The role of vitamin D in corticosteroid-induced osteoporosis: a meta-analytic approach.

OBJECTIVE: To determine if vitamin D is more effective than no therapy or calcium alone in the management of corticosteroid-induced osteoporosis, and to determine how vitamin D compares with other osteoporosis therapies, e.g., bisphosphonates, calcitonin, or fluoride, for this condition. METHODS: We evaluated all formulations of vitamin D, including its active metabolites and analogs. A systematic search for published and unpublished studies was conducted using MEDLINE (1966-December 1997), bibliographic references, abstracts from proceedings of recent national meetings, and contact with pharmaceutical companies and content experts. We included all randomized controlled trials lasting at least 6 months (and reporting extractable results), of patients receiving oral corticosteroids, that compared vitamin D with either 1) no therapy or calcium alone, or 2) bisphosphonates, calcitonin, or fluoride. The primary outcome measure of interest was change in lumbar spine bone mineral density. RESULTS: We found a moderate beneficial effect of vitamin D plus calcium versus no therapy or calcium alone (9 trials) (effect size 0.60; 95% confidence interval [95% CI] 0.34, 0.85; P < 0.0001). In comparisons of vitamin D with other osteoporosis therapies, bisphosphonates were more effective than vitamin D (6 trials) (effect size 0.57; 95% CI 0.09, 1.05). Calcitonin was similar in efficacy to vitamin D (4 trials) (effect size 0.03; 95% CI -0.39, 0.45). Fluoride was more effective than vitamin D, but there were only 2 trials. CONCLUSION: Vitamin D plus calcium is superior to no therapy or calcium alone in the management of corticosteroid-induced osteoporosis. Vitamin D is less effective than some osteoporosis therapies. Therefore, treatment with vitamin D plus calcium, as a minimum, should be recommended to patients receiving long-term corticosteroids.

Systemic sclerosis-associated pulmonary hypertension: short- and long-term effects of epoprostenol (prostacyclin).

OBJECTIVE: To evaluate the short- and long-term effects of intravenous epoprostenol in patients with pulmonary hypertension (PH) associated with systemic sclerosis (SSc). METHODS: Sixteen patients with SSc-associated PH and New York Heart Association (NYHA) class III or IV symptomatology underwent right heart catheterization for determination of baseline hemodynamic values. Vasoreactivity was assessed with either inhaled nitric oxide or intravenous adenosine. After a medication washout period, all patients received intravenous epoprostenol in incrementally increasing doses; tolerance was assessed according to symptoms and hemodynamic findings at each dose increment and at the conclusion of the medication trial. Once a stable medication regimen was established, patients were discharged and followed up as outpatients for assessment of symptoms and exercise tolerance as measured by change in the NYHA class. Repeat hemodynamic testing was performed in 4 patients at 1 year and in 2 patients at 2 years of treatment. RESULTS: Therapeutic response to epoprostenol, defined by a reduction in the pulmonary vascular resistance of > or =25%, was achieved in the short-term treatment period in 13 of 16 patients (81.3%). Improvement in symptoms and exercise tolerance occurred in all patients, and a significant short-term hemodynamic response was observed. Followup hemodynamic tests revealed persistent favorable responses in all 4 of the patients studied. CONCLUSION: Most patients with PH secondary to SSc manifest favorable hemodynamic responses to epoprostenol in the short term. Long-term epoprostenol was generally well tolerated and provides a potential therapeutic option for patients with PH secondary to SSc.

Fibromyalgia is not a muscle disorder.

Originally described as "fibrositis," fibromyalgia has long been considered a muscle disorder, and many studies have investigated the possible pathologic basis of the disorder by examining muscle tissue, using various methodologic approaches. Although initial studies suggested a possible pathologic basis in muscle, most had serious methodologic limitations. More recent studies, however, have avoided methodologic pitfalls and indicate that the muscles of patients with fibromyalgia are normal. When data from studies of tenderness are also taken into account, the weight of evidence suggests that fibromyalgia is a chronic pain syndrome which has a central rather than peripheral or muscular basis.

Oral iloprost treatment in patients with Raynaud's phenomenon secondary to systemic sclerosis: a multicenter, placebo-controlled, double-blind study.

