Scleroderma-polymyositis Overlap Syndrome Research Articles

Calcinosis cutis universalis secondary to scleroderma-polymyositis overlap syndrome.

A 51-year-old woman with a diagnosis of scleroderma-polymyositis overlap syndrome presented to our rheumatology department with widespread subcutaneous skin lesions. On examination, widespread subcutaneous calcification was noted, affecting the elbows, shoulders, hips, knees, buttocks, and ankles. She was positive for anti-nuclear antibodies, anti-La, anti-Ro, and anti-PM-SCL-75 antibodies. Tests for parathyroid hormone, renal function, calcium, and vitamin D were normal. Extensive investigation including PET-CT and upper gastrointestinal endoscopy, and chest, abdomen, and pelvis CT excluded malignancy.

Anti-Ku Antibody-Related Scleroderma-Polymyositis Overlap Syndrome Associated With Hypothyroid Myopathy.

Anti-Ku Antibody-Related Scleroderma-Polymyositis Overlap Syndrome Associated With Hypothyroid Myopathy.

Management of extensor digitorum communis enlargement in a patient with scleroderma-polymyositis overlap syndrome

Overlap syndrome is a very rare condition defined by the coexistence of two connective tissue diseases in the same patient. We describe our experience with the surgical treatment of extensor digitorum communis involvement in the context of this infrequent disorder. A 42-year-old female with scleroderma-polymyositis overlap syndrome presented to our department with a suspected right-hand flexor tenosynovitis. Physical examination, imaging, and electromyographic studies demonstrated, however, an enlargement of the extensor digitorum communis tendons with an extension deficit of the fingers. Conservative management was unsuccessful, so we performed surgery to shorten the extensor tendons of the second, third, and fourth fingers of the right hand. The patient recovered hand mobility and her finger extension improved. She continues to maintain 160° extension of the metacarpophalangeal joints and is able to make a complete fist with her hand 18 months after surgery. Level of evidence: Level V, therapeutic study.

Relevance of clinical and autoantibody profiles in systemic sclerosis among Thais.

Autoantibody profiles in systemic sclerosis (SSc) and their relative clinical association vary between studies. The rate for being anti-topoisomerase-I (ATA) positive and the association with diffuse cutaneous the SSc subset (dcSSc) is higher among Thais than among Caucasians. The objective was to evaluate the relevance of clinical presentation, namely being positive for one or more autoantibodies among Thai SSc patients. A retrospective, cohort study was performed among SSc patients over 18years of age at Srinagarind Hospital, Khon Kaen University, Thailand, during January 2006 to December 2013. Autoantibodies comprising 13 SSc-specific antigens were evaluated using the EUROIMMUN AG (Lübeck, Germany) in order to define their clinical association(s). Two hundred and eighty-five scleroderma patients (200 female; 85 male) were included. The majority (66.7%) were dcSSc subset. ATA was the most common antibody profile in our patients (231 cases; 81.1%), followed by anti-Ro 52 (87 cases; 30.5%). Eleven of our patients (3.9%) were negative for all antibody profiles and 44 cases (15.4%) were negative for ATA and anti-centromere antibody (anti-CENP). Almost 40% (112 cases) were positive for at least two autoantibodies. There was an association between the presence of ATA and hand deformity (odds ratio [OR] 3.94; 95% CI 1.12-13.84), anti-CENP and hand deformity (OR 0.20; 95% CI 0.02-0.90), anti-Ku and scleroderma-polymyositis overlap syndrome (OR 6.58; 95% CI 2.16-19.39) and the absence of both ATA and anti-CENP with female sex (OR 2.90; 95% CI 1.12-7.51), limited cutaneous SSc subset (OR 2.70; 95% CI 1.30-5.55) and scleroderma-polymyositis overlap syndrome (OR 2.53; 95% CI 1.04-6.16). Neither ATA nor anti-CENP were associated with the SSc subset. ATA and anti-CENP were not helpful in differentiating the SSc subset in Thai SSc patients, albeit they were good for predicting hand function. Coexisting ATA and anti-CENP negativity were associated with less extensive skin tightness and SSc overlap syndrome.

