March 2018Housecalls

In this first issue of 2018 we examine a case of chronic granulomatous disease (CGD), one disease of the larger category of immune deficiency disorders. These disorders are often associated with genetic abnormalities that may become prime candidates for genetic therapy. Also in this issue, Dr. Rosace presents a case of Henoch-Schőnlein Purpura. And Dr. Rooney follows up with an ECG Puzzler.

On December 19, 2017, the US Food and Drug Administration approved Luxturna (voretigene neparvovec-rzyl) for the treatment of biallelic RPE65 mutation associated retinal dystrophy. Known as Leber’s congenital amaurosis 2, this disorder causes a lack of production of an enzyme that is essential for converting light to electrical signals in the retina. Patients experience a loss of vision in childhood or adolescence that progresses to complete blindness.

An estimated 1,000-3,000 patients are affected in the US. Treatment is delivered via subretinal injection. The viral vector is a modified adeno-associated virus. This was the first FDA approval for a gene therapy that was not for the treatment of cancer.

The FDA plans to issue a suite of guidance documents in 2018 “for the evaluation and review of gene therapy for different high-priority diseases where the platform is being targeted.” This particular example of gene therapy is in vivo (in living tissue), while the currently approved cancer gene therapies involve extracting human cells, modifying them in the laboratory, increasing the numbers and reintroducing them to the patient. This in vitro model may become the most effective, because of the benefits of reducing immune response to vectors, targeting specific cell types and increasing the number of “repaired” cells prior to the reinfusion for maximal benefit.

The field of gene therapy has progressed greatly since five of 20 patients treated for Severe Combined Immunodeficiency (SCID) developed acute lymphocytic leukemia or another T-cell lymphoproliferative disorder because of vector activation of proto-oncogenes. Research into vector composition and function has greatly reduced the risk

INSIDE THIS ISSUE

FDA APPROVES NEW TREATMENT

Genetic Therapies AdvancingBy Richard Braun, MD

Vice President & Chief Medical Officerrbraun@scor.com

Continued, P7

CHRONIC GRANULOMATOUS DISEASE P2

HENOCH-SHőNLEIN PURPURA A.K.A. IGA VASCULITIS P4

PUZZLER P8

Housecalls | March 2018 | 2

CASE #1

Chronic Granulomatous Disease

What is Chronic Granulomatous Disease, and what are the mortality implications?

CGD is a disorder of immune function resulting in severe bacterial and fungal infections and the formation of granuloma. It has a heterogeneous basis that results in defective phagocytosis and killing of certain bacteria and fungi by the immune system. It is estimated to affect one out of 200,000 born in the US.

The disease predominantly affects males due to most defects being X-linked. There is not necessarily a family history, as about one-third of X-linked mutations cannot be found in parents. There is also an autosomal recessive form more common in some ethnic populations.

The median age of diagnosis of CGD is three years, but it may present at any age. Antimicrobial therapy may delay the formation of granulomas and cause a later diagnosis. The X-linked form tends to have earlier onset and be more severe than the recessive form.

Presentation of CGD usually involves recurrent infections with bacterial and fungal pathogens. Viral infections are handled normally by CGD patients. There is usually fever and elevated white blood cell counts in bacterial infections.

But fungal infections are often subtle and can be difficult to detect. Pneumonia, abscesses, suppurative adenitis, osteomyelitis, septicemia and skin infections are the most common types of serious infections. Staphylococcus aureus and Aspergillus species are two of the more common organisms causing infections in CGD.

The defect in phagocytic cells in CGD contributes to a failure to degrade destroyed inflammatory cells, resulting in the formation of granulomata. These can be found in many organs but are often symptomatic in the urinary and gastrointestinal tracts due to obstruction and/or strictures.

Chronic pulmonary disease is a major cause of morbidity and mortality in CGD. Recurrent infections may lead to bronchiectasis, obliterative bronchiolitis and chronic pulmonary fibrosis. In turn these may lead to pulmonary hypertension.

