What is psoriatic spondylitis? Symptoms, diagnosis, and treatment

<h1>What is psoriatic spondylitis? Symptoms, diagnosis, and treatment</h1>

What is psoriatic spondylitis? Symptoms, diagnosis, and treatment

Table of contents What is it? Prevalence Symptoms Causes Complications Diagnosis Treatments Natural remedies Summary Psoriatic spondylitis is the medical term for a type of psoriatic arthritis that affects the spine and the joints in the pelvis. The symptoms may develop anywhere between the pelvis and the neck. People with psoriatic spondylitis may experience pain, inflammation , and stiffness in their neck and lower back. It can also affect the sacroiliac joints in the pelvis. Over time, the condition may make it more difficult for a person to move their spine.
In this article, we take a closer look at psoriatic spondylitis, including its causes, symptoms, and treatments.
What is psoriatic spondylitis?
Psoriatic spondylitis can cause pain, inflammation, and stiffness in the neck and lower back. Psoriatic spondylitis is a form of psoriatic arthritis .
Psoriatic arthritis refers to a group of inflammatory joint problems related to psoriasis . However, not everyone who has psoriatic arthritis has psoriasis.
Psoriatic spondylitis occurs when the body’s immune system attacks its own tissue, which leads to inflammation and often painful symptoms.
How common is it? Psoriasis is one of the most common autoimmune diseases in the United States, affecting more than 8 million people in America, according to the National Psoriasis Foundation (NPF) .
The NPF also estimate that 10–30 percent of people with psoriasis will develop psoriatic arthritis, though different sources give different estimates.
About 20 percent of people with psoriatic arthritis develop psoriatic spondylitis, according to the Spondylitis Association of America.
Symptoms Psoriatic spondylitis causes symptoms that are similar to other forms of arthritis that affect the spine and the sacroiliac joints in the pelvis, such as ankylosing spondylitis and reactive arthritis.
Symptoms of psoriatic spondylitis include:
back pain stiffness in the back or neck that improves when moving around stiffness made worse by periods of staying still, such as sleep trouble bending or moving the back fatigue These symptoms can cause extreme pain and some people experience difficulty in their daily lives. Left untreated, the inflammation can cause long-term damage to the spine and joints.
Medical treatments aim to keep inflammation under control and prevent long-term joint problems and damage. Medication can also reduce a person’s risk of heart disease that can occur due to inflammation.
The symptoms of psoriatic spondylitis may seem to come and go. When symptoms get worse, this is known as a flare. The location of pain and swelling may also change over time.
Causes Doctors are still unsure why some people develop psoriatic disease, but others do not.
Certain infections, such as strep throat , may trigger the overactive immune response that causes psoriatic spondylitis. However, psoriatic spondylitis is not contagious.
The condition tends to run in families.
One of the most significant risk factors for psoriatic spondylitis is the HLA-B27 gene. This gene also has links to several different autoimmune diseases.
Blood tests can detect whether a person carries the HLA-B27 gene. However, testing positive for the HLA-B27 gene does not mean a person will get psoriatic spondylitis. Other genes may cause psoriatic spondylitis.
Psoriatic spondylitis usually develops in people who already have psoriasis, but this is not always the case.
Age is also a risk factor. Psoriatic arthritis typically occurs in people between 30 and 50 years old.
How does psoriatic arthritis affect the body? Psoriatic arthritis can have wide-ranging effects on the body. In this article, we look at how the condition can affect 8 areas of the body, including the muscles, bones, and organs. Read now Complications
A person with psoriatic spondylitis may experience hearing loss. Psoriatic spondylitis can cause long-term damage to the bones and joints in the spine, neck, and pelvis. It may also cause complications such as:
hearing loss some types of cancer , including lymphoma and nonmelanoma skin cancer heart disease depression metabolic syndrome diabetes Crohn’s disease liver disease inflammation of the eyes, known as uveitis osteoporosis Not every person who has psoriatic spondylitis will experience these complications. The best way to prevent complications occurring is to receive prompt treatment and follow a doctor’s recommendations.
Diagnosis The NPF website has an online quiz that people can do to help them work out whether they may have psoriatic arthritis. Anyone who thinks they may have the condition can visit their doctor to find out more.
Initially, a doctor may ask the person to fill out a screening tool for psoriatic arthritis .
They may also use a variety of other tests to determine whether a person has psoriatic spondylitis. Firstly, they rule out other types of arthritis and other causes of back pain. This is important because treatment for psoriatic spondylitis and other types of arthritis are different.
Along with joint-related symptoms, a doctor may also look for signs of psoriasis, such as silvery scales on the skin and pitted or crumbling nails.
Doctors may also use imaging tests, such as X-rays, MRI scans , ultrasounds , and CT scans to look at the bones and joints in the spine.
Doctors also do blood tests to help diagnose psoriatic spondylitis because people with this condition can have high levels of inflammation in the blood. People who have psoriatic spondylitis also may have lower red blood cell counts.
Doctors can use blood tests to rule out other forms of arthritis.
Treatments Psoriatic spondylitis symptoms can be difficult and painful, but doctors can treat the condition.
The aim of treatment for psoriatic spondylitis treatment is to prevent damage to the bones and joints, help a person manage symptoms, and achieve remission. Remission means a person has no symptoms and the disease is not getting worse.
However, people will need to use medications long-term to stay symptom-free.
A variety of medications are available to treat psoriatic spondylitis, including:
Anti-inflammatory drugs Nonsteroidal anti-inflammatory drugs ( NSAIDs ) can help relieve mild psoriatic spondylitis pain, reduce inflammation, and relieve stiffness. However, NSAIDs can have side effects, such as stomach bleeding and kidney impairment, especially when a person takes them for long periods. Talk to a doctor about how to use NSAIDs safely.
NSAIDs include ibuprofen, naproxen, and aspirin , as well as prescription options.
Disease-modifying antirheumatic drugs Disease-modifying antirheumatic drugs (DMARDs) control inflammation or the body’s overactive immune response. They can help relieve symptoms of psoriatic spondylitis and prevent damage to joints. A person may take them as a pill or get an injection.
DMARDs include the following classes of drugs:
drugs that suppress the immune system response, such as methotrexate, azathioprine, leflunomide, and cyclosporine drugs that control inflammation in the body, including sulfasalazine and acthar therapy biologics, which target specific immune cells to reduce inflammation Biologics Biologics are a newer, more targeted therapy than DMARDs. Doctors administer this medicine through injections. Biologics work by interfering with natural immune pathways, mimicking the natural molecules, and reducing inflammation.
Biologics include:
tumor necrosis factor-alpha (TNF) inhibitors, including etanercept , adalimumab , and infliximab T-cell inhibitors, such as abatacept other inhibitors target specific inflammatory proteins, such as ustekinumab, secukinumab, and ixekizumab Not everyone will need biologics as a primary treatment. Biologics may increase a person’s risk of infection or cause specific side effects, such as flu-like symptoms or airway infections. Rarely, they can cause blood disorders, cancer, and other autoimmune symptoms. Talk to a doctor about the benefits, risks, and costs of biologics.
Corticosteroids Corticosteroids are powerful anti-inflammatory drugs. A person may take a corticosteroid pill such as prednisone, or a doctor may inject the medicine directly into the affected joint. These can provide short-term relief.
Doctors usually prescribe corticosteroids to treat severe severe flares until other medication, such as biologics or DMARDs, start to work.
Corticosteroid medication can have side effects that include weight gain, osteoporosis, and high blood pressure . Psoriasis may flare up when a person stops using steroids.
Small molecule medications Small molecule medications stop certain immune molecules from attacking the joints and skin. They include:
apremilast tofacitinib Physical therapy Exercise helps lessen the inflammation around the joints and helps to relieve pain. Stronger muscles also help support the joints, putting less stress on them.
A physical therapist can recommend specific stretches and exercises to help a person who has psoriatic spondylitis. An occupational therapist can recommend ways that a person can prevent joint stress and suggest how they can adapt their work environment to reduce pain and injury.
Some home remedies may also be useful for milder cases.
Natural remedies
Partaking in low-impact exercise, such as biking, can help keep joints flexible. Using home remedies for psoriatic spondylitis can help ease symptoms. These remedies work alongside a doctor’s treatment plan. Follow a doctor’s advice on medications or other treatments to avoid future bone and joint damage.
The following natural and home remedies may help a person manage their psoriatic spondylitis:
Exercise. Being active can help keep joints flexible. It can also help people maintain a healthful weight, which can take pressure off painful joints. Exercise boosts endorphins, which may help improve a person’s emotional well-being. Walking, biking, yoga , and Tai Chi are good low-impact choices. Some people find swimming to be easier on painful joints. Follow a regular sleep schedule. Fatigue can make psoriatic spondylitis symptoms feel worse. It can also trigger more inflammation in the body. Focus on getting enough sleep and maintaining a regular bedtime. Know the triggers. Keep a journal with foods, activities, and life events and write down when the psoriatic spondylitis gets worse. This can help identify the causes of flares so that people can avoid them in the future. Try acupuncture. A recent meta-analysis found that acupuncture was an effective option for reducing chronic musculoskeletal pain. Get a massage. A licensed massage therapist may use a variety of techniques to relieve tension and loosen stiff joints. Make sure the massage therapist has experience in treating people with psoriatic spondylitis or arthritis. Eat an anti-inflammatory diet. Nutritious whole foods can help fight fatigue. A Mediterranean Diet can help fight inflammation. Learn more about anti-inflammatory foods here . Limit or avoid alcohol. Drinking alcohol may interfere with medications a person takes for psoriatic spondylitis and may cause unwanted side effects. Quit smoking. Smoking makes the symptoms of psoriatic arthritis worse. Quitting smoking can have a wide range of health benefits alongside relieving joint pain. Try hot or cold therapy. Some people find relief from the pain by using heating pads or cold packs on sore areas. Take periodic breaks to avoid burning the skin or getting frostbite . Manage stress. High stress levels can make psoriatic spondylitis symptoms worse. Summary Many people find the symptoms of psoriatic spondylitis challenging, but with the variety of treatments available today, many people can manage their symptoms, prevent further joint damage, and carry out normal activities.
While there is no cure for psoriatic spondylitis, a person can keep symptoms under control with the help and guidance of their healthcare team. Following an effective treatment plan can help people with psoriatic spondylitis lead healthy and active lives.
Related coverage What is the link between psoriatic arthritis and depression? Psoriatic arthritis (PsA) can contribute to some mental health conditions, including depression. In this article, we look at the link between PsA and depression, as well as treatments and coping strategies. Read now How to recognize ankylosing spondylitis Ankylosing spondylitis is a type of arthritis. Symptoms usually appear around the age of 30 years and become progressively more severe, although there may be periods of remission. In time, vision and breathing problems may occur. Physical therapy and anti-inflammatory and other drugs may help relieve symptoms. Read now Exercises and postures for ankylosing spondylitis Following an exercise routine can help people with ankylosing spondylitis manage their symptoms and slow the progression of the condition. Read now How does psoriatic arthritis affect the spine? Psoriatic arthritis can cause stiffness and pain in the spinal joints, but early diagnosis and treatment can prevent complications. Here, learn more about how psoriatic arthritis affects the spine. Read now What is the link between psoriasis and psoriatic arthritis? Psoriasis and psoriatic arthritis are related autoimmune conditions. Psoriasis may cause psoriatic arthritis, though they can develop independently. Learn more about the link between these conditions, along with their symptoms, causes, and treatments, here. Psoriatic Arthritis Back Pain Psoriasis Rheumatology Additional information Article last reviewed by Wed 13 March 2019.
Visit our Psoriatic Arthritis Psoriatic Arthritis.
About psoriatic arthritis. (2018). https://www.psoriasis.org/about-psoriatic-arthritis
Anti-inflammatory diet. (n.d.). https://www.arthritis.org/living-with-arthritis/arthritis-diet/anti-inflammatory/anti-inflammatory-diet.php
Are you at risk for psoriatic arthritis? (n.d.). https://www.psoriasis.org/psa-screening/quiz
Disease-modifying antirheumatic drugs (DMARDs). (n.d.). https://www.psoriasis.org/psoriatic-arthritis/treatments/dmards
Ibrahim, G. H., et al (2009). Screening tool for psoriatic arthritis. https://www.psoriasis.org/sites/default/files/screening_tool_for_psoriatic_arthritis.pdf
Nonsteroidal anti-inflammatory drugs (NSAIDs). (n.d.). https://www.psoriasis.org/psoriatic-arthritis/treatments/nsaids
Overview of psoriatic arthritis. (n.d.). https://www.spondylitis.org/Psoriatic-Arthritis
Psoriatic arthritis. (2017). https://www.rheumatology.org/I-Am-A/Patient-Caregiver/Diseases-Conditions/Psoriatic-Arthritis
Psoriatic statistics. (n.d). https://www.psoriasis.org/content/statistics
Vickers, A. J., et al. (2018). Acupuncture for chronic pain: Update of an individual patient data meta-analysis. https://www.ncbi.nlm.nih.gov/pubmed/29198932
What is psoriatic arthritis? (n.d.). https://www.arthritis.org/about-arthritis/types/psoriatic-arthritis/what-is-psoriatic-arthritis.php
Berry, Jennifer. “What to know about psoriatic spondylitis.” 13 Mar. 2019. Web.
14 Mar. 2019.
APA
Berry, J. (2019, March 13). “What to know about psoriatic spondylitis.” Medical News Today . Retrieved from
https://www.medicalnewstoday.com/articles/324701.php .
Please note: If no author information is provided, the source is cited instead.
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Medical News Today: What to know about psoriatic spondylitis

