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ID PMID Title PublicationDate abstract
12915160 The impact of total joint replacement in rheumatoid arthritis. 2003 Oct Management of the patient with rheumatoid arthritis (RA) requires a multidisciplinary approach, the role of the surgeon being to improve functional ability for the patient by reconstructing a deteriorated joint by total joint arthroplasty (TJA). An advantage of prosthetic evaluation over pharmacological medication evaluations is that the 'compliance' of the patient with the treatment (i.e. the TJA) is 100%, even at long-term follow-up. However, long-term follow-up of prosthesis evaluation is as difficult as the evaluation of any other intervention. Although the goal of any intervention on an RA patient is to improve functional ability, and thus self-support, of the patient, objective evaluation of the surgical procedure, and of its impact on the patient, can be difficult. The potential chronic course of RA makes evaluation of a specific surgical procedure and its effect on the patient difficult to interpret. The success of the TJA is generally judged on a survivorship analysis at 10 or 15 years in national registries (i.e. >40000 implants); revision surgery is used as an end-point for survival of the TJA. With a mean 90% survival at 10-year follow-up, total hip arthroplasty and total knee arthroplasty may be considered gold-standard TJA procedures for the patient. While revision is the end-point, the course to this end-point starts with progressive micromotion of the prosthesis. The effect of prosthetic changes, and of medication on prosthesis migration, can be measured very accurately by radiostereometry. The latter measures the actual performance of the TJA in the bone. Next to these more procedure-oriented evaluations, patient-oriented evaluations (e.g. quality of life, patient expectations) are of importance in judging the impact of the TJA on the RA patient. These evaluations provide evidence that the pre-operative status of the joint/extremity determines the extent of post-operative functional gain. Thus, postponing TJA for too long will give less functional benefit.
12769749 Anti-cytokines and cytokines in the treatment of rheumatoid arthritis. 2003 The treatment approach to rheumatoid arthritis has undergone a major evolutionary change in recent years in part as a consequence of growing appreciation of the severity of this condition and in part due to very considerable progress in understanding the important role of cytokines in the immunopathogenesis of this disease. The major focus of this review is on the rationale for targeting TNFalpha and IL-1 in rheumatoid arthritis and the results of clinical studies designed to assess the validity of this therapeutic approach. Recently published studies confirm that the long term use of a several biological agents targeting TNFalpha give rise to sustained improvements in symptoms and signs of rheumatoid disease and, furthermore, that TNFalpha blockade protects joints from structural damage. Although these drugs are well tolerated and have a good overall safety profile, pitfalls to the use of anti-TNFalpha agents apparent with increasing clinical experience include rare cases of tuberculosis. The mechanism of action of anti-TNFalpha therapy is discussed. Clinical trials of interleukin-1 receptor antagonist show relatively modest anti-inflammatory efficacy and an effect on X-ray indicative of retardation of joint damage. Other pro-inflammatory cytokines representing potential therapeutic targets include interferon-beta, interferon-alpha, IL-6, IL-15, IL-17 and IL-18. I will consider preliminary data, where available, arising from clinical trials designed to inhibit the activity of such molecules. In this review I will also discuss the rationale and preliminary data for other potential therapeutic strategies designed to augment the activity of anti-inflammatory cytokines such as IL-4, IL-10, and IL-11 in rheumatoid disease.
12412196 Neutrophils from systemic lupus erythematosus patients demonstrate increased nuclear DNA d 2002 Sep OBJECTIVE: (i) To determine the levels of nuclear DNA damage in freshly isolated and cultured neutrophils from SLE patients (SLE), rheumatoid arthritis patients (RA) and healthy individuals and relate these to the percentage of apoptotic neutrophils. (ii) To assess rates of repair of neutrophil oxidative DNA damage. METHODS: The comet assay was used to quantify nuclear DNA damage in neutrophils from SLE patients (n = 20), control subjects (n = 15) and RA patients (n = 15). Levels of DNA damage were related to apoptosis as assessed by annexin V binding and morphology. Rates of repair of neutrophil oxidative DNA damage was measured by incorporating formamidopyrimidine-DNA glycosylase (FPG) into the comet assay. RESULTS: Nuclear DNA damage in freshly isolated and cultured (20 h) neutrophils was significantly greater in SLE patients (median = 12.5%, 27.3%; respectively) compared with RA patients (median = 9.4%, p = 0.002; 19.3%, p = 0.002; respectively) and control subjects (median = 8.2%, p = 0.003; 18.7%, p = 0.01, respectively). Significantly higher levels of circulating apoptotic neutrophils were demonstrated in SLE patients compared to RA and control subjects. Similar findings were observed following 20 h cultured neutrophil preparations. However, no significant direct correlation between neutrophil apoptosis and DNA damage was observed. Neutrophils from 3 of 5 SLE patients demonstrated an impaired ability to repair oxidatively modified DNA. CONCLUSION: Neutrophils from SLE patients display increased DNA damage and, additionally, may demonstrate defective repair of oxidative DNA damage. These features, in addition to increased rates of neutrophil apoptosis, may act as contributing factors to autoantigen excess and immune activation.
