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Context.— Systems-based practice (SBP) is 1 of 6 core competencies required in all resident training programs accredited by the Accreditation Council for Graduate Medical Education. Reliable methods of assessing resident competency in SBP have not been described in the medical literature.Objective.— To develop and validate an analytic grading rubric to assess pathology residents' analyses of SBP problems in clinical chemistry.Design.— Residents were assigned an SBP project based upon unmet clinical needs in the clinical chemistry laboratories. Using an iterative method, we created an analytic grading rubric based on critical thinking principles. Four faculty raters used the SBP project evaluation rubric to independently grade 11 residents' projects during their clinical chemistry rotations. Interrater reliability and Cronbach α were calculated to determine the reliability and validity of the rubric. Project mean scores and range were also assessed to determine whether the rubric differentiated resident critical thinking skills related to the SBP projects.Results.— Overall project scores ranged from 6.56 to 16.50 out of a possible 20 points. Cronbach α ranged from 0.91 to 0.96, indicating that the 4 rubric categories were internally consistent without significant overlap. Intraclass correlation coefficients ranged from 0.63 to 0.81, indicating moderate to strong interrater reliability.Conclusions.— We report development and statistical analysis of a novel SBP project evaluation rubric. The results indicate the rubric can be used to reliably assess pathology residents' critical thinking skills in SBP.

Anti-IgA may cause anaphylactic transfusion reactions in IgA-deficient individuals. Testing for IgG anti-IgA is useful to identify persons at risk. This report describes an immunoassay for anti-IgA that uses polyclonal IgA coupled to fluorescent microspheres as an immunosorbent. Anti-IgA is detected by phycoerythrin-labeled anti-IgG. The assay is calibrated in arbitrary units by use of a serum that contains anti-IgA. Dose-response studies with sera that contain anti-IgA showed positive responses at dilutions up to 32-fold greater than the dilution used to test patients’ samples. Inhibition studies with purified IgA and IgA-deficient serum showed no inhibition with IgA-deficient serum and complete inhibition with soluble IgA. Clinical tests performed in more than 90 assays had a CV of 13.6 percent for measurements of an internal positive control. The fluorescent immunoassay method is rapid, reproducible, and sensitive to low concentrations of IgG anti-IgA. Immunohematology 2009;25:24–28.

Summary Background Tissue transglutaminase (TTG) antibodies and newly developed deamidated gliadin peptide (DGP) antibodies have better accuracy than native gliadin antibodies. Multiplex immunoassay (MIA) measures multiple antibodies simultaneously providing a complete antibody phenotype with reduced turnaround time and cost. Aim To evaluate the agreement between MIA and enzyme-linked immunosorbent assay (ELISA) test results for coeliac antibodies in biopsy-proven coeliac patients and controls and to model the diagnostic utility of combination testing. Methods We compared the sensitivity, specificity and accuracy of MIA and ELISA methods for TTG and DGP antibodies in mainly adult untreated coeliac patients (n = 92) and controls (n = 124). Results There was excellent agreement and a significant correlation between the results of MIA and ELISA methods (κ > 0.8, r > 0.7) for all tests, except TTG IgG. Diagnostic indices of individual and combination tests measured by the MIA method did not differ significantly from those measured by ELISA. The combination tests slightly increased sensitivity (if any test was positive) and specificity (if all tests were positive) compared to the individual tests. Conclusions Multiplex immunoassay testing for antibodies is as accurate as ELISA for coeliac disease diagnosis and has practical advantages over ELISA method. Rational combination testing can help identify patients who need intestinal biopsy and may reduce unnecessary biopsies.

Summary Serum and plasma are used interchangeably to measure anti-neutrophil cytoplasmic antibodies (ANCA), even though the release of ANCA target antigens during the preparation of serum could affect ANCA assays and cause discrepancies between the results obtained from serum and plasma. To what extent ANCA test results obtained from serum agree and correlate with results from plasma remains unknown. Therefore, a comprehensive comparison was performed using serum and plasma samples which were collected in 175 patients with active Wegener's granulomatosis at enrolment of a recent randomized trial. These paired serum and plasma samples were subjected to parallel ANCA testing by standard indirect immunofluoresence on ethanol-fixed neutrophils, a direct enzyme-linked immunoassay (ELISA) for proteinase 3 (PR3)-ANCA and myeloperoxidase (MPO)-ANCA, and two different capture ELISAs for PR3-ANCA. The concordance of categorical serum and plasma ANCA results was assessed using κ-coefficients. These were > 0·8 for all assays, indicating a very good concordance between positive and negative serum and plasma results. Spearman's correlation coefficients for serum and plasma PR3-ANCA values obtained by direct ELISA and both capture ELISAs were ≥ 0·95 (P

Systemic lupus erythematosus (SLE) rarely presents with a negative antinuclear antibody (ANA). Although antibodies to extractable nuclear antigens (ENA) are sometimes ordered despite a negative ANA, it is unclear if this contributes to the diagnosis of SLE or other forms of connective tissue disease (CTD). We reviewed 39 patients with anti-ENA antibodies despite a negative ANA during a 1-year period to determine the presence of SLE or other CTD. Several patients had clinical features suggestive of CTD, including 1 with possible SLE. A number of patients had neurologic disorders, especially peripheral neuropathy. In this study, the finding of anti-ENA despite negative ANA was associated with neurologic disorders and CTD. This may represent test bias or false-positive anti-ENA assays or false-negative ANA assays, or may imply immune-related mechanisms not previously described.

(CHEST 2005; 127:1045–1050) A 70-year-old white man was referred for evaluation of pulmonary infiltrates and bronchiectases associated with cough and constitutional symptoms. He was in his usual state of health until he acquired B-cell non-Hodgkin lymphoma (NHL) in 1990. The lymphoma was localized to his stomach, and he was treated with surgical resection; chemotherapy with cyclophosphamide, vincristine, prednisone, and hydroxyurea; and radiation to the gastric bed. One year later, left lower lobe pneumonia developed that was treated with antibiotics. Because of persistent infiltrates, bronchoscopy was performed, with biopsy specimens revealing no abnormalities, and bronchiectases was diagnosed based on radiographic features. Three years prior to presentation, a cough productive of green-to-yellow sputum without hemoptysis developed. One year prior to presentation, progressive fatigue, anorexia, low-grade fevers, significant night sweats, and subsequent 20-lb weight loss developed. He denied other respiratory complaints. CT of the chest revealed patchy areas of consolidation in both lower lungs and in the right middle lobe along with mild mediastinal lymph node enlargement. Multiple sputum samples for acid-fast bacilli, bacteria, and fungi were negative. Endoscopic evaluations of his upper and lower intestinal tracts did not reveal recurrence of the lymphoma. Established medical problems included hypothyroidism and a previous myocardial infarction with subsequent revascularization surgery. He never smoked, and his family, social, and exposure history were otherwise noncontributory. He was referred to our tertiary care center for evaluation of productive cough, pulmonary infiltrates, worsening fatigue, persistent low-grade fevers with night sweats, and weight loss.

