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ID PMID Title PublicationDate abstract
26794912 Mimotope mimicking epidermal growth factor receptor alleviates mononuclear cell infiltrati 2016 Feb The muscarinic type 3 receptor (M3R) plays a pivotal role in the pathogenesis of Sjögren's syndrome (SS). Characterization of the crosstalk between M3R and EGFR has been investigated in some human malignancies. In the current study, we sought to investigate whether EGFR mimic immunization could alleviate the abnormal immune responses in an experimental SS-like model triggered by M3R peptides. After immunization with the combination of mimotope and M3R peptide, the active immunization targeting EGFR induced by the mimotope could reduce the marked infiltration of mononuclear cells, the high titer of antibodies against M3R and the accumulation of crucial pro-inflammatory cytokines in mice immunized with M3R peptide. Mechanistic analysis showed that mimotope immunization could alleviate the autoimmune response through inhibiting mitochondrion-mediated anti-apoptosis and up-regulating the FAS apoptosis pathway. These results may help to clarify the role of M3R in the pathogenesis of SS and suggested that transactivation of the EGFR signaling pathway may help M3R activate the autoimmune response in the pathogenesis of SS.
25891013 The anergy induction of M3 muscarinic acetylcholine receptor-reactive CD4+ T cells suppres 2015 May OBJECTIVE: Autoreactive CD4+ T cells are involved in the pathogenesis of Sjögren's syndrome (SS). The aim of the present study was to clarify the dominant T cell epitopes of M3 muscarinic acetylcholine receptor (M3R) and to establish a new antigen-specific therapy for SS using an experimental mouse model. METHODS: Production of cytokines from M3R-reactive CD4+ T cells, after culture with various M3R peptides, was analyzed by enzyme-linked immunosorbent assay. Adoptive cell transfer was performed using splenocytes from M3R(-/-) mice that were immunized with M3R peptides or phosphate buffered saline plus H37Ra as a control. Rag1(-/-) mice were inoculated with the splenocytes and examined for the development of sialadenitis. Altered peptide ligands (APLs) of the T cell epitopes, with substitutions in amino acid residues at T cell receptor contact sites, were synthesized, and the ability of the APLs to suppress sialadenitis was evaluated. The mechanisms underlying such effects were assessed. RESULTS: CD4+ M3R-reactive T cells produced interleukin-17 (IL-17) and interferon-γ (IFNγ) in response to the N-terminal 1 (N1) and 1st extracellular loop peptides of M3R, and Rag1(-/-) mice that received N1- and/or 1st peptide-immunized splenocytes developed sialadenitis. Among the designed APLs, N1-APL7 (N→S at amino acid 15) significantly suppressed IFNγ production in vitro, and also suppressed sialadenitis in vivo. Levels of early growth response 2 in CD4+ T cells from the cervical lymph nodes of N1-APL7-treated mice were significantly higher than those of control mice, and cell proliferation was reversed by administration of exogenous IL-2. Levels of the anergy-related molecules itchy homolog E3 ubiquitin-protein ligase, Casitas B-lineage lymphoma b, gene related to anergy in lymphocytes, and Deltex-1 were significantly higher in CD4+ T cells cultured with N1-APL7. CONCLUSION: The major T cell epitopes were from the N1 and 1st peptide regions. Moreover, N1-APL7, selected as the antagonistic APL in vitro, also suppressed sialadenitis through the induction of anergy. This is a potentially useful strategy for regulating pathogenic T cell infiltration in SS.
25854827 Development of mixed connective tissue disease and Sjögren's syndrome in a patient with t 2015 Oct Increased risk of developing systemic lupus erythematosus (SLE) has been reported in patients with Klinefelter syndrome. Here, we describe a 16-year-old Japanese patient with trisomy X (47,XXX) who developed mixed connective tissue disease (MCTD) and Sjögren's syndrome. She had polyarthritis, edematous fingers with Raynaud's phenomenon, sicca syndrome, interstitial lung disease, possible myositis, and was positive for anti-nuclear antibody, anti-nRNP antibody and rheumatoid factor. This is the first report in the literature of a case of MCTD with female polysomy X, which further supports the link between the presence of extra X chromosome(s) and the development of autoimmune diseases.