15457305 Increased pulse wave velocity and shortened pulse wave propagation time in young patients 2004 Sep BACKGROUND: Rheumatoid arthritis (RA) is a systemic immune and inflammatory disease associated with excess cardiovascular morbidity and mortality. Pulse wave velocity (PWV) is an index of arterial stiffness and a marker of cardiovascular events. OBJECTIVE: To investigate arterial stiffness using carotid-femoral (aortic) PWV measurements in young patients with RA. PATIENTS AND METHODS: Eight patients (aged 21 to 34 years, seven women, mean RA duration 13.8+/-12.6 months) with RA according to the criteria of the American College of Rheumatology, and eight age- and sex-matched control subjects (aged 22 to 34 years, seven women) were recruited. Aortic PWV was determined using an automatic device, the Complior (Complior Colson, France), which allowed on-line pulse wave recording and automatic calculation of PWV. RESULTS: The carotid-femoral PWV, systolic blood pressure and heart rate were higher in young patients with RA than in sex- and age-matched control subjects (P=0.03, P=0.02 and P=0.002, respectively). In the young patients with RA, pulse wave propagation time between measurement sites was significantly shorter than in the control group (P=0.02). There were no significant differences in the sex, age, body mass index, waist to hip ratio, diastolic blood pressure, mean blood pressure or pulse pressure between the two groups (P=1.00, P=0.71, P=0.20, P=0.66, P=0.55, P=0.07 and P=0.11, respectively). CONCLUSION: The carotid-femoral PWV is increased and pulse wave propagation time is decreased in young patients with RA. Measurements of carotid-femoral PWV may provide a simple and noninvasive technique for identifying patients at increased risk of vascular disease.
15225683 The pharmacokinetics of interleukin-1 receptor antagonist in Chinese subjects with rheumat 2004 Sep To characterize the pharmacokinetic (PK) profile of interleukin-1 receptor antagonist (IL-1ra) after a single injection, and to assess the safety and tolerability of IL-1ra, a total of 15 adult Chinese subjects with rheumatoid arthritis (RA) were enrolled into this study. Study medication was administered on day 1. Blood samples for PK testing were collected predose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, and 48 h postdose. Adverse events data was collected and monitored throughout the study. Plasma IL-1ra concentrations were measured by enzyme-linked immunosorbent assay. Individual IL-1ra PK parameters were estimated by noncompartmental analysis. After subcutaneous (s.c.) injection of 1mg/kg IL-1ra, the T(max) was reached at 2-6h postdose. The mean (S.D.) of C(max) was 687 ng/ml (197 ng/ml). Plasma concentration subsequently declined with a mean (S.D.) of T(1/2) value of 3.76 h (1h). The mean (S.D.) of plasma clearance after administration value was 150 ml/min (52.1 ml/min). No deleterious effects, serious adverse events, or withdrawals due to adverse events occurred during this study. The PK parameters for Chinese subjects with RA were comparable to those for non-Chinese subjects with RA. IL-1ra was well tolerated during this study, and no significant safety concerns were identified after administration.
