Georgia Lupus Registry that was presented at the annual meeting of the American College of Rheumatology.

The greatest risk was in the first 2 years after diagnosis, which has been reported before in white patients, but not before in a mostly (75%) black cohort.

Lupus is known to strike earlier and be more aggressive in black patients, so “we were expecting racial disparities in incident CVD, but” the magnitude of the increased risk “was very surprising. This study [identifies] a population that needs more attention, more targeted CVD prevention. We have to intervene early and be on top of everything,” especially for black patients, said lead investigator Shivani Garg, MD, an assistant professor of rheumatology at the University of Wisconsin–Madison.

Lipids, blood pressure, and the other usual CVD risk factors, as well as lupus itself, have to be optimally controlled; glucocorticoid use limited as much as possible; and there needs to be improved adherence to hydroxychloroquine, which has been shown to reduce CVD events in lupus patients, she said in an interview.

The 336 patients, mostly women (87%) from the Atlanta area, were diagnosed during 2002-2004 at a mean age of 40 years. Dr. Garg and associates reviewed CVD events – ischemic heart disease, stroke, transient ischemic attack, and peripheral vascular disease – and death over 16 years, beginning 2 years before diagnosis.

About 22% of subjects had a CVD event, most commonly within 2 years after diagnosis. The risk was 500% higher in black patients overall (adjusted hazard ratio, 6.4; 95% confidence interval, 2.4-17.5; P = .0003), and markedly higher in the first 10 years (aHR, 18; 95% CI, 2.2-141; P less than .0001). The findings were not adjusted for socioeconomic factors.

In the first 12 years of the study, the mean age at lupus diagnosis was 46 years and the first CVD event occurred at an average of 48 years. From 12 to 16 years follow-up, the mean age of diagnosis was 38 years, and the first CVD event occurred at 52 years.

Age older than 65 years (aHR, 7.9; 95% CI, 2.2-29) and the presence of disease-associated antibodies (aHR, 2.1; 95% CI, 1.01-4.4) increased CVD risk, which wasn’t surprising, but another predictor – discoid lupus – was unexpected (aHR, 3.2; 95% CI, 1.5-6.8). “A lot of times, we’ve considered discoid rash to be a milder form, but these patients have some kind of chronic, smoldering inflammation that is leading to atherosclerosis,” Dr. Garg said.

At diagnosis, 84% of the subjects had lupus hematologic disorders, 69% immunologic disorders, and 14% a discoid rash. CVD risk factor data were not collected.

There was no external funding, and the investigators reported no disclosures.

[email protected]

SOURCE: Garg S et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 805.

The European League Against Rheumatism has released its first recommendations for the management of Sjögren’s syndrome with topical and systemic treatments.

First author Manuel Ramos-Casals, MD, PhD, of Hospital Clinic de Barcelona Institut Clinic de Medicina i Dermatologia and colleagues on the multinational, multispecialty EULAR Sjögren Syndrome Task Force Group said the EULAR recommendations “synthesize current thinking” of management for Sjögren’s syndrome, which is complicated by individualized treatment that does not address the systemic disease and for which therapeutic decisions are often made based on expert opinion and personal experience because of a lack of data.

“Sjögren’s syndrome is generally treated through symptom management,” noted Sara McCoy, MD, who is director of the University of Wisconsin Health Sjögren’s Syndrome Clinic and was not involved in the recommendations, which were published in Annals of the Rheumatic Diseases. “Although we have measures to address these symptoms, we do not have any approved therapy that ameliorates the driving cause.”

There is limited high-quality evidence for many of the therapies discussed in the recommendations: In total, 9 randomized controlled trials, 18 prospective studies, and 5 case-control studies were included as evidence in the recommendations, and many involved a small number of patients.

The first overarching recommendation says that patients with Sjögren’s syndrome should be managed at centers of expertise using a multidisciplinary approach, the authors wrote. Two other overarching recommendations focus on how to manage certain patient cases. In cases of dryness, first-line therapy should include topical therapies for symptomatic relief, while clinicians should consider systemic therapies for patients with active systemic disease. All three overarching recommendations had a high level of agreement among task force members.

The task force also offered 12 specific recommendations on disease management, which take an “algorithmic approach” to Sjögren’s syndrome management that is guided by the EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI), Dr. McCoy said in an interview.

“The EULAR recommendations structure a clear approach to treatment of Sjögren’s manifestations, ranging from oral and ocular sicca management, to treatment of uncommon but severe systemic involvement of Sjögren’s,” she said.

Before treating patients for oral dryness symptoms, clinicians should evaluate salivary function at baseline using unstimulated whole salivary flows. First-line therapeutic approaches for oral dryness can include nonpharmacologic stimulation in cases of mild salivary gland dysfunction, pharmacologic stimulation in cases of moderate dysfunction, and substitution of saliva in cases of severe dysfunction, the authors said.

Ocular dryness should be assessed using ocular staining score followed by ocular surface–disease index, and once identified, it can be managed with artificial tears and ocular gels or ointments as first-line therapy. Topical immunosuppressive-containing drops and autologous serum eye drops are options for more severe or refractory ocular dryness.

Patients who have fatigue or pain associated with Sjögren’s syndrome should have their fatigue or pain scored with the EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI), and any concomitant disease should also be evaluated. Clinicians should consider acetaminophen and NSAIDs for treatment of acute musculoskeletal pain and other pain-modifying agents, such as hydroxychloroquine in cases of articular pain, despite a lack of evidence showing its efficacy in trials.

For systemic disease, the task force advised matching treatment to the organ(s) involved and using the ESSDAI to evaluate disease severity., They said that “patients presenting with at least moderate activity in one clinical domain, or with a global moderate disease activity score” of 5 or higher can be considered for systemic therapy.

Although many clinicians use glucocorticoids (GCs) for managing Sjögren’s syndrome, there is no evidence of the treatment’s efficacy in systemic disease. The task force recommended using glucocorticoids such as methylprednisolone at the minimum dose and withdrawing use “as soon as possible” in patients with inactive disease. “Based on the potential development of chronic damage in patients with uncontrolled systemic disease, some patients may require long-term therapy with GCs, especially those with severe organ impairments,” Dr. Ramos-Casals and colleagues wrote. “In these patients, the addition of immunosuppressive agents as GC-sparing agents is justified, always weighing the potential benefits and risks.” Because of a lack of head-to-head studies of different immunosuppressive agents, the task force did not recommend one particular agent over another.

One recommendation that contained a high level of evidence was for the use of B-cell targeted therapies for patients with severe, refractory systemic disease. Efficacy of rituximab was mixed in studies totaling more than 400 patients, but generally showed a positive outcome in at least one of the following areas: global response, organ-specific response, ESSDAI reduction, and prednisone reduction. The task force recommended that rituximab “may be considered” in “patients with severe, refractory systemic disease” and may be best for those with symptoms linked to cryoglobulinemic-associated vasculitis, with the potential of using belimumab (Benlysta) as rescue therapy. While systemic organ-specific therapeutic approaches vary, the general rule should be to treat with GCs first, followed by immunosuppressive agents and biologics as second-line therapy in cases refractory to GCs, either sequentially or in combination, the authors said.

