Continuing Education Activity

Undifferentiated connective tissue disease is a clinical entity defined as serological and clinical manifestations of systemic autoimmune disease, however, not fulfilling any criteria of defined connective tissue disease. This disease is considered a diagnosis of exclusion. The presenting symptoms can suggest any other connective tissue disease so that the presentation can vary widely among patients. Up to 90% of the cases are females between 32 and 44 years old. This activity reviews the evaluation and management of undifferentiated connective tissue disease and highlights the role of the interprofessional team in improving care for patients with this condition.

Objectives:

• Describe the epidemiology of undifferentiated connective tissue disease.
• Summarize the pathophysiology of undifferentiated connective tissue disease.
• Explain the common physical exam findings associated with undifferentiated connective tissue disease.
• Review the importance of collaboration and coordination among the interprofessional team to enhance the care of patients with undifferentiated connective tissue disease.

Introduction

The connective tissues play a crucial role within organs by supporting and binding several types of tissues. If these tissues are targeted by the immune system, a connective tissue disease may occur, resulting in a wide range of signs and symptoms.

The connective tissue disease is an umbrella for a wide variety of diseases. For each one, there are diagnostic criteria. However, if the signs and symptoms of a patient do not meet any of these diagnostic criteria, the diagnosis of undifferentiated connective tissue disease will be established.[1][2]

Undifferentiated connective tissue disease is a clinical entity defined as serological and clinical manifestations of systemic autoimmune disease. However, not fulfilling any criteria of defined connective tissue disease such as systemic lupus erythematosus, mixed connective tissue disease, Sjögren syndrome, systemic sclerosis, polymyositis, dermatomyositis, or rheumatoid arthritis. In clinical practice, the presence of undifferentiated connective tissue disease can be common.

The early phase of a major rheumatic disease was defined earlier by LeRoy et al. in 1980 as undifferentiated connective tissue disease in patients whose features did not meet other classification criteria.[3][4][5]

Etiology

In general, the etiology of autoimmune diseases is not completely understood. However, most autoimmune diseases are known to be caused by a combination of genetic and environmental factors.

Autoimmune diseases are characterized by the presence of spontaneous and exaggerated activity of the immune system, which may result in the formation of autoantibodies or by activation of antigen-specific T-cells, which can target autoantigens within different organs.

Autoimmune connective tissue diseases occur when the immune system targets connective tissues. It can also be triggered following exposure to certain environmental factors. Examples of environmental factors include exposure to harmful chemicals, like those found in cigarette smoke, pollutants in the air, and ultraviolet light.[4]

These diseases can have different presentations and may develop rapidly or slowly, and may start with very few abnormalities before exhibiting definitive disease features.[6]

Researchers have tried to investigate the underlying cause of this condition and what can trigger these disease flares. T-regulatory cell populations were thought to be the culprit in starting such a disease. When these cells decrease in their numbers, disease manifestations start to appear, giving a clue about the vital role of these cells in preventing autoimmune diseases. In addition, a further decrease in the number of the T- regulatory cells may, unfortunately, worsen the disease condition and result in the differentiation of undifferentiated connective tissue disease into a differentiated connective tissue disease which carries a worse prognosis.[7][3]

Epidemiology

Up to 90% of undifferentiated connective tissue disease cases occur in females, especially those between 32 and 44 years old, and the majority of these cases do not progress into a full-blown connective tissue disease. These patients tend to remain stable over time by only showing mild clinical symptoms with a sole autoantibody profile.[3]

Due to the wide range of variations in the inclusion criteria, up to 50% of patients diagnosed with a connective tissue disease may have an underlying undifferentiated connective tissue disease.[8]

In the United States, up to 72% of patients diagnosed with undifferentiated connective tissue disease were of the White race. Up to 78% of patients were females compared to 93 to 95% in Italy and 94% in Hungary.[4][9][10][11]

Pathophysiology

In general, undifferentiated connective tissue disease, like many autoimmune diseases, is thought to exist in consecutive phases. However, the initial phase may start years before the diagnosis can be established due to the absence of signs and symptoms and the lack of serological biomarkers.

