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Exploring 6 Years of Safety Data

When considering LEMTRADA infusion treatment for relapsing MS, it’s important to discuss potential common and serious side effects with your patients. Select a section to read about potential side effects and pre-medications.

Infusion Reactions

LEMTRADA can only be administered in certified healthcare settings that have on-site access to equipment and personnel trained to manage infusion reactions (including anaphylaxis and cardiac and respiratory emergencies).1

LEMTRADA can cause serious infusion reactions that may cause death. Serious infusion reactions may happen when patients receive, or up to 24 hours or longer after they receive, LEMTRADA. Consider discontinuation of LEMTRADA infusion if severe infusion reactions occur.1

Incidence of infusion reactions

92%

of LEMTRADA-treated patients experienced infusion reactions in MS clinical studies1

3%

of these reactions were serious1

<1%

discontinued treatment due to infusion reactions. Infusion reactions were generally highest
on day 1 of each course1,2

Some infusion reactions were reported more than 24 hours after LEMTRADA infusion

Before, during, and after infusion

LEMTRADA can only be administered in certified healthcare settings that have on-site access to equipment and personnel trained to manage infusion reactions (including anaphylaxis and cardiac and respiratory emergencies).

Patients should always be monitored before, during, and after their infusion.1

MONITOR

Vital signs should be monitored before the infusion and periodically during the infusion

Observe

Observe patients for infusion reactions during and for at least 2 hours after each LEMTRADA infusion

advise

Encourage patients to report symptoms during and after each infusion because prompt medical
intervention may be needed

consider

Additional monitoring in patients with medical conditions that predispose them to cardiovascular or
pulmonary compromise should be considered. Consider pretreatment with antihistamines and/or antipyretics. Infusion reactions may occur despite pretreatment. Physicians should alert patients that an infusion reaction
could occur within 48 hours of infusion

Note icon

Patients should always be monitored before, during, and after their infusion. View more information on monitoring.

Symptoms of serious infusion reactions

The following are symptoms of a serious infusion reactions that may happen during the infusion, or up to 24 hours or longer after the patient receives the infusion1:

  • Anaphylaxis (including anaphylactic shock)
  • Angioedema
  • Bronchospasm
  • Hypotension
  • Chest pain
  • Bradycardia
  • Tachycardia (including atrial fibrillation)
  • Transient neurologic symptoms
  • Hypertension
  • Headache
  • Pyrexia
  • Rash

Select Adverse Events Associated With LEMTRADA

Stroke and cervicocephalic arterial dissection

In the postmarketing setting1:

  • Serious and life-threatening stroke (including ischemic and hemorrhagic stroke) has been reported within 3 days of LEMTRADA administration, with most cases occurring within 1 day
  • Cases of cervicocephalic (eg, vertebral, carotid) arterial dissection involving multiple arteries have been reported within 3 days of LEMTRADA administration
Note icon

Educate patients on the symptoms of stroke and cervicocephalic arterial dissection. Instruct patients to seek immediate medical attention if symptoms of stroke or cervicocephalic arterial dissection occur.1

Malignancies

Thyroid Cancer

0.3% of LEMTRADA-treated patients developed thyroid cancer vs 0% of Rebif patients in controlled clinical studies.* Screening for thyroid cancer was performed more frequently in the LEMTRADA-treated group because of the higher incidence of autoimmune thyroid disorders in those patients.1

*In uncontrolled studies, 2 additional cases of thyroid cancer occurred in LEMTRADA-treated patients.

Melanoma

In MS clinical studies (controlled and open-label extension), 0.3% of LEMTRADA-treated patients developed melanoma or melanoma in situ, one of whom had evidence of locally advanced disease.1

Blood Cancers

Cases of lymphoproliferative disorders and lymphoma have occurred in LEMTRADA-treated patients with MS, including mucosa-associated lymphoid tissue (MALT) lymphoma, Castleman’s disease, and a fatality from Burkitt’s lymphoma.1

Note icon

Because LEMTRADA is an immunomodulatory therapy, caution should be exercised in initiating LEMTRADA in patients with pre-existing or ongoing malignancies.1

Autoimmune Incidence Rates Over 6 Years

If autoimmune events are suspected, consider prompt intervention, including potentially referring patients to a specialist for additional diagnostic tests and/or treatment.1

Incidence of First ITP Event
(CARE-MS I and II Core and Extension Studies, Pooled Analysis)3,4
Percent of Patients

0.2%

0.6%

0.3%

1.1%

0.1%

0.4%

  • 30
  • 20
  • 10
  • 0
  • Year
  • 1(n=811)
  • 2(n=810)
  • 3(n=772)
  • 4(n=731)
  • 5(n=707)
  • 6(n=692)
  • 2% of all LEMTRADA-treated patients in MS clinical studies (controlled and open-label extension) developed ITP and were diagnosed more than 3 years after the last LEMTRADA dose1†
  • One clinical study patient developed ITP that went unrecognized before monthly monitoring was required and died from intracerebral hemorrhage1
  • Other autoimmune cytopenias occurred in LEMTRADA-treated patients (eg, neutropenia [0.1%], hemolytic anemia [0.3%], and pancytopenia [0.2%])1
  • One LEMTRADA-treated clinical study patient with autoimmune pancytopenia died from sepsis1
  • If ITP onset or cytopenias are confirmed, promptly initiate appropriate medical intervention1
Incidence of First Nephropathy Event
(CARE-MS I and II Core and Extension Studies, Pooled Analysis)2,3
Percent of Patients

