Muscle weakness can also affect:. When gluten is in the small intestine, the immune system attacks this part of the GI tract and causes inflammation. People with celiac disease may experience digestive issues after consuming gluten.

Symptoms can include:. Autoimmune vasculitis happens when your immune system attacks blood vessels. The inflammation that results narrows your arteries and veins, allowing less blood to flow through them.

Pernicious anemia may happen when an autoimmune disorder causes your body to not produce enough of a substance called intrinsic factor.

Having a deficiency in this substance reduces the amount of vitamin B12 your small intestine absorbs from food. It can cause a low red blood cell count.

This rare autoimmune disease typically occurs in people ages 60 to 70 and older. Some autoimmune disorders can have similar symptoms at early stages.

These can include fatigue, dizziness or lightheadedness, low grade fever, muscle aches, and swelling. Many researchers recognize giant cell myocarditis, a rare autoimmune condition that can lead to heart failure, as one of the most serious autoimmune diseases.

Blood tests that look for autoantibodies can help doctors diagnose these conditions. Treatments include medications to calm the overactive immune response and bring down inflammation in the body.

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The subsequent accumulation of other causative factors induces a transition to a stage of pre-clinical autoimmunity in which functional changes for example, dysglycaemia or symptoms for example, arthralgia occur but remain below a threshold that would cause the patient to seek medical attention or prompt the provider to order more testing.

Once such a threshold has been reached, clinical autoimmune disease can be diagnosed and therapy started. The various stages probably represent a continuum, with more intensive screening moving each of the stages back in time.

Post-clinical autoimmunity refers to the changes that may occur after clinical recognition and initiation of therapy. For diseases such as immune dependent diabetes mellitus, therapy might focus on agents such as insulin that aim to correct the functional disturbance without monitoring for autoimmunity or treatment with immunosuppressive agents.

For other diseases, such as anti-neutrophil cytoplasmic autoantibody ANCA -associated vasculitis and systemic lupus erythematosus, management may involve immunosuppressive therapy of varying intensity, in some instances guided by biomarkers such as anti-DNA, ANCA or complement.

It is useful to distinguish between clinical autoimmunity and post-clinical autoimmunity because current therapy can induce remission in at least some diseases for example, rheumatoid arthritis.

Pre-clinical autoimmunity can be recognized in various ways. The first involves retrospective analysis of blood from patients collected as part of longitudinal population-based studies such as that performed by the USA military. For patients who develop disease, the stored samples can be tested for autoantibodies to determine when they arise Pre-clinical autoimmunity can also be characterized prospectively as part of public health efforts to improve disease outcomes by early detection and treatment Although an entire population could be monitored, a more efficient approach involves testing of individuals who are at high risk of disease on the basis of family history or the presence of disease in a first-degree relative; identical twins are the most informative relatives but they are not common Pre-clinical autoimmunity can also be discovered accidentally or incidentally.

In the evaluation of patients with musculoskeletal complaints, providers may order tests such as the rheumatoid factor an IgM anti-IgG antibody , anti-CCP, or an antinuclear antibody Supplementary Box 3.

Since these tests may be ordered in patients with a low pre-test probability of disease for example, patients with degenerative arthritis or widespread pain , positive results are most probably false-positive.

Some positive results, however, may represent the pre-clinical autoimmune state. Both retrospective and prospective studies confirm that the presence of autoantibodies can pre-date disease by many years and that, during the pre-clinical autoimmune setting, autoantibody production can evolve and lead to the expression of antibodies to either more epitopes epitope spreading on a target antigen or additional antigens, which may accompany the progression to clinical disease.

For instance, several different autoantibodies including anti-GAD, anti-insulin, anti-islet antigen-2 and anti-z-transporter 8 are associated with IDDM. The likelihood of developing clinical diabetes increases with the number of different autoantibodies present Similarly, in rheumatic diseases, the chance of developing SLE rises as the number of different antinuclear antibodies increases over time.

