Tumor Necrosis Factor Inhibitors In Patients Research Articles

Trends in the use of biologic disease-modifying antirheumatic drugs in patients with rheumatoid arthritis and recently diagnosed colorectal, lung, or prostate cancer.

Biologic disease-modifying antirheumatic drugs (bDMARD) are often discontinued when a patient with rheumatoid arthritis (RA) is diagnosed with cancer. Our aim was to determine trends in bDMARD utilization in patients with RA and recently diagnosed cancer. We examined two national claims databases to identify adults with RA and recently diagnosed colorectal, lung, or prostate cancer (Optum's de-identified Clinformatics® Data Mart Database 2008-2022, and Surveillance, Epidemiology, and End Results Program (SEER) Medicare-linked 2008-2017). We determined time trends in bDMARD and tumor necrosis factor inhibitor (TNFi) prescriptions during the first 3years after cancer with Cochram-Armitage tests and multivariable logistic regression. Cancer cohorts were analyzed separately. We included 3595 patients in all six cohorts (in Clinformatics® 503 with colorectal, 468 with lung, and 440 with prostate cancer; in SEER-Medicare 580 with colorectal, 1010 with lung, and 594 with prostate cancer). No significant increase was observed in bDMARD or TNFi utilization over time. Overall, use of bDMARD within the first 3years of follow-up ranged from 16.7% (Clinformatics® lung cohort) to 29.7% (SEER-Medicare colorectal cohort). The major predictor of bDMARD utilization was prior use in the 3months before cancer diagnosis (p < 0.001 for all cancers) and earlier cancer stage (p < 0.001 in colorectal and lung cancer and p = 0.05 in prostate cancer). Use of bDMARD in patients with RA and recently diagnosed common cancers has not increased since 2008. Additional evidence on the safety of bDMARD in patients with early cancer is needed to ensure appropriate management of their RA. Key Points • Use of bDMARD and TNFi in patients with RA and early colorectal, lung, or prostate cancer has been stable since 2008, with no significant increases over time. • The major determinant of receiving bDMARD after cancer diagnosis was prior treatment with bDMARD in the prior 3months before cancer. • Patients with advanced cancer stage and distant metastases were less likely to receive bDMARD and TNFi than those at early stages of disease.

Risk of Venous Thromboembolism With Tofacitinib Versus Tumor Necrosis Factor Inhibitors in Cardiovascular Risk-Enriched Rheumatoid Arthritis Patients.

The ORAL Surveillance trial found a dose-dependent increase in venous thromboembolism (VTE) and pulmonary embolism (PE) events with tofacitinib versus tumor necrosis factor inhibitors (TNFi). We aimed to assess VTE incidence over time and explore risk factors of VTE, including disease activity, in ORAL Surveillance. Patients with rheumatoid arthritis (RA) aged 50 years or older with at least one additional cardiovascular risk factor received tofacitinib 5 or 10 mg twice daily (BID) or TNFi. Post hoc, cumulative probabilities and incidence rates (patients with first events/100 patient-years) by 6-month intervals were estimated for adjudicated VTE, deep vein thrombosis, and PE. Cox regression models identified risk factors. Clinical Disease Activity Index leading up to the event was explored in patients with VTE. Cumulative probabilities for VTE and PE were higher with tofacitinib 10 mg BID, but not 5 mg BID, versus TNFi. Incidence rates were consistent across 6-month intervals within treatments. Across treatments, risk factors for VTE included prior VTE, body mass index greater than or equal to 35 kg/m2, older age, and history of chronic lung disease. At the time of the event, most patients with VTE had active disease as defined by Clinical Disease Activity Index. Incidences of VTE and PE were higher with tofacitinib (10 > 5 mg BID) versus TNFi and were generally consistent over time. Across treatments, VTE risk factors were aligned with previous studies in the general RA population. These data highlight the importance of assessing VTE risk factors, including age, body mass index, and VTE history, when considering initiation of tofacitinib or TNFi in patients with active RA.

