Longitudinal patterns of analgesic and central acting drug use and associated effectiveness in fibromyalgia.

BACKGROUND: We describe the changing pattern of analgesic and new central acting drug (NCAD) use (pregabalin, duloxetine, milnacipran) in fibromyalgia and measure NCAD effectiveness in clinical practice. METHODS: About 3123 US adult patients with fibromyalgia participated in an 11-year longitudinal study of fibromyalgia outcomes. We assessed severity-adjusted treatment prevalence and measured the effect of any use of NCAD on pain and fatigue, and functional status using the Health Assessment Questionnaire (HAQ) disability index. RESULTS: In 2010, 46.7% of patients used opioids, including 12.5% who used strong opioids. During the 11 years, severity-adjusted strong opioid use increased from 6.3% to 11.7% and any opioid use from 40.0% to 46.6%. Nonsteroidal anti-inflammatory drug (NSAID) use decreased from 74% to 44%. Tricyclic use dropped in half, from 27% to 15%, while NCAD use increased from less than 10% to 39%. The estimated 25th and 50th percentiles for NCAD discontinuation time were 1 and 2.5 years. Overall pain, fatigue and HAQ scores were unchanged over the 11 years. For patients treated with NCAD, pain scores were reduced significantly by 0.17 (0.03, 0.30) units following the start of NCAD, an improvement of 2.8%. Some sensitivity analyses showed improvements of up to 4.3%. There was no significant improvement in fatigue or functional status. CONCLUSIONS: There is a changing pattern of drug treatment in fibromyalgia, consisting mostly of decreased NSAID and amitriptyline use and an increase in NCAD. Drug costs are substantially higher because of NCAD use, but we found no evidence of clinical benefit for NCAD compared with prior therapy.

Evidence of concurrent immunopathological mechanisms determining the pathology of severe lupus nephritis.

The purpose of this study is to determine whether two distinct histopathological-immunopathological lesions, which have been reported in severe lupus nephritis, diffuse global glomerulonephritis (GN) (WHO IV) and a segmental and necrotising GN (WHO III) can be reported to coexist in a single patient. We examine the evidence of coexistence of these disparate lesions and the prognostic significance in a group of patients with severe lupus nephritis who have been subjected to a common therapeutic regimen by protocol. The simple, reproducible parameter indicating the presence of glomerular capillary necrosis was the presence of crescents. We, therefore, reviewed 39 renal biopsies with diffuse global lupus GN (WHO IV) (Churg, J, Sobin, LH. Lupus nephritis. Renal disease, classification and atlas of glomerular diseases. New York: Igaku-Shoin; 1982. p. 127-149). and used crescents as a surrogate for glomerular necrosis. Peripheral capillary immune deposits were less prominent in WHO IV with crescents compared with those without and resembled the reduced immune deposits seen in severe segmental GN (WHO III >or= 50%). Patients with WHO IV with crescents had decreased survival without end-stage renal disease (P = 0.02), fewer remissions (P = 0.04) and more adverse outcomes (12/22 vs 3/17) (P = 0.02) than those without crescents, and this was similar to patients with WHO III >or=50%. We conclude that, on the basis of immunological and morphological features, WHO IV with crescents appears to be the result of two distinct pathogenetic mechanisms. We propose that diffuse global lupus GN, associated with crescents, is best described as WHO class IV + WHO class III.

Pre-treatment affinity for LJP 394 influences pharmacodynamic response in lupus patients.

Five prospective clinical studies in lupus patients have shown that LJP 394 can reduce circulating anti-dsDNA antibody levels without causing generalized immunosuppression. The compound is currently being evaluated in a phase III clinical trial for the prevention of renal flares in patients with high-affinity antibodies to LJP 394 and a history of lupus nephritis. The current study analyzed the affinity of patient IgG for LJP 394 prior to and following 4 months of treatment with LJP 394 to determine if pretreatment affinity influenced pharmacodynamic response. Patient serum samples from a multicenter, double-blind, placebo-controlled trial were evaluated prior to and following 4 months of weekly, biweekly or monthly treatment with placebo (n = 9) or weekly treatment with 10 mg LJP 394 (n = 6) or 50 mg LJP 394 (n = 4). After treatment there was a dose-dependent reduction in affinity in the 10 mg/week and 50 mg/week groups (P < 0.05 and P < 0.01, respectively), whereas the placebo group was unchanged. This study demonstrates that weekly treatment with LJP 394 produces a dose-dependent reduction in titer-weighted average affinity. These results suggest it may be possible to use an affinity assay to define prospectively patients that are most likely to exhibit the desired pharmacodynamic response to LJP 394.

