Deleterious role of hepatitis B virus infection in therapeutic response among patients with rheumatoid arthritis in a clinical practice setting: a case-control study

Deleterious role of hepatitis B virus infection in therapeutic response among patients with... Background: Previous studies have revealed that hepatitis B virus (HBV) infection may be associated with rheumatoid arthritis (RA), while there are no further clinical studies regarding the role of HBV infection in RA progression during disease-modifying anti-rheumatic drug (DMARD) therapy. Here, we aimed to explore the influence of HBV infection on radiographic and clinical outcomes among patients with RA in a clinical practice setting. Methods: Thirty-two consecutive patients with RA (Disease Activity Score 28-joint assessment based on C-reactive protein (DAS28-CRP) ≥2.6) with chronic HBV infection (CHB) were retrospectively recruited as the CHB group and 128 age-matched, sex-matched, and disease activity-matched contemporary patients with RA without CHB were included in the non-CHB group. Clinical data were collected at baseline and visits at month 1, 3, 6, and 12. The therapeutic target was defined as DAS28-CRP <2.6 in all patients or <3.2 in patients with long disease duration (>24 months). The primary outcome was the percentage of patients with one-year radiographic progression (a change in modified total Sharp score ≥0.5). Results: Compared with the non-CHB group, a significantly higher percentage of patients with one-year radiographic progression was observed in the CHB group (53% vs. 17%, p < 0.001), with smaller proportions of patients achieving therapeutic target at month 6 and month 12 (53% vs. 82% and 53% vs. 75%, both p < 0.05), remission at month 6 (DAS28-CRP <2.6, 50% vs. 72%, p = 0.039), and American College of Rheumatology (ACR)20/50 responses and good or moderate European League Against Rheumatism (EULAR) responses mainly at month 6 and 12 (all p < 0.05). Multivariate logistic regression analysis revealed that CHB status was significantly associated with one-year radiographic progression and failure to achieve therapeutic target within 6 months. HBV reactivation occurred in 34% of patients with CHB during one-year follow up, with two patients suffering hepatitis flare. Conclusions: HBV infection may play a deleterious role in radiographic and clinical outcomes in patients with RA, and HBV reactivation should be paid close attention during immunosuppressive therapy. Keywords: Hepatitis B virus, Rheumatoid arthritis, Radiographic progression, Clinical response * Correspondence: zhengouyang@sina.com; dailie@mail.sysu.edu.cn Department of Rheumatology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People’s Republic of China Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Chen et al. Arthritis Research & Therapy (2018) 20:81 Page 2 of 13 Background between June 2012 and August 2016 at Sun Yat-Sen Rheumatoid arthritis (RA) is a systemic autoimmune Memorial Hospital from a prospective cohort, as de- disease affecting millions of people worldwide, which scribed in our previous study [17]. All patients were is characterized by synovitis with bone and cartilage treated according to the “treat-to-target” strategy [18, destruction. The etiology of RA remains largely un- 19] and completed at least one year of follow up. known [1]. Genetic predisposition is not sufficient to Consecutive patients with RA with HBsAg positivity explain RA development, and environmental triggers, persisting in serum for more than 6 months were re- especially infectious agents such as Epstein-Barr virus, cruited as the CHB group. Each patient with RA in cytomegalovirus, and Proteus mirablis, have been re- the CHB group was matched by age (± 5 years), sex, ported to be linked with RA pathogenesis [2]. New and disease activity at baseline to four subjects with- evidence shows that the oral and gut microbiomes out HBsAg positivity or HBV DNA in serum, who are perturbed in patients with RA and partly normal- comprised the non-CHB group. The timing of base- ized after RA treatment, suggesting a significant role line for the four matched patients in the non-CHB of microbiomes in RA [3]. Despite these studies, the group was as close as possible to baseline for the cor- identity and pathogenicity of most factors implicating responding patient in the CHB group. Other inclusion a role in RA are not yet clear. criteria were patients aged ≥ 18 years and patients Hepatitis B virus (HBV) infection continues to be one of with active disease defined as Disease Activity Score worldwide leading disease burdens. About 248 million 28-joint assessment (DAS28) with four variables in- (3.61%) individuals globally have been reported as HBV cluding C-reactive protein (DAS28-CRP) ≥2.6. The ex- surface antigen (HBsAg)-positive, with 74 million Chinese clusion criteria were elevated aminotransferase at baseline; patients (5.49%) in 2010 [4]. HBV primarily infects human other overlapping autoimmune diseases (e.g. systemic hepatocytes, and also leads to a series of extrahepatic lupus erythematosus, scleroderma, dermatomyositis, poly- manifestations or diseases such as polyarthritis, glomer- arteritis nodosa, cryoglobulinaemia, nephritis); Wilson’s ulonephritis, polyarteritis nodosa, and cryoglobulinemia disease, steatohepatitis, hemochromatosis, Schistosomiasis [5]. HBV-related antigens and nucleic acids have been japonica, or drug-induced hepatitis; concomitant infection demonstrated in a variety of extrahepatic tissues, including with hepatitis C virus, hepatitis D virus, or human lymph nodes, kidney, skin, colon, stomach, testis, and immunodeficiency virus; other serious infection, organ ovaries [6]. Only a few studies have revealed a possibility dysfunction, or malignancy; and lactating or pregnant of the presence of HBV proteins and DNA in synovial tis- women. This study was conducted in compliance with the sues from patients with HBV infection [7, 8]. Surprisingly, Helsinki Declaration. Due to the retrospective nature of several patients with concurrent HBV infection who ful- the study, informed consent was waived. The study was filled the diagnostic criteria of American College of approved by the Medical Ethics Committee of Sun Yat- Rheumatology (ACR) for RA were shown to have disease Sen Memorial Hospital (identifier SYSEC-KY-KS-011). resolved by anti-HBV treatment [9, 10]. Additionally, prior studies have documented higher serum HBsAg positivity Treatment and clinical data collection in patients with RA than in non-RA controls [11, 12]. Our All patients were treated according to the 2008/2012 previous studies identified 11.2% HBsAg positivity in ACR [20, 21] and the 2010/2013 EULAR [18, 19] recom- Chinese patients with RA and HBV reactivation as a com- mendations for the management of RA. The therapeutic mon but tricky complication in HBsAg-positive patients target was defined as DAS28-CRP <2.6 in all patients or with RA undergoing immunosuppressive therapy [13, 14]. <3.2 in patients with long disease duration (>24 months) Thus, HBV infection and RA are somehow linked. How- [18, 19]. Available clinical data on patients with RA were ever, until now, no longitudinal studies have examined the collected in this study at baseline and at visits at months role of HBV infection in disease progression during RA 1, 3, 6, and 12, as described before [17], including 28- treatment. Therefore, the aim of the present study was to joint tender and swollen joint counts (TJC28 and explore the influence of HBV infection on therapeutic SJC28), patient and provider global assessment of disease response and the safety of immunosuppressive therapy in activity (PtGA and PrGA, respectively), pain visual ana- patients with RA with CHB. log scale (pain VAS), the Stanford Health Assessment Questionnaire (HAQ), erythrocyte sedimentation rate Methods (ESR), CRP, rheumatoid factor (RF), and anti-cyclic Study patients and design citrullinated peptide antibody (ACPA). Besides DAS28- Patients with RA who fulfilled the 1987 revised cri- CRP, disease activity was also assessed using the Simpli- teria of the ACR [15] or the 2010 ACR/European fied Disease Activity Index (SDAI), the Clinical Disease League Against Rheumatism (EULAR) criteria for the Activity Index (CDAI), and the Routine Assessment of classification of RA [16] were retrospectively recruited Patient Index Data 3 (RAPID3) [22]. Cumulative doses Chen et al. Arthritis Research & Therapy (2018) 20:81 Page 3 of 13 of oral glucocorticosteroids (GCs) and disease-modifying remission, rates of EULAR responses and ACR20/50/70 anti-rheumatic drugs (DMARDs) were recorded during responses [27], and changes in disease activity indicators. one-year follow up. GC doses were converted to a prednisone-equivalent dose. Safety assessments Serological markers of HBV infection, including HBsAg, Side effects were recorded and evaluated at each visit. HBV e antigen (HBeAg), the corresponding antibodies to Neutropenia was defined as neutrophil count <2.0 × these antigens (anti-HBs and anti-HBe, respectively), and 10 /L. HBV reactivation was defined as the reappearance antibodies to HBV core antigen (anti-HBc), were tested in of HBsAg in a patient with resolved HBV infection, the all patients with RA using enzyme-linked immunosorbent detection of previously undetectable HBV DNA or > 1 assay (Zhongshan Biotechnology CO., LTD, Guangdong, log10 (10-fold) IU/mL increase in serum HBV DNA, China) or electrochemluminescence-immunoassay (Roche and rise in HBV DNA level above an arbitrary cutoff Diagnostics, Mannheim, Germany). HBV DNA was mea- (for example, 20,000 IU) in patients with biochemical sured using a commercially available quantitative real- worsening [28–30]. A hepatitis flare was determined to time polymerase chain reaction kit (Da An Gene Co., Ltd. be present when ALT was greater than two times the of Sun Yat-Sen University, Guangdong, China), with the upper limit of the normal range (ULN) [30]. lowest detection threshold of 500 IU/mL. Liver function including alanine aminotransferase (ALT, U/L, normal Statistical analysis range 5–40 U/L) and aspartate transaminase (AST, U/L, Statistical analyses were performed using IBM SPSS Sta- normal range 5–40 U/L) was tested at each visit during tistics version 20.0 software (IBM, Armonk, NY, USA). follow up. HBV serological markers and HBV DNA levels Descriptive statistics (median, interquartile range (IQR) were evaluated in all patients with RA at baseline and or 5th/95th percentile ranges) were calculated for every 1–3 months during follow up in the CHB group. continuous variables and categorical variables were pre- These parameters in the non-CHB group were re- sented as frequencies and percentages. Conditional logis- examined if aminotransferase was elevated during follow tic regression analysis was used to compare continuous up. Antiviral prophylaxis by entecavir or tenofovir was and categorical variables between the CHB group and suggested for all patients with RA with CHB before RA the non-CHB group, and odds ratios (ORs) and 95% treatment. Moreover, serum levels of soluble matrix me- confidence intervals (CIs) were calculated to identify risk talloproteinase (MMP-3) were tested as described before factors for one-year radiological progression and failure [23]. The normal ranges of serum MMP-3 concentrations to achieve therapeutic target within 6 months. Variables were 18–60 ng/mL (women) and 24–120 ng/mL (men). were included in the equation when the p value was < 0.05 or removed when the p value was > 0.10, following Radiographic assessments the step-forward selection rule. A two tailed p value Radiographs of the bilateral hands and wrists (antero- <0.05 was considered statistically significant. posterior view) of all patients were performed at baseline and month 12. The Sharp/van der Heijde-modified total Results Sharp score (mTSS), joint erosion (JE), and joint space Demographic characteristics of patients with RA at narrowing (JSN) were scored by two experienced baseline observers (MJD from the Department of Rheumatology A total of 32 patients with RA with CHB were included in and YZH from the Department of Radiology), who were the study, of whom 27 (84%) were female. There were blinded to the patients’ clinical data. As described previ- 72% of patients who were both RF and ACPA positive, ously [17], reliability and agreement were assessed based and 78% of patients had bony erosion at baseline. Eleven on the intra-class correlation coefficient (ICC): the mean (34%) patients were treatment-naïve, without previous GC ICC for inter-observer agreement was 0.950. Bony ero- or DMARD therapy for 6 months before enrollment. sion was defined as a cortical break identified on radiog- Fourteen (44%) patients had a level of HBV DNA above raphy [24]. Radiographic progression was defined as a 500 IU/mL, of whom 11 (34%) had levels above 10 IU/ change in mTSS (ΔmTSS) ≥0.5 units [25], and rapid mL and 8 (25%) had levels above 10 IU/mL, all with nor- radiographic progression (RRP) was defined as ΔmTSS mal liver function. A total of 128 age-matched, sex- ≥5 units from baseline to month 12 [26]. matched, and baseline disease activity-matched RA con- trols in the non-CHB group were compared with patients Outcome assessments with RA with CHB. There was no significant difference in The primary outcome was the percentage of patients with baseline demographic and clinical characteristics between one-year radiographic progression. The secondary out- groups, except for significantly higher levels of JE subscore comes were determined at each visit. These were the per- and mTSS, and significantly greater proportions of pa- centages of patients achieving therapeutic target and tients using sulfasalazine (SSZ) and hydroxychloroquine Chen et al. Arthritis Research & Therapy (2018) 20:81 Page 4 of 13 (HCQ) in the previous 6 months before enrollment in the 17%, p < 0.001), with a