Cryoglobulinemic vasculitis in primary Sj\uf6gren's Syndrome: Clinical presentation, association with lymphoma and comparison with Hepatitis C-related disease

Objective: To describe the clinical spectrum of cryoglobulinemic vasculitis (CV) in primary Sj\uf6gren's syndrome (pSS), investigate its relation to lymphoma and identify the differences with hepatitis C virus (HCV) related CV. Methods: From a multicentre study population of consecutive pSS patients, those who had been evaluated for cryoglobulins and fulfilled the 2011 classification criteria for CV were identified retrospectively. pSS-CV patients were matched with pSS patients without cryoglobulins (1:2) and HCV-CV patients (1:1). Clinical, laboratory and outcome features were analyzed. A data driven logistic regression model was applied for pSS-CV patients and their pSS cryoglobulin negative controls to identify independent features associated with lymphoma. Results: 1083 pSS patients were tested for cryoglobulins. 115 (10.6%) had cryoglobulinemia and 71 (6.5%) fulfilled the classification criteria for CV. pSS-CV patients had higher frequency of extraglandular manifestations and lymphoma (OR=9.87, 95% CI: 4.7\u201320.9) compared to pSS patients without cryoglobulins. Purpura was the commonest vasculitic manifestation (90%), presenting at disease onset in 39% of patients. One third of pSS-CV patients developed B-cell lymphoma within the first 5 years of CV course, with cryoglobulinemia being the strongest independent lymphoma associated feature. Compared to HCV-CV patients, pSS-CV individuals displayed more frequently lymphadenopathy, type II IgMk cryoglobulins and lymphoma (OR = 6.12, 95% CI: 2.7\u201314.4) and less frequently C4 hypocomplementemia and peripheral neuropathy. Conclusion: pSS-CV has a severe clinical course, overshadowing the typical clinical manifestations of pSS and higher risk for early lymphoma development compared to HCV related CV. Though infrequent, pSS-CV constitutes a distinct severe clinical phenotype of pSS

Case Review of Sarcoidosis Resembling Sjogren's Syndrome

We would like to report a case of a 29-year-old male patient who presented with multiple lymphadenopathy and vague symptoms of low grade fever, cough, weight loss, rashes, vomiting, dry eyes and dry mouth. Physical examination revealed submandibular lymphadenopathy, vasculitic rashes over both lower limbs, and parotid gland enlargement. Blood investigations showed mild anemia with leukocytosis, predominantly eosinophilia and high erythrocyte sedimentation rate and C-reactive protein. Computed tomography of the neck, thorax and abdomen showed bilateral submandibular, submental adenopathy, mediastinal and para-aortic lymphadenopathy with generalized reticulonodular densities in both lower lobes. There were hepatomegaly and bilateral enlarged kidneys with renal cyst. Histopathological examination from the cervical lymph node later revealed non-caseating granuloma, consistent of sarcoidosis. Patient responded well to prednisolone 50 mg daily with subsequent reduction in the size of cervical lymphadenopathy and parotid swelling

New insights into the pathogenesis of giant cell arteritis

Giant cell arteritis (GCA) is an inflammatory chronic disease occurring exclusively in elderly individuals. Until recently, the disease has been considered a unique disease resulting from the interaction in the walls of susceptible arteries, between an unknown infectious agents with local dendritic cells (DCs), activated CD4 T cells and effector macrophages. Recent evidence has shown that this view was too simplistic and has clarified many of the pathogenetic aspects of the disease. Many genetic studies recently published have identified different new genes, including cytokines, adhesion molecules and regulators of innate immunity, as crucial players in the development and progression of GCA. Recent evidence suggests that there is heterogeneity of histological lesions in GCA, that are correlated with different immunological Th9 and Th17 signature. The recent demonstration that Varicella-zoster virus (VZV) antigen is present in the 64% of GCA-negative TAs and in the 73% of GCA-positive TAs could represent an important point of arrival in the search for a causative agent in the pathogenesis of a metameric disease such as GCA. In this context, cytokines such as IL-32 and IL-33 that act as a danger signal following tissue damage and infection are over-expressed in GCA arteries. Artery tertiary lymphoid organs, present in up to 50% of GCA-positive arteries, could represent the sites were primary immune responses and T- and B-cell autoimmune responses against viral antigens are organized. The recently demonstrated disturbed distribution of B cells in GCA could be also relevant in the pathogenesis of the disease, possibly contributing to the enhanced IL-6 response. Altogether, these evidences may clarify many pathogenetic aspect of the disease, also suggesting complexity greater than first imagined

