Objectives: The aim of this study was to investigate the clinical characteristics of patients with difficult-to-treat RA (D2T RA) and the usefulness of switching to drugs with different modes of action in real-world. Methods: We reviewed all consecutive patients with RA treated at Keio University Hospital between 2016 and 2017 with a definition of D2T RA. We analysed clinical characteristics and evaluated the usefulness of changing drugs according to mode of action. Results: Among 1709 patients with RA, 173 (10.1%) were D2T RA. The reason for the D2T RA was multi-drug resistance in 59 patients (34.1%), comorbidity in 17 (9.8%), and socio-economic reasons in 97 (56.1%). The multi-drug-resistance group had significantly higher tender joint count and evaluator global assessment than the other groups, despite receiving the most intensive treatment. The comorbidity group showed a significantly older age and higher rheumatic disease comorbidity index. Although changing the drug to another with a different mode of action was useful, the proportion of patients who achieved remission or low disease activity decreased as the number of switches increased. Conclusion: Of the patients with RA, 10.1% were still difficult to treat in clinical practice, despite intensive treatment. Their characteristics were distinct by the reasons of D2T RA, which suggests the need for a personalized approach to D2T RA.

Immunoglobulin G4-related disease (IgG4-RD) is a fibroinflammatory disease characterized by elevated serum IgG4 levels with infiltration of IgG4+ plasma cells and severe fibrosis in affected tissues. Recently, idiopathic fibrosing mediastinitis (FM), an extremely rare fibroinflammatory disorder, has been recognized as a form of IgG4-RD. As IgG4-RD can be treated by glucocorticoids, identification of the etiology of FM by surgical biopsy is essential; however, mediastinal biopsy is often difficult. We report 2 cases of IgG4-related FM successfully diagnosed with computed tomography (CT)-guided percutaneous needle biopsy. Case 1 was a 66-year-old woman with elevated serum C-reactive protein without any symptoms and case 2 was 78-year-old woman with abnormal mediastinal contour on chest x-ray. By further work-up, both cases were found to have mediastinitis accompanied by elevated serum IgG4. CT-guided percutaneous needle biopsy revealed massive infiltration of IgG4+plasma cells along with storiform fibrosis. IgG4-related FM. Glucocorticoid therapy. The treatment resulted in significant improvement of the lesions after 3 months. Early recognition and diagnosis of IgG4-related FM is essential because a delay in appropriate treatment initiation leads to progressive fibrosis with irreversible organ damage and poor prognosis. Our cases highlight CT-guided percutaneous needle biopsy as a promising option for histological examination in patients with IgG4-related FM.

To identify biomarkers for assessing myositis-associated interstitial lung disease (ILD). We reviewed consecutive patients from our institution who had been newly diagnosed with PM, DM, or clinically amyopathic DM during the years 2002-2017. The patients were divided into two groups according to the presence of ILD, and the ILD group was further subdivided into three groups according to the clinical courses of induction failure, relapse and non-relapse. Baseline and time-course changes in the parameters were compared between groups. Among 110 patients enrolled, 75 (68%) had ILD. Baseline serum Krebs von den Lungen-6 (KL-6) was significantly higher in the ILD group than in the non-ILD group (1120 vs 236 U/ml; P < 0.001). In the ILD group consisting of the induction failure cases (n = 3), the relapse group (n = 24) and the non-relapse group (n = 48), baseline serum KL-6 was significantly different between the three groups [1971 vs 1870 vs 935 U/ml, respectively; P = 0.003 (relapse group vs non-relapse group)]. The time-course changes in serum KL-6 revealed that KL-6 significantly increased along with relapse, with the increase of 625 U/ml relevant to relapse. Serum KL-6 is a useful biomarker for assessing the disease activity of myositis-associated ILD.

To elucidate the long-term outcomes of patients with difficult-to-treat rheumatoid arthritis (D2T RA). We collected data on the clinical course of patients who had been identified as D2T RA in 2018 until 2023. We stratified the patients according to outcomes at the last visit: resolved D2T RA, persistent D2T RA, and mortality. We compared their clinical characteristics and investigated the predictive factors for the resolution of D2T RA or mortality. Furthermore, we investigated the impact of the causes of D2T RA identified in 2018, multidrug resistance, comorbidities, and socioeconomic factors on outcomes in 2023. Of 173 patients identified as D2T RA in 2018, 150 were included in the analysis. Among them, D2T RA was resolved in 67 (45%), 75 (50%) remained as D2T RA, and 8 (5%) died. Patients with resolved D2T RA were significantly younger at the latest visit (p= 0.02), had a higher proportion of treatment changes during five years (p= 0.002), and had a higher proportion of interleukin-6 receptor inhibitors use in 2023 (p= 0.04) than those in patients with persistent D2T RA or those who died. D2T RA resolved in 38% of patients with multidrug resistance, mainly with treatment changes. Rheumatic disease comorbidity index and glucocorticoid dose escalation were independent risk factors for mortality (odds ratio [OR], 3.50; p= 0.02 and OR, 31.9; p= 0.002, respectively). Further modifications in RA treatment are useful for resolving D2T RA. Multiple comorbidities and glucocorticoid use are associated with mortality.

Despite remarkable advances in the management of RA, there are still unmet needs that rheumatologists need to address. In this review, we focused on difficult-to-treat RA (D2T RA) and late-onset RA (LORA), and summarized their characteristics and management. The prevalence of D2T RA is reported to be 6–28% and many factors have been identified as risk factors for D2T RA, including female sex, long disease duration, seropositivity for rheumatoid factor and anti-cyclic citrullinated peptide antibody and their high titer, baseline high disease activity, and comorbidities. D2T RA is broadly divided into inflammatory and non-inflammatory conditions, and clinical features differ according to background. A proportion of D2T RA can be managed with treatment modification, mainly with interleukin-6 receptor inhibitors or Janus kinase inhibitors, but some D2T RA patients have a poor prognosis; thus, the implementation of precision medicine by stratifying patients according to disease status is needed. In the aging society, the epidemiology of RA is changing and the prevalence of LORA is increasing worldwide. LORA has distinct clinical features compared with young-onset RA, such as acute onset, low seropositivity, and high inflammation. The pathogenesis of LORA remains to be elucidated, but proinflammatory cytokines, including interleukin-6, have been reported to be significantly elevated. LORA has several management concerns other than RA itself, such as geriatric syndrome and multimorbidity. The treat-to-target strategy is effective for LORA, but the evidence is still lacking; thus, it is important to accumulate clinical and related basic data to establish the optimal treatment strategy for LORA.