IgG4-related disease complicated with diffuse and chronic gastrointestinal inflammation leading to small intestinal perforation.

Immunoglobulin (Ig) G4-related disease (IgG4-RD) is a systemic inflammatory disease characterised by elevated serum IgG4, IgG4+ cell infiltration, storiform fibrosis, and obliterative phlebitis. While IgG4-RD can affect various organs, gastrointestinal tract involvement is less common. Here, we report a 70-year-old female with IgG4-RD complicated with diffuse and chronic gastrointestinal inflammation, which led to small intestinal perforation. She had been suffering from anorexia, abdominal pain, vomiting, and diarrhoea and hospitalised due to recurrent ileus. Consequently, she was referred due to small intestinal perforation required for surgical intervention. Pathology revealed acute and chronic inflammation with massive IgG4+ plasmacyte infiltration into mucosa of the small intestine and ischaemic change secondarily caused by chronic inflammation. Random biopsies from the mucosa of stomach, duodenum, ileum, and colon also revealed diffuse and massive IgG4+ plasmacyte infiltration in stomach, duodenum, small intestine, and colon. She was diagnosed with IgG4-RD based on the pathological findings and elevated serum IgG4 levels. Glucocorticoid rapidly ameliorated the symptoms. IgG4-RD may cause gastrointestinal manifestations, and histopathological assessment should be considered, even in the absence of specific characteristics of IgG4-RD.

A case of dupilumab combination therapy for exacerbation of atopic dermatitis in a patient with eosinophilic granulomatosis with polyangiitis treated with mepolizumab.

We report a 60-year-old male with eosinophilic granulomatosis with polyangiitis (EGPA) complicated with atopic dermatitis (AD). The patient was initially treated with prednisolone, cyclosporine A, and mepolizumab (MEPO). Due to worsening skin symptoms after prednisolone tapering, dupilumab (DUP) was added as an adjunctive therapy for AD confirmed by skin biopsy. The combination therapy of MEPO and DUP resulted in rapid improvement of skin symptoms, suggesting it may be an effective therapeutic option for patients with EGPA and AD. This case report emphasises the importance of a multidisciplinary approach in treating complex diseases such as EGPA and AD.

Involvement of the complement system in immune thrombocytopenia: review of the literature.

Immune thrombocytopenia (ITP) is a thrombocytopenic condition induced by autoimmune mechanisms and includes secondary ITP with underlying diseases such as connective tissue diseases (CTD). In recent years, it has been elucidated that the subsets of the ITP are associated with complement abnormalities but much remains unclear. To perform a literature review and identify the characteristics of complement abnormalities in ITP. PUBMED was used to collect the literature published up to June 2022 related to ITP and complement abnormalities. Primary and secondary ITP (CTD-related) were examined. Out of the collected articles, 17 were extracted. Eight articles were related to primary ITP (pITP) and 9 to CTD-related ITP. Analysis of the literature revealed that the ITP severity was inversely correlated with serum C3, C4 levels in both ITP subgroups. In pITP, a wide range of complement abnormalities was reported, including abnormalities of initial proteins, complement regulatory proteins, or the end products. In CTD-related ITP, reported complement abnormalities were limited to the initial proteins. Activation of the early complement system, mainly through activation of C3 and its precursor protein C4, was reported for both ITPs. On the other hand, more extensive complement activation has been reported in pITP.

A patient with Castleman's disease initially manifesting symmetrical synovitis with pitting oedema.

Castleman's disease (CD), especially multicentric CD (MCD) has been known to manifest a variety of clinical features such as fatigue, anaemia, fever, and hypergammaglobulinaemia. Here, we report a 72-year-old female patient who had complicated severe synovitis, as an initial manifestation of the disease, lastly diagnosed as MCD. Initially, she had been diagnosed as remitting seronegative symmetrical synovitis with pitting oedema (RS3PE) syndrome because of bilateral leg pitting oedema with significant C-reactive protein and matrix metalloproteinase-3 elevation but no disease-specific autoantibodies. Promptly, corticosteroid and additionally weekly methotrexate were introduced, but her leg oedema and inflammatory findings did not adequately come to be a remission. A lymph node biopsy from the groin region was performed because multiple lymph node swelling in ultrasound examination appeared even after introducing treatments, which revealed mixed-type CD. Multiple lymphadenopathies were observed in the axilla and inguinal region; finally, we diagnosed her as idiopathic MCD and introduced tocilizumab, which significantly improved leg oedema as well as inflammatory findings. As is shown in this case, manifestations included in RS3PE syndrome could be one of the clinical phenotypes in MCD, which should be considered as a differential diagnosis of MCD.

