Citrullination of histone H3 drives IL-6 production by bone marrow mesenchymal stem cells in MGUS and multiple myeloma.

Multiple myeloma (MM), an incurable plasma cell malignancy, requires localisation within the bone marrow. This microenvironment facilitates crucial interactions between the cancer cells and stromal cell types that permit the tumour to survive and proliferate. There is increasing evidence that the bone marrow mesenchymal stem cell (BMMSC) is stably altered in patients with MM-a phenotype also postulated to exist in patients with monoclonal gammopathy of undetermined significance (MGUS) a benign condition that precedes MM. In this study, we describe a mechanism by which increased expression of peptidyl arginine deiminase 2 (PADI2) by BMMSCs in patients with MGUS and MM directly alters malignant plasma cell phenotype. We identify PADI2 as one of the most highly upregulated transcripts in BMMSCs from both MGUS and MM patients, and that through its enzymatic deimination of histone H3 arginine 26, PADI2 activity directly induces the upregulation of interleukin-6 expression. This leads to the acquisition of resistance to the chemotherapeutic agent, bortezomib, by malignant plasma cells. We therefore describe a novel mechanism by which BMMSC dysfunction in patients with MGUS and MM directly leads to pro-malignancy signalling through the citrullination of histone H3R26.

Reactive arthritis following culture-confirmed infections with bacterial enteric pathogens in Minnesota and Oregon: a population-based study.

OBJECTIVE: To describe the epidemiology and clinical spectrum of reactive arthritis (ReA) following culture-confirmed infection with bacterial enteric pathogens in a population-based study in the USA. METHODS: We conducted telephone interviews of persons age>1 year with culture confirmed Campylobacter, Escherichia coli O157, Salmonella, Shigella and Yersinia infections reported to FoodNet (http://www.cdc.gov/FoodNet/) in Minnesota, USA and Oregon, USA between 2002 and 2004. SUBJECTS: with new onset joint pain, joint swelling, back pain, heel pain and morning stiffness lasting >or=3 days within 8 weeks of culture (possible ReA) were invited to complete a detailed questionnaire and physical examination. RESULTS: A total of 6379 culture-confirmed infections were reported; 70% completed screening interviews. Of these, 575 (13%) developed possible ReA; incidence was highest following Campylobacter (2.1/100,000) and Salmonella (1.4/100,000) infections. Risk was greater for females (relative risk (RR) 1.5, 95% CI, 1.3 to 1.7), adults (RR 2.5, 95% CI, 2.0 to 3.1) and subjects with severe acute illness (eg, fever, chills, headache, persistent diarrhoea). Risk was not associated with antibiotic use or human leukocyte antigen (HLA)-B27. A total of 54 (66%) of 82 subjects examined had confirmed ReA. Enthesitis was the most frequent finding; arthritis was less common. The estimated incidence of ReA following culture-confirmed Campylobacter, E coli O157, Salmonella, Shigella and Yersinia infections in Oregon was 0.6-3.1 cases/100,000. CONCLUSIONS: This is the first population-based study of ReA following infections due to bacterial enteric pathogens in the USA. These data will help determine the burden of illness due to these pathogens and inform clinicians about potential sequelae of these infections.

A multicenter two by two factorial trial of cognitive behavioral therapy and aerobic exercise for Gulf War veterans' illnesses: design of a veterans affairs cooperative study (CSP #470).

The Department of Veterans Affairs (VA) Cooperative Studies Program (CSP) Study #470 is a 2 x 2 factorial trial designed to evaluate the hypothesis that both cognitive behavioral therapy (CBT) and aerobic exercise will significantly improve physical function in participants with Gulf War veterans' illnesses (GWVI), and that adding CBT to aerobic exercise will provide further incremental benefit. One thousand three hundred fifty-six veterans will be randomized to one of four treatment arms: CBT plus aerobic exercise plus usual and customary care, aerobic exercise plus usual and customary care, CBT plus usual and customary care, or usual and customary care alone. The study duration is 2.5 years with 1.5 years of intake and 1 year of follow-up. The primary outcome measure is the proportion of veterans improved more than seven units on the physical component summary (PCS) scale of the Short Form Health Survey for Veterans (SF-36V) measured 12 months after randomization. This generic quality-of-life measure was chosen because there is no disease-specific measure for GWVI and the symptoms of GWVI span a wide range of physical manifestations that are related to the domains covered by the PCS scale. Sample size was determined to detect all six pairwise comparisons between the four treatment arms with 90% power and a Bonferroni adjustment for an overall type I error of 0.05 or 0.05/6 = 0.0083. CSP #470 was initiated in May 1999 in 18 VA and two Department of Defense medical centers. To date this represents the largest randomized trial designed to evaluate treatments for individuals with unexplained physical symptoms. This paper will focus on the rationale and unique features of the study design. Control Clin Trials 2001;22:310-332

Pharmacologic treatment of fibromyalgia.

