Undifferentiated connective tissue disease

Auto-immune disease

Medical condition

Undifferentiated connective tissue disease

Other names| latent Lupus, incomplete lupus
Specialty| Immunology, rheumatology
Symptoms| dry eyes, dry mouth, hair loss, joint inflammation, joint pain, mouth ulcers, positive ANA test, raynaud's phenomenon, sun-sensitive rash...

Undifferentiated connective tissue disease (UCTD) (also known as latent lupus or incomplete lupus[1]) 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 does not correspond to any criterion of specific autoimmune disease (such as systemic lupus erythematosus (SLE), scleroderma,[2] mixed connective tissue disease, Sjögren syndrome, systemic sclerosis, polymyositis, dermatomyositis, or rheumatoid arthritis). This is also the case of major rheumatic diseases whose early phase was defined by LeRoy et al.[3] in 1980 as undifferentiated connective tissue disease.

The term is sometimes used interchangeably with mixed connective tissue disease (MCTD), as it is an overlap syndrome. However, some researchers believe that MCTD 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]

There are many people who have features of connective tissue disease, such as blood test results and external characteristics, but do not fulfill the diagnostic criteria established for any one disease. These people are considered to have undifferentiated connective tissue disease (UCTD).[6][3]

## Signs and symptoms

[edit]

The presentation of the disease varies considerably from one patient to another.[7]

Generally, the symptoms include nonspecific symptoms common to connective tissue diseases such as

* fatigue – this is common in autoimmune diseases, and is the patient's primary concern[8]
* malaise; and
* fever.[9]

These can be the initial presentation for some patients.[3]

Other symptoms associated with UCTD include :[10]

* joint pain – the most common symptom, occurring in up to 86% of patients.[3] The pain is often an aching or arthritis-like pain in the elbows, wrists, hands, and knees, in a symmetrical pattern.[11]
* dry eyes
* dry mouth
* hair loss
* joint inflammation
* mouth ulcers
* Raynaud's phenomenon
* sun-sensitive rash

Clinical presentation in some people diagnosed with UCTD may show :[12]

* positive antinuclear antibody (ANA) test. Patients with UCTD usually have positive ANA.[13]
* a decrease in the number of white blood cells
* anemia
* abnormal nerve sensations in the extremities
* inflammation of the lining of the heart and/or lungs
* a decrease in platelet count

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

## Mechanism

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UCTD is caused[citation needed] by genetic and environmental factors. It may be triggered[citation needed] by factors such as:

* Exposure to harmful products such as cigarette smoke.
* Exposure to an atmospheric pollutant, primary air pollutants (nitrogen oxides [NOx], sulfur dioxide [SO2], volatile organic compounds [VOCs], hydrocarbons and certain metals [such as lead or cadmium]) or secondary (created in the atmosphere through chemical reactions between pollutants).
* Exposure to UV light.

### T-cell hypothesis

[edit]

Populations of regulatory T cells are believed to be responsible[citation needed] for the onset of the disease. When there is a decline of these cells, manifestations of diseases 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.

## Diagnosis and research inclusion

[edit]

### Diagnosis

[edit]

There are no formal diagnostic criteria for UCTD. It is determined by a differential diagnosis. Diagnostic tests are undertaken to determine whether a patient has a disease assured or undifferentiated of the connective tissues.[9]

Patients with UCTD usually have positive ANA (antinuclear antibody), and raised ESR (erythrocyte sedimentation rate) values, without typical autoantibody specificities.[13] Some 20% of the general population,[14] and up to 15% of completely healthy people,[15] test positive for ANA, but nonetheless this is regarded by some as almost always a sign of an autoimmune disorder.[11] If more specific types of ANAs or other proteins are present, other autoimmune conditions (not UCTD) are implied.[11][16]

Other mechanisms that may be used[citation needed] are tests for Anti-histone antibodies, Chromatin and vitamin D, and chest X-ray to show signs of pericardial effusion.[citation needed]

### Classification criteria

[edit]

Patients may be included for UCTD research if they have:

* Signs and symptoms which (a) are suggestive of a connective tissue disease, but (b) do not meet the criteria of any defined connective tissue diseases,[11] and (c) have lasted for at least three years. (Note if less than three years may be regarded as early UCTD).
* Positive ANA test on two different occasions.[3][17]

## Treatment

[edit]

UCTD is normally managed primarily as an outpatient. Meds can be used to manage aspects of the disease.[3]

Treatment depends largely on the progression of the individual disease and the nature of the symptoms presented. Antimalarial medications, corticosteroids and other medications may be prescribed, as the treating physician considers appropriate:[18]

* Nonsteroidal anti-inflammatory drugs for pain.
* Anti-inflammatory corticosteroids

In severe cases, immunosuppressive drugs may be used.

