Biological treatment in elderly and young patients with ankylosing spondylitis: TURKBIO real-life data results.

Objectives: This study aims to investigate the effect of age on disease activity and biological treatment in patients with ankylosing spondylitis (AS). Patients and methods: A total of 811 AS patients registered in the TURKBIO registry database between 2011 and 2019 were categorized according to their age at the time of entry into the registry and assigned to one of two groups: young patients, defined as <60 years of age (n=610), and those aged ≥60 years (n=201) were recorded as elderly patients. Demographic, clinical, and laboratory characteristics, along with disease activity markers and other follow-up parameters, as well as current and prior treatments, were electronically recorded during each visit using open-source software. Results: The mean age of the elderly patients was 67±5.8 years, while the mean age of the younger patients was 49.2±10.9 years. Male predominance was lower in the older AS group compared to the younger AS group (p=0.002). During follow-up period, 397 patients (comprising 318 young and 79 elderly individuals) had a history of using at least one biological disease-modifying agent (bDMARD). There was no significant difference between the groups in terms of DMARD and bDMARD-use distributions. First tumor necrosis factor inhibitor (TNFi) retention rates were found to be similar in both groups over 10 years of follow-up. Adverse events were found to be similar in young (19.9%) and elderly (26.8%) AS patients. Conclusion: Research in the TURKBIO cohort reveals that both older and younger patients with AS exhibited similar disease activity levels with comparable treatment approaches. Moreover, the results of TNFi treatments in elderly patients were the same as those observed in younger patients, with no notable increase in safety concerns.

[Head-to-head trials in rheumatoid arthritis]. / Head-to-Head-Therapiestudien zur rheumatoiden Arthritis.

BACKGROUND: Head-to-head studies are important to select the optimal treatment in terms of efficacy and side effect profiles when several drugs are available. AIM OF THE WORK: This article describes all studies comparing the use of disease-modifying antirheumatic drugs (DMARD) in rheumatoid arthritis (RA) in head-to-head studies or in which a DMARD was at least included in an active comparison arm. RESULTS: A total of 23 studies comparing DMARDs were identified. These included comparisons of Janus kinase (JAK) inhibitors with methotrexate and with adalimumab as well as the oral surveillance study. DISCUSSION: There are already an exceptionally large number of head-to-head studies in RA, both for comparisons of efficacy and safety of DMARDs. Nevertheless, more such comparative studies are needed, for example to clarify whether adverse events of tofacitinib observed in the oral surveillance study are specific to the JAK 1/JAK 3 inhibitor or are a class effect of all JAK inhibitors.

Risk of disease flare in spondyloarthritis patients after tapering tumor necrosis factor inhibitors: A meta-analysis and literature review.

BACKGROUND: Tumor necrosis factor inhibitors (TNFis) have shown dramatic benefit in patients with spondyloarthritis (SpA). Tapering of TNFi medication may be considered in patients with sustained low disease activity because continued use of TNFis at standard doses may increase the risk of side effects including infections and impose an economic burden. However, the optimal TNFi tapering strategy for SpA patients with inactive disease has not been established. In the present study, we investigated whether tapering TNFi doses is associated with similar risk of disease flare to maintaining SpA patients on TNFis at the standard dosage. METHODS: The MEDLINE, Embase, and Cochrane databases were systemically searched to retrieve randomized control trials (RCTs) and observational studies published prior to August 2023, that compared disease flare in SpA (including axial SpA [axSpA], psoriatic arthritis [PsA], and SpA with IBD) patients who received standard TNFi doses and those who received a tapered dose of TNFi. Odds ratios (ORs) and 95% confidence intervals (CIs) were directly retrieved or calculated, and meta-analyses were performed. Bias was assessed using funnel plots with Begg and Mazumdar rank correlation / Egger's regression method. RESULTS: Among 2,237 SpA patients in the 12 studies (9 RCTs and 3 observational studies) retrieved, 1,301 received the standard TNFi dose, while 936 SpA patients underwent TNFi tapering. Of these, 216 (16.6%) standard-dose TNFi and 217 (23.2%) TNF-tapering patients experienced disease flares. The pooled OR for disease flare in TNFi-tapering patients was 1.601 (95% CI 1.276 - 2.008) compared with the standard-dose patients. The funnel plot showed no publication bias. CONCLUSIONS: The strategy of TNFi tapering was associated with a significantly increased risk of disease flare compared to maintaining SpA patients at the standard TNF dose. Further studies are needed to determine which patients can safely undergo tapering of TNFi and to develop safe tapering strategies.

