The terminologies of transient, migratory, or localized osteoporosis, and bone marrow edema syndrome: a scoping review.

There is no formally defined terminology for the related entities transient osteoporosis of the hip (TOH), localized or regional migratory osteoporosis (RMO) and bone marrow edema syndrome (BMES). This study aimed to map the diversity and frequency of diagnostic terms and vocabulary utilized in the literature. A comprehensive search of electronic databases and reference lists was conducted. Publications that reported on patients with TOH, RMO, BMES, or related variants were eligible for inclusion. The terminologies were categorized based on the wording of the titles, abstracts, or texts. We included 561 publications, of which 423 were case reports, involving 2921 patients. Overall, TOH was the most commonly used term, occurring in 257 (45.8%). RMO was used in 34 (6.1%) and BMES in 57 (10.2%). The remaining used various combinations of transient, migratory, and regional in conjunction with either osteoporosis or bone marrow edema. Localized osteoporosis was not used. We identified three different terms related to pregnancy. In 76.3% of the publications, the terminology was related to osteoporosis and in 18.2% to bone marrow edema, although terminology did not correspond to actual findings. Bone marrow edema occurred as often as osteoporosis, and osteoporosis was generally ascertained by visual inspection of radiographs, seldom by bone densitometry. Many publications used osteoporosis-related terms without evidence that osteoporosis had been detected. The terminology of these closely related entities is confusing and unstandardized. The lack of formal definitions impedes accurate diagnosis, research on disease mechanisms, and effective treatment.

Longitudinal Relationship Between Reduced Modic Change Edema and Disability and Pain in Patients With Chronic Low Back Pain.

STUDY DESIGN: Secondary analyses of a randomized trial [Antibiotics In Modic changes (MCs) study]. OBJECTIVE: To assess whether or not reduced MC edema over time is related to reduced disability and pain in patients with chronic low back pain (LBP). SUMMARY OF BACKGROUND DATA: It is not clear whether or not reduced MC edema implies improved clinical outcomes. PATIENTS AND METHODS: Linear regression was conducted separately in 2 subgroups with MC edema at baseline on short tau inversion recovery (STIR) or T1/T2-weighted magnetic resonance imaging, respectively. Independent variable: reduced edema (yes/no) at 1 year on STIR or T1/T2-series, respectively. Dependent variable: 1-year score on the Roland-Morris Disability Questionnaire (RMDQ), Oswestry Disability Index (ODI), or 0 to 10 numeric rating scale for LBP intensity, adjusted for the baseline score, age, smoking, body mass index, physical workload, and baseline edema on STIR (STIR analysis only). Post hoc, we, in addition, adjusted all analyses for baseline edema on STIR, treatment group (amoxicillin/placebo), and prior disc surgery-or for disc degeneration. RESULTS: Among patients with MC edema on STIR at baseline (n = 162), reduced edema on STIR was not significantly related to the RMDQ ( B : -1.0, 95% CI: -2.8, 0.8; P = 0.27), ODI ( B :-1.4, 95% CI: -5.4, 2.6; P = 0.50), or LBP intensity scores ( B : -0.05, 95% CI: -0.8, 0.7; P = 0.90) after 1 year. Among patients with MC edema on T1/T2-series at baseline (n = 116), reduced edema on T1/T2 ( i.e ., reduced volume of the type 1 part of MCs) was not significantly related to RMDQ ( B: -1.7, 95% CI: -3.8, 0.3; P = 0.10) or ODI score ( B : -2.3, 95% CI: -7.1, 2.5; P = 0.34) but was significantly related to LBP intensity at 1 year ( B : -0.9, 95% CI: -1.8, -0.04; P = 0.04; correlation coefficient: 0.24). The post hoc analyses supported these results. CONCLUSION: Reduced MC edema over 1 year was not significantly associated with pain-related disability but was (on T1/T2-series) significantly but weakly related to reduced LBP intensity. LEVEL OF EVIDENCE: Level 3.

Symptom descriptors and patterns in lumbar radicular pain caused by disc herniation: a 1-year longitudinal cohort study.

