Anti-neutrophil cytoplasmic antibodies in patients with chronic liver diseases: prevalence, antigen specificity and predictive value for diagnosis of autoimmune liver disease. Swedish Internal Medicine Liver Club (SILK)

BACKGROUND: Anti-neutrophil cytoplasmic antibodies (ANCA) against proteinase 3 are diagnostic of Wegener's granulomatosis, but ANCA occur also in patients with other inflammatory disorders, such as ulcerative colitis, primary sclerosing cholangitis (PSC) and autoimmune hepatitis. As their predictive value for autoimmune liver disease remains unknown, we analysed the prevalence and antigen specificity of ANCA in patients with various chronic liver diseases (CLD). METHODS: We studied sera from 100 patients with primary biliary cirrhosis (PBC), from 76 with PSC and from 279 with various CLD, consecutively drawn during a 5-year period at the time of liver biopsy. The ANCA were detected by indirect immunofluorescence (IIF) while the antigen specificity was characterized by ELISA by using lactoferrin, neutrophil elastase, cathepsin G and BPI (bactericidal/permeability increasing protein) as antigens. RESULTS: In PBC, ANCA were detected by IIF in 39 patients (39%). The antigen reactivity by ELISA was lactoferrin in seven, elastase in 15, BPI in 20 and cathepsin G in four patients. Four patients had reactivity against more than one antigen. In PSC, IIF demonstrated ANCA in 49 patients (65%). The antigen reactivity was lactoferrin in 17, elastase in 14, BPI in 20 and cathepsin G in four patients. Twelve patients showed reactivity against more than one antigen. In CLD, ANCA were observed in sera from 55 patients (20%). Nineteen of 45 patients (42%) with autoimmune liver disease were ANCA positive versus 36/234 (15%) with non-autoimmune liver disease (P = 0.0002). Among IIF-positive patients, antibody reactivity against lactoferrin was noted in 14, elastase in 28, BPI in 25 and cathepsin G in five patients. Twenty-one patients had reactivity against more than one antigen. Elastase and BPI antibodies occurred more frequently in patients with autoimmune compared to non-autoimmune liver disease (P < 0.01). CONCLUSIONS: Anti-neutrophil cytoplasmic antibodies are prevalent in patients with chronic liver diseases, but although they occur more frequently in patients with autoimmune liver disease their specificity and sensitivity for autoimmune liver disease is low. The predominant antigens are lactoferrin, elastase and BPI, but the correlation between IIF findings and ELISA reactivity against these antigens is weak.     

Minocycline induced arthritis associated with fever, livedo reticularis, and pANCA.

OBJECTIVE: To describe a novel iatrogenic immunological reaction produced by minocycline. CASE REPORTS: The clinical course and laboratory results of three women who presented with similar rheumatological manifestations after a prolonged exposure to minocycline are described. All three presented a unique reaction manifested by fever, arthritis/arthralgia and livedo reticularis during treatment with minocycline for acne vulgaris. The clinical syndrome was associated with high titre of serum perinuclear anticytoplasmatic antibodies (p-ANCA) and antimyeloperoxidase antibody (anti-MPO). Symptoms resolved after stopping the drug and recurred promptly after rechallenge in all three patients. CONCLUSIONS: Minocycline, which is widely used in the treatment of acne, often without adequate supervision, may induce arthritis and livedo vasculitis associated with anti-MPO.     

Bactericidal/permeability-increasing protein and cathepsin G are the major antigenic targets of antineutrophil cytoplasmic autoantibodies in systemic sclerosis