A Machine Learning Approach for Prediction of CDAI Remission with TNF Inhibitors: A Concept of Precision Medicine from the FIRST Registry.

INTRODUCTION: This study aimed to develop low-cost models using machine learning approaches predicting the achievement of Clinical Disease Activity Index (CDAI) remission 6 months after initiation of tumor necrosis factor inhibitors (TNFi) as primary biologic/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) for rheumatoid arthritis (RA). METHODS: Data of patients with RA initiating TNFi as first b/tsDMARD after unsuccessful methotrexate treatment were collected from the FIRST registry (August 2003 to October 2022). Baseline characteristics and 6-month CDAI were collected. The analysis used various machine learning approaches including logistic regression with stepwise variable selection, decision tree, support vector machine, and lasso logistic regression (Lasso), with 48 factors accessible in routine clinical practice for the prediction model. Robustness was ensured by k-fold cross validation. RESULTS: Among the approaches tested, Lasso showed the advantages in predicting CDAI remission: with a mean area under the curve 0.704, sensitivity 61.7%, and specificity 69.9%. Predicted TNFi responders achieved CDAI remission at an average rate of 53.2%, while only 26.4% of predicted TNFi non-responders achieved remission. Encouragingly, the models generated relied solely on patient-reported outcomes and quantitative parameters, excluding subjective physician input. CONCLUSIONS: While external cohort validation is warranted for broader applicability, this study highlights the potential for a low-cost predictive model to predict CDAI remission following TNFi treatment. The approach of the study using only baseline data and 6-month CDAI measures, suggests the feasibility of establishing regional cohorts to generate low-cost models tailored to specific regions or institutions. This may facilitate the application of regional/in-house precision medicine strategies in RA management.

This study aims to enhance the management of rheumatoid arthritis by predicting the likelihood of achieving the treatment target­Clinical Disease Activity Index remission within 6 months of initiating tumor necrosis factor inhibitors. In rheumatoid arthritis, the goal is often Clinical Disease Activity Index remission, and the standard approach involves using medications like methotrexate and biologic/targeted synthetic disease-modifying antirheumatic drugs. However, not all patients respond to these treatments, leading to a trial-and-error process of changing medications. Tumor necrosis factor inhibitors are commonly used as the initial biologic/targeted synthetic disease-modifying antirheumatic drugs for patients who do not respond adequately to methotrexate; however, tumor necrosis factor inhibitor treatment may not achieve effective outcomes for all patients. The study, using a cohort of patients with rheumatoid arthritis treated with tumor necrosis factor inhibitor, has developed a model predicting Clinical Disease Activity Index remission with tumor necrosis factor inhibitors. The models use only standard clinical parameters, therefore no special examination or additional cost is required for the predictions. This approach holds the potential to improve rheumatoid arthritis management by reducing the need for trial-and-error approaches and facilitating more personalized and effective treatment strategies. While further validation is necessary, the study also suggests that creating cost-effective models tailored to specific regions or institutions is possible.

Switching from intravenous to subcutaneous infliximab maintenance therapy in inflammatory bowel disease: Post hoc longitudinal analysis of a randomized trial.

BACKGROUND: Pharmacokinetic non-inferiority of subcutaneous (SC) to intravenous (IV) CT-P13 maintenance therapy was demonstrated in a randomized trial (NCT02883452). This post hoc analysis evaluated longitudinal clinical outcomes with the two infliximab treatment strategies. METHODS: Patients with Crohn's disease or ulcerative colitis received CT­P13 IV loading doses (5 mg/kg; Week [W] 0 and W2) before randomization (1:1) to receive CT-P13 SC (body weight-based dosing every 2 weeks [Q2W]; W6-54; 'SC maintenance group') or CT­P13 IV (5 mg/kg Q8W; W6-22) then CT-P13 SC (Q2W; W30-54; 'IV-to-SC switch group'). Paired W30/W54 patient-level data were analyzed. RESULTS: Fifty-three (IV-to-SC switch) and fifty-nine (SC maintenance) patients were analyzed. Median trough serum CT-P13 concentrations were significantly higher at W54 versus W30 in the IV-to-SC switch group (20.4 versus 2.3 µg/mL; p < 0.00001), while remaining consistent in the SC maintenance group. Statistically significant improvements in pharmacokinetics, efficacy, fecal calprotectin levels, and quality of life were seen following switch to SC administration at W30 in the IV-to-SC switch group; safety findings were similar pre- and post-switch. CONCLUSION: Formulation switching from IV to SC infliximab maintenance therapy was well tolerated and may provide additional clinical improvements. Findings require confirmation in larger prospective studies.

