Radiographic damage in rheumatoid arthritis correlates with functional disability but not direct medical costs.

OBJECTIVE: Few longitudinal data exist on the relationship between radiographic damage and self-reported functional disability and direct medical costs in rheumatoid arthritis (RA). We assessed these relationships. METHODS: One hundred thirty patients with RA (at time of the first available radiograph, mean age 56.6 yrs, 16.9% male, mean disease duration 16.8 yrs) were followed for up to 13.4 years. Semiannually, they reported on functional disability (0 = no difficulty, 3 = unable to do), global severity (0 = very well, 100 = very poor), pain (0 = no pain, 3 = severe pain), and health services utilization through completion of the Stanford Health Assessment Questionnaire (HAQ). Concurrent hand radiographs were scored for erosions and joint space narrowing using the Genant method and a single score summing both erosions and joint space narrowing for both hands was calculated (0 = no damage, 200 = maximum damage). The univariate association of functional disability, global severity, pain, or direct medical costs with concurrent radiographic damage was assessed through Spearman correlations and hierarchical regression models. The hierarchical models permit exploitation of the between-patient and within-patient variation present in our longitudinal data. RESULTS: At the time of the first available radiograph, mean (SD) levels of functional disability, global severity, and pain were 1.3 (0.7), 39.4 (21.0), and 1.1 (0.7), respectively. At entry into the study, the average radiograph score was 49.7 and upon leaving the study it was 66.9. Patients were followed an average of 6.7 years, with radiograph scores increasing at an average rate of 2.5 units/yr. The Spearman correlation [95% confidence interval (CI)] between average per-patient radiograph score and average per-patient HAQ disability index, average per-patient global severity, average per-patient pain score, and average per-patient direct medical costs was, respectively, 0.42 (0.26, 0.55), 0.23 (0.06, 0.39), 0.20 (0.03, 0.36), and 0.06 (-0.11, 0.23). The mean slope (95% CI) for disability on radiograph score was 0.0186 (0.0132, 0.0226), for severity on radiographs 0.1889 (0.1295, 0.2498), and for pain on radiographs 0.0057 (0.0027, 0.0084). As an example, over 10 years, a 25 unit (i.e., 50%) increase in radiograph scores would, on average, be associated with a 0.46 unit (i.e., 35%) increase in disability, a 4.72 unit (12%) increase in global severity score, and a 0.14 unit (13%) increase in pain, all expressed on the HAQ scales. There was little association between radiograph score and direct medical costs. CONCLUSION: A clinically meaningful association exists between radiographic damage and self-reported functional disability, suggesting that interventions that slow radiographic progression may improve the patient's health status. Such a relationship was not observed between radiographic damage and direct medical costs.

Predicting the short term direct medical costs incurred by patients with rheumatoid arthritis.

OBJECTIVE: With increasing interest in revising the mechanisms of health care funding, the ability to anticipate patients' medical expenditures as well as to identify potentially modifiable predictors would be informative for health care providers, payers, and policy makers. METHODS: Eight hundred fifty-eight patients with rheumatoid arthritis from 2 Canadian centers reported semi-annually on their health services utilization and health status for up to 12 years. Annual direct costs were calculated using 1994 Canadian prices. Regression models for the variation in total direct costs and the individual resource components (i.e., physicians, tests, medications, acute and non-acute hospital care) were estimated using previous values of age, sex, disease duration, education, methotrexate availability, employment status, global well being, pain, duration of morning stiffness, and functional disability as predictor variables. The models were developed using all available data except the last 2 observations (i.e., data collected on the last 2 self-report questionnaires) from each patient, which were reserved for model validation. The predictive abilities of the models were assessed by comparing the most recent costs with those predicted by the model using values of the predictor variables from the previous time period. Further, to assess whether the models conferred any advantage over cost estimates based only on previous costs, most recent observed costs were also compared with costs observed in the preceding time period. RESULTS: Self-reported indices of either global well being, pain, or functional disability predicted total direct costs as well as the costs of the 5 individual resource components. Being younger, female, disabled from the work force, having shorter disease duration, and receiving more formal education also predicted higher costs in at least on health resource category. However, being older predicted higher acute and non-acute care hospital costs. Regression models incorporating longitudinal data did not perform better than average costs in the preceding time period in predicting future short term costs. CONCLUSION: Global well being, pain, functional disability, and previous costs are the most important predictors of short term direct medical costs. Although we have demonstrated that regression models do not perform better than previous costs in predicting future short term costs, previous costs are a much less informative predictor than health status variables. Variables such as functional disability and pain identify potentially modifiable disease features and suggest interventions that may improve patient well being and reduce costs.

