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Abstract
Objectives As ultrasound is sensitive for detecting crystal depositions in patients with gout, our objectives were to explore the main locations for depositions and the extent of dissolution of depositions during a treat-to-target approach with urate lowering treatment (ULT) in patients with gout.
Methods Patients with a recent flare of gout were consecutively included in this single-centre study and managed by a treat-to-target approach with ULT. All patients were assessed at baseline, 3, 6 and 12 months including bilateral ultrasound examinations of joints/tendons/entheses of hands, elbows, knees, ankles and feet. A new semiquantitative scoring system of 0–3 of elementary lesions (double contour (DC), tophi and aggregates) was applied to quantify the amount of depositions during the follow-up.
Results 209 of the patients were evaluated with ultrasound at baseline (mean (SD) age 56.4 (13.8) years and disease duration 7.9 (7.7) years, 95.2% men). The serum urate levels decreased from baseline to 12 months (mean (SD) 500 (77) to 312 (49) µmol/L) (p<0.001)). The first metatarsophalangeal joint was the most frequent location for all the elementary lesions and erosions were associated with higher levels of crystal depositions. From baseline to 12 months, mean sum scores decreased for DC (4.3 to 1.3), tophi (6.5 to 3.8) and aggregates (9.3 to 6.7) (p<0.001 for all), with DC being most sensitive to change.
Conclusions The ultrasound scoring system for crystal depositions was sensitive to change and showed that a treat-to-target approach with ULT resulted in significant reductions of all the depositions, most extensively for DC.
- gout
- ultrasonography
- arthritis
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Key messages
What is already known about this subject?
Ultrasound detects depositions of urate crystals as the elementary lesions double contour, tophi and aggregates in gout patients.
What does this study add?
This is the largest longitudinal study of gout patients with a treat-to-target approach of urate lowering therapy and the ultrasound detected urate crystal depositions were substantially reduced after 12 months.
Double contour was the elementary lesion being most sensitive to change.
The first metatarsophalangeal joint was most frequently affected with double contour, tophi and aggregates and erosions of the metatarsal head were at joint level associated with the ultrasound semiquantitative score of the different forms of crystal depositions.
How might this impact on clinical practice or future developments?
Ultrasound assessments demonstrate that the crystal load is reduced during targeted therapy, encouraging clinicians to practice a persistent treat-to-target approach of urate lowering treatment in patients with gout.
Introduction
The prevalence of gout is about 1.5%–2.0%,1 with increasing prevalence and incidence in many developed countries and with male preponderance.1–4 Longstanding elevated urate levels (>360 µmol/L or >6 mg/dL) may lead to depositions of monosodium urate (MSU) crystals in predisposed persons.5 A classical clinical presentation is an acute attack of joint pain, including swelling and erythema of the affected joint, and these patients have usually elevated serum urate levels.5 Depositions of MSU crystals have been found in joints, tendons and soft tissues by the use of ultrasound,6 and microscopic detection of MSU crystals from joint fluid or tophi will ascertain a correct diagnosis.5 Effective medication with urate lowering treatment (ULT) (eg, allopurinol or febuxostat) will usually decrease the serum urate levels and may over time prevent further gout flares.7 Several studies have shown that a treat-to-target approach in gout may be successful.7–9 However, it is still discussed among general practitioners whether such an extensive approach is necessary.10
Ultrasound is a sensitive imaging method for detection of MSU depositions.11–13 The Outcome Measures in Rheumatology (OMERACT) ultrasound group has defined three specific types of depositions (elementary lesions): double contour (DC), tophi and aggregates.14 Several studies have shown moderate to excellent intrarater and inter-rater reliability of detecting these primary lesions.15–17 The DC is caused by depositions of MSU crystals on the surface of the cartilage and is detected by ultrasound as a white line superficial to the usually anechoic (black) cartilage covering the hyperechoic (white) bone surface (which gives a double white contour). When assessing the cartilage for DC, perpendicular insonation to the cartilage should be avoided, as the cartilage interphase sign may be a pitfall. Tophi are larger aggregates of MSU crystals, usually well delineated, often with an anechoic rim, and may be up to several centimetres in diameter. Aggregates are small white spots, typically found inside the joint (in the synovium or in the effusion) or tendons.14 Flares of gout may cause bone erosions. Erosions are on ultrasound detected by discontinuity of the bone surface (visible in two perpendicular planes)14 and ultrasound has in metatarsophalangeal (MTP)1 joints been shown to be more sensitive than X-rays for detection of erosions in gout patients.18 Dual-energy CT (DECT) is a radiographic examination where MSU depositions can be visualised. There are conflicting results whether DECT or ultrasound is the most sensitive assessment for MSU depositions.19–21 However, both ultrasound (DC and tophi) and DECT have been included in the recent ACR/EULAR classification criteria for gout.22
A few, mostly small, longitudinal studies have shown that ultrasound detected crystal depositions gradually decrease in size and often disappear during ULT,23–27 and DC appeared to be most sensitive to change.26 The objectives of our observational study were to explore the most frequent locations for depositions, the extent of erosions in MTP1 joints as well as the resolution of the different forms of ultrasound detected MSU depositions (elementary lesions) in patients with gout during ULT in a treat-to-target approach .
