Lupus In 'Overlap' With Other Connective Tissue Diseases

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Lupus In 'Overlap' With Other Connective Tissue Diseases

Thomas A. Medsger, Jr., M.D.
University of Pittsburgh School of Medicine

Pittsburgh , PA


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Connective Tissue Disease And Overlap Syndromes
Lupus and Rheumatoid Arthritis
Lupus and Myositis
Lupus and Scleroderma
Mixed Connective Tissue Disease
Sjogren's Syndrome and Lupus
Frequency Of Overlap Syndromes In People With Lupus
Heredity And Overlap
Prognosis For People With Lupus And Overlap Syndromes
The Lupus Foundation of America
Related Information

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Connective Tissue Disease And Overlap Syndromes
The connective tissue diseases are a family of closely related disorders. They include:

rheumatoid arthritis (RA)
systemic lupus erythematosus (SLE or lupus)
polymyositis-dermatomyositis (PM-DM)
systemic sclerosis (SSc or scleroderma)
Sjogren's syndrome (SS)
various forms of vasculitis.
These diseases have a number of common features:
They affect females much more frequently than males.
They are "multisystem" diseases, capable of affecting the function of many organs.
They "overlap" with one another, sharing certain clinical symptoms, signs, and laboratory abnormalities.
Blood vessels are the most common target of injury in all of these diseases.
The immune system is abnormal and accounts, at least in part, for the observed tissue damage.
Although lupus most often occurs alone, many people with lupus also have symptoms characteristic of one or more of the other connective tissue diseases. In this circumstance, a physician may use the term “overlap” to describe the illness. There are several well-recognized overlaps that may affect people with lupus.




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Lupus and Rheumatoid Arthritis

Lupus

Joint pain (arthralgia) is common.
Joint swelling (arthritis) may be present in some cases.
The majority of those with lupus experience joint pain without swelling or only intermittent swelling.
If a person with lupus develops severe arthritis with joint deformities, he/she should be considered to have rheumatoid-like arthritis.
RA
Joint swelling is always present.
Joint pain is common but less prominent.
Because rheumatoid arthritis is more likely than lupus to cause joint deformities and bone destruction, joint replacement or reconstructive surgery is more often required in RA than in lupus.
Overlap
In some instances, the physician might have reason to believe that both diseases-SLE and RA-have occurred in the same person.

Treatments

When arthritis develops in the course of lupus, treatment with these agents can be helpful:
- non-steroidal anti-inflammatory drugs (NSAIDs)
- low doses of cortisone
- the antimalarial drug hydroxychloroquine (Plaquenil).
People with lupus who have typical rheumatoid arthritis are prescribed the standard forms of RA treatment:
- methotrexate
- sulfasalazine
- In some cases, more potent drugs to suppress inflamation




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Lupus and Myositis

Lupus
Many persons with lupus have muscle pain (myalgia), but few have muscle weakness due to inflammation (myositis).
The "muscle weakness" that people with lupus report is most commonly due to fatigue or high doses of cortisone.
Myositis
In polymyositis-dermatomyositis, the primary problem is muscle weakness due to muscle inflammation.
Weakness especially affects:
- the hips (inability to rise from a chair or toilet seat, or to climb stairs unassisted)
- the shoulders (inability to lift a weight onto a high shelf or comb one's hair).
- typically, there is little or no pain associated with the weakness.
People with myositis also have:
- increased blood levels of creatine kinase (CK), a substance that leaks from injured muscle
- abnormal electrical activity of muscles detected by electromyogram (EMG)
- muscle biopsy showing muscle cell degeneration and inflammation that is found in a muscle biopsy.

Treatments

Prednisone or other cortisone-like drugs are most often recommended for the treatment of myositis, and may be used in combination with other immune-suppressing drugs..
Cortisone itself, in high doses, may actually cause muscle weakness of the hips and shoulders, very similar to what occurs in myositis. But in this condition, called "steroid myopathy," the CK, EMG, and the muscle biopsy do not suggest inflammation, and recovery of strength promptly follows reduction of the cortisone dose.


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Lupus and Scleroderma

Lupus
The variety of skin rashes seen in lupus are due to inflammation, rather than fibrosis. Features of these rashes are limited to the skin surfaces exposed. They include:
- the facial "butterfly" rash
- a photosensitivity reaction (rash, hives or blisters) seen immediately after exposure to sunlight or other sources of ultraviolet light.
An exception is "discoid" or "cutaneous" lupus, which consists of spots or patches of rash, mostly in sun-exposed areas (face, ears, extremities), which typically cause scarring and skin pigment changes. The appearance of scleroderma and discoid lupus are entirely different, and should be easily distinguished from one another by your physician.
Scleroderma
The hallmark of scleroderma (SSc) is thickened skin (sclero=hard; derma=skin). If skin thickening is widespread, it may extend to the upper arms, thighs, chest, and abdomen.
These changes are due to the excessive production and uncontrolled "laydown" of collagen, the substance normally present in scar tissue.

If skin fibrosis (hardening) is widespread, it may extend to:
- the upper arms
- thighs
- chest
- abdomen.

The variety of skin rashes seen in lupus are due to inflammation, rather than fibrosis. These include the facial “butterfly” rash and photosensitivity reaction (rash, hives or blisters ) seen immediately after exposure to sunlight or other sources of ultraviolet light ). The latter is limited to the skin surfaces exposed. An exception is discoid lupus , which consists of spots or patches of rash, mostly in sun exposed areas (face, ears, extremities), which typically cause scarring and skin pigment changes. The appearance of scleroderma and discoid lupus are entirely different, and should be easily distinguished from one another by your physician.

Other features less common in lupus than in SSc include:
- pulmonary fibrosis: scarring of the lower portions of the lung
- difficulty in swallowing solid foods such as bread or meat
- heartburn or indigestion from stomach acid "refluxing" ( coming back) into the esophagus. Difficulty swallowing and reflux are due to sluggish and uncoordinated motion of the muscle layer of the esophagus (esophageal dysmotility).
-Scleroderma often leads to finger and hand deformities as well, due to the combination of skin thickening, arthritis, tendinitis and tenosynovitis (inflammation and scarring of tendons and their lining tissues). These processes ultimately result in limited movement of the fingers-Raynaud's phenomenon: fingers turn blue or white with cold. This occurs in 95 percent of persons with scleroderma and in 40 percent of persons with lupus.
Treatment
The primary treatment approaches to SSc are quite different from those for lupus.
Therefore, treatment for scleroderma like problems in persons with lupus should be individualized and directed at the particular problems present at any given time.



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Mixed Connective Tissue Disease

Some individuals have symptoms and signs of three connective tissue diseases:
lupus
polymyositis-dermatomyositis
scleroderma.
At any given time, the combination of problems encountered by the patient may vary considerably, from no active disease to features of one, two, or all three of these conditions at the same time.
These persons often (but not always) have one specific blood antibodyin their blood (anti-U1RNP antibody) but not the other antibodies commonly associated with SLE, SSc, or PM-DM.
Whether this is an entirely separate disease, or a situation in which one person has three diseases, remains uncertain. However, the presence of a single blood antibody is a strong point in favor of a distinctive disease.
Treatment

Treatment should be individualized and directed at the particular problems present at any given time.




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Sjogren's Syndrome and Lupus
Sjogren's syndrome
Henrik Sjögren was a Swedish ophthalmologist and the first to recognize that dry eyes and dry mouth were often found in people with connective tissue diseases.

These symptoms are caused by the accumulation of immune system cells (lymphocytes) in and around tear and saliva producing glands.
The build-up of cells disturbs the function of these glands and leads to reduced production of tears and saliva.
This condition also interferes with the protective mechanisms of the eye and mouth.
Eye inflammation and ulcers of the cornea, as well as fungal infections of the mouth (thrush), occur with increased frequency in those with Sjogren's.
Rarely, a person with this disorder develops a malignancy (cancer) affecting lymphocytes (lymphoma).
Today, Sjogren's syndrome is itself accorded the status of a distinct connective tissue disorder.
Lupus
Sjogren's syndrome also occurs in some people with lupus:
They have an increased frequency of sun-sensitive rashes and Sjogren's-related blood antibodies (anti-SSA and anti-SSB antibodies).
Women with anti-SSA antibodies are at increased risk of having babies with "neonatal lupus." Symptoms in the infant can be as minor as a temporary lupus-like skin rash, or as serious as permanent damage to the electrical system of the heart which results in a very slow heart rate (complete heart block)
Treatments

The best treatments for Sjogren's syndrome include : artificial tears (usually satisfactory) and either artificial saliva (most often unsatisfactory) or a saliva stimulant such as pilocarpine and hydroxychloroquine (Plaquenil). Eye drops containing cyclosporin have also just been introduced and have significant benefit for dry eyes in some cases . Arthritis, fatigue and skin rash in people with Sjogren's is often treated with Plaquenil.

 



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Frequency Of Overlap Syndromes In People With Lupus
The majority of people with lupus have lupus alone. Between 5 and 30 percent of people with lupus report having overlap symptoms. The likelihood of a person with lupus also having an overlap disease is 15 percent, distributed as follows:

Overlap Disease Rate of Occurrence
Rheumatoid Arthritis  1%
Polymyositis-Dermatomyositis 2%
Mixed Connective Tissue Disease 3%
Scleroderma 4%
Sjogren's syndrome  5%





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Heredity And Overlap

It is unusual (less than 10 percent of the time) for a person with lupus to have a close family member (parent, child, brother, or sister) who also suffers from lupus.
However, it is common for persons with lupus to have relatives (including grandparents, aunts/uncles, cousins) with other connective tissue diseases such as rheumatoid arthritis, Sjogren's syndrome, scleroderma, etc.
These co-occurrences raise the possibility that heredity may be a factor in all of the connective tissue diseases.
Most scientists agree that important hereditary associations with these diseases are present in some families. Additional research is needed to shed light on this important question.



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Prognosis For People With Lupus And Overlap Syndromes
It is important for those with lupus to be aware of the symptoms that might indicate the development of "overlap" features, since these symptoms and abnormalities may be best managed with treatments not typically used for lupus. Fortunately, when an overlap syndrome is present, the symptoms characteristic of the other connective tissue diseases involved are usually mild and not life-threatening.




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The Lupus Foundation of America
The Lupus Foundation of America (LFA) was established in 1977 to educate and support those affected by lupus and find the cure. The LFA supports research, education, awareness, patient services, and advocacy.

The Lupus Foundation of America is the only nationwide organization exclusively serving individuals, families and friends affected by lupus. The LFA has local chapters and support groups throughout the United States, as well as international affiliates around the world. Contact the LFA or the chapter that serves your area to find out how you can become involved in our mission.

