Michael Rozenbaum

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.

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.

The synergistic efficacy of adalimumab and pamidronate in a patient with ankylosing spondylitis

A patient with ankylosing spondylitis, after demonstrating incomplete clinical response to adalimumab, received three monthly infusions of pamidronate along with continuing TNF-α blockade. Complete disappearance of the back pain was reported after the second pamidronate infusion. The perspectives of the combination therapy with TNF-α inhibitor and pamidronate are discussed.

Pamidronate treatment in rheumatology practice: a comprehensive review

Pamidronate, along with other bisphosphonates, has been used for treatment of bone pain secondary to malignant involvement or metastatic disease for years. Some data, however, have also accumulated on the utility of pamidronate in a variety of benign conditions frequently handled by rheumatologists. This study aims to review the available published data regarding the potential use of pamidronate in rheumatology practice. Methods include the review of relevant articles retrieved by a PUBMED search utilizing the index term “pamidronate”. All available randomized control trials, open trials, and case series, as well as properly reported case studies evaluating usage of pamidronate in rheumatic disorders, have been included in the literature review. The efficacy of pamidronate in patients with spondyloarthropathies; synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome; hypertrophic osteoarthropathy; osteoporotic vertebral fractures; chronic back pain due to disk disease or spinal stenosis; Charcot arthropathy; transient osteoporosis; and complex regional pain syndrome-I, has been demonstrated in more than 40 reports, the majority of which, however, were not controlled studies. In some of reviewed conditions, aside from providing analgesic relief, pamidronate may also have disease-modifying properties. While used in different doses in a variety of rheumatic disorders, pamidronate was generally reported to be well tolerated with an overall good safety profile. Pamidronate may represent an effective and safe choice for a spectrum of rheumatic patients, suffering from intractable musculoskeletal pain, unresponsive to traditionally recommended therapies. Large randomized, controlled studies examining the efficacy of pamidronate in the rheumatic conditions are urgently needed.

Weight change during pharmacological blockade of interleukin-6 or tumor necrosis factor-α in patients with inflammatory rheumatic disorders: A 16-week comparative study

BACKGROUND Interleukin (IL)-6 -/- mice develop spontaneous mature onset obesity, while the influence of the pharmacological blockade of IL-6 on body weight in humans has not been previously reported. The aim of the present study was to observe weight change in patients treated with tocilizumab (TCZ). METHODS Twenty-one consecutive patients who started new treatment with TCZ were enrolled in the study. Sixteen consecutive patients who started treatment with infliximab (IFX) formed the control group. Height and weight of all patients were registered and Body Mass Index (BMI) calculated before the first treatment and at week 16. The Mann-Whitney or paired Wilcoxon test were used for comparisons between or within groups, respectively. RESULTS The study demonstrated that treatment with TCZ was accompanied with significant weight gain and BMI increase (p=0.04), while IFX treatment did not result in any significant weight change during the 16-week period. CONCLUSIONS Weight gain can be seen in some patients during the pharmacological blockade of IL-6. The phenomenon and metabolic pathways involved should be further investigated.

Brucella aortitis: the missing link.

Dear Editor, Brucella is an endemic zoonotic infection in the Middle East. The spectrum of manifestations of Brucellosis is wide and includes: fever, weight loss, endocarditis, arthritis, discitis and rash. Brucella-associated aortic aneurysms have been rarely reported. Although an aortic aneurysm is the result of untreated aortitis, brucella aortitis has not been reported in the English literature. We herein report a case of brucella infection that manifested with a rare triad of abdominal aortitis, discitis/osteomyelitis and cutaneous leukocytoclastic vasculitis (Fig. 1). A 58-year-old man was admitted to our ward. He was suffering from fever and necrotizing palpable purpura with onset 1 week prior toadmission and low back pain for 1 year before admission. His laboratory results revealed mild normocytic anemia and elevated sedimentation rate, 70 mm/h, and C-reactive protein (CRP) level 80 g/dL. Immunological studies including antinuclear antibody, rheumatoid factor, anti-neutrophil cytoplasmic antibodies, C4, cryoglobulins, antistreptolysin-o and angiotensin converting enzyme levels were negative. Urinalysis was normal and blood cultures were sterile. Vegetations were not seen on echocardiography and ophthalmologic fundus examination was unrevealing. A skin biopsy was consistent with necrotizing leukocytoclastic vasculitis. Further evaluation included a computed tomography (CT) angiogram that demonstrated abdominal aortitis with adjacent lymphadenopathy and severe discitis and osteomyelitis of the fourth lumbar vertebra (L4), which were confirmed by technetium bone scan. A magnetic resonance imaging (MRI) scan also revealed a small abscess invading the right psoas. At that point, a Rose Bengal brucellosis screening test was found positive, with Brucella melitensis antibodies at a titer of 1 : 320 subsequently confirming the Brucella infection. A polymerse chain reaction (PCR) of the skin biopsy was negative for Brucella. On further questioning, the patient recalled that his brother had undergone orthopedic surgery due to Brucella discitis 3 months earlier and admitted consuming unpasteurized goat cheese. When vasculitis was initially diagnosed, the patient was treated with an intravenous (IV) pulse of methylprednisolone, IV gentamicin for 2 weeks along with rifampicin 600 mg daily and doxycyclin 200 mg daily for 6 months, with rapid improvement of the cutaneous vasculitis and resolution of the fever. A follow-up MRI 6 month later demonstrated compression of L4 but resolution of the abscess and no signs of active osteomyelitis or aortitis. Low back pain resolved gradually as well within 6 months and CRP levels were normalized. Brucella aortic infection is a rare complication of brucellosis. In the English literature there are no reports of brucella aortitis although some authors refer to aortic aneurysm as aortitis. Overall there are 12 case reports of aortic aneurisms, five of which involved the ascending aorta and seven involved the abdominal aorta. Most of the cases of abdominal aortic aneurysms presented with dull low back pain, sometimes radiating to the hips. The route of infection may be hematogenous or contiguous from either adjacent infective endocarditis or spondylitis. Although some authors have suggested