Comparative effectiveness of abatacept versus TNF inhibitors in rheumatoid arthritis patients who are ACPA and shared epitope positive

BackgroundThe HLA-DRB1 shared epitope (SE) is a risk factor for the development of rheumatoid arthritis (RA) and the production of anti-citrullinated protein antibodies (ACPAs) in RA patients. Our objective was to examine the real-world effectiveness of abatacept versus tumor necrosis factor inhibitors (TNFi) in patients with RA who were SE and anti-cyclic citrullinated peptide antibody (anti-CCP3) positive.MethodsAbatacept or TNFi initiators who were SE + and anti-CCP3+ (> 20 U/mL) at or prior to treatment and had moderate or high CDAI score (> 10) at initiation were identified. The primary outcome was mean change in CDAI score over six months. Analyses were conducted in propensity score (PS)-trimmed and -matched populations overall and a biologic-experienced subgroup. Mixed-effects models were used.ResultsIn the overall PS-trimmed (abatacept, n = 170; TNFi, n = 157) and PS-matched cohorts (abatacept, n = 111; TNFi, n = 111), there were numerically greater improvements in mean change in CDAI between abatacept and TNFi but were not statistically significant. Similar trends were seen for biologic-experienced patients, except that statistical significance was reached for mean change in CDAI in the PS-trimmed cohort (abatacept, 12.22 [95% confidence interval (95%CI) 10.13 to 14.31]; TNFi, 9.28 [95%CI 7.08 to 11.48]; p = 0.045).ConclusionIn this real world cohort, there were numerical improvements in efficacy outcomes with abatacept over TNFi in patients with RA who were SE + and ACPA+, similar to results from a clinical trial population The only statistically significant finding after adjusting for covariates was greater improvement in CDAI with abatacept versus TNFi in the bio-experienced PS-trimmed cohort..

Haematological malignancies in patients with psoriatic arthritis overall and treated with TNF inhibitors: a Nordic cohort study

ObjectivesTo evaluate the risk of haematological malignancies in patients with psoriatic arthritis (PsA) overall, and in relation to treatment with tumour necrosis factor inhibitors (TNFi).MethodsWe identified that patients with PsA...

Risk of major adverse cardiovascular events with tofacitinib versus tumour necrosis factor inhibitors in patients with rheumatoid arthritis with or without a history of atherosclerotic cardiovascular disease: a post hoc analysis from ORAL Surveillance

ObjectivesEvaluate risk of major adverse cardiovascular events (MACE) with tofacitinib versus tumour necrosis factor inhibitors (TNFi) in patients with rheumatoid arthritis (RA) with or without a history of atherosclerotic cardiovascular...

Efficacy of Abatacept Versus Tumor Necrosis Factor Inhibitors in Anti-citrullinated Protein Antibody-Positive Patients with Rheumatoid Arthritis: Results from a Korean Nationwide Biologics Registry.

Introduction To compare the efficacy of abatacept and tumor necrosis factor inhibitor (TNFi) in patients with anti-citrullinated protein antibody (ACPA)-positive rheumatoid arthritis (RA) and identify those who benefit most from abatacept over TNFi.MethodsThis observational study identified RA patients who were ACPA-positive and initiated abatacept or TNFi from the Korean College of Rheumatology Biologics and Targeted therapy registry. Propensity score (PS) matching was performed to balance baseline confounding in abatacept- or TNFi-treated patients. The major endpoints were changes in Clinical Disease Activity Index (CDAI) and achievement of CDAI remission/low disease activity after 1 year of treatment. Subgroup analysis was mainly performed stratified by prior biologics use.ResultsA total of 291 PS-matched, ACPA-positive RA patients who initiated abatacept (n = 97) and TNFi (n = 194) were included. From baseline CDAI scores of 26.52 in the abatacept group and 26.38 in the TNFi group, the mean changes after 1 year were − 16.78 and − 13.61, respectively (difference − 3.17, p = 0.020). The proportion of patients achieving CDAI remission/low disease activity was 68.0% with abatacept and 52.6% with TNFi (p = 0.013). In the subgroup analysis, patients that were biologics-naïve had better improvement in CDAI after treatment with abatacept than TNFi (difference − 3.35, p = 0.021).ConclusionsThis real-world study suggests that abatacept may have better clinical response compared to TNFi in patients with established ACPA-positive RA, especially in those that were biologics-naïve.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40744-022-00467-4.

