Tumor Necrosis Factor Inhibitor Therapy Research Articles

Tumor necrosis factor-α inhibitor-induced psoriasis in juvenile idiopathic arthritis patients.

The development of psoriasis while on tumor necrosis factor inhibitors (TNFi) is a paradoxical effect of agents that treat psoriasis. There is a paucity of data available on this entity in juvenile idiopathic arthritis (JIA). Our objectives were to determine the prevalence of TNFi-induced psoriasis in patients with JIA at two pediatric centers, and psoriasis response to therapeutic modifications. We performed retrospective chart review on patients with JIA treated with TNFi (adalimumab, etanercept, infliximab) who developed psoriasis. TNFi-induced psoriasis was defined as an incident diagnosis of psoriasis after starting a TNFi. Patients with personal histories of psoriasis prior to TNFi therapy were excluded. Following diagnosis, responses to medication changes were defined based on physician assessments. Nine of 166 (5.4%) patients on TNFi for JIA were diagnosed with TNFi-induced psoriasis. All cases were female. One had a family history of psoriasis. The median age was 10 (range 2-16) years. Five (55%) patients experienced scalp psoriasis, including four (44%) with alopecia. Two (22%) patients achieved significant improvement after switching to different classes of biologic agents, while three (33%) patients had significant improvement following discontinuation of biologic therapy. One of fivepatients who switched to a different TNFi had complete resolution, while four had worsening symptoms or partial improvement. Our findings demonstrate the prevalence of TNFi-induced psoriasis in JIA at two centers. Though larger studies are needed, our data suggest discontinuation of TNFi or biologic class switching should be considered as treatment strategies in select patients.

Association between seropositivity and discontinuation of tumor necrosis factor inhibitors due to ineffectiveness in rheumatoid arthritis.

Discontinuation of biologic therapy in rheumatoid arthritis is attributable to various reasons, with the most important cause being insufficient response. In this study, we investigated the association between rheumatoid factor (RF) and anti-citrullinated protein autoantibody (ACPA) status and the discontinuation of tumor necrosis factor inhibitors (TNFi) therapy due to insufficient response in bio-naïve rheumatoid arthritis (RA) patients. This study included patients enrolled in the Tsurumai Biologic Communication Registry in Japan. The crude comparison of TNFi discontinuation due to ineffectiveness between seropositive and seronegative patients was analyzed using the cumulative incidence function of competing events and Gray test. We assessed the associations between baseline patient characteristics and discontinuation of TNFi therapy due to insufficient response using Fine-Gray proportional hazard regression. Fine-Gray proportional hazard analysis considered competing events of interest, including insufficient response, adverse event, palliation, and personal reasons. Of 1237 patients evaluated, 79.3% were positive for RF and 85.4% for ACPA; 72.6% were double positive and 11.1% were double negative. TNFi therapy had been discontinued because of insufficient response at 200weeks in 19.8% RF-positive, 16.7% RF-negative, 23.0% ACPA-positive, and 13.8% ACPA-negative patients. There was a significantly higher discontinuation rate due to insufficient response in ACPA-positive patients than in ACPA-negative patients using Gray test, with a similar trend as that for RF status. RF positivity was significantly predictive of the discontinuation of TNFi therapy due to ineffectiveness using Fine-Gray proportional hazard regression analysis after adjusting for baseline characteristics, including age, sex, stage, class, disease activity at baseline, methotrexate use, and prednisolone use [hazard ratio 1.73 (95% confidence interval 1.07-2.80)]. Using Fine-Gray proportional hazard regression, we demonstrated that RF positivity was related to a higher discontinuation rate of TNFi therapy due to ineffectiveness in bio-naïve RA patients. Key Points • RF positivity is related to a higher discontinuation rate of TNFi therapy due to ineffectiveness. • ACPA is not predictive of a discontinuation of TNFi therapy due to ineffectiveness.

Predictive clinical-genetic model of long-term non-response to tumor necrosis factor-alpha inhibitor therapy in spondyloarthritis.

