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ID PMID Title PublicationDate abstract
27789216 Artesunate suppresses RANKL-induced osteoclastogenesis through inhibition of PLCγ1-Ca(2+) 2017 Jan 15 Bone lytic diseases including osteoporosis, rheumatoid arthritis, and bone metastatic tumors affect hundreds of millions people worldwide. Targeting over-activated osteoclasts as an anti-resorptive treatment becomes an important strategy to treat osteolytic diseases. Artesunate is a compound derived from artemisinin (qinghaosu) and has been used to treat malaria and rheumatoid arthritis clinically in China, but its role in osteolysis is unknown. Here, we found that artesunate could suppress RANKL-induced osteoclastogenesis and bone resorption from 1.56 to 12.5μM. Artesunate obviously reduced RANKL-induced NF-κB-luc activity at 50μM, but had no effects on RANKL-induced NF-κB activation (NF-κB luciferase activity, IκB-α degradation and nuclear NF-κB p65 protein level) from 3.125 to 12.5μM in pre-osteoclastic RAW264.7 cells. Interestingly, artesunate could significantly inhibit RANKL-induced NFATc1 activation measured by NFAT luciferase activity, NFATc1 mRNA and nuclear NFATc1 protein levels from 3.125 to 12.5μM. Further study revealed that artesunate inhibited RANKL up-regulated PLCγ1 activation, intracellular calcium, and calcineurin (PP2B-Aα) protein expression from 3.125 to 12.5μM. In addition, the NFATc1 targeted osteoclast-specific genes expression including cathepsin K, MMP-9, and TRAP was reduced by artesunate. Finally, we showed that artesunate was able to reverse the bone loss in an ovariectomized mouse model in vivo accompanied with reduced RANKL, RANKL/OPG, and TRAP-5b levels. This study indicates that artesunate inhibits RANKL-induced osteoclastogenesis and bone loss by inhibiting PLCγ1-Ca(2+)-calcineurin-NFATc1 pathway. Collectively, our data suggest that artesunate is a potential treatment option against RANKL-mediated osteolytic bone disease.
29328034 CHARACTERISTICS OF ARTICULAR SYNDROME IN SYSTEMIC VASCULITIS. 2017 Dec The purpose of the study - investigation the separate joint lesion in systemic vasculitis, their X-ray sonographic characteristics, the correlation of the articular syndrome severity with extra-articular manifestations of the diseases, as well as aspects of the arthritis pathogenesis in this category of patients. The study included 525 patients in the ratio of the examined with Henoch-Schonlen purpura, microscopic polyangiitis, cryoglobulinemic vasculitis, polyarteritis nodosa, Takayasu's arteritis, Wegener's granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis Churg-Strauss as a 7:4:3:1:1:1:1. Joint's damage in the form of arthritis or arthralgia observed in 32-67% different groups of patients, that depending on the disease duration, the degree of the pathological process's activity, extraarticular signs severity, lung parenchyma involving and hemodynamic status in the pulmonary circulation. The frequency of the certain bone lesions, existence of tenosynovitis and enthesopathies, X-ray sonographic signs of articular syndrome in different kind of vasculitis has its own gender dimorphism. The immune system malfunction, the rheological properties of blood and endothelial function of vessels collaborate in pathogenetic constructions of arthropathy. What is more, the high value of rheumatoid factor in blood associates with severe course of joint damage. Joint syndrome at different variants of systemic vasculitis is progressing in 1/3-2/3 of cases, this syndrome has definite features of clinical course and pathogenesis.
