Von Willebrand factor: a possible biomarker for disease activity in vasculitis.

OBJECTIVE: Inflammation markers, e.g. C- reactive protein (CRP) and sedimentation rate, can be normal despite active vasculitis. Von Willebrand factor (vWF) is secreted from endothelial cells in response to vascular damage. Some reports suggest increased vWF levels in vasculitis. This study aimed to evaluate vWF serum concentration in vasculitis patients as a possible biomarker of disease activity and to review the current literature. METHOD: Adult patients with systemic vasculitis were prospectively enrolled. Disease activity was recorded using the Birmingham Vasculitis Activity Score (BVAS) version 3. Blood group-adjusted vWF antigen serum level was evaluated at diagnosis and, when available, after treatment. RESULTS: Twenty-five vasculitis patients were compared to 15 healthy controls. The mean age of patients was 56 ± 17 years and 56% were women. Forty percent had anti-neutrophil cytoplasmic autoantibody-associated vasculitis, 20% giant cell arteritis, 16% polyarteritis nodosa, 8% Takayasu arteritis, and the rest had other vasculitides. The mean disease duration was 3.4 ± 4.8 years. Mean vWF was higher in patients with active vasculitis than in healthy controls (212 ± 81% vs 106 ± 26%, p < 0.001). vWF levels directly correlated with BVAS. In 13 patients with active vasculitis who reached remission or low disease activity after treatment, vWF level at follow-up decreased significantly. In three out of five patients who were treated with interleukin-6 inhibitors, vWF was elevated despite normal CRP levels, while vasculitis was clinically active. CONCLUSION: vWF antigen serum level is increased in active vasculitis and could potentially serve as a biomarker for active disease.

Aortic involvement in rheumatic diseases.

OBJECTIVE: To review the prevalence, mechanisms, presentations and clinical significance of aortic involvement in rheumatic inflammatory diseases. METHODS: The medical literature, available through a PUBMED search was reviewed and the relevant information was summarized. In addition, selected articles related to aortic involvement in rheumatic diseases were included in this review. RESULTS: Rheumatic disorders may be categorized by their propensity to involve the aorta: conditions with a prevalence of 10% and more (Takayasu's arteritis, temporal arteritis, long-standing ankylosing spondylitis, Cogan's syndrome and relapsing polychondritis), disorders with uncommon but well documented aortic involvement and rheumatic conditions with rare case reports of such involvement. Clinical presentation of aortic disease is dependent on the part of aorta involved and may manifest by aortic pain and/or other symptoms caused by aortic dilatation, narrowing or aneurysm. The histopathology of inflammatory aortitis is characterized by lymphoplasmacytic infiltration with or without giant cells or granulomas. On the other hand, non-inflammatory aortic damage in rheumatic diseases may include Marfan-like cystic disintegration of the aortic media as well as accelerated atherosclerosis. Awareness of rheumatic conditions with a high potential for clinically significant aortic involvement may promote referral of such patients for aortic imaging and sometimes surgery before fatal complications intervene. CONCLUSION: Early diagnosis of aortic involvement can be advanced by informed consideration of such a complication in a rheumatic patient.

Pseudopodagra: A presenting manifestation of infective endocarditis.

Podagra is a term used to describe acute monoarthritis of the first metatarsophalangeal (1st MTP) joint. The most common diagnoses of arthritis in this joint are: crystal-induced synovitis, septic arthritis, traumatic conditions and reactive arthritis. When etiologies other than gout are involved this is frequently referred to as pseudopodagra. We report the case of a patient who presented with pain and swelling of the 1st MTP The absence of intraarticular crystals and hyperuricemia encouraged further evaluation of the patient. A cardiac murmur was investigated by echocardiography, which revealed valvular vegetations and the diagnosis of infective endocarditis (IE) was established. This is the first reported case of a podagra-like presentation of IE. As in this case, the diagnosis of gout should rest on findings beyond the presence at 1st MTP arthritis, with evaluation of all extraarticular signs in order to rule out other possible diagnoses.

Behçet's disease, myelodysplastic syndrome, trisomy 8, gastroenterological involvement--an association.

