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Investigates the prevalence of hyperimmunoglobulinaemia D (IgD) concentrations, in 30 serum samples of patients with Behcet's disease (BD). Symptoms of the disease; Identification of the treatment procedure used; Details on the use of anti-serum to coat a multititre plate.

Background: Granulomatosis with polyangiitis (GPA) is a rare small vessel vasculitis. It usually involves the respiratory tract and kidney. Rarely, tumor-resembling inflammatory changes ensue., Objectives: To report three unique cases of GPA presenting with tumor-like lesions in various organs., Methods: We presented three cases of GPA. Case 1 presented with typical upper respiratory symptoms of GPA and a mediastinal mass. Case 2 presented with low back pain, a large retroperitoneal mass, and nodular skin lesions. Case 3 presented with epigastric pain and a paravertebral inflammatory mass., Results: The patients were treated successfully with rituximab., Conclusions: Clinicians should be aware of this presentation of granulomatosis with polyangiitis, which is known as Tumefaction Wegener's granulomatosis.

Background: Infectious diseases and vaccines can occasionally cause new-onset or flare of immune-mediated diseases (IMDs). The adjuvanticity of the available SARS-CoV-2 vaccines is based on either TLR-7/8 or TLR-9 agonism, which is distinct from previous vaccines and is a common pathogenic mechanism in IMDs., Methods: We evaluated IMD flares or new disease onset within 28-days of SARS-CoV-2 vaccination at five large tertiary centres in countries with early vaccination adoption, three in Israel, one in UK, and one in USA. We assessed the pattern of disease expression in terms of autoimmune, autoinflammatory, or mixed disease phenotype and organ system affected. We also evaluated outcomes., Findings: 27 cases included 17 flares and 10 new onset IMDs. 23/27 received the BNT - 162b2 vaccine, 2/27 the mRNA-1273 and 2/27 the ChAdOx1 vaccines. The mean age was 54.4 ± 19.2 years and 55% of cases were female. Among the 27 cases, 21 (78%) had at least one underlying autoimmune/rheumatic disease prior the vaccination. Among those patients with a flare or activation, four episodes occurred after receiving the second-dose and in one patient they occurred both after the first and the second-dose. In those patients with a new onset disease, two occurred after the second-dose and in one patient occurred both after the first (new onset) and second-dose (flare). For either dose, IMDs occurred on average 4 days later. Of the cases, 20/27 (75%) were mild to moderate in severity. Over 80% of cases had excellent resolution of inflammatory features, mostly with the use of corticosteroid therapy. Other immune-mediated conditions included idiopathic pericarditis ( n = 2), neurosarcoidosis with small fiber neuropathy ( n = 1), demyelination ( n = 1), and myasthenia gravis ( n = 2). In 22 cases (81.5%), the insurgence of Adverse event following immunization (AEFI)/IMD could not be explained based on the drug received by the patient. In 23 cases (85.2%), AEFI development could not be explained based on the underlying disease/co-morbidities. Only in one case (3.7%), the timing window of the insurgence of the side effect was considered not compatible with the time from vaccine to flare., Interpretation: Despite the high population exposure in the regions served by these centers, IMDs flares or onset temporally-associated with SARS-CoV-2 vaccination appear rare. Most are moderate in severity and responsive to therapy although some severe flares occurred., Funding: none.

Background: Tocilizumab is an interleukin 6 (IL-6) receptor antagonist used treat moderate to severe active rheumatoid arthritis (RA). Both intravenous (IV) and subcutaneous (SC) routes are approved for the treatment of adults with RA., Objectives: To evaluate SC tocilizumab in a real-life clinical setting., Methods: Our study was a multi-center, open-label, single-arm study. Participants were adults with a diagnosis of active RA, previously treated with disease-modifying antirheumatic drugs (DMARDs), with or without biologic agents. Participants received a weekly SC injection of tocilizumab 162 mg as monotherapy or in combination with methotrexate or DMARDs for 24 weeks. Efficacy, safety, and immunogenicity were assessed., Results: Treatment of 100 patients over 24 weeks resulted in improvement in all efficacy parameters assessed: Clinical Disease Activity Index, Disease Activity Score using 28 joint counts and erythrocyte sedimentation rate, American College of Rheumatology response scores, Simplified Disease Activity Index, tender and swollen joint counts, and patient-reported outcomes including fatigue, global assessment of disease activity, pain, and Health Assessment Quality of Life Disease Index. Improvement was achieved as early as the second week of treatment. There were 473 adverse events (AEs)/100 patient-years (PY) and 16.66 serious AEs/100 PY. The most common AEs were neutropenia (12%), leukopenia (11%), and increased hepatic enzymes (11%). Of a total of 42 PY, the rates of serious infections and AEs leading to discontinuation were 4.8, and 11.9 events/100 PY, respectively., Conclusions: The safety, tolerability, and efficacy profile of tocilizumab SC were comparable to those reported in other studies evaluating the IV and SC routes of administration.