Chronic rhinosinusitis (CRS) is one of the most common long-term illnesses in the United States. The etiology of CRS is unknown, and no effective treatment has been established.We investigated the hypothesis that abnormal immunologic responses to ubiquitous airborne fungi contribute to the pathogenesis of this disease.The proliferative and cytokine responses of PBMCs to extracts from 4 common airborne fungi-including Alternaria , Aspergillus , Cladosporium , and Penicillium -were examined by in vitro culture. Serum specimens were tested for specific IgE and IgG to these fungi.PBMCs from approximately 90% of the patients with CRS, but not those from normal individuals, produced both IL-5 and IL-13 when exposed to Alternaria. Furthermore, PBMCs from patients with CRS produced significantly more IFN-gamma than PBMCs from normal individuals in response to Alternaria (median, 553 pg/mL vs 98 pg/mL; P.01). Levels of serum IgG antibodies to Alternaria and Cladosporium were clearly increased in patients with CRS compared with normal individuals ( P.01). Less than 30% of the patients with CRS had specific IgE antibodies to Alternaria or Cladosporium. The increased humoral (serum IgG) response strongly correlated with the increased cellular (IL-5 production) response to Alternaria ( r = 0.619; P.01).Patients with CRS show exaggerated humoral and cellular responses, both T(H)1 and T(H)2 types, to common airborne fungi, particularly Alternaria. The anomalous immune and inflammatory responses to ubiquitous fungi may explain the chronicity of airway inflammation in CRS.

In the environment of managed care, children with allergic diseases are increasingly likely to be evaluated by nonallergist physicians. While the presumptive diagnosis of an allergic disease can often be suspected on clinical grounds, signs and symptoms are not reliable for establishing a definitive diagnosis or for deciding on management options. This article discusses the use of immunoglobulin E antibody tests to classify children with allergic symptoms. The information is intended for pathologists who offer consultative laboratory services to nonallergist physicians. Emphasis is placed on defining the minimum number of tests necessary to identify allergic children at different ages.

To assess the performance of 4 clotting assays for lupus anticoagulant (LA) detection, to determine the prevalence of LA and anticardiolipin antibodies (aCL), and to correlate LA and aCL prevalence with systemic disease and thrombosis.We studied 664 consecutive patients at the Mayo Clinic in Rochester, Minn, who were referred for laboratory testing because of a clinical suspicion of LA or thrombophilia between June 25, 1990, and July 1, 1991.Of 664 patients tested for LA, 584 also were tested for aCL. Of patients tested for both LA and aCL, 137 (235%) had positive results for one or both tests (13 [95%], LA-positive only; 76 [555%], aCL-positive only; and 48 [35.0%], positive for both). The dilute Russell viper venom time (DRVVT) was the most frequently positive LA assay (74% of the 61 patients with positive results for LA). Twenty-two patients (36.1% of the 61) had positive results for all 4 LA assays, whereas 21 (34.4% of the 61) had positive results for only 1 LA assay: activated partial thromboplastin time (3 patients [4.9%]), plasma clot time (5 patients [8.2%]), kaolin clot time (5 patients [8.2%]), or DRVVT (8 patients [13.1%]). Thromboembolism prevalence was not definitely associated with positive test results (LA only, aCL only, or LA plus aCL), nor was it strongly associated with aCL isotype or titer. Furthermore, thromboembolism prevalence was not increased when all LA assays were positive, although a history of deep venous thrombosis or pulmonary embolism was nonsignificantly associated with positive results for all 4 LA tests. The likelihood of having both LA- and aCL-positive test results was higher among patients with systemic lupus erythematosus (26 [19.0%] of 137 patients with positive results for one or both tests), but they had no more thrombotic events or fetal loss than other patients in our study group.The DRVVT identified more patients with LA than the other LA tests, but more than 1 LA test was required to identify all patients with LA. Positive results were much more common for aCL than for LA. No single LA test or anticardiolipin isotype correlated with thrombosis or systemic disease in this population.

Anti-neutrophil cytoplasmic antibodies (ANCA) are a useful diagnostic tool for Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA). To maximize diagnostic utility, current guidelines recommend dual testing by standard indirect immunofluorescence (IIF) and target antigen-specific assays. Most published data come from specialized research laboratories, not reflecting the performance of assays under routine clinical conditions. Therefore, we compared the performance of standard IIF, PR3-, and MPO-ANCA-specific direct ELISA, and a PR3-ANCA-specific capture ELISA used alone and in combination under routine clinical conditions. Consecutive serum samples (615) submitted for routine ANCA testing over a 10-month period were assayed. Diagnoses were WG/MPA (n = 86), other autoimmune disease (n = 118), and various others (n = 411). The combination of PR3-ANCA and MPO-ANCA ELISA had the highest sensitivity (72.1%), and C-ANCA determination using IIF, the highest specificity (99.6%). While maintaining maximal diagnostic accuracy, significant labor savings are achieved by screening for WG/MPA by ELISA followed by confirmatory IIF.

