The safety and efficacy of TNF inhibitors in patients with Behçet's disease: Retrospective study from eastern Turkey.

OBJECTIVE: We aimed to evaluate the clinical features, disease course, and associated factors for outcome in severe/refractory BD patients receiving TNF-i treatment. MATERIAL AND METHODS: This retrospective study was conducted by reviewing medical records from a tertiary referral center in Van province in Eastern Turkey. Data were obtained from patients' charts followed up between June 2019 and June 2022. RESULTS: We included 469 BD patients (59.3% male) whose 80 patients (17%) received TNF-i treatment in the study. The mean ± standard deviation of the patient age was 36.7 ± 10.1 years and the median (IQR) disease duration was 12 (12) years. IFX and ADAwere initiated in 67.5% (n = 54) and 32.5% (n = 26) patients, respectively. Overall and first-line retention rates of TNF-i were 84.7% and 92.6% for IFX and 83.3% and 80.8% for ADA, respectively. IFX was discontinued in 9 patients which were in 2 patients due to allergic reaction and tuberculosis, 3 patients for inefficacy, one patient for heart failure, and one patient for orbital zona. Although no serious adverse event was observed with ADA, 5 patients switched to IFX due to inefficacy. Overall, 72 patients (90%) resumed TNF-i at the end of the study; TNF-i was discontinued in 3 patients (3.8%) due to severe adverse events and in 5 patients (6.2%) with prolonged remission. CONCLUSION: In our study, no case of death was observed in TNF-i receiving patients. Most patients achieved attack-free and CS-free disease and retained TNF-i treatment. TNF inhibitors appear to be safe and effective in patients with severe/refractory Behçet's disease.

Safety of the JAK and TNF inhibitors in rheumatoid arthritis: real world data from the Hong Kong Biologics Registry.

OBJECTIVES: To compare the incidence of major adverse cardiovascular events (MACEs), cancer and infective complications in RA patients using Janus kinase (JAKis) and TNF (TNFis) inhibitors. METHOD: A retrospective analysis of data from the Hong Kong Biologics Registry 2008-2021 was performed. RA patients who had ever used JAKis or TNFis were included. The incidence of MACEs, cancer and infections were compared between the two groups, with adjustment for confounding factors. RESULTS: A total of 2471 courses of JAKis (n = 551) and TNFis (n = 1920) were used in 1732 RA patients (83.7% women, age 53.8 [12.5] years; follow-up 6431 patient-years). JAKi users had significantly older age, more atherosclerotic risk factors and higher frequency of past malignancies. A total of 15 and 40 MACEs developed in the JAKi and TNFi users, respectively (incidence 1.34 vs 0.75 per 100 patient-years; P = 0.22). There was no significant difference in the incidence of cancers between the two groups (0.81 [JAKi] vs 0.85 [TNFi] per 100 patient-years; P = 0.25). The adjusted hazard ratios of MACE and cancer in the JAKi users were 1.36 (95% CI: 0.62, 2.96) (P = 0.44) and 0.87 (95% CI: 0.39, 1.95) (P = 0.74), respectively. Rates of infections were significantly higher in the JAKi than TNFi users (16.3 vs 9.9 per 100 patient-years; P = 0.02), particularly herpes zoster (3.49 vs 0.94 per 100 patient-years; P < 0.001). CONCLUSIONS: In a real-life setting, there is no increase in MACEs or cancers in users of JAKis compared with TNFis. However, the incidence of non-serious infections, including herpes zoster, was increased in users of JAKis.

Exploring relief for Behçet's disease refractory oral ulcers: a comparison of TNF inhibitors versus apremilast.