Background: Chronic fatigue is common among patients with rheumatoid arthritis (RA), affecting quality of life. Osteoporosis is a prevalent co-morbidity in RA patients., Objectives: To assess the effect of long-term treatment with tocilizumab on fatigue and bone mineral density (BMD) in RA patients with inadequate response to synthetic or biologic disease-modifying anti-rheumatic drugs., Methods: In this multicenter, open-label, non-controlled, single-arm study, patients ≥ 18 years of age received intravenous tocilizumab 8 mg/kg every 4 weeks for 96 weeks. The primary outcome was the change in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score from baseline to weeks 24, 48, 72, and 96. BMD was assessed before and 96 weeks after treatment., Results: The study comprised 145 patients (mean age 53.4 ± 13.4 years, 83.4% women). Of these, 88 (60.7%) completed the 2 year treatment period. The mean FACIT-Fatigue score improved consistently starting from week 4 and showed a statistically significant increase of 5.0 ± 9.7, 6.8 ± 10.5, 7.3 ± 10.9, and 7.3 ± 10.4 from baseline to weeks 24, 48, 72, and 96, respectively (P < 0.0001). Mean BMD of femoral neck and total spine remained stable. Disease activity, acute phase reactants, and composite efficacy measures decreased during the study, while hemoglobin levels increased. Adverse events and serious adverse events were as expected for the known and previously described data., Conclusions: Tocilizumab therapy for 2 years significantly and clinically decreased fatigue. BMD remained stable and no new safety issue was reported.

Objectives: To evaluate the prevalence of immunogenicity of TNF-α blockers in axial spondyloarthritis (SpA) patients and to assess the effect of immunogenicity on drug levels and clinical response., Methpds: Patients with axial SpA treated with either infliximab (INF), adalimumab (ADA) or etanercept (ETN) were recruited to our observational cross-sectional study. Demographic and clinical data were collected and disease activity scores were assessed. Drug trough levels and anti-drug antibodies were measured in serum samples and collected before the next administration., Results: Thirty-nine patients with axial SpA with a mean age of 46.3±12.7 (10 women) were recruited to the study (14 receiving INF, 16 ADA and 9 ETN). Patients' mean therapy duration was 50.6 months (±46.4) and 6 (15%) of them were using MTX concomitantly with the TNF-α blockers. Anti-drug antibodies were found in 6 (15%) patients (4 with INF and 2 with ADA), all of which had undetectable drug level. No anti-drug antibodies were detected in patients treated with ETN. Immunogenicity was associated with higher BASDAI (Bath Ankylosing Spondylitis Disease Index), ASDAS-CRP (Ankylosing Spondylitis Disease Activity Score) and ASDAS-ESR., Conclusions: Axial SpA patients failure to respond to TNF-α blockers may be at least partially related to immunogenicity. Measurement of anti-drug antibodies and drug levels in these patients may assist in determining further treatment strategies.

Objectives: Autoantibodies to the dense fine speckled 70 (DFS70) antigen are common among antinuclear antibodies (ANA) positive healthy individuals (HI). We assessed the prevalence of anti-DFS70 antibodies in patients with and without ANA-associated rheumatic diseases (AARDs) by two methods: chemiluminescent immunoassay (CIA) and an indirect immunofluorescence (IIF) assay based on immunoadsorption for DFS70., Methods: Fifty-one ANA-positive sera samples from patients with confirmed clinical diagnosis of AARD, 92 samples from HI and 85 samples submitted to a reference laboratory for routine ANA testing were evaluated for the presence of anti-DFS70 antibodies. The samples were evaluated by QUANTA Flash DFS70 CIA using BIO-FLASH instrument and by NOVA Lite selected HEp-2 kit on NOVA View - an automated IIF system. Sera with DFS positive pattern were pre-absorbed with highly purified human DFS70 antigen, and then tested again., Results: Twenty-four samples (10.5%) tested by QUANTA Flash DFS70 CIA were positive for anti-DFS70 antibodies. The prevalence of monospecific anti-DFS70 antibodies was significantly higher in healthy subjects than in patients with AARDs (10.9% vs. 1.9%, p=0.02). The frequency of anti-DFS70 antibodies in samples submitted for routine ANA testing was 15.2%. A very good agreement was found between CIA and the DFS pattern identified by the automated HEp-2 IIF (kappa=0.97). In 80% of the samples obtained from patients without AARDs, immunoadsorption effectively inhibited the anti-DFS70 antibodies., Conclusions: The data confirm that mono-specific anti-DFS70 antibodies are a strong discriminator between ANA positive HI and AARD patients, and their evaluation should be included in ANA testing algorithms.