P200 Combining protein quantitative trait and genetic risk score analysis to identify biomarkers of treatment response to TNFi in patients with rheumatoid arthritis

Abstract Background/Aims Rheumatoid arthritis (RA) is an inflammatory joint disease that can lead to disability if inflammation is not controlled. Biologic disease modifying anti-rheumatic drugs (bDMARDs), including tumour necrosis factor inhibitors (TNFi), are an effective line of therapy for moderate to severe RA. However, treatment response to TNFi is not universal and cannot be predicted from clinical factors. In this study, a protein quantitative trait loci (pQTL) study and genetic risk score (GRS) analysis were combined to identify protein-based biomarkers that are predictive of TNFi treatment response. Methods Protein expression data were generated using Sequential Window Acquisition of All Theoretical Mass Spectra (SWATH-MS) in serum samples taken from 80 RA patients about to commence therapy with etanercept. Protein expression was log2 transformed and the k-nearest neighbour model was used to impute missing values. A pQTL study was performed in patients with available imputed genome-wide genetic variation data to detect cis-acting genetic markers (p &amp;lt; 1E-05). GRS for pQTLs were subsequently tested in 1,430 RA patients with available genome-wide genetic and TNFi treatment response data (improvement in DAS28 between pre-treatment and 3/6 months on drug). The GRS analysis was adjusted for baseline disease activity, sex, conventional synthetic DMARD co-therapy and the first 10 principal components, calculated from the genetic datasets. Results Following imputation, expression levels for 271 proteins were analysed in 69 RA patients with available genotype data. 514 cis-pQTLs were found for 16 proteins. GRS for the proteins Apolipoprotein(a) (UniProt ID P08519, p = 0.017) and Carboxypeptidase N subunit 2 (P22792, p = 0.027) were found to be modestly associated with treatment response; however, scores for both proteins explained less than 1% of the variance in DAS28 difference between time-points. Conclusion This study identified two protein-based genetic biomarkers of treatment response to TNFi. However, genetic scores based on these proteins are unlikely to be useful predictors, explaining little variance in on-treatment disease activity. Disclosure Z. Li: None. S.F. Ling: None. N. Nair: None. J.D. Isaacs: None. K.L. Hyrich: Honoraria; Abbvie. A.W. Morgan: None. A.G. Wilson: None. A. Barton: None. D. Plant: None.

PBMC CDC42 reveals the disease activity and treatment efficacy of TNF inhibitor in patients with ankylosing spondylitis.

ObjectiveCell division cycle 42 (CDC42) regulates the polarization of M2 macrophage and maintains the T cell homeostasis, to participate in multiple autoimmune diseases, while its clinical involvement in ankylosing spondylitis (AS) remains unclear. Hence, the current study aimed to investigate the correlation of CDC42 with clinical characteristics and treatment outcome in AS patients receiving tumor necrosis factor (TNF) inhibitor therapy.MethodsPeripheral blood mononuclear cell (PBMC) CDC42 expression was detected at baseline, week (W) 4, W8, and W12 after TNF inhibitor treatment in 91 AS patients and in 50 HCs after enrollment. Furthermore, serum TNF‐α, interferon‐γ (IFN‐γ), interleukin‐10 (IL‐10), and interleukin‐17A (IL‐17A) from AS patients were detected at baseline.ResultsBlood CDC42 was lower in AS patients compared with HCs (p < 0.001). Additionally, blood CDC42 was negatively linked with CRP (r = −0.349, p = 0.001), BASDAI score (r = −0.243, p = 0.020), and ASDASCRP score (r = −0.238, p = 0.023) in AS patients; however, blood CDC42 was not correlated with other clinical characteristics. Besides, CDC42 was negatively correlated with TNF‐α (r = −0.237, p = 0.024) and IL‐17A (r = −0.339, p = 0.001) but not with IFN‐γ (p = 0.083) or IL‐10 (p = 0.280). Moreover, blood CDC42 was elevated after TNF inhibitor treatment (p < 0.001). Meanwhile, blood CDC42 was not varied at baseline and W4 between response patients and non‐response patients, while it was higher at W8 (p = 0.019) and W12 (p = 0.002) in response patients than in non‐response patients after treatment.ConclusionBlood CDC42 deficiency links with elevated pro‐inflammatory cytokines, disease activity and unsatisfying response to TNF inhibitor in AS patients.

