Symptomatic efficacy of avocado/soybean unsaponifiables in the treatment of osteoarthritis of the knee and hip: a prospective, randomized, double-blind, placebo-controlled, multicenter clinical trial with a six-month treatment period and a two-month followup demonstrating a persistent effect.

OBJECTIVE: To assess the efficacy and safety of avocado/soybean unsaponifiables (ASU) in the treatment of patients with symptomatic osteoarthritis (OA) of the knee or hip, as well as the potential residual effects of ASU after stopping treatment, to determine whether ASU might be a symptomatic slow-acting drug for the treatment of OA. METHODS: One hundred sixty-four patients with regular, painful, primary OA of the knee (n = 114) or hip (n = 50) entered a prospective, randomized, double-blind, placebo-controlled, parallel-group, multicenter trial with a 6-month treatment period and a 2-month posttreatment followup. A 15-day washout period for nonsteroidal antiinflammatory drugs (NSAIDs) preceded the study. Efficacy was judged according to 1) Lequesne's functional index (LFI) and 2) pain on Huskisson's visual analog scale (VAS; 100-mm scale), intake of NSAIDs/analgesics, and overall disability score (by 100-mm VAS). RESULTS: Eighty-five patients received ASU; 79 received placebo. One hundred forty-four patients were evaluable at month 6 (75 taking ASU; 69 taking placebo). The mean +/- SEM LFI score decreased from 9.7 +/- 0.3 to 6.8 +/- 0.4 in the ASU group and from 9.4 +/- 0.3 to 8.9 +/- 0.4 in the placebo group (P < 0.001 for intergroup difference at month 6). Pain decreased from 56.1 +/- 1.6 mm to 35.3 +/- 2.3 in the ASU group and from 56.1 +/- 1.8 mm to 45.7 +/- 2.6 in the placebo group (P = 0.003 at month 6). NSAID consumption was slightly lower in the ASU group. Fewer patients in the ASU group required NSAIDs (48%, versus 63% in the placebo group; P = 0.054). The success rate was 39% in the ASU group and 18% in the placebo group. Overall functional disability was significantly reduced in the ASU group. Improvement appeared more marked in patients with hip OA. A residual effect was observed at month 8. Tolerance was good to excellent for most patients. CONCLUSION: ASU treatment showed significant symptomatic efficacy over placebo in the treatment of OA, acting from month 2 and showing a persistent effect after the end of treatment.

How do French rheumatologists treat early rheumatoid arthritis?

Although factors that appear to predict long-term outcomes of rheumatoid arthritis have been identified, there is no consensus about the treatment early in the disease. To determine how French office- and hospital-based rheumatologists treat early rheumatoid arthritis, we created three clinical vignettes corresponding to different levels of severity of early rheumatoid arthritis (less than six months' disease duration). Cases 1 and 2 were relatively young patients (35 and 50 years), and Case 1 had numerous poor prognosis factors. Case 3 was 80 years of age. Rheumatologists were asked to indicate which medications they would use at presentation and after one year of a favorable or unfavorable course. The study was conducted by questionnaire (response rate, 58%). Of the 185 rheumatologists who completed the questionnaire, 81% were male and 19% female; mean age was 42 +/- 8 years. In Cases 1 and 2, nonsteroidal antiinflammatory drugs were given by 99% of respondents; second-line drugs were prescribed at presentation by 93% of respondents in Case 1 and 86% in Case 2, and methotrexate was more likely to be used in the presence of poor prognosis factors (23% in case 1 and 7% in Case 2). In the event of an unfavorable course after one year, a larger proportion of rheumatologists prescribed glucocorticoid therapy (65% in Case 1 and 20% in Case 2), and there was a shift from "conventional" to "modern" second-line drugs, with more widespread use of methotrexate (65% in case 1 and 18% in case 2). In the 80-year-old patient, glucocorticoid therapy was used more often than nonsteroidal antiinflammatory drugs and second-line drugs (gold salts, hydroxychloroquine, sulfasalazine) were prescribed by 40% of rheumatologists at presentation and by 67% after one year of an unfavorable course; in the latter situation, methotrexate was selected in 24% of cases. In contrast to conventional recommendations, many French office- or hospital-based rheumatologists use second-line drugs very early and base their choice of medications on the estimated risk of severe disease and on the age of the patient.