Become a Lupus E-Advocate and help pass federal legislation that will benefit people with lupus. You'll receive periodic advocacy updates and other breaking lupus news and information.

For more information about lupus of to lacate the chapter nearest you, visit our website at www.lupus.org or call our information request line toll-free at 1-800-558-0121. (en Espanol, 800-558-0231).


Approved by the Lupus Foundation of America's
Patient Education Committee

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What are connective tissues?

The connective tissues are the structural portions of our body that essentially hold the cells of the body together. These tissues form a framework or matrix for the body. The connective tissues are composed of two major structural molecules, collagen and elastin. There are many different collagen proteins that vary in amount in each tissue of the body. Elastin is another protein that has the capability of stretching and returning to original length like a spring. Elastin is the major component of ligaments (tissues which attach bone to bone).

Connective tissue diseases are disorders featuring abnormalities involving the collagen and elastin. Connective tissue diseases are often characterized by a variety of immune abnormalities that are common for each particular type of illness.

What diseases characteristically affect connective tissue?

Diseases of connective tissue that are strictly inheritable (due to genetic inheritance) include Marfan syndrome (can have tissue abnormalities in the heart, aorta, lungs, eyes, and skeleton), and Ehlers-Danlos syndrome (may have loose, fragile skin or loose [hyperextensible] joints).

Other diseases of connective tissue do not have specific gene abnormalities as their sole cause. These connective tissue diseases occur for unknown reasons. They are characterized as a group by the presence of spontaneous over activity of the immune system, which results in the production of unusual antibodies into the blood.

The classic immune-related connective tissue diseases include systemic lupus erythematosus, rheumatoid arthritis, scleroderma, polymyositis, and dermatomyositis. Each of these diseases has a characteristic presentation with typical clinical findings that doctors can recognize during an examination. Each also has characteristic blood test abnormalities and abnormal antibody patterns. However, each of these diseases can evolve slowly or rapidly from very subtle abnormalities before demonstrating the classic features that help in the diagnosis. When these conditions have not developed the classic features of a particular disease, doctors will often refer to the condition as "undifferentiated connective tissue disease." This implies that the characteristic features that are used to define the classic connective tissue disease are not present, but some symptoms or signs of connective disease exist. Individuals with undifferentiated connective tissue disease may never develop a fully definable condition or they may eventually develop a classic connective tissue disease.

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What is mixed connective tissue disease?

Mixed connective tissue disease, as first described in 1972, is "classically" considered as an "overlap" of three diseases, systemic lupus erythematosus, scleroderma, and polymyositis. Patients with this pattern illness have features of each of these three diseases. They also typically have very high quantities of antinuclear antibodies (ANAs) and antibodies to ribonucleoprotein (anti-RNP) detectable in their blood. The symptoms of many of these patients eventually evolve to become dominated by features of one of three component illnesses, most commonly scleroderma features.

It is now known that overlap syndromes can occur that involve any combination of the connective tissue diseases. Therefore, for example, patients can have a combination of rheumatoid arthritis and systemic lupus erythematosus (hence, the coined name "rhupus").

How is MCTD diagnosed?

Today, true mixed connective tissue disease is diagnosed when patients demonstrate the clinical features (exam findings) of overlap illnesses (as described above) and have high amounts of the antibodies ANA and anti-RNP in their blood. MCTD patients do not typically have antibodies such as dsDNA, Scl70, which are particularly common in systemic lupus erythematosus and scleroderma respectively.

How is MCTD treated?

The treatment of mixed connective tissue disease is based on which features are causing symptoms. The prognosis (outlook) varies accordingly. Therapies must be targeted for each of the organ systems affected. In general, treatment is often directed at suppressing the inflammation present in the tissues by using anti-inflammatory and immunosuppressive medications. These medications include nonsteroidal anti-inflammatory drugs (NSAIDs), cortisone drugs/steroids (such as prednisone), antimalarial drugs (hydroxychloroquine), and cytotoxic drugs (such as methotrexate, azathioprine, and cyclophosphamide). Organ damage, such as in the kidneys, can require additional treatments directed at high blood pressure, etc.

For the joint and muscle pains of MCTD, treatment options include NSAIDs, low-dose prednisone, hydroxychloroquine, and methotrexate can be helpful. Physical therapy for certain joints is sometimes helpful. For pulmonary hypertension, prednisone, angiotensin converting enzyme inhibitors, and cyclophosphamide are used. For interstitial lung disease, prednisone and cyclophosphamide are considered. To prevent damage to the kidneys, angiotensin converting enzyme inhibitors, such as captopril (Capoten), enalapril (Vasotec) are used, especially if blood pressure is elevated. Esophagus irritation and heartburn can be prevented by elevating the head of the bed and relieved with omeparazole (Prilosec) or lansoprazole (Prevacid). Antacids can also be helpful. Constipation, cramping and diarrhea is sometimes caused by bacteria that can be treated with tetracycline or erythromycin.

For Raynaud's phenomenon, patients are recommended to use hand and body warming techniques while protecting the fingers from injury. Nifedipine (Procardia), losartan (Cozaar, Hyzaar) and nitroglycerin cream are used to dilate the constricted blood vessels. Severe RP can lead to gangrene and the loss of digits. In rare cases of severe disease, nerve surgery called "sympathectomy" is sometimes considered. In order to prevent blood vessel spasming, the nerves that stimulate the constriction of the vessels (sympathetic nerves) are surgically interrupted. Usually this is performed during an operation that is localized to the sides of the base of the fingers at the hand. Through small incisions the tiny nerves around the blood vessels are stripped away. This procedure is referred to as a digital sympathectomy.

Mixed Connective Tissue Disease At A Glance
Connective tissues are the framework of the cells of the body.
MCTD is an "overlap" combination of connective tissue diseases.
Diagnosis of MCTD is supported by detecting abnormal antibodies in the blood.
Treatment of MCTD is directed at suppressing immune-related inflammation of tissues.
For more specific information related to the individual connective tissue diseases, please read the following articles: Systemic Lupus Erythematosus, Rheumatoid Arthritis, Scleroderma, and Polymyositis.

Reference:
Clinical Primer of Rheumatology, Lippincott Williams & Wilkens, edited by William Koopman, et. al., 2003.
Kelley's Textbook of Rheumatology, W B Saunders Co, edited by Shaun Ruddy, et.al.,  www.LupusMCTD.com

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Symptoms, Signs and Tests
Because many symptoms of systemic lupus erythematosus (SLE) mimic those of other illnesses, lupus can be a difficult disease to diagnose. Diagnosis is usually made by a careful review of three factors:
the individual's entire medical history
an analysis of the results obtained in routine laboratory tests and
some specialized tests related to immune status.

To make a diagnosis of SLE, an individual must show clinical evidence of a multi-system disease (i.e. has shown abnormalities in several different organ systems). Typical symptoms or signs that might lead to suspicion of SLE are:

*Skin: Butterfly rash across the cheeks; ulcers in the mouth; hair loss.

*Joints: Pain; redness, swelling.
*Kidney: Abnormal urinalysis suggesting kidney disease.
*Lining membranes: Pleurisy (inflammation of the lining of the lung); pericarditis (inflammation of the heart lining); and/or peritonitis (inflammation around the abdomen). Taken together, these types of inflammation are known as polyserositis.
*Blood: Hemolytic anemia (the red cells are destroyed by autoantibodies); leukopenia (low white blood cell count); ஐﻬthrombocytopenia (low number of platelets).
*Lungs: Infiltrates (shadowy areas seen on a chest x-ray) that come and go
*Nervous system Convulsions (seizures); psychosis; nerve abnormalities that cause strange sensations or alter muscular control or strength.
*
If an individual has several of these symptoms, the physician will then usually order a series of tests to examine how well the individual's immune system is functioning. In general, physicians look for evidence ஐﻬof autoantibodies. Although there is no one test that can definitely say whether or not a person has lupus, there are many laboratory tests which aid the physician in making a lupus diagnosis.

Routine clinical tests which suggest that the person has an active systemic disease include:

sedimentation rate (ESR) and CRP (C-reactive protein) binding, both of which are frequently elevated in inflammation from any cause
serum protein electrophoresis which may reveal increased gammaglobulin and decreased albumin
routine blood counts which may reveal anemia and low platelet and white cell counts
routine chemistry panels which may reveal
kidney ஐﻬinvolvement by increases in serum blood urea nitrogen and creatinine
abnormalities of liver function tests
increased muscle enzymes (such as CPK) if muscle involvement is present.
These kinds of abnormalities alert the doctor to the presence of a systemic disease with multiple organ involvement.

Commonly used blood tests in the diagnosis of SLE are:

Anti-nuclear antibody test (ANA) to determine if autoantibodies to cell nuclei are present in the blood
Anti-DNA antibody test to determine if there are antibodies to the genetic material in the cell
Anti-Sm antibody test to determine if there are antibodies to Sm, which is a ribonucleoprotein found in the cell nucleus
Serum (blood)ஐﻬ complement test to examine the total level of a group of proteins which can be consumed in immune reactions
Complement proteins C3 and C4 test to examine specific levels


The Antinuclear Antibody (ANA or FANA) Test
Positive ANA
The immunofluorescent antinuclear antibody (ANA or FANA) test is positive in almost all individuals with systemic lupus (97 percent), and is the most sensitive diagnostic test currentlyஐﻬ available for confirming the diagnosis of systemic lupus when accompanied by typical clinical findings. When three or more typical clinical features are present, such as skin, joint, kidney, pleural, pericardial, hematological, or centralஐﻬ nervous system findings as described above, a positive ANA test confirms the diagnosis of systemic lupus.

However, a positive ANA test, by itself, is not proof of lupus since the test may also be positive in:

other connective tissue diseases, such as:
scleroderma
Sjogren's syndrome
rheumatoid arthritis
thyroid disease
liver disease
juvenile arthritis
individuals being treated with certain drugs, including:
procainamide
hydralazine
isoniazid
chlorpromazine
viral illnesses, such as:
infectious mononucleosis
other chronic infectious diseases, such as:
hepatitis
lepromatous leprosy
subacute bacterial endocarditis
malaria
other autoimmune diseases, including:
thyroiditis
multiple sclerosis
as many as 30-40 percent of asymptomatic first-degree relatives of people with lupus (siblings, parents, and children).
Weakly positive ANA
The test can even be weakly positive in about 20 percent of healthy individuals. While a few of these healthy people may eventually develop ஐﻬlupus symptoms, the majority will never develop any signs of lupus or related conditions. The chances of a person having a positive ANA test increases as he or she ages.