OBJECTIVE: The objective of the present study was to explore the diversity, quality, severity and distribution of symptoms in patients with radicular pain and a lumbar disc herniation. DESIGN: Longitudinal cohort study. SETTING: Hospital-based back clinic. PARTICIPANTS: Ninety patients referred to secondary healthcare with (a) low back-related leg pain, (b) age between 18 and 65 years and (c) MRI confirmed lumbar disc herniation at a relevant side and level. OUTCOME MEASURES: Neuropathic pain symptoms were assessed using the Short-Form McGill Pain Questionnaire-2 (SF-MPQ-2) and the painDETECT Questionnaire. In a subsample classified with neuropathic pain, in-depth interviews were performed, and symptomatic areas were drawn on standardised body charts. RESULTS: At baseline, the most frequently used painDETECT symptom descriptor was numbness sensation, reported by 94%, followed by sudden pain attacks and tingling or prickling. The mean (SD) SF-MPQ-2 score (0-10) for aching pain was 5.9 (2.8); numbness 4.3 (3.3); tingling 4.0 (3.4); burning 2.6 (3.1); pain caused by light touch 1.5 (2.6). Leg pain was rated as extremely bothersome by 73%, numbness and tingling by 38%, weakness by 24% and back pain by 17%. In the subsample (n=52), deep-lying pain and non-painful abnormal sensations were frequent, at 71% and 85%. Drawings demonstrated substantial overlap between symptoms from compromised L5 and the S1 nerve roots. Painful and non-painful symptoms improved at approximately the same rate. At the 1-year follow-up, 45% (14/31) of patients who had received disc surgery, and 34% (18/53) of those who had received conservative treatment reported no bothersome back pain, leg pain, numbness/tingling or weakness. CONCLUSION: Patients reported several highly bothersome symptoms, but not all are described as painful. The overall symptom profile of lumbar disc-related radicular pain differs from other neuropathic pain conditions with limited allodynia and thermal hyperalgesia. Symptomatic areas for the L5 and S1 nerve roots have a large overlap.

Minimal important change was on the lower spectrum of previous estimates and responsiveness was sufficient for core outcomes in chronic low back pain.

OBJECTIVES: The objective of this study was to estimate the minimal important change (MIC) and responsiveness of core patient reported outcome measures for chronic low back pain (LBP) and Modic changes. STUDY DESIGN AND SETTING: In the Antibiotics in Modic changes (AIM) trial we measured disability (RMDQ, ODI), LBP intensity (NRS) and health-related quality of life (EQ5D) electronically at baseline, three- and 12-month follow-up. MICs were estimated using Receiver Operating Curve (ROC) curve and Predictive modeling analyses against the global perceived effect. Credibility of the estimates was assessed by a standardized set of criteria. Responsiveness was assessed by a construct and criterion approach according to COSMIN guidelines. RESULTS: The MIC estimates of RMDQ, ODI and NRS scores varied between a 15-40% reduction, depending on including "slightly improved" in the definition of MIC or not. The MIC estimates for EQ5D were lower. The credibility of the estimates was moderate. For responsiveness, five out of six hypotheses were confirmed and AUC was >0.7 for all PROMs. CONCLUSION: When evaluated in a clinical trial of patients with chronic LBP and Modic changes, MIC thresholds for all PROMs were on the lower spectrum of previous estimates, varying depending on the definition of MIC. Responsiveness was sufficient.

Strategies to manage auxiliary pain medications in chronic pain trials: a topical review.

Chronic pain trials commonly allow auxiliary pain medications such as rescue and concomitant analgesics in addition to the randomized treatment. Changes in auxiliary pain medications after randomization represent intercurrent events that may affect either the interpretation or the existence of the measurements associated with the clinical question of interest, complicating the assessment of treatment efficacy. In chronic pain trials, pain intensity typically varies and patients may take the auxiliary medications 1 day but not the next or increase and decrease the dosages temporarily while continuing their randomized study medication. This distinctive feature of auxiliary pain medications as an intercurrent event has received little attention in the literature. Further clarifications on how to manage these issues are therefore pressing. Here we provide perspectives on issues related to auxiliary pain medication-related intercurrent events in randomized controlled chronic pain trials considering the strategies suggested in the E9(R1) addendum to the ICH guideline on statistical principles for clinical trials.

