Kenneth D. Brandt

A clinical analysis of the course and prognosis of forty-two patients with amyloidosis

Abstract The clinical aspects of systemic amyloidosis in forty-two patients are reviewed, and the presenting manifestations, prognosis, mode of death and certain aspects of particular organ-system involvement are discussed in detail. No categoric differences in the clinical manifestations of amyloid disease were found among patients with primary amyloidosis, myeloma-associated amyloidosis and secondary amyloidosis. The kidney was the major site of involvement in most patients. Sixty per cent excreted more than 4 gm. of protein per day and uremia was the cause of death in 43 per cent. The profile of amyloid renal disease in this series was reviewed. Heart disease was present in 67 per cent of the patients. Our experience with cardiac amyloidosis underscores the problem of digitalis-sensitivity which such patients may present. Amyloid infiltration of the digestive system was responsible for a diversity of clinical manifestations. Among these, bleeding in the gastrointestinal tract was common and occurred in over 50 per cent of the patients. Data are presented which suggest that the prognosis in systemic amyloid disease and in amyloid nephrosis, in particular, may be better than generally believed.

Acute arthritis caused by gram-negative bacilli: a clinical characterization.

ACUTE ARTHRITIS CAUSED BY GRAM-NEGATIVE BACILLI: A CLINICAL CHARACTERIZATION DON GOLDENBERG;KENNETH BRANDT;EDGAR CATHCART;ALAN COHEN; Medicine

Immunoglobulins and amyloidosis: An immunologic study of sixty-two patients with biopsy-proved disease

Abstract Immunoglobulin abnormalities have been studied in sixty-two patients with biopsy-proved amyloidosis. In ten of eleven cases associated with well defined lymphoproliferative disorders the patients were found to have M-components in their serum or urine. A similar abnormality was demonstrable in seven of fourteen cases of primary amyloidosis, but M-components were not present in the serum or urine of eight patients with localized amyloidosis, six patients with hereditary amyloidosis and twenty-three patients with secondary amyloid disease. Despite the absence of M-components in the majority of patients, nonspecific immunoglobulin abnormalities (elevated or depressed serum levels of immunoglobulins G, A and M) were frequently encountered in patients with secondary amyloidosis as well as in patients with idiopathic disease and lymphoproliferative disorders. These results suggest that immune mechanisms may be involved in the pathogenesis of human amyloidosis.

The effect of synovial hyaluronate on the ingestion of monosodium urate crystals by leukocytes.

Abstract To extend previous studies which showed that large-sized hyaluronate molecules inpeded chemotactic movement of leukocytes, the effect of synovial hyaluronate on the rate at which crystals of monosodium urate were ingested by leukocytes was examined. Hyaluronates with viscometry-average molecular weights ranging from 1.13 · 106 to 0.56 · 105 were isolated and purified after treatment of synovial fluid with hyaluronidase for varying periods of time. Crystals of monosodium urate and normal peripheral blood leukocytes were suspended in buffer or in various concentrations of the hyaluronate preparations and the percentage of cells containing intracellular crystals was determined by polarization microscopy after incubation for 15 minutes. Results indicated that the rate of phagocytosis in all solutions of macromolecular hyaluronate was reduced in comparison with that in buffer. With increasing concentration of hyaluronate progressively greater impedence to the ingestion of crystals was observed. Moreover, at equimolar concentrations of uronic acid, the number of cells which ingested crystals was inversely proportional to the molecular weight of the hyaluronate. Thus, the physicochemical state of synovial hyaluronate may modify the response of leukocytes to monosodium urate crystals. The relatively small polymeric size of hyaluronate in gouty synovial fluid, therefore, may facilitate the phagocytosis of urate crystals and, through the consequent release of mediators of tissue injury from phagocytic cells, augment the inflammatory response within the joint.

