A case of cryopyrin-associated periodic syndrome due to somatic mosaic mutation complicated with recurrent circinate erythematous psoriasis.

Cryopyrin-associated periotic syndrome (CAPS) is a rare autoinflammatory disease (AID) caused by genetic variants in innate immunity genes. AIDs, including CAPS, mediate proinflammatory cytokines such as interleukin (IL)-1 and IL-18 and result in severe systemic inflammation. A gain-of-function mutation in the NLRP3 gene, which encodes the protein cryopyrin, was identified to be responsible for CAPS in 2001, and since then several additional pathogenic mutations have been found. Moreover, other phenotypes have been identified based on severity and symptomatology, including familial cold autoinflammatory syndrome, Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID)/chronic neurologic cutaneous articular syndrome (CINCA). Prompt diagnosis of CAPS remains challenging, however, due to unspecific, extensive clinical signs, and delayed diagnosis and treatment targeting IL-1 lead to multiorgan damage. Another factor complicating diagnosis is the existence of somatic mosaic mutations in the NLRP3 gene in some cases, resulting in symptoms and clinical courses that are atypical. The frequency of somatic mosaic mutations in CAPS was estimated to be 19% in a systematic review. Psoriasis is a chronic inflammatory skin disease that affects about 3% of the global population. Although no reports have shown complication between CAPS and psoriasis, these diseases have several similarities and potential relationships, for instance activation of Th17 cells in the dermis and increased NLRP3 gene expression in psoriatic skin compared with normal skin. Here we report a case of CAPS due to a somatic mosaic mutation with recurrent circinate erythematous psoriasis.

Polyarteritis nodosa diagnosed in a young male after COVID-19 vaccine: A case report.

In response to the coronavirus disease 2019 pandemic, the coronavirus disease 2019 vaccine was rapidly developed and the effectiveness of the vaccine has been established. However, various adverse effects have been reported, including the development of autoimmune diseases. We report a case of new-onset polyarteritis nodosa in a 32-year-old male following the coronavirus disease 2019 vaccination. The patient developed limb pain, fever, pulmonary embolism, multiple subcutaneous nodules, and haematomas. Skin biopsy revealed necrotising inflammation accompanied by fibrinoid necrosis and high inflammatory cell infiltration in the walls of medium to small arteries. The symptoms resolved following corticosteroid treatment. Although it is difficult to prove a relationship between the vaccine and polyarteritis nodosa, similar cases have been reported and further reports and analyses are therefore necessary.

Performance of classification and diagnostic criteria for IgG4-related disease and comparison of patients with and without IgG4-related disease.

IgG4-related disease (IgG4-RD) was recently described in Japan. It is characterised by extensive organ involvement with tissue fibrosis. We assessed the performance of the 2019 American College of Rheumatology and European League Against Rheumatism (ACR/EULAR) classification criteria and the 2020 revised comprehensive diagnostic (RCD) criteria as well as differences between patients with and without IgG4-RD. In this retrospective, single-centre study of 50 patients admitted with suspected IgG4-RD, we evaluated the sensitivity and specificity of both criteria. We also compared clinical characteristics and laboratory data of patients with IgG4-RD (n = 42) and patients without IgG4-RD (n = 8). The ACR/EULAR classification criteria had 88.1% sensitivity and 87.5% specificity for IgG4-RD diagnosis. The RCD criteria had 100% sensitivity and 50% specificity. Patients with IgG4-RD had significantly more affected organs (p = 0.002). Patients with a single affected organ and IgG4-RD had significantly higher serum IgG4/IgG ratios (p = 0.027), lower serum C-reactive protein levels (p = 0.020), and lower total haemolytic complement activity (p = 0.044) than those without IgG4-RD. The ACR/EULAR classification criteria have high specificity and the RCD criteria have high sensitivity for diagnosing IgG4-RD. The number of affected organs is important for diagnosing IgG4-RD.

Changes in anti-MDA5 antibody titres and serum cytokine levels before and after diagnosis of anti-MDA5 antibody-positive dermatomyositis.