Direct and indirect medical costs incurred by Canadian patients with rheumatoid arthritis: a 12 year study.

OBJECTIVE: To perform the first prospective longitudinal study of direct (health services utilized) and indirect costs (diminished productivity represented by income loss) incurred by patients with rheumatoid arthritis (RA) in Saskatoon and Montreal, followed for up to 12 and 4 years, respectively. METHODS: 1063 patients reported on health status, health services utilization, and diminished productivity every 6 months. RESULTS: Annual direct costs were $3788 (1994 Canadian dollars) in the late 1980s and $4656 in the early 1990s. Given that the average age exceeded 60 years, few participated in labor force activities or considered themselves disabled from the labor force and their indirect costs were substantially less, $2165 in the late 1980s and $1597 in the early 1990s. Institutional stays and medications made up at least 80% of total direct costs. Lengths of stay in acute care facilities remained constant, but the rate of hospitalization increased in the early 1990s, increasing average hospital costs per patient from $1563 in the late 1980s to $2023 in the early 1990s. For nonacute care facilities, rate of admission as well as length of stay increased over time, increasing costs per patient in Saskatoon 5-fold, from $291 to $1605. Those with greater functional disability incurred substantially higher direct and those under 65 years incurred higher indirect costs. CONCLUSION: Direct costs are higher than indirect costs. The major component is due to institutional stays that, in contrast to other direct cost components, is increased in the older and more disabled. Measures to reduce longterm disability by earlier, more aggressive intervention have the potential to produce considerable cost savings. However, it is unknown which strategies will have the greatest effect on outcome and accordingly, how resources can be optimally allocated.

Analysis of synaptic distribution within single retinal axonal arbors after chronic NMDA treatment.

Activation of the NMDA subtype of glutamate receptor has been implicated in structural synaptic plasticity in many developing sensory systems. In the frog retinotectal system, chronic exposure of the optic tectum to NMDA, which decreases the effectiveness of NMDA receptors (Debski et al., 1991), results in the pruning of the branches of retinal terminal arbors (Cline and Constantine-Paton, 1990). However, it is difficult from these studies to relate the involvement of NMDA receptors to changes in synapse distribution. In this study, we have developed an EM sampling procedure to quantitatively compare the amount and the distribution of synaptic contact within single retinal arbors. We report that within each retinal arbor, synaptic contact gradually increases from the main branches to the end branches of the arbor. Chronic NMDA treatment, however, significantly reduces the total amount of synaptic contact within each arbor. This reduced synaptic contact appears to be due to the pruning of the end branches, and the synapses these branches bear. The results are consistent with the hypothesis that NMDA receptor is an integral part of the mechanism that stabilizes coactive synapses, and that maintenance of an axonal branch requires a minimum density of synapses that are correlated with converging neighbors.

Altered poly(ADP-ribose) metabolism in family members of patients with systemic lupus erythematosus.

