OBJECTIVESWhile myeloid-derived suppressor cells (MDSCs) were previously shown to promote a proinflammatory T helper (Th) 17 response in autoimmune conditions, a potential impact of the MDSC-Th17 immune axis on abnormal bone destruction in RA remains largely unknown.METHODSWe investigated the correlation between the frequency of MDSCs or its subsets and joint destruction in RA patients. The reciprocal actions of patient-derived MDSCs and Th17 cells were studied using osteoclast (OC) differentiation and bone resorption assays in vitro, which were further validated using mouse models of RA. Contribution of MDSCs to osteoclastogenesis and bone erosion in vivo was determined by depletion or transfer of MDSCs.RESULTSHuman MDSCs, particularly monocytic MDSCs (M-MDSCs), exhibit inherent OC-differentiating capacity and positively correlate with clinical bone erosion in RA patients. Strikingly, patient-derived M-MDSCs can program Th17 cells towards a pro-osteoclastogenic phenotype, which in return potentiates OC differentiation via the receptor activator of nuclear factor κΒ ligand (RANK-L)-RANK signalling. This enhanced osteolysis driven by the reciprocal actions of M-MDSCs and Th17 cells is further confirmed using mouse models of RA. Selective depletion of M-MDSCs significantly ameliorates osteoclastogenesis and disease severity in arthritic mice, whereas transfer of M-MDSCs aggravates bone erosion associated with increased OCs in recipient mice.CONCLUSIONOur findings highlight the functional plasticity of MDSCs and identify a novel pro-osteoclastogenic pathway governed by interplay between myeloid cells and T lymphocytes in autoimmune RA.