In addition to expanding serological findings, the pre-clinical autoimmune state can be associated with evidence of immune dysfunction for example, increased cytokine production that can intensify as clinical findings develop , A transition from pre-clinical autoimmunity to clinical disease may not be inevitable.

Prospective studies may facilitate the identification of factors that drive this transition and may be targeted for early therapy Interestingly, studies have demonstrated that autoantibody responses may revert, with the risk of disease diminishing Better prediction of the transition from pre-clinical to clinical disease may require adjunctive information from genetic and genomic studies to identify more precisely the individuals at greatest risk.

The opportunity to initiate early or pre-emptive therapy depends on serological tests that can predict disease as well as the availability of treatments with a favourable efficacy-to-safety ratio.

This approach also depends on the extent of the organ damage that has occurred by the time pre-clinical autoimmunity can be recognized by laboratory findings or symptomatology. Nevertheless, early treatment can have the enormous benefit of limiting subsequent tissue injury.

IDDM and rheumatoid arthritis are two diseases that enable the testing of strategies to treat pre-clinical autoimmunity.

In IDDM, family members can be screened for evidence of autoantibody production; the function of pancreatic beta cells can be assessed by testing for glucose tolerance and insulin production, and a number of studies are under way to identify therapeutic agents that are effective during early stages of autoimmunity.

For the pancreas as a targeted organ, various approaches, including insulin therapy, are being tested to decrease stress and thereby blunt the effects of autoimmune attack , , , , , In contrast to IDDM, for which several marker autoantibodies herald the onset of autoimmunity, anti-CCP antibodies are the only specific marker of rheumatoid arthritis; rheumatoid factors are much less specific.

In the absence of a functional test for rheumatoid arthritis comparable to a glucose tolerance test in IDDM, pain that is, arthralgia can serve as a marker of incipient disease although, arguably, pain may indicate ongoing synovitis.

Treatments such as hydroxychloroquine, methotrexate or rituximab have all been explored to prevent inflammatory arthritis in patients with arthralgia at risk of rheumatoid arthritis, although early treatment may only delay disease onset rather than foster a more significant shift in the immunological profiles of patients , In considering early or preventive therapy, benefits attributable to immunomodulatory therapies or immunosuppressive agents may actually reflect spontaneous remission, which can occur in certain autoimmune diseases depending on factors such as patient age and serological status 14 , , Once disease manifestations occur, however, therapy may be necessary to prevent organ damage, limiting the ability to observe spontaneous remission and the immunological changes that terminate autoreactivity and restore homeostasis.

In this regard, for remissions induced by therapy, autoantibody production may continue despite clinical quiescence. Not surprisingly, research on autoimmune disease has focused on factors that initiate autoreactivity and induce inflammation. Fewer studies have addressed subsequent events in disease, particularly the long-term impact of treatment on underlying B cell and T cell disturbances.

Studies of this kind require informative biomarkers as well as an understanding of the mode of action of immunosuppressive therapies. Many currently available agents have broad actions, with anti-proliferative agents capable of modifying the number or function of both B cells and T cells.

Even agents that seemingly target a specific cell population can have complex and unexpected actions. For instance, although rituximab can eliminate B cells, it can also affect T cell function because B cells are effective antigen-presenting cells and are required for the maintenance of T follicular helper cells For some autoimmune diseases, once irreversible damage has occurred, the need for ongoing immunosuppressive treatment lessens or disappears.

In these conditions, long-term treatment focuses on the organ dysfunction for example, thyroid replacement for hypothyroidism from thyroiditis, or insulin therapy for IDDM.

In instances in which autoimmune damage is permanent, further serological testing would be mostly of academic interest. For other diseases such as rheumatoid arthritis or multiple sclerosis, autoreactivity and inflammation can persist for many years at varying intensity, waxing and waning during flares.

The basis of flares is unknown, although flares may result from a nonspecific increase in immune reactivity for example, from infection or stress or a change in the exposure of the immune system to self-antigen.

For autoimmune diseases mediated by B cells, characteristic changes in B cell populations can occur and signal the diverse roles of these cells in antigen presentation, cytokine production and autoantibody production.

