Itzhak Rosner

Rheumatic syndromes: Clues to occult neoplasia

Rheumatic disorders associated with cancer include a variety of conditions, most of which have no features distinguishing them from idiopathic rheumatic disorders. It is generally held that an extensive search for occult malignancy in most rheumatic syndromes is not recommended unless the case is accompanied by specific findings suggestive of malignancy. Within the past year information has accumulated on the role of long-standing rheumatic disorders as premalignant conditions and the role of autoantibodies as screening tests for occult cancer. The present article discusses cancer-associated rheumatic syndromes, calls attention to aspects that may suggest the presence of a hidden cancer, and examines the role of laboratory tests as clues of a possible neoplastic etiology of those syndromes.

Pulse transit time by R-wave-gated infrared photoplethysmography : Review of the literature and personal experience

Objective. Pulse transit time (PTT) is the time it takes a pulse wave to travel between two arterial sites. A relatively short PTT is observed with high blood pressure (BP), aging, arteriosclerosis and diabetes mellitus. Most methods used for measuring the PTT are cumbersome and expensive. In contrast, the interval between the peak of the R-wave on the electrocardiogram and the onset of the corresponding pulse in the finger pad measured by photoplethysmography can be easily measured. We review herein the literature and impart the experience at our institution on clinical applications of R-wave-gated photoplethysmography (RWPP) as measurement of PTT. Methods. The MEDLINE data base on clinical applications of RWPP was reviewed. In addition, studies performed in the author’s institution are presented. Results. When used as a surrogate for beat-to-beat BP monitoring, RWPP did not meet the level of accuracy required for medical practice (two studies). RWPP produced accurate and reproducible signals when utilized as a surrogate for intra-thoracic pressure changes in obstructive sleep apnea, as well as BP arousals which accompany central sleep apnea (five studies). In estimation of arterial stiffness, RWPP was unsatisfactory (one study). In assessment of cardiovascular reactivity, abnormal values of RWPP were noted in autonomic failure (one study), while disease-specific reactivity patterns were identified utilizing a method involving RWPP (two studies). Conclusions. In clinical practice, sleep-apnea may be accurately monitored by RWPP. RWPP seems to reflect autonomic influences and may be particularly well-suited for the study of vascular reactivity. Thus, further descriptions of disease-specific cardiovascular reactivity patterns may be possible with techniques based on RWPP. Other clinical uses of RWPP are investigational.

Increased Spontaneous Apoptosis of CD4+CD25+ T Cells in Patients with Active Rheumatoid Arthritis Is Reduced by Infliximab

Abstract: Increased secretion of tumor necrosis factor‐alpha (TNF‐α), along with interleukin‐1 (IL‐1) and interleukin‐6 (IL‐6), is important in the pathogenesis of rheumatoid arthritis (RA). T regulatory CD4+CD25+ cells play a role in maintaining self‐tolerance by downregulating Th1‐induced proinflammation. This function has been found to be altered in active RA, whereas anti‐TNF‐α therapy has been found to improve the suppressive abilities of these cells. Our objectives were to investigate whether T regulatory cells in patients with active RA display a higher sensitivity to spontaneous apoptosis than in normals, and to look into the potential of infliximab (anti‐TNF‐α therapy) to reduce the sensitivity of these cells to spontaneous apoptosis. Seventeen patients suffering from active RA, having failed multiple disease‐modifying antirheumatic drug (DMARD) therapies, were treated with infliximab. Spontaneous apoptosis (as detected by annexin V binding) was determined in all patients and compared with a group of normal individuals at baseline and after three months on infliximab treatment. Peripheral blood mononuclear cells were incubated in 24‐well plates at 1 × 106 cells/mL for 48 hours. Annexin V binding on CD4+CD25+ was assessed using three‐color assay by flow cytometry. Prior to infliximab initiation, spontaneous apoptosis of T regulatory cells from active RA patients was found to be increased in comparison with controls (26 ± 4.2% vs. 19.8 ± 4.8%, respectively; P= 0.01). Three months later (while still on infliximab) spontaneous apoptosis was comparable in the two groups (20.7 ± 5.2% vs. 20.9 ± 3.4%; P 5 0.8). The absolute number of CD4+CD25+ cells/mL in the peripheral blood at baseline was reduced in 11 out of 17 active RA patients when compared with that of the control group (24 ± 7 vs. 32 ± 11, respectively; P= 0.02). Following anti‐TNF‐α therapy, CD4+CD25+ cell counts of patients were equivalent to those of normals. The alteration and reversal in both spontaneous apoptosis and cell count of T regulatory cells was found to correlate with RA disease activity. CD4+CD25+ T regulatory cells display increased proclivity to undergo spontaneous apoptosis in active RA. Alterations in CD4+CD25+ cell apoptosis and cell count were found to correlate with RA disease activity. Reversal of these deviations from normal was documented in association with the beneficial outcome of infliximab therapy.