OBJECTIVE: To evaluate the efficacy and tolerability of an oral preparation of iloprost, a prostacyclin analog, in patients with Raynaud's phenomenon (RP) secondary to systemic sclerosis (scleroderma). METHODS: A multicenter, randomized, parallel-group, placebo-controlled double-blind study was performed at university and community-based medical centers. Patients were randomly assigned to receive either 50 microg of iloprost orally twice daily or an identical gelatin-coated capsule containing placebo for 6 weeks. Outcome measures included average total daily duration of RP attacks, average number of RP attacks, and RP condition scored via a standardized daily diary. RESULTS: Three hundred eight patients with scleroderma (272 women, 36 men, mean age 49 years [range 18-80]) were enrolled. One hundred fifty seven were assigned to receive iloprost and 151 to receive placebo. One hundred forty-three patients in the iloprost group (91.1%) and 144 in the placebo group (95.4%) completed the 6-week treatment phase. Fifteen of these treated patients (8 iloprost, 7 placebo) failed to complete all of the followup visits. The mean reduction in the average duration of attacks from baseline to week 5-6 was 24.32 minutes in the iloprost group and 34.34 minutes in the placebo group (P = 0.569). Likewise, the mean reduction from baseline to week 5-6 in the daily frequency of attacks was 1.02 in the iloprost group and 0.83 in the placebo group (P = 0.459). The Raynaud's condition score, a patient-completed assessment of the severity of RP attacks, was reduced by 1.32 in the iloprost group and 1.00 in the placebo group (P = 0.323). The lack of significant difference between treatment groups did not change when a variety of factors, including use of other vasodilators, duration of disease, classification of scleroderma (limited versus diffuse), or number of baseline digital ulcers were taken into account. Premature withdrawal from the study due to adverse events occurred in 10 patients (6.4%) in the iloprost group and 3 (2.0%) in the placebo group (P = 0.058). CONCLUSION: Oral iloprost at a dosage of 50 microg twice daily is no better than placebo for management of RP secondary to scleroderma, either during 6 weeks of treatment or during 6 weeks of posttreatment followup.

Scintigraphic functional hyposplenism in amyloidosis.

UNLABELLED: Functional asplenia or hyposplenism may predispose patients to spontaneous splenic rupture and potentially increase the risk of serious infection. In addition, hyposplenism may be a marker of more extensive systemic amyloidosis and has been correlated to a reduction in survival. Decreased splenic function is generally diagnosed by the presence of abnormal red blood cell morphology and decreased splenic uptake on 99mTc-sulfur colloid or microlite scans. We compared liver spleen scans with red cell morphology and anatomic imaging results in all patients with biopsy-proven amyloidosis who presented to the nuclear medicine department over a 12-yr period. Patients were referred from a center for amyloid disease for work-up of suspected hepatic involvement. METHODS: Between 1983 and 1995, 23 liver spleen scans from 21 patients (one patient had three scans) with known amyloidosis were referred for the assessment of degree of hepatic involvement with amyloid. All scans were retrospectively reviewed, and the degree of splenic uptake was graded. Medical records were reviewed for evidence of splenomegaly on physical exam. Extent of splenic involvement also was assessed by anatomical imaging (CT or MRI) in 45% of cases. Peripheral smear reports were reviewed for the presence of abnormal red cell morphology consistent with hyposplenism. RESULTS: Splenic activity was moderately or markedly reduced in 22 of 23 liver spleen scans (21 patients). Eight of these scans had correlative anatomic splenic imaging: four were abnormal and four were normal. Forty-one percent of available peripheral smears contained abnormal red cell morphology. Nine patients had palpable splenomegaly at the time of the liver spleen scan. Splenic pathologic studies were available for three patients (two autopsy, one surgical) and demonstrated diffuse splenic infiltration with amyloidosis. One patient had spontaneous splenic rupture. Fourteen patients died, four of overwhelming infection. CONCLUSION: Reduced splenic uptake on liver spleen scans for patients with suspected hepatic infiltration with amyloid is a common finding. Liver spleen scanning appears to be a more sensitive marker of splenic amyloidosis than clinical parameters or anatomical imaging.

Dose-intensive melphalan with blood stem cell support for the treatment of AL amyloidosis: one-year follow-up in five patients.

