The use of biologic agents in autoimmune and inflammatory rheumatic diseases, has greatly increased in recent years, providing new treatment options to conventional anti-inflammatory and immunosuppressive strategies. Biologic drugs very often show selectivity of action towards specific targets and are currently used to induce disease remission or treat specific organ involvements in various inflammatory and autoimmune diseases. Given the variability in biological and clinical response between patients and the lack of knowledge in the mechanism influencing individual responses, it has become urgent to identify biomarkers of response to therapy, especially to distinguish/individuate patients who may potentially benefit from these therapies. This is also in view of the possible role of biomarkers as indicators of personalized treatment. This research topic contains description of various diseases treated with biological drugs in 11 articles: 4 reviews, 1 systematic review, 5 original research papers, and 1 clinical trial.Systemic lupus erythematosus (SLE) is one of the most severe among autoimmune rheumatic diseases characterized by complex and not well known pathogenesis and involvement of a high number of body organs. A study included in this research topic from Piantoni et al. (Front. Pharmacol. 2021 May 21;12:666971) has reported the characterization of circulating peripheral B and T lymphocytes and the evaluation of soluble B-cell related factors belonging to the TNF/TNFR superfamily in a cohort of clinically active SLE patients treated with belimumab. It was found that the baseline BAFF serum levels are the strongest predictor of response to belimumab after twelve months of therapy.Rheumatoid arthritis (RA) is another common autoimmune rheumatic disease characterized by involvement at joints and, in more severe cases, of different organs with increased mortality. RA has been dealt with in four papers of our research topic. A Phase Ib/IIa clinical trial from Tang et al, has investigated the pharmacokinetics and pharmacodynamics of WBP216, a long half-life fully human monoclonal antibody against interleukin 6, in a limited number of Chinese RA patients to optimize the dosage regimen for future clinical trials (Front Pharmacol. 2021 Feb 18;12:617265). Another study from Li and co-workers aimed to illustrate the regulation of Treg cells in the pathogenesis of early RA by arsenic trioxide (As2O3). The researchers identified significantly modulated pathways and/or functional categories of genes regulating metabolism in Treg cells, a finding that might be important in the treatment-naïve RA (Front Pharmacol. 2021 May 24;12:656124). Alternative approach with respect to conventional anti-inflammatory and immunomodulatory drugs is presented in the review from Cai and co-workers which summarized the roles of the main enzymes and their derivatives involved in the pathogenesis of RA and explored the explicit and potential targeted actions of herbal medicinal products with anti-RA activity (Front Pharmacol. 2021 Mar 16;12:626342). A new perspective in RA treatment can be inferred by the data reported in the paper from Xiao et al. In this study, an animal model of RA, the collagen-induced arthritis (CIA) model, has been used to evaluate alterations in the gut microbial communities in the ileum and cecum of CIA and control rats including microbial richness, diversity and taxa as well as the expression of interleukin (IL)-1β and IL-17A in the ileum and cecum of CIA rats. The ileal microbiota of CIA rats presented main alterations together with a significant increase in IL-1β and IL-17A mRNA expression, consistently with the immune-mediated inflammatory features of CIA (Fron Pharmacol. 2020 Nov 24;11:587534).A review from Choida et al. (Front Pharmacol 2021 Feb 2;11:635823.) presented the results of a comprehensive search of the literature to identify clinical, serological, genetic, cellular, and imaging biomarkers that can assist clinicians in efforts to personalize disease-modifying anti-rheumatic drugs (DMARDs) prescription and adjust treatment strategies for Juvenile idiopathic arthritis (JIA) patients, with particular attention to studies investigating etanercept treatment in the most severe JIA phenotype. This study has led to the conclusion that, although there are no ideal biomarkers in JIA, serological biomarkers with potential clinical utility have been identified and strategies of combining biomarkers of response to biologics in JIA is suggested.A narrative review by Silvagni et al. (Front Pharmacol. 2021 Jun 15;12:672515) provided an up-to-date overview of targeted therapies and treatment response biomarkers in psoriatic arthritis. This review focused on TNF-α-, IL-23/IL-17-, and JAK/STAT-dependent signal transduction axes, in the optics, to define the relationship among different activated proinflammatory processes suitable for targeting by different currently available drugs. Dermatomyositis (DM) is a rare autoimmune disease defined as an idiopathic inflammatory myopathy characterised by cutaneous manifestations. The study from Li et al (Front Pharmacol. 2021 Sep 17;12:727901), identified the profiles of noncoding RNAs, both lncRNAs and miRNAs, carried in exosomes (EXOs) from peripheral neutrophils of DM patients. This revealed a high number of upregulated and downregulated noncoding RNAs in DM neutrophil EXOs. The study also explored their potential functional roles and utility as new biomarkers and therapeutic targets.A study from Lu and co-workers (Front Pharmacol. 2021 Mar 16;12:635654) has evaluated the efficacy of tocilizumab (TCZ) in adult patients with refractory immune-mediated necrotizing myopathies and investigated possible predictive biomarkers of the response to treatment with TCZ. Baseline serum IL-6 and muscle IL-6 mRNA levels and the percentage of CD56-positive muscle fibres have been found useful to predict the response to TCZ treatment in these patients.Non-infectious uveitis (NIU) is believed to be an immune-mediated ocular inflammation frequently associated to systemic autoimmune diseases such as JIA. The systematic review from Li et al. (Front Pharmacol. 2021 Apr 26;12:673984) summarised the current evidence from randomised controlled trials regarding the efficacy and safety of adalimumab (ADA) treatment in NIU. Metanalysis performed on seven RCTs confirmed that ADA considerably lowered the risk of treatment failure or visual loss as compared to placebo, leading to the conclusion that ADA is both effective and safe in treating NIU.Biologic therapies are employed in many inflammatory and immune mediated diseases, such as psoriasis, a chronic inflammatory disease characterised by erythematous scaly plaques frequently accompanied by systemic damages. The review from Shi et al. explored the most life-threatening associations between psoriasis and cardiometabolic comorbidities (cardiovascular diseases, obesity, diabetes mellitus and metabolic syndrome), emphasizing benefits and precautions of biologic therapy in the management of psoriatic patients with cardiometabolic comorbidities and outlining the positive effects of different biologics on cardiovascular biomarkers (Front Pharmacol. in press).In conclusion, this research topic explored and summarised many different aspects of therapies with biological treatments in inflammatory and immune mediated diseases. The effects of monoclonal antibodies (belimumab, ADA, TCZ, etanercept, WBP216) as well as chemical compounds (arsenic trioxide) and medicinal herbs have been evaluated in addition to the investigation of different aspects influencing autoimmune and inflammatory diseases ranging from non-coding RNA in exosomes to gut microbial communities' activity.
