Anti-CD20 therapy corrects a CD8 regulatory T cell deficit in multiple sclerosis.

OBJECTIVE: To determine the effect of long-term anti-CD20 B-cell-depleting treatment on regulatory T cell immune subsets that are subnormal in untreated MS patients. METHODS: 30 clinically stable MS patients, before and over 38 months of ocrelizumab treatment, were compared to 13 healthy controls, 29 therapy-naïve MS, 9 interferon-ß-treated MS, 3 rituximab-treated MS, and 3 rituximab-treated patients with other autoimmune inflammatory diseases. CD8, CD28, CD4, and FOXP3 expression in peripheral blood mononuclear cells was quantitated with flow cytometry. RESULTS: CD8+ CD28- regulatory cells rose from one-third of healthy control levels before ocrelizumab treatment (2.68% vs 7.98%), normalized by 12 months (13.5%), and rose to 2.4-fold above healthy controls after 18 months of ocrelizumab therapy (19.0%). CD4+ FOXP3+ regulatory cells were lower in MS than in healthy controls (7.98%) and showed slight long-term decreases with ocrelizumab. CD8+ CD28- and CD4+ FOXP3+ regulatory T cell percentages in IFN-ß-treated MS patients were between those of untreated MS and healthy controls. INTERPRETATION: Long-term treatment with ocrelizumab markedly enriches CD8+ CD28- regulatory T cells and corrects the low levels seen in MS before treatment, while slightly decreasing CD4+ FOXP3+ regulatory T cells. Homeostatic enrichment of regulatory CD8 T cells provides a mechanism, in addition to B cell depletion, for the benefits of anti-CD20 treatment in MS.

Force-plate analyses of balance following a balance exercise program during acute post-operative phase in individuals with total hip and knee arthroplasty: A randomized clinical trial.

OBJECTIVES: Typical rehabilitation programs following total hip arthroplasty and total knee arthroplasty include joint range of motion and muscle-strengthening exercises. Balance and balance exercises following total hip arthroplasty and total knee arthroplasty have not received much attention. The purpose of this study was to determine whether an intervention of balance exercises added to a typical rehabilitation program positively affects patients' balance. METHODS: A total of 63 patients were provided with outpatient physical therapy at their home. Patients were randomly assigned to either typical (n = 33) or balance (n = 30) exercise group. The typical group completed seven typical surgery-specific joint range of motion and muscle-strengthening exercises, while the balance group completed the typical exercises plus three balance exercises. After 5 weeks of administering the rehabilitation program, patients' balance was assessed on a force plate using 95% ellipse area of the center of pressure amplitude. RESULTS: Patients in the balance group demonstrated significant reduction in the 95% ellipse area for the anterior and posterior lean standing conditions (p < 0.01). CONCLUSION: Balance exercises added to the typical outpatient physical therapy program resulted in significantly greater improvements in balance for participants with total hip arthroplasty or total knee arthroplasty, compared to the typical exercise program alone. Physical therapists might consider the use of balance exercises to improve balance in individuals in the acute post-operative phase following total hip arthroplasty or total knee arthroplasty.

Consensus Management of Gastrointestinal Events Associated with Delayed-Release Dimethyl Fumarate: A Delphi Study.

INTRODUCTION: Delayed-release dimethyl fumarate (DMF, also known as gastro-resistant DMF) is indicated for the treatment of patients with relapsing multiple sclerosis. Gastrointestinal (GI) adverse events (AEs) occur with DMF therapy. METHODS: We used a Delphi process to reach consensus among North American clinicians on effective real-world management strategies for GI AEs associated with DMF. Clinicians were asked to complete two rounds of questionnaires developed by a steering committee; consensus in round 2 was attained if ≥70% of respondents agreed on a particular strategy. RESULTS: Consensus was reached on several strategies to manage GI AEs, including administering DMF with food, slow titration, dose reduction, and use of symptomatic therapies. CONCLUSION: These consensus strategies provide clinicians with information on real-world approaches used to address the tolerability of DMF in patients with multiple sclerosis. FUNDING: Biogen.

Effectiveness of balance exercises in the acute post-operative phase following total hip and knee arthroplasty: A randomized clinical trial.

