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ID PMID Title PublicationDate abstract
24671001 A novel human anti-interleukin-1β neutralizing monoclonal antibody showing in vivo effica 2014 May The pro-inflammatory cytokine interleukin (IL)-1β is a clinical target in many conditions involving dysregulation of the immune system; therapeutics that block IL-1β have been approved to treat diseases such as rheumatoid arthritis (RA), neonatal onset multisystem inflammatory diseases, cryopyrin-associated periodic syndromes, active systemic juvenile idiopathic arthritis. Here, we report the generation and engineering of a new fully human antibody that binds tightly to IL-1β with a neutralization potency more than 10 times higher than that of the marketed antibody canakinumab. After affinity maturation, the derived antibody shows a>30-fold increased affinity to human IL-1β compared with its parent antibody. This anti-human IL-1β IgG also cross-reacts with mouse and monkey IL-1β, hence facilitating preclinical development. In a number of mouse models, this antibody efficiently reduced or abolished signs of disease associated with IL-1β pathology. Due to its high affinity for the cytokine and its potency both in vitro and in vivo, we propose that this novel fully human anti-IL-1β monoclonal antibody is a promising therapeutic candidate and a potential alternative to the current therapeutic arsenal.
24906903 The outcome of total elbow arthroplasty in juvenile idiopathic arthritis (juvenile rheumat 2014 Sep BACKGROUND: Elbow prosthetic replacement in patients with juvenile idiopathic arthritis (JIA) can be complicated and technically challenging. Thus, we sought to evaluate the clinical benefit and the prosthetic longevity of primary semiconstrained linked total elbow arthroplasty (TEA) performed to treat these patients. METHODS: Between 1983 and 2005, 29 elbows in 24 patients (20 women and 4 men) had been replaced because of JIA. The mean age was 37 years (range, 24-68 years). Because of underlying deformity, the implant contour was modified for 9 elbows (31%) and a customized implant was inserted in 5 elbows (17%). The mean follow-up duration was 10.5 years (range, 4.6-20.1 years). RESULTS: During the follow-up period, 8 elbows underwent reoperation, including 6 (21%) that underwent implant revision. At most recent follow-up, 22 elbows (76%) subjectively had a satisfactory overall functional result. The mean Mayo Elbow Performance Score was 78 points (range, 50-100 points), with 18 elbows graded as having an excellent or good result. Compared with preoperative range of motion, the mean extension-flexion arc improved from 65° ± 44° to 89° ± 35° (P = .01), mean flexion improved from 113° ± 23° to 126° ± 26° (P = .02), and mean extension improved from 48° ± 25° to 37° ± 26° (P = .08). By use of the Kaplan-Meier survivorship method, the rate of TEA survival from any revision was 96.4% (95% confidence interval, 89.8%-100%) and 79.9% (95% confidence interval, 65.1%-97.5%) at 5 years and 10 years, respectively. CONCLUSION: Primary TEA for JIA patients is technically challenging and frequently requires implant modification or custom designs. These patients might have high complication and revision rates. However, most benefit from the intervention for a long term.
24820142 Remission criteria and activity indices in psoriatic arthritis. 2014 Sep Remission criteria and activity indices used in rheumatoid arthritis (RA) are often applied in psoriatic arthritis (PsA). Some new indices have been specifically developed for PsA. Our objective was to evaluate the performance of different remission criteria and activity indices in PsA. This is a cross-sectional study that includes consecutive patients with PsA. Information necessary to complete the following indices was captured: Composite Psoriatic Disease Activity Index (CPDAI), Psoriatic Arthritis Screening and Evaluation (PASE), Disease Activity Index for Psoriatic Arthritis (DAPSA), Disease Activity Score in 28 Joints (DAS28), Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI), and American College of Rheumatology and European League Against Rheumatism (ACR/EULAR) Boolean RA remission criteria. Patients were classified according to activity categories (remission, low, medium, or high disease activity). Correlation between indices was established. Fifty-five patients were included. Mean age was 53 years (SD = 12), and 35 (63.6 %) were males. Mean PsA disease duration was 5.9 years (SD = 8.5), and mean psoriasis duration was 15.9 (SD = 12.6). We found important differences in the percentage of patients classified as in remission by applying different remission criteria: DAS28 = 33 % (95 % confidence interval (CI) 20-45) vs ACR/EULAR = 4 % (95 % CI 1-17). Particularly, DAS28 and minimal disease activity seemed to be less stringent in PsA than the other indices. Of the specific PsA indices evaluated, CPDAI showed the poorest correlation with all the other activity measurements, although differences were not statistically significant in most cases. Disease activity in PsA is measured by many different indices. In spite they all showed good correlations between them, they classified different patients in different disease status.
