BackgroundDysregulated production of cytokines has a critical role in systemic lupus. The aim of this work is to identify, by a comprehensive analysis of IL-1 family cytokines and receptors in serum, correlation between cytokines/receptors’ levels and the clinical and serological features of the disease.MethodsA full clinical evaluation was performed in 74 patients with systemic lupus erythematosus (SLE). C3, C4, anti-dsDNA and anti-C1q antibodies were measured. Cytokines of the IL-1 family (IL-1α, IL-1β, IL-33, IL-18), soluble receptors (sIL-1R1, sIL-1R2, sIL-1R3, ST2/sIL-1R4) and antagonists (IL-1Ra, IL-18 binding protein (IL-18BP)) were measured in serum by multiarray ELISA. Free IL-18 was calculated as the amount of IL-18 not inhibited by IL-18BP. Data were analysed by non-parametric tests and by multivariate analysis, using partial least squares (PLS) models.ResultsTotal IL-18, IL-18BP, sIL-1R4 and IL-1Ra levels were higher in SLE vs. controls. Total and free IL-18 and sIL-1R4 were higher in patients with active vs. inactive disease and correlated with ECLAM, anti-C1q and anti-dsDNA antibodies. sIL-1R2 was higher in patients with inactive disease, was negatively correlated with ECLAM and anti-C1q antibodies and was positively correlated with C3 levels. PLS identified sIL-1R4, sIL-1R2 and anti-dsDNA as variables distinguishing patients with active from those with inactive disease; sIL-1R4, IL-18BP and anti-dsDNA identified patients with active nephritis; sIL-1R4, C3, IL-18 and free IL-18 identified patients with haematological involvement.ConclusionThe data support the use of IL-18, sIL-1R2 and sIL-1R4 as biomarkers of disease activity and organ involvement, and suggest that failure in the inhibition of IL-1 activation may be a critical event in the active stages of SLE.
Chronic urticaria (CU) is a mast cell-driven disease characterized by the development of wheals, angioedema, or both for more than 6 weeks. The two major sub-types are chronic spontaneous urticaria (CSU) and inducible urticaria. In the last decade different pathophysiological mechanisms, potentially responsible for the development of the disease, have been described. It is likely that the activation of mast cells and basophils in CSU can be the results of immune system dysregulation, activation of the inflammatory cascade, and of the extrinsic coagulation pathway. Some of the mediators involved in the pathophysiological mechanisms of CSU have recently been identified as potential biomarkers useful for the diagnosis, follow-up, and management of the disease, even if they are not yet available in clinical practice. Thus, in this review we discuss new insights in the mediators involved in the pathogenesis of CSU, highlighting their potential role as biomarkers in the activity and progression of the disease and response to therapies.
Objective Glucocorticoids (GC) are associated with side effects in giant cell arteritis (GCA). Immunosuppressive therapies (ITs) have given conflicting results in GCA, regarding GC sparing effect. Primary endpoint is to evaluate whether very early introduction of ITs in GCA minimize the rate of GC-induced adverse events, in terms of infections, new onset systemic arterial hypertension, GC-induced diabetes and osteoporotic fractures. Methods A multicenter retrospective case-control study included 165 patients. One group included 114 patients who were treated with at least one IT given at diagnosis or within 3 months from the start of GC. A second group included 51 GCA who received only GC or an IT more than 3 months later. Results The most frequently used ITs were: methotrexate (138 patients), cyclophosphamide (48 patients) and tocilizumab (27 patients). No difference was observed as concerns the follow-up time between groups [48.5 (IQR 26–72) vs 40 (IQR 24–69), p = 0.3)]. The first group showed a significantly lower incidence of steroid-induced diabetes (8/114, 7% vs 12/51, 23.5%; p = 0.003) and no differences for the rate of infections (p = 0.64). The group was also exposed to lower doses of GC at first (p < 0.0001) and third (p < 0.0001, rank-sum test) month. Forty-four patients in the first group (38.6%) compared with 34 in the second one (66.7%) experienced at least one relapse (p = 0.001). Conclusion Very early introduction of IT in GCA lowered the incidence of steroid-induced diabetes, possibly due to the lower doses of GC in the first three months. Relapse rate was even lower.