In the subsequent phase, autoantibodies can be detected in the serum despite the absence of clinical manifestations. This phase can be considered an interval phase between detecting autoantibodies and the onset of significant signs or symptoms and can be significantly variable among patients.[7] 

The final phase begins when notable signs and symptoms start to appear, leading to a definitive diagnosis. These patients can remain undifferentiated, or they may evolve later into an identifiable connective tissue disease.[3]

Various autoantibodies are associated the undifferentiated connective tissue disease, but it is unknown whether these antibodies are causes or innocent markers of this disease.[4] Anti-Ro/SSA and anti-U1-RNP are considered the most frequently detected markers in this disease.

To evaluate the disease features, studies were established. For example, Szodoray et al. assessed the association between various immune-competent T-cell numbers and the progression of connective tissue disease. They also evaluated certain immune phenotypes to predict the consecutive progression of defined connective tissue disease. The absolute and relative number of the natural regulatory T-cells were found to be decreased in patients with undifferentiated connective tissue disease when compared with the control groups. Besides, the decrease in the number of natural regulatory T-cells was found to be associated with the progression of the undifferentiated connective tissue disease to a differentiated connective tissue disease. In addition, the number of regulatory T-cells was significantly decreased in patients with a differentiated disease as systemic sclerosis compared to undifferentiated connective tissue disease patients, suggesting that the levels of these cells might represent a useful marker of the disease progression.[3] 

Furthermore, vitamin D deficiency can result in pathological changes in the function and number of the CD4+ T-helper cells in patients with undifferentiated connective tissue disease, and the supplementation of vitamin D showed an improvement in the balance of anti-inflammatory and pro-inflammatory processes in the disease.[7]

History and Physical

In 1999, preliminary yet frequently used criteria were proposed to be used in the diagnosis of undifferentiated connective tissue disease. These criteria significantly depend on the absence of any other defined or major connective tissue disease.[1][12] 

In detail, these criteria include the following: (1) clinical presentation suggestive of a defined connective tissue disease, but not meeting its criteria, (2) positive serological markers on two separate occasions including positive antinuclear antibody marker, and (3) the duration of symptoms to be at least three years.[4] 

As mentioned earlier, the symptoms can suggest any other connective tissue disease so that the presentation can vary widely among patients.

However, some symptoms can be very common in the majority of patients. For instance, arthralgia can be present in up to 86% of patients; various skin lesions, including livedo, purpura, acrocyanosis, telangiectasias, and urticaria, can also be common (37%). Other common symptoms include the Raynaud phenomenon (33%), sicca symptoms (30%), mucocutaneous symptoms, such as oral ulcers (23%), and arthritis (22%), fever (15%), and thyroid disease (7%).[7][8] 

Undifferentiated connective tissue disease appears to have a mild clinical course. It is marked by the absence of severe organ damage or involvement, especially in the renal and neurological systems.

Other minor symptoms include dry eyes or mouth, hair loss, and sun-sensitive rash.

Additional signs include leukopenia, anemia, pleuritis, pericarditis, thrombocytopenia, abnormal nerve sensations in limbs, and interstitial pneumonia.[11] 

Constitutional symptoms, such as fever, feeling unwell, and fatigue, can be the initial presentation for some patients.[13][7]

With this disease, the physical findings can be localized or diffuse, and it is best illustrated by organ systems, as the following:

• Skin - Sclerodactyly, calcinosis, discoid rash, erythema nodosum, periungual erythema, heliotrope rash, dilated or irregular nail fold capillaries, or subcutaneous nodules.
• Eyes – Iritis, uveitis, scleral-episcleral disease, or conjunctivitis.
• Lungs - Rales, pleural effusion, wheezing, or pleural rub.
• Heart - Cardiomegaly, heart murmur, pericardial rub, irregular heartbeat, dependent edema, or irregular P2 heart sound.
• Gastrointestinal – Splenomegaly, abdominal tenderness, or hepatomegaly.
• Genitalia – Rashes, abnormal discharge, or ulcerations.
• Muscles – Proximal muscle weakness, muscle tenderness, tendon friction rubs, or muscle atrophy.[9][8][14][10][15][16]

Evaluation

Positive serological markers are considered essential in the diagnostic criteria for undifferentiated connective tissue disease, so the laboratory measures are beneficial in diagnosis, especially anti-Ro/SSA and anti-U1-RNP. Other tests helpful in diagnosis include routine screening tests, which include: complete blood count, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), serum creatinine, urinalysis with microscopic analysis, rheumatoid factor (RF), and antinuclear antibodies (ANA).[7][11]