23529837 Reduced joint counts misclassify patients with oligoarticular psoriatic arthritis and miss 2013 Jun OBJECTIVE: To evaluate joint counts in patients with oligoarticular psoriatic arthritis (PsA) for their correlation with treatment decisions and to determine the proportion of patients in whom active disease was missed using reduced joint counts. METHODS: The international Group for Research and Assessment of Psoriasis and Psoriatic Arthritis Composite Exercise cohort was used for this study. Oligoarthritis was defined as <5 tender and/or swollen joints. At baseline, a tender joint count (TJC) using 68 joints and a swollen joint count (SJC) using 66 joints (66/68-joint counts) were assessed. Reduced joint counts designed for use in rheumatoid arthritis (RA), including 28- and 44-joint counts, were analyzed. In addition, the following proposed joint counts for PsA were tested: the PsA-44 (which includes elbows, wrists, metacarpophalangeal joints, finger proximal interphalangeal [PIP] joints, distal interphalangeal joints, knees, and metatarsophalangeal joints) and the PsA-56 (which includes the same joints as those assessed for the PsA-44 plus ankles and toe PIP joints). Receiver operating characteristic (ROC) curve analysis was used to assess whether joint counts predict treatment changes. The proportion of patients in whom active disease was missed using reduced joint counts designed for RA was also assessed. RESULTS: Among 503 patients recruited to the study, 266 (53%) had oligoarthritis. ROC curve analysis revealed that no TJC or active joint count (AJC), even a 66/68-joint count, predicted treatment change (for the TJC, area under the curve [AUC] 0.57, P = 0.125; for the AJC, AUC 0.56, P = 0.159). Use of the SJC in 66 joints did predict treatment change (AUC 0.62, P = 0.006), as did the SJC using the PsA-44 and the PsA-56 (P < 0.03). Neither of the reduced joint counts designed for RA predicted treatment change. A 28-joint count designed for RA missed 21% of patients with tender joints (n = 29) and 27% of patients with swollen joints (n = 23). The PsA-44 and PsA-56 joint counts missed tender joints in 25 patients and 13 patients, respectively, and missed swollen joints in 11 patients and 2 patients, respectively. CONCLUSION: Patients with oligoarticular PsA cannot be accurately assessed for active disease using reduced joint counts designed for RA. Full 66/68-joint counts should be performed to assess patients with PsA.
24893776 Intra-articular injection of mesenchymal stem cells leads to reduced inflammation and cart 2014 Jun 3 BACKGROUND: Rheumatoid arthritis (RA) is a debilitating and painful disease leading to increased morbidity and mortality and novel therapeutic approaches are needed. The purpose of this study was to elucidate if mesenchymal stem cells (MSCs) injected in the joints of mice with arthritis are therapeutic, reducing joint swelling and cartilage destruction. METHODS: Murine mesenchymal stem cells (mMSCs) were isolated from bone marrow of C57Bl/6 mice and expanded in culture. Cells were tested for immunophenotype and their ability to form colonies and to differentiate into chondrocytes, osteocytes and adipocytes. Antigen-induced arthritis (AIA) was induced by intra-articular injection of methylated bovine serum albumin into the knee joints of preimmunized C57Bl/6 mice. After one day, when peak swelling occurs, 500,000 mMSCs labelled with red fluorescent cell tracker CM-DiI were injected intra-articularly in the right knee joint. Left knee joints were treated as controls by receiving PBS injections. Differences between groups were calculated by Mann Whitney U test or unpaired t tests using GraphPad Prism software version 5. RESULTS: Knee joint diameter (swelling) was measured as a clinical indication of joint inflammation and this parameter was significantly less in MSC-treated mice compared to control-treated animals 48 hours after arthritis induction. This difference continued for ~7 days. CM-DiI-labelled MSCs were clearly visualised in the lining and sublining layers of synovium, in the region of the patella and femoral and tibial surfaces. By day 3, parameters indicative of disease severity, including cartilage depletion, inflammatory exudate and arthritic index were shown to be significantly reduced in MSC-treated animals. This difference continued for 7 days and was further confirmed by histological analysis. The serum concentration of tumour necrosis factor α was significantly decreased following MSC administration. CONCLUSIONS: Our results reveal that MSCs injected in the joints of mice with AIA are therapeutic, reducing inflammation, joint swelling and cartilage destruction. These cells also integrate into the synovium in AIA.
