Mixed connective tissue disease, undifferentiated connective tissue disease and overlap syndromes

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Systemic lupus erythematosus, systemic sclerosis, inflammatory myopathy and rheumatoid arthritis are systemic connective tissue disorders which are characterized by heterogeneous clinical symptoms and variable course. To date, updated diagnostic criteria for early diagnosis of each of the diseases of this group have been proposed. At the same time, a proportion of patients already have at the onset of the disease or over time, a combination of signs characteristic of different diseases. Such conditions are referred to as mixed connective tissue disease, undifferentiated connective tissue disease or overlap-syndrome, whose nosological identity remains the subject of discussion. Formerly there has been a kind of terminological confusion and similar conditions were described under different names, depending on the author's preferences. It was also believed that these conditions were an early stage or a clinically "incomplete" form of a connective tissue disease. However, as the observations of large patient groups have shown, whose disease was represented by a number of individual signs of several connective tissue diseases, the clinical manifestation remains unchanged for many years in the majority of them. To recognize the right for nosological independence, one should account for the fact that only for a mixed connective tissue disease various authors and research groups have proposed four variants of diagnostic criteria. These criteria have small differences in the number of clinical signs; however, all criteria include a mandatory sign, i.e. the presence of antibodies to U1-ribonucleoprotein in high titers. Clinical signs common to all these diagnostic criteria include the Raynaud's syndrome, arthritis, myositis and finger swelling or sclerodactyly. Another patient category includes those with mono- or oligosymptomatic manifestations characteristic of systemic connective tissue diseases, but without any specific immunological markers. Some of these patients in a fairly short time, usually from several months to 1–2 years, develop other clinical symptoms and signs corresponding to a reliable diagnosis of a connective tissue disease. At the same time, a significant part of patients with the oligosymptomatic course demonstrate a long-term stability without any further evolution of the disease. Such cases are defined as an undifferentiated connective tissue disease. To avoid the erroneous diagnosis of the transient form or an early stage of any connective tissue disease, the proposed classification criteria, along with the inclusion criteria, also embrace clinical and serological exclusion criteria. A separate category consists of patients with a combination of clinical signs sufficient for a definitive diagnosis of at least two systemic connective tissue diseases. These patients are diagnosed with the overlap-syndrome with indication of the components of connective tissue diseases in each individual case, as it largely determines the individual treatment and prognosis. The possibility of such clinical variants of systemic connective tissue diseases is becoming increasingly justified due to the concept of polyautoimmunity, which has attracted great interest of researchers in the last few years.

About the authors

R. T. Alekperov

Moscow Regional Research and Clinical Institute (MONIKI);
V.A. Nasonova Research Institute of Rheumatology, Russian Academy of Medical Sciences

Author for correspondence.
Email: ralekperov@list.ru

Rizvan Tair oglu Alekperov – MD, PhD, Professor, Chair of Internal Diseases, Postgraduate Training Faculty Moscow Regional Research and Clinical Institute (MONIKI), Senior Research Fellow V.A. Nasonova Research Institute of Rheumatology, Russian Academy of Medical Sciences