The morbidity and lethality of AL amyloidosis is caused by the deposition of lg light chains as fibrillar amyloid protein in vital organs, disrupting their function, and not by the generally low burden of clonal plasma cells that produce the paraproteins. Survival of patients with AL amyloidosis is no more than 1 to 2 years from the time of diagnosis with current management approaches. Clearly, more effective therapies are needed for this rapidly lethal disease. Five patients were treated with dose-intensive melphalan and blood stem cell support and followed for a period of 1 year. Patients were diagnosed with AL amyloidosis by tissue biopsy and categorized by performance status and organ involvement. Their plasma cell dyscrasias were evaluated with immunofixation electrophoresis of serum and urine specimens, quantitative serum lgs, and immunohistochemical staining of bone marrow biopsy specimens. After treatment with dose-intensive intravenous melphalan followed by infusion of autologous growth-factor-mobilized blood stem cells, clinical evaluations and plasma cell studies were repeated at 3 and 12 months. Three men and 2 women aged 38 to 53 years were treated. Median performance status (SWOG) was 2 (1 to 3), and clinical presentations included nephrotic syndrome (n = 1), symptomatic cardiomyopathy (n = 1), gastrointestinal involvement with polyneuropathy (n = 2), and hepatomegaly (n = 1). With a median follow-up of 13 months (12 to 17 months), all five patients are well and have shown stable or improved performance status and clinical remission of organ-related dysfunction, including a 50% reduction in daily proteinuria with no change in creatinine, reversal of symptoms of cardiomyopathy and reductions of posterior wall and septal thickening, reversal of polyneuropathy and gastric atony, and resolution of hepatomegaly by computed tomographic scan. In 3 of the 5 patients (60%) at 12 months after treatment, plasma cell dyscrasias could not be detected. Dose-intensive chemotherapy with intravenous melphalan and growth-factor-mobilized blood stem cell support is feasible therapy for patients with AL amyloidosis, even when there is clinical evidence of cardiac involvement. At least some patients with AL amyloidosis achieve complete remission of their plasma cell dyscrasia, improvement in performance status, and clinical remission of organ-specific disease after this form of treatment.

Improvement in the polyneuropathy associated with familial amyloid polyneuropathy after liver transplantation.

OBJECTIVE: To study, following liver transplantation, the neurologic progression or regression of the polyneuropathy in a cohort of patients with familial amyloidotic polyneuropathy (FAP). BACKGROUND: FAP is characterized by the relentless progression of neurologic and cardiac impairment, leading to death within 7 to 15 years after disease onset. No effective treatment to slow or halt the progression of this disease has been found to date. DESIGN/METHODS: Over the past 3 years, our FAP patients were offered liver transplantation as treatment. We report on nine patients who were followed longitudinally with serial neurologic examinations since transplantation. RESULTS: Clinically, all patients evaluated for neurologic progression reported significant improvement in general well being. No patient showed any progression in neurologic disease since receiving a liver transplant. Improvements are documented in symptomatic, autonomic, and sensorimotor neurologic disease in all patients. CONCLUSION: Our experience suggests that liver transplantation may offer hope for arrest of progression and neurologic improvement in patients with FAP.

Is there muscle pathology in fibromyalgia syndrome?

A number of studies have reported abnormalities in the muscles of fibromyalgia patients. The early studies, some of which indicated morphologic abnormalities, had major problems with patient selection and lacked adequate control groups. More recent studies of morphology have shown only nonspecific or mild changes, perhaps consistent with subtle metabolic abnormalities, especially at tender point sites. Studies of muscle metabolism, however, particularly the more rigorous studies using MR spectroscopy, have failed to confirm abnormalities in muscle metabolism, both at tender and nontender point locations. The abnormalities detected in earlier studies appear to have been confounded by subtle metabolic changes resulting from muscle deconditioning. Studies of muscle blood flow also demonstrate abnormalities that can be explained by deconditioning alone. Studies of muscle strength that show differences between patients and controls can be explained by lack of voluntary effort. A popular theory of the genesis of pain in fibromyalgia syndrome was that excessive muscle tension led to increased excitability of nociceptors in muscle leading to muscle hypertension and chronic pain. Furthermore, defective sympathetic control was proposed to result in disturbed microcirculation and nociceptor excitation. In aggregate, however, studies using EMG techniques show no evidence of excessive muscle tension or defective sympathetic nervous function. Therefore, although muscular pain has been a central feature of fibromyalgia syndrome, controlled studies of muscle fail to support a convincing role for muscle in the pathophysiology of the condition. Muscle tenderness in fibromyalgia cannot be explained on the basis of primary muscle abnormalities, either structural or functional. Future pathophysiologic studies in fibromyalgia should focus on central mechanisms.

Relapsing polychondritis and aseptic meningitis.

Aseptic meningitis is a rare complication of relapsing polychondritis. We describe a 60-year-old man who developed a prolonged episode of aseptic meningitis for which no cause could be determined and, that resolved spontaneously. He then developed classic relapsing polychondritis 14 months later. He subsequently had another episode of prolonged meningitis complicated by hydrocephalus. No infectious cause for the meningitis could be determined after extensive investigation including meningeal biopsy. The patient responded to corticosteroids and antituberculous therapy.

