Antineutrophil cytoplasmic antibodies in children

To define the diagnostic meaning of antineutrophil cytoplasmic antibodies (ANCA) positivity in children, we analysed 1485 consecutive sera sent for routine immunological investigation to our department from January to August 1996. Using this large screening, we identified the most typical clinical disorders associated with ANCA in childhood. Out of 1485 indirect immunofluorescence (IIF) tests for ANCA, 143 were ANCA positive, 70 had a cytoplasmic IIF pattern (c-ANCA), and 73 a perinuclear IIF pattern (p-ANCA). The ANCA associated diseases in childhood were cystic fibrosis (CF) (31 c-ANCA, 7 p-ANCA positive out of 71 CF children investigated), juvenile chronic arthritis (JCA) (21 p-ANCA positive out of 78), auto-immune hepatitis (AIH) (4 c-ANCA and 12 p-ANCA positive out of 19), and ulcerative colitis (UC) (2 c-ANCA, 5 p-ANCA positive out of 15). In cases of c-ANCA positivity we determined the antigenic specificity of ANCA for proteinase 3 and/or bactericidal/permeability increasing protein. Borderline anti-proteinase 3 levels were found in CF, and in high levels in one boy with Wegener granulomatosis. Bactericidal/permeability increasing protein was characteristic target antigen in children with CF. p-ANCA positive children were further tested for the specificity for myeloperoxidase, which was detected mostly in children with JCA. CONCLUSION: The spectrum of diseases associated with ANCA in children includes, besides the diagnostic associations typical for adults, several typical pediatric entities, mainly juvenile chronic arthritis and cystic fibrosis.     

Antineutrophil cytoplasmic autoantibodies (ANCA) and their target antigens in Chinese patients with lupus nephritis

BACKGROUND: ANCA have been found in patients with systemic lupus erythematosus (SLE); however, the prevalence of ANCA and their target antigens is still not certain. This study is to investigate the prevalence of ANCA and their target antigens in Chinese patients with lupus nephritis. METHODS: Ninety-five serum samples were collected from 95 renal-biopsy-proven lupus nephritis patients. Indirect immunofluorescence using ethanol-fixed leukocytes as substrate and ELISA using six highly purified known ANCA antigens as solid-phase ligands were performed. The specific ANCA antigens included proteinase 3, myeloperoxidase, bactericidal/permeability-increasing protein, human leukocyte elastase, cathepsin G, and lactoferrin. The prevalence of ANCA in patients with (n=65) and without (n=30) active renal pathological lesions was also compared to reveal whether ANCA correlates with disease activity. RESULTS: (i) None of the sera recognized proteinase 3, myeloperoxidase, and human leukocyte elastase, and only one serum recognized bactericidal/permeability-increasing protein. The striking finding was that 59/95 (62.1%) sera recognized cathepsin G and the titres of some sera reached 1/3200. Eight of 95 sera (8.4%) recognized lactoferrin. (ii) The percentage of anti-cathepsin G antibody positive samples in patients with active renal lesions was significantly higher than in patients without active lesions (73.4 vs 36.7%, P<0.0001), whereas, anti-lactoferrin antibodies had no correlation with active renal lesions. (iii) By indirect immunofluorescence, only 22% of the 95 sera were ANCA positive. CONCLUSIONS: Our results suggest that the majority of lupus nephritis patients have ANCA and that the major target antigens is cathepsin G. Anti-cathepsin G antibodies seem to be correlated with renal disease activity.     

