Tietze’s syndrome was first described in 1921 as a cause of chest pain. It can be defined as a benign, painful, non-suppurative localized swelling of the costosternal（most often involving the second or the third rib）or the sternoclavicular joints, in the absence of other evident causes which could be responsible for this syndrome. Reports on painful inflammatory episodes involving particularly the Tietze’s area and the sternoclavicular region have addressed differentiating between sternoclavicular hyperostosis and rheumatoid arthritis, arthritis associated with palmoplantar-pustulosis, severe acne, psoriasis, reactive arthritis（Reiter’s syndrome）, ankylosing spondylitis, Crohn’ disease, and ulcerative colitis, etc. The purpose of this review is to re-evaluate the importance of Tietze’s syndrome in the differential diagnosis of chest pain, taking into account knowledge on rheumatic diseases affecting the anterior chest wall.

One case with rheumatoid arthritis（RA）who had who developed tuberculosis of the lung despite T-SPOT test as a pre-initiating screening for baricitinib being negative, was observed. He was an 84-year-old male patient. His RA history was 2 years at initial consultation, and simplified disease activity index（SDAI）was 13.0. Treatment was initiated with methotrexate（MTX）at a dosage of 6 mg per week and gradually increased to 12 mg. When MTX dosage tapered due to recognition of renal disorder, his disease activity quickly rose to an SDAI of 36.4. Before initiating baricitinib, preinitiating screening was performed including T-SPOT and confirmed to be negative. His chest CT appeared to show slight interstitial lung change, however he did not complain of cough or sputum. Baricitinib was initiated 4 months after first consultation with a dosage of 4 mg per day, upon which disease activity rapidly settled, and his SDAI went into remission in 6 weeks. Five months later, he complained of general fatigue, while his chest CT revealed lung tuberculosis with Gafky No.5. At this time anti-tuberculosis therapy started. Baricitinib was discontinued thereafter, while predonisolone at a dose of 7.5 mg per day was administrated. His SDAI remained in remission, and there was no discharge of sputum. This case suggested that even though T-SPOT was negative, careful attention should be paid for tuberculosis during concomitant baricitinib administration especially in elderly patients.

A 64 year-old, female was diagnosed as rheumatoid arthritis（RA）in x-28 year. Administration of methotrexate（MTX）was started However, she developed immunodeficiency-associated lymphoproliferative disorders associated with MTX. MTX was stopped, and she received rituximab-CHOP chemotherapy, and the lymphoproliferative disorder attained remission. RA disease activity was stabilized after tocilizumab was started in x-9 year. After 8 days since the last tocilizumab administration, pain and swelling of the left thigh developed. She was hospitalized, and was suspected to have necrotizing fasciitis. However, necrotizing fasciitis was not confirmed because the Laboratory Risk Indicator for Necrotizing Fasciitis score（LRINEC score）was 3 points. She died due to multiple organ failure on the same day in spite of collective treatment. Blood culture revealed positive for streptococcus pyogenes infection. Finally, she was diagnosed as toxic shock syndrome complicated with necrotizing fasciitis caused by streptococcus pyogenes infection. In RA patients treated with biologics such as tocilizumab, the diagnosis of necrotizing fasciitis could be difficult due to the strong immunosuppressive effect of IL-6 inhibition.

Objective: Biologics have led to successful therapy for rheumatoid arthritis（RA）; however, adverse events have also increased. Thus, nurses require risk-management skills based on clinical pharmacology. We investigated the effect of clinical pharmacology and risk-management teaching intervention for nurses. We compared the effect in two groups of nurses: those with experience in RA therapy（Group E）and those with no experience（Group NE）. Methods: Fifty-two nurses（39 in group E, 13 in NE）participated. A 2-hour lecture program consisted of education in（1）pathophysiology,（2）therapeutic drugs,（3）risk-management and（4）the use of package inserts. The comprehension of nurses was assessed through a questionnaire on the topics covered（23 questions in total, 3 for（1）, 8 for（2）, 8 for（3）, 4 for（4）. Results: There were no differences between the two groups on the base line assessments. After the lecture, Group E performed better（16 correct answers out of 23 questions; correct answers for all items increased: 1/3, 5/8, 6/8, 4/4 for each item, respectively）compared to before the lecture program. Group NE improved on only 2 items（correct answers increased by 2 points）. Conclusion: We need to educate nurses about clinical pharmacology and these risk-management skills to provide comprehensive care for RA.

