Idiopathic inflammatory myopathies represent a heterogeneous group of autoimmune diseases with systemic involvement. Even though numerous specific autoantibodies have been recognized, they have not ...been included, with the only exception of anti-Jo-1, into the 2017 Classification Criteria, thus perpetuating a clinical-serologic gap. The lack of homogeneous grouping based on the antibody profile deeply impacts the diagnostic approach, therapeutic choices and prognostic stratification of these patients. This review is intended to highlight the comprehensive scenario regarding myositis-related autoantibodies, from the molecular characterization and biological significance to target antigens, from the detection tools, with a special focus on immunofluorescence patterns on HEp-2 cells, to their relative prevalence and ethnic diversity, from the clinical presentation to prognosis. If, on the one hand, a notable body of literature is present, on the other data are fragmented, retrospectively based and collected from small case series, so that they do not sufficiently support the decision-making process (i.e. therapeutic approach) into the clinics.
Infliximab (IFX) is a chimeric mAb that can lead to the appearance of anti-drug Abs. Recent research has identified the presence of circulating IFX-specific T cells in treated patients. The aim of ...the study was to analyze the functional characteristics of IFX-specific T cells, in particular their capability to produce biologically active regulatory cytokines. Drug-stimulated PBMCs or coculture systems were used to detect memory T cells in treated patients. The cytokines produced by IFX-specific T cells, T cell lines, and T cell clones were evaluated at the mRNA and protein levels. Drug infusion induced an increase in IL-10 serum levels in vivo, whereas other cytokines were unchanged. IL-10 mRNA was higher in IFX-stimulated PBMCs from treated patients compared with untreated patients. When analyzed longitudinally, an early IL-10 mRNA expression was observed. HLA class II-restricted IL-10 production by drug-specific T cells from exposed patients was observed in different experimental settings, such as a coculture system, sorted CD154
T cells, IFX peptide-stimulated PBMCs, and IFX-specific T cell clones. Finally, IL-10-producing drug-specific T cell clones downregulated the response of autologous effector T cells to IFX. Overall, these findings identify IFX-specific T cells as a source of biologically active IL-10 and suggest interference by IL-10-producing cells in the detection of drug-specific T cells.
Background
Primary angiitis of the CNS (PACNS) is a process causing variously combined neurological disturbances. Its rarity and kaleidoscopic presentation make it difficult to diagnose and even to ...suspect.
Objective
(1) To provide an up-to-date review on PACNS and (2) to create a preliminary screening algorithm based on clinical and radiological first-level data, useful to suspect PACNS and guide further investigations.
Methods
Review of PUBMED case series on PACNS, published from 2002 to 2017, collection of frequencies of clinical and neuroimaging features and calculation of median values. Classification of features as “major” or “minor” if frequency was higher or lower than median value. Combination of features in sets of criteria represented by all possible combinations of major and minor clinical and neuroradiological features. Application of criteria to published PACNS case reports and selection of the ones best identifying patients with definite PACNS.
Results
We reviewed 24 case series. “Major” clinical features were headache, stroke, cognitive impairment, focal neurological deficits; “minor” were seizures, altered consciousness, psychiatric disorders. “Major” neuroradiological features were multiple parenchymal lesions, parenchymal/meningeal contrast enhancement, magnetic resonance angiography vessel abnormalities, vessel wall enhancement; “minor” were parenchymal/subarachnoid hemorrhage, single parenchymal lesion. The selected sets of criteria able to identify all PACNS patients were (1) one clinical (major/minor) + one major neuroradiological feature; and (2) Two clinical (≥ 1 major) + one minor neuroradiological feature.
Conclusion
Our review provides a detailed clinical/neuroradiological picture of PACNS. The proposed algorithm should be regarded as a preliminary screening tool to move the first steps towards PACNS diagnosis that needs validation.
A few studies have reported the safety profile of interleukin (IL)-1 blockers from real life. The aim of this study is to describe anakinra (ANA) and canakinumab (CAN) safety profile in children and ...adults, based on data from a real-life setting. Demographic, clinical, and therapeutic data from patients treated with ANA and CAN were retrospectively collected and analyzed. Four hundred and seventy five patients were enrolled; ANA and CAN were prescribed in 421 and 105 treatment courses, respectively. During a mean follow-up of 24.39 ± 27.04 months, 89 adverse events (AE) were recorded; 13 (14.61%) were classified as serious AE (sAE). The overall estimated rate of AE and sAE was 8.4 per 100 patients/year. Safety concerns were more frequent among patients aged ≥ 65 years compared with patients < 16 years (
p
= 0.002). No differences were detected in the frequency of safety concerns between monotherapy and combination therapy with immunosuppressants (
p
= 0.055), but a significant difference was observed when injection site reactions were excluded from AE (
p
= 0.01). No differences were identified in relation to gender (
p
= 0.462), different lines of biologic therapy (
p
= 0.775), and different dosages (
p
= 0.70 ANA;
p
= 0.39 CAN). The overall drug retention rate was significantly different according to the occurrence of safety concerns (
p
value < 0.0001); distinguishing between ANA and CAN, significance was maintained only for ANA (
p
< 0.0001 ANA;
p >
0.05 CAN). Treatment duration was the only variable associated with onset of AE (OR = 0.399 C.I. 0.250–0.638,
p
= 0.0001). ANA and CAN have shown an excellent safety profile; the risk for AE and sAE tends to decrease over time from the start of IL-1 inhibition.
