"Eculizumab First" in the Management of Posttransplant Thrombotic Microangiopathy.

Introduction: Posttransplant thrombotic microangiopathy (PT-TMA) is an uncommon event that characterizes approximately 3% to 14% of kidney transplants (KTs), and that is associated with a higher risk of delayed graft function and graft loss. PT-TMA occurs more frequently within the first 3 months after transplant and can be a manifestation of de novo disease or the recurrence of previous atypical hemolytic uremic syndrome (aHUS). Abnormalities in complement regulation genes could explain the increased susceptibility of some patients to PT-TMA. Eculizumab is a humanized monoclonal antibody that inhibits the formation of the membrane attack complex C5b-9. The aim of this study is to evaluate the efficacy of eculizumab as treatment for PT-TMA. Methods: We retrospectively analyzed clinical records of 45 KT patients who received eculizumab immediately after the clinical diagnosis of PT-TMA. Results: Kidney biopsy was performed in 91.1% of patients, and complement genetic study was performed in 64.4%. Of the kidney biopsies, 85.4% showed signs of TMA; genetic analysis revealed 1 pathogenetic variant, 2 variants of uncertain significance, 1 likely benign variant, 8 risk polymorphisms, and 27 risk haplotypes. After 2 weeks from the treatment starting, hemoglobin and platelets significantly increased. A remarkable improvement in kidney function was also observed. After 6 months, 28.8% of patients had a complete renal recovery whereas 44.4% had a partial recovery. Conclusion: This is, to our knowledge, the largest series of KT patients with PT-TMA treated with eculizumab. These data suggest that eculizumab is associated with a normalization of hemolysis indices and an important and progressive improvement of graft function.

Cluster Analysis to Explore Clinical Subphenotypes of Eosinophilic Granulomatosis With Polyangiitis.

OBJECTIVE: Previous studies suggested that distinct phenotypes of eosinophilic granulomatosis with polyangiitis (EGPA; formerly known as Churg-Strauss syndrome) could be determined by the presence or absence of antineutrophil cytoplasmic antibodies (ANCA), reflecting predominant vasculitic or eosinophilic processes, respectively. This study explored whether ANCA-based clusters or other clusters can be identified in EGPA. METHODS: This study used standardized data of 15 European centers for patients with EGPA fulfilling widely accepted classification criteria. We used multiple correspondence analysis, hierarchical cluster analysis, and a decision tree model. The main model included 10 clinical variables (musculoskeletal [MSK], mucocutaneous, ophthalmological, ENT, cardiovascular, pulmonary, gastrointestinal, renal, central, or peripheral neurological involvement); a second model also included ANCA results. RESULTS: The analyses included 489 patients diagnosed between 1984 and 2015. ANCA were detected in 37.2% of patients, mostly perinuclear ANCA (85.4%) and/or antimyeloperoxidase (87%). Compared with ANCA-negative patients, those with ANCA had more renal (P < 0.001) and peripheral neurological involvement (P = 0.04), fewer cardiovascular signs (P < 0.001), and fewer biopsies with eosinophilic tissue infiltrates (P = 0.001). The cluster analyses generated 4 (model without ANCA) and 5 clusters (model with ANCA). Both models identified 3 identical clusters of 34, 39, and 40 patients according to the presence or absence of ENT, central nervous system, and ophthalmological involvement. Peripheral neurological and cardiovascular involvement were not predictive characteristics. CONCLUSION: Although reinforcing the known association of ANCA status with clinical manifestations, cluster analysis does not support a complete separation of EGPA in ANCA-positive and -negative subsets. Collectively, these data indicate that EGPA should be regarded as a phenotypic spectrum rather than a dichotomous disease.

Occupational Exposures and Smoking in Eosinophilic Granulomatosis With Polyangiitis: A Case-Control Study.

