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ID PMID Title PublicationDate abstract
28513593 Jak3 deficiency blocks innate lymphoid cell development. 2018 Jan Loss-of-function mutations in the tyrosine kinase JAK3 cause autosomal recessive severe combined immunodeficiency (SCID). Defects in this form of SCID are restricted to the immune system, which led to the development of immunosuppressive JAK inhibitors. We find that the B6.Cg-Nr1d1(tm1Ven)/LazJ mouse line purchased from Jackson Laboratories harbors a spontaneous mutation in Jak3, generating a SCID phenotype and an inability to generate antigen-independent professional cytokine-producing innate lymphoid cells (ILCs). Mechanistically, Jak3 deficiency blocks ILC differentiation in the bone marrow at the ILC precursor and the pre-NK cell progenitor. We further demonstrate that the pan-JAK inhibitor tofacitinib and the specific JAK3 inhibitor PF-06651600 impair the ability of human intraepithelial ILC1 (iILC1) to produce IFN-γ, without affecting ILC3 production of IL-22. Both inhibitors impaired the proliferation of iILC1 and ILC3 and differentiation of human ILC in vitro. Tofacitinib is currently approved for the treatment of moderate-to-severely active rheumatoid arthritis. Both tofacitinib and PF-06651600 are currently in clinical trials for several other immune-mediated conditions. Our data suggest that therapeutic inhibition of JAK may also impact ILCs and, to some extent, underlie clinical efficacy.
30380863 Required Immunoproteasome Subunit Inhibition Profile for Anti-Inflammatory Efficacy and Cl 2018 Dec 27 Selective immunoproteasome inhibition is a promising approach for treating autoimmune disorders, but optimal proteolytic active site subunit inhibition profiles remain unknown. We reveal here our design of peptide epoxyketone-based selective low molecular mass polypeptide-7 (LMP7) and multicatalytic endopeptidase complex subunit-1 (MECL-1) subunit inhibitors. Utilizing these and our previously disclosed low molecular mass polypeptide-2 (LMP2) inhibitor, we demonstrate a requirement of dual LMP7/LMP2 or LMP7/MECL-1 subunit inhibition profiles for potent cytokine expression inhibition and in vivo efficacy in an inflammatory disease model. These and additional findings toward optimized solubility led the design and selection of KZR-616 disclosed here and presently in clinical trials for treatment of rheumatic disease.
30035365 Brief Report: How Do Patients With Newly Diagnosed Systemic Lupus Erythematosus Present? A 2019 Jan OBJECTIVE: Systemic lupus erythematosus (SLE) presents with nonspecific signs and symptoms that are also found in other conditions. This study aimed to evaluate manifestations at disease onset and to compare early SLE manifestations to those of diseases mimicking SLE. METHODS: Academic lupus centers in Asia, Europe, North America, and South America collected baseline data on patients who were referred to them during the previous 3 years for possible SLE and who had a symptom duration of <1 year. Clinical and serologic manifestations were compared between patients diagnosed as having SLE and those diagnosed as having SLE-mimicking conditions. Diagnostic performance of the 1997 American College of Rheumatology (ACR) SLE classification criteria and the 2012 Systemic Lupus International Collaborating Clinics (SLICC) SLE classification criteria was tested. RESULTS: Data were collected on 389 patients with early SLE and 227 patients with SLE-mimicking conditions. Unexplained fever was more common in early SLE than in SLE-mimicking conditions (34.5% versus 13.7%, respectively; P < 0.001). Features less common in early SLE included Raynaud's phenomenon (22.1% versus 48.5%; P < 0.001), sicca symptoms (4.4% versus 34.4%; P < 0.001), dysphagia (0.3% versus 6.2%; P < 0.001), and fatigue (28.3% versus 37.0%; P = 0.024). Anti-double-stranded DNA, anti-β(2) -glycoprotein I antibodies, positive Coombs' test results, autoimmune hemolytic anemia, hypocomplementemia, and leukopenia were more common in early SLE than in SLE-mimicking conditions. Symptoms detailed in the ACR and SLICC classification criteria were significantly more frequent among those with early SLE. Fewer patients with early SLE were not identified as having early SLE with use of the SLICC criteria compared to the ACR criteria (16.5% versus 33.9%), but the ACR criteria demonstrated higher specificity than the SLICC criteria (91.6% versus 82.4%). CONCLUSION: In this multicenter cohort, clinical manifestations that could help to distinguish early SLE from SLE-mimicking conditions were identified. These findings may aid in earlier SLE diagnosis and provide information for ongoing initiatives to revise SLE classification criteria.
