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Risk factors for losing hepatitis B virus surface antibody in patients with HBV surface antigen negative/surface antibody positive serostatus receiving biologic disease-modifying anti-rheumatic drugs: a nested case-control study

Risk factors for losing hepatitis B virus surface antibody in patients with HBV surface antigen... Background: Hepatitis B virus (HBV) reactivation consequent to immunosuppressive therapy is an increasingly prevalent problem with serious clinical implications. Treatment with biologic agents conduces to the loss of protective antibody to HBV surface antigen (anti-HBs), which significantly increases the risk of HBV reactivation. Hence, we investigated the risk factors for losing anti-HBs in patients with rheumatic diseases and HBV surface antigen negative/anti-HBs positive (HBsAg−/anti-HBs+) serostatus during treatment with biologic disease-modifying anti-rheumatic drugs (DMARDs). Methods: Using a nested case-control design, we prospectively enrolled patients with rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis/psoriasis, or juvenile idiopathic arthritis, who were treated with biologic DMARDs at Changhua Christian Hospital, Taiwan, from January 2013 to June 2019 and had HBsAg−/anti-HBs+ serostatus; the analytic sample excluded all patients with HBsAg+ or anti-HBs− serostatus. Anti-HBs titers were monitored 6-monthly and cases were defined as anti-HBs < 10 mIU/ml during follow-up. Cases were matched one- to-all with controls with anti-HBs ≥ 10 mIU/ml on the same ascertainment date and equivalent durations of biologic DMARDs treatment (control patients could be resampled and could also become cases during follow-up). Between-group characteristics were compared and risk factors for anti-HBs loss were investigated by conditional logistic regression analyses. (Continued on next page) * Correspondence: ymcgreen@yahoo.com.tw Department of Allergy, Immunology, and Rheumatology, Tungs’ Taichung MetroHarbor Hospital, 699, Sec. 8, Taiwan Blvd., Taichung City 43503, Taiwan Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Hung et al. Advances in Rheumatology (2021) 61:22 Page 2 of 9 (Continued from previous page) Results: Among 294 eligible patients, 23 cases were matched with 311 controls. The incidence of anti-HBs loss was ~ 2.7%/person-year during biologic DMARDs treatment. Besides lower baseline anti-HBs titer (risk ratio 0.93, 95% CI 0.89–0.97), cases were significantly more likely than controls to have diabetes mellitus (risk ratio 4.76, 95% CI 1.48– 15.30) and chronic kidney disease (risk ratio 14.00, 95% CI 2.22–88.23) in univariate analysis. Risk factors remaining significantly associated with anti-HBs loss in multivariate analysis were lower baseline anti-HBs titer (adjusted risk ratio 0.93, 95% CI 0.88–0.97) and chronic kidney disease (adjusted risk ratio 45.68, 95% CI 2.39–871.5). Conclusions: Besides lower baseline anti-HBs titer, chronic kidney disease also strongly predicts future anti-HBs negativity in patients with HBsAg−/anti-HBs+ serostatus who receive biologic DMARDs to treat rheumatic diseases. Patients with low anti-HBs titer (≤ 100 mIU/ml) and/or chronic kidney disease should be monitored during biologic DMARDs therapy, to enable timely prophylaxis to preempt potential HBV reactivation. Keywords: Hepatitis B virus (HBV), HBV surface-antigen negative/surface antibody positive (HBsAg−/anti-HBs+), Rheumatic diseases, Biologic disease-modifying anti-rheumatic drug (DMARD), Anti-HBs loss, Chronic kidney disease Background risk factors for anti-HBs loss. To this end, we prospectively Hepatitis B virus (HBV) infection is a global public health studied patients with HBsAg−/anti-HBc+ serostatus dur- concern [1]. Morbid HBV reactivation is characterized by ing/after biologic DMARDs therapy for rheumatic diseases. viral replication and the recurrence of active necro- inflammatory liver disease, which may presage severe Methods hepatitis or even death [1–6]. Rising prevalence of cancer Study subjects and autoimmune diseases and more frequent use of che- The study sample comprised patients at Changhua motherapeutic or immunosuppressive treatment strat- Christian Hospital, Taiwan, with rheumatoid arthritis, egies, have made HBV reactivation consequent to such ankylosing spondylitis, psoriasis, psoriatic arthritis, or therapies an exigent problem [1–5]. Iatrogenic HBV re- juvenile idiopathic arthritis, who were treated with activation is best known in HBV surface-antigen carriers biologic DMARDs from January 2013 to June 2019. (HBsAg+), and comprehensive guidelines cover this high- Only patients with HBsAg−/anti-HBs+ serostatus risk group [1–8]. Recently, attention has increasingly fo- were included and all with HBsAg+ or HBsAg−/anti- cused on patients who are HBsAg-negative with anti- HBs− serostatus were excluded (Fig. 1). All study bodies against HBV core-antigen or surface-antigen subjects fulfilled international diagnostic criteria for (HBsAg−/anti-HBc+ or anti-HBs+), among whom baseline these diseases and were treated according to Taiwan HBV DNA and anti-HBs negative (anti-HBs−)seros- Rheumatology Association guidelines for screening tatus are known risk factors for HBV reactivation and management of viral hepatitis [15]. [9–13]. Although serum HBV DNA is a defining characteristic Hepatitis B serologic testing and HBV DNA of HBV reactivation [1–4], it does not inevitably pro- HBV serology and DNA assays were done every 6 gress to morbid viremia but may manifest transiently months according to Taiwan Rheumatology Association without symptoms, especially whilst anti-HBs serostatus recommendations [15]. HBV assays included serum remains positive [5, 6, 10–12]. On the other hand, anti- HBsAg, anti-HBs and anti-HBc, measured by Architect HBs loss consequent to immunosuppressive treatment i2000SR chemiluminescent microparticle immunoassay of patients with HBsAg−/anti-HBc+ serostatus signifi- (Abbott Laboratories, Abbot Park, Illinois, USA). HBV cantly increases the risk of progression from clinically immunization history of people with anti-HBs+/anti- silent to symptomatic HBV reactivation [9, 10, 12, 13]. HBc− serostatus was not ascertained. Previous studies have shown that anti-HBs can decline Anti-HBs titer < 10 mIU/ml was defined as sero- to seronegative during immunosuppressive therapies, negative. Low anti-HBs titer was defined as 10–100 especially in patients with a low baseline anti-HBs titer mIU/ml, based on evidence of significantly increased [11, 14], but none have systematically investigated likelihood of anti-HBs loss and detectable HBV DNA whether there are other predisposing factors. at anti-HBs titers below 100 mIU/ml and protection In this context, especially given burgeoning use of tumor against HBV reactivation above this threshold [11, necrosis factor inhibitors (anti-TNF) and other biologic 14]. Serum HBV DNA viral load was quantified by disease-modifying anti-rheumatic drugs (DMARDs) to treat Abbott RealTime HBV (Abbott Laboratories, Abbott autoimmune diseases, and elevated HBV reactivation rates Park,Illinois, USA),withaminimalsensitivity