For patients with B-cell lymphoma, clinicians should use individualized treatment based on the World Health Organization 2016 histologic subtype and the stage of the disease. While some clinicians employ a “watchful waiting” approach to treating low-grade hematologic neoplasia, “the decision to treat low-grade lymphomas or not must be discussed in a multidisciplinary committee, taking into account the fact that they are linked to the disease activity and are the ultimate stage of autoimmune B-cell activation,” the authors wrote.

The task force also defined a number of future research agenda goals for Sjögren’s syndrome treatment management, including developing personalized therapeutic approaches, finding predictors of biological response to agents used in treatment, and identifying biomarkers of poor outcomes.

In addition, EULAR acknowledged some research gaps exist in the guidelines for particular symptoms of Sjögren’s syndrome, such as in the case of fatigue. “The EULAR recommendations mention the common association of fatigue with Sjögren’s syndrome, though acknowledge that fatigue is more commonly seen in the same demographic cohort as Sjögren’s,” Dr. McCoy said. “Aside from exercise, there remains little available to address this common and burdensome symptom amongst Sjögren’s patients. Overall, this is a pertinent gap in knowledge in our Sjögren’s patients.”

The Sjögren’s syndrome recommendations were funded by EULAR. Many task force members reported relationships with industry in the form of advisory board and speaker’s bureau memberships, consultancies, and grants. Dr. McCoy reported serving on a data monitoring committee for Bristol-Myers Squibb unrelated to the data in the EULAR recommendations.

SOURCE: Ramos-Casals M et al. Ann Rheum Dis. 2019 Oct 31. doi: 10.1136/annrheumdis-2019-216114

The European League Against Rheumatism has released its first recommendations for the management of Sjögren’s syndrome with topical and systemic treatments.

First author Manuel Ramos-Casals, MD, PhD, of Hospital Clinic de Barcelona Institut Clinic de Medicina i Dermatologia and colleagues on the multinational, multispecialty EULAR Sjögren Syndrome Task Force Group said the EULAR recommendations “synthesize current thinking” of management for Sjögren’s syndrome, which is complicated by individualized treatment that does not address the systemic disease and for which therapeutic decisions are often made based on expert opinion and personal experience because of a lack of data.

“Sjögren’s syndrome is generally treated through symptom management,” noted Sara McCoy, MD, who is director of the University of Wisconsin Health Sjögren’s Syndrome Clinic and was not involved in the recommendations, which were published in Annals of the Rheumatic Diseases. “Although we have measures to address these symptoms, we do not have any approved therapy that ameliorates the driving cause.”

There is limited high-quality evidence for many of the therapies discussed in the recommendations: In total, 9 randomized controlled trials, 18 prospective studies, and 5 case-control studies were included as evidence in the recommendations, and many involved a small number of patients.

The first overarching recommendation says that patients with Sjögren’s syndrome should be managed at centers of expertise using a multidisciplinary approach, the authors wrote. Two other overarching recommendations focus on how to manage certain patient cases. In cases of dryness, first-line therapy should include topical therapies for symptomatic relief, while clinicians should consider systemic therapies for patients with active systemic disease. All three overarching recommendations had a high level of agreement among task force members.

The task force also offered 12 specific recommendations on disease management, which take an “algorithmic approach” to Sjögren’s syndrome management that is guided by the EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI), Dr. McCoy said in an interview.

“The EULAR recommendations structure a clear approach to treatment of Sjögren’s manifestations, ranging from oral and ocular sicca management, to treatment of uncommon but severe systemic involvement of Sjögren’s,” she said.

Before treating patients for oral dryness symptoms, clinicians should evaluate salivary function at baseline using unstimulated whole salivary flows. First-line therapeutic approaches for oral dryness can include nonpharmacologic stimulation in cases of mild salivary gland dysfunction, pharmacologic stimulation in cases of moderate dysfunction, and substitution of saliva in cases of severe dysfunction, the authors said.

Ocular dryness should be assessed using ocular staining score followed by ocular surface–disease index, and once identified, it can be managed with artificial tears and ocular gels or ointments as first-line therapy. Topical immunosuppressive-containing drops and autologous serum eye drops are options for more severe or refractory ocular dryness.

Patients who have fatigue or pain associated with Sjögren’s syndrome should have their fatigue or pain scored with the EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI), and any concomitant disease should also be evaluated. Clinicians should consider acetaminophen and NSAIDs for treatment of acute musculoskeletal pain and other pain-modifying agents, such as hydroxychloroquine in cases of articular pain, despite a lack of evidence showing its efficacy in trials.

For systemic disease, the task force advised matching treatment to the organ(s) involved and using the ESSDAI to evaluate disease severity., They said that “patients presenting with at least moderate activity in one clinical domain, or with a global moderate disease activity score” of 5 or higher can be considered for systemic therapy.

Although many clinicians use glucocorticoids (GCs) for managing Sjögren’s syndrome, there is no evidence of the treatment’s efficacy in systemic disease. The task force recommended using glucocorticoids such as methylprednisolone at the minimum dose and withdrawing use “as soon as possible” in patients with inactive disease. “Based on the potential development of chronic damage in patients with uncontrolled systemic disease, some patients may require long-term therapy with GCs, especially those with severe organ impairments,” Dr. Ramos-Casals and colleagues wrote. “In these patients, the addition of immunosuppressive agents as GC-sparing agents is justified, always weighing the potential benefits and risks.” Because of a lack of head-to-head studies of different immunosuppressive agents, the task force did not recommend one particular agent over another.

One recommendation that contained a high level of evidence was for the use of B-cell targeted therapies for patients with severe, refractory systemic disease. Efficacy of rituximab was mixed in studies totaling more than 400 patients, but generally showed a positive outcome in at least one of the following areas: global response, organ-specific response, ESSDAI reduction, and prednisone reduction. The task force recommended that rituximab “may be considered” in “patients with severe, refractory systemic disease” and may be best for those with symptoms linked to cryoglobulinemic-associated vasculitis, with the potential of using belimumab (Benlysta) as rescue therapy. While systemic organ-specific therapeutic approaches vary, the general rule should be to treat with GCs first, followed by immunosuppressive agents and biologics as second-line therapy in cases refractory to GCs, either sequentially or in combination, the authors said.

For patients with B-cell lymphoma, clinicians should use individualized treatment based on the World Health Organization 2016 histologic subtype and the stage of the disease. While some clinicians employ a “watchful waiting” approach to treating low-grade hematologic neoplasia, “the decision to treat low-grade lymphomas or not must be discussed in a multidisciplinary committee, taking into account the fact that they are linked to the disease activity and are the ultimate stage of autoimmune B-cell activation,” the authors wrote.

The task force also defined a number of future research agenda goals for Sjögren’s syndrome treatment management, including developing personalized therapeutic approaches, finding predictors of biological response to agents used in treatment, and identifying biomarkers of poor outcomes.

