Mixed Connective Tissue Disease: A Detailed Look

Introduction

MCTD (mixed connective tissue disease), also known as a sharp syndrome, is a rare systemic inflammatory rheumatic condition with overlapping characteristics with two or more connective tissue disorders like, scleroderma, polymyositis, and systemic lupus erythematosus (SLE).

Who Is Susceptible to MCTD?

MCTD is found in about two individuals (1.9, to be exact) in a population of 100,000. Individuals over the age of 50 are most susceptible. However, the average age of onset is around 37 years. Females dominate males with a ratio of 3:1. Norwegian studies have shown a prevalence of 3.8 individuals per 100,000 of their population, while Japan reports a higher count. This may have resulted from Japan being a ‘super-aged’ country. There is no racial or ethnic distinction.

What Causes MCTD?

• Since MCTD is an auto-immune disorder, it manifests when the body’s immune system attacks the healthy cells of the body, failing to differentiate between its own and foreign cells.

• Environmental factors include bacterial or viral infections, drugs, toxins, UV radiation, and chemicals like Vinyl chloride and silica.

• Ribonucleoprotein or RNP helps in RNA synthesis—these molecules are found in the human cell nucleus, hidden from the immune system. These RNP molecules are similar to the ones found in single-celled organisms. Introduction of those cells via an infection (bacterial or viral) or genetic mutation in genes that control the immune response or the exposure to RNP cells from the debris of dead human cells may contribute to the occurrence of MCTD.

What Is the Pathophysiology of MCTD?

Anti-RNP antibodies in the peripheral blood are an indicator of MCTD. MCTD is developed from two mechanisms -

• Apoptotic Modification- Changes to the normal process of cell death.

• Molecular Mimicry- Different molecules with similar features.

Changes to the normal process of cell death result in presenting the RNP molecules, by the antigen-presenting cells, to T-cells (cells of the immune response) which produce cytokines (immunity regulation cells) which in turn signal the B-cells (another cell of the immune response) to produce anti-RNP antibodies and reactive lymphocytes. The presence of these cells indicates the attack on the healthy connective tissues.

Amino acids from various bacteria, viruses, drugs, toxins, and chemicals can mimic the anti-RNP antibodies and induce auto-immune responses.

What Are the Signs and Symptoms of MCTD?

The symptoms of MCTD overlap with two or more systemic rheumatic conditions. The median time from the appearance of the first symptom to diagnosis is 3.6 years.

Non-specific symptoms include joint and body pain, weakness, and fever. MCTD can induce changes in all organs.

1. Skin:

• Numb, cool, and pale fingers (Raynaud’s phenomenon).

• Hand edema, atherosclerosis, calcinosis cutis, telangiectasia, erythema nodosum, hair loss, and vasculitis of digits.

• Discoid eczema and malar rash - similar to systemic lupus erythematosus.

• Changes to the nail bed.

• Inflammation of subcutaneous fats in the abdomen, leg, and breast.

2. Joints: Joint involvement is more severe than SLE, similar to deformities seen in RA.

3. Muscle: Inflammation of the muscles is observed, resulting in pain and weakness.

4. Lungs:

• Shortness of breath.

• Sharp chest pain that increases on breathing.

• Wheezing.

• Hemoptysis (blood in cough).

• Pleural effusion (fluid accumulation around lungs).

• Pulmonary arterial hypertension.

• Interstitial lung disease (progressive scarring of lungs).

• Pulmonary vasculitis (destruction of the blood vessels supplying the lungs).

• Thromboembolic disease (blood clots in the lungs).

• Alveolar hemorrhage (bleeding in the lungs).

• Infections.

• Obstructive airway disease.

5. Heart:

• Pericarditis (inflammation of the pericardium- the outer layer of the heart).

• Pericardial effusion (fluid accumulation between the heart muscle and the pericardium).

• Mitral valve prolapse (fault in the functioning of the mitral valve).

• Myocarditis (inflammation of the heart muscle).

• Atherosclerosis (narrowing of the artery walls due to plaque build-up).

6. Kidney:

• Membranous nephropathy (small blood vessels of the kidney thickens and get damaged).

• Systemic hypertension.

• Chronic kidney diseases.

7. Central Nervous System:

• Trigeminal neuralgia (pain in the trigeminal nerve region of the face).

• Psychosis (disconnection from reality).

• Seizures.

• Peripheral neuropathy (numbness and weakness in hands and feet due to nerve damage).

• Headaches.

• Nuchal rigidity (soreness of neck muscles).

• Aseptic meningitis (inflammation of the meninges - membranes of brain and spinal cord).

• Hearing loss.

8. Gastrointestinal Tract:

• Esophageal hypomotility (lack of peristalsis of the food pipe).

• Gastroesophageal reflux disorder (GERD) (backflow of stomach acid into the food pipe).

• Pancreatitis (inflammation of the pancreas).

• Megacolon (abnormal dilation of the colon-a part of the large intestine).

• Duodenal bleeding (bleeding from the first part of the small intestine).

