Systemic autoimmune diseases (SAIDs), such as systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and rheumatoid arthritis (RA), are caused by unregulated immune systems leading to tissue damage. Current treatments, like glucocorticoids and immunosuppressants, have limited efficacy and side effects. Novel immunotherapies, including monoclonal and bispecific antibodies, and CAR-T cell therapy, are being explored. CAR-T cells, which target specific antigens on immune cells, show promise in treating SAIDs, with recent successes in SLE and SSc. Monoclonal antibodies like belimumab, which target BAFF, and bispecific antibodies, which block multiple pathways, are also being developed. CAR-T therapy, particularly anti-CD19 CAR-T cells, has shown effectiveness in reducing B cells and autoantibodies in SLE and SSc. Other approaches, such as targeting TLRs and IFN-α, are also under investigation. CAR-Treg cells, which modulate immune responses, and CAAR-T cells, which target autoantibodies, are emerging as potential therapies. While CAR-T therapy is promising, it has challenges like immunogenicity and cost. Monoclonal antibodies are more accessible and have fewer side effects, making them a viable alternative. Future research aims to improve the safety, specificity, and affordability of these therapies to effectively treat SAIDs.Systemic autoimmune diseases (SAIDs), such as systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and rheumatoid arthritis (RA), are caused by unregulated immune systems leading to tissue damage. Current treatments, like glucocorticoids and immunosuppressants, have limited efficacy and side effects. Novel immunotherapies, including monoclonal and bispecific antibodies, and CAR-T cell therapy, are being explored. CAR-T cells, which target specific antigens on immune cells, show promise in treating SAIDs, with recent successes in SLE and SSc. Monoclonal antibodies like belimumab, which target BAFF, and bispecific antibodies, which block multiple pathways, are also being developed. CAR-T therapy, particularly anti-CD19 CAR-T cells, has shown effectiveness in reducing B cells and autoantibodies in SLE and SSc. Other approaches, such as targeting TLRs and IFN-α, are also under investigation. CAR-Treg cells, which modulate immune responses, and CAAR-T cells, which target autoantibodies, are emerging as potential therapies. While CAR-T therapy is promising, it has challenges like immunogenicity and cost. Monoclonal antibodies are more accessible and have fewer side effects, making them a viable alternative. Future research aims to improve the safety, specificity, and affordability of these therapies to effectively treat SAIDs.