Comparative efficacy and safety of tumor necrosis factor inhibitors and their biosimilars in patients with rheumatoid arthritis having an insufficient response to methotrexate : Anetwork meta-analysis.

This study aimed to compare the effectiveness and safety of tumor necrosis factor inhibitor (TNFI) biosimilars to TNFI originators in patients with active rheumatoid arthritis (RA) who responded inadequately to methotrexate (MTX). We conducted ameta-analysis of randomized controlled trials (RCTs) to compare the effectiveness and safety of TNFI biosimilars to TNFIs in patients with RA who had not responded adequately to MTX. A total of 18 RCTs (8adalimumab, 7infliximab, and 3etanercept) comprising 4039patients randomized to TNFI biosimilars and 3905 to TNFI treatment were included. The American College of Rheumatology 20% improvement (ACR20) response rate was significantly higher for TNFI biosimilar-treated patients than for TNFI-treated patients (odds ratio, OR 1.140, 95% confidence interval, CI 1.031-1.261, P = 0.011); however, subgroup analysis by the TNFI type showed that the ACR20 response rates were not different among the biosimilars of adalimumab, infliximab, and etanercept compared with the originators. The ACR50 response rate was significantly higher for TNFI biosimilar-treated patients than for TNFI treated patients (OR 1.096, 95% CI 1.001-1.200, P = 0.047). Subgroup analysis by the TNFI type showed that the ACR50 response rates did not differ among the biosimilars of adalimumab and infliximab compared with the originators; however, the ACR50 response rate was significantly higher in etanercept biosimilar-treated patients than in etanercept-treated patients (OR 1.406, 95% CI 1.111-1.780, P = 0.005). No significant difference was observed between the TNFI biosimilars and TNFIs as per ACR70. There was no significant difference in the number of patients who experienced adverse events (AEs) between TNFI biosimilars and TNFIs (OR 0.961, 95% CI 0.876-1.055, P = 0.402); however, subgroup analysis by the TNFI type showed that the adalimumab biosimilar caused fewer AEs than adalimumab (OR 0.865, 95% CI 0.756-0.989, P = 0.034). Serious AEs and withdrawals due to AEs did not differ between TNFI biosimilars and TNFIs. This meta-analysis showed that TNFI biosimilars had an overall comparable efficacy and safety profile compared with their originators in RA patients.

Association Between Baseline Anti-cyclic Citrullinated Peptide Antibodies and 6-Month Clinical Response Following Abatacept or TNF Inhibitor Treatment: A Real-World Analysis of Biologic-Experienced Patients with RA.

IntroductionAnti-cyclic citrullinated peptide (anti-CCP) antibodies are associated with poor prognosis in patients with rheumatoid arthritis (RA). Previous data from randomized controlled trials and clinical practice have shown anti-CCP-positive (+) patients had a better response to treatment with abatacept or tumor necrosis factor inhibitor (TNFi) treatment than those who were anti-CCP negative. This study assessed the association between baseline anti-CCP2 [a surrogate for anti-citrullinated protein antibody (ACPA)] concentration and 6-month treatment responses to abatacept or TNFi in patients with RA.MethodsThis real-world analysis included biologic-experienced patients from CERTAIN (Comparative Effectiveness Registry to study Therapies for Arthritis and Inflammatory CoNditions) who initiated abatacept or TNFi, had prior biologic disease-modifying drug exposure and baseline anti-CCP2 concentration/serostatus and serum samples (baseline and 6 months). Baseline demographics and disease characteristics were compared. Change from baseline at 6 months in Clinical Disease Activity Index (CDAI) score and patient-reported outcomes [PROs: pain, fatigue, patient global assessment (PtGA), modified Health Assessment Questionnaire (mHAQ) score], by baseline anti-CCP2 quartile and binary cut-off (> 10–250 and > 250 U/ml), were evaluated separately in the abatacept and TNFi groups using a linear regression model adjusted for age, sex, CDAI/PROs, comorbidity index, and methotrexate use.ResultsIncluded were 138 abatacept and 137 TNFi initiators who were anti-CCP2+. At baseline, there were significant differences between anti-CCP2 quartiles and mean CDAI, swollen joint count 28, C-reactive protein (CRP), Disease Activity Score 28 (CRP), rheumatoid factor (RF), mHAQ and physician global assessment among abatacept initiators, and in mean RF, mHAQ, and PtGA among TNFi initiators. Among abatacept (but not TNFi) initiators, CDAI numerically improved (p = 0.208) and PROs significantly improved (p < 0.05) with increasing baseline anti-CCP2.ConclusionsIn patients treated with abatacept, not TNFi, higher anti-CCP2 concentrations at baseline were associated with numerically greater improvements in CDAI and significant improvements in PROs after 6 months.Clinical Trial NumberNCT01625650.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40744-021-00310-2.