BackgroundThe detection of anti-dsDNA antibodies is critical for the diagnosis and follow-up of systemic lupus erythematosus (SLE) patients. The presently available assays are characterized by a non-optimal specificity (solid phase assays) or sensitivity (Crithidia Luciliae immunofluorescence test (CLIFT)). To overcome the limits of CLIFT and solid phase chromatin assays, we explored the diagnostic potential of an assay based on plasmid DNA containing a highly bent fragment of 211 bp from Crithidia Luciliae minicircles, complexed with histone peptides.MethodsElectrically neutral complexes of PK201/CAT plasmid (PK) DNA and histone 4 (H4) peptides were evaluated by electromobility shift assay. Complexes of H4 peptides and PK were absorbed to the solid phase to detect specific immunoglobulin G (IgG) in sera. Sera from 109 SLE patients, 100 normal healthy subjects, and 169 disease controls were tested.ResultsH4(14-34) containing the consensus sequence for DNA binding interacts with PK, retarding its migration. H4(14-34)/PK complexes were used to test sera by ELISA. Anti-H4-PK antibodies were detected in 56 % of SLE sera (more frequently in patients with skin or joint involvement) versus 5.9 % in disease controls; inhibition assays show that sera react with epitopes present on DNA or on the complex, not on the peptide. Antibody titer is correlated with European Consensus Lupus Activity Measurement (ECLAM) score and anti-complement component 1q (C1q) antibodies, negatively with C3 levels. Anti-H4-PK antibodies compared with CLIFT and solid phase dsDNA assays display moderate concordance.ConclusionsThe H4/PK assay is a simple and reliable test which is useful for the differential diagnosis and evaluation of disease activity in SLE patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1117-8) contains supplementary material, which is available to authorized users.
Objective. Large-vessel vasculitis (LVV) are chronic inflammatory diseases that affect arteries. While a mere clinical-serological approach does not seem sensitive either in the initial evaluation nor in long-term monitoring, 18-FDG positron emission tomography ( 18-FDG PET) is currently considered a useful assessment tool in LVV. We aimed at exploring the utility of 18-FDG, compared with traditional assessments, in the short-and long-term follow-up of patients with LVV. In addition, we compared patterns of vascular involvement in patients with Takayasu's arteritis (TAK) and giant cell arteritis (GCA). Method. We retrospectively analysed 47 patients affected by LVV, evaluating clinics, blood chemistry and 18-FDG PET results, at two time points, shortterm (average 8 months after diagnosis) and long-term (average 29 months).Results. 18-FDG PET uptake, expressed as mean value of SUV max, decreased significantly during follow-up in all the patients. A low concordance between 18-FDG PET and acute phase reactants levels was observed, but also a good sensitivity in detecting the response to treatment. Conclusion.The results confirm the role of 18-FDG PET as a powerful tool in the evaluation of LVV, both at the time of diagnosis and during monitoring. Furthermore, the data confirm that GCA and TAK are part of the same disease spectrum.
BackgroundRituximab (RTX) represents a milestone in the treatment of mixed cryoglobulinemic vasculitis (MCV). Despite usually well-tolerated, RTX may induce different types of adverse drug reactions, including exacerbation of vasculitis. RTX biosimilars have been recently approved in Europe in the treatment of rheumatoid arthritis, but no data are available about effectiveness and safety of RTX biosimilars in the treatment of MCV.ObjectivesAim of the study was to analyse the safety of RTX biosimilar in patients with MCV treated in first-line or after a shift by RTX originator.MethodsIn a multicenter, prospective, open-label study, we enrolled all MCV patients treated with RTX biosimilar, both in first-line or after a shift by RTX originator. Nineteen consecutive MCV patients (F/M 13/6, mean age 68.3±11.5 months, mean disease duration 94±86 months, 10/19 HCV+ and 6/19 HBV+) were treated with RTX in a six-month period (July-December, 2018). Nine patients were treated with RTX for the first time, while the other 9 patients have been already treated with RTX originator and were switched to RTX biosimilar. Twelve patients received a dose of 250 mg/m2 of RTX every other week, while 6 were treated with 1 gram of RTX every other week.ResultsDuring a month-period after the last infusion, 5 adverse events (AE) were observed, namely 2 vasculitis flares, and 1 urticaria, atrial fibrillation occurred during