<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Rheumatoid arthritis and explain in detail? [/INST] Rheumatoid arthritis  (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involved, with the same joints typically involved on both sides of the body. The disease may also affect other parts of the body, including skin, eyes, lungs, heart, nerves and blood. This may result in a low red blood cell count, inflammation around the lungs, and inflammation around the heart. Fever and low energy may also be present. Often, symptoms come on gradually over weeks to months.While the cause of rheumatoid arthritis is not clear, it is believed to involve a combination of genetic and environmental factors. The underlying mechanism involves the bodys immune system attacking the joints. This results in inflammation and thickening of the joint capsule. It also affects the underlying bone and cartilage. The diagnosis is made mostly on the basis of a persons signs and symptoms. X-rays and laboratory testing may support a diagnosis or exclude other diseases with similar symptoms. Other diseases that may present similarly include systemic lupus erythematosus, psoriatic arthritis, and fibromyalgia among others.The goals of treatment are to reduce pain, decrease inflammation, and improve a persons overall functioning. This may be helped by balancing rest and exercise, the use of splints and braces, or the use of assistive devices. Pain medications, steroids, and NSAIDs are frequently used to help with symptoms. Disease-modifying antirheumatic drugs (DMARDs), such as hydroxychloroquine and methotrexate, may be used to try to slow the progression of disease. Biological DMARDs may be used when disease does not respond to other treatments. However, they may have a greater rate of adverse effects. Surgery to repair, replace, or fuse joints may help in certain situations.RA affects about 24.5 million people as of 2015. This is between 0.5 and 1% of adults in the developed world with 5 and 50 per 100,000 people newly developing the condition each year. Onset is most frequent during middle age and women are affected 2.5 times as frequently as men. It resulted in 38,000 deaths in 2013, up from 28,000 deaths in 1990. The first recognized description of RA was made in 1800 by Dr. Augustin Jacob Landré-Beauvais (1772–1840) of Paris. The term rheumatoid arthritis is based on the Greek for watery and inflamed joints.

Signs and symptoms
RA primarily affects joints, but it also affects other organs in more than 15–25% of cases. Associated problems include cardiovascular disease, osteoporosis, interstitial lung disease, infection, cancer, feeling tired, depression, mental difficulties, and trouble working.

Joints
Arthritis of joints involves inflammation of the synovial membrane. Joints become swollen, tender and warm, and stiffness limits their movement. With time, multiple joints are affected (polyarthritis). Most commonly involved are the small joints of the hands, feet and cervical spine, but larger joints like the shoulder and knee can also be involved.: 1098  Synovitis can lead to tethering of tissue with loss of movement and erosion of the joint surface causing deformity and loss of function. The fibroblast-like synoviocytes (FLS), highly specialized mesenchymal cells found in the synovial membrane, have an active and prominent role in these pathogenic processes of the rheumatic joints.RA typically manifests with signs of inflammation, with the affected joints being swollen, warm, painful and stiff, particularly early in the morning on waking or following prolonged inactivity. Increased stiffness early in the morning is often a prominent feature of the disease and typically lasts for more than an hour. Gentle movements may relieve symptoms in early stages of the disease. These signs help distinguish rheumatoid from non-inflammatory problems of the joints, such as osteoarthritis. In arthritis of non-inflammatory causes, signs of inflammation and early morning stiffness are less prominent.
The pain associated with RA is induced at the site of inflammation and classified as nociceptive as opposed to neuropathic. The joints are often affected in a fairly symmetrical fashion, although this is not specific, and the initial presentation may be asymmetrical.: 1098 As the pathology progresses the inflammatory activity leads to tendon tethering and erosion and destruction of the joint surface, which impairs range of movement and leads to deformity. The fingers may develop almost any deformity depending on which joints are most involved. Specific deformities, which also occur in osteoarthritis, include ulnar deviation, boutonniere deformity (also "buttonhole deformity", flexion of proximal interphalangeal joint and extension of distal interphalangeal joint of the hand), swan neck deformity (hyperextension at proximal interphalangeal joint and flexion at distal interphalangeal joint) and "Z-thumb." "Z-thumb" or "Z-deformity" consists of hyperextension of the interphalangeal joint, fixed flexion and subluxation of the metacarpophalangeal joint and gives a "Z" appearance to the thumb.: 1098  The hammer toe deformity may be seen. In the worst case, joints are known as arthritis mutilans due to the mutilating nature of the deformities.

Skin
The rheumatoid nodule, which is sometimes in the skin, is the most common non-joint feature and occurs in 30% of people who have RA. It is a type of inflammatory reaction known to pathologists as a "necrotizing granuloma". The initial pathologic process in nodule formation is unknown but may be essentially the same as the synovitis, since similar structural features occur in both. The nodule has a central area of fibrinoid necrosis that may be fissured and which corresponds to the fibrin-rich necrotic material found in and around an affected synovial space. Surrounding the necrosis is a layer of palisading macrophages and fibroblasts, corresponding to the intimal layer in synovium and a cuff of connective tissue containing clusters of lymphocytes and plasma cells, corresponding to the subintimal zone in synovitis. The typical rheumatoid nodule may be a few millimetres to a few centimetres in diameter and is usually found over bony prominences, such as the elbow, the heel, the knuckles, or other areas that sustain repeated mechanical stress. Nodules are associated with a positive RF (rheumatoid factor) titer, ACPA, and severe erosive arthritis. Rarely, these can occur in internal organs or at diverse sites on the body.Several forms of vasculitis occur in RA, but are mostly seen with long-standing and untreated disease. The most common presentation is due to involvement of small- and medium-sized vessels. Rheumatoid vasculitis can thus commonly present with skin ulceration and vasculitic nerve infarction known as mononeuritis multiplex.Other, rather rare, skin associated symptoms include pyoderma gangrenosum, Sweets syndrome, drug reactions, erythema nodosum, lobe panniculitis, atrophy of finger skin, palmar erythema, and skin fragility (often worsened by corticosteroid use).Diffuse alopecia areata (Diffuse AA) occurs more commonly in people with rheumatoid arthritis. RA is also seen more often in those with relatives who have AA.

Lungs
Lung fibrosis is a recognized complication of rheumatoid arthritis. It is also a rare but well-recognized consequence of therapy (for example with methotrexate and leflunomide). Caplans syndrome describes lung nodules in individuals with RA and additional exposure to coal dust. Exudative pleural effusions are also associated with RA.

Heart and blood vessels
People with RA are more prone to atherosclerosis, and risk of myocardial infarction (heart attack) and stroke is markedly increased.
Other possible complications that may arise include: pericarditis, endocarditis, left ventricular failure, valvulitis and fibrosis. Many people with RA do not experience the same chest pain that others feel when they have angina or myocardial infarction. To reduce cardiovascular risk, it is crucial to maintain optimal control of the inflammation caused by RA (which may be involved in causing the cardiovascular risk), and to use exercise and medications appropriately to reduce other cardiovascular risk factors such as blood lipids and blood pressure. Doctors who treat people with RA should be sensitive to cardiovascular risk when prescribing anti-inflammatory medications, and may want to consider prescribing routine use of low doses of aspirin if the gastrointestinal effects are tolerable.

Blood
Anemia is by far the most common abnormality of the blood cells which can be caused by a variety of mechanisms. The chronic inflammation caused by RA leads to raised hepcidin levels, leading to anemia of chronic disease where iron is poorly absorbed and also sequestered into macrophages. The red cells are of normal size and color (normocytic and normochromic). A low white blood cell count usually only occurs in people with Feltys syndrome with an enlarged liver and spleen. The mechanism of neutropenia is complex. An increased platelet count occurs when inflammation is uncontrolled.

Other
Kidneys
Renal amyloidosis can occur as a consequence of untreated chronic inflammation. Treatment with penicillamine or gold salts such as sodium aurothiomalate are recognized causes of membranous nephropathy.

Eyes
The eye can be directly affected in the form of episcleritis or scleritis, which when severe can very rarely progress to perforating scleromalacia. Rather more common is the indirect effect of keratoconjunctivitis sicca, which is a dryness of eyes and mouth caused by lymphocyte infiltration of lacrimal and salivary glands. When severe, dryness of the cornea can lead to keratitis and loss of vision as well as being painful. Preventive treatment of severe dryness with measures such as nasolacrimal duct blockage is important.

Liver
Liver problems in people with rheumatoid arthritis may be due to the underlying disease process or as a result of the medications used to treat the disease. A coexisting autoimmune liver disease, such as primary biliary cirrhosis or autoimmune hepatitis may also cause problems.

Neurological
Peripheral neuropathy and mononeuritis multiplex may occur. The most common problem is carpal tunnel syndrome caused by compression of the median nerve by swelling around the wrist. Rheumatoid disease of the spine can lead to myelopathy. Atlanto-axial subluxation can occur, owing to erosion of the odontoid process and/or transverse ligaments in the cervical spines connection to the skull. Such an erosion (>3mm) can give rise to vertebrae slipping over one another and compressing the spinal cord. Clumsiness is initially experienced, but without due care, this can progress to quadriplegia or even death.

Constitutional symptoms
Constitutional symptoms including fatigue, low grade fever, malaise, morning stiffness, loss of appetite and loss of weight are common systemic manifestations seen in people with active RA.

