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.

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.

Fibromyalgia syndrome in patients infected with human immunodeficiency virus. The Boston City Hospital Clinical AIDS Team.

PURPOSE: To prospectively assess rheumatic manifestations of human immunodeficiency virus (HIV) disease in a municipal hospital clinic population in which intravenous drug use was the most common risk factor for HIV infection. PATIENTS AND METHODS: Patients with documented HIV infection were evaluated for rheumatic disease using a standardized questionnaire and examination. Patients with fibromyalgia were compared with HIV-infected patients without fibromyalgia and with fibromyalgia patients without known risk factors for HIV infection. RESULTS: Thirty-seven of 140 patients with HIV infection had muskuloskeletal symptoms. Three of these 37 patients had arthritis, but none had Reiter's syndrome or psoriatic arthritis. Thirty (81%) of 37 patients had chronic musculoskeletal symptoms (for 3 months or longer). Twenty of 30 patients with chronic musculoskeletal symptoms had polyarthralgia, and of those, 15 (75%) were found to have either definite or probable fibromyalgia syndrome. Therefore, fibromyalgia syndrome was found in 41% of HIV-infected patients with musculoskeletal symptoms and in approximately 11% of all HIV-infected patients. Fibromyalgia patients with HIV infection had a longer duration of HIV infection (p = 0.01) and more frequently reported past depressed mood (p = 0.001) than HIV-infected patients without fibromyalgia. Compared with 301 patients with fibromyalgia syndrome and no known risk behavior for HIV, known HIV-infected patients with fibromyalgia were more commonly male (p = 0.001) and reported current depressed mood more frequently (p = 0.0001). CONCLUSION: Few patients with arthritis were noted among HIV-infected patients who had intravenous drug use as risk behavior. By comparison, fibromyalgia syndrome appeared to be a common cause of musculoskeletal symptoms in this patient population.

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.

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.

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.

Extrapulmonary thoracic restriction (hidebound chest) complicating eosinophilic fasciitis.

Eosinophilic fasciitis (EF) is an unusual disorder characterized by diffuse skin thickening and induration due to inflammation within the deep fascia; visceral involvement is generally mild or absent. A patient with biopsy-proved EF developed progressive respiratory limitation. Physical examination revealed marked induration of the thoracic integument with a severely limited chest wall excursion. Total lung capacity was 62 percent of predicted with a normal corrected Dco and maximal inspiratory force; a chest computed tomogram with thin sections showed no evidence of parenchymal lung disease. Extrapulmonary thoracic restriction ("hidebound chest") has not been previously reported to complicate EF.

Excessive fibrinolysis in amyloidosis associated with elevated plasma single-chain urokinase.

Severe bleeding resulting from excessive fibrinolysis has been observed in patients with primary amyloidosis. The authors studied a patient with this hemostatic disorder before and during therapy with epsilon-aminocaproic acid. Excessive fibrinolysis was associated with depressed plasma concentrations of coagulation Factors XII, XI, high-molecular-weight kininogen, and Factors VIII and V; and plasminogen and alpha-2-plasmin inhibitor. These deficiencies were corrected with treatment. The functional and antigenic concentrations of tissue plasminogen activator and plasminogen activator inhibitor in the patient's plasma were normal. Urokinase-type activator activity and antigen were three to five times elevated in the patient's plasma. Results of immunoprecipitation showed that single-chain urokinase-type activator was the primary urokinase-type activator species in the patient's plasma. Excessive fibrinolysis in patients with amyloidosis results from increased plasma single-chain urokinase-type activator activity.

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.

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.

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.

Symptoms mimicking neurologic disorders in fibromyalgia syndrome.

Recent reports have not emphasized the presence of paresthesias in fibromyalgia syndrome. In our retrospective review of 161 patients with fibromyalgia we found that 84% complained of numbness or tingling at initial evaluation. Most had either bilateral upper and lower extremity or bilateral upper extremity paresthesias. None had concurrent diseases commonly associated with peripheral neuropathy. Thirty-six patients with paresthesias had electromyograms performed before the diagnosis of fibromyalgia and 32 were normal. At a second assessment performed at a mean of 25 months from time of diagnosis, 56 of these 57 patients reported current paresthesias. Paresthesias are common in fibromyalgia and may mimic a neurologic disorder, although objective abnormalities are rare. Judicious use of neurodiagnostic tests are therefore indicated in the clinical setting of fibromyalgia.

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.

Bowel dysfunction in fibromyalgia syndrome.

