Modern Therapeutics in Rheumatic Diseases (None)

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These actions are not yet fully understood. Anakinra blocks the action of an immune system protein called interleukin-1 IL IL-1 is often called a master cytokine. This is because it controls local and systemic inflammation in the body. Tofacitinib is in a new class by itself. It works by blocking a cellular signaling pathway inside cells. This stops components that cause inflammation from being made. Older biologics block inflammation from the outside of cells, but JAK-inhibitors work from within cells. It comes as a pill, taken twice per day. Biologics work for more people because they target specific parts of the immune system to reduce inflammation in the joints.

They have fewer side effects than older drugs. However, any drug that suppresses the immune system carries risks. Tell your doctor about any unusual symptoms you have. For instance, biologics can cause a dormant infection to become active again. For this reason, you should have a tuberculosis test before taking one of these drugs. People with liver disease may not be able to take a biologic drug. If you have liver issues, ask your doctor if biologics are safe for you.

Biologics are the newest type of drugs to treat RA. If you and your doctor are considering a biologic drug, keep the following in mind:. Subsequently, T and B lymphocytes participate in a targeted and specific response following presentation of pathogen-derived or disease associated antigens [ 1 ].

Management of rheumatoid arthritis: Impact and risks of various therapeutic approaches (Review)

This powerful system is critical for defence against pathogens. The severe and often lethal phenotypes exhibited by patients with defects in immune cell function illustrate all too clearly the importance of immune system integrity. However this essential system has great potential to harm the host. Lymphocytes gain tolerance to host tissues through clonal deletion, anergy or via suppression by regulatory T cells. When these processes fail autoreactive lymphocytes can cause autoimmune and inflammatory conditions, often resulting in significant morbidity [ 2 , 3 ].

The diverse roles served by PI3K in the innate and adaptive immune system offer hope that inhibition of this axis may provide new treatments for autoimmune conditions [ 4 ]. The ultimate goal must be to alleviate pathological inflammation while leaving resistance to infection intact. We examine how targeting these isoforms shows promise as a therapeutic strategy in autoimmunity, focussing on two systemic rheumatic diseases, rheumatoid arthritis RA and systemic lupus erythematosus SLE , but also allude to other immune-related conditions that may be treated using PI3K inhibitors.

Phosphoinositide 3-kinases PI3Ks are lipid kinases that phosphorylate the 3-hydroxyl position of the inositol ring of phosphatidylinositol PI substrates within the plasma membrane and intracellular compartments. The phosphorylated effector products recruit and activate proteins expressing the lipid-binding Pleckstrin Homology PH , phox homology and FYVE domains.

PI3Ks control a wide variety of cellular processes, including migration, proliferation, differentiation and vesicular trafficking [ 5 - 7 ].

PI3Ks are classified according to their sequence homology and substrate specificity. Class I PI3Ks are the most extensively studied and form the principle focus of this review.

The Therapeutic Potential for PI3K Inhibitors in Autoimmune Rheumatic Diseases

The class 1A PI3K enzymes are heterodimers comprised of a regulatory subunit p85 and a catalytic subunit p Class 1A PI3K regulatory subunits contain SH2 domains which enable recruitment to tyrosine phosphorylated proteins at the plasma membrane, thus receptor tyrosine kinases RTKs form their principle means of activation. Targeted inhibition of these isoforms should provide immunotherapeutic benefit while minimising organ toxicity.

Key signalling cascades are initiated in neutrophils, macrophages, dendritic cells, T cells, B cells and mast cells summarised in Fig. The production of PIP 3 is a critical signalling hub. PIP 3 then acts on a variety of downstream effectors expressing PH domains to promote cellular responses. The PI3K-Akt signalling axis has a profound influence on cellular functions, and must therefore be tightly regulated.

Constitutive activation of class 1 PI3K signalling predisposes to autoimmunity and cancer, while inactivation of isoforms has varying effects ranging from embryonic lethality to immune deficiency, demonstrating the critical importance of maintaining physiological balance in this cellular cascade. Interestingly, drugs that activate SHIP may be used as anti-inflammatory drugs, presumably by inhibiting PI3K signalling in blood cells [ 32 ]. Rapamycin-based drugs are commonly used immunosuppressants in kidney transplant recipients [ 34 ].

Although rapamycin has been evaluated as a potential therapeutic in RA [ 35 ] and SLE [ 36 ], the associated adverse effects may be too severe for routine use in autoimmunity. The interrogation of signalling pathways in which the class I PI3Ks play a key role has been facilitated by the availability of small molecule inhibitors with high selectivity for the various class 1A isoforms and the development of mice with inactivating mutations in PI3K genes. These strategies provided a considerable advance on earlier approaches which utilised wortmannin or LY pan-PI3K inhibitors with known off-target effects on class II and III PI3K's, mTOR and casein kinase 2 allowing the dissection of the contributions of specific PI3K isoforms to lymphocyte signalling, trafficking, proliferation and development.

