Showing papers in "Arthritis & Rheumatism in 1990"

The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee.

Abstract: To develop criteria for the classification of fibromyalgia, we studied 558 consecutive patients: 293 patients with fibromyalgia and 265 control patients. Interviews and examinations were performed by trained, blinded assessors. Control patients for the group with primary fibromyalgia were matched for age and sex, and limited to patients with disorders that could be confused with primary fibromyalgia. Control patients for the group with secondary-concomitant fibromyalgia were matched for age, sex, and concomitant rheumatic disorders. Widespread pain (axial plus upper and lower segment plus left- and right-sided pain) was found in 97.6% of all patients with fibromyalgia and in 69.1% of all control patients. The combination of widespread pain and mild or greater tenderness in greater than or equal to 11 of 18 tender point sites yielded a sensitivity of 88.4% and a specificity of 81.1%. Primary fibromyalgia patients and secondary-concomitant fibromyalgia patients did not differ statistically in any major study variable, and the criteria performed equally well in patients with and those without concomitant rheumatic conditions. The newly proposed criteria for the classification of fibromyalgia are 1) widespread pain in combination with 2) tenderness at 11 or more of the 18 specific tender point sites. No exclusions are made for the presence of concomitant radiographic or laboratory abnormalities. At the diagnostic or classification level, the distinction between primary fibromyalgia and secondary-concomitant fibromyalgia (as defined in the text) is abandoned.

The American College of Rheumatology criteria for the classification and reporting of osteoarthritis of the hip.

Abstract: Clinical criteria for the classification of patients with hip pain associated with osteoarthritis (OA) were developed through a multicenter study. Data from 201 patients who had experienced hip pain for most days of the prior month were analyzed. The comparison group of patients had other causes of hip pain, such as rheumatoid arthritis or spondylarthropathy. Variables from the medical history, physical examination, laboratory tests, and radiographs were used to develop different sets of criteria to serve different investigative purposes. Multivariate methods included the traditional "number of criteria present" format and "classification tree" techniques. Clinical criteria: A classification tree was developed, without radiographs, for clinical and laboratory criteria or for clinical criteria alone. A patient was classified as having hip OA if pain was present in combination with either 1) hip internal rotation greater than or equal to 15 degrees, pain present on internal rotation of the hip, morning stiffness of the hip for less than or equal to 60 minutes, and age greater than 50 years, or 2) hip internal rotation less than 15 degrees and an erythrocyte sedimentation rate (ESR) less than or equal to 45 mm/hour; if no ESR was obtained, hip flexion less than or equal to 115 degrees was substituted (sensitivity 86%; specificity 75%). Clinical plus radiographic criteria: The traditional format combined pain with at least 2 of the following 3 criteria: osteophytes (femoral or acetabular), joint space narrowing (superior, axial, and/or medial), and ESR less than 20 mm/hour (sensitivity 89%; specificity 91%). The radiographic presence of osteophytes best separated OA patients and controls by the classification tree method (sensitivity 89%; specificity 91%). The "number of criteria present" format yielded criteria and levels of sensitivity and specificity similar to those of the classification tree for the combined clinical and radiographic criteria set. For the clinical criteria set, the classification tree provided much greater specificity. The value of the radiographic presence of an osteophyte in separating patients with OA of the hip from those with hip pain of other causes is emphasized.

Cytokines and cytokine inhibitors or antagonists in rheumatoid arthritis.

Abstract: This review has summarized some of the evidence suggesting that cytokines may play an important role in mediating pathophysiologic events in RA. However, these proteins are capable of mediating both stimulatory (agonist) and inhibitory (antagonist) effects in the rheumatoid synovium. GM-CSF, IL-1, TNF alpha, and PDGF are all produced in the rheumatoid synovium and may function to induce inflammation, enzyme release, fibroblast proliferation, and tissue destruction. Local release of IL-6 may alter the effects of IL-1 and TNF alpha, as well as induce Ig production and hepatic synthesis of acute-phase proteins. However, specific inhibitors of IL-1 and TNF alpha exist, which, if also released into the synovium, may antagonize the proinflammatory effects of these cytokines. In addition, IL-1 may have antiinflammatory effects, such as the induction of the synthesis of collagen and enzyme inhibitors by chondrocytes and synovial fibroblasts. Stimulation of these latter cells by TGF beta also may result in decreased matrix degradation and increased formation of scar tissue. The developing scenario is one of cell-cell interactions that are influenced in positive and negative manners by the local release of various mediators. A further understanding of cytokines and cytokine inhibitors in the rheumatoid synovium may lead to the development of more specific and effective therapeutic agents.

