Efficacy of combined local mechanical vibrations, continuous passive motion and thermotherapy in the management of osteoarthritis of the knee.

OBJECTIVES: We evaluated the efficacy of combined mechanical vibrations, continuous passive motion (CPM) and heat on the severity of pain in management of osteoarthritis of the knee (OA-K). METHODS: In this controlled, double crossover study, 71 OA-K patients were randomized in Phase 1 to receive 4 weeks active treatment consisting of two 20-min sessions per day (34 patients, Group AB) or treatment with a sham device (37 patients, Group BA). This was followed by a 2-week washout period (Phase 2). In Phase 3, patients crossed over so that Group AB was treated with the sham device and Group BA received active treatment for an additional 4 weeks. Patient assessments of pain (visual analog scale, VAS) and Western Ontario and McMaster Universities (WOMAC) OA index were performed at baseline and at study weeks 2, 4, 6, and 10. Net treatment effects were estimated by comparing outcomes between active and sham treatment study phases. RESULTS: Treatment benefits were noted for both of the trial's two pre-specified primary endpoints, VAS and WOMAC. VAS was reduced at all follow-up time points for patients receiving active treatment compared to sham treatment with a net treatment effect of 14.4+/-4.1 mm (P=0.001). Similarly, the WOMAC score was reduced significantly with active treatment at all measured points with a net effect of 8.8+/-1.9 points (P<0.001). The secondary endpoints, range of motion (ROM) and treatment satisfaction, also improved with active vs sham treatment. CONCLUSION: Four weeks treatment with combined CPM, vibration and local heating significantly decreases pain, improves ROM and the quality of life in patients with OA-K (ClinicalTrials.gov registration number: NCT00858416).

Results of a randomized, dose-ranging trial of etoricoxib in patients with osteoarthritis.

OBJECTIVES: To evaluate the clinical efficacy and tolerability of etoricoxib in the treatment of osteoarthritis (OA) of the knee and define the clinically active dose range for further clinical trials. METHODS: This two-part, randomized, double-blind, placebo- and active comparator-controlled trial was conducted in 617 adults with knee OA. In Part 1 (6 weeks), patients received placebo, etoricoxib 5, 10, 30, 60 or 90 mg q.d. In Part 2 (8 weeks), patients received etoricoxib 30, 60 or 90 mg q.d. or diclofenac 50 mg t.i.d., predetermined at Part 1 allocation. Efficacy and safety were evaluated. Primary efficacy end-points were the Western Ontario and McMaster's University Osteoarthritis Index (WOMAC) Pain subscale, Patient Global Assessment of Response to Therapy, and Investigator Global Assessment of Disease Status. RESULTS: At 6 weeks, etoricoxib 5, 10, 30, 60 and 90 mg each demonstrated clinical efficacy superior to placebo. Maximal efficacy was seen with 60 mg. In Part 2, etoricoxib 30, 60 and 90 mg were generally similar to diclofenac. Patients receiving etoricoxib 30, 60 or 90 mg in Parts I and II had sustained effects over 14 weeks. All treatments were well tolerated. CONCLUSIONS: Etoricoxib 60 mg once daily showed maximal efficacy in treating OA in this study. Etoricoxib 5-90 mg once daily was generally well tolerated in OA patients for up to 14 weeks.

A randomized, double-blind, crossover clinical trial of diclofenac plus misoprostol versus acetaminophen in patients with osteoarthritis of the hip or knee.