Tumor necrosis factor inhibitors (TNFi) are effective in controlling disease activity in spondyloarthritis (SpA). However, in a proportion of patients these treatments are ineffective or lead to adverse events. Recently, alternative therapies, such as interleukin (IL)-17 or IL-23 inhibitors, have emerged in the treatment of these pathologies. This study aimed to determine clinical and genetic predictors of non-response to TNFi treatment in 118 spondyloarthritis patients diagnosed according to Assessment in SpondyloArthritis International Society(ASAS) criteria. From the literature, 41 single nucleotide polymorphisms (SNPs) were selected that had previously been associated with TNFi treatment response in spondyloarthropathies, rheumatoid arthritis and psoriasis. A clinical non-response was defined as a decrease of <50% of initial Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) in axial involvement, or a reduction of less than 1.2 of initial Disease Activity Score of 28 joints-C-reactive protein (DAS28-CRP) in patients with only peripheral involvement. Univariate and multivariate hazard ratios (HR) were determined using Cox proportional hazard models to analyze the potential prognostic factors affecting non-response to TNFi treatment. The clinical factors that significantly increased the non-response rate were: global visual analog scale(VAS), CRP, BASDAI, Bath Ankylosing Spondylitis Functional Index (BASFI), and the number of TNFi used. Only rs11591741 SNP showed an association with non-response. In the multivariate analysis, females had a non-response rate 4.46 times higher than males; each one-point increase in the BASFI index increased the non-response rate by 75%, and being a genotype GG vs GC or CC carrier was associated with an almost 4 times greater non-response rate. We developed a clinical-genetic model to identify SpA patients with a long-term non-response to TNFi therapy.

248 Sustained improvements in disease activity for up to two-years with ixekizumab in patients with active psoriatic arthritis who were either biologic-naïve or with previous inadequate response to tumour necrosis factor inhibitor therapy

248 Sustained improvements in disease activity for up to two-years with ixekizumab in patients with active psoriatic arthritis who were either biologic-naïve or with previous inadequate response to tumour necrosis factor inhibitor therapy

Association of Ustekinumab vs TNF Inhibitor Therapy With Risk of Atrial Fibrillation and Cardiovascular Events in Patients With Psoriasis or Psoriatic Arthritis

Accumulating evidence indicates that there is an increased risk of cardiovascular disease among patients with psoriatic disease. Although an emerging concern that the risk of atrial fibrillation (AF) may also be higher in this patient population adds to the growing support of initiating early interventions to control systemic inflammation, evidence on the comparative cardiovascular safety of current biologic treatments remains limited. To evaluate the risk of AF and major adverse cardiovascular events (MACE) associated with use of ustekinumab vs tumor necrosis factor inhibitors (TNFi) in patients with psoriasis or psoriatic arthritis. This cohort study included data from a nationwide sample of 78 162 commercially insured patients in 2 US commercial insurance databases (Optum and MarketScan) from September 25, 2009, through September 30, 2015. Patients were included if they were 18 years or older, had psoriasis or psoriatic arthritis, and initiated ustekinumab or a TNFi therapy. Exclusion criteria included history of AF or receipt of antiarrhythmic or anticoagulant therapy during the baseline period. Initiation of ustekinumab vs TNFi therapy. Incident AF and MACE, including myocardial infarction, stroke, or coronary revascularization. A total of 60 028 patients with psoriasis or psoriatic arthritis (9071 ustekinumab initiators and 50 957 TNFi initiators) were included in the analyses. The mean (SD) age was 46 (13) years in Optum and 47 (13) in MarketScan, and 29 495 (49.1%) were male. Overall crude incidence rates (reported per 1000 person-years) for AF were 5.0 (95% CI, 3.8-6.5) for ustekinumab initiators and 4.7 (95% CI, 4.2-5.2) for TNFi initiators, and for MACE were 6.2 (95% CI, 4.9-7.8) for ustekinumab initiators and 6.1 (95% CI, 5.5-6.7) for TNFi initiators. The combined adjusted hazard ratio for incident AF among ustekinumab initiators was 1.08 (95% CI, 0.76-1.54) and for MACE among ustekinumab initiators was 1.10 (95% CI, 0.80-1.52) compared with TNFi initiators. No substantially different risk of incident AF or MACE after initiation of ustekinumab vs TNFi was observed in this study. This information may be helpful when weighing the risks and benefits of various systemic treatment strategies for psoriatic disease.

