Challenges, Progress, and Prospects of Developing Therapies to Treat Autoimmune Diseases

Autoimmune diseases are a result of the immune system being misdirected toward its host and have major and increasing unmet clinical needs. In general, present therapies are broadly acting and non-disease specific; consequently, they are associated with numerous side effects. Precise and early intervention strategies are urgently needed. We highlight the challenges, progress, and prospects in achieving these goals. Autoimmune diseases are a result of the immune system being misdirected toward its host and have major and increasing unmet clinical needs. In general, present therapies are broadly acting and non-disease specific; consequently, they are associated with numerous side effects. Precise and early intervention strategies are urgently needed. We highlight the challenges, progress, and prospects in achieving these goals. The human immune system is a multi-faceted network of functionally diverse cells expressing a broad array of receptors that collectively function to respond to infection, eliminate pre-cancerous cells, and maintain metabolic health. Breakdown of this delicately poised immune response is typically life limiting; however, even subtle changes in its ability to distinguish an invading pathogen from the host can give rise to a spectrum of autoimmune diseases. Indeed, autoimmune diseases affect approximately 5%–8% of the world population and cause tremendous suffering to patients while also representing a major global socioeconomic issue. Presently, more than 80 autoimmune diseases have been described. They can be systemic, such as systemic lupus erythematosus, which can affect the skin, joints, kidneys, and CNS, or organ specific, such as type 1 diabetes, which primarily affects the pancreas. Loss of B cell or T cell tolerance is frequently implicated in autoimmunity, and indeed, the human leukocyte antigen (HLA) locus is commonly associated with increased risk of autoimmune disease susceptibility (Table 1). Although detailed molecular, immunological, genetic, and clinical studies have provided an increasingly sophisticated understanding of the mechanisms that underpin some autoimmune diseases, the drivers of human autoimmune diseases, including environmental triggers, and the ensuing pathogenesis remain poorly understood.Table 1Examples of Autoimmune Diseases Affecting Different OrgansPrimary Target Organ(s)DiseasePrevalenceaPrevalence varies according to, e.g., diagnostic criteria, ethnicity, and race; in this context, meant to give a rough indication.Typical First SymptomsMechanismSkin and HairSkinpsoriasis~2%–3%skin redness, thickening, and scalesabnormal keratinocyte proliferation in the dermis and epidermisSkin and oral mucosapemphigus vulgaris~0.01%blisters and erosionsloss of cell adhesion in stratified squamous epitheliaSkinvitiligo~0.5%–1%milky white skin patchesdestruction of melanocytesHair folliclesalopecia areata~0.1%patchy hair loss on the scalpweakness in the hair shaft leading to hair shaft breakingCNSOptic nerve, brain, spinal cordmultiple sclerosis~0.1%visual loss, numbness, tingling, paresis, and spasticitydestruction of myelinHypothalamusnarcolepsy~0.03%excessive daytime sleepiness, sleep attacks, sudden loss of muscular controldestruction of orexin-producing neuronsOptic nerve, spinal cordneuromyelitis optica~0.004%resembles MS, but attacks are more severedestruction of myelin, autoantibodies against aquaporin-4Endocrine and Exocrine GlandsPancreastype 1 diabetes~0.4%increased thirst, frequent urination, weight loss,destruction of insulin- producing β cellsThyroid glandGraves disease (hyperthyroidism)~0.5%anxiety, irritability, hand tremors, weight loss, enlarged thyroid gland, bulging eyes, palpitationsautoantibodies against the thyrotropin receptor on thyroid follicular cells leading to increased synthesis of thyroid hormoneThyroid glandHashimoto's disease (hypothyroidism)~0.1%many, changeable and unspecific, including fatigue, sensitivity to cold, puffy face, constipation, pale and dry skinfibrosis and atrophy of thyrocytes leading to decreased synthesis of thyroid hormoneTear and salivary glandsSjögren's syndrome~0.2%–1%dry eyes and mouthloss of function