Disease: Juvenile Idiopathic Arthritis (Arthritis in Childhood, Juvenile Rheumatoid Arthritis, Juvenile Chronic Arthritis)

    Juvenile idiopathic arthritis (JIA) facts

    • Epidemiologic studies estimate that approximately 294,000 American children are affected by JIA.
    • Children of European ancestry are more likely to develop the condition while those of Japanese and Filipino background are less likely.
    • When considering the manifestation options of JIA, those children with European background are more likely to experience the oligoarticular version of JIA (see below) while those of African-American heritage are more likely have the rheumatoid factor (RF) positive, polyarticular juvenile idiopathic arthritis version (see below).
    • Among Caucasian children developing oligoarticular JIA, younger girls (2-4 years of age) are the most commonly affected.
    • The various epidemiologic patterns provide strong evidence of genetic influences for both the development of JIA as well as the clinical manifestations that may affect a child.

    What is juvenile idiopathic arthritis?

    Juvenile idiopathic arthritis (JIA) is the umbrella term under which several forms of chronic arthritis in children are categorized. Regardless of type, all of these conditions have several historical and/or clinical characteristics in common. One or more joints must demonstrate evidence of inflammation characterized by swelling of the joint area, limitation in the range of motion of the involved joint(s), tenderness when the joint is moved, and increased warmth of the joint region. These symptoms must be present (even intermittently) for at least six weeks and affect a child less than 16 years of age.

    JIA is the most frequent chronic rheumatologic disease of childhood, and the cause(s) are not well understood. Both environmental and genetic influences are felt to contribute to the development of signs and symptoms of JIA. Knowledgeable specialists (pediatric rheumatologists usually affiliated with pediatric teaching hospitals) can help to limit the possibility of complications of juvenile idiopathic arthritis including leg-length discrepancy, joint contractures, and destruction and blindness due to inflammation of the eye (iritis).

    Until the late 1990s, JIA was known in the U.S. as JRA (juvenile rheumatoid arthritis) and JCA (juvenile chronic arthritis) in Europe. The revised name was devised in order to better distinguish the childhood disease from rheumatoid arthritis (RA) that affects adults. This new nomenclature has enabled the categorization of six JIA subtypes. This updated classification has helped to foster better communication among those doing research on causation, clinical manifestations, and therapy of JIA.

    JIA is considered a diagnosis of exclusion; the diagnosis can only be confidently made when (1) the patient's history, physical exam, and laboratory findings are consistent with those described in the literature by the International League of Associations for Rheumatology and (2) other conditions have been excluded. These include infection, malignancy, trauma, reactive arthritis, immunodeficiency, and connective tissue/rheumatologic diseases (for example, systemic lupus erythematosus).

    What are causes and risk factors of juvenile idiopathic arthritis?

    While no specific cause(s) of JIA have been determined, there is strong evidence of both genetic and environmental factors being implicated in the development of the disease. Studies of the frequency of JIA have shown that if one identical twin develops the disease that the likelihood of their identical sibling developing JIA is 25%-40%. Studies of nonidentical siblings show evidence that if one child develops JIA there is a 15 to 30 times increased risk that a sibling will develop the condition when compared to the general pediatric population.

    The biologic and clinical manifestations of JIA provide strong evidence that a general theme of an immune system misdirection is evident. The immune system has two "arms" -- the cell based (lymphocytes, etc.) and humeral based (antibodies). Rheumatologists have demonstrated that both of these elements of the immune system react against the patient's own body structures (joints, muscles, eye tissues, etc.). Much research is currently focused in an effort to better understand this autoinflammatory process in the hope that understanding the cause of JIA will enable better and more effective treatments and ultimately a cure for the condition.

    What are juvenile idiopathic arthritis symptoms and signs, and how are the different types of juvenile idiopathic arthritis diagnosed?

    The International League of Associations of Rheumatology has classified JIA into six distinct patterns that vary by clinical presentation and evolution of symptoms, laboratory implications, potential complications, and therapeutic options. While some similarities exist among these diseases, the uniqueness of each manifestation of JIA is strong enough to justify the breakdown into the six patterns. One characteristic common to all six forms of JIA is that of "morning stiffness" that improves during the day as more movement is done. Likewise, spontaneous patterns of worsening and lessening of symptoms (which may be independent of therapy) is characteristic.