Interleukin (IL)-1 plays a crucial role in the pathogenesis of Adult onset Still's disease (AOSD).
To evaluate the efficacy and safety of anakinra (ANA) and canakinumab (CAN) in a large group of AOSD ...patients.
Data on clinical, serological features, and concomitant treatments were retrospectively collected at baseline and after 3, 6, and 12 months from AOSD patients (Yamaguchi criteria) referred by 18 Italian centers. Pouchot's score was used to evaluate disease severity.
One hundred forty patients were treated with ANA; 4 were subsequently switched to CAN after ANA failure. The systemic pattern of AOSD was identified in 104 (74.2%) of the ANA-treated and in 3 (75%) of the CAN-treated groups; the chronic-articular type of AOSD was identified in 48 (25.8%) of the ANA-treated and in 1 (25%) of the CAN-treated groups. Methotrexate (MTX) was the most frequent disease modifying anti-rheumatic drug (DMARD) used before beginning ANA or CAN 91/140 (75.8%), 2/4 (50%), respectively. As a second-line biologic DMARD therapy in 29/140 (20.7%) of the patients, ANA was found effective in improving all clinical and serological manifestations (
< 0.0001), and Pouchot's score was found to be significantly reduced at all time points (
< 0.0001). No differences in treatment response were identified in the ANA-group when the patients were stratified according to age, sex, disease pattern or mono/combination therapy profile. ANA primary and secondary inefficacy at the 12-month time point was 15/140 (10.7%) and 11/140 (7.8%), respectively. Adverse events (AEs) mainly represented by in situ (28/47, 59.5%) or diffuse (12/47, 25.5%) skin reactions and infections (7/47, 14.8%) were the main causes for discontinuation. Pouchot's score and clinical and serological features were significantly ameliorated at all time points (
< 0.0001) in the CAN-group, and no AEs were registered during CAN therapy. Treatment was suspended for loss of efficacy only in one case (1/4, 25%).
This is the largest retrospective observational study evaluating the efficacy and safety of IL-1 inhibitors in AOSD patients. A good response was noted at 3 months after therapy onset in both the ANA- and CAN-groups. Skin reaction may nevertheless represent a non-negligible AE during ANA treatment.
This study aimed to evaluate the proportion of infliximab (IFX)-exposed patients exhibiting cellular response to the drug in a longitudinal way and to establish whether it is predictive for anti-drug ...antibodies (ADA) development. Seventeen patients suffering from immuno-mediated disorders were enrolled. Blood was sampled at baseline and before each of the first eight infusions of IFX. The proliferation of PBMCs to 15-mer peptides covering VH/VL frames of IFX was assessed as well as transcription factors and cytokines mRNA expression of memory T cells in IFX-stimulated PBMCs. The number of peptides recognized by T cells after four infusions was higher than those recognized by the same patients before treatment. IFX-stimulated PBMCs from more than 90% of patients were able to express the main regulators and adaptive cytokines of memory T cells. While IFN-γ mRNAs increased after the first infusion and declined during the subsequent ones, IL-10 mRNA was upregulated throughout the treatment. IL-10 was functionally active because its neutralization improved IFN-γ and IL-13 mRNA expression
. The IL-10/IFN-γ ratio was shown to be lower in patients who developed ADAs solely at the early infusions. IL-10 production consistently preceded or paralleled the IFN-γ onset in ADA- patients, while it was not produced or followed IFN-γ onset in ADA+ patients. In conclusion, this study provides evidence that the majority of exposed patients undergo a cellular response to IFX with the upregulation of IL-10. The development of ADA is associated with the early impairment of IL-10 and low levels of the IL-10/IFN-γ ratio.
