Approach Considerations

A patient with undifferentiated connective-tissue disease (UCTD) can be evaluated and treated primarily as an outpatient. Nonsteroidal anti-inflammatory drugs (NSAIDs), antimalarials (eg, hydroxychloroquine), and corticosteroids are the mainstay of therapy. Immunosuppressive drugs are generally reserved for treating specific clinical manifestations and when there is major organ involvement. In the INBUILD trial of patients with progressive fibrosing interstitial lung diseases, including cases that occurred in the context of UCTD, treatment with the antifibrotic agent nintedanib significantly slowed the rate of decline in forced vital capacity.^[57]

Surgery for patients with UCTD is not routinely necessary and should be initiated only when indicated for diagnosis or treatment.

Consultations

See the list below:

A rheumatologist should be consulted.
Consultations with other specialists may be clinically indicated, including with a dermatologist, ophthalmologist, pulmonologist, cardiologist, neurologist, physical medicine specialist, physical therapist, and/or occupational therapist.

Activity

See the list below:

In general, activities are not restricted in the absence of specific functional limitations associated with UCTD.
Patients with photosensitivity should minimize prolonged exposure to sunlight and should use protective clothing and sunblock lotions/creams to protect against ultraviolet light.
Patients with severe Raynaud phenomenon should avoid prolonged exposure to severe cold temperatures (< 40° F) to avoid digital vasospasm. Layered clothing, hats, and gloves help to maintain a warm core body temperature and decreased vasospastic symptoms. Tobacco use should be avoided.