Intravenous aminohydroxypropylidene bisphosphonate does not modify 99mTc-hydroxymethylene bisphosphonate bone scintigraphy. A prospective study.

Bisphosphonates have marked affinity for bone that makes them useful in both the treatment and imaging of bone lesions. Bone scintigraphy is very sensitive for the detection of bone metastases, which can cause life-threatening hypercalcemia requiring emergency treatment. This prospective study was done to determine whether intravenous administration of pamidronate, a second-generation bisphosphonate used to treat hypercalcemia, affects the affinity of the radiopharmaceutical 99m technetium-labeled hydroxymethylene bisphosphonate (99mTc-HMDP) for bone and bone lesions. Six patients with metastatic bone disease and five with Paget's disease of bone had a 99mTc-HMDP bone scan before and two to four days after an intravenous infusion of pamidronate. The number and activity of metastatic bone lesions were unchanged after pamidronate, even when the second bone scan was done only 24 hours after the pamidronate infusion. Our data suggest that emergency treatment of life-threatening hypercalcemia by intravenous pamidronate does not decrease the sensitivity of subsequent bone scanning done to detect bone metastases.

Severe lupus with infectious thyroiditis and lethal cardiomyopathy.

Clinical cardiomyopathy is an uncommon complication of systemic lupus erythematosus (SLE) and intracavitary thrombosis is rare. We describe a patient with active SLE who developed rapidly progressive cardiomyopathy, the fatal course of which was complicated by an intracavitary thrombus. Repeat cardiac echography studies and the endomyocardial biopsy proved to be helpful in diagnosing the lupus myocarditis and aided the regulation of therapy. Furthermore, the patient presented an acute suppurative thyroiditis never before described, to our knowledge, in SLE.

[Study of femoro-tibial cartilage diseases with MRI]. / Exploration des chondropathies fémoro-tibiales en IRM.

Magnetic resonance imaging provides excellent tissue contrast resolution and can therefore be used to visualize joint cartilage. The goal of this study was to evaluate the value of magnetic resonance imaging for the diagnosis of femorotibial cartilage lesions. Spin-echo magnetic resonance imaging was performed in 37 patients. As compared with arthroscopy, the accuracy, sensitivity, and specificity of magnetic resonance imaging were 72.5%, 47%, and 95.5%, respectively. Only advanced cartilage lesions with exposure of subchondral bone were clearly seen on magnetic resonance sections. Limiting factors included insufficient spatial resolution and the chemical shift phenomenon. Spin-echo sequences used in everyday practice are not appropriate for detecting small cartilage lesions. Controlled studies are needed to determine whether gradient echo sequences are more satisfactory.

Intraosseous fat necrosis and metaphyseal osteonecrosis in a patient with chronic pancreatitis: MR imaging and CT scanning.

Necrosis of fatty bone marrow is an unusual complication of several pancreatic disorders. We describe a patient with polyarthritis, sterile subcutaneous abscess and osteolysis arising during the course of alcoholic chronic pancreatitis. MR images of one knee showed multiple foci of abnormal signal intensity within the marrow of the distal femur and proximal tibia, consistent with intraosseous fat necrosis. CT scans showed significant changes in the cancellous bone in these areas compatible with metaphyseal osteonecrosis.

[Effect of diacerhein (ART 50) on the matrix synthesis and collagenase secretion by cultured joint chondrocytes in rabbits]. / Effet de la diacerhéine (ART 50) sur la synthèse de la matrice et la sécrétion de collagénase par des chondrocytes articulaires de lapin en culture.