Only a limited number of cases of Behçet's disease and hematological malignancies have been reported in the literature. We report the case of a 45 year old female patient with Behçet's disease who developed myelodysplastic syndrome, refractory anemia with excess blasts in transformation subtype, with complex chromosomal abnormalities, including excess of chromosome 8, following several years of treatment with chlorambucil for Behçet's disease. As has been described in most such cases, gastrointestinal involvement was most prominent. This case is described and the occurrence of myelodysplastic syndrome in Behçet's disease reviewed.

Increased C-reactive protein levels in the polycystic ovary syndrome: a marker of cardiovascular disease.

The polycystic ovary syndrome (PCOS), one of the most common reproductive abnormalities, shares some components of the metabolic cardiovascular syndrome. Therefore, PCOS patients may represent the largest group of women at high risk for the development of early-onset cardiovascular disease (CVD) and/or diabetes. C-reactive protein (CRP) is a strong independent predictor of future CVD and/or stroke. Only one small published study has looked for such an association (17 PCOS patients vs. 15 controls). The objective of this study was to compare the levels of CRP and other risk factors of CVD in a large group of PCOS patients and controls. CRP measurements were undertaken in 116 PCOS patients and 94 body mass index-matched controls with regular menstrual cycles. Whereas 36.8% of the PCOS patients had CRP levels above 5 mg/liter, only 9.6% of the controls exhibited high CRP levels (P < 0.001). The mean +/- SD was 5.46 +/- 7.0 in the PCOS group vs. 2.04 +/- 1.9 mg/liter in the control (P < 0.001). The body mass index, white blood cell count, TSH, glucose, cholesterol, and homocysteine levels were not significantly different between the two groups. CRP levels are elevated in patients with PCOS and may be a marker of early cardiovascular risk in these patients. High CRP levels may explain why some PCOS women may possibly be at an increased risk for the development of early-onset CVD. Consequently, whether treatment regimens directed toward lowering CVD risk factors should be more aggressive for those PCOS women with increased CRP levels, awaits further clinical experience.

The role of regulatory T cells in familial Mediterranean fever (FMF).

The role of regulatory T cells (T-regs) in familial Mediterranean fever (FMF) was never evaluated. Preliminary studies that we have conducted suggested a rise in the number of regulatory T cells after FMF attacks reaching a maximal level at 7 days. The aim of this study was to evaluate the percentage and activity of regulatory T cells in FMF. Six patients with refractory FMF and six healthy controls were evaluated. The percentage of T-reg cells and forkhead box protein 3 (Foxp3) expression was evaluated and compared between four states: FMF in remission, FMF at the first day of an attack, FMF 7 days after the start of the attack, and healthy controls. Four females and two males were included. All patients had FMF with high severity score, 2.8 ± 0.4 (0-3). The mean age was 31.6 ± 6.2. The mean age at onset was 9.3 ± 9.3. The mean colchicine dose was 2.6 mg ± 0.4. The expression of Foxp3 7 days after the attacks was significantly higher than in FMF at the first day of the attack, FMF in remission, and healthy controls 10.08 ± 2.36 vs. 7.005 ± 0.3 vs. 5.3 ± 1.06 vs. 4.44 ± 1.8; p < 0.05 (Fig.1). The percentage of T-regs in peripheral blood was not statistically different between the four groups. Theexpression of Foxp3 by T-regs increases 7 days after attacks of FMF. Anti-inflammatory cytokines interleukin-10 and TGF-ß are known to activate T-regs and have been reported to increase in FMF attacks in line with the present findings. It is suggested that T-regs may have a role in terminating FMF attacks.

Changes in macrophage function after rituximab treatment in patients with rheumatoid arthritis.

