Pain behavior of rheumatoid arthritis patients enrolled in experimental drug trials.

OBJECTIVE: This study examined the sensitivity of a behavioral observation method for the assessment of arthritis pain as an outcome measure in clinical drug trials. METHODS: The subjects were 33 rheumatoid arthritis patients who were receiving either an active experimental drug or a placebo. Disease activity measures, self-reports of pain, and pain behavior observations were completed for each subject prior to drug initiation, 6 weeks after drug initiation, and 12 weeks after drug initiation. RESULTS: Significant reductions in measures of disease activity and self-report of pain were found for the subjects who received an active drug, relative to those who received the placebo. The pain behavior scores produced by both groups of subjects remained relatively stable during the study. CONCLUSION: The lack of change in pain behavior suggests that arthritis pain behavior may lack sensitivity to short-term changes accompanying drug therapy.

Comparison of aminobenzoate potassium and placebo in the treatment of scleroderma.

OBJECTIVE: To determine the safety and efficacy of aminobenzoate potassium (KPAB) in treating the skin manifestations of scleroderma. METHODS: Via a 48-week prospective, randomized, double blind, placebo controlled trial we compared the efficacy of KPAB 12 g/day with matching placebo. Outcome measures included skin mobility and thickening scores, patient and physician global assessments and, measurements of maximal oral aperture and hand range of motion. RESULTS: Of 146 patients who entered the study, 76 (52%) completed. Demographics of the study population included age 49 +/- 13 years, 83% women, mean (range) disease duration was 104 (7-600) months. There were no differences in the demographics of the KPAB vs placebo nor the group that completed the study compared with the withdrawal group. There were no clinical or statistically significant differences between the KPAB and the placebo treated groups in any of the outcome measures. Subgroup analyses of skin mobility and skin thickening based on age, extent of disease, severity of disease, duration of disease and involved vs uninvolved skin were performed, but no differences were noted. The overall compliance to the medical regimen was > or = 75% in 93% of patients completing the study. Eighteen patients in the KPAB group and 6 placebo patients withdrew due to adverse drug reactions (ADR). The most common withdrawals for ADR were gastrointestinal intolerance and headaches. All ADR resolved following withdrawal of medication. CONCLUSION: KPAB did not alter the skin changes of scleroderma in a group of patients with relatively longstanding stable disease. KPAB was reasonably well tolerated in this group of patients.

Observation of pain behavior in rheumatoid arthritis patients during physical examination. Relationship to disease activity and psychological variables.

This study examined the reliability and validity of a behavioral observation method for the assessment of arthritis pain in a clinical practice setting. Trained observers measured the occurrence of seven pain behaviors in a group of 61 rheumatoid arthritis patients undergoing physical examinations. These observations were compared with videotaped observations of the patients in a laboratory setting. Significant differences were found between the pain behavior frequencies observed during the examinations and those observed during videotaped sessions. Total pain behavior scores obtained in both settings were significantly correlated with patients' self-reports of pain and with disease activity measures. Pain behavior observed during the exams was significantly associated with patients' self-reports of anxiety and depression.

Chronic syphilitic polyarthritis mimicking systemic lupus erythematosus/rheumatoid arthritis as the initial presentation of human immunodeficiency virus infection.

Syphilitic arthritis has been well characterized but not previously described as the initial presentation of human immunodeficiency virus (HIV) infection. Our patient presented with chronic symmetric polyarthritis and autoimmune abnormalities, including positive rheumatoid factor, antinuclear antibody, dsDNA, and initially negative syphilis serologies. Subsequent investigations revealed HIV seropositivity, depletion of CD4 cells, and strongly positive syphilis serologies. Our patient's arthritis completely resolved with penicillin therapy.

Antineutrophil cytoplasmic antibodies: clinical characteristics of 10 patients with the perinuclear pattern of immunofluorescence on ANCA testing.