Additional laboratory tests can be used in some cases, which include: complement components (c3, c4, ch50), creatine kinase, aldolase, anti-cyclic citrullinated peptide (CCP), anti-La/SSB, thyroid-stimulating hormone, anti-jo1, anti-smith, anti-mi2, anti-cardiolipins, lupus anticoagulant, anti-beta-2 glycoprotein 1, Anti-Ku, rapid plasma reagin (RPR), anti-scl70 (topoisomerase antibody), anti-chromatin, anti-histone and vitamin D (25[OH]D3).[7][17] 

Regarding imaging studies, chest radiography can be normal or may display signs of pleural or pericardial effusion, longstanding pulmonary hypertension, cardiomegaly, or interstitial lung disease. Computed tomography of the chest may be needed in the assessment of interstitial lung disease. Additionally, ultrasonography of the salivary glands was found to be a good test in differentiating between undifferentiated connective tissue disease and Sjögren syndrome.[18][19] 

Other tests can be helpful: Pulmonary function tests, including lung volumes, spirometry, and carbon monoxide-diffusing capacity, assist in diagnosing interstitial lung disease. When patients have cardiac symptoms, electrocardiography can be helpful in the detection of ischemic changes, chamber enlargement, or axis deviation. The Schirmer test can also be used in patients with dry eyes due to high sensitivity but can be nonspecific in patients who take anticholinergic medications.[20][21][15]

Treatment / Management

Undifferentiated connective tissue disease usually has a mild clinical course and can be managed primarily as an outpatient. Many drugs can be used, including nonsteroidal anti-inflammatory drugs, corticosteroids, calcium channel blockers, and antimalarial drugs such as hydroxychloroquine. These drugs are considered the cornerstone of therapy. In severe cases, immunosuppressive drugs can be used, especially when there is severe organ damage or involvement. The surgical option is not routinely used in this disease. In addition, some simple things could help patients, such as applying sunblock lotions and using protective clothing in patients with photosensitivity. Despite the mild clinical course, specialty consultations can sometimes be required to improve management in some patients.[14][22][23] 

To be specific, NSAIDs can be useful for their antipyretic, analgesic, and anti-inflammatory effects. Naproxen is a good example, and it is used for mild-to-moderate pain relief. Another choice is COX-2 selective medication such as celecoxib, which is used to minimize adverse effects seen with non-selective NSAIDs as gastric ulcers and gastrointestinal bleeding. 

Systemic corticosteroids are often used to induce remission in case of flaring-up. These are usually prescribed in combination with other drugs to control the systemic inflammation associated with this disease. Prednisone is a common type of systemic corticosteroid and is considered an immunosuppressant agent. It is often used for autoimmune disorders since it can decrease the inflammation caused by the immune system. 

If the manifestations of undifferentiated connective tissue disease are not well controlled with the previous medications or if the symptoms are severe, immunosuppressant agents are the key treatment. A couple of drugs are typically utilized in this disease, such as methotrexate or azathioprine. Both have been shown to control severe symptoms. Methotrexate is considered a steroid-sparing agent. This drug decreases symptoms of inflammation associated with undifferentiated connective tissue disease. Azathioprine is typically effective for joint and extra-articular symptoms.[24][25] 

Antimalarial drugs are usually used in case of a severe rash or photosensitivity. These drugs have anti-chemotactic effects on inflammatory leukocytes. They can prevent intracellular processing of the autoantigens. These drugs are usually used in combination with NSAIDs to control articular, mucocutaneous, and constitutional symptoms. Hydroxychloroquine is a common example, and it can inhibit the chemotaxis of neutrophils and eosinophils, which prevent the activation of complement systems.[26][27][23] 

Calcium channel blockers are commonly used in connective tissue diseases. They can relax the vascular smooth muscles and decrease the resistance of peripheral vessels, which helps in the management of the Raynaud phenomenon. Nifedipine and diltiazem are examples of calcium channel blockers.[22][23][14][28][24]

Differential Diagnosis

Since undifferentiated connective tissue disease is considered a diagnosis of exclusion, the diagnosis of this disease should not be established until an extensive workup has been evaluated. Other connective tissue diseases should be considered while evaluating any patient presenting with features of this disease. Nonetheless, features of connective tissue diseases can overlap; thus, early differentiation is a must to initiate appropriate treatment, monitor patients, and predict the prognosis. However, some disease criteria can also overlap and further complicate the diagnostic workup in some patients who present with a possible connective tissue disease. 