Antinuclear antibodies and patterns of nuclear immunofluorescence in type 1 autoimmune hepatitis

To determine the significance of antinuclear antibodies and their patterns of indirect immunofluorescence in type 1 autoimmune hepatitis, sera from 99 patients were evaluated. Patients with antinuclear antibodies had a lower frequency of liver transplantation (6% vs 22%, P = 0.04) than seronegative patients. They were also more commonly HLA-DR4-positive than seronegative patients (56% vs 30%, P = 0.05) and normal subjects (56% vs 30%, P = 0.004). The 42 patients with antinuclear antibodies and a diffuse pattern of indirect immunofluorescence had higher serum titers of ANA (serum titers > or = 1:500, 71% vs 14%, P < 0.0001) and SMA (serum titers > or = 1:500, 69% vs 27%, P = 0.003) than the 22 patients with antinuclear antibodies and a speckled pattern. These patients, however, were otherwise not distinguished by clinical features and treatment response. Patients with a speckled pattern had A1-B8-DR3 more frequently than patients with a diffuse pattern (65% vs 23%, P = 0.005) and normal subjects (65% vs 13%, P < 0.0001), but they had no other salient features. We conclude that patients with antinuclear antibodies have a better long-term prognosis than seronegative patients, and they have HLA-DR4 more commonly. The patterns of indirect immunofluorescence associated with ANA positivity have no practical clinical implications.     

Antineutrophil cytoplasmic antibodies in primary Sj?gren's syndrome: prevalence and clinical significance

OBJECTIVE: To evaluate the prevalence of cytoplasmic (c) and perinuclear (p) antineutrophil cytoplasmic antibodies (ANCA) in patients with primary Sjogren's syndrome (SS), and to correlate the presence of ANCA with extraglandular and immunological manifestations related to SS. METHODS: In a cross-sectional study, we included 82 consecutive patients (75 female and seven male; mean age 61 yr; range 33-87 yr) attending our unit. All patients fulfilled four or more of the diagnostic criteria for SS proposed by the European Community Study Group in 1993. Extraglandular manifestations such as arthralgia and/or arthritis, Raynaud's phenomenon, autoimmune thyroiditis, peripheral neuropathy, renal involvement and cutaneous vasculitis were also recorded. Serum samples were examined by indirect immunofluorescence (IIF) and by ELISA using as substrates myeloperoxidase (MPO) and proteinase 3 (PR3). RESULTS: ANCA were detected in nine (11%) patients: seven had pANCA and two an atypical pattern. These two atypical ANCA became cANCA when paraformaldehyde fixation was applied. ELISA findings showed that two patients had antibodies against MPO, and no patient had antibodies to PR3. The most common extraglandular manifestations in the ANCA-positive patients were articular involvement in six (66%) patients, peripheral neuropathy in five (55%), Raynaud's phenomenon in four (44%) and cutaneous vasculitis in four (44%). Of the four patients with cutaneous vasculitis and ANCA, two had a mononuclear inflammatory vascular disease (MIVD) in the biopsy specimen. When compared with patients without ANCA, those with these antibodies had a higher prevalence of cutaneous vasculitis (44% vs 8%, P = 0.01), Raynaud's phenomenon (44% vs 8%, P = 0.01) and peripheral neuropathy (55% vs 7%, P < 0.001). CONCLUSION: ANCA positivity can be found in patients with primary SS and its detection is associated with the presence of clinical manifestations attributable to vascular involvement (cutaneous vasculitis, peripheral neuropathy and Raynaud's phenomenon).     