Measurement of increases in anti-double-stranded DNA antibody levels as a predictor of disease exacerbation in systemic lupus erythematosus. A long-term, prospective study.

Abstract: To evaluate the predictive power of changes in levels of antibodies to double-stranded DNA (anti-dsDNA) as a predictor of disease exacerbations in systemic lupus erythematosus (SLE), we performed a prospective study on 72 unselected patients with SLE (mean duration of study 18.5 months, range 6-35 months). Patients were seen at least once every 3 months, and disease activity was scored according to a specific protocol. Plasma samples were obtained at least once every month and were assessed for anti-dsDNA antibody (by the Crithidia luciliae assay, an enzyme-linked immunosorbent assay [ELISA], and the Farr assay) and for complement components C3 and C4. Twenty-seven of 33 disease exacerbations observed during the study period were accompanied by a positive test result for anti-dsDNA antibody (27 by the Farr assay, 19 by the C luciliae assay, and 23 by the ELISA). Twenty-four of these exacerbations were preceded by a significant increase in anti-dsDNA antibody levels (23 by the Farr assay, 12 by the C luciliae assay, and 17 by the ELISA). The first observance of a significant increase in anti-dsDNA antibody levels preceded the exacerbation by 8-10 weeks. Significant increases in anti-dsDNA antibody levels not followed by an exacerbation were observed in 5 cases by the Farr assay, in 7 cases by the C luciliae assay, and in 3 cases by the ELISA; however, in 3 cases, 2 cases, and 1 case, respectively, these increases were followed by an increase in disease activity that did not fulfill the criteria for an exacerbation. Serial measurement of anti-dsDNA antibody levels was more sensitive for predicting exacerbations than was measurement of C3 and/or C4 levels (P less than 0.03). Serial assessment of anti-dsDNA antibody levels, especially by the Farr assay, is a sensitive and reasonably specific method for predicting disease exacerbations in SLE.

Evidence for impaired T cell DNA methylation in systemic lupus erythematosus and rheumatoid arthritis.

Abstract: Procainamide and hydralazine inhibit T cell DNA methylation and induce autoreactivity in cloned CD4+ T cells. These drugs also induce an autoimmune syndrome, suggesting a possible relationship between DNA hypomethylation, T cell autoreactivity, and certain autoimmune diseases. To test this relationship, DNA methylation was studied in T cells from patients with rheumatoid arthritis and patients with systemic lupus erythematosus, and was found to be impaired. These results support a relationship between DNA hypomethylation and some forms of autoimmune disease.

Dietary fish oil and olive oil supplementation in patients with rheumatoid arthritis. Clinical and immunologic effects.

Abstract: Forty-nine patients with active rheumatoid arthritis completed a 24-week, prospective, double-blind, randomized study of dietary supplementation with 2 different dosages of fish oil and 1 dosage of olive oil. Clinical evaluations were performed at baseline and every 6 weeks thereafter, and immunologic variables were measured at baseline and after 24 weeks of study. The 3 groups of patients were matched for age, sex, disease severity, and use of disease-modifying antirheumatic drugs (DMARDs). Subjects continued receiving DMARDs and other background medications without change during the study. Twenty patients consumed daily dietary supplements of n3 fatty acids containing 27 mg/kg eicosapentaenoic acid (EPA) and 18 mg/kg docosahexaenoic acid (DHA) (low dose), 17 patients ingested 54 mg/kg EPA and 36 mg/kg DHA (high dose), and 12 patients ingested olive oil capsules containing 6.8 gm of oleic acid. Significant improvements from baseline in the number of tender joints were noted in the low-dose group at week 24 (P = 0.05) and in the high-dose group at week 18 (P = 0.04) and 24 (P = 0.02). Significant decreases from baseline in the number of swollen joints were noted in the low-dose group at weeks 12 (P = 0.003), 18 (P = 0.002), and 24 (P = 0.001) and in the high-dose group at weeks 12 (P = 0.0001), 18 (P = 0.008), and 24 (P = 0.02). A total of 5 of 45 clinical measures were significantly changed from baseline in the olive oil group, 8 of 45 in the low-dose fish oil group, and 21 of 45 in the high-dose fish oil group during the study (P = 0.0002). Neutrophil leukotriene B4 production decreased by 19% from baseline in the low-dose fish oil group (P = 0.0003) and 20% in the high-dose group (P = 0.03), while macrophage interleukin-1 production decreased by 38.5% in the olive oil group (P not significant), 40.6% in the low-dose group (P = 0.06), and 54.7% in the high-dose group (P = 0.0005). Tritiated thymidine incorporation in peripheral blood mononuclear cells after stimulation with concanavalin A increased significantly in all 3 groups after 24 weeks, compared with baseline values. We conclude that the clinical benefits of dietary supplementation with omega-3 fatty acids are more commonly observed in patients consuming higher dosages of fish oil for time intervals that are longer than those previously studied. Dietary supplementation with olive oil is also associated with certain changes in immune function, which require further investigation.

