Effect of Recent Antirheumatic Drug on Features of Rheumatoid Arthritis-Associated Lymphoproliferative Disorders.

OBJECTIVE: In this study, we examine how advancements in novel antirheumatic drugs affect the clinicopathologic features of lymphoproliferative disorder (LPD) in patients with rheumatoid arthritis (RA). METHODS: In this multicenter study across 53 hospitals in Japan, we characterized patients with RA who developed LPDs and visited the hospitals between January 1999 and March 2021. The statistical tools used included Fisher's exact test, the Mann-Whitney U-test, the log-rank test, logistic regression analysis, and Cox proportional hazards models. RESULTS: Overall, 752 patients with RA-associated LPD (RA-LPD) and 770 with sporadic LPD were included in the study. We observed significant differences in the clinicopathologic features between patients with RA-LPD and those with sporadic LPD. Histopathological analysis revealed a high frequency of LPD-associated immunosuppressive conditions. Furthermore, patients with RA-LPD were evaluated based on the antirheumatic drugs administered. The methotrexate (MTX) plus tacrolimus and MTX plus tumor necrosis factor inhibitor (TNFi) groups had different affected site frequencies and histologic subtypes than the MTX-only group. Moreover, MTX and TNFi may synergistically affect susceptibility to Epstein-Barr virus infection. In case of antirheumatic drugs administered after LPD onset, tocilizumab (TCZ)-only therapy was associated with lower frequency of regrowth after spontaneous regression than other regimens. CONCLUSION: Antirheumatic drugs administered before LPD onset may influence the clinicopathologic features of RA-LPD, with patterns changing over time. Furthermore, TCZ-only regimens are recommended after LPD onset.

Multicenter Prospective Study of the Efficacy and Safety of Combined Immunosuppressive Therapy With High-Dose Glucocorticoid, Tacrolimus, and Cyclophosphamide in Interstitial Lung Diseases Accompanied by Anti-Melanoma Differentiation-Associated Gene 5-Positive Dermatomyositis.

OBJECTIVE: Interstitial lung disease (ILD) accompanied by anti-melanoma differentiation-associated gene 5 (anti-MDA-5)-positive dermatomyositis (DM) is often rapidly progressive and associated with poor prognosis. Because there is no established treatment, we undertook this study to prospectively evaluate the efficacy and safety of a combined immunosuppressive regimen for anti-MDA-5-positive DM patients with ILD. METHODS: Adult Japanese patients with new-onset anti-MDA-5-positive DM with ILD (n = 29) were enrolled at multiple study centers from 2014 to 2017. They were treated with a regimen of high-dose glucocorticoids (GCs), tacrolimus, and intravenous cyclophosphamide (IV CYC). Plasmapheresis was used if a patient's condition worsened after the regimen started. The primary end point was 6-month survival, which was compared between this group of patients and a historical control group (n = 15) consisting of anti-MDA-5-positive DM patients with ILD who received step-up treatment (high-dose GC and stepwise addition of immunosuppressant). Secondary end points were 12-month survival rate, adverse events, and changes in laboratory data. RESULTS: The combined immunosuppressive regimen group showed significantly higher 6-month survival rates than the step-up treatment group (89% versus 33%; P < 0.0001). Over a period of 52 weeks, improvements in anti-MDA-5 titers, serum ferritin levels, vital capacity, and chest high-resolution computed tomography scores were observed. The combined immunosuppressive regimen group received IV CYC nearly 20 days earlier with shorter intervals and tended to receive plasmapheresis more often than patients undergoing step-up treatment. Cytomegalovirus reactivation was frequently observed over 52 weeks. CONCLUSION: A combined immunosuppressive regimen is effective for anti-MDA-5-positive DM patients with ILD. Plasmapheresis can be used for additional effect in intractable disease. Patients should be carefully monitored for opportunistic infections during treatment.

Intravascular large B-cell lymphoma with a high titer of proteinase-3-anti-neutrophil cytoplasmic antibody mimicking granulomatosis with polyangiitis.

A 63-year-old man presented with fever, sinusitis, otitis, and high titers of proteinase-3 anti-neutrophil cytoplasmic antibody (PR3-ANCA). Granulomatosis with polyangiitis (GPA) was first suspected. However, nasal mucosa and skin biopsies revealed the presence of intravascular large B-cell lymphoma (IVLBCL). We present a rare case of IVLBCL with a high titer of PR3-ANCA mimicking GPA.

Presepsin and procalcitonin as biomarkers of systemic bacterial infection in patients with rheumatoid arthritis.

