Comparison of anti-IL-6 receptor and JAK inhibitors in patients with rheumatoid arthritis from the real-world practice FIRST study.

OBJECTIVES: A molecular-targeted drug that is suitable as the second choice for patients with rheumatoid arthritis (RA) who show an inadequate response to the first biological disease-modifying antirheumatic drug (bDMARD) is unknown. This study aimed to analyze the efficacy and safety of interleukin-6 receptor (IL-6Ri) and Janus kinase inhibitors (JAKis), often selected as molecular-targeted drugs for second or subsequent treatments. METHODS: The efficacy and safety of JAKis and IL-6Ri were compared using propensity score-based inverse probability of treatment weighting (PS-IPTW) using propensity scores after 26 weeks of therapy in patients with RA. RESULTS: The remission rate at week 26, determined by the clinical disease activity index (CDAI), and the incidence of infection were higher in the JAKis than in the IL-6Ri group. The CDAI trajectories were divided into four according to the growth mixture modeling. IL-6Ri demonstrated greater efficacy in RA patients with ineffective to single bDMARD therapy compared with those with multiple ineffective bDMARDs. In patients who failed to respond to one bDMARD, there was no significant difference in the CDAI remission rate at week 26 between the JAKis (29.1%) and IL-6Ri (21.8%) groups (p= 0.21). However, for patients who did not respond to at least two bDMARDs, the CDAI remission rate at week 26 was higher in the JAKis than in the IL-6Ri group. CONCLUSIONS: IL-6Ri offers a superior balance of efficacy and safety compared with JAKis for RA patients unresponsive to one bDMARD. However, JAKis may suit patients who do not respond to multiple bDMARDs.

Safety and efficacy of anifrolumab therapy in systemic lupus erythematosus in real-world clinical practice: LOOPS registry.

OBJECTIVES: To determine the safety and efficacy of anifrolumab in patients with systemic lupus erythematosus (SLE) classified based on the Lupus Low Disease Activity State (LLDAS) in real-world clinical practice. METHODS: This retrospective observational study involved SLE patients who started anifrolumab therapy. The primary end point was the retention rate over 26 weeks after initiating anifrolumab therapy; 45 patients followed up for 12 weeks or longer were analyzed in the following groups to determine the safety and efficacy up to week 12 after treatment initiation: 1) non-LLDAS achievement group and 2) minor flare group. Safety and efficacy were compared between the minor flare group and the standard of care (SoC) group (treated by adding glucocorticoids (GCs) or immunosuppressants) after adjustment with inverse probability of treatment weighting using propensity score (PS-IPTW). RESULTS: The retention rate of anifrolumab was 89.7% at week 26.The LLDAS achievement rates at week 12 were 42.9% and 66.7% in the non-LLDAS achievement and minor flare groups, respectively. In both groups, GC doses and SELENA-SLEDAI score significantly decreased. When the anifrolumab group with minor flare was compared with the SoC group or the GC dose increase group, the GC dose and SLEDAI score were significantly lower in the anifrolumab group than in both groups; there was no significant difference in LLDAS achievement. CONCLUSIONS: At week 26 after initiating anifrolumab therapy, ∼90% patients remained on therapy. Anifrolumab might lower disease activity without initiating GCs and reduce GC doses, especially in patients who experience minor flares after LLDAS achievement.

Nailfold microvascular abnormalities are associated with a higher prevalence of pulmonary arterial hypertension in patients with MCTD.

