"The added value of 18f-FDG PET/CT in the assessment of onset and steroid resistant polimyalgia rheumatica".

PMR is a common inflammatory rheumatic disease. Although its clinical characteristics are fully recognized, no specific test for its diagnosis has been established to date. Several studies have described a wide variety of diseases that present with polymyalgic symptoms. A 18FDG-PET/CT scan could help to deal with these differential diagnoses. The goal of our study is to describe the findings of the 18FDG-PET/CT scan in a cohort of PMR patients and to detail how the 18FDG-PET/CT scan improves accuracy when diagnosing other underlying conditions. This cross-sectional study enrolled patients with a diagnosis of PMR who underwent to a 18FDG-PET/CT scan to rule out other diagnosis. The 18FDG-PET/CT scan was performed either following clinical criteria at the onset of clinical symptoms or when the patient became PMR steroid resistant. Patients' demographic, clinical and analytical data at the moment of the 18FDG-PET/CT scan were recorded. The final diagnosis was confirmed according to clinical judgement. A total of 103 patients with PMR were included. In 49.51% of patients, the 18FDG-PET/CT scan was ordered to study resistance to steroid therapy. The final diagnoses of patients were PMR in 70.9% patients, large vessel vasculitis in 15.5%, neoplasms 4.8% and another diagnosis in the rest. The 18FDG-PET/CT scan is a very useful technique for the study of Polymyalgia Rheumatica, not only to help in the diagnostic process, but also due to its role in the identification of a variety of PMR-like patrons.

Leukocyte Dynamics Reveal a Persistent Myeloid Dominance in Giant Cell Arteritis and Polymyalgia Rheumatica.

Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are inflammatory diseases requiring long-term glucocorticoid treatment. Limited data on dynamics in leukocyte counts before, during and after treatment are available. Leukocyte counts were measured, as cellular markers of inflammation, at fixed time points in our prospectively studied cohort of pre-treatment glucocorticoid-naive GCA (N = 42) and PMR (N = 31) patients. Values were compared with age-matched healthy controls (HCs; N = 51) and infection controls (N = 16). We report that before start of treatment monocyte and neutrophil counts were higher in GCA and PMR patients than in HCs, while NK- and B-cell counts were lower. C-reactive protein (CRP) levels correlated positively with monocyte counts in GCA, and negatively with B-cell and NK-cell counts in PMR. During glucocorticoid treatment, myeloid subsets remained elevated whereas lymphoid subsets tended to fluctuate. Interestingly, erythrocyte sedimentation rate (ESR) outperformed CRP as marker for relapses in GCA. We defined stable treatment-free remission groups in both GCA and PMR. GCA patients in treatment-free remission still demonstrated elevated monocytes, neutrophils, ESR, and platelets. PMR patients in treatment-free remission had normalized levels of inflammation markers, but did have elevated monocytes, lowered CD8+ T-cell counts and lowered NK-cell counts. Finally, we showed that low hemoglobin level was predictive for long-term GC treatment in PMR. Overall, leukocyte composition shifts toward the myeloid lineage in GCA and PMR. This myeloid profile, likely induced by effects of inflammation on hematopoietic stem cell differentiation, persisted during glucocorticoid treatment. Surprisingly, the myeloid profile was retained in treatment-free remission, which may reflect ongoing subclinical inflammation.

Disturbed B cell homeostasis in newly diagnosed giant cell arteritis and polymyalgia rheumatica.