29457414 [Clinical research of popliteal cyst excision combined with debridement of the knee under 2017 Oct 25 OBJECTIVE: To evaluate the clinical effects of popliteal cyst excision combined with debridement of the knee under arthroscopy with local anesthesia. METHODS: From February 2009 to August 2014, 52 patients with popliteal cysts were treated in our hospital, including 34 males and 18 females with an average age of 43.6 years old ranging from 14 to 62 years old; 29 cases were on the right knee and 23 on the left knee. Preoperative diagnosis was performed according to MRI findings and to determine whether other knee disorders were associated with the disease, 52 patients were diagnosed as popliteal cyst before operation; 23 cases of simple meniscus injury or cartilage injury, 18 cases of osteoarthritis, 7 cases of cruciate ligament injury, 2 cases of gouty arthritis, 1 case of rheumatoid arthritis, 1 case of pigmented villonodular arthritis. The preoperative clinical manifestations involved knee swelling in 21 cases, knee joint pain in 16 cases, joint lock in 8 cases, leg weakness in 4 cases, and knee joint snapping in 4 cases. Cyst size was 4.0 cm× 3.3 cm to 6.2 cm× 5.3 cm. According to the Rauschning and Lindgren standards, 1 case was grade I, 9 cases were grade II, 42 cases were class III. The rehabilitation plan should be made according to the patient's specific injuries and intraoperative management. During the postoperative follow-up, the postoperative curative effect was evaluated by the standard grading of Rauschning and Lindgren of popliteal cyst. RESULTS: All the incisions healed by first intention, and no complications occurred. All the cases were followed up from 25 to 64 months (averaged 39.6 months). For the Rauschning and Lindgren grading, 43 cases were grade 0, 8 cases were grade I, 1 case were grade II. CONCLUSIONS: Local anesthesia under arthroscopy and popliteal cyst removal knee joint cavity debridement is effective, less trauma, quick recovery, short term effect is good. The recurrence rate is also low because of the primary disease of the knee joint is also treated. After the operation, the rehabilitation plan should be made according to the intraoperative treatment and actively trained so as to recover at an early date.
28377641 The Correlation of CD206, CD209, and Disease Severity in Behçet's Disease with Arthritis. 2017 The purpose of this study was to clarify the role of pattern recognition receptors in Behçet's disease (BD). The frequencies of several pattern recognition receptors (CD11b, CD11c, CD32, CD206, CD209, and dectin-1) were analyzed in patients with BD by flow cytometry, and cytokine levels, interleukin- (IL-) 18, IL-23, and IL-17A, were compared in plasma. The analysis was performed in active (n = 13) and inactive (n = 13) stages of BD patients. Rheumatoid arthritis patients (n = 19), as a disease control, and healthy control (HC) (n = 19) were enrolled. The frequencies of CD11b+ and CD32+ cells were significantly increased in active BD patients compared to HC. Disease severity score was correlated to CD11c+, CD206+, and CD209+ in whole leukocytes and CD11b+, CD11c+, CD206+, CD209+, and Dectin-1+ in granulocytes. The plasma levels of IL-17A were significantly different between HC and active BD. IL-18 showed significant difference between active and inactive BD patients. From this study, we concluded the expressions of several pattern recognition receptors were correlated to the joint symptoms of BD.
29277097 Systemic review: agreement between the latent tuberculosis screening tests among patients 2018 Nov BACKGROUND/AIMS: To estimate the level of agreement and positivity rates of latent tuberculosis infection (LTBI) tests prior to the use of tumor necrosis factor (TNF) inhibitors in relation to underlying rheumatic diseases and endemic tuberculosis levels. METHODS: The Ovid-Medline, Embase, and Cochrane Libraries were searched for articles before October 2013 involving LTBI screening in rheumatic patients, including rheumatoid arthritis (RA), ankylosing spondylitis (AS), juvenile idiopathic arthritis (JIA), and psoriatic arthritis. RESULTS: In pooled analyses, 5,224 rheumatic patients had undergone both a tuberculin skin test (TST) and an interferon-gamma release assay (IGRA) before TNF inhibitors use. The positivity of TST, QuantiFERON-TB Gold In Tube (QFT-GIT), and T-SPOT.TB (T-SPOT) tests were estimated to be 29%, 17%, and 18%, respectively. The agreement percentage between the TST and QFT-GIT, and between the TST and T-SPOT were 73% and 75%. Populations from low-to-moderate endemic TB presented with slightly less agreement (71% between TST and QFT-GIT, and 74% between TST and T-SPOT) than patients from high endemic countries (73% between TST and QFT-GIT, and 81% between TST and T-SPOT). By underlying disease stratification, a lower level of agreement between TST and QFT-GIT was found among AS (64%) than among JIA (77%) and RA patients (73%). CONCLUSION: We reaffirm the current evidence for accuracy of LTBI test done by TST and IGRA among rheumatic patients is inconsistent. Our stratified analysis suggests different screening strategies might be needed in clinical settings considering the endemic status in the patient's country of origin and the precise nature of underlying diseases.