Antineutrophil cytoplasmic antibodies (ANCA) have recently been described in association with necrotizing glomerulonephritis, systemic vasculitis, and other autoimmune-mediated connective tissue diseases, including systemic lupus erythematosus (SLE) and polychondritis. At least two distinct classes of ANCA have been described, differentiated by characteristic immunofluorescence patterns using neutrophils as substrate for indirect immunofluorescence assay (IFA). A focal, centrally accentuated, finely granular cytoplasmic staining pattern (c-ANCA) is both sensitive and specific for Wegener's granulomatosis (WG) and is thus a useful clinical adjunct in the diagnosis and monitoring of disease activity in WG. The second class of ANCA, defined by a perinuclear immunofluorescent staining pattern (p-ANCA) on standardized IFA, has not been studied as extensively. It appears to occur in a variety of connective tissue diseases, most often necrotizing glomerulonephritis other than WG, systemic vasculitis with renal involvement, and SLE. In screening more than 2000 serum samples received in our rheumatology laboratory for ANA testing, we found p-ANCA in 10 patients. All 10 had evidence of systemic autoimmune disease, though with wide variation in extent and severity of disease. All 10 had other autoantibodies, most frequently ANA (60%). Our studies suggest that p-ANCA define a heterogeneous patient population with a spectrum of autoimmune disease, most frequently necrotizing glomerulonephritis and systemic vasculitis. Future studies will establish the role of p-ANCA in clinical medicine and broaden our understanding of the origin and possible pathogenesis of ANCA and autoantibodies in general.

Detection of anti-neutrophil cytoplasmic autoantibodies using the promyelocytic HL-60 cell-line.

IgG autoantibodies against antigen in the cytoplasm of cells of the neutrophil-monocyte cell lineage have been found in the sera of patients with Wegener's granulomatosis (WG). The indirect immunofluorescence test (IFT) is proving to be a valuable screening test for these antibodies, but obtaining neutrophils for substrate is time-consuming, and interpretation of the fluorescence patterns in ethanol-fixed cells requires considerable experience. We report an improved IFT using HL-60 cells as substrate. The myeloid reactivity of HL-60 cells was characterized and compared to that of neutrophils, with and without prior ethanol fixation. In contrast to neutrophils, myeloperoxidase (MPO) was more completely extracted from HL-60 cells by prior ethanol fixation, eliminating the confusion inherent in trying to distinguish anti-MPO antibodies from Wegener's granulomatosis associated anti-neutrophil cytoplasmic autoantibodies (WG-ANCA) in the IFT. The WG-ANCA reactivity remained intact with ethanol fixation, producing a distinct crescent and half-moon pattern of specific immunofluorescence. This WG-ANCA positive pattern was found in 25 sera from 11 WG patients and was absent in over 1200 control sera from patients referred for autoantibody testing.

Vasculitis. A practical approach to management.

Vasculitis encompasses a wide variety of diseases. Because diagnosis may be difficult, a careful evaluation is essential, including a detailed patient history, thorough physical examination, and appropriate laboratory studies. Diagnosis is based on clinicopathologic features that permit identification of the condition. Biopsies are often necessary to confirm a diagnosis. It is important to accurately categorize the vasculitic disorders, since prompt, aggressive therapy with potentially toxic drugs is necessary to avoid irreversible organ system dysfunction.

Magnetic resonance imaging of the craniovertebral junction in rheumatoid arthritis.

Conventional radiography and magnetic resonance imaging (MRI) of the craniovertebral junction were evaluated in 12 patients with longstanding rheumatoid arthritis (RA) and neck pain with or without other neurologic signs or symptoms of cervical myelopathy. MRI demonstrated abnormal soft tissue masses thought to represent pannus in 9 patients. Three patients showed cord or brainstem compression due to pannus or atlantoaxial subluxation. The 3 patients with MRI evidence of cord or brainstem compression had neurologic signs or symptoms of cervical myelopathy, and appropriate therapy was instituted based on these findings. This study indicates that MRI is able to detect abnormal soft tissue masses which probably represent pannus and their relationship to the spinal cord or brainstem, and confirms the utility of the procedure in the management of craniovertebral involvement in RA.

Decreased production of suppressive-B-cell factor by synovial membrane B-lymphocytes in rheumatoid arthritis.