• Dermatomyositis
• Antiphospholipid syndrome
• Fibromyalgia
• Linear scleroderma and regional fibrosis
• Systemic lupus erythematosus (SLE)
• Overlap syndromes
• Mixed connective tissue disease (MCTD)
• Raynaud phenomenon
• Polymyositis
• Sjögren syndrome
• Systemic sclerosis
• Rheumatoid arthritis (RA)

Prognosis

The prognosis of undifferentiated connective tissue disease usually relies on the degree of organ involvement. However, up to 60% of cases will remain undifferentiated, and others may progress into a defined connective tissue disease. A couple of factors may help in the prediction of this progression, for instance, the presence of cytopenias at the time of diagnosis, the degree of changes of the nail fold-capillaroscopy test during the follow-up sessions, and the antinuclear antibody titers, all of which may prove predictive about the disease in the future.[23][29] 

Up to 10 to 20% of patients diagnosed with undifferentiated connective tissue disease will never progress into a defined disease, and their symptoms will remit or subside. The progression rate into a defined connective tissue disease is the highest within the first five years of the disease onset; this rate tends to decrease over time, and patients who have progressed late to a defined disease appear to have a milder disease course with a lower chance to develop complications and adverse events. Additionally, the survival rates in these patients appear to be similar to those with systemic lupus erythematosus and rheumatoid arthritis.[11][30][9][31][32][14][33]

It is mentioned in a recent study which was published in 2019 that clinical practice guidelines or recommendations were not defined yet, and potential areas of intervention and a precise definition of undifferentiated connective tissue disease are still absent. This uncertainty regarding the name of the disease makes patients feel uncertain about the education and understanding of this disease. [1]

Complications

Undifferentiated connective tissue disease is considered one of the systemic autoimmune diseases. Patients diagnosed with this disease can present with a wide variety of signs and symptoms since this disease may involve any connective tissue in our body.

The first problem that arises when assessing the patients with undifferentiated connective tissue disease is whether this condition will progress to a defined connective tissue disease and when this progression will be most likely to happen. Although this condition is relatively stable over a long period and usually requires only mild therapeutic intervention, many patients may show an impaired quality of life both mentally and physically. 

 Complications are dependent upon what system is affected or injured. For example, when the pulmonary system sustains a long-term injury and inflammation, interstitial lung disease or even lung fibrosis can occur. Additionally, if the heart was affected, an enlargement can occur, resulting in cardiomegaly. Aside from lung and heart involvement, there is an up to 40% chance of progressing into a defined connective tissue disease.[34][35] 

 Severe organ involvements (such as neurological or renal manifestations) or even life-threatening conditions are sometimes reported. Besides, severe interstitial lung involvement can also occur. In addition, around 88% of the patients with idiopathic nonspecific interstitial pneumonia may meet the diagnostic criteria for undifferentiated connective tissue disease.[35][36][37] 

Regarding the evolution of a stable undifferentiated connective tissue disease, it is rare for this condition to progress into a defined disease, such as systematic lupus erythematosus, which only occurs in 10% of patients, especially if the condition remains stable for more than three years. The presence of photosensitivity, Raynaud's phenomenon, or sicca symptoms is associated with a lower chance of the disease progression into SLE.

Some patients may not fulfill the diagnostic criteria for SLE and will be diagnosed with a latent form of lupus. Moreover, pregnant females with undifferentiated connective tissue disease deserve careful clinical observation since they are more liable to have disease exacerbation or even evolution. The majority of patients with undifferentiated connective tissue disease at the onset of the pregnancy period will remain undifferentiated, while about 25% of them will evolve into a defined connective tissue disease by the end of pregnancy. In addition, up to 45% of pregnancies ended as preterm deliveries.[38][39]

Deterrence and Patient Education

Early recognition and proper awareness of the occurrence of undifferentiated connective tissue disease can help patients to manage and control their condition optimally.

Patients should be educated about the common offending agents and the triggering factors and help manage their symptoms.

It is also mandatory to educate patients about the symptoms that require immediate medical attention. All of these may help patients lessen the discomfort and shorten the duration of illness and prevent any complications.

