Undifferentiated Connective Tissue Disease
Other nameslatent Lupus, incomplete lupus
SpecialtyImmunology, rheumatology Edit this on Wikidata
Symptomsdry eyes, dry mouth, haïr lost, joint inflammation, joint pain, mouth ulcers, positive ANA test, raynaud's phenomenon, sun-sensitive rash, ...

The Undifferentiated connective tissue disease (UCTD) is a disease in which the connective tissues are targeted by the immune system. It is a serological and clinical manifestation of an autoimmune disease. When there is proof of an autoimmune disease, it will be diagnosed as UCTD if the disease doesn't answer to any criterion of specific autoimmune disease. Such as systemic lupus erythematosus (SLE), la scleroderma,[1] mixed connective tissue disease, Sjögren syndrome, systemic sclerosis, polymyositis, dermatomyositis, or the rheumatoid arthritis. This is also the case of major rheumatic diseases whose early phase was defined by LeRoy et al.[2] in 1980 as undifferentiated connective tissue disease. The latent Lupus and the incomplete lupus are alternative terms used to describe this condition.[3]

The term is sometimes used interchangeably with the mixed connective tissue disease, it is an overlap syndrome. However, some researchers believe that UCTD is a clinically distinct entity and is strongly associated with the presence of titer high in antibodies Ribonucleoproteins (RNP).[4]

It is estimated that up to 25% of people with systemic autoimmune disease could be considered to have UCTD.[5]

Signs and symptoms

The presentation of the disease varies considerably from one patient to another, the UCTD being by definition non-specific,[6] it is a differential diagnosis. If the symptoms of a patient do not fit into a conventional diagnosis, it is the undifferentiated disease of connective tissue. Generally, the symptoms include Nonspecific symptoms common to connective tissue diseases such as fatigue, a malaise and fever.[7] Other symptoms associated with UCTD include :[8]

Clinical presentation in some people diagnosed with UCTD may show :[9]

Pulmonary involvement, such as nonspecific interstitial pneumonia, can be a complication of the disease.[5]

Diagnostic

If connective tissues are targeted by the immune system, connective tissue disease may occur. There are no formal diagnostic criteria for UCTD. Diagnostic tests are generally designed to determine whether a patient has a disease assured or undifferentiated of the connective tissues .[7]

A severe vitamin D deficiency has been associated with progression of UCTD to defined connective tissue diseases.[10] It has been shown that the presence of autoantibodies anti-dsDNA, anti-Sm and anti-cardiolipin correlate with the development of systemic lupus erythematosus in particular.[11]

Most patients will maintain a diagnosis of undifferentiated connective tissue disease. However, about a third of UCTD patients will differentiate into a specific autoimmune disease, such as rheumatoid arthritis or the systemic scleroderma. About 12% of patients will go into remission.[12]

In 90% of cases, the disease affects women aged 32 to 44 years old.[2] In addition, in the United States, up to 72% of patients diagnosed with one were white skinned, up to 78% of patients were female against 93 to 95% in Italy and 94% in Hungary.[2] 60% of cases will remain undifferentiated diseases and others will progress to a defined disease, several factors can help to predict this progression such as :

  • the presence of cytopenia at the time of the diagnostic.
  • The degree of modification of the capillaroscopy test (skin blood vessel study technique) of nail fold during the follow-up.
  • The presence of antinuclear antibodies.

Up to 10-20% of patients diagnosed with undifferentiated connective tissue disease will never progress to a defined disease and their symptoms will decrease or disappear, the rate of progression is higher in the first five years following the onset of the disease and tends to decrease over time. Patients progressing to a defined disease seem to see a slight progression of the disease with an mitigated risk of developing complications.[2] However, there is uncertainty about the name of the disease, making patients uncertain about what to do and understanding the disease.

Undifferentiated connective tissue disease is determined by a differential diagnosis. The diagnosis of this disease should not be established until a thorough examination has been evaluated because the characteristics of different connective tissue diseases can be the same.