The comparative efficacy and toxicity of second‐line drugs in rheumatoid arthritis results of two metaanalyses

Abstract: We performed 2 metaanalyses of placebo-controlled and comparative clinical trials to examine the relative efficacy and toxicity of methotrexate (MTX), injectable gold, D-penicillamine (DP), sulfasalazine (SSZ), auranofin (AUR), and antimalarial drugs, the second-line drugs most commonly used to treat rheumatoid arthritis (RA). For the efficacy study, we applied a set of inclusion criteria and focused on trials which provided information on tender joint count, erythrocyte sedimentation rate, or grip strength. We found 66 clinical trials that contained 117 treatment groups of interest, and for each drug, we combined the treatment groups. For each outcome, results showed that AUR tended to be weaker than other second-line drugs. The results of the 3 outcome measures were synthesized into a composite measure of outcomes, and AUR was significantly weaker than MTX (P = 0.006), injectable gold (P < 0.0001), DP (P < 0.0001), and SSZ (P = 0.009) and was slightly, but not significantly, weaker than antimalarial agents (P = 0.11). We also found heterogeneity among antimalarial agents, in that patients treated with chloroquine did better than those treated with hydroxychloroquine. We found little difference in efficacy between MTX, injectable gold, DP, and SSZ. A power analysis showed that a trial should contain at least 170 patients per treatment group to successfully differentiate between more effective and less effective (e.g., AUR) second-line drugs. None of the reported interdrug comparative trials we reviewed were this large. For the toxicity study, our inclusion criteria captured RA trials which reported the proportion of patients who discontinued therapy because of drug toxicity and the total proportion who dropped out. We found 71 clinical trials that contained 129 treatment groups. The average proportion who dropped out and the average proportion who dropped out because of drug toxicity were computed for each drug. Overall, 30.2% of the patients in these trials dropped out; 50% of them did so because of drug toxicity. Injectable gold had higher toxicity rates (P < 0.05) and higher total dropout rates (P < 0.01) than any other drug; 30% of goldtreated patients dropped out because of side effects versus 15% of all trial patients. Antimalarial drugs and AUR had relatively low rates of toxicity; the rate for MTX was imprecise because of discrepancies between trials. Thus, of the commonly used second-line drugs, AUR is the weakest, and injectable gold is the most toxic. Agents introduced in the future will be compared with these drugs. If a curative drug is not found, large multicenter trials or data synthesis from multiple drug trials may be necessary to identify new treatment regimens that have promise.

Prognosis in systemic lupus erythematosus

Abstract: To assess the impact of demographic and clinical factors on prognosis in patients with systemic lupus erythematosus (SLE), we examined survivorship by life-table analysis in 389 patients. There were approximately equal numbers of Caucasian patients and American black patients in this study group. On both univariate and multivariate analyses, we found that both American black race and increasing age at SLE onset independently worsened the probability of survival. Of all the clinical factors we analyzed, thrombocytopenia emerged as the only independent risk factor for a worse prognosis in SLE. In all clinical and demographic groups considered, the leading cause of death was infection.

