Tumor Necrosis Factor-α Inhibitor Treatment Research Articles

Tumor necrosis factor-α inhibitor treatment of acne fulminans - a clinical and literature review.

Acne fulminans (AF) is a rare, serious, sudden-onset and long-lasting skin disease that causes scarring of face and body. Standard treatment with combined long-term isotretinoin and prednisolone is not always sufficient and has a well-known propensity for adverse effects leaving an unmet need for improved therapy. Case reports suggest that tumor necrosis factor (TNF)-α inhibitors may play a role in the management of AF. In a 3-year retrospective data collection from two dermatology centers and literature review of clinical cases of acne fulminans treated with anti-TNF-α therapy, three clinical cases and twelve literature cases were identified. A total of five different TNF-α inhibitors have been tested, with adalimumab being the most commonly used. Clinical response was seen after 1month in 2/3 (67%) clinical cases and 5/12 (42%) literature cases, respectively, and treatment was successful in 2/3 (67%) and 11/12 (92%) after a median 3-7months. All reported adverse effects were mild and reversible. Anti-TNF-α treatment may provide rapid improvement in patients with AF when initial treatment with isotretinoin and prednisolone fails. However, randomized controlled trials are lacking, and exact dosage and timing need to be explored before clinical implementation.

The impact of smoking on response to tumor necrosis factor-α inhibitor treatment in patients with ankylosing spondylitis.

To investigate the impact of smoking on disease activity, treatment retention, and response in patients with ankylosing spondylitis (AS) treated with their first tumor necrosis factor-α inhibitor (TNFi). AS patients who started their first TNFi treatment for the active axial disease (BASDAI ≥ 4) from TURKBIO Registry were included. Treatment response of smoker (current and ex-smokers) and nonsmoker (never smoker) patients were primarily evaluated as achievement of BASDAI50 or improvement in BASDAI at least 20 mm at 3 months and 6 months compared to baseline. There were 322 patients with AS (60% male, 59% smoker, mean age: 38.3 years). The median follow-up time was 2.8 years (Q1- Q3: 1.3-3.8), and disease duration was 3.5 years (Q1-Q3: 0.7-8.2). Smokers had male predominance (p < 0.001), lower ESR (p = 0.03), higher BASDAI (p = 0.02), BASFI (p = 0.05), HAQ-AS (p = 0.007), and ASDAS-CRP (p = 0.04) compared with nonsmokers at baseline. In the multivariate analysis, male gender [OR 2.7 (95%CI 1.4-5), p = 0.002], and concomitant conventional synthetic disease-modifying antirheumatic drug use [OR 2.4 (95%CI 1.1-5.2), p = 0.03] were associated with better treatment response. There was an association of male gender [HR 2.4 (95%CI 1.6-3.7), p < 0.001], older age (≥30years) [HR 1.8 (95%CI 1.1-2.8), p = 0.01], and response to treatment [HR 1.8 (95%CI 1.2-2.9), p = 0.008] with better treatment retention. No impact of smoking status was found on treatment retention and response in univariate and multivariate analyses. This study suggested that smoking was associated with poorer patient-reported outcomes in biologic naïve AS patients initiating their first TNFi treatment, but it had no impact on the TNFi treatment response and retention rate.

Absolute and Relative Risk of New-Onset Psoriasis Associated With Tumor Necrosis Factor-α Inhibitor Treatment in Patients With Immune-Mediated Inflammatory Diseases

