Main characteristics of the included studies: measured outcome, definitions of failure and immunogenicity to anti-TNFα treatment, determination and prevalence of HLA-DQA1*05, and relevant conclusions.
| First author, year . | Outcome . | Failure definition . | Measure of immunogenicity . | Therapeutic drug monitoring . | Line of treatment with anti-TNFα . | Determination of HLA . | Prevalence of HLA . | Main outcome for failure [HLA +/-] . | Immunogenicity outcome [HLA +/-] . |
|---|---|---|---|---|---|---|---|---|---|
| Aleman Gonzalez, 202223 | Failure | TD | NA | No info | No info | No info | 46.7% | No difference according to HLA carriage p = 0.3 | NA |
| Angulo McGrath, 202112 | Failure | LOR | NA | No info | No info | No info | 42.0% | HLA + had increased probability of LOR Multivariate: HR = 2.32, 95% CI 1.07–5.02, p = 0.03 | NA |
| Bangma, 202024 | Immunogenicity | NA | Radio-immunoassay, Drug-tolerant Cut-off: ≥12 AU/mL | No info | No info | SNP WGS and genome-wide genotyping array | 39.6% | NA | No difference according to HLA carriage HLA+: 27%, HLA–: 20% OR = 1.65, 95% CI 0.95–2.85, p = 0.075 |
| Colman, 202113,25 | Failure Immunogenicity | LOR | ECLIA, Drug tolerant Cut-off [ng/mL]: low [22–200], medium [201–1000], high [>1000] | Proactive | 1st line: 100% | PCR-SSO | 49.0% | No difference according to HLA carriage HLA+: 24%, HLA–: 46%, p = 0.17 | No difference according to HLA carriage HLA+: 60.0%, HLA –: 69.2%, p = 0.69 |
| Davis Gonzalez, 20229 | Failurea | PNR, LOR, TD, AE | NA | No info | First-line CD: 41.1%b First-line UC: 45.2%b | PCR-SSP | CD: 41.0% UC: 38.0% | No difference according to HLA carriage p >0.30 for the 4 outcomes assessed | NA |
| Doherty, 202326 | Failure | TD | NA | No info | 1st line: 100% | HLA imputation | 38.1% | HLA + had increased probability of shorter TD but only for homozygous carriers p = 0.007 | NA |
| Fuentes Valenzuela, 202327 | Failure | PNR, LOR, TD, AE | ΝΑ | Proactive | First-line: 92.9% Second-line: 7.1% | PCR-SSO | CD: 42.2% UC: 63.6% | HLA + had decreased probability of TD HLA+: 15.4%, HLA–: 38.3% HR = 0.31, 95% CI 0.12–0.81, p = 0.02 | NA |
| Gonzalez, 202128 | Failure Immunogenicity | TD | No info | No info | No info | No info | 39.1% | No difference according to HLA carriage HR = 2.36, 95% CI = 0.89–6.25, p = 0.06 | HLA + had increased probability of ADA formation HLA+: 59%, HLA–: 24%, p = 0.002 HR = 4.54, 95% CI = 1.73–11.89 |
| Gu, 202218 | Failurea Immunogenicity | TD | No info | No info | No info | PCR-SSO | 42.9% | No difference according to HLA carriage p = 0.89 | HLA + had increased probability of ADA formation HLA+: 27.0%, HLA–: 10.7%, p = 0.01 |
| Guardiola, 201929 | Failure | LOR | NA | No info | No info | No info | 31.0% | HLA + had increased probability of LOR Multivariate: HR = 3.5, 95% CI 1.6–7.5, p = 0.002 | NA |
| Guardiola Capon, 202010 | Failure | LOR | NA | No info | No info | No info | 45.0% | HLA + had increased probability of LOR Multivariate HR = 2.74, 95% CI 1.2–6.2, p = 0.02 | NA |
| Hu, 202119 | Immunogenicity | NA | Time to ADA detection by IC assay Cut-off ≥ 30 ng/mL | Reactive | First-line: 100% | SNP genotyping | No info | NA | No difference according to HLA carriage No statistical data provided |
| Ioannou, 202130 | Immunogenicity | NA | Cut-off: ≥ 10 AU/mL | No info | No info | SNP WGS | IFX: 41.9% ADL: 50.9% | NA | HLA + had increased probability of ADA formation, but only for ADL IFX: HLA+: 32.2%, HLA–: 25.6%, p = 0.28 ADL: HLA+: 41.5%, HLA–: 15.7%, p = 0.004 |