0.0%

0.1%

0.1%

0.0%

0.0%

0.0%

  • 30
  • 20
  • 10
  • 0
  • Year
  • 1(n=811)
  • 2(n=810)
  • 3(n=772)
  • 4(n=731)
  • 5(n=707)
  • 6(n=692)
  • 0.3% of LEMTRADA-treated patients in MS clinical studies (controlled and open-label extension) developed glomerular nephropathies, including 3 cases of membranous glomerulonephritis and 2 cases of anti-glomerular basement membrane (anti-GBM) disease. Cases of anti-GBM disease have been diagnosed up to 40 months after the last dose of LEMTRADA1
  • One clinical study patient developed ITP that went unrecognized before monthly monitoring was required and died from intracerebral hemorrhage
  • Other autoimmune cytopenias occurred in LEMTRADA-treated patients (eg, neutropenia [0.1%], hemolytic anemia [0.3%], and pancytopenia [0.2%])
  • One LEMTRADA-treated clinical study patient with autoimmune pancytopenia died from sepsis
  • If ITP onset or cytopenias are confirmed, promptly initiate appropriate medical intervention
  • Hemophagocytic lymphohistiocytosis (HLH) has occurred in patients taking LEMTRADA. Symptoms have been reported to occur within approximately thirteen months to thirty-three months following the initiation of treatment.
Incidence of First Thyroid Event
(CARE-MS I and II Core and Extension Studies, Pooled Analysis)2,3
Percent of Patients

7.6%

10.9%

16.6%

6.3%

3.0%

3.2%

  • 30
  • 20
  • 10
  • 0
  • Year
  • 1(n=811)
  • 2(n=810)
  • 3(n=772)
  • 4(n=731)
  • 5(n=707)
  • 6(n=692)
  • 37% of LEMTRADA-treated patients in MS clinical studies (controlled and open-label extension) experienced thyroid events, peaking 3 years after the first dose of LEMTRADA then generally declining in subsequent years. Newly diagnosed thyroid disorders have been reported more than 7 years after the first LEMTRADA dose1†
  • In postmarketing cases, some LEMTRADA-treated patients with anti-GBM disease developed end-stage renal disease requiring dialysis or renal transplantation
  • Alveolar hemorrhage, manifested as hemoptysis, is a common component of anti-GBM disease and has been reported in postmarketing cases
  • Urgent evaluation and treatment is required, because early treatment can improve the preservation of renal function. Anti-GBM disease can be life-threatening if left untreated
  • Early detection and treatment of nephropathies may decrease the risk of poor outcomes

In MS clinical studies (controlled and open-label extension), overall, a total of 1217 patients received LEMTRADA. Patients had a median of 6 years of follow-up from the first LEMTRADA dose with approximately 14% having at least 7 years of follow-up.1

Hear from HCPs on secondary autoimmune events

Immune Thrombocytopenia (ITP)

Cindy Neunert, MD
NewYork-Presbyterian/Columbia
Morgan Stanley Children’s Hospital

Hello, my name is Cindy Neunert. I’m a pediatric hematologist oncologist affiliated with NewYork-Presbyterian/Columbia and Morgan Stanley Children’s Hospital in New York.

Today, I am going to review the pathophysiology, incidence rate, clinical presentation, diagnosis, and treatment of immune thrombocytopenia.

ITP is an autoimmune syndrome involving antibody- and cell-mediated destruction of platelets and suppression of platelet production that may predispose patients to bleeding.1-5

The incidence of ITP among adults in the United States is estimated to be 3.3 per 100,000 adults per year. The prevalence, or how many adults have ITP at any time, is about 9.5 cases per 100,000.6

ITP is classified by duration and includes newly diagnosed, defined as a 3-month duration from diagnosis; persistent, defined as a 3- to 12-month duration from diagnosis; and chronic, defined as a duration greater than 12 months from diagnosis.7,8

The incidence of ITP in adults is bimodal, which peaks in young adults and the elderly.9 ITP in adults typically appears with no preceding viral or other illness and normally follows a chronic course.8,9 The incidence in adults is approximately equal between the sexes, except between 30 to 60 years of age when the disease is more prevalent in women.8

Cases of ITP are categorized as primary, with no identified cause, or secondary, which can be attributed to an identified cause such as an underlying disease or drug exposure.1,2

Next, let’s review the clinical presentation of ITP.

