published by nonprofit Johns Hopkins Press
posted in Connective Tissue Diseases, MCTD, UCTD, Sjogren's, RA, etc on March 10, 2024 by
Updated January 27, 2025
Undifferentiated connective tissue disease (UCTD) is one of the most common rheumatologic diagnoses. Many systemic lupus patients start off having a UCTD, which can be confusing. Some may feel it is a “wishy-washy” term or a problem with the doctor making a correct diagnosis. However, it is an actual autoimmune disease that attacks the body and is important to understand.
UCTD is real!
UCTD is also often confused with mixed connective tissue disease and overlap syndromes. Therefore, we will also discuss these.
Understand more about antinuclear antibodies: The medical newspaper, The Rheumatologist, published my article about “A Practical Guide to Autoantibody Testing in Rheumatic Diseases.” Though it is written for healthcare providers, it gives lots of interesting information about these tests.
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To understand UCTD, it is essential to understand connective tissue diseases.
Connective tissue diseases (CTD) are a group of diseases also called “collagen vascular diseases,” “systemic rheumatic diseases,” “autoimmune rheumatic diseases,” or “systemic autoimmune diseases.” These are diseases where the body’s immune system is “overactive” and causes inflammation in many body parts. Therefore, they are systemic.
The CTDs are named depending on what body parts are affected, how they are affected, and what lab tests are abnormal. All of these disorders can cause pain in the joints and muscles. That is why rheumatologists are usually the specialists who treat these diseases the most.
The term UCTD is highly inaccurate. Connective tissues are tissues like the ligaments, tendons, and cartilage.
There are other diseases of connective tissue that are not autoimmune. Examples include Marfan’s syndrome and Ehler’s Danlos syndrome. Strictly speaking, these are CTDs, but they are not autoimmune.
Therefore, I much prefer the term “undifferentiated autoimmune syndrome.” (I believe first coined by Dr. Jill Buyon in 1993).
This term specifically states that someone has a problem that:
Nonetheless, UCTD is so widely used by rheumatologists at the moment that I will use UCTD throughout this blog post article. I UCTD is changed in the future.
The term connective tissue disease is an outdated term. When it is used to refer to diseases like lupus, it is referring to systemic autoimmune disease. However, other unrelated diseases, like Marfan’s syndrome and Ehlers-Danlos syndrome, also affect the connective tissues. Hence, these are also “connective tissue diseases.” However, these disorders are not autoimmune or inflammatory. They are genetic disorders that cause defects in the strength and function of connective tissues (like the joints, tendons, cartilage, and even blood vessel walls).
Therefore, most of us prefer to use the terms “systemic autoimmune diseases” or “autoimmune rheumatic diseases.” However, undifferentiated connective disease was coined at the time when CTD was popular. The term has stuck since then, and getting rid of something as ingrained as UCTD is difficult. The same goes for MCTD.
Since CTD is so ingrained into the terms of UCTD and MCTD, I will use the term CTD instead of my usual “systemic autoimmune disease” throughout this blog post.
We don’t know the exact cause of these diseases, and much research is being done on this topic. We do know that people are born with genes that cause these diseases. However, they usually occur when something in the environment (such as possibly a viral infection) “turns on” these genes to cause the disease. These diseases sometimes run in families, while other times, only one person in a family may have the disease.
The immune system in patients with these diseases appears more active than normal and causes inflammation. The immune system normally protects us from foreign things, such as infections and cancer. However, for various reasons, it begins attacking the body itself in people with a CTD.
UCTD is a common diagnosis, accounting for 10% to 35% of all referrals to major medical centers’ rheumatologists. The CTDs share many of the same symptoms. For example, all of them can cause arthritis, Raynaud’s phenomenon (where the fingers turn blue or white when cold), rashes, pleurisy/pleuritis/pericarditis (where inflammation outside the lungs/heart causes chest pain), interstitial lung disease (inflammation and scarring of the lungs), heart problems, anemia, and certain abnormal lab tests such as a positive ANA (anti-nuclear antibody), anti-SSA, anti-RNP, anti-centromere, or rheumatoid factor (RF).