* Antimalarial medications (like hydroxychloroquine) can inhibit chemotaxis of neutrophil and eosinophil.
* Calcium channel blockers can be used to relax smooth muscles and decrease the resistance of the peripheral vascular system. This can help in managing Raynaud's phenomenon.

### Possible complications

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Complications are present with an affected or injured system, such as the lesions and long-term inflammation in the pulmonary system, interstitial lung disease (in 88% of cases, severe interstitial lung disease) or pulmonary fibrosis. If the heart is affected, hypertrophy can occur, leading to cardiomegaly.[3] Organs can also be affected (neurological or renal manifestations) and life-threatening conditions can occur.

Affected pregnant women follow careful clinical observation because they are more likely to see disease progression. 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.

### Prevention and patient education

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Early recognition and knowledge of the onset of UCTD 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.[citation needed]

### Improving health care team outcomes

[edit]

Undifferentiated connective tissue disease occurs for various reasons; underlying factors may affect several organs depending on individual sensitivity. Coordination of care between primary clinicians and experts (like rheumatologists) can help achieve optimal patient outcomes.[citation needed]

## Outlook

[edit]

### Progression

[edit]

30–40% of UCTD cases may develop into a defined connective tissue disease as more diagnostic criteria are progressively met.[3] This generally happens within five years of onset.[19]

Several factors may help predict progression:

* the presence of cytopenia at the time of diagnosis.
* the degree of modification of the capillaroscopy test (skin blood vessel study technique) of nail fold during follow-up.
* the presence of antinuclear antibodies.
* young age.[20]
* severe vitamin D deficiency.[21]
* the presence of anti-dsDNA, anti-Sm and anti-cardiolipin autoantibodies correlates with the development of systemic lupus erythematosus in particular.[18]

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 a mitigated risk of developing complications.[3]

### Remaining undifferentiated

[edit]

Most UCTD cases will remain undifferentiated. UCTD itself usually has a mild clinical course, particularly if there is low organ involvement. Most patients who remain undifferentiated tend to not experience major organ involvement.[22]

Up to 10–20% of patients diagnosed with UCTD will never progress to a defined disease and their symptoms will decrease or disappear.[3]

About 12% of patients will go into remission.[23][22]

### Particular studies

[edit]

* In a Bulgarian study, after five years, 34% had developed into a defined connective tissue disease (with the highest probability of development being within the first two years after onset of symptoms), 54% continued undifferentiated and 12% were in remission.[22]
* In a US study, after 10 years, 37% had developed into a defined connective tissue disease, 43% continued undifferentiated and 20% were in remission.[22]
* In a Spanish study, after a mean follow-up of 11±3 years, 14% had developed a definite CTD, 62% continued undifferentiated, and 24% were in remission.[24]
* In an Italian study (in which 58% had ANA abnormalities), after five years, 6% had developed a defined autoimmune disease. The remaining 94% saw clinical and serological features little changed in the period and quite stable. 11% of these were and remained asymptomatic.[25]

## Epidemiology

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Up to 90% of UCTD cases are females between 32 and 44 years old.[3][26] In the United States up to 78% of patients were female, against 93 to 95% in Italy and 94% in Hungary. Higher female prevalence is common in autoimmune diseases.[citation needed]

In the United States, up to 72% of patients diagnosed with UCTD had white skin.[3]

Prevalence of UCTD has been estimated at 2 people per 100,000 people per year.[27] Annual incidence has been estimated as varying from 41 to 149 per 100,000 adults.[28][29][30] It has also been suggested that UCTD is a relatively common condition seen in rheumatology practice, making up 10–20% of referrals to tertiary care clinics.[31]