<h1>Medical News Today: What to know about psoriatic spondylitis</h1>

Medical News Today: What to know about psoriatic spondylitis

Medical News Today: What to know about psoriatic spondylitis You are here: Wellness Medical News Today: What to know about psoriatic spondylitis Psoriatic spondylitis is the medical term for a type of psoriatic arthritis that affects the spine and the joints in the pelvis. The symptoms may develop anywhere between the pelvis and the neck.
People with psoriatic spondylitis may experience pain, inflammation , and stiffness in their neck and lower back. It can also affect the sacroiliac joints in the pelvis. Over time, the condition may make it more difficult for a person to move their spine.
In this article, we take a closer look at psoriatic spondylitis, including its causes, symptoms, and treatments. What is psoriatic spondylitis? Psoriatic spondylitis can cause pain, inflammation, and stiffness in the neck and lower back.
Psoriatic spondylitis is a form of psoriatic arthritis .
Psoriatic arthritis refers to a group of inflammatory joint problems related to psoriasis . However, not everyone who has psoriatic arthritis has psoriasis.
Psoriatic spondylitis occurs when the body’s immune system attacks its own tissue, which leads to inflammation and often painful symptoms. How common is it?
Psoriasis is one of the most common autoimmune diseases in the United States, affecting more than 8 million people in America, according to the National Psoriasis Foundation (NPF) .
The NPF also estimate that 10–30 percent of people with psoriasis will develop psoriatic arthritis, though different sources give different estimates.
About 20 percent of people with psoriatic arthritis develop psoriatic spondylitis, according to the Spondylitis Association of America. Symptoms
Psoriatic spondylitis causes symptoms that are similar to other forms of arthritis that affect the spine and the sacroiliac joints in the pelvis, such as ankylosing spondylitis and reactive arthritis.
Symptoms of psoriatic spondylitis include: stiffness in the back or neck that improves when moving around stiffness made worse by periods of staying still, such as sleep trouble bending or moving the back fatigue
These symptoms can cause extreme pain and some people experience difficulty in their daily lives. Left untreated, the inflammation can cause long-term damage to the spine and joints.
Medical treatments aim to keep inflammation under control and prevent long-term joint problems and damage. Medication can also reduce a person’s risk of heart disease that can occur due to inflammation.
The symptoms of psoriatic spondylitis may seem to come and go. When symptoms get worse, this is known as a flare. The location of pain and swelling may also change over time. Causes
Doctors are still unsure why some people develop psoriatic disease, but others do not.
Certain infections, such as strep throat , may trigger the overactive immune response that causes psoriatic spondylitis. However, psoriatic spondylitis is not contagious.
The condition tends to run in families.
One of the most significant risk factors for psoriatic spondylitis is the HLA-B27 gene. This gene also has links to several different autoimmune diseases.
Blood tests can detect whether a person carries the HLA-B27 gene. However, testing positive for the HLA-B27 gene does not mean a person will get psoriatic spondylitis. Other genes may cause psoriatic spondylitis.
Psoriatic spondylitis usually develops in people who already have psoriasis, but this is not always the case.
Age is also a risk factor. Psoriatic arthritis typically occurs in people between 30 and 50 years old. Complications A person with psoriatic spondylitis may experience hearing loss.
Psoriatic spondylitis can cause long-term damage to the bones and joints in the spine, neck, and pelvis. It may also cause complications such as:
Not every person who has psoriatic spondylitis will experience these complications. The best way to prevent complications occurring is to receive prompt treatment and follow a doctor’s recommendations. Diagnosis
The NPF website has an online quiz that people can do to help them work out whether they may have psoriatic arthritis. Anyone who thinks they may have the condition can visit their doctor to find out more.
Initially, a doctor may ask the person to fill out a screening tool for psoriatic arthritis .
They may also use a variety of other tests to determine whether a person has psoriatic spondylitis. Firstly, they rule out other types of arthritis and other causes of back pain. This is important because treatment for psoriatic spondylitis and other types of arthritis are different.
Along with joint-related symptoms, a doctor may also look for signs of psoriasis, such as silvery scales on the skin and pitted or crumbling nails.
Doctors may also use imaging tests, such as X-rays, MRI scans , ultrasounds , and CT scans to look at the bones and joints in the spine.
Doctors also do blood tests to help diagnose psoriatic spondylitis because people with this condition can have high levels of inflammation in the blood. People who have psoriatic spondylitis also may have lower red blood cell counts.
Doctors can use blood tests to rule out other forms of arthritis. Treatments
Psoriatic spondylitis symptoms can be difficult and painful, but doctors can treat the condition.
The aim of treatment for psoriatic spondylitis treatment is to prevent damage to the bones and joints, help a person manage symptoms, and achieve remission. Remission means a person has no symptoms and the disease is not getting worse.
However, people will need to use medications long-term to stay symptom-free.
A variety of medications are available to treat psoriatic spondylitis, including: Anti-inflammatory drugs
Nonsteroidal anti-inflammatory drugs ( NSAIDs ) can help relieve mild psoriatic spondylitis pain, reduce inflammation, and relieve stiffness. However, NSAIDs can have side effects, such as stomach bleeding and kidney impairment, especially when a person takes them for long periods. Talk to a doctor about how to use NSAIDs safely.
NSAIDs include ibuprofen, naproxen, and aspirin , as well as prescription options. Disease-modifying antirheumatic drugs
Disease-modifying antirheumatic drugs (DMARDs) control inflammation or the body’s overactive immune response. They can help relieve symptoms of psoriatic spondylitis and prevent damage to joints. A person may take them as a pill or get an injection.
DMARDs include the following classes of drugs: drugs that suppress the immune system response, such as methotrexate, azathioprine, leflunomide, and cyclosporine drugs that control inflammation in the body, including sulfasalazine and acthar therapy biologics, which target specific immune cells to reduce inflammation Biologics
Biologics are a newer, more targeted therapy than DMARDs. Doctors administer this medicine through injections. Biologics work by interfering with natural immune pathways, mimicking the natural molecules, and reducing inflammation.
Biologics include: tumor necrosis factor-alpha (TNF) inhibitors, including etanercept , adalimumab , and infliximab T-cell inhibitors, such as abatacept other inhibitors target specific inflammatory proteins, such as ustekinumab, secukinumab, and ixekizumab
Not everyone will need biologics as a primary treatment. Biologics may increase a person’s risk of infection or cause specific side effects, such as flu-like symptoms or airway infections. Rarely, they can cause blood disorders, cancer, and other autoimmune symptoms. Talk to a doctor about the benefits, risks, and costs of biologics. Corticosteroids
Corticosteroids are powerful anti-inflammatory drugs. A person may take a corticosteroid pill such as prednisone, or a doctor may inject the medicine directly into the affected joint. These can provide short-term relief.
Doctors usually prescribe corticosteroids to treat severe severe flares until other medication, such as biologics or DMARDs, start to work.
Corticosteroid medication can have side effects that include weight gain, osteoporosis, and high blood pressure . Psoriasis may flare up when a person stops using steroids. Small molecule medications
Small molecule medications stop certain immune molecules from attacking the joints and skin. They include: apremilast tofacitinib Physical therapy
Exercise helps lessen the inflammation around the joints and helps to relieve pain. Stronger muscles also help support the joints, putting less stress on them.
A physical therapist can recommend specific stretches and exercises to help a person who has psoriatic spondylitis. An occupational therapist can recommend ways that a person can prevent joint stress and suggest how they can adapt their work environment to reduce pain and injury.
Some home remedies may also be useful for milder cases. Natural remedies Partaking in low-impact exercise, such as biking, can help keep joints flexible.
Using home remedies for psoriatic spondylitis can help ease symptoms. These remedies work alongside a doctor’s treatment plan. Follow a doctor’s advice on medications or other treatments to avoid future bone and joint damage.
The following natural and home remedies may help a person manage their psoriatic spondylitis: Exercise. Being active can help keep joints flexible. It can also help people maintain a healthful weight, which can take pressure off painful joints. Exercise boosts endorphins, which may help improve a person’s emotional well-being. Walking, biking, yoga , and Tai Chi are good low-impact choices. Some people find swimming to be easier on painful joints. Follow a regular sleep schedule. Fatigue can make psoriatic spondylitis symptoms feel worse. It can also trigger more inflammation in the body. Focus on getting enough sleep and maintaining a regular bedtime. Know the triggers. Keep a journal with foods, activities, and life events and write down when the psoriatic spondylitis gets worse. This can help identify the causes of flares so that people can avoid them in the future. Try acupuncture. A recent meta-analysis found that acupuncture was an effective option for reducing chronic musculoskeletal pain. Get a massage. A licensed massage therapist may use a variety of techniques to relieve tension and loosen stiff joints. Make sure the massage therapist has experience in treating people with psoriatic spondylitis or arthritis. Eat an anti-inflammatory diet. Nutritious whole foods can help fight fatigue. A Mediterranean Diet can help fight inflammation. Learn more about anti-inflammatory foods here . Limit or avoid alcohol. Drinking alcohol may interfere with medications a person takes for psoriatic spondylitis and may cause unwanted side effects. Quit smoking. Smoking makes the symptoms of psoriatic arthritis worse. Quitting smoking can have a wide range of health benefits alongside relieving joint pain. Try hot or cold therapy. Some people find relief from the pain by using heating pads or cold packs on sore areas. Take periodic breaks to avoid burning the skin or getting frostbite . Manage stress. High stress levels can make psoriatic spondylitis symptoms worse. Summary
Many people find the symptoms of psoriatic spondylitis challenging, but with the variety of treatments available today, many people can manage their symptoms, prevent further joint damage, and carry out normal activities.
While there is no cure for psoriatic spondylitis, a person can keep symptoms under control with the help and guidance of their healthcare team. Following an effective treatment plan can help people with psoriatic spondylitis lead healthy and active lives.

Read More…

Low Dose Ipilimumab With Pembrolizumab in Treating Patients With Melanoma That Has Spread to the Brain

<h1>Low Dose Ipilimumab With Pembrolizumab in Treating Patients With Melanoma That Has Spread to the Brain</h1>

Low Dose Ipilimumab With Pembrolizumab in Treating Patients With Melanoma That Has Spread to the Brain