OBJECTIVES: Oral and genital ulcers are the hallmark manifestation of Behçet's disease (BD), significantly impacting patients' quality of life. Our study focuses on comparing the effectiveness and safety of TNF inhibitors (TNFis) and apremilast in controlling oral ulcers of BD, aiming to provide evidence-based guidance for physicians in selecting appropriate treatment modalities. METHODS: A retrospective analysis was performed on BD patients treated between December 2016 and December 2021 with TNFis or apremilast for refractory oral ulcers. The study assessed treatment response by the absence of oral ulcers at 3 and 6 months, with additional evaluations for genital ulcers and articular involvement. RESULTS: The study included 78 patients, equally allocated between TNFis and apremilast treatments. Both groups showed significant oral ulcer reduction at 3 (p< 0.001) and 6 months (p= 0.01) with no significant difference between the treatments. Apremilast had a notable corticosteroid-sparing effect by the 3-month follow-up, persisting through 6 months. Both treatments were equally effective in reducing genital ulcers, with TNFis showing greater effectiveness in addressing articular involvement. Apremilast had a higher discontinuation rate due to gastrointestinal side effects. CONCLUSION: TNFis and apremilast are both effective for treating BD refractory oral ulcers. While TNFis may offer broader benefits for other disease manifestations, apremilast is distinguished by its corticosteroid-sparing effect, especially for patients with a milder disease phenotype. Treatment selection should consider individual disease severity and clinical features to ensure a personalized and effective management strategy.

Anti-citrullinated protein antibody profiles predict changes in disease activity in patients with rheumatoid arthritis initiating biologics.

OBJECTIVES: To determine whether an expanded antigen-specific ACPA profile predicts changes in disease activity in patients with RA initiating biologics. METHODS: The study included participants from a prospective, non-randomized, observational RA cohort. For this sub-study, treatment groups of interest included biologic-naïve initiating anti-TNF, biologic-exposed initiating non-TNF, and biologic-naïve initiating abatacept. ACPAs to 25 citrullinated peptides were measured using banked enrolment serum. Principal component analysis (PCA) was performed and associations of resulting principal component (PC) scores (in quartiles) and anti-CCP3 antibody (≤15, 16-250 or >250 U/ml) with EULAR (good/moderate/none) treatment response at 6 months were examined using adjusted ordinal regression models. RESULTS: Participants (n = 1092) had a mean age of 57 (13) years and 79% were women. At 6 months, 68.5% achieved a moderate/good EULAR response. There were three PCs that cumulatively explained 70% of variation in ACPA values. In models including the three components and anti-CCP3 antibody category, only PC1 and PC2 were associated with treatment response. The highest quartile for PC1 (odds ratio [OR] 1.76; 95% CI: 1.22, 2.53) and for PC2 (OR 1.74; 95% CI: 1.23, 2.46) were associated with treatment response after multivariable adjustment. There was no evidence of interaction between PCs and treatment group in EULAR responses (P-value for interaction >0.1). CONCLUSION: An expanded ACPA profile appears to be more strongly associated with biologic treatment response in RA than commercially available anti-CCP3 antibody levels. However, further enhancements to PCA will be needed to effectively prioritize between different biologics available for the treatment of RA.

Disease activity-guided dose optimisation including discontinuation of TNF-inhibitors in rheumatoid arthritis is effective for up to 10 years: an observational follow-up of the DRESS study.

OBJECTIVES: To investigate safety and effectiveness of disease activity-guided dose optimisation of TNF-inhibitors in rheumatoid arthritis over 10 years. METHODS: Observational long-term extension of a randomised study of participants who completed the 3-year extension of the DRESS-study. After the randomised phase (month 0-18), disease activity-guided dose optimisation was allowed for all. Main outcomes were mean time-weighted DAS28-CRP; biological and targeted synthetic anti-rheumatic drug (b/tsDMARD) use per year as proportion of daily defined dose; proportion of patients reaching discontinuation; durability, effectiveness of subsequent dose reduction attempts; and radiographic progression between 3 and 10 years using the Sharp-van der Heijde score. RESULTS: 170 patients were included of whom 127 completed 10-year follow-up. The mean disease activity remained low (DAS28-CRP 2.13, 95% confidence interval 2.10-2.16), whilst the b/tsDMARD dose reduced from 97% at baseline (95%CI 96% to 99%, n = 170)% to56% at year 10 (49% to 63%, n = 127). 119 of 161 participants (74%) with an optimisation attempt reached discontinuation, with a median duration of 7 months (interquartile range 3-33 months), and 25 participants never had to restart their b/tsDMARD (21%, 14% to 29%). The mean dose reduction after dose optimisation was 48% (n = 159) for the first optimisation attempt and 33% for subsequent attempt (n = 86). 48% (41/86) of participants had radiographic progression exceeding the smallest detectable change (5.7 units), and progression was associated with disease activity, not b/tsDMARD use. CONCLUSION: Long-term disease activity-guided dose optimisation of TNF-inhibitors in rheumatoid arthritis, including discontinuation and multiple tapering attempts, remains safe and effective.