OBJECTIVE: To determine whether the previously detected decrease in poly(ADP-ribose) synthesis in systemic lupus erythematosus (SLE) is familial. METHODS: Poly(ADP-ribose) metabolism was studied in the peripheral blood lymphocytes of members of 3 families with lupus and in healthy controls. RESULTS: Synthesis, as determined by the incorporation of 3H NAD into acid precipitable counts was 30% of normal in the patients with SLE (p < 0.001) and 70% of normal in the unaffected family members (p < 0.05). Family members also had increased prevalence of antinuclear antibodies but the presence of these antibodies did not correlate with abnormalities in poly(ADP-ribose) metabolism. CONCLUSION: The healthy biologic relatives of patients with SLE have a decrease in poly(ADP-ribose) synthesis similar to, but less marked than, their affected relatives. Poly(ADP-ribose) polymerase activity appears to be an inherited trait and abnormalities in it may be one of the susceptibility factors for SLE. If this is the case, then further investigation of this gene and its regulation is warranted.

Decreased mRNA levels coding for poly(ADP-ribose) polymerase in lymphocytes of patients with SLE.

Poly(ADP-ribose) metabolism is altered in patients with SLE. In order to localize the defect, the levels of poly(ADP-ribose) polymerase-specific mRNA were measured from dot blots of total RNA from peripheral blood lymphocytes. In this preliminary study, eleven patients with SLE and two with antiphospholipid syndrome were compared to three controls. It was found that the mean levels of specific mRNA were ten fold lower in the PBL from SLE patients compared to controls and no overlap of values was seen between the two groups. No such decrease was seen in the PBL from the patients with antiphospholipid syndrome. It is concluded that the defect in poly(ADP-ribose) polymerase metabolism that is seen in SLE patients occurs at the level of transcription or mRNA turnover.

The mortality of rheumatoid arthritis.

OBJECTIVE: To determine the risk and causes of death and to quantify mortality predictors in patients with rheumatoid arthritis (RA). METHODS: RA patients (n = 3,501) from 4 centers (Saskatoon n = 905, Wichita n = 1,405, Stanford n = 886, and Santa Clara n = 305) were followed for up to 35 years; 922 patients died. RESULTS: The overall standardized mortality ratio (SMR) was 2.26 (Saskatoon 2.24, Wichita 1.98, Stanford 3.08, Santa Clara 2.18) and increased with time. Mortality was strikingly increased for specific causes: infection, lymphoproliferative malignancy, gastroenterologic, and RA. In addition, as an effect of the SMR of 2.26, the expected number of deaths was increased nonspecifically across all causes (except cancer), with a large excess of deaths attributable to cardiovascular and cerebrovascular diseases. Independent predictors of mortality included age, education, male sex, function, rheumatoid factor, nodules, erythrocyte sedimentation rate, joint count, and prednisone use. CONCLUSION: Mortality rates are increased at least 2-fold in RA, and are linked to clinical severity.

Fine-structural alterations and clustering of developing synapses after chronic treatments with low levels of NMDA.

In the visual pathway of frogs it is possible to apply low levels of NMDA chronically to the optic tectum and study the mechanisms underlying the stabilization of synapses developing within the CNS. Earlier studies (Cline and Constantine-Paton, 1990) found that chronic NMDA treatment of tecta innervated by two retinas results in a reduction of branching within the terminal arbors of retinal ganglion cells (RGCs). We now report that this same chronic NMDA treatment produces fine-structural changes in synaptic morphology as well as local synaptic rearrangements within the retinotectal neuropil. Chronic NMDA treatment of doubly innervated tecta was associated with a thickening or darkening of both pre- and postsynaptic densities. These changes in synapse morphology were restricted to the superficial neuropil of tecta in regions where reductions in branches of RGC axonal arbors were observed at the light microscopic level. The fine-structural effects were absent from similarly treated tecta innervated by only one eye, where RGC axonal arbor pruning was not observed. Stereological analyses indicated that the incidence of two or more presynaptic profiles converging on the same postsynaptic process was significantly increased in the NMDA-treated, doubly innervated tecta. This observed increase in synaptic clustering was not associated with a larger synaptic active zone, or with an increase in the number of synapses per unit volume. These data are discussed in the context of the hypothesis that chronic NMDA treatment raises the threshold for synapse stabilization in tectal neurons, causing the selective loss of poorly correlated synapses of both retinal and non-retinal origin from tectal neuropil that is innervated by two retinas: increased pre- and postsynaptic thickening could reflect greater efficiency in the remaining synaptic contacts and their closer spatial proximity on the same postsynaptic process is consistent with greater cooperativity and less competition.