Diagnosis

The diagnosis of CGD is made by testing the function of the neutrophils. Nitroblue tetrazolium test (NBT) was the first test for CGD. Superoxide in normally functioning neutrophils will turn them blue/black, and the NBT test is negative for CGD if 95+% turn. However, the test is qualitative and has a lower sensitivity.

The dihydrorhodamine 123 (DHR) test is the most commonly used test for neutrophil function. In this test oxidase present in normal neutrophils can be stimulated to produce a green fluorescence that can be measured. CGD cells lacking this function do not fluoresce. With heterozygotes for CGD, one can see two populations of neutrophils, one functioning and one not. In addition, the amount of fluorescence correlates with the function of the neutrophil population, which correlates with the severity of disease.

Treatment

Treatment of CGD includes chronic prophylactic antibiotics and antifungal medications. Maintenance of these regimens have been shown to reduce the number of severe infections and to prolong life. More controversial is the chronic administration of Interferon, which is commonly done in the US but not necessarily done in other countries.

Aggressive monitoring for and treatment of infections is a priority. Avoidance of exposure to fungi as might be contained in soil, mulch, etc. is recommended.

A life application was submitted on a 17-year-old male. He had a history of Inflammatory Bowel Disease for several years. He had surgery eight months prior to relieve rectal stenosis. He was recently diagnosed with Chronic Granulomatous Disease (CGD), but there were no details of that diagnosis in the medical records.

By Richard Braun, MDVice President & Chief Medical Officer

rbraun@scor.com

3

Hematopoietic Cell Transplantation (HCT), if successful, can be a definitive cure for CGD. Multiple factors contribute to the decision to pursue HCT. Prognosis without HCT is a major factor, and other considerations include donor availability, access to HCT and patient preference. HCT during an active infection has been noted to have a worse prognosis.

Gene therapy for CGD is an area of active investigation, especially for those without a matching HCT donor. It has been successful in restoring myeloid function in a mouse model of CGD and awaits results of trials in humans.

Prognosis

Prognosis in CGD is variable. When first described CGD was often fatal in childhood. Since that time survival has improved dramatically.

One study included 268 patients followed over four decades. The median age of death was 15.5 years before 1990 which increased to 28 years in the most recent decade studied. There was a clear association of early death with lower neutrophil superoxide production (a measure of neutrophil function). About 76% of patients were found to have lung infections at the time of death. And fungal infections accounted for 55% of deaths. Successful HCT may be curative, but damage sustained prior to HCT should also be considered in prognosis.

Returning to the case

It would be important to know how the diagnosis of CGD was made. The level of neutrophil function would provide important prognostic information. And any history of fungal infections or end organ damage could portend a worse prognosis. It would be prudent to ask for additional information.

Seger RA, et al., “Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft: a survey of the European experience, 1985-2000”, Blood (2002);100:4344-4350.

Martire B, et al. “Clinical features, long-term follow-up and outcome of a large cohort of patients with Chronic Granulomatous Disease: An Italian multicenter study”, Clinical Immunology (2008);126(2):155-164.

Holland S, “Chronic Granulomatous Disease”, Hematol Oncol Clin N Am (2013);27:89–99.

Marciano BE, et al. “Common Severe Infections in Chronic Granulomatous Disease”, CID (2015);60:1176-83.

Jones LBKR, et al. “Special Article: Chronic granulomatous disease in the United Kingdom and Ireland: a comprehensive national patient-based registry”, Clinical and Experimental Immunology (2008);152:211–218.

De Ravin SS, eta l., “CRISPR-Cas9 gene repair of hematopoietic stem cells from patients with X-linked chronic granulomatous disease”, Science Translational Medicine (2017);9(372):3480.

www.uptodate.com last accessed 2/14/2018

REFERENCES

Housecalls | March 2018 | 4

What are the mortality considerations for someone with a diagnosis of Henoch-Shőnlein Purpura?

Definition

Henoch Shőnlein Purpura (HSP) is an acute small vessel vasculitis and the most common vasculitis in children. 90% of cases occur in children younger than 10 years old. Incidence is between 10-20 per 100,000 children less than 17 years old.

