New Therapy in Rheumatoid Arthritis ˜ Biological DMARDs and JAK Inhibitors ˜

With the advent of biological disease modifying anti-rheumatic drugs (DMARDs) and Janus kinase (JAK) inhibitors as a new treatment for rheumatoid arthritis (RA), the treatment of RA has made a dramatic progress. The new treatment not only suppresses the joint swelling and tenderness but also it can maintain the function of daily life, further suppress joint destruction and aim for remission. Biological DMARDs and JAK inhibitor have the advantage that their effect is prompt and high efficacy is sustained over a long period of time, while disadvantages such as high risk of infection and high cost of treatment. Especially infection is serious side effect, but patients themselves should seek medical institutions promptly without missing a change in their physical condition, regularly conduct inspections even when there is no symptoms prevent infectious diseases in advance. It is important to have correct knowledge and share direction of treatment with their doctor.


Introduction
Rheumatoid arthritis (RA) is a disease that occurs mainly in women in their 40s and causes swelling and destruction of the peripheral joints. Although various studies are conducted around the world, the etiology is not clear. It has been used conventional non-steroidal anti-inflammatory drugs (NSAIDs) and disease-modifying anti-rheumatic drugs (DMARDs) including immunosuppressive drug. However, these treatments can not suppress joint destruction, and some patients have problems with daily life activities. The onset of RA accompanied by immune abnormality, as a factor that causes it, is being gradually elucidated smoking and involvement of periodontitis bacteria. In addition, some kind of cells and cytokines that are greatly involved in the disease state have been clarified, and a biological treatment that is a new treatment by controlling them has appeared, and the treatment of RA has dramatically progressed. In other words, not only clinical remission that can suppress symptoms but also functional remission that maintains function and improves quality of life, and structural remission that can suppress joint destruction as well. This article describes new therapeutic agents, biologic DMARDs and JAK inhibitors.

Pathophysiology of RA and new therapeutic agents
RA has the largest number of patients among rheumatic diseases, and research is being conducted to find out the cause around the world. It has long been known that RA patients are positive for rheumatoid factor, but rheumatoid factors are not always found only in RA patients, and may be found 34 Health Topics for Tokyoites in healthy people without RA. Recently, anti-cyclic citrullinated peptide antibody (anti-CCP antibody) has been shown to be useful as it has high sensitivity and high specificity as a blood test that is more useful for diagnosis 1) . The antigen of this anti-CCP antibody is a citrullinated protein, and it has been found that smoking and periodontal disease are related to the cause of this citrullination 2) 3) . In addition, genetic factors are also studied from the family history of RA, and association with HLA-DR4 (DRB1*0405) has also been reported 4) . Although research has been conducted toward such etiological investigations, the cause of the onset of RA has not been identified. However, the pathological conditions occurring in RA patients are gradually being elucidated. T cells activated by antigen presenting cells such as citrullinated peptides, produces proinflammatory cytokines such as TNFα (tumor necrosis factor alpha), IL-1 (interleukin-1), IL-6 (interleukin-6) through activation of B cells and macrophages. It has been clarified that this inflammatory cytokine causes synovial fibroblast proliferation, osteoclast proliferation and activation and joint destruction 5) . Then, biological agent has been developed as treatments targeting these inflammatory cytokines. The biological agent is a treatment that controls proteins present in the body using a biochemical approach, and the first developed RA is an antibody or receptor that neutralizes inflammatory cytokines.
In addition, fusion proteins have been developed which suppress the costimulatory signal between T cells and antigen presenting cells that are the origin of inflammation. Also, as new treatments, inhibitors of tyrosine kinases involved in intracellular signals after binding of these inflammatory cytokines to synovial cell and osteoclast receptors have been developed, and are as effective as biological agents 6) .
Among the TNF inhibitors, infliximab, adalimumab, golimumab and certolizumab are antibody against TNFα and etanercept is a receptor which binds to TNFα. Both exert an effect of suppressing inflammation by binding to and neutralizing TNFα. Infliximab is administered in infusion while other TNF inhibitors are in subcutaneous injection.    Infliximab must be combined with methotrexate, also known as an anchor drug, however other TNF inhibitors are basically considered to be more effective when combined with methotrexate 7)-9) . Unlike TNF inhibitors, IL-6 inhibitors are thought to have the same efficacy with and without methotrexate 10) , and can be expected to be highly effective in patients who can not use methotrexate.
Abatacept provides costimulatory regulation between T cells and antigen presenting cells that trigger inflammation to occur. A fusion protein of CTLA4 (cytotoxic T lymphocyte association antigen 4) that suppresses T cell activation and the FC portion of human immunoglobulin IgG1, and is competitively inhibited by binding to CD28, leading to suppress the stimulus 11) . In case of infusion, abatacept is administered 0, 2, 4 weeks and every 4 weeks thereafter, and for subcutaneous injection, it is administered every week. All biologic agents have been reported to shown approximately equivalent efficacy, and not only improve symptoms and data, but also show the effect of suppressing joint destruction. With the advent of these biological agents, it has become possible to treat RA in a remission, that is, aiming for a state equivalent to a cured state.