OBJECTIVE: To study the prevalence and antigenic specificity of antineutrophil cytoplasmic autoantibodies (ANCA) in patients with systemic sclerosis (SSc). METHODS: Sera from 68 patients with SSc were screened for ANCA by indirect immunofluorescence (IIF) assay and for antibodies to myeloperoxidase (MPO) by ELISA. All sera positive for ANCA on IIF were analyzed for reactivity against antigenic targets other than MPO [bactericidal/permeability-increasing protein (BPI), cathepsin G, lysozyme, elastase, PR3, and lactoferrin]. Twenty-three sera negative for ANCA were also tested for antibodies to BPI and cathepsin G using ELISA. RESULTS: The study included 33 patients with diffuse and 35 with limited SSc. ANCA was detected in 24 of the 68 sera (35.3%). In these 24 sera the antigenic targets were BPI in 14, cathepsin G in 13, and MPO in 8. Sera of 11 patients had reactivity against both BPI and cathepsin G. In sera, that were negative for ANCA, antibodies to BPI (4/23), cathepsin G (3/23), and MPO (1/44) were found in a small proportion of patients. Patients with antibodies to BPI had lower skin score, whereas no patient with antibodies to MPO had renal disease. CONCLUSION: BPI and cathepsin G are the major antigenic targets of ANCA seen in patients with SSc. Patients with antibodies to BPI had lower skin scores.     

Minocycline-induced autoimmune syndromes: An overview

OBJECTIVE: To increase awareness of minocycline-induced autoimmune syndromes. METHODS: Review of relevant publications from the American and European literature. RESULTS: Four minocycline-induced syndromes have been described in 82 patients: serum sickness, drug-induced lupus, autoimmune hepatitis, and vasculitis. Aside from sporadic cases of serum sickness, all other syndromes occurred in patients treated for acne. Drug-induced lupus and hepatitis were by far the most common events (66 cases). Except for serum sickness, which presented shortly (mean, 16 days) after minocycline, the autoimmune syndromes manifested after protracted use (mean, 25.3 months). As expected, the patients with acne were young (mean, 19.7 years). The most frequent symptoms were arthralgia, followed by arthritis, fever, and rash (73, 45, 38, and 29 patients, respectively). Serologically, antinuclear antibodies were the most common finding (63 positive of 68 tests); perinuclear anti-neutrophilic cytoplasmic antibodies (pANCA), when assayed, were similarly frequent (20 of 24 tests). Surprisingly, anti-histone antibodies were uncommon, even among patients with drug-induced lupus (4 of 31 tests). The clinical and serological features of the separate syndromes may overlap. The diagnostic value of pANCA, as well as its possible role in minocycline-induced autoimmunity, are discussed. CONCLUSIONS: Minocycline has the potential to evoke a variety of clinical and serological autoimmune expressions. The number of published reports may underestimate the frequency of this condition, which should be suspected and investigated in young patients with autoimmune manifestations.     

Autoimmune cholangiopathy associated with rheumatoid arthritis

We herein describe a patient with autoimmune cholangiopathy complicated with rheumatoid arthritis. A 58-year-old female was admitted to our hospital due to complications of arthralgia in her fingers, shoulders, elbows, knees and ankles. She presented with abnormally elevated levels of transaminases, alkaline phosphatase and was also negative for hepatitis B virus, hepatitis C virus and the serum mitochondrial antibody test, but had high titers of serum antinuclear antibody, rheumatoid factor and rheumatoid arthritis hemagglutination. A liver biopsy specimen showed chronic non-suppurative destructive cholangitis. She was thus diagnosed to have autoimmune cholangiopathy and rheumatoid arthritis. She began treatment with prednisolone 40 mg per day. After 20 days of steroid therapy, her hepatic function tests improved and the arthralgia symptoms disappeared. This is, to our knowledge, the first case of autoimmune cholangiopathy associated with rheumatoid arthritis, in which both symptoms improved with steroid therapy.     

Antineutrophil cytoplasmic antibodies in Japanese patients with inflammatory bowel disease: prevalence and recognition of putative antigens