Systemic lysis therapy in retinal vascular occlusions

AIM: To describe the neutrophil fluorescent patterns produced by antineutrophil cytoplasmic antibodies (ANCA) with different antigen specificities, and by other auto- and alloantibodies. BACKGROUND: Most sera from patients with active generalised Wegener's granulomatosis result in diffusely granular cytoplasmic neutrophil fluorescence with internuclear accentuation (cANCA) and proteinase 3 (PR3) specificity. About 80% of the sera from patients with microscopic polyangiitis result in perinuclear neutrophil fluorescence with nuclear extension (pANCA) and myeloperoxidase (MPO) specificity, or a cANCA pattern with PR3 specificity. However, many different neutrophil fluorescence patterns are noted on testing for ANCA in routine immunodiagnostic laboratories. METHODS: Sera sent for ANCA testing, or containing a variety of auto- and alloantibodies, were studied. They were examined by indirect immunofluorescence according to the recommendations of the first international ANCA workshop, and for PR3 and MPO specificity in commercial and in-house enzyme linked immunosorbent assays (ELISA). RESULTS: Sera with typical cANCA accounted for only half of all neutrophil cytoplasmic fluorescence. Other sera had "flatter" fluorescence without internuclear accentuation, and the corresponding antigens included MPO and bactericidal/permeability increasing protein (BPI), but were usually unknown. Peripheral nuclear fluorescence without nuclear extension occurred typically when the antigens were BPI, lactoferrin, lysozyme, elastase, or cathepsin G. Most types of ANA were evident on ethanol fixed neutrophil nuclei. AntidsDNA, antiRo, and antilamin antibodies resembled pANCA. Antimicrobial and antiribosomal antibodies produced cytoplasmic fluorescence, and antiGolgi antibodies, a pANCA. Sera from patients with anti-smooth muscle antibodies were associated with cytoplasmic fluorescence. There was no neutrophil fluorescence with anti-skeletal muscle and anti-heart muscle antibodies, anti-liver/kidney microsomal, antithyroid microsomal, or antiadrenal antibodies. Alloantibodies such as antiNB1 typically resulted in cytoplasmic fluorescence of only a subpopulation of the neutrophils. CONCLUSIONS: The ability to distinguish between different neutrophil fluorescence patterns, and the patterns seen with other auto- and alloantibodies is helpful diagnostically. However, the demonstration of MPO or PR3 specificity by ELISA will indicate that the neutrophil fluorescence is probably clinically significant, and that the diagnosis is likely to be Wegener's granulomatosis or microscopic polyangiitis.     

Anti-endothelial cell antibodies in Takayasu arteritis

BACKGROUND: Although a specific etiology for Takayasu arteritis has not been found, the bulk of evidence favors an autoimmune mechanism. We examined the sera of 19 patients with Takayasu arteritis for antineutrophil cytoplasmic antibodies (ANCA), antinuclear antibodies (ANA), anti-DNA antibodies, antibodies to extractable nuclear antigens (ENA), anti-Ro anti-bodies, anticardiolipin antibodies, circulating immune complexes, and anti-endothelial cell antibodies (AECA). METHODS AND RESULTS: We used enzyme-linked immunoassays, immunofluorescence, counterimmunoelectrophoresis, fluorescent-activated cell sorter (FACS) analysis, and confocal microscopy. We found that although no patient had positive ANCA, ANA, anti-DNA antibodies, ENA antibodies, anti-Ro antibodies, or anticardiolipin antibodies, 18 of the 19 patients had AECA. The AECA titers of the patients were 2561 +/- 1458 compared with 126 +/- 15 arbitrary units in a normal group of control subjects (P < .001). To verify the specificity of AECA, we performed cytofluorimetry on human endothelial cells with the sera from patients and control subjects. Two entirely separate patterns of fluorescence intensity were identified. We next performed immunocytochemistry and confocal microscopy with human endothelial cells subjected to patients' sera and to sera from normal subjects. The cells subjected to sera from patients with Takayasu arteritis demonstrated specific immunofluorescent staining of their plasma membrane and cytosol. CONCLUSIONS: AECA are frequently present in patients with Takayasu arteritis. They may play a role in the pathogenesis. Furthermore, they may be useful as an additional diagnostic tool.     