POS1021 THE PsABio STUDY IN ITALY: A REAL-WORLD COMPARISON OF THE PERSISTENCE, EFFECTIVENESS AND SAFETY OF USTEKINUMAB AND TUMOUR NECROSIS FACTOR INHIBITORS IN PATIENTS WITH PSORIATIC ARTHRITIS

POS1021 THE PsABio STUDY IN ITALY: A REAL-WORLD COMPARISON OF THE PERSISTENCE, EFFECTIVENESS AND SAFETY OF USTEKINUMAB AND TUMOUR NECROSIS FACTOR INHIBITORS IN PATIENTS WITH PSORIATIC ARTHRITIS

Tumor necrosis factor inhibitors prevent structural damage in hips in ankylosing spondylitis-time to reconsider treatment guidelines? A case series and review of literature.

Tumor necrosis factor inhibitors (TNFi) are indicated to treat ankylosing spondylitis (AS), also termed radiographic axial spondyloarthritis (axSpA). The main indication for TNFi is symptom relief, and whether they retard spinal structural damage as assessed by radiography is debated. Hips are the most common "non-spinal" joints involved in AS patients leading to major incapacitation. No major treatment guidelines mention measures to prevent peripheral joint damage, especially hips, in individuals with AS. We present our experience of prevention of structural damage in hips by TNFi in 4 AS patients from our practice. We conducted a literature review looking for articles describing prevention of structural damage progression in hips by TNFi. Over a 10-year period, three out of four patients were treated with TNFi and had no progression in hip damage as assessed by imaging. Only one patient that withdrew the TNFi due to infectious complications developed rapid worsening and required hip arthroplasty. Our literature review showed multiple case series with similar results suggesting that use of TNFi in patients with AS may prevent structural damage and at least postpone a hip replacement at a young age. Based on our experience, as well as from the literature review, we believe that treatment guidelines in axSpA should recommend prompt institution of TNFi following identification of hip involvement in patients to prevent a major source of disability. Whether interleukin (IL)-17 inhibitors or targeted synthetic anti-rheumatic drugs have hip sparing effects in patients with AS should also be investigated. Key Points • Hip involvement in ankylosing spondylitis is a major source of disability. • TNFi prevent hip damage in ankylosing spondylitis. • Prompt institution of TNFi should follow suspicion of hip involvement in ankylosing spondylitis.

Association Between Tumor Necrosis Factor Inhibitor Exposure and Inflammatory Central Nervous System Events

