Persistent Flares Research Articles

The use of photodynamic therapy in the management of darier disease and Hailey-Hailey disease: a systematic review.

Darier disease and Hailey-Hailey disease are rare autosomal dominant genodermatoses that negatively impact patient quality of life. In addition, they pose challenges to dermatologists who manage these diseases. There is currently no treatment that reliably induces remission for either disease, leaving patients dependent on symptom management. Oral and topical retinoids are the most commonly used therapies but have numerous side effects that often lead to discontinuation or inability to tolerate long-term treatment (Burge and Wilkinson in J Am Acad Dermatol 27:40-50, 1992). Due to the rarity of these diseases, there are no clinical trials investigating treatment options for the persistent flares patients experience. In light of this, dermatologists have tried various methods used in the management of other inflammatory disorders including photodynamic therapy (PDT). A systematic review was conducted to investigate this treatment option which yielded a total of 12 studies that had reported the use of photodynamic therapy (PDT) as a treatment option for Darier or Hailey-Hailey disease. Though results showed that PDT can induce disease remission for up to several months or years, there are many unanswered questions that need to be addressed before adopting PDT as a leading treatment option for those genodermatoses. In particular, cost, tolerability, and efficacy and safety in patients who are skin of color need to be further studied. Lastly, recommendations on treatment duration, number of sessions, photosensitizing agents, lasers, and continuation or discontinuation of topical and systemic medications need to be appraised before formal recommendations can be made.

Defining Criteria for Disease Activity States in Systemic Juvenile Idiopathic Arthritis Based on the Systemic Juvenile Arthritis Disease Activity Score.

Our objective was to develop and validate cutoff values in the systemic Juvenile Arthritis Disease Activity Score 10 (sJADAS10) that distinguish the states of inactive disease (ID), minimal disease activity (MDA), moderate disease activity (MoDA), and high disease activity (HDA) in children with systemic juvenile idiopathic arthritis, based on subjective disease state assessment by the treating pediatric rheumatologist. The cutoff definition cohort was composed of 400 patients enrolled at 30 pediatric rheumatology centers in 11 countries. Using the subjective physician rating as an external criterion, six methods were applied to identify the cutoffs: mapping, calculation of percentiles of cumulative score distribution, the Youden index, 90% specificity, maximum agreement, and receiver operating characteristic curve analysis. Sixty percent of the patients were assigned to the definition cohort, and 40% were assigned to the validation cohort. Cutoff validation was conducted by assessing discriminative ability. The sJADAS10 cutoffs that separated ID from MDA, MDA from MoDA, and MoDA from HDA were ≤2.9, ≤10, and >20.6, respectively. The cutoffs discriminated strongly among different levels of pain, between patients with and without morning stiffness, and among patients whose parents judged their disease status as remission or persistent activity or flare or were satisfied or not satisfied with current illness outcome. The sJADAS cutoffs revealed good metrologic properties in both definition and validation cohorts and are therefore suitable for use in clinical trials and routine practice.

A Prediction Model for Successful Increase of Adalimumab Dose Intervals in Patients with Crohn’s Disease: Secondary Analysis of the Pragmatic Open-Label Randomised Controlled Non-inferiority LADI Trial

BackgroundIn the pragmatic open-label randomised controlled non-inferiority LADI trial we showed that increasing adalimumab (ADA) dose intervals was non-inferior to conventional dosing for persistent flares in patients with Crohn’s disease (CD) in clinical and biochemical remission.AimsTo develop a prediction model to identify patients who can successfully increase their ADA dose interval based on secondary analysis of trial data.MethodsPatients in the intervention group of the LADI trial increased ADA intervals to 3 and then to 4 weeks. The dose interval increase was defined as successful when patients had no persistent flare (> 8 weeks), no intervention-related severe adverse events, no rescue medication use during the study, and were on an increased dose interval while in clinical and biochemical remission at week 48. Prediction models were based on logistic regression with relaxed LASSO. Models were internally validated using bootstrap optimism correction.ResultsWe included 109 patients, of which 60.6% successfully increased their dose interval. Patients that were active smokers (odds ratio [OR] 0.90), had previous CD-related intra-abdominal surgeries (OR 0.85), proximal small bowel disease (OR 0.92), an increased Harvey-Bradshaw Index (OR 0.99) or increased faecal calprotectin (OR 0.997) were less likely to successfully increase their dose interval. The model had fair discriminative ability (AUC = 0.63) and net benefit analysis showed that the model could be used to select patients who could increase their dose interval.ConclusionThe final prediction model seems promising to select patients who could successfully increase their ADA dose interval. The model should be validated externally before it may be applied in clinical practice.Clinical Trial Registration NumberClinicalTrials.gov, number NCT03172377.

