Discontinuation of biologic therapy due to lack/loss of response and adverse events is similar between TNFi and non-TNFi class: Results from a real-world rheumatoid arthritis cohort.

OBJECTIVES: Time to discontinuation of biologic therapy may be related to mechanism of action. We aimed to compare discontinuation of tumor necrosis factor inhibitors (TNFi) versus non-TNFi in an observational rheumatoid arthritis cohort. METHODS: Patients enrolled in the Ontario Best Practices Research Initiative (OBRI) starting biologic agents on or after 1st January 2010 were included. Time to discontinuation due to (1) any reason, (2) any of lack/loss of response, adverse events (AEs), physician, or patient decision, (3) lack/loss of response, and (4) AEs were assessed using Kaplan-Meier survival and Cox proportional hazards regression analysis. RESULTS: A total of 932 patients were included of whom 174 (18.7%) received non-TNFi and 758 (81.3%) received TNFi. Over a median follow-up of 1.7 years, discontinuation was reported for 416 (44.6%) due to any reason, 367 (39.4%) due to any of lack/loss of response, AEs, physician, or patient decision, 192 (20.6%) due to lack/loss of response, and 102 (10.9%) due to AEs. After adjusting for propensity score, there was no significant difference in discontinuation between the two classes due to any reason [HR 1.14 (0.90-1.46), p = 0.28], lack/loss of response [HR: 1.01 (0.70-1.47), p = 0.95], and AEs [HR: 1.06 (0.64-1.73), p = 0.83]. Similar results were found in biologic naïve patients. CONCLUSIONS: This analysis demonstrates that discontinuation of therapy is similar in patients started on TNFi and non-TNFi therapies. There was also no significant difference in stopping due to lack/loss of response or AEs, suggesting that these reasons should not drive the selection of one treatment over another.

Effect of active TENS versus de-tuned TENS on walking capacity in patients with lumbar spinal stenosis: a randomized controlled trial.

Background context: Lumbar spinal stenosis (LSS) leads to diminished blood flow to the spinal nerves causing neurogenic claudication and impaired walking ability. Animal studies have demonstrated increased blood flow to the spinal nerves and spinal cord with superficial para-spinal electrical stimulation of the skin. Purpose: The aim of this study was to assess the effectiveness of active para-spinal transcutaneous electrical nerve stimulation (TENS) compared to de-tuned TENS applied while walking, on improving walking ability in LSS. Study design: This was a two-arm double-blinded (participant and assessor) randomized controlled trial. Patient sample: We recruited 104 participants 50 years of age or older with neurogenic claudication, imaging confirmed LSS and limited walking ability. Outcome measures: The primary measure was walking distance measured by the self-paced walking test (SPWT) and the primary outcome was the difference in proportions among participants in both groups who achieved at least a 30% improvement in walking distance from baseline using relative risk with 95% confidence intervals. Methods: The active TENS group (n = 49) received para-spinal TENS from L3-S1 at a frequency of 65-100 Hz modulated over 3-s intervals with a pulse width of 100-200 usec, and turned on 2 min before the start and maintained during the SPWT. The de-tuned TENS group (n = 51) received similarly applied TENS for 30 s followed by ramping down to zero stimulus and turned off before the start and during the SPWT.Study funded by The Arthritis Society ($365,000 CAN) and salary support for Carlo Ammendolia funded by the Canadian Chiropractic Research Foundation ($500,000 CAN over 5 years). Results: From August 2014 to January 2016 a total of 640 potential participants were screened for eligibility; 106 were eligible and 104 were randomly allocated to active TENS or de-tuned TENS. Both groups showed significant improvement in walking distance but there was no significant difference between groups. The mean difference between active and de-tuned TENS groups was 46.9 m; 95% CI (- 118.4 to 212.1); P = 0.57. A total of 71% (35/49) of active TENS and 74% (38/51) of de-tuned TENS participants achieved at least 30% improvement in walking distance; relative risk (RR), 0.96; 95% CI, (0.7 to 1.2) P = 0.77. Conclusions: Active TENS applied while walking is no better than de-tuned TENS for improving walking ability in patients with degenerative LSS and therefore should not be a recommended treatment in clinical practice. Registration: ClinicalTrials.gov ID: NCT02592642. Registration October 30, 2015.

Effect of a prototype lumbar spinal stenosis belt versus a lumbar support on walking capacity in lumbar spinal stenosis: a randomized controlled trial.

