Search PubMed⌕ Search

Biomedical subjects

C A Stegeman

Publications and source records attributed to C A Stegeman.

At least 19 recordsLinked to original sources
PubMed2006

Persistent expansion of CD4+ effector memory T cells in Wegener's granulomatosis.

In order to test the hypothesis that Wegener's granulomatosis (WG) is associated with an ongoing immune effector response, even in remission, we examined the distribution of peripheral naive and memory T-lymphocytes in this disease, and analyzed the function-related phenotypes of the memory T-cell population. Peripheral blood mononuclear cells (PBMCs) were freshly isolated from WG-patients in remission (R-WG, n=40), active WG-patients (A-WG, n=17), and age-matched healthy controls (HCs, n=21). Expression of CD4, CD8, CD45RO, CCR7, interleukin (IL)-18Ralpha, ST2L, and FoxP3 were determined by four-color flow cytometric analysis. CD45RO and CCR7 were used for distinction between naive and memory T cells, IL-18Ralpha, ST2L, and FoxP3 for the assessment of Type1, Type2, and regulatory T-cells, respectively. In R-WG, the CD4+CD45RO+CCR7- effector memory T-cell subpopulation (TEM) was relatively increased, whereas the CD4+CD45RO-CCR7+ naive T-cell population (TNaive) was decreased as compared to HC. The distribution of naive and memory CD8+T cells did not differ between R-WG, A-WG, and HC, nor did CD4+CD45RO+CCR7+ central memory T cells (TCM). In contrast to HC, the percentage of CD4+TNaive cells in R-WG correlated negatively with age, whereas CD4+TEM cells showed a positive correlation. In R-WG, a skewing towards Type2 T cells was observed in CD4+TEM cells. No differences were detected in FoxP3+CD4+TEM cells between R-WG and A-WG, whereas the FoxP3-CD4+TEM cells were increased in R-WG and decreased in A-WG as compared to HC. Collectively, peripheral blood homeostasis of CD4+T cells is disturbed in R-WG with the persistent expansion of non-regulatory CD4+TEM cells. These cells might be involved in relapse and may constitute a target for therapy.

Adult↗
PubMed2006

Plasma levels of soluble interleukin 2 receptor, soluble CD30, interleukin 10 and B cell activator of the tumour necrosis factor family during follow-up in vasculitis associated with proteinase 3-antineutrophil cytoplasmic antibodies: associations with disease activity and relapse.

OBJECTIVES: To evaluate whether T cell activation, as reflected by levels of soluble interleukin 2 receptor (sIL2R), soluble CD30 (sCD30), IL-10 and B cell activator of the tumour necrosis factor family (BAFF) at diagnosis and during initial follow-up, is predictive for persistent or renewed antineutrophil cytoplasmic antibody (ANCA) positivity and clinical relapse in patients with vasculitis associated with proteinase 3-antineutrophil cytoplasmic antibodies (PR3-ANCA). METHODS: 87 Patients with PR3-ANCA-associated vasculitis and at least 2 years of follow-up were included in the study. At diagnosis, and at 3, 6, 12, 18 and 24 months after diagnosis, cytoplasmic ANCA titres were detected by indirect immunofluorescence (IIF), and PR3-ANCA, sIL2R, sCD30, IL-10 and BAFF levels were assessed by ELISA. 31 healthy volunteers provided plasma samples for comparison. Levels of immune markers were related to ANCA positivity and relapse during follow-up. RESULTS: Plasma levels of sIL2R, sCD30 and BAFF were higher in patients than in controls at all time points. Plasma levels of sIL2R, sCD30 and IL-10 were higher at diagnosis and relapse than during remission. At 18 months, sCD30 (p<0.001) and sIL2R levels (p = 0.01) were significantly higher in PR3-ANCA-positive patients (detected by ELISA) than in PR3-ANCA-negative patients. ANCA-positive patients detected by ELISA or IIF at 24 months had significantly higher plasma sCD30 levels (p = 0.02 and p = 0.03, respectively) than ANCA-negative patients. CONCLUSION: Increased T cell activation in patients with ANCA-associated vasculitis in remission during and after immunosuppressive treatment is associated with persistent or renewed ANCA positivity.