Innate immune memory in inflammatory arthritis.

The concept of immunological memory was demonstrated in antiquity when protection against re-exposure to pathogens was observed during the plague of Athens. Immunological memory has been linked with the adaptive features of T and B cells; however, in the past decade, evidence has demonstrated that innate immune cells can exhibit memory, a phenomenon called 'innate immune memory' or 'trained immunity'. Innate immune memory is currently being defined and is transforming our understanding of chronic inflammation and autoimmunity. In this Review, we provide an up-to-date overview of the memory-like features of innate immune cells in inflammatory arthritis and the crosstalk between chronic inflammatory milieu and cell reprogramming. Aberrant pro-inflammatory signalling, including cytokines, regulates the metabolic and epigenetic reprogramming of haematopoietic progenitors, leading to exacerbated inflammatory responses and osteoclast differentiation, in turn leading to bone destruction. Moreover, imprinted memory on mature cells including terminally differentiated osteoclasts alters responsiveness to therapies and modifies disease outcomes, commonly manifested by persistent inflammatory flares and relapse following medication withdrawal.

Rapid and sustained improvements in Generalized Pustular Psoriasis Physician Global Assessment scores with spesolimab for treatment of generalized pustular psoriasis flares in the randomized, placebo-controlled Effisayil 1 study

Effisayil 1 was a randomized, placebo-controlled study of spesolimab, an anti-IL-36 receptor antibody, in patients presenting with a generalized pustular psoriasis (GPP) flare. We present the effects of spesolimab over the 12-week study. The primary endpoint was a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation subscore of 0 at Week 1. Patients (N=53) were randomized (2:1) to receive a single intravenous dose of 900 mg spesolimab or placebo on Day 1. Patients could receive open-label spesolimab for persistent flare symptoms on Day 8. Most patients receiving spesolimab achieved a GPPGA pustulation subscore of 0 (60.0%) and GPPGA total score of 0 or 1 (60.0%) by Week 12. In patients randomized to placebo who received open-label spesolimab, the proportion with a GPPGA pustulation subscore of 0 increased from 5.6% at Day 8 to 83.3% at Week 2. No factors predictive of spesolimab response were identified in patient demographics or clinical characteristics. The effect of initial randomization was not determined conventionally beyond Week 1 due to patients receiving OL spesolimab. Rapid control of GPP flare symptoms with spesolimab was sustained over 12 weeks, further supporting its potential use as a therapeutic option for patients.

Disease activity-guided tapering of biologics in patients with inflammatory arthritis: a pragmatic, randomized, open-label, equivalence trial