Rheumatoid arthritis (RA) is among the most common rheumatologic diseases, affecting approximately 1% of the population, with millions of affected subjects worldwide [ [1] Silman A.J. Hochberg M.C. Epidemiology of the rheumatic diseases. 2nd ed. Oxford University Press, New York2001 Google Scholar ]. In such patients, RA is a cause for significant disability and also confers a significantly increased risk of premature death [ [2] Naz S.M. Symmons D.P.M. Mortality in established rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2007; 21: 871-883 Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar ]. Not surprisingly being the most common cause of death in the entire population, cardiovascular disease represents the cause of death in nearly half of RA patients [ 2 Naz S.M. Symmons D.P.M. Mortality in established rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2007; 21: 871-883 Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar , 3 Nicola P.J. Crowson C.S. Maradit-Kremers H. et al. Contribution of congestive heart failure and ischemic heart disease to excess mortality in rheumatoid arthritis. Arthritis Rheum. 2006; 54: 60-67 Crossref PubMed Scopus (148) Google Scholar ], however the overall risk of dying from a cardiovascular cause is more than double in RA vs general population for both genders and any age [ 2 Naz S.M. Symmons D.P.M. Mortality in established rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2007; 21: 871-883 Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar , 3 Nicola P.J. Crowson C.S. Maradit-Kremers H. et al. Contribution of congestive heart failure and ischemic heart disease to excess mortality in rheumatoid arthritis. Arthritis Rheum. 2006; 54: 60-67 Crossref PubMed Scopus (148) Google Scholar , 4 Crowson C.S. Nicola P.J. Kremers H.M. et al. How much of the increased incidence of heart failure in rheumatoid arthritis is attributable to traditional cardiovascular risk factors and ischemic heart disease?. Arthritis Rheum. 2005; 52: 3039-3044 Crossref PubMed Scopus (118) Google Scholar ] and cannot be explained by excess cardiovascular risk factors [ [4] Crowson C.S. Nicola P.J. Kremers H.M. et al. How much of the increased incidence of heart failure in rheumatoid arthritis is attributable to traditional cardiovascular risk factors and ischemic heart disease?. Arthritis Rheum. 2005; 52: 3039-3044 Crossref PubMed Scopus (118) Google Scholar ]. While the formation of autoantibodies is considered a key step in RA, many of the synovial and systemic effects are mediated by a humoral inflammatory response (tumor necrosis factor-α [TNF-α] and interleukin-1β [IL-1β]) [ [5] Scott D.L. Wolfe F. Huizinga T.W.J. Rheumatoid arthritis. Lancet. 2010; 376: 1094-1108 Abstract Full Text Full Text PDF PubMed Scopus (2308) Google Scholar ]. As such targeted TNF-α or IL-1β blockade changes the natural history of the disease [ [5] Scott D.L. Wolfe F. Huizinga T.W.J. Rheumatoid arthritis. Lancet. 2010; 376: 1094-1108 Abstract Full Text Full Text PDF PubMed Scopus (2308) Google Scholar ]. TNF-α blockers are the most commonly prescribed cytokine antagonist in RA, and appear to be more efficacious than IL-1 blocker, anakinra [ 5 Scott D.L. Wolfe F. Huizinga T.W.J. Rheumatoid arthritis. Lancet. 2010; 376: 1094-1108 Abstract Full Text Full Text PDF PubMed Scopus (2308) Google Scholar , 6 Singh J.A. Christensen R. Wells G.A. et al. Biologics for rheumatoid arthritis: an overview of Cochrane reviews. Cochrane Database Syst Rev. 2009 Oct 7; 4: CD007848 PubMed Google Scholar ]. The use of TNF-α blockers in RA is however hindered by an increased risk of heart failure exacerbation with TNF-α blockers [ 7 Mann D.L. Inflammatory mediators and the failing heart: past, present, and the foreseeable future. Circ Res. 2002; 91: 988-998 Crossref PubMed Scopus (795) Google Scholar , 8 Setoguchi S. Schneeweiss S. Avorn J. et al. Tumor necrosis factor-alpha antagonist use and heart failure in elderly patients with rheumatoid arthritis. Am Heart J. 2008; 156: 336-341 Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar ]. On the other hand, accumulating preclinical evidence and results from pilot clinical trials suggest that IL-1β blockade may be beneficial in patients with or at risk for cardiovascular disease [ [9] Van Tassell B.W. Toldo S. Mezzaroma E. Abbate A. Targeting interleukin-1 in heart disease. Circulation. 2013; 128: 1910-1923 Crossref PubMed Scopus (218) Google Scholar ].

Since the original descriptions of the involvement of crystals in arthritis, our understanding of the clinical syndromes of gout and pseudogout, and the role of basic calcium crystals in arthritis has increased. Gout is usually considered an affliction confined to middle-aged men, but has an increasing prevalence in older populations, with unique and often atypical features. Calcium pyrophosphate dihydrate crystal deposition disease is common in elderly patients. The diagnosis of both of these common forms of arthritis and the need to individualize therapy in patients with other medical problems remain important clinical challenges to the practicing physician.

Synovial fluid white blood cell counts are considered to be useful in diagnosing infectious arthritis, however, considerable overlap exists between infectious and noninfectious types of inflammatory arthritis. We undertook this review of synovial fluid studies at our institution to better define this degree of overlap and characterize the features of infectious arthritis in relationship to synovial fluid white cell counts. The records of 202 consecutive patients with synovial fluid white blood cell counts >2000/mm3 were reviewed. Infectious arthritis was diagnosed in 77% (10/13) of patients with counts >100,000, 47% (8/17) in the 50,000–100,000 range, and 5% (9/172) with counts <50,000. Crystal-induced arthritis and rheumatoid arthritis made up 81% of patients in the 15,000–50,000 range. Overall, 10 of 27 (37%) cases of infectious arthritis had white cell counts >100,000, and 18 of 27 (67%) had counts >50,000. A majority of these infections (14/18) were related to Staphylococcus aureus, while 5 of 7 infections associated with counts <20,000 were associated with atypical organisms. This study confirms that a majority of patients with very high synovial fluid white blood cell counts have infectious arthritis, and that the likelihood of infection is markedly reduced, but certainly not excluded, below this level. The presence of atypical infections in a small percentage of patients with low counts emphasizes the importance of clinical judgment in evaluating all patients with inflammatory arthritis, regardless of synovial fluid white cell counts.