similar trend in RRP (16% vs. 5%, CHB group (both p <0.05, Table 1). p = 0.059). Significantly higher levels of JE subscore, JSN subscore, and mTSS at month 12 were observed and Comparison of treatment after enrollment there were more increases in JE subscore and mTSS in Initial treatment after enrollment and therapy adjust- the CHB group than those in the non-CHB group (all p ment were according to the “treat-to-target” strategy and < 0.05). The cumulative probability distribution of radio- patient’s willingness. There was no significant difference graphic change from baseline to month 12 in patients between groups in the initial therapy using GCs, metho- with RA in both groups and the space between the trexate (MTX), iguratimod, or biologic agents after en- curves indicated there was a significantly higher percent- rollment (all p > 0.05, Table 2). Compared with the non- age of patients with CHB who had one-year radiographic CHB group, significantly higher percentages of patients progression (Fig. 1a-c). in the CHB group took SSZ and HCQ (44% vs. 2% and 75% vs. 11%, respectively; both p < 0.001), while a signifi- Patients with RA with CHB achieved a lower level of cantly smaller proportion of patients with CHB took clinical response leflunomide (LEF) (16% vs. 84%, p < 0.001). Accordingly, At month 6, the proportions of patients achieving thera- patients in the CHB group received significantly higher peutic target (53% vs. 82%, p = 0.003) and remission cumulative doses of SSZ, HCQ, and cyclosporin A (50% vs. 72%, p = 0.039) were significantly smaller in the (CysA), while taking significantly lower cumulative doses CHB group than those in the non-CHB group, with a of methotrexate (MTX) and LEF both within the initial similar trend of achieving therapeutic target and remis- 6 months after enrollment and during one-year follow sion at month 12 (53% vs. 75%, p = 0.034 and 44% vs. up (all p < 0.05). Combined DMARDs were used in 31 63%, p = 0.077, respectively) (Fig. 2a, b). The percentages (97%) patients in the CHB group and 125 (98%) in the of ACR20 and ACR50 responders were also significantly non-CHB group. Compared with the non-CHB group, a lower in the CHB group versus the non-CHB group at greater proportion of CHB patients used the regimen of month 6 (56% vs. 81%, p = 0.013 and 47% vs. 70%, p = MTX combined with SSZ and HCQ (34% vs. 1%, p < 0.029, respectively) (Fig. 2c, d). Additionally, compared 0.001), while a smaller percentage of patients in the with the non-CHB group, the percentage of patients CHB group used the regimen of MTX combined with achieving good or moderate EULAR response was sig- LEF (9% vs. 72%, p < 0.001). Six (19%) patients in the nificantly lower in the CHB group at month 3 (75% vs. CHB group and 38 (30%) in the non-CHB group were 91%, p = 0.038) and month 12 (69% vs. 91%, p = 0.004); treated with a combination of conventional synthetic a significantly smaller proportion of patients achieving a DMARDs (csDMARDs) and biologic agents (toci- good EULAR response was observed in the CHB group lizumab, infliximab, or recombinant human tumor ne- at month 6 (56% vs. 79%, p = 0.022) and month 12 (53% crosis factor-α receptor-II (Yi Sai Pu, biosimilar)). and 74%, p = 0.041) (Fig. 2e, f). Antiviral prophylaxis by entecavir or tenofovir was The results of dynamic disease activity indicators dur- suggested for all patients with RA with CHB. However, ing one-year follow up are shown in Fig. 2g-n. Disease due to economic reasons, only 14 (44%) patients finally activity indicators, except for ESR, TJC28, HAQ, were accepted, of whom 5 (36%) chose lamivudine, 6 (43%) significantly higher in the CHB group than those in the adefovir, and only 3 (21%) entecavir. Notably, there were control group mainly at month 6 and month 12 (all p < no significant differences in GC therapy, DMARD ther- 0.05). An additional file shows the other clinical re- apy, or cumulative doses of the medications after enroll- sponses that were not demonstrated in Fig. 2 (Additional ment between patients with and without antiviral file 1). Moreover, a significantly higher serum MMP-3 prophylaxis. Antiviral therapy was commenced or level was observed in female patients from the CHB switched to agents with a high barrier to resistance, such group compared with that in the non-CHB group at as entecavir or tenofovir, when HBV reactivation oc- month 12 (p = 0.020, Fig. 2o). Regardless of gender, a curred. In addition, liver function was closely monitored similar trend in the serum MMP-3 level was also seen at as frequently as 2 to 4 weeks and GC, MTX, or LEF month 6 (p = 0.086, Additional file 1). therapies were tapered or withdrawn, especially if hepa- titis flare occurred. Risk factors for one-year radiographic progression and failure to achieve therapeutic target within 6 months Patients with RA with CHB had more pronounced To determine risk factors for one-year radiographic pro- radiographic progression at month 12 gression, univariate logistic regression analysis was per- Compared with the non-CHB group, there was a signifi- formed on variables including baseline characteristics, cantly higher percentage of patients in the CHB group CHB status, and RA medications after enrollment (in- experiencing one-year radiographic progression (53% vs. cluding categories of medications, one-year cumulative Chen et al. Arthritis Research & Therapy (2018) 20:81 Page 5 of 13 Table 1 Demographic and disease characteristics at baseline Table 1 Demographic and disease characteristics at baseline (Continued) Parameters CHB group Non-CHB group p value (n = 32) (n = 128) Parameters CHB group Non-CHB group p value (n = 32) (n = 128) Matched parameters LEF 6 (19) 34 (27) 0.417 Female, n (%) 27 (84) 108 (84) 1.000 SSZ 4 (13) 1 (1) 0.005 Age (years) 49 (38–56) 49 (38–57) 0.964 HCQ 10 (31) 12 (9) 0.006 DAS28-CRP 4.6 (3.5–5.0) 4.6 (3.8–5.3) 0.791 CysA 1 (3) 5 (4) 0.853 Demographic characteristics Biologic agents 1 (3) 3 (2) 0.821 Age of onset (years) 44 (31–52) 45 (33–53) 0.948 Data are presented as median (interquartile range (IQR)) or number Disease duration 36 (9–113) 36 (12–84) 0.805 (percentage (%)) (months) ACPA anti-cyclic citrullinated peptide antibody, ALT alanine aminotransferase, AST aspartate transaminase, CDAI Clinical Disease Activity Index, CHB chronic Short duration 3 (9) 19 (15) 0.476 hepatitis B virus infection, CRP C-reactive protein, CysA cyclosporin A, DAS28 (<6 months) Disease Activity Score 28-joint assessment, DMARD disease-modifying anti- Intermediate duration 12 (38) 39 (30) 0.501 rheumatic drug, ESR erythrocyte sedimentation rate, GC glucocorticosteroid, (6–24 months) HAQ Stanford Health Assessment Questionnaire, HCQ hydroxychloroquine, JE joint erosion, JSN joint space narrowing, LEF leflunomide, mTSS modified total Long duration 17 (53) 70 (55) 0.887 Sharp score, MMP-3 matrix metalloproteinase-3, MTX methotrexate, NA not (>24 months) applicable, Pain VAS pain visual analog scale, PrGA provider global assessment of disease activity, PtGA patient global assessment of disease activity, RA rheumatoid Disease characteristics arthritis, RAPID3 Routine Assessment of Patient Index Data 3, RF rheumatoid TJC28 6 (2–10) 6 (3–10) 0.914 factor, SDAI Simplified Disease Activity Index, SJC28 28-joint swollen joint counts, SSZ sulfasalazine, TJC28 28-joint tender joint count SJC28 4 (1–8) 4 (2–6) 0.523 Compared between the CHB group and the non-CHB group using conditional logistic regression analysis: bold p values are significant PainVAS 4 (2–5) 4 (3–6) 0.131 Without glucocorticosteroid or DMARD therapy for 6 months PtGA 5 (3–6) 5 (3–6) 0.355 before enrollment PrGA 5 (3–5) 5 (3–6) 0.276 doses of medications, and different regimens of com- HAQ 0.6 (0–1.3) 0.6(0.1–1.2) 0.888 bined therapies) (Table 3). The results revealed that CRP (mg/L) 12.1 (3.8–44.2) 12.1 (4.8–32.0) 0.543 CHB status (OR 3.129, 95% CI 1.661–5.895; p < 0.001), ESR (mm/h) 36 (20–62) 50 (24–75) 0.162 higher baseline mTSS (OR 1.016, 95% CI 1.006–1.026; p = 0.001), and higher one-year cumulative dose of GCs RF positivity, n (%) 23 (72) 96 (75) 0.746 (OR 1.000282, 95% CI 1.000067–1.000497, p = 0.010) ACPA positivity, n (%) 23 (72) 101 (79) 0.448 were significant factors for one-year radiographic pro- SDAI 22.1 (13.6– 21.2 (14.6–29.3) 0.320 gression. In bivariate analyses that adjusted for baseline 31.3) mTSS and one-year cumulative dose of GCs, one factor CDAI 19 (12–28) 20 (13–26) 0.332 at a time, CHB status was still positively associated with RAPID3 3.3 (2.1–4.6) 3.6 (2.7–5.2) 0.128 one-year radiographic progression (OR 2.610 and OR MMP-3 (ng/mL) 184 (86–453) 155 (86–358) 0.440 2.881, respectively; both p < 0.01). Moreover, multivari- Liver function ate logistic regression analysis that adjusted for all AST (U/L) 18 (14–25) 16 (14–21) 0.630 significant factors from univariate analyses showed that CHB status was independently associated with one-year ALT (U/L) 18 (12–29) 15 (10–21) 0.769 radiographic progression (OR 2.403, 95% CI 1.218– Radiographic status 4.743; p = 0.011). Bony erosions, n (%) 25 (78) 96 (75) 0.742 Both ACR and EULAR recommendations for the man- JSN subscore 5.5 (0–18.8) 3.0 (1.0–9.8) 0.078 agement of RA emphasize tight control of disease activ- JE subscore 6.0 (1.0–22.0) 4.0 (0.3–10.0) 0.009 ity and attaining therapeutic target within 6 months [19, mTSS 11.0 (1.3–36.3) 8.0 (2.0–20.8) 0.021 21]. Therefore, logistic regression analysis was also per- formed to determine risk factors for failure to achieve Previous medications, n (%) b therapeutic target within 6 months (Table 4). The results Treatment-naïve 11 (34) 55 (43) 0.431 of univariate logistic regression analysis revealed that GCs 14 (44) 48 (38) 0.562 CHB status (OR 3.077, 95% CI 1.349–7.017; p = 0.008), MTX 16 (50) 49 (38) 0.283 being medication-naïve (OR 0.300, 95% CI 0.102–0.881; p = 0.029), MTX therapy (OR 0.266, 95% CI 0.099– 0.716; p = 0.009), a regimen of MTX combined with LEF (OR 0.365, 95% CI 0.155–0.861; p = 0.021), 6-month cumulative dose of MTX (OR 0.997, 95% CI 0.993– Chen et al. Arthritis Research & Therapy (2018) 20:81 Page 6 of 13 Table 2 Medications after enrollment Table 2 Medications after enrollment (Continued) a a Medication CHB group Non-CHB group p value Medication CHB group Non-CHB group p value (n = 32) (n = 128) (n = 32) (n = 128) Initial medications, n (%) CysA 0(0–37,575) 0 (0–12,825) 0.016 GCs 23 (72) 89 (70) 0.817 Iguratimod 0(0–5775) 0 (0–9000) 0.393 <5 mg/day 1 (3) 3 (2) 0.821 Tocilizumab 0(0–1880) 0 (0–2800) 0.184 ≥5, ≤10 mg/day 19 (59) 81 (63) 0.715 Yi Sai Pu 0(0–600) 0 (0–0) 0.606 >10, ≤20 mg/ 2 (6) 4 (3) 0.462 Infliximab 0(0–0) 0 (0–0) NA day Data are presented as median (interquartile range (IQR)) or number (percentage (%)) unless stated otherwise >20 mg/day 1 (3) 1 (1) 0.357 CHB chronic hepatitis B virus (HBV) infection, CysA cyclosporin A, GC MTX 28 (87) 121 (95) 0.217 glucocorticosteroid, HCQ hydroxychloroquine, LEF leflunomide, MTX methotrexate, NA not applicable, SSZ sulfasalazine ≤10 mg/week 21 (66) 79 (62) 0.715 Compared between the CHB group and the non-CHB group using conditional logistic regression analysis: bold p values are significant >10, ≤15 mg/ 6 (19) 40 (31) 0.217 Within the initial 6 months after enrollment week Data were analyzed as median (5th/95th percentile ranges) due to the small >15 mg/week 1 (3) 2 (2) 0.606 number of patients using these medications LEF 5 (16) 107 (84) <0.001 1.000; p = 0.049), and 6-month cumulative dose of CysA SSZ 14 (44) 2 (2) <0.001 (OR 1.000077, 95% CI 1.000011–1.000143; p = 0.023) HCQ 24 (75) 14 (11) <0.001 were recognized as significant factors for failure to CysA 4 (13) 4 (3) 0.062 achieve therapeutic target within 6 months. Bivariate Iguratimod 1 (3) 10 (8) 0.415 analyses that adjusted for the significant factors in the Biologic agents 6 (19) 38 (30) 0.273 univariate analyses, one factor at a time, demonstrated that CHB status was always an independent risk factor Tocilizumab 4 (13) 30 (23) 0.234 (OR 2.722–3.077, p = 0.019–0.008). Further multivariate Yi Sai Pu 2 (6) 5 (4) 0.606 logistic regression analysis was performed by adjusting Infliximab 0 (0) 3 (2) NA for all significant factors in the univariate analyses. Due Six-month cumulative dose of medications (mg) to the multicollinearity between MTX therapy and 6- GCs 900 (0–1406) 1069 (0–1556) 0.506 month cumulative dose of MTX, two multivariate MTX 260 (201–315) 288 (260–348) 0.024 models were set up respectively and the results of both models showed that CHB status remained significantly LEF 0 (0–0) 1800 (1500– <0.001 3263) associated with failure to achieve therapeutic target SSZ 0 (0–270,000) 0 (0–0) <0.001 within 6 months (MTX therapy model, OR 2.617, 95% CI 1.140–6.007, p = 0.023; 6-month cumulative dose of HCQ 54,000 (3000– 0(0–0) <0.001 72,000) MTX model, OR 2.844, 95% CI 1.245–6.498, p = 0.013). CysA 0(0–19,515) 0 (0–4500) 0.020 Safety Iguratimod 0(0–2625) 0 (0–9000) 0.330 Table 5 presents an overview of side effects during one- Tocilizumab 0(0–1880) 0 (0–2400) 0.218 year follow up. Infections occurred in 16% of patients Yi Sai Pu 0(0–600) 0 (0–0) 0.606 with CHB and 13% of patients in the non-CHB group. Infliximab 0(0–0) 0 (0–0) NA The most common infections were respiratory tract in- One-year cumulative dose of medications (mg) fection, with one patient (3%) in the CHB group and six paitents (5%) in the control group diagnosed as GCs 1800 (0–2790) 1744 (0–2475) 0.418 pneumonia respectively. One patient in the non-CHB MTX 520 (413–650) 585 (520–715) 0.023 group suffered from herpes zoster 7 months after initi- LEF 0 (0–0) 3600 <0.001 ation with tocilizumab. There was no significant differ- (2719–6600) ence between groups in the incidence of infections, SSZ 68,000 (0–536,000) 0 (0–0) <0.001 trichomadesis, neutropenia, or gastrointestinal discom- HCQ 90,000 0(0–0) <0.001 fort (all p > 0.05). No deaths occurred due to these side (3000–144,000) effects in this study. The main side effects of