Objective To evaluate whether disease activity-guided tapering of biologics compared to continuation as usual care enables a substantial dose reduction while disease activity remains equivalent. Method In this pragmatic, randomized, open-label, equivalence trial, adults with rheumatoid arthritis, psoriatic arthritis, or axial spondyloarthritis in low disease activity on stable-dose biologics for ≥ 12 months were randomized 2:1 into either the tapering group, i.e. disease activity-guided prolongation of the biologic dosing interval until flare or withdrawal, or the control group, i.e. maintaince of baseline biologics with a possible small interval increase at the patients request. The co-primary outcome in the intention-to-treat population was met if superiority in ≥ 50% biologic reduction at 18 months was demonstrated and disease activity was equivalent (equivalence margins ± 0.5). Results Ninety-five patients were randomized to tapering and 47 to control, of whom 37% (35/95) versus 2% (1/47) achieved ≥ 50% biologic reduction at 18 months. The risk difference was statistically significant [35%, 95% confidence interval (CI) 24%–45%], while disease activity remained equivalent [mean difference 0.05, 95% CI −0.12–0.29]. A statistically significant flare risk was observed [tapering 41% (39/95) vs control 21% (10/47), risk difference 20%, 95% CI 4%–35%]; but, only 1% (1/95) and 6% (3/47) had persistent flare and needed to switch to another biological drug. Conclusions Disease activity-guided tapering of biologics in patients with inflammatory arthritis enabled one-third to achieve ≥ 50% biologic reduction, while disease activity between groups remained equivalent. Flares were more frequent in the tapering group but were managed with rescue therapy.

Increased versus conventional adalimumab dose interval for patients with Crohn's disease in stable remission (LADI): a pragmatic, open-label, non-inferiority, randomised controlled trial

Despite its effectiveness in treating Crohn's disease, adalimumab is associated with an increased risk of infections and high health-care costs. We aimed to assess clinical outcomes of increased adalimumab dose intervals versus conventional dosing in patients with Crohn's disease in stable remission. The LADI study was a pragmatic, open-label, multicentre, non-inferiority, parallel, randomised controlled trial, done in six academic hospitals and 14 general hospitals in the Netherlands. Adults (aged ≥18 years) diagnosed with luminal Crohn's disease (with or without concomitant perianal disease) were eligible when in steroid-free clinical and biochemical remission (defined as Harvey-Bradshaw Index [HBI] score <5, faecal calprotectin <150 μg/g, and C-reactive protein <10 mg/L) for at least 9 months on a stable dose of 40 mg subcutaneous adalimumab every 2 weeks. Patients were randomly assigned (2:1) to the intervention group or control group by the coordinating investigator using a secure web-based system with variable block randomisation (block sizes of 6, 9, and 12). Randomisation was stratified on concomitant use of thiopurines and methotrexate. Patients and health-care providers were not masked to group assignment. Patients allocated to the intervention group increased adalimumab dose intervals to 40 mg every 3 weeks at baseline and further to every 4 weeks if they remained in clinical and biochemical remission at week 24. Patients in the control group continued their 2-weekly dose interval. The primary outcome was the cumulative incidence of persistent flares at week 48 defined as the presence of at least two of the following criteria: HBI score of 5 or more, C-reactive protein 10 mg/L or more, and faecal calprotectin more than 250 μg/g for more than 8 weeks and a concurrent decrease in the adalimumab dose interval or start of escape medication. The non-inferiority margin was 15% on a risk difference scale. All analyses were done in the intention-to-treat and per-protocol populations. This trial was registered at ClinicalTrials.gov, NCT03172377, and is not recruiting. Between May 3, 2017, and July 6, 2020, 174 patients were randomly assigned to the intervention group (n=113) or the control group (n=61). Four patients from the intervention group and one patient from the control group were excluded from the analysis for not meeting inclusion criteria. 85 (50%) of 169 participants were female and 84 (50%) were male. At week 48, the cumulative incidence of persistent flares in the intervention group (three [3%] of 109) was non-inferior compared with the control group (zero; pooled adjusted risk difference 1·86% [90% CI -0·35 to 4·07). Seven serious adverse events occurred, all in the intervention group, of which two (both patients with intestinal obstruction) were possibly related to the intervention. Per 100 person-years, 168·35 total adverse events, 59·99 infection-related adverse events, and 42·57 gastrointestinal adverse events occurred in the intervention group versus 134·67, 75·03, and 5·77 in the control group, respectively. The individual benefit of increasing adalimumab dose intervals versus the risk of disease recurrence is a trade-off that should take patient preferences regarding medication and the risk of a flare into account. Netherlands Organisation for Health Research and Development.