Autoantibodies are immunoglobulins that react against normal host proteins and may be natural or pathologic.1 Natural autoantibodies are germline responses that develop from genetically programmed clones of B cells and are typically present in low serum titers as isotypes of immunoglobulin M.2–5 Natural autoantibodies do not fix complement and usually have weak antigen-binding affinities, multiple reactivities, and no disease associations.6,7 They occur more commonly in women than in men,8 the repertoires remain stable with aging,9,10 and they may bind products of natural cell death or foreign antigens that resemble selfantigens.11,12 In this fashion, natural autoantibodies may prevent the emergence of autoreactive immunocytes and have a protective function.2,4,6,11,12 Pathologic autoantibodies are produced by antigenspecific B-cell activation and subsequent clonal expansion of dedicated plasma cells.1,2 These autoantibodies typically are present in high serum titers as isotypes of immunoglobulin G. Pathologic autoantibodies fix complement, have high antigen-binding affinities, inhibit autoantigen activity in vitro, and have disease associations.2,6 They are rarely pathogenic, but their presence in serum does imply the existence of an antigen-driven immunopathic process. This process may be crucial for disease expression, a consequence of other cytodestructive mechanisms, or coincidental with the main disorder. Natural and pathologic autoantibodies can be distinguished from each other by class-specific attributes (Table 1). The presence of low-titer autoantibodies in the absence of hypergammaglobulinemia or a compatible clinical liver disease usually indicates the presence of natural autoantibodies. Any component of the liver cell can trigger the production of pathologic autoantibodies, and reactivities have been described against nuclear, microsomal, cytosolic, and mitochondrial proteins.13 Expression of the antigen on the surface of professional antigen-presenting cells is the principal mechanism for activation of B cells, and antigen presentation to CD4 T-helper cells is restricted by the class II molecules of the major histocompatibility complex.14–16 Intracellular antigens can be expressed on the surface of the liver cell membrane, and the hepatocyte can present autoantigens that generate autoantibodies.17,18 Mechanisms for pathologic autoantibody production include the discovery of self-antigens that had been poorly recognized or sequestered during ontogeny (cryptic or sequestered epitopes) or the generation of new antigens by the degradation of viruses, xenobiotics, and chemicals within the hepatocyte (neoepitopes).19,20 Selfantigens can be targeted by an exuberant immune response to an infectious agent (superantigen effect), and nonspecific mediators of inflammation, including cytokines, chemotactic substances, macrophages, and natural killer cells, can extend the immune response (bystander effects). Epitopes within the same antigen or between different antigens can become involved (epitope spread); autologous antigens can combine with infectious or environmental agents (adjuvant effects); or foreign antigens can mimic self-antigens (molecular mimicry).19,20 Autoantibodies may lack disease specificity or pathogenic importance, and bystander effects, adjuvant effects, and molecular mimicry may explain in part the occurrence of autoantibodies in nonautoimmune diseases. Importantly, autoantibodies are not found in all forms of hepatocellular injury and are not simply the trappings of liver cell destruction. Autoantibody titers do not correlate closely with the severity of liver cell damage, and changes in autoantibody expression do not reflect disease behavior.21

Background & Aims: The epidemiology of primary biliary cirrhosis (PBC) has not been studied systematically in the United States. We report the incidence and prevalence of this condition in the general population. We also examined the validity of the Mayo natural history model for PBC among these unselected patients from the community. Methods: The Rochester Epidemiology Project entails a computerized index of diagnoses from the health care encounters of residents of Olmsted County, Minnesota. For potential cases identified using this database, the complete (inpatient and outpatient) medical records were reviewed to verify the diagnosis and extract information necessary for the application of the Mayo model. We estimated the incidence and prevalence of PBC in this population and compared the actual survival of patients with PBC in the community with the survival predicted for PBC patients by the Mayo natural history model. Results: The age-adjusted (to 1990 U.S. whites) incidence of PBC per 100,000 person-years for years 1975–1995 was 4.5 (95% confidence interval [CI], 3.1–5.9) for women, 0.7 (95% CI, 0.1–1.3) for men, and 2.7 (95% CI, 1.9–3.5) overall. The age- and sex-adjusted prevalence per 100,000 persons as of 1995 was 65.4 (95% CI, 43.0–87.9) for women, 12.1 (95% CI, 1.1–23.1) for men, and 40.2 (95% CI, 27.2–53.1) overall. The Mayo natural history model accurately predicted the actual survival of these patients. Conclusions: This first description of the epidemiology of PBC in the United States indicates that its incidence and prevalence in this country are among the highest reported. Outcomes among these unselected patients from a community population further validated the Mayo natural history model of PBC. GASTROENTEROLOGY 2000;119:1631-1636

OBJECTIVE To investigate survival and renal recovery after dialysis in patients with acute renal failure with use of synthetic membranes compared with substituted cellulose membranes. PATIENTS AND METHODS We prospectively studied survival and recovery of renal function of 66 patients with acute renal failure who required intermittent heinodialysis. Patients were randomized to exclusive treatment with either cellulose acetate (CA) or polysulfone (PS) hemodialysis membranes. Additionally, markers of bio compatibility (complement, leukocyte counts, cytokine concentration) were measured at initiation and 1 hour after initiation of dialysis among 10 patients equally distributed between the CA and PS groups . RESULTS The cohorts were indistinguishable with respect to age, sex, presence of diabetes mellitus, Acute Physiology and Chronic Health Evaluation II scores, per centage in the intensive care unit (ICU), and adequacy of dialysis. Survival (76% CA, 73% PS; P=.78) and recovery of renal function at 30 days (58% CA, 39% PS; P=.14) were not statistically different in the 2 groups. Among 26 CA patients and 27 PS patients treated in the ICU, survival was not statistically different (73% CA, 67% PS; P=.61); however, the proportion of patients recovering renal function suggested a benefit favoring CA membranes (65% CA, 37% PS; P=.04). Additionally, markers of biocompatibility were not significantly different between groups among the 10 patients equally distributed between the CA and PS groups. CONCLUSIONS Overall clinical outcomes among patients with acute renal failure treated with CA hemodialysis membranes and those treated with PS membranes were not significantly different. The observed advantage favoring renal recovery among this ICU population treated with CA hemodialysis membranes warrants further investigation.

The following guideline presents a series of recommendations based on published medical literature for use of the antinuclear antibody (ANA) test and tests for specific autoantibodies to nuclear antigens in the diagnostic evaluation, prognostic assessment, and monitoring of patients with systemic rheumatic diseases. The guideline emphasizes the need for clinical evaluation to improve the usefulness of test results in patient management. Consideration is given to appropriate use of the generic ANA test in the initial evaluation of patients with signs and symptoms of a systemic rheumatic disease, the evaluation of patients suspected of having lupus erythematosus, use in clinical situations in which the ANA test is required to establish a disease diagnosis, and identification of clinical situations in which the ANA test has little value. Sections are also devoted to recommendations aimed at improving the analytic methods used to detect and measure ANA and specific autoantibodies to nuclear antigens and to the appropriate use of tests for specific autoantibodies in several disease situations that commonly occur in patients with suspected or documented systemic rheumatic diseases. Emphasis is placed on the use of these tests only in situations in which the test results can be expected to provide information necessary for clinical decision making. Those tests of limited medical usefulness and situations in which test results are likely to be misleading are also identified.

