David G. Borenstein

The value of magnetic resonance imaging of the lumbar spine to predict low-back pain in asymptomatic subjects : a seven-year follow-up study.

Background: In 1989, a group of sixty-seven asymptomatic individuals with no history of back pain underwent magnetic resonance imaging of the lumbar spine. Twenty-one subjects (31%) had an identifiable abnormality of a disc or of the spinal canal. In the current study, we investigated whether the findings on the scans of the lumbar spine that had been made in 1989 predicted the development of low-back pain in these asymptomatic subjects. Methods: A questionnaire concerning the development and duration of low-back pain over a seven-year period was sent to the sixty-seven asymptomatic individuals from the 1989 study. A total of fifty subjects completed and returned the questionnaire. A repeat magnetic resonance scan was made for thirty-one of these subjects. Two neuroradiologists and one orthopaedic spine surgeon interpreted the original and repeat scans in a blinded fashion, independent of clinical information. At each disc level, any radiographic abnormality, including bulging or degeneration of the disc, was identified. Radiographic progression was defined as increasing severity of an abnormality at a specific disc level or the involvement of additional levels. Results: Of the fifty subjects who returned the questionnaire, twenty-nine (58%) had no back pain. Low-back pain developed in twenty-one subjects during the seven-year study period. The 1989 scans of these subjects demonstrated normal findings in twelve, a herniated disc in five, stenosis in three, and moderate disc degeneration in one. Eight individuals had radiating leg pain; four of them had had normal findings on the original scans, two had had spinal stenosis, one had had a disc protrusion, and one had had a disc extrusion. In general, repeat magnetic resonance imaging scans revealed a greater frequency of disc herniation, bulging, degeneration, and spinal stenosis than did the original scans. Conclusions: The findings on magnetic resonance scans were not predictive of the development or duration of low-back pain. Individuals with the longest duration of low-back pain did not have the greatest degree of anatomical abnormality on the original, 1989 scans. Clinical correlation is essential to determine the importance of abnormalities on magnetic resonance images.

Role of Intravenous Cyclophosphamide in the Treatment of Severe Neuropsychiatric Systemic Lupus Erythematosus

PURPOSE We assessed the outcome of 31 patients with severe neuropsychiatric (NP) systemic lupus erythematosus (NPSLE) treated with intravenous cyclophosphamide (IV-CYC), and identified clinical predictors of response to therapy. METHODS The authors performed a retrospective chart review and classified patients by NP manifestation and response to therapy as measured by serial anatomic imaging and neurodiagnostic studies coupled with clinical assessment of improvement. RESULTS Neuropsychiatric manifestations occurred with the following frequencies: organic brain syndromes (OBS) 55%, stroke syndromes 35%, peripheral or mononeuropathy 32%, seizures 29%, psychiatric symptoms 26%, transverse myelitis 16%, cranial neuropathies 13%, other 16%. Most patients had multiple NP manifestations, with a median of two. Ninety percent of patients had failed therapy with corticosteroids with or without cytotoxic drugs prior to treatment with IV-CYC. Eight patients received synchronous plasmapheresis along with IV-CYC. After treatment with IV-CYC, NP deficits substantially improved in 61% (group I), stabilized in 29% (group S), and progressively deteriorated in 10% (group P). Patients in group I had significantly fewer NP manifestations than combined group S+P, two versus four, and a lower frequency of OBS, 37% versus 83%. CONCLUSION Intravenous cyclophosphamide appears to be an effective treatment for some patients with severe NPSLE refractory to other forms of therapy. Higher number of NP manifestations and presence of OBS may predict poor outcome and identify a group of patients for whom early aggressive therapy may be indicated.

Efficacy and safety of tanezumab in the treatment of chronic low back pain.

Summary Intravenous tanezumab produces clinically and statistically superior analgesic efficacy compared to placebo and naproxen, with few adverse events in patients with chronic low back pain. Abstract Increased nerve growth factor levels are associated with chronic pain conditions, including chronic low back pain (LBP). This study examined safety and analgesic efficacy of tanezumab, a humanized anti‐nerve growth factor antibody, in adults with chronic LBP. Patients received intravenous tanezumab 200 &mgr;g/kg plus oral placebo (n = 88), intravenous placebo plus oral naproxen 500 mg twice a day (n = 88), or intravenous placebo plus oral placebo (n = 41). Primary outcome was average LBP intensity (aLBPI) at Week 6. Secondary outcomes were proportion of patients with ≥30% or ≥50% reduction in aLBPI, Roland–Morris Disability Questionnaire and Brief Pain Inventory–short form scores, Patients’ Global Assessment of LBP, Patients’ Global Evaluation of study medication, and rescue medication use. Mean aLBPI change from baseline to Week 6 was greater with tanezumab vs naproxen (P = 0.004) and placebo (P < 0.001). Greater proportions of patients reported ≥30% and ≥50% reduction in aLBPI with tanezumab vs naproxen (P ≤ 0.013) and placebo (P < 0.001), and greater improvements in Roland–Morris Disability Questionnaire (P < 0.001) and other secondary outcomes except rescue medication use. Tanezumab was associated with adverse events (AEs) of abnormal peripheral sensation that were generally mild and resolved before study completion; however, there were no serious AEs. Nine patients (4 of whom were tanezumab‐treated) discontinued due to AEs. In conclusion, tanezumab resulted in analgesic efficacy that was clinically and statistically superior to placebo and naproxen in patients with chronic LBP. Tanezumab clinical development is on regulatory hold due to AEs in osteoarthritis patients.

