Reduction of cortisol levels after single intra-articular and intramuscular steroid injection.

BACKGROUND: This study was undertaken to determine the influence of single intra-articular or intra muscular injections of methylprednisolone acetate on the hypothalamic-pituitary-adrenal axis. PATIENTS AND METHODS: Twenty-one patients with rheumatic disease who had never been treated with systemic glucocorticoids and had not received local injections of these agents for the preceding 2 months, were given 40 mg of methylprednisolone acetate. Group I (11 patients) received one intra-articular injection into the knee, and Group II (10 patients) received the same dose intramuscularly. RESULTS: In Group I, serum cortisol levels were significantly decreased 24 hours after injection (228.2 +/- 8.7 nmol/L versus 193 +/- 16.3 nmol/L; P < 0.05). Serum cortisol levels were decreased in 9 of the 11 patients, by an average of 21.5%. Two patients' levels were below 138 nmol/L, which is considered to be the lower limit of normal range. Serum cortisol levels were below normal range in 3 patients 72 hours after intra-articular steroid injection. In Group II, serum cortisol levels were significantly decreased at 72 hours after injection (239.6 +/- 10.3 nmol/L versus 175.6 +/- 21.4 nmol/L; P < 0.01). Three patients' levels were below normal. By 72 hours postinjection, serum cortisol concentrations in 9 of 10 patients were decreased by an average of 31% compared to preinjection values. CONCLUSION: The present study suggests that decreased adrenocortical secretion, as reflected in depressed cortisol levels, can result from a single, low-dose, intra-articular or intramuscular injection of depot corticosteroids.

Can foot orthoses prevent hallux valgus deformity in rheumatoid arthritis? A randomized clinical trial.

Hallux valgus deformity is the most commonly observed forefoot deformity in patients with rheumatoid arthritis. This 5-year, double-blind, randomized clinical trial compared treatment orthoses with placebo orthoses for the prevention of hallux valgus deformity in the rheumatoid arthritic foot.One hundred and two subjects with active rheumatoid arthritis and with foot pain and minimal radiographic changes of the feet participated in the study. They were recruited from five arthritis clinics in the Chicago metropolitan area that are affiliated with or are teaching clinics of area medical schools. Patients were followed for 3 years.Eighty-one subjects completed the study. In a logistic regression analysis, the treatment group was 73% less likely to develop hallux valgus deformity compared with the control group (adjusted odds ratio 0.27, 95% confidence interval 0.078, 0.916 p = .04). These findings suggest that foot orthoses can prevent or slow the progression of hallux valgus deformity.

Comparison of hydroxychloroquine and placebo in the treatment of the arthropathy of mild systemic lupus erythematosus.

OBJECTIVE: To compare the relative safety and efficacy of hydroxychloroquine (HCQ) and placebo (Pl) in the treatment of the articular complaints of systemic lupus erythematosus (SLE). METHODS: Seventy-one patients with mild SLE requiring < or = 10 mg of prednisone or equivalent daily and with arthritis or arthralgias were entered into a 48-week prospective, controlled, double blind multicenter trial and randomly assigned to either HCQ or Pl. RESULTS: Both HCQ and Pl were well tolerated in the 48-week trial. There were no remissions. With the exception of the patient assessment of joint pain, all other joint measures were similar between the groups. Twenty-nine patients withdrew before the end of the trial although only 2 patients withdrew for adverse drug effects. CONCLUSION: Our study found subjective pain relief as the only statistically significant difference in joint count variables from HCQ in the treatment of the articular manifestations of SLE.

Cholesterol crystals in synovial and bursal fluid.

Cholesterol crystals were found in two patients with classic rheumatoid arthritis (RA). In one patient, cholesterol crystals were found in synovial fluid from both shoulder joints, and in the second they were in an olecranon bursa. To examine the possible systemic etiology of cholesterol crystals in synovial and bursal fluid, lipid concentrations and the presence of serum antilipoprotein antibodies were measured. Antilipoprotein antibodies were not found. The concentration of lipid and lipoproteins, as well as the normal pattern of lipoprotein on agarose gel, eliminates the possibility of hyperlipoproteinemia. Results seemed to exclude a systemic etiology for the formation of cholesterol crystals in synovial and bursal fluid in the RA patients. It appears that several local factors such as defective drainage, local destruction, increased permeability of synovial membrane, and intraarticular (bursal) bleeding are possible etiologies.