Ex-vivo Cell-based Assay for Assessment of Response to TNF Inhibitors in Patients with Rheumatic Diseases.

OBJECTIVE: TNF inhibitors (TNFi) comprise 5 products whose structure and signalling differ. An individual patient with a rheumatic disease may respond to one TNFi but not to another. In addition, 30-40% of the patients respond inadequately to TNFi. The different TNFi downstream signalling may lead to their clinical efficacy. Several reports showed that TNFi exhibited differential effects on Th17 cells. We analyzed the different TNFi effects on IL-17A expression in the peripheral blood mononuclear cells (PBMCs) of patients with rheumatic diseases in order to evaluate the predictive capability of responses in an ex-vivo setting. METHODS: PBMCs were co-cultured with the different TNFi or medium (control), and IL-17A mRNA levels were analyzed by qPCR. IL-17A expression levels in response to 4 TNFi (except certolizumab pegol) were compared with control. IL-17A expression in the assay was correlated to the clinical responses. Assay sensitivity and specificity for distinguishing responders from non-responders was calculated by receiver-operating characteristic (ROC) analysis. RESULTS: The results of a retrospective cohort of patients with rheumatic diseases (n = 82) correlated with their therapeutic responses to the different TNFi with 89.5% accuracy. The assay predicted the responses of a prospective cohort (n = 54) to specific TNFi with 79% accuracy. CONCLUSION: This functional assay could assist in predicting the odds for response to TNFi therapy, indicating whether a given patient is likely to respond to a specific TNFi.

Sex differences in patient-reported outcomes and the association with clinical factors in axial spondyloarthritis patients treated with tumour necrosis factor inhibitors.

OBJECTIVES: To investigate sex differences in patient-reported outcome measures (PROMs) among axSpA patients initiating their first TNFi and identify factors contributing to these disparities over the follow-up. METHODS: Data were included from 15 EuroSpA registries and consisted of axSpA patients initiating their first TNFi, with ≥2 measurements for each analysed PROM (BASDAI and BASFI, scale 0-100) taken at any time point. Linear mixed models were employed to analyse sex differences in PROMs over 24 months and to evaluate how baseline characteristics were related to the observed sex differences. RESULTS: We analysed 13 102 (38% women) in the BASDAI analyses and 10 623 (38% women) in the BASFI analyses. At follow-up, mean sex differences in BASDAI increased from 4.3 units at baseline (95% CI, 3.5-5.1)-8.0 (7.2-8.8) at 6 months, and in BASFI from 2.2 (1.4-3.1)-4.6 (3.6-5.5), with consistently worse scores in women. Baseline characteristics could not substantially account for the observed sex differences over time; however, the magnitude of the sex differences was reduced by HLA-B27 positivity, longer disease duration, and increased CRP levels, but increased by TNFi initiation in later years and peripheral arthritis. CONCLUSION: In axSpA patients initiating their first TNFi, baseline sex differences in BASDAI and BASFI increased two-fold after 6 months of treatment and persisted thereafter, with worse scores in women. Several baseline characteristics moderated the sex differences, though none could fully account for them. These findings improve our understanding of sex differences and underscore their importance in axSpA.

"Long-term MRI findings in Ankylosing spondylitis patients treated with TNF inhibitors for a decade".

