Systemic Lupus Erythematosus Yi Zhao, MD & PhD, vice-director, associate professor Department of Rheumatology & Immunology

AIMS To establish a definition of SLE To introduce some background epidemiology To recognise the clinical features of SLE To develop an awareness of the drug therapy related to SLE

AIMS By the end of this session you will be able to describe the presenting clinical features of SLE Outline the investigations required to confirm the diagnosis Describe the drug therapy used in the management of SLE

a damage variety of of multiple autoantibodies organs Definition Of SLE SLE is a systemic autoimmune disease in which the body loses tolerance to self: a variety of autoantibodies damage of multiple organs

Epidemiology: Race, Gender and Age More prevalent in African Americans, Caribbean populations, Hispanics and Asians Female > Male Most commonly seen in women of childbearing age

SLE Onset By Sex And Age

What Causes Lupus? Genetics Environment Hormones Lupus is an extremely complex disease, and although scientists are making progress in understanding the causes of lupus, there is still no single known cause. It is thought that a combination of genetics, environment, and possibly hormones act together to trigger the disease. Genetics: There is considerable evidence indicating that genes play a major role in the disease process. Researchers believe that there may be as many as 100 genes, which contribute to the genetic predisposition and development of SLE, and they have recently discovered a single gene that causes a lupus-like illness in mice. Hormones: The effect of hormones in humans with lupus is not clear. However, because the majority of lupus patients are women in their childbearing years, it seemed a logical aspect to study. Female hormones tend to stimulate the immune system or promote an immune response, (remember that having lupus means having an overactive immune system), whereas male hormones have the opposite effect and are more immunosuppressive. There does not seem to be any evidence that men or women with lupus produce abnormal levels of hormones, however, there may be differences in the way people with lupus process these hormones. Environment: Although it has not yet been fully proven, there may be certain environmental factors that play a role in initiating or triggering lupus in a genetically predisposed person.

Environmental Factors — UVA and UVB light can stimulate/ up-regulate autoimmunity stimulating keratinocytes to produce cytokines -> activate B cells to produce ab —Viruses/Bacteria: molecular mimicry SLE patients have higher titers of antibodies to Epstein-Barr virus (EBV), increased circulating EBV viral loads; SSA ab has a sequence similar to EBV nuclear ag 1 Parvovirus B19 —Drugs —Silica exposure, tobacco smoke, emotional stress

Genetics of Lupus —High concordance in monozygotic twins —5-12% or relatives with lupus have the disease —No single lupus gene —Disease is polygenic —At least 30 susceptiblility genes identified —HLADR2, HLADR3, HLADR4, HLADR8 (present in 75%)

Immunological Mechanisms Two Stage Disease Loss of self-tolerance /Auto-Abs generation Immune complex formation, causes inflammation/disease

Immunological Mechanisms Stage One: Loss of Self-tolerance Involves self-antigen presentation by DCs Role of Apoptosis Impaired clearance of apoptotic cells Results from defective complement system C2, C4, C1q defects Reduced CR1 receptors Cells serve as immunogens Induce auto-reactive T/B cells

Immunological Mechanisms Aberrant DC activity —DC’s present self antigens from apoptotic cells Mostly nucleosomes, apoptotic blebs — DCs present to CD4 cells Aberrant Lymphocyte Activity —Unregulated T-cell dependent B-cell activation Aberrant Germinal Center Activity — Ligation between certain CD pairings —Somatic Hypermutation Autoantibody Production —95% are antinuclear Abs (anti-Sm, Anti-DNA)

Immunological Mechanisms Stage Two: Immune Complex Formation Auto-Abs bind to: Pieces of DNA Nucleosomes Proteoglycans Immune complex formation Accumulate in organ basement membranes Results of Immune Complexes Local inflammation Local complement activation Local apoptosis Positive feedback loop

Pathologic Change inflammatory response vascular abnormalities The inflammation and necrosis of the blood vessel walls cause secondary thrombosis the deposition of immune complexes ischemia and dysfunction of local tissue Direct invasion of antibodies

The Characteristic Changes lupus cells Onion skin change in Arteriole fluorescence：Immunoglobulin and complement deposition

lupus cells The LE cell is a neutrophil that has engulfed the antibody-coated nucleus of another neutrophil. LE cells may appear in rosettes where there are several neutrophils vying for an individual complement covered protein.