30194773 STAT6 and IL-10 are required for the anti-arthritic effects of Schistosoma mansoni via dif 2019 Jan To investigate possible roles of T helper type 2 (Th2) cytokines in the anti-arthritic effects of a blood fluke, Schistosoma mansoni (Sm), for mouse collagen-induced arthritis (CIA), wild-type (WT), signal transducer and activator of transcription 6 (STAT6) knock-out (KO) and interleukin (IL)-10 KO mice were infected with Sm. Three weeks after infection, the mice were immunized with bovine type II collagen (IIC). Arthritis severity was monitored by scoring, measurement of paw thickness and the presence of ankylosis. Serum anti-IIC IgG levels, splenic cytokine production and cytokine gene expression in the popliteal lymph nodes (PLNs) were measured and compared among WT and gene-KO mice. Consistent with our previous findings, Sm infection reduced the arthritis severity in WT mice. Splenic production of IL-17A and tumor necrosis factor (TNF)-α was reduced by the infection. In contrast, Sm infection markedly exacerbated CIA in STAT6 KO mice. In the KO mice, IL-17A production was increased by the infection. Conversely, Sm infection did not affect the exacerbated arthritis in IL-10 KO mice, although IL-17A production was reduced by the helminth. Our results suggest that signaling via STAT6 (presumably IL-4 and/or IL-13) and IL-10 is required for the suppression of CIA by Sm infection, but through different mechanisms. STAT6 was essential for helminth-induced reduction of IL-17A, whereas regulation of the basal arthritis severity by IL-10 was needed in order for it to be sufficiently suppressed by the helminth.
29728741 Residual medial tightness in extension is corrected spontaneously after total knee arthrop 2019 Mar PURPOSE: Although soft tissue balancing is considered important for successful total knee arthroplasty (TKA), it is unclear whether the laxity and balance achieved intraoperatively change postoperatively. A recent study demonstrated anaesthesia significantly influenced knee joint laxity after TKA; however, there has been no comparison of the varus-valgus laxity immediately after TKA and in the postoperative period under the same anesthetic conditions. Therefore, quantitative stress arthrometric studies were conducted under identical conditions to identify changes in coronal ligament laxity after TKA spontaneously. METHODS: A consecutive series of 28 knees with varus of more than 5° in 28 patients undergoing staged bilateral TKAs was prospectively evaluated. Postoperative varus-valgus laxity was measured immediately after surgery, with the patient still under spinal anaesthesia; and again at the time of the contralateral TKA, again under anaesthesia. The mean time between the first and second operations was 9.7 ± 7.3 months. RESULTS: Mean medial laxity significantly changed from 2.4° ± 1.6° just after the first operation under anaesthesia to 3.8° ± 1.4° just after contralateral TKA under anaesthesia (p < 0.001), but no significant change occurred in lateral laxity (5.6° ± 2.4° just after the first operation and 5.7° ± 2.1° after contralateral TKA, n.s.). Significant negative correlations were identified between laxity immediately after surgery and the amount of laxity change on both the medial (R = - 0.63, p < 0.001) and lateral sides (R = - 0.53, p < 0.001). CONCLUSION: Spontaneous soft tissue correction occurs after TKA. The findings from this study provides a rationale that it is not necessary for surgeons to perform the medial soft tissue release until the soft tissue tension is equalized on both the medial and lateral sides which has the risk of excessive release leading to instability. In situations where the surgeon is confronted with a knee that becomes too tight or too loose depending on the insert thickness, it is recommended to choose the thicker insert with the understanding that the knee will initially have a slightly tighter medial compartment that will loosen over time. The results of this study provide technical considerations that can help a surgeon achieve adequate postoperative stability. LEVEL OF EVIDENCE: IV.
