How Connective Tissue Diseases Are Diagnosed

Connective tissue diseases are autoimmune disorders that cause inflammation of collagen and elastin fibers. Connective tissues are found all throughout the body. A connective tissue disorder not only affects blood vessels, tendons, ligaments, bone, and skin but also the nearby organs.

Examples of common connective tissue diseases include:

• Lupus
• Rheumatoid arthritis
• Scleroderma

About 25% of patients with one of the above conditions (or another connective tissue disease like dermatomyositis or Sjogren's syndrome) will end up developing a secondary connective tissue disease with time. Healthcare providers refer to this as overlap syndrome.

Types of Connective Tissue Diseases

There are more than 200 types of connective tissue diseases. Some of the more common conditions include:

• Eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss syndrome): Inflammation in the blood vessels of the digestive system, skin, nerves, or lungs
• Dermatomyositis or polymyositis: Inflammation and degradation of muscle tissue (though dermatomyositis may eventually impact the skin as well)
• Granulomatosis with polyangiitis: Blood vessel inflammation in organs like the nose, kidneys, or lungs
• Microscopic polyangiitis: A rare autoimmune disease that impacts blood vessels in various organs
• Rheumatoid arthritis: Inflammation in the membranes that surround the joints (a common autoimmune condition that affects women more often than men)
• Scleroderma: Autoimmune condition that causes scars to form in the skin, internal organs, or small blood vessels and disproportionately impacts women of childbearing age
• Systemic lupus erythematosus: Connective tissue inflammation throughout the body

Some individuals experience symptoms of the above conditions but don't meet the criteria of a specific diagnosis. When this happens, it's referred to as undifferentiated connective tissue disease.

Self-Checks

A rheumatologist is trained to officially diagnose autoimmune diseases, but many patients notice the following symptoms before reaching out to their provider:

• Feeling unwell
• Knuckle discoloration (red or brown patches)
• Joint pain
• Muscle pain
• Numb fingertips in cold weather
• Shortness of breath
• Swollen fingers
• Trouble swallowing
• Unexplained fatigue

Physical Examination

Your healthcare provider will look for signs of dry eyes or dry mouth, swollen hands and joints, and limited range of motion among joints. Raynaud's syndrome is typical for patients with connective tissue diseases, causing patches of the fingers to become noticeably pale and numb in response to the cold or emotional stress. When this happens the skin color may change from white to blue to red.

Skin tightening on the fingers can be a sign of sclerosis. Your practitioner will look for rashes that are characteristic of lupus, as well as thinning hair.

Joint swelling and arthritis pain are some of the most common symptoms. Your practitioner may ask you to do basic motions like lifting your arms above your shoulders, climbing stairs, or getting in and out of a chair to see if you have difficulty with these tasks.

You'll be assessed for fatigue, high blood pressure, fever, abdominal pain, swollen lymph nodes, and kidney function (via blood tests) to check for other common signs of connective tissue disease. A questionnaire to review your family history is also helpful since many autoimmune disorders run in families.

Labs and Tests

A variety of tests will help pinpoint the cause of your symptoms and find the right diagnosis. Blood and urine tests, tissue biopsies, magnetic resonance imaging (MRI), X-rays, and testing for dry eyes or mouth are some of the ways you can be evaluated for connective tissue diseases.

Sometimes the absence of specific symptoms is most telling. For instance, severe central nervous system and kidney issues are common in patients with lupus but not mixed connective tissue disease.

Genetic Testing

Genetic testing isn't recommended for most connective tissue diseases, since the role of inheritance hasn't been established. A general overview of your family history can provide some insight into your likelihood of developing an autoimmune disease, but there are no specific genetic markers to diagnose the condition.

CBC and Inflammatory Markers

Patients with connective tissue disease may show signs of mild anemia (low numbers of oxygen-carrying red blood cells), thrombocytopenia (low numbers of platelets, which assist in blood clotting), and leukopenia (low numbers of infection-fighting white blood cells), which may be detected with a complete blood count (CBC).

Elevated inflammatory markers, like erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP), are common in any autoimmune disease.

Protein and Antibody Tests

Specific antibodies are primary markers for connective tissue disease. Your blood will be tested for antinuclear antibodies (ANA), antibodies to U1 ribonucleoprotein, anti-DNA antibodies, and Smith antibodies.

Several different types of immunoassays may be used for ANA testing, each with their own advantages and disadvantages. Examples include:

• IFA: Preferred method since it's very sensitive, but it requires expertise for interpretation
• ELISA: Results are easier to interpret and the test is more widely available, but it isn't as sensitive
• CLIA: More sensitive than ELISA but not as sensitive as IFA; can be automated
• Multiplex assay (LIA, MBA): Can analyze clusters of antibodies

Measuring muscle enzymes, like creatine kinase, aminotransferases, and lactic dehydrogenase, can help detect symptoms of myositis.

Urine Testing

A urine analysis is useful for patients with connective tissue diseases and kidney disease. Elevated protein, red blood cells, or white blood cells may be found in the urine.

Tissue Biopsy

Tissue biopsies can be helpful in diagnosing various connective tissue diseases, including lupus and myositis. Skin changes occur in 80% of lupus patients, and specific characteristics can be attributed to certain variant subtypes of lupus.

For inflammatory myositis, muscle biopsies are required. Microscopic observations, like the thickness and arrangement of collagen fibers, edema within vessel walls, or the presence of certain immune cells, help point to a clearer diagnosis and provide information about the disease stage and progression.

Joint Fluid Analysis

A joint fluid analysis evaluates the synovial fluid for microorganisms, immune cells (like leukocytes), amyloid fragments, fat globules, and other biomarkers to indicate a particular diagnosis. Getting an in-depth look at fluid in the joints helps to differentiate between inflammatory arthritis such as gout or rheumatoid arthritis, osteoarthritis, or septic arthritis due to an infection.

Imaging

Various imaging modalities such as functional magnetic resonance imaging (fMRI), positron emission tomography (PET scans), computed tomography (CAT scans), or X-rays can assess tissues underneath the skin to check for the more severe signs of a connective tissue disease, like fluid around the lungs or brain function issues.

For instance, ultrasound imaging with color duplex can give healthcare providers a closer look at the soft tissues of the neck, including cervical lymph nodes and salivary glands.

Your provider may use imaging to check for scleroderma (characterized by excessive collagen deposits in the skin, blood vessels, or other organs) or thyroid changes, and muscle weakness from myositis.

For pediatric patients, imaging is more critical since connective tissue diseases can result in long-term developmental delays. Pediatric specialists may use chest radiography to look at the lungs, barium swallow tests for the esophagus, echocardiography to estimate arterial pressure in the lungs, and renal ultrasound for kidney function.

Differential Diagnosis

Many of the characteristics associated with connective tissue disorders are also found with injuries or other physical and mental health conditions.

For instance, just because you have pain, fatigue, skin changes, swelling, or memory issues doesn't necessarily mean you have an autoimmune disorder. It's possible that fibromyalgia, allergies, stress injuries, or even depression could be causing your symptoms.

To diagnose a connective tissue disease, your healthcare provider will need to review a variety of factors. You never want to assume the worst when trying to figure out why you're not feeling your best. Instead, seek the help of a qualified professional to guide you toward a proper diagnosis and treatment plan to regain control of your health.