OBJECTIVE: Our aim was to investigate the prevalence of antineutrophil cytoplasmic antibodies (ANCA) in Japanese patients with ulcerative colitis (UC) and Crohn's disease (CD), and the putative antigens recognized by perinuclear staining pattern ANCA (p-ANCA)-positive sera. METHODS: Sera from UC (n = 52) and CD (n = 43) patients, and from healthy controls (n = 74) were studied. The indirect immunofluorescence (IIF) method was used for the detection of ANCA and its binding pattern. p-ANCA-positive sera were studied further for putative antigens. ELISAs using lactoferrin (Lf), myeloperoxidase (MPO), and cathepsin G (Cat G) as antigens were performed. RESULTS: ANCA was positive in 40 of the 52 (76.9%) UC (p-ANCA in 33) and in 32 of the 43 (74.4%) CD (p-ANCA in 31) patients. UC and CD patients showed significantly higher titers of p-ANCA than controls; however, no significant difference was observed between UC and CD. In UC, 23, 17, and nine of the 33 patients with p-ANCA-positive sera showed reactivity with Lf, MPO, and Cat-G, respectively. In CD, 21, 20, and 11 of the 31 patients with p-ANCA-positive sera showed reactivity with Lf, MPO, and Cat-G, respectively. Fourteen of the UC and six of the CD patients showed reactivity with two different antigens, and seven of the UC and 11 of the CD patients showed reactivity with all three antigens. The presence of anti-Lf and anti-MPO antibodies was further confirmed by Western blotting. CONCLUSIONS: ANCA is useful in distinguishing patients with IBD from normal subjects but is not sufficient for the differential diagnosis of CD and UC. p-ANCA reactivity might be derived from the recognition of heterogeneous neutrophil-associated antigens.     

Rheumatoid arthritis preceding microscopic polyangitis. Report of two cases

INTRODUCTION: Although joint manifestations are common in microscopic polyangiitis (MPA), including arthralgia reported in 15-65% of cases and arthritis in 6-17%, there have been only two published cases of polyarthritis as the first manifestation of the disease. We report on two new cases. EXEGESIS: A 71-year-old woman had symmetric polyarthritis of the hands which initially suggested the existence of seronegative rheumatoid arthritis. A 52-year-old woman had seropositive asymmetric oligoarthritis. The diagnosis was not established until renal insufficiency appeared, prompting a renal biopsy which showed in both cases an extra-capillary glomerulonephritis and an anti-myeloperoxydase (p-ANCA) assay which was postive in both patients. The incidence and specificity of antineutrophil cytoplasmic antibodies (ANCA), including MPA, in rheumatoid arthritis are reviewed. CONCLUSION: Our two observations show that in cases of polyarthritis or oligoarthritis with renal involvement, testing for and typing of ANCA should be performed so as not to misdiagnose vasculitis.     

Antineutrophil cytoplasmic antibodies: a still-growing class of autoantibodies in inflammatory disorders.

Antineutrophil cytoplasmic antibodies (ANCA) have been described as sensitive and specific markers for active Wegener's granulomatosis (WG). ANCA in WG produce a characteristic cytoplasmic staining pattern of neutrophils (c-ANCA) and are directed against proteinase 3 (Pr3), a serine protease from the azurophilic granules. c-ANCA, more or less equivalent to anti-Pr3, occur in more than 90% of patients with extended WG, in 75% of patients with limited WG without renal involvement, and in some 40% to 50% of patients with vasculitic overlap syndromes suggestive of WG such as microscopic polyarteritis. The presence of c-ANCA is highly specific for those diseases (greater than 98%). Changes of levels of c-ANCA precede disease activity and may be used as guidelines for treatment. Antibodies producing a perinuclear staining of ethanol-fixed neutrophils (p-ANCA) occur in a wide range of diseases. They are directed against different cytoplasmic constituents of neutrophils. Among those, antibodies to myeloperoxidase are found in patients with idiopathic crescentic glomerulonephritis, the Churg-Strauss syndrome, polyarteritis nodosa with visceral involvement, and vasculitic overlap syndromes. Their specificity for this group of necrotizing vasculitides is high (94% to 99%), although they may occur in patients with hydralazine-induced glomerulonephritis, anti-glomerular basement membrane disease, and possibly in some patients with idiopathic systemic lupus erythematosus. Antibodies to leukocyte elastase are incidentally found in patients with vasculitic disorders, whereas lactoferrin antibodies are detected in patients with primary sclerosing cholangitis with or without ulcerative colitis and in rheumatoid arthritis. Their diagnostic significance awaits further studies. p-ANCA of undefined specificity may distinguish ulcerative colitis (sensitivity of 75%) from Crohn's disease (sensitivity of 20%). p-ANCA also occur in autoimmune liver diseases: in 75% of patients with chronic active hepatitis, in 60% to 85% of those with primary sclerosing cholangitis, and in about 30% of patients with primary biliary cirrhosis. Finally, p-ANCA are detected in chronic arthritides and in some 5% of healthy controls. Assessment of their diagnostic value has to await further characterization of the antigens involved, allowing the development of antigen-specific assays.     