Adolescent↗
PubMed2006

Prediction of relapses in PR3-ANCA-associated vasculitis by assessing responses of ANCA titres to treatment.

OBJECTIVE: We performed a retrospective evaluation of whether c-ANCA titres (indirect immunofluorescence) and anti-proteinase 3 (PR3)-ANCA levels (ELISA) at diagnosis and following immunosuppressive treatment are predictive of relapse of ANCA-associated vasculitis. METHODS: Patients diagnosed with PR3-ANCA-associated vasculitis between 1991 and 2002, with at least 2 yr of follow-up, and treated with cyclophosphamide and corticosteroids only (1991-1996) or switched to azathioprine after induction of remission with cyclophosphamide and corticosteroids (1997-2002) were included. ANCA were assessed by immunofluorescence and direct PR3-specific ELISA at diagnosis and 3, 6, 12, 18 and 24 months after diagnosis. Actuarial relapse-free survival was analysed with the log rank test. RESULTS: We studied 87 patients positive for PR3-ANCA: 46 were on cyclophosphamide maintenance therapy and 41 switched to azathioprine. Overall actuarial relapse-free survival was 72% at 2 yr and 34% at 5 yr. Relapse-free survival did not differ between patients on cyclophosphamide maintenance and patients switched to azathioprine maintenance (P = 0.34). Patients who became and stayed negative for c-ANCA (immunofluorescence) or PR3-ANCA (ELISA) until 24 months after diagnosis had a lower risk of relapse (P = 0.01 and P = 0.02, respectively). Positive c-ANCA (immunofluorescence) titres at 3 [relative risk (RR) 2.0; 95% confidence interval (CI) 1.2-3.8], 12 (RR 1.9; 95% CI 1.1-3.3), 18 (RR 2.9; 95% CI 1.3-4.6) and 24 months (RR 2.6; 95% CI 1.2-5.0) were significantly associated with relapse within 5 yr after diagnosis. PR3-ANCA levels >10 U/ml at 18 (RR 2.7, 95% CI 1.1-4.3) and 24 months (RR 4.6; 95% CI 1.2-6.3) were predictive of relapse within 5 yr. In the azathioprine group, a positive c-ANCA titre at the time of switching to azathioprine (RR 2.2; 95% CI 1.0-5.4) was associated with relapse. CONCLUSION: Positive c-ANCA (immunofluorescence) and PR3-ANCA (ELISA) titres during early follow-up identify patients at increased risk of relapse.

Adolescent↗
PubMed2006

Upregulation of ADAM19 in chronic allograft nephropathy.

ADAM19 (a disintegrin and metalloproteinase 19) is involved in cell-cell and cell-matrix interactions and tumor necrosis factor (TNF)-alpha shedding. We studied ADAM19 in chronic allograft nephropathy (CAN) nephrectomies and in normal human kidneys. Reverse transcriptase (RT) PCR revealed an upregulation of ADAM19 mRNA in CAN when compared with control kidneys (p = 0.002). Using RNA in situ hybridization (ISH), we detected moderate ADAM19 mRNA expression in vascular smooth muscle cells (SMCs) and distal tubuli of control kidneys. In CAN, massive ADAM19 expression was detected in SMCs, distal tubuli, glomerular sclerotic lesions and inflammatory CD4+ cells. To determine whether ADAM19 is specifically related to CAN, we studied transplant biopsies with and without CAN, acute rejection and non-transplant-related kidney diseases: interstitial fibrosis (IF), interstitial atrophy, glomerular fibrosis and interstitial inflammation. In various renal structures, ADAM19 mRNA was significantly higher in CAN when compared with renal allografts without CAN or acute rejection. ADAM19 expression in renal endothelium was significantly higher in acute rejection when compared with renal allografts without CAN. When compared to CAN, ADAM19 was expressed to a similar extent in non-transplant-related interstitial and glomerular fibrosis, interstitial atrophy and inflammation. Although these observational data do not establish a cause and effect relationship, ADAM19 may have a modulatory role in the dysfunctional renal allograft state.

ADAM Proteins↗
PubMed2006

Quantitation of autoantibodies in systemic autoimmune diseases: clinically useful?