Suppressive-B-cell factor (SBF) is an autoregulatory B-cell lymphokine produced by heat-aggregated-IgG stimulated B-lymphocytes which suppresses polyclonal immunoglobulin production. SBF production by rheumatoid arthritis (RA) patients' peripheral blood B-lymphocytes inversely correlates with disease activity and in vitro rheumatoid factor production. To further define the role of SBF in the pathogenesis of RA, the present study measured SBF production by surgically-obtained synovial membrane mononuclear leukocytes. SBF production by RA synovial leukocytes was similar to the levels previously described for RA peripheral blood leukocytes. Both RA and osteoarthritis (OA) synovial leukocytes produced significantly less SBF than leukocytes obtained from otherwise healthy patients with plica. OA patients produced less SBF than RA patients, but the difference was not statistically significant. SBF values for combined RA patients and controls with OA or plica correlated with the degree of histological plasma cell infiltration providing further evidence for SBF production by cells of the B-lymphocyte lineage. Depletion studies also demonstrated that synovial SBF was produced by B-lymphocytes. The molecular weight (34,000) of synovial SBF was similar to the molecular weight of peripheral blood SBF. Decreased SBF production by RA synovial B-lymphocytes is a functional abnormality in RA which may contribute to the perpetuation of synovial rheumatoid factor production and chronic synovial inflammation.

Six-month multi-center study comparing nabumetone with naproxen in the treatment of osteoarthritis.

This six-month, double-blind, controlled, randomized, parallel study at 13 medical centers compared the safety and efficacy of nabumetone (1,000 mg taken at bedtime) with that of naproxen (250 mg twice daily) in the treatment of osteoarthritis in symptomatic adult outpatients. Five efficacy parameters were measured: patients' assessment of overall osteoarthritis activity and pain, physicians' assessment of overall osteoarthritis activity and pain, and physicians' assessment of pain with respect to a declined activity. All 489 patients who took medication were included in the evaluation of safety, and 455 patients (227 in the nabumetone group and 228 in the naproxen group) were evaluated for efficacy. Significant improvement in all five efficacy parameters occurred in both groups. No significant differences were found between the two groups at the end of the study in any of the five efficacy parameters. Twenty-three percent of nabumetone and 17 percent of naproxen patients withdrew from the study for lack of efficacy. At least one possible or probable treatment-related adverse experience was reported for 45 percent of nabumetone-treated patients and 42 percent of those given naproxen, and in 19 percent of the nabumetone-treated and 18 percent of the naproxen-treated patients these experiences were moderate or severe. However, only 7 percent of patients in each group withdrew from the study due to adverse experiences. Nabumetone and naproxen have comparable safety and efficacy, suggesting that a single, nighttime dose of nabumetone is a convenient, effective, and safe treatment for osteoarthritis.

Effects of psychological therapy on pain behavior of rheumatoid arthritis patients. Treatment outcome and six-month followup.

A randomized clinical trial was performed to evaluate a psychological treatment intervention and a social support program, compared with a control program in which no adjunct treatment was rendered, and their effects upon pain behavior, affect, and disease activity of 53 patients with rheumatoid arthritis. The psychological intervention produced significant reductions in patients' pain behavior and disease activity at posttreatment. Significant reductions were also observed in trait anxiety at posttreatment and 6-month followup. Relaxation training may have been the most important component of the psychological intervention. The social support program produced a significant reduction in trait anxiety only at posttreatment. This is the first well-controlled study to demonstrate reduced pain behavior, disease activity, and trait anxiety following psychological treatment.

The assessment of pain in rheumatoid arthritis: disease differentiation and temporal stability of a behavioral observation method.

An observation method for the assessment of pain behaviors in patients with rheumatoid arthritis (RA) has been developed. We investigated the extent to which the frequencies of pain behaviors differentiated patients with RA and patients with chronic low back pain from depressed and nondepressed, pain free, control subjects. The reliability of the pain behavior frequencies of patients with RA across 2 observation sessions also was determined. Total pain behavior scores clearly differentiated patients with RA and low back pain from depressed and nondepressed, pain free, control subjects. Pain behavior observed in patients with RA showed a high degree of stability over time. The results of our study suggest that the behavioral observation method will prove useful in the assessment of RA pain in clinical and research settings.

Multiple myeloma presenting with primary meningococcal arthritis.

