The term spondyloarthritis (SpA) encompasses a heterogeneous group of inflammatory musculoskeletal diseases with several common genetic background and clinical features, including the possible ...involvement of the axial skeleton with peripheral mono- or oligo- arthritis and frequently coexisting skin, eye and intestinal manifestations. When the sacroiliac joints or other parts of the spine or thoracic wall are predominantly affected at magnetic resonance or X-ray imaging with inflammatory back pain, the disease is classified as axial SpA and the therapeutic choices are significantly different compared to cases of peripheral arthritis. Moving from the narrow effectiveness and safety profiles of non-steroidal anti-inflammatory drugs, there has been a significant research effort aimed at identifying new treatments based on our better understanding of the pathogenesis of SpA. Indeed, in parallel with the solid data demonstrating that IL-17 and IL-23 are key cytokines in the development of enthesitis and spondylitis, monoclonal antibodies interfering with this pathway have been developed for the treatment of axial SpA. Furthermore, the IL-17/IL-23 axis is key to extra-articular manifestations such as inflammatory bowel disease, uveitis, and psoriasis which are frequent comorbidities of SpA. Currently available drugs act through these mechanisms recognizing IL-23 and targeting IL-17, such as secukinumab and ixekizumab. These therapeutic approaches are now envisioned in the international treatment recommendations for psoriatic arthritis with an axial phenotype as well as for ankylosing spondylitis (AS). We will provide herein a concise comprehensive overview of the clinical evidence supporting the use of these and other drugs acting on IL-23 and IL-17 in axial SpA.
Introduction
The SARS-CoV-2 infection has been advocated as an environmental trigger for autoimmune diseases, and a paradigmatic example comes from similarities between COVID-19 and the ...myositis-spectrum disease associated with antibodies against the melanoma differentiation antigen 5 (MDA5) in terms of clinical features, lung involvement, and immune mechanisms, particularly type I interferons (IFN).
Case Report
We report a case of anti-MDA5 syndrome with skin manifestations, constitutional symptoms, and cardiomyopathy following a proven SARS-CoV-2 infection.
Systematic Literature Review
We systematically searched for publications on inflammatory myositis associated with COVID-19. We describe the main clinical, immunological, and demographic features, focusing our attention on the anti-MDA5 syndrome.
Discussion
MDA5 is a pattern recognition receptor essential in the immune response against viruses and this may contribute to explain the production of anti-MDA5 antibodies in some SARS-CoV-2 infected patients. The activation of MDA5 induces the synthesis of type I IFN with an antiviral role, inversely correlated with COVID-19 severity. Conversely, elevated type I IFN levels correlate with disease activity in anti-MDA5 syndrome. While recognizing this ia broad area of uncertainty, we speculate that the strong type I IFN response observed in patients with anti-MDA5 syndrome, might harbor protective effects against viral infections, including COVID-19.
Background
Systemic sclerosis (SSc) is an autoimmune connective tissue disease that affects multiple organs, leading to elevated morbidity and mortality with limited treatment options. The early ...detection of organ involvement is challenging as there is currently no serum marker available to predict the progression of SSc. The aptamer technology proteomic analysis holds the potential to correlate SSc manifestations with serum proteins up to femtomolar concentrations.
Methods
This is a two-tier study of serum samples from women with SSc (including patients with interstitial lung disease - ILD - at high-resolution CT scan) and age-matched healthy controls (HC) that were first analyzed with aptamer-based proteomic analysis for over 1300 proteins. Proposed associated proteins were validated by ELISA first in an independent cohort of patients with SSc and HC, and selected proteins subject to further validation in two additional cohorts.
Results
The preliminary aptamer-based proteomic analysis identified 33 proteins with significantly different concentrations in SSc compared to HC sera and 9 associated with SSc-ILD, including proteins involved in extracellular matrix formation and cell-cell adhesion, angiogenesis, leukocyte recruitment, activation, and signaling. Further validations in independent cohorts ultimately confirmed the association of specific proteins with early SSc onset, specific organ involvement, and serum autoantibodies.