Adult HSP, in contrast, is less common but often is associated with a worse clinical course and outcome. In some areas of the world, as many as 25%-30% of patients with HSP are adults.

The clinical features of HSP are atypical at the extremes of age, with adults being more severely affected and children under 2 years old being mildly affected. HSP occurs primarily in the fall to spring months and often follows an upper respiratory infection, although other pathogens, drugs and environmental factors have been implicated as triggers. HSP is often, though not always, self-limited. It may eventually develop into chronic kidney disease with the long-term prognosis depending on the severity of the renal involvement.

HSP was renamed IgA Vasculitis (IgAV) by the International Chapel Hill Consensus Conference Nomenclature of Vasculitides in 2012, yet the new name is not universally used, and in this article, will be referred to as HSP.

Presentation

The presentation varies, but universally, a non-thrombocytopenic palpable purpura mostly located on the buttocks and lower extremities is present either initially or shortly into the course. Any of the following may also be present: arthritis, abdominal pain and renal involvement.

Diagnostic criteria

Although there is more than one set of criteria in existence, the most universally used consensus criteria were developed by the European League Against Rheumatism (EULAR) and the Paediatric Rheumatology European Society (PRES) and validated in conjunction with the Paediatric Rheumatology International Trials Organisation (PRINTO).

Mandatory Criteria: Rash (Purpura), usually palpable and in clusters with lower limb predominance and without thrombocytopenia or coagulopathy

Must have one or more of the following: ~ Abdominal pain (usually diffuse

with acute onset)

~ Arthritis or arthralgia

~ Renal involvement (proteinura, hematuria)

~ Leukoclastic vasculitis or prolif-erative glomerulonephritis with predominant IgA deposition

CASE #2

Henoch-Shőnlein Purpura (also Known as IgA Vasculitis)

A 31-year-old male applies for life insurance. He states that he is in good health except for hypertension (current and treated) and a diagnosis of Henoch-Shőnlein Purpura at the age of 27 years. His medical records reveal that he presented with a rash, hematuria, trace proteinuria and diarrhea. The rash and diarrhea resolved in about one month, but the hematuria persisted for about 12 months.

Urology has been following him every six months, and for the last three visits, he has had normal blood pressure (treated), no proteinuria and no hematuria neither macroscopic nor microscopic, along with normal renal function studies. His insurance labs have the same normal results including liver function tests, renal function tests and urinalysis.

By Regina Rosace, MD Assistant Vice President,

Medical Director rrosace@scor.com

5

Continued

There are no current lab values that are diagnostic for HSP. To receive this diagnosis, platelet levels must be normal or elevated, they cannot be low. Common findings might include: leukocytosis, elevated Erythrocyte Sedimentation Rate (ESR), elevated IgA serum levels, hematuria, positive throat culture for beta-hemolytic strep or low complement levels.

In cases where the diagnosis cannot be made reliably on clinical findings and routine laboratory values, the presence of leukocytoclastic vasculitis and IgA-immune deposits on skin or on kidney biopsies point strongly toward HSP as the diagnosis.

There is some exciting research on the horizon with the possible identification of a urinary protein as a marker for HSP nephritis. A definitive marker would be especially beneficial for those presentations which are atypical or cases in which a biopsy would be difficult.

Clinical course and differential diagnosis

Cutaneous palpable purpura are an essential feature in this illness (see Figure 1). They are most prominent in the buttocks and lower extremities but may present elsewhere. There may also be scattered petechiae and coalescing ecchymosis.

This is differentiated from immune thrombocytopenia purpura (ITP) simply by checking a platelet count. The platelet count will be low in ITP. Other vasculitides would need to be considered, especially if the illness presents in a piecemeal fashion.

Arthritis and arthralgias are the second leading feature in this condition. These most often involve the joints of the lower extremities, making it painful to walk. In some cases, young children simply refuse to walk. Arthritis will precede the skin findings by up to one week in 15%-25% of cases.