• Portal hypertension.

• Auto-immune hepatitis.

• Anasarca (accumulation of fluid in the interstitial space).

9. Blood:

• Anemia (decreased red blood cell count).

• Leukopenia (decreased white blood cell count).

• Thrombocytopenia (decreased platelet count).

What Are the Investigations Required to Diagnose MCTD?

Laboratory Studies:

1. Complete blood count may reveal:

• Anemia.

• Leukopenia.

• Hypergammaglobulinemia (white blood cells make too many proteins).

• Raised erythrocyte sedimentation rate.

• Positive Anti-CCP.

• Raised muscle enzymes.

• Presence of antiphospholipid antibodies.

2. Urine analysis may reveal proteinuria.

Imaging Studies:

1. Chest X-ray might show:

• Pulmonary infiltrates.

• Pleural effusion.

• Cardiomegaly.

2. Joint X-rays might show:

• Asymmetrical erosion around the joints.

• Soft tissue swelling.

• Deformities.

• Destructive arthritis.

3. An echocardiogram might show:

• Pericardial effusion.

• Mitral valve prolapse.

• Left ventricular hypertrophy (walls of left ventricle gradually turn non-elastic).

• Changes due to pulmonary hypertension.

4. EKG (electrocardiogram) might show:

• Hemiblock.

• Bundle branch block

• AV block.

• Changes secondary to pericarditis.

• Pericardial effusion.

5. Pulmonary function tests might show:

• Reduction in diffusion capacity for carbon monoxide.

• Forced vital capacity.

• Forced expiratory volume.

6. CT (computed tomography) of the lung might show (in the peripheral and lower lobe):

• Ground-glass opacities.

• Linear opacities.

• Subpleural micronodules.

• Septal thickening.

• Traction bronchiectasis.

7. An angiogram might show medium-sized occlusions in peripheral blood vessels, especially in patients exhibiting Reynaud's phenomenon.

How to Treat and Manage MCTD?

MCTD, by many scientists, is considered a secondary classification to the broader class of rheumatic overlap syndromes. Drug trials or treatment studies have not been conducted exclusively against MCTD, but such patients have been included in the trials focused on SLE, scleroderma, RA, myositis, etc. This subgroup has responded similarly to the patients of the original study.

Doctors recommend conditional treatment that each pertaining state is treated independently as a separate disease, keeping cross-reactions in mind.

Treatment regimens include:

• Antimalarials are prescribed for lupus-like symptoms.

• Vasodilators are prescribed against Raynaud’s phenomenon.

• Proton pump inhibitors to treat GERD.

• Anti-rheumatic drugs for polyarthritis.

• Anti-fibrotic drugs against MCTD-related pulmonary fibrosis.

• Treatment for fibrosis-related pulmonary hypertension is duplicated.

• Immunosuppressants.

• Corticosteroids to counteract flare-ups (they have long-term drug toxicity effects).

• Nonsteroidal anti-inflammatory drugs (NSAIDs) keep mild flare-ups in check.

What Is the Differential Diagnosis of MCTD?

• Systemic lupus erythematosus.

• Rheumatoid arthritis.

• Polymyositis.

• Dermatomyositis.

• Scleroderma.

• Bacterial or viral infections.

• Raynaud disease.

What Dietary Modifications Are Needed to Manage MCTD?

• Foods to Avoid: Grains, legumes, nightshades, eggs, dairy, nuts, seeds, coffee, alcohol, refined or processed sugars, industrial seed oils, and food additives.

• Foods to Intake: Fresh, nutrient-dense foods, fermented foods and probiotics, and bone broth.

What Are the Complications of MCTD?

• Pulmonary hypertension leading to heart failure.

• Interstitial lung disease.

• Heart diseases like pericarditis, dilated cardiomyopathy, cardiac tamponade, coronary sclerosis, ischemic cardiomyopathy, arrhythmias, and atherosclerosis.

• Kidney damage leads to kidney failure and renal crisis.

• Digestive tract damage, including ulcerations and perforation.

• Anemia.

• Tissue death from gangrene due to Reynaud’s phenomenon.

• Nerve damage: Trigeminal neuralgia, Sjogren's.

• Thrombotic thrombocytopenic purpura.

• Nephrosclerosis (arterial and venous capillary walls get hardened)

• Immunosuppressant consumption-related cancers.

• Partial or total inflammation of the spinal cord.

Conclusion:

MCTD poses life-threatening challenges, but most of the symptoms can be managed by early diagnosis and multidisciplinary care. Lifestyle and dietary modifications go a long way in leading a normal life. It is of utmost importance that the patient recognizes the early symptoms and visits a rheumatologist for early intervention.

Healthcare professionals need to educate the patient about their condition, the proper regimen of medications, their ill effects, and the changes that need to be implemented. If necessary, a psychiatric consultation may be requested to aid in complete care, including mental health. The patient and the support group need to understand that the road to recovery would be bumpy, the destination far away, but the journey has to be done in the same automobile.