ABSTRACT
OBJECTIVES: To assess the efficacy of a cannabis-based medicine (CBM) in the treatment of pain due to rheumatoid arthritis (RA). METHODS: We compared a CBM (Sativex) with placebo in a randomized, double-blind, parallel group study in 58 patients over 5 weeks of treatment. The CBM was administered by oromucosal spray in the evening and assessments were made the following morning. Efficacy outcomes assessed were pain on movement, pain at rest, morning stiffness and sleep quality measured by a numerical rating scale, the Short-Form McGill Pain Questionnaire (SF-MPQ) and the DAS28 measure of disease activity. RESULTS: Seventy-five patients were screened and 58 met the eligibility criteria. Thirty-one were randomized to the CBM and 27 to placebo. Mean (S.D.) daily dose achieved in the final treatment week was 5.4 (0.84) actuations for the CBM and 5.3 (1.18) for placebo. In comparison with placebo, the CBM produced statistically significant improvements in pain on movement, pain at rest, quality of sleep, DAS28 and the SF-MPQ pain at present component. There was no effect on morning stiffness but baseline scores were low. The large majority of adverse effects were mild or moderate, and there were no adverse effect-related withdrawals or serious adverse effects in the active treatment group. CONCLUSIONS: In the first ever controlled trial of a CBM in RA, a significant analgesic effect was observed and disease activity was significantly suppressed following Sativex treatment. Whilst the differences are small and variable across the population, they represent benefits of clinical relevance and show the need for more detailed investigation in this indication.
Subject(s)
Analgesics/therapeutic use , Arthritis, Rheumatoid/complications , Pain/prevention & control , Plant Extracts/therapeutic use , Administration, Oral , Cannabidiol , Double-Blind Method , Dronabinol , Drug Combinations , Female , Humans , Male , Middle Aged , Pain/etiology , Pain Measurement , Plant Extracts/adverse effects , Treatment OutcomeABSTRACT
The primary objective of this study was to investigate structural changes, as measured by joint space narrowing (JSN), within the knee joint during treatment with intra-articular sodium hyaluronate (HA) of molecular weight 500-730 kDa in patients with osteoarthritis (OA) of the knee. Patients received a weekly intra-articular injection of either 20 mg2/ml HA or a 2 ml vehicle placebo (saline) for three weeks. This course was repeated twice more at four-monthly intervals. Concomitant treatment with analgesics or NSAIDs was allowed. The primary efficacy measure was the reduction in mean joint space width (JSW) of the medial compartment at 52 weeks. A total of 408 patients were randomised and 319 completed the one-year study (HA: n=160, placebo: n=159); 273 of the 319 were included in the primary analysis. Analysis of variance on these 273 patients did not show a statistically significant difference between the two treatment groups. However, there was a significant difference in response to treatment in terms of the baseline JSW (p=0.01), indicating that outcome of treatment may depend on-baseline JSW. Therefore, a subgroup analysis by baseline JSW was conducted. This compared patients with a JSW >4.6 mm with those with a JSW <4.6 mm. In those with radiologically milder disease at baseline and receiving HA, the JSN was significantly reduced compared with placebo (p=0.02). In patients with radiologically more severe disease there was no difference in JSN between the two treatments. Although, in this one-year study, no overall treatment effect was seen, those with radiologically milder disease at baseline had less progression of joint space narrowing when treated with HA.
Subject(s)
Adjuvants, Immunologic/therapeutic use , Hyaluronic Acid/therapeutic use , Osteoarthritis, Knee/drug therapy , Aged , Analysis of Variance , Double-Blind Method , Female , Humans , Male , Middle Aged , Osteoarthritis, Knee/diagnostic imaging , Radiography , Treatment OutcomeABSTRACT
OBJECTIVE: To compare the safety, tolerability and efficacy of the new oral microemulsion formulation of cyclosporin A (CyA; Sandimmun Neoral) and the original CyA formulation (Sandimmun), in patients with severe active rheumatoid arthritis (RA), over a 12-month period. METHODS: In this double-blind, multicentre study, patients were randomized to treatment with Neoral or Sandimmun, starting with 2.5 mg/kg/day, with dose adjustments after 4 weeks. Primary efficacy criteria included patients' assessment of disease activity. Pharmacokinetic and safety assessments were performed at regular intervals. RESULTS: Compared with Sandimmun, Neoral showed a consistent trend towards greater clinical efficacy from week 12 onwards, including a significant difference in patients' assessment of disease activity at the study end-points. A significantly lower increase in dose from baseline was observed with Neoral at week 24. Pharmacokinetic assessments at week 24 showed increased absorption and decreased variability with Neoral. No differences in safety were found between treatment groups. CONCLUSION: These observations indicate that Neoral is as safe and at least as effective as Sandimmun and have important implications for patient management given the increasing role for CyA in the treatment of severe, active RA.