Tofacitinib: A Review in Psoriatic Arthritis.

Tofacitinib (Xeljanz®) is the first Janus kinase (JAK) inhibitor approved at a dosage of 5mg twice daily (BID) in the EU and the USA for the treatment of active psoriatic arthritis (PsA), where it is indicated in combination with methotrexate for patients who have had an inadequate response or who have been intolerant to a prior therapy with a disease-modifying antirheumatic drug (DMARD). Two well-designed phaseIII trials (OPAL Broaden and OPAL Beyond) in patients with PsA with or without prior tumour necrosis factor inhibitor (TNFi) therapy showed that tofacitinib 5mg BID (co-administered with methotrexate or another approved conventional synthetic DMARD) significantly improved the key clinical signs/symptoms and disability associated with PsA after 3months of treatment, while also improving skin psoriasis, enthesitis, dactylitis, physical function and fatigue. According to interim data, the improvements in clinical signs/symptoms were maintained for up to 30months in the ongoing long-term extension study OPAL Balance, with minimal radiographic progression seen after 12months' therapy in the OPAL Broaden study. Tofacitinib 5mg BID had an acceptable tolerability profile, with low incidences of serious infections, malignancies, cardiovascular events and gastrointestinal perforations over 36months. Changes in laboratory parameters generally remained stable over 36months of treatment. Although further studies are required to more definitively establish its efficacy and safety, currently available evidence indicates that tofacitinib expands the treatment options available for the treatment of PsA in patients who have had an inadequate response or who have been intolerant to a prior DMARD therapy.

Persistence, Discontinuation, and Switching Patterns of Newly Initiated TNF Inhibitor Therapy in Ankylosing Spondylitis Patients in the United States.

IntroductionThe primary goals of treating ankylosing spondylitis (AS) patients are to maximize long-term health-related quality of life through control of symptoms and inflammation, prevention of progressive structural damage, and preservation of function. The objective of this study was to describe treatment patterns (persistence, discontinuations, and switch) in the 2 years following the initiation of tumor necrosis factor inhibitors (TNFi) therapy in AS patients.MethodsAdult patients with ≥ 2 AS diagnostic codes (ICD-9: 720.0 and/or ICD-10:M45.x) by a healthcare provider were included in this retrospective analysis of data from the IBM MarketScan Commercial Claims database. Patients who newly initiated a TNFi from 01/01/2009 to 12/31/2013 were indexed on their first TNFi. Patients were required to have a 1-year pre-index period free of TNFi and continuous enrollment 1-year pre-index and 2-year post-index. Patients were excluded if they had ≥ 2 diagnostic codes for any of the following conditions: rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, Crohn’s disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa, or uveitis. Demographic, clinical, and treatment patterns were analyzed. Treatment patterns included switching to a new TNFi, discontinuation (≥ 90-day gap in therapy without starting a new TNFi), or persistence (no gaps in therapy ≥ 90 days) during the 2-year follow-up period. Logistic regression analyses predicting persistent vs. non-persistent and switching vs. discontinuation were conducted.ResultsA total of 1372 AS patients (846 males/526 females) met the inclusion criteria for this study. Males had a mean age of 44.3 years, while females had a mean age of 42.3 years. Adalimumab was the first biologic for the majority of patients (44.6% males/43.3% females), followed by etanercept (40.4% males/41.6% females), infliximab (10.4% males/10.8% females), golimumab (4.6% males/3.8% females), and certolizumab pegol (0.0% males/0.4% females). During the follow-up period, 33.1% of patients (n = 454) were persistent on their index TNFi, 40.7% (n = 559) discontinued their index TNFi and did not restart a TNFi, and 26.1% (n = 359) switched to a second TNFi. Patients prescribed cDMARDs were more likely to be persistent, while females and opioid users were less likely to be persistent on their first TNFi. Among those that discontinued their first TNFi, 32.8% (n = 187) of males and 43.6% (n = 177) of females switched to a second TNFi.ConclusionsThis study suggests that approximately 67% of male AS patients and 77% of female AS patients newly initiating a TNFi do not remain on the index therapy 2 year post initiation.FundingEli Lilly and Company.