29155428 Small-molecule inhibition of TLR8 through stabilization of its resting state. 2018 Jan Endosomal Toll-like receptors (TLR3, TLR7, TLR8, and TLR9) are highly analogous sensors for various viral or bacterial RNA and DNA molecular patterns. Nonetheless, few small molecules can selectively modulate these TLRs. In this manuscript, we identified the first human TLR8-specific small-molecule antagonists via a novel inhibition mechanism. Crystal structures of two distinct TLR8-ligand complexes validated a unique binding site on the protein-protein interface of the TLR8 homodimer. Upon binding to this new site, the small-molecule ligands stabilize the preformed TLR8 dimer in its resting state, preventing activation. As a proof of concept of their therapeutic potential, we have demonstrated that these drug-like inhibitors are able to suppress TLR8-mediated proinflammatory signaling in various cell lines, human primary cells, and patient specimens. These results not only suggest a novel strategy for TLR inhibitor design, but also shed critical mechanistic insight into these clinically important immune receptors.
29973155 Extra-haematological manifestations related to human parvovirus B19 infection: retrospecti 2018 Jul 4 BACKGROUND: To describe extra-haematological manifestations associated with human parvovirus B19 (HPV-B19) infection. METHODS: We conducted a nationwide multicentre study to retrospectively describe the characteristics and outcome of extra-haematological manifestations in French adults. RESULTS: Data from 25 patients followed from 2001 to 2016 were analysed. Median age was 37.9 years (range: 22.7-83.4), with a female predominance (sex ratio: 4/1). Only 3 patients had an underlying predisposing condition (hemoglobinopathy or pregnancy). The most common manifestations were joint (80%) and skin (60%) involvement. Four patients (16%) had renal involvement (endocapillary proliferative or membranoproliferative glomerulonephritis, focal segmental glomerulosclerosis). Three patients (12%) had peripheral nervous system involvement (mononeuritis, mononeuritis multiplex, Guillain-Barré syndrome) and 2 (8%) presented muscle involvement. Other manifestations included hemophagocytic lymphohistiocytosis (n = 1), myopericarditis and pleural effusion (n = 1), and lymphadenopathy and splenomegaly mimicking lymphoma with spleen infarcts (n = 1). Immunological abnormalities were frequent (56.5%). At 6 months, all patients were alive, and 54.2% were in complete remission. In 2 patients, joint involvement evolved into rheumatoid arthritis. Six patients (24%) received intravenous immunoglobulin (IVIg), with a good response in the 3 patients with peripheral nervous system involvement. CONCLUSIONS: HPV-B19 infection should be considered in a wide range of clinical manifestations. Although the prognosis is good, IVIg therapy should be discussed in patients with peripheral nerve involvement. However, its efficacy should be further investigated in prospective studies.
29142036 Effect of Glucocorticoids on the Clinical and Radiographic Efficacy of Tofacitinib in Pati 2018 Feb OBJECTIVE: Tofacitinib has been investigated for the treatment of rheumatoid arthritis (RA) in phase III studies in which concomitant glucocorticoids (GC) were allowed. We analyzed the effect of GC use on efficacy outcomes in patients with RA receiving tofacitinib and/or methotrexate (MTX) or conventional synthetic disease-modifying antirheumatic drugs (csDMARD) in these studies. METHODS: Our posthoc analysis included data from 6 phase III studies (NCT01039688; NCT00814307; NCT00847613; NCT00853385; NCT00856544; NCT00960440). MTX-naive patients or patients with inadequate response to csDMARD or biological DMARD received tofacitinib 5 or 10 mg twice daily alone or with csDMARD, with or without concomitant GC. Patients receiving GC (≤ 10 mg/day prednisone or equivalent) before enrollment maintained a stable dose throughout. Endpoints included the American College of Rheumatology (ACR) 20/50/70 response rates, rates of Clinical Disease Activity Index (CDAI)-defined low disease activity (LDA; CDAI ≤ 10) and remission (CDAI ≤ 2.8), and changes from baseline in CDAI, 28-joint count Disease Activity Score (DAS28-4)-erythrocyte sedimentation rate (ESR), Health Assessment Questionnaire-Disability Index (HAQ-DI), pain visual analog scale (VAS), and modified total Sharp score. RESULTS: Of 3200 tofacitinib-treated patients, 1258 (39.3%) received tofacitinib monotherapy and 1942 (60.7%) received tofacitinib plus csDMARD; 1767 (55.2%) received concomitant GC. ACR20/50/70 response rates, rates of CDAI LDA and remission, and improvements in CDAI, DAS28-4-ESR, HAQ-DI, and pain VAS with tofacitinib were generally similar with or without GC in monotherapy and combination therapy studies. GC use did not appear to affect radiographic progression in tofacitinib-treated MTX-naive patients. MTX plus GC appeared to inhibit radiographic progression to a numerically greater degree than MTX alone. CONCLUSION: Concomitant use of GC with tofacitinib did not appear to affect clinical or radiographic efficacy. MTX plus GC showed a trend to inhibit radiographic progression to a greater degree than MTX alone.