P526 A prediction model for successful increase of adalimumab dose intervals: analysis of the pragmatic open-label randomised controlled non-inferiority LADI trial

Abstract Background We showed in the pragmatic open-label randomised controlled non-inferiority LADI trial that increasing adalimumab (ADA) dose intervals was non-inferior to conventional dosing for persistent flares in CD patients in stable remission, while infection-related adverse events (AE) were reduced. This was counterbalanced by lower rates of clinical remission and more gastro-intestinal AEs after 48 weeks. In the current study we aimed to develop a prediction model to identify patients who could successfully increase their ADA dose interval. Methods This is a secondary analysis of the intervention group of the LADI trial. In this group, patients in steroid-free clinical remission for ≥ 9 months (Harvey-Bradshaw Index (HBI) &amp;lt; 5, CRP &amp;lt; 10 mg/L and faecal calprotectin (FCP) &amp;lt; 150 µg/g), on conventional ADA dosing increased ADA intervals to 3 and then to 4 weeks. A successful dose interval increase was defined as: no persistent flare (&amp;gt;8 weeks), no intervention-related severe AE, no rescue medication use, and an increased dose interval while in clinical and biochemical remission at week 48. Candidate baseline predictors were selected after a study group consensus meeting (Table 1). Prediction models were based on logistic regression. Four variable selection strategies were used: inclusion of all variables as a naïve reference model, stepwise backwards regression, LASSO with minimal lambda, and LASSO using the ‘one standard error’ rule. Models were evaluated on discrimination and calibration. Missing data were multiply imputed and models were internally validated using bootstrap optimism correction. Results The four models were developed on 109 patients, of which 59.1% experienced the outcome of successful dose interval increase (Table 1). Apparent performance of the models was adequate, with areas under the receiver operating characteristic curves (AUC) between 0.60 and 0.67 (Table 2 and Figure 1). Predicted probabilities from LASSO-based models were too modest (Table 2 and Figure 2). Internal validation showed optimism-corrected AUCs around 0.5 (Table 2), meaning that models could not identify patients who successfully increased their ADA dose interval. Optimism-corrected calibration estimates for the naïve model and backwards selection showed overfitting on the data. Internally validated predicted probabilities from LASSO-based models were too modest. Conclusion After 48 weeks, approximately 60% of patients could successfully increase their ADA dose interval without major negative clinical impact, but these could not be identified with a series of different prediction models. Risks and benefits of this strategy should be discussed with individual patients based on their risk perception and medication preferences.

094 Characterisation of the immunogenicity of spesolimab in patients with a generalized pustular psoriasis (GPP) flare

We investigated the immunogenicity of spesolimab, and its impact on PK, efficacy, and safety in patients with a GPP flare. Plasma samples were analysed from three trials. In trial 1 (proof of concept, NCT02978690), 7 patients received IV spesolimab 10 mg/kg. In trial 2 (Effisayil 1, NCT03782792), 53 patients were randomised 2:1 to receive IV spesolimab 900 mg or placebo on Day 1, with optional open-label (OL) spesolimab on Day 8 for persistent flare symptoms. At Week 12, patients could enroll into trial 3 (Effisayil ON, NCT03886246), a 5-year OL extension, to receive SC spesolimab 300 mg Q12W or Q6W; interim data are reported (N=39; September 2021).

Efficacy and safety of progressively reducing biologic disease-modifying antirheumatic drugs in patients with rheumatoid arthritis in persistent remission: a study protocol for a non-inferiority randomized, controlled, single-blind trial