Bilateral coxitis in scleroderma-polymyositis overlap syndrome.

Joint manifestations in scleroderma (Scl) and polymyositis (PM) are dominated by inflammatory arthralgia. Arthritis is less common and preferentially affects the hands, wrists, knees, and ankles. Involvement of the hip has been rarely reported in the literature. We report a case of coxitis diagnosed in a patient suffering from scleroderma-polymyositis overlap syndrome successfully treated by ultrasound-guided infiltration of triamcinolone hexacetonide.

Scleroderma-polymyositis overlap syndrome versus idiopathic polymyositis and systemic sclerosis: a descriptive study on clinical features and myopathology.

IntroductionThe objective was to characterize the clinical and myopathologic features of patients with scleroderma-polymyositis (SSc-PM) overlap compared with a population of patients with systemic sclerosis (SSc) and polymyositis (PM).MethodsA three-way comparison of patients with SSc-PM overlap (n = 25) with patients with SSc (n = 397) and PM (n = 40) on clinical and myopathologic features and causes of death. One neuropathologist blinded for the diagnosis evaluated all recent available muscle biopsies. Biopsies were scored for presence of inflammation, necrotic muscle fibers, rimmed vacuoles, fibrosis, and immunohistochemical staining. Clinical or myopathologic characteristics were compared by using the χ2 test or one-way analysis of variance (ANOVA).ResultsThe prevalence of SSc-PM overlap in the Nijmegen Systemic Sclerosis cohort was 5.9%. The mortality was 32% (eight of 25) in SSc-PM, of which half was related to cardiac diseases. The prevalence of pulmonary fibrosis was significantly increased in SSc-PM (83%) (P = 0.04) compared with SSc (49%) and PM (53%). SSc or myositis-specific antibodies were nearly absent in the SSc-PM group. In almost all biopsies (96%) of SSc-PM patients, necrotic muscle fibers were present, which was significantly increased compared with PM patients (P = 0.02).ConclusionsPatients with SSc-PM have increased prevalence of pulmonary fibrosis and cardiac disease as the cause of death compared with patients with SSc and PM . In addition, we found that necrotizing muscle fibers with inflammation characterize SSc-PM overlap in muscle biopsies. Further research should focus on underlying mechanisms causing necrosis, inflammation, and fibrosis and their relation to pulmonary involvement and mortality in patients with SSc-PM overlap.

PReS-FINAL-2125: A Japanese girl with childhood-onset anti-Ku antibody positive generalized morphea-myositis overlap syndrome

Anti-Ku antibodies are autoantibodies against the P70/80 DNA-PK activated factor. These antibodies were identified in patients with scleroderma-polymyositis overlap syndrome by Mimori et al., and have subsequently been identified in approximately 1% of children with overlap syndromes.

A case of scleroderma-polymyositis overlap syndrome in which octreotide exacerbated abdominal symptoms

A case of sclerodermapolymyositis overlap syndrome in which octreotide exacerbated abdominal symptoms Chisako SUZUKI1, Mikiko OHARA1, Motohisa YAMAMOTO1, Yasuyoshi NAISHIRO1, Hiroyuki YAMAMOTO1, Hiroki TAKAHASHI1, Takashi ABE2 and Kohzoh IMAI1 1First Department of Internal Medicine, Sapporo Medical University, School of Medicine 2Department of Internal MedicineRheumatology, Kushiro City General Hospital

Expression of the costimulatory molecule BB-1 and its receptors in patients with scleroderma–polymyositis overlap syndrome

We investigated expression of costimulatory molecules BB-1, B7-1 (CD80), B7-2 (CD86), and their counter-receptors CD28 and CTLA-4 (CD152) in muscle biopsy specimens of patients with scleroderma–polymyositis overlap syndrome (SSc–PM), primary polymyositis (PM), and other related diseases to examine whether the muscle fibers in patients with SSc–PM behave as antigen-presenting cells (APCs). The major histocompatibility (MHC) class II-positive muscle fibers of SSc–PM patients reacted with monoclonal antibodies (mAb) against BB-1 but not against B7-1 or B7-2. The CD4+ T cells expressed the counter-receptors CD28 and CTLA-4, and bound with the BB-1-positive muscle fibers in cell-to-cell contact. Our findings show that muscle fibers in patients with SSc–PM function as “professional” APCs in a way distinct from muscle fibers in patients with primary PM.