Treatment of systemic lupus erythematosus with LJP 394.

OBJECTIVE: LJP 394 is a novel therapy under development for the treatment of systemic lupus erythematosus (SLE). We investigated the optimal LJP 394 dosing regimen required to maximally reduce serum dsDNA antibodies. We also evaluated the safety and tolerability of repeated doses of LJP 394 as well as the effects of therapy on SLE related disease activity and health related quality of life. METHODS: This was a multicenter, partially randomized, placebo controlled, double blind, dose-ranging trial. Study drug or placebo was administered at weekly, biweekly, or monthly intervals for a total of 17, 9, or 5 doses, respectively. Fifty-eight patients were randomly assigned to receive 1, 10, or 50 mg LJP 394 or placebo. After a 2 month pretreatment period, dosing visits continued for 16 weeks, after which there was a 2 month posttreatment period. RESULTS: The greatest reductions in mean dsDNA antibody titers were observed in the group of patients who received 50 mg LJP 394 weekly (38.1% and 37.1 % at Weeks 16 and 24, respectively). A reduction (29.3%) in dsDNA antibody titers was also observed at Week 24 in the group of patients who received 10 mg LJP 394 weekly. The frequencies of adverse events were comparable in the placebo and active treatment groups. CONCLUSION: This clinical trial, in which a large number of patients with SLE were treated with LJP 394, expanded the safety profile of LJP 394 and demonstrated its capacity to reduce dsDNA antibodies.

Fibromyalgia, depression, and alcoholism: a family history study.

OBJECTIVE: Fibromyalgia (FM) syndrome may be part of an "affective spectrum disorder." The diseases in this group have in common high rates of major depression in first degree relatives (FDR) and a response to antidepressant treatment. In this familial aggregation study, we tested the hypothesis that depression in patients with FM is related to a family history of depression or alcoholism in their FDR. METHODS: To assess the relationship between FM and lifetime histories of depression (DEP) and alcoholism (ALC), personal and family histories of mood and substance use disorders were obtained from 60 probands with FM. DEP and ALC among the probands were diagnosed using the Schedule for Affective Disorders and Schizophrenia, a standardized, structured psychiatric interview, and the Research Diagnostic Criteria (RDC). Family psychopathology in the FDR (parents, full siblings, children) was assessed using the Family History RDC. The odds ratio (OR) for DEP and/or ALC in FDR of probands with a history of DEP versus those without DEP were calculated. Confidence intervals (CI) not including 1 were significant at p < 0.05 (95% CI). RESULTS: The odds of identifying FDR with DEP and/or ALC were significantly higher among probands with FM with a lifetime history of DEP than among probands with FM who had no history of DEP (OR = 2.10, 95% CI = 1.23-3.57). This may be accounted for by the significantly higher odds for ALC among the FDR of probands with both FM and DEP compared with the FDR of probands with FM but no history of depression (OR = 2.30, 95% CI = 1.21-4.37). Although alcoholism was increased in the FDR of probands with FM with a history of depression, the odds for DEP were nonsignificantly higher among these FDR (OR = 1.71, 95% CI = 0.87-3.31). OR in the same range of magnitude were obtained when the data were analyzed by family unit, but these results were not statistically significant. CONCLUSION: Our data suggest that the tendency toward DEP in patients with FM may be a manifestation of a familial depressive spectrum disorder (alcoholism and/or depression in the family members), not simply a "reactive" depression secondary to the pain and other symptoms.