OBJECTIVE: MCTD manifests with microvasculopathy and overlapping clinical features of SLE, SSc and idiopathic inflammatory myopathies (IIM). The aim of this study was to investigate the clinical significance of microvasculopathy in patients with MCTD using nailfold videocapillaroscopy (NVC). METHODS: Fifty patients with newly diagnosed and untreated MCTD were enrolled in this multicentre, prospective and observational study. Clinical features and NVC findings were assessed at baseline and after 1 year post-intervention, along with disease controls [SLE (n = 40), SSc (n = 70) and IIM (n = 50)]. RESULTS: All MCTD patients presented Raynaud's phenomenon and were positive for anti-U1 RNP antibodies, and 22.0% (11/50) had pulmonary arterial hypertension (PAH). The prevalence of NVC scleroderma patterns in MCTD was 38.0%, which was lower than SSc (88.6%) but higher than SLE (10.0%). In addition, when we divided MCTD patients into two groups by presence or absence of NVC scleroderma patterns, we found a higher prevalence of PAH in patients with NVC scleroderma patterns. Namely, NVC scleroderma patterns were observed in all MCTD patients with PAH, and in 21.0% of those without PAH. After intensive immunosuppressive therapy, NVC scleroderma patterns disappeared in half of the MCTD patients but were not changed in SSc patients. CONCLUSIONS: MCTD differed from SLE, SSc and IIM in terms of the prevalence and responsiveness of NVC scleroderma patterns to immunosuppressive therapy. Detection of nailfold microvascular abnormalities in MCTD could contribute to predicting PAH and help us to understand further aspects of the pathogenesis of MCTD.

Efficacy and safety of high-dose of mycophenolate mofetil compared with cyclophosphamide pulse therapy as induction therapy in Japanese patients with proliferative lupus nephritis.

OBJECTIVES: To clarify the effectiveness and safety of induction therapy with mycophenolate mofetil (MMF) in patients with lupus nephritis (LN). METHODS: Patients with LN administered MMF (n = 35) or intravenous cyclophosphamide pulse therapy (IVCY) (n = 25) plus high-dose corticosteroids between July 2015 and June 2020 were included. MMF was increased from 2 to 3 g/day, with no adverse events (AEs). The primary endpoint was the 6 month renal remission rate. Secondary endpoints were retention rate and AEs. RESULTS: There were no significant differences in age, sex, disease duration, renal histological type, SLE disease activity index, and urine protein creatinine ratio between the two groups. Twenty-six patients (74%) continued with MMF therapy, whereas 12 (48%) completed six IVCY courses. The retention rate was significantly higher in the MMF than in the IVCY group (p = 0.048). Twenty-four and 14 patients in MMF and IVCY groups, respectively, achieved renal remission with insignificant differences. Grade 3 or higher AEs were observed in 8 and 14 patients in the MMF and IVCY groups, respectively (p = 0.014). CONCLUSIONS: The efficacy of high-dose MMF was comparable to that of IVCY in Japanese patients with proliferative LN, with fewer AEs and a higher retention rate than IVCY, suggesting the high tolerability of MMF.

Clinical aspects in patients with rheumatoid arthritis complicated with lymphoproliferative disorders without regression after methotrexate withdrawal and treatment for arthritis after regression of lymphoproliferative disorders.

OBJECTIVES: To identify predictive factors for lymphoproliferative disorders (LPDs) that persist after methotrexate (MTX) withdrawal (Persistent-LPD) and the optimal treatment for rheumatoid arthritis (RA) after LPD regression. METHODS: Among 3666 patients with RA treated with MTX in our department from 2006 to 2017, 26 cases of LPD that regressed after MTX withdrawal (Regressive-LPD) and 25 cases of Persistent-LPD were compared. Multivariate logistic analysis was performed to identify predictive factors for Persistent-LPD. Retention rates of biological disease-modifying antirheumatic drugs (bDMARDs) were calculated using the Kaplan-Meier Method. RESULTS: In Persistent-LPD, the incidence of diffuse large B-cell lymphoma was higher (76%). The overall 2-year survival rate was 83.9%: 95.8% for Regressive-LPD and 71.0% for Persistent-LPD. The International Prognostic Index (IPI) risk classification was useful for predicting Persistent-LPD. bDMARDs were introduced in 38 RA patients after LPD regression. Unadjusted retention rate of bDMARDs in the 51 LPD patients was significantly lower than that in the 1668 non-LPD RA patients in our bDMARD cohort (controls) (p = 0.029). The 1-year retention rates for bDMARDs were 69% and 64% for tocilizumab and abatacept, respectively vs. 46% for TNF-inhibitor (TNFi). CONCLUSION: Risk assessment using IPI predicted Persistent-LPD. After LPD regression, non-TNFi tended to have higher retention rates.