SUMMARY We have expressed conformationally intact, enzymatically active recombinant PR3 in HMC-1 cells (HMC-1/PR3 cells) that is recognized by C-ANCA. Here we directly compared the clinical utility of C-ANCA testing by indirect immunofluorescence (IIF) using HMC-1/PR3 cell cytospin versus polymorphonuclear neutrophil (PMN) cytospin preparations and commercially available anti-PR3 ELISA kits. Two hundred sera were tested independently by three investigators: 101 previously determined to be C-ANCA-positive by routine clinical laboratory testing using standard IIF on PMN cytospins, and 99 control samples chosen primarily because they contained antibodies against other cytoplasmic target antigens. Discrepant test results between the two cellular substrates were found in seven samples: 2/7 were PMN-positive and HMC-1/PR3 cell-negative (one Sjögren's syndrome, one hand injury); 5/7 were PMN-negative and HMC-1/PR3-positive (all Wegener's granulomatosis (WG)). All C-ANCA-positive WG patients were also positive on HMC-1/PR3 cells. IIF using HMC-1/PR3 cells was as sensitive as the most sensitive anti-PR3 ELISA (79.8% versus 80.7%, P = 0.739), and more sensitive than standard IIF C-ANCA testing using PMN cytospins (79.8% versus 75.2%, P = 0.025) or the anti-PR3 ELISA with the least false-positive test results (79.8% versus 63%, P

We examined the clinical usefulness of measurements of antimitochondrial autoantibodies (AMA) in predicting disease progression in patients with primary biliary cirrhosis (PBC). We determined the relationships between AMA levels measured by indirect immunofluorescence (IF) and those measured by quantitative enzyme immunoassays (EIAs) using recombinant 2-oxo-acid dehydrogenase complex (2-OADC) proteins and the Mayo Risk Score, an established indicator of disease progression in primary biliary cirrhosis (PBC). Results of tests for AMA by either method correlated weakly (r = .24 to .30) with disease progression as indicated by Mayo Risk Scores. The levels of AMA to 2-OADC proteins varied by more than 200-fold between patients but remained relatively constant over time in individual patients. Despite being positively correlated with Mayo Risk Score results, the levels of AMA to 2-OADC proteins were not useful for predicting disease progression in individual patients with PBC. In addition, we found no significant differences in the levels of autoantibodies to 2-OADC proteins among patients with different histological stages of disease. Our results show that measurements of AMA by IF or by quantitative EIA methods with recombinant 2-OADC proteins are not useful parameters for predicting disease progression in patients with PBC.

Hepatic dysfunction following liver transplantation is often caused by cellular rejection or infection with cytomegalovirus. These etiologies can at times be difficult to differentiate. We measured the levels of soluble T lymphocyte markers sIL2R, sCD4, and sCD8 in serum as possible diagnostic indicators of cellular rejection and cytomegalovirus hepatitis. Pretransplant levels, and serial post-transplant levels of soluble T lymphocyte markers were measured in five control patients without cellular rejection or cytomegalovirus infection, ten patients with cellular rejection, and six patients with cytomegalovirus hepatitis. In all cases, cellular rejection and cytomegalovirus hepatitis were documented with liver histology. For each group of patients, we calculated the mean ratio of the post-transplant marker level divided by the pre-transplant level. We found an elevation in the mean ratio of sIL2R in patients with cellular rejection shortly before or at the time of diagnosis of rejection as compared to the transplant control group. Levels of sCD8 were not significantly increased in patients with cellular rejection. We found a more pronounced elevation in the mean marker ratios of both sIL2R and sCD8 in patients with cytomegalovirus hepatitis which were higher compared not only to the transplant control group but also compared to the cellular rejection group. The rise of serum levels preceded the histologic diagnosis of cytomegalovirus hepatitis and detection of cytomegalovirus in blood cultures. Increased serum levels of sIL2R with concomitant elevation of sCD8 suggest the diagnosis of cytomegalovirus hepatitis over cellular rejection. We conclude that serial measurements of sIL2R and sCD8 may be useful to differentiate cytomegalovirus hepatitis from episodes of acute cellular allograft rejection, particularly those rejection episodes occurring late (>20 days posttransplantation).

To determine if the hepatitis viruses are important etiologic factors in autoimmune hepatitis, the clinical, immunoserologic, virologic and HLA phenotypes of 105 of the latter patients were assessed prospectively and compared to 45 patients with chronic viral hepatitis. Patients with autoimmune hepatitis were more often women with higher serum aspartate aminotransferase and immunoglobulin levels than patients with viral disease. Only eight patients (8%) were seropositive for anti-HBc and anti-HBs (four patients) or anti-HCV (four patients) and none with anti-HCV were reactive by second generation immunoassay or recombinant immunoblot assay. Smooth muscle (90 vs. 22%, P0.001) and antinuclear (70 vs. 22%, P0.001) antibodies were more common in patients with autoimmune hepatitis and the titers more frequently exceeded 1:80 (84 vs. 11%, P0.0001). Patients with autoimmune hepatitis were more often positive for HLA B8 (48 vs. 20%, P0.01) and DR3 (49 vs. 20%, P0.003) and they more frequently had the HLA A1-B8-DR3 phenotype (38 vs. 10%, P0.003). Only one of the 120 patients tested for anti-LKM1 was seropositive. We conclude that in an American referral population autoimmune hepatitis usually lacks virologic markers and has a distinctive clinical, immunoserologic and HLA phenotype. Hepatitis viruses are not important immunogenic stimuli for non-organ specific antibodies and they are unlikely to be important causes of this form of autoimmune hepatitis.

To assess the frequency of antibodies to liver/kidney microsome type 1 (anti-LKM1) in patients with chronic active hepatitis, 131 such patients were tested by an indirect immunofluorescence assay. Of 62 patients with type 1 autoimmune hepatitis, none were seropositive. In contrast, 3 of 11 patients with autoimmune hepatitis and antimitochondrial antibodies (27%) were seropositive for anti-LKM1. Each had responded to corticosteroid therapy, and retesting of sera confirmed that each had been misclassified as antimitochondrial antibody positive. None of the patients with chronic active hepatitis B (14 patients) or C (24 patients) had anti-LKM1. Similarly, none of the 20 patients with cryptogenic disease had these antibodies. It is concluded that anti-LKM1 is specific for type 2 autoimmune hepatitis and is infrequent in adult patients seen at a referral center in the United States for chronic active hepatitis. Anti-LKM1 reactivity may be misinterpreted as antimitochondrial antibody reactivity by indirect immunofluorescence. Chronic hepatitis B and C virus infections are not important stimuli for the production of anti-LKM1, and testing for anti-LKM 1 is unlikely to clarify the nature of cryptogenic disease.

The final part of this series describes the measurement methods for allergenspecific immunoglobulin E (IgE) antibodies. The IgE antibody test is discussed and evaluated.