Antineutrophil cytoplasmic antibodies in Bulgarian patients with rheumatoid arthritis: characterization and clinical associations

Objective The aim of this study was to study the prevalence, subspecificities, and immunoglobulin (Ig)G subclass distribution of antineutrophil cytoplasmic antibodies (ANCA) in 90 Bulgarian patients with rheumatoid arthritis (RA) and to investigate the clinical associations of ANCA in these patients.Methods The ANCA were detected by indirect immunofluorescence, while antigen specificities were determined by enzyme-linked immunosorbent assay (ELISA) directed against myeloperoxidase (MPO), proteinase 3 (PR3), bactericidal/permeability-increasing protein (BPI), lactoferrin (LF), leukocyte elastase (LE), and cathepsin G (CG). The IgG subclass reactivity of antibodies to BPI and LF was measured.Results Antineutrophil cytoplasmic antibodies were found in 18 RA patients. Only a P-ANCA fluorescence pattern was seen. Six sera reacted to BPI, five to LF, one to MPO, one to PR3, and one to CG by ELISA testing. Immunoglobulin-G1 was the predominant subclass for LF-ANCA, whereas IgG1/3 contributed mainly to BPI-ANCA. Compared to P-ANCA-negative RA patients, the P-ANCA-positive patients exhibited significantly higher inflammatory activity, as estimated by disease activity score, C-reactive protein, erythrocyte sedimentation rate, and higher levels of IgM rheumatoid factor.Conclusion Twenty percent of Bulgarian patients with RA have P-ANCA in their sera. These antibodies are directed against variable antigen specificities, while ANCA positivity in RA reflects disease and inflammatory activity.     

Dual anca positivity in a child with moyamoya-like cerebral vascular changes: an unusual presentation with sudden homonymous hemianopsia

A 12-year-old girl presented with a sudden decrease in her right visual acuity and homonymous hemianopsia. An angiography of the retinal arteries demonstrated recanalized occlusion of the right retinal artery. Cerebral angiography showed bilateral internal carotid artery stenosis associated with the development of collateral circulation. Laboratory evaluations revealed dual antineutrophil cytoplasmic antibodies (ANCA) positivity [anti-proteinase (anti-PR3) ANCA and anti-myeloperoxidase (anti-MPO) ANCA], anticardiolipin (aCL) antibodies, and low titers of antinuclear antibodies (ANA). There was no evidence of active systemic lupus erythematosus (SLE), ANCA-related vasculitis, or other risk factors for cerebral occlusion, such as antiphospholipid syndrome (APS). Dual positivity for both cytoplasmic (c-ANCA) and perinuclear (p-ANCA) antineutrophil antibodies has been found previously in a small number of reports, but to our knowledge, this case represents the first case of moyamoya disease associated with dual ANCA positivity.     

"Atypical p-ANCA" in IBD and hepatobiliary disorders react with a 50-kilodalton nuclear envelope protein of neutrophils and myeloid cell lines

BACKGROUND & AIMS: Atypical "antineutrophil cytoplasmic antibodies" (ANCA) are present in patients with ulcerative colitis (UC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH). Recently, we showed that atypical p-ANCA react with nuclear envelope proteins of neutrophils. Based on this observation, we aimed to characterize the nuclear antigen recognized by atypical p-ANCA. METHODS: We prepared cytoplasmic and nuclear extracts of human neutrophils, human HL-60, and murine 32D myeloid cells. Proteins were resolved by 1- and 2-dimensional gel electrophoresis. Reactive proteins were detected by immunoblotting with sera from 118 individuals (UC, 25; PSC, 28; AIH, 35; disease and normal controls, 30). Atypical p-ANCA (n = 64) were affinity-purified against the reactive protein and investigated for their immunofluorescence pattern using confocal microscopy. RESULTS: Immunoblotting showed reactivity to a myeloid-specific 50-kilodalton nuclear protein with an isoelectric point of pH 6.0 detected in 92% (59 of 64) of the patients with inflammatory bowel or hepatobiliary diseases and atypical p-ANCA. Affinity-purified antibodies against the 50-kilodalton protein gave a nuclear rim-like fluorescence on myeloid cells examined by immunofluorescence microscopy. Affinity-purified antibodies did not recognize antigens in nonmyeloid cells. CONCLUSIONS: Atypical p-ANCA in UC, PSC, or AIH recognize a 50-kilodalton myeloid-specific nuclear envelope protein.     