30477063 Clinical Profile of Primary Sjogren's Syndrome with Hypokalemic Periodic Paralysis. 2018 May INTRODUCTION: Primary Sjogren's Syndrome (pSS) with Hypokalemic Periodic Paralysis(HPP) whether an association or a different clinical subset needs review. METHODS: Cross-sectional retrospective study of subjects of Primary Sjogren's Syndrome with Hypokalemic Periodic Paralysis(HPP) identified from database maintained at Centre For Rheumatic Diseases, Pune since 1996 with records of over 50000 patients. The diagnosis was clinical. Clinical and investigations data was extracted pertaining to initial examination and follow up. Standard investigations & ELISA, immunoblot and nephelometry to assay autoantibodies (AAb) were done. RESULTS: 16 patients of Primary Sjogren's Syndrome (pSS) with Hypokalemic Periodic Paralysis (HPP) were identified in the period 2000-2014. Presenting feature was HPP in 86% with Dry eye (4%) and Arthralgias (10%) in remaining. Distal Renal Tubular Acidosis was identified in all. All were females with average age of 26 years. Symptomatic ocular sicca noted in 60% & Oral sicca in 50% patients. Other features - Arthralgias (91%), arthritis (42%), mucositis (38%), Neuropathy (30%), skin rash (20%) cytopenias (19%), Erosive arthritis (10%), interstitial lung disease (10%) and Raynaud Phenomenon (10%). 100% were positive for ANA. SSA was positive in 100%, SSB in 50% of patients & Rheumatoid Factor in 70 %. Hypothyroidism was associated in 70% patients. CONCLUSION: We present a large series of Primary Sjogren's Syndrome with Hypokalemic Periodic Paralysis(HPP) from India. Prominent features of female dominance, younger age of onset and SSA positivity noted in this cohort of patients on Routine clinical and serology phenotype suggests existence of a distinct subset. HPP was presenting feature in majority.
30078588 Detection of IgM-rheumatoid factor and anti-citrullinated protein antibodies in healthy ho 2018 Aug Rheumatoid factor (RF) is used in human and veterinary medicine in the form of IgM RF traditionally to support the diagnosis of rheumatoid arthritis (RA). In the latest diagnostic criteria, presence of anti - citrullinated protein antibodies (ACPA) was added to the grading system for the diagnosis of RA in humans. A change which is not integrated or routinely used in veterinary medicine. The criteria changed partly because of RF's diagnostic shortcomings, which include its increased titer detection in humans with non-rheumatoid diseases, inability to predict the disease and increased titers over the limit in the older population. Clinical signs similar to human RA were reported in horses in a condition known as idiopathic polysynovitis. Similarities in the clinical presentation to RA raised a question to the usability of RF and ACPA in horses. In our study, sixty clinically healthy horses, ranging from 3 days to 30 years of age, were evaluated for their serum levels of IgM RF. 55 of these horses were tested for ACPA, using methods of ELISA measuring Anti - CFG (Anti citrullinated fibrinogen antibody). The results of the study demonstrated the existence of an age-dependent increase in the level of IgM RF up to the age of about 9 years and ACPA's independence of the horse's age as well as both markers independence of the horse sex.