Analysis of improvement in individual rheumatoid arthritis patients treated with disease‐modifying antirheumatic drugs, based on the findings in patients treated with placebo

Abstract: A composite index for estimating improvement in individual rheumatoid arthritis (RA) patients during trials of slow-acting, disease-modifying antirheumatic drugs (DMARDs) was developed by analyzing the responses of 130 placebo-treated participants in Cooperative Systematic Studies of Rheumatic Diseases studies. If responses in 4 of 6 selected measures were required for improvement (by greater than or equal to 20% for morning stiffness, Westergren erythrocyte sedimentation rate, joint pain/tenderness score, and joint swelling score, and by greater than or equal to 2 grades on a 5-grade scale, or from grade 2 to grade 1 for patient's and physician's overall assessments of current disease severity), few placebo-treated patients qualified as improved, whereas significantly more DMARD-treated patients demonstrated improvement. The proposed index appears to be useful in estimating the probability that an RA patient will improve if taking a placebo during a DMARD trial, and may be a useful tool for analysis of DMARD studies.

High frequency of fibromyalgia in patients with chronic fatigue seen in a primary care practice.

Abstract: We administered a standardized history questionnaire and performed a tender point examination on 27 patients with debilitating fatigue of at least 6 months duration, seen in a primary care practice, as well as on 20 patients with fibromyalgia. Sixteen of the 27 patients with chronic fatigue met the full criteria for the working case definition of chronic fatigue syndrome (CFS). Eight patients with chronic fatigue denied having any current persistent, diffuse musculoskeletal pain, and their tender point scores were similar to those in 10 normal control subjects. In contrast, 19 patients with chronic fatigue (70%) had persistent, diffuse musculoskeletal pain. The results of their tender point examinations were similar to those of the patients with fibromyalgia. Thus, the majority of these patients with debilitating chronic fatigue, including those who met criteria for CFS, met the historical and tender point diagnostic criteria for fibromyalgia. The presence of current musculoskeletal pain will identify those CFS patients who have fibromyalgia.

Antibody to signal recognition particle in polymyositis

Abstract: Using immunoprecipitation, we identified 13 patients with antibodies to the signal recognition particle (SRP) from a collection of sera representing 265 polymyositis/dermatomyositis (PM/DM) patients. Antibody reactivity with SRP was confirmed by enzyme-linked immunosorbent assay and immunoprecipitation with isolated dog pancreas SRP. The antibody was present in the serum of 4% of PM/DM patients, and 18% of PM/DM patients with anticytoplasmic antibodies other than anti-Jo-1, but not in patients with other conditions who had anticytoplasmic antibodies. Anti-SRP was associated with classic adult PM, and some of these cases were unusually severe and/or of rapid onset; it was not found in patients with overlap syndromes or with DM involvement. Unlike patients with antibodies to aminoacyl-transfer RNA synthetases, patients with anti-SRP had a low frequency of pulmonary fibrosis, as well as of arthritis and Raynaud's phenomenon. Anti-SRP antibodies may serve as a marker for a second, distinct subgroup of adult PM.

Elevated levels of interleukin-6 in cerebrospinal fluid from patients with systemic lupus erythematosus and central nervous system involvement

Abstract: Paired serum and cerebrospinal fluid (CSF) specimens from 14 patients with systemic lupus erythematosus (SLE) and central nervous system (CNS) involvement were studied for interleukin-6 (IL-6) activity using the IL-6-dependent murine hybridoma, MH60.BSF2. We also studied 23 patients with noninflammatory neurologic diseases, and 9 SLE patients without CNS involvement. CSF IL-6 activity was elevated only in SLE patients with CNS involvement, although there was no significant difference in serum IL-6 activity among the 3 groups. CSF IL-6 activity was not correlated with either the CSF-serum albumin quotient (Q albumin; an indicator of blood-brain barrier function) or serum IL-6 activity in SLE patients with CNS involvement. The CSF IL-6 activity decreased significantly when CNS manifestations subsided after successful treatment. These results indicate that determination of CSF IL-6 activity may be useful in the evaluation of CNS disease activity in SLE. Moreover, the data confirm the presence of immune system activation within the CNS in patients with SLE-associated CNS disease.

The effect of folic acid supplementation on the toxicity of low-dose methotrexate in patients with rheumatoid arthritis.