Clinical course of Japanese patients with early systemic sclerosis: A multicenter, prospective, observational study.

OBJECTIVES: To investigate the clinical course of Japanese patients with early diffuse cutaneous systemic sclerosis (dcSSc) and early SSc with interstitial lung disease (ILD). METHODS: We prospectively analyzed the clinical features of 207 Japanese patients with early dcSSc (n = 150) and limited cutaneous SSc (lcSSc) with ILD (n = 57) in 10 medical centers every year for 7 consecutive years. RESULTS: Mean modified Rodnan total skin thickness score (mRSS) was 18.3 and 67.4% of the cohort had ILD. Most patients started immunosuppressive therapy and vasodilators during 7 years (83.4% and 87.9%, respectively). Mean value of mRSS of total patients was significantly reduced from the initial registration after the first year. However, other parameters for physical function associated with skin sclerosis including fist closure, hand extension, and oral aperture were not so ameliorated during the study period. Health Assessment Questionnaire-disability index and serum KL-6 levels were constant throughout the course. Percent vital capacity and the presence of ILD, clinically suspected pulmonary arterial hypertension, and digital ulcers were gradually exacerbated during the period. CONCLUSION: In Japanese early dcSSc patients and SSc patients with ILD, mRSS was continuously reduced during 7 years of follow-up, but there was little improvement of physical disability and organ involvement.

A case of anti-MDA5 antibody-positive dermatomyositis developing reversible cerebral vasospasm syndrome successfully treated by multi-immunosuppressant combination including mycophenolate mofetil.

A 39-year-old woman admitted with multiple joint pain, hand rashes, and shortness of breath was diagnosed with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis (DM) with interstitial pneumonia (IP). Because of progressive dyspnoea and hypoxaemia, her IP was considered rapidly progressive interstitial lung disease. Initially, prednisolone 60 mg/day, cyclosporine A (CyA), and intravenous cyclophosphamide (IVCY) were initiated. A few days following the initiation of treatment, she experienced massive thunderclap headache, which was diagnosed as reversible cerebral vasospasm syndrome based on the findings of contraction in cerebral arteries with brain magnetic resonance imaging. Treatment with CyA and IVCY was discontinued, and diltiazem and mycophenolate mofetil (MMF) were initiated as an alternative immunosuppressant. Considering IVCY as the cause of Reversible cerebral vasospasm syndrome based on her clinical course, tacrolimus was commenced, which improved both DM and IP. DM patients who are anti-MDA5 antibody-positive are considered to have poor prognosis and require aggressive immunosuppressive treatments. In patients experiencing adverse events with standard IVCY, MMF with high-dose steroids and alternative calcineurin inhibitor should be considered.

Haemophilus influenzae Non-type b Infection in an Adult Patient with Systemic Lupus Erythematosus.

A 40-year-old man with systemic lupus erythematosus taking consecutive oral corticosteroids developed a high-grade fever and disorder of consciousness following acute rhinitis. Haemophilus influenzae type f (Hif) was found and isolated from the blood and cerebrospinal fluid by culture, leading to a diagnosis of meningitis. The prevalence of H. influenzae type b (Hib) infections has decreased due to routine immunization. As a result, the prevalence of invasive non-Hib, including Hif infection, is increasing as a common H. influenzae infection in children and adults. Physicians should be aware of non-Hib H. influenzae infection, even though the Hib vaccine is widely used in Japan.

Safety and tolerability of bosentan for digital ulcers in Japanese patients with systemic sclerosis: Prospective, multicenter, open-label study.

