Genetic variant could dictate rituximab response in lupus

It is well known that not everyone with SLE will respond well to rituximab, but that some will, first author Md Yuzaiful Md Yusof, MBChB, PhD, explained in an interview at the European Congress of Rheumatology.

Although data from clinical trials with rituximab in this patient setting have been essentially negative, the methodology of those trials has since been disputed, he observed. Indeed, subsequent data (Ann Rheum Dis. 2017;76:1829-36) have suggested that as many as 80% of patients could achieve a response with rituximab, particularly if there is complete B-cell depletion.

Previous researchers (Ann Rheum Dis. 2012;71:875-7) have shown that a polymorphism (158V) in the Fc gamma receptor IIIA (FCGR3A) gene is associated with the response to rituximab-based therapy in patients with rheumatoid arthritis (RA). This gene is important for antibody-dependent cellular-mediated cytotoxicity (ADCC).

The objective of the current study – an observational, prospective, longitudinal cohort study conducted in Leeds (England) – was therefore to see if the FCGR3A-158V polymorphism might influence response in patients with SLE.

“We were trying to find pretreatment biomarkers that could predict response to rituximab in SLE,” Dr. Md Yusof explained.

For the study, 85 patients who were treated with rituximab were assessed. The cohort was predominantly female (96%), with a mean age of 40 years. All of the patients had antinuclear antibodies, with just over half having anti–double-stranded DNA antibodies, and two-thirds having extractable nuclear antigens. One-third had low complement (C3/C4) levels.

Complete B-cell depletion occurred in 63% of patients with the FCGR3A-158V allele, a significantly higher rate than the 40% observed among those with 158 FF genotype (odds ratio, 2.73; P = .041). A significantly higher percentage of patients with the FCGR3A-158V allele also achieved a major BILAG (British Isles Lupus Assessment Group) response when compared against patients with the 158 FF variant (48% vs. 23%), with an odds ratio of 3.06 (P = .033).

Rituximab’s effect on NK cell-mediated B-cell killing may have played a key role in treatment response. Carrying the FCGR3A-158V allele was associated with greater degranulation activity versus the 158 FF variant.

Lastly, patients were more likely to remain on treatment with rituximab over a 10-year period if they had the FCGR3A-158V allele, compared with the 158 FF variant.

“These data suggest one mechanism by which patients with SLE might become resistant to the effects of rituximab, and could be used to guide therapy in the future,” Dr. Md Yusof suggested.

“Once this finding is validated, the clinical implication is that this genetic testing could be done prior to rituximab to identify those who will respond to therapy,” he postulated. “People with SLE who have this genetic variant with high affinity for rituximab are the ones that are better suited for rituximab therapy,” he added, otherwise a different CD20-directed antibody or alternative B-cell blockade therapies should be used.

The U.K. National Institute for Health Research funded the study. Dr. Md Yusof had no conflicts of interest to disclose; some coauthors disclosed ties to Roche, GlaxoSmithKline, and AstraZeneca, among other companies.

SOURCE: Md Yusof MY et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):1069-70. Abstract SAT0009, doi: 10.1136/annrheumdis-2019-eular.6919.

It is well known that not everyone with SLE will respond well to rituximab, but that some will, first author Md Yuzaiful Md Yusof, MBChB, PhD, explained in an interview at the European Congress of Rheumatology.

Although data from clinical trials with rituximab in this patient setting have been essentially negative, the methodology of those trials has since been disputed, he observed. Indeed, subsequent data (Ann Rheum Dis. 2017;76:1829-36) have suggested that as many as 80% of patients could achieve a response with rituximab, particularly if there is complete B-cell depletion.

Previous researchers (Ann Rheum Dis. 2012;71:875-7) have shown that a polymorphism (158V) in the Fc gamma receptor IIIA (FCGR3A) gene is associated with the response to rituximab-based therapy in patients with rheumatoid arthritis (RA). This gene is important for antibody-dependent cellular-mediated cytotoxicity (ADCC).

The objective of the current study – an observational, prospective, longitudinal cohort study conducted in Leeds (England) – was therefore to see if the FCGR3A-158V polymorphism might influence response in patients with SLE.

“We were trying to find pretreatment biomarkers that could predict response to rituximab in SLE,” Dr. Md Yusof explained.

For the study, 85 patients who were treated with rituximab were assessed. The cohort was predominantly female (96%), with a mean age of 40 years. All of the patients had antinuclear antibodies, with just over half having anti–double-stranded DNA antibodies, and two-thirds having extractable nuclear antigens. One-third had low complement (C3/C4) levels.