Abstract: Thirty-two patients with rheumatoid arthritis completed a 24-week, placebo-controlled, double-blind trial of folic acid (FA) supplementation during low-dose methotrexate (MTX) therapy. Administration of the daily FA supplement significantly lowered toxicity scores without affecting efficacy, as measured by joint counts, joint indices, and patient and physician evaluation of disease activity. Fifteen patients experienced some sort of toxicity; 67% were in the placebo group, and 33% were in the FA supplement group. Four patients in the placebo group had toxicity levels serious enough to require discontinuation of the MTX, while no patients in the FA supplement group discontinued MTX because of toxicity. Low-normal initial plasma and red blood cell folate levels were predictive of future toxicity with MTX therapy. We conclude that a daily supplement of 1 mg of FA during low-dose MTX therapy (median dose 7.5 mg/week [16.4 mumoles]) is usefull in lessening toxicity without altering efficacy during the first 6 months of treatment.

Detection of serum antibodies to retroviral proteins in patients with primary sjögren's syndrome (autoimmune exocrinopathy)

Abstract: Primary Sjogren's syndrome (SS) is considered a benign autoimmune disease; it is characterized by lymphoid infiltration of salivary and lacrimal glands, often accompanied by the presence of serum autoantibodies, particularly anti-Ro (SS-A) and anti-La (SS-B). There are important immunologic similarities between primary SS and acquired immunodeficiency syndrome. To investigate for a possible immune response to retroviral proteins in primary SS, we performed immunoblotting against human immunodeficiency virus-1 (HIV-1) proteins using sera from 47 patients with primary SS. Moderate-to-strong reactivity, suggesting the presence of serum antibodies, was found in 14 patients (30%). Of 120 normal subjects, only 1 showed moderate positivity. All 14 positive SS sera reacted against p24 (gag) but failed to react against gp41 or gp120 (env). This response did not reflect hypergammaglobulinemia since immunoglobulin concentrations among the 29 SS patients studied were the same in sera that contained and sera that did not contain anti-gag reactivity. Two sera also reacted against p17 gag. Four reacted against HIV-2 core proteins, but none reacted with core proteins of human T lymphotropic virus-I. Only 1 of the 14 sera reacted against Ro (SS-A), and 1 other reacted against La (SS-B). These results identify a subset of SS patients characterized by 1) the presence of serum antibodies to HIV-1 group-specific, but not type-specific, proteins, and 2) the relative absence of anti-Ro (SS-A) and anti-La (SS-B) autoantibodies. In this latter respect, these SS patients constitute a subpopulation that resembles patients with HIV-induced SS-like disease.

The role of stromelysin in the cartilage destruction that accompanies inflammatory arthritis.

Abstract: Articular cartilage from arthritic joints of rats immunized with type II collagen is severely depleted of proteoglycans. Depletion begins within 48 hours after the onset of inflammation, prior to extensive pannus formation, and may represent a critical first step in cartilage destruction. We have immunolocalized stromelysin, an enzyme that is believed to play a major role in the pathologic degradation of proteoglycans, in the joints of rats with collagen-induced arthritis. Immunoperoxidase staining of frozen tissue sections demonstrated the presence of stromelysin in both the synovium and chondrocytes. In contrast, collagenase was localized primarily to the pannus-cartilage junction. Neither enzyme was detectable in joints from normal animals. To test the hypothesis that chondrocytes respond directly to inflammatory mediators by increasing the production of stromelysin, isolated chondrocytes were incubated with various concentrations of interleukin-1. The culture media were also assayed for the presence of stromelysin by immunoreactivity on Western blots and by analysis of enzymatic activity on casein substrate gels. A 3-fold increase in a doublet of proteins synthesized in response to 10 units/ml of interleukin-1 was observed. These proteins also immunoreacted with the stromelysin antibody and degraded casein. Northern blotting results established that the increased levels of stromelysin were accompanied by increases in stromelysin-specific messenger RNA levels. These results suggest that stromelysin is responsible for proteoglycan degradation in early inflammatory arthritis, and that chondrocytes may play a direct role in the earliest stages of the degradation of their own matrices.

Specificity of antibodies to type II collagen in rheumatoid arthritis.