OBJECTIVES: To determine the effectiveness of balance exercises in the acute post-operative phase following total hip arthroplasty or total knee arthroplasty. METHODS: Patients who had total hip arthroplasty (n = 30) or total knee arthroplasty (n = 33) were seen in their residence 1-2 times per week for 5 weeks. At the first post-operative home visit, patients were randomly assigned to either typical (TE, n = 33) or typical plus balance (TE + B, n = 30) exercise groups. The TE group completed seven typical surgery-specific joint range-of-motion and muscle strengthening exercises, while the TE + B group completed the typical exercises plus three balance exercises. Patients were assessed before and 5 weeks after administering the rehabilitation program using four outcome measures: (1) the Berg Balance Scale, (2) the Timed Up and Go test, (3) the Western Ontario McMaster Universities Osteoarthritis Index, and (4) the Activities-specific Balance Confidence Scale. RESULTS: Post-intervention scores for all four outcome measures were significantly improved (p < 0.01) over baseline scores. Patients who participated in the TE + B group demonstrated significantly greater improvement on the Berg Balance Scale and the Timed Up and Go tests (p < 0.01). CONCLUSION: Balance exercises added to a typical rehabilitation program resulted in significantly greater improvements in balance and functional mobility compared to typical exercises alone.

The TRUST (EvaluaTion of Bladder Function in Relapsing-Remitting MUltiple Sclerosis Patients Treated with Natalizumab) Observational Study.

BACKGROUND: Bladder dysfunction is a common symptom of multiple sclerosis (MS). This study was designed to evaluate effects of natalizumab on bladder function in patients with relapsing-remitting MS. METHODS: The TRUST (EvaluaTion of Bladder Function in Relapsing-Remitting MUltiple Sclerosis Patients Treated with Natalizumab) study was an open-label, single-arm, two-center study. Natalizumab-naive MS patients with disabling bladder dysfunction and initiating natalizumab were enrolled and followed for 6 months. The primary endpoint was change in the Urogenital Distress Inventory short form (UDI-6) score from baseline. Change in Incontinence Impact Questionnaire short form (IIQ-7) score from baseline was a secondary endpoint. RESULTS: Thirty patients were enrolled. Mean baseline characteristics were age 49.9 years, Expanded Disability Status Scale score 4.6, number of relapses in previous year 2.4, UDI-6 score 10.4, and IIQ-7 score 12.3. Mean changes in UDI-6 and IIQ-7 scores were significantly improved from baseline beginning at week 4 and up to week 24; mean improvements at 24 weeks were 4.4 (P < .0001) and 4.9 (P = .0005) points, respectively. At week 24, 85.7% and 78.6% of patients demonstrated improvements from baseline in UDI-6 and IIQ-7 scores, respectively. CONCLUSIONS: Incontinence-related quality of life as measured by UDI-6 and IIQ-7 scores improved significantly during natalizumab treatment.

Comparison of the original and reduced versions of the Berg Balance Scale and the Western Ontario and McMaster Universities Osteoarthritis Index in patients following hip or knee arthroplasty.

PURPOSE: To compare the original and reduced versions of the Berg Balance Scale (BBS) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), as completed by patients following total hip arthroplasty (THA) or total knee arthroplasty (TKA), with respect to their potential utility in clinical and research settings. METHOD: Patients with THA (n=26) or TKA (n=28) were evaluated before and after 5 to 7 weeks' participation in a home-based exercise programme. They were assessed using the original versions of the BBS and the WOMAC; scores for the reduced versions of the BBS and the WOMAC were extracted from the original versions. RESULTS: Good to excellent correlations (r≥0.80) were observed between the original and the reduced versions of the BBS and the WOMAC. The index of responsiveness, evaluated using standardized response means (SRM), was similar for the original and the reduced versions of the BBS and the WOMAC function sub-scale. CONCLUSIONS: The reduced versions of the BBS and the WOMAC provided similar information to the original versions and were equally responsive. These reduced versions comprise fewer questions and may be completed in considerably less time, which suggests that they may be advantageous for clinical and research use.

Current and emerging multiple sclerosis therapeutics.