In addition, EULAR acknowledged some research gaps exist in the guidelines for particular symptoms of Sjögren’s syndrome, such as in the case of fatigue. “The EULAR recommendations mention the common association of fatigue with Sjögren’s syndrome, though acknowledge that fatigue is more commonly seen in the same demographic cohort as Sjögren’s,” Dr. McCoy said. “Aside from exercise, there remains little available to address this common and burdensome symptom amongst Sjögren’s patients. Overall, this is a pertinent gap in knowledge in our Sjögren’s patients.”

The Sjögren’s syndrome recommendations were funded by EULAR. Many task force members reported relationships with industry in the form of advisory board and speaker’s bureau memberships, consultancies, and grants. Dr. McCoy reported serving on a data monitoring committee for Bristol-Myers Squibb unrelated to the data in the EULAR recommendations.

SOURCE: Ramos-Casals M et al. Ann Rheum Dis. 2019 Oct 31. doi: 10.1136/annrheumdis-2019-216114

The European League Against Rheumatism has released its first recommendations for the management of Sjögren’s syndrome with topical and systemic treatments.

First author Manuel Ramos-Casals, MD, PhD, of Hospital Clinic de Barcelona Institut Clinic de Medicina i Dermatologia and colleagues on the multinational, multispecialty EULAR Sjögren Syndrome Task Force Group said the EULAR recommendations “synthesize current thinking” of management for Sjögren’s syndrome, which is complicated by individualized treatment that does not address the systemic disease and for which therapeutic decisions are often made based on expert opinion and personal experience because of a lack of data.

“Sjögren’s syndrome is generally treated through symptom management,” noted Sara McCoy, MD, who is director of the University of Wisconsin Health Sjögren’s Syndrome Clinic and was not involved in the recommendations, which were published in Annals of the Rheumatic Diseases. “Although we have measures to address these symptoms, we do not have any approved therapy that ameliorates the driving cause.”

There is limited high-quality evidence for many of the therapies discussed in the recommendations: In total, 9 randomized controlled trials, 18 prospective studies, and 5 case-control studies were included as evidence in the recommendations, and many involved a small number of patients.

The first overarching recommendation says that patients with Sjögren’s syndrome should be managed at centers of expertise using a multidisciplinary approach, the authors wrote. Two other overarching recommendations focus on how to manage certain patient cases. In cases of dryness, first-line therapy should include topical therapies for symptomatic relief, while clinicians should consider systemic therapies for patients with active systemic disease. All three overarching recommendations had a high level of agreement among task force members.

The task force also offered 12 specific recommendations on disease management, which take an “algorithmic approach” to Sjögren’s syndrome management that is guided by the EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI), Dr. McCoy said in an interview.

“The EULAR recommendations structure a clear approach to treatment of Sjögren’s manifestations, ranging from oral and ocular sicca management, to treatment of uncommon but severe systemic involvement of Sjögren’s,” she said.

Before treating patients for oral dryness symptoms, clinicians should evaluate salivary function at baseline using unstimulated whole salivary flows. First-line therapeutic approaches for oral dryness can include nonpharmacologic stimulation in cases of mild salivary gland dysfunction, pharmacologic stimulation in cases of moderate dysfunction, and substitution of saliva in cases of severe dysfunction, the authors said.

Ocular dryness should be assessed using ocular staining score followed by ocular surface–disease index, and once identified, it can be managed with artificial tears and ocular gels or ointments as first-line therapy. Topical immunosuppressive-containing drops and autologous serum eye drops are options for more severe or refractory ocular dryness.

Patients who have fatigue or pain associated with Sjögren’s syndrome should have their fatigue or pain scored with the EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI), and any concomitant disease should also be evaluated. Clinicians should consider acetaminophen and NSAIDs for treatment of acute musculoskeletal pain and other pain-modifying agents, such as hydroxychloroquine in cases of articular pain, despite a lack of evidence showing its efficacy in trials.

For systemic disease, the task force advised matching treatment to the organ(s) involved and using the ESSDAI to evaluate disease severity., They said that “patients presenting with at least moderate activity in one clinical domain, or with a global moderate disease activity score” of 5 or higher can be considered for systemic therapy.

Although many clinicians use glucocorticoids (GCs) for managing Sjögren’s syndrome, there is no evidence of the treatment’s efficacy in systemic disease. The task force recommended using glucocorticoids such as methylprednisolone at the minimum dose and withdrawing use “as soon as possible” in patients with inactive disease. “Based on the potential development of chronic damage in patients with uncontrolled systemic disease, some patients may require long-term therapy with GCs, especially those with severe organ impairments,” Dr. Ramos-Casals and colleagues wrote. “In these patients, the addition of immunosuppressive agents as GC-sparing agents is justified, always weighing the potential benefits and risks.” Because of a lack of head-to-head studies of different immunosuppressive agents, the task force did not recommend one particular agent over another.

One recommendation that contained a high level of evidence was for the use of B-cell targeted therapies for patients with severe, refractory systemic disease. Efficacy of rituximab was mixed in studies totaling more than 400 patients, but generally showed a positive outcome in at least one of the following areas: global response, organ-specific response, ESSDAI reduction, and prednisone reduction. The task force recommended that rituximab “may be considered” in “patients with severe, refractory systemic disease” and may be best for those with symptoms linked to cryoglobulinemic-associated vasculitis, with the potential of using belimumab (Benlysta) as rescue therapy. While systemic organ-specific therapeutic approaches vary, the general rule should be to treat with GCs first, followed by immunosuppressive agents and biologics as second-line therapy in cases refractory to GCs, either sequentially or in combination, the authors said.

For patients with B-cell lymphoma, clinicians should use individualized treatment based on the World Health Organization 2016 histologic subtype and the stage of the disease. While some clinicians employ a “watchful waiting” approach to treating low-grade hematologic neoplasia, “the decision to treat low-grade lymphomas or not must be discussed in a multidisciplinary committee, taking into account the fact that they are linked to the disease activity and are the ultimate stage of autoimmune B-cell activation,” the authors wrote.

The task force also defined a number of future research agenda goals for Sjögren’s syndrome treatment management, including developing personalized therapeutic approaches, finding predictors of biological response to agents used in treatment, and identifying biomarkers of poor outcomes.

In addition, EULAR acknowledged some research gaps exist in the guidelines for particular symptoms of Sjögren’s syndrome, such as in the case of fatigue. “The EULAR recommendations mention the common association of fatigue with Sjögren’s syndrome, though acknowledge that fatigue is more commonly seen in the same demographic cohort as Sjögren’s,” Dr. McCoy said. “Aside from exercise, there remains little available to address this common and burdensome symptom amongst Sjögren’s patients. Overall, this is a pertinent gap in knowledge in our Sjögren’s patients.”

The Sjögren’s syndrome recommendations were funded by EULAR. Many task force members reported relationships with industry in the form of advisory board and speaker’s bureau memberships, consultancies, and grants. Dr. McCoy reported serving on a data monitoring committee for Bristol-Myers Squibb unrelated to the data in the EULAR recommendations.

