Language：English  

DOI： 10.1093/mr/roae058

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PubMed

Language：English   Publisher：Scandinavian Journal of Rheumatology  

Objective: This study aimed to analyse whether initiating nintedanib treatment at a reduced dose could improve the treatment continuation rate while maintaining efficacy in patients with connective tissue disease (CTD)-associated interstitial lung disease. Method: In total, 51 patients (age 61.6 ± 13.2 years; 38 women, 13 men) were retrospectively analysed. The primary endpoint was the cumulative discontinuation rate due to adverse events. Secondary endpoints included changes in drug dosage, efficacy evaluated based on annual changes in forced vital capacity (FVC), and safety assessed based on the frequency of adverse events. Results: Eighteen patients who started treatment at the standard dose of 300 mg (standard dosage group) were compared with 33 patients who started treatment at a reduced dose (reduced dosage group). Systemic sclerosis was the most common CTD (n = 32), followed by idiopathic inflammatory myopathies and, rarely, rheumatoid arthritis. Both groups exhibited comparable cumulative discontinuation rates due to adverse events and similar frequencies of adverse events. No significant differences were observed in maintenance doses between the two groups; however, patients in the reduced dosage group had a lower cumulative dose for up to 52 weeks than those in the standard dosage group. No significant differences were observed in changes in FVC between the two groups. Conclusion: There was no evidence for a difference between the two groups in terms of discontinuation rates, efficacy, and safety. To provide further evidence, future studies using more precise dose-escalation protocols are warranted.

