Mutations in osteoprotegerin account for the CCAL1 locus in calcium pyrophosphate deposition disease.

OBJECTIVE: Mutations on chromosomes 5p (CCAL2) and 8q (CCAL1) have been linked to familial forms of calcium pyrophosphate deposition disease (CPDD). Mutations in the ANKH gene account for CCAL2, but the identity of CCAL1 has been elusive. Recently, a single Dutch kindred with a mutation in the Tumor Necrosis Factor Receptor Super Family member 11B (TNFRSF11B) gene coding for osteoprotegerin (OPG) was described as a gain-of-function mutation. Affected family members had premature generalized osteoarthritis (PGOA) and CPDD. As the TNFRSF11B gene is on 8q, we sought additional evidence that TNFRSF11B was CCAL1, and investigated potential disease mechanisms. DESIGN: DNA from two novel PGOA/CPDD families was screened for sequence variants in the TNFRSF11B gene. Mutations were verified by genotype analysis of affected and unaffected family members. We also investigated effects of normal and mutant OPG on regulators of CPP crystal formation in porcine cartilage. RESULTS: The identical TNFRSF11B mutation described in the Dutch family was present in two novel PGOA/CPDD families. ANKH was normal in affected patient fibroblasts. Exogenous OPG did not alter ANKH mRNA or protein levels, affect translocation of ANKH to the membrane, nor increase [pyrophosphate (PPi)] or other key regulators of CPDD. CONCLUSION: We have firmly established the identity of CCAL1 as TNFRSF11B (OPG). Our findings suggest that this mutation produces disease in an ANKH-independent manner via novel mechanisms not primarily targeting cartilage. This work rationalizes further investigation of OPG pathway components as potential druggable targets for CPDD.

Dose-limiting toxicity of rifabutin in AIDS-related complex: syndrome of arthralgia/arthritis.

We studied the tolerance of humans to rifabutin, a rifamycin with antimycobacterial and in vitro anti-HIV activity. Sixteen subjects with AIDS-related complex were treated for 4-66 weeks with stepwise increasing oral doses of rifabutin from 300 to 2400 mg/day. The highest dose attained was twice that previously reported for humans. Serum and cerebrospinal fluid levels of drug were detected by high-pressure liquid chromatography. A reversible syndrome of arthritis/arthralgia, not previously described, was seen in most (nine out of 10) of those given doses exceeding 1050 mg/day. Uveitis and aphthous stomatitis developed at doses of approximately 1800 mg in two of those with joint manifestations. Typical manifestations of Reiter's syndrome were not seen in any patient. An orange-tan skin pigmentation was almost universal. Other toxicities resembled those previously associated with rifampin. Serum levels did not approach those found to inhibit HIV significantly in vitro. No consistent antiviral or immunological effects were observed; even at the highest doses, rifabutin did not appear to inhibit cellular immunity. Rifabutin was well tolerated at daily doses blow 1 g.

The diversity of neurologic events in systemic lupus erythematosus. Prospective clinical and computed tomographic classification of 82 events in 71 patients.

To investigate outcome and pathophysiology of central nervous system (CNS) systemic lupus erythematosus (SLE), we prospectively codified all cases of CNS SLE. Eighty-two events occurred in 71 patients. Four events in four patients were due to infection and were excluded. Twelve events occurred in 11 women with positive antinuclear antibody but negative anti-DNA antibody test reactions and no other manifestation of SLE. Of the remaining 66 events (56 patients), 26 events were "isolated" and 40 "complex." Non-CNS SLE was "active" during 47 events and "inactive" during 19 events. "Isolated" CNS events were equally likely in clinically "active" and "inactive" SLE. Patients with active SLE were as likely to have an episodic or remittent course as were patients with inactive SLE. "Complex" events, however, were more likely to have favorable outcome than were "isolated" events. "Isolated" events without focal CT abnormalities, the only component of CNS SLE that can be called diffuse lupus encephalitis, accounted for only 20% of all neurologic events.

A naturalistic evaluation of cortisol secretion in persons with fibromyalgia and rheumatoid arthritis.