Mechanism

Undifferentiated connective tissue disease is caused by genetic recombination and environmental factor such as, for example :

  • Exposure to harmful products such as cigarette smoke.
  • Exposure to an atmospheric pollutant, there are primaries air pollutants (nitrogen oxides (NOx), sulfur dioxide (SO2), volatile organic compounds (VOCs), hydrocarbons and certain metals (plomb, cadmium…)) or secondaries (created in the atmosphere through chemical reactions between pollutants).
  • The UV light.

These diseases can develop quickly or slowly, they can start with very little abnormality and then have definitive characteristics causing their increase.

Hypothesis

Populations of Regulatory T cells are believed to be responsible for the onset of the disease. When there is a decline of these cells, manifestations of diseases would begin to appear giving an idea of the vital role of these cells in the prevention of autoimmune diseases. Moreover, an additional decrease could unfortunately worsen the pathological state and lead to the differentiation of an undifferentiated connective tissue disease into a differentiated connective tissue disease with a poorer prognosis. Due to the wide range of variation in the inclusion criteria of the disease, up to 50% of patients diagnosed with connective tissue disease may have undifferentiated disease of the underlying connective tissue.

Formation phases

The initial phase may begin years before the diagnosis can be made due to the absence of signs, symptoms and lack of serological biomarker. In the next phase, autoantibodies can be detected in the serum despite the absence of clinical manifestations, this phase is variable according to the patients. Several antibodies are associated with it, but it is unclear whether they are innocent causes or markers of this disease. The most frequently detected antibodies are Anti-Ro/SSA et anti-U1-RNP. The final phase begins when noticeable signs and symptoms begin to appear, leading to a definitive diagnosis. These diseases can remain undifferentiated or later evolve into an identifiable connective tissue disease.

Anti-Ro/SSA type marker

Anti-Ro/SSA type is part of a family of autoantibodies recognizing polypeptide chains attached to small Y-RNA (from Y1 to Y5, these RNAs are included in the composition of Ro60 ribonucleoprotein). 70% of these RNAs are present in the cytoplasm and 30% in the nucleus.

These ribonucleoprotein complexes can be expressed on the cell membrane or apoptosis vesicles in case of stimulation to UV-B, 17-𝜷-oestradiol, viral infection, production of TNF-𝜶 or any other stimulants of apotosis.

Anti-Ro/SSA are frequently detected, in a very early phase of a pre-clinical stage, in the serum of 30% of systemic lupus. They are also markers of systemic Sjögren syndrome in 50% to 60% of cases and undifferentiated connectivities.[13]

AntiU1-RNP type marker

These autoantibodies against ribonucleoprotein U1 are part of the family of anti-nuclear autoantibodies (AAN). They are markers of the sharp syndrome (at least, signs of two connectabilities in a patient) and mixed connectivity.

Studies about these markers are few and contradictory.[13]

Assess and recognize the disease

To assess and recognize the disease, several mechanisms are available, including:

The use of image can also help in recognition, this is the case of chest X-ray which can show signs of pericardial effusion

Treatment

Treatment depends largely on the progression of the individual disease and the nature of the symptoms presented. The antimalarial medication, the corticosteroid and other medications may be prescribed, as the treating physician considers appropriate:[11]

Complications

Undifferentiated Connective Tissue Disease is thought as a systemic disease, patients have a wide variety of signs and symptoms as it can affect any connective tissue in the body. The first problem is whether the disease will progress to a defined disease and when the progression will occur. Although this disease can be treated with mild therapeutic intervention, patients may end up with a mentally and physically impaired quality of life.

Complications are present with an affected or injured system, such as the pulmonary system present a lesion and inflammation in the long term, an interstitial lung disease (in 88% of cases, severe interstitial lung disease) or a pulmonary fibrosis. If the heart is affected, a hypertrophy can occur, leading to a cardiomegaly.[2] Organs can also be affected (neurological or renal manifestations) and life-threatening conditions can occur. Some patients do not meet the diagnostic criteria for SLE and are diagnosed with latent lupus. Affected pregnant women follow a careful clinical observation because they are more likely to see a progression of the disease. Those with the disease at the beginning of pregnancy will keep the disease undifferentiated against 25% who progress to a defined disease at the end of pregnancy. In addition, 45% of pregnancies with the disease end in preterm birth.