12759292 Costs of rheumatoid arthritis in Germany: a micro-costing approach based on healthcare pay 2003 Jun OBJECTIVE: To develop a systematic set of German cost data in rheumatoid arthritis (RA) based solely on valid healthcare payer's cost data sources. METHODS: Retrospectively one year cost data of 338 patients with RA were generated and analysed. The cost data were derived from a major statutory health insurance plan ("Allgemeine Ortskrankenkasse Niedersachsen") and the regional physicians' association ("Kassenärztliche Vereinigung Niedersachsen"). The recently published matrix of cost domains in RA was applied to structure the analysis. Descriptive statistics were used to analyse the data. RESULTS: The total direct costs for the 338 patients during one year (third quarter 2000 to second quarter 2001) were euro 3815 per patient-year. RA related direct costs were euro 2312 per patient-year. Outpatient costs accounted for 73.7%, inpatient costs for 24.0%, and other disease related costs for 2.3% of RA related direct costs. Outpatients cost drivers were RA related drugs (euro 1019 per patient-year), physician visits (euro 323 per patient-year), diagnostic and therapeutic procedures and tests (euro 185 per patient-year), and devices and aids (euro;168 per patient-year). 98 patients were retired prematurely owing to RA related work disability and incurred costs of euro;8358 per retired patient-year. 96 patients were gainfully employed and incurred sick leave costs of euro 2835 per employed patient-year. CONCLUSION: Micro-costing based on healthcare payer's data provides a relatively conservative albeit highly accurate estimate of costs in RA. Both RA related and non-RA related costs must be taken into account. In gainfully employed patients and in patients who receive RA related retirement payments productivity costs exceed direct costs.
12747278 Glucocorticoid receptor up-regulation in early rheumatoid arthritis treated with low dose 2003 Mar OBJECTIVE: Low or medium dose prednisone in early rheumatoid arthritis (RA), albeit with significant variation in clinical efficacy, reduces the progression of joint damage. The glucocorticoid receptor (GR) number in peripheral mononuclear cells (PBMC) might be helpful to predict which patients will respond to low or medium dose prednisone and therefore do not or will not need higher doses. With this in mind we determined in a double blind, placebo controlled study at baseline and yearly the GR number in PBMC. METHODS: Eighty-one early RA patients (disease duration less than one year) were included. All patients fulfilled the ACR criteria and were disease modifying antirheumatic drugs (DMARD) and glucocorticoid-naive. They were randomly assigned to treatment with 10 mg prednisone daily or placebo. From all patients disease activity (CRP, number of tender and swollen joints), the radiological joint score, bone mineral density, and the GR number in PBMC were measured annually. RESULTS: In females the GR number was up-regulated over time in both the prednisone and the placebo group. The same trend was observed in males. No correlations were found between the GR number in the prednisone users at the start of their treatment and changes in radiological scores or bone density after 2 years of treatment. No correlations were found between the GR number at the start and the clinical characteristics after a follow-up of 2 years. CONCLUSION: The GR number in the PBMC of early RA patients did not predict which patients would be prednisone responders based on clinical or radiological parameters. However, the up-regulation of the GR number in PBMC in early RA patients towards the GR number of healthy subjects during the first two years of their disease course seems to reflect a recovery or compensatory mechanism as a response to an ongoing inflammatory process. This recovery may be not enough to efficiently control the inflammatory situation.
12852371 Worsening injection site reactions with continued use of etanercept. 2003 Apr We report the case of a patient with persistent and worsening injection site reactions associated with subcutaneous etanercept therapy. Injection site reactions are well documented to occur early in therapy; however they typically decrease in frequency over time. This patient developed early injection site reactions that have persisted and worsened into his tenth month of treatment with etanercept.