Onion skin change there are significantly centripetal fiber hyperplasia around the small artery，especially in the spleen central artery，this results from vasculitis.

Immunoglobulin and complement deposition

LUPUS IS… Different for each person. Myriad of symptoms Symptoms are often non-specific A disease that ranges from mild to life threatening. Characterized by flares and remissions. Since lupus can attack any organ or organ system in the body, it affects everyone differently and there are no two cases that are alike. It can range from mild to life threatening and anywhere in between. People with lupus generally go through periods of flares, which are sudden increases in disease activity or development of new symptoms, and remissions, which are periods of disease-free activity.

What are the initial symptoms The initial manifestations of SLE are: fatigue, fever, malaise, weight loss, musculoskeletal manifestations similar to arthritis. SLE can affect multiple systems. Let’s take a look at each of those systems.

Clinical Manifestations

What Are The Dermatological Signs? The client may have Cutaneous Lupus Erythematosus Malar "butterfly" rash Photosensitivity Vasculitis Alopecia Oral Ulcers

Malar Rash Fixed erythema, flat or raised, over the malar eminences Tending to spare the nasolabial folds 30-60 %

Photosensitivity Rash over the sun exposed areas. Face,neck and V shaped area of chest. See rash varies in severity depending on exposure. Less under the orbit protected areas.

Discoid lupus Erythematous hyper pigmented margins flat scarred hypo pigmented centers This can be seen in SLE and pure cutaneous lupus

Discoid Rash Erythematous raised patches with adherent keratotic scaling and follicular plugging Atrophic scarring may occur in older lesions Atrophic scarring 萎缩性瘢痕

Subacute Cutaneous Lupus 32

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Alopecia 36

SLE — Vasculopathy Small vessel vasculitis Raynaud’s phenomenon Antiphospholipid antibody syndrome

Oral Lesions Erythema of hard and soft palate, papules ,vesicles and petechiae Erythematous rash of the tongue

Oral Ulcers Oral or nasopharyngeal ulceration usually painless observed by physician

Neurological Symptoms A client may have the following symptoms: Neuropathies (peripheral and central) Seizures Depression Psychosis A client may have the following complications from an exacerbation of SLE: CVA Organic Brain Syndrome Intellectual impairment Memory Loss Personality Changes Disorientation

Neuropsychiatric Systemic Lupus Erythematosus (NPSLE) CNS (diffuse & central) PNS Acute confusional state Psychosis Anxiety Depressive disorders Cognitive dysfunction Seizures CVA Chorea Myelopathy Demyelinating syndrome Headaches Neuropathies Acute inflammatory demyelination

Ocular Changes Conjunctivitis Photophobia Retinal vasculitis with transient blindness Cotton-wool spots on retina Cotton wool spots are small areas of yellowish white coloration in the retina. They occur because of swelling of the surface layer of the retina, which consists of nerve fibers. This swelling almost always occurs because the blood supply to that area has been impaired and in the absence of normal blood flow through the retinal vessels the nerve fibers are injured in a particular location resulting in swelling and the appearance of a "cotton wool spot. "

Musculoskeletal Changes Synovitis-90% patients, often the earliest sign Osteoporosis From SLE itself and therapy (usually steroids) Osteonecrosis (avascular necrosis) Can occur with & without history of steroid therapy

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SLE Arthropathy Non erosive arthritis Hand may show diffuse soft tissue swelling,ulnar deviation,swan neck deformity,MCP subluxation.

努力要趁早

How Can SLE Effect The Renal System Proteinuria Cellular casts Potential complications resulting from SLE are: Nephrotic syndrome Renal failure 50% of all lupus patients will have kidney involvement during their life of these, 50 % will have serious kidney disease

Persistent proteinuria greater than 0 Persistent proteinuria greater than 0.5 grams per day or greater than 3+ Cellular casts--may be red cell, hemoglobin, granular, tubular, or mixed Impaired kidney function Lupus nephritis predict out come (prognosis) Major cause of mortality

How Does Lupus Damage The Kidneys Autoantibodies are formed against antigens in the glomerulus basement membrane Circulating immune complexes bind to the basement membrane of the glomeruli These result in inflammation of the glomeruli (glomerulonephritis) 49