OBJECTIVE: To compare cortisol levels, diurnal cycles of cortisol, and reactivity of cortisol to psychological stress in fibromyalgia (FM) and rheumatoid arthritis (RA) patients in their natural environment, and to examine the effect on results of accounting for differences among the groups in psychological stress and other lifestyle and psychosocial variables. METHODS: Participants were 21 FM patients, 18 RA patients, and 22 healthy controls. Participants engaged in normal daily activities were signaled with a preprogrammed wristwatch alarm to complete a diary (assessing psychosocial- and lifestyle-related variables) or provide a saliva sample (for cortisol assessment). Participants were signaled to provide 6 diary reports and 6 saliva samples on each of two days. Reports of sleep quality and sleep duration were also made upon awakening. RESULTS: FM and RA patients had higher average cortisol levels than controls; however, there were no differences between the groups in diurnal cycles of cortisol or reactivity to psychological stress. While the groups differed on stress measures, surprisingly, the patient groups reported less stress. Furthermore, statistically accounting for psychosocial- and lifestyle-related differences between the groups did not change the cortisol findings. CONCLUSION: The results provide additional evidence of hypothalamic-pituitary-adrenal axis disturbance in FM and RA patients. While such elevations are consistent with other studies of chronically stressed groups, the elevations in cortisol in this study did not appear to be due to ongoing daily stress, and there was no evidence of disturbed cortisol reactivity to acute stressors.

The experience of rheumatoid arthritis pain and fatigue: examining momentary reports and correlates over one week.

OBJECTIVE: To evaluate the daily experience of patients with rheumatoid arthritis (RA) in an ecologically valid manner; Ecological Momentary Assessment (EMA) was employed. Diurnal cycles and within-day variation of self-reported pain and fatigue were examined as were relationships between pain, fatigue, daily stressful events, and sleep. METHODS: Thirty-five patients with RA were alerted with an electronic beep 7 times per day for 7 consecutive days. Assessments were recorded at each beep. Upon awakening each day, sleep information was reported. RESULTS: There were large individual differences in variation of pain and fatigue. Stressors were associated with increased pain but not fatigue. Subjects with poor sleep had higher levels of pain and fatigue. Diurnal cycles of pain and fatigue were found, yet were observed for only some patients (37% and 34%, respectively). CONCLUSION: The use of EMA deepens our understanding of the pain and fatigue experienced by RA patients. This method may help identify subgroups of patients who are highly "psychoreactive" to environmental stimuli and/or who have diurnal patterns to their symptoms. It may also be used to improve existing instruments.

Does the peak-end phenomenon observed in laboratory pain studies apply to real-world pain in rheumatoid arthritics?

Laboratory studies and investigations of patients undergoing painful procedures have compared recalled pain to an average of multiple momentary reports taken throughout the painful experience. This work has shown that recalled ratings of pain are more closely associated with a combination of peak pain and pain proximal to the recall ratings than an average of all momentary reports. However, these studies have examined recalled pain over relatively short periods, usually under 1 hour. In this study of 32 patients with rheumatoid arthritis, momentary pain ratings taken over a 7-day period were compared with pain recalled on the eighth day. Analyses confirmed that a combination of peak and recent pain was a better predictor of recalled patient pain than was a simple average of all momentary pain reports. These results extend our understanding of how individuals remember pain and suggest alternative methods for assessing recalled pain.

Positive Lyme serology in subacute bacterial endocarditis. A study of four patients.

Lyme borreliosis is a multisystem inflammatory disorder caused by the tick-borne spirochete Borrelia burgdorferi. Clinical manifestations are protean, involving the skin, joints, peripheral and central nervous systems, and the heart. However, the presentation of Lyme disease often overlaps with that of other conditions. We describe four patients from a region endemic for Lyme disease who had elevated levels of antibodies reactive to B burgdorferi and whose signs and symptoms were initially attributed to Lyme borreliosis but whose subsequent blood cultures established a diagnosis of nonspirochetal subacute bacterial endocarditis. Although immunoblots on serum samples from three of the four patients were consistent with prior infection from B burgdorferi, a positive immunoblot does not establish active infection. Similarly, seropositivity to B burgdorferi only indicates possible exposure to this organism. The occurrence of positive serologies to B burgdorferi in the presence of other diseases can lead to diagnostic confusion.

