The definition and clinical features of the mutilans type of rheumatoid arthritis.

Abstract The mutilans type of rheumatoid arthritis (RA) is refractory to several treatments and involves many types of surgical application. It is difficult to prevent its progress, and it has a poor functional prognosis. However, the definition is not always distinct. In this report, I attempt to clarify the clinical features of the mutilans type of RA and establish an accurate definition of the disease. Previous definitions have been divided into three groups: (1) the mutilans group (Mu-G), which has more than three joints showing severe resorptive bone destruction and joint instability; (2) the suspected mutilans group (sMu-G) which has one to two joints with joint instability or showing no instability but with highly resorptive bone destruction; (3) the Larsen V group (LV-G), which has radiological findings indicating Larsen grade V disease. Patients suffering from rheumatoid arthritis for over 10 years and who do not fall into any of the above groups are referred to as the control group. Among 337 patients who suffered from RA for more than 10 years, 58 were classified as being in the mutilans group, 59 in the suspected Mu-G, 47 in the LV-G, and 173 in the control group. The mutilans group had distinctive features which were different from those of the other groups, which had a radiological finding of Larsen grade V disease or severe resorptive bone destruction without instability. From these data, the definition of the mutilans type of RA should be specified as the Mu-G. Thus, the Mu-G shows a distinctive clinical picture which is unlike that in the other groups. It is important to define the mutilans type of RA clearly because it has a poor prognosis. Early identification will help in the establishment of a treatment plan.

Hyaluronan, cartilage destruction and hydrarthrosis in traumatic arthritis.

The concentrations of hyaluronan (HA) and chondroitin sulfate (CS) in synovial fluids from patients with traumatic arthritis (TA) with and without hydrarthrosis were measured. The CS in synovial fluids was determined as a marker of cartilage destruction by high performance liquid chromotography. The concentration of HA in synovial fluids was lower in patients with hydrarthrosis than in healthy volunteers and patients with TA without hydrarthrosis, whereas the total amounts of HA and CS and the concentration of CS were higher in patients with hydrarthrosis. To investigate the relation between hydrarthrosis and production of HA in synovial tissues, TA synovial tissue biopsies were stained for HA with biotinylated HA binding region. The intensity of HA staining was higher in specimens from patients with hydrarthrosis than in normal and TA without hydrarthrosis specimens. Thus, there may be a correlation between hyperproduction of HA, cartilage destruction and increase in fluid volume in TA.

[Experimental knee pain model in rats and analgesic effect of sodium hyaluronate (SPH)].

Using the model of knee pain reaction induced by intra-articular injection of endogenous pain substances, especially bradykinin (BK) in rats, the mechanism of the analgesic effect of sodium hyaluronate (SPH) was investigated. The simultaneous administration of prostaglandin E2 with BK or hyaluronidase digestion of endogenous hyaluronic acid (HA) in our experiments brought remarkable hyperalgesia on BK-induced knee pain. These results suggest that higher sensitivity to the pain reaction is induced in a diseased joint (higher prostaglandin content, lower concentration and molecular size of HA in synovial fluid) than in a normal one. SPH definitely decreased BK-induced pain, and its analgesic effect was observed for a longer period, depending on its dose in pre-treatment and the degree of its distribution in synovial tissues. As the analgesic effect of SPH was observed in the hyaluronidase-treated joint as well, it is suggested that the increasing viscosity of synovial fluid caused by increasing HA concentration can decrease the pain even without normalizing molecular size of HA in the joint. HA oligomer and other compounds with similar viscosity or with similar polyanionic character as SPH showed no analgesic effect. From these results, it seems that the characteristic steric configurations of higher molecular HA are needed for the manifestation of the analgesic effect. SPH seems to show its analgesic effect by covering pain receptors in synovial tissues and holding endogenous pain substances in its molecule.

Therapeutic effect of intra-articular injection of high molecular weight hyaluronic acid on osteoarthritis of the knee.

Intra-articular injections of high molecular hyaluronic acid (1% solution) were given at 1- or 2-week intervals to 43 patients with osteoarthritis of the knee. Of the 45 treated knees, 32 (71%) responded favorably. This therapy was effective if the osteoarthritis was of a grade less than moderate; it was not effective in cases with considerable effusion or in those with gross architectural changes. No serious side effects were encountered. We suggest that the beneficial effects of hyaluronic acid may be attributable to improved lubrication of the affected joint, to normalization of synovial fluid production by the action of hyaluronic acid on synovial tissue, and/or to the improvement of the intra-articular environment by the contribution of hyaluronic acid to the rebuilding of the barrier that protects the synovial membrane and articular surface.

Secondary reconstruction of the lateral ligaments of the ankle.

Due to the increased number of participants in athletic activities and because such people continue to participate for many years, secondary reconstructions of the lateral ligaments of the ankle are performed with greater frequency. Physical examination and review of the patient's history are of more value than stress X-rays of the tibiotalar joint in determining whether or not secondary reconstructive surgery is advisable. The modified Chrisman-Snook procedure presented reconstructs the anterior talofibular ligament and the calcaneofibular ligament, thereby reducing excessive subtalar motion. The results are predictable and appear to be lasting.