SOURCE: Ramos-Casals M et al. Ann Rheum Dis. 2019 Oct 31. doi: 10.1136/annrheumdis-2019-216114

A computer-based, self-administered test for cognitive impairment could be used to screen for cognitive impairment in adults with systemic lupus erythematosus, new research suggests.

In a paper published in Arthritis Care & Research, researchers assessed the validity of the Automated Neuropsychological Assessment Metrics (ANAM) test in 211 adult patients with systemic lupus erythematosus (SLE).

First author Oshrat E. Tayer-Shifman, MD, of the University of Toronto Lupus Clinic and coauthors wrote that current assessment of cognitive impairment in adults with SLE is done using the American College of Rheumatology neuropsychological battery (ACR-NB). However, this approach involves protected tests that require specialized personnel and takes around 1 hour to administer, as well as time for scoring and interpretation.

“For many clinics, these are notable barriers to accessing CI [cognitive impairment] assessment, as health care payers do not cover these costs,” the investigators wrote. And although briefer cognitive screening tools, such as the Montreal Cognitive Assessment, the Controlled Oral Word Association Test, and the Hopkins Verbal Learning Test–Revised, have been examined in studies of patients with SLE, “they also require specialized personnel for administration and interpretation and cannot be self-administered. In addition, their validity for the screening for CI in SLE has not been well established. Thus, there is an unmet need for a screening assessment for CI that is validated for SLE and that can be applied in an ambulatory clinic setting without specialized personnel.”

The full ANAM battery requires about 40 minutes and has been used to screen cognitive performance in a range of clinical contexts.

A total of 96 patients (46%) had CI and 52 (25%) did not, according to the ACR-NB, while the results were indeterminate in the remaining 63 (30%).

The study showed that patients without CI performed significantly better on the majority of the ANAM subtests in comparison with patients who have cognitive impairment. This was particularly evident on mean reaction time and the number of correct responses per minute (a measure of cognitive efficiency), but less so for percentage of correct responses and consistency of response speed.

“Three of the most affected cognitive domains in the CI patients in this cohort, as well as in previous studies, were learning and memory, visual spatial construction, and simple attention and speed of processing,” the researchers wrote.

The investigators created testing models using the subtests that were most discriminative for CI. The two best models included one encompassing the percentage of correct responses, consistency of response speed, and mean reaction time, as well as one encompassing these three factors as well as the number of correct responses per minute. The investigators then derived candidate ANAM composite indices from these two models. For one composite index that used 8 of the 15 ANAM subtests and included five of the six cognitive domains tested on the ACR-NB, a high and a low cutoff value gave an area under the curve of 79%, sensitivity of 80%-89%, specificity of 54%-70%, positive predictive value of 78%-83%, and negative predictive value of 65%-74%.

The composite index performed similarly well among patients with or without neuropsychiatric lupus.

“This approach not only enables us to use a cost-effective screening approach without specialized personnel, but we have reduced the duration of the ANAM battery itself. The ANAM [version 4 General Neuropsychological Screening] full battery requires approximately 40 minutes to administer, while our analyses enable us to limit the number of ANAM subtests used, shortening the testing duration to 20 minutes,” they wrote.

The investigators noted that the study included only individuals with sufficient English language ability to complete the tests, and they also excluded patients with indeterminate cognitive status. “We reasoned that they represented a nonhomogeneous group, and without a clear consensus on the definition of CI in SLE patients, we chose to concentrate on the more clearly defined CI SLE patients.”

The study was supported by grants from the Arthritis Society of Canada, Physician’s Services, the Kathi and Peter Kaiser Family, and the Lou and Marissa Rocca Family. One author was supported by the Arthritis Society and the Canadian Rheumatology Association. No conflicts of interest were declared.

SOURCE: Tayer-Shifman OE et al. Arthritis Care Res. 2019 Oct 18. doi: 10.1002/acr.24096.

A computer-based, self-administered test for cognitive impairment could be used to screen for cognitive impairment in adults with systemic lupus erythematosus, new research suggests.

In a paper published in Arthritis Care & Research, researchers assessed the validity of the Automated Neuropsychological Assessment Metrics (ANAM) test in 211 adult patients with systemic lupus erythematosus (SLE).

First author Oshrat E. Tayer-Shifman, MD, of the University of Toronto Lupus Clinic and coauthors wrote that current assessment of cognitive impairment in adults with SLE is done using the American College of Rheumatology neuropsychological battery (ACR-NB). However, this approach involves protected tests that require specialized personnel and takes around 1 hour to administer, as well as time for scoring and interpretation.

“For many clinics, these are notable barriers to accessing CI [cognitive impairment] assessment, as health care payers do not cover these costs,” the investigators wrote. And although briefer cognitive screening tools, such as the Montreal Cognitive Assessment, the Controlled Oral Word Association Test, and the Hopkins Verbal Learning Test–Revised, have been examined in studies of patients with SLE, “they also require specialized personnel for administration and interpretation and cannot be self-administered. In addition, their validity for the screening for CI in SLE has not been well established. Thus, there is an unmet need for a screening assessment for CI that is validated for SLE and that can be applied in an ambulatory clinic setting without specialized personnel.”

The full ANAM battery requires about 40 minutes and has been used to screen cognitive performance in a range of clinical contexts.

A total of 96 patients (46%) had CI and 52 (25%) did not, according to the ACR-NB, while the results were indeterminate in the remaining 63 (30%).

The study showed that patients without CI performed significantly better on the majority of the ANAM subtests in comparison with patients who have cognitive impairment. This was particularly evident on mean reaction time and the number of correct responses per minute (a measure of cognitive efficiency), but less so for percentage of correct responses and consistency of response speed.

“Three of the most affected cognitive domains in the CI patients in this cohort, as well as in previous studies, were learning and memory, visual spatial construction, and simple attention and speed of processing,” the researchers wrote.

The investigators created testing models using the subtests that were most discriminative for CI. The two best models included one encompassing the percentage of correct responses, consistency of response speed, and mean reaction time, as well as one encompassing these three factors as well as the number of correct responses per minute. The investigators then derived candidate ANAM composite indices from these two models. For one composite index that used 8 of the 15 ANAM subtests and included five of the six cognitive domains tested on the ACR-NB, a high and a low cutoff value gave an area under the curve of 79%, sensitivity of 80%-89%, specificity of 54%-70%, positive predictive value of 78%-83%, and negative predictive value of 65%-74%.

The composite index performed similarly well among patients with or without neuropsychiatric lupus.

“This approach not only enables us to use a cost-effective screening approach without specialized personnel, but we have reduced the duration of the ANAM battery itself. The ANAM [version 4 General Neuropsychological Screening] full battery requires approximately 40 minutes to administer, while our analyses enable us to limit the number of ANAM subtests used, shortening the testing duration to 20 minutes,” they wrote.

