{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T12:15:47Z","timestamp":1791807347512,"version":"4.3.4"},"reference-count":30,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,12,1]],"date-time":"2019-12-01T00:00:00Z","timestamp":1575158400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2019,12,2]],"date-time":"2019-12-02T00:00:00Z","timestamp":1575244800000},"content-version":"vor","delay-in-days":1,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Arthritis Res Ther"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n<jats:title>Background\/purpose<\/jats:title>\n<jats:p>Elevated levels of C-reactive protein (CRP) in systemic sclerosis (SSc) have been linked to early inflammatory stages of the disease. This study has been designed to investigate CRP levels longitudinally in a cohort of SSc patients and to correlate these findings with comorbidities and disease characteristics.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Methods<\/jats:title>\n<jats:p>In this retrospective study, patients with SSc treated at the outpatient clinic of the Department of Rheumatology and Clinical Immunology, University Medical Center Freiburg, were analyzed. Only patients with at least three consecutive visits and at least 1\u00a0year follow-up were included in this study. CRP serum levels were measured at every visit and categorized as positive if CRP concentrations were \u2265\u20095\u2009mg\/l. Subjects with elevated CRP levels at more than 80% of visits were defined as inflammatory SSc. The longitudinal CRP profiles were correlated with disease characteristics and comorbidities.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Results<\/jats:title>\n<jats:p>A total of 1815 consecutive visits of 131 SSc patients were analyzed. Over the observed time span (7.6 (1.0\u201319.5) years), 18.3% (<jats:italic>n<\/jats:italic>\u2009=\u200924) of patients had continuously elevated CRP levels (inflammatory SSc), whereas in 29% (<jats:italic>n<\/jats:italic>\u2009=\u200938), CRP levels were always in the normal range. There was no association between disease duration and CRP levels at first visit. Inflammatory SSc was associated with male gender (<jats:italic>p<\/jats:italic>\u2009=\u20090.022), anti-Scl-70 antibodies (<jats:italic>p<\/jats:italic>\u2009=\u20090.009), diffuse cutaneous SSc (<jats:italic>p<\/jats:italic>\u2009=\u20090.036), pulmonary fibrosis (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001), rheumatoid arthritis (<jats:italic>p<\/jats:italic>\u2009=\u20090.007), and cardiac arrhythmia (<jats:italic>p<\/jats:italic>\u2009=\u20090.048). Moreover, patients with inflammatory SSc revealed higher modified Rodnan skin scores (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001); lower forced vital capacity (FVC) (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001), total lung capacity (<jats:italic>p<\/jats:italic>\u2009=\u20090.001), and diffusing capacity (<jats:italic>p<\/jats:italic>\u2009=\u20090.008); and faster decline of FVC per year (<jats:italic>p<\/jats:italic>\u2009=\u20090.007). Even treatment with cyclophosphamide (CYC) did not decrease CRP levels (<jats:italic>p<\/jats:italic>\u2009=\u20090.754).<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Conclusion<\/jats:title>\n<jats:p>Inflammatory SSc is characterized by a more severe phenotype, high morbidity, and a large proportion of male patients. Even treatment with CYC does not alter CRP levels in this subpopulation with a high unmet medical need.