An old disease with new insights: Update on diagnosis and treatment of gout.

Gout is an acute and chronic inflammatory disorder associated with high morbidity and impaired quality of life. There has been a substantial increase in the prevalence and incidence of gout in recent years. Novel diagnostic and therapeutic options have provided new insights into the pathogenesis and management of hyperuricemia and gout in the last decade. This clinical review aims to summarize the diagnostic process and management of acute and chronic gout.

Anti-cyclic citrullinated peptides positivity rate in patients with familial Mediterranean fever.

OBJECTIVES: To investigate the prevalence and levels of anti-cyclic citrullinated peptide antibodies (anti-CCP) in patients with familial Mediterranean fever (FMF) with and without arthritis. METHODS: Eighty-three patients with FMF and 43 healthy controls were included in the study. Thirty seven FMF patients had a history of arthritis, and 46 patients did not. Serum antibodies directed to the anti-CCP were assessed with a commercial enzyme-linked immunosorbent assay (ELISA) kit. Values <20U were considered negative, between 20 and 39U low, 40-99U moderate, and >100U high positive. RESULTS: Positivity rate of anti-CCP in the whole FMF group (14.5%) was three-fold higher than the control group (4.7%). However, the difference failed to achieve a statistically significant level (p=0.09). Anti-CCP levels were 21±30.1 in patients with arthritis and 13.1±10.3 in the non arthritic group (p<0.05). Anti-CCP positivity rates were 10/37 (27%) in patients with arthritis and 2/46 (4.3%) in patients without arthritis (p<0.005). Five FMF patients with arthritis (13.5%) had moderate-high anti-CCP levels (>40U/ml). Anti-CCP levels were between 20-39U/ ml in 2FMF patients without arthritis and in 2 healthy controls. Anti-CCP positivity rate is higher in FMF patients with arthritis (27%) than healthy controls (4.7%) (p<0.005). CONCLUSIONS: Anti-CCP prevalence is higher in FMF patients with arthritis than without arthritis, and that a significant proportion of FMF patients with arthritis (13.5%) had moderate-high titers of anti-CCP. Therefore, anti-CCP antibodies may not be a reliable indicator to differentiate between FMF arthritis and rheumatoid arthritis.

Demographic, clinical and mutational characteristics of Turkish familial Mediterranean fever patients: results of a single center in Central Anatolia.

Clinical and genetic findings of familial Mediterranean fever (FMF) may be variable in different populations. Environmental factors may also affect phenotypic features of FMF. In this study, we investigated demographic, clinical and mutational features of FMF patients who were treated in a single reference hospital in Turkey. Two hundred and sixty patients (169 females, 91 males, mean age 30.44 +/- 10.29 years) were included in this study. All patients were evaluated regarding MEFV gene mutations. The mean age of disease onset was 17.21 +/- 8.66 years (range 2-40 years). The mean duration between the disease onset and diagnosis was 9.39 +/- 8.92 years. Seventy percent of patients had symptoms before 20 years of age (early onset FMF). Arthritis and erysipelas like erythema (ELE) were more common, and the mean duration between the disease onset and diagnosis was longer in early onset FMF patients. The frequency of attacks per year, and disease severity score (DSS) was higher in early onset patients. Homozygote mutation of M694V was detected in 37 (20.2%) and 4 (5.2%) patients in early onset FMF and adult onset FMF groups, respectively (p < 0.05). Histological diagnosis of amyloidosis was established in 7 patients (2.7%). The age of disease onset was earlier, and arthritis and ELE were more frequent, and DSS was higher in patients with M694V/M694V mutation. In conclusion, mean delay to diagnosis in our FMF population is quite high. Early and adult onset forms may differ regarding some clinical, molecular and prognostic characteristics. Disease activity was higher in patients with homozygote mutation of M694V.

Atraumatic osteonecrosis after estrogen replacement therapy associated with low protein S level in a patient with Turner syndrome.

Atraumatic osteonecrosis has been associated with a variety of clinical conditions including corticosteroid usage, alcoholism, infections, hyperbaric events, storage disorders, marrow-infiltrating diseases, coagulation defects, and some autoimmune diseases. Osteonecrosis due to thrombophilia is an extremely rare condition with only few cases reported previously in the literature. Hormone-replacement therapies cause increased risk of venous thrombosis, probably by causing a synergistic effect with inherited clotting defects. In this article, we report a young female with Turner syndrome, who developed avascular necrosis of the femoral head during treatment with oral estrogen, which was associated with low protein S levels.

