Overview Of Current Therapies For Rheumatoid Arthritis

Rheumatoid arthritis (RA) is an autoimmune disease whereby the immune system which normally protects the body from invading pathogens and foreign materials, attacks the joints between the bones. This occurs as the white blood cells of the immune system move into the joints and release cytokines, attacking the synovial membrane, the inner lining of the joint. As a result, this causes the synovium to thicken, forming an abnormal layer of tissue to grow over the surface of the inner joints. Swelling, inflammation and pain are responses to this process and if not attended to, the cartilage and bones inside the joint can be destroyed and the space between one bone and the next can become narrower, allowing the bones to rub against each other making it more difficult to move. Joints can become irreversibly deformed, losing their firmness, stability and flexibility. RA can affect most joints in the body, including that of the wrists, elbows, hands, ankles, knees and feet. The disease usually occurs symmetrically, meaning that if the right elbow is affected, the left elbow is likely affected also.

The causes of RA are unknown, although genetics and environmental factors such as trauma and exposures to chemicals are also considered to be triggers, as well as hormones. It is known that the abnormal reaction of the immune system is the main role in the inflammatory response but there is still uncertainty as to why the immune system reacts in this manner.

There is currently no cure for this chronic disease, but there are drugs such as Disease Modifying Antirheumatic Drugs (DMARDs) and Biological DMARDs (bDMARDs) that slow down the disease progression. The main aim of these drugs is to obtain the lowest level of disease action by maintaining the patient in remission, as well as reducing bone harm and improve quality of life and physical function of the patient. The use of these drugs depends upon many factors, including the stage of progression and severity of the damage. DMARDs, or conventional drugs, are often the first line treatment for mild to moderate RA and include methotrexate, sulfasalazine, hydroxychloroquine and leflunomid.

Methotrexate is often used first, as a low weekly dose and can be taken alone or in combination with one of the other conventional drugs but for active RA with significant functional impairment, triple therapy of methotrexate with sulfasalazine and Hydroxychloroquine is used. These agents should be commenced as soon as possible, as they are used to induce inflammatory remission and prevent joint damage. The response to these drugs should be within 12 weeks of use, and during that period of time, corticosteroids can also be used to aid in the reduction of the inflammation. The immunosuppressive and anti-inflammatory activities of the DMARDs often reasons for significant toxicities, hence, careful monitoring is required to identify adverse effects. If there is minimal response to DMARDs, or higher doses are not tolerated well, bDMARDs are then considered. They may be used as monotherapy or in combination with other DMARDs such as methotrexate, and they tend to work within 2 to 6 weeks. Biologics bind to Tumour Necrosis Factor (TNF) molecules and inhibit its activity, where these molecules are cytokines responsible for the inflammatory response. Etanercept, Adalimumab and Infliximab are examples of TNF inhibitors. As bDMARDs hinder with the immune system’s capability to battle infections, testing the patient for infections such as TB is critical before initiating treatment as there is an increased chance of reinfection.

Drugs used in conjunction with RA medications to control the symptoms such as pain and inflammation include Paracetamol, Corticosteroids, Non-Steroidal Anti-inflammatory Drugs (NSAIDs) such as ibuprofen, as well as COX-2 Inhibitors such as Celecoxib. In May 2018, Baricitinib (Olumiant), a new drug therapy was marketed for the treatment of moderate to severe RA unresponsive to monotherapy or combination therapy with the biological treatment. Baricitinib is a Janus Kinase (JAK) Inhibitor, blocking the subtypes JAK-1 and JAK-2. JAKs are enzymes inside the cells which conduct signals from cytokines that impact immune cell function. JAKs phosphorylate and activate STATs (Signal Transducers and Activators of Transcription) which regulate actions such as gene expression within the cell, at this point, Baricitinib inhibits the phosphorylation activity and hence prevents the initiation of STATs, controlling the immune reaction and hence the inflammatory process. Nevertheless, the significance of the blockage of JAK enzymes to therapeutic value is presently unknown.

Many clinical trials have been completed and in progress to provide evidence of this drug. As it has only been recently approved, it is still in Phase 2 of trials as of September 3rd, 2018, collecting initiatory figures on whether Baricitinib works in participants who present with RA, establishing the efficacy of the drug. In the journal Clinical Rheumatology, a randomised double blinded placebo study with varying doses was conducted for patients with active RA who have not responded well to other treatments. The study was completed over a course of 6 months and patients were assessed at 3-month intervals. The results showed that 18-20% of patients showed more than 20% improvement in tender and swollen joints as well as pain and a further 37-40% showed a 50% improvement, 28-30% showed a 70% improvement and 11-12% showed a 90% improvement. Overall, there is a solid increase in improvement in all patients trailed on Baricitinib.

Another randomised controlled trial conducted in the journal Experimental and Therapeutic Medicine, assessed the effectiveness of Baricitinib for patients with unresponsive RA, on a dose of 4mg daily for 3-6 months. The patients showed significant improvements compared to the placebo within and there were no adverse effects identified, until the latter 3 months. Overall, the study showed Baricitinib was beneficial in treating RA. Rheumatoid arthritis is an autoimmune disease whereby the body’s immune system attacks the joints causing irreversible bone damage. The causes of RA are unknown, and it is a lifelong progressive disease.

There is no current cure for RA, but there are drugs available that slow down the disease progression and the improve quality of life of the patient. Baricitinib is a new drug therapy for treatment of moderate to severe RA unresponsive to current therapies. Many clinical trials have been completed and are still in progress to deliver evidence of this drug. So far, these trials have shown that the drug is beneficial in patients and there is a marked improvement in their RA.