| Laserna Mendieta, 202311 | Failure | TD | NA | Reactive | First-line: 90.8% Second-line: 9.2% | PCR-SSO & SNP genotyping | PCR-SSO: 40.5% SNP: 38.2% | No difference according to HLA carriage PCR-SSO: HLA+: 52.8%, HLA–: 47.4%, p = 0.544 SNP: HLA+: 52.0%, HLA–: 48.1%, p = 0.668 | NA |
| Lopez Blanco, 202231 | Immunogenicity | NA | ELISA Cut-off ≥ 10 AU/mL | No info | No info | PCR-SSO | 57.7% | NA | No difference according to HLA carriage HLA+: 11.6%, HLA–: 10.2% |
| Pascual Oliver, 202332 | Failure | PNR, LOR, AE | NA | No [specified that proactive approach was not followed] | First-line: 100% | PCR-SSO | 42.4% | No difference according to HLA carriage p >0.30 for the three outcomes assessed | NA |
| Salvador Martín, 202333 | Failure | TD | NA | No info | First-line: 93.5% Second-line: 6.5% | SNP genotyping | CD: 45.8% UC: 40.8% IFX: 43.0% ADL: 48.2% | HLA + had increased probability of TD only for CD and ADL CD, Multivariate: HR = 2.07, 95% CI 1.07–3.99, p = 0.030 UC, Multivariate: HR = 1.40, 95% CI, 0.68–2.89, p = 0.358 IFX, Multivariate: HR = 1.44, 95% CI 0.79–2.62, p = 0.237 ADL, Multivariate: HR = 2.32, 95% CI 1.02–5.26, p = 0.044 | NA |
| Sazonovs, 20207 | Failure Immunogenicity | TD | ELISA, Drug tolerant cut-off: >10 AU/mL | Proactive | First-line: 100% | SNP genotyping/HLA imputation | 39.0% | HLA + had increased probability of TD only for ADL in monotherapy No statistical data provided | HLA + had increased probability of ADA formation IFX: HR = 1.92, 95% CI, 1.57–2.33 ADL: HR = 1.89, 95% CI, 1.32–2.70 |
| Shimoda, 202334 | Failure | TD | NA | No info | First-line: 100% | SNP array genotyping | 19.6% | HLA + had increased probability of TD Multivariate: HR = 2.23, 95% CI 1.10–4.51, p = 0.026 | NA |
| Spencer, 202214 | Failure Immunogenicity | TD | Homogeneous mobility shift assay, Drug-tolerant Cut-off: ≥ 1.19 µg/mL | Proactive | First-line: 77.9% Second-line: 23.1% | SNP Risk immune test | 45.6% | No difference according to HLA carriage p = 0.58 | No difference according to HLA carriage HLA+: 10.6%, HLA–: 13.8% HR = 0.7, 95% CI 0.2–2.0, p = 0.55 |
| Suris Marin, 202135 | Failure | LOR, TD | NA | No info | No info | No info | 39.4% | HLA + had increased probability of LOR Multivariate: HR = 1.90, 95% CI 1.14–3,31, p = 0.015 | NA |
| Wilson, 201936 | Failure Immunogenicity | LOR, TD, AE | ELISA, Drug-sensitive Cut-off: no info | No info | No info | SNP allelic discrimination | 40.1% | HLA + had increased probability of LOR and TD LOR: HR = 2.34, 95% CI 1.41–3.88, p = 0.001 TD: HR = 2.27, 95% CI 1.46–3.43, p = 2.5 × 10–4 | HLA + had increased probability of ADA formation HLA+: 25.7%, HLA –: 4.5%, HR = 7.29, 95% CI 2.97–17.19, p = 1.5 × 10–5 |
| Zhu, 202337 | Immunogenicity | NA | ELISA, Drug-tolerant Cut-off: titres of 1:20 and ≥1.:60 were considered low- and high-titre, respectively. | Proactive | First-line: 94.2% Second-line: 5.8%c | SNP genotyping | 36.5% | NA | HLA + had increased probability of ADA formation HLA+: 71.1%, HLA–: 43.9%, p = 0.01 OR = 2.94, 95% CI 1.19–7.3, p = 0.02 |
| First author, year . | Outcome . | Failure definition . | Measure of immunogenicity . | Therapeutic drug monitoring . | Line of treatment with anti-TNFα . | Determination of HLA . | Prevalence of HLA . | Main outcome for failure [HLA +/-] . | Immunogenicity outcome [HLA +/-] . |
|---|---|---|---|---|---|---|---|---|---|