Background: In adult patients, autoantibodies targeting the water channel aquaporin-4 (AQP4) are a biomarker for a spectrum of CNS inflammatory demyelinating disorders with predilection for optic nerves and spinal cord (neuromyelitis optica [NMO]). Here we describe the neurologic, serologic, and radiographic findings associated with CNS AQP4 autoimmunity in childhood. Methods: A total of 88 consecutive seropositive children were identified through service evaluation for NMO-IgG. Sera of 75 were tested for coexisting autoantibodies. Clinical information was available for 58. Results: Forty-two patients (73%) were non-Caucasian, and 20 (34%) had African ethnicity. Median age at symptom onset was 12 years (range 4–18). Fifty-seven (98%) had attacks of either optic neuritis (n = 48; 83%) or transverse myelitis (n = 45; 78%), or both. Twenty-six (45%) had episodic cerebral symptoms (encephalopathy, ophthalmoparesis, ataxia, seizures, intractable vomiting, or hiccups). Thirty-eight (68%) had brain MRI abnormalities, predominantly involving periventricular areas (in descending order of frequency): the medulla, supratentorial and infratentorial white matter, midbrain, cerebellum, thalamus, and hypothalamus. Additional autoantibodies were detected in 57 of 75 patients (76%), and 16 of 38 (42%) had a coexisting autoimmune disorder recorded (systemic lupus erythematosus, Sjogren syndrome, juvenile rheumatoid arthritis, Graves disease). Attacks were recurrent in 54 patients (93%; median follow-up, 12 months). Forty-three of 48 patients (90%) had residual disability: 26 (54%) visual impairment and 21 (44%) motor deficits (median Expanded Disability Status Scale 4.0 at 12 months). Conclusions: Aquaporin-4 autoimmunity is a distinctive recurrent and widespread inflammatory CNS disease in children.

Serologic tests are used frequently in celiac disease diagnosis. Gliadin antibodies generally lack the accuracy required for proper diagnosis. We evaluated the value of deamidated gliadin antibody measurements in the diagnosis and follow-up evaluation of celiac disease and compared their potential usefulness with that of gliadin and tissue-transglutaminase antibodies.We tested deamidated gliadin, gliadin, and tissue-transglutaminase-immunoglobulin (Ig)A and -IgG in 216 biopsy-selected subjects including 92 biopsy-proven untreated celiac patients (46% with total villous atrophy and 54% with partial villous atrophy) and 124 biopsy-proven nonceliac controls. Fifty-nine celiac patients also were tested after treatment with a gluten-free diet. Antibodies were measured by commercial enzyme-linked immunosorbent assays. Deamidated gliadin-IgA+G was detected using a conjugate reactive to both isotypes, which gives a positive if either isotype is present.The sensitivity, specificity, and accuracy of deamidated gliadin-IgA (74%, 95%, and 86%), deamidated gliadin-IgG (65%, 98%, and 84%), and deamidated gliadin-IgA+G (75%, 94%, and 86%) were superior to gliadin-IgA (63%, 90%, and 79%) (P.05) and gliadin-IgG (42%, 90%, and 69%) (P.01), and were similar to tissue-transglutaminase-IgA (78%, 98%, and 90%) before treatment. The sensitivity of IgA isotype for all tests was significantly greater in celiac patients with total villous atrophy compared with those with partial villous atrophy (P.05). The proportion of positive test results for all tests decreased significantly after treatment (P.0001).Deamidated gliadin antibody is a better diagnostic test for celiac disease than the conventional gliadin antibody testing; although histopathology remains the gold standard test for diagnosis of celiac patients.

Background Neuromyelitis optica (NMO) is often associated with other clinical or serological markers of non–organ-specific autoimmunity. Objective To evaluate the relationship between NMO spectrum disorders (NMOSDs), including NMO, longitudinally extensive transverse myelitis, and recurrent optic neuritis, and autoimmune disease. We concentrated on the association with systemic lupus erythematosus (SLE), Sjogren syndrome (SS), or serological evidence of these disorders, which commonly is a source of diagnostic confusion. Design Retrospective blinded serological survey. Setting Mayo Clinic College of Medicine, Rochester, and Centre Hospitalier Regional Universitaire de Lille. Methods Group 1 included 153 US patients with NMOSDs (78 with NMO and 75 with longitudinally extensive transverse myelitis) and 33 control subjects with SS/SLE. Group 2 included 30 French patients with SS/SLE, 14 with NMOSDs (6 with NMO, 6 with longitudinally extensive transverse myelitis, and 2 with recurrent optic neuritis), 16 without NMOSDs, and 4 with NMO without SS/SLE. Results For group 1, NMO-IgG was detected in 66.7%, antinuclear antibodies in 43.8%, and Sjogren syndrome A (SSA) antibodies in 15.7% of patients with NMO and longitudinally extensive transverse myelitis. Five NMO-IgG–seropositive patients with NMOSDs had coexisting SLE, SS, or both. Antinuclear antibodies and SSA antibodies were more frequent in NMO-IgG–seropositive patients than in NMO-IgG–seronegative patients ( P = .001). For group 2, NMO-IgG was detected in 5 of 14 patients (35.7%) with NMOSDs and SS/SLE and in 2 of 4 patients (50.0%) with NMO without SS/SLE ( P = .59). We detected NMO-IgG only in patients with NMOSDs and not in 49 controls with SS/SLE but without optic neuritis or myelitis from the 2 cohorts ( P = .01). Conclusion Neuromyelitis optica spectrum disorders with seropositive findings for NMO-IgG occurring with SS/SLE or non–organ-specific autoantibodies is an indication of coexisting NMO rather than a vasculopathic or other complication of SS/SLE.

We developed rapid 24-h immunoblot assays for detecting autoantibodies to Scl 70 and Jo 1 antigens in serum. In comparative studies, we evaluated the analytical sensitivity of the immunoblot assays and commercial immunodiffusion assays for anti-Scl 70 and anti-Jo 1 autoantibodies with the use of positive control sera, and compared the frequencies of positive and negative results in a group of 116 sera, including specimens from 34 healthy controls and 82 patients with various connective-tissue diseases. The immunoblot assays were greater than 100-fold more sensitive than immunodiffusion for detecting both autoantibodies. Despite greater analytical sensitivity, there were no false-positive results by the immunoblot assay for anti-Scl 70 or anti-Jo 1 autoantibodies in sera from either the controls or the patients. The diagnostic sensitivity of the immunoblot assay for anti-Scl 70 autoantibodies in patients with scleroderma was greater than that of the immunodiffusion assay, 70% vs 20%, and was equivalent in patients with polymyositis, 43%. We conclude that rapid immunoblot assays for anti-Scl 70 and anti-Jo 1 autoantibodies are superior to immunodiffusion assays for clinical use and are suitable for routine use in the clinical laboratory.

