<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Monkeypox and can you explain it in depth? [/INST] Monkeypox is an infectious viral disease that can occur in humans and some other animals. Symptoms include fever, swollen lymph nodes, and a rash that forms blisters and then crusts over. The time from exposure to onset of symptoms ranges from five to twenty-one days. The duration of symptoms is typically two to four weeks. There may be mild symptoms, and it may occur without any symptoms being known. The classic presentation of fever and muscle pains, followed by  swollen glands, with lesions all at the same stage, has not been found to be common to all outbreaks. Cases may be severe, especially in children, pregnant women or people with suppressed immune systems.The disease is caused by the monkeypox virus, a zoonotic virus in the genus Orthopoxvirus. The variola virus, the causative agent of smallpox, is also in this genus. Of the two types in humans, clade II (formerly West African clade) causes a less severe disease than the Central African (Congo basin) type. It may spread from infected animals by handling infected meat or via bites or scratches. Human-to-human transmission can occur through exposure to infected body fluids or contaminated objects, by small droplets, and possibly through the airborne route. People can spread the virus from the onset of symptoms until all the lesions have scabbed and fallen off; with some evidence of spread for more than a week after lesions have crusted. Diagnosis can be confirmed by testing a lesion for the viruss DNA.There is no known cure. A study in 1988 found that the smallpox vaccine was around 85% protective in preventing infection in close contacts and in lessening the severity of the disease. A newer smallpox and monkeypox vaccine based on modified vaccinia Ankara has been approved, but with limited availability. Other measures include regular hand washing and avoiding sick people and animals. Antiviral drugs, cidofovir and tecovirimat, vaccinia immune globulin and the smallpox vaccine may be used during outbreaks. The illness is usually mild and most of those infected will recover within a few weeks without treatment. Estimates of the risk of death vary from 1% to 10%, although few deaths as a consequence of monkeypox have been recorded since 2017.Several species of mammals are suspected to act as a natural reservoir of the virus. Although it was once thought to be uncommon in humans, the quantity and severity of outbreaks has significantly increased since the 1980s, possibly as a result of waning immunity since the stopping of routine smallpox vaccination. The first cases in humans were found in 1970 in the Democratic Republic of the Congo (DRC). There have been sporadic cases  in Central and West Africa, and it is endemic in the DRC.   The 2022 monkeypox outbreak represents the first incidence of widespread community transmission outside of Africa, which was initially identified in the United Kingdom in May 2022, with subsequent cases confirmed in at least 74 countries in all continents except Antarctica. On 23 July 2022, the World Health Organization (WHO) declared the outbreak a Public Health Emergency of International Concern (PHEIC) with more than 53,000 reported cases in 75 countries and territories.

Signs and symptoms
It is possible for a person to be infected with monkeypox without showing any symptoms. Monkeypox symptoms tend to begin 5 to 21 days after infection, with early symptoms including headache, muscle pains, fever and fatigue, initially resembling influenza. Within a few days of the fever, lesions characteristically appear on the face before appearing on the trunk then elsewhere such as palms of the hands and soles of the feet. The disease can resemble chickenpox, measles and smallpox but is distinguished by the presence of swollen glands which may appear behind the ear, below the jaw, in the neck or in the groin, before the onset of the rash. Many cases in the 2022 monkeypox outbreak presented with genital and peri-anal lesions, fever, swollen lymph nodes, and pain when swallowing, with  some patients manifesting only single sores from the disease.Three-quarters of affected people have lesions on the palms and soles, more than two-thirds in the mouth, a third on the genitals and one in five have lesions in the eyes. They begin as small flat spots, before becoming small bumps which then fill with at first clear fluid and then yellow fluid, which subsequently burst and scab over, persisting for around ten days. There may be a few lesions or several thousand, sometimes merging to produce large lesions. After healing, the lesions may leave pale marks before becoming dark scars.An unwell person may remain so for two to four weeks.