Subject(s)
Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Cyclosporine/therapeutic use , Antirheumatic Agents/administration & dosage , Antirheumatic Agents/adverse effects , Arthritis, Rheumatoid/blood , Blood Pressure/drug effects , Chemistry, Pharmaceutical , Creatinine/blood , Cyclosporine/administration & dosage , Cyclosporine/adverse effects , Double-Blind Method , Emulsions , Humans , Joints/drug effects , Joints/pathology , Middle Aged , Patient Satisfaction , Prospective Studies , Safety , Severity of Illness Index , Treatment OutcomeABSTRACT
Consecutive new attendees at a rheumatology clinic were randomly allocated to one of three groups. All groups received routine care, but one received no other intervention, one an educational booklet on arthritis and one the booklet plus instruction from a health professional. Prior to intervention, all groups had similar knowledge. Nottingham Health Profile (NHP) and Health Assessment Questionnaire (HAQ) score. After 6 weeks, the knowledge score was significantly increased in both groups given the booklet, but not in the control group. The group instructed by a health professional showed no greater increase than the group given the booklet alone. Increased knowledge was not associated with improved clinical status and no group showed a significant change in NHP or HAQ scores. Nearly all patients said they found the booklet useful.
Subject(s)
Arthritis , Health Knowledge, Attitudes, Practice , Health Status Indicators , Pamphlets , Patient Education as Topic , Adult , Aged , Arthritis/complications , Chronic Disease , Female , Humans , Male , Middle Aged , Severity of Illness Index , Single-Blind MethodABSTRACT
OBJECTIVE: To compare the rate of radiographic progression in knee osteoarthritis (OA) comparing indomethacin with placebo and tiaprofenic acid with placebo. METHODS: Rate of radiographic progression of OA of the knees was studied in 812 patients randomized double blind parallel group study at 20 rheumatology clinics in the United Kingdom and analyzed sequentially. Patients received either indomethacin 25 mg three times daily, tiaprofenic acid 300 mg twice daily, or matched placebo. All had access to paracetamol as a rescue analgesic. Joint space narrowing was measured by a 6 point grading scale, using radiographs taken with a standardized technique at recruitment and annually thereafter. RESULTS: Three hundred and seventy six patients completed at least one year of study medication and therefore contributed evaluable results. More than twice as many patients showed deterioration in the indomethacin group as in the placebo group; of 170 available patients at the 3rd interim analysis, 40 of 85 receiving indomethacin had deteriorated compared to 19 of 85 receiving placebo, a statistically significant difference (p = 0.009). No statistically significant difference (p = 0.308) was found between tiaprofenic acid and placebo at the 7th interim analysis, the conclusion of the study. CONCLUSION: Indomethacin increased the rate of radiological deterioration of joint space in patients with OA of the knee; tiaprofenic acid did not.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Knee Joint , Osteoarthritis/drug therapy , Adult , Aged , Aged, 80 and over , Arthrography , Disease Progression , Double-Blind Method , Female , Humans , Indomethacin/therapeutic use , Knee Joint/diagnostic imaging , Longitudinal Studies , Male , Middle Aged , Osteoarthritis/diagnostic imaging , Placebos , Propionates/therapeutic use , Prospective StudiesABSTRACT
Contrary to standard teaching in magnetic resonance imaging (MRI), recent reports have documented calcification appearing as areas of increased signal intensity (SI) on T1-weighted images. Intervertebral disc calcification is a frequent finding on radiographs in chronic ankylosing spondylitis (AS). This study was performed to investigate the appearance of variable degrees of disc calcification in MRI. Thirty-six patients with AS of variable duration underwent an MRI scan of the thoraco-lumbar spine and the MR appearances, particularly of the discs, were compared with plain radiographs. Increased SI of the discs on T1-weighted images were found in 17 of 36 patients, occurring over a range of disc levels, and correlating with disc calcification on the radiographs in 78% of cases. This group tended to be older and have a longer duration of disease than those with normal appearing discs. Four different patterns of increased signal within the discs termed Type A (marginal), Type B (annular), Type C (central) and Type D (solid) were identified. In those with less than six discs involved Type A was the most common pattern. In those with more than six discs involved Type D was the most common pattern, suggesting a progression of disc involvement with more advanced disease. Although these findings will not affect the management of the disease, they do highlight the recently described phenomenon of calcification appearing as increased SI on T1-weighted images, likely to be related to the surface area of the calcium crystal. This should lead to the consideration of calcium in the differential diagnosis of increased SI on T1-weighted images. End-plate marrow changes were a relatively frequent finding in this study but did not correlate with the signal changes seen within the discs; in a number of cases they related to variable degrees of bony bridging.