25248373 Abrogation of CC chemokine receptor 9 ameliorates collagen-induced arthritis of mice. 2014 Sep 24 INTRODUCTION: Biological drugs are effective in patients with rheumatoid arthritis (RA), but increase severe infections. The CC chemokine receptor (CCR) 9 antagonist was effective for Crohn's disease without critical adverse effects including infections in clinical trials. The present study was carried out to explore the pathogenic roles of chemokine (C-C motif) ligand (CCL) 25 and its receptor, CCR9, in autoimmune arthritis and to study if the CCR9 antagonist could be a new treatment for RA. METHODS: CCL25 and CCR9 expression was examined with immunohistochemistry and Western blotting. Concentration of interleukin (IL)-6, matrix metalloproteinase (MMP)-3 and tumor necrosis factor (TNF)-α was measured with enzyme-linked immunosorbent assays. Effects of abrogating CCR9 on collagen-induced arthritis (CIA) was evaluated using CCR9-deficient mice or the CCR9 antagonist, CCX8037. Fluorescence labeled-CD11b+ splenocytes from CIA mice were transferred to recipient CIA mice and those infiltrating into the synovial tissues of the recipient mice were counted. RESULTS: CCL25 and CCR9 proteins were found in the RA synovial tissues. CCR9 was expressed on macrophages, fibroblast-like synoviocytes (FLS) and dendritic cells in the synovial tissues. Stimulation with CCL25 increased IL-6 and MMP-3 production from RA FLS, and IL-6 and TNF-α production from peripheral blood monocytes. CIA was suppressed in CCR9-deficient mice. CCX8037 also inhibited CIA and the migration of transferred CD11b+ splenocytes into the synovial tissues. CONCLUSIONS: The interaction between CCL25 and CCR9 may play important roles in cell infiltration into the RA synovial tissues and inflammatory mediator production. Blocking CCL25 or CCR9 may represent a novel safe therapy for RA.
24996416 Discriminant validity, responsiveness and reliability of the arthritis-specific Work Produ 2014 Jul 4 INTRODUCTION: The novel arthritis-specific Work Productivity Survey (WPS) was developed to estimate patient productivity limitations associated with arthritis within and outside the home, which is an unmet need in psoriatic arthritis (PsA). The WPS has been validated in rheumatoid arthritis. This report assesses the discriminant validity, responsiveness and reliability of the WPS in adult-onset PsA. METHODS: Psychometric properties were assessed using data from the RAPID-PsA trial (NCT01087788) investigating certolizumab pegol (CZP) efficacy and safety in PsA. WPS was completed at baseline and every 4 weeks until Week 24. Validity was evaluated at baseline via known-groups defined using first and third quartiles of patients' Disease Activity Score 28 based on C-reactive protein (DAS28(CRP)), Health Assessment Questionnaire-Disability Index (HAQ-DI), Short Form-36 (SF-36) items and PsA Quality of Life (PsAQoL) scores. Responsiveness and reliability were assessed by comparing WPS mean changes at Week 12 in American College of Rheumatology 20% improvement criteria (ACR20) or HAQ-DI Minimal Clinically Important Difference (MCID) 0.3 responders versus non-responders, as well as using standardized response means (SRM). All comparisons were conducted on the observed cases in the Randomized Set, regardless of the randomization group, using a non-parametric bootstrap-t method. RESULTS: Compared with patients with a better health state, patients with a worse health state had on average 2 to 6 times more household work days lost, more days with reduced household productivity, more days missed of family/social/leisure activities, more days with outside help hired and a significantly higher interference of arthritis per month. Among employed patients, those with a worse health state had 2 to 4 times more workplace days lost, more days with patient workplace productivity reduced, and a significantly higher interference of arthritis on patient workplace productivity versus patients with a better health state. WPS was also responsive to clinical changes, with responders having significantly larger improvements at Week 12 in WPS scores versus non-responders. The effect sizes for changes in productivity in ACR20 or HAQ-DI MCID responders were moderate (0.5 < SRM < 0.8) or small. CONCLUSIONS: These analyses demonstrate the validity, responsiveness and reliability of the WPS, as an instrument for the measurement of patient productivity within and outside the home in an adult-onset PsA population.