Comparison of naproxen and acetaminophen in a two-year study of treatment of osteoarthritis of the knee.

OBJECTIVE: To compare the relative safety and efficacy of naproxen and acetaminophen in the treatment of osteoarthritis (OA) of the knee. The major outcome measures were radiographic progression and withdrawal from the trial due to lack of efficacy. METHODS: One hundred seventy-eight patients with OA of the knee were enrolled in a 2-year prospective, controlled, double-blind multicenter trial and were randomly assigned to receive acetaminophen (ACT) or naproxen (NPX) treatment. RESULTS: After 6 weeks of treatment, modest improvement in pain on motion and in physician's global assessment was seen in both the ACT and the NPX groups, and the NPX group also had modest improvement in pain at rest and in 50-foot walk time. Sixty-two patients completed the 2-year study. Among these patients, radiographic progression was similar in the 2 treatment groups. Withdrawal from the trial due to lack of drug efficacy was slightly more frequent among patients in the ACT group (22% versus 16%), but withdrawal due to adverse drug effects was slightly more common in the NPX group (23% versus 18%). CONCLUSION: The efficacy of ACT treatment and NPX treatment was similar, although it was slightly better for NPX. The toxicity rate was slightly lower with ACT. However, the high rate of withdrawal in both treatment groups suggests that neither is satisfactory for the treatment of OA.

Systemic lupus erythematosus and Hodgkin's lymphoma.

OBJECTIVE: Systemic lupus erythematosus (SLE) is associated with lymphoproliferative diseases such as Hodgkin's lymphoma. Since there is considerable overlap between the features of SLE and Hodgkin's lymphoma (SLE/HL) there can be a great difficulty in diagnosing Hodgkin's lymphoma in the presence of SLE. Our objective was to determine the features that can suggest coexistent SLE/HL: METHODS: We describe 3 cases of Hodgkin's lymphoma that occurred in the setting of SLE and review the features of 11 reported cases in which the diseases occurred simultaneously. We compare the features of these cases with those of Hodgkin's lymphoma and SLE occurring alone. RESULTS: Mediastinal adenopathy was seen in 58% and retroperitoneal adenopathy in 17% of patients with SLE/HL, while it was seen only rarely in these sites in cases with SLE. Severe generalized pruritus, which occurs in only 2.8% of cases of SLE, was seen in 63% of cases with SLE/HL: Features such as fever, weight loss, peripheral lymphadenopathy, splenomegaly and hepatomegaly are common to both Hodgkin's lymphoma and SLE. Renal disease is seen in half of the cases of SLE. It is rare in Hodgkin's lymphoma where, unlike SLE, it is only of minimal change or membranous type. Arthritis and positive antinuclear antibodies are rare in Hodgkin's lymphoma. CONCLUSIONS: Persistent lymphadenopathy, especially mediastinal and/or retroperitoneal lymphadenopathy, eosinophilia and generalized pruritus in a patient with SLE not responding to treatment may be indicative of coexistent Hodgkin's lymphoma.

Myasthenia gravis and scleroderma.

Myasthenia gravis is an autoimmune disease that is associated with antibodies to acetylcholine receptors. It is associated with other autoimmune diseases such as thyroiditis (10%), systemic lupus erythematosus (2-8%), rheumatoid arthritis (4-7%), Sjögren's syndrome and polymyositis. It is not commonly found with scleroderma. We describe a case of scleroderma developing in a patient 6 years after the onset of myasthenia gravis. HLA-B8/DR3 may play a role in the association of the 2 conditions.

Antilipoprotein antibodies in rheumatoid arthritis.