Recovery of the hypothalamic-pituitary-adrenal (HPA) axis in patients with rheumatic diseases receiving low-dose prednisone

PURPOSE To assess the status of the hypothalamic-pituitary-adrenal (HPA) axis in cortico-steroid-treated patients whose prednisone dose had been tapered to physiologic doses. PATIENTS AND METHODS The design of the study was a retrospective chart review of 50 consecutive patients receiving 10 mg or less of prednisone daily at a university teaching hospital rheumatology clinic. Patients were given a rapid adrenocorticotropic hormone stimulation test, with cortisol levels obtained at baseline and after intravenous administration of cosyntropin. Charts were reviewed for duration of therapy, highest, current, and total cumulative steroid dose, and average daily steroid dose in each month of the preceding 2 years. RESULTS Current steroid dose was the only significant indicator of HPA axis function. Patients receiving less than 5 mg of prednisone daily had a normal HPA axis response, whereas those receiving 5 mg or more had widely varied responses. Neither the total, the highest prednisone dose, nor the duration of therapy was a significant indicator of HPA axis recovery. CONCLUSIONS Spontaneous recovery of the HPA axis is usual for patients who are taking prednisone at daily doses of 5 mg or less. Return of normal HPA axis function can be achieved without alternate-day therapy in patients whose disease allows tapering to daily prednisone doses of 5 mg or less.

American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network 2015 Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis

To provide evidence‐based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA).

Efficacy of a low-dose regimen of cyclobenzaprine hydrochloride in acute skeletal muscle spasm: Results of two placebo-controlled trials

BACKGROUND Cyclobenzaprine hydrochloride is a muscle relaxant that is effective in improving muscle spasm, reducing local pain and tenderness, and increasing range of motion in acute, painful musculoskeletal conditions. Sedation is the most common adverse event associated with its use at the usual dosage of 10 mg TID. Studies in healthy adults suggest that a lower dose may produce less sedation. Because cyclobenzaprines duration of action is 4 to 6 hours, reducing the dosing frequency to 10 mg BID would create a potentially painful untreated interval between doses. The alternative is administration of a lower dose (eg, 5 or 2.5 mg) TID. OBJECTIVE These studies were designed to assess the efficacy and tolerability of cyclobenzaprine 2.5, 5, and 10 mg TID compared with placebo in patients with acute musculoskeletal spasm. METHODS In 2 randomized, double-blind, placebo-controlled, parallel-group trials conducted at primary care centers in the United States, adult patients with acute painful muscle spasm of the lumbar or cervical region were randomly assigned to receive treatment with 2.5, 5, or 10 mg cyclobenzaprine TID or placebo for 7 days (study 1: cyclobenzaprine 5 or 10 mg TID or placebo; study 2: cyclobenzaprine 2.5 or 5 mg TID or placebo). The primary efficacy measures were patient-rated clinical global impression of change, medication helpfulness, and relief from starting backache. Neither study included a nonsteroidal anti-inflammatory drug (NSAID) as an active control. Although physicians frequently prescribe an analgesic or NSAID in addition to cyclobenzaprine, these studies were not designed to assess whether adding cyclobenzaprine provides a benefit over that of an analgesic. RESULTS One thousand four hundred five patients (737 study 1; 668 study 2), two thirds with low back pain and one third with neck pain, were randomized to treatment. Their mean age was 42 years, and approximately 89% were white. In both studies, patients receiving cyclobenzaprine 5 or 10 mg had significantly higher mean scores on the primary efficacy measures compared with those receiving placebo (study 1-P</=0.001 cyclobenzaprine 5 and 10 mg vs placebo, all measures at visits 2 and 3; study 2-P</=0.03 cyclobenzaprine 2.5 mg vs placebo, relief from starting backache on day 3 only; cyclobenzaprine 5 mg vs placebo, patient-rated clinical global impression of change, medication helpfulness, and relief from starting backache at visit 3 or day 7 only). On day 7, significantly more patients receiving cyclobenzaprine 5 or 10 mg reported relief compared with placebo recipients (P < 0.05 all cyclobenzaprine groups vs placebo). Onset of relief was apparent within 3 or 4 doses of the 5-mg regimen. In the subanalysis of the proportion of responders in the pooled 5-mg groups who did and did not report somnolence, a meaningful treatment effect was observed on all primary efficacy variables in patients who did not report somnolence, suggesting that efficacy was independent of sedation. Cyclobenzaprine was well tolerated. Somnolence and dry mouth, the most common adverse effects, were mild and dose related. Overall, >/= 1 adverse event was reported in 54.1%, 61.8%, and 35.4% of patients receiving cyclobenzaprine 5 or 10 mg or placebo, respectively, in study 1 and by 43.9%, 55.9%, and 35.4% of patients receiving cyclobenzaprine 2.5 or 5 mg or placebo, respectively, in study 2. Adverse events were the primary reason for discontinuation of treatment in the cyclobenzaprine 5- and 10-mg groups in both studies. In study 2, ineffectiveness of therapy was the main reason for discontinuation of therapy in the group receiving cyclobenzaprine 2.5 mg. CONCLUSIONS Cyclobenzaprine 2.5 mg TID was not significantly more effective than placebo. The cyclobenzaprine 5- and 10-mg TID regimens were associated with significantly higher mean efficacy scores compared with placebo. Cyclobenzaprine 5 mg TID was as effective as 10 mg TID, and was associated with a lower incidence of sedation.