Editorial10 December 2021
Editorial: Autoimmune and Inflammatory Rheumatic Diseases: Identifying Biomarkers of Response to Therapy With Biologics
Psoriatic arthritis (PsA) is a chronic inflammatory immune-mediated disease with a burdensome impact on quality of life and substantial healthcare costs. To date, pharmacological interventions with different mechanisms of action, including conventional synthetic (cs), biological (b), and targeted synthetic (ts) disease-modifying antirheumatic drugs (DMARDs), have been proven efficacious, despite a relevant proportion of failures. The current approach in clinical practice and research is typically ‘predictive’: the expected response is based on stratification according to clinical, imaging and laboratory data, with a ‘heuristic’ approach based on ‘trial and error’. Several available therapeutic options target the TNF-α pathway, while others are directed against the IL-23/IL-17A axis. Janus Kinase inhibitors (JAKis), instead, simultaneously block different pathways, endowing these drugs with a potentially ‘broad-spectrum’ mechanism of action. It is not clear, however, whether targeting a specific pathway (e.g., TNF-α or the IL-23/IL-17 axis) could result in discordant effects over other approaches. In particular, in the case of ‘refractory to a treatment’ patients, other pathways might be hyperactivated, with opposing, synergistic or redundant biological significance. On the other hand, refractory states could be purely resistant to treatment as a whole. Since chronic synovitis is one of the primary targets of inflammation in PsA, synovial biomarkers could be useful in depicting specific biological characteristics of the inflammatory burden at the single-patient level, and despite not yet being implemented in clinical practice, these biomarkers might help in selecting the proper treatment.
In this narrative review, we will provide an up-to-date overview of the knowledge in the field of psoriatic synovitis with regard to studies investigating the relationships among different activated proinflammatory processes suitable for targeting by different available drugs. The final objective is to clarify the state of the art in the field of personalized medicine for psoriatic disease, aiming at moving beyond the current treatment schedules towards a patient-centered approach.
Objective To evaluate the efficacy of tocilizumab (TCZ) in adult patients with refractory immune-mediated necrotizing myopathies (IMNMs) and investigate possible predictive biomarkers of the response to treatment with TCZ.
Methods Patients with refractory IMNM were enrolled in this open-label pilot observational study and received intravenous TCZ treatment. The clinical response was assessed after 6 months of TCZ treatment according to the 2016 American College of Rheumatology–European League Against Rheumatism (ACR–EULAR) response criteria for adult dermatomyositis and polymyositis. Muscle biopsies were performed to investigate muscle fiber regeneration by immunohistochemical staining of CD56. Serum levels of interleukin (IL)-6 were measured using a multiplex bead-based flow fluorescent immunoassay. The levels of muscle IL-6 mRNA were detected by real-time polymerase chain reaction.
Results A total of 11 patients with refractory IMNM were enrolled in the study, including 3 anti-3-hydroxy-3-methylglutaryl-CoA reductase- and 8 anti-signal recognition particle-positive patients. Seven (63.6%) of these patients achieved clinically significant responses according to the 2016 ACR–EULAR myositis response criteria. Responders had higher baseline serum IL-6 and muscle IL-6 mRNA levels and percentage of CD56-positive muscle fibers than non-responders. Baseline serum IL-6 levels and the percentage of CD56-positive muscle fibers were positively correlated with total improvement score after 6 months of TCZ treatment. Furthermore, muscle fiber necrosis and muscle fiber size variation decreased in repeated muscle biopsies in five responders.
Conclusion Patients with refractory IMNM may respond to TCZ. Baseline serum IL-6 and muscle IL-6 mRNA levels and the percentage of CD56-positive muscle fibers may predict the response to TCZ treatment in these patients.