The investigators noted that the study included only individuals with sufficient English language ability to complete the tests, and they also excluded patients with indeterminate cognitive status. “We reasoned that they represented a nonhomogeneous group, and without a clear consensus on the definition of CI in SLE patients, we chose to concentrate on the more clearly defined CI SLE patients.”

The study was supported by grants from the Arthritis Society of Canada, Physician’s Services, the Kathi and Peter Kaiser Family, and the Lou and Marissa Rocca Family. One author was supported by the Arthritis Society and the Canadian Rheumatology Association. No conflicts of interest were declared.

SOURCE: Tayer-Shifman OE et al. Arthritis Care Res. 2019 Oct 18. doi: 10.1002/acr.24096.

A computer-based, self-administered test for cognitive impairment could be used to screen for cognitive impairment in adults with systemic lupus erythematosus, new research suggests.

In a paper published in Arthritis Care & Research, researchers assessed the validity of the Automated Neuropsychological Assessment Metrics (ANAM) test in 211 adult patients with systemic lupus erythematosus (SLE).

First author Oshrat E. Tayer-Shifman, MD, of the University of Toronto Lupus Clinic and coauthors wrote that current assessment of cognitive impairment in adults with SLE is done using the American College of Rheumatology neuropsychological battery (ACR-NB). However, this approach involves protected tests that require specialized personnel and takes around 1 hour to administer, as well as time for scoring and interpretation.

“For many clinics, these are notable barriers to accessing CI [cognitive impairment] assessment, as health care payers do not cover these costs,” the investigators wrote. And although briefer cognitive screening tools, such as the Montreal Cognitive Assessment, the Controlled Oral Word Association Test, and the Hopkins Verbal Learning Test–Revised, have been examined in studies of patients with SLE, “they also require specialized personnel for administration and interpretation and cannot be self-administered. In addition, their validity for the screening for CI in SLE has not been well established. Thus, there is an unmet need for a screening assessment for CI that is validated for SLE and that can be applied in an ambulatory clinic setting without specialized personnel.”

The full ANAM battery requires about 40 minutes and has been used to screen cognitive performance in a range of clinical contexts.

A total of 96 patients (46%) had CI and 52 (25%) did not, according to the ACR-NB, while the results were indeterminate in the remaining 63 (30%).

The study showed that patients without CI performed significantly better on the majority of the ANAM subtests in comparison with patients who have cognitive impairment. This was particularly evident on mean reaction time and the number of correct responses per minute (a measure of cognitive efficiency), but less so for percentage of correct responses and consistency of response speed.

“Three of the most affected cognitive domains in the CI patients in this cohort, as well as in previous studies, were learning and memory, visual spatial construction, and simple attention and speed of processing,” the researchers wrote.

The investigators created testing models using the subtests that were most discriminative for CI. The two best models included one encompassing the percentage of correct responses, consistency of response speed, and mean reaction time, as well as one encompassing these three factors as well as the number of correct responses per minute. The investigators then derived candidate ANAM composite indices from these two models. For one composite index that used 8 of the 15 ANAM subtests and included five of the six cognitive domains tested on the ACR-NB, a high and a low cutoff value gave an area under the curve of 79%, sensitivity of 80%-89%, specificity of 54%-70%, positive predictive value of 78%-83%, and negative predictive value of 65%-74%.

The composite index performed similarly well among patients with or without neuropsychiatric lupus.

“This approach not only enables us to use a cost-effective screening approach without specialized personnel, but we have reduced the duration of the ANAM battery itself. The ANAM [version 4 General Neuropsychological Screening] full battery requires approximately 40 minutes to administer, while our analyses enable us to limit the number of ANAM subtests used, shortening the testing duration to 20 minutes,” they wrote.

The investigators noted that the study included only individuals with sufficient English language ability to complete the tests, and they also excluded patients with indeterminate cognitive status. “We reasoned that they represented a nonhomogeneous group, and without a clear consensus on the definition of CI in SLE patients, we chose to concentrate on the more clearly defined CI SLE patients.”

The study was supported by grants from the Arthritis Society of Canada, Physician’s Services, the Kathi and Peter Kaiser Family, and the Lou and Marissa Rocca Family. One author was supported by the Arthritis Society and the Canadian Rheumatology Association. No conflicts of interest were declared.

SOURCE: Tayer-Shifman OE et al. Arthritis Care Res. 2019 Oct 18. doi: 10.1002/acr.24096.

While the symptoms of Takayasu’s and giant cell arteritis do not differ greatly, they are associated with different imaging findings of vascular inflammation and luminal damage, a retrospective cohort study has found.

“Clinical symptoms were not sensitive markers of underlying vascular pathology but were specific when present,” Despina Michailidou, MD, PhD, and colleagues wrote in Annals of the Rheumatic Diseases. “Vascular imaging should be considered in the management of these patients since reliance on the presence of clinical symptoms may not be sensitive to detect vascular pathology within an acceptable window to prevent or minimize damage.”

Dr. Michailidou and coauthors in the Systemic Autoimmunity Branch of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) examined the relationships between clinical presentation and imaging findings in 110 patients involved in an ongoing observational cohort study at the National Institutes of Health, including 56 with Takayasu’s arteritis (TAK) and 54 with giant cell arteritis (GCA). The study included data from 270 visits. Dr. Michailidou conducted the study while she was a research fellow at NIAMS, and she is now a rheumatology fellow at the University of Washington, Seattle.

The team looked at 11 symptoms (lightheadedness, positional lightheadedness, carotidynia, arm claudication vertigo, frontotemporal and posterior headache, posterior neck pain, blurred vision, vision loss, and major CNS events, including stroke, transient ischemic attack, or syncope). These were related to findings on MR angiography (MRA) and 18F-fluorodeoxyglucose PET (FDG-PET).

There were no significant between-group differences in six of the symptoms. However, those with TAK had significantly higher rates of carotidynia (21% vs. 0%), lightheadedness (30% vs. 9%), positional lightheadedness (29% vs. 5%), major CNS events (25% vs. 9%), and arm claudication (52% vs. 28%). Arm claudication was the most common symptom in those with TAK (52%), and blurred vision the most common in patients with GCA (37%).

On the day of evaluation, 8% of patients with TAK reported carotidynia; none of the GCA patients reported this. On FDG-PET, carotidynia was more strongly associated with inflammation of the carotid artery than with damage of the carotid artery on MRA.

The sensitivity of this association was low, which indicates “that an absence of carotidynia could still be associated with imaging abnormalities in the carotid artery, particularly on MRA compared with FDG-PET,” the authors wrote. But specificity was high for both FDG-PET and MRA, suggesting that carotidynia was strongly associated with corresponding carotid artery abnormalities on both FDG-PET and MRA.

More of those with GCA than those with TAK reported posterior neck pain (18% vs. 7%). It was significantly associated with vertebral artery inflammation in those with GCA, but not in those with TAK. There was no significant association with vertebral artery damage in either group.

While sensitivity was low for posterior neck pain and imaging abnormalities, specificity was very high in both groups, which indicates “the presence of posterior neck pain was strongly associated with corresponding vertebral artery abnormalities on both FDG-PET and MRA.”