OBJECTIVE: Several lines of evidence indicate that B cells may be involved in the immunopathology of giant cell arteritis (GCA) and polymyalgia rheumatica (PMR). This study was undertaken to examine the distribution of defined B cell subsets, including effector B (Beff) cells and regulatory B (Breg) cells, in patients with GCA and patients with PMR before and after corticosteroid treatment. METHODS: Circulating B cells were analyzed in 34 newly diagnosed, untreated patients with GCA or PMR, and in 44 followup samples from patients with GCA or PMR who received corticosteroids for 2 weeks or 3 months. For comparison, 40 age-matched healthy controls and 11 rheumatoid arthritis (RA) patients were included. Serum BAFF levels were determined, and temporal arteries were studied by immunohistochemistry. RESULTS: Patients newly diagnosed as having GCA or PMR, but not patients with RA, had decreased numbers of circulating B cells compared to healthy controls. B cell numbers recovered rapidly in treated patients with GCA and PMR in remission. This recovery was not achieved by compensatory hyperproliferation or enhanced bone marrow production. B cell numbers inversely correlated with erythrocyte sedimentation rates, C-reactive protein levels, and serum BAFF levels. Tumor necrosis factor α-positive Beff cells, but not interleukin-10 (IL-10)-positive Breg cells, were decreased in patients newly diagnosed as having GCA or PMR. Following treatment, circulating numbers of Beff cells normalized. The returning Beff cells demonstrated an enhanced capacity to produce IL-6. Few B cells were found in temporal artery biopsy specimens from GCA patients. CONCLUSION: We show for the first time that the distribution of B cells is highly disturbed in GCA and PMR and that B cells likely contribute to the enhanced IL-6 response in both diseases.

NKG2D stimulated T-cell autoreactivity in giant cell arteritis and polymyalgia rheumatica.

OBJECTIVE: To investigate functional expression of NKG2D on CD4 and CD8 T-cells in patients with giant cell arteritis (GCA) and polymyalgia rheumatica (PMR). METHODS: Peripheral blood was drawn from patients with GCA (n=16), PMR (n=78) and healthy controls (HC, n=64). Tissue samples were obtained from GCA patients and controls. Proliferation and cytokine production assays were performed using CFSE and intracellular IFN-γ or TNF-α staining, respectively, and flow cytometry analysis. Immunofluorescence and immunohistology were applied to analyse the presence of NKG2D-expressing T-cells and NKG2D-ligands in temporal arteries, respectively. mRNA levels of NKG2D-ligands were determined by RT-PCR. RESULTS: In both GCA and PMR patients, NKG2D was preferentially expressed on senescent CD4CD28(-) and CD8CD28(-), as well as on CD8CD28 T-cells. Frequencies of senescent T-cells were increased in GCA and PMR patients compared to HC. In GCA tissue samples, infiltrating T-cells were predominately CD28(-). NKG2D expressing T-cells concentrated around the vasa vasorum of the adventitia. Antigenic stimulation induced rapid up-regulation of NKG2D on CD4CD28(-) and CD4CD28 T-cells, whereas TNF-α and interleukin-15 enhanced NKG2D expression on senescent CD4 and CD8 T-cells only. NKG2D cross-linkage augmented anti-CD3 triggered proliferation, IFN-γ and TNF-α production of CD8 T-cells. In CD4CD28(-) T-cells, NKG2D ligation resulted in increased IFN-γ production only. NKG2D ligands were expressed in temporal arteries from GCA patients, particularly in the adventitial and medial layers of affected vessels. CONCLUSIONS: NKG2D is functionally expressed on CD4CD28(-) and CD8 T-cells in GCA and PMR. NKG2D-ligands are present in temporal arteries and may co-stimulate NKG2D expressing T-cells.

Elevated muscle interstitial levels of pain-inducing substances in symptomatic muscles in patients with polymyalgia rheumatica.

Polymyalgia rheumatica (PMR) is characterized by aching proximal muscles and systemic inflammation. We explored the pain-eliciting mechanisms by measuring interstitial levels in muscle of potentially pain-inducing substances as well as local blood flow. Twenty glucocorticoid-naive patients with newly diagnosed PMR and 20 controls were examined before and after 14 days of prednisolone (20 mg/day). Concentrations of glutamate, prostaglandin E(2) (PGE(2)), bradykinin, serotonin, adenosine triphosphate, lactate, pyruvate, and potassium as well as extraction of (3)H(2)O were measured in symptomatic vastus lateralis and trapezius muscles using microdialysis. Plasma levels were measured simultaneously. To be considered potentially pain inducing, interstitial concentrations of candidates should be higher in patients vs. controls, be normalized by prednisolone, and be higher in muscle vs. plasma. Prednisolone abolished symptoms in all patients within 2 days. Before treatment glutamate in both muscles (vastus: 60±7 vs. 38±7 µmol/L; trapezius: 60±6 vs. 43±7 µmol/L) and PGE(2) in vastus (911±200 vs. 496±122 pg/mL) were higher in patients than in controls (P<0.05), and higher in muscle than in plasma (P<0.05). Prednisolone abolished the differences between patients and controls. No other candidate completely fulfilled the predefined requirements for pain-inducing substances in PMR. (3)H(2)O extraction was identical between groups. In conclusion, local release of glutamate and PGE(2), but not ischemia, may contribute to the muscle pain in PMR. This supports the view that intramuscular mechanisms are important in PMR.