Lipid composition of adipose tissue from "membranous lipodystrophy".

The lipid composition of the adipose tissue from the bone marrow and that of the subcutaneous depot fat of four patients of membranous lipodystrophy were investigated. It was found that the lipid composition of the samples from the cases of membranous lipodystrophy was almost similar to that in controls. Also discussions were made on mechanism related to the accumulation of abnormal depot fat.

Urinary keratan sulfate of Morquio's disease.

To elucidate precise chemical nature of urinary keratan sulfate (KS) of Morquio's disease, crude glycosaminoglycans (GAG) were separated from 24-hr urines of 3 patients with Morquio's disease and from pooled urine of a healthy boy, using cetylpyridinium chloride. KS fractions were then separated from the crude GAG after removal of other GAG and acidic glycopeptide by successive digestion with testicular hyaluronidase and chondroitinase ABC, and by nitrous acid treatment, followed by Dowex 1 column chromatography. The distribution of KS in several fractions (1.5 M Fr-5.0 M Fr) obtained by Dowex 1 column chromatography suggested polydispersity of urinary KS. The relative amounts (micrograms/24-hr urine/kg body weight) of the KS fractions excreted into Morquio's urine were 52-63 times as much as that excreted into normal urine. The KS fractions contained galactose, glucosamine and sulfate as the major constituents, together with fairly amounts of galactosamine and sialic acid, and small amounts of mannose, L-fucose and glucose. The KS fractions resembled sulfated glycopeptide with respect to the sugar composition. The contents of sulfate and sialic acid in each KS fraction from Morquio's urine were higher than those in the corresponding one from normal urine, whereas opposite was the case for the ratio of glucosamine to galactosamine. The sulfate contents in the KS fractions from Morquio's urine indicated that the patient excreted over-sulfated KS into urine. The chemical compositions of the KS fractions from Morquio's urine suggest that the sulfatase specific for 6-sulfate linked to sugars with the galactose configuration may act in a early step of the catabolism of oversulfated KS in the normal tissues.

Reducing terminals and molecular weights of glycosaminoglycans in normal human urine.

To elucidate the reducing terminals and the molecular weights of urinary glycosaminoglycans (GAG), the reducing power of the GAG in the acidic subfractions obtained in a previous paper (Endo et al. 1980a) was determined by the methods of Park and Johnson and of Milner and Avigard. Number-average molecular weight was calculated from the value obtained by the Park-Johnson method according to the equation of Partridge et al. The results suggested that xylose and hexuronic acid were present at the reducing terminals of the carbohydrate chains of urinary GAG, and also that 10-65% of the reducing terminals were occupied by the hexuronic acid residues. This finding strongly suggested the exertion of endoglucuronidase activity in the catabolism of the tissue GAG, specifically of chondroitin sulfate isomers. On the other hand, number-average molecular weights of urinary GAG in the subfractions ranged from 5,600 to 15,500, although most of them were within the range between 6,000 and 7,500.

Terminal monosaccharides of carbohydrate chains of glycosaminoglycans in normal human urine.

To elucidate the mode of the exertion of glycosidase activities in the catabolism of the tissue glycosaminoglycans (GAG), the terminal monosaccharides of the carbohydrate chains of urinary GAG in the most prominent subfraction (40% Fr-1.25 M Fr) among the subfractions obtained in a previous paper (Endo et al. 1980a) were investigated. The results of determination of the reducing hexuronic acid and N-acetylhexosamine before and after digestion of the subfraction with beta-glucuronidase and beta-N-acetylhexosaminidase, together with previous data indicated that 0.36 and 0.37 mol of glucuronic acid and N-acetylgalactosamine, respectively, per mol of the subfraction were located at the non-reducing terminals of the carbohydrate chains. The remaining portion (0.27 mol per mol) of the non-reducing ends might be mostly occupied by the sulfated N-acetylgalactosamine residues. On the other hand, 0.25, 0.16 and 0.34 mol of glucuronic acid, N-acetylgalactosamine and xylose, respectively, per mol of the subfraction were indicated to the present at the reducing terminals of the carbohydrate chains. The remaining portion (0.25 mol per mol) of the reducing ends might be mostly occupied by the galactose residues and/or the N-acetylgalactosamine 4-sulfate residues. The present observations provided with evidence for the action of endo-beta-glucuronidase and endo-beta-N-acetylhexosaminidase on the tissue GAG, specifically on chondroitin sulfates.

Polydispersity of glycosaminoglycans in normal human urine.