Adult Still’s disease（ASD）is a systemic inflammatory disease of unknown etiology, characterized by fever, rash and articular manifestations. The current concept of ASD includes a carry-over of systemic juvenile idiopathic arthritis（sJIA; disease onset < 16 years old）and adult（≥16 years old）-onset Still’s disease. The activation of macrophages and hypercytokinemia of interleukin（IL）-1β, IL-6 and IL-18 are crucial in the pathogenesis of ASD, and consequently, the efficacy of targeted therapies with biological agents against inflammatory cytokines has been demonstrated. In Japan, tocilizumab was approved for refractory ASD for the first time in the world in May 2019 according to the results obtained from an investigator-initiated multicenter clinical trial（KCCR-D002 study）.

Ankylosing spondylitis classified axial spondyloarthritis mainly affects axial joints, including sacroiliac joints and the spine. Inflammation in AS starts from entheses. It induces consequent bone erosions, and then new bone formation occurs and syndesmophytes slowly develops, resulting in bridging between vertebral bodies in the long disease duration. For early intervention of the disease, ASAS proposed classification criteria for axial spondyloarthritis. Under these criteria, non-radiographic axial SpA（nr-axSpA）can be classified, however, nr-axSpA does not always progress to AS. In the treatment of AS, physical therapy, such as stretching and swimming, is highly recommended. In active AS despite of NSAIDs, salazosulfapyridine can be used for peripheral arthritis, while methotrexate is generally ineffective. TNF inhibitors, infliximab and adalimumab, are used alongside NSAIDs. It is recommended to switch to another TNF inhibitor in the event of secondary failure to respond to TNF inhibitors and to switch to IL-17 inhibitors in the event of primary failure. Clinical trials of JAK inhibitors for AS are now ongoing.

Autoimmune and rheumatic diseases are characterized by multiple organ manifestations but are molecularly and genetically heterogeneous which makes it difficult to manage every case based on one kinetic molecular theory. The appropriate use of molecular-targeting therapies such as biological DMARDs and JAK inhibitors allowed rheumatologists to aim for clinical remission and to control joint destruction in all patients with rheumatoid arthritis. Such therapeutic strategies are applied to the treatment of various rheumatic and autoimmune diseases. However, how to select different targeted therapies to each patient remains unclear and it is necessary to develop new therapeutic strategies involving the differential use of them. We have reported that patients with psoriatic arthritis were classified into four groups based on the expression of chemokine receptors on peripheral T cells by 8-color flow cytometry: Th17-dominant, Th1-dominant, hybrid, and normal type in the FLOW registry. Patients treated with the strategic selection of different biologics based on the phenotypic differences in individuals revealed significantly higher proportion of improvement in arthritis and psoriasis than those who were conventionally treated with biologics. Thus, for the treatment of psoriatic arthritis, therapeutic drugs can be optimized according to pathological conditions through the analysis of peripheral blood lymphocytes. In other words, precision medicine may be possible. The objective of precision medicine is the stratification or subgrouping of patients to improve diagnosis and treatment, which would encourage treatment strategies of various rheumatic and autoimmune diseases with clinical and molecular heterogeneity.