Effect of etanercept in polymyalgia rheumatica: a randomized controlled trial.

INTRODUCTION: To elucidate in polymyalgia rheumatica (PMR) the role of tumor necrosis factor (TNF) α and the therapeutic potential of blockade with soluble TNF-α receptor, we carried out the first randomized controlled trial with etanercept in PMR. METHODS: Twenty newly diagnosed, glucocorticoid (GC) naïve patients with PMR and 20 matched non-PMR control subjects completed the trial. Subjects were randomized in a 1:1 ratio to monotherapy with etanercept (25 mg s.c. biweekly) or placebo (saline) for 14 days. Study outcomes were assessed at baseline and after 14 days. The primary outcome was the change in PMR activity score (PMR-AS). Secondary outcomes were: changes in erythrocyte sedimentation rate (ESR) and plasma levels of TNF-α and interleukin (IL) 6; patients' functional status (health assessment questionnaire) and cumulative tramadol intake during the trial. RESULTS: At baseline, plasma TNF-α was higher in patients than in controls (P < 0.05). The concentration always increased with etanercept treatment (P < 0.05). In patients, etanercept decreased PMR-AS by 24% (P = 0.011), reflecting significant improvements in shoulder mobility, physician's global assessment and C-reactive protein, and insignificant (P > 0.05) improvements in duration of morning stiffness and patient's assessment of pain. In parallel, ESR and IL-6 were reduced (P < 0.05). Placebo treatment did not change PMR-AS, ESR and IL-6 (P > 0.05). Functional status did not change and tramadol intake did not differ between patient groups. In controls, no changes occurred in both groups. CONCLUSIONS: Etanercept monotherapy ameliorates disease activity in GC naïve patients with PMR. However, the effect is modest, indicating a minor role of TNF-α in PMR. TRIAL REGISTRATION: ClinicalTrials.gov (NCT00524381).

Increased muscle interstitial levels of inflammatory cytokines in polymyalgia rheumatica.

OBJECTIVE: Polymyalgia rheumatica (PMR) is characterized by aching of the proximal muscles and increased blood levels of markers of inflammation. Despite the muscle complaints, the current view is that symptoms are caused by inflammation in synovial structures. The purpose of this study was to elucidate the disease mechanisms in symptomatic muscles by measuring interstitial levels of cytokines before and after prednisolone treatment. METHODS: Twenty glucocorticoid-naive patients newly diagnosed as having PMR and 20 control subjects were studied before and after 14 days of prednisolone therapy (20 mg/day). Interstitial concentrations of interleukin-1α/ß (IL-1α/ß), IL-1 receptor antagonist, IL-6, IL-8, tumor necrosis factor α (TNFα), and monocyte chemoattractant protein 1 were measured in symptomatic vastus lateralis and trapezius muscles using the microdialysis technique. Plasma levels were measured simultaneously. RESULTS: Prednisolone abolished symptoms in all of the PMR patients within 1-2 days; the erythrocyte sedimentation rate and C-reactive protein levels were normalized on day 14. In both muscles, interstitial concentrations of all cytokines were markedly higher (P < 0.05) in the PMR patients than in the controls before treatment. In both patients and controls, interstitial levels of most cytokines were higher than plasma levels, with the exception of IL-1α and TNFα, which were lower in both groups. In the PMR patients, interstitial concentrations were normalized after prednisolone treatment. CONCLUSION: This study introduces a novel view of PMR, indicating that increased interstitial levels of inflammatory cytokines in symptomatic muscles play a role in the pathophysiology of the disease and that cytokines may be released locally. To explore the disease specificity, similar studies in other primary inflammatory conditions are warranted.