    1. Systemic onset JIA: By definition, systemic onset JIA must have arthritis (swelling, pain, and warmth) of one or more joints associated with a minimum of two weeks of daily spiking fevers. The fever is often greater than 102 F (39 C) and usually spikes once or twice a day and may have the unique pattern of returning to below normal between rises. In addition, a characteristic intermittent salmon-colored rash, enlargement of lymph nodes, liver, and spleen, inflammation of the lungs, pericardium (the "sack" surrounding the heart), and other organs may occur. During febrile episodes, children appear moderately sick, but with resolution of fever they are much improved. Systemic onset JIA affects approximately 10%-15% all children suffering from JIA. There is no gender preference (the frequency in boys and girls is equal), with symptoms generally starting between 3-5 years of age. There is no unique laboratory test for JIA, but children typically have anemia and elevation of white blood cell and platelet counts, as well as alterations of general markers of inflammation. Complications of systemic onset JIA may include slower than expected growth, weakening of bones, abnormalities of liver and lung function, and consequences of therapy (see below). The prognosis is generally noted to depend upon the severity of arthritis with many/most of the systemic symptoms resolving over months to years. The low mortality rate (<0.3% in North America) is reassuring. Since the diagnosis of systemic onset of JIA is one of exclusion, the possibility of infection, malignancy, collagen vascular disease, and rheumatic fever are also considered.

    2. Oligoarticular JIA: Oligoarticular is defined as arthritis that affects four or fewer joints in the first six months of the disease. This form of JIA accounts for about 50% of all cases of pediatric chronic arthritis and may be subdivided into two groups. One group consists of those children who continue throughout the entire course of their disease having four or fewer joints involved. The other group eventually develops greater than four-joint involvement after the first six months of illness. The onset of disease is between 2-4 years of age with a female gender bias of approximately 3:1. Children with oligoarticular JIA most commonly have a single large joint (knee in approximately 90% of cases) involvement. Symptoms of joint pain and tenderness are worse in the morning in association with the previously described morning stiffness (see systemic onset JIA). The primary complication of oligoarticular JIA is inflammation of the iris (the colored region of the eye). Iritis is found in approximately 15%-20% with this form of JIA and is often without symptoms. Complications of iritis may include clouding of the cornea (cataracts), glaucoma, and visual loss. Since outcome is linked to early diagnosis, it is imperative an ophthalmologist evaluate children with oligoarticular JIA every three to four months. Conditions that should be eliminated prior to establishing a diagnosis of oligoarticular JIA include trauma, infection, malignancy, and arthritis following an infection.

    3. Polyarticular juvenile idiopathic arthritis: Children who have five or more joints involved with arthritis during the first six months of their disease are classified into the polyarticular JIA form of illness. Two subgroups of polyarticular JIA exist based upon a constellation of various laboratory studies. One group (rheumatoid factor "RF" positive) affects between 5%-10% of all patients with JIA. Late childhood through young teenage girls are the most likely to develop this pattern. Generally, small joints (such as the hands and feet) tend to be involved, and a more aggressive course has been observed. "RF negative" polyarticular JIA affected individuals tend to have a milder course and thus a better outcome. Fatigue, anemia, suboptimal growth, and iritis (to a lesser degree than oligoarticular JIA) are complications. Other conditions that must be considered and eliminated prior to establishing the diagnosis of polyarticular JIA include infection, malignancy, and collagen vascular disease (including systemic lupus erythematosus).

    4. Psoriatic arthritis (PsA): Establishing the diagnosis of psoriatic arthritis involves demonstration of both large and small joint arthritis and a characteristic rash (psoriasis). Should the rash not be present, two of the following must exist: (a) family history of psoriasis in an immediate family member, (b) diffuse swelling of the fingers, and (c) pitting of the nails. Children with psoriatic arthritis may also develop iritis and should have ophthalmologic evaluation every six months.

    5. Enthesitis-related arthritis (ERA): Enthesitis (inflammation at the site of tendon insertion on the bone) most profoundly affects males over 8 years of age and often involves the lower back, sacroiliac joints, and joints of the legs, ankles, and feet. Patients with a particular genetic marker (HLA-B27) may also develop iritis, inflammatory bowel disease, psoriasis, and/or ankylosing spondylitis (inflammation of the pelvic joints -- most commonly the sacroiliac region). The male to female ratio is 7:1.