How Does Lupus Damage The Kidneys The basement membrane is damaged by the inflammation Appearance of protein, white and red blood cells and ‘casts’ in the urine Low albumin levels in the blood resulting in leakage of fluid from the vessels into the tissues (edema) Accumulation of waste proteins (uremia) Hypertension 49

How can SLE effect the GI system? Uncommon Severe abdominal pain often indicate mesenteric vasculitis, resembling medium vessel vasculitis (PAN) Hepatic abnormalities more often due to therapy than to SLE itself Less common manifestations of lupus involving the gastrointestinal tract include mesenteric ischemia from mesenteric vasculitis and pancreatitis

How can SLE effect the Cardiovascular system? Pericarditis Myocarditis Endocarditis Vasculitis Venous or arterial thrombosis (anywhere in the body) Pericarditis: most common cardiac manifestation and usually responds to NSAIDs. Myocarditis (rare) and fibrinous endocarditis (Libman-Sacks) may occur. Steroids plus treatment for CHF/arrhythmia or embolic events. MI due to atherosclerosis can occur in <35 y/o

hematologic system Anemia Leukopenia Thrombocytopenia Splenomegaly Anemia: usually Normochromic, normocytic Leukopenia: almost always consists of lymphopenia, not granulocytopenia Thrombocytopenia

Antiphospholipid Syndrome（APS） thrombocytopenia APS Arteriovenous thrombosis recurrent spontaneous abortions Antiphospholipid Syndrome (APS) Hypercoagulability with recurrent thrombosis of either venous or arterial circulation Thrombocytopenia-common Pregnancy complication-miscarriage in first trimester Lifelong anticoagulation warfarin is currently recommended for patients with serious complications due to common recurrence of thrombosis Antiphospholipid Antibodies Primary when present without other SLE feature. Secondary when usual SLE features present

Respiratory System Pleuritis with or without effusion Life-threatening manifestations: interstitial inflammation which can lead to fibrosis and intra-alveolar hemorrhage Also pneumothorax and pulmonary HTN can occur

What Lab Assessments help in the diagnosis general inspection autoantibody complement lupus band test renal biopsy imaging tests blood routine urinalysis ESR APL antibody ANA profile AOCA C3 C4 CH50 SLE50%-70%（+） Means disease activity diagnosis treatment prognosis MRI CT antinuclear antibody 抗组织细胞抗体 AOCA 抗磷脂抗体 antiphospholipid（APL）antibody RNP Antinuclear antibody profile Sm SSA Anti-dsDNA antibody rRNP SSB Anti-ENA antibody

Laboratory Findings in SLE 97% positive ANA 61% low complement levels (C3, C4) 50% dsDNA ab 46% leukopenia 42% anemia 40% proteinuria, nephritis 35% anticardiolipin antibodies 25% sjogren’s syndrome with positive SSA, SSB 12% pleural effusion Others: thrombocytopenia, anti SM, antiRNP, elevated LFTs, splenomegaly, thrombophilia, miscarriages

ANA in Lupus Sensitivity 93-99% in SLE Sensitivity 95-100% in drug induced Lupus Specificity is not great Higher the titer, higher the specificity 1:40- 30% normal population 1:160- seen in 5% of the population

How is a diagnosis of SLE made? SLE often a diagnostic challenge Multisystem (cutaneous, renal, respiratory, CV, CNS, GI) Manifestations may characterize numerous other conditions Use ACR classification criteria as a guide Patients need to fulfil 4 of the 11 criteria to reach a diagnosis of SLE Sensitivity 96% Specificity 96%

Diagnostic Criteria Of SLE 狼疮的诊断标准

Diagnostic criteria of SLE（MD+SOAP＋BRAIN） Malar rash Discoid lesions MD Serositis Oral ulcer Arthritis Photosensitivity SOAP Blood disorder disorderRenal disorder Antinuclear antibody Immunological disorder Neurological disorder BRAIN

2012 SLICC Classification Criteria Need at least 4 criteria (1 clinical and 1 lab) Or biopsy proven Lupus Nephritis with Pos ANA or pos dsDNA

Differential Diagnosis Rheumatic: RA, Sjogren’s syndrome, systemic sclerosis, dermatomyositis Nonrheumatic: HIV, endocarditis, viral infections, hematologic malignancies, vasculitis, ITP, other causes of nephritis 69