The ANA, anti-SSA, anti-RNP, antichromatin, RF, and many other autoantibody tests can occur in all these diseases and are not specific to anyone. They are blood tests that reflect that the immune system is overactive. These blood tests can be seen in ordinary people as well. But these are handy tests to screen for the possibility of a CTD.
Some of these diseases share other problems, such as low white blood cell or platelet counts, ulcers in the mouth, inflammation of the eyes, myositis (inflammation of the muscles), kidney disease, and nerve problems.
Other diseases can mimic connective tissue diseases and are often difficult to diagnose. Your doctors will look for these possibilities through a history, physical exam, and lab tests. They include disorders such as viral infections (like parvovirus or Lyme disease) and other inflammatory diseases (such as sarcoidosis).
Some patients will develop other diseases, such as sarcoidosis. Other patients will continue to have evidence of a systemic rheumatic disease but still have rather nonspecific problems shared by some of the CTDs. These patients will continue to be diagnosed with UCTD. These patients often have a better prognosis than those who evolve into classic systemic lupus or one of the other CTDs.
Yet, some patients’ UCTD will resolve independently, allowing medications to be discontinued. One study showed that about one-third of people diagnosed with UCTD ended up having no persistent disease at all after following them for over ten years. We assume that these were due to disorders, such as an infection, that the body got rid of.
Studies show that some patients with UCTD will continue to evolve into one of the well-known CTDs (like systemic lupus) over time. The disease may take time to develop as new problems begin to occur with the disease. This can take weeks or even years in some cases. Therefore, close follow-up is essential to see if one of the well-defined CTDs does occur.
Sometimes, well-defined connective tissue diseases (like systemic lupus, scleroderma, and rheumatoid arthritis) will initially present with nonspecific problems or abnormal blood tests shared by more than one of the CTDs. A definite diagnosis (such as SLE) may be impossible in this case. When there is evidence for a systemic, inflammatory, autoimmune disease, but the problems can occur in more than one CTD, the patient is diagnosed with “undifferentiated connective tissue disease” (UCTD).
In other words, the problem appears to be a connective tissue disease. However, it hasn’t yet “differentiated” into one of the well-defined CTDs (such as lupus, etc). Other terms often used by rheumatologists for UCTD include: “lupus-like disease,” “possible lupus,” or “collagen vascular disease.”
Suppose someone begins to have problems with their fingers turning white and blue with exposure to cold (Raynaud’s phenomenon), develops joint pain without definite inflammatory arthritis, anemia of inflammation (also called anemia of chronic disease), and has a positive ANA and anti-SSA. This person could have any of the well-defined CTDs.
Someone with SLE could first have nonspecific problems (like joint pains and Raynaud’s) and then, over time, add more specific problems (like discoid lupus or positive anti-Smith antibody) that help clarify the diagnosis. All systemic autoimmune diseases can begin gradually in this way. During the early stage of the disease, when it is clear that the person has a systemic autoimmune disease, but the problems are nonspecific, we use the term UCTD. Think of UCTD as being the early stages of SLE in this example.
Or, let’s say that the person above starts off with a UCTD with joint pains, Raynaud’s, ANA, and anti-SSA, then develops swollen salivary glands, dry mouth, and dry eyes over time. In this example, the person had Sjögren’s disease the entire time. Yet, we call it a UCTD during the early stages.
Many other conditions, such as infections, can mimic a systemic autoimmune disorder. One such infection is parvovirus, which can cause arthritis, anemia, rash, and a positive ANA and RF. Parvovirus can be diagnosed using blood tests (IgM parvovirus test), as can other infections. However, blood tests are often not available to detect many viral infections. Since most viral infections resolve within 4-6 weeks, doctors may choose to wait and see if the problems go away on their own before considering a diagnosis of a UCTD.
Studies show that about 10% to 20% of people with UCTD develop SLE within five years. Over an extended period, 20% to 35% of UCTD patients evolve into some form of a well-defined systemic autoimmune disease, including SLE.