Gastrointestinal involvement occurs in 50%-75% of patients. Colicky abdominal pain, diarrhea, vomiting and gastrointestinal bleeding are the predominant symptoms. Guaiac positive stools are found in >50% of patients with HSP.

If these symptoms predate the rash (they do in 10%-20% of patients), as they can by one to two weeks, other causes of abdominal pain must be ruled out. GI bleeding is not uncommon and about 30% of HSP patients will have melanotic stools.

Renal involvement occurs in 40%-50% of patients with microscopic hematuria being most common followed by proteinuria and gross hematuria. Proteinuria accompanies hematuria 60% of the time but is rarely the sole renal finding.

Nephritis rarely if ever precedes the purpura, predominantly manifests within four weeks of the skin finding and nearly always within three months of the presentation of the other symptoms. As a result, urinalysis should be done weekly during the active disease and then each month for three months. If at any time there is evidence of nephritis, long term monitoring of urine, renal function and blood pressure is warranted.

Image accessed 2/5/2018 from Bing search, free to use and share

FIGURE 1 — PURPURA CHARACTERISTIC OF HSP

Housecalls | March 2018 | 6

Differences between adult & children with HSP

A 10-year retrospective study was done in Korea to investigate the differences in clinical manifestations and outcomes between adult and child patients with HSP.

Findings Adults ChildrenPurpura in upper extremities 41.7% 19.3%

Arthralgias 27.1% 55.4%

Anemia 25% 7.1%

Diarrhea 20% 1.6%

Elevated serum IgA 26.3% 3.5%

Renal involvement 79.2% 30.4%

Chronic renal failure at follow up 10.4% 1.8%

These findings are in line with previous comparisons between children and adults with HSP. Generally, adults tend to have slightly different non-skin symptoms as well as more serious renal manifestations, both acutely and chronically.

Treatment

Treatment is generally supportive as the disease course is usually self-limited. The rare cases of bowel perforation or intussusception would require surgical intervention. Corticosteroids early in the course tend to alleviate gastrointestinal and joint symptoms but do not prevent delayed nephritis.

There are a number of different treatments used for HSP with moderate to severe renal involvement, including steroids and adjuvant treatments such as cyclophosphamide, enalapril, dipyridamole and IVIG. There is no clearly superior treatment, and close monitoring is required.

Prognosis

Symptoms last, on average, four weeks. Recurrences are not unusual and generally subside after six months. Renal signs and symptoms such as hematuria and proteinuria can persist for months to years.

Fortunately only 1%-3% of children and about 10% of adult patients progress to end stage kidney disease. Microscopic hematuria with trivial proteinuria portends a favorable prognosis, while nephritis complicated by nephrotic syndrome as well as >50% crescent formation on renal biopsy suggest a less favorable prognosis.

Current research

While the pathogenesis of HSP is still largely unknown, the disease is characterized by IgA1 immune deposits, complement factors and neutrophil infiltration accompanied by vascular inflammation. HSP nephritis—also known as IgA vasculitis with nephritis (IgAVN)—resembles IgA nephropathy (IgAN). Both are associated with galactose-deficient IgA1 deposits in the kidney. Several labs across the world are currently working to better delineate the pathogenesis and aid in the treatment.

Returning to the case

As this gentleman was an adult when he developed HSP, his renal status needs to be assessed and monitored. While he had hematuria and trace proteinuria at presentation, he has been well followed by urology and appears to no longer have the renal manifestations of HSP. His labs and clinical course seem to put him in the fortunate category of no long term renal sequelae and, therefore, no expected excess mortality.

CASE #2

Henoch-Shőnlein Purpura Cont.

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Calviño, Maria C., et al. “Henoch-Schönlein Purpura in Children from Northwestern Spain: a 20-year Epidemiologic and Clinical Study.” Medicine 80.5 (2001): 279-290.

Chan, Han, et al. “Risk Factors Associated with Renal Involvement in Childhood Henoch-Schönlein Purpura: a Meta-analysis.” PloS One 11.11 (2016): e0167346.

