The introduction of anti-tumor necrosis factor α (TNFα) biologics significantly innovated inflammatory bowel disease (IBD) treatment and increased medical costs. The recent expiration of patents of some anti-TNFα biologics (such as infliximab and adalimumab) facilitated the development of biosimilars. Comparable pharmacokinetic, efficacy, safety, and immunogenicity profiles between anti-TNFα originators and biosimilars were demonstrated in different studies. Anti-TNFα biosimilars hold promise for reducing the high cost of biologics and increasing patient access to biologics. In this review, we outline the current data on the use of anti-TNFα originators and biosimilars in patients with IBD, with a focus on the efficacy, safety, and immunogenicity profiles of infliximab and adalimumab biosimilars. The potential benefits, challenges, and future directions of anti-TNFα biosimilars are also discussed in the review.

Background and Aims: Angiotensin-converting enzyme II (ACE2) is the key molecule for understanding the pathophysiology of COVID-19. The risk of COVID-19 and impact of immunosuppressive treatment on disease course in patients with inflammatory bowel disease (IBD) remain controversial. We aimed to determine the change of intestinal ACE2 expression before and after biologics treatment including anti-tumor necrosis factor α (anti-TNFα), anti-integrin, and anti-interleukin (IL)12/23 in IBD patients. Methods: We analyzed the ACE2 expression through the public database of paired intestinal biopsies from IBD patients before and after biologic therapy. Change of ACE2 RNA and protein expression were validated in two independent cohorts (Birmingham cohort and Guangzhou cohort). The correlation between ACE2 expression and disease activity was also analyzed. Results: Mining information from the GEO database showed that compared with healthy control, intestinal ACE2 expression was downregulated in ileum of CD patients, while upregulated in colon of both CD and UC patients. Colonic ACE2 RNA expression was decreased significantly in patients responding to anti-TNFα but not anti-integrin and anti-IL12/23, which was validated in the Birmingham cohort. Using the Guangzhou cohort including 53 patients matched by pre- and post-anti-TNFα therapy, colonic ACE2 protein expression was significantly downregulated after anti-TNFα treatment in responders (P < 0.001) rather than non-responders. Colonic ACE2 expression was significantly higher in patients with severe histologically active disease compared with those with moderate (P < 0.0001) and mild (P = 0.0002) histologically active disease. Conclusion: Intestinal inflammation influences the expression of intestinal ACE2 in IBD patients, with different alterations in the ileum and colon. Colonic ACE2 expression was downregulated after anti-TNFα therapy in IBD patients responding to treatment. This might provide new clues regarding the risk of SARS-CoV-2 infection and the potential benefit of sustaining anti-TNFα treatment in patients with IBD.

Repeated intra-articular hemorrhages lead to hemophilic arthropathy in severe hemophilia. Inflammation and pro-inflammatory cytokines (e.g., tumor necrosis factor alpha (TNFα)) might be involved in this pathogenesis. We hypothesized that anti-TNFα may provide adjuvant protection for hemophilic arthropathy management. We measured TNFα in synovial lavage from hemophilia mice subjected to hemarthrosis induction and synovial fluid from patients with hemophilic arthropathy (n = 5). In hemophilia mice, recurrent hemarthroses were induced, anti-TNFα was initiated either from day (D)7 after one hemarthrosis episode or D21 after three hemarthroses episodes (n ≥ 7/treatment group). In patients with hemophilic arthropathy (16 patients with 17 affected joints), a single dose of anti-TNFα was administered intra-articularly. Efficacy, characterized by synovial membrane thickness and vascularity, was determined. Elevated TNFα in synovial lavage was found in the hemophilia mice and patients with hemophilic arthropathy. Hemophilia mice subjected to three hemarthroses developed severe synovitis (Synovitis score of 6.0 ± 1.6). Factor IX (FIX) replacement alone partially improved the pathological changes (Synovitis score of 4.2 ± 0.8). However, anti-TNFα treatment initiated at D7, not D21, significantly provided protection (Synovitis score of 1.8 ± 0.9 vs. 3.9 ± 0.3). In patients with hemophilic arthropathy, intra-articular anti-TNFα significantly decreased synovial thickness and vascularity during the observed period from D7 to D30. Collectively, this preliminary study seems to indicate that TNFα may be associated with the pathogenicity of hemophilic arthropathy and anti-TNFα could provide adjuvant protection against hemophilic arthropathy. Further studies are required to confirm the preliminary results shown in this study.