Autoimmune disease complicating antiviral therapy for hepatitis C virus infection

OBJECTIVE: To review autoimmune disease complicating therapy with type I interferons (IFNs), specifically in the setting of hepatitis C virus (HCV) infection. METHODS: This study describes 13 reported cases of drug-induced systemic lupus erythematosus (SLE) associated with IFN therapy for the period reported during 1990-2002 by searching MEDLINE. In addition, 2 additional patients are presented, 1 with SLE and 1 with an antineutrophil cytoplasmic antibody (ANCA)-positive nephritis, with long-term follow-up. RESULTS: Of 13 cases of SLE-like syndromes caused by IFN, 2 occurred in patients being treated for HCV infection. Two occurred in patients with rheumatoid arthritis (RA); 1 had Sjogren's syndrome (SS), and 1 laryngeal papillomatosis. The rest were receiving IFN for hematologic malignancies. Symptoms developed between 2 weeks and 7 years after initiation of therapy. Most developed fever and arthralgias/arthritis. Other findings included serositis manifested by tachycardia, dyspnea and pleural effusions, headaches, and hair loss. All had a positive antinuclear antibody (ANA), and the majority had double stranded (ds) DNA antibodies. Two additional patients with chronic HCV infection developed autoimmune disease after combination treatment with IFN-alpha and ribavirin. In each patient, autoimmune disease manifested as severe joint pains, myalgias, fever, rash, and proteinuria. Skin and renal biopsy specimens showed vasculitis and crescentic glomerulonephritis (GN) in the first case, and typical histologic findings of lupus nephritis in the second; clinical and laboratory features were consistent with Wegener's granulomatosis and SLE, respectively. Although both patients had mixed polyclonal cryoglobulins, they were HCV RNA and HCVAb negative. Both received corticosteroids, with gradual clinical and biochemical improvement and without recurrence of viremia. CONCLUSIONS: Autoimmune disorders occur in 4% to 19% of patients receiving IFN-alpha, though SLE-like syndromes are only seen in 0.15% to 0.7%. Clinical and laboratory features of SLE in this setting resemble idiopathic disease, with a generally good outcome after discontinuance of the drug. RELEVANCE: Type I IFNs may cause autoimmune disease such as SLE. As the armamentarium of drugs expands to include other biologics, such as the tumor necrosis factor (TNF)-alpha-inhibiting drugs, the development of autoimmune diseases induced by these drugs is an important consideration for diagnosis and appropriate treatment. Semin Arthritis Rheum 32:163-173.     

Immunoallergic reaction with hepatitis induced by minocycline

We report the case of a 19-year old black West Indian woman who had been treated for acne for two years with oral minocycline (50 mg per day) and topical of benzoyle peroxide (5%). She was admitted for fatigue, arthralgia, myalgia and widespread pruritus. We observed several skin lesions of hyperpigmentation, biological signs of hepatitis, and significant levels of antinuclear, anti-mitochondrial and anti-smooth muscle antibodies. Minocycline was immediately stopped. Two months later, all of the biological abnormalities had disappeared but the skin lesions seemed to be irreversible. Minocycline is largely used for the treatment of acne and may induce severe immuno-allergic reactions. Several cases of induced lupus, autoimmune hepatitis, eosinophilic pneumonia, hypersensitivity syndrome, serum-sickness-like illness and Sweet's syndrome have already been described. These side effects are rare but may be life-threatening. So, minocycline should be used as a second-line treatment for acne and should be avoided in black people whom seem to be at risk of such reactions. If, despite those precautions, minocycline-induced immuno-allergic reactions occur, the treatment should be immediately stopped and never prescribed again.     