Signs and symptoms of ITP may include easy bruising, purpura, petechiae, hematoma, and mucocutaneous bleeding. Examples include nosebleeds and bleeding from the gums that is new or takes longer than usual to stop, blood in the urine or blood in the stool, bleeding from a cut that’s hard to stop, or menstrual bleeding that’s heavier than normal.10-12

Bleeding episodes are mostly mucocutaneous.13

Intracranial hemorrhage and other major internal bleeding are rare but can be life threatening without early intervention.2,10-12

Cutaneous signs of ITP may include easy bruising, oral petechiae, and petechiae of the skin, such as small, scattered spots that are red, pink, or purple.10,11

There is currently no definitive laboratory test to diagnose ITP.6

ITP is typically diagnosed based on a complete blood count, or CBC, and additional urine and blood tests, such as a blood smear and antiplatelet antibody test.10,11

A bone marrow aspiration may be done to examine the production of platelets and to rule out disorders that affect the bone marrow and reduce platelet production, such as acute leukemia or aplastic anemia.6,11

A normal platelet count is generally between 150,000 to 450,000 platelets per microliter of blood.11,14

According to an international working group of recognized expert clinicians, a diagnosis of immune thrombocytopenia requires a platelet count below 100,000 platelets per microliter of blood, with exclusion of other causes of thrombocytopenia.2,7

Treatment of ITP is typically considered for patients with a platelet count below 30,000 platelets per microliter.15

The goal of therapy for ITP is to achieve a safe platelet count that prevents or stops major bleeding, rather than correcting the platelet count to normal levels.7,15

The majority of patients with no or mild bleeding, defined as skin manifestations only such as petechiae and bruising, may not require treatment, just observation and regular monitoring of the platelet levels.15,16

The 2 most common forms of first-line treatment used to stop bleeding and increase the platelet count to more than 30,000 platelets per microliter are corticosteroids and intravenous immunoglobulin, or IVIg. Steroids, if effective, increase platelet counts within several days to 2 to 3 weeks, whereas IVIg does the same, but is rapid, typically within 24 to 48 hours.2,10,11,15

IVIg is usually reserved for patients with serious hemorrhage.3,16

Second-line treatments include splenectomy, thrombopoietin, or thyroid peroxidase (TPO), receptor agonists, as well as more potent immunosuppressants.15,16

References:

  1. Cines DB, Bussel JB, Liebman HA, Luning Prak ET. The ITP syndrome: pathogenic and clinical diversity. Blood. 2009;113(26):6511-6521.
  2. Cuker A, Cines DB. Immune thrombocytopenia. Hematology Am Soc Hematol Educ Program. 2010;2010:377-384.
  3. Cines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med. 2002;346(13):995-1008.
  4. Stasi R, Evangelista ML, Stipa E, Buccisano F, Venditti A, Amadori S. Idiopathic thrombocytopenic purpura: current concepts in pathophysiology and management. Thromb Haemost. 2008;99(1):4-13.
  5. Houwerzijl EJ, Blom NR, van der Want JJL, et al. Ultrastructural study shows morphologic features of apoptosis and para-apoptosis in megakaryocytes from patients with idiopathic thrombocytopenic purpura. Blood. 2004;103(2):500-506.
  6. Immune thrombocytopenia. National Organization for Rare Disorders website. https://rarediseases.org/rare-diseases/immune-thrombocytopenia/. Published 2015. Accessed July 6, 2018.
  7. Rodeghiero F, Stasi R, Gernsheimer T, et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood. 2009;113(11):2386-2393.
  8. Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of primary thrombocytopenia. Blood. 2010;115(2):168-186.
  9. Lambert MP, Gernsheimer TB. Clinical updates in adult immune thrombocytopenia. Blood. 2017;129(21):2829-2835.
  10. What is immune thrombocytopenia? National Heart, Lung, and Blood Institute website. https://www.nhlbi.nih.gov/health/health-topics/topics/itp/. Accessed July 6, 2018.
  11. Immune thrombocytopenic purpura. Johns Hopkins Medicine website. https://www.hopkinsmedicine.org/healthlibrary/conditions/adult/hematology_and_blood_disorders/idiopathic_thrombocytopenic_ purpura_85,p00096. Accessed July 6, 2018.
  12. Cines DB, Bussel JB. How I treat idiopathic thrombocytopenic purpura (ITP). Blood. 2005;106(7):2244-2251.
  13. Liebman HA, Pullarkat V. Diagnosis and management of immune thrombocytopenia in the era of thrombopoietin mimetics. Hematology Am Soc Hematol Educ Program. 2011;2011:384-390.
  14. Williams M. What are platelets and why are they important? Johns Hopkins Medicine website. https://www.hopkinsmedicine.org/heart_ vascular_institute/clinical_services/centers_excellence/womens_ cardiovascular_health_center/patient_information/health_topics/platelets.html. Accessed July 6, 2018.
  15. 2011 Clinical Practice Guideline on the Evaluation and Management of Immune Thrombocytopenia (ITP): Quick Reference. Washington, DC: American Society of Hematology; 2011. American Society of Hematology website. http://www.hematology.org/Clinicians/Guidelines-Quality/Quick-Reference.aspx. Published 2011. Accessed July 6, 2018.
  16. Idiopathic thrombocytopenia purpura (ITP). Mayo Clinic website. https://www.mayoclinic.org/diseases-conditions/idiopathic-thrombocytopenic-purpura/diagnosis-treatment/drc-20352330. Updated August 9, 2017. Accessed July 6, 2018.

