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.

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.

Anti-IL-6 receptor antibody (tocilizumab): a B cell targeting therapy.

BACKGROUND: IL-6 mediated inflammation is induced by binding to IL-6 receptor (IL-6R) or IL-6/IL-6R complex binding gp130. Tocilizumab, a recombinant humanised monoclonal antibody that acts as IL-6R antagonist has been recently introduced for the treatment of rheumatoid arthritis (RA). OBJECTIVES: To evaluate whether tocilizumab therapy may induce B cells to undergo phenotypic changes compatible with regulatory function. METHODS: B cells from treated RA patients were isolated before and after 3 months of treatment with tocilizumab and were stained for the expression of intracellular TGF-ß, IL-10, membrane CD69, and MHCII. These markers were assessed in CD25(high) B cells considered to belong to a regulatory/suppressive subset of B cells. All markers were expressed in mean flow cytometry intensity (MFI), with results given in mean ± SEM. Data was compared before and after tocilizumab treatment. RESULTS: Clinical improvement was noted three months following the initiation of tocilizumab, namely: DAS improvement from 6.8 ± 0.3 at baseline to 3.1 ± 0.4, p<0.002, and ESR decrease from 44.4 ± 8.6 at baseline to 7.4 ± 2.3, p<0.006. This clinical benefit was found to occur in association with the expansion of a B cell subset with regulatory properties namely: the expression of intracellular TGF-ß in CD25-high B cells was significantly increased (from 5.2 ± 2.3 at baseline to 8.1 ± 2.8; p<0.02); In addition, the expression of MHC-II and of CD69 on B cells were significantly reduced (from 9.1 ± 2.2 at baseline to 4.2 ± 0.4; p<0.04), and (from 7.6 ± 2.4 at baseline to 2.7 ± 0.7; p<0.03) respectively. CONCLUSIONS: The present finding of a shift in B cell properties following tocilizumab treatment, namely the increase in TGF-ß expression and the alteration in the activation status (CD69 expression) and APC properties (MHC-II expression) in CD25(high) B cells, suggests that the induction/expansion of B regulatory cells may be one of the mechanisms by which tocilizumab may possibly produce its beneficial clinical effects.

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.

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.

The emergency room in systemic rheumatic diseases.

Complications of systemic rheumatic diseases frequently have protean manifestations and may present a diagnostic problem. Patients with connective tissue diseases and vasculitides may have dangerous or life threatening conditions, which must be recognised and treated promptly to prevent rapidly evolving morbidity and mortality. Knowledge of possible emergencies in the context of a defined rheumatic disease may aid in promoting a high index of suspicion and contribute significantly to the timely diagnosis of many potentially dangerous conditions. This review is written for the emergency room physician and discusses the early recognition of selected emergencies in the context of a defined rheumatic 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.

The patient with supine hypertension and orthostatic hypotension: a clinical dilemma.

Coexistent supine hypertension and orthostatic hypotension (SH-OH) pose a particular therapeutic dilemma, as treatment of one aspect of the condition may worsen the other. Studies of SH-OH are to be found by and large on patients with autonomic nervous disorders as well as patients with chronic arterial hypertension. In medical practice, however, the aetiologies and clinical presentation of the syndrome seem to be more varied. In the most typical cases the diagnosis is straightforward and the responsible mechanism evident. In those patients with mild or non-specific symptoms, the diagnosis is more demanding and the investigation may benefit from results of the tilt test, bedside autonomic tests as well as haemodynamic assessment. Discrete patterns of SH-OH may be recognisable. This review focuses on the management of the patient with coexistent SH-OH.

Nonspecific dizziness: frequency of supine hypertension associated with hypotensive reactions on head-up tilt.

The clinical syndrome of supine hypertension associated with orthostatic hypotension (OH) in given individuals is recognized by specialists, but is underdiagnosed in the community. The objective of this study was to assess supine hypertension associated with hypotensive reactions on head-up tilt (SH-HRT) among patients evaluated for nonspecific dizziness. Consecutive patients with nonspecific dizziness were studied with a 10-min supine 30-min head-up tilt test. Supine hypertension (SH) was diagnosed when supine systolic blood pressure (SBP) was > or = 140 mmHg and/or supine diastolic blood pressure (DBP) was > or = 90 mmHg. Hypotensive reactions on tilt (HRT) were diagnosed when SBP decreased by > or = 30 mmHg on tilt and/or DBP decreased by > or = 15 mmHg. Of 430 patients tested, 42 (9.8%) had SH-HRT. The median age was 67 years; 37 had a pretest diagnosis of hypertension, with treatment. The median supine BP was 162/90 mmHg; the median nadir BP on tilt was 118/78 mmHg. Four SH-HRT patterns were recognized: (I) SH with typical neurogenic OH (n = 6), (II) SH with vasovagal reaction on tilt (n = 4), (III) SH with sustained HRT (n = 28), and (IV) SH with mixed orthostatic-vasovagal reaction on tilt (n = 4). Dizziness on tilt occurred in 25% of patients category III (SH with sustained HRT), while appearing universally in other SH-HRT patterns. In conclusion, nonspecific dizziness may be the chief complaint in patients with SH-HRT, a disorder often unrecognized by clinicians. Different patterns of SH-HRT on HUTT may reflect different aberrations in cardiovascular homeostasis and may require differentiated management strategies.