To elucidate precise nature of urinary glycosaminoglycans (GAG) GAG in the acidic subfractions obtained in a previous paper (Endo et al. 1980) were quantitated by digestion with mucopolysaccharidases, nitrous acid treatment and by quantitative cellulose acetate membrane (Separax) electrophoresis. Hyaluronic acid, chondroitin sulfates and chondroitin, dermatan sulfate and dermatan, heparan sulfate, keratan sulfate, and acidic glycopeptide were found in wide distribution in these subfractions. The results suggested the presence of various degree of the depolymerization products of each GAG and of wide range of the desulfation products of each sulfated GAG. Distribution map of each GAG in the subfractions showed more detailed polydispersity of GAG in normal human urine than that reported previously.

Chemical nature of human urinary glycosaminoglycans.

To elucidate precise chemical nature of urinary glycosaminoglycans (GAG), GAG in the seven major acidic subfractions in a previous paper (Endo et al. 1980a) were analyzed for the chemical compositions and studied on the linkage between carbohydrate and peptide. All the subfractions examined contained galactosamine, hexuronic acid as the major constituent sugars, and xylose, galactose, L-fucose as the minor ones. Some of the subfractions contained additional glucosamine. Sulfate was also found in all the subfractions as their major constituent. The contents of total amino acids ranged from 1.20 to 17.9%. Serine, threonine, aspartic acid, glutamic acid, glycine, alanine and leucine were found as major amino acids. Pronase digestion did not significantly change their molecular size. The presence of O-xylosyl-serine linkage between carbohydrate chains and peptide moieties ws verified byan alkali treatment. Nevertheless, the presence of small portions of galactose and xylose residues at the reducing ends of the carbohydrate chains suggested a possibility of exertion of endo-beta-galactosidase and endo-beta-xylosidase activities for the linkage regions.

Heterogeneity of human urinary glycosaminoglycans.

Crude urinary glycosaminoglycans (GAG) obtained from normal adult men were fractionated by ethanol-fractionation, followed by Dowex 1 column chromatography. The resulting acidic subfractions were qualitatively analyzed for monosaccharide composition and examined by electrophoresis on cellulose acetate membrane and paper chromatography before and after mucopolysaccharidase digestions. Some of the major subfractions were also examined by gel filtration and infrared spectral analysis. The result showed that urinary GAG were extremely heterogeneous in the molecular size, negative charge and the chemical composition. Hyaluronic acid, heparan sulfate, chondroitin sulfates A and C, chondroitin, dermatan sulfate and keratan sulfate were found in wide distribution in these acidic subfractions. Of these GAG, chondroitin sulfate isomers were distributed into almost all acidic subfractions, indicating to be the most heterogeneous.

Fractionation with ethanol of human urinary glycosaminoglycans.

Crude glycosaminoglycans (GAG) separated from normal human urine by cetylpyridinium chloride-precipitation were fractionated with ethanol. The resulting fractions were then examined by electrophoresis on cellulose acetate membranes before and after enzymatic digestions and nitrous acid treatment. Analytical data for these fractions and the electrophoretograms suggested that ethanol-fractionation was useful to separate roughly chondroitin sulfate A, C-type GAG and heparan sulfate in human urine.

Synthesis of glycosaminoglycans by cultured rabbit smooth muscle cells.

Rabbit aortic smooth muscle cells were evaluated for their ability to synthesize and accumulate glycosaminoglycans (GAGs). Because of the sensitivity of the microtechniques utilized, it is possible to determine the specific radioactivity of the GAGs obtained after radioactive incorporation of [35S]SO4(2-) and [14C]glucosamine. Data obtained at various incubation times indicate that the distribution of the GAGs secreted by the cells into the medium is different from that retained by the cell layer. Hyaluronic acid was shown to be the most abundantly produced GAG, and much of this GAG does not appear to be incorporated into the extracellular matrix. Also, a high percentage of the total chondroitin sulfate B synthesized was secreted into the medium. On the other hand, most of the heparan sulfate and chondroitin sulfate C/A synthesized seems to be associated with the cell layer. These results are consistent with those found in whole rabbit aorta.

Proteochondroitin sulfate A in the euglobulin fraction of human plasma.

Euglobulin fraction of human plasma was extracted with 0.01 M phosphate buffer (pH 7.3) (PB) containing 1 M NaCl. The substances in the extract were separated by DEAE-cellulose column chromatography into two uronic acid-containing fractions (0.5 Fr and 0.75 Fr). The major fraction (0.75 Fr) was eluted at the void volume in gel filtration on Sephadex G-200, yielding 0.75-G Fr. 0.5 Fr and 0.75 Fr and their pronase digestion products (0.5-P Fr and 0.75-P Fr) together with 0.75-G Fr were examined by electrophoresis on cellulose acetate membrane. The results of electrophoresis and the digestibility with mucopolysaccharidases of these fractions indicated that 0.5 Fr and 0.75 Fr contained proteochondroitin sulfate A. It is suggested that chondroitin sulfate A in 0.5 Fr might be less sulfated than that in 0.75 Fr. Furthermore, analytical data and the infrared spectrum of 0.75-G Fr supported the above view.