12913923 The predictive value of anti-cyclic citrullinated peptide antibodies in early arthritis. 2003 Aug OBJECTIVE: To assess the additional predictive value of anti-cyclic citrullinated peptide (anti-CCP) antibodies above conventional variables for progressive erosive or disabling disease in a cohort of patients with early inflammatory oligo- and polyarthritis. Methods. Consecutive new patients with peripheral arthritis of > 2 joints and < 2 years of symptom duration, referred between 1995 and 1999 were studied. Excluded were patients with bacterial, psoriatic, crystal-induced arthritis or spondyloarthropathy. Optimal cut-off values for serum IgM-rheumatoid factor (RF) and anti-CCP were deduced from receiver operating characteristics curves. At 2 year followup, progressive erosive disease was defined as: radiographic progression > 5 (Sharp-van der Heijde units) and low functional capacity as a Health Assessment Questionnaire score > 1. For the statistical analysis, a logistic regression model was used. RESULTS: A total of 282 patients [68% female, median age 56 yrs (18-83)] were included. Thirty-two percent of the patients were positive for anti-CCP at baseline. Anti-CCP correlated significantly (p < 0.001) with a progressive erosive disease after 2 years, but not with a low functional capacity. The combination of a positive anti-CCP status and radiographic damage at baseline could predict the radiographic progression with a sensitivity, specificity, and accuracy of 78%, 82%, and 81%, respectively. The positive predictive value (PPV) for radiographic progressive disease was 63%, while the negative predictive value (NPV) was 90%. The accuracy of the model decreased from 81 to 76% after leaving out anti-CCP from the model. In a subgroup of 178 IgM-RF negative patients, the PPV for radiographic progressive disease was 40%, while the NPV was 95%. CONCLUSION: Anti-CCP positivity has a small additional value above the conventional prognostic variables for progressive erosive disease in a cohort of patients with early inflammatory oligo- and polyarthritis. The prognostic value of anti-CCP lies mainly in its ability to predict mild disease. This effect is accentuated in the subgroup of IgM-RF negative patients.
12126683 Is routine splintage following primary total knee replacement necessary? A prospective ran 2002 Sep It was hypothesised that routine splintage following primary total knee replacement has no affect on flexion deformity and offers no benefit over simple wool and crepe. Fifty-five patients undergoing primary total knee replacement were entered into a prospective study. The patients were randomly assigned to two groups: The first group was rehabilitated without a splint and the second received an adjustable semi-rigid extension splint (Richards splint) for the first 48 h after surgery. Range of motion measurements were recorded pre-operatively and at 2 days, 1 week and 3 months post-operation by a research nurse blinded to the allocation. No statistically significant difference in flexion deformity was found at any stage (P>0.5). No difference was found in general or wound complications, or requirement for blood transfusion, and the post-operative stay was equal in the two groups. We conclude that routine use of a semi-rigid splint following primary total knee replacement has no advantage over simple wound dressings.
14607859 Measurement of inflammatory biomarkers in synovial tissue extracts by enzyme-linked immuno 2003 Nov We developed methods for measuring inflammatory biomarkers (cytokines, chemokines, and metalloproteinases) in synovial biopsy specimens from patients with rheumatoid arthritis (RA) and osteoarthritis (OA). Soluble extracts of synovial fragments were prepared with mild detergent and analyzed by enzyme-linked immunosorbent assay (ELISA) for interleukin 1beta (IL-1beta), IL-6, IL-8, tumor necrosis factor alpha (TNF-alpha), and matrix metalloproteinase 3. The optimal detergent was 0.1% Igepal CA-630, which interfered minimally with ELISA detection but extracted 80% of IL-6 from synovial tissue. Upon spiking, 81 to 107% of added biomarkers could be recovered. To determine within-tissue variability, multiple biopsy specimens from each RA synovial extract were analyzed individually. A resulting coefficient of variation of 35 to 62% indicated that six biopsy specimens per synovial extract would result in a sampling error of < or = 25%. Preliminary power analysis suggested that 8 to 15 patients per group would suffice to observe a threefold difference before and after treatment in a serial biopsy clinical study. The previously described significant differences in IL-1beta, IL-6, IL-8, and TNF-alpha levels between RA and OA could be detected, thereby validating the use of synovial extracts for biomarker analysis in arthritis. These methods allow monitoring of biomarker protein levels in synovial tissue and could potentially be applied to early-phase clinical trials to provide a preliminary estimate of drug efficacy.
15508789 [Change in biomarkers of osteoporosis in rheumatoid arthritis patients treated with inflix 2004 Jun A study was made to evaluate bone turn-over in rheumatoid arthritis (RA) patients treated with infliximab. Twenty-two patients with established RA were included. In all patients, biochemical markers of osteoporosis: osteocalcin (BGP), alkaline phosphatase (bone isoenzyme), deoxypyridinoline (Dpd), acute phase proteins (CRP, AGP, ACT, AGP-RC), and interleukin 6 (IL-6) were determined before treatment, at week 30, and at week 46. Two markers (BGP, Dpd) were significantly decreased at both weeks 30 and 46. Moreover, a fall in serum levels of acute phase proteins and IL-6 was seen. The results suggest that anti-TNF treatment with infliximab not only decreases activity of inflammation but also may slow down bone turn-over. Further research is needed to assess its potential in reducing risk of osteoporosis in RA.
