Antineutrophil cytoplasmic autoantibodies-antigen specificity and associated diseases

Antineutrophil cytoplasmic antibodies (ANCA) are widely used as a useful diagnostic marker for small vessel vasculitides, although the test may occasionally be positive in various other conditions. The aim of this study was to assess ANCA in various clinical-pathological settings. ANCA were tested by indirect immunofluorescence and enzyme-linked immunosorbent assay and were found to be positive in 423 patients in the period from 1989-1999. Patients were grouped in accordance with their clinical-pathological setting as follows: 1. pauci-immune vasculitis confirmed by biopsy (n = 151), 2. clinically suspected vasculitis (n = 59), 3. inflammatory bowel diseases and autoimmune hepato-biliary disorders (n = 83), and 4. miscellaneous diseases (n = 130). The association of proteinase 3 ANCA with Wegener's granulomatosis (45/56) and myeloperoxidase ANCA with microscopic polyangiltis (45/54) and pauci-immune necrotising glomerulonephritis (24/28) was established. However, ANCA with other specificities were also shown to be present in these forms of vasculitides. ANCA, specific mostly for myeloperoxidase but also for other or unknown ANCA antigens, frequently revealing atypical immunofluorescence patterns, were characteristically found in other diseases. The titres of ANCA were significantly higher (p < 0.05) in patients with pauci-immune vasculitis than in those with clinically suspected vasculitis and other diseases. In conclusion, well standardised techniques for ANCA testing in conjunction with the clinical picture and histopathologic findings, if available, may significantly contribute to the diagnosis of small vessel vasculitides.     

Pulmonary hypertension in patients with connective tissue diseases]

Pulmonary hypertension (PH) is said to be frequently associated with connective tissue diseases (CTD). The national surveillance of CTD associated PH (CTD-PH) by the study groups of the Ministry of Health and Welfare (MHW) revealed that mixed connective tissue disease (MCTD) had the highest incidence of PH (5.02%), next to systemic sclerosis (SSc) (2.64%). Patients with CTD-PH could be divided into two groups according to the prognosis: poor prognosis group and fairly good prognosis group. Poor prognosis was associated statistically with polyarthritis and high level of CK. Treatment of CTD-PH was still difficult, but adrenocoticosteroids could be tried in some patients, and drip infusion therapy of prostacyclin seemed very promising, but it has not been accepted by the MHW so far.     

Abnormalities of serum antielastin antibodies in connective tissue diseases.

BACKGROUND: Antibodies (Abs) to alpha-elastin (elastin breakdown product) and tropoelastin (elastin precursor) are found in the serum of all human subjects and correlate with their respective serum peptide levels; however, peptide levels vary with age and some disease states. This study was undertaken to determine if serum elastin Abs, peptides, and elastin metabolism were altered in autoimmune diseases by detecting a changing ratio of serum anti-alpha:tropoelastin Ab levels. METHODS: Serum from patients with a variety of connective tissue diseases, including 28 with systemic lupus erythematosus (SLE), 24 with scleroderma, 18 with rheumatoid arthritis (RA), 10 with polymyositis, and 39 with vasculitis, was compared with serum from 19 age-matched healthy subjects for levels of antitropoelastin and anti-alpha-elastin Abs. RESULTS: We found an increase in IgG anti-alpha-elastin and a decrease in antitropoelastin Abs in the sera of patients with scleroderma (p < .02 and .00005) and SLE (p < .006 and .011). There was also a marked increase in anti-alpha-elastin Abs in patients with polyarteritis nodosa (p < .0005) and decreases in antitropoelastin Abs in patients with RA (p < .05), polymyositis (p < .01), and a variety of other vasculidities (p < .0003). CONCLUSIONS: Abnormal variations in elastin metabolism may be detected in several connective tissue diseases by measuring ratios of alpha- and tropoelastin IgG Abs as markers of elastin degradation and synthesis.     

Glycosaminoglycan excretion in connective tissue diseases

Abnormal glycosaminoglycan metabolism has been widely studied in cases of mucopolysaccharidoses (MPSD) with increased acid glycosaminoglycan (aGAG) excretion. A disorder in aGAG metabolism can be confirmed in several diseases with known etiology. We have carried out a comparative study on the urinary aGAG output in systemic connective tissue diseases and in childhood cases of MPSD. In children suffering from rheumatoid arthritis or scleroderma, the urinary aGAG output did not surpass 80% of the value excreted in MPSD; furthermore, 20 to 30% was uronic acid. In the case of osteogenesis imperfecta the remarkably high amount of excreted aGAG contained over 60% uronic acid.     

Antineutrophil cytoplasmic antibodies: clinical characteristics of 10 patients with the perinuclear pattern of immunofluorescence on ANCA testing.

