Prospective Observational Study Evaluating the Safety and Efficacy of Immunomodulatory Therapies in Refractory Inflammatory and Autoimmune Diseases

Inflammatory and/or autoimmune diseases represent a very broad group of diseases with highly variable clinical features, including - but not limited to - systemic connectivites and vasculitis. Individually, they are very rare diseases, generally estimated in terms of the number of cases per 100,000 or 1,000,000 inhabitants. However, if we consider all immune-mediated inflammatory diseases, it is estimated that they affect 4.5% of the world's population .

Despite their extreme heterogeneity in terms of clinical presentation, these diseases share several key pathogenic mechanisms. For example, over the past two decades, adaptive immunity has been successfully targeted with several monoclonal antibodies directed against B lymphocytes (e.g. rituximab, an anti-CD20) and co-stimulation between B and T lymphocytes (e.g. abatacept, a CTLA-4 agonist). Targeting cytokines common to several of these diseases has also proved effective in their management, in particular anti-TNF alpha and anti-IL-6, produced by cells of the innate and adaptive immune systems.

Although these molecules have ushered in a new era in the management of inflammatory and/or autoimmune diseases, not all patients are yet fully controlled, representing a major challenge in clinical practice.

Refractory cases are then treated with drugs that are already available on the market for other indications in more frequent and clinically homogeneous diseases, such as inflammatory rheumatism and haematological malignancies.

Certain therapeutic targets stand out. The first is the cytokine IL-17, which plays a crucial role in the polarization of T helper 17 (Th17) lymphocytes and orchestrates the adaptive response detectable in the blood and target tissues of various inflammatory and/or autoimmune diseases.

Another interesting modern strategy is the inhibition of the Janus kinase and signal transducer/activator of transcription (JAK/STAT) pathways, which act on several downstream cytokine receptors. The development of targeted oral therapies based on small molecules such as JAK inhibitors (JAKi) represents an effective means of simultaneously attenuating several downstream inflammatory pathways, and has enabled a paradigm shift in the treatment of various autoimmune and inflammatory conditions refractory to conventional therapy, with cortisone sparing as well.

Bispecific antibodies (BsAb) are a new class of drugs and one of the most promising immunotherapies for solid tumors and hematological malignancies. BsAbs combine the specificities of two therapeutic antibodies and simultaneously target different antigens or epitopes. They have attracted a great deal of interest over the past decade, thanks to their unique and versatile modes of action.

In summary, the prescription of commercially available treatments from other specialties (e.g. rheumatology and oncohaematology) is a reality in the clinical practice of internists and immunologists, often representing an excellent solution for difficult-to-treat inflammatory and/or autoimmune diseases. As these molecules are prescribed without the availability of standardized data, it is essential to collect them prospectively to better characterize the efficacy and tolerability of these new therapeutic options in inflammatory and/or autoimmune diseases.

• Evaluate the proportion of patients in clinical, biological or radiological remission [Time frame: week 12 and week 48]
• Cumulative incidence of relapse (i.e., recurrence of clinical symptoms associated with biological and/or radiological inflammatory activity following complete remission) [Time frame: weeks 12, 24, 36 and 52]
• Cumulative incidence of remission according to primary endpoint definitions [Time frame: weeks 12, 36 and 52]
• Evaluate changes in median disease-specific activity scores [Time frame: weeks 12, 24, 36 and 52]
• Cumulative prednisone dose [Time frame: weeks 12, 24, 36 and 52]
• Cumulative incidence of serious adverse events (i.e., those requiring hospitalization or death) at weeks 12, 24, 36 and 52 [Time frame: weeks 12, 24, 36 and 52]
• Evolution of circulating immune cell populations & cytokines under treatment [Time frame: Weeks 0, 1, 2, 4, 12, 24, and 52]