Having any of the following problems increases the chances of UCTD evolving to SLE. The more of these you have, the higher your risk:
Even though an exact name cannot be given in a UCTD, the treatment is usually similar for the same problems when seen in different diseases. For example, the arthritis of lupus and rheumatoid arthritis are often times treated with the same medicines. Sometimes, your doctor may put you on Plaquenil (hydroxychloroquine, HCQ) and/or methotrexate. Hydroxychloroquine may reduce the chances for UCTD to worsen and evolve into severe SLE. Therefore, many rheumatologists will recommend HCQ to most UCTD patients.
Regarding treatment, blood pressure medicines help treat Raynaud’s phenomenon (they dilate and open the arteries to the fingers and toes, increasing the blood flow). Similarly, anti-inflammatory drugs and medicines that calm the immune system (such as hydroxychloroquine and methotrexate) may be helpful for inflammatory arthritis, eye inflammation, or pleurisy.
Studies suggest that taking hydroxychloroquine can decrease the risk of a UCTD evolving into severe systemic lupus erythematosus. Hydroxychloroquine is a medication that calms down the immune system without suppressing it. Therefore, it does not cause infections or other significant side effects.
We ask that patients see an ophthalmologist once a year to monitor two to three eye tests while on this medicine. However, getting eye problems is rare if these tests are done regularly. Hydroxychloroquine is by far the safest immunomodulating medication we have. Taking it is a nice safeguard to prevent severe problems. Many lupus experts call it “lupus life insurance” to prevent bad problems from lupus.
HCQ has many positive benefits (such as extending lifespan) while rarely having severe side effects. If you are interested in taking hydroxychloroquine, discuss this with your rheumatologist.
Mixed connective tissue disease (MCTD) is another systemic autoimmune disease. It has features of different systemic autoimmune diseases occurring in the same person. These individuals also have a positive ANA and high RNP antibody level without other autoantibodies suggestive of another autoimmune disease. For example, they cannot have anti-Smith or anti-dsDNA (as seen in SLE), anti-Scl-70 (as seen in scleroderma), or anti-Jo-1 (as seen in polymyositis), to name a few. High RNP antibody levels occur in everyone with MCTD.
Most MCTD patients have Raynaud’s phenomenon. The other common problems include inflammatory arthritis, muscle pain and weakness, and swollen fingers. Over time, MCTD sometimes evolves into more of an SLE-like disease in some people. In other individuals, it will act more like scleroderma. Doctors should follow MCTD patients closely to look for pulmonary hypertension. In this potentially dangerous condition, the blood pressure is elevated in the lung’s blood vessels.
Doctors have devised several classification criteria to help rheumatologists diagnose mixed connective tissue disease.
Merely being positive for RNP antibody does not mean that someone has MCTD. Anti-RNP and anti-Smith/RNP (which is not the same as Smith antibody) can be found in any of the systemic autoimmune diseases, and can even be seen in normal individuals. About 30% to 40% of people with SLE are anti-RNP positive. Those positive for anti-RNP have an increased chance of having the same problems as people with MCTD, including Raynaud’s and pulmonary hypertension. Unfortunately, many patients are told they have MCTD because they have a positive anti-RNP. Yet, they have something else (such as UCTD or SLE). It is wise to get a second opinion if there is any question.
MCTD is often confused with UCTD (undifferentiated connective tissue disease, discussed above). However, people with UCTD usually have better long-term health outcomes than those with MCTD. In some people with UCTD, their symptoms disappear over time or remain mild and do not worsen. By contrast, those with MCTD have a long-lasting disease and may require treatment all their lives.
MCTD is often incorrectly used when “overlap syndrome” is the proper term. If someone satisfies classification criteria for more than one systemic autoimmune disease, “overlap syndrome” is more correct. This is especially true if autoantibodies are present typical of other conditions (such as anti-dsDNA, anti-Smith, anti-ribosomal-P, anti-Jo1, ANCA, and anti-SSA). An example is having both SLE and Sjögren’s disease is common. That person is said to have an overlap syndrome of both SLE and Sjogren’s disease. Mixed connective tissue disease would be incorrect, even if this person’s anti-RNP is positive.