2019 Diagnostic criteria for mixed connective tissue disease (MCTD): From the Japan research committee of the ministry of health, labor, and welfare for systemic autoimmune diseases.

OBJECTIVE: To update and revise the diagnostic criteria for mixed connective tissue disease (MCTD) issued by the Japan Research Committee of the Ministry of Health, Labor, and Welfare (MHLW), a round table discussion by experts from rheumatology, dermatology, and pediatric medicine was conducted in multiple occasions. METHODS: The definition of MCTD, and items included in the diagnostic criteria were generated by consensus method and evaluation using clinical data of typical and borderline cases of MCTD, by applying to the diagnostic criteria for MCTD proposed in 1996 and 2004 by the Research Committee of MHLW. RESULTS: To the end, all committee members reached consensus. Then, the criteria were assessed in an independent validation cohort and tested against preexisting criteria. The revised criteria facilitate an understanding of the overall picture of this disease by describing the concept of MCTD, common manifestations, immunological manifestation and characteristic organ involvement. Conditions with characteristic organ involvement include pulmonary arterial hypertension, aseptic meningitis and trigeminal neuropathy. Even if the overlapping manifestations are absent, MCTD can be diagnosed based on the presence of the characteristic organ involvement. Furthermore, the criteria were validated for applicability in actual clinical cases, and public comments were solicited from the Japan College of Rheumatology and other associated societies. CONCLUSION: After being reviewed through public comments, the revised diagnostic criteria have been finalized.

Precision medicine using different biological DMARDs based on characteristic phenotypes of peripheral T helper cells in psoriatic arthritis.

Objectives: We sought to investigate the selection of specific biological DMARDs (bDMARDs) based on characteristic lymphocyte phenotypes for treating PsA. Methods: Of 64 patients with PsA resistant to MTX, 26 underwent bDMARDs therapy selected according to phenotypic differences in peripheral helper T cells on 8-colour flow cytometry. The efficacies of this strategic treatment and the standard treatment administered to the other 38 patients were evaluated at 6 months. Results: The 26 patients with PsA in the strategic treatment group were classified into the following four types based on peripheral blood analysis: (i) CXCR3+CCR6-CD38+HLA-DR+ activated Th1 cell-predominant type, (ii) CXCR3-CCR6+ CD38+HLA-DR+ activated Th17 cell-predominant type, (iii) Th1/Th17-high type and (iv) Th1/Th17-low type. Accordingly, ustekinumab was administered to the activated Th1 cell-predominant patients, secukinumab to the activated Th17 cell-predominant patients, secukinumab or TNF inhibitor to the Th1/Th17-high patients, and TNF inhibitor to the Th1/Th17-low patients. After 6 months of strategic treatment, there was a significant decrease in simplified disease activity index (SDAI) (from 16.2 to 3.52), DAS28 (ESR) (from 4.13 to 2.27) and psoriasis area and severity index (from 8.36 to 2.40). Low disease activity by SDAI was achieved in 24 (92.3%) of the 26 patients. The rate of low disease activity achievement according to SDAI at 6 months was significantly higher in the strategic bDMARDs treatment group compared with that of the standard bDMARDs treatment group. Conclusion: Strategic treatment in which different bDMARDs were selected according to phenotypic differences in helper T cells showed significantly higher efficacy than standard bDMARD therapy, indicating the value of precision medicine.

Significance of nailfold videocapillaroscopy in patients with idiopathic inflammatory myopathies.