OBJECTIVE: This study aims to evaluate the active and chronic lesions in sacroiliac joints and lumbar spine over a decade of TNFi therapy in patients with AS. METHODS: The study enrolled patients with AS under treatment with a TNFi for over a decade. The patients underwent a new MRI scan of their lumbar spine and sacroiliac joint (SIJ). Two readers evaluated all images. Inflammation of SIJ (SIS), SIJ structural damage (SSS) including Fat Metaplasia, Erosions, Backfill and Ankylosis, and Spondyloarthritis Research Consortium of Canada Bone marrow edema (SPARCC) spine score were recorded. RESULTS: In the study, 15 patients were included, with 80% being male. The mean age during their first MRI was 38.1 (± 11.9) years old, and the majority (86.7%) tested positive for HLA-B27. While TNFi improved both BASDAI and BASFI scores, there was a noticeable increase in MRI acute lesions in the SIJ over time, where the median score increased from 0 (0-4) to 3 (0-10) after ten years (p = 0.028). After a decade of treatment, the median SPARCC spine score also increased from 0 (0-9) to 5 (0-16), p = 0.093. Finally, it was observed that there was a significant positive correlation between ESR and SIS erosions in cases of chronic lesions (r = 0.819, p < 0.001). CONCLUSIONS: While TNFi have significantly improved the treatment of AS, this study shows that acute lesions can still develop despite treatment. A personalized approach that adapts MRI assessment to each patient's specific requirements may help detect changes early and enable doctors to intervene promptly to prevent further damage.

Janus kinase inhibitors versus tumor necrosis factor inhibitors in rheumatoid arthritis: meta-analytical comparison of efficacy and safety.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic systemic autoimmune disorder characterized by persistent inflammation leading to progressively worse disability. Janus kinase (JAK) inhibitors and tumor necrosis factor (TNF) inhibitors are pivotal in RA treatment, yet their comparative efficacy remains underexplored. AIM: This study aimed to compare the efficacy and safety of JAK inhibitors and TNF inhibitors in treating RA using data from randomized controlled trials (RCTs). METHODS: A meta-analysis and outcomes analysis were based on results of the Health Assessment Questionnaire Disability Index (HAQ-DI), Clinical Disease Activity Index (CDAI), Visual Analogue Scale (VAS), and Patient Global Assessment Scale (PtGA) and other indices as incidences of venous thromboembolism (VTE) and malignancy. RESULTS: The JAK inhibitors caused a statistically significant improvement in the HAQ-DI score [MD = 0.08, 95% CI (0.03, 0.12), p = 0.0008] compared with the TNF inhibitors. However, no significant difference was observed between the two drug classes in the CDAI score [MD = - 2.03, 95% CI (- 9.27, 5.22), p = 0.58]. JAK inhibitors were associated with an increase in the VAS score [MD = 3.62, 95% CI (0.86, 6.38), p = 0.01], but there was no significant difference in the PtGA score [MD = 1.91, 95% CI (- 3.25, 7.08), p = 0.47]. CONCLUSION: JAK inhibitors demonstrated superior efficacy in improving the functional status and reducing the disease activity in RA patients compared with TNF inhibitors. Both drug classes exhibited comparable safety profiles for VTE and malignancies, though JAK inhibitors had a higher risk for thromboembolism.

Preexisting Autoimmunity Is Associated With Increased Severity of Coronavirus Disease 2019: A Retrospective Cohort Study Using Data From the National COVID Cohort Collaborative (N3C).

BACKGROUND: Identifying individuals with a higher risk of developing severe coronavirus disease 2019 (COVID-19) outcomes will inform targeted and more intensive clinical monitoring and management. To date, there is mixed evidence regarding the impact of preexisting autoimmune disease (AID) diagnosis and/or immunosuppressant (IS) exposure on developing severe COVID-19 outcomes. METHODS: A retrospective cohort of adults diagnosed with COVID-19 was created in the National COVID Cohort Collaborative enclave. Two outcomes, life-threatening disease and hospitalization, were evaluated by using logistic regression models with and without adjustment for demographics and comorbidities. RESULTS: Of the 2 453 799 adults diagnosed with COVID-19, 191 520 (7.81%) had a preexisting AID diagnosis and 278 095 (11.33%) had a preexisting IS exposure. Logistic regression models adjusted for demographics and comorbidities demonstrated that individuals with a preexisting AID (odds ratio [OR], 1.13; 95% confidence interval [CI]: 1.09-1.17; P < .001), IS exposure (OR, 1.27; 95% CI: 1.24-1.30; P < .001), or both (OR, 1.35; 95% CI: 1.29-1.40; P < .001) were more likely to have a life-threatening disease. These results were consistent when hospitalization was evaluated. A sensitivity analysis evaluating specific IS revealed that tumor necrosis factor inhibitors were protective against life-threatening disease (OR, 0.80; 95% CI: .66-.96; P = .017) and hospitalization (OR, 0.80; 95% CI: .73-.89; P < .001). CONCLUSIONS: Patients with preexisting AID, IS exposure, or both are more likely to have a life-threatening disease or hospitalization. These patients may thus require tailored monitoring and preventative measures to minimize negative consequences of COVID-19.