Immunohistochemical localization of MUC 1 and keratin 14 in the invasive regions of malignant eyelid tumors

BACKGROUND: Two types of antineutrophil cytoplasmic antibodies (ANCA), antiproteinase 3 antibodies (anti-PR3) and antimyeloperoxidase antibodies (anti-MPO), are useful in the diagnosis of such types of vasculitis as Wegener granulomatosis and microscopic polyangiitis. Connective tissue diseases frequently appear in the differential diagnosis of this spectrum of vasculitis. OBJECTIVE: To determine the prevalence of ANCA in patients with connective tissue disease. DESIGN: Blinded, controlled study of a 5-year inception cohort. SETTING: Tertiary-care university teaching hospitals. PATIENTS: 70 patients with rheumatoid arthritis, 70 patients with systemic lupus erythematosus, 45 patients with scleroderma, 36 patients with inflammatory myositis, 44 patients with the sj?gren syndrome, 33 patients with the antiphospholipid syndrome, and 165 patients with early undifferentiated connective tissue disease (EUCTD). Serum was taken from 200 blood donors and 52 patients who had known vasculitis and positive results on tests for anti-PR3 or anti-MPO; these patients served as controls. MEASUREMENTS: The presence of anti-PR3 and anti-MPO was determined by combining the results of indirect immunofluorescence tests for cytoplasmic (C-ANCA) and perinuclear (P-ANCA) patterns with the results of enzymelinked immunosorbent assays (ELISAs) directed to measure antigen. RESULTS: Cytoplasmic ANCA was not detected in any study or control patient. Perinuclear ANCA was commonly detected among patients with lupus (31%) but was uncommon among patients in other groups (0% to 5%). In all cases, P-ANCA was associated with the presence of antinuclear antibodies. Atypical ANCA immunofluorescence patterns were fairly common in all groups (11% to 39%). Antiproteinase 3 was detected by ELISA in study patients (1 patient with rheumatoid arthritis, 1 with lupus, 1 with polymyositis, and 6 with EUCTD). Antimyeloperoxidase was detected by ELISA in 2 study patients (1 with rheumatoid arthritis and 1 with lupus). None of the patients with positive ELISA results had evidence of renal vasculitis during follow-up. When an ANCA scoring system that combines immunofluorescence and ELISA was used, the test specificity for vasculitis was 99.5% among patients with connective tissue disease. CONCLUSIONS: Patients with connective tissue disease are known to develop multiple autoantibodies; positivity for anti-PR3 and anti-MPO ANCA in such patients is highly specific for anti-PR3. However, P-ANCA immunofluorescence, which may have positive results because of the presence of antinuclear antibodies, is not a specific marker of anti-MPO. A rigorous ANCA testing system that combines the results of immunofluorescence with those of ELISA is highly specific for Wegener granulomatosis and related vasculitides even in patients with connective tissue disease.     

Antineutrophil cytoplasmic autoantibodies (ANCA)--markers in diagnosis and monitoring systemic vasculitides

We present a new class of autoantibodies--ANCA (antineutrophil cytoplasmic autoantibodies) which recognize as target antigen different enzyme constituents of primary granules of neutrophil granulocytes. These autoantibodies are present in a large number of diseases, such as: systemic vasculitides, idiopathic crescentic glomerulonephritis, inflammatory bowel diseases and in some other conditions, including rheumatoid arthritis, SLE, Felty syndrome, acute and chronic infections. ANCA not only facilitate the diagnosis but also have a pathophysiological role for some of the idiopathic vasculitides. In our study, including 110 patients referred to the laboratory for ANCA testing by indirect immunofluorescence technique, only 25 patients were positive with a diffuse cytoplasmic (c ANCA) or perinuclear (p-ANCA) pattern on alcohol fixed slides. Some relevant cases are presented in order to emphasize that ANCA antibodies are a useful marker in the early diagnosis of systemic vasculitides, allowing effective therapeutic handling.     

The clinical instrumental characteristics of the locomotor involvement in patients who have had Lyme disease

Locomotor system has been studied in 24 patients with a history of Lyme's disease. All of them had arthralgia, 11 had relapsing arthritis, chronic arthritis occurred in 6 examinees. Arthritis presented as recurrent asymmetric mono-oligoarthritis affecting primarily joints of the lower limbs. Periarticular disorders were detected in 12 patients. Serologically, 18 of 24 patients had elevated titers of antibodies to Borrelia burgdorferi in indirect immunofluorescence test. Scintigraphy revealed polyarticular lesions in many cases, ultrasound investigation of the joints confirmed inflammatory nature of the pathological changes. It is inferred that combined methods of examination in diagnosis of Lyme's arthritis (titers to antibodies to Borrelia burgdorferi, ultrasound investigations, scintigraphy of the joints) provide most complete information.     

