Polymyalgia rheumatica shows metabolomic alterations that are further altered by glucocorticoid treatment: Identification of metabolic correlates of fatigue.

OBJECTIVE: In polymyalgia rheumatica (PMR), glucocorticoids (GCs) relieve pain and stiffness, but fatigue may persist. We aimed to explore the effect of disease, GCs and PMR symptoms in the metabolite signatures of peripheral blood from patients with PMR or the related disease, giant cell arteritis (GCA). METHODS: Nuclear magnetic resonance spectroscopy was performed on serum from 40 patients with untreated PMR, 84 with new-onset confirmed GCA, and 53 with suspected GCA who later were clinically confirmed non-GCA, and 39 age-matched controls. Further samples from PMR patients were taken one and six months into glucocorticoid therapy to explore relationship of metabolites to persistent fatigue. 100 metabolites were identified using Chenomx and statistical analysis performed in SIMCA-P to examine the relationship between metabolic profiles and, disease, GC treatment or symptoms. RESULTS: The metabolite signature of patients with PMR and GCA differed from that of age-matched non-inflammatory controls (R2 > 0.7). There was a smaller separation between patients with clinically confirmed GCA and those with suspected GCA who later were clinically confirmed non-GCA (R2 = 0.135). In PMR, metabolite signatures were further altered with glucocorticoid treatment (R2 = 0.42) but did not return to that seen in controls. Metabolites correlated with CRP, pain, stiffness, and fatigue (R2 ≥ 0.39). CRP, pain, and stiffness declined with treatment and were associated with 3-hydroxybutyrate and acetoacetate, but fatigue did not. Metabolites differentiated patients with high and low fatigue both before and after treatment (R2 > 0.9). Low serum glutamine was predictive of high fatigue at both time points (0.79-fold change). CONCLUSION: PMR and GCA alter the metabolite signature. In PMR, this is further altered by glucocorticoid therapy. Treatment-induced metabolite changes were linked to measures of inflammation (CRP, pain and stiffness), but not to fatigue. Furthermore, metabolite signatures distinguished patients with high or low fatigue.

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.

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.

"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.

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.

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.

Diagnosing polymyalgia rheumatica on 18F-FDG PET/CT: typical uptake patterns.

OBJECTIVE: The diagnosis of polymyalgia rheumatica (PMR) is often challenging, since similar clinical features and laboratory findings can be observed in several inflammatory conditions. PMR involves affected sites in a specific manner, and 18F-FDG PET/CT has the advantage for assessing the disease activity of each site. The purpose of this study was to identify the patterns of 18F-FDG uptake that suggest the diagnosis of PMR. METHODS: We studied 60 patients who had undergone 18F-FDG PET/CT scans for workup of suspected PMR, arthritis, enthesitis, or myopathy. Final diagnoses were made by board-certified rheumatologists. The incidence of significant 18F-FDG uptake, higher than mediastinal blood pool, of the following sites were compared among PMR patients and patients with other diseases: wrists, elbows, shoulders, sternoclavicular joints, acromioclavicular joints, spinous processes, ischial tuberosities, and greater trochanters. For the spinous processes, the incidence of "Y"-shaped uptake along the interspinous bursae was also evaluated. RESULTS: A definitive diagnosis of PMR was given to 16 of 60 patients. The incidence of significant 18F-FDG uptake in the definitive PMR group was 6% for wrists and for elbows, 88% for glenohumeral and sternoclavicular joints, 25% for acromioclavicular joints, 81% for spinous processes, 69% for ischial tuberosities, and 81% for greater trochanters. Patients with PMR showed a significantly higher incidence of "Y"-shaped uptake along the interspinous bursae than the other patients (38 vs. 9%) (P = 0.016). CONCLUSION: 18F-FDG uptake distribution patterns and morphology can contribute to the diagnosis of PMR. Significant 18F-FDG uptake in the sternoclavicular joints is one of the characteristic findings in patients with PMR as well as the uptake in the shoulders, ischial tuberosities, and greater trochanters. "Y"-shaped spinous process uptake may be one of the specific findings for PMR.

Torsades de Pointes in Patients with Polymyalgia Rheumatica.

Polymyalgia rheumatica (PMR) represents the most common inflammatory rheumatic disease of the elderly. It is characterized by synovitis of proximal joints and extra-articular synovial structures, along with chronic high-grade systemic inflammation. PMR is closely related to giant cell arteritis (GCA), a large-vessel vasculitis that involves the major branches of the aorta, particularly the extracranial branches of carotid artery including temporal arteries. It is currently believed that PMR and GCA may represent different manifestations of the same disease process. Chronic systemic inflammation is presently recognized as one of the key pathogenic mechanisms underlying cardiovascular disease and associated complications, including cardiac arrhythmias and sudden death. In this regard, several studies demonstrated that besides promoting structural heart disease, inflammatory activation may also be per se arrhythmogenic, via cytokine-mediated effects on cardiac electrophysiology. In particular, increasing evidence points to inflammation as a novel risk factor for QTc prolongation and related life-threatening arrhythmias, specifically Torsade de Pointes (TdP). Starting from the report of two cases of TdP occurring in PMR patients with active disease and elevated circulating IL-6 levels, we here reviewed literature data regarding heart involvement and arrhythmic events in PMR/GCA, as well as TdP risk in inflammatory diseases. Potential underlying mechanisms were dissected, by focusing on the driving role of inflammatory activation.