You have reached the maximum number of saved studies (100). Please remove one or more studies before adding more. Low Dose Ipilimumab With Pembrolizumab in Treating Patients With Melanoma That Has Spread to the Brain The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. ClinicalTrials.gov Identifier: NCT03873818 Recruitment Status : Not yet recruiting First Posted : March 13, 2019 Last Update Posted : March 13, 2019 Information provided by (Responsible Party): M.D. Anderson Cancer Center Study Description Go to Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information Brief Summary: This phase II trial studies the side effects and how well low dose ipilimumab works in combination with pembrolizumab in treating patients with melanoma that has spread to the brain. Immunotherapy with monoclonal antibodies, such as ipilimumab and pembrolizumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Condition or disease Intervention/treatment Phase Clinical Stage IV Cutaneous Melanoma Metastatic Malignant Neoplasm in the Brain Metastatic Melanoma Pathologic Stage IV Cutaneous Melanoma Biological: Ipilimumab Biological: Pembrolizumab Detailed Description: PRIMARY OBJECTIVE: I. To assess clinical benefit rate (CBR, defined as complete response [CR] + partial response [PR] + stable disease [SD]) > 6 months in the brain in subjects with melanoma metastatic to the brain per modified RECIST (Response evaluation criteria in solid tumors) 1.1 criteria and RANO-BM (Response Assessment in Neuro-Oncology Brain Metastases), and who had experienced prior progression on anti-PD1 (Programmed cell death protein). SECONDARY OBJECTIVES: I. Clinical benefit rate (CBR, defined as complete response [CR] + partial response [PR] + stable disease [SD]) > 6 months in the brain in subjects with melanoma metastatic to the brain per modified RECIST 1.1 and RANO-BM criteria, and who are treatment naive to anti- PD-1 agents. II. To assess overall survival (OS) and progression free survival (PFS). III. To evaluate the brain-specific safety and tolerability of the combination regimen in patients with or without stereotactic radiotherapy (SRT) received prior to study entry, or on study. IV. To evaluate cytokine levels and changes in the T-cell population in the cerebrospinal fluid (CSF) and blood in patients treated with combination low dose ipilimumab and pembrolizumab. V. Changes in relative apparent diffusion coefficient as measured by MRI magnetic resonance imaging as an early predictor of response. VI. To assess changes in circulating cfDNA (cell-free deoxyribonucleic acid) as determinants of response and/or markers of early progression. VII. Evaluate molecular and immunological changes in extracranial lesions. OUTLINE: Patients receive ipilimumab intravenously (IV) over 90 minutes and pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 4 courses for ipilimumab and up to 35 courses for pembrolizumab in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days, every 6 weeks for the first year, and then every 12 weeks thereafter. Study Design Go to
Layout table for study information Study Type : Treatment Official Title: A Phase II Study of Open Label Low Dose Ipilimumab in Combination With Pembrolizumab in Metastatic Melanoma Patients With Brain Metastases Estimated Study Start Date : Arms and Interventions Go to
Intervention/treatment Experimental: Treatment (ipilimumab, pembrolizumab) Patients receive ipilimumab IV over 90 minutes and pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 4 courses for ipilimumab and up to 35 courses for pembrolizumab in the absence of disease progression or unacceptable toxicity. Biological: Ipilimumab Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody BMS-734016 Outcome Measures Go to Clinical benefit rate (CBR) [ Time Frame: Up to 1 year ] CBR rate will be estimated along with a corresponding 95% credible interval by cohort. Secondary Outcome Measures : Overall survival (OS) [ Time Frame: From the start of first treatment to death, assessed up to 1 year ] OS will be assessed using the Kaplan-Meier method. Associations between OS and PFS and demographic and clinical covariates of interest will be assessed by Cox proportional hazards regression models. Progression-free survival (PFS) [ Time Frame: From start of first treatment to disease progression or death, assessed up to 1 year ] PFS will be assessed using the Kaplan-Meier method. Associations between OS and PFS and demographic and clinical covariates of interest will be assessed by Cox proportional hazards regression models. Cytokine levels [ Time Frame: Up to 1 year ] Cell-free CSF and serum samples from the same timepoints used for the characterization of immune cell populations will be analyzed for levels of immunomodulatory cytokines and chemoattractants. Multiplex assay will be used to measure the levels of soluble factors involved in 1) T-cell mediated antitumor activity (IFN, TNF), inflammation pathways (IL-1β, IL-6) or 3) immunosuppressive mechanisms (IL-10, TGFβ), markers and mediators of inflammation (IL-6 and IL-8). We will also measure the levels of well-characterized immunosuppressive soluble factors (i.e., IL-10 and IDO). Both absolute levels and changes from baseline will be determined. Changes in the T-cell population in the cerebrospinal fluid (CSF) and blood [ Time Frame: Baseline up to 1 year ] Will be summarized using means, standard deviations, medians, minimums, and maximums. Within group changes will be evaluated using either paired t-test or Wilcoxon signed rank test, depending on the data distribution. Change in relative apparent diffusion coefficient [ Time Frame: Baseline up to 1 year ] Will be evaluated by MRI response Incidence of adverse events [ Time Frame: Up to 1 year ] Safety will be assessed by adverse events as well as by vital signs and laboratory assessments for all patients. AEs, vital signs and laboratory assessments defined and graded according to NCI CTCAE v4.03. Incidence of serious adverse events [ Time Frame: Up to 1 year ] Safety will be assessed by serious adverse events. as well as by vital signs and laboratory assessments for all patients. AEs, vital signs and laboratory assessments defined and graded according to NCI CTCAE v4.03. Assess changes in circulating cell-free deoxyribonucleic acid (cfDNA) [ Time Frame: Baseline up to 1 year ] MRI response and/or markers of early progression Eligibility Criteria Go to Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information Information from the National Library of Medicine
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies. Layout table for eligibility information Ages Eligible for Study: 18 Years and older (Adult, Older Adult) Sexes Eligible for Study: Inclusion Criteria: Life Expectancy > 12 weeks. Subjects must have signed and dated an IRB/IEC (Institutional Review Board/Independent Ethics Committee) approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal subject care. Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study. Histologically confirmed malignant melanoma with measurable metastases in the brain. At least one measurable intracranial target lesion for which all of the following criteria are met: (1) Previously untreated or progressive after previous local therapy (2) Immediate local therapy clinically not indicated or patient is not a suitable candidate to receive immediate local therapy (3) Largest diameter of >= 0.5 cm, but == 2 weeks before the start of dosing for this study. Subjects must be free of neurologic signs and symptoms related to metastatic brain lesions and must not have required or received systemic corticosteroid therapy in the 10 days prior to beginning protocol therapy. ECOG (Eastern Cooperative Oncology Group) performance status == 1500/uL. Platelets >= 100,000/uL. Hemoglobin >= 9.0 g/dL or >= 5.6 mmol/L. Creatinine == 30L/min with creatinine levels > 1.5 x institutional ULN. GFR (glomerular filtration rate) can also be used in place of creatinine or CrCl (creatinine clearance). Total bilirubin =< 1.5 ULN OR direct bilirubin = 1.5 x ULN. AST (aspartate aminotransferase) and ALT (alanine aminotransferase) =< 2.5 x ULN (=< 5 x ULN for participants with liver metastasis). International normalized ratio (INR) OR prothrombin time (PT) and activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants. Women of child-bearing potential (WOCBP) must not be breastfeeding and must have a negative pregnancy test within 3 days prior to initiation of dosing. She must agree to use an acceptable method of birth control from the time of the negative pregnancy test up to 120 days after the last dose of study drug. WOCBP must agree to adhere to the contraceptive guidance in the protocol. Note: A female participant is eligible to participate if she is not a woman of childbearing potential as defined by the protocol. Fertile men must agree to use an acceptable method of birth control as described in the protocol while on study drug and up to 120 days after the last dose of study drug and also refrain from donating sperm during this period. All associated toxicity from previous or concurrent cancer therapy must be resolved (to = 5 lesions in the brain Brain lesion size > 3 cm. (Cohort A) Prior PD-1 therapy. Note: Prior anti-PD1 therapy within the last 6 weeks of enrollment on this protocol is allowed for Cohort B. Subjects with an active, known or suspected autoimmune disease. Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll. Subjects with major medical, neurologic or psychiatric condition who are judged as unable to fully comply with study therapy or assessments should not be enrolled. Active secondary malignancy unless the malignancy is not expected to interfere with the evaluation of safety and is approved by the Medical Monitor. Examples of the latter include basal or squamous cell carcinoma of the skin, in-situ carcinoma of the cervix, and isolated elevation of prostate-specific antigen. Subjects with a completely treated prior malignancy and no evidence of disease for >= 2 years are eligible. Has a known history of or is positive for hepatitis B (hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (hepatitis C virus [HCV] ribonucleic acid (RNA) [qualitative] is detected). Note: Without known history, testing needs to be performed to determine eligibility. Hepatitis C antibody (Ab) testing is allowed for screening purposes in countries where HCV RNA is not part of standard of care. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority. The use of corticosteroids is not allowed for 10 days prior to initiation of therapy (based upon 5 times the expected half-life of dexamethasone) except patients who are taking steroids for physiological replacement. If alternative corticosteroid therapy has been used, consultation with the sponsor medical monitor is required to determine the washout period prior to initiating study treatment. Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of study initiation. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease. Subjects with history of life-threatening toxicity related to prior ipilimumab adjuvant therapy except those that are unlikely to re-occur with standard countermeasures (e.g. hormone replacement after adrenal crisis). Major surgical procedure, open biopsy (excluding skin cancer resection), or significant traumatic injury within 14 days of initiating study drug (unless the wound has healed) or anticipation of the need for major surgery during the study. Non-healing wound, ulcer, or bone fracture. Women who are breast-feeding or pregnant. Uncontrolled intercurrent illness (i.e., active infection >= grade 2) or concurrent condition that, in the opinion of the Investigator, would interfere with the study endpoints or the subject’s ability to participate. Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within the 6 months before start of study medication (except for adequately treated catheter-related venous thrombosis occurring more than 1 month before the start of study medication). History of clinically significant cardiac disease or congestive heart failure > New York Heart Association (NYHA) class 2. Subjects must not have unstable angina (anginal symptoms at rest) or new-onset angina within the last 3 months or myocardial infarction within the past 6 months. Investigational drug use within 14 days (or 5 half-lives, whichever is longer) of the first dose of ipilimumab and pembrolizumab. Has a history of non-infectious pneumonitis that required steroids or current pneumonitis. Contacts and Locations Go to Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03873818 Contacts Layout table for location contacts Contact: Isabella C Glitza