<\/jats:p>\n<\/jats:sec>","DOI":"10.1186\/s13075-019-2057-x","type":"journal-article","created":{"date-parts":[[2019,12,2]],"date-time":"2019-12-02T10:09:09Z","timestamp":1575281349000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Inflammatory stays inflammatory: a subgroup of systemic sclerosis characterized by high morbidity and inflammatory resistance to cyclophosphamide"],"prefix":"10.1186","volume":"21","author":[{"given":"Aleksey","family":"Mitev","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Christ","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daria","family":"Feldmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moritz","family":"Binder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim","family":"M\u00f6ller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna-Maria","family":"Kanne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"H\u00fcgle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter M.","family":"Villiger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reinhard E.","family":"Voll","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Finzel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8172-1285","authenticated-orcid":false,"given":"Florian","family":"Kollert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,12,2]]},"reference":[{"issue":"11","key":"2057_CR1","doi-asserted-by":"publisher","first-page":"1747","DOI":"10.1136\/annrheumdis-2013-204424","volume":"72","author":"F van den Hoogen","year":"2013","unstructured":"van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, et al. 2013 classification criteria for systemic sclerosis: an American college of rheumatology\/European league against rheumatism collaborative initiative. Ann Rheum Dis. 2013;72(11):1747\u201355.","journal-title":"Ann Rheum Dis"},{"issue":"24","key":"2057_CR2","doi-asserted-by":"publisher","first-page":"2490","DOI":"10.1001\/jama.2014.6368","volume":"311","author":"JM van Laar","year":"2014","unstructured":"van Laar JM, Farge D, Sont JK, Naraghi K, Marjanovic Z, Larghero J, et al. Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial. Jama. 2014;311(24):2490\u20138.","journal-title":"Jama."},{"issue":"1","key":"2057_CR3","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1056\/NEJMoa1703327","volume":"378","author":"KM Sullivan","year":"2018","unstructured":"Sullivan KM, Goldmuntz EA, Keyes-Elstein L, McSweeney PA, Pinckney A, Welch B, et al. Myeloablative autologous stem-cell transplantation for severe scleroderma. N Engl J Med. 2018;378(1):35\u201347.","journal-title":"N Engl J Med"},{"issue":"9013","key":"2057_CR4","doi-asserted-by":"publisher","first-page":"1453","DOI":"10.1016\/S0140-6736(96)91687-6","volume":"347","author":"C.P. Denton","year":"1996","unstructured":"Denton CP, Black CM, Korn JH, de Crombrugghe B. Systemic sclerosis: current pathogenetic concepts and future prospects for targeted therapy. Lancet. 1996;347(9013):1453\u20138.","journal-title":"The Lancet"},{"issue":"3","key":"2057_CR5","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1042\/bj2650621","volume":"265","author":"PC Heinrich","year":"1990","unstructured":"Heinrich PC, Castell JV, Andus T. Interleukin-6 and the acute phase response. Biochem J. 1990;265(3):621\u201336.","journal-title":"Biochem J"},{"issue":"9","key":"2057_CR6","doi-asserted-by":"publisher","first-page":"1405","DOI":"10.1002\/acr.21716","volume":"64","author":"C Muangchan","year":"2012","unstructured":"Muangchan C, Harding S, Khimdas S, Bonner A, Canadian Scleroderma Research g, Baron M, et al. Association of C-reactive protein with high disease activity in systemic sclerosis: results from the Canadian Scleroderma Research Group. Arthritis Care Res. 2012;64(9):1405\u201314.","journal-title":"Arthritis Care Res"},{"issue":"8","key":"2057_CR7","doi-asserted-by":"publisher","first-page":"1375","DOI":"10.1002\/acr.21968","volume":"65","author":"X Liu","year":"2013","unstructured":"Liu X, Mayes MD, Pedroza C, Draeger HT, Gonzalez EB, Harper BE, et al. Does