The cost diary: a method to measure direct and indirect costs in cost-effectiveness research.

From a societal perspective long-term clinical trials or follow-up studies should preferably not only include an evaluation of the health effect for the patient, but also an economic evaluation. In order to yield comprehensive medical and nonmedical resource use data, we at least partly depend on respondents' recall for collecting these costing data. A patient cost diary was developed in order to estimate total resource use, expenses, and lost production due to illness and treatment. We applied the cost diary in two randomized clinical trials evaluating the cost-effectiveness of behavioral rehabilitation in 205 fibromyalgia and chronic low back pain patients. The use of the diary was evaluated, studying the feasibility, the influence of the period of data collection on the results, and some aspects of validity. Eighty-five percent of the patients completed at least one diary and in total 68% of the diaries were returned. Although the results for the three alternative periods of data collection (keeping the diary 1 week every month, 2 weeks every 2 months, or a full year) were not significantly different, they were only moderately correlated. Finally, self-reported specialist care contacts were generally in agreement with data from an insurance company. However, for physiotherapy contacts there were differences between the self-reported and insurance data. This study shows how the cost diary might be used successfully in cost-effectiveness studies.

Patient utilities in chronic musculoskeletal pain: how useful is the standard gamble method?

The main goal of current pain management approaches is to increase the patients' quality of life by improving pain coping skills and by reducing the levels of disability in daily life, often despite persistent pain. Direct measurement of quality of life is of crucial importance in economic evaluation research, in which not only is the estimation of financial costs and benefits included, but so is the evaluation of costs and benefits in terms of changes in health states. The purpose of this study is to compare the psychometric qualities of two instruments for assessing patients' utilities, the rating scale (RS) and the standard gamble (SG). Such instruments are designed for their application in economic evaluation research, but have seldomly been used in chronic pain trials. Both methods provide a single measure between 0 and 1. The relationship between these utility measures and descriptive and domain-specific quality of life measures was examined in 133 fibromyalgia patients and 148 patients with chronic non-specific low back pain. Mean utility score at baseline was 0.43 with the RS and 0.78 for the SG. The correlation between both methods was found to be poor (r = 0.21). Both measures appeared to be fairly stable in a 2-week test-retest period (intra class correlation coefficient (ICC) = 0.74 and 0.77). Scores on the description of patient's own health on six domains, global assessment of change and domain specific measures correlated moderately with the RS scores and low with the SG. Multiple regression analyses demonstrated that 32% of the variance in RS values and only 13% of the variance in SG utilities could be explained by domain-specific measures. These results suggest an acceptable construct validity for the RS but insufficient construct validity for the SG. Valuations of ones own health appear only partially to be related to the assessment of the pain-specific measures and measures of distress. It can be concluded that the RS and domain-specific measures assess partly different, but nevertheless complementary aspects of health-related quality of life. It is therefore recommended to include in economic evaluation studies both domain-specific measures and valuation measures. Finally, in chronic musculoskeletal pain patients, RS scores were found to be more responsive in detecting significant changes in preferences than SG scores. For use in patients with chronic musculoskeletal pain, the RS is preferred to the SG for establishing accurate decisions about the impact of new interventions on their health outcomes.

Patients with ankylosing spondylitis and healthy relatives do not show increased small intestinal permeability with the lactulose-mannitol test.

Small intestinal permeability was measured in 71 subjects: 26 (24 B27+) patients with ankylosing spondylitis (AS); 20 healthy first degree relatives (13 B27+); 6 patients with active Crohn's disease and 19 healthy controls. We determined the urinary excretion ratio of two ingested sugar probes, lactulose (10 g) and mannitol (0.5 g) by gas-liquid chromatography. The median lactulose/mannitol excretion ratio in AS patients (0.0099) and relatives (0.0090) was not significantly different from the median ratio in healthy controls (0.0095). HLA status or use of NSAIDs did not significantly influence the results. In patients with Crohn's disease, on the other hand, the median lactulose/mannitol ratio (0.021) was significantly increased in comparison to healthy controls (0.0095). Our results confirm that the lactulose-mannitol test can be used to demonstrate increased intestinal permeability in Crohn's disease. For patients with AS and their relatives the lactulose-mannitol test may not be sufficiently sensitive. Alternatively, significantly increased permeability may not occur in most patients with AS.

Diffuse idiopathic skeletal hyperostosis (DISH) of the elbow: a cause of elbow pain? A controlled study.