NSAIDs in sciatica (NIS): study protocol for an investigator-initiated multicentre, randomized placebo-controlled trial of naproxen in patients with sciatica.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to treat sciatica, despite insufficient evidence from placebo-controlled trials. NSAIDs may cause serious side effects; hence, there is a strong need to clarify their potential beneficial effects in patients with sciatica. METHODS: This is a multicentre, randomized, placebo-controlled, parallel-group superiority trial. Participants will be recruited among sciatica patients referred to outpatient clinics at hospitals in Norway who have radiating pain below the knee with a severity score of ≥ 4 on a 0-10 numeric rating scale and clinical signs of nerve root or spinal nerve involvement. The intervention consists of oral naproxen 500 mg or placebo twice daily for 10 days. Participants will report the outcomes and adverse events daily using an electronic case report form. The primary endpoint is change in leg pain intensity from baseline to day 10 based on daily observations. The secondary outcomes are back pain intensity, disability, sciatica symptom severity, rescue medication (paracetamol) consumption, opioid use, ability to work or study, 30% and 50% improvement in leg pain, and global perceived change of sciatica/back problem. The outcomes will be analysed using mixed effects models for repeated measurements. The total duration of follow-up is 12 (± 2) days. DISCUSSION: This trial aims to evaluate the benefits of naproxen, a non-selective NSAID, in patients with sciatica. No important differences in efficacy have been demonstrated between different NSAIDs in the management of musculoskeletal disorders; hence, the results of this trial will likely be applicable to other NSAIDs. TRIAL REGISTRATION: ClinicalTrials.gov NCT03347929 . Registered on November 20, 2017.

Correlation between gene expression and MRI STIR signals in patients with chronic low back pain and Modic changes indicates immune involvement.

Disability and distress caused by chronic low back pain (LBP) lacking clear pathoanatomical explanations cause huge problems both for patients and society. A subgroup of patients has Modic changes (MC), identifiable by MRI as vertebral bone marrow lesions. The cause of such changes and their relationship to pain are not yet understood. We explored the pathobiology of these lesions using profiling of gene expression in blood, coupled with an edema-sensitive MRI technique known as short tau inversion recovery (STIR) imaging. STIR images and total RNA from blood were collected from 96 patients with chronic LBP and MC type I, the most inflammatory MC state. We found the expression of 37 genes significantly associated with STIR signal volume, ten genes with edema abundancy (a constructed combination of STIR signal volume, height, and intensity), and one gene with expression levels significantly associated with maximum STIR signal intensity. Gene sets related to interferon signaling, mitochondrial metabolism and defense response to virus were identified as significantly enriched among the upregulated genes in all three analyses. Our results point to inflammation and immunological defense as important players in MC biology in patients with chronic LBP.

Impact of rescue medication in placebo-controlled trials of pharmacotherapy for neuropathic pain and low back pain.

ABSTRACT: Rescue medication (RM) consumption is commonly used as a secondary outcome in placebo-controlled trials of chronic pain, but its validity has yet to be established. If participants randomized to placebo take more RM than those randomized to an active drug, the difference in pain between the 2 groups may be reduced, potentially masking effects of the active drug. This study assessed proportional RM consumption in the placebo and active groups according to results of 42 randomized controlled trials of neuropathic pain (NeP), and 29 trials of low back pain, which were included in 2 systematic reviews and meta-analyses. Trial results were assessed based on effect size, statistical significance, and whether the drug was recommended as first-line treatment by the systematic reviews. In trials indicating effect of the investigational drug, RM consumption was generally higher in the placebo groups than in the active groups. In trials reporting a small or a medium effect size of the investigational drug, subjects receiving placebo consumed 17% to 30% more RM than subjects receiving active drug, potentially leading to underestimation of the effects of the investigational drugs. Few trials reported a large effect size. Differences in RM consumption between participants receiving placebo and those receiving active drug were seldom taken in account by the individual trials and not at all by the systemic reviews when making treatment recommendations for NeP or low back pain. Elaboration on analytical methods to assess treatment effects in chronic pain trials using RM is warranted.

Effect of Therapeutic Drug Monitoring vs Standard Therapy During Maintenance Infliximab Therapy on Disease Control in Patients With Immune-Mediated Inflammatory Diseases: A Randomized Clinical Trial.