Medication

Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988 Mar. 31(3):315-24. [QxMD MEDLINE Link].
Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010 Sep. 62(9):2569-81. [QxMD MEDLINE Link].
Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982 Nov. 25(11):1271-7. [QxMD MEDLINE Link].
Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997 Sep. 40(9):1725. [QxMD MEDLINE Link].
Aringer M, Costenbader K, Daikh D, et al. 2019 European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus. Ann Rheum Dis. 2019 Sep. 78 (9):1151-1159. [QxMD MEDLINE Link]. [Full Text].
American Rheumatism Association. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum. 1980 May. 23(5):581-90. [QxMD MEDLINE Link].
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. Arthritis Rheum. 2013 Nov. 65(11):2737-47. [QxMD MEDLINE Link].
Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med. 1975 Feb 13. 292(7):344-7. [QxMD MEDLINE Link].
Alarcón-Segovia D, Cardiel MH. Comparison between 3 diagnostic criteria for mixed connective tissue disease. Study of 593 patients. J Rheumatol. 1989 Mar. 16(3):328-34. [QxMD MEDLINE Link].
Vitali C, Bombardieri S, Moutsopoulos HM, Balestrieri G, Bencivelli W, Bernstein RM. Preliminary criteria for the classification of Sjögren's syndrome. Results of a prospective concerted action supported by the European Community. Arthritis Rheum. 1993 Mar. 36(3):340-7. [QxMD MEDLINE Link].
Fox RI, Saito I. Criteria for diagnosis of Sjogren's syndrome. Rheum Dis Clin North Am. 1994 May. 20(2):391-407. [QxMD MEDLINE Link].
Shiboski SC, Shiboski CH, Criswell L, Baer A, Challacombe S, Lanfranchi H, et al. American College of Rheumatology classification criteria for Sjögren's syndrome: a data-driven, expert consensus approach in the Sjögren's International Collaborative Clinical Alliance cohort. Arthritis Care Res (Hoboken). 2012 Apr. 64(4):475-87. [QxMD MEDLINE Link]. [Full Text].
LeRoy EC, Maricq HR, Kahaleh MB. Undifferentiated connective tissue syndromes. Arthritis Rheum. 1980 Mar. 23(3):341-3. [QxMD MEDLINE Link].
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 Sep-Oct. 17(5):615-20. [QxMD MEDLINE Link].
Danieli MG, Fraticelli P, Franceschini F, et al. Five-year follow-up of 165 Italian patients with undifferentiated connective tissue diseases. Clin Exp Rheumatol. 1999 Sep-Oct. 17(5):585-91. [QxMD MEDLINE Link].
Greer JM, Panush RS. Incomplete lupus erythematosus. Arch Intern Med. 1989 Nov. 149(11):2473-6. [QxMD MEDLINE Link].
Ganczarczyk L, Urowitz MB, Gladman DD. "Latent lupus". J Rheumatol. 1989 Apr. 16(4):475-8. [QxMD MEDLINE Link].
Swaak AJ, van de Brink H, Smeenk RJ, Manger K, Kalden JR, Tosi S. 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 Jan. 40(1):89-94. [QxMD MEDLINE Link].
Bodolay E, Csiki Z, Szekanecz Z, et al. Five-year follow-up of 665 Hungarian patients with undifferentiated connective tissue disease (UCTD). Clin Exp Rheumatol. 2003 May-Jun. 21(3):313-20. [QxMD MEDLINE Link].
Cavazzana I, Franceschini F, Belfiore N, et al. Undifferentiated connective tissue disease with antibodies to Ro/SSa: clinical features and follow-up of 148 patients. Clin Exp Rheumatol. 2001 Jul-Aug. 19(4):403-9. [QxMD MEDLINE Link].
Vaz CC, Couto M, Medeiros D, Miranda L, Costa J, Nero P. Undifferentiated connective tissue disease: a seven-center cross-sectional study of 184 patients. Clin Rheumatol. 2009 Aug. 28(8):915-21. [QxMD MEDLINE Link].
Mosca M, Tani C, Bombardieri S. A case of undifferentiated connective tissue disease: is it a distinct clinical entity?. Nat Clin Pract Rheumatol. 2008 Jun. 4(6):328-32. [QxMD MEDLINE Link].
Doria A, Mosca M, Gambari PF, Bombardieri S. Defining unclassifiable connective tissue diseases: incomplete, undifferentiated, or both?. J Rheumatol. 2005 Feb. 32(2):213-5. [QxMD MEDLINE Link].
Conti V, Esposito A, Cagliuso M, Fantauzzi A, Pastori D, Mezzaroma I. Undifferentiated connective tissue disease - an unsolved problem:revision of literature and case studies. Int J Immunopathol Pharmacol. 2010 Jan-Mar. 23(1):271-8. [QxMD MEDLINE Link].
Bizzaro N, Tozzoli R, Shoenfeld Y. Are we at a stage to predict autoimmune rheumatic diseases?. Arthritis Rheum. 2007 Jun. 56(6):1736-44. [QxMD MEDLINE Link].
Cappelli S, Bellando Randone S, Martinovic D, Tamas MM, Pasalic K, Allanore Y, et al. "To Be or Not To Be," Ten Years After: Evidence for Mixed Connective Tissue Disease as a Distinct Entity. Semin Arthritis Rheum. 2011 Sep 27. [QxMD MEDLINE Link].
Horvath L, Czirjak L, Fekete B, et al. Levels of antibodies against C1q and 60 kDa family of heat shock proteins in the sera of patients with various autoimmune diseases. Immunol Lett. 2001 Jan 1. 75(2):103-9. [QxMD MEDLINE Link].
Spain TA, Sun R, Gradzka M, et al. The transcriptional activator Sp1, a novel autoantigen. Arthritis Rheum. 1997 Jun. 40(6):1085-95. [QxMD MEDLINE Link].
Szodoray P, Nakken B, Barath S, Gaal J, Aleksza M, Zeher M. Progressive divergent shifts in natural and induced T-regulatory cells signify the transition from undifferentiated to definitive connective tissue disease. Int Immunol. 2008 Aug. 20(8):971-9. [QxMD MEDLINE Link].
Cordiali-Fei P, Mussi A, D'Agosto G, Trento E, Bordignon V, Trincone S, et al. Assessment of T regulatory cells and expanded profiling of autoantibodies may offer novel biomarkers for the clinical management of systemic sclerosis and undifferentiated connective tissue disease. Clin Dev Immunol. 2013. 2013:390563. [QxMD MEDLINE Link]. [Full Text].