Negative ANA
A negative ANA test is strong evidence against lupus as the cause of a person's illness, although there are very infrequent instances where SLE is present without detectable antinuclear antibodies. ஐﻬANA-negative lupus can be found in people who have anti-Ro (SSA) or antiphospholipid antibodies.

ANA Titers and Patterns
ANA laboratory reports include a titer (pronounced TY-tur) and a pattern.

The titer indicates how many times the lab technician had to dilute plasma from the blood to get a sample free of the antinuclear antibodies.
For example, a titer of 1:640 shows a greater concentration of anti-nuclear antibodies than a titer of 1:320 or 1:160.
The apparent great difference between various titers can be misleading.

Since each dilution involves doubling the amount of test fluid, it is not surprising that titer numbers increase rather rapidly.
In actuality, the difference between a 1:160 titer and a 1:320 titer is only a single dilution. This does not necessarily represent a major difference in disease activity.

ANA titers go up and down during the course of the disease, and a high or low titer does not necessarily mean the disease is more or less active.
Therefore, it is notஐﻬ always possible to determine the activity of the disease from the ANA titer.
A titer above 1:80 is usually considered positive.
Some laboratories may interpret different titer levels as positive, so one cannot compare titers from different laboratories.


The pattern of the ANA test can sometimes be helpful in determining which autoimmune disease is present and which treatment program is appropriate.
The homogeneous, or smooth pattern is found in a variety of connective tissue diseases, as well as in people ஐﻬtaking particular drugs, such as certain antiarrhythmics, anticonvulsants or antihypertensives.
This homogenous pattern is also the one most commonly seen in healthy individuals who have positive ANA tests.
The speckled pattern is found in SLE and other connective tissue diseases
The peripheral, or rim pattern is found almost exclusively in SLE.
The nucleolar pattern, with a few large spots, is found primarily in people who have scleroderma.
 

Because the ANA is positive in so many conditions, the results of the ANA test have to be interpreted in light of the person's medical history, as well as his or her clinical symptoms. Thus, a positive ANAஐﻬ alone is never enough to diagnose lupus. On the other hand, a negative ANA argues against lupus but does not rule out the disease completely.

A Positive ANA Does Not Equate to Having a Disease
The ANA should be ஐﻬlooked at as a screening test. If it is positive in a person who is not feeling well and who has other symptoms or signs of lupus, the physician will probably want to conduct further tests for lupus.

If the ANA is positive in a person who is feeling well and in whom there are no other signs of lupus, it can be ignored. If there is any doubt, a consultation with a rheumatologist should clarify the situation.


Other Autoantibodies
In those individuals with a positive ANA, additional tests can be done for certain particular antibodies that may better establish a diagnosis of SLE. The knowledge of which particular antibody is responsible for the positive ANA test can sometimes be helpful in determining which autoimmune disease is present.

Antibodies to DNA (the protein that makes up the body's genetic code) are found primarily in SLE.
Antibodies to histones (DNA packaging proteins) are usually found in people with drug-induced lupus (DIL), but may also be found in those with SLE.
Antibodies to the ஐﻬSm antigen are found almost exclusively in lupus, and often help to confirm the diagnosis of SLE.
Antibodies to RNP (ribonucleoprotein) are found in a number of connective tissue diseases. When present in very high levels, RNP antibodies are suggestive of mixed connective tissue disease (MCTD), a condition with symptoms like those of SLE, ஐﻬpolymyositis, and scleroderma.
Antibodies to Ro/SS-A are found in people with either lupus or Sjogren's syndrome, and are almost always found in babies who are born with neonatal lupus.
Antibodies to Jo-1 are associated with polymyositis.
Antibodies to PM-Scl are associated with certain cases of polymyositis that also have features of scleroderma.
Antibodies to Scl-70 are found in people with a generalized form of scleroderma.
Antibodies to the centromere (a ஐﻬstructure involved in cell division) are found in people with a limited form of scleroderma which tends to have a chronic course.


Complement
Laboratory tests which measure complement levels in the blood may also be helpful to the physician in making a diagnosis of SLE.

Complement is a blood protein that destroys bacteria and also influences inflammation.
Complement proteins are identified by the letter "C" and a number.
The most common complement tests are C3, C4, and CH50.
If the total blood ஐﻬcomplement level is low, or the C3 or C4 complement values are low and the person also has a positive ANA, some weight is added to the diagnosis of lupus. Low C3 and C4 complement levels in individuals with a positive ANA may signify the presence of active disease, especially kidney disease.

Biopsy
Sometimes examination of a tissue sample (biopsy) can be helpful in making a diagnosis. The biopsy is one of ஐﻬthe best ways to evaluate an organ or tissue. The procedure involves removal of a small sliver of tissue, which is then examined under a microscope.

The doctor can use the biopsy to identify the amount of inflammation and damage to the tissue.
Further tests can be performed on the specimen to determine whether the problem is due to lupus or is caused by some other factor such as infection or medication.
Almost any tissue can be biopsied. The most ஐﻬcommon sites biopsied in lupus are the skin and kidney.
The results of the biopsy, like any other laboratory test, should be examined in combination with the individual's medical history and clinical findings.


Tests to Assess Disease Activity
When a person diagnosed with lupus develops new or recurring symptoms, laboratory testing of blood or urine can help determine if the symptoms are due to an increase in lupus activity.

Disease activity correlates with a rise in:

CRP (C-reactive protein) binding
ESR, or sedimentation rate
Anti-DNA
Liver and kidney function tests (AST, ALT, BUN, creatinine)
CPK (muscle enzyme)
Urine protein or cellular casts
Disease activity also correlates with a fall in:

CBC or complete blood count (white blood cell count, hemoglobin, platelets)
Complement components
Serum albumin

Putting It All Together
The interpretation of all these tests, and their relationship to symptoms, can be difficult. When a person has many symptoms and signs of lupus and has positive tests for lupus, it is easier for physicians to make a correct diagnosis and begin treatment. However it is more common for an individual to report vague, ஐﻬseemingly unrelated symptoms of achy joints, fever, fatigue, or pain, and to have negative or borderline test results.

Fortunately, with growing awareness of SLE, an increasing number of physicians will consider the possibility of lupus in the diagnosis. While these tests are useful only when their strengths and limitations are understood, in the handsஐﻬ of skilled physicians these are important tools that assist in diagnosing lupus.

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MCTD vs. UCTD
(Mixed Connective Tissue Disease vs. Undifferentiated Connective Tissue Disease)
Medical Author: William C. Shiel Jr., MD, FACP, FACR

I note that some viewers have been requesting some clarification of the meaning of the terms "mixed connective tissue disease" (MCTD) and "undifferentiated connective tissue disease" (UCTD).

Connective tissue diseases are a special group of rheumatic diseases (diseases that feature abnormalities of the muscles and/or joints) that can be associated with arthritis. The cause(s) for the connective tissue diseases is (are) unknown. They are characterized as a group by the presence of spontaneous over-activity of the body's immune (defense) system. This over-activity results in the production of unusual antibodies that are found in the blood. The antibodies themselves may or may not cause any problems in patients with connective tissues diseases, but they are commonly found in the blood as an characteristic feature.

The connective tissues are the structural portions of our body that essentially hold the cells of the body together. These tissues form a framework, or matrix, for the body. The connective tissues are composed of two major structural protein molecules, collagen and elastin. There are many different types of collagen protein that vary in amount in each of the body's tissues. Elastin has the capabilityஐﻬ of stretching and returning to its original length - like a spring or rubber band. Elastin is the major component of ligaments (tissues that attach bone to bone) and skin. In patients with connective tissue diseases, it is common for collagen and elastin to become injured by inflammation. Diseases in which inflammation of collagen tends to occur are also referred to as collagen diseases.

The classic connective tissue diseases include systemic lupus erythematosus, rheumatoid arthritis, scleroderma, polymyositis, and dermatomyositis. Each of these diseases affects people in a characteristic way and causes typical findings that doctors can recognize during an examination.ஐﻬ Each also has characteristic blood test abnormalities and abnormal antibody patterns. For example, systemic lupus erythematosus has dsDNA antibodies, while scleroderma has Sc170 antibodies. Additionally, each of these diseases can evolve either slowly or rapidly from very subtle abnormalities before demonstrating the classic features that help in the diagnosis.

When these conditions have not developed the classic features of a particular disease, doctors will often refer to the condition as "undifferentiated connective tissue disease," or UCTD. This designation implies that the characteristic features that are used to define the classic connective tissue diseases are not present, but that some symptoms or signs of a connective tissue disease exist.ஐﻬ For example, a person may have a special antibody in the blood, such as antinuclear antibody and muscle pains, but no other definable features of a classic connective tissue disease. Individuals with undifferentiated connective tissue disease may never develop a fully definable condition or they may eventually develop a classic connective tissue disease.

Mixed connective tissue disease, which was first described in 1972, is "classically" considered as an "overlap," or mix, of three specific connective tissue diseases; systemic lupus erythematosus, scleroderma, and polymyositis. Patients with this pattern of illness (that is, with MCTD) have features of each of these three diseases. They also typically have very high quantities of antinuclear ஐﻬantibodies (ANAs) and antibodies to ribonucleoprotein (anti-RNP) detectable in their blood. The symptoms of many of these patients eventually evolve to become dominated by features of one of the three component illnesses, most commonly the scleroderma features.

It is now known, however, that overlap syndromes can involve any combination of the connective tissue diseases. Therefore, for example, patients can have a combination of rheumatoid arthritis and systemic lupus erythematosus (hence, the coined name "rhupus"). Accordingly, today, true mixed connective tissue disease is diagnosed when patients demonstrate the ஐﻬclinical features (exam findings) of overlap illnesses. These patients also have high amounts of ANA and anti-RNP without having such other antibodies as the dsDNA antibodies of systemic lupus erythematosus and the Scl70 antibodies of scleroderma. 

[Adminஐﻬ]

Mixed connective tissue disease
Overview
Mixed connective tissue disease (MCTD) is a rare autoimmune disorder that causes signs and symptoms of other connective tissue diseases. People with mixed connective tissue disease experience features ஐﻬof three other diseases — lupus, scleroderma and polymyositis. For this reason, mixed connective tissue disease is sometimes referred to as an overlap disease.

Signs and symptoms of these three other diseases usually don't appear all at once. This makes diagnosing mixed connective tissue disease somewhat complicated. Often people with mixed connective tissue disease are first diagnosed with lupus. As the disease progresses and other signs and symptoms become apparent, the diagnosis is corrected.

Mixed connective tissue disease occurs most often in women and is usually diagnosed in young adults in their 20s and 30s. Children have also been diagnosed with mixed connective tissue disease.