Importance: Proactive therapeutic drug monitoring (TDM), consisting of individualized treatment based on scheduled assessments of serum drug levels, has been proposed as an alternative to standard therapy to optimize efficacy and safety of infliximab and other biologic drugs. However, it remains unclear whether proactive TDM improves clinical outcomes during maintenance therapy. Objective: To assess whether proactive TDM during maintenance therapy with infliximab improves treatment efficacy by preventing disease worsening compared with standard infliximab therapy without TDM. Design, Setting, and Participants: Randomized, parallel-group, open-label clinical trial including 458 adults with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn disease, or psoriasis undergoing maintenance therapy with infliximab in 20 Norwegian hospitals. Patients were recruited from June 7, 2017, to December 12, 2019. Final follow-up took place on December 14, 2020. Interventions: Patients were randomized 1:1 to proactive TDM with dose and interval adjustments based on scheduled monitoring of serum drug levels and antidrug antibodies (TDM group; n = 228) or to standard infliximab therapy without drug and antibody level monitoring (standard therapy group; n = 230). Main Outcome and Measures: The primary outcome was sustained disease control without disease worsening, defined by disease-specific composite scores or consensus about disease worsening between patient and physician leading to a major change in treatment (switching to another biologic drug, adding an immunosuppressive drug including glucocorticoids, or increasing the infliximab dose), during the 52-week study period. Results: Among 458 randomized patients (mean age, 44.8 [SD, 14.3] years; 216 women [49.8%]), 454 received their randomly allocated intervention and were included in the full analysis set. The primary outcome of sustained disease control without disease worsening was observed in 167 patients (73.6%) in the TDM group and 127 patients (55.9%) in the standard therapy group. The estimated adjusted difference was 17.6% (95% CI, 9.0%-26.2%; P < .001) favoring TDM. Adverse events were reported in 137 patients (60%) and 142 patients (63%) in the TDM and standard therapy groups, respectively. Conclusions and Relevance: Among patients with immune-mediated inflammatory diseases undergoing maintenance therapy with infliximab, proactive TDM was more effective than treatment without TDM in sustaining disease control without disease worsening. Further research is needed to compare proactive TDM with reactive TDM, to assess the effects on long-term disease complications, and to evaluate the cost-effectiveness of this approach. Trial Registration: ClinicalTrials.gov Identifier: NCT03074656.

Effect of Therapeutic Drug Monitoring vs Standard Therapy During Infliximab Induction on Disease Remission in Patients With Chronic Immune-Mediated Inflammatory Diseases: A Randomized Clinical Trial.

Importance: Proactive therapeutic drug monitoring (TDM), defined as individualized drug dosing based on scheduled monitoring of serum drug levels, has been proposed as an alternative to standard therapy to maximize efficacy and safety of infliximab and other biological drugs. However, whether proactive TDM improves clinical outcomes when implemented at the time of drug initiation, compared with standard therapy, remains unclear. Objective: To assess whether TDM during initiation of infliximab therapy improves treatment efficacy compared with standard infliximab therapy without TDM. Design, Setting, and Participants: Randomized, parallel-group, open-label clinical trial of 411 adults with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn disease, or psoriasis initiating infliximab therapy in 21 hospitals in Norway. Patients were recruited from March 1, 2017, to January 10, 2019. Final follow-up occurred on November 5, 2019. Interventions: Patients were randomized 1:1 to receive proactive TDM with dose and interval adjustments based on scheduled monitoring of serum drug levels and antidrug antibodies (TDM group; n = 207) or standard infliximab therapy without drug and antibody level monitoring (standard therapy group; n = 204). Main Outcomes and Measures: The primary end point was clinical remission at week 30. Results: Among 411 randomized patients (mean age, 44.7 [SD, 14.9] years; 209 women [51%]), 398 (198 in the TDM group and 200 in the standard therapy group) received their randomized intervention and were included in the full analysis set. Clinical remission at week 30 was achieved in 100 (50.5%) of 198 and 106 (53.0%) of 200 patients in the TDM and standard therapy groups, respectively (adjusted difference, 1.5%; 95% CI, -8.2% to 11.1%; P = .78). Adverse events were reported in 135 patients (68%) and 139 patients (70%) in the TDM and standard therapy groups, respectively. Conclusions and Relevance: Among patients with immune-mediated inflammatory diseases initiating treatment with infliximab, proactive therapeutic drug monitoring, compared with standard therapy, did not significantly improve clinical remission rates over 30 weeks. These findings do not support routine use of therapeutic drug monitoring during infliximab induction for improving disease remission rates. Trial Registration: ClinicalTrials.gov Identifier: NCT03074656.