26525549 Effect of Chinese herbal medicines for nourishing yin, supplementing qi, and activating bl 2015 Oct OBJECTIVE: To investigate the effect of Chinese herbal medicines for nourishing yin, supplementing qi, and activating blood on the reproductive endocrine-immune network and its mechanisms in patients with primary Sjogren's syndrome (pSS). METHODS: Seventy pSS patients were randomly assigned to two groups using a randomized digital table: the integrative therapy group (36 cases) and the control group (34 cases). Thirty healthy subjects were taken as a normal group. The control group was treated with hydroxychloroquine sulfate tablets alone, and the integrative therapy group was treated by Chinese herbal medicines for nourishing yin, supplementing qi, and activating blood combined with hydroxychloroquine sulfate tablets. The treatment course was 6 months for both groups. Before and after treatment, serum estradiol (E2), testosterone (T), luteinizing hormone (LH), prolactin (PRL) by radioimmunoassay and immunoglobulin (IgG) by immunodiffusion, erythrocyte sedimentation rate (ESR) by Westergren, interferon-γ (IFN-γ) and interleukin-4 (IL-4) by enzyme linked immunosorbent assay were determined. RESULTS: E2 and T levels in all patients were lower than those of normal subjects before treatment (P<0.05) and were increased significantly after 6-month treatment (P<0.05). ESR, FSH, LH, IgG, IFN - γ, IL - 4 and ratios of E2/T, and IFN -γ/IL in the patients were higher than those of normal subjects before the treatments (P<0.05), and were reduced significantly after the treatments (P<0.05). The T and IFN - γ levels and E2/T ratio in the patients treated with integrative therapy were reduced significantly compared with the control group (P<0.05). However, the PRL levels before and after treatment were not significantly changed in the two groups (P>0.05). The ratios of E2/T and IFN -γ/IL-4, and levels of IgG and ESR were positively correlated before and after treatment (P<0.05). CONCLUSIONS: The ratios of E2/T and IFN -γ/IL-4 might be used as indicators of pSS activity. Chinese herbal medicines for nourishing yin, supplementing qi, and activating blood combined with Western medicine could improve the therapeutic effect by regulating the reproductive endocrine-immune network in pSS patients.
25411202 A crucial role of RORγt in the development of spontaneous Sialadenitis-like Sjögren's sy 2015 Jan 1 The nuclear receptor retinoic acid-related orphan receptor (ROR)γt is required for the generation of Th17 cells, which are involved in various autoimmune diseases, including Sjögren's syndrome (SS). However, the pathological role of RORγt in SS remains to be elucidated. The present study was designed to clarify the role of RORγt in the pathogenesis of sialadenitis-like SS. Histological analysis of RORγt transgenic (Tg) mice was determined, and then Tg mice developed severe spontaneous sialadenitis-like SS. The analysis of infiltrating cells showed that most infiltrating cells were CD4(+) T cells. RORγt-overexpressing CD4(+) T cells induced sialadenitis as a result of transferred CD4(+) T cells from Tg mice into Rag2(-/-) mice. The examination of IL-17-deficient Tg mice indicated that IL-17 was not essential for the development of sialadenitis. The number of CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells was significantly decreased in Tg mice, and CD25 expression and IL-2 stimulated STAT5 activation were inhibited in Treg cells. The inhibitory function of Treg cells of Tg mice was equal to that of wild-type mice in vitro. The abundant Treg cells of Tg mice could suppress the development of sialadenitis, but the reduced Treg cells of Tg mice could not inhibit the induction of sialadenitis in Rag2(-/-) mice transferred with effector cells from Tg mice. These results suggest that both RORγt-overexpressed CD4(+) T cells and reduced Treg cells might contribute to the development of SS-like sialadenitis.
27854003 Health-related quality of life and function in middle-aged individuals with thalidomide em 2016 Dec OBJECTIVES: The aim of this study was to evaluate the effect of limb malformations on health-related quality of life (HRQL) and function of the extremities in middle-aged individuals with thalidomide embryopathy (TE). Between 1959 and 1962, approximately 150 children with multiple malformations were born in Sweden following the maternal intake of thalidomide during pregnancy, of whom 100 survived. METHODS: Thirty-one individuals with TE underwent evaluations of musculoskeletal manifestations by clinical examination. Validated questionnaires were used for the assessment of general HRQL [the 36-Item Short Form Health Survey (SF-36) and the EuroQ Five Dimensions health questionnaire (EQ-5D)]. The function of the upper and lower extremities was evaluated using specific questionnaires (Disabilities of the Arm, Shoulder and Hand scale and Rheumatoid and Arthritis Outcome Score, respectively). The lower limbs were evaluated by computed tomography. The median age of the study group was 46 years, and 42% were females. Twenty-five individuals had malformations of the hand, but 27 had a grip function. Five individuals had severe lower limb malformations. Individuals with at least one extremity with major malformation(s) that affected function (n = 15) were compared with those without (n = 16). RESULTS: The physical HRQL for the entire study group [mean 40.6, 95% confidence interval (CI) 35.4-45.8], as evaluated by the Physical Composite Score (PCS) of the SF-36, was significantly lower than the national norm value (population-based norm) of 50.0, and the physical HRQL of the subgroup with major limb malformations (15/31) was even lower (mean 34.6, 95% CI 25.9-43.4). The mental aspects of HRQL, based on SF-36 and EQ-5D scores, were not affected in the entire study group or in the subgroups. CONCLUSION: The physical quality of life was significantly lower in individuals with TE compared with the general national population, while the mental aspects were not affected. LEVEL OF EVIDENCE: IV.
