[Highlights of rheumatology 1999: new developments between immunology and pain of movement mechanisms].
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Biomedical subjects
Publications and source records attributed to A Tyndall.
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To test the hypothesis that muscle weakness associated with aging is in part due to low serum levels of vitamin D, we investigated the relationship between muscle strength and serum levels of vitamin D metabolites in ambulatory elderly people who were not receiving vitamin D supplementation. We enrolled 319 ambulatory elderly subjects (103 women: mean age 74.2, age range 65-86; 216 men: mean age 76.6, age range 66-95) between April and August 1995. The study design was cross-sectional. Muscle strength was measured as leg extension power in watts (LEP). Mean 25-hydroxyvitamin D serum concentrations were higher in male participants at 36.2 ng/ml (range 3.0-85.0) versus 27.4 ng/ml (range 5.0-88.0) in female subjects (p = 0.008). We found 12 percent of female and 18 percent of male subjects with 25-hydroxyvitamin D values below the lower threshold (< 12 ng/ml). Mean 1,25-dihydroxyvitamin D levels were similar in both sexes: 39.8 pg/ml (range 15.0-73.0) in women and 37.9 pg/ml (range 13.0-69.0) in men. LEP declined with age in women and men (f: r = -0.35, p = 0.001; m: r = -0.48, p < 0.0001). Men were significantly stronger than women (p < 0.0001). In men both 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D showed pairwise correlation with LEP (r = 0.24; p = 0.0004/r = 0.14; p = 0.045). In women only 1,25-hydroxyvitamin D was significantly correlated with LEP (r = 0.22; p = 0.03). In ANCOVA, including all participants, explaining LEP by sex (p < 0.0001), age (p < 0.0001), BMI (p = 0.013), 1,25-dihydroxyvitamin D (p = 0.02), 25-hydroxyvitamin D (p = 0.18) and iPTH (p = 0.82), all factors showed significant effects except 25-hydoxyvitamin D and iPTH (r2 of the whole model: 0.41). In conclusion our results support the view that, in concert with other factors, deficiency of both 25-hydroxyvitamin D and 1,25-hydroxyvitamin D contributes to the age-related decline in muscle strength. Modest, but significant relationships between 1,25-dihydroxyvitamin D and muscle strength in both sexes, and 25-hydroxyvitamin D in male participants could be documented. Whether the impact of vitamin D on calcium homeostasis and bone mineral density or directly on the muscle tissue level is more important for prevention of hip fractures remains unclear. Further prospective and comparative treatment studies should be performed, in order to evaluate whether and in which dose requirements, vitamin D supplementation can improve muscle strength in the elderly.
Recent reports suggest the possible beneficial effects of haemopoietic stem cell transplantation (HSCT) in autoimmune diseases such as multiple sclerosis (MS). The definition of the risk/benefit ratio for such a treatment is perceived as a major issue for the neurological community worldwide. The First Consensus Conference on Bone Marrow Transplantation in Patients with Multiple Sclerosis was held in Milan, Italy on 21 February 1998. Participants from 16 European, North American, and South American countries discussed the guidelines for performing HSCT in MS. This conference was organized in order to: (a) define criteria for patient selection; (b) define transplantation procedures to maximize efficacy of the treatment and minimize its toxicity; (c) standardize patient outcome evaluation; and (d) establish an international working group to evaluate the efficacy and safety of HSCT in MS and to study the immunological changes related to HSCT in MS patients. During the meeting in Milan agreement was reached on: (a) the preparation and distribution of a consensus report on HSCT in MS and (b) the design of an open trial for an initial assessment of the safety and efficacy of HSCT in MS. The consensus reached during the meeting and the design of the clinical trial are summarized in this contribution.
The authors report a case of a young woman with adult-onset Still's disease (AOSD) with massive hyperferritinaemia who developed acute florid hepatitis with intraparenchymatous histiocytic infiltration following oral iron substitution for presumed iron deficiency, which settled on withdrawal of the iron. This suggests that the iron exacerbated the macrophage hyperactivity which is presumed to be present in AOSD. Oral iron substitution in the acute phase of this disease may be inadvisable.
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The rationale for stem cell transplantation is feasible and tests the hypothesis that the immune system is important in the pathogenesis of SSc in carefully selected patients. At the present time, results from pilot studies of SCT in systemic sclerosis are moderately encouraging, although further refinements in SCT treatment protocols are probably necessary. Finally, the time for a controlled study of SCT is rapidly approaching.
