Immune dysregulation syndrome with de novo CTLA4 germline mutation responsive to abatacept therapy.

Regulatory T-cells (Tregs) are major mediators of mammalian self-tolerance via cytotoxic T-lymphocyte antigen 4 (CTLA4) signaling pathways. An immune dysregulation syndrome associated with heterozygous germline mutations in CTLA4 was recently reported. Clinical features include recurrent infections, systemic lymphadenopathy, various autoimmune conditions, hypogammaglobulinemia, and autosomal dominant inheritance, characteristic of primary immunodeficient disease (PID). PID symptoms are variable and few patients with sporadic de novo CTLA4 germline mutations have been described. Here, we report the case of a 26-year-old man with an immune dysregulation syndrome and a de novo CTLA4 germline mutation. The patient exhibited several clinical features associated with PID. Next-generation sequencing revealed a CTLA4 germline mutation, c.436G>A; p.G146R, in exon 2 of CTLA4. Sanger sequencing confirmed the patient was the only member of his family with this germline mutation. The patient was diagnosed with an immune dysregulation syndrome associated with de novo germline CTLA4 mutation, complicated by steroid-refractory rheumatoid arthritis. Treatment with abatacept, a CTLA4-immunoglobulin fusion molecule, was initiated, resulting in dramatic resolution of the patient's clinical symptoms. As PID with CTLA4 germline mutation is rare and patients may be under-diagnosed, physicians should be aware of the features of PID.

The relationship between type 1 IFN and vasculopathy in anti-MDA5 antibody-positive dermatomyositis patients.

OBJECTIVE: Based on the antibody profiles of inflammatory myositis patients, we investigated the type 1 IFN (T1-IFN) signature in serum and DM skin to determine the relationship between T1-IFN and vasculopathy in anti-melanoma differentiation-associated 5 gene (MDA5) antibody-positive DM patients. METHODS: We examined 47 patients with new-onset inflammatory myositis. We divided them into three groups: the anti-MDA5 antibody-positive patients (MDA5 group, n = 16), the anti-aminoacyl-tRNA synthetase antibody-positive patients (aminoacyl-tRNA synthetase group, n = 12), and the double-negative patients (n = 19). Serum T1-IFN signatures were revealed by a functional reporter assay, and we evaluated the T1-IFN signatures of skin based on Mx1 expression by immunohistochemistry. RESULTS: The numbers of patients with classical DM, clinically amyopathic DM and interstitial lung disease were 1, 15 and 13 in the MDA5 group, 2, 3 and 11 in the aminoacyl-tRNA synthetase group, and 10, 1 and 4 in the double-negative group, respectively. The signs of vasculopathies (i.e. palmer papules, skin ulcers and mononeuritis multiplex) were identified only in the MDA5 patients. Most of the MDA5 group showed the highest serum T1-IFN signatures among the three groups. In the histological analysis of DM skin, perivascular inflammations were significant in the MDA5 group. The MDA5 group's Mx1 expression was significantly strong, distributed in blood vessels and interstitial fibroblasts, and had spread to deep dermis. CONCLUSION: Anti-MDA5 antibody-positive DM patients showed high T1-IFN signatures in serum and affected skin. The high T1-IFN signatures of the MDA5 antibody-positive DM patients in serum and deep vasculatures suggested that T1-IFN may have important roles in the vasculopathy of these patients.

Nocardiosis in adult-onset Still's disease and vasculitis syndrome.

Four cases of nocardiosis in patients with adult-onset Still disease and vasculitis syndrome are presented. Three patients developed lung abscesses and 1 case developed a brain abscess. All were treated with high-dose corticosteroids, and 3 were given cyclosporine when they developed nocardiosis. All patients were successfully treated with antibiotics; cyclosporine was discontinued in 2 cases. These cases indicate that systemic nocardiosis can develop in patients with various rheumatologic diseases who are treated with corticosteroid and immunosuppressive drugs such as cyclosporine.

High-resolution computed tomography characterization of interstitial lung diseases in polymyositis/dermatomyositis.