Antineutrophil cytoplasm antibodies (ANCA): description and immunopathological role

These antibodies are specific for antigens in the cytoplasm of neutrophils. The main antigenic targets are proteinase 3(PR3) and myeloperoxydase (MPO) but other targets have been described without determinant conclusions for clinical practice. Staining patterns can be distinguished by an indirect immunofluorescence test (IFI), in which ethanol fixed neutrophils from healthy donors are incubated with patient's sera. Two patterns are distinguished: cytoplasmic pattern (c-ANCA) and perinuclear pattern (p-ANCA). When ANCA are detected by IFI, from a practical point of view, anti -MPO and anti-PR3 antibodies are tested. ANCA have been strongly associated with a spectrum of necrotizing small vessel vasculitides that includes Wegener's granulomatosis, microscopic polyangiitis, Churg and Strauss syndrome, pauci-immune focal necrotizing and crescentic glomerulonephritis. ANCA are a diagnosic marker and useful for the follow-up of the patients. ANCA can be observed in other pathologies: rhumatismal autoimmune diseases, inflammatory gut diseases, after drugs (hydralazine, minocycline, propylthiouracil), after silical exposition, infections (cystic fibrosis, endocarditis, HIV infection). The specificity is different and rarely anti-MPO. The ANCA role for the development of vasculitis is not completely elucidated. Some arguments are against a primary role of ANCA in the development of vasculitis. Certainly, amplification role for neutrophil activation is demonstrated but the primary event responsible of neutrophil activation is not yet defined.     

Autoantibodies and target antigens in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides

In this study of antineutrophil cytoplasmic antibody (ANCA)-associated diseases, we determined the prevalence of other autoantibodies and the antigen specificities of ANCA. ANA were common, occurring in 7 of 36 (19%) patients with Wegener's granulomatosis, in 16 of 34 (47%) patients with microscopic polyarteritis, in 6 of 11 (55%) patients with segmental necrotising glomerulonephritis and in 8 of 18 (44%) of those with ANCA-associated systemic vasculitis without renal involvement. ANA were associated more often with pANCA and microscopic polyarteritis than with cANCA (P<0.05). Patterns were speckled (n=23), homogeneous (n=10) or nucleolar (n=4). Anticardiolipin antibodies were also common, occurring in 10 of 25 (40%) patients with Wegener's granulomatosis, in 8 of 14 (57%) patients with microscopic polyarteritis and in 6 of 18 (33%) of those with a systemic vasculitis. However, anticardiolipin antibodies did not correlate with the presence of ANCA in any of the disease groups. Anti-GBM antibodies were demonstrated in only 2 of 25 (8%) patients with Wegener's granulomatosis, in I patient with microscopic polyarteritis (1/14, 7%) and in 1 with segmental nectrotising glomerulonephritis (1/11, 9%). All four patients with anti-GBM antibodies had either cANCA or pANCA. In the second part of the study, the target antigens of ANCA were determined in Wegener's granulomatosis, microscopic polyarteritis, systemic vasculids, inflammatory bowel disease, rheumatoid arthritis and systemic lupus erythematosus (SLE). Of the 19 sera with cANCA, 13 (68%) were directed against proteinase 3; other antigens were myeloperoxidase (1/19,5%), elastase and lactoferrin together (1/19, 5%), lysozyme (1/19, 5%) or unknown (3/19,16%). Of the 12 (58%) sera from patients with Wegener's granulomatosis who had cANCA, 7 bound to proteinase 3. Antimyeloperoxidase antibodies were present in 14 of 45 (31%) sera with pANCA; other antigens were proteinase 3 (5/45,11 %), elastase (3/45, 78%), lactoferrin (1/45, 2%), cathepsin G (5/45, 11 %) or unknown (17/45, 38%). Antimyeloperoxidase antibodies were common in microscopic polyarteritis (6/14, 43%) and systemic vasculitis (5/16, 31%). However, the majority of target antigens in systemic vasculitis and rheumatoid arthritis with pANCA were not determined. Atypical ANCA were present in four patients, one with inflammatory bowel disease (1/8, 13%) and three with SLE (3/15, 20%). The specificities were cathepsin G, cathepsin G plus lactoferrin, or unknown in two sera. A recent report has suggested that bactericidal /permeability-increasing protein may be the target in patients with inflammatory bowel disease.     