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Residents of a long-stay geriatric ward at the University Hospital Basel were included in a study to investigate the effects of hypovitaminosis D and immobility. All 91 women (mean age 82.5 years) and 92 men (mean age 78.7 years) were enrolled in the study. Measurements included bone resorption, as measured by urinary deoxypyridinoline (dpd), serum 25-hydroxyvitamin D (25OHD), serum intact parathyroid hormone (iPTH), and their correlations with a four grade mobility score. Mobility score reflected the degree of weight bearing, ranging from walking independently to primarily bed bound. In 86% of all residents, serum 25OHD levels were below the normal limit of 12 ng/ml. Secondary hyperparathyroidism (HPT) was detected in 24% of all patients, using 55 pg/ml as the upper limit for serum iPTH. No significant correlation was found between urinary dpd and serum 25OHD or serum iPTH. Mobility index and both urinary dpd (f: P = 0.001, r = 0.37; m: P < 0.0001, r = 0.47) and serum calcium (female: P = 0.007, r = 0.28; male: P = 0.02, r = 0.24) were positively related. In institutionalized elderly people with a high prevalence of vitamin D deficiency serum intact PTH levels did not correlate with bone resorption as measured by urinary deoxypyridinolin. However, more immobile subjects had significantly higher excretion rates for urinary dpd and higher serum calcium levels. Our results suggest that in elderly people immobility may contribute to bone loss that might preempt the development of secondary HPT through elevation of serum calcium.
A 65-year-old woman presented with vertebral fractures of the lumbar spine and a history of pathological fractures following minor trauma, which had occurred before the onset of menopause. Her past medical history was significant for intermittent low back pain since childhood, which was attributed to thoracolumbar scoliosis. A diagnosis of unclassifiable osteoporosis was made until invasive diagnostic procedures suggested a mild form of type I osteogenesis imperfecta (OI). In unclear or atypical perimenopausal osteoporosis and diagnosis of OI should be considered.
OBJECTIVES: To document lifestyle-associated variations in biochemical markers of bone metabolism in advanced age. STUDY DESIGN: Cross-sectional study. SETTING: Department of Geriatrics, University Hospital, Basel, Switzerland. SUBJECTS: Three hundred twelve ambulatory and 193 institutionalized men and women, aged 54 to 99 yrs. OUTCOME MEASUREMENTS: Biochemical markers of bone resorption (urinary deoxypyridinolin and N-telopeptides), serum vitamin D metabolites, and serum intact parathyroid hormone (iPTH) concentrations were assessed. Mean values of all parameters were correlated with a six-grade activity score. Physical activity score reflected the degree of weight bearing, ranging from walking independently to primarily bed-bound. Ambulatory subjects were measured in summertime and institutionalized subjects in wintertime to accentuate seasonality of vitamin D hormone levels. RESULTS: Excretion of bone resorption markers was significantly higher in the institutionalized and physically inactive patients compared with those who were ambulatory and physically active (p = .0001). Vitamin D deficiency (25-hydroxyvitamin D of <12 ng/mL) was present in 86% of institutionalized and 15% of ambulatory subjects, and 1,25-dihydroxyvitamin D serum concentrations were lower in institutionalized than in ambulatory subjects (p = .0001). Mean serum concentrations for iPTH were similar for both the institutionalized and ambulatory groups. When subjects were arranged according to activity score, mean excretion of urinary bone resorption markers increased with degree of inactivity. CONCLUSION: Despite the difference in vitamin D metabolites, iPTH serum concentrations did not differ significantly between the institutionalized and ambulatory groups. However, institutionalized and physically inactive participants had markedly elevated excretion of urinary bone resorption markers compared with ambulatory and physically active subjects. These results suggest that high bone turnover in the elderly may be caused by physical inactivity related to low mechanical loading rather than secondary hyperparathyroidism.
OBJECTIVE: To identify a relation between loss of muscle strength and vitamin D deficiency in ambulatory elderly persons not receiving vitamin D supplementation. DESIGN: Cross-sectional study. SETTING: All measurements were taken at the Department of Geriatrics, University Hospital, Basel, Switzerland. SUBJECTS: Three hundred nineteen patients (103 women, 216 men) selected by random sampling from participants in an ongoing interdisciplinary study on aging (mean age for women, 74.2 yrs; for men, 76.7 yrs). OUTCOME MEASURES: Leg extension power (LEP) and body mass index (BMI); serum values of 25-hydroxyvitamin D [calcidiol, 25(OH)D], 1,25-hydroxyvitamin D [calcitriol, 1,25(OH)2D], and intact parathyroid hormone (iPHT). RESULTS: Twelve percent of women and 18% of men had 25(OH)D values below the normal range (<12 ng/mL). Muscle strength was lower in older subjects (female: r = -.35; p = .0005/male: r = -.48; p < .0001) and was lower in women than in men (p < .0001). In men both 25(OH)D and 1,25(OH)2D was significantly correlated with LEP (r = 0.24; p = .0004/r = .14; p = .045). In women, only 1,25(OH)2D was significantly correlated with LEP (r = 0.22; p = .034). In an ANCOVA including all participants and explaining LEP by sex, age, BMI, 1,25(OH)2D, 25(OH)D, and iPTH, all factors showed significant effects except 25(OH)D and iPTH (r2 = .41). CONCLUSION: Muscle strength declined with age in ambulatory elderly people and showed modest, but significant, positive correlation with 1,25(OH)2 vitamin D in both sexes and with 25(OH)D in male subjects. Therefore vitamin D deficiency appears to contribute to the age-related loss of muscle strength, which might be more pronounced in institutionalized elderly people with a high prevalence of vitamin D deficiency.
