Sustained durability and tolerability of etanercept in ankylosing spondylitis for 96 weeks.

OBJECTIVE: To evaluate the continued safety and durability of clinical response in patients with ankylosing spondylitis receiving etanercept. METHODS: 277 patients who had participated in a previous randomised, double blind, placebo controlled 24 week trial were eligible to continue in this open label extension study. All patients who enrolled in the open label extension (n = 257) received subcutaneous etanercept 25 mg twice weekly for up to 72 weeks, for a combined 96 weeks of cumulative trial and open label experience. For the patients who had received etanercept for 24 weeks in the double blind trial, this represented almost 2 years of continuous etanercept treatment. RESULTS: Patients continuing etanercept treatment had a sustained response for almost 2 years, with 74% achieving an ASsessments in Ankylosing Spondylitis 20% (ASAS 20) response after 96 weeks of etanercept treatment. Patients who had received placebo in the preceding double blind trial had similar responses, with 70% of patients attaining an ASAS 20 response after 24 weeks of etanercept treatment and 78% achieving an ASAS 20 response after 72 weeks. Improved spinal mobility was seen in both groups. Etanercept was well tolerated in patients treated for up to 96 weeks. CONCLUSION: The subcutaneous administration of twice weekly doses of etanercept provided sustained durability of response in the improvement of signs and symptoms of ankylosing spondylitis for nearly 2 years.

Errors in precise examiner head placement during cervical range-of-motion measurements.

OBJECTIVE: To quantify errors associated with examiner-assisted neutral head placement in cervical range of motion measurements in normal subjects and to investigate the influence of these errors on range of motion measurements. DESIGN: Repeated-measures design with cervical range of motion and errors in placement measured in 20 volunteers with no symptoms with the OSI CA-6000. METHODS: Examiner placement of head position was achieved with inclinometers and triangulation. Subjects estimated pain experienced during measurements with numeric pain scales. Angular data around 3 axes were analyzed with descriptive statistics. Possible correlations between errors and other variables were investigated. RESULTS: Drift, defined as displacement from original head positioning at first data acquisition and before initiation of motion, was negligible (+/-0.8 degrees ). Standard errors in neutral head placement ranged from 1.0 degrees in axial rotation to 3.2 degrees in flexion/extension. Within-trial variability of neutral position did not correlate with between-trial differences in ranges of motion. CONCLUSION: Head position errors were not the primary sources of variability for between-trial measurements of cervical range of motion. The largest errors were in flexion/extension, and least, in axial rotation. Neutral position errors up to approximately 5 degrees for lateral bending, 3 degrees for rotation, and 9 degrees for flexion and extension fall within 95% CI and are the recommended lower limits for significant changes in clinical settings.

Standardized initial head position in cervical range-of-motion assessment: reliability and error analysis.

OBJECTIVE: To assess the clinical reliability and precision of the OSI CA-6000 Spinal Motion Analyzer for measurement of range of motion in cervical spines of pain-free subjects by using a novel procedure designed to minimize variability and quantitatively evaluate sources of errors. METHODS: Twenty asymptomatic volunteer subjects were evaluated twice by each of two trained examiners in one session. Subject position was carefully standardized. Rotation, lateral bending, and flexion-extension were evaluated in repeated movements (cycles) from extreme to extreme. ANALYSIS: Descriptive statistics and reliability coefficients (interclass correlation coefficients [ICCs]) were calculated for all full- and half-cycle motions. Possible sources of systematic errors were evaluated, and random errors were estimated. RESULTS: ICCs indicate that the instrument performs very reliably for rotation and lateral bending (0.93-0.97) and acceptably for flexion-extension (0.75-0.93) measurements. Differences in instrument placement, subject posture, or both in different trials correlate neither with differences in measured values nor with variances. Within-trial errors did not correlate with ranges of motion. Standardizing head position resulted in increases in reliability of from 3% to 15% for axial rotation and lateral bending but actually decreased the ICCs for flexion-extension (up to 14%) compared with data collected under a less-stringent protocol. Errors in clinical use are estimated at 4.5 degrees. CONCLUSIONS: By using our modifications to the accessories and standardization of subject position, the CA-6000 is a highly precise and reliable instrument for measuring active cervical motion about the 3 Cartesian axes. Individuals can repeat the same patterns of motion in sequential trials on the same day with very little variation. Ease of repetitious measurement without examiner intervention contributes to the instrument's ability to obtain highly reliable data. Changes in instrument placement or subject body posture between trials do not give rise to systematic errors. Design of the instrument for flexion-extension could be improved.