Antibodies against very low-density lipoproteins and low-density lipoproteins (aLA) were found in 26 of 69 (38%) patients with active rheumatoid arthritis (RA) but not in any control subjects (ie, 40 patients with psoriatic arthritis, 21 patients with osteoarthritis, and 65 healthy blood donors). In 21 RA patients (30%), lipoproteins were found in the dissociated components of circulating immune complexes. RA patients with aLA had significantly decreased cholesterol levels in all lipoprotein fractions and total serum lipids, while serum triglycerides were significantly increased compared with RA patients without aLA. Anticardiolipin antibodies as measured by the Venereal Disease Research Laboratory test were not found in any subject in this study. These findings suggest a possible autoimmune origin of dyslipoproteinemia in some patients with active RA.

Elevated breath pentane in heart failure reduced by free radical scavenger.

UNLABELLED: Pentane, a product of lipid peroxidation, has been detected in situations involving ischemic injury. Such injury may be limited if lipid peroxidation can be controlled by antioxidants. The role of lipid peroxidation in chronic heart failure (CHF) was assessed by measuring breath pentane in patients with CHF vs. age matched controls. The effect of a free radical scavenger on pentane released during CHF was also measured. Pentane levels were correlated with the daily dose of captopril, a sulfhydril-containing drug used to treat CHF, which is an angiotensin converting enzyme inhibitor. To separate the scavenging effects of captopril from the pharmacologic effects of converting enzyme inhibitors, a crossover study using a nonsulfhydril inhibitor was used. Patients with CHF excreted (p < 0.005) high concentrations of pentane (5.7 +/- 2.1 vs. control 3.6 +/- 1.2 nmol/l). Patients treated with captopril also had significantly higher (p < 0.05) excretion of pentane than the control patients (4.7 +/- 1.3 vs. 3.6 +/- 1.2 nmol/l). The dose of captopril was inversely proportional to the concentration of pentane excreted (r = 0.55, p < 0.05). Pentane excretion during captopril therapy was significantly lower before (p < 0.01) and after (p < 0.02) nonsulfhydril inhibitor therapy. CONCLUSION: breath pentane is elevated in CHF and it can be reduced by a free radical scavenger. This reduction of pentane excretion is not a converting enzyme inhibitor class effect.

Dyslipoproteinemia in the course of active rheumatoid arthritis.

Concentrations of serum lipids and serum very low-density lipoproteins and low-density lipoproteins (VLDL+LDL, originally called beta lipoproteins) were measured and agarose gel electrophoresis of serum lipoproteins was performed in 69 patients with active rheumatoid arthritis (RA), 40 patients with psoriatic arthritis (PA), 21 patients with osteoarthritis (OA), and 65 healthy blood donors. These lipid parameters were also compared in 21 RA and 40 PA patients during periods of severe disease activity (SA) versus minimal disease activity (MA). RA patients had significantly decreased concentrations of total serum lipids, total serum cholesterol, cholesterol in LDL, and cholesterol in high-density lipoproteins (HDL) compared with healthy blood donors. RA patients with SA had significantly decreased cholesterol in LDL and HDL compared with patients with MA. As the disease activity decreased, RA patients had normalization of almost all serum lipid concentrations. Electrophoresis of serum lipoproteins showed heterogeneous patterns in RA patients. Patients with PA also had some evidence of dyslipoproteinemia. Serum lipids changed with disease activity in PA patients in a manner similar to that in RA patients. These data show that patients with RA and PA have a dyslipoproteinemia that is related to disease activity.

Effect of gold compounds on the activity of adenylyl cyclase in human lymphocyte membranes.

OBJECTIVE: To determine the effects of aurothioglucose, aurothiomalate, and auranofin on basal and forskolin-activated adenylyl cyclase activity in human total lymphocyte membranes, and in membranes of T and B lymphocyte subsets. METHODS: Membranes were isolated from human total lymphocytes and T and B cell subsets. The effects of gold compounds on basal and forskolin-stimulated activity of adenylyl cyclase were measured by radioassay. RESULTS: The gold compounds inhibited adenylyl cyclase activity. This inhibitory effect required the presence of both the sulfhydryl ligands and aurous cation. CONCLUSION: Regulation of lymphocyte adenylyl cyclase by gold compounds represents a potential mode of action of these drugs in rheumatic diseases.