25582995 [Autoimmune diseases and autoantibodies in pediatric patients and their first-degree relat 2015 May INTRODUCTION: Clinical manifestations of Immunoglobulin A Deficiency (IgAD) include recurrent infections, atopy and autoimmune diseases. However, to our knowledge, the concomitant evaluations of autoimmune diseases and autoantibodies in a cohort of IgAD patients with current age > 10 years-old and their relatives have not been assessed. OBJECTIVES: To evaluate autoimmune diseases and the presence of autoantibodies in IgAD patients and their first-degree relatives. METHODS: A cross-sectional study was performed in 34 IgAD patients (current age > 10 years-old) and their first-degree relatives. All of them were followed at a tertiary Brazilian primary immunodeficiency center: 27 children/adolescents and 7 of their first-degree relatives with a late diagnosis of IgAD. Autoimmune diseases and autoantibodies (antinuclear antibodies, rheumatoid factor, and anti-thyroglobulin, anti-thyroperoxidase and IgA class anti-endomysial antibodies) were also assessed. RESULTS: Autoimmune diseases (n=14) and/or autoantibodies (n=10, four of them with isolated autoantibodies) were observed in 18/34 (53%) of the patients and their relatives. The most common autoimmune diseases found were thyroiditis (18%), chronic arthritis (12%) and celiac disease (6%). The most frequent autoantibodies were antinuclear antibodies (2%), anti-thyroglobulin and/or anti-thyroperoxidase (24%). No significant differences were observed in the female gender, age at diagnosis and current age in IgAD patients with and without autoimmune diseases and/or presence of autoantibodies (p>0.05). The frequencies of primary immunodeficiency's in family, autoimmunity in family, atopy and recurrent infections were similar in both groups (p>0.05). CONCLUSION: Autoimmune diseases and autoantibodies were observed in IgAD patients during follow-up, reinforcing the necessity of a rigorous and continuous follow-up during adolescence and adulthood.
27050250 RS3PE revisited: a systematic review and meta-analysis of 331 cases. 2016 May OBJECTIVES: Remitting seronegative symmetrical synovitis with pitting oedema (RS(3)PE) syndrome is a rare inflammatory arthritis, characterised by symmetrical distal synovitis, pitting oedema of the hands and feet, absence of rheumatoid factor, and favourable response to glucocorticoids. The aim of our study is to further delineate the clinical and laboratory features, and response to treatment. METHODS: We performed a systematic electronic search of Medline, PubMed, EMBASE, ACR and EULAR databases for case reports, case series, and related articles of RS(3)PE. Statistical analysis was done comparing categorical variables with Chi-square tests and frequencies of means via t-tests. Binary logistic regression analysis was performed to identify predictors of erosions, recurrence, malignancy and rheumatologic disorders. RESULTS: 331 cases of RS(3)PE were identified from 121 articles. RS(3)PE was found in older patients (71±10.42 years) predominantly in males (n= 211, 63.36%), was symmetrical (n=297/311, 95.50%) involved the hands (n=294/311, 94.53%) A concurrent rheumatologic condition was reported in 22 cases (6.65%), and malignancy in 54 cases (16.31%). Radiographic joint erosions were found in 5.5%. Most patients responded to medium-dose glucocorticoids (16.12±9.5 mg/day). Patients with concurrent malignancy requiring non-significantly higher doses of prednisone (18.12 vs. 15.76 mg, p 0.304) and higher likelihood of recurrence of disease (OR 4.04, 95% CI 1.10-14.88, p=0.03). CONCLUSIONS: The symptoms and unique findings that make up RS(3)PE appear to represent a steroid-responsive disease that may be a harbinger of an underlying malignancy. More study is needed to understand the molecular origins of RS(3)PE in order to determine whether it is a separate disease process. Patients with concurrent cancer tend to have more severe presentations and higher rates of recurrence.
29173689 Esophageal abnormalities in juvenile localized scleroderma: is it associated with other ex 2017 Nov OBJECTIVE: To assess esophageal involvement (EI) in juvenile localized scleroderma (JLS) population and the possible association between this gastrointestinal manifestation and demographic data, clinical features, laboratory exams, treatments and outcomes. METHODS: For a period of 30 years, 5881 patients with rheumatic diseases were followed in our Pediatric Rheumatology Division. EI was defined by the presence of symptoms (solid/liquid dysphagia, heartburn, esophageal regurgitation, nausea/vomiting and epigastralgia) and confirmed by at least one EI exam abnormality: barium contrast radiography, upper gastrointestinal endoscopy and 24-hour esophageal pH-monitoring. RESULTS: JLS was observed in 56/5881 patients (0.9%), mainly linear morphea subtype. EI was observed in 23/56(41%) of JLS patients. Eight(35%) of 23 EI patients with JLS were symptomatic and presented heartburn(5/8), solid and liquid dysphagia(3/8), nausea and epigastralgia(1/8). The frequency of any cumulative extracutaneous manifestations (calcinosis, arthritis/arthralgia, central nervous system, interstitial pneumonitis, mesangial nephritis and/or arrhythmia) was significantly higher in JLS patients with EI compared to those without this complication (56% vs. 24%, p=0.024). No differences were evidenced in demographic data, JLS subtypes and in each extracutaneous manifestation in both groups (p>0.05). The frequency of methotrexate use was significantly higher in JLS patients with EI compared to those without (52% vs. 12%, p=0.002). Autoantibody profile (antinuclear antibodies, anti-SCL-70, rheumatoid factor, anticentromere, anti-cardiolipin, anti-Ro/SSA and anti-La/SSB) was similar in both groups (p>0.05). CONCLUSIONS: Our study demonstrated that EI was frequently observed in JLS patients, mainly in asymptomatic patients with linear subtype. EI occurred in JLS patients with other extracutaneous manifestations and required methotrexate therapy.