22749778 Inhibitory effect of the antimalarial agent artesunate on collagen-induced arthritis in ra 2013 Feb Recent evidence indicates that the antimalarial agent artesunate (ART) has immunomodulatory properties that may be useful for treating rheumatoid arthritis (RA). However, the effects of ART on the RA animal model have not been described. The current study aimed to evaluate the antiarthritic effect of ART and explore the potential mechanism on type II collagen-induced arthritis (CIA) in rats. From the day of arthritis onset, rats were treated daily by gavage with leflunomide (Lef) or ART at a dosage of 10 mg/kg/d or 5 mg/kg/d, respectively, for 16 days. The severity of arthritis and levels of pro- and anti-inflammatory cytokines in site were measured. The expression and activity of metalloproteinase (MMP)-2 and MMP-9 were determined. The activation of nuclear factor kappa B and mitogen-activated protein kinase signaling pathways was investigated in rats with CIA and in Raw264.7 cells. Our results showed that ART treatment significantly attenuated inflammation symptoms and prevented cartilage and bone destruction. ART decreased expression of the proinflammatory cytokines interleukin-1β, tumor necrosis factor-α, and interleukin-17α. Both expression and activity of MMP-9 were efficiently inhibited by ART. ART significantly inhibited the degradation of IκB and activation of extracellular signal-regulated kinase and c-Jun N-terminal kinase in rats with CIA and in lipopolysaccharide-stimulated Raw264.7 cells. The present study demonstrated that ART ameliorated rat CIA. The antiarthritic effect might be achieved by inhibiting the action of proinflammatory cytokines and the activity of MMP-9 via suppression of nuclear factor kappa B and mitogen-activated protein kinase signaling pathway. These results show that ART may be used as an adjuvant therapy for patients with RA.
24022986 Is there subclinical synovitis in early psoriatic arthritis? A clinical comparison with gr 2014 Mar OBJECTIVE: Arthritis activity assessments in psoriatic arthritis (PsA) have traditionally relied on tender and swollen joint counts, but in rheumatoid arthritis, multiple studies have demonstrated subclinical inflammation using modern imaging. The aim of this study was to compare clinical examination and ultrasound (US) findings in an early PsA cohort. METHODS: Forty-nine disease-modifying antirheumatic drug-naive patients with recent-onset PsA (median disease duration 10 months) underwent gray-scale (GS) and power Doppler (PD) US of 40 joints plus tender and swollen joint counts of 68/66 joints. GS and PD were scored on a 0-3 semiquantitative scale for each joint. Clinically active joints were defined as tender and/or swollen and US active joints were defined as a GS score ≥2 and/or a PD score ≥1. RESULTS: The most common sites for subclinical synovitis were the wrist (30.6%), knee (21.4%), metatarsophalangeal (MTP) joints (26.5-33.7%), and metacarpophalangeal joints (10.2-19.4%). Excluding MTP joints and ankles, 37 (75.5%) of 49 patients had subclinical synovitis with a median of 3 (interquartile range [IQR] 1-4) joints involved. In contrast, clinical overestimation of synovitis occurred most commonly at the shoulder (38%) and ankle (28.6%). Twelve of 49 patients were classified clinically as having oligoarthritis; of these, subclinical synovitis identified 8 (75%) as having polyarthritis with an increase in their median joint count from 3 (IQR 1-4) to 6 (IQR 5-7). CONCLUSION: This study has demonstrated that subclinical synovitis, as identified by US, is very common in early PsA and led to the majority of oligoarthritis patients being reclassified as having polyarthritis. Further research is required into the relationship of such subclinical synovitis to structural progression.