This study aims to evaluate (1) the efficacy and safety of tocilizumab (TCZ) as a steroid-sparing agent in patients with giant cell arteritis (GCA) and (2) the usefulness of 18F-fluorodeoxyglucose ...positron emission tomography (FDG-PET) in the follow-up and to detect disease activity. We retrospectively evaluated 12 patients with GCA treated with TCZ (8 mg/kg/mo). Pre- and posttherapy data about clinical signs and symptoms, laboratory results, FDG-PET imaging study, and the mean glucocorticoid (GC) dose were used to assess disease activity. Tocilizumab achieved complete disease remission in all patients. Mean FDG-PET-detected standard uptake value decreased from 2.05 ± 0.64 to 1.78 ± 0.45 (P = .005). In 2 patients in whom temporal arteries color Doppler sonography examination was consistent with temporal arteritis, the hypoechoic halo disappeared after TCZ treatment. Mean GC dose was tapered from 26.6 ± 13.4 mg/d to 3.3 ± 3.1 mg/d (P < .0001). One-half of the patients discontinued GC therapy. Three patients experienced severe adverse reactions and had to stop TCZ therapy. In accordance with previous reports, TCZ is an effective steroid-sparing agent for GCA, although careful monitoring of adverse drug reactions is needed. 18F-fluorodeoxyglucose positron emission tomography could be used to monitor disease activity in TCZ-treated patients, but prospective studies are needed to confirm these data.
Only a few studies have reported long-term efficacy of interleukin (IL)-1 inhibition in systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still disease (AOSD). Herein we report on the ...effectiveness of anakinra (ANA), expressed in terms of drug retention rate (DRR), and evaluate the predictive factors of drug survival in a cohort of patients with sJIA and AOSD.
This is a multicenter study reviewing retrospectively the medical records from 61 patients with sJIA and 76 with AOSD, all treated with ANA in 25 Italian tertiary referral centers.
The cumulative retention rate of ANA at 12-, 24-, 48-, and 60-month of follow-up was 74.3%, 62.9%, 49.4%, and 49.4%, respectively, without any significant differences between sJIA and AOSD patients (
= 0.164), and between patients treated in monotherapy compared with the subgroup coadministered with conventional disease-modifying antirheumatic drugs (cDMARDs) (
= 0.473). On the other hand, a significant difference in DRR was found between biologic-naïve patients and those previously treated with biotechnologic drugs (
= 0.009), which persisted even after adjustment for pathology (
= 0.013). In the regression analysis, patients experiencing adverse events (AEs) {hazards ratio (HR) = 3.029 confidence interval (CI) 1.750-5.242,
< 0.0001} and those previously treated with other biologic agents HR = 1.818 (CI 1.007-3.282),
= 0.047 were associated with a higher HR of ANA discontinuation. The median treatment delay was significantly higher among patients discontinuing ANA (
< 0.0001). Significant corticosteroid-sparing (
= 0.033) and cDMARD-sparing effects (
< 0.0001) were also recorded. Less than one-third of our cohort developed AEs, and 85% were deemed mild in nature, with 70% of them involving the skin.
Our findings display an overall excellent DRR of ANA on the long run for both sJIA and AOSD, that may be further optimized by closely monitoring patient's safety issues and employing this IL-1 inhibitor as a first-line biologic as early as possible. Moreover, ANA allowed a significant drug-sparing effect and showed an overall good safety profile.
The association between MPO-ANCA-associated vasculitis (AAV) and interstitial lung disease (ILD) has been well established. Pulmonary fibrosis may coexist with, follow, or even precede the diagnosis ...of AAV, and its presence adversely affects the prognosis. The optimal approach to investigating ANCA in patients with ILD remains a subject of ongoing debate. Here we aim to describe presentation and progression of MPO-ANCA ILD. We conducted a retrospective evaluation of a cohort of individuals diagnosed with MPO-ANCA ILD, with or without accompanying renal impairment, at the Immunology and Cell Therapy Unit, Careggi University Hospital, Florence, Italy, between June 2016 and June 2022. Clinical records, imaging studies, pathologic examinations, and laboratory test results were collected. Among the 14 patients identified with MPO-ANCA ILD, we observed a significant association between MPO-ANCA titers assessed at the time of ILD diagnosis and renal involvement. Renal impairment in these cases often manifested as subclinical or slowly progressive kidney damage. Interestingly, complement C3 deposits were consistently found in all renal biopsy specimens, thereby suggesting the potential for novel therapeutic targets in managing renal complications associated with MPO-ANCA ILD. The presentation of MPO-ANCA vasculitis as ILD can be the first and only clinical manifestation. MPO-ANCA levels at ILD diagnosis could warn on the progression to renal involvement in patients with MPO-ANCA ILD, hence caution is needed because renal disease can be subclinical or smoldering.
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