Objective To evaluate whether a disease activity guided strategy of dose reduction of two tumour necrosis factor (TNF) inhibitors, adalimumab or etanercept, is non-inferior in maintaining disease ...control in patients with rheumatoid arthritis compared with usual care.Design Randomised controlled, open label, non-inferiority strategy trial.Setting Two rheumatology outpatient clinics in the Netherlands, from December 2011 to May 2014.Participants 180 patients with rheumatoid arthritis and low disease activity using adalimumab or etanercept; 121 allocated to the dose reduction strategy, 59 to usual care.Interventions Disease activity guided dose reduction (advice to stepwise increase the injection interval every three months, until flare of disease activity or discontinuation) or usual care (no dose reduction advice). Flare was defined as increase in DAS28-CRP (a composite score measuring disease activity) greater than 1.2, or increase greater than 0.6 and current score of at least 3.2. In the case of flare, TNF inhibitor use was restarted or escalated.Main outcome measures Difference in proportions of patients with major flare (DAS28-CRP based flare longer than three months) between the two groups at 18 months, compared against a non-inferiority margin of 20%. Secondary outcomes included TNF inhibitor use at study end, functioning, quality of life, radiographic progression, and adverse events.Results Dose reduction of adalimumab or etanercept was non-inferior to usual care (proportion of patients with major flare at 18 months, 12% v 10%; difference 2%, 95% confidence interval −12% to 12%). In the dose reduction group, TNF inhibitor use could successfully be stopped in 20% (95% confidence interval 13% to 28%), the injection interval successfully increased in 43% (34% to 53%), but no dose reduction was possible in 37% (28% to 46%). Functional status, quality of life, relevant radiographic progression, and adverse events did not differ between the groups, although short lived flares (73% v 27%) and minimal radiographic progression (32% v 15%) were more frequent in dose reduction than usual care.Conclusions A disease activity guided, dose reduction strategy of adalimumab or etanercept to treat rheumatoid arthritis is non-inferior to usual care with regard to major flaring, while resulting in the successful dose reduction or stopping in two thirds of patients.Trial registration Dutch trial register (www.trialregister.nl), NTR 3216.
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BFBNIB, CMK, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
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 events and is costly. The aim of this study is to demonstrate non-inferiority and cost-effectiveness of disease activity guided adalimumab interval lengthening compared to standard dosing of every other week (EOW).Methods and analysisThe Lengthening Adalimumab Dosing Interval (LADI) study is a pragmatic, multicentre, open label, randomised controlled non-inferiority trial. Non-inferiority is reached if the difference in cumulative incidence of persistent (>8 weeks) flares does not exceed the non-inferiority margin of 15%. 174 CD patients on adalimumab maintenance therapy in long-term (>9 months) clinical and biochemical remission will be included (C-reactive protein (CRP) <10 mg/L, faecal calprotectin (FC) <150 µg/g, Harvey-Bradshaw Index (HBI) <5). Patients will be randomised 2:1 into the intervention (adalimumab interval lengthening) or control group (adalimumab EOW). The intervention group will lengthen the adalimumab administration interval to every 3 weeks, and after 24 weeks to every 4 weeks. Clinical and biochemical disease activity will be monitored every 12 weeks by physician global assessment, HBI, CRP and FC. In case of disease flare, dosing will be increased. A flare is defined as two of three of the following criteria; FC>250 µg/g, CRP≥10 mg/l, HBI≥5. Secondary outcomes include cumulative incidence of transient flares, adverse events, predictors for successful dose reduction and cost-effectiveness.Ethics and disseminationThe study is approved by the Medical Ethics Committee Arnhem-Nijmegen, the Netherlands (registration number NL58948.091.16). Results will be published in peer-reviewed journals and presented at international conferences.Trial registration numbersEudraCT registry (2016-003321-42); Clinicaltrials.gov registry (NCT03172377); Dutch trial registry (NTRID6417).
