Pathogenic autoimmunity occurs when specific self-molecules trigger a massive inflammatory response by autoreactive T or B cells and/or autoantibodies, which recruit innate and more adaptive immune cells. The consequent inflammation can be limited to a single organ (e.g., in autoimmune thyroiditis) or can affect several tissues in the body. These latter conditions, systemic autoimmune diseases, affect a significant proportion of the population. Their incidence is growing, they often appear as severe/organ- or life-threatening disorders, and a group of patients still cannot reach clinical remission.

Autoimmune disorders are characterized by chronic inflammation, which can affect and damage various organs and tissues. Despite many differences in the pathogenesis and clinical manifestations of autoimmune diseases, there are also many similarities. Autoimmune disorders are believed to have three phases ( Figure 1 ). In the first so-called “immunization” phase, patients are typically unaware of clinical symptoms (1). Often genetic factors (modified alleles) and environmental triggers (e.g., smoking, UV light, and microbial infections) collectively predispose to the development of autoimmunity (1). This process leads to the loss of immune tolerance to self-antigens by the appearance of autoreactive T lymphocytes, which escape central tolerance (2). As a consequence, self-reactive T lymphocytes can contribute to autoreactive B-lymphocyte development and autoantibody production (2). During the transition phase, complex immunological processes occur, such as immune complex formation or deposition (e.g., in the joints or the kidney) and the initiation of immune cell recruitment (3, 4). As a result, in the effector phase, many cell types become activated and initiate cellular responses. These effector functions mediate host tissue damage and maintain chronic inflammation. Based on these similar steps of pathogenesis, drug candidates targeting common participating factors may have beneficial effects in the treatment of various autoimmune disorders.

Patients living with systemic autoimmune diseases require lifelong therapy, and therefore, the choice of the right medication is key to the long-term outcome. Although several therapies are available, the desired complete remission is not achieved in a significant proportion of patients. However, the range of available therapies is constantly expanding due to the large number of drugs successfully tested in clinical trials. Here, we collected the most recently approved and the majority of the most promising forthcoming drugs to have an overview of this expanding field ( Table 1 and Figure 2 ).

Rheumatoid arthritis (RA) has a prevalence of 0.5%–1% in the population and can cause irreversible joint damage and loss of articular function in patients, while it is associated with higher cardiovascular morbidity and mortality (3, 89). Despite the fact that there is a growing number of available therapies, a significant proportion of patients still do not respond at all or adequately to treatment (difficult-to-treat RA) (90). Several cell types and mediators play important roles in the pathogenesis: resident cells in the synovium (e.g., macrophage-like synoviocytes and synovial fibroblasts) and recruited leukocytes (e.g., T and B cells and neutrophils), which become activated, leading to the release of proinflammatory cytokines, like tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) (which became therapeutic targets in the everyday clinical routine) or granulocyte macrophage colony-stimulating factor (GM-CSF) (3). Different mediators signal through various tyrosine kinases [e.g., Janus kinases (JAKs)] and contribute to the development of joint damage, bone erosions, and the maintenance of chronic inflammation (3).

JAK inhibitors are important drugs for the treatment of RA. In addition to the three “older” agents (tofacitinib, baricitinib, and upadacitinib), filgotinib is a relatively new candidate. Filgotinib is mainly a JAK1 inhibitor, which interferes with the pathogenesis of rheumatoid arthritis by modulating the effects of proinflammatory cytokines (91). When tested as a monotherapy in a phase 3 clinical trial, patients receiving filgotinib had a significantly higher response rate compared to patients receiving placebo (23). It has also been shown that filgotinib (at both 100 and 200 mg/day dosages) was significantly more effective (in the context of the ACR20 response rate at week 24) in combination with methotrexate compared to methotrexate monotherapy (92). In a 52-week, placebo-controlled, phase 3 trial, 200 mg filgotinib was non-inferior to adalimumab therapy when the DAS28-CRP score was examined (both therapies were combined with methotrexate) (24). Filgotinib has been shown to be safe and effective both in combination with methotrexate or as monotherapy in a 4-year open-label extension study (25). As a consequence, filgotinib has been approved for moderate-to-severe RA by the EMA. In parallel with selectivity, the safety profile is expected to be more favorable than for non-selective JAK inhibitors (e.g., baricitinib); for instance, it has been suggested that filgotinib therapy is associated with a reduced risk of herpes zoster infection compared to other JAK inhibitors (93).

