**Abstract**

Rheumatoid arthritis (RA) is a progressive autoimmune inflammatory disorder characterized by cellular infiltration in synovium causing joint destruction and bone erosion. The heterogeneous nature of the disease manifests in different clinical forms, hence treatment of RA still remains obscure. Treatments are limited owing to systemic toxicity by dose-escalation and lack of selectivity. To overcome these limitations, Smart drug delivery systems (SDDS) are under investigation to exploit the arthritic microenvironment either by passive targeting or active targeting to the inflamed joints *via* folate receptor, CD44, angiogenesis, integrins. This review comprehensively deliberates upon understanding the pathophysiology of RA and role of SDDSs, highlighting the emerging trends for RA nanotherapeutics.

**Keywords:** smart drug delivery systems, active & passive targeting, Stimuliresponsive nanoparticles, polymer-drug conjugates, Arthritic microenvironment

### **1. Introduction**

Rheumatoid arthritis (RA) is an autoimmune-mediated systemic, chronic inflammatory disorder characterized by progressive inflammation of joints, cell infiltration, pannus formation, synovial dysplasia resulting in cartilage destruction and bone erosion [1]. The worldwide prevalence rate of RA in adult population has been predicted between 0.5–1% and 0.92% in India [2]. Generally, prevalent in women when compared to men (3,1) at any age group. According to recent statistics given in 2019 by the Global RA network and WHO, 23 million people are affected by RA, globally [3]. RA etiology is implicated to be linked to metabolic, genetic, environmental factors, and life style of the patient [4]. While it is considered non-lethal, RA is debilitating and severely compromises the quality of life, further reducing life expectancy in patients.

Despite tremendous progress in evolving efficient pharmacological molecules for RA therapy, their efficacious delivery at the diseased joint remains a long-lasting challenge. Over the last two decades, disease-modifying anti-rheumatic drugs (DMARDs: such as methotrexate (MTX), hydroxychloroquine (HCQ ), sulfasalazine (SSZ), leflunomide (LFM), have attracted attention for effective attenuation of disease progression. Patient compliance is the primary treatment goal with glucocorticoids(GCs); e.g., prednisolone, dexamethasone, hydrocortisone, triamcinolone acetonide, and NASAID (such as ibuprofen, diclofenac, indomethacin etc) result in reducing pain and curbing disease progression [5]. Unfortunately, the associated toxicity caused by dose-escalation and long-term use with undesirable side-effects are limiting the therapeutic success. Continued medication of NSAIDs causes gastro-intestinal and renal toxicity; glucocorticoids cause hypertension, hyperglycemia, muscle wasting, osteoporosis, etc.; nausea and vomiting are common side-effects of conventional DMARDs, including gastro-intestinal irritations, headaches, insomnia, cytopenia, skin and hair damage, etc.; giving biologicals run the risk of anaphylaxis, infections, malignancy, psoriasis and other autoimmune disorders [6, 7]. Biosimilars/biologicals/Biological response modifiers like infliximab, adalimumab, rituximab etc. that have approval of Food and Drug Administration (FDA), were considered for their selective site-specific action, achieved extensive success in clinics for RA treatment. Prior reports suggest combination therapy with biologics, and synthetic DMARDs were found to be highly effective [8].

To circumvent the off-target drug induced systemic toxicity, direct drug delivery *via* the intra-articular injection to the affected joints was explored. Nevertheless, this mode of administration has several limitations, as it necessitates repeat injections in the joint, risk of infection, and joint disability. Therefore, a concerted effort for development of novel therapies are clearly warranted with a focus on targeting the inflamed joints.

Nanotherapeutics has emerged as an innovative approach enabling efficient delivery of drug for mitigating several diseases. The past decade, has seen an avalanche of publications that have increased our understanding of the pathophysiology of the affected synovial tissue in RA and equivalent progress in nanotechnology and material chemistry, generating tremendous interest in developing Smart drug delivery system (SDDS). Entrapping the anti-inflammatory drugs in SDDS strategically has potential to overcome all the barriers of normal delivery, projecting it as a promising option for site-specific delivery. Currently, RA targeting nanotherapeutics has progressed rapidly because the inflammatory microenvironments of arthritic joints mimic the tumor environment that has typical angiogenic features of neo-vessels coupled with impaired peripheral lymphatic drainage [9, 10]. This review comprehensively deliberates upon the understanding the pathophysiology of RA and role of SDDSs, highlighting the emerging trends for RA nanotherapeutics.

#### **2. RA microenvironment**

Chronic inflammation is the hallmark of RA that advances to destructive synovitis [11]. It develops in a genetically susceptible person largely due to environmental factors and related epigenetic mechanisms [12]. It predominantly indicates leukocyte infiltration, dysregulated angiogenesis, proliferation of lining layer, that alters the synovial tissue into an invasive pannus. The microvasculature of synovium is dysregulated, hence, in spite of enhanced flow of blood, the increased metabolic needs outdo the vascular blood supply, thereby creating an intense hypoxic microenvironment. However, rheumatoid factor (RF) and anticitrullinated peptide

*Smart Drug-Delivery Systems in the Treatment of Rheumatoid Arthritis: Current, Future… DOI: http://dx.doi.org/10.5772/intechopen.99641*

antibodies(ACPA) are induced and must exist before the onset of this disease. The heterogeneous nature of the disease manifests in different clinical forms, hence treatment of RA still remains obscure. It is well documented that synovial microenvironment has abundance of macrophages, multifaceted crosslink of immune cells secreting granulocyte colony-stimulating factor, pro-inflammatory cytokines, tumor necrosis factor(TNF-α), interleukin (IL-1), IL-6, chemokines, and degrading like MMPs that are particularly responsible for RA pathogenesis [13, 14]. **Figure 1** illustrates the network of cytokines secreted by multitude of cells involved in RA development that can be useful for assessment of disease progression along with biomarkers present on these cells.