Secukinumab: A Review in Ankylosing Spondylitis.

Secukinumab (Cosentyx®), a first-in-class fully human monoclonal antibody against interleukin-17A, is approved in several countries, including the USA and those of the EU, for the treatment of ankylosing spondylitis (AS). Subcutaneous secukinumab significantly improved the clinical signs and symptoms of AS versus placebo in three of four phase III trials. The benefits of secukinumab were generally seen regardless of whether patients had or had not received previous tumour necrosis factor (TNF) inhibitor therapy, and were sustained during longer-term (up to 5 years) treatment. Secukinumab was also associated with improvements in spinal mobility, physical function, health-related quality of life and work productivity in some of the trials. In MEASURE 1, secukinumab reduced inflammation in the sacroiliac joint, and slowed radiographic progression. Secukinumab was generally well tolerated during up to 5 years’ treatment; the most commonly reported adverse event was nasopharyngitis. In the minority of patients who developed anti-drug antibodies (ADAs), ADAs did not decrease efficacy or increase adverse events. In conclusion, secukinumab is an effective therapy for TNF inhibitor-naive patients with active AS, and provides a useful treatment option for patients who have an inadequate response to or are intolerant of TNF inhibitors.

Association between concomitant csDMARDs and clinical response to TNF inhibitors in overweight patients with axial spondyloarthritis

BackgroundThe aim of our study was to investigate the influence of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) and body mass index (BMI) on circulating drug levels and clinical response to tumour necrosis factor inhibitor (TNFi) therapy in axial spondyloarthritis (axSpA) patients.MethodsProspective observational study during 1 year with 2 cohorts (Madrid and Amsterdam) including 180 axSpA patients treated with standard doses of infliximab or adalimumab. Patients were stratified by BMI, being 78 (43%) normal weight (18.5–24.9 kg/m2) and 102 (57%) overweight/obese (≥ 25.0 kg/m2). After the first year of treatment, TNFi trough levels were measured by capture ELISA. Clinical response to TNFi was defined as ∆BASDAI ≥ 2 and clinical remission as BASDAI < 2 and CRP ≤ 5 mg/L. Logistic regression models were employed to analyse the association between concomitant csDMARDs and BMI with drug levels and clinical response.ResultsSeventy-nine patients (44%) received concomitant csDMARDs. The administration of concomitant csDMARDs (OR 3.82; 95% CI 1.06–13.84) and being normal weight (OR 18.38; 95% CI 2.24–150.63) were independently associated with serum TNFi drug persistence. Additionally, the use of concomitant csDMARDs contributed positively to achieve clinical response (OR 7.86; 95% CI 2.39–25.78) and remission (OR 4.84; 95% CI 1.09–21.36) in overweight/obese patients, but no association was found for normal-weight patients (OR 1.10; 0.33–3.58).ConclusionsThe use of concomitant csDMARDs with TNFi may increase the probability of achieving clinical response in overweight/obese axSpA patients. Further research studies including larger cohorts of patients need to be done to confirm it.

Long-Term Efficacy of Tumor Necrosis Factor Inhibitors for the Treatment of Methotrexate-Naïve Rheumatoid Arthritis: Systematic Literature Review and Meta-Analysis.

Synthesis of evidence on the long-term use of first-line biologic therapy in patients with early rheumatoid arthritis (RA) is required. We compared the efficacy of up to 5years' treatment with first-line tumor necrosis factor inhibitors (TNFis) versus other treatment strategies in this population. Previous systematic reviews, PubMed and the Cochrane Central Register of Controlled Trials were searched for randomized controlled trials (RCTs) involving treatment of methotrexate-naïve RA patients with first-line TNFis. Literature was synthesized qualitatively, and a meta-analysis conducted to evaluate American College of Rheumatology (ACR) responses, clinical remission defined by any standard measure, and Health Assessment Questionnaire Disability Index (HAQ) at Years 2 and/or 5. Ten RCTs involving 4306 patients [first-line TNFi, n = 2234; other treatment strategies (control), n = 2072] were included in the meta-analysis. Three studies were double-blind for the first 2years, while seven were partly/completely open label during this period. Five studies reported data at Year 5; all were open label at this time point. At Year 2, ACR50 response, ACR70 response and remission rates were significantly improved with first-line TNFi versus control in double-blind RCTs [log-odds ratio (OR) 0.32 [95% confidence interval (CI) 0.02, 0.62; p = 0.035], log-OR 0.48 (95% CI 0.20, 0.77; p = 0.001), and log-OR 0.44 (95% CI 0.13, 0.74; p = 0.005), respectively], but not in open-label studies. No significant between-group differences were observed in mean HAQ at Year 2 in double-blind or open-label RCTs or in ACR response or remission outcomes at Year 5. In double-blind studies, 2-year efficacy outcomes were significantly improved with first-line TNFi versus other treatment strategies in patients with MTX-naïve RA. No significant differences in these outcomes were observed when data from open-label RCTs were considered on their own. Further data on the efficacy of TNFi therapy over ≥ 2years in patients with methotrexate-naïve RA are required. Plain language summary available for this article.