Complications
Complications include secondary infections, pneumonia, sepsis, encephalitis, and loss of vision with severe eye infection. If infection occurs during pregnancy, still birth or birth defects may occur. The disease may be milder in people vaccinated against smallpox in childhood. Patel and colleagues, in the BMJ, demonstrate that this virus can produce severe symptoms, particularly in HIV-positive people. The  descriptive case series reveal that symptoms can be so severe that hospitalization is required in 10% of cases. The study also shows that 75% of patients (15 out of 20 participants) admitted to the hospital were HIV-positive individuals. Overall, the study depict a new variety of clinical manifestations including proctitis and rectal perforation. The pictures of genital lesions published in the BMJ show the severity of monkeypox, which is often described as causing moderate symptoms.

In other animals
The disease has also been reported in dormice, tree squirrels, rope squirrels and non human primates. Rodents such as rats and mice are likely susceptible but not known.
Signs and symptoms in animals vary among different species. Monkeypox infected Gambian pouched rats may have mild symptoms. During the 2003 US outbreak, affected prairie dogs presented with fever, cough, sore eyes, poor feeding and rash. Non-human primates present similarly. They may have breathing problems, facial swelling, mouth ulcers and swollen glands. In cynomolgus monkeys, the time from exposure to symptoms was noted to be around a week. Rabbits and rodents typically present with fever, cough, runny nose, sore eyes and swollen glands. They develop small bumps that fill with yellow fluid and may have patches of hair loss and pneumonia.
Spread among animals occurs via the fecal-oral route and through the nose, through wounds and eating infected meat. Death is more likely in baby monkeys. The CDC recommend that animals exposed to monkeypox be quarantined for six weeks.

Causes
Monkeypox in both humans and animals is caused by infection with the monkeypox virus – a double-stranded DNA virus in the genus Orthopoxvirus, family Poxviridae. The virus was first identified in captive monkeys and is found mainly in tropical rainforest regions of Central and West Africa. The two subtypes of virus are clade I and clade II (formerly Congo Basin and West African clades, matching the geographical areas).In addition to monkeys, the virus has been identified in Gambian pouched rats (Cricetomys gambianus), dormice (Graphiurus spp.) and African squirrels (Heliosciurus, and Funisciurus). The use of these animals as food may be an important source of transmission to humans.

Transmission
Humans can be infected by an animal via a bite or scratch, bush meat preparation, or by contact with an infected animal’s bodily fluids or lesion material. The virus is thought to enter the body through broken skin, the respiratory tract, or the mucous membranes of the eyes, nose, or mouth.Once a human is infected, transmission to other humans is common, with family members and hospital staff at particularly high risk of infection. The virus can spread by respiratory (airborne) contact or by direct contact with an infected persons bodily fluids  or during pregnancy from mother to fetus. There are indications that transmission can occur during sexual contact, with infectious monkeypox virus able to be isolated from semen samples. Prolonged shedding in seminal fluids has raised the possibility of a genital reservoir for monkeypox virus. It is not known if the virus can spread through vaginal fluids.The virus can also spread via fomites or through indirect contact with lesion material, such as through contaminated bedding, even with standard personal protective equipment, likely through inhalation. Risk factors for transmission include sharing a bed or room, or using the same utensils as an infected person. Increased transmission risk is associated with factors involving the introduction of virus to the oral mucosa. It is not yet known if people without symptoms of monkeypox can spread the virus.Further research about the transmission of the strain responsible for the 2022 outbreak is ongoing, but it is not thought to be different from other strains of the clade II.

People living with HIV
According to a CDC report, 41% of cases of monkeypox were among HIV-positive patients (136 out of 334 patients) between May and July 2022. The New England Journal of Medicine (NEJM) also looked at more than 500 cases from different countries and found that 41% of them were among HIV patients. In addition, a study published in The Lancet that looked at nearly 200 cases in Barcelona and Madrid discovered that 40% were HIV-positive.  Patel and colleagues observed 197 patients from sexual health centres in south London between May and July 2022. They reported 35.5% patients had HIV-1 co-infection. 91.4% of these participants were receiving antiretroviral therapy and 78.6% had an undetectable HIV-1 viral load (<200 copies). The median CD4 count was 664 cells (interquartile range 522-894 cells). The proportion of HIV-positive individuals in these reports is significantly higher than the HIV rate among men who have sex with other men. The reasons for this heavy overrepresentation of men living with HIV among monkeypox cases are not fully understood yet.