The relationship of preexisting lung disease to the development of methotrexate pneumonitis in patients with rheumatoid arthritis.

OBJECTIVE: To test the hypothesis that preexisting lung disease is a risk factor for the development of methotrexate (MTX) pneumonitis in patients with rheumatoid arthritis (RA) treated with low dose MTX. METHODS: We measured the proportion of patients with and without preexisting lung disease who developed MTX pneumonitis in a historical cohort from a university affiliated rheumatology private practice in Chicago. Patients comprised 93 women and 32 men with RA treated with MTX for any period of time between January, 1980 and July, 1989. RESULTS: MTX pneumonitis occurred in 4 of 77 patients without preexisting lung disease (5.2%) and 5 of 29 (17.2%) patients with preexisting lung disease (p = 0.0610, Fisher's exact test). Five of 24 (20.1%) patients with preexisting lung disease characterized by the report of an abnormal chest radiograph developed MTX pneumonitis (p = 0.2328, Fisher's exact test) and 4 of 16 (25%) patients with interstitial infiltrates reported on their chest radiograph developed MTX pneumonitis (p = 0.0276, Fisher's exact test). CONCLUSION: The presence of preexisting lung disease characterized by radiographic interstitial infiltrates predisposes patients with RA to develop MTX pneumonitis.

Fibromyalgia: a study of family history of depression.

Previous research has suggested that some fibromyalgia may be part of an "affective spectrum disorder," pathophysiologically related to major depression. To examine the suspected association between fibromyalgia syndrome and depression, we conducted a family history study of depression among the first degree relatives (parents, siblings, and children) of two groups of probands with fibromyalgia, one with and one without a lifetime history of major depressive disorder. We tested the hypothesis that depression in patients with fibromyalgia is associated with a family history of depression. Major psychopathology in the probands was assessed with the Schedule for Affective Disorders and Schizophrenia and diagnosed using the Research Diagnostic Criteria. Forty fibromyalgia probands with and 14 fibromyalgia probands without a lifetime history of depression were interviewed about their parents, siblings, and children using the Family History Research Diagnostic Criteria format. Odds ratios were calculated, comparing the proportions of relatives with a history of depression in the two fibromyalgia proband groups. Lifetime histories of depression were found in 18% (n = 16) of the relatives of the probands with fibromyalgia and depression and in 9% (n = 25) of the relatives of the probands who did not have depression. Probands who had fibromyalgia and a history of major depression had more than twice the odds of having a relative who had depression than did the probands who had fibromyalgia but did not have a history of depression (odds ratio = 2.17 (95% confidence interval = 1.02-4.47)). These results suggest that depression in patients with fibromyalgia is associated with a family history of depression. Thus major depressive disorder in patients with fibromyalgia may be attributed more to their familial predisposition to depression than to a reaction to the pain and disability associated with fibromyalgia.

Personality trait correlates of attitudes toward older people.

The objective of this study is to determine whether personality is related to attitudes toward older people. To address this question, a sample of 228 students and gerontology practitioners completed the Aging Opinion Survey, the Cattell 16 Personality Factors Test, and a demographic questionnaire. When the influence of age, sex, education, and social desirability are controlled, a constellation of personality traits remains significantly related to attitudes toward older people. Specific trait-attitude correlations are described, and traits related to positive attitudes toward older people are shown to fit within three personality groupings: low anxiety traits, sensitive-intuition traits, and intellectual ability. These traits combined with demographic variables account for up to 30 percent of the variance in attitudes toward older people. The results of this study indicate that personality traits are clearly related to attitudes toward older people.

Is the MMPI invalid for assessing psychological disturbance in pain related organic conditions?