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disorder that can progress to cirrhosis, shortening life expectancy. PBC patients are often asymptomatic, present with biochemical cholestasis, and test positive (≥90%) for antimitochondrial antibodies (AMAs) in serum. Although AMA positivity without biochemical cholestasis may indicate increased risk of future PBC development, the contribution of these antibodies to pathogenesis remains enigmatic. Environmental risks and genetic determinants are likely implicated in PBC etiology. Given the familial aggregation of PBC, we hypothesized that AMAs also aggregate among relatives of PBC probands. We investigated the prevalence of AMAs in first-degree relatives (FDRs) of PBC probands to examine whether AMAs aggregate in such pedigrees. Using a PBC family registry, we prospectively screened for AMAs in the serum of 306 FDRs in 145 pedigrees, 350 PBC probands, and 196 controls who were age-matched, sex-matched, race-matched, and residence-matched to probands. The prevalence of AMA in FDRs and controls was 13.1% and 1%, respectively. Greater prevalence of AMA was found in female FDRs of PBC probands [sisters (20.7%), mothers (15.1%), and daughters (9.8%)] than in male FDRs [brothers (7.8%), fathers (3.7%), and sons (0%)]. Conclusions: AMAs aggregate among FDRs of PBC probands. Our data have clinical implications for FDRs of PBC probands because AMA positivity may suggest susceptibility to PBC. Thus, the identification and follow-up of these relatives may lead to earlier disease diagnosis and treatment. Furthermore, if AMA development is heritable, this trait will provide a basis to dissect the genetic predisposition to PBC. (HEPATOLOGY 2007.)

We conducted a prospective, multicenter evaluation of autoantibody testing by multiplex immunoassay in patients with known or suspected connective tissue diseases (CTD). We evaluated agreement between multiplex immunoassay and enzyme immunoassay (EIA) and assessed the diagnostic utility of autoantibody profiles.Samples from 908 patients with suspected CTD seen in rheumatology clinics were collected prospectively at 3 tertiary care centers. Diagnoses were established according to recognized classification criteria. Tests for autoantibodies were obtained by multiplex immunoassay and by EIA. The results of the multiplex immunoassay were analyzed using a previously validated interpretative algorithm, MDSS (Medical Decision Support Software), that suggests possible disease associations based on the pattern of results for the autoantibodies.The median patient age was 49.7 years; 83% were female. The most common diagnoses were rheumatoid arthritis in 352 patients and systemic lupus erythematosus (SLE) in 332 patients. Agreement between multiplex and EIA testing ranged from a high of 99% (95% CI 98% to 100%) for Jo-1 to a low of 79% (95% CI 76% to 82%) for antinuclear antibodies. The MDSS algorithm suggested an appropriate disease association in 75% to 100% of patients with SLE. The results varied depending on the disease and the autoantibodies present.These results suggest that patterns of autoantibodies detected by multiplex immunoassay testing, when analyzed by an interpretative algorithm, are useful in the evaluation of patients with CTD in situations of high disease prevalence. Further testing is necessary to determine its utility in settings of low disease prevalence.

Background Linear scleroderma occurs as two clinically distinct variants: the frontoparietal en coup de sabre type, and the torso-extremity type. Antihistone antibodies (AHAs), which traditionally are markers for drug-induced lupus, may also be linked to linear scleroderma. Methods Retrospective review of all patients presenting with linear scleroderma who had AHA titers measured. Results A total of 35 patients were identified. Twenty patients with linear scleroderma of the torso and/or extremities comprised 14 pediatric patients (≤ 18 years old; positive AHA, 10/14 = 71%; positive ANA, 3/13 = 23%) and six adults (four positive AHA; five positive ANA). Among the 15 patients with frontoparietal linear scleroderma, en coup de sabre type, 11 were pediatric patients (positive AHA, 5/11 = 45%; positive ANA, 4/11 = 36%) and four were adults (1 positive AHA/ANA). Conclusion The two clinical variants of linear scleroderma are not only clinically distinct, but also may be serologically different. The AHA titers may be related to the extent of involvement as well as disease activity in linear scleroderma.

Context.—The American Board of Medical Specialties Maintenance of Certification (MOC) process will become effective in 2006. The College of American Pathologists (CAP) Education Committee defined pathology-specific competencies within MOC categories and used data from a survey of pathologists to create education courses targeted to each MOC category. Objective.—To define pathology-specific competencies within MOC categories and to identify priority learning needs for pathologists. Design.—A 5-step process was completed for defining pathology-specific competencies within MOC categories and creating education courses targeted to competencies identified in each MOC category. A random survey was distributed to identify priority learning needs based on the gap between the importance rating of each knowledge and skill statement and a rating of current level of proficiency in 3 areas. Results.—Specific competencies and knowledge and skill statements were identified for each MOC competency category. Findings indicate pathologists believe they are poorly prepared for practice in competency categories related to systems-based practice and practice-based learning and improvement. Conclusions.—The CAP has focused education efforts on identifying a process for defining and responding to the MOC challenge. Pathologists have told us that they have significant needs for learning in specified areas and the CAP will focus development of education courses to meet those identified needs.

In the environment of managed care, children with allergic diseases are increasingly likely to be evaluated by nonallergist physicians. While the presumptive diagnosis of an allergic disease can often be suspected on clinical grounds, signs and symptoms are not reliable for establishing a definitive diagnosis or for deciding on management options. This article discusses the use of immunoglobulin E antibody tests to classify children with allergic symptoms. The information is intended for pathologists who offer consultative laboratory services to nonallergist physicians. Emphasis is placed on defining the minimum number of tests necessary to identify allergic children at different ages.

Quantification of thyrotropin-receptor antibodies is important in the diagnosis and management of patients with Graves disease (1). Antibodies with stimulating activity (TSI) have traditionally been detected in bioassays that measure their effect on cloned rat thyroid cells (FRTL-5) or on Chinese hamster ovary (CHO) cells transfected with recombinant human thyrotropin-stimulating hormone (TSH) receptor (2)(3). These assays can detect antibodies in up to 95% of untreated hyperthyroid Graves patients, but, with few exceptions (4), they require cell culture facilities and are labor intensive and time consuming. As an alternative to bioassays, several manufacturers have developed competitive immunoassays that measure the inhibition of the binding of labeled TSH by antibodies in patients’ sera. These methods use porcine TSH receptors and claim clinical sensitivities of ∼90%. They cannot, however, distinguish whether the autoantibodies have blocking or stimulating capabilities, which can be important in a subset of patients. The more recent LUMItest® TRAK (TRAK) human assay (BRAHMS AG) uses human recombinant TSH receptors and luminescence-labeled bovine TSH. The manufacturer’s literature cites a clinical trial that achieved a diagnostic sensitivity of almost 99% with the research version of the DYNOtest® TRAK human assay (5). We have been performing the TSI bioassay with FRTL-5 cells routinely for more than 15 years. The TSI test volumes have increased steadily over that time, requiring an ever-increasing number of assays each week. In 1998, we added the Kronus® TRAb radioreceptor assay (TRAb) to our test menu to reduce the number of requests for TSI. During the preimplementation evaluation of the Kronus reagents, we found equivalent results in 80 of 89 random patient samples. Of the remaining nine samples, five were positive by TSI and not by TRAb, and four were positive by TRAb and not by TSI. The availability of the BRAHMS reagents as well as …

