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There are several possible mechanisms by which B lineage cells may contribute to the disease  process, including antigen presentation, activation of T cells by providing costimulatory signals, production of proinflammatory cytokines and production of autoantibodies  including RF and ACPA.28 Immune complexes containing RF or ACPA may directly activate macrophages, resulting in increased
production of cytokines and chemokines like tumour necrosis factor and CXCL8 that are associated with the manifestations of clinical signs and symptoms.29 30

the autoreactive B cells that drive autoimmunity during the preclinical stage of the disease.5

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RA is one of the most common chronic immune-mediated
inflammatory diseases with a significant impact on the individual
patient as well as society. Current treatment options are still not
sufficiently effective as most patients do not achieve disease
remission, which is the treatment goal.24 25
Early initiation of treatment in patients diagnosed with RA increases the chance of
better radiographic outcome and reaching long-term remission, a phenomenon referred to as the ‘therapeutic window of opportunity’.

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The presence of circulating autoantibodies and changes in
BCR repertoire years before the clinical onset of the disease, the
specificity of ACPA for the diagnosis of RA and the presence
of B cells and plasma cells at the site of inflammation in early
established disease15 highlight the importance of B cells in the
pathogenesis of RA

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Elevated levels of autoantibodies such as IgM rheumatoid factor (IgM-RF), anti-citrullinated peptide antibodies (ACPA) and other RA-specific anti-bodies against post-translationally modified proteins can be detected in blood samples of individuals later diagnosed with seropositive RA with a median of 5 years before arthritis becomes evident.3 During this stage, clonal changes in the peripheral blood B-cell receptor (BCR) repertoire can be detected 5 but the synovial tissue is usually completely normal.6 7

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Autoantibody positive rheumatoid arthritis (RA) is a common and prototypic autoimmune disease. This condition can be preceded by a phase of systemic
autoimmunity during which circulating autoantibodies, increased acute phase reactants, proinflammatory cytokines and chemokines are found, even years before the development of clinically evident arthritis.1–4

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From earlier research reports we learnt that rheumatoid factor (RF) and Anti-Citrullinated Peptide Antibodies (ACPAs) can be found in the peripheral blood of individuals >10 years before the development of autoantibody positive
rheumatoid arthritis.
► Research leading to the recognition of this phase of systemic autoimmunity has not only supported the view that the pathogenetic process might not be initiated in the joint but created an opportunity to potentially delay the clinical onset of disease by a targeted intervention in this early phase.
► B-cells play a pivotal role in this process as apart from being predecessors of cells that produce immunoglobulins including RF and ACPAs, B-cells are efficient antigen presenting cells, may activate T cells in the context of co-stimulatory signals, and produce a variety of cytokines.
► Indeed, B-cell targeted therapy is effective in early as well as in late established RA.

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project template for MTX-treated RA

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-Blood-based biomarkers, such as antibodies in the blood or RNA transcripts in peripheral blood cells, are another promising class of biomarkers in rheumatic diseases. In RA, a new set of antibodies, anticarbamylated protein antibodies, have been identified as a potential biomarker for early diagnosis and assessing prognosis
-A promising approach to the development of next-generation therapeutics is the investigation of epigenetic biomarkers in rheumatic disorders.Epigenetic regulators, including DNA methylation, histone modification, and microRNAs
(miRNAs), have been implicated in pathogenic mechanisms underlying autoimmunity [67

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Progress in biomarker development has been hampered by a number of challenges inherent in rheumatology
-most rheumatic diseases are highly heterogeneous in their pathophysiology,
disease course, and therapeutic response. This makes identification and validation of biomarkers in these diseases a monumental task, but also highlights the need for next-generation biomarkers to aid patient stratification and targeting therapies.
-peripheral blood, saliva, and urine are the most accessible materials for biomarker studies, they are often not the sites of rheumatic  diseases-unique, mechanistic biomarkers are more likely to be found in the diseased tissues but certain mechanistic biomarkers can be found in the peripheral blood.
-, rheumatic diseases are frequently multi-factorial
The success of predictive biomarkers in oncology stems in part from the fact that many cancers are caused by a single-gene mutation or a discrete chromosomal event In contrast, RA and other rheumatic diseases are not driven by single-gene mutations, and single or multiple-gene biomarkers have not proven useful as predictive biomarkers [41].

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Current disease activity scores and remission criteria are largely based on clinical
findings, and do not integrate subclinical molecular inflammation. Potential biomarkers for assessing remission include imaging and immunological bio-
markers.