RA treatment on HBV infec- tion were HBV reactivation and aminotransferase eleva- tion. No patient in the non-CHB group developed HBV reactivation. However, 34% of CHB patients developed Chen et al. Arthritis Research & Therapy (2018) 20:81 Page 7 of 13 Fig. 1 One-year radiographic change in patients with rheumatoid arthritis (RA) in the chronic hepatitis B virus infection (CHB) group and the non- CHB group. Comparison of cumulative probability of △mTSS (a), △JSN subscore (b) and △JE subscore (c) during one-year follow up between the CHB group and the non-CHB group: *p < 0.05, **p < 0.01, ***p < 0.001. JE, joint erosion; JSN, joint space narrowing; mTSS, modified total Sharp score virus reactivation, of whom 8 (72%) refused to accept response among patients with RA in clinical practice, antiviral prophylaxis, with hepatitis flare occurring in 2 which revealed that HBV infection is implicated in RA patients (6%) during follow up. There was no significant progression. difference in the incidence of aminotransferase elevation HBV infection was complicated due to extrahepatic between groups (19% vs. 31%, p > 0.05). A flowchart of manifestations including polyarthritis mainly affecting HBV reactivation and hepatitis flare occurring in small joints, which seemed to mimic that of RA and patients with CHB is shown in Additional file 2. Fortu- was considered to be immune-complex mediated [31]. nately, serum HBV DNA level and aminotransferase in Use of recombinant HBsAg could induce the appearance all patients with RA returned to undetectable or normal of RA-like symptoms [32, 33], which might result from after commencing antiviral therapy or adjusting GC, the common HLA-DR haplotypes for RA [34]. Some MTX, or LEF therapy. No liver cirrhosis, liver failure, or patients with HBV infection who fulfilled the 1987 ACR HBV-related deaths occurred during follow up in this criteria for RA could have symptoms resolved by anti- study. HBV treatment [9, 10]. Furthermore, a recent large study from Taiwan demonstrated that patients with RA Discussion had a higher HBV period prevalence than did the non- In this study, we performed a retrospective case-control RA subjects [11]. Results in the present study showed study to investigate the influence of HBV infection on that patients with RA with CHB had more pronounced therapeutic response among patients with RA in a clin- one-year radiographic progression and achieved a lower ical practice setting. The Sharp/van der Heijde score level of clinical response than the non-CHB group, showed that patients with RA with CHB suffered more which was in accordance with most previously proposed pronounced one-year radiographic progression than the hypotheses of HBV infection acting as an adverse factor non-CHB group. Compared with the control group, in RA. smaller proportions of patients with RA with CHB Previous studies have shown that even though some achieved therapeutic target and remission, and the trend patients with HBV infection may have long-lasting was also seen in attaining ACR20/50 responses and good polyarthritis, joint destruction remains an almost rare or moderate EULAR responses, mainly at month 6 and complication. However, a case report describes a pa- month 12. Conditional logistic regression analysis tient with positive HBsAg and HBeAg in serum, who showed that CHB status was independently associated suffered worsened pain after a steroid injection for with one-year radiographic progression. Both ACR and knee osteoarthritis. Radiographs on admission showed EULAR recommendations for the management of RA a large bone defect in the medial tibia and slight nar- emphasize that therapeutic target should be attained rowing of the articular gap. Further analysis revealed within 6 months [19, 21]. Thus, conditional logistic re- diffuse expression of HBsAg in the synovium, suggest- gression analysis was further performed and the result ing destructive knee arthropathy possibly caused by showed that CHB status was also significantly associated HBV infection [7]. Another report demonstrated that a with failure to achieve therapeutic target within 6 woman with acute RA onset after receiving the first months. Therefore, HBV infection may play a deleteri- dose of HBV vaccine experienced erosions with min- ous role in radiographic and clinical outcomes in pa- imal periarticular osteoporosis 10 months later [35]. In tients with RA. To our knowledge, this is the first study this study, a larger proportion of patients with CHB to investigate the role of HBV infection in therapeutic suffered one-year radiographic progression, which Chen et al. Arthritis Research & Therapy (2018) 20:81 Page 8 of 13 Fig. 2 (See legend on next page.) Chen et al. Arthritis Research & Therapy (2018) 20:81 Page 9 of 13 (See figure on previous page.) Fig. 2 Clinical responses in the chronic hepatitis B virus infection (CHB) group and the non-CHB group. a-f Comparison of the rates of patients achieving therapeutic target, remission, American College of Rheumatology (ACR)20/50 responses, and European League Against Rheumatism (EULAR) responses at each visit. g-n Comparison of dynamic disease activity indicators at each visit. o Comparison of dynamic matrix metalloproteinase-3 (MMP-3) levels in female patients at each visit. Data are represented by the median and interquartile range: *p <0.05, **p <0.01, ***p <0.001. CDAI, Clinical Disease Activity Index; CRP, C-reactive protein; DAS28, Disease Activity Score 28-joint assessment; Pain VAS, pain visual analog scale; PrGA, provider global assessment of disease activity; PtGA, patient global assessment of disease activity; RAPID3, Routine Assessment of Patient Index Data 3; SDAI, Simplified Disease Activity Index; SJC28, 28-joint swollen joint counts; TJC28, 28-joint tender joint counts implies that HBV infection might directly or indirectly A, while MTX and LEF were contraindicated for all contribute to joint damage. On the other hand, MMP-3 Child-Pugh classifications [19, 21]. However, the guide- is a proteinase secreted by synovial fibroblasts and lines for antiviral prophylaxis made by the American chondrocytes in joints, which can accelerate joint de- Gastroenterological Association in 2015 recommended struction in RA. Recently, the reduction in serum low-dose GC therapy (prednisone (or equivalent) at < MMP-3 was considered as a possible therapeutic target 10 mg/day) for > 4 weeks in the moderate-risk group together with disease activity. Urata et al. reported that and MTX in the low-risk group for HBV reactivation treating to target MMP-3 normalization combined with in patients with CHB [30]. LEF is not recommended in disease activity yielded better effects than each target patients with a history of hepatitis and might increase alone in patients with RA [36]. the risk of HBV reactivation [14, 38]. In the present Our previous studies also have shown that serum study, although not all patients with CHB agreed to re- MMP-3 level was positively correlated with disease ac- ceive recommended antiviral prophylaxis due to eco- tivity and continuously elevated serum MMP-3 for 3 to nomic reasons, there was no significant difference in 6 months could predict one-year radiographic progres- RA treatment between patients with and without anti- sion [17, 23]. In this study, compared with the non-CHB viral prophylaxis. However, there were significant dif- group, serum MMP-3 level was higher in the CHB group ferences in the medications taken by patients with and at month 6, and was significantly higher in women from without CHB. Patients with RA with CHB were more the CHB group at month 12, which further confirmed likely to use SSZ and HCQ rather than LEF, and that patients with RA with CHB had a lower level of received significantly lower cumulative doses of MTX. clinical response and radiographic outcome. Moreover, Accordingly, a significantly greater proportion of pa- studies have revealed that HBV X protein could promote tients with CHB used the regimen of MTX combined cell migration by inducing the transcription, translation, with SSZ and HCQ, while a smaller percentage of and secretion of MMP-3 [37]. In this scenario, it is pos- patients with CHB used the regimen of MTX com- sible that CHB status may negatively affect the radio- bined with LEF. Nevertheless, patients with CHB had a graphic and clinical outcomes of patients with RA partly significantly higher possibility of HBV reactivation through upregulating MMP-3. Both ACR and EULAR compared to the non-CHB group (including patients recommendations for the management of RA emphasize with resolved HBV infection or patients never infected tight control of disease activity and therapeutic target with HBV), which may preclude escalation of therapy should be attained within 6 months [19, 21]. Patients and might result in not reaching a full dose of some of with CHB in this study had more pronounced one-year the drugs and not achieving therapeutic target within radiographic progression probably due to a lower level the recommended time frame. of clinical response during one-year follow up, especially Multivariate logistic regression analysis revealed that within 6 months. That is, HBV infection may act as a both CHB status and MTX therapy were independently “regulatory factor” or even a “driver factor” during dis- associated with failure to achieve therapeutic target ease progression in patients with RA with CHB. There- within 6 months. Hence, it is reasonable to speculate fore, it could be speculated that patients with CHB that patients with CHB had more pronounced one-year could be classified as having a specific phenotype of RA radiographic progression and a lower level of clinical re- that may need adjusted regimens or routes of adminis- sponse probably due to both CHB status and different tration to achieve sufficient therapeutic response. regimens, especially MTX therapy, used in the patients HBV reactivation is a well-recognized complication with CHB. In light of the pros and cons, it is indeed dif- that may cause high morbidity and mortality in pa- ficult to find a balance during RA treatment. Therefore, tients who undergo immunosuppressive therapy. The besides CHB status, regimen adjustments for preventing 2008 ACR recommended that SSZ under antiviral HBV reactivation during RA treatment might also prophylaxis and HCQ could be used for patients with explain part of the adverse role of HBV infection in RA RA with CHB and liver function of Child-Pugh class radiographic and clinical outcomes. On the other hand, Chen et al. Arthritis Research & Therapy (2018) 20:81 Page 10 of 13 Table 3 Logistic regression analyses of risk factors for one-year Table 3 Logistic regression analyses of risk factors for one-year radiographic progression radiographic progression (Continued) OR 95% CI p value* OR 95% CI p value* Univariate analyses One-year cumulative dose 1.000 (0.998–1.003) 0.817 of Yi Sai Pu Female 0.845 (0.373–1.915) 0.687 One-year cumulative dose 0.997 (0.989–1.006) 0.564 Age 0.993 (0.969–1.018) 0.598 of infliximab Disease duration 1.004 (1.000–1.008) 0.076 Bivariate models CHB status 3.129 (1.661–5.895) <0.001 CHB status adjusted for 2.610 (1.338–5.092) 0.005 baseline mTSS TJC28 0.996 (0.934–1.063) 0.914 CHB status adjusted for 2.881 (1.511–5.493) 0.001 SJC28 0.982 (0.908–1.062) 0.651 one-year cumulative dose Pain VAS 1.056 (0.905–1.232) 0.491 of GCs PtGA 1.094 (0.939–1.274) 0.248 Multivariate model PrGA 1.086 (0.921–1.281) 0.326 CHB status adjusted for baseline 2.403 (1.218–4.743) 0.011 mTSS and one-year cumulative HAQ 1.346 (0.990–1.830) 0.058 dose of GCs CRP 1.001 (0.998–1.014) 0.876 ACPA anti-cyclic citrullinated peptide antibody, CHB chronic hepatitis B virus ESR 0.999 (0.989–1.008) 0.786 (HBV) infection, CI confidence interval, CRP C-reactive protein, CysA cyclosporin A, DAS28 Disease Activity Score 28-joint assessment, ESR erythrocyte RF positivity 2.355 (0.921–6.023) 0.074 sedimentation rate, GC glucocorticosteroid, HAQ Stanford Health Assessment Questionnaire, HCQ hydroxychloroquine, LEF ACPA positivity 1.983 (0.775–5.070) 0.153 leflunomide, mTSS modified total Sharp score, MTX methotrexate, OR odds DAS28-CRP 1.011 (0.742–1.378) 0.944 ratio, Pain VAS pain visual analog scale, PrGA provider global assessment of disease activity, PtGA patient global assessment of disease activity, RF MMP-3 1.001 (0.999–1.002) 0.292 rheumatoid factor, SJC28 28-joint swollen joint count, SSZ sulfasalazine, TJC28 28-joint tender joint count mTSS 1.016 (1.006–1.026) 0.001 Calculated using conditional logistic regression analysis. Univariate logistic Treatment-naïve 0.710 (0.365–1.381) 0.313 regression analysis was performed on variables, including baseline characteristics, CHB status, and rheumatoid arthritis medications after enrollment (including GCs 2.300 (0.964–5.489) 0.061 categories of medications, one-year cumulative doses of medications, and different regimens of combined therapies); bivariate analysis was performed by adjusting MTX 1.369 (0.330–5.678) 0.666 for baseline mTSS and one-year cumulative dose of GCs respectively; multivariate LEF 0.684 (0.359–1.304) 0.248 logistic regression analysis was performed by adjusting for all significant univariate factors: bold p values are significant SSZ 1.984 (0.876–4.495) 0.101 Without glucocorticosteroid or DMARD therapy for 6 months HCQ 1.611 (0.828–3.135) 0.160 before enrollment One-year cumulative dose of GCs: OR 1.000282, 95% CI 1.000067–1.000497; CysA 1.591 (0.490–5.167) 0.440 p = 0.010 One-year cumulative dose of LEF: OR 0.999888, 95% CI 0.999766–1.000011; Iguratimod 1.130 (0.348–3.670) 0.839 p = 0.074 Biologic agents 0.477 (0.200–1.139) 0.095 One-year cumulative dose of CysA: OR 1.000025, 95% CI 0.999993–1.000057; p = 0.124 MTX combined with SSZ 2.265 (0.949–5.406) 0.066 f One-year cumulative dose of iguratimod: OR 1.000013, 95% CI 0.999926– and HCQ 1.000101; p = 0.761 One-year cumulative dose of tocilizumab: OR 