DOI： 10.1080/03009742.2024.2327159

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Scopus

PubMed

Language：English   Publisher：Oxford University Press  

Language：English   Publisher：Oxford University Press  

Language：English   Publisher：Clinical Rheumatology  

The correct affiliation is presented in this article. In the original published version of the above article the affiliation for the co-author Takaaki Fukuda was incorrectly presented as "Department of Rheumatology, Rheumatology Center, 3-3-8 Miyanojin, Koga Hospital 21 Kurume City 839-0801, Japan". The affiliation has been corrected in this article. Also, the captions of Tables 2, 3, 4, and 5 were also incorrectly presented. The correct tables are shown as follows: (Table presented.) (Table presented.) (Table presented.) (Table presented.) Characteristics of patients in the groups with high or low BMI before and after IPTW-adjustment Factor Unadjusted p value IPTW-adjusted p value BMI<25 (n=72) BMI≥25 (n=35) BMI<25 (n=71) BMI≥25 (n=33.8) n (%) n (%) n (%) n (%) Age (years) 1 0.166 <65 27 (37.5) 13 (37.1) 25.4 (35.8) 7.3 (21.6) ≥65 45 (62.5) 22 (62.9) 45.6 (64.2) 26.5 (78.4) Sex 0.246 0.077 male 19 (26.4) 5 (14.3) 27.9 (39.3) 5.1 (15.1) female 53 (73.6) 30 (85.7) 43.1 (60.7) 28.7 (84.9) Weight (kg) <0.001 0.726 <57 50 (69.4) 4 (11.4) 36.4 (51.2) 15.5 (45.8) ≥57 22 (30.6) 31 (88.6) 34.6 (48.8) 18.3 (54.2) Steinbrocker class 0.384 0.196 1 / 2 67 (93.1) 30 (85.7) 67.2 (94.7) 29.1 (86.0) 3 / 4 5 ( 6.9) 5 (14.3) 3.8 ( 5.3) 4.7 (14.0) Steinbrocker stage 0.238 0.414 I / II 35 (48.6) 22 (62.9) 36.1 (50.9) 21.3 (63.0) III / IV 37 (51.4) 13 (37.1) 34.9 (49.1) 12.5 (37.0) CCI 0.998 0.689 0 54 (75.0) 27 (77.1) 54.5 (76.7) 27.4 (81.0) ≥1 18 (25.0) 8 (22.9) 16.5 (23.3) 6.4 (19.0) MTX 0.845 0.674 - 32 (44.4) 17 (48.6) 31.2 (43.9) 17.0 (50.1) + 40 (55.6) 18 (51.4) 39.8 (56.1) 16.9 (49.9) Failure of b/tsDMARDs 0.207 0.354 ≤1 43 (59.7) 26 (74.3) 43.8 (61.7) 25.3 (75.0) ≥2 29 (40.3) 9 (25.7) 27.2 (38.3) 8.5 (25.0) mean [range] mean [range] p value mean [range] mean [range] p value Duration of RA (years) 10.9 [0.2, 40.0] 10.6 [0.4, 35.8] 0.873 10.9 [0.2, 40.0] 10.1 [0.4, 35.8] 0.971 ACPA (U/mL) 209.6 [0.5, 1260.0] 256.0 [0.5, 1285.8] 0.745 216.9 [0.5, 1260.0] 229.8 [0.5, 1285.8] 0.902 RF (IU/mL) 183.9 [4.0, 1920.0] 114.9 [4.0, 769.0] 0.623 175.0 [4.0, 1920.0] 106.1 [4.0, 769.0] 0.831 TJC 3.6 [0.0, 19.0] 3.0 [0.0, 12.0] 0.677 3.2 [0.0, 19.0] 4.3 [0.0, 12.0] 0.299 SJC 3.0 [0.0, 16.0] 1.3 [0.0, 12.0] 0.002 2.5 [0.0, 16.0] 2.5 [0.0, 12.0] 0.867 PGA (mm) 45.0 [0.0, 99.0] 34.7 [3.0, 90.0] 0.051 43.0 [0.0, 99.0] 37.6 [3.0, 90.0] 0.406 EGA (mm) 41.2 [7.0, 88.0] 32.9 [2.0, 90.0] 0.053 39.8 [7.0, 88.0] 38.3 [2.0, 90.0] 0.902 CDAI 15.3 [1.0, 46.7] 11.1 [1.3, 36.0] 0.032 14.0 [1.0, 46.7] 14.3 [1.3, 36.0] 0.827 CRP (mg/dL) 1.82 [0.00, 8.51] 1.68 [0.02, 9.26] 0.852 1.78 [0.00, 8.51] 1.86 [0.02, 9.26] 0.327 WBC 7278.8 [2000.0, 17500.0] 8298.0 [4900.0, 13910.0] 0.058 7280.6 [2000.0, 17500.0] 7819.8 [4900.0, 13910.0] 0.508 Hb (g/dL) 12.4 [9.1, 17.4] 12.6 [9.4, 15.4] 0.395 12.6 [9.1, 17.4] 12.3 [9.4, 15.4] 0.965 Plt 26.0 [6.7, 49.6] 27.0 [15.5, 43.1] 0.528 25.4 [6.7, 49.6] 27.6 [15.5, 43.1] 0.11 ALT (U/L) 18.9 [6.0, 58.0] 22.7 [7.0, 77.0] 0.049 19.1 [6.0, 58.0] 18.3 [7.0, 77.0] 0.828 AST (U/L) 22.8 [10.0, 51.0] 21.7 [12.0, 46.0] 0.464 23.3 [10.0, 51.0] 20.7 [12.0, 46.0] 0.321 eGFR (mL/min/1.73 m2) 71.8 [6.2, 229.0] 66.3 [27.0, 104.0] 0.313 73.6 [6.2, 229.0] 64.9 [27.0, 104.0] 0.19 csDMARD except MTX 0.5 [0.0, 2.0] 0.6 [0.0, 2.0] 0.512 0.5 [0.0, 2.0] 0.7 [0.0, 2.0] 0.283 Dose of PSL (mg/day) 2.5 [0.0, 12.5] 3.4 [0.0, 12.0] 0.267 2.1 [0.0, 12.5] 2.8 [0.0, 12.0] 0.714 IPTW inverse probability of treatment weighting, MTX methotrexate, BMI body mass index, CCI Charlson comorbidity index, b/tsDMARD biologic or target synthetic disease-modifying anti-rheumatic drugs, ACPA anticitrullinated protein/peptide antibody, RF rheumatoid factor, TJC tender Joint count, SJC swollen joint count, PGA patient`s global assessment, EGA evaluator`s global assessment, CDAI clinical disease activity index, CRP C-reactive protein, WBC white blood cell, Hb hemoglobin, Plt platelet, ALT alanine aminotransferase, AST aspartate aminotransferase, csDMARD conventional synthetic disease modifying anti-rheumatic drug, PSL prednisolone Characteristics of patients in the groups with CCI score 0 or ≥1 before and after IPTW-adjustment Factor Unadjuste p value IPTW-adjusted p value CCI- (n=81) CCI+ (n=26) CCI- (n=80.6) CCI+ (n=27) n (%) n (%) n (%) n (%) Age (years) 0.015 0.832 <65 36 (44.4) 4 (15.4) 30.3 (37.6) 11.0 (40.8) ≥65 45 (55.6) 22 (84.6) 50.3 (62.4) 16.0 (59.2) Sex 0.718 0.578 male 17 (21.0) 7 (26.9) 17.4 (21.5) 4.5 (16.6) female 64 (79.0) 19 (73.1) 63.3 (78.5) 22.6 (83.4) Weight (kg) 1 0.382 <57 41 (50.6) 13 (50.0) 42.8 (53.0) 11.1 (41.1) ≥57 40 (49.4) 13 (50.0) 37.9 (47.0) 15.9 (58.9) BMI (kg/m2) 0.998 0.309 <25 54 (66.7) 18 (69.2) 54.0 (66.9) 14.2 (52.5) ≥25 27 (33.3) 8 (30.8) 26.7 (33.1) 12.8 (47.5) Steinbrocker class 0.407 0.841 1 / 2 75 (92.6) 22 (84.6) 74.6 (92.5) 24.7 (91.4) 3 / 4 6 ( 7.4) 4 (15.4) 6.1 ( 7.5) 2.3 ( 8.6) Steinbrocker stage 0.049 0.741 I / II 48 (59.3) 9 (34.6) 43.5 (53.9) 15.8 (58.4) III / IV 33 (40.7) 17 (65.4) 37.2 (46.1) 11.3 (41.6) MTX 0.471 0.808 - 35 (43.2) 14 (53.8) 36.6 (45.4) 11.4 (42.1) + 46 (56.8) 12 (46.2) 44.0 (54.6) 15.7 (57.9) Failure of b/tsDMARDs 1 0.793 ≤1 52 (64.2) 17 (65.4) 50.8 (63.0) 16.0 (59.3) ≥2 29 (35.8) 9 (34.6) 29.8 (37.0) 11.0 (40.7) mean [range] mean [range] p value mean [range] mean [range] p value Duration of RA (years) 10.2 [0.2, 37.8] 12.6 [0.4, 40.0] 0.282 10.6 [0.2, 37.8] 8.8 [0.4, 40.0] 0.323 ACPA (U/mL) 224.3 [0.5, 1285.8] 226.2 [0.6, 1200.0] 0.808 221.6 [0.5, 1285.8] 209.4 [0.6, 1200.0] 0.973 RF (IU/mL) 144.8 [4.0, 1440.0] 212.6 [4.0, 1920.0] 0.769 148.7 [4.0, 1440.0] 143.3 [4.0, 1920.0] 0.565 TJC 3.3 [0.0, 19.0] 3.7 [0.0, 13.0] 0.277 3.5 [0.0, 19.0] 3.8 [0.0, 13.0] 0.238 SJC 2.2 [0.0, 16.0] 3.2 [0.0, 10.0] 0.09 2.3 [0.0, 16.0] 2.3 [0.0, 10.0] 0.948 PGA (mm) 39.9 [0.0, 99.0] 47.0 [13.0, 90.0] 0.115 40.9 [0.0, 99.0] 43.4 [13.0, 90.0] 0.21 EGA (mm) 37.5 [2.0, 90.0] 41.7 [15.0, 80.0] 0.177 38.8 [2.0, 90.0] 39.8 [15.0, 80.0] 0.345 CDAI 13.3 [1.0, 46.7] 15.8 [6.0, 32.5] 0.043 11.5 [1.0, 46.7] 13.5 [6.0, 32.5] 0.133 CRP (mg/dL) 1.63 [0.00, 9.26] 2.22 [0.01, 6.00] 0.225 1.65 [0.00, 9.26] 1.69 [0.01, 6.00] 0.981 WBC 7600.1 [2000.0, 17500.0] 7649.6 [2860.0, 11400.0] 0.603 7601.4 [2000.0, 17500.0] 7578.4 [2860.0, 11400.0] 0.784 Hb (g/dL) 12.6 [9.5, 17.4] 12.1 [9.1, 14.4] 0.504 12.5 [9.5, 17.4] 12.1 [9.1, 14.4] 0.719 Plt 26.0 [6.7, 49.6] 27.3 [13.5, 43.2] 0.461 25.7 [6.7, 49.6] 29.2 [13.5, 43.2] 0.219 ALT (U/L) 20.9 [6.0, 77.0] 17.7 [7.0, 49.0] 0.245 20.9 [6.0, 77.0] 18.2 [7.0, 49.0] 0.483 AST (U/L) 22.5 [10.0, 48.0] 22.4 [12.0, 51.0] 0.841 22.9 [10.0, 48.0] 20.2 [12.0, 51.0] 0.265 eGFR (mL/min/1.73 m2) 72.1 [25.0, 229.0] 63.5 [6.2, 114.2] 0.204 70.2 [25.0, 229.0] 74.0 [6.2, 114.2] 0.496 csDMARD except MTX 0.5 [0.0, 2.0] 0.5 [0.0, 2.0] 0.967 0.5 [0.0, 2.0] 0.4 [0.0, 2.0] 0.159 Dose of PSL (mg/day) 2.8 [0.0, 12.5] 2.8 [0.0, 8.0] 0.54 2.9 [0.0, 12.5] 2.4 [0.0, 8.0] 0.787 IPTW inverse probability of treatment weighting, CCI Charlson comorbidity index, BMI body mass index, MTX methotrexate, b/tsDMARD biologic or target synthetic disease-modifying anti-rheumatic drugs, ACPA anticitrullinated protein/peptide antibody, RF rheumatoid factor, TJC tender joint count, SJC swollen joint count, PGA