Theory of small vertebral motions: an analytical model compared to data.

OBJECT: Develop an analytical theory describing the dynamics of small impulses applied to vertebrae, such as in chiropractic adjustments or spinal manipulative therapy. DESIGN: Data were compared with damped harmonic oscillator models of vertebrae. BACKGROUND: Evidence accumulates that chiropractic adjustments are effective in addressing a variety of health problems. However, the biomechanics characterizing spinal manipulation is largely unknown. Recently, relative separations of the L2-L3 vertebrae subsequent to activator adjusting instrument thrusts were measured in vivo at 2048 Hz. RESULTS: Nine-parameter models for axial, shear and angular motions were fit to sets of 350 data points. They required frequencies of 5, 8 and 11 Hz, corresponding to well-known spinal resonances. The fits are excellent, with 0.75 < corrected R(2) < 0.96. Stiffnesses are calculated to be less than 10% of elastic zone values. Viscosities of the paravertebral medium are predicted to be between 6 and 30 poise, comparable to synovial fluids. CONCLUSIONS: This model ties together vertebral responses to small impulses with spinal resonances and other spinal/vertebral characteristics. Stiffness dominates damping resistance except in angular motions. Coupling appears unimportant in adjacent vertebral responses to small impulses. Further research is needed to clarify this issue. RELEVANCE: This study indicates how both force (determining amplitude) and thrust speed or duration (determining frequencies excited) may enter in terms of optimizing the efficacy of chiropractic adjustments. If stimulation of specific spinal frequencies, say as central nervous input, were most essential, then many chiropractic thrusts could be clinically similar. This may explain how over 90 chiropractic techniques can co-exist.

Meta-analysis of normative cervical motion.

STUDY DESIGN: Meta-analysis of normative cervical range of motion literature performed by applying summary statistics to range of motion and reliability values reported among studies. OBJECTIVES: To identify reliable and valid methods for measuring active and passive cervical range of motion and to estimate normative values. SUMMARY OF BACKGROUND DATA: Range of motion studies use a variety of measuring instruments and statistical analyses, making it difficult to select the most suitable instruments, procedures, and normative values for clinical application. Reviews of the literature, being limited in scope, have not quantitatively synthesized the literature. METHODS: Range of motion and reliability data were grouped by technology and types of motion, then summarized by deriving means and variabilities. Clinical validity was assessed by examining discrepancies, variabilities, and correlations. Change in range of motion as a function of age was determined by comparing range of motion ratios (fourth:third and seventh:third decades). RESULTS: Nine technologies were identified. Overall, passive motion was greater than active motion, and range of motion decreased as age increased, with women exhibiting greater range of motion than men. Variations within each technology were as large as or larger than those between technologies, indicating that clinical procedures are as important as the accuracy and precision of the technology itself. Reliability has not been adequately tested for the majority of technologies. CONCLUSIONS: Clinical procedures appear to be as important as accuracy and precision in determining the reported range of motion values. Further research is needed to establish a gold standard for normative values and to identify an instrument that is reliable for all motions.

Immunologic response to the dual murine anti-Id vaccine Melimmune-1 and Melimmune-2 in patients with high-risk melanoma without evidence of systemic disease.