28238882 Rheumatic manifestations associated with Chikungunya virus infection: A study of 307 patie 2018 Mar OBJECTIVES: In the wake of the Chikungunya epidemic which struck Reunion Island in 2005 and 2006, we conducted a prospective, multicentre study (RHUMATOCHIK) whose main objective was analyse the characteristics and progression of rheumatic manifestations in patients with post-Chikungunya joint pain. METHODS: A cohort of 307 consecutively included patients underwent rheumatological examinations for pain secondary to Chikungunya virus infection. The long-term evaluation was conducted by telephone survey 1 and 2 years after the onset of the viral infection. RESULTS: At inclusion, mean age was 54 years (24-87) and 83.1% of the patients were female. Chronic joint pain was associated with synovitis in 64.2% of the patients, affecting primarily the wrists, the proximal interphalangeal joints of the fingers, and the ankles. Attempts to detect the viral genome in joint fluid (10 patients) and synovial tissue (6 patients) using the RT-PCR technique were repeatedly unsuccessful. With a mean follow-up of 32 months, joint pain persisted in 83.1% of the patients. Functional impairment, however, was moderate, with a HAQ score of 0.44±0.5. CONCLUSION: Chikungunya virus infection is frequently the cause of joint manifestations that can persist for several months, or even several years. In some cases, the clinical symptoms closely resemble those usually associated with rheumatoid arthritis. Further studies are necessary to improve the therapeutic management of these patients.
28871434 Cutaneous and Mucosal Manifestations of Sjögren's Syndrome. 2017 Dec Sjögren's syndrome is currently considered an "autoimmune epithelitis," as exocrine glands, especially salivary and lacrimal, are progressively destructed by an immune-mediated process associated with specific serum autoantibodies and local lymphocyte infiltrate. Xerostomia remains a key complain in patients with Sjögren's syndrome but should be evaluated also for other causes such as xerogenic medications, followed by radiation and chemotherapy for head and neck cancers, hormone disorders, infections, or other connective tissue diseases. Further, xerophtalmia (also known as dry eye) frequently associated with keratoconjunctivitis sicca cumulatively affects approximately 10-30% of the general population with increasing incidence with age and is more frequently secondary to non-autoimmune diseases. On the other hand, numerous patients with Sjögren's syndrome manifest signs of systemic dryness involving the nose, the trachea, the vagina, and the skin, suggesting that other glands are also affected beyond the exocrine epithelia. Skin involvement in Sjögren's syndrome is relatively common, and various manifestations may be present, in particular xeroderma, eyelid dermatitis, annular erythema, and cutaneous vasculitis. Additional skin non-vasculitic manifestations include livedo reticularis which may occur in the absence of vasculitis, and localized nodular cutaneous amyloidosis possibly representing lymphoproliferative diseases related to Sjögren's syndrome. The treatment of skin and mucosal manifestations in Sjögren's syndrome is similar regardless of the cause, starting from patient education to avoid alcohol and tobacco smoking and to pursue dental hygiene. In conclusion, a strict collaboration between the dermatologist and the rheumatologist is essential in the adequate management of Sjögren's syndrome skin and mucosal manifestations.