A multicenter, open-label study was performed to investigate the safety and tolerability of bosentan in Japanese patients with systemic sclerosis (SSc) and secondary digital ulcers. Twenty-eight patients were enrolled. The safety and tolerability of bosentan was monitored over 52 weeks of study treatment (primary end-point), while incidence and healing of digital ulcers were also assessed up to week 16. The following adverse events occurred in 5% or more of patients during the 52-week treatment period: upper respiratory tract infection (50.0%), abnormal liver function tests (42.9%), digital ulcers (25.0%), anemia (17.9%), peripheral edema (14.3%), diarrhea (10.7%), urinary tract infection (7.1%), arthralgia (7.1%), constipation (7.1%) and herpes zoster (7.1%). Eight patients experienced at least one serious adverse event, including drug-related serious adverse events in two patients, which were abnormal liver function tests and fluid retention (pericardial effusion) in one patient each. During the 16-week observation period, seven out of 28 patients (25%) developed new digital ulcers. In this study, adverse events were comparable with those previously reported with bosentan. Approximately half of the patients had adverse events associated with abnormal liver function tests, thus we conclude that liver function should be monitored regularly during treatment with bosentan.

Transverse myelitis extended to disseminated encephalitis in systemic lupus erythematosus: Histological evidence for vasculitis.

A 42-year-old woman was admitted due to systemic lupus erythematosus complicated with glomerulonephritis and pulmonary hypertension. During the treatment for these complications, she presented motor paresis and sensory loss caused by transverse myelitis. In spite of methyl prednisolone pulse therapy, she further developed acute confusional state due to disseminated encephalitis and fell into respiratory arrest. On laboratory examination, elevation of anti-NR2 antibodies in serum as well as in cerebrospinal fluid was noted. Although she recovered from the disseminated encephalitis after extensive treatment with high doses of corticosteroid and intravenous cyclophosphamide, she suddenly died of pulmonary hypertension. Autopsy findings confirmed the presence of liquefaction necrosis in the entire circumference of the whole spinal cord along with intimal hyperplasia and obliteration of the small arteries, accompanied by mononuclear cell infiltration and disruption of internal elastic lamina. It is therefore most likely that our patient developed longitudinal transverse myelitis through spinal cord vasculitis, which extended to brainstem and brain parenchyma, leading to the development of disseminated encephalitis.

Brain MRI in patients with diffuse psychiatric/neuropsychological syndromes in systemic lupus erythematosus.

BACKGROUND: Manifestations in neuropsychiatric systemic lupus erythematosus (NPSLE), especially active diffuse NPSLE syndromes, are some of the most difficult complications of the disease. For the evaluation and the diagnosis of central nervous system manifestations, including NPSLE, MRI is a very useful tool to detect the various abnormalities. However, the relationship between brain MRI findings and clinical variables has not yet been clarified in patients with diffuse NPSLE. OBJECTIVES: The aim of this study is to investigate the pathogenesis of diffuse NPSLE, by comparing various parameters such as serum autoantibodies and cytokines in cerebrospinal fluid (CSF) with abnormal findings revealed on brain MRIs in patients with diffuse NPSLE. METHODS: Fifty-three patients with diffuse NPSLE admitted to our University Hospital from 1992 to 2012 were exhaustively enrolled in this study. Their medical charts and brain MRI scans were reviewed. The relationship of MRI abnormalities with various parameters was analysed. RESULTS: As many as 25 of 53 patients (47.2%) had abnormal MRI findings. MRI findings improved after treatment in 10 of 17 patients for whom follow-up studies were available. MRI abnormalities were not correlated with age at the onset of diffuse NPSLE. However, the disease duration of SLE was significantly longer in patients with abnormal MRI findings (p=0.0009). MRI abnormalities were not significantly associated with serum autoantibodies. However, there were significant elevations of the CSF protein level (p=0.0106) and the CSF interleukin 6 level (p=0.0225) in patients with abnormal MRI findings. Patients with MRI abnormalities showed significantly higher overall mortality (p=0.0348). CONCLUSIONS: The results revealed that MRI abnormalities in diffuse NPSLE might be heterogeneous with regard to their reversibility. These data also indicate that patients with diffuse NPSLE and MRI abnormalities have more severe inflammation in the central nervous system related to the activity of diffuse NPSLE, as evidenced by poorer prognosis.

