A gene-centric approach to biomarker discovery identifies transglutaminase 1 as an epidermal autoantigen.

Autoantigen discovery is a critical challenge for the understanding and diagnosis of autoimmune diseases. While autoantibody markers in current clinical use have been identified through studies focused on individual disorders, we postulated that a reverse approach starting with a putative autoantigen to explore multiple disorders might hold promise. We here targeted the epidermal protein transglutaminase 1 (TGM1) as a member of a protein family prone to autoimmune attack. By screening sera from patients with various acquired skin disorders, we identified seropositive subjects with the blistering mucocutaneous disease paraneoplastic pemphigus. Validation in further subjects confirmed TGM1 autoantibodies as a 55% sensitive and 100% specific marker for paraneoplastic pemphigus. This gene-centric approach leverages the wealth of data available for human genes and may prove generally applicable for biomarker discovery in autoimmune diseases.

Mechanistic insights into immune checkpoint inhibitor-related hypophysitis: a form of paraneoplastic syndrome.

BACKGROUND: Immune checkpoint inhibitors (ICIs) as a cancer immunotherapy have emerged as a treatment for multiple advanced cancer types. Because of enhanced immune responses, immune-related adverse events (irAEs), including endocrinopathies such as hypophysitis, have been associated with the use of ICIs. Most underlying mechanisms of ICI-related hypophysitis remain unclear, especially for programmed cell death-1 (PD-1)/PD-1 ligand 1 (PD-L1) inhibitors. We hypothesized that ICI-related hypophysitis is associated with paraneoplastic syndrome caused by ectopic expression of pituitary-specific antigens. METHODS: Twenty consecutive patients with ICI-related hypophysitis between 2017 and 2019 at Kobe University Hospital were retrospectively analyzed. Circulating anti-pituitary antibodies were detected using immunofluorescence staining and immunoblotting. Ectopic expression of pituitary autoantigens in tumor specimens was also examined. RESULTS: Eighteen patients were treated with PD-1/PD-L1 inhibitors, and two were treated with a combination of cytotoxic T-lymphocyte antigen-4 (CTLA-4) and PD-1 inhibitors. All patients showed adrenocorticotropic hormone (ACTH) deficiency and additionally, three showed thyroid-stimulating hormone (TSH) deficiency, and one showed gonadotropin-releasing hormone (GnRH) deficiency. Among these patients, three exhibited anti-pituitary antibodies, two with anti-corticotroph antibody and one with anti-somatotroph antibody. Interestingly, the anti-corticotroph antibody recognized proopiomelanocortin (POMC) and those two patients exhibited ectopic ACTH expression in the tumor, while the patients without anti-corticotroph antibody did not. CONCLUSIONS: We demonstrated 10% of PD-1/PD-L1 inhibitors-related hypophysitis were associated with the autoimmunity against corticotrophs and maybe caused as a form of paraneoplastic syndrome, in which ectopic expression of ACTH in the tumor was observed. It is also suggested that the pathophysiology is heterogenous in ICI-related hypophysitis.

Contribution of Immune-Mediated Paraneoplastic Syndromes to Neurological Manifestations of Neuroendocrine Tumours: A Retrospective Study.

INTRODUCTION: Neurological symptoms associated with neuroendocrine tumours (NETs) may be related to metastatic disease or paraneoplastic syndromes (PNSs); these last are often associated with autoantibodies targeting various onconeural antigens. To better characterize neurological PNSs related to NETs, we report the largest case-series study to date. METHODS: We retrospectively reviewed the charts of all patients diagnosed with NETs of the gastrointestinal tract who presented with neurological symptoms at either of 2 tertiary academic hospitals (Henri Mondor and Beaujon, France) between 1994 and 2016. All patients underwent extensive neurological tests including clinical, laboratory, and radiological investigations. The clinical response to immunomodulating agents was recorded. RESULTS: In the 13 identified patients, the most common presentations were peripheral neuropathy (46.2%) and encephalopathy (26.6%). Of the 6 (53.3%) patients whose serum anti-neuronal antibodies were assayed, 5 had high titres. Short-term oral corticosteroid and immunosuppressant drug therapy was given to 4 of these patients, of whom 3 had a clinical response and 1 no response. Repeated high-dose intravenous immunoglobulin therapy induced a complete clinical response in 1 patient. Encephalopathy resolved fully after hepatectomy or intrahepatic chemoembolization for liver metastases in another 2 patients. DISCUSSION: The neurological symptoms associated with NETs may be due in part to autoimmune PNS. Based on experience at our 2 centres, we estimate that autoimmune PNS occurs in about 1% of patients with NETs. Early symptom recognition allows the initiation of effective treatments including corticosteroids, immunosuppressive drugs, and/or intravenous immunoglobulins.

