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OBJECTIVE To analyze the characteristics of drug-induced autoimmune hepatitis （DIAIH） induced by tumor necrosis factor-α inhibitor （TNFi）， and to provide reference for clinical drug treatment. METHODS Retrieved from PubMed， Embase， China Academic Journal full-text Database， VIP and Wanfang database， the case reports of TNFi-induced DIAIH were collected to conduct descriptive analysis. RESULTS A total of 33 case reports involving 44 patients were collected， including 31 females and 13 males， with an average age of （41.14±2.20） years old， mostly aged 30 to 60 years （77.27%）. The primary diseases were Crohn disease （CD）， ulcerative colitis （UC） and rheumatoid arthritis （RA） （68.18%）. Of the 44 patients， 35 were treated with infliximab （IFX）， 7 with adalimumab， and 2 with etanercept. The dosage of 37 patients was within the scope of the instructions， and 31 received other drugs additionally； DIAIH mainly occurred ≤24 weeks after medication （68.18%）； 21 patients （47.73%） had no clinical manifestations； alanine aminotransferase and aspartate aminotransferase were abnormally elevated in all patients； anti-nuclear antibodies were positive in 38 patients. Except for 3 patients who required liver transplantation， all the other patients improved after drug withdrawal and/or symptomatic treatment such as glucocorticoid therapy. CONCLUSIONS TNFi- induced DIAIH is more common in female patients and can occur with conventional doses， with significant differences in occurrence time. However， the intervention measures are basically the same for DIAIH induced by different types of TNFi. Clinical use of TNFi， especially the use of IFX， requires close attention to the clinical manifestations， liver function and autoantibody level， and a detailed evaluation should be conducted to detect DIAIH as soon as possible. If liver function continues to not improve， it is necessary to stop taking medicine as soon as possible and receive symptomatic treatment to avoid developing acute or severe DIAIH or liver failure.
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Tumor necrosis factor-α (TNF-α) inhibitors have been widely used and proven to be effective in the treatment of various inflammatory disorders in recent years, but there is a noteworthy and paradoxical adverse drug reaction that cannot be ignored, that is, TNF-α inhibitor-induced psoriasis. Its pathological manifestations could be psoriasiform or spongiotic changes, and its pathogenesis may be related to the imbalance between TNF-α and type Ⅰinterferon, the involvement of interleukin-23/T helper 17 axis, or infection. This review elaborates the epidemiological, histopathological features and possible pathogenesis of TNF-α inhibitor-induced psoriasis, and provides a basis for recognition and treatment of TNF-α inhibitor-induced psoriasis.
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Adalimumab, one of the tumor necrosis factor-α (TNF-α) inhibitors, has been approved as a therapeutic drug for non-infectious intermediate, posterior and pan-uveitis by FDA.Due to the good efficacy, TNF-α inhibitors are being applied widely in ophthalmology.However, some researches based on the application of TNF-α inhibitor in treating inflammatory bowel diseases and rheumatoid arthritis, etc.have showed that it can bring out some adverse effects such as infection and tumor occurrence and/or progression.The main safety problems in the application of TNF-α inhibitors lie in its increased risk of serious infection, postoperative infection, the occurrence or progression of tuberculosis and hepatitis, as well as the tumorigenesis and tumor progression.With the wider application of adalimumab in refractory uveitis, ophthalmologists should not only focus on its therapeutic effect, but also get to know the adverse effects of the drug, so as to standardize the examination, prevention and control of primary diseases before and after the administration of adalimumab and observe closely clinical manifestations of patients with administration of adalimumab, select the treating method and timing reasonably to reduce and avoid the adverse drug reactions, and improve the therapeutic outcome.
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Objective To investigate the predictive value of serum survivin for clinical efficacy of tumor necrosis factor-α (TNF-α) inhibitor treatment in rheumatoid arthritis (RA) patients. Methods This study enrolled 63 consecutive patients with moderate or severe RA who received TNF-α inhibitor via subcutaneous injection 2 times/week, 25 mg/dose, for 24 weeks. According to disease activity, patients were also administered a disease-modifying antirheumatic drug. Serum survivin level was measured by enzyme-linked immunosorbent assay. The Disease Activity Score 28 was assessed, and clinical response and clinical remission were investigated. Results After treatment, 41 patients had a clinical response and 22 had no response. Baseline serum survivin level was reduced in the responder group compared to that in the non-responder group (P = 0.004). Receiver operating characteristic curve analysis showed that survivin level had good predictive value for non-response to TNF-α inhibitor treatment in RA patients (area under the curve:0.717, 95％ confidence interval:0.583-0.852). High survivin level (≥672.75 pg/mL) was an independent predictor of non-response to TNF-α inhibitor treatment in RA patients (P = 0.011), while a high C-reactive protein (CRP) level was an independent predictor of a better response to TNF-α inhibitor treatment (P = 0.011). High survivin level predicted non-response to TNF-α inhibitor treatment, independent of CRP level. However, baseline survivin level showed no difference between remission (16 cases) and non-remission groups (47 cases) (P = 0.265). A high survivin level did not affect remission in RA patients after TNF-α inhibitor treatment. Conclusion Baseline serum survivin level can predict the response of RA patients to TNF-α inhibitor treatment.
