Paraproteins with antibody activity in acute viral hepatitis and chronic autoimmune liver diseases

Of 27 patients with liver disease and cryoglobulinaemia 18 proved to have paraproteins. Six of these monoclonal immunoglobulins were shown to have antibody activity, directed to human gamma globulin, alpha₁-fetoprotein, smooth muscle, and mitochondria.

Eight of the patients suffered from acute viral hepatitis, five of whom were HB Ag positive; in all these cases the monoclonal spikes were transient and their antibody activities were directed against IgG in two cases and alpha₁-fetoprotein in one.

Seven of the patients had active chronic hepatitis and in these the paraproteinaemia persisted, though remaining quantitatively unchanged over several years. One of them had a cryoprecipitable monoclonal smooth muscle antibody. Three patients had primary biliary cirrhosis and in two of them monoclonal IgM mitochondrial antibodies were demonstrated.

In three out of the 18 cases there was a double M-component.

Since these monoclonal antibodies are directed to autoantigens not unlike the polyclonal ones usually seen in autoimmune hepatic diseases, it is suggested that the factor which triggers the uncontrolled plasma cell proliferation to produce paraproteins must meet cells from an already expanding clone.

     

Hematologic malignancies in the Japanese patients with inflammatory bowel disease

Background

Although attention has been focused for over 20 years on the possible increased risk for hematologic malignancies (HM) in patients with inflammatory bowel diseases (IBD) receiving immune-modulators or anti-TNF-alpha antibodies, the association is still controversial. To understand the actual conditions of HM in the Japanese patients with IBD, the research committee for IBD supported by the Ministry of Health, Welfare and Labor of Japan (IBD-MHWL) conducted a multi-center retrospective study.

Methods

Questionnaires for the development of HM in IBD patients were sent to the 70 facilities participating with IBD-MHWL in the first survey, followed by the second survey using a more detailed questionnaire, sent to the 27 members with HM patients.

Results

Out of a total of 36,939 IBD patients in 70 facilities, 28 cases of HM related with IBD [12 of 10,500 UC patients (0.11 %), 16 of 6,310 CD patients (0.25 %)] were analyzed. The numbers of UC patients who developed HM were 2 (0.15 %) from the group receiving and 10 (0.13 %) from the group non-receiving thiopurine, without significant differences. The numbers of CD patients who developed HM were 4 (0.39 %) from the group receiving and 12 (0.21 %) from the group non-receiving thiopurine, without significant differences. The odds ratios of developing HM by thiopurine were 1.37 (95 % CI 0.30–6.24) in UC patients and 1.86 (95 % CI 0.60–5.78) in CD patients.

Conclusions

Our results suggested that thiopurine therapy may not be a risk factor for HM in Japanese patients with IBD. Further accumulation of cases and prospective studies are necessary to conclude this important issue.     

伴有自身免疫性疾病的慢性乙型肝炎患者的抗病毒治疗

慢性乙型肝炎患者伴有自身免疫性疾病在临床上比较常见,大部分这类患者需要抗乙型肝炎病毒治疗.核苷(酸)类似物和干扰素等抗乙型肝炎病毒药物在治疗此类患者时各有优劣,收益与风险并存.因此,临床实践中应该充分评估患者伴发的自身免疫性疾病种类和严重程度,选择最合适的抗乙型肝炎病毒药物,避免造成医源性损伤.     

Cancer and autoimmunity: autoimmune and rheumatic features in patients with malignancies