patient’s global assessment, EGA evaluator’s global assessment, CDAI clinical disease activity index, CRP C-reactive protein, WBC white blood cell, Hb hemoglobin, Plt platelet, ALT alanine aminotransferase, AST aspartate aminotransferase, eGFR estimated glomerular filtration rate, csDMARD conventional synthetic diseasemodifying anti-rheumatic drug, PSL prednisolone Characteristics of patients in the two groups with or without MTX before and after IPTW-adjustment Factor Unadjuste p value IPTW-adjusted p value MTXー (n=49) MTX+ (n=58) MTXー (n=49.2) MTX+ (n=57.7) n (%) n (%) n (%) n (%) Age (years) 0.02 0.966 <65 12 (24.5) 28 (48.3) 18.6 (37.7) 21.5 (37.3) ≥65 37 (75.5) 30 (51.7) 30.6 (62.3) 36.2 (62.7) Sex 0.243 0.794 male 14 (28.6) 10 (17.2) 11.2 (22.7) 11.8 (20.4) female 35 (71.4) 48 (82.8) 38.0 (77.3) 45.9 (79.6) Weight (kg) 0.765 0.883 <57 26 (53.1) 28 (48.3) 25.2 (51.2) 28.7 (49.6) ≥57 23 (46.9) 30 (51.7) 24.0 (48.8) 29.1 (50.4) BMI (kg/m2) 0.845 0.59 <25 32 (65.3) 40 (69.0) 32.0 (65.1) 40.6 (70.4) ≥25 17 (34.7) 18 (31.0) 17.2 (34.9) 17.1 (29.6) Steinbrocker class 0.2 0.168 1 / 2 42 (85.7) 55 (94.8) 43.0 (87.4) 54.8 (94.9) 3 / 4 7 (14.3) 3 ( 5.2) 6.2 (12.6) 3.0 ( 5.1) Steinbrocker stage 0.073 0.109 I / II 21 (42.9) 36 (62.1) 21.5 (43.7) 35.0 (60.7) III / IV 28 (57.1) 22 (37.9) 27.7 (56.3) 22.7 (39.3) CCI 0.471 0.857 0 35 (71.4) 46 (79.3) 37.4 (76.0) 44.8 (77.6) ≥1 14 (28.6) 12 (20.7) 11.8 (24.0) 12.9 (22.4) Failure of b/tsDMARDs 0.968 0.273 ≤1 31 (63.3) 38 (65.5) 28.1 (57.1) 39.4 (68.2) ≥2 18 (36.7) 20 (34.5) 21.1 (42.9) 18.4 (31.8) mean [range] mean [range] p value mean [range] mean [range] p value Duration of RA (years) 11.8 [0.2, 37.8] 10.0 [0.4, 40.0] 0.213 12.4 [0.2, 37.8] 10.9 [0.4, 40.0] 0.393 ACPA (U/mL) 210.6 [0.5, 1260.0] 236.7 [0.5, 1285.8] 0.632 188.7 [0.5, 1260.0] 245.4 [0.5, 1285.8] 0.992 RF (IU/mL) 197.3 [4.0, 1920.0] 130.9 [4.0, 1440.0] 0.766 179.6 [4.0, 1920.0] 127.9 [4.0, 1440.0] 0.827 TJC 3.4 [0.0, 19.0] 3.5 [0.0, 16.0] 0.164 3.6 [0.0, 19.0] 3.6 [0.0, 16.0] 0.255 SJC 2.7 [0.0, 16.0] 2.3 [0.0, 10.0] 0.664 2.6 [0.0, 16.0] 2.3 [0.0, 10.0] 0.37 PGA (mm) 40.3 [0.0, 99.0] 42.7 [3.0, 98.0] 0.428 42.9 [0.0, 99.0] 44.2 [3.0, 98.0] 0.574 EGA (mm) 37.7 [6.0, 90.0] 39.2 [2.0, 88.0] 0.651 36.5 [6.0, 90.0] 41.1 [2.0, 88.0] 0.213 CDAI 13.8 [1.0, 46.7] 13.9 [2.0, 34.0] 0.348 14.1 [1.0, 46.7] 14.4 [2.0, 34.0] 0.229 CRP (mg/dL) 1.79 [0.00, 7.49] 1.76 [0.00, 9.26] 0.757 1.50 [0.00, 7.49] 1.82 [0.00, 9.26] 0.702 WBC 7420.6 [2860.0, 12300.0] 7774.0 [2000.0, 17500.0] 0.646 7412.9 [2860.0, 12300.0] 7748.6 [2000.0, 17500.0] 0.673 Hb (g/dL) 12.3 [9.1, 17.4] 12.6 [9.4, 16.9] 0.261 12.4 [9.1, 17.4] 12.5 [9.4, 16.9] 0.555 Plt 24.9 [13.1, 38.3] 27.6 [6.7, 49.6] 0.19 25.0 [13.1, 38.3] 26.9 [6.7, 49.6] 0.361 ALT (U/L) 18.3 [6.0, 77.0] 21.7 [6.0, 58.0] 0.023 20.4 [6.0, 77.0] 20.2 [6.0, 58.0] 0.517 AST (U/L) 21.9 [11.0, 46.0] 22.9 [10.0, 51.0] 0.443 22.4 [11.0, 46.0] 23.0 [10.0, 51.0] 0.633 csDMARD except MTX 0.7 [0.0, 2.0] 0.3 [0.0, 2.0] 0.012 0.5 [0.0, 2.0] 0.5 [0.0, 2.0] 0.882 Dose of PSL (mg/day) 3.2 [0.0, 12.5] 2.4 [0.0, 10.0] 0.22 3.1 [0.0, 12.5] 2.5 [0.0, 10.0] 0.341 IPTW inverse probability of treatment weighting, MTX methotrexate, BMI body mass index, CCI Charlson comorbidity index, b/tsDMARD biologic or target synthetic disease-modifying anti-rheumatic drugs, ACPA anticitrullinated protein/peptide antibody, RF rheumatoid factor, TJC tender Joint count, SJC swollen joint count, PGA patient`s global assessment, EGA evaluator`s global assessment, CDAI clinical disease activity index, CRP C-reactive protein, WBC white blood cell, Hb hemoglobin, Plt platelet, ALT alanine aminotransferase, AST aspartate aminotransferase, csDMARD conventional synthetic disease modifying anti-rheumatic drug, PSL prednisolone Characteristics of patients in the two groups with prior b/tsDMARDs ≤1 or ≥2 before and after IPTW-adjustment Factor Unadjusted p value IPTW-adjusted p value Failure of b/ts DMARD ≤ 1 (n=69) ≥ 2 (n=38) failure of b/ts DMARD ≤ 1 (n=69) ≥ 2 (n=37.3) n (%) n (%) n (%) n (%) Age (years) 0.589 0.836 <65 24 (34.8) 16 (42.1) 25.3 (36.6) 12.9 (34.5) ≥65 45 (65.2) 22 (57.9) 43.7 (63.4) 24.4 (65.5) Sex 0.62 0.94 male 17 (24.6) 7 (18.4) 15.1 (21.9) 8.4 (22.6) female 52 (75.4) 31 (81.6) 53.9 (78.1) 28.9 (77.4) Weight (kg) 0.593 0.724 <57 33 (47.8) 21 (55.3) 33.9 (49.1) 19.8 (53.0) ≥57 36 (52.2) 17 (44.7) 35.1 (50.9) 17.5 (47.0) BMI (kg/m2) 0.207 0.374 <25 43 (62.3) 29 (76.3) 43.8 (63.5) 27.2 (72.9) ≥25 26 (37.7) 9 (23.7) 25.2 (36.5) 10.1 (27.1) Steinbrocker class 0.466 0.179 1 / 2 61 (88.4) 36 (94.7) 61.4 (89.0) 35.9 (96.0) 3 / 4 8 (11.6) 2 ( 5.3) 7.6 (11.0) 1.5 ( 4.0) Steinbrocker stage 0.267 0.058 I / II 40 (58.0) 17 (44.7) 41.6 (60.4) 14.9 (40.0) III / IV 29 (42.0) 21 (55.3) 27.3 (39.6) 22.4 (60.0) CCI 1 0.954 0 52 (75.4) 29 (76.3) 51.5 (74.7) 28.1 (75.2) ≥1 17 (24.6) 9 (23.7) 17.5 (25.3) 9.3 (24.8) MTX 0.968 0.243 - 31 (44.9) 18 (47.4) 28.8 (41.8) 20.3 (54.3) + 38 (55.1) 20 (52.6) 40.2 (58.2) 17.1 (45.7) mean [range] mean [range] p.value mean [range] mean [range] p.value Duration of RA (years) 10.9 [0.2, 40.0] 10.6 [0.7, 37.8] 0.496 10.60 [0.18, 40.00] 11.50 [0.69, 37.83] 0.156 ACPA (U/mL) 252.8 [0.5, 1285.8] 173.7 [0.5, 807.1] 0.772 237.29 [0.50, 1285.80] 181.23 [0.50, 807.10] 0.806 RF (IU/mL) 122.6 [4.0, 798.0] 231.5 [4.0, 1920.0] 0.642 122.32 [4.00, 798.00] 297.82 [4.00, 1920.00] 0.608 TJC 3.5 [0.0, 19.0] 3.4 [0.0, 12.0] 0.374 3.96 [0.00, 19.00] 3.23 [0.00, 12.00] 0.915 SJC 2.5 [0.0, 16.0] 2.3 [0.0, 10.0] 0.327 2.67 [0.00, 16.00] 2.28 [0.00, 10.00] 0.495 PGA (mm) 38.2 [0.0, 99.0] 47.8 [0.0, 98.0] 0.065 41.50 [0.00, 99.00] 43.04 [0.00, 98.00] 0.784 EGA (mm) 38.0 [6.0, 88.0] 39.5 [2.0, 90.0] 0.847 39.80 [6.00, 88.00] 37.96 [2.00, 90.00] 0.675 CDAI 13.6 [1.0, 46.7] 14.4 [2.5, 29.2] 0.254 13.0 [1.00, 46.70] 10.9 [2.50, 29.20] 0.98 CRP (mg/dL) 1.78 [0.00, 9.26] 1.77 [0.00, 7.49] 0.667 1.83 [0.00, 9.26] 2.11 [0.00, 7.49] 0.89 WBC 7493.3 [2000.0, 13910.0] 7827.9 [3700.0, 17500.0] 0.628 7548.34 [2000.00, 13910.00] 7892.98 [3700.00, 17500.00] 0.579 Hb (g/dL) 12.4 [9.1, 17.4] 12.6 [9.4, 17.4] 0.927 12.37 [9.10, 17.40] 12.52 [9.40, 17.40] 0.893 Plt 26.9 [6.7, 49.6] 25.3 [13.1, 49.2] 0.108 27.39 [6.70, 49.60] 25.40 [13.10, 49.20] 0.096 ALT (U/L) 20.2 [7.0, 58.0] 20.0 [6.0, 77.0] 0.341 20.45 [7.00, 58.00] 20.69 [6.00, 77.00] 0.316 AST (U/L) 22.0 [11.0, 51.0] 23.2 [10.0, 48.0] 0.876 22.17 [11.00, 51.00] 23.90 [10.00, 48.00] 0.74 eGFR (mL/min/1.73 m2) 66.7 [25.0, 110.0] 76.1 [6.2, 229.0] 0.175 67.60 [25.00, 110.00] 71.46 [6.20, 229.00] 0.898 csDMARD except MTX 0.6 [0.0, 2.0] 0.3 [0.0, 2.0] 0.011 0.51 [0.00, 2.00] 0.47 [0.00, 2.00] 0.852 Dose of PSL (mg/day) 2.9 [0.0, 12.5] 2.5 [0.0, 10.0] 0.802 2.81 [0.00, 12.50] 2.27 [0.00, 10.00] 0.698 IPTW inverse probability of treatment weighting, b/tsDMARD biologic or target synthetic disease-modifying antirheumatic drugs, BMI body mass index, CCI Charlson comorbidity index, MTX methotrexate, ACPA anticitrullinated protein/peptide antibody, RF rheumatoid factor, TJC tender joint count, SJC swollen joint count, PGA patient’s global assessment, EGA evaluator’s global assessment, CDAI clinical disease activity index, CRP Creactive protein, WBC white blood cell, Hb hemoglobin, Plt platelet, ALT alanine aminotransferase, AST aspartate aminotransferase, eGFR estimated glomerular filtration rate, csDMARD conventional synthetic diseasemodifying anti-rheumatic drug, PSL prednisolone The original article has been corrected.