Background The sensitivity of assays for antineutrophil cytoplasmic antibody (ANCA), anti-Saccharomyces cerevisiae antibody (ASCA), and antipancreatic antibody (PAB) in different laboratories is unknown. Likewise, the sensitivity and diagnostic usefulness of these assays in patients with inflammatory bowel disease (IBD) in the community is unknown. Methods An incidence cohort of 290 patients with IBD were offered participation in the study. Blood was obtained from 162 patients (56%) (83 with ulcerative colitis, 79 with Crohn's disease) who agreed to participate. ANCA was determined in five laboratories, ASCA in two laboratories, and PAB in one laboratory. Results In ulcerative colitis, the sensitivity of ANCA determined in five laboratories varied widely, ranging from 0–63%. In Crohn's disease, the sensitivity of ASCA determined in two laboratories did not vary significantly, ranging from 39–44%; and the sensitivity of PAB determined in one laboratory was 15%. The optimal diagnostic usefulness was obtained from one laboratory where the positive predictive values of a positive ANCA assay combined with a negative ASCA assay for ulcerative colitis, and a negative ANCA combined with a positive ASCA for Crohn's disease, were 75% and 86%, respectively. Conclusions In patients with IBD, the sensitivity of ANCA varied widely in different laboratories, whereas the prevalence of ASCA was similar. The positive predictive values of the ANCA assay combined with the ASCA assay for ulcerative colitis and Crohn's disease are high enough to be clinically useful.

During the past several years, immunoassays for specific IgE antibodies have been refined to permit reporting results in mass units. Thus quantitative immunoassays for IgE antibodies may be an adjunct to skin tests. In cases of food allergy among children with atopic dermatitis, cutoff values for IgE antibody concentrations to egg, milk, peanut, and fish have been derived to provide 95% positive and 90% negative predictive values. Food-specific IgE antibody determinations can also be used to predict which food allergies are resolving spontaneously. Elevated egg-specific IgE antibody levels in infancy are associated with significantly increased risk for development of inhalant allergies later in childhood. In cases of inhalant allergy, specific IgE antibody levels correlate closely with results of inhalation challenge studies in cat-sensitive persons. Also, mite-specific IgE antibody levels correlate significantly with the mite allergen contents of reservoir dust in the homes of mite-sensitive persons. Immunoassays for quantitation of specific IgE antibodies may be used to document allergen sensitization over time and to evaluate the risk of reaction on allergen exposure. However, immunoassays and skin tests are not entirely interchangeable, and neither will replace the other in appropriate circumstances.

The use of laboratory testing in the diagnosis of allergic diseases is discussed in this article. This is the first part of a two-part series.

Objectives To reevaluate the current criteria for diagnosing allergic fungal sinusitis (AFS) and determine the incidence of AFS in patients with chronic rhinosinusitis (CRS). Methods This prospective study evaluated the incidence of AFS in 210 consecutive patients with CRS with or without polyposis, of whom 101 were treated surgically. Collecting and culturing fungi from nasal mucus require special handling, and novel methods are described. Surgical specimen handling emphasizes histologie examination to visualize fungi and eosinophils in the mucin. The value of allergy testing in the diagnosis of AFS is examined. Results Fungal cultures of nasal secretions were positive in 202 (96%) of 210 consecutive CRS patients. Allergic mucin was found in 97 (96%) of 101 consecutive surgical cases of CRS. Allergic fungal sinusitis was diagnosed in 94 (93%) of 101 consecutive surgical cases with CRS, based on histopathologic findings and culture results. Immunoglobulin E-mediated hypersensitivity to fungal allergens was not evident in the majority of AFS patients. Conclusion The data presented indicate that the diagnostic criteria for AFS are present in the majority of patients with CRS with or without polyposis. Since the presence of eosinophils in the allergic mucin, and not a type I hypersensitivity, is likely the common denominator in the pathophysiology of AFS, we propose a change in terminology from AFS to eosinophilic fungal rhinosinusitis.

SUMMARYANCA directed against PR3 are highly specific for Wegener's granulomatosis and microscopic polyangiitis, and have been implicated in the pathogenesis of small vessel vasculitis. Most PR3-ANCA are directed against conformational epitopes on PR3. This study was designed to determine whether the cleavage of the N-terminal activation dipeptide of PR3 is required for the binding of PR3-ANCA. Recombinant PR3 (rPR3) variants were expressed in the epithelial cell line, 293. As confirmed by radiosequencing, the rPR3 secreted into the 293 cell culture supernatant is N-terminally unprocessed. Two enzymatically inactive rPR3 mutants were expressed in 293 cells: rPR3-S176A and δ-rPR3-S176A. rPR3-S176A contains the N-propetide Ala-2-Glu-1, δ-rPR3-S176A does not. Culture supernatants of rPR3-S176A and δ-rPR3-S176A expressing 293 cells were used as sources of target antigen for PR3-ANCA testing by capture ELISA. Forty unselected consecutive PR3-ANCA+ sera were tested. With δ-rPR3-S176A as antigen all 40 were recognized, compared with only 34 of 40 when rPR3-S176A served as target antigen. The majority of the serum samples contained a mixture of antibodies reacting with epitopes accessible on the mature and on the proform of PR3. In conclusion, the cleavage of the N-terminal activation dipeptide of PR3 is not an absolute requirement for recognition by all PR3-ANCA. However, a substantial proportion of PR3-ANCA recognize (a) target antigen(s) exposed only after the conformational change of PR3 associated with the N-terminal processing. In 15% of sera this PR3-ANCA subset occurred exclusively. PR3-ANCA subtypes can be differentiated using specifically designed rPR3 variants as target antigens, and non-haematopoietic mammalian cells without regulated secretory pathway can be used for their expression.