Putting Some Muscle into Osteoarthritis

Osteoarthritis, the most common joint disease, results from the complex interplay of biochemical, metabolic, and biomechanical factors and is characterized, in part, by the progressive loss of articular cartilage. Aggrecan and collagen, the major molecular constituents of articular cartilage, confer stiffness on compression and tensile strength, respectively. Evidence that the metabolic turnover rates of these molecules are increased in osteoarthritic cartilage has led investigators to search for enzymes responsible for their degradation in the hope that pharmacologic inhibitors might be developed to prevent the development or slow the progression of osteoarthritis. In vitro, several matrix metalloproteinases (MMPs) degrade the core protein of aggrecan through the cleavage of the interglobular domain between Asn341 and Phe342. However, the predominant fragment of the core protein found in the synovial fluid of patients with osteoarthritis and in the medium of chondrocyte cultures after stimulation with interleukin-1 is generated by cleavage between Glu373 and Ala374, suggesting that in vivo proteolysis at the more distal site is important in the breakdown of cartilage in osteoarthritis. Efforts to produce primary Glu373 -Ala374 cleavage with a large number of proteases have been unsuccessful; this suggests that an unidentified enzyme, aggrecanase, is responsible for this cleavage [1]. Recent evidence [2] suggests that aggrecanase may be a novel MMP. The predominant collagen in articular cartilage, type II collagen, is responsible for the structural integrity of the tissue. Chondrocytes can produce three collagenases that are capable of cleaving the triple helical region of this collagen: MMP-1 (collagenase 1), MMP-8 (collagenase 2), and MMP-13 (collagenase 3). The last of these represents a major product of cartilage stimulated with interleukin-1, and it hydrolyzes type II collagen much more efficiently than do the other collagenases in cartilage [3]. Whether pharmacologic inhibition of collagenase or other MMPs would ameliorate cartilage breakdown in patients with osteoarthritis-and whether this inhibition can be accomplished without major adverse effects-remains to be determined. The possibility is currently being tested. Tetracyclines have been shown to inhibit several cartilage MMPs. Doxycycline is a more effective inhibitor of MMP-13 than of the other cartilage collagenases, gelatinase or stromelysin [4]. Oral administration of this drug reduces joint damage in animal models of osteoarthritis [5]. Doxycycline not only inhibits active MMPs by chelating zinc at the catalytic site but also reduces levels of total collagenase and total gelatinase in osteoarthritic cartilage, apparently by affecting enzyme stability through the chelation of intramolecular calcium [6]. Tetracyclines also reduce the stability of messenger RNA for nitric oxide synthase [7]. Because nitric oxide can activate latent MMPs in cartilage [8], this may provide an additional reason for the efficacy of doxycycline in animal models of osteoarthritis. On the basis of the above observations, a placebo-controlled trial of this drug in humans with osteoarthritis has been initiated. Although advances in our understanding of the biochemical changes underlying the breakdown of cartilage may lead to new pharmacologic agents for osteoarthritis, all of the tissues of the involved joint are abnormal. We should not dismiss the possibility that pharmacologic, biological, or physical measures that modify disease processes in subchondral bone, synovium, joint capsule, ligaments, or periarticular muscles will be more effective than a chondroprotective drug. The role of the neuromuscular system in protecting against joint damage deserves consideration in this respect. In the dog, transection of the anterior cruciate ligament leads to osteoarthritis of the knee, although full-thickness loss of cartilage requires years to develop. However, if sensory input from the hind limb is interrupted before the induction of joint instability (for example, by ipsilateral L4-S1 dorsal root ganglionectomy), blocking proprioceptive impulses transmitted by neurons whose axons ascend in the dorsal column of the spinal cord, end-stage osteoarthritis is seen within only weeks. This striking acceleration of joint breakdown is associated with increased extension of the unstable limb at touchdown, which causes greater stresses on the knee than in the neurologically intact cruciate-deficient dog [9]. The pathology is very similar to that of the severe joint degeneration that characterizes the secondary form of osteoarthritis seen in neuropathic (Charcot) arthropathy in humans. Of note, a deficit in proprioception has been documented in humans who have (apparently) primary osteoarthritis of the knee. Whether this deficit is due to a primary neurologic abnormality or to damage to mechanoreceptors in or around the involved joint is unclear, but persons