61/2–9 Shchepkina ul., Moscow, 129110, 

34А Kashirskoe shosse, Moscow, 115522


Russian Federation


  1. Sharp GC, Irvin WS, Tan EM, Gould RG, Holman HR. Mixed connective tissue disease – an apparently distinct rheumatic disease syndrome associated with a specific antibody to an extractable nuclear antigen (ENA). Am J Med. 1972;52(2): 148–59. doi: 10.1016/0002-9343(72)90064-2.
  2. Martínez-Barrio J, Valor L, López-Longo FJ. Facts and controversies in mixed connective tissue disease. Med Clin (Barc). 2018;150(1): 26–32. doi: 10.1016/j.medcli.2017.06.066.
  3. Cappelli S, Bellando Randone S, Martinović D, Tamas MM, Pasalić K, Allanore Y, Mosca M, Talarico R, Opris D, Kiss CG, Tausche AK, Cardarelli S, Riccieri V, Koneva O, Cuomo G, Becker MO, Sulli A, Guiducci S, Radić M, Bombardieri S, Aringer M, Cozzi F, Valesini G, Ananyeva L, Valentini G, Riemekasten G, Cutolo M, Ionescu R, Czirják L, Damjanov N, Rednic S, Matucci Cerinic M. "To be or not to be," ten years after: evidence for mixed connective tissue disease as a distinct entity. Semin Arthritis Rheum. 2012;41(4): 589–98. doi: 10.1016/j.semarthrit.2011.07.010.
  4. Flåm ST, Gunnarsson R, Garen T; Norwegian MCTD Study Group, Lie BA, Molberg Ø. The HLA profiles of mixed connective tissue disease differ distinctly from the profiles of clinically related connective tissue diseases. Rheumatology (Oxford). 2015;54(3): 528–35. doi: 10.1093/rheumatology/keu310.
  5. Ungprasert P, Crowson CS, Chowdhary VR, Ernste FC, Moder KG, Matteson EL. Epidemiology of mixed connective tissue disease, 1985–2014: A population-based study. Arthritis Care Res (Hoboken). 2016;68(12): 1843–8. doi: 10.1002/acr.22872.
  6. Nakae K, Furusawa F, Kasukawa R, Tojo T, Homma M, Aoki K. A nationwide epidemiological survey on diffuse collagen disease: Estimation of prevalence rate in Japan. In: Kasukawa R, Sharp GC, editors. Mixed connective tissue disease and antinuclear antibodies. Amsterdam: Elsevier; 1987. p. 9–20.
  7. Gunnarsson R, Molberg O, Gilboe IM, Gran JT; PAHNOR1 Study Group. The prevalence and incidence of mixed connective tissue disease: a national multicentre survey of Norwegian patients. Ann Rheum Dis. 2011;70(6): 1047–51. doi: 10.1136/ard.2010.143792.
  8. Farhey Y, Hess EV. Mixed connective tissue disease. Arthritis Care Res. 1997;10(5): 333–42.
  9. Alarcón-Segovia D, Villareal M. Classification and diagnostic criteria for classification of mixed connective tissue disease. In: Kasukawa R, Sharp GC, editors. Mixed connective tissue diseases and antinuclear antibodies. Amsterdam: Elsevier; 1987. p. 33–40.
  10. Kasukawa R, Tojo T, Miyawaki S, Yoshida H, Tanimoto K, Nobunaga M, Suzuki T, Takasaki Y, Tamura T. Preliminary diagnostic criteria for classification of mixed connective tissue disease. In: Kasukawa R, Sharp GC, editors. Mixed connective tissue diseases and antinuclear antibodies. Amsterdam: Elsevier; 1987. p. 41–7.
  11. Kahn MF, Bourgeois P, Aeschlimann A, de Truchis P. Mixed connective tissue disease after exposure to polyvinyl chloride. J Rheumatol. 1989;16(4): 533–5.
  12. Amigues JM, Cantagrel A, Abbal M, Mazieres B. Comparative study of 4 diagnosis criteria sets for mixed connective tissue disease in patients with anti-RNP antibodies. Autoimmunity Group of the Hospitals of Toulouse. J Rheumatol. 1996;23(12): 2055–62.