24782185 Ankylosing spondylitis, psoriatic arthritis, and risk of malignant lymphoma: a cohort stud 2014 May OBJECTIVE: Data on lymphoma risk in ankylosing spondylitis (AS) and psoriatic arthritis (PsA) are scarce. This study was undertaken to assess the risk of lymphoma in AS and PsA overall and in relation to therapies, including tumor necrosis factor inhibitor (TNFi), for which lymphoma risks are a concern. METHODS: Through the Swedish National Patient Register we assembled nationwide prevalence cohorts of patients with AS (n = 8,707) and patients with PsA (n = 19,283) for whom data were obtained between 2001 and 2010. Each cohort member was matched to 5 population comparator subjects. Linkage with the nationwide Cancer Register identified all lymphomas recorded from 2001 to 2010. Through the Swedish Biologics Register (Anti-Rheumatic Therapy in Sweden [ARTIS]), we identified patients exposed to TNFi in the AS cohort (n = 1,908) and the PsA cohort (n = 2,605) before lymphoma diagnosis. Hazard ratios (HRs) for lymphoma were estimated by Cox regression. Crude incidences of lymphoma in TNFi-exposed and TNFi-naive patients were compared. RESULTS: For AS patients, the HR of having lymphoma versus the general population was 0.9 (95% confidence interval [95% CI] 0.5-1.6) (14 lymphomas). For PsA patients, the corresponding HR was 1.2 (95% CI 0.9-1.7) (45 lymphomas). For PsA patients treated with methotrexate and/or sulfasalazine, the HR of having lymphoma was 1.7 (95% CI 1.0-3.1). The numbers and incidence of lymphoma were not materially different in TNFi-exposed versus TNFi-naive AS and PsA patients, although the numbers of lymphomas were small. CONCLUSION: In contrast to rheumatoid arthritis, the average risks of lymphoma in AS or PsA are not elevated, although increased risks in a subset of PsA patients cannot be excluded. Our findings indicate that TNFi does not affect the risk of lymphoma in AS or in PsA.
23184090 Curcumin protects against collagen-induced arthritis via suppression of BAFF production. 2013 Apr PURPOSE: The aim of the present study was to evaluate whether the anti-Rheumatoid arthritis (RA) effect of curcumin is associated with the regulation of B cell-activating factor belonging to the TNF family (BAFF) production. METHODS: Collagen-induced arthritis (CIA) was induced in DBA/1 J mice by immunization with bovine type II collagen. To investigate the anti-arthritic effect of curcumin in the CIA model, mice were injected intraperitoneally with curcumin (50 mg/kg) on every other day either from day 1 or from day 28 after the first immunization. The clinical severity of arthritis was monitored. BAFF, interleukin-6 (IL-6) and interferon-γ (IFNγ) production in serum were measured. Furthermore, the effect of curcumin on IFNγ-induced BAFF expression and transcriptional activation in B lymphocytes was determined by qPCR, Western Blot, and luciferase assay. Finally, IFNγ related signal transducers and activators of transcription 1 (STAT1) signaling in B lymphocytes were studied using Western Blot. RESULTS: Curcumin dramatically attenuated the progression and severity of CIA in DBA/1 J mice, accompanied with decrease of BAFF production in serum and spleen cells as well as decrease of serum IFNγ and IL-6. Treatment of B lymphocytes with curcumin suppressed IFNγ-induced BAFF expression, STAT1 phosphorylation and nuclear translocation, suggesting that curcumin may repress IFNγ-induced BAFF expression via negatively interfering with STAT1 signaling. CONCLUSION: The results of the present study suggest that suppression of BAFF production may be a novel mechanism by which curcumin improves RA.
24974063 Macrophage activation syndrome and cytokine-directed therapies. 2014 Apr Macrophage activation syndrome (MAS) is an episode of overwhelming inflammation that occurs most commonly in children with systemic juvenile idiopathic arthritis (SJIA). It is characterized by expansion and activation of T lymphocytes and hemophagocytic macrophages and bears great similarity to hemophagocytic lymphohistiocytosis (HLH). This disorder has substantial morbidity and mortality, and there is frequently a delay in recognition and initiation of treatment. Here, we will review what is known about the pathogenesis of MAS and, in particular, its similarities to HLH. The development of MAS is characterized by a cytokine storm, with the elaboration of numerous pro-inflammatory cytokines. We will examine the evidence for various cytokines in the initiation and pathogenesis of MAS and discuss how new biologic therapies may alter the risk of MAS. Finally, we will review current treatment options for MAS and examine how cytokine-directed therapy could serve as novel treatment modalities.
22923003 Immunomodulatory and anti-inflammatory effect of p-coumaric acid, a common dietary polyphe 2013 Feb In this study, p-coumaric acid was evaluated for its immunomodulatory and anti-inflammatory properties in vivo. The immunomodulatory effect of p-coumaric acid (100 mg/kg body weight) was assessed by evaluating its effect on cell-mediated immune responses (delayed type hypersensitivity reaction), serum immunoglobulin levels, and macrophage phagocytic index in rats. The anti-inflammatory effects of p-coumaric acid (100 mg/kg body weight) were investigated by examining its effect on expression of tumor necrosis factor (TNF-α) in synovial tissue by immunofluorescence confocal microscopy and circulating immune complexes in serum of adjuvant-induced arthritic rats. The increased cell-mediated immune responses and macrophage phagocytic index observed in control rats were significantly reduced (p < 0.05) upon treatment with p-coumaric acid implying its immunosuppressive property, whereas serum immunoglobulin levels were found to be increased in p-coumaric acid treated control rats. p-coumaric acid also showed significant (p < 0.05) anti-inflammatory effects in adjuvant-induced arthritic rats by effecting a decrease in the expression of inflammatory mediator TNF-α and circulating immune complexes. Indomethacin was used as a reference drug for anti-inflammatory studies. Thus, our results show that p-coumaric acid could be considered a potential immunosuppressive agent in treating autoimmune inflammatory diseases like rheumatoid arthritis.