Unclear about prophylaxis against Rh-immunization. Much is missing from the guidelines of the National Board of Health and Welfare

A 39-year-old female visited our hospital because of morning stiffness, arthralgia, skin rash of the extremities and general fatigue. On examination, she also had a malar rash and an oral ulcer. Laboratory findings revealed that antinuclear antibodies were positive and complement component levels (C3, C4, CH50) were all low. Serology for human parvovirus B19 (HPV-B19) was positive for both immunoglobulin (Ig)M and IgG. Gradually, her symptoms improved and laboratory data returned to normal range without medications. This case suggests that HPV-B19 infection may be attributed to the pathogenesis of systemic lupus erythematosus.     

Medial collateral knee ligament healing. Combined medial collateral and anterior cruciate ligament injuries studied in rabbits

BACKGROUND: Antineutrophil cytoplasmic antibodies (ANCA), particularly perinuclear ANCA (p-ANCA), have been found more frequently in sera from patients with ulcerative colitis (UC) than in sera from Crohn's disease (CD) or unclassified enterocolitis (UE) patients. This 2-center study examined sera from 102 pediatric patients with inflammatory bowel disease (IBD) to evaluate their diagnostic value and assess their relationship with disease features, distribution, activity and treatment. METHODS: The serum ANCA of 102 children with IBD were measured: 33 UC, 64 CD and 5 UE with various disease locations and degrees of activity. The mean age at the onset of symptoms was 10.7 years (1 to 16.3 years). Sera from 26 unaffected first degree relatives and 20 children without IBD were also investigated. ANCA were detected using indirect immunofluorescence of ethanol-fixed granulocytes. RESULTS: There were ANCA in the sera of 24/33 children with UC (73%), 9/64 with CD (14%) and 4/5 with UE (80%). p-ANCA were more frequent than cytoplasmic-ANCA in positive sera: UC = 67%, CD = 57% and UE = 75%. The presence of ANCA was 73% sensitive and 81% specific for a diagnosis of UC, compared to other IBD (p < 0.001). Three children with proved sclerosing cholangitis associated with UC were all positive. There was no link between ANCA-positive sera and disease activity, or other endoscopic or clinical criteria. ANCA were detected in 4/26 first degree relatives (15%) and in 1/20 control subjects (5%). CONCLUSIONS: Because of their sensitivity and specificity, ANCA may be helpful in the clinical assessment of patients with IBD, and especially those with UC. However, there is no link between the pressure of p-ANCA and the site of UC or its activity, so that it cannot be used to monitor medical treatment or surgical indications.     

HLA association and occurrence of autoantibodies in Asian-Indian patients with ulcerative colitis

OBJECTIVES: The purpose of the present study was to determine the profile of HLA class I antigens, antinuclear antibodies (ANA), and antineutrophil cytoplasmic antibodies (ANCA) in ulcerative colitis (UC) patients from Northern India. METHODS: The study consisted of 100 UC patients with or without extraintestinal manifestations. Data on HLA, ANA, and ANCA were analyzed with respect to age at onset, sex, duration of disease, and occurrence of extraintestinal manifestations, and data were correlated with those of healthy controls from the same population. RESULTS: The most common extraintestinal manifestations in order of occurrence were arthralgia (53.8%), ocular lesions (18%), sacroiliitis (12.7%), hepatobiliary (7.7%), cutaneous (5%), and vascular (2.6%). ANA and ANCA were positive in only 3% of cases. Of the HLA class I antigens, HLA-A19 was significantly increased in UC patients compared with controls (63.4% vs. 33.5%, p < 0.001, RR = 3.4), particularly its subtype HLA-A33 (20.7% vs. 4%, p < 0.001, RR = 6.3). There was no deviation in the frequency of HLA-B locus antigens, whereas HLA-Cw6 was increased significantly in patients compared with controls (14.6% vs. 3.5%, p < 0.001, RR = 4.4). CONCLUSIONS: The occurrence of extraintestinal manifestations in Indian patients with UC is similar to that reported elsewhere, although ANA and ANCA positivity is lower. HLA studies revealed that A19(33) and Cw6 are associated with UC.     

