Undifferentiated Connective Tissue Disease

History and Epidemiology

Undifferentiated connective tissue disease (UCTD) refers to a condition presenting with symptoms and laboratory test results that suggest a systemic autoimmune disorder or connective tissue disease — such as systemic lupus erythematosus (lupus), Sjogren’s syndrome, or scleroderma — but for which symptoms are not extensive or specific enough to meet the normal criteria for such a disease.

The term was first suggested by American rheumatologist E. Carwile LeRoy, MD in 1980,1 and the first classification criteria were proposed two decades later.2 Classical epidemiological data for undifferentiated connective tissue disease are not available due to the limited literature exploring the disease. Furthermore, differences in patient selection criteria in existing studies make comparisons between them difficult.3

Undifferentiated Connective Tissue Disease Etiology & Risk Factors

The exact cause of undifferentiated connective tissue disease is unknown, but, as a combination of genetic and environmental factors cause most autoimmune diseases, these factors are thought to play a significant role. Autoimmune diseases involve sudden and magnified activity in the immune system, which can lead to the production of autoantibodies or the activation of T-cells, which then attacks autoantigens across the body in varying organs.

In UCTD, an autoimmune connective tissue disease, the immune system activation results in inflammation of connective tissue. The magnified activity in the immune system can also be triggered by environmental factors, such as:

  • Chemicals
  • Pollutants
  • UV light4

Despite the uncertainty surrounding the epidemiology and etiology of undifferentiated connective tissue disease, there is agreement that up to 90% of cases occur in females. The mean age of disease onset ranges from 32 to 44 years.3

Undifferentiated Connective Tissue Disease
Diagnosis & Presentation

The presentation of undifferentiated connective tissue disease can vary among patients, but there are some commonly occurring symptoms. These include:

  • Arthralgia
  • Raynaud’s phenomenon
  • Skin lesions
  • Oral ulcers

Other symptoms include:

  • Dry eyes and/or mouth
  • Hair loss
  • Fever
  • Fatigue
  • Thyroid issues
  • Sun-sensitive rash 10,11

Unlike other connective tissue diseases, no accepted diagnostic or classification criteria for undifferentiated connective tissue disease have been developed.12 Preliminary classification criteria were proposed in the 1990s. These criteria are commonly used in research studies investigating undifferentiated connective tissue disease. To meet these classification criteria for undifferentiated connective tissue disease, patients must display:

  • Signs and symptoms of a connective tissue disease, but not fulfilling the criteria for a separate disease for at least three years
  • A positive antinuclear antibody (ANA) on two separate occasions.2

Diagnostic Workup & Physical Examination Findings

There are a variety of diagnostic tests which doctors can use to determine if a patient has undifferentiated connective tissue disease. A physical exam and evaluating a patient’s medical history are key parts of the workup.

Physical Exam

Symptom information is collected, such as joint pain and times when the pain is worse. Other symptoms, such as rashes, dry eyes, and oral ulcers, could also be present.

Diagnostic Tests

Testing the blood for immunological abnormalities is a key part of the diagnostic workup. Blood tests are usually done as part of an initial consultation and repeated over time.

Tests may include:

  • ANA
  • C-reactive protein
  • Rheumatoid factor
  • Lupus anticoagulant
  • Anti-chromatin
  • Serum creatinine
  • Erythrocyte sedimentation rate10

Other blood tests looking at blood cell levels can also be used to determine the presence of leukopenia, anemia, or thrombocytopenia. These abnormalities are often seen in undifferentiated connective tissue disease patients. However, it is uncommon for them to be severe enough to require treatment.12

Imaging tests such as X-rays (to determine joint damage) and CT scans (to assess for interstitial lung disease or pleural and pericardial effusion) may be used depending on the specific symptoms the patient presents with. Ultrasonography of the salivary glands can also be used to differentiate between undifferentiated connective tissue disease and Sjogren’s syndrome.13

Undifferentiated Connective Tissue Disease Management

Most often, treatment of for undifferentiated connective tissue disease focuses on the symptom relief. Hydroxychloroquine has been suggested to reduce the likelihood of undifferentiated connective tissue disease progressing to lupus, but this has not been confirmed in randomized clinical trials.8

Prognosis

Most patients (70%) diagnosed with undifferentiated connective tissue disease will have persistent symptoms and do not develop a defined connective tissue disease, while the remaining 30% will eventually progress to a more established autoimmune disease and be reclassified within 3 to 5 years of the initial diagnosis.3

Most patients who go one to develop a defined connective tissue disease are diagnosed with lupus, but symptom severity may influence subsequent diagnoses.5-7 A proportion of patients (24%) can experience a complete remission of their symptoms.9 Survival rates for undifferentiated connective tissue disease appear to be similar to those for lupus or rheumatoid arthritis.9

Differential Diagnosis

Undifferentiated connective tissue disease is considered a diagnosis of exclusion so it is often challenging to diagnose as other systemic autoimmune disorders or connective tissue diseases — such as lupus, Sjogren’s syndrome, scleroderma, rheumatoid arthritis, and myositis — display similar symptoms. These conditions have very different treatment approaches to undifferentiated connective tissue disease, so it is important to consider and rule out these alternatives when diagnosing undifferentiated connective tissue disease.

