Psoriatic disease is a systemic inflammatory disease, and is complicated by various pathologies other than skin and musculoskeletal conditions, including steatohepatitis. In particular, psoriatic diseases have a high risk of death from cardiovascular disease, and psoriatic arthritis has a significantly higher risk than psoriasis vulgaris. Enthesitis is reflected as a patient-reported outcome（PRO）and is significantly involved in QOL impairment in psoriasis patients. For these reasons, the degree of satisfaction with the treatment of psoriatic diseases is still low, and aggressive systemic therapeutic intervention from an early stage is desired. Although there are several treatment recommendations for psoriatic diseases, the final choice of therapeutic agent is left to the physician. IL-23 inhibitors are effective not only for skin lesions and enthesitis, but also for peripheral arthritis. It has also been reported that it may suppress the onset of psoriatic arthritis in psoriasis patients, and it is considered to be a drug that should be considered from an early stage.

To date, 5 JAK inhibitors are available in Japan, and post-marketing surveillance（all cases）during 6-month observation has been completed and reported for tofacitinib and baricitinib. Because the major infections often occur within a relatively short period after initiation, Japanese evidence regarding infections has been established for these two drugs. As a result, when used in accordance with the guide or instructions provided by the Japanese Society of Rheumatology, the frequency of serious infections does not increase compared to biological antirheumatic drugs, but the development of herpes zoster is frequent. Elderly patients, use of glucocorticoids, and a history of herpes zoster infection have been suggested as risk factors for herpes zoster development. In serious infections, it is also necessary to pay attention to the lymphocyte count. Rheumatologists should keep such risk factors in mind. In addition, if glucocorticoids are being used, they should be reduced to the minimal dose and then discontinued. Also, administration of pneumococcal and/or shingles vaccines is strongly recommended. To reduce the severity and frequency of infectious diseases, selecting appropriate patients for JAK inhibitors is most important.

Rheumatoid arthritis is a systemic autoimmune disease with persistent inflammation primarily characterized by synovitis and joint destruction. Because joint damage progresses rapidly after onset, resulting in irreversible physical dysfunction and deformation of the affected joints, proper diagnosis and treatment are required from the early stages of the disease. The standard treatment of rheumatoid arthritis should be initiated by methotrexate if it is not contraindicated. However, in patients with inadequate responses to methotrexate, the addition of biological DMARDs or Janus kinase（JAK）inhibitors is recommended. The JAK proteins and STAT transcription factors mediate intracellular signal transduction at the downstream of cytokine receptors, which are implicated in the pathological processes of rheumatic diseases. JAK inhibitors, including tofacitinib, baricitinib, peficitinib, upadacitinib and filgotinib, are used for the treatment of rheumatoid arthritis and differ in their selectivity for different JAK isoforms. Although they are orally administered drugs, they have multi-target effects based on the inhibition of intracellular signaling and exert clinical effects just as promptly and strongly as biological DMARDs. JAK inhibitors should not be used without careful consideration as they are orally administered drugs with multi-target effects. Screening of risk factors and the indication before their use and monitoring adverse events during the treatment should be strictly performed for infection, cardiovascular disorders, thrombosis, malignancies and many.

While tofacitinib was the initial oral medication to exhibit similar efficacy to that of biological disease-modifying anti-rheumatic drugs, it was also the first JAK inhibitor to exhibit increased herpes zoster（HZ）, and could not demonstrate non-inferiority to TNF inhibitors in regard to safety. The ORAL Surveillance study（OS study）was launched during the ENTRACTE study, which aimed to demonstrate non-inferiority of an IL-6 inhibitor in comparison to a TNF inhibitor in regard to safety. The OS trial also had the identical aim for a JAK inhibitor in comparison to a TNF inhibitor. Although both drugs are known to cause dyslipidemia with no substantial increase in cardiovascular events in clinical trials, a new approach was adopted to prove the safety of the drug. Non-inferiority was observed for the IL-6, but not for the JAK inhibitor. It is essential to note that the TNF inhibitor was used as a control treatment and not as an indicator of a safe drug. Although there has been a growing concern on cardiovascular events in the Western world, the OS trials have revealed that when RA patients with active disease and high risk who receive regular or excessive doses of tofacitinib are more likely to develop malignancies. A recent study from Japan suggests that mortality decreased by one-tenth in patients who underwent CT screening during biologic agent induction rather than those who received only plain radiographs. This indicates the potential for deploying molecular-targeted therapy with enhanced safety in Japan, as CT is more prevalent compared to Western nations. Subunit vaccines are highly efficacious to prevent herpes zoster and require strategizing efforts to facilitate immunization while considering financial strain of the patient.