Electrocardiography and Doppler echocardiography in secondary (AA) amyloidosis.

The fibrils in AL and AA amyloidosis, although similar in appearance, have different biochemical composition and staining characteristics. Whereas electrocardiographic and echocardiographic features of heart involvement in AA amyloidosis resemble those for AL amyloidosis, our findings support the concept that the constituent amyloid fibrils may play a decisive role in the clinical pattern and significance of heart infiltration.

The clinical significance of liver disease in systemic lupus erythematosus.

The spectrum of hepatic disease in systemic lupus erythematosus (SLE) ranges from subclinical elevations of liver enzymes to rare reports of hepatic arteritis and infarction. Whether liver disease occurs as a consequence of (or is merely coincident with) lupus activity is not known. In our example, an episode of unexplained acute hepatitis occurred in association with pancytopenia. Both responded to increased doses of prednisone and were believed to be manifestations of SLE. The importance of hepatic disease and its contribution to morbidity and mortality in patients with SLE is controversial. Based on a critical review of the literature, we conclude that, although liver disease in SLE occurs more frequently than previously believed, it is usually limited to asymptomatic hepatomegaly and/or isolated elevations in liver function tests.

Recurrence of primary (AL) amyloidosis in a transplanted heart with four-year survival.

Cardiac amyloidosis has a poor prognosis, with a median survival of approximately 6 months once symptoms develop. This patient had a markedly improved quality of life with cardiac transplantation. We would suggest that with refinement of pretransplant chemotherapy, prolonged survival may be possible in carefully selected cases.

Controlled trials of therapy in fibromyalgia syndrome.

Many different interventions have been studied in the therapy of fibromyalgia syndrome (Tables 1 and 2). While most have been effective, in general these trials have been short term. Furthermore, important or substantial improvement, when it has been assessed, occurs in only small proportions of patients. Long-term, comparative trials of both efficacy and toxicity are necessary. Trials such as these require large numbers of patients (compared with placebo-controlled trials, which are generally impractical in long-duration trials due to the large numbers of dropouts in the placebo arm) and therefore are expensive and difficult to accomplish. Two other approaches offer potential solutions to the problem of adequate long-term comparative trials: (a) N-of-1 trials and (b) meta-analysis. N-of-1 trials have the advantage of random assignment, double-blinding and multiple potential comparisons in the same patient. Meta-analysis involves combining the results of studies, which individually may have conflicting results and lack adequate statistical power, to reach an overall result with sufficient statistical power to make meaningful conclusions, especially with respect to comparative efficacy. Peluso and colleagues (1993) have performed a recent meta-analysis of available therapies in fibromyalgia syndrome and found that the effect-size (a standardized measure of the efficacy of a given therapy) of several non-medication therapies such as electroacupuncture exceeded that of traditional medication therapies. Unfortunately, lack of uniformity in the use of outcome measures across included trials and the small numbers of comparable non-medication trials makes definitive conclusions regarding relative efficacy of therapies difficult. Nevertheless, application of meta-analytic methods such as these should facilitate future comparisons of different interventions. Ideally, future clinical trials in fibromyalgia syndrome should employ the same outcome measures to permit application of these methods. Few trials have assessed improvement in functional status. Functional status measures such as the HAQ (Fries et al., 1980), the Fibromyalgia Impact Questionnaire (Burckhardt et al, 1991) or similar instruments should be employed in future studies of therapy in fibromyalgia. Given that individual modalities appear to confer relatively modest benefit on average. Combination approaches are reasonable, although randomized, blinded trials to assess these approaches are methodologically complex. Several preliminary studies which have addressed this approach appear promising (see Chapter 12; Goldenberg et al, 1993). Finally, no studies have yet assessed the comparative cost-efficacy of available treatments. Controlled trials which address the cost-efficacy of commonly employed, but unproven treatments such as physiotherapy chiropractic manipulation and injection techniques are urgently needed.

The epidemiology of AL and AA amyloidosis.

The limited available epidemiological information on AL amyloidosis suggests that there may be differences between population-based studies and case series data with respect to variables such as age and racial patterns. Much more work in this area is required before specific aetiologic hypotheses can be tested. Most available data to approximate the epidemiology of AA amyloidosis are derived from autopsies. Most patients with AA amyloidosis die from causes other than amyloidosis, therefore mortality data based on death certificates is of limited value in AA amyloidosis. Case ascertainment in autopsy studies may be difficult due to the frequent lack of adequate histological controls. Establishment of registries for both AL and AA amyloidosis would facilitate epidemiological research in these disorders.