of 10 in this setting [2, 4, 5], it is imperative to further elucidate IU/ml. HBV DNA titer ≥ 10 mIU/ml was defined as Hung et al. Advances in Rheumatology (2021) 61:22 Page 3 of 9 Fig. 1 Case-control selection flow chart. DMARDs, disease-modifying anti-rheumatic drugs; HBV, hepatitis B virus; DNA, deoxyribonucleic acid; anti-HBs, HBV surface antibody; HBsAg, HBV surface-antigen; mIU, million International Units. One patient could serve as a control repeatedly during follow-up and control subjects could become cases during the study detectable viral load [11], while the criteria defining criteria for liver surface, liver parenchyma, hepatic clinical HBV reactivation at any serial 6-monthly vessels, and spleen size [16]. follow-up check, were HBV replication ≥ 2log in- crease from baseline or a new appearance of HBV Nested case-control design DNA to ≥ 100 IU/ml in people with previously stable We used a nested case-control design, which enables or undetectable levels [1]. efficient analysis of time-dependent exposures on rare outcomes where only a limited sample from a larger population is practical, without compromising statistical Covariate information power [17–19]. Unlike conventional cohort studies, which Baseline data included: age, sex, type of rheumatic compare cases versus controls from a fully enumer- disease (rheumatoid arthritis, ankylosing spondylitis, ated population, a nested case-control design identi- psoriatic arthritis/psoriasis, juvenile idiopathic arth- fies occurrences of events of interest in a defined ritis), accumulated doses of conventional DMARDs sub-population and matches these with a specified (prednisolone, hydroxychloroquine, sulfasalazine, number of control subjects drawn from the same methotrexate, leflunomide, cyclosporine) and biologic sub-sample, but who were not yet affected by the DMARDs (etanercept, adalimumab, golimumab, uste- same event when it occurred in their corresponding kinumab, secukinumab, tocilizumab, rituximab, abata- case [18, 19]. This design means that controls can cept, tofacitinib). Chronic kidney disease was defined become cases later during follow-up and that each as estimated glomerular filtration rate < 60 ml/min/ patient may serve as a control repeatedly (though at 1.73 m . Chronic liver disease status was determined different times); thus, cases are compared with con- from medical charts or hepatic ultrasound results and trols from the same patient sample, which lessens included cirrhosis, fatty liver, and “parenchymal liver the likelihood of selection bias [17–20]. disease”, which is a term used in Taiwan, to denote The first prescription of a biologic DMARD defined the ultrasound findings intermediate between “normal” start point. Cases were defined upon occurrences of serum and “cirrhosis”, based on sonographic evaluation anti-HBs titer < 10 mIU/ml during follow-up, with the Hung et al. Advances in Rheumatology (2021) 61:22 Page 4 of 9 date when anti-HBs loss was ascertained designated the 0.88–0.97) and chronic kidney disease (adjusted risk event date. Each case was matched one-to-all with ratio 45.68, 95% CI 2.39–871.5). subjects whose serum HBsAb titer was ≥ 10 mIU/ml on the respective case ascertainment date and who had an Clinical features and outcomes of subjects with anti-HBs equivalent duration of biologic DMARDs treatment. loss Thirteen cases had rheumatoid arthritis (Table 3). All cases’ baseline anti-HBs titers were low (≤ 100 mIU/ml), Data analysis and statistics mean 22.6. Fourteen were prescribed anti-TNF agents: All analyses were done using nonparametric statistical four etanercept, six adalimumab, and four golimumab. software (LogXact 11, Cytel Software Corp, Cambridge, Three were prescribed tofacitinib. Two cases each were MA, USA) with penalized maximum likelihood to prescribed ustekinumab or tocilizumab, while one each remove first-order bias. A p-value < 0.05 for two-sided received abatacept or rituximab. tests was considered statistically significant. Continuous No cases (nor anti-HBs+ controls) had clinical HBV variables were expressed as means plus/minus standard reactivation during follow-up (852 person-years), and no deviation or mean [range], categorical variables as cases developed alanine transaminase elevation, or re- numbers (percentages). Conditional logistic regression ceived any anti-viral treatment during median follow-up analysis was used to estimate risk ratios and 95% confi- of 30 months (range 0–77) after anti-HBs loss. Only one dence intervals for loss of anti-HBs; putative associated of the 16/23 cases whose serum HBV DNA was moni- factors included age, sex, type of rheumatic disease, tored after anti-HBs loss ever had a detectable viral load conventional DMARDs, biologic DMARDs (anti-TNF or (Table 3), which was observed only once, with no recur- others), comorbidity, and baseline anti-HBs titer. rence as of August 2020. Results Discussion Demographic characteristics and clinical status We believe this to be the first report of risk factors asso- The analytic samples drawn from 294 patients with ciated with loss of anti-HBs in rheumatic patients during HBsAg−/anti-HBs+ serostatus at baseline, comprised 23 biologic DMARDs therapy, after controlling for putative cases and 311 matched controls (Fig. 1); Table 1 shows risk factors. We discovered that besides lower baseline their demographic and clinical characteristics. Mean age anti-HBs titer, chronic kidney disease independently pre- and rheumatic disease types were similar between case dicts anti-HBs loss. and control groups. No patients with HBsAg−/anti- Our finding that lower pretreatment anti-HBs titer HBs+ serostatus had detectable HBV DNA at enrolment. (≤ 100 mIU/ml) is a risk factor for loss of anti-HBs, Compared with controls, cases had lower baseline serum is consistent with a study of rituximab-based therapy anti-HBs titers, more prevalent comorbidities (including for lymphoma [14]. Moreover, baseline anti-HBs posi- hepatitis C virus infection, chronic liver disease, diabetes tivity was protective against HBV reactivation among mellitus, chronic kidney disease), and relatively higher patients with HBsAg−/anti-HBc+ serostatus who re- accumulated doses of sulfasalazine, leflunomide, and ceived immunosuppressive or biologic agents [9–14]. prednisolone. Most people in both groups used anti- Therefore, our results suggest that anti-HBs may be TNF agents (etanercept, adalimumab, golimumab). No lost during/after immunosuppressive/biologic therapy, study subjects were kidney transplant recipients. especially in people with a low baseline titer, with consequently elevated risk of HBV reactivation. Incidence of anti-HBs loss and associated risk factors Although we detected no cases of morbid viremia and The incidence rate of anti-HBs loss in 294 patients with just one occurrence of minimal HBV DNA during HBsAg−/anti-HBs+ serostatus during biologic DMARDs follow-up, this was not necessarily inconsistent with evi- treatment was 23/852 person-years: ~ 2.7%/person-year. dence that anti-HBs negativity increases the risk of HBV Table 2 shows risk factors associated with loss of anti- reactivation