24159176 Germline and somatic genetic variations of TNFAIP3 in lymphoma complicating primary Sjogre 2013 Dec 12 Several autoimmune diseases, including primary Sjögren's syndrome (pSS), are associated with an increased risk for lymphoma. Polymorphisms of TNFAIP3, which encodes the A20 protein that plays a key role in controlling nuclear factor κB activation, have been associated with several autoimmune diseases. Somatic mutations of TNFAIP3 have been observed in the mucosa-associated lymphoid tissue lymphoma subtype frequently associated with pSS. We studied germline and somatic abnormalities of TNFAIP3 in 574 patients with pSS, including 25 with lymphoma. Nineteen additional patients with pSS and lymphoma were available for exome sequence analysis. Functional abnormalities of A20 were assessed by gene reporter assays. The rs2230926 exonic variant was associated with an increased risk for pSS complicated by lymphoma (odds ratio, 3.36 [95% confidence interval, 1.34-8.42], and odds ratio, 3.26 [95% confidence interval, 1.31-8.12], vs controls and pSS patients without lymphoma, respectively; P = .011). Twelve (60%) of the 20 patients with paired germline and lymphoma TNFAIP3 sequence data had functional abnormalities of A20: 6 in germline DNA, 5 in lymphoma DNA, and 1 in both. The frequency was even higher (77%) among pSS patients with mucosa-associated lymphoid tissue lymphoma. Some of these variants showed impaired control of nuclear factor κB activation. These results support a key role for germline and somatic variations of A20 in the transformation between autoimmunity and lymphoma.
24802131 Sequential therapy with belimumab followed by rituximab in Sjögren's syndrome associated 2014 Jul OBJECTIVES: The overexpression of B-cell activating factor (BAFF) in mucosa-associated lymphoid tissue (MALT) may decrease the efficacy of rituximab treatment in Sjögren's syndrome (SS). Anti-CD20 therapy was effective on marginal zone B cells, in the murine model for human CD20 expression only when preceded by anti-BAFF therapy. The possible efficacy of a sequential anti-BAFF/anti-CD20 therapy in SS was investigated. METHODS: We treated with belimumab, a monoclonal anti-BAFF antibody, and soon after with rituximab a patient with severe, refractory SS, parotid low-grade B-cell MALT lymphoma and cryoglobulinaemic vasculitis. Previous treatments with rituximab and with rituximab plus high dose glucocorticoids, as well as with cyclophosphamide, azathioprine, plasma exchange, hyperbaric therapy, VAC therapy, prostacyclin, mycophenolate mofetil and surgery, had previously failed. Treatment with belimumab was then given, but it also failed. A new course of rituximab (375 mg/m2; four weekly infusions) was started 49 days after the last infusion of belimumab. RESULTS: This sequential belimumab-rituximab treatment was followed by a marked amelioration, with the complete and persistent regression of lymphoma and healing of a refractory skin ulcer. A full cycle of rituximab was then repeated 6 and 12 months later; no further treatment was given in the following 22 months up to now. Serum cryoglobulins and rheumatoid factor became persistently negative and serum BAFF and C4 persistently normal. No relevant side effects were noticed, except for a marked decrease in serum IgM. The follow up after belimumab-rituximab sequential therapy is now three and a half years. CONCLUSIONS: Therapy with belimumab followed by rituximab may be effective for SS-related B-cell lymphoproliferation. The efficacy and safety of the sequential or concomitant targeting of BAFF and CD20 deserves further evaluation in SS.
