EXXELERATE: New Thoughts on High RF Titer Sponsored by: UCB Save
Two leading rheumatologists share insights into why RF levels are important to consider when identifying treatment options for patients with RA.
Transcription
Hello. My name is Doctor. Soha Dolatobadi. I'm a rheumatologist in a private practice in Los Angeles, California. We will explore data of Cimzia, also known as Sertralizumab peggle, which delivered outcomes across different clinical manifestations in patients with moderate to severe rheumatoid arthritis, including in patients with high rheumatoid factor levels.
Specifically, in clinical studies, Cimzia reduced tender and swollen joints, helped inhibit the progression of structural damage, and improved pain and physical function in a rapid and sustained fashion, with improvements seen at one year of treatment. In addition, Cimzia has a consistent safety profile with more than twenty years of clinical use and more than one million patient years of exposure, across various approved indications. Now, some key clinical trial results. In the pivotal Phase III RAPID-one trial evaluating Cimzia in moderate to severe rheumatoid arthritis, Cimzia treated patients experienced significant joint improvement versus placebo treated patients. Specifically, the co primary endpoint of ACR20 response at week twenty four was met.
The ACR20 response rate for the treatment group receiving Cimzia two hundred mg and methotrexate was fifty nine percent at week twenty four, compared with fourteen percent for patients receiving placebo with methotrexate. Now let's examine the safety outcomes associated with Cimzia in RAPID-one. Notably, seventy four point seven percent of Cimzia treated patients experienced treatment emergent adverse events at week fifty two, compared to fifty seven point eight percent of placebo treated patients. Let's shift gears to another trial of CIMZIA in moderate to severe rheumatoid arthritis called ACCELERATE. The ACCELERATE trial was a one hundred and four week phase four head to head study comparing the efficacy of Cimzia and adalimumab in combination with methotrexate in providing short term twelve week efficacy as well as long term two year efficacy.
In ACCELERATE, the primary endpoints of superiority were not met. However, the results showed that Cynziq and adalimumab were numerically comparable. In a post hoc analysis of EXCELERATE, patients were stratified into subgroups according to baseline rheumatoid factor levels. Patients in the highest quartile were defined as the high rheumatoid factor subgroup. In this analysis, patients in quartiles one, two, and three had rheumatoid factor levels less than or equal to two zero three international units per milliliter, while quartile four, the high rheumatoid factor subgroup, included patients with rheumatoid factor levels greater than two zero three international units per milliliter.
In patients treated with Cimzia, the rates of achieving DAS28 CRP remission of low disease activity were consistent across all rheumatoid factor subgroups at week one hundred and four, with similar rates of response between those with higher rheumatoid factor levels and those with lower levels of rheumatoid factor. Within the adalimumab subgroups, results were numerically lower in patients with higher baseline rheumatoid factor levels at week one hundred and four, versus patients with lower rheumatoid factor levels defined as less than or equal to two zero three international units per milliliter. Accelerate also examined drug pharmacokinetics in Cimzia and adalimumab treated patients. In patients treated with Cimzia, drug plasma concentrations were similar across all rheumatoid factor subgroups through week one hundred and four. In the adalimumab subgroups, drug concentration were lower in patients with higher rheumatoid factor levels versus lower levels of rheumatoid factor through week one hundred and four.
In summary, these data from EXCELERATE demonstrate that Cimzia delivered clinical outcomes regardless of baseline rheumatoid factor levels. The EXCELERATE data that I just shared with you represent a post hoc analysis. Because this is a post hoc analysis, the results were not powered to show statistical significance, and clinical significance has not been established. For this reason, UCB cannot state this evidence as conclusive. Interpret this data with caution.
Hello, my name is Doctor. Aaron Arnold. I am a rheumatologist in private practice along the North Shore Of Chicago in Skokie, Illinois. When managing patients with moderate to severe rheumatoid arthritis, it's important to consider their individual disease presentation. Because rheumatoid arthritis is a heterogeneous disease, patients may present differently and require personalized considerations when managing their disease.