25994030 Association of large intergenic noncoding RNA expression with disease activity and organ d 2015 May 21 INTRODUCTION: Despite growing evidence that large intergenic noncoding RNAs (lincRNAs) can regulate gene expression and widely take part in normal physiological and disease conditions, our knowledge of systemic lupus erythematosus (SLE)-related lincRNAs remains limited. The aim of this study was to detect the levels of four lincRNAs (ENST00000500949: linc0949, ENST00000500597: linc0597, ENST00000501992: linc1992, and ENST00000523995: linc3995) involved in innate immunity in the peripheral blood mononuclear cells (PBMCs) of patients with SLE and correlate these lincRNA levels with disease activity, organ damage, clinical features and medical therapies. METHODS: PBMCs were obtained from 102 patients with SLE, 54 patients with rheumatoid arthritis (RA) and 76 healthy donors. lincRNA expression levels were measured by real-time quantitative polymerase chain reaction. Disease activity was assessed using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) scores, and organ damage was evaluated with the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index. RESULTS: linc0949 and linc0597 were significantly decreased in patients with SLE compared with patients with RA and healthy control subjects. linc0949 was correlated with SLEDAI-2K score (r = -0.329, P = 0.0007), as well as with complement component C3 level (r = 0.348, P = 0.0003). The level of linc0949 was also reduced in patients with SLE who had the presence of cumulative organ damage. In addition, decreasing expression of linc0949 was associated with lupus nephritis. linc0949 expression significantly increased after treatment, whereas neither disease activity nor organ damage correlated with linc0597 expression. CONCLUSIONS: Our results provide novel empirical evidence that linc0949 could be a potential biomarker for diagnosis, disease activity and therapeutic response in SLE.
26939927 PROMIS Fatigue Item Bank had Clinical Validity across Diverse Chronic Conditions. 2016 May OBJECTIVE: To evaluate the comparability and responsiveness of Patient-Reported Outcomes Measurement Information System (PROMIS) fatigue item bank across six chronic conditions. STUDY DESIGN AND SETTING: Individuals (n = 1,430) with chronic obstructive pulmonary disease (n = 125), chronic heart failure (n = 60), chronic back pain (n = 218), major depressive disorder (n = 196), rheumatoid arthritis (n = 521), and cancer (n = 310) completed assessments from the PROMIS fatigue item bank at baseline and a clinically relevant follow-up. The cancer and arthritis samples were followed in observational studies; the other four groups were enrolled immediately before a planned clinical intervention. All participants completed global ratings of change at follow-up. Linear mixed-effects models and standardized response means were estimated to examine clinical validity and responsiveness to change. RESULTS: All patient groups reported more fatigue than the general population (range = 0.2-1.29 standard deviation worse). The four clinical groups with pretreatment baseline data experienced significant improvement in fatigue at follow-up (effect size range = 0.25-0.91). Individuals reporting better overall health usually experienced larger fatigue changes than those reporting worse overall health. CONCLUSION: The results support the PROMIS fatigue measures's responsiveness to change in six different chronic conditions. In addition, these results support the ability of the PROMIS fatigue measures to compare differences in fatigue across a range of chronic conditions, thereby enabling comparative effectiveness research.