Serial assessment of levels of autoantibodies has been proposed as being clinically useful in certain systemic autoimmune diseases. In particular, attention has been given to anti-dsDNA antibodies in systemic lupus erythematosus (SLE) and ANCA in the ANCA-associated vasculitides (AAV). Much controversy exists, however, concerning the value of serial testing in these diseases. We here review the various tests available for quantitation of anti-dsDNA and ANCA, and their capacity to detect changes in autoantibody levels that are associated with changes in clinical disease activity of the respective diseases. It is concluded that changes in anti-dsDNA as measured by the Farr assay and changes in ANCA as assessed by ELISA have predictive value for the occurrence of disease relapses, although this relationship is far from absolute. Consequently, treatment based on changes in levels of the respective autoantibodies only seems at present not justified, in view of the toxicity of currently available immunosuppressive regimens.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed2005

[Prevention of contrast nephropathy; guidelines from the Department Nephrology of the University Medical Centre Groningen].

Contrast nephropathy' is commonly defined as an increase in serum creatinine concentration of more than 44 micromol/l or 25% of the reference value within 48 hours after administration of radiological contrast media. Risk factors are pre-existing renal dysfunction, diabetes mellitus, heart failure, paraproteinaemia, advanced age, use of nephrotoxic medication, intra-arterial use of contrast media and use of large volumes of contrast media. The only form of therapy possible is supportive care, such as renal function replacement therapy. Prevention of contrast nephropathy is of great importance. For patients with risk factors, the treatment of first choice is hydration with intravenous sodium chloride 0.9% combined with oral acetylcysteine given before and after the administration of contrast media.

Contrast Media↗
PubMed2005

Evaluation of a new fluorescent-enzyme immuno-assay for diagnosis and follow-up of ANCA-associated vasculitis.

In this study we have evaluated a new, fully automated fluorescent-enzyme immuno-assay (FEIA) for detection and quantification of anti-PR3 and anti-MPO ANCA in diagnosis and follow-up of ANCA-associated small vessel vasculitis (AAV). PR3- and MPO-ANCA were determined by FEIA technology in (1) sera of 87 consecutive patients with biopsy-proven, pauci-immune necrotizing crescentic glomerulonephritis (NCGN) and 72 controls; (2) 120 sera (60 patients with Wegener's granulomatosis and 60 controls) that were previously used in a multicentre comparison of direct and capture ELISAs for PR3-ANCA; (3) in samples preceding relapse in 23 PR3-AAV patients with and 23 matched PR3-AAV patients without relapse for prediction of relapses. PR3- and/or MPO-ANCA detection in pauci-immune NCGN by FEIA revealed an overall sensitivity of 82.8%. The FEIA specificity was 96% and 100% for PR3- and MPO-ANCA, respectively. The overall sensitivity of MPO- and PR3-ANCA could be increased to 88.5% by lowering the cut-off values without affecting the specificity (ROC-curve analysis), which is similar to a multistep ANCA procedure that combines indirect immunofluorescence with direct and capture ELISAs. The sensitivity for Wegener's granulomatosis (WG) of the PR3-ANCA FEIA (60%) was more comparable to direct ELISAs (64%) than to capture ELISAs (74%). A rise of 100% in ANCA level as measured by FEIA appeared optimal (ROC-curve) for prediction of relapses and such a rise was observed in 26 patients. In 18 of these 26 patients the rise was followed by a relapse (PPV 69%), whereas in 15 of the 20 patients without a rise no relapse was observed (NPV 75%). In conclusion, detection of PR3- and MPO-ANCA by FEIA has excellent performance in terms of diagnosis of AAV patients. Furthermore, detection of rises in PR3-ANCA by FEIA for prediction of relapses gives results comparable to other techniques.

Adult↗
PubMed2005

Stridor and Horner's syndrome, weeks after attempted right subclavian vein cannulation.

A 23-year-old woman presented with renal failure resulting from polycystic kidney disease (PKD) aggravated by tubulo-interstitial nephritis. Emergency haemodialysis was planned, and cannulation of the right subclavian vein was attempted, but failed. During this procedure, inadvertent arterial puncture occurred. Transient mild ischaemia of the right arm, and a transient Horner's syndrome were noted. Seven weeks later she presented with severe stridor with impending respiratory failure necessitating emergency intubation; the right-sided Horner's syndrome had recurred. CT imaging showed a large pseudo-aneurysm of the brachiocephalic artery resulting in severe compression of the trachea. Using a prosthetic graft, the operation for the pseudo-aneurysm was successful; there were mild neurological sequelae. Although her family history was negative, autosomal dominant PKD should be considered, and we discuss the possible role of a pre-existing PKD-associated aneurysm.

