Gleb Slobodin

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.

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.

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.

A regulatory role for CD72 expression on B cells in systemic lupus erythematosus.

BACKGROUND B regulatory cells and their regulatory products/markers, such us semaphorin 3A (sema3A) and its receptor NP-1, FcγIIB, IL-10, and others, act at the very base of self-tolerance, maintenance, and prevention of autoimmune disease development. OBJECTIVES The aim of the present study was to assess the involvement of CD72, a regulatory receptor on B cells, in systemic lupus erythematosus (SLE). In addition, the potential of soluble sema3A in enhancing the expression of CD72 on B cells of SLE patients was investigated. RESULTS CD72 expression on activated B cells of SLE patients was significantly lower than that of normal controls. This lower expression of CD72 in SLE patients correlated inversely with SLE disease activity and was associated with lupus nephritis, the presence of anti-dsDNA antibodies, and low levels of complement. Co-culture of purified B cells from healthy controls with condition-media containing recombinant sema3A resulted in significant enhancement of CD72. Similar enhancement of CD72 on activated B cells from SLE patients, though significant, was still lower than in normal individuals. CONCLUSIONS The lower expression of CD72 on activated B cells from SLE patients correlates with SLE disease activity, lupus nephritis, the presence of anti-dsDNA antibodies, and low levels of complement. The improvement of CD72 expression following the addition of soluble semaphorin 3A suggests that CD72 may be useful as a biomarker to be followed during the treatment of SLE.

Regulatory T Cells in Systemic Sclerosis: a Comprehensive Review

Systemic sclerosis (SSc) is a chronic inflammatory disease with complex pathogenesis, based on the sophisticated interplay of injury to the vascular endothelium, exaggerated tissue regeneration and fibrosis, and extensive immune abnormalities. The role of regulatory T cells (Tregs) in the development of SSc has started being studied during the last decade with new aspects being disclosed continuously, in parallel with the better understanding of Tregs physiology. There is a general agreement in the medical literature regarding the decreased functional capacity of circulating Tregs in SSc. Some patients, particularly those with active disease, may have increased numbers of circulating Tregs, representing the inhibitory response of the immune system to its inappropriate activation or occurring as a compensatory move for Tregs’ decreased suppressive ability. Decreased pool of circulating Tregs can be seen in other SSc patients, with even lower Treg percentages seen in patients with long-standing disease. Skin-resident Tregs are depleted in advanced SSc but can be active and have a role in earlier disease stages. In addition to diminished suppressive ability, Tregs can contribute to SSc evolution by their microenvironment-dependent transformation to pathogenic effector T cells of Th17 or Th2 lineages with respective pro-inflammatory or pro-fibrotic activity. The current data on the effects of existing treatment modalities, including autologous stem cell transplantation, on Tregs function in SSc, is controversial, not being sufficiently elaborated.

Increased aortic wall thickness for the diagnosis of aortitis: a computed tomography-based study.

To evaluate the usefulness of computed tomography (CT)‐measured aortic wall thickness (AWT) as a sole imaging finding for the confirmation of clinically suspected aortitis.

Endothelin-1 Does Not Change the Function of Monocyte-Derived Dendritic Cells Grown from Patients with Systemic Sclerosis

Systemic sclerosis (SSc) is characterized by both vasculopathy and autoimmunity. The interplay between these pathogenetic links requires further exploration. The aim was to assess the interrelationship of endothelin-1 (ET-1), a vasoconstrictor peptide, whose levels are usually elevated in the plasma of the patients with SSc and the function of monocyte-derived dendritic cells (MDDCs), which serve as organizers of the immune response. MDDCs were grown from 5 patients with SSc and severe Raynauds phenomenon and 5 healthy volunteers. The cells were further stimulated by synthetic ET-1, lipopolysaccharide (LPS) or both. The production of endogenous ET-1, TNFα and IL-12 was assessed by RT-PCR and/or ELISA. The plasma levels of ET-1 were significantly higher in patients with SSc compared to healthy controls (p = 0.0005). The production of ET-1 by MDDCs was negligible in all examined conditions, while the release of TNFα and IL-12 was stimulated by LPS but not by ET-1. The in vitro concentration of the exogenous ET-1, where added, was comparable to the plasma levels of ET-1 in patients with SSc. High plasma levels of ET-1 are characteristic for the patients with SSc and severe Raynauds phenomenon. An in vitro model with concentrations of ET-1 comparable to those in the plasma of SSc patients has been elaborated. The examined function of MDDCs from SSc patients and healthy volunteers did not differ under these conditions and was not dependent on the presence of ET-1.