C-reactive protein predict the long-term progression of interstitial lung disease and survival in patients with early systemic sclerosis? Arthritis Care Res. 2013;65(8):1375\u201380.","journal-title":"Arthritis Care Res"},{"issue":"6","key":"2057_CR8","doi-asserted-by":"publisher","first-page":"1112","DOI":"10.1093\/rheumatology\/kew017","volume":"55","author":"M Cossu","year":"2016","unstructured":"Cossu M, Andracco R, Santaniello A, Marchini M, Severino A, Caronni M, et al. Serum levels of vascular dysfunction markers reflect disease severity and stage in systemic sclerosis patients. Rheumatology. 2016;55(6):1112\u20136.","journal-title":"Rheumatology."},{"issue":"1","key":"2057_CR9","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1136\/ard.2006.066340","volume":"67","author":"L Czirjak","year":"2008","unstructured":"Czirjak L, Kumanovics G, Varju C, Nagy Z, Pakozdi A, Szekanecz Z, et al. Survival and causes of death in 366 Hungarian patients with systemic sclerosis. Ann Rheum Dis. 2008;67(1):59\u201363.","journal-title":"Ann Rheum Dis"},{"issue":"1","key":"2057_CR10","first-page":"68","volume":"30","author":"Y Allanore","year":"2003","unstructured":"Allanore Y, Borderie D, Lemarechal H, Cherruau B, Ekindjian OG, Kahan A. Correlation of serum collagen I carboxyterminal telopeptide concentrations with cutaneous and pulmonary involvement in systemic sclerosis. J Rheumatol. 2003;30(1):68\u201373.","journal-title":"J Rheumatol"},{"issue":"2","key":"2057_CR11","first-page":"165","volume":"23","author":"Z Nagy","year":"2005","unstructured":"Nagy Z, Czirjak L. Increased levels of amino terminal propeptide of type III procollagen are an unfavourable predictor of survival in systemic sclerosis. Clin Exp Rheumatol. 2005;23(2):165\u201372.","journal-title":"Clin Exp Rheumatol"},{"issue":"2 Suppl 76","key":"2057_CR12","first-page":"122","volume":"31","author":"C Muangchant","year":"2013","unstructured":"Muangchant C, Pope JE. The significance of interleukin-6 and C-reactive protein in systemic sclerosis: a systematic literature review. Clin Exp Rheumatol. 2013;31(2 Suppl 76):122\u201334.","journal-title":"Clin Exp Rheumatol"},{"issue":"Suppl 113(4)","key":"2057_CR13","first-page":"126","volume":"36","author":"L Ross","year":"2018","unstructured":"Ross L, Stevens W, Rabusa C, Wilson M, Ferdowsi N, Walker J, et al. The role of inflammatory markers in assessment of disease activity in systemic sclerosis. Clin Exp Rheumatol. 2018;36(Suppl 113(4)):126\u201334.","journal-title":"Clin Exp Rheumatol"},{"issue":"8","key":"2057_CR14","doi-asserted-by":"publisher","first-page":"816","DOI":"10.1016\/j.autrev.2018.02.008","volume":"17","author":"S Panopoulos","year":"2018","unstructured":"Panopoulos S, Bournia VK, Konstantonis G, Fragiadaki K, Sfikakis PP, Tektonidou MG. Predictors of morbidity and mortality in early systemic sclerosis: long-term follow-up data from a single-centre inception cohort. Autoimmun Rev. 2018;17(8):816\u201320.","journal-title":"Autoimmun Rev"},{"issue":"4","key":"2057_CR15","doi-asserted-by":"publisher","first-page":"999","DOI":"10.1007\/s10067-017-3936-7","volume":"37","author":"M Rubio-Rivas","year":"2018","unstructured":"Rubio-Rivas M, Corbella X, Pestana-Fernandez M, Tolosa-Vilella C, Guillen-Del Castillo A, Colunga-Arguelles D, et al. First clinical symptom as a prognostic factor in systemic sclerosis: results of a retrospective nationwide cohort study. Clin Rheumatol. 2018;37(4):999\u20131009.","journal-title":"Clin Rheumatol"},{"issue":"4","key":"2057_CR16","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1016\/j.semarthrit.2008.06.002","volume":"39","author":"FF Al-Dhaher","year":"2010","unstructured":"Al-Dhaher FF, Pope JE, Ouimet JM. Determinants of morbidity and mortality of systemic sclerosis in Canada. Semin Arthritis Rheum. 