Serum adhesion molecule levels as prognostic markers in patients with early systemic sclerosis: a multicentre, prospective, observational study.

OBJECTIVE: To assess the utility of circulating adhesion molecule levels as a prognostic indicator of disease progression in systemic sclerosis (SSc) patients with early onset disease. METHODS: Ninety-two Japanese patients with early onset SSc presenting with diffuse skin sclerosis and/or interstitial lung disease were registered in a multicentre, observational study. Concentrations of intercellular adhesion molecule (ICAM) -1, E-selectin, L-selectin, and P-selectin in serum samples from all patients were measured by enzyme-linked immunosorbent asssay (ELISA). In 39 patients, adhesion molecule levels were measured each year for four years. The ability of baseline adhesion molecule levels to predict subsequent progression and severity in clinical and laboratory features were evaluated statistically. RESULTS: At their first visit, serum levels of ICAM-1, E-selection, P-selectin were significantly elevated and serum L-selectin levels were significantly reduced in patients with SSc compared with healthy controls. Overall, serum ICAM-1 levels at each time point were significantly inversely associated with the %vital capacity (VC) of the same time and subsequent years by univariate analysis. The initial serum ICAM-1 levels were significantly inversely associated with the %VC at the fourth year by multiple regression analysis. The initial serum P-selectin levels were significantly associated with the health assessment questionnaire disability index (HAQ-DI) at the fourth year by multiple regression analysis. Initial adhesion molecule levels were not significantly associated with other clinical features including skin thickness score. Baseline adhesion molecule levels were not significantly associated with subsequent rate of change of clinical parameters. CONCLUSION: In patients with SSc, serum levels of ICAM-1 and P-selectin may serve as prognostic indicators of respiratory dysfunction and physical disability, respectively. Further longitudinal studies of larger populations are needed to confirm these findings.

Serum chemokine levels as prognostic markers in patients with early systemic sclerosis: a multicenter, prospective, observational study.

OBJECTIVE: To assess the utility of serum chemokine levels as a prognostic indicator of disease progression in systemic sclerosis (SSc) patients with early onset disease. METHODS: Seventy Japanese patients with early onset SSc presenting with diffuse skin sclerosis and/or interstitial lung disease were registered in a multicenter, observational study. Concentrations of CCL2, CCL5, CXCL8, CXCL9, and CXCL10 in serum samples from all patients were measured using cytometric beads array. In 33 patients, chemokine levels were measured each year for 4 years. The ability of baseline chemokine levels to predict changes in clinical features were evaluated statistically by multiple regression analysis. RESULTS: At their first visit, serum levels of CCL2, CCL5, CXCL8, CXCL9, and CXCL10 were significantly elevated in patients with SSc compared with healthy controls. There were significant associations between CCL2 and CXCL8 levels and between CXCL9 and CXCL10 levels in patients. The initial serum CXCL8 levels were significantly associated with the HAQ-DI at the fourth year while the %VC of baseline tended to be negatively associated with HAQ-DI at the fourth year. Initial chemokine levels were not associated with other clinical features including skin thickness score and the respiratory function. CONCLUSION: Serum CXCL8 level may serve as a prognostic indicator of the physical dysfunction in SSc. Further longitudinal studies of larger populations are needed to confirm these findings.

Incidence and the risk factor of malignancy in Japanese patients with systemic sclerosis.