Elbow pain is a common complaint and elbow hyperostosis a frequent radiological condition. However, little is known about the association between the clinical and radiological findings. To evaluate the relationship between spinal and extraspinal hyperostotic features and the clinical relevance of elbow hyperostosis we have performed the first controlled, double-blinded study of 85 hospitalized probands, 33 with and 52 without thoracospinal hyperostosis on lateral chest X-ray. Elbow and shoulder hyperostosis were graded on bilateral standard radiographs. Elbow pain was assessed by an interviewer using a standardized questionnaire and extraskeletal causes of elbow pain were recorded. The prevalence of elbow hyperostosis was increased in cases with thoracospinal hyperostosis compared to controls (82% versus 58%, chi 2 = 5.32, P less than 0.025, n = 85, olds ratio (OR) 3.30 (95% CI 1.16-9.35)). Similarly, the prevalence of elbow hyperostosis was increased in cases with shoulder hyperostosis compared to controls (83% versus 60%, chi 2 = 4.51, P less than 0.05, n = 84, OR = 3.20 (95% CI 1.06-9.66)), emphasizing the multifocal nature of hyperostotic features. Elbow pain was only slightly more prevalent in cases with elbow hyperostosis compared to controls (21% versus 13%, chi 2 = 0.75, NS, OR = 1.84 (95% CI 0.46-7.44)). We conclude that elbow hyperostosis is a radiological finding of doubtful clinical relevance.

Polymorphism of the tumor necrosis factor region in relation to disease: an overview.

HLA antigens have been shown to be associated with several immunoinflammatory diseases. The mechanisms by which these antigens confer susceptibility to disease continue to be of major interest. Rapid progress has been made in the elucidation of the structure and function of class I and II MHC molecules, and several genes located within the HLA complex have been identified which are potentially involved in immunologic processes. Because of the HLA localization of the TNF-alpha and -beta genes and the biologic activities of the gene products, recent investigation has focused on a possible role of polymorphic TNF genes in the pathogenesis of HLA-associated diseases. Allelic variations have only been detected in the TNF-beta gene. No evidence has been found so far that a particular TNF-beta allele contributes significantly in the susceptibility to the diseases studied. Although it has been postulated that the TNF beta*2 allele contributes to susceptibility to IDDM in HLA-DR3, 4 heterozygous individuals, a larger group of HLA-typed patients and controls is needed to provide more conclusive evidence for this hypothesis. The increasing number of genes of unknown function encoded by the class III region leaves the possibility that the observed HLA associations in some diseases may be related to the presence of these genes. In AS, the lack of association with the TNF-beta alleles furthermore supports the function of the HLA-B27 molecule in the disease and underlines the improbability that HLA-B27 is merely a marker for a closely linked susceptibility gene.

Restriction fragment length polymorphism of the tumor necrosis factor region in patients with ankylosing spondylitis.

Although ankylosing spondylitis (AS) is known to be strongly associated with the class I major histocompatibility complex antigen HLA-B27, B27 is probably not the only genetic factor involved in the pathogenesis of AS. Because of the involvement of tumor necrosis factor (TNF) in cartilage damage and the localization of the TNF genes in the proximity of the HLA-B locus, we investigated the association between AS and TNF alleles. The frequencies of the restriction fragment length polymorphisms linked to the TNF genes were determined in 73 AS patients and 81 controls. No differences were observed between AS patients and controls with respect to the frequencies of the TNF restriction fragment length polymorphisms.

The prevalence and incidence of clinical and asymptomatic Lyme borreliosis in a population at risk.

A past history of clinical Lyme borreliosis and the 6-month incidence of clinical and asymptomatic Lyme borreliosis was studied prospectively in a high-risk population. In the spring, blood samples were drawn from 950 Swiss orienteers, who also answered a questionnaire. IgG anti-Borrelia burgdorferi antibodies were detected by ELISA. Positive IgG antibodies were seen in 248 (26.1%), in contrast to 3.9%-6.0% in two groups of controls (n = 101). Of the orienteers, 1.9%-3.1% had a past history of definite or probable clinical Lyme borreliosis. Six months later a second blood sample was obtained from 755 participants, 558 (73.9%) of whom were seronegative initially; 45 (8.1%) had seroconverted from negative to positive. Only 1 (2.2%) developed clinical Lyme borreliosis. Among all participants, the 6-month incidence of clinical Lyme borreliosis was 0.8% (6/755) but was much higher (8.1%) for asymptomatic seroconversion (45/558). In conclusion, positive Lyme serology was common in Swiss orienteers, but clinical disease occurred infrequently.

A wider spectrum of spondyloarthropathies.

As in other diseases of undetermined etiology, the diagnosis of ankylosing spondylitis (AS) and related spondyloarthropathies (SpA) is based on clinical and roentgenographic features. The current criteria for diagnosis of some of these diseases are too restricted, and do not recognize the existence of a much wider disease spectrum. For example, radiographically detected sacroiliitis is extremely frequent in AS, but may not be an obligate manifestation, especially in early or atypical forms of the disease. Arthritis involving the axial skeleton, including the sacroiliac joints, can be present in some patients without evidence of erosive disease roentgenographically. The disease spectrum of Reiter's syndrome has also been broadened considerably, and "incomplete" forms of Reiter's syndrome are observed much more commonly than the classical triad of arthritis, conjunctivitis, and urethritis. The term "B27-associated reactive arthritis" has been used in recent years to refer to SpA following enteric or urogenital infections, and the disease spectrum includes the clinical picture of typical Reiter's syndrome. The clinical spectrum of psoriatic SpA has been better clarified. Some of the less well defined B27-associated clinical syndromes include seronegative oligoarthritis, polyarthritis, or dactylitis ("sausagelike" toes) of the lower extremities, and heel pain caused by calcaneal (and tarsal) periostitis. These and other undifferentiated SpA have been ignored in previous epidemiological studies because of the inadequacy of the existing classification criteria. The European Spondylarthropathy Study Group (ESSG) has completed a study aimed at developing preliminary classification criteria for the whole group of SpA patients, with the specific intention of encompassing patients with undifferentiated SpA.