CD8+ Lymphogranulomatous Dermatitis as a Manifestation of Malignancy-Associated Immunodeficiency: Rethinking Paraneoplastic Granulomas.

ABSTRACT: Paraneoplastic granulomatous disease occurs in approximately 7.3% of patients with non-Hodgkin lymphoma, most commonly among patients with chronic lymphocytic leukemia (CLL). These lesions are often reported to appear similar to sarcoidosis in clinical presentation and under light microscopy. However, comprehensive descriptions of the cytomorphologic characteristics of these paraneoplastic granulomas are lacking, and the mechanisms involved in their formation remain ill-defined. Noninfectious dermal granulomatous reactions have also been reported in many primary immunodeficiencies, including common variable immune deficiency and ataxia-telangiectasia. We present a case of noninfectious CD8+ predominant granulomatous dermatitis with ocular involvement occurring in the setting of CLL and marked hypogammaglobulinemia. Based on the analysis of shared factors in patients with primary immunodeficiencies and CLL, we conclude that the presence of pan-humoral immunodeficiency could itself be a risk factor for developing a CD8+ lymphogranulomatous reaction. This report and associated discussion evince that CD8+ predominant granulomatous reactions, distinct from sarcoidosis, may represent a previously unappreciated segment of the paraneoplastic granulomas observed in hematologic malignancies.

A large screen for paraneoplastic neurological autoantibodies; diagnosis and predictive values.

BACKGROUND: Paraneoplastic neurological syndromes (PNS) are a group of syndromes that affect the central and peripheral neuromuscular system in association with cancer. Specific antibodies may assist in the diagnosis of PNS. The antibodies tested can be classified into those directed against intracellular neuronal proteins ("well characterized" PNS: Hu, Yo, RI, CV2, amphiphysin, Ma1, Ma2) and those directed against neural surface antigens (autoimmune encephalitis syndromes: NMDA, AMPA, LGI1, CASPR2, GABAR). We aimed to characterize patients with unexplained neuropsychiatric symptoms, in whom positive PNS antibodies were detected in the Sheba medical center, a large referral hospital. METHODS: Clinical and demographic data of patients with positive PNS antibodies were collected during the years 2002-2016. Antibodies were tested by either Line immunoassay or by cell-based indirect immunofluorscent assay. RESULTS: During the follow up of 14 years, 4010 PNS tests were performed in patients with unexplained neuropsychiatric symptoms. Seventy-two were found to be positive; among them we had full clinical data access to 44. The most frequent antibodies were anti-Hu (31.8%), anti-Yo (18.2%), anti-CV2 (13.6%), and anti-NMDA (9.1%), and the most common cancers were small-cell lung (SCLC) and ovarian cancers. In the well characterized paraneoplastic group, cancer was diagnosed in 55.9% of the patients, and in the autoimmune encephalitis group, 40.0% were diagnosed with cancer. A positive correlation between antibody titer and the presence of cancer was found. Ninety percent of the tests in patients who were found positive were ordered by a neurologist or neuro-oncologist. CONCLUSIONS: The titers of PNS auto-antibodies can predict cancer in patients whom anti-PNS antibodies are tested. In addition, consultation with a specialist should be considered before this test is ordered.

The role of cancer-associated autoantibodies as biomarkers in paraneoplastic myositis syndrome.