Anti-U5 snRNP antibody as a possible serological marker for scleroderma-polymyositis overlap.

To determine the prevalence of the anti-U5 small nuclear ribonucleoprotein (snRNP) antibody in patients with systemic sclerosis. Sera from 281 patients with systemic sclerosis, including 10 patients with overlapping polymyositis, were assayed using RNA immunoprecipitation and protein immunoprecipitation. Only one serum sample showed precipitation of U5 snRNA with scarce precipitation of U2, U1, U4 and U6 snRNAs. In addition, the serum precipitated a 200 kDa protein. The serum was from a 35-yr-old Japanese male patient with overlapping systemic sclerosis and polymyositis accompanied by large-cell lung carcinoma. The clinical appearance was similar to that of a case reported previously. The presence of the anti-U5 snRNP antibody in serum may be specific for scleroderma-polymyositis overlap syndrome.

Autoantibodies against DNA double-strand break repair proteins.

Autoantibodies against cellular components are commonly present in sera from patients with systemic rheumatic diseases and may play an important role in pathogenesis. The Ku protein was recognized 20 years ago as a major target of autoantibodies in a subset of Japanese patients with scleroderma-polymyositis overlap syndrome, and anti-Ku antibodies have since been shown to occur in 10-20% of patients with these and other systemic rheumatic diseases, including systemic lupus erythematosus. Ku functions physiologically in the repair of DNA double-strand breaks, where it carries out the initial recognition of damaged DNA ends. The three dimensional structure of the Ku-DNA complex has recently been solved, and helps illuminate the relationship between the autoimmune epitopes and other features of the protein. In addition to Ku, three other polypeptides in the same DNA repair pathway have more recently been identified as autoantigens: the DNA-dependent protein kinase catalytic subunit, DNA ligase IV, and XRCC4. Two hypotheses have been invoked to explain the ability of these proteins to elicit an autoimmune response in susceptible individuals. One is that DNA damage induces formation of nucleoprotein complexes that present novel composite or conformational epitopes. The other is that cleavage of these proteins by caspases or Granzyme B leads to presentation of immunocryptic peptides capable of stimulating autoreactive T lymphocytes. In the case of DNA double-strand break repair proteins, there is evidence that both of these mechanisms may be at work. Because of their role in the maintenance of genome stability, DNA double-strand break repair proteins have been the subject of intense study, and a wealth of new structural, biochemical and functional information makes them excellent models for investigation of the humoral autoimmune response.

CT appearance of pulmonary vasculitis in children.

The aim of this study was to determine whether a CT pattern that may represent early or subtle changes of pulmonary vasculitis in children exists. High-resolution CT scans of the chest for 107 children were retrospectively reviewed by two radiologists who were unaware of the original study findings. Chest CT scans (conventional) for another 54 children who had symptoms or a diagnosis of vasculitis also were reviewed. We identified hazy or fluffy centrilobular, perivascular densities in 10 children, two of whom had small airways disease and eight of whom had vasculitis (Wegener's granulomatosis [n = 5], systemic lupus erythematosus [n = 1], scleroderma-polymyositis overlap syndrome [n = 1], and Churg-Strauss syndrome [n = 1]). The latter eight children underwent 35 scans, 17 of which were positive for these perivascular densities. All positive scans were associated with active disease of new onset (5/17) or with clinical exacerbation of preexisting systemic disease (12/17). The positive scans also were associated with an elevated erythrocyte sedimentation rate (13/17) and biopsy evidence of vasculitis from a variety of sites, including the lungs (n = 1), kidneys (n = 7), oropharynx (n = 5), skin (n = 9), lymph nodes (n = 1), and myocardium (n = 2). The single lung biopsy showed an angiocentric inflammatory-hemorrhagic process. Of the five patients who had positive scans, underwent therapy, and then had repeat studies, four patients had scans revert to normal in association with inactive disease. The remaining patient whose scan did not normalize failed to respond to treatment. The fluffy centrilobular pattern likely represents subtle changes of pulmonary vasculitis. In the appropriate clinical setting, such a finding may obviate the need for a lung biopsy.