Enhancing Healthcare Team Outcomes

Undifferentiated connective tissue disease can occur due to various reasons, and underlying factors can affect multiple organs, depending on individual susceptibility. Therefore, coordination of care between primary clinicians and specialists (rheumatologists) can help achieve optimal outcomes for these patients.

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References

1.

Antunes M, Scirè CA, Talarico R, Alexander T, Avcin T, Belocchi C, Doria A, Franceschini F, Galetti I, Govoni M, Hachulla E, Launay D, Lepri G, Macieira C, Matucci-Cerinic M, Montecucco CM, Moraes-Fontes MF, Mouthon L, Paolino S, Ramoni V, Tani C, Tas SW, Tincani A, Van Vollenhoven R, Zen M, Fonseca J, Bombardieri S, Fonseca JE, Schneider M, Smith V, Cutolo M, Mosca M, Beretta L. Undifferentiated connective tissue disease: state of the art on clinical practice guidelines. RMD Open. 2018;4(Suppl 1):e000786. [PMC free article: PMC6397427] [PubMed: 30886731]

2.

LeRoy EC, Maricq HR, Kahaleh MB. Undifferentiated connective tissue syndromes. Arthritis Rheum. 1980 Mar;23(3):341-3. [PubMed: 7362686]

3.

Mosca M, Tani C, Talarico R, Bombardieri S. Undifferentiated connective tissue diseases (UCTD): simplified systemic autoimmune diseases. Autoimmun Rev. 2011 Mar;10(5):256-8. [PubMed: 20863913]

4.

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. [PubMed: 10544849]

5.

Kamrani P, Marston G, Arbor TC, Jan A. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Mar 5, 2023. Anatomy, Connective Tissue. [PubMed: 30860769]

6.

Bodolay E, Szegedi G. [Undifferentiated connective tissue disease]. Orv Hetil. 2009 May 10;150(19):867-72. [PubMed: 19403430]

7.

Mosca M, Tani C, Neri C, Baldini C, Bombardieri S. Undifferentiated connective tissue diseases (UCTD). Autoimmun Rev. 2006 Nov;6(1):1-4. [PubMed: 17110308]

8.

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 Sep-Oct;17(5):585-91. [PubMed: 10544842]

9.

Mosca M, Tani C, Bombardieri S. Undifferentiated connective tissue diseases (UCTD): a new frontier for rheumatology. Best Pract Res Clin Rheumatol. 2007 Dec;21(6):1011-23. [PubMed: 18068858]

10.

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 Sep;18(9):1332-9. [PubMed: 1757934]

11.

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. [PubMed: 12415590]

12.

Mosca M, Tani C, Carli L, Bombardieri S. Undifferentiated CTD: a wide spectrum of autoimmune diseases. Best Pract Res Clin Rheumatol. 2012 Feb;26(1):73-7. [PubMed: 22424194]

13.

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. [PubMed: 9694051]

14.

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 May-Jun;21(3):313-20. [PubMed: 12846049]

15.

Kelly BT, Moua T. Overlap of interstitial pneumonia with autoimmune features with undifferentiated connective tissue disease and contribution of UIP to mortality. Respirology. 2018 Jun;23(6):600-605. [PubMed: 29320807]

16.

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. [PubMed: 14501291]

17.

González C, Garcia-Berrocal B, Herráez O, Navajo JA, González-Buitrago JM. Anti-nucleosome, anti-chromatin, anti-dsDNA and anti-histone antibody reactivity in systemic lupus erythematosus. Clin Chem Lab Med. 2004 Mar;42(3):266-72. [PubMed: 15080558]

18.

Luciano N, Baldini C, Tarantini G, Ferro F, Sernissi F, Varanini V, Donati V, Martini D, Mosca M, Caramella D, Bombardieri S. 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. [PubMed: 26206346]

19.

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. [PubMed: 18328157]

20.

Tozzoli R, Bizzaro N, Tonutti E, Villalta D, Bassetti D, Manoni F, Piazza A, Pradella M, Rizzotti P., Italian Society of Laboratory Medicine Study Group on the Diagnosis of Autoimmune Diseases. 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. [PubMed: 11863229]

21.