28834867 Cortical blindness and not optic neuritis as a cause of vision loss in a Sjögren's syndro 2017 Aug RATIONALE: The conception that multiple sclerosis may be challenging to distinguish from demyelinating manifestations of Sjögren's syndrome (SS) was introduced more than 30 years ago. However, it is now recognized that the neuromyelitis optica spectrum disorder (NMOSD) may occur more frequently in SS as opposed to multiple sclerosis. Characteristic NMOSD features can include severe attacks of optic neuritis, myelitis which is frequently longitudinally-extensive (spanning at least three vertebral segments on magnetic resonance imaging [MRI]), and an association with anti-aquaporin-4 antibodies. In addition, whereas NMOSD was initially thought to spare the brain, it is now recognized that brain lesions occur in a majority of NMOSD patients. Therefore, it is important for the multi-disciplinary team of physicians who care for SS patients to understand this widening spectrum of NMOSD as encompassing brain lesions. In this case-report we describe clinical features, radiographic findings, and treatment of a SS NMOSD patient presenting with severely decreased visual acuity, visual hallucinations, and encephalopathy. PATIENT CONCERNS: The SS NMOSD patient presented with rapid, bilateral onset of severely decreased visual acuity and was therefore suspected as having bilateral optic neuritis. DIAGNOSIS: However, the patient lacked stigmata of optic neuritis, instead had visual hallucinations and encephalopathy suggestive of cortical blindness, and was noted to have occipital lobe lesions on brain MRI. Other radiographic findings included simultaneous enhancement of brainstem and periventricular lesions. INTERVENTIONS: The patient was initially treated with methylprednisolone with no change in her neurological deficits. She was then treated with plasma exchange therapy. OUTCOMES: The patient had resolution of decreased visual acuity, visual hallucinations, encephalopathy, and contrast-enhancing brain lesions in response to plasma exchange therapy. LESSON: We provide the first example of severely decreased visual acuity in a NMOSD patient due to cortical blindness and not bilateral optic neuritis. This finding expands the spectrum of central nervous system syndromes and brain lesions which may occur in NMOSD. The synchronous enhancement of a brainstem lesion (known to occur in NMOSD) with occipital lobe lesions also suggests that our patient's occipital lobe findings were due to NMOSD. All of our patient's findings had an excellent clinical and radiographic response to plasma exchange therapy.
28552951 Common variants near IKZF1 are associated with primary Sjögren's syndrome in Han Chinese. 2017 Primary Sjögren's syndrome (pSS) is a systematic autoimmune disease with evidence of genetic predisposition. The IKZF1 (IKAROS family zinc finger 1 (Ikaros)) gene is located at 7p12.2, encodes a transcription factor related to chromatin remodeling, regulates lymphocyte differentiation, and has been reported to be associated with some autoimmune diseases. However, there have been no reports of an association between IKZF1 and pSS. To investigate the possibility of an association between the IKZF1 locus and pSS, we selected two single nucleotide polymorphisms (SNPs) in the IKZF1 locus, rs4917129 and rs4917014, based on a detailed analysis of genome-wide association study (GWAS) data and performed genotyping in 665 Han Chinese pSS patients and 863 healthy controls. The results of an association test showed significant association signals (rs4917129: P-value = 5.5e-4, OR (odds ratio) = 0.72, 95% CI (confidence interval) = 0.60-0.87; rs4917014: P-value = 1.2e-3, OR = 0.76, 95% CI = 0.64-0.89). A meta-analysis that combined the above results with data from previous GWAS, further confirmed these associations (rs4917129: Pmeta = 4.24e-8, ORmeta = 0.70, 95% CI = 0.61-0.79; rs4917014: Pmeta = 6.0e-8, ORmeta = 0.72, 95% CI = 0.64-0.81). A bioinformatics analysis indicated that both SNPs were located in a putative enhancer area in immune-related cell lines and tissues. A protein-protein interaction analysis found that IKZF1, together with GTF2I (an SS susceptibility gene newly identified through GWAS), could interact with histone deacetylase family proteins. In summary, this is the first study to report an association between IKZF1 and SS in Han Chinese.
26496782 No Zinc Deficiency But a Putative Immunosuppressive Role for Labile Zn in Patients with Sy 2017 BACKGROUND: Zn (Zn) is an essential trace element with important roles in protein structure and function. Labile Zn is the fraction available for regulatory functions through it loose binding to albumin. As Zn deprivation reduces labile Zn levels and leads to an immune compromised state, we investigated labile Zn levels in the context of systemic autoimmune disease. METHODS: Cross sectional case control study in patients with Systemic Lupus Erythematosus (SLE; n= 45), primary Sjögren's Syndrome (n= 53) and healthy controls (HC; n= 27). Serum labile Zn levels were measured by an in-house assay using the UV-excitable fluorophore zinquin ethyl ester. Associations between labile Zn levels and SLE manifestations were investigated by nonparametric methods. RESULTS: None of the SLE or pSS patients was found to be Zn deficient. Labile Zn levels were significantly higher in SLE (31.7 mcg/dl) than in pSS patients (22.3 mcg/dl) and HC (19.7 mcg/dl) (p<0.001). Labile Zn levels did not associate with demographics, disease activity scores, or inflammatory cytokine levels, but correlated inversely with lymphocyte counts (Rs -0.37, p<0.01), antidsDNA, anticardiolipin (Rs -0.29, p=0.01), anti-rib P antibody levels (Rs -0.24, p=0.02) and with circulating NK-cell numbers in SLE patients (Rs .27, p= 0.02). CONCLUSIONS: There is no evidence of Zn deficiency in patients with pSS or SLE. Labile Zn levels are unexpectedly high in SLE patients, independent of cytokine levels and may play a role in immune modulation through increased NK numbers and autoantibody containment.