Preliminary observations on the role of magnetic resonance imaging for polymyositis and dermatomyositis.

The potential use of magnetic resonance imaging (MRI) for inflammatory muscle disorders was evaluated in 13 patients with polymyositis and dermatomyositis. Abnormalities in signal intensity (p = 0.0076) and fat replacement (p = 0.0177) were identified and correlated significantly with clinical disease activity. In addition, MRI was useful in directing muscle biopsy of selected abnormal areas.

Distress and disease status among patients with rheumatoid arthritis: roles of coping styles and perceived responses from support providers.

Previous research has shown that social support can have a beneficial impact on coping processes and psychological adjustment in patients with rheumatoid arthritis (RA). The association of individual coping styles and perceived responses from others to one's pain episodes with patients 'distress and disease status over time was investigated. The sample consisted of 42 middle-aged patients with RA who were predominantly White (98%), female (64%), and married (88%). Participants completed surveys and their rheumatologist completed clinical assessments of patient disease status at 2 time points over a 9-month period. Although punishing responses from others (e.g., getting irritated or angry when the patient is in pain) were perceived as relatively infrequent, they were associated with a patient coping style of focusing on and venting of negative emotion as well as elevated negative affect (NA). Findings also indicated that those who perceived punishing responses from close others and coped by venting negative emotions reported increased NA over time and were rated by their rheumatologist as having more severe RA disease status over time. Implications for psychosocial intervention and directions for future research are discussed.

Occurrence of antibodies to Borrelia burgdorferi in patients with nonspirochetal subacute bacterial endocarditis.

OBJECTIVE: To determine the prevalence and specificity of antibodies to Borrelia burgdorferi in patients with nonspirochetal subacute bacterial endocarditis and assess whether increased levels of antibodies to B. burgdorferi were attributable to rheumatoid factor. DESIGN: Retrospective case-control study. SETTING: Urban referral center in an area devoid of infected ticks as a source of endocarditis sera. PATIENTS: Sera from 30 consecutive patients with culture-proven subacute endocarditis between 1979 and 1981 were compared with 30 control sera collected between 1989 and 1990. In addition, sera from 20 consecutive patients with rheumatoid arthritis who were positive for rheumatoid factor were collected between 1991 and 1992. Sera were compared with a convenience sample from 15 patients who met the criteria for Lyme disease. MEASUREMENTS: Antibodies to B. burgdorferi were assessed by enzyme-linked immunosorbent assay (ELISA) and immunoblot analysis. IgM rheumatoid factor was quantified using solid-phase radioimmunoassay or latex agglutination techniques. RESULTS: Thirteen of 30 patients with endocarditis (43%) compared with 3 of 30 normal controls (10%) had increased levels of antibodies to B. burgdorferi (P < 0.01). Of these 13 patients, only 1 had an immunoblot consistent with previous infection. The others had nonspecific immunoblots: 5 showed isolated 60-kd reactivity; 1 patient had isolated 41-kd reactivity; and 6 had no bands of reactivity. Immunoblots of the 3 controls with increased antibodies showed only isolated 41-kd reactivity. Thus, the specificity of the B. burgdorferi antibody test in patients with endocarditis was only 60% (95% CI, 42% to 78%), compared with 90% (CI, 79% to 100%) in controls. No correlation was noted between IgM rheumatoid factor and antibodies to B. burgdorferi in patients with endocarditis (r = 0.2; P > 0.2). Only 1 of 20 patients with rheumatoid arthritis without known bacterial infections had antibodies to B. burgdorferi. CONCLUSIONS: Although a positive ELISA test for B. burgdorferi may be a "true positive," a positive serologic test alone does not ensure that the clinical problem is due to Lyme borreliosis. Cross-reactive antibodies to shared epitopes between B. burgdorferi and the endocarditis organism may account for the high false-positive results.