BackgroundTo compare the effects of two biologic disease-modifying antirheumatic drug (bDMARD) administration strategies on the maintenance effect and safety of patients with rheumatoid arthritis (RA) in remission, to analyze the effects of gradual drug reduction and dose maintenance treatment on clinical outcomes in patients who have achieved remission with different types of bDMARDs, to search and screen out people who may benefit from drug reduction strategies, and to provide references for drug reduction strategies and treatment options for patients with RA in remission, so as to help improve the safety of the treatment and reduce the economic burden.MethodsThe study will be a 24-month non-inferiority randomized, controlled, single-blind trial and is planned to be launched in our hospital from September 2021 to August 2023. Patients will be randomized in a ratio of 2:1 to two groups: maintenance or injection spacing by 50%/gradual reduction of dosage every 3 months up to complete stop. When the patient relapses, return to the last effective dose. If the remission can be maintained, the medication of bDMARDs can be stopped 9 months after enrollment. The primary outcome will be the persistent flare rate.DiscussionOur study may provide a reference for the selection of drug reduction strategies and treatment options for patients with RA in remission, so as to help improve the safety of the treatment and reduce the economic burden.Trial registrationChinese Clinical Trial Registry ChiCTR2100044751. Registered on 26 March 2021

The Disease Burden of Generalized Pustular Psoriasis: Real-World Evidence From CorEvitas' Psoriasis Registry.

Background: Generalized pustular psoriasis (GPP) is a rare, systemic disease characterized by persistent or recurrent flares of painful neutrophilic pustules. There is limited real-world evidence characterizing patients with GPP. Objectives: To establish the distinguishing characteristics of GPP relative to plaque psoriasis, and help inform future treatment decisions and improve patient outcomes. Methods: North American adults with GPP or plaque psoriasis (without pustules) identified from CorEvitas' Psoriasis Registry were included in this dataset. Registry enrollment data, including patient sociodemographics, disease characteristics, medication use, and patient-reported outcome measures were compared for patients with GPP vs those with plaque psoriasis. This study was descriptive, and no hypothesis tests were performed. Results: In this sample, patients with GPP (N = 60) reported greater median (interquartile range) pain (20 [3-62] vs 5 [0-35]), fatigue (44 [15-73] vs 20 [4-50]), and itch (59 [10-85] vs 22 [5-70]) than those with plaque psoriasis (N = 4894). Descriptively, patients with GPP also reported more anxiety and depression (EQ-5D-3L: 38% vs 26%) and had more treatment experience (≥2 previous systemics: 15% vs 7%). Conclusions: A greater degree of symptom severity and impact on quality of life was reported by patients with GPP compared with plaque psoriasis in this sample. Importantly, patients with GPP had more treatment experience, suggesting that current treatment options do not adequately resolve the disease-highlighting the need to develop more effective GPP treatments.

Risk of flare after tapering or withdrawal of biologic/targeted synthetic disease-modifying anti-rheumatic drugs in patients with rheumatoid arthritis or axial spondyloarthritis: a systematic review and meta-analysis.

To evaluate flare risk when tapering or withdrawing biologic or targeted synthetic DMARDs (bDMARDs or tsDMARDs) compared with continuation in patients with inflammatory arthritis in sustained remission or with low disease activity. Articles were identified in the Cochrane Library, PubMed, Embase and Web of Science. Eligible trials were randomized controlled trials comparing tapering and/or withdrawal of bDMARDs and/or tsDMARDs with the standard dose in inflammatory arthritis. Random effects meta-analysis was performed with risk ratio (RR) or Peto's odds ratio (POR) for sparse events and 95% CI. The meta-analysis comprised 22 trials: 11 assessed tapering and 7 addressed withdrawal (4 assessed both). Only trials with an RA or axial SpA (axSpA) population were identified. An increased flare risk was demonstrated when b-/tsDMARD tapering was compared with continuation [RR 1.45 (95% CI 1.19, 1.77), I2 = 42.5%] and potentially increased for persistent flare [POR 1.56 (95% CI 0.97, 2.52), I2 = 0%]. Comparing TNF inhibitor (TNFi) withdrawal with continuation, a highly increased flare risk [RR 2.28 (95% CI 1.78, 2.93), I2 = 78%] and increased odds of persistent flare [POR 3.41 (95% CI 1.91, 6.09), I2 = 49%] were observed. No clear difference in flare risk between RA or axSpA was observed. A high risk for flare and persistent flare was demonstrated for TNFi withdrawal, whereas an increased risk for flare but not for persistent flare was observed for b-/tsDMARD tapering. Thus tapering seems to be the more favourable approach. PROSPERO (CRD42019136905).