Idiopathic hypoparathyroidism mimicking diffuse idiopathic skeletal hyperostosis.

Idiopathic hypoparathyroidism is an uncommon disease caused by insufficient secretion of parathyroid hormone. Idiopathic hypoparathyroidism may cause various musculoskeletal findings, including diffuse ligamentous and entheseal ossifications. Diffuse idiopathic skeletal hyperostosis is a disorder of the elderly characterized by ossification of the anterior longitudinal ligament of the spine and various extraspinal ligaments. We present a 50-year-old man with idiopathic hypoparathyroidism who had been diagnosed as having DISH at 40 years of age. Resistant neck, left shoulder, and left hip pain did not improve with calcium and calcitriol treatment after diagnosis of idiopathic hypoparathyroidism.

Current perspectives on familial Mediterranean fever.

PURPOSE OF REVIEW: The gene responsible for familial Mediterranean Fever (FMF), MEditerranean FeVer (MEFV), was identified two decades ago; however, only recent studies have shed light on its pathogenesis. This review focuses on recent studies that have led us to more fully understand FMF pathogenesis. RECENT FINDINGS: The vast majority of FMF-associated mutations are located in the B30.2 (SPRY) domain, which functions as a ligand binding or a signal transduction domain, at the carboxy terminus of the protein. As a result, B30.2 mutations may lead to postponed apoptosis and inflammation due to the reduced ability of pyrin to control interleukin-1beta (IL-1beta) activation. Development of AA amyloidosis is rare in FMF patients without amyloidogenic single nucleotide polymorphisms (SNPs) (713T allele) of the SAA1 gene. High macrophage inflammatory protein-1alpha levels during FMF attacks might be responsible for the enhancement of T-cell mediated immunity in FMF. IL-1beta-511 (C/T), IL-1beta+3953 (C/T) and IL-1Ra VNTR polymorphisms were not associated with the development of amyloid in FMF patients. SUMMARY: Future studies should focus on defining the impact of MEFV and other mutations on the pathological course of FMF, and to understand the exact pathophysiology of those patients who are unresponsive to colchicine, which may help to develop novel therapeutic options for the management and improvement of prognosis.

Circulating hepcidin in the crossroads of anemia and inflammation associated with rheumatoid arthritis.

OBJECTIVE: To investigate the role of circulating hepcidin, which is a homeostatic regulator of iron metabolism and a mediator of inflammation, in anemia associated with rheumatoid arthritis. METHODS: Forty patients with rheumatoid arthritis (19 with anemia and 21 without anemia), 12 patients with iron deficiency anemia and 14 healthy adults were studied. Serum hepcidin levels were analyzed with hepcidin prohormone solid phase enzyme-linked immunosorbent assay. RESULTS: The mean serum hepcidin levels were significantly higher in patients with rheumatoid arthritis with anemia compared to healthy adults and those with iron deficiency anemia. The active rheumatoid arthritis group had significantly higher mean serum hepcidin levels than the inactive rheumatoid arthritis group. In the rheumatoid arthritis group, serum hepcidin levels were positively correlated with disease activity, but inversely correlated with hemoglobin levels. The serum hepcidin level was found to be a significant predictor for hemoglobin level. CONCLUSION: Serum hepcidin levels are closely associated with disease activity in rheumatoid arthritis patients and might play a role in the pathobiology of chronic disease anemia associated with rheumatoid arthritis.

Severe arterial thrombophilia associated with a homozygous MTHFR gene mutation (A1298C) in a young man with Klinefelter syndrome.

Klinefelter syndrome (KS) is the most common sex chromosome disorder in men. It may be associated with an increased risk for venous thrombosis and thromboembolism, which is partially explained by hypofibrinolysis due to androgen deficiency. Additional genetic or acquired thrombophilic states have been shown in KS patients complicated with venous thrombosis as isolated case reports. Arterial thrombotic events had not been previously reported in KS. In this study, a young man with KS who developed acute arterial thrombosis during testosterone replacement therapy is presented. He was homozygous for the A1298C mutation of the methylenetetrahydrofolate reductase (MTHFR) gene.

