Fall 2011
Advances in rheumatoid arthritis

synapse: University of Nevada, Reno School of Medicine

Ewa Olech looking at x-ray

Ewa Olech, M.D., looking at a patient x-ray.

Ewa Olech, M.D. is a rheumatologist and scientist, researching rheumatoid arthritis and new therapies for the disease.

Interview by Edgar Antonio Nunez

In the past 10 to 15 years, several effective biologic agents have been approved for rheumatoid arthritis. These have revolutionized the treatment of the disease. Despite advances in rheumatoid arthritis management, new drugs continue to be developed and studied in clinical trials.

Synapse: What is rheumatoid arthritis and what are the symptoms of this disease?

Olech: Rheumatoid arthritis is a chronic, autoimmune disease causing inflammation of the joints with results of pain, swelling and subsequent joint damage. This usually leads to long-term disability. While it is not as common as osteoarthritis, this disease is still quite prevalent.

Almost one percent of the population is affected with this disease. Onset usually occurs between 30 and 50 years of age, but it can affect anyone, including children. Rheumatoid arthritis is more common in women. About 70 percent of people with rheumatoid arthritis are women.

Rheumatoid arthritis can affect any joint, but it most commonly begins in the smaller joints of the hands, wrists and feet. Joint involvement is usually symmetrical. Other common physical symptoms include:

  • stiffness, particularly in the morning and when sitting for long periods of time;
  • weakness;
  • fatigue;
  • flu-like symptoms, including a low-grade fever and night sweats;
  • loss of appetite and subsequent weight loss;
  • depression;
  • anemia;
  • dry eyes and mouth;
  • approximately one-fifth of people with the disease have rheumatoid nodule; and
  • occasionally, though rarely, patients with severe rheumatoid arthritis have other extra-articular joint manifestations.

Synapse: What is the impact of rheumatoid arthritis on patients and society?

Olech: Rheumatoid arthritis is usually a progressive disease, which means that over time it can cause irreversible damage to the joints. The damage starts when the immune system begins to attack the joints. As time passes, joint cartilage breaks down, narrowing the joint space until there's nothing left but bone rubbing against bone.

In addition to cartilage, tendons and ligaments may be damaged and the bones can also erode. All these processes result in deformities and instability of the joints, which can lead to limited range of motion and difficulties in daily tasks: opening jars, combing hair, buttoning a shirt or grasping a fork.

There are several published studies showing that joint destruction seen on radiographs strongly correlates with patients' disability.

Rheumatoid arthritis frequently leaves a person unable to maintain a full-time, paid job. Studies have shown that about half of all patients employed at disease onset leave the workforce within 10 years. Many employees with rheumatoid arthritis either change their job or pursue a different career altogether.

In surveys, researchers found that over a three-month period, employees with rheumatoid arthritis took off an average of two to three weeks from work. Fortunately, with more aggressive and early treatment, especially with biologic agents, this rate of work disability is currently on the decline.

Synapse: How is rheumatoid arthritis diagnosed?

Olech: A diagnosis of rheumatoid arthritis is made from a medical history, a physical exam, lab tests and traditionally x-rays of the small joints of hands and feet.

Since patients who have joint destruction visible on x-ray are more likely to become disabled due to their rheumatoid arthritis, joint imaging is very important. However, standard x-rays are limited in finding bone changes. One of the advancements in the care for patients is increasing use of modern imaging techniques, such as MRI or ultrasound.

The studies are showing that these imaging techniques are much more sensitive than x-ray in finding rheumatoid arthritis changes and these allow physicians to find the changes earlier. This would mean earlier treatment.

There are multiple studies that have shown that early diagnosis and treatment is better for patients and it can prevent joint damage and subsequent disability.

Synapse: What are the current therapies for rheumatoid arthritis?

Olech: Unfortunately, we don't have drugs to cure rheumatoid arthritis, but we have now many medications to manage the pain and slow or even stop the progression of this disease. Over the past decade it has been easier than ever to control rheumatoid arthritis through the use of new biologic drugs.