Nephropathies

Gerald B. Appel, MD
Director of the Center for Glomerular Diseases

Hello, my name is Gerald Appel. I’m a nephrologist at Columbia University Medical Center in New York.

I’m going to review the incidence rate, pathophysiology, clinical presentation, diagnosis, and treatment of anti-glomerular basement membrane, or anti-GBM, disease and membranous nephropathy, also called membranous glomerulonephritis.

Now let’s take a look at the first type of glomerular nephropathy: anti-GBM disease. The incidence of anti-GBM disease in the general population approaches 0.5 to 1.0 case per million each year. Although all age groups are affected, there is a bimodal age distribution with males predominating in the younger age group and females in the older group. Overall, there is a slight male preponderance.1,2

Both genetic and environmental factors appear to be important in the etiology of anti-GBM disease.2

Like many other autoimmune diseases, anti-GBM disease shows strong genetic linkage with human leukocyte antigen, or HLA, alleles. Infectious agents, smoking, and exposure to hydrocarbons have been causally associated with disease onset.1

Anti-glomerular basement membrane disease is rare in the general population, but it is a well-characterized autoimmune disorder with autoantibodies directed at specific component antigenic targets within the glomerular and pulmonary basement membrane.1-4

Signs and symptoms of anti-GBM disease may include elevated serum creatinine levels, swelling of feet or legs, hematuria, proteinuria, and in those with pulmonary involvement, shortness of breath, cough, and hemoptysis.2,5-7

Patients may also report dark-colored urine and oliguria.2,3

Several test results may be used to suggest a diagnosis of anti-GBM disease, including a urinalysis, blood analysis, complete blood cell count, or CBC, and a chest X-ray, particularly if pulmonary disease is present.7

The presence of serum anti-GBM antibodies is extremely suggestive of this diagnosis.7

A definitive diagnosis of anti-GBM disease is confirmed with either kidney or pulmonary tissue showing the presence of linear antibody staining along the glomerular or pulmonary basement membranes. Lung tissue is typically not sought due to the invasiveness of the procedure and the more technically difficult immunofluorescence process.7-9

If anti-GBM disease is suspected, urgent evaluation and treatment is needed,3,9 including potentially referring patients to a specialist for additional diagnostic tests and/or treatments. Renal outcome depends on the degree of renal damage at initiation of effective treatment.2

Without early intervention and treatment, the outcome can be very poor, because anti-GBM disease can lead to renal failure requiring dialysis or transplantation and can be life threatening if left untreated.2,3

Once diagnosis is confirmed, there are 2 steps involved in the treatment. The first step is to remove the circulating anti-GBM antibody from the blood by plasmapheresis. The second step is to prevent further autoimmune antibody production through immunosuppression. Most patients are given large-dose intravenous (IV) corticosteroids, followed by daily oral steroid therapy. An oral or IV immunosuppressant is used in conjunction with steroid therapy to reduce new antibody production.2,4

Now, let’s take a look at membranous nephropathy, or MN.

Membranous nephropathy is the leading cause of nephrotic syndrome in Caucasian adults,10 with symptoms including proteinuria, low blood protein level, high cholesterol levels, and swelling.11

Membranous nephropathy affects more men than women, and it is seen more often in patients older than 40 years of age.11,12

In approximately two-thirds of membranous nephropathy cases, the etiology is idiopathic.10 Up to 70% of such patients will have circulating antibodies to the phospholipase A2 receptor. In the remaining one-third of patients, who rarely if ever have circulating antibodies to this receptor, membranous nephropathy is considered secondary.13 It may be associated with or caused by other conditions—such as systemic lupus erythematosus, lung and colon cancer, and hepatitis B and C infection—or induced by certain medications.10,11,14-16

Membranous nephropathy is caused by the thickening of a part of the glomerular basement membrane, resulting in increased permeability of the glomerular capillary walls and leakage of large amounts of protein into the urinary filtrate. If this persists over a long period of time, the glomerular capillary walls become thickened and eventually the glomeruli scar, leading to renal failure.11,12,17,18

Signs and symptoms of membranous nephropathy often begin slowly and progress over time. The most noticeable symptom is edema, which typically starts in the feet and legs and may move into the hips and abdomen. Other symptoms may include swelling around the eyes, weight gain, foamy urine caused by proteinuria, excessive urination at night, high cholesterol, high blood pressure, and fatigue due to low levels of protein in the blood.11,12,16,19,20

Several test results can suggest a diagnosis of membranous nephropathy. Urinalysis findings may demonstrate proteinuria and microscopic hematuria.10,11

The glomerular filtration rate, or GFR, which is the speed at which the kidneys cleanse the blood, is often normal or decreased.10,11,21

Blood analysis may demonstrate elevated serum creatinine, decreased serum albumin, and the presence of anti-phospholipase A2 receptor antibodies.22-24

A kidney biopsy is used to confirm the diagnosis of membranous nephropathy.11

Light microscopy will show thickened glomerular basement membrane.12

Electron microscopy will show subepithelial electron-dense deposits and basement membrane spikes separating the deposits.10

If membranous nephropathy is suspected, prompt evaluation and treatment is advisable,10,25 including potentially referring patients to a kidney specialist for additional diagnostic tests, treatments, or both.