Diagnosis
Clinical differential diagnosis must consider other rash illnesses, such as chickenpox, measles, bacterial skin infections, scabies, syphilis and medication-associated allergies. Lymphadenopathy during the prodromal stage of illness can distinguish monkeypox from chickenpox or smallpox. Diagnosis can be verified by testing for the virus.Polymerase chain reaction (PCR) testing of samples from skin lesions is the preferred laboratory test. PCR blood tests are usually inconclusive because the virus remains in blood only a short time. To interpret test results, information is required on date of onset of fever, date of onset of rash, date of specimen collection, current stage of rash, and patient age.

Prevention
Vaccination against smallpox is assumed to protect against human monkeypox infection because they are closely related viruses, and the vaccine protects animals from experimental lethal monkeypox challenges. This has not been conclusively demonstrated in humans because routine smallpox vaccination was discontinued following the eradication of smallpox.Smallpox vaccine has been reported to reduce the risk of monkeypox among previously vaccinated persons in Africa. The decrease in immunity to poxviruses in exposed populations is a factor in the prevalence of monkeypox. It is attributed to waning cross-protective immunity among those vaccinated before 1980, when mass smallpox vaccinations were discontinued, and to the gradually increasing proportion of unvaccinated individuals.The United States Centers for Disease Control and Prevention (CDC) recommends that persons investigating monkeypox outbreaks and involved in caring for infected individuals or animals should receive a smallpox vaccination to protect against monkeypox. Persons who have had close or intimate contact with individuals or animals confirmed to have monkeypox should also be vaccinated. However, the CDC does not recommend pre-exposure vaccination for unexposed veterinarians, veterinary staff, or animal control officers, unless such persons are involved in field investigations. No smallpox or monkeypox vaccine has been approved for use during pregnancy. The CDC recommends that healthcare providers don a full set of personal protective equipment (PPE) before caring for an infected person. This includes a gown, mask, goggles, and a disposable filtering respirator (such as an N95). An infected person should be isolated in preferably a negative air pressure room or at least a private exam room to keep others from possible contact.Monkeypox prevention cannot be simplified to just providing a vaccine. There are more pressing challenges to address, such as access to treatment, veracity and availability of information, and quality of health care. Public health messaging is perhaps the most important challenge. The multiple levels of interconnectivity and negotiated social meanings inherent to the disease require cooperation between medical professionals and patients to achieve correct public health communication. Therefore, Scalvini argues in the BMJ that it is necessary a "new ethic of shared responsibility" to educate people about dangers and give people from underprivileged groups the tools they need to make better decisions.

Treatment
In the European Union and the United States, tecovirimat is approved for the treatment of several poxviruses, including monkeypox. BMJ Best Practice recommends tecovirimat or the smallpox treatment brincidofovir as the first line antiviral treatment if required, alongside supportive care (including antipyretic, fluid balance and oxygenation). Empirical antibiotic therapy or aciclovir may be used if secondary bacterial or varicella zoster infection is suspected, respectively.

Outcome
After healing, the scabs may leave pale marks before becoming darker scars. The risk of death in those infected ranges from 0% to 11%, depending on the type of monkeypox and location in the world. Fatality rates have been reported as around 3.6% in West Africa and 10.6% in Central Africa. Most reported deaths have occurred in young children and people with HIV infection.