OBJECTIVE: To perform a randomized, double-blind, crossover clinical trial of diclofenac + misoprostol versus acetaminophen in ambulatory patients with osteoarthritis of the hip or knee. METHODS: Patients in 12 ambulatory care settings were eligible if they were age >40 years and if they had Kellgren/Lawrence radiographic grade 2-4 osteoarthritis of the knee or hip and a score of > or =30 mm on a 100-mm visual analog pain scale. Patients were randomized to one of two groups, 75 mg diclofenac + 200 microg misoprostol twice daily or 1,000 mg acetaminophen 4 times daily (each for 6 weeks), and were then crossed over to the other treatment for 6 weeks. A placebo was included in each treatment regimen to enable double blinding. The primary outcome measures were the Western Ontario and McMaster Universities Osteoarthritis Index and the visual analog pain scale of the Multidimensional Health Assessment Questionnaire. Safety was assessed using a standard form to review adverse events. RESULTS: We enrolled 227 patients, of whom 218 provided data for the first treatment period and 181 provided data for both treatment periods. Significantly higher levels of improvement in the primary outcomes were seen for diclofenac + misoprostol than for acetaminophen (P < 0.001). Adverse events were more common when patients took diclofenac + misoprostol (P = 0.046). Diclofenac + misoprostol was rated as "better" or "much better" by 57% of the 174 patients who provided such ratings for both treatment periods, while acetaminophen was rated as "better" or "much better" by 20% of these patients, and 22% reported no difference (P < 0.001). Differences favoring diclofenac + misoprostol over acetaminophen were greater in patients with more severe osteoarthritis according to baseline pain scores, radiographs, or number of involved joints. CONCLUSION: Patients with osteoarthritis of the hip or knee had significantly greater improvements in pain scores over 6 weeks with diclofenac + misoprostol than with acetaminophen, although patients with mild osteoarthritis had similar improvements with both drugs. Acetaminophen was associated with fewer adverse events.

A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis.

BACKGROUND: Etanercept, which blocks the action of tumor necrosis factor, reduces disease activity in patients with long-standing rheumatoid arthritis. Its efficacy in reducing disease activity and preventing joint damage in patients with active early rheumatoid arthritis is unknown. METHODS: We treated 632 patients with early rheumatoid arthritis with either twice-weekly subcutaneous etanercept (10 or 25 mg) or weekly oral methotrexate (mean, 19 mg per week) for 12 months. Clinical response was defined as the percent improvement in disease activity according to the criteria of the American College of Rheumatology. Bone erosion and joint-space narrowing were measured radiographically and scored with use of the Sharp scale. On this scale, an increase of 1 point represents one new erosion or minimal narrowing. RESULTS: As compared with patients who received methotrexate, patients who received the 25-mg dose of etanercept had a more rapid rate of improvement, with significantly more patients having 20 percent, 50 percent, and 70 percent improvement in disease activity during the first six months (P<0.05). The mean increase in the erosion score during the first 6 months was 0.30 in the group assigned to receive 25 mg of etanercept and 0.68 in the methotrexate group (P= 0.001), and the respective increases during the first 12 months were 0.47 and 1.03 (P=0.002). Among patients who received the 25-mg dose of etanercept, 72 percent had no increase in the erosion score, as compared with 60 percent of patients in the methotrexate group (P=0.007). This group of patients also had fewer adverse events (P=0.02) and fewer infections (P= 0.006) than the group that was treated with methotrexate. CONCLUSIONS: As compared with oral methotrexate, subcutaneous [corrected] etanercept acted more rapidly to decrease symptoms and slow joint damage in patients with early active rheumatoid arthritis.

Evaluation of the functional status aspects of health-related quality of life of patients with osteoarthritis treated with celecoxib.

STUDY OBJECTIVE: To evaluate the functional status of patients with signs and symptoms of osteoarthritis of the knee after treatment with celecoxib compared with placebo and naproxen. DESIGN: Prospective, randomized, double-blind, parallel-group, 12-week trial. SETTING: Multicenter study conducted at 71 sites in the United States and Canada. PATIENTS: One thousand four patients with active osteoarthritis of the knee in a flare state. INTERVENTIONS: Patients were assigned randomly to one of five treatment groups: placebo; celecoxib 50 mg twice/day, 100 mg twice/day, and 200 mg twice/day; and naproxen 500 mg twice/day. MEASUREMENTS AND MAIN RESULTS: The Western Ontario and McMaster Universities Osteoarthritis Index was used to measure functional status. At the end of the treatment period, patients in the four active treatment groups had significantly better functional status than those receiving placebo. Patients treated with celecoxib 100 mg twice/day had significantly better improvements in pain scores than those treated with placebo and naproxen. CONCLUSION: Celecoxib was better than placebo and comparable with naproxen in improving aspects of functional status in patients with osteoarthritis.

T cell receptor peptide vaccination in rheumatoid arthritis: a placebo-controlled trial using a combination of Vbeta3, Vbeta14, and Vbeta17 peptides.