Subject(s)
Intervertebral Disc/pathology , Spondylitis, Ankylosing/pathology , Thoracic Vertebrae/pathology , Adult , Calcinosis/pathology , Diagnosis, Differential , Female , Humans , Magnetic Resonance Imaging , Male , Middle AgedABSTRACT
Epidemiologic and clinical observations have suggested a relationship between generalised osteoarthritis (GOA) and hormonal and menopausal factors in women. We explored the hypothesis that postmenopausal women with GOA have altered sex hormone status compared with control women. We studied 112 women (mean age 64) with GOA. Controls were 151 women (mean age 54) from the general population without clinical evidence of hand or knee OA. All women were postmenopausal. Serum was assayed by RIA for testosterone, oestradiol, sex hormone binding globulin (SHBG), and dyhydroepiandrosterone sulphate (DHEAS). Because of the differences in mean ages, the results were compared according to equal age groups divided on the basis of tertiles. SHBG was lower in the GOA group, reaching significance in the middle group 53-61 years (58.0 vs 67.9 nmol/l p less than 0.05). Testosterone was slightly higher in GOA women aged under 53. No consistent differences were seen in the older age group or for the other sex steroids. These preliminary data suggest that middle-aged women with GOA have lower circulating SHBG levels. This implies that higher circulating free oestrogens and androgens are present suggesting a role in the aetiopathogenesis of GOA.
Subject(s)
Dehydroepiandrosterone/analogs & derivatives , Estradiol/blood , Osteoarthritis/blood , Sex Hormone-Binding Globulin/analysis , Testosterone/blood , Adult , Aged , Aged, 80 and over , Dehydroepiandrosterone/blood , Dehydroepiandrosterone Sulfate , Female , Humans , Middle Aged , Osteoarthritis/etiology , RadioimmunoassayABSTRACT
An in-vitro study has been made of the response of aged human articular cartilage to the catabolic agent retinol. Weight bearing cartilage from the femoral condyle degrades and releases proteoglycan with an associated reduction of sulphate incorporation. Similar cartilage from the femoral head responds to the retinol with an inhibition of sulphate incorporation but no degradation or loss of proteoglycan. Extraction of the proteoglycan from the femoral head samples failed to demonstrate any evidence of breakdown.
Subject(s)
Cartilage, Articular/drug effects , Vitamin A/pharmacology , Adult , Aged , Animals , Cartilage, Articular/metabolism , Cattle , Femur Head , Glycosaminoglycans/metabolism , Humans , Organ Culture Techniques , Proteoglycans/metabolism , Sulfates/metabolismABSTRACT
A study has been made with porcine tissues in organ culture of the effect of vascular tissue on articular cartilage. Isolated explants of cartilage were maintained alive for 14 days without breakdown of the matrix. Contact with vascular tissue produced extensive loss of proteoglycan and collagen with fibroblastic transformation of the chondrocytes. The breakdown was partly due to a direct effect on the matrix and partly to activation of catabolic processes in the chondrocytes. Vascular tissue produced exactly the same loss of matrix as synovial tissue.
Subject(s)
Cartilage, Articular/drug effects , Tissue Extracts/pharmacology , Animals , Arteries , Cartilage, Articular/cytology , Collagen/metabolism , Connective Tissue , Organ Culture Techniques , Proteoglycans/metabolism , Swine , Synovial Membrane , Time FactorsABSTRACT
Demineralization of cartilage with alcoholic EDTA provides cartilage staining that is no better, as measured by scanning microdensitometry, than that of adequately fixed specimens demineralized with aqueous EDTA. Aqueous EDTA is a faster demineralizing agent than alcoholic EDTA. Certain fixatives can preserve maximal proteoglycan staining in articular cartilage even with subsequent rapid demineralization in formate buffer at pH 3.3. Although alcoholic formalin fixation provided optimum quantitative cartilage staining, cetylpyridinium chloride (CPC) in aqueous buffered formalin improved cellular detail, but CPC partially suppressed matrix staining.