Impact of TNF inhibitor therapy on joint replacement rates in rheumatoid arthritis: a matched cohort analysis of BSRBR-RA UK registry data.

ObjectivesPrevious ecological data suggest a decline in the need for joint replacements in RA patients following the introduction of TNF inhibitor (TNFi) therapy, although patient-level data are lacking. Our primary aim was to estimate the association between TNFi use and subsequent incidence of total hip replacement (THR) and total knee replacement.MethodsA propensity score matched cohort was analysed using the British Society for Rheumatology Biologics Registry (2001–2016) for RA data. Propensity score estimates were used to match TNFi users to similar conventional synthetic DMARD users (with replacement) using a 1:1 ratio. Weighted multivariable Cox regression was used to estimate the impact of TNFi on study outcomes. Effect modification by baseline age and disease severity were investigated. Joint replacement at other sites was also analysed. An instrumental variable sensitivity analysis was also performed.ResultsThe matched analysis contained a total of 19 116 patient records. Overall, there was no significant association between TNFi use vs conventional synthetic DMARD on rates of THR (hazard ratios = 0.86 [95% CI: 0.60, 1.22]) although there was significant effect modification by age (P < 0.001). TNFi was associated with a reduction in THR among those >60 years old (hazard ratio = 0.60 [CI: 0.41, 0.87]) but not in younger patients. No significant associations were found for total knee replacement or other joint replacement.ConclusionOverall, no association was found between the use of TNFi and subsequent incidence of joint replacement. However, TNFi was associated with a 40% relative reduction in THR rates among older patients.

Erratum: Budget impact analysis of sarilumab for the treatment of rheumatoid arthritis in patients with an inadequate response to conventional synthetic DMARD or TNF inhibitor therapies [Corrigendum

[This corrects the article on p. 805 in vol. 10, PMID: 30532571.].

Secondary organizing pneumonia (bronchiolitis obliterans with organizing pneumonia) associated with adalimumab for treatment of chronic plaque psoriasis

Organizing pneumonia is defined histopathologically by intra-alveolar buds of granulation tissue, consisting of intermixed myofibroblasts and connective tissue. The pathological pattern of organizing pneumonia may be idiopathic or related to a determined cause, termed secondary organizing pneumonia. We report a 68-year-old woman with a longstanding history of chronic plaque psoriasis, treated with the tumor necrosis factor (TNF) inhibitor, adalimumab. After 8 years of treatment, she developed a gradual-onset, non-productive cough with associated generalized fatigue and mild dyspnea. Radiological investigations demonstrated ground-glass opacities in the left lower lobe and bronchoscopy revealed a fibroinflammatory process consistent with organizing pneumonia. Her biologic treatment was ceased and corticosteroid treatment commenced, with resolution of both her symptoms and the radiological findings. Given the increasing incidence of biologic treatment in the management of dermatological conditions, clinicians should be aware of secondary organizing pneumonia as a possible side effect of TNF inhibitor therapy.