12180718 Hyperhomocysteinemia in rheumatoid arthritis: influence of methotrexate treatment and foli 2002 Aug OBJECTIVE: To examine the effect of methotrexate (MTX) and folic acid supplementation on the homocysteine level in patients with rheumatoid arthritis (RA). METHODS: A cross sectional study was performed in 81 patients with RA, comprising a standardized clinical interview, an examination, and a blood specimen test. RESULTS: P-homocysteine tended to be lower in 41 patients receiving MTX, compared with 40 patients not receiving MTX. Of the MTX treated patients, 76% received folic acid supplementation. Multivariate analysis revealed a statistically significant association between P-homocysteine and P-creatinine (p < 0.001), and disease activity/progression measured by the Health Assessment Questionnaire score (p < 0.001). There was a tendency to negative association between P-homocys-teine and folic acid supplementation. CONCLUSION: P-homocysteine in patients with RA receiving MTX and folic acid supplementation did not differ significantly from P-homocysteine in RA patients receiving other types of treatment.
12164794 Leukocytapheresis using a leukocyte removal filter. 2002 Aug Leukocytapheresis (LCAP) long has been investigated with a leukocyte removal filter for the treatment of various kinds of autoimmune related and inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, and so on. A lot of patients with such diseases have been reported to respond to LCAP. Asahi Medical Co. has developed the leukocyte removal filter Cellsorba and an extracorporeal treatment unit Plasauto LC so that the LCAP technique can be performed easily with a high performance filter, easy attachment of the blood circuit tubing set, and automatic operation. Cellsorba E has been listed as a medical device reimbursed by Japanese national health insurance to be used in LCAP for active ulcerative colitis since October 2001. Although the effective mechanism of LCAP is still controversial, the removal of activated leukocyte from the peripheral blood and the reaction by blood contacting materials in Cellsorba can be triggers of the immunomodulation for the treatment of immune disorder. This review introduces the development of LCAP technologies and several reports on therapeutic results.
12106498 Molecular action of methotrexate in inflammatory diseases. 2002 Despite the recent introduction of biological response modifiers and potent new small-molecule antirheumatic drugs, the efficacy of methotrexate is nearly unsurpassed in the treatment of inflammatory arthritis. Although methotrexate was first introduced as an antiproliferative agent that inhibits the synthesis of purines and pyrimidines for the therapy of malignancies, it is now clear that many of the anti-inflammatory effects of methotrexate are mediated by adenosine. This nucleoside, acting at one or more of its receptors, is a potent endogenous anti-inflammatory mediator. In confirmation of this mechanism of action, recent studies in both animals and patients suggest that adenosine-receptor antagonists, among which is caffeine, reverse or prevent the anti-inflammatory effects of methotrexate.
12548452 Technique of synovial biopsy of metacarpophalangeal joints using the needle arthroscope. 2003 Jan We demonstrate the technique, advantages, and disadvantages of metacarpophalangeal joint examination with needle arthroscope. We evaluated our experience from biopsies of 10 metacarpophalangeal joints of eight rheumatoid women aged 41-45 years. The procedures were performed using a 1-mm needle arthroscope. The synovium biopsy was taken with a microforceps. The procedure was performed under local anesthesia. The tight tension of the joint and traction of the finger is necessary for good visualization, but despite this visibility can be difficult. Needle biopsy is a useful method for the early diagnosis of rheumatoid arthritis.