The use of a tumor necrosis factor inhibitor-adalimumab-in the management of arthritis in an adolescent with HIV: A case report.

Human immunodeficiency virus (HIV) infection is associated with a myriad of musculoskeletal manifestations. Inflammatory arthritis has been described in association with HIV in both adults and children. Biologic disease-modifying anti-rheumatic drugs, particularly tumor necrosis factor inhibitors (TNFi), have been reported to manage inflammatory arthritis in adults with HIV when conventional therapy fails to control arthritis. In this report, we describe the management of arthritis and enthesitis in a 12-year-old adolescent male with HIV using the TNFi adalimumab. At the time of presentation, the patient was on highly active antiretroviral therapy for 1 year. His viral load was <40 copies/mL, and the CD4+ T-cell count was 1280 cells/mm3 . He had a positive antinuclear antibody and HLA-B27. Rheumatoid factor was negative. After screening for hepatitis B and C and latent tuberculosis, the patient was started on adalimumab. This report describes the successful control of recalcitrant arthritis and enthesitis in a pediatric patient with HIV infection using adalimumab.

Longitudinal variation of serum PCSK9 in ulcerative colitis: association with disease activity, T helper 1/2/17 cells, and clinical response of tumor necrosis factor inhibitor.

AIMS: Proprotein convertase subtilisin/kexin type 9 (PCSK9) modulates CD4+ T cell differentiation and inflammatory response, the latter ones mediate ulcerative colitis (UC) initiation. This study intended to explore the correlation of serum PCSK9 with disease activity, T helper (h)1/Th2/Th17 cells, and clinical response of tumor necrosis factor inhibitor (TNFi) in UC patients. METHODS: In 65 UC patients underwent TNFi treatment, serum PCSK9 was evaluated at baseline (W0), week (W)2, W6, and W12 by enzyme-linked immunosorbent assays; meanwhile, Th1/Th2/Th17 cells were determined at W0 by flow cytometry. Besides, serum PCSK9 was detected in 65 healthy controls (HCs). RESULTS: Serum PCSK9 was increased in UC patients compared to HCs (P<0.001), which also positively correlated with C-reactive protein (P=0.009), total Mayo score (P=0.018), Mayo-defined disease activity (P=0.020), Th1 (P=0.033), and Th17 (P=0.003) cells, but not Th2 cells (P=0.086) in UC patients. Interestingly, serum PCSK9 was steadily declined from W0 to W12 (P<0.001). W2-W0, W6-W0, and W12-W0 serum PCSK9 change (PCSK9 at W2, W6, or W12 minus PCSK9 at W0, respectively) was gradually becoming greater during TNFi treatment (P<0.001). Furthermore, forty-five (69.2%) patients achieved clinical response at W12, whose serum PCSK9 at W6 (P=0.041) and W12 (P=0.001) was lower, and W6-W0 (P=0.043), W12-W0 (P=0.019) serum PCSK9 change was more obvious compared to patients without clinical response at W12. CONCLUSIONS: Serum PCSK9 is positively related to disease activity, Th1, and Th17 cells in UC patients; further, its decline correlates with TNFi response achievement in these patients.

Distinct long-term disease activity trajectories differentiate early on treatment with etanercept in both rheumatoid arthritis and spondylarthritis patients: a prospective cohort study.

To characterize disease activity trajectories and compare long-term drug retention between rheumatoid (RA) and spondylarthritis (SpA) patients initiating tumor necrosis factor inhibitor (TNFi) treatment (etanercept). Prospective observational study of RA, axial (AxSpA) and peripheral SpA (PerSpA) patients initiating etanercept during 2004-2020. Kaplan-Meier plots were used for drug retention comparisons and multivariable Cox regression models for predictors of discontinuation. Long-term disease activity trajectories were identified by latent class growth models using DAS28-ESR or ASDAS-CRP as outcome for RA and AxSpA respectively. We assessed 711 patients (450 RA, 178 AxSpA and 83 PerSpA) with a median (IQR) follow-up of 12 (5-32) months. At 5 years, 22%, 30% and 21% of RA, AxSpA and PerSpA patients, respectively, remained on therapy. Etanercept discontinuation was independent of the diagnosis and was predicted by gender and obesity in both RA and SpA groups. Four disease activity (DA) trajectories were identified from 6th month of treatment in both RA and AxSpA. RA patients in remission-low DA groups (33.7%) were younger, had shorter disease duration, fewer comorbidities and lower baseline disease activity compared to moderate (40.6%) & high DA (25.7%) groups. In AxSpA 74% were in inactive-low DA and they were more often males, non-obese and had lower number of comorbidities compared to higher ASDAS-CRP trajectories. In RA and AxSpA patients, disease activity trajectories revealed heterogeneity of TNFi treatment responses and prognosis. Male gender, lower baseline disease activity and fewer comorbidities, characterize a favourable outcome in terms of disease burden accrual and TNFi survival.