Methods
This is a prospective, one-centre, observational study with consecutive inclusion of patients with gout confirmed by arthrocentesis with aspiration of joint fluid and microscopy with confirmed MSU crystals (Gout in Norway (NOR-Gout) study). Both patients being naïve to ULT or with previous or present ULT treatment were included, but they must have had a gout flare within the last month as well as increased serum urate levels (>360 μmol/L/>6 mg/dL) and no contraindication for ULT (ACTRN12618001372279). Since the diagnosis was ascertained by microscopic detection of MSU crystals, we accepted one single measurement of increased baseline urate level. Patients gave written informed consent according to the Declaration of Helsinki.
The present study focuses on ultrasound outcomes from the NOR-Gout study. In short, the study used ULT in a treat-to-target approach, aiming for achieving serum urate levels of <360 μmol/L (<6 mg/dL) (or <300 μmol/L (<5 mg/dL) if clinical tophi were present).
Clinical and laboratory assessments
All patients were assessed by a study nurse and a rheumatologist (performing the ultrasound examinations) at baseline and after 3, 6 and 12 months including laboratory examinations (C reactive protein (CRP) mg/L, erythrocyte sedimentation rate (ESR) mm/hour, creatinine (µmol/L) and estimated glomerular filtration rate (eGFR) (ml/min/1.73 m2)). All patients not already treated with ULT initiated allopurinol 100 mg once daily. The patients were followed monthly with assessment of the urate level and visit or telephone consultation with a trained study nurse who decided on dosage increases of 100 mg if the urate levels were >360 μmol/L (>6 mg/dL) (or >300 μmol/L (>5 mg/dL) if clinical tophi were present) until the treatment target on urate level was met (with maximum allowed allopurinol dosage of 900 mg). If a patient had intolerance for allopurinol, the treatment was changed to febuxostat with starting dose of 40 mg once daily and with increasing dosages of 40 mg as needed (with maximum allowed febuxostat dosage of 120 mg). If without intolerance, all patients were given prophylaxis for gout flares after initiation of ULT, and flares were treated according to the discretion of the physician.
The ultrasound semiquantitative scoring system
The ultrasound examinations were performed by one of two rheumatologists (HBH or LK) using a GE E9 or E10 machine with a 6-15 MHz probe, scoring grey scale pathologies at 15 MHz. MSU depositions were assessed according to the OMERACT definitions for the elementary lesions; DC, tophi and aggregates.14 We introduced a semiquantitative scoring system in order to obtain a sum score for the total burden of each of the elementary lesions, with the following scores for the three forms of depositions: score 0=none, score 1=possible, score 2=certain and score 3=major. In addition, erosions were scored semiquantitatively using the OMERACT definition of an erosion,28 with the presently used scoring definitions; 0=none, 1=possible, 2=certain, 3=major erosion.