27149136 Paraneoplastic Scleroderma: Are There Any Clues? 2016 Apr Dear Editor, Scleroderma associated with neoplasia is rare, with only a small number of cases reported. We describe 4 patients with paraneoplastic scleroderma who were treated at the I. Department of Dermatovenereology, St. Anna Hospital, during the period between 2004 and 2014. The patients were diagnosed with cholangiogenic carcinoma, endometrial carcinoma, prostatic adenocarcinoma, and adenoma of the suprarenal gland. In the case of concurrent scleroderma and tumor, four situations may occur: they can develop independently of each other; scleroderma may be induced by the tumor; the tumor can develop in the scleroderma; or the tumor can be induced by immunosuppressive therapy. Sclerotization of the skin was described in association with lung cancer, carcinoid, plasma cell dyscrasia, cancer of the ovary, cervix, breast, esophagus, stomach, nasopharynx, melanoma, and sarcoma (1,2,5,7,10). Symptoms may be induced by substances secreted by the tumor (hormones, cytokines, etc.) (9). Tumorous cells further induce cytotoxic and autoantibody response. Scleroderma is characterized by immunological dysregulation, vasculopathy, and hyperproduction of the extracellular matrix by activated fibroblasts. Endothelial, inflammatory, and mesenchymal cells produce cytokines, chemokines, and growth factors e.g. Interleukin-1 (IL1), Interleukin-6 (IL6), tumor necrosis factor alpha (TNF α), collagen alpha 1, connective tissue growth factor (CTGF) (3), and basic fibroblast growth factor (bFGF). This factor is also produced by lung cancer cells (4). The clinical picture of scleroderma and paraneoplastic scleroderma is similar. Diffuse thickening of the skin and/or sclerodermatous plaques can be seen. The histological picture is consistent with scleroderma. Capillaroscopy changes, antinuclear antibodies (ANA), sclerodactyly, and Raynaud phenomenon suggest the diagnosis of systemic scleroderma (SS) (4). Our patients did not fulfill enough of the criteria for SS. Both diffuse and localized scleroderma was seen in 3 patients and generalized localized scleroderma in one case. All patients had a histological picture consistent with scleroderma, negative ANA and ENA antibodies (Table 1, Figure 1). A 66-year-old woman presented with a 10 months history of sclerodermatous plaques on her neck, trunk, and upper and lower extremities. The skin on her breasts and cheeks was diffusely indurated. Examination showed thrombocytopenia, elevated transaminases, Cancer antigen 19-9 (Ca 19-9), thyroid stimulating hormone (TSH), and anti-thyroid peroxidase antibodies, dysmotility of the lower part of esophagus, hepatosplenomegaly, cholecystolithiasis, and benign polyps of colon. She was given prednisone 40 mg/day but did not return for follow up. After 6 months she was diagnosed with cholangiogenic carcinoma with metastatic disease and died shortly afterwards. A 74-year-old woman had localized scleroderma on the trunk for three years. She was treated with procaine penicillin for positive borrelia Immunoglobulin M (IgM) antibodies. Her condition worsened suddenly with confluent scleroderma plaques on her trunk, extremities, and genital region, and vasoneurosis on her lower extremities; she was started on prednisone 35 mg/day. Examination revealed endometrial cancer. The patient underwent a hysterectomy, adnexectomy, and radiotherapy with curative effect. Scleroderma patches softened with residual hyperpigmentation, and prednisone was stopped two years later. A 80-year-old man had a month-long history of diffuse thickening and toughening of the skin on the forearms and lower legs and scleroderma patches on the thighs and shins. Examination revealed prostate adenocarcinoma, and therapy with antiandrogen bicalutamide and prednisone 15 mg/day was started. Two years after the diagnosis he continues with bicalutamide treatment, prednisone 5 mg q.a.d. and has residual toughening of the skin on his lower legs. A 62-year-old woman with seronegative rheumatoid arthritis presented with diffusely tough skin on her extremities and trunk, present for 2 months. Examination revealed cervicitis with a benign endometric polyp, cholecystolithiasis, borderline pulmonary hypertension, and a hormonally inactive suprarenal adenoma. She was given prednisone 40 mg/day and penicillamine with effect. In the 3rd year of therapy she has residual induration of her lower legs and a scleroderma plaque in the lumbar region. She is monitored for her suprarenal adenoma. Two patients had scleroderma at the same time as a malignant tumor; in one patient the localized scleroderma worsened rapidly at the time of the tumor diagnosis, and in one patient a clinically silent adenoma was found. Adrenal tissue can secrete molecules such as serotonine or bFGF involved in fibroplasia (3,6). One patient died of a metastatic disease, two patients after the successful treatment of the tumor, and the patient with suprarenal adenoma experienced softening of the skin and regression of scleroderma. Although paraneoplastic scleroderma is often classified as a pseudoscleroderma, we regard neoplasia as a distinct triggering impulse for scleroderma. Recently, an association between RNA polymerase I/III antibodies in systemic scleroderma and cancer was suggested (8). Such studies may confirm the true link between scleroderma and malignancy. These patients are characterized by older age, sudden onset, diffuse thickening of the skin, and/or generalized morphea with a concurrent neoplastic process. In the case of a successful tumor treatment, skin changes regress.