The abdominal wall is often neglected as a cause of chronic abdominal pain. The aim of this study was to identify chronic abdominal wall pain syndromes, such as anterior cutaneous nerve entrapment ...syndrome (ACNES), in a patient population diagnosed with functional abdominal pain, including irritable bowel syndrome, using a validated 18-item questionnaire as an identification tool.
In this cross-sectional analysis, 4 Dutch primary care practices employing physicians who were unaware of the existence of ACNES were selected. A total of 535 patients ≥18 years old who were registered with a functional abdominal pain diagnosis were approached when they were symptomatic to complete the questionnaire (maximum 18 points). Responders who scored at least the 10-point cutoff value (sensitivity, 0.94; specificity, 0.92) underwent a diagnostic evaluation to establish their final diagnosis. The main outcome was the presence and prevalence of ACNES in a group of symptomatic patients diagnosed with functional abdominal pain.
Of 535 patients, 304 (57%) responded; 167 subjects (31%) recently reporting symptoms completed the questionnaire. Of 23 patients who scored above the 10-point cutoff value, 18 were available for a diagnostic evaluation. In half of these subjects (n = 9) functional abdominal pain (including IBS) was confirmed. However, the other 9 patients were suffering from abdominal wall pain syndrome, 6 of whom were diagnosed with ACNES (3.6% prevalence rate of symptomatic subjects; 95% confidence interval, 1.7-7.6), whereas the remaining 3 harbored a painful lipoma, an abdominal herniation, and a painful scar.
A clinically relevant portion of patients previously diagnosed with functional abdominal pain syndrome in a primary care environment suffers from an abdominal wall pain syndrome such as ACNES.
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.
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.
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.
The proposed dose reduction strategy is effective for a significant part of patients and remains safe up to 2 years of follow-up.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Summary
Background
Predictors for successful treatment are important for personalized medicine. Predictors for drug survival of biologics in psoriasis have been assessed, but not split for different ...biologics or for the reason of discontinuation.
Objectives
To compare long‐term drug survival between the outpatient biologics adalimumab, etanercept and ustekinumab in patients with psoriasis, and to elucidate predictors for overall survival and drug discontinuation due to ineffectiveness and side‐effects for each biologic separately.
Methods
Ten years of data were extracted from the prospective, multicentre, long‐term BioCAPTURE registry. Kaplan–Meier survival analyses and confounder‐corrected multivariate Cox regression analysis for drug survival (MCR‐DS) were performed to compare drug survival between biologics. To elucidate the predictors for different reasons of discontinuation for each biologic, univariate Cox regression analyses and multivariate Cox regression analyses for predictors (MCR‐P) with backward selection were performed.
Results
In total, 526 treatment episodes – 186 adalimumab, 238 etanercept and 102 ustekinumab – were included covering 1333 treatment years. MCR‐DS showed a significantly higher overall survival for ustekinumab compared with adalimumab and etanercept. MCR‐P showed that higher body mass index (BMI) was a predictor for discontinuation due to ineffectiveness for etanercept and ustekinumab and that female sex was a predictor for discontinuation due to side‐effects for adalimumab, etanercept and ustekinumab.
Conclusions
Ustekinumab has the highest confounder‐corrected long‐term drug survival in psoriasis treatment, compared with adalimumab and etanercept. Higher BMI is a predictor for discontinuation due to ineffectiveness in etanercept and ustekinumab, and female sex is a consistent predictor for discontinuation due to side‐effects in all three outpatient biologics.
What's already known about this topic?
Drug survival of biologics for psoriasis has been analysed, but few publications used prospective multicentre daily‐practice data.
These studies found that ustekinumab had the highest confounder‐corrected overall drug survival, but they did not split survival analysis for the different biologics or for different reasons of discontinuation.
Different predictors for overall drug survival were found in prospective and retrospective studies.
What does this study add?
This study reports on a longer period of drug survival than previous studies.
Ustekinumab has a higher confounder‐corrected drug survival and higher survival for discontinuation due to ineffectiveness and side‐effects than adalimumab and etanercept.