Pinprick and Light Touch Are Adequate to Establish Sensory Dysfunction in Patients with Lumbar Radicular Pain and Disc Herniation.

BACKGROUND: The frequency with which sensory disturbances occur in patients with radicular leg pain and disc herniation is not well known, and the efficacy of tests to identify such changes are not firmly established. The presence of sensory disturbances is a key sign of nerve root involvement and may contribute to the diagnosis of a lumbar disc herniation, identify patients for referral to spinal imaging and surgery, and improve disease classification. QUESTIONS/PURPOSES: In this study, we sought: (1) to determine the frequency with which abnormal sensory findings occur in patients with lumbar disc herniation-related radicular pain, using a standard neurological sensory examination; (2) to determine what particular standard sensory test or combination of tests is most effective in establishing sensory dysfunction; and (3) to determine whether a more detailed in-depth sensory examination results in more patients being identified as having abnormal sensory findings. METHODS: Between October 2013 and April 2016, 115 patients aged 18 to 65 years referred to secondary health care with radicular leg pain and disc herniation were considered potentially eligible for inclusion in the study. Based on these inclusion criteria, 79% (91) were found eligible. Ten percent (11) were excluded because of other illness that interfered with the study purpose, 3% (3) because of cauda equina syndrome, 2% (2) because of spinal stenosis, 2% (2) because of prior surgery at the same disc level, and 2% (2) because of poor Norwegian language skills. Three percent (4) of the patients did not want to participate in the study. Of the 91 eligible patients, 56% (51) consented to undergo a comprehensive clinical examination and were used for analysis here. The sample for the purposes of the present study was predetermined at 50. These patients were first examined by a standard procedure, including sensory assessment of light touch, pinprick, vibration, and warmth and cold over the back and legs. Second, an in-depth semiquantitative sensory testing procedure was performed in the main pain area to assess sensory dysfunction and improve the detection of potential positive sensory signs, or sensory gain of function more precisely. Sensory loss was defined as sensations experienced as distinctly reduced in the painful side compared with the contralateral reference side. In contrast, sensory gain was defined as sensations experienced as abnormally strong, unpleasant, or painful and distinctly stronger than the contralateral side. Ambiguous test results were coded as a normal response to avoid inflating the findings. The proportions of abnormal findings were calculated for each sensory modality and for all combinations of the standard examination tests. RESULTS: The standard examination identified at least one abnormal finding in 88% (45 of 51) of patients. Sensory loss was present in 80% (41), while sensory gain was present in 35% (18). The combination of pinprick and light touch identified all patients who were classified as having abnormal findings by the full standard examination. The semiquantitative procedure identified an additional three patients with an abnormal finding. CONCLUSION: We suggest that the combination of pinprick and light touch assessment is an adequate minimal approach for diagnostic and classification purposes in patients with lumbar radicular pain. LEVEL OF EVIDENCE: Level I, diagnostic study.

The effect of infliximab in patients with chronic low back pain and Modic changes (the BackToBasic study): study protocol of a randomized, double blind, placebo-controlled, multicenter trial.

BACKGROUND: Low back pain is common and a significant number of patients experience chronic low back pain. Current treatment options offer small to moderate effects. Patients with vertebral bone marrow lesions visualized as Modic changes on magnetic resonance imaging may represent a subgroup within the low back pain population. There is evidence for inflammatory mediators being involved in development of Modic changes; hence, suppression of inflammation could be a treatment strategy for these patients. This study examines the effect of anti-inflammatory treatment with the TNF-α inhibitor infliximab in patients with chronic low back pain and Modic changes. METHODS/DESIGN: The BackToBasic trial is a multicenter, double blind, randomized controlled trial conducted at six hospitals in Norway, comparing intravenous infusions with infliximab with placebo. One hundred twenty-six patients aged 18-65 with chronic low back pain and type 1 Modic changes will be recruited from secondary care outpatients' clinics. The primary outcome is back pain-specific disability at day 154 (5 months). The study is designed to detect a difference in change of 10 (SD 18) in the Oswestry Disability Index at day 154/ 5 months. The study also aims to refine MRI-assessment, investigate safety and cost-effectiveness and explore the underlying biological mechanisms of Modic changes. DISCUSSION: Finding treatments that target underlying mechanisms could pose new treatment options for patients with low back pain. Suppression of inflammation could be a treatment strategy for patients with low back pain and Modic changes. This paper presents the design of the BackToBasic study, where we will assess the effect of an anti-inflammatory treatment versus placebo in patients with chronic low back pain and type 1 Modic changes. The study is registered at ClinicalTrials.gov under the identifier NCT03704363 . The EudraCT Number: 2017-004861-29.