Melimmune is a dual preparation of two murine anti-idiotypic antibodies (anti-Ids), Melimmune-1 and Melimmune-2, which mimic separate epitopes of the melanoma-associated high molecular weight proteoglycan antigen. In an animal model, vaccination with either anti-Id leads to tumor rejection, and Phase I clinical trials have demonstrated the tolerance of each reagent in humans. We conducted a Phase IB trial of different doses of a one-to-one composition to Melimmune-1 and Melimmune-2 administered with SAF-m adjuvant in patients with resected melanoma without evidence of metastatic disease. A total of 21 patients were enrolled in this multicenter trial. Detailed immune response analysis was conducted on 13 patients enrolled at a single institution. Following vaccination, 12 of the 13 patients demonstrated antibodies to both Melimmune-1 and Melimmune-2, including significant anti-V-region reactivity. Maximum anti-V-region reactivity was generally detected following the last vaccination. Anti-V-region reactivity directed at Melimmune-1 and Melimmune-2 in excess of 1 microgram/ml was detected in 4 and 10 of 12 patients, respectively. Sera from patients obtained at time of peak anti-V-region reactivity did not demonstrate the ability to inhibit Ab1 binding to tumor cells or direct anti-tumor cell reactivity. However, in vitro cellular proliferation was observed in response to Melimmune-1 and/or Melimmune-2 F(Ab')2 in all patients with a mean stimulation index of 12.0 and 27.8, respectively. Overall, the antibody and cellular immune response to Melimmune-2 was more potent than to Melimmune-1, and all antibody doses elicited an immune response. The optimal biologic dose of Melimmune could not be determined in this small patient population.

Clinical and immunologic effects of a PRIMATIZED anti-CD4 monoclonal antibody in active rheumatoid arthritis: results of a phase I, single dose, dose escalating trial.

OBJECTIVE: The goal of this single infusion, dose escalation study was to evaluate the safety of the PRIMATIZED anti-CD4 monoclonal antibody (Mab), IDEC-CE9.1, in patients with rheumatoid arthritis (RA). METHODS: Twenty-five patients received single infusions of IDEC-CE9.1 in dose escalation form (0.03 to 4 mg/kg). Cohorts consisted of 3 patients each with seropositive RA. Following treatment, patients were monitored for 2 weeks before initiation of treatment of the next cohort. Peripheral blood samples were taken during and after treatment to measure immune function. Flow cytometry of peripheral blood mononuclear cells and in vitro proliferative responses to antigens and recall antigens were assessed pre and post-treatment. Cell surface markers CD3, CD4 (OKT4 and Leu 3a), CD8, CD20, CD25, CD45Ro, CD45Ra and DR were analyzed, and proliferation to mitogens and recall antigens was measured. RESULTS: No infusion related adverse events were noted and other drug related adverse events were mild. Reduction in peripheral CD4 T cell number was brief (3 to 7 days) and not associated with infection. CD4 cell surface antigen downmodulation was observed postinfusion. Suppression of CD25 expression was associated with a positive clinical response. In vitro proliferative responses to mitogens and antigen were inhibited for up to one month with no association to positive clinical response. CONCLUSION: IDEC-CE9.1 appears to have a benign safety profile and may modulate immune function rather than deplete CD4+ T cells.

Oscillations of the vertebrae in spinal manipulative therapy.

OBJECTIVE: To determine the general nature of the biomechanical response of the vertebrae to small forces, such as spinal manipulative therapy (SMT). DESIGN: Perturbation theoretical methods of physics and mechanical energy considerations are used to derive the equations of motion of the vertebral bodies moving under the combined influences of ligamentous and discogenic forces, applied forces and dissipative forces attributable to surrounding tissues. RESULTS: The allowable solutions to the equations of motion determine that the mechanical response of any vertebra to SMT should consist of a superposition of damped oscillations. This is based on the most general assumptions about the spine that are consistent with clinical observations, namely, that patients can lie stably motionless, and is independent of the specifics of any spinal model. DISCUSSION: The extant data are shown to be consistent with this theory. The implications for future research and clinical practice are explored. CONCLUSIONS: Vertebral motion in response to SMT seems to occur in two distinct phases: an initial, (passive) oscillatory response to the SMT thrust, governed by ligamentous and discogenic forces, and a later, less regular motion, probably caused by muscular reflex contractions. Evidence of this includes direct measurement of oscillations, surface electromyogram measurements of muscle responses and detection of multiple spinal resonances. Further research on the muscular reflex responses to SMT is necessary. Most SMT should initiate some of the normal-mode oscillations of the vertebrae. There may be up to 144 different frequencies of vertebral oscillatory motion in each individual in any posture; those frequencies detected thus far are consistent with the predicted relationship between frequencies, vertebral body masses and coefficients of stiffness. Further data are needed to confirm the detailed validity of this theory.