OBJECTIVE: Restricted T cell receptor (TCR) gene usage has been demonstrated in animal models of autoimmune disease and has resulted in the successful use of TCR peptide therapy in animal studies. This clinical trial was undertaken to determine the safety and efficacy of a combination of Vbeta3, Vbeta14, and Vbeta17 TCR peptides in Freund's incomplete adjuvant (IFA) in patients with rheumatoid arthritis (RA). METHODS: A double-blind, placebo-controlled, multicenter, phase II clinical trial was undertaken using IR501 therapeutic vaccine, which consists of a combination of 3 peptides derived from TCRs (Vbeta3, Vbeta14, and Vbeta17) in IFA. A total of 99 patients with active RA received either 90 microg (n = 31) or 300 microg (n = 35) of IR501 or IFA alone (n = 33) as a control. The study medication and placebo were administered as a single intramuscular injection (1 ml) at weeks 0, 4, 8, and 20. RESULTS: Treatment with IR501 was safe and well tolerated. None of the patients discontinued the trial because of treatment-related adverse events. Efficacy was measured according to the American College of Rheumatology 20% improvement criteria. Using these criteria, patients in both IR501 dosage groups showed improvement in disease activity. In the most conservative analysis used to evaluate efficacy, an intent-to-treat analysis including all patients who enrolled, the 90-microg dosage group showed a statistically significant improvement compared with control patients at the 20-week time point after the third injection. Trends toward improvement were shown in both the 90-microg and the 300-microg dosage groups at week 24 after the fourth injection. CONCLUSION: IR501 therapeutic vaccine therapy was safe and well tolerated, immunogenic, and demonstrated clinical improvement in RA patients. Additional clinical trials are planned to confirm and extend these observations.

Mechanisms of chronic pain.

Chronic pain differs from acute pain in that it serves no useful function, causes suffering, limits activities of daily living, and increases costs of healthcare payments, disability, and litigation fees. Pain perception begins with activation of peripheral nociceptors and conduction through myelinated A delta and unmyelinated C fibers to the dorsal root ganglion. From here, signals travel via the spinothalamic tract to the thalamus and the somatosensory cortex. Modulation of sensory input (i.e., pain) occurs at many levels. Nociceptors are also neuroeffectors, and transmission can be modulated by their cell bodies, which secrete inflammatory mediators, neuropeptides, or other pain-producing substances. Descending pathways from the hypothalamus, which has opioid-sensitive receptors and is stimulated by arousal and emotional stress, can transmit signals to the dorsal horn that modulate ascending nociceptive transmissions. Modulation to alter the perception of pain also can occur at higher centers (e.g., frontal cortex, midbrain, medulla) by opioids, anti-inflammatory agents, as well as antagonists and agonists of neurotransmitters. This article will review our current knowledge of the mechanisms involved in (1) the transduction of tissue injury or disease signals (nociception and nociceptive receptors); (2) the transmission of signals rostrally to the thalamus and higher nervous system centers (involving perception of the quality, location, and intensity of noxious signals); and (3) the modulation of ascending sensory messages at all levels (periphery, spinal cord, and higher centers).

Worldwide trends in the socioeconomic impact and long-term prognosis of rheumatoid arthritis.

Rheumatoid arthritis (RA), once considered a benign and nonprogressive disease, is a debilitating condition with serious physical, emotional, and economic consequences. It afflicts approximately 1% of the adult population worldwide; prevalence increases with age, with twice as many women as men affected. In the United States, age, lack of formal education, and lower socioeconomic class correlate with both the incidence and poor prognosis of RA. The patient with RA faces increasing functional disability, the likelihood of work disability within 10 years after the onset of the disease, and a drastic reduction in earnings. Compared with individuals without the disease, patients with RA incur higher medical care costs, increased hospitalization, and a greater number of physician visits. As in the general population, the leading cause of death among patients with RA is cardiovascular disease, and deaths due to malignancy occur at a comparable incidence; however, patients with RA are at greater risk of mortality due to infection, renal disease, respiratory conditions, and gastrointestinal disease. Life expectancy is shorter among patients with RA than in the general population, and survival rates are comparable to those for Hodgkin's disease, diabetes mellitus, stroke, and three-vessel coronary artery disease. Efforts must be made to develop improved therapeutic strategies and rehabilitative programs to improve the quality of life of patients with RA.