Fibromyalgia and irritable bowel syndrome frequently coexist. In this study, we utilized a previously validated self-administered questionnaire to assess the prevalence of symptoms of bowel dysfunction and irritable bowel syndrome in 123 patients with fibromyalgia as compared to 54 patients with degenerative joint disease (DJD) and 46 normal controls. Ninety (73%) of the fibromyalgia patients reported altered bowel function as compared to 20 (37%) DJD patients and none of the normal controls (P less than 0.001). Ninety-nine patients (81%) reported normal alternating with irregular bowel pattern, and 77 (63%) had alternating diarrhea and constipation. In contrast, only 24 (44%) of DJD patients and six (13%) of controls had regular alternating with irregular bowel pattern and only 12 (22%) of the DJD patients and none of the healthy controls had alternating constipation and diarrhea (P less than 0.01). Other bowel dysfunction complaints noted in the fibromyalgia group were abdominal gas (59%), nausea (21%), diarrhea (9%), and constipation (12%). Seventy-nine (64%) fibromyalgia patients reported frequent abdominal pain that was stress-related 47% of the time. Laxative use was frequent in the fibromyalgia group (19%) and absent in the other two groups. Fifty percent of fibromyalgia patients, compared to 28% of DJD patients, felt that their bowel complaints were worse during exacerbations of their joint disease (P less than 0.05). In conclusion, patients with fibromyalgia have a high prevalence of gastrointestinal complaints that should be carefully assessed. If the diagnosis of IBS is confirmed, appropriate treatment may improve patients' symptoms, although this approach requires further study.

Development of preliminary criteria for response to treatment in fibromyalgia syndrome.

We developed a set of preliminary response criteria for use in future clinical trials in fibromyalgia syndrome. We determined outcome measures from a previously reported clinical trial which best distinguished patients treated with effective medication from those treated with placebo or ineffective medication, using stepwise logistic regression analysis. Several combinations of outcome measures were identified and plotted in the form of receiver operating characteristic (ROC) curves. The combination of variables possessing the greatest area under the ROC curve included (1) physician global assessment score less than or equal to 4 (0 = extremely well, 10 = extremely poorly), (2) patient sleep score less than or equal to 6 (0 = sleeping extremely well, 10 = sleeping extremely poorly), and (3) tender point score less than or equal to 14 (maximum possible tender point score equalled 20). These criteria accurately distinguished those treated with effective drug from those treated with placebo when tested in an unreported therapeutic trial of cyclobenzaprine. The criteria identified 11 of 14 patients in the amitriptyline trial and 4 of 6 patients in the cyclobenzaprine trial who attained improvement measured independently. The methodology used to define these preliminary criteria may be applied to refine the criteria as additional sensitive and clinically relevant outcomes are developed.

Established fibromyalgia syndrome and parvovirus B19 infection.

OBJECTIVE: To determine the seroprevalence of prior and persistent parvovirus B19 (B19) infection in a group of patients with fibromyalgia (FS) compared with controls. METHODS: Fifteen female patients with FS who recalled a viral prodrome (+VP) preceding the onset of FS symptoms and eleven patients with FS who did not recall any such illness (-VP) were selected from a referral practice. We excluded patients with FS who described a history of trauma prior to the onset of FS symptoms. Twenty-six female medical workers served as controls. Serum IgM and IgG anti-B19 antibodies were measured by ELISA: Polymerase chain reaction (PCR) products from serum were analyzed by dot blot hybridization for B19 DNA. Fisher's 2-tailed exact test was used to compare the proportion of positive serologies in each group. RESULTS: No patient or control had positive IgM levels. For all patients with FS, the prevalence of prior B19 infection was comparable to that of healthy controls (11/26 vs 12/26, p = 1.00) and that of the general population. No significant difference was found in the prevalence of prior B19 infection in FS + VP and FS-VP patients (8/15 vs 3/11, p = 0.25). None of the patients or controls showed evidence for persistent B19 viremia, as determined by PCR analysis. CONCLUSION: Our data do not suggest that B19 plays a pathogenic role in this population of patients with FS. Testing for IgM against B19 within 2-3 months of symptom onset may prove more helpful in further defining the role of B19 in FS.

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.

Tenderness in 75 anatomic sites. Distinguishing fibromyalgia patients from controls.

We studied tenderness at 75 unilateral anatomic locations in 10 fibromyalgia patients and 10 normal control subjects to determine which sites best identified patients with fibromyalgia. Using a dolorimeter, the mean amount of pressure required to elicit tenderness was significantly lower in patients than in controls at 19 sites (P less than 0.001). Of the previously proposed tender points, only 2 were included in those 19 best discriminating points. Fifteen of the 19 best discriminating points were clustered in regions around the anterior shoulder, anterior chest, posterior scapula, and medial knee. The 19 sites that we have identified best separate patients with fibromyalgia from controls, although the discriminating power of these sites in other chronic pain syndromes will require further study. Examination of specific regions may be more useful clinically than the exact anatomic sites within these regions.

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.