Cultured rabbit joint chondrocytes were exposed to diacerhein (DAR : ART 50, Negma, 10(-6) to 10(-4) M), which has proved effective and safe when given for two months for the treatment of osteoarthritis. Experiments were performed with and without 500 pg/ml human recombinant interleukin-1 to determine whether diacerhein antagonizes the effects of this monokine. Glycosaminoglycan production was measured by 35S-sulfate incorporation followed by cetylpyridinium precipitation, collagen production by 3H-proline labeling and bacterial collagenase digestion, and collagenase production by determination of the amount of 3H-collagen that underwent degradation. Incubation of chondrocytes with diacerhein for 24 hours was not associated with substantial changes in glycosaminoglycan or collagen production but substantially antagonized interleukin-1-mediated enhancement of collagenase production. With longer incubation periods (6 days) with the 10(-6) M concentration of diacerhein, production of glycosaminoglycans and collagen increased. Incubation with both diacerhein and interleukin-1 for six days partly antagonized the cytokine's inhibitory effect on glycosaminoglycan and collagen production. During these experiments, the medium's ability to break down collagen was consistently reduced by diacerhein, even in the presence of interleukin-1. These data demonstrate that diacerhein can reduce or even abolish interleukin-1-mediated enhancement of collagenase production by joint chondrocytes. This effect may lead to less erosion of cartilage in degenerative joint diseases.

Rabbit articular chondrocytes (RAC) express distinct transforming growth factor-beta receptor phenotypes as a function of cell cycle phases.

We previously showed that TGF-beta 1 exerted a bifunctional effect on the proliferation of cultured rabbit articular cells (RAC), depending on the serum level present in the medium. Slowly proliferating cells (2% fetal calf serum, FCS) were growth-inhibited by TGF-beta 1, whereas actively dividing cells (10% FCS) exhibited a transient growth increase in response to the factor. Here we demonstrate that both of these cycling populations of RAC display two distinct systems of high-affinity binding sites for TGF-beta 1. However, a significant increase (60%) in the number of the highest affinity receptors was observed in the 2% FCS-treated cells compared to those cultured in 10% FCS (in 2% FCS: Kd1 = 295 +/- 78 pM, 1899 +/- 99 sites/cell; Kd2 = 1106 +/- 61 pM, 9935 +/- 940 sites/cell; in 10% FCS:Kd1 = 287 +/- 10 pM, 1054 +/- 65 sites/cell; Kd2 = 1128 +/- 101 pM, 8257 +/- 61 sites/cell). This finding was correlated with the greater number of G0/G1 cells in the population cultured in 2% FCS (70%) compared to that exposed to 10% FCS (55%). The data was further confirmed using cells synchronized in late G1/early S phase (> 80% of S phase). This cell population exhibited a single class of TGF-beta 1 high-affinity binding sites (Kd = 1140 +/- 85 pM, 6836 +/- 1787 sites/cell). In contrast, cells synchronized in G0/G1 (> 80% of cells in G0/G1) expressed one binding system of Kd = 402 +/- 59 pM (940 +/- 56 sites/cell). These results clearly demonstrate that cultured RAC express different TGF-beta 1 receptor systems as a function of the cell cycle.

Interleukin-1 and naproxen down-regulate the expression of IL-1 receptors in cultured human rheumatoid synovial cells (HRSC).

Using affinity binding of [125I]-IL-1 alpha and Scatchard analysis, we demonstrate here that exposure of cultured synovial cells (HRSC) to NPX (10(-4) M) for 96 h decreased the binding of IL-1 by 20 to 35%. This effect results from a down-regulation of the IL-1 receptors without change in the apparent binding affinity (kD: 770 pM). Pretreatment of cultures with IL-1 alpha (500 pg/ml) reduced the total binding of [125I]-IL-1 alpha on HRSC by 65%, indicating that IL-1 decreases the expression of its own receptors.

Transforming growth factor beta exerts opposite effects from interleukin-1 beta on cultured rabbit articular chondrocytes through reduction of interleukin-1 receptor expression.