2010;39(4):269\u201377.","journal-title":"Semin Arthritis Rheum"},{"issue":"10","key":"2057_CR17","doi-asserted-by":"publisher","first-page":"1809","DOI":"10.1136\/ard.2009.114264","volume":"69","author":"AJ Tyndall","year":"2010","unstructured":"Tyndall AJ, Bannert B, Vonk M, Airo P, Cozzi F, Carreira PE, et al. Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database. Ann Rheum Dis. 2010;69(10):1809\u201315.","journal-title":"Ann Rheum Dis"},{"issue":"11","key":"2057_CR18","doi-asserted-by":"publisher","first-page":"1897","DOI":"10.1136\/annrheumdis-2017-211448","volume":"76","author":"M Elhai","year":"2017","unstructured":"Elhai M, Meune C, Boubaya M, Avouac J, Hachulla E, Balbir-Gurman A, et al. Mapping and predicting mortality from systemic sclerosis. Ann Rheum Dis. 2017;76(11):1897\u2013905.","journal-title":"Ann Rheum Dis"},{"issue":"Suppl 106(4)","key":"2057_CR19","first-page":"89","volume":"35","author":"M Freire","year":"2017","unstructured":"Freire M, Rivera A, Sopena B, Tolosa Vilella C, Guillen-Del Castillo A, Colunga Arguelles D, et al. Clinical and epidemiological differences between men and women with systemic sclerosis: a study in a Spanish systemic sclerosis cohort and literature review. ClinExp Rheumatol. 2017;35(Suppl 106(4)):89\u201397.","journal-title":"ClinExp Rheumatol"},{"issue":"2","key":"2057_CR20","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1093\/rheumatology\/kel252","volume":"46","author":"C Salliot","year":"2007","unstructured":"Salliot C, Mouthon L, Ardizzone M, Sibilia J, Guillevin L, Gottenberg JE, et al. Sjogren\u2019s syndrome is associated with and not secondary to systemic sclerosis. Rheumatology. 2007;46(2):321\u20136.","journal-title":"Rheumatology."},{"issue":"5","key":"2057_CR21","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1002\/art.1780370518","volume":"37","author":"A Akesson","year":"1994","unstructured":"Akesson A, Scheja A, Lundin A, Wollheim FA. Improved pulmonary function in systemic sclerosis after treatment with cyclophosphamide. Arthritis Rheum. 1994;37(5):729\u201335.","journal-title":"Arthritis Rheum"},{"issue":"12","key":"2057_CR22","doi-asserted-by":"publisher","first-page":"1425","DOI":"10.1111\/1346-8138.14669","volume":"45","author":"Hayakazu Sumida","year":"2018","unstructured":"Sumida H, Asano Y, Tamaki Z, Aozasa N, Taniguchi T, Toyama T, et al. Prediction of therapeutic response before and during i.v. cyclophosphamide pulse therapy for interstitial lung disease in systemic sclerosis: a longitudinal observational study. J Dermatol. 2018;45(12):1425\u201333.","journal-title":"The Journal of Dermatology"},{"issue":"10038","key":"2057_CR23","doi-asserted-by":"publisher","first-page":"2630","DOI":"10.1016\/S0140-6736(16)00232-4","volume":"387","author":"D Khanna","year":"2016","unstructured":"Khanna D, Denton CP, Jahreis A, van Laar JM, Frech TM, Anderson ME, et al. Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial. Lancet. 2016;387(10038):2630\u201340.","journal-title":"Lancet."},{"issue":"9","key":"2057_CR24","doi-asserted-by":"publisher","first-page":"1362","DOI":"10.1136\/annrheumdis-2018-213031","volume":"77","author":"CP Denton","year":"2018","unstructured":"Denton CP, Ong VH, Xu S, Chen-Harris H, Modrusan Z, Lafyatis R, et al. Therapeutic interleukin-6 blockade reverses transforming growth factor-beta pathway activation in dermal fibroblasts: insights from the faSScinate clinical trial in systemic sclerosis. Ann Rheum Dis. 2018;77(9):1362\u201371.","journal-title":"Ann Rheum Dis"},{"issue":"1","key":"2057_CR25","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/j.clim.2010.06.017","volume":"137","author":"DV Pechkovsky","year":"2010","unstructured":"Pechkovsky DV, Prasse A, Kollert F, Engel KM, Dentler J, Luttmann W, et al. Alternatively activated alveolar macrophages in pulmonary fibrosis-mediator production and intracellular signal transduction. Clin Immunol. 