Immunomodulatory Drugs for Autoimmune Diseases: Mechanisms, Development and Clinical Translation

Dear Colleagues,

Immunomodulatory drugs are therapeutic strategies that modulate the immune system's response to reduce autoimmunity without completely suppressing it. They are used in autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, lupus and celiac disease, among others.

General mechanisms of these drugs are the inhibition of T or B cell activation and proliferation, the blockade of inflammatory cytokines (e.g., TNF, IL-6) or their signals, interference with costimulatory signals (e.g., CD28 and CTLA-4), the regulation of innate immunity and antimicrobial responses, the modulation of specific autoimmune responses (e.g., tolerance induction) and effects on inflammation and tissue repair.

Immunomodulatory drugs can be divided into the following main categories:

• Symptomatic and anti-inflammatory immunomodulators: NSAIDs and glucocorticoids (rituals for flare control).
• Traditional immunosuppressants: methotrexate, azathioprine and mycophenolate mofetil.
• Monoclonal antibodies and biologics: infliximab, adalimumab (anti-TNF), rituximab (anti-CD20), ocrelizumab, secukinumab (anti-IL-17) and tocilizumab (anti-IL-6).
• JAK/STAT inhibitors (targeted immunomodulators): tofacitinib and baricitinib.
• T cell modulation and tolerance: abatacept (CTLA-4Ig) and metrics for tolerance induction.
• Agents that alter the microbiota or innate responses: experimental and personalized approaches.

The long process from research to clinical application of immunomodulatory drugs is divided into the following stages:

• Discovery: Identification of relevant immunological targets in preclinical models and clinical data.
• Preclinical phase: Safety and mechanism evaluation in cultures and animal models.
• Phase I–III clinical trials: Evaluation of safety, tolerability, optimal dose, and efficacy in humans.
• Regulatory approval: Submission of data to regulatory agencies (FDA, EMA, etc.) for approval for clinical use.
• Clinical use and monitoring: Incorporation into clinical guidelines; monitoring of adverse effects, long-term efficacy, and personalization based on biomarkers.
• Innovation and personalization: Response biomarkers, combination therapies, and treatments tailored to disease subtypes.

The therapeutic selection of immunomodulatory drugs is based on the disease, severity, comorbidities, and safety profile. It is necessary to monitor these treatments using laboratory tests (complete blood count, liver/kidney function and inflammatory markers), opportunistic infections, and prior vaccinations.

Common adverse effects, such as infections, hepatotoxicity, immunosuppression, dermatological effects and thrombosis (depending on the class), can also be detected. Moreover, it is necessary to have clear strategies for flare management and dose adjustment. Special consideration must be made for the use of immunomodulatory drugs in pregnancy and breastfeeding; age, comorbidities, and cost/access to biologic therapies should also be carefully taken into account.

As is well known, autoimmune diseases are a group of chronic conditions represented by the immune system's aberrant response against self-antigens, leading to chronic inflammation and functional decline. Given the challenges in managing these diseases, the scientific community makes constant efforts to develop therapies that can precisely regulate immune function.

In recent years, immunomodulatory drugs are a main focus in the pharmaceutical research field. These agents act through complex mechanisms, focusing on specific immune pathways to restore the immune homeostasis, while lowering the collateral damage. From standard immunosupressants and biologic therapies to small molecules, the field of treatment is evolving at a fast pace.

This Special Issue aims at bringing together innovative treatment approaches that explore the mechanisms of action, preclinical models and clinical applications of immunomodulatory drugs in autoimmune disease. The main focus of this collection is to discover novel therapeutic targets, biomarkers of response or resistance, drug repurposing or combinant therapies and innovation in treatment management.

We invite the scientific community to contribute to this Special Issue and help reshape the future of immunotherapy.

Dr. Patricia Fanlo-Mateo
Guest Editor

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• autoimmune diseases
• immunomodulatory drugs
• biologic therapies
• immunosupressants
• immunotherapy
• drug repurposing