infusion, and septicaemia, respectively.Three of 5 aE were observed in patients treated with the higher dose of RTX (in particular both cases of vasculitis flare were recorded in patients treated with 1 gram of RTX), while no differences were observed according to the previous treatment with RTX originator (2/9 vs 3/9 aE in patients switch or naïve, respectively).ConclusionDespite the low number of patients, the switch among RTX originator and biosimilar appear to be safe and the number of aE were in line with previous reports about RTX originator. The main limit of this study is the absence of a control group, that doesn’t allow a direct comparison of the safety between RTX originator and biosimilar. Previous reports suggested that higher dosage of RTX are associated to a higher risk of side effects. Also, in our study the occurrence of aE, mainly vasculitis flare, seem to be associated to the dose of RTX, rather than to the switch to biosimilarReferences[1] Ferri C, Cacoub P, Mazzaro C, Roccatello D, Scaini P, Sebastiani M, Tavoni a, Zignego aL, De Vita S. Treatment with rituximab in patients with mixed cryoglobulinemia syndrome: results of multicenter cohort study and review of the literature. Autoimmun Rev. 2011;11:48-55[2] Sène D, Ghillani-Dalbin P, amoura Z, Musset L, Cacoub P. Rituximab may form a complex with IgMkappa mixed cryoglobulin and induce severe systemic reactions in patients with hepatitis C virus-induced vasculitis. Arthritis Rheum. 2009;60:3848-55.Disclosure of interestsNone declared
BackgroundGlucocorticoids (GC) remain the mainstay of treatment of giant cell arteritis (GCA). However, relapses occur in up to 50% of patients when GC are tapered and prolonged courses of GC are associated with serious side effects. In this setting, the outcome is frequently determined by GC-related adverse events (AEs). Thus, several studies have been conducted on the effectiveness of a GC-sparing immunosuppressive therapy (IT), with conflicting results.ObjectivesTo evaluate the effectiveness of IT in a series of GCA patients, in: 1) reducing the risk of GCA relapse; 2) lowering the exposure to GC therapy; 3) minimising the occurrence of steroid-induced AEs.MethodsWe performed a multicenter retrospective observational study including 69 patients (75,4% females; mean age ±SD 68,7±7,8 y; median follow-up time 40 months [range 26–65]) diagnosed with GCA, all receiving an adjunctive IT given ab initio (71%) or within 3 months from the start of GC. All but 17 patients (with extracranic involvement) fulfilled the GCA ACR classification criteria. Risk of first relapse of GCA, GC exposure and main AEs were retrospectively analysed. Results were compared with those reported in other studies, all characterised by a lower use of IT.Resultsall patients received GC plus IT: methotrexate up to 20 mg/week in 63 patients, cyclophosphamide in 22, tocilizumab in 12. In the follow-up, a first relapse of GCA occurred in 14 (20,3%) of patients. The rates of first relapse at 12, 24, 36 and 48 weeks were 4,3%, 11,6%, 15,9% and 15,9%, respectively, in comparison with rates of 24,3%, 41,6%, 61%, 64,9%, respectively, in the GC monotherapy arm in the meta-analysis by Mahr,1 where similar data were available. The median daily prednisone dose at beginning was 50 mg, and decreased to 10 mg at 3 months and to 5 mg at 6 months. The median time required to reduce prednisone to 7.5 mg/day and 5 mg/ was 3 and 5 months respectively (vs. 6.5 and 7.5 months in series by Proven,2 where similar data were available). In our cohort, lower cumulative GC use was accompanied by a reduction of AEs, without further toxicity (tab.1).Present workProven 20032Mahr 20071Souza 20143Alba 20144Labarca 20165 Number of patients691207745106286% use of IT100%2%0%55,6%14,2%0%Follow up, months4012013,754,993,661,2Fragility fractures11,6%38%8%NANA27%Diabetes4.3%9%12%33,4%8,5%NAHypertension8.7%22%NA66,7%51%1,7%Infections10,1% (2,9% needing hospitalisation)31%NA23%NA17% (all needing hospitalisation)ConclusionsThe use of IT ab initio or very early in the treatment of GCA appears to be effective and safe, lowering the risk of relapses, reducing GC dose and the rate of GC-related AEs. Therefore, the present data support the early introduction of IT in the treatment of GCA.References[1] Mahr AD, et al. Arthritis Rheum2007;56(8):2789–97.[2] Proven A, et al. Arthritis Rheum 2003 49(5):703–8.[3] Souza AW, Okamoto KY, Abrantes F, et al. Clinics (Sao Paulo) 2013;68:317–322.[4] Alba MA, et al. Medicine (Baltimore) 2014;93(5:194–201.[5] Labarca C, et al. Rheumatology (Oxford) 2016;55(2...
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