A 64-year-old white man presented with Neisseria meningitidis primary septic arthritis. Further evaluation revealed multiple myeloma. Increased susceptibility to infection occurs early in multiple myeloma; thus, a rare cause of primary septic arthritis, such as N. meningitidis, warrants a full evaluation for immunocompromise.

Analysis of combined rheumatoid factor determinations by the rheumatoid arthritis latex and sheep cell agglutination tests and the American Rheumatism Association criteria for rheumatoid arthritis.

The clinical records of randomly selected patients receiving both the sheep cell agglutination test (SCAT) and the latex agglutination test (RA latex) for rheumatoid factor (RF) were analyzed for the presence of American Rheumatism Association (ARA) criteria for rheumatoid arthritis (RA). When both tests were positive there was a 3-fold increase compared to only one test positive in the relative risk that a patient met ARA criteria for RA, and there was a 2-fold increase in the probability that a patient with 2 positive tests had classical RA compared to only a positive RA latex. The occurrence of RF reactive with both human and rabbit IgG identifies a population of patients likely to have more ARA criteria for RA and classical disease.

The assessment of pain in rheumatoid arthritis. Validity of a behavioral observation method.

It is difficult to objectively measure pain in rheumatoid arthritis (RA). A behavioral observation method for the assessment of RA pain has been developed. In this study, videotapes were made of 53 RA patients while they performed standardized maneuvers. Trained raters viewed the videotapes and recorded the frequencies of 7 pain behaviors. Clinical and laboratory measures of rheumatoid disease activity also were recorded for each patient. Rheumatology fellows viewed 20 randomly chosen video recordings of the patients and made global estimates of the intensity and unpleasantness of pain. Significant positive correlations were found between total pain behavior scores and measures of disease activity. The fellows' estimates of the intensity and unpleasantness of the patients' pain also were significantly and positively correlated with the total pain behavior scores. The behavioral observation method may be useful in the assessment of RA pain and may be included as an objective outcome measure in clinical trials with RA patients.

A 6-month, double-blind study comparing nabumetone to naproxen in the treatment of osteoarthritis.

A 6-month, double-blind, controlled, randomized, parallel study was performed to compare the efficacy and tolerance of nabumetone (1000 mg at bedtime) with naproxen (250 mg twice daily) in the treatment of osteoarthritis. Five efficacy parameters were evaluated: patient's assessment of overall osteoarthritis activity and pain, physician's assessment of overall osteoarthritis activity and pain, and physician's assessment of pain with respect to a defined activity. All 40 patients entered (20 in each group) were available for evaluation of tolerance and 36 patients for efficacy analysis (18 in each group). The efficacy results revealed significant improvement in all five parameters for each medication except measurement of pain with respect to a defined activity for naproxen (p less than 0.07). The frequency of possible or probable drug-related adverse experiences was high for both drugs. However, only 1 patient left the study because of a probable drug-related adverse experience (abdominal pain in a nabumetone patient). Six nabumetone and 4 naproxen patients dropped out of the study because of lack of efficacy. The results indicate that nabumetone and naproxen have comparable efficacy and tolerance at the dosage used, and suggest that a single night-time dosage of nabumetone may be a convenient and useful treatment for osteoarthritis.

Successful symptomatic treatment of melorheostosis with nifedipine.

Melorheostosis is an unusual sclerotic dysplasia of bone. We describe a patient with melorheostosis who showed improvement in pain and vasomotor function after treatment with nifedipine. Peripheral vascular disturbances may be responsible for the pain associated with this disorder and vascular abnormalities could possibly be related to the pathogenesis of this disease.

Decreased suppressive B cell factor (SBF) in rheumatoid arthritis: evidence for a defect in B cell autoregulation.