Epidemiology
In 1970, monkeypox was first associated with an illness as a disease in humans in the Democratic Republic of the Congo (formerly Zaire), in the town of Basankusu, Équateur Province.
Although it was once thought to be uncommon in humans, cases increased since the 1980s, possibly as a result of waning immunity since the stopping of routine smallpox vaccination.Between 1981 and 1986  WHO surveillance in DRC/Zaire recorded 338 confirmed cases and 33 deaths (CFR 9.8%). In 1996–1997, a second outbreak of human illness was identified in DRC/Zaire and between 1991 and 1999, 511 cases were reported in DRC/Zaire. Clade I of disease remains endemic in DRC and has a higher CFR than the other genetic clade in Western Africa.By May 2022, the case fatality rate (CFR) of past outbreaks was around 3%–6%, while the CFR of the 2022 outbreak remains below 1%. No human-to-human transmission was documented until the 2022 monkeypox outbreak in Europe. Clade II had an outbreak – the first outbreak of monkeypox outside of Africa – in Midwestern United States among owners of pet prairie dogs in 2003. Seventy-one people were reportedly infected, of whom none died.As of 2018, monkeypox was traditionally restricted to the ecology of tropical rainforests. although the pattern was broken in 2005, when 49 cases were reported in Sudan (areas now South Sudan), with no fatalities. The genetic analysis suggested that the virus did not originate in Sudan but was imported, most likely from DRC.Many more monkeypox cases have been reported in Central and West Africa, and in the Democratic Republic of Congo in particular: 2000 cases per year are known between 2011 and 2014. The collected data is often incomplete and unconfirmed, which hinders realistic estimations of the number of cases of monkeypox over time. Nevertheless, it was suggested that the number of reported monkeypox cases had increased and the geographical occurrence broadened as of 2018.

2003 U.S. outbreak
In May 2003, a young child became ill with fever and rash after being bitten by a prairie dog purchased at a local swap meet near Milwaukee, Wisconsin. In total, 71 cases of monkeypox were reported through June 20, 2003. All cases were traced to Gambian pouched rats imported from Accra, Ghana, in April 2003 by a Texas exotic animal distributor. No deaths resulted. Electron microscopy and serologic studies were used to confirm that the disease was human monkeypox.People with monkeypox typically experienced prodromal symptoms of fever, headaches, muscle aches, chills, and drenching sweats. Roughly one-third of infected people had nonproductive coughs. This prodromal phase was followed 1–10 days later by the development of a papular rash that typically progressed through stages of vesiculation, pustulation, umbilication, and crusting. In some people, early lesions had become ulcerated.Rash distribution and lesions occurred on head, trunk, and extremities. Many of the people had initial and satellite lesions on palms, soles, and extremities. Rashes were generalized in some people. After onset of the rash, people generally manifested rash lesions in different stages. Everyone affected reported direct or close contact with prairie dogs, later found to be infected with the monkeypox virus.

2017–2019 Nigeria outbreak
According to the Nigeria Centre for Disease Control (NCDC), between 1971 and 1978, only 10 human monkeypox infections were reported in the country.In September 2017, human monkeypox re-emerged in Nigeria, 39 years since it had been last reported. The subsequent 2017–18 Nigerian human monkeypox outbreak was, at that time, the largest ever outbreak of clade II of the virus, with 118 confirmed cases. Unlike previous outbreaks of this clade, infection was predominantly among young male adults and human-to-human transmission appears to have readily occurred. Seven deaths (5 male, 2 female, case fatality rate of 6%) were reported, including a baby and four HIV/AIDS patients. Additionally, a pregnant woman in her second trimester had a spontaneous miscarriage due to monkeypox infection.The Niger Delta University Teaching Hospital reported that a substantial number of its young adult cases had concomitant genital ulcers, syphilis and HIV infection.
Monkeypox spread around southeast and south Nigeria with some states and the federal government of Nigeria seeking ways to contain it. By December 2017 it spread to Akwa Ibom, Abia, Bayelsa, Benue, Cross River, Delta, Edo, Ekiti, Enugu, Imo, Lagos, Nasarawa, Oyo, Plateau, Rivers and Federal Capital Territory. The outbreak started in September 2017 and remained ongoing across multiple states as of May 2019.
The Centers for Disease Control and Prevention reported cases of American travelers contracting Monkeypox upon return from Lagos and Ibadan. Agam Rao, a medical officer in the Division of Pathogens and High Consequence Pathology at the CDC, said that since 2018 all cases reported outside Africa have come from Nigeria.In a 2021 article Oyewale Tomori pointed out that the number of monkeypox infections in Nigeria through 2021 was likely to be under-represented, because much of the Nigerian population had been avoiding healthcare facilities due to fear of contracting COVID-19.In May 2022, the Nigerian government released a report stating that between 2017 and 2022, 558 cases were confirmed across 32 states and the Federal Capital Territory. The Rivers State was the most affected by monkeypox followed by Bayelsa and Lagos. There were 8 deaths reported, making for a 3.5% Case Fatality Ratio. In 2022, NCDC implemented a National Technical Working Group for reporting and monitoring infections, strengthening response capacity.