Calprotectin strongly and independently predicts relapse in rheumatoid arthritis and polyarticular psoriatic arthritis patients treated with tumor necrosis factor inhibitors: a 1-year prospective cohort study

BackgroundCalprotectin is a biomarker of disease activity in rheumatoid arthritis (RA) and psoriatic arthritis (PsA) and predicts relapse in juvenile idiopathic arthritis. Higher drug trough serum levels are associated with a good response in patients treated with tumor necrosis factor inhibitors (TNFi). Power Doppler ultrasound synovitis is predictive of relapse and structural damage progression in patients in clinical remission. The purpose of this study was to analyze the accuracy of serum calprotectin levels, drug trough serum levels (TSL), and power Doppler (PD) activity as predictors of relapse in RA and PsA patients in remission or with low disease activity receiving TNFi.MethodsThis was a longitudinal, prospective, 1-year single-center study of 103 patients (47 RA, 56 PsA) receiving TNFi in remission or with low disease activity (28-joint Disease Activity Score (DAS28) ≤ 3.2). The predictive value of serum calprotectin, TNFi TSL, and PD were assessed using receiver operating characteristic (ROC) analyses. To illustrate the predictive performance of calprotectin, TNFi TSL, and PD score, Kaplan-Meier curves were constructed from baseline to relapse. Associations between baseline factors and relapse were determined using Cox regression models. Multivariate models were constructed to analyze the effect of covariates and to fully adjust the association between calprotectin, TNFi TSL, and PD score with relapse. A generalized estimating equation model with an identity link for longitudinal continuous outcomes was used to assess the effect of covariates on TNFi TSL.ResultsNinety-five patients completed 1 year of follow-up, of whom 12 experienced a relapse. At baseline, relapsers had higher calprotectin levels, lower TNFi TSL, and higher PD activity than nonrelapsers. ROC analysis showed calprotectin fully predicted relapse (area under the curve (AUC) = 1.00). TNFi TSL and PD had an AUC of 0.790 (95% confidence interval (CI) 0.691–0.889) and 0.877 (95% CI 0.772–0.981), respectively. Survival analyses and log rank tests showed significant differences between groups according to calprotectin serum levels (p < 0.001), TNFi TSL (p = 0.004), and PD score (p < 0.001). Univariate Cox regression models showed that time-to-remission/low disease activity (hazard ratio (HR) = 1.17, p < 0.001), calprotectin levels (HR = 2.38, p < 0.001), TNFi TSL (HR = 0.47, p = 0.018), and PD score (HR = 1.31, p < 0.001) were significantly associated with disease relapse. In the multivariate analysis, only baseline calprotectin levels independently predicted disease relapse (HR = 2.41, p = 0.002). The generalized estimating equation analysis showed that only disease activity by DAS28-erythrocyte sedimentation rate (ESR) was significantly associated with longitudinal changes in TNFi TSL (regression coefficient 0.26 (0.0676 to 0.0036), p = 0.001).ConclusionTime-to-remission/low disease activity, calprotectin serum levels, TNFi TSL, and PD score were significantly associated with disease relapse. However, only baseline calprotectin serum levels independently predicted disease relapse in RA and PsA patients under TNFi therapy.

753. Screening for Latent Mycobacterium tuberculosis Infection (LTBI): A Clinical Conundrum of Public Health Concern

BackgroundTumor necrosis factor (TNF)-α inhibitors increase the risk of reactivating LTBI, hence screening is crucial prior to starting therapy. There is a lack of evidence to support a preferred screening regimen in this population, and either tuberculin skin tests (TST) or interferon-γ release assays (IGRAs) are acceptable. Although difficult to assess, the sensitivity of IGRAs and TST are similar (80–95%), while IGRAs are considered to be more specific.MethodsA 48-year-old White female in rural Iowa with a 30-year history of Crohn’s disease was evaluated for TNF inhibitor therapy. She had no known risk factors for LTBI and was screened using an IGRA which yielded an indeterminate result. A repeat IGRA and a two-step TST were both negative. Subsequently, adalimumab was initiated. Adalimumab was discontinued after 9 months due to progression of Crohn’s, and the patient underwent bowel surgery at a California hospital. Her course was complicated by bilateral pleural effusions requiring thoracentesis twice.ResultsThe patient presented 1 month later with upper lobe infiltrative changes and mediastinal adenopathy. A third IGRA was performed and was non-reactive. A bronchoscopy with biopsy was then performed. The next day her dyspnea, cough and fevers worsened. She was admitted to an Iowa hospital where she was immediately put in airborne precautions. Her bronchoalveolar lavage acid-fast bacilli (AFB) smear was 4+, and an induced sputum showed 3+ AFB. Standard TB treatment was initiated. At least 59 patients (17 immunocompromised) and five employees in a private office and 13 employees at the Iowa hospital were exposed, in addition to an unknown number in California.ConclusionAlthough rare, there appears to be a risk for patients on TNF inhibitors who have multiple negative screening tests to become infected with TB. It is unclear whether this represents reactivation of undetected LTBI or new infection, although new TB cases are less likely in rural Iowa where the incidence is 1.53 per 100,000. Patients should be counseled to report any pulmonary symptoms to providers. As demonstrated by this case, airborne precautions should be implemented as soon as possible if clinical suspicion of TB is high despite negative screening tests to reduce exposure to others.Disclosures All authors: No reported disclosures.