Clinical effect modifiers of antibiotic treatment in patients with chronic low back pain and Modic changes - secondary analyses of a randomised, placebo-controlled trial (the AIM study).

BACKGROUND: Randomised trials on antibiotic treatment for patients with chronic low back pain and vertebral endplate changes visible on MRI (Modic changes) have shown mixed results. A possible explanation might be a real treatment effect in subgroups of the study populations. The purpose of the present study was to explore potential clinical effect modifiers of 3-months oral amoxicillin treatment in patients with chronic low back pain and type I or II Modic changes at the level of a previous lumbar disc herniation. METHODS: We performed analyses of effect modifiers on data from AIM, a double-blind parallel-group multicentre trial. One hundred eighty patients with chronic low back pain, previous disc herniation, Modic change type I (n = 118) or type II (n = 62) were randomised to 3-months oral treatment with 750 mg amoxicillin (n = 89) or placebo (n = 91) three times daily. The primary outcome was the Roland-Morris Disability Questionnaire (RMDQ) score (possible values 0-24) at 1-year follow-up in the intention-to-treat population. The predefined minimal clinically important between-group mean difference was 4 RMDQ points (not reached in the primary analysis of AIM). Predefined baseline characteristics were analysed as potential effect modifiers, four primary (type I Modic changes, previous disc surgery, positive pain provocation test, high CRP) and five exploratory (disturbed sleep, constant low back pain, short duration of low back pain, younger age, and male) using ANCOVA with interaction terms. RESULTS: None of the four primary potential effect modifiers had strong evidence of modifying the treatment effect. In patients younger than 40 years the difference in mean RMDQ score between the treatment groups was - 4.0 (95%CI, - 6.9 to - 1.2), compared to - 0.5 (95%CI, - 2.3 to 1.3) in patients 40 years or older, both in favour of amoxicillin treatment (exploratory analysis). CONCLUSIONS: We did not find evidence for convincing clinical effect modifiers of antibiotic treatment in patients with chronic low back pain and Modic changes. Our results for younger age in these explorative analyses should not affect clinical treatment decisions without confirmation in future studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT02323412 , First registered 23 December 2014.

Association of Modic change types and their short tau inversion recovery signals with clinical characteristics- a cross sectional study of chronic low back pain patients in the AIM-study.

BACKGROUND: Modic Changes (MCs, magnetic resonance imaging (MRI) signal changes in the vertebral bone marrow extending from the vertebral endplate) may represent a subgroup of nonspecific chronic low back pain that could benefit from a specific management. The primary aim was to compare clinical characteristics between patients with type 1 versus type 2 MCs. The secondary aim was to explore associations between clinical characteristics and MC related short tau inversion recovery (STIR) signals. METHODS: This cross-sectional study used baseline data prospectively collected between 2015 and 2017 on the 180 patients included in the AIM-study (Antibiotics In Modic changes), a randomized controlled trial in a Norwegian hospital out-patient setting of patients with chronic low back pain, a lumbar disc herniation within the last 2 years, low back pain intensity score ≥ 5 (on a 0-10 scale) and current type 1 or type 2 MCs at the previously herniated lumbar disc level. We used prespecified clinical characteristics including self-report measures, physiologic measures and functional measures from clinical history and examination. The diagnostic accuracy of various clinical characteristics to discriminate between patients with type 1 MCs (with or without additional type 2 MCs) and patents with type 2 MCs only (not type 1) were assessed by calculating the area under the receiver-operating curve. We assessed the correlations of clinical characteristics with details of MC related STIR signal increase. RESULTS: No clinical characteristic differed between patients with type 1 (n = 118) versus type 2 (but not type 1) (n = 62) MCs. The clinical characteristics showed no/minor differences or no/weak correlations with MC related STIR signal increase. Patients with a positive Springing test (at any lumbar level) had slightly less volume of STIR signal increase than those with a negative test (mean difference 1.3 on a 0-48 scale, 95% CI 0.3 to 2.3). CONCLUSION: Clinical characteristics were similar for patients with type 1 MCs and patients with type 2 MCs, and showed no clinically relevant correlations with MC related STIR signal increase. TRIAL REGISTRATION: ClinicalTrials.gov NCT02323412, First registered 23 December 2014.