Conclusions
Our multi-tier proteomic analysis identified serum proteins discriminating patients with SSc and HC or associated with different SSc subsets, disease duration, and manifestations, including ILD, skin involvement, esophageal disease, and autoantibodies.
The pathogenesis of idiopathic inflammatory myositis (IIMs, including polymyositis and dermatomyositis) remains largely enigmatic, despite advances in the study of the role played by innate immunity, ...adaptive immunity, genetic predisposition, and environmental factors in an orchestrated response. Several factors are involved in the inflammatory state that characterizes the different forms of IIMs which share features and mechanisms but are clearly different with respect to the involved sites and characteristics of the inflammation. Cellular and non-cellular mechanisms of both the immune and non-immune systems have been identified as key regulators of inflammation in polymyositis/dermatomyositis, particularly at different stages of disease, leading to the fibrotic state that characterizes the end stage. Among these, a special role is played by an interferon signature and complement cascade with different mechanisms in polymyositis and dermatomyositis; these differences can be identified also histologically in muscle biopsies. Numerous cellular components of the adaptive and innate immune response are present in the site of tissue inflammation, and the complexity of idiopathic inflammatory myositis is further supported by the involvement of non-immune mechanisms such as hypoxia and autophagy. The aim of this comprehensive review is to describe the major pathogenic mechanisms involved in the onset of idiopathic inflammatory myositis and to report on the major working hypothesis with therapeutic implications.
Progressive pulmonary fibrosis is generally diagnosed when interstitial lung disease progression occurs in the absence of any other cause, and a subset of patients with myositis and associated ...interstitial lung disease may develop progressive pulmonary fibrosis. Numerous autoantibodies (e.g., against tRNA-synthetase, MDA5, Ro52) increase the risk of this clinical feature in myositis and we speculate that serum biomarkers, sought using the most sensitive laboratory techniques available (i.e., immunoprecipitation) may predict pulmonary involvement and allow the early identification of progressive pulmonary fibrosis. We herein provide a narrative review of the literature and also present original data on pulmonary fibrosis in a cohort of patients with myositis and serum anti-Ro52 with interstitial lung disease. Our results fit into the previous evidence and support the association between anti-Ro52 and signs of pulmonary fibrosis in patients with inflammatory myositis. We believe that the combination of available and real-life data has significant clinical relevance as a paradigm of serum autoantibodies that prove useful in determining precision medicine in rare connective tissue diseases.
The prevalence of ANA and anti-ENA in the general population is not well established, especially their clinical significance in healthy subjects. We herein determined the prevalence and predictive ...value of serum ANA and anti-ENA for connective tissue diseases (CTD), cancer, and mortality. We took advantage of a randomly selected sample of the 1998 general population (Isola I) consisting of 2828 subjects (53% women, age 43±13 years) from a well-defined Northern Italian area. Serum ANA and anti-ENA were tested on the 2690 samples available in 2012 (Isola II, 50% women, age 58±13 years). Administrative databases were searched for CTD, cancer diagnosis, and death cases occurring between enrollment and December 31, 2013. The hazard ratio (HR) was calculated for incident cases. Serum ANA is positive in 18.1% for any titer and 6.1% for titers ≥1:160, 23% in subjects over 50 years and 13.1% and 6.1% for any titer and titers ≥1:160, respectively, in women. The HR for CTD development was significantly high for all ANA titers, with the highest for ANA ≥1:160 (HR 14.19, 95% CI 3.07–65.68). ANA positivity was not associated with cancer (HR 1.03; 95% CI 0.75–1.43), or with mortality (HR adjusted for age and sex 1.40; 95% CI 0.94–2.09). Serum anti-ENA is positive in a minority of subjects with highest figures for anti-nucleosome (1.9%), -histone (1.6%) and -PM/Scl (1.5%). In conclusion, serum ANA prevalence in the general population is highest in senior subjects and in women, while the female predominance is significantly lower compared to overt CTD. Serum ANA is associated with an increased probability of CTD development over time, but does not influence survival or cancer risk.