Predictors for treatment success and expression of glucocorticoid receptor in giant cell arteritis and polymyalgia rheumatica.

OBJECTIVE: Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) generally respond well to treatment with glucocorticoids (GC). We sought to determine the value of clinical, histopathologic, immunohistochemical, and genetic findings and the expression of the glucocorticoid receptor (GR) for discriminating between patients who achieve complete remission, or partial remission, or who do not improve with glucocorticoid treatment. METHODS: We examined biopsies of the temporal artery from 60 patients, of whom 27 had GCA, 13 PMR, and 20 arteriosclerosis. RESULTS: Of the clinical variables evaluated, jaw claudication was correlated with the histologic classification of the biopsies (p < 0.0001). Erythrocyte sedimentation rate was significantly higher in patients with PMR and GCA than in patients with arteriosclerosis (p < 0.0001). There were significant differences between patients with GCA versus PMR in the numbers of CD3-, CD8-, and CD4-positive T cells, in CD68-positive monocytes (p < 0.0001), and antigen-presenting cells (p < 0.0001). CD138-positive and CD20-positive cells were absent in patients with PMR but present in patients with GCA (p < 0.0001). In GCA and chronic inflammation most monocytes and lymphocytes expressed GR (88.9%). The number of CD68-positive cells and the extent of GR-staining in chronic inflammation reflected the success of treatment in logistic regression analysis (p < 0.05). GR polymorphism showed that more than 90% of patients had the wild-type (homozygote) of the R23K or N363S polymorphism. There was no evidence that this polymorphism influenced response to treatment with GC (Fisher's exact test 1.0). CONCLUSION: Expression of GR and the presence of CD20-, CD3-, CD4-, CD8-, CD68-, CD138-positive cells and antigen-presenting cells differ between GCA and PMR. The presence of CD68-positive cells and the extent of GR-staining in chronic inflammation are suitable to predict complete remission in GCA.

Expression of the class I interferon-related MxA protein in temporal arteries in polymyalgia rheumatica and temporal arteritis.

OBJECTIVE: The aim of this study was to assess the expression of the interferon type I (IFN-I)-associated MxA protein in polymyalgia rheumatica (PMR) and temporal arteritis (TA). METHODS: Non-inflamed temporal artery biopsies from 11 PMR patients were compared with biopsies from 13 patients given other diagnoses. Coded sections were screened immunocytochemically for MxA protein, CD83, CD68, CD3, and S100 protein. Inflamed temporal artery biopsies from four patients with TA were also investigated. RESULTS: Focal MxA expression was seen in non-inflamed arteries, more frequently in PMR than in controls (p = 0.0124). MxA expression was also more common in adventitial dendritic cells (DCs) in PMR (p = 0.0124). Activated adventitial DCs were detected in PMR. Focal MxA expression in the inflamed biopsies from the patients with TA was not related spatially to the inflammation. CONCLUSIONS: The expression of MxA protein in arteries from patients with PMR and TA shows that non-inflamed and inflamed vessel walls are influenced by IFN-I. Further studies are required to elucidate whether IFN-I plays a role in the initiation of PMR and/or TA, serving as a link between the innate and the adaptive immune responses, as in some other autoimmune disorders.

Synovial expression of vasoactive intestinal peptide in polymyalgia rheumatica.

