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Minimum Infliximab Dosage for Keeping Serum Infliximab Levels Greater than 1 µg/mL among Patients with Rheumatoid Arthritis.

Infliximab shows drastic efficacy for controlling inflammation in rheumatoid arthritis (RA), though the ideal dose of infliximab to keep suppressing inflammation has not yet been identified. Recently, it has been evidenced that the minimum trough serum infliximab levels required for suppressing inflammation are greater than 1 µg/mL. This cross-sectional study was designed to identify the minimum dosage of infliximab for maintaining serum infliximab levels greater than 1 µg/mL. Thirty seven RA patients were enrolled in this study and they were divided into two groups (high-infliximab vs. low-infliximab) in reference to Remi-check Q®, a kit for examining serum infliximab levels above/below 1 µg/mL by LC. Infliximab dosage (p=0.06) and dosage interval (p=0.05) had trends to have differences between groups. A formula calculated by infliximab dosage divided by dosage interval and body weight (mg/weeks/kg) was shown to have significantly higher levels among high-infliximab group (p=0.04). Based on whether serum infliximab levels above/below 1 µg/mL and values led by the equation, infliximab dosage/infliximab interval/body weight (mg/weeks/kg), a receiver operating characteristic curve (ROC) was depicted with area under the ROC curve 0.750 and the cut-off point for the serum infliximab levels greater than 1 µg/mL was identified as infliximab dosage/infliximab interval/body weight ≧0.750 with the sensitivity 0.393 and the specificity 1.000. In conclusion, we identified that the minimum infliximab dosage to maintain serum infliximab levels greater than 1 µg/mL was infliximab dose/dosage interval/body weight (mg/weeks/kg)≥0.750.

Rheumatoid arthritis (RA) is the most common chronic, inflammatory disease associated with joint destruction and disability. 1) Tumor necrosis factor-alpha (TNF-alpha) works critically and primarily in an inflammatory cascade of RA. Infliximab is an anti-TNF-alpha antibody which significantly suppresses inflammation in RA. 2) Infliximab has shown drastic efficacy for controlling disease activity in RA, though the ideal dosage of inflixi mab for suppressing inflammation in well-controlled RA patients has not yet been identified. Takeuchi et al. described that the minimum trough serum inflixi mab levels required for clinical response were more than 1 µg/mL at 54 weeks of inflixi mab treatment. Very recently, Remi-check Q ® (LSI Medience Corporation, Tokyo, Japan), a kit for examining serum Infliximab levels whether more than 1 µg/mL or not by LC has begun to be used in clinic, covered by insurance in Japan since October 1st, 2017. Referring to package insert information, Remi-check Q ® represented high consistency with serum inflixi mab levels examined by enzyme-linked immunosorbent assay (ELISA) with sensitivity 0.96 and specificity 1.00. 3) This cross-sectional study was designed to identify the minimum dosage of inflixi mab for maintaining serum infliximab levels greater than 1 µg/mL in well-controlled RA patients treated with inflixi mab for more than 54 weeks.

PATIENTS AND METHODS
Patients and Blood Tests RA patients treated with inflixi mab for more than 54 weeks were recruited into this study. Of these, patients with serum C-reactive protein (CRP) levels more than 1 mg/dL were excluded as not well-controlled and 37 RA patients were finally included. They were diagnosed with RA according to the 1987 revised American College of Rheumatology classification criteria for RA. 4) This study was approved by the Ethical Committees (ID: 2017010) in our institution and informed consent was obtained from the patients. A blood test was used to measure CRP, erythrocyte sedimentation rate (ESR), matrix metalloproteinase-3 (MMP-3), serum amyloid A (SAA), white blood cell counts (WBC), hemoglobin, platelet, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and creatinine. In addition, clinical parameters in RA such as the Clinical Disease Activity Index (CDAI), the Simplified Disease Activity Index (SDAI), the 28-joint Disease Activity Score based on CRP (DAS28-CRP) and the 28-joint Disease Activity Score based on ESR (DAS28-ESR) were also examined. Serum inflixi mab levels were examined with Remi-check Q ® (LSI Medience Corporation, Tokyo, Japan).
Statistical Analysis Values are expressed as the mean±standard deviation (S.D.) unless otherwise stated. For our calculations, we used the statistical software XLSTAT (Addinsoft, Inc., Paris, France). When p-value was less than 0.05 (5%), it was considered statistically significant. Based on the inflixi mab serum levels examined with Remi-check Q ® , patients were categorized into two groups: high infliximab concentration (high-inflixi mab) with serum inflixi mab levels greater than 1 µg/mL and low inflixi mab concentration (low-inflixi mab) with less than 1 µg/mL. Between the highinflixi mab and low-inflixi mab groups, each parameter was compared with an unpaired t-test and if there was a significant difference in a parameter among groups, the parameter was set as an explanatory variable and a receiver operating characteristic (ROC) curve was depicted for predicting the serum inflixi mab levels greater than 1 µg/mL. The cut-off point was identified using Youden index with ROC curve. Remission rates in RA disease activity indexes such as CDAI, SDAI, DAS28-CRP and DAS28-ESR were compared between highinflixi mab and low-inflixi mab groups using Fisher's exact test.
There were significant differences in scores calculated the following equation: serum inflixi mab levels divided by the inflixi mab dosage intervals and body weight (mg/weeks/kg). Infliximab dosage and dosage intervals also had trends to differ between high-inflixi mab and low-inflixi mab groups. Based on the equation (inflixi mab dosage/inflixi mab interval/body weight), an ROC curve was depicted with area under the ROC curve (AUC)=0.750 as seen in Figure and the cut-off point for the serum inflixi mab levels greater than 1 µg/mL was clarified as inflixi mab dosage/inflixi mab interval/body weight ≧0.750 with the sensitivity 0.393 and the specificity 1.000. The 2×2 contingency table was depicted without any false positive cases, as shown in Table 2.