[Therapy of rheumatic polymyalgia: the pathophysiologic management]. / Trattamento della polimialgia reumatica: l'approccio fisiopatologico.

Polymyalgia rheumatica (PMR) is an inflammatory syndrome affecting older people whose prevalence has increased in recent years. The suppression of the hypothalamic-pituitary-adrenal axis (HPA) and ageing may contribute to the pathogenesis of PMR. Chronic stress (i.e. interpersonal, chronic infections etc.) in elderly people may represent a risk factor for the development of PMR. In fact, elderly represent per se a condition of endocrine senescence including adrenal hypofunction, in addition chronic stress represents a further harmful stimulus to seriously compromise endogenous glucocorticoid production. Synovitis and vasculitis characterize the majority of the patients. Serum cytokine and steroidal hormone patterns suggest that patients with PMR have an intensive inflammatory reaction. As a matter of fact, glucocorticoids represent the most useful temporary "replacement" treatment during the active phase of PMR. The use of modified-release glucocorticoids that might induce higher levels during the night (circadian rhythms as in physiological conditions), will represent another important approach to optimize PMR treatment and reduce the side effects. Combination therapy between glucocorticoids and inhibitors of pro-inflammatory cytokines should be tested in large studies and early cases of PMR.

Is the course of steroid-treated polymyalgia rheumatica more severe in women?

Polymyalgia rheumatica (PMR) has a marked preponderance in women. The female sex has been claimed to be a risk factor for longer-course corticosteroid therapy and to be associated with more severe systemic symptoms and lower hemoglobin levels. Eighty consecutive patients affected by PMR, seen at two tertiary referral centers, were followed-up for a mean period of 14.9 months after initiating corticosteroid treatment. At presentation, women had longer disease duration and lower hemoglobin levels (both P = 0.05) than men. In contrast, their systemic signs of PMR were less common (P = 0.01). Women were treated with a slightly higher mean daily dose of prednisone (P = 0.055), and assumed a significantly higher cumulative dosage of the drug (P = 0.01). Accordingly, the mean number of steroid-related side effects was higher among women (P = 0.003). The number of relapses during steroid treatment (P = 0.02), but not that of recurrences, was increased in women. ESR, which was raised at presentation, significantly declined during follow-up to normal values in both subgroups (P < 0.00001 by analysis of variance [ANOVA]). Its decrease was significantly more pronounced in men than in women. Hemoglobin at follow-up was significantly higher in men than in women at any given time point. In conclusion, sex is probably modulating the response to corticosteroids. This finding emphasizes the need to consider differences between males and females in the clinical and therapeutic approach to PMR patients.

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.

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.

Von Willebrand factor in polymyalgia rheumatica and giant cell arteritis.

Patients with giant cell arteritis (GCA) and with polymyalgia rheumatica (PMR) have increased plasma levels of von Willebrand factor (vWF) even during corticosteroid therapy. The association between vWF, subclinical inflammation and cardiovascular complications in GCA/PMR remains to be investigated.

Polymyalgia rheumatica with normal erythrocyte sedimentation rate: clinical aspects.

Polymyalgia rheumatica is a relatively common syndrome of the elderly characterized by severe pain and stiffness in the neck shoulder and pelvic girdles, along with increased acute phase reactants. The current diagnostic criteria include as a requirement an erythrocyte sedimentation rate (ESR) higher than 30 or 40 mm/1 hr. Nevertheless, in several reports, a sizable proportion of patients with PMR, from 7% up to 22%, had an ESR that was either normal or slightly increased at the time of diagnosis, supporting the notion that an increased ESR should not be an absolute requirement for its diagnosis. This subset is characterized by a younger age, a less marked predominance of females, a longer diagnostic delay and a lower frequency of constitutional symptoms such as fever or weight loss. When determined, a majority of these patients had increased levels of C reactive protein. The recognition of this subset of patients with PMR and a low ESR can be very useful to the clinician, avoiding unnecessary suffering of the patients and the risks of ineffective therapy with nonsteroidal antiinflammatory drugs. To avoid the over-diagnosis of PMR in patients with a low ESR, we propose a set of criteria that can be easily applied in daily practice to patients with a clinical picture consistent with PMR but with a normal or slightly increased ESR.

Prednisolone pharmacokinetics in patients with rheumatoid arthritis, polymyalgia rheumatica and asthma.