Recognition of bactericidal/permeability-increasing protein by perinuclear anti-neutrophil cytoplasmic antibody-positive sera from ulcerative colitis patients: prevalence and clinical significance

BACKGROUND: The aim of this study was to evaluate a) the role of bactericidal/permeability-increasing protein (BPI) as a possible antigen determining perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA) reactivity in ulcerative colitis and b) the prevalence and clinical correlates of anti-BPI antibodies in patients with ulcerative colitis on the basis of their p-ANCA status. METHODS: p-ANCA and anti-BPI antibodies were evaluated by means of indirect immunofluorescence and enzyme-linked immunosorbent assay methods in a group of 112 ulcerative colitis patients (including 42 patients subjected to proctocolectomy) well defined as far as their clinical features and p-ANCA status. RESULTS: Anti-BPI antibodies were detected in 24% of non-operated patients and were significantly more frequent in p-ANCA-positive patients (32% versus 5% in p-ANCA-negative patients; P < 0.015). The prevalence of anti-BPI antibodies was similar in non-operated and operated patients and was high in men, in patients with an extensive and aggressive disease, and in patients developing pouchitis after surgery. CONCLUSIONS: These data indicate that BPI is a neutrophil antigen frequently recognized by p-ANCA-positive ulcerative colitis sera. The presence of anti-BPI antibodies appears to identify further immunologic and clinical heterogeneity in ulcerative colitis.     

Minocycline-related autoimmune hepatitis: case series and literature review

BACKGROUND: Minocycline is an antibiotic commonly used in the treatment of adolescent acne. OBJECTIVES: To describe the clinical, laboratory, and histological features in 3 cases of minocycline-related autoimmune hepatitis and to review the literature of similar cases in the adolescent population. DESIGN: Case series. SETTING: Patients were cared for in the Division of Gastroenterology, Children's Hospital, Boston, Mass. RESULTS: Three adolescents (age, 15-16 years), while being treated with therapeutic doses of minocycline for periods of 12 to 20 months, met the 1993 International Autoimmune Hepatitis Group criteria for autoimmune hepatitis. All had a positive antinuclear antibody titer. Other features included hypergammaglobulinemia and a positive anti-smooth muscle antibody titer. Two patients underwent liver biopsy that revealed severe chronic lymphoplasmacytic inflammation, necrosis, and fibrosis. All other causes of liver disease were excluded. One patient had resolution of symptoms with withdrawal of the drug, while 2 required immunosuppression therapy. A review of the literature yielded only 18 similar cases, none in the pediatric literature, the majority of which contained incomplete pertinent data. CONCLUSIONS: Minocycline is related to the development of autoimmune hepatitis in some adolescents. Pediatricians who use this drug for treatment of acne should be aware of this serious potential relation and stop the drug immediately when suspicion is raised.     