30418121 α-enolase is an antigenic target in primary Sjögren's syndrome. 2019 May OBJECTIVES: Although anti-cyclic citrullinated peptides antibodies are specific markers for rheumatoid arthritis (RA), they might be present in other diseases. Our aim was to assess the native or citrullinated antigens recognised by patients with primary Sjögren's syndrome (pSS) and to evaluate their association with clinical and serological features. METHODS: In an initial screening, we assessed the serum reactivity of 12 patients with pSS against native or in vitro citrullinated antigens of HEp-2 cells by immunoblotting. We identified a 47kDa band, which was preferentially recognised and corresponded to α-enolase. Thus, levels of IgA and IgG anti-native and citrullinated α-enolase antibodies were measured in 50 pSS patients, 20 RA patients and 20 healthy subjects (HS) by ELISA. RESULTS: We identified α-enolase as a predominant antigen recognised in pSS. These patients had higher levels of anti-citrullinated α-enolase IgG antibodies compared with RA or HS (p=0.003 and p<0.0001, respectively). Furthermore, there was an increase of IgG anti-citrullinated α-enolase vs IgG anti-non-citrullinated α-enolase antibodies in pSS patients (p=0.001), by contrast no difference was found in RA. The presence of IgA and IgG anti-non-citrullinated and anti-citrullinated α-enolase antibodies were not associated with any clinical manifestation whatsoever, including non-erosive arthritis among pSS, but an association of IgA anti-citrullinated α-enolase with anti-Ro/SSA antibodies was found. CONCLUSIONS: We characterised α-enolase as a dominant antigen in lysates of HEp- 2 cells in pSS. Nevertheless, their precise role in pSS remains to be elucidated.
30003689 ADAM15 in Apoptosis Resistance of Synovial Fibroblasts: Converting Fas/CD95 Death Signals 2019 Jan OBJECTIVE: To investigate mechanisms underlying the capability of ADAM15 to transform FasL-mediated death-inducing signals into prosurvival activation of Src and focal adhesion kinase (FAK) in rheumatoid arthritis synovial fibroblasts (RASFs). METHODS: Caspase 3/7 activity and apoptosis rate were determined in RASFs and ADAM15-transfected T/C28a4 cells upon Fas/CD95 triggering using enzyme assays and annexin V staining. Phosphorylated Src and FAK were analyzed by immunoblotting. Interactions of ADAM15 and CD95 with calmodulin (CaM), Src, or FAK were analyzed by pull-downs using CaM-Sepharose and coimmunoprecipitations with specific antibodies. Protein binding assays were performed using recombinant CaM and ADAM15. Immunofluorescence was performed to investigate subcellular colocalization of ADAM15, Fas/CD95, and CaM. RESULTS: The antiapoptotic effect of ADAM15 in FasL-stimulated cells was demonstrated either by increased apoptosis of cells transfected with an ADAM15 construct lacking the cytoplasmic domain compared to cells transfected with full-length ADAM15 or by reduced apoptosis resistance of RASFs upon RNA interference silencing of ADAM15. Fas ligation triggered a Ca(2+)  release-activated Ca(2+) /calcium release-activated calcium channel protein 1 (CRAC/Orai1) channel-dependent CaM recruitment to Fas/CD95 and ADAM15 in the cell membrane. Simultaneously, Src associated with CaM was shown to become engaged in the ADAM15 complex also containing cytoplasmic-bound FAK. Accordingly, Fas ligation in RASFs led to ADAM15-dependent phosphorylation of Src and FAK, which was associated with increased survival. Pharmacologic interference with either the CaM inhibitor trifluoperazine or the CRAC/Orai inhibitor BTP-2 simultaneously applied with FasL synergistically enhanced Fas-mediated apoptosis in RASFs. CONCLUSION: ADAM15 provides a scaffold for formation of CaM-dependent prosurvival signaling complexes upon CRAC/Orai coactivation by FasL-induced death signals and a potential therapeutic target to break apoptosis resistance in RASFs.