BACKGROUND: To review the frequency with which anti-TNF-α loses its effect and dose \"intensification\" is required for Crohn\'s disease (CD) treatment.
METHODS: Electronic databases were searched for eligible studies. Raw data from studies meeting inclusion criteria were pooled for effect estimates. Subgroup analyses were performed for exploration of heterogeneity regarding all outcomes.
RESULTS: Eighty-six eligible studies were included. Estimates of loss of response (LOR) incidence ranged from 8 to 71%. The random effects pooled incidence of LOR with a median follow-up of 1-year was 33% (95% CI 29-38, 55 studies, n = 6135). The effect estimate based on data from patients with infliximab was 33% (95% CI 27-40), 30% (95% CI 22-39) for adalimumab, and 41% (95% CI 30-53) for certolizumabpegol. Overall, the mean percentage of patients\' LOR to anti-TNFs was 38.5%. The annual risk for LOR was 20.9% per patient-year. The random-effects pooled rate of need for dose intensification with a median follow-up of 1 year was 34% (95% CI 28-41, 38 studies, n = 10,690). The effect estimate for infliximab was 38% (95% CI 28-50), 36% (95% CI 30-43) for adalimumab, and 2% (95% CI 2-3) for certolizumab-pegol. The mean percentage of patients who needed an anti-TNF dose escalation was 23% with an annual risk of 18.5% per patient-year. There was no evidence of publication bias for incidence of LOR but not for the dose intensification (p = 0.001).
CONCLUSIONS: Overall, around one-third of CD patients experience a LOR and required dose intensification in primary anti-TNF-α responders.

This study aimed to assess the responsiveness of ultrasonography (US)-7 in patients with rheumatoid arthritis (RA). Eighty-two RA patients were recruited and followed up for 22 weeks. The clinical, laboratory, and X-ray assessments, along with grayscale US (GSUS) and power Doppler US (PDUS) examinations were performed at baseline, 6, 14, and 22 weeks after infliximab treatment. GSUS for synovitis and PDUS for synovitis and paratendinitis/tenosynovitis were assessed by a semi-quantitative (0 to 3) score, while GSUS for paratendinitis/tenosynovitis and bone erosion was qualitatively assessed as absent or present (0 or 1). US scores in both 7-joint (US7) and 12-joint (US12) systems were evaluated. After 6, 14, and 22 weeks of treatment with infliximab, indices such as US scores, 28-joint disease activity (DAS28) score, and tender and swelling joint count were all significantly improved compared to baseline. US7 scores were significantly correlated with that of US12. Strong correlations were identified between most US7 scores with DAS28, health assessment questionnaire (HAQ), and C-reactive protein (CRP) levels. When DAS28 was used as a reference, the US7 cutoff for disease remission was less than 35 for GS + PD and also less than 29 for GS and 1 for PD, respectively. Additionally, the positive percent agreement, negative percent agreement, and overall percent agreement for GS + PD were 77.78, 76.19, and 76.67 %, respectively, which were all higher than that of GS or PD. US7 may be a feasible tool to assess the therapeutic response in RA patients.

BACKGROUND: Psoriasis is a T-cell-mediated chronic inflammatory dermatosis. Th1, Th17 and Th22 cells are suggested to contribute to the pathogenesis of psoriasis.
OBJECTIVE: To determine whether treatment with the anti-tumor-necrosis-factor antagonist, adalimumab, induces significant modulation of the Th1, Th17 and Th22 pathways, and correlates cellular activity with clinical response.
METHODS: This study included 21 patients with moderate-to-severe psoriasis who were treated with adalimumab, and 10 healthy control subjects. Blood samples were collected at baseline and at week 12. Flow cytometry was used to analyze the frequency of circulating Th1, Th17 and Th22 cells. Real-time polymerase chain reaction was used to analyze the expression of T-bet (Th1-related), retinoid-acid receptor-related orphan receptor gamma t (RORγt, Th17-related) and aryl hydrocarbon receptor (AHR, Th22-related). An enzyme-linked immunosorbent assay was used to analyze the serum levels of IFN-γ, IL-17, IL-22, IL-6 and tumor necrosis factor-α (TNF-α).
RESULTS: At baseline, the frequencies of Th1, Th17 and Th22 cells were higher in psoriasis patients compared to the healthy controls. The expression of transcription factors T-bet, RORγt and AHR, and the serum levels of IFN-γ, IL-17, IL-22, IL-6 and TNF-α were higher in psoriasis patients compared to the healthy controls. After adalimumab therapy, there was a significant decline in the frequencies of Th1, Th17 and Th22 cells, and a concomitant decrease in the levels of their associated transcription factors and cytokines.
CONCLUSIONS: The results suggest that the anti-tumor-necrosis-factor antagonist, adalimumab, disrupts the Th1, Th17 and Th22 pathways, resulting in clinical improvement of psoriasis.