The pharmacokinetic profile of a single 10 mg oral dose of prednisolone was studied in three groups of six patients with rheumatoid arthritis (RA), polymyalgia rheumatica (PMR) and bronchial asthma (BA) who were already receiving steroid therapy. A fourth group of age and sex-matched normal controls was also studied. Kinetic parameters (including elimination half-life, area under the plasma concentration curve, apparent volume of distribution and total body clearance) were similar for all four groups but there was considerable inter-subject variability. The correlations between these kinetic parameters and age, body weight and serum albumin were poor. The results suggest that any differences in the effects of corticosteroids in these inflammatory diseases are unlikely to be due to pharmacokinetic factors. The duration of steroid therapy and the reduction in patient mobility would appear to be more likely explanations for the reduction in bone mass observed in patients with RA.

Prevention of glucocorticoid-induced osteopenia: effect of oral 25-hydroxyvitamin D and calcium.

Twenty-four patients (9 M and 15 F, age range 51-82) with polymyalgia rheumatica receiving 6-methylprednisolone for a period of 9 months (16 mg/daily/two weeks, 14 mg/daily/two weeks, 12 mg/daily/1 month, 10 mg/daily/1 month, 8 mg/daily/1 month, 6 mg/daily/1 month and 4 mg/daily for the last four months) were randomly assigned to receive either 250HD3 (35 mcg/day for 25 days/month) (Group A) or placebo (Group B) in a double-blind study. All patients also received 500 mg elemental calcium daily. Before and at 3, 6 and 9 months ESR, tenderness on palpation and subjective pain were evaluated. At the same times, mineral metabolism parameters (serum calcium, phosphorus, alkaline phosphatase, 24-h urinary calcium, phosphate and 24-h hydroxyproline excretion) and radial bone mineral content (BMC) were evaluated. Activity indexes (ESR and clinical parameters) improved in both groups. Furthermore, serum alkaline phosphatase and 24-h hydroxyproline excretion decreased significantly only in Group A, and BMC decreased significantly in Group B but rose slightly in Group A. No side effects were observed in any of the patients.

Increased RAHA titer and interleukin-6 levels in the synovial fluid in a patient with polymyalgia rheumatica.

We report a patient with polymyalgia rheumatica (PMR) accompanied by an increased Rheumatoid Arthritis Hemagglutinin Test (RAHA) titer and interleukin-6 level in the synovial fluid. A 60-year-old female was admitted because of polymyalgia, a body temperature of 39.2 degrees C, and an erythrocyte sedimentation rate increased to 94 mm/h. Since a muscle biopsy failed to show a specific finding, she was diagnosed as PMR. The titer of RAHA and the interleukin-6 level were increased only in the synovial fluid; prednisolone treatment decreased both. The present case raised the possibility that a similar mechanism in rheumatoid arthritis may involve the development of synovitis in PMR.

Plasma fibrinogen along with patient-reported outcome measures enhances management of polymyalgia rheumatica: a prospective study.

OBJECTIVE: We sought to prospectively examine the responsiveness of a number of patient-reported outcome (PRO) measures in polymyalgia rheumatica (PMR), as well as their relationship to the biomarkers erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and plasma fibrinogen. METHODS: Sixty patients with PMR were divided into active (n = 25) or inactive (n = 35) disease groups based on symptoms; physician assessment; and the biomarkers ESR, CRP, and plasma fibrinogen. Groups underwent assessment at baseline and 6 weeks. Disease activity measures and relevant PRO measures were recorded. Measures of responsiveness were compared for all PRO and biomarkers. RESULTS: Visual analog scale disease activity (VASDA) and VAS quality of life (VASQOL) are more responsive to change in disease activity than VAS pain, morning stiffness, Health Assessment Questionnaire (HAQ), and PMR-activity score (AS). Analysis of PMR-AS versus VASDA, VASQOL, and HAQ showed correlation coefficients of 0.87 (p < 0.001), 0.80 (p < 0.001), and 0.68 (p < 0.001), respectively. Receiver-operating curve (ROC) analysis revealed VASDA to be more specific than either HAQ (0.95 vs 0.85; p < 0.001) or VASQOL (0.95 vs 0.93; p < 0.001) for the detection of response to treatment in active PMR. Overall, fibrinogen showed superior correlation coefficients with the various PRO than either of the standard biomarkers ESR or CRP. In addition, standardized response means for fibrinogen, ESR, and CRP were 1.63, 1.2, and 1.05, respectively, indicating that plasma fibrinogen was the most responsive biomarker for assessment of change in disease activity. CONCLUSION: VASDA and VASQOL are the most responsive PRO to changes in disease activity in PMR. In addition, plasma fibrinogen demonstrated greater responsiveness to changes in disease activity and superior correlation with the various PRO measures recorded than did the standard biomarkers ESR and CRP.

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.