Posterior headache was present in 5% of GCA patients and was significantly associated with vertebral artery damage, but it was not associated with such damage in patients with TAK.

“While posterior headaches in the occipital region are uncommon in patients with GCA, this study emphasizes that presence of a posterior headache should alert the clinician to the likelihood of associated vascular inflammation and damage in the corresponding vertebral artery,” the researchers wrote.

About 6% of patients with TAK and 10% of those with GCA reported frontotemporal headache. The headache was not associated with carotid PET activity or damage in either group of patients.

“While frontotemporal headaches frequently occur in patients with TAK, and are a cardinal feature of GCA, headaches in this region may reflect inflammation in smaller branches of cranial arteries, rather than the corresponding larger arteries of the neck,” the investigators wrote.

Arm claudication was the most commonly reported symptom overall, present in 52% of those with TAK and 28% of those with GCA. It was more strongly associated with subclavian artery damage on MRA than with inflammation on FDG-PET.

The investigators also assessed the association between specific clinical symptoms and the number of affected neck arteries. Patients with large vessel vasculitis and an increased number of damaged neck arteries on MRA were significantly more likely to experience lightheadedness (odds ratio, 2.61), positional lightheadedness (OR, 3.51), or a major CNS event (OR, 3.23). But those with large vessel vasculitis and inflamed neck arteries on FDG-PET were more likely to experience posterior headache (OR, 2.84).

The study isn’t intended to dictate how MRA and FDG-PET should be employed with these patients, the authors noted.

“Rather, these findings may help clinicians predict imaging pathology in specific vascular territories based on patient-reported symptoms and may inform which type of imaging modality would be the most useful to obtain in certain clinical scenarios, recognizing that additional sequences to detect wall morphology may augment the ability of MR-based assessments to detect vascular inflammation in addition to luminal damage.”

The Division of Intramural Research at NIAMS funded the research. The authors had no financial disclosures.

[email protected]

SOURCE: Michailidou D et al. Ann Rheum Dis. 2019 Oct 24. doi: 10.1136/annrheumdis-2019-216145.

While the symptoms of Takayasu’s and giant cell arteritis do not differ greatly, they are associated with different imaging findings of vascular inflammation and luminal damage, a retrospective cohort study has found.

“Clinical symptoms were not sensitive markers of underlying vascular pathology but were specific when present,” Despina Michailidou, MD, PhD, and colleagues wrote in Annals of the Rheumatic Diseases. “Vascular imaging should be considered in the management of these patients since reliance on the presence of clinical symptoms may not be sensitive to detect vascular pathology within an acceptable window to prevent or minimize damage.”

Dr. Michailidou and coauthors in the Systemic Autoimmunity Branch of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) examined the relationships between clinical presentation and imaging findings in 110 patients involved in an ongoing observational cohort study at the National Institutes of Health, including 56 with Takayasu’s arteritis (TAK) and 54 with giant cell arteritis (GCA). The study included data from 270 visits. Dr. Michailidou conducted the study while she was a research fellow at NIAMS, and she is now a rheumatology fellow at the University of Washington, Seattle.

The team looked at 11 symptoms (lightheadedness, positional lightheadedness, carotidynia, arm claudication vertigo, frontotemporal and posterior headache, posterior neck pain, blurred vision, vision loss, and major CNS events, including stroke, transient ischemic attack, or syncope). These were related to findings on MR angiography (MRA) and 18F-fluorodeoxyglucose PET (FDG-PET).

There were no significant between-group differences in six of the symptoms. However, those with TAK had significantly higher rates of carotidynia (21% vs. 0%), lightheadedness (30% vs. 9%), positional lightheadedness (29% vs. 5%), major CNS events (25% vs. 9%), and arm claudication (52% vs. 28%). Arm claudication was the most common symptom in those with TAK (52%), and blurred vision the most common in patients with GCA (37%).

On the day of evaluation, 8% of patients with TAK reported carotidynia; none of the GCA patients reported this. On FDG-PET, carotidynia was more strongly associated with inflammation of the carotid artery than with damage of the carotid artery on MRA.

The sensitivity of this association was low, which indicates “that an absence of carotidynia could still be associated with imaging abnormalities in the carotid artery, particularly on MRA compared with FDG-PET,” the authors wrote. But specificity was high for both FDG-PET and MRA, suggesting that carotidynia was strongly associated with corresponding carotid artery abnormalities on both FDG-PET and MRA.

More of those with GCA than those with TAK reported posterior neck pain (18% vs. 7%). It was significantly associated with vertebral artery inflammation in those with GCA, but not in those with TAK. There was no significant association with vertebral artery damage in either group.

While sensitivity was low for posterior neck pain and imaging abnormalities, specificity was very high in both groups, which indicates “the presence of posterior neck pain was strongly associated with corresponding vertebral artery abnormalities on both FDG-PET and MRA.”

Posterior headache was present in 5% of GCA patients and was significantly associated with vertebral artery damage, but it was not associated with such damage in patients with TAK.

“While posterior headaches in the occipital region are uncommon in patients with GCA, this study emphasizes that presence of a posterior headache should alert the clinician to the likelihood of associated vascular inflammation and damage in the corresponding vertebral artery,” the researchers wrote.

About 6% of patients with TAK and 10% of those with GCA reported frontotemporal headache. The headache was not associated with carotid PET activity or damage in either group of patients.

“While frontotemporal headaches frequently occur in patients with TAK, and are a cardinal feature of GCA, headaches in this region may reflect inflammation in smaller branches of cranial arteries, rather than the corresponding larger arteries of the neck,” the investigators wrote.

Arm claudication was the most commonly reported symptom overall, present in 52% of those with TAK and 28% of those with GCA. It was more strongly associated with subclavian artery damage on MRA than with inflammation on FDG-PET.

The investigators also assessed the association between specific clinical symptoms and the number of affected neck arteries. Patients with large vessel vasculitis and an increased number of damaged neck arteries on MRA were significantly more likely to experience lightheadedness (odds ratio, 2.61), positional lightheadedness (OR, 3.51), or a major CNS event (OR, 3.23). But those with large vessel vasculitis and inflamed neck arteries on FDG-PET were more likely to experience posterior headache (OR, 2.84).

The study isn’t intended to dictate how MRA and FDG-PET should be employed with these patients, the authors noted.

“Rather, these findings may help clinicians predict imaging pathology in specific vascular territories based on patient-reported symptoms and may inform which type of imaging modality would be the most useful to obtain in certain clinical scenarios, recognizing that additional sequences to detect wall morphology may augment the ability of MR-based assessments to detect vascular inflammation in addition to luminal damage.”

The Division of Intramural Research at NIAMS funded the research. The authors had no financial disclosures.

[email protected]

SOURCE: Michailidou D et al. Ann Rheum Dis. 2019 Oct 24. doi: 10.1136/annrheumdis-2019-216145.

While the symptoms of Takayasu’s and giant cell arteritis do not differ greatly, they are associated with different imaging findings of vascular inflammation and luminal damage, a retrospective cohort study has found.

