Leflunomide added to glucocorticoids reduces relapse in IgG4-related disease

MADRID – The addition of leflunomide to standard glucocorticoids (GCs) in the treatment of IgG4-related disease increases the median duration of response, reduces the proportion of patients with relapse within 12 months, and permits GCs to be tapered, according to results of a randomized trial presented at the European Congress of Rheumatology.

“The rate of adverse events with the addition of leflunomide was numerically higher, but there were no significant differences in risks of any specific adverse event,” reported Feng Huang, MD, of the department of rheumatology at Chinese People’s Liberation Army General Hospital in Beijing.

GCs are highly effective in IgG4-related disease, which is an autoimmune process driven by elevated concentrations of the antibody IgG4 in the tissue of affected organs and in the serum. It has been described in a broad array of sites, including the heart, lung, kidneys, and meninges. It has been widely recognized only in the last 10 years, according to Dr. Huang. Although most patients respond to GCs, he said the problem is that about 50% of patients relapse within 12 months and more than 90% within 3 years.

This randomized, controlled study was conducted after positive results were observed with leflunomide in a small, uncontrolled pilot study published several years ago (Intern Med J. 2017 Jun;47[6]:680-9. doi: 10.1111/imj.13430). In this randomized trial, the objectives were to confirm that leflunomide extends the relapse-free period and has acceptable safety relative to GC alone.

Patients with confirmed IgG4-related disease were enrolled. Patients randomized to GC were started on 0.5 to 0.8 mg/kg per day. A predefined taper regimen was employed in those with symptom control. Those randomized to the experimental arm received GC in the same dose and schedule plus 20 mg/day of leflunomide.

The 33 patients in each group were well matched at baseline for age, comorbidities, and disease severity.

At the end of 12 months, 50% of those treated with GC alone versus 21.2% of those treated with GC plus leflunomide had relapse. That translated into a significantly higher hazard ratio (HR) for relapse in the GC monotherapy group (HR, 1.75; P = .034).

The mean duration of remission was 7 months on the combination versus 3 months on GC alone. Dr. Huang also reported a significantly higher proportion of complete responses in the group receiving the combination.

In addition, “more patients on the combination therapy were able to adhere to the steroid-tapering schedule without relapse,” Dr. Huang reported. The rate of 54.5% of patients on combination therapy who were able to reach a daily GC dose of 5 mg/day or less proved significantly higher than the 18.2% rate seen with GC alone (P = .002).


Adverse events were reported by 54% of those on the combination versus 42% of those on monotherapy, but this difference did not reach statistical significance. The biggest differences in adverse events were the proportions of patients with infections (18.2% vs. 12.1%) and elevated liver enzymes (12.1% vs. 3.0%), both of which were more common in the combination therapy group. Neither of these differences was statistically significant.

Of patients with relapses, the most common organs involved were the salivary gland, the pancreas, and the bile ducts, each accounting for relapse in five patients. Other organs in which relapse occurred included the lacrimal gland and the skin. There were three cases of relapse characterized by retroperitoneal fibrosis.

Over the course of follow-up, new-onset diabetes mellitus occurred in 21.2% and 27.3% of the combination and GC-only groups, respectively. This difference also did not reach statistical significance.

Although this study was small with an open-label design, Dr. Huang said the data strongly suggest that a combination of leflunomide and GC is superior to GC alone. Based on these results, he said a starting dose of 20 mg/day of leflunomide is a reasonable standard in this setting.

Dr. Huang and colleagues reported no potential conflicts of interest.

SOURCE: Wang Y et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):157. Abstract OPO164, doi: 10.1136/annrheumdis-2019-eular.5717

MADRID – The addition of leflunomide to standard glucocorticoids (GCs) in the treatment of IgG4-related disease increases the median duration of response, reduces the proportion of patients with relapse within 12 months, and permits GCs to be tapered, according to results of a randomized trial presented at the European Congress of Rheumatology.

“The rate of adverse events with the addition of leflunomide was numerically higher, but there were no significant differences in risks of any specific adverse event,” reported Feng Huang, MD, of the department of rheumatology at Chinese People’s Liberation Army General Hospital in Beijing.

GCs are highly effective in IgG4-related disease, which is an autoimmune process driven by elevated concentrations of the antibody IgG4 in the tissue of affected organs and in the serum. It has been described in a broad array of sites, including the heart, lung, kidneys, and meninges. It has been widely recognized only in the last 10 years, according to Dr. Huang. Although most patients respond to GCs, he said the problem is that about 50% of patients relapse within 12 months and more than 90% within 3 years.

This randomized, controlled study was conducted after positive results were observed with leflunomide in a small, uncontrolled pilot study published several years ago (Intern Med J. 2017 Jun;47[6]:680-9. doi: 10.1111/imj.13430). In this randomized trial, the objectives were to confirm that leflunomide extends the relapse-free period and has acceptable safety relative to GC alone.

Patients with confirmed IgG4-related disease were enrolled. Patients randomized to GC were started on 0.5 to 0.8 mg/kg per day. A predefined taper regimen was employed in those with symptom control. Those randomized to the experimental arm received GC in the same dose and schedule plus 20 mg/day of leflunomide.

The 33 patients in each group were well matched at baseline for age, comorbidities, and disease severity.