Bones
Local osteoporosis occurs in RA around inflamed joints. It is postulated to be partially caused by inflammatory cytokines. More general osteoporosis is probably contributed to by immobility, systemic cytokine effects, local cytokine release in bone marrow and corticosteroid therapy.

Cancer
The incidence of lymphoma is increased, although it is uncommon and associated with the chronic inflammation, not the treatment of RA. The risk of non-melanoma skin cancer is increased in people with RA compared to the general population, an association possibly due to the use of immunosuppression agents for treating RA.

Teeth
Periodontitis and tooth loss are common in people with rheumatoid arthritis.

Risk factors
RA is a systemic (whole body) autoimmune disease. Some genetic and environmental factors affect the risk for RA.

Genetic
Worldwide, RA affects approximately 1% of the adult population and occurs one in 1000 children. Studies show RA primarily affects individuals between the ages of 40–60 years and is seen more commonly in females. A family history of RA increases the risk around three to five times; as of 2016, it was estimated that genetics may account for between 40 and 65% of cases of seropositive RA, but only around 20% for seronegative RA.  RA is strongly associated with genes of the inherited tissue type major histocompatibility complex (MHC) antigen. HLA-DR4 is the major genetic factor implicated – the relative importance varies across ethnic groups.Genome-wide association studies examining single-nucleotide polymorphisms have found around one hundred alleles associated with RA risk. Risk alleles within the HLA (particularly HLA-DRB1) genes harbor more risk than other loci.  The HLA encodes proteins which controls recognition of self versus nonself molecules. Other risk loci include genes affecting co-stimulatory immune pathways, for example CD28 and CD40, cytokine signaling, lymphocyte receptor activation threshold (e.g., PTPN22), and innate immune activation appear to have less influence than HLA mutations.

Environmental
There are established epigenetic and environmental risk factors for RA. Smoking is an established risk factor for RA in Caucasian populations, increasing the risk three times compared to non-smokers, particularly in men, heavy smokers, and those who are rheumatoid factor positive. Modest alcohol consumption may be protective.Silica exposure has been linked to RA.

Vitamin D deficiency
There are claims that patients that have lower vitamin D levels by 8-10 ng/mL are at risk for rheumatoid arthritis.

Negative findings
No infectious agent has been consistently linked with RA and there is no evidence of disease clustering to indicate its infectious cause, but periodontal disease has been consistently associated with RA.The many negative findings suggest that either the trigger varies, or that it might, in fact, be a chance event inherent with the immune response.

Pathophysiology
RA primarily starts as a state of persistent cellular activation leading to autoimmunity and immune complexes in joints and other organs where it manifests. The clinical manifestations of disease are primarily inflammation of the synovial membrane and joint damage, and the fibroblast-like synoviocytes play a key role in these pathogenic processes. Three phases of progression of RA are an initiation phase (due to non-specific inflammation), an amplification phase (due to T cell activation), and chronic inflammatory phase, with tissue injury resulting from the cytokines, IL–1, TNF-alpha, and IL–6.

Non-specific inflammation
Factors allowing an abnormal immune response, once initiated, become permanent and chronic. These factors are genetic disorders which change regulation of the adaptive immune response. Genetic factors interact with environmental risk factors for RA, with cigarette smoking as the most clearly defined risk factor.Other environmental and hormonal factors may explain higher risks for women, including onset after childbirth and hormonal medications. A possibility for increased susceptibility is that negative feedback mechanisms – which normally maintain tolerance – are overtaken by positive feedback mechanisms for certain antigens, such as IgG Fc bound by rheumatoid factor and citrullinated fibrinogen bound by antibodies to citrullinated peptides (ACPA - Anti–citrullinated protein antibody). A debate on the relative roles of B-cell produced immune complexes and T cell products in inflammation in RA has continued for 30 years, but neither cell is necessary at the site of inflammation, only autoantibodies to IgGFc, known as rheumatoid factors and ACPA, with ACPA having an 80% specificity for diagnosing RA. As with other autoimmune diseases, people with RA have abnormally glycosylated antibodies, which are believed to promote joint inflammation.

Amplification in the synovium
Once the generalized abnormal immune response has become established – which may take several years before any symptoms occur – plasma cells derived from B lymphocytes produce rheumatoid factors and ACPA of the IgG and IgM classes in large quantities. These activate macrophages through Fc receptor and complement binding, which is part of the intense inflammation in RA. Binding of an autoreactive antibody to the Fc receptors is mediated through the antibodys N-glycans, which are altered to promote inflammation in people with RA.This contributes to local inflammation in a joint, specifically the synovium with edema, vasodilation and entry of activated T-cells, mainly CD4 in microscopically nodular aggregates and CD8 in microscopically diffuse infiltrates. Synovial macrophages and dendritic cells function as antigen-presenting cells by expressing MHC class II molecules, which establishes the immune reaction in the tissue.

Chronic inflammation
The disease progresses by forming granulation tissue at the edges of the synovial lining, pannus with extensive angiogenesis and enzymes causing tissue damage. The fibroblast-like synoviocytes have a prominent role in these pathogenic processes. The synovium thickens, cartilage and underlying bone disintegrate, and the joint deteriorates, with raised calprotectin levels serving as a biomarker of these events. Importantly inflammatory events are not limited to synovium but it appear to be systemic, evidence suggest that alterations in T helper profile favoring inflammation such as inflammatory IL-17A producing T helper cells and pathogenic Th17 cells are come from both memory and effector compartment in RA patients peripheral blood.Cytokines and chemokines attract and accumulate immune cells, i.e. activated T- and B cells, monocytes and macrophages from activated fibroblast-like synoviocytes, in the joint space. By signalling through RANKL and RANK, they eventually trigger osteoclast production, which degrades bone tissue. The fibroblast-like synoviocytes that are present in the synovium during rheumatoid arthritis display altered phenotype compared to the cells present in normal tissues. The aggressive phenotype of fibroblast-like synoviocytes in rheumatoid arthritis and the effect these cells have on the microenvironment of the joint can be summarized into hallmarks that distinguish them from healthy fibroblast-like synoviocytes. These hallmark features of fibroblast-like synoviocytes in rheumatoid arthritis are divided into 7 cell-intrinsic hallmarks and 4 cell-extrinsic hallmarks. The cell-intrinsic hallmarks are: reduced apoptosis, impaired contact inhibition, increased migratory invasive potential, changed epigenetic landscape, temporal and spatial heterogeneity, genomic instability and mutations, and reprogrammed cellular metabolism.  The cell-extrinsic hallmarks of FLS in RA are: promotes osteoclastogenesis and bone erosion, contributes to cartilage degradation, induces synovial angiogenesis, and recruits and stimulates immune cells.

Diagnosis
Imaging
X-rays of the hands and feet are generally performed when many joints affected. In RA, there may be no changes in the early stages of the disease or the x-ray may show osteopenia near the joint, soft tissue swelling, and a smaller than normal joint space. As the disease advances, there may be bony erosions and subluxation. Other medical imaging techniques such as magnetic resonance imaging (MRI) and ultrasound are also used in RA.Technical advances in ultrasonography like high-frequency transducers (10 MHz or higher) have improved the spatial resolution of ultrasound images depicting 20% more erosions than conventional radiography. Color Doppler and power Doppler ultrasound are useful in assessing the degree of synovial inflammation as they can show vascular signals of active synovitis. This is important, since in the early stages of RA, the synovium is primarily affected, and synovitis seems to be the best predictive marker of future joint damage.

Blood tests
When RA is clinically suspected, a physician may test for rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs measured as anti-CCP antibodies).
It is positive in 75–85%, but a  negative RF or CCP antibody does not rule out RA, rather, the arthritis is called seronegative, which is in about 15–25% of people with RA. During the first year of illness, rheumatoid factor is more likely to be negative with some individuals becoming seropositive over time. RF is a non-specific antibody and seen in about 10% of healthy people, in many other chronic infections like hepatitis C, and chronic autoimmune diseases such as Sjögrens syndrome and systemic lupus erythematosus. Therefore, the test is not specific for RA.Hence, new serological tests check for anti-citrullinated protein antibodies ACPAs. These tests are again positive in 61–75% of all RA cases, but with a specificity of around 95%. As with RF, ACPAs are many times present before symptoms have started.The by far most common clinical test for ACPAs is the anti-cyclic citrullinated peptide (anti CCP) ELISA. In 2008 a serological point-of-care test for the early detection of RA  combined the detection of RF and anti-MCV with a sensitivity of 72% and specificity of 99.7%.To improve the diagnostic capture rate in the early detection of patients with RA and to risk stratify these individuals, the rheumatology field continues to seek complementary markers to both RF and anti-CCP. 14-3-3η (YWHAH) is one such marker that complements RF and anti-CCP, along with other serological measures like c-reactive protein. In a systematic review, 14-3-3η has been described as a welcome addition to the rheumatology field. The authors indicate that the serum based 14-3-η marker is additive to the armamentarium of existing tools available to clinicians, and that there is adequate clinical evidence to support its clinical benefits.Other blood tests are usually done to differentiate from other causes of arthritis, like the erythrocyte sedimentation rate (ESR), C-reactive protein, full blood count, kidney function, liver enzymes and other immunological tests (e.g., antinuclear antibody/ANA) are all performed at this stage. Elevated ferritin levels can reveal hemochromatosis, a mimic of RA, or be a sign of Stills disease, a seronegative, usually juvenile, variant of rheumatoid arthritis.