23533183 Type I interferon receptor deficiency prevents murine Sjogren's syndrome. 2013 May In Sjögren's Syndrome (SS), inherent glandular defects, autoimmunity, and mononuclear cell infiltration within the salivary glands cause reduced salivation leading to xerostomia. Excessive production of type I interferons (IFN), triggered by environmental and genetic factors, is considered pathogenic in this disorder. However, whether type I IFN production is causative or an outcome of the disease process is not known. To address this question, we introduced a deficiency of interferon alpha receptor 1 (Ifnar1) into B6.Aec1Aec2 mice, which are known to have the genetic loci necessary for developing a SS-like disorder. This new mouse strain, B6.Aec1Aec2Ifnar1 (-/-), lacking type I IFN-mediated signaling, was characterized for pilocarpine-induced salivation, the presence of serum autoantibodies, sialoadenitis, and dacryoadenitis. Compared with the B6.Aec1Aec2Ifnar1 (+/+) (wild-type) mice, the B6.Aec1Aec2Ifnar1 (-/-) (knockout) mice had significantly lower mononuclear cell infiltration in the salivary and lacrimal glands. The knockout mice were completely protected from salivary gland dysfunction. Surprisingly, they had a robust autoantibody response comparable with that of the wild-type mice. These findings demonstrate that, in the absence of type I IFN-mediated signaling, systemic autoantibody responses can be dissociated from glandular pathology. Our study suggests that, in genetically susceptible individuals, the type I IFN pathway can instigate certain features of SS.
23343785 Overlap of ACA-positive systemic sclerosis and Sjögren's syndrome: a distinct clinical en 2013 Mar OBJECTIVES: We aimed to assess the prevalence of patients with either primary Sjögren's syndrome (pSS) and positive anticentromere antibodies (ACA) and secondary Sjögren's syndrome (sSS) and limited cutaneous ACA positive-systemic sclerosis (SSc) in two large cohorts of patients with pSS and SSc¸ and also to compare the clinical features of these two subsets with those of patients affected by 'ACA-positive SSc without sicca symptoms' and 'pSS'. METHODS: In this retrospective monocentric study, the case records of 'overlap' patients fulfilling both the classification criteria for SS and the LeRoy criteria for early SSc were identified from two datasets of patients with limited cutaneous ACA positive SSc (209 subjects) and with pSS (402 subjects) who attended our Rheumatology Unit in the years between 1989 and 2011. Control groups were represented by SSc subjects without sicca symptoms ('SSc group') and ACA negative Pss patients ('pSS group'). SSc patients with sicca symptoms ('Sicca-SSc group') who did not complete the diagnostic algorithm for SS were excluded from the analysis. Demographic, clinical and immunological data of the patients enrolled were collected cumulatively over the entire follow up period. Statistical analysis was performed using SPSS 13 (SPSS Inc., Chicago IL, USA). RESULTS: Out of the two datasets 41 'overlap' patients were selected. The control groups were represented by 102/209 SSc subjects without sicca symptoms ('SSc group') and 387/402 pSS patients ('pSS group'). Eighty-one 'sicca-SSc' with an incomplete work-up for SS were excluded from the analysis. The prevalence of ACA positive pSS patients among pSS was 3.7% (15/402), while the frequency of patients with definite sSS in the SSc cohort was 20% (26/128). No differences were detected between 'overlap' patients and control groups, relatively to demographic characteristics. 'Overlap patients' were characterised by a milder SSc disease (i.e. lower frequency of sclerodactily, negative evolution of the capillaroscopy pattern or absence of severe systemic involvement) whereas, as far as the SS-related manifestations were concerned, although often lacking in specific autoantibodies (i.e. rheumatoid factor, anti-Ro/SSA, anti-La/SSB), the 'overlap patients' displayed a full blown SS phenotype with recurrent salivary gland enlargement, purpura, fatigue, arthralgias, and leukocytopenia. It is noteworthy that the prevalence of non-Hodgkin's lymphoma in the 'overlap patients' was higher than in pSS. CONCLUSIONS: Taken together, the results of our work emphasise the existence of a novel distinct clinical entity which might tentatively be called 'ACA-positive limited scleroderma/SS overlap syndrome' characterised by a benign SSc clinical course but at a high risk of non-Hodgkin's lymphoma.