BACKGROUND CONTEXT: Lumbar spinal stenosis (LSS) can impair blood flow to the spinal nerves giving rise to neurogenic claudication and limited walking ability. Reducing lumbar lordosis can increases the volume of the spinal canal and reduce neuroischemia. We developed a prototype LSS belt aimed at reducing lumbar lordosis while walking. PURPOSE: The aim of this study was to assess the short-term effectiveness of a prototype LSS belt compared to a lumbar support in improving walking ability in patients with degenerative LSS. STUDY DESIGN: This was a two-arm, double-blinded (participant and assessor) randomized controlled trial. PATIENT SAMPLE: We recruited 104 participants aged 50 years or older with neurogenic claudication, imaging confirmed degenerative LSS, and limited walking ability. OUTCOME MEASURES: The primary measure was walking distance measured by the self-paced walking test (SPWT) and the primary outcome was the difference in proportions among participants in both groups who achieved at least a 30% improvement in walking distance from baseline using relative risk with 95% confidence intervals. METHODS: Within 1 week of a baseline SPWT, participants randomized to the prototype LSS belt group (n=52) and those randomized to the lumbar support group (n=52) performed a SPWT that was conducted by a blinded assessor. The Arthritis Society funded this study ($365,000 CAN) with salary support for principal investigator funded by the Canadian Chiropractic Research Foundation ($500,000 CAN for 5 years). RESULTS: Both groups showed significant improvement in walking distance, but there was no significant difference between groups. The mean group difference in walking distance was -74 m (95% CI: -282.8 to 134.8, p=.49). In total, 62% of participants wearing the prototype LSS belt and 82% of participants wearing the lumbar support achieved at least 30% improvement in walking distance (relative risk, 0.7; 95% CI: 0.5-1.3, p=.43). CONCLUSIONS: A prototype LSS belt demonstrated significant improvement in walking ability in degenerative LSS but was no better than a lumbar support.

Methotrexate monotherapy and methotrexate combination therapy with traditional and biologic disease modifying anti-rheumatic drugs for rheumatoid arthritis: A network meta-analysis.

BACKGROUND: Methotrexate is considered the preferred disease-modifying anti-rheumatic drug (DMARD) for the treatment of rheumatoid arthritis, but controversy exists on the additional benefits and harms of combining methotrexate with other DMARDs. OBJECTIVES: To compare methotrexate and methotrexate-based DMARD combinations for rheumatoid arthritis in patients naïve to or with an inadequate response (IR) to methotrexate. METHODS: We systematically identified all randomised controlled trials with methotrexate monotherapy or in combination with any currently used conventional synthetic DMARD , biologic DMARDs, or tofacitinib. Three major outcomes (ACR50 response, radiographic progression and withdrawals due to adverse events) and multiple minor outcomes were evaluated. Treatment effects were summarized using Bayesian random-effects network meta-analyses, separately for methotrexate-naïve and methotrexate-IR trials. Heterogeneity was explored through meta-regression and subgroup analyses. The risk of bias of each trial was assessed using the Cochrane risk of bias tool, and trials at high risk of bias were excluded from the main analysis. The quality of evidence was evaluated using the GRADE approach. A comparison between two treatments was considered statistically significant if its credible interval excluded the null effect, indicating >97.5% probability that one treatment was superior. MAIN RESULTS: 158 trials with over 37,000 patients were included. Methotrexate-naïve: Several treatment combinations with methotrexate were statistically superior to oral methotrexate for ACR50 response: methotrexate + sulfasalazine + hydroxychloroquine ("triple therapy"), methotrexate + several biologics (abatacept, adalimumab, etanercept, infliximab, rituximab, tocilizumab), and tofacitinib. The estimated probability of ACR50 response was similar between these treatments (range 56-67%, moderate to high quality evidence), compared with 41% for methotrexate. Methotrexate combined with adalimumab, etanercept, certolizumab, or infliximab was statistically superior to oral methotrexate for inhibiting radiographic progression (moderate to high quality evidence) but the estimated mean change over one year with all treatments was less than the minimal clinically important difference of five units on the Sharp-van der Heijde scale. Methotrexate + azathioprine had statistically more withdrawals due to adverse events than oral methotrexate, and triple therapy had statistically fewer withdrawals due to adverse events than methotrexate + infliximab (rate ratio 0.26, 95% credible interval: 0.06 to 0.91). Methotrexate-inadequate response: In patients with an inadequate response to methotrexate, several treatments were statistically significantly superior to oral methotrexate for ACR50 response: triple therapy (moderate quality evidence), methotrexate + hydroxychloroquine (low quality evidence), methotrexate + leflunomide (moderate quality evidence), methotrexate + intramuscular gold (very low quality evidence), methotrexate + most biologics (moderate to high quality evidence), and methotrexate + tofacitinib (high quality evidence). There was a 61% probability of an ACR50 response with triple therapy, compared to a range of 27% to 64% for the combinations of methotrexate + biologic DMARDs that were statistically significantly superior to oral methotrexate. No treatment was statistically significantly superior to oral methotrexate for inhibiting radiographic progression. Methotrexate + cyclosporine and methotrexate + tocilizumab (8 mg/kg) had a statistically higher rate of withdrawals due to adverse events than oral methotrexate and methotrexate + abatacept had a statistically lower rate of withdrawals due to adverse events than several treatments. AUTHORS' CONCLUSIONS: We found moderate to high quality evidence that combination therapy with methotrexate + sulfasalazine+ hydroxychloroquine (triple therapy) or methotrexate + most biologic DMARDs or tofacitinib were similarly effective in controlling disease activity and generally well tolerated in methotrexate-naïve patients or after an inadequate response to methotrexate. Methotrexate + some biologic DMARDs were superior to methotrexate in preventing joint damage in methotrexate-naïve patients, but the magnitude of these effects was small over one year.

Methotrexate monotherapy and methotrexate combination therapy with traditional and biologic disease modifying antirheumatic drugs for rheumatoid arthritis: abridged Cochrane systematic review and network meta-analysis.