in patients with HBsAg−/anti-HBc+ serosta- HBs in univariate and multivariate conditional logistic tus. Anti-HBs may remain persistently low or negative regression analyses. Besides lower baseline anti-HBs titer during treatment, with HBV DNA detected periodically (risk ratio 0.93, 95% CI 0.89–0.97), cases were signifi- but without progression to morbid reactivation [5, 6, 11, cantly more likely than controls to have diabetes mellitus 12]. Reported rates of HBV DNA manifestation during/ (risk ratio 4.76, 95% CI 1.48–15.30) and chronic kidney after immunosuppressive therapy in patients with disease (risk ratio 14.00, 95% CI 2.22–88.23) in the HBsAg−/anti-HBs−/anti-HBc+ serostatus are in the univariate analysis. However, the only factors remaining order of 1–10%, with symptomatic reactivation in a significant in the multivariate model, were lower baseline smaller fraction of cases [9–12]; therefore, 23 cases may serum anti-HBs titer (adjusted risk ratio 0.93, 95% CI have been too few to detect occasional reactivation Hung et al. Advances in Rheumatology (2021) 61:22 Page 5 of 9 Table 1 Baseline characteristics of cases and controls treated with biologic DMARDs Data show mean ± standard deviation, mean [range], or number (%) Cases Controls Number 23 311 Age (years) 52.2 ± 17.9 47.5 ± 14.2 Sex Female 15 (65.2%) 148 (47.6%) Male 8 (34.8%) 163 (52.4%) Rheumatic disease Rheumatoid arthritis 13 (56.5%) 155 (49.8%) Ankylosing spondylitis 5 (21.7%) 100 (32.2%) Psoriatic arthritis/Psoriasis 4 (17.4%) 52 (16.7%) Juvenile idiopathic arthritis 1 (4.4%) 4 (1.3%) Detectable HBV DNA (≥10 IU/ml) 0 0 Anti-HBV core antigen positive 15 (65.2%) 189 (60.8%) Baseline serum anti-HBs titer (mIU/ml) Mean [Min–Max] 22.6 [10.1–64.7] 284.5 [11.5–1000] ≤ 100 23 (100%) 128 (41.2%) > 100 0 183 (58.8%) Biologic DMARDs Anti-TNF (Etanercept, Adalimumab, Golimumab) 14 (60.9%) 231 (74.3%) Not anti-TNF 9 (39.1%) 80 (25.7%) Abatacept 1 (4.4%) 11 (3.5%) Rituximab 1 (4.4%) 11 (3.5%) Tocilizumab 2 (8.7%) 12 (3.9%) Tofacitinib 3 (13.0%) 19 (6.1%) Ustekinumab 2 (8.7%) 25 (8.0%) Secukinumab 0 2 (0.6%) Conventional DMARDs (accumulated dose) Methotrexate (mg) 536 ± 869 537 ± 734 Leflunomide (mg) 748 ± 2083 707 ± 3021 Sulfasalazine (g) 350 ± 354 242 ± 318 Hydroxychloroquine (g) 67 ± 102 54 ± 100 Cyclosporine (g) 9 ± 22 8 ± 27 Prednisolone (accumulated dose, mg) 2244 ± 2614 1422 ± 1910 Comorbidities Prior alanine transaminase elevation 2 (8.7%) 10 (3.2%) Hepatitis C virus antibody positive 2 (8.7%) 11 (3.5%) Diabetes mellitus 4 (17.4%) 12 (3.9%) Chronic liver disease 5 (21.7%) 30 (9.7%) Chronic kidney disease 3 (13.0%) 3 (1.0%) HBV Hepatitis B virus, DNA Deoxyribonucleic acid, Anti-HBs HBV surface antibody, IU International Units, DMARD Disease-modifying anti-rheumatic drug, TNF Tumor necrosis factor Maximum detectable limit More than five-fold upper reference of 40 IU/L events. The follow-up duration (median 30 months after cycles of therapy have diminished anti-HBs to undetect- anti-HBs loss) may also have been insufficient. HBV able levels [6], and clinical reactivation may not occur DNA in such patients usually appears late, after several until several years since commencing immunosuppressive Hung et al. Advances in Rheumatology (2021) 61:22 Page 6 of 9 Table 2 Risk factors associated with loss of HBV surface antibody Univariate analysis Multivariate analysis Risk ratio (95% CI) p-value Risk ratio (95% CI) p-value Age 1.02 (0.99–1.05) 0.153 Sex Female 1 (reference) 0.097 Male 0.48 (0.20–1.14) Rheumatic disease Rheumatoid arthritis 1 (reference) 0.582 Ankylosing spondylitis 0.60 (0.21–1.72) Psoriatic arthritis/Psoriasis 0.87 (0.28–2.76) Juvenile idiopathic arthritis 2.73 (0.29–25.57) Anti-HBV core antigen positive 1.23 (0.51–2.95) 0.641 Baseline serum anti-HBs titer (mIU/ml) Lower vs higher (continuous) 0.93 (0.89–0.97) 0.001 0.93 (0.88–0.97) 0.002 > 100 1 (reference) 1 (reference) ≤ 100 46.8 (10.09–∞) < 0.001 43.98 (9.34–∞) < 0.001 Biologic DMARDs Anti-TNF 1 (reference) 0.204 Not anti-TNF 1.80 (0.73–4.49) Conventional DMARDs Methotrexate 1.00 (1.00–1.00) 0.942 Sulfasalazine 1.00 (1.00–1.00) 0.135 Hydroxychloroquine 1.00 (1.00–1.01) 0.515 Cyclosporine 1.00 (0.99–1.02) 0.888 Leflunomide 1.00 (1.00–1.00) 0.958 Prednisolone 1.00 (1.00–1.00) 0.064 Comorbidity Prior alanine transaminase elevation 2.93 (0.59–14.54) 0.188 Hepatitis C virus antibody positive 2.64 (0.54–12.92) 0.232 Diabetes mellitus 4.76 (1.48–15.30) 0.009 0.85 (0.19–3.92) 0.838 Chronic liver disease 2.62 (0.90–7.66) 0.079 Chronic kidney disease 14.00 (2.22–88.23) 0.005 45.68 (2.39–871.5) 0.011 Anti-HBs Hepatitis B virus surface antibody, DMARD Disease-modifying anti-rheumatic drug, TNF Tumor necrosis factor More than five-fold upper reference of 40 IU/L Baseline anti-HBs as continuous variable Baseline anti-HBs continuous + chronic kidney disease + diabetes mellitus therapy [10–12]; median time from starting immunosup- related nephropathy, and widespread use of nephrotoxic pressive therapy to HBV reactivation in a cohort of 1042 medications such as non-steroidal anti-inflammatory rheumatic disease patients with resolved HBV infections drugs or cyclosporine. Studies have shown that patients was 66 months [12]. However, 18/23 cases in our study with chronic kidney disease lose anti-HBs faster than had total follow-up of < 66 months. healthy subjects do [21, 22]; anti-HBs loss in chronic This is the first indication of which we know that kidney disease or dialysis patients has been attributed to chronic kidney disease might be a risk factor for loss of diminished interleukin-2 secretion, impaired macro- anti-HBs in patients treated with biologic DMARDs. phage function, decreasing memory B cell counts, and a This is an important contemporary issue because weak amnestic response [23–25]. chronic kidney disease is prevalent among patients with Consistent with reports of increased likelihood of anti- rheumatic diseases, consequent to older age, diabetes- HBs loss in patients with diabetes mellitus [26, 27], we Hung et al. Advances in Rheumatology (2021) 61:22 Page 7 of 9 Table 3 Characteristics of patients with anti-HBs loss during treatment with biologic DMARDs Baseline Time to Medication when anti-HBs loss occurred Comorbidities Total HBV status and treatment after anti-HBs loss anti-HBs follow-up Disease Serum HBV antibodies Biologic Conventional DMARD (accumulated dose, g) HCV Chronic DM CKD Viral load HBV Antiviral loss (months) b c DMARD liver (IU/ml) reactivation therapy HBs (mIU/ml) HBc (months) Pd MTX LEF HCQ SSZ CsA disease RA 10.1 – 15 TOF 3.0 0.6 0 181 236 0 – ND –– 32 ND –– RA 13.2 + 25 ETA 3.9 0 0 280 699 34 + Fatty liver + + 74 U –– RA 13.4 – 11 TOF 0 0.8 0 141 0 0 – ND –– 23 ND –– RA 14.8 – 13 TOF 2.1 0.5 0 90 394 0 – ND –– 30 U –– RA 16.1 + 22 TCZ 4.4 0 9.2 0 713 0 – PLD + – 47 U –– RA 16.5 + 17 ABT 2.6 0 0 40 588 0 – ND – +39 U –– RA 17.3 + 7 ADA 1.1 0.5 0 84 294 0 – Normal + – 65 10 –– RA 17.7 + 61 GOL 7.2 3.3 0 363 714 0 – ND –– 61 U –– RA 18.3 + 18 ETA 2.7 1.2 0 218 1092 0 – Normal –– 68 U –– RA 23.4 + 60 ADA 5.8 2.6 0 74 0 0 – Normal –– 76 ND –– RA 41.9 + 3 ETA 0.7 0 0 45 224 4 – Normal –– 80 U –– RA 