Let's discuss how Cimzia, also known as cerdulizumab pegol, can be used for patients with different rheumatoid factor levels and treatment histories. There are many individualized, patient specific factors to consider when making a treatment choice. For example, some patients may have experience with biologics while others might be biologic naive. Some may present with severe disease activity while others may present with moderate or low disease activity. Additionally, some patients may present with higher risk for severe disease activity due to high levels of rheumatoid factor, while others may present with lower levels of rheumatoid factor.
Let's consider Emily. Emily is a 37 year old female who works as a dental hygienist and is an assistant coach three times a week. She was diagnosed with rheumatoid arthritis five years ago and is currently taking corticosteroids and a TNF inhibitor. Since her diagnosis, Emily has experienced joint pain and swelling, limited range of motion in her hands, knees, and hips, as well as high levels of low density lipoprotein and rheumatoid factor levels equivalent to two zero nine international units per milliliter. Patients like Emily were studied in a clinical trial of Cimzia called Accelerate.
The Accelerate trial was a one hundred and four week, phase four, head to head study comparing the efficacy of Cimzia and adalimumab in combination with methotrexate in providing short term twelve week efficacy as well as long term two year efficacy. In ACCELERATE, the primary endpoints of superiority were not met. However, the results showed that Cimzia and adalimumab were numerically comparable. In a post hoc analysis of ACCELERATE, patients were stratified into subgroups according to baseline rheumatoid factor levels. Patients in the highest quartile were defined as the high rheumatoid factor subgroup.
Emily would have been a member of this latter subgroup. Next, let's consider Mark. Mark works as a personal chef and creates menus, cooks meals, and serves dinner parties for multiple clients. Despite current DMARD treatment, his rheumatoid arthritis symptoms impact his work. He experiences severe joint pain that makes it difficult for him to get out of bed, shop for ingredients, and prepare meals.
Mark is a social drinker, so methotrexate is not an option. Patients like Mark were evaluated in the Fast Forward study. In this study, Cimzia monotherapy was evaluated in patients with active rheumatoid arthritis who had failed at least one prior DMARD. In this double blind, placebo controlled study, patients were randomized one to one to receive Cimzia or placebo every four weeks. The primary endpoint was ACR20 at week twenty four.
In Fast Forward, treatment with Cimzia every four weeks demonstrated a significantly superior ACR20 response versus placebo at week twenty four. Finally, let's consider Nick. Nick is a 51 year old male who works as a high school principal and enjoys woodworking in his free time. He was diagnosed with moderate to severe rheumatoid arthritis one year ago and is currently taking methotrexate. Since his diagnosis Nick has experienced pain, swelling, and morning stiffness in his hands.
Nick's labs indicated high levels of low density lipoprotein as well as anemia. He also presented with elevated C reactive protein and erythrocyte sedimentation rate as well as rheumatoid factor levels equivalent to two zero nine international units per milliliter. Patients like Nick were evaluated in the C EARLY study, evaluating the efficacy of Cimzia in DMARRed naive patients. C EARLY was a phase three, double blind, placebo controlled study consisting of two consecutive periods of fifty two weeks each. Patients were randomized to receive Cimzia four hundred milligrams subcutaneously at weeks zero, two, and four, followed by two hundred milligrams every two weeks to week fifty two plus methotrexate, or placebo plus methotrexate.
The C EARLY study met its primary endpoint as treatment of biologic naive patients with Cimzia and methotrexate significantly reduced disease activity and provided durable response versus placebo and methotrexate. Next we'll go through important safety information. Thank you for your time and attention as we reviewed these three patients and their disease characteristics. For additional information about Cimzia, please visit cimziahcp.com.
Important Contraindications. Cimzia, cerdulizumab pegol is contraindicated in patients with a history of hypersensitivity reaction to cerdulizumab pegol or to any of the excipients. Reactions have included angioedema, anaphylaxis, serum sickness, and urticaria. Serious infections. Patients treated with are at increased risk for developing serious infections that may lead to hospitalization or death.
Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Discontinue Cimzia if a patient develops a serious infection or sepsis. Reported infections include active tuberculosis including reactivation of latent TB. Patients with TB have frequently presented with disseminated or extrapulmonary disease. Test patients for latent TB before Cimzia use and during therapy.