AIM: To assess the diagnostic values of presepsin and procalcitonin in patients with rheumatoid arthritis (RA) by identifying those with bacterial infection METHOD: During June 2014-September 2015, 126 patients with RA and 25 healthy controls were enrolled. RA patients were divided into an infection group and a non-infection group. Infection was diagnosed by clinical symptoms, microbiological or radiographic methods, and good response to antibiotics. Concentrations of plasma presepsin, serum procalcitonin, C-reactive protein (CRP), and white blood cell counts (WBC) were measured and compared in each group. The correlations with the Sequential Organ Failure Assessment (SOFA) Score and these markers were calculated. RESULTS: RA patients included 26 patients in the infection group, 45 patients in the CRP-positive non-infection group (CRP > 0.3 mg/dL), and 55 patients in the CRP-negative non-infection group (CRP < 0.3 mg/dL). Levels of presepsin and procalcitonin in the infection group were highest and significantly higher than those in the CRP-positive non-infection group (presepsin 682.8 ± 158.1 pg/mL vs. 192.0 ± 12.0 pg/mL [P < 0.0001]; procalcitonin 4.052 ± 1.637 ng/mL vs. 0.120 ± 0.032 ng/mL [(P < 0.0001]). According to receiver operating characteristic curve (ROC) analysis, presepsin and procalcitonin levels appeared to have a higher diagnostic accuracy for infection than CRP or WBC. For the infection group, the SOFA Score positively correlated with the concentration of presepsin but not with that of procalcitonin. CONCLUSION: Presepsin and procalcitonin may be useful to identify infection in RA patients. Presepsin may better reflect infection severity than procalcitonin.

Hypertrophic Pachymeningitis in Sjögren's Syndrome.

Although central nervous system manifestations seem common in primary Sjögren's syndrome, hypertrophic pachymeningitis is rare. We herein describe a case of Sjögren's syndrome that was associated with hypertrophic pachymeningitis. Sjögren's syndrome should be considered as a cause of hypertrophic pachymeningitis.

Dermatomyositis Associated with Lung Neuroendocrine Carcinoma.

Dermatomyositis is associated with various types of malignancy. However, the association of dermatomyositis with lung neuroendocrine carcinoma is rare. We herein report a case of dermatomyositis with lung neuroendocrine carcinoma.

Atypical Presenting Symptoms of Acute Onset Systemic Lupus Erythematosus with Enteritis and Cystitis.

Lupus enteritis and lupus cystitis are relatively rare manifestations of systemic lupus erythematosus. Some patients develop severe complications such as bowel perforation, infarction, obstruction, or irreversible bladder dysfunction. Early diagnosis is critical for management of lupus enteritis and cystitis. We report a 48-year-old Japanese man who presented with initial manifestations of abdominal pain, severe diarrhea, and bloody feces. The diagnosis was delayed due to atypical initial symptoms, resulting in clinical worsening. Physicians should be aware of typical computed tomography findings of lupus enteritis and lupus cystitis.

Successful Use of Plasma Exchange in the Treatment of Corticosteroid-Refractory Eosinophilic Granulomatosis with Polyangiitis Associated with Gastrointestinal Manifestations.

We describe the case of a 33-year-old woman having corticosteroid-refractory eosinophilic granulomatosis with polyangiitis (EGPA) who presented with abdominal pain and responded dramatically to plasma exchange. Eosinophilia, asthma history, neuropathy, pulmonary infiltrates, and paranasal sinus abnormalities confirmed the diagnosis of EGPA. Treatment was initiated with 1 g/day of methylprednisolone pulse therapy for 3 days followed by 60 mg/day of intravenous prednisolone without relieving abdominal pain. Then, plasma exchange was performed thrice. Abdominal pain disappeared after the first plasma exchange. Indication of plasma exchange for EGPA remains controversial; however, it may represent a valid option in cases with gastrointestinal involvement.

Peripheral neuropathies during biologic therapies.

Peripheral neuropathies should be recognized as the adverse effects of biological agents, especially anti-TNF agents. However, no solid clinical databases for biological agent-associated peripheral neuropathies (BAPN) have been established in Japan. Here we report two cases of peripheral neuropathy associated with anti-TNF agents. One was peroneal motor neuropathy. The other case was chronic inflammatory demyelinating polyradiculoneuropathy. In addition, we summarize the previous reports on BAPN and discuss their prevalence rate, pathogenesis and management.

Reversible IgA deficiency after severe Gram-negative bacteria infection in a patient with systemic sclerosis.