A case of granulomatous myositis as a manifestation of chronic graft-versus-host disease is presented. The clinical presentation, MR imaging appearances, pathologic features and excellent response to treatment with immunosuppression are described. To the best of our knowledge, based on a world literature search, this is the first report of graft-versus-host disease presenting as granulomatous polymyositis.,

Objective: To determine if daily dietary supplementation with Chlorella for three months helps normalize body functions, relieve symptoms, and improve quality of life in patients with fibromyalgia syndrome [FMS].Methods: A total of 43 subjects with FMS were enrolled and randomized such that approximately half consumed 50 Sun Chlorella(TM) tablets and 100 mL of liquid Chlorella extract known as Wakasa Gold(TM) each day for three months and the other half consumed 50 placebo tablets and 100 mL of placebo liquid each day for a comparable period. Neither the patient nor the physician conducting the assessments knew which of the dietary supplements the subject was consuming. Following a one month washout period, Subjects crossed-over from Chlorella to placebo or vice versa.Results: Thirty-four subjects completed the entire trial. Six parameters of response were followed while each subject consumed each study diet: subjects answered questions relating to sleep. pain, global well-being, and fatigue while the physician assessed tender point index and global well-being. Subjects were considered as having a positive response to a diet if they demonstrated a 50 percent or more improvement in at least four parameters. Of the 37 FMS subjects who completed the Chlorella arm, seven [19 percent] were responders versus only 3/34 19 percent] who completed the placebo arm [P = 0.311]. For the four self-assessment parameters, significantly more [21/37 or 57 percent] subjects who completed the Chlorella arm noted a 50 percent or better improvement in at least two parameters while only 10/34 [29 percent] who completed the placebo arm did [P = 0.031]. Patient self-assessment of functional abilities by the Fibromyalgia Impact Questionnaire [FIQ] showed that when they were consuming Chlorella, there was a steady, statistically significant, drop in the FIQ score while, when taking placebo, levels of improvement varied and were not statistically significant at the end of the three-month period. Comparisons of the FIQ for Chlorella and placebo indicated that the better response of participants in the Chlorella arm of the crossover was nearly statistically significant [P = 0.058]. A questionnaire dealing with issues of pain, anxiety, sleep, and gastrointestinal difficulties indicated that while participants were consuming Chlorella, there were steady, statistically significant improvements [P < 0.001] in scores compared to baseline. Comparing the two arms. there was a statistically significant [P = 0.004] improvement in FMS symptoms while the subjects were taking Chlorella.Conclusion: Taken together, the results of this randomized, placebo-controlled, double-blind crossover study lead us to conclude that dietary Chlorella supplementation may be useful in relieving symptoms of FMS.

OBJECTIVE To describe our experience with low dose weekly methotrexate (MTX) in the management of immune mediated cochleovestibular disorder (IMCVD). METHODS Between 1991 and 1999, we treated 53 patients with IMCVD with MTX. Patients were selected on the basis of progressive vestibular symptoms that had responded to corticosteroids and in most cases, relapsed. MTX was initiated at a dose of 7.5 mg weekly and increased to doses up to 25 mg weekly as needed. Response was assessed by audiologic studies and history of change in tinnitus and vertigo. MTX was discontinued after 4-6 mo in patients showing no improvement, and after 12-18 mo in patients with improved and stable symptoms. RESULTS Three patients were still in early therapy and had not improved. Of the 50 remaining patients, significant improvement was seen in vertigo in 27/39 (69%) patients, hearing loss in 25/47 (53%), and tinnitus in 11/42 (26%). Overall improvement in symptoms was seen in 35/50 (70%) patients. Four patients stopped MTX due to toxicity, and 11 due to lack of response. In 28 patients, MTX was stopped after 12-18 mo when symptoms had stabilized, and restarted in 5 of these after relapse. Seven patients remain on therapy with improved and stable symptoms after 17.3 mo. CONCLUSION In this open label experience, a majority of patients with IMCVD improved with weekly low dose MTX therapy with minimal toxicity.