OBJECTIVE: To compare methotrexate based disease modifying antirheumatic drug (DMARD) treatments for rheumatoid arthritis in patients naive to or with an inadequate response to methotrexate. DESIGN: Systematic review and Bayesian random effects network meta-analysis of trials assessing methotrexate used alone or in combination with other conventional synthetic DMARDs, biologic drugs, or tofacitinib in adult patients with rheumatoid arthritis. DATA SOURCES: Trials were identified from Medline, Embase, and Central databases from inception to 19 January 2016; abstracts from two major rheumatology meetings from 2009 to 2015; two trial registers; and hand searches of Cochrane reviews. STUDY SELECTION CRITERIA: Randomized or quasi-randomized trials that compared methotrexate with any other DMARD or combination of DMARDs and contributed to the network of evidence between the treatments of interest. MAIN OUTCOMES: American College of Rheumatology (ACR) 50 response (major clinical improvement), radiographic progression, and withdrawals due to adverse events. A comparison between two treatments was considered statistically significant if its credible interval excluded the null effect, indicating >97.5% probability that one treatment was superior. RESULTS: 158 trials were included, with between 10 and 53 trials available for each outcome. In methotrexate naive patients, several treatments were statistically superior to oral methotrexate for ACR50 response: sulfasalazine and hydroxychloroquine ("triple therapy"), several biologics (abatacept, adalimumab, etanercept, infliximab, rituximab, tocilizumab), and tofacitinib. The estimated probability of ACR50 response was similar between these treatments (range 56-67%), compared with 41% with methotrexate. Methotrexate combined with adalimumab, etanercept, certolizumab, or infliximab was statistically superior to oral methotrexate for inhibiting radiographic progression, but the estimated mean change over one year with all treatments was less than the minimal clinically important difference of 5 units on the Sharp-van der Heijde scale. Triple therapy had statistically fewer withdrawals due to adverse events than methotrexate plus infliximab. After an inadequate response to methotrexate, several treatments were statistically superior to oral methotrexate for ACR50 response: triple therapy, methotrexate plus hydroxychloroquine, methotrexate plus leflunomide, methotrexate plus intramuscular gold, methotrexate plus most biologics, and methotrexate plus tofacitinib. The probability of response was 61% with triple therapy and ranged widely (27-70%) with other treatments. No treatment was statistically superior to oral methotrexate for inhibiting radiographic progression. Methotrexate plus abatacept had a statistically lower rate of withdrawals due to adverse events than several treatments. CONCLUSIONS: Triple therapy (methotrexate plus sulfasalazine plus hydroxychloroquine) and most regimens combining biologic DMARDs with methotrexate were effective in controlling disease activity, and all were generally well tolerated in both methotrexate naive and methotrexate exposed patients.

Herbal Medicine for Low Back Pain: A Cochrane Review.

STUDY DESIGN: Systematic review of randomized controlled trials (RCTs). OBJECTIVES: To determine the effectiveness of herbal medicine for nonspecific low back pain (LBP). SUMMARY OF BACKGROUND DATA: Many people with chronic LBP use complementary and alternative medicine (CAM), visit CAM practitioners, or both. Several herbal medicines have been purported for use in treating people with LBP. This is an update of a Cochrane Review first published in 2006. METHODS: We searched numerous electronic databases up to September 2014; checked reference lists in review articles, guidelines and retrieved trials; and personally contacted individuals with expertise in this area. We included RCTs examining adults (over 18 years of age) suffering from acute, sub-acute, or chronic nonspecific LBP. The interventions were herbal medicines that we defined as plants used for medicinal purposes in any form. Primary outcome measures were pain and function. Two review authors assessed risk of bias, GRADE criteria (GRADE 2004), and CONSORT compliance and a random subset were compared with assessments by a third individual. Two review authors assessed clinical relevance and resolved any disagreements by consensus. RESULTS: Fourteen RCTs (2050 participants) were included. Capsicum frutescens (cayenne) reduces pain more than placebo. Although Harpagophytum procumbens (devil's claw), Salix alba (white willow bark), Symphytum officinale L. (comfrey), Solidago chilensis (Brazilian arnica), and lavender essential oil also seem to reduce pain more than placebo, evidence for these substances was of moderate quality at best. No significant adverse events were noted within the included trials. CONCLUSIONS: Additional well-designed large trials are needed to test these herbal medicines against standard treatments. In general, the completeness of reporting in these trials was poor. Trialists should refer to the CONSORT statement extension for reporting trials of herbal medicine interventions. LEVEL OF EVIDENCE: N/A.

Herbal medicine for low-back pain.