Familial systemic lupus erythematosus characterized by digital ischemia.

We describe a family in which 3 members each developed systemic lupus erythematosus complicated by ischemic vasculopathy. The calendar years and patient ages of disease onset and the clinical courses were remarkably similar for all 3 patients, although their genotypes were not. The potential contributions of heredity and environment to the concordance of disease expression in this family are discussed.

The incidence and prognosis of central nervous system disease in systemic lupus erythematosus.

In a review of our experience with systemic lupus erythematosus (SLE) since 1975, we found 48 of 266 patients with major central nervous system (CNS) manifestations for which a non-SLE explanation could not be identified. Eleven patients developed more than one type of CNS event. The commonest symptom was seizure (18 patients), followed by brainstem dysfunction (12 patients), psychosis (11 patients), organic brain syndrome (11 patients) and stroke (7 patients). In 19% of cases, CNS manifestations were accompanied by a flare of multisystem SLE disease activity. Anticonvulsants were able to be discontinued safely in the majority of patients with seizures. Most CNS events were self-limited, reversible and not associated with poor outcome unless accompanied by multisystem disease activity. Therapy with corticosteroids did not appear to offer substantial benefit.

The clinical course of Felty's syndrome compared to matched controls.

In a cohort of 919 patients with definite or classic rheumatoid arthritis followed prospectively since 1966, we identified 36 patients with Felty's syndrome (FS). Their clinical course was compared to that of 72 matched controls from the same cohort. Patients with FS had more extraarticular features and more infections than control patients. The presence of joint erosions, serial Lansbury indices, and death rates were similar in both groups. Cardiovascular disease was the commonest cause of death in both groups, accounting for 32% of all deaths. Sepsis accounted for 10% of deaths in the group with FS and 13% of deaths in the controls.

Clinical course and predictors of length of stay in hospitalized patients with rheumatoid arthritis.

Patients admitted for therapy of active rheumatoid arthritis were prospectively followed throughout their hospital stay. Average length of stay was 17.1 days. Serial global assessments, whether determined by rheumatologist, physiotherapist or patient appeared to improve linearly until at least hospital day 21. From admission to discharge, mean global assessment scores improved by about one third. Poor global assessment, high disability index, and the presence of comorbid disease and anemia on admission, as well as admission late in the week, were predictive of prolonged hospital stay.

Concurrent onset of adult onset Still's disease and insulin dependent diabetes mellitus.

Within two weeks after symptoms of an upper respiratory tract infection a 32 year old man developed Still's disease and insulin dependent diabetes mellitus, both of which have persisted for 24 months. Investigations failed to confirm acute infection but did show isolated persistent increase of serum antibodies to rubella virus. The simultaneous onset of these two diseases suggests a shared cause, possible associated with rubella infection.

Altered metabolism of poly(ADP-ribose) in the peripheral blood lymphocytes of patients with systemic lupus erythematosus.

A method was developed to measure poly(ADP-ribose) metabolism in peripheral blood lymphocytes. The technique involved the isolation of lymphocytes on Ficoll gradients, followed by lysis with 5M NaCl. The synthesis and degradation of poly(ADP-ribose) in this crude lysate, measured by the incorporation of 3H-labeled NAD into acid-precipitable counts, was compared in 18 patients with systemic lupus erythematosus (SLE), 10 patients with rheumatoid arthritis, and in 10 control patients without rheumatoid arthritis. Patients with SLE showed a 70% decrease in poly(ADP-ribose) synthesis (P less than 0.001); this decreased synthesis persisted even with the addition of histones or DNase. We present possible explanations of the role of poly(ADP-ribose) in SLE.

Detection of unusual nucleic acids with monoclonal antibodies specific for triplexes, poly(ADP-ribose), DNA-RNA hybrids, and Z-DNA.