OBJECTIVES: To review the autoimmune and rheumatic manifestations of patients with malignancy. METHODS: A Medline search of all published papers using keywords related to malignancies, autoimmunity, rheumatic diseases, and paraneoplastic syndromes. RESULTS: Patients with malignant diseases may develop autoimmune phenomena and rheumatic diseases as a result of (a) generation of autoantibodies against various autoantigens, including oncoproteins (P185, 1-myc, c-myc, c-myb), tumour suppression genes (P53), proliferation associated antigens (cyclin A, B1, D1, E; CENP-F; CDK, U3-RNP), onconeural antigens (Hu, Yo, Ri, Tr), cancer/testis antigens (MAGE, GAGE, BAGE, SSX, ESO, SCP, CT7), and rheumatic disease associated antigens (RNP, Sm). The clinical significance of the various autoantibodies is not clear. Anti-oncoprotein and anti-tumour suppression gene antigens are detected before the diagnosis of the cancer or in the early stages of the malignant disease, suggesting a potential diagnostic or prognostic role. Anti-onconeural antibodies are pathogenic and are associated with specific clinical neurological syndromes (anti-Hu syndrome and others). (b) Paraneoplastic syndromes, a wide range of clinical syndromes, including classic autoimmune rheumatic diseases that develop among patients with cancer. (c) Rheumatism after chemotherapy, a clinical entity characterised by the development of musculoskeletal symptoms after combination chemotherapy for malignancy. CONCLUSION: Autoimmune and rheumatic features are not rare among patients with malignancies. They are the result of various diverse mechanisms and occasionally they may be associated with serious clinical entities.     

Intrahepatic status of regulatory T cells in autoimmune liver diseases and chronic viral hepatitis.

Aim: Regulatory T cells (Tregs) maintain immunological tolerance and suppress autoreactive immune responses. We evaluated the intrahepatic status of Tregs in patients with autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), chronic hepatitis C (CH-C), or chronic hepatitis B (CH-B). Methods: We analyzed 85 patients (20 AIH, 22 PBC, 27 CH-C, and 16 CH-B) and 14 controls. Using liver tissue samples obtained by needle biopsy or from marginal parts of resected metastatic liver tumors in the controls, immunohistochemical analyses of forkhead box P3(+), which is a specific marker for Tregs, CD4(+), and CD8(+) cells were performed. Results: Intrahepatic Tregs were significantly more infiltrated in patients with liver diseases than in the controls. There were significantly fewer intrahepatic Tregs in the AIH patients than in the PBC patients (P = 0.037). Patients with alow frequency of intrahepatic Tregs were detected significantly more in the AIH and CH-B groups than in the PBC and CH-C groups (P < 0.05). In addition, the frequency of Tregs decreased in the liver of PBC patients as the pathological stage of the disease advanced. We found significantly less infiltration of CD4(+) T cells in AIH than in other diseases (P < 0.05). Liver-infiltrating CD8(+) T cells were detected more frequently in the CH-B group than in other groups (P < 0.003). Conclusion: Intrahepatic Tregs were increased in both patients with autoimmune liver diseases and those with viral hepatitis. In autoimmune liver diseases, intrahepatic Tregs were fewer in the AIH patients than in the PBC patients.     

Plasmacytoid dendritic cells: Key players in viral infections and autoimmune diseases

Objective

Describe the main activation and inhibitory pathways and receptors by which pDC regulate type I interferon secretion, as well as its association with autoimmune pathology.

Methods

A PubMed search for articles was conducted using the following key words: plasmacytoid dendritic cells, autoimmune diseases, viral infections and type I interferon. The search was limited to publications in English and from 1957 to 2012. Sixty-five of these articles are included in this review. The most relevant primary research articles identified were critically evaluated and compiled together. Particularly, areas of consensus and controversy were identified and analyzed.

Results

Plasmacytoid dendritic cells have been closely related to viral infections and autoimmune disease, mainly because of these immune cells are able to secrete large amounts of type I interferon. This function is linked with their expression of Toll-like receptors, specially TLR7 and TLR9, which are designed to sense nucleic acids in the early endosomes. Activated pDC can promote immunity and autoimmunity, however, the exact mechanisms by which pDC promote one vs. the other are not well understood.

Conclusions

Plasmacytoid dendritic cells play a key role in both, immunity and autoimmunity. Current evidence suggests that the sustained overproduction of type-I interferon drives aberrant immune responses and the development of autoimmune pathology.     

Ins and outs of Helicobacter pylori association with autoimmune rheumatic diseases

Helicobacter pylori (H. pylori) infection is widely prevalent throughout worldwide. H. pylori manage a long-term survival in hostile environment of human stomach leading to peptic ulcer diseases and gastric cancer. But mostly infected person remains asymptomatic. Its chronic interaction with immune system makes H. pylori as an attractive candidate for the researchers to study its association with autoimmune diseases. This article presents a review of the literature on the association of H. pylori infection in selective autoimmune rheumatic diseases (RD). The authors used MeSH terms “Helicobacter pylori” with “rheumatoid arthritis,”“systemic lupus erythematosus,” or “fibromyalgia” to search PubMed database. All relevant studies identified were included. Despite extensive medical advancement many questions on role of H. pylori infection in autoimmune RD still remain unanswered. Further studies are therefore needed to address the role of H. pylori in pathogenesis of RD.     