Classical epidemiological data for UCTD are not available due to the limited literature exploring the disease. Also, differences in patient selection criteria in existing studies make comparisons between them difficult.[1]

## History

[edit]

The term was first suggested in 1980,[32] as connective tissue disease in patients whose features did not meet other classification criteria.[3] In 1999 a study noted, "In recent years there has been growing concern regarding the diagnosis of incomplete forms of the autoimmune diseases"[25] and the first classification criteria were proposed in that year.[1]

Historically the condition was sometimes called undifferentiated connective tissue syndrome, latent lupus or incomplete lupus.[1]

## References

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1. ^ a b c d 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): 615–620. PMID 10544849.
2. ^ Bodolay E, Szegedi G (May 2009). "[Undifferentiated connective tissue disease]". Orvosi Hetilap (in Hungarian). 150 (19): 867–872. doi:10.1556/OH.2009.28610. PMID 19403430. S2CID 39614044.
3. ^ a b c d e f g h i j k l m Marwa K, Anjum F (2024). "Undifferentiated Connective Tissue Disease". StatPearls. StatPearls Publishing. PMID 34283427.
4. ^ Hoffman RW, Greidinger EL (2002). "Chapter 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 2024-09-18). ISBN 978-1-59259-239-5.`{{cite book}}`: CS1 maint: DOI inactive as of September 2024 (link)
5. ^ a b Lunardi F, Balestro E, Nordio B, Cozzi F, Polverosi R, Sfriso P, 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. ^ "Undifferentiated connective tissue disease (UCTD)". Clinton Township, MI: Autoimmune Association.
7. ^ Owlia MB (2006). "Clinical spectrum of connective tissue disorders" (PDF). Journal, Indian Academy of Clinical Medicine. 7 (3): 218.
8. ^ Zielinski MR, Systrom DM, Rose NR (2019). "Fatigue, Sleep, and Autoimmune and Related Disorders". Frontiers in Immunology. 10: 1827. doi:10.3389/fimmu.2019.01827. PMC 6691096. PMID 31447842.
9. ^ a b Doria A, Mosca M, Gambari PF, Bombardieri S (February 2005). "Defining unclassifiable connective tissue diseases: incomplete, undifferentiated, or both?" (PDF). The Journal of Rheumatology. 32 (2): 213–215. PMID 15693073.
10. ^ Vaz CC, Couto M, Medeiros D, Miranda L, Costa J, Nero P, 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.
11. ^ a b c d Rodgers L (September 27, 2020). "What Is Undifferentiated Connective Tissue Disease? Here's How to Know If You Have It".
12. ^ Berman JR (2017). "Undifferentiated Connective Tissue Disease - In-Depth Overview". Hospital for Special Surgery.
13. ^ a b Talotta R (2023). "The diagnostic laboratory tests in rheumatic diseases". Translational Autoimmunity. pp. 113–148. doi:10.1016/B978-0-323-85831-1.00007-3. ISBN 978-0-323-85831-1.
14. ^ Zanussi JT, Zhao J, Wei WQ, Karakoc G, Chung CP, Feng Q, et al. (August 2023). "Clinical diagnoses associated with a positive antinuclear antibody test in patients with and without autoimmune disease". BMC Rheumatology. 7 (1): 24. doi:10.1186/s41927-023-00349-4. PMC 10405518. PMID 37550754.
15. ^ "Antinuclear Antibodies (ANA)". rheumatology.org.
16. ^ "For example: People with lupus may also test positive for anti-double-stranded DNA antibody (anti-dsDNA) and anti-Smith (anti-Sm) antibody. People with myositis may have elevated levels of a muscle enzyme called creatine kinase (CK) that could be a sign of polymyositis. People with rheumatoid arthritis may test positive for the antibodies anti-cyclic citrullinated peptides (anti-CCP) and rheumatoid factor. People with Sjögren’s may test positive for anti-Ro (SS-A) and anti-La (SS-B) antibodies as well as rheumatoid factor."