Background: Anti-BLyS treatment with the human belimumab monoclonal antibody was shown to be a safe and effective therapeutic modality in lupus patients with active disease (i.e., without significant neurological/renal involvement) despite standard treatment., Objectives: To evaluate the "real-life" safety and efficacy of belimumab added to standard therapy in patents with active lupus in five Israeli medical centers., Methods: We conducted a retrospective open-labeled study of 36 lupus patients who received belimumab monthly for at least 1 year in addition to standard treatment. Laboratory tests (C3/C4, anti dsDNA autoantibodies, chemistry, urinalysis and complete blood count) were done every 3-4 months. Adverse events were obtained from patients' medical records. Efficacy assessment by the treating physicians was defined as excellent, good/partial, or no response., Results: The study group comprised 36 lupus patients (8 males, 28 females) with a mean age of 41.6 } 12.2 years. Belimumab was given for a mean period of 2.3 } 1.7 years (range 1-7). None of the patients discontinued belimumab due to adverse events. Four patients (11.1%) had an infection related to belimumab. Only 5 patients (13.9%) stopped taking belimumab due to lack of efficacy. The response was excellent in 25 patients (69.5%) and good/partial in the other 6 (16.6%). Concomitantly, serological response (reduction of C3/C4 and anti-dsDNA autoantibodies) was also observed. Moreover, following belimumab treatment, there was a significant reduction in the usage of corticosteroids (from 100% to 27.7%) and immunosuppressive agents (from 83.3% to 8.3%)., Conclusions: Belimumab, in addition to standard therapy, is a safe and effective treatment for active lupus patients.

In the course of investigating anti-DNA autoantibodies, we examined IgM and IgG antibodies to poly-G and other oligonucleotides in the sera of healthy persons and those diagnosed with systemic lupus erythematosus (SLE), scleroderma (SSc), or pemphigus vulgaris (PV); we used an antigen microarray and informatic analysis. We now report that all of the 135 humans studied, irrespective of health or autoimmune disease, manifested relatively high amounts of IgG antibodies binding to the 20-mer G oligonucleotide (G20); no participants entirely lacked this reactivity. IgG antibodies to homo-nucleotides A20, C20 or T20 were present only in the sera of SLE patients who were positive for antibodies to dsDNA. The prevalence of anti-G20 antibodies led us to survey human, mouse and Drosophila melanogaster (fruit fly) genomes for runs of T20 and G20 or more: runs of T20 appear > 170,000 times compared with only 93 runs of G20 or more in the human genome; of these runs, 40 were close to brain-associated genes. Mouse and fruit fly genomes showed significantly lower T20/G20 ratios than did human genomes. Moreover, sera from both healthy and SLE mice contained relatively little or no anti-G20 antibodies; so natural anti-G20 antibodies appear to be characteristic of humans. These unexpected observations invite investigation of the immune functions of anti-G20 antibodies in human health and disease and of runs of G20 in the human genome., (© 2015 John Wiley & Sons Ltd.)

Objective: Exertional leg pain is a characteristic musculoskeletal manifestation of familial Mediterranean fever (FMF). We aimed to define the frequency and characteristics of exertional leg pain in a large cohort of FMF patients and to evaluate for additional signs and symptoms of spondyloarthritis (SpA) in this patient population., Methods: FMF patients were allocated into study or control groups based on the presence or absence of exertional leg pain. Randomly selected patients underwent magnetic resonance imaging (MRI) of the ankle as well as plain radiography of the sacroiliac joints., Results: The prevalence of exertional leg pain among the 170 FMF patients included in the study was 58.2%. Patients with exertional leg pain had significantly more joint attacks (74.7% versus 40.8%; P < 0.0001), fever attacks (35.4% versus 15.5%; P = 0.004), and pleuritis attacks (48.5% versus 29.6%; P = 0.013) as well as more attacks per year. Elevations of inflammation markers were significantly more frequent among the study group (for the erythrocyte sedimentation rate, 44.4% of patients versus 21.1% of patients; P = 0.016) (for the C-reactive protein level, 48.4% of patients versus 31.8% of patients; P = 0.013), and M694V homozygosity was more prevalent among the study group (45.5% versus 21.1%; P = 0.001). Signs compatible with enthesopathy on MRI were observed in 73.5% of patients in the study group and in 33.3% of patients in the control group (P = 0.046). Definite SpA was diagnosed in 41.2% of the patients in the study group compared to none of the controls (P = 0.07) (odds ratio 1.7 [95% confidence interval 1.2-2.3])., Conclusion: Exertional leg pain is a common manifestation of FMF and is a marker of a more severe disease phenotype. Additionally, exertional leg pain is frequently associated with sacroiliitis and an underlying ankle enthesopathy and should therefore be considered a new feature of SpA., (Copyright © 2014 by the American College of Rheumatology.)