Higher body mass index (BMI) predicts discontinuation due to ineffectiveness in etanercept and ustekinumab, and female sex is a consistent predictor for discontinuation due to side‐effects in all three biologics.
Linked Comment: Egeberg. Br J Dermatol 2016; 175:247–248
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Summary
Background
Long‐term data of ciclosporin A (CsA) treatment in daily practice in patients with severe atopic dermatitis (AD) are lacking.
Objectives
To perform a detailed analysis of drug ...survival, which is the length of time a patient continues to take a drug, for CsA in a long‐term daily practice cohort of patients with AD. The secondary objective was to identify determinants of drug survival.
Methods
Data were extracted from a retrospective cohort of patients treated with CsA for AD. Drug survival was analysed using Kaplan–Meier survival curves. Determinants of drug survival were analysed using uni‐ and multivariate Cox regression analyses with backward selection.
Results
In total, 356 adult patients were analysed (386 patient‐years). The overall drug survival rates were 34%, 18%, 12% and 4% after 1, 2, 3 and 6 years, respectively. Reasons for discontinuation were controlled AD (26·4%), side‐effects (22·2%), ineffectiveness (16·3%), side‐effects plus ineffectiveness (6·2%) or other reasons (11·0%). Older age was associated with a decreased drug survival related to controlled AD hazard ratio (HR) 0·91. Older age was also associated with a decreased drug survival related to side‐effects (HR 1·14). An intermediate‐to‐high starting dose (> 3·5–5·0 mg kg−1 daily) was associated with an increased drug survival related to ineffectiveness (HR 0·63).
Conclusions
This is the first study on drug survival for CsA treatment in AD. Older age was associated with decreased drug survival related to controlled AD and side‐effects. An intermediate‐to‐high starting dose was associated with an increased drug survival related to ineffectiveness.
What's already known about this topic?
Earlier studies demonstrate that ciclosporin A (CsA) is a safe and potent drug in the treatment of adult patients with severe atopic dermatitis (AD).
What does this study add?
Drug survival is a reflection of daily practice.
This is the first detailed analysis on drug survival for CsA treatment in adult patients with AD.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Summary
Background
Polycystic liver disease is associated with impaired health‐related quality of life (HRQL). Somatostatin analogues reduce hepatomegaly in polycystic liver disease.
Aim
To determine ...whether somatostatin analogues improve HRQL and to identify factors associated with change in HRQL in polycystic liver disease.
Methods
We pooled data from two randomized, double‐blind, placebo‐controlled trials that evaluated HRQL using the Short‐Form 36 (SF‐36) in 96 polycystic liver disease patients treated 6‐12 months with somatostatin analogues or placebo. The SF‐36 contains a summarizing physical and mental component score and was administered at baseline and at the end of treatment. We used random effect models to delineate the effect of somatostatin analogues on HRQL. We determined the effect of demographics, height‐adjusted liver volume, change in liver volume, somatostatin analogue‐associated side effects with change in HRQL. In patients with autosomal dominant polycystic kidney disease, we estimated the effect of height‐adjusted kidney volume and change in kidney volume in relation to HRQL.
Results
Physical component scores improved with somatostatin analogues, but remained unchanged with placebo (3.41 ± 1.29 vs. −0.71 ± 1.54, P = 0.044). Treatment had no impact on the mental component score. Large liver volume was independently associated with larger HRQL decline during follow up (−4.04 ± 2.02 points per logarithm liver volume, P = 0.049). In autosomal dominant polycystic kidney disease, patients with large liver and kidney volumes had larger decline in HRQL (5.36 ± 2.54 points per logarithm liver volume; P = 0.040 and −4.00 ± 1.88 per logarithm kidney volume; P = 0.039).
Conclusion
Somatostatin analogues improve HRQL in symptomatic polycystic liver disease. Halting the progressive nature of polycystic liver disease is necessary to prevent further decline of HRQL in severe hepatomegaly.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Summary
Background
Localized scleroderma (LoS) is characterized by a phase of disease activity followed by remission. However, disease recurrences occur. Knowledge concerning these recurrences can ...help prompt treatment, thereby preventing disease damage.