Hematologic malignancies associated with primary mediastinal germ-cell tumors

Three men with primary mediastinal germ-cell tumors subsequently developed a malignant hematologic disorder characterized by pancytopenia and marrow infiltration with hematopoietic blast cells. Two of these patients were classified as having acute megakaryocytic leukemia and the third was believed to have a myelodysplastic syndrome with a prominent megakaryocytic component. Analysis of clinical characteristics of these patients and review of the literature suggest that the proximate association of mediastinal germ-cell tumors with malignant hematologic disorders is neither a coincidence nor a consequence of chemotherapy given for the germ-cell tumor. We believe this association represents the evolution of a neoplastic disorder that initially involves a totipotent germ cell. These germ cells, when located in the mediastinum, apparently acquire hematologic phenotypes and are manifested clinically as a hematologic malignancy.     

Presence of systemic autoimmune disorders in patients with autoimmune thyroid diseases

Methods: 168 consecutive patients with ATD with positive antithyroid antibodies and 75 healthy subjects were tested for the presence of ANA. ANA positive patients were further evaluated by complete history, physical examination, blood and urine tests, and immunological studies. Patients with subjective xerophthalmia and xerostomia were examined by objective tests. Results: 58/168 (35%) patients with ATD were ANA positive compared with 7/75 (9%) healthy controls (p = 0.001). Of 58 ANA positive patients, 6 (10%) had anti-Ro antibodies, 1 had anti-Ro and anti-La antibodies, 7 (12%) had anti-dsDNA antibodies, and 7 (12%) had medium levels of IgG and/or IgM anticardiolipin antibodies (aCL). No healthy subjects had positive anti-dsDNA, antibodies against the extractable nuclear antigens, or aCL. 5/58 (9%) patients fulfilled the criteria for Sjögren''s syndrome (SS). Two patients had features related to systemic lupus erythematosus. No healthy subjects had clinical or laboratory characteristics of systemic autoimmune disorders. Conclusion: ANA are detected in 1/3 of patients with ATD. Anti-dsDNA, anti-Ro, and aCL can also be found in ANA positive patients with ATD. SS occurs in about 1/10 of ANA positive patients with ATD.     

Thoracic malignancies in patients with chronic tuberculous empyema

OBJECTIVES: To clarify features of thoracic malignancies occurred in patients with chronic tuberculous empyema. MATERIALS AND METHODS: We analyzed clinicopathological data of 15 patients with thoracic malignancies who had chronic tuberculous empyema, encountered at Tokyo National Hospital during the period from 1977 to 2002. RESULTS: There were 13 men and 2 women, with a mean age of 67 years. Most of all (13/15) patients had history of surgery for tuberculosis including artificial pneumothorax (9 cases). Malignancies consisted of pyothorax-associated lymphoma (PAL; 9 cases), lung cancer (4 cases), malignant fibrous histiocytoma (1 case), and angiosarcoma (1 case). There were no differences in background factors between PAL patients and the other patients. Common symptoms were chest pain (10 cases), fever (7 cases), and bloody sputum (4 cases) and it seemed that these symptoms were more evident in patients with PAL than in patients with other diseases. Plain chest X-ray films often failed to detect the tumor, and the diagnosis was often obtained by sputum cytology, bronchofiberscopy, transcutaneous biopsy, and resection with support of CT and/or MRI films. On radiographs, all tumors located in empyema cavities or around empyema walls, and a pulmonary mass adjacent to the empyema wall was characteristic of lung cancer. PAL showed certainly good outcome; 40% 5-year survival rate with resection or chemoradiotherapy. On the other hand, all of lung cancer cases were diagnosed at stage III, and had poor outcome, and the remaining patients with the other malignancies also had poor outcome. CONCLUSION: Clinicians should keep in mind occurrence of several thoracic malignancies during the follow-up of patients with chronic tuberculous empyema.     