Analysis of the mechanism of interaction of simian Ku protein with DNA

Ku protein is a relatively abundant DNA-binding protein which was first detected as the autoantigen in a patient with scleroderma-polymyositis overlap syndrome (hence the name 'Ku'). It is a heterodimer of two polypeptide chains of molecular weights 85,000 and 72,000, and it characteristically binds, in vitro, to the ends of DNA fragments, and translocates to form regular multimeric complexes, with one protein bound per 30 bp of DNA. We have studied the mechanism of interaction of Ku protein with DNA in vitro, using protein extracted from cultured monkey cells. We find that the precise structure of the DNA ends is not important for binding, as Ku protein can bind to hairpin loops and to mononucleosomes. Bound protein also does not require DNA ends for continued binding, since complexes formed with linear DNAs can be circularized by DNA ligase. Dissociation of the complex also appears to require DNA ends, since ligase closed circular complexes were found to be extremely stable even in the presence of 2 M NaCl. We also found that Ku molecules slide along DNA, with no preferential binding to specific sequences. Thus, Ku protein behaves like a bead threaded on a DNA string, a binding mechanism which allows us to make a new hypothesis concerning the function of this protein in the nucleus.

Isolation and characterization of cDNA encoding the 80-kDa subunit protein of the human autoantigen Ku (p70/p80) recognized by autoantibodies from patients with scleroderma-polymyositis overlap syndrome.

Anti-Ku (p70/p80) autoantibodies in patients with scleroderma-polymyositis overlap syndrome recognize a 70-kDa/80-kDa protein heterodimer which binds to terminal regions of double-stranded DNA. In the present study, we isolated full-length cDNAs that encode the 80-kDa Ku subunit. Initial screening of a human spleen cDNA library with anti-Ku antibodies yielded a cDNA of 1.0 kilobase (kb) (termed K71) encoding a portion of the 80-kDa Ku polypeptide (identification based on immunological criteria). In RNA blots, this cDNA hybridized with two mRNAs of 3.4 and 2.6 kb. In rescreening of a cDNA library constructed from simian virus 40-transformed human fibroblast mRNA with the K71 cDNA as a hybridization probe, three positive clones were isolated, and that bearing the longest insert (termed Ku80-6) was selected for further characterization. In vitro transcription and translation experiments produced an immunoprecipitable polypeptide which comigrated with the 80-kDa Ku subunit. The Ku80-6 cDNA proved to be 3304 nucleotides in length, with an additional poly(A) tail, closely approximating the size of the larger mRNA. It contains a single long open reading frame encoding 732 amino acids (Mr = 82,713). The putative polypeptide has a high content of acidic amino acids and a region with periodic repeat of leucine in every seventh position which may form the "leucine zipper" structure. In genomic DNA blots, probes derived from the opposite ends of cDNA Ku80-6 hybridized with several nonoverlapping restriction fragments from human leukocyte DNA, indicating that the gene encoding the 80-kDa Ku polypeptide is divided into several exons by intervening sequences.

Scleroderma-polymyositis overlap syndrome. Clinical and serologic aspects.

Scleroderma-polymyositis overlap syndrome. Clinical and serologic aspects.