“Clinical symptoms were not sensitive markers of underlying vascular pathology but were specific when present,” Despina Michailidou, MD, PhD, and colleagues wrote in Annals of the Rheumatic Diseases. “Vascular imaging should be considered in the management of these patients since reliance on the presence of clinical symptoms may not be sensitive to detect vascular pathology within an acceptable window to prevent or minimize damage.”

Dr. Michailidou and coauthors in the Systemic Autoimmunity Branch of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) examined the relationships between clinical presentation and imaging findings in 110 patients involved in an ongoing observational cohort study at the National Institutes of Health, including 56 with Takayasu’s arteritis (TAK) and 54 with giant cell arteritis (GCA). The study included data from 270 visits. Dr. Michailidou conducted the study while she was a research fellow at NIAMS, and she is now a rheumatology fellow at the University of Washington, Seattle.

The team looked at 11 symptoms (lightheadedness, positional lightheadedness, carotidynia, arm claudication vertigo, frontotemporal and posterior headache, posterior neck pain, blurred vision, vision loss, and major CNS events, including stroke, transient ischemic attack, or syncope). These were related to findings on MR angiography (MRA) and 18F-fluorodeoxyglucose PET (FDG-PET).

There were no significant between-group differences in six of the symptoms. However, those with TAK had significantly higher rates of carotidynia (21% vs. 0%), lightheadedness (30% vs. 9%), positional lightheadedness (29% vs. 5%), major CNS events (25% vs. 9%), and arm claudication (52% vs. 28%). Arm claudication was the most common symptom in those with TAK (52%), and blurred vision the most common in patients with GCA (37%).

On the day of evaluation, 8% of patients with TAK reported carotidynia; none of the GCA patients reported this. On FDG-PET, carotidynia was more strongly associated with inflammation of the carotid artery than with damage of the carotid artery on MRA.

The sensitivity of this association was low, which indicates “that an absence of carotidynia could still be associated with imaging abnormalities in the carotid artery, particularly on MRA compared with FDG-PET,” the authors wrote. But specificity was high for both FDG-PET and MRA, suggesting that carotidynia was strongly associated with corresponding carotid artery abnormalities on both FDG-PET and MRA.

More of those with GCA than those with TAK reported posterior neck pain (18% vs. 7%). It was significantly associated with vertebral artery inflammation in those with GCA, but not in those with TAK. There was no significant association with vertebral artery damage in either group.

While sensitivity was low for posterior neck pain and imaging abnormalities, specificity was very high in both groups, which indicates “the presence of posterior neck pain was strongly associated with corresponding vertebral artery abnormalities on both FDG-PET and MRA.”

Posterior headache was present in 5% of GCA patients and was significantly associated with vertebral artery damage, but it was not associated with such damage in patients with TAK.

“While posterior headaches in the occipital region are uncommon in patients with GCA, this study emphasizes that presence of a posterior headache should alert the clinician to the likelihood of associated vascular inflammation and damage in the corresponding vertebral artery,” the researchers wrote.

About 6% of patients with TAK and 10% of those with GCA reported frontotemporal headache. The headache was not associated with carotid PET activity or damage in either group of patients.

“While frontotemporal headaches frequently occur in patients with TAK, and are a cardinal feature of GCA, headaches in this region may reflect inflammation in smaller branches of cranial arteries, rather than the corresponding larger arteries of the neck,” the investigators wrote.

Arm claudication was the most commonly reported symptom overall, present in 52% of those with TAK and 28% of those with GCA. It was more strongly associated with subclavian artery damage on MRA than with inflammation on FDG-PET.

The investigators also assessed the association between specific clinical symptoms and the number of affected neck arteries. Patients with large vessel vasculitis and an increased number of damaged neck arteries on MRA were significantly more likely to experience lightheadedness (odds ratio, 2.61), positional lightheadedness (OR, 3.51), or a major CNS event (OR, 3.23). But those with large vessel vasculitis and inflamed neck arteries on FDG-PET were more likely to experience posterior headache (OR, 2.84).

The study isn’t intended to dictate how MRA and FDG-PET should be employed with these patients, the authors noted.

“Rather, these findings may help clinicians predict imaging pathology in specific vascular territories based on patient-reported symptoms and may inform which type of imaging modality would be the most useful to obtain in certain clinical scenarios, recognizing that additional sequences to detect wall morphology may augment the ability of MR-based assessments to detect vascular inflammation in addition to luminal damage.”

The Division of Intramural Research at NIAMS funded the research. The authors had no financial disclosures.

[email protected]

SOURCE: Michailidou D et al. Ann Rheum Dis. 2019 Oct 24. doi: 10.1136/annrheumdis-2019-216145.

NEW ORLEANS – Real-world data support the use of macitentan to treat pulmonary arterial hypertension (PAH) associated with connective tissue disease, according to a speaker at the annual meeting of the American College of Chest Physicians.

Jen Smith/MDedge News

Outcomes of macitentan (Opsumit) treatment were similar in patients who had PAH associated with systemic sclerosis (PAH-SSc) and patients who had idiopathic PAH (IPAH) or heritable PAH (HPAH), Vallerie McLaughlin, MD, of the University of Michigan, Ann Arbor, said at the meeting.

“Within the limits of a real-world registry, these data add to the growing body of evidence supporting the use of macitentan for treatment in patients with CTD [connective tissue disease],” Dr. McLaughlin said.

She and her colleagues evaluated data from the prospective OPUS registry (NCT02126943) and the retrospective OrPHeUS study (NCT03197688), both of which included patients who were newly started on macitentan.

Dr. McLaughlin presented data on 2,311 patients with IPAH/HPAH and 668 patients with PAH-SSc. She also presented data on patients with PAH-systemic lupus erythematosus and PAH-mixed CTD, but numbers in these groups were small, and outcomes were similar to those in the PAH-SSc group.

Demographic and disease characteristics at the start of macitentan were similar between the IPAH/HPAH and PAH-SSc groups. The median age was 64 years in both groups. The median time from PAH diagnosis was 7.6 months in the IPAH/HPAH group and 8.5 months in the PAH-SSc group.

The median duration of macitentan exposure was 13.4 months in the IPAH/HPAH group and 14.4 months in the PAH-SSc group. The proportion of patients receiving macitentan in combination with other therapies (double or triple combinations) increased from baseline to 6 months in both groups.

Hepatic adverse events occurred in 7.4% of IPAH/HPAH patients and 7.9% of PAH-SSc patients. The most common adverse events among the IPAH/HPAH and PAH-SSc groups in the OPUS registry alone were dyspnea (19% and 26.1%, respectively), peripheral edema (9.8% and 12.4%), fatigue (6.8% and 11.7%), anemia (6.7% and 11.7%), headache (10.2% and 11%), and dizziness (6.7% and 10.7%).

About 39% of patients in both groups discontinued macitentan. Similar proportions in each group discontinued because of adverse events (17% in the IPAH/HPAH group and 18.3% in the PAH-SSc group) and hepatic adverse events (0.2% and 0.7%, respectively).