Objective: The aim of this study was to investigate the clinical and immunological significance of nailfold videocapillaroscopy (NVC) abnormalities in patients with idiopathic inflammatory myopathies (IIMs). Methods: Seventy consecutive Japanese patients with untreated IIMs, enrolled between April 2014 and August 2017, were prospectively studied. Clinical features, NVC findings, autoantibody profile by immunoprecipitation and ELISA, and histopathological findings of skin biopsies of DM rash were assessed at baseline and after 1-year of immunosuppressive therapy. Results: NVC abnormalities were found in 55.7% (39/70) of IIM patients, with significantly higher prevalence in DM (65.4%) compared with PM (27.8%) (P = 0.01). In subsets of patients classified by autoantibody specificities, the prevalence of NVC abnormalities was significantly higher in patients with anti-MDA5 (87.5%) and anti-transcriptional intermediary factor 1γ (88.9%) vs anti-aminoacyl-tRNA synthetase (26.9%, P < 0.001). Perivascular lymphocytic infiltration in the upper dermis of skin rash biopsy of DM was more severe in patients with NVC abnormalities (P < 0.05). Unexpectedly, NVC abnormalities disappeared in 75% of IIM patients after 1-year of immunosuppressive therapy in contrast to stable NVC changes seen in scleroderma patients. Conclusion: Nailfold microvascular abnormalities were common in DM patients, associated with anti-MDA5 and transcriptional intermediary factor 1γ antibodies, and perivascular inflammation in skin histology. NVC abnormalities in IIMs may become clinically useful markers for defining subsets of DM and understanding the pathogenesis of the clinical features seen in these patients.

Regulatory Mechanism of The Induction of Regulatory T Cells through Growth Factors Released by Human Mesenchymal Stem Cells.

Mesenchymal stem cells (MSCs) undergo self-renewal and differentiation into multiple lineages. They exert anti-inflammatory and immunomodulatory effects via either cell-cell contact or via the production of soluble factors. Various anti-inflammatory and immunomodulatory mechanisms have been identified using experimental murine MSCs. The most representative mechanism is the induction of FOXP3+ regulatory T cells (Treg cells) via the production of transforming growth factor (TGF)-ß, which has also been reported in human MSCs. Recent studies have demonstrated that insulin-like growth factor (IGF) is also involved in the induction of FOXP3+ Treg cells. We previously demonstrated that the induction of FOXP3+ Treg cells by IGF is suppressed by the expression of IGF-binding protein-4 (IGFBP-4), which is an inhibitor of IGF. Because human MSCs produce both IGFs and IGFBP4, they may be considered to maintain immunological homeostasis by positive regulation of Treg cells through the production of growth factors as well as by a negative regulatory mechanism. Although human MSCs have already been applied in regenerative therapy and autoimmune disease treatment, control of their positive and negative regulatory mechanisms is expected to lead to more efficient clinical applications.

Optimal Biologic Selection for Treatment of Psoriatic Arthritis: the Approach to Precision Medicine.

PURPOSE OF REVIEW: This review describes previously reported findings on optimal biologic agent selection for psoriatic arthritis (PsA) treatment and outlines our approach to developing precision medicine techniques for targeted treatment of this disease. RECENT FINDINGS: Clinical trials have reported the effectiveness of numerous biologics with different targets, such as tumor necrosis factor-α, interleukin (IL)-17A, IL-17 receptor, IL-12/23(p40), and IL-23(p19) for the treatment of PsA. Although several studies have suggested specific predictors of treatment responses to each biologic, how biologics are differentially chosen in each patient remains unclear. Recent reports indicate the possibility of treating PsA using precision medicine based on individual immunological phenotypes. Because PsA exhibits numerous symptoms, selecting an optimal biologic for each patient may be important. The establishment of appropriate selection guidelines will require further clinical trials.

Induction of Regulatory T Cells and Its Regulation with Insulin-like Growth Factor/Insulin-like Growth Factor Binding Protein-4 by Human Mesenchymal Stem Cells.