OBJECTIVE: To evaluate the incidence and risk factors for malignancy in Japanese patients with systemic sclerosis (SSc). METHODS: A cohort of 405 Japanese patients with SSc who visited Kitasato University hospital between 1973 and 2008 was analyzed retrospectively until the end of 2009. The incidence of malignancy was compared with that of the general population, with calculation of the standardized incidence ratio (SIR) and 95% confidence interval (CI). RESULTS: The cohort represented 4,787 person-years of total disease duration after the diagnosis of SSc. Of 27 malignancies clinically found, lung cancer (n=10, 37%), especially adenocarcinoma, was the most frequent, followed by breast (n=4, 15%) or gastric (n=3, 11%) cancer. SSc patients with overlapping CTD tended to have less malignancy. Multivariable analysis revealed heart involvement of SSc as a significant risk factor for breast cancer (RR 8.2, 95% CI 1.2-72.8). Other than gastric cancer, the calculated SIRs of malignancies in SSc patients were above 1 (SIR of overall malignancy 1.24, 95% CI 0.77-1.71), even though only lung cancer had a significantly elevated incidence (SIR 5.73, 95% CI 2.18-9.29). Every patient with lung cancer had interstitial lung disease (ILD) and every autopsy performed on patients with lung cancer found a primary lesion of lung cancer in their ILD lesion (n=4). CONCLUSION: Lung cancer was significantly frequent in SSc patients, which could develop on the basis of complicated ILD.

Investigation of prognostic factors for skin sclerosis and lung function in Japanese patients with early systemic sclerosis: a multicentre prospective observational study.

OBJECTIVE: To clarify the clinical course of SSc in Japanese patients with early-onset disease. It is well known that ethnic variations exist in the clinical features and severity of SSc. However, neither the clinical course nor prognostic factors have been thoroughly investigated in the Japanese population. METHODS: Ninety-three Japanese patients of early-onset SSc (disease duration: <3 years) with diffuse skin sclerosis and/or interstitial lung disease were registered in a multi-centre observational study. All patients had a physical examination with laboratory tests at their first visit and at each of the three subsequent years. Factors that could predict the severity of skin sclerosis and lung involvement were examined statistically by multiple regression analysis. RESULTS: Two patients died from SSc-related myocardial involvement and four patients died from other complications during the 3-year study. Among various clinical data assessed, the initial modified Rodnan total skin thickness score (MRSS) and maximal oral aperture were associated positively and negatively with MRSS at Year 3, respectively. Additionally, initial ESR tended to be associated with final MRSS. Pulmonary vital capacity (VC) in the third year was significantly associated with initial %VC. Furthermore, patients with anti-topo I antibody tended to show reduced %VC at Year 3. CONCLUSIONS: Several possible prognostic factors for skin sclerosis and lung function were detected in Japanese patients with early SSc. Further longitudinal studies of larger populations will be needed to confirm these findings.

IgA and IgG antineutrophil cytoplasmic antibody engagement of Fc receptor genetic variants influences granulomatosis with polyangiitis.

Granulomatosis with polyangiitis (Wegener's) is a rare autoimmune neutrophil-mediated vasculitis that can cause renal disease and mucosal manifestations. Antineutrophil cytoplasmic antibodies (ANCA) are present in many patients, vary in level over time, and induce neutrophil activation through engagement with Fc receptors (FcRs). Given roles for FcRs in ANCA-mediated neutrophil activation and IgA antibodies in mucosal immunity, we hypothesized that FcR genetics and previously unappreciated IgA ANCA affect clinical presentation. We assembled a total of 673 patients and 413 controls from two multicenter cohorts, performed ELISA and immunofluorescence assays to determine IgA and IgG ANCA positivity, and used Illumina, TaqMan, or Pyrosequencing to genotype eight haplotype-tagging SNPs in the IgA FcR (FCAR) and to determine NA1/NA2 genotype of FCGR3B, the most prevalent neutrophil IgG FcR. We evaluated neutrophil activation by measuring degranulation marker CD11b with flow cytometry or neutrophil extracellcular trap formation with confocal microscopy. Functional polymorphisms in FCGR3B and FCAR differed between patient groups stratified by renal involvement. IgA ANCA were found in ∼30% of patients and were less common in patients with severe renal disease. Neutrophil stimulation by IgA or IgG ANCA led to degranulation and neutrophil extracellcular trap formation in a FcR allele-specific manner (IgA:FCAR P = 0.008; IgG:FCGR3B P = 0.003). When stimulated with IgA and IgG ANCA together, IgG ANCA induced neutrophil activation was reduced (P = 0.0001). FcR genotypes, IgA ANCA, and IgG ANCA are potential prognostic and therapeutic targets for understanding the pathogenesis and presentation of granulomatosis with polyangiitis (Wegener's).