Fibromyalgia is a chronic syndrome characterized by widespread pain, unrefreshed sleep, disturbed mood, and fatigue. Until such time as we have a clearer understanding of the trigger and/or pathophysiologic mechanisms producing these symptoms, pharmacologic treatment should be aimed at individual symptoms. Such treatment should ideally be offered as part of a multidisciplinary treatment program using both pharmacologic and nonpharmacologic treatment modalities. Critical components of any successful fibromyalgia treatment program include addressing physical fitness, work and other functional activities, and mental health, in addition to symptom-specific therapies. The main symptoms that should be addressed include pain, sleep disturbances including restless leg syndrome, mood disturbances, and fatigue. Pharmacologic therapy should also be considered for syndromes commonly associated with fibromyalgia including irritable bowel syndrome, interstitial cystitis, migraine headaches, temporomandibular joint dysfunction, dysequilibrium including neurally mediated hypotension, sicca syndrome, and growth hormone deficiency. This article provides general guidelines in initiating a successful pharmacologic treatment program for fibromyalgia.

Symptom factor analysis, clinical findings, and functional status in a population-based case control study of Gulf War unexplained illness.

Few epidemiological studies have been conducted that have incorporated clinical evaluations of Gulf War veterans with unexplained health symptoms and healthy controls. We conducted a mail survey of 2022 Gulf War veterans residing in the northwest United States and clinical examinations on a subset of 443 responders who seemed to have unexplained health symptoms or were healthy. Few clinical differences were found between cases and controls. The most frequent unexplained symptoms were cognitive/psychological, but significant overlap existed with musculoskeletal and fatigue symptoms. Over half of the veterans with unexplained musculoskeletal pain met the criteria for fibromyalgia, and a significant portion of the veterans with unexplained fatigue met the criteria for chronic fatigue syndrome. Similarities were found in the clinical interpretation of unexplained illness in this population and statistical factor analysis performed by this study group and others.

Musculoskeletal pain and fatigue are associated with chronic hepatitis C: a report of 239 hepatology clinic patients.

OBJECTIVE: The aim of this study was to identify the frequency of fatigue and musculoskeletal pain in hepatitis C compared with other liver diseases. METHODS: Hepatology outpatients were evaluated by questionnaire for musculoskeletal pain and fatigue. Charts were reviewed for diagnoses, aminotransferases, histology, treatment, and presence of hepatitis C by second generation ELISA and/or polymerase chain reaction. The frequency of symptoms in patients with and without hepatitis C were compared. RESULTS: In 239 patients (mean age 46.7 +/- 11.6 yr; 52% male) musculoskeletal pain was present in 70% for 6.7 +/- 8.3 yr and fatigue in 56% for 3.3 +/- 5.1 yr. Backache was the most common complaint (54%), followed by morning stiffness (45%), arthralgia (42%), myalgia (38%), neck pain (33%), pain "all over" (21%), and subjective joint swelling (20%). Diffuse body pain was present in 23% on a pain diagram and was strongly associated with fatigue. There was a significant association between hepatitis C positivity and the presence of musculoskeletal pain (81% of HCV-positive compared with 56% of HCV-negative patients, respectively; p = 0.0001), and fatigue (67% compared with 44%; p = 0.001). Musculoskeletal pain was more frequent among patients with isolated hepatitis C infection than among patients with isolated hepatitis B or alcoholic liver disease (91%, 59%, and 48%, respectively; p = 0.004). Similarly, fatigue was more frequent among patients with isolated hepatitis C than among those with isolated alcoholic liver disease or hepatitis B (66%, 30%, and 29%, respectively; p = 0.004). There was no relationship between musculoskeletal complaints and possible route of acquiring hepatitis C, levels of aminotransferases, liver disease severity on biopsy, or interferon treatment. CONCLUSIONS: Musculoskeletal pain and fatigue are frequent in hepatology clinic attendees, particularly those with hepatitis C and are unrelated to severity of liver disease, route of infection, or interferon therapy.