All examinations included bilateral assessments of DC, tophi and aggregates in the following joints: wrist (radiocarpal, mid-carpal, radioulnar), metacarpophalangeal (MCP)2 and MTP1. In addition, DC at the cartilage surface was assessed in the distal femur condyle with maximally flexed knee as well as at the lateral and medial cartilage of talus (flexed knee and the foot resting flat on the bench). The following tendons and insertion of tendons were examined for tophi and aggregates: Triceps, quadriceps, patellar (proximal and distal) and Achilles tendons. To ensure that we detected all depositions, we examined the whole dorsal circumference of all the joints/cartilage with flexion of the joint as needed as well as the whole width of tendons longitudinally and in addition transverse when deemed appropriate. Erosions were assessed at the medial part of the head of the first metatarsal bone. In addition, all patients were at baseline explored by ultrasound for the presence of a large tophus (either clinically visible or the largest tophus detected by ultrasound in the regions of elbow, hand, knee, ankle and foot being accessible for measurements) which was defined as the index tophus. The size of this tophus was followed during the study with measurement by ultrasound of the largest length, width and depth in millimetres.
Prior to the study the two sonographers agreed on the semiquantitative scoring system both on images and in gout patients. To increase reliability of scoring, the same sonographer (HBH) (who previously had participated in international reliability studies on gout15 16) performed most of the current ultrasound examinations during follow-up. In addition, after the study a formal reliability assessment was performed on 78 images including similar number of each of the elementary lesions and including all the different scores, with a second round after 8 days with the images in another random order.
Statistics
Differences between groups were explored by use of independent samples t-test. At each visit sum scores of DC, tophi and aggregates were calculated separately, as well as calculation of total sum score of all the elementary lesions. Changes from baseline were explored by paired samples t-test and sensitivity to change by standardised response mean (SRM) (mean change divided by the SD of the change). All gradings were included for calculations of sum scores. However, for exploring the presence of any ultrasound elementary lesion or erosion, a conservative approach was used with no presence defined as score 0–1 and presence as score 2–3. Correlations between continuous variables were examined by the use of Pearson. The change of the size of the index tophus was explored by paired samples t-test of length, width and depth from baseline to 12 months. The reliability of scoring images was assessed by use of quadratic weighted kappa. In addition, the percentages of close agreement (ie, ±one score level) was calculated. The statistical calculations were performed by SPSS V.21 or STATA V.16, and a p<0.05 was defined as significant.
Patient and public involvement
A patient research partner with gout participated in the project and took part in the discussion of the research questions and outcome measures. Further, the patient research partner evaluated the burden of study participation and supported how patients were recruited.
Results
Patients and laboratory variables
Of the 211 patients included in the NOR-Gout study, 209 were assessed by ultrasound and included in the present study (mean (SD) age 56.4 (13.8) years and the time since first flare (disease duration) was 7.9 (7.7) years, 95.2% men). During the 12 months prior to inclusion, 27.0% of the patients had only one flare, 21.6% had two flares, 34.8% had three to five flares and 16.7% had more than five flares. The number of patients available for study visits at 3 months was 186, at 6 and 12 months 184. Baseline serum urate levels as well as sum scores of DC, tophi or aggregates were similar between patients completing and not completing the study.
The mean (SD) baseline serum urate level was 500 (77) µmol/L, which decreased to 312 (49) µmol/L after 12 months (p<0.001). From baseline to 12 months, the mean (SD) CRP levels decreased from 6.7 (13.6) mg/L to 4.0 (7.2) mg/L (p=0.015) and ESR decreased from 14.3 (13.9) mm/hour to 10.3 (10.5) mm/hour (p<0.001). There was no significant change in creatinine or eGFR from baseline to 12 months (96.3 (18.5) µmol/L to 94.7 (19.5) µmol/L and 78.0 (18.8) ml/min/1.73 m2 to 78.7 (19.2) ml/min/1.73 m2, respectively).
The intrarater reliability (SD) was 0.96 (0.11) and 0.88 (0.11) for the two sonographers, while the inter-rater reliability was 0.89 (0.11) in the first round and 0.81 (0.11) in the second round. The intra-rater close agreement was 100% for both sonographers and the inter-rater close agreement was 98.7% in the first round and 96.2% in the second round.
Baseline localisation and frequencies of the elementary lesions
Table 1 describes the percentages at baseline of patients with presence of the different elementary lesions at the different locations. Only a few regions showed significant differences between right and left side and the MTP1 joint was by far the most frequent location for all the elementary lesions. DC was most frequently found in the MTP1 joints bilaterally, followed by femur condyle and talus. Figure 1 gives examples of the different elementary lesions, erosion and an index tophus presently assessed by ultrasound.