0.999719, 95% CI 0.999259– MTX combined with LEF 0.719 (0.384–1.346) 0.302 1.000180; p = 0.232 One-year cumulative dose 1.000 (1.000–1.000) 0.010 of GCs baseline radiographic status is an important feature that One-year cumulative dose 0.999 (0.998–1.000) 0.224 could influence radiographic progression in patients with of MTX RA. In this study, levels of JE subscore and mTSS at One-year cumulative dose 1.000 (1.000–1.000) 0.074 baseline were significantly higher in the CHB group than of LEF in the non-CHB group, and baseline mTSS was one of One-year cumulative dose 1.001 (1.000–1.003) 0.133 the significant factors for one-year radiographic progres- of SSZ sion according to the results of logistic regression ana- One-year cumulative dose 1.004 (0.998–1.009) 0.160 lysis. However, CHB status was independently associated of HCQ with one-year radiographic progression after adjusted for One-year cumulative dose 1.000 (1.000–1.000) 0.124 of CysA all confounding factors including baseline mTSS. There are several limitations in this study. First, it was One-year cumulative dose 1.000 (1.000–1.000) 0.761 of iguratimod a real-world observational study from a single center and patients were treated with different medications. One-year cumulative dose 1.000 (0.999–1.000) 0.232 of tocilizumab Although multivariate logistic regression was performed to remove the confounding effect of different Chen et al. Arthritis Research & Therapy (2018) 20:81 Page 11 of 13 Table 4 Logistic regression analyses of risk factors for failure to Table 4 Logistic regression analyses of risk factors for failure to achieve therapeutic target within 6 months achieve therapeutic target within 6 months (Continued) a a OR 95% CI p value OR 95% CI p value Univariate analyses Six-month cumulative dose 1.001 (0.999–1.004) 0.322 of Yi Sai Pu Female 1.235 (0.367–4.155) 0.734 Six-month cumulative dose 0.997 (0.986–1.009) 0.659 Age 1.012 (0.979–1.045) 0.488 of infliximab Disease duration 1.000 (0.994–1.007) 0.969 Bivariate models CHB status 3.077 (1.349–7.017) 0.008 CHB status adjusted for 2.844 (1.245–6.498) 0.013 treatment-naïve status TJC28 1.059 0.986–1.137 0.115 CHB status adjusted for MTX 2.722 (1.177–6.298) 0.019 SJC28 1.035 0.951–1.127 0.421 CHB status adjusted for the 3.077 (1.349–7.017) 0.008 Pain VAS 1.096 0.897–1.338 0.369 regimen of MTX combined PtGA 1.192 0.977–1.455 0.083 with LEF PrGA 1.142 0.920–1.418 0.230 CHB status adjusted for 6-month 3.077 (1.349–7.017) 0.008 cumulative dose of MTX HAQ 1.318 0.880–1.975 0.180 CHB status adjusted for 6-month 3.077 (1.349–7.017) 0.008 CRP 1.004 (0.988–1.020) 0.616 cumulative dose of CysA ESR 1.000 (0.987–1.021) 0.949 Multivariate models RF positivity 1.637 (0.557–4.811) 0.371 CHB status adjusted for 2.617 (1.140–6.007) 0.023 ACPA positivity 0.452 (0.195–1.043) 0.063 treatment-naïve status, MTX therapy, the regimen of MTX combined with DAS28-CRP 1.394 (0.936–2.077) 0.102 LEF, and 6-month cumulative dose MMP-3 1.000 (0.999–1.002) 0.751 of CysA mTSS 1.010 (0.995–1.024) 0.195 CHB status adjusted for treatment- 2.844 (1.245–6.498) 0.013 b naïve status, 6-month cumulative Treatment-naïve 0.300 (0.102–0.881) 0.029 dose of MTX, the regimen of MTX GCs 1.178 (0.465–2.989) 0.729 combined with LEF, and 6-month cumulative dose of CysA MTX 0.266 (0.099–0.716) 0.009 ACPA anti-cyclic citrullinated peptide antibody, CHB chronic hepatitis B (HBV) LEF 0.468 (0.206–1.060) 0.069 infection, CI confidence interval, CRP C-reactive protein, CysA cyclosporin A, DAS28 Disease Activity Score 28-joint assessment, ESR erythrocyte sedimenta- SSZ 1.350 (0.401–4.543) 0.628 tion rate, GCs glucocorticosteroids, HAQ Stanford Health Assessment Question- HCQ 2.064 (0.893–4.768) 0.090 naire, HCQ hydroxychloroquine, LEF leflunomide, mTSS modified total Sharp score, MTX methotrexate, OR odds ratio, Pain VAS pain visual analogue scale, CysA 2.850 (0.847–9.591) 0.091 PrGA provider global assessment of disease activity, PtGA patient global assess- ment of disease activity, RF rheumatoid factor, SJC28 28-joint swollen joint Iguratimod 2.032 (0.604–6.837) 0.252 count, SSZ sulfasalazine, TJC28 28-joint tender joint count Biologic agents 0.555 (0.189–1.631) 0.285 Calculated using conditional logistic regression analysis: univariate logistic regression analysis was performed on variables, including baseline MTX combined with SSZ 1.175 (0.275–5.009) 0.828 characteristics, CHB status, and rheumatoid arthritis medications after and HCQ enrollment (including categories of medications, 6-month cumulative doses of medications, and different regimens of combined therapies); bivariate analysis MTX combined with LEF 0.365 (0.155–0.861) 0.021 was performed by adjusting for the significant univariate factors individually; Six-month cumulative dose 1.000 (1.000–1.001) 0.340 due to the multicollinearity between MTX therapy and 6-month cumulative of GCs dose of MTX, two multivariate models (MTX therapy model and 6-month cumulative dose of MTX model) were set up respectively by adjusting for all Six-month cumulative dose 0.997 (0.993–1.000) 0.049 significant univariate factors: bold p values are significant of MTX b Without glucocorticosteroid or DMARD therapy for 6 months before enrollment Six-month cumulative dose of GCs: OR 1.000220, 95% CI 0.999768–1.000671; Six-month cumulative dose 1.000 (0.999–1.000) 0.113 p = 0.340 of LEF Six-month cumulative dose of LEF: OR 0.999738, 95% CI 0.999414–1.000062; p Six-month cumulative dose 1.000 (0.995–1.005) 0.890 = 0.113 Six-month cumulative dose of CysA: OR 1.000077, 95% CI 1.000011–1.000143; of SSZ p = 0.023 Six-month cumulative dose 1.008 (0.994–1.022) 0.245 Six-month cumulative dose of iguratimod: OR 1.000080, 95% CI 0.999941– of HCQ 1.000218; p = 0.259 Six-month cumulative dose of tocilizumab: OR 0.999656, 95% CI 0.998954– Six-month cumulative dose 1.000 (1.000–1.000) 0.023 e 1.000358; p = 0.337 of CysA Six-month cumulative dose 1.000 (1.000–1.000) 0.259 of iguratimod medications, it would be necessary to carry out further multicenter studies and balance the combined therapy Six-month cumulative dose 1.000 (0.999–1.000) 0.337 of tocilizumab between groups. Second, over 70% of patients suffered bony erosion at baseline in this study, which was a risk Chen et al. Arthritis Research & Therapy (2018) 20:81 Page 12 of 13 Table 5 Safety profile of rheumatoid arthritis treatment Abbreviations a ACPA: Anti-cyclic citrullinated peptide antibody; ACR: American College of Side effect CHB group Non-CHB group p value Rheumatology; ALT: Alanine aminotransferase; AST: Aspartate transaminase; (n = 32) (n = 128) CDAI: Clinical Disease Activity Index; CHB: Chronic hepatitis B virus infection; Total side effects, n (%) 15 (47) 68 (53) 0.572 CI: Confidence interval; CRP: C-reactive protein; CysA: Cyclosporin A; DAS28: Disease Activity Score 28-joint assessment; DMARD: Disease- Infections 5 (16) 16 (13) 0.676 modifying anti-rheumatic drug; ESR: Erythrocyte sedimentation rate; Gastrointestinal discomfort 7 (22) 22 (17) 0.583 EULAR: European League Against Rheumatism; GC: Glucocorticosteroid; HAQ: Stanford Health Assessment Questionnaire; HBcAg: Hepatitis B virus Trichomadesis 2 (6) 13 (10) 0.547 core antigen; HBeAg: Hepatitis B virus e antigen; HBsAg: Hepatitis B virus surface antigen; HBV: Hepatitis B virus; HCQ: Hydroxychloroquine; Neutropenia 2 (6) 14 (11) 0.484 IQR: Interquartile range; JE: Joint erosion; JSN: Joint space narrowing; Aminotransferase elevation 6 (19) 39 (30) 0.244 LEF: Leflunomide; MMP-3: Matrix metalloproteinase-3; mTSS: Modified total Sharp score; MTX: Methotrexate; NA: Not applicable; OR: Odds ratio; Pain < two fold ULN 4 (13) 30 (23) 0.234 VAS: Pain visual analog scale; PrGA: Provider global assessment of disease ≥ two fold, < three fold ULN 1 (3) 7 (6) 0.630 activity; PtGA: Patient global assessment of disease activity; RA: Rheumatoid arthritis; RAPID3: Routine Assessment of Patient Index Data 3; ≥ three fold ULN 1 (3) 2 (2) 0.606 RF: Rheumatoid factor; RRP: Rapid radiographic progression; SDAI: Simplified Antiviral prophylaxis 14 (44) 0 (0) NA Disease Activity Index; SJC28: 28-Joint swollen joint counts; SSZ: Sulfasalazine; TJC28: 28-Joint tender joint counts; ULN: Upper limit of the normal range HBV reactivation 11 (34) 0 (0) NA Antiviral prophylaxis (+) 3 (9) 0 (0) NA Acknowledgements The authors wish to thank the patients and medical staff for their contribution Antiviral prophylaxis (−) 8 (25) 0 (0) NA to the study, and Nan Li from Perking University Third Hospital and Yan-Fang CHB chronic HBV infection, HBV hepatitis B virus, NA not applicable, ULN upper Ye from Sun Yat-Sen Memorial Hospital for their statistical assistance. limit of the normal range Compared between the CHB group and the non-CHB group using conditional Funding logistic regression analysis This work was supported by the National Natural Science Foundation of China (grant numbers 81471597, 81671612, and 81601427), Guangdong factor for one-year radiographic progression. Hence, Natural Science Foundation (grant numbers 2014A030313074, 2016A030313307, and 2017A030313576), Guangdong Medical Scientific more patients with early RA without baseline bony Research Foundation (grant number A2017109), and Key Program of Young erosion are needed in future to confirm our results. Teachers Foundation of Sun Yat-sen University (grant number 17ykjc12). Third, the relatively small number of patients with RA with CHB in this study precluded a robust conclusion. Availability of data and materials The datasets used and/or analyzed during the current study are available Whether clearance of HBV would lead to a good thera- from the corresponding author on reasonable request. peutic response in RA remains to be clarified in a larger, placebo-controlled study. Authors’ contributions All authors contributed to the final manuscript. Y-LC conceived and designed the study, analyzed the data, and drafted the manuscript. Corresponding Conclusions authors LD and D-HZ conceived and participated in the study, read and Our results showed that patients with RA with CHB had analyzed documents, and revised the manuscript. J-ZL and Y-QM participated more pronounced one-year radiographic progression in clinical assessment at each visit during the follow up. Q-HL, X-YW, and TY collected and analyzed the data. J-DM and Z-HY performed the radiographic and achieved a lower level of clinical response than assessment. All authors have read and approved the final submitted version. those without CHB. HBV reactivation remained a tricky issue in patients with CHB during RA treatment. Thus, Ethics approval and consent to participate This study was conducted in compliance with the Helsinki Declaration. Due to HBV infection may play a deleterious role in radio- the retrospective nature of the study, informed consent was waived. The study graphic and clinical outcomes among patients with RA, was approved by the Medical Ethics Committee of Sun Yat-Sen Memorial and HBV reactivation should be paid close attention Hospital (identifier SYSEC-KY-KS-011). during immunosuppressive therapy. Consent for publication All participants have approved publication of the data in this manuscript. Additional files Competing interests The authors declare that they have no competing interests. Additional file 1: The other clinical responses between the CHB group and the non-CHB group. Comparison of the other clinical responses at each visit, including ACR70, PrGA, Pain VAS, HAQ, ESR, and serum MMP-3 levels. Publisher’sNote ACR: American College of Rheumatology; CHB: chronic HBV infection; ESR: Springer Nature remains neutral with regard to jurisdictional claims in erythrocyte sedimentation rate; HAQ: Stanford Health Assessment Question- published maps and institutional affiliations. naire; MMP-3: matrix metalloproteinase-3; Pain VAS: pain visual analog scale; PrGA: provider global assessment of disease activity. (PDF 1468 kb) Author details Department of Rheumatology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen Additional file 2: A flowchart of HBV reactivation occurring in patients University, Guangzhou 510120, People’s Republic of China. Department of with RA with CHB showing antiviral prophylaxis, HBV reactivation, and Radiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, hepatitis flare in these patients during one-year follow up. CHB: chronic Guangzhou, People’s Republic of China. Zhongshan School of Medicine, HBV infection; HBV: hepatitis B virus; RA: rheumatoid arthritis. (PDF 33 kb) Sun Yat-sen University, Guangzhou, People’s Republic of China. Chen et al. Arthritis Research & Therapy (2018) 20:81 Page 13 of 13 Received: 24 October 2017 Accepted: 19 February 2018 22. Anderson J, Caplan L, Yazdany J, Robbins ML, Neogi T, Michaud K, et al. Rheumatoid arthritis disease activity measures: American College of Rheumatology recommendations for use in clinical practice. Arthritis Care Res (Hoboken). 2012;64(5):640–7. References 23. Ma JD, Zhou JJ, Zheng DH, Chen LF, Mo YQ, Wei XN, et al. Serum matrix 1. McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J metalloproteinase-3 as a noninvasive biomarker of histological synovitis for Med. 2011;365(23):2205–19. diagnosis of rheumatoid arthritis. Mediators Inflamm. 2014;2014:179284. 2. Ebringer A, Wilson C. HLA molecules, bacteria and autoimmunity. 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Smolen JS, Landewé R, Breedveld FC, Buch M, Burmester G, Dougados M, et al. • We accept pre-submission inquiries EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. � Our selector tool helps you to find the most relevant journal Ann Rheum Dis. 2014;73(3):492–509. � We provide round the clock customer support 20. Saag KG, Teng GG, Patkar NM, Anuntiyo J, Finney C, Curtis JR, et al. � Convenient online submission American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in � Thorough peer review rheumatoid arthritis. Arthritis Rheum. 2008;59(6):762–84. � Inclusion in PubMed and all major indexing services 21. Singh JA, Furst DE, Bharat A, Curtis JR, Kavanaugh AF, Kremer JM, et al. 2012 � Maximum visibility for your research Update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in Submit your manuscript at the treatment of rheumatoid arthritis. Arthritis Care Res. 2012;64(5):625–39. www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Arthritis Research & Therapy Springer Journals