OBJECTIVE: Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Environmental agents and occupational exposures may confer susceptibility to EGPA, but data are scarce. This study was undertaken to investigate the association between occupational exposures (e.g., silica, farming, asbestos, and organic solvents) and other environmental agents (e.g., smoking) and the risk of EGPA. METHODS: Patients with newly diagnosed EGPA (n = 111) and general population controls (n = 333) who were matched for age, sex, and geographic area of origin were recruited at a national referral center for EGPA. Exposures were assessed using a dedicated questionnaire administered by a specialist in occupational medicine, under blinded conditions. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. RESULTS: Exposures to silica (OR 2.79 [95% CI 1.55-5.01], P = 0.001), organic solvents (OR 3.19 [95% CI 1.91-5.34], P < 0.001), and farming (OR 2.71 [95% CI 1.71-4.29], P < 0.001) were associated with an increased risk of EGPA. Co-exposure to silica and farming yielded an OR of 9.12 (95% CI 3.06-27.19, P < 0.001), suggesting a multiplicative effect between these 2 exposures. Smoking (current and former smokers combined) was significantly less frequent among patients with EGPA compared to controls (OR 0.49 [95% CI 0.29-0.70], P < 0.001). The pack-year index was also lower among patients with EGPA (OR 0.96 [95% CI 0.94-0.98], P < 0.001). The association of silica and farming was primarily aligned with ANCA-positive EGPA, while the association of smoking status and organic solvents was primarily aligned with ANCA-negative EGPA. CONCLUSION: The environment can influence susceptibility to EGPA. Exposure to silica, farming, or organic solvents is associated with an increased risk of EGPA, while smoking is associated with a lower risk. These exposures seem to have distinct effects on different EGPA subsets.

Slowly progressive anti-neutrophil cytoplasmic antibody-associated renal vasculitis: clinico-pathological characterization and outcome.

BACKGROUND: Although rapidly progressive glomerulonephritis is the main renal phenotype of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), slow renal disease progression is sometimes observed. These forms have been rarely discussed; we analysed their prevalence, clinico-pathological characteristics and outcome. METHODS: We screened patients with microscopic  polyangiitis (MPA) and granulomatosis with polyangiitis followed at seven referral centres and selected those with estimated glomerular filtration rate (eGFR) reduction <50% over a 6-month period preceding diagnosis. Data regarding patient features and response to treatment were retrieved. RESULTS: Of 856 patients, 41 (5%) had slowly progressive renal AAV. All had MPA and all but one was P-ANCA/myeloperoxidase (MPO) ANCA-positive. At diagnosis, the median age was 70 years [interquartile range (IQR) 64-78] and extra-renal manifestations were absent or subclinical (interstitial lung lesions in 10, 24%). The median (IQR) eGFR was 23 mL/min/1.73 m2 (15-35); six patients (15%) had started renal replacement therapy (RRT). All had proteinuria (median 1180 mg/24 h, IQR 670-2600) and micro-haematuria. Main histologic findings were extracapillary proliferation at chronic stages and glomerulosclerosis; following Berden's classification, 6/28 biopsies (21%) were 'focal', 1/28 (4%) 'crescentic', 9/28 (32%) 'mixed' and 12/28 (43%) 'sclerotic'. At last follow-up (median 32 months, IQR 12-52), 20/34 patients (59%) treated with immunosuppression had eGFR improvement >25% as compared with diagnosis, while 4/34 (12%) had started RRT. CONCLUSIONS: AAV may present with slow renal disease progression; this subset is hallmarked by advanced age at diagnosis, positive MPO-ANCA, subclinical interstitial lung lesions and chronic damage at kidney biopsy. Partial renal recovery may occur following immunosuppression.

Into Clinical Practice: Diagnosis and Therapy of Retroperitoneal Fibrosis.

PURPOSE OF THE REVIEW: We aim to review the most relevant diagnostic features and treatment options of retroperitoneal fibrosis, in order to provide a useful guide for clinical practice. RECENT FINDINGS: The recent literature highlights the role of imaging studies such as computed tomography, magnetic resonance imaging and positron emission tomography as useful tools for the diagnosis of retroperitoneal fibrosis, with retroperitoneal biopsy being reserved to atypical cases. The treatment approach is mainly conservative and is based on the use of medical therapies plus urological interventions. Medical therapies essentially comprise glucocorticoids and immunosuppressants-either traditional or biological agents such as rituximab. Surgical ureterolysis is only left for refractory cases. Recent findings in retroperitoneal fibrosis highlight the possibility of a non-invasive diagnostic approach and a conservative treatment strategy.

Fibrocytes in Chronic Periaortitis: A Novel Mechanism Linking Inflammation and Fibrosis.

OBJECTIVE: Chronic periaortitis (CP) is a rare disease characterized by periaortic and periiliac fibroinflammatory tissue. The pathogenic mechanisms leading to tissue accumulation and activation of fibroblasts are unclear. This study was undertaken to explore the role of fibrocytes, circulating precursors of tissue fibroblasts, in patients with CP. METHODS: We studied 44 patients with newly diagnosed CP and 30 healthy controls. Circulating fibrocytes were identified as Col1+CD45+ cells using flow cytometry. Retroperitoneal tissue biopsy samples from 9 CP patients were stained with anti-type I procollagen, anti-CXCR4, and anti-CD45 antibodies and analyzed by confocal microscopy to detect tissue-infiltrating fibrocytes. Circulating levels and tissue expression of CXCL12, a CXCR4 ligand that promotes fibrocyte homing, were investigated using enzyme-linked immunosorbent assay and immunohistochemistry, respectively. We also characterized T helper polarization in biopsy samples from CP patients and measured serum levels of a panel of cytokines that are hallmarks of T helper responses and capable of influencing fibrocyte differentiation. RESULTS: The frequency of circulating Col1+CD45+ fibrocytes was higher in patients than in controls (P = 0.0371). CD45+proCol1+ and CXCR4+proCol1+ cells were detected in all examined biopsy samples from CP patients. Serum levels of CXCL12 were also higher in CP patients than controls (P = 0.0056), and tissue-infiltrating inflammatory cells intensely expressed CXCL12. Increased serum levels of Th2 cytokines (e.g., interleukin-13 [IL-13] and IL-10) were found in patients, and immunohistochemistry revealed a dominant infiltration of GATA-3+ cells, also indicating Th2 polarization; Th2-skewed responses are known to promote fibrocyte differentiation. CONCLUSION: Our findings indicate that fibrocytes are enriched in the peripheral blood of CP patients and infiltrate target lesions. The accumulation of fibrocytes in the pathologic tissue might be driven by CXCL12, and Th2-skewed immune responses are likely to facilitate their differentiation.

Clinical and Prognostic Significance of Serum IgG4 in Chronic Periaortitis. An Analysis of 113 Patients.

Objective: Chronic periaortitis (CP) is a rare fibro-inflammatory disorder that incorporates idiopathic retroperitoneal fibrosis, inflammatory abdominal aortic aneurysms, and perianeurysmal retroperitoneal fibrosis. CP is included in the spectrum of IgG4-related disease. Since CP patients rarely undergo diagnostic biopsies, serum IgG4 levels are often used to classify CP as IgG4-related. However, the clinical and prognostic significance of serum IgG4 in CP is unknown. Methods: We measured serum IgG4 in active CP patients and compared the clinical characteristics, response to therapy and outcome of patients with high and normal levels. We also tested the diagnostic significance of IgG4 by comparing its levels in CP patients, healthy and disease controls (malignancies, Erdheim-Chester disease, large-, and small-vessel vasculitis). Results: We studied 113 consecutive patients with active CP. Twenty-four (21.2%) had high serum IgG4 (>135 mg/dL). The demographic, laboratory, and clinical characteristics of patients with high and normal IgG4 were similar, and so were the rates of ureteral obstruction and the disease characteristics on CT, MRI, and 18F-FDG-PET. Patients with high IgG4 only had a higher frequency of extra-retroperitoneal fibro-inflammatory lesions (p = 0.005). There were no significant differences in response to therapy and relapses between the two groups. Serum IgG4 levels did not discriminate CP from controls. Conclusions: Serum IgG4 levels are high in a minority of CP patients and do not identify specific clinical or prognostic subgroups; only a higher frequency of extra-retroperitoneal lesions is found in high-IgG4 patients. Serum IgG4 levels do not help in the differential diagnosis between CP and its mimics.