    6. Undifferentiated arthritis: Children who either do not fit clearly into the above unique subtypes of JIA or who have symptoms/laboratory studies that overlap more than one subtype are classified as having undifferentiated arthritis. By their nature, the patient population with this form of JIA often presents with nonclassical history and/or findings on physical exam and laboratory studies. Providing an accurate prognosis and developing a treatment program are challenges.

    What is the treatment for juvenile idiopathic arthritis?

    While there currently is no cure for JIA, an integrated and coordinated approach has been shown to be helpful in lessening the morbidity (nonlethal side effects) of JIA. Goals include lessening pain, joint contractures, and growth disturbances (see above). Monitoring for the development of iritis and aggressive treatment are also paramount. Often patients are best served at a pediatric teaching hospital where access to pediatric rheumatologists, physical and occupational therapists, pharmacologists, and social support providers may allow "one stop shopping."

    Therapies for JIA patients include the following:

    1. Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used as the first line of therapy due to their positive effect on mild arthritis and relatively few side effects. Medications such as ibuprofen (Advil, Motrin), naproxen (Aleve), and indomethacin (Indocin) are examples of this class of therapy.

    Learn more about: Indocin

    2. Steroids are another common class of medications for those experiencing moderate to severe arthritis or nonarthritis inflammatory consequences of JIA. These medications may be administered orally, intravenously, or injected directly into an involved joint. Side effects of steroids may be considerable, and pediatric rheumatologists strive to have the lowest possible dosage schedule. Side effects are most commonly seen at dosages over 20 mg/day and may include immune system depression, increased appetite resulting in weight gain, acne, mood changes, osteoporosis, cataracts, glaucoma, and diabetes.

    3. Antirheumatic medications are needed to control the joint changes of JIA in approximately two-thirds of children. These medications are generally considered when the medications previously described are not providing effective control of the patient's illness. Medicines in this category include methotrexate (Trexall, now considered the "gold standard" for those with JIA), sulfasalazine (Azulfidine), azathioprine (Imuran), cyclosporine (Sandimmune, Neoral), and several others. These medications may be administered orally or intravenously. Antirheumatic medications are more potent in effect but are also more problematic in side effects. Problems include immune suppression, which may result in an increased risk of infection and rarely certain cancers, pulmonary toxicity, liver function abnormalities, abdominal pain, and decrease in appetite.

    Learn more about: Trexall | Azulfidine | Imuran | Sandimmune | Neoral

    4. Biologic agents have more recently developed a substantial following due to their ability to lessen the morbidity (nonlethal side effects) for those children with JIA. All of these agents are administered either by superficial injection under the skin or intravenously. Their general chemical classification is that of "monoclonal antibodies" that work by targeting various mechanisms of the immune system and as such carry the potential for serious bacterial infections and (rarely) development of certain malignancies. As such, close clinical monitoring and various laboratory studies are required.

    5. Autologous stem cell transplantation is reserved only for those children with JIA who have failed all of the above therapeutic options. This procedure requires hospitalization and is a two-step process. The initial portion is utilization of high-dose immune suppression medications to remove the patient's lymphocytes (a type of white blood cell) which are attacking the patient's joint(s). Once removed, new stem cells from the patient (autologous) that were previously harvested and treated are introduced back into the patient's body via the bloodstream. This process requires expertise found only in a few pediatric referral centers.

    What are juvenile idiopathic arthritis symptoms and signs, and how are the different types of juvenile idiopathic arthritis diagnosed?

    The International League of Associations of Rheumatology has classified JIA into six distinct patterns that vary by clinical presentation and evolution of symptoms, laboratory implications, potential complications, and therapeutic options. While some similarities exist among these diseases, the uniqueness of each manifestation of JIA is strong enough to justify the breakdown into the six patterns. One characteristic common to all six forms of JIA is that of "morning stiffness" that improves during the day as more movement is done. Likewise, spontaneous patterns of worsening and lessening of symptoms (which may be independent of therapy) is characteristic.