Monoclonal antibodies which are specific for several unusual nucleic acids are now available. These include Jel 318 which is specific for triplexes, ADP-1 specific for poly(ADP-ribose), Jel 99 specific for RNA-DNA duplexes, and Jel 150 specific for Z-DNA. With the aid of these antibodies and an immunoblotting procedure, unusual nucleic acids can be detected and the amount estimated from a variety of sources. The method involves binding the nucleic acid to either nitrocellulose or Zeta Probe (a cationic nylon membrane), probing with the appropriate monoclonal antibody, followed by addition of an 125I-labeled anti-mouse second antibody. The blot is then developed by autoradiography. The technique is extremely sensitive and can be used to estimate unusual nucleic acids from crude cell extracts.

Shared idiotypes on anti-DNA and anti-poly (ADP-ribose) antibodies.

Hed 10 is a ssDNA-specific mAb derived from an NZB/W autoimmune mouse. ADP 1 is a poly(ADP-ribose)-specific mAb derived from a C57BL/6 mouse. Rabbit anti-idiotypic sera were raised against Hed 10 and ADP 1. By affinity chromatography it was shown that at least 20 to 30% of DNA-binding antibodies contained these idiotypes. The sera were also used to evaluate idiotypic cross-reactivity among 26 diverse, predominantly anti-nucleic acid, murine mAb. Each serum bound directly to several mAb and in addition inhibited the binding of several antibodies to their appropriate Ag. The anti-Hed 10 serum detected an idiotype which was restricted to antibodies that bound to poly(dT) and/or poly(ADP-ribose). The anti-ADP 1 serum detected a more widely distributed idiotype contained in antibodies which bound to a variety of nucleic acids. Although both sera bound directly to Hed 10, only the anti-Hed 10 serum could compete for the binding of Hed 10 to poly(dT). On the other hand, both sera could compete for the binding of ADP 1 to poly(ADP-ribose) as well as bind directly to ADP 1. In addition anti-ADP 1 serum appeared to enhance, rather than inhibit, the binding of one mAb to native calf thymus DNA and poly[d(AT)] but had no effect on the binding to several ssDNA. These results demonstrate that many antibodies which recognize DNA and poly(ADP-ribose) have shared idiotypes. This may be of relevance to the development of autoimmunity because poly(ADP-ribose) is ubiquitous and immunogenic.

Undiagnosed chronic monarthritis. Clinical and evolutionary profile.

The features and clinical course in 38 patients (25 women, 13 men) who had chronic monarthritis of undetermined origin (UCM) were surveyed over a mean followup period of 24.6 months. At the end of the study, the cause was still unknown in 26 patients (65.7%). In 10 patients, symptoms resolved spontaneously. In the remaining 12 patients, a diagnosis became apparent after a mean period of 17.2 months; diagnoses included spondylarthritis (6 patients), rheumatoid arthritis (3 patients), osteoarthritis (1 patient), erosive arthropathy (1 patient), and glomus tumor (1 patient). Patients in whom a diagnosis emerged were more likely to have positive findings on the following studies: rheumatoid factor (2 of 12); HLA-B27 typing (6 of 11); bone scan, positive over the sacroiliac joint or non-index joint(s) (4 of 6); and roentgenograms of the sacroiliac joint (3 of 8). Findings of these same studies were notably negative in the subgroup of patients with UCM that spontaneously resolved.

Increased synthesis of poly(ADP-ribose) in isolated liver nuclei from autoimmune NZB/NZW mice.

The synthesis and degradation of poly(ADP-ribose) were investigated in isolated liver nuclei from autoimmune NZB/W mice and four strains of normal mice. Compared to normal mice the maximum levels of incorporation of [3H]NAD into poly(ADP-ribose) were increased about 2-fold in the autoimmune mice. The kinetics of incorporation suggested that this change was due to an increase in the activity of the polymerase rather than a decrease in the level of degradative enzymes. Thus there may be a connection between autoimmunity and poly(ADP-ribose) metabolism.