Connective Tissue Disease and Overlap Syndromes

By Prof Graham Hughes, Consultant Rheumatologist, London Lupus Centre,
London Bridge Hospital

Half a century ago, the name ‘connective tissue diseases’ was coined to cover a group of conditions distinct from each other, but with a number of features in common. They include lupus, myositis, Sjogren’s Syndrome, scleroderma, mixed connective tissue disease and vasculitis. In 1983, another related condition the anti-phospholipid syndrome (Hughes syndrome) was added.


The features in common are:

  1. Women are affected more frequently than men
  2. The diseases are capable of affecting many organs
  3. They ‘overlap’ with one another, both in clinical features as well as in laboratory abnormalities.
  4. Blood vessels are commonly affected.

Lupus
This is recognised throughout the world and predominantly affects women (female: male 9:1) between the ages of 15-50. Any organ can be affected, but especially common are skin rashes, hair loss, pleurisy and joint pains. The disease can also lead to more serious complications, including kidney, brain or cardiac involvement. Lupus differs from rheumatoid arthritis (RA) in a number of ways. Unlike RA, it rarely causes joint damage, for example. Although the causes of lupus are unknown, both genetic, hormonal and environmental, (for example sunlight) factors are known to play a part. Central to the disease process is an overactivity of the immune system, leading to an overproduction of antibodies, notable anti-DNA antibodies, important in both diagnosis and disease management. Medical treatment includes hydroxycholorquine (Plaquenil), widely used as maintenance therapy, steroids for more acute or severe cases, and munosuppressives such as azathioprine,methotrexate and mycophenolatemofeti. More recently so-called agents such as rituximab (Mabthera) and belimumab (Benlysta) have proved an important advance in treatment.


Sjögren’s Syndrome
This syndrome, originally described as a triad of dry eyes, dry mouth and aches and pains, is now regarded as a ‘cousin’ of lupus. Again, the central defect is an overactive immune system, leading to over production of antibodies and widespread clinical features including rashes, enlarged glands, cystitis, joint and muscle pain, and fatigue. Sjögren’s differs from lupus in being more common in an older age group (40s to 60s) and less likely to result in kidney or other major organ damage. Nevertheless, it can cause considerable disability, with fatigue and muscle aches being marked, many patients being wrongly diagnosed as having fibromyalgia. The dry eyes and mouth are a result of the lachrymal and salivary glands by lymphocytes and inflammatory cells, leading to impaired secretion of tears and saliva, and to an increased risk of corneal damage and of dental and oral problems. A very rare complication of Sjögren’s Syndrome is lymphoma, usually presenting with chronic, marked swelling of the lymph glands. As with mild lupus, the ‘maintenance’ treatment for Sjögren’s is Hydroxycholroquine (Plaquenil). 

Hughes Syndrome and Antiphospholipid (Aps)
This is a condition in which abnormal clotting (in arteries as well as in veins) can lead to a wide variety of clinical features. The clotting abnormality is secondary to a group of anti-bodies known as antiphospholipid antibodies. Clinical features include clots in arms or legs, or in internal organs such as liver, kidney and heart. Two organs especially vulnerable are the placenta and the brain. Clotting in the placenta in the pregnant woman leads to oxygen starvation in the foetus and a risk of abortion. Hughes syndrome is now known to be the commonest, treatable cause of recurrent pregnancy loss. The symptoms of brain involvement include stroke, balance difficulties, and the multiple sclerosis-like features. Particularly common are memory problems (many patients fearing Alzheimer’s disease ) and headache and migraine – it has been suggested that Hughes syndrome is a potentially treatable link between migraine and stroke. Treatment is with anti-clotting drughs, including aspirin, heparin or wayfarin, depending on the severity. There are overlaps between Sjögren’s, lupus and Hughes syndrome. Some 20-30% of lupus patients are positive for antiphosphilipid antibodies and carry the same risk of thrombosis and miscarriage as patients with Hughes syndrome

Scleroderma
In this rare syndrome there is a progressive stiffening of the skin, affecting the fingers, hands, forearms and face. More widespread thickening can affect the thighs, chest and abdomen. The process is due to an overproduction of collagen (scar-like tissue). In more severe cases, internal organs can become scarred and immobile, including the oesophagus (difficulty in swallowing, heartburn), tendons, gut (diarrhoea and malabsorbtion) and the lungs leading to shortness of breath and , in extreme cases, pressure on the heart. Raynaud’s phenomenon (fingers and toes frequently turning white) is common.

Mixed Connective Tissue Disease
First described in the 1960s by Dr. Gordon Sharpe (in the United States), this condition, as the name implies, can include ‘mixed’ features of lupus, scleroderma and myositis. It is very distinctive, and immunologically marked by a single antibody– antiRNP. The clinical features are arthritis, especially in the hands, with characteristic ‘sausage fingers’, marked Raynaud’s (much more sever than lupus), slight skin thickening (but distinct from scleroderma), frequent muscle pain (and sometimes prominent muscle weakness), and pleurisy and pericarditis. Unlike lupus, kidney involvement is the exception. The disease often takes a ‘grumbling’ course and treatment is geared to the severity of symptoms.

Myositis
Myositis ‘polymositis’ if muscles alone are affected or ‘dermatomysitis’ if the characteristic skin rash (violaceous rash on the face, eyelids and knuckles) is present—is characterised by weakness rather than muscle pain. The ‘proximal’ muscles, upper arms, thighs, neck muscles, are most prominently affected. A common presentation is with difficulty in rising from a sitting or crouching position. In more severe cases, there is difficulty in dressing, or even , in extreme  yositis, in breathing due to weakness of diaphragm and chest wall muscles. The condition is caused by an infiltration of the muscles by inflammatory cells, leading, if untreated, to muscle fibre damage and scarring. Treatment in the acute stage is with corticosteroids plus or minus immunosuppressive drugs such as methotrexate.

Vasculitis
This term is given to a rather wide variety of conditions in which the primary pathology is inflammation of the blood vessels. There are almost certainly a number of different causes, including viral infection and allergy, and the vessels involved range from small (capillaries) to medium/ large arteries (e.g. polyarteritisnodosa). Tests include an increased blood level of the muscle enzyme creatine kinase (CK), and abnormal muscle electrical activity (see in an electromyogram or EMG). One clinically somewhat distinct vasculitic condition is Wegener’s granulomatosis, in which inflammation in arteries and veins is compounded by socalled granuloma formation in the sinuses and lungs. Fortunately, this life threatening condition usually responds to the immunosuppressive drug cyclophosphomide.


Thank you to Professor Hughes for permission to print this article. More information can be obtained on his website www.hughes-syndrome.org