    1. Systemic onset JIA: By definition, systemic onset JIA must have arthritis (swelling, pain, and warmth) of one or more joints associated with a minimum of two weeks of daily spiking fevers. The fever is often greater than 102 F (39 C) and usually spikes once or twice a day and may have the unique pattern of returning to below normal between rises. In addition, a characteristic intermittent salmon-colored rash, enlargement of lymph nodes, liver, and spleen, inflammation of the lungs, pericardium (the "sack" surrounding the heart), and other organs may occur. During febrile episodes, children appear moderately sick, but with resolution of fever they are much improved. Systemic onset JIA affects approximately 10%-15% all children suffering from JIA. There is no gender preference (the frequency in boys and girls is equal), with symptoms generally starting between 3-5 years of age. There is no unique laboratory test for JIA, but children typically have anemia and elevation of white blood cell and platelet counts, as well as alterations of general markers of inflammation. Complications of systemic onset JIA may include slower than expected growth, weakening of bones, abnormalities of liver and lung function, and consequences of therapy (see below). The prognosis is generally noted to depend upon the severity of arthritis with many/most of the systemic symptoms resolving over months to years. The low mortality rate (<0.3% in North America) is reassuring. Since the diagnosis of systemic onset of JIA is one of exclusion, the possibility of infection, malignancy, collagen vascular disease, and rheumatic fever are also considered.

    2. Oligoarticular JIA: Oligoarticular is defined as arthritis that affects four or fewer joints in the first six months of the disease. This form of JIA accounts for about 50% of all cases of pediatric chronic arthritis and may be subdivided into two groups. One group consists of those children who continue throughout the entire course of their disease having four or fewer joints involved. The other group eventually develops greater than four-joint involvement after the first six months of illness. The onset of disease is between 2-4 years of age with a female gender bias of approximately 3:1. Children with oligoarticular JIA most commonly have a single large joint (knee in approximately 90% of cases) involvement. Symptoms of joint pain and tenderness are worse in the morning in association with the previously described morning stiffness (see systemic onset JIA). The primary complication of oligoarticular JIA is inflammation of the iris (the colored region of the eye). Iritis is found in approximately 15%-20% with this form of JIA and is often without symptoms. Complications of iritis may include clouding of the cornea (cataracts), glaucoma, and visual loss. Since outcome is linked to early diagnosis, it is imperative an ophthalmologist evaluate children with oligoarticular JIA every three to four months. Conditions that should be eliminated prior to establishing a diagnosis of oligoarticular JIA include trauma, infection, malignancy, and arthritis following an infection.

    3. Polyarticular juvenile idiopathic arthritis: Children who have five or more joints involved with arthritis during the first six months of their disease are classified into the polyarticular JIA form of illness. Two subgroups of polyarticular JIA exist based upon a constellation of various laboratory studies. One group (rheumatoid factor "RF" positive) affects between 5%-10% of all patients with JIA. Late childhood through young teenage girls are the most likely to develop this pattern. Generally, small joints (such as the hands and feet) tend to be involved, and a more aggressive course has been observed. "RF negative" polyarticular JIA affected individuals tend to have a milder course and thus a better outcome. Fatigue, anemia, suboptimal growth, and iritis (to a lesser degree than oligoarticular JIA) are complications. Other conditions that must be considered and eliminated prior to establishing the diagnosis of polyarticular JIA include infection, malignancy, and collagen vascular disease (including systemic lupus erythematosus).

    4. Psoriatic arthritis (PsA): Establishing the diagnosis of psoriatic arthritis involves demonstration of both large and small joint arthritis and a characteristic rash (psoriasis). Should the rash not be present, two of the following must exist: (a) family history of psoriasis in an immediate family member, (b) diffuse swelling of the fingers, and (c) pitting of the nails. Children with psoriatic arthritis may also develop iritis and should have ophthalmologic evaluation every six months.

    5. Enthesitis-related arthritis (ERA): Enthesitis (inflammation at the site of tendon insertion on the bone) most profoundly affects males over 8 years of age and often involves the lower back, sacroiliac joints, and joints of the legs, ankles, and feet. Patients with a particular genetic marker (HLA-B27) may also develop iritis, inflammatory bowel disease, psoriasis, and/or ankylosing spondylitis (inflammation of the pelvic joints -- most commonly the sacroiliac region). The male to female ratio is 7:1.