OBJECTIVE: Interstitial lung disease (ILD) associated with polymyositis (PM) and dermatomyositis (DM) sometimes progresses rapidly and is resistant to therapy. Clinical features that forecast the prognosis of the disease remain to be elucidated. Our aim was to assess if selected clinical features and high-resolution computed tomography (HRCT) findings can assist in predicting the clinical course of ILD in PM/DM. METHODS: We examined HRCT findings retrospectively for ILD identified in 17 patients with PM and 16 with DM. Radiological patterns and clinical features are analyzed in comparison with clinical course. RESULTS: Mortality rates were 12% and 44% for ILD associated with PM and DM, respectively. Most patients with DM died of rapidly progressive lung deterioration. No patient in the PM group died of respiratory failure. In the DM group, all patients with fatal ILD had ground-glass attenuation and reticular opacity as the principal radiological findings. Consolidation was recognized frequently as the principal pattern in nonfatal cases. Radiological patterns were categorized into 3 groups; A: consolidation dominant, B: ground-glass attenuation/reticular opacity dominant without chronic fibrosing process, and C: ground-glass attenuation/reticular opacity dominant with chronic fibrosing process. Occurrences of fatal disease were 0%, 83%, and 20%, in groups A, B, and C. CONCLUSION: The prognosis of ILD associated with DM differs from that with PM. The former can be classified into 3 subgroups on the basis of radiological findings, which are closely associated with clinical course.

Antifibrotic effects of hepatocyte growth factor on scleroderma fibroblasts and analysis of its mechanism.

We investigated the effect of hepatocyte growth factor (HGF) on collagen metabolism in cultured fibroblasts from scleroderma (SSc) patients and discussed the possible mechanism of its effect. Synthesis of matrix metalloproteinase-1 (MMP-1) and collagen and mRNA levels of various cytokines were examined by enzyme-linked immunosorbent assay and real-time polymerase chain reaction, respectively. Hepatocyte growth factor enhanced MMP-1 production and mRNA levels of MMP-1 and Ets-1 (a transcriptional factor of MMPs). In addition, HGF suppressed collagen synthesis and mRNA levels of procollagenalpha1(I) and connective tissue growth factor (CTGF) in SSc fibroblasts. Expression of transforming growth factor (TGF)-beta1 was not inhibited significantly in SSc or control fibroblasts. Hepatocyte growth factor also increased interferon (IFN)-gamma mRNA significantly in SSc and control fibroblasts. Addition of anti-HGF antibody neutralized these effects of HGF on MMP-1 and collagen synthesis. The results suggest that HGF can suppress collagen accumulation in SSc fibroblasts by increasing MMP-1 levels possibly via activation of Ets-1 and also by decreasing collagen synthesis, which may be partly related to inhibition of CTGF, and increasing IFN-gamma levels rather than the effect on TGF-beta1. The present study indicates that HGF may be a promising therapeutic agent for this intractable disease.

Frequency and analysis of factors closely associated with the development of depressive symptoms in patients with scleroderma.

OBJECTIVE: To examine the frequency of depressive symptoms and also to identify factors closely associated with their development in patients with scleroderma (systemic sclerosis, SSc). METHODS: We evaluated 50 patients with SSc for factors associated with depressive symptoms using the following established scales: the Beck Depression Inventory (BDI); the Rheumatology Attitude Index for measuring helplessness; the Sense of Coherence (SOC) scale (a measure of an individual's resilience in the face of stress and capacity to cope with it); the modified Health Assessment Questionnaire for physical disability, working, and social function; support domains of Arthritis Impact Measurement Scales version 2; and a visual analog pain scale. In addition, disease severity of SSc, including skin thickness and internal organ involvement, was also examined in each patient. Multiple regression analysis was used to determine which factors correlated with depressive symptoms. RESULTS: Depressive symptoms ranging from mild to severe state were seen in 46% of the patients. Total BDI scores were significantly correlated with low working ability, low social activity, low SOC, pain, and helplessness, and not associated with disease severity variables including skin score and internal organ involvement. Multiple regression analysis showed that a high level of helplessness and a low level of SOC might be closely associated with depressive symptoms in SSc. CONCLUSION: Our results indicate that depressive symptoms are frequent in SSc patients. Medical staffs should pay attention to the possible risk factors for depressive symptoms, such as patient's helplessness and SOC.