Effects of valdecoxib in the treatment of chronic low back pain: results of a randomized, placebo-controlled trial

BACKGROUND Valdecoxib, a cyclooxygenase (COX)-2 specific inhibitor, is indicated for relief of the signs and symptoms of rheumatoid arthritis, osteoarthritis, and primary dysmenorrhea. Therapeutic doses of COX-2 specific inhibitors are as effective as nonspecific nonsteroidal anti-inflammatory drugs in reducing inflammatory pain while sparing the gastrointestinal and platelet toxicity associated with nonspecific COX-1 inhibition. OBJECTIVE The aim of this study was to assess the analgesic efficacy and tolerability of valdecoxib 40 mg/d compared with placebo in the treatment of chronic low back pain. METHODS This 4-week, prospective, randomized, double-blind placebo-controlled, parallel-group study was conducted at 37 centers across the United States and 5 centers in Canada. Patients aged > or =18 years with chronic low back pain in flare were enrolled. Patients were randomized to receive valdecoxib 40-mg/d or placebo tablets, once daily for 4 weeks. Patients rated low back pain intensity on a visual analog scale and completed the Roland-Morris Disability Questionnaire and the modified Brief Pain Inventory-Short Form (mBPI-SF) at each visit. RESULTS Two hundred ninety-three patients were enrolled. The valdecoxib group comprised 148 patients (81 women, 67 men; mean [SD] age, 48.6 [13.3] years; mean [SD] body weight, 86.6 [20.9] kg), and the placebo group included 145 patients (85 women, 60 men; mean [SD] age, 48.7 [12.6] years; mean [SD] body weight, 85.6 [19.9] kg). Of the enrolled patients, 249 completed the study: 134 patients (91%) who received valdecoxib and 115 patients (79%) who received placebo. No statistically significant differences in patient baseline characteristics were noted between treatment groups, except in response to 1 mBPI-SF question; patients in the valdecoxib group reported significantly greater interference in relations with other people due to pain than did those in the placebo group (P = 0.048). Changes from baseline in low back pain intensity were significantly greater in valdecoxib-treated patients at each assessment (all, P < 0.001 vs placebo). Pain scores on the mBPI-SF indicated significantly greater pain relief with valdecoxib at each assessment (all, P < or = 0.014 vs placebo). Improvements in mean Roland-Morris Disability Questionnaire score with valdecoxib were significantly greater than with placebo at each assessment (all, P < or = 0.003). Although the overall incidence of adverse events (AEs) was significantly higher among patients receiving valdecoxib than those receiving placebo (35.1% vs 24.1%, respectively; P = 0.042), no significant differences were found between groups for the incidence of any individual AE. Most AEs (89% [77/87 total events]) were mild or moderate in severity. CONCLUSIONS In this study of patients with chronic low back pain, valdecoxib 40 mg/d provided rapid relief (within 1 week) and consistent relief (over 4 weeks). In addition, significant improvement in function and decreased disability were found with valdecoxib compared with placebo.

Efficacy and safety of rofecoxib in patients with chronic low back pain: results from two 4-week, randomized, placebo-controlled, parallel-group, double-blind trials.