Is low-dose tumor necrosis factor inhibitor effective and safe in patients with ankylosing spondylitis flare-up after renal transplantation? A case report and literature review.

Rheumatic diseases, the immunosuppressant drugs used after solid organ transplantation to prevent graft rejection, and the biologics used for controlling rheumatic disease, especially tumor necrosis factor inhibitors (TNFi)-all of these could increase the risk of malignancy. The roles of biologics for disease control in rheumatic disease patients after kidney transplantation (KT) are not well established because only a few cases are reported, and the possibility of increasing infection and malignancy rates. Here, we present the first case of ankylosing spondylitis (AS) successfully treated with low-dose TNFi for disease activity flare-up 5 months after KT and review the literature to see whether the use of biologics, especially TNFi, in AS patients with disease activity flare-ups after receiving KT is effective and safe.

How to Use Janus Kinase Inhibitors in the Treatment of Rheumatoid Arthritis? A Clinical Assessment of Risks and Benefits.

PURPOSE OF REVIEW: To provide an updated understanding of risks and benefits of Janus kinase inhibitors (JAKi) versus biologic disease-modifying antirheumatic drugs (bDMARDs) in the management of rheumatoid arthritis (RA). RECENT FINDINGS: Shared decision-making is needed in choosing between JAKi and bDMARDs. Cardiovascular disease, malignancy, and thromboembolic events guide this choice. In patients with active RA despite methotrexate use, tumor necrosis factor inhibitor is conditionally favored over JAKi for low-cardiovascular-risk patients and strongly favored in those with pre-existing cardiovascular disease or multiple cardiovascular risk factors. Suboptimal treatment of treatment-refractory RA patients may pose a greater absolute cardiovascular risk than with JAKi use. Use of aspirin and statin may be considered to reduce cardiovascular risk. New safety data on JAKi has redefined the treatment approach in RA. JAKi remains an important oral medication option in active RA despite treatment with bDMARDs, especially in those with low cardiovascular risk.

Prevalence and predictors of sustained remission/low disease activity after discontinuation of induction or maintenance treatment with tumor necrosis factor inhibitors in rheumatoid arthritis: a systematic and scoping review.

BACKGROUND: To determine the prevalence of sustained remission/low disease activity (LDA) in patients with rheumatoid arthritis (RA) after discontinuation of tumor necrosis factor inhibitors (TNFi), separately in induction treatment and maintenance treatment studies, and to identify predictors of successful discontinuation. METHODS: We performed a systematic literature review of studies published from 2005 to May 2022 that reported outcomes after TNFi discontinuation among patients in remission/LDA. We computed prevalences of successful discontinuation by induction or maintenance treatment, remission criterion, and follow-up time. We performed a scoping review of predictors of successful discontinuation. RESULTS: Twenty-two induction-withdrawal studies were identified. In pooled analyses, 58% (95% confidence interval (CI) 45, 70) had DAS28 < 3.2 (9 studies), 52% (95% CI 35, 69) had DAS28 < 2.6 (9 studies), and 40% (95% CI 18, 64) had SDAI ≤ 3.3 (4 studies) at 37-52 weeks after discontinuation. Among patients who continued TNFi, 62 to 85% maintained remission. Twenty-two studies of maintenance treatment discontinuation were also identified. At 37-52 weeks after TNFi discontinuation, 48% (95% CI 38, 59) had DAS28 < 3.2 (10 studies), and 47% (95% CI 33, 62) had DAS28 < 2.6 (6 studies). Heterogeneity among studies was high. Data on predictors in induction-withdrawal studies were limited. In both treatment scenarios, longer duration of RA was most consistently associated with less successful discontinuation. CONCLUSIONS: Approximately one-half of patients with RA remain in remission/LDA for up to 1 year after TNFi discontinuation, with slightly higher proportions in induction-withdrawal settings than with maintenance treatment discontinuation.