Adult↗
PubMed2004

B cell epitope specificity in ANCA-associated vasculitis: does it matter?

Pauci-immune idiopathic small-vessel vasculitis is strongly associated with the presence of antineutrophil cytoplasm autoantibodies (ANCA). Antibodies to PR3 predominate in patients with Wegener's granulomatosis; antibodies to myeloperoxidase (MPO) are found more frequently in patients with microscopic polyangiitis. There is increasing in vivo and in vitro evidence for a pathogenic role of ANCA in systemic vasculitis based on associations of ANCA with disease activity. If ANCA are pathogenic, why is the course of disease different from one patient to another? Antibodies can recognize different binding sites (epitopes) on their corresponding antigens. Differences in binding specificity may influence the pathogenic potential of the antibodies. Differences between epitope specificity of ANCA between patients or changes in epitope specificity of ANCA in time in an individual patient may, accordingly, result in differences in disease expression. This review will focus on epitope specificity of autoantibodies in systemic autoimmune diseases and especially on the epitope specificity of PR3- and MPO-ANCA. We will discuss whether PR3-ANCA or MPO-ANCA recognize different epitopes on PR3 and MPO, respectively, and whether the epitopes recognized by ANCA change in parallel with the disease activity of ANCA-associated vasculitis. Finally, we will speculate if the direct pathogenic role of ANCA can be ascribed to one relapse- or disease-inducing epitope. Characterization of relapse- or disease-inducing epitopes bound by PR3-ANCA and MPO-ANCA is significant for understanding initiation and reactivation of ANCA-associated vasculitis. Elucidating a disease-inducing epitope bound by ANCA may lead to the development of epitope-specific therapeutic strategies.

Amino Acid Sequence↗
PubMed2004

Risk factors for relapse in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis: tools for treatment decisions?

Current treatment based on the use of cyclophosphamide and corticosteroids has changed anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides from highly fatal into more chronic relapsing diseases. Relapses are a major problem in these diseases and cause increased morbidity and mortality. Current clinical research mainly focuses on achieving control of active disease while minimizing treatment-related toxicity. Risks for longterm relapse and their sequelae have been less thoroughly studied. It is noteworthy that, besides treatment, several other factors have been associated with the occurrence of relapses. Thus, compared to MPO-ANCA positive patients, patients with PR3-ANCA associated vasculitis run a significantly increased risk of experiencing relapses. ANCA-status during follow-up, levels of T cell activation, genetic background, and infectious and other exogenous factors have been linked to relapse as well. With a few exceptions, these associations are merely descriptive and not pathophysiologically proven. Furthermore, data on adapting treatment in accordance with risk factors for relapse are scarce. We review here the risk factors for relapse in ANCA-associated vasculitis, their potential pathogenic implications, and their possible role in preventive strategies and adaptations of current treatment policies.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed2003

[Treatment of patients with Wegener's granulomatosis or ANCA-associated vasculitis].

Standard therapy of Wegener's granulomatosis is prednisolone in combination with cyclophosphamide. Cyclophosphamide is continued for 15-18 months after diagnosis. During therapy 26% of the patients have severe or life-threatening side effects, mostly infections. Furthermore, there are multiple long-term side effects such as an increased incidence of malignancies, especially bladder carcinoma. During the last 10 years the European vasculitis study group (www.vasculitis.org) organized several randomized clinical trials to determine optimal treatment. Recently, it was demonstrated in one of these trials that in patients with generalized ANCA-associated vasculitis (vasculitis associated with antineutrophil cytoplasmic autoantibodies) withdrawal of cyclophosphamide and substitution by azathioprine after remission did not increase the rate of relapse and was safe. Wegner's granulomatosis is not a fatal disease anymore. Sometimes, however, patients lose their job. Fortunately, this occurs only in a small percentage of patients.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed2003

[Clinical reasoning and decision-making in practice. A woman with hypokalaemia].