DOI： 10.1007/s10067-024-06907-6

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PubMed

Language：English   Publisher：Clinical Rheumatology  

Objective: The efficacy and safety of sarilumab (SARI) were investigated in real-world clinical practice in Japan. Method: Subjects were 121 rheumatoid arthritis (RA) patients in 23 medical institutions in Fukuoka Prefecture, Japan, who started treatment with SARI between May 2018 and November 2021. Data on the SARI starting dose, patients’ baseline characteristics, disease activity, and blood test data at the start of treatment, as well as follow-up data on the SARI dose, disease activity, and adverse events until Week 52. Safety and the continuation rate calculated by the Kaplan–Meier method were evaluated, and the effectiveness of treatment at 1 year was assessed using the clinical disease activity index (CDAI). Patients’ baseline characteristics for which significant differences were evident were adjusted with a propensity score by using the inverse probability of treatment-weighting (IPTW) method. Results: The continuation rate at Week 52 was 66.1%. The CDAI showed significant improvement from Week 4 that was maintained until Week 52. Comparisons conducted after IPTW adjustment for patients’ baseline characteristics for which significant differences were evident revealed no significant differences at Week 52 between the groups classified by higher or lower body mass index (BMI) (p = 0.231), serious comorbidities (p = 0.973), MTX use (p = 0.321), or prior treatment with ≤ 1 or ≥ 2 biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) (p = 0.765). Conclusions: The results showed that the efficacy of SARI is not affected by BMI, comorbidities, MTX use, or the number of prior b/tsDMARDs, and no new safety concerns were apparent. (Table presented.)

DOI： 10.1007/s10067-023-06862-8

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Language：English   Publisher：Rheumatology International  

This study aimed to clarify the efficacy and safety of treatment escalation by initiating therapeutic agents in serologically active clinically quiescent (SACQ) patients with systemic lupus erythematosus (SLE). We retrospectively evaluated SACQ patients with SLE for ≥ 180 days, with the introduction of a therapeutic agent for SLE defined as exposure. The efficacy endpoints included the time to flare and time to remission, whereas the safety endpoint was the incidence of adverse events. The efficacy endpoints were assessed via Cox proportional hazards model with time-dependent covariates, which included exposure, serological activity, and prednisolone dose. Among 109 SACQ patients, 24 were initiated on the following therapeutic agents for SLE: hydroxychloroquine (10 patients), belimumab (6 patients), and immunosuppressive agents (8 patients). A total of 37 patients experienced a flare (8 and 29 patients during exposure and nonexposure periods, respectively). The time to flare was comparable between the exposure and control groups. Among 68 patients who were not in remission at the start of observation, 27 patients achieved remission (5 and 22 patients during exposure and nonexposure periods, respectively). Although both groups had a similar time to remission, the exposure group treated with belimumab had a significantly higher rate of remission than the control group. The adverse events were more frequent during the exposure period than during the nonexposure period. Thus, this study did not reveal a clear influence of treatment escalation on flare prevention and remission achievement.

DOI： 10.1007/s00296-024-05593-6

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1080/03009742.2024.2327159.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s00296-024-05593-6. Online ahead of print.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3389/fimmu.2024.1377911

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s10067-023-06862-8.

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DOI： 10.1093/mr/road046

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Language：English   Publisher：Oxford University Press  

Language：English   Publisher：Modern Rheumatology  

Objectives: The objective of the study is to investigate the relationships between Type 1 interferon (T1-IFN) signatures and clinical characteristics of lupus patients. Methods: We examined 49 new-onset lupus patients who were diagnosed between 1999 and 2017. The patients treated with >10 mg of prednisolone or hydroxychloroquine were excluded from this study. Serum T1-IFN signatures were revealed by a functional reporter assay and standardized by recombinant IFN-α. Patient backgrounds, clinical findings, and treatments were retrospectively extracted from their electrical medical records. Clinical data were also available, including SLE Disease Activity Index of SLE patients on admission. Results: T1-IFN signatures of lupus patients closely correlated with lupus disease activities, such as SLE Disease Activity Index-2K, white blood cell, C3 levels, and the titre of double-strand DNA antibody. We found fever and acute lupus dermatitis closely associated with T1-IFN signature. Conclusions: In lupus patients, fever and acute lupus dermatitis are good indicators of a strong T1-IFN signature.

DOI： 10.1093/mr/road015

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Publisher：医歯薬出版  

DOI： 10.32118/ayu28805346

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1093/mr/road015.