2018 and 2019 United Kingdom cases
In September 2018, the United Kingdoms first case of monkeypox was recorded. The person, a Nigerian national, is believed to have contracted monkeypox in Nigeria before travelling to the United Kingdom. According to Public Health England, the person was staying in a naval base in Cornwall before being moved to the Royal Free Hospitals specialised infectious disease unit. People who had been in contact with the person since he contracted the disease were contacted.A second case was confirmed in the town of Blackpool, with a further case that of a medical worker who cared for the case from Blackpool. A fourth case occurred on 3 December 2019, when monkeypox was diagnosed in a person in south west England. They were travelling to the UK from Nigeria.

2019 Singapore case
On 8 May 2019, a 38-year-old man who travelled from Nigeria was hospitalised in an isolation ward at the National Centre for Infectious Diseases in Singapore, after being confirmed as the countrys first case of monkeypox. As a result, 22 people were quarantined. The case may have been linked to a simultaneous outbreak in Nigeria.

2021 cases in United Kingdom, United States
On 24 May in the UK, three cases of monkeypox from a single household were identified by Public Health Wales. The cases were also announced by Health Secretary Matt Hancock while addressing MPs. The index case was diagnosed on 24 May after traveling from Nigeria. The second case was reported on 2 June, and the third on 24 June. One of the three patients, an adult female, was treated with tecovirimat. On day 7 of tecovirimat, she was discharged from hospital to complete her second week of treatment at home.On 14 July in the US, an American returning from a trip in Nigeria was diagnosed with monkeypox. Subsequent testing identified the virus as belonging to clade II. The patient was hospitalized and treated with tecovirimat and was discharged after 32 days, at which time monkeypox virus DNA could no longer be detected in residual skin lesions.

2022 outbreak
History
Monkeypox was first identified as a distinct illness in 1958 among laboratory monkeys in Copenhagen, Denmark.
The first documented cases in humans was in 1970, in six unvaccinated children during the smallpox eradication efforts; the first being a 9-month old boy in the Democratic Republic of the Congo (formerly Zaire). The others, including three who were playmates, were in Liberia and Sierra Leone. It was noted to be less easily transmissible than smallpox. From 1981 to 1986, over 300 cases of human monkeypox were reported in the DRC, the majority being due to contact with animals. In 1996, the disease reemerged in the DRC with 88% of cases resulting from human-to-human transmission. Small viral outbreaks with a death rate in the range of 10% and a secondary human-to-human infection rate of about the same amount occur routinely in equatorial Central and West Africa </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Macrophagic myofasciitis and can you explain it in depth? [/INST] Macrophagic myofasciitis (MMF) is a histopathological finding involving inflammatory microphage formations with aluminium-containing crystal inclusions and associated microscopic muscle necrosis in biopsy samples of the deltoid muscle. Based on the presence of aluminium and the common practice of administering vaccines into the deltoid, it has been proposed that the abnormalities are a result of immunisation with aluminium adjuvant-containing vaccines. The findings were observed in a minority of persons being evaluated for "diffuse myalgias, arthralgias or muscle weakness" who underwent deltoid muscle biopsies. The individuals had a history of receiving aluminium-containing vaccines, administered months to several years prior to observation of MMF histopathology, however this link is tenuous and unsustainable </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Tonsil carcinoma and can you explain it in depth? [/INST] Carcinoma of the tonsil is a type of squamous cell carcinoma. The tonsil is the most common site of squamous cell carcinoma in the oropharynx. It comprises 23.1% of all malignancies of the oropharynx. The tumors frequently present at advanced stages, and around 70% of patients present with metastasis to the cervical lymph nodes.
. The most reported complaints include sore throat, otalgia or dysphagia. Some patients may complain of feeling the presence of a lump in the throat. Approximately 20% patients present with a node in the neck as the only symptom.Main risk factors of developing carcinoma tonsil include tobacco smoking and regular intake of high amount of alcohol. It has also been linked to human papilloma virus (HPV type HPV16). Other risk factors include poor maintenance of oral hygiene, a genetic predisposition leading to inclination towards development of throat cancer, immunocompromised states (such as post solid-organ transplant), and chronic exposure to agents such as asbestos and perchloroethylene in certain occupations, radiation therapy and dietary factors.