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Therapeutic Plasma Exchange as Management of Complicated Systemic Lupus Erythematosus and Other Autoimmune Diseases

<h1>Therapeutic Plasma Exchange as Management of Complicated Systemic Lupus Erythematosus and Other Autoimmune Diseases</h1>

Therapeutic Plasma Exchange as Management of Complicated Systemic Lupus Erythematosus and Other Autoimmune Diseases

Research Article Therapeutic Plasma Exchange as Management of Complicated Systemic Lupus Erythematosus and Other Autoimmune Diseases
1 Grupo de Investigación en Reumatología, Autoinmunidad y Medicina Traslacional (GIRAT), Fundación Valle del Lili and Universidad Icesi, Cali, Colombia 2 Blood Bank and Transfusion Service, Fundación Valle del Lili, Cali, Colombia 3 Laboratory of Immunology, Fundación Valle del Lili, Cali, Colombia
Correspondence should be addressed to Gabriel J. Tobón ;
Received 3 November 2018; Revised 16 January 2019; Accepted 10 February 2019; Published 11 March 2019
Academic Editor: Ricard Cervera
Copyright © 2019 David Aguirre-Valencia et al. This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract
Introduction . Autoimmune diseases include a diverse and complex group of pathologies with a broad clinical spectrum due to the production of autoantibodies, which generates multisystemic compromise. Therapeutic plasma exchange (TPE) is a good additive treatment for immunosuppression due to its action over the autoantibodies. Objectives . To describe the main clinical characteristics and outcomes of patients with systemic lupus erythematosus and other systemic autoimmune diseases managed with TPE. Methodology . This descriptive retrospective study enrolled patients with systemic autoimmune diseases who received TPE. Results . In total, 66 patients with a median age of 33.5 years (24-53 years) were included; the majority were females [n=51 (77.27%)]. Forty (60.61%) patients were diagnosed with systemic lupus erythematosus. In these cases, the main indication for TPE was diffuse alveolar hemorrhage (DAH; n=20, 30.3%) and neurolupus (n=9, 13.6%). No TPE-related deaths occurred, and the main complication was hemorrhage, without significant differences among the four types of TPE solutions used. The overall outcome was improvement in 41 (62.12%) patients. Conclusion . TPE is safe and effective in patients with severe manifestations of autoimmune diseases. 1. Introduction
Autoimmune diseases include a broad spectrum of pathologies, compromising diverse organs, tissues, systems, or, in some cases, systemic involvement, and these affect up to 7% of the population worldwide. The pathophysiology of these diseases can be mediated by both cellular and humoral immunity. When there is an exaggerated production of autoantibodies against certain antigens, damage is induced and immune complexes are formed, increasing organ injury, which is irreversible in some cases if timely interventions are not performed [ 1 ]. Among the group of autoimmune diseases with severe multisystemic compromise, systemic lupus erythematosus (SLE); antiphospholipid syndrome (APS); ANCA-positive vasculitis, such as granulomatosis with polyangiitis (previously known as Wegener’s granulomatosis), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (previously known as Churg-Straus syndrome); autoimmune hemolytic anemia (AHAI); idiopathic thrombocytopenic purpura (ITP); and systemic sclerosis (scleroderma) are well described. Although all these entities are treated with different immunosuppressive agents, each with different levels of evidence and outcomes, when there is severe compromise, positive outcomes have been shown following the removal of autoantibodies with therapeutic plasma exchange (TPE) procedure in critical patients [ 2 – 4 ]. The American Society for Apheresis (ASFA) guidelines of 2016, define the term plasmapheresis as “a procedure in which blood of the patient or the donor is passed through a medical device which separates plasma from other components of blood and the plasma is removed (i.e., less than 15% of total plasma volume) without the use of colloid replacement solution” and TPE as “a therapeutic procedure in which blood of the patient is passed through a medical device which separates plasma from other components of blood. The plasma is removed and replaced with a replacement solution such as colloid solution (e.g., albumin and/or plasma) or a combination of crystalloid/colloid solution” [ 4 ].
TPE is an extracorporeal blood purification technique for the removal of high molecular weight substances (>15,000 Da), such as pathogenic autoantibodies, immune complexes, cryoglobulins, myeloma light chains, endotoxins, and lipoproteins that contain cholesterol. The basic premise of this treatment is to reverse the pathological process mediated by these substances. Other potential benefits of TPE include the discharge of the reticuloendothelial system, the stimulation of lymphocyte clones to increase cytotoxic therapy, and the possibility of reinfusion of large amounts of plasma without the risk of intravascular volume overload [ 2 , 5 , 6 ]. Although this technique has been used and has been proven to be a good therapeutic option, evidence is still scarce. The objective of this study was to describe the demographic and clinical characteristics, whether the election treatment was TPE, and the outcome of patients with systemic autoimmune diseases who received either of those management options at a high-complexity center. 2. Methods
This descriptive retrospective study enrolled every patient, male and female that met the inclusion criteria of receiving TPE as treatment for systemic autoimmune diseases (SLE, ANCA-associated vasculitis, inflammatory myopathies, diffuse scleroderma, autoimmune meningoencephalitis, rheumatoid arthritis, cryoglobulinemia, and primary APS), at the Fundación Valle del Lili, which is a high-complexity hospital in Cali-Colombia, from January 1, 2011, to May 31, 2017. Patients with solid organ and hematopoietic neoplasia, myasthenia gravis, acute demyelinating polyneuropathy (Güillain–Barré syndrome), and chronic idiopathic demyelinating polyneuropathy (CIDP), who received TPE, as well as those with incomplete clinical records were excluded. This study was approved by the ethics committee in Fundación Valle del Lili, which accepted the nonperformance of patient consent. 2.1. Procedures
TPE was performed by continuous flow centrifugation (Fenwal Amicus®; Com.Tec Fresenius Kabi®). The venous access was always central line. As separation is achieved by centrifugation, patients receive regional anticoagulation with citrate, which varies in proportion from 1:12 to 1:16 as well as the replacement solution, depending on the volume, time and type of solution for each subject. Prophylactic calcium was not part of the protocol. Plasma exchanges were performed with 5% albumin, fresh frozen plasma (FFP), 5% albumin combined solution and FFP, or 4% polysuccinate gelatin (Infukoll®), according to the indication of the attending physician and intensive care group. The procedures were performed by trained nurses in charge of apheresis and hemodialysis.
Descriptive statistical analysis was conducted, and continuous variables were expressed as average and standard deviation or median and interquartile range (IQR) according to the assumption of normality. Categorical variables were presented in proportions, and the Chi-square test or Fisher’s exact test was performed to determine the correlation between them as appropriate. Statistical significance was defined as p 500 μ mol/L or hemodialysis), and/or DAH; seven sessions in a period of 14 days with a volume of 60 mL/kg/session are recommended [ 35 , 36 ].
The fatal outcomes of TPE versus immunosuppression in renal involvement due to ANCA vasculitis are not significant different [ 37 , 38 ]. In a recent Latin American study, Caffagi et al. compared 48 patients with ANCA vasculitis (GPA and MAP), whereby 24 patients received plasma exchange and the other 24 immunosuppressive therapy only. After 12 months, both groups showed eGFR improvement, and the survival rate was 79% in the plasma exchange group and 96% in the control group; the main cause of death was infections [ 39 ]. Regarding DAH secondary to ANCA vasculitis and Goodpasture syndrome, there are no randomized trials on the use of TPE. Klemmer et al. analyzed 20 cases of ANCA vasculitis with DAH and showed that alveolar hemorrhage was resolved in 20 patients with an average of 6.4 plasma exchange sessions, 55% of the 20 DAH patients improved, and 35% died [ 40 ].
In our study, two cases of diffuse scleroderma received plasma exchange due to DAH and severe fibrous and cutaneous involvement with rapid progression. The DAH associated with systemic sclerosis is very controversial; few cases have been reported [ 41 ]. Cozzi et al. performed TPE in 28 patients with SSc compared to 25 controls with D-penicillamine, the TPE regimen used was 4% albumin every 2–3 days in the first two weeks, then once a week for three months, and finally once every two weeks as a maintenance regimen. Serum aminoterminal type III procollagen peptide and interleukin 2 soluble receptor levels and DR+ T cells blood percentages before and after TPE were measured, in addition to skin and visceral scores. They concluded that there was a statistically significant decrease in the serum levels of these substances due to disease progression, as well as the clinical scores [ 42 ]. In our series, neither of the two patients improved their signs and symptoms related to scleroderma; however, alveolar hemorrhage was resolved in one patient.
None of the three patients with inflammatory myopathies improved. Consistent with similar evidence in the literature, the use of TPE in these entities would not be recommended, because in many cases they are mediated by cellular cytotoxicity and not by antibodies [ 7 , 43 ].
Primary CNS vasculitis is a rare condition (2.4 cases per million people), with mortality rate of 10–17% and moderate to severe neurological sequelae in up to 20% of cases. Due to the lack of randomized clinical trials, treatment is based on other vasculitis and case reports, with pulses of steroids and cyclophosphamide [ 44 ]. In a series of 163 patients reported by Salvarani et al., two patients received TPE [ 45 ]. The only case in our series with this condition showed symptom improvement.
A case of type II cryoglobulinemia has been described, with excellent response to TPE and subsequent Rituximab with sufficient evidence in this entity [ 7 , 46 ].
From our data, we can conclude that TPE is a safe procedure with good responses observed in patients with systemic autoimmune pathologies mediated by autoantibodies. The overall outcomes were improvement in 41 (62.12%) patients, with no changes in 13 (19.6%), and death in 12 (18%), none of which was secondary to TPE. More studies should be performed to determine the best solution to perform plasma exchange. Data Availability
The data used to support the findings of this study are available from the corresponding author upon request. Additional Points
Study Limitations. Although our study sample is relevant, with the enrollment of patients with any of the systemic autoimmune diseases, the sample for each one diminishes their representative attribute, whereby obtaining definitive conclusions for every pathology is limited. Other limitations are that it was a retrospective study, the lack of some data, and having a better antibody profile before and after TPE. Conflicts of Interest
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Treatment of chronic non-infectious uveitis and scleritis