OBJECTIVE: Polymyalgia rheumatica (PMR) is an inflammatory disease that typically affects elderly people. Its clinical hallmark is the severity of pain in the shoulder and pelvic girdle. Mild to moderate synovitis and/or bursitis of the joints involved has been described. Neuropeptides are involved in nociception and modulation of inflammatory reaction. To evaluate whether neuropeptides have a role in PMR pathophysiology, we studied the expression of substance P (SP), calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP) and somatostatin (SOM) in shoulder synovial tissues of PMR patients. METHODS: Synovial expression of neuropeptides was investigated by immunohistochemical analysis, in two groups of PMR patients: the first one at the onset of disease and the second one after corticosteroid treatment, and in other joint diseases, rheumatoid arthritis (RA) and osteoarthritis (OA). RESULTS: The only significant expression of VIP was found in PMR and, to a lesser extent, in RA synovial tissue. In PMR, we observed VIP immunostaining both in the lining layer and in the sublining area. In patients on corticosteroid treatment VIP lining layer expression was not significantly different while VIP positive cells in the sublining area were almost absent. CONCLUSION: Local VIP production in PMR synovial tissue might contribute to the typical musculoskeletal discomfort and it may have a role in the immunomodulation of synovial inflammation.

Impaired redox status and cytochrome c oxidase deficiency in patients with polymyalgia rheumatica.

OBJECTIVE: To evaluate redox status and muscular mitochondrial abnormalities in patients with polymyalgia rheumatica (PMR). METHODS: Prospective evaluation of deltoid muscle biopsy in 15 patients with PMR. Fifteen subjects matched for age and sex, with histologically normal muscle and without clinical evidence of myopathy, were used as controls. Cryostat sections of muscle were processed for conventional dyes, cytochrome c oxidase (COX), usual histochemical reactions, and Sudan black. A total of 300-800 fibres was examined in each case. Blood lactate, pyruvate, and lactate/pyruvate ratio were determined in all patients. RESULTS: Ragged red fibres were found in eight patients with PMR and accounted for 0-0.5% of fibres. Focal COX deficiency was found in 14 (93%) of 15 patients and in nine (60%) of 15 controls. COX deficient fibres were more common in patients with PMR (range 0-2.5%; mean 0.9%) than in controls (range 0-1.2%; mean 0.3%) (paired t test, p=0.001). Seven (47%) of 15 patients had high blood lactate levels (1.50-2.60 mmol/l) or high blood lactate/pyruvate ratios (22-25). CONCLUSIONS: PMR is associated with mitochondrial abnormalities not solely related to the aging process.

Vascular endothelial growth factor production in polymyalgia rheumatica.

OBJECTIVE: To evaluate peripheral production and synovial expression of vascular endothelial growth factor (VEGF) in polymyalgia rheumatica (PMR). METHODS: Circulating levels of VEGF in PMR (serum concentration and in vitro release by peripheral blood mononuclear cells [PBMC]) were investigated by enzyme-linked immunosorbent assay. Local expression of VEGF in shoulder synovial tissue was investigated by immunohistochemical analysis. Investigations were performed in patients with active, untreated disease and in patients treated with corticosteroids. RESULTS: VEGF serum concentrations were significantly higher in untreated PMR patients than in normal control subjects. During steroid treatment, VEGF serum concentrations reached their lowest level after the sixth month of treatment. PBMC isolated from untreated PMR patients spontaneously secreted a higher amount of VEGF compared with PBMC from control subjects. Corticosteroid therapy did not affect the ability of PBMC to produce VEGF. Immunohistochemical staining performed on shoulder synovial tissue showed VEGF expression in both the lining layer and the sublining area. In 3 of 4 treated patients, no VEGF staining was found in synovial tissue during corticosteroid therapy. VEGF expression correlated with vessel density, but was not associated with alphavbeta3 and alphavbeta5 integrin expression. CONCLUSION: Peripheral and local VEGF releases have different responses to steroid treatment in PMR. The lack of response to corticosteroids by peripheral VEGF production supports the hypothesis that systemic involvement is dominant in PMR. At the synovial level, VEGF production is linked to vascular proliferation and is thus directly involved in the pathogenesis of synovitis.

Monocyte chemoattractant protein 1 (MCP-1) in temporal arteritis and polymyalgia rheumatica.