Antineutrophil cytoplasmic antibodies (ANCA) have recently been described in association with necrotizing glomerulonephritis, systemic vasculitis, and other autoimmune-mediated connective tissue diseases, including systemic lupus erythematosus (SLE) and polychondritis. At least two distinct classes of ANCA have been described, differentiated by characteristic immunofluorescence patterns using neutrophils as substrate for indirect immunofluorescence assay (IFA). A focal, centrally accentuated, finely granular cytoplasmic staining pattern (c-ANCA) is both sensitive and specific for Wegener's granulomatosis (WG) and is thus a useful clinical adjunct in the diagnosis and monitoring of disease activity in WG. The second class of ANCA, defined by a perinuclear immunofluorescent staining pattern (p-ANCA) on standardized IFA, has not been studied as extensively. It appears to occur in a variety of connective tissue diseases, most often necrotizing glomerulonephritis other than WG, systemic vasculitis with renal involvement, and SLE. In screening more than 2000 serum samples received in our rheumatology laboratory for ANA testing, we found p-ANCA in 10 patients. All 10 had evidence of systemic autoimmune disease, though with wide variation in extent and severity of disease. All 10 had other autoantibodies, most frequently ANA (60%). Our studies suggest that p-ANCA define a heterogeneous patient population with a spectrum of autoimmune disease, most frequently necrotizing glomerulonephritis and systemic vasculitis. Future studies will establish the role of p-ANCA in clinical medicine and broaden our understanding of the origin and possible pathogenesis of ANCA and autoantibodies in general.     

Cyclophosphamide induces more chromosome damage than chlorambucil in patients with connective tissue diseases

The potential for damaging chromosomes of the powerful and widely-used immunosuppressive agent cyclophosphamide has been tested by measuring sister chromatid exchanges in blood lymphocytes of patients with connective tissue diseases. This agent induces more chromosome damage than chlorambucil emphasising the need for sensitive means of predicting patients at particular risk of drug-induced malignant disease.     

Anti-(U1) small nuclear RNA antibodies in anti-small nuclear ribonucleoprotein sera from patients with connective tissue diseases.

Small nuclear ribonucleoprotein (snRNP) particles are a class of RNA-containing particles in the nucleus of eukaryotic cells. Sera from patients with connective tissue diseases often contain antibodies against the proteins present in these snRNPs. Antibodies against the RNA components of snRNPs, the U snRNAs, are thought to be rare. We tested 118 anti-snRNP sera for the presence of anti-snRNA antibodies and found them in 45 sera (38%). In all sera the antibodies (IgG and F(ab)2 fragments thereof) were exclusively directed against U1 snRNA. The anti-(U1) RNA antibodies were always accompanied by anti-(U1)RNP antibodies but were not found in sera which contain antibodies of the Sm serotype directed against all nucleoplasmic U snRNP particles. Like anti-RNP antibodies, anti-U1 RNA activity is confined to sera from patients with SLE or SLE overlap syndromes and is rarely found in patients with other connective tissue diseases. By analyzing binding to subfragments of U1 snRNA made in vitro, it was demonstrated that anti-(U1)RNA antibodies recognize epitopes distributed throughout the U1 RNA molecule. In most sera, however, either the second or the fourth hairpin loop is the main target of the antibody. The possible mechanisms that could lead to the production of this new type of autoantibody are discussed.     

Treatment of chronic pain with millimetre wave therapy (MWT) in patients with diffuse connective tissue diseases: a pilot case series study.

BACKGROUND: Pain relief is reported to be the most common clinical application of electromagnetic millimetre waves. AIM: To evaluate safety and pain relief effect of millimetre wave therapy (MWT) for treatment of chronic joint pain in a group of patients with diffuse connective tissue diseases. METHODS: Twelve patients with diffuse connective tissue diseases received MWT in addition to their analgesic medication with non-steroidal anti-inflammatory drugs. MWT procedure included the exposure of tender points around the painful joints to electromagnetic waves with frequency 54-78GHz and power density of 2.5mW/cm(2). The time of exposure was 35 +/-5 min and the total number of sessions ranged from 5 to 10 (median 6). Intensity of pain, medication requirement, joint stiffness and subjective assessment of therapy success were measured before, during and immediately after the treatment, and after a 6-months follow-up. RESULTS: No adverse effects of MWT were noted. Pain intensity and required medication decreased significantly after the treatment (p<0.05) and remained at the same level throughout the follow-up period. The joint stiffness decreased and the subjective assessment of the treatment success after 6 month did not change except in only one patient. CONCLUSION: MWT applied to tender points around the affected joints was safe under the conditions of our study and after an appropriate full-scale double-blind clinical study, may be recommended as an effective adjunct therapy for chronic pain treatment in patients with diffuse connective tissue diseases.