  13. Nicoll D, Lu CM, Pignone M, McPhee SJ. Pocket Guide to Diagnostic Tests. 5th edition. McGraw-Hill Medical / Jaypee Brothers Medical Publishers; 2007.
  14. Williamson MA, Snyder LM, Wallach JB. Wallach's Interpretation of Diagnostic Tests. Philadelphia: Wolters Kluwer / Lippincott Williams & Wilkins; 2011. 1035 p.
  15. Dima A, Jurcut C, Baicus C. The impact of anti-U1-RNP positivity: systemic lupus erythematosus versus mixed connective tissue disease. Rheumatol Int. 2018;38(7): 1169–78. doi: 10.1007/s00296-018-4059-4.
  16. LeRoy EC, Maricq HR, Kahaleh MB. Undifferentiated connective tissue syndromes. Arthritis Rheum. 1980;23(3): 341–3. doi: 10.1002/art.1780230312.
  17. Mosca M, Neri R, Bombardieri S. Undifferentiated connective tissue diseases (UCTD): a review of the literature and a proposal for preliminary classification criteria. Clin Exp Rheumatol. 1999;17(5): 615–20.
  18. Danieli MG, Fraticelli P, Franceschini F, Cattaneo R, Farsi A, Passaleva A, Pietrogrande M, Invernizzi F, Vanoli M, Scorza R, Sabbadini MG, Gerli R, Corvetta A, Farina G, Salsano F, Priori R, Valesini G, Danieli G. Five-year follow-up of 165 Italian patients with undifferentiated connective tissue diseases. Clin Exp Rheumatol. 1999;17(5): 585–91.
  19. Greer JM, Panush RS. Incomplete lupus erythematosus. Arch Intern Med. 1989;149(11): 2473–6. doi: 10.1001/archinte.1989.00390110061013.
  20. Ganczarczyk L, Urowitz MB, Gladman DD. "Latent lupus". J Rheumatol. 1989;16(4): 475–8.
  21. Swaak AJ, van de Brink H, Smeenk RJ, Manger K, Kalden JR, Tosi S, Marchesoni A, Domljan Z, Rozman B, Logar D, Pokorny G, Kovacs L, Kovacs A, Vlachoyiannopoulos PG, Moutsopoulos HM, Chwalinska-Sadowska H, Dratwianka B, Kiss E, Cikes N, Anic B, Schneider M, Fischer R, Bombardieri S, Mosca M, Graninger W, Smolen JS; Study group on incomplete SLE and SLE with disease duration longer than 10 years. Incomplete lupus erythematosus: results of a multicentre study under the supervision of the EULAR Standing Committee on International Clinical Studies Including Therapeutic Trials (ESCISIT). Rheumatology (Oxford). 2001;40(1): 89–94. doi: 10.1093/rheumatology/40.1.89.
  22. Vaz CC, Couto M, Medeiros D, Miranda L, Costa J, Nero P, Barros R, Santos MJ, Sousa E, Barcelos A, Inês L. Undifferentiated connective tissue disease: a seven-center cross-sectional study of 184 patients. Clin Rheumatol. 2009;28(8): 915–21. doi: 10.1007/s10067-009-1175-2.
  23. Mosca M, Tani C, Bombardieri S. A case of undifferentiated connective tissue disease: is it a distinct clinical entity? Nat Clin Pract Rheumatol. 2008;4(6): 328–32. doi: 10.1038/ncprheum0799.
  24. Doria A, Mosca M, Gambari PF, Bombardieri S. Defining unclassifiable connective tissue diseases: incomplete, undifferentiated, or both? J Rheumatol. 2005;32(2): 213–5.
  25. Conti V, Esposito A, Cagliuso M, Fantauzzi A, Pastori D, Mezzaroma I, Aiuti F. Undifferentiated connective tissue disease – an unsolved problem: revision of literature and case studies. Int J Immunopathol Pharmacol. 2010;23(1): 271–8. doi: 10.1177/039463201002300125.