Treatment Individualized Evaluate their risks for organ involvement dsDNA ab: renal and neurologic SSA/SSB ab: rashes, pregnancy risks APL ab: clotting RNP ab: may develop overlap diseases

Treatment: Patient Education 1. Avoidance sun 2. Use of SPF > 35 sunblocks UVA and UVB 3. Sun-protective clothing 4. Promote exercise 5. Healthy diet (low chol, low sugar, low salt) 6. Smoking cessation 7. Avoidance of stress (animal models) 8. Good sleep hygiene Good patient care is just as important, if not more important than medications Emotional stress flares autoimmune disease in animal models 74

What medications are used to treat lupus? Glucocorticoids First-line agents for most manifestations Dosage and duration based on clinical experience don’t forget side effects, osteoporosis, atherosclerosis Antimalarials Hydroxychloroquine: cornerstone of SLE treatment To prevent disease flares Clinicians use a broad range of medications to treat lupus, including glucocorticoids, antimalarials, and nonsteroidal anti-inflammatory drugs (NSAIDs) (Table 2). Hydroxychloroquine prevents disease flares and is considered the cornerstone of SLE treatment. Glucocorticoids are first-line agents for most SLE manifestations, with dosage and treatment duration based on clinical experience and consensus. Immunosuppressive treatment in lupus nephritis is based on histopathologic classifications. Treatment of other lupus manifestations is based on sparse evidence from clinical trials and clinical experience and often requires immunosuppressive therapy and a multidisciplinary approach. 67

What medications are used to treat lupus? NSAIDs Immunosuppressive treatment （eg.cyclophosphamide/azathioprine/ cyclosporine ） In lupus nephritis: based on histopathologic classifications Other manifestations: treatment often includes immunosuppressives and a multidisciplinary approach Biological agents Clinicians use a broad range of medications to treat lupus, including glucocorticoids, antimalarials, and nonsteroidal anti-inflammatory drugs (NSAIDs) (Table 2). Hydroxychloroquine prevents disease flares and is considered the cornerstone of SLE treatment. Glucocorticoids are first-line agents for most SLE manifestations, with dosage and treatment duration based on clinical experience and consensus. Immunosuppressive treatment in lupus nephritis is based on histopathologic classifications. Treatment of other lupus manifestations is based on sparse evidence from clinical trials and clinical experience and often requires immunosuppressive therapy and a multidisciplinary approach. 68

How should clinicians initiate therapy in a stable patient who is not having a flare?

Hydroxychloroquine and other antimalarials Used to treat inflammatory arthritides for >50 years Prevents relapses Reduces risk for congenital heart block in neonatal SLE Well-tolerated with rare side effects (retinopathy; skin hyperpigmentation; neuromuscular or cardiac toxicity) Need eye examination every 6 months Hydroxychloroquine and other antimalarial agents have been used to treat inflammatory arthritides for at least 50 years (20). In addition to preventing lupus relapses and reducing the risk for congenital heart block in neonatal SLE, hydroxychloroquine has antithrombotic effects that are particularly important to SLE patients with antiphospholipid antibody-related prothrombotic diathesis (21). Hydroxychloroquine is generally well-tolerated and the rare risk for retinopathy is directly related to the years of exposure to the drug and the age of the patient. In a study of 29 cases of antimalarial retinal toxicity over a period of 30 years, all patients were older than 40 years and had had exposure to the agents over 5 years. (22). Skin hyperpigmentation and rare cases of neuromuscular or cardiac toxicity have also been reported. 70

How should clinicians choose therapy for a patient who is having a flare?