Treatment of chronic non-infectious uveitis and scleritis

a Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, Ophthalmology Department, University of Lausanne, Switzerland b Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois CHUV, Lausanne, Switzerland Summary Ocular inflammations such as uveitis and scleritis can lead to significant visual impairment if not treated properly. To limit potentially sight-threatening complications, good control of the inflammation in the acute phase is necessary. Corticosteroids have been the mainstay of ocular therapies for many years, but high doses of corticosteroids, which are required to maintain quiescence in severe uveitis, can be associated with many systemic and ocular complications. In order to limit steroid side-effects, classic immunosuppressant and immunobiologic agents have been widely used as steroid-sparing agents. In this review, we summarise the immunosuppressive drug therapy utilised in the treatment of ocular inflammatory diseases. Keywords: uveitis, scleritis, azathioprine, methotrexate, mycophenolate mofetil, immunosuppressive agents, anti-TNF agents, biological therapy Introduction Ocular inflammatory diseases, such as severe uveitis and scleritis, may require intense immunosuppressive therapy to control ocular inflammation and prevent irreversible visual impairment. Non-infectious uveitis consists of a wide group of ocular inflammatory diseases and ocular complications and accounts for 10‒15% of preventable blindness in developed countries [ 1 , 2 ]. Ocular inflammation may be restricted to the eye or can be associated with systemic disease. According to the Standardization of Uveitis Nomenclature (SUN) working group, uveitis can be classified, according to the primary anatomical location of the inflammation, as anterior, intermediate, posterior, or panuveitis when affecting all three areas [ 3 ]. Intermediate, posterior and panuveitic disease have a higher risk of vision loss compared to anterior uveitis. Recent epidemiological data give yearly incidences of uveitis of between 14 and 17 per 100,000. The prevalence is between 58 and 115 per 100,000 [ 4 – 6 ]. The large variation in prevalence is due to variation in diagnostic workup, heterogeneity of the disease, lack of uniform classification and referral or selection bias [ 7 ]. The median age of onset of uveitis is around 35 years [ 8 ]. About 35% of all uveitis patients have been reported to suffer significant visual impairment or legal blindness [ 1 , 9 ]. Prompt therapy and rapid control of ocular inflammation are the key to maintaining good visual acuity. Uveitis and scleritis can have a devastating effect on visual acuity. Before the era of corticosteroids, about 50% of juvenile idiopathic arthritis-associated uveitis cases had a poor visual outcome of legal blindness [ 10 , 11 ]. Corticosteroids have been the mainstay of ocular therapies for many years, but high doses of corticosteroids are necessary to maintain quiescence in severe uveitis, particularly in severe ocular inflammatory diseases. However, their long-term use is associated with many systemic and ocular complications. Common systemic complications include cortico-induced diabetes, systemic hypertension, osteoporosis and mood disorders [ 12 ]. Ocular complications include cataracts and a rise of ocular pressure in steroid responder patients. The risk of ocular hypertension increases with the potency of the steroids and is directly related to the administered dose. In order to limit steroid side-effects, classic immunosuppressant agents have been widely used as steroid-sparing agents, particularly with steroid doses still over 10mg/day after six months of therapy [ 13 – 15 ]. Current disease-modifying antirheumatic drugs (DMARDs) include methotrexate, mycophenolate mofetil, cyclosporine A and azathioprine. However, in severe uveitis, systemic steroid therapy remains necessary to control ocular inflammation. The recent development of biological agents, particularly anti-TNFα agents, has opened up a new era in the treatment of uveitis. The aim of this paper is to review recent ophthalmological literature concerning new treatment modalities for non-infectious uveitis and scleritis, and to offer a practical guide for internists and general practitioners. Uveitis generalities The standardization of uveitis nomenclature (SUN) project considerably improved the assessment of drug efficacy in uveitis, with classification based on the primary site of inflammation within the eye and standardised use of clinical grading as a tool for assessing the degree of inflammation [ 3 ]. Uveitis can be classified as anterior, intermediate or posterior uveitis, according to the primary site of inflammation [ 3 ]. In anterior uveitis, the anterior chamber is the main site of inflammation and it includes iritis, iridocyclitis and anterior cyclitis. In intermediate uveitis, the vitreous is the main site of inflammation and it includes posterior cyclitis, hyalitis and pars planitis. Finally, posterior uveitis affects the retina and/or choroid. If all three eye segments are involved, the term panuveitis is used. Uveitis can also be classified, according to the type of presentation, as acute, recurrent or chronic [ 3 ]. In terms of etiology, the two major categories are infectious and non-infectious uveitis. The latter includes the following etiologies: sarcoidosis, Behçet’s disease, ankylosing spondylitis, inflammatory bowel disease, Juvenile idiopathic arthritis, seronegative arthropathy, reactive arthritis, multiple sclerosis and Vogt-Koyanagi-Harada syndrome. Scleritis generalities Scleritis is associated with a systemic inflammatory disease in over 50% of cases [ 16 ]. The disease is classified as anterior or posterior, diffuse or nodular, necrotising or non-necrotising and infectious or non-infectious [ 17 ]. In severe, non-infectious scleritis, therapy is mostly guided by the presence of an underlying systemic disease, mainly rheumatoid arthritis, relapsing polychondritis, granulomatosis with polyangiitis (GPA, formerly Wegener’s granulomatosis) and systemic lupus erythematosus. According to Baeten et al, disease entities should be classified by pathogenesis rather than phenotypic disease classification [ 18 ], but anatomical localisation of inflammation will also guide the speed of introduction of therapies. Necrotising scleritis (also referred to as scleromalacia perforans) associated with granulomatosis with polyangiitis or rheumatoid arthritis requires the introduction of bDMARDs such as rituximab at an early stage to avoid ocular perforation [ 19 ]. Treatments generalities To limit potentially sight-threatening complications, good control of the inflammation in the acute phase is necessary. Two strategies can be used to control intraocular inflammation, the classical “step-up” approach and the “top-down” approach. In the step-up approach, therapies are progressively introduced in a stepladder fashion until sufficient control of the intraocular inflammation is reached [ 20 ]. First-line therapy consists of topical corticosteroids. In the absence of response or if topical corticosteroids induce ocular hypertension/glaucoma or cataracts, systemic corticosteroids are introduced at an initial dosage of 1 mg/kg/day, followed by immunosuppressive drugs 2–3 months later, in an attempt to minimise corticosteroid systemic side effects (steroid-sparing agents) [ 20 ]. Immunosuppressive therapy is introduced in the following cases: to control inflammation in the case of failure of or insufficient response to treatment with corticosteroids, particularly in the case of high-risk uveitis syndrome, and/or to prevent cortico-induced toxicity (steroid-sparing agents). It should be noted that, despite an increasing number of randomised clinical trials studying the effectiveness of immunosuppressive therapies in uveitis, most of our knowledge in this area comes from retrospective studies. This is principally due to the large heterogeneity, and also the relative rarity, of uveitides. Several promising new treatments for inflammatory ocular diseases are under investigation, such as JAK inhibitors [ 21 ], but here we shall mainly focus on the currently approved treatments for inflammatory eye diseases, namely glucocorticoids, anti-metabolites (azathioprine, methotrexate and mycophenolate mofetil), T cell/calcineurin inhibitors (cyclosporine A) and biologics. Glucocorticoids Corticosteroids have inhibitory effects on a broad range of immune responses, via inhibitory effects on the gene transcription of several pro-inflammatory cytokines, effects on post-translational events, including the suppression of COX-2 synthesis, and also through the non-genomic activation of anti-inflammatory proteins [ 22 ]. In uveitis, corticosteroids can be used topically, periocularly, intraocularly or systemically. The limits and risks of local therapies compared to systemic therapies are the key factors determining the therapeutic decision. Local corticosteroids have an efficacy mainly on anterior uveitis, with poor efficacy on the posterior segment of the eye. Corticosteroids are associated with multiple ocular complications, such as ocular hypertension in steroid responder patients. Amarly et al demonstrated that about one third of patients had an increased ocular pressure after initiation of topical dexamethasone drops TID [ 23 ]. The severity of ocular hypertension is directly correlated with the potency of corticosteroids. The two topical steroids with the greatest potency, 0.1% dexamethasone and 1% prednisolone acetate, had the greatest effect on ocular pressure, with rises in IOP of 22.9 ± 2.9 and 10 ± 1.7 mmHg respectively [ 24 ]. A recent study was able to stratify the relative risk of ocular hypertension, which was directly correlated with the number of daily doses administered. With a mean administration of eight drops per day, the adjusted hazard ratio (HR) of increase in IOP was around eight in children, while one drop daily had almost no effect on ocular pressure, with an HR of 1 [ 25 ]. In the adult population, the same trend was observed but with lower limits, eight drops a day producing an HR of about 3 [ 26 ]. Periocular administration of corticosteroids is particularly interesting for the avoidance of systemic side effects. This consists of the subconjunctival injection of betamethasone, the sub-tenon injection of triamcinolone acetonide suspension and the intravitreal injection of a long-term dexamethasone delivery system, used for inflammatory cystoid macular edema in particular [ 27 ]. Periocular or intraocular steroid injections are, however, mainly used as adjuvant therapy to systemic therapies [ 28 ]. Systemic steroid therapy is reserved for bilateral, intermediate and posterior uveitis, panuveitis, or any form of sight-threatening uveitis. The classical dosage is 1–1.5 mg/kg/day of prednisone/prednisolone p.o. or 250‒1,000 mg of methylprednisolone IV daily for three days, followed by oral therapy [ 29 ]. The rate of corticosteroid decrease should be adapted by ophthalmologists according to the uveitis activity and should not be more than 10% every 2-3 weeks to avoid a relapse of inflammation. Cyclosporine A Cyclosporine A (CycA) is a lipophilic cyclic peptide, comprised of 11 amino acids and derived from fungi, which selectively inhibits calcineurin, thereby impairing the transcription of interleukin-2, TNFα and several other cytokines in T lymphocytes. Unlike other immunosuppressive agents such as azathioprine and the alkylating agents, CycA lacks clinically significant myelosuppressive activity [ 30 ]. Calcineurin inhibitors have been used for immunosuppression in solid organ transplantation for over three decades. Nephrotoxicity and arterial hypertension represent the major side effects of cyclosporine [ 31 ]. Classical dosage for ophthalmologic indications is 150–200 mg/day (2.5–5 mg/kg/day). Typical ocular indications for CycA are ocular Behçet’s disease, birdshot chorioretinopathy, ocular sarcoidosis, pars planitis, VKH syndrome, tubulointerstitial nephritis and uveitis syndrome (TINU), sympathetic ophthalmia, idiopathic posterior uveitis, peripheral ulcerative keratitis and scleritis (particularly in GPA) [ 20 ]. However, in recent studies, biological therapies such as anti-TNFα agents were preferred for first-line therapy in sight-threatening uveitis, and cyclosporine was usually used as second- or third-line therapy [ 20 , 32 , 33 ]. Interestingly, CycA was shown to selectively attenuate Th17 cells, a T-helper memory-derived cell population that seems to play an important role in the mechanism of corticosteroid-resistance in inflammatory conditions. This finding opens up new possibilities for the development of drugs that could be used in cases of corticosteroid-resistant intraocular inflammation [ 34 ]. Azathioprine The prodrug azathioprine (AZA) is an immunosuppressive agent, metabolised in the liver to its active form 6-mercapto-purine, that inhibits maturation of B and T lymphocytes through its activity as an antagonist of purine metabolism, resulting in the inhibition of DNA, RNA, and consequently protein synthesis. AZA is widely used in the management of uveitis [ 35 , 36 ]. AZA is generally used at an initial dose of 1mg/kg/day, and the dose is then progressively increased to 2‒2.5mg/day in the absence of haematological and hepatic adverse events. AZA has been shown to successfully controlled ocular inflammatory disease in 62% of patients [ 37 ]. As AZA is moderately effective for controlling inflammation when used in monotherapy, it is typically used in combination with other immunosuppressive agents. AZA seems to be more effective in patients with intermediate uveitis (90% with sustained inactivity within one year) [ 37 ]. AZA is typically prescribed for juvenile idiopathic arthritis (JIA) iridocyclitis, Behçet’s disease, GPA, sympathetic ophthalmia, VKH’s syndrome, ocular sarcoidosis and pars planitis. Patients under AZA should be regularly monitored with a complete blood counts and hepatic tests. Both AZA and CicA are considered safe options for pregnant women that need to pursue treatment in sight-threatening ocular inflammatory disease. Methotrexate Methotrexate (MTX) is a structural analogue of folic acid that can competitively inhibit the binding of dihydrofolic acid (FH2) to the enzyme dihydrofolate reductase (DHFR), thereby interfering with purine and pyrimidine metabolism and therefore inhibiting DNA and RNA synthesis, DNA repair and cell division. At lower doses MTX achieves anti-inflammatory effects. MTX can be administered for ocular sarcoidosis, JIA-associated uveitis, reactive arthritis-, ankylosing spondylitis- and inflammatory bowel disease (IBD)-associated uveitis, scleritis, and sympathetic ophthalmia [ 20 ]. It can be used as a first-line corticosteroid-sparing drug or in combined therapy. MTX has been shown to successfully control ocular inflammation in 66-76.2% of patients in combination with low doses of corticosteroids (<10 mg/day) [ 38 , 39 ]. In a prospective study of a large cohort of 3,512 JIA patients, Tappeiner et al. showed that the early use of MTX or MTX + TNFα inhibitors within the first year of active arthritis has a highly protective effect against development of uveitis [ 40 ]. In adults, MTX should be preferentially administered as weekly subcutaneous injections. Biodisponibility of oral MTX is erratic, digestive side-effects are common and there is a risk of accidental daily intake. Subcutaneous MTX is started at an initial dose of 7.5–15 mg/week and may be increased to 20–25 mg/week. Five mg of oral folic acid is administered the day after the weekly MTX injection to limit haematologic toxicity. The main side effects of MTX include myelosuppression (leucopenia and thrombocytopenia) due to folic acid antagonism, infections, liver toxicity and pneumonitis. MTX is contra-indicated in pregnancy. Mycophenolate mofetil Mycophenolate mofetil (MMF) is a selective inhibitor of inosine monophosphate dehydrogenase that interrupts guanosine synthesis. It suppresses T and B lymphocyte proliferation, reduces antibody production and inhibits transmigration of leukocytes. This drug is used as an anti-rejection drug in transplant patients and has shown efficacy in the treatment of systemic autoimmune disease [ 41 ]. MMF has been widely tested for treating refractory uveitis and severe scleritis [ 42 ]. Complete control of inflammation was achieved in 53% of patients at six months and 73% within one year [ 43 , 44 ]. MMF is teratogenic, and contraceptive measures are needed in women of child-bearing age. Anti-TNFα TNFα is a pleiotropic, pro-inflammatory cytokine which plays an important role not only in host