Subject(s)
Cartilage/cytology , Animals , Densitometry/methods , Edetic Acid , Ethanol , Hydrogen-Ion Concentration , Mast Cells/cytology , Rats , Staining and LabelingABSTRACT
Safranin O in the orthochromatic form stains articular cartilage proteoglycan quantitatively in histological sections of demineralized cartilage. This was shown by scanning microdensitometry of stained sections of undemineralized and demineralized articular cartilage and by biochemical analysis of 35S labelled cartilage subjected to demineralization. In contrast, Alcian Blue staining is affected by unknown factors other than simply the amount of proteoglycan present. Alcoholic formalin fixes articular cartilage proteoglycan more successfully than formol Zenker for subsequent rapid demineralization. Alcoholic formalin does not preserve cellular appearance as well as formol Zenker. Staining of articular cartilage with PAS appears unaffected by demineralization.
Subject(s)
Cartilage, Articular/cytology , Proteoglycans/analysis , Aged , Cartilage, Articular/pathology , Densitometry/methods , Femoral Neck Fractures/pathology , Humans , Phenazines , Staining and LabelingABSTRACT
Explants of pig articular cartilage were grown in organ culture in the presence of synovial tissue; controls consisted of paired explants that were cultivated in isolation. To find whether the synovial tissue affected synthesis of sulfated proteoglycan by the cartilage, 35SO4 was added to the medium and its incorporation into the cartilage examined by both biochemical assay and autoradiography. The synovial tissue severely inhibited the uptake of 35SO4, but if the synovium was removed after 8 days cultivation and the cartilage was grown in isolation for a further 4 days, incorporation of 35SO4 equalled and sometimes surpassed that of controls which had been grown without synovium continuously for 12 days. Synovium did not prevent the formation of new cartilage on the cut surfaces of the explants, but it reduced the incidence of newly formed cartilage.
Subject(s)
Cartilage, Articular/metabolism , Proteoglycans/biosynthesis , Synovial Membrane , Animals , Autoradiography , Organ Culture Techniques , SwineABSTRACT
The chondrocytes of pure articular cartilage from young pigs display collagenolytic activity when the cartilage is cultivated by an organ culture method in medium containing 5--10 IU retinol/ml. Breakdown of collagen occurs in all regions of the cartilage; in the thicker explants it is greatest and most frequent in those that contain the deepest zone composed of proliferating and hypertrophic chondrocytes; it is also very drastic in thin explants composed mainly of superficial fibro-cartilage.
Subject(s)
Cartilage, Articular/cytology , Collagen/metabolism , Animals , Cartilage, Articular/drug effects , Cartilage, Articular/metabolism , Cell Division/drug effects , Cell Movement/drug effects , Hydroxyproline/metabolism , Metacarpus , Organ Culture Techniques , Proteoglycans/metabolism , Swine , Vitamin A/pharmacologyABSTRACT
The effect of hyperoxia on pig articular tissue has been studied in organ culture. Hyperoxia (55% O2) causes an increased release of hydroxyproline and collagenolytic activity from synovial tissue as compared with control explants in 20% O2, but neither 55% nor 95% O2 has any effect on the breakdown of isolated cartilage during 10 days in culture. When synovium and cartilage are cultured in contact, the breakdown of cartilage collagen is greater in the hyperoxic (55% O2) group than in the controls (20% O2), but the breakdown of proteoglycan is not increased. The enhanced collagenolytic action is due to an increase in the direct effect of the synovial tissue on the cartilage matrix. In 20% O2 the synovium causes the chondrocytes to degrade the cartilage matrix, but this effect is inhibited by 55% O2.
Subject(s)
Cartilage, Articular/metabolism , Oxygen/pharmacology , Synovial Membrane/metabolism , Animals , Cartilage, Articular/drug effects , Collagen/metabolism , Culture Techniques , Proteoglycans/metabolism , Swine , Synovial Membrane/drug effectsABSTRACT
UNLABELLED: Living (pig) cartilage in contact with synovium lost both proteoglycan and collagen and sometimes became reduced to a mass of fibroblast-like chondrocytes without matrix; dead cartilage lost proteoglycan but less collagen. Similar changes appeared in living cartilage grown at a distance from the synovium but in the same dish; dead cartilage was unaffected. CONCLUSION: the synovium has a) a direct, presumably enzymatic action on cartilage matrix and b) an indirect effect mediated through the chondrocytes.