Intensified, intermittent, low-dose intravenous cyclophosphamide together with oral alternate-day steroid therapy in lupus nephritis (long-term outcome).

The objective of this study is to evaluate the efficacy, toxicity, and long-term outcome of low-dose IV cyclophosphamid therapy with repeated frequent intervals in combination with oral and IV methylprednisolone in patients with SLE nephritis. In this study, 113 patients diagnosed as having SLE and glomerulonephritis were assessed in between 1993 and 2002, with a median follow-up of 44.1+/-41.2 months. The patients were treated with 500 mg IV cyclophosphamide and 1 g IV methylprednisolone together with 60 mg/alternate-day oral methylprednisolone in a given schedule. The clinical and laboratory data were evaluated. There were significant improvements in the clinical and the laboratory parameters. Six patients died shortly after being hospitalized due to the disease activity itself. Eight patients were excluded from the study because of low compliance. The renal functions of the patients remained stable throughout the therapy; only 16/99 patients needed one or two additional pulses. Temporary leukopenia developed in 18/99 patients and diminished with the suspension or prolongation of the IV cyclophosphamide administration. Gastrointestinal side effects, which needed extra medication, developed in 20 patients. Hematuria was observed in 6/99 patients. Menstrual abnormalities were seen in 7/99 patients. No serious infections due to immunosuppression were observed with the given regimen. Hypertension was observed in 13 patients (minimum of 140/90 mmHg, maximum of 190/110 mmHg) and controlled with angiotensine-converting enzyme inhibitors. Mild central obesity was observed in 15 of the patients. Leimyosarcoma was observed in one patient who died during the follow-up period. Therapy starting with the weekly low-dose IV cyclophosphamide to induce remission together with IV and oral steroids, followed by prolonged intervals with the same doses for 2 years, appears to be useful in preserving renal function without major side effects in patients with lupus nephritis, in comparison to other studies.

Myocardial infarction and deep venous thrombosis in a young patient with Behçet disease.

Behçet disease (BD) is a chronic relapsing systemic vasculitic disorder affecting the arteries, veins, and vessels of any size. Vascular lesions in BD usually represent an occlusive nature suggesting a hypercoagulable/ prothrombotic state. Coronary arteries are rarely involved in BD. In this report, a 27-year-old male patient in whom myocardial infarction developed secondary to coronary arterial thrombosis together with deep venous thrombosis was presented. This is a review of the pathologic hemostasis and the prothrombotic state of BD.

Wegener's granulomatosis: clinical and laboratory results of a university hospital study of 20 patients from Turkey.

The aim of this study was to evaluate the clinical and laboratory features, the treatment approaches, and the long-term outcome of patients with Wegener's granulomatosis (WG) who were followed up in our hospital. The hospital files of the patients with the diagnosis of WG who were followed up between the years 1985 and 2003 in Hacettepe University Hospital were retrospectively evaluated. Male/female ratio was 12:8. The mean age was 39 years (range 20-65 years). Constitutional symptoms and upper and lower airway involvement were seen in 95% of all patients. Renal and musculoskeletal symptoms were seen in 90 and 80% of the patients, respectively. Five patients were treated with oral monotherapy (three with methylprednisolone and two with cyclophosphamide). Three patients were given a combination of orally administered cyclophosphamide and methylprednisolone. Ten patients were treated with pulse cyclophosphamide and methylprednisolone combination together with oral alternate-day methylprednisolone therapy. The remaining two resistant patients were treated with pulse cyclophosphamide, methylprednisolone, and intravenous immunoglobulin combination together with oral alternate-day methylprednisolone. Four patients died because of the disease activity. Intravenous pulse therapies with oral, alternate-day methylprednisolone were well tolerated. Sixteen patients experienced long-term remission after immunosuppressive treatment. Eleven patients have been asymptomatic for more than 12 months. In five patients, residual symptoms persisted: constitutional symptoms and renal and respiratory tract symptoms in varying combinations. The demographic and laboratory findings in this trial were similar with those of the previous results. Alternate-day glucocorticoids plus cyctotoxic drugs may be beneficial in patients with WG.

A multicenter study of patients with adult-onset Still's disease compared with systemic juvenile idiopathic arthritis.