Mixed connective tissue disease is somewhat of a controversial term among arthritis specialists (rheumatologists). Some question whether mixed connective tissue disease is its own specific disease or whether it's a precursor to another connective tissue disease.

Signs and symptoms
Mixed connective tissue disease doesn't have a unique set of signs and symptoms. Instead, people with ஐﻬmixed connective tissue disease usually have signs and symptoms of lupus, scleroderma and polymyositis, including:

Fatigue
Muscle weakness
Joint pain
Joint swelling
Swollen fingers
Mild fever
Raynaud's phenomenon — blood vessel spasms that interrupt blood flow to the fingers, toes, ears and nose
Causes
Doctors don't know what causes mixed connective tissue disease. The disease is part of a larger group of diseases known as autoimmune disorders. When you have an autoimmune disorder, your immune system — the part of your body responsible for fighting off disease — mistakes normal, healthy cells for intruders. As a result, healthy tissue in your body is damaged, causing signs and symptoms of disease.

It isn't clear what causes your immune system to attack your body. Doctors believe a complex mix of viruses, chemicals and genetic factors may be at play.

Risk factors
Doctors don't know what puts you at risk of mixed connective tissue disease. Some research shows the disease may occur more frequently in people with a family history of connective tissue diseases. Other findings show an increased risk in people exposed to certain chemicals, including vinyl chloride and silica. More research is needed to confirm these findings.

When to seek medical advice
Signs and symptoms of mixed connective tissue disease usually begin mildly and may not prompt you to seek medical attention. But if signs and symptoms become bothersome or interfere with your daily routine, make an appointment with your doctor.

Also see your doctor if you've been diagnosed with lupus or another connective tissue disease and you begin developing new signs and symptoms.

Screening and diagnosis
Your doctor may suspect mixed connective tissue disease based on your signs and symptoms. He or she will conduct a physical exam to look for signs such as swollen hands and painful, swollen joints.

A blood test determines whether you have a certain antibody in your blood that indicates mixed connective tissue disease. The presence of this specific antibody — called U1-RNP — can confirm your doctor's suspicions.

Mixed connective tissue disease usually develops slowly, making it difficult to diagnose. As your signs and symptoms evolve over time — sometimes many years — your diagnosis may change. Many people are first diagnosed with lupus and later re-diagnosed with mixed connective tissue disease. ஐﻬOthers begin with a diagnosis of mixed connective tissue disease only to later find they have lupus or another connective tissue disorder.

Complications
Mixed connective tissue disease and its treatment can lead to serious complications, including:

Pulmonary hypertension. High blood pressure affecting the arteries in your lungs (pulmonary hypertension) is the most common cause of death in people with mixed connective tissue disease. You might experience difficulty breathing or chest pain if you have pulmonary hypertension. People with mixed connective tissue disease usually need to take medications to control pulmonary hypertension.
Heart disease. People with mixed connective tissue disease are at risk of developing heart conditions, including enlargement of parts of the heart and inflammation around the heart (pericarditis). ஐﻬYour doctor may routinely monitor your heart with an electrocardiogram.
Side effects of long-term steroid use. Steroids are commonly used to manage the signs and symptoms of mixed connective tissue disease. While these medications are effective, they don't come without risks. If you take steroids, your doctor will likely monitor you for adverse effects, such as bone loss due to osteoporosis or avascular necrosis, muscle weakness and infection.
Pregnancy complications. Women with mixed connective tissue disease may experience flares during pregnancy. Babies born to women with mixed connective tissue disease are at risk of being born with a low birth weight. If you're planning to become pregnant, talk with your doctor about this risk.
Treatment
No cure exists for mixed connective tissue disease, although treatments can help manage the signs and symptoms of the disease. Your treatment may vary from another person's because your signs and symptoms may be different.

While no standard treatment exists, the most common treatment for mixed connective tissue disease is corticosteroids, such as prednisone.

People with mild forms of mixed connective tissue disease may not need any treatment. You may require treatment only during flares or you may require constant medication. Work with your doctor to ensure that your signs and symptoms are adequately controlled.

Coping skills
Living with a chronic disease that has no cure requires effective coping skills. Consider trying to:

Find out as much as you can about mixed connective tissue disease. Learn as much as you can about the disease. Ask your doctor and other health care team members for assistance in locating reliable resources. The more you know about the disease, the easier it is to understand what's happening to your body.
Take care of yourself. Control your health as best you can. Eat a balanced diet with plenty of fruits and vegetables. Get exercise on days you feel up to it. Keeping your body healthy makes you better able to deal with the daily stress of living with a chronic illness. And it better prepares you ஐﻬto cope with your next flare.
Seek support from others. Social support helps you cope with the stress of mixed connective tissue disease. Ask your doctor about support groups in your area for people with chronic illnesses. Go online to connect with other people living with mixed connective tissue disease.

[Adminஐﻬ]

Mixed connective tissue disease

Overview
Mixed connective tissue disease (MCTD) is a rare autoimmune disorder that causes signs and symptoms of other connective tissue diseases. People with mixed connective tissue disease experience features of three other diseases — lupus, scleroderma and polymyositis. For this reason, mixed connective tissue disease is sometimes referred to as an overlap disease.

Signs and symptoms of these three other diseases usually don't appear all at once. This makes diagnosing mixed connective tissue disease somewhat complicated. Often people with mixed connective tissue disease are ஐﻬfirst diagnosed with lupus. As the disease progresses and other signs and symptoms become apparent, the diagnosis is corrected.

Mixed connective tissue disease occurs most often in women and is usually diagnosed in young adults in their 20s and 30s. Children have also been diagnosed with mixed connective tissue disease.

Mixed connective tissue disease is somewhat of a controversial term among arthritis specialists (rheumatologists). Some question whether mixed connective tissue disease is its own specific disease or whether it's a precursor to another connective tissue disease.

Signs and symptoms
Mixed connective tissue disease doesn't have a unique set of signs and symptoms. Instead, people with mixed connective tissue disease usually have signs and symptoms of lupus, scleroderma and polymyositis, including:

Fatigue
Muscle weakness
Joint pain
Joint swelling
Swollen fingers
Mild fever
Raynaud's phenomenon — blood vessel spasms that interrupt blood flow to the fingers, toes, ears and nose
Causes
Doctors don't know what causes mixed connective tissue disease. The disease is part of a larger group of diseases known as autoimmune disorders. When you have an autoimmune disorder, your immune system — the part of your body responsible for fighting off disease — mistakes normal, healthy cells for intruders. As a result, healthy tissue in your body is damaged, causing signs and symptoms of disease.

It isn't clear what causes your immune system to attack your body. Doctors believe a complex mix of viruses, chemicals and genetic factors may be at play.

Risk factors
Doctors don't know what puts you at risk of mixed connective tissue disease. Some research shows the disease may occur more frequently in people with a family history of connective tissue diseases.ஐﻬ Other findings show an increased risk in people exposed to certain chemicals, including vinyl chloride and silica. More research is needed to confirm these findings.

When to seek medical advice
Signs and symptoms of mixed connective tissue disease usually begin mildly and may not prompt you to seek medical attention. But if signs and symptoms become bothersome or interfere with your daily routine, make an appointment with your doctor.

Also see your doctor if you've been diagnosed with lupus or another connective tissue disease and you begin developing new signs and symptoms.

Screening and diagnosis
Your doctor may suspect mixed connective tissue disease based on your signs and symptoms. He or she will conduct a physical exam to look for signs such as swollen hands and painful, swollen joints.

A blood test determines whether you have a certain antibody in your blood that indicates mixed connective tissue disease. The presence of this specific antibody — called U1-RNP — can confirm your doctor's suspicions.

Mixed connective tissue disease usually develops slowly, making it difficult to diagnose. As your signs and symptoms evolve over time — sometimes many years — your diagnosis may change. Many people are first diagnosed with lupus and later re-diagnosed with mixed connective tissue ஐﻬdisease. Others begin with a diagnosis of mixed connective tissue disease only to later find they have lupus or another connective tissue disorder.

Complications
Mixed connective tissue disease and its treatment can lead to serious complications, including:

Pulmonary hypertension. High blood pressure affecting the arteries in your lungs (pulmonary hypertension) is the most common cause of death in people with mixed connective tissue disease. You might experience difficulty breathing or chest pain if you have pulmonary hypertension. People with mixed connective tissue disease usually need to take medications to control pulmonary hypertension.

Heart disease. People with mixed connective tissue disease are at risk of developing heart conditions, including enlargement of parts of the heart and inflammation around the heart (pericarditis). Your doctor may routinely monitor your heart with an electrocardiogram.
Side effects of long-term steroid use.
 Steroids are commonly used to manage the signs and symptoms of mixed connective tissue disease. While these medications are effective, they don't come without risks. If you take steroids, your doctor will likely monitor you for adverse effects, such as bone loss due to osteoporosis or avascular necrosis, muscle weakness and infection.
Pregnancy ஐﻬcomplications. Women with mixed connective tissue disease may experience flares during pregnancy. Babies born to women with mixed connective tissue disease are at risk of being born with a low birth weight. If you're planning to become pregnant, talk with your doctor about this risk.


Treatment
No cure exists for mixed connective tissue disease, although treatments can help manage the signs and symptoms of the disease. Your treatment may vary from another person's because your signs and symptoms may be different.

While no standard treatment exists, the most common treatment for mixed connective tissue disease is corticosteroids, such as prednisone.

People with mild forms of mixed connective tissue disease may not need any treatment. You may require treatment only during flares or you may require constant medication. Work with your doctor to ensure that your signs and symptoms are adequately controlled.

Coping skills
Living with a chronic disease that has no cure requires effective coping skills. Consider trying to:

Find out as much as you can about mixed connective tissue disease. Learn as much as you can about the disease. Ask your doctor and other health care team members for assistance in locating reliable resources. The more you know about the disease, the easier it is to understand what's happening to your body.
Take care of yourself. Control your health as best you can. Eat a balanced diet with plenty of fruits and ஐﻬvegetables. Get exercise on days you feel up to it. Keeping your body healthy makes you better able to deal with the daily stress of living with a chronic illness. And it better prepares you to cope with your next flare.
Seek support from others. Social support helps you cope with the stress of mixed connective tissue disease. Ask your doctor about support groups in your area for people with chronic illnesses. Go online to connect with other people living with mixed connective tissue disease.

www.LupusMCTD.com

[Adminஐﻬ]

Systemic Sclerosis
A chronic disease of unknown cause, characterized by diffuse fibrosis; degenerative changes; and vascular abnormalities in the skin (scleroderma), articular structures, and internal organs (especially the esophagus, GI tract, lung, heart, and kidney).