Dose reduction of the new generation biologics (IL-17 and IL-23 inhibitors) in psoriasis: study protocol for an international, pragmatic, multicenter, randomized, controlled, non-inferiority study\u2014the BeNeBio study

BackgroundPsoriasis is a chronic immune-mediated inflammatory skin disease for which biologics are effective treatments. Dose reduction (DR) of the first generation biologics seems a promising way for more efficient use of expensive biologics. A substantial part of patients on tumor necrosis factor (TNF)-alfa inhibitors and ustekinumab could successfully lower their dose, after following a tightly controlled DR strategy. The objective of this study is to assess whether controlled DR of interleukin (IL)-17 and IL-23 inhibitors in psoriasis patients with low disease activity is non-inferior (NI) to usual care (UC).MethodsThis is an international, prospective, multicenter, pragmatic, randomized, non-inferiority trial. A total of 244 patients with stable low disease activity (Psoriasis Area and Severity Index (PASI) ≤ 5) for at least 6 months and using secukinumab, ixekizumab, brodalumab, guselkumab, risankizumab, or tildrakizumab in the standard dose, together with stable low disease activity, defined as a PASI ≤ 5 and Dermatology Life Quality Index (DLQI) ≤ 5 at the moment of inclusion, will be randomized 2:1 to DR or UC. In the DR group, dosing intervals will be prolonged stepwise to achieve 66% and 50% of the original dose. Disease activity is monitored every 3 months by PASI and DLQI. In case of disease flare (i.e., PASI and/or DLQI increase), treatment is adjusted to the previous effective dose. The primary outcome is the incidence proportion of persistent flares (PASI > 5 for ≥ 3 months), which will be compared between arms. Secondary outcomes include proportion of patients with successful DR, (course of) PASI and DLQI, serious adverse events (SAEs), health-related quality of life, costs, and pharmacokinetic profile. Outcomes of DR will be compared to UC.DiscussionWith this study, we aim to assess whether DR of IL-17 and IL-23 inhibiting biologics can be achieved for psoriasis patients with low disease activity, without losing disease control. Reducing the dose may lead to more efficient use of biologics.Trial registrationClinicalTrials.govNCT04340076. Registered on April 9 2020.

Cost-Effectiveness of Therapeutic Drug Monitoring-Guided Adalimumab Therapy in Rheumatic Diseases: A Prospective, Pragmatic Trial.

IntroductionTo assess the clinical and cost-effectiveness of therapeutic drug monitoring (TDM) based on serum adalimumab levels compared to standard of care in patients with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. MethodsThis was a non-inferiority, multicentric, non-randomized, pragmatic trial including adult patients diagnosed with moderate-to-severe, clinically stable rheumatic diseases treated with adalimumab. Consecutive patients were assigned 1:2 to the control (CG) or the intervention group (IG), based on the site of inclusion, and followed up for 18 months. Adalimumab serum levels were measured at each study visit and released to the IG only to modify dosing strategy. Data on disease activity, healthcare resource utilization and health-related quality of life (HRQoL) measured through the EQ-5D-5L were collected. Number of persistent and overall flares, time to first flare, days experiencing high disease activity, total direct costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER) were calculated.ResultsOf the 169 recruited patients, 150 were included in the analysis (52 and 98 patients in the CG and IG, respectively). The primary endpoint was not met as persistent flares were not significantly lower in the IG, although mean (SD) number of flares was numerically lower in the IG (0.67 [0.70] versus 0.90 [0.82], P = 0.073), respectively. Based on EQ-5D-5L utilities, HRQoL was significantly higher in the IG at 3 (P = 0.001) and 6 months (P = 0.035), which overall translated into 0.075 QALYs gained per patient for the IG at month 18. Overall, direct costs were significantly lower for the IG patients (€15,311.59 [4,870.04] versus €17,378.46 [6,556.51], P = 0.030), resulting in the intervention being dominant, leading to increased QALY at a lower overall costConclusionAdalimumab dose tapering based on TDM for rheumatic patients led to an increased quality of life and QALY gain and entailed lower costs, being a more cost-effective alternative than clinically guided management.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40744-021-00345-5.