Comparison of auranofin, methotrexate, and the combination of both in the treatment of rheumatoid arthritis. A controlled clinical trial.

OBJECTIVE: To compare the relative safety and efficacy of auranofin (AUR), methotrexate (MTX), and the combination of both in the treatment of active rheumatoid arthritis (RA). METHODS: Three hundred thirty-five patients with active RA were entered into a 48-week, prospective, controlled, double-blind, multicenter trial and were randomly assigned to 1 of 3 treatment groups. RESULTS: Two hundred eleven patients completed the trial. No remissions were seen, and there were no statistically significant differences among the treatment groups in the clinical or laboratory variables measured. Patients taking AUR alone had a slower onset of response than did patients taking MTX alone or in combination. Withdrawals because of adverse drug reactions were slightly more common for those taking combination therapy, but the differences were not statistically significant. Withdrawals because of lack of response were more common for single-drug therapy, with the difference between AUR and the combination reaching statistical significance. No unexpected adverse drug effects were identified, and all reactions resolved without sequelae. CONCLUSION: Except for fewer withdrawals because of lack of response, combination therapy did not demonstrate any advantage in efficacy over single-drug treatment within the time frame of the study.

Covalent disulfide binding of human IL-1 beta to alpha 2-macroglobulin: inhibition by D-penicillamine.

Secreted human IL-1 beta is known to have two free SH groups due to unpaired cysteines (positions 8 and 71). Alpha 2-Macroglobulin (alpha 2-M) has internal thioester bonds between cysteine and glutamate residues. Free SH groups may be generated at these alpha 2M residues through the action of proteinases, amines such as methylamine, or at a slow rate, by H2O ("aging" of alpha 2M). Thus, the possibility that IL-1 beta forms a disulfide bond with alpha 2M was investigated. 125I-labeled human rIL-1 beta (15 kDa) was incubated with fresh normal human serum or with purified alpha 2M, treated or not with methylamine. The mixtures were submitted to nondenaturing and denaturing polyacrylamide gel electrophoresis (PAGE) followed by autoradiography. IL-1 beta bound to commercially purified "aged" alpha 2M and to alpha 2M in methylamine-treated serum but not to native serum alpha 2M. It did not bind detectably to any other serum proteins. The addition of D-penicillamine (D-pen) during the reaction of [125I]rIL-1 beta with serum or purified alpha 2M blocked the covalent binding of rIL-1 beta to alpha 2M. [125I]rIL-1 beta was removed from alpha 2M by 2-mercaptoethanol in SDS. Thus, disulfide bonds were formed between the free SH groups on [125I]rIL-1 beta and those resulting from the cleavage of the internal thioester bonds of alpha 2M. "Cold" rIL-1 beta and a Cys71----Ser71 rIL-1 beta mutant effectively competed with [125I]rIL.1 beta for binding sites on alpha 2M. When complexes of rIL-1 beta or the mutant rIL-1 beta and alpha 2M were subjected to nonreducing SDS-PAGE and subsequent Western blot analysis, the rIL-1 beta molecules were found to be present in the alpha 2M bands in a dose-dependent manner. rIL-1 beta attached to alpha 2M in the presence or absence of D-pen showed similar biological activity in the mouse thymocyte-assay. Thus, rIL-1 beta attached noncovalently to alpha 2M is biologically active. The lack of inhibition of rIL-1 beta activity by binding to methylamine-treated alpha 2M in the absence of D-pen suggests, but does not prove, that the covalently bound rIL-1 beta is also active. We concluded that human rIL-1 beta binds to alpha 2M through the Cys at position 8 and that D-pen inhibits this binding. We speculate that this inhibitory effect may contribute to the therapeutic benefits of D-pen in patients with rheumatoid arthritis.

High breath pentane concentrations during acute myocardial infarction.