Lack of association between fibromyalgia syndrome and abnormalities in muscle energy metabolism.

OBJECTIVE: To compare parameters of muscle energy metabolism in patients with fibromyalgia syndrome (FMS) and sedentary controls. METHODS: Thirteen female FMS patients and 13 female sedentary controls underwent a standardized clinical assessment (including dolorimeter measurements of the upper trapezius and tibialis anterior muscles) and a standardized aerobic fitness test including measurement of maximum oxygen uptake (VO2max). Phosphorus (31P) magnetic resonance spectroscopy studies of the upper trapezius and tibialis anterior muscles were then performed in FMS patients and controls, at rest and during and following a muscle-fatiguing exercise protocol. RESULTS: FMS patients and controls had similar levels of VO2max and of maximum voluntary contraction (MVC) of the upper trapezius and tibialis anterior muscles. After controlling for VO2max and MVC, measurements of phosphocreatine (PCr), inorganic phosphate (P(i)), and intracellular pH in these muscles were not significantly different in FMS patients versus sedentary controls either at rest, during exercise, or during recovery. In the patients with FMS, no correlation was found between overall or local pain severity and the principal muscle metabolic parameter, PCr/P(i). Inverse correlations between dolorimeter scores at 2 muscle sites and tibialis anterior PCr/P(i) were found both in patients and in controls. CONCLUSION: This study demonstrates that under the conditions studied, muscle energy metabolism in FMS is no different than that in sedentary controls. These findings do not support the hypothesis that detectable defects in muscle energy metabolism occur in FMS.

Orthotopic liver transplantation for familial amyloidotic polyneuropathy.

Orthotopic liver transplantation for inborn errors of metabolism has become a standard indication for transplantation in pediatric and adult patients with alpha-1 antitrypsin deficiency, Wilson's disease and tyrosinemia, amongst several less common diseases. Familial amyloidotic polyneuropathy (FAP) is a rare autosomal dominant disease whose metabolic origin lies in an abnormal protein synthesized primarily in the liver. FAP, also discussed as the autosomal dominant form of amyloidosis, is characterized as a hereditary form of amyloidosis. It is the rarest form of amyloidosis affecting kindreds of specific ethnic backgrounds. The true incidence of this disease in the United States is not known. The mutant protein, called transthyretin or prealbumin, forms amyloid fibrils which accumulate in vital tissues ultimately leading to the patient's death. Liver transplantation for this inherited disease leads to the production of normal transthyretin protein. This theoretically should arrest the disease process. The first 5 patients in the United States with FAP who have undergone transplantation are presented.

A study of manufacturer-supported trials of nonsteroidal anti-inflammatory drugs in the treatment of arthritis.

BACKGROUND: To study the relation between reported drug performance in published trials and support of the trials by the manufacturer of the drug under evaluation, we studied a sample of trials of nonsteroidal anti-inflammatory drugs (NSAIDs) used in the treatment of arthritis. METHODS: All randomized control trials of NSAIDs published between September 1987 and May 1990 identified by MEDLINE were reviewed. If an article met the following criteria (n = 61), it was selected: trials involving adult patients with osteoarthritis or rheumatoid arthritis (n = 180), use of nonsalicylate NSAIDs marketed in the United States (n = 101), randomized control trial (n = 81), duration of the trial 4 or more days (n = 78), and use of an efficacy outcome measure (n = 61). Reviewers, "blinded" to manufacturer status, evaluated the narrative interpretation of results and extracted numeric data on efficacy and toxicity. Manufacturer-associated trials were defined as those that acknowledged an association with a pharmaceutical manufacturer. Because of the scarcity of non-manufacturer-associated trials (n = 9), we report only on the manufacturer-associated articles. RESULTS: Fifty-two publications (85.2%) representing 56 trials were associated with a manufacturer. The manufacturer-associated drug was reported as comparable with (71.4%) or superior to (28.6%) the comparison drug in all 56 trials. These narrative claims of superiority were usually justified with trial data. Of the trials identifying one drug as less toxic (n = 22), the manufacturer-associated drug's safety was reported as superior to the comparison drug in 86.4% of cases. Justification for the narrative interpretation of the trial findings regarding less toxicity was provided in only 12 (54.5%) of 22 trials. CONCLUSION: The manufacturer-associated NSAID is almost always reported as being equal or superior in efficacy and toxicity to the comparison drug. These claims of superiority, especially in regard to side effect profiles, are often not supported by trial data. These data raise concerns about selective publication or biased interpretation of results in manufacturer-associated trials.