A CD8+ T cell transcription signature predicts prognosis in autoimmune disease.

Autoimmune diseases are common and debilitating, but their severe manifestations could be reduced if biomarkers were available to allow individual tailoring of potentially toxic immunosuppressive therapy. Gene expression-based biomarkers facilitating such tailoring of chemotherapy in cancer, but not autoimmunity, have been identified and translated into clinical practice. We show that transcriptional profiling of purified CD8(+) T cells, which avoids the confounding influences of unseparated cells, identifies two distinct subject subgroups predicting long-term prognosis in two autoimmune diseases, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), a chronic, severe disease characterized by inflammation of medium-sized and small blood vessels, and systemic lupus erythematosus (SLE), characterized by autoantibodies, immune complex deposition and diverse clinical manifestations ranging from glomerulonephritis to neurological dysfunction. We show that the subset of genes defining the poor prognostic group is enriched for genes involved in the interleukin-7 receptor (IL-7R) pathway and T cell receptor (TCR) signaling and those expressed by memory T cells. Furthermore, the poor prognostic group is associated with an expanded CD8(+) T cell memory population. These subgroups, which are also found in the normal population and can be identified by measuring expression of only three genes, raise the prospect of individualized therapy and suggest new potential therapeutic targets in autoimmunity

The Many faces of vasculitis: diagnostic challenges and economic burden

The systemic vasculitides are characterized by inflammation of the blood vessel walls. Most vasculitides are idiopathic but sometimes a triggering event, e.g., medication, can be identified. Vessels of any type and size can be affected, resulting in a wide spectrum of symptoms ranging from mild to multisystemic life-threatening disorders. The rarity of vasculitides and the heterogeneous nature of the diseases present a diagnostic challenge causing diagnostic delay and numerous examinations. Imaging, including positron emission tomography with computed tomography (PET/CT), has an increasing role in the diagnostic work-up. The aim of this study was to evaluate the performance of PET/CT prospectively, in a real-life cohort of patients with suspected vasculitis, to assess the diagnostic delay and total costs of the diagnostic process of systemic vasculitis and to explore the rare association between large vessel vasculitis (LVV), chemotherapy and granulocyte-colony stimulating factor (G-CSF). PET/CT was found effective in diagnosing vasculitis in a cohort of 82 patients. Lower dose and shorter duration of glucocorticoid medication were significantly associated with positive PET/CT vasculitis finding. Overall, PET/CT revealed clinically significant information in 56% of the patients. Among systemic vasculitides, the diagnostic delay was substantial with great individual variability. Diagnostic delay was correlated with higher total costs, but PET/CT was not a significant contributor. LVV and neutropenic infections might present with similar clinical symptoms. We identified six patients with breast cancer who unexpectedly developed acute, non-infectious LVV during chemotherapy. This patient series and a systematic literature review support the previous reports of a rare causal association between LVV, chemotherapy and G-CSF.Vaskuliitin monet kasvot: diagnoosivaiheen haasteet ja taloudellinen taakka Vaskuliitit ovat verisuonen seinämän tulehduksia, jotka immunologisella mekanismilla vaurioittavat suonen seinämää. Vaskuliitin syy on usein tuntematon, mutta joissain harvoissa tapauksissa laukaiseva tekijä, kuten lääkeaine, voidaan tunnistaa. Sairastuneen suonen koko ja sijainti vaikuttavat taudinkuvaan, joka vaihtelee lievistä paikallisoireista vaikeisiin elinvaurioihin. Vaskuliittien harvinaisuus ja oireiden epämääräisyys aiheuttavat diagnoosiviivettä ja laaja-alaisia tutkimuksia. Kuvantamistutkimuksilla, kuten positroniemissiotomografia-tietokonetomografialla (PET/TT), on lisääntyvä merkitys vaskuliittien diagnostiikassa. Tämän tutkimuksen tarkoituksena oli selvittää PET/TT-kuvantamisen merkitystä vaskuliittiepäilyssä, systeemistä vaskuliittia sairastavien potilaiden diagnoosivaiheen viivettä ja kustannuksia sekä tutkia harvinaista yhteyttä suurten suonten vaskuliitin (SSV), kemoterapian ja valkosolukasvutekijähoidon välillä. PET/TT osoittautui hyödylliseksi vaskuliittidiagnostiikassa. Glukokortikoidilääkityksen matalampi annos ja lyhyempi käyttöaika olivat merkitsevästi yhteydessä positiiviseen PET/TT-vaskuliittilöydökseen. PET/TT-kuvantamisessa 56 %:lla potilaista todettiin kliinisesti merkitsevä löydös. Potilailla, joilla oli systeeminen vaskuliitti, diagnoosiviive oli huomattava ja viiveen yksilöllinen vaihtelu suurta. Diagnoosiviiveen ja korkeampien kustannusten välillä oli merkittävä yhteys. Sen sijaan PET/TT ei ollut yksinään merkittävä kustannustekijä. SSV ja neutropeeniset infektiot voivat olla taudinkuvaltaan samankaltaisia. Tunnistimme kuusi rintasyöpää sairastavaa potilasta, joille kehittyi yllättäen akuutti, ei-infektiivinen SSV kemoterapiahoidon aikana. Tämä potilassarja ja aiheesta laadittu systemaattinen kirjallisuuskatsaus puoltavat harvinaista syy-yhteyttä SSV:n, kemoterapian ja valkosolukasvutekijän välillä