The Minnesota Multiphasic Personality Inventory (MMPI) was analyzed in 30 patients with fibromyalgia and 30 patients with rheumatoid arthritis (RA). Eighteen statements on the hypochondriasis, depression and hysteria scales and 14 statements on the schizophrenia scale differentiated patients with fibromyalgia and RA. Patients with fibromyalgia had higher scores on 29 of the 32 statements. Patients with RA seemed appropriately concerned about health and the possibility of additional illness. By contrast, patients with fibromyalgia were more symptomatic and presented a more unusual and complex syndrome, raising the possibility of a somatoform disorder and also greater personal distress in these patients. On the basis of analyzing the scores of patients with RA, one can also conclude that physical illness alone is not sufficient to drive MMPI profiles into the abnormal range. Patients with fibromyalgia who have a similar degree of pain intensity compared with patients with RA (61.3 vs 60 on a scale of 100) have significantly more abnormal MMPI, and analysis of their MMPI suggest a more complex somatic syndrome and greater psychological disturbance.

Acute non-dilating obstructive renal failure in a patient with AIDS.

A 30-year-old male who presented with acute renal failure was found to have acquired immunodeficiency syndrome (AIDS). Although sonography and computerized tomography did not show urinary tract dilatation, obstructive renal failure was demonstrated by retrograde pyelography. Relief of obstruction(s) due to encasement of the renal pelves and ureters with histiocytic lymphoma led to immediate return of normal renal function. Although the etiology of renal failure in this patient is highly unusual, the high incidence of lymphoma in patients with AIDS should make tumor-related renal disease a consideration in all such patients with renal dysfunction.

Kidney function during naproxen therapy in patients at risk for renal insufficiency.

The effects of naproxen on renal function in 34 patients with minimally elevated serum creatinine (Scr) or subnormal creatinine clearance (Ccr) were evaluated in a parallel-design study. All patients received open-label naproxen 375 mg twice daily for 2 weeks (phase I); patients were then randomly assigned to receive naproxen 750 mg twice daily (n = 26) or to continue naproxen 375 mg twice daily (n = 8) double-blind for an additional 2 weeks (phase II). Renal function was assessed by Scr, Ccr, and BUN measurements at baseline and at the end of each treatment phase. Neither treatment group had a clinically meaningful change in median laboratory values between baseline and the end of phase I, or between baseline and the end of phase II. During the first 2 weeks of treatment with naproxen 375 mg twice daily, there was no change in Scr. At the time of the first Scr measurement following the increase in naproxen dose to 750 mg twice daily, 13 of 26 patients had Scr levels of 1.1 mg/dL or higher, but four days later, only three patients had Scr levels of 1.1 mg/dL or higher, suggesting that a transient increase in Scr may accompany dosage increase. Chronic administration of naproxen 375 mg twice daily in patients at risk for renal insufficiency based on laboratory evidence of renal impairment was not associated with further deterioration in renal function. An increase in dosage to 750 mg twice daily in such patients appeared to be associated with only small, transient changes in laboratory measures of renal function.

Comparison of pain properties in fibromyalgia patients and rheumatoid arthritis patients.

Pain properties of 50 fibromyalgia patients were examined and compared with pain properties of 50 rheumatoid arthritis patients. In both fibromyalgia and rheumatoid arthritis, pain was bilateral, involved multiple sites, and was of equal intensity (60.8 versus 58.7, respectively, on a scale of 100). Fibromyalgia pain, however, was less localized to the joints and suggested greater spatial diffusion. It involved more kinds of pain experiences (radiating, steady, spreading, spasms, gnawing, unlocalized, pricking, crushing, shooting, pressing, splitting, cramping, nagging, and pins and needles), and was dispersed over larger areas of the body. The anatomic sites best for discrimination between patients with fibromyalgia and patients with rheumatoid arthritis were the lower back, thigh, abdomen, head, and hips for fibromyalgia, and wrist, foot, and fingers for rheumatoid arthritis. The traditional clinical description of aching and stiffness does not appear to accurately describe the complexity of the fibromyalgia pain syndrome.

Fatal warm antibody autoimmune hemolysis with marked erythrocyte autoagglutination and liver necrosis.

We have described a fatal case of autoimmune hemolysis associated with marked organ ischemia and lactic acidosis. Serologically the case was unusual because of the marked autoagglutination due to a warm antibody. Red cell agglutination at normal body temperature may have contributed to massive liver necrosis, lactic acidosis, and death.