Human mesenchymal stem cells (MSCs) are multipotent and exert anti-inflammatory effects, but the underlying mechanism remains to be elucidated. In the current study, we investigated the regulatory mechanism of regulatory T cell (Treg) induction through the growth factors released by human MSCs. Human naive CD4+ T cells were stimulated with anti-CD3/28 Abs and cocultured with human MSC culture supernatant for 48 h. The proliferation and cytokine production of CD4+ T cells and surface molecule expression on CD4+ T cells were evaluated. The proliferation of anti-CD3/28 Abs-stimulated CD4+ T cells was suppressed by the addition of human MSC culture supernatant; in addition, the production of IL-10 and IL-4 increased. The human MSC culture supernatant induced CD4+FOXP3+ Tregs that expressed CD25, CTLA-4, glucocorticoid-induced TNFR-related protein, insulin-like growth factor (IGF)-1R, and IGF-2R, showing antiproliferative activity against CD4+ T cells. In addition, the induction of Tregs by human MSC culture supernatant was enhanced by the addition of IGF and suppressed by the inhibition of IGF-1R. In contrast, a significant amount of IGF binding protein (IGFBP)-4, an inhibitor of IGF action, was detected in the human MSC culture supernatant. After neutralization of IGFBP-4 in the human MSC culture supernatant by anti-IGFBP-4 Ab, Treg numbers increased significantly. Thus, our results raise the possibility that human MSC actions also involve a negative-regulatory mechanism that suppresses Treg proliferation by releasing IGFBP-4. The results of this study suggest that regulation of IGF may be important for treatments using human MSCs.

Differential effects of biological DMARDs on peripheral immune cell phenotypes in patients with rheumatoid arthritis.

Objective: The aim of this study was to assess the therapeutic effects of biological DMARDs (bDMARDs) on the diversity of immune cell phenotypes in peripheral blood of patients with RA. Methods: Peripheral immune cell phenotypes were determined in 108 RA patients who were non-responsive to conventional DMARDs and 33 healthy control subjects by eight-colour flow cytometry. We also examined the correlation between the phenotypes and clinical findings and assessed the effects of 24-week treatment with bDMARDs. Results: The proportions of T follicular helper (Tfh) cells, IgD- CD27- double negative B cells and plasmacytoid dendritic cells (pDCs) were higher in patients with active RA than in healthy control. The percentages of memory T cells, Th17 and Tfh cells correlated with autoantibody titres, whereas that of plasmablasts correlated with disease activity scores. Treatment with TNF inhibitors reduced the proportion of pDCs, while tocilizumab reduced the proportion of double-negative B cells but increased naïve and activated Treg cells. Abatacept treatment resulted in marked decrease in the proportion of activated Tfh but slightly reduced Th17 and Treg cells. The proportion of Tfh cells was an independent and significant predictor of the response to abatacept therapy. Conclusion: Molecular targeted therapies induced different changes in different immune cell phenotypes. Among the phenotypes, Tfh cells seem a potential target for abatacept. Immunophenotypic analysis might be useful for prediction of the response to bDMARDs.

Comparison of the efficacies of abatacept and tocilizumab in patients with rheumatoid arthritis by propensity score matching.

OBJECTIVE: To compare the clinical outcomes at 1 year after the treatment with either abatacept or tocilizumab in patients with rheumatoid arthritis in routine clinical practice. METHODS: To overcome potential bias in allocation to treatment with abatacept or tocilizumab, a propensity score based on multiple baseline characteristics variables was calculated and 102 of 194 patients treated with abatacept and 102 of 273 patients treated with tocilizumab were statistically extracted. Clinical outcomes were assessed. RESULTS: The baseline characteristics were statistically comparable. At week 52, 72%/69% of patients (abatacept/tocilizumab) were still receiving treatment. The Simplified Disease Activity Index (SDAI) decreased from 28.7/27.7 at baseline to 14.0/12.5 at week 52 with abatacept/tocilizumab, respectively. At week 52, the remission rates for abatacept/tocilizumab were 18%/20%, respectively. No statistical difference in clinical efficacy between abatacept and tocilizumab was seen. Moreover, a subanalysis showed that abatacept and tocilizumab had similar effectiveness with or without methotrexate. However, prognostic factors at baseline contributing to the Clinical Disease Activity Index at week 52 were different between the two groups by multiple regression analysis. A higher rheumatoid factor (RF) titre and lower SDAI at baseline were associated with lower SDAI at week 52 in patients treated with abatacept, whereas patients receiving tocilizumab with a lower Health Assessment Questionnaire Disability Index and who were biologics-naïve at baseline had a lower SDAI at week 52. CONCLUSIONS: We compared patients treated with abatacept or tocilizumab after statistical adjustment by propensity score matching. Clinical efficacies, including SDAI, were comparable in both treatment groups. However, the predictive factors were different: abatacept appears to benefit patients with higher RF titres, and early induction of tocilizumab is an important factor for good clinical efficacy.