OBJECTIVE: The aim of the study was to determine whether transforming growth factor beta (TGF beta) modulates the effects and the receptor expression of interleukin-1 (IL-1) in rabbit articular chondrocytes (RAC). METHODS: Collagen, glycosaminoglycan, and collagenase production, together with 125I-labeled IL-1 binding, were analyzed in RAC cultures. RESULTS: TGF beta reduced both IL-1 effects on matrix metabolism and IL-1 receptor expression. CONCLUSION: TGF beta acts as an antagonist of the effects of IL-1 through down-regulation of its receptor expression.

Transforming growth factor-beta 1 (TGF-beta 1) up-regulation of collagen type II in primary cultures of rabbit articular chondrocytes (RAC) involves increased mRNA levels without affecting mRNA stability and procollagen processing.

The effect of transforming growth factor-beta 1 (TGF-beta 1) on collagen biosynthesis was investigated in confluent primary monolayer cultures of rabbit articular chondrocytes (RAC). Exposure to TGF-beta (0.1, 1, and 10 ng/ml) in serum-free medium caused a dose- and time-dependent stimulation of collagen biosynthesis associated with an increase of steady-state levels of procollagen type II mRNA. Elevation of the mRNA steady-state did not result from a stabilization of the transcript, as shown by measure of the mRNA half-life. Electrophoresis (SDS-PAGE) showed that TGF-beta stimulates the synthesis of most collagen isotypes, including type II, without qualitative change in their distribution. Moreover, pulse-chase experiments revealed that TGF-beta did not affect the processing rate of type II procollagen. TGF-beta slightly stimulated the production of prostaglandin E2 (PGE2), which could in turn exert an inhibition on collagen synthesis. However, addition of indomethacin to block prostaglandin synthesis did not further enhance the TGF-beta-induced stimulation of collagen production, suggesting that this mediator was not implicated in the effect. Moreover, TGF-beta increased steady-state levels of procollagen type II, I, and III mRNAs even in the presence of indomethacin. Despite these increased mRNA levels, only the production of type II collagen was significantly augmented, suggesting that type I procollagen mRNA was not fully translated. In addition, the TGF-beta-induced stimulation of collagen synthesis was observed whenever ascorbic acid is added or not in the culture medium. In conclusion, TGF-beta, which is present in great amount in bone and cartilage, can increase the collagen production of cultured RAC and might therefore play a role in the early events of cartilage repair, such as those observed in osteoarthritis.

[Polyarthritis revealing hairy cell leukemia]. / Polyarthrite révélatrice d'une leucémie à tricholeucocytes.

A female patient simultaneously developed hematologic evidence of hairy cell leukemia and marked but short-lived inflammatory involvement of a number of joints. Both these groups of symptoms resolved simultaneously and rapidly under alpha-2 interferon therapy. This course suggests that the arthritis was a rheumatologic manifestation of the hematologic disease. The concomitant occurrence in this patient of arthritis, splenomegaly and leukopenia was suggestive of Felty syndrome: these two conditions need to be differentiated.

[Chondroitin sulfate in the treatment of gonarthrosis and coxarthrosis. 5-months result of a multicenter double-blind controlled prospective study using placebo]. / Le chondroïtine sulfate dans le traitement de la gonarthrose et de la coxarthrose. Résultats à 5 mois, d'une étude prospective multicentrique, contrôlée, en double aveugle, versus placebo.