29806294 [Mid-term effectiveness of large-head metal-on-metal total hip arthroplasty]. 2018 Apr 15 OBJECTIVE: To explore the mid-term effectiveness of large-head metal-on-metal total hip arthroplasty (THA). METHODS: A retrospective analysis was made on the clinical date of 40 patients (43 hips) who were treated with the large-head metal-on-metal THA between April 2009 and June 2010. There were 18 males (20 hips) and 22 females (23 hips) with an average age of 55.1 years (range, 20-85 years). Unilateral hip was involved in 37 cases and bilateral hips in 3 cases. The disease causes included osteonecrosis of the femoral head in 14 cases (15 hips), osteoarthritis in 6 cases (7 hips), rheumatoid arthritis in 4 cases (4 hips), femoral neck fracture in 4 cases (4 hips), and developmental dysplasia of the hip in 12 cases (13 hips). Before operation, the Harris score and University of California Los Angeles (UCLA) score were 38.51±5.62 and 4.21±1.43, respectively. The visual analogue scale (VAS) score was 6.78±0.95. RESULTS: All patients were followed up 6.7-8.3 years (mean 7.5 years). All incisions healed primarily and no neurovascular injury, infection, and hip dislocation occurred. At last follow-up, the Harris score and UCLA score were 93.33±3.21 and 7.32±1.45, respectively, showing significant differences when compared with preoperative scores ( t=51.753, P=0.000; t=23.232, P=0.000). The thigh pain occurred in 3 cases (3 hips) in whom the inflammatory pseudotumor of soft tissues was found in 1 case (1 hip). Postoperative X-ray films showed that the acetabular abduction angle and anteversion angle were (46.5±3.2)° and (14.8±3.6) °, respectively. The initial stability of femoral stem prosthesis was excellent in 39 hips and good in 4 hips according to Mulliken standard. Osteolysis occurred in 2 hips and revision was performed in 1 hip of secondary loosening of prosthesis. The rest patients had no prosthesis loosening or sinking. CONCLUSION: The mid-term effectiveness of large-head mental-on-mental THA in treatment of the terminal diseases of hips are good.
29150737 Risk of active tuberculosis in patients with inflammatory arthritis receiving TNF inhibito 2018 Sep Tuberculosis (TB) is a major concern in patients receiving TNF inhibitors (TNFi). This study aimed to assess the incidence of active TB and the efficacy of TB prevention measures used over the years, and to determine risk factors for developing TB, in a single-centre cohort of patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS) receiving TNFi. Data of all patients in whom treatment with TNFi was initiated in our rheumatology clinic until December 1st 2014 have been retrospectively analysed. The cohort was divided into 3 groups per the mandatory LTBI screening method at baseline: tuberculin skin test (TST) with a positive threshold of either 10 mm (group TST1), or 5 mm (group TST2), and QuantiFERON®-TB Gold test (group QFT). The incidence of active TB was analysed for each group and compared to TB incidence data in general population. Five hundred fifty patients were included (305 RA, 42 PsA, 203 AS); 97 patients belonged to the TST1, 229 to the TST2 and 224 to the QFT group. The number of active TB cases/time of exposure to TNFi (person-years, PY) was 8/593.5, 9/1044.0 and 3/555.3, respectively, accounting for an incidence of 1348.0, 862.1 and 540.2 cases per 10(5) PY. Active TB cases occurring in the first year of TNFi treatment (early TB) per total TB cases were only 3/8, 1/9 and 1/3, respectively, too few to identify statistically significant differences between the 3 LTBI screening protocols. However, less TB cases per total observation time were registered in the QFT group, probably due to the reduced duration of exposure to TNFi. All cases of active TB were registered among patients receiving monoclonal antibodies TNFi agents. We have found no significant risk factors for developing active TB. In our cohort, TB occurring after 1 year of TNFi treatment exceeds 'early TB', suggesting the necessity of further TB prevention measures besides baseline screening for LTBI.
29173190 Migraine in Systemic Autoimmune Diseases. 2018 Feb 13 BACKGROUND AND OBJECTIVE: Migraine and systemic autoimmune diseases are 2-3-fold more common in women and various studies have reported an association between the two pathologies. METHODS: This review takes into account epidemiological studies involving migraine and systemic lupus erythematosus, antiphospholipid syndrome, Sjogren's syndrome, and other diffuse connective tissue diseases. This scientific literature analysis consists of the main articles found in Medline with a search up to April 2017. RESULTS: Many epidemiological studies were carried out on patients suffering from systemic lupus erythematosus. Results showed that headache and migraine are more prevalent in systemic lupus erythematosus patients compared to controls, especially migraine with aura. Patients with Lupus and migraine show a higher lupus activity and association with Raynaud and/or antiphospholipids in these populations are contradictory. There are not enough data to establish an association between antiphospholipid syndrome and migraine. However, data are more consistent between antiphospholipid carrier condition and migraine. Systemic sclerosis is a rare disease, for this reason the amount of available data on this disorder are scanty. However, some studies reported an association between headache, migraine and systemic sclerosis, especially where gliotic brain lesions and Raynaud are coexisting. Finally, large propensity cohort population based studies suggested that systemic autoimmune diseases are more frequent in patients suffering from migraine. CONCLUSION: An attempt at explaining the possible link between these disorders and migraine is discussed at the end of the review. Several autoimmune alterations are shared by most autoimmune diseases and headache types. Endothelial dysfunction is the only alteration that is common among all these disorders.