26633184 Ipilimumab Therapy in Patients With Advanced Melanoma and Preexisting Autoimmune Disorders 2016 Feb IMPORTANCE: Ipilimumab and other immune therapies are effective treatment options for patients with advanced melanoma but cause frequent immune-related toxic effects. Autoimmune diseases are common, and the safety and efficacy of ipilimumab therapy in patients with preexisting autoimmune disorders is not known. OBJECTIVE: To determine the safety and efficacy of ipilimumab therapy in patients with advanced melanoma with preexisting autoimmune disorders. DESIGN, SETTING, AND PARTICIPANTS: Retrospective review of patients with advanced melanoma and preexisting autoimmune disorders who received ipilimumab at 9 academic tertiary referral centers from January 1, 2012, through August 1, 2015. The data analysis was performed on August 24, 2015. EXPOSURE: Ipilimumab therapy. MAIN OUTCOMES AND MEASURES: Safety, in terms of frequency of autoimmune flares and conventional immune-related adverse events (irAEs), and efficacy, in terms of response rates and overall survival, were evaluated descriptively. RESULTS: Of the 30 patients who received ipilimumab (17 [57%] male; median [range] age, 59.5 [30-80] y), 6 had rheumatoid arthritis, 5 had psoriasis, 6 had inflammatory bowel disease, 2 had systemic lupus erythematosus, 2 had multiple sclerosis, 2 had autoimmune thyroiditis, and 7 had other conditions. Thirteen patients (43%) were receiving immunosuppressive therapy at the time of initiation of ipilimumab therapy, most commonly low-dose prednisone or hydroxychloroquine. With ipilimumab treatment, 8 patients (27%) experienced exacerbations of their autoimmune condition necessitating systemic treatment; all were managed with corticosteroids. Conventional grade 3 to 5 irAEs occurred in 10 patients (33%) and were reversible with corticosteroids or with infliximab therapy in 2 cases. One patient with baseline psoriasis died of presumed immune-related colitis after a 1-week delay prior to reporting symptoms. Fifteen patients (50%) had neither autoimmune disease flares nor irAEs. Six patients experienced an objective response (20%), including 1 with a durable complete response. CONCLUSIONS AND RELEVANCE: To our knowledge, this is the largest series of patients with preexisting autoimmune disease treated with immune checkpoint inhibitors. Ipilimumab was clinically active and was associated with exacerbations of autoimmune disease and conventional ipilimumab-induced irAEs that were readily manageable with standard therapies when started in a timely fashion. Ipilimumab therapy may be considered in this setting with vigilant clinical monitoring.
26061388 Discovery of 1-{4-[3-fluoro-4-((3s,6r)-3-methyl-1,1-dioxo-6-phenyl-[1,2]thiazinan-2-ylmeth 2015 Jul 9 Retinoic acid receptor-related orphan receptor C (RORc, RORγ, or NR1F3) is a nuclear receptor that plays a major role in the production of interleukin (IL)-17. Considerable efforts have been directed toward the discovery of selective RORc inverse agonists as potential treatments of inflammatory diseases such as psoriasis and rheumatoid arthritis. Using the previously reported tertiary sulfonamide 1 as a starting point, we engineered structural modifications that significantly improved human and rat metabolic stabilities while maintaining a potent and highly selective RORc inverse agonist profile. The most advanced δ-sultam compound, GNE-3500 (27, 1-{4-[3-fluoro-4-((3S,6R)-3-methyl-1,1-dioxo-6-phenyl-[1,2]thiazinan-2-ylmethyl)-phenyl]-piperazin-1-yl}-ethanone), possessed favorable RORc cellular potency with 75-fold selectivity for RORc over other ROR family members and >200-fold selectivity over 25 additional nuclear receptors in a cell assay panel. The favorable potency, selectivity, in vitro ADME properties, in vivo PK, and dose-dependent inhibition of IL-17 in a PK/PD model support the evaluation of 27 in preclinical studies.
24451241 Hormone replacement therapy and mid-term implant survival following knee or hip arthroplas 2015 Mar OBJECTIVES: Osteolysis and subsequent prosthesis loosening is the most common cause for revision following total knee arthroplasty (TKA) or total hip arthroplasty (THA). Hormone replacement therapy (HRT) could reduce osteolysis through its antiresorptive effects. We studied whether HRT use is associated with reduced revision rates in a community-based cohort of women undergoing TKA or THA for osteoarthritis. METHODS: Female participants in the General Practice Research Database undergoing a primary TKA or THA from 1986 to 2006 were included. We excluded patients aged <40 years at the date of primary, and those with a history of previous hip fracture or rheumatoid arthritis. Women with at least 6 months of HRT were identified as HRT users. We further explored the associations among HRT use of ≥12 months, adherence (medication possession ratio) and cumulative use and revision risk. Cox models were fitted to model implant survival in years. Propensity score matching was used to control for confounding. RESULTS: We matched 2700 HRT users to 8100 non-users, observed for a median (IQR) of 3.3 (1.5-6.1) years after TKA/THA. HR for HRT ≥6 months was 0.62 (95% CI 0.41 to 0.94), whereas HR for ≥12 months was 0.48 (0.29 to 0.78). Higher adherence and therapy duration were associated with further reductions in revision rates. Preoperative HRT appeared unrelated to implant survival. CONCLUSIONS: HRT use is associated with an almost 40% reduction in revision rates after a TKA/THA. These findings require replication in external cohorts and experimental studies.