Two-year follow-up of a dose reduction strategy trial of biologics adalimumab, etanercept, and ustekinumab in psoriasis patients in daily practice

Background/objectives Tightly-controlled dose reduction was possible during 1 year in psoriasis patients on adalimumab, etanercept or ustekinumab with low disease activity (CONDOR trial). Extended observation is needed to ensure long-term effectiveness and safety of the strategy. With prolonged follow-up, we investigated the clinical effects and safety of the strategy, the proportion of patients with successful dose reduction, and assessed if patients with a disease flare regained remission. Methods Two-year follow up of a subgroup of patients previously included in a randomized pragmatic study comparing usual care (UC) with stepwise dose reduction (DR). Effectiveness (Psoriasis Area and Severity Index, PASI), Dermatology Life Quality Index (DLQI), adverse events, proportion of patients with successful DR and proportion of persistent disease flares were analyzed. Results DR leads temporarily to a slightly increased PASI groupwise, but on the long-term patients regained low PASI. DLQI scores remained stable during follow-up. No serious adverse events due to DR were reported. Forty-one percent of patients remained on a low dose up to 2 years. The number of persistent flares was low in DR and UC. Conclusions The proposed dose reduction strategy is effective for a significant part of patients and remains safe up to 2 years of follow-up.

Homologous Flaring Activity over a Sunspot Light Bridge in an Emerging Active Region

Abstract Sunspot light bridges are known to exhibit a variety of dynamic and persistent phenomena such as surges, small-scale jets, etc., in the chromosphere and transition region. While it has generally been proposed that magnetic reconnection is responsible for this small-scale dynamism, persistent flaring activity lasting several hours from the same spatial location on a sunspot light bridge has rarely been reported. We combine observations from the Atmospheric Imaging Assembly and the Helioseismic Magnetic Imager on board the Solar Dynamics Observatory to investigate homologous flaring activity over a small sunspot light bridge in an emerging flux region. The homologous flares all produced broad, collimated jets including a B6.4 class flare. The jets rise at a speed of about 200 km s−1, reach projected heights of about 98 Mm, and emerge from the same spatial location for nearly 14 hrs, after which they cease completely. A nonlinear force-free extrapolation of the photospheric magnetic field shows a low-lying flux rope connecting the light bridge to a remote opposite-polarity network. The persistent flares occur as a result of the rapid horizontal motion of the leading sunspot that causes the relatively vertical magnetic fields in the adjacent umbra to reconnect with the low-lying flux rope in the light bridge. Our results indicate that the flaring ceases once the flux rope has lost sufficient twist through repeated reconnections.

Lengthening adalimumab dosing interval in quiescent Crohn’s disease patients: protocol for the pragmatic randomised non-inferiority LADI study

IntroductionAdalimumab is effective for maintenance of remission in patients with Crohn’s disease (CD) at a dose of 40 mg subcutaneously every 2 weeks. However, adalimumab is associated with (long-term) adverse...

Comparison of Tightly Controlled Dose Reduction of Biologics With Usual Care for Patients With Psoriasis