OBJECTIVE: To examine the localisation of monocyte chemoattractant protein 1 (MCP-1) in the inflamed vessel wall in temporal arteritis (TA) and to measure MCP-1 in plasma both in patients with TA and patients with polymyalgia rheumatica (PMR). METHODS: By immunohistochemical techniques MCP-1 was localised to the vessel wall in patients with TA. In TA, PMR, and healthy controls MCP-1 was quantified by enzyme linked immunosorbent assay (ELISA) in plasma. RESULTS: MCP-1 was localised to the majority of mononuclear cells, some smooth muscle cells, and giant cells in the arterial biopsy specimens from 12 patients with histologically verified TA. In all sections, including the vasa vasorum, the endothelium stained positive. In the intima 73% (range 57-91%), in the media 49% (range 32-67%), and in the adventitia 74% (range of 62-91%) of all cells stained positive. In plasma MCP-1 was significantly raised in untreated TA (n=33) and untreated PMR (n=27) compared with healthy controls (n=12). Untreated TA plasma levels of MCP-1 (mean 391 pg/ml (range 82-778 pg/ml)) were similar to untreated PMR plasma levels (mean 402 pg/ml (range 29-1153 pg/ml)), and no significant difference was found between the two groups of patients. In both patients with TA and patients with PMR no correlation was found between the plasma level of MCP-1 and the erythrocyte sedimentation rate, haemoglobin concentration, and CD4/CD8 ratio. CONCLUSIONS: These results show that MCP-1 plays a part in the disease processes of TA and PMR.

The adrenal steroid status in relation to inflammatory cytokines (interleukin-6 and tumour necrosis factor) in polymyalgia rheumatica.

OBJECTIVES: To determine the correlation between inflammatory cytokines and adrenal hormones in patients with polymyalgia rheumatica (PMR) and to compare the ratio of serum cortisol and androstenedione (ASD) or dehydroepiandrosterone sulphate (DHEAS) in normal subjects with PMR patients. METHODS: In 102 patients with PMR (32 beginning and 70 chronic disease) and 31 age-matched and sex-matched healthy subjects, ASD, cortisol, DHEAS, interleukin-6 (IL-6), and tumour necrosis factor (TNF) were measured by immunometric assays. RESULTS: Serum levels of IL-6 were elevated in patients with PMR as compared with normal subjects (10.0 +/- 1.6 vs 2.1 +/- 0.1 pg/ml, P = 0.01), which was not found for TNF. In PMR patients, serum levels of IL-6 were positively correlated with serum levels of ASD (P < 0.001), cortisol (P < 0.001), and DHEAS (P = 0. 038) irrespective of corticosteroid treatment. Serum levels of cortisol in relation to IL-6 were significantly lower in patients with chronic disease and long-standing corticosteroid administration as compared with patients with recent onset of the disease and without corticosteroid therapy (P < 0.01). CONCLUSIONS: In PMR, as expected, there was an increase in IL-6 serum levels that was associated with elevated serum levels of ASD, DHEAS, and cortisol which was more marked in patients with recent-onset disease and without corticosteroids. However, serum levels of cortisol in patients with and without corticosteroids were lower than expected by considering the inflammatory status (increased IL-6). This may indicate a change in the hypothalamic-pituitary-adrenal (HPA) axis responsiveness to inflammatory stimuli such as IL-6 during chronic disease. Furthermore, there seems to be a shift of biosynthesis to cortisol in relation to DHEAS or ASD in chronic disease.

Intercellular adhesion molecule 1 gene polymorphisms in polymyalgia rheumatica/giant cell arteritis: association with disease risk and severity.