Prognostic factors for remission in early rheumatoid arthritis: a multiparameter prospective study

OBJECTIVE: To determine prognostic factors for remission in early rheumatoid arthritis. METHODS: 191 patients with rheumatoid arthritis whose disease duration was less than one year were followed up prospectively for five years. Remission, defined by a disease activity score (DAS) of <1.6, was used as the outcome measure. Baseline clinical, laboratory, genetic, and radiographic data (with radiographic scores determined by Sharp's method, modified by van der Heijde) were obtained. RESULTS: 48 patients (25.1%) fulfilled the remission criteria at the three year follow up visit, and 30 (15.7%) at three and five years. On univariate analysis by Fisher's exact test, remission at three years and persistent remission at five years were closely correlated with baseline DAS values, C reactive protein level, Ritchie score, health assessment questionnaire score, duration of morning stiffness, and to a lesser extent baseline total radiological scores and rheumatoid factor negativity. No significant correlation was found with sex, age, extra-articular manifestations, erythrocyte sedimentation rate, anti-cyclic citrullinated protein antibodies, anti-keratin antibodies, anti-HSP 90, anticalpastatin antibodies, antinuclear antibodies, or HLA-DRB1* genotypes. Logistic regression analysis showed that the baseline independent variables predictive of remission were low DAS, Ritchie score, morning stiffness duration, and total radiographic score. CONCLUSIONS: Baseline prognostic factors for remission in early rheumatoid arthritis were mainly clinical markers of disease activity and radiological scores.     

Clinical significance of anti-neutrophil cytoplasmic antibodies (ANCA) in autoimmune liver diseases

BACKGROUND/AIMS: The clinical relevance of anti-neutrophil cytoplasmic antibodies (ANCA) in autoimmune liver disease is unclear. Defining the antigenic specificities of ANCA in these diseases may improve their clinical significance. METHODS: We studied the target antigens of ANCA in 88 patients with autoimmune hepatitis, 53 patients with primary biliary cirrhosis, and 55 patients with primary sclerosing cholangitis by indirect immunofluorescence, antigen-specific enzyme-linked immunosorbent assays, and immunodetection on Western blot, using an extract of whole neutrophils as a substrate. We related the data to clinical symptoms of autoimmune liver disease. RESULTS: By indirect immunofluorescence, ANCA were present in 74% of patients with autoimmune hepatitis, 26% of patients with primary biliary cirrhosis, and 60% of patients with primary sclerosing cholangitis. Major antigens were catalase, alpha-enolase, and lactoferrin. The presence of ANCA as detected by indirect immunofluorescence was associated with the occurrence of relapses in autoimmune hepatitis, with decreased liver synthesis function in primary biliary cirrhosis and in primary sclerosing cholangitis, and with increased cholestasis in primary sclerosing cholangitis. ANCA of defined specificities had only limited clinical relevance. CONCLUSIONS: ANCA as detected by indirect immunofluorescence seem associated with a more severe course of autoimmune liver disease. The target antigens for ANCA in these diseases include catalase, alpha-enolase, and lactoferrin. Assessment of the antigenic specificities of ANCA in autoimmune liver disease does not significantly contribute to their clinical significance.     

ANTINEUTROPHIL CYTOPLASMIC ANTIBODIES IN INFLAMMATORY ARTHRITIS--POTENTIAL FOR MISDIAGNOSIS?