OBJECTIVE: To assess changes in macrophage phenotype and function after rituximab-induced B cell depletion in patients with rheumatoid arthritis (RA). METHODS: 10 patients with RA were treated with rituximab, achieving significant B cell depletion 4 months later. Clinical improvement, rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP) antibodies, mRNA of B cell activating factor (BAFF), interleukin (IL) 10 and CD86 in human monocyte-derived macrophages (HMDMs) and tumour necrosis factor alpha (TNFalpha) secretion from cultured HMDMs were assessed at baseline and after the depletion. RESULTS: A clinical response of American College of Rheumatology (ACR) 50% improvement was noted in six patients, and another two patients responded with moderate improvement, equivalent to ACR 20-50% improvements. RF and anti-CCP antibodies were positive at baseline in seven of ten patients. RF disappeared or declined in six patients 4 months after treatment, correlating with clinical improvement. By contrast, anti-CCP remained unchanged in six patients. After rituximab treatment, and in association with clinical improvement, BAFF, IL10 and CD86 mRNA expression in HMDM were significantly upregulated compared with values at baseline. A significant decrease in TNFalpha in the supernatant of cultured HMDM was also noted. CONCLUSIONS: In addition to B cell depletion and attenuation in some of the specific autoantibodies, clinical improvement in rituximab-treated patients with RA occurred in association with changes in macrophage function.

Behcet disease in adult Druzes in north Israel: the influence of ethnic origin on disease expression and severity.

BACKGROUND: Behcet's disease (BD) is known to vary in severity and manifestations in different populations. OBJECTIVE: In an attempt to sort out genetic and environmental influences on disease expression, we carried out a study to assess the clinical features of BD in the adult Druze and Arab populations in north Israel, comparing 2 disparate ethnic groups of similar genetic background inhabiting the same geographic region. METHODS: We compared 23 Druze and 30 Arab patients with BD. All patients fulfilled the classification criteria of the International Study Group for BD. RESULTS: Manifestations were similar in 2 groups. The most frequent BD manifestations among the Druzes were recurrent oral aphthae (100%) and genital aphthae (61%) versus 100% and 53% in Arab patients, followed by inflammatory ocular involvement, 65% versus 53%, respectively. Arthritis was noted in 39% of Druze, with 27% in Arabs. Anterior uveitis occurred in 9 Druze patients (48%) and panuveitis in 4, with no case of blindness when compared with 30% with anterior uveitis, 4 with panuveitis, and 4 cases of blindness (P < 0.04) among the Arabs. One Druze BD patient had deep vein thrombosis versus 8 Arab patients (P < 0.017). No pulmonary embolism, aortic aneurysm, nor valvular involvement was documented in the Druze versus 1 case of each in Arabs. No case of neuro-Behcet was reported in Druzes versus 6 cases of neuro-Behcet among Arabs (P < 0.023). The severity score was 4.0 (SD, 1.2) in Druze and 5.8 (SD, 1.9) in Arabs (P = 0.0004). The prevalence of HLA B51 did not differ significantly between the groups. CONCLUSION: Druze BD patients in Israel have a milder disease than do Arabs, similar to observations in familial Mediterranean fever. Druze BD patients had significantly less severe ocular disease and neurologic manifestations. Our results suggest an ethnic influence on expression of BD not related to HLA B 51.

High C-reactive protein levels are associated with oral hormonal menopausal therapy but not with intrauterine levonorgestrel and transdermal estradiol.

OBJECTIVE: Oral hormone replacement therapy (HRT) has been linked to increased cardiovascular (CVD) morbidity. HRT causes a sustained increase in C-reactive protein (CRP), an excellent marker of subclinical inflammation and CVD. The aim of the study was to support our hypothesis that CRP, which is synthesized in the liver, is not increased in association with transdermal/intrauterine HRT. MATERIAL AND METHODS: A case-control study was performed in which CRP measurements in women receiving levonorgestrel intrauterine system combined with transdermal estradiol (LNG/TDE, n=27) were followed for 9 months or longer. CRP concentrations in these women were compared with those of either oral HRT users (n=20) or controls (n=19). RESULTS: No significant differences were found in CRP concentrations between the LGN/TDE and control groups (1.8+/-1.2 and 1.8+/-1.8 mg/L, respectively). However, CRP was significantly increased in the oral HRT group (5.5+/-2.9 mg/L, p<0.001). CONCLUSIONS: CRP is significantly increased by oral HRT but not by the LNG/TDE combination after 9 months of treatment. This trend may explain the preponderance of some menopausal women on HRT being at increased risk for the development of CVD. Therefore, the use of LNG/TDE is acceptable for relief of severe climacteric symptoms possibly not imposing an increased CVD risk documented upon oral HRT.