Systemic sclerosis is about four times more common in women than men and is comparatively rare in children.

Localized forms of scleroderma occur as circumscribed patches (morphea) or linear sclerosis of the integument and immediately subjacent tissues without systemic involvement. Mixed connective tissue disease (MCTD--see below) ஐﻬcombines features of scleroderma (eg, Raynaud's phenomenon, esophageal dysfunction) with clinical and serologic features of SLE, polymyositis, or RA. Patients with MCTD have extremely high titers of a serum antibody that reacts with nuclear ribonucleoprotein.

Symptoms, Signs, and Diagnosis
Systemic sclerosis varies in severity and progression, ranging from generalized cutaneous thickening (systemic sclerosis with diffuse scleroderma), which may cause rapidly progressive and often fatal visceral involvement, to a form distinguished by restricted skin involvement (often just the fingers and face) and slow progression, often several decades, before full manifestation of characteristic internal involvement. This latter form is termed limited cutaneous scleroderma or CREST syndrome (Calcinosis, Raynaud's phenomenon, Esophageal dysfunction, Sclerodactyly, Telangiectasia). In addition, overlap syndromes exist; eg, sclerodermatomyositis (tight skin and muscle weakness indistinguishable from polymyositis); MCTD; and a musculoskeletal syndrome chemically induced by certain systemic poisons, as occurred in the ingested toxic oil syndrome in Madrid in 1981, which affected about 20,000 people.ஐﻬ A syndrome of incapacitating myalgias and eosinophilia was associated with the ingestion of L-tryptophan, although the exact cause is unknown, and the toxicity probably resulted from a contaminant.

The most common initial complaints in systemic sclerosis are Raynaud's phenomenon and insidious swelling of the acral portions of the extremities, with gradual thickening of the skin of the fingers. Polyarthralgia is also prominent. GI disturbances (eg, heartburn, dysphagia) or respiratory complaints (eg, dyspnea) are occasionally the first manifestations of the disease.

Skin: Induration is symmetric and may be confined to the fingers (sclerodactyly) and distal portions of the upper extremities, or it may affect most or all of the body. As the disease progresses, the skin becomes taut, shiny, and hyperpigmented; the face becomes masklike; and telangiectases appear on the fingers, chest, face, lips, and tongue. Subcutaneous calcifications may develop (calcinosis circumscripta), usually on the fingertips (pulps) and over bony eminences.ஐﻬ Capillary microscopy of the nail folds reveals dilated capillary loops mixed with areas of loss of the microvascular loops normally visible at that site. Biopsy of indurated skin shows an increase in compact collagen fibers in the reticular dermis, epidermal thinning, loss of rete pegs, and atrophy of dermal appendages. There may be variably large accumulations of T lymphocytes in the dermis and subcutis, which also may be the site of extensive fibrosis.

Musculoskeletal system: Friction rubs may develop over the joints (particularly the knees), tendon sheaths (tendinitis), and large bursae because of fibrin deposition on synovial surfaces. Flexion contractures of the fingers, wrists, and elbows result from fibrosis of the synovial membrane, periarticular soft tissues, and skin. Trophic ulcers are common, especially on the fingertips, overlying the finger joints, or over calcinotic nodules.

GI tract: Esophageal dysfunction is the most frequent visceral disturbance and eventually occurs in most patients. Dysphagia (manifested by various abnormal swallowing sensations) is initially caused by impaired esophageal motility but later can result from gastroesophageal reflux disease and secondary stricture formation. Acid reflux resulting from lower esophageal sphincter incompetence, and peptic esophagitis with possible ulceration and stricture are common. Barrett's esophagus occurs in 1/3 of patients with scleroderma; these patients have an increased risk of complications (eg, stricture, adenocarcinoma). Hypomotility of the small intestine may be ஐﻬassociated with malabsorption resulting from anaerobic bacterial overgrowth. Pneumatosis cystoides intestinalis may follow degeneration of the muscularis mucosa and entry of air into the submucosa of the intestinal wall. Characteristic large-mouthed sacculations can develop in the colon and ileum because of atrophy of the smooth muscle of these segments. Biliary cirrhosis may be associated with the CREST syndrome.

Cardiorespiratory system: Lung fibrosis causes early impairment in gas exchange leading to exertional dyspnea. Pleurisy and pericarditis with effusion may occur. Lung involvement generally progresses indolently, with substantial individual variability. Pulmonary hypertension may result from long-standing interstitial and peribronchial fibrosis or intimal hyperplasia of small pulmonary arteries; the latter is associated with the CREST syndrome. Cardiac arrhythmias,ஐﻬ conduction disturbances, and other ECG abnormalities are common. Ambulatory ECG in patients with cardiac or pulmonary involvement revealed ventricular ectopy in 67%; the finding was strongly correlated with sudden death. Heart failure may develop because of pulmonary hypertension and secondary cor pulmonale or because of diffuse fibrous replacement of cardiac muscle. Heart failure tends to be chronic and difficult to treat.

Renal system: Severe renal disease may occur as a consequence of intimal hyperplasia of interlobular and arcuate arteries and usually is heralded by the abrupt onset of accelerated or malignant hypertension. If untreated, renal insufficiency rapidly progresses, becomes irreversible, and is lethal within a few months. However, modern aggressive antihypertensive therapy has made survival for >= 2 yr common, although not all patients respond and some progress to renal failure despite good BP control (see Treatment, below).

Laboratory Findings
Full-blown systemic sclerosis is readily diagnosed on clinical grounds. The nonspecific antibody and HLA typing are largely of research interest. Rheumatoid factor tests are positive in 33% of systemic sclerosis patients, and serum ANA are present in >= 90%. The ANA often show an antinucleolar pattern. An antibody that reacts with centromeric protein (anticentromere antibody) occurs in the serum of a high proportion of patients with the CREST syndrome. SCL-70 antigen (topoisomerase I) is a DNA-binding protein sensitive to nucleases. Patients with diffuse scleroderma are more likely to have anti-SCL-70 antibodies. Anti-SCL-70 antibodies were associated with peripheral ஐﻬvascular disease and pulmonary interstitial fibrosis but were not predictive of cardiac or renal involvement or survival. Analysis of various HLA types and scleroderma shows a significant correlation only between systemic sclerosis and HLA-DR5 and an increased frequency of HLA-DR1 in patients with the CREST syndrome.

Prognosis
The course is variable and unpredictable and often progresses slowly. Most patients eventually show evidence of visceral involvement. Prognosis is poor if cardiac, pulmonary, or renal manifestations are present early. However, the disease may remain limited and nonprogressive for long periods in patients with the CREST syndrome; other visceral changes (eg, pulmonary hypertension caused by vascular disease of the lung, a peculiar form of biliary cirrhosis) eventually develop, but the course of this form of systemic sclerosis often is remarkably benign.

Treatment
No drug has significantly influenced the natural history of systemic sclerosis, but various drugs are of value in treating specific symptoms or organ systems. Corticosteroids may be helpful for disabling myositis, synovitis, or MCTD. Prolonged oral administration (> 1.5 yr) of penicillamine (0.5 to 1.0 g/day) can reduce skin thickening and may delay the rate of new visceral involvement. The drug is usually started at 250 mg/day and increased at several monthly intervals to improve tolerance. Various immunosuppressive drugs, including methotrexate, have been anecdotally useful in some cases of systemic sclerosis; a double-blind study of 65 patients revealed no benefit after 3 yr of immunosuppressive treatment with chlorambucil. Nifedipine 20 mg tid or as tolerated may help control Raynaud's phenomenon. Reflux esophagitis is relieved byஐﻬ frequent small feedings, antacids, and H2 blockers (eg, cimetidine 300 mg qid 30 min before meals and at bedtime) or with proton pump inhibitors and by having the patient sleep with the head of the bed elevated. Esophageal strictures may require periodic dilation; successful correction of gastroesophageal reflux by gastroplasty has been reported. Tetracycline 1 g/day po or another broad-spectrum antibiotic suppresses overgrowth of intestinal flora and may alleviate intestinal malabsorption symptoms caused by bacterial colonization of dilated bowel loops. Physiotherapy may help preserve muscle strength but is ineffective in preventing joint contractures.

For renal disease, ACE inhibitors are the drugs of choice. Other vasodilators (eg, minoxidil) also have been used with some success. All of these drugs effectively control hypertension and help preserve renal function. When end-stage renal disease is unpreventable, dialysis and transplantation can be used, although the mortality rate remains high.

[Adminஐﻬ]

What is Mixed Connective Tissue Disease (MCTD)?

A few decades ago, scientists discovered that patients with a connective tissue disease had symptoms of both lupus, scleroderma, myositis, etc. These diseases are called ‘overlap-syndromes’. In 1969 Sharp and his co-workers found out that there is one specific type of overlap-syndromeஐﻬ with symptoms of lupus, scleroderma, myositis and rheumatoid arthritis, together with a large quantity of antibodies against one specific antigen, namely U1RNP. They believed it to be a distinct disease entity and called it MCTD. Meanwhile, it is known that Sjogren’s Syndrome is very common in MCTD.
It is still a matter of debate whether or not this disorder is diverse from the other overlap-syndromes. In general, however, this disorder is considered a distinct clinical entity.
 
Most important symptoms
Raynaud’s phenomenon
Is basically always present in the early phase of the disease, mostly without other symptoms at the level of the fingers, unless scleroderma is also present at the onset of the disease. 
 
Swollen fingers
Mostly all the fingers are swollen in the overall length and become ‘sausage-like’. Sometimes this is only temporary, but occasionally it evolves into sclerodactyly (thin fingers with hard skin and limited mobility). 

Arthritis
In the early phase there is painful swelling of the joints of the hands and feet like in rheumatoid arthritis. ஐﻬDamage to the cartilage or bone, however, is rare. As such, malformations do not occur or only seldom and the function of the joints remains intact. This kind of arthritis is comparable to the arthritis seen in lupus. 
 
Muscle inflammation
In 10 to 20% of the cases, patients develop a real form of myositis, muscle inflammation (see polymyositis). Two out of three patients suffer from significant muscle pain (no weakening or paralysis), without demonstrable abnormalities in the laboratory test, electromyography or biopsy. Patients complain mostly of pain at the level of the large muscle groups of the shoulder girdle and the upper arms.

Lungs
The lungs may show the same abnormalities and problems as in scleroderma. Reduced lung volume is common, sometimes reduced absorption of oxygen and rarely overpressure in the lung vessels with fatal outcome occurs.

Oesophagus
The same complaints as in scleroderma may occur. 
 