Language：English   Publisher：Nature Communications  

Here we report the largest Asian genome-wide association study (GWAS) for systemic sclerosis performed to date, based on data from Japanese subjects and comprising of 1428 cases and 112,599 controls. The lead SNP is in the FCGR/FCRL region, which shows a penetrating association in the Asian population, while a complete linkage disequilibrium SNP, rs10917688, is found in a cis-regulatory element for IRF8. IRF8 is also a significant locus in European GWAS for systemic sclerosis, but rs10917688 only shows an association in the presence of the risk allele of IRF8 in the Japanese population. Further analysis shows that rs10917688 is marked with H3K4me1 in primary B cells. A meta-analysis with a European GWAS detects 30 additional significant loci. Polygenic risk scores constructed with the effect sizes of the meta-analysis suggest the potential portability of genetic associations beyond populations. Prioritizing the top 5% of SNPs of IRF8 binding sites in B cells improves the fitting of the polygenic risk scores, underscoring the roles of B cells and IRF8 in the development of systemic sclerosis. The results also suggest that systemic sclerosis shares a common genetic architecture across populations.

DOI： 10.1038/s41467-023-44541-z

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Language：English  

DOI： 10.7759/cureus.52506

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Language：English   Publisher：Modern Rheumatology Case Reports  

A 53-year-old man with adult-onset Still’s disease developed severe streptococcal toxic shock syndrome (STSS) due to Streptococcus dysgalactiae subsp. equisimilis (SDSE), following retroperitoneal panniculitis. He was receiving tocilizumab (TCZ), an interleukin-6 receptor inhibitor. The modifying effect of TCZ on the immune response and the pathophysiology of SDSE infection may have led to retroperitoneal panniculitis and atypical STSS with delayed shock and flare of soft tissue inflammation.

DOI： 10.1093/mrcr/rxae001

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41467-023-44541-z.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/1756-185X.15009.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1136/rmdopen-2023-003693

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DOI： 10.1093/rheumatology/kead275

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Language：English   Publisher：International Journal of Rheumatic Diseases  

Objective: To evaluate trends in results of care and management for antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). Methods: We employed multicenter cohort data collected during 2011–2021, recruiting 43 patients with granulomatosis with polyangiitis (GPA) and 91 with microscopic polyangiitis (MPA). According to the median registration date of September 2015, patients have split into two groups: an early group and a late group (both of them, n = 67). To prevent bias, a propensity score according to numerous baseline characteristics variables was calculated; 50 matching members of each group were statistically extracted. Their treatments and clinical outcomes were examined at 6, 12, and 24 months after initial remission therapy. Results: Statistics demonstrated that the baseline characteristics were similar. The late group used rituximab (RTX) more often for both remission induction and maintenance therapy, compared with the early group. The mean daily PSL doses of the late group were significantly lower than those of early group at each time point. The late group discontinued PSL 14.0% at 12 months and 23.3% at 24 months. Despite their intensive glucocorticoids (GC) tapering, the remission rates and the relapse rates were significantly fairer in the late group. The Vasculitis Damage Index (VDI) and VDI due to GC at each time point were lower in the late group, and those differences had become wider over time. Conclusion: Recent developments in AAV treatment have allowed efficient remission and prevention of relapses, which in turn enabled extensive GC tapering causing fewer sequelae.

DOI： 10.1111/1756-185X.15009

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DOI： 10.1136/ard-2023-224303

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DOI： 10.1016/j.jaci.2023.11.916

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Language：English   Publisher：Frontiers in Oncology  

The anti-programmed cell death-1 (PD-1) antibody nivolumab has been shown to significantly prolong the survival of patients with unresectable advanced or recurrent gastric cancer (AGC). However, immune-related adverse events (irAEs), which show different profiles from those of cytotoxic agents or conventional molecular-targeted drugs including tyrosine kinase inhibitors, have been reported. Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) is a rare autoimmune disorder with acute-onset, rheumatoid factor-negative, symmetric synovitis associated with limb edema observed in elderly persons. A case of RS3PE syndrome that developed after administration of nivolumab for advanced gastric cancer is reported. This is the first report of a case of RS3PE syndrome as an irAE caused by nivolumab in a patient with gastric cancer.

DOI： 10.3389/fonc.2023.1260818

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41467-023-42718-0

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1093/rheumatology/kead082

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Language：English   Publisher：Oxford University Press  

全身性エリテマトーデス(SLE)患者に対する免疫抑制剤切り替えの有効性と安全性について検討し、薬剤切り替え後の治療不応の予測因子を評価した。SLE患者39例(男性4例、女性35例、平均41.5±12.6歳)を対象に後ろ向きコホート研究を行った。有効性評価項目はSLE疾患重症度指数(SLEDAI)2000スコアの変化、プレドニゾロンの用量、12ヵ月以上にわたるSLEの状況、治療継続率、安全性評価項目は有害事象の発現頻度とした。患者の約70%は作用機序が同じ薬剤間のスイッチングであり、タクロリムスの処方が最も多く、ミコフェノール酸モフェチルがこれに続いていた。薬剤切り替えの理由は効果不十分が20例、有害事象が14例、その他が5例となっていた。SLEDAIスコアは薬剤切り替えの9ヵ月後に有意に減少し、プレドニゾロンの用量は中央値13mgから12ヵ月後に8.25mgに減少しており、3例を除いてSLE症状の安定が得られていた。治療継続率は1年後が71.4%、2年後が62.3%、3年後が53.4%、治療不応率は1年後が29.0%、2年後が46.7%、3年後が46.7%であった。投与中止に至る有害事象の発現は10例に認められたが、感染症や重篤な有害事象の発現はみられなかった。多重Coxハザード回帰分析では、治療不応の予測因子として効果不十分を理由とする薬剤切り替えが示された。SLE患者に対する免疫抑制剤の切り替えは有効かつ安全であることが明らかになった。

Language：English   Publisher：Modern Rheumatology  

Objectives: We aim to clarify the efficacy and safety of switching immunosuppressive drugs and to identify the predictive factors for treatment failure after switching in patients with systemic lupus erythematosus (SLE). Methods: We retrospectively evaluated patients with SLE who switched immunosuppressive drugs for any reason in our hospital between 2015 and 2020. The efficacy endpoints were the change in SLE Disease Activity Index 2000 score, prednisolone dose, and disease status over 12 months, as well as treatment continuation rates. The safety endpoint was the frequency of adverse events over 1 year before and after switching. Cox hazard regression analyses were used to identify the predictive factors for treatment failure. Results: Thirty-nine patients (age, 41.5 ± 12.6 years; 35 women and 4 men) were analysed. The SLE Disease Activity Index score and prednisolone dose were significantly reduced after switching, with few disease exacerbations over 12 months. The 1- and 2-year continuation rates were 71.4% and 62.3%, respectively. The frequency of adverse events was similar in the year before and after switching the drug. Drug switching due to inadequate efficacy was a predictive factor of less likely treatment failure. Conclusions: Immunosuppressive drug switching led to reduced disease activity and decreased glucocorticoid dose without disease exacerbations and severe adverse events.

DOI： 10.1093/mr/roac100

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DOI： 10.1093/mr/roac100.

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publisher：Modern rheumatology  

OBJECTIVES: To evaluate the impact of medication on antibody response to severe acute respiratory syndrome coronavirus-2 mRNA vaccines in Japanese patients with rheumatic diseases. METHODS: This prospective multicentre cohort study evaluated the humoral response in 12 different medication groups. Antibody levels before the first vaccination and 3-6 weeks after the second vaccination were measured using the Elecsys Anti-SARS-CoV-2 S assay. Statistical analysis included comparing antibody titres among the different medication groups using the Kruskal-Wallis test followed by the Bonferroni-Dunn test and multiple linear regression analysis. RESULTS: 295 patients were analysed. The seroconversion rate was 92.2% and the median antibody titre was 255 U/ml (interquartile range, 34.1-685) after the second mRNA vaccination. Antibody levels were significantly lower in the groups treated with Tumour necrosis factor inhibitor with methotrexate, abatacept, mycophenolate mofetil (MMF), MMF or mizoribine combined with calcineurin inhibitor, and rituximab or cyclophosphamide compared with those treated with sulfasalazine and/or bucillamine or calcineurin inhibitor (p < 0.01). The correlation between antibody titre and treatment was significant after adjusting for age, gender, and glucocorticoid dose (p < 0.01). CONCLUSIONS: Additional early vaccination is required in patients treated with Tumour necrosis factor inhibitor and methotrexate, abatacept, MMF, MMF or mizoribine combined with calcineurin inhibitor and rituximab or cyclophosphamide.