of exocrine glandsGastrointestinal SystemEntire gastrointestinal tract, but especially the ileum, patchy lesionsCrohn's disease~0.2%–0.3%diarrhea, abdominal pain, bloody stool, fever, fatiguetransmural inflammationRectum and sometimes also the colon, uninterrupted lesionsulcerative colitis~0.2%–0.4%abdominal pain, rectal pain and bleeding, urgency but inability to defecate, fever, fatiguemucosal inflammationSmall intestineceliac disease~0.7%loose stools, abdominal discomfortflattening of villi and elongation of cryptsStomachautoimmune gastritisuncertainanemia, gastritis, vitamin B12 deficiency, and impaired food protein degradationdestruction of acid-producing parietal cellsLiverprimary biliary cholangitis~0.03%tiredness, itchingdestruction of small bile ductsLiverautoimmune hepatitis~0.02%nonspecific, mild fatigue, often no symptoms of liver disease but elevation of liver enzymes in peripheral blooddestruction of hepatocytesKidneysKidneys, CNSlupus nephritis~0.008%–0.2%blood in the urine, foamy urine, swelling in the legs, and high blood pressureinflammatory response to endogenous chromatinKidneys and lungsGoodpasture syndrome~0.0001%–0.001%blood in the urine, foamy urine, swelling in the legs, high blood pressure, coughing, bleeding from the lungsautoantibodies to the α3 chain of collagen IV in the basement membrane in the lungs and kidneysJointsProximal small joints of the hands and feet in a symmetrical distributionrheumatoid arthritis~0.5%–1%joint swelling, morning stiffness, and tendernesssynovial hyperplasia leading to invasion and damage of cartilage and boneDistal joints in an asymmetrical distribution, tendons or ligaments at bone insertionspsoriatic arthritis~0.06%–0.25%joint swelling, morning stiffness, and tendernesssynovial hyperplasia leading to invasion and damage of cartilage and boneSacroiliac jointsaxial spondyloarthritis~0.3%unexplained chronic back pain and stiffnesserosion, bone growth, and fusion of vertebraeMusclesMusclesmyasthenia gravis~0.02%muscle weakness, drooping of the upper eyelid, double visionblockade of acetylcholine receptors and muscle-specific kinases in the postsynaptic muscle membraneMusclespolymyositis~0.007%weakness of muscles around the neck, shoulders, upper arms, hips, thighsCD8+ T cell invasion of muscle fibersReproductive OrgansOvariesautoimmune oophoritisuncertainamenorrhea, infertility, hot flushes, vaginal atrophyinflammation of theca cells of growing folliclesTestesautoimmune orchitisuncertaininfertilityapoptosis of spermatocytes and spermatids by anti-sperm antibodiesa Prevalence varies according to, e.g., diagnostic criteria, ethnicity, and race; in this context, meant to give a rough indication. Open table in a new tab In general, current immune-modulatory drugs used in the treatment of autoimmune diseases are broadly acting, non-disease specific, and, consequently, associated with side effects such as infection and malignant disease. Furthermore, it is clear that the majority of patients are not responding optimally, if at all, to these therapies (Table 2). Thus, there is a pressing need for development of new drugs or repositioning of drugs based on a molecular and clinical understanding of the specific autoimmune diseases in individual patients in combination with high-throughput analysis of integrated datasets. Such personalized medicines may go hand in hand with inclusion of new diagnostics, leading to a better disease understanding and more patient-centric clinical trials that also consider ethnic diversity and patient-reported outcome measures. Prevention should also be part of future early intervention. This perspective will highlight the different types of current therapies and showcase how future basic studies, new technologies, and clinical trials could dynamically and reciprocally inform each other, leading to a better understanding of disease mechanisms and, hence, more refined treatments.Table 2Examples of Synthetic and Biologic Drugs for Treating Autoimmune DiseasesTargetDrugFunctionExamples of Clinical UseJAKstofacitinibinhibits JAK1, JAK2, JAK3rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and ulcerative colitisbaricitinibinhibits JAK1, JAK2rheumatoid arthritisCytokinesTNFinfliximabinhibits TNFCrohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritisIl-17asecukinumabinhibits IL-17Apsoriasis, ankylosing spondylitis, and psoriatic arthritisIL-12/23p40ustekinumabinhibits IL-12 and IL-23psoriasisIL-23p19guselkumabinhibits IL23psoriasisIL-6Rtocilizumabinhibits IL-6Rrheumatoid arthritis, juvenile idiopathic arthritis, neuromyelitis opticaB Cellsrituxandepletes CD20+ B cellsmultiple sclerosis, rheumatoid arthritisbelimumabinhibits BAFFsystemic lupus erythematosusIntegrinsnatalizumabblocks α4β1 and α4β7multiple sclerosisvedolizumabblocks a4b7ulcerative colitis, Crohn's diseaseCo-stimulatory Moleculesabataceptblocks CD80 and CD86rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis Open table in a new tab Treatment of autoimmune diseases has drastically changed over the last 20 years with development and routine clinical use of synthetic or biologic drugs that block various pathways and components of the immune system, such as cytokines, cell adhesion molecules, and co-stimulatory molecules, or delete entire immune cell populations (Table 2). Presently, synthetic drugs approved for treatment of autoimmune diseases are dominated by Janus kinase (JAK) inhibitors (Schwartz et al., 2017Schwartz D.M. Kanno Y. Villarino A. Ward M. Gadina M. O'Shea J.J. JAK inhibition as a therapeutic strategy for immune and inflammatory diseases.Nat. Rev. Drug Discov. 2017; 16: 843-862Crossref PubMed Scopus (133) Google Scholar). JAK1, JAK2, JAK3, and the non-receptor tyrosine-protein kinase TYK2 are intracellular tyrosine kinases that act in concert with seven different signal transducer and activator of transcription (STAT) transcription factors in mediating the signaling of more than 50 distinct cytokines, as well as hormones and growth factors. Upon cytokine-receptor binding at the cell membrane and phosphorylation by JAKs, the recruited STAT translocates to the nucleus, where it exerts its effect on gene transcription. Different cytokine receptors associate with different JAK complexes. For example, interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, and IL-21 signaling is mediated by the JAK1-JAK3 complex; IL-6 signaling is mediated by JAK1, JAK2, and TYK2; and signaling of IL-10, IL-20, IL-22, and IL-28 is mediated by JAK1 and TYK2. Notably, signaling of some cytokines, such as tumor necrosis factor (TNF), IL-1, and IL-17, does not depend on JAKs. Pharmacological inhibition of cytokine signaling by blocking the JAK-STAT pathway is increasingly used to treat autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis, psoriasis, inflammatory bowel disease, and alopecia areata. The first generation of JAK inhibitors, or jakinibs, are orally administered small-molecule drugs that bind to a kinase domain that is, however, highly similar across the different JAKs. For instance, tofacitinib, which is approved for treatment of rheumatoid arthritis, primarily inhibits JAK3 and JAK1 but also blocks JAK2 to a certain extent. This lack of selectivity and, thus, inhibition of a variety of cytokines may cause side effects such as bacterial, fungal, mycobacterial, and viral infection and, in particularly, herpes zoster infection. Assessment of malignancy risk requires longer-term observational studies. A novel generation of more selective JAK inhibitors is under development with the aim of diminishing side effects without losing efficacy. A novel oral selective TYK2 small-molecule inhibitor has recently shown good effects and tolerability in a clinical trial with psoriasis patients (Papp et al., 2018Papp K. Gordon K. Thaçi D. Morita A. Gooderham M. Foley P. Girgis I.G. Kundu S. Banerjee S. Phase 2 Trial of Selective Tyrosine Kinase 2 Inhibition in Psoriasis.N. Engl. J. Med. 2018; 379: 1313-1321Crossref PubMed Scopus (49) Google Scholar). Biologic drugs are typically monoclonal antibodies, and their clinical use has provided a better understanding of their efficacy and side effects and revealed new layers of the complexity of autoimmune diseases. Currently, biologic drugs that bind immune molecules are a mainstay in the treatment of autoimmune diseases and have been extensively reviewed. Here we discuss a few of these examples to exhibit the breadth of the field and the challenges associated with drugs that are in clinical trials or already approved for use. Further, the wealth of structural information gleaned from structural studies of cytokine-receptor complexes (Spangler et al., 2015Spangler J.B. Moraga I. Mendoza J.L. Garcia K.C. Insights into cytokine-receptor interactions from cytokine engineering.Annu. Rev. Immunol. 2015; 33: 139-167Crossref PubMed Scopus (60) Google Scholar) is now providing a rational basis for developing cytokines and/or their receptors with enhanced specificity. For example, although pleiotropy is a basic mechanism underpinning many cytokine-receptor interactions, this property makes targeting this axis for any therapy problematic. However, sophisticated strategies and protein engineering approaches, which include altering cytokine-receptor docking topology and increased IL-2 selectivity, have overcome such issues and offer great promise to treat autoimmune diseases (Sockolosky et al., 2018Sockolosky J.T. Trotta E. Parisi G. Picton L. Su L.L. Le A.C. Chhabra A. Silveria S.L. George B.M. King I.C. et al.Selective targeting of engineered T cells using orthogonal IL-2 cytokine-receptor complexes.Science. 2018; 359: 1037-1042Crossref PubMed Scopus (0) Google Scholar, Trotta et al., 2018Trotta E. Bessette P.H. Silveria S.L. Ely L.K. Jude K.M. Le D.T. Holst C.R. Coyle A. Potempa M. Lanier L.L. et al.A human anti-IL-2 antibody that potentiates regulatory T cells by a structure-based mechanism.Nat. Med. 2018; 24: 1005-1014Crossref PubMed Scopus (9) Google Scholar) The first group of biologic drugs was TNF inhibitors, which radically changed the therapeutic landscape, and they are now routinely used to treat patients with rheumatic diseases, psoriasis, and inflammatory bowel disease. Their development and clinical use have been intensively reviewed over the last decades, and it will suffice to say, in this context, that their clinical use was met with skepticism, as it was argued that blocking a single cytokine would be futile in the context of a network of cytokines with overlapping biological effects (Monaco et al., 2015Monaco C. Nanchahal J. Taylor P. Feldmann M. Anti-TNF therapy: past, present and future.Int. Immunol. 2015; 27: 55-62Crossref PubMed Scopus (167) Google Scholar). Having established a key role for TNF in this network of cytokines, the concern was that serious side effects would be associated with TNF inhibition. However, serious side effects, such as tuberculosis and demyelinating disease, are rare. Importantly, a significant number of patients do not respond or show loss of clinical response over time to TNF inhibitors. With an improved molecular understanding of this unresponsiveness, new treatment options targeting other pathways central to regulation of tissue inflammation are now emerging. It has been shown recently for inflammatory bowel disease that disturbances in an intestinal microbial network that produce short-chain fatty acids as a carbon source for intestinal epithelial cells and induction of regulatory T cells are linked to poor responsiveness to TNF inhibitors (Yilmaz et al., 2019Yilmaz B. Juillerat P. Øyås O. Ramon C. Bravo F.D. Franc Y. Fournier N. Michetti P. Mueller C. Geuking M. et al.Swiss IBD Cohort InvestigatorsMicrobial network disturbances in relapsing refractory Crohn's disease.Nat. Med. 2019; 25: 323-336Crossref PubMed Scopus (31) Google Scholar). An overexpressed IL-7 receptor (IL-7R) signaling pathway in the colon has also been associated with non-responsiveness to anti-TNF therapy in inflammatory bowel disease, which might be explained by findings in a mouse model showing that this pathway is important for T cell homing to the gut and colonic inflammation (Belarif et al., 2019Belarif L. Danger R. Kermarrec L. Nerrière-Daguin V. Pengam S. Durand T. Mary C. Kerdreux E. Gauttier V. Kucik A. et al.IL-7 receptor influences anti-TNF responsiveness and T cell gut homing in inflammatory bowel disease.J. Clin. Invest. 2019; 129: 1910-1925Crossref PubMed Scopus (0) Google Scholar). More recently, expansion of apoptosis-resistant intestinal TNFR2+IL-23R+ T cells was associated with resistance to anti-TNF therapy in Crohn's disease (Schmitt et al., 2019Schmitt H. Billmeier U. Dieterich W. Rath T. Sonnewald S. Reid S. Hirschmann S. Hildner K. Waldner M.J. Mudter J. et al.Expansion of IL-23 receptor bearing TNFR2+ T cells is associated with molecular resistance to anti-TNF therapy in Crohn's disease.Gut. 2019; 68: 814-828Crossref PubMed Scopus (22) Google Scholar), and single-cell analysis of inflamed tissues from Crohn's patients has identified a unique cellular module associated with failure to respond to TNF inhibitors (Martin et al., 2019Martin J.C. Chang C. Boschetti G. Ungaro R. Giri M. Grout J.A. Gettler K. Chuang L.S. Nayar S. Greenstein A.J. et al.Single-Cell Analysis of Crohn's Disease Lesions Identifies a Pathogenic Cellular Module Associated with Resistance to Anti-TNF Therapy.Cell. 2019; 178: 1493-1508.e20Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar). Taken together, these studies are beginning to provide cellular and molecular bases for resistance to TNF blockade. Patients who are not responding to anti-TNF therapy may respond to biologic drugs targeting the IL-23/IL-17 axis, which plays a central role in regulation of tissue inflammation. These cytokine inhibitors have, however, very different effects on autoimmune diseases. Increased IL-23 and IL-17 levels have been found in the colon of inflammatory bowel disease patients, but IL-17 inhibitors led to disease exacerbation. In contrast, initial clinical trials with antibodies binding the p40 unit shared between IL-12 and IL-23 and subsequent clinical trials with antibodies targeting the IL-23-specific p19 unit showed efficacy in patients with inflammatory bowel disease. The efficacy of IL-12/IL-23 dual inhibitors and of IL-23-selective inhibitors suggests that the disease is primarily mediated by IL-23 and not IL-12 (Feagan et al., 2017Feagan B.G. Sandborn W.J. D'Haens G. Panés J. Kaser A. Ferrante M. Louis E. Franchimont D. Dewit O. Seidler U. et al.Induction therapy with the selective interleukin-23 inhibitor risankizumab in patients with moderate-to-severe Crohn's disease: a randomised, double-blind, placebo-controlled phase 2 study.Lancet. 2017; 389: 1699-1709Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar, Neurath, 2019Neurath M.F. Targeting immune cell circuits and trafficking in inflammatory bowel disease.Nat. Immunol. 2019; 20: 970-979Crossref PubMed Scopus (14) Google Scholar). However, a recent study in a mouse model of inflammatory bowel disease suggests that, early in disease, IL-12 is the dominant cytokine rather than IL-23 and, thus, indicates temporally distinct roles for these two cytokines in driving inflammation. Likewise, preclinical studies might also explain why IL-17 inhibitors led to exacerbation of disease in patients with Crohn's disease because it has been shown that IL-17 may control intestinal barrier integrity in mice and that inhibition of IL-17A or its receptor leads to weakening of barrier function and exacerbation of experimental colitis (Eftychi et al., 2019Eftychi C. Schwarzer R. Vlantis K. Wachsmuth L. Basic M. Wagle P. Neurath M.F. Becker C. Bleich A. Pasparakis M. Temporally Distinct Functions of the Cytokines IL-12 and IL-23 Drive Chronic Colon Inflammation in Response to Intestinal Barrier Impairment.Immunity. 2019; 51: 367-380.e4Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar, Neurath, 2019Neurath M.F. Targeting immune cell circuits and trafficking in inflammatory bowel disease.Nat. Immunol. 2019; 20: 970-979Crossref PubMed Scopus (14) Google Scholar). In psoriasis skin lesions, dysregulated IL-17 levels are associated with neutrophil influx and keratinocyte hyperproliferation, which are disease drivers. Biologic drugs that block IL-17 have shown good efficacy in psoriasis patients but are also associated with Candida infection. Furthermore, selective inhibition of IL-23 is superior over IL-17 inhibition and is not associated with Candida infection (Reich et al., 2019Reich K. Armstrong A.W. Langley R.G. Flavin S. Randazzo B. Li S. Hsu M.-C. Branigan P. Blauvelt A. Guselkumab versus secukinumab for the treatment of moderate-to-severe psoriasis (ECLIPSE): results from a phase 3, randomised controlled trial.Lancet. 