Heineke, Marieke H., et al. “New Insights in the Pathogenesis of Immunoglobulin-A Vasculitis (Henoch-Schönlein Purpura).” Autoimmunity Reviews (2017).

Jennette, John C., et al. “2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides.” Arthritis & Rheumatology 65.1 (2013): 1-11.

Kang, Yoon, et al. “Differences in Clinical Manifestations and Outcomes Between Adult and Child Patients with Henoch-Schönlein Purpura.” Journal of Korean Medical Science 29.2 (2014): 198-203.

López-Mejías, Raquel, et al. “Genetics of Immunoglobulin-A Vasculitis (Henoch-Schönlein Purpura): An Updated Review.” Autoimmunity Reviews (2018).

Pillebout, Evangéline, et al. “Henoch-Schönlein Purpura in Adults: Outcome and Prognostic Factors.” Journal of the American Society of Nephrology 13.5 (2002): 1271-1278

Saulsbury, Frank T. “Clinical Update: Henoch-Schönlein Purpura.” The Lancet 369.9566 (2007): 976-978.

Suzuki, Hitoshi, et al. “IgA Nephropathy & IgA Vasculitis with Nephritis Have a Shared Feature Involving Galactose-Deficient IgA1-oriented Pathogenesis.” Kidney international (2018).

Wang, Jiapei, et al. “Elevated Urinary Monocyte Chemoattractant Protein-1 Levels in Children with Henoch-Schonlein Purpura Nephritis.” Pediatrics & Neonatology(2017).

Yang, Yao-Hsu, Hsin-Hui Yu, and Bor-Luen Chiang. “The Diagnosis and Classification of Henoch–Schönlein Purpura: An Updated Review.” Autoimmunity Reviews 13.4-5 (2014): 355-358.

Zaffanello, Marco, et al. “Adjuvant Treatments for Henoch-Schönlein Purpura Nephritis in Children: A Systematic Review.” Current Therapeutic Research 70.3 (2009): 254-265.

Up To Date, last accessed 2/14/2018

FDA APPROVES NEW TREATMENT

Genetic Therapies Cont., P1

of therapy, and there are at least a dozen US clinical trials ongoing using lentiviral vectors to alter hematopoietic stem cells (HSC).

The diseases being studied include not only CGD but also Beta-Thalassemia, Sickle Cell disease and SCID among others. In addition, there was a recent encouraging report of treatment of Hemophilia B with an adeno-associated viral vector combined with a factor IX transgene. The treatment halted bleeding episodes in nine of 10 patients treated.

One possible impediment to gene therapy is the cost. It was reported that the cost of Luxturna is $850,000 USD for a one-time treatment. But costs may be a bargain when compared to the life-long treatment for such diseases as hemophilia or cystic fibrosis. Research is proceeding cautiously and a lot more needs to be done, but today gene therapy is an exciting area of research that has the potential to cure some debilitating chronic conditions.

George LA, et al. “Hemophilia B Gene Therapy with a High-Specific-Activity Factor IX Variant”, N Engl J Med (2017);377:2215-2227.

Kohn DB, “Historical Perspective on the Current Renaissance for Hematopoietic Stem Cell Gene Therapy”, Hematol Oncol Clin N Am (2017);31:721–735.

Up To Date, last accessed March 2018.

REFERENCES

REFERENCES

Housecalls | March 2018 | 8

The information conveyed and the views expressed in this newsletter are provided for informational purposes only and are based on opinions and interpretations made by SCOR Global Life Americas. The opinions and interpretations expressed by SCOR Global Life Americas may not be the only interpretation available. This publication should not be copied or shared with any other company, reinsurer or consultant without obtaining prior approval from SCOR Global Life Americas.

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SOLVE

ECG Puzzler...

Here is the latest ECG Puzzler to solve.

A 57-year-old male applied for life insurance with no cardiac history. What is the major abnormality in this ECG?

To find the answer, visit the Housecalls page at www.scorgloballifeamericas.com. Click on March 2018 Puzzler to confirm your findings.

By Bill Rooney, MD Vice President,

Medical Director brooney@scor.com