    6. Undifferentiated arthritis: Children who either do not fit clearly into the above unique subtypes of JIA or who have symptoms/laboratory studies that overlap more than one subtype are classified as having undifferentiated arthritis. By their nature, the patient population with this form of JIA often presents with nonclassical history and/or findings on physical exam and laboratory studies. Providing an accurate prognosis and developing a treatment program are challenges.

    What is the treatment for juvenile idiopathic arthritis?

    While there currently is no cure for JIA, an integrated and coordinated approach has been shown to be helpful in lessening the morbidity (nonlethal side effects) of JIA. Goals include lessening pain, joint contractures, and growth disturbances (see above). Monitoring for the development of iritis and aggressive treatment are also paramount. Often patients are best served at a pediatric teaching hospital where access to pediatric rheumatologists, physical and occupational therapists, pharmacologists, and social support providers may allow "one stop shopping."

    Therapies for JIA patients include the following:

    1. Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used as the first line of therapy due to their positive effect on mild arthritis and relatively few side effects. Medications such as ibuprofen (Advil, Motrin), naproxen (Aleve), and indomethacin (Indocin) are examples of this class of therapy.

    Learn more about: Indocin

    2. Steroids are another common class of medications for those experiencing moderate to severe arthritis or nonarthritis inflammatory consequences of JIA. These medications may be administered orally, intravenously, or injected directly into an involved joint. Side effects of steroids may be considerable, and pediatric rheumatologists strive to have the lowest possible dosage schedule. Side effects are most commonly seen at dosages over 20 mg/day and may include immune system depression, increased appetite resulting in weight gain, acne, mood changes, osteoporosis, cataracts, glaucoma, and diabetes.

    3. Antirheumatic medications are needed to control the joint changes of JIA in approximately two-thirds of children. These medications are generally considered when the medications previously described are not providing effective control of the patient's illness. Medicines in this category include methotrexate (Trexall, now considered the "gold standard" for those with JIA), sulfasalazine (Azulfidine), azathioprine (Imuran), cyclosporine (Sandimmune, Neoral), and several others. These medications may be administered orally or intravenously. Antirheumatic medications are more potent in effect but are also more problematic in side effects. Problems include immune suppression, which may result in an increased risk of infection and rarely certain cancers, pulmonary toxicity, liver function abnormalities, abdominal pain, and decrease in appetite.

    Learn more about: Trexall | Azulfidine | Imuran | Sandimmune | Neoral

    4. Biologic agents have more recently developed a substantial following due to their ability to lessen the morbidity (nonlethal side effects) for those children with JIA. All of these agents are administered either by superficial injection under the skin or intravenously. Their general chemical classification is that of "monoclonal antibodies" that work by targeting various mechanisms of the immune system and as such carry the potential for serious bacterial infections and (rarely) development of certain malignancies. As such, close clinical monitoring and various laboratory studies are required.

    5. Autologous stem cell transplantation is reserved only for those children with JIA who have failed all of the above therapeutic options. This procedure requires hospitalization and is a two-step process. The initial portion is utilization of high-dose immune suppression medications to remove the patient's lymphocytes (a type of white blood cell) which are attacking the patient's joint(s). Once removed, new stem cells from the patient (autologous) that were previously harvested and treated are introduced back into the patient's body via the bloodstream. This process requires expertise found only in a few pediatric referral centers.

    Source: http://www.rxlist.com

    The International League of Associations of Rheumatology has classified JIA into six distinct patterns that vary by clinical presentation and evolution of symptoms, laboratory implications, potential complications, and therapeutic options. While some similarities exist among these diseases, the uniqueness of each manifestation of JIA is strong enough to justify the breakdown into the six patterns. One characteristic common to all six forms of JIA is that of "morning stiffness" that improves during the day as more movement is done. Likewise, spontaneous patterns of worsening and lessening of symptoms (which may be independent of therapy) is characteristic.