A 43-year-old woman with systemic sclerosis (SSc) developed IgA deficiency (IgAD) after cholecystitis. The severe decrease of IgA (<10 mg/dl) partially recovered after 5 years. She had repeated episodes of infection during IgAD. Anti-IgA antibody was not detected. Flow cytometric analysis showed that peripheral CD19(+)IgA(+) and CD38(+)IgA(+) cells were normally present. Although the mechanism of secondary IgAD is still vague, its association with autoimmune diseases including SSc and also with bacterial infection is discussed.

CD8(+) T-cell lymphoproliferative disorder associated with Epstein-Barr virus in a patient with rheumatoid arthritis during methotrexate therapy.

A 75-year-old woman with rheumatoid arthritis (RA) who was receiving methotrexate (MTX) therapy developed Epstein-Barr virus (EBV)-associated CD8(+) T-cell lymphoproliferative disorder (LPD) and meningoencephalitis. She was successfully treated with acyclovir and corticosteroids plus MTX cessation. T-cell LPD is relatively rare in RA patients receiving MTX. To our knowledge, this is the first report of CD8(+) T-cell LPD with EBV genome occurring during MTX therapy for RA. EBV infection should be carefully monitored to assess severe EBV-associated complications.

A Case of Transient ACTH Deficiency Associated with Polymyalgia Rheumatica.

We report a case of 79-year-old man, who was diagnosed to have transient ACTH deficiency associated with polymyalgia rheumatica (PMR). The patient presented with sudden onset bilateral shoulder pain, which was gradually aggravated. Plasma ACTH was undetectable, and both serum cortisol and urinary 17-OHCS were very low. Other pituitary hormones were normal, suggesting that hypothalamo-pituitary-adrenal (HPA) axis is selectively damaged. However, within several weeks, plasma ACTH returned to normal, and showed a normal increase response to corticotropin-releasing hormone stimulation test. These results indicated that ACTH deficiency was only transient. After hydrocortisone (10 mg/day) was administered, his symptoms became suddenly improved. Based on those results and clinical course, ie, elevated erythrocyte sedimentation rate, negative rheumatoid factor and the typical symptoms, which showed improvement to glulcocorticoid therapy, the final diagnosis was PMR, which was associated with transient ACTH deficiency. This is the first report of a case of PMR, in which the HPA axis was examined in its very acute phase. It was demonstrated that the case was associated with the transient adrenocortical hypofunction, which was recovered during a short time. It is therefore possible that PMR may show a different responsiveness of HPA axis depending on its phases.

Dermatomyositis associated with thyroid cancer.

We describe herein dermatomyositis (DM) associated with thyroid cancer in a 54-year-old woman. She was resistant to corticosteroids at first, but removal of the coexisting cancer resulted in improvement of DM. Reports on the association of DM with thyroid cancer are very few. However, recently, increasing incidence of thyroid cancer is pointed out. It is thought that increasing incidence reflects increased detection of subclinical disease due to increased diagnostic scrutiny, not an increase in the true occurrence of thyroid cancer. Thus, DM associated with thyroid cancer may be more frequent than we generally expected. We recommend that thyroid studies should be included in cancer investigations, particularly in DM cases resistant to corticosteroids.

Reversible posterior leukoencephalopathy syndrome in a patient with Takayasu arteritis.

Reversible posterior leukoencephalopathy syndrome (RPLS) has been identified in several connective tissue diseases. However, there are no reports of RPLS associated with Takayasu arteritis (TA). We report the first case of TA associated with RPLS. A 23-year-old woman presented with sudden headache and vomiting, followed by generalized tonic-clonic seizures and mental changes two weeks after administration of oral prednisolone. MRI showed hyperintense signals on T2 and FLAIR images in the bilateral temporal-parietal-occipital lobes, left frontal lobe, and left cerebellar hemisphere. Three weeks after starting control of convulsions and blood pressure with plasmapheresis, high-dose methylprednisolone, and cyclophosphamide, the clinical manifestations and abnormal signals on MRI completely resolved. These reversible clinical and radiological changes are consistent with vasogenic edema in the central nervous system, indicating RPLS. Although high-dose methylprednisolone and cyclophosphamide are thought to cause RPLS, we think that it is justified to use these agents, at least in difficult cases, for making a clear-cut differentiation from CNS vasculitis, as long as blood pressure and fluid volume are well controlled. Moreover, we suggest that RPLS should be included in differential diagnosis of acute neurological changes in connective tissue diseases, including TA.

Comprehensive analysis of ADAMTS13 in patients with liver cirrhosis.