| Aleman Gonzalez, 202223 | Failure | TD | NA | No info | No info | No info | 46.7% | No difference according to HLA carriage p = 0.3 | NA |
| Angulo McGrath, 202112 | Failure | LOR | NA | No info | No info | No info | 42.0% | HLA + had increased probability of LOR Multivariate: HR = 2.32, 95% CI 1.07–5.02, p = 0.03 | NA |
| Bangma, 202024 | Immunogenicity | NA | Radio-immunoassay, Drug-tolerant Cut-off: ≥12 AU/mL | No info | No info | SNP WGS and genome-wide genotyping array | 39.6% | NA | No difference according to HLA carriage HLA+: 27%, HLA–: 20% OR = 1.65, 95% CI 0.95–2.85, p = 0.075 |
| Colman, 202113,25 | Failure Immunogenicity | LOR | ECLIA, Drug tolerant Cut-off [ng/mL]: low [22–200], medium [201–1000], high [>1000] | Proactive | 1st line: 100% | PCR-SSO | 49.0% | No difference according to HLA carriage HLA+: 24%, HLA–: 46%, p = 0.17 | No difference according to HLA carriage HLA+: 60.0%, HLA –: 69.2%, p = 0.69 |
| Davis Gonzalez, 20229 | Failurea | PNR, LOR, TD, AE | NA | No info | First-line CD: 41.1%b First-line UC: 45.2%b | PCR-SSP | CD: 41.0% UC: 38.0% | No difference according to HLA carriage p >0.30 for the 4 outcomes assessed | NA |
| Doherty, 202326 | Failure | TD | NA | No info | 1st line: 100% | HLA imputation | 38.1% | HLA + had increased probability of shorter TD but only for homozygous carriers p = 0.007 | NA |
| Fuentes Valenzuela, 202327 | Failure | PNR, LOR, TD, AE | ΝΑ | Proactive | First-line: 92.9% Second-line: 7.1% | PCR-SSO | CD: 42.2% UC: 63.6% | HLA + had decreased probability of TD HLA+: 15.4%, HLA–: 38.3% HR = 0.31, 95% CI 0.12–0.81, p = 0.02 | NA |
| Gonzalez, 202128 | Failure Immunogenicity | TD | No info | No info | No info | No info | 39.1% | No difference according to HLA carriage HR = 2.36, 95% CI = 0.89–6.25, p = 0.06 | HLA + had increased probability of ADA formation HLA+: 59%, HLA–: 24%, p = 0.002 HR = 4.54, 95% CI = 1.73–11.89 |
| Gu, 202218 | Failurea Immunogenicity | TD | No info | No info | No info | PCR-SSO | 42.9% | No difference according to HLA carriage p = 0.89 | HLA + had increased probability of ADA formation HLA+: 27.0%, HLA–: 10.7%, p = 0.01 |
| Guardiola, 201929 | Failure | LOR | NA | No info | No info | No info | 31.0% | HLA + had increased probability of LOR Multivariate: HR = 3.5, 95% CI 1.6–7.5, p = 0.002 | NA |
| Guardiola Capon, 202010 | Failure | LOR | NA | No info | No info | No info | 45.0% | HLA + had increased probability of LOR Multivariate HR = 2.74, 95% CI 1.2–6.2, p = 0.02 | NA |
| Hu, 202119 | Immunogenicity | NA | Time to ADA detection by IC assay Cut-off ≥ 30 ng/mL | Reactive | First-line: 100% | SNP genotyping | No info | NA | No difference according to HLA carriage No statistical data provided |
| Ioannou, 202130 | Immunogenicity | NA | Cut-off: ≥ 10 AU/mL | No info | No info | SNP WGS | IFX: 41.9% ADL: 50.9% | NA | HLA + had increased probability of ADA formation, but only for ADL IFX: HLA+: 32.2%, HLA–: 25.6%, p = 0.28 ADL: HLA+: 41.5%, HLA–: 15.7%, p = 0.004 |
| Laserna Mendieta, 202311 | Failure | TD | NA | Reactive | First-line: 90.8% Second-line: 9.2% | PCR-SSO & SNP genotyping | PCR-SSO: 40.5% SNP: 38.2% | No difference according to HLA carriage PCR-SSO: HLA+: 52.8%, HLA–: 47.4%, p = 0.544 SNP: HLA+: 52.0%, HLA–: 48.1%, p = 0.668 | NA |
| Lopez Blanco, 202231 | Immunogenicity | NA | ELISA Cut-off ≥ 10 AU/mL | No info | No info | PCR-SSO | 57.7% | NA | No difference according to HLA carriage HLA+: 11.6%, HLA–: 10.2% |