Statin escape phenomenon: Does it really exist?

BACKGROUND: The normalization of blood lipid profile has become an accepted method of primary and secondary prevention of vascular disease, with statins being the most popular group of medicines prescribed to lower cholesterol and LDL cholesterol levels. The failure of statins, administered in an appropriate dose, to maintain the optimal level of LDL cholesterol is a rare phenomenon, and is still not well understood in patients compliant for both medication and diet. The entity of "statin escape phenomenon", proposed to explain the failure of statins in some of these patients, has not been studied or characterized extensively, and reports of its prevalence are scarce. METHODS: Patients with hyperlipidemia type 2a or 2b who had been treated with statins for at least 1 year and who were followed up in the lipid clinic on a regular basis every 3-4 months were included in this study. The charts of patients whose LDL cholesterol levels were elevated by 15% or more while receiving the same treatment were analyzed, and patients with putative statin escape phenomenon were included in the study and further characterized. RESULTS: Forty-five of 358 statin-treated patients demonstrated a 15% increase in LDL cholesterol levels, leading to suspicion of statin escape phenomenon. However, a strict exclusion analysis left only two patients without evident potential triggers for the observed elevation in LDL cholesterol. CONCLUSIONS: Whether a statin escape phenomenon really exists is still not certain, but if it does exist, it is probably an uncommon event with a low prevalence.

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.

Hyperventilation and amplified blood pressure response: is there a link?

Based on prior studies, the hypothesis that hyperventilation (HV) may have a pressor effect and play a causal role in hypertension has been suggested. The objective of this study was to correlate HV with blood pressure (BP)-change during a postural challenge. Consecutive subjects referred for evaluation of syncope, dizziness, chronic fatigue syndrome (CFS), fibromyalgia, or non-CFS fatigue were assessed with a 10-min supine 30-min head-up tilt test combined with capnography. We selected for analysis the records of patients aged 17-70 years, not taking vasoactive medications, having sitting systolic BP (SBP) < 140 mmHg, sitting diastolic BP (DBP) < 90 mmHg, and who completed 30 min of tilt. HV was diagnosed when end-tidal pressure of CO2 < 30 mmHg was recorded consecutively for > or = 10 min. Postural hypertension (PHT) was diagnosed when DBP on tilt > or = 90 mmHg was recorded consecutively for > or = 10 min. DBP-change was computed as (median DBP on tilt) -(median DBP supine). PHT and DBP-change were correlated with HV. A total of 320 patient charts were reviewed. PHT was present in 30 cases. The mean DBP-change in patients with PHT was +9.9 mmHg (s.d. 5.8), with three patients manifesting HV. Of the remaining 290 patients, 56 had HV, their mean DBP-change was -0.3 mmHg (s.d. 7.2). The other 234 patients without HV had a mean DBP-change +0.95 mmHg (s.d. 5.7), comparable to the DBP-change in patients with HV. In, conclusion, posturally induced HV was not associated with an increase in BP, nor was PHT associated with HV, except in a small minority of cases.

Peripheral B-cell CD5 expansion and CD81 overexpression and their association with disease severity and autoimmune markers in chronic hepatitis C virus infection.