Initiate treatment for latent TB prior to Cimzia use. Invasive fungal infections including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocytosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated rather than localized disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Consider empiric antifungal therapy in patients at risk for invasive fungal infections who develop severe systemic illness.
Bacterial, viral, and other infections due to opportunistic pathogens including Legionella and Listeria. Carefully consider the risks and benefits of treatment with Cimzia prior initiating therapy in the following patients with chronic or recurrent infection, who have been exposed to TB, with a history of opportunistic infection, who resided in or traveled in regions where mycosis are endemic, with underlying conditions that may predispose them to infection. Monitor patients closely for the development of signs and symptoms of infection during and after treatment with Cimzia, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy. Do not start Cimzia during an active infection including localized infections. Patients older than 65 years, patients with comorbid conditions, and or patients taking concomitant immunosuppressants may be at greater risk of infection.
If an infection develops, monitor carefully and initiate appropriate therapy. Malignancy. Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, of which Cimzia, cerdulizumab pegyl, is a member. Cimzia is not indicated for use in pediatric patients. Consider the risks and benefits of Cimzia treatment prior to initiating or continuing therapy in a patient with known malignancy.
In clinical trials, more cases of malignancies were observed among Cimzia treated patients compared to control patients. In Cimzia clinical trials, there was an approximately twofold higher rate of lymphoma than expected in the general US population. Patients with rheumatoid arthritis, particularly those with highly active disease, are at a higher risk of lymphoma than the general population. Malignancies, some fatal, have been reported among children, adolescents, and young adults being treated with TNF blockers. Approximately half of the cases were lymphoma, while the rest were other types of malignancies, including rare types associated with immunosuppression and malignancies not usually seen in this patient population.
Post marketing cases of hepatosplenic T cell lymphoma, HSTCL, a rare type of T cell lymphoma, have been reported in patients treated with TNF blockers, including Cimzia. These cases have had a very aggressive disease course and have been fatal. The majority of reported TNF blocker cases have occurred in patients with Crohn's disease or ulcerative colitis and the majority were in adolescent and young adult males. Almost all of these patients had received treatment with azathioprine or six mercaptopurine concomitantly with a TNF blocker at or prior to diagnosis. Carefully assess the risks and benefits of treating with Cimzia in these patient types.
Cases of acute and chronic leukemia were reported with TNF blocker use. Heart failure. Worsening and new onset congestive heart failure, CHF, have been reported with TNF blockers. Exercise caution and monitor carefully. Hypersensitivity, angioedema, anaphylaxis, dyspnea, hypotension, rash, serum sickness, and urticaria have been reported following Cimzia administration.
If a serious allergic reaction occurs, stop Cimzia and institute appropriate therapy. The needle shield inside the removable cap of the Cimzia pre filled syringe contains a derivative of natural rubber latex, which may cause an allergic reaction in individuals sensitive to latex. Hepatitis B virus reactivation. Use of TNF blockers including Cimzia, cerdulizumab pegol, may increase the risk of reactivation of hepatitis B virus, HBV, in patients who are chronic carriers. Some cases have been fatal.
Test patients for HBV infection before initiating treatment with Cimzia. Exercise caution in patients who are carriers of HPV and monitor them before and during Cimzia treatment. Discontinue Cimzia and begin antiviral therapy in patients who develop HPV reactivation. Exercise caution when resuming Cimzia after HPV treatment. Neurologic reactions.
TNF blockers, including Cimzia, have been associated with rare cases of new onset or exacerbation of central nervous system and peripheral demyelinating diseases, including multiple sclerosis, seizure disorder, optic neuritis, peripheral neuropathy, and Guillain Barre syndrome. Hematologic reactions. Rare reports of pancytopenia, including aplastic anemia, have been reported with TNF blockers. Medically significant cytopenia has been infrequently reported with Cimzia. Consider stopping Cimzia if significant hematologic abnormalities occur.
Drug interactions. Do not use Cimzia in combination with other biological DMARDs. Autoimmunity. Treatment with Cimzia may result in the formation of autoantibodies and rarely in development of a lupus like syndrome. Discontinue treatment if symptoms of a lupus like syndrome develop.