OBJECTIVES: Anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive DM is characterized by rapidly progressive interstitial lung disease and has a poor prognosis. We aimed to investigate whether anti-MDA5 antibody titres and cytokine levels predict clinical course, and evaluate changes in both parameters before and after diagnosis. METHODS: This was a retrospective, single-centre study in 38 patients with anti-MDA5 antibody-positive DM. We compared clinical characteristics and laboratory data at diagnosis between patients in the treatment response (n = 23) and non-response (n = 15) groups, and between those in the relapse (n = 5) and non-relapse (n = 24) groups. We also measured serum anti-MDA5 antibody titres and cytokine levels before and after diagnosis. RESULTS: The non-response group was older, had a higher ground-glass opacity score, lower PaO2/FiO2, higher CRP level, and higher anti-MDA5 antibody titre than the response group. No cytokines significantly differed between groups at diagnosis. The relapse group had a significantly higher anti-MDA5 antibody titre than the non-relapse group. In the survivor group, the anti-MDA5 antibody titre and levels of IFN-α, IFN-γ, monocyte chemotactic protein-1 (MCP-1), IL-6, IL-33, CRP, and ferritin were significantly lower 6 months post-treatment than at diagnosis. Macrophage-associated cytokines such as IL-6, IL-8, IL-18 and MCP-1 increased after anti-MDA5 antibody positivity in three patients who were anti-MDA5 antibody-positive before diagnosis. CONCLUSION: The anti-MDA5 antibody titre at diagnosis may predict the clinical course. Levels of macrophage-associated cytokines significantly declined at 6 months post-treatment, and they may have increased after anti-MDA5 antibody titre positivity.

Systematic review and meta-analysis for 2023 clinical practice guidelines of the Japan Research Committee of the Ministry of Health, Labour, and Welfare for Intractable Vasculitis for the management of ANCA-associated vasculitis.

OBJECTIVES: The objective of this study is to provide evidence for the revision of clinical practice guidelines for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis by the Japan Research Committee for Intractable Vasculitis. METHODS: PubMed, CENTRAL, and the Japan Medical Abstracts Society databases were searched for articles published between 2015 and 2020 to update the systematic review for existing clinical questions, while PubMed, CENTRAL, EMBASE, and the Japan Medical Abstracts Society were searched for articles published between 2000 and 2020 to conduct a systematic review for newly developed clinical questions. The certainty of evidence was assessed with the GRADE approach. RESULTS: For remission induction, when used in conjunction with cyclophosphamide or rituximab, reduced-dose glucocorticoid lowered the risk of serious adverse events compared to standard-dose glucocorticoid. Avacopan improved sustained remission at 12 months compared to high-dose glucocorticoid. Addition of plasma exchange to remission induction therapy did not reduce the risk of death, end-stage kidney disease, or relapse. For remission maintenance, rituximab reduced the risk of relapse compared to azathioprine. Long-term rituximab or azathioprine reduced the risk of relapse compared to short-term rituximab or azathioprine, respectively. CONCLUSIONS: This systematic review provided evidence required to develop the 2023 clinical practice guideline for the management of ANCA-associated vasculitis.

[Resolution of dasatinib-associated lymphadenopathy following discontinuation of dasatinib in patients with chronic myeloid leukemia].

This study reports two cases of dasatinib-associated lymphadenopathy (DAL). Case 1 involved a 58-year-old man diagnosed with chronic myelogenous leukemia (CML). After 13 months of starting on dasatinib treatment, a molecular response (MR) 4.5 was achieved. Due to the loss of MMR, dasatinib was discontinued at 39 months but restarted at 42 months. Right cervical lymphadenopathy appeared 51 months after starting the treatment. DAL was diagnosed based on the findings of a cervical lymph node biopsy. After dasatinib was switched to ponatinib, the lymphadenopathy disappeared without recurrence. In case 2, a 54-year-old man was diagnosed with CML. He was started on dasatinib and MR 4.5 was achieved after 6 months. Left cervical lymph node adenopathy appeared 21 months later, and a diagnosis of DAL was made based on the findings of a cervical lymph node biopsy. After discontinuation of dasatinib, cervical lymph node adenopathy disappeared without recurrence. The possibility of DAL should be considered if lymphadenopathy is observed during dasatinib treatment.

Clinical impact of cigarette smoking on the outcomes of allogeneic hematopoietic stem cell transplantation: a multicenter retrospective study.