Paradoxical gastrointestinal reactions in patients taking tumor necrosis factor inhibitors: a rare event that broadens the histologic spectrum of medication–associated injury

Tumor necrosis factor (TNF) inhibitors are widely used in the therapy of certain autoimmune disorders. Paradoxical immunologic reactions manifesting as new-onset autoimmune disease or exacerbation of the underlying condition have been reported in association with these drugs. In this study, we reviewed gastrointestinal biopsies and clinical findings in patients with rheumatologic disease on TNF inhibitor therapy and compared to patients with rheumatologic disease not on TNF inhibitors. Eighteen biopsies from 9 patients treated with TNF inhibitor therapy and 249 biopsies from 120 control patients not treated with TNF inhibitors were included. Among patients taking a TNF inhibitor, 55.6% were female, and the median age was 47 (range, 30-67 years). Four (44.4%) patients were taking etanercept, 4 (44.4%) adalimumab, and 1 (11.1%) certolizumab pegol. Of the 120 control patients, 75 (62.5%) were female and the median age was 62 (range, 26-85 years). Paradoxical reactions were observed in 3 (33.3%) of 9 patients on TNF inhibitors, including 2 (22.2%) with inflammatory bowel disease-like changes and 1 (11.1%) with sarcoid-like granulomas. All 3 patients showed symptomatic and histologic improvement or resolution after discontinuation of therapy. These reactions were not observed in any of the control patients (P = .0002). Our results indicate that among patients with rheumatologic disease, paradoxical reactions of the gastrointestinal tract are associated with TNF inhibitor therapy. Knowledge of this association is important because symptoms and histologic features may improve following medication switch.

Budget impact analysis of sarilumab for the treatment of rheumatoid arthritis in patients with an inadequate response to conventional synthetic DMARD or TNF inhibitor therapies.

ObjectiveTo estimate the 5-year budget impact (BI) on a US health plan of introducing sarilumab – a human immunoglobulin G1 anti-IL-6 receptor α monoclonal antibody – as combination treatment with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or monotherapy in patients with moderate-to-severe rheumatoid arthritis (RA).MethodsBI analysis was conducted from a commercial payer perspective. Treatment-eligible populations included adult patients with moderate-to-severe RA and inadequate response (IR) to csDMARDs or tumor necrosis factor (TNF)-α inhibitors-IR. All licensed biologic treatments recommended by the American College of Rheumatology guidelines were included.ResultsFor a hypothetical plan of one million members, 409 csDMARD-IR and 345 TNF-IR patients were annually eligible for combination therapy and 226 csDMARD and TNF-IR patients for monotherapy with sarilumab. Based on 2018 US direct treatment costs, the introduction of sarilumab was estimated to save $526,424, $322,637 and $264,306 over 5 years for csDMARD-IR combination therapy patients, TNF-IR combination therapy patients, and csDMARD-IR/TNF-IR monotherapy patients, respectively. As sarilumab absorbed a greater market share over the horizon, annual savings increased from years 1 to 5, $28,610 (−0.14%) to $194,646 (−0.83%) in csDMARD-IR, $16,986 (−0.11%) to $120,893 (−0.67%) in TNF-IR, and $14,256 (−0.13%) to $98,040 (−0.79%) in monotherapy. One-way sensitivity analyses revealed that the model was most sensitive to variations in sarilumab adherence.ConclusionTotal cost savings of introducing sarilumab to a health-care plan accrued from years 1 to 5, attributable to the lower treatment cost, stable dosing paradigm, and price parity for the two available doses (150 and 200 mg every 2 weeks) compared with alternative biologic DMARDs that have substantial variability in dose titration/schedules.