Large-scale real-world data analyses of cancer risks among patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) affects 24.5 million people worldwide and has been associated with increased cancer risks. However, the extent to which the observed risks are related to the pathophysiology of rheumatoid arthritis or its treatments is unknown. Leveraging nationwide health insurance claims data with 85.97 million enrollees across 8 years, we identified 92 864 patients without cancers at the time of rheumatoid arthritis diagnoses. We matched 68 415 of these patients with participants without rheumatoid arthritis by sex, race, age and inferred health and economic status and compared their risks of developing all cancer types. By 12 months after the diagnosis of rheumatoid arthritis, rheumatoid arthritis patients were 1.21 (95% confidence interval [CI] [1.14, 1.29]) times more likely to develop any cancer compared with matched enrollees without rheumatoid arthritis. In particular, the risk of developing lymphoma is 2.08 (95% CI [1.67, 2.58]) times higher in the rheumatoid arthritis group, and the risk of developing lung cancer is 1.69 (95% CI [1.32, 2.13]) times higher. We further identified the five most commonly used drugs in treating rheumatoid arthritis, and the log-rank test showed none of them is implicated with a significantly increased cancer risk compared with rheumatoid arthritis patients without that specific drug. Our study suggested that the pathophysiology of rheumatoid arthritis, rather than its treatments, is implicated in the development of subsequent cancers. Our method is extensible to investigating the connections among drugs, diseases and comorbidities at scale.

A Cohort Study on Deficiency of ADA2 from China.

PURPOSE: Deficiency of adenosine deaminase 2 (DADA2), an autosomal recessive autoinflammatory disorder caused by biallelic loss-of-function variants in adenosine deaminase 2 (ADA2), has not been systemically investigated in Chinese population yet. We aim to further characterize DADA2 cases in China. METHODS: A retrospective analysis of patients with DADA2 identified through whole exome sequencing (WES) at seventeen rheumatology centers across China was conducted. Clinical characteristics, laboratory findings, genotype, and treatment response were analyzed. RESULTS: Thirty patients with DADA2 were enrolled between January 2015 and December 2021. Adenosine deaminase 2 enzymatic activity was low in all tested cases to confirm pathogenicity. Median age of disease presentation was 4.3 years and the median age at diagnosis was 7.8 years. All but one patient presented during childhood and two subjects died from complications of their disease. The patients most commonly presented with systemic inflammation (92.9%), vasculitis (86.7%), and hypogammaglobinemia (73.3%) while one patient presented with bone marrow failure (BMF) with variable cytopenia. Twenty-three (76.7%) patients were treated with TNF inhibitors (TNFi), while two (6.7%) underwent hematopoietic stem cell transplantation (HSCT). They all achieved clinical remission. A total of thirty-nine ADA2 causative variants were identified, six of which were novel. CONCLUSION: To establish early diagnosis and improve clinical outcomes, genetic screening and/or testing of ADA2 enzymatic activity should be performed in patients with suspected clinical features. TNFi is considered as first line treatment for those with vascular phenotypes. HSCT may be beneficial for those with hematological disease or in those who are refractory to TNFi.

Second and third TNF inhibitors in European patients with axial spondyloarthritis: Effectiveness and impact of the reason for switching.