27914689 Efficacy of biologic therapy across individual juvenile idiopathic arthritis subtypes: A s 2017 Apr OBJECTIVE: To determine the efficacy of differing biologic therapies amongst individual juvenile idiopathic arthritis (JIA) subtypes rather than JIA overall. METHODS: A systematic literature review was conducted between January 1975 and November 2014. Studies included were randomised controlled trials, controlled trials, non-randomised prospective studies or case-control studies. Subjects were required to have a diagnosis of JIA and were ≤20 years of age at study entry. Studies were deemed suitable for inclusion only when the authors reported the efficacy of biologic drugs within individual ILAR subtypes rather than JIA overall. RESULTS: Of 7663 articles identified in the original search, 25 were deemed eligible for inclusion in this review. These articles included over 4000 participants classified as having JIA, with mean age groups ranging from 3 to 13 years. Systemic JIA was the largest represented subtype, whilst the persistent oligoarthritis subtype was represented by the lowest number of participants (n = 54). Concerning etanercept, children with extended oligoarticular JIA were more likely to achieve inactive disease than other subtypes, with rheumatoid factor (RF) negative patients achieving inactive disease more frequently than RF positive children. Prospective data showed similar responses to etanercept in persistent oligoarticular groups compared to other subtypes. Etanercept was also shown to be efficacious in ERA and PsA, although the drug was not successfully discontinued in any of these patients without recurrence of the disease. In a study of abatacept, no differences were seen across subtypes. Systemic JIA appeared to be less responsive to etanercept when compared to tocilizumab over 12 weeks (etanercept: ACR30 58-78% and tocilizumab: ACR30 85%). However, longer term response over 12 months was more similar (etanercept: ACR30 83-100% and tocilizumab: ACR30 87-98%). CONCLUSIONS: This review has provided some evidence of a differing response to individual biologics according to JIA subtype and highlighted the under-representation of certain subtypes in published studies. Comparison of efficacy of individual biologics within subtypes is limited as published studies use variable methodology and head-to-head trials of biologics are lacking. Future trial design should consider differences in treatment response across and within ILAR subtypes to enable clinicians to make more relevant treatment decisions and achieve better patient outcomes.
28470759 Phosphorylated signal transducer and activator of transcription 3 in the epidermis in adul 2017 Oct Adult-onset Still's disease (AOSD) is characterized by multiple systemic inflammation of unknown etiology. Although the typical eruption of AOSD is salmon-pink rheumatoid rash on the trunk and extremities, persistent pruritic papules and plaques have also been reported. Correlations between serum cytokines, including interleukin-6 and -18, and disease activity in AOSD have been reported. Activated signal transducer and activator of transcription 3 (STAT3) is transported into the nucleus, where it functions as a transcription factor that regulates genes involved in cell survival and inflammation. To assess whether STAT3 was phosphorylated in skin samples from AOSD patients, we conducted immunohistochemical analysis of affected and unaffected lesions from four AOSD patients in comparison with 10 normal controls. Quantitative analysis was conducted by measuring the ratio of epidermal keratinocytes with phosphorylated STAT3 (p-STAT3)-positive nuclei to total epidermal keratinocytes. p-STAT3 was found to be more strongly expressed in the nuclei in the epidermis of AOSD than in normal controls. Quantification of the data revealed significant differences in staining for p-STAT3 between AOSD and normal skin. Our findings suggest that phosphorylation of STAT3 may be a potential therapeutic target for AOSD.