BACKGROUND: Low-back pain (LBP) is a common condition and imposes a substantial economic burden upon people living in industrialized societies. A large proportion of people with chronic LBP use complementary and alternative medicine (CAM), visit CAM practitioners, or both. Several herbal medicines have been purported for use in treating people with LBP. This is an update of a Cochrane Review first published in 2006. OBJECTIVES: To determine the effectiveness of herbal medicine for non-specific LBP. SEARCH METHODS: We searched the following electronic databases up to September 2014: MEDLINE, EMBASE, CENTRAL, CINAHL, Clinical Trials.gov, World Health Organization International Clinical Trials Registry Portal and PubMed; checked reference lists in review articles, guidelines and retrieved trials; and personally contacted individuals with expertise in this area. SELECTION CRITERIA: We included randomized controlled trials (RCTs) examining adults (over 18 years of age) suffering from acute, sub-acute, or chronic non-specific LBP. The interventions were herbal medicines which we defined as plants used for medicinal purposes in any form. Primary outcome measures were pain and function. DATA COLLECTION AND ANALYSIS: A library scientist with the Cochrane Back Review Group conducted the database searches. One review author contacted content experts and acquired relevant citations. We downloaded full references and abstracts of the identified studies and retrieved a hard copy of each study for final inclusion decisions. Two review authors assessed risk of bias, GRADE criteria (GRADE 2004), and CONSORT compliance and a random subset were compared to assessments by a third individual. Two review authors assessed clinical relevance and resolved any disagreements by consensus. MAIN RESULTS: We included 14 RCTs (2050 participants) in this review. One trial on Solidago chilensis M. (Brazilian arnica) (20 participants) found very low quality evidence of reduction in perception of pain and improved flexibility with application of Brazilian arnica-containing gel twice daily as compared to placebo gel. Capsicum frutescens cream or plaster probably produces more favourable results than placebo in people with chronic LBP (three trials, 755 participants, moderate quality evidence). Based on current evidence, it is not clear whether topical capsicum cream is more beneficial for treating people with acute LBP compared to placebo (one trial, 40 participants, low quality evidence). Another trial found equivalence of C. frutescens cream to a homeopathic ointment (one trial, 161 participants, very low quality evidence). Daily doses of Harpagophytum procumbens (devil's claw), standardized to 50 mg or 100 mg harpagoside, may be better than placebo for short-term improvements in pain and may reduce use of rescue medication (two trials, 315 participants, low quality evidence). Another H. procumbens trial demonstrated relative equivalence to 12.5 mg per day of rofecoxib (Vioxx®) but was of very low quality (one trial, 88 participants, very low quality). Daily doses of Salix alba (white willow bark), standardized to 120 mg or 240 mg salicin, are probably better than placebo for short-term improvements in pain and rescue medication (two trials, 261 participants, moderate quality evidence). An additional trial demonstrated relative equivalence to 12.5 mg per day of rofecoxib (one trial, 228 participants) but was graded as very low quality evidence. S. alba minimally affected platelet thrombosis versus a cardioprotective dose of acetylsalicylate (one trial, 51 participants). One trial (120 participants) examining Symphytum officinale L. (comfrey root extract) found low quality evidence that a Kytta-Salbe comfrey extract ointment is better than placebo ointment for short-term improvements in pain as assessed by VAS. Aromatic lavender essential oil applied by acupressure may reduce subjective pain intensity and improve lateral spine flexion and walking time compared to untreated participants (one trial, 61 participants,very low quality evidence). No significant adverse events were noted within the included trials. AUTHORS' CONCLUSIONS: C. frutescens (Cayenne) reduces pain more than placebo. Although H. procumbens, S. alba, S. officinale L., S. chilensis, and lavender essential oil also seem to reduce pain more than placebo, evidence for these substances was of moderate quality at best. Additional well-designed large trials are needed to test these herbal medicines against standard treatments. In general, the completeness of reporting in these trials was poor. Trialists should refer to the CONSORT statement extension for reporting trials of herbal medicine interventions.

Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis.

OBJECTIVE: To perform a systematic review of the benefits and harms of folic acid and folinic acid in reducing the mucosal, gastrointestinal, hepatic, and hematologic side effects of methotrexate (MTX); and to assess whether folic or folinic acid supplementation has any effect on MTX benefit. METHODS: We searched the Cochrane Library, MEDLINE, EMBASE, and US National Institutes of Health clinical trials registry from inception to March 2012. We selected all double-blind, randomized, placebo-controlled clinical trials in which adult patients with rheumatoid arthritis (RA) were treated with MTX (dose ≤ 25 mg/week) concurrently with folate supplementation. We included only trials using low-dose folic or folinic acid (a starting dose of ≤ 7 mg weekly) because the high dose is no longer recommended or used. Data were extracted from the trials, and the trials were independently assessed for risk of bias using a predetermined set of criteria. RESULTS: Six trials with 624 patients were eligible for inclusion. Most studies had low or unclear risk of bias for key domains. The quality of the evidence was rated as "moderate" for each outcome as assessed by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) working group, with the exception of hematologic side effects, which were rated as "low." There was no significant heterogeneity between trials, including where folic acid and folinic acid studies were pooled. For patients supplemented with any form of exogenous folate (either folic or folinic acid) while receiving MTX therapy for RA, a 26% relative (9% absolute) risk reduction was seen for the incidence of gastrointestinal side effects such as nausea, vomiting, or abdominal pain (RR 0.74, 95% CI 0.59 to 0.92; p = 0.008). Folic and folinic acid also appear to be protective against abnormal serum transaminase elevation caused by MTX, with a 76.9% relative (16% absolute) risk reduction (RR 0.23, 95% CI 0.15 to 0.34; p < 0.00001), as well as reducing patient withdrawal from MTX for any reason [60.8% relative (15.2% absolute) risk reduction, RR 0.39, 95% CI 0.28 to 0.53; p < 0.00001]. CONCLUSION: The results support a protective effect of supplementation with either folic or folinic acid for patients with RA during treatment with MTX. There was a clinically important significant reduction shown in the incidence of GI side effects and hepatic dysfunction (as measured by elevated serum transaminase levels), as well as a clinically important significant reduction in discontinuation of MTX treatment for any reason.

Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis.

BACKGROUND: Methotrexate (MTX) is a disease modifying antirheumatic drug (DMARD) used as a first line agent for treating rheumatoid arthritis (RA). Pharmacologically, it is classified as an antimetabolite due to its antagonistic effect on folic acid metabolism. Many patients treated with MTX experience mucosal, gastrointestinal, hepatic or haematologic side effects. Supplementation with folic or folinic acid during treatment with MTX may ameliorate these side effects. OBJECTIVES: To identify trials of supplementation with folic acid or folinic acid during MTX therapy for rheumatoid arthritis and to assess the benefits and harms of folic acid and folinic acid (a) in reducing the mucosal, gastrointestinal (GI), hepatic and haematologic side effects of MTX, and (b) whether or not folic or folinic acid supplementation has any effect on MTX benefit. SEARCH METHODS: We originally performed MEDLINE searches, from January 1966 to June 1999. During the update of this review, we searched additional databases and used a sensitive search strategy designed to retrieve all trials on folic acid or folinic acid for rheumatoid arthritis from 1999 up to 2 March 2012. SELECTION CRITERIA: We selected all double-blind, randomised, placebo-controlled clinical trials (RCTs) in which adult patients with rheumatoid arthritis were treated with MTX (at a dose equal to or less than 25 mg/week) concurrently with folate supplementation. In this update of the review we only included trials using 'low dose' folic or folinic acid (a starting dose of ≤ 7 mg weekly). DATA COLLECTION AND ANALYSIS: Data were extracted from the trials, and the trials were independently assessed for risk of bias using a predetermined set of criteria. MAIN RESULTS: Six trials with 624 patients were eligible for inclusion. Most studies had low or unclear risk of bias for key domains. The quality of the evidence was rated as 'moderate' for each outcome as assessed by GRADE, with the exception of haematologic side effects which were rated as 'low'. There was no significant heterogeneity between trials, including where folic acid and folinic acid studies were pooled.For patients supplemented with any form of exogenous folate (either folic or folinic acid) whilst on MTX therapy for rheumatoid arthritis, a 26% relative (9% absolute) risk reduction was seen for the incidence of GI side effects such as nausea, vomiting or abdominal pain (RR 0.74, 95% CI 0.59 to 0.92; P = 0.008). Folic and folinic acid also appear to be protective against abnormal serum transaminase elevation caused by MTX, with a 76.9% relative (16% absolute) risk reduction (RR 0.23, 95% CI 0.15 to 0.34; P < 0.00001), as well as reducing patient withdrawal from MTX for any reason (60.8% relative (15.2% absolute) risk reduction, RR 0.39, 95% CI 0.28 to 0.53; P < 0.00001).We analysed the effect of folic or folinic acid on the incidence of stomatitis / mouth sores, and whilst showing a trend towards reduction in risk, the results were not statistically significant (RR 0.72, 95% CI 0.49 to 1.06)It was not possible to draw meaningful conclusions on the effect of folic or folinic acid on haematologic side effects of methotrexate due to small numbers of events and poor reporting of this outcome in included trials.It does not appear that supplementation with either folic or folinic acid has a statistically significant effect on the efficacy of MTX in treating RA (as measured by RA disease activity parameters such as tender and swollen joint counts, or physician's global assessment scores). AUTHORS' CONCLUSIONS: The results support a protective effect of supplementation with either folic or folinic acid for patients with rheumatoid arthritis during treatment with MTX.There was a significant reduction shown in the incidence of GI side effects, hepatic dysfunction (asmeasured by elevated serum transaminase levels) as well as a significant reduction in discontinuation of MTX treatment for any reason. A trend towards a reduction in stomatitis was demonstrated however this did not reach statistical significance.This updated review with its focus on lower doses of folic acid and folinic acid and updated assessment of risk of bias aimed to give a more precise and more clinically relevant estimate of the benefit of folate supplementation for patients with rheumatoid arthritis receiving methotrexate.

An empirical study using permutation-based resampling in meta-regression.