Predictors of survival and causes of death in Japanese patients with systemic sclerosis.

OBJECTIVE: To clarify the mortality rates, causes of death, and contributing clinical factors in Japanese patients with systemic sclerosis (SSc). METHODS: A cohort of 405 patients with SSc, who attended our institution during the period 1973 to 2008, was retrospectively analyzed until the end of 2009. Clinical data were obtained from medical records or autopsy reports. RESULTS: The 405 patients with SSc consisted of 310 (76.5%) survivors, 86 (21.2%) who died, and 9 who were lost to followup. Diffuse cutaneous SSc and involvement of organs other than the gastrointestinal tract were more frequent in patients who died, and were associated with a worse prognosis according to Kaplan-Meier analysis. Female sex, limited cutaneous SSc, anticentromere antibody (ACA), and overlap with Sjögren's syndrome (SS) were factors favoring a better prognosis, while overlap with myositis contributed to a poor prognosis. The overall 10-year survival rate was 88%. The patients with SSc had a significantly higher mortality than the general population (standardized mortality ratio 2.76), but the patients with ACA or overlapping SS did not. The most common causes of death were unknown ones including sudden death, followed by malignancy and infection. In patients with pulmonary arterial hypertension, sudden death was the most common cause of mortality. CONCLUSION: The overall mortality rate of patients with SSc was higher than that of the general population, probably because of poor prognostic factors including organ involvement. These factors should be carefully monitored during followup.

Henoch-Schönlein pupura complicated by perforation of the gallbladder.

Henoch-Schönlein purpura is a systemic vasculitis of small vessels characterized by purpura, arthralgias, glomerulonephritis and gastrointestinal involvements which can cause intestinal perforation. A 75-year-old man with renal dysfunction and palpable purpura (petechiae) of which dermal specimen showed leukocytoclastic vasculitis was diagnosed as Henoch-Schönlein purpura. Corticosteroid and cyclosporine were effective, but subsequently he developed pneumocystis pneumonia. After he improved by treatment with trimethoprim-sulfamethoxazole, he presented sudden abdominal pain, caused by perforation of the gallbladder. Histological analysis revealed infiltration of inflammatory cells with bleeding in the gallbladder wall at the site of perforation. It is suggested that inflammatory disruption of capillary walls might lead to the perforation of the gallbladder.

Reversible focal neurological deficits in systemic lupus erythematosus: report of 2 cases and review of the literature.

We report two cases presenting focal neurological deficits with high intensity lesions in fluid attenuated inversion recovery (FLAIR) images on brain magnetic resonance imaging (MRI), which almost completely improved by corticosteroid therapy. Marked elevation of cerebrospinal fluid IL-6 was also noted when these patients showed neurological deficits. As far as we explored, there have been thirteen published case reports of systemic lupus erythematosus patients with reversible focal neurological deficits. The neurological symptoms varied from case to case, but could be attributed to the lesions on MRI scans. The completely reversible feature of neurological manifestations as well as MRI findings on corticosteroid therapy is distinct from any other disorder, including cerebrovascular disease and demyelinating syndrome, in the 1999 American College of Rheumatology nomenclature. Therefore, we propose that reversible focal neurological deficits should be added to the 1999 nomenclature and classification and case definitions.

Comparison of trimethoprim-sulfamethoxazole and aerosolized pentamidine for primary prophylaxis of Pneumocystis jiroveci pneumonia in immunocompromised patients with connective tissue disease.

To evaluate the efficacy of primary prophylaxis for Pneumocystis jiroveci pneumonia (PCP) in patients with connective tissue disease (CTD) and immunosuppression, we compared trimethoprim-sulfamethoxazole (TMP-SMZ) with aerosolized pentamidine. Forty-eight CTD patients of Kitasato University Hospital whose CD4+ lymphocyte count in the peripheral blood was less than 300 microl(-1) were reviewed from 2002 to 2004. Twenty-seven patients received TMP-SMZ and none of them developed PCP. Among 18 patients receiving aerosolized pentamidine, three patients developed PCP. These data indicate that TMP-SMZ is better for prophylaxis than aerosolized pentamidine.