25400173 Curcumin loaded solid lipid nanoparticles ameliorate adjuvant-induced arthritis in rats. 2015 Aug BACKGROUND: Rheumatoid arthritis (RA), a chronic and systemic inflammation, results in destruction of joints and cartilages. Effectiveness of curcumin has been established in a wide variety of inflammatory disorders, but its utility as a therapeutic agent is limited by its poor absorption, rapid metabolism and fast systemic elimination. To apprehend these limitations, we propose to use highly bioavailable curcumin loaded solid lipid nanoparticles (C-SLNs) for the treatment of RA. METHODS: In the present study, the protective effect of curcumin and its SLNs was evaluated in complete Freund's adjuvant (CFA)-induced arthritis in rats. RESULTS: Arthritic rats exhibited marked decrease in paw withdrawal threshold in Randall-Selitto and von Frey hair test along with decreased reaction time in hot plate. Arthritic rats also showed significant joint hyperalgesia, joint stiffness and increased paw volume along with marked decrease in mobility score. Arthritic rats showed a significant increase in blood leukocyte count, oxidative-nitrosative stress, tumour necrosis factor-α, C-reactive protein, cyclic citrullinated peptide antibody levels and radiological alterations in tibiotarsal joint. C-SLN administration (10 and 30 mg/kg), when compared with free curcumin (10 and 30 mg/kg), significantly and dose dependently ameliorated various symptoms of arthritis in rats, improved biochemical markers and preserved radiological alterations in joints of arthritic rats. CONCLUSIONS: The current findings suggest the protective potential of curcumin-SLNs in ameliorating CFA-induced arthritis in rats through attenuation of oxido-inflammatory and immunomodulatory cascade. Further, the results emphasize that SLNs are a novel approach to deliver curcumin into the inflamed joints and improve its biopharmaceutical performance.
24866156 Anti-inflammatory effects of rebamipide eyedrop administration on ocular lesions in a muri 2014 BACKGROUND: Topical therapy is effective for dry eye, and its prolonged effects should help in maintaining the quality of life of patients with dry eye. We previously reported that the oral administration of rebamipide (Reb), a mucosal protective agent, had a potent therapeutic effect on autoimmune lesions in a murine model of Sjögren's syndrome (SS). However, the effects of topical treatment with Reb eyedrops on the ocular lesions in the murine model of SS are unknown. METHODS AND FINDING: Reb eyedrops were administered to the murine model of SS aged 4-8 weeks four times daily. Inflammatory lesions of the extraorbital and intraorbital lacrimal glands and Harderian gland tissues were histologically evaluated. The direct effects of Reb on the lacrimal glands were analyzed using cultured lacrimal gland cells. Tear secretions of Reb-treated mice were significantly increased compared with those of untreated mice. In addition to the therapeutic effect of Reb treatment on keratoconjunctivitis, severe inflammatory lesions of intraorbital lacrimal gland tissues in this model of SS were resolved. The mRNA expression levels of IL-10 and mucin 5Ac in conjunctival tissues from Reb-treated mice was significantly increased compared with those of control mice. Moreover, lactoferrin production from lacrimal gland cells was restored by Reb treatment. CONCLUSION: Topical Reb administration had an anti-inflammatory effect on the ocular autoimmune lesions in the murine model of SS and a protective effect on the ocular surfaces.
25343284 Anti-inflammatory effect of glycosaminoglycan derived from Gryllus bimaculatus (a type of 2014 Anti-inflammatory effects of glycosaminoglycan (GAG) derived from cricket (Gryllus bimaculatus, Gb) were investigated in a complete Freund's adjuvant (CFA)-treated chronic arthritic rat model. This GAG produced a significant anti-edema effect as evidenced by inhibition of C-reactive protein (CRP) and rheumatoid factor, and interfered with atherogenesis by reducing proinflammatory cytokine levels of (1) vascular endothelial growth factor (VEGF) production in human umbilical vein endothelial cells (HUVEC), (2) interleukin-6, (3) prostaglandin E2-stimulated lipopolysaccharide in RAW 264.7 cells, and (4) tumor necrosis factor (TNF)-α production in normal splenocytes, in a dose-dependent manner. This GAG was also found to induce nitric oxide (NO) production in HUVEC cells and elevated endothelial nitric oxide synthase (eNOS) activity levels. Histological findings demonstrated the fifth lumbar vertebrae (LV) dorsal root ganglion, which was linked to the paw treated with Gb GAG, was repaired against CFA-induced cartilage destruction. Further, combined indomethacin (5 mg/kg)-Gb GAG (10 mg/kg) inhibited more effectively CFA-induced paw edema at 3 h and 2 or 3 d after treatment to levels comparable to only the anti-inflammatory drug indomethacin. Ultraviolet (UV)-irritated skin inflammation also downregulated nuclear factor κB (NFκB) activity in transfected HaCaT cells. Data suggest that the anti-inflammatory effects of GAG obtained from cricket (Gb) may be useful for treatment of inflammatory diseases including chronic arthritis.