Osmic acid synovectomy in the era of biologics

InWltration of synovial tissue by inXammatory cells, with consequent release of inXammatory cytokines, is considered a central event in the pathogenesis of arthritis, leading to the destruction of articular bone and cartilage in the course of the inXammatory arthropathies. Reduction or “debulking” of the inXammatory synovial mass (synovectomy) should potentially ameliorate the disease process in an involved joint, slowing the process of destruction. Chemical synovectomy via intraarticular osmic acid injection may have a clinical eYcacy of 50–70% at 1 year and 20–50% at 3 years after treatment [1–5]. The aim of the present study was to assess long-term follow up (>3 years) of patients treated with intraarticular injection of osmic acid and to evaluate potential factors predictive of a long-term favorable response in this cohort of patients.

AB0141 Lysyl oxidase is correlated with fibrosis in systemic sclerosis

Background Fibrosis is a major concern in patients with systemic sclerosis (SSc), the pathogenesis of which is not clear. Lysyl oxidase (LOX) is an extracellular copper enzyme that cross-links collagen and elastin, thus stabilizing collagen fibrils [1]. LOX was found to be overexpressed in patients with primary myelofibrosis (PMF), a disease with severe fibrosis [2]. In SSc, LOX was found to be elevated in the skin but has not been evaluated in the serum [3] in correlation with clinical parameters. Objectives To evaluate LOX serum level of patients with SSc compared to normal controls and to patients with PMF. To correlate this serum level to clinical parameters. Methods We prospectively evaluated patients with SSc for demographics, clinical manifestations and laboratory results including blood count, chemistry, urine examination, autoantibodies and serum LOX concentration determined by ELISA. We further evaluated lung function tests, echocardiography, lung high resolution CT scans, as needed, and determined lung involvement, modifies Rodnan skin score (mRSS), Medsger disease severity scale and Valentini activity index [4]. Results Twenty four women and 2 men with SSc at a mean age of 48±12.6 were evaluated and compared with 25, age and gender matched healthy controls and 9 patients with PMF. Of the SSc patients, 10 had diffuse disease- 8 of them with lung fibrosis, and 17 had limited disease. LOX concentration in SSc was higher than healthy controls and similar to PMF, 58.4±4.8 ng/ml vs. 28.4±2.5 ng/ml vs. 44.6±9.4 ng/ml (p< 0.001), respectively. LOX was higher in patients with diffuse SSc compared with limited disease 73±6.6 ng/ml vs. 49.3±5.5 ng/ml (p<0.01) and in those with lung fibrosis compared to patients with limited SSc without lung involvement 69.4±7.2 ng/ml vs. 49.3±5.5 ng/ml (p=0.04). LOX concentration was found to be correlated in linear regression with mRSS in limited disease and to severity score in all patients with SSc, correlation coefficients 0.64 (p=0.004) and 0.54 (p=0.004), respectively. Activity score, DLCO, capillaroscopy pattern and pulmonary hypertension, did not correlate with LOX concentration. Conclusions This is the first study to demonstrate high serum levels of LOX in SSc patients. These levels specifically correlate with skin fibrosis, lung fibrosis and disease severity - which reflects organ damage including fibrosis. We suggest that LOX has an important role in the pathophysiology of SSc and may serve as an objective assay for evaluation of disease severity. Our results suggest that LOX may be a promising future target of therapy in SSc. Future studies are warranted in order to determine the precise effects of such therapy. References Csiszar K et al. “Lysyl oxidases: a novel multifunctional amine oxidase family”. Prog. Nucleic Acid Res. Mol. Biol. 2001;70: 1–322. Papadantonakis N, Matsuura S, Ravid K. Megakaryocyte pathology and bone marrow fibrosis: the lysyl oxidase connection. Blood 2012;120(9):1774-81 Chanoki M, et al. Increased expression of lysyl oxidase in skin with scleroderma. Br J Dermatol 1995;133(5):710-5. Hudson M, et al. Update on indices of disease activity in systemic sclerosis. Semin Arthritis Rheum 2007;37(2):93-8. Disclosure of Interest None Declared