Biologic Agents for the Treatment of Rheumatoid Arthritis

Maria Victoria Hernandez MD, PhD
Medical Director, Rheumatology – Medical Affairs

OCTOBER 9, 2018

Rheumatoid arthritis (RA) is a chronic, inflammatory, autoimmune disease affecting around 1.5 million people in the USA and 0.5-1% of adults worldwide. RA primarily affects adults between the ages of 40 and 60, with a female to male ratio of 3:1.

Although the etiology of RA is unknown, studies in RA twins suggest that genetic factors may contribute to around 50% of the predisposing factors, with the rest due to environmental factors, including smoking, various microbial agents such as Porphyromonas gingivalis, and asbestos/silica exposure.

RA is characterized by bilateral, symmetrical polyarthritis due to persistent synovial inflammation, affecting multiple joints, with the small joints of the hands and feet the most frequently involved. Approximately two-thirds of RA patients have serum autoantibodies (rheumatoid factor (RF) or anti-citrullinated protein antibodies (ACPA)), with ACPA being the most specific serological marker of RA.

This persistent synovitis leads to different degrees of joint destruction and deformities that may cause permanent disability affecting the quality of life and work productivity, with an impact on physical and mental functions. High disease activity and erosive disease at disease onset has been associated with a more severe disease course and poor outcome. Patients may suffer joint damage in as little as 3-6 months after onset.

RA patients also have a lower life expectancy than the normal population, mainly due to the development of cardiovascular events caused by the rheumatoid inflammation.

Thus, RA is a condition with a high social and economic cost and early disease diagnosis and treatment is crucial to avoid joint damage and disability.

Initiation of effective antirheumatic treatment in the early phases of RA plays an important role in better disease outcomes (‘window of opportunity’). To facilitate the diagnosis of RA in the early phases of the disease a new classification criterion for RA diagnosis was developed in 2010 by a consensus between the ACR and EULAR scientific societies.

Management and treatment strategies for RA have changed substantially during the last decade. Currently, the goal for RA treatment is to achieve clinical remission (absence of joint pain and inflammation) or low disease activity, in which inflammation is minimized, joint damage prevented, and general symptoms alleviated.

Nowadays, remission is a realistic goal in many RA patients due, in part, to the advent of a new class of drugs known as biologics, which has revolutionized the treatment of RA. Moreover, new therapeutic strategies for RA focused on achieving RA remission (‘treat-to-target strategy’), and using close, proactive disease monitoring, the so called “tight control,” have also contributed to achieving better results with higher remission rates than routine disease monitoring.

To evaluate the response to a specific RA treatment, valid and standardized methods are needed. The most commonly used are composite indices, including the Disease Activity Score (DAS), the Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI). The DAS28, which uses a reduced 28-joint count, is also a widely-used index for the assessment of disease activity. These indices are useful in both clinical trials and clinical practice.

Patient reported outcomes (PRO) are self-administered questionnaires commonly used in RA patients to evaluate the effect of the response to a specific treatment on functional disability (HAQ), quality of life (SF-36) or fatigue (FACIT), among others.

RA treatment is based on the very-early introduction of effective anti-rheumatic therapy at disease diagnosis. Currently, the initial treatment recommended is conventional synthetic disease-modifying anti-rheumatic drugs (cs-DMARDs), mainly methotrexate (MTX), sulfasalazine or leflunomide. MTX is the most widely-used cs-DMARD and is part of virtually all current RA treatment strategies, considered as the “gold-standard.”

However, around 30% of RA patients may not respond (primary or secondary inefficacy) or have intolerance to cs-DMARDs. New biological agents have shown efficacy in RA patients refractory to MTX or other cs-DMARD, revolutionizing RA treatment.

Biologic DMARDs (b-DMARD) are complex molecules, including both monoclonal antibodies and fusion proteins, which work by targeting individual molecules involved in the inflammation process that cause damage to joints.

Several of these biologics, known as anti-TNF drugs, target a protein called tumor necrosis factor (TNF) that causes inflammation, pain and damage to the joints. There are five TNF inhibitors (TNF-i): infliximab, etanercept, adalimumab, golimumab and certolizumab.

B-DMARD are usually administered alongside a cs-DMARD.

In addition to TNF-i, other biological agents target specific cells, including rituximab (B-cell depletion) and abatacept (inhibiting the co-stimulatory signal of T-cell activation), or block cytokines pathways such as IL-6, including tocilizumab and sarilumab (anti-IL6 receptor).

Recently, a new type of drugs for RA patients has become available: JAK (Janus kinase)-inhibitors. These agents, called target synthetic DMARDS (ts-DMARD), are small molecules that inhibit one or more enzymes of the JAK family (JAK-1, JAK-2, JAK-3 or TYK-2), blocking the JAK-STAT signaling pathway, which plays a critical role in RA. Currently, there are two JAK inhibitors available: tofacitinib (blocking JAK-1 and JAK-3), and baricitinib (blocking JAK-1 and JAK-2).

The forthcoming treatment era in RA may involve novel therapeutics targeting molecules inhibiting or regulating other cytokines, factors or cells, such as IL-33, the human granulocyte macrophage colony-stimulating factor receptor (GM-CSF-R), synovial fibroblast cells, or angiogenic factors.

Personalized medicine looks toward inventive combinations of therapeutics. As is being seen in breakthrough cancer treatments, the treatment of RA will follow a similar route. There are still many obstacles to overcome, such as fully understanding the disease pathogenesis. However, novel strategies targeting multiple pathways and the identification of disease-specific genes will offer patients a more tailored approach to the treatment of this progressive and debilitating illness.