Immunizations. Patients on Cimzia should not receive live or live attenuated vaccines. Adverse reactions. The most common adverse reactions in Cimzia clinical trials greater than or equal to eight percent were upper respiratory infections eighteen percent, rash nine percent, and urinary tract infections eight percent.
Specifically, in clinical studies, Cimzia reduced tender and swollen joints, helped inhibit the progression of structural damage, and improved pain and physical function in a rapid and sustained fashion, with improvements seen at one year of treatment. In addition, Cimzia has a consistent safety profile with more than twenty years of clinical use and more than one million patient years of exposure, across various approved indications. Now, some key clinical trial results. In the pivotal Phase III RAPID-one trial evaluating Cimzia in moderate to severe rheumatoid arthritis, Cimzia treated patients experienced significant joint improvement versus placebo treated patients. Specifically, the co primary endpoint of ACR20 response at week twenty four was met.
The ACR20 response rate for the treatment group receiving Cimzia two hundred mg and methotrexate was fifty nine percent at week twenty four, compared with fourteen percent for patients receiving placebo with methotrexate. Now let's examine the safety outcomes associated with Cimzia in RAPID-one. Notably, seventy four point seven percent of Cimzia treated patients experienced treatment emergent adverse events at week fifty two, compared to fifty seven point eight percent of placebo treated patients. Let's shift gears to another trial of CIMZIA in moderate to severe rheumatoid arthritis called ACCELERATE. The ACCELERATE trial was a one hundred and four week phase four head to head study comparing the efficacy of Cimzia and adalimumab in combination with methotrexate in providing short term twelve week efficacy as well as long term two year efficacy.
In ACCELERATE, the primary endpoints of superiority were not met. However, the results showed that Cynziq and adalimumab were numerically comparable. In a post hoc analysis of EXCELERATE, patients were stratified into subgroups according to baseline rheumatoid factor levels. Patients in the highest quartile were defined as the high rheumatoid factor subgroup. In this analysis, patients in quartiles one, two, and three had rheumatoid factor levels less than or equal to two zero three international units per milliliter, while quartile four, the high rheumatoid factor subgroup, included patients with rheumatoid factor levels greater than two zero three international units per milliliter.
In patients treated with Cimzia, the rates of achieving DAS28 CRP remission of low disease activity were consistent across all rheumatoid factor subgroups at week one hundred and four, with similar rates of response between those with higher rheumatoid factor levels and those with lower levels of rheumatoid factor. Within the adalimumab subgroups, results were numerically lower in patients with higher baseline rheumatoid factor levels at week one hundred and four, versus patients with lower rheumatoid factor levels defined as less than or equal to two zero three international units per milliliter. Accelerate also examined drug pharmacokinetics in Cimzia and adalimumab treated patients. In patients treated with Cimzia, drug plasma concentrations were similar across all rheumatoid factor subgroups through week one hundred and four. In the adalimumab subgroups, drug concentration were lower in patients with higher rheumatoid factor levels versus lower levels of rheumatoid factor through week one hundred and four.
In summary, these data from EXCELERATE demonstrate that Cimzia delivered clinical outcomes regardless of baseline rheumatoid factor levels. The EXCELERATE data that I just shared with you represent a post hoc analysis. Because this is a post hoc analysis, the results were not powered to show statistical significance, and clinical significance has not been established. For this reason, UCB cannot state this evidence as conclusive. Interpret this data with caution.
Hello, my name is Doctor. Aaron Arnold. I am a rheumatologist in private practice along the North Shore Of Chicago in Skokie, Illinois. When managing patients with moderate to severe rheumatoid arthritis, it's important to consider their individual disease presentation. Because rheumatoid arthritis is a heterogeneous disease, patients may present differently and require personalized considerations when managing their disease.
Let's discuss how Cimzia, also known as cerdulizumab pegol, can be used for patients with different rheumatoid factor levels and treatment histories. There are many individualized, patient specific factors to consider when making a treatment choice. For example, some patients may have experience with biologics while others might be biologic naive. Some may present with severe disease activity while others may present with moderate or low disease activity. Additionally, some patients may present with higher risk for severe disease activity due to high levels of rheumatoid factor, while others may present with lower levels of rheumatoid factor.