44.7 + 10 RTX 2.5 0.6 0 28 182 8 + PLD –– 57 U –– RA 56.3 – 42 TCZ 9.8 1.3 3.8 6 1295 0 – Normal – +54 ND –– AS 11.5 + 22 GOL 0 0 0 0 172 0 – Normal –– 33 U – − AS 14.3 – 7 GOL 0 0 0 0 163 0 – Normal –– 51 ND –– AS 21.7 + 34 ADA 0.4 0 0 0 294 0 – Normal –– 75 U –– AS 26.3 – 42 ADA 0.4 0 0 0 456 0 – Normal –– 60 ND –– AS 64.7 – 4 ADA 0.3 0 0 0 228 0 – Normal –– 36 U –– PsO 10.1 + 5 GOL 0.6 0 2.8 0 0 22 – Fatty liver + – 46 U –– PsO 12.3 + 16 UST 0 0.5 0 0 0 90 – Normal –– 62 U –– PsO 17.3 + 17 UST 0 0 0 0 0 53 – Fatty liver –– 47 U –– PsA 27 + 28 ADA 3.8 0 1.4 0 56 0 – ND –– 35 U –– JIA 10.1 – 4 ETA 0.4 0.3 0 0 256 0 – Normal –– 60 ND –– RA Rheumatoid arthritis, AS Ankylosing spondylitis, PsO Psoriatic arthritis, PSA Psoriasis, JIA Juvenile idiopathic arthritis, HBV Hepatitis B virus, HBs HBV surface antigen, HBc HBV core protein, DMARD Disease-modifying anti-rheumatic drug, Pd Prednisolone, MTX Methotrexate, LEF Leflunomide, HCQ Hydroxychloroquine, SSZ Sulfasalazine, CsA Cyclosporine, TOF Tofacitinib, ETA Etanercept, TCZ Tocilizumab, ABT Abatacept, ADA Adalimumab, GOL Golimumab, RTX Rituximab, UST Ustekinumab, HCV Hepatitis C virus, DM Diabetes mellitus, CKD Chronic kidney disease, PLD Parenchymal liver disease, U Undetectable, ND Not done Based on ultrasound findings At any serial 6-monthly check during follow-up HBV replication > 2 log increase from baseline or a new appearance of HBV DNA to > 100 IU/ml in people with previously stable or undetectable levels In Taiwan, ultrasound findings intermediate between “normal” and “cirrhosis” based on sonographic evaluation criteria for liver surface, liver parenchyma, hepatic vessels and spleen size, are diagnosed as “parenchymal liver disease” [16] First prescribed biologic DMARD May 2013, anti-HBs loss December 2013; HBV DNA detected only once, in September 2017, with no recurrence as of August 2020 Hung et al. Advances in Rheumatology (2021) 61:22 Page 8 of 9 found a significant association in univariate analysis; therapy. More research is needed to elucidate other risk however, statistical significance was lost in multivariate factors for loss of anti-HBs and so refine the monitoring analysis, probably because only 4/23 cases had diabetes. strategy to prevent HBV reactivation in patients receiving Previous guidelines or reviews have propounded base- biologic DMARDs to treat rheumatic diseases. line anti-HBs screening prior to using biologic DMARDs, Abbreviations because patients with baseline anti-HBs− serostatus have HBV: Hepatitis B virus; HBsAg: HBV surface antigen; anti-HBc: Antibody to HBV higher risk of HBV reactivation [1, 5, 7, 8]. However, core antigen; anti-HBs: Antibody to HBV surface antigen; DNA: Deoxy- ribonucleic acid; anti-TNF: Tumor necrosis factor inhibitor; DMARD: Disease- current guidelines, particularly those focused on biologic modifying anti-rheumatic drug DMARDs users, neither describe nor elucidate the poten- tial risk of anti-HBs loss during biologic DMARDs therapy Acknowledgements [2, 5, 8]. Our results imply that there is a window of op- David Neil, of Dr. Word Ltd., Taiwan, provided professional editorial services, which were funded by Dr Ying-Ming Chiu. Ya-Chu Yang provided technical portunity to prevent morbid HBV reactivation in patients assistance with laboratory work. at increased risk. We contend that clinicians should closely monitor patients with low baseline anti-HBs titer Authors’ contributions MHH made substantial contributions to conceiving and designing the study, (≤ 100 mIU/ml) and/or chronic kidney disease during analyzing and interpreting data, and drafting the manuscript. YMC made subsequent biologic DMARDs therapy, including follow- substantial contributions to conceiving and designing the study, analyzing up of anti-HBs and HBV DNA titers upon anti-HBs loss, and interpreting data, and critical revision of the manuscript for intellectually important content. YCT was involved in revising the manuscript. All authors to enable timely intervention with appropriate prophylaxis had full control of all primary data, read and approved the final article, and to preempt potential HBV reactivation. Expert opinion agree to be accountable for all aspects of the work described. supports this approach; for example, advocating HBV follow-up and immunization to reduce the risk of reactiva- Authors’ information Not applicable. tion during anti-TNF treatment [4]. This study had limitations, foremost the small sample Funding size. With few cases or control group patients with No specific funding was received from any funding bodies in the public, commercial, or not-for-profit sectors to carry out the work described in this chronic kidney disease, the result of multivariate analysis report. could reflect over-fitting, as the wide confidence interval suggests; larger-scale studies are warranted to corrobor- Availability of data and materials ate this novel but tentative finding. We acknowledge The datasets used and/or analysed during this study are available from the corresponding author on reasonable request. that direct serum HBV DNA assays are the ideal way to monitor patients at risk of HBV reactivation; neverthe- Declarations less, based on our findings, monitoring patients with risk Ethics approval and consent to participate factors for anti-HBs loss may be a convenient and cost- This study was performed in accordance with the ethical standards effective way of targeting hepatitis B prevention, espe- established by the 1964 Declaration of Helsinki and its later amendments. All cially in HBV-endemic regions. Admittedly, only direct participants provided written informed consent before any study-related procedure ensued. monitoring can detect HBV reactivation due to immune- Changhua Christian Hospital Institutional Review Board approved the study escape HBsAg mutations in anti-HBs+ biologic DMARDs protocol. recipients; however, this is a very rare phenomenon [28, 29] and, excepting such cases, detectable HBV DNA loads in Consent for publication Not applicable. anti-HBs+ patients otherwise occur only sporadically, and are self-limiting and clinically benign [11]. Despite consid- Competing interests erable research into whether or not the risks of anti-HBs The authors declare that they have no competing interests. loss or HBV reactivation differ between biologic DMARDs, Author details results to date have been inconclusive [30, 31]; with only 23 Division of Allergy, Immunology and Rheumatology, Department of Internal cases, we were unable to ascertain whether individual Medicine, Changhua Christian Hospital, 135 Nanxiao St., Changhua City 500-06, Taiwan. Department of Allergy, Immunology, and Rheumatology, biologic DMARDs carried similar risks of anti-HBs loss. Tungs’ Taichung MetroHarbor Hospital, 699, Sec. 8, Taiwan Blvd., Taichung City 43503, Taiwan. 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Long-term immunogenicity and efficacy of hepatitis B vaccine in hemodialysis patients. Am J Nephrol. 1992;12:144–7. 22. Tsouchnikas I, Dounousi E, Xanthopoulou, Papakonstantinou S, Thomoglou V, Tsakiris D. Loss of hepatitis B immunity in hemodialysis patients acquired either naturally or after vaccination. Clin Nephrol. 2007;68:228–34. 23. Sester U, Sester M, Hauk M, Kaul H, Köhler H, Girndt M. T-cell activation follows Th1 rather than Th2 pattern in haemodialysis patients. Nephrol Dial Transplant. 2000;5:1217–23. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Advances in Rheumatology Springer Journals