BACKGROUND: In meta-regression, as the number of trials in the analyses decreases, the risk of false positives or false negatives increases. This is partly due to the assumption of normality that may not hold in small samples. Creation of a distribution from the observed trials using permutation methods to calculate P values may allow for less spurious findings. Permutation has not been empirically tested in meta-regression. The objective of this study was to perform an empirical investigation to explore the differences in results for meta-analyses on a small number of trials using standard large sample approaches verses permutation-based methods for meta-regression. METHODS: We isolated a sample of randomized controlled clinical trials (RCTs) for interventions that have a small number of trials (herbal medicine trials). Trials were then grouped by herbal species and condition and assessed for methodological quality using the Jadad scale, and data were extracted for each outcome. Finally, we performed meta-analyses on the primary outcome of each group of trials and meta-regression for methodological quality subgroups within each meta-analysis. We used large sample methods and permutation methods in our meta-regression modeling. We then compared final models and final P values between methods. RESULTS: We collected 110 trials across 5 intervention/outcome pairings and 5 to 10 trials per covariate. When applying large sample methods and permutation-based methods in our backwards stepwise regression the covariates in the final models were identical in all cases. The P values for the covariates in the final model were larger in 78% (7/9) of the cases for permutation and identical for 22% (2/9) of the cases. CONCLUSIONS: We present empirical evidence that permutation-based resampling may not change final models when using backwards stepwise regression, but may increase P values in meta-regression of multiple covariates for relatively small amount of trials.

Diagnostic and prognostic value of antibodies and soluble biomarkers in undifferentiated peripheral inflammatory arthritis: a systematic review.

OBJECTIVE: When patients present with undifferentiated peripheral inflammatory arthritis (UPIA), early diagnosis and evaluation of prognostic factors are decisive steps for therapeutic success. We reviewed published evidence on the diagnostic and prognostic performance of autoantibodies and soluble biomarkers in UPIA. METHODS: We conducted a systematic literature search covering studies published until January 2009. Additionally, we screened conference abstracts presented at European League Against Rheumatism and American College of Rheumatology meetings in 2007 and 2008. RESULTS: We included 52 full-text articles and 12 abstracts. The association of anti-cyclic citrullinated peptide antibody (anti-CCP) and rheumatoid factor (RF) with diagnosis of rheumatoid arthritis at followup is compelling, supported by positive likelihood ratios (LR+) ranging between 1.2 and 20.5 for anti-CCP and 1.1 to 13.5 for RF. The same applies to radiographic outcome. For antikeratin antibodies (AKA) and antiperinuclear factor, existing evidence suggests diagnostic usefulness; AKA also showed prognostic value. Diagnostic and prognostic evidence for other autoantibodies and for bone and cartilage biomarkers was scarce, negative, or controversial. CONCLUSION: Among serological tests, unanimous evidence of substantial diagnostic value exists only for anti-CCP and RF, but is scarce for other markers.

Randomized controlled trials of herbal interventions underreport important details of the intervention.

OBJECTIVE: To examine the quality of reporting and predictors of reporting in randomized clinical trials (RCTs) of herbal medicine interventions. STUDY DESIGN AND SETTING: We searched Medical Literature Analysis and Retrieval System Online, Excerpta Medica Database, and Academy of Microscope Enhanced Dentistry up to December 2007 for any English language RCT of 11 commonly used herbal medicine interventions. Two individuals separately and independently assessed all trials using the Consolidated Standards of Reporting Trials (CONSORT) checklist for herbal medicines interventions. We randomly selected 100 of these trials, extracted a set of potential predictor variables identified through a literature search and consultation with experts, and performed a conceptually driven stepwise elimination regression analyses for predictor variables. RESULTS: The 406 trials reported on average 38% of the information suggested in the checklist. Regression analyses revealed better overall reporting in trials with a participant flow diagram (P=0.008), those of Panax quinquefolius (P=0.018), and those published in more recent years (P=0.02). CONCLUSION: Our results indicate that RCTs of herbal medicine interventions frequently do not report important characteristics of the intervention. Trialists should refer to the CONSORT for herbal medicines when reporting their trials.

Utilization and costs of lumbar and full spine radiography by Ontario chiropractors from 1994 to 2001.

BACKGROUND CONTEXT: In Ontario, chiropractors see one-third of patients who seek care for low back pain. Previous studies suggest that chiropractors have high utilization rates of lumbar and full spine radiography. There has been a proliferation of evidence-based guidelines recommending that plain film radiography be used only to assess high-risk patients with low back pain. Evidence for the use of full spine radiography, except for the evaluation of scoliosis is lacking. It is uncertain what impact the growing evidence against their use has had on radiography utilization by Ontario chiropractors. PURPOSE: To describe the annual costs and use of lumbar and full spine plain film radiography among Ontario chiropractors between 1994 and 2001. STUDY DESIGN/SETTING: Time-trend analysis of radiography utilization by Ontario chiropractors. PATIENT SAMPLE: Chiropractic claims data submitted to the Ontario Health Insurance Plan or the Workplace Safety & Insurance Board from 1994/1995 to 2000/2001. OUTCOME MEASURES: Change in the annual cost and proportion of claimants receiving lumbar and full spine radiography. METHODS: Time-trend analysis of chiropractic claims submitted to the Ontario Health Insurance Plan (OHIP) or Workplace Safety & Insurance Board (WSIB) from 1994/1995 to 2000/2001 fiscal years. RESULTS: During the 7-year period, the proportion of OHIP claimants receiving lumbar spine radiography decreased from 4.54% to 3.25% and for full spine radiography from 3.87% to 3.04%. For WSIB claimants, lumbar spine radiography deceased from 6.49% to 3.30% of claimants and full spine radiography from 1.51% to 0.94%. OHIP payments for lumbar spine radiography decreased 12.7% to $562,944, whereas full spine radiography payments decreased 5.3% to $1,071,408. WSIB lumbar and full spine radiography payments decreased 44.2% and 34.3% to $31,202 and $11,713 respectively. CONCLUSIONS: Claims data from the two largest third-party payers of chiropractic services in Ontario, suggest that lumbar and full spine radiography, and their associated costs decreased steadily between 1994 and 2001.