To investigate whether reperfusion after myocardial ischaemia leads to free-radical-mediated peroxidation of membrane lipids and cell damage, we measured pentane, a product of lipid peroxidation, in the breath of 10 healthy control subjects and in 20 consecutive patients with suspected acute myocardial infarction. 10 of these patients showed no myocardial damage on electrocardiography (patient control group) and 10 satisfied standard diagnostic criteria for acute myocardial infarction. The three groups were well matched for age, sex, underlying disease, and smoking habits. The time from onset of chest pain to breath collection was similar in the patient control and acute myocardial infarction groups. The breath pentane concentration was higher (p less than 0.0001) in the acute myocardial infarction group (4.96 [1.15] nmol/l) than in the patient control (1.96 [1.04] nmol/l) and healthy control groups (1.71 [0.87] nmol/l). Lipid peroxidation during acute myocardial infarction reflects action of oxygen radicals and their potential for contribution to the pathogenesis of tissue damage.

Clinical value of an integrated ELISA system for the detection of 6 autoantibodies (ssDNA, dsDNA, Sm, RNP/Sm, SSA, and SSB).

An ELISA panel assay (ANA/6) which simultaneously detects IgG autoantibodies against 6 antigens (ssDNA, dsDNA, Sm, RNP/Sm, SSA, and SSB) was evaluated with sera from 98 patients with systemic lupus erythematosus (SLE) and related conditions, 68 disease controls, who were positive or negative by fluorescent ANA (FANA), and 100 healthy controls. The antigen panel specifically identified the particular autoantibodies present and had a high level of sensitivity which was reflected by the frequency of detection of autoantibodies in different patient groups. All active patients with SLE were positive for at least one autoantibody and 80% of these patients had 3 or more autoantibodies compared to only 20% of inactive patients. A large heterogeneity in antibody profiles was also noted. About 90% of patients with positive FANA, but no detectable autoimmune rheumatic disorder, i.e., false positive, were negative by the panel. A new method of standardization was designed to use the ANA/6 quantitatively. Very large differences in the level of all 6 autoantibodies were observed between sera from patients with active and inactive SLE, suggesting a potential usefulness of ANA/6 for patient management.

Clinical relapse in systemic lupus erythematosus: correlation with antecedent elevation of urinary free light-chain immunoglobulin.

This paper reports preliminary evidence suggesting that measurements of free light-chain Ig (FLIg) in urine may represent quantitative markers of in vivo polyclonal B-cell activation. Thus, longitudinal levels of urinary FLIg in patients with systemic lupus erythematosus (SLE) may be used to track or monitor the in vivo immunopathologic B-cell activity of SLE and be helpful in predicting a disease relapse. Our findings showed that dramatic rises in urinary FLIg occurred during asymptomatic intervals that preceded by 4-8 weeks the first symptomatic signs of acute SLE relapse. These results suggest that a sizable lead time may exist between the occurrence of immunopathologic B-cell stimulation and the resultant symptoms and tissue damage of immune complex-induced acute inflammation. In these studies the measurement of urinary FLIg was accomplished by an indirect method using ng-sensitive radioimmunoassays (RIAs) that measured isotypic IgG, IgA, IgM, total kappa-Ig, and total lambda-Ig. As a control for the assessment of renal tubular function and the excretion of low molecular weight proteins in SLE patients, longitudinal measurements of beta-2-microglobulin (B2M) and lysozyme were made using a novel solid-phase 3H-biotin RIA technique.

Covalent binding to alpha-macroglobulins of a protein with free SH groups produced by activated B cells: blocking by D-penicillamine and gold compounds.