Smoking is associated with a high risk for different diseases including respiratory tract infections in immunocompetent patients. However, data about the effects of cigarette smoking on the outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) are limited. Therefore, we retrospectively investigated 608 patients aged ≥20 years with hematological disorders who received their first allo-HSCT at our group of hospitals between 2000 and 2015, and evaluated the impact of cigarette smoking before allo-HSCT on clinical outcomes by dividing patients into two groups according to the Brinkman index (BI) (nonsmokers or light smokers [BI: 0-500] and heavy smokers [BI: ≥ 500]). Multivariate analyses showed that heavy smoking was associated with a high 5-year cumulative incidence of chronic graft-versus-host disease (cGVHD) (hazard ratio [HR]: 1.73, 95% confidence interval [CI]: 1.15-2.61, p < 0.01). The 5-year overall survival (HR: 1.16, 95% CI: 0.86-1.58, p = 0.33) and disease-free survival (HR: 1.12, 95% CI: 0.83-1.52, p = 0.45) were similar between the two groups. Hence, cigarette smoking is correlated with cGVHD, although prospective studies must be conducted to further verify this result.

A case series of patients treated with inotuzumab ozogamicin for acute lymphoblastic leukemia relapsed after allogeneic hematopoietic cell transplantation.

This single-center retrospective study was performed in consecutive patients with acute lymphoblastic leukemia who relapsed after allogeneic hematopoietic cell transplantation (HCT) and received salvage therapy using inotuzumab ozogamicin (InO). Ten patients (median age: 27 years) treated between June 2018 and July 2020 who met the eligibility criteria were included in this study. Nine patients received InO in one cycle and seven of these patients achieved complete hematological remission after salvage chemotherapy including InO. Negative minimal residual disease was confirmed in all four evaluable patients. Eight patients were successfully bridged to the subsequent HCT. After HCT, veno-occlusive disease (VOD) developed in three patients, and caused the death of one. No patient received maintenance therapy. At present, five patients are disease-free and alive, and the overall and progression-free survival rates at 1 year were 60% and 40%, respectively. High rates of disease remission and bridging to HCT with comprehensive treatments including InO may have contributed to favorable outcomes. However, further investigation is needed to reduce post-HCT complications including VOD.

Successful treatment with lenalidomide for relapsed adult T-cell leukemia/lymphoma after cord blood cell transplantation.

The prognosis for relapsed adult T-cell leukemia/lymphoma (ATL) after allogeneic hematopoietic stem cell transplantation is poor. Here, we report the case of a 67-year-old man who survived for 26 months after treatment with lenalidomide for post-transplant relapsed ATL. He underwent induction therapy with two cycles of modified VCAP-AMP-VECP and achieved complete remission. He received cord blood cell transplantation following a reduced-intensity conditioning regimen. Seven months after transplantation, swelling of the systemic lymph nodes appeared, and relapsed ATL was diagnosed based on a biopsy of the cervical lymph node. Treatment with 10 mg of lenalidomide induced partial remission. At 18 months after transplantation, skin tumors were successfully treated by increasing the dose of lenalidomide to 15 mg with the emergence of skin graft-versus-host disease. Although he died from ATL at 34 months after transplantation, systemic relapsed lesions were controlled by treatment with lenalidomide for 26 months. Our case suggests that lenalidomide is well tolerated and is an effective option for the treatment of post-transplant relapsed ATL.

Computed tomography-defined sarcopenia: prognostic predictor of nonrelapse mortality after allogeneic hematopoietic stem cell transplantation: a multicenter retrospective study.

We analyzed clinical cutoffs for defining computed tomography (CT) methods for sarcopenia and examined the prognostic value of CT for allogeneic hematopoietic stem cell transplantation (allo-HCST) outcomes of patients with myeloid malignancy. One hundred twenty-five adult patients with acute myeloid leukemia and myelodysplastic syndrome who underwent first allo-HSCT between 2000 and 2017 were included. Sarcopenia was assessed using CT-based skeletal muscle index (SMI) and mean muscle attenuation at L3. A statistical difference in SMI was confirmed between sarcopenia (n = 52) and nonsarcopenia (n = 73) patients. There were no significant correlations of muscularity with age, performance status, or other characteristics of HSCT. After 2 years, overall survival (OS) was 43.5% and 70.1%, disease-free survival was 52.9% and 68.6%, nonrelapse mortality (NRM) was 20.8% and 8.4%, incidence of acute GVHD (≥ grade 2) was 38.8% and 39.1%, that of chronic GVHD was 53.2% and 37.3%, and median duration of hospitalization was 88 days and 74 days (P = 0.026), respectively, in the sarcopenia and nonsarcopenia groups. Multivariate analysis showed that presence of sarcopenia is a novel adverse factor for high NRM and poor OS. Pretransplant CT-defined sarcopenia is correlated with decreased OS, increased NRM, and prolonged hospitalization.