Heart
Inflammation of the heart sac or pericardium (pericarditis) may be acute. Unlike in polymyositis, inflammation of the heart muscle (myocarditis), which may cause heart failure or arrhythmia, occurs rarely. These complications are very serious and may be life threatening. 
 
Neurological damage
Meningitis, psychological abnormalities due to brain damage, damage to the spinal marrow or facial nerves have been described. These symptoms occur often in Sjogren’s Syndrome, which often occurs in MCTD.
 
Renal involvement
Renal involvement is very rare and can be similar to the damage caused in scleroderma (especially damage to the renal blood vessels) as well as to the damage caused in lupus lupus (damage to the renal filtering units).

Skin and mucous membranes
The skin may show symptoms of scleroderma as well as of lupus. The mucous membranes (mouth, vagina) and the eyes may be dry due to the Sjogren’s Syndrome .
 
Who can get MCTD and is it hereditary?
MCTD is a rare disease. In most cases the age of onset lies between 20 and 50 and 8 to 9 out of 10 patients are female. MCTD is not hereditary. There can be a difference in the disease’s genetic susceptibility: the same susceptibility often seen in lupus, rheumatoid arthritis or Sjogren’s Syndrome, can occur in combination.
External factors may also play a role. Some cases of MCTD have been described after the patients had worked professionally with PVC (polyvinylchloride).

  Evolution
Since MCTD overlaps (‘mixes’) different connective tissue disorders, there are many different types, and consequently, many prognoses. Complaints and symptoms depend on the organs involved, the degree ofஐﻬ inflammation and the general degree of disease activity. In general the prognosis is favourable if the disease is adequately treated. Life expectancy is comparable to the life expectancy in lupus, i.e. favourable with a few exceptions.

Diagnosis
The diagnosis is based on complaints, symptoms and organ involvement and on the presence of anti-U1RNP antibodies in high titre (concentration). It is the only connective tissue disease for which one specific type of antibody is necessary to make a diagnosis (at least in most centres). If the doctor suspects the diagnosis of MCTD, some additional tests like lung function tests, heart check-up, examination of the kidneys and blood pressure need to be carried out. In case of muscle complaints or nerve pains an electromyography is necessary. The results of these examinations may also contribute to a diagnosis.

Treatment
Although treatments with a low dose of corticosteroids have been successful, there is no standard procedure for MCTD. The treatment is based on the type and degree of organ involvement, and can be a treatment for lupus or for scleroderma. The treatment has to be individualised for each patient.
 
MCTD and pregnancy
Surveys on the subject are quite different. The influence of pregnancy on MCTD or vice versa can be compared to pregnancy in lupus.
 
Overlapping syndromes
Besides MCTD there exist also other overlap syndromes which are less clearly definable or which do not have anti-U1RNP antibodies. As in MCTD, treatment is based on the type and degree of organ involvement and it is individualised for each patient. The evolution and prognosis are also comparable to MCTD, except that there may be more individual dissimilarities among patients.
 
Undefined Connective Tissue Disease (UCTD)
 In the early phase of a connective tissue disease and especially at the onset of an overlap syndrome or MCTD, the symptoms can be very limited and unusual. Although the onset of a connective tissue disease can be certain in such cases, it is impossible to define the type of disease with certainty. ஐﻬThat is why the term UCTD (= undefined connective tissue disease) is used. Mostly Raynaud’s phenomenon, joint pains, sometimes arthritis and muscle pains are present. The evolution is very diverse: some patients remain in this phase while others evolve quickly into a real form of lupus or another type of connective tissue disease. Again, treatment has to be individualised according to each patient.

 


www.LupusMCTD.com

[Adminஐﻬ]

MCTD vs. UCTD
(Mixed Connective Tissue Disease vs. Undifferentiated Connective Tissue Disease)
Medical Author: William C. Shiel Jr., MD, FACP, FACR

I note that some viewers have been requesting some clarification of the meaning of the terms "mixed connective tissue disease" (MCTD) and "undifferentiated connective tissue disease" (UCTD).

Connective tissue diseases are a special group of rheumatic diseases (diseases that feature abnormalities of the muscles and/or joints) that can be associated with arthritis. The cause(s) for the connective tissue diseases is (are) unknown.ஐﻬ They are characterized as a group by the presence of spontaneous over-activity of the body's immune (defense) system. This over-activity results in the production of unusual antibodies that are found in the blood. The antibodies themselves may or may not cause any problems in patients with connective tissues diseases, but they are commonly found in the blood as an characteristic feature.

The connective tissues are the structural portions of our body that essentially hold the cells of the body together. These tissues form a framework, or matrix, for the body. The connective tissues are composed of two major structural protein molecules, collagen and elastin. There are many different types of collagen protein that vary in amount in each of the body's tissues. Elastin has the capability of stretching and returning to its original length - like a spring or rubber band.ஐﻬ Elastin is the major component of ligaments (tissues that attach bone to bone) and skin. In patients with connective tissue diseases, it is common for collagen and elastin to become injured by inflammation. Diseases in which inflammation of collagen tends to occur are also referred to as collagen diseases.

The classic connective tissue diseases include systemic lupus erythematosus, rheumatoid arthritis, scleroderma, polymyositis, and dermatomyositis. Each of these diseases affects people in a characteristic way and causes typical findings that doctors can recognize during an examination. Each also has characteristic blood test abnormalities and abnormal antibody patterns. For example, systemic lupus erythematosus has dsDNA antibodies, while scleroderma has Sc170 antibodies. Additionally, each of these diseases can evolve either slowly or rapidly from very subtle abnormalities before demonstrating the classic features that help in the diagnosis.

When these conditions have not developed the classic features of a particular disease, doctors will often refer to the condition as "undifferentiated connective tissue disease," or UCTD. This designation implies that the characteristic features that are used to define the classic connective tissue diseases are not present, but that some symptoms or signs of a connective tissue disease exist.ஐﻬ For example, a person may have a special antibody in the blood, such as antinuclear antibody and muscle pains, but no other definable features of a classic connective tissue disease. Individuals with undifferentiated connective tissue disease may never develop a fully definable condition or they may eventually develop a classic connective tissue disease.

Mixed connective tissue disease, which was first described in 1972, is "classically" considered as an "overlap," or mix, of three specific connective tissue diseases; systemic lupus erythematosus, scleroderma, and polymyositis. Patients with this pattern of illness (that is, with MCTD) have features of each of these three diseases. They also typically have very high quantities of antinuclear antibodies (ANAs) and antibodies to ribonucleoprotein (anti-RNP) detectable in their blood. The symptoms of many of these patients eventually evolve to become dominated by features of one of the three component illnesses, most commonly the scleroderma features.

It is now known, however, that overlap syndromes can involve any combination of the connective tissue diseases. Therefore, for example, patients can have a combination of rheumatoid arthritis and systemic lupus erythematosus (hence, the coined name "rhupus"). Accordingly, today, true mixed connective tissue disease is diagnosed when patients demonstrate the clinical features ஐﻬ(exam findings) of overlap illnesses. These patients also have high amounts of ANA and anti-RNP without having such other antibodies as the dsDNA antibodies of systemic lupus erythematosus and the Scl70 antibodies of scleroderma.

[Adminஐﻬ]

Understanding Fatigue in Lupus - and What Can Be Done



If you have lupus, you probably know how bad fatigue can be. It's one of the most common symptoms reported by people with lupus. Most lupus patients suffer with it. But exactly what causes this fatigue that goes far beyond just being tired?

A study done at Hospital for Special Surgery almost 10 years ago suggested that depression and sleep problems might contribute to fatigue in people with lupus.1 But in the women studied, those who had lupus did not have more ஐﻬdepression than those who did not. However, those who had lupus took longer to fall asleep - and slept for longer periods of time.

Over the years, other researchers have also tried to figure out how sleep and depression might play a role. Others have suggested that lack of exercise might be involved - because exercise can actually give you energy when your muscles get fit.

New Research

Recently, a Canadian group of researchers explored the question and reported at a recent meeting of the American College of Rheumatology.2 They studied 100 women with lupus. The women were given a series of different tests to look at:

the type of their fatigue,


how bad their fatigue was,


how bad their pain was,


whether they were depressed - and if so how badly,


how well - or poorly - they slept,


how much physical activity they did in their leisure time,


whether they were satisfied with the support they received from family and friends.
Finally, the women were examined by a doctor to see the level of their lupus disease activity and the impact lupus already had on their bodies.

What They Learned

As in other studies, they found that people with lupus have much more fatigue than others.

Fatigue can be influenced by everything they explored and more: depression, pain, quality of sleep, quantity sleep, exercise, ஐﻬseverity of illness, and satisfaction with your social support network - as well as flares, medications, and stress. And it varies from one patient to the next.

Because fatigue arises from so many different factors, they said treatment should try to find out what factors were involved in the patient being treated - and treat all of them to get at the fatigue. These factors can be treated - modified - changed.

Two Types of Fatigue

One thing that was different about their study was that they separated physical fatigue from mental fatigue. Many other studies have just looked at "fatigue" as one thing.

Think of physical fatigue as "I'm too tired to stand up," or "I just can't walk another block." That's easy to recognize - and you should listen to it. Rest. Sit down or just collapse in bed for awhile.

Mental fatigue can be more difficult to get a grasp on sometimes. "I can't think straight" or "I can't concentrate" or "I keep rereading this paragraph again and again" may be mental fatigue. Or it may be a sign of theஐﻬ cognitive (thinking) difficulties that are part of neuropsychiatric lupus. So any changes in your thinking or concentration should be reported to your doctor - because a change in medication may help. In the meantime, again, rest. Put the book down. Veg out in front of the TV. Cuddle up with your pet. (Studies have proven that stroking a pet can be very relaxing.) Or take a nap.

Physical Fatigue

It was not a surprise that people with more pain and poorer sleep were more likely to have physical fatigue.

Lots of research - in people without lupus - has shown exercise helps reduce depression. But this study had an interesting surprise. Only the lupus-fatigued women who did not score high on depression tests seemed to be helped by exercise. Lupus-fatigued women who were depressed did not get an improvement in physical fatigue from exercise. Does this mean you shouldn't exercise? No! You need exercise for heart fitness, muscle strength and to keep up your energy. It may even help your physical fatigue - because a finding from one research study doesn't apply to everyone.

But look to other means as well. Talk with your doctor about ways to improve your sleep and lower your pain level, especially by reducing your disease activity.