Classification criteria
In 2010, the 2010 ACR / EULAR Rheumatoid Arthritis Classification Criteria were introduced.The new criteria are not diagnostic criteria, but are classification criteria to identify disease with a high likelihood of developing a chronic form. However a score of 6 or greater unequivocally classifies a person with a diagnosis of rheumatoid arthritis.These new classification criteria overruled the "old" ACR criteria of 1987 and are adapted for early RA diagnosis. The "new" classification criteria, jointly published by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) establish a point value between 0 and 10. Four areas are covered in the diagnosis:
joint involvement, designating the metacarpophalangeal joints, proximal interphalangeal joints, the interphalangeal joint of the thumb, second through fifth metatarsophalangeal joint and wrist as small joints, and shoulders, elbows, hip joints, knees, and ankles as large joints:
Involvement of 1 large joint gives 0 points
Involvement of 2–10 large joints gives 1 point
Involvement of 1–3 small joints (with or without involvement of large joints) gives 2 points
Involvement of 4–10 small joints (with or without involvement of large joints) gives 3 points
Involvement of more than 10 joints (with involvement of at least 1 small joint) gives 5 points
serological parameters – including the rheumatoid factor as well as ACPA – "ACPA" stands for "anti-citrullinated protein antibody":
Negative RF and negative ACPA gives 0 points
Low-positive RF or low-positive ACPA gives 2 points
High-positive RF or high-positive ACPA gives 3 points
acute phase reactants: 1 point for elevated erythrocyte sedimentation rate, ESR, or elevated CRP value (c-reactive protein)
duration of arthritis: 1 point for symptoms lasting six weeks or longerThe new criteria accommodate to the growing understanding of RA and the improvements in diagnosing RA and disease treatment. In the "new" criteria, serology and autoimmune diagnostics carries major weight, as ACPA detection is appropriate to diagnose the disease in an early state, before joints destructions occur. Destruction of the joints viewed in radiological images was a significant point of the ACR criteria from 1987. This criterion no longer is regarded to be relevant, as this is just the type of damage that treatment is meant to avoid.

Differential diagnoses
Several other medical conditions can resemble RA, and need to be distinguished from it at the time of diagnosis:
Crystal induced arthritis (gout, and pseudogout) – usually involves particular joints (knee, MTP1, heels) and can be distinguished with an aspiration of joint fluid if in doubt. Redness, asymmetric distribution of affected joints, pain occurs at night and the starting pain is less than an hour with gout.
Osteoarthritis – distinguished with X-rays of the affected joints and blood tests, older age, starting pain less than an hour, asymmetric distribution of affected joints and pain worsens when using joint for longer periods.
Systemic lupus erythematosus (SLE) – distinguished by specific clinical symptoms and blood tests (antibodies against double-stranded DNA)
One of the several types of psoriatic arthritis resembles RA – nail changes and skin symptoms distinguish between them
Lyme disease causes erosive arthritis and may closely resemble RA – it may be distinguished by blood test in endemic areas
Reactive arthritis – asymmetrically involves heel, sacroiliac joints and large joints of the leg. It is usually associated with urethritis, conjunctivitis, iritis, painless buccal ulcers, and keratoderma blennorrhagica.
Axial spondyloarthritis (including ankylosing spondylitis) – this involves the spine, although an RA-like symmetrical small-joint polyarthritis may occur in the context of this condition.
Hepatitis C – RA-like symmetrical small-joint polyarthritis may occur in the context of this condition. Hepatitis C may also induce rheumatoid factor auto-antibodies.Rarer causes which usually behave differently but may cause joint pains:
Sarcoidosis, amyloidosis, and Whipples disease can also resemble RA.
Hemochromatosis may cause hand joint arthritis.
Acute rheumatic fever can be differentiated by a migratory pattern of joint involvement and evidence of antecedent streptococcal infection.
Bacterial arthritis (such as by Streptococcus) is usually asymmetric, while RA usually involves both sides of the body symmetrically.
Gonococcal arthritis (a bacterial arthritis) is also initially migratory and can involve tendons around the wrists and ankles.Sometimes arthritis is in an undifferentiated stage (i.e. none of the above criteria is positive), even if synovitis is witnessed and assessed with ultrasound imaging.

Difficult-to-treat
Rheumatoid arthritis (D2T RA) is a specific classification RA by the European League against Rheumatism (EULAR).Signs of illness:

Persistence of signs and symptoms
Drug resistance
Does not respond on two or more biological treatments
Does not respond on anti-rheumatic drugs with different mechanism of actionFactors contributing to difficult-to-treat disease:

Genetic risk factors
Environmental factors (diet, smoking, physical activity)
Overweight and obese

Genetic factors
Genetic factors such as HLA-DR1B1, TRAF1, PSORS1C1 and microRNA 146a are associated with difficult to treat rheumatoid arthritis, other gene polymorphisms seem to be correlated with response to biologic modifying anti-rheumatic drugs (bDMARDs). Next one is FOXO3A gene region been reported as associated with worst disorder. The minor allele at FOXO3A summon a differential response of monocytes in RA patients. FOXO3A can provide an increase of pro-inflammatory cytokines, including TNFα. Possible gene polymorphism: STAT4, PTPN2, PSORS1C1 and TRAF3IP2 genes had been correlated with response to TNF inhibitors.

HLA-DR1 and HLA-DRB1 gene
The HLA-DRB1 gene is part of a family of genes called the human leukocyte antigen (HLA) complex. The HLA complex is the human version of the major histocompatibility complex (MHC). Currently, have been identified at least 2479 different versions of the HLA-DRB1 gene. The presence of HLA-DRB1 alleles seems to predict radiographic damage, which may be partially mediated by ACPA development, and also elevated sera inflammatory levels and high swollen joint count. HLA-DR1 is encoded by the most risk allele HLA-DRB1 which share a conserved 5-aminoacid sequence that is correlated with the development of anti-citrullinated protein antibodies. HLA-DRB1 gene have more strong correlation with disease development. Susceptibility to and outcome for rheumatoid arthritis (RA) may associate with particular  HLA-DR alleles, but these alleles vary among ethnic groups and geographic areas.

MicroRNAs
MicroRNAs are a factor in the development of that type of disease. MicroRNAs usually operate as a negative regulator of the expression of target proteins and their increased concentration after biologic treatment (bDMARDs) or after anti-rheumatic drugs. Level of miRNA before and after anti-TNFa/DMRADs combination therapy are potential novel biomarkers for predicting and monitoring outcome. For instance, some of them were found significantly upregulated by anti-TNFa/DMRADs combination therapy. For example, miRNA-16-5p, miRNA-23-3p, miRNA125b-5p, miRNA-126-3p, miRNA-146a-5p, miRNA-223-3p. Curious fact is that only responder patients showed an increase in those miRNAs after therapy, and paralleled the reduction of TNFα, interleukin (IL)-6, IL-17, rheumatoid factor (RF), and C-reactive protein (CRP).

Monitoring progression
Many tools can be used to monitor remission in rheumatoid arthritis.

DAS28: Disease Activity Score of 28 joints (DAS28) is widely used as an indicator of RA disease activity and response to treatment. Joints included are (bilaterally): proximal interphalangeal joints (10 joints), metacarpophalangeal joints (10), wrists (2), elbows (2), shoulders (2) and knees (2). When looking at these joints, both the number of joints with tenderness upon touching (TEN28) and swelling (SW28) are counted. The erythrocyte sedimentation rate (ESR) is measured and the affected person makes a subjective assessment (SA) of disease activity during the preceding 7 days on a scale between 0 and 100, where 0 is "no activity" and 100 is "highest activity possible". With these parameters, DAS28 is calculated as:

        D
        A
        S
        28
        =
        0.56
        ×

            T
            E
            N
            28

        +
        0.28
        ×

            S
            W
            28

        +
        0.70
        ×
        ln

        (
        E
        S
        R
        )
        +
        0.014
        ×
        S
        A

    {\displaystyle DAS28=0.56\times {\sqrt {TEN28}}+0.28\times {\sqrt {SW28}}+0.70\times \ln(ESR)+0.014\times SA}

From this, the disease activity of the affected person can be classified as follows:
It is not always a reliable indicator of treatment effect. One major limitation is that low-grade synovitis may be missed.
Other: Other tools to monitor remission in rheumatoid arthritis are: ACR-EULAR Provisional Definition of Remission of Rheumatoid arthritis, Simplified Disease Activity Index and Clinical Disease Activity Index. Some scores do not require input from a healthcare professional and allow self-monitoring by the person, like HAQ-DI.

Prevention
There is no known prevention for the condition other than the reduction of risk factors.

Supplementation
Evidence suggests that increasing vitamin D levels to the range of  40–60 ng/mL could reduce the risk of rheumatoid arthritis.