Impact of graft sources on immune reconstitution and survival outcomes following allogeneic stem cell transplantation.

We evaluated the kinetics of immune reconstitution (IR) after allogeneic hematopoietic cell transplantation (HSCT) and analyzed the clinical effect of IR on posttransplant outcomes. Absolute lymphocyte and its subset counts were measured using flow cytometry on days 28, 100, 180, 365, and 730 after transplantation in 358 adult patients who underwent HSCT between 2009 and 2017. On day 100 after HSCT, 310 surviving patients were analyzed. Bone marrow transplantation (BMT), peripheral blood stem cell transplantation (PBSCT), and cord blood transplantation (CBT) were performed in 119, 55, and 136 patients, respectively. Mature B-cell and differentiated natural killer (NK) cell subset counts significantly increased after CBT. The 2-year overall survival (OS), nonrelapse mortality (NRM), cumulative incidence of relapse, and chronic GVHD in BMT, PBSCT, and CBT were 62%, 67%, and 76% (P = .021); 17%, 17%, and 13% (P = .82); 33%, 40%, and 27% (P = .063); and 43%, 45%, and 28% (P = .025), respectively. Multivariate analysis showed that higher CD16+CD57- NK cell counts correlated with lower disease relapse, whereas higher CD20+ B-cell counts correlated with lower NRM. OS-favoring factors were higher CD16+CD57- NK cell count (hazard ratio, 0.36; 95% confidence interval, 0.22-0.60; P < .001) and CD20+ B-cell count (hazard ratio, 0.53; 95% confidence interval, 0.30-0.93; P < .001) and lower Disease Risk/HCT-Specific Comorbidity index score. Collective contribution of graft source-specific and event-related immune reconstitution might yield better posttransplant outcomes in CBT.

Predictive Values of Early Suppression of Tumorigenicity 2 for Acute GVHD and Transplant-related Complications after Allogeneic Stem Cell Transplantation: Prospective Observational Study

Objective: A soluble form of suppression of tumorigenicity 2 (sST2) has emerged as a biomarker for acute graft-versus-host disease (GVHD) and non-relapse mortality (NRM). We prospectively monitored sST2 levels during the early phase of hematopoietic stem cell transplantation (HSCT) and evaluated the clinical association with transplant-related complications including acute GVHD. Materials and Methods: Thirty-two adult Japanese patients who received a first allogeneic HSCT were enrolled in this study. Levels of sST2 were measured at fixed time points (pre-conditioning, day 0, day 14, day 21, and day 28). Results: The median age was 50.5 years (range=16-66). With a median follow-up of 21.5 months (range=0.9-35.4), 9 patients developed grade II-IV acute GVHD. Median sST2 levels on the day of HSCT were higher than baseline and reached the maximum value (92.7 ng/mL; range=0-419.7) on day 21 after HSCT. The optimal cut-off value of sST2 on day 14 for predicting grade II-IV acute GVHD was determined as 100 ng/mL by ROC analysis. The cumulative incidence of acute GVHD was 56.7% and 16.5% in the high- and low-sST2 groups, respectively (p<0.01). Multivariate analyses showed that high sST2 levels at day 14 were associated with a higher incidence of acute GVHD (hazard ratio=9.35, 95% confidence interval=2.92-30.0, p<0.01). The cumulative incidence of NRM was increased in the highs-ST2 group (33% vs 0%, p<0.01), but all the patients died of non-GVHD complications. Among 6 patients in the high-sST2 group without grade II-IV GVHD, 5 patients developed veno-occlusive disease (VOD) and one also had thrombotic microangiopathy (TMA). Conclusion: The early assessment of sST2 after HSCT yielded predictive values for the onset of acute GVHD and other transplant-related complications including VOD and TMA.

Impact of Cytomegalovirus Reactivation and Natural Killer Reconstitution on Outcomes after Allogeneic Hematopoietic Stem Cell Transplantation: A Single-Center Analysis.