Study on the safety and efficacy of tocilizumab, an anti-IL-6 receptor antibody, in patients with rheumatoid arthritis complicated with AA amyloidosis.

OBJECTIVES: Although treatment of rheumatoid arthritis (RA) has progressed by the use of biologics, amyloid A (AA) amyloidosis is still an intractable complication in patients with RA. In the present study, safety and efficacy of 1-year treatment with an anti-IL-6 receptor antibody tocilizumab (TCZ) on RA and AA amyloidosis were estimated. METHODS: TCZ (8 mg/kg every 4 weeks) was administered to five RA patients complicated with AA amyloidosis. The primary end point was improvement in renal dysfunction and the secondary end point was CDAI at 1 year after the treatment. RESULTS: An improvement in the renal dysfunction, including urinary protein secretion, was found, in four patients including two patients who were refractory to etanercept, with a remarkable decrease of SAA concentration, and the progression of organ dysfunction was prevented at 1 year in all patients treated with TCZ. The mean clinical disease activity index decreased from 33.9 to 4.7 (p = 0.012) in five patients treated with TCZ for 1 year. Three non-serious adverse events were observed in two patients. CONCLUSIONS: TCZ ameliorates renal dysfunction in RA patients complicated with AA amyloidosis who are refractory to conventional therapies, thereby suggesting that TCZ has a potential to regulate AA amyloidosis.

CT informs detection and treatment options in rheumatoid arthritis complicated by pulmonary non-tuberculous mycobacterial disease from the FIRST registry.

OBJECTIVE: To investigate the early detection of pulmonary non-tuberculous mycobacterial (PNTM) disease by CT before the initiation of molecular-targeted therapeutic drugs in patients with rheumatoid arthritis (RA) and the efficacy and safety of combined treatment with antibiotics. METHODS: Patients with RA underwent chest CT before the introduction of molecular-targeted therapies in the Further Improvement of Rheumatoid arthritis Treatment registry. The primary endpoint was the number of patients who were detected by CT as having PNTM disease, complicating RA. RESULTS: Of 4447 patients with RA who underwent chest CT, 107 had suspected PNTM disease, and 33 diagnoses were confirmed by culture. In 14 of the 33 patients, plain radiographs showed no abnormalities; PNTM disease was only observed on CT scans. The prevalence of PNTM disease in patients with RA requiring molecular-targeted treatment was six times higher than that in healthy individuals. 31 patients initiated molecular-targeted therapeutic drugs in combination with anti-NTM treatment, and 28 were followed up for 24 months. No significant difference was observed in the retention rate and RA disease activity at 24 months between the PNTM and non-PNTM groups. Coexisting PNTM disease did not affect treatment discontinuation. None of the 28 patients in the PNTM group experienced exacerbation of PNTM disease. CONCLUSION: CT screening before the initiation of molecular-targeted treatment enabled the detection of asymptomatic PNTM that was undetectable on plain radiographs. This study showed that molecular-targeted therapeutic drugs in combination with anti-NTM treatment could control the disease activity of both PNTM and RA.

CCL19-Positive Lymph Node Stromal Cells Govern the Onset of Inflammatory Arthritis via Tropomyosin Receptor Kinase.