| Pascual Oliver, 202332 | Failure | PNR, LOR, AE | NA | No [specified that proactive approach was not followed] | First-line: 100% | PCR-SSO | 42.4% | No difference according to HLA carriage p >0.30 for the three outcomes assessed | NA |
| Salvador Martín, 202333 | Failure | TD | NA | No info | First-line: 93.5% Second-line: 6.5% | SNP genotyping | CD: 45.8% UC: 40.8% IFX: 43.0% ADL: 48.2% | HLA + had increased probability of TD only for CD and ADL CD, Multivariate: HR = 2.07, 95% CI 1.07–3.99, p = 0.030 UC, Multivariate: HR = 1.40, 95% CI, 0.68–2.89, p = 0.358 IFX, Multivariate: HR = 1.44, 95% CI 0.79–2.62, p = 0.237 ADL, Multivariate: HR = 2.32, 95% CI 1.02–5.26, p = 0.044 | NA |
| Sazonovs, 20207 | Failure Immunogenicity | TD | ELISA, Drug tolerant cut-off: >10 AU/mL | Proactive | First-line: 100% | SNP genotyping/HLA imputation | 39.0% | HLA + had increased probability of TD only for ADL in monotherapy No statistical data provided | HLA + had increased probability of ADA formation IFX: HR = 1.92, 95% CI, 1.57–2.33 ADL: HR = 1.89, 95% CI, 1.32–2.70 |
| Shimoda, 202334 | Failure | TD | NA | No info | First-line: 100% | SNP array genotyping | 19.6% | HLA + had increased probability of TD Multivariate: HR = 2.23, 95% CI 1.10–4.51, p = 0.026 | NA |
| Spencer, 202214 | Failure Immunogenicity | TD | Homogeneous mobility shift assay, Drug-tolerant Cut-off: ≥ 1.19 µg/mL | Proactive | First-line: 77.9% Second-line: 23.1% | SNP Risk immune test | 45.6% | No difference according to HLA carriage p = 0.58 | No difference according to HLA carriage HLA+: 10.6%, HLA–: 13.8% HR = 0.7, 95% CI 0.2–2.0, p = 0.55 |
| Suris Marin, 202135 | Failure | LOR, TD | NA | No info | No info | No info | 39.4% | HLA + had increased probability of LOR Multivariate: HR = 1.90, 95% CI 1.14–3,31, p = 0.015 | NA |
| Wilson, 201936 | Failure Immunogenicity | LOR, TD, AE | ELISA, Drug-sensitive Cut-off: no info | No info | No info | SNP allelic discrimination | 40.1% | HLA + had increased probability of LOR and TD LOR: HR = 2.34, 95% CI 1.41–3.88, p = 0.001 TD: HR = 2.27, 95% CI 1.46–3.43, p = 2.5 × 10–4 | HLA + had increased probability of ADA formation HLA+: 25.7%, HLA –: 4.5%, HR = 7.29, 95% CI 2.97–17.19, p = 1.5 × 10–5 |
| Zhu, 202337 | Immunogenicity | NA | ELISA, Drug-tolerant Cut-off: titres of 1:20 and ≥1.:60 were considered low- and high-titre, respectively. | Proactive | First-line: 94.2% Second-line: 5.8%c | SNP genotyping | 36.5% | NA | HLA + had increased probability of ADA formation HLA+: 71.1%, HLA–: 43.9%, p = 0.01 OR = 2.94, 95% CI 1.19–7.3, p = 0.02 |
ADA, anti-drug antibodies; ADL, adalimumab; AE, adverse events; AU, arbitrary units; CD, Crohn’s disease; HLA, human leukocyte antigens; HLA-, non-carrier of HLA-DQA1*05; HLA+, carrier of HLA-DQA1*05; HR, hazard ratio; IC, immunochromatography; IFX, infliximab; OR, odds ratio; PCR-SSO, polymerase chain reaction-sequence specific oligonucleotide; PCR-SSP, polymerase chain reaction-sequence specific primer; PNR, primary non-response; SNP, single nucleotide polymorphism, LOR, secondary loss of response; TD, treatment discontinuation; UC, ulcerative colitis; WGS, whole-genome sequencing; wPCDAI, weighted Paediatric Crohn’s Disease Activity Index.
aThe outcomes were measured for events per each treatment, and not for patients as in the remaining included studies.
bThe data correspond to number of biologic treatments.
cHad received IFX previously.