For a disease whose cause remains elusive, there has been a paradoxical growth in multiple sclerosis (MS) therapeutics. During the past 17 years, six therapeutic drugs for MS were brought to market. All of these disease-modifying therapies (DMTs) have shown a beneficial effect in reducing the number of exacerbations in double-blind placebo-controlled trials, and three drugs (subcutaneous [SC]/IM interferon beta-1a, natalizumab) have been shown to reduce relapses, decrease MRI activity, and reduce the risk of sustained disability after 2 years of treatment. No controlled studies exist to show long-term benefit with any of the current DMTs. Immunosuppressive drug (ISD) therapies continue to play a role in the management of patients who fail to respond to immunomodulatory agents. These agents, however, have shown mixed data in terms of efficacy and put patients at higher risk for the development of secondary cancers. Plasma exchange for severe relapses not responsive to corticosteroid therapy has regained interest in the past few years. Furthermore, six new agents that will dramatically impact our ability to prevent disability in patients with MS are in late-stage or have completed phase 3 clinical development. Determining the risk-benefit calculations that we will need to employ toward these new drugs and the algorithms for switching therapies will be critical issues in the next 5 years. This article highlights the clinical efficacy of the current DMTs/ISDs and discusses the current treatment options for clinically isolated syndrome, relapsing-remitting MS (RRMS), and exacerbations of RRMS. It also addresses the management of a suboptimal response to the DMTs; discusses the challenge of primary progressive MS; and presents an overview of emerging therapeutic options.

A randomized controlled trial comparing the effectiveness of functional knee brace and neoprene sleeve use after anterior cruciate ligament reconstruction.

BACKGROUND: Despite a lack of evidence for their effectiveness, functional knee braces are commonly prescribed to patients after anterior cruciate ligament (ACL) reconstruction. PURPOSE: This trial was conducted to compare postoperative outcomes in patients using an ACL functional knee brace and patients using a neoprene knee sleeve. HYPOTHESIS: Patients using a brace will have superior outcomes than those using a sleeve. STUDY DESIGN: Randomized controlled clinical trial; Level of evidence, 1. METHODS: One hundred fifty patients were randomized to receive a brace (n = 76) or neoprene sleeve (n = 74) at their 6-week postoperative visit after primary ACL reconstruction with hamstring autograft. Patients were assessed preoperatively, then 6 weeks and 6, 12, and 24 months postoperatively. Outcome measures included disease-specific quality of life (Anterior Cruciate Ligament-Quality of Life [ACL-QOL] Questionnaire), anterior tibial translation (KT-1000 arthrometer side-to-side difference), the single-limb forward hop test (limb symmetry index), and Tegner Activity Scale. Outcomes at 1 and 2 years were compared after adjusting for baseline scores. Subjective ratings of how patients felt while using the brace/sleeve were also collected for descriptive purposes using a questionnaire. Four a priori directional subgroup hypotheses were evaluated using tests for interactions. RESULTS: There were no significant differences between brace (n = 62) and sleeve (n = 65) groups for any of the outcomes at 1- and 2-year follow-ups. Adjusted mean differences at 2 years were as follows: -0.94 (95% confidence interval [CI], -7.52 to 5.64) for the ACL-QOL Questionnaire, -0.10 mm (95% CI, -0.99 to 0.81) for KT-1000 arthrometer side-to-side difference, -0.87% (95% CI, -8.89 to 7.12) for hop limb symmetry index, and -0.05 (95% CI, -0.72 to 0.62) for the Tegner Activity Scale. Subjective ratings of confidence in the knee provided by the brace/sleeve were higher for the brace group than the sleeve group. Subgroup findings were minimal. Adverse events were few and similar between groups. CONCLUSIONS: A functional knee brace does not result in superior outcomes compared with a neoprene sleeve after ACL reconstruction. Current evidence does not support the recommendation of using an ACL functional knee brace after ACL reconstruction.

Quantitative vibration threshold testing in carpal tunnel syndrome: analysis strategies for optimizing reliability.