OBJECTIVE: Intercellular adhesion molecule 1 (ICAM-1) is widely distributed in shoulder synovial membrane of active polymyalgia rheumatica (PMR) and strongly expressed in granulomatous inflammatory infiltrate of the temporal artery in giant cell arteritis (GCA). ICAM-1 genes may contribute to the inflammatory PMR/GCA processes. We examined potential associations of ICAM-1 gene polymorphisms with PMR/GCA susceptibility and severity. METHODS: We enrolled 121 consecutive patients with "pure" PMR and 56 patients with biopsy positive GCA residing in Reggio Emilia, Italy. Among patients with PMR, 91 had a followup duration of at least one year. Selected as control subjects were 228 healthy blood donors, 75 patients with nonarteritic central retinal artery occlusion, and 116 cataract surgery patients from the same geographic area. All PMR/GCA patients and controls were genotyped by polymerase chain reaction and allele-specific oligonucleotide techniques for ICAM-1 polymorphism at codon 241 (exon 4) and codon 469 (exon 6). RESULTS: The frequency of R241 was significantly higher in PMR/GCA patients [p = 0.00001, odds ratio (OR) 5.0 (95% confidence intervals, CI 2.6-9.6) ], in pure PMR patients [p = 0.00001, OR 5.0 (95% CI 2.5-10.0)], and in GCA patients [p = 0.00005; OR 5.0 (95% CI 2.2-11.5)] compared to the healthy controls. The frequency of R241 was significantly higher in total PMR/GCA patients compared to patients with nonarteritic central retinal artery occlusion [p = 0.0007; OR 5.3 (95% CI 1.8-15.5)] and cataract surgery patients [p = 0.0003; OR 4.1 (95% CI 1.8-9.0)]. The distribution of E/K 469 genotype was similar in PMR/GCA patients and in the 3 control groups. Cox proportional hazards modeling identified 2 variables that independently increased the risk of PMR relapse/recurrence: erythrocyte sedimentation rate at diagnosis > 72 mm/h [relative risk 1.6 (95% CI 1.1-2.3)] and the presence of R241 allele [relative risk 1.6 (95% CI 1.1-2.4)]. CONCLUSION: Our findings show that G/R 241 polymorphism of ICAM-1 is associated with PMR/GCA susceptibility and confers an increased risk of relapse/recurrence in PMR.

Absence of mitochondrial dysfunction in polymyalgia rheumatica. Evidence based on a simultaneous molecular and biochemical approach.

OBJECTIVE: To investigate the molecular and biochemical profile of skeletal muscle mitochondria of patients with isolated polymyalgia rheumatica (PMR). PATIENTS AND METHODS: We included patients with a recent diagnosis of PMR and as control healthy individuals submitted to orthopedic surgery. Skeletal muscle was obtained from quadriceps, thus was mitochondria immediately isolated. Long polymerase chain reaction and Southern blot transference were performed to detect deleted mtDNA molecules. Mitochondrial oxidative activity using different substrates and individual enzyme activity of respiratory chain complexes were assessed to search for any biochemical dysfunction. RESULTS: Fifty-one individuals (PMR=25, controls=26) were included. Mean age was 72 (11) years; 45% were females. We found no significant increase of deleted mtDNA molecules in PMR patients compared to controls. Both groups differed neither on oxygen consumption (p=NS for all substrates) nor enzymatic activity (p=NS for all complexes). CONCLUSIONS: Skeletal muscle mitochondria are molecularly and biochemically unaffected in PMR.

Effects of inflammation and treatment on bone turnover and bone mass in polymyalgia rheumatica.

OBJECTIVE: Polymyalgia rheumatica (PMR) has an abrupt onset of inflammatory symptoms, making it a useful model for studying the effects of inflammation in bone. PMR requires corticosteroid treatment, which may itself have a detrimental effect on bone. This study used serially measured biochemical markers of bone turnover and bone density to address the relative contributions of systemic inflammation and corticosteroid therapy to bone loss. METHODS: Fifty untreated patients with PMR were randomized to receive oral prednisolone or intramuscular methylprednisolone. Biochemical bone markers (pyridinoline [PYR], deoxypyridinoline [DPYR], procollagen type I carboxy-terminal peptide [PICP]) and bone mineral density (BMD) were measured at baseline and at 6, 12, and 24 months. RESULTS: The median disease duration at presentation was 12 weeks (range 5-32 weeks). Levels of urinary crosslinks were increased in patients with untreated PMR compared with controls (PYR 74.9 +/- 30.0 nmoles/mmole creatinine, DPYR 14.6 +/- 6.4 nmoles/mmole creatinine [mean +/- SD]; P = 0.0001); the PICP level was normal (115.0 +/- 39.0 microg/liter). With treatment, the crosslinks levels fell and PICP levels rose within 6 months (P = 0.01). Bone resorption (PYR) correlated with untreated disease activity (erythrocyte sedimentation rate [ESR]) (r = 0.5, P = 0.003) and with interleukin-6 levels (r = 0.48, P = 0.05). There was a significant reduction in BMD of both the hip and the spine after 12 months of treatment (P = 0.0002), with no difference between treatment groups. As the steroid dosage was reduced, bone mass improved. Initial ESR influenced the percent change in BMD at 1 year (r = 0.35, P = 0.05), while cumulative steroid dose, mean ESR, and type of steroid used did not. CONCLUSION: Inflammation in PMR increases bone resorption and appears to have a more detrimental effect on bone than does low-dose corticosteroid. If corticosteroids can be tapered and discontinued, bone loss in PMR can be a transient phenomenon.