27989618 Pharmacokinetic Interactions Between Pelubiprofen and Eperisone Hydrochloride: A Randomize 2017 Jan PURPOSE: Pelubiprofen is a novel nonsteroidal anti-inflammatory, analgesic, and antipyretic drug with at least similar efficacy and better tolerability compared with other nonsteroidal anti-inflammatory, analgesic, and antipyretic drugs such as naproxen and aceclofenac. Eperisone hydrochloride is a centrally acting muscle relaxant that performs by blocking calcium channels. The combined use of pelubiprofen and eperisone hydrochloride is increasingly anticipated to promote the clinical effectiveness of pelubiprofen in relieving musculoskeletal symptoms of osteoarthritis, rheumatoid arthritis, and low back pain. No published data are yet available, however, regarding the pharmacokinetic interactions between these 2 drugs when administered concurrently. The objective of this study was to evaluate any pharmacokinetic interactions between pelubiprofen and eperisone hydrochloride in healthy Korean male volunteers. METHODS: This was a randomized, open-label, crossover study. Each participant was randomly assigned to 1 of 6 treatment sequences and orally received either 45-mg sustained-release pelubiprofen, 75-mg sustained-release eperisone hydrochloride, or both as a single dose in each treatment period, with a 7-day washout period between each treatment. Serial blood samples were collected over 24 hours after dosing, and plasma concentrations of each drug and the major active metabolite of pelubiprofen (trans-alcohol pelubiprofen) were determined by using a validated HPLC-MS/MS system. Pharmacokinetic analyses were conducted by using noncompartmental methods. FINDINGS: A total of 24 men (mean ± standard deviation of: age, 29 ± 4 years; weight, 72.5 ± 7.8 kg; body mass index, 23.4 ± 1.9 kg/m(2)) were enrolled, and 23 participants completed the study. For pelubiprofen, the geometric mean ratios (90% CIs) of C(max) and AUC(0-∞) were 1.02 (0.87-1.19) and 0.97 (0.88-1.07), respectively. For the major active metabolite of pelubiprofen (trans-alcohol pelubiprofen), the geometric mean ratios (90% CIs) of C(max) and AUC(0-∞) were 1.05 (0.98-1.13) and 1.04 (1.01-1.07). For eperisone, the geometric mean ratios (90% CIs) of C(max) and AUC(0-∞) were 0.87 (0.67-1.15) and 1.05 (0.85-1.30). None of the study participants experienced serious adverse events during the study. IMPLICATIONS: No clinically significant changes were noted in the pharmacokinetic interactions of pelubiprofen, the major active metabolite of pelubiprofen (trans-alcohol pelubiprofen), and eperisone hydrochloride between monotherapy and combination therapy with 45-mg sustained-release pelubiprofen and 75-mg sustained-release eperisone hydrochloride.
27821712 Bruton's Tyrosine Kinase Small Molecule Inhibitors Induce a Distinct Pancreatic Toxicity i 2017 Jan Bruton's tyrosine kinase (BTK) is a member of the Tec family of cytoplasmic tyrosine kinases involved in B-cell and myeloid cell signaling. Small molecule inhibitors of BTK are being investigated for treatment of several hematologic cancers and autoimmune diseases. GDC-0853 ((S)-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydro-[3,4'-bipyridin]-2'-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one) is a selective and reversible oral small-molecule BTK inhibitor in development for the treatment of rheumatoid arthritis and systemic lupus erythematosus. In Sprague-Dawley (SD) rats, administration of GDC-0853 and other structurally diverse BTK inhibitors for 7 days or longer caused pancreatic lesions consisting of multifocal islet-centered hemorrhage, inflammation, fibrosis, and pigment-laden macrophages with adjacent lobular exocrine acinar cell atrophy, degeneration, and inflammation. Similar findings were not observed in mice or dogs at much higher exposures. Hemorrhage in the peri-islet vasculature emerged between four and seven daily doses of GDC-0853 and was histologically similar to spontaneously occurring changes in aging SD rats. This suggests that GDC-0853 could exacerbate a background finding in younger animals. Glucose homeostasis was dysregulated following a glucose challenge; however, this occurred only after 28 days of administration and was not directly associated with onset or severity of pancreatic lesions. There were no changes in other common serum biomarkers assessing endocrine and exocrine pancreatic function. Additionally, these lesions were not readily detectable via Doppler ultrasound, computed tomography, or magnetic resonance imaging. Our results indicate that pancreatic lesions in rats are likely a class effect of BTK inhibitors, which may exacerbate an islet-centered pathology that is unlikely to be relevant to humans.