Let's consider Emily. Emily is a 37 year old female who works as a dental hygienist and is an assistant coach three times a week. She was diagnosed with rheumatoid arthritis five years ago and is currently taking corticosteroids and a TNF inhibitor. Since her diagnosis, Emily has experienced joint pain and swelling, limited range of motion in her hands, knees, and hips, as well as high levels of low density lipoprotein and rheumatoid factor levels equivalent to two zero nine international units per milliliter. Patients like Emily were studied in a clinical trial of Cimzia called Accelerate.
The Accelerate trial was a one hundred and four week, phase four, head to head study comparing the efficacy of Cimzia and adalimumab in combination with methotrexate in providing short term twelve week efficacy as well as long term two year efficacy. In ACCELERATE, the primary endpoints of superiority were not met. However, the results showed that Cimzia and adalimumab were numerically comparable. In a post hoc analysis of ACCELERATE, patients were stratified into subgroups according to baseline rheumatoid factor levels. Patients in the highest quartile were defined as the high rheumatoid factor subgroup.
Emily would have been a member of this latter subgroup. Next, let's consider Mark. Mark works as a personal chef and creates menus, cooks meals, and serves dinner parties for multiple clients. Despite current DMARD treatment, his rheumatoid arthritis symptoms impact his work. He experiences severe joint pain that makes it difficult for him to get out of bed, shop for ingredients, and prepare meals.
Mark is a social drinker, so methotrexate is not an option. Patients like Mark were evaluated in the Fast Forward study. In this study, Cimzia monotherapy was evaluated in patients with active rheumatoid arthritis who had failed at least one prior DMARD. In this double blind, placebo controlled study, patients were randomized one to one to receive Cimzia or placebo every four weeks. The primary endpoint was ACR20 at week twenty four.
In Fast Forward, treatment with Cimzia every four weeks demonstrated a significantly superior ACR20 response versus placebo at week twenty four. Finally, let's consider Nick. Nick is a 51 year old male who works as a high school principal and enjoys woodworking in his free time. He was diagnosed with moderate to severe rheumatoid arthritis one year ago and is currently taking methotrexate. Since his diagnosis Nick has experienced pain, swelling, and morning stiffness in his hands.
Nick's labs indicated high levels of low density lipoprotein as well as anemia. He also presented with elevated C reactive protein and erythrocyte sedimentation rate as well as rheumatoid factor levels equivalent to two zero nine international units per milliliter. Patients like Nick were evaluated in the C EARLY study, evaluating the efficacy of Cimzia in DMARRed naive patients. C EARLY was a phase three, double blind, placebo controlled study consisting of two consecutive periods of fifty two weeks each. Patients were randomized to receive Cimzia four hundred milligrams subcutaneously at weeks zero, two, and four, followed by two hundred milligrams every two weeks to week fifty two plus methotrexate, or placebo plus methotrexate.
The C EARLY study met its primary endpoint as treatment of biologic naive patients with Cimzia and methotrexate significantly reduced disease activity and provided durable response versus placebo and methotrexate. Next we'll go through important safety information. Thank you for your time and attention as we reviewed these three patients and their disease characteristics. For additional information about Cimzia, please visit cimziahcp.com.
Important Contraindications. Cimzia, cerdulizumab pegol is contraindicated in patients with a history of hypersensitivity reaction to cerdulizumab pegol or to any of the excipients. Reactions have included angioedema, anaphylaxis, serum sickness, and urticaria. Serious infections. Patients treated with are at increased risk for developing serious infections that may lead to hospitalization or death.
Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Discontinue Cimzia if a patient develops a serious infection or sepsis. Reported infections include active tuberculosis including reactivation of latent TB. Patients with TB have frequently presented with disseminated or extrapulmonary disease. Test patients for latent TB before Cimzia use and during therapy.
Initiate treatment for latent TB prior to Cimzia use. Invasive fungal infections including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocytosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated rather than localized disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Consider empiric antifungal therapy in patients at risk for invasive fungal infections who develop severe systemic illness.