Another new JAK inhibitor, that has been studied in RA, is the pan-JAK inhibitor peficitinib (94). In two 52-week, placebo-controlled, phase 3 trials, peficitinib treatment as monotherapy (at both 100-mg or 150-mg once-daily dosages) or in combination with methotrexate resulted in a significant reduction in RA symptoms (26, 27). Peficitinib has been approved for the treatment of RA in South Korea and Japan.

Mavrilimumab is a fully human monoclonal antibody against the GM-CSF receptor α chain. GM-CSF plays a central role in the development of RA, and the binding of the cytokine to its receptor leads to the activation of the JAK/STAT signaling route (95). Compared to placebo, subcutaneous mavrilimumab monotherapy at 30-mg and 100-mg doses helped more patients to achieve a more than 1.2 decrease in the DAS28-CRP score by week 12 in a phase 2a clinical trial (96). Moreover, no major safety concerns were raised about its tolerability (28, 97).

CD40L–CD40 binding is required for the development of humoral immune response since it has a major role in B cell activation and the generation of plasma cells (98). Dazodalibep binds CD40L and inhibits the attachment of the ligand to its receptor. In a placebo-controlled, phase 2 trial, the authors found that the intravenous administration of dazodalibep led to a significant reduction in the DAS28-CRP score by day 113, while no major safety concerns were raised (30, 31).

Olokizumab is a humanized monoclonal antibody against the proinflammatory cytokine IL-6, which is involved in the pathogenesis of RA in various ways (99). Subcutaneous administration of olokizumab (64 mg every 2 weeks or 64 mg every 4 weeks in combination with methotrexate) resulted in significant improvements in symptoms and physical function in patients with inadequate response to methotrexate or TNF-α inhibitors, while olokizumab therapy was non-inferior to adalimumab considering the ACR20 response rate at 12 weeks in another trial (33–35). Meanwhile, a similar safety profile was observed as with other approved IL-6 blockers (33–35). One can speculate whether there are any major differences in the therapeutic features of blocking IL-6 rather than IL-6R. The efficacy and safety of olokizumab were compared to those of the two IL-6R blockers (tocilizumab and sarilumab) in a meta-analysis among methotrexate (MTX) non-responder RA patients (100). According to this, all three drugs showed very similar efficacy and safety (100).

The programmed cell death protein 1 (PD-1) on T cells has an important role in the downregulation of T cell activation upon its ligation to PD-L1. Peresolimab is a humanized anti-PD-1 monoclonal antibody that activates this inhibitory pathway (in other words, it has the opposite effects as checkpoint inhibitors) (101). In a phase 2a clinical trial, peresolimab treatment led to a significantly greater reduction in the DAS28-CRP score at week 12 compared to placebo, which raises the possibility to control autoimmune inflammation by influencing the PD-1 inhibitory pathway (101).

In summary, recently, two JAK inhibitors (filgotinib and peficitinib) have gained approval in the treatment of rheumatoid arthritis, while several monoclonal antibodies (altering the pathomechanism of RA from different directions) are the subject of promising research in the RA field.

Sjögren’s syndrome, with a prevalence of 0.01%–0.72%, is mainly associated with exocrine gland dysfunction and consequent dryness of the mucous membranes but can also affect several internal organs (e.g., the respiratory tract) over time (102). In primary Sjögren’s syndrome (pSS) epithelial cells express a variety of immune regulatory molecules, which — through increased cytokine and chemokine production (e.g., IL-7, IL-17, and IL-23) — induce abnormal T and B cell function and autoantibody production, participate in the activation of interferon signaling, and induce the accumulation and activation of various immune cells, triggering chronic inflammation and dysfunction of the exocrine glands (102). Several cytokines that are involved in the pathogenesis signal through the JAK/STAT route. Since pSS is a relatively frequent systemic autoimmune disease with symptoms that significantly reduce the quality of life and which has no licensed targeted therapies at the moment, developing new potential drugs is highly necessary.

Efgartigimod is an antibody fragment that binds neonatal Fc receptors, which are important in the recycling of IgG molecules, thus prolonging the half-life of the antibodies. Efgartigimod, which is already used in the treatment of myasthenia gravis patients, is investigated in a phase 2 clinical trial (ClinicalTrials.gov Identifier: NCT05817669).

A possible target in pSS therapy is the BAFF/BLyS pathway; thus, ianalumab, a monoclonal antibody against the BAFF receptor, is being tested in a phase 3 study (ClinicalTrials.gov Identifier: NCT05349214). Ianalumab was tested in a multicenter, phase 2b clinical trial in pSS patients (103). The findings were promising, and the reduction of EULAR Sjögren’s syndrome disease activity index score from baseline could be detected at all doses (103). It is important to note that higher doses were related to a greater reduction of the ESSDAI score (103). Administering 300 mg ianalumab significantly reduced the Physician Global Assessment (PGA) score, and an increased stimulated salivary flow (mL/min) could be seen (103). In addition, two open-label, phase 2 clinical trials have been fulfilled, where the BAFF/BLyS targeting belimumab as monotherapy seemed to be efficient for pSS patients (9, 10).

In a further study, the combination of belimumab and rituximab was tested in a phase 2 clinical trial in pSS patients (104). Patients were randomized into four groups: placebo, i.v. rituximab, s.c. belimumab, and i.v. rituximab combined with s.c. belimumab. The safety profile of the combined therapy was similar to the safety of monotherapies (104). Furthermore, a near-complete depletion of CD20⁺ B cells in minor salivary glands and a greater and more sustained depletion of peripheral CD19⁺ B cells were observed with belimumab combined with rituximab compared to monotherapies (104).

Another B cell-targeting therapy, telitacicept, has shown good efficacy and safety in a phase 2 clinical trial while reducing IgG, IgM, and IgA levels and CD19-positive B cell numbers (105). Telitacicept was administered subcutaneously every week in a 160-mg or 240-mg dose, and statistically significant improvements were found in the ESSDAI score in the 160 mg telitacicept group compared to the placebo group; however, there was no statistically significant difference between the 240-mg and the placebo groups (106).

Dazodalibep is a CD40 ligand antagonist that blocks the interaction between B cells and T cells. In a phase 2 clinical trial, dazodalibep was found to be tolerable and effective in patients with Sjögren’s syndrome (32). Therefore, recently, a phase 3 clinical trial was started, evaluating the efficacy and safety of dazodalibep in participants with Sjögren’s syndrome with moderate-to-severe systemic disease activity (ClinicalTrials.gov Identifier: NCT06104124). Iscalimab is an anti-CD40 monoclonal antibody. The effect of iscalimab was investigated in a multicenter, double-blind, placebo-controlled, phase 2 clinical trial, where patients received either subcutaneous iscalimab (at a 3 mg/kg dose) or intravenous iscalimab (at a 10 mg/kg dose) (107). The findings were promising, as the intravenous treatment resulted in a significant lowering of the ESSDAI score compared to placebo; however, there was no significant difference in regard to the ESSDAI score between subcutaneous iscalimab and the placebo group (107).

Type I interferons have important roles in the pathogenesis. Currently, there is an ongoing phase 2 clinical trial investigating the safety and efficacy of anifrolumab in pSS subjects (ClinicalTrials.gov Identifier: NCT05383677).

Deucravacitinib, a TYK2 inhibitor, is already in use for treating plaque psoriasis in multiple countries and demonstrated positive outcomes during phase 2 clinical trials in patients with psoriatic arthritis and patients with SLE (88, 108, 109). Deucravacitinib could suppress IFN and B cell pathway markers in lupus patients; therefore, it could be useful in the treatment of patients with Sjögren’s syndrome, where IFN and B cell pathways have important roles in the pathogenesis (110). Accordingly, a phase 3 clinical trial is ongoing (ClinicalTrials.gov Identifier: NCT05946941).