15468352 Adverse events with disease modifying antirheumatic drugs (DMARD): a cohort study of leflu 2004 Oct OBJECTIVE: To determine and compare the incidence of serious adverse events (AE) during treatment of rheumatoid arthritis (RA) with disease modifying antirheumatic drugs (DMARD), focusing on leflunomide (LEF). METHODS: A retrospective cohort study of a large US insurance claims database was performed. Study groups were patients with RA classified by DMARD exposure as either no-DMARD therapy, single-agent DMARD (monotherapy), or combination-DMARD therapy. Specific DMARD examined were leflunomide (LEF) and methotrexate (MTX), compared to other DMARD (penicillamine, hydroxychloroquine, sulfasalazine, gold, etanercept, infliximab) and no DMARD (nonsteroidal antiinflammatory drugs, COX-2 inhibitors). All AE reported were considered endpoints; primary endpoints included hepatic, dermatologic, hematologic, infectious, respiratory, hypertension, and pancreatitis AE. RESULTS: The 40,594 RA patients of the study period (September 1998 to December 2000) accumulated 83,143 person-years (PY) of followup. Followup for each of the groups was: DMARD-monotherapy, 46,054 PY (55% of total); combination-DMARD, 25,830 PY (14%); and no-DMARD, 11,259 PY (14%). The incidence rate of all AE combined was significantly lower for LEF monotherapy (94 events/1000 PY) than MTX (145 events/1000 PY), other DMARD (143 events/1000 PY), or no DMARD (383 events/1000 PY) (p < 0.001 for all comparisons). The "all-AE" rates during combination therapy with LEF + MTX (43/1000 PY) and LEF + other DMARD (59/1000 PY) were lower than the "all-AE" rate for DMARD + MTX (70/1000 PY; p = 0.002). LEF monotherapy had the lowest rate of hepatic events in the DMARD monotherapy groups. CONCLUSION: The rates of AE in the LEF group, alone and combined with MTX, were generally lower than or comparable to the AE rates seen with MTX and other agents.
15570634 Clinical outcomes of patients with rheumatoid arthritis after switching from infliximab to 2004 Dec OBJECTIVE: To assess the efficacy and monitor serious adverse events in patients with rheumatoid arthritis (RA) switching treatment from infliximab to etanercept. METHODS: Adult patients with active RA who were discontinuing treatment with infliximab were eligible to enroll in this prospective, 12-week, open label, single-arm, observational study. Four to 10 weeks after their last infusion of infliximab, patients began treatment with etanercept (twice weekly subcutaneous injections of 25 mg). Clinical assessments using the American College of Rheumatology (ACR) criteria for improvement were performed at baseline and at Weeks 6 and 12, and serious adverse events were monitored throughout the study. RESULTS: Twenty-five patients were enrolled, 18 of whom had discontinued infliximab because of lack of efficacy, and 22 completed 12 weeks of etanercept treatment. After 12 weeks, 14 of 22 patients (64%) achieved at least a 20% improvement in ACR criteria (ACR20), 13 (59%) experienced improvements in physical function that were considered clinically important (> or = 0.22 point decrease in overall Health Assessment Questionnaire score), and mean values of all individual components of the ACR criteria had improved. No serious adverse events were reported during the study and no patient discontinued because of lack of efficacy. CONCLUSION: Etanercept, a soluble tumor necrosis factor (TNF) receptor, provided a well tolerated and effective treatment option for some patients even when infliximab, a monoclonal antibody to TNF, had been ineffective.
15302336 Stem cell transplantation for autoimmune disorders. Coincidental autoimmune disease in pat 2004 Jun The practice of stem cell transplantation for severe autoimmune diseases refractory to conventional therapy originated from two landmark discoveries: the excellent results of animal experiments, and serendipitous observations in human coincidental diseases. The latter include patients with an often long-standing autoimmune disease who have developed a haematological condition (aplasia, leukaemia, lymphoma) requiring stem cell transplantation (from marrow as well as from blood). Allogeneic and autologous transplants have been performed. The initial information deriving from both procedures is their feasibility, even more convincing since the patients were affected by two simultaneous severe diseases. The information derived from autologous transplants has, however, now been superseded by the considerable and increasing number of those transplants performed for primary autoimmune diseases. On the other hand, allogeneic stem cell transplantation for very severe autoimmune diseases is being cautiously explored in current protocols. Allogeneic transplants in coincidental disease have also suggested a graft-versus-autoimmunity effect, which may become relevant in conjunction with non-myeloablative, less toxic condition regimens.
12068402 Case challenges in shoulder surgery: what would you do? 2002 Jun The management of complex shoulder issues was discussed in an interactive case presentation session. Patient scenarios discussed included reoperation of a rotator cuff repair with a subscapularis tear; uncemented hemiarthroplasty presenting with pain and osteolysis; severe osteoarthritis with all nonoperative options exhausted; rheumatoid arthritis with pain and diminished function; and significant pain, limited motion, and weakness in an active patient.