17. ^ "Undifferentiated Connective Tissue Disease – In-Depth". Hospital for Special Surgery (HSS).
18. ^ a b 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.
19. ^ Herrick A, Hughes M (2013). "Overlap/Undifferentiated syndromes". Oxford Textbook of Rheumatology. pp. 1069–1078. doi:10.1093/med/9780199642489.003.0129_update_001. ISBN 978-0-19-964248-9.
20. ^ Dyball S, Rodziewicz M, Mendoza-Pinto C, Bruce IN, Parker B (November 2022). "Predicting progression from undifferentiated connective tissue disease to definite connective tissue disease: A systematic review and meta-analysis". Autoimmunity Reviews. 21 (11): 103184. doi:10.1016/j.autrev.2022.103184. PMID 36031048.
21. ^ Zold E, Szodoray P, Gaal J, Kappelmayer J, Csathy L, Gyimesi E, 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.
22. ^ a b c d Pepmueller PH (January 23, 2016). "Undifferentiated Connective Tissue Disease, Mixed Connective Tissue Disease, and Overlap Syndromes in Rheumatology". Missouri Medicine. 113 (2): 136–140. PMC 6139943. PMID 27311225.
23. ^ Bodolay E, Csiki Z, Szekanecz Z, Ben T, Kiss E, Zeher M, 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.
24. ^ García-González M, Rodríguez-Lozano B, Bustabad S, Ferraz-Amaro I (2017). "Undifferentiated connective tissue disease: predictors of evolution into definite disease". Clinical and Experimental Rheumatology. 35 (5): 739–745. PMID 28770704.
25. ^ a b Danieli MG, Fraticelli P, Franceschini F, Cattaneo R, Farsi A, Passaleva A, et al. (1999). "Five-year follow-up of 165 Italian patients with undifferentiated connective tissue diseases". Clinical and Experimental Rheumatology. 17 (5): 585–591. PMID 10544842.
26. ^ Angum F, Khan T, Kaler J, Siddiqui L, Hussain A (May 2020). "The Prevalence of Autoimmune Disorders in Women: A Narrative Review". Cureus. 12 (5): e8094. doi:10.7759/cureus.8094. PMC 7292717. PMID 32542149.
27. ^ Purohit R, Shahu Khal R, Gokalp G, Sambandan R, Bhanusali N (June 2023). "Undifferentiated Connective Tissue Disease With Isolated Diaphragmatic Dysfunction". Cureus. 15 (6): e40515. doi:10.7759/cureus.40515. PMC 10350301. PMID 37461764.
28. ^ Deane KD, El-Gabalawy H (April 2014). "Pathogenesis and prevention of rheumatic disease: focus on preclinical RA and SLE". Nature Reviews. Rheumatology. 10 (4): 212–228. doi:10.1038/nrrheum.2014.6. PMC 4090326. PMID 24514912.
29. ^ Spinillo A, Beneventi F, Caporali R, Ramoni V, Montecucco C (December 2017). "Undifferentiated connective tissue diseases and adverse pregnancy outcomes. An undervalued association?". American Journal of Reproductive Immunology. 78 (6). doi:10.1111/aji.12762. PMID 28921728. S2CID 13081256.
30. ^ Serena C, Clemenza S, Simeone S, Zullino S, Ottanelli S, Rambaldi MP, et al. (January 23, 2022). "Undifferentiated Connective Tissue Disease in Pregnancy: A Topic Yet to be Explored". Frontiers in Pharmacology. 13: 820760. doi:10.3389/fphar.2022.820760. PMC 8811283. PMID 35126164.
31. ^ Olsen NJ (2019). "Incomplete Lupus, Undifferentiated Connective Tissue Disease, and Mixed Connective Tissue Disease". Dubois' Lupus Erythematosus and Related Syndromes. pp. 606–613. doi:10.1016/B978-0-323-47927-1.00048-7. ISBN 978-0-323-47927-1.
32. ^ LeRoy EC, Maricq HR, Kahaleh MB (March 1980). "Undifferentiated connective tissue syndromes". Arthritis and Rheumatism. 23 (3): 341–343. doi:10.1002/art.1780230312. PMID 7362686.

Classification|

* ICD-10: M35.9
* ICD-9-CM: 710.9
* MeSH: D000074079

|

External resources|

* Orphanet: 90002