Systemic lupus erythematosus (SLE) is an autoimmune disease that can attack many different body organs; the triggering event is unknown. SLE has been associated with more than 100 different autoantibody reactivities - anti-dsDNA is prominent. Nevertheless, autoantibodies to dsDNA occur in only two-thirds of SLE patients. We previously reported the use of an antigen microarray to characterize SLE serology. We now report the results of an expanded study of serology in SLE patients and scleroderma (SSc) patients compared with healthy controls. The analysis validated and extended previous findings: two-thirds of SLE patients reacted to a large spectrum of self-molecules that overlapped with their reactivity to dsDNA; moreover, some SLE patients manifested a deficiency of natural IgM autoantibodies. Most significant was the finding that many SLE patients who were negative for autoantibodies to dsDNA manifested abnormal antibody responses to Epstein-Barr virus (EBV): these subjects made IgG antibodies to EBV antigens to which healthy subjects did not respond or they failed to make antibodies to EBV antigens to which healthy subjects did respond. This observation suggests that SLE may be associated with a defective immune response to EBV. The SSc patients shared many of these serological abnormalities with SLE patients, but differed from them in increased IgG autoantibodies to topoisomerase and centromere B; 84% of SLE patients and 58% of SSc patients could be detected by their abnormal antibodies to EBV. Hence an aberrant immune response to a ubiquitous viral infection such as EBV might set the stage for an autoimmune disease., (© 2013 John Wiley & Sons Ltd.)

Summary: Patients with systemic lupus erythematosus (SLE) produce antibodies to many different self-antigens. Here, we investigated antibodies in SLE sera using an antigen microarray containing many hundreds of antigens, mostly self-antigens. The aim was to detect sets of antibody reactivities characteristic of SLE patients in each of various clinical states--SLE patients with acute lupus nephritis, SLE patients in renal remission, and SLE patients who had never had renal involvement. The analysis produced two novel findings: (i) an SLE antibody profile persists independently of disease activity and despite long-term clinical remission, and (ii) this SLE antibody profile includes increases in four specific immunoglobulin G (IgG) reactivities to double-stranded DNA (dsDNA), single-stranded DNA (ssDNA), Epstein-Barr virus (EBV) and hyaluronic acid; the profile also includes decreases in specific IgM reactivities to myeloperoxidase (MPO), CD99, collagen III, insulin-like growth factor binding protein 1 (IGFBP1) and cardiolipin. The reactivities together showed high sensitivity (> 93%) and high specificity for SLE (> 88%). A healthy control subject who had the SLE antibody profile was later found to develop clinical SLE. The present study did not detect antibody reactivities that differentiated among the various subgroups of SLE subjects with statistical significance. Thus, SLE is characterized by an enduring antibody profile irrespective of clinical state. The association of SLE with decreased IgM natural autoantibodies suggests that these autoantibodies might enhance resistance to SLE.

Inflammatory bowel disease, a collective term for ulcerative colitis and Crohn's disease, is a chronic, immune-mediated disease of the gastrointestinal tract that develops in genetically susceptible individuals. The role of infection in the development of inflammatory bowel disease is underscored by various clinical observations, such as the delayed age of onset, suggesting that childhood exposure to pathogens is essential, and the clinical improvement that follows decreasing bacterial intestinal load. Over the years, many a pathogen has been linked to the development and exacerbation of inflammatory bowel disease, notably; Mycobacterium paratuberculosis, Escherichia coli, Listeria monocytogenes and Chlamydia as well as viruses such as measles, mumps, rubella, Epstein-Barr virus and cytomegalovirus. Presently, leading theories of disease pathogenesis suggest loss of immune tolerance to normal commensal bacteria coupled with excessive exposure to bacterial antigenic products. This review describes the most commonly implicated pathogens in the causation of IBD and presents the evidence supporting their pathogenic role as well as data that offset their importance.