The goals of treatment are to reduce the symptoms and slow the progression of the disease.11

Early detection and treatment of nephropathies may decrease the risk of poor outcomes.25

Therapy directed to improve the nephrotic state includes ACE inhibitors, A2 receptor blockers, or both to help control blood pressure and reduce intraglomerular pressures and proteinuria, which is the most important way to delay kidney damage.10,11

Patients should also be instructed to follow a low-salt diet because a high intake can significantly impair the beneficial effects of the ACE inhibitors and A2 receptor blockers.10

Diuretics may also be prescribed to help with edema.11

In patients with medium to high risk of membranous nephropathy progression, immunosuppressive agents may be used.10,24

In terms of outcomes seen in the general population, some patients may have persistent, fluctuating degrees of proteinuria but stable renal function; others may undergo spontaneous remission; and still others may develop progressive renal impairment, eventually leading to end-stage renal disease or failure.25,26

References:

  1. Cui Z, Zhao M-H. Advances in human antiglomerular basement membrane disease. Nat Rev Nephrol. 2011;7(12):697-705.
  2. Phelps RG, Turner AN. Chapter 22. Antiglomerular basement membrane disease and Goodpasture’s disease. In: Floege J, Johnson RJ, Feehally J, authors. Comprehensive Clinical Nephrology. 4th ed. Elsevier; 2010:282-291.
  3. Kluth DC, Rees AJ. Anti-glomerular basement membrane disease. J Am Soc Nephrol. 1999;10(11):2446-2453.
  4. Anti-GBM disease. UNC Kidney Center website. https://unckidney center.org/kidneyhealthlibrary/glomerular-disease/ anti-gbm-disease. Accessed July 6, 2018.
  5. Goodpasture syndrome. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) website. April 2012. https://www.niddk. nih.gov/health-information/kidney-disease/glomerular-diseases/goodpasture-syndrome. Accessed July 5, 2018.
  6. A to Z health guide: Goodpasture’s syndrome. National Kidney Foundation website. https://www.kidney.org/atoz/content/goodpasture. Reviewed July 2009. Accessed July 5, 2018.
  7. Greco A, Rizzo MI, De Virgilio A, et al. Goodpasture’s syndrome: a clinical update. Autoimmun Rev. 2015;14(3):246-253.
  8. Pusey CD. Anti-glomerular basement membrane disease. Kidney Int. 2003;64(4):1535-1550.
  9. DeVrieze BW, Hurley JA. Goodpasture syndrome (anti-glomerular basement membrane antibody disease). NCBI bookshelf website. https://www.ncbi.nlm.nih.gov/books/NBK459291/. Updated October 5, 2017. Accessed July 6, 2018.
  10. Fervenza FC, Sethi S, Specks U. Idiopathic membranous nephropathy: diagnosis and treatment. Clin J Am Soc Nephrol. 2008;3(3):905-919.
  11. Membranous nephropathy. MedlinePlus website. https://medlineplus. gov/ency/article/000472.htm. Updated June 4, 2018. Accessed July 8, 2018.
  12. Membranous nephropathy. UNC Kidney Center website. https://unckidneycenter.org/kidneyhealthlibrary/glomerular-disease/membranous-nephropathy. Accessed July 6, 2018.
  13. Cattran DC, Brenchley PE. Membranous nephropathy: integrating basic science into improved clinical management. Kidney Int. 2017;91(3):566-574.
  14. Couser WG. Primary membranous nephropathy. Clin J Am Soc Nephrol. 2017;12(6):983-997.
  15. Beck LH Jr, Salant DJ. Membranous nephropathy: recent travels and new roads ahead. Kidney Int. 2010;77(9):765-770.
  16. Membranous nephropathy (MN). National Kidney Foundation website. https://www.kidney.org/ atoz/content/membranous-nephropathy-mn. Updated August 9, 2016. Accessed July 6, 2018.
  17. Mayo Clinic staff. Membranous nephropathy. Mayo Clinic website. https://www.mayoclinic.org/diseases-conditions/membranous-nephropathy/symptoms-causes/syc-20365189?p=1. Accessed July 6, 2018.
  18. Glomerular disease: what you need to know. National Kidney Foundation website. 2014. https://www.kidney.org/sites/default/files/12-10-6139_glomerulardisease.pdf. Accessed July 6, 2018.
  19. Kelepouris E. Patient education: the nephrotic syndrome (beyond the basics). UpToDate website. https://www.uptodate.com/contents/the-nephrotic-syndrome-beyond-the-basics. Updated August 3, 2017. Accessed July 6, 2018.
  20. Membranous nephropathy: fatigue is due to low levels of protein in the blood. Gerald B. Appel, MD; Professor of Medicine, Director of the Center for Glomerular Diseases, Columbia University Medical Center; New York, NY. Professional Opinion. November 25, 2017.
  21. Estimating glomerular filtration rate (GFR). National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) website. https://www.niddk.nih.gov/health-information/communication-programs/nkdep/laboratory-evaluation/glomerular-filtration-rate/estimating. Accessed July 6, 2018.
  22. Couser WG, Cattran DC. Chapter 20. Membranous Nephropathy. In: Floege G, et al, eds. Comprehensive Clinical Nephrology. 4th ed. Elsevier Inc; 2010.
  23. Zhang B, Cheng M, Yang M, et al. Analysis of the prognostic risk factors of idiopathic membranous nephropathy using a new surrogate end-point. Biomed Rep. 2016;4(2):147-152.
  24. Waldman M, Austin HA III. Treatment of idiopathic membranous nephropathy. J Am Soc Nephrol. 2012;23(10):1617-1630.
  25. Cattran D, Brenchley P. Membranous nephropathy: thinking through the therapeutic options. Nephrol Dial Transplant. 2017;32(suppl 1):i22-i29.
  26. Mansur A. Membranous glomerulonephritis. Epidemiology section. Emedicine Medscape website. http://emedicine. medscape.com /article/239799-overview#a6. Updated October 23, 2016. Accessed July 6, 2018.