The goals of drug treatment for rheumatoid arthritis include:

  • reduction of inflammation and symptoms of pain and swelling;
  • prevention of damage of the joints;
  • joint movement preservation;
  • prevention of disability; and
  • being free from side effects as possible over the long-term.

The main drugs used for treating rheumatoid arthritis are disease-modifying anti-rheumatic Drugs or DMARDs. They can be divided into traditional and conventional DMARDs, methotrexate is the most commonly used, and biologic response modifiers biologic DMARDs. DMARDs may be used alone or in combination.

The tumor necrosis factor or TNF alpha blockers/inhibitors were the first of the biologic drugs approved for treatment. They modify or block TNF, a destructive immune factor

Inflximab and etanercept, followed by adalimumab, were the first TNFalpha blockers.

Subsequent to TNFalpha inhibitors, new agents with different mechanisms of action became available. These included rituximab, which targets CD20-positive B cells; abatacept, the T cell co-stimulation modulator; and most recently tocilizumab anti IL6 receptor inhibitor.

In addition, two newer generation antiTNFalpha blockers have been recently approved, certolizumab pegol and golimumab. We also have an interleukin-1 antagonist available, though not much used, anakinra.

All of these give us a total of nine biologic DMARDs approved for rheumatoid arthritis.

Synapse: What are the new emerging treatments for rheumatoid arthritis?

Olech: Here is what's on the horizon. First, new formulation of existing biologic agents. The flexibility and convenience of subcutaneous medications over the intravenous approach, has led to exploring subcutaneous forms of two currently approved intravenous drugs, abatacept and tocilizumab. Subcutaneous abatacept has recently been approved. Tocilizumab studies are currently ongoing.

Second, a newer-generation of existing drug technology and targeted pathways. Because of the success of rituximab in the treatment of rheumatoid arthritis, which has highlighted the significance of B cells in the pathogenesis of rheumatoid arthritis, we are witnessing development of several other anti-B cell therapies.

Atacicept is a human recombinant fusion protein that prevents certain cytokines, important in the regulation of B cell function, from binding to their receptors on B lymphocytes. Therefore, this compound is related to rituximab, yet targets alternative components of the B cell pathway.

Additionally, newer generation, fully human anti-IL-6 receptor antibody, and antibodies against IL-6 itself, are currently in development. They may be potentially more efficacious and safer blockers of IL-6 pathway than tocilizumab.
Three, new targets. Anti-IL17 antibody is one of them. Other new targets in early stage of development are regulatory T cell activation agonist, granulocyte colony-stimulating factor (GCSF) and granulocyte-macrophage colony-stimulating factor (GMCSF) antagonists.

And four, small molecules. These are drugs of small molecular weight that share highly potent biological action targeting cellular structures and intracellular signaling proteins. Compared with biologic drugs, the manufacturing time is shorter so they are more cost-effective therapies. Plus the fact that they are oral makes them even more attractive.

Protein kinase inhibitors have received most attention recently for the treatment of rheumatoid arthritis, in particular janus kinases or JAKs, spleen tyrosine kinase or SyK, and p38 mitogen-activated protein kinases or MAPK. Initial trial results with new JAK and SyK inhibitors look very promising.

Synapse: You recently joined the University of Nevada School of Medicine in Las Vegas as faculty. What are your goals in regards to rheumatoid arthritis patients?

Olech: Currently, we are in the process of starting a large rheumatoid arthritis clinical trial program at the medical school in Las Vegas, where patients will have an opportunity to try these new therapies earlier while still in studies, and at the same time, they will be able to contribute to the development of these medications.

Improvements in drug technology and a greater understanding of underlying mechanisms are leading to the continued emergence of novel drug therapies. These are exciting times.

I tell my patients, while there is never good time to have rheumatoid arthritis, this is the best time. Due to the advancement in research and drug development, more and more people with rheumatoid arthritis are living happier, healthier and basically normal lives.