OBJECTIVE: The study objective was to assess the role of CCL19+ lymph node stromal cells of the joint-draining popliteal lymph node (pLN) for the development of arthritis. METHODS: CCL19+ lymph node stromal cells were spatiotemporally depleted for five days in the pLN before the onset of collagen-induced arthritis (CIA) using Ccl19-Cre × iDTR mice. In addition, therapeutic treatment with recombinant CCL19-immunoglobulin G (IgG), locally injected in the footpad, was used to confirm the results. RNA sequencing of lymph node stromal cells combined with T cell coculture assays using tropomyosin receptor kinase (Trk) family inhibitors together with in vivo local pLN small interfering RNA (siRNA) treatments were used to elucidate the pathway by which CCL19+ lymph node stromal cells initiate the onset of arthritis. RESULTS: Spatiotemporal depletion of CCL19+ lymph node stromal cells prevented disease onset in CIA mice. These inhibitory effects could be mimicked by local CCL19-IgG treatment. The messenger RNA sequencing analyses showed that CCL19+ lymph node stromal cells down-regulated the expression of the tropomyosin receptor kinase A (TrkA) just before disease onset. Blocking TrkA in lymph node stromal cells led to increased T cell proliferation in in vitro coculture assays. Similar effects were observed with the pan-Trk inhibitor larotrectinib in cocultures of lymph node stromal cells of patients with rheumatoid arthritis and T cells. Finally, local pLN treatment with TrkA inhibitor and TrkA siRNA led to exacerbated arthritis scores. CONCLUSION: CCL19+ lymph node stromal cells are crucially involved in the development of inflammatory arthritis. Therefore, targeting of CCL19+ lymph node stromal cells via TRK could provide a tool to prevent arthritis.

Dermal mast cell density in fingers reflects severity of skin sclerosis in systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc) is characterized by skin sclerosis, which develops from the distal extremities and spreads to the trunk. Although several reports have implied the involvement of mast cells in SSc based on examination of forearm skin specimens, there have been no studies that examined digital skin specimens. METHODS: Skin biopsies were obtained from the distal one-third of the forearm and between distal and proximal interphalangeal joints from 46 SSc patients, as well as from 29 non-SSc patients and normal controls. Dermal mast cells were detected histologically using NanoZoomer digital pathology. RESULTS: Dermal mast cell density was significantly higher in both the forearms and fingers in SSc patients compared with non-SSc patients and normal controls. Digital dermal mast cell density was significantly higher in patients with diffuse cutaneous SSc than in local cutaneous SSc patients and also in the anti-topoisomerase I antibody-positive group than in the negative group, though such tendency was not noted in the forearm dermis. Interestingly, digital dermal mast cell density tended to correlate negatively but significantly with disease duration, suggesting the possible involvement of dermal mast cells in the early pathological process. CONCLUSION: Digital accumulation of toluidine blue- and/or c-Kit-positive dermal mast cells appears to be involved in the early stages of the pathological processes of SSc, especially in patients positive for anti-topoisomerase I antibody.

A case of glucocorticoid-resistant adult Still's disease complicated by pulmonary hypertension and interstitial lung disease.

Adult Still's disease (ASD) is rarely complicated by pulmonary hypertension (PH). A 76-year-old woman experienced ASD relapse with repeated exacerbation of PH and interstitial lung disease. Although she had been treated with immunosuppressive agents and pulmonary vasodilators, the ASD relapsed with fever, rash, increased inflammatory responses and exacerbated interstitial lung disease, and PH. The pathology of PH appeared to encompass groups 1 [pulmonary arterial hypertension (PAH)], 1' [pulmonary veno-occlusive disease (PVOD)], and 3. Remission induction therapy with high-dose glucocorticoid and tocilizumab was administered, and switching or adding pulmonary vasodilators was also attempted. As the disease activity of ASD decreased, the mean pulmonary arterial pressure and pulmonary vascular resistance improved. PH is an extremely rare form of organ dysfunction in individuals with ASD. Like other systemic autoimmune diseases, PH (PAH or PVOD) can determine the prognosis of ASD. Because of PH's rarity, it is important to sufficiently evaluate its pathology, considering the possibility that PH is not clinically classified as PAH (group 1), and to administer immunosuppressive therapy and vasodilators according to the pathology.