Cytomegalovirus (CMV) reactivation and natural killer (NK) cell reconstitution are well-recognized immunologic events occurring after allogeneic stem cell transplantation (allo-SCT). We aimed to study the outcome of CMV reactivation (CMVR) and NK cell reconstitution in patients with hematologic malignancies after allo-SCT. We retrospectively studied 246 adult patients (152 men, 94 women; median age, 51 years [range, 18 to 69]) who underwent allo-SCT for hematologic malignancies at the Kanagawa Cancer Center. CMVR was defined as initiation of preemptive CMV therapy after pp65 antigenemia surveillance. All patients' lymphocyte subsets were monitored by flow cytometry at 180, 365, and 730 days post-transplant. The median follow-up period was 3.2 years (range, .8 to 9.6 years). CMVR occurred in 141 patients (57%) at a median of 45 days (range, 15 to 93). In patients without CMVR (CMVR-) versus those with CMVR (CMVR+), 5-year overall survival (OS), nonrelapse mortality (NRM), and cumulative incidence of relapse (CIR) were 79% versus 55% (P < .001), 3% versus 16% (P = .012), and 28% versus 38% (P = .09), respectively. CD8+ T cell and CD3-CD56+ NK cell subset were higher in CMVR+ patients at day 100 post-transplant. Multivariate analysis showed that adverse factors for OS were represented by no remission, CMVR, and lower CD16+CD57-NK cell counts. Overall, a higher NK cell subset significantly contributed to a lower CIR. Among subgroups of CMVR+ patients, CD16+CD57-NK cells represented a favorable factor for OS, NRM, and CIR. CMVR was an adverse event after allo-SCT. NK cell reconstitution may contribute to improved outcomes, especially in CMVR+ subgroups.

Impact of treatment-related weight changes from diagnosis to hematopoietic stem-cell transplantation on clinical outcome of acute myeloid leukemia.

We hypothesized that treatment-related weight loss is associated with worse outcomes following HSCT. Overall, 184 patients with AML who underwent induction therapy were classified according to d-BMI (BMI at transplant minus BMI at diagnosis) (kg/m2) as < -2, - 2 to + 2, and > + 2. At 1 year, OS was 67.9% (95% CI, 60.7-74.2), DFS was 64.1% (95% CI, 56.7-70.6), and GRFS was 40.2% (95% CI, 33.1-47.2). For d-BMI groups < - 2, - 2 to + 2, and > + 2, GRFS at 1 year was 16.1% (95% CI, 5.1-31.4), 45.4% (95% CI, 36.4-53.7), and 41.7% (95% CI, 22.2-60.1), respectively (P = 0.0067). Multivariate analysis showed that both worse OS (HR, 1.78; 95% CI, 1.02-3.14; P = 0.007) and GRFS (HR, 2.34; 95% CI, 1.26-4.35; P = 0.007) were associated with reduced BMI (d-BMI < - 2). Treatment-related weight reduction in AML was associated with poor outcome after HSCT.

The Association between Absence of Abdominal Pain and Mortality in Lower Intestinal Perforation in Patients with Autoimmune Rheumatic Diseases.

OBJECTIVE: To determine mortality and predictive factors for lower intestinal perforation (LIP) among patients with autoimmune rheumatic diseases. METHODS: This retrospective, single-center, observational study analyzed mortality rates in 31 autoimmune rheumatic disease patients with LIP who were admitted to our hospital from January 2002 to June 2017. The primary outcome was the mortality rate during hospitalization. RESULTS: The median age at the time of LIP was 61 years, and the survival rate at discharge was 64.5%. Eleven patients died of sepsis during hospitalization. Cox univariable analysis for mortality during hospitalization showed that absence of abdominal pain (hazard ratio (HR) 5.61, 95% confidence interval (CI) 1.38-22.9), higher age (HR 1.06, 95% CI 1.01-1.11), chronic kidney disease (HR 6.89, 95% CI 1.85-25.7), systemic vasculitis (HR 3.95, 95% CI 1.14-13.6), higher blood urea nitrogen (HR 1.02, 95% CI 1.01-1.04), higher serum creatinine (HR 1.41, 95% CI 1.06-1.87), and LIP due to malignancy (HR 14.3, 95% CI 1.95-105.1) significantly increased mortality. CONCLUSION: Abdominal pain was absent in 16% of LIP patients with autoimmune rheumatic diseases, and this absence was a poor prognostic factor in this cohort. Moreover, higher age, chronic kidney disease, systemic vasculitis, and LIP due to malignancy were associated with significantly increased mortality. Physicians should be aware of LIP in autoimmune disease patients with higher age, chronic kidney diseases, or systemic vasculitis even if patients reveal mild abdominal symptoms.