•Serum ANA is detected in 18.1% of the general population and the prevalence increases with age.•Serum ANA is associated with an increased risk of connective tissue disease over 15 years.•Serum ANA is not related to an increased risk of cancer over 15 years.•Serum ANA positivity is not associated with increased mortality over 15 years.
The sequencing of the human genome is now well recognized as the starting point of personalized medicine. Nonetheless, everyone is unique and can develop different phenotypes of the same disease, ...despite identical genotypes, as well illustrated by discordant monozygotic twins. To recognize these differences, one of the easiest and most familiar examples of biomarkers capable of identifying and predicting the outcome of patients is represented by serum autoantibodies. In this review, we will describe the concept of personalized medicine and discuss the predictive, prognostic and preventive role of antinuclear antibodies (ANA), anti-citrullinated peptide antibodies (ACPA), rare autoantibodies and anti-drug antibodies (ADA), to evaluate how these can help to identify different disease immune phenotypes and to choose the best option for treating and monitoring rheumatic patients in everyday practice. The importance of ANA resides in the prediction of clinical manifestations in systemic sclerosis and systemic lupus erythematosus and their association with malignancies. ACPA have a predictive role in rheumatoid arthritis, they are associated with the development of a more aggressive disease, extra-articular manifestations and premature mortality in RA patients; moreover, they are capable of predicting therapeutic response. Rare autoantibodies are associated with different disease manifestations and also with a greater incidence of cancer. The determination of ADA levels may be useful in patients where the clinical efficacy of TNF-α inhibitor has dropped, for the assessment of a right management. The resulting scenario supports serum autoantibodies as the cornerstone of personalized medicine in autoimmune diseases.
Abstract Background: Anti-mitochondrial antibodies (AMA) are found in >90% of primary biliary cholangitis patients. Anti-rods/rings antibodies (anti-RR) are most commonly associated with interferon-α ...and ribavirin treatment in hepatitis C patients. Clinical laboratories routinely screen for AMA and anti-RR using indirect immunofluorescence on HEp-2 cells (HEp-2-IFA). Therefore, we sought to establish reference materials for use in AMA and anti-RR testing. Methods: AMA-positive and anti-RR-positive human plasma samples (AMA-REF and RR-REF), identified as potential reference materials based on preliminary data, were further validated by multiple laboratories using HEp-2-IFA, immunoprecipitation (IP), western blotting, IP-western, line immunoassay (LIA), addressable laser bead immunoassay (ALBIA) and enzyme-linked immunosorbent assay (ELISA). Results: AMA-REF showed a strong positive cytoplasmic reticular/AMA staining pattern by HEp-2-IFA to ≥1:1280 dilution and positive signal on rodent kidney/stomach/liver tissue. AMA-REF reacted with E2/E3, E3BP, E1α and E1β subunits of the pyruvate dehydrogenase complex by IP and western blotting and was positive for AMA antigens by LIA, ALBIA and ELISA. RR-REF showed a strong positive rods and rings staining pattern by HEp-2-IFA to ≥1:1280 dilution. RR-REF reacted with inosine monophosphate dehydrogenase by IP, IP-western and ALBIA. RR-REF also produced a nuclear homogenous staining pattern by HEp-2-IFA, immunoprecipitated proteins associated with anti-U1RNP antibody and reacted weakly with histones, nucleosomes, Sm and nRNP/Sm by LIA. Conclusions: AMA-REF and RR-REF are useful reference materials for academic or commercial clinical laboratories to calibrate and establish internal reference standards for immunodiagnostic assays. AMA-REF and RR-REF are now available for free distribution to qualified laboratories through Plasma Services Group.
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