Management
There is no cure for RA, but treatments can improve symptoms and slow the progress of the disease. Disease-modifying treatment has the best results when it is started early and aggressively. The results of a recent systematic review found that combination therapy with tumor necrosis factor (TNF) and non-TNF biologics plus methotrexate (MTX) resulted in improved disease control, Disease Activity Score (DAS)-defined remission, and functional capacity compared with a single treatment of either methotrexate or a biologic alone.The goals of treatment are to minimize symptoms such as pain and swelling, to prevent bone deformity (for example, bone erosions visible in X-rays), and to maintain day-to-day functioning. This is primarily addressed with disease-modifying antirheumatic drugs (DMARDs); dosed physical activity; analgesics and physical therapy may be used to help manage pain. RA should generally be treated with at least one specific anti-rheumatic medication. The use of benzodiazepines (such as diazepam) to treat the pain is not recommended as it does not appear to help and is associated with risks.

Lifestyle
Regular exercise is recommended as both safe and useful to maintain muscle strength and overall physical function. Physical activity is beneficial for people with rheumatoid arthritis who experience fatigue, although there was little to no evidence to suggest that exercise may have an impact on physical function in the long term, a study found that carefully dosed exercise has shown significant improvements in patients with RA. Moderate effects have been found for aerobic exercises and resistance training on cardiovascular fitness and muscle strength in RA. Furthermore, physical activity had no detrimental side effects like increased disease activity in any exercise dimension. It is uncertain if eating or avoiding specific foods or other specific dietary measures help improve symptoms. Occupational therapy has a positive role to play in improving functional ability in people with rheumatoid arthritis. Weak evidence supports the use of wax baths (thermotherapy) to treat arthritis in the hands.Educational approaches that inform people about tools and strategies available to help them cope with rheumatoid arthritis may improve a persons psychological status and level of depression in the shorter-term. The use of extra-depth shoes and molded insoles may reduce pain during weight-bearing activities such as walking. Insoles may also prevent the progression of bunions.

Disease-modifying agents
Disease-modifying antirheumatic drugs (DMARDs) are the primary treatment for RA. They are a diverse collection of drugs, grouped by use and convention. They have been found to improve symptoms, decrease joint damage, and improve overall functional abilities.  DMARDs should be started early in the disease as they result in disease remission in approximately half of people and improved outcomes overall.The following drugs are considered DMARDs: methotrexate, sulfasalazine, leflunomide, hydroxychloroquine, TNF inhibitors (certolizumab, adalimumab, infliximab and etanercept), abatacept, and anakinra. Additionally, rituximab and tocilizumab are monoclonal antibodies and are also DMARDs. Use of tocilizumab is associated with a risk of increased cholesterol levels.The most commonly used agent is methotrexate with other frequently used agents including sulfasalazine and leflunomide. Leflunomide is effective when used from 6–12 months, with similar effectiveness to methotrexate when used for 2 years. Sulfasalazine also appears to be most effective in the short-term treatment of rheumatoid arthritis.Hydroxychloroquine, in addition to its low toxicity profile, is considered effective for treatment of moderate RA treatment.Agents may be used in combination, however, people may experience greater side effects.  Methotrexate is the most important and useful DMARD and is usually the first treatment. A combined approach with methotrexate and biologics improves ACR50, HAQ scores and RA remission rates. Triple therapy consisting of methotrexate, sulfasalazine  and hydroxychloroquine may also effectively control disease activity. Adverse effects should be monitored regularly with toxicity including gastrointestinal, hematologic, pulmonary, and hepatic. Side effects such as nausea, vomiting or abdominal pain can be reduced by taking folic acid.A 2015 Cochrane review found rituximab with methotrexate to be effective in improving symptoms compared to methotrexate alone. Rituximab works by decreasing levels of B-cells (immune cell that is involved in inflammation). People taking rituximab had improved pain, function, reduced disease activity and reduced joint damage based on x-ray images. After 6 months, 21% more people had improvement in their symptoms using rituximab and methotrexate.Biological agents should generally be used only if methotrexate and other conventional agents are not effective after a trial of three months.  They are associated with a higher rate of serious infections as compared to other DMARDs. Biological DMARD agents used to treat rheumatoid arthritis include: tumor necrosis factor alpha inhibitors (TNF inhibitors) such as infliximab; interleukin 1 blockers such as anakinra, monoclonal antibodies against B cells such as rituximab, interleukin 6 blockers such as tocilizumab, and T cell co-stimulation blockers such as abatacept. They are often used in combination with either methotrexate or leflunomide. Biologic monotherapy or tofacitinib with methotrexate may improve ACR50, RA remission rates and function. Abatacept should not be used at the same time as other biologics. In those who are well controlled (low disease activity) on TNF inhibitors, decreasing the dose does not appear to affect overall function. Discontinuation of TNF inhibitors (as opposed to gradually lowering the dose) by people with low disease activity may lead to increased disease activity and may affect remission, damage that is visible on an x-ray, and a persons function. People should be screened for latent tuberculosis before starting any TNF inhibitor therapy to avoid reactivation of tuberculosis.TNF inhibitors and methotrexate appear to have similar effectiveness when used alone and better results are obtained when used together. Golimumab is effective when used with methotraxate. TNF inhibitors may have equivalent effectiveness with etanercept appearing to be the safest. Injecting etanercept, in addition to methotrexate twice a week may improve ACR50 and decrease radiographic progression for up to 3 years. Abatacept appears effective for RA with 20% more people improving with treatment than without but long term safety studies are yet unavailable. Adalimumab slows the time for the radiographic progression when used for 52 weeks. However, there is a lack of evidence to distinguish between the biologics available for RA. Issues with the biologics include their high cost and association with infections including tuberculosis. Use of biological agents may reduce fatigue. The mechanism of how biologics reduce fatigue is unclear.

Gold (sodium aurothiomalate) and cyclosporin
Sodium aurothiomalate (gold) and cyclosporin are less commonly used due to more common adverse effects. However, cyclosporin was found to be effective in the progressive RA when used up to one year.

Anti-inflammatory and analgesic agents
Glucocorticoids can be used in the short term and at the lowest dose possible for flare-ups and while waiting for slow-onset drugs to take effect. Combination of glucocorticoids and conventional therapy has shown a decrease in rate of erosion of bones. Steroids may be injected into affected joints during the initial period of RA, prior to the use of DMARDs or oral steroids.Non-NSAID drugs to relieve pain, like paracetamol may be used to help relieve the pain symptoms; they do not change the underlying disease. The use of paracetamol may be associated with the risk of developing ulcers.NSAIDs reduce both pain and stiffness in those with RA but do not affect the underlying disease and appear to have no effect on peoples long term disease course and thus are no longer first line agents. NSAIDs should be used with caution in those with gastrointestinal, cardiovascular, or kidney problems. Rofecoxib was withdrawn from the global market as its long-term use was associated to an increased risk of heart attacks and strokes. Use of methotrexate together with NSAIDs is safe, if adequate monitoring is done. COX-2 inhibitors, such as celecoxib, and NSAIDs are equally effective. A 2004 Cochrane review found that people preferred NSAIDs over paracetamol. However, it is yet to be clinically determined whether NSAIDs are more effective than paracetamol.The neuromodulator agents topical capsaicin may be reasonable to use in an attempt to reduce pain. Nefopam by mouth and cannabis are not recommended as of 2012 as the risks of use appear to be greater than the benefits.Limited evidence suggests the use of weak oral opioids but the adverse effects may outweigh the benefits.Alternatively, physical therapy has been tested and shown as an effective aid in reducing pain in patients with RA. As most RA is detected early and treated aggressively, physical therapy plays more of a preventative and compensatory role, aiding in pain management alongside regular rheumatic therapy.

Surgery
Especially for affected fingers, hands, and wrists, synovectomy may be needed to prevent pain or tendon rupture when drug treatment has failed. Severely affected joints may require joint replacement surgery, such as knee replacement.  Postoperatively, physiotherapy is always necessary.: 1080, 1103  There is insufficient evidence to support surgical treatment on arthritic shoulders.

Physiotherapy
For people with RA, physiotherapy may be used together with medical management. This may include cold and heat application, electronic stimulation, and hydrotherapy. Although medications improve symptoms of RA, muscle function is not regained when disease activity is controlled.Physiotherapy promotes physical activity. In RA, physical activity like exercise in the appropriate dosage (frequency, intensity, time, type, volume, progression) and physical activity promotion is effective in improving cardiovascular fitness, muscle strength, and maintaining a long term active lifestyle. In the short term, resistance exercises, with or without range of motion exercises, improve self-reported hand functions. Physical activity promotion according to the public health recommendations should be an integral part of standard care for people with RA and other arthritic diseases.  Additionally, the combination of physical activities and cryotherapy show its efficacy on the disease activity and pain relief.  The combination of aerobic activity and cryotherapy  may be an innovative therapeutic strategy to improve the aerobic capacity in arthritis patients and consequently reduce their cardiovascular risk while minimizing pain and disease activity.

Compression gloves
Compression gloves are handwear designed to help prevent the occurrence of various medical disorders relating to blood circulation in the wrists and hands. They can be used to treat the symptoms of arthritis, though the medical benefits may be limited.