At the end of 12 months, 50% of those treated with GC alone versus 21.2% of those treated with GC plus leflunomide had relapse. That translated into a significantly higher hazard ratio (HR) for relapse in the GC monotherapy group (HR, 1.75; P = .034).

The mean duration of remission was 7 months on the combination versus 3 months on GC alone. Dr. Huang also reported a significantly higher proportion of complete responses in the group receiving the combination.

In addition, “more patients on the combination therapy were able to adhere to the steroid-tapering schedule without relapse,” Dr. Huang reported. The rate of 54.5% of patients on combination therapy who were able to reach a daily GC dose of 5 mg/day or less proved significantly higher than the 18.2% rate seen with GC alone (P = .002).


Adverse events were reported by 54% of those on the combination versus 42% of those on monotherapy, but this difference did not reach statistical significance. The biggest differences in adverse events were the proportions of patients with infections (18.2% vs. 12.1%) and elevated liver enzymes (12.1% vs. 3.0%), both of which were more common in the combination therapy group. Neither of these differences was statistically significant.

Of patients with relapses, the most common organs involved were the salivary gland, the pancreas, and the bile ducts, each accounting for relapse in five patients. Other organs in which relapse occurred included the lacrimal gland and the skin. There were three cases of relapse characterized by retroperitoneal fibrosis.

Over the course of follow-up, new-onset diabetes mellitus occurred in 21.2% and 27.3% of the combination and GC-only groups, respectively. This difference also did not reach statistical significance.

Although this study was small with an open-label design, Dr. Huang said the data strongly suggest that a combination of leflunomide and GC is superior to GC alone. Based on these results, he said a starting dose of 20 mg/day of leflunomide is a reasonable standard in this setting.

Dr. Huang and colleagues reported no potential conflicts of interest.

SOURCE: Wang Y et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):157. Abstract OPO164, doi: 10.1136/annrheumdis-2019-eular.5717

MADRID – The addition of leflunomide to standard glucocorticoids (GCs) in the treatment of IgG4-related disease increases the median duration of response, reduces the proportion of patients with relapse within 12 months, and permits GCs to be tapered, according to results of a randomized trial presented at the European Congress of Rheumatology.

“The rate of adverse events with the addition of leflunomide was numerically higher, but there were no significant differences in risks of any specific adverse event,” reported Feng Huang, MD, of the department of rheumatology at Chinese People’s Liberation Army General Hospital in Beijing.

GCs are highly effective in IgG4-related disease, which is an autoimmune process driven by elevated concentrations of the antibody IgG4 in the tissue of affected organs and in the serum. It has been described in a broad array of sites, including the heart, lung, kidneys, and meninges. It has been widely recognized only in the last 10 years, according to Dr. Huang. Although most patients respond to GCs, he said the problem is that about 50% of patients relapse within 12 months and more than 90% within 3 years.

This randomized, controlled study was conducted after positive results were observed with leflunomide in a small, uncontrolled pilot study published several years ago (Intern Med J. 2017 Jun;47[6]:680-9. doi: 10.1111/imj.13430). In this randomized trial, the objectives were to confirm that leflunomide extends the relapse-free period and has acceptable safety relative to GC alone.

Patients with confirmed IgG4-related disease were enrolled. Patients randomized to GC were started on 0.5 to 0.8 mg/kg per day. A predefined taper regimen was employed in those with symptom control. Those randomized to the experimental arm received GC in the same dose and schedule plus 20 mg/day of leflunomide.

The 33 patients in each group were well matched at baseline for age, comorbidities, and disease severity.

At the end of 12 months, 50% of those treated with GC alone versus 21.2% of those treated with GC plus leflunomide had relapse. That translated into a significantly higher hazard ratio (HR) for relapse in the GC monotherapy group (HR, 1.75; P = .034).

The mean duration of remission was 7 months on the combination versus 3 months on GC alone. Dr. Huang also reported a significantly higher proportion of complete responses in the group receiving the combination.

In addition, “more patients on the combination therapy were able to adhere to the steroid-tapering schedule without relapse,” Dr. Huang reported. The rate of 54.5% of patients on combination therapy who were able to reach a daily GC dose of 5 mg/day or less proved significantly higher than the 18.2% rate seen with GC alone (P = .002).


Adverse events were reported by 54% of those on the combination versus 42% of those on monotherapy, but this difference did not reach statistical significance. The biggest differences in adverse events were the proportions of patients with infections (18.2% vs. 12.1%) and elevated liver enzymes (12.1% vs. 3.0%), both of which were more common in the combination therapy group. Neither of these differences was statistically significant.

Of patients with relapses, the most common organs involved were the salivary gland, the pancreas, and the bile ducts, each accounting for relapse in five patients. Other organs in which relapse occurred included the lacrimal gland and the skin. There were three cases of relapse characterized by retroperitoneal fibrosis.

Over the course of follow-up, new-onset diabetes mellitus occurred in 21.2% and 27.3% of the combination and GC-only groups, respectively. This difference also did not reach statistical significance.

Although this study was small with an open-label design, Dr. Huang said the data strongly suggest that a combination of leflunomide and GC is superior to GC alone. Based on these results, he said a starting dose of 20 mg/day of leflunomide is a reasonable standard in this setting.

Dr. Huang and colleagues reported no potential conflicts of interest.

SOURCE: Wang Y et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):157. Abstract OPO164, doi: 10.1136/annrheumdis-2019-eular.5717