Biologics revolutionized the treatment of psoriasis. Biologics are given in a fixed dose, but lower doses might be possible. To investigate whether dose reduction (DR) of biologics in patients with stable psoriasis is noninferior to usual care (UC). This pragmatic, open-label, prospective, controlled, noninferiority randomized clinical trial was conducted from March 1, 2016, to July 22, 2018, at 6 dermatology departments in the Netherlands. A total of 120 patients with plaque psoriasis and stable low disease activity who were receiving treatment with adalimumab, etanercept, or ustekinumab were studied. Patients were randomized 1:1 to DR (n = 60) or UC (n = 60). In the DR group, injection intervals were prolonged stepwise, leading to 67% and 50% of the original dose. The primary outcome was between-group difference in disease activity corrected for baseline at 12 months compared with the predefined noninferiority margin of 0.5. Secondary outcomes were Psoriasis Area and Severity Index (PASI) score and health-related quality of life (including Dermatology Life Quality Index [DLQI] and Medical Outcomes Study 36-Item Short Form Health Survey scores), proportion of patients with short and persistent flares (defined as PASI and/or DLQI scores >5 for ≥3 months), and proportion of patients with successful dose tapering. Of 120 patients (mean [SD] age, 54.0 [13.2] years; 82 [68%] male), 2 patients were lost to follow-up, 2 patients had a protocol violation, and 5 patients had a protocol deviation, leaving 111 patients for the per-protocol analysis (53 in the DR group and 58 in the UC group). The median PASI scores at month 12 were 3.4 (interquartile range [IQR], 2.2-4.5) in the DR group and 2.1 (IQR, 0.6-3.6) in the UC group (mean difference, 1.2; 95% CI, 0.7-1.8). This indicates that noninferiority was not demonstrated for DR compared to UC. The median DLQI score at month 12 was 1.0 (IQR, 0.0-2.0) in the DR group and 0.0 (IQR, 0.0-2.0) in the UC group (mean difference, 0.8; 95% CI, 0.3-1.3), indicating noninferiority for DR compared with UC. No significant difference was found regarding persistent flares between groups (n = 5 in both groups). Twenty-eight patients (53%; 95% CI, 39%-67%) in the DR group tapered their dose successfully at 12 months. No severe adverse events related to the intervention occurred. In this trial, noninferiority was not demonstrated for DR of adalimumab, etanercept, and ustekinumab based on the PASI in patients with psoriasis compared with UC with the chosen noninferiority margin. However, the strategy was noninferior based on the DLQI. Dose tapering did not lead to persistent flares or safety issues. ClinicalTrials.gov Identifier: NCT02602925.

Bacterial biofilm product Curli/eDNA induces NETs and serum anti-Curli/eDNA levels correlate with bacteriuria and lupus activity.

Abstract Infections are a major contributor to lupus disease. We have previously demonstrated that bacterial amyloid curli, produced by E.coli, can accelerate disease in mouse models of lupus. Interestingly curli incorporates extracellular DNA, which in turn can be both adjuvant and a self-antigen in lupus. Finally, uropathogenic E. coli (UPEC) is responsible for the majority of urinary tract infections in SLE. Based on our previous results, we hypothesize that exposure to UPEC triggers anti-curli/eDNA antibodies and curli/eDNA complexes can stimulate the innate immune system. We investigated 98 lupus patients who met at least 4 SLICC criteria. Results were compared to 54 age, sex and race matched healthy controls. We tested the production of anti-curli/DNA complex of both IgG and IgA subclasses. We than correlated the levels of anti-curli/DNA antibodies with clinical parameters. Finally, we stimulated human neutrophils with curli/eDNA complexes. We found that anti-curli/eDNA IgG levels were detected in both lupus and controls plasma. In lupus patients, anti-curli/eDNA levels correlated with persistent bacteriuria and disease flares (p&amp;lt;0.05). In addition, anti-curli/eDNA antibodies recognized dsDNA suggesting a potential molecular mimicry mechanism for curli/eDNA with self-antigens such as dsDNA. We also found that IgA anti-curli/eDNA levels were higher (p&amp;lt;0.01) in lupus donors compared to controls. Finally we found that curli/eDNA induced neutrophil extracellular traps (NETs) and the induction was ROS-dependent. We conclude that curli/eDNA complexes from UTIs can activate the innate immune system and IgG and IgA anti-curli/eDNA are strong biomarkers for disease activity and severity.

Flares assessed weekly in patients with rheumatoid arthritis or axial spondyloarthritis and relationship with physical activity measured using a connected activity tracker: a 3-month study

BackgroundThe evolution of rheumatoid arthritis (RA) and axial spondyloarthritis (axSpA) is marked by flares, although their frequency is unclear. Flares may impact physical activity. Activity can be assessed objectively using...