Scleroderma-polymyositis Overlap 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.

Scleroderma overlap syndromes

Scleroderma overlap syndromes

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.

SP0099 Myopathy in systemic sclerosis

Patients with systemic sclerosis (SSc) frequently report muscle weakness. The prevalence of muscle involvement in SSc, however, varies largely, and numbers range from 5-96%. Muscle weakness due to direct involvement...

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

Autoantibodies in systemic sclerosis and fibrosing syndromes: clinical indications and relevance

Systemic sclerosis, or scleroderma, is associated with a variety of autoantibodies, each of them having their own clinical associations. The fibrosing disorders, other than systemic sclerosis, represent a diverse group of diseases with systemic or localized effect and with limited understanding of their pathogenesis. The purpose of this review is to analyze the literature on the clinical usefulness of examining serum autoantibodies in patients with known or suspected scleroderma and fibrosing disorders. Studies on autoantibodies within the past year highlight their clinical utility in systemic sclerosis. Anticentromere antibodies are most often seen with limited cutaneous involvement and lower frequency of pulmonary fibrosis and lower mortality (despite an increased risk for pulmonary hypertension) compared with anti-Scl-70 and antinucleolar antibodies. Anti-Scl-70 antibodies are associated with diffuse cutaneous involvement, increased frequency of pulmonary fibrosis, and higher mortality. The anti-polymyositis-scleroderma autoantibody is associated with the polymyositis-scleroderma overlap syndrome. Anti-Th/To antibodies are associated with milder skin and systemic involvement but with more severe pulmonary fibrosis and overall worse prognosis. Anti-RNA-polymerase family antibodies and antifibrillarin antibodies are predictive of diffuse cutaneous and systemic involvement and greater mortality. Less specific autoantibodies for systemic sclerosis and limited data on some other autoantibodies limit their clinical utility in patients with systemic sclerosis. For the most part, the association between autoantibodies and fibrosing disorders other than systemic sclerosis remains inconclusive. Autoantibodies in systemic sclerosis provide important and prognostic information and are useful in defining clinical subsets of the disease. When used appropriately, they can be a useful instrument in the management of scleroderma.

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.

Identification of an alpha-helical epitope region on the PM/Scl-100 autoantigen with structural homology to a region on the heterochromatin p25beta autoantigen using immobilized overlapping synthetic peptides.

The polymyositis-scleroderma overlap syndrome (PM/Scl) autoantigen is a nucleolar multiprotein particle, presumably participating in the maturation of 5.8S rRNAs. The major target antigens of this particle are two polypeptides with apparent molecular masses of 100 and 75 kDa. In this study we identified the major linear epitopes along the PM/Scl-100 protein sequence by probing overlapping oligopeptides with anti-PM/Scl autoantisera. A major epitope region was identified between amino acids 231 and 245 of the PM/Scl-100 polypeptide. Mutational analysis of the corresponding peptide LDVPPALADFIHQQR by glycine-walk followed by immunodetection of the resulting peptides indicated that amino acids 234, 237, 240, and 241 of the PM/Scl-100 autoantigen are essential for binding of the corresponding antibodies. These results allow us to propose a local alpha-helical secondary structure for the PM/Scl-100 major epitope region. A homology search with the peptide LDVPPALADFIHQQR against the Swiss-Model three-dimensional database reveals some topological homology of the PM/Scl-100 major epitope region with the heterochromatin modifier protein p25beta, a known autoantigen recognized by antibodies from a subset of scleroderma patients.

The yeast exosome and human PM-Scl are related complexes of 3' --> 5' exonucleases.

We previously identified a complex of 3' --> 5' exoribonucleases, designated the exosome, that is expected to play a major role in diverse RNA processing and degradation pathways. Further biochemical and genetic analyses have revealed six novel components of the complex. Therefore, the complex contains 11 components, 10 of which are predicted to be 3' --> 5' exoribonucleases on the basis of sequence homology. Human homologs were identified for 9 of the 11 yeast exosome components, three of which complement mutations in the respective yeast genes. Two of the newly identified exosome components are homologous to known components of the PM-Scl particle, a multisubunit complex recognized by autoimmune sera of patients suffering from polymyositis-scleroderma overlap syndrome. We demonstrate that the homolog of the Rrp4p exosome subunit is also a component of the PM-Scl complex, thereby providing compelling evidence that the yeast exosome and human PM-Scl complexes are functionally equivalent. The two complexes are similar in size, and biochemical fractionation and indirect immunofluorescence experiments show that, in both yeast and humans, nuclear and cytoplasmic forms of the complex exist that differ only by the presence of the Rrp6p/PM-Scl100 subunit exclusively in the nuclear complex.

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.

Cloning of a complementary DNA coding for the 100-kD antigenic protein of the PM-Scl autoantigen.

Anti-PM-Scl antibodies are associated with polymyositis-scleroderma overlap or either disease alone. Among sera from 39 patients with anti-PM-Scl, 23 recognized the 100-kD band in immunoblot against HeLa cell extract, 16 of which also stained the 70-kD band. A human thymocyte lambda gt11 cDNA expression library was screened with anti-PM-Scl serum, and two clones were identified whose products reacted with 33 and 37 of 39 anti-PM-Scl sera, respectively, but none of 26 negative control sera. Affinity-purified antibody reacting specifically with plaques of the clone stained the 100-kD band on immunoblot, reacted with nucleoli of HEp-2 cells, and immunoprecipitated the PM-Scl protein complex. Partial sequences of both inserts were identical. One insert was fully sequenced, and additional 5' and 3' sequence was obtained using a gene-specific primer to form a cDNA with HeLa cell RNA as template followed by PCR. The complete nucleotide sequence included 2,739-bp coding for a predicted full-length protein of 98,088 D. There was no homology with the PM-Scl 75-kD protein and no significant homology with other proteins. A mixed-charge cluster was identified, with 22 charged amino acids of 37. In conclusion, the full-length cDNA sequence was determined coding for the PM-Scl 100-kD protein, the most commonly antigenic protein of the PM-Scl complex.

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.