26809250 Attention-Deficit/Hyperactivity Disorder in Offspring of Mothers With Inflammatory and Imm 2017 Mar 1 BACKGROUND: Prenatal inflammatory mechanisms may play a role in the pathogenesis of psychiatric disorders and could be relevant for attention-deficit/hyperactivity disorder (ADHD). We investigated maternal chronic somatic diseases with immune components as possible risk factors for ADHD in offspring. METHODS: We performed a population-based nested case-control study by linking data from longitudinal Norwegian registers. We included all individuals born during the period 1967-2008 and alive at record linkage (2012). Individuals receiving ADHD medication during the years 2004-2012 were defined as patients with ADHD (N = 47,944), and all remaining individuals (N = 2,274,713) were defined as control subjects. The associations between maternal diseases and ADHD in offspring were analyzed using logistic regression models. RESULTS: The following chronic diseases with immune components were related to ADHD in offspring: multiple sclerosis (adjusted odds ratio [OR] = 1.8; 95% confidence interval [CI] = 1.2-2.5), rheumatoid arthritis (adjusted OR = 1.7; 95% CI = 1.5-1.9), type 1 diabetes (adjusted OR = 1.6; 95% CI = 1.3-2.0), asthma (adjusted OR = 1.5; 95% CI = 1.4-1.6), and hypothyroidism (adjusted OR = 1.2; 95% CI = 1.1-1.4). In contrast, chronic hypertension and type 2 diabetes showed no significant associations. Estimates were almost unchanged with additional adjustment for parental ADHD, infant birth weight, and gestational age. Although point estimates for male and female offspring were different for some diseases (e.g., maternal asthma [adjusted OR = 1.7; 95% CI = 1.5-1.8 for female offspring and adjusted OR = 1.5; 95% CI = 1.4-1.6 for male offspring]), none of the associations differed significantly by offspring sex. CONCLUSIONS: Several maternal somatic diseases with immune components were found to increase the risk of ADHD in offspring. The associations could involve several causal pathways, including common genetic predisposition and environmental factors, and increased insight into the mechanisms behind these relationships could enhance our understanding of the etiology of ADHD.
25986135 Underuse and Overuse of Osteoporosis Screening in a Regional Health System: a Retrospectiv 2015 Dec BACKGROUND: The United States Preventive Services Task Force (USPSTF) recommends screening for osteoporosis with dual-energy x-ray absorptiometry (DXA) for women aged ≥ 65 years and younger women with increased risk. "Choosing Wisely" initiatives advise avoiding DXA screening in women younger than 65 years without osteoporosis risk factors. OBJECTIVE: We aimed to determine the extent to which DXA screening is used in accordance with USPSTF recommendations within a regional health system. DESIGN: This was a retrospective longitudinal cohort study within 13 primary care clinics in the Sacramento, CA region. PATIENTS: The study included 50,995 women aged 40-85 years without prior osteoporosis screening, diagnosis, or treatment attending primary care visits from 2006 to 2012, observed for a mean of 4.4 years. MAIN MEASURES: We examined incidence of DXA screening. Covariates included age, race/ethnicity, and osteoporosis risk factors (body mass index < 20, glucocorticoid use, secondary osteoporosis, prior high-risk facture, rheumatoid arthritis, alcohol abuse, and current smoking). KEY RESULTS: Among previously unscreened women for whom the USPSTF recommends screening, 7-year cumulative incidence of DXA screening was 58.8 % among women aged 60-64 years with ≥ 1 risk factor (95 % CI: 51.9-65.8 %), 57.8 % for women aged 65-74 years (95 % CI: 55.6-60.0 %), and 42.7 % for women aged ≥ 75 years (95 % CI: 38.7-46.7 %). Among women for whom the USPSTF does not recommend screening, 7-year cumulative incidence was 45.5 % among women aged 50-59 years (95 % CI 44.1-46.9 %) and 58.6 % among women aged 60-64 years without risk factors (95 % CI 55.9-61.4 %). CONCLUSIONS: DXA screening was underused in women at increased fracture risk, including women aged ≥ 65 years. Meanwhile, DXA screening was common among women at low fracture risk, such as younger women without osteoporosis risk factors. Interventions may be needed to augment the value of population screening for osteoporosis.
25700363 Repurposing auranofin as a lead candidate for treatment of lymphatic filariasis and onchoc 2015 Feb Two major human diseases caused by filariid nematodes are onchocerciasis, or river blindness, and lymphatic filariasis, which can lead to elephantiasis. The drugs ivermectin, diethylcarbamazine (DEC), and albendazole are used in control programs for these diseases, but are mainly effective against the microfilarial stage and have minimal or no effect on adult worms. Adult Onchocerca volvulus and Brugia malayi worms (macrofilariae) can live for up to 15 years, reproducing and allowing the infection to persist in a population. Therefore, to support control or elimination of these two diseases, effective macrofilaricidal drugs are necessary, in addition to current drugs. In an effort to identify macrofilaricidal drugs, we screened an FDA-approved library with adult worms of Brugia spp. and Onchocerca ochengi, third-stage larvae (L3s) of Onchocerca volvulus, and the microfilariae of both O. ochengi and Loa loa. We found that auranofin, a gold-containing drug used for rheumatoid arthritis, was effective in vitro in killing both Brugia spp. and O. ochengi adult worms and in inhibiting the molting of L3s of O. volvulus with IC50 values in the low micromolar to nanomolar range. Auranofin had an approximately 43-fold higher IC50 against the microfilariae of L. loa compared with the IC50 for adult female O. ochengi, which may be beneficial if used in areas where Onchocerca and Brugia are co-endemic with L. loa, to prevent severe adverse reactions to the drug-induced death of L. loa microfilariae. Further testing indicated that auranofin is also effective in reducing Brugia adult worm burden in infected gerbils and that auranofin may be targeting the thioredoxin reductase in this nematode.