defence against intracellular pathogens, but also in the pathogenesis of numerous inflammatory diseases such as non-infectious uveitis (NIU). TNFα was shown to be up-regulated in the aqueous humour and serum of patients with uveitis and is thought to play a key role in the physiopathology of uveitic inflammation [ 45 ]. At the molecular level, TNFα is synthetised as a transmembrane protein that is then cleaved by a TNFα converting enzyme (TACE) to release soluble TNFα. TNFα exerts its function by acting on two distinct receptors: TNF receptor 1 (TNFR1) and TNFR2. The understanding of TNFα-induced signalling has been enriched in the last few decades, revealing the formation of distinct signalling protein complexes that lead to different functional outcomes such as inflammation, apoptosis and necroptosis [ 46 ]. Interestingly, TNFR1 binds both soluble (sTNFα) and membrane bound TNFα (mTNFα), and principally mediates inflammation and cell death. In contrast, TNFR2 binds only mTNFα and plays a role in tissue homeostasis, regeneration and immune regulation. The current approved anti-TNFα treatments inhibit both pathways and therefore interfere with the homeostatic functions of TNFα. A new concept in the therapeutics of TNF-mediated diseases is to selectively inhibit the pathogenic effects of TNFα, preserving its homeostatic functions by targeting specifically sTNFα or TNFR1 [ 47 ]. Currently, five biologic agents targeting TNFα are approved for the treatment of rheumatoid arthritis, inflammatory bowel disease, psoriasis, psoriatic arthritis, ankylosing spondylitis and juvenile idiopathic arthritis (JIA). These are infliximab (Remicade ® ), adalimumab (Humira ® ), certolizumab pegol (Cimzia ® ), golimumab (Simponi ® ) and etanercept (Enbrel ® ) [ 46 ]. In addition to the approved indications, anti-TNFα is also used, off-label, in sarcoidosis, Behçet disease, non-infectious ocular inflammation, pyoderma gangrenosum and in patients with TNF receptor-associated periodic fever syndrome (TRAPS) and adult-onset Still’s disease [ 48 ]. To date, adalimumab (Humira ® ) is the only immunobiologic agent that has been approved in Switzerland in the indication of non-infectious intermediate or posterior uveitis, or panuveitis, as a corticosteroid sparing agent in the absence of adequate response to corticosteroids with or without immunosuppressive agents. Recent studies have shown the beneficial role of the anti-TNFα adalimumab in active and inactive, non-infectious intermediate and posterior uveitis and panuveitis (NIIPPU). The VISUAL I study, a multicentre, double-masked, randomised, placebo-controlled phase 3 trial, showed that patients with active NIIPPU who were treated with adalimumab presented a lower risk of uveitic flare or visual impairment than patients who received a placebo [ 49 ]. The parallel study, VISUAL II, a multicentre, double-masked, randomised, placebo-controlled phase 3 trial, showed that adalimumab significantly lowered the risk of uveitic flare or loss of visual acuity upon corticosteroid withdrawal in patients with inactive NIIPPU controlled by systemic corticosteroids [ 50 ]. VISUAL III is the open label extension of VISUAL I and II. This study was able to demonstrate a numerical improvement in steroid-free quiescence and steroid dose reduction [ 51 ]. Finally, among children and adolescents with active JIA-associated uveitis who were taking a stable dose of methotrexate, the SYCAMORE study showed control of inflammation in the adalimumab treated group compared with a placebo, as observed in the adult population [ 52 ]. Anti-TNFα represents an extraordinarily effective treatment for many auto-immune diseases, including NIIPPU, even though these compounds may, in rare cases, cause autoimmune conditions such as drug-induced lupus (DIL), demyelinating disease, autoimmune hepatitis, psoriasis and even uveitis [ 53 ]. The mechanisms underlying these auto-immune conditions is unclear, but could be partially due to the TNFα antagonists-induced production of autoantibodies such as antinuclear antibodies (ANA) and anti-double-stranded DNA antibodies (anti-dsDNA) [ 54 , 55 ]. The risk of developing auto-antibodies is lower if TNFα antagonists are administered in combination with an immunosuppressive treatment, such as MTX. The exact molecular mechanisms responsible for autoantibody formation remain unknown. Multiple sclerosis-associated uveitis (MS-associated uveitis) may be present in 5-16% of intermediate uveitis cases [ 56 ]. A brain MRI should be performed in the presence of uveitis associated with neurologic systemic symptoms in order to rule out the presence of MS before the introduction of an anti-TNF agent. According to the SABER Study, a retrospective, population-based cohort study, optic neuritis is rare among patients who initiate anti-TNF therapy, and occurs with similar frequency among those with classic immunosuppressant exposure [ 57 ]. Finally, the use of monoclonal antibody therapies targeting TNFα can result in immunisation, with the apparition of anti-drug antibodies. The latter may give rise to low serum drug levels, loss of therapeutic response, and adverse events such as infusion reactions. The use of concomitant MTX may attenuate the frequency of anti-drug antibodies (ADA) [ 58 ]. The ARMADA trial showed an incidence of anti-adalimumab antibodies lower than 1% in rheumatoid arthritis patients who were taking concomitant MTX, compared to an incidence of 12% in patients treated with adalimumab as monotherapy [ 59 , 60 ]. Conclusion In summary, non-infectious uveitides represent a heterogenous group of ocular inflammatory diseases affecting a broad range of age groups, with a high potential for blindness if not treated adequately. Increasing evidence supports the effectiveness and safety of using immunosuppressive drug therapy to treat ocular inflammatory diseases. The antimetabolites (AZA, MTX) and the biologics (anti-TNFα), in particular, appear to offer the best balance between effectiveness and safety, and represent an excellent alternative to corticosteroid therapy. Immunosuppressive drugs should be used in the case of corticosteroids failure or insufficient control of inflammation to prevent corticosteroid-induced side effects, and to treat high-risk uveitis syndromes. Disclosure statement No financial support and no other potential conflict of interest relevant to this article was reported. Correspondence Prof. Yan Guex-Crosier , Jules-Gonin Eye Hospital , 15 av. de France , CH-1004 Lausanne , yan.guex[at]fa2.ch References 1 Rothova A, Suttorp-van Schulten MS, Frits Treffers W, Kijlstra A. Causes and frequency of blindness in patients with intraocular inflammatory disease. Br J Ophthalmol. 1996 Apr;80(4):332–6. 2 Durrani OM, Tehrani NN, Marr JE, Moradi P, Stavrou P, Murray PI. Degree, duration, and causes of visual loss in uveitis. Br J Ophthalmol. 2004 Sep;88(9):1159–62. 3 Jabs DA, Nussenblatt RB, Rosenbaum JT; Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data. 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Klin Monatsbl Augenheilkd. 2017;234(4):567–70. doi:. http://dx.doi.org/10.1055/s-0042-121315 PubMed 20 Foster CS, Kothari S, Anesi SD, Vitale AT, Chu D, Metzinger JL, et al.The Ocular Immunology and Uveitis Foundation preferred practice patterns of uveitis management. Surv Ophthalmol. 2016;61(1):1–17. doi:. http://dx.doi.org/10.1016/j.survophthal.2015.07.001 PubMed 21 Pleyer U, Algharably EA-H, Feist E, Kreutz R. Small molecules as therapy for uveitis: a selected perspective of new and developing agents. Expert Opin Pharmacother. 2017;18(13):1311–23. doi:. http://dx.doi.org/10.1080/14656566.2017.1361408 PubMed 22 Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids–new mechanisms for old drugs. N Engl J Med. 2005 Oct 20;353(16):1711–23. 23 Armaly MF, Becker B. Intraocular pressure response to topical corticosteroids. Fed Proc. 1965;24(6):1274–8. PubMed 24 Cantrill HL, Palmberg PF, Zink HA, Waltman SR, Podos SM, Becker B. Comparison of in vitro potency of corticosteroids with ability to raise intraocular pressure. Am J Ophthalmol. 1975;79(6):1012–7. doi:. http://dx.doi.org/10.1016/0002-9394(75)90687-X PubMed 25 Kothari S, Foster CS, Pistilli M, Liesegang TL, Daniel E, Sen HN, et al.; Systemic Immunosuppressive Therapy for Eye Diseases Research Group. The Risk of Intraocular Pressure Elevation in Pediatric Noninfectious Uveitis. Ophthalmology. 2015;122(10):1987–2001. doi:. http://dx.doi.org/10.1016/j.ophtha.2015.06.041 PubMed 26 Daniel E, Pistilli M, Kothari S, Khachatryan N, Kaçmaz RO, Gangaputra SS, et al.; Systemic Immunosuppressive Therapy for Eye Diseases Research Group. Risk of Ocular Hypertension in Adults with Noninfectious Uveitis. Ophthalmology. 2017;124(8):1196–208. doi:. http://dx.doi.org/10.1016/j.ophtha.2017.03.041 PubMed 27 Goldhardt R, Rosen BS. Uveitic Macular Edema: Treatment Update. Curr Ophthalmol Rep. 2016;4(1):30–7. doi:. http://dx.doi.org/10.1007/s40135-016-0090-3 PubMed 28 Writing Committee for the Multicenter Uveitis Steroid Treatment (MUST) Trial and Follow-up Study Research Group, Kempen JH, Altaweel MM, Holbrook JT, Sugar EA, Thorne JE, et al. Association Between Long-Lasting Intravitreous Fluocinolone Acetonide Implant vs Systemic Anti-inflammatory Therapy and Visual Acuity at 7 Years Among Patients With Intermediate, Posterior, or Panuveitis. JAMA. 2017 May 16;317(19):1993–2005. 29 Charkoudian LD, Ying G-S, Pujari SS, Gangaputra S, Thorne JE, Foster CS, et al.High-dose intravenous corticosteroids for ocular inflammatory diseases. Ocul Immunol Inflamm. 2012;20(2):91–9. doi:. http://dx.doi.org/10.3109/09273948.2011.646382 PubMed 30 Ishida Y, Matsuda H, Kida K. Effect of cyclosporin A on human bone marrow granulocyte-macrophage progenitors with anti-cancer agents. Acta Paediatr Jpn. 1995;37(5):610–3. doi:. http://dx.doi.org/10.1111/j.1442-200X.1995.tb03386.x PubMed 31 Burdmann EA, Andoh TF, Yu L, Bennett WM. Cyclosporine nephrotoxicity. Semin Nephrol. 2003;23(5):465–76. doi:. http://dx.doi.org/10.1016/S0270-9295(03)00090-1 PubMed 32 Yamada Y, Sugita S, Tanaka H, Kamoi K, Takase H, Mochizuki M. Timing of recurrent uveitis in patients with Behcet’s disease receiving infliximab treatment. Br J Ophthalmol. 2011;95(2):205–8. doi:. http://dx.doi.org/10.1136/bjo.2009.168856 PubMed 33 Lindstedt EW, Baarsma GS, Kuijpers RWAM, van Hagen PM. Anti-TNF-alpha therapy for sight threatening uveitis. Br J Ophthalmol. 2005;89(5):533–6. doi:. http://dx.doi.org/10.1136/bjo.2003.037192 PubMed 34 Schewitz-Bowers LP, Lait PJP, Copland DA, Chen P, Wu W, Dhanda AD, et al.Glucocorticoid-resistant Th17 cells are selectively attenuated by cyclosporine A. Proc Natl Acad Sci USA. 2015;112(13):4080–5. doi:. http://dx.doi.org/10.1073/pnas.1418316112 PubMed 35 Trotter JL, Rodey GE, Gebel HM. Azathioprine decreases suppressor T cells in patients with multiple sclerosis. N Engl J Med. 1982;306(6):365–6. doi:. http://dx.doi.org/10.1056/NEJM198202113060615 PubMed 36 Elion GB. The purine path to chemotherapy. Science. 1989;244(4900):41–7. doi:. http://dx.doi.org/10.1126/science.2649979 PubMed 37 Pasadhika S, Kempen JH, Newcomb CW, Liesegang TL, Pujari SS, Rosenbaum JT, et al.Azathioprine for ocular inflammatory diseases. Am J Ophthalmol. 2009;148(4):500–509.e2. doi:. http://dx.doi.org/10.1016/j.ajo.2009.05.008 PubMed 38 Gangaputra S, Newcomb CW, Liesegang TL, Kaçmaz RO, Jabs DA, Levy-Clarke GA, et al.; Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study. Methotrexate for ocular inflammatory diseases. Ophthalmology. 2009;116(11):2188–98.e1. doi:. http://dx.doi.org/10.1016/j.ophtha.2009.04.020 PubMed 39 Samson CM, Waheed N, Baltatzis S, Foster CS. Methotrexate therapy for chronic noninfectious uveitis: analysis of a case series of 160 patients. Ophthalmology. 2001;108(6):1134–9. doi:. http://dx.doi.org/10.1016/S0161-6420(01)00576-0 PubMed 40 Tappeiner C, Schenck S, Niewerth M, Heiligenhaus A, Minden K, Klotsche J. Impact of Antiinflammatory Treatment on the Onset of Uveitis in Juvenile Idiopathic Arthritis: Longitudinal Analysis From a Nationwide Pediatric Rheumatology Database. Arthritis Care Res (Hoboken). 2016 ;68(1):46–54. 41 Lipsky JJ. Mycophenolate mofetil. Lancet. 1996;348(9038):1357–9. doi:. http://dx.doi.org/10.1016/S0140-6736(96)10310-X PubMed 42 Kilmartin DJ, Forrester JV, Dick AD. Rescue therapy with mycophenolate mofetil in refractory uveitis. Lancet. 1998;352(9121):35–6. doi:. http://dx.doi.org/10.1016/S0140-6736(05)79515-5 PubMed 43 Sobrin L, Christen W, Foster CS. Mycophenolate mofetil after methotrexate failure or intolerance in the treatment of scleritis and uveitis. Ophthalmology. 2008 Aug;115(8):1416–21–1421. 44 Teoh SC, Hogan AC, Dick AD, Lee RWJ. Mycophenolate mofetil for the treatment of uveitis. Am J Ophthalmol. 2008 Nov;146(5):752–60–760. 45 Santos Lacomba M, Marcos Martín C, Gallardo Galera JM, Gómez Vidal MA, Collantes Estévez E, Ramírez Chamond R, et al.Aqueous humor and serum tumor necrosis factor-alpha in clinical uveitis. Ophthalmic Res. 2001;33(5):251–5. doi:. http://dx.doi.org/10.1159/000055677 PubMed 46 Kalliolias GD, Ivashkiv LB. TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nat Rev Rheumatol. 2016;12(1):49–62. doi:. http://dx.doi.org/10.1038/nrrheum.2015.169 PubMed 47 Fischer R, Kontermann R, Maier O. Targeting sTNF/TNFR1 Signaling as a New Therapeutic Strategy. Antibodies. Multidisciplinary Digital Publishing Institute. 2015;4(1):48–70. 48 Karampetsou MP, Liossis S-NC, Sfikakis PP. TNF-α antagonists beyond approved indications: stories of success and prospects for the future. QJM. 2010;103(12):917–28. doi:. http://dx.doi.org/10.1093/qjmed/hcq152 PubMed 49 Jaffe GJ, Dick AD, Brézin AP, Nguyen QD, Thorne JE, Kestelyn P, et al. Adalimumab in Patients with Active Noninfectious Uveitis. N Engl J Med. 2016 Sep 8;375(10):932–43. 50 Nguyen QD, Merrill PT, Jaffe GJ, Dick AD, Kurup SK, Sheppard J, et al.Adalimumab for prevention of uveitic flare in patients with inactive non-infectious uveitis controlled by corticosteroids (VISUAL II): a multicentre, double-masked, randomised, placebo-controlled phase 3 trial. Lancet. 2016;388(10050):1183–92. doi:. http://dx.doi.org/10.1016/S0140-6736(16)31339-3 PubMed 51 Suhler EB, Adán A, Brézin AP, Fortin E, Goto H, Jaffe GJ, et al.Safety and Efficacy of Adalimumab in Patients with Noninfectious Uveitis in an Ongoing Open-Label Study: VISUAL III. Ophthalmology. 2018;125(7):1075–87. doi:. http://dx.doi.org/10.1016/j.ophtha.2017.12.039 PubMed 52 Ramanan AV, Dick AD, Jones AP, McKay A, Williamson PR, Compeyrot-Lacassagne S, et al.; SYCAMORE Study Group. Adalimumab plus Methotrexate for Uveitis in Juvenile Idiopathic Arthritis. N Engl J Med. 2017;376(17):1637–46. doi:. http://dx.doi.org/10.1056/NEJMoa1614160 PubMed 53 Alessandri C, Scrivo R, Spinelli FR, Ceccarelli F, Magrini L, Priori R, et al. Autoantibody production in anti-TNF-alpha-treated patients. Ann N Y Acad Sci. 2007 Sep;1110(1):319–29. 54 Charles PJ, Smeenk RJ, De Jong J, Feldmann M, Maini RN. Assessment of antibodies to double-stranded DNA induced in rheumatoid arthritis patients following treatment with infliximab, a monoclonal antibody to tumor necrosis factor alpha: findings in open-label and randomized placebo-controlled trials. Arthritis Rheum. 2000 Nov;43(11):2383–90. 55 De Rycke L, Kruithof E, Van Damme N, Hoffman IEA, Van den Bossche N, Van den Bosch F, et al. Antinuclear antibodies following infliximab treatment in patients with rheumatoid arthritis or spondylarthropathy. Arthritis Rheum. Wiley-Blackwell; 2003 Apr;48(4):1015–23. 56 Zein G, Berta A, Foster CS. Multiple sclerosis-associated uveitis. Ocul Immunol Inflamm. 2004;12(2):137–42. doi:. http://dx.doi.org/10.1080/09273940490895344 PubMed 57 Winthrop KL, Chen L, Fraunfelder FW, Ku JH, Varley CD, Suhler E, et al.Initiation of anti-TNF therapy and the risk of optic neuritis: from the safety assessment of biologic ThERapy (SABER) Study. Am J Ophthalmol. 2013;155(1):183–189.e1. doi:. http://dx.doi.org/10.1016/j.ajo.2012.06.023 PubMed 58 Jani M, Barton A, Warren RB, Griffiths CEM, Chinoy H. The role of DMARDs in reducing the immunogenicity of TNF inhibitors in chronic inflammatory diseases. Rheumatology (Oxford). 2014;53(2):213–22. doi:. http://dx.doi.org/10.1093/rheumatology/ket260 PubMed 59 Weinblatt ME, Keystone EC, Furst DE, Moreland LW, Weisman MH, Birbara CA, et al. Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum. 2003 Jan;48(1):35–45. 60 van de Putte LBA, Atkins C, Malaise M, Sany J, Russell AS, van Riel PLCM, et al. Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug treatment has failed. Ann Rheum Dis. 2004 May;63(5):508–16. Copyright
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Things To Know Before Shopping for Low cost Contacts From On-line Shops