The current standard of care and the unmet needs for axial spondyloarthritis.

The aim of this article is to explore the benefits and limitations of the established treatments for axial SpA (axSpA), including physiotherapy, NSAIDs, conventional synthetic DMARDs and biologic DMARDs such as TNF inhibitors (TNFis). It also briefly discusses the emerging role of anti-IL-17 therapy, which could be used as a valuable alternative to first-line biologic DMARD treatment or as a second-line treatment for patients who are inadequate responders to TNFi therapy, as evidenced by various studies. Exercise programmes improve health-related quality of life and hydrotherapy improves disease activity and functional parameters in AS. NSAIDs have been proven to substantially relieve symptoms in 70–80% of patients and enhance physiotherapy by reducing pain and stiffness. The role of NSAIDs in preventing radiographic progression remains unclear. The use of conventional synthetic DMARDs (csDMARDs) is limited to peripheral arthritis; there is insufficient evidence to support the use of csDMARDs for axial disease. TNFi therapy reduces the disease activity of axSpA, however, as not all patients respond to treatment in the same way, it is good to have other therapeutic options available. Finally, this article explores the potential for IL-17 inhibition in AS and introduces clinical data for secukinumab, a fully human monoclonal antibody targeting IL-17A.

Therapies in ankylosing spondylitis-from clinical trials to clinical practice.

Until recently, the therapeutic options for patients suffering from active AS comprised NSAIDs and TNF inhibitor therapy. Although these are effective in a significant proportion of patients, not all patients respond and some are intolerant to these therapies. Therefore, there is a clear unmet treatment need in AS patients. This article reviews the evidence for targets currently being studied in AS. This includes the IL-12/23 inhibitor ustekinumab, the pan-Janus kinase inhibitor tofacitinib and the anti-IL-17A antibody secukinumab.

Comparative effectiveness of secukinumab and adalimumab in ankylosing spondylitis as assessed by matching-adjusted indirect comparison.

ObjectiveMatching-adjusted indirect comparison was used to assess the comparative effectiveness of secukinumab 150 mg and adalimumab 40 mg in biologic-naïve patients with ankylosing spondylitis (AS) for up to 1 year.MethodsPooled individual patient data from the secukinumab arms of MEASURE 1 (NCT01358175) and MEASURE 2 (NCT01649375) trials (n=197) were matched against the ATLAS (NCT00085644) adalimumab population (n=208). Logistic regression analysis was used to determined weights to match for age, sex, Bath AS Functional Index, C-reactive protein levels, and previous tumor necrosis factor inhibitor therapy. Recalculated Assessment of SpondyloArthritis International Society (ASAS) 20 and 40 responses at weeks 8, 12, 16, 24, and 52 from MEASURE 1/2 (effective sample size=120) were compared with those of ATLAS. Anchored (placebo-adjusted) comparisons were possible until week 12, and unanchored (non-placebo-adjusted) comparisons were necessary thereafter.ResultsFor placebo-anchored ASAS 20 and 40 comparisons up to week 12, there were no differences between secukinumab and adalimumab. For unanchored comparisons at week 16, ASAS 20 was higher for secukinumab [odds ratio 1.60 (95% confidence interval, 1.01–2.54); p=0.047]; at week 24, ASAS 20 and 40 were higher for secukinumab [1.76 (1.11–2.79); p=0.017 and 1.79 (1.14–2.82); p=0.012, respectively]; and at week 52, ASAS 40 was higher for secukinumab [1.54 (1.06–2.23); p=0.023] than for adalimumab.ConclusionThere were no differences observed in placebo-adjusted ASAS 20 and 40 responses up to 12 weeks between secukinumab- and adalimumab-treated patients with ankylosing spondylitis. After week 12, secukinumab demonstrated signs of greater improvement in non-placebo-adjusted ASAS 20 and 40 responses than adalimumab.