Tuning forks and electronic vibrometers have been used to quantify vibration sensation thresholds, which are thought to be affected early in carpal tunnel syndrome (CTS). The purpose of this study was to identify a reliable testing procedure for a newly designed, computer-controlled vibrometer (PCV50; Ztech, Salt Lake City, UT). Fifty-two patients (mean age 48+/-8 years) with electromyographically confirmed CTS were tested on one occasion. The computer-controlled vibrometer, with a fixed frequency of 50 Hz, used stepwise changes in amplitude to determine vibration sensation threshold. Each patient had three vibrometer measures (trials) taken on the pulp of the third digit of their right and left hands during the first test session and were retested by a single repetition 40 to 60 minutes later (retest). Intraclass correlation coefficients (ICCs) were used to examine several data analysis strategies. The strategy that generated the highest ICCs for both the right and left hands assumed that the first trial was a learning or practice attempt, and compared the average of the second and third trials with the score from the second session (ICC=0.86 and 0.89, respectively). The computer-controlled vibrometer offered an easily administered, quantitative, and comfortable means to assess median nerve function. Using this reliable testing procedure will allow for additional investigations to determine its usefulness in the early detection and accurate quantification of CTS-related impairment.

Comparison of clinic- and home-based rehabilitation programs after total knee arthroplasty.

One hundred sixty patients (mean age, 68 +/- 8 years) having primary total knee arthroplasty were assigned randomly to two rehabilitation programs: (1) clinic-based rehabilitation provided by outpatient physical therapists; or (2) home-based rehabilitation monitored by periodic telephone calls from a physical therapist. Both rehabilitation programs emphasized a common home exercise program. Before surgery, and at 12 and 52 weeks after surgery, no statistically significant differences were observed between the clinic- and the home-based groups on any of the following measures: (1) total score on the Knee Society clinical rating scale; (2) total score on the Western Ontario and McMaster Universities Osteoarthritis Index; (3) total score on the Medical Outcomes Study Short Form; (4) pain scale of the Knee Society clinical rating scale; (5) pain scale of the Western Ontario and McMaster Universities Osteoarthritis Index; (6) functional scale of the Western Ontario and McMaster Universities Osteoarthritis Index; (7) distance walked in 6 minutes; (8) number of stairs ascended and descended in 30 seconds; and (9) knee flexion range of motion, on either the per protocol or the intent-to-treat or the analyses. After primary total knee arthroplasty, patients who completed a home exercise program (home-based rehabilitation) performed similarly to patients who completed regular outpatient clinic sessions in addition to the home exercises (clinic-based rehabilitation). Additional studies need to determine which patients are likely to benefit most from clinic-based rehabilitation programs.

Effect of a functional knee brace on knee flexion and extension strength after anterior cruciate ligament reconstruction.

OBJECTIVES: To investigate the effect of a knee brace on knee flexion and extension muscular strength of patients after anterior cruciate ligament (ACL) reconstruction and to evaluate whether the effect of the brace depends on patient symptoms and muscular strength. DESIGN: Repeated measures. SETTING: A university-based outpatient orthopedic clinic and musculoskeletal assessment laboratory. PARTICIPANTS: Twenty-seven patients (14 women, 13 men; mean age, 28+/-11 y) having undergone arthroscopically assisted ACL reconstruction by using a semitendinosus and gracilis autograft. INTERVENTION: A custom-fit ACL functional knee brace. MAIN OUTCOME MEASURES: The brace effect was calculated as the change in peak torque observed with the brace, expressed as a percentage of peak torque observed without the brace, during isokinetic concentric knee flexion and extension movements performed at 90 degrees /s. Patient symptoms were quantified by using a disease-specific health-related quality of life questionnaire. RESULTS: Knee flexion strength decreased significantly with the brace (mean brace effect=-7.3%, P<.05). The brace effect during knee flexion varied considerably (-52% to 47%) and was significantly related to peak torque observed without the brace (r=-.50, P<.01). All other comparisons and correlations were not significant. CONCLUSIONS: These findings suggest that brace effects depend on patient strength. A brace may inhibit knee flexion strength of stronger patients, yet result in no change or even improvements in strength of weaker patients. Future research is required to further elucidate which patients may derive most benefit or detriment from bracing.