Some rheumatologists do not like the term MCTD. They do not consider it a distinct entity. They may instead diagnose someone with a UCTD when the disease begins and doesn’t satisfy criteria for SLE, rheumatoid arthritis (RA), scleroderma, or polymyositis. Many patients do appear to evolve into one of these patterns over time. In other words, some people look more like scleroderma, while others look more like SLE, RA, or polymyositis.
I am in the MCTD camp. The purpose of ascribing names to systemic autoimmune diseases is to help define what can happen in that group of people. For example, someone with SLE has a 40% chance of developing lupus nephritis (kidney inflammation), and someone with Sjögren’s disease has an increased risk of developing lymphoma.
People with MCTD all have high anti-RNP in common and have various combinations of Raynaud’s, arthritis, muscle inflammation, and swollen/puffy fingers. One of the most important reasons for identifying this disorder is that people with MCTD are at increased risk of pulmonary hypertension, which is a significant source of death in MCTD. If doctors know this, they can ensure their patient gets an echocardiogram and full pulmonary function tests each year to look for this possibility. If pulmonary hypertension is diagnosed and treated early, people do markedly better.
Occasionally more than one systemic autoimmune disease may occur in the same person. “Overlap syndrome” is the term for this occurrence. Having Sjögren’s disease and another disorder is one of the most common combinations.
About one-third of people with SLE will have an added systemic autoimmune disease (overlap syndrome). A Hospital for Special Surgery (New York City) study showed that 38% of their SLE patients had an overlap syndrome. One out of 20 of their SLE patients even had two or more other autoimmune diseases (polyimmunity, discussed further down).
Of their rheumatoid arthritis patients, 8% also had SLE.
Likewise, 8% of their Sjögren’s patients also had SLE.
Overlap syndrome patients tended to be older, which probably points to the additive nature of these diseases over time.
The same study also showed that diagnoses could change repeatedly over time. These changing diagnoses and overlaps with other autoimmune diseases can confuse patients. However, one of the known characteristics of systemic autoimmune diseases is that they can evolve over time.
Another truth is that systemic autoimmune diseases may be called different names by different rheumatologists. This is because these diseases share similar problems, blood tests, and antibodies.
For example, someone with autoimmune hemolytic anemia, multiple swollen lymph nodes, and a positive antinuclear antibody, anti-dsDNA level, and anti-Coombs antibody could be labeled as SLE by one doctor.
However, another doctor may label this same person as having UCTD. The latter doctor may like to follow the SLE classification criteria exactly and, therefore, label this person as UCTD since they do not satisfy at least four criteria. Yet, the former rheumatologist may realize that a patient must not fulfill the criteria to have SLE.
Another example would be a patient with four knuckles on each hand inflamed with swelling, tenderness, and prolonged morning stiffness for the previous three months and who is positive for antinuclear antibody (ANA), rheumatoid factor (RF), and anti-CCP antibody. One rheumatologist may label this person as having rheumatoid arthritis since they fulfill the classification criteria for rheumatoid arthritis. ANA is found in around 30% of RA patients.
However, another rheumatologist, realizing that this patient is early on in their disease and could easily evolve to any of the systemic autoimmune diseases (such as SLE), may feel more comfortable labeling the patient as UCTD.
If this patient were to develop a sun-sensitive butterfly rash and kidney inflammation (nephritis), the 1st rheumatologist would need to change the diagnosis to SLE (realizing it was SLE the entire time).
The medical newspaper, The Rheumatologist, published my article about “A Practical Guide to Autoantibody Testing in Rheumatic Diseases.” Though it is written for healthcare providers, it gives lots of interesting information about these tests.
Note that none of the above diagnoses are incorrect in either example. Most doctors would treat both of these patients similarly.
The first patient would easily be treated with steroids and rituximab by both the doctor diagnosing the patient as UCTD and by the doctor labeling the patient as SLE.
The second patient would easily be treated with methotrexate by both doctors initially, then adding hydroxychloroquine, sunscreen, and lupus nephritis medications when the patient evolved into SLE with lupus nephritis.
Having an overlap syndrome can also potentially complicate treatment. For instance, some rheumatoid arthritis (RA) drugs (like TNF inhibitors) are often avoided in SLE. Therefore, an overlap of these two diseases requires selecting effective and safe treatments for both.