Abstract: To reassess the role of autoantibodies to type II collagen in the pathogenesis of diseases, we studied antibodies from patients with rheumatoid arthritis (RA) and from patients with relapsing polychondritis for species specificity and collagen type specificity, using an improved enzyme-linked immunosorbent assay. Antibodies were found in the sera of 15% of the RA patients and 50% of the relapsing polychondritis patients, as well as in the cartilage of 69% of the RA patients examined. Reaction with both homologous and heterologous type II collagens was common. Analysis of 19 selected RA sera revealed that autoantibodies were generally associated with specific antibodies to some species of heterologous type II collagen. In contrast, antibodies found in 4% of the non-RA controls were specific for either bovine or chick type II collagen. These findings indicate that autoantibody formation in RA and relapsing polychondritis may occur as a result of an immune response to heterologous type II collagen. However, since RA and relapsing polychondritis patient sera differed in their reactivity with the cyanogen bromide-digested peptides, it is possible that the clinical manifestation of collagen autoimmunity might be influenced by the epitope specificity of the antibodies.

Substance P and arthritis: analysis of plasma and synovial fluid levels.

Abstract: The uncadecapeptide substance P (SP), which is localized in peripheral and central terminals of afferent nerve fibers with polymodal nociceptors, has recently been implicated as having a neurogenic, inflammatory role in experimental arthritis. We used a radioimmunoassay to measure SP levels in plasma and synovial fluid samples from patients with rheumatoid arthritis (RA), osteoarthritis (OA), Reiter's syndrome (RS), and posttraumatic arthritis, as well as in plasma samples from 13 normal subjects. Plasma SP levels in RS patients exceeded levels in RA and OA patients, which in turn exceeded levels in posttrauma patients and in normal subjects. Synovial fluid SP levels exceeded respective plasma levels for all groups, except in RS patients, in whom the plasma level was not significantly different from that in synovial fluid. SP levels in synovial fluid of RA, OA, and RS patients did not differ significantly from each other, but the level in posttrauma patients was higher than in all other groups (P less than 0.005). These studies demonstrate localized intraarticular SP release, and significant plasma/synovial fluid SP concentration gradients in several forms of arthritis.

Constitutive production of interleukin‐6 and immunologic features in cardiac myxomas

Abstract: The constitutive production of interleukin-6 (IL-6), a potent hepatocyte-stimulating factor and B cell-differentiating factor, was demonstrated in 3 patients with cardiac myxomas. Tumor cells from the only patient who presented with immunologic features produced 14-23-fold higher levels of IL-6 than those from the 2 patients who lacked such features. A significant serum IL-6 level (56 pg/ml), greater than that observed in patients with active rheumatoid arthritis, was also observed only in this patient, with a subsequent return to an undetectable level after surgical removal of the tumor. This was associated with a regression of the immunologic features. This same patient was observed to have an IL-6-dependent, proliferative polyclonal plasmacytosis of the bone marrow. These observations demonstrate that an overproduction of IL-6 by cardiac myxoma cells, in association with a systemic passage of this IL-6, may be responsible for the immunologic features similar to those observed in true autoimmune diseases such as rheumatoid arthritis.

Rheumatologic manifestations of human parvovirus B19 infection in adults. Initial two-year clinical experience.

Abstract: During 1987 and 1988, we identified 9 adults at the Medical and Rheumatology Services of the University of Iowa Hospitals and Clinics who had a clinical diagnosis of fifth disease; 8 of the 9 had symptoms of joint involvement. Another 12 adults with serologic positivity for anti-parvovirus B19 IgM antibody presented with polyarthralgia/polyarthritis. Patients were usually found to be seronegative for rheumatoid factor, and none developed nodules or erosive disease. Many patients with chronic disease met criteria for a diagnosis of rheumatoid arthritis. A diagnosis of parvovirus B19 infection should be considered during the initial visit of patients with polyarthralgia/polyarthritis.

Dissociation of immune responses to the SS-A (Ro) 52-kd and 60-kd polypeptides in systemic lupus erythematosus and Sjögren's syndrome.