Tumor necrosis factor (TNF) inhibitors are common therapies for certain autoimmune diseases, such as rheumatoid arthritis. An association between TNF inhibitor exposure and inflammatory central nervous system (CNS) events has been postulated but is poorly understood. To evaluate whether TNF inhibitor exposure is associated with inflammatory demyelinating and nondemyelinating CNS events in patients with an indication for TNF inhibitor use and to describe the spectrum of those CNS events. A nested case-control study was conducted using the medical records of patients with autoimmune diseases treated at 3 Mayo Clinic locations (Rochester, Minnesota; Scottsdale, Arizona; and Jacksonville, Florida) between January 1, 2003, and February 20, 2019. Patients were included if their records reported International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, diagnostic codes for US Food and Drug Administration-approved autoimmune disease indication for TNF inhibitor use (ie, rheumatoid arthritis, ankylosing spondylitis, psoriasis and psoriatic arthritis, Crohn disease, and ulcerative colitis) and diagnostic codes for inflammatory CNS events of interest. Patients were matched 1:1 with control participants by year of birth, type of autoimmune disease, and sex. TNF inhibitor exposure data were derived from the medical records along with type of TNF inhibitor, cumulative duration of exposure, and time of exposure. The main outcome was either inflammatory demyelinating (multiple sclerosis and other diseases such as optic neuritis) or nondemyelinating (meningitis, meningoencephalitis, encephalitis, neurosarcoidosis, and CNS vasculitis) CNS event. Association with TNF inhibitor was evaluated with conditional logistic regression and adjusted for disease duration to determine the odds ratios (ORs) and 95% CIs. Secondary analyses included stratification of outcome by inflammatory demyelinating and nondemyelinating CNS events and by autoimmune disease (rheumatoid arthritis and non-rheumatoid arthritis). A total of 212 individuals were included: 106 patients with inflammatory CNS events and 106 control participants without such events. Of this total, 136 were female (64%); the median (interquartile range) age at disease onset for patients was 52 (43-62) years. Exposure to TNF inhibitors occurred in 64 patients (60%) and 42 control participants (40%) and was associated with an increased risk of any inflammatory CNS event (adjusted OR, 3.01; 95% CI, 1.55-5.82; P = .001). These results were similar when the outcome was stratified by demyelinating and nondemyelinating CNS events. Secondary analyses found the association was predominantly observed in patients with rheumatoid arthritis (adjusted OR, 4.82; 95% CI, 1.62-14.36; P = .005). This study found that exposure to TNF inhibitors in patients with autoimmune diseases appeared to be associated with increased risk for inflammatory CNS events. Whether this association represents de novo or exacerbated inflammatory pathways requires further research.

Is Takayasu arteritis the result of a Mycobacterium tuberculosis infection? The use of TNF inhibitors may be the proof-of-concept to demonstrate that this association is epiphenomenal.

Although the association between Takayasu arteritis (TA) and latent or active Mycobacterium tuberculosis infection has been suggested for a long time, studies conducted in recent years are challenging this notion. Until recently, the possibility of a pathogenic relationship between TA and tuberculosis (TB) was considered a medical curiosity, but the advent of tumor necrosis factor (TNF) inhibitors as therapy for recalcitrant TA cases, as well as the widespread use of Bacille Calmette-Guérin (BCG) for vaccination purposes, has relocated this association as a top priority issue. In an attempt to define whether both diseases are pathogenically linked or if their association is only epiphenomenal in nature, we conduct a thorough literature search on the development of TB in patients with TA receiving TNF inhibitors. From a total of 13 studies that included 214 patients, the occurrence of TB was observed only in two individuals exposed to infliximab. This frequency of 0.93% is similar to that encountered in patients with other rheumatic diseases exposed to TNF inhibitors. Finally, we propose a novel pathogenic model that could reconcile the epidemiological, clinical, and immunological evidence that links TA and TB, while providing rationality for the use of TNF inhibitors in patients with TA.

2019 Update of the American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis.

To update evidence-based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA). We conducted updated systematic literature reviews for 20 clinical questions on pharmacologic treatment addressed in the 2015 guidelines, and for 26 new questions on pharmacologic treatment, treat-to-target strategy, and use of imaging. New questions addressed the use of secukinumab, ixekizumab, tofacitinib, tumor necrosis factor inhibitor (TNFi) biosimilars, and biologic tapering/discontinuation, among others. We used the Grading of Recommendations, Assessment, Development and Evaluation methodology to assess the quality of evidence and formulate recommendations and required at least 70% agreement among the voting panel. Recommendations for AS and nonradiographic axial SpA are similar. TNFi are recommended over secukinumab or ixekizumab as the first biologic to be used. Secukinumab or ixekizumab is recommended over the use of a second TNFi in patients with primary nonresponse to the first TNFi. TNFi, secukinumab, and ixekizumab are favored over tofacitinib. Co-administration of low-dose methotrexate with TNFi is not recommended, nor is a strict treat-to-target strategy or discontinuation or tapering of biologics in patients with stable disease. Sulfasalazine is recommended only for persistent peripheral arthritis when TNFi are contraindicated. For patients with unclear disease activity, spine or pelvis magnetic resonance imaging could aid assessment. Routine monitoring of radiographic changes with serial spine radiographs is not recommended. These recommendations provide updated guidance regarding use of new medications and imaging of the axial skeleton in the management of AS and nonradiographic axial SpA.