U.S. Gulf War Veterans: service periods in theater, differential exposures, and persistent unexplained illness. Portland Environmental Hazards Research Centre.

Approximately 80,000 of the 697,000 American men and women who were stationed in SW Asia during the Gulf War (GW) report unexplained illness consisting of symptoms of persistent fatigue, cognitive difficulties, such as mild memory loss, diffuse muscle and joint pain, gastrointestinal symptoms, skin lesions, and respiratory problems, among others. Associations between major symptom groups and periods of deployment in the theater of operations have been sought in a population-based, clinical case-control study of GW veterans resident in the north-western region of the United States. No statistically significant differences were evident in the proportion of cases with unexplained fatigue, cognitive/psychological or musculoskeletal symptoms among veterans present in SW Asia in 3 specific time periods: (a) 8/1/1990-12/31/1990 (which includes Desert Shield), (b) the period surrounding Desert Storm (1/1/1991-3/31/1991), and (c) the (post-combat) period immediately following hostilities (4/1/1991-7/31/1991). There was a trend for all 3 case symptoms to be more common among GW veterans who served in the post-combat period. As numbers in these deployment groups were small, and power to detect differences low, the apparent absence of significant differences in the frequency of major symptom groups among these veterans requires confirmation in a larger study. Deployment for discrete periods in SW Asia is a method to separate distinct constellations of environmental factors; these are useful for analyses of associations among symptoms and exposures given the near-total absence of objective data on chemical and other possible exposures in the theater of operations.

A novel model of bacterially-induced acute anterior uveitis in rats and the lack of effect from HLA-B27 expression.

BACKGROUND: Humans with the major histocompatibility antigen B27 (HLA-B27) are especially at risk for developing rheumatic disorders such as ankylosing spondylitis and Reiter's syndrome. Acute anterior uveitis (AAU) often occurs in association with these diseases or in HLA B27 positive individuals without joint disease. METHODS: We induced acute anterior uveitis in Lewis rats by a standard model, the intraperitoneal injection of 200 micrograms of Escherichia coli endotoxin. We also developed a novel model of uveitis secondary to gram-negative infection. RESULTS: Transgenic rats that expressed a low copy number of the B27 gene did not differ statistically from litter mate controls in the intensity of anterior uveitis as judged by histology, enumeration of cells in aqueous humor, protein in aqueous humor, or slit lamp examination. The majority of rats exposed to live Salmonella enteritidis or Yersinia enterocolitica 0:3 using either an oral or intravenous route of infection developed anterior uveitis. In contrast to the disease induced by endotoxin that is most intense 24 hours after the endotoxin challenge, uveitis induced by live bacteria usually began 7 to 9 days after exposure to bacterial products, was more often unilateral, persisted for as long as 3 weeks, and was sometimes recurrent. The expression of HLA-B27 did not appear to influence the incidence or severity of uveitis in B27+ low copy heterozygous animals. CONCLUSION: This rat model of AAU should facilitate evaluation of bacterial antigenic component(s) involved in the pathogenesis of live gram-negative bacteria induced AAU.

Fibromyalgia: a prominent feature in patients with musculoskeletal problems in chronic hepatitis C: a report of 12 patients.

Ten female and 2 male patients with chronic hepatitis C infection had fibromyalgia as a prominent musculoskeletal problem. In 9 patients, the fibromyalgia developed a mean of 13.4 years after the hepatitis C infection. In 2 patients, the 2 diseases occurred within weeks to a few months of each other, and in 1 patient, preexisting fibromyalgia was apparently aggravated by the hepatitis C infection. All patients had a possible blood or body fluid exposure event or high risk activity: intravenous blood products in 3, occupational needle stick in 1, tattoos in 3, intravenous drug use in 3 and promiscuous sexual practices in 2. Transaminases were moderately elevated in 10 patients, and chronic active hepatitis was found in 4 patients who were biopsied. All patients had prominent fatigue. Additional features not commonly seen in fibromyalgia patients included fluctuating synovitis in 5 patients, biopsy-proven leukocytoclastic vasculitis in 5, sicca symptoms in 3, Raynaud's phenomenon in 3, and cryoglobulinemia in 2. One patient died in multi-organ failure after treatment for systemic vasculitis. Rheumatologists and internists should be aware that patients with hepatitis C infection can have fibromyalgia that occurs concomitantly with other extrahepatic manifestations of hepatitis C.