PURPOSE OF REVIEW: The aim of this study is to provide a comprehensive overview of the current insight about the clinical utility of cancer-associated autoantibodies (CAAs) as biomarkers in paraneoplastic myositis syndrome (PMS). In addition, the possible mechanisms of the relationship between malignancy and myositis onset are discussed. RECENT FINDINGS: It has become increasingly clear that a subgroup of the myositis-specific autoantibodies could be considered as CAAs because they are closely related to the PMS. Increased risk of cancer was found in patients with antitranscriptional intermediary factor 1-γ (TIF1-γ), antinuclear matrix protein-2 (NXP-2), anti3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) or antismall ubiquitin-like modifier 1-activating enzyme (SAE) antibodies. However, the diagnosing sensitivity and specificity of these CAAs for PMS are different among different cohort studies. Abnormally expressed or mutated autoantigen genes in tumor could possibly induce cross immunity against self-proteins and subsequently lead to the development of PMS. SUMMARY: Anti-TIF1-γ, anti-NXP-2, anti-HMGCR and anti-SAE antibodies may act as CAAs in PMS. It is necessary to closely screen and monitor for cancer in patients with CAAs. The recent studies of the relationship between CAAs and PMS provided important new insights into the disease mechanisms.

Unusual Imaging Findings Associated with Germ Cell Tumors.

Germ cell tumors, because they contain immature and mature elements, can differentiate into different tissue types. They can exhibit unusual imaging features or manifest in a syndromic fashion. The authors describe these features and assign them to one of the following categories: (a) unusual manifestations of metastatic disease (growing teratoma syndrome, choriocarcinoma syndrome, ossified metastases, and gliomatosis peritonei); (b) autoimmune manifestations (sarcoidlike reaction and paraneoplastic syndromes); (c) endocrine syndromes (sex hormone production, struma ovarii, and struma carcinoid); or (d) miscellaneous conditions (ruptured dermoid cyst, squamous cell carcinoma arising from a mature teratoma, Currarino triad, fetus in fetu, pseudo-Meigs syndrome, and pancreatitis). Rare conditions associated with germ cell tumors demonstrate characteristic imaging findings that can help lead to the appropriate diagnosis and management recommendations. When evaluating for potential metastatic disease, alternative benign diagnoses should be considered (eg, growing teratoma syndrome, ossified metastases, ruptured dermoid cyst, gliomatosis peritonei, and sarcoidlike reaction), which may impact management. Germ cell tumors may also lead to life-threatening complications such as extensive hemorrhage from choriocarcinoma metastases or the rupture of mature teratomas, cases in which timely diagnosis is crucial. Autoimmune and endocrine manifestations such as paraneoplastic encephalitis, autoimmune hemolytic anemia, and hyperthyroidism may occur owing to the presence of germ cell tumors and can create a diagnostic dilemma for clinicians. Knowledge of the syndromic and unusual imaging findings associated with germ cell tumors helps guide appropriate management. ©RSNA, 2019.

Paraneoplastic and Therapy-Related Immune Complications in Thymic Malignancies.

OPINION STATEMENT: The thymus is a key organ involved in establishing central immune tolerance. Thymic epithelial tumors (TETs) include thymomas and thymic carcinomas. Thymomas, which are histologically distinct from thymic carcinomas, lead to dysregulated thymopoiesis via decreased thymic epithelial expression of AIRE and MHC Class II, as well as via alterations in thymic architecture, thereby resulting in autoimmune complications that manifest as paraneoplastic disorders (PNDs). Although progress has been made in elucidating the mechanisms underlying thymoma-associated PNDs, there remains a great need to further define the underlying mechanisms and to identify additional immune biomarkers, such as novel antibodies (in "seronegative" cases) to facilitate diagnosis and monitoring of patients. In addition, a better understanding of the pathogenesis of PNDs could lead to improved treatment strategies for both thymomas and their immune complications. In advanced, refractory cases of TETs (both thymoma and thymic carcinoma), additional therapeutic approaches are needed. Immune checkpoint inhibitors have revolutionized the treatment of several malignancies and hold promise in the treatment of TETs; however, the risks for immune-related adverse events (especially for inducing PNDs as well as in the setting of pre-existing PNDs) underscore the need to optimize patient selection and improve clinical management before there can be widespread acceptance of checkpoint inhibitor therapy in patients with TETs.

Thrombospondin type-1 domain-containing 7A-associated membranous nephropathy after resection of rectal cancer: a case report.