Thyroid Disorders

Jennifer Perkins, MD, MBA
Duke University Hospital

Hello, my name is Jennifer Perkins, an endocrinologist at Duke University Hospital in Durham, North Carolina.

I am going to review the pathophysiology, incidence, clinical presentation, diagnosis, and treatment of hyperthyroidism and hypothyroidism.

First, let’s take a look at hyperthyroidism.

Hyperthyroidism is a condition caused by the thyroid gland either making or releasing too much preformed thyroid hormone, which can enlarge the thyroid gland and accelerate the body’s metabolism.1

Hyperthyroidism occurs in about 1% of people, or 1 person out of 100, in the United States.2 Graves’ disease accounts for 60% to 80% of these cases.3

Hyperthyroidism can present with multiple symptoms that vary according to the age of the patient, duration of illness, magnitude of hormone excess, and presence of comorbid conditions.3

Some of the most common signs and symptoms of an overactive thyroid in hyperthyroidism may include racing heart, tremor, palpitations, weight loss, diarrhea, heat intolerance, and amenorrhea.1,6,9

Hyperthyroidism is typically diagnosed by measuring the level of thyroid-stimulating hormone, or TSH, in the blood.1

Although reference ranges are not necessarily standardized nor agreed upon and are assay dependent, according to the American Thyroid Association guidelines, patients with TSH levels below 0.1 milli-international units of hormone per liter of blood should be diagnosed with and treated for hyperthyroidism. Patients with comorbidities such as heart disease and osteoporosis should be treated when their TSH levels are below <0.35 milli-international units of hormone per liter of blood.7

The goals of therapy are to help correct the hypermetabolic state with the fewest side effects and the lowest risk of hypothyroidism possible.1

Treatment options will depend on several factors, including patient age, physical condition, the underlying cause and severity of the hyperthyroidism, and patient preferences.3

There are several common mainstay options for treating persistent hyperthyroidism and Graves’ disease, including oral antithyroid drugs, oral radioactive iodine, and surgery.1,3,8

Beta blockers, iodides, and corticosteroids can be used together with the primary treatment as adjunctive therapy to increase effectiveness.3,7,8

Beta blockers help to relieve the adrenergic symptoms of hyperthyroidism, such as tremors, palpitations, and heat intolerance.3,8

Iodides are used for rapid reduction of thyroid hormone levels, typically only used as a bridge to surgery. They may also be used in those who do not tolerate antithyroid drugs and in those with severe cardiac disease.3,7,8 However, if iodides are used for more than 2 to 3 weeks, a recurrence of hyperthyroidism may occur.7,11

Now, let’s take a look at hypothyroidism.

In contrast, hypothyroidism is a condition where the thyroid gland does not secrete the necessary amount of hormones.12 The thyroid gland can be larger earlier in the disease when inflamed and then may shrink and become fibrotic over time.13,14

Hypothyroidism occurs in about 5% of people, or 5 people out of 100, in the United States.15

Chronic autoimmune thyroiditis, also called Hashimoto’s thyroiditis, is the most common cause of hypothyroidism.14

Hypothyroidism can present with a myriad of clinical signs and symptoms that vary according to the severity of the hormone deficiency, age, and sex. The most common symptoms of hypothyroidism are fatigue and cold intolerance.16

Other common symptoms include weight gain, constipation, depression, and forgetfulness.4,12,16

The best method for diagnosing hypothyroidism is the TSH blood test, followed by a thyroid hormone test, if needed.12

Patients with TSH levels above 10 milli-international units of hormone per liter of blood should be treated for primary hypothyroidism.12,19

Symptomatic patients with TSH levels of 4.5 to 10 milli-international units of hormone per liter of blood may benefit from treatment, too.19

Women with thyroid disease or positive antibodies with TSH levels above 2.5 milli-international units of hormone per liter of blood should seek care prior to conception.20

Standard of care for patients who are overtly hypothyroid, with little residual thyroid function, includes taking an oral synthetic thyroid hormone.12,19

The dosage will depend on the patient’s age, sex, and body size. Those without a thyroid gland may need higher doses, while those patients with milder thyroid hormone deficiencies may require lower doses.