alpha 2-Macroglobulin (alpha 2M) complexed with proteinases or modified by the action of amines has been shown to affect immune responses in vitro, though as yet the mechanisms are poorly understood. Supernates from rabbit lymphoid cells cultured in medium with normal rabbit serum and 35S-methionine (or 14C-leucine) were found to contain intensely radiolabeled alpha-macroglobulins (alpha M) (alpha 1 and alpha 2) on electrophoresis. When human alpha 2 M, instead of rabbit serum, was added to cultures, it also appeared radiolabeled, suggesting that lymphocyte-produced proteins (LyP) formed complexes with serum alpha M. These alpha M-associated LyP were produced in greater quantity when lymphocytes were cultured in the presence of mitogens; they were not produced by cells cultured in the presence of cycloheximide; they were produced primarily by B cells rather than T cells or macrophages. Pretreatment of serum or alpha M with methylamine, enhanced rather than inhibited the formation of LyP-alpha M complexes, a finding which is contrary to that expected if the LyP were a proteinase. Since this methylamine treatment of alpha M also results in the generation of free SH groups from the internal thioester bonds of alpha M, the formation of disulfide bonds between LyP and alpha M was considered. Indeed, (a) the LyP-alpha M complex formation was inhibited by N-ethylmaleimide, aurothiomalate, sodium aurothioglucose or D-penicillamine; (b) blocking the SH groups with NEM, of either culture fluid supernates or serum, had an inhibitory effect on the formation of these complexes; (c) the LyP-alpha M complexes were dissociated by sodium dodecyl sulfate (SDS) only after their reduction with 2-mercaptoethanol (2-ME). Thus, a disulfide bond was formed between alpha M and LyP with free SH groups (SH-LyP). Molecular sieving by high performance liquid chromatography (HPLC) of the serum-free radiolabeled supernates indicated that SH-LyP eluted at a position corresponding to a polypeptide of mol. wt of about 22,000. However, SDS-PAGE of the 22,000 mol. wt HPLC fraction showed that the major protein was approximately mol. wt 11,000 under both reducing and non-reducing conditions. In addition, the SH-LyP reduced by 2-ME from its binding site on alpha 2M had a mol. wt of about 11,000 in SDS-PAGE, suggesting that it was a non-covalent homodimer of mol. wt 11,000 polypeptides. We suggest that alpha 2M as well as SH-LyP may affect the immune system by functioning as SH-reactive agents.

The effects of hyaluronic acid on macrophage Fc receptor binding and phagocytosis are independent of the mode of depolymerization.

In order to determine whether exposure of hyaluronic acid to oxygen radicals caused an alteration in its properties, independent of the change in molecular weight induced, we examined its effect upon macrophage Fc receptor binding. High molecular weight hyaluronic acid (Healon-Pharmacia) caused a dose dependent inhibition of binding between the concentrations of 0.2-1 mg/ml. At a concentration of 0.3 mg/ml both oxygen radical depolymerized and enzymatically degraded hyaluronic acid caused an inhibition of Fc receptor binding at molecular weights of 1 x 10(6), 1.5 x 10(6) and 2 x 10(6). Oxygen radical degraded hyaluronic acid caused a stimulation of Fc receptor binding at molecular weights of 2 x 10(5) and 3.5 x 10(5), and enzyme degraded hyaluronic acid causes stimulation at a molecular weight of 2.5 x 10(6). Thus this "biological property" of hyaluronic acid is dependent upon molecular weight solely and not upon the mode of depolymerization.

Comparison of responses to and adverse effects of graded doses of sulfasalazine in the treatment of rheumatoid arthritis.

Sulfasalazine (0, 0.5, 1, or 2 g daily in divided doses) was given to patients with definite or classical rheumatoid arthritis (RA) insufficiently controlled by a nonsteroidal antiinflammatory drug. Grip strength, Westergren sedimentation rate, and physician and patient global assessment improved in those patients given 2 g/day. Inadequate response was the primary reason for withdrawal in the groups given placebo or 0.5 g/day, while adverse reactions (mainly gastrointestinal upset or rash) accounted for most withdrawals from the groups that received 1 or 2 g/day. Although its use is limited by adverse reactions, sulfasalazine is effective in the treatment of patients with RA.

Breath pentane excretion as a marker of disease activity in rheumatoid arthritis.

Activated inflammatory cells are capable of stimulating lipid peroxidation. In 27 patients with rheumatoid arthritis, we measured the pulmonary excretion of pentane, a product released during lipid peroxidation. We found highly significant correlations between pentane excretion and both joint inflammation (r = 0.88, p less than 0.001) and the erythrocyte sedimentation rate (r = 0.80, p less than 0.001). Patients treated with gold compounds or D-penicillamine excreted diminished amounts of pentane. The data suggest that lipid peroxidation may be related in part to the mechanism of injury in rheumatoid arthritis.