BACKGROUND: Thrombospondin type-1 domain-containing 7A (THSD7A) is a target antigen in idiopathic membranous nephropathy (MN). Patients with THSD7A-associated MN are known to have a high possibility of developing malignancy. However, there are few case reports on THSD7A-associated MN with malignancy, and details of its characteristics have not been clarified thoroughly. Here, we report the case of a 77-year-old male patient who was diagnosed with THSD7A-associated MN after resection of rectal cancer. CASE PRESENTATION: A 77-year-old man who had developed bilateral peripheral edema, persistent proteinuria, and nephrotic syndrome was admitted to our hospital. He was diagnosed with MN based on a renal biopsy 3 years after resection of rectal cancer, and positive staining for THSD7A in both kidney and rectal cancer tissues suggested that these two diseases were related. Furthermore, THSD7A staining of metastatic lymph nodes revealed deposition of THSD7A in the secondary lymph follicles and sinus. Recurrence of rectal cancer was suspected; however, tumor recurrence was not observed on chest and abdominal computed tomography (CT) and colonoscopy. There was no lymph node enlargement. The patient was kept on observation with supportive therapy. Consequently, although nephrotic syndrome persisted, obvious recurrence and metastasis of the primary tumor were not observed. CONCLUSION: This is the first case in which pathological examination results suggested that THSD7A-associated MN was caused by rectal cancer. Based on the reports of THSD7A-associated MN with malignancy and the pathogenesis of MN, lymph node metastasis may be a risk for cancer-related MN.

A novel case of TIF1 gamma autoantibody positive dermatomyositis associated with a non-functional pancreatic neuroendocrine tumor.

Dermatomyositis (DM) is an idiopathic inflammatory myopathy characterized by proximal muscle weakness associated with a distinct cutaneous eruption. The association of DM with malignancy has been extensively described in the literature. Patients with DM that also have transcriptional intermediary factor 1γ (TIF1γ) autoantibodies (anti-p155, anti-p155/140) have higher rates of malignancy when compared to those without the autoantibody. We report the case of a 65-year-old woman with TIF1γautoantibody positive dermatomyositis associated with a non-functional pancreatic neuroendocrine tumor (PNET). Surgical resection of the PNET resulted in significant clinical improvement and a reduction of TIF1γ autoantibody levels in our patient.

Rheumatic paraneoplastic syndromes - A clinical link between malignancy and autoimmunity.

Paraneoplastic syndromes are rare but can have enormous clinical impact on diagnosis and outcome of neoplastic diseases. The rheumatologist should be familiar with a few typical musculoskeletal manifestations of malignancies to be able to diagnose them early for a timely initiation of anti-tumour therapies. This review describes the characteristic features of various paraneoplastic arthritides and vasculitides, cancer-associated myositis, hypertrophic osteoarthropathy, and tumour-induced osteomalacia. In addition, the current knowledge about underlying pathomechanisms of these syndromes is discussed.

Splenic marginal zone lymphoma: from genetics to management.

Splenic marginal zone lymphoma (SMZL) is a rare B-cell malignancy involving the spleen, bone marrow, and frequently the blood. SMZL lymphomagenesis involves antigen and/or superantigen stimulation and molecular deregulation of genes (NOTCH2 and KLF2) involved in the physiological differentiation of spleen marginal zone B cells. Diagnosis requires either spleen histology or, alternatively, the documentation of a typical cell morphology and immunophenotype on blood cells coupled with the detection of intrasinusoidal infiltration by CD20(+) cells in the bone marrow. Among B-cell tumors, deletion of 7q and NOTCH2 mutations are almost specific lesions of SMZL, thus representing promising diagnostic biomarkers of this lymphoma. Although the majority of SMZLs show an indolent course with a median survival of approximately 10 years, nearly 30% of patients experience a poor outcome. No randomized trials are reported for SMZL, and few prospective trials are available. A watch-and-wait approach is advisable for asymptomatic patients. Treatment options for symptomatic patients ranges from splenectomy to rituximab alone or combined with chemotherapy. In some geographic areas, a subset of patients with SMZL associates with hepatitis C virus infection, prompting virus eradication as an effective lymphoma treatment. It would be worthwhile to explore deregulated cellular programs of SMZL as therapeutic targets in the future; improved clinical and biological prognostication will be essential for identifying patients who may benefit from novel approaches.

An Overview of Autoimmune and Paraneoplastic Encephalitides.