2019 Update of the American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis.

To update evidence-based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA). We conducted updated systematic literature reviews for 20 clinical questions on pharmacologic treatment addressed in the 2015 guidelines, and for 26 new questions on pharmacologic treatment, treat-to-target strategy, and use of imaging. New questions addressed the use of secukinumab, ixekizumab, tofacitinib, tumor necrosis factor inhibitor (TNFi) biosimilars, and biologic tapering/discontinuation, among others. We used the Grading of Recommendations, Assessment, Development and Evaluation methodology to assess the quality of evidence and formulate recommendations and required at least 70% agreement among the voting panel. Recommendations for AS and nonradiographic axial SpA are similar. TNFi are recommended over secukinumab or ixekizumab as the first biologic to be used. Secukinumab or ixekizumab is recommended over the use of a second TNFi in patients with primary nonresponse to the first TNFi. TNFi, secukinumab, and ixekizumab are favored over tofacitinib. Co-administration of low-dose methotrexate with TNFi is not recommended, nor is a strict treat-to-target strategy or discontinuation or tapering of biologics in patients with stable disease. Sulfasalazine is recommended only for persistent peripheral arthritis when TNFi are contraindicated. For patients with unclear disease activity, spine or pelvis magnetic resonance imaging could aid assessment. Routine monitoring of radiographic changes with serial spine radiographs is not recommended. These recommendations provide updated guidance regarding use of new medications and imaging of the axial skeleton in the management of AS and nonradiographic axial SpA.

The Safety Profile of Tumor Necrosis Factor Inhibitors in Ankylosing Spondylitis: Are TNF Inhibitors Safer Than We Thought?

Tumor necrosis factor (TNF) inhibitors significantly improved the treatment options for patients with ankylosing spondylitis. Unfortunately, currently, there is no strategy for sustaining remission of the disease with TNF inhibitors; after discontinuation, a high percentage of patients experience flares in a short time. Therefore, up-to-date, long-term use of TNF inhibitors in patients with ankylosing spondylitis remains necessary. For this reason, the issue of the long-term safety of TNF inhibitors in patients with ankylosing spondylitis raises concerns. Although TNF inhibitors are well established in ankylosing spondylitis treatment, the majority of studies on TNF inhibitors' safety have been performed in patients with rheumatoid arthritis. Until recently, there were very few studies of TNF inhibitors' safety in ankylosing spondylitis. Meanwhile, TNF inhibitors appear to have different safety profiles in ankylosing spondylitis and rheumatoid arthritis. In this review, we describe available data on the occurrence of adverse events associated with TNF inhibitor treatment in ankylosing spondylitis, including serious adverse events, infections, serious infections, tuberculosis, opportunistic infections, hepatitis B reactivation, malignancies, laboratory test abnormalities, autoimmune diseases, paradoxical adverse events, and heart failure.

Treatment persistence of subcutaneous TNF inhibitors among Australian patients with immune-mediated rheumatic disease (IMRD).