28298559 The Risk of Deep Venous Thrombosis and Pulmonary Embolism in Primary Sjögren Syndrome: A 2017 Aug OBJECTIVE: To estimate the future risk and time trends of venous thromboembolism (VTE) in individuals with newly diagnosed primary Sjögren syndrome (pSS) in the general population. METHODS: Using a population database that includes all residents of British Columbia, Canada, we created a study cohort of all patients with incident SS and up to 10 controls from the general population matched for age, sex, and entry time. We compared incidence rates (IR) of pulmonary embolism (PE), deep vein thrombosis (DVT), and VTE between the 2 groups according to SS disease duration. We calculated HR, adjusting for confounders. RESULTS: Among 1175 incident pSS cases (mean age 56.7 yrs, 87.6% women), the IR of PE, DVT, and VTE were 3.9, 2.8, and 5.2 per 1000 person-years (PY), respectively; the corresponding rates in the comparison cohort were 0.9, 0.8, and 1.4 per 1000 PY. Compared with non-SS individuals, the multivariable HR for PE, DVT, and VTE among SS cases were 4.07 (95% CI 2.04-8.09), 2.80 (95% CI 1.27-6.17), and 2.92 (95% CI 1.66-5.16), respectively. The HR matched for age, sex, and entry time for VTE, PE, and DVT were highest during the first year after SS diagnosis (8.29, 95% CI 2.57-26.77; 4.72, 95% CI 1.13-19.73; and 7.34, 95% CI 2.80-19.25, respectively). CONCLUSION: These findings provide population-based evidence that patients with pSS have a substantially increased risk of VTE, especially within the first year after SS diagnosis. Further research into the involvement of monitoring and prevention of VTE in SS may be warranted.
27813150 Impact of a sodium carbonate spray combined with professional oral hygiene procedures in p 2017 Jun OBJECTIVES: The aim of this study was to make an initial estimation on the effects of a sodium bicarbonate and xylitol spray (Cariex(®) ), associated with non-surgical periodontal therapy, in participants with primary Sjögren's syndrome. BACKGROUND: Sjögren's syndrome (SS) is a multisystem autoimmune disease that predominantly involves salivary and lachrymal glands, with the clinical effect of dry eyes and mouth. MATERIALS AND METHODS: A prospective cohort of 22 women and two men has been evaluated. They were randomized into three groups (eight patients each): Group A) those treated once with non-surgical periodontal therapy, education and motivation to oral hygiene, associated with the use of Cariex(®) ; Group B) treated only with Cariex(®) ; Group C) treated only with non-surgical periodontal therapy, education and motivation to oral hygiene. Clinical variables described after treatment were unstimulated whole salivary flow, stimulated whole salivary flow, salivary pH, reported pain (using Visual Analogue Scale) and the Periodontal Screening and Recording index. RESULTS: Salivary flow rate improved in all groups, but the difference was statistically significant only in those treated with Cariex(®) , alone or in combination with periodontal therapy. Gingival status improved in participants who underwent periodontal non-surgical therapy while remained unchanged in those only treated with Cariex(®) . Reported pain decreased in all groups, showing the best result in participants treated with periodontal therapy together with Cariex(®) . CONCLUSIONS: We propose a practical approach for improving gingival conditions and alleviating oral symptoms in patients with SS. Future randomized and controlled trials are however required to confirm these results as well as larger population, and also assessing other parameters due to oral dryness, possible oral infections and more comprehensive periodontal indices.