  26. Szodoray P, Nakken B, Barath S, Gaal J, Aleksza M, Zeher M, Sipka S, Szilagyi A, Zold E, Szegedi G, Bodolay E. Progressive divergent shifts in natural and induced T-regulatory cells signify the transition from undifferentiated to definitive connective tissue disease. Int Immunol. 2008;20(8): 971–9. doi: 10.1093/intimm/dxn056.
  27. Bodolay E, Csiki Z, Szekanecz Z, Ben T, Kiss E, Zeher M, Szücs G, Dankó K, Szegedi G. Five-year follow-up of 665 Hungarian patients with undifferentiated connective tissue disease (UCTD). Clin Exp Rheumatol. 2003;21(3): 313–20.
  28. Williams HJ, Alarcon GS, Joks R, Steen VD, Bulpitt K, Clegg DO, Ziminski CM, Luggen ME, St Clair EW, Willkens RF, Yarboro C, Morgan JG, Egger MJ, Ward JR. Early undifferentiated connective tissue disease (CTD). VI. An inception cohort after 10 years: disease remissions and changes in diagnoses in well established and undifferentiated CTD. J Rheumatol. 1999;26(4): 816–25.
  29. Pepmueller PH. Undifferentiated Connective Tissue Disease, Mixed Connective Tissue Disease, and Overlap Syndromes in Rheumatology. Mo Med. 2016;113(2): 136–40.
  30. Mosca M, Tani C, Bombardieri S. Defining undifferentiated connective tissue diseases: a challenge for rheumatologists. Lupus. 2008;17(4): 278–80. doi: 10.1177/0961203307088004.
  31. Mosca M, Neri R, Bencivelli W, Tavoni A, Bombardieri S. Undifferentiated connective tissue disease: analysis of 83 patients with a minimum followup of 5 years. J Rheumatol. 2002;29(11): 2345–9.
  32. Gupta D, Roppelt H, Bowers B, Kunz D, Natarajan M, Gruber B. Successful remission of thrombotic thrombocytopenic purpura with rituximab in a patient with undifferentiated connective tissue disorder. J Clin Rheumatol. 2008;14(2): 94–6. doi: 10.1097/RHU.0b013e31816b4ab1.
  33. Martorell EA, Hong C, Rust DW, Salomon RN, Krishnamani R, Patel AR, Kalish RA. A 32-yearold woman with arthralgias and severe hypotension. Arthritis Rheum. 2008;59(11): 1670–5. doi: 10.1002/art.24195.
  34. Kelly BT, Moua T. Overlap of interstitial pneumonia with autoimmune features with undifferentiated connective tissue disease and contribution of UIP to mortality. Respirology. 2018;23(6): 600–5. doi: 10.1111/resp.13254.
  35. Deng XL, Liu XY. Comparative study of 181 cases of diffuse connective tissue disease complicated by cardiovascular disease. Int J Rheum Dis. 2008;11(Suppl 1):A462.
  36. Oh CW, Lee SH, Heo EP. A case suggesting lymphocytic vasculitis as a presenting sign of early undifferentiated connective tissue disease. Am J Dermatopathol. 2003;25(5): 423–7.
  37. Oishi Y, Arai M, Kiraku J, Doi H, Uchiyama T, Hasegawa A, Kurabayashi M, Nagai R. Unclassified connective tissue disease presenting as cardiac tamponade: a case report. Jpn Circ J. 2000;64(8): 619–22. doi: 10.1253/jcj.64.619.
  38. Zhang Y, Zhang FK, Wu XN, Wang TL, Jia JD, Wang BE. Undifferentiated connective tissue diseases-related hepatic injury. World J Gastroenterol. 2008;14(17): 2780–2. doi: 10.3748/wjg.14.2780.
  39. Alarcón GS, Williams GV, Singer JZ, Steen VD, Clegg DO, Paulus HE, Billingsley LM, Luggen ME, Polisson RP, Willkens RF. Early undifferentiated connective tissue disease. I. Early clinical manifestation in a large cohort of patients with undifferentiated connective tissue diseases compared with cohorts of well established connective tissue disease. J Rheumatol. 1991;18(9): 1332–9.