Hepatitis C virus (HCV) infection is associated with immune-mediated abnormalities and B-cell lymphoproliferation evolving to an overt lymphoma. Recently, CD81 was identified as an HCV receptor on B-lymphocytes, providing a mechanism by which B cells are infected and activated by the virus. In addition, expansion of CD5+ B lymphocytes was described to be associated with various non-HCV related autoimmune disorders. Therefore, we studied the possible role of peripheral B cells CD81 and CD5 over-expression in the development of HCV-related autoimmunity and their association with disease severity in chronic HCV infection. Peripheral B cells CD5 expression and mean fluorescence intensity (MFI) of CD81 were determined in 30 HCV-infected patients, 30 healthy controls and 15 patients with hepatitis B virus infection using fluorescence-activated cell scan (FACS). We have also investigated the association between peripheral CD5 and CD81 B-cell over-expression and markers of autoimmunity and disease severity in patients chronically infected by HCV. CD5+ B-cells were increased in chronic HCV infection (23.2 +/- 7.2%) compared with those of healthy controls (15 +/- 5.5%) (P < 0.0001) and chronic HBV infection (19 +/- 3.7%) (P = 0.08). CD81 MFI was significantly higher in HCV-infected compared to HBV-infected patients and healthy controls. Both increased CD81 MFI and CD5+ B-cell expansion were associated with the production of rheumatoid factor and mixed cryoglobulins and positively correlated with HCV viral load and histological activity index. The overexpression of CD81 and the expansion of CD5+ peripheral B-cells in HCV-infected patients may possibly play a role in the development of HCV-associated autoimmunity and lymphoproliferation.

Enhanced peripheral T-cell apoptosis in chronic hepatitis C virus infection: association with liver disease severity.

BACKGROUND/AIMS: It has been suggested that enhanced T-cell apoptosis in hepatitis C virus (HCV) infection may lead to down-regulation of their cellular immune response, thus contributing to the persistency of HCV infection. In the present study we have investigated the role of bcl-2 and nuclear factor kappa B (NFkappaB) in dexamethasone-induced apoptosis of peripheral T cells in chronic HCV infection. METHODS: The expression of bcl-2 and NFkappaB in peripheral T cells as well as spontaneous and dexamethasone-induced T-cell apoptosis were studied in HCV-infected patients (n=21), hepatitis B virus (HBV)-infected patients (n=14) and healthy individuals (n=19). These parameters were correlated with markers of autoimmunity and disease severity. RESULTS: NFkappaB, but not bcl-2 expression, was significantly decreased in the HCV-infected patients. This decrease was associated with the presence of mixed cryoglobulins (MC) and rheumatoid factor and was positively correlated with alanine aminotransferase (ALT) levels and histological activity index (HAI). Both spontaneous and dexamethasone-induced T-cell apoptosis were enhanced in HCV-infected patients; however, only the latter was correlated with the presence of MC, ALT levels and HAI. CONCLUSIONS: We confirm previous reports that enhanced T-cell apoptosis in HCV infection may play an important role in disease severity. Decreased expression of NFkappaB is important in the development of peripheral T-cell apoptosis, thus contributing to viral persistence and autoimmunity in these patients.

Hepatitis C virus-related arthritis: characteristics and response to therapy with interferon alpha.

OBJECTIVE: To characterize hepatitis C virus (HCV)-related arthropathy and to evaluate the response to treatment with interferon-alpha (INF-alpha). METHODS: We studied 28 HCV-infected patients with arthritis. All patients underwent complete clinical, laboratory and radiological evaluation, including assessment and follow-up by a rheumatologist. Twenty-five patients were treated with INF-alpha for a median period of 12 months. RESULTS: All patients were HCV-RNA positive (genotype 1b in 65%). The mean duration of arthropathy-related symptoms prior to the diagnosis of HCV infection was 12 months. 19 patients (68%) had symmetric polyarthritis and 19 (68%) had morning stiffness > or = 60 min. None of the patients had erosive disease or subcutaneous nodules. 12 (43%) had detectable cryoglobulin (mean cryocrit: 3.6 +/- 3.5%), 17 (61%) had rheumatoid factor (RF) (median titer: 1:80), and only 15 (54%) had elevated ESR. 14 patients (50%) had > or = 4 ACR (American College of Rheumatology) criteria for the diagnosis of rheumatoid arthritis (RA), 9 of whom were mistakenly diagnosed and previously treated as RA patients. Only 3 patients had a satisfactory response to previous treatment with anti-inflammatory or disease modifying drugs. Complete or partial response of arthritis-related symptoms in INF-alpha treated patients was observed in 44% and 32%, respectively. Cryoglobulin became undetectable in 9 of 12 patients. However, a complete biochemical and virological end-of-treatment response was achieved in only 8 (36%) and 5 patients (20%), respectively. CONCLUSION: HCV arthropathy should be considered in the differential diagnosis of any patient with arthritis, even in the absence of liver disease. Treatment with interferon-alpha may lead to substantial clinical improvement of HCV-related arthritis even without a complete biochemical or virological response.