DOI： 10.1093/mr/roac030

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1093/mr/roac030.

Language：English   Publisher：Oxford University Press  

日本人リウマチ患者を対象に12種類の投薬群において、SARS-CoV-2 mRNAワクチン接種前と2回目の接種3～6週後および6ヵ月後に抗体価を測定する前向き多施設コホート研究を実施した。本研究では、2回目接種後3～6週目までの中間解析をまとめた。1回目のワクチン接種前と2回目のワクチン接種の3～6週間後に、Elecsys抗SARS-CoV-2 Sアッセイを用いて抗体レベルを測定した。統計解析として、Kruskal-Wallis検定とBonferroni-Dunn検定、および重回帰分析を用いて、異なる投薬群間で抗体価を比較した。患者295例(年齢中央値57歳)を分析した。その結果、セロコンバージョン率は92.2%で、2回目のmRNAワクチン接種後の抗体価中央値は255U/mL(四分位範囲34.1～685)であった。メトトレキサート(MTX)を併用したTNF阻害剤、MTXを併用しないアバタセプト、ミコフェノール酸モフェチル(MMF)、MMF/ミゾリビンとカルシニューリン阻害剤(CNI)の併用、およびリツキシマブ/シクロホスファミド群の患者は、スルファサラジン/ブシラミン群およびCNI群の患者よりも有意に抗体価が低かった(p<0.01)。さらに、抗体価と治療との相関は、年齢、性別、グルココルチコイド投与量で調整した後でも有意であった(p<0.01)。

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publisher：The Japanese Society of Internal Medicine  

<p>We herein report a case of systemic sclerosis (SSc)-related pericarditis successfully treated with mycophenolate mofetil (MMF) and low-dose prednisolone (PSL). The patient was a 72-year-old woman with anti-centromere antibody. Her clinical manifestations were Raynaud phenomenon, bilateral pleural effusion, pericardial effusion and skin tightness. Based on the findings of exudative pericardial effusion with the absence of pulmonary arterial hypertension from the results of the cardiac catheter and pericardiocentesis, she was diagnosed with SSc-related pericarditis and treated with PSL10 mg and MMF 1 g per day, leading to the complete resolution of pericarditis. These findings suggested that MMF and low-dose PSL were effective for SSc-related pericarditis. </p>

DOI： 10.2169/internalmedicine.8844-21

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Frontiers in Immunology  

Background: Systemic sclerosis (SSc) is a multiple-organ disease characterized by vascular damage, autoimmunity, and tissue fibrosis. Organ injuries such as interstitial lung diseases (ILD), resulting from inflammatory and fibrosis processes, lead to poor prognosis. Although autoantibodies are detected in the serum of patients with SSc, the mechanisms by which immune cells are involved in tissue inflammation and fibrosis is not fully understood. Recent studies have revealed carcinoembryonic antigen related cell adhesion molecule (CEACAM)-positive monocytes are involved in murine bleomycin-induced lung fibrosis. We investigated CEACAM-positive monocytes in patients with SSc to clarify the role of monocytes in the pathogenesis of SSc. Methods: The proportion of of CEACAM-positive classical monocytes in healthy controls (HCs) and patients with rheumatoid arthritis (RA) and SSc was evaluated using flow cytometry. The correlation between the proportion of CEACAM-positive monocytes and clinical parameters was analyzed in patients with SSc. Gene expression microarrays were performed in CEACAM-positive and negative monocytes in patients with SSc. Infiltration of CEACAM-positive monocytes into scleroderma skin was evaluated by immunohistochemical staining. Results: The proportion of CEACAM-positive classical monocytes was increased in patients with early SSc within 2 years after diagnosis, which positively correlated with ESR, serum IgG, and serum KL-6 and negatively correlated with %forced vital capacity. The percentage of CEACAM-positive monocytes decreased after immunosuppressive therapy. CEACAM6-positive cells among classical monocytes were significantly increased in patients with SSc compared with HCs and patients with rheumatoid arthritis. SSc serum induced CEACAM6 expression on monocytes from HCs. Functionally, CEACAM-positive monocytes produced higher levels of TNF-α and IL-1β compared to CEACAM-negative cells and showed activation of the NF-κB pathway. Furthermore, CEACAM6-positive monocytes infiltrated the dermis of SSc. Conclusions: CEACAM-positive monocytes showed inflammatory phenotypes and may be involved in the tissue inflammation and fibrosis in early SSc. CEACAM-positive monocytes may be one of biomarkers to detect patients with progressive ILD, requiring therapeutic intervention.

DOI： 10.3389/fimmu.2022.1016914

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Language：English   Publisher：(一社)日本内科学会  

症例は72歳女性で、右足底潰瘍とレイノー現象のために当科紹介となった。局所治療によって右足底潰瘍は改善したが、抗セントロメア抗体が陽性となった。胸部X線検査とCTで両側胸水と心膜液が判明した。胸腔穿刺で漏出性胸水が認められた。心臓カテーテル検査では肺動脈性肺高血圧症を認めなかった。心膜液は滲出性で、悪性または感染の所見はみられなかったことから、心膜炎が心タンポナーデを誘発し、右心不全の発生をきたし、両側性胸水が出現したと考えられた。び漫性皮膚型全身性強皮症(SSc)およびSSc関連心膜炎と診断し、プレドニゾロン(10mg/日)とミコフェノール酸モフェチル(1g/日)の経口投与を行った。心膜液と胸水は速やかに消失し、SScも改善した。治療開始から4ヵ月後の時点で症状の再発は認められていない。

Language：English   Publisher：Oxford University Press  

厚生労働省の難治性血管炎に関する調査研究班の大型血管炎臨床分科会では、高安動脈炎の寛解基準、治療目標、治療目標を達成するためのtreat-to-target(T2T)アルゴリズムを策定するため、専門家によるメンバーあるいは患者会の代表メンバーを含めて対面会議およびDelphi法による意見統一を行った。寛解基準候補117項目から56項目を抽出し、疾患活動性ドメインと治療/併発症ドメインから構成される高安動脈炎の寛解基準案を作成した。また高安動脈炎のT2Tアルゴリズムにおける6つの基本原則および9つのリコメンデーション(うち2つは治療目標、5つは疾患活動性と画像検査所見の評価、2つは強化治療)を提唱した。

Language：English   Publisher：Modern Rheumatology  

Objectives: To develop a proposal for remission criteria and a framework for a treat-to-target (T2T) algorithm for Takayasu arteritis (TAK). Methods: A study group of the large-vessel vasculitis group of the Japanese Research Committee of the Ministry of Health, Labour and Welfare for Intractable Vasculitis consists of 10 rheumatologists, 5 cardiologists, 1 nephrologist, 1 vascular surgeon, 1 cardiac surgeon, and 2 paediatric rheumatologists. A Delphi survey of remission criteria items was circulated among the study group over four reiterations. To develop the T2T algorithm, the study group conducted four face-to-face meetings and two rounds of Delphi together with three patients. Results: Initial literature review resulted in a list of 117 candidate items for remission criteria, of which 56 items with a mean score of ≥4 (0–5) were extracted including disease activity domains and treatment/comorbidity domains. The study group provided six overarching principles for the T2T algorithm, two recommendations on treatment goals, five on evaluation of disease activity and imaging findings including positron emission tomography–computed tomography, and two on treatment intensification. Conclusions: We developed a T2T algorithm and proposals for standardised remission criteria by means of a Delphi exercise. These will guide future evaluation of different TAK treatment regimens.

DOI： 10.1093/mr/roab081

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1093/mr/roab081.