Objectives
To investigate the frequency and characteristics of disease recurrences in paediatric‐ and adult‐onset LoS, and to identify patient variables that are associated with a higher risk of disease recurrence.
Methods
Retrospective chart reviews were performed of patients with LoS. Data concerning the frequency and characteristics of the disease recurrences were collected. A multivariate analysis was performed to identify patient variables that were associated with a higher risk of disease recurrence.
Results
In total, 344 patients were included in the analysis, of whom 119 (35%) had paediatric‐onset LoS and 225 (65%) had adult‐onset LoS. Disease recurrence was present in 27% (n = 32) of the paediatric‐onset group and 17% (n = 39) of the adult‐onset group (P = 0·037). Multivariate analysis identified a statistically significant association between disease recurrence and the linear LoS of the limbs subtype, independent of age at disease onset.
Conclusions
Recurrences in LoS occurred in almost one‐quarter of the patients and were most frequent in the linear LoS of the limbs subtype, independent of age at disease onset. These disease recurrences can occur even after many years of quiescent disease. Awareness of the high recurrence rates may help treating physicians to recognize reactivation of the disease, leading to a decreased delay in treatment reinitiation.
What's already known about this topic?
Localized scleroderma is characterized by a phase of disease activity followed by remission. However, disease recurrences occur.
What does this study add?
Recurrences occur in almost one‐quarter of patients and are more frequent in the linear localized scleroderma of the limbs subtype, independent of age at disease onset.
Awareness of high recurrence rates may help treating physicians to recognize reactivation of the disease, leading to a decreased delay in treatment reinitiation.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Summary
Background
It is important to assess which patients with psoriasis are more likely to achieve high clinical responses on biologics.
Objectives
To assess the number of treatment episodes (TEs) ...that achieve a 100% improvement in Psoriasis Area and Severity Index (PASI 100), PASI 90 or PASI ≤ 5 at week 24 of biological treatment, and which baseline patient characteristics predict treatment response.
Methods
Data from patients with psoriasis treated with adalimumab, etanercept, infliximab or ustekinumab were extracted from a prospective cohort. TEs with high clinical responses were described. Uni‐ and multivariate regression analyses were performed with the generalized estimating equation method to elucidate which baseline patient characteristics were predictors for PASI 90 and PASI ≤ 5 at week 24.
Results
In total, 454 TEs were extracted (159 adalimumab; 193 etanercept; 19 infliximab; 83 ustekinumab) from 326 patients. At week 24, in 3%, 15% and 59% of TEs, respectively, PASI 100, PASI 90 and PASI ≤ 5 was reached. In TEs without a PASI 100 or PASI 90 response, PASI ≤ 5 was still achieved in 58% and 52%, respectively. Baseline PASI ≥ 10 was a strong predictor for achieving PASI 90; baseline PASI < 10 and a lower baseline body mass index (BMI) were significant predictors for PASI ≤ 5 at week 24.
Conclusions
A limited number of patients achieved PASI 100 or PASI 90 at 24 weeks of biological treatment. Including an absolute PASI score in the assessment of psoriasis severity is important. Baseline BMI was an important, modifiable predictor for a high response.
What's already known about this topic?
A high clinical response in patients with psoriasis is shifting towards a 90% improvement compared with baseline Psoriasis Area and Severity Index (PASI 90).
To date, no studies have assessed which patients with psoriasis are more likely to achieve a high clinical response at week 24 of biological treatment.
What does this study add?
We focused on high responders, defined as achieving PASI 100, PASI 90 or PASI ≤ 5.
Frequency of reaching high clinical responses at 24 weeks of biological treatment was assessed, as were predictors that could identify patients with the ability to respond well to biological treatment.
In only a limited number of treatment episodes are PASI 90 (15%) or PASI 100 (3%) achieved.
Lower baseline body mass index is a predictor for achieving PASI ≤ 5.
Linked Comment: Zheng. Br J Dermatol 2017; 176:576.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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