IV glucocorticoids + immunosuppressive medications For severe manifestations (lupus nephritis, alveolar hemorrhage, CNS vasculitis) Withdraw glucocorticoids once remission achieved Oral prednisone or methlyprednisolone Severe SLE manifestations, such as lupus nephritis, alveolar hemorrhage, or CNS vasculitis, should be treated with glucocorticoids administered intravenously (IV) in conjunction with immunosuppressive medications. Glucocorticoids can be gradually withdrawn once remission is achieved. Oral prednisone or methlyprednisolone is used for arthritis, pleuropericarditis, cutaneous vasculitis, and uveitis. Early studies demonstrated that glucocorticoids could ameliorate SLE, although subsequent controlled trials showed that the therapeutic effect was not sustained (23). Early studies also linked glucocorticoids to improved survival in severe SLE (24), but similar studies have not been done for mild or moderate disease. Current decisions about glucocorticoid dosage and the duration of treatment for specific manifestations rely largely on clinical experience, because too few clinical trials have been done. An early study comparing 100 mg versus 1000 mg IV methylprednisolone, suggested that 3 daily doses of 1000 mg did not have significant advantage over 3 daily doses of 100 mg (25). A more recent randomized study showed that a dose of 1000 mg to 1500 mg over 3 days is as effective as doses ranging from 2000 mg to 5000 mg over 3 days and is associated with a decreased risk for infections (26). Significant overlap exists between lupus manifestations and some glucocorticoid complications, including osteoporosis, avascular bone necrosis, myopathy, and psychosis. Furthermore, despite the abundance of observational data on glucocorticoid toxicity, evidence from randomized controlled clinical trials (RCTs) is limited. Table 2 summarizes the 2002 European League Against Rheumatism recommendations on glucocorticoid treatment (27). These recommendations define a low daily dose of prednisone (or equivalent) as ≤7 mg. Low doses are associated with relatively low risk for toxicity, although monitoring for cushingoid symptoms, osteoporosis, cataracts, glaucoma, hyperglycemia, and hypertension is probably justified. Prolonged treatment with medium to high dose carries higher risk of complications, including myopathy, psychosis, hyperlipidemia, and atherosclerosis. However, the prevalence and incidence of these complications in different corticosteroid regimens are still unclear (28).

Overlap: lupus manifestations, glucocorticoid complications Osteoporosis, avascular bone necrosis, myopathy, psychosis Glucocorticoid dosage, duration: rely on clinical experience Prolonged medium-to-high dosing increases complications

How should clinicians choose and dose drug therapy for lupus nephritis?

Class I or II: no immunosuppressive therapy Class III or IV: treat aggressively Standard therapy: cyclophosphamide + IV glucocorticoids Dose cyclophosphamide by total body surface area, adjusted for decreased creatinine clearance Dose glucocorticoids using ACR recommendations Newer regimen: mycophenolate mofetil + glucocorticoids GI and hematologic toxicity common Contraindicated in pregnancy (possibly teratogenic)

For patients who don’t respond to either Maintenance therapy Mycophenolate mofetil Azathioprine Both superior to cyclophosphamide For patients who don’t respond to either Calcineurin inhibitors (cyclosporine, tacrolimus) Rituximab (monoclonal antibody against CD20) Either in combination with glucocorticoids Maintenance therapy Current guidelines recommend either mycophenolate mofetil or azathioprine for maintenance therapy in lupus nephritis. Both are superior to cyclophosphamide for this purpose (39). Evidence from 2 studies of comparative efficacy of mycophenolate mofetil vs. azathioprine is conflicting (40,41). Treatment duration is guided by clinical experience. In a study of 227 patients with lupus nephritis class III, IV or V, who showed a clinical response to a 24-week induction with either cyclophosphamide or mycophenolate mofetil patients were randomly assigned to treatment with mycophenolate mofetil (2 gm/d) or azathioprine (2 mg/kg/d). After 3 years of follow up, mycophenolate mofetil was significantly superior to azathioprine with respect to time to treatment failure (primary end point), time to renal flare, and time to rescue therapy (40). In contrast, an open-label study demonstrated no significant difference in patients treated with mycophenolate mofetil vs. azathioprine for maintenance treatment of lupus nephritis over a period of 4 years. All patients in this study were initially treated with low-dose cyclophosphamide for induction therapy (41). Calcineurin inhibitors such as cyclosporine are also used for maintenance therapy. A multicenter, randomized, open pilot trial compared the efficacy of cyclosporine vs. azathioprine for maintenance therapy of lupus nephritis. Seventy five patients with lupus nephritis IV, Vc or Vd, initially treated with IV glucocorticoids (1 mg/kg/3 d) followed by oral cyclophosphamide and prednisone for a median of 90 days, were randomized to treatment with azathioprine or cyclosporine for 2 (core study) and 4 years. