The promise of precision medicine in rheumatology

Abstract

Systemic autoimmune rheumatic diseases (SARDs) exhibit extensive heterogeneity in clinical presentation, disease course, and treatment response. Therefore, precision medicine - whereby treatment is tailored according to the underlying pathogenic mechanisms of an individual patient at a specific time - represents the 'holy grail' in SARD clinical care. Current strategies include treat-to-target therapies and autoantibody testing for patient stratification; however, these are far from optimal. Recent innovations in high-throughput 'omic' technologies are now enabling comprehensive profiling at multiple levels, helping to identify subgroups of patients who may taper off potentially toxic medications or better respond to current molecular targeted therapies. Such advances may help to optimize outcomes and identify new pathways for treatment, but there are many challenges along the path towards clinical translation. In this Review, we discuss recent efforts to dissect cellular and molecular heterogeneity across multiple SARDs and future directions for implementing stratification approaches for SARD treatment in the clinic.

Fig. 1.. Molecular mechanisms and signatures may differ according to disease stages.

The disease course of systemic autoimmune rheumatic diseases is complex with various disease stages. In patients with a genetic predisposition, autoimmunity may be initiated following environmental triggers, such as viral infection, the microbiome, low vitamin D, and smoking. Patients experience a preclinical phase following autoimmunity initiation with soluble mediator and autoantibody (autoab) production but no clinical symptoms. As the disease progresses, patients experience periods of active disease, in which clinical features are present, and the patients are diagnosed. This stage is characterized by increases in the levels of autoantibodies and soluble mediators, as well as alterations in the soluble mediator profiles and epitope spreading. Active disease can be followed by periods of remission and disease flare, as well as disease suppression following treatment. Changes in levels or the profiles of soluble mediators and antibodies may occur in each of these disease phases, highlighting the need for longitudinal studies incorporating multiple disease stages.

Fig. 2. Potential tailored treatment regimens based on recently identified molecular subgroups.

Systemic autoimmune rheumatic diseases (SARDs) share common features, including the dominant affected organs, presence of autoantibodies (autoabs), association with human leukocyte antigen (HLA) regions, and FDA-approved biologic disease-modifying antirheumatic drugs (bDMARDs). For some SARDs, molecular subgroups suggest the potential for precision use of these bDMARDs. (A) Patients with rheumatoid arthritis (RA) can be stratified according to B cell, myeloid cell, and fibroblast molecular synovial signatures. Patients with a myeloid cell signature respond well to TNF inhibition, while those with low B cells respond better to the IL-6 receptor inhibitor tocilizumab than to B cell depletion with rituximab (which may be more effective in patients with a B cell signature). (B) Patients with psoriatic arthritis (PsA) can be stratified based on T cell phenotypes. A proof-of-concept study tailored treatments based on these T cell phenotypes – whereby patients with a Th1 cell predominant phenotype received the IL-12p40 inhibitor ustekinumab, those with a Th17 cell-predominant phenotype received the IL-17 inhibitor secukinumab, and those with a mixed phenotype received TNF inhibitors – and showed better outcomes compared to the current treatment recommendations. (C) Subsets of patients with systemic lupus erythematosus (SLE) with B cell/plasmablast, neutrophil, and IFN signatures have been identified. Both plasmablasts and neutrophils can contribute to the IFN signature via immune complex (IC) formation or uncleared neutrophil extracellular traps (NETs), respectively, suggesting that these patients may respond to the IFN receptor antagonist anifrolumab. Furthermore, patients with a plasmablast signature may respond to the BLyS inhibitor belimumab. (D) Patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) differ in their ANCA specificity, which may be associated with differing responses to rituximab^,. Patients with AAV who have poor prognoses exhibit CD8 effector memory T cell gene expression profiles; however, the role of these cells in AAV is unknown. (E) Patients with systemic sclerosis (SSc) can be grouped according to the expression of cell proliferation, platelet-derived growth factor (PDGF), and fibrotic gene signatures or inflammatory gene signatures — suggesting the use of nintedanib (which inhibits the growth factor receptors FGFR, PDGFR, and VEGFR), or tocilizumab, respectively. (F) Although no FDA-approved bDMARDs exist for primary Sjögren’s syndrome (pSS), patients can be stratified based on the predominance of type I or type II IFN, suggesting that th