Percentages of patients (n=209) with presence at baseline of the different ultrasound elementary lesions (defined as a score ≥2) at the different locations
Double contour in metatarsophalangeal (MTP) 1 joint (score 3), tophus in MTP1 joint (score 3), intratendinous aggregates in distal patellar tendon (score 2), erosion medially of the first metatarsal head (score 3) and measurement of the length of a subcutaneous tophus superficial to the proximal interphalangeal joint (PIP) of the 2.toe. Arrows are pointing to the different pathologies.
Associations between disease duration and elementary lesions
There was no association between serum urate level and disease duration at baseline. However, there were weak, but significant correlations between disease duration and sum scores of each of the elementary lesions (DC; r=0.31 (p<0.001), tophi; r=0.29 (p<0.001) and aggregates; r=0.25 (p<0.001).
Associations between erosions of the first metatarsal head and elementary lesions
Erosions were a frequent finding; at baseline 44% of the patients had erosions at the right side and 49.5% at the left side. Presence of erosion in one or both metatarsal heads was found in 62.5% of the patients. MTP1 joints with erosions had at baseline significantly higher scores of DC, tophi and aggregates as compared with MTP1 joints with no erosion (mean (SD) scores in MTP1 joints with erosion vs no erosion were 1.54 (0.85) vs 0.53 (0.73) for DC, 1.91 (0.84) vs 0.57 (0.85) for tophi and 1.81 (0.62) vs 0.71 (0.85) for aggregates, p<0.001 for all elementary lesions). In addition, the joint scores for erosions were significantly correlated with the joint scores for DC, tophi as well as aggregates at both right and left MTP1 joints at baseline (right side; r=0.60–0.68, left side; r=0.59–0.71 (p<0.001 for all)).
Follow-up data
Associations between serum urate levels and elementary lesions
At baseline, weak, but statistically significant correlations were found between serum urate levels and the different elementary lesions (sum score DC; r=0.35 (p<0.001), sum score tophi; r=0.22 (p=0.002) and sum score aggregates; r=0.18 (p=0.01)). However, no significant correlations were found at 12 months. The patients who did not reach the serum urate target had non-significantly higher mean sum scores for DC, tophi and aggregates during the study than the patients achieving target levels <360 µmol/L at 12 months. However, both patients who reached the urate target and those not reaching the target had a significant decrease from baseline to 12 months of sum scores for all the elementary lesions (p≤0.001). This is illustrated in online supplementary figure 1. In addition, there was a weak, but significant correlation between reduction of serum urate levels and reduction in sum score DC (r=0.29, p<0.001), while no significant correlations were found for sum scores of tophi or aggregates.
Supplemental material
Changes in ultrasound scores
The change of elementary lesions during the follow-up is shown in table 2, describing the decreases of sum scores of DC, tophi and aggregates as well as sum of all elementary lesions from baseline during follow-up (p<0.001 for all). The decrease was most pronounced for DC, demonstrated in figure 2 (with the SRMs for the different elementary lesions). Online supplementary figure 2 illustrates the results by use of error bar plots showing the decrease in sum scores of all the elementary lesions.
Supplemental material
Standardised response means (mean change divided on SD) for the reduction of sum scores of DC, tophi and aggregates from baseline during 12 months follow-up. DC, double contour.
Sum scores of double contours, tophi, aggregates as well as sum of all the three elementary lesions during 12 months follow-up
The DC scores in each of MTP1, talus and femur condyle decreased significantly from baseline to 12 months follow-up (p<0.001 for all joints). Sum score of DC from the two MTP1 joints had a more pronounced decrease than sum score of DC from bilateral femur condyle or talus (p<0.001) (mean (SD) sum score DC in MTP1 at baseline/12 months were 2.0 (1.6)/0.7 (1.1) vs talus 1.1 (1.4)/0.3 (0.7) and distal femur condyle 1.0 (1.5)/0.2 (0.7)).
SRMs were used to explore potential differences between tendons and joints in reduction of tophi and aggregates from baseline to 12 months. The SRM for tophi was slightly higher in joints than in tendons (0.78 vs 0.66), while for aggregates it was opposite, with higher SRM in tendons than in joints (0.74 vs 0.46).
Changes in the frequency of elementary lesions
DC was present in 92.9% of the patients at baseline, decreasing to 44.4% of the patients at 12 months. At baseline, 93.4% of the patients had tophi, decreasing to 80.2% at 12 months, and aggregates were present at baseline in 99.1% and at 12 months in 95.7% of the patients.