OBJECTIVE: To investigate real-world effectiveness of tumor necrosis factor inhibitors (TNFi) in patients with axial spondyloarthritis (axSpA) and the association with 1) treatment line (second and third TNFi-series) and 2) reason for withdrawal from the preceding TNFi (lack of efficacy (LOE) versus adverse events (AE)). METHODS: Prospectively collected routine care data from 12 European registries were pooled. Rates for 12-month drug retention and 6-month remission (Ankylosing Spondylitis Disease Activity Score C-reactive protein inactive disease (ASDAS-ID)) were assessed in second and third TNFi-series and stratified by withdrawal reason. RESULTS: We included 8254 s and 2939 third TNFi-series; 12-month drug retention rates were similar (71%). Six-month ASDAS-ID rates were higher for the second (23%) than third TNFi (16%). Twelve-month drug retention rates for patients withdrawing from the preceding TNFi due to AE versus LOE were similar for the second (68% and 67%) and third TNFi (both 68%), while for the second TNFi, rates were lower in primary than secondary non-responders (LOE < 26 versus ≥26 weeks) (58% versus 71%, p< 0.001). Six-month ASDAS-ID rates for the second TNFi were higher if the withdrawal reason was AE (27%) versus LOE (17%), p< 0.001, while similar for the third TNFi (19% versus 13%, p= 0.20). CONCLUSION: A similar proportion of axSpA patients remained on a second and third TNFi after one year, but with low remission rates for the third TNFi. Remission rates on the second TNFi (but not the third) were higher if the withdrawal reason from the preceding TNFi was AE versus LOE.

Adalimumab serum levels and anti-drug antibodies: associations to treatment response and drug survival in inflammatory joint diseases.

OBJECTIVES: To explore associations between serum adalimumab level, treatment response and drug survival in order to identify therapeutic drug levels for therapeutic drug monitoring of adalimumab. Also, to assess occurrence and risk factors of anti-drug antibody (ADAb) formation. METHODS: Non-trough adalimumab and ADAb levels were measured by automated fluorescence assays in serum collected after 3 months of adalimumab treatment in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) or axial spondyloarthritis (axSpA) included in the observational NOR-DMARD study. Treatment response was evaluated after 3 months, and drug survival during long-term follow-up. RESULTS: In 340 patients (97 RA, 69 PsA, 174 axSpA), median adalimumab level was 7.3 mg/l (IQR 4.0-10.3). 33 (10%) patients developed ADAb. Findings were comparable across diagnoses. In RA and PsA, adalimumab levels ≥6.0 mg/l were associated with treatment response (Odds Ratio [OR] 2.2 [95% CI 1.0, 4.4]) and improved drug survival (Hazard Ratio [HR] 0.49 [0.27, 0.80]). In axSpA, a therapeutic level could not be identified, but higher adalimumab levels were associated with response. Factors associated with ADAb formation were previous bDMARD use, no methotrexate comedication and use of adalimumab originator compared with GP2017. CONCLUSION: Higher adalimumab levels were associated with better response and improved drug survival for all diagnoses, with a suggested lower threshold of 6.0 mg/l for RA/PsA. This finding, the large variability in drug levels among patients receiving standard adalimumab dose, and the high proportion of patients developing ADAb, encourages further investigations into the potential role of therapeutic drug monitoring of adalimumab.

Immunogenicity 6 months post COVID-19 mRNA vaccination among adolescents with juvenile idiopathic arthritis on treatment with TNF inhibitors.

