Symptoms of rheumatic diseases are treated not only with rheumatology but also with various clinical departments because the many symptoms are extremely varied and related with various medical areas. In the real world of clinical medicine, the boundary region of overlapping symptoms is ambiguous, and because of this ambiguity, rheumatology can still be said to be “frontier medicine”. The clinician is in the process of moving from “frontier medicine” to the “core” by facing the challenges presented by “frontier medicine” and solving the mysteries of unknown rheumatic diseases and various symptoms of rheumatic diseases. Biologics brought about a major paradigm shift in treatment of various rheumatic diseases. Therefore, treatment of rheumatic diseases has rapidly developed and rheumatology is trying to escape from “frontier medicine”.
　Artificial intelligence (AI) will become essential in clinical medicine in the near future. Even now, patients and their families can easily obtain advanced knowledge and information about their own diseases on the internet. Clinicians must have enough medical knowledge and experience to surpass the overflowing information and provide a clinical setting. On the other hand, it is also important to make use of AI for diagnosis and treatment from the viewpoint of cost reduction.
　In the field of clinical rheumatology, there are still many unknown diseases that clinicians have never experienced. The clinician does not rely on AI, continues to pioneer “frontier medicine” with deeper and wider specialized knowledge and experience, and must face up to the era of new medical care.

OBJECTIVES: Patients with methotrexate-associated lymphoproliferative disorders (MTX-LPD) treated in our rheumatology department were studied to investigate unresolved problems.
METHODS: The medical records of 27 patients with MTX-LPD diagnosed from 2005 to 2015 were investigated..
RESULTS: The occurrence of LPD increased since 2011, when the maximum dose of MTX was approved, increasing from 8 to 16 mg/week. The detected lesions were lymph node (n = 8), extranodal organ (n = 5), and both (n = 14). In the histopathological examination (total 25 cases), 13 cases of diffuse large B-cell lymphoma and 6 cases of Hodgkin’s lymphoma were identified. EBER-ISH test was positive in 9 out of 11 patients tested. sIL-2R value at LPD onset was 8047 ± 10496 U/ml (n=24), which was higher as the clinical stage advanced. Patients with good prognosis, who achieved remission only by discontinuation of MTX and whose LPD did not recur, had a significantly lower sIL-2R value than the patients with other clinical courses. Fourteen out of 27 patients achieved remission with just cessation of MTX, but 5 of them had relapsed. Exacerbation of RA was observed in 18 out of 26 patients. Five patients received biological agents, and one of them showed recurrence of LPD. There were 7 cases of LPD relapse from 18 patients with RA exacerbation, whereas only a case from 8 patients without RA exacerbation..
CONCLUSIONS:The development of MTX-LPD is related to MTX dose and EB virus. Furthermore, sIL-2R value at LPD onset is useful for the prognostic prediction of MTX-LPD and recurrence of LPD is often seen after RA exacerbation.

Objectives: Rheumatoid arthritis (RA) treatments have problems in terms of efficiency, adverse effects, and secondary failure. We evaluated the medical histories of patients seen in our department and examined the drug persistency rate.
Methods: Data on 1078 patients from our RA database from January 2006 to September 2015 were examined, including onset age, complications, and dose and duration of methotrexate (MTX) and biologics. Using Kaplan-Meier curves, the reason for stopping drugs was identified.
Results: The MTX use rate was 79.4%; the persistency rate was 75.0% at 6.3 years and 50.0% at 20 years [4,337 person-years]. After discontinuation, MTX was changed to biologics or other drugs in most patients. Patient preference was the main reason for discontinuation, followed by hepatic dysfunction. In all, 48.8% of the patients with hepatic dysfunction continued MTX after dose reduction of 3.1 mg per week. The persistency rate of the seven biologics was highest for etanercept (40.0% at 7 years) [1,363 person-years], although there were no significant differences among the drugs. Biologics were changed mainly because of adverse events, but were sustainable by changing drugs. The RA treatment did not cause deterioration or onset of viral hepatitis.
Conclusion: Control of RA was more manageable in the longer term with MTX. After the failure of biologics, RA control can be attained by changing drugs appropriately.

Objective: To investigate comprehension of adverse effects of methotrexate (MTX) in patients with rheumatoid arthritis (RA).
Patients: A survey was conducted with 547 RA patients who were treated with MTX.
Results: Average age, disease duration, and period of MTX treatment were 60.5±11.3 years old, 11.7±10.3 years, and 6.0±4.7 years, respectively. Before starting MTX, 20.1% of patients knew about this drug, and 30.4% of those patients had a positive image of the “silver bullet”, while the half of the patients had a negative image such as fear of adverse effects or as a terrible drug. Almost all patients were provided medication therapy management by doctors and pharmaceutists and 41.5% of the patients understood the adverse effects properly, whereas the half of the patients did not recognize stomatitis as an adverse effect of MTX. There were some patients who had the wrong perception about transient cessation of MTX; they would not stop MTX when they had cough, fever, or infections. The elderly and patients with a short duration of RA tended to have the wrong perception. Although seminars for RA conducted by our hospital were known to 78.4% of patients, the rate of attending seminars was only 25.8%.
Conclusions: Although doctors and pharmaceutists provide medication therapy management for adverse effects and transient cessation of MTX, some patients had the wrong perception. Nurses should participate in a multidisciplinary team and let patients correctly understand the adverse effects of MTX through continuous medication therapy management.