Changes in index tophus and associations with elementary lesions
At baseline, 51 of the patients had an index tophus, and these tophi were localised at different locations, but mostly in the feet. At 12 months, 39 still had their index tophus present. The length and width of the tophi had decreased at 12 months (p≤0.003), while the depth did not decrease significantly. The 51 patients with index tophi at baseline did not have significantly different serum urate levels from those without an index tophi, but had significantly higher sum scores level for all three elementary lesions (having index tophus vs not having index tophus; mean (SD) sum scores of DC; 7.1 (3.9) vs 3.4 (2.8), tophi; 12.6 (9.2) vs 4.5 (3.6) and aggregates 13.5 (6.1) vs 7.9 (4.7) (p<0.001 for all)). This difference persisted at 12 months, where patients with versus without an index tophus still had significantly higher sum scores of all the elementary lesions (p<0.001), but serum urate levels were similar.
Discussion
This is the largest ultrasound study of MSU crystal depositions in gout patients. The patients were followed for 1 year by a treat-to-target approach with ULT resulting in a significant decrease of the serum urate level. Of major clinical importance is that the sum scores of DC, tophi and aggregates decreased considerably during the study, with DC being the lesion with earliest as well as most extensive decrease. Thus, this study shows that patients in clinical practice during a treat-to-target schedule with escalating ULT will reduce their burden of crystals as measured by ultrasound. In addition, we found that the different manifestations of MSU crystal depositions were most frequently found in the MTP1 joints, and the extent of erosions in MTP1 joints were highly associated with the scores of each of the elementary lesions at joint level. In addition, patients with an index tophus had the highest load of all the elementary lesions.
In addition to the MTP1 joint being the most frequent location for all the three elementary lesions, DC at the distal femur and the proximal talar cartilage was seen in about one of six patients and almost the same frequency was found for tophi in the triceps and distal patellar tendon. The finding of these locations as being the most frequent is supported by a study by Naredo et al.29 Further studies are needed to determine the most sensitive regions for assessing crystal depositions for diagnostic and monitoring purposes.
A small study has previously indicated that DC disappears during effective medical treatment of patients with gout.23 In our large study, we applied the OMERACT validated definitions for the different ultrasound lesions and found that all the elementary lesions decreased during ULT, however, by different degrees. In a study of 23 gout patients, Peiteado et al 26 described DC to be sensitive to change during the follow-up. This is supported by our study where less than half of the patients had no DC at 12 months. The early disappearance of DC during effective ULT may be explained by the close contact between the MSU crystals at the cartilage surface and the joint fluid. Since the chemical substances between blood and joint fluid will equalise, a low serum uric acid level during treatment may cause a gradual dissolvement of the MSU crystals in the joint.
Ultrasound has been suggested used for assessment of tophi size,30 and we found reduced length and width, but not depth of the index tophi after 12 months. This finding is supported by a recent study where pegloticase effectively reduced the serum uric acid level, and many of the tophi were shown to disappear on DECT, while still present by ultrasound.31 The definition of tophi by ultrasound is a localised aggregation with clear margins. However, during effective ULT the morphology of the tophi may change, and it may be increasingly difficult by ultrasound to define the outer margins of the tophi. The MSU crystals being organised inside the tophus with fibrotic tissue surrounding them, may gradually be dissolved, while the fibrotic tissue may still be present. This could influence the possibility of correct assessments of crystal depositions in tophi by ultrasound during effective ULT. However, this may be explored in further studies including use of three-dimensional probes.
Aggregate was the lesion with less tendency to decrease during the study. This may be caused by the transition of larger tophi into smaller aggregates of MSU crystals during the dissolution of tophi. In addition, calcifications of aggregates or calcifications misinterpreted as aggregates may be other causes. However, sum score of aggregates decreased during our study. Thus, this lesion was also shown to be sensitive to change during effective treatment.
In contrast to the study by Peiteado et al,26 we found no significant difference in serum uric acid level between patients with versus without DC at 12 months. However, our study showed a weak, but significant association between reduction of urate levels and reduction in sum score DC. In addition, our study supports the finding of DC in the MTP1 joints to decrease more profoundly than in the other joints.26 In general, our large study supports the few smaller studies showing DC to be highly sensitive to decrease during effective ULT. In addition, we showed that the two other elementary lesions also decreased significantly during treatment.
