Development and validation of a fluorescent microsphere immunoassay for anti-IgA.

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.

CNS aquaporin-4 autoimmunity in children.

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, Sjögren 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.

Combination testing for antibodies in the diagnosis of coeliac disease: comparison of multiplex immunoassay and ELISA methods.

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 autibodies 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 (k > 0.8, r > 0.7) for all tests, except 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.

Agreement of anti-neutrophil cytoplasmic antibody measurements obtained from serum and plasma.

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 enrollment of a recent randomized trial. These paired serum and plasma samples were subjected to parallel ANCA testing by standard indirect immunofluorescence 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 kappa-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 > or = 0.95 (P < 0.0001). Our study shows that serum and plasma samples can be used interchangeably for measuring ANCA.

Quantitation of 14-3-3 and neuron-specific enolase proteins in CSF in Creutzfeldt-Jakob disease.

CSF 14-3-3 and neuron-specific enolase (NSE) proteins were quantitated from patients who had Creutzfeldt-Jakob disease (CJD) or other rapidly dementing disorders initially considered to be CJD. Thirty-one patients were diagnosed as having CJD among 152 studied. CSF 14-3-3 values more than 8 ng/mL correlated with CJD. CSF NSE values less than 30 ng/mL and 14-3-3 values less than 8 ng/mL made a diagnosis of CJD unlikely, but did not exclude it.

Evaluation of serologic disease markers in a population-based cohort of patients with ulcerative colitis and Crohn's disease.

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.

Epidemiology and natural history of primary biliary cirrhosis in a US community.

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.

Patient survival and renal recovery in acute renal failure: randomized comparison of cellulose acetate and polysulfone membrane dialyzers.

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 hemodialysis. Patients were randomized to exclusive treatment with either cellulose acetate (CA) or polysulfone (PS) hemodialysis membranes. Additionally, markers of biocompatibility (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, percentage 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.

Quantitative IgE antibody assays in allergic diseases.

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.

Guidelines for clinical use of the antinuclear antibody test and tests for specific autoantibodies to nuclear antigens. American College of Pathologists.

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.

The diagnosis and incidence of allergic fungal sinusitis.

OBJECTIVE: 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 histologic 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.

A proportion of proteinase 3 (PR3)-specific anti-neutrophil cytoplasmic antibodies (ANCA) only react with PR3 after cleavage of its N-terminal activation dipeptide.

ANCA 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 delta-rPR3-S176A. rPR3-S176A contains the N-propetide Ala-2-Glu-1, delta-rPR3-S176A does not. Culture supernatants of rPR3-S176A and delta-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 delta-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.

Detection of antinuclear antibodies: comparative evaluation of enzyme immunoassay and indirect immunofluorescence methods.

OBJECTIVE: To evaluate a commercial microtiter enzyme immunoassay for antinuclear antibodies (ANA) by comparing the results of tests performed with this assay to an established indirect immunofluorescence method performed on human epitheliod cell substrate slides. DESIGN: Both analytical methods were used to test for the presence and levels of ANA in stored sera from 313 patients previously shown to have detectable ANA and from 102 healthy control subjects. Follow-up tests for specific autoantibodies (anti-dsDNA antibodies and antibodies to extractable nuclear antigens [ENA]) were performed on all sera from patients. The medical histories of all patients were reviewed to determine the presence of systemic rheumatic diseases (SRDs). Different cut-off levels of positivity were examined to determine the sensitivity and predictive values of positive results on the enzyme immunoassay for detecting patients with SRDs or sera with positive tests for specific autoantibodies. RESULTS: Among patients with clinically diagnosed SRDs (n = 197), the enzyme immunoassay was positive for ANA (> or =1 U) in 100% and the indirect immunofluorescence method was positive (titer > or =40) in 95.4% of cases. Among ANA-positive patients with no SRDs (n = 116), testing by enzyme immunoassay and indirect immunofluorescence yielded positive results in 97.6% and 75.6% of cases, respectively. Among healthy control subjects, each of the two methods was positive in 15% of cases. As expected, most patients with SRDs had higher levels of ANA than did ANA-positive patients with other clinical diagnoses. A cut-off level of > or =3 U on the enzyme immunoassay correctly classified 77% of patients with a SRD as "positive" and 88% of patients with other clinical diagnoses as "negative." The probability of detecting a positive result for specific autoantibodies on second-order testing increased directly with the level of ANA. A cut-off level of > or =3 U had a sensitivity of 92% for identifying sera with positive specific autoantibodies, and results > or =3 U had a predictive value of 52% for a positive second-order test result. CONCLUSION: Enzyme immunoassay is substantially equivalent to indirect immunofluorescence for detecting clinically important ANA. Cut-off levels for positive results on the enzyme immunoassay can be established that optimize the usefulness of this method in diagnostic algorithms for specific autoantibodies.

Capture-ELISA based on recombinant PR3 is sensitive for PR3-ANCA testing and allows detection of PR3 and PR3-ANCA/PR3 immunecomplexes.

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.

Octreotide inhibition of flushing and colonic motor dysfunction in carcinoid syndrome.

OBJECTIVES: Previous studies showed increased plasma motilin and substance P concentrations and accelerated motor function in the small bowel and colon in patients with carcinoid diarrhea. Octreotide is beneficial in patients with carcinoid syndrome. Our hypothesis was that octreotide inhibits accelerated motility and gut neuropeptides in carcinoid syndrome. METHODS: In 12 patients with metastatic carcinoid syndrome, we investigated the effect of octreotide 50 microg s.c. t.i.d (n = 6) or placebo (n = 6) on postprandial symptoms, GI transit, colonic motility, and circulating levels of selected circulating peptides and amines. RESULTS: Octreotide reduced postprandial flushing (p = 0.03) but not pain. Octreotide significantly retarded overall colonic transit and proximal colonic emptying (p < 0.05); it tended to prolong small bowel transit time (p = 0.13) and to reduce postprandial colonic tone (p = 0.08) compared with placebo. Octreotide also reduced circulating levels of peptide YY, neurotensin, vasoactive intestinal polypeptide, and substance P but had no effect on plasma motilin, neuropeptide Y, calcitonin gene-related peptide, or histamine after meal ingestion. CONCLUSION: Octreotide ameliorates gut motor dysfunctions that characterize carcinoid diarrhea; the potential role of specific antagonism of serotonin, substance P, and vasoactive intestinal polypeptide alone or in combination with agents that inhibit their release in carcinoid diarrhea deserves further study.

Human mast cells expressing recombinant proteinase 3 (PR3) as substrate for clinical testing for anti-neutrophil cytoplasmic antibodies (ANCA).

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 Sjogren'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 < 0.01). These findings indicate that HMC-1/PR3 cells are a very sensitive antigen-specific substrate for clinical anti-PR3 ANCA testing which appears superior to standard C-ANCA testing using PMN cytospin substrates and anti-PR3 ELISA. Our results also suggest that in WG the C-ANCA fluorescence pattern is not caused by antibodies against target antigens other than PR3.

Does antimitochondrial antibody status affect response to treatment in patients with primary biliary cirrhosis? Outcomes of ursodeoxycholic acid therapy and liver transplantation.

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 associated with sicca complex.

Peripheral neuropathy occurs in Sjögren'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 Sjögren'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 Sjögren'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.