Risk factors for losing hepatitis B virus surface antibody in patients with HBV surface antigen negative/surface antibody positive serostatus receiving biologic disease-modifying anti-rheumatic drugs: a nested case-control study

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Abstract

Background: Hepatitis B virus (HBV) reactivation consequent to immunosuppressive therapy is an increasingly prevalent problem with serious clinical implications. Treatment with biologic agents conduces to the loss of protective antibody to HBV surface antigen (anti-HBs), which significantly increases the risk of HBV reactivation. Hence, we investigated the risk factors for losing anti-HBs in patients with rheumatic diseases and HBV surface antigen negative/anti-HBs positive (HBsAg−/anti-HBs+) serostatus during treatment with biologic disease-modifying anti-rheumatic drugs (DMARDs). Methods: Using a nested case-control design, we prospectively enrolled patients with rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis/psoriasis, or juvenile idiopathic arthritis, who were treated with biologic DMARDs at Changhua Christian Hospital, Taiwan, from January 2013 to June 2019 and had HBsAg−/anti-HBs+ serostatus; the analytic sample excluded all patients with HBsAg+ or anti-HBs− serostatus. Anti-HBs titers were monitored 6-monthly and cases were defined as anti-HBs < 10 mIU/ml during follow-up. Cases were matched one- to-all with controls with anti-HBs ≥ 10 mIU/ml on the same ascertainment date and equivalent durations of biologic DMARDs treatment (control patients could be resampled and could also become cases during follow-up). Between-group characteristics were compared and risk factors for anti-HBs loss were investigated by conditional logistic regression analyses. (Continued on next page) * Correspondence: ymcgreen@yahoo.com.tw Department of Allergy, Immunology, and Rheumatology, Tungs’ Taichung MetroHarbor Hospital, 699, Sec. 8, Taiwan Blvd., Taichung City 43503, Taiwan Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Hung et al. Advances in Rheumatology (2021) 61:22 Page 2 of 9 (Continued from previous page) Results: Among 294 eligible patients, 23 cases were matched with 311 controls. The incidence of anti-HBs loss was ~ 2.7%/person-year during biologic DMARDs treatment. Besides lower baseline anti-HBs titer (risk ratio 0.93, 95% CI 0.89–0.97), cases were significantly more likely than controls to have diabetes mellitus (risk ratio 4.76, 95% CI 1.48– 15.30) and chronic kidney disease (risk ratio 14.00, 95% CI 2.22–88.23) in univariate analysis. Risk factors remaining significantly associated with anti-HBs loss in multivariate analysis were lower baseline anti-HBs titer (adjusted risk ratio 0.93, 95% CI 0.88–0.97) and chronic kidney disease (adjusted risk ratio 45.68, 95% CI 2.39–871.5). Conclusions: Besides lower baseline anti-HBs titer, chronic kidney disease also strongly predicts future anti-HBs negativity in patients with HBsAg−/anti-HBs+ serostatus who receive biologic DMARDs to treat rheumatic diseases. Patients with low anti-HBs titer (≤ 100 mIU/ml) and/or chronic kidney disease should be monitored during biologic DMARDs therapy, to enable timely prophylaxis to preempt potential HBV reactivation. Keywords: Hepatitis B virus (HBV), HBV surface-antigen negative/surface antibody positive (HBsAg−/anti-HBs+), Rheumatic diseases, Biologic disease-modifying anti-rheumatic drug (DMARD), Anti-HBs loss, Chronic kidney disease Background risk factors for anti-HBs loss. To this end, we prospectively Hepatitis B virus (HBV) infection is a global public health studied patients with HBsAg−/anti-HBc+ serostatus dur- concern [1]. Morbid HBV reactivation is characterized by ing/after biologic DMARDs therapy for rheumatic diseases. viral replication and the recurrence of active necro- inflammatory liver disease, which may presage severe Methods hepatitis or even death [1–6]. Rising prevalence of cancer Study subjects and autoimmune diseases and more frequent use of che- The study sample comprised patients at Changhua motherapeutic or immunosuppressive treatment strat- Christian Hospital, Taiwan, with rheumatoid arthritis, egies, have made HBV reactivation consequent to such ankylosing spondylitis, psoriasis, psoriatic arthritis, or therapies an exigent problem [1–5]. Iatrogenic HBV re- juvenile idiopathic arthritis, who were treated with activation is best known in HBV surface-antigen carriers biologic DMARDs from January 2013 to June 2019. (HBsAg+), and comprehensive guidelines cover this high- Only patients with HBsAg−/anti-HBs+ serostatus risk group [1–8]. Recently, attention has increasingly fo- were included and all with HBsAg+ or HBsAg−/anti- cused on patients who are HBsAg-negative with anti- HBs− serostatus were excluded (Fig. 1). All study bodies against HBV core-antigen or surface-antigen subjects fulfilled international diagnostic criteria for (HBsAg−/anti-HBc+ or anti-HBs+), among whom baseline these diseases and were treated according to Taiwan HBV DNA and anti-HBs negative (anti-HBs−)seros- Rheumatology Association guidelines for screening tatus are known risk factors for HBV reactivation and management of viral hepatitis [15]. [9–13]. Although serum HBV DNA is a defining characteristic Hepatitis B serologic testing and HBV DNA of HBV reactivation [1–4], it does not inevitably pro- HBV serology and DNA assays were done every 6 gress to morbid viremia but may manifest transiently months according to Taiwan Rheumatology Association without symptoms, especially whilst anti-HBs serostatus recommendations [15]. HBV assays included serum remains positive [5, 6, 10–12]. On the other hand, anti- HBsAg, anti-HBs and anti-HBc, measured by Architect HBs loss consequent to immunosuppressive treatment i2000SR chemiluminescent microparticle immunoassay of patients with HBsAg−/anti-HBc+ serostatus signifi- (Abbott Laboratories, Abbot Park, Illinois, USA). HBV cantly increases the risk of progression from clinically immunization history of people with anti-HBs+/anti- silent to symptomatic HBV reactivation [9, 10, 12, 13]. HBc− serostatus was not ascertained. Previous studies have shown that anti-HBs can decline Anti-HBs titer < 10 mIU/ml was defined as sero- to seronegative during immunosuppressive therapies, negative. Low anti-HBs titer was defined as 10–100 especially in patients with a low baseline anti-HBs titer mIU/ml, based on evidence of significantly increased [11, 14], but none have systematically investigated likelihood of anti-HBs loss and detectable HBV DNA whether there are other predisposing factors. at anti-HBs titers below 100 mIU/ml and protection In this context, especially given burgeoning use of tumor against HBV reactivation above this threshold [11, necrosis factor inhibitors (anti-TNF) and