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AIM: The aim of the present study was to measure concentrations of vitamin D metabolites and intact parathyroid hormone (iPTH) serum concentrations and an urinary bone resorption marker in two groups of elderly subjects, who differed markedly in their sedentary status and seasonality. DESIGN: 193 institutionalized elderly people of a long-stay geriatric ward (106 women: mean age 82; 87 men: mean age 78) were studied during wintertime. 312 ambulatory elderly people (109 women: mean age 74; 203 men: mean age 76) were studied during summertime. Concentrations of calcidiol (25(OH)D), calcitriol (1,25(OH)2D) and serum iPTH, as well as urinary N-telopeptides (NTX) were measured. RESULTS: Vitamin D deficiency (defined as serum 25(OH)D < 12 ng/ml) was present in 86% of institutionalized at the expected nadir (wintertime), compared to 15% of the ambulatory elderly subjects at the expected maximum (summertime). Serum calcitriol concentrations were significantly lower in institutionalized subjects (p = .0001). However intact PTH concentrations did not differ significantly between institutionalized and ambulatory elderly. Institutionalized and female subjects showed higher urinary NTX excretion (female institutionalized: 131.9; female ambulatory: 66.8/male institutionalized: 76.3 male ambulatory: 45.8 nmol/mmol). CONCLUSION: This cross-sectional study documented very low serum calcidiol and calcitriol concentrations and high urinary N-telopeptide excretion in institutionalized elderly people. There was no difference in serum iPTH concentrations between institutionalized and ambulatory elderly. This finding could not be explained by the differences in calcidiol and calcitriol concentration, nor urinary NTX excretion. These results suggest that other factors than vitamin D deficiency, such as lower mobility status and sedentary life style, might have an important role in the regulation of iPTH and mechanisms of bone loss in the elderly.
This ongoing multicentre prospective phase I/II trial enrolled 74 consecutive patients from 22 centres worldwide with severe autoimmune disease, 35 with rheumatological disorders, 31 with neurological, five with haematological and three with vasculitides. They were treated with autologous peripheral blood or bone marrow transplants according to predetermined criteria. Two patients died after mobilisation before transplant. Seventy-two patients were given 73 transplants, seven bone marrow, and 66 mobilised peripheral blood stem cell transplants. The graft was manipulated to remove T and/or B cells in 43 cases. All 73 transplants engrafted. Five patients died of transplant-related complications: two from bleeding, three from infections. Two patients died of progressive disease. The transplant-related mortality at 1 year of 9% (1-17%; 95% CI) is comparable to the transplant-related mortality of 6% (3-9%; 95% CI) in patients transplanted during the same period in Europe for non-Hodgkin's lymphoma in sensitive relapse (P = 0.39). Sixty patients are evaluable for response, 40 patients (65%) showed some improvement in their disease. Haematopoietic stem cell transplants are feasible for patients with severe refractory autoimmune disease. Transplant-related mortality is comparable to results in patients with non-Hodgkin's lymphoma in responsive relapse. Two-thirds of the patients show at least some response. These preliminary data are promising. Although associated with considerable risk, randomised trials comparing autologous stem cell transplants to conventional therapy are warranted.
Some severe auto-immune diseases, including rheumatoid arthritis, require immunosuppression to save life or vital organ function. One major limiting factor in such immunosuppression is the unwanted and dangerous haematoablation occurring at the same time. It is now possible to give supralethal doses of haematoimmunoablative drugs, and to 'rescue' the patient with haematopoietic stem cell transplantation. There are case reports of patients with rheumatoid arthritis who have received bone marrow transplantation, now called haematopoietic stem cell transplantation (HSCT), for a conventional indication such as aplastic anaemia or malignancy, in whom a long lasting improvement of the arthritis was observed. However, not all cases have responded, and there are still many open questions concerning optimal treatment regimens. In addition, some animal model research has supported the concept of HSCT as a permanent treatment of auto-immune disease including arthritis. In the past three years, HSCT has been applied to treat auto-immune disease alone in around 180 patients, 20 of whom having had rheumatoid arthritis and 13 juvenile arthritis. Early results are encouraging, but many issues require further clarification through co-ordinated clinical trials. The evolution of this project, details of the early results, the remaining open questions and possible strategies to resolve these are the subject of this chapter.