A 39-year-old woman had been investigated elsewhere due to symptomatic hypokalaemia, renal potassium wasting and metabolic alkalosis. Vomiting was considered to be the underlying cause but the patient repeatedly denied this behaviour. After extensive investigations, Bartter's syndrome was finally diagnosed. Eighteen months later the patient was readmitted due to progressive renal insufficiency. On the basis of a very low urinary chloride excretion and the aforementioned laboratory results, it was concluded that the metabolic disturbances were due to vomiting and the diagnosis of Bartter's syndrome was rejected. Upon being confronted with these findings, the patient finally admitted to vomiting, but stated that this happened involuntarily after meals. She had a stenotic ulcer in the pylorus and a gastric biopsy demonstrated the presence of Helicobacter pylori associated gastritis. Eradication therapy was given and the symptoms disappeared. The renal insufficiency was partly accounted for by hypovolaemia and partly by tubulointerstitial nephropathy (demonstrated by kidney biopsy) which was probably due to the chronic hypokalaemia. This case illustrates the difficulty of establishing the differential diagnosis of hypokalaemia, especially in the case of denied vomiting. However, it also shows that in such cases the correct diagnosis can be made if objective parameters are used.

Adult↗
PubMed2003

Staphylococcal superantigens and T cell expansions in Wegener's granulomatosis.

In Wegener's granulomatosis (WG), a form of autoimmune systemic vasculitis, chronic carriage of Staphylococcus aureus constitutes a risk factor for the development of exacerbations. Circulating T cells in this disease are persistently activated, suggesting the presence of a chronic stimulus. A causal link between chronic carriage of S. aureus and chronic T cell activation in WG is conceivable, because S. aureus produces superantigens (SAg), which are potent T cell stimulators. Superantigenic stimulation of T cells results in expansion of T cell subsets expressing SAg-binding T cell receptor V-beta (Vbeta) chains. In the present study we hypothesized that in WG the presence of staphylococcal SAg is accompanied by expansion of SAg-reacting T cell subsets. We tested our hypothesis in a cross-sectional and a longitudinal study in which the association between seven staphylococcal SAg genes [typed by poplymerase chain reaction (PCR)], eight SAg-binding Vbeta chains and four SAg-non-binding Vbeta chains (assessed by flow-cytometry) was assessed. Both studies showed that T cell expansions were present at a significantly higher rate in WG patients than in healthy individuals, but were not associated with the presence of either S. aureus or its SAg. Moreover, T cell expansions were generally of small extent, and did not appear simultaneously in both CD4 and CD8 subsets. We conclude that in WG S. aureus effects its supposed pathogenic function by a mechanism other than superantigenic T cell activation.

Adult↗
PubMed2003

Clinical value of gallium-67 scintigraphy in assessment of disease activity in Wegener's granulomatosis.

BACKGROUND: Diagnosis of active pulmonary and paranasal involvement in patients with Wegener's granulomatosis (WG) can be difficult. The diagnostic value of gallium-67 scintigraphy in WG is unclear. OBJECTIVE: To evaluate the added diagnostic value of gallium-67 scintigraphy in patients with WG with suspected granulomatous inflammation in the paranasal and chest regions. METHODS: Retrospectively, the diagnostic contribution of chest and head planar gallium scans in 40 episodes of suspected vasculitis disease activity in 28 patients with WG was evaluated. Scans were grouped into normal or increased uptake for each region. Histological proof or response to treatment was the "gold standard" for the presence of WG activity. RESULTS: WG activity was confirmed in 8 (20%) episodes, with pulmonary locations in three, paranasal in four, and both in one (n=7 patients); all these gallium scans showed increased gallium uptake (sensitivity 100%). Gallium scans were negative for the pulmonary area in 23/36 scans (specificity 64%), and negative for paranasal activity in 13/16 scans (specificity 81%) in episodes without WG activity. Positive predictive value of WG activity for lungs and paranasal region was 24% and 63%, respectively, negative predictive value was 100% for both regions. False positive findings were caused by bacterial or viral infections. CONCLUSION: Gallium scans are clinically helpful as a negative scan virtually excludes active WG. Gallium scintigraphy of chest and nasal region has a high sensitivity for the detection of disease activity in WG. However, because of positive scans in cases of bacterial or viral infections, specificity was lower.