27863149 Expression of Cyclic GMP-AMP Synthase in Patients With Systemic Lupus Erythematosus. 2017 Apr OBJECTIVE: Type I interferon (IFN) is implicated in the pathogenesis of systemic lupus erythematosus (SLE) and interferonopathies such as Aicardi-Goutières syndrome. A recently discovered DNA-activated type I IFN pathway, cyclic GMP-AMP synthase (cGAS), has been linked to Aicardi-Goutières syndrome and mouse models of lupus. The aim of this study was to determine whether the cGAS pathway contributes to type I IFN production in patients with SLE. METHODS: SLE disease activity was measured by the Safety of Estrogens in Lupus Erythematosus National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index. Expression of messenger RNA for cGAS and IFN-stimulated genes (ISGs) was determined by quantitative polymerase chain reaction analysis. Cyclic GMP-AMP (cGAMP) levels were examined by multiple reaction monitoring with ultra-performance liquid chromatography tandem mass spectrometry. RESULTS: Expression of cGAS in peripheral blood mononuclear cells (PBMCs) was significantly higher in SLE patients than in normal controls (n = 51 and n = 20 respectively; P < 0.01). There was a positive correlation between cGAS expression and the IFN score (P < 0.001). The expression of cGAS in PBMCs showed a dose response to type I IFN stimulation in vitro, consistent with it being an ISG. Targeted measurement of cGAMP by tandem mass spectrometry detected cGAMP in 15% of the SLE patients (7 of 48) but none of the normal (0 of 19) or rheumatoid arthritis (0 of 22) controls. Disease activity was higher in SLE patients with cGAMP versus those without cGAMP. CONCLUSION: Increased cGAS expression and cGAMP in a proportion of SLE patients indicates that the cGAS pathway should be considered as a contributor to type I IFN production. Whereas higher cGAS expression may be a consequence of exposure to type I IFN, detection of cGAMP in patients with increased disease activity indicates potential involvement of this pathway in disease expression.
28320056 Health-Related Quality of Life in an Inception Cohort of Children With Juvenile Idiopathic 2018 Jan OBJECTIVE: To describe changes in health-related quality of life (HRQoL) over time in children with juvenile idiopathic arthritis (JIA), relative to other outcomes, and to identify predictors of unfavorable HRQoL trajectories. METHODS: Children with JIA in the Research in Arthritis in Canadian Children emphasizing Outcomes (ReACCh-Out) cohort were included. The Juvenile Arthritis Quality of Life Questionnaire (JAQQ, a standardized instrument), health-related Quality of My Life (HRQoML, an instrument based on personal valuations), and JIA core variables were completed serially. Analyses included median values, Kaplan-Meier survival curves, and latent trajectory analysis. RESULTS: A total of 1,249 patients enrolled at a median of 0.5 months after diagnosis were followed for a median of 34.2 months. The degree of initial HRQoL impairment and probabilities of reaching the best possible HRQoL scores varied across JIA categories (best for oligoarthritis, worst for rheumatoid factor-positive polyarthritis). Median times to attain best possible HRQoL scores (JAQQ 59.3 months, HRQoML 34.5 months), lagged behind those for disease activity, pain, and disability measures. Most patients followed trajectories with minimal or mild impairment; however, 7.6% and 13.8% of patients, respectively, followed JAQQ and HRQoML trajectories with persistent major impairment in HRQoL. JIA category, aboriginal ethnicity, and baseline disease activity measures distinguished between membership in trajectories with major and minimal impairments. CONCLUSION: Improvement in HRQoL is slower than for disease activity, pain, and disability. Improvement of a measure based on respondents' preferences (HRQoML) is more rapid than that of a standardized measure (JAQQ). Higher disease activity at diagnosis heralds an unfavorable HRQoL trajectory.
28732131 The Evolving Landscape for Complement Therapeutics in Rheumatic and Autoimmune Diseases. 2017 Nov The complement system is increasingly understood to play major roles in the pathogenesis of human inflammatory and autoimmune diseases. Because of this situation, there are rapidly expanding commercial efforts to develop novel complement inhibitors and effector pathway-modulating drugs. This review provides insights into the evolving understanding of the complement system components, mechanisms of activation within and across the 3 pathways (classical, alternative, and lectin), how the pathways are normally controlled and then dysregulated in target tissues, and what diseases are known to be, in large part, complement-dependent through the successful development and approval of complement therapeutics in patients. Mechanisms of complement activation in rheumatoid arthritis, lupus, and thrombotic microangiopathies are also illustrated. In addition, the specific therapeutic drugs that are both approved and under development are discussed in the context of both nonrheumatic and rheumatic diseases. Finally, the methods by which the complement system can be assessed in humans through biomarker studies are outlined, with the goal of understanding, in specific patients, how the system is functioning.