The effect of other JAK inhibitors is intensively investigated. Baricitinib is tested in a phase 2 clinical trial that examines the efficacy of hydroxychloroquine (HCQ) and baricitinib combination therapy versus HCQ alone (ClinicalTrials.gov Identifier: NCT05016297). Tofacitinib is also in a phase 2 trial for pSS, which investigates the improvements in EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) with a 5-mg twice-daily dose (ClinicalTrials.gov Identifier: NCT04496960).

Systemic sclerosis is triggered by microvascular damage and immune activation, which leads to systemic fibrosis and can result in multi-organ failure, while the disease itself is really difficult to treat (111). The development of systemic sclerosis requires the activation of various immune (e.g., T or B cells, macrophages, and dendritic cells) and non-immune cell types (e.g., endothelial cells, fibroblasts, and smooth muscle cells) (111). Danger-associated molecular pattern (DAMP)- or immune complex-activated immune cells produce various cytokines, such as type I IFN or IL-6, which signal through the JAK/STAT pathway, and contribute to angiogenesis, wound healing, and fibrosis (111).

Interstitial lung disease (ILD) is a life-threatening complication of systemic sclerosis (SSc). Pirfenidone is an anti-inflammatory, anti-fibrotic drug inhibiting TGF-β and TNF-α. A phase 2 clinical trial failed to find any significant difference between the pirfenidone and placebo groups (112). However, 94.1% of the patients in the pirfenidone group showed stabilization or improvement in forced vital capacity (FVC), which led to a phase 3 trial (112). As a consequence of a successful phase 3 clinical trial that investigated the efficacy and safety of nintedanib, a small molecule tyrosine kinase inhibitor, the molecule is now a possible therapeutic option for SSc-associated lung fibrosis (36).

Previous studies showed that the classic proinflammatory cytokine IL-6 has a massive profibrotic effect; IL-6 levels are elevated in SSc patients and correlate with the thickness of the skin (113). In a phase 3 trial, the IL-6 receptor-blocking tocilizumab could preserve lung function in early SSc patients with ILD and elevated acute-phase reactants; however, it had a poor effect on skin fibrosis (37).

Skin fibrosis and pruritus cause a life-quality reduction in SSc patients; therefore, it is necessary to have more available therapeutic options. One of the cytokines that play important roles in the pathophysiology of SSc is IL-31, which is associated with pruritus (114). Nemolizumab (an IL-31 receptor inhibitor) is now in phase 2 clinical trial (ClinicalTrials.gov Identifier: NCT05214794). An encouraging multicenter, phase 3 trial has shown great efficacy of brodalumab, an anti-IL-17A-receptor monoclonal antibody on decreasing skin thickening (38). Brodalumab achieved a rapid, significant, and sustained reduction of the modified Rodnan skin score (mRSS) and inhibited the development of new digital ulcers (38). Brodalumab also demonstrated a positive effect on respiratory function and suppressed the progression of lung lesions (38). Abatacept, the inhibitor of the costimulatory molecules CD80 and CD86 on antigen-presenting cells, which, as a consequence, blocks T cell activation, was investigated in two separate double-blind, phase 2 trials and had positive outcomes (both clinical trials evaluated the change in mRSS) (115, 116). Despite the fact that the change in mRSS was not statistically significant, both studies found that abatacept was clinically effective, therefore suggesting the initiation of phase 3 clinical trials (115, 116). CD30⁺ lymphocytes are present in the skin biopsies from SSc patients, who tend to have increased serum CD30 levels (117). A chimeric anti-CD30 antibody, brentuximab, was tested in a phase 2b clinical trial, where the results were promising, as a significant decline of the mRSS score was detected (118). A further potential therapy for skin involvement could be the tyrosine kinase inhibitor imatinib according to a phase 2 trial, which showed significant mRSS score reduction, while the efficacy on lung involvement seemed to be poor (119).