Among these changes, age-associated B cells can increase in number and distribution. These cells have unique functional and migratory properties and may also be found in tissue for example, in synovium or synovial fluid.

The expansion of age-associated B cells during active SLE and rheumatoid arthritis suggests that the expression of these cells contributes to disease initiation and persistence , In addition to changes in certain B cell populations, such as the decrease in anergic B cells in IDDM , an important determinant of disease course is the nature of the autoantibody-producing cells and the respective roles of newly emergent B cells, memory populations and long-lived plasma cells LLPCs Unlike the transient role of plasmablasts or short-lived plasma cells, antibody production by LLPCs can persist for many years, with antibody production to some antigens being essentially lifelong.

LLPCs can survive in specialized niches in the bone marrow as well as secondary lymphoid organs; LLPCs may also reside in sites of inflammation such as the kidney in SLE or the joints in rheumatoid arthritis Since LLPCs do not express CD20, they are not affected by rituximab, a monoclonal anti-CD20 agent.

Other approaches aimed at eliminating plasma cells include proteasome inhibitors such as bortezomid and monoclonal antibodies to CD38 or SLAMF7 — agents developed to treat the plasma cell malignancy multiple myeloma. The elimination of LLPCs can affect protective antibody responses as well as autoantibodies , The role of LLPCs in many autoimmune responses is unclear because sequential autoantibody testing is often not performed after disease onset owing to the uncertainty of the role of antibodies as markers of disease activity or prognosis.

For example, it has been difficult to establish whether ANCA testing helps to predict disease activity in ANCA vasculitis; the relationship between ANCAs and disease activity may vary depending on clinical manifestations renal versus non-renal , the specificity of the autoantibodies myeloperoxidase versus proteinase 3 and the performance characteristics of the assays The role of autoantibodies as a biomarker has been more extensively explored in SLE.

In this disease, levels of anti-DNA antibodies fluctuate widely and can rise and fall with disease activity and therapy. In some patients, these antibodies can essentially vanish only to reappear months or years later This variability may reflect antibody secretion by plasmablasts derived from a memory cell population or the emergence of new B cells.

By contrast, antibodies to RBPs show a more stable level of expression, consistent with their production by LLPCs In general, levels of anti-RBPs are not assessed in patient follow-up, although antibodies to both DNA and RBPs have been associated with the formation of immune complexes that induce interferon.

This terminology does not mean that autoimmunity has ended or that B and T cell reactivity is eliminated; rather, it focuses attention on the subsequent disease course, especially the effects of therapy.

Thus, anti-inflammatory or immunosuppressive agents may attenuate or modify the immune system changes that led to disease onset. The natural history of disease may also determine the post-clinical autoimmune state since some diseases for example, autoimmune haemolytic anaemia can be monophasic and may remit after a single course of therapy; other diseases may enter into a state of low disease activity or even remission with therapy Studies of SLE point to the heuristic value of the concept of post-clinical onset autoimmunity.

Importantly, in the phase II trials, patients who were seropositive had much better treatment responses than those who were seronegative Thus, although at disease onset, essentially all patients with active SLE are autoantibody positive, in the post-clinical-onset state, some patients may have active disease despite seronegativity.

Some aspect of the immune system has changed profoundly in patients with this state, either as a consequence of therapy, natural disease history or both. Much can happen during this time, including reductions in autoantibody production in response to therapy.

Without periodic assessment, it can be difficult to understand the relationship of autoantibodies and disease manifestations given that both may evolve during the course of disease. It is possible that T cell autoreactivity also ebbs and flows. Autoimmune diseases are a diverse collection of conditions that arise from a breakdown in the mechanisms of tolerance and self—nonself discrimination.

Tolerance is enormously complicated and involves many different mechanisms and interactions, perhaps accounting for the heterogeneity of the various diseases classified as autoimmune.

Future studies will delineate more precisely both the genetic and genomic architecture of the different diseases in the hopes of developing more effective, more targeted and less toxic therapies for both treatment and prevention.

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