Chronic Periaortitis: an Update.

PURPOSE OF REVIEW: We aim to review traditional concepts and recent developments on the nosology, pathophysiology, clinical phenotypes and treatment of chronic periaortitis (CP). RECENT FINDINGS: CP is a rare disorder hallmarked by a periaortic fibro-inflammatory tissue. It can present as an isolated disease, but it can also be associated with other autoimmune and fibro-inflammatory lesions (e.g., fibrosing mediastinitis, sclerosing pancreato-cholangitis) that are part of the spectrum of IgG4-related disease. In a subgroup of patients, it also involves the thoracic aorta (so-called "diffuse periaortitis"), which supports the notion of an inflammatory disorder of large arteries. The pathogenesis of CP is multifactorial: recent studies have elucidated the predisposing role of immunogenetic variants and exposures to environmental agents such as smoking and asbestos. CP is a rare immune-mediated disease that affects the abdominal aorta and the iliac arteries and, in some cases, the thoracic aorta. It may overlap with manifestations of IgG4-related disease, and its treatment comprises glucocorticoids, conventional and biological immunosuppressive agents.

Methotrexate versus cyclophosphamide for remission maintenance in ANCA-associated vasculitis: A randomised trial.

OBJECTIVES: The treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is based on remission-induction and remission-maintenance. Methotrexate is a widely used immunosuppressant but only a few studies explored its role for maintenance in AAV. This trial investigated the efficacy and safety of methotrexate as maintenance therapy for AAV. METHODS: In this single-centre, open-label, randomised trial we compared methotrexate and cyclophosphamide for maintenance in AAV. We enrolled patients with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA), the latter with poor-prognosis factors and/or peripheral neuropathy. Remission was induced with cyclophosphamide. At remission, the patients were randomised to receive methotrexate or to continue with cyclophosphamide for 12 months; after treatment, they were followed for another 12 months. The primary end-point was relapse; secondary end-points included renal outcomes and treatment-related toxicity. RESULTS: Of the 94 enrolled patients, 23 were excluded during remission-induction or did not achieve remission; the remaining 71 were randomised to cyclophosphamide (n = 33) or methotrexate (n = 38). Relapse frequencies at months 12 and 24 after randomisation were not different between the two groups (p = 1.00 and 1.00). Relapse-free survival was also comparable (log-rank test p = 0.99). No differences in relapses were detected between the two treatments when GPA+MPA and EGPA were analysed separately. There were no differences in eGFR at months 12 and 24; proteinuria declined significantly (from diagnosis to month 24) only in the cyclophosphamide group (p = 0.0007). No significant differences in adverse event frequencies were observed. CONCLUSIONS: MTX may be effective and safe for remission-maintenance in AAV. TRIAL REGISTRATION: clinicaltrials.gov NCT00751517.

Idiopathic Mediastinal Fibrosis: a Systemic Immune-Mediated Disorder. A Case Series and a Review of the Literature.

Mediastinal fibrosis is a rare disease characterised by fibrous proliferation in the mediastinum. It can be idiopathic or secondary to several conditions such as infections and malignancies. Anecdotal reports have described idiopathic mediastinal fibrosis (IMF) in association with other fibro-inflammatory or autoimmune diseases. We report nine new IMF cases recently seen at our Fibro-Inflammatory Disease Clinic and reviewed the IMF cases reported in the English language literature throughout 2006-2016. The purposes of our literature search were to assess the frequency of the association between IMF and other immune-mediated disorders and to analyse which disorders most often coexist with IMF. Of our nine IMF cases, one was associated with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, one with large-vessel arteritis, three with idiopathic retroperitoneal fibrosis (one of which was IgG4-related), one with pancreatitis and one with IgG4-related seminal vesicle involvement. The remaining two cases, in which IMF was not associated with any other disease, were both classifiable as IgG4-related. The literature review showed that, of the 84 IMF cases identified, 27 (32 %) were associated with other idiopathic autoimmune or fibro-inflammatory disorders, particularly small-vessel vasculitis, Behçet disease, retroperitoneal fibrosis and other conditions belonging to the IgG4-related disease spectrum. Based on our own data and the literature review, we conclude that IMF is often associated with other autoimmune or fibro-inflammatory diseases; therefore, its clinical management requires an accurate screening of associated conditions. Immune-mediated mechanisms may be shared by these disorders.