Baricitinib is a molecularly targeted synthetic anti-rheumatic drug（tsDMARD）targeting JAK1/2. Results of phase III clinical trials using baricitinib for rheumatoid arthritis（RA）have shown feasible efficacy and tolerable safety in patients who showed inadequate response to biological DMARDs（bDMARDs）as well as conventional synthetic DMARDs such as methotrexate（MTX）. In particular, baricitinib is the first JAK inhibitor to show significantly higher clinical efficacy than TNF inhibitors for MTX-refractory RA. In Japan, baricitinib 4 mg once daily orally is approved for the treatment of RA, atopic dermatitis, alopecia areata and pneumonia caused by SARS-CoV-2. Approximately 70% of this drug is renally excreted and the dose should be reduced to 2 mg or avoided for patients with renal dysfunction. Serious side effects of baricitinib include infection, gastrointestinal perforation, lymphopenia, liver dysfunction and interstitial lung disease. Since serious infections occur at a rate similar to other bDMARDs, the patients should be monitored carefully and regularly for adverse effects. Although JAK inhibitors are potent therapies for RA, more cautious consideration and measurement for their risk-benefit ratio are needed, after considering the safety results of ongoing post marketing surveillance.

Peficitinib is a Janus kinase（JAK）inhibitor, that was developed and approved for rheumatoid arthritis（RA）in Japan. Among five kinds of JAK inhibitors approved for RA in Japan, pefecitinib has a unique feature that demonstrates the inhibition of all kinds of JAK molecules. i.e JAK1, JAK2, JAK3 and Tyk2. Plasma concentration of peficitinib is similar between individuals with normal and impaired renal function, so dose adjustment based on renal function is not needed. To date, there are three phase 2b trials（RA21, RA22, RAJ1）and two phase 3 trials（RAJ3, RAJ4）conducted in global and Asia. In the phase 2b trials conducted in global, pefecitinib could not demonstrate the superiority due to high ACR20 response rate in the placebo group. In the phase 3 trials conducted in Asia, both the peficitinib 100 mg/day and 150 mg/day showed significant improvement in ACR20, 50, 70 response compared to the placebo group. In addition, RAJ4 trial showed the superiority on suppressing joint destruction. Regarding safety, the incidence of herpes zoster was comparable with other JAK inhibitors. The long-term safety for malignancy and major adverse cardiovascular events needs to be further investigated in the future.

Upadacitinib is a small molecule compound that is highly selective for JAK1 and is approved in Japan for the treatment of rheumatoid arthritis, spondyloarthritides, inflammatory bowel diseases, and atopic dermatitis. Since the daily dosage ranges from 7.5mg to 45mg depending on the disease and patient’s condition, it is expected to be of great help in understanding the relationship between efficacy/safety and dosage. Although the drug has shown efficacy in patients refractory to multidrug therapy, as with other JAK inhibitors, herpes zoster and other infectious diseases should be kept in mind. However, there is no evidence to date to suggest that upadacitinib increases the risk of cardiovascular events or malignancy.

Filgotinib is a novel JAK1 preferential inhibitor with high clinical and radiographic efficacy, a favorable safety and tolerability profile, and few drug-drug interactions. This review focuses on the results from basic research and clinical trials on filgotinib, which may have an impact on unmet needs in the treatment of rheumatoid arthritis, such as difficult-to-treat rheumatoid arthritis, rapid radiographic progression, precision medicine, JAK inhibitor cycling.

Objectives: Although previous reports on the use of romosozumab for osteoporosis in patients with rheumatoid arthritis suggested that romosozumab increases bone mineral density, there have not been enough yet. Therefore, this study aimed to investigate the efficacy of romosozumab for treating osteoporosis in patients with rheumatoid arthritis to evaluate whether there was a difference in bone mineral density between patients who were taking glucocorticoids and those who were not.

Patients: Twenty-nine patients with rheumatoid arthritis who received romosozumab at our hospital were analyzed. Lumbar spine bone mineral density was measured at baseline, 6, and 12 months after romosozumab treatment. Additionally, the levels of bone turnover markers and the clinical parameters of rheumatoid arthritis were measured at baseline and 3, 6, and 12 months. These data were investigated separately for patients who were or were not undergoing glucocorticoid therapy.

Results: Lumbar spine bone mineral density was increased by 13.5% at 12 months after romosozumab treatment. However, patients taking glucocorticoids had a lower percentage change in bone mineral density than those not taking glucocorticoids. Also, at 6 months, patients taking glucocorticoids had significantly higher percentage change in serum type I collagen cross-linked N-telopeptide levels than those not taking glucocorticoids. Serum bone-specific alkaline phosphatase levels were increased as early as 3 months after treatment. There were not any significant changes in the clinical parameters of rheumatoid arthritis.

Discussion and Conclusions: Romosozumab treatment in rheumatoid arthritis resulted in increased levels of bone formation markers and increased bone mineral density. However, glucocorticoids had a weak inhibitory effect of bone resorption; therefore, reducing or discontinuing glucocorticoids should be considered in treatment of rheumatoid arthritis.