The parthogenesis of ulcerative colitis: The role of autoimmunity and microvascular injury.

Aims: To investigate the roles of autoimmunity and microvascular injury in the pathogenesis of ulcerative colitis. Background: The aetiology of ulcerative colitis is unknown. A putative mucosal autoantigen, (UCAg), had been identified as tropomyosin, the presence of ANCA in ulcerative colitis suggested involvement of vascular factors; and disease demarcation suggested vascular anatomical distribution of disease. Methods: Using the monoclonal antibody 7E12H12, cellular localisation of the target antigen, UCAg, was studied. Comparative immunohistochemical studies were made of the staining patterns of 7E12H12 and anti-tropomyosin antibodies. The nature of the UCAg was examined further using SDS-PAGE and Western blotting. A novel dot-blot technique examined potential binding between tropomyosin and 7E12H12. In-vitro angiography examined the relation between vascular factors and the distribution of disease. The frequency of ANCA and the target antigen(s) was examined in patients with inflammatory bowel disease. Results: Immunohistochemistry demonstrated plasma membrane localisation of UCAg and revealed additional supranuclear staining. Comparative immunostaining experiments failed to show a similar localisation pattern for tropomyosin. There was no relation between UCAg expression and disease activity. SDS-PAGE, Western blotting and dot-blot experiments confirmed the presence of UCAg and tropomyosin in colon protein extracts, but no reactivity between 7E12H12 and tropomyosin. In-vitro angiography of resected ulcerative colitis colon specimens revealed a consistent relationship between the marginal artery of the colon and disease extent. ANCA were found in 57% of patients with ulcerative colitis. Novel antigenic targets for ANCA were identified: ANCA directed against bactericidal/permeability increasing protein were found in 27% of patients. Conclusions: UCAg is not tropomyosin, but the nature of this antigen remains to be determined. Novel target antigens for ANCA, present in vasculitis, have been identified in ulcerative colitis. The extent of disease appears to be determined by the anatomy of the marginal artery. These data suggest a microvascular pathogenesis for ulcerative colitis