with clinical and radiographic evidence of unilateral osteoarthritis of the knee exhibit impaired proprioception in both lower extremities; this suggests an underlying, generalized neurologic defect [10]. Because a proprioception deficit puts the joint at risk by impairing protective muscular reflexes, this observation requires follow-up. Even in the neurologically normal person, periarticular muscle weakness poses a threat to the joint. Quadriceps weakness is common in patients with osteoarthritis of the knee, and muscle strengthening exercise can reduce joint pain and improve function [11]. Although this quadriceps weakness is generally presumed to be due to muscle atrophy caused by reduced loading of the painful extremity, it may be seen in persons with radiographic evidence of osteoarthritis of the knee who have no history of recent knee pain and no loss of quadriceps mass. In some cases, it may be due to reflex inhibition of the quadriceps, with altered afferent input from the diseased joint resulting in abnormal efferent output to the muscle [12]. However, there is more to this story. Among persons with medial tibiofemoral compartment osteoarthritis, a decrease in pain led to an increase in adductor and flexor moments at the knee [13]; this suggests that the alleviation of joint pain could increase loading of damaged cartilage. The concept of analgesic arthropathy is not new; for years, there has been concern that drugs that relieve joint pain may lead to detrimental overloading of the arthritic joint. Furthermore, some nonsteroidal anti-inflammatory drugs (NSAIDs) used for osteoarthritis pain inhibit proteoglycan synthesis [14] and could, theoretically, blunt the repair capacity of the chondrocyte. However, evidence that any NSAID accelerates progression of osteoarthritis in humans is far from clear cut. Even if relief of joint pain were to increase joint loading, some have suggested that it may not be the magnitude of the load as much as the rate of loading that is the important determinant of joint damage [15]. Within physiologic limits, impulsive loads (in which the rate of loading is high) are more damaging to articular cartilage and subchondral bone than are forces of greater magnitude applied more gradually (Radin E. Personal communication). Very rapid application of load does not allow sufficient time for the periarticular muscles, the major shock absorbers protecting the joint, to absorb the load [16]. It has been suggested that normal persons walking at the same speed use various strategies to decelerate the leg at the end of the swing phase of gait [17]. Some persons use the braking action of their quadriceps to control the effect of gravity on the rate of descent of the leg, whereas deceleration of the leg by quadriceps contraction may be less effective in other persons, in whom the rate of descent is slowed only by contact with the ground. The large heel-strike transient that develops under the latter condition may generate contact forces in the knee that are several times greater than those produced when effective quadriceps contraction occurs before heel strike [18]. The basis for the differences in gait patterns among normal persons is unknown, but these differences could reflect individual differences in the central neurologic mechanisms that coordinate limb movements during gait. Whether a quadriceps-deficient pattern of gait leads to osteoarthritis of the knee is still unclear. However, preliminary analyses of a cohort of elderly persons living in the community suggest that persons who have quadriceps weakness at baseline are more likely than those with greater initial strength to exhibit progression of radiographic changes of osteoarthritis of the knee (Slemenda C, Brandt KD. Unpublished data). Regardless of its cause, weakness could impair protective reflexes originating from proprioceptive nerve endings in muscle spindles or mechanoreceptors within the joint. Considerable effort is being expended on the development of drugs to counteract the underlying pathologic changes of osteoarthritis. It remains to be seen whether any drug that modifies chondrocyte metabolism will modify the pathology of osteoarthritis if the mechanical environment of the joint remains abnormal. Drug development should not preclude evaluation of the possibility that physical measures that improve neuromuscular function (for example, coordination or periarticular muscle strength) may have a favorable effect on the pathology and symptoms of osteoarthritis. Indeed, improvement in joint mechanics could enhance the efficacy of a disease-modifying drug. Even in elderly persons, quadriceps strength can be increased through training [19]. Although it may not be possible to completely reverse the neuropathologic changes that are responsible for initiating joint damage (for example, a deficit in proprioception), persons with such defects may be trained to alter their movement patterns to protect their joints from traumatic injury.