COVID-19 in patients with rheumatological diseases in the Eastern Province of Saudi Arabia.

The severity of the 2019 coronavirus disease (COVID-19) and its effects remain unpredictable. Certain factors, such as obesity, hypertension, and type 2 diabetes mellitus, may increase the severity of the disease. Rheumatology experts suggest that patients with active autoimmune conditions and controlled autoimmune diseases on immunosuppressive therapy may be at higher risk of developing severe COVID-19. In this retrospective observational study, we aimed to examine the patterns of COVID-19 in patients with underlying rheumatological diseases and their association with disease severity and hospital outcomes. A total of 34 patients with underlying rheumatological diseases who tested positive for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) by polymerase chain reaction (PCR) were included between March 2020 and April 2021 at King Fahd Hospital of the University. The study population consisted of 76.47% female and 23.53% male patients, with a mean age ranging from 20 to 40 years. Female gender (p=0.0001) and younger age (p=0.004) were associated with milder disease. The most frequent rheumatological disease was systemic lupus erythematosus (SLE) (38.24%), which was associated with a milder infection (p=0.045). Patients treated with mycophenolate mofetil (MMF) had a milder disease course (p=0.0037). Hypertension was significantly associated with severe COVID-19 disease (p=0.037). There was no significant relationship between SLE and the need for ICU admission. Patients on hydroxychloroquine and MMF tended to develop milder disease, and there was no association between the severity of the infection and the treatment with steroids.

One-Year Medication Adherence and Persistence in Rheumatoid Arthritis in Clinical Practice: A Retrospective Analysis of Upadacitinib, Adalimumab, Baricitinib, and Tofacitinib.

INTRODUCTION: This study evaluated 12 months adherence and persistence among Janus kinase inhibitors (upadacitinib, baricitinib, tofacitinib) and adalimumab, a tumor necrosis factor inhibitor (TNFi), in patients with rheumatoid arthritis (RA). METHODS: This retrospective analysis used administrative claims data from the Merative™ MarketScan® Research Databases (2018-2022). Eligible adults had ≥ 1 RA diagnosis before the index date, ≥ 1 pharmacy claim for index medication, and ≥ 12 months of continuous insurance enrollment pre- and post-index. Adherence to treatment [defined as proportion of days covered (PDC) ≥ 80%], risk of treatment discontinuation, and mean time to discontinuation were assessed during the 12 months follow-up. Adjusted odds ratios (aOR), adjusted hazard ratios (aHR), and 95% confidence intervals (CI) were reported. RESULTS: In total, 6317 patients were included (683 upadacitinib, 3732 adalimumab, 132 baricitinib, 1770 tofacitinib). Compared with upadacitinib, patients initiating adalimumab [aOR (95% CI): 0.82 (0.69, 0.96)], baricitinib [0.46 (0.31, 0.68)], and tofacitinib [0.74 (0.62, 0.88)] were significantly less likely to achieve PDC ≥ 80%. Risk of treatment discontinuation was significantly higher in patients treated with adalimumab [aHR (95% CI): 1.14 (1.01, 1.29)], baricitinib [1.48 (1.16, 1.90)], and tofacitinib [1.22 (1.07, 1.38)] compared with upadacitinib. Mean time to discontinuation was 256 (upadacitinib), 249 (adalimumab), 221 (baricitinib), and 239 (tofacitinib) days. Similar results were observed in patients with prior TNFi use. CONCLUSIONS: Patients with RA, regardless of recent TNFi experience, initiating upadacitinib were significantly more likely to be adherent and less likely to discontinue therapy compared to adalimumab, baricitinib, and tofacitinib in the first 12 months of treatment.

Superior Efficacy of Infliximab Versus Adalimumab for First-Line Treatment of Crohn's Perianal Fistulae.