JAK inhibitors
Although the treatment of RA has made great strides with the advent of biologic agents, it has not led all RA patients to happiness. TNF inhibitors are not effective in about 30% of RA patients, and only 30 to 50% of patients lead to remission. In addition, although biological agents are administered by infusion or subcutaneous injection (self-injection), administration may be difficult in patients with deformed finger joint, and administration may be hampered by fear of self-injection. Development of an orally administrable and inexpensive antirheumatic drug has been desired. In recent years, inhibitors targeting Janus kinase (JAK), which is a tyrosine kinase important for intracellular signaling of inflammatory cytokines, have been developed and their efficacy has been shown. After binding of the cytokine to the receptor, the JAK family is activated in the cell to activate STAT, which is a downstream transcription factor, to cause production of inflammatory cytokines and proliferation of synoviocytes and osteoclasts. The JAK family includes JAK1, JAK2, JAK3 and TYK2, and JAK inhibitors used for rheumatoid arthritis selectively inhibit JAK3 with tofacitinib (Xeljanz ® ) and JAK1/JAK2 with baricitinib (Olumiant ® ). Both show high efficacy, high continuation rate, and the effect is considered to be equivalent to that of biologic DMARDs.

The problems of new treatment
As mentioned above, biologic DMARDs and JAK inhibitors show high efficacy in the treatment of RA, and the goal of treatment is not only clinical remission (suppression of joint swelling and pain) but also functional remission (joint maintain their function and improve the quality of life), and even structural remission (suppressing joint deformity and destruction). However, it can not be administered to all RA patients, the risk of infection as a side effect is increased, and it is expensive.
Although TNF and IL-6 are cytokines that cause inflammation, they also play a role in protection against infections as another function. Therefore, suppressing these increases the risk for infections including pneumonia 12) . It is necessary to search for infectious diseases before starting biologic DMARDs and JAK inhibitors. Among them, tuberculosis is one of the infections to be noted, and confirm the history of tuberculosis infection by using a chest x-ray, chest CT, T-SPOT, and if it is suspected of previous infection, certain infection prevention by isoniazid doses need to be administered for a period of time. For Non-tuberculous mycobacterial disease, it is recommended that these therapeutic agents should not be administered because there is no currently established effective antimicrobial treatment, but the benefit from administering the therapeutic agents outweighs the risks. If determined, administration may be considered in conjunction with a respiratory specialist. In addition, Pneumocystis jirovecii infection may develop, so if there are risk factors such as elderly aged, oral corticosteroid intake, or existing lung disease, take sulfamethoxazole and trimethoprim to prevent it, and during administration, βD glucan, KL-6, chest x-ray must be checked appropriately. Furthermore, in recent years, reactivation of hepatitis B virus has become problem. Normally, when hepatitis B virus infects hepatocytes, double stranded closed circular DNA remains in the cell during its replication process. Therefore, HBs antigen-negative and HBc antibody or HBs antibody-positive HBV-infected persons are also considered to be equivalent to carriers with HBs antigen persistent positive at the gene level. When immunosuppression / chemotherapy is given to an HBV carriers, the serum amount of HBV-DNA increases, the immunological balance breaks down during or after treatment, and fetal severe hepatitis may develop 13) . This is called HBV reactivation and has also been reported in biological DMARDs for RA. Therefor, before starting immunosuppressive therapy including a biological DMARDs, HBs antigen is measured, and if it is positive, consult a hepatologist and consider treatment with a nucleic acid analogue. Even if HBs antigen negative, HBs antibody and HBc antibody are measured, and if positive, HBV-DNA quantitative test is performed. If it is less than the detection sensitivity, treatment can be performed while monitoring HBV-DNA regularly. Post-marketing surveillance has shown that with JAK inhibitors, the incidence of herpes virus infection is greater than with other agents, and caution is needed in patients who have already recurred.
Another problem is that it is expensive. The cost of biological DMARDs and JAK inhibitors is approximately 35,000 yen to 45,000 yen per month, and some patients can not introduce these treatments due to economic problems. However, joint destruction in rheumatoid arthritis is irreversible, and it may be necessary to resign work from joint deformation due to inadequate treatment, and it may require surgery. When it is necessary to intensify treatment, such as when the disease activity is high, it is important to give new treatment (with the patientʼs consent, of course).

Conclusion
With the advent of biologic DMARDs and JAK inhibitors, the treatment of RA has made great strides. The early diagnosis using joint ultrasonography and MRI, and the administration of methotrexate, biological DMARDs and JAK inhibitors have led to the era of remission. However, there are also problems such as infections, which require careful use.