    1. Systemic onset JIA: By definition, systemic onset JIA must have arthritis (swelling, pain, and warmth) of one or more joints associated with a minimum of two weeks of daily spiking fevers. The fever is often greater than 102 F (39 C) and usually spikes once or twice a day and may have the unique pattern of returning to below normal between rises. In addition, a characteristic intermittent salmon-colored rash, enlargement of lymph nodes, liver, and spleen, inflammation of the lungs, pericardium (the "sack" surrounding the heart), and other organs may occur. During febrile episodes, children appear moderately sick, but with resolution of fever they are much improved. Systemic onset JIA affects approximately 10%-15% all children suffering from JIA. There is no gender preference (the frequency in boys and girls is equal), with symptoms generally starting between 3-5 years of age. There is no unique laboratory test for JIA, but children typically have anemia and elevation of white blood cell and platelet counts, as well as alterations of general markers of inflammation. Complications of systemic onset JIA may include slower than expected growth, weakening of bones, abnormalities of liver and lung function, and consequences of therapy (see below). The prognosis is generally noted to depend upon the severity of arthritis with many/most of the systemic symptoms resolving over months to years. The low mortality rate (<0.3% in North America) is reassuring. Since the diagnosis of systemic onset of JIA is one of exclusion, the possibility of infection, malignancy, collagen vascular disease, and rheumatic fever are also considered.

    2. Oligoarticular JIA: Oligoarticular is defined as arthritis that affects four or fewer joints in the first six months of the disease. This form of JIA accounts for about 50% of all cases of pediatric chronic arthritis and may be subdivided into two groups. One group consists of those children who continue throughout the entire course of their disease having four or fewer joints involved. The other group eventually develops greater than four-joint involvement after the first six months of illness. The onset of disease is between 2-4 years of age with a female gender bias of approximately 3:1. Children with oligoarticular JIA most commonly have a single large joint (knee in approximately 90% of cases) involvement. Symptoms of joint pain and tenderness are worse in the morning in association with the previously described morning stiffness (see systemic onset JIA). The primary complication of oligoarticular JIA is inflammation of the iris (the colored region of the eye). Iritis is found in approximately 15%-20% with this form of JIA and is often without symptoms. Complications of iritis may include clouding of the cornea (cataracts), glaucoma, and visual loss. Since outcome is linked to early diagnosis, it is imperative an ophthalmologist evaluate children with oligoarticular JIA every three to four months. Conditions that should be eliminated prior to establishing a diagnosis of oligoarticular JIA include trauma, infection, malignancy, and arthritis following an infection.

    3. Polyarticular juvenile idiopathic arthritis: Children who have five or more joints involved with arthritis during the first six months of their disease are classified into the polyarticular JIA form of illness. Two subgroups of polyarticular JIA exist based upon a constellation of various laboratory studies. One group (rheumatoid factor "RF" positive) affects between 5%-10% of all patients with JIA. Late childhood through young teenage girls are the most likely to develop this pattern. Generally, small joints (such as the hands and feet) tend to be involved, and a more aggressive course has been observed. "RF negative" polyarticular JIA affected individuals tend to have a milder course and thus a better outcome. Fatigue, anemia, suboptimal growth, and iritis (to a lesser degree than oligoarticular JIA) are complications. Other conditions that must be considered and eliminated prior to establishing the diagnosis of polyarticular JIA include infection, malignancy, and collagen vascular disease (including systemic lupus erythematosus).

    4. Psoriatic arthritis (PsA): Establishing the diagnosis of psoriatic arthritis involves demonstration of both large and small joint arthritis and a characteristic rash (psoriasis). Should the rash not be present, two of the following must exist: (a) family history of psoriasis in an immediate family member, (b) diffuse swelling of the fingers, and (c) pitting of the nails. Children with psoriatic arthritis may also develop iritis and should have ophthalmologic evaluation every six months.

    5. Enthesitis-related arthritis (ERA): Enthesitis (inflammation at the site of tendon insertion on the bone) most profoundly affects males over 8 years of age and often involves the lower back, sacroiliac joints, and joints of the legs, ankles, and feet. Patients with a particular genetic marker (HLA-B27) may also develop iritis, inflammatory bowel disease, psoriasis, and/or ankylosing spondylitis (inflammation of the pelvic joints -- most commonly the sacroiliac region). The male to female ratio is 7:1.

    6. Undifferentiated arthritis: Children who either do not fit clearly into the above unique subtypes of JIA or who have symptoms/laboratory studies that overlap more than one subtype are classified as having undifferentiated arthritis. By their nature, the patient population with this form of JIA often presents with nonclassical history and/or findings on physical exam and laboratory studies. Providing an accurate prognosis and developing a treatment program are challenges.

    Source: http://www.rxlist.com

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