Things To Know Before Shopping for Low cost Contacts From On-line Shops

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Clinical Spectrum of Complications Induced by Intravesical Immunotherapy of Bacillus Calmette-Guérin for Bladder Cancer

<h1>Clinical Spectrum of Complications Induced by Intravesical Immunotherapy of Bacillus Calmette-Guérin for Bladder Cancer</h1>

Clinical Spectrum of Complications Induced by Intravesical Immunotherapy of Bacillus Calmette-Guérin for Bladder Cancer

Urology Department, Peking University Third Hospital, Beijing, China
Correspondence should be addressed to Jian Lu ;
Received 27 August 2018; Revised 24 January 2019; Accepted 12 February 2019; Published 10 March 2019
Academic Editor: Reza Izadpanah
Copyright © 2019 Yuqing Liu et al. This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract
Because of its proven efficacy, intravesical Bacillus Calmette-Guérin (BCG) immunotherapy is an important treatment for nonmuscle invasive bladder cancer at high risk of recurrence or progression. However, approximately 8% of patients have to stop BCG instillation as a result of its complications. Complications induced by BCG therapy can have a variety of clinical manifestations. These adverse reactions may occur in conjunction with BCG instillation or may not develop until months or years after BCG cessation. An essential step in the management complications arising from BCG is early establishment of diagnosis, particularly for distant, disseminated, and obscure infections. Therefore we reviewed the literature on the potential complications after intravesical BCG immunotherapy for bladder cancer and provide an overview on the incidence, diagnosis, and treatment modality of genitourinary and systemic BCG-induced complications. 1. Introduction
Bladder cancer is the ninth most commonly diagnosed cancer and the thirteenth leading cause of cancer deaths worldwide, with an estimated 429,000 new cases and 165,000 deaths worldwide in 2012 [ 1 ]. The majority of patients diagnosed with bladder cancer present with nonmuscle invasive bladder cancer (NMIBC), including carcinoma in situ (CIS) and Ta and T1 stage. Although the gold standard management for NMIBC is complete removal of all papillary lesions via transurethral resection (TUR), there is a high rate of recurrence after the initial surgery. For all high grade and some low grade NMIBC, intravesical immunotherapy of bacillus Calmette-Guérin (BCG) is the one recommended in all the guidelines [ 2 ]. The meta-analyses of randomized trials have shown that intravesical maintenance BCG after TUR reduced the recurrence rates significantly [ 3 ], and BCG significantly reduces the risk of progression to muscle invasive disease after TUR in patients who receive maintenance BCG [ 4 ].
Despite the fact that adjuvant intravesical BCG immunotherapy is significantly more active than surgery alone, a retrospective chart review showed that only 50% of high-risk patients of NMIBC received BCG maintenance therapy as recommended by the EAU and AUA guidelines [ 5 ]. The substantial occurrence of complications was regarded as one of the main reasons for poor compliance to BCG therapy. Besides this, it was reported that only 16% of patients on maintenance BCG were able to receive all instillations of the 3-year immunotherapy, mainly because of adverse events [ 6 ]. In a more recent report on European Organization for Research and Treatment of Cancer (EORTC) trial 30911, 19% of patients who accepted intravesical BCG had to stop the treatment because of complications, and 29% completed the 3-year immunotherapy [ 7 ].
Since the precise immunological mechanism of BCG therapy is still unclear, the pathogeneses of adverse reactions following intravesical BCG instillation have been not fully explained. A controversy exists between the inflammatory hypersensitivity hypothesis, supported by histological findings of granulomas in the absence of microorganisms, and the bacteria invasion hypothesis based on the reports about the positive finding of active bacilli in a variety of tissues. [ 8 ] The first essential step following BCG instillation is attachment of live BCG to the urothelium, which brings about recruitment of immune cells to the area, initially granulocytes, followed by macrophages and lymphocytes, and the urinary release of cytokines, which is more pronounced in the case of BCG exposure, reflecting recall immune activation [ 9 ]. However, from another point of view, the microbiological identification of Mycobacterium bovis ( M. bovis ) from cases of focal disease sites and the fact that ofloxacin administration following intravesical BCG significantly reduced the incidence of BCG-related complications favor argument for direct and hematogenous BCG invasion and infection [ 10 ].
Complications induced by BCG can occur and may vary from self-limited irritative voiding symptoms to severe systemic sepsis. According to the results of the largest and most recent published study by the EORTC Genito-Urinary Cancers Group, of the 1316 patients who started BCG, 69.5% reported with local (62.8%) or systemic (30.6%) complications [ 11 ]. Chemical cystitis (35.0%) and general malaise (15.5%) were most frequent, and a total of 103 patients (7.8%) stopped treatment because of complications. From a case series and literature review, 282 cases of BCG infection after intravesical instillation were analyzed, and the most common presentations included disseminated (34.4%), genitourinary (23.4%), and osteomuscular (19.9%) infections [ 8 ]. The reported incidence of complications induced by intravesical BCG therapy was listed in Table 1 . Table 1: Incidence of complications induced by intravesical BCG immunotherapy for NMIBC [ 6 , 8 , 11 – 13 , 17 , 23 , 26 , 27 , 34 , 39 , 52 ].
There are some difficulties in diagnosis of the complications induced by BCG immunotherapy, especially of severe ones. Many complications occur late up to years after cessation of BCG therapy, and symptoms may involve elsewhere beyond the lower urinary tract. Even if there are obvious alarm symptoms induced by BCG, it may be difficult to prove the suspected BCG-related complications. Acid-fast bacilli staining, mycobacterial culture, and polymerase chain reaction (PCR) testing are often negative. Frequently, tissue biopsies are required to evaluate noncaseating granuloma formation, and specimen cultures are helpful to identify the presence of M. bovis . The overall rate of positive findings is 48% on microbiological studies (acid-fast bacilli stain, culture, and PCR assay) and 65.5% on tissue biopsy, and identification of granulomatous inflammation on specimen is available in 86.3% of cases [ 8 ]. It is a key point that the prognosis of a complication is usually dependent on early treatment initiation, so a high clinical suspicion is important to avoid delay in management. Considering the fact that most complications occur when the patient is already at home, it is quite important that primary care doctors be informed that the patient has received intravesical BCG and be familiar with possible adverse events of BCG, alarming symptoms, and practical knowledge on how to deal with the problems.
In this review, we summarized updated clinical studies and illustrative case reports to provide an overview on the incidence, presentation, diagnosis, and treatments of potential genitourinary and systemic complications resulting from intravesical BCG immunotherapy for NMIBC. 2. Genitourinary Complications 2.1. Cystitis
Irritative lower urinary tract symptoms are the most common complication after intravesical BCG instillation [ 12 ]. Typically, these voiding symptoms can be accompanied by gross hematuria with absence of positive urine cultures. In the EORTC study with BCG instillation, 23.6% cases suffered frequency of more than once per hour, and 22.6% cases complained with macroscopic hematuria [ 11 ]. Urine and blood cultures are necessary to exclude bacterial urinary tract infection and/or sepsis.
If the symptoms are considered as the consequence of immune stimulation and the associated inflammatory response, usually accompanied with flu-like illness, spontaneous recovery is expected within 48 hours without intervention [ 13 ]. When these symptoms last for a longer time or become increasingly intolerable, symptomatic treatment with spasmolytics, anticholinergics, or nonsteroidal anti-inflammatory drugs is empirically advised. It should be noted that no randomized clinical trials on these drugs even with extended release formulas versus placebo have ever been conducted with the exception of oxybutynin which failed to be proven effective [ 14 ].
If bacterial cystitis is diagnosed, antibiotics administration is recommended. Ofloxacin had been proved to diminish BCG-related local complications by a randomized, double-blind clinical trial [ 15 ]. Considering the rather high risk of associated bacterial cystitis in persisting voiding symptoms, in a pragmatic way, the antibiotics therapy could start with ofloxacin blindly and then be adjusted when the result of the urine culture is available [ 16 ]. Further BCG intravesical therapy should be withheld, not only because BCG microorganisms can be sensitive to antibiotic therapy, but also for avoiding severe inflammatory reactions induced by combination of BCG-induced response and bacterial cystitis. Therefore, BCG instillation should be postponed until completion of a course of culture specific antibiotics. There is little literature to suggest that BCG efficacy is compromised by such adjustments. 2.2. Bladder Contracture
Bladder contracture induced by BCG is an uncommon but severe complication [ 17 ]. Decreased bladder capacity significantly worsens patients’ quality of life and makes patients unable to tolerate BCG instillation. Although published cases of bladder contractures were observed primarily in patients in a maintenance intravesical BCG immunotherapy, there were also cases as early as in the induction phase [ 18 ]. Since all patients undergo TUR before BCG therapy, it is difficult to ascertain that BCG alone is the specific cause of bladder contractures [ 19 ]. Bladder hydrodistension was reported as an effective treatment option in patients with severely decreased bladder capacity after BCG treatment [ 20 ], and the median bladder capacity of five male and one female patients increased from 40 ml (range 30-100 ml) to 200 ml (175-250 ml) within 2 weeks following bladder hydrodistension, with stable volumes during a median follow-up period of 32 months. However, if patients with incapacitating symptoms are refractory to conservative treatment, a short 2-4-week course of oral steroids sandwiched during anti-tuberculous therapy should be considered [ 21 ]. It is only the exceptional case that major surgery such as bladder augmentation or cystectomy is required [ 22 ]. 2.3. Bladder Ulcerations
Persisting BCG infections with large inflammatory lesions in bladder can represent tuberculous-like ulcers. In a study of 858 patients with intravesical BCG immunotherapy, thirteen patients developed large bladder ulcerations (10 to 50 mm) [ 23 ]. All these patients were male (1.8% of all male patients), all with high grade tumors and seven with invasion to the lamina propria (T1) before BCG treatment. The duration from the initial BCG instillation to the discovery of a visible lesion by routine cystoscopy was 2-34 months (median 8 months). No patient had more than one ulceration or inflammatory lesion despite the fact that seven patients had undergone TURs for multifocal tumors. Urine specimens for mycobacterial culture showed eleven patients were positive, and anti-tuberculosis (anti-TB) therapy (rifampin and isoniazid) given to 8 patients for 6 months resulted in negative urine BCG cultures and resolution of the bladder lesions. 2.4. Granulomatous Balanitis
The most widely reported penile complication of BCG is granulomatous balanitis, with symptoms including penile edema, papules, and ulcers, occasionally associated with inguinal lymphadenopathies, typically presenting after multiple cycles of BCG [ 24 ]. The time interval between BCG immunotherapy and the onset of skin lesions has been variable, and it ranged from immediately after the instillation to 1 year after the last instillation [ 25 ]. The mechanism of infection has been thought to be associated to direct penis inoculation by traumatic urethral catheterization prior to BCG instillation, but the risk factors have been not confirmed. BCG associated granulomatous balanitis lesions were reported previously in 13 cases, including 5 with history of difficult catheterization during BCG instillation. Lymphadenopathy developed in 8 of 9 cases and histological changes (granulomas, necrosis, and ulcer) were reported in 10 cases with adequate information, and 7 of them demonstrated acid-fast bacilli in lymph node biopsies. All cases responded to anti-TB therapy (various combinations of isoniazid, rifampin, and ethambutol without a standard protocol) within 6 to 12 months [ 26 ]. 2.5. Tuberculous Epididymo-Orchitis
Tuberculous epididymo-orchitis, referred to as “BCGitis,” is a rare granulomatous infection resulting from intravesical BCG therapy [ 27 ]. It typically manifests as scrotal swelling, pain, dysuria, and fever, commonly occurs within a few weeks of BCG instillation, but may develop as late as 17 years after cessation of BCG therapy [ 28 ]. Various distinct gray scale sonographic patterns have been described, including epididymal enlargement or nodules with hypoechoic heterogeneous or homogeneous appearance [ 29 ]. Orchitis can demonstrate a miliary sonographic pattern, and multiple intratesticular hypoechoic nodules are thought to be characteristic of tuberculous orchitis [ 30 ]. Besides this, other typical findings are also possible, including hydrocele, scrotal skin swelling, intrascrotal calcifications, abscesses, and scrotal sinus formation. Tuberculous epididymo-orchitis can be diagnosed by granulomatous changes, caseous necrosis, and positive acid-fast bacilli in the biopsy specimen. If the development of epididymo-orchitis is delayed from cessation of BCG instillation, a multiplex PCR method can help to confirm whether the BCG strain is the responsible microbe over other mycobacterium species [ 31 ]. BCG-induced epididymo-orchitis is usually sensitive to anti-TB therapy, consisting of 300 mg isoniazid and 600 mg rifampin daily for three to six months [ 29 ]. To M. bovis infection with isoniazid resistance, the regimen includes a fluoroquinolone or an anti-TB aminoglycoside is an option [ 32 ]. If the lesion presents persistent pain, swelling, fever, and/or leukocytosis refractory to anti-TB therapy, scrotal exploration and epididymo-orchiectomy may be required. 2.6. Prostatitis
Granulomatous prostatitis is one of the most common complications in patients who underwent intravesical BCG immunotherapy, but its incidence is likely to be underestimated by the series of symptomatic cases [ 33 ]. In fact, of male patients with BCG instillation, only about 10% developed clinical prostatitis associated with discomfort. More than 40% presented with an elevated serum prostate specific antigen (PSA), and vast majority have histological evidence of BCG granulomatous prostatitis [ 34 ].
Despite of the high rate of histological evidence to granulomatous prostatitis, it is difficult to translate this rate to imaging findings due to the limits of radiological technology. In a study of 38 patients evaluated by contrast-enhanced CT scans before TUR and after BCG therapy, abnormal prostatic findings were found in 11 of patients (28.9%), none of whom with any signs or symptoms associated with prostatitis [ 35 ]. The MRI characteristics of granulomatous prostatitis after intravesical BCG immunotherapy have not been described extensively and can be represented as a suspicious lesion for harboring prostate cancer [ 36 ].
Patients with clinical BCG-induced prostatitis may present with untypical symptoms or signs, including perineal pain, enlarged tender prostate, firm prostate nodules, and elevated prostate specific antigen (PSA). PSA elevation in patients with intravesical BCG is self-limited, and it typically returns to basal levels within 3 months in the absence of maintenance therapy [ 37 ]. Prostatic fluid staining for acid-fast bacilli is helpful to identify tuberculous prostatitis. There are sporadic reports of tubercular prostatic abscess as a complication of intravesical BCG immunotherapy [ 38 ]. Accompanied with surgical drainage, anti-TB administration is available in controlling the prostatic abscess. 2.7. Ureteral Obstruction
Ureteral obstruction is an uncommon complication resulting from intravesical BCG therapy [ 39 ]. In most instances, ureteral obstruction is transient and self-limiting after conclusion of BCG therapy. If symptomatic obstruction occurs in the upper urinary tract, a regimen of 300 mg isoniazid and 600 mg rifampin should be given for 3-6 months. Furthermore, temporary drainage is recommended for new onset hydronephrosis. Because of only a few reports on ureteral obstruction following intravesical BCG, there is no evidence for the superiority of either ureteral stenting or percutaneous nephrostomy. In an extremely uncommon case of acute anuria after BCG instillation, the complete obstruction of the vesicoureteral junction resolved spontaneously within 6 days after percutaneous nephrostomy [ 40 ]. 2.8. Kidney Infections
BCG-induced renal infections have involved pyelonephritis and associated renal granulomas. A meta-analysis of 2602 patients revealed a mere 0.1% frequency of renal abscess following BCG instillation [ 39 ]. Post-intravesical BCG pyelonephritis may present with systemic symptoms, including persistent low grade fever, chills, fatigue, or weight loss. A hypovascular renal mass may be found by contrast-enhanced CT. Given the fact that post-TUR vesicoureteral reflux has been shown in up to 77% of patients with resection close to the ureteral orifice, the mechanism of renal BCG infections is more likely to be related to reflux of the intravesical BCG rather than hematogenous spread [ 41 ]. Renal biopsies can help to establish histopathological diagnosis based on epithelioid cell granulomas; however, acid-fast bacilli may not be present. While granulomas can sometimes be managed conservatively without anti-TB medications, a regimen of 300 mg isoniazid, 600 mg rifampin, and 1200 mg ethambutol daily for 6 months is advised for BCG-induced pyelonephritis or granulomatous masses of the kidney. The treatment modality of genitourinary complications induced by intravesical BCG immunotherapy was listed in Table 2 . Table 2: Treatment modality of genitourinary complications induced by intravesical BCG immunotherapy for NMIBC [ 13 , 15 , 17 , 20 – 23 , 26 , 29 , 32 , 38 , 39 ]. 3. Systemic Complications