2019; 394: 831-839Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar). This indicates that targeting a cytokine upstream of the IL-17 axis is more efficacious but with fewer side effects because of IL-23-independent IL-17 production being seemingly sufficient for local antimicrobial responses (Zwicky et al., 2020Zwicky P. Unger S. Becher B. Targeting interleukin-17 in chronic inflammatory disease: A clinical perspective.J. Exp. Med. 2020; 217: 217Crossref Scopus (1) Google Scholar). Despite some preclinical evidence, targeting the IL-23/IL-17 axis in non-barrier-associated autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis, has no or little clinical effect. The molecular explanation for this lack of efficacy is unclear but might indicate that targeting this axis is preferential in barrier-associated autoimmune diseases (Zeggini et al., 2019Zeggini E. Gloyn A.L. Barton A.C. Wain L.V. Translational genomics and precision medicine: Moving from the lab to the clinic.Science. 2019; 365: 1409-1413Crossref PubMed Scopus (3) Google Scholar). Members of the IL-1 family, such as IL-1, IL-18, and IL-36, have been associated with a broad spectrum of diseases, including autoimmune diseases, through their role in innate immunity and basal inflammation. Anti-IL-1b antibodies are not commonly prescribed for rheumatoid arthritis patients as a first-line biologic drug choice but can be used for patients not responding to TNF inhibitors. Cardiovascular disease is one of the comorbidities in rheumatoid arthritis patients, and because anti-IL-1b antibodies have shown efficacy in an atherosclerotic disease clinical trial, it has been suggested that this drug might be beneficial in the later stages of rheumatoid arthritis, exemplifying how different biologic drugs can be used at different stages of an autoimmune disease when the original target organ, the joint, is no longer the major therapeutic challenge (Mantovani et al., 2019Mantovani A. Dinarello C.A. Molgora M. Garlanda C. Interleukin-1 and Related Cytokines in the Regulation of Inflammation and Immunity.Immunity. 2019; 50: 778-795Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). Different lines of evidence implicate IL-18 in the pathogenesis of inflammatory bowel disease. A Mendelian form of severe enterocolitis is due to an activating NLRC4 inflammasome mutation and leads to upregulation of the IL-18 signaling pathway, and pharmacologic inhibition of IL-18 reverse this enterocolitis. Intestinal biopsies from inflammatory bowel disease patients show increased IL-18 expression in epithelial cells, which seems to promote goblet cell dysfunction, impairing intestinal barrier function in experimental colitis. Clinical trials with IL-18 in Crohn's disease are underway and will give a better understanding of its role in inflammatory bowel disease (Neurath, 2019Neurath M.F. Targeting immune cell circuits and trafficking in inflammatory bowel disease.Nat. Immunol. 2019; 20: 970-979Crossref PubMed Scopus (14) Google Scholar). IL-36 cytokines are mainly expressed on the barrier sites of the body. Generalized pustular psoriasis is a rare, life-threatening disease, and even though it is sometimes seen in the context of psoriasis, clinical, histologic, and genetic differences suggest that the two diseases have distinct pathogenic mechanisms. This is supported by the observation that TNF inhibitors have less efficacy in generalized pustular psoriasis than in psoriasis. IL-36 has been implicated in the pathogenesis of generalized pustular psoriasis because the lesions have heightened IL-36 cytokine activity, their neutrophilic environment activates IL-36, and missense mutations in the IL-36 receptor are associated with generalized postular psoriasis. In line with this, a phase 1 proof-of concept clinical trial has shown that a monoclonal antibody against IL-36 has efficacy in generalized pustular psoriasis lesions (Bachelez et al., 2019Bachelez H. Choon S.E. Marrakchi S. Burden A.D. Tsai T.F. Morita A. Turki H. Hall D.B. Shear M. Baum P. et al.Inhibition of the Interleukin-36 Pathway for the Treatment of Generalized Pustular Psoriasis.N. Engl. J. Med. 2019; 380: 981-983Crossref PubMed Scopus (21) Google Scholar). In line with the original observation that IL-6 knockout mice are protected in an arthritis model, it has been shown that an anti-IL-6R monoclonal antibody has efficacy in rheumatoid