Language：English   Publisher：Modern Rheumatology Case Reports  

A 25-year-old woman was admitted to our hospital with severe pulmonary arterial hypertension associated with systemic lupus erythematosus (SLE-PAH). Her mean pulmonary arterial pressure was 56 mmHg, and her SLE Disease Activity Index-2 K score was 14 on admission. In addition to a strong immunosuppressive regimen, which included steroid pulse therapy followed by high-dose oral prednisolone (1 mg/kg) and intravenous cyclophosphamide, an upfront combination of vasodilator therapy, including oral tadalafil, macitentan, and intravenous epoprostenol, was administered in the early phase. Two months later, her mean pulmonary arterial pressure was 29 mmHg, and her other haemodynamic markers showed significant improvement. She refused to start life-long intravenous epoprostenol therapy and so was switched to oral selexipag and inhaled iloprost. The transition was successful, and she has experienced no exacerbations of SLE-PAH during the 10 months since the onset of pulmonary arterial hypertension. To the best of our knowledge, this is the first report of intravenous epoprostenol being switched to alternative oral and inhaled therapy in a patient with SLE-PAH. In combination with adequate immunosuppressive therapy, it is probably easier to make this transition in patients with SLE-PAH than in those with pulmonary arterial hypertension of a different aetiology. Continuous infusion of epoprostenol can have potentially life-threatening complications and a detrimental effect on the quality of life. Our alternative treatment strategy was successful, and we hope that it will prove beneficial in other cases.

DOI： 10.1093/mrcr/rxac009

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DOI： 10.1186/s13075-022-02820-y

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Language：English   Publisher：Oxford University Press  

症例は25歳女性で、咳嗽および労作時呼吸困難を主訴に来院した。7年前に全身性エリテマトーデス(SLE)と診断され、プレドニゾロン(PSL)5mgを服用していた。SLEの再燃を疑い、入院となった。抗核抗体は2560倍、抗dsDNA抗体は11.3IU/mL、抗Sm抗体96.2U/mLであった。右心カテーテル検査で平均肺動脈圧は56mmHg、心係数は1.25L/min/m2、肺血管抵抗は27.1 Wood単位であった。SLEに伴う肺動脈高血圧症と診断した。心不全の重症度はNYHA心機能分類でIV度、SLEの重症度はSLEDAIスコアで14点であった。ステロイドパルス療法を施行し、経口PSLおよびシクロホスファミド静注療法を開始した。肺高血圧症に対してマシテンタンとタダラフィルを投与したが、効果は限定的であった。エポプロステノール静注を開始したところ、2ヵ月後にSLEDAIスコアは2点に改善した。エポプロステノール在宅持続静注療法を勧めたが患者が拒否したため、経口セレキシパグおよびイロプロスト吸引投与に切り替えた。10ヵ月後の再診で症状の再燃はなかった。

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1177/1759720X221096367

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DOI： 10.1136/annrheumdis-2022-222345

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PubMed

Language：English   Publisher：Human Molecular Genetics  

Osteonecrosis of the femoral head (ONFH) involves necrosis of bone and bone marrow of the femoral head caused by ischemia with unknown etiology. Previous genetic studies on ONFH failed to produce consistent results, presumably because ONFH has various causes with different genetic backgrounds and the underlying diseases confounded the associations. Steroid-associated ONFH (S-ONFH) accounts for one-half of all ONFH, and systemic lupus erythematosus (SLE) is a representative disease underlying S-ONFH. We performed a genome-wide association study (GWAS) to identify genetic risk factors for S-ONFH in patients with SLE. We conducted a two-staged GWAS on 636 SLE patients with S-ONFH and 95 588 non-SLE controls. Among the novel loci identified, we determined S-ONFH-specific loci by comparing allele frequencies between SLE patients without S-ONFH and non-SLE controls. We also used Korean datasets comprising 148 S-ONFH cases and 37 015 controls to assess overall significance. We evaluated the functional annotations of significant variants by in silico analyses. The Japanese GWAS identified 4 significant loci together with 12 known SLE susceptibility loci. The four significant variants showed comparable effect sizes on S-ONFH compared with SLE controls and non-SLE controls. Three of the four loci, MIR4293/MIR1265 [odds ratio (OR) = 1.99, P-value = 1.1 × 10-9)], TRIM49/NAALAD2 (OR = 1.65, P-value = 4.8 × 10-8) and MYO16 (OR = 3.91, P-value = 4.9 × 10-10), showed significant associations in the meta-analysis with Korean datasets. Bioinformatics analyses identified MIR4293, NAALAD2 and MYO16 as candidate causal genes. MIR4293 regulates a PPARG-related adipogenesis pathway relevant to S-ONFH. We identified three novel susceptibility loci for S-ONFH in SLE.

DOI： 10.1093/hmg/ddab306

Web of Science

Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1093/hmg/ddab306.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.4049/jimmunol.2100323

Web of Science

Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publisher：Oxford University Press  

標準治療後にも活動性が持続するSLEに対するヒドロキシクロロキン(HCQ)とタクロリムス(TAC)の有効性を比較検討した。SLE患者45例をHCQ投与群18例(全例女性、平均41.0±9.2歳)とTAC投与群27例(男性2例、女性25例、平均42.7±11.2歳)に分類し、有効性評価項目はループス低疾患活動性(LLDAS)達成率、退薬率、治療継続生存期間とし、安全性評価項目は有害事象の発現率とした。観察期間中にLLDASを呈したのはHCQ群が8例(44.4%)、TAC群が10例(37.0%)であり、累積LLDAS達成率に群間差はみられなかった。投与中止はHCQ群が3例、TAC群が5例であり、中止理由はHCQが全例有害事象であり、TAC群は有害事象が2例、不応が2例、禁忌薬剤の使用が1例となっていた。1年投与継続率はHCQ群が88.5%、TAC群が81.0%とほぼ同等であった。また、有害事象の発現率に有意な群間差はみられず、両群とも感染症が最も多かった。持続する活動性SLEに対するヒドロキシクロロキンとタクロリムスの治療効果と安全性はほぼ同等であることが示された。

Web of Science

PubMed

Language：English   Publisher：Modern Rheumatology  

Objectives: We aimed to reveal the effectiveness of hydroxychloroquine (HCQ) compared with tacrolimus (TAC), an immunosuppressive agent, in patients with systemic lupus erythematosus (SLE) with persistent activity on standard treatment. Methods: We retrospectively compared the efficacy and safety of the treatment between 18 patients receiving HCQ and 27 patients receiving TAC. None of the patients were in the lupus low disease activity state (LLDAS) at the beginning of this study. The efficacy end points were the cumulative incidence of LLDAS attainment without additional immunosuppressive agents, drug continuation rate, and treatment failure-free survival. The safety end point was the frequency of adverse events. Results: Eight (44.4%) patients in the HCQ group and 10 (37.0%) patients in the TAC group achieved LLDAS during the follow-up period; thus, the cumulative incidences of LLDAS attainment of the two treatments were nearly identical. The drug continuation and treatment failure-free survival rates were also not different between the two groups. The frequency of adverse events showed no clear differences between the two groups. Conclusions: The efficacy and safety of an add-on treatment with HCQ are similar to those with TAC. Patients with persistently active SLE can benefit from HCQ in efforts to achieve at least low disease activity.