Regulatory B cells were first identified in mice and subsequently in humans, and mediate their regulatory function via the production of IL [ 97 - 99 ], leading some authors to describe them as B10 cells [ 96 ]. Abnormalities in the number [ 95 ] or function [ 99 ] of regulatory B cells have been described in patients with autoimmune diseases, suggesting that this subset may be of relevance to the development of treatments for autoimmunity.

In one study, all chronic lymphocytic leukaemia CLL patients treated with this inhibitor showed a reduction in lymph node size which was often associated with an increase in blood lymphoblast count [ 18 ]. Further studies have shown that CAL inhibits CLL cell chemotaxis and migration beneath stromal cells and sensitises CLL cells toward standard chemotherapeutic agents [ ]. PI3K also plays an important role in T follicular helper T FH cells, a subset of T cells which are critical for the provision of help to germinal centre B cells during affinity maturation and for their differentiation into long-lived plasma cells [ ].

T FH cells are likely to be crucial pathogenic mediators in SLE, as it is the long-lived plasma cells they create that exhibit most resistance to B cell depleting therapies and are the predominant source of high-affinity pathogenic autoantibodies [ , ]. Regulatory T cells Tregs develop both in the thymus and the periphery from mature CD4 T cells and serve a critical role in controlling the adaptive immune system and preventing unrestrained inflammatory responses [ ]. Rapamycin also promotes the expansion of Tregs [ ].

Moreover, Foxo transcription factors control the pivotal transcription factor Foxp3 which is both necessary and sufficient for the induction of regulatory T cell Treg function [ ].

PI3K signalling can therefore suppress Foxp3 expression by activating Akt which phosphorylates and sequesters Foxo1 and Foxo3a [ 1 ]. Neutrophils are the most abundant circulating phagocyte and form the cornerstone of the innate immune system, playing a central role in the destruction of invading pathogens [ ].

Neutrophil dysfunction is also known to contribute to the pathogenesis of a number of autoimmune diseases, including SLE and RA.

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Thus, inhibition of neutrophil activation is a potential therapeutic goal in the treatment of these conditions and pathways implicated in dysfunctional intracellular signalling may provide promising routes of enquiry. Effective neutrophil function is dependent on several related activities ranging from chemotaxis, endothelial adhesion, diapedesis, phagocytosis, activation, phagolysosomal maturation, free radical production and later apoptosis. Class 1 PI3K control neutrophil spreading on endothelium [ ], migration [ 57 , 70 ] and pathogen killing [ ].

A phenotype reproduced in in vivo models of pulmonary inflammation and arthritis [ ].

What is rheumatoid arthritis?

At the site of infection, neutrophils kill pathogens by generating reactive oxygen species ROS via the respiratory burst process. Mast cells reside in tissues such as the skin and mucosa and are characterised by the ability to release large amounts of heparin and histamine from their cytoplasmic granules.

Mast cell degranulation plays an important role in allergic inflammatory disorders such as asthma and allergic rhinitis, and in anaphylaxis. Dendritic cells DCs are potent antigen-presenting cells with roles in initiating cellular and humoral immune responses and in tolerance induction. Prior to antigen encounter DCs reside in tissues in an immature state, becoming activated upon contact with antigen in the context of inflammatory or pathogen-derived stimuli.

This activation leads to DC migration to the T-cell rich paracortex of draining lymph nodes where they present antigen to CD4 T cells, initiating immune responses. Eosinophils infiltrate release pro-inflammatory cytokines and ROS in response to IgE immune complexes.

The Therapeutic Potential for PI3K Inhibitors in Autoimmune Rheumatic Diseases

Studies using the pan-PI3K inhibitor wortmannin have implicated PI3K in eosinophil chemotaxis and release from the bone marrow [ ], and inhibitor-treated mice show a reduction in eosinophilia in allergen-induced bronchial inflammation [ ]. RA is characterised by synovitis and systemic inflammation secondary to autoantibody production particularly rheumatoid factor and citrullinated peptide. It is common, disabling and can have a significant impact on patients' quality of life [ ].

Current treatment strategies centre on the use of disease-modifying antirheumatic drugs DMARDs as a first line treatment [ - ]. However, these are agents are non-specific, may be associated with problematic side effects and disease flares occur despite such treatments. Advances in RA therapies have been considerable in recent years with a number of biological agents receiving approval. Although these biological treatments have demonstrated impressive efficacy in subsets of patients, their widespread use remains limited by cost and susceptibility to infection [ ].

Furthermore, not all patients respond to such treatments.

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Modern Therapeutics in Rheumatic Diseases (None) Modern Therapeutics in Rheumatic Diseases (None)
Modern Therapeutics in Rheumatic Diseases (None) Modern Therapeutics in Rheumatic Diseases (None)
Modern Therapeutics in Rheumatic Diseases (None) Modern Therapeutics in Rheumatic Diseases (None)
Modern Therapeutics in Rheumatic Diseases (None) Modern Therapeutics in Rheumatic Diseases (None)
Modern Therapeutics in Rheumatic Diseases (None) Modern Therapeutics in Rheumatic Diseases (None)
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