other biologic 14]. Serum HBV DNA viral load was quantified by disease-modifying anti-rheumatic drugs (DMARDs) to treat Abbott RealTime HBV (Abbott Laboratories, Abbott autoimmune diseases, and elevated HBV reactivation rates Park,Illinois, USA),withaminimalsensitivity of 10 in this setting [2, 4, 5], it is imperative to further elucidate IU/ml. HBV DNA titer ≥ 10 mIU/ml was defined as Hung et al. Advances in Rheumatology (2021) 61:22 Page 3 of 9 Fig. 1 Case-control selection flow chart. DMARDs, disease-modifying anti-rheumatic drugs; HBV, hepatitis B virus; DNA, deoxyribonucleic acid; anti-HBs, HBV surface antibody; HBsAg, HBV surface-antigen; mIU, million International Units. One patient could serve as a control repeatedly during follow-up and control subjects could become cases during the study detectable viral load [11], while the criteria defining criteria for liver surface, liver parenchyma, hepatic clinical HBV reactivation at any serial 6-monthly vessels, and spleen size [16]. follow-up check, were HBV replication ≥ 2log in- crease from baseline or a new appearance of HBV Nested case-control design DNA to ≥ 100 IU/ml in people with previously stable We used a nested case-control design, which enables or undetectable levels [1]. efficient analysis of time-dependent exposures on rare outcomes where only a limited sample from a larger population is practical, without compromising statistical Covariate information power [17–19]. Unlike conventional cohort studies, which Baseline data included: age, sex, type of rheumatic compare cases versus controls from a fully enumer- disease (rheumatoid arthritis, ankylosing spondylitis, ated population, a nested case-control design identi- psoriatic arthritis/psoriasis, juvenile idiopathic arth- fies occurrences of events of interest in a defined ritis), accumulated doses of conventional DMARDs sub-population and matches these with a specified (prednisolone, hydroxychloroquine, sulfasalazine, number of control subjects drawn from the same methotrexate, leflunomide, cyclosporine) and biologic sub-sample, but who were not yet affected by the DMARDs (etanercept, adalimumab, golimumab, uste- same event when it occurred in their corresponding kinumab, secukinumab, tocilizumab, rituximab, abata- case [18, 19]. This design means that controls can cept, tofacitinib). Chronic kidney disease was defined become cases later during follow-up and that each as estimated glomerular filtration rate < 60 ml/min/ patient may serve as a control repeatedly (though at 1.73 m . Chronic liver disease status was determined different times); thus, cases are compared with con- from medical charts or hepatic ultrasound results and trols from the same patient sample, which lessens included cirrhosis, fatty liver, and “parenchymal liver the likelihood of selection bias [17–20]. disease”, which is a term used in Taiwan, to denote The first prescription of a biologic DMARD defined the ultrasound findings intermediate between “normal” start point. Cases were defined upon occurrences of serum and “cirrhosis”, based on sonographic evaluation anti-HBs titer < 10 mIU/ml during follow-up, with the Hung et al. Advances in Rheumatology (2021) 61:22 Page 4 of 9 date when anti-HBs loss was ascertained designated the 0.88–0.97) and chronic kidney disease (adjusted risk event date. Each case was matched one-to-all with ratio 45.68, 95% CI 2.39–871.5). subjects whose serum HBsAb titer was ≥ 10 mIU/ml on the respective case ascertainment date and who had an Clinical features and outcomes of subjects with anti-HBs equivalent duration of biologic DMARDs treatment. loss Thirteen cases had rheumatoid arthritis (Table 3). All cases’ baseline anti-HBs titers were low (≤ 100 mIU/ml), Data analysis and statistics mean 22.6. Fourteen were prescribed anti-TNF agents: All analyses were done using nonparametric statistical four etanercept, six adalimumab, and four golimumab. software (LogXact 11, Cytel Software Corp, Cambridge, Three were prescribed tofacitinib. Two cases each were MA, USA) with penalized maximum likelihood to prescribed ustekinumab or tocilizumab, while one each remove first-order bias. A p-value < 0.05 for two-sided received abatacept or rituximab. tests was considered statistically significant. Continuous No cases (nor anti-HBs+ controls) had clinical HBV variables were expressed as means plus/minus standard reactivation during follow-up (852 person-years), and no deviation or mean [range], categorical variables as cases developed alanine transaminase elevation, or re- numbers (percentages). Conditional logistic regression ceived any anti-viral treatment during median follow-up analysis was used to estimate risk ratios and 95% confi- of 30 months (range 0–77) after anti-HBs loss. Only one dence intervals for loss of anti-HBs; putative associated of the 16/23 cases whose serum HBV DNA was moni- factors included age, sex, type of rheumatic disease, tored after anti-HBs loss ever had a detectable viral load conventional DMARDs, biologic DMARDs (anti-TNF or (Table 3), which was observed only once, with no recur- others), comorbidity, and baseline anti-HBs titer. rence as of August 2020. Results Discussion Demographic characteristics and clinical status We believe this to be the first report of risk factors asso- The analytic samples drawn from 294 patients with ciated with loss of anti-HBs in rheumatic patients during HBsAg−/anti-HBs+ serostatus at baseline, comprised 23 biologic DMARDs therapy, after controlling for putative cases and 311 matched controls (Fig. 1); Table 1 shows risk factors. We discovered that besides lower baseline their demographic and clinical characteristics. Mean age anti-HBs titer, chronic kidney disease independently pre- and rheumatic disease types were similar between case dicts anti-HBs loss. and control groups. No patients with HBsAg−/anti- Our finding that lower pretreatment anti-HBs titer HBs+ serostatus had detectable HBV DNA at enrolment. (≤ 100 mIU/ml) is a risk factor for loss of anti-HBs, Compared with controls, cases had lower baseline serum is consistent with a study of rituximab-based therapy anti-HBs titers, more prevalent comorbidities (including for lymphoma [14]. Moreover, baseline anti-HBs posi- hepatitis C virus infection, chronic liver disease, diabetes tivity was protective against HBV reactivation among mellitus, chronic kidney disease), and relatively higher patients with HBsAg−/anti-HBc+ serostatus who re- accumulated doses of sulfasalazine, leflunomide, and ceived immunosuppressive or biologic agents [9–14]. prednisolone. Most people in both groups used anti- Therefore, our results suggest that anti-HBs may be TNF agents (etanercept, adalimumab, golimumab). No lost during/after immunosuppressive/biologic therapy, study subjects were kidney transplant recipients. especially in people with a low baseline titer, with consequently elevated risk of HBV reactivation. Incidence of anti-HBs loss and associated risk factors Although we detected no cases of morbid viremia and The incidence rate of anti-HBs loss in 294 patients with just one occurrence of minimal HBV DNA during HBsAg−/anti-HBs+ serostatus during biologic DMARDs follow-up, this was not necessarily inconsistent with evi- treatment was 23/852 person-years: ~ 2.7%/person-year. dence that anti-HBs negativity increases the risk of HBV Table 2 shows risk factors associated with loss of anti- reactivation in patients with HBsAg−/anti-HBc+ serosta- HBs in univariate and multivariate conditional logistic tus. Anti-HBs may remain persistently low or negative regression analyses. Besides lower baseline anti-HBs titer during treatment, with HBV DNA detected periodically (risk ratio 0.93, 95% CI 0.89–0.97), cases were signifi- but without progression to morbid reactivation [5, 6, 11, cantly more likely than controls to have diabetes mellitus 12]. Reported rates of HBV DNA manifestation during/ (risk ratio 4.76, 95% CI 1.48–15.30) and chronic kidney after immunosuppressive therapy in patients with disease (risk ratio 14.00, 95% CI 2.22–88.23) in the HBsAg−/anti-HBs−/anti-HBc+ serostatus are in the univariate analysis. However, the only factors remaining order of 1–10%, with symptomatic reactivation in a significant in the multivariate model, were lower baseline smaller fraction of cases [9–12]; therefore, 23 cases may serum anti-HBs titer (adjusted risk ratio 0.93, 95% CI have been too few to detect occasional reactivation Hung et al. Advances in Rheumatology (2021) 61:22 Page 5 of 9 Table 1 Baseline characteristics of cases and controls treated with biologic DMARDs Data show mean ± standard deviation, mean [range], or number (%) Cases Controls Number 23 311 Age (years) 52.2 ± 17.9 47.5 ± 14.2 Sex Female 15 (65.2%) 148 (47.6%) Male 8 (34.8%) 163 (52.4%) Rheumatic disease Rheumatoid arthritis 13 (56.5%) 155 (49.8%) Ankylosing spondylitis 5 (21.7%) 100 (32.2%) Psoriatic arthritis/Psoriasis 4 (17.4%) 52 (16.7%) Juvenile idiopathic arthritis 1 (4.4%) 4 (1.3%) Detectable HBV DNA (≥10 IU/ml) 0 0 Anti-HBV core antigen positive 15 (65.2%) 189 (60.8%) Baseline serum anti-HBs titer (mIU/ml) Mean [Min–Max] 22.6 [10.1–64.7] 284.5 [11.5–1000] ≤ 100 23 (100%) 128 (41.2%) > 100 0 183 (58.8%) Biologic DMARDs Anti-TNF (Etanercept, Adalimumab, Golimumab) 14 (60.9%) 231 (74.3%) Not anti-TNF 9 (39.1%) 80 (25.7%) Abatacept 1 (4.4%) 11 (3.5%) Rituximab 1 (4.4%) 11 (3.5%) Tocilizumab 2 (8.7%) 12 (3.9%) Tofacitinib 3 (13.0%) 19 (6.1%) Ustekinumab 2 (8.7%) 25 (8.0%) Secukinumab 0 2 (0.6%) Conventional DMARDs (accumulated dose) Methotrexate (mg) 536 ± 869 537 ± 734 Leflunomide (mg) 748 ± 2083 707 ± 3021 Sulfasalazine (g) 350 ± 354 242 ± 318 Hydroxychloroquine (g) 67 ± 102 54 ± 100 Cyclosporine (g) 9 ± 22 8 ± 27 Prednisolone (accumulated dose, mg) 2244 ± 2614 1422 ± 1910 Comorbidities Prior alanine transaminase elevation 2 (8.7%) 10 (3.2%) Hepatitis C virus antibody positive 2 (8.7%) 11 (3.5%) Diabetes mellitus 4 (17.4%) 12 (3.9%) Chronic liver disease 5 (21.7%) 30 (9.7%) Chronic kidney disease 3 (13.0%) 3 (1.0%) HBV Hepatitis B virus, DNA Deoxyribonucleic acid, Anti-HBs HBV surface antibody, IU International Units, DMARD Disease-modifying anti-rheumatic drug, TNF Tumor necrosis factor Maximum detectable limit More than five-fold upper reference of 40 IU/L events. The follow-up duration (median 30 months after cycles of therapy have diminished anti-HBs to undetect- anti-HBs loss) may also have been insufficient. HBV able levels [6], and clinical reactivation may not occur DNA in such patients usually appears late, after several until several years since commencing immunosuppressive Hung et al. Advances in Rheumatology (2021) 61:22 Page 6 of 9 Table 2 Risk factors associated with loss of HBV surface antibody Univariate analysis Multivariate analysis Risk ratio (95% CI) p-value Risk ratio (95% CI) p-value Age 1.02 (0.99–1.05) 0.153 Sex Female 1 (reference) 0.097 Male 0.48 (0.20–1.14) Rheumatic disease Rheumatoid arthritis 1 (reference) 0.582 Ankylosing spondylitis 0.60 (0.21–1.72) Psoriatic arthritis/Psoriasis 0.87 (0.28–2.76) Juvenile idiopathic arthritis 2.73 (0.29–25.57) Anti-HBV core antigen positive 1.23 (0.51–2.95) 0.641 Baseline serum anti-HBs titer (mIU/ml) Lower vs higher (continuous) 0.93 (0.89–0.97) 0.001 0.93 (0.88–0.97) 0.002 > 100 1 (reference) 1 (reference) ≤ 100 46.8 (10.09–∞) < 0.001 43.98 (9.34–∞) < 0.001 Biologic DMARDs Anti-TNF 1 (reference) 0.204 Not anti-TNF 1.80 (0.73–4.49) Conventional DMARDs Methotrexate 1.00 (1.00–1.00) 0.942 Sulfasalazine 1.00 (1.00–1.00) 0.135 Hydroxychloroquine 1.00 (1.00–1.01) 0.515 Cyclosporine 1.00 (0.99–1.02) 0.888 Leflunomide 1.00 (1.00–1.00) 0.958 Prednisolone 1.00 (1.00–1.00) 0.064 Comorbidity Prior alanine transaminase elevation 2.93 (0.59–14.54) 0.188 Hepatitis C virus antibody positive 2.64 (0.54–12.92) 0.232 Diabetes mellitus 4.76 (1.48–15.30) 0.009 0.85 (0.19–3.92) 0.838 Chronic liver disease 2.62 (0.90–7.66) 0.079 Chronic kidney disease 14.00 (2.22–88.23) 0.005 45.68 (2.39–871.5) 0.011 Anti-HBs Hepatitis B virus surface antibody, DMARD Disease-modifying anti-rheumatic drug, TNF Tumor necrosis factor More than five-fold upper reference of 40 IU/L Baseline anti-HBs as continuous variable Baseline anti-HBs continuous + chronic kidney disease + diabetes mellitus therapy [10–12]; median time from starting immunosup- related nephropathy, and widespread use of nephrotoxic pressive therapy to HBV reactivation in a cohort of 1042 medications such as non-steroidal anti-inflammatory rheumatic disease patients with resolved HBV infections drugs or cyclosporine. Studies have shown that patients was 66 months [12]. However, 18/23 cases in our study with chronic kidney disease lose anti-HBs faster than had total follow-up of < 66 months. healthy subjects do [21, 22]; anti-HBs loss in chronic This is the first indication of which we know that kidney disease or dialysis patients has been attributed to chronic kidney disease might be a risk factor for loss of diminished interleukin-2 secretion, impaired macro- anti-HBs in patients treated with biologic DMARDs. phage function, decreasing memory B cell counts, and a This is an important contemporary issue because weak amnestic response [23–25]. chronic kidney disease is prevalent among patients with Consistent with reports of increased likelihood of anti- rheumatic diseases, consequent to older age, diabetes- HBs loss in patients with diabetes mellitus [26, 27], we Hung et al. Advances in Rheumatology (2021) 61:22 Page 7 of 9 Table 3 Characteristics of patients with anti-HBs loss during treatment with biologic DMARDs Baseline Time to Medication when anti-HBs loss occurred Comorbidities Total HBV status and treatment after anti-HBs loss anti-HBs follow-up Disease Serum HBV antibodies Biologic Conventional DMARD (accumulated dose, g) HCV Chronic DM CKD Viral load HBV Antiviral loss (months) b c DMARD liver (IU/ml) reactivation therapy HBs (mIU/ml) HBc (months) Pd MTX LEF HCQ SSZ CsA disease RA 10.1 – 15 TOF 3.0 0.6 0 181 236 0 – ND –– 32 ND –– RA 13.2 + 25 ETA 3.9 0 0 280 699 34 + Fatty liver + + 74 U –– RA 13.4 – 11 TOF 0 0.8 0 141 0 0 – ND –– 23 ND –– RA 14.8 – 13 TOF 2.1 0.5 0 90 394 0 – ND –– 30 U –– RA 16.1 + 22 TCZ 4.4 0 9.2 0 713 0 – PLD + – 47 U –– RA 16.5 + 17 ABT 2.6 0 0 40 588 0 – ND – +39 U –– RA 17.3 + 7 ADA 