Recently, genome studies have been progressing remarkably and increased in scale upsizing such as a national projects. The method of applying genomes to pathological elucidation or drug discovery has been explored, and the era of genomic precision medicine is approaching. For example, genetic tests of human leukocyte antigen（HLA）are recommended before administration of specific medicine because some HLA genotypes are associated with severe cutaneous adverse reactions. As for rheumatoid arthritis（RA）, we identified a risk of non-classical HLA genes in addition to that of classical HLA genes previously reported. We also found that HLA genotypes of Japanese individuals consisted of 11 clusters by applying non-linear machine learning. For applying the results of genome-wide association study（GWAS）to precision medicine, studies that predict future disease development based on disease-sensitive single nucleotide polymorphisms are increasing. Our group analyzed the data of international biobanks of approximately 670,000 participants and identified the biomarker associated with a human lifespan. Promotion of preventive medical care is expected to be achieved by comprehensive assessments of such an individual’s genetic risk factor and the known risk factors to identify high-risk groups. As for precision medicine to treat RA, microbiome is attracting attention. We conducted a metagenome-wide association study of the RA gut microbiome by using whole-genome shotgun sequencing. We found the novel characteristics of the RA gut metagenome.

Interstitial lung disease（ILD）and airway disease（AD）are frequently associated with rheumatoid arthritis（RA）patients. Lung diseases including ILD and AD in RA are extra-articular manifestations. Since ILD and AD cause a poor prognosis in RA, biomarkers for lung diseases in RA were eagerly desired. Acute exacerbation of ILD, drug-induced ILD, and Pneumocystis pneumonia occasionally occur in RA, and are included in acute-onset diffuse ILD（AoDILD）. AoDILD in RA causes poor prognosis.

Krebs von den lungen-6（KL-6）and surfactant protein-D（SP-D）were originally generated for biomarkers of idiopathic pulmonary fibrosis and the sensitivity of these markers were lower for RA patients with ILD. However, few biomarker studies on ILD, AD, or AoDILD in RA have been reported to date. Thus, we have been trying to generate biomarkers for RA patients with lung diseases. Genome, cytokine, amino acid, antibody, micro RNA, and metabolomic profiles of lung diseases in RA were investigated in order to generate better potential biomarkers. In this review, we have attempted to summarize the investigated biomarkers for RA patients with lung diseases.

IL-6 is one of the major pro-inflammatory cytokines involved in the regulation of local and systemic immune responses. IL-6, which is produced by various cells in inflammatory lesions and has various functions during the immune response, is deeply involved in the etiology of immune disorders such as rheumatoid arthritis（RA）. Accumulated evidence indicates that IL-6 is an important therapeutic target for various immune disorders. Since IL-6 plays a key role in the synthesis of the acute phase proteins such as CRP in hepatocytes, the administration of IL-6 inhibitors results in normalization of serum CRP levels in RA patients. In addition, IL-6 inhibitors suppress serum amyloid A（SAA）induction, and are expected to be used for the therapy of secondary amyloidosis. Since IL-6 promotes the antibody production in B lineage cells, its inhibition may lead to suppression of hypergammaglobulinemia and autoantibody production. In addition, since IL-6 is involved in the differentiation of Th17 and Tfh subsets, IL-6 inhibitors may improve the immunopathology by modulating the adoptive immune response. These pharmacological actions are unique to IL-6 inhibitors and probably explain the reason why IL-6 inhibitors are applied to a wide range of immune disorders. However, like other biologics, not all patients can benefit from IL-6 inhibitors. Possible biomarkers for predicting the effects of IL-6 inhibitors have been proposed so far, but there are currently no established markers. Another problem with the use of IL-6 inhibitors is that existing biomarkers such as CRP are normalized during the therapy, making it difficult to assess disease activity and detect complications such as infection. Leucinerich α2 glycoprotein（LRG）, newly identified by our group as an inflammatory biomarker, is useful for evaluation of inflammation that is difficult to evaluate by CRP. LRG may be applicable as an inflammatory biomarker during treatment with IL-6 inhibitors.