Ozoralizumab, a novel tumor necrosis factor（TNF）inhibitor, is an antibody drug that utilizes variable domains of heavy chain of heavy chain antibody（VHH）. It was approved in September 2022 in Japan for rheumatoid arthritis. Ozoralizumab is a trivalent bispecific antibody consisting of anti–human TNFα-VHHs and an anti–human serum albumin-VHH, with a molecular weight of 38 kDa, approximately one-fourth that of conventional IgG antibodies. Due to such low molecular weight and serum albumin binding ability, it is expected to be rapidly absorbed into the systemic circulation after subcutaneous administration and efficiently distributed to inflamed tissues. In fact, ozoralizumab was shown to enter the circulation more rapidly and distribute to inflamed joint tissue compared to IgG-type TNF inhibitors in a mouse model of collagen-induced arthritis. In a clinical study in combination with methotrexate, improvement in clinical symptoms was observed on day 3 of subcutaneous administration of ozoralizumab 30mg and the efficacy was maintained for 52 weeks. Based on these findings, ozoralizumab is considered to be a new type of TNF inhibitor that is expected to improve clinical symptoms rapidly.

Methotrexate: MTX（aminopterin）, a folate antagonist was first reported in 1948 to induce temporary remission of acute leukemia of children. In the 1950s, the efficacy of MTX for RA and psoriasis patients was reported. Now, MTX is globally considered as the anchor drug for the treatment of RA because of long-term efficacy and safety. Therefore, MTX is used in more than 70% of RA patients by monotherapy or combination therapy. In Japan, MTX was firstly introduced into the market in 1999, about 10 year behind the approval by FDA in US. However, after high-dose MTX up to 16 mg/week was approved in 2011, MTX has been used more aggressively. Although the recent aggressive treatment with lead to better disease outcome, serious infections and lymphoproliferative disorders（LPD）due to long-term immunosuppression tend to increase, especially in elderly RA patients. This paper reviews the history of the development of MTX as an anti-rheumatic drug.

Seventy years after its development, methotrexate（MTX）remains an anchor drug that plays a central role in the treatment of rheumatoid arthritis, even in the era of biologic agents and JAK inhibitors. The reason for this is that MTX has confidential effects such as suppressing disease activity, preventing joint destruction, reducing cardiovascular disorders, and improving mortality. The basic action of MTX is an antifolate action, that is, a cell proliferation inhibitory action. When MTX is attached polyglutamates in cells, it has a wide variety of other effects, including anti-inflammatory effects via adenosine, suppressive effects on the production of adhesion molecules and inflammatory cytokines, and suppressive effects on matrix metalloproteinases. MTX easily increases in blood concentration due to decreased renal function, causing bone marrow suppressive effects. There are also other side effects related to MTX, and it is desirable to know the characteristics and pleiotropic mechanism of action of MTX so that it can be used appropriately in the treatment against rheumatoid arthritis.

  In 1999, MTX was approved for the treatment of rheumatoid arthritis（RA）, and Rheumatorex^® 2mg capsules, which are different from the conventional 2.5mg tablets, were introduced in Japan.

  According to the drug treatment algorithm of the RA Clinical Practice Guidelines 2020, once RA is diagnosed, MTX is first selected in Phase I, taking into account contraindications, age, renal function, and pulmonary complications, and becomes the mainstay of RA treatment. It is positioned as an “anchor drug”.

  In 2011, the Japan College of Rheumatology created the MTX treatment guidelines for RA treatment, and the second edition was created in 2016 and the third edition was created in 2023 under the name “Guidance for the use and treatment of MTX in RA.” It has become a “yosuga（the point of reference）” that can be used properly.

  We focused on what our department has already reported in the Japanese Society of Clinical Rheumatology and the academic journal “Clinical Rheumatology.” This article describes the actual usage of MTX, including how to use the subcutaneous injection preparation.