Signs and symptoms
The early lesions are usually asymptomatic. The patients presenting with an advanced stage of the disease comprises around 66–77% of the cases.
The most important signs include a lump in the neck when palpated and weight loss.
People may also present with fatigue as a symptom.The primary tumor does not have readily discernible signs or symptoms as they grow within the tonsillar capsule. It is difficult to notice anything suspicious on examination of the tonsil other than slight enlargement or the development of firmness around the area.
The carcinoma may occur in one or more sites deep within the tonsillar crypts. It may be accompanied by the enlargement of the tonsil. The affected tonsil grows into the oropharyngeal space making it noticeable by the patient in the form of a neck mass mostly in the jugulodigastric region.
As the tonsils consist of a rich network of lymphatics, the carcinoma may metastasize to the neck lymph nodes which many are cystic.
Extension of tumor to skull or mediastinum can occur.
The additional symptoms include a painful throat, dysphagia, otalgia (due to cranial nerve involvement), foreign body sensation, bleeding, fixation of tongue (infiltration of deep muscles) and trismus (if the pterygoid muscle is involved in the parapharyngeal space).On the other hand, the tumor may also present as a deep red or white fungating wound growing outwards, breaking the skin surface with a central ulceration. This wound-like ulcer fails to heal (non-healing) leading to bleeding and throat pain and other associated symptoms.During biopsy, the lesion may show three signs: gritty texture, firmness and cystification owing to keratinization, fibrosis and necrosis respectively.Cervical lymphydenopathy may be present.

Cause
Smoking and alcohol abuse are the major risk factors. Viral causes have recently been taken under consideration as one of the risk factors. Viruses such as Epstein-Barr virus (EBV) (majorly involved in causing nasopharyngeal carcinoma) and human papilloma virus are included in this category. Chewing of betel nut (Areca catechu) quid has been directly associated to cause oral cancers. It has also been stated under the FDA poisonous plant data base by the U.S Food and Drug Administration
An unbalanced diet, deficit in fruits and vegetables has shown to increase the risk of cancer.

Pathophysiology
Metastasis to regional lymphnodes is common as the tonsil has a rich supply of lymphatics giving way to the tumor cells to metastasis to other lymph nodes (commonly the lymph nodes of neck) and cause lymphydenopathy. The cervical lyphydenopathy can be ipsilateral (70% or more patients) or bilateral (30% and fewer patients). The carcinoma of tonsil usually spreads through the cervical lymph node levels II, III, IV, V, and retropharyngeal lymph nodes.The fourth edition of WHO s classification of head and neck tumors subdivides squamous cell carcinoma of the tonsil into two types: HPV positive or negative. HPV positive tumors arise from the deep lymphoid tissue of the tonsillar crypts and are non-keratinizing. On the other hand HPV negative tumors develop from the tonsillar surface epithelium and hence have keratinizing dysplasia.

Routes of metastasis
Metastasis is common in tonsillar carcinoma. It largely depends on the stage of the cancer and the route through with the cancer cells metastasize.
The cancer cells may spread to adjacent structures, to lymphatics or to distant locations in the body producing secondary tumors.

Local
The tumor may spread locally to soft palate and pillars, base of tongue, pharyngeal wall and hypopharynx. It may invade pterygoid muscles and mandible, resulting in pain and trismus. Parapharyngeal space may also get invaded.

Lymphatic
50% of patients have initial cervical node involvement at the time of presentation. Jugulardigastric nodes are the first to be involved.

Distant metastasis
The occurrence of distant metastasis varies extensively, ranging between 4–31% in clinical studies.
Factors influencing the incidence of distant metastasis are:
Location of primary tumor.
Initial staging
Histological differentiation
Loco-regional control of the primary tumor.The records of 471 male patients with tonsillar carcinoma seen at the Veterans Administration Medical Center, Hines, Illinois, have been reviewed to establish the incidence and site of distant metastasis. All the patients were histological diagnosed and proven cases of tonsillar carcinoma. 72 (15%) out of 471 patients and 33 (29%) of 155 autopsied patients were reported to have distant metastasis.
Squamous cell carcinoma was the most common reported cell type (88%); cases with Lymphoepithelioma had the highest incidence of distant metastasis. The most common anatomical sites of incidence of distant metastasis include lung, liver and bones.
Thorough investigation of these organs is highly recommended before treatment as well as during follow ups.