DOI： 10.1093/mr/roab010

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Scopus

PubMed

Language：English   Publisher：Arthritis Research and Therapy  

Background: To further improve rheumatoid arthritis (RA) treatment, it is necessary to understand each RA patient’s satisfaction and to identify the factors affecting their satisfaction. Despite the rise in medical costs for RA, little is known about the factors that influence patient satisfaction with the cost of treatment in RA patients. Methods: This is a multicenter observational study of Japanese RA patients from the FRANK Registry with data analyzed from March 2017 to August 2020. We collected data on demographic characteristics, clinical data, quality of life which was evaluated using the EuroQol 5-dimensional questionnaire (EQ5D), and patient satisfaction. The four categories of patient satisfaction were evaluated individually (i.e., cost, treatment efficacy, activities of daily living [ADL], and global treatment satisfaction). We analyzed the factors that affected each patient’s satisfaction, such as age, sex, EQ5D, disease duration, disease activity, and treatment. Results: This study included 2235 RA outpatients (406 males, 1829 females). In RA patients, “very satisfied” and “satisfied” were given for nearly half of each satisfaction aspect (cost 49%; efficacy 72%; ADL 58%; global treatment 66%) at the time of the initial registration. To investigate the factors influencing each satisfaction, multivariate analysis has revealed that the use of b/tsDMARDs increased satisfaction of treatment effect (odds ratio [OR] 0.66) and ADL (OR 0.78) but decreased cost satisfaction (OR 2.21). Age (50–64 years; OR 0.91; 65–74 years, 0.55: ≥ 75 years, 0.35), female (OR 0.81), and history of musculoskeletal surgery (OR 0.60) all increased cost satisfaction. Patients with lower disease activity and higher EQ5D scores had higher levels of satisfaction in all areas. Conclusions: In this study, patient satisfaction in terms of cost, treatment effect, ADL, and overall treatment was generally higher, but some patients were dissatisfied. The cost of satisfaction increased with age and a history of musculoskeletal surgery, while it decreased with a lower EQ5D score and the use of b/tsDMARDs.

DOI： 10.1186/s13075-022-02746-5

Web of Science

Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1093/mr//road010.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1186/s13075-022-02746-5.

Language：English   Publisher：Clinical and Experimental Rheumatology  

Objective Emerging evidence has shown the importance of inflammasome activation in the progression of autoimmune diseases. In this study, we aimed to identify the main cell types activating inflammasome in autoimmune diseases and to clarify the intracellular pathway of inflammasome activation in systemic lupus erythematosus (SLE). Methods Active caspase-1 in each subset of human peripheral blood cells from healthy controls (n=18), SLE (n=51), and other rheumatic diseases (n=36) were fluorescently probed with FLICA™-caspase-1 followed by flow cytometric analysis. The correlation of caspase-1 activation in monocytes and clinical parameters in SLE patients were evaluated. In-vitro experiments were performed to identify the pathway involved in caspase-1 activation induced by SLE serum in monocytes. Results Active caspase-1 in monocytes was upregulated in SLE patients. Cluster of differentiation 14 (CD14)-positive and CD16-positive monocytes showed considerable activation of caspase-1 compared with the other subsets of monocytes. Serum titres of anti-double stranded DNA antibodies were positively correlated with active caspase-1 in monocytes, and serum complement component 3 and platelet count were negatively correlated with active caspase-1 in monocytes. The SLE serum-induced activation of caspase-1 and IL-1β secretion were down-regulated by inhibition of NLR family pyrin domain containing 3 (NLRP3), cyclic GMP-AMP synthase (cGAS), or stimulator of interferon genes (STING). Conclusion These findings suggest that targeting inflammasome by regulating cGAS/STING and NLRP3 are potential therapeutic strategies for SLE.

DOI： 10.55563/CLINEXPRHEUMATOL/EAKVLV

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PubMed

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DOI： 10.1186/s13075-021-02618-4.

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DOI： 10.1177/09612033211031989

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DOI： 10.1038/s41598-021-95711-2.

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DOI： 10.3389/fimmu.2021.713225

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DOI： 10.1136/annrheumdis-2020-219209.

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DOI： 10.1097/MD.0000000000025406.

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DOI： 10.1111/bjh.17456

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DOI： 10.1080/14397595.2020.1790778

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DOI： 10.3899/jrheum.190373

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DOI： 10.3389/fimmu.2021.654623

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DOI： 10.1016/j.cellimm.2020.104263.

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DOI： 10.1093/rheumatology/keaa005.

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DOI： 10.3389/fimmu.2020.02042

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DOI： 10.1007/s00296-020-04512-9.

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DOI： 10.1186/s12865-020-00361-0

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DOI： 10.1111/cei.13477

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DOI： 10.4049/jimmunol.1901304

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DOI： 10.1093/rheumatology/kez630

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DOI： 0.1186/s13075-019-1984-x

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DOI： 10.1186/s13075-019-1823-0.

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DOI： 10.1186/s12868-017-0382-z

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DOI： 10.1111/imm.12667

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DOI： 10.3109/14397595.2015.1079292

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DOI： 10.1016/j.jdermsci.2015.10.009

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DOI： 10.4049/jimmunol.1403046

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DOI： 10.1007/s00296-014-3106-z

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DOI： 10.3109/14397595.2013.852838

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DOI： 10.1097/MIB.0b013e318280b169

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DOI： 10.1182/blood-2012-05-431429

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DOI： 10.1016/j.jaci.2012.03.014.

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Language：Japanese   Book type：Scholarly book

Language：Japanese   Book type：General book, introductory book for general audience

Language：Japanese   Book type：General book, introductory book for general audience

Responsible for pages：1660-1661   Language：Japanese   Book type：Scholarly book

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Venue：東京   Country：Japan  

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Venue：京都府立京都学・歴彩館/稲盛記念会館   Country：Japan  

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Venue：Atlanta, GA   Country：Japan  

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Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

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Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：English   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：English   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publisher：(株)日本医事新報社  

Language：Japanese   Publisher：(有)科学評論社  

Language：Japanese   Publisher：(有)科学評論社  

Language：Japanese   Publisher：(有)科学評論社  

Language：Japanese   Publisher：医歯薬出版(株)  

免疫系が適切に機能するには,自己と非自己の正確な区別が必要である.自己免疫疾患とはこのシステム(自己寛容)の機能不全に起因する病態である.膠原病は皮膚,関節,肺,腎臓など全身の臓器に炎症や障害を生じる疾患であるが,病因の根源は自己免疫である.本疾想の病態解明によって,細胞・分子標的療法など画期的な治療法も近年登場し,効果を上げている.一方で,治療抵抗例など治療へのアンメットニーズもいまだ高く,膠原病の病態についてはさらなる解明が必要である.本稿では,自己免疫の理解に必要なT細胞,B細胞の自己寛容についてまずは概説し,続いて代表的膠原病の全身性エリテマトーデス(SLE)を取り上げ,その病態を適応免疫の部分に着目し,最近の知見を交えて概説する.(著者抄録)

Language：Japanese   Publisher：(有)科学評論社  

Language：Japanese   Publisher：(有)科学評論社  

Language：Japanese   Publisher：(株)日本医事新報社  

Language：Japanese   Publisher：九州リウマチ学会  

Language：Japanese   Publisher：(有)科学評論社  

Language：Japanese   Publisher：(有)科学評論社  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publisher：(有)科学評論社  

Language：Japanese   Publisher：(株)日本臨床社  

Language：Japanese   Publisher：(株)日本臨床社  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publisher：(株)日本臨床社  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

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Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Type：Competition, symposium, etc. 

Type：Peer review 

Number of peer-reviewed articles in foreign language journals：12

Type：Peer review 

Number of peer-reviewed articles in foreign language journals：12

Type：Peer review 

Number of peer-reviewed articles in foreign language journals：13

Type：Competition, symposium, etc. 

Type：Competition, symposium, etc. 

Type：Peer review 

Number of peer-reviewed articles in foreign language journals：8

Type：Competition, symposium, etc. 

Type：Peer review 

Number of peer-reviewed articles in foreign language journals：7

Type：Peer review 

Number of peer-reviewed articles in foreign language journals：5

Number of peer-reviewed articles in Japanese journals：0

Type：Peer review 

Number of peer-reviewed articles in foreign language journals：7

Number of peer-reviewed articles in Japanese journals：0

Type：Competition, symposium, etc. 

Type：Competition, symposium, etc. 

Type：Competition, symposium, etc. 

Type：Competition, symposium, etc. 

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Number of participants：438