Selective in vivo removal of rheumatoid factor by an extracorporeal treatment device in rheumatoid arthritis patients.

A prospective phase II trial was conducted to assess the feasibility, tolerance, and efficacy of a device designed for selective removal of rheumatoid factor from the plasma of rheumatoid arthritis patients. The device contained terpolymer hydrogel-coated plates with chemically attached, aggregated human immunoglobulin G, and it operated as an immunoaffinity column. Sixty-one patients aged 25 to 73 underwent weekly plasmapheresis treatments (the primary therapy phase). During the trial, patients continued current rheumatoid arthritis medications without dose adjustments. All patients received two to six treatments (primary therapy). Responding patients were eligible to continue apheresis treatment every 2 to 6 weeks (maintenance therapy). No serious, untoward side effects were noted in the course of this study; of 640 treatments, only 2 (in different patients) were aborted, one because of complaints of dizziness and angioedema and the other because of chest tightness and shortness of breath. Except for a significant (p less than 0.05) decrease in serum iron, no significant changes in complete blood count, serum electrolytes, renal and hepatic function tests, or serum C3 and C4 were noted. Although the trial was not designed to determine clinical efficacy, patients noted less morning stiffness, longer time to onset of fatigue, and improved global pain assessment (p less than 0.004); significant objective improvements were noted in joint pain, tenderness, swelling, and the number of affected joints (p less than 0.001). One-half of the treated patients had at least a 50 percent improvement in objective measures of antirheumatic activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Reactivity of antisera to endogenous primate retrovirus with a human T cell membrane protein: recognition of a nonviral glycoprotein by antibodies directed only against carbohydrate components.

A glycosylated protein of approximately 70,000 daltons (gp70) from the surface of human peripheral blood T cells was immunoprecipitated by antisera to the baboon endogenous retrovirus (BEV-M7) and the serologically related feline endogenous retrovirus (RD114) but not by antisera to other retroviruses. Whereas preliminary absorption experiments were consistent with a possible viral specificity for this reaction, detailed biochemical and serologic characterization of the purified cellular protein suggested that it was not related to the gp70 of either M7 or RD114 viruses. The specificity of the reaction was further analyzed by assays of cellular gp70 antigenicity after exposure to exo- and endoglycosidases or trypsin and carbohydrate hapten inhibition studies. The results of these experiments were consistent with the interpretation that the glycoprotein was being recognized by antibody binding to the carbohydrate moiety of the molecule. These results provide an example of an antibody activity that could lead to inappropriate conclusions when sensitive radioimmunoprecipitation techniques are used for the biochemical analysis of antigenic systems. They emphasize the necessity of purifying cellular antigens as a prerequisite to determining the exact basis for a serologic reaction.

Monocyte-induced inhibition of lymphocyte response to phytohaemagglutinin in progressive systemic sclerosis.

In patients with progressive systemic sclerosis (PSS) lymphocyte responses to phytohaemagglutinin (PHA) are abnormal (27.2 +/- 3.5 X 10(-3) counts per minute (cpm) versus 69.8 +/- 4.4 X 10(-3) for normal persons, p less than 0.005). Removal of adherent peripheral blood mononuclear cells improves the response of PSS lymphocytes (42.3 +/- 3.4 X 10(-3) cpm, 155% of control) but diminishes the response of normal lymphocytes (60.3 +/- 5.9 +/- 10(-3), 86% of control). Supernatant fluids from cultures of PSS unfractionated and adherent cells depress normal T cell response to PHA (64% and 55% of control respectively), but supernatant fluids from normal unfractionated and adherent cells do not (104% and 101% of control). Supernatant fluids of PSS and normal adherent cells, cultured in the presence of indomethacin, are not inhibitory to normal T cells (109 +/- 15% and 124 +/- 14% of control respectively). Supernatant fluids from PSS patients are more inhibitory than comparable fluids from patients with systemic lupus erythematosus (60 +/- 8% of control versus 80 +/- 5% of control). These data support the hypothesis that cellular immunity is abnormal in patients with PSS and indicate that adherent mononuclear cells mediate at least one component of the abnormality via an indomethacin-sensitive mechanism.