Having three or more autoimmune disorders is called polyautoimmunity or multiple autoimmune syndrome.
A large 2019 Spanish study of 3,679 SLE patients showed that 14% of them had polyautoimmunity. The other most common additional autoimmune disorders were (in decreasing frequency) Sjögren’s disease, antiphospholipid syndrome, and autoimmune thyroid disease. Having anti-SSA, anti-SSB, or anti-RNP antibodies increased the risk of polyautoimmunity.
Those SLE patients taking antimalarials such as hydroxychloroquine were half as likely to develop polyautoimmunity.
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Hello Dr Thomas-
I do not totally understand. If I have ITP is that considered another autoimmune disease or just a manifestation of my lupus? Likewise I always have abnormally low white blood cells. Is that another autoimmune disease or just an SLE manifestation? I have sjogrens symptoms and hashimotos. Again same ? SLE manifestations or another autoimmune disease? Thank you for helping me to better understand. I love your blog postings. ♥️
Penelope: I would consider the low platelets and WBC as part of your SLE.
However, the “new” name for ITP is “immune thrombocytopenic purpura.” Therefore, going by the name, it is an ITP and SLE is the “immune” cause of that ITP. A complicating factor is if you are positive for antiphospholipid antibodies. If so, then it is uncertain whether the low platelets are due to immune system destruction (as in ITP and SLE thrombocytopenia), or due to platelet consumption as occurs in antiphospholipid syndrome (ie different mechanisms).
Hashimoto’s is a separate organ-specific autoimmune disorder that occurs commonly in our patients with Sjogren’s and SLE. We call this “polyimmunity” when someone has 3 or more AI disorders.
Thanks for your kind words.
Donald Thomas, MD
Diagnosed with SLE and AIH 16 years ago. No major flare ups until 2022.
Onset of Vasculitis (possible Giant cell arteritis) and severe AIH flare up 2024. Poor kidney function and stents in both kidneys.
What category would these come under. Possible overlap or connective tissue disorder.
Thank you.
Deborah:
If you were my patient I would label you as an overlap syndrome with SLE and AIH. However, if you were a new patient to me, I’d double check how they diagnosed AIH. Many patients actually have lupus-induced hepatitis rather than authentic AIH. It is a big difference because the prognosis for lupus-associated hepatitis (which is also autoimmune, just not AIH) is markedly better than patients who truly have AIH with their SLE. If it is lupus hepatitis, then the diagnosis is SLE manifested by lupus hepatitis etc.
Regarding the vasculitis. That is a toughy. It is rare to have GCA and SLE (but not impossible). Many SLE patients also get vasculitis as a part of their lupus. So, the question for me would be is it actual GCA or a vasculitis that is due to the SLE.
These questions can be difficult even when a doctor has all the information available. However, our treatments for AIH is usually slightly different from that of lupus-hepatitis, and the treatments for GCA can be markedly different than for lupus-associated vasculitis. For example, we often use an IL-6 inhibitor for GCA but would very rarely use them for lupus vasculitis.
Only your rheumatologist can adequately answer these questions. Feel free to show them my answer and I am sure they can give you a much better, clear answer.
Good luck and I hope no more flares!