Zold E, Szodoray P, Nakken B, Barath S, Kappelmayer J, Csathy L, et al. Alfacalcidol treatment restores derailed immune-regulation in patients with undifferentiated connective tissue disease. Autoimmun Rev. 2011 Jan. 10(3):155-62. [QxMD MEDLINE Link].
Berardi S, Giardullo L, Corrado A, Cantatore FP. Vitamin D and connective tissue diseases. Inflamm Res. 2020 May. 69 (5):453-462. [QxMD MEDLINE Link].
Guerrero LF, Rueda JC, Arciniegas R, Rueda JM. Undifferentiated connective tissue disease in a rheumatology center in Cali, Colombia: clinical features of 94 patients followed for a year. Rheumatol Int. 2011 Nov 25. [QxMD MEDLINE Link].
García-González M, Rodríguez-Lozano B, Bustabad S, Ferraz-Amaro I. Undifferentiated connective tissue disease: predictors of evolution into definite disease. Clin Exp Rheumatol. 2017 Sep-Oct. 35 (5):739-745. [QxMD MEDLINE Link].
Mosca M, Tani C, Bombardieri S. Defining undifferentiated connective tissue diseases: a challenge for rheumatologists. Lupus. 2008. 17(4):278-80. [QxMD MEDLINE Link].
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 Nov. 29(11):2345-9. [QxMD MEDLINE Link].
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 Apr. 14(2):94-6. [QxMD MEDLINE Link].
Martorell EA, Hong C, Rust DW, Salomon RN, Krishnamani R, Patel AR. A 32-year-old woman with arthralgias and severe hypotension. Arthritis Rheum. 2008 Nov 15. 59(11):1670-5. [QxMD MEDLINE Link].
Kelly BT, Moua T. Overlap of interstitial pneumonia with autoimmune features with undifferentiated connective tissue disease and contribution of UIP to mortality. Respirology. 2018 Jan 10. 176(7):691-7. [QxMD MEDLINE Link].
Deng XL, Liu XY. Comparative Study of 181 Cases of Diffuse Connective Tissue Disease Complicated by Cardiovascular Disease. International Journal of Rheumatic Diseases. Nov 2008. 11 (Suppl. 1):A462.
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 Oct. 25(5):423-7. [QxMD MEDLINE Link].
Oishi Y, Arai M, Kiraku J, Doi H, Uchiyama T, Hasegawa A. Unclassified connective tissue disease presenting as cardiac tamponade: a case report. Jpn Circ J. 2000 Aug. 64(8):619-22. [QxMD MEDLINE Link].
Zhang Y, Zhang FK, Wu XN, Wang TL, Jia JD, Wang BE. Undifferentiated connective tissue diseases-related hepatic injury. World J Gastroenterol. 2008 May 7. 14(17):2780-2. [QxMD MEDLINE Link].
Williams HJ, Alarcon GS, Joks R, et al. 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 Apr. 26(4):816-25. [QxMD MEDLINE Link].
Alarcón GS, Williams GV, Singer JZ, Steen VD, Clegg DO, Paulus HE. 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 Sep. 18(9):1332-9. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
Calvo-Alen J, Alarcon GS, Burgard SL, et al. 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 Mar. 23(3):469-75. [QxMD MEDLINE Link].
Heinlen LD, McClain MT, Merrill J, Akbarali YW, Edgerton CC, Harley JB. Clinical criteria for systemic lupus erythematosus precede diagnosis, and associated autoantibodies are present before clinical symptoms. Arthritis Rheum. 2007 Jul. 56(7):2344-51. [QxMD MEDLINE Link].
Mosca M, Baldini C, Bombardieri S. Undifferentiated connective tissue diseases in 2004. Clin Exp Rheumatol. 2004 Jan-Feb. 17(5):22(3 Suppl 33). [QxMD MEDLINE Link].
Meroni PL, Schur PH. ANA screening: an old test with new recommendations. Ann Rheum Dis. 2010 Aug. 69(8):1420-2. [QxMD MEDLINE Link].
Tozzoli R, Bizzaro N, Tonutti E, Villalta D, Bassetti D, Manoni F, et al. Guidelines for the laboratory use of autoantibody tests in the diagnosis and monitoring of autoimmune rheumatic diseases. Am J Clin Pathol. 2002 Feb. 117(2):316-24. [QxMD MEDLINE Link].
Ceribelli A, Cavazzana I, Franceschini F, Quinzanini M, Rizzini FL, Cattaneo R. Isotype switching and titer variation of anti-Ro/SSA antibodies over time in 100 patients with undifferentiated connective tissue disease (UCTD). Clin Exp Rheumatol. 2008 Jan-Feb. 26(1):117-20. [QxMD MEDLINE Link].
Zold E, Szodoray P, Gaal J, Kappelmayer J, Csathy L, Gyimesi E. Vitamin D deficiency in undifferentiated connective tissue disease. Arthritis Res Ther. 2008. 10(5):R123. [QxMD MEDLINE Link].
Luciano N, Baldini C, Tarantini G, Ferro F, Sernissi F, Varanini V, et al. Ultrasonography of major salivary glands: a highly specific tool for distinguishing primary Sjögren's syndrome from undifferentiated connective tissue diseases. Rheumatology (Oxford). 2015 Dec. 54 (12):2198-204. [QxMD MEDLINE Link].
Smith V, et al; EULAR Study Group on Microcirculation in Rheumatic Diseases and the Scleroderma Clinical Trials Consortium Group on Capillaroscopy. Standardisation of nailfold capillaroscopy for the assessment of patients with Raynaud's phenomenon and systemic sclerosis. Autoimmun Rev. 2020 Mar. 19 (3):102458. [QxMD MEDLINE Link]. [Full Text].
Cortes S, Clemente-Coelho P. [Nailfold capillaroscopy in the evaluation of Raynaud's phenomenon and undifferentiated connective tissue disease]. Acta Reumatol Port. 2008 Apr-Jun. 33(2):203-9. [QxMD MEDLINE Link].
Wells AU, Flaherty KR, Brown KK, Inoue Y, Devaraj A, Richeldi L, et al. Nintedanib in patients with progressive fibrosing interstitial lung diseases-subgroup analyses by interstitial lung disease diagnosis in the INBUILD trial: a randomised, double-blind, placebo-controlled, parallel-group trial. Lancet Respir Med. 2020 May. 8 (5):453-460. [QxMD MEDLINE Link].