IntroductionTo describe the persistence of treatment with subcutaneous tumor necrosis factor inhibitors (TNFi) adalimumab, etanercept, and golimumab in immune-mediated rheumatic disease (rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis) by treatment sequence (first-line treatment, second-line or further lines of treatment).MethodsA retrospective cohort analysis was conducted using the Australian Commonwealth Department of Human Services Pharmaceutical Benefits Scheme 10% sample data from January 1, 2010, to June 30, 2016. Pharmaceutical Benefits Scheme indications were used to identify patient prescriptions for rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. A patient was considered persistent until a 3-month gap period where a prescription was not dispensed. The 3-month gap interval was chosen because only 1% of all discontinuations occurred beyond this 3-month period.ResultsData from 2,612 first-line patients were included. Treatment discontinuation among first-line patients treated with etanercept or adalimumab was not significantly different from those treated with golimumab (HR 1.10, 95% CI 0.95–1.28, P=0.22; HR 1.06, 95% CI 0.93–1.22, P=0.39; respectively). Among the 1,276 patients in the second-line cohort (etanercept=41%, adalimumab=41%, golimumab=18%) discontinuation was significantly higher for patients on etanercept compared with golimumab (HR 1.24, 95% CI 1.03–1.50, P=0.03); but not for adalimumab compared with golimumab (HR 1.11, 95% CI 0.91–1.34, P=0.31). In the third-line setting, treatment persistence with etanercept was longer than golimumab (HR 0.75, 95% CI 0.59–0.96, P=0.02), but there was no difference between golimumab and adalimumab. Similar findings occurred in the propensity score matched population.ConclusionOur study shows there is variance in real-world persistence to TNFi in patients with immune-mediated rheumatic disease by line of therapy, with the time on therapy decreasing by line. Australian persistence has been reported at lower overall rates than international evidence.

Switching tumor necrosis factor inhibitors in the treatment of axial spondyloarthritis.

To assess the impact of switching tumor necrosis factor (TNF)-alpha inhibitors on patients with axial spondyloarthritis (axSpA). PubMed literature searches were conducted using combinations of search terms including ankylosing spondylitis, spondyloarthropathy, spondyloarthritis, switch/switching, drug survival, and TNF/tumor necrosis factor to identify published articles with data on outcomes related to switching biologic therapies in patients with axSpA. Of the 134 studies screened, 21 were identified as reporting data on switching TNF inhibitors in patients carrying a diagnosis of axSpA or ankylosing spondylitis. The most common reasons for switching from the first TNF inhibitor were lack of efficacy (14-68%), loss of efficacy (13-61%), and adverse events/poor tolerability (13-57%). Switching TNF inhibitors was beneficial for a substantial proportion of patients with axSpA who failed to respond to initial or even second TNF inhibitor therapy and adverse effects were not enhanced. Drug survival rates were generally lower for the second (47-72% at 2 years) or third TNF inhibitor (49% at 2 years) than for the first TNF inhibitor (58-75% at 2 years). Predictors of responses in TNF-naïve patients included HLA-B27 positivity, absence of enthesitis, age ≤40 years, elevated C-reactive protein level, good functional status, and shorter disease duration. Predictors of drug survival included male sex and peripheral arthritis. Common characteristics of patients who switched TNF inhibitors included female sex, older age, more severe disease, greater symptom burden, higher erythrocyte sedimentation rate, complete ankyloses, and enthesitis. When the first or even the second TNF inhibitor fails, switching to an alternate one is not an unreasonable clinical therapeutic decision.

Treatment persistence during therapeutic sequences with adalimumab and infliximab in the treatment of Crohn's disease.

Tumor necrosis factor (TNF) inhibitors have demonstrated efficacy and safety in the treatment Crohn's disease (CD). However, the loss of response over time means that they are usually used sequentially. The aim of this study was to compare treatment persistence with different sequences of TNF inhibitors in patients with active luminal CD. A Markov model (3-month cycles) was developed to simulate the therapeutic sequences of beginning biological treatment with infliximab or adalimumab, with a time horizon of three years. Each state of the model represented treatment (induction, standard dose or escalated dose) with each TNF inhibitor or the state without biological treatment. The transition probabilities between states were determined by the clinical response to TNF inhibitors obtained from the literature. The likelihood of discontinuation due to adverse effects was also considered. After three years, the percentage of CD patients receiving infliximab and adalimumab as a first TNF inhibitor that remained in treatment was 52.8% and 59.3% (p = 0.1) respectively. Median time to discontinuation of the standard dose was 26.26 months in patients who started with adalimumab and 24.39 months in patients who started with infliximab. In the model, there were no significant differences in persistence after three years with the initial drug among patients with active luminal CD starting treatment with infliximab or adalimumab.