Cerebral Disorders of Vision in Systemic Lupus Erythematosus

Sensory neuroophthalmic abnormalities due to cerebral lupus erythematosus, with involvement of visual pathways posterior to the optic chiasm, occurred in 12 patients with systemic lupus erhthematosus. Five underwent detailed evaluation because of an hallucination, 4 for visual loss, and 3 for both. Hallucinations were either unformed (for example, bright lights, straight lines) or highly formed (for example, faces), in which case they were invariably recognized by the patient as inappropriate. In no instance did they occur in association with delirium, confusion, or use of hallucinogenic drugs. Patients with loss of vision had scotomas, homonymous field defects, and cortical blindness. These features indicate disease in the posterior cerebral artery circulation, a localization often supported by ancillary neurologic findings, for example, vocal cord paralysis, diminished gag reflex. Thus, various visual dysfunctions may occur in systemic lupus erythematosus due to cerebral vasculitis. At times they may be the most prominent and disabling feature of the disorder.

Herniation of mitral leaflets in the ehlers-danlos syndrome

A 47 year old patient with the Ehlers-Danlos syndrome (hypermobility of the joints, hyperextensibility of the skin and atrophic cutaneous scars) was evaluated because of a mitral regurgitant murmur and paroxysmal atrial tachycardia. Angiocardiography and echocardiography demonstrated marked systolic herniation of the posterior leaflets of the mitral valve. An echocardiogram from the patients daughter, who also had paroxysmal atrial tachycardia, revealed the same abnormality. Although a floppy valve is common in Marfans syndrome, this report emphasizes that it may also occur in patients with other heritable disorders of connective tissue.

Toward pharmacologic modification of joint damage in osteoarthritis.