Media Gallery

of 0

Table 1. Preliminary Classification Criteria for Undifferentiated Connective-Tissue Disease

Inclusion Criteria

Clinical

Exclusion Criteria (Applicable to patients at disease onset)

Laboratory Exclusion Criteria (Applicable to patients at disease onset)

1. Signs and symptoms suggestive of a CTD but not fulfilling the diagnostic or classification criteria for any of the defined CTDs (using previously established classification criteria for SLE, MCTD, SSc, PM/DM, RA and SS) for at least 3 years. If the disease duration is less than 3 years, patients may be defined as having an early UCTD.

Adapted from Mosca et al^[14]and Doria et al.^[23]

2. Presence of antinuclear antibodies determined on two different occasions

Malar rash

Subacute cutaneous lupus

Discoid lupus

Cutaneous sclerosis

Heliotrope rash

Gottron papules

Erosive arthritis

Anti-dsDNA

Anti-Smith

Anti-U1-RNP

Anti-Scl70

Anticentromere

Anti-La/SSB

Anti-Jo1

Anti-Mi2

Table 2. Predictors of Progression to Definite Connective-Tissue Disease

Connective-Tissue Disease Association	Signs or Symptoms	Laboratory Data
Systemic lupus erythematosus	Age, fever, photosensitivity, serositis, alopecia	ANA, Anti-dsDNA, Anti-Smith, Anti-cardiolipin antibodies, Coombs positivity, leukopenia
Systemic sclerosis	Sclerodactyly, Raynaud phenomenon, sicca symptoms, esophageal dysfunction	ANA with nucleolar pattern
Sjögren syndrome	Xerostomia, xerophthalmia, Raynaud phenomenon	Anti-SSA, Anti-SSB
Rheumatoid arthritis	Symmetric polyarthritis	RF, elevated ESR (>70 mm/h)
Mixed connective-tissue disease	Esophageal reflux, polyarthritis, Raynaud phenomenon	ANA, Anti-U1-RNP