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Objective To investigate whether prolonged the interval of tumor necrosis factor (TNF)-α inhibitors (TNF-i) injection could continuously improve inflammatory biomarkers and imaging changes of sacroiliac joint and spine in spondyloarthritis (SpA).Methods A total of 154 SpA patients were included and 95 of them received TNF-α inhibitor therapy.TNF-i used in this study included etanercept,infliximab and adalimumab.The dose of etanercept was gradually reduced from 50 mg per week to every two weeks,every three weeks and then per month.The infusion of Infliximab was reduced from 4 mg/kg at 0,2,6 week to every 8 weeks,every 12 weeks and then every 16 weeks.The interval of Adalimumub injection was changed from 40 mg every two weeks to 3 weeks to 4 weeks and then to two months.The levels of inflammatory parameters,bath ankylosing spondylitis disease activity index (BASDAI),bath ankylosing spondylitis functional index (BASFI),ankylosing spondylitis disease activity score (ASDAS),spondyloarthritis research consortium of canada (SPARCC) scores of sacroiliac joint and fat metaplasia,bone erosion,sclerosis and ankylosis changes on magnetic resonance imaging (MRI) were investigated every 3 to 6 months.Radiograhs of spine were assessed by modified stoke ankylosing spondylitis spinal score (mSASSS) scores at baseline and 2 years.Analyses were performed by Paired t-test,Wilcoxon test,Mann-Whitney U test,Kruskal-Wallis and Chi-square test.Results After 3 months of treatment,erythrocyte sedimentation rate (ESR),c reactive protein (CRP),immunoglobulin A (IgA),BASDAI,BASFI,ASDAS and SPARCC scores were significantly lower than those of the baseline [13.00(6.00,31.00) mm/1 h vs 3.00 (2.00,6.00) mm/1 h,Z=-5.61;7.39(2.52,17.90) mg/L vs 1.88(1.21,3.75) mg/L,Z=-5.57;2.89(2.52,17.90) g/L vs 2.27(1.60,2.85) g/L,Z=-4.69;(2.57±1.43) vs (1.17±0.92),t=9.81;17.50(5.00,27.00) vs 4.00(0,11.00),Z=-6.69;2.62(2.02,3.52) vs 1.22(0.92,1.59),Z=-6.96;25.00(10.00,37.00) vs 12.00 (6.00,20.25),Z=-6.68;all P＜0.05].Compared to 3-6 months,SPARCC scores were significantly reduced during 2-3 years in the TNF-i group [12.00 (6.00,20.25) vs 7.00 (3.25,14.75),P=0.02].There were no significant progresses in fat metaplaisa,bone erosions,sclerosis or ankylosis during the follow-up period (61％,57％,x2=0.07,P=1.00;53％,43％,x2=0.40,P=0.75;31％,57％,x2=3.02,P=0.11;14％,7％,x2=0.43,P=0.66).The mSASSS scores were not different between TNF-i group and TNF-i group after 2 years of treatment [2.50 (0,8.00) vs 3.00 (0,8.00),Z=-0.30,P=0.76].Conclusion Prolonged the interval of TNF-i treatment could continuously improve bone marrow edema in SPA,whereas structural damages of sacroiliac joints and spine are not deteriorated.
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Objective To explore the effect of tumor necrosis factor (TNF)-α inhibitors therapy on bone mineral density (BMD) in active rheumatoid arthritis (RA) patients with low bone mass.Methods Sixtytwo active RA patients with low bone mass were treated with a standard treatment of calcium carbonate 0.5 g/d and alfacalcidol 0.25 μg/d,and were divided into two groups.Patients of the control group were treated with methotrexate 10 mg per week,while patients of the experimental group were treated with combined recombinant human type Ⅱ tumor necrosis factor receptor-antibody fusion protein 50 mg per week or adalimumab 40 mg/2 week subcutaneously for 12 months with methotrexate.BMD of lumbar spine (L2-4),femoral neck,trochanter and Ward's triangle region by dual energy X-ray absorptiometry (DEXA),as well as the bone turnover markers serum C telopeptide of type-Ⅰ collagen (CTX-Ⅰ) and serum procollagen type-Ⅰ N propeptide (PINP) were measured by enzyme-linkedimmunosorbent assay (ELISA) in both groups at the baseline,treatment for six-month and twelve-month.T test and Chi-square test was used to process the data.Results ① After 6 months of treatment,the BMD of lumbar spine,femoral neck and trochanter in the group with TNF-α inhibitors were higher than the control group [(0.68±0.08) g/cm2 vs (0.65±0.06) g/cm2,t=2.269,P=0.027; (0.63±0.08) g/cm2 vs (0.58±0.09) g/cm2,t=2.111,P=0.040; (0.61±0.10) g/cm2 vs (0.56±0.07) g/cm2,t=2.203,P=0.032; respectively].And after 12 months,the BMD of all regions were significantly higher thanthe control group [spine,(0.68±0.07) g/cm2 vs (0.62±0.08) g/cm2,t=5.115,P=0.000; femoral neck,(0.63±0.08)g/cm2 vs (0.56±0.08) g/cm2,t=3.475,P=0.001; Ward's triangle region (0.60±0.08) g/cm2 vs (0.56±0.08) g/cm2,t=2.309,P=0.025; trochanter,(0.61±0.10) g/cm2 vs (0.53±0.08) g/cm2,t=3.254,P=0.002; respectively].② Compared to the baseline,BMD of lumbar spine was significantly decreased in the control group after 12 months.While in the group of TNF-α inhibitors,BMD of lumbar spine was increased[(0.66±0.08) g/cm2 vs (0.68±0.07)g/cm2,t=3.411,P=0.001].③ Compared to the baseline,CTX-Ⅰ,a marker of bone resorption was significantly decreased at 6 months and 12 months in the group with TNF-αinhibitors [6 months,(0.33±0.2) ng/ml vs (0.46±0.22) ng/ml,t=5.548,P＜0.01; 12 months,(0.31±0.21) ng/ml vs (0.46±0.22) ng/ml,t=5.974,P＜0.01],while this decline was not found in the control group.PINP,a marker of bone formation was stable in both 2 groups during the study.Conclusion In active RA patients with low bone mass,loss of BMD in the spine and hip can be arrested by the treatmentof TNF-α inhibitors.