Main characteristics of the included studies: measured outcome, definitions of failure and immunogenicity to anti-TNFα treatment, determination and prevalence of HLA-DQA1*05, and relevant conclusions.
| First author, year . | Outcome . | Failure definition . | Measure of immunogenicity . | Therapeutic drug monitoring . | Line of treatment with anti-TNFα . | Determination of HLA . | Prevalence of HLA . | Main outcome for failure [HLA +/-] . | Immunogenicity outcome [HLA +/-] . |
|---|---|---|---|---|---|---|---|---|---|
| Aleman Gonzalez, 202223 | Failure | TD | NA | No info | No info | No info | 46.7% | No difference according to HLA carriage p = 0.3 | NA |
| Angulo McGrath, 202112 | Failure | LOR | NA | No info | No info | No info | 42.0% | HLA + had increased probability of LOR Multivariate: HR = 2.32, 95% CI 1.07–5.02, p = 0.03 | NA |
| Bangma, 202024 | Immunogenicity | NA | Radio-immunoassay, Drug-tolerant Cut-off: ≥12 AU/mL | No info | No info | SNP WGS and genome-wide genotyping array | 39.6% | NA | No difference according to HLA carriage HLA+: 27%, HLA–: 20% OR = 1.65, 95% CI 0.95–2.85, p = 0.075 |
| Colman, 202113,25 | Failure Immunogenicity | LOR | ECLIA, Drug tolerant Cut-off [ng/mL]: low [22–200], medium [201–1000], high [>1000] | Proactive | 1st line: 100% | PCR-SSO | 49.0% | No difference according to HLA carriage HLA+: 24%, HLA–: 46%, p = 0.17 | No difference according to HLA carriage HLA+: 60.0%, HLA –: 69.2%, p = 0.69 |
| Davis Gonzalez, 20229 | Failurea | PNR, LOR, TD, AE | NA | No info | First-line CD: 41.1%b First-line UC: 45.2%b | PCR-SSP | CD: 41.0% UC: 38.0% | No difference according to HLA carriage p >0.30 for the 4 outcomes assessed | NA |
| Doherty, 202326 | Failure | TD | NA | No info | 1st line: 100% | HLA imputation | 38.1% | HLA + had increased probability of shorter TD but only for homozygous carriers p = 0.007 | NA |
| Fuentes Valenzuela, 202327 | Failure | PNR, LOR, TD, AE | ΝΑ | Proactive | First-line: 92.9% Second-line: 7.1% | PCR-SSO | CD: 42.2% UC: 63.6% | HLA + had decreased probability of TD HLA+: 15.4%, HLA–: 38.3% HR = 0.31, 95% CI 0.12–0.81, p = 0.02 | NA |
| Gonzalez, 202128 | Failure Immunogenicity | TD | No info | No info | No info | No info | 39.1% | No difference according to HLA carriage HR = 2.36, 95% CI = 0.89–6.25, p = 0.06 | HLA + had increased probability of ADA formation HLA+: 59%, HLA–: 24%, p = 0.002 HR = 4.54, 95% CI = 1.73–11.89 |
| Gu, 202218 | Failurea Immunogenicity | TD | No info | No info | No info | PCR-SSO | 42.9% | No difference according to HLA carriage p = 0.89 | HLA + had increased probability of ADA formation HLA+: 27.0%, HLA–: 10.7%, p = 0.01 |
| Guardiola, 201929 | Failure | LOR | NA | No info | No info | No info | 31.0% | HLA + had increased probability of LOR Multivariate: HR = 3.5, 95% CI 1.6–7.5, p = 0.002 | NA |
| Guardiola Capon, 202010 | Failure | LOR | NA | No info | No info | No info | 45.0% | HLA + had increased probability of LOR Multivariate HR = 2.74, 95% CI 1.2–6.2, p = 0.02 | NA |
| Hu, 202119 | Immunogenicity | NA | Time to ADA detection by IC assay Cut-off ≥ 30 ng/mL | Reactive | First-line: 100% | SNP genotyping | No info | NA | No difference according to HLA carriage No statistical data provided |
| Ioannou, 202130 | Immunogenicity | NA | Cut-off: ≥ 10 AU/mL | No info | No info | SNP WGS | IFX: 41.9% ADL: 50.9% | NA | HLA + had increased probability of ADA formation, but only for ADL IFX: HLA+: 32.2%, HLA–: 25.6%, p = 0.28 ADL: HLA+: 41.5%, HLA–: 15.7%, p = 0.004 |