DISCUSSION
Infliximab is the first biological agent approved in Japan for treating RA and it has been widely used with clinical ef-   ficacy. 5) Now biologic-naïve RA patients have many options for selecting a biologic agent with similar efficacy, 6) though only inflixi mab requires concomitant use of methotrexate for decreasing risks of anti-inflixi mab antibodies formation in RA. 7) Owing to the advent of new biological agents, opportunities to start inflixi mab therapy for biologic-naïve RA patients have been limited. In contrast, inflixi mab is widely used for maintaining disease remission among RA patients previously treated with inflixi mab, because inflixi mab is the first approved biologic in Japan and switching of biologics increases potential risks of immunogenicity. For that reason, this cross-sectional study was designed to focus on RA patients continuing inflixi mab in chronic phase. The most important finding in our study was the identification of a minimum inflixi mab dosage required for clinical response for suppressing inflammation among RA patients. There is a consensus that inflixi mab is truly beneficial in suppressing inflammation and recently, the RISING study, a prospective, multicenter, double-blind study conducted at 88 institutions in Japan 8) clarified that the minimum serum inflixi mab level required for clinical response was 1 µg/mL. However, it had not yet examined what inflixi mab dosage is required to maintain serum inflixi mab levels greater than 1 µg/mL. In this study, we identified the minimum infliximab dosage to maintain serum inflixi mab levels greater than 1 µg/mL was as follows: inflixi mab dose/dosage interval/body weight ≥0.750.
The approved dosage of inflixi mab in RA ranges from 3 mg/kg every 8 weeks to 6-10 mg/kg every 4 weeks. 9) With the approved dosage, the minimum inflixi mab dose (mg)/dosage interval (weeks)/body weight (kg) is 0.375. In contrast, our study newly evidenced that the inflixi mab dose (mg)/dosage interval (weeks)/body weight (kg)≥0.750 is necessary for maintaining serum inflixi mab levels greater than 1 µg/mL. If the inflammation is not suppressed even though the inflixi mab dose (mg)/dosage interval (weeks)/body weight (kg) exceeds more than 0.750, it may be recommended to switch from inflixi mab to other biological agents or Janus kinase (JAK) inhibitors such as Tofacinib. 10) In our study, though remission rates in RA disease activity indexes did not differ between high-inflixi mab and lowinflixi mab groups, the low-inflixi mab group had a trend showing an increase in remission rates in SDAI and DAS28-CRP. This is potentially because of selection bias of RA patients in the low-inflixi mab group in this study. It was obvious that RA patients in low-inflixi mab group were well-controlled and thus, they were treated with a relatively small amount of inflixi mab dosage.
We did have several limitations however. The most noteworthy limitation is that we did not examine serum inflixi mab levels using Remi-checkQ ® during the active inflammatory phase. Longitudinal studies should be conducted to scrutinize optimal inflixi mab dosage for suppressing RA inflammation in early phase. Second, we did not directly examine serum inflixi mab levels, instead, we used Remi-checkQ ® (LSI Medience Corporation, Tokyo, Japan), a kit for measuring infliximab serum levels by LC to evaluate whether serum infliximab levels are greater than 1 µg/mL. To scrutinize the serum inflixi mab levels more precisely, it may be necessary to be de-termined by enzyme linked immunosorbent assay (ELISA). 11) Third, this study was conducted in one institution. To more clearly emphasize differences between high-inflixi mab and low-inflixi mab groups, a multi-center study may be required with a larger sample size.

CONCLUSION
In this study, we identified that the minimum inflixi mab dosage for maintaining serum inflixi mab levels greater than 1 µg/mL was inflixi mab dose/dosage interval/body weight (mg/weeks/kg)≥0.750 among well-controlled RA patients treated with inflixi mab for more than 54 weeks of inflixi mab treatment.