Rheumatoid Arthritis: Risks and Benefits of Latest Treatments

Introduction

Rheumatoid arthritis (RA) is a form of arthritis characterized by swelling and tenderness; recent studies have revealed that approximately 1% of adults suffer from this condition. A common symptom is symmetric polyarticular inflammation of the synovium, typically affecting the small joints of the hands (MCP and PIP), wrists, and feet. This swelling causes discomfort and difficulty of movement and can result in gradual joint injury characterized by deformity and disability.

The major compound used in treating RA is methotrexate (MTX). This compound has been used for over 40 years in treating various types of rheumatic diseases and remains one of the most effective treatment methods for RA. Its combination with modern treatments that address disorders of the immune system — conditions treated by biological DMARDs — has transformed the approach to managing RA. This review provides a concise analysis of the risks and benefits of various therapies for rheumatic diseases, with emphasis on rheumatoid arthritis.

Bird and Littlejohn (2014) found that the earliest documented application of methotrexate was largely unnoticed, yet that moment marked the beginning of MTX's journey to becoming a widely accepted modern medication for rheumatic diseases. This journey from obscurity to prominence took the better part of thirty years; however, MTX eventually became a standard treatment for rheumatic conditions. The exact mechanism by which MTX treats rheumatic diseases remains incompletely understood. The most widely held belief is that MTX inhibits de novo pyrimidine and purine synthesis, thereby halting lymphocyte proliferation. Other proposed mechanisms include increased apoptosis of T cells, modification of the expression of cellular adhesion molecules, a surge in the release of the endogenous anti-inflammatory compound adenosine, and anti-angiogenesis effects via indirect mechanisms such as disruption of macrophage interaction (Bird & Littlejohn, 2014).

Methotrexate: Efficacy and Safety Profile

The effectiveness of MTX in treating RA is well established. In addition to reducing the signs and symptoms of RA, it slows the progression of joint damage, improves quality of life, and reduces mortality rates. Notably, combining MTX therapy with anti-TNF agents has been shown to produce greater positive effects than applying anti-TNF agents alone. This finding reinforces the view that, despite new technologies developed to treat RA, MTX remains an important treatment for a large number of patients (Bird & Littlejohn, 2014).

Several concerns have been identified regarding the safety of MTX use in treating rheumatic disease. These concerns are addressed below using a risk-benefit framework.

Psychological side effects of MTX include fatigue, headaches, and reduced alertness. These adverse effects may limit treatment escalation but can be mitigated by supplementation with folic acid (Bird & Littlejohn, 2014).

The most common gastrointestinal side effects include mucositis, mouth ulceration, nausea, and diarrhea. These do not occur frequently because they are largely prevented by proper use of folic acid supplements and can be resolved by reducing or discontinuing the medication (Bird & Littlejohn, 2014).

Side Effects of Methotrexate

Weekly administration of low doses of MTX can have adverse effects on the liver; reversible transaminase elevation, liver fibrosis, and liver cirrhosis are the most commonly reported. In practice, however, reversible transaminase elevation is the most frequently recorded outcome, while fibrosis and cirrhosis are rarely seen — largely because their known precursors, such as excessive alcohol intake or pre-existing liver disease, can be identified in advance. Patients on low-dose MTX are routinely monitored for transaminase levels, and decisions to reduce or discontinue the drug are made based on the degree of elevation (Bird & Littlejohn, 2014).

A very rare side effect — occurring in approximately 0.08% of treated patients — is lung disease, which may occur in patients on MTX treatment alone or in combination with other medications. Additional factors that increase susceptibility to MTX-induced lung damage include pre-existing interstitial lung disease (ILD), cigarette smoking, and low body weight (Bird & Littlejohn, 2014).

Small weekly doses of MTX provide effective, low-cost, and widely accepted treatment for RA. Medical personnel, however, must be well versed in the risks associated with its administration and remain vigilant in monitoring for them (Bird & Littlejohn, 2014).

Kahlenberg and Fox (2011) noted that over the preceding two decades, treatment mechanisms for RA had been transformed by new knowledge of its systemic processes and by the development of drugs that target those processes. These newer drugs have proved highly effective in improving treatment outcomes but are also associated with side effects that can create lasting management challenges and complications when surgery becomes necessary.

RA is a well-recognized disease associated with joint damage and disability resulting from inflammation and tenderness. Therapy methods developed on the basis of advanced disease knowledge have produced significant advances in treatment. The sustained use of DMARD and biological DMARD therapies has produced encouraging outcomes, including improved joint function and reduced joint damage. However, these drugs also carry certain side effects and long-term consequences. A thorough understanding of these drawbacks will help ensure the best possible treatment in both medical and surgical settings (Kahlenberg & Fox, 2011).