Proteinase 3 (PR3), a constituent of azurophil granules of neutrophils (polymorphonuclear cells, PMNs), is the target antigen for most anti-neutrophil cytoplasmic antibodies (c-ANCA) in Wegener's granulomatosis (WG). We have recently developed an expression system for recombinant PR3 (rPR3) that is recognized by c-ANCA. Here, we report on the development and characterization of two monoclonal antibodies (moABs) and a rabbit polyclonal antiserum generated against this rPR3. Epitope competition analysis indicates that the moABs MCPR3-1 and MCPR3-2 recognize overlapping epitopes on the PR3 molecule that are distinct from the ones recognized by moABs 4A5 and 6A6 developed by others. Since MCPR3-2 does not appear to compete for epitopes recognized by a sizable proportion of PR3-ANCA, we used it to develop a sensitive capture enzyme linked immunosorbent assay (ELISA) for clinical PR3-ANCA testing. Both purified PMN PR3 and crude human mast cell line (HMC-1)/PR3-S176A cell lysates were used as sources of PR3 target antigen in this assay with equal analytical sensitivity and specificity. Of 109 patients with ANCA-associated disease, 91 (83.5%) and 90 (82.6%) were PR3-ANCA positive by capture ELISA when PMN-PR3 and HMC-1/PR3-S176A cell lysates were used as antigen, respectively. When HMC-1/PR3 and HMC-1/PR3-S176A cells were used as indirect immunofluorescence (IIF) substrate, 88 (80.7%) and 92 (84.4%) were PR3-ANCA positive, respectively. These differences were not statistically significant. Only 1 of 151 controls without defined ANCA-associated disease tested positive by capture ELISA with either target antigen (both negative by PR3-ANCA specific IIF). The capture ELISA can also be used to detect of PR3-ANCA immunecomplexes and, in combination with the rabbit antiserum, for the quantitative measurement of PR3 in biological fluids.

Approximately 5% to 10% of patients with features otherwise consistent with primary biliary cirrhosis (PBC) lack antimitochondrial antibodies (AMA). Most of these patients have other autoantibodies, a syndrome recently named "autoimmune cholangitis." We report our experience in patients with AMA-negative PBC treated with ursodeoxycholic acid (UDCA) and/or liver transplantation (OLT). The study of response to UDCA was performed as follows. While recruiting patients for a previously reported multicenter trial, we identified 8 patients with AMA-negative PBC. The patients were given UDCA and followed up at regular intervals. The characteristics of AMA-negative patients at presentation were similar to those of AMA-positive patients with PBC. The clinical outcomes and sequential liver biochemistries of UDCA treatment were also comparable with those of AMA-positive patients. The study of outcome of OLT was performed as follows. We identified OLT recipients at the Mayo Clinic who had clinical, radiological, and histological features compatible with PBC. Their pretransplant AMA status was determined, and each AMA-negative patient was paired with 2 AMA-positive patients. Of 85 OLT recipients with a diagnosis of PBC, 6 (7.1%) were AMA negative, including 1 who had undergone UDCA therapy. After a median of 36 months of follow-up, graft and patient survival rates and subsequent histological changes (disease recurrence and steroid-resistant or late rejections) were comparable in AMA-negative and -positive PBC patients. In summary, in our experience of 13 AMA-negative PBC patients (including 9 who met the criteria for a diagnosis of autoimmune cholangitis), treatment with UDCA or OLT resulted in similar outcomes to those found in AMA-positive patients. We conclude that AMA status does not affect the response in PBC patients to treatment with UDCA or OLT.

Peripheral neuropathy occurs in Sjogren's syndrome, a disorder in which systemic immunologic phenomena, including vasculitis, are common. Neuropathy also occurs with isolated sicca complex (keratoconjunctivits sicca and xerostomia); whether this represents a distinct syndrome is unclear. We retrospectively studied 54 patients with sicca complex and peripheral neuropathy to determine mode of presentation, neuropathic patterns, frequency and pattern of serologic abnormalities, and frequency of systemic disease, including necrotizing vasculitis. Peripheral neuropathy was the presenting problem in 87%. Although sicca symptoms occurred in 93%, they were a presenting complaint in only 11% and were usually mild, reported only after specific inquiry. Minor salivary gland biopsy was positive in 73%. Sensory neuropathies strongly predominated; 61% of patients manifested either sensory polyneuropathy or polyganglionopathy. Less common patterns included sensorimotor polyneuropathy (17%) and polyradiculoneuropathy (11%). Vasculitic neuropathy was demonstrated in only two patients, but nonspecific epineurial inflammation was present in 70% of nerve biopsies. Clinical evidence of systemic disease was uncommon, particularly in the sensory polyganglionopathy group, in whom extraglandular features other than weight loss occurred in only 1 of 12 patients. Antibodies to extractable nuclear antigens, the most specific serologic marker of Sjogren's syndrome, were present in 10.4%. We conclude that peripheral neuropathy and isolated sicca complex form a distinctive syndrome in which neuropathy is the presenting feature and sicca is easily overlooked; sensory polyneuropathy and polyganglionopathy predominate; serology is confirmatory but very insensitive; and extraglandular disease, including vasculitis, is uncommon compared with typical Sjogren's syndrome. Tests of ocular or salivary involvement are needed for diagnosis, and demonstration of inflammation in biopsied nerve is supportive. Improved definition of this disorder should permit further studies of natural history and efficacy of immunotherapy.

Background: Cryptogenic chronic active hepatitis may be an autoimmune or viral disease. Our aims were to determine the clinical features, human leukocyte antigen phenotype, and response to corticosteroid therapy of severe Cryptogenic chronic active hepatitis and to compare it with these other diseases. Methods: Twelve patients with Cryptogenic hepatitis were compared with 94 patients with autoimmune hepatitis and 30 patients with chronic viral hepatitis. Results: Patients with cryptogenic hepatitis were indistinguishable from those with autoimmune hepatitis by age, gender, and individual laboratory and histological findings. HLA B8 (75% vs. 49%, P = 0.2), DR3 (71% vs. 51%, P = 0.5), and A1-B8-DR3 (57% vs. 38%, P = 0.6) occurred as commonly in each group. Patients with cryptogenic hepatitis entered remission (83% vs. 78%, P > 0.9) and failed treatment (9% vs. 11%, P > 0.8) as frequently as those with autoimmune hepatitis during corticosteroid therapy. In contrast, patients with chronic viral hepatitis had lower biochemical abnormalities, less frequent multilobular necrosis at presentation, and different human leukocyte phenotypes than those with cryptogenic or autoimmune disease. Conclusions: Severe cryptogenic hepatitis has a clinical expression, genetic phenotype, and corticosteroid responsiveness that is similar to autoimmune hepatitis. It may be an autoimmune disorder that has escaped detection by conventional immunoserological markers.