Among the complications discussed above, women with anti-Ro/SS-A and anti-La/SS-B antibodies who become pregnant, have an increased rate of neonatal lupus erythematosus with congenital heart block requiring a pacemaker. Type I cryoglobulinemia is a known complication of SS.

Published studies on the survival of SS patients are limited in varied respects, perhaps owing to the relatively small sample sizes, and secondary SS is associated with other autoimmune diseases. However, results from a number of studies indicated, compared to other autoimmune diseases, SS is associated with a notably high incidence of malignant non-Hodgkin lymphoma (NHL). NHL is the cancer derived from white blood cells. About 5% of patients with SS will develop some form of lymphoid malignancy. Patients with severe cases are much more likely to develop lymphomas than patients with mild or moderate cases. The most common lymphomas are salivary extranodal marginal zone B cell lymphomas (MALT lymphomas in the salivary glands) and diffuse large B-cell lymphoma.

Lymphomagenesis in primary SS patients is considered as a multistep process, with the first step being chronic stimulation of autoimmune B cells, especially B cells that produce rheumatoid factor at sites targeted by the disease. This increases the frequency of oncogenic mutation, leading to any dysfunction at checkpoints of autoimmune B-cell activation to transform into malignancy. A study's finding has concluded the continuous stimulation of autoimmune B cells, leading to subtle germinal abnormalities in genes having specific consequences in B cells, which underlies the susceptibility to lymphoma.

Apart from this notably higher incidence of malignant NHL, SS patients show only modest or clinically insignificant deterioration in specific organ-related function, which explains the only slight increases in mortality rates of SS patients in comparison with the remainder of the population.

An overlap syndrome is an autoimmune disease of connective tissue in which a person presents with symptoms of two or more diseases.

Examples of overlap syndromes include mixed connective tissue disease and scleromyositis. Diagnosis depends on which diseases the patient shows symptoms and has positive antibodies for in their lab serology.

In overlap syndrome, features of the following diseases are found (most common listed):

- Systemic lupus erythematosus (SLE),

- Systemic sclerosis,

- Polymyositis,

- Dermatomyositis,

- Rheumatoid arthritis (RA)

- Sjögren's syndrome

- Eosinophilic granulomatosis with polyangiitis (EGPA)

- Autoimmune thyroiditis

- Antiphospholipid antibody syndrome

The treatment of overlap syndrome is mainly based on the use of corticosteroids and immunosuppressants. Biologic drugs, i.e. anti-TNFα or anti-CD20 monoclonal antibodies, have been recently introduced as alternative treatments in refractory cases. There are some concerns with the use of anti-TNF agents in patients with systemic autoimmune diseases due to the risk of triggering disease exacerbations.

These are also referred to as systemic autoimmune diseases. The autoimmune CTDs may have both genetic and environmental causes. 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 that results in the production of extra antibodies into the circulation. The classic collagen vascular diseases have a "classic" presentation with typical findings that doctors can recognize during an examination. 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 that help in the diagnosis. The classic collagen vascular diseases include:

- 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 – an activation of immune cells that 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.

- 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.

- 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); anti-synthetase syndrome; 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.

- Undifferentiated connective tissue disease (UCTD) is a disease in which the body mistakenly attacks its own tissues. It is diagnosed when there is evidence of an existing autoimmune condition which does not meet the criteria for any specific autoimmune disease, such as systemic lupus erythematosus or scleroderma. Latent lupus and incomplete lupus are alternative terms that have been used to describe this condition.

- Psoriatic arthritis is also a collagen vascular disease.

Most patients will maintain a diagnosis of undifferentiated connective tissue disease. However, about one third of UCTD patients will differentiate to a specific autoimmune disease, like rheumatoid arthritis or systemic sclerosis. About 12 percent of patients will go into remission.

Severe vitamin D deficiency has been associated with the progression of UCTD into defined connective tissue diseases. The presence of the autoantibodies anti-dsDNA, anti-Sm, and anti-cardiolipin has been shown to correlate with the development of systemic lupus erythematosus, specifically.

