Patients with difficult-to-treat rheumatoid arthritis (RA) remain symptomatic despite treatment according to current European League Against Rheumatism (EULAR) management recommendations. These focus on early phases of the disease and pharmacological management. We aimed to identify characteristics of difficult-to-treat RA and issues to be addressed in its workup and management that are not covered by current management recommendations.
An international survey was conducted among rheumatologists with multiple-choice questions on disease characteristics of difficult-to-treat RA. Using open questions, additional items to be addressed and items missing in current management recommendations were identified.
410 respondents completed the survey: 50% selected disease activity score assessing 28 joints >3.2 OR presence of signs suggestive of active disease as characteristics of difficult-to-treat RA; 42% selected fatigue; 48% selected failure to ≥2 conventional synthetic disease-modifying antirheumatic drugs (DMARDs) AND ≥2 biological/targeted synthetic DMARDs; 89% selected inability to taper glucocorticoids below 5 mg or 10 mg prednisone equivalent daily. Interfering comorbidities, extra-articular manifestations and polypharmacy were identified as important issues missing in current management recommendations.
There is wide variation in concepts of difficult-to-treat RA. Several important issues regarding these patients are not addressed by current EULAR recommendations.
To evaluate the long-term efficacy and safety of canakinumab in patients with active systemic juvenile idiopathic arthritis (JIA).
Patients (2–19 years) entered two phase III studies and continued in the long-term extension (LTE) study. Efficacy assessments were performed every 3 months, including adapted JIA American College of Rheumatology (aJIA-ACR) criteria, Juvenile Arthritis Disease Activity Score (JADAS) and ACR clinical remission on medication criteria (CRACR). Efficacy analyses are reported as per the intent-to-treat population.
144 of the 177 patients (81%) enrolled in the core study entered the LTE. Overall, 75 patients (42%) completed and 102 (58%) discontinued mainly for inefficacy (63/102, 62%), with higher discontinuation rates noted in the late responders group (n=25/31, 81%) versus early responders (n=11/38, 29%). At 2 years, aJIA-ACR 50/70/90 response rates were 62%, 61% and 54%, respectively. CRACR was achieved by 20% of patients at month 6; 32% at 2 years. A JADAS low disease activity score was achieved by 49% of patients at 2 years. Efficacy results were maintained up to 5 years. Of the 128/177 (72.3%) patients on glucocorticoids, 20 (15.6%) discontinued and 28 (22%) tapered to 0.150 mg/kg/day. Seven patients discontinued canakinumab due to CR. There were 13 macrophage activation syndrome (three previously reported) and no additional deaths (three previously reported). No new safety findings were observed.
Response to canakinumab treatment was sustained and associated with substantial glucocorticoid dose reduction or discontinuation and a relatively low retention-on-treatment rate. No new safety findings were observed on long-term use of canakinumab.
To evaluate the efficacy and safety of tocilizumab, an interleukin-6 receptor antibody, in patients with adult-onset Still’s disease.
In this double-blind, randomised, placebo-controlled phase III trial, 27 patients with adult-onset Still’s disease refractory to glucocorticoids were randomised to tocilizumab at a dose of 8 mg/kg or placebo given intravenously every 2 weeks during the 12-week, double-blind phase. Patients received open-label tocilizumab for 40 weeks subsequently. The primary outcome was American College of Rheumatology (ACR) 50 response at week 4. The secondary outcomes included ACR 20/50/70, systemic feature score, glucocorticoid dose and adverse events at each point.
In the full analysis set, ACR50 response at week 4 was achieved in 61.5% (95% CI 31.6 to 86.1) in the tocilizumab group and 30.8% (95% CI 9.1 to 61.4) in the placebo group (p=0.24). The least squares means for change in systemic feature score at week 12 were –4.1 in the tocilizumab group and –2.3 in the placebo group (p=0.003). The dose of glucocorticoids at week 12 decreased by 46.2% in the tocilizumab group and 21.0% in the placebo group (p=0.017). At week 52, the rates of ACR20, ACR50 and ACR70 were 84.6%, 84.6% and 61.5%, respectively, in both groups. Serious adverse events in all participants who received one dose of tocilizumab were infections, aseptic necrosis in the hips, exacerbation of adult-onset Still’s disease, drug eruption and anaphylactic shock.
The study suggests that tocilizumab is effective in adult-onset Still’s disease, although the primary endpoint was not met and solid conclusion was not drawn.
To evaluate the reliability of consensus-based ultrasound (US) definitions of elementary components of enthesitis in spondyloarthritis (SpA) and psoriatic arthritis (PsA) and to evaluate which of them had the highest contribution to defining and scoring enthesitis.
Eleven sonographers evaluated 40 entheses from five patients with SpA/PsA at four bilateral sites. Nine US elementary lesions were binary-scored: hypoechogenicity, thickened insertion, enthesophytes, calcifications, erosions, bone irregularities, bursitis and Doppler signal inside and around enthesis. Kappa statistics were used to evaluate reliability. Sonographers were also asked to state which lesions can be considered as inflammatory or structural and should be included in the final definition of enthesitis. Only the lesions, scored as present in at least 75% of the entheses considered as having an enthesitis, were included in the final definition.
The prevalence of detected lesions was quite low except for enthesophytes (55%) and bone irregularities (54%). Reliability ranged from poor to good (the lowest for thickened enthesis (kappa 0.1 (95% CI 0 to 0.7)) and the highest for enthesophytes (kappa 0.6 (95% CI 0.5 to 0.7)). When adjusted for low prevalence, kappa values increased for all lesions, with the best result observed for detecting Doppler signal at insertion (0.9) and for bursitis (0.8). The US components included in the final definition were hypoechogenicity, increased thickness at enthesis, erosions and calcifications/enthesophytes and Doppler signal at insertion.
By using a consensus-based stepwise approach, a final reliable US score and definition of enthesitis in SpA/PsA were produced. Further studies are sought for implementing this score in clinical trials and practice.
To test the psychometric performance of a modified Disease Activity index for PSoriatic Arthritis (DAPSA) using 28 instead of 66 swollen/68 tender joint counts (SJC/TJC).
We included patients with psoriatic arthritis (PsA) from the Danish national quality registry DANBIO, divided into examination (n=3157 patients, 23987 visits) and validation cohorts (n=3154 patients, 24160 visits). We defined DAPSA28 = (28TJC x conversion factor1) + (28SJC x conversion factor2) + patient global (0–10VAS) + pain (0–10VAS) + C reactive protein (CRP) (mg/dL). Identification of the conversion factors was performed by generalised estimating equations in the examination cohort and evaluation of criterion, correlational and construct validity in the validation cohort.
We estimated DAPSA28 = (28TJC x 1.6) + (28SJC x 1.6) + patient global (0–10VAS) + pain (0–10VAS) + CRP (mg/dL). Criterion validity: DAPSA/DAPSA28 had comparable discriminative power expressed as standardised mean difference (DAPSA, 0.90; DAPSA28, 0.93) to distinguish between patients in high and low disease activity. Kappa with quadratic weighting of DAPSA/DAPSA28 disease activity states was high: 0.92 (95% CI 0.92 to 0.92). Standardised response means for DAPSA/DAPSA28 were –0.96/–0.92 for visits after biological DMARD-initiation. Correlational validity: Baseline DAPSA/DAPSA28 had high correlation with 28-joint disease activity score with CRP (r=0.87/r=0.93), simplified disease activity index (r=0.92/r=0.99), p<0.001. Bland-Altman plot showed better agreement between DAPSA/DAPSA28 for low than high disease activity. Construct validity: DAPSA/DAPSA28 were similarly correlated to Health Assessment Questionnaire; r=0.60/0.62, p<0.001. DAPSA/DAPSA28 discriminated patients reporting their symptom state as acceptable versus not acceptable equally well: mean (SD) 9.1 (8.7)/8.4 (8.0) and 24.2 (14.9)/22.5 (13.8), respectively.
Our study suggests that data sets with only 28-joint counts available can be used to calculate DAPSA28, especially in patients with low disease activity. DAPSA28 showed good criterion, correlational and construct validity and sensitivity to change. Still, our results support that 66/68 joint count should be performed and the original DAPSA should be preferred in PsA.
Cutaneous neonatal lupus (cNL) occurs in possibly 5%–16% of anti-Ro±anti-La antibody–exposed infants. Data suggest in utero exposure to hydroxychloroquine (HCQ) may prevent cardiac NL. The aim was to assess whether in utero exposure to HCQ decreases the risk of cNL and/or delays onset.
A multicentre case–control study was performed with 122 cNL cases and 434 controls born to women with a rheumatological disease who had documentation of maternal anti-Ro±anti-La antibodies at pregnancy and confirmation of medication use and the child’s outcome. A secondary analysis was performed on 262 cNL cases, irrespective of maternal diagnosis, to determine if HCQ delayed time to cNL onset.
Twenty (16%) cNL cases were exposed to HCQ compared with 146 (34%) controls (OR 0.4 (95% CI 0.2 to 0.6); p<0.01). Exposure to HCQ was associated with a reduced risk of cNL; exposure to anti-La antibody and female gender were associated with an increased risk of cNL. Exposure to HCQ remained significantly associated with a reduced cNL risk in the analyses limited to mothers with systemic lupus erythematosus and those who developed rash ≤1 month. When analysing all 262 cNL cases, HCQ-exposed infants were older (6.0 (95% CI 5.7 to 6.3) weeks) at cNL onset versus HCQ-non-exposed infants (4.4 (95% CI 3.9 to 5.0) weeks), but the difference was not statistically significant (p=0.21).
Exposure to HCQ was associated with a reduced risk of cNL. Among cNL cases, those exposed to HCQ tend to have later onset of rash. Both findings suggest a protective effect of HCQ on cNL.
Polymyalgia rheumatica (PMR) is the most common inflammatory rheumatic disease in older people. Contemporary estimates of the incidence and prevalence are lacking, and no previous study has assessed treatment patterns at a population level. This study aims to address this.
We extracted anonymised electronic medical records of patients over the age of 40 years from the Clinical Practice Research Datalink in the period 1990–2016. The absolute rate of PMR per 100 000 person-years was calculated and stratified by age, gender and calendar year. Incidence rate ratios were calculated using a Poisson regression model. Among persons with PMR, continuous and total duration of treatment with glucocorticoids (GC) were assessed.
5 364 005 patients were included who contributed 44 million person-years of follow-up. 42 125 people had an incident diagnosis of PMR during the period. The overall incidence rate of PMR was 95.9 per 100 000 (95% CI 94.9 to 96.8). The incidence of PMR was highest in women, older age groups and those living in the South of England. Incidence appears stable over time. The prevalence of PMR in 2015 was 0.85 %. The median (IQR) continuous GC treatment duration was 15.8 (7.9–31.2) months. However, around 25% of patients received more than 4 years in total of GC therapy.
The incidence rates of PMR have stabilised. This is the first population-based study to confirm that a significant number of patients with PMR receive prolonged treatment with GC, which can carry significant risks. The early identification of these patients should be a priority in future research.
Hand osteoarthritis is a prevalent disease with limited treatment options. Since joint inflammation is often present, we investigated tumour necrosis factor (TNF) as treatment target in patients with proven joint inflammation in a proof-of-concept study.
This 1-year, double-blind, randomised, multicentre trial (NTR1192) enrolled patients with symptomatic erosive inflammatory hand osteoarthritis. Patients flaring after non-steroidal anti-inflammatory drug washout were randomised to etanercept (24 weeks 50 mg/week, thereafter 25 mg/week) or placebo. The primary outcome was Visual Analogue Scale (VAS) pain at 24 weeks. Secondary outcomes included clinical and imaging outcomes (radiographs scored using Ghent University Scoring System (GUSS, n=54) and MRIs (n=20)).
Of 90 patients randomised to etanercept (n=45) or placebo (n=45), respectively, 12 and 10 discontinued prematurely. More patients on placebo discontinued due to inefficacy (6 vs 3), but fewer due to adverse effects (1 vs 6). The mean between-group difference (MD) in VAS pain was not statistically significantly different (–5.7 (95% CI –15.9 to 4.5), p=0.27 at 24 weeks; – 8.5 (95% CI –18.6 to 1.6), p=0.10 at 1 year; favouring etanercept). In prespecified per-protocol analyses of completers with pain and inflammation at baseline (n=61), MD was –11.8 (95% CI –23.0 to –0.5) (p=0.04) at 1 year. Etanercept-treated joints showed more radiographic remodelling (delta GUSS: MD 2.9 (95% CI 0.5 to 5.4), p=0.02) and less MRI bone marrow lesions (MD –0.22 (95% CI –0.35 to –0.09), p = 0.001); this was more pronounced in joints with baseline inflammation.
Anti-TNF did not relieve pain effectively after 24 weeks in erosive osteoarthritis. Small subgroup analyses showed a signal for effects on subchondral bone in actively inflamed joints, but future studies to confirm this are warranted.