BACKGROUND: Crohn's disease perianal fistulae (CD-PAF) occur in 25% of patients and are notoriously challenging to manage. Tumor necrosis factor inhibitors are first line agents. AIMS: The aim of this study was to compare infliximab (IFX) versus adalimumab (ADA) efficacy in CD-PAF healing over time. METHODS: A retrospective study at two large-tertiary medical centers was performed. Inclusion criteria were actively draining CD-PAF and initial treatment with IFX or ADA following CD-PAF diagnosis. The primary endpoints were perianal fistula response and remission at 6 and 12 months. Secondary endpoints included biologic persistence over time and dose escalation at 6 and 12 months. RESULTS: Among 151 patients included in the study, 92 received IFX and 59 received ADA as first line agents after CD-PAF diagnosis. At 6 months, the 64.9% of the IFX group and 34.8% of the ADA group demonstrated CD-PAF clinical improvement (p < 0.01). Univariate and multivariate analyses demonstrated significant differences among the IFX and ADA groups for clinical response at 6-months and 12-months (p = 0.002 and p = 0.042, respectively). There were no factors that predicted response, with the exception of concomitant immunomodulator affecting the 6-month clinical response (p = 0.021). Biologic persistence, characterized by Kaplan Meier methods, was significantly longer in the IFX group compared to the ADA group (Log-rank p = 0.01). CONCLUSION: IFX induction and maintenance is associated with higher rates of response and remission in CD-PAF healing as well as higher treatment persistence compared to ADA. Additionally, our study supports the use of concomitant immunomodulator therapy for CD-PAF healing and remission.

Unmet Needs in Real-World Advanced Therapy-Naïve and -Experienced Patients with Moderately to Severely Active Ulcerative Colitis in the United States.

INTRODUCTION: Despite availability of advanced therapies (ATs) for ulcerative colitis (UC), many patients fail to respond to treatment. This study examined real-world clinical and humanistic outcomes associated with current treatments in patients with UC. METHODS: This cross-sectional study used US data from the Adelphi Real World Disease Specific Programme for inflammatory bowel disease from before (2017-2018) and during the COVID-19 pandemic (2020-2021). Physicians (gastroenterologists) seeing > 5 patients/month reported patients' disease characteristics, current symptoms and treatments, and reasons for treatment choices for their next seven consecutive patients aged ≥ 18 years with moderately to severely active UC before current treatment. Patients were asked to complete the EQ-5D-5L health-related quality of life (HRQoL) measure. ATs included tumor necrosis factor inhibitors (TNFis), integrin receptor antagonists, interleukin-12/23 antagonists, and Janus kinase inhibitors. Patients were classified as AT-naïve or AT-experienced based on current treatment received for ≥ 8 weeks and further classified as responders or non-responders based on symptoms, disease flare status, and remission. Descriptive analyses are presented. RESULTS: The 2017-2018 cohort included 92 physicians and 539 patients (208 [38.6%] AT-experienced). The 2020-2021 cohort included 73 physicians and 448 patients (349 [77.9%] AT-experienced). TNFis were the most common ATs. In 2017-2018, 195 (58.9%) AT-naïve and 113 (54.3%) AT-experienced patients were non-responders; in 2020-2021 this was 57 (57.6%) and 182 (52.1%). Efficacy and induction of remission were physicians' most common reasons for AT choice. Dislike of injections/infusions was the most common reason for eligible patients not receiving biologic therapy. Numerically, non-responders (both AT-naïve and AT-experienced) had more symptoms, overall pain and fatigue, and lower HRQoL scores than responders. CONCLUSIONS: Before (2017-2018) and during the pandemic (2020-2021), over half of patients with UC did not respond to AT. Non-responders carried a high burden of disease. Alternative therapies are urgently needed to treat UC.

Use of Immunosuppression and the Risk of Subsequent Overall or Cancer Mortality.

PURPOSE: To determine the incidence of all-cause and cancer mortality (CM) in association with immunosuppression. DESIGN: Retrospective cohort study at ocular inflammatory disease (OID) subspecialty centers. We harvested exposure and covariate data retrospectively from clinic inception (earliest in 1979) through 2010 inclusive. Then we ascertained overall and cancer-specific mortalities by National Death Index linkage. We constructed separate Cox models to evaluate overall and CM for each class of immunosuppressant and for each individual immunosuppressant compared with person-time unexposed to any immunosuppression. PARTICIPANTS: Patients with noninfectious OID, excluding those with human immunodeficiency infection or preexisting cancer. METHODS: Tumor necrosis factor (TNF) inhibitors (mostly infliximab, adalimumab, and etanercept); antimetabolites (methotrexate, mycophenolate mofetil, azathioprine); calcineurin inhibitors (cyclosporine); and alkylating agents (cyclophosphamide) were given when clinically indicated in this noninterventional cohort study. MAIN OUTCOME MEASURES: Overall mortality and CM. RESULTS: Over 187 151 person-years (median follow-up 10.0 years), during which 15 938 patients were at risk for mortality, we observed 1970 deaths, 435 due to cancer. Both patients unexposed to immunosuppressants (standardized mortality ratio [SMR] = 0.95, 95% confidence interval [CI], 0.90-1.01) and those exposed to immunosuppressants but free of systemic inflammatory diseases (SIDs) (SMR = 1.04, 95% CI, 0.95-1.14) had similar mortality risk to the US population. Comparing patients exposed to TNF inhibitors, antimetabolites, calcineurin inhibitors, and alkylating agents with patients not exposed to any of these, we found that overall mortality (adjusted hazard ratio [aHR] = 0.88, 0.89, 0.90, 1.11) and CM (aHR = 1.25, 0.89, 0.86, 1.23) were not significantly increased. These results were stable in sensitivity analyses whether excluding or including patients with SID, across 0-, 3-, or 5-year lags and across quartiles of immunosuppressant dose and duration. CONCLUSIONS: Our results, in a cohort where the indication for treatment was proven unassociated with mortality risk, found that commonly used immunosuppressants-especially the antimetabolites methotrexate, mycophenolate mofetil, and azathioprine; the TNF inhibitors adalimumab and infliximab, and cyclosporine-were not associated with increased overall and CM over a median cohort follow-up of 10.0 years. These results suggest the safety of these agents with respect to overall and CM for patients treated with immunosuppression for a wide range of inflammatory diseases. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Factors influencing prescribing the first add-on disease-modifying antirheumatic drugs in patients initiating methotrexate for rheumatoid arthritis.