Among disease-modifying anti-rheumatic drugs, methotrexate（MTX）is the anchor, being prescribed for over 60–70% of the rheumatoid arthritis（RA）patients. Adverse event related to MTX use in RA is most frequently lymphoproliferative disorders（LPD）, accounting for one third of the whole adverse events reported to Japanese Adverse Drug Event Report database（JADER）, in contrast to that the most is infectious pneumonitis in TAC, ADA, TCZ and ABT users. EB virus infection to B lymphocyte, sometimes to T or NK cell, has been considered as the etiology. However, as 90% of the whole world population has lifelong EB virus infection, through mother to baby transmission, immune-suppression or immune-escape would be additionally crusial for LPD to develop. Diffuse large B-cell lymphoma（DLBCL）is the most, followed by Hodgikin lymphoma, and both intra-nodal and extra-nodal ones are observed. Risks for or concurrent findings with LPD development include a higher dose, good response, lymphocytopenia, sIL-2R level increase, and IgE level increase. Spontaneous regression after MTX withdrawal may occur in nearly half of the cases, but re-worsening is seen even without re-use. In case without a regression, R-CHOP immunochemotherapy is adopted. Immune checkpoint inhibitor would be an issue in the future. In conclusion, intra- and extra-nodal lesions should be especially monitored during MTX use for RA.

Methotrexate（MTX）is the essential drug to control rheumatoid arthritis（RA）and it is very important for any rheumatologists to understand the characteristics of MTX. To grasp profiles and risk management of side effects is especially important because most RA patients take MTX lifelong. Hematological or myeloid disorder, interstitial lung disease, infectious diseases, liver dysfunction, and malignancy including lymphoproliferative disorder are paid attention in the post-marketing surveillance of MTX in Japan. Not only these side effects but also erroneous or overdose administration of MTX is critical for RA patients because of its unique dosage. Therefore, it is important to share information and communication among any medical stuff including patients, to handle MTX effectively and safely.

Objective: SARS（severe acute respiratory syndrome）-CoV2 emerged at the end of 2019, and the infection quickly spread throughout the world. The mRNA vaccines against an unknown infectious disease was developed at an astonishing speed, and in Japan, vaccination was actively promoted for the public. However, rheumatoid arthritis（RA）patients often use immunosuppressive drugs, and expectations and concerns about vaccines were swirling. Therefore, we conducted a survey of RA patientsʼ awareness of vaccination and attempted to identify risk factors for the occurrence of adverse events（AEs）by vaccination.

Subjects and methods: Of the 479 RA patients who visited Shirahama Hamayu Hospital, a questionnaire survey was conducted between February 4, 2022 and May 31, 2022. A logistic analysis was also conducted with local and systemic AEs as endpoints.

Results: Nearly 90% of patients received two or more doses of vaccine in a population with a median age of 71.2 years. Pain was the most common administration site reaction, and malaise was the most common systemic reaction. Logistic analysis revealed that age was extracted as a significant inhibitory factor for the occurrence of AEs.

Conclusion: RA patients were vaccinated in the same way as the general population in accordance with government directives, and age alone was a significant influencing factor for AEs, with no effect by the medicines used or disease activity.

Objective: In recent years, malignancies have become the leading cause of death among rheumatoid arthritis（RA）patients. Although blood test and urinalysis are regularly performed in rheumatology outpatient clinics, malignancies may still be found in an advanced stage. We analyzed the clinical information of RA patients with solid tumors and summarized the triggers of detection.

Subjects and Methods: A single-center, retrospective, observational study. Subjects were 41 RA patients（33 women; 80%）, 48 cancers, who visited our department between April 2011 and June 2023 and attended our clinic for more than 6 months, and who were diagnosed with solid malignancies（cancers）after RA diagnosis. We collected information on age at cancer diagnosis, type of cancer, triggers of detection, duration of RA, and RA treatment at and after cancer diagnosis.

Results: The organs in which cancer occurred were breast, lung, colon, uterus, stomach, skin, prostate, pancreas, and others, in that order. the mean age at RA diagnosis was 54.1 years, the mean age at cancer diagnosis was 67.5 years, and the median duration of RA disease before cancer diagnosis was 9.0 years. The most common reason for cancer detection was self-examination for breast cancer, while lung and colorectal cancers were often detected during outpatient or inpatient examinations. Regarding RA treatment, methotrexate（MTX）and TNF inhibitors were often discontinued after cancer diagnosis, and the use of glucocorticoids（GC）was increasing.

Conclusion: It was found that early detection of cancers is difficult to be achieved only by regular examinations.