Gout is a common form of arthritis, in which many of the risk factors, pathogenetic mechanisms, and clinical features have been recognized for years. Nevertheless, new information has become available regarding the normal physiologic role of uric acid as an antioxidant, and greater insight has been obtained regarding the inflammatory process in acute gout. New studies have improved our understanding of the role of genetic and environmental factors responsible for hyperuricemia, and we know more about the significance of the association of hyperuricemia with other diseases. Clinically, rare complications and disease manifestations in new populations continue to be discussed, and diagnostic methods continue to be refined.

Fibromyalgia syndrome is a common, chronic musculoskeletal disorder of unknown aetiology, While available therapy is often disappointing, most patients can be helped with a combination of medication, exercise and maintenance of a regular sleep schedule. The objective of the present study was to determine if adding nutritional supplements derived from the unicellular green alga, Chlorella pyrenoidosa, produced any improvements in the clinical and functional status in patients with moderately severe symptoms of fibromyalgia syndrome. Eligible patients had 2+ palpable tenderness at 11 or more of 18 defined tender points and had a tender point index (TPI) of at least 22, Each day for 2 months, participants consumed two commercially available Chlorella-based products, 10 g of 'Sun Chlorella' tablets and 100 mL of liquid 'Wakasa Gold'. Any amelioration of symptoms was validated and quantified using semi-objective and subjective outcome measures systematically administered at clinic visits on days 0, 30 and 60 of the diet therapy. Eighteen of the 20 patients enrolled completed the 2 month trial, The average TPI for the group which at onset was 32, decreased to a mean of 25 after 2 months. This decrease was statistically significant (p = 0.01), representing a 22% decrease in pain intensity. Blood samples taken on each occasion indicated no significant alterations in serum chemistries, formed elements, and circulating lymphocyte subsets. Compilations of the results of patient interviews and self-assessment questionnaires revealed that seven patients felt that the dietary supplement had improved their fibromyalgia symptoms, while six thought they had experienced no change, and five believed the symptoms had worsened over the time of the trial. The results of this pilot study suggest that dietary Chlorella supplementation may help relieve the symptoms of fibromyalgia in some patients and that a larger, more comprehensive double-blind, placebo-controlled clinical trial in these patients is warranted. Copyright (C) 2000 John Wiley & Sons, Ltd.

In this retrospective clinical trial, we evaluated the effectiveness of low-dose oral methotrexate in the management of bilateral Ménière's disease of immune-mediated origin. At our tertiary-care referral center, we evaluated ten men and eight women who had longstanding bilateral Ménière's disease that had been unresponsive to traditional conservative medical management. Sixteen of these patients had steroid-responsive bilateral Ménière's disease. Two patients had contraindications to steroids, but their clinical and laboratory evaluations were consistent with an immune-mediated process. Patients were treated with 7.5 to 20 mg/week of oral methotrexate. The mean duration of treatment was 16.7 months (range: 8 to 35), with a mean followup of 2 years (range: 9 mo to 5 yr). Changes in clinical symptoms (vertigo, hearing loss, tinnitus, and aural fullness), audiometric changes, and side effects of therapy were evaluated. Vertigo resolved in 14 patients (78%), was substantially alleviated in three patients (17%), and remained unchanged in one patient (6%). Hearing improved in five patients (28%) and stabilized in seven patients (39%). Tinnitus and aural fullness resolved or was relieved in 11 of 17 (65%) and 13 of 14 (93%) patients, respectively. Side effects were minimal and reversible. We conclude that low-dose oral methotrexate is effective and safe for treating bilateral Ménierè's disease of immune-mediated origin. In this study, methotrexate alleviated vertiginous symptoms and improved or stabilized hearing in most patients. Low-dose methotrexate can be considered for patients with immune-mediated bilateral Meniérè's disease when long-term treatment is required or when a steroid or cyclophosphamide is contraindicated.