Identifying the best treatment among common nonsurgical neck pain treatments: a decision analysis.

STUDY DESIGN: Decision analysis. OBJECTIVE: To identify the best treatment for nonspecific neck pain. SUMMARY OF BACKGROUND DATA: In Canada and the United States, the most commonly prescribed neck pain treatments are nonsteroidal anti-inflammatory drugs (NSAIDs), exercise, and manual therapy. Deciding which treatment is best is difficult because of the trade-offs between beneficial and harmful effects, and because of the uncertainty of these effects. METHODS: (Quality-adjusted) life expectancy associated with standard NSAIDs, Cox-2 NSAIDs, exercise, mobilization, and manipulation were compared in a decisionanalytic model. Estimates of the course of neck pain, background risk of adverse events in the general population, treatment effectiveness and risk, and patient-preferences were input into the model. Assuming equal effectiveness, we conducted a baseline analysis using risk of harm only. We assessed the stability of the baseline results by conducting a second analysis that incorporated effectiveness data from a high-quality randomized trial. RESULTS: There were no important differences across treatments. The difference between the highest and lowest ranked treatments predicted by the baseline model was 4.5 days of life expectancy and 3.4 quality-adjusted life-days. The difference between the highest and lowest ranked treatments predicted by the second model was 7.3 quality-adjusted life-days. CONCLUSION: When the objective is to maximize life expectancy and quality-adjusted life expectancy, none of the treatments in our analysis were clearly superior.

Adherence to radiography guidelines for low back pain: a survey of chiropractic schools worldwide.

OBJECTIVE: This study describes instruction provided at chiropractic schools worldwide on the use of spine radiography and compares instruction with evidence-based guidelines for low back pain. METHODS: Individuals responsible for radiology instruction at accredited chiropractic schools throughout the world were contacted and invited to participate in a Web-based survey. The survey included questions on the role of conventional radiography in chiropractic practice and instruction given to students for its use in patients with acute low back pain. RESULTS: Of the 33 chiropractic schools identified worldwide, 32 (97%) participated in the survey. Consistent with the guidelines, 25 (78%) respondents disagreed that "routine radiography should be used prior to spinal manipulative therapy," 29 (91%) disagreed that there "was a role for full spine radiography for assessing patients with low back pain," and 29 (91%) disagreed that "oblique views should be part of a standard radiographic series for low back pain." However, only 14 (44%) respondents concurred with the guidelines and disagreed with the statement that there "is a role for radiography in acute low back pain in the absence of 'red flags' for serious disease." CONCLUSIONS: This survey suggests that many aspects of radiology instruction provided by accredited chiropractic schools appear to be evidence based. However, there appears to be a disparity between some schools and existing evidence with respect to the role of radiography for patients with acute low back pain without "red flags" for serious disease. This may contribute to chiropractic overutilization of radiography for low back pain.

Do chiropractors adhere to guidelines for back radiographs? A study of chiropractic teaching clinics in Canada.

STUDY DESIGN: Clinical cohort. OBJECTIVES: To measure the adherence to 3 radiography guidelines for low back pain in chiropractic teaching clinics. SUMMARY OF BACKGROUND DATA: Evidence-based guidelines for low back pain suggest that plain radiography should be restricted to patients with suspected serious disease. Among primary healthcare providers who can request radiographs, chiropractors are thought to have utilization rates that exceed what is recommended by practice guidelines. It is uncertain whether this gap between evidence and practice begins in undergraduate training. METHODS: We screened 1241 consecutive patients with a new episode of low back pain who presented to any of the 6 out-patient teaching clinics of the Canadian Memorial Chiropractic College between January 2004 and September 2004. We collected information about red flags and radiography recommendations from patients and chiropractic trainees using self-administered questionnaires. Radiography recommendations were compared with criteria used in 3 radiography guidelines. Adherence was measured as the proportion of patients without red flags who were not recommended for radiography. RESULTS: Of the 503 eligible patients, 448 (89.1%) agreed to participate in the study. Radiography was recommended for 12.3% of patients. According to the selected radiography guidelines, the proportion of patients with red flags ranged from 45.3% to 70.5%. The proportion of patients without red flags who were not recommended for radiography ranged from 89.4% (95% confidence interval, 85.5%-93.2%) to 94.7% (95% confidence interval, 90.9%-98.5%) for the selected guidelines. CONCLUSIONS: The results suggest a strong adherence to radiography guidelines for patients with a new episode of low back pain who presented to chiropractic teaching clinics. Although a high proportion of patients had red flags, radiography utilization was lower than rates reported in previous studies suggesting that adherence to guidelines may help prevent unnecessary radiography.

Early aggressive care and delayed recovery from whiplash: isolated finding or reproducible result?