Tumor necrosis factor-α inhibitor (TNFi)-associated psoriasis is a rare adverse event following TNFi treatment. Data on the risk of developing TNFi-associated psoriasis when treated with TNFi are sparse. To investigate the associated risk between new-onset psoriasis and TNFi treatment compared with nonbiologic conventional treatment. Using Danish national registries (1995-2018), this cohort study included patients with inflammatory bowel disease (IBD) and/or rheumatoid arthritis (RA) who received either conventional therapy or TNFi treatment. Patients may not have been diagnosed with psoriasis prior to initiation of treatment. Patients were followed up for up to 5 years. Cox regression models with robust variance were used to compare the risk of developing any type of psoriasis, nonpustular psoriasis, and pustular psoriasis. Patients receiving conventional therapy were used as reference. Data analysis was performed from January 1995 to December 2018. For the present study, the term conventional therapy was used for the nonbiological therapy. For biological therapy, a distinction was made between TNFi treatment and non-TNFi biological therapy. The outcome of psoriasis was defined as a registered International Statistical Classification of Diseases and Related Health Problems, Tenth Revision code of psoriasis and/or having 2 consecutive prescriptions of topical vitamin D analogues. The study included 109 085 patients, of which 62% were female. Median (IQR) age was 50 (34-64) years. Of the included patients, 108 024 received conventional therapy and 20 910 received TNFi treatment. During follow-up, 1471 (1.4%) patients developed any type of psoriasis, of which 1332 developed nonpustular psoriasis, 127 patients developed palmoplantar pustulosis, and 12 patients developed generalized pustulosis. The incidence rates for developing any type of psoriasis per 1000 patient-years were 3.0 (95% CI, 2.9-3.2) for conventional therapy and 7.8 (95% CI, 7.5-8.9) for TNFi. During treatment with TNFi, the hazard ratio was 2.12 (95% CI, 1.87-2.40; P < .001) for developing nonpustular psoriasis and 6.50 (95% CI, 4.60-9.23; P < .001) for pustular psoriasis compared with conventional treatment. Exposure needed for 1 additional patient to be harmed was 241 patient-years for any type of TNFi-associated psoriasis, 342 patient-years for nonpustular psoriasis, and 909 patient-years for pustular psoriasis. In a Danish nationwide cohort of patients with immune-mediated inflammatory diseases treated with TFNi or conventional treatment and no history of psoriasis, in TFNi-treated patients, nonpustular types of psoriasis constituted the most events, whereas pustular types of psoriasis had the highest relative risk. Although the risk of new-onset psoriasis increased for both nonpustular and pustular types of psoriasis in TFNi-treated patients, the absolute risk remained modest at 241 patient-years of exposure need for 1 additional event and an estimated absolute risk difference around 5 per 1000 patient-years, indicating that the approach to treatment of patients in need of TNFi treatment should not change.

Relapse of ankylosing spondylitis and its predictors after withdrawal of tumor necrosis factor-α inhibitors: a 52-week follow-up study

To investigate the recurrence of ankylosing spondylitis (AS) that has been relieved by standard-dose adalimumab (ADA) after dose reduction or withdrawal of tumor necrosis factor-α inhibitor (TNFi) and explore the factors that predict AS occurrence. This study was conducted among 63 patients with AS who reduced the dose of or discontinued TNFi after completing at least 12 treatment cycles with ADA (40 mg/2 weeks) to achieve ASAS20 improvement with a BATH disease activity index (BASDAI) < 4 for more than 8 weeks. The patients were followed up every 12 weeks for a total of 52 weeks, and the recurrence of AS, changes of BASDAI, C-reactive protein (CRP)-based disease activity score (ASDASCRP), low back pain (LBP) score, Bath Ankylosing Spondylitis Metrology Index (BASMI), CRP and ESR were recorded and analyzed. Cox regression model and ROC curve analyses were performed to analyze the risk factors of AS relapse after dose reduction or discontinuation of TNFi. Of the 63 patients enrolled, 57 completed the follow-up study, among whom 22 (38.6%) patients experienced AS relapse within 52 weeks, with a median clinical recurrence time of 31 weeks. The recurrence rate of AS was significantly higher in patients with complete withdrawal of medications (89.0%) than in those with TNFi dose reduction and TNFi discontinuation (P < 0.001), and did not differ significantly between the latter two groups of patients (χ2= 0.071, P=0.791). The Cox regression model showed that a high baseline LBP score (HR=1.438, P=0.027) and a high BASMI score (HR=1.29, P=0.049) were the risk factors for AS recurrence after TNFi dose reduction or discontinuation, while maintenance of medication during follow-up was a protective factor (HR=0.209, P=0.001). ROC curve analysis showed that the combination of baseline LBP score, BASMI and medication during follow-up had a good predictive value for AS relapse (AUC=0.819) with a sensitivity of 0.772 and a specificity of 0.718. Dose reduction or discontinuation of TNFi is associated with a high recurrence rate of AS that has been relieved by TNFi treatment. A high LBP score, a high BASMI score and discontinuation of maintenance medication are the risk factors for AS recurrence in patients after dose reduction or withdrawal of TNFi.