Regulatory T cells (CD4+CD25brightFoxP3+) expansion in systemic sclerosis correlates with disease activity and severity

BACKGROUND The role and function of T regulatory (Treg) cells have not been fully investigated in patients with systemic sclerosis (SSc). METHODS Ten patients with SSc donated 20ml of peripheral blood. Activity (Valentini) and severity (Medsger) scores for SSc were calculated for all patients. Healthy volunteers (controls) were matched to each patient by gender and age. CD4(+) cells were separated using the MACS system. The numbers of Treg cells were estimated by flow cytometry after staining for CD4, CD25, and FoxP3 and calculated as patient-to-control ratio separately for each experiment. Correlations with activity and severity indices of the disease were performed. Twenty-four-hour production of TGF-beta and IL-10 by activated CD4(+) cells was measured by ELISA in culture supernatants. RESULTS The numbers of Treg cells, expressed as patient-to-control ratio, correlated significantly with both activity and severity indices (r=0.71, p=0.034 and r=0.67, p=0.044, respectively). ELISA-measured production of TGF-beta and IL-10 by CD4(+) cells was similar in patients and controls. CONCLUSIONS Increased numbers of Treg cells are present in patients with SSc, correlating with activity and severity of the disease. This expansion of Treg cells was not accompanied, however, by heightened TGF-beta or IL-10 production. Further studies to elaborate the causes and functional significance of Treg cell expansion in SSc are needed.

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 α (TNFα) 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 TNFα 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.

Rituximab: Beyond Simple B Cell Depletion

Rituximab, a chimeric anti-CD20 monoclonal antibody, has a proven track record for over a decade in the treatment of lymphomas, where it has been used to eradicate malignant lymphocytes. In appreciation of the putative role of B cells, especially with respect to autoantibody production, in the pathogenesis of autoimmune diseases, successful trials of B-cell depletion therapy in RA, SLE, and other autoimmune diseases have been carried out. In these trials, clinical benefit has generally correlated with the extent and duration of B-cell depletion, but at times imperfectly, and autoantibody reduction only selectively. Additional mechanisms whereby rituximab may assert its clinical benefit in autoimmune diseases have been examined including a look at B-cell functions as T-cell modulator and antigen-presenting cell, T-regulatory cell behavior, NK cell activity, and macrophage activities in immune inflammation. The available data on rituximab’s action in autoimmune diseases is reviewed.

Prevalence and clinical aspects of Behcet's disease in the north of Israel.