| Laserna Mendieta, 202311 | Failure | TD | NA | Reactive | First-line: 90.8% Second-line: 9.2% | PCR-SSO & SNP genotyping | PCR-SSO: 40.5% SNP: 38.2% | No difference according to HLA carriage PCR-SSO: HLA+: 52.8%, HLA–: 47.4%, p = 0.544 SNP: HLA+: 52.0%, HLA–: 48.1%, p = 0.668 | NA |
| Lopez Blanco, 202231 | Immunogenicity | NA | ELISA Cut-off ≥ 10 AU/mL | No info | No info | PCR-SSO | 57.7% | NA | No difference according to HLA carriage HLA+: 11.6%, HLA–: 10.2% |
| Pascual Oliver, 202332 | Failure | PNR, LOR, AE | NA | No [specified that proactive approach was not followed] | First-line: 100% | PCR-SSO | 42.4% | No difference according to HLA carriage p >0.30 for the three outcomes assessed | NA |
| Salvador Martín, 202333 | Failure | TD | NA | No info | First-line: 93.5% Second-line: 6.5% | SNP genotyping | CD: 45.8% UC: 40.8% IFX: 43.0% ADL: 48.2% | HLA + had increased probability of TD only for CD and ADL CD, Multivariate: HR = 2.07, 95% CI 1.07–3.99, p = 0.030 UC, Multivariate: HR = 1.40, 95% CI, 0.68–2.89, p = 0.358 IFX, Multivariate: HR = 1.44, 95% CI 0.79–2.62, p = 0.237 ADL, Multivariate: HR = 2.32, 95% CI 1.02–5.26, p = 0.044 | NA |
| Sazonovs, 20207 | Failure Immunogenicity | TD | ELISA, Drug tolerant cut-off: >10 AU/mL | Proactive | First-line: 100% | SNP genotyping/HLA imputation | 39.0% | HLA + had increased probability of TD only for ADL in monotherapy No statistical data provided | HLA + had increased probability of ADA formation IFX: HR = 1.92, 95% CI, 1.57–2.33 ADL: HR = 1.89, 95% CI, 1.32–2.70 |
| Shimoda, 202334 | Failure | TD | NA | No info | First-line: 100% | SNP array genotyping | 19.6% | HLA + had increased probability of TD Multivariate: HR = 2.23, 95% CI 1.10–4.51, p = 0.026 | NA |
| Spencer, 202214 | Failure Immunogenicity | TD | Homogeneous mobility shift assay, Drug-tolerant Cut-off: ≥ 1.19 µg/mL | Proactive | First-line: 77.9% Second-line: 23.1% | SNP Risk immune test | 45.6% | No difference according to HLA carriage p = 0.58 | No difference according to HLA carriage HLA+: 10.6%, HLA–: 13.8% HR = 0.7, 95% CI 0.2–2.0, p = 0.55 |
| Suris Marin, 202135 | Failure | LOR, TD | NA | No info | No info | No info | 39.4% | HLA + had increased probability of LOR Multivariate: HR = 1.90, 95% CI 1.14–3,31, p = 0.015 | NA |
| Wilson, 201936 | Failure Immunogenicity | LOR, TD, AE | ELISA, Drug-sensitive Cut-off: no info | No info | No info | SNP allelic discrimination | 40.1% | HLA + had increased probability of LOR and TD LOR: HR = 2.34, 95% CI 1.41–3.88, p = 0.001 TD: HR = 2.27, 95% CI 1.46–3.43, p = 2.5 × 10–4 | HLA + had increased probability of ADA formation HLA+: 25.7%, HLA –: 4.5%, HR = 7.29, 95% CI 2.97–17.19, p = 1.5 × 10–5 |
| Zhu, 202337 | Immunogenicity | NA | ELISA, Drug-tolerant Cut-off: titres of 1:20 and ≥1.:60 were considered low- and high-titre, respectively. | Proactive | First-line: 94.2% Second-line: 5.8%c | SNP genotyping | 36.5% | NA | HLA + had increased probability of ADA formation HLA+: 71.1%, HLA–: 43.9%, p = 0.01 OR = 2.94, 95% CI 1.19–7.3, p = 0.02 |
| First author, year . | Outcome . | Failure definition . | Measure of immunogenicity . | Therapeutic drug monitoring . | Line of treatment with anti-TNFα . | Determination of HLA . | Prevalence of HLA . | Main outcome for failure [HLA +/-] . | Immunogenicity outcome [HLA +/-] . |
|---|---|---|---|---|---|---|---|---|---|