Equations of motion for the "Flopping Doctor" model of spinal manipulative therapy.

OBJECTIVE: To rigorously develop the physics and mathematics of the model of spinal manipulative therapy (SMT) consisting of a damped linear oscillator representing the vertebra impacted by a spring system representing the doctor, to interpret the results and to compare and contrast them with an earlier similar study originally developed in approximation. DESIGN: Mathematical physics analysis. RESULTS: Careful consideration of the exact equations and their meaning leads one to eliminate as unnecessary the picture of the doctor as a spring system, replacing it with the force function, which represents the applied SMT thrust as a function of time. Thus, with correct application of the principles of physics to the original model, one is led directly to a linear harmonic oscillator model for the vertebral system, with a forcing function for the SMT thrust and possible preload. The details of the application of such a model are developed elsewhere. CONCLUSIONS: The distraction resultant from an SMT thrust is shown to be a function of the momentum transfer, not, as asserted by the originator of the model, the velocity. The quickness of the application of the SMT thrust must be measured relative to normal mode frequencies of the spine. Further detailed examination of the physics of the model leads one to modify or contradict several other conclusions of the model's originator. Most importantly, the fact that the details of the physics of this model can be worked out analytically (as opposed to having to employ numerical methods) holds out the promise of additional insights to be gained by further development of this approach.

Rheumatic diseases and AIDS--is the association real?

There have been many reports of an association of certain musculoskeletal disorders especially Reiter's syndrome and psoriatic arthritis with human immunodeficiency virus (HIV) infection. A review of the first 1,100 HIV positive patients at the University of Cincinnati AIDS Clinic and Treatment Center has revealed 9 with psoriasis of whom 4 developed arthritis, 1 with Reiter's syndrome which predated HIV infection, 9 with nonspecific arthralgias, 7 with diffuse myalgias of whom 5 were AZT and one alpha-interferon related. Three patients with temporal arteritis/polymyalgia rheumatica, 2 of whom are biopsy proven, have been observed. The frequency distribution for race, age, sex for this population was contrasted to that expected. The only increased frequencies were in psoriatic arthritis with 4 cases observed and 0.73 expected and in temporal arteritis/polymyalgia rheumatica with 3 cases observed and 0.3 expected. Whether there is a coincidental or real increase is an important question requiring prospective, epidemiological studies to help determine if the differences reported are demographic or genetic.

Human immunodeficiency virus infection is not associated with Reiter's syndrome. Data from three large cohort studies.

The cohorts presented are the largest available and the only ones for which suitable controls exist. They suggest that RS occurs in less than 1% of individuals infected with HIV. Additionally, infection with HIV is no independently associated with RS. Rather, previously described arthritogenic agents are implicated.

Induction of autoantibodies by human immunodeficiency virus infection and their significance.

Although many of the changes in HIV and AIDS appear to be global, on closer investigation the defects are specific and can be explained by recognized mechanisms. Despite a demonstrated concurrent polyclonal B-cell activation, studies fail to show any evidence to date of significant dysregulation of the immune system leading to serologic or clinical autoimmunity.

Prolonged cutaneous herpes zoster in acquired immunodeficiency syndrome.