Behcet’s disease (BD) has a higher prevalence in countries along the ancient silk route, but the actual prevalence in Israel is unknown. We evaluated the occurrence and clinical expression of BD in the northern region of Israel: in the whole population and by ethnic groups. The sample included all adult patients with BD (International Study Group criteria) treated at three medical centers in northern Israel. Patient data were collected by file review and physician survey. Relevant demographic data for the population served by the medical centers were obtained from the official Israeli authorities. A total of 112 patients were identified. The overall prevalence of BD was 15.2/100,000 and was similar in men and women. The prevalence rates among the Jewish, Arab, and Druze populations were 8.6, 26.2, and 146.4 per 100,000, respectively. Age at disease onset was similar in all ethnic groups and significantly lower in males (28.6±9.7 vs 32.9±11.3, p=0.03). There were no differences in disease manifestations by sex or ethnicity. All Druze patients were HLA-B5 positive, compared to 80.8% of the Arab patients and 72.0% of the Jewish patients. Recurrent oral ulcers in family members were more common in Arab patients (p=0.004). The BD severity index was significantly lower in Druze patients (p=0.05), mainly in males (p=0.03). This study confirms the high prevalence of BD in Israel and the variability in disease rates and expression by ethnic origin. Our findings, particularly regarding the Druze population, call for further field surveys and genetic studies.

Semaphorin 3A is a marker for disease activity and a potential immunoregulator in systemic lupus erythematosus

IntroductionSemaphorin 3A (sema3A) and neuropilin-1 (NP-1) play a regulatory role in immune responses and have a demonstrated effect on the course of collagen induced arthritis. This study was undertaken to evaluate the role of sema3A and NP-1 in the pathogenesis of systemic lupus erythematosus (SLE) and the specific effect of sema3A on the auto-reactive properties of B cells in SLE patients.MethodsThirty two SLE and 24 rheumatoid arthritis (RA) patients were assessed and compared with 40 normal individuals. Sema3A serum levels were measured and correlated with SLE disease activity. The in vitro effect of sema3A in reducing Toll-like receptor 9 (TLR-9) expression in B cells of SLE patients was evaluated.ResultsSema3A serum levels in SLE patients were found to be significantly lower than in RA patients (55.04 ± 16.30 ng/ml versus 65.54 ± 14.82 ng/ml, P = 0.018) and lower yet than in normal individuals (55.04 ± 16.30 ng/ml versus 74.41 ± 17.60 ng/ml, P < 0.0001). Altered serum sema3A levels were found to be in inverse correlation with SLE disease activity, mainly with renal damage. The expression of both sema3A and NP-1 on B cells from SLE patients was significantly different in comparison with normal healthy individuals. Finally, when sema3A was co-cultured with cytosine-phosphodiester-guanine oligodeoxynucleotides (CpG-ODN)-stimulated B cells of SLE patients, their TLR-9 expression was significantly reduced, by almost 50% (P = 0.001).ConclusionsThis is the first study in which a reduced serum level of sema3A was found in association with SLE disease activity. It also raises the possibility that sema3A may have a regulatory function in SLE.

Recently diagnosed axial spondyloarthritis: gender differences and factors related to delay in diagnosis

A cohort of patients with recently diagnosed axial spondyloarthritis (SpA) was characterized with emphasis on gender differences and factors leading to delay in diagnosis. Clinical, laboratory, and imaging data of 151 consecutive patients diagnosed with ankylosing spondylitis or undifferentiated SpA in 2004–2009 and satisfying the new ASAS classification criteria for axial SpA, was collected and analyzed. Seventy-nine men and 72 women were enrolled. Both groups (men and women) had similar age of onset of disease-related symptoms, as well as similar delay time to diagnosis, follow-up duration and frequency of anti-TNF treatment. Inflammatory back pain, as a first symptom related to SpA, was reported more often by men, while women had more pelvic, heel, and widespread pain (WP) during the course of the disease. At the time of diagnosis, men were more limited in chest expansion and showed increased occiput-to-wall distance compared to women. Elevated erythrocyte sedimentation rate and/or C-reactive protein were detected in a similar proportion of men and women. Presence of WP in women almost doubled the delay in the diagnosis of SpA. No other differences in disease presentation or burden were demonstrated to correlate with delay in diagnosis.

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.