Diagnosis
The first step to diagnosing tonsil carcinoma is to obtain an accurate history from the patient. The physician will also examine the patient for any indicative physical signs. A few tests then, maybe conducted depending on the progress of the disease or if the doctor feels the need for. The tests include:
Fine needle aspiration, blood tests, MRI, x-rays and PET scan.

Staging
The staging of a tumor mass is based on TNM staging.T staging is the based on the tumor mass. The N staging is based on the extent of spread of cancer to the lymph nodes. Finally, the M stage indicates if the cancer has spread beyond the head and neck or not.

T Staging
The basis of deciding the T stage depends on physical examination and imaging of the tumor.

N staging
This stage is decided through the assessment of the lymph nodes.

M staging
Based on the examination of the entire body.

FInally, the stage is decided by concluding the above results and referring the following chart:

Treatment
The treatment for tonsil carcinoma includes the following methods:

Radiotherapy
Early radio-sensitive tumors are treated by radiotherapy along with irradiation of cervical nodes. The radiation uses high-energy X-rays, electron beams, or radioactive isotopes to destroy cancer cells.

Chemotherapy
Induction chemotherapy is the treatment adapted for shrinking the tonsil tumor. It is given prior to other treatments, hence, the term induction. After the therapy is completed, the patient is asked to rest and is evaluated over a period of time. Then the patient is given chemo-radiation therapy (a combination of chemotherapy and radiation) to completely destroy the tumor cells.

Surgery
If radiation and chemotherapy are unable to destroy the tumor, surgical intervention is considered. Excision of the tonsil can be done for early superficial lesions. Large lesions and those which invade bone require wide surgical excision with hemimandibulectomy and neck dissection (Commando operation)

Combination therapy
Surgery may be combined with pre- or post operative radiation.
Chemotherapy may be given as an adjunct to surgery or radiation.

Prognosis
Prognosis is determined by various factors such as stage, Human Papilloma Virus (HPV) status, Lymph infiltration of cancer cells, spread of cancer cells beyond the lymph node capsule, margins of the tumor and the extent of metastasis.
Many factors are unique to each individual patient and may affect the chances of success of the treatment.
Factors determining the prognosis of tonsillar carcinoma are as follows:

HPV status
Tonsillar carcinoma can be either HPV related or HPV unrelated. It is shown that cases which are HPV positive have a better prognosis than those with HPV negative oropharyngeal cancer.

Stage
The stage at which the cancer presents itself affects the type of definitive treatment, chance of cure, recurrence of cancer and survival rate of the patient. Generally the patient presents very late due to the lack of definitive symptoms in the early stages of the disease. Nearly three fourths of the patients present in Stage III or later.The stages of oropharyngeal cancer are as follows:
• Stage 0 (carcinoma in situ): This stage indicates a good prognosis as most patients with stage 0 survive for a long period without the requirement of an intensive treatment. Although, the patient must cease smoking as it can increase the risk of developing a new cancer.• Stage I and II: Most patients presenting at this stage receive successful treatment, showing a good prognosis. The modes of treatment for this stage include chemotherapy, surgery, radiation therapy or chemoradiation. The main treatment at this stage is radiation, targeting the tumor and the cervical lymph nodes. Surgical removal of the tumor and lymphadenectomy of the cervical (neck) lymph nodes can also be taken up at the main treatment method instead of radiation. And remaining cancer cells post surgery are treated with chemoradiation.• Stage III and IVA: In this stage the cancer cells metastasize into the local tissues and cervical lymph nodes. The treatment used in these cases is chemo radiation </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Rheumatoid arthritis and can you explain it in depth? [/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 responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Black hairy tongue and can you explain it in depth? [/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 responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Ganglioneuroma and can you explain it in depth? [/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>