Deterrence and patients education

Early recognition and knowledge of the onset of undifferentiated connective tissue disease can help patients manage and control their disease. Patients should be informed of common agents and triggers to help manage symptoms to shorten the duration of the disease and prevent complications.

Improving health care team outcomes

Undifferentiated connective tissue disease occurs for various reasons, underlying factors affect several organs depending on individual sensitivity. Coordination of care between primaries clinicians and experts (like rheumatologist) can help achieve optimal patient outcomes.

References

  1. ↑ Bodolay E, Szegedi G (May 2009). "Undifferentiated connective tissue disease". Orvosi Hetilap (in Hungarian). 150 (19): 867–872. doi:10.1556/OH.2009.28610. ISSN 1788-6120. PMID 19403430. S2CID 39614044.
  2. 1 2 3 4 5 Khaled, Marwa; Anjum, Fatima (January 2023). "Undifferentiated Connective Tissue Disease". StatPearls. PMID 34283427.
  3. ↑ Mosca M, Neri R, Bombardieri S (1999). "Undifferentiated connective tissue diseases (UCTD): a review of the literature and a proposal for preliminary classification criteria" (PDF). Clinical and Experimental Rheumatology. 17 (5): 615–20. PMID 10544849.
  4. ↑ Hoffman, Robert W.; Greidinger, Eric L. (2002). "23: Mixed connective tissue disease". In George C. Tsokos (ed.). Modern Therapeutics in Rheumatic Diseases. Humana Press. pp. 347–357. doi:10.1007/978-1-59259-239-5_23 (inactive 1 August 2023). ISBN 978-1-59259-239-5.{{cite book}}: CS1 maint: DOI inactive as of August 2023 (link)
  5. 1 2 Lunardi F, Balestro E, Nordio B, Cozzi F, Polverosi R, et al. (June 2011). "Undifferentiated connective tissue disease presenting with prevalent interstitial lung disease: Case report and review of literature". Diagnostic Pathology. 6 (50): 50. doi:10.1186/1746-1596-6-50. PMC 3126759. PMID 21645423.
  6. ↑ Owlia MB (2006). "Clinical spectrum of connective tissue disorders" (PDF). Journal, Indian Academy of Clinical Medicine. 7 (3): 218.
  7. 1 2 Doria A, Mosca M, Gambari P, Bombardieri S (February 2005). "Defining unclassifiable connective tissue diseases: incomplete, undifferentiated, or both?" (PDF). The Journal of Rheumatology. 32 (2): 213–215. PMID 15693073.
  8. ↑ Vaz C, Couto M, Medeiros D, Miranda L, Costa J, et al. (August 2009). "Undifferentiated connective tissue disease: a seven-center cross-sectional study of 184 patients". Clinical Rheumatology. 28 (8): 915–921. doi:10.1007/s10067-009-1175-2. hdl:10400.4/500. PMID 19390908. S2CID 3133285.
  9. ↑ Berman JR (2017). "Undifferentiated Connective Tissue Disease - In-Depth Overview". Hospital for Special Surgery.
  10. ↑ Zold E, Szodoray P, Gaal J, Kappelmayer J, Csathy L, et al. (2008). "Vitamin D deficiency in undifferentiated connective tissue disease". Arthritis Research & Therapy. 10 (5): R123. doi:10.1186/ar2533. PMC 2592813. PMID 18928561.
  11. 1 2 Mosca M, Baldini C, Bombardieri S (2004). "Undifferentiated connective tissue diseases in 2004" (PDF). Clinical and Experimental Rheumatology. 22 (3 Suppl 33): S14–S18. PMID 15344591.
  12. ↑ Bodolay E, Csiki Z, Szekanecz Z, Ben T, Kiss E, et al. (2003). "Five-year follow-up of 665 Hungarian patients with undifferentiated connective tissue disease (UCTD)". Clinical and Experimental Rheumatology. 21 (3): 313–320. PMID 12846049.
  13. 1 2 Meyer, Olivier (2002). "Actualités sur les anti-SSA/Ro et anti-SSB/La". EMConsulte (in French).
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