OBJECTIVE: To study the factors associated with withdrawal of the and tumor necrosis factor alpha (anti-TNFα) biologics in the treatment of rheumatic diseases.
METHODS: Data from the Hong Kong Biologics Registry were retrieved. The cumulative rates of withdrawal of different biological agents were studied by Kaplan-Meier plot and the incidence of serious adverse events (SAEs) was calculated. Factors associated with the withdrawal of the anti-TNFα agents were studied by Cox regression.
RESULTS: Between 2005 and 2013, 2059 courses of biologics were used in 1345 patients. After 3454 patient-years, 1171 (57%) courses were terminated because of clinical inefficacy (38.1%), SAEs (22.3%) and financial reasons (15.9%). The most frequent SAEs (per 100-patient-years) were allergy (2.90), serious infections (1.34), tuberculosis (0.93) and infusion/injection site reaction (0.75). Among the anti-TNFα agents, the cumulative probability of drug withdrawal for either inefficacy or SAEs in 5 years was highest with infliximab (IFX) (64.5%), followed by etanercept (ETN) (44.2%) and adalimumab (ADA) (36.9%). The incidence of serious infections and tuberculosis (per 100 patient-years) for IFX, ETN and ADA users was 1.99, 0.85 and 0.63; and 1.68, 0.43 and 0.85, respectively. Infusion/injection site reaction was highest with IFX (1.38/100 patient-years). Cox regression revealed increasing age, female sex, not having a diagnosis of spondyloarthritis (SpA) and IFX use were significantly associated with drug withdrawal for either inefficacy or SAEs. Rheumatoid arthritis (RA) had the highest hazard ratio for drug withdrawal but SpA was favorable for drug retention, after adjustment for age, sex, disease duration and the choice of anti-TNFα agents.
CONCLUSIONS: In our registry, the retention rate of the anti-TNFα agents was lowest but the incidence of tuberculosis, serious infections and infusion reaction was highest with IFX. Older female patients with RA and the use of IFX were independently associated with drug withdrawal.

OBJECTIVE: To study the efficacy of rituximab in active rheumatoid arthritis (RA) patients refractory to disease modifying anti-rheumatic drugs (DMARDs) including the tumor necrosis factor (TNF)-alpha antagonists.
METHODS: Adult patients with active RA despite adequate therapies with conventional DMARDs or anti-TNFalpha agents for at least 3 months were recruited. Inclusion criteria were: (1) Positive RF / anti-CCP; (2) >/= 6 swollen joints and >/= 8 tender joints; (3) ESR >/= 28 mm/hr or CRP >/= 10 mg/L. Eligible patients were given intravenous rituximab infusions at a dose of 1000 mg on days 1 and 15. Assessment was performed 4-weekly thereafter and included tender joint counts (TJC), swollen joint counts (SJC), physician\'s and patient\'s global assessment, patient\'s pain assessment (VAS 0-100 mm), disability index (HAQ-DI), quality of life (SF36), fatigue score (FACIT-F), ESR and CRP. The DAS28, EULAR and ACR responses at week 24 were evaluated.
RESULTS: 10 patients (8 women and 2 men) were studied (mean age: 49 years; mean RA duration 7.4 years). Baseline TJC and SJC were 25.1 +/- 13.2 and 12.8 +/- 5.4 respectively. The mean DAS28 score was 7.1 +/- 0.7, and the mean CRP and ESR levels were 52.3 +/- 60 mg/L and 95.8 +/- 32 mm/hr, respectively. The median number of failed DMARDs was 4 and two patients had failed anti-TNFalpha treatment. At week 24, there was a significant drop in TJC, SJC, ESR and CRP. The HAQ-DI score also decreased from 2.1 to 1.7 (p=0.04) while the total SF-36 score improved from 24.8 to 38.3 (p=0.008). Sixty percent of patients achieved EULAR moderate-to-good response. Half of the patients achieved ACR20 and two achieved ACR50 / 70 response. Only one patient experienced a minor infusion reaction.
CONCLUSIONS: Rituximab is effective and well tolerated in patients with refractory RA.