Ankylosing spondylitis and other spondyloarthropathies.

Ankylosing spondylitis and related spondyloarthropathies show a remarkable association with a genetic marker--HLA-B27--and also illustrate the relationship between host and environmental factors. HLA-B27 has revitalized the epidemiology of spondyloarthropathies and has helped to broaden the clinical spectrum of these diseases. These and other aspects of descriptive and genetic epidemiology are reviewed.

Genetics of non-HLA marker genes in HLA-B27-positive and -negative ankylosing spondylitis families.

In families of HLA-B27+ ankylosing spondylitis (AS) patients, the occurrence of secondary cases of sacro-iliitis (SI) among B27+ first degree relatives is more than tenfold higher than expected from the population association of AS with HLA-B27. Secondary cases of SI also occur in relatives of HLA-B27- AS patients. We addressed the question whether other genetic factors than HLA-B27 played a role in the familial occurrence of AS and SI in B27+ and B27- AS cases. To this we tested 24 genetic marker systems including GM and PI in first degree relatives of AS patients: 118 first degree relatives with 16 secondary SI cases in families of 23 B27+ AS probands and 74 relatives with 6 secondary SI cases in families of 14 B27- AS probands. With a LIPED analysis we found no significant evidence for linkage for any of the markers tested, including HLA. In a co-segregation analysis we found a significant deviation from random segregation for HLA-B27 (p = 0.0005) and for HLA haplotypes (p = 0.052) to affected B27+ AS/SI siblings. No such deviation was found to B27- AS/SI cases. For GM and PI we found no significant cosegregation with AS/SI in B27+ and B27- families. In conclusion, apart from HLA-B27, we found no significant effect of any of the genetic marker systems tested in explaining the familial clustering of AS and SI among B27+ and B27- AS patients.

HLA-Bw60 increases susceptibility to ankylosing spondylitis in HLA-B27+ patients.

We examined the distribution of non-B27 alleles of the HLA-B locus among B27+ patients with ankylosing spondylitis (AS), to detect any additional HLA-B locus allele(s) that may act in conjunction with B27 to increase susceptibility to AS. HLA-Bw60 (or B40 when the Bw60,61 split of B40 was not typed for) was shown to be increased among B27+ AS patients in each of 5 independent data sets. This increase was statistically significant in 4 of the 5 data sets studied, and the overall significance was P less than 0.00001. Susceptibility to AS in B27+ individuals was further increased by a factor of approximately 3 when Bw60 was also present. The distribution of HLA-A alleles on the B27-bearing haplotypes in AS patients was not significantly different from that in normal controls. On the other hand, the distribution of HLA-A alleles on Bw60-bearing haplotypes was significantly different from the distribution of A alleles on Bw60 haplotypes in the general population (P less than 0.0005). Bw60 was not increased in B27- patients with AS. A dominant mode of inheritance generally fits AS; however, our sib pair analysis indicates that the B27,Bw60 disease subgroup follows a more recessive mode of inheritance.

Chest pain without radiographic sacroiliitis in relatives of patients with ankylosing spondylitis.

The prevalence of complaints of thoracic pain or stiffness in the past 6 months was assessed by examination, HLA typing and sacroiliac radiographs in 420 relatives of 275 B27+ probands with ankylosing spondylitis (AS). AS or sacroiliitis was found in 15 of 420 relatives (3.6%). The gender of the proband did not influence the probability of AS or sacroiliitis among the relatives. In the absence of sacroiliitis, B27+ relatives had chest pain more often (31 of 208, or 14.9%) than B27- relatives (13 of 197, or 6.6%) (p less than 0.01). Chest pain assessed by questionnaire was associated with pain on pressure at the costosternal junctions. The concept of AS as a combination of radiographic sacroiliitis plus clinical signs or symptoms may be too narrow.

The association between ankylosing spondylitis, acute anterior uveitis and HLA-B27: the results of a Swiss family study.

Patients with HLA-B27 positive ankylosing spondylitis (AS) in a Swiss family study developed non-granulomatous acute anterior uveitis (AAU) 11 times more often than their healthy relatives sharing the same HLA-B27 positive haplotype (4.4% versus 0.4%; p less than 0.01) during a period of 6 months.