OBJECTIVE: To test the reproducibility of the finding that early intensive care for whiplash injuries is associated with delayed recovery. METHODS: We analyzed data from a cohort study of 1,693 Saskatchewan adults who sustained whiplash injuries between July 1, 1994 and December 31, 1994. We investigated 8 initial patterns of care that integrated type of provider (general practitioners, chiropractors, and specialists) and number of visits (low versus high utilization). Cox models were used to estimate the association between patterns of care and time to recovery while controlling for injury severity and other confounders. RESULTS: Patients in the low-utilization general practitioner group and those in the general medical group had the fastest recovery even after controlling for important prognostic factors. Compared with the low-utilization general practitioner group, the 1-year rate of recovery in the high-utilization chiropractic group was 25% slower (adjusted hazard rate ratio [HRR] 0.75, 95% confidence interval [95% CI] 0.54-1.04), in the low-utilization general practitioner plus chiropractic group the rate was 26% slower (HRR 0.74, 95% CI 0.60-0.93), and in the high-utilization general practitioner plus chiropractic combined group the rate was 36% slower (HRR 0.64, 95% CI 0.50-0.83). CONCLUSION: The observation that intensive health care utilization early after a whiplash injury is associated with slower recovery was reproduced in an independent cohort of patients. The results add to the body of evidence suggesting that early aggressive treatment of whiplash injuries does not promote faster recovery. In particular, the combination of chiropractic and general practitioner care significantly reduces the rate of recovery.

Herbal medicine for low back pain: a Cochrane review.

STUDY DESIGN: A systematic review of randomized controlled trials. OBJECTIVES: To determine the effectiveness of herbal medicine compared with placebo, no intervention, or "standard/accepted/conventional treatments" for nonspecific low back pain. SUMMARY OF BACKGROUND DATA: Low back pain is a common condition and a substantial economic burden in industrialized societies. A large proportion of patients with chronic low back pain use complementary and alternative medicine (CAM) and/or visit CAM practitioners. Several herbal medicines have been purported for use in low back pain. METHODS: The following databases were searched: Medline (1966 to April 2003), Embase (1980 to April 2003), Cochrane Controlled Trials Register (Issue 1, 2003), and Cochrane Complementary Medicine (CM) field Trials Register. Additionally, reference lists in review articles, guidelines, and in the retrieved trials were checked. Randomized controlled trials (RCTs), using adults (>18 years of age) suffering from acute, subacute, or chronic nonspecific low back pain. Types of interventions included herbal medicines defined as a plant that is used for medicinal purposes in any form. Primary outcome measures were pain and function. Two reviewers (J.J.G. and M.W.T.) conducted electronic searches in all databases. One reviewer (J.J.G.) contacted content experts and acquired relevant citations. Authors, title, subject headings, publication type, and abstract of the isolated studies were downloaded or a hard copy was retrieved. Methodologic quality and clinical relevance were assessed separately by two individuals (J.J.G. and M.W.T.). Disagreements were resolved by consensus. RESULTS: Ten trials were included in this review. Two high-quality trials utilizing Harpagophytum procumbens (Devil's claw) found strong evidence for short-term improvements in pain and rescue medication for daily doses standardized to 50 mg or 100 mg harpagoside with another high-quality trial demonstrating relative equivalence to 12.5 mg per day of rofecoxib. Two moderate-quality trials utilizing Salix alba (White willow bark) found moderate evidence for short-term improvements in pain and rescue medication for daily doses standardized to 120 mg or 240 mg salicin with an additional trial demonstrating relative equivalence to 12.5 mg per day of rofecoxib. Three low-quality trials using Capsicum frutescens (Cayenne) using various topical preparations found moderate evidence for favorable results against placebo and one trial found equivalence to a homeopathic ointment. CONCLUSIONS: Harpagophytum procumbens, Salix alba, and Capsicum frutescens seem to reduce pain more than placebo. Additional trials testing these herbal medicines against standard treatments will clarify their equivalence in terms of efficacy. The quality of reporting in these trials was generally poor; thus, trialists should refer to the CONSORT statement in reporting clinical trials of herbal medicines.

Recommendations for reporting randomized controlled trials of herbal interventions: Explanation and elaboration.

Controlled trials that use randomized allocation are the best tool to control for bias and confounding in trials testing clinical interventions. Investigators must be sure to include information that is required by the reader to judge the validity and implications of the findings in the reports of these trials. In part, complete reporting of trials will allow clinicians to modify their clinical practice to reflect current evidence toward the improvement of clinical outcomes. The consolidated standards of reporting trials (CONSORT) statement was developed to assist investigators, authors, reviewers, and editors on the necessary information to be included in reports of controlled clinical trials. The CONSORT statement is applicable to any intervention, including herbal medicinal products. Controlled trials of herbal interventions do not adequately report the information suggested in CONSORT. Recently, reporting recommendations were developed in which several CONSORT items were elaborated to become relevant and complete for randomized controlled trials of herbal medicines. We expect that these recommendations will lead to more complete and accurate reporting of herbal trials. We wrote this explanatory document to outline the rationale for each recommendation and to assist authors in using them by providing the CONSORT items and the associated elaboration, together with examples of good reporting and empirical evidence, where available, for each. These recommendations for the reporting of herbal medicinal products presented here are open to revision as more evidence accumulates and critical comments are collected.