Deleterious role of hepatitis B virus infection in therapeutic response among patients with rheumatoid arthritis in a clinical practice setting: a case-control study

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Medicine & Public Health; Rheumatology; Orthopedics
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Abstract

Background: Previous studies have revealed that hepatitis B virus (HBV) infection may be associated with rheumatoid arthritis (RA), while there are no further clinical studies regarding the role of HBV infection in RA progression during disease-modifying anti-rheumatic drug (DMARD) therapy. Here, we aimed to explore the influence of HBV infection on radiographic and clinical outcomes among patients with RA in a clinical practice setting. Methods: Thirty-two consecutive patients with RA (Disease Activity Score 28-joint assessment based on C-reactive protein (DAS28-CRP) ≥2.6) with chronic HBV infection (CHB) were retrospectively recruited as the CHB group and 128 age-matched, sex-matched, and disease activity-matched contemporary patients with RA without CHB were included in the non-CHB group. Clinical data were collected at baseline and visits at month 1, 3, 6, and 12. The therapeutic target was defined as DAS28-CRP <2.6 in all patients or <3.2 in patients with long disease duration (>24 months). The primary outcome was the percentage of patients with one-year radiographic progression (a change in modified total Sharp score ≥0.5). Results: Compared with the non-CHB group, a significantly higher percentage of patients with one-year radiographic progression was observed in the CHB group (53% vs. 17%, p < 0.001), with smaller proportions of patients achieving therapeutic target at month 6 and month 12 (53% vs. 82% and 53% vs. 75%, both p < 0.05), remission at month 6 (DAS28-CRP <2.6, 50% vs. 72%, p = 0.039), and American College of Rheumatology (ACR)20/50 responses and good or moderate European League Against Rheumatism (EULAR) responses mainly at month 6 and 12 (all p < 0.05). Multivariate logistic regression analysis revealed that CHB status was significantly associated with one-year radiographic progression and failure to achieve therapeutic target within 6 months. HBV reactivation occurred in 34% of patients with CHB during one-year follow up, with two patients suffering hepatitis flare. Conclusions: HBV infection may play a deleterious role in radiographic and clinical outcomes in patients with RA, and HBV reactivation should be paid close attention during immunosuppressive therapy. Keywords: Hepatitis B virus, Rheumatoid arthritis, Radiographic progression, Clinical response * Correspondence: zhengouyang@sina.com; dailie@mail.sysu.edu.cn Department of Rheumatology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People’s Republic of China Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Chen et al. Arthritis Research & Therapy (2018) 20:81 Page 2 of 13 Background between June 2012 and August 2016 at Sun Yat-Sen Rheumatoid arthritis (RA) is a systemic autoimmune Memorial Hospital from a prospective cohort, as de- disease affecting millions of people worldwide, which scribed in our previous study [17]. All patients were is characterized by synovitis with bone and cartilage treated according to the “treat-to-target” strategy [18, destruction. The etiology of RA remains largely un- 19] and completed at least one year of follow up. known [1]. Genetic predisposition is not sufficient to Consecutive patients with RA with HBsAg positivity explain RA development, and environmental triggers, persisting in serum for more than 6 months were re- especially infectious agents such as Epstein-Barr virus, cruited as the CHB group. Each patient with RA in cytomegalovirus, and Proteus mirablis, have been re- the CHB group was matched by age (± 5 years), sex, ported to be linked with RA pathogenesis [2]. New and disease activity at baseline to four subjects with- evidence shows that the oral and gut microbiomes out HBsAg positivity or HBV DNA in serum, who are perturbed in patients with RA and partly normal- comprised the non-CHB group. The timing of base- ized after RA treatment, suggesting a significant role line for the four matched patients in the non-CHB of microbiomes in RA [3]. Despite these studies, the group was as close as possible to baseline for the cor- identity and pathogenicity of most factors implicating responding patient in the CHB group. Other inclusion a role in RA are not yet clear. criteria were patients aged ≥ 18 years and patients Hepatitis B virus (HBV) infection continues to be one of with active disease defined as Disease Activity Score worldwide leading disease burdens. About 248 million 28-joint assessment (DAS28) with four variables in- (3.61%) individuals globally have been reported as HBV cluding C-reactive protein (DAS28-CRP) ≥2.6. The ex- surface antigen (HBsAg)-positive, with 74 million Chinese clusion criteria were elevated aminotransferase at baseline; patients (5.49%) in 2010 [4]. HBV primarily infects human other overlapping autoimmune diseases (e.g. systemic hepatocytes, and also leads to a series of extrahepatic lupus erythematosus, scleroderma, dermatomyositis, poly- manifestations or diseases such as polyarthritis, glomer- arteritis nodosa, cryoglobulinaemia, nephritis); Wilson’s ulonephritis, polyarteritis nodosa, and cryoglobulinemia disease, steatohepatitis, hemochromatosis, Schistosomiasis [5]. HBV-related antigens and nucleic acids have been japonica, or drug-induced hepatitis; concomitant infection demonstrated in a variety of extrahepatic tissues, including with hepatitis C virus, hepatitis D virus, or human lymph nodes, kidney, skin, colon, stomach, testis, and immunodeficiency virus; other serious infection, organ ovaries [6]. Only a few studies have revealed a possibility dysfunction, or malignancy; and lactating or pregnant of the presence of HBV proteins and DNA in synovial tis- women. This study was conducted in compliance with the sues from patients with HBV infection [7, 8]. Surprisingly, Helsinki Declaration. Due to the retrospective nature of several patients with concurrent HBV infection who ful- the study, informed consent was waived. The study was filled the diagnostic criteria of American College of approved by the Medical Ethics Committee of Sun Yat- Rheumatology (ACR) for RA were shown to have disease Sen Memorial Hospital (identifier SYSEC-KY-KS-011). resolved by anti-HBV treatment [9, 10]. Additionally, prior studies have documented higher serum HBsAg positivity Treatment and clinical data collection in patients with RA than in non-RA controls [11, 12]. Our All patients were treated according to the 2008/2012 previous studies identified 11.2% HBsAg positivity in ACR [20, 21] and the 2010/2013 EULAR [18, 19] recom- Chinese patients with RA and HBV reactivation as a com- mendations for the management of RA. The therapeutic mon but tricky complication in HBsAg-positive patients target was defined as DAS28-CRP <2.6 in all patients or with RA undergoing immunosuppressive therapy [13, 14]. <3.2 in patients with long disease duration (>24 months) Thus, HBV infection and RA are somehow linked. How- [18, 19]. Available clinical data on patients with RA were ever, until now, no longitudinal studies have examined the collected in this study at baseline and at visits at months role of HBV infection in disease progression during RA 1, 3, 6, and 12, as described before [17], including 28- treatment. Therefore, the aim of the present study was to joint tender and swollen joint counts (TJC28 and explore the influence of HBV infection on therapeutic SJC28), patient and provider global assessment of disease response and the safety of immunosuppressive therapy in activity (PtGA and PrGA, respectively), pain visual ana- patients with RA with CHB. log scale (pain VAS), the Stanford Health Assessment Questionnaire (HAQ), erythrocyte sedimentation rate Methods (ESR), CRP, rheumatoid factor (RF), and anti-cyclic Study patients and design citrullinated peptide antibody (ACPA). Besides DAS28- Patients with RA who fulfilled the 1987 revised cri- CRP, disease activity was also assessed using the Simpli- teria of the ACR [15] or the 2010 ACR/European fied Disease Activity Index (SDAI), the Clinical Disease League Against Rheumatism (EULAR) criteria for the Activity Index (CDAI), and the Routine Assessment of classification of RA [16] were retrospectively recruited Patient Index Data 3 (RAPID3) [22]. Cumulative doses Chen et al. Arthritis Research & Therapy (2018) 20:81 Page 3 of 13 of oral glucocorticosteroids (GCs) and disease-modifying remission, rates of EULAR responses and ACR20/50/70 anti-rheumatic drugs (DMARDs) were recorded during responses [27], and changes in disease activity indicators. one-year follow up. GC doses were converted to a prednisone-equivalent dose. Safety assessments Serological markers of HBV infection, including HBsAg, Side effects were recorded and evaluated at each visit. HBV e antigen (HBeAg), the corresponding antibodies to Neutropenia was defined as neutrophil count <2.0 × these antigens (anti-HBs and anti-HBe, respectively), and 10 /L. HBV reactivation was defined as the reappearance antibodies to HBV core antigen (anti-HBc), were tested in of HBsAg in a patient with resolved HBV infection, the all patients with RA using enzyme-linked immunosorbent detection of previously undetectable HBV DNA or > 1 assay (Zhongshan Biotechnology CO., LTD, Guangdong, log10 (10-fold) IU/mL increase in serum HBV DNA, China) or electrochemluminescence-immunoassay (Roche and rise in HBV DNA level above an arbitrary cutoff Diagnostics, Mannheim, Germany). HBV DNA was mea- (for example, 20,000 IU) in patients with biochemical sured using a commercially available quantitative real- worsening [28–30]. A hepatitis flare was determined to time polymerase chain reaction kit (Da An Gene Co., Ltd. be present when ALT was greater than two times the of Sun Yat-Sen University, Guangdong, China), with the upper limit of the normal range (ULN) [30]. lowest detection threshold of 500 IU/mL. Liver function including alanine aminotransferase (ALT, U/L, normal Statistical analysis range 5–40 U/L) and aspartate transaminase (AST, U/L, Statistical analyses were performed using IBM SPSS Sta- normal range 5–40 U/L) was tested at each visit during tistics version 20.0 software (IBM, Armonk, NY, USA). follow up. HBV serological markers and HBV DNA levels Descriptive statistics (median, interquartile range (IQR) were evaluated in all patients with RA at baseline and or 5th/95th percentile ranges) were calculated for every 1–3 months during follow up in the CHB group. continuous variables and categorical variables were pre- These parameters in the non-CHB group were re- sented as frequencies and percentages. Conditional logis- examined if aminotransferase was elevated during follow tic regression analysis was used to compare continuous up. Antiviral prophylaxis by entecavir or tenofovir was and categorical variables between the CHB group and suggested for all patients with RA with CHB before RA the non-CHB group, and odds ratios (ORs) and 95% treatment. Moreover, serum levels of soluble matrix me- confidence intervals (CIs) were calculated to identify risk talloproteinase (MMP-3) were tested as described before factors for one-year radiological progression and failure [23]. The normal ranges of serum MMP-3 concentrations to achieve therapeutic target within 6 months. Variables were 18–60 ng/mL (women) and 24–120 ng/mL (men). were included in the equation when the p value was < 0.05 or removed when the p value was > 0.10, following Radiographic assessments the step-forward selection rule. A two tailed p value Radiographs of the bilateral hands and wrists (antero- <0.05 was considered statistically significant. posterior view) of all patients were performed at baseline and month 12. The Sharp/van der Heijde-modified total Results Sharp score (mTSS), joint erosion (JE), and joint space Demographic characteristics of patients with RA at narrowing (JSN) were scored by two experienced baseline observers (MJD from the Department of Rheumatology A total of 32 patients with RA with CHB were included in and YZH from the Department of Radiology), who were the study, of whom 27 (84%) were female. There were blinded to the patients’ clinical data. As described previ- 72% of patients who were both RF and ACPA positive, ously [17], reliability and agreement were assessed based and 78% of patients had bony erosion at baseline. Eleven on the intra-class correlation coefficient (ICC): the mean (34%) patients were treatment-naïve, without previous GC ICC for inter-observer agreement was 0.950. Bony ero- or DMARD therapy for 6 months before enrollment. sion was defined as a cortical break identified on radiog- Fourteen (44%) patients had a level of HBV DNA above raphy [24]. Radiographic progression was defined as a 500 IU/mL, of whom 11 (34%) had levels above 10 IU/ change in mTSS (ΔmTSS) ≥0.5 units [25], and rapid mL and 8 (25%) had levels above 10 IU/mL, all with nor- radiographic progression (RRP) was defined as ΔmTSS mal liver function. A total of 128 age-matched, sex- ≥5 units from baseline to month 12 [26]. matched, and baseline disease activity-matched RA con- trols in the non-CHB group were compared with patients Outcome assessments with RA with CHB. There was no significant difference in The primary outcome was the percentage of patients with baseline demographic and clinical characteristics