New insight to the characteristics and clinical course of clusters of patients with imaging confirmed disc-related sciatica.

BACKGROUND: Referral to secondary care is common for a considerable proportion of patients with persistent sciatica symptoms. It is unclear if information from clinical assessment can further identify distinct subgroups of disc-related sciatica, with perhaps different clinical courses. AIMS: This study aims to identify and describe clusters of imaging confirmed disc-related sciatica patients using latent class analysis, and compare their clinical course. METHODS: The study population were 466 patients with disc-related sciatica. Variables from clinical assessment were included in the analysis. Characteristics of the identified clusters were described and their clinical course over 2 years was compared. RESULTS: A four-cluster solution was optimal. Cluster 1 (n = 110) had mild back and leg pain; cluster 2 (n = 59) had moderate back and leg pain; cluster 3 (n = 158) had mild back pain and severe leg pain; cluster 4 (n = 139) had severe back and leg pain. Patients in cluster 4 had the most severe profile in terms of disability, distress and comorbidity and the lowest reported global change and the smallest proportion of patients with a successful outcome at 2 years. Of the 135 patients who underwent surgery, 42% and 41% were in clusters 3 and 4, respectively. CONCLUSIONS: Using a strict diagnosis of sciatica, this work identified four clusters of patients primarily differentiated by back and leg pain severity. Patients with severe back and leg pain had the most severe profile at baseline and follow-up irrespective of intervention. This simple classification system may be useful when considering prognosis and management with sciatica patients. SIGNIFICANCE: Using data from a large observational prospective study, this work identifies four distinct clusters of patients with imaging confirmed disc-related sciatica. This classification could be used when considering prognosis and management with sciatica patients at their initial consultation.

Rescue and concomitant analgesics in placebo-controlled trials of pharmacotherapy for neuropathic pain and low back pain.

Rescue medication is commonly offered to participants in placebo-controlled trials of analgesic drugs. The use of pain medication in addition to the placebo or experimental drug may complicate the interpretation of effects and tolerability, but this issue has received little methodological attention. This study examined the handling and reporting of rescue and concomitant analgesic use in trials of pharmacotherapy for neuropathic pain and low back pain. We based our review on 265 trials included in 2 recent systematic reviews: 83 trials of low back pain and 182 of neuropathic pain. In total, 117 (44%) trials permitted rescue medication and 126 (48%) allowed participants to continue all or some of their usual analgesics. The utilization of rescue medication increased over time, occurring in 18% of trials before 2000 compared with 55% after 2000. Forty-one trials (16%) permitted both rescue analgesics and continued use of prestudy analgesics. More than one-third of the trials permitting rescue medication did not report the actual rescue drug consumption, and over half of the trials allowing concomitant analgesics did not report whether intake changed during the trial. Only 22 (19%) of the trials permitting rescue medication included complete information about whether rescue medication was used as an outcome, specified the drugs used, specified how consumption was assessed and measured, and reported and analyzed the use of rescue medication in each trial arm. Our findings suggest that poorly described procedures and incomplete reporting are likely to hinder the interpretation, critical appraisal, and replication of trial results.

Joint Distribution and Two-Year Outcome in 347 Patients With Monoarthritis of Less Than Sixteen Weeks' Duration.