Immune-mediated cochleovestibular disorders continue to present a management challenge to the otolaryngologist. The traditional treatment of these disorders, corticosteroids and/or cyclophosphamide (Cytoxan), has been associated with serious and occasionally life-threatening complications. In this study we report our experience in treating 25 patients with immune-mediated cochleovestibular disorders with methotrexate, a less toxic immunosuppressive agent that has been used extensively in patients with rheumatoid arthritis. Mean duration of treatment was 12.9 months, and adverse reactions were acceptable and reversible. Hearing improved in 69.6% of patients, and vestibular symptoms subsided or improved in 80% of patients. The results of this study suggest that methotrexate treatment is effective in a substantial number of patients with immune-mediated cochleovestibular disorders and has acceptable adverse reactions. A prospective, randomized study is needed to compare the efficacy of methotrexate with that of other immunosuppressive agents.

Although a diagnosis of gout can be confirmed by the presence of monosodium urate crystals in synovial fluid, arriving at the suspected diagnosis and managing the disease can be a challenge for primary care physicians and specialists alike. Symptoms of gout can mimic other forms of inflammatory arthritis such as rheumatoid arthritis, pseudogout, or septic arthritis. Treatment can be complicated by the patient's need for drugs that contribute to hyperuricemia. Once other diagnoses are ruled out and urate crystals are detected under polarized light microscopy, treatment to end the acute attack and follow-up treatment designed to lower serum urate levels can be undertaken.

Since the original descriptions of the involvement of crystals in arthritis, understanding of the clinical syndromes of gout and pseudogout and the role of basic calcium crystals in arthritis has increased. Gout is a common problem in middle-aged males but has an increasing prevalence in older patients, particularly women. Calcium pyrophosphate dihydrate (CPPD) crystal deposition disease is now a well-recognized problem in older patients. The diagnosis of both of these common forms of arthritis and the need to individualize therapy in patients with other medical problems remain important clinical challenges to the practicing physician.

Electroimmunodiffusion (Laurell rocket) determinations of factor VIII-related antigen in plasma were ordered to determine the cost/benefit ratio for factor VIII-related antigen as a putative test for endothelial damage in suspected vasculitis. Twenty-seven consecutive patients referred for vasculitis or suspected vasculitis were identified and followed up for an average of 9.1 ±months (range: one to thirty-three months) in a prospective, unblinded study performed in a clinic, associated with a 1054- bed inner-city university hospital. There was no difference in Westergren erythrocyte sedimentation rate (WESR) in patients with final diagnosis of systemic vasculitis (SV) (38 ± 12 mm/hour) compared to those without vasculitis (NV) (27 ± 7) as the final diagnosis. The mean plasma concentration of factor VIII-related antigen was significantly elevated in SV (344 ±100%) when compared with NV (147 ±39%) (P < 0.016). The factor VIII- related antigen test in this study was 2.56 times more likely (crude odds ratio) than the WESR to contribute to a change in diagnosis or therapy (P=0.016). Positive and negative predictive values (PPV and NPV) for factor VIII-related antigen (abnormal at greater than 220% of the normal value) were both 70%. PPV and NPV for WESR were 56% and 86%, respectively. The factor VIII-related test was less cost-effective than the WESR in the follow-up period unless it was important to define complete remission or differentiate vasculitis flare from infection. The authors conclude that factor VIII-related antigen is a useful test in the initial diagnosis of vasculitis.