between one-year radiographic progression. The secondary out- groups, except for significantly higher levels of JE subscore comes were determined at each visit. These were the per- and mTSS, and significantly greater proportions of pa- centages of patients achieving therapeutic target and tients using sulfasalazine (SSZ) and hydroxychloroquine Chen et al. Arthritis Research & Therapy (2018) 20:81 Page 4 of 13 (HCQ) in the previous 6 months before enrollment in the 17%, p < 0.001), with a similar trend in RRP (16% vs. 5%, CHB group (both p <0.05, Table 1). p = 0.059). Significantly higher levels of JE subscore, JSN subscore, and mTSS at month 12 were observed and Comparison of treatment after enrollment there were more increases in JE subscore and mTSS in Initial treatment after enrollment and therapy adjust- the CHB group than those in the non-CHB group (all p ment were according to the “treat-to-target” strategy and < 0.05). The cumulative probability distribution of radio- patient’s willingness. There was no significant difference graphic change from baseline to month 12 in patients between groups in the initial therapy using GCs, metho- with RA in both groups and the space between the trexate (MTX), iguratimod, or biologic agents after en- curves indicated there was a significantly higher percent- rollment (all p > 0.05, Table 2). Compared with the non- age of patients with CHB who had one-year radiographic CHB group, significantly higher percentages of patients progression (Fig. 1a-c). in the CHB group took SSZ and HCQ (44% vs. 2% and 75% vs. 11%, respectively; both p < 0.001), while a signifi- Patients with RA with CHB achieved a lower level of cantly smaller proportion of patients with CHB took clinical response leflunomide (LEF) (16% vs. 84%, p < 0.001). Accordingly, At month 6, the proportions of patients achieving thera- patients in the CHB group received significantly higher peutic target (53% vs. 82%, p = 0.003) and remission cumulative doses of SSZ, HCQ, and cyclosporin A (50% vs. 72%, p = 0.039) were significantly smaller in the (CysA), while taking significantly lower cumulative doses CHB group than those in the non-CHB group, with a of methotrexate (MTX) and LEF both within the initial similar trend of achieving therapeutic target and remis- 6 months after enrollment and during one-year follow sion at month 12 (53% vs. 75%, p = 0.034 and 44% vs. up (all p < 0.05). Combined DMARDs were used in 31 63%, p = 0.077, respectively) (Fig. 2a, b). The percentages (97%) patients in the CHB group and 125 (98%) in the of ACR20 and ACR50 responders were also significantly non-CHB group. Compared with the non-CHB group, a lower in the CHB group versus the non-CHB group at greater proportion of CHB patients used the regimen of month 6 (56% vs. 81%, p = 0.013 and 47% vs. 70%, p = MTX combined with SSZ and HCQ (34% vs. 1%, p < 0.029, respectively) (Fig. 2c, d). Additionally, compared 0.001), while a smaller percentage of patients in the with the non-CHB group, the percentage of patients CHB group used the regimen of MTX combined with achieving good or moderate EULAR response was sig- LEF (9% vs. 72%, p < 0.001). Six (19%) patients in the nificantly lower in the CHB group at month 3 (75% vs. CHB group and 38 (30%) in the non-CHB group were 91%, p = 0.038) and month 12 (69% vs. 91%, p = 0.004); treated with a combination of conventional synthetic a significantly smaller proportion of patients achieving a DMARDs (csDMARDs) and biologic agents (toci- good EULAR response was observed in the CHB group lizumab, infliximab, or recombinant human tumor ne- at month 6 (56% vs. 79%, p = 0.022) and month 12 (53% crosis factor-α receptor-II (Yi Sai Pu, biosimilar)). and 74%, p = 0.041) (Fig. 2e, f). Antiviral prophylaxis by entecavir or tenofovir was The results of dynamic disease activity indicators dur- suggested for all patients with RA with CHB. However, ing one-year follow up are shown in Fig. 2g-n. Disease due to economic reasons, only 14 (44%) patients finally activity indicators, except for ESR, TJC28, HAQ, were accepted, of whom 5 (36%) chose lamivudine, 6 (43%) significantly higher in the CHB group than those in the adefovir, and only 3 (21%) entecavir. Notably, there were control group mainly at month 6 and month 12 (all p < no significant differences in GC therapy, DMARD ther- 0.05). An additional file shows the other clinical re- apy, or cumulative doses of the medications after enroll- sponses that were not demonstrated in Fig. 2 (Additional ment between patients with and without antiviral file 1). Moreover, a significantly higher serum MMP-3 prophylaxis. Antiviral therapy was commenced or level was observed in female patients from the CHB switched to agents with a high barrier to resistance, such group compared with that in the non-CHB group at as entecavir or tenofovir, when HBV reactivation oc- month 12 (p = 0.020, Fig. 2o). Regardless of gender, a curred. In addition, liver function was closely monitored similar trend in the serum MMP-3 level was also seen at as frequently as 2 to 4 weeks and GC, MTX, or LEF month 6 (p = 0.086, Additional file 1). therapies were tapered or withdrawn, especially if hepa- titis flare occurred. Risk factors for one-year radiographic progression and failure to achieve therapeutic target within 6 months Patients with RA with CHB had more pronounced To determine risk factors for one-year radiographic pro- radiographic progression at month 12 gression, univariate logistic regression analysis was per- Compared with the non-CHB group, there was a signifi- formed on variables including baseline characteristics, cantly higher percentage of patients in the CHB group CHB status, and RA medications after enrollment (in- experiencing one-year radiographic progression (53% vs. cluding categories of medications, one-year cumulative Chen et al. Arthritis Research & Therapy (2018) 20:81 Page 5 of 13 Table 1 Demographic and disease characteristics at baseline Table 1 Demographic and disease characteristics at baseline (Continued) Parameters CHB group Non-CHB group p value (n = 32) (n = 128) Parameters CHB group Non-CHB group p value (n = 32) (n = 128) Matched parameters LEF 6 (19) 34 (27) 0.417 Female, n (%) 27 (84) 108 (84) 1.000 SSZ 4 (13) 1 (1) 0.005 Age (years) 49 (38–56) 49 (38–57) 0.964 HCQ 10 (31) 12 (9) 0.006 DAS28-CRP 4.6 (3.5–5.0) 4.6 (3.8–5.3) 0.791 CysA 1 (3) 5 (4) 0.853 Demographic characteristics Biologic agents 1 (3) 3 (2) 0.821 Age of onset (years) 44 (31–52) 45 (33–53) 0.948 Data are presented as median (interquartile range (IQR)) or number Disease duration 36 (9–113) 36 (12–84) 0.805 (percentage (%)) (months) ACPA anti-cyclic citrullinated peptide antibody, ALT alanine aminotransferase, AST aspartate transaminase, CDAI Clinical Disease Activity Index, CHB chronic Short duration 3 (9) 19 (15) 0.476 hepatitis B virus infection, CRP C-reactive protein, CysA cyclosporin A, DAS28 (<6 months) Disease Activity Score 28-joint assessment, DMARD disease-modifying anti- Intermediate duration 12 (38) 39 (30) 0.501 rheumatic drug, ESR erythrocyte sedimentation rate, GC glucocorticosteroid, (6–24 months) HAQ Stanford Health Assessment Questionnaire, HCQ hydroxychloroquine, JE joint erosion, JSN joint space narrowing, LEF leflunomide, mTSS modified total Long duration 17 (53) 70 (55) 0.887 Sharp score, MMP-3 matrix metalloproteinase-3, MTX methotrexate, NA not (>24 months) applicable, Pain VAS pain visual analog scale, PrGA provider global assessment of disease activity, PtGA patient global assessment of disease activity, RA rheumatoid Disease characteristics arthritis, RAPID3 Routine Assessment of Patient Index Data 3, RF rheumatoid TJC28 6 (2–10) 6 (3–10) 0.914 factor, SDAI Simplified Disease Activity Index, SJC28 28-joint swollen joint counts, SSZ sulfasalazine, TJC28 28-joint tender joint count SJC28 4 (1–8) 4 (2–6) 0.523 Compared between the CHB group and the non-CHB group using conditional logistic regression analysis: bold p values are significant PainVAS 4 (2–5) 4 (3–6) 0.131 Without glucocorticosteroid or DMARD therapy for 6 months PtGA 5 (3–6) 5 (3–6) 0.355 before enrollment PrGA 5 (3–5) 5 (3–6) 0.276 doses of medications, and different regimens of com- HAQ 0.6 (0–1.3) 0.6(0.1–1.2) 0.888 bined therapies) (Table 3). The results revealed that CRP (mg/L) 12.1 (3.8–44.2) 12.1 (4.8–32.0) 0.543 CHB status (OR 3.129, 95% CI 1.661–5.895; p < 0.001), ESR (mm/h) 36 (20–62) 50 (24–75) 0.162 higher baseline mTSS (OR 1.016, 95% CI 1.006–1.026; p = 0.001), and higher one-year cumulative dose of GCs RF positivity, n (%) 23 (72) 96 (75) 0.746 (OR 1.000282, 95% CI 1.000067–1.000497, p = 0.010) ACPA positivity, n (%) 23 (72) 101 (79) 0.448 were significant factors for one-year radiographic pro- SDAI 22.1 (13.6– 21.2 (14.6–29.3) 0.320 gression. In bivariate analyses that adjusted for baseline 31.3) mTSS and one-year cumulative dose of GCs, one factor CDAI 19 (12–28) 20 (13–26) 0.332 at a time, CHB status was still positively associated with RAPID3 3.3 (2.1–4.6) 3.6 (2.7–5.2) 0.128 one-year radiographic progression (OR 2.610 and OR MMP-3 (ng/mL) 184 (86–453) 155 (86–358) 0.440 2.881, respectively; both p < 0.01). Moreover, multivari- Liver function ate logistic regression analysis that adjusted for all AST (U/L) 18 (14–25) 16 (14–21) 0.630 significant factors from univariate analyses showed that CHB status was independently associated with one-year ALT (U/L) 18 (12–29) 15 (10–21) 0.769 radiographic progression (OR 2.403, 95% CI 1.218– Radiographic status 4.743; p = 0.011). Bony erosions, n (%) 25 (78) 96 (75) 0.742 Both ACR and EULAR recommendations for the man- JSN subscore 5.5 (0–18.8) 3.0 (1.0–9.8) 0.078 agement of RA emphasize tight control of disease activ- JE subscore 6.0 (1.0–22.0) 4.0 (0.3–10.0) 0.009 ity and attaining therapeutic target within 6 months [19, mTSS 11.0 (1.3–36.3) 8.0 (2.0–20.8) 0.021 21]. Therefore, logistic regression analysis was also per- formed to determine risk factors for failure to achieve Previous medications, n (%) b therapeutic target within 6 months (Table 4). The results Treatment-naïve 11 (34) 55 (43) 0.431 of univariate logistic regression analysis revealed that GCs 14 (44) 48 (38) 0.562 CHB status (OR 3.077, 95% CI 1.349–7.017; p = 0.008), MTX 16 (50) 49 (38) 0.283 being medication-naïve (OR 0.300, 95% CI 0.102–0.881; p = 0.029), MTX therapy (OR 0.266, 95% CI 0.099– 0.716; p = 0.009), a regimen of MTX combined with LEF (OR 0.365, 95% CI 0.155–0.861; p = 0.021), 6-month cumulative dose of MTX (OR 0.997, 95% CI 0.993– Chen et al. Arthritis Research & Therapy (2018) 20:81 Page 6 of 13 Table 2 Medications after enrollment Table 2 Medications after enrollment (Continued) a a Medication CHB group Non-CHB group p value Medication CHB group Non-CHB group p value (n = 32) (n = 128) (n = 32) (n = 128) Initial medications, n (%) CysA 0(0–37,575) 0 (0–12,825) 0.016 GCs 23 (72) 89 (70) 0.817 Iguratimod 0(0–5775) 0 (0–9000) 0.393 <5 mg/day 1 (3) 3 (2) 0.821 Tocilizumab 0(0–1880) 0 (0–2800) 0.184 ≥5, ≤10 mg/day 19 (59) 81 (63) 0.715 Yi Sai Pu 0(0–600) 0 (0–0) 0.606 >10, ≤20 mg/ 2 (6) 4 (3) 0.462 Infliximab 0(0–0) 0 (0–0) NA day Data are presented as median (interquartile range (IQR)) or number (percentage (%)) unless stated otherwise >20 mg/day 1 (3) 1 (1) 0.357 CHB chronic hepatitis B virus (HBV) infection, CysA cyclosporin A, GC MTX 28 (87) 121 (95) 0.217 glucocorticosteroid, HCQ hydroxychloroquine, LEF leflunomide, MTX methotrexate, NA not applicable, SSZ sulfasalazine ≤10 mg/week 21 (66) 79 (62) 0.715 Compared between the CHB group and the non-CHB group using conditional logistic regression analysis: bold p values are significant >10, ≤15 mg/ 6 (19) 40 (31) 0.217 Within the initial 6 months after enrollment week Data were analyzed as median (5th/95th percentile ranges) due to the small >15 mg/week 1 (3) 2 (2) 0.606 number of patients using these medications LEF 5 (16) 107 (84) <0.001 1.000; p = 0.049), and 6-month cumulative dose of CysA SSZ 14 (44) 2 (2) <0.001 (OR 1.000077, 95% CI 1.000011–1.000143; p = 0.023) HCQ 24 (75) 14 (11) <0.001 were recognized as significant factors for failure to CysA 4 (13) 4 (3) 0.062 achieve therapeutic target within 6 months. Bivariate Iguratimod 1 (3) 10 (8) 0.415 analyses that adjusted for the significant factors in the Biologic agents 6 (19) 38 (30) 0.273 univariate analyses, one factor at a time, demonstrated that CHB status was always an independent risk factor Tocilizumab 4 (13) 30 (23) 0.234 (OR 2.722–3.077, p = 0.019–0.008). Further multivariate Yi Sai Pu 2 (6) 5 (4) 0.606 logistic regression analysis was performed by adjusting Infliximab 0 (0) 3 (2) NA for all significant factors in the univariate analyses. Due Six-month cumulative dose of medications (mg) to the multicollinearity between MTX therapy and 6- GCs 900 (0–1406) 1069 (0–1556) 0.506 month cumulative dose of MTX, two multivariate MTX 260 (201–315) 288 (260–348) 0.024 models were set up respectively and the results of both models showed that CHB status remained significantly LEF 0 (0–0) 1800 (1500– <0.001 3263) associated with failure to achieve therapeutic target SSZ 0 (0–270,000) 0 (0–0) <0.001 within 6 months (MTX therapy model, OR 2.617, 95% CI 1.140–6.007, p = 0.023; 6-month cumulative dose of HCQ 54,000 (3000– 0(0–0) <0.001 72,000) MTX model, OR 2.844, 95% CI 1.245–6.498, p = 0.013). CysA 0(0–19,515) 0 (0–4500) 0.020 Safety Iguratimod 0(0–2625) 0 (0–9000) 0.330 Table 5 presents an overview of side effects during one- Tocilizumab 0(0–1880) 0 (0–2400) 0.218 year follow up. Infections occurred in 16% of patients Yi Sai Pu 0(0–600) 0 (0–0) 0.606 with CHB and 13% of patients in the non-CHB group. Infliximab 0(0–0) 0 (0–0) NA The most common infections were respiratory tract in- One-year cumulative dose of medications (mg) fection, with one patient (3%) in the CHB group and six paitents (5%) in the control group diagnosed as GCs 1800 (0–2790) 1744 (0–2475) 0.418 pneumonia respectively. One patient in