OBJECTIVE: The present study was undertaken to investigate the joint distribution and 2-year outcome of patients with recent-onset monoarthritis. METHODS: Adult patients with clinically apparent monoarthritis of ≤16 weeks' duration were included in a multicenter 2-year longitudinal study. Clinical characteristics, joint distribution, development of chronic inflammatory rheumatic disease (CIRD), as well as classification criteria according to the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) 2010 criteria for RA were studied. Predictors for development of CIRD were analyzed by multivariable logistic regression analyses. RESULTS: The knee (49.3%), ankle (16.7%), and wrist (14.1%) were the most frequently affected joints among the 347 included patients. A total of 91 patients (26.2%) developed CIRD during follow-up; 21 (6.1%) were diagnosed with RA, and 16 (4.6%) with psoriatic arthritis. Longer duration of joint swelling, joint localization, and anti-citrullinated protein antibody (ACPA) and rheumatoid factor (RF) positivity were independent predictors of CIRD. Six of 58 patients (10.3%) with ankle monoarthritis and 21 of 49 patients (42.9%) with wrist monoarthritis developed CIRD during follow-up. The 2010 ACR/EULAR Criteria for RA identified all patients diagnosed with seropositive RA at an early stage, mostly within 3 months. CONCLUSION: Approximately one-fourth of patients with recent-onset monoarthritis developed CIRD over 2 years. Patients presenting with ankle arthritis rarely developed CIRD, whereas patients presenting with wrist arthritis more frequently did so. Longer duration of joint swelling and ACPA and RF positivity were also predictive of CIRD. Our findings facilitate the early identification of patients with monoarthritis who have an unfavorable prognosis.

Efficacy of antibiotic treatment in patients with chronic low back pain and Modic changes (the AIM study): double blind, randomised, placebo controlled, multicentre trial.

OBJECTIVE: To assess the efficacy of three months of antibiotic treatment compared with placebo in patients with chronic low back pain, previous disc herniation, and vertebral endplate changes (Modic changes). DESIGN: Double blind, parallel group, placebo controlled, multicentre trial. SETTING: Hospital outpatient clinics at six hospitals in Norway. PARTICIPANTS: 180 patients with chronic low back pain, previous disc herniation, and type 1 (n=118) or type 2 (n=62) Modic changes enrolled from June 2015 to September 2017. INTERVENTIONS: Patients were randomised to three months of oral treatment with either 750 mg amoxicillin or placebo three times daily. The allocation sequence was concealed by using a computer generated number on the prescription. MAIN OUTCOME MEASURES: The primary outcome was the Roland-Morris Disability Questionnaire (RMDQ) score (range 0-24) at one year follow-up in the intention to treat population. The minimal clinically important between group difference in mean RMDQ score was predefined as 4. RESULTS: In the primary analysis of the total cohort at one year, the difference in the mean RMDQ score between the amoxicillin group and the placebo group was -1.6 (95% confidence interval -3.1 to 0.0, P=0.04). In the secondary analysis, the difference in the mean RMDQ score between the groups was -2.3 (-4.2 to-0.4, P=0.02) for patients with type 1 Modic changes and -0.1 (-2.7 to 2.6, P=0.95) for patients with type 2 Modic changes. Fifty patients (56%) in the amoxicillin group experienced at least one drug related adverse event compared with 31 (34%) in the placebo group. CONCLUSIONS: In this study on patients with chronic low back pain and Modic changes at the level of a previous disc herniation, three months of treatment with amoxicillin did not provide a clinically important benefit compared with placebo. Secondary analyses and sensitivity analyses supported this finding. Therefore, our results do not support the use of antibiotic treatment for chronic low back pain and Modic changes. TRIAL REGISTRATION: ClinicalTrials.gov NCT02323412.

Up-regulation of circulating microRNA-17 is associated with lumbar radicular pain following disc herniation.

BACKGROUND: Previous studies suggest that regulatory microRNAs (miRs) may modulate neuro-inflammatory processes. The purpose of the present study was to examine the role of miR-17 following intervertebral disc herniation. METHODS: In a cohort of 97 patients with leg pain and disc herniation verified on MRI, we investigated the association between circulating miR-17 and leg pain intensity. A rat model was used to examine possible changes in miR-17 expression in nucleus pulposus (NP) associated with leak of NP tissue out of the herniated disc. The functional role of miR-17 was addressed by transfection of miR-17 into THP-1 cells (human monocyte cell line). RESULTS: An association between the level of miR-17 in serum and the intensity of lumbar radicular pain was shown. Up-regulation of miR-17 in the rat NP tissue when applied onto spinal nerve roots and increased release of TNF following transfection of miR-17 into THP-1 cells were also observed. Hence, our data suggest that miR-17 may be involved in the pathophysiology underlying lumbar radicular pain after disc herniation. CONCLUSIONS: We conclude that miR-17 may be associated with the intensity of lumbar radicular pain after disc herniation, possibly through a TNF-driven pro-inflammatory mechanism.