Background: Anti-ribosomal-P antibodies have been associated with central nervous system manifestations of systemic lupus erythematosus. However, inconsistencies in their prevalence and clinical correlations have become an obstacle to their use as a diagnostic marker of the disease. This lack of consistency might stem from several factors, such as the lag period between clinical manifestations and the time blood was drawn; or the different methods used for antibodies detection., Objectives: To evaluate three different enzyme-linked immunosorbent assay tests for the detection of anti-Rib-P Abs in patients with SLE and in normal controls., Methods: Sera from 50 SLE outpatients and 50 healthy subjects were tested with three ELISA kits: Kit-1, using synthetic peptide comprising the 22 C-terminal aminoacids; Kit-2, using native human ribosomal proteins (P0, P1, P2); and Kit-3, which is coated with affinity-purified human ribosomal proteins. ELISA studies were performed according to the manufacturers' instructions., Results: The prevalence of anti-Rib-P Abs in SLE patients and controls was 30% vs. 0%, 17% vs. 21%, and 30% vs. 14% in kits 1-3 respectively. Anti-Rib-P Abs detected by Kit-1 correlated with the SLEDAI score (SLE Disease Activity Index). No correlation between prior CNS manifestations and anti-Rib-P Abs was observed., Conclusions: A significant difference was documented between the ELISA kits used for the detection of anti-Rib-P Abs. A correlation was found between these antibodies (evaluated by Kit-1) and concurrent SLEDAI scores, in contrast to the lack of correlation with previous CNS manifestations. This supports the notion of "active serology" that is evaluated at the same time manifestations are present, as well as the need for standardization of laboratory assays in the future which will enable a better assessment of anti-Rib-P Abs presence and clinical significance.

Objective: To assess the olfactory functions in systemic lupus erythematosus (SLE) patients compared with age- and sex-matched healthy controls, and to examine the association between the sense of smell and disease activity and central nervous system (CNS) involvement., Methods: Olfactory functions in 50 SLE patients and 50 age- and sex-matched controls were evaluated using the Sniffin' Sticks test, the 3 stages of which are threshold, discrimination, and identification (TDI) of different odors. TDI scores were analyzed according to SLE disease activity and CNS involvement., Results: In both the SLE and control groups, smell deficit correlated with male sex and older age. A decrease in the sense of smell was observed in SLE patients (46%) and controls (25%) (P

Background: Abdominal attacks of familial Mediterranean fever (FMF) may simulate acute appendicitis and bring about considerable uncertainty. The similar presentation of the two clinical entities often leads to an unnecessary appendectomy., Methods: 182 consecutive FMF patients were retrospectively reviewed for this study. Clinical and genetic data was compared between those who had undergone an appendectomy (n=71) and those who had not (n=111)., Results: The frequency of appendectomy found in FMF was far above the reported rate in the general population (40% vs. 12-25%). The rate of non-inflamed appendectomies was extremely high (80% vs. 20%) and remained constant over time. Tertiary hospitals and improved therapeutic and diagnostic measures that have evolved over the years did not reduce misdiagnosis of acute appendicitis in FMF. Severe phenotype and homozygosity for M694V were identified as risk factors for appendectomy in FMF. A change from the regular diffuse involvement to right lower quadrant abdominal pain was found to be the best predictor of inflamed appendix in FMF patients undergoing appendectomy for suspected acute appendicitis., Conclusion: Reliance on clinical parameters should improve diagnostic accuracy of acute appendicitis in the FMF patient population.

Objective: The mechanism by which low dose methotrexate (MTX, the gold standard treatment for rheumatoid arthritis) exerts its anti-inflammatory effect in rheumatoid arthritis (RA) patients is still debated. Lately, the MTX immunosuppressive effect has been related to apoptosis, especially in active RA patients, with ROS involvement., Methods: In the present research we investigated MTX oxidative effect and its ability to modulate immune balance in active versus non-active RA patients., Results: Our results show that MTX induces IL-10 secretion (a TH2 cytokine) and significantly reduces TH1 profile in Peripheral Mononuclear Cells (PMNC) derived from active RA patients (n=28). Additionally, we found that MTX modulates the immune status towards TH2 dominance by decreasing the IL-12R and the CXCR3 receptors typical for the TH1 population. Moreover, MTX was found to inhibit the production of nitric oxide (NO) in these patients, a phenomenon that might contribute to MTX action toward cytokine homeostasis. A significant correlation was found between MTX IL-10 induction and NO inhibition in active RA patients., Conclusion: Our data suggest that, in active RA patients, apoptosis induction by MTX may be primarily due to IL-10 production via modulation of oxidative stress, which may restore the critically important immune balance. These findings may contribute to determining which group of RA patients may better respond to MTX therapy.