Mental Fatigue

The factors most related to mental fatigue were slightly different. They were clearly:

greater pain severity - again, talk with your doctor about how to reduce your pain level;


higher levels of depression - ask your doctor about referral to a licensed psychotherapist such as a social worker or psychologist. In some cases,r antidepressant medication may also be useful.


lower satisfaction with social support networks - talk with family and friends about what you need from them. Often they may not be aware of how you are feeling inside. Let them know what can help. ஐﻬEstablishing an understanding together of the impact of fatigue and how to problem-solve around this is important.
How Do You Cope

Fatigue is profound. It touches you to the core. It can totally disrupt your life. Fatigue itself can be stressful and fatiguing. Because you cannot "see" fatigue, and it can change so much from hour-to-hour and day-to-day, your fatigue can also be confusing to those with whom you live and work. But it's not something you can point to like a swollen joint or a rash. You can be exhausted with fatigue and your friend or family member says, "You look great."

This can be very frustrating. You feel that others just don't get it. Over time, see if you can learn to respond comfortably and assertively to such comments. "I wish I felt as great as I look - but I'm really fatigued right now, and it's important that I rest and take care of myself."

Those words may not be right for you - but you need to find the words that are. Because when fatigue hits, you need to let go and rest. Give in to fatigue when necessary - so you can spring back. Take that temporary break - so you can stand up and think clearly later. Whether it's an hour later or a day later doesn't matter. You will find the right moment. And only you can. Because lupus fatigue is different for everyone - what causes it, when it hits, what helps, when it goes.

Be kind to yourself, work with your doctor, and you will find the path that's best for you. Just don't give up.
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Encephalopathy and severe neuropathy due to probable systemic vasculitis as an initial manifestation of mixed connective tissue disease

Matsui Hideaki, Udaka Fukashi, Oda Masaya, Kubori Tamotsu, Nishinaka Kazuto, Kameyama Masakuni
 Department of Neurology, Sumitomo Hospital, Osaka, Japan



Correspondence Address:
Matsui Hideaki
Department of Neurology, Sumitomo Hospital, 5-3-20 Nakanoshima, Kita-ku, Osaka, 530-0005
Japan
matsui-hideaki@sumitomo-hp.or.jp

 
  Abstract   

We described a 69-year-old woman with neurological manifestations due to mixed connective tissue disease (MCTD). The patient demonstrated subacute cognitive decline, seizure and gait disturbance with no connective tissue manifestation. She had been diagnosed with dementia at another hospital, later in our hospital, serological examinations disclosed high titers of anti-RNP antibody. Cognitive dysfunction in this patient was dramatically ameliorated by steroid therapy. Three months later, she developed edema of the hands, synovitis and acrosclerosis. The patient was finally diagnosed as having MCTD. We emphasized MCTD as a rare cause of "treatable dementia".



Keywords: Mixed connective tissue disease, treatable dementia, cognitive dysfunction


The occurrence of neurological or psychiatric disturbances in association with rheumatic diseases has been an area of considerable interest for many years.[1] Mixed connective tissue disease (MCTD) is characterized by clinical features of systemic lupus erythematosus (SLE), scleroderma and polymyositis occurring simultaneously or sequentially, in the presence of high titers of antibody to an Rnase-sensitive ribonuclear protein complex, U1 small nuclear RNP (ribonucleoprotein). Neurological problems in MCTD are seen in approximately 10~20% of cases;[2] however, it is difficult to diagnose patients with just neurological manifestations. We present a patient demonstrating subacute cognitive dysfunction, seizure and gait disturbance with no connective tissue manifestation. The patient was later disclosed as having MCTD. Cognitive dysfunction and seizure in this patient were ameliorated by steroid therapy. We emphasize MCTD as a rare cause of "treatable dementia".


  Case Report   


A 69-year-old woman demonstrated gait disturbance from April 2004 and the gait disturbance gradually and symmetrically progressed. The patient had no congenital disorders, no regular medicine, no history of diseases such as hypertension, diabetes mellitus or sleep disorders, no history of toxin exposure and no smoking or alcohol. In October 2004, cognitive dysfunction appeared and subacutely deteriorated. She also demonstrated aphasia and experienced transient seizure once in the previous month. The patient had been diagnosed as having dementia in another hospital, but in November 2004 was admitted to our hospital. On admission, the patient was alert and awake. She could not stay standing nor walk. There were no trophic changes in the feet. She had cognitive impairment, mainly memory disturbance. The score on a Mini-mental state examination (MMSE) was 10/30. She demonstrated incomplete transcortical motor aphasia, and sometimes palilalia, but apraxia or agnosia was not seen. Cranial nerves were intact except for right facial sensory disturbance in touch, pain and temperature. Muscle strength in upper limbs was slightly diminished, while in lower limbs all muscles revealed distal dominant weakness, as reflected by the 3 score on a manual muscle test. There was moderate atrophy in bilateral tibialis anterior muscles. Deep tendon reflexes were all symmetrical and normal in upper limbs but were absent in the lower limbs. Bilateral palmomental reflexes were positive, as was right Babinski's reflex, while left plantar reflex was equivocal. Vibration, touch, pain and temperature senses in the bilateral lower limbs were greatly and symmetrically diminished. Voluntary pain was not seen. There was no sensory level in the distribution of sensory disturbances. The neuropathy was painless. No cerebellar or autonomic manifestations were present. Neck stiffness and Kernig's sign were negative. The patient did not show any symptoms in connective tissues such as Raynaud's syndrome, synovitis, acrosclerosis, myositis, edema or sclerodactylia

Blood analysis disclosed mild inflammatory responses, and high indexes of SS (Sj φgren syndrome) -A, RNP and TPO (thyroid peroxidase = thyroid myeloperoxidase) antibody, and hypothyroidism. Other antibodies such as DNA, SS-B, cardiolipin, Sm, or ANCA (antineutrophil cytoplasmic antibodies) were not detected. The tests for lupus anticoagulant were not performed. Antinuclear antibodies were detected at low titers. Vitamin B1, B12 and folic acid were normal. Hepatitis B surface antigen, Hepatitis C antibody, rapid plasma reagin test and treponemal tests: hemagglutination test were all negative. Cerebrospinal fluid examinations showed high total protein and increased cell counts. No bacteria or malignant cells were detected, neither was tubercle bacillus on a culture test and by DNA-PCR. Oligoclonal bands were positive while myelin basic protein was not detected. Herpes simplex virus, herpes zoster virus, mumps, measles and toxoplasma were negative during the entire clinical course. Urine examinations were normal. Ultrasonic cardiography demonstrated pulmonary hypertension (Tricuspid regurgitation peak pressure gradient = 37 mmHg). Chest computed tomography (CT) was normal. Magnetic resonance imaging (MRI) showed multiple high intensity signals in T2 and FLAIR sequences [Figure - 1]. These lesions were not enhanced. Brain and cervical magnetic resonance angiography did not show any abnormal lesions. Electroencephalography demonstrated diffuse slow activity. Motor action potentials in the bilateral tibial nerves were not evoked, while a motor conduction study demonstrated low amplitude (amplitude: 0.6 mV, conduction velocity: 30 ms) in the bilateral peroneal nerves. Motor action potentials in the bilateral ulnar nerves were intact and those in the bilateral median nerves showed slightly delayed distal latency. Action potentials in the bilateral sural nerves were not evoked, and somatosensory evoked potentials could not be detected. There was no evidence of conduction block. These nerve conduction studies demonstrated the mononeuritis multiplex pattern; severe damage in the tibial nerves in contrast to relative preservation of the peroneal nerves, which are more prone to be impaired by polyneuropathic pathology. Blink reflex test disclosed right trigeminal neuropathy [Figure - 2]. No malignant tumor was detected on chest and abdominal CT, endoscopy, sonography and tumor marker studies.

The patient was tentatively diagnosed as having neurological deteriorations due to MCTD. Corticosteroid pulse therapy was given and thereafter 60mg/day prednisolone was prescribed orally. Oral prednisolone was gradually tapered and her cognitive function improved. MMSE score was 24/30 one month after therapy. Aphasia had completely disappeared, and there were no seizures after treatment. However the trigeminal and peripheral neuropathies, and gait disturbance did not ameliorate, and brain MRI did not change significantly. Inflammatory response in blood and cerebrospinal fluid disappeared. Three months after admission, she gradually developed edema of the hands, synovitis and acrosclerosis. The patient was finally diagnosed as having MCTD. The patient did not show remarkable clinical change in further three months after the final diagnosis.


  Discussion   


The patient fulfilled the diagnostic criteria of MCTD by Japanese study group[2] and probable diagnosis by Sharp.[3] While we could not exclude Hashimoto's encephalopathy, MCTD was strongly suggested by the concomitant pulmonary hypertension, trigeminal neuropathy and peripheral neuropathy. Especially, trigeminal neuropathy has been reported to have a close relation with MCTD compared to other collagen disease or Hashimoto's disease,[4],[5] therefore this suggested strongly that neurological manifestations in this patients were due to MCTD. Pulmonary hypertension also has been considered as a unique complication of MCTD,[6] however some authors pointed out the correlation between thyroid dysfunction and pulmonary hypertension.[7] It is unnatural to consider encephalopathy was due to Hashimoto's disease and other symptoms were due to MCTD, while all symptoms appeared in succession.

In this case, the symptoms and inflammatory response in cerebrospinal fluid and serum were ameliorated but the brain MRI after steroid therapy showed little change. This may be because the abnormal lesions in brain MRI represented irreversible damage and the symptoms in the central nervous system were ameliorated due to improvement of the encephalopathy.

Neurological problems sometimes seen in MCTD include headache, seizures, psychosis, encephalopathy, transverse myelitis, ataxia, aseptic meningitis, monocular blindness, trigeminal sensory neuropathy, polyneuropathy and entrapment neuropathy.[1],[8],[9] The neurologic features observed tend to be characteristic of the dominant clinical syndrome exhibited by each patient. For example, trigeminal and peripheral neuropathy tend to occur in MCTD patients with predominant scleroderma features, while optic neuropathy, transverse myelitis, encephalopathy and ataxia occur in patients with prominent SLE features.[1]

In this case, encephalopathy and severe neuropathy might be due to systemic vasculitis as a manifestation of MCTD. Although vasculitis is a rare feature of MCTD, there were some reports about concomitant vasculitis in patients with MCTD.[10],[11] It might account for the mononeuritis multiplex pattern peripheral neuropathy and the brain MRI findings. However, because tissue biopsy was not done in this patient, the presence of vasculitis was not confirmed in this patient.