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APPLICATION OF BIOMARKERS IN RHEUMATOLOGY
3.Prediction of response to therapy:
Predictive biomarkers allow clinicians to assess the likelihood that a patient will respond to a particular therapy before therapy is started
4. Assessment of response to therapy and drug toxicity:
Pharmacodynamic biomarkers measure the effect of therapy on the disease, and can be mechanistic or descriptive. These biomarkers can facilitate and reduce the costs of therapeutic development, particularly by enabling more rapid assessment of response to treatment compared with clinical assessment
Pharmacodynamic biomarkers of response to rituximab therapy in RA include flow cytometry analysis of peripheral blood B cells and peripheral blood plasmablasts, or immunoglobin J transcripts, a marker for antibody-secreting plasmablasts [33

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mechanistic biomarkers, which are rooted in the biologic mechanisms of disease, have the greatest potential for guiding clinical decision making [13].
....Because they are directly involved in disease pathogenesis,
...mechanistic biomarkers make for more useful predictive and pharmacodynamic biomarkers as they reflect the dysregulation of molecular pathways directly involved in pathogenesis.

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Descriptive biomarkers reflect the state of a disease but are not directly involved in disease pathogenesis
...these clinical laboratory biomarkers are not specific to RA and are also elevated in many infectious and inflammatory diseases
....do not directly mediate disease pathogenesis, the value of the diagnostic and prognostic information that they provide is limited [13].

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APPLICATION OF BIOMARKERS IN RHEUMATOLOGY
1.Diagnosis of disease:
-established disease e.g detection of autoantibodies RF & ACPA are important components of the diagnostic criterion for RA
-identifying individuals with disease before the onset of clinical symptoms,
- as well as individuals with susceptibility to disease, thus offering an opportunity for therapeutic intervention aimed at preventing or slowing the development of symptomatic disease
2. Assessment of disease activity and prognosis:
-Biomarkers that allow monitoring of disease activity, such as erythrocyte sedimentation rate, CRP, and complement proteins C3 and C4, provide information about disease activity but have not exhibited sufficient predictive utility to date for their results in isolation to be actionable
-clinical disease remissio n to identify individuals in which disease-modifying
therapies should be tapered or discontinued.

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1.Objective, quantitative measurements of molecular biomarkers through a variety of techniques serve as indicators of normal or pathologic processes, or indicators of response to therapy

2.Compared with molecular biomarkers, to date imaging biomarkers have frequently been more closely associated with the phenotypic manifestations of
established diseases. Moreover, imaging allows structural and functional assessments of disease activity and therapy

3. Although contributing to the diagnosis and assessment of established disease, clinical biomarkers have generally not provided utility in guiding selection of therapies for the treatment of patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), or vasculitis

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common types of biomarkers in rheumatology:
1. Molecular biomarkers are biochemical variables.. or biomolecules in the blood, synovial fluid and other bodily fluids, and tissues
2.Imaging biomarkers provide biomarkers that enable assessment of disease
activity and response to treatments by visualizing anatomical and structural changes.
3.Clinical biomarkers are typically physical variables or symptoms... other clinical findings

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A biomarker is defined as a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes,or pharmacologic responses to a therapeutic intervention [1
....potential for guiding both the clinical management of rheumatic diseases and
therapeutic development

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Even though some biomarkers are already routinely used to diagnose and treat rheumatic diseases, there is an unmet need for novel biomarkers both in clinical practice and in drug development. For instance, biomarkers that can facilitate early clinical diagnosis offer the potential to enable therapeutic intervention to prevent development of disease

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compared with descriptive biomarkers, better biomarkers, ideally mechanistic ones, have greater potential for guiding clinical decision making in rheumatology.
Identification of biomarkers with robust diagnostic and predictive utility would enable precision medicine in rheumatology.

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Therapies targeted against TNF-a, IL-1 and IL-6, in addition to T- and B-cell inhibitors, when used alone or in combination with MTX, have resulted in favourable clinical outcomes in patients with RA [81]. However, although biologic agents are promising, they are not without limitations [82]. For example, the hierarchy of the pathophysiological response is unclear. As many immune mediators work in concert with one another during the disease process, the question becomes what should be targeted first—B cells, T cells or a cytokine. Additionally, it is unclear how the depletion of a subset of lymphocytes (e.g. B cells or T cells) affects RA or the mechanism by which inflammation is actually
reduced [81].

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The pathobiology of RA is multifaceted and involves T cells, B cells and the complex interaction of many pro-inflammatory cytokines, including TNF-a and IL-6. These cytokines are messengers that activate and differentiate effector cells that cause local and systemic symptoms associated with this disease

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. Additionally, the ubiquitous expression of IL-17 receptor (IL-17R) on fibroblasts, endothelial cells, epithelial cells and neutrophils indicates that this cytokine has the potential to influence a number of pathways and effector cells involved in RA

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An IL-17-secreting subset of CD4+ cells [i.e. Th 17 (TH17)]that has a critical role in synovitis has recently been implicated in the pathogenesis of many inflammatory and autoimmune diseases, including RA [33]. The presence of TH17 cells in the SF and peripheral blood of patients with RA suggests the involvement of this potent pro-inflammatory cytokine in RA pathology [36, 37
Chen Dong &... (TH17):
Effector molecules secreted: IL-17A, IL-17F, IL-21, IL-22, CCL20, Human TH17 cells also produce IL-26
Function: Promote protective immunity against extracellular bacteria and fungi, mainly at mucosal surfaces. Also promote autoimmune and inflammatory diseases. Generated in the presence of TGFβ and IL-6 and/or IL-21 and are maintained by IL-23 and IL-1.