Erdheim-Chester Disease as a Mimic of IgG4-Related Disease: A Case Report and a Review of a Single-Center Cohort.

Immunoglobulin-G4 (IgG4)-related disease (IgG4RD) is a fibro-inflammatory disorder characterized by tissue-infiltrating IgG4 plasma cells, and, often, high serum IgG4. Several autoimmune, infectious, or proliferative conditions mimic IgG4RD. Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis, characterized by foamy histiocytic infiltration, fibrosis, and chronic inflammation. ECD and IgG4RD manifestations may overlap.A patient presented with huge fibrous retroperitoneal masses causing compression on neighboring structures; the case posed the challenge of the differential diagnosis between IgG4RD and ECD mainly because of a prominent serum and tissue IgG4 response.Retroperitoneal biopsy led to the diagnosis of ECD; the V600E BRAF mutation was found. Treatment with the BRAF inhibitor vemurafenib was started.Treatment failed to induce mass regression and the patient died after 3 months of therapy. Prompted by this case, we examined serum and tissue IgG4 in a series of 15 ECD patients evaluated at our center, and found that approximately one-fourth of the cases have increased IgG4 in the serum and often in the tissue.The differential diagnosis between IgG4RD and ECD can be challenging, as some ECD patients have prominent IgG4 responses. This suggests the possibility of common pathogenic mechanisms between ECD and IgG4RD.

Chronic periaortitis with thoracic aorta and epiaortic artery involvement: a systemic large vessel vasculitis?

OBJECTIVE: Chronic periaortitis (CP) is a rare disease characterized by fibro-inflammatory tissue surrounding the abdominal aorta and the iliac arteries. Anecdotal reports have shown that CP may also involve other vascular districts, particularly the thoracic aorta. The aim of this study was to investigate the thoracic aorta and epiaortic artery involvement in CP. METHODS: Patients were eligible if they had undergone imaging studies assessing inflammatory involvement of the thoracic aorta and its major branches (e.g. contrast CT, MRI or PET-CT). We explored the patterns of thoracic vessel involvement and compared the clinical characteristics of patients with and without thoracic disease. Where available, we also reviewed the thoracic vascular/perivascular tissue biopsies. RESULTS: Of 153 CP patients seen between 1999 and 2012, 77 were eligible. Of these, 28 (36%) had thoracic involvement: 15 (54%) had thoracic periaortitis, with 7 also showing epiaortic artery involvement; 6 (21%) had periaortitis surrounding a thoracic aortic aneurysm, 2 of them with epiaortic artery involvement; 7 (25%) had a thoracic aortic aneurysm without periaortitis. Patients with thoracic disease were more frequently female (P = 0.01), were older (P = 0.001) and had a higher frequency of pain and constitutional symptoms (P = 0.02). Thoracic (peri)vascular biopsies revealed adventitial and peri-adventitial fibro-inflammatory patterns similar to those observed in abdominal CP. CONCLUSION: In about one-third of patients, CP also involves the thoracic aorta and the epiaortic arteries, which supports the hypothesis of a systemic inflammatory disease of the large arteries.