Donald Thomas, MD
I have hypermobile Ehlers-Danlos with several systemic manifestations (chronic intractable migraines, IBS, dysautonomia, MVP, abd hernias, congenital pes cavus with acquired pes planus, dry eye, OA…). We’ve only recently put it together and had a formal diagnosis (Beighton 8/9 and genetics) for less than a year perhaps. It all began in June 2019 with some intermittent peripheral neuropathy symptoms (numbness, tingling, pain, weakness, falls; but negative exam, MRI, EMG, NCT, SNF bx). I also have an objective intermittent peripheral neuropathy with decreased reflexes, and a weird vibratory sense exam, but not at the same time as my studies. I have an incidental inert cystic pituitary microadenoma vs Rathke’s cleft pouch cyst being followed by neurosurgery to cover some behinds. I have a history of Vitamin D insufficiency and low bone density. OA on x-ray is mild involving R scaphoid, C 5-7, L5-S1, b/l elbows, b/l heels, b/l dorsal ?tarsals…). I’ve been treated for central sensitization syndrome and CPTSD. Lately the areflexia has persisted/progressed even without neuropathy symptoms. After being referred to rheumatology in ‘21, then developing joint pain and subjective swelling (in that order), I have been followed for a few years at Duke. I was diagnosed in Nov ‘23 by screening musculoskeletal ultrasound of hands and wrists with bilateral mild-moderate inflammatory arthropathy that a Cleveland Clinic rheumatologist thinks is “probable seronegative RA or possible UCTD, probably not Sjogren’s, no sign of overlap syndrome”. My feet and ankles may be involved, but anecdotally the US tech doesn’t think the test is as sensitive there. We haven’t discussed MRI. I took Hcq for 3+ mo with no improvement. I have been taking Mtx & folic acid for about a month. I’ve been evaluated for SAPHO by x-rays which were negative (so it probably isn’t). I’ve been referred for immunology workup for recent development of recurrent thrush—I had been on my current asthma maintenance inhaler for perhaps a year before it became a problem. Maybe in 2010 I had an RF of 11. Since at least 2019 I’ve had a mild macrocytic anemia. So far 2 hematologists haven’t found a cause, but I’m being followed. One suspects an underlying autoimmune inflammatory process. The other agrees RA could cause it but won’t call it anemia of chronic inflammation because of course the indices are all wrong. CC Rheumatology disagrees that RA would cause it regardless of its name. 2021 I had 1:160 speckled and nucleolar ANA+ and mildly elevated CRP after sinus surgery and steroids. All other labs have been negative several times, and even those have become negative/normal since. I have had nose and mouth sores and Reynaud’s that rheum haven’t seen/pictures don’t do justice. I have experienced alopecia off and on of body hair for years, but it just started in my scalp in Feb for which I have been referred to dermatology. I’m going to also discuss various potential skin changes and even perhaps panniculitis around at least my ankles… I’m being referred to yet another neurologist because my EDS specialist isn’t satisfied that EDS explains all of my neuropathy.
Pain, stiffness, swelling, hyperemia and effusion don’t always match up. Does it matter or not if I also have synovitis in SI joints, shoulders, elbows, and/or knees? Does it matter if it is caused by OA or IA? How might we tell? Does that strengthen the case for RA? Are all my symptoms gradually pointing to SLE instead? Or would that be in addition? Or do I have RA vs UCTD + polyimmunity if we include whichever type of alopecia this turns out to be (alopecia areata vs FFA)?
My eyebrows have also been affected, btw.
And I may have nail changes c/w RA.
Kidney & urine labs are also fine. Except I have had a microalbumin right at 10 more than once before, which could just be from stress??
Do you think my neuropathy is autoimmune/autoinflammatory (not MS or transverse myelitis), and how might we treat it other than what we’re doing (DMARDS…pregabalin, duloxetine)?
Dear Dr. Thomas,
I hope this note finds you well. Your expertise and thoughtful approach to an autoimmune disease SLE have not only helped me feel more informed about my health issues but have also provided me immense comfort and reassurance during a challenging time.
The book that you wrote is an absolute treasure, explaining the conditions, symptoms, pathology results and the treatment options available.
Thank you once again for your outstanding care and compassion. Please know that your efforts have made a significant difference in my life, and I am sure, in many other lives.
Olena Luggassi
This makes me all confused more. I got diagnosed with lupus last year. Hydroxychloroquine was my first treatment and got blisters all over my body.
I’ve tried Humira. Caused neuropathy
Tried Cyclobenazoprine (spelling?) put me in the ER three times.
I’ve been on cellcept for over six months and I feel worse than before the diagnosis.
I know that not everyone that has lupus has the antibodies. But I have had 2 positive ANA’s and one negative. On the negative ANA it had SCL70 and SMITH DP positive. I also have VUS of the ADAMST2 which could cause dEDS (have all the symptoms)
What questions could I ask my doctor to take me seriously?!
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