Serum anti-Müllerian hormone levels in women with rheumatoid arthritis during tumor necrosis factor-α inhibitor treatment: Exploratory research

We evaluated serum anti-Müllerian hormone in women with rheumatoid arthritis newly introduced to tumor necrosis factor-α inhibitor treatment for 54 weeks to investigate the treatment's effect on ovarian reserve. A total of 12 premenopausal women with rheumatoid arthritis aged 20-50 years were recruited at our division, who had been newly treated with tumor necrosis factor-α inhibitor (infliximab or etanercept) from 1 April 2008 to 31 March 2014. Serial serum anti-Müllerian hormone levels and disease activity scores (DAS28-CRP) were examined at defined periods: start of treatment and 14, 30, and 54 weeks after start of treatment. DAS28-CRP scores in 12 women were significantly decreased from a mean of 4.6 (±SD: 0.4) to 2.3 (±0.4) after 54 weeks of treatment (p < 0.001). Serum anti-Müllerian hormone levels and its z scores did not change significantly. Treatment with a tumor necrosis factor-α inhibitor did not affect serum anti-Müllerian hormone levels in 12 women with rheumatoid arthritis during 54-week treatment.

Reduced Occurrence Rate of Acute Anterior Uveitis in Ankylosing Spondylitis Treated with Golimumab - The GO-EASY Study.

Acute anterior uveitis (AAU) is common in ankylosing spondylitis (AS). Golimumab (GOL), a tumor necrosis factor-α inhibitor (TNFi), has proven to be effective in the treatment of AS. To date, the effect of GOL on the incidence of AAU in AS is unknown. The objective was to study the AAU occurrence rate in patients with AS during GOL treatment and secondarily, the efficacy of GOL in daily clinical practice. The study was a multicenter prospective study in a real-world setting in patients with AS who were treated with GOL for 12 months. The occurrence of AAU was assessed in the year before the initial TNFi treatment and during GOL treatment and calculated for the period at risk for a new AAU. Measures for disease activity [Ankylosing Spondylitis Disease Activity Score (ASDAS)] and treatment response [Assessment of Spondyloarthritis international Society (ASAS20 score)] were collected. In total, 93 patients (65% male, 55% TNFi-naive, 27% history of AAU) were included, with a median disease duration of 7 years and ASDAS score of 3.1. During GOL treatment, the AAU occurrence rate was reduced from 11.1 to 2.2 per 100 patient-years (rate-ratio 0.20, 95% CI 0.04-0.91). After 3 months of treatment, 41% of the patients experienced a clinically important improvement of the ASDAS score (p < 0.001) and 36% an ASDAS20 response (p < 0.001). At month 12, 49% had achieved an ASAS20 response (p < 0.001). In AS, the AAU occurrence rate and disease activity decreased significantly during GOL treatment. Therefore, GOL can be considered a good choice in patients with AS who need a TNFi, especially in cases of recurrent AAU. (EudraCT number: 2012-002458-21).

The effect of extra-articular manifestations on tumor necrosis factor-α inhibitor treatment duration in patients with ankylosing spondylitis: nationwide data from the Korean College of Rheumatology BIOlogics (KOBIO) registry.

Tumor necrosis factor-α inhibitor (TNFi) therapy has shown to be remarkably effective for treating ankylosing spondylitis (AS); however, nearly 30% of AS patients every year either stop TNFi therapy or switch to a different TNFi due to inefficacy or adverse effects. The goal of this study was to identify predictors of TNFi treatment duration, including extra-articular manifestations, using a nationwide registry in Korea. Data obtained from the Korean College of Rheumatology Biologics (KOBIO) registry, a nationwide, multi-center database representing 58 tertiary care hospitals in Korea. Demographics, clinical features, laboratory findings, disease activity indices (BASDAI, ASDAS-ESR, ASDAS-CRP), peripheral arthritis, and extra-articular manifestations (uveitis, enthesitis, dactylitis, psoriasis, and inflammatory bowel disease) were studied in patients with AS during TNFi therapy. We also analyzed treatment duration outcomes for five TNFi agents (etanercept, infliximab, infliximab biosimilar, adalimumab, and golimumab), as well as factors associated with treatment duration, particularly in terms of extra-articular manifestations. Univariable and multivariable Cox regression analyses were performed to verify preliminary results. A total 1482 AS patients starting TNFi drug therapy between Dec. 2012 and Jan. 2017 were included. No differences in demographics, disease activity, or extra-articular manifestations were evident between continued and discontinued TNFi groups at baseline, though baseline differences were detected for gender distribution, CRP, platelet counts, and HLA-B27 positivity. During treatment period, the effects of extra-articular manifestations, including uveitis (unadjusted hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.57 to 1.48, p = 0.74), enthesitis, dactylitis, psoriasis, and inflammatory bowel disease, on TNFi treatment duration were not statistically significant. By contrast, the occurrence of peripheral arthritis was significantly associated with shorter TNFi treatment duration (unadjusted HR 2.21, 95% CI 1.66 to 2.95; adjusted HR 1.38, 95% CI 1.01 to 1.88). Among disease activity indices, higher ASDAS-ESR levels were significantly associated with shortening of the TNFi treatment duration (unadjusted HR 1.87, 95% CI 1.73 to 2.03; adjusted HR 2.23, 95% CI 2.00 to 2.63). Among TNFi drugs, golimumab had a lower discontinuation rate than that of etanercept over a 3-year follow-up period (unadjusted HR 0.46, 95% CI 0.31 to 0.68; adjusted HR 0.65, 95% CI 0.43 to 0.99). In a nationwide KOBIO registry, extra-articular manifestations, including uveitis, were not associated with TNFi treatment duration. Among clinical cofactors, the development of peripheral arthritis during TNFi therapy was associated with a higher risk of TNFi treatment discontinuance in AS patients.