Antineutrophil cytoplasmic antibodies (ANCA) are well describedin Wegener's granulomatosis and some forms of vasculitis. Theyhave also been described in patients with arthritis, but thespecificity of these ANCA and their relationship to the presenceof vasculitis, antinuclear antibodies (ANA) and granulocyte-specificANA (GS-ANA), and to disease activity are uncertain. We studied101 patients with forms of inflammatory arthritis and detectedfour cytoplasmic ANCA, eight perinuclear ANCA and 16 atypicalANCA. There was no association between the presence of ANCAand ANA or rheumatoid factor. No anti-PR3 antibodies were foundand no strong anti-myeloperoxidase antibodies were detected.Four GS-ANA were detected and were distinct from ANCA. Therewas no association between rheumatoid arthritis disease activityor disability and ANCA status. ANCA did not predict vasculitisover a 3 yr follow-up. These ANCA appear to be epiphcnomcna.Their importance lies in their potential to mislead physicianstowards a misdiagnosis of vasculitis. KEY WORDS: ANCA, Wegener's granulomatosis, Vasculitis, RA, Myeloperoxidase, Proteinase 3     

Occurrence of autoantibodies against neutrophil granulocyte components in juvenile chronic arthritis.

This study included 96 patients with juvenile chronic arthritis of whom 47% had antinuclear antibodies (ANA). The highest frequency (58%) was seen in the oligoarticular subset, followed by the polyarticular and systemic subsets with ANA in 42% and 17% of the patients, respectively. Sixteen patients (17%) of whom 13 belonged to the polyarticular subset had granulocyte specific ANA (GS-ANA) with a titre greater than or equal to 1/50. Still another 22 patients (23%) had a borderline titre 1/25. GS-ANA were not found in any patient belonging to the systemic subset. Two of 16 patients with chronic iridocyclitis were GS-ANA positive while 9 were positive for ANA. None of the patients had circulating antibodies to neutrophil cytoplasmatic antigens (ANCA) detected by immunofluorescence or antibodies to elastase measured by ELISA. Antibodies to myeloperoxidase were found by ELISA in one patient, who showed no deviating clinical characteristics.     

Serial measurements of antineutrophil cytoplasmic autoantibodies in patients with systemic vasculitis.

PURPOSE: To assess the value of serial determinations of antineutrophil cytoplasmic autoantibodies (ANCA) for monitoring disease activity in patients with systemic vasculitis. PATIENTS AND METHODS: Forty-three patients with histologically proven vasculitis (21 with Wegener's granulomatosis, 17 with microscopic polyangiitis, and 5 with renal-limited vasculitis) were studied for a median follow-up of 22 months. Disease activity was prospectively assessed and quantified by the Birmingham Vasculitis Activity Score. A total of 347 sera were analyzed for ANCA determination. RESULTS: Relapses occurred in 23 (54%) of 43 patients. Diagnostic category (Wegener's granulomatosis vs micropolyangiitis and renal-limited vasculitis), severity of initial symptoms (mean vasculitis activity score, mean number of organs involved), and ANCA pattern [cytoplasmic-ANCA (c-ANCA) vs perinuclear-ANCA (p-ANCA)] did not significantly differ between relapsers and nonrelapsers. Lung involvement was more frequent at onset among relapsers [16 of 23 (70%) vs 6 of 20 (30%); P = 0.02]. Relapses were slightly, but not significantly, more frequent in patients with Wegener's granulomatosis or a c-ANCA pattern. The percentage of relapsers was greater in patients with persistently positive ANCA than in patients with negative or decreasing ANCA titers (86% vs 20%, P = 0.0001). However, the predictive value of an increase in ANCA titers for the occurrence of a subsequent relapse was only 28% (4 of 14) for c-ANCA, 12% (2 of 17) for anti-proteinase 3-ANCA, and 43% (6 of 14) for anti-myeloperoxidase-ANCA. An increase in ANCA occurred before or during relapse in 33% (10 of 30) of cases for c-ANCA/anti-proteinase 3 antibodies, and 73% (11 of 15) of cases for anti-myeloperoxidase antibodies. CONCLUSION: The persistence of ANCA positivity is strongly associated with relapses. However, an increase in ANCA titers has a poor value for the early prediction of a subsequent relapse and should not be used as a sole parameter for therapeutic intervention. In addition, our results suggest that serial anti-myeloperoxidase determination may be useful as a prognostic marker in patients who are p-ANCA positive.