Dose adjustments are guided by serum TSH determinations following initiation of therapy.19

Periodic TSH tests are also crucial for determining the optimal starting dosage of medication and for making any necessary adjustments over time.12

References:

  1. Hyperthyroidism (overactive thyroid). Mayo Clinic website. https://www. mayoclinic.org/diseases-conditions/hyperthyroidism/symptoms-causes/syc-20373659. Published October 28, 2015. Accessed July 6, 2018.
  2. Hyperthyroidism (overactive thyroid). National Institute of Diabetes and Digestive and Kidney Diseases website. https://www.niddk.nih.gov/health-information/endocrine-diseases/hyperthyroidism. Published August 2016. Am Fam Physician. 2005;72(4):623-630.
  3. Reid JR, Wheeler SF. Hyperthyroidism: diagnosis and treatment. Am Fam Physician. 2005;72(4):623-630.
  4. General information/press room. American Thyroid Association website. https://www.thyroid.org/media-main/press-room/. Accessed July 6, 2018.
  5. Hershman JM. Hyperthyroidism (thyrotoxicosis). Merck Manual website. https://www.merckmanuals.com/ professional/endocrine-and-metabolic-disorders/thyroid-disorders/hyperthyroidism. Updated April 2018. Accessed July 6, 2018.
  6. Milas K. Hyperthyroidism symptoms: signs and symptoms caused by excessive amounts of thyroid hormones. EndocrineWeb website. https://www.endocrineweb.com/conditions/hyperthyroidism/hyperthyroidism-symptoms. Updated July 6, 2018. Accessed July 6, 2018.
  7. Ross DS, Burch HB, Cooper DS, et al. 2016 American Thyroid Association guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis. Thyroid. 2016;26(10):1343-1421.
  8. Brent GA. Clinical practice. Graves‘ disease. N Engl J Med. 2008;358(24):2594-2605.
  9. Amenorrhea. Mayo Clinic website. https://www.mayoclinic.org/diseasesconditions/amenorrhea/symptomscauses/syc-20369299. Updated April 26, 2018. Accessed August 20, 2018.
  10. Wians FH Jr. Blood tests: normal values. Merck Manual website. https://www.merckmanuals.com/professional/ appendixes/normal-laboratory-values/blood-tests-normal-values. Accessed July 6, 2018.
  11. Braga M, Cooper DS. Oral cholecystographic agents and the thyroid. J Clin Endocrinol Metab. 2001;86(5):1853-1860.
  12. Hypothyroidism (underactive thyroid). Mayo Clinic website. https://www. mayoclinic.org/diseases-conditions/hypothyroidism/symptoms-causes/syc-20350284. Updated May 22, 2018. Accessed July 6, 2018.
  13. Hypothyroidism. MedlinePlus website. https://medlineplus.gov/ency/article/000353.htm. Updated June 4, 2018. Accessed July 6, 2018.
  14. Pearce EN, Farwell AP, Braverman LE. Thyroiditis. N Engl J Med. 2003;348(26):2646-2655.
  15. Hypothyroidism (underactive thyroid). National Institute of Diabetes and Digestive and Kidney Diseases website. https://www.niddk.nih.gov/health-information/endocrine-diseases/hypothyroidism. Updated August 2016. Accessed July 6, 2018.
  16. Gaitonde DY, Rowley KD, Sweeney LB. Hypothyroidism: an update. Am Fam Physician. 2012;86(3):244-251.
  17. Wiersinga WM. Adult hypothyroidism. Thyroid Disease Manager website. http://www.thyroidmanager.org/chapter/adult-hypothyroidism/. Updated March 28, 2014. Accessed July 6, 2018.
  18. Thyroid gland disorders. Chapter 179. In: Fauci AS, Braunwald D, Kasper AL, et al; eds. Harrison’s Manual of Medicine. 17th ed. McGraw-Hill; 2008:925-933.
  19. Garber JR, Cobin RH, Gharib H, et al. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocrin Pract. 2012;18(6):988-1028.
  20. Alexander AK, Pearce EN, Brent GA, et al. 2017 guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum. Thyroid. 2017;27(3):315-389.

Proactive monitoring may help identify potential adverse
events early1

Because of the risk of autoimmunity, infusion reactions, and malignancies, LEMTRADA is available only through restricted distribution under a Risk Evaluation and Mitigation Strategy (REMS) to help ensure safe use.1

  • Pharmacies, prescribers, healthcare facilities, and patients must be enrolled and comply with all program requirements.
  • Healthcare facilities must have onsite access to equipment and personnel trained to manage infusion reactions.
  • Call 1-855-676-6326 to enroll and learn more about the LEMTRADA REMS.
  • Initiate monitoring at baseline and after the first treatment course, and continue until 48 months after the last course of LEMTRADA, or longer, if clinically indicated.