Bacterial, viral, and other infections due to opportunistic pathogens including Legionella and Listeria. Carefully consider the risks and benefits of treatment with Cimzia prior initiating therapy in the following patients with chronic or recurrent infection, who have been exposed to TB, with a history of opportunistic infection, who resided in or traveled in regions where mycosis are endemic, with underlying conditions that may predispose them to infection. Monitor patients closely for the development of signs and symptoms of infection during and after treatment with Cimzia, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy. Do not start Cimzia during an active infection including localized infections. Patients older than 65 years, patients with comorbid conditions, and or patients taking concomitant immunosuppressants may be at greater risk of infection.
If an infection develops, monitor carefully and initiate appropriate therapy. Malignancy. Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, of which Cimzia, cerdulizumab pegyl, is a member. Cimzia is not indicated for use in pediatric patients. Consider the risks and benefits of Cimzia treatment prior to initiating or continuing therapy in a patient with known malignancy.
In clinical trials, more cases of malignancies were observed among Cimzia treated patients compared to control patients. In Cimzia clinical trials, there was an approximately twofold higher rate of lymphoma than expected in the general US population. Patients with rheumatoid arthritis, particularly those with highly active disease, are at a higher risk of lymphoma than the general population. Malignancies, some fatal, have been reported among children, adolescents, and young adults being treated with TNF blockers. Approximately half of the cases were lymphoma, while the rest were other types of malignancies, including rare types associated with immunosuppression and malignancies not usually seen in this patient population.
Post marketing cases of hepatosplenic T cell lymphoma, HSTCL, a rare type of T cell lymphoma, have been reported in patients treated with TNF blockers, including Cimzia. These cases have had a very aggressive disease course and have been fatal. The majority of reported TNF blocker cases have occurred in patients with Crohn's disease or ulcerative colitis and the majority were in adolescent and young adult males. Almost all of these patients had received treatment with azathioprine or six mercaptopurine concomitantly with a TNF blocker at or prior to diagnosis. Carefully assess the risks and benefits of treating with Cimzia in these patient types.
Cases of acute and chronic leukemia were reported with TNF blocker use. Heart failure. Worsening and new onset congestive heart failure, CHF, have been reported with TNF blockers. Exercise caution and monitor carefully. Hypersensitivity, angioedema, anaphylaxis, dyspnea, hypotension, rash, serum sickness, and urticaria have been reported following Cimzia administration.
If a serious allergic reaction occurs, stop Cimzia and institute appropriate therapy. The needle shield inside the removable cap of the Cimzia pre filled syringe contains a derivative of natural rubber latex, which may cause an allergic reaction in individuals sensitive to latex. Hepatitis B virus reactivation. Use of TNF blockers including Cimzia, cerdulizumab pegol, may increase the risk of reactivation of hepatitis B virus, HBV, in patients who are chronic carriers. Some cases have been fatal.
Test patients for HBV infection before initiating treatment with Cimzia. Exercise caution in patients who are carriers of HPV and monitor them before and during Cimzia treatment. Discontinue Cimzia and begin antiviral therapy in patients who develop HPV reactivation. Exercise caution when resuming Cimzia after HPV treatment. Neurologic reactions.
TNF blockers, including Cimzia, have been associated with rare cases of new onset or exacerbation of central nervous system and peripheral demyelinating diseases, including multiple sclerosis, seizure disorder, optic neuritis, peripheral neuropathy, and Guillain Barre syndrome. Hematologic reactions. Rare reports of pancytopenia, including aplastic anemia, have been reported with TNF blockers. Medically significant cytopenia has been infrequently reported with Cimzia. Consider stopping Cimzia if significant hematologic abnormalities occur.
Drug interactions. Do not use Cimzia in combination with other biological DMARDs. Autoimmunity. Treatment with Cimzia may result in the formation of autoantibodies and rarely in development of a lupus like syndrome. Discontinue treatment if symptoms of a lupus like syndrome develop.
Immunizations. Patients on Cimzia should not receive live or live attenuated vaccines. Adverse reactions. The most common adverse reactions in Cimzia clinical trials greater than or equal to eight percent were upper respiratory infections eighteen percent, rash nine percent, and urinary tract infections eight percent.
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