The proportion of patients with at least one hospitalization was 36.2% in the IPAH/HPAH group and 40.1% in the PAH-SSc group.

The 12-month Kaplan-Meier survival estimate was 92.9% in the IPAH/HPAH group and 91.3% in the PAH-SSc group. The 24-month estimated survival rate was 85.6% and 82.1%, respectively.

The OPUS registry and OrPHeUS study are sponsored by Actelion. Dr. McLaughlin disclosed relationships with Actelion, Acceleron, Bayer, Caremark, CiVi Biopharma, Reata, Sonovie, and United Therapeutics.

[email protected]

SOURCE: McLaughlin V et al. CHEST 2019. Abstract, doi: 10.1016/j.chest.2019.08.827.

NEW ORLEANS – Real-world data support the use of macitentan to treat pulmonary arterial hypertension (PAH) associated with connective tissue disease, according to a speaker at the annual meeting of the American College of Chest Physicians.

Jen Smith/MDedge News

Outcomes of macitentan (Opsumit) treatment were similar in patients who had PAH associated with systemic sclerosis (PAH-SSc) and patients who had idiopathic PAH (IPAH) or heritable PAH (HPAH), Vallerie McLaughlin, MD, of the University of Michigan, Ann Arbor, said at the meeting.

“Within the limits of a real-world registry, these data add to the growing body of evidence supporting the use of macitentan for treatment in patients with CTD [connective tissue disease],” Dr. McLaughlin said.

She and her colleagues evaluated data from the prospective OPUS registry (NCT02126943) and the retrospective OrPHeUS study (NCT03197688), both of which included patients who were newly started on macitentan.

Dr. McLaughlin presented data on 2,311 patients with IPAH/HPAH and 668 patients with PAH-SSc. She also presented data on patients with PAH-systemic lupus erythematosus and PAH-mixed CTD, but numbers in these groups were small, and outcomes were similar to those in the PAH-SSc group.

Demographic and disease characteristics at the start of macitentan were similar between the IPAH/HPAH and PAH-SSc groups. The median age was 64 years in both groups. The median time from PAH diagnosis was 7.6 months in the IPAH/HPAH group and 8.5 months in the PAH-SSc group.

The median duration of macitentan exposure was 13.4 months in the IPAH/HPAH group and 14.4 months in the PAH-SSc group. The proportion of patients receiving macitentan in combination with other therapies (double or triple combinations) increased from baseline to 6 months in both groups.

Hepatic adverse events occurred in 7.4% of IPAH/HPAH patients and 7.9% of PAH-SSc patients. The most common adverse events among the IPAH/HPAH and PAH-SSc groups in the OPUS registry alone were dyspnea (19% and 26.1%, respectively), peripheral edema (9.8% and 12.4%), fatigue (6.8% and 11.7%), anemia (6.7% and 11.7%), headache (10.2% and 11%), and dizziness (6.7% and 10.7%).

About 39% of patients in both groups discontinued macitentan. Similar proportions in each group discontinued because of adverse events (17% in the IPAH/HPAH group and 18.3% in the PAH-SSc group) and hepatic adverse events (0.2% and 0.7%, respectively).

The proportion of patients with at least one hospitalization was 36.2% in the IPAH/HPAH group and 40.1% in the PAH-SSc group.

The 12-month Kaplan-Meier survival estimate was 92.9% in the IPAH/HPAH group and 91.3% in the PAH-SSc group. The 24-month estimated survival rate was 85.6% and 82.1%, respectively.

The OPUS registry and OrPHeUS study are sponsored by Actelion. Dr. McLaughlin disclosed relationships with Actelion, Acceleron, Bayer, Caremark, CiVi Biopharma, Reata, Sonovie, and United Therapeutics.

[email protected]

SOURCE: McLaughlin V et al. CHEST 2019. Abstract, doi: 10.1016/j.chest.2019.08.827.

NEW ORLEANS – Real-world data support the use of macitentan to treat pulmonary arterial hypertension (PAH) associated with connective tissue disease, according to a speaker at the annual meeting of the American College of Chest Physicians.

Jen Smith/MDedge News

Outcomes of macitentan (Opsumit) treatment were similar in patients who had PAH associated with systemic sclerosis (PAH-SSc) and patients who had idiopathic PAH (IPAH) or heritable PAH (HPAH), Vallerie McLaughlin, MD, of the University of Michigan, Ann Arbor, said at the meeting.

“Within the limits of a real-world registry, these data add to the growing body of evidence supporting the use of macitentan for treatment in patients with CTD [connective tissue disease],” Dr. McLaughlin said.

She and her colleagues evaluated data from the prospective OPUS registry (NCT02126943) and the retrospective OrPHeUS study (NCT03197688), both of which included patients who were newly started on macitentan.

Dr. McLaughlin presented data on 2,311 patients with IPAH/HPAH and 668 patients with PAH-SSc. She also presented data on patients with PAH-systemic lupus erythematosus and PAH-mixed CTD, but numbers in these groups were small, and outcomes were similar to those in the PAH-SSc group.

Demographic and disease characteristics at the start of macitentan were similar between the IPAH/HPAH and PAH-SSc groups. The median age was 64 years in both groups. The median time from PAH diagnosis was 7.6 months in the IPAH/HPAH group and 8.5 months in the PAH-SSc group.

The median duration of macitentan exposure was 13.4 months in the IPAH/HPAH group and 14.4 months in the PAH-SSc group. The proportion of patients receiving macitentan in combination with other therapies (double or triple combinations) increased from baseline to 6 months in both groups.

Hepatic adverse events occurred in 7.4% of IPAH/HPAH patients and 7.9% of PAH-SSc patients. The most common adverse events among the IPAH/HPAH and PAH-SSc groups in the OPUS registry alone were dyspnea (19% and 26.1%, respectively), peripheral edema (9.8% and 12.4%), fatigue (6.8% and 11.7%), anemia (6.7% and 11.7%), headache (10.2% and 11%), and dizziness (6.7% and 10.7%).

About 39% of patients in both groups discontinued macitentan. Similar proportions in each group discontinued because of adverse events (17% in the IPAH/HPAH group and 18.3% in the PAH-SSc group) and hepatic adverse events (0.2% and 0.7%, respectively).

The proportion of patients with at least one hospitalization was 36.2% in the IPAH/HPAH group and 40.1% in the PAH-SSc group.

The 12-month Kaplan-Meier survival estimate was 92.9% in the IPAH/HPAH group and 91.3% in the PAH-SSc group. The 24-month estimated survival rate was 85.6% and 82.1%, respectively.

The OPUS registry and OrPHeUS study are sponsored by Actelion. Dr. McLaughlin disclosed relationships with Actelion, Acceleron, Bayer, Caremark, CiVi Biopharma, Reata, Sonovie, and United Therapeutics.

[email protected]

SOURCE: McLaughlin V et al. CHEST 2019. Abstract, doi: 10.1016/j.chest.2019.08.827.