Adult↗
PubMed2003

The Th1 and Th2 paradigm in ANCA-associated vasculitis.

In the pathogenesis of anti-neutrophil cytoplasm antibodies (ANCA)-associated vasculitis, T cell contribution is indicated by T cell-dependent ANCA production combined with the presence of T cells in inflammatory infiltrates. However, the exact pathogenic role of T cells in ANCA-associated vasculitis remains to be determined. The Th1/Th2 concept is useful for understanding T cell involvement in pathological processes. This review focuses on T cells and particularly the Th1/Th2 paradigm in ANCA-associated vasculitis. Most research has been done in Wegener's granulomatosis, where a shift in T cell response, from a Th1 pattern in localized disease towards a Th0/Th2 pattern in generalized disease, appears to occur. Although less thoroughly studied, data in Churg-Strauss syndrome and microscopic polyangiitis indicate that these diseases are predominantly associated with Th2 patterns. Further studies elucidating the true nature of the polarization towards Th1 or Th2 in ANCA-associated vasculitis are clearly needed.

Animals↗
PubMed2002

[Gastrointestinal surgery and gastroenterology. XIV. Mesenteric abnormalities in generalised vascular disease].

Various forms of vasculitis may result in mesenteric ischaemia, ischaemic colitis or aneurysm formation in the aorta or intestinal blood vessels. Vasculitides may involve large- and/or medium-sized vessels, medium- and/or small-sized vessels, or small-sized vessels only. It is essential to differentiate between the different forms of vasculitis since diagnostic tests and therapies differ greatly. Gastrointestinal manifestations of vasculitis can generally be detected using angiography, digital subtraction angiography and/or magnetic resonance angiography (MRA). Various laboratory tests are helpful in establishing the diagnosis in patients in whom vasculitis is clinically suspected. In addition, the diagnosis should be confirmed using histology or angiography if possible. Treatment of vasculitis not caused by chronic infection consists of high dose corticosteroids and, in the case of polyarteritis nodosa or vasculitis associated with anti-neutrophil cytoplasmic antibodies (ANCA), cyclophosphamide.

Aneurysm↗
PubMed2002

Prevalence of reduced bone mineral density in patients with anti-neutrophil cytoplasmic antibody associated vasculitis and the role of immunosuppressive therapy: a cross-sectional study.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a relapsing-remitting disease, which is treated with corticosteroids (CS) in combination with cyclophosphamide. One of the major side-effects of this treatment is osteoporosis, which may result in the increased occurrence of fractures. In the present study we measured the prevalence of reduced bone mineral density (BMD) in a cross-sectional cohort of patients and correlated BMD findings with cumulative doses of CS and/or cyclophosphamide. BMD was measured by dual-energy X-ray absorptiometry (DXA) of the lumbar spine, radius and proximal femur between January 1998 and December 1999. Cumulative doses of CS and cyclophosphamide were calculated by chart review. Ninety-nine consecutive patients (48 men, 51 women) aged 55 +/- 16 years (mean +/- SD) were studied 50 months (median; range 0-400 months) after a diagnosis of ANCA-associated vasculitis had been made. Sixty-nine patients were treated with 10.7 g (median cumulative dose; range 0.4-67.2 g) of CS, and 88 patients were treated with 34.1 g (median cumulative dose; range 0.8-324.3 g) of cyclophosphamide. Fifty-seven percent of the patients had osteopenia (T-score: -1 to -2.5 SD), and 21% had osteoporosis (T-score: <-2.5 SD) at least at one site. Thirty-four of 37 (92%) postmenopausal women, 9 of 14 (64%) premenopausal women, and 34 of 48 (71%) men had either osteopenia or osteoporosis. The mean age- and sex-adjusted BMD (Z-score) of the proximal femur in men was found to be significantly lower than zero. Cumulative dose of CS therapy showed an inverse relation with Z-scores at the lumbar spine (p = 0.035) and proximal femur (p = 0.011). Cumulative dose of cyclophosphamide was not correlated with Z-scores. Osteopenia and osteoporosis are thus frequently observed in patients with ANCA-associated vasculities. However, only in men is the mean Z-score significantly lower than zero. Cumulative dose of CS therapy is significantly associated with bone loss at the spine and femur.

Adult↗