Pulmonary arterial hypertension (PAH) is a severe consequence of SSc, which can result in heart failure. Ambrisentan, an endothelin receptor type A-selective antagonist, caused significant improvements in hemodynamic parameters like cardiac index or pulmonary vascular resistance. However, the mean pulmonary arterial pressure, the primary endpoint, only showed a tendency of improvement (120). In a multicenter, double-blind study, the efficacy of rituximab was investigated in SSc-ILD, where the 6-minute walk test showed a non-statistical improvement (121).

The JAK/STAT signaling pathway is significantly activated in SSc patients (122). The JAK inhibitor tofacitinib and baricitinib can cause improvement in lung function in ILD and mRSS score in skin fibrosis according to a systematic review of the literature (123). Tofacitinib showed trends of improvement during phase 1 and 2 clinical trials in clinical outcome measures (e.g., in mRSS) in patients with early diffuse cutaneous systemic sclerosis (39). In a phase 2 trial, baricitinib showed significant improvement in mRSS score and a favorable clinical effect on lung function and healing digital ulcers (124). Despite the fact that no information could be found on the results of a phase 3 trial, a phase 4 clinical trial is currently ongoing investigating the effects of baricitinib (ClinicalTrials.gov Identifier: NCT05300932). Itacitinib, another JAK/STAT pathway inhibitor, is being investigated in a phase 2 clinical trial (ClinicalTrials.gov Identifier: NCT04789850).

Since increased expression and activation of type-1 IFN-regulated genes have been reported in SSc patients, it might be beneficial to use treatments against these targets (125). Therefore, anifrolumab is undergoing a phase 3 clinical trial in scleroderma patients (ClinicalTrials.gov Identifier: NCT05925803).

Another promising therapeutic option in SSc patients is B cell inhibition. For instance, phase 2 clinical trials testing belimumab with or without rituximab (in combination with MMF) are currently ongoing (ClinicalTrials.gov Identifiers: NCT01670565 and NCT03844061). Moreover, the previously approved drug for neuromyelitis optica, inebilizumab (a CD19 inhibitor), is under phase 3 trial investigations for possible use in SSc (ClinicalTrials.gov Identifier: NCT05198557); however, there are no data on phase 2 results. During a phase 1 trial, inebilizumab therapy had a tendency to lower the mRSS score; however, it had no effect on FVC in ILD-associated SSc (126). Anti-CD19 CAR T cell therapy was used in a 60-year-old man with diffuse cutaneous systemic sclerosis who had lung and myocardial fibrosis, pulmonary arterial hypertension, Raynaud’s phenomenon, and arthritis (127). The therapy showed great efficacy: pulmonary fibrosis remained stable; right ventricular strain, arthritis, and skin fibrosis displayed a tendency of improvement; RNA polymerase III autoantibodies were no longer detectable (127).

The group of idiopathic inflammatory myopathies consists of heterogeneous disorders, such as polymyositis, dermatomyositis, antisynthetase syndrome, immune-mediated necrotizing myopathy, inclusion body myositis, and overlap myositis syndromes (143). These chronic diseases are mediated by various humoral and cellular factors such as T cells and myositis-specific autoantibodies (143). A frequent common symptom is muscle weakness and muscle pain, but there can be several other manifestations (e.g., lung involvement) (143). Due to various mediators involved in the pathogenesis, a whole range of potential novel therapeutic targets are available.

Despite the fact that there are growing everyday clinical experiences with the off-label use of IVIG in idiopathic inflammatory myopathies (IIMs), the results of its effect in dermatomyositis (DM) patients in a phase 3 trial only came out recently (48). Here, the every 4 week use of IVIG at a 2 g/kg dose was compared to placebo for 16 weeks, followed by an open-label extension phase for another 24 weeks (48). While IVIG was superior to placebo according to the Total Improvement Score, the therapy caused more thromboembolic events (48).

Apremilast is a selective inhibitor of the phosphodiesterase-4 (PDE-4) enzyme. In a phase 2a clinical trial, apremilast was tested as an add-on treatment in eight dermatomyositis patients (49). In this study, apremilast was well-tolerated, and there were no severe adverse events, while the overall response rate (ORR) was 87.5%, and the decrease of the cutaneous disease activity severity index (CDASI) score was significant after 3 months of treatment (49). These results raise the possibility that investigating the potential therapeutic benefit of apremilast in an extended clinical study is reasonable.