| Aleman Gonzalez, 202223 | Failure | TD | NA | No info | No info | No info | 46.7% | No difference according to HLA carriage p = 0.3 | NA |
| Angulo McGrath, 202112 | Failure | LOR | NA | No info | No info | No info | 42.0% | HLA + had increased probability of LOR Multivariate: HR = 2.32, 95% CI 1.07–5.02, p = 0.03 | NA |
| Bangma, 202024 | Immunogenicity | NA | Radio-immunoassay, Drug-tolerant Cut-off: ≥12 AU/mL | No info | No info | SNP WGS and genome-wide genotyping array | 39.6% | NA | No difference according to HLA carriage HLA+: 27%, HLA–: 20% OR = 1.65, 95% CI 0.95–2.85, p = 0.075 |
| Colman, 202113,25 | Failure Immunogenicity | LOR | ECLIA, Drug tolerant Cut-off [ng/mL]: low [22–200], medium [201–1000], high [>1000] | Proactive | 1st line: 100% | PCR-SSO | 49.0% | No difference according to HLA carriage HLA+: 24%, HLA–: 46%, p = 0.17 | No difference according to HLA carriage HLA+: 60.0%, HLA –: 69.2%, p = 0.69 |
| Davis Gonzalez, 20229 | Failurea | PNR, LOR, TD, AE | NA | No info | First-line CD: 41.1%b First-line UC: 45.2%b | PCR-SSP | CD: 41.0% UC: 38.0% | No difference according to HLA carriage p >0.30 for the 4 outcomes assessed | NA |
| Doherty, 202326 | Failure | TD | NA | No info | 1st line: 100% | HLA imputation | 38.1% | HLA + had increased probability of shorter TD but only for homozygous carriers p = 0.007 | NA |
| Fuentes Valenzuela, 202327 | Failure | PNR, LOR, TD, AE | ΝΑ | Proactive | First-line: 92.9% Second-line: 7.1% | PCR-SSO | CD: 42.2% UC: 63.6% | HLA + had decreased probability of TD HLA+: 15.4%, HLA–: 38.3% HR = 0.31, 95% CI 0.12–0.81, p = 0.02 | NA |
| Gonzalez, 202128 | Failure Immunogenicity | TD | No info | No info | No info | No info | 39.1% | No difference according to HLA carriage HR = 2.36, 95% CI = 0.89–6.25, p = 0.06 | HLA + had increased probability of ADA formation HLA+: 59%, HLA–: 24%, p = 0.002 HR = 4.54, 95% CI = 1.73–11.89 |
| Gu, 202218 | Failurea Immunogenicity | TD | No info | No info | No info | PCR-SSO | 42.9% | No difference according to HLA carriage p = 0.89 | HLA + had increased probability of ADA formation HLA+: 27.0%, HLA–: 10.7%, p = 0.01 |
| Guardiola, 201929 | Failure | LOR | NA | No info | No info | No info | 31.0% | HLA + had increased probability of LOR Multivariate: HR = 3.5, 95% CI 1.6–7.5, p = 0.002 | NA |
| Guardiola Capon, 202010 | Failure | LOR | NA | No info | No info | No info | 45.0% | HLA + had increased probability of LOR Multivariate HR = 2.74, 95% CI 1.2–6.2, p = 0.02 | NA |
| Hu, 202119 | Immunogenicity | NA | Time to ADA detection by IC assay Cut-off ≥ 30 ng/mL | Reactive | First-line: 100% | SNP genotyping | No info | NA | No difference according to HLA carriage No statistical data provided |
| Ioannou, 202130 | Immunogenicity | NA | Cut-off: ≥ 10 AU/mL | No info | No info | SNP WGS | IFX: 41.9% ADL: 50.9% | NA | HLA + had increased probability of ADA formation, but only for ADL IFX: HLA+: 32.2%, HLA–: 25.6%, p = 0.28 ADL: HLA+: 41.5%, HLA–: 15.7%, p = 0.004 |
| Laserna Mendieta, 202311 | Failure | TD | NA | Reactive | First-line: 90.8% Second-line: 9.2% | PCR-SSO & SNP genotyping | PCR-SSO: 40.5% SNP: 38.2% | No difference according to HLA carriage PCR-SSO: HLA+: 52.8%, HLA–: 47.4%, p = 0.544 SNP: HLA+: 52.0%, HLA–: 48.1%, p = 0.668 | NA |
| Lopez Blanco, 202231 | Immunogenicity | NA | ELISA Cut-off ≥ 10 AU/mL | No info | No info | PCR-SSO | 57.7% | NA | No difference according to HLA carriage HLA+: 11.6%, HLA–: 10.2% |