Osteoarthritis is the most common joint disease, and osteoarthritis of the knee is the most common cause of chronic disability among elderly persons in the United States. Current pharmacologic therapy is based chiefly on the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and analgesics that, in most cases, are only moderately effective. The elderlythose at greatest risk for osteoarthritisare also at greatest risk for serious NSAID side effects such as gastroenteropathy. Joint replacement is often effective but is generally recommended only after years of pain and disability. Because of the limitations of current therapy, interest has arisen in agents that are not principally analgesic but that alter pathogenic mechanisms within the osteoarthritic jointdisease-modifying drugs [1]. Although claims have been made that various agents are chondroprotective, no agent has yet been shown to modify osteoarthritis in a placebo-controlled clinical trial in humans. However, recent studies in animals show that pharmacologic modification is indeed feasible. In considering guidelines for testing new drugs, a committee of the International League of Associations for Rheumatology [1] recommended that the designation disease-modifying drug for osteoarthritis be reserved for agents that prevent, retard progression of, or reverse morphologic changes; an effect only on the biochemistry or metabolism of cartilage matrix molecules or the concentration in body fluids of molecules derived from cartilage or bone in the joint (osteoarthritis marker molecules) was considered insufficient to qualify an agent as a disease-modifying drug. In animal models, several agents meet the criterion defined above. They range from empirical compounds (for example, tissue extracts) to site-specific inhibitors designed to fit precisely into the catalytic site of collagenase; they include tribenoside, tamoxifen, diacerein, chloroquine, hyaluronic acid, glucocorticoids, and tranexamic acid. Excellent reviews have been published [2-4]. In this editorial, I summarize the evidence about the disease-modifying activity of NSAIDs, heparinoids, and tetracyclines. Claims that some NSAIDs have a disease-modifying effect have been based almost exclusively on in vitro evidence that the drugs modify proteoglycan or collagen metabolism, cytokine-mediated matrix degeneration, secretion or activity of neutral matrix metalloproteinases, or the effects of toxic oxygen metabolites. Because fatal NSAID-induced gastrointestinal hemorrhage (related to inhibition of prostaglandin synthesis) often develops before arthritis becomes apparent in the species typically used in models of osteoarthritis (for example, mice, guinea pigs, dogs, rabbits), it has not been possible to extensively test the in vivo disease-modifying capacity of NSAIDs in animal models. No evidence indicates that NSAIDs have this effect in humans. However, in two studies [5, 6], tiaprofenic acid (a proprionic acid derivative) has been shown to reduce the severity of osteoarthritis in dogs with cruciate ligament deficiency. In the same model, when gastrointestinal toxicity was prevented by administration of omeprazole [7], diclofenac did not significantly protect against joint damage, although tenidap (which inhibits synthesis of prostaglandins and leukotrienes and which may modulate synthesis of interleukin-1 [8]) had a striking disease-modifying effect [7]. Whether concomitant gastroprotective treatment will show that other NSAIDs also have this effect remains to be seen. Similarly, the disease-modifying activity of NSAIDs that selectively inhibit cyclo-oxygenase II should be assessed. Several heparinoids have been shown to modify osteoarthritis in animal models of the disease [2-4]. Glycosaminoglycan polysulfate (Arteparon; an extract of bovine tracheal and bronchial cartilage) and glycosaminoglycan peptide complex (Rumalon; an extract of calf cartilage and bone marrow) contain chondroitin-4-sulfate, chondroitin-6-sulfate, and peptides. Both stimulate cartilage matrix synthesis and have activities as protease inhibitors. Sodium pentosan polysulfate (a polysaccharide sulfate ester prepared from beech hemicellulose) is a heparinoid (like glycosaminoglycan polysulfate and glycosaminoglycan peptide complex), but sodium pentosan has the advantage of lacking antigenic protein constituents. It is a potent inhibitor of matrix metalloproteinases and leukocyte elastase, and it may down-regulate metalloproteinase levels by interfering with the binding of transcription factor [9]. Each of these heparinoids requires intramuscular or intra-articular administration. It is therefore notable that calcium pentosan polysulfate, which is well absorbed after oral administration, reduced loss of cartilage proteoglycans in an animal model of inflammatory arthritis [10]; it has not yet been evaluated as a disease-modifying drug. Neither of the above pentosans has been tested in humans. In patients with knee osteoarthritis who received a series of intramuscular injections of glycosaminoglycan polysulfate or glycosaminoglycan peptide complex every 6 months for 5 years, radiographic progression of osteoarthritis was reported to be slower in patients who received either agent than in controls, and improvement was noted in several functional measures [11]. However, failure of the study to include a placebo group or to control for NSAID use cast doubt on the importance of these findings. The lack of convincing evidence of a disease-modifying effect in humans, reports of bleeding attributed to the heparinoid structure of glycosaminoglycan polysulfate, reports of anaphylaxis related to the presence of antigenic protein components, and concern about possible transmission of the agent responsible for bovine spongiform encephalopathy have led to the removal of glycosaminoglycan polysulfate and glycosaminoglycan peptide complex from the market in the European countries in which they had been available. Evidence that doxycycline inhibits the activity of collagenase and gelatinase in extracts of articular cartilage recently led to in vivo studies in a canine model of osteoarthritis that showed a marked disease-modifying effect with oral administration of the drug [12]. Reports that cartilage damage in guinea pig [13] and rabbit [14] models of osteoarthritis was also reduced by tetracycline administration bolster the observations in the canine model. Previous studies suggested that the pathologic changes of osteoarthritis progress very slowly. This led to the assumption that many participants and years of treatment would be needed to show a disease-modifying effect in humans; this assumption deterred efforts by the pharmaceutical industry to develop disease-modifying drugs. How-ever, the mean rate of cartilage loss in osteoarthritis (based on the reduction of joint-space width in standard radiographs) is much more rapid than previously believed [1, 15]. Further, standardization of radioanatomical positioning of the knee can reduce the variability in measurements of joint space to only 1% to 2% [16], and computerized analysis of the digitized radiograph can reduce the variability inherent in manual measurements. Clinical trials of a disease-modifying drug can be facilitated by focusing on a joint at high risk for osteoarthritis; for example, 50% of middle-age obese women with radiographic evidence of unilateral knee osteoarthritis will develop the disease in the contralateral knee within the next 2 years [17]. Several strategies can optimize retention of participants in a long-term clinical trial and can optimize compliance with the dosing regimen [18], as shown by the 82% retention rate in a 48-week trial of minocycline in patients with rheumatoid arthritis [19]. A faintness-of-heart test [20] (to exclude noncompliers before random assignment into treatment groups) and use of computerized medicine caps (to permit study personnel to direct their efforts toward enhancing compliance among those patients who can best benefit from such efforts) may further increase retention and compliance. With the use of these techniques, the logistics of a clinical trial of a disease-modifying drug need not be daunting; efficacy might be shown in a controlled clinical trial with only 2 to 2.5 years of treatment and with enrollment of fewer than 500 participants. Clinical researchers in osteoarthritis, members of the pharmaceutical industry, and representatives of regulatory authorities (for example, the Food and Drug Administration) need to agree on the appropriate outcome measures and assessment tools for evaluation of disease-modifying drugs. Once a drug possessing this activity in humans has been identified, it will be possible to determine whether reduction in the rate of cartilage loss is accompanied by reductions in joint pain, the frequency of joint arthroplasty, and the rate of disability.