Waitlist mortality in patients with autoimmune liver diseases

Introduction and ObjectivesAutoimmune liver diseases such as autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis are the primary indication for ～24% of total liver transplants. The liver transplant allocation system is currently based upon the Model for End-Stage Liver Disease and it often underestimates the severity of autoimmune liver diseases. We aim to compare the rate of adverse waitlist removal among patients with all autoimmune liver diseases and other indications for liver transplant in the Model for End-Stage Liver -Na era.Materials and MethodsUsing the United Network for Organ Sharing database, we identified all patients listed for liver transplant from 2016 to 2019. The outcome of interest was waitlist survival defined as the composite outcome of death or removal for clinical deterioration. Competing risk analysis was used to evaluate the waitlist survival.ResultsPatients with autoimmune hepatitis had a higher risk of being removed from the waitlist for death or clinical deterioration (SHR 1.37, 95% CI 1.08–1.72; P<0.007), followed by primary biliary cholangitis (SHR 1.34, 95% CI 1.07–1.68; P<0.011).ConclusionsHigh waitlist death or removal for clinical deterioration was observed in patients with PBC and AIH when compared to other etiologies. It may be useful to reassess the process of awarding MELD exception points to mitigate such disparity.     

Overlap syndromes with autoimmune hepatitis in chronic cholestatic liver diseases

Conditions exhibiting features of two different autoimmune liver diseases are commonly designated overlap syndromes, although there is no current agreement on what constitutes an overlap syndrome or specific diagnostic criteria. As in the classic autoimmune liver diseases, such as autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), the etiology is unknown but presumed to be related to alterations of immune regulation. Distinction of these clinical entities is important for management as outcomes may differ from outcomes of patients with diagnosis of classic autoimmune liver diseases. Due to their presumed rarity, no large therapeutic trials are available and treatment of overlap conditions is empirical and based upon extrapolation of data from the primary autoimmune liver diseases. PBC–AIH overlap is the most frequently described overlap syndrome and may be associated with a poor prognosis. This may represent an important and unrecognized cause of resistance to ursodeoxycholic acid in patients with PBC. PSC–AIH overlap is less commonly reported. Prognosis may be better than in patients with PSC alone; however, worse than in patients with AIH alone. Further studies are needed for determining diagnosis, natural history and optimal therapeutic strategies of overlap syndromes of autoimmune liver disease.     

Serum isoamylases in patients with autoimmune rheumatic diseases

We studied sera of 107 patients with autoimmune rheumatic diseases (46 with classical rheumatoid arthritis (RA), 36 with systemic lupus erythematosus (SLE) and 25 with primary Sj?gren's syndrome (SS). None of these patients had abdominal pain or gastrointestinal symptoms at the time of blood collection. We used as controls 81 normal age and sex matched volunteers. The presence of hyperamylasemia i) of P-type in 6 of 46 patients (13%) with RA and ii) of P-type and S-type in 11 of 36 patients (30.5%) with SLE and 6 of the 25 patients (24%) with primary SS suggests that asymptomatic pancreatic damage in autoimmune rheumatic diseases may occur frequently especially in patients with SLE. We conclude that the hyperamylasemia in these patients probably reflects a slow, subclinical, inflammatory process of the exocrine glands.     

Effect of viral infections on pulmonary function in patients with chronic obstructive pulmonary diseases

The effect of 100 separate viral infections of the respiratory tract on pulmonary function was evaluated prospectively over an eight-year period in 84 patients with chronic obstructive pulmonary diseases and in eight normal subjects. Some viral infections were associated with small acute declines in forced vital capacity and/or 1-sec forced expiratory volume of 25-300 ml. These declines were detectable only during the 90-day period after infection. The greatest abnormalities of pulmonary function followed infections with influenza virus, and the mean acute changes in 1-sec forced expiratory volume (-118.5 ml) were significantly greater than expected (-15.2 ml; P = 0.03). Smaller, statistically insignificant declines followed infections with parainfluenza virus, rhinovirus, adenovirus, and respiratory syncytial virus, and no changes were detectable after infections with coronavirus, herpes simplex virus, Mycoplasma pneumoniae, and Haemophilus influenzae. Long-term effects of influenza or other viral infections on the course of chronic obstructive pulmonary disease were not detected in this study population.