    We experienced the case of a 26-year old female patient with rheumatoid arthritis (RA) who was treated with subcutaneous (SC) tocilizumab (TCZ). We discontinued bucillamine and started iguratimod (IGU) to reduce her dose of prednisolone (PSL). However, her pain worsened and the dose of PSL was increased from 1.5 mg/day to 3 mg/day at 8 weeks after the introduction of IGU. Since she was 171 cm tall and weighed 65 kg, we switched from SC TCZ to intravenous (IV) TCZ. Her disease activity ―as measured by the clinical disease activity index and the level of matrix metalloproteinase-3― was ameliorated and we were able to reduce the dose of PSL to 2 mg/day. Introduction of IGU and switching to IV TCZ might be useful when the response to SC TCZ is insufficient in a patient who is relatively large in size.

    A 71-years-old man admitted to our institution because of neck swelling, pain and high fever. Due to elevated level of serum CRP (14.3 mg/dl) and bilateral cervical lymph node enlargement on computed tomography, he was considered to have an infection and treatment with some antibacterial agents was started, however these showed no response. His lymph node biopsy specimen revealed patchy infiltration of histiocytes containing small lymphocytes in an abundant cytoplasm, known as emperipolesis. Immunohistologically, infiltrating histiocytes were positive for S-100 protein and CD68. He was diagnosed with Rosai-Dorfman disease (RDD) from these findings. Furthermore, IgG4 positive plasma cells were occupied about 50% of IgG positive cells in the specimen and serum IgG4 showed high level (160 mg/dl). These findings met the IgG4-related disease (IgG4-RD) classification criteria. After the treatment with prednisolone 40 mg/day, his high level of serum inflammatory markers and lymph node enlargement improved. RDD is a rare histiocytic proliferative disorder of unknown etiology that is clinically characterized by cervical lymphadenopathy, fever, elevated level of serum CRP and erythrocyte sedimentation rate (ESR). Several recent articles reported that RDD could be associated with IgG4-RD because some patients with RDD have increased numbers of IgG4 positive cells and an elevated IgG4/IgG ratio. Our case exhibited features characteristic for IgG4-RD. This indicates that there are some pathological overlaps between these two diseases.

    Psoriatic arthritis (PsA) is an inflammatory arthritis that is associated with psoriasis. The cardinal manifestations of PsA include peripheral arthritis, dactylitis, tenosynovitis, nail involvement, and spondylitis. The reported prevalence of spondylitis among patients with PsA ranges from 25% to 55%. The vast difference may be the result of the definition of spondylitis or disease duration. Nevertheless, the prevalence will be at least 25% of patients with PsA. A lower frequency of neck pain and back pain, and less marked limitation of spinal joint movements were noted among patients with PsA compared with patients with ankylosing spondylitis (AS). By contrast, peripheral joint involvement is more common in patients with PsA than in patients with AS. The radiological changes of the spine and sacroiliac joints are more severe in patients with AS than in those with PsA. However, disease activity, functional ability, and quality of life were comparable between patients with AS and those with PsA. It is important to note that patients with asymptomatic spondylitis exist. Treatment with nonsteroidal anti-inflammatory drugs is the recommended first-line therapy in patients with psoriatic spondylitis. However, for those patients whose response is insufficient to control disease activity, tumor necrosis factor inhibitors are recommended.

    Spondyloarthritis (SpA) is an inflammatory disease which affects the spine and sacroiliac joints, causing inflammatory back pain. This includes ankylosing spondylitis, psoriatic arthritis, reactive arthritis, the arthritis associated with inflammatory bowel disease. The Chronic inflammation causes progressive ossification of the spinal ligaments resulting in a rigid thoracolumbar kyphosis. Severe thoracolumbar kyphosis prevents the head from adopting a straight position. The surgical treatment is recommended to restore the sagittal balance and improve the quality of life in patients with severe thoracolumbar kyphosis. Spinal pseudoarthrosis is less common, causing severe pain and a progressive spinal kyphotic deformity. Therefore, most patients with spinal pseudoarthrosis require the surgical treatment. A major surgery in SpA is spinal corrective osteotomy, carrying increased technical demands. The appropriate timing of surgery is important to minimize the risk for complications and yields satisfactory surgical results.