Study Design. Two replicate, 4-week, randomized, double-blind, placebo-controlled, trials of rofecoxib 25 and 50 mg versus placebo for chronic low back pain. Objectives. To determine the efficacy and safety of two doses of rofecoxib compared to placebo in the treatment of chronic low back pain. Summary of Background Data. Although nonsteroidal anti-inflammatory drugs are commonly prescribed for chronic low back pain, their efficacy is unproven and toxicity can be serious. These studies evaluated the efficacy and tolerability of rofecoxib, a selective COX-2 inhibitor, in the treatment of chronic low back pain. Methods. Patients with chronic low back pain were randomized 1:1:1 to rofecoxib 25 mg, 50 mg, or placebo once daily. Primary endpoint: Low Back Pain Intensity. Secondary endpoints: Pain Bothersomeness, Global Assessments of Response to Therapy, Global Assessment of Disease Status, Roland-Morris Disability Questionnaire, SF-12 Health Survey, Use of Rescue Acetaminophen, and Discontinuations Due to Lack of Efficacy. Results. Combining both studies, 690 patients were randomized to placebo (N = 228), rofecoxib 25 mg (N = 233), or rofecoxib 50 mg (N = 229). Mean (± SD) age was 53.4 (± 12.9) years, pain duration 12.1 (± 11.8) years, 62.3% female. Both rofecoxib groups improved significantly. Mean differences from placebo in pain intensity were −13.50 mm, −13.81 mm (25, 50 mg doses) respectively (P < 0.001). Both regimens were superior to placebo in eight of nine secondary endpoints. Fifty mg provided no advantage over 25 mg. Both rofecoxib regimens were well tolerated, although 25 mg had a slightly better safety profile. Conclusions. Rofecoxib significantly reduced chronic low back pain in adults and was well tolerated.

Autoantibodies to the insulin receptor as a cause of autoimmune hypoglycemia in systemic lupus erythematosus

A 52-year-old black woman presented with clinical features of systemic lupus erythematosus (SLE) and severe fasting hypoglycemia. Hypoglycemia was secondary to autoantibodies to the insulin receptor that were detected in the patients serum. There were no anti-insulin antibodies, and other causes of hypoglycemia were excluded. Treatment with high-dose glucocorticoids resulted in restoration of euglycemia associated with resolution of circulating anti-receptor antibodies and parallel improvement in clinical and laboratory features of SLE. This case is compared with other cases of autoimmune hypoglycemia due to anti-receptor antibodies.

Low-dose cyclobenzaprine versus combination therapy with ibuprofen for acute neck or back pain with muscle spasm: a randomized trial

ABSTRACT Objective: This prospective, randomized, open-label, multicenter, community-based study was conducted to compare cyclobenzaprine 5 mg three times daily (TID) orally (CYC5) given for 7 days as monotherapy or in combination with ibuprofen 400 mg TID (CYC5/IBU400) or 800 mg TID (CYC5/IBU800) in adults with acute neck or back pain with muscle spasm. Study design: Eligible patients were 18–65 years old, had cervical or thoracolumbar pain and spasm for ≤ 14 days, and, aside from the prescribed study medications, discontinued treatment with all analgesics, anti-inflammatory agents, and skeletal muscle relaxants during the study period. Randomization was 1:1:1 to the three treatment groups. Treatment outcome was assessed after 3 and 7 days of therapy using five patient-rated scales: spasm, pain, patient global impression of change (PGIC), medication helpfulness, and Oswestry Disability Index (ODI). Results: A total of 867 patients provided postbaseline data and were included in the intent-to-treat population (CYC5, n = 288; CYC5/IBU400, n = 286; CYC5/IBU800, n = 293). All three treatment groups demonstrated significant improvements from baseline in PGIC, spasm, pain, ODI, and medication helpfulness ( p < 0.001 for all comparisons) after 3 and 7 days of therapy. There were no significant differences in mean PGIC among groups after 3 days of therapy ( p = 0.65 for treatment effect) or after 7 days of therapy (primary endpoint; p = 0.41). A PGIC responder analysis of changes from baseline showed that 88% and 93% of patients reported at least mild improvement after 3 and 7 days of therapy, respectively. All three treatments were well tolerated, with no significant differences between treatments regarding the number of adverse events (AEs) reported or number of patients reporting AEs. The most common AEs in all groups were fatigue, somnolence, dizziness, sedation, and nausea. Limitations of this study include an unblinded design and possible introduction of bias into efficacy and safety results by use of a voluntary telephone reporting system. Conclusions: This randomized, community-based clinical trial demonstrated that combination therapy with cyclobenzaprine 5 mg TID plus ibuprofen was not superior to cyclobenzaprine 5 mg TID alone in adult patients with acute neck and back pain with muscle spasm. All treatments were well tolerated.