Central nervous disorders in MCTD patients are rare, and MCTD has been never discussed in the context of "treatable dementia". Many factors have been reported to contribute to "treatable dementia", including cerebrovascular disease, tumor, normal pressure hydrocephalus, toxicity, depression, encephalopathy, multiple sclerosis, sarcoidosis, hormonal abnormalities, vitamin insufficiency, organ failure, Behηet's disease, and collagen disease.[12] In collagen disease, symptoms such as SLE, temporal arteritis, and Sj φgren syndrome have been described as a rare cause of "treatable dementia".[12] We described here "treatable dementia" due to MCTD, which while it may be rare state, it has corresponding significance because of the fact: that it is indeed treatable. Further studies will be needed to better understand the circumstances surrounding this condition.

   References   
1. Nadeau SE. Neurologic manifestations of connective tissue disease. Neurol Clin 2002;20:151-78.    [PUBMED]   
2. Miyata M, Nishimaki T. Neural disorders in mixed connective tissue disease (MCTD) and overlap syndrome. Nihon Rinsho Bessatsu Nihon Rinsho c! 2000;279-81.       
3. Sharp GC, Irvin WS, Tan EM, Gould RG, Holman RH. Mixed connective tissue disease - an apparently distinct rheumatic disease syndrome associated with a specific antibody to an extractable nuclear antigen (ENA). Am J Med 1972;52:145-59.       
4. Lecky BR, Hughes RA, Murray NM. Trigeminal sensory neuropathy. A study of 22 cases. Brain 1987;110:1463-85.    [PUBMED]   
5. Hagen NA, Stevens JC, Michet CJ Jr. Trigeminal sensory neuropathy associated with connective tissue diseases. Neurology 1990;40:891-6.    [PUBMED]   
6. Haroon N, Nisha RS, Chandran V, Bharadwaj A. Pulmonary hypertension not a major feature of early mixed connective tissue disease: A prospective clinicoserological study. J Postgrad Med 2005;51:104-8.       
7. Marvisi M, Ajolfi C, Civardi G, Delsignore R. Thyroid dysfunction and pulmonary hypertension. Recenti Prog Med 2004;95:443-6.    [PUBMED]   
8. Bennett RM, O'Connell DJ. Mixed connective tisssue disease: a clinicopathologic study of 20 cases. Semin Arthritis Rheum 1980;10:25-51.    [PUBMED]   
9. Bennett RM, Bong DM, Spargo BH. Neuropsychiatric problems in mixed connective tissue disease. Am J Med 1978;65:955-62.    [PUBMED]   
10. Kimber TE, Scott G, Thompson PD, Beare JH. Vasculitic neuropathy and myopathy occurring as a complication of mixed connective tissue disease. Aust N Z J Med 1999;29:82-3.    [PUBMED]   
11. Graf WD, Milstein JM, Sherry DD. Stroke and mixed connective tissue disease. J Child Neurol 1993;8:256-9.    [PUBMED]   
12. Abe K, Yanagihara T. Treatable dementia. Clin Neurosci 1995;13:644-5.     

 
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Decision on breast implants welcomed
2 Richmond surgeons back FDA approval of silicone-gel product

 Nov 25, 2006


Plastic surgeons Lewis Ladocsi and Andrea Pozez say they never understood the U.S. Food and Drug Administration's rationale for restricting silicone gel-filled breast implants in the first place.

The federal agency last week agreed to allow silicone gel-filled implants back on the market, reversing a decision in the early 1990s to limit the implants because of concerns that ruptured or leaking implants caused health problems in patients, including connective-tissue disorders.

Two companies, Allergan Corp. (formerly Inamed Corp.) of Irvine, Calif., and Mentor Corp. of Santa Barbara, Calif., are being allowed to market their silicone gel-filled implants for breast reconstruction in women of all ages and for breast augmentation in women ages 22 and older.

Before Nov. 17, women received silicone gel-filled implants only as part of research studies after certain protocols. In addition, those women had to be undergoing breast reconstruction after trauma or cancer, for instance, or breast revision surgery to replace implants.

The FDA over the years has rejected applications to market the implants.

Saline-filled breast implants were still available as an option. Doctors say silicone gel-filled implants feel and behave more like natural breast tissue.

"They feel dramatically different. They are softer, warmer, more pliable," said Ladocsi of Richmond Plastic Surgeons.

"This is the most studied medical device," Ladocsi said. "They have been studied more than pacemakers. There has never been any credible evidence they were harmful."

Pozez, professor and chair of the division of plastic and reconstructive surgery at Virginia Commonwealth University, said the 1991 action to allow silicone gel-filled implants for some women and not others sent a mixed message.

"The science of implants is the same for augmentation or for reconstruction," Pozez said. "Over those 14 years, implants have been registered, and the data has been collected and analyzed. And based on continued science," the FDA approved the Mentor and Allergan products, she said.

The FDA approval comes with requirements for the companies. They have to:

conduct a large study following about 40,000 women for 10 years after receiving breast implants;
conduct a focus-group study of the patient-information labels;
continue laboratory studies to further characterize types of device failure; and
track each implant so that health professionals and patients can be notified of updated product information.
There are also requirements about what is included in information provided to patients.

Women considering implants have to be told that breast implants typically don't last forever and may have to be replaced.

"The majority of patients with breast implants of any kind can have the potential need for replacement due to implant failure or other conditions, including infection and scarring," Pozez said.

In addition, patients have to be advised about the importance of routine screening to monitor for implant rupture. Women will be told to receive a screening MRI three years after implant surgery and then every two years. Those costs can add up.

Other points that have to be highlighted include:

Many of the changes to a woman's breast after implantation are irreversible. Some women experience something called capsular contracture in which the scar tissues that form around the implant harden to the degree that it flattens the implant and increases risk of rupture.
Rupture of a silicone gel-filled breast implant is often undetectable to a woman and her doctor.
Now that the FDA is allowing silicone-filled breast implants back on the market, doctors expect many women to choose them.

Ladocsi said saline-filled implants were not a good option for some patients, particularly slim women without a lot of breast tissue. The natural folds of the implants are seen through the skin, causing a rippling or wrinkling effect.

Ladocsi said women generally do not aim for the Pamela Anderson look; most just want to better balance their figures. Some come after pregnancy and breast-feeding have changed the appearance of their breasts. Some have lost a lot of weight and want firmer breasts.

"The typical breast-enhancement patient is in her 30s, a mom, well-educated and has considered surgery for a year," Ladocsi said.
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Connective tissue disease

A connective tissue disease is any disease that has the connective tissues of the body as a primary target of pathology. Connective tissue is any type of biological tissue with an extensive extracellular matrix that supports, binds together, and protects organs. These tissues form a framework, or matrix, for the body, and are composed of two major structural protein molecules, collagen and elastin. There are many different types of collagen protein in each of the body's tissues.

Elastin has the capability of stretching and returning to its original length - like a spring or rubber band. Elastin is the major component of ligaments (tissues that attach bone to bone) and skin. In patients with connective tissue disease, it is common for collagen and elastin to become injured by inflammation.ஐﻬ Many connective tissue diseases feature abnormal immune system activity with inflammation in tissues as a result of an immune system that is directed against one's own body tissues (autoimmunity).

Diseases in which inflammation or weakness of collagen tends to occur are also referred to as collagen diseases. Collagen vascular disease is a somewhat antiquated term used to describe diseases of the connective tissues that typically include diseases which can be (but are not necessarily) associated with blood vessel abnormalities.

Connective tissue diseases can have strong or weak inheritance risks, and can also be caused by environmental factors.


Heritable Connective Tissue Disorders
Marfan syndrome - a genetic disease causing abnormal fibrillin.
Ehlers-Danlos syndrome - causes progressive deterioration of collagens, with different EDS types affecting different sites in the body, such as joints, heart valves, organ walls, arterial walls
Osteogenesis imperfecta (brittle bone disease) - caused by insufficient production of good quality collagen to produce healthy, strong bones.

 Weakly or Non-Heritable Connective Tissue Disorders
These are the autoimmune CTDs, where the cause is unknown but may have both genetic and environmental links. Weaker genetic factors may create a predisposition towards developing these autoimmune diseases.

They are characterized as a group by the presence of spontaneous overactivity of the immune system which results in the production of extra antibodies into the circulation. The classic collagen vascular have a "classic" presentation with typical findings that doctors can recognize during an examination. ஐﻬ Each also has "classic" blood test abnormalities and abnormal antibody patterns. However, each of these diseases can evolve slowly or rapidly from very subtle abnormalities before demonstrating the classic features which help in the diagnosis. The classic collagen vascular diseases include:

Scurvy - caused by a dietary deficiency in vitamin C, leading to abnormal collagen.

Systemic Lupus Erythematosus (SLE) - An inflammation of the connective tissues, SLE can afflict every organ system. It is up to nine times more common in women than men and strikes black women three times as often as white women. The condition is aggravated by sunlight.

Rheumatoid Arthritis - Rheumatoid arthritis is a systemic disorder in which immune cells attack and inflame the membrane around joints. It also can affect the heart, lungs, and eyes. Of the estimated 2.1 million Americans with rheumatoid arthritis, approximately 1.5 million (71 percent) are women.
 
Scleroderma - Scleroderma is an activation of immune cells which produces scar tissue in the skin, internal organs, and small blood vessels. It affects women three times more often than men overall, but increases to a rate 15 times greater for women during childbearing years, and appears to be more common among black women.
 
Sjogren's Syndrome - Sjögren's syndrome (also called Sjögren's disease) is a chronic, slowly progressing inability to secrete saliva and tears. It can occur alone or with rheumatoid arthritis, scleroderma, or systemic lupus erythematosus. Nine out of 10 cases occur in women, most often at or around mid-life.
 
Myositis - Myositis involves inflammation that results in damage to muscle fibers and skin. Myositis is a term that describes several illnesses including polymyositis, dermatomyositis and inclusion body myositis. Polymyositis involves inflammation of the muscles and can affect many parts of the body. Dermatomyositis involves inflammation of skin. Inclusion myositis is similar to polymositis, but its onset is generally slower and more relentlessly progressive. All of these fall into the category of inflammatory muscle diseases — "myo" means "muscles" in Greek; "itis" means "inflamed." "Derma," which means "skin," implies the skin-related signs and symptoms that accompany the muscle inflammation of dermatomyositis
.
Mixed Connective Tissue Disease - Mixed connective-tissue disease (MCTD) is a disorder in which features of various connective-tissue diseases (CTDs) such as systemic lupus erythematosus (SLE); systemic sclerosis (SSc); dermatomyositis (DM); polymyositis (PM); and, occasionally, Sjögren syndrome can coexist and overlap. The course of the disease is chronic and usually milder than other CTDs. In most cases, MCTD is considered an intermediate stage of a disease that eventually becomes either SLE or Scleroderma.
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