Rheumatoid arthritis (RA) is a disorder characterized by defective immunoregulation. Hypergammaglobulinemia, circulating immune complexes (IC), and autoantibodies such as rheumatoid factor (RF) are common serum abnormalities. To assess IC-mediated feedback suppression in RA, we evaluated the ability of a suppressive B cell factor (SBF) generated by culturing heat-aggregated IgG (HAIgG) with peripheral blood mononuclear leukocytes (PBL) from patients with RA and normal controls to suppress the pokeweed mitogen (PWM)-induced RF plaque-forming cell (PFC) response of normal PBL. RA patients generated less SBF than age-matched controls. Background suppression (supernatants obtained from PBL cultured without HAIgG) was similar in the RA patients and age-matched controls. To determine the effects of nonsteroidal antiinflammatory drug (NSAID) therapy on suppression, RA patients and age-matched controls were studied before and after NSAID therapy. NSAID therapy significantly reduced background suppression in RA patients who were not on immunosuppressive drugs and in age-matched controls, but there was no effect on SBF in RA patients or controls. There was a small increase in background suppression when NSAID were administered to RA patients on immunosuppressives, suggesting an ameliorative effect of NSAID in this group of patients, which tended to increase their level of suppression when compared with RA patients only on NSAID. Spontaneous RF-PFC were measured in normal controls and RA patients and were compared with suppressor activity. There were increased numbers of spontaneous RF-PFC in RA patients. Total suppressor activity was greatest in young adult controls, who also had the least RF-PFC. The percentage of suppression correlated inversely with the number of RF-PFC in patients and controls. Additionally, disease activity in RA as measured by total joint count and erythrocyte sedimentation rate (ESR) was shown to correlate inversely with total suppressor activity. We conclude that the PBL from patients with RA produce decreased SBF after HAIgG stimulation and that loss of suppression is also associated with aging. This study suggests a defect in IC-stimulated B cell suppressor activity in RA leading to decreased ability to suppress antibody and further IC formation. The combination of increased RF-PFC and decreased SBF suggests that there is defective B cell autoregulation in RA, which may be involved in the pathogenesis and chronicity of this disease.

Suppression of a pokeweed mitogen-stimulated plaque-forming cell response by a human B lymphocyte-derived aggregated IgG-stimulated suppressor factor: suppressive B cell factor (SBF).

The mechanisms whereby formed immune complexes (IC) or immunoglobulin aggregates can suppress further antibody production were explored by culturing normal human peripheral blood mononuclear leukocytes (PBL) with heat-aggregated IgG (HAIgG) and collecting the culture supernatants at 24 hr. These supernatants were found to suppress a pokeweed mitogen (PWM)-induced rheumatoid factor plaque-forming cell (RF-PFC) response in normal individuals. PWM-induced anti-trinitrophenylated sheep red blood cell (TNP-SRBC) PFC were also inhibited by suppressor supernatants from HAIgG-stimulated PBL, suggesting that the polyclonal PFC response was inhibited by a suppressor factor. The suppressor factor inhibited PWM stimulated RF-PFC throughout the culture period, but suppression was maximal at the peak of the RF-PFC response. Suppressor factor was only effective at the initiation of cultures, suggesting that it inhibited early events in the PWM-stimulated RF-PFC response. Molecular weight determination of the suppressor factor by differential membrane fractionation suggested a m.w. range of 30,000 to 50,000, and chromatography on Sephadex G-100 showed a peak activity at an approximate m.w. of 32,000. Studies suggested the factor was not an interferon. Depletion of T lymphocytes by E rosetting and macrophages/monocytes by G-10 adherence did not affect the generation of suppressor factor. Depletion of T lymphocytes (OKT4, OKT8) and NK cells (Leu-11b) by antibody-dependent, complement-mediated cytotoxicity also did not affect the generation of suppressor factor. Depletion of B lymphocytes with OKB7 resulted in the generation of significantly less suppressor factor. Suppression produced by unstimulated purified B lymphocytes was approximately one-half that seen when B lymphocytes were stimulated with HAIgG. Differential membrane fractionation studies suggested that only HAIgG-stimulated B cell cultures contained peak activity in the 30,000 to 50,000 m.w. fraction. Supernatants from unstimulated purified T cells also generated suppression, which was approximately one-half of that seen with HAIgG-stimulated B cells, but no increase in suppressor activity was seen in T cell cultures after incubation with HAIgG. These studies demonstrate that HAIgG is capable of stimulating B lymphocytes to produce a lymphokine, suppressive B cell factor (SBF), which is capable of suppressing a polyclonal PFC response. SBF may be important in feedback control of human immunoglobulin production.