Adult-onset Still's disease (AOSD) has often been regarded as the adult spectrum of systemic juvenile idiopathic arthritis (sJIA). The present study aims to compare the clinical and laboratory features, the disease course and the response to treatment in patients having AOSD with those having sJIA. Retrospective review of all available data that were filled out by adult and paediatric rheumatologists from six centers using a standard data extraction form was performed. A total of 95 patients with AOSD and 25 patients with sJIA were recruited for the study. The frequency of fever, rash, myalgia, weight loss and sore throat was higher in patients with AOSD. The pattern of joint involvement differed slightly. Laboratory findings were similar in both groups, except that liver dysfunction and neutrophilia were more common among adults. A multiphasic pattern dominated the childhood cases, whereas the most frequent course was a chronic one in adults. Corticosteroids and methotrexate were the most commonly employed therapy; however, chloroquine was another popular therapy in the adult group. We showed a difference in the rate of clinical and laboratory features between patients with AOSD and those with sJIA. AOSD and sJIA may still be the same disease, and children may simply be reacting differently as the result of the first encounter of the putative antigens with the immune system.

Development of calciphylaxis after long-term steroid and methotroxate use in a patient with rheumatoid arthritis.

Calciphylaxis may be considered a small vessel vasculopathy which is generaly associated with end-stage renal disease and hyperparathyroidism. The precise pathogenesis of the disease is not known. It needs sensitizers and challengers to occur. Steroids and immunosuppressive drugs including methotrexate are among those challenger agents. Calciphylaxis in collagen vascular diseases is rare. Only one case in rheumatoid arthritis was recently reported. Here we describe a case of calciphylaxis associated with active rheumatoid arthritis. This patient had active disease despite treatment of steroids and methotrexate for a long time. She died shortly after the diagnosis of calciphylaxis due to sepsis.

Association between neopterin and carotid intima-media thickness in hemodialysis patients.

BACKGROUND: Atherosclerotic lesions are heavily infiltrated by macrophages. Neopterin can be used as a marker of the activity of macrophages. Serum neopterin levels were elevated in non-renal patients with atherosclerosis. The intima-media thickness (IMT) of the carotid arteries in hemodialysis patients was significantly higher than in control subjects. In this study, we measured serum neopterin levels in hemodialysis patients and evaluated a possible correlation between neopterin levels and carotid IMT. PATIENTS AND METHODS: Thirty-seven hemodialysis patients (26 male/11 female, mean age 47 +/- 15 years) and 12 healthy subjects (8 male/4 female, mean age 43 +/- 10 years) were included in this study. Serum neopterin levels were measured by using a commercial ELISA kit. Carotid IMT of the subjects were measured by high-resolution B-mode ultrasonography. RESULTS: Carotid IMT values were 1.04 +/- 0.29 and 0.77 +/- 0.25 mm in hemodialysis patients and healthy controls, respectively (p < 0.01). Serum neopterin levels were 110.9 +/- 19.1 and 3.8 +/- 2.3 ng/ml in hemodialysis patients and healthy controls, respectively (p < 0.01). Serum neopterin levels were 103.2 +/- 21.3 ng/ml in hemodialysis patients with IMT < 1 mm (n = 15), and 116.7 +/- 15.4 ng/ml in hemodialysis patients with IMT > or = 1 mm (n = 22) (p < 0.05). Moreover, there was a significant correlation between serum neopterin levels and carotid IMT (p < 0.05, r = 0.363). CONCLUSION: Our findings suggest that neopterin could be associated with the severity of carotid atherosclerosis in hemodialysis patients.

Neutrophil CD64 expression in Behçet's disease.