Increased heat shock protein (HSP) production as a response to toxic cellular changes is often not sufficient in patients with inclusion body myositis (IBM). In recent years, the “heat shock response” amplifier, arimoclomol, was the candidate drug of two phase 2 clinical trials. In the first clinical trial, a slower decline was observed in almost all physical function and muscle strength parameters in the arimoclomol group (50). However, in the second study, arimoclomol did not show beneficial effects compared to placebo (144). Despite these controversial results, the effect of arimoclomol is being tested in patients with IBM in a phase 3 trial (ClinicalTrials.gov Identifier: NCT04049097).

In a recently published case report, anti-CD19 CAR T cell therapy was used in a patient with refractory antisynthetase syndrome (145). After the treatment, transient myalgia appeared, and an increased creatinine kinase level was detected; however, shortly after, an improvement was observed in the physical function parameters (145). In parallel with this, the activity of the disease-associated interstitial lung disease also greatly declined with a massive drop in the serum anti-Jo-1 titer (145). (It is important to emphasize that since CAR T cell therapy showed efficacy on a small group of patients with SLE, one SSc patient, and one IIM patient; a phase 1 clinical trial was recently started with increased numbers of SLE, SSc, pSS, and IIM patients (ClinicalTrials.gov Identifier: NCT06056921).

A number of phase 2 or 3 clinical trials with IIM patients are currently ongoing, for example, with tofacitinib (ClinicalTrials.gov Identifier: NCT05400889), baricitinib (ClinicalTrials.gov Identifiers: NCT04972760 and NCT04208464), abatacept (ClinicalTrials.gov Identifier: NCT03215927), or rituximab (146). In the latter study, rituximab was not superior to cyclophosphamide in the treatment of ILD, while both therapies increased FVC by week 24; however, rituximab caused fewer adverse events (146).

Despite several available therapies, some systemic autoimmune diseases are still difficult to treat in general (e.g., Sjögren’s syndrome, systemic sclerosis) or have a significant proportion of patients, where refractory conditions can be considered (e.g., rheumatoid arthritis and SLE). With the help of significant basic, translational, and clinical research, more and more information became available on the pathogenesis of systemic autoimmune diseases. As a consequence, during the last few years, some new therapies have been approved by the FDA and/or by the EMA. These include filgotinib for RA, anifrolumab and voclosporin for SLE, or avacopan for GPA and microscopic polyangiitis (MPA). Meanwhile, intensive research also contributed to the development and testing of several promising new candidates, which may cause smaller or bigger revolutions in the management of these diseases. It is important to note that study design is crucial to gain relevant information out of clinical trials; it is especially true for autoimmune connective tissue diseases (e.g., SLE), where some off-label therapies (e.g., rituximab) seem to work in selected cases in the everyday clinical routine but failed to show significant differences over placebo in clinical trials (56). Another important issue is safety: several drugs in clinical studies have massive immunosuppressive effects; in addition to showing beneficial features in the treatment, some therapies may have harmful side effects that need to be closely followed.

Despite the fact that there are many differences in the pathogenesis of systemic autoimmune diseases, many aspects are similar, leading to common molecular targets, like type I IFN/IFN receptor, IL-17, GM-CSF receptor, BAFF, CD40/40L, or JAK/STAT ( Table 2 ). If only a quarter of the reviewed drugs targeting these molecules appear on the market and can be used in the therapy of systemic autoimmune diseases, a better new era will be guaranteed. The appearance of novel therapeutic options will surely cause several comparison studies and will lead to newer treatment recommendation guidelines. Well-working and approved novel therapeutic agents may also help to identify new disease subtypes and might potentiate the development of more drugs with similar modes of action (causing a positive feedback loop in drug development in this field). However, we should not forget that optimism cannot substitute carefulness, and the new therapies should be handled with care.

All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.