Alternative medicine
In general, there is not enough evidence to support any complementary health approaches for RA, with safety concerns for some of them. Some mind and body practices and dietary supplements may help people with symptoms and therefore may be beneficial additions to conventional treatments, but there is not enough evidence to draw conclusions. A systematic review of CAM modalities (excluding fish oil) found that " The available evidence does not support their current use in the management of RA.". Studies showing beneficial effects in RA on a wide variety of CAM modalities are often affected by publication bias and are generally not high quality evidence such as randomized controlled trials (RCTs).A 2005 Cochrane review states that low level laser therapy can be tried to improve pain and morning stiffness due to rheumatoid arthritis as there are few side-effects.There is limited evidence that Tai Chi might improve the range of motion of a joint in persons with rheumatoid arthritis. The evidence for acupuncture is inconclusive with it appearing to be equivalent to sham acupuncture.A Cochrane review in 2002 showed some benefits of the electrical stimulation as a rehabilitation intervention to improve the power of the hand grip and help to resist fatigue. D‐penicillamine may provide similar benefits as DMARDs but it is also highly toxic. Low-quality evidence suggests the use of therapeutic ultrasound on arthritic hands. Potential benefits include increased grip strength, reduced morning stiffness and number of swollen joints. There is tentative evidence of benefit of transcutaneous electrical nerve stimulation (TENS) in RA. Acupuncture‐like TENS (AL-TENS) may decrease pain intensity and improve muscle power scores.Low-quality evidence suggests people with active RA may benefit from assistive technology. This may include less discomfort and difficulty such as when using an eye drop device. Balance training is of unclear benefits.

Dietary supplements
Fatty acids
There has been a growing interest in the role of long-chain omega-3 polyunsaturated fatty acids to reduce inflammation and alleviate the symptoms of RA. Metabolism of omega-3 polyunsaturated fatty acids produces docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), which inhibits pro-inflammatory eicosanoids and cytokines (TNF-a, IL-1b and IL-6), decreasing both lymphocyte proliferation and reactive oxygen species. These studies showed evidence for significant clinical improvements on RA in inflammatory status and articular index. Gamma-linolenic acid, an omega-6 fatty acid, may reduce pain, tender joint count and stiffness, and is generally safe. For omega-3 polyunsaturated fatty acids (found in fish oil, flax oil and hemp oil), a meta-analysis reported a favorable effect on pain, although confidence in the effect was considered moderate. The same review reported less inflammation but no difference in joint function. A review examined the effect of marine oil omega-3 fatty acids on pro-inflammatory eicosanoid concentrations; leukotriene4 (LTB4) was lowered in people with rheumatoid arthritis but not in those with non-autoimmune chronic diseases. (LTB4) increases vascular permeabiltity and stimulates other inflammatory substances. A third meta-analysis looked at fish consumption. The result was a weak, non-statistically significant inverse association between fish consumption and RA. A fourth review limited inclusion to trials in which people eat ≥2.7 g/day for more than three months. Use of pain relief medication was decreased, but improvements in tender or swollen joints, morning stiffness and physical function were not changed. Collectively, the current evidence is not strong enough to determine that supplementation with omega-3 fatty acids or regular consumption of fish are effective treatments for rheumatoid arthritis.

Diets
Patients with RA often claim that their symptoms are alleviated by special diets or by simple elimination of certain foods. In contrast, some foods might provoke hypersensitivity responses, which may increase symptoms of RA.The Dong diet has been suggested for a benefit in RA. This diet is rich in oils, seafood, vegetables, and rice which improve symptoms of RA. It eliminates citrus fruits, chocolate, dairy produce, flour products, alcohol, additives, spices, fizzy drinks, and red meat which are implicated in the aggravation of symptoms.The Mediterranean diet is a well‐balanced, nutritionally adequate diet that encompasses all the food groups. This diet is rich in fresh fruits and vegetables, whole grains, seafood, nuts and legumes, and olive oil. In contrast, it limits red meat, sugary foods, and dairy, in small portions of yogurt and cheese. The foods in this category parallel the Dong Diet closely and show evidence of overlap. There is beneficial effect in using a Mediterranean diet and Dong diet for a reduction in the number of tender joints, stiffness, and pain.Vitamins
Adequate Vitamin concentrations may provide an important defence against the increased oxidant stress in patients with RA. Here we look at the effects of vitamins E, C and B on the management of RA.
In general vitamin E deficiency enhances components of the inflammatory response and suppresses components of the immune response. Molecular studies have demonstrated that the formation of the pro-inflammatory prostaglandin E2 is inhibited 95% by aspirin when combined with vitamin E compared to control. This suggests that vitamin E supplementation reduces the need for high dosage of aspirin needed by patients with RA to relieve joint symptoms. This can offer double benefits because lowering the dose of aspirin can also reduce the gastric irritation side effect for patients. Even though there is no evidence of only taking vitamin E supplementation alone, I believe patients with RA should be encouraged to increase their consumption of vitamin E rich cereals, fruit, and vegetables.
Vitamin C is necessary for the growth and development of all body tissues and plays an important role in antioxidant defences. In animal studies biochemical markers of antioxidant defence mechanisms were increased with vitamin C supplementation and infiltration of inflammatory cells into synovial fluid were decreased. From these studies I can conclude that vitamin C supplementation may be more effective for the pain associated with RA however long-term use might aggravate onset of osteoarthritis.
Vitamin B6 and B9 play a role in RA management as well. Studies have shown that low plasma levels of pyridoxal-5-phosphate, the metabolically active form of vitamin B6, have been reported in RA patients, which may be associated with the elevated TNF-a production. Folate supplies are also decreased in RA patients who are taking Methotrexate, an anti-rheumatic drug. We see that folate supplementation can reduce the mucosal and gastrointestinal side effects of low dose Methotrexate in patients with RA. This works in a similar pattern to aspirin and vitamin E supplementation. Therefore, RA patients should be advised to consume dietary sources of vitamin B6 and B9 up to the dietary reference value, until further research is undertaken into the toxicity and effectiveness of large dose supplementation.
Food containing high source of vitamin E to help treat Rheumatoid Arthritis include almonds, avocados, spinach, sunflower seeds and peanut butter. Vitamin C foods include oranges, orange juice, strawberry, broccoli, brussel sprouts and potatoes. Brown rice, barley, and fish contain sources of vitamin B6 and B9. Lastly, Vitamin D can be included in the diet by incorporating tuna, salmon, orange juice and almond Milk into diet.Minerals
Minerals including fluoride, iron, calcium, and zinc have been studied in the role of RA management. The effects of fluoride supplementation in preventing RA-induced bone loss were examined in a randomized control trial. Results suggest that fluoride therapy may increase vertebral bone mass in RA patients.Approximately, one-third of cases of anaemia in RA patients may be caused by depletion of iron stores. A major cause for iron deficiency anaemia is the poor dietary intake. Deferioxamine, an iron-chelating agent, which has possible anti-inflammatory properties, causes haemoglobin and serum iron levels to increases. This shows that iron stores are needed within the body and an adequate dietary intake to meet the recommended intakes should be encouraged, even though there is no evidence for additional routine supplementation for patients with RA.
Studies have examined the effect of calcium supplementation on bone mineral density among subjects taking corticosteroids. A study of calcium combined with vitamin D3 in RA patients taking low-dose corticosteroids demonstrated a reduction in bone mineral density loss in both the spine and trochanter, but not the femoral neck. However, no change was seen in BMD with calcium and vitamin D3 supplementation in RA patients not receiving corticosteroids. Therefore, there is little evidence to support calcium and vitamin D supplementation in corticosteroid receiving RA patients.
Lastly, low levels of serum zinc have been reported in patients with RA which may be caused by elevated IL-1b levels. However, Zinc supplementations yield contradictory results and at present do not support a therapeutic use of zinc.
Food containing high source of fluoride to help treat Rheumatoid Arthritis include tomatoes, oranges, bell peppers and grapefruit, which you should eat in moderation. Iron can be incorporated into the diet by eating seafood, spinach, and peas. Moderate amounts of calcium should be included into the diet by having milk, cheese, dairy products, curly kale, okra, bread and fortified flour products such as cereals.

Herbal
The American College of Rheumatology states that no herbal medicines have health claims supported by high-quality evidence and thus they do not recommend their use. There is no scientific basis to suggest that herbal supplements advertised as "natural" are safer for use than conventional medications as both are chemicals. Herbal medications, although labelled "natural", may be toxic or fatal if consumed.
Due to the false belief that herbal supplements are always safe, there is sometimes a hesitancy to report their use which may increase the risk of adverse reaction.The following are under investigation for treatments for RA, based on preliminary promising results (not recommended for clinical use yet): boswellic acid, curcumin, devils claw, Euonymus alatus, and thunder god vine (Tripterygium wilfordii). NCCIH has noted that, "In particular, the herb thunder god vine (Tripterygium wilfordii) can have serious side effects."There is conflicting evidence on the role of erythropoiesis-stimulating agents for treatment of anemia in persons with rheumatoid arthritis.

Pregnancy
More than 75% of women with rheumatoid arthritis have symptoms improve during pregnancy but might have symptoms worsen after delivery. Methotrexate and leflunomide are teratogenic (harmful to foetus) and not used in pregnancy. It is recommended women of childbearing age should use contraceptives to avoid pregnancy and to discontinue its use if pregnancy is planned. Low dose of prednisolone, hydroxychloroquine and sulfasalazine are considered safe in pregnant persons with rheumatoid arthritis. Prednisolone should be used with caution as the side effects include infections and fractures.