30056525 Clinical outcomes and feasibility of the multidisciplinary management of patients with pso 2018 Oct Psoriatic arthritis (PsA) is a chronic inflammatory autoimmune arthritis, occurring in patients with psoriasis (Pso), that may affect the whole musculoskeletal system but also nails, eye, and gastrointestinal tract. Dermatologists and rheumatologists usually manage Pso and PsA separately, but early diagnosis and integrated management could achieve better outcomes of both skin and musculoskeletal manifestations, thus improving the health-related quality of life (HRQoL) of patients. In this work, we have described a model of integrated dermo-rheumatologic approach for the early diagnosis of PsA and to present the outcomes of the multidisciplinary management of PsA patients after 48 weeks of follow-up. Pso patients complaining musculoskeletal symptoms were enrolled in a DErmo-Rheumatologic Clinic (DERC) in order to screen, classify, and treat patients with PsA, employing an operative working procedure and a specific flowchart. The integrated dermatologic and rheumatologic management of PsA patients allowed a prompt establishment of the diagnosis and the best therapeutic approach in these patients, with a significant improvement of skin and articular diseases and, eventually, a consistent amelioration of HRQoL. Dermatologists and rheumatologists usually manage the "psoriatic disease" in separated outpatient clinics. In our study, we have demonstrated that a combined DERC, by means of a tight cooperation between the dermatologist and the rheumatologist, which use a specific working procedure and treatment flowchart, may achieve the optimal clinical management of these patients, with a consistent clinical remission of the disease and a significant amelioration of the HRQoL.
30041668 Polygenic analysis of inflammatory disease variants and effects on microglia in the aging 2018 Jul 24 BACKGROUND: The role of the innate immune system in Alzheimer's disease (AD) and neurodegenerative disease susceptibility has recently been highlighted in genetic studies. However, we do not know whether risk for inflammatory disease predisposes unaffected individuals to late-life cognitive deficits or AD-related neuropathology. We investigated whether genetic risk scores for seven immune diseases and central nervous system traits were related to cognitive decline (n(max) = 1601), classical AD neuropathology (n(max) = 985), or microglial density (n(max) = 184). METHODS: Longitudinal cognitive decline, postmortem amyloid and tau neuropathology, microglial density, and gene module expression from bulk brain tissue were all measured in participants from two large cohorts (the Rush Religious Orders Study and Memory and Aging Project; ROS/MAP) of elderly subjects (mean age at entry 78 +/- 8.7 years). We analyzed data primarily using robust regression methods. Neuropathologists were blind to clinical data. RESULTS: The AD genetic risk scores, including and excluding APOE effects, were strongly associated with cognitive decline in all domains (min P(uncor) = 3.2 × 10(- 29)). Multiple sclerosis (MS), Parkinson's disease, and schizophrenia risk did not influence cognitive decline in older age, but the rheumatoid arthritis (RA) risk score alone was significantly associated with microglial density after correction (t(146) = - 3.88, P(uncor) = 1.6 × 10(- 4)). Post-hoc tests found significant effects of the RA genetic risk score in multiple regions and stages of microglial activation (min P(uncor) = 1.5 × 10(- 6)). However, these associations were driven by only one or two variants, rather than cumulative polygenicity. Further, individual MS (P(one-sided) < 8.4 × 10(- 4)) and RA (P(one-sided) = 3 × 10(- 4)) variants associated with higher microglial density were also associated with increased expression of brain immune gene modules. CONCLUSIONS: Our results demonstrate that global risk of inflammatory disease does not strongly influence aging-related cognitive decline but that susceptibility variants that influence peripheral immune function also alter microglial density and immune gene expression in the aging brain, opening a new perspective on the control of microglial and immune responses within the central nervous system. Further study on the molecular mechanisms of peripheral immune disease risk influencing glial cell activation will be required to identify key regulators of these pathways.