the non-CHB MTX 520 (413–650) 585 (520–715) 0.023 group suffered from herpes zoster 7 months after initi- LEF 0 (0–0) 3600 <0.001 ation with tocilizumab. There was no significant differ- (2719–6600) ence between groups in the incidence of infections, SSZ 68,000 (0–536,000) 0 (0–0) <0.001 trichomadesis, neutropenia, or gastrointestinal discom- HCQ 90,000 0(0–0) <0.001 fort (all p > 0.05). No deaths occurred due to these side (3000–144,000) effects in this study. The main side effects of RA treatment on HBV infec- tion were HBV reactivation and aminotransferase eleva- tion. No patient in the non-CHB group developed HBV reactivation. However, 34% of CHB patients developed Chen et al. Arthritis Research & Therapy (2018) 20:81 Page 7 of 13 Fig. 1 One-year radiographic change in patients with rheumatoid arthritis (RA) in the chronic hepatitis B virus infection (CHB) group and the non- CHB group. Comparison of cumulative probability of △mTSS (a), △JSN subscore (b) and △JE subscore (c) during one-year follow up between the CHB group and the non-CHB group: *p < 0.05, **p < 0.01, ***p < 0.001. JE, joint erosion; JSN, joint space narrowing; mTSS, modified total Sharp score virus reactivation, of whom 8 (72%) refused to accept response among patients with RA in clinical practice, antiviral prophylaxis, with hepatitis flare occurring in 2 which revealed that HBV infection is implicated in RA patients (6%) during follow up. There was no significant progression. difference in the incidence of aminotransferase elevation HBV infection was complicated due to extrahepatic between groups (19% vs. 31%, p > 0.05). A flowchart of manifestations including polyarthritis mainly affecting HBV reactivation and hepatitis flare occurring in small joints, which seemed to mimic that of RA and patients with CHB is shown in Additional file 2. Fortu- was considered to be immune-complex mediated [31]. nately, serum HBV DNA level and aminotransferase in Use of recombinant HBsAg could induce the appearance all patients with RA returned to undetectable or normal of RA-like symptoms [32, 33], which might result from after commencing antiviral therapy or adjusting GC, the common HLA-DR haplotypes for RA [34]. Some MTX, or LEF therapy. No liver cirrhosis, liver failure, or patients with HBV infection who fulfilled the 1987 ACR HBV-related deaths occurred during follow up in this criteria for RA could have symptoms resolved by anti- study. HBV treatment [9, 10]. Furthermore, a recent large study from Taiwan demonstrated that patients with RA Discussion had a higher HBV period prevalence than did the non- In this study, we performed a retrospective case-control RA subjects [11]. Results in the present study showed study to investigate the influence of HBV infection on that patients with RA with CHB had more pronounced therapeutic response among patients with RA in a clin- one-year radiographic progression and achieved a lower ical practice setting. The Sharp/van der Heijde score level of clinical response than the non-CHB group, showed that patients with RA with CHB suffered more which was in accordance with most previously proposed pronounced one-year radiographic progression than the hypotheses of HBV infection acting as an adverse factor non-CHB group. Compared with the control group, in RA. smaller proportions of patients with RA with CHB Previous studies have shown that even though some achieved therapeutic target and remission, and the trend patients with HBV infection may have long-lasting was also seen in attaining ACR20/50 responses and good polyarthritis, joint destruction remains an almost rare or moderate EULAR responses, mainly at month 6 and complication. However, a case report describes a pa- month 12. Conditional logistic regression analysis tient with positive HBsAg and HBeAg in serum, who showed that CHB status was independently associated suffered worsened pain after a steroid injection for with one-year radiographic progression. Both ACR and knee osteoarthritis. Radiographs on admission showed EULAR recommendations for the management of RA a large bone defect in the medial tibia and slight nar- emphasize that therapeutic target should be attained rowing of the articular gap. Further analysis revealed within 6 months [19, 21]. Thus, conditional logistic re- diffuse expression of HBsAg in the synovium, suggest- gression analysis was further performed and the result ing destructive knee arthropathy possibly caused by showed that CHB status was also significantly associated HBV infection [7]. Another report demonstrated that a with failure to achieve therapeutic target within 6 woman with acute RA onset after receiving the first months. Therefore, HBV infection may play a deleteri- dose of HBV vaccine experienced erosions with min- ous role in radiographic and clinical outcomes in pa- imal periarticular osteoporosis 10 months later [35]. In tients with RA. To our knowledge, this is the first study this study, a larger proportion of patients with CHB to investigate the role of HBV infection in therapeutic suffered one-year radiographic progression, which Chen et al. Arthritis Research & Therapy (2018) 20:81 Page 8 of 13 Fig. 2 (See legend on next page.) Chen et al. Arthritis Research & Therapy (2018) 20:81 Page 9 of 13 (See figure on previous page.) Fig. 2 Clinical responses in the chronic hepatitis B virus infection (CHB) group and the non-CHB group. a-f Comparison of the rates of patients achieving therapeutic target, remission, American College of Rheumatology (ACR)20/50 responses, and European League Against Rheumatism (EULAR) responses at each visit. g-n Comparison of dynamic disease activity indicators at each visit. o Comparison of dynamic matrix metalloproteinase-3 (MMP-3) levels in female patients at each visit. Data are represented by the median and interquartile range: *p <0.05, **p <0.01, ***p <0.001. CDAI, Clinical Disease Activity Index; CRP, C-reactive protein; DAS28, Disease Activity Score 28-joint assessment; Pain VAS, pain visual analog scale; PrGA, provider global assessment of disease activity; PtGA, patient global assessment of disease activity; RAPID3, Routine Assessment of Patient Index Data 3; SDAI, Simplified Disease Activity Index; SJC28, 28-joint swollen joint counts; TJC28, 28-joint tender joint counts implies that HBV infection might directly or indirectly A, while MTX and LEF were contraindicated for all contribute to joint damage. On the other hand, MMP-3 Child-Pugh classifications [19, 21]. However, the guide- is a proteinase secreted by synovial fibroblasts and lines for antiviral prophylaxis made by the American chondrocytes in joints, which can accelerate joint de- Gastroenterological Association in 2015 recommended struction in RA. Recently, the reduction in serum low-dose GC therapy (prednisone (or equivalent) at < MMP-3 was considered as a possible therapeutic target 10 mg/day) for > 4 weeks in the moderate-risk group together with disease activity. Urata et al. reported that and MTX in the low-risk group for HBV reactivation treating to target MMP-3 normalization combined with in patients with CHB [30]. LEF is not recommended in disease activity yielded better effects than each target patients with a history of hepatitis and might increase alone in patients with RA [36]. the risk of HBV reactivation [14, 38]. In the present Our previous studies also have shown that serum study, although not all patients with CHB agreed to re- MMP-3 level was positively correlated with disease ac- ceive recommended antiviral prophylaxis due to eco- tivity and continuously elevated serum MMP-3 for 3 to nomic reasons, there was no significant difference in 6 months could predict one-year radiographic progres- RA treatment between patients with and without anti- sion [17, 23]. In this study, compared with the non-CHB viral prophylaxis. However, there were significant dif- group, serum MMP-3 level was higher in the CHB group ferences in the medications taken by patients with and at month 6, and was significantly higher in women from without CHB. Patients with RA with CHB were more the CHB group at month 12, which further confirmed likely to use SSZ and HCQ rather than LEF, and that patients with RA with CHB had a lower level of received significantly lower cumulative doses of MTX. clinical response and radiographic outcome. Moreover, Accordingly, a significantly greater proportion of pa- studies have revealed that HBV X protein could promote tients with CHB used the regimen of MTX combined cell migration by inducing the transcription, translation, with SSZ and HCQ, while a smaller percentage of and secretion of MMP-3 [37]. In this scenario, it is pos- patients with CHB used the regimen of MTX com- sible that CHB status may negatively affect the radio- bined with LEF. Nevertheless, patients with CHB had a graphic and clinical outcomes of patients with RA partly significantly higher possibility of HBV reactivation through upregulating MMP-3. Both ACR and EULAR compared to the non-CHB group (including patients recommendations for the management of RA emphasize with resolved HBV infection or patients never infected tight control of disease activity and therapeutic target with HBV), which may preclude escalation of therapy should be attained within 6 months [19, 21]. Patients and might result in not reaching a full dose of some of with CHB in this study had more pronounced one-year the drugs and not achieving therapeutic target within radiographic progression probably due to a lower level the recommended time frame. of clinical response during one-year follow up, especially Multivariate logistic regression analysis revealed that within 6 months. That is, HBV infection may act as a both CHB status and MTX therapy were independently “regulatory factor” or even a “driver factor” during dis- associated with failure to achieve therapeutic target ease progression in patients with RA with CHB. There- within 6 months. Hence, it is reasonable to speculate fore, it could be speculated that patients with CHB that patients with CHB had more pronounced one-year could be classified as having a specific phenotype of RA radiographic progression and a lower level of clinical re- that may need adjusted regimens or routes of adminis- sponse probably due to both CHB status and different tration to achieve sufficient therapeutic response. regimens, especially MTX therapy, used in the patients HBV reactivation is a well-recognized complication with CHB. In light of the pros and cons, it is indeed dif- that may cause high morbidity and mortality in pa- ficult to find a balance during RA treatment. Therefore, tients who undergo immunosuppressive therapy. The besides CHB status, regimen adjustments for preventing 2008 ACR recommended that SSZ under antiviral HBV reactivation during RA treatment might also prophylaxis and HCQ could be used for patients with explain part of the adverse role of HBV infection in RA RA with CHB and liver function of Child-Pugh class radiographic and clinical outcomes. On the other hand, Chen et al. Arthritis Research & Therapy (2018) 20:81 Page 10 of 13 Table 3 Logistic regression analyses of risk factors for one-year Table 3 Logistic regression analyses of risk factors for one-year radiographic progression radiographic progression (Continued) OR 95% CI p value* OR 95% CI p value* Univariate analyses One-year cumulative dose 1.000 (0.998–1.003) 0.817 of Yi Sai Pu Female 0.845 (0.373–1.915) 0.687 One-year cumulative dose 0.997 (0.989–1.006) 0.564 Age 0.993 (0.969–1.018) 0.598 of infliximab Disease duration 1.004 (1.000–1.008) 0.076 Bivariate models CHB status 3.129 (1.661–5.895) <0.001 CHB status adjusted for 2.610 (1.338–5.092) 0.005 baseline mTSS TJC28 0.996 (0.934–1.063) 0.914 CHB status adjusted for 2.881 (1.511–5.493) 0.001 SJC28 0.982 (0.908–1.062) 0.651 one-year cumulative dose Pain VAS 1.056 (0.905–1.232) 0.491 of GCs PtGA 1.094 (0.939–1.274) 0.248 Multivariate model PrGA 1.086 (0.921–1.281) 0.326 CHB status adjusted for baseline 2.403 (1.218–4.743) 0.011 mTSS and one-year cumulative HAQ 1.346 (0.990–1.830) 0.058 dose of GCs CRP 1.001 (0.998–1.014) 0.876 ACPA anti-cyclic citrullinated peptide antibody, CHB chronic hepatitis B virus ESR 0.999 (0.989–1.008) 0.786 (HBV) infection, CI confidence interval, CRP C-reactive protein, CysA cyclosporin A, DAS28 Disease Activity Score 28-joint assessment, ESR erythrocyte RF positivity 2.355 (0.921–6.023) 0.074 sedimentation rate, GC glucocorticosteroid, HAQ Stanford Health Assessment Questionnaire, HCQ hydroxychloroquine, LEF ACPA positivity 1.983 (0.775–5.070) 0.153 leflunomide, mTSS modified total Sharp score, MTX methotrexate, OR odds DAS28-CRP 1.011 (0.742–1.378) 0.944 ratio, Pain VAS pain visual analog scale, PrGA provider global assessment of disease activity, PtGA patient global assessment of disease activity, RF MMP-3 1.001 (0.999–1.002) 0.292 rheumatoid factor, SJC28 28-joint swollen joint count, SSZ sulfasalazine, TJC28 28-joint tender joint count mTSS 1.016 (1.006–1.026) 0.001 Calculated using conditional logistic regression analysis. Univariate logistic Treatment-naïve 0.710 (0.365–1.381) 0.313 regression analysis was performed on variables, including baseline characteristics, CHB status, and rheumatoid arthritis medications after enrollment (including GCs 2.300 (0.964–5.489) 0.061 categories of medications, one-year cumulative doses of medications, and different regimens of combined therapies); bivariate analysis was performed by adjusting MTX 1.369 (0.330–5.678) 0.666 for baseline mTSS and one-year cumulative dose of GCs respectively; multivariate LEF 0.684 (0.359–1.304) 0.248 logistic regression analysis was performed by adjusting for all significant univariate factors: bold p values are significant SSZ 1.984 (0.876–4.495) 0.101 Without glucocorticosteroid or DMARD therapy for 6 months HCQ 1.611 (0.828–3.135) 0.160 before enrollment One-year cumulative dose of GCs: OR 1.000282, 95% CI 