Identification of human anti-DNA, anti-RNP, anti-SM, and anti-SS-A serum antibodies bearing the cross-reactive 16/6 idiotype.

The human idiotype 16/6, characteristic of lupus-derived anti-DNA autoantibodies, was detected in sera of Japanese patients with autoimmune diseases. The 16/6-positive sera were from patients with active SLE and, in one case, a scleroderma-polymyositis overlap syndrome; all contained anti-ssDNA antibody. Affinity chromatography was used to isolate 16/6-bearing Ig from sera of seven patients having anti-DNA and other autoantibodies. In a preliminary step, rheumatoid factors and nonspecific binding were removed by four passes of the serum through a column of immobilized normal rabbit gamma-globulin. The absorbed sera were then applied to a column of immobilized specific rabbit anti-16/6 globulin. This combined procedure depleted anti-ssDNA activity selectively. From 44 to 60% of total Ig but only 6 to 25% of anti-ssDNA activity was recovered in the material that passed through both columns. Approximately 40% of the anti-RNP/Sm and anti-SS-A/SS-B activities were recovered, reflecting a lesser degree of selective depletion of these antibodies. The specific eluate from the anti-idiotype column contained more IgG than IgM; anti-DNA activity; anti-RNP, anti-Sm, or anti-SS-A activity. Soluble DNA inhibited the binding of one eluate to RNP/Sm but not of another eluate to SS-A/SS-B. The results confirm that the genes encoding the 16/6 idiotype are widely represented in ethnically different human populations, and indicate that 16/6-bearing Ig may bind to other autoantigens as well as to DNA.

Characterization of the DNA-binding protein antigen Ku recognized by autoantibodies from patients with rheumatic disorders.

We have characterized the biochemical nature of the Ku protein, the antigen recognized by autoantibodies from certain patients with scleroderma-polymyositis overlap syndrome. From extracts of HeLa cells labeled with [32P]orthophosphate, anti-Ku antibodies precipitated a high molecular weight nucleic acid identified as DNA because of sensitivity to DNase I and resistance to RNase. From extracts of cells labeled with [35S] methionine, these antibodies precipitated two polypeptides of 70,000 and 80,000 Da. These proteins were purified using immunoaffinity column chromatography. In immunoblots most sera containing anti-Ku antibodies recognized both Ku proteins but one serum bound only to the 70,000-Da subunit. When nucleosomal segments of chromatin were used as antigen, anti-Ku antibodies precipitated dinucleosomes and larger forms of chromatin but not mononucleosomes. Thus, the Ku antigen is a novel DNA-binding protein that is at least partially exposed on nucleosomal segments of chromatin.

Autoantibodies to the U2 small nuclear ribonucleoprotein in a patient with scleroderma-polymyositis overlap syndrome.

Autoantibodies directed against the U2 small nuclear ribonucleoprotein (snRNP) have been found in the serum of a patient with scleroderma-polymyositis overlap syndrome. This specificity, called anti-(U2)-RNP, is distinct from all previously described autoantibodies, including those that precipitate related snRNPs: anti-Sm antibodies, which react with the entire set of U1, U2, U4, U5, and U6 snRNPs, and anti-(U1)RNP antibodies, which recognize only U1 snRNPs. From HeLa cell extracts, anti-(U2)RNP immunoprecipitates predominantly one 32P-labeled RNA species, identified as U2 small nuclear RNA, and six [35S]methionine-labeled protein bands, A' (Mr = 32,000), B (Mr = 28,000), D (Mr = 16,000), E (Mr = 13,000), F (Mr = 12,000), and G (Mr = 11,000). Protein blot analysis reveals that the A' protein carries (U2)RNP antigenic determinant(s) and therefore represents a polypeptide unique to the U2 snRNP; the B protein associated with U2 snRNPs may also be unique. Like U1 and the other Sm snRNPs, U2 snRNPs occupy a nuclear, non-nucleolar location and are antigenically conserved from insects to man. An antibody specific for the U2 snRNP will be useful in deciphering the function of this particle.