Eosinophilic granulomatosis with polyangiitis: an overview.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a multisystemic disorder, belonging to the small vessel anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, defined as an eosinophil-rich and necrotizing granulomatous inflammation often involving the respiratory tract, and necrotizing vasculitis predominantly affecting small to medium-sized vessels, associated with asthma and eosinophilia. EGPA pathogenesis is not well known: HLA-DRB1*04 and *07, HLA-DRB4 and IL10.2 haplotype of the IL-10 promoter gene are the most studied genetic determinants. Among the acquired pathogenetic factors, the exposure to different allergens, infections, vaccinations, drugs, and silica exposure have been involved. Eosinophils are the most characteristic cells in EGPA and different studies have demonstrated their role as effector and immunoregulatory cells. EGPA is considered as a disease with a prevalent activation of the Th-2 cellular-mediated inflammatory response and also humoral immunity plays an important role. A link between B and T inflammatory responses may explain different disease features. EGPA typically develops into three sequential phases: the allergic phase, distinguished by the occurrence of asthma, allergic rhinitis, and sinusitis, the eosinophilic phase, in which the main pathological finding is the eosinophilic organ infiltrations (e.g., lungs, heart, and gastrointestinal system), and the vasculitic phase, characterized by purpura, peripheral neuropathy, and constitutional symptoms. ANCA (especially pANCA anti-myeloperoxidase) are present in 40-60% of the patients. An elevation of IgG4 is frequently found. Corticosteroids and cyclophosphamide are classically used for remission induction, while azathioprine and methotrexate are the therapeutic options for remission maintenance. B-cell depletion with rituximab has shown promising results for remission induction.

PTPN22 R620W polymorphism in the ANCA-associated vasculitides.

OBJECTIVES: PTPN22 is involved in T-cell activation and its R620W single-nucleotide polymorphism (SNP) has been shown to predispose to different autoimmune diseases. The aims of this study were to investigate the role of the PTPN22 R620W SNP in conferring susceptibility to the ANCA-associated vasculitides (AAVs), and to explore potential associations between the PTPN22 genotype and the disease manifestations. METHODS: PTPN22 R620W SNP was genotyped in a cohort of 344 AAV patients [143 with granulomatosis with polyangiitis (Wegener's) (GPA), 102 with microscopic polyangiitis (MPA) and 99 with Churg-Strauss syndrome (CSS)] and in 945 healthy controls. RESULTS: The frequency of the minor allele (620W) was significantly higher in GPA patients than in controls [P = 0.005, χ(2 )= 7.858, odds ratio (OR) = 1.91], while no statistically significant association was found with MPA or CSS. Among GPA patients, the 620W allele was particularly enriched in ANCA-positive patients as compared with controls (P = 0.00012, χ(2 )= 14.73, OR = 2.31); a particularly marked association was also found with ENT involvement (P = 0.0071, χ(2 )= 7.258, OR = 1.98), lung involvement (P = 0.0060, χ(2 )= 7.541, OR = 2.07) and skin manifestations of all kinds (P = 0.000047, χ(2 )= 16.567, OR = 3.73). CONCLUSION: The PTPN22 620W allele confers susceptibility to the development of GPA (but not of MPA or CSS), and particularly of its ANCA-positive subset.

IgG4 immune response in Churg-Strauss syndrome.

OBJECTIVE: T-helper type 2 responses are crucial in Churg-Strauss syndrome (CSS) and may enhance the production of IgG4 antibodies. The authors assessed the IgG4 immune response in CSS patients. METHODS: The authors included 46 consecutive patients with CSS (24 with active and 22 with quiescent disease), 26 with granulomatosis with polyangiitis (GPA, Wegener's), 25 with atopic asthma and 20 healthy controls and determined serum IgG, IgM, IgA, IgE and IgG subclass levels. Tissue infiltration by IgG4 plasma cells was assessed in nine patients with CSS, 10 with GPA, 22 with chronic sinusitis (11 with and 11 without eosinophilia). RESULTS: IgG4 levels were markedly higher in active CSS patients than in controls (p<0.001 vs all control groups). Serum IgG4 correlated with the number of disease manifestations (r=0.52, p=0.01) and the Birmingham vasculitis activity score (r=0.64, p=0.001). Longitudinal analysis in 12 CSS cases showed that both the IgG4 level and IgG4/IgG ratio dropped during disease remission (p=3×10(-5) and p=6×10(-4), respectively). Tissue analysis did not show an increased IgG4 plasma cell infiltration in CSS biopsies compared with control groups. CONCLUSIONS: Serum IgG4 levels are markedly elevated in active CSS and correlate with the number of organ manifestations and disease activity.