One hundred twenty patients with osteoarthritis of the knees and hips were entered into a randomized, placebo-controlled, double-blind trial designed to evaluate the effectiveness of chondroitin sulfate (Structum). The three-month treatment phase was followed by a two-month treatment-free phase to allow evaluation of carry-over effects. The main endpoint was use of nonsteroidal antiinflammatory drugs (expressed as mg of diclofenac equivalent). At completion of the three-month treatment phase, patients taking chondroitin sulfate (4 capsules/day) were using significantly less NSAIDs; this decrease persisted throughout the two-month treatment-free follow-up phase. The other parameters studied including visual analog scale assessment of pain, the Lequesne pain-function index, and overall patient and physician assessments, all showed a similar significant tendency. Tolerance was outstanding and no patients required premature withdrawal. These findings indicate that chondroitin sulfate is useful for the treatment of osteoarthritis, both as an agent slowly effective against symptoms and to reduce the need for NSAIDs. The carry-over effect of the drug suggests that intermittent administration may be appropriate.

Effect of transforming growth factor-beta 1 (TGF-beta 1) on matrix synthesis by monolayer cultures of rabbit articular chondrocytes during the dedifferentiation process.

Since transforming growth factor-beta (TGF-beta) has been shown earlier to induce the chondrocyte phenotype in embryonic rat mesenchymal cells with production of cartilage-specific type II collagen and proteoglycans, it was of interest to determine whether the factor could also influence the differentiation state of articular chondrocytes maintained in monolayer culture. Using rabbit articular chondrocytes (RAC) in primary and passaged cultures, we demonstrate that the loss of the phenotype accompanying the subculture was not significantly influenced by the presence of TGF-beta. The factor exerted an inhibitory effect on collagen synthesis in a 6-day exposure of primary cultures whereas it stimulated that production throughout the subsequent passages. Steady-state levels of mRNAs encoding type I, II, and III procollagens were correlated with the amounts of cognate proteins produced, suggesting that both inhibition and stimulation were exerted at a transcriptional level. The pattern of proteoglycans produced in primary culture, essentially chondroitin sulfate-containing molecules, was altered by the subculture-induced RAC dedifferentiation, as shown by decrease in chondroitin sulfate formation and progressive appearance of hyaluronic acid. Contrasting with its effect on collagen synthesis, TGF-beta did not significantly change the proteoglycan production of RAC in our conditions whenever it was added at the beginning of the primary cultures or in the subsequent passages. Altogether, our data indicate that the effect of TGF-beta on RAC collagen synthesis depends on whether they are fully differentiated. Moreover, the data show that the factor does not prevent the loss of RAC phenotype but rather contributes to the dedifferentiation process since it exerts differential effects on the major components of extracellular matrix, collagen, and proteoglycans.

TGF-beta-induced G2/M delay in proliferating rabbit articular chondrocytes is associated with an enhancement of replication rate and a cAMP decrease: possible involvement of pertussis toxin-sensitive pathway.

This study was undertaken to gain more insight into the mechanism whereby TGF-beta influences the cell cycle progression of cultured rabbit articular chondrocytes. Using proliferating chondrocytes in fetal calf serum-containing medium, we have previously shown that TGF-beta induced a recruitment of cells at the end of the S phase (G2/M) observed 24 h after addition. The delayed cells may then be released, producing a proliferative effect at 48 h, provided a substantial amount of FCS (10%) is present in the medium. Otherwise, in low level of serum (2% FCS, for example), only inhibition of cell proliferation is observed. In chondrocytes synchronized in S phase by a thymidine block, we investigated here the time-course incorporation of [3H]-thymidine into DNA, the cell cycle traverse by flow cytofluorometric study of DNA content, the expression of PCNA (Proliferating Cell Nuclear Antigen), and cAMP levels. The data demonstrate that TGF-beta provoked a decrease of cAMP content (0.5-1 h) followed by an enhancement of the DNA synthesis rate (4 h) which was detectable through cytofluorometric analysis and [3H]-thymidine labeling and correlated with the PCNA expression. In contrast, addition of cAMP analogues to the cultures resulted in an inhibition of replication rate. We also showed that pertussis toxin produced a decrease of the DNA synthesis rate, in a transient manner and only in the presence of TGF-beta. All these results suggest that TGF-beta may accelerate the replication process of cyclized chondrocytes, making then accumulate at the G2/M boundary, via a mechanism that could involve the adenylate cyclase activity and a Gi-protein. The factor might be responsible for producing a pool of cells having already replicated their DNA and therefore capable of re-entering the cell cycle without delay. This cell population could serve as a tissue reserve able to induce a mitosis wave when necessary--for example, in the repair of tissue damage.