Systemic complications occur less frequently (3%-7%) but are usually much more severe. They include disseminated M. bovis infection (“BCG-osis”), persistent fever, or any organ involvement beyond genitourinary system. In a review of 282 cases, disseminated infection was defined to consist of sepsis with fever, hypotension, multiorgan failure and coagulopathy, miliary tuberculosis or fever associated with bone marrow and/or liver involvement and/or pulmonary symptoms, accounting for the largest proportion (34.4%) of BCG-induced complications [ 8 ]. The mechanism of systemic complication induced by BCG therapy is still under investigation. Although the evidence of viable organisms in tissue supports the theory of systemic spread and dissemination of Mycobacterium spp. , it has also been postulated that the systemic response is due to a systemic type IV hypersensitivity reaction to BCG [ 42 ]. Diagnosis of disseminated infection is a challenging task due to the diverse array of problems and the lack of evidence from organisms and requires a high index of clinical suspicion on the role of BCG in development of any condition. In fact, the most important clinical clue usually comes from a detailed medical history that elicits prior intravesical BCG therapy.
Clinically, an increased temperature higher than 38.5°C after BCG instillation should arouse a suspicion of disseminated infection, and further intravesical BCG should be withheld. Blood tests often reveal leukopenia and abnormal liver function tests, and chest X-ray may show infiltrates in the lower lung bases [ 43 ]. According to EAU guidelines on management for BCG-induced side effects, if the high-grade fever (>38.5°C) persists more than 48 hours, a diagnostic evaluation including urine culture, blood tests, and chest X-ray and a consultation with an infectious disease specialist are necessary, along with prompt treatment with more than two antimicrobial agents. While the evaluation is conducted, no further BCG should be given [ 44 ]. 3.1. Mycotic Aneurysms
The most commonly reported location of mycotic aneurysms after intravesical BCG immunotherapy is aortic (thoracic and abdominal). Moreover, mycotic aneurysms in carotid, iliac, femoral, and popliteal arteries have also been reported. Most reported aneurysms developed within 7-77 months after initial BCG instillation, and more than half of cases presented with rupture of their aneurysms [ 45 ]. In a review of 31 aneurysms found in 21 patients after BCG therapy, the most common clinical symptoms were abdominal or back pain (57%), general malaise (52%), fever (38%), and pulsatile or painful mass (19%) [ 46 ]. Psoas abscesses have been reported to occur nearly exclusively in patients with mycotic aneurysms and may be caused by the infected aneurysmal leak [ 47 ]. Only a few reported cases have shown evidence of typical caseating granuloma in histopathologic examination, so the definitive diagnosis of mycotic aneurysms is based on culture of the aneurysm specimen [ 45 ]. Besides this gold standard, microbiological acid-fast bacilli detection and PCR from various tissue samples have been reported [ 48 ]. Treatment of mycotic aneurysms includes anti-TB therapy and vascular surgery. The typical surgical repair entails resection of all infected arterial tissues for large aneurysms and revascularization with in situ biological conduits or extra anatomic bypasses. The use of in situ prosthetic conduits was also reported, but the etiology of these aneurysms was not well defined during the surgical repair [ 46 ]. 3.2. Miliary Pulmonary Tuberculosis
Pulmonary complications following intravesical BCG immunotherapy are not common, with an incidence of 0.3%-0.7% of treated patients, presenting as interstitial pneumonitis or miliary dissemination [ 8 , 39 ]. Symptom onset of miliary dissemination may be abrupt or subacute, and most patients initially present with fever without apparent focus. In a study enrolling 23 male patients after 4 to 16 BCG instillations, 13 patients presented a variety of untypical symptoms, including fever, chills, and weight loss, in addition to respiratory symptoms like cough and dyspnea [ 49 ]. Whenever a suspicion of miliary pulmonary tuberculosis is suspected, a chest CT scan should be performed as chest X-ray imaging may miss up to 25% of cases [ 50 ]. The detection of acid-fast bacilli positive culture and positive PCR test from sputum or bronchoalveolar lavage can confirm the diagnosis. Considering the fact that 5.4% attributable mortality was observed by a review of the literature [ 8 ], it is essential to establish a prompt diagnosis and to initiate anti-TB therapy without delay. Instead of a standardized protocol, a variety of combined isoniazid, ethambutol, streptomycin, or rifampin for 6 to 12 months can provide effective treatment for miliary pulmonary tuberculosis induced by BCG therapy. 3.3. Granulomatous Hepatitis
Hepatic complication, typically granulomatous hepatitis, is a rare but fatal complication after intravesical BCG immunotherapy [ 6 , 8 ]. Granulomatous hepatitis can develop within hours to months or longer following intravesical BCG therapy and present with symptoms and signs of hepatitis, including fever, anorexia, and jaundice [ 51 ]. Whereas the diagnosis may be established through detection of acid-fast bacilli in patient’s serum or liver tissue by staining techniques, the best differential diagnosis is histopathologic lobular hepatitis by liver biopsy. Initial anti-TB treatment is essential, and the recommended regimen consists of 300 mg isoniazid, 600 mg rifampin, and 1200 mg ethambutol daily for 6 months. 3.4. Reactive Arthritis
Osteoarticular complications associated with intravesical BCG therapy are uncommon [ 52 ]. Although the mechanisms of rheumatic adverse events of BCG immunotherapy remain not fully clarified, the reactive arthritis is most likely invoked by a systemic immune-mediated response generated by repeated stimuli with live attenuated strains of M. bovis and their antigens spreading from the bladder to the circulation [ 53 ]. In a systematic review of 89 patients of reactive arthritis following BCG instillation, the symptom of reactive arthritis appeared after a mean number of instillations of 5.8, 13.5 days on average from the last instillation [ 54 ]. According to the prevalence, the more frequently affected joints were knee (84.3%), ankle (55.1%), hand (39.3%), wrist (32.6%), and foot (28.1%), and polyarthritis is the most common clinical feature (55.1%) of reactive arthritis related to BCG immunotherapy. Only 20.2% of the patients presented with warning symptoms, including fever, urinary symptoms, unspecific arthralgias, and myalgias. Although the inflammatory joint involvement is induced by an autoimmune reaction, synovial fluid analysis is required to rule out septic arthritis. Therapeutic strategies for BCG reactive arthritis are not well established in the literatures, but the outcome was reported favourable, with no recurrence under nonsteroidal anti-inflammatory drugs, in association with corticosteroids suggested by some authors, and after discontinuation of BCG therapy. For severe cases or those without response to initial therapy, disease-modifying antirheumatic drugs (methotrexate) could be indicated, and addition of isoniazid has also been proposed [ 55 ]. 3.5. Tuberculous Spondylitis
Osteitis is rare secondary to BCG immunization, occurring in less than 37 per 100,000 cases [ 56 ]. Updated to 2018, only 23 cases of tuberculous spondylitis or vertebral osteomyelitis following intravesical BCG were reported in the English literature [ 57 ]. All these patients were male, with a mean age of 73.2 (35-94) years and with a median interval of 1.3 years (0.5 months-12 years) between BCG instillation and the onset of spondylitis. Chronic back pain was the most common complaint, and serious neurological symptoms might occur as a result of neurosurgical spinal cord decompression [ 58 ]. BCG spondylitis is thought to develop by hematogenous spread from the deep pelvic veins to the internal vertebral venous plexuses, which may explain its high incidence in the thoracolumbar spine [ 59 ]. The growth of Mycobacterium in culture specimens obtained from the infected tissue is the most confirmatory diagnostic test of tuberculous spondylitis; however, histopathological granulomas and acid fast bacilli stain are considered as reference standards for all other diagnostic modalities [ 60 ]. Without standard protocol for managing tuberculous spondylitis or vertebral osteomyelitis, most patients were treated by multidrug anti-TB therapy (isoniazid, rifampin, and ethambutol) for an average of 12 months (9-15 months). Surgical intervention will be necessary when the patient has further complications, including spinal cord injury, spinal instability, and abscess formation. 3.6. BCG Sepsis
Although a life-threatening septic reaction occurs in an estimated incidence of approximately 1 of 15,000 patients treated with intravesical BCG immunotherapy [ 39 ], systemic BCG infection should be suspected in any patient who presents with persistent fever after BCG instillation. Characterized by chills, fever, and hypotension with potential progression to multisystem organ failure, this most dangerous complication is a result of either systemic mycobacterial sepsis and/or a systemic hypersensitivity reaction to BCG [ 42 ]. Recommended anti-TB treatment for BCG sepsis consists of 300 mg isoniazid, 600 mg rifampin, and 1200 mg ethambutol daily for 3 to 6 months. In addition, steroid treatment of 40 mg prednisolone should be given intravenously from the beginning of therapy and be tapered gradually after the sepsis is controlled [ 11 ]. The treatment modality of systemic complications induced by intravesical BCG immunotherapy was listed in Table 3 . Table 3: Treatment modality of systemic complications induced by intravesical BCG immunotherapy for NMIBC [ 8 , 11 , 43 , 44 , 46 , 51 , 54 , 55 , 57 ]. 3.7. Rare Complications
Central nervous system infections caused by M. bovis are very rare; only two cases of cerebellar tuberculomas were reported caused by M. bovis BCG in immunocompetent patients without any evidence of systemic dissemination after intravesical BCG immunotherapy [ 61 , 62 ]. Both cases occurred in elderly male patients with neurological symptoms and signs. Magnetic resonance imaging or contrasted CT scan revealed cerebral nodular foci or mass effect. Although the pathological diagnosis showed chronic granulomatous inflammation from a stereotactic biopsy, the acid-fast smear of the tissue sample was negative. Both patients had a successful response to a 12-month anti-TB medication. In addition, one case used a concomitant steroid therapy, which included dexamethasone transitioned to a 3-month prednisone taper.
There are 15 cases of ocular inflammation after intravesical BCG instillations in the literature. Although cross-reactivity and immunologic reactions are possibly implicated in uveitis after BCG instillations, culture-positive M. bovis endophthalmitis was reported in 4 cases which confirmed a direct vitreous invasion after hematogenous dissemination of the microorganism [ 63 ]. These cases highlighted a poor ocular outcome despite of an adequate systemic anti-TB therapy, and intravitreal therapy targeted toward M. bovis or additional therapy may be required.
Haemophagocytic syndrome is a very rare but potentially fatal complication of intravesical BCG immunotherapy. This challenging syndrome consists of a sepsis-like state together with variable cytopenia, hepatosplenomegaly, coagulation disorders, and lymphadenopathy; eventually multiple organ failure ensues with a high mortality rate [ 64 ]. Early diagnosis is essential to initiate appropriate treatment and improve the survival and quality of life. The immediate aim of therapy is suppression of the increased immune response and specific treatment of the underlying disease [ 65 ]. Immunomodulatory regimen depends on the severity of the conditions, including corticosteroids, intravenous immunoglobulins, cyclosporine A, etoposide, antithymocyte globulin, plasma exchange, and splenectomy. Water-soluble steroids such as dexamethasone or methylprednisolone are preferred because of their permeability through blood brain barrier. 4. Predisposing Factors Endorsing Complications 4.1. Immunosuppression
The incidence of BCG induced adverse events in immunosuppressed patients is unclear because of paucity of data in the literature. In the largest case series of 45 immunosuppressed patients (12 with solid organ transplants, 23 receiving systemic chemotherapy for unrelated cancer, and 10 on steroids for autoimmune disease) treated with intravesical BCG for bladder cancer, BCG therapy was found well-tolerated, and no BCG sepsis was reported [ 66 ]. In the literature, only one case of disseminated BCG-induced sepsis was reported 7 years after a 6-week induction course of intravesical BCG therapy for high-grade noninvasive papillary urothelial carcinoma and 1.5 years following immunosuppression for a renal transplantation [ 67 ]. Given the fact that this patient’s urine and blood mycobacterial culture was positive for the strain of intravesical BCG, the sepsis was most likely caused by organism spreading in the setting of immunosuppression therapy for transplant, rather than systemic hypersensitivity reaction. Therefore, EAU guideline suggests that BCG should be used with caution in immunocompromised patients, despite the comparable incidences of BCG-induced complications reported between patients with and without immunocompromised status [ 44 ]. Although BCG is not recommended as vaccination in patients with autoimmune inflammatory rheumatic diseases [ 68 ], there is little literature to prove that the safety of intravesical BCG immunotherapy is compromised by administration of synthetic or biological disease-modifying antirheumatic drugs [ 69 ]. 4.2. Geriatric Patients
In the treatment for geriatric patients, age-related deterioration of innate and adaptive immunities and declines in performance status may influence the therapeutic toxicity risk. For elderly patients, the potential side effects and complications of intravesical BCG immunotherapy may be more problematic and not well tolerated. In a study of series of 58 patients, a nearly three-fold higher rate of complications was found in patients older than 70 years compared to younger patients (48.6% vs. 17.6%, respectively) following maintenance BCG therapy [ 70 ]. In a recent retrospective study on 200 patients older than 80 years, the elderly patients with multiple comorbidities received a tailored regimen of BCG administration with biweekly scheme, which maintained optimal oncological responses with a significantly lower rate of complications (15% vs. 27%) than that in the elderly patients with better conditions under standard weekly BCG therapy [ 71 ]. 4.3. Chronic Comorbidities
Although chronic comorbidities were regarded as potential predisposing factors of increasing the risk of systemic side effects [ 42 ], there was no difference in the incidence of chronic comorbidities such as hypertension, diabetes mellitus, renal insufficiency, and liver disease between 11 patients with BCG infection and 245 others without BCG infection in a review of adjunctive BCG therapy for bladder cancer [ 8 ]. In a recent investigation on the influence to intravesical BCG immunotherapy from metabolic syndrome, defined as having three of four components: diabetes mellitus, hyperlipidemia, hypertension, or body mass index ≥ 30kg/m 2 , there was no significant association between metabolic syndrome and the type of BCG failure consisting of recurrence, progression, or intolerance of therapy [ 72 ]. 5. Prevention
Adjunctive BCG administration is imperatively initiated a minimum of 2 weeks after TUR to allow for adequate healing of the urothelium and to prevent systemic absorption of this agent. Moreover, intravesical BCG instillation is contraindicated in patients with visible hematuria, after traumatic catheterization, or with symptomatic urinary tract infection [ 44 ]. The potential effect of some antibiotics, notably the fluoroquinolones on BCG viability, and consequent effectiveness should be taken into account.
Reduced dose of intravesical BCG has been reported helpful to decrease the potential toxicity of BCG. In a randomized prospective study, the percentage of no local toxicity in 248 patients with reduced dose of 27 mg intravesical BCG was significantly lower than that in 252 patients with standard dose of 81 mg (33.3% vs. 45.3%) with similar outcomes for recurrence and progression, but the differences in severe systemic toxicity were not significant between reduced dose arm (4.4%) and standard dose arm (3.6%) [ 73 ]. However, in a more recent study of 1316 patients, one-third dose was compared to a full dose of BCG given for 1 year or 3 years, and no significant differences in side effects were detected according to dose or duration of BCG treatment in the four arms [ 11 ].
Prophylactic medication has been used effectively to decrease the potential toxicity of intravesical BCG. In a randomized prospective, double-blind, multicentre study of 120 patients who received 6 weekly instillations of BCG for urothelial cancer, local side-effects confined to the bladder were significantly lower among those with a 3-day course of isoniazid 300 mg than with placebo (35% vs. 48%) [ 74 ]. On the contrary, in a subsequent larger randomized trial, the incidence of cystitis, frequency, hematuria, or severe fever was not reduced significantly in patients treated with BCG and isoniazid, and one case of BCG-induced lung infection developed in this group. Preventive isoniazid therapy also led to treatment discontinuation in significantly more patients (13% vs. 7%) [ 75 ]. Beside this, prophylactic 3-day course of prulifloxacin 600 mg was reported to have a significant effect to prevent overall, moderate, and severe adverse events after the fourth intravesical BCG instillation for intermediate- or high-risk NMIBC in a prospective, randomized open-label controlled clinical trial [ 76 ]. In addition, a lower proportion that stopped or delayed the full induction course of BCG instillations was noted in patients treated by prior prulifloxacin than in those without prophylactic medication (19% vs. 34%), and the recurrence rates at 3-month or 6-month postoperative cystoscopy were not affected by prulifloxacin treatment. Similarly, in a randomized, prospective, double-blind, placebo controlled, multicenter study, ofloxacin significantly decreased by 18.5% the incidence of moderate and severe adverse events associated with BCG intravesical therapy, particularly class III events, which are primarily associated with patient dropout [ 15 ]. 6. Conclusions
Intravesical BCG immunotherapy has been proved to be effective in the prevention of recurrence and progression of NMIBC for over 40 years; its use is still problematic due to a diverse array of complications that may develop within days to years following the initiation of BCG instillation. Despite these severe complications being uncommon, every physician faced with a patient who has a history of intravesical BCG therapy should be aware of the potential adverse events and the management. Considering the fact that BCG infections and reactions can occur at any organ or position in the body, a detailed medical history provides important clinical value. Because acid-fast staining, culture, and PCR testing are not always positive, tissue biopsies should be performed to evaluate histopathological formation and presence of M. bovis . Whereas the most common side effects are self-limited, anti-TB therapy must be used as soon as the diagnosis is established to avert more severe downstream complications. Multidrug anti-TB therapy for 3-12 months may be required along with the rare use of surgery. Conflicts of Interest
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