Background: Advances in Disease-Modifying Antirheumatic Drugs (DMARDs) have expanded the treatment landscape for Rheumatoid Arthritis (RA). Guidelines recommend adding either conventional synthetic (cs), biologic (b), or targeted synthetic (ts) DMARDs to methotrexate (MTX) for managing RA. Limited evidence exists regarding the factors that contribute to adding a DMARD agent to the MTX regimen. This study examined the factors associated with adding the first DMARD in RA patients initiating MTX. Methods: This retrospective cohort study utilized the MarketScan data (2012-2014) involving adults (aged ≥18) with RA initiating an MTX (index date) between Jul 1, 2012 and Dec 30, 2013, and with continuous enrollment for the 6-month pre-index period. The combination therapy users received the first treatment addition of DMARD starting from day 30 after the index MTX over one year period. The study focused on the addition of csDMARDs, Tumor Necrosis Factor Inhibitors (TNFi) bDMARDs, non-TNFi bDMARDs, or tsDMARDs. Baseline covariates were measured in the 6-month pre-index and grouped into predisposing, enabling, and need factors, as per the Andersen Behavior Model. Multivariable logistic regression examined the factors associated with the addition of TNFi compared to adding a csDMARD. An additional regression model evaluated the factors associated with adding any biologic (combining TNFi and non-TNFi biologics). Results: Among 8350 RA patients starting MTX, 31.92% (n = 2665) initiated any DMARD within the 1-year post-index period. Among RA patients initiating a DMARD prescription after starting MTX, 945 (11.32%) received combination therapy with treatment addition of a DMARD to MTX regimen; majority added TNFi (550, 58%), followed by csDMARD (352, 37%); non-TNF biologic (40, 4%), or tsDMARD (3, 0.3%). The tsDMARD group was limited and was not included for further analysis. The multivariable model found Preferred Provider Organization insurance coverage (odds ratio [OR], 1.43; 95% confidence interval (CI), 1.06-1.93), chronic pulmonary disease (OR, 1.98; 95% CI, 1.14-3.44), liver disease (OR, 5.24; 95% CI, 1.77-15.49), and Elixhauser score (OR, 0.91; 95% CI, 0.86-0.97) were significantly associated with the addition of TNF-α inhibitors. The separate multivariable model additionally found that patients from metropolitan areas (OR, 1.50; 95% CI, 1.04-2.16) were positively associated with adding any biological agent. Conclusions: TNFi are often added to MTX for managing RA. Enabling and need factors contribute to the prescribing of a TNFi add-on therapy in RA. Future research should examine the impact of these combination therapies on RA management.

Effectiveness of tumor necrosis factor inhibitors in children with enthesitis-related arthritis: a single-center retrospective analysis.