2010;137(1):89\u2013101.","journal-title":"Clin Immunol"},{"issue":"7","key":"2057_CR26","doi-asserted-by":"publisher","first-page":"781","DOI":"10.1164\/rccm.200509-1518OC","volume":"173","author":"A Prasse","year":"2006","unstructured":"Prasse A, Pechkovsky DV, Toews GB, Jungraithmayr W, Kollert F, Goldmann T, et al. A vicious circle of alveolar macrophages and fibroblasts perpetuates pulmonary fibrosis via CCL18. Am J Respir Crit Care Med. 2006;173(7):781\u201392.","journal-title":"Am J Respir Crit Care Med"},{"issue":"5","key":"2057_CR27","doi-asserted-by":"publisher","first-page":"1685","DOI":"10.1002\/art.22559","volume":"56","author":"A Prasse","year":"2007","unstructured":"Prasse A, Pechkovsky DV, Toews GB, Schafer M, Eggeling S, Ludwig C, et al. CCL18 as an indicator of pulmonary fibrotic activity in idiopathic interstitial pneumonias and systemic sclerosis. Arthritis Rheum. 2007;56(5):1685\u201393.","journal-title":"Arthritis Rheum"},{"issue":"1","key":"2057_CR28","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1038\/s41572-019-0106-z","volume":"5","author":"P Libby","year":"2019","unstructured":"Libby P, Buring JE, Badimon L, Hansson GK, Deanfield J, Bittencourt MS, et al. Atherosclerosis. Nature Reviews Disease Primers. 2019;5(1):56.","journal-title":"Nature Reviews Disease Primers"},{"issue":"7","key":"2057_CR29","doi-asserted-by":"publisher","first-page":"1488","DOI":"10.3899\/jrheum.091165","volume":"37","author":"J Avouac","year":"2010","unstructured":"Avouac J, Walker U, Tyndall A, Kahan A, Matucci-Cerinic M, Allanore Y, et al. Characteristics of joint involvement and relationships with systemic inflammation in systemic sclerosis: results from the EULAR Scleroderma Trial and Research Group (EUSTAR) database. J Rheumatol. 2010;37(7):1488\u2013501.","journal-title":"J Rheumatol"},{"issue":"6","key":"2057_CR30","doi-asserted-by":"publisher","first-page":"989","DOI":"10.1093\/rheumatology\/kem021","volume":"46","author":"G Szucs","year":"2007","unstructured":"Szucs G, Szekanecz Z, Zilahi E, Kapitany A, Barath S, Szamosi S, et al. Systemic sclerosis-rheumatoid arthritis overlap syndrome: a unique combination of features suggests a distinct genetic, serological and clinical entity. Rheumatology. 2007;46(6):989\u201393.","journal-title":"Rheumatology."}],"container-title":["Arthritis Research &amp; Therapy"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13075-019-2057-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s13075-019-2057-x\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13075-019-2057-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,11,30]],"date-time":"2020-11-30T20:01:29Z","timestamp":1606766489000},"score":1,"resource":{"primary":{"URL":"https:\/\/arthritis-research.biomedcentral.com\/articles\/10.1186\/s13075-019-2057-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12]]},"references-count":30,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2019,12]]}},"alternative-id":["2057"],"URL":"https:\/\/doi.org\/10.1186\/s13075-019-2057-x","relation":{},"ISSN":["1478-6362"],"issn-type":[{"value":"1478-6362","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12]]},"assertion":[{"value":"10 May 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 November 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 December 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"This study has been approved by the Ethics Committee of the University of Freiburg (ethic vote 290\/17).","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"262"}}