Cardiovascular event risk assessment in psoriasis patients treated with tumor necrosis factor-α inhibitors versus methotrexate

Psoriasis is associated with increased risk for cardiovascular disease. To compare major cardiovascular event risk in psoriasis patients receiving methotrexate or tumor necrosis factor-α inhibitor (TNFi) and to assess TNFi treatment duration impact on major cardiovascular event risk. Adult psoriasis patients with ≥2 TNFi or methotrexate prescriptions in the Truven MarketScan Databases (Q1 2000-Q3 2011) were classified as TNFi or methotrexate users. The index date for each of these drugs was the TNFi initiation date or a randomly selected methotrexate dispensing date, respectively. Cardiovascular event risks and cumulative TNFi effect were analyzed by using multivariate Cox proportional-hazards models. By 12months, TNFi users (N=9148) had fewer cardiovascular events than methotrexate users (N=8581) (Kaplan-Meier rates: 1.45% vs 4.09%: P<.01). TNFi users had overall lower cardiovascular event hazards than methotrexate users (hazard ratio=0.55; P<.01). Over 24months' median follow-up, every 6months of cumulative exposure to TNFis were associated with an 11% cardiovascular event risk reduction (P=.02). Lack of clinical assessment measures. Psoriasis patients receiving TNFis had a lower major cardiovascular event risk compared to those receiving methotrexate. Cumulative exposure to TNFis was associated with a reduced risk for major cardiovascular events.

Chondrocyte activity is increased in psoriatic arthritis and axial spondyloarthritis.

BackgroundPsoriatic arthritis (PsA) and axial spondyloarthritis (axSpA) are chronic inflammatory rheumatic diseases with complex origins. Both are characterized by altered extracellular matrix remodeling in joints and entheses that results in destructive and osteochondral proliferative lesions. There is a need for biomarkers reflecting core disease pathways for diagnosis and disease mapping. Pro-C2 reflects mature cartilage collagen type IIB formation, while C-Col10 represents turnover of type X collagen, which is exclusively expressed by hypertrophic chondrocytes. The objectives of this study were to study cartilage metabolism in axSpA and PsA by assessing Pro-C2 and C-Col10 and to evaluate their diagnostic utility against a healthy reference population.MethodsPatients with PsA (n = 101) or axSpA (n = 110) were recruited consecutively from three rheumatology outpatient clinics. Demographic and clinical disease measures were recorded. Pro-C2 and C-Col10 were quantified in serum by using newly developed and specific competitive enzyme-linked immunosorbent assays based on monoclonal antibodies. One-way analysis of variance and Tukey’s multiple comparison tests were performed on log-transformed data. ROC curve analysis was carried out to evaluate their discriminative power.ResultsPro-C2 levels in serum were significantly increased in both axSpA (median concentration 1.11 ng/ml, 0.67–1.64) and PsA (median concentration 1.03 ng/ml, 0.53–1.47) compared with healthy controls (median concentration 0.30 ng/ml, 0.16–0.41) (p < 0.0001). Pro-C2 did not differ according to treatment. C-Col10 was slightly but equally elevated in the PsA and axSpA groups vs. the control group, but it was significantly lower in patients with axSpA undergoing tumor necrosis factor-α inhibitor (TNFi) treatment. ROC curve analysis revealed AUCs of 0.85 (95 % CI 0.79–0.89) for axSpA and 0.81 (95 % CI 0.75–0.86) for PsA.ConclusionsThese findings indicate that cartilage collagen metabolism was enhanced in the axSpA and PsA groups compared with the healthy control group. The lower C-Col10 level in patients with axSpA undergoing TNFi treatment may reflect that hypertrophic chondrocytes in axSpA are targeted by TNFi. ROC curve analysis showed a diagnostic potential for Pro-C2 in axSpA and PsA.