Zold E, Szodoray P, Gaal J, Kappelmayer J, Csathy L, Gyimesi E, Zeher M, Szegedi G, Bodolay E. Vitamin D deficiency in undifferentiated connective tissue disease. Arthritis Res Ther. 2008;10(5):R123. [PMC free article: PMC2592813] [PubMed: 18928561]

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 Aug;28(8):915-21. [PubMed: 19390908]

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 Jun;4(6):328-32. [PubMed: 18414458]

24.

Koo SM, Uh ST. Treatment of connective tissue disease-associated interstitial lung disease: the pulmonologist's point of view. Korean J Intern Med. 2017 Jul;32(4):600-610. [PMC free article: PMC5511941] [PubMed: 28704913]

25.

Gao Y, Moua T. Treatment of the Connective Tissue Disease-Related Interstitial Lung Diseases: A Narrative Review. Mayo Clin Proc. 2020 Mar;95(3):554-573. [PubMed: 32138882]

26.

Pepmueller PH. Undifferentiated Connective Tissue Disease, Mixed Connective Tissue Disease, and Overlap Syndromes in Rheumatology. Mo Med. 2016 Mar-Apr;113(2):136-40. [PMC free article: PMC6139943] [PubMed: 27311225]

27.

Yang S, Ni R, Lu Y, Wang S, Xie F, Zhang C, Lu L. A three-arm, multicenter, open-label randomized controlled trial of hydroxychloroquine and low-dose prednisone to treat recurrent pregnancy loss in women with undifferentiated connective tissue diseases: protocol for the Immunosuppressant regimens for LIving FEtuses (ILIFE) trial. Trials. 2020 Sep 09;21(1):771. [PMC free article: PMC7488113] [PubMed: 32907619]

28.

Mathai SC, Danoff SK. Management of interstitial lung disease associated with connective tissue disease. BMJ. 2016 Feb 24;352:h6819. [PMC free article: PMC6887350] [PubMed: 26912511]

29.

Mosca M, Tani C, Bombardieri S. Defining undifferentiated connective tissue diseases: a challenge for rheumatologists. Lupus. 2008 Apr;17(4):278-80. [PubMed: 18413407]

30.

Mosca M, Baldini C, Bombardieri S. Undifferentiated connective tissue diseases in 2004. Clin Exp Rheumatol. 2004 Jan-Feb;22(3 Suppl 33):S14-8. [PubMed: 15344591]

31.

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. [PubMed: 28770704]

32.

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 Aug;20(8):971-9. [PubMed: 18550583]

33.

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 Apr;26(4):816-25. [PubMed: 10229402]

34.

Riccardi A, Marcoccia A, Borgia A, Guastafierro T, Bondanini F, Fasano S, Irace R, Messiniti V, Sanduzzi A, Bocchino M, Ciani A, D'Alto M, Argiento P, De Matteis GM, Spanò A, Valentini G. Undifferentiated connective tissue disease at risk of systemic sclerosis: A weighted score to identify patients who will evolve. Autoimmun Rev. 2019 Sep;18(9):102358. [PubMed: 31323358]

35.

Chernau AK, Leone PM, Swigris JJ. Interstitial Pneumonia with Autoimmune Features and Undifferentiated Connective Tissue Disease. Semin Respir Crit Care Med. 2019 Apr;40(2):271-277. [PubMed: 31137065]

36.

Mosca M, Tani C, Vagnani S, Carli L, Bombardieri S. The diagnosis and classification of undifferentiated connective tissue diseases. J Autoimmun. 2014 Feb-Mar;48-49:50-2. [PubMed: 24518855]

37.

Kinder BW, Collard HR, Koth L, Daikh DI, Wolters PJ, Elicker B, Jones KD, King TE. Idiopathic nonspecific interstitial pneumonia: lung manifestation of undifferentiated connective tissue disease? Am J Respir Crit Care Med. 2007 Oct 01;176(7):691-7. [PMC free article: PMC1994238] [PubMed: 17556720]

38.

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. 2013 Apr;33(4):1085-8. [PubMed: 22116525]

39.

Mosca M, Tani C, Carli L, Della Rossa A, Talarico R, Baldini C, Bombardieri S. Analysis of the evolution of UCTD to defined CTD after a long term follow-up. Clin Exp Rheumatol. 2013 May-Jun;31(3):471. [PubMed: 23075608]

Disclosure: Khaled Marwa declares no relevant financial relationships with ineligible companies.

Disclosure: Fatima Anjum declares no relevant financial relationships with ineligible companies.