arthritis. However, anti-IL-6 treatment is associated with bacterial infection and induces psoriasis in patients with no history of psoriasis and intestinal perforation, reflecting the multi-functional role of IL-6. Although the risk of bacterial infection is likely to reflect its role in the immune system, induction of psoriasis and intestinal perforations may not. For example, RNA transcriptomic studies of skin from a mouse model of psoriasis compared with human psoriasis skin have shown that, in the absence of IL-6, keratinocytes increase production of numerous additional proinflammatory cytokines, which might explain the molecular basis for this particular side effect (Fritz et al., 2017Fritz Y. Klenotic P.A. Swindell W.R. Yin Z.Q. Groft S.G. Zhang L. Baliwag J. Camhi M.I. Diaconu D. Young A.B. et al.Induction of Alternative Proinflammatory Cytokines Accounts for Sustained Psoriasiform Skin Inflammation in IL-17C+IL-6KO Mice.J. Invest. Dermatol. 2017; 137: 696-705Abstract Full Text Full Text PDF PubMed Google Scholar). Anti-IL-6-associated intestinal perforation, observed in patients with rheumatoid arthritis and anti-IL-6-treated patients with inflammatory bowel disease, is likely to be associated with a role of IL-6 in intestinal epithelial proliferation and repair after injury (Danese et al., 2019Danese S. Vermeire S. Hellstern P. Panaccione R. Rogler G. Fraser G. Kohn A. Desreumaux P. Leong R.W. Comer G.M. et al.Randomised trial and open-label extension study of an anti-interleukin-6 antibody in Crohn's disease (ANDANTE I and II).Gut. 2019; 68: 40-48Crossref PubMed Scopus (6) Google Scholar). Anti-IL-6R inhibition has efficacy in neuromyelitis optica and in models of systemic lupus erythematosus, which are characterized by signature autoantibodies, indicating that IL-6 in these diseases is exerting its effect via B cells (Kang et al., 2019Kang S. Tanaka T. Narazaki M. Kishimoto T. Targeting Interleukin-6 Signaling in Clinic.Immunity. 2019; 50: 1007-1023Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar). Co-stimulatory molecules are also potential biological targets in autoimmune diseases. The CD40/CD40L axis plays a key role in generation of humoral immune responses; CD40 is expressed on antigen-presenting cells, including B cells, and interacts with CD40L on activated T cells, resulting in maturation of functional T and B cells and antibody isotype switching. Clinical trials with anti-CD40L antibodies for autoimmune diseases were halted because of thrombotic complications because the antibodies also co-bound platelet CD40L and an Fc receptor on adjacent platelets. To avoid this side effect, a non-antibody CD40L binding protein lacking an Fc domain, VIB4920, has been developed and trialed in a proof-of-concept study in patients with rheumatoid arthritis. VIB4920 significantly decreased disease activity, and, importantly, no thrombotic complications were reported (Karnell et al., 2019Karnell J.L. Albulescu M. Drabic S. Wang L. Moate R. Baca M. Oganesyan V. Gunsior M. Thisted T. Yan L. et al.A CD40L-targeting protein reduces autoantibodies and improves disease activity in patients with autoimmunity.Sci. Transl. Med. 2019; 11: eaar6584Crossref PubMed Scopus (9) Google Scholar). Interactions between the costimulatory molecules CD80 and CD86 on antigen-presenting cells and their ligand CD28 on T cells are important for activation of effector T cells. A CTLA4-IgG1 Fc fusion protein that binds with a higher affinity to CD80 and CD86 than CD28 can block T cell stimulation, which is considered its dominant mode of action. However, it is also known to act in a less well-defined manner in other cell populations, including regulatory T cells, B cells, monocytes, macrophages, and osteoclasts. The CTLA4-IgG1 Fc fusion protein has shown a good effect in rheumatoid arthritis, juvenile idiopathic arthritis, and psoriatic arthritis but has not had any efficacy in other autoimmune diseases, such as inflammatory bowel disease, multiple sclerosis, or lupus nephritis. The basis of this differential efficacy is not understood and might indicate, for instance, that blocking this co-stimulatory pathway is disease- and organ-specific or that this drug's effect on osteoclasts might at least partly explain