OBJECTIVES: Mass vaccination is the most effective strategy for controlling the COVID-19 pandemic. This study aimed to evaluate the 6-month immunogenicity after BNT162b2-COVID-19 vaccination in adolescents with JIA on TNFi treatment. METHODS: This single-centre study included adolescents with JIA treated with TNFi for at least 18 months. Patients received two doses of COVID-19 vaccine (Pfizer-BioNTech) from 15 April to 15 May 2021. Quantitative measurement of IgG antibodies to SARS-CoV-2-spike-protein-1 was performed at 1, 3 and 6 months post-vaccination. RESULTS: Overall, 21 adolescents with JIA in clinical remission at the time of vaccinations were enrolled. None of them discontinued TNFi/MTX treatment at the time of vaccine administration or during the follow-up period. All patients developed a sustained humoral response against SARS-CoV-2 at 1 and 3 months after vaccination (P < 0.05). The antibody levels decreased significantly at 6 months post-vaccination (P < 0.01). The type of JIA did not reveal any differences in the humoral response at 3 (P = 0.894) or 6 months post-vaccination (P = 0.72). No difference was detected upon comparison of the immunogenicity between the different treatment arms (adalimumab vs etanercept) at 3 (P = 0.387) and 6 months (P = 0.526), or TNFi monotherapy vs combined therapy (TNFi plus methotrexate) at 3 (P = 0.623) and 6 months (P = 0.885). CONCLUSIONS: Although mRNA vaccines develop satisfactory immunogenicity at 1 month and 3 months post-vaccination in adolescents with JIA on TNFi, SARS-CoV-2 antibody titres decrease significantly overtime, remaining at lower levels at 6 months. Further collaborative studies are required to determine long-term immunogenicity, real duration of immune protection and the need for a booster vaccine dose.

Effectiveness of biological targeted therapies may discriminate seronegative from seropositive rheumatoid arthritis.

OBJECTIVE: To assess the real-world effectiveness of targeting biologic drugs (bDMARD) in rheumatoid arthritis (RA) patients negative for rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA). METHODS: We retrospectively selected 81 seronegative and 404 seropositive RA patients receiving treatment with abatacept, anti-tumor necrosis factor (TNF) alpha, or tocilizumab. Effectiveness was evaluated by analyzing drug survival using Kaplan-Meyer analysis over 10-year follow-up. Survival rates were compared by log rank test, and hazard ratios (HRs) of therapy discontinuation were estimated through multivariate Cox-regression. RESULTS: Clinical characteristics were similar between the two groups, except for a significantly higher percentage of inadequate responders to prior bDMARDs in the seronegative RA patients (p= 0.02). Among seronegative RA, tocilizumab demonstrated a survival rate of 73.9% with a mean survival time (MST) of 76.8 months (95% CI 61-92), which was significantly higher than abatacept (37.5%, MST 37.1 months (95% CI 22-51; p= 0.01). Anti-TNF alpha therapy fell in the middle (50.0%, MST 63.5 months (95% CI 47-79) but the difference was not significant. Nevertheless, seropositive RA patients did not show significantly different drug survival rates. Negative predictors of drug discontinuation were RF/ACPA positivity (HR 0.56) and sex male (HR 0.58), but treatment with abatacept (HR 1.88) or anti-TNF alpha (HR 1.79), no co-therapy with cDMARD (HR 1.74), absence of bone erosions (HR 1.41), and higher HAQ (HR 1.58) were positive predictors. CONCLUSIONS: To confirm these preliminary findings and to explore the hypothesis of a distinctive therapeutic algorithm in seronegative RA, prospective studies on larger cohorts are needed.

Sex-oriented perspectives in immunopharmacology.

Several immunopharmacological agents are effective in the treatment of cancer and immune-mediated conditions, with a favorable impact on life expectancy and clinical outcomes for a large number of patients. Nevertheless, response variation and undesirable effects of these drugs represent major issues, and overall efficacy remains unpredictable. Males and females show a distinct difference in immune system responses, with females generally mounting stronger responses to a variety of stimuli. Therefore, exploring sex differences in the efficacy and safety of immunopharmacological agents would strengthen the practice of precision medicine. As a pharmacological target highlight, programmed cell death 1 ligand 1 (PD-L1) is the first functionally characterized ligand of the coinhibitory programmed death receptor 1 (PD-1). The PD-L1/PD-1 crosstalk plays an important role in the immune response and is relevant in cancer, infectious and autoimmune disease. Sex differences in the response to immune checkpoint inhibitors are well documented, with male patients responding better than female patients. Similarly, higher efficacy of and adherence to tumor necrosis factor inhibitors in chronic inflammatory conditions including rheumatoid arthritis and Crohn's disease have been reported in male patients. The pharmacological basis of sex-specific responses to immune system modulating drugs is actively investigated in other settings such as stroke and type 1 diabetes. Advances in therapeutics targeting the endothelium could soon be wielded against autoimmunity and metabolic disorders. Based on the established sexual dimorphism in immune-related pathophysiology and disease presentation, sex-specific immunopharmacological protocols should be integrated into clinical guidelines.