Common Side Effects Associated With LEMTRADA

The most common side effects are based on 2-year active, controlled studies in patients with relapsing-remitting multiple sclerosis. Side effects occurred in ≥10% of LEMTRADA patients and more frequently than interferon beta-1a.1

  • Rash
  • Headache
  • Pyrexia
  • Nasopharyngitis
  • Nausea
  • Urinary tract infection
  • Fatigue
  • Insomnia
  • Upper respiratory tract infection
  • Herpes viral infection
  • Urticaria
  • Pruritis
  • Thyroid gland disorders
  • Fungal Infection
  • Arthralgia
  • Pain in extremity
  • Back pain
  • Diarrhea
  • Sinusitis
  • Oropharyngeal pain
  • Parasthesia
  • Dizziness
  • Abdominal Pain
  • Flushing
  • Vomiting

Pre- and Concomitant Medications

Get more information on proactive monitoring.

For infusion reactions:

Corticosteroids

  • Premedicate patients with high-dose corticosteroids (1000 mg methylprednisolone or equivalent) immediately prior to LEMTRADA administration and for the first 3 days of each treatment course1

Antihistamines and Antipyretics

  • Consider pretreatment with antihistamines and/or antipyretics prior to LEMTRADA administration1

Infusion reactions may occur despite pretreatment.

For herpetic infections:

Antivirals

  • Administer antiviral prophylaxis for herpetic viral infections starting on the first day of each treatment course and continue for a minimum of 2 months following treatment with LEMTRADA or until the CD4+ lymphocyte count is at least 200 cells per microliter, whichever occurs later1

INDICATION

LEMTRADA is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include relapsing-remitting disease and active secondary progressive disease, in adults. Because of its safety profile, the use of LEMTRADA should generally be reserved for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS.

Limitations of Use: LEMTRADA is not recommended for use in patients with clinically isolated syndrome (CIS) because of its safety profile.

IMPORTANT SAFETY INFORMATION

WARNING: AUTOIMMUNITY, INFUSION REACTIONS, STROKE AND MALIGNANCIES

CONTRAINDICATIONS

LEMTRADA is contraindicated in patients:

WARNINGS AND PRECAUTIONS

Most Common Adverse Reactions

In controlled clinical trials, the most common adverse reactions (incidence ≥10% and >interferon beta-1a) with LEMTRADA vs interferon beta-1a were: rash (53% vs 6%), headache (52% vs 23%), pyrexia (29% vs 9%), nasopharyngitis (25% vs 19%), nausea (21% vs 9%), urinary tract infection (19% vs 8%), fatigue (18% vs 13%), insomnia (16% vs 15%), upper respiratory tract infection (16% vs 13%), herpes viral infection (16% vs 3%), urticaria (16% vs 2%), pruritus (14% vs 2%), thyroid gland disorders (13% vs 3%), fungal infection (13% vs 4%), arthralgia (12% vs 9%), pain in extremity (12% vs 9%), back pain (12% vs 8%), diarrhea (12% vs 6%), sinusitis (11% vs 8%), oropharyngeal pain (11% vs 5%), paresthesia (10% vs 8%), dizziness (10% vs 5%), abdominal pain (10% vs 5%), flushing (10% vs 4%), and vomiting (10% vs 3%).

Use in Specific Populations

Physicians are encouraged to register patients in the pregnancy exposure registry by calling 1-866-758-2990. Antibodies, including anti-CD52 and autoantibodies, may be transferred from the mother to the fetus during pregnancy. Placental transfer of anti-thyroid antibodies resulting in neonatal Graves’ disease has been reported.

Safety and effectiveness in pediatric patients less than 17 years of age have not been established. Use of LEMTRADA is not recommended in pediatric patients due to the risks of autoimmunity and infusion reactions, stroke, and because it may increase the risk of malignancies.

Please see full Prescribing Information, including Boxed WARNING.

References:

  1. LEMTRADA [prescribing information]. Cambridge, MA: Genzyme Corporation.
  2. Data on file. Genzyme Corporation.
  3. Havrdova E, Arnold DL, Cohen JA, et al. Alemtuzumab CARE-MS I 5-year follow-up: durable efficacy in the absence of continuous MS therapy. Neurology. 2017;89(11):1107–1116. doi:10.1212/WNL.0000000000004313
  4. Coles AJ, Cohen JA, Fox EJ, et al; on behalf of CARE-MS II and CAMMS03409 investigators. Alemtuzumab CARE-MS II 5-year follow-up: efficacy and safety findings. Neurology. 2017;89(11):1117-1126. doi:10.1212/WNL.0000000000004354

Indication

LEMTRADA is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include relapsing-remitting disease and active secondary progressive disease, in adults. Because of its safety profile, the use of LEMTRADA should generally be reserved for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS.

Limitations of Use: LEMTRADA is not recommended for use in patients with clinically isolated syndrome (CIS) because of its safety profile.

IMPORTANT SAFETY INFORMATION

WARNING: AUTOIMMUNITY, INFUSION REACTIONS, STROKE AND MALIGNANCIES

  • LEMTRADA causes serious, sometimes fatal, autoimmune conditions such as immune thrombocytopenia and anti-glomerular basement membrane (anti-GBM) disease. Monitor complete blood counts with differential, serum
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