OBJECTIVE: Hyperfunction of neutrophils is a characteristic finding in Behçet's disease (BD). Microbial agents have been proposed as causative agents in the disease flares. Fc gamma receptor 1 (CD64) is not normally expressed by neutrophils of healthy individuals, but is upregulated by these cells in response to microbial wall components and proinflammatory cytokines. The degree of polymorphonuclear leukocyte (PMN) CD64 expression is different in autoimmune diseases and systemic infectious diseases. We investigated PMN CD64 expression in patients with BD. METHODS: Thirty-seven patients with active BD (M/F: 18/19, mean age: 34.4 +/- 9.7 yrs), 35 patients with inactive BD (M/F: 11/24, mean age: 35.9 +/- 11.6 yrs), 27 patients with culture proven infections (M/F: 19/8, mean age: 54.4 +/- 15.2 yrs), 31 healthy controls (M/F: 14/17, mean age: 37.7 +/- 8.7 yrs), and 42 patients with active inflammatory disease (M/F: 13/29, mean age: 39.3 +/- 14.9 yrs) were enrolled in this study. Flow cytometry was used to assess the prevalence of CD64-bearing PMN in whole blood samples. RESULTS: The prevalence of CD64-bearing PMN was significantly higher in patients with infectious disease (77.1 +/- 18.4), inflammatory disease (37.1 +/- 27.5), and active BD (48.9 +/- 22.5) than in healthy controls (9.5 +/- 7.8) or patients with inactive BD (12.9 +/- 9.5). CD64 expression was similar in controls and patients with inactive BD. In the infectious disease group, expression of CD64 was significantly higher than in the active BD and active inflammatory disease groups, while there was no significant difference between the groups of patients with active BD and inflammatory disorders. CONCLUSION: Neutrophil CD64 expression increases during exacerbation of BD. This increase appears to be a non-specific inflammatory response and does not reflect PMN activation triggered by a living microorganism.

Transverse myelitis in a patient with Behcet's disease: favorable outcome with a combination of interferon-alpha.

We report here on a 24-year-old patient with Behcet's disease who had been diagnosed with acute transverse myelitis. He was successfully treated with a combination regimen of a steroids, cyclophosphamide, and interferon-alpha. The treatment strategy with specific emphasis on interferon-alpha is discussed in the light of the pertinent literature.

How hematopoietic stem cells know and act in cardiac microenvironment for stem cell plasticity? Impact of local renin-angiotensin systems.

Bone marrow-derived hematopoietic stem cells (HSC) can exhibit tremendous differentiation activity in numerous non-hematopoietic organs. This enigmatic process is called as 'stem cell plasticity' (SCP). HSC may promote structural and functional repair in several organs such as heart, liver, brain, and skeletal muscle via the SCP. The differentiation capacity of HSC is dependent on the specific signals present in the local tissue microenvironment. Those specific molecular signals required for the interactions of HSC and host tissues are currently unknown. The aim of this report is to propose a hypothesis on how HSC reach, recognize, and function in cardiac tissues in the context of SCP. Locally signaling cardiac microenvironment is essential for the seeding, expansion, and 'cardiomyocyte differentiation' of the HSC in the heart. Our hypothesis is that the receptors, ligands, and signaling pathways of the tissue renin-angiotensin system (RAS) serve as the link between HSC and local cardiac microenvironment in SCP. The RAS is considered as a 'tissue-based system' exhibiting paracrine functions within many organs. The presence of local hematopoietic bone marrow RAS and local cardiac RAS have been suggested. Both local tissue RASs share similar angiotensin peptide-signaling pathways such as JAK-STAT and mitogen-activated protein kinases. HSC have angiotensin type I (AT1a) receptors for the binding of angiotensin II, the active component of the RAS. Binding of angiotensin II to AT1a can increase hematopoietic progenitor cell proliferation. Local cardiac RAS has critical (patho)biological functions in the cardiomyocyte survival, renewal, and growth, as well as in cardiac remodeling. Therefore, the components of the local cardiac RAS and hematopoietic RAS could interact with each other during the SCP through myocardial tissue repair. Activation of the local myocardial RAS after injury may be related to homing and engraftment of the HSC to the cardiac tissue. Regenerating myocardial tissue may exert regulatory functions on circulating or resident HSC via the locally active RAS. Understanding the exact molecular basis of SCP in relation to local tissue RAS could offer new frontiers in the better management of ischemic cardiac diseases.

The efficacy of interferon-alpha in a patient with resistant familial Mediterranean fever complicated by polyarteritis nodosa.

Familial Mediterranean fever (FMF) is a recurrent self-limiting polyserositis. Polyarteritis nodosa (PAN) complicating FMF is very rare. Here, we present a 17-year-old male patient with FMF who subsequently developed PAN 2 weeks after hepatitis A infection. This case was also complicated with perirenal haematoma, and right nephrectomy was performed. The clinical condition of the patient was improved after therapy with intravenous and oral corticosteroid and intravenous cyclophosphamide. However, the FMF attacks and vasculitic skin lesions again occurred while he was using colchicine plus immunosuppressive agents a few months later. Interferon-alpha therapy was administered and the attacks were resolved within 3 months. He has not experienced any other symptom during the follow-up period of 28 months.