Complete B-cell depletion occurred in 63% of patients with the FCGR3A-158V allele, a significantly higher rate than the 40% observed among those with 158 FF genotype (odds ratio, 2.73; P = .041). A significantly higher percentage of patients with the FCGR3A-158V allele also achieved a major BILAG (British Isles Lupus Assessment Group) response when compared against patients with the 158 FF variant (48% vs. 23%), with an odds ratio of 3.06 (P = .033).

Rituximab’s effect on NK cell-mediated B-cell killing may have played a key role in treatment response. Carrying the FCGR3A-158V allele was associated with greater degranulation activity versus the 158 FF variant.

Lastly, patients were more likely to remain on treatment with rituximab over a 10-year period if they had the FCGR3A-158V allele, compared with the 158 FF variant.

“These data suggest one mechanism by which patients with SLE might become resistant to the effects of rituximab, and could be used to guide therapy in the future,” Dr. Md Yusof suggested.

“Once this finding is validated, the clinical implication is that this genetic testing could be done prior to rituximab to identify those who will respond to therapy,” he postulated. “People with SLE who have this genetic variant with high affinity for rituximab are the ones that are better suited for rituximab therapy,” he added, otherwise a different CD20-directed antibody or alternative B-cell blockade therapies should be used.

The U.K. National Institute for Health Research funded the study. Dr. Md Yusof had no conflicts of interest to disclose; some coauthors disclosed ties to Roche, GlaxoSmithKline, and AstraZeneca, among other companies.

SOURCE: Md Yusof MY et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):1069-70. Abstract SAT0009, doi: 10.1136/annrheumdis-2019-eular.6919.

It is well known that not everyone with SLE will respond well to rituximab, but that some will, first author Md Yuzaiful Md Yusof, MBChB, PhD, explained in an interview at the European Congress of Rheumatology.

Although data from clinical trials with rituximab in this patient setting have been essentially negative, the methodology of those trials has since been disputed, he observed. Indeed, subsequent data (Ann Rheum Dis. 2017;76:1829-36) have suggested that as many as 80% of patients could achieve a response with rituximab, particularly if there is complete B-cell depletion.

Previous researchers (Ann Rheum Dis. 2012;71:875-7) have shown that a polymorphism (158V) in the Fc gamma receptor IIIA (FCGR3A) gene is associated with the response to rituximab-based therapy in patients with rheumatoid arthritis (RA). This gene is important for antibody-dependent cellular-mediated cytotoxicity (ADCC).

The objective of the current study – an observational, prospective, longitudinal cohort study conducted in Leeds (England) – was therefore to see if the FCGR3A-158V polymorphism might influence response in patients with SLE.

“We were trying to find pretreatment biomarkers that could predict response to rituximab in SLE,” Dr. Md Yusof explained.

For the study, 85 patients who were treated with rituximab were assessed. The cohort was predominantly female (96%), with a mean age of 40 years. All of the patients had antinuclear antibodies, with just over half having anti–double-stranded DNA antibodies, and two-thirds having extractable nuclear antigens. One-third had low complement (C3/C4) levels.

Complete B-cell depletion occurred in 63% of patients with the FCGR3A-158V allele, a significantly higher rate than the 40% observed among those with 158 FF genotype (odds ratio, 2.73; P = .041). A significantly higher percentage of patients with the FCGR3A-158V allele also achieved a major BILAG (British Isles Lupus Assessment Group) response when compared against patients with the 158 FF variant (48% vs. 23%), with an odds ratio of 3.06 (P = .033).

Rituximab’s effect on NK cell-mediated B-cell killing may have played a key role in treatment response. Carrying the FCGR3A-158V allele was associated with greater degranulation activity versus the 158 FF variant.

Lastly, patients were more likely to remain on treatment with rituximab over a 10-year period if they had the FCGR3A-158V allele, compared with the 158 FF variant.

“These data suggest one mechanism by which patients with SLE might become resistant to the effects of rituximab, and could be used to guide therapy in the future,” Dr. Md Yusof suggested.

“Once this finding is validated, the clinical implication is that this genetic testing could be done prior to rituximab to identify those who will respond to therapy,” he postulated. “People with SLE who have this genetic variant with high affinity for rituximab are the ones that are better suited for rituximab therapy,” he added, otherwise a different CD20-directed antibody or alternative B-cell blockade therapies should be used.

The U.K. National Institute for Health Research funded the study. Dr. Md Yusof had no conflicts of interest to disclose; some coauthors disclosed ties to Roche, GlaxoSmithKline, and AstraZeneca, among other companies.

SOURCE: Md Yusof MY et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):1069-70. Abstract SAT0009, doi: 10.1136/annrheumdis-2019-eular.6919.