Application value of tumor necrosis factor inhibitors in in vitro fertilization-embryo transfer in infertile women with polycystic ovary syndrome.

BACKGROUND: Clinical value of tumor necrosis factor (TNF) inhibitors in in vitro fertilization-embryo transfer (IVF-ET) in infertile women with polycystic ovary syndrome (PCOS) was investigated in this study. METHODS: A retrospective analysis was performed on the clinical data of 100 PCOS patients who received IVF-ET for the first time at Hebei Institute of reproductive health science and technology from January 2010 to June 2020. The patients were divided into Inhibitor group and Control group according to whether they were treated with or without TNF inhibitors. Next, the two groups were subject to comparison in terms of the days of gonadotropin (Gn) use, total dosage of Gn, trigger time, hormone level and endometrial condition on the day of human chorionic gonadotropin (HCG) injection, the effects of two different regimens on controlled ovarian hyperstimulation (COH) and pregnancy outcomes. RESULTS: There were no significant differences in baseline characteristics between the two groups, including age, duration of infertility, body mass index (BMI), ovarian volume, antral follicle count, and basal hormone levels. Compared with the Control group, the days of Gn use and trigger time of patients in the Inhibitor group were significantly shortened, and the total Gn dosage was notably reduced. In terms of sex hormone levels on the HCG injection, the Inhibitor group displayed much lower serum estradiol levels while higher serum luteinizing hormone and progesterone (P) levels than the Control group. Notably, the high-quality embryo rate was also significantly increased with the use of TNF inhibitors. However, significant differences were not observed in endometrial thickness (on the day of HCG injection), proportion of endometrial A, B and C morphology (on the day of HCG injection), cycle cancellation rate, number of oocytes retrieved, fertilization rate, and cleavage rate between the two groups. Importantly, the clinical pregnancy rate in the Inhibitor group was significantly higher than that in the Control group, but there was no significant difference in the biochemical pregnancy rate, early abortion rate, multiple birth rate, ectopic pregnancy rate and number of live births between the two groups. CONCLUSION: Collectively, after application of TNF-α inhibitor regimen, superior overall treatment effect can be observed in infertile PCOS patients receiving IVF-ET. Therefore, TNF inhibitors have certain application value in IVF-ET in infertile women with PCOS.

TNFα inhibitor biosimilar associated with polychondritis. A case-based review.

Relapsing polychondritis (RP) is a rare autoimmune disease characterized by inflammation of the cartilage structures of the body with typical features of auricular chondritis, nasal and ocular inflammation, audio-vestibular damage, as well as respiratory tract manifestations. It is associated with several autoimmune diseases and many other disorders. Tumor necrosis factor alpha (TNFα) inhibitors treat many chronic inflammatory disorders. They have proven effective and relatively safe in many clinical trials and observational studies. However, several autoimmune phenomena and paradoxical inflammation have been described with TNFα inhibitors, among them RP. This report presents a 43-year-old man with psoriatic arthritis treated with ABP-501 (Amgevita), an adalimumab (ADA) biosimilar and who developed RP, 8 months after the initiation of the treatment. This, is the first report of RP development during TNFα inhibitors biosimilar. We concluded that rheumatologists dealing with patients treated with TNFα inhibitors (originators or biosimilars), should be aware of several paradoxical reactions which may emerge and RP, is one of them.

Complete disappearance of pulmonary rheumatoid nodules after long term rituximab treatment: case report.

The natural history of pulmonary rheumatoid nodules in rheumatoid arthritis remains uncertain. We present a case of a patient with rheumatoid arthritis with pulmonary rheumatoid nodules diagnosed while receiving etanercept in whom pulmonary nodules resolved completely after 5 years of rituximab treatment. Rituximab has been evaluated in case series of patients with pulmonary rheumatoid nodules, resulting in most cases in no progression or a reduction in the size of the nodules, although the complete resolution is uncommon probably due to the short follow-up period. Complete disappearance of pulmonary rheumatoid nodules may be expected after long-term treatment with rituximab.