  40. Danieli MG, Fraticelli P, Salvi A, Gabrielli A, Danieli G. Undifferentiated connective tissue disease: natural history and evolution into definite CTD assessed in 84 patients initially diagnosed as early UCTD. Clin Rheumatol. 1998;17(3): 195–201.
  41. Calvo-Alen J, Alarcon GS, Burgard SL, Burst N, Bartolucci AA, Williams HJ. Systemic lupus erythematosus: predictors of its occurrence among a cohort of patients with early undifferentiated connective tissue disease: multivariate analyses and identification of risk factors. J Rheumatol. 1996;23(3): 469–75.
  42. Heinlen LD, McClain MT, Merrill J, Akbarali YW, Edgerton CC, Harley JB, James JA. Clinical criteria for systemic lupus erythematosus precede diagnosis, and associated autoantibodies are present before clinical symptoms. Arthritis Rheum. 2007;56(7): 2344–51. doi: 10.1002/art.22665.
  43. Mosca M, Baldini C, Bombardieri S. Undifferentiated connective tissue diseases in 2004. Clin Exp Rheumatol. 2004;22(3 Suppl 33):S14–8.
  44. Iaccarino L, Gatto M, Bettio S, Caso F, Rampudda M, Zen M, Ghirardello A, Punzi L, Doria A. Overlap connective tissue disease syndromes. Autoimmun Rev. 2013;12(3): 363–73. doi: 10.1016/j.autrev.2012.06.004.
  45. Jury EC, D'Cruz D, Morrow WJ. Autoantibodies and overlap syndromes in autoimmune rheumatic disease. J Clin Pathol. 2001;54(5): 340–7. doi: 10.1136/jcp.54.5.340.
  46. Rodríguez-Reyna TS, Alarcón-Segovia D. Overlap syndromes in the context of shared autoimmunity. Autoimmunity. 2005;38(3): 219–23. doi: 10.1080/08916930500050145.
  47. Elhai M, Avouac J, Kahan A, Allanore Y. Systemic sclerosis at the crossroad of polyautoimmunity. Autoimmun Rev. 2013;12(11): 1052–7. doi: 10.1016/j.autrev.2013.05.002.
  48. Koumakis E, Dieudé P, Avouac J, Kahan A, Allanore Y; Association des Sclérodermiques de France. Familial autoimmunity in systemic sclerosis – results of a French-based case-control family study. J Rheumatol. 2012;39(3): 532–8. doi: 10.3899/jrheum.111104.
  49. Wielosz E, Majdan M, Dryglewska M, Targońska-Stępniak B. Overlap syndromes in systemic sclerosis. Postepy Dermatol Alergol. 2018;35(3): 246–50. doi: 10.5114/ada.2018.72662.
  50. Aguila LA, Lopes MR, Pretti FZ, Sampaio-Barros PD, Carlos de Souza FH, Borba EF, Shinjo SK. Clinical and laboratory features of overlap syndromes of idiopathic inflammatory myopathies associated with systemic lupus erythematosus, systemic sclerosis, or rheumatoid arthritis. Clin Rheumatol. 2014;33(8): 1093–8. doi: 10.1007/s10067-014-2730-z.
  51. Troyanov Y, Targoff IN, Tremblay JL, Goulet JR, Raymond Y, Senécal JL. Novel classification of idiopathic inflammatory myopathies based on overlap syndrome features and autoantibodies: analysis of 100 French Canadian patients. Medicine (Baltimore). 2005;84(4): 231–49. doi: 10.1097/01.md.0000173991.74008.b0.
  52. Allanore Y, Vignaux O, Arnaud L, Puéchal X, Pavy S, Duboc D, Legmann P, Kahan A. Effects of corticosteroids and immunosuppressors on idiopathic inflammatory myopathy related myocarditis evaluated by magnetic resonance imaging. Ann Rheum Dis. 2006;65(2): 249–52. doi: 10.1136/ard.2005.038679.
  53. Mahler M, Raijmakers R. Novel aspects of autoantibodies to the PM/Scl complex: clinical, genetic and diagnostic insights. Autoimmun Rev. 2007;6(7): 432–7. doi: 10.1016/j.autrev.2007.01.013.