29351998 Detection of Experimental and Clinical Immune Complexes by Measuring SHIP-1 Recruitment to 2018 Mar 1 Fc γ receptors (FcγR) are involved in multiple aspects of immune cell regulation, are central to the success of mAb therapeutics, and underpin the pathology of several autoimmune diseases. However, reliable assays capable of accurately measuring FcγR interactions with their physiological ligands, IgG immune complexes (IC), are limited. A method to study and detect IC interactions with FcγRs was therefore developed. This method, designed to model the signaling pathway of the inhibitory FcγRIIB (CD32B), used NanoLuc Binary Interaction Technology to measure recruitment of the Src homology 2 domain-containing inositol phosphatase 1 to the ITIM of this receptor. Such recruitment required prior cross-linking of an ITAM-containing activatory receptor, and evoked luciferase activity in discrete clusters at the cell surface, recapitulating the known biology of CD32B signaling. The assay detected varying forms of experimental IC, including heat-aggregated IgG, rituximab-anti-idiotype complexes, and anti-trinitrophenol-trinitrophenol complexes in a sensitive manner (≤1 μg/ml), and discriminated between complexes of varying size and isotype. Proof-of-concept for the detection of circulating ICs in autoimmune disease was provided, as responses to sera from patients with systemic lupus erythematosus and rheumatoid arthritis were detected in small pilot studies. Finally, the method was translated to a stable cell line system. In conclusion, a rapid and robust method for the detection of IC was developed, which has numerous potential applications including the monitoring of IC in autoimmune diseases and the study of underlying FcγR biology.
30120124 CSF-1 in Inflammatory and Arthritic Pain Development. 2018 Oct 1 Pain is one of the most debilitating symptoms in many diseases for which there is inadequate management and understanding. CSF-1, also known as M-CSF, acts via its receptor (CSF-1R, c-Fms) to regulate the development of the monocyte/macrophage lineage and to act locally in tissues to control macrophage numbers and function. It has been implicated in the control of neuropathic pain via a central action on microglia. We report in this study that systemic administration of a neutralizing anti-CSF-1R or CSF-1 mAb inhibits the development of inflammatory pain induced by zymosan, GM-CSF, and TNF in mice. This approach also prevented but did not ameliorate the development of arthritic pain and optimal disease driven by the three stimuli in mice, suggesting that CSF-1 may only be relevant when the driving inflammatory insults in tissues are acute and/or periodic. Systemic CSF-1 administration rapidly induced pain and enhanced the arthritis in an inflamed mouse joint, albeit via a different pathway(s) from that used by systemic GM-CSF and TNF. It is concluded that CSF-1 can function peripherally during the generation of inflammatory pain and hence may be a target for such pain and associated disease, including when the clinically important cytokines, TNF and GM-CSF, are involved. Our findings have ramifications for the selection and design of anti-CSF-1R/CSF-1 trials.
29143979 Analysis of anti-tumour necrosis factor-induced skin lesions reveals strong T helper 1 act 2018 May BACKGROUND: Psoriasiform and eczematous eruptions are the most common dermatological adverse reactions linked to anti-tumour necrosis factor (TNF)-α therapy. Yet, a detailed characterization of their immune phenotype is lacking. OBJECTIVES: To characterize anti-TNF-α-induced inflammatory skin lesions at a histopathological, cellular and molecular level, compared with psoriasis, eczema (atopic dermatitis) and healthy control skin. METHODS: Histopathological evaluation, gene expression (quantitative real-time polymerase chain reaction) and computer-assisted immunohistological studies (TissueFAXS) were performed on 19 skin biopsies from patients with inflammatory bowel disease (n = 17) and rheumatoid arthritis (n = 2) with new-onset inflammatory skin lesions during anti-TNF-α-therapy. RESULTS: Although most biopsies showed a psoriasiform and/or spongiotic (eczematous) histopathological architecture, these lesions were inconsistent with either psoriasis or eczema on a molecular level using an established chemokine (C-C motif) ligand 27/inducible nitric oxide synthase classifier. Despite some differences in immune skewing depending on the specific histopathological reaction pattern, all anti-TNF-α-induced lesions showed strong interferon (IFN)-γ activation, at higher levels than in psoriasis or eczema. IFN-γ was most likely produced by CD3/CD4/Tbet-positive T helper 1 lymphocytes. CONCLUSIONS: New-onset anti-TNF-α-induced eruptions previously classified as psoriasis or spongiotic dermatitis (eczema) exhibit a molecular profile that is different from either of these disorders.