Objective: In children with enthesitis-related arthritis (ERA), the hip and sacroiliac joint function might be impaired if not properly treated. We sought to evaluate the effectiveness of anti-tumor necrosis factor-α (TNF-α) therapy using the inflammatory indicators, Juvenile Arthritis Disease Activity Score 27 (JADAS27) and magnetic resonance imaging (MRI). Methods: We conducted a single-center retrospective study of 134 patients with ERA. We evaluated the effect of anti-TNF therapy on the inflammatory indicators, active joint count, MRI quantitative score, and JADAS27 over 18 months. We used the Spondyloarthritis Research Consortium of Canada (SPARCC) and the Hip Inflammation MRI Scoring System (HIMRISS) scoring systems for hip and sacroiliac joints scoring. Results: The average age of onset of children with ERA was 11.62 ± 1.95 years, and they were treated with disease-modifying antirheumatic drugs (DMARDs) combined with biologics (n = 87, 64.93%). There were no differences in HLA-B27 positivity between the biologics and non-biologics treatment groups [66 (49.25%) vs. 68 (50.75%), P > 0.05]. Children who received anti-TNF (71 received etanercept, 13 adalimumab, 2 golimumab, and 1 infliximab) therapy improved significantly. Children with ERA used DMARDs and biologics at baseline (Group A) were followed up to 18 months, and their active joint count (4.29 ± 1.99 vs. 0.76 ± 1.33, P = 0.000), JADAS27 (13.70 ± 4.80 vs. 4.53 ± 4.52, P = 0.000) and MRI quantitative scores (P = 0.001) were significantly lower than those at baseline. Some of the patients (n = 13, 9.70%) were treated with DMARDs at the onset of the disease, but did not show significant improvement (Group B). After 6-18 months of switching to anti-TNF therapy, related indicators of the children were significantly lower than at baseline and 1 month (P < 0.013). At 18 months, a total of 33 patients (n = 74, 44.59%) in Group A and 7 (n = 13, 53.85%) in Group B reached inactive state. Conclusion: Eighteen months after diagnosis, anti-TNF therapy was found to be effective in children diagnosed with ERA. MRI is important for the early diagnosis of juvenile idiopathic arthritis. TNF-α inhibitors can significantly improve the clinical manifestations of sacroiliac joint and hip involvement in patients with ERA. Overall, the real-world study provides more evidence for precision diagnosis and treatment for other hospitals, families and patients.

Syndesmophyte Growth in Ankylosing Spondylitis: from Laboratory to Bedside.

PURPOSE OF REVIEW: This study aims to review recent studies on risk factors for syndesmophyte growth in ankylosing spondylitis (AS) and on treatment effects. RECENT FINDINGS: New genetic studies, including a genome-wide association study, provided only limited evidence of specific genetic associations with radiographic severity. Measures of inflammation, including vertebral osteitis and C-reactive protein level, were strongly associated with radiographic progression, while studies of adipokines had mixed results. Mesenchymal stem cells from HLA-B27 positive AS patients were found to promote vertebral ossification via a pathway of B27 misfolding, retinoic acid receptor-ß activation, and increased bone alkaline phosphatase. Low vertebral trabecular bone density is associated with syndesmophyte growth, with reciprocal effects when bridged. Several observational studies suggested radiographic severity was reduced by treatment with tumor necrosis factor inhibitors, particularly when longer than 2 years. Syndesmophyte development in AS is the result of a complex, incompletely understood, interplay of inflammatory and mechanical factors.

Change in Serum KL-6 Level during Biologic Treatment for Psoriasis.

BACKGROUND: We previously analyzed data from blood examination screenings, including serum Krebs von den Lungen (KL) -6 level, before starting biologic treatment for psoriasis in a real-world setting. However, we did not follow change in KL-6 level after the initiation of biologics. Furthermore, there has been no follow-up study of certolizumab pegol, risankizumab, or tildrakizumab. This study evaluated change in serum KL-6 levels in patients during treatment with biologics, including certolizumab pegol, risankizumab, and tildrakizumab. METHODS: We analyzed data from 111 patients. Change in KL-6 level was regarded as significant if it increased to greater than 500 U/mL at least once and if the maximum level after treatment with biologics was at least 1.5 times that of the baseline level. RESULTS: KL-6 level significantly changed during treatment with TNF inhibitors, IL-17 inhibitors, and IL-23 inhibitors in 9 (20.9%), 2 (6.3%), and 2 (5.6%) patients, respectively. Mean age, mean baseline KL-6 level, and frequency of TNF inhibitor use were higher in patients with a significant change in KL-6 level than those in patients without a significant change. Ten patients had minor interstitial changes on chest CT scans but no clinical signs suggesting interstitial pneumonia. CONCLUSIONS: Older patients with psoriasis and high baseline KL-6 levels must be carefully monitored during treatment with biologics, especially TNF inhibitors. Monitoring of KL-6 level and chest CT scans is necessary to exclude the possibility of drug-induced interstitial pneumonia.