FAQ

What does it mean to have undifferentiated connective tissue disease?

Patients who present with clinical and serological manifestations that suggest a systemic autoimmune disease but do not fulfill criteria for defined connective tissue disease are classified to have undifferentiated connective tissue disease (UCTD).3 Most patients (~70%) with undifferentiated connective tissue disease will not progress into a defined disease.3,4 Stable undifferentiated connective tissue disease is associated with arthralgias and arthritis, mild Raynaud’s phenomenon, and hematological manifestations.3 

What is the treatment for undifferentiated connective tissue disease?

Medications part of the cornerstone of treatment include nonsteroidal antiinflammatory drugs (NSAIDs) such as naproxen and celecoxib, corticosteroids (prednisone), calcium channel blockers, and antimalarials (hydroxychloroquine). If there is severe organ damage, immunosuppressive drugs, including methotrexate and azathioprine, can also be used. Antimalarials are usually used in combination with NSAIDs. Systemic corticosteroids are also concomitantly prescribed with a medication to control systemic inflammation.4

Is undifferentiated connective tissue disease the same as lupus?

No. Lupus, also known as systemic lupus erythematosus, is one of 5 defined autoimmune connective tissue diseases, along with scleroderma, myositis, rheumatoid arthritis, and Sjogren’s syndrome. Patients  who have features of autoimmune diseases but do not meet criteria for systemic lupus erythematosus, scleroderma, myositis, rheumatoid arthritis, or Sjogren’s syndrome are diagnosed with undifferentiated connective tissue disease.14

References

1. LeRoy EC, Maricq HR, Kahaleh MB, Bashar Kahaleh M. Undifferentiated connective tissue syndromes. Arthritis Rheum. 1980;23(3):341-343. doi: 10.1002/art.1780230312

2. 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):615-620.

3. Mosca M, Tani C, Talarico R, Bombardieri S. Undifferentiated connective tissue diseases (UCTD): simplified systemic autoimmune diseases. Autoimmun Rev. 2011;10(5):256–258. doi: 10.1016/j.autrev.2010.09.013

4. Marwa K, Anjum F. Undifferentiated connective tissue disease. StatPearls. Published January 2022. Updated March 15, 2022. Accessed June 24, 2022.

5. 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;26(4):816-825.

6. 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):2345-2349.

7. Radin M, Rubini E, Cecchi I, Foddai SG , Barinotti A, Rossi D, et al. Disease evolution in a long-term follow-up of 104 undifferentiated connective tissue disease patients. Clin Exp Rheumatol. 2022;40(3):575-580. doi: 10.55563/clinexprheumatol/7vp1bo

8. James JA, Kim-Howard XR, Bruner BF, Jonsson MK, McClain MT, Arbuckle MR, et al. Hydroxychloroquine sulfate treatment is associated with later onset of systemic lupus erythematosus. Lupus. 2007;16(6):401-409. doi: 10.1177/0961203307078579. PMID: 17664230.

9. Garcia-Gonzalez M, Rodriguez-Lozano B, Bustabad S, Ferraz-Amaro I. Undifferentiated connective tissue disease: predictors of evolution into definite disease. Clin Exp Rheumatol. 2017;35(5):739-745.

10. Mosca M, Tani C, Neri C, Baldini C, Bombardieri S. Undifferentiated connective tissue diseases (UCTD). Autoimmun Rev. 2006;6(1):1-4. doi: 10.1016/j.autrev.2006.03.004

11. 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;17(5):585-591.

12. Antunes M, Scirè CA, Talarico R, Alexander T, Avcin T, Belocchi C, et al. Undifferentiated connective tissue disease: state of the art on clinical practice guidelines. RMD Open. Published online Feb. 26, 2019. doi: 10.1136/rmdopen-2018-000786

13. 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;54(12):2198-2204. doi: 10.1093/rheumatology/kev253.

14. Pepmueller PH. Undifferentiated connective tissue disease, mixed connective tissue disease, and overlap syndromes in rheumatology. Mo Med. 2015;113(2):136-140.

Author Bio

Lincoln Tracy, PhD, is a researcher and freelance writer based in Melbourne, Australia. You can follow him on Twitter @lincolntracy.