Induction of interleukin-1 beta production in human dermal fibroblasts by interleukin-1 alpha and tumor necrosis factor-alpha. Involvement of protein kinase-dependent and adenylate cyclase-dependent regulatory pathways.

It has previously been demonstrated that interleukin-1 (IL-1) is expressed in a variety of fibroblast cell lines. In this study, we investigated the mechanisms involved in the regulation of IL-1 beta production by cultured human dermal fibroblasts. We have shown that IL-1 beta is constitutively expressed as a cell-associated form, with no soluble form detectable in control cell or in stimulated cell supernatants. IL-1 alpha and tumor necrosis factor-alpha (TNF-alpha) exerted a dose-dependent stimulation on the production of the cell-associated IL-1 beta, as estimated using a specific enzyme linked immunosorbent assay (ELISA). As expected, this effect was accompanied by a huge release of prostaglandin E2 (PGE2) and a transient rise in intracellular cyclic AMP. Furthermore, IL-1 beta production was elevated to a lesser extent by the addition of increasing concentrations of the protein kinase C activator phorbol myristate acetate or by low concentration (0.001 microgram/ml) of PGE2. In contrast, higher concentrations (0.1 and 1 micrograms/ml) of PGE2, as well as exogenous dibutyryl-cyclic AMP, were clearly inhibitory. H7, an inhibitor of protein kinases also reduced the stimulatory effect of IL-1 alpha and TNF-alpha. Together with the results obtained with phorbol myristate acetate, these data suggest that protein kinase C may play a role in the upregulation of IL-1 beta expression in normal skin fibroblasts. The addition of indomethacin not only suppressed prostaglandin synthesis, but also dramatically reduced cyclic AMP formation, probably because the PGE2-induced stimulation of adenylate cyclase was abolished. This resulted in a strong potentiation of the stimulatory effect of IL-1 alpha and TNF-alpha, supporting the role of both the cyclooxygenase and adenylate cyclase pathways in the endogenous downregulation of IL-1 beta induction by the two cytokines studied.

Characterization of proteoglycans synthesized by rabbit articular chondrocytes in response to transforming growth factor-beta (TGF-beta).

The effect of transforming growth factor-beta (TGF-beta, 1 ng/ml) on proteoglycan synthesis by rabbit articular chondrocytes in culture was studied in the presence of fetal bovine serum. Exposure of confluent cells for 24 h to the factor resulted in a marked increase of 35S-labeled sulfate incorporation in the newly synthesized proteoglycans (PG), as estimated by glycosaminoglycan (GAG) radioactivity (+58%). The onset was observed 6 h after addition of the factor but was significant after 12 h. TGF-beta also enhanced the uptake of [35S]sulfate by chondrocytes, but had no effect on the release of PG by these cells. The effect of TGF-beta on the distribution of PG between the medium and the cell layer was shown to be dependent on the serum concentration in the medium: the relative proportion of cell-layer associated GAG of TGF-beta-treated cells decreased with increasing concentration of fetal bovine serum. The proportion of aggregated PG, the hydrodynamic size of PG monomers and GAG chains were not modified by TGF-beta, but the relative distribution of disaccharides 6- and 4-sulfate in GAG chains was altered by the factor: the proportion of chondroitin 6-sulfate (C6S) was decreased while that of chondroitin 4-sulfate (C4S) was augmented in presence of TGF-beta, leading to a decrease of the ratio C6S/C4S (-11 to -22%, P less than 0.01). The present study indicates that TGF-beta promotes the synthesis of a modified extracellular matrix in cultured articular chondrocytes. This mechanism could be relevant to some aspects of cartilage repair in osteoarticular diseases.