Generation-Dependent Retention Rates and Reasons for Discontinuation of Molecular Targeted Therapies in Patients with Rheumatoid Arthritis: From FIRST Registry.

INTRODUCTION: The study aimed to optimize medical care for elderly patients with rheumatoid arthritis (RA) by examining the 3-year continuation rate of different molecular targeted therapies across age groups in Japan, which has a significant elderly population. METHODS: The study included patients with RA who started molecular targeted therapies between 2013 and 2019 and divided them into three age groups. The primary outcome was to assess the 3-year continuation rate of each drug and analyze reasons for treatment discontinuation using inverse probability of treatment weighting. RESULTS: Among 2292 patients analyzed, tumor necrosis factor (TNF) inhibitors were most commonly used in those younger than 65 years of age (43.5%), while Janus kinase (JAK) inhibitors were also utilized (17.1%). In contrast, JAK inhibitors were less frequently used in patients aged 75 years and older (7.8%), with cytotoxic T lymphocyte antigen 4 immunoglobulin fusion proteins (CTLA4-Ig) being the most common (39.2%). JAK inhibitors and anti-interleukin-6 receptor (IL-6R) antibodies had higher continuation rates than other drugs in patients under 65 years (p < 0.001). For those aged 65-74 years, JAK inhibitors and CTLA4-Ig had higher continuation rates (p < 0.001), while among those aged 75 years and older, CTLA4-Ig and IL-6R antibodies had higher continuation rates (p < 0.001). Inadequate efficacy was the main reason for discontinuation in all age groups, while infection leading to discontinuation increased with age. CONCLUSIONS: The study highlights the need to consider different age groups separately in elderly RA care. Among patients aged 75 years and older, abatacept and anti-IL-6R antibodies showed the highest continuation rates, suggesting their potential suitability and efficacy for this specific age cohort.

Structural damages disturb functional improvement in patients with rheumatoid arthritis treated with etanercept.

Tumor necrosis factor (TNF) inhibitors have produced improvements in clinical, radiographic, and functional outcomes in rheumatoid arthritis (RA) patients. However, it remains unclear whether factors affecting physical functions remain following TNF therapy. The objective of our study was to assess factors affecting improvement of physical functions and to shed light on relations to disease activity and structural changes in patients with RA treated with etanercept. The study enrolled 208 patients, all of whose composite measures regarding clinical, radiographic, and functional estimation both at 0 and 52 weeks after etanercept therapy were completed. Mean disease duration of 208 patients was 9.6 years, mean Disease Activity Score for 28 joints (DAS28) was 5.4, and mean van der Heijde modified total Sharp score (mTSS) was 94.6. Mean Health Assessment Questionnaire Disability Index (HAQ-DI) improved from 1.4 at 0 weeks to 1.0 at 52 weeks after etanercept therapy, a 31% reduction, which was much less than changes in DAS28 and mTSS. By multivariate analysis, HAQ-DI and mTSS at baseline were significantly correlated HAQ remission. Median HAQ-DI improved in 100 versus 20% of the HAQ-DI ≤ 0.6 versus ≥ 2.0 groups, respectively. The mTSS cutoff point at baseline to obtain HAQ remission was 55.5. During etanercept treatment in the mTSS <55.5 versus >55.5 groups, median HAQ-DI improved in 70 versus 39%; remission was achieved in 59 versus 33%; and there was no improvement in 14 versus 30%, respectively. HAQ-DI improvement was significantly correlated with that of DAS28 but not of mTSS. In conclusion, higher HAQ and mTSS at baseline inhibits HAQ-DI improvement within 1 year of etanercept treatment, and the cutoff point necessary for mTSS to improve physical functions in patients with RA was 55.5.