Scleroderma in pregnancy is a complex situation; it increases the risk to both mother and child. Overall scleroderma is associated with reduced fetal weight for gestational age. The treatment for scleroderma often includes known teratogens such as cyclophosphamide, methotrexate, mycophenolate, etc. and hence careful avoidance of such drugs during pregnancy is advised. In these cases hydroxychloroquine and low-dose corticosteroids might be used for disease control.

Adenocarcinoma of the bowel has been associated with coeliac disease.

The prognosis of mixed connective tissue disease is in one third of cases worse than that of systemic lupus erythematosus (SLE). In spite of prednisone treatment, this disease is progressive and may in many cases evolve into a progressive systemic sclerosis (PSS), also referred to as diffuse cutaneous systemic scleroderma (dcSSc) which has a poor outcome. In some cases though the disease is mild and may only need aspirin as a treatment and may go into remission where no Anti-U1-RNP antibodies are detected, but that is rare or within 30% of cases. Most deaths from MCTD are due to heart failure caused by pulmonary arterial hypertension (PAH).

A connective tissue disease is any disease that has the connective tissues of the body as a 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 (ICT). 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 diseases can be (but are not necessarily) associated with collagen and blood vessel abnormalities and that are autoimmune in nature. See also vasculitis.

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

There is no clear obvious cause for scleroderma and systemic sclerosis. Genetic predisposition appears to be limited: genetic concordance is small; still, there is often a familial predisposition for autoimmune disease. Polymorphisms in "COL1A2" and "TGF-β1" may influence severity and development of the disease. There is limited evidence implicating cytomegalovirus (CMV) as the original epitope of the immune reaction, as well as parvovirus B19. Organic solvents and other chemical agents have been linked with scleroderma.

One of the suspected mechanisms behind the autoimmune phenomenon is the existence of microchimerism, i.e. fetal cells circulating in maternal blood, triggering an immune reaction to what is perceived as foreign material.

A distinct form of scleroderma and systemic sclerosis may develop in patients with chronic renal failure. This form, nephrogenic fibrosing dermopathy or nephrogenic systemic fibrosis, has been linked to exposure to gadolinium-containing radiocontrast.

Bleomycin (a chemotherapeutic agent) and possibly taxane chemotherapy may cause scleroderma, and occupational exposure to solvents has been linked with an increased risk of systemic sclerosis.

Vasculitis secondary to connective tissue disorders. Usually secondary to systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), relapsing polychondritis, Behçet's disease, and other connective tissue disorders.

Vasculitis secondary to viral infection. Usually due to hepatitis B and C, HIV, cytomegalovirus, Epstein-Barr virus, and Parvo B19 virus.

Scleroderma overlap syndrome: Scleroderma is a connective tissue disease that causes fibrosis and vascular abnormalities, but that also has an autoimmune component.

It is described by connective tissues complications. Blood testing includes screening for the positive antinuclear antibody.

Patients have symptoms of both systemic scleroderma and/or polymyositis and dermatomyositis.

1. Scleroderma: a group of rare diseases that involve the hardening and tightening of the skin and connective tissues

and/or:

Polymyositis: a rare inflammatory disease that causes muscle weakness affecting both sides of your body

Dermatomyositis: an inflammatory disease of skin and muscle marked especially by muscular weakness and skin rash.

Undifferentiated connective tissue disease (UCTD) is a disease in which the body mistakenly attacks its own tissues. It is diagnosed when there is evidence of an existing autoimmune condition which does not meet the criteria for any specific autoimmune disease, such as systemic lupus erythematosus or scleroderma. Latent lupus and incomplete lupus are alternative terms that have been used to describe this condition.

The term is sometimes used interchangeably with mixed connective tissue disease, an overlap syndrome. However, MCTD is thought by some researchers to be a clinically distinct entity and is strongly associated with the presence of high titers of ribonucleoprotein (RNP) antibodies.