1.000067–1.000497; CysA 1.591 (0.490–5.167) 0.440 p = 0.010 One-year cumulative dose of LEF: OR 0.999888, 95% CI 0.999766–1.000011; Iguratimod 1.130 (0.348–3.670) 0.839 p = 0.074 Biologic agents 0.477 (0.200–1.139) 0.095 One-year cumulative dose of CysA: OR 1.000025, 95% CI 0.999993–1.000057; p = 0.124 MTX combined with SSZ 2.265 (0.949–5.406) 0.066 f One-year cumulative dose of iguratimod: OR 1.000013, 95% CI 0.999926– and HCQ 1.000101; p = 0.761 One-year cumulative dose of tocilizumab: OR 0.999719, 95% CI 0.999259– MTX combined with LEF 0.719 (0.384–1.346) 0.302 1.000180; p = 0.232 One-year cumulative dose 1.000 (1.000–1.000) 0.010 of GCs baseline radiographic status is an important feature that One-year cumulative dose 0.999 (0.998–1.000) 0.224 could influence radiographic progression in patients with of MTX RA. In this study, levels of JE subscore and mTSS at One-year cumulative dose 1.000 (1.000–1.000) 0.074 baseline were significantly higher in the CHB group than of LEF in the non-CHB group, and baseline mTSS was one of One-year cumulative dose 1.001 (1.000–1.003) 0.133 the significant factors for one-year radiographic progres- of SSZ sion according to the results of logistic regression ana- One-year cumulative dose 1.004 (0.998–1.009) 0.160 lysis. However, CHB status was independently associated of HCQ with one-year radiographic progression after adjusted for One-year cumulative dose 1.000 (1.000–1.000) 0.124 of CysA all confounding factors including baseline mTSS. There are several limitations in this study. First, it was One-year cumulative dose 1.000 (1.000–1.000) 0.761 of iguratimod a real-world observational study from a single center and patients were treated with different medications. One-year cumulative dose 1.000 (0.999–1.000) 0.232 of tocilizumab Although multivariate logistic regression was performed to remove the confounding effect of different Chen et al. Arthritis Research & Therapy (2018) 20:81 Page 11 of 13 Table 4 Logistic regression analyses of risk factors for failure to Table 4 Logistic regression analyses of risk factors for failure to achieve therapeutic target within 6 months achieve therapeutic target within 6 months (Continued) a a OR 95% CI p value OR 95% CI p value Univariate analyses Six-month cumulative dose 1.001 (0.999–1.004) 0.322 of Yi Sai Pu Female 1.235 (0.367–4.155) 0.734 Six-month cumulative dose 0.997 (0.986–1.009) 0.659 Age 1.012 (0.979–1.045) 0.488 of infliximab Disease duration 1.000 (0.994–1.007) 0.969 Bivariate models CHB status 3.077 (1.349–7.017) 0.008 CHB status adjusted for 2.844 (1.245–6.498) 0.013 treatment-naïve status TJC28 1.059 0.986–1.137 0.115 CHB status adjusted for MTX 2.722 (1.177–6.298) 0.019 SJC28 1.035 0.951–1.127 0.421 CHB status adjusted for the 3.077 (1.349–7.017) 0.008 Pain VAS 1.096 0.897–1.338 0.369 regimen of MTX combined PtGA 1.192 0.977–1.455 0.083 with LEF PrGA 1.142 0.920–1.418 0.230 CHB status adjusted for 6-month 3.077 (1.349–7.017) 0.008 cumulative dose of MTX HAQ 1.318 0.880–1.975 0.180 CHB status adjusted for 6-month 3.077 (1.349–7.017) 0.008 CRP 1.004 (0.988–1.020) 0.616 cumulative dose of CysA ESR 1.000 (0.987–1.021) 0.949 Multivariate models RF positivity 1.637 (0.557–4.811) 0.371 CHB status adjusted for 2.617 (1.140–6.007) 0.023 ACPA positivity 0.452 (0.195–1.043) 0.063 treatment-naïve status, MTX therapy, the regimen of MTX combined with DAS28-CRP 1.394 (0.936–2.077) 0.102 LEF, and 6-month cumulative dose MMP-3 1.000 (0.999–1.002) 0.751 of CysA mTSS 1.010 (0.995–1.024) 0.195 CHB status adjusted for treatment- 2.844 (1.245–6.498) 0.013 b naïve status, 6-month cumulative Treatment-naïve 0.300 (0.102–0.881) 0.029 dose of MTX, the regimen of MTX GCs 1.178 (0.465–2.989) 0.729 combined with LEF, and 6-month cumulative dose of CysA MTX 0.266 (0.099–0.716) 0.009 ACPA anti-cyclic citrullinated peptide antibody, CHB chronic hepatitis B (HBV) LEF 0.468 (0.206–1.060) 0.069 infection, CI confidence interval, CRP C-reactive protein, CysA cyclosporin A, DAS28 Disease Activity Score 28-joint assessment, ESR erythrocyte sedimenta- SSZ 1.350 (0.401–4.543) 0.628 tion rate, GCs glucocorticosteroids, HAQ Stanford Health Assessment Question- HCQ 2.064 (0.893–4.768) 0.090 naire, HCQ hydroxychloroquine, LEF leflunomide, mTSS modified total Sharp score, MTX methotrexate, OR odds ratio, Pain VAS pain visual analogue scale, CysA 2.850 (0.847–9.591) 0.091 PrGA provider global assessment of disease activity, PtGA patient global assess- ment of disease activity, RF rheumatoid factor, SJC28 28-joint swollen joint Iguratimod 2.032 (0.604–6.837) 0.252 count, SSZ sulfasalazine, TJC28 28-joint tender joint count Biologic agents 0.555 (0.189–1.631) 0.285 Calculated using conditional logistic regression analysis: univariate logistic regression analysis was performed on variables, including baseline MTX combined with SSZ 1.175 (0.275–5.009) 0.828 characteristics, CHB status, and rheumatoid arthritis medications after and HCQ enrollment (including categories of medications, 6-month cumulative doses of medications, and different regimens of combined therapies); bivariate analysis MTX combined with LEF 0.365 (0.155–0.861) 0.021 was performed by adjusting for the significant univariate factors individually; Six-month cumulative dose 1.000 (1.000–1.001) 0.340 due to the multicollinearity between MTX therapy and 6-month cumulative of GCs dose of MTX, two multivariate models (MTX therapy model and 6-month cumulative dose of MTX model) were set up respectively by adjusting for all Six-month cumulative dose 0.997 (0.993–1.000) 0.049 significant univariate factors: bold p values are significant of MTX b Without glucocorticosteroid or DMARD therapy for 6 months before enrollment Six-month cumulative dose of GCs: OR 1.000220, 95% CI 0.999768–1.000671; Six-month cumulative dose 1.000 (0.999–1.000) 0.113 p = 0.340 of LEF Six-month cumulative dose of LEF: OR 0.999738, 95% CI 0.999414–1.000062; p Six-month cumulative dose 1.000 (0.995–1.005) 0.890 = 0.113 Six-month cumulative dose of CysA: OR 1.000077, 95% CI 1.000011–1.000143; of SSZ p = 0.023 Six-month cumulative dose 1.008 (0.994–1.022) 0.245 Six-month cumulative dose of iguratimod: OR 1.000080, 95% CI 0.999941– of HCQ 1.000218; p = 0.259 Six-month cumulative dose of tocilizumab: OR 0.999656, 95% CI 0.998954– Six-month cumulative dose 1.000 (1.000–1.000) 0.023 e 1.000358; p = 0.337 of CysA Six-month cumulative dose 1.000 (1.000–1.000) 0.259 of iguratimod medications, it would be necessary to carry out further multicenter studies and balance the combined therapy Six-month cumulative dose 1.000 (0.999–1.000) 0.337 of tocilizumab between groups. Second, over 70% of patients suffered bony erosion at baseline in this study, which was a risk Chen et al. Arthritis Research & Therapy (2018) 20:81 Page 12 of 13 Table 5 Safety profile of rheumatoid arthritis treatment Abbreviations a ACPA: Anti-cyclic citrullinated peptide antibody; ACR: American College of Side effect CHB group Non-CHB group p value Rheumatology; ALT: Alanine aminotransferase; AST: Aspartate transaminase; (n = 32) (n = 128) CDAI: Clinical Disease Activity Index; CHB: Chronic hepatitis B virus infection; Total side effects, n (%) 15 (47) 68 (53) 0.572 CI: Confidence interval; CRP: C-reactive protein; CysA: Cyclosporin A; DAS28: Disease Activity Score 28-joint assessment; DMARD: Disease- Infections 5 (16) 16 (13) 0.676 modifying anti-rheumatic drug; ESR: Erythrocyte sedimentation rate; Gastrointestinal discomfort 7 (22) 22 (17) 0.583 EULAR: European League Against Rheumatism; GC: Glucocorticosteroid; HAQ: Stanford Health Assessment Questionnaire; HBcAg: Hepatitis B virus Trichomadesis 2 (6) 13 (10) 0.547 core antigen; HBeAg: Hepatitis B virus e antigen; HBsAg: Hepatitis B virus surface antigen; HBV: Hepatitis B virus; HCQ: Hydroxychloroquine; Neutropenia 2 (6) 14 (11) 0.484 IQR: Interquartile range; JE: Joint erosion; JSN: Joint space narrowing; Aminotransferase elevation 6 (19) 39 (30) 0.244 LEF: Leflunomide; MMP-3: Matrix metalloproteinase-3; mTSS: Modified total Sharp score; MTX: Methotrexate; NA: Not applicable; OR: Odds ratio; Pain < two fold ULN 4 (13) 30 (23) 0.234 VAS: Pain visual analog scale; PrGA: Provider global assessment of disease ≥ two fold, < three fold ULN 1 (3) 7 (6) 0.630 activity; PtGA: Patient global assessment of disease activity; RA: Rheumatoid arthritis; RAPID3: Routine Assessment of Patient Index Data 3; ≥ three fold ULN 1 (3) 2 (2) 0.606 RF: Rheumatoid factor; RRP: Rapid radiographic progression; SDAI: Simplified Antiviral prophylaxis 14 (44) 0 (0) NA Disease Activity Index; SJC28: 28-Joint swollen joint counts; SSZ: Sulfasalazine; TJC28: 28-Joint tender joint counts; ULN: Upper limit of the normal range HBV reactivation 11 (34) 0 (0) NA Antiviral prophylaxis (+) 3 (9) 0 (0) NA Acknowledgements The authors wish to thank the patients and medical staff for their contribution Antiviral prophylaxis (−) 8 (25) 0 (0) NA to the study, and Nan Li from Perking University Third Hospital and Yan-Fang CHB chronic HBV infection, HBV hepatitis B virus, NA not applicable, ULN upper Ye from Sun Yat-Sen Memorial Hospital for their statistical assistance. limit of the normal range Compared between the CHB group and the non-CHB group using conditional Funding logistic regression analysis This work was supported by the National Natural Science Foundation of China (grant numbers 81471597, 81671612, and 81601427), Guangdong factor for one-year radiographic progression. Hence, Natural Science Foundation (grant numbers 2014A030313074, 2016A030313307, and 2017A030313576), Guangdong Medical Scientific more patients with early RA without baseline bony Research Foundation (grant number A2017109), and Key Program of Young erosion are needed in future to confirm our results. Teachers Foundation of Sun Yat-sen University (grant number 17ykjc12). Third, the relatively small number of patients with RA with CHB in this study precluded a robust conclusion. Availability of data and materials The datasets used and/or analyzed during the current study are available Whether clearance of HBV would lead to a good thera- from the corresponding author on reasonable request. peutic response in RA remains to be clarified in a larger, placebo-controlled study. Authors’ contributions All authors contributed to the final manuscript. Y-LC conceived and designed the study, analyzed the data, and drafted the manuscript. Corresponding Conclusions authors LD and D-HZ conceived and participated in the study, read and Our results showed that patients with RA with CHB had analyzed documents, and revised the manuscript. J-ZL and Y-QM participated more pronounced one-year radiographic progression in clinical assessment at each visit during the follow up. Q-HL, X-YW, and TY collected and analyzed the data. J-DM and Z-HY performed the radiographic and achieved a lower level of clinical response than assessment. All authors have read and approved the final submitted version. those without CHB. HBV reactivation remained a tricky issue in patients with CHB during RA treatment. Thus, Ethics approval and consent to participate This study was conducted in compliance with the Helsinki Declaration. Due to HBV infection may play a deleterious role in radio- the retrospective nature of the study, informed consent was waived. The study graphic and clinical outcomes among patients with RA, was approved by the Medical Ethics Committee of Sun Yat-Sen Memorial and HBV reactivation should be paid close attention Hospital (identifier SYSEC-KY-KS-011). during immunosuppressive therapy. Consent for publication All participants have approved publication of the data in this manuscript. Additional files Competing interests The authors declare that they have no competing interests. Additional file 1: The other clinical responses between the CHB group and the non-CHB group. Comparison of the other clinical responses at each visit, including ACR70, PrGA, Pain VAS, HAQ, ESR, and serum MMP-3 levels. Publisher’sNote ACR: American College of Rheumatology; CHB: chronic HBV infection; ESR: Springer Nature remains neutral with regard to jurisdictional claims in erythrocyte sedimentation rate; HAQ: Stanford Health Assessment Question- published maps and institutional affiliations. naire; MMP-3: matrix metalloproteinase-3; Pain VAS: pain visual analog scale; PrGA: provider global assessment of disease activity. (PDF 1468 kb) Author details Department of Rheumatology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen Additional file 2: A flowchart of HBV reactivation occurring in patients University, Guangzhou 510120, People’s Republic of China. Department of with RA with CHB showing antiviral prophylaxis, HBV reactivation, and Radiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, hepatitis flare in these patients during one-year follow up. CHB: chronic Guangzhou, People’s Republic of China. Zhongshan School of Medicine, HBV infection; HBV: hepatitis B virus; RA: rheumatoid arthritis. (PDF 33 kb) Sun Yat-sen University, Guangzhou, People’s Republic of China. Chen et al. Arthritis Research & Therapy (2018) 20:81 Page 13 of 13 Received: 24 October 2017 Accepted: 19 February 2018 22. Anderson J, Caplan L, Yazdany J, Robbins ML, Neogi T, Michaud K, et al. Rheumatoid arthritis disease activity measures: American College of Rheumatology recommendations for use in clinical practice. Arthritis Care Res (Hoboken). 2012;64(5):640–7. References 23. Ma JD, Zhou JJ, Zheng DH, Chen LF, Mo YQ, Wei XN, et al. Serum matrix 1. McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J metalloproteinase-3 as a noninvasive biomarker of histological synovitis for Med. 2011;365(23):2205–19. diagnosis of rheumatoid arthritis. Mediators Inflamm. 2014;2014:179284. 2. Ebringer A, Wilson C. HLA molecules, bacteria and autoimmunity. 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Arthritis Research & TherapySpringer Journals

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