27591675 Sarcoidosis-Like Lesions: Another Paradoxical Reaction to Anti-TNF Therapy? 2017 Mar 1 BACKGROUND: Since the introduction of anti-tumour necrosis factor [TNF] therapy in inflammatory diseases, paradoxical reactions are increasingly being reported. One of these paradoxical reactions is the development of sarcoidosis-like lesions. This presentation is paradoxical since anti-TNF therapy can also be therapeutic in refractory cases of sarcoidosis. METHODS: We report two cases of sarcoidosis-like lesions under anti-TNF therapy. Both were patients with inflammatory bowel disease [IBD], treated successfully with adalimumab. Next, we reviewed the literature for similar cases. Medical subject heading terms 'adalimumab', 'infliximab', 'etanercept', 'golimumab' or 'certolizumab', and 'sarcoidosis' were used to perform key word searches of the PubMed database. RESULTS: We identified 90 reported cases of sarcoidosis-like lesions, which developed during anti-TNF therapy. In most cases, the anti-TNF drug involved was etanercept. The median age was 43 years and there was a predominance of female patients. The underlying disease was rheumatoid arthritis in most cases, followed by ankylosing spondylitis and psoriasiform arthritis. In six cases, the underlying disease was IBD. In 71 cases there was at least a partial resolution by discontinuation of the anti-TNF treatment, initiation of steroids or both. Re-initiation of anti-TNF therapy gave relapse in seven out of 20 cases. CONCLUSION: Sarcoidosis-like lesions are increasingly reported during anti-TNF treatment. Vigilance is appropriate when patients present with symptoms compatible with sarcoidosis.
27859030 Model-Informed Development and Registration of a Once-Daily Regimen of Extended-Release To 2017 Jun Extended-release (XR) formulations enable less frequent dosing vs. conventional (e.g., immediate release (IR)) formulations. Regulatory registration of such formulations typically requires pharmacokinetic (PK) and clinical efficacy data. Here we illustrate a model-informed, exposure-response (E-R) approach to translate controlled trial data from one formulation to another without a phase III trial, using a tofacitinib case study. Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). E-R analyses were conducted using validated clinical endpoints from phase II dose-response and nonclinical dose fractionation studies of the IR formulation. Consistent with the delay in clinical response dynamics relative to PK, average concentration was established as the relevant PK parameter for tofacitinib efficacy and supported pharmacodynamic similarity. These evaluations, alongside demonstrated equivalence in total systemic exposure between IR and XR formulations, provided the basis for the regulatory approval of tofacitinib XR once daily by the US Food and Drug Administration.
29576918 Nonspanning Total Wrist Arthrodesis with a Low-Profile Locking Plate. 2018 Apr Purpose  This study aims to compare the outcomes and complications of our technique for nonspanning total wrist arthrodesis using a locking plate with the standard carpometacarpal spanning technique. Methods  A retrospective review of charts was performed to identify patients who underwent total wrist arthrodesis by the senior author (S.W.W.). We compared the outcomes of 15 cases of nonspanning wrist fusion with a 2.4/2.7 mm locking T plate to 11 cases of spanning wrist fusion with a 2.7/3.5 mm locking compression plate. Minimum follow-up was 3 months. Indications for fusion included rheumatoid arthritis, posttraumatic arthritis, Kienböck's disease, primary osteoarthritis, juvenile inflammatory arthropathy, psoriasis, brachial plexopathy, failed hemi or total wrist arthroplasty, failed four-corner fusion, and failed proximal row carpectomy. The primary outcome was fusion. Secondary outcomes included time to union, patient-rated wrist evaluation score, numerical rating scale pain score, grip strength, and complications. Results  All the wrists got fused. There were no significant differences in objective and subjective outcomes between cohorts. There were three complications (27%) in the spanning group, including tendon rupture and peri-implant fracture at the third metacarpal. This was compared with three complications (20%) in the nonspanning group, consisting of hardware removal. Discussion  We achieved similar fusion rates employing both spanning and nonspanning total wrist arthrodesis techniques, without necessitating carpometacarpal arthrodesis in the latter. Complications associated with our method were comparably less severe than those reported in the literature. We advocate nonspanning arthrodesis as an alternative method for total wrist fusion with a high union rate and minimal risk of complications at the carpometacarpal joint. Level of Evidence  Therapeutic level IV.