It is estimated that up to 25 percent of people with systemic autoimmune disease could be considered to have UCTD.

Squamous carcinoma of the esophagus is more prevalent in coeliac disease. The increased prevalence may be secondary to GERD that results from chronic delayed gastric emptying. Other studies implicate the malabsorption of vitamin A and zinc as a result of multi-vitamin and mineral deficiencies seen in Coeliac disease.

Scleromyositis or the PM/Scl overlap syndrome is a complex autoimmune disease (a disease in which the immune system attacks the body). Patients with scleromyositis have symptoms of both systemic scleroderma and either polymyositis or dermatomyositis, and is therefore considered an overlap syndrome. Although it is a rare disease, it is one of the more common overlap syndromes seen in scleroderma patients, together with MCTD and Antisynthetase syndrome. Autoantibodies often found in these patients are the anti-PM/Scl (anti-exosome) antibodies.

The symptoms that are seen most often are typical symptoms of the individual autoimmune diseases and include Raynaud's phenomenon, arthritis, myositis and scleroderma. Treatment of these patients is therefore strongly dependent on the exact symptoms with which a patient reports to a physician and is similar to treatment for the individual autoimmune disease, often involving either immunosuppressive or immunomodulating drugs.

- Clinical characteristics:

- Overlap Syndrome: scleroderma overlap syndrome

- Autoimmune disease

- Scleroderma myositis overlap syndrome

Scleroderma most commonly first presents between the ages of 20 and 50 years, although any age group can be affected. Women are four to nine times more likely to develop scleroderma than men.

This disease is found worldwide. In the United States, prevalence is estimated at 240 per million and the annual incidence of scleroderma is 19 per million people. Likewise in the United States, it is slightly more common in African Americans than in their white counterparts, Scleroderma occurs much more often in women than it does in men. Choctaw Native Americans are more likely than Americans of European descent to develop the type of scleroderma that affects internal organs. In Germany, the prevalence is between 10 and 150 per million people, and the annual incidence is between 3 and 28 per million people. In South Australia, the annual incidence is 23 per million people, and the prevalence 233 per million people. Scleroderma is less common in the Asian population.

Systemic scleroderma is a rare disease with an annual incidence of 1 to 2 per 100,000 individuals in the United States. The interval of peak onset starts at age 30 to 35 and ends at age 50 to 55.

In the United States, the prevalence of systemic scleroderma is about 50,000, with different studies giving different estimates, usually ranging between 40,000 and 165,000.

Annual incidence of systemic sclerosis is 19 per million, and prevalence is 19–75 per 100,000, with a female:male ratio of 3:1 (8:1 in mid- to late childbearing years). Incidence is twice as high among African Americans. The Choctaw Native Americans in Oklahoma have the highest prevalence in the world (469 per 100,000).

The disease has some hereditary association. It may also be caused by an immune reaction to a virus (molecular mimicry) or by toxins.

Incidence of DM peaks at ages 40–50, but the disease can affect people of all ages. The prevalence of DM ranges from 1 to 22 per 100,000 people.

Collagen disease is a term previously used to describe systemic autoimmune diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis), but now is thought to be more appropriate for diseases associated with defects in collagen, which is a component of the connective tissue.

The term "collagen disease" was coined by Dr. Alvin F. Coburn in 1932, on his quest to discover streptococcal infection as the cause for rheumatic fever.

Patients usually present with systemic symptoms with single or multiorgan dysfunction. Common (and nonspecific) complaints include fatigue, weakness, fever, arthralgias, abdominal pain, hypertension, renal insufficiency, and neurologic dysfunction. The following symptoms should raise a strong suspicion of a vasculitis:

- Mononeuritis multiplex. Also known as asymmetric polyneuropathy, in a non-diabetic this is suggestive of vasculitis.