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pro-inflammatory cytokines (e.g.IL-6 and TNF-a) are involved in the pathogenesis of RA [20, 21]. TNF-a and IL-6 play dominant roles in the pathobiology of RA; however, IL-1, VEGF and perhaps IL-17 also have a significant impact on the disease process.  Through complex signal pathways, these cytokines activate genes associated with inflammatory responses, including additional cytokines and MMPs involved in tissue degradation [12]

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Within the synovial membrane there is a great increase in activated fibroblast-like synoviocytes, which also produce inflammatory cytokines, PGs and MMPs [13]. Synoviocytes contribute to the destruction of cartilage and bone
by secreting MMPs into the SF and by direct invasion into these tissues [13

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In addition to antigen presentation, macrophages are involved in osteoclastogenesis and are a major source of cytokines, including TNF-a, IL-1 and IL-6 [12, 13].

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T- and B-cell activation result in increased production of cytokines and chemokines, leading to a feedback loop for additional T-cell, macrophage and B-cell interactions [12, 13].

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B cells contribute to RA pathogenesis not only through antigen presentation, but also through the production of antibodies, autoantibodies and cytokines (Fig. 2) [13]. RF and anti-CCP autoantibodies are common in patients with RA. B lymphocytes express cell surface proteins, including immunoglobulin and differentiation antigens such as CD20 and CD22 [13]. Autoantibodies can form larger immune complexes that can further stimulate the production of pro-inflammatory cytokines, including TNF-a, through complement and Fc-receptor activation [13].

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CD4+ T cells(TH1) that secrete IL-2 and IFN-g infiltrate the synovial membrane.
Chen Dong &... T-cell subsets
Effector molecules secreted: IFNγ, IL-2, LTα
Function: Promote protective immunity against intracellular pathogens. By secreting IFNγ, they induce activation of macrophages and upregulation of iNOS, leading to the killing of intracellular pathogens such as Leishmania major, Listeria monocytogenes and Mycobacterium spp. Their development is regulated by IL-12.

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. Antigen-presenting cells, including dendritic cells, macrophages and activated B cells, present arthritis-associated antigens(exogenous material and autologous antigen) to T cells.

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Extra-articular manifestations include rheumatoid nodules, vasculitis, pericarditis, keratoconjunctivitis sicca, uveitis and rheumatoid lung [17]. Systemic manifestations include acute-phase protein production, anaemia, cardiovascular disease (CVD), osteoporosis, fatigue and depression [18, 19].

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Various immune modulators (cytokines and effector cells) and signalling pathways are involved in the pathophysiology of RA [12]. The complex interaction of immune modulators is responsible for the joint damage that begins at the synovial membrane and covers most IA structures (Fig. 1) [12].

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RA is a chronic, progressive, inflammatory autoimmune disease associated with articular, extra-articular and systemic effects

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Environmental factors, such as smoking and infection, may also influence the development, rate of progression and severity of RA [15, 16].

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a genetic basis for disease development. More than 80% of patients carry the epitope of the HLA-DRB1*04 cluster [13], and patients expressing two HLA-DRB1*04 alleles are at elevated risk for nodular disease, major organ involvement and surgery related to joint destruction [14]. Single-nucleotide polymorphism genotyping across the MHC has identified additional alleles related to RA risk, including those found on the conserved A1-B8-DR3 (8.1) haplotype and those near the  HLA-DPB1 gene [9]. Other RA-associated loci are PTPN22, PADI4, STAT4, TRAF1-C5 and TNFAIP3, although non-MHC risk alleles may represent only 35% of the genetic burden of RA [9].

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Antigen-activated CD4+ T cells amplify the immune response by stimulating other mononuclear cells, synovial fibroblasts, chondrocytes and osteoclasts. The release of cytokines, especially TNF-a, IL-6 and IL-1, causes synovial inflammation. In addition to their articular effects, pro-inflammatory cytokines promote the development of systemic effects, including production of acute-phase proteins (such as CRP), anaemia of chronic disease, cardiovascular disease and osteoporosis and affect the hypothalamicpituitaryadrenal axis, resulting in fatigue and depression

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T cells, B cells and the orchestrated interaction of pro-inflammatory cytokines play key roles in the pathophysiology of RA. Differentiation of naı¨ve T cells into Th 17 (TH17) cells results in the production of IL-17, a potent cytokine that promotes synovitis. B cells further the pathogenic process through antigen presentation and autoantibody and cytokine production