  54. Balbir-Gurman A, Braun-Moscovici Y. Scleroderma overlap syndrome. Isr Med Assoc J. 2011;13(1): 14–20.
  55. Avouac J, Sordet C, Depinay C, Ardizonne M, Vacher-Lavenu MC, Sibilia J, Kahan A, Allanore Y. Systemic sclerosis-associated Sjögren's syndrome and relationship to the limited cutaneous subtype: results of a prospective study of sicca syndrome in 133 consecutive patients. Arthritis Rheum. 2006;54(7): 2243–9. doi: 10.1002/art.21922.
  56. Marrone M, Chialà A, Tampoia M, Iannone F, Raho L, Covelli M, Grattagliano V, Pansini N, Lapadula G. Prevalence of anti-CCP antibodies in systemic sclerosis. Reumatismo. 2007;59(1): 20–4. doi: 10.4081/reumatismo.2007.20.
  57. Horimoto AM, da Costa IP. Overlap between systemic sclerosis and rheumatoid arthritis: a distinct clinical entity? Rev Bras Reumatol Engl Ed. 2016;56(4): 287–98. doi: 10.1016/j.rbre.2014.12.011.
  58. Arslan Tas D, Erken E, Sakalli H, Yucel AE. Evaluating hand in systemic sclerosis. Rheumatol Int. 2012;32(11): 3581–6. doi: 10.1007/s00296-011-2205-3.
  59. Chung L, Lin J, Furst DE, Fiorentino D. Systemic and localized scleroderma. Clin Dermatol. 2006;24(5): 374–92. doi: 10.1016/j.clindermatol.2006.07.004.
  60. Ingegnoli F, Galbiati V, Zeni S, Meani L, Zahalkova L, Lubatti C, Soldi A, Paresce E, Murgo A, Crapanzano C, Fantini F. Use of antibodies recognizing cyclic citrullinated peptide in the differential diagnosis of joint involvement in systemic sclerosis. Clin Rheumatol. 2007;26(4): 510–4. doi: 10.1007/s10067-006-0313-3.
  61. Polimeni M, Feniman D, Skare TS, Nisihara RM. Anti-cyclic citrullinated peptide antibodies in scleroderma patients. Clin Rheumatol. 2012;31(5): 877–80. doi: 10.1007/s10067-011-1930-z.
  62. Payet J, Goulvestre C, Bialé L, Avouac J, Wipff J, Job-Deslandre C, Batteux F, Dougados M, Kahan A, Allanore Y. Anticyclic citrullinated peptide antibodies in rheumatoid and nonrheumatoid rheumatic disorders: experience with 1162 patients. J Rheumatol. 2014;41(12): 2395–402. doi: 10.3899/jrheum.131375.
  63. Morita Y, Muro Y, Sugiura K, Tomita Y. Anti-cyclic citrullinated peptide antibody in systemic sclerosis. Clin Exp Rheumatol. 2008;26(4): 542–7.
  64. Ueda-Hayakawa I, Hasegawa M, Kumada S, Tanaka C, Komura K, Hamaguchi Y, Takehara K, Fujimoto M. Usefulness of anti-cyclic citrullinated peptide antibody and rheumatoid factor to detect rheumatoid arthritis in patients with systemic sclerosis. Rheumatology (Oxford). 2010;49(11): 2135–9. doi: 10.1093/rheumatology/keq205.
  65. Allali F, Tahiri L, Senjari A, Abouqal R, Hajjaj-Hassouni N. Erosive arthropathy in systemic sclerosis. BMC Public Health. 2007;7:260. doi: 10.1186/1471-2458-7-260.
  66. Avouac J, Clements PJ, Khanna D, Furst DE, Allanore Y. Articular involvement in systemic sclerosis. Rheumatology (Oxford). 2012;51(8): 1347–56. doi: 10.1093/rheumatology/kes041.
  67. Alharbi S, Ahmad Z, Bookman AA, Touma Z, Sanchez-Guerrero J, Mitsakakis N, Johnson SR. Epidemiology and survival of systemic sclerosis-systemic lupus erythematosus overlap syndrome. J Rheumatol. 2018;45(10): 1406–10. doi: 10.3899/jrheum.170953.
  68. Horn HC, Ottosen P, Junker P. Renal crisis in asclerodermic scleroderma – lupus overlap syndrome. Lupus. 2001;10(12): 886–8. doi: 10.1191/096120301701548382.

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