Small proteoglycans of cartilage: Confirmation of their presence by non-disruptive extraction

Abstract Previous studies have characterized a uniquely small proteoglycan, retarded on Sepharose 6B chromatography, in extracts of cartilage prepared by homogenization of the tissue in neutral salt. Since shear forces generated during such homogenization may disrupt some proteoglycans, however, the significance of the small proteoglycan has been questioned. The present study shows for the first time that small proteoglycans, similar in hydrodynamic size and composition and immunologically identical to those extracted by homogenization in sodium acetate, are present also in a cartilage extract prepared without homogenization. The results suggest strongly that the small proteoglycans exist in vivo and are not artifacts of the extraction procedure.

Immunological relationships between proteoglycans of different hydrodynamic size from articular cartilage of foetal and mature pigs

Abstract Proteoglycans were extracted from articular and laryngeal cartilages of foetal and mature pigs. Antisera were prepared to extracts containing protoglycans whose size had been determined by gel chromatography. The smallest, which were separated on 6% agarose, gave a single precipitin line without needing prior digestion with hyaluronidase. Proteoglycans large enough to be excluded from 6% agarose failed to react in double diffusion and were inacapable of absorbing specific antibody unless first digested with hyaluronides, implying a difference in structure between proteoglycans of different size. After digestion, however, the larger proteoglycans effectively absorbed specific antibody and produced multiple precipitation line, consistent with the presence of several core proteins. One of these lines which developed more rapidly than the rest appeared towards the antibody well and showed identify with the determinant of the smallest proteoglycans. This determinant however, was not dissociated from the intact proteoglycans by treatment with quanidine · HCl. When the largest proteoglycans were digested with hyaluronidase and diffused against antiserum to purified small proteoglycans two precipitin lines were produced. The one nearer the antibody well showed complete identity with the determinant of the small proteoglycans, while the other, nearer the antigen well, fused with the above, suggesting that this determinant may also be amongst those on the core proteins of larger proteglycans.