We described the development of prolonged disseminated cutaneous herpes zoster in two patients with acquired immunodeficiency syndrome. Both patients developed hyperkeratotic, verrucous lesions that progressed despite acyclovir therapy. The biopsy specimens were typical of herpes infection. The development of acyclovir-resistant varicella-zoster virus during therapy was suspected clinically in the first patient and documented in vitro in the second patient. The inability to mount an effective cell-mediated immune response contributed to the prolonged course of cutaneous zoster in our patients. The hyperkeratotic nature of the skin lesions may reflect their chronic nature. Treatment with inadequate doses of acyclovir, allowing viral persistence and the selection of resistant strains of virus, may also be implicated. We recommend prolonged high-dose intravenous acyclovir therapy in the initial management of herpes zoster in patients with acquired immunodeficiency syndrome.

Emergence of acyclovir-resistant varicella zoster virus in an AIDS patient on prolonged acyclovir therapy.

We demonstrate for the first time the appearance of acyclovir resistance in serial varicella zoster isolates from a patient treated with acyclovir. We recovered varicella zoster virus three times over a period of 5 months from the skin lesions of this patient with AIDS who was treated with three courses of intravenous acyclovir and prolonged low-dose oral acyclovir. The isolate recovered from a typical zoster lesion before acyclovir, and one obtained from a hyperkeratotic lesion 2 months later, after intravenous and oral acyclovir, were sensitive to acyclovir and produced normal amounts of thymidine kinase. In contrast, virus recovered from lesions 5 months after the onset, when the patient had received repeated courses of acyclovir, was acyclovir-resistant and thymidine-kinase-deficient. Resistance to acyclovir was associated with persistence of lesions which failed to improve with intravenous acyclovir, but was not associated with new lesion formation.

Successful treatment of a patient with Reiter's syndrome and acquired immunodeficiency syndrome using etretinate.

In a 30-year-old homosexual man with a 3-year history of localized psoriasis, an oligoarthropathy and severe cutaneous lesions of Reiter's syndrome developed 6 months after acquired immunodeficiency syndrome (AIDS) was diagnosed. Reiter's syndrome and psoriasis may be a continuum of similarly expressed cutaneous diseases that develop in genetically predisposed individuals. We discuss the possible involvement of T lymphocytes and Langerhans cells in the cutaneous lesions of AIDS patients with psoriasis and Reiter's syndrome. In these AIDS patients, skin disease tends to be severe and recalcitrant to conventional therapy. Etretinate plus topical fluorinated steroids was an excellent treatment, producing near clearance of skin lesions and significant improvement in the oligoarthropathy.

Drug-related lupus. Clinical and etiologic considerations.

Drug-related lupus (DRL) was first described in 1945 in association with sulfadiazine. Since that time, more than 50 medications have been implicated in this syndrome and its associated laboratory abnormalities. Several mechanisms for these findings have been postulated, but no one mechanism has been established as pre-eminent. The clinical spectrum, when it does occur, is characterized by polyserositis: arthritis, pleuritis, pericarditis, and peritonitis. Many of the well-known features of SLE are rarely, if ever, seen in DRL.

Acquired immune deficiency syndrome (AIDS) and autoimmunity--mutually exclusive entities?

Loss of normal immune homeostasis occurs in acquired immune deficiency syndrome (AIDS). We evaluated patients at the University of Cincinnati and New York University Medical Centers for serologic evidence of autoimmune changes. Specifically, tests for antinuclear and organ-specific antibodies by immunofluorescence, antisperm and anti-seminal plasma antibodies, rheumatoid factor by latex and sensitized sheep cell agglutination techniques, anti-polyadenosine (poly A), and single-stranded DNA antibodies were performed in human immunodeficiency virus (HIV) antibody-positive sera. A parallel study of mitogen responsiveness was performed and showed inhibition of response by AIDS and AIDS-related complex (ARC) sera. In spite of evidence of polyclonal B-cell activation, hyperglobulinemia, and the presence of antibodies to many infectious agents, as well as the known cellular immune abnormalities, the patients tested had a striking absence of these autoantibodies. The only major difference noted from normal controls, was a low but significant level of antibody binding to poly A. The autoimmune connective tissue diseases were not observed in this group of patients.