Abstract: The cellular RNA particle SS-A (Ro) is a target of autoimmune response in many patients with Sjogren's syndrome (SS) and systemic lupus erythematosus (SLE). Recent immunologic, biochemical, and DNA cloning studies have shown that the SS-A particle consists of at least 2 polypeptide components, of 52 kd and 60 kd. Immunodiffusion analysis of 60 sera from patients with primary SS revealed 47 (78%) to be SS-A precipitin positive. Western blotting studies of the sera showed 3 groups of reactivities: 22 (47%) possessed autoantibodies against both the 60-kd and the 52-kd polypeptides, 19 (40%) reacted only with the 52-kd protein, and 6 (13%) were nonreactive in Western blots although positive in immunodiffusion. Fifty-one of 90 SLE sera (57%) were SS-A precipitin positive by immunodiffusion. In Western blots, 24 (47%) possessed antibodies against both the 60-kd and the 52-kd antigens, while 9 (18%) reacted only with the 60-kd protein. Eighteen (35%) were nonreactive by Western blot, although positive by immunodiffusion. Antibody to the 52-kd antigen without concomitant antibody to the 60-kd antigen was seen only in patients with primary SS, whereas antibody to the 60-kd antigen without concomitant antibody to the 52-kd antigen was seen only in SLE patients. Although antibodies to SS-A are detected in both SS and SLE, our findings show that there is dissociation of immune responses to the 2 component antigens of the particle, which may be evidence of different events initiating the autoimmune process in these diseases.

Estrogen use and radiographic osteoarthritis of the knee in women. The Framingham Osteoarthritis Study.

Abstract: Female participants of the Framingham Osteoarthritis Study (n = 831, mean age 73, age range 63–93) were evaluated for osteoarthritis with weight-bearing radiographs of the knee during 1983–1985. At each biennial examination (1963–1981), the women were asked about their use of estrogen during the previous 2 years. We categorized estrogen use as no use reported, use reported at 1 examination, or use reported at 2 or more examinations. We found no positive association of estrogen use with radiographic knee osteoarthritis after controlling for age, body mass index, age at menopause, physical activity, history of knee injury, and smoking. In fact, a modest but nonsignificant protective effect for both radiographic osteoarthritis (odds ratio 0.71, 95% confidence interval 0.42, 1.20) and severe radiographic osteoarthritis (odds ratio 0.66, 95% confidence interval 0.33, 1.32) was seen in women who reported estrogen use at 2 or more examinations. Subgroup analyses also showed no association between estrogen use and radio-graphic knee osteoarthritis. We conclude that estrogen use in women is not associated with an increased risk of radiographic knee osteoarthritis.

The effect of marginal osteophytes on reduction of varus‐valgus instability in osteoarthritic knees

Abstract: The varus-valgus stability of 20 knees with unicompartmental osteoarthritis was studied in vivo at the time of total knee replacement. Intact osteoarthritic knees had an average of 11.0 degrees of varus-valgus motion. Removal of osteophytes from the osteoarthritic compartment significantly increased the motion to 13.1 degrees (P less than 0.05), while subsequent removal of osteophytes from the nonosteoarthritic compartment further increased motion to 14.7 degrees (P less than 0.025). In primarily unicompartmental osteoarthritis, marginal osteophytes appear to stabilize osteoarthritic knees, but can cause fixed deformity.

The pill, parity, and rheumatoid arthritis.

Abstract: The authors report on a case-control study investigating the relationship of oral contraceptive (OC) use and parity to the development of rheumatoid arthritis (RA). Women with RA were compared with 2 separate control groups women with osteoarthritis (OA) and women randomly selected from a population=based electoral register. Nulliparity was found to be a risk factor for the development of RA with age-adjusted odds ratios of 1.82 (95% confidence interval [CI] 1.09-3.03) vs the OA control group and 1.83 (95% CI 1.03-3.06) vs the population control group. Use of OCs before the age of 35 was negatively associated with RA (odds ratio 0.56 95% CI 0.29-1.12 vs the OA control group; odds ratio 0.6 95% CI 0.30-1.17 vs the population control group). Some evidence of a duration response effect was seen although the numbers were small. The 2 variables were also multiplicative with nulliparous non-OC users having a 4-fold risk of RA compared with parous OC users. These findings suggest that pregnancy and OC use have a protective effect on the development of RA although the mechanism remains unclear. (authors)

Contribution of renal biopsy data in predicting outcome in lupus nephritis. Analysis of 116 patients.

Abstract: We reassessed renal biopsy specimens from 116 patients with systemic lupus erythematosus and clinical manifestations of lupus nephritis to determine the contributions of the World Health Organization classification system, the activity and chronicity indexes of the National Institutes of Health scoring system, and various clinical parameters at the time of biopsy to predicting disease outcome. Multivariate analysis showed that only a chronicity index greater than 3 was predictive for decreased renal survival, while age greater than 31 years at biopsy and a chronicity index greater than 3 were associated with decreased patient survival. Clinical tests of renal function were not reliable in discriminating between active lesions and chronic renal damage.