Antilactoferrin antibodies in autoimmune liver diseases

OBJECTIVE: Lactoferrin, an immunoregulatory protein in mucosal secretions, is one of the target antigens to perinuclear antineutrophil cytoplasmic antibodies (P-ANCAs). Circulating lactoferrin is cleared in the liver, but little is known about the implication of lactoferrin in hepatic inflammation. To evaluate the implication of immunological response to lactoferrin, we examined antilactoferrin antibodies in autoimmune liver diseases. METHODS: Fourteen patients with primary biliary cirrhosis (PBC), 14 with autoimmune hepatitis (AIH), five with autoimmune cholangitis (AIC), six with chronic hepatitis C, and five with chronic hepatitis B were studied. We evaluated autoantibodies to lactoferrin in the sera of the patients by the Western Immunoblotting method. RESULTS: Sera of five of the 14 patients (35.7%) with PBC, four of the 14 patients (28.6%) with AIH, and five of the five patients (100%) with AIC contained autoantibodies to human lactoferrin, but none with hepatitis B or C had them. The higher prevalence of serum antibodies to human lactoferrin was shown to be higher in patients with AIC than with hepatitis B (p < 0.01), hepatitis C (p < 0.01), PBC (p < 0.05), and AIH (p < 0.05). CONCLUSION: Lactoferrin located in bile ducts and liver cells is one of the candidates of target antigens in autoimmune liver diseases, especially in AIC.     

Autoimmune hepatitis overlapping with primary sclerosing cholangitis in five cases

OBJECTIVE: We report five cases (four male; median age 20 yr, range 14-38 yr) of an autoimmune hepatitis/primary sclerosing cholangitis overlap syndrome. The patients presented with jaundice, elevated serum aminotransferase and alkaline phosphatase activities, hyperglobulinemia with high immunoglobulin G (IgG) levels, circulating antinuclear and/or smooth muscle autoantibodies (> or = 1:40), and moderate to severe interface hepatitis on liver biopsy (with biliary features in four). METHODS: All five fulfilled criteria for diagnosis of "definite" autoimmune hepatitis and showed marked responses to prednisolone and azathioprine therapy, with relapses occurring during reduction or withdrawal of treatment. Cholangiographic features of primary sclerosing cholangitis were found in three patients at presentation and after intervals of 7 and 14 yr in the other two. Only two had evidence of inflammatory bowel disease. Diagnostic criteria for identifying those patients who may benefit from immunosuppressive therapy were reviewed. RESULTS: Review of the literature revealed only 11 similar cases that were sufficiently well described for comparison. However, in contrast to these and the present cases, preliminary data from other studies have suggested a marked association with ulcerative colitis and a poor response to immunosuppressive therapy. CONCLUSIONS: It is recommended that the possibility of an autoimmune hepatitis/primary sclerosing cholangitis overlap syndrome responsive to immunosuppressive therapy should be considered in any patient presenting with a hepatitic illness with hyperglobulinemia, antinuclear or smooth muscle autoantibodies, and biliary changes on liver biopsy. Cholangiography should be considered in such patients.     

Perinuclear antineutrophil cytoplasmic antibody in rheumatoid arthritis: a marker of severe disease with associated nephropathy

OBJECTIVE: To evaluate the clinical significance of antineutrophil cytoplasmic antibodies (ANCA) in patients with rheumatoid arthritis (RA), and especially in those with clinically suspected or histologically proven nephropathy. METHODS: A total of 246 RA patients with (n = 149) and without (n = 97) histologically proven (n = 99) or clinically suspected (n = 50) nephropathy were studied for the presence of ANCA by immunofluorescence and enzyme immunoassay. RESULTS: Perinuclear ANCA (pANCA) were found in 52 (21%) of the 246 patients. Patients with clinically suspected or histologically proven nephropathy were significantly more frequently positive for pANCA (30% versus 7%; P < 0.00005) and had significantly higher mean (+/- SD) pANCA log titers (103 +/- 5.6 versus 27 +/- 3.0; P = 0.0011) than patients without clinically evident renal disease. Positivity for pANCA was associated with clinical and laboratory findings indicating severe basic disease and increased inflammatory activity. Irrespective of this association, pANCA acted as a significant and independent predictor of RA-associated nephropathy. CONCLUSION: Perinuclear ANCA in RA indicate severe disease with increased inflammatory activity. There is an especially strong and independent association between pANCA and RA-associated nephropathy.     