Adverse Events During Anti-TNFα Therapies in IBD (Excluding Infections and Malignancies): When to Stop, Continue, or Switch Therapies.

There are several adverse events that can occur in the setting of tumor necrosis factor-α inhibitor treatment for inflammatory bowel disease. The most common side effects include infection and malignancy. There are however several less frequent adverse events that can be classified as dermatologic, neurologic, cardiac, and hepatic. The aim of this review was to assist clinicians to recognize and manage these infrequent adverse events that occur during use of tumor necrosis factor-α antagonists.

Hospital Admissions, Biological Therapy, and Surgery in Familial and Sporadic Cases of Inflammatory Bowel Disease: A Population-Based Cohort Study 1977-2011.

Easily accessible predictors of disease course in inflammatory bowel disease (IBD) are scarce, and it remains largely unknown whether a family history of IBD predicts the course of Crohn's disease (CD) and ulcerative colitis (UC). We aimed to compare the course of disease in familial and sporadic cases of IBD in a nationwide cohort study. From national registries, covering a population of 8,295,773 individuals, we obtained information on date and year of diagnosis of IBD cases, gender, age, and family ties. Using Cox regression, we estimated hazard ratios for IBD-related hospitalization, biological treatment, and surgery in familial versus sporadic cases of IBD. A total of 27,886 IBD cases, including 1006 IBD-relative pairs, were followed-up for up to 16 years, totaling 164,979 person-years. We observed no difference in risk of hospital admissions between familial and sporadic cases of IBD. However, patients with familial CD had significantly higher risk of major surgery than sporadic CD cases after 2 years of disease duration (hazard ratio, 1.62; 95% confidence interval, 1.26-2.07). Also, sensitivity analysis suggested a slightly reduced time from diagnosis to first tumor necrosis factor-α inhibitor treatment among familial CD and UC cases as compared with sporadic cases. We found only minor differences in surgery rates and tumor necrosis factor exposure, between familial and sporadic cases of IBD. These findings may represent purely social rather than functional effects, which is consoling for newly diagnosed CD or UC patients with a family history of IBD.

How Qualitative Studies Can Improve the Quality of Clinical Studies

Can qualitative studies improve the quality of clinical studies? Let me answer in the affirmative and outline below five ways in which this is possible, drawing on several excellent textbooks regarding how to perform qualitative research1–6, and on the study that appears in the March 2013 issue of the Journal from Lipstein and colleagues regarding parents’ perceptions of tumor necrosis factor-α inhibitor treatment for their children with either Crohn’s disease or juvenile idiopathic arthritis.7

A prospective study of cigarette smoking and risk of cataract in men

Psoriasis is associated with increased risk for cardiovascular disease.To compare major cardiovascular event risk in psoriasis patients receiving methotrexate or tumor necrosis factor-α inhibitor (TNFi) and to assess TNFi treatment duration impact on major cardiovascular event risk.Adult psoriasis patients with ≥2 TNFi or methotrexate prescriptions in the Truven MarketScan Databases (Q1 2000–Q3 2011) were classified as TNFi or methotrexate users. The index date for each of these drugs was the TNFi initiation date or a randomly selected methotrexate dispensing date, respectively. Cardiovascular event risks and cumulative TNFi effect were analyzed by using multivariate Cox proportional-hazards models.By 12 months, TNFi users (N = 9148) had fewer cardiovascular events than methotrexate users (N = 8581) (Kaplan-Meier rates: 1.45% vs 4.09%: P < .01). TNFi users had overall lower cardiovascular event hazards than methotrexate users (hazard ratio = 0.55; P < .01). Over 24 months' median follow-up, every 6 months of cumulative exposure to TNFis were associated with an 11% cardiovascular event risk reduction (P = .02).Lack of clinical assessment measures.Psoriasis patients receiving TNFis had a lower major cardiovascular event risk compared to those receiving methotrexate. Cumulative exposure to TNFis was associated with a reduced risk for major cardiovascular events.