| Pascual Oliver, 202332 | Failure | PNR, LOR, AE | NA | No [specified that proactive approach was not followed] | First-line: 100% | PCR-SSO | 42.4% | No difference according to HLA carriage p >0.30 for the three outcomes assessed | NA |
| Salvador Martín, 202333 | Failure | TD | NA | No info | First-line: 93.5% Second-line: 6.5% | SNP genotyping | CD: 45.8% UC: 40.8% IFX: 43.0% ADL: 48.2% | HLA + had increased probability of TD only for CD and ADL CD, Multivariate: HR = 2.07, 95% CI 1.07–3.99, p = 0.030 UC, Multivariate: HR = 1.40, 95% CI, 0.68–2.89, p = 0.358 IFX, Multivariate: HR = 1.44, 95% CI 0.79–2.62, p = 0.237 ADL, Multivariate: HR = 2.32, 95% CI 1.02–5.26, p = 0.044 | NA |
| Sazonovs, 20207 | Failure Immunogenicity | TD | ELISA, Drug tolerant cut-off: >10 AU/mL | Proactive | First-line: 100% | SNP genotyping/HLA imputation | 39.0% | HLA + had increased probability of TD only for ADL in monotherapy No statistical data provided | HLA + had increased probability of ADA formation IFX: HR = 1.92, 95% CI, 1.57–2.33 ADL: HR = 1.89, 95% CI, 1.32–2.70 |
| Shimoda, 202334 | Failure | TD | NA | No info | First-line: 100% | SNP array genotyping | 19.6% | HLA + had increased probability of TD Multivariate: HR = 2.23, 95% CI 1.10–4.51, p = 0.026 | NA |
| Spencer, 202214 | Failure Immunogenicity | TD | Homogeneous mobility shift assay, Drug-tolerant Cut-off: ≥ 1.19 µg/mL | Proactive | First-line: 77.9% Second-line: 23.1% | SNP Risk immune test | 45.6% | No difference according to HLA carriage p = 0.58 | No difference according to HLA carriage HLA+: 10.6%, HLA–: 13.8% HR = 0.7, 95% CI 0.2–2.0, p = 0.55 |
| Suris Marin, 202135 | Failure | LOR, TD | NA | No info | No info | No info | 39.4% | HLA + had increased probability of LOR Multivariate: HR = 1.90, 95% CI 1.14–3,31, p = 0.015 | NA |
| Wilson, 201936 | Failure Immunogenicity | LOR, TD, AE | ELISA, Drug-sensitive Cut-off: no info | No info | No info | SNP allelic discrimination | 40.1% | HLA + had increased probability of LOR and TD LOR: HR = 2.34, 95% CI 1.41–3.88, p = 0.001 TD: HR = 2.27, 95% CI 1.46–3.43, p = 2.5 × 10–4 | HLA + had increased probability of ADA formation HLA+: 25.7%, HLA –: 4.5%, HR = 7.29, 95% CI 2.97–17.19, p = 1.5 × 10–5 |
| Zhu, 202337 | Immunogenicity | NA | ELISA, Drug-tolerant Cut-off: titres of 1:20 and ≥1.:60 were considered low- and high-titre, respectively. | Proactive | First-line: 94.2% Second-line: 5.8%c | SNP genotyping | 36.5% | NA | HLA + had increased probability of ADA formation HLA+: 71.1%, HLA–: 43.9%, p = 0.01 OR = 2.94, 95% CI 1.19–7.3, p = 0.02 |
ADA, anti-drug antibodies; ADL, adalimumab; AE, adverse events; AU, arbitrary units; CD, Crohn’s disease; HLA, human leukocyte antigens; HLA-, non-carrier of HLA-DQA1*05; HLA+, carrier of HLA-DQA1*05; HR, hazard ratio; IC, immunochromatography; IFX, infliximab; OR, odds ratio; PCR-SSO, polymerase chain reaction-sequence specific oligonucleotide; PCR-SSP, polymerase chain reaction-sequence specific primer; PNR, primary non-response; SNP, single nucleotide polymorphism, LOR, secondary loss of response; TD, treatment discontinuation; UC, ulcerative colitis; WGS, whole-genome sequencing; wPCDAI, weighted Paediatric Crohn’s Disease Activity Index.
aThe outcomes were measured for events per each treatment, and not for patients as in the remaining included studies.
bThe data correspond to number of biologic treatments.
cHad received IFX previously.
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