Frequency and significance of antibodies to actin in type 1 autoimmune hepatitis

Antibodies to actin have been proposed as diagnostic markers for type 1 autoimmune hepatitis. Our aims were to determine 1) if testing for antibodies to actin is superior to testing for smooth muscle antibodies (SMA); 2) if these antibodies identify patients with distinctive clinical features; and 3) if the production of antibodies to actin is associated with genetic risk factors for autoimmune hepatitis. Sera from 99 patients with type 1 autoimmune hepatitis were tested. The frequencies of HLA B8, DR3, DR4, and A1-B8-DR3 in patient subsets were compared with those in 80 normal subjects. Seventy-three patients (74%) had antibodies to actin. Antibodies to actin were found more commonly in patients with SMA than in patients without them (86% vs. 7%, P < .0001). Screening only for antibodies to actin and antinuclear antibodies (ANA) failed to establish the diagnosis of autoimmune hepatitis in 5 patients. Patients with antibodies to actin were younger than seronegative patients. They were also more commonly DR3-positive than normal subjects and more frequently B8-positive than patients with non-actin-associated SMA (49% vs. 0%, P = .004). Only patients with antibodies to actin died of liver failure (6% vs. 0%), and 10 of 11 patients requiring liver transplantation were seropositive for these antibodies. Indeed, death and liver transplantation occurred more frequently in these patients than in actin-negative patients with ANA (19% vs. 0%, P = .03). We conclude that routine screening for antibodies to actin may miss patients with type 1 autoimmune hepatitis. Antibodies to actin are associated with HLA B8 and DR3, and they identify patients with a poor prognosis.     

Antibodies to soluble liver antigen, P450IID6, and mitochondrial complexes in chronic hepatitis

BACKGROUND: Antibodies to soluble liver antigen, P450IID6, and the E2 subunits of mitochondrial dehydrogenase complexes occur in autoimmune liver diseases, but their specificities and implications are uncertain. The aims of the present study were to assess the importance of these autoantibodies in different types of chronic hepatitis. METHODS: Sera from 62 patients with autoimmune hepatitis, 37 patients with cryptogenic hepatitis, and 19 patients with chronic hepatitis C were assessed under code by enzyme immunoassay. RESULTS: Antibodies to soluble liver antigen were found in 7 patients with autoimmune hepatitis (11%) and 5 patients with cryptogenic disease (14%). Patients with antibodies to soluble liver antigen were indistinguishable from seronegative counterparts with autoimmune hepatitis. Seropositive patients with cryptogenic hepatitis had autoimmune features, and they responded to corticosteroid therapy. Five patients (8%) with autoimmune hepatitis were seropositive for antibodies to mitochondrial complexes. Three lacked antimitochondrial antibodies. None of the patients had antibodies to P450IID6, and patients with chronic hepatitis C were seronegative for all markers. CONCLUSIONS: Antibodies to soluble liver antigen do not define a distinct subgroup of patients with autoimmune hepatitis. They may be found in some patients with corticosteroid-responsive cryptogenic hepatitis. Antibodies to E2 subunits and P450IID6 are uncommon in adults with chronic hepatitis.     

Unusual coexistence of systemic lupus erythematosus and primary biliary cirrhosis

Systemic lupus erythematosus (SLE) and primary biliary cirrhosis (PBC) are distinct clinical disorders which rarely occur in the same patient. We report on a 65-year-old woman with coexistence of both conditions. Diagnosis of SLE was ascertained by the presence of seven ACR criteria (cutaneous lesions, photosensitivity, antinuclear and anti-double-stranded-DNA antibodies, pancytopenia, arthritis, oral lesions). PBC was disclosed by clinical investigation, liver histology and highly positive antimitochondrial M2 antibodies. The most important differential diagnoses of lupus hepatitis are PBC and autoimmune hepatitis. Diagnostic criteria for these conditions are discussed, and previous reports on overlap between SLE and PBC are reviewed.