Systemic lupus erythematosus in men. Genetic and endocrine features.

Sixteen men with systemic lupus erythematosus (SLE) were examined to assess their genetic and hormonal status. The results of buccal smears in 13 patients examined were normal. Hormonal profiling was done in eight patients receiving no steroid therapy. Four patients had elevated plasma estradiol levels (30, 35, 55, and 103 pg/mL; normal, 12 to 23 pg/mL) and elevated plasma estrone levels (115, 150, 155, and 160 pg/mL; normal, 48 to 100 pg/mL). One patient had a decreased serum testosterone level (134 ng/dL; normal, 300 to 1,000 ng/dL), with an elevated luteinizing hormone (LH) level (4.2 ng/mL; normal, 1.6 to 4.0 ng/mL). One patient had an elevation in both levels of serum follicle-stimulating hormone (17.6 ng/mL; normal, 1 to 5 ng/mL) and LH (10.0 ng/mL). Two patients given infusions of 3H-androstenedione and 14C-testosterone had normal findings from kinetic studies of these hormones. Hyperestrogenemia and hypoandrogenemia observed in some men with SLE suggest that female sex hormones may create an immunologic milieu that facilitates the autoimmune phenomena.

Supressor monocytes in patients with systemic lupus erythematosus. Evidence of suppressor activity associated with a cell-free soluble product of monocytes.

Abnormal SLE mononuclear cell responses to PHA can be corrected by removal of adherent mononuclear cells. The present study demonstrates that cell-free supernatants from allogeneic adherent cell cultures inhibit lymphocyte response and that addition of indomethacin to cultures partly blocks the inhibitory effect of the resulting supernatant. Supernatants from SLE monocyte cultures suppressed allogeneic normal T cell responses by 36% (response in supernatant 33,515 +/- 3814 cpm, media control 51,947 +/- 3173 cpm) but normal monocyte culture supernatants did not suppress (48,384 +/- 4172 vs. 47,477 +/- 3221 cpm). Early (less than 24 hr) addition of indomethacin to monocyte cultures prevented elaboration of inhibitory material. In normals, indomethacin-treated supernatants were strikingly stimulatory (response 178% +/- 24 of control), whereas similarly treated supernatants of SLE monocyte cultures were not stimulatory (response 103% +/- 8 of control). The data indicate that a soluble inhibitor of lymphocyte blastogenesis is produced by SLE monocytes.

Attenuated live fowl cholera vaccine. I. Development of vaccine strain M3G of Pasteurella multocida.

A live cholera vaccine was developed from a virulent avian septicemia strain of Pasteurella multocida serotype 1. The virulent parental strain was mutagenized with N-methyl-N'-nitro-N-nitroso guanidine. Mutants were selected that had either smaller colonies at 37 C or temperature sensitivity for growth at 41 C. Four small-colony mutants and 2 temperature-sensitive mutants were studied. All the mutants were avirulent for turkeys. Sixteen days after turkeys were vaccinated with each mutant, both the vaccinates and unvaccinated controls were challenge-exposed to virulent P. multocida of the homologous serotype and the heterologous serotype 3. Two of the small-colony mutant strains protected against both homologous and heterologous challenge. Suggested for a live cholera vaccine is P. multocida M3G, a small-colony-forming mutant, innocuous for both mice and turkeys and stable against reversion.

Attenutated live fowl cholera vaccine. III. Laboratory and field vaccination trials in turkeys and chickens.

Administered via the drinking water, M-3-G, an attenuated strain of Pasteurella multocida of serotype 1, was found to immunize turkeys and chickens against fowl cholera. Immunity was tested by challenging birds intramuscularly, by palatine cleft swab, or orally after 3 vaccinations. No reactions to vaccination were noted in 390 turkeys in 12 laboratory trials, nor in 20,245 vaccinated in field trials. Chickens showed no vaccination reactions, and immunity was elicited by challenge in a laboratory trial and in face of natural outbreaks in the field, where 11,600 chickens were vaccinated. No vaccination reactions were noted, although most birds involved in the trials were carrying Mycoplasma spp. Immunity was found to last about 10 weeks after the last vaccination. The immunizing properties of M-3-G are compared with the CU strain.