Vaccinations
People with RA have an increased risk of infections and mortality and recommended vaccinations can reduce these risks. The inactivated influenza vaccine should be received annually. The pneumococcal vaccine should be administered twice for people under the age 65 and once for those over 65. Lastly, the live-attenuated zoster vaccine should be administered once after the age 60, but is not recommended in people on a tumor necrosis factor alpha blocker.

Prognosis
The course of the disease varies greatly. Some people have mild short-term symptoms, but in most the disease is progressive for life. Around 25% will have subcutaneous nodules (known as rheumatoid nodules); this is associated with a poor prognosis.

Prognostic factors
Poor prognostic factors include,

Persistent synovitis
Early erosive disease
Extra-articular findings (including subcutaneous rheumatoid nodules)
Positive serum RF findings
Positive serum anti-CCP autoantibodies
Positive serum 14-3-3η (YWHAH) levels above 0.5 ng/ml
Carriership of HLA-DR4 "Shared Epitope" alleles
Family history of RA
Poor functional status
Socioeconomic factors
Elevated acute phase response (erythrocyte sedimentation rate [ESR], C-reactive protein [CRP])
Increased clinical severity.

Mortality
RA reduces lifespan on average from three to twelve years. Young age at onset, long disease duration, the presence of other health problems, and characteristics of severe RA—such as poor functional ability or overall health status, a lot of joint damage on x-rays, the need for hospitalisation or involvement of organs other than the joints—have been shown to associate with higher mortality. Positive responses to treatment may indicate a better prognosis. A 2005 study by the Mayo Clinic noted that individuals with RA have a doubled risk of heart disease, independent of other risk factors such as diabetes, excessive alcohol use, and elevated cholesterol, blood pressure and body mass index. The mechanism by which RA causes this increased risk remains unknown; the presence of chronic inflammation has been proposed as a contributing factor. It is possible that the use of new biologic drug therapies extend the lifespan of people with RA and reduce the risk and progression of atherosclerosis. This is based on cohort and registry studies, and still remains hypothetical. It is still uncertain whether biologics improve vascular function in RA or not. There was an increase in total cholesterol and HDLc levels and no improvement of the atherogenic index.

Epidemiology
RA affects between 0.5 and 1% of adults in the developed world with between 5 and 50 per 100,000 people newly developing the condition each year. In 2010 it resulted in about 49,000 deaths globally.Onset is uncommon under the age of 15 and from then on the incidence rises with age until the age of 80. Women are affected three to five times as often as men.The age at which the disease most commonly starts is in women between 40 and 50 years of age, and for men somewhat later. RA is a chronic disease, and although rarely, a spontaneous remission may occur, the natural course is almost invariably one of the persistent symptoms, waxing and waning in intensity, and a progressive deterioration of joint structures leading to deformations and disability.There is an association between periodontitis and rheumatoid arthritis (RA), hypothesised to lead to enhanced generation of RA-related autoantibodies. Oral bacteria that invade the blood may also contribute to chronic inflammatory responses and generation of autoantibodies.

History
The first recognized description of RA in modern medicine was in 1800 by the French physician Dr Augustin Jacob Landré-Beauvais (1772–1840) who was based in the famed Salpêtrière Hospital in Paris. The name "rheumatoid arthritis" itself was coined in 1859 by British rheumatologist Dr Alfred Baring Garrod.The art of Peter Paul Rubens may possibly depict the effects of RA. In his later paintings, his rendered hands show, in the opinion of some physicians, increasing deformity consistent with the symptoms of the disease. RA appears to some to have been depicted in 16th-century paintings. However, it is generally recognized in art historical circles that the painting of hands in the 16th and 17th century followed certain stylized conventions, most clearly seen in the Mannerist movement </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Black hairy tongue and explain in detail? [/INST] Black hairy tongue  syndrome (BHT) is a condition of the tongue in which the small bumps on the tongue elongate with black or brown discoloration, giving a black and hairy appearance. The appearance may be alarming, but it is a harmless condition. Predisposing factors include smoking, xerostomia (dry mouth), soft diet, poor oral hygiene and certain medications. Management is facilitated by improving oral hygiene, especially scraping or brushing the tongue.

Signs and symptoms
Hairy tongue largely occurs in the central part of the dorsal tongue, just anterior (in front) of the circumvallate papillae, although sometimes the entire dorsal surface may be involved. Discoloration usually accompanies hairy tongue, and may be yellow, brown or black. Apart from the appearance, the condition is typically asymptomatic, but sometimes people may experience a gagging sensation or a bad taste. There may also be associated oral malodor (intra-oral halitosis).The term "melanoglossia is also used to refer to there being black discolorations on the tongue without "hairs", which are also harmless and unrelated to black hairy tongue.

Causes
The cause is uncertain, but it is thought to be caused by accumulation of epithelial squames and proliferation of chromogenic (i.e., color-producing) microorganisms. There may be an increase in keratin production or a decrease in normal desquamation (shedding of surface epithelial cells). Many people with BHT are heavy smokers. Other possible associated factors are poor oral hygiene, general debilitation, hyposalivation (i.e., decreased salivary flow rate), radiotherapy, overgrowth of fungal or bacterial organisms, and a soft diet. Occasionally, BHT may be caused by the use of antimicrobial medications (e.g., tetracyclines), or oxidizing mouthwashes or antacids. A soft diet may be involved as normally food has an abrasive action on the tongue, which keeps the filiform papillae short. Pellagra, a condition caused by niacin (vitamin B3) deficiency, may cause a thick greyish fur to develop on the dorsal tongue, along with other oral signs.Transient surface discoloration of the tongue and other soft tissues in the mouth can occur in the absence of hairy tongue. Causes include smoking (or betel chewing), some foods and beverages (e.g., coffee, tea or liquorice), and certain medications (e.g., chlorhexidine, iron salts, or bismuth subsalicylate (Pepto-Bismol)).

Diagnosis
Diagnosis is usually made on the clinical appearance without the need for a tissue biopsy. However, when biopsies have been taken, the histologic appearance is one of marked elongation and hyperparakeratosis of the filiform papillae and numerous bacteria growing on the epithelial surface.Hairy tongue may be confused with hairy leukoplakia, however the latter usually occurs on the sides of the tongue and is associated with an opportunistic infection with Epstein–Barr virus on a background immunocompromise (almost always human immunodeficiency virus infection but rarely other conditions which suppress the immune system).

Classification
Hairy tongue (lingua villosa) refers to a marked accumulation of keratin on the filiform papillae on the dorsal surface of the tongue, giving a hair-like appearance. Black tongue (lingua nigra) refers to a black discoloration of the tongue, which may or may not be associated with hairy tongue </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Ganglioneuroma and explain in detail? [/INST] Ganglioneuroma is a rare and benign tumor of the autonomic nerve fibers arising from neural crest sympathogonia, which are completely undifferentiated cells of the sympathetic nervous system. However, ganglioneuromas themselves are fully differentiated neuronal tumors that do not contain immature elements.Ganglioneuromas most frequently occur in the abdomen, however these tumors can grow anywhere sympathetic nervous tissue is found. Other common locations include the adrenal gland, paraspinal retroperitoneum, posterior mediastinum, head, and neck </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Rheumatoid lung disease and explain in detail? [/INST] Rheumatoid lung disease is a disease of the lung associated with RA, rheumatoid arthritis. Rheumatoid lung disease is characterized by pleural effusion, pulmonary fibrosis, lung nodules and pulmonary hypertension. Common symptoms associated with the disease include shortness of breath, cough, chest pain and fever. It is estimated that about one quarter of people with rheumatoid arthritis develop this disease, which are more likely to develop among elderly men with a history of smoking.Rheumatoid lung is separate from but often associated with Interstitial lung disease(ILD).

Signs and symptoms
Most common:

Chest Pain
Cough
Fever
Shortness of breath
Joint pain, stiffness, swelling
Skin nodulesPeople may not present with all these symptoms or none at all.
From most to least common:

Pleural involvement (pleurisy, effusions)
Pulmonary parenchymal nodules, more common in men than in women
Rheumatoid-associated interstitial lung disease
Bronchiolitis obliterans organizing pneumonia
Obliterative bronchiolitis (obstructive lung disease/bronchiectasis)
Rheumatoid-associated pulmonary hypertension
Pulmonary vasculitis/arteritis
Shrinking lung syndrome
Miscellaneous: MTX, cricoarytenoid arthritis, infection, cancer

Causes
The exact cause of rheumatoid lung disease is unknown. However, associated factors could be due largely to smoking. Sometimes, the medicines used to treat rheumatoid arthritis, especially methotrexate, may result in lung disease.Prevention:

Stop smoking: Chemicals found in cigarettes can irritate already delicate lung tissue, leading to further complications.
Having regular checkups: The doctor could listen to lungs and monitor breathing, because lung problems that are detected early can be easier to treat.