- Palpable purpura. If patients have this in isolation, it is most likely due to cutaneous leukocytoclastic vasculitis. If the purpura is in combination with systemic organ involvement, it is most likely to be Henoch-Schonlein purpura or microscopic polyarteritis.

- Pulmonary-renal syndrome. Individuals who are coughing up blood and have kidney involvement are likely to have granulomatosis with polyangiitis, microscopic polyangiitis, or anti-GBM disease (Goodpasture's syndrome).

Relapsing polychondritis is an autoimmune disease in which the body's immune system begins to attack and destroy the cartilage tissues in the body. It has been postulated that both cell-mediated immunity and humoral immunity are responsible.

Reasons for disease onset are not known, but there is no evidence of a genetic predisposition to developing relapsing polychondritis. However, there are cases where multiple members of the same family have been diagnosed with this illness. Studies indicate that some genetic contribution to susceptibility is likely.

Many individuals have mild symptoms, which recur infrequently, while others may have persistent problems that become debilitating or life-threatening.

The strong genetic component is borne out in studies on monozygotic twins, with a concordance of 38-55%, with an even higher concordance of circulating thyroid antibodies not in relation to clinical presentation (up to 80% in monozygotic twins). Neither result was seen to a similar degree in dizygotic twins, offering strong favour for high genetic aetiology.

Hashimoto's thyroiditis is associated with "CTLA-4" ("Cytotoxic T-lymphocyte Antigen-4") gene polymorphisms. CTLA-4 downregulates., i.e. transmits an inhibitory signal to T cells so reduced functioning is associated with increased T-lymphocyte activity. A family history of thyroid disorders is common, with the "HLA-DR5" gene most strongly implicated conferring a relative risk of 3 in the UK.

Having other autoimmune diseases is a risk factor to develop Hashimoto’s thyroiditis, and the opposite is also true. Autoimmune diseases most commonly associated to Hashimoto’s thyroiditis include celiac disease, type 1 diabetes, vitiligo, and alopecia.

Preventable environmental factors, including high iodine intake, selenium deficiency, as well as infectious diseases and certain drugs, have been implicated in the development of autoimmune thyroid disease in genetically predisposed individuals.

The genes implicated vary in different ethnic groups and the incidence is increased in people with chromosomal disorders, including Turner, Down, and Klinefelter syndromes usually associated with autoantibodies against thyroglobulin and thyroperoxidase. Progressive depletion of these cells as the cytotoxic immune response leads to higher degrees of primary hypothyroidism, presenting with a poverty of T3/T4 levels, and compensatory elevations of TSH.

Distinguishing laboratory characteristics are a positive, speckled anti-nuclear antibody and an anti-U1-RNP antibody.

Pregnant women who are positive for Hashimoto's thyroiditis may have decreased thyroid function or the gland may fail entirely. If a woman is TPOAb-positive, clinicians can inform her of the risks for themselves and their infants if they go untreated. "Thyroid peroxidase antibodies (TPOAb) are detected in 10% of pregnant women," which presents risks to those pregnancies. Women who have low thyroid function that has not been stabilized are at greater risk of having an infant with: low birth weight, neonatal respiratory distress, hydrocephalus, hypospadias, miscarriage, and preterm delivery. The embryo transplantion rate and successful pregnancy outcomes are improved when Hashimoto's is treated. Recommendations are to only treat pregnant women who are TPOAb-positive throughout the entirety of their pregnancies and to screen all pregnant women for thyroid levels. Close cooperation between the endocrinologist and obstetrician benefits the woman and the infant. The Endocrine Society recommends screening in pregnant women who are considered high-risk for thyroid autoimmune disease.

Thyroid peroxides antibodies testing is recommended for women who have ever been pregnant regardless of pregnancy outcome. "...[P]revious pregnancy plays a major role in development of autoimmune overt hypothyroidism in premenopausal women, and the number of previous pregnancies should be taken into account when evaluating the risk of hypothyroidism in a young women ["sic"]."