Decreased plasma ADAMTS13 activity (ADAMTS13:AC) results in the accumulation of unusually large von Willebrand factor multimer (UL-VWFM) and the formation of platelet thrombi. It remains controversial whether or not plasma ADAMTS13:AC decreases in patients with liver cirrhosis (LC), and its relationship to clinical features has not been fully investigated. We measured ADAMTS13:AC and its related parameters in plasma in 33 patients with chronic hepatitis (CH) and in 109 patients with LC. ADAMTS13:AC decreased with increasing severity of liver disease (controls means 100%, CH 87%, Child A-LC 79%, Child B-LC 63%, and Child C-LC 31%), and showed severe deficiency (<3% of controls) in five end-stage LC. Activities measured by act-ELISA strongly correlated with those determined by the VWFM assay and ADAMTS13 antigen. Multivariate analysis showed Child-Pugh score and spleen volume independent factors contributing to ADAMTS13:AC. VWFM patterns were normal in 53% of cases, degraded in 31%, and unusually large in 16%. Patients with unusually large VWFM had the lowest ADAMTS13:AC as well as the highest Child-Pugh score, serum creatinine and blood ammonia levels. Plasma inhibitor against ADAMTS13 detected in 83% of patients with severe to moderate ADAMTS13:AC deficiency mostly showed marginal zone between 0.5 and 1.0 BU/ml. The IgG-type autoantibodies specific to plasma derived-ADAMTS13 was detected by Western blot in only five end-stage LC with severe ADAMTS13:AC deficiency. In conclusion, both plasma ADAMTS13 activity and antigen levels decreased with increasing severity of cirrhosis. An imbalance between the decreased ADAMTS13:AC and its increased substrate may reflect the predisposing state for platelet thrombi formation in patients with advanced LC.

Immunohistochemically proven cytomegalovirus gastrointestinal diseases in three patients with autoimmune diseases.

Cytomegalovirus (CMV) disease is a serious infectious complication in compromised hosts. Therefore, there are several studies on the diagnosis and prophylactic/pre-emptive therapy of CMV diseases in patients with solid organ transplants, bone marrow transplants, hematopoietic stem cell transplants, and HIV diseases. However, in patients with autoimmune disease, there are only few studies on the diagnosis and prediction of CMV diseases. In the present article, we described three autoimmune cases that developed CMV gastrointestinal disease because of therapy-related immunosuppression. Although all three patients had a low-level CMV antigenemia without diarrhea or melena, CMV was detected in the gastrointestinal tract tissue. We concluded that CMV-antigenemia assay has a limited value in the diagnosis and prediction of CMV gastrointestinal disease in patients with autoimmune diseases, and that immunohistochemical confirmation of CMV tissue involvement should be recommended especially when the typical clinical gastrointestinal manifestations are lacking.

Uneventful splenectomy and cholecystectomy in a patient treated with anti-interleukin-6 receptor antibody therapy.

INTRODUCTION: Interleukin-6 (IL-6) is a multifunctional cytokine that regulates various aspects of the immune responses, acute phase reactions, and hematopoiesis. In rodent models, IL-6 has been suggested to be one of the essential mediators for optimal acute phase responses to infection and tissue damage. However, in humans, the roles of IL-6 in acute phase responses after surgery remain poorly understood. CASE REPORT: We present the first case report of successful splenectomy and cholecystectomy in a severe autoimmune-associated hemolytic anemia patient during treatment with a humanized anti-IL-6 receptor antibody. DISCUSSION: This unique case suggests that IL-6 is not an essential cytokine to safely perform surgical intervention and to prevent postoperative complications and that surgical intervention may not be contraindicated but can be selected as a therapeutic modality in patients treated with anti-IL-6 receptor antibody therapy.

Bone marrow transplantation with a reduced-intensity conditioning regimen in a patient with Wegener granulomatosis and therapy-related leukemia.

We describe a patient with Wegener granulomatosis (WG) who underwent long-term cyclophosphamide treatment and thereafter developed acute myelogenous leukemia (AML). After the AML was induced into remission, the patient received an allogeneic stem cell transplant (allo-SCT) from his sibling after undergoing a reduced-intensity conditioning regimen. His clinical course shortly after allo-SCT was uneventful. No clinically apparent acute or chronic graft-versus-host disease developed. Repeated analysis of the peripheral blood lymphocytes after transplantation showed complete donor chimerism. The level of proteinase 3 antineutrophil cytoplasmic antibody (PR3-ANCA) remained undetectable until 4 months after transplantation, when it began to increase. When the level of PR3-ANCA peaked, the patient suddenly presented with fever and joint pain, which later spontaneously resolved in parallel with the declining titer of PR3-ANCA. He is now in remission for both AML and WG at 22 months after transplantation. The patient's clinical course after allo-SCT may provide us with valuable information regarding the establishment of allo-SCT as a therapeutic option for WG.