The understanding of the manifestations, mechanisms, and management of autoimmune encephalitis has expanded dramatically in recent decades. Immune-mediated encephalitides are comparable in incidence and prevalence to infectious etiologies, and are associated with significant morbidity, especially when there is a delay in recognition and treatment. As such, clinicians from many specialties must develop a functional understanding of these disorders. Herein we provide an overview of the autoimmune and paraneoplastic encephalitides, including those associated with either intracellular or cell surface/synaptic neuronal autoantibodies. After briefly reviewing the current understanding of the pathobiology of autoimmune encephalitis, we combine a neuroanatomical approach with specific antibody syndromes to provide the reader with a clinically relevant review of these disorders. The clinical manifestations, diagnosis, and management of autoimmune encephalitis are reviewed, with an emphasis on clinical relevance. We also introduce updates in the field, including autoimmune encephalitis associated with novel cancer immunotherapies, infectious triggers of autoimmune encephalitis, and autoimmune encephalitis with demyelinating overlap syndromes.

The Positive Predictive Value of Onconeural Antibody Testing: A Retrospective Review.

Paraneoplastic syndromes (PNS) are immune-mediated neurologic diseases that occur as an indirect effect of malignancy, and can be challenging to diagnose. Onconeural antibodies have a greater than 95% association with cancer, and their presence in a patient with neurologic symptoms is reportedly highly indicative of PNS. However, we performed a single-centre retrospective review to determine the positive predictive value of onconeural antibody testing, and found it to be concerningly low (39%). Recognising the limitations of onconeural antibody testing is critical to ensure accurate test interpretation, avoid unnecessary repeated malignancy screening and prevent the use of potentially hazardous immunotherapy.

[Update on anti-N-methyl-D-aspartate receptor encephalitis]. / Update Anti-N-Methyl-D-Aspartat-Rezeptor-Enzephalitis.

Autoimmune encephalitis is a group of autoimmune inflammatory disorders affecting both grey and white matter of the central nervous system. Encephalitis with autoantibodies against the N­methyl-D-aspartate receptor (NMDA-R) is the most frequent autoimmune encephalitis syndrome presenting with a characteristic sequence of psychiatric and neurological symptoms. Treatment necessitates a close interdisciplinary cooperation. This article provides an update on the current knowledge on diagnostic standards, pathogenesis, and treatment strategies for anti-NMDA-R encephalitis from psychiatric and neurological perspectives.

Paraneoplastic pemphigus without antibodies to desmoglein 1 and 3.

Paraneoplastic pemphigus is a severe autoimmune blistering disease presenting in the setting of underlying malignancy. Paraneoplastic pemphigus is associated with diffuse painful stomatitis throughout the oral cavity with extension to the lips. The cutaneous findings are varied and have been described as lichenoid, pemphigoid, and targetoid lesions. Herein, we report a patient with paraneoplastic pemphigus whose routine testing led to a diagnosis of pemphigus vulgaris. However, further testing was pursued revealing an antibody profile consistent with paraneoplastic pemphigus. Subsequent neoplastic workup revealed an intra-abdominal mass. Our case represents a subtle, non-classic presentation of paraneoplastic pemphigus and suggests the importance of a comprehensive investigative work-up in atypical cases of pemphigus.

Chronic Localized Fibrosing Leukocytoclastic Vasculitis Associated With Lymphedema, Intralymphatic and Intravascular Lymphocytosis, and Chronic Myelogenous Leukemia: A Case Report of Unilateral Erythema Elevatum Diutinum.