Homologous type II collagen-induced arthritis in rats. Characterization of the disease and demonstration of clinically distinct forms of arthritis in two strains of rats after immunization with the same collagen preparation.

Abstract: Arthritis was induced in Lewis and DA rat strains after immunization with native homologous type II collagen (CII). Differences were noted in the clinical signs of arthritis in the 2 rat strains, which were immunized with the same arthritogenic preparation of CII. DA rats showed disease onset characterized by symmetric involvement of the interphalangeal joints of the hind feet. Lewis rats showed disease onset characterized by involvement of only the ankle or knee joints. Moreover, the arthritis tended to be chronic (i.e., persistent and variable redness and swelling seen in interphalangeal joints) in DA rats, but not in Lewis rats. Analysis of the delayed-type hypersensitivity reaction to CII and anti-CII autoantibody production demonstrated the presence of T cell, as well as B cell, reactivity to rat CII in both strains of rat. A spontaneous T cell reactivity to CII, as measured by rat CII-induced ear swelling, was observed in nonimmunized DA rats, but not in nonimmunized Lewis rats. The demonstration that clinical features of arthritis induced with identical arthritogenic stimuli are different depending on the genetic background of the affected animal may be relevant in understanding the heterogeneity of the clinical features of human inflammatory joint disease.

Imbalance between the mechanisms of activation and inhibition of metalloproteases in the early lesions of experimental osteoarthritis.

Abstract: Levels of tissue inhibitor of metalloproteases (TIMP) and plasminogen activator (PA)/plasmin were measured and the distribution of PA was studied by immunohistochemical techniques in cartilage and synovium samples from dogs subjected to sectioning of the anterior cruciate ligament of their right knees and sham operation of their left knees (controls). Twenty-three animals were divided into 3 groups and killed at 2, 4, or 8 weeks after surgery. The levels of PA and plasmin were found to be significantly elevated in the osteoarthritic (OA) knee cartilage and synovium at all times after surgery, except for levels of PA in the OA cartilage at 2 weeks. There was a positive correlation between the levels of PA and plasmin in the synovial membrane (r = 0.64, P less than 0.001). In OA knees, the presence of high levels of total and active collagenase was detected in cartilage and in synovium. The levels of these 2 forms of collagenase showed a positive correlation both in cartilage (r = 0.65, P less than 0.001) and in synovium (r = 0.77, P less than 0.001). The levels of TIMP in cartilage from OA and sham operated knees were similar. Although the TIMP level was increased in the OA synovium, it was found only in trace amounts in cartilage. Immunohistochemical studies revealed that both forms of PA, urokinase-type PA and tissue-type PA, and TIMP were present in OA tissues. In the synovium, they were found mainly in monocyte/macrophages, synovial lining cells, and blood vessel cells. In OA cartilage, PA was present only at the superficial level in chondrocytes and in cartilage matrix, whereas TIMP was present in chondrocyte lacunae throughout the full thickness of the cartilage. TIMP was also detected in the superficial level of cartilage from sham operated knees. The results of this study indicate that in OA tissues, there are conditions that favor the synthesis and activation of metalloproteases. PA and plasmin are likely to play an important role in the physiologic activation of metalloproteases, although they are probably not the only system involved in this process. The lack of increased TIMP levels in the OA cartilage, in the presence of increased metalloprotease activity, is also a possible contributing factor in the enzymatic degradation of this tissue.

Dermal mast cell degranulation in systemic sclerosis.

Abstract: Paired biopsy samples from involved and uninvolved skin were obtained from 19 patients with generalized scleroderma (11 with early, progressive disease and 8 with late, improving disease). Skin biopsy samples were double stained for mast cell granules and for mast cell membrane. The number of mast cells was increased in patients with systemic sclerosis (SSc), in both involved and uninvolved skin and in both early and late disease. There was an increase in the number of degranulated mast cells in the involved skin of patients with both early and late disease and in the not-yet-involved skin of patients with early disease; however, there was no increase in the number of degranulated mast cells in areas of previously involved but now normal skin of patients with late disease. Increases in mast cell number and degranulation precede clinically apparent dermal fibrosis in SSc. These observations and the absence of mast cell degranulation in regressing skin suggest a participatory role of the mast cell in the clinical progression of skin changes in SSc.