P-31 magnetic resonance spectroscopy demonstrates unaltered muscle energy utilization in polymyalgia rheumatica.

OBJECTIVE: To characterize muscle metabolic anomalies associated with polymyalgia rheumatica (PMR) using P-31 magnetic resonance spectroscopy (MRS). METHODS: Seventeen patients with PMR and 9 age-matched control subjects were investigated. The forearm flexor muscles were examined by P-31 MRS in a 4.7 T superconducting horizontal magnet (Biospec Bruker 47/30) during a rest-exercise-recovery protocol. The intracellular pH and the relative concentrations of phosphocreatine (PCr), inorganic phosphate (Pi), ATP, and phosphomonoesters were measured every minute during the protocol. Based on the PCr and pH time-dependent changes during exercise and recovery, the rates of ATP production from PCr hydrolysis, glycogenolysis, and aerobic metabolism were calculated for each minute of exercise. RESULTS: At rest, the metabolic parameters [PCr]:[Pi], pH, and [PCr]:[ATP] were not significantly different between the PMR patients and the control subjects. During exercise, the energetic cost and the contribution of anaerobic and oxidative pathways to energy supply were similar in the 2 groups, as were the recovery kinetics of the phosphorylated compounds and pH. CONCLUSION: Muscle MRS does not confirm the findings of histologic and biochemical studies that suggest an alteration of mitochondrial function in PMR. No other modifications in glycolytic or glycogenolytic pathways or in proton handling were found that could indicate an alteration of muscle energetics in patients with PMR.

Use of enzyme immunoassay for measurement of skeletal troponin-I utilizing isoform-specific monoclonal antibodies.

OBJECTIVE: To determine the serum level of fast skeletal troponin I (fsTnl) resulting from skeletal muscle damage, we have developed a sensitive two-site enzyme immunoassay to measure skeletal troponin I. DESIGN AND METHODS: Twelve monoclonal antibodies were raised against human fsTnl. Of these antibodies, 8 were fsTnl-specific and the remaining 4 reacted with both skeletal and cardiac troponin I (cTnl). Two monoclonals were utilized for a development of this fsTnl immunoassay. Standards were made with purified recombinant human fsTnl for the range of 0-25 micrograms/mL. RESULTS: Total assay variance (CV) ranged from 1.7% to 9.6%. The upper limit of the normal reference range was established as 0.2 microgram/L by determining fsTnl concentration in sera of 108 healthy donors without evidence of muscle damage. Purified human cTnl up to 500 micrograms/L and cTnl-positive clinical serum samples yielded negative results in the fsTnl assay. The serum levels of fsTnl were determined in trauma patients, patients with chronic degenerative muscle disease, and marathon runners. In the study populations, the serum levels of fsTnl were correlated with other biochemical markers that are traditionally used to monitor striated muscle damage. CONCLUSIONS: In the present preliminary studies, measuring the serum levels of fsTnl in patients with various forms of muscle damage is more accurate than using the classical non muscle-specific biochemical markers.

Immunofluorescence study of immune complexes in polymyalgia rheumatica.

Two elderly patients with polymyalgia rheumatica (PMR), one with and the other without temporal arteritis (TA), are presented. Immunofluorescence study of muscle biopsy specimens showed IgG, IgA, and fibrinogen deposits in the perifascicular area in the perimysium. This finding suggests that immune complexes play a role in the pathogenesis of this condition and that the pathophysiology of PMR involves an interstitial inflammatory process.