One of the pathogenic causes of cutaneous inflammatory pseudotumors is chronic localized fibrosing leukocytoclastic vasculitis (CLFLCV), a vasculitic reaction pattern seen in granuloma faciale (GF), a localized vasculitis, and erythema elevatum diutinum (EED), a generalized vasculitis. Patients with myelodysplastic syndromes (MDSs) are at risk for a diverse spectrum of cutaneous neutrophilic dermatoses such as EED. Herein, we report a 74-year-old man who presented with a large ulcerative, fungating tumor affecting the right flexor ankle caused by CLFLCV. During his workup and management, MDS and Philadelphia chromosome-negative chronic myeloid leukemia was diagnosed. Surgical excision of the inflammatory mass promptly triggered tumor recurrence, whereas antineutrophil therapy (dapsone coupled with hydroxyurea, and prednisone) lead to tumor regression. Histopathologic examination revealed an eosinophilic-rich small-vessel neutrophilic vasculitis associated with storiform and angiocentric fibrosis (GF-like). In the regions of fibrosis, dilated lymphatic and vascular spaces were numerous, some of which were congested with small CD3-positive lymphocytes (intralymphatic and intravascular lymphocytosis). These findings indicate coexisting localized lymphedema. By direct immunofluorescence, IgM and C4d vessel deposits were detected. The pathogenesis of the fibrotic nodules and plaques of CLFLCV is suspected to be due to recurring bouts of immune-complex vasculitis, creating a cycle of vessel damage followed by reparative granulation tissue. Poor lymphatic drainage may be the underlying factor initiating and maintaining recurrent, localized episodes of immune-complex vasculitis and progressive fibrosis. Although his tumor histopathology resembled GF-eosinophilic rich CLFLCV-the clinical context points to a solitary and paraneoplastic case of EED.

Anti-NXP2-Positive Paraneoplastic Dermatomyositis With Histopathologic Changes Confined to the Acrosyringia.

BACKGROUND: Paraneoplastic syndromes consist of a group of disorders that are not related to the extension of the primary tumor or its metastases and that might be the first manifestation of a hidden neoplasm. It is a well-known association between dermatomyositis (DM) and cancer, especially gynecological tumors in women and lung cancer in men. METHODS: We describe the case of a 67-year-old male who developed muscular weakness and pruritic skin lesions. Skin biopsies were performed and histologic findings were consistent with DM. RESULTS: Skin biopsy showed interface dermatitis with vacuolar degeneration of the basal layer, dermal mucin deposits, and necrotic keratinocytes in the acrosyringia, a finding that has been previously reported in lupus erythematous but not in DM. Autoimmunity tests showed positivity for antinuclear antibodies and anti-NXP2, a recently described antibody associated with juvenile DM and, more rarely, with paraneoplastic DM. CONCLUSION: We present the first case in the literature with histopathologic changes of DM affecting the acrosyringia. Besides, our patient autoimmunity results support the utility of the new myositis-specific autoantibodies and its relation with a clinical phenotype.

Inflammatory Myopathies with Cutaneous Involvement: from Diagnosis to Therapy.

The group of idiopathic inflammatory myopathies (IIM) include various disorders of skeletal muscles with or without skin involvement. The most common types are dermatomyositis (DM), polymyositis (PM), inclusion body myositis (IBM) and necrotizing autoimmune myopathy (NAM). Dermatomyositis subdivides into various clinical forms such as juvenile, amyopathic or paraneoplastic dermatomyositis, scleromyositis, overlap or anti-synthetase syndromes, etc. Recently, numerous new antibodies defining the characteristic clinical phenotype have been described as anti-MDA5 antibodies associated with interstitial lung disease and amyopathic dermatomyositis or anti-TIF1γ antibodies as markers for paraneoplastic dermatomyositis. Moreover, new clinical entities as drug-induced dermatomyositis are presumed, since some medications may induce, or trigger inflammatory myopathies. Knowledge of the complex methods and techniques required to diagnose the disease is of great importance in clinical practice. The variety of clinical variants needs diagnosis because of the differing prognosis and therapeutic modalities.

Pathogenic and physiological autoantibodies in the central nervous system.

In this article, we review the current knowledge on pathological and physiological autoantibodies directed toward structures in the central nervous system (CNS) with an emphasis on their regulation and origin. Pathological autoantibodies in the CNS that are associated with autoimmunity often lead to severe neurological deficits via inflammatory processes such as encephalitis. In some instances, however, autoantibodies function as a marker for diagnostic purposes without contributing to the pathological process and/or disease progression. The existence of naturally occurring physiological autoantibodies has been known for a long time, and their role in maintaining homeostasis is well established. Within the brain, naturally occurring autoantibodies targeting aggregated proteins have been detected and might be promising candidates for new therapeutic approaches for neurodegenerative disorders. Further evidence has demonstrated the existence of naturally occurring antibodies targeting antigens on neurons and oligodendrocytes that promote axonal outgrowth and remyelination. The numerous actions of physiological autoantibodies as well as their regulation and origin are summarized in this review.