Even if there are ultrasound definitions by OMERACT for the elementary lesions (DC, tophi and aggregates),14 there is currently no validated scoring system for the different types of ultrasound depositions. However, a recent study by Christiansen et al 32 used a binary scoring system in a longitudinal evaluation of the different elementary lesions, and they also found a significant reduction during ULT. In the present study, we have applied a semiquantitative scoring system for all three lesions individually depending on the severity of the depositions and we found that this scoring system was sensitive to change during treatment. However, the scoring system should be validated further in future studies.
With the present finding of reduction of the elementary lesions during treat-to-target treatment, routine use of ultrasound during follow-up of gout patients may not be necessary. However, it may be encouraging for patients when they are informed about and see on the screen that the depositions are decreased during treatment, and ultrasound may therefore support improved adherence to ULT.
Strengths of the present study include the high number of participants followed for 1 year during effective ULT. Patients in this study were included from clinical practice in an outpatient rheumatology clinic with good capacity and very short waiting lists. In addition, only high-end ultrasound machines were used, and high intrarater and inter-rater reliability was shown for scoring of the elementary lesions.
In conclusion, this is the largest longitudinal study using ultrasound to assess MSU crystal depositions by use of a new semiquantitative scoring system. We found that during a treat-to-target approach with ULT all the different forms of ultrasound detected depositions decreased, with DC having the most extensive reduction. MTP1 was found to be most frequently involved, and the score of MTP1 erosion was at joint level associated with the score of the elementary lesions. Presence of an ultrasound detected index tophus was highly associated with sum scores of all the elementary lesions both at baseline and after 12 months. The present study gives important results by showing that patients in clinical practice who are followed by a treat-to-target approach regarding ULT reduced their burden of MSU crystals as measured by ultrasound.
Acknowledgments
We want to thank Gina Stenberg, Anita Reinhard, Heidi Lunøe and Ingerid Müller who contributed as trained study nurses in the monthly follow-up of the treat-to-target approach. We are also very thankful to Sara Nysom Christiansen, MD, PhD student, Copenhagen, for organising the reliability study on ultrasound images from gout patients.
References
Footnotes
Handling editor Josef S Smolen
Presented at Some of the results from this study have been presented in a poster at EULAR 2019, and in oral presentations both at EULAR 2018 and at ACR 2019 [EULAR 2018 OP 0211, 2019 ACR/ARP Annual Meeting 898, EULAR 2019 SAT0423].
Contributors HBH has made a substantial contributions to the conception and design of the work; the acquisition of data, some of the analysis, interpretation of data for the work; and drafted the manuscript as well as revising it critically for important intellectual content; and given a final approval of the version to be published; and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. LK, EAH, TKK and TU has given substantial contributions to the design of the manuscript as well as the interpretation of data for the work; and revised the manuscript critically for important intellectual content; and given a final approval of the version to be published; and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. LT has given substantial contributions to the design of the manuscript as well as the analysis and interpretation of data for the manuscript; and revising the manuscript critically for important intellectual content; and given final approval of the version to be published; and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Funding There was no external funding, and the study was performed as employees at National Advisory Unit on Rehabilitation in Rheumatology (NKRR) and Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway.
Competing interests HBH reports personal fees from AbbVie, Lilly and Novartis, outside the submitted work. LT reports personal fees from Novartis, Roche, BMS and Pfizer outside the submitted work. EAH reports personal fees from Pfizer, UCB, Eli Lilly, Celgene, Janssen-Cilag, AbbVie and Gilead outside the submitted work. TKK reports grants and personal fees from AbbVie, MSD, UCB, Hospira/Pfizer, Eli-Lilly, grants from BMS, personal fees from Roche, Hikma, Orion, Sanofi, Celltrion, Sandoz, Biogen, Amgen, Egis, Ewopharma and Mylan, outside the submitted work. TU reports personal fees from Grünenthal and Novartis, outside the submitted work.
Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.
Patient consent for publication Not required.
Ethics approval The study was approved by the Norwegian Regional Committee for Medical and Health Research Ethics South East (reference number 2015/990).
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available on reasonable request. Deidentified participant data are available on reasonable request.