1.1 0.5 0 84 294 0 – Normal + – 65 10 –– RA 17.7 + 61 GOL 7.2 3.3 0 363 714 0 – ND –– 61 U –– RA 18.3 + 18 ETA 2.7 1.2 0 218 1092 0 – Normal –– 68 U –– RA 23.4 + 60 ADA 5.8 2.6 0 74 0 0 – Normal –– 76 ND –– RA 41.9 + 3 ETA 0.7 0 0 45 224 4 – Normal –– 80 U –– RA 44.7 + 10 RTX 2.5 0.6 0 28 182 8 + PLD –– 57 U –– RA 56.3 – 42 TCZ 9.8 1.3 3.8 6 1295 0 – Normal – +54 ND –– AS 11.5 + 22 GOL 0 0 0 0 172 0 – Normal –– 33 U – − AS 14.3 – 7 GOL 0 0 0 0 163 0 – Normal –– 51 ND –– AS 21.7 + 34 ADA 0.4 0 0 0 294 0 – Normal –– 75 U –– AS 26.3 – 42 ADA 0.4 0 0 0 456 0 – Normal –– 60 ND –– AS 64.7 – 4 ADA 0.3 0 0 0 228 0 – Normal –– 36 U –– PsO 10.1 + 5 GOL 0.6 0 2.8 0 0 22 – Fatty liver + – 46 U –– PsO 12.3 + 16 UST 0 0.5 0 0 0 90 – Normal –– 62 U –– PsO 17.3 + 17 UST 0 0 0 0 0 53 – Fatty liver –– 47 U –– PsA 27 + 28 ADA 3.8 0 1.4 0 56 0 – ND –– 35 U –– JIA 10.1 – 4 ETA 0.4 0.3 0 0 256 0 – Normal –– 60 ND –– RA Rheumatoid arthritis, AS Ankylosing spondylitis, PsO Psoriatic arthritis, PSA Psoriasis, JIA Juvenile idiopathic arthritis, HBV Hepatitis B virus, HBs HBV surface antigen, HBc HBV core protein, DMARD Disease-modifying anti-rheumatic drug, Pd Prednisolone, MTX Methotrexate, LEF Leflunomide, HCQ Hydroxychloroquine, SSZ Sulfasalazine, CsA Cyclosporine, TOF Tofacitinib, ETA Etanercept, TCZ Tocilizumab, ABT Abatacept, ADA Adalimumab, GOL Golimumab, RTX Rituximab, UST Ustekinumab, HCV Hepatitis C virus, DM Diabetes mellitus, CKD Chronic kidney disease, PLD Parenchymal liver disease, U Undetectable, ND Not done Based on ultrasound findings At any serial 6-monthly check during follow-up HBV replication > 2 log increase from baseline or a new appearance of HBV DNA to > 100 IU/ml in people with previously stable or undetectable levels In Taiwan, ultrasound findings intermediate between “normal” and “cirrhosis” based on sonographic evaluation criteria for liver surface, liver parenchyma, hepatic vessels and spleen size, are diagnosed as “parenchymal liver disease” [16] First prescribed biologic DMARD May 2013, anti-HBs loss December 2013; HBV DNA detected only once, in September 2017, with no recurrence as of August 2020 Hung et al. Advances in Rheumatology (2021) 61:22 Page 8 of 9 found a significant association in univariate analysis; therapy. More research is needed to elucidate other risk however, statistical significance was lost in multivariate factors for loss of anti-HBs and so refine the monitoring analysis, probably because only 4/23 cases had diabetes. strategy to prevent HBV reactivation in patients receiving Previous guidelines or reviews have propounded base- biologic DMARDs to treat rheumatic diseases. line anti-HBs screening prior to using biologic DMARDs, Abbreviations because patients with baseline anti-HBs− serostatus have HBV: Hepatitis B virus; HBsAg: HBV surface antigen; anti-HBc: Antibody to HBV higher risk of HBV reactivation [1, 5, 7, 8]. However, core antigen; anti-HBs: Antibody to HBV surface antigen; DNA: Deoxy- ribonucleic acid; anti-TNF: Tumor necrosis factor inhibitor; DMARD: Disease- current guidelines, particularly those focused on biologic modifying anti-rheumatic drug DMARDs users, neither describe nor elucidate the poten- tial risk of anti-HBs loss during biologic DMARDs therapy Acknowledgements [2, 5, 8]. Our results imply that there is a window of op- David Neil, of Dr. Word Ltd., Taiwan, provided professional editorial services, which were funded by Dr Ying-Ming Chiu. Ya-Chu Yang provided technical portunity to prevent morbid HBV reactivation in patients assistance with laboratory work. at increased risk. We contend that clinicians should closely monitor patients with low baseline anti-HBs titer Authors’ contributions MHH made substantial contributions to conceiving and designing the study, (≤ 100 mIU/ml) and/or chronic kidney disease during analyzing and interpreting data, and drafting the manuscript. YMC made subsequent biologic DMARDs therapy, including follow- substantial contributions to conceiving and designing the study, analyzing up of anti-HBs and HBV DNA titers upon anti-HBs loss, and interpreting data, and critical revision of the manuscript for intellectually important content. YCT was involved in revising the manuscript. All authors to enable timely intervention with appropriate prophylaxis had full control of all primary data, read and approved the final article, and to preempt potential HBV reactivation. Expert opinion agree to be accountable for all aspects of the work described. supports this approach; for example, advocating HBV follow-up and immunization to reduce the risk of reactiva- Authors’ information Not applicable. tion during anti-TNF treatment [4]. This study had limitations, foremost the small sample Funding size. With few cases or control group patients with No specific funding was received from any funding bodies in the public, commercial, or not-for-profit sectors to carry out the work described in this chronic kidney disease, the result of multivariate analysis report. could reflect over-fitting, as the wide confidence interval suggests; larger-scale studies are warranted to corrobor- Availability of data and materials ate this novel but tentative finding. We acknowledge The datasets used and/or analysed during this study are available from the corresponding author on reasonable request. that direct serum HBV DNA assays are the ideal way to monitor patients at risk of HBV reactivation; neverthe- Declarations less, based on our findings, monitoring patients with risk Ethics approval and consent to participate factors for anti-HBs loss may be a convenient and cost- This study was performed in accordance with the ethical standards effective way of targeting hepatitis B prevention, espe- established by the 1964 Declaration of Helsinki and its later amendments. All cially in HBV-endemic regions. Admittedly, only direct participants provided written informed consent before any study-related procedure ensued. monitoring can detect HBV reactivation due to immune- Changhua Christian Hospital Institutional Review Board approved the study escape HBsAg mutations in anti-HBs+ biologic DMARDs protocol. recipients; however, this is a very rare phenomenon [28, 29] and, excepting such cases, detectable HBV DNA loads in Consent for publication Not applicable. anti-HBs+ patients otherwise occur only sporadically, and are self-limiting and clinically benign [11]. Despite consid- Competing interests erable research into whether or not the risks of anti-HBs The authors declare that they have no competing interests. loss or HBV reactivation differ between biologic DMARDs, Author details results to date have been inconclusive [30, 31]; with only 23 Division of Allergy, Immunology and Rheumatology, Department of Internal cases, we were unable to ascertain whether individual Medicine, Changhua Christian Hospital, 135 Nanxiao St., Changhua City 500-06, Taiwan. Department of Allergy, Immunology, and Rheumatology, biologic DMARDs carried similar risks of anti-HBs loss. Tungs’ Taichung MetroHarbor Hospital, 699, Sec. 8, Taiwan Blvd., Taichung City 43503, Taiwan. 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