Mechanism
RA is a complex and poorly understood disease.
However, the characteristic presence of antibodies to citrullinated proteins (anti-CCP) suggests that there are pathogenic mechanisms unique to RA. Recent studies suggest a link between smoking, HLA-DRBSE, anti-CCP and RA. Smoking has long been linked to RA and worsens articular disease as well as rheumatoid lung disease. Exposure to cigarette smoke leads to the activation of PADI enzymes that deaminate arginine to citrulline, producing autoantigens like citrullinated collagen and fibrinogen. Autoantigenic peptides containing citrulline residues are preferentially bound by HLA-DRB SE proteins and are presented to T cells, which interact with CCP-specific B cells found at sites containing autoantigen and produce inflammatory cytokines and autoantibodies, which accelerate disease. Bacterial or viral infections of the respiratory tract may also exacerbate pulmonary inflammation and rheumatoid lung disease.

Diagnosis
The diagnosis of RA was formerly based on detection of rheumatoid factor (RF). However, RF is also associated with other autoimmune diseases. The detection of anti-CCP is currently considered the most specific marker of RA. The diagnosis of rheumatoid lung disease is based on evaluation of pulmonary function, radiology, serology and lung biopsy. High resolution CT scans are preferred to chest X-rays due to their sensitivity and specificity.Associated doctors to diagnosis this properly would be a Rheumatologists or Pulmonologist.
Within a physical examination doctors could find possible indications, such as hearing crackles (rales) when listening to the lungs with a stethoscope. Or, there may be decreased breath sounds, wheezing, a rubbing sound, or normal breath sounds. When listening to the heart, there may be abnormal heart sounds.  Bronchoscopic, video-assisted, or open lung biopsy allows the histological characterization of pulmonary lesions, which can distinguish rheumatoid lung disease from other interstitial lung diseases.The following tests may also show signs of rheumatoid lung disease:
Chest x-ray may show:
pleural effusion
lower zone predominant reticular or reticulonodular pattern
volume loss in advanced disease
skeletal changes, e.g. erosion of clavicles, glenohumeral erosive arthropathy, superior rib notching
Chest CT or HRCT features include:
pleural thickening or effusion
interstitial fibrosis
bronchiectasis
bronchiolitis obliterans
large rheumatoid nodules
single or multiple
tend to be based peripherally
may cavitate (necrobiotic lung nodules)
cavitation of a peripheral nodule can lead to pneumothorax or haemopneumothorax.
follicular bronchiolitis
small centrilobular nodules or tree-in-bud
rare
Caplan syndrome
Echocardiogram (may show pulmonary hypertension)
Lung biopsy (bronchoscopic, video-assisted, or open), which may show pulmonary lesions
Lung function tests
Needle inserted into the fluid around the lung (thoracentesis)
Blood tests for rheumatoid arthritis

Treatment
Many people with this condition have no symptoms. Treatment is aimed at the health problems causing the lung problem and the complications caused by the disorder.Fast-acting drugs for RA include aspirin and corticosteroids, which alleviate pain and reduce inflammation. Slow-acting drugs termed disease modifying antirheumatic drugs (DMARDs), include gold, methotrexate and hydroxychloroquine (Plaquenil), which promote disease remission and prevent progressive joint destruction. In patients with less severe RA, pain relievers, anti-inflammatory drugs and physical rest are sufficient to improve quality of life. In patients with joint deformity, surgery is the only alternative for recovering articular function.Prognosis is related to the underlying disorder and the type and severity of lung disease. In severe cases, lung transplantation can be considered. This is more common in cases of bronchiolitis obliterans, pulmonary fibrosis, or pulmonary hypertension </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Infantile acropustulosis and explain in detail? [/INST]  </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Traction alopecia and explain in detail? [/INST] Traction alopecia is a type of hair loss caused by a pulling force being applied to the hair.This commonly results from a person frequently wearing their hair in a particularly tight ponytail, pigtails, or braids. It is also seen occasionally in long-haired people who use barrettes to keep hair out of their faces. Traction alopecia is recession of the hairline due to chronic traction, or hair pulling, and is characterized by a fringe along the marginal hairline on physical exam. Even though this "fringe sign" is considered a useful clinical marker of this condition, cases of frontal fibrosing alopecia presenting with an unusual retention of the hairline (pseudo-fringe sign) have been described.

Cause
It is commonly seen with certain hair styles or braiding patterns that pull the hairline forcefully towards the vertex of the scalp, and has been reported more often in African American women (as some wear their hair tightly pulled back), in whom it can cause scarring. It has also been seen in female ballerinas, and in cultural traditions where the hair is voluntarily not cut in religious obeisance, the latter caused by progressively increasing weight of the hair itself. Traction alopecia is mechanical in cause, rather than androgenic, and treatment is typically not pharmaceutical. Management includes cessation of the chronic traction, cosmeses, with surgical restoration reserved for more severe cases.Traction alopecia is a substantial risk in hair weaves, which can be worn either to conceal hair loss, or purely for cosmetic purposes.  The former involves creating a braid around the head below the existing hairline, to which an extended-wear hairpiece, or wig, is attached.  Since the hair of the braid is still growing, it requires frequent maintenance, which involves the hairpiece being removed, the natural hair braided again, and the piece snugly reattached </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Macrocytic anemia and explain in detail? [/INST] The term macrocytic is from Greek words meaning "large cell". A macrocytic class of anemia is an anemia (defined as blood with an insufficient concentration of hemoglobin) in which the red blood cells (erythrocytes) are larger than their normal volume. The normal erythrocyte volume in humans is about 80 to 100 femtoliters (fL= 10−15 L). In metric terms the size is given in equivalent cubic micrometers (1 μm3 = 1 fL). The condition of having erythrocytes which (on average) are too large, is called macrocytosis. In contrast, in microcytic anemia, the erythrocytes are smaller than normal.
In a macrocytic anemia, the larger red cells are always associated with insufficient numbers of cells and often also insufficient hemoglobin content per cell. Both of these factors work to the opposite effect of larger cell size, to finally result in a total blood hemoglobin concentration that is less than normal (i.e., anemia).
Macrocytic anemia is not a disease in the sense of having a single pathology but, rather, is a condition. As such, it is the class name for a set of pathologies that all produce somewhat the same red blood cell abnormality. Different pathologies result in macrocytic-type anemias. Some of these pathologies produce slightly different sets of appearances in blood cells that are detectable from red and white cell morphology, and others are only detectable with chemical testing.

Causes
Megaloblastic anemias
Megaloblastic anemias represent a type of macrocytic anemia characterized by certain morphologic abnormalities noted on a peripheral blood smear examination. These abnormalities include the presence of enlarged oval shaped red blood cells (macroovalocytes) and hypersegmented neutrophils (defined as a neutrophil with six or more lobes). Hypersegmented neutrophils may be seen in the absence of macroovalocytes as hypersegmentation of neutrophils is an early sign of megaloblastic anemia and may precede the appearance of macroovalocytes; they may also be seen in other anemias (e.g., iron deficiency anemia) and thus are suggestive of megaloblastic anemia but not specific for it. An increased red cell distribution width (anisocytosis) also suggests megaloblastosis and is commonly seen in Vitamin B12 deficiency and folic acid deficiency. This type of anemia is caused by impaired DNA synthesis and repair, often from deficient thymidine production. Thiamine responsive megaloblastic anemia syndrome also causes megaloblastic anemia.The red blood cells grow larger because they cannot produce DNA quickly enough to divide at the right time as they grow and thus grow too large before division. Additional causes of megaloblastic anemia include medications that interfere with DNA synthesis or with the absorption or metabolism of Vitamin B12 or folate such as methotrexate, sulfasalazine, metformin, anticonvulsant medications (e.g., valproic acid or phenytoin), certain antibiotics (e.g., trimethoprim/sulfamethoxazole), antiretroviral medications, cholestyramine, triamterene,  and nitrous oxide.

Non-Megaloblastic anemias
Red cell membrane disorders producing codocytes
Other disorders which cause macrocytosis without DNA replication problems (i.e., non-megaloblastic macrocytic anemias), are disorders associated with increased red cell membrane surface area, such as pathologies of the liver and spleen which produce codocytes or "target cells" which have a central collection of hemoglobin surrounded by a pallor (a thin area) then followed by a thicker collection of hemoglobin at the rim of the cell.

Alcohol
Round macrocytes which are not codocytes are produced in chronic alcoholism (which produces a mild macrocytosis even in the absence of vitamin deficiency), apparently as a direct toxic effect of alcohol specifically on the bone marrow </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Primordial dwarfism and explain in detail? [/INST] Primordial dwarfism (PD) is a form of dwarfism that results in a smaller body size in all stages of life beginning from before birth. More specifically, primordial dwarfism is a diagnostic category including specific types of profoundly proportionate dwarfism, in which individuals are extremely small for their age, even as a fetus. Most individuals with primordial dwarfism are not diagnosed until they are about 3–5 years of age.
Medical professionals typically diagnose the fetus as being small for gestational age, or as showing intrauterine growth restriction when an ultrasound is conducted. Typically, people with primordial dwarfism are born with very low birth weights. After birth, growth continues at a much slower rate, leaving individuals with primordial dwarfism perpetually years behind their peers in stature and in weight.
Most cases of short stature are caused by skeletal or endocrine disorders. The five subtypes of primordial dwarfism are among the most severe forms of the 200 types of dwarfism.
There are as yet no effective treatments for primordial dwarfism. It is rare for individuals affected by primordial dwarfism to live past the age of 30 </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Pemphigus vegetans and explain in detail? [/INST]  </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Chondromalacia patellae and explain in detail? [/INST] Chondromalacia patellae (also known as CMP) is an inflammation of the underside of the patella and softening of the cartilage.
The cartilage under the kneecap is a natural shock absorber, and overuse, injury, and many other factors can cause increased deterioration and breakdown of the cartilage. The cartilage is no longer smooth and therefore movement and use is very painful. While it often affects young individuals engaged in active sports, it also afflicts older adults who overwork their knees.Chondromalacia patellae is sometimes used synonymously with patellofemoral pain syndrome. However, there is general consensus that patellofemoral pain syndrome applies only to individuals without cartilage damage. This condition is also known as Chondrosis. The term literally translates to softening (malakia) of cartilage (chondros) behind patella in Greek.

Cause
The condition may result from acute injury to the patella or chronic friction between the patella and a groove in the femur through which it passes during knee flexion. Possible causes include a tight iliotibial band, neuromas, bursitis, overuse, malalignment, core instability, and patellar maltracking.Pain at the front or inner side of the knee is common in adults of all ages especially when engaging in soccer, gymnastics, cycling, rowing, tennis, ballet, basketball, horseback riding, volleyball, running, combat sports, figure skating, snowboarding, skateboarding and even swimming. The pain is typically felt after prolonged sitting. Skateboarders most commonly experience this injury in their non-dominant foot due to the constant kicking and twisting required of it. Swimmers acquire it doing the breaststroke, which demands an unusual motion of the knee. People who are involved in an active lifestyle with high impact on the knees are at greatest risk. Proper management of physical activity may help prevent worsening of the condition. Athletes are advised to talk to a physician for further medical diagnosis, as symptoms may be similar to more serious problems within the knee. Tests are not necessarily needed for diagnosis, but in some situations they may confirm diagnosis or rule out other causes for pain </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Persistent hyperplastic primary vitreous and explain in detail? [/INST]  </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Congenital hereditary endothelial dystrophy and explain in detail? [/INST] Congenital hereditary corneal dystrophy (CHED) is a form of corneal endothelial dystrophy that presents at birth.
CHED was previously subclassified into two subtypes: CHED1 and CHED2. However in 2015, the International Classification of Corneal Dystrophies (IC3D) renamed the condition "CHED1" to become posterior polymorphous corneal dystrophy, and renamed the condition "CHED2" to become, simply, CHED </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Pulseless electrical activity and explain in detail? [/INST] Pulseless electrical activity (PEA) refers to cardiac arrest in which the electrocardiogram shows a heart rhythm that should produce a pulse, but does not. Pulseless electrical activity is found initially in about 55% of people in cardiac arrest.Under normal circumstances, electrical activation of muscle cells precedes mechanical contraction of the heart (known as electromechanical coupling). In PEA, there is electrical activity but insufficient cardiac output to generate a pulse and supply blood to the organs, whether the heart itself is failing to contract or otherwise. While PEA is classified as a form of cardiac arrest, significant cardiac output may still be present, which may be determined and best visualized by bedside ultrasound (echocardiography).
Cardiopulmonary resuscitation (CPR) is the first treatment for PEA, while potential underlying causes are identified and treated. The medication epinephrine (aka adrenaline) may be administered. Survival is about 20%.

Signs and symptoms
Pulseless electrical activity leads to a loss of cardiac output, and the blood supply to the brain is interrupted. As a result, PEA is usually noticed when a person loses consciousness and stops breathing spontaneously. This is confirmed by examining the airway for obstruction, observing the chest for respiratory movement, and feeling the pulse (usually at the carotid artery) for a period of 10 seconds.

Causes
These possible causes are remembered as the 6 Hs and the 6 Ts. See Hs and Ts

Hypovolemia
Hypoxia
Hydrogen ions (Acidosis)
Hyperkalemia or Hypokalemia
Hypoglycemia
Hypothermia
Tablets or Toxins
Cardiac Tamponade
Tension pneumothorax
Thrombosis (e.g., myocardial infarction, pulmonary embolism)
Tachycardia
Trauma (e.g., hypovolemia from blood loss)The possible mechanisms by which the above conditions can cause pulseless in PEA are the same as those recognized as producing circulatory shock states. These are (1) impairment of cardiac filling, (2) impaired pumping effectiveness of the heart, (3) circulatory obstruction and (4) pathological vasodilation causing loss of vascular resistance and excess capacitance. More than one mechanism may be involved in any given case.

Diagnosis
The absence of a pulse confirms a clinical diagnosis of cardiac arrest, but PEA can only be distinguished from other causes of cardiac arrest with a device capable of electrocardiography (ECG/EKG). In PEA, there is organised or semi-organised electrical activity in the heart as opposed to asystole (flatline) or to the disorganised  electrical activity of either ventricular fibrillation or ventricular tachycardia.

Treatment
Cardiac resuscitation guidelines (ACLS/BCLS) advise that cardiopulmonary resuscitation should be initiated promptly to maintain cardiac output until the PEA can be corrected </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Hawkinsinuria and explain in detail? [/INST] Hawkinsinuria is an autosomal dominant metabolic disorder affecting the metabolism of tyrosine.Normally, the breakdown of the amino acid tyrosine involves the conversion of 4-hydroxyphenylpyruvate to homogentisate by 4-hydroxyphenylpyruvate dioxygenase </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Lithium toxicity and explain in detail? [/INST] Lithium toxicity, also known as lithium overdose, is the condition of having too much lithium. Symptoms may include a tremor, increased reflexes, trouble walking, kidney problems, and an altered level of consciousness. Some symptoms may last for a year after levels return to normal. Complications may include serotonin syndrome.Lithium toxicity can occur due to excessive intake or decreased excretion. Excessive intake may be either a suicide attempt or accidental. Decreased excretion may occur as a result of dehydration such as from vomiting or diarrhea, a low sodium diet, or from kidney problems. The diagnosis is generally based on symptoms and supported by a lithium level of greater than 1.2 mEq/L.Gastric lavage and whole bowel irrigation may be useful if done early. Activated charcoal is not effective. For severe toxicity hemodialysis is recommended. The risk of death is generally low. Acute toxicity generally has better outcomes than chronic toxicity. In the United States about 5,000 cases are reported to poison control centers a year. Lithium toxicity was first described in 1898.

Signs and symptoms
Symptoms of lithium toxicity can be mild, moderate, or severe.Mild symptoms include nausea, feeling tired, and tremor occur at a level of 1.5 to 2.5 mEq/L. Moderate symptoms include confusion, an increased heart rate, and low muscle tone occur at a level of 2.5 to 3.5 mEq/L. Severe symptoms include coma, seizures, low blood pressure and increased body temperature which occur at a lithium concentration greater than 3.5 mEq/L. When lithium overdoses produce neurological deficits or cardiac toxicity, the symptoms are considered serious and can be fatal.

Acute toxicity
In acute toxicity, people have primarily gastrointestinal symptoms such as vomiting and diarrhea, which may result in volume depletion. During acute toxicity, lithium distributes later into the central nervous system causing dizziness and other mild neurological symptoms.

Chronic toxicity
In chronic toxicity, people have primarily neurological symptoms which include nystagmus, tremor, hyperreflexia, ataxia, and change in mental status. During chronic toxicity, the gastrointestinal symptoms seen in acute toxicity are less prominent. The symptoms are often vague and nonspecific.

Acute on chronic toxicity
In acute on chronic toxicity, people have symptoms of both acute and chronic toxicity.

Complications
People who survive an intoxication episode may develop persistent health problems. This group of persistent health symptoms are called syndrome of irreversible lithium-effectuated neurotoxicity (SILENT). The syndrome presents with irreversible neurological and neuro-psychiatric effects. The neurological signs are cerebellar dysfunction, extrapyramidal symptoms, and brainstem dysfunction. The neuro-psychiatric findings present with memory deficits,  cognitive deficits, and sub-cortical dementia. For a diagnosis, the syndrome requires the absence of prior symptoms and persistence of symptoms for greater than 2 months after cessation of lithium.

Pathophysiology
Lithium is readily absorbed from the gastrointestinal tract. It is distributed to the body with higher levels in the kidney, thyroid, and bone as compared to other tissues. Since lithium is almost exclusively excreted by the kidneys, people with preexisting chronic kidney disease are at high risk of developing lithium intoxication. The drug itself is also known to be nephrotoxic, opening up the possibility of spontaneous emergence of toxicity at doses that were previously well-tolerated. Lithium toxicity can be mistaken for other syndromes associated with antipsychotic use, such as serotonin syndrome because lithium increases serotonin metabolites in the cerebrospinal fluid.There are several drug interactions with lithium. Interactions can occur from typical antipsychotics or atypical antipsychotics. In particular, certain drugs enhance lithium levels by increasing renal re-absorption at the proximal tubule. These drugs are angiotensin-converting enzyme inhibitors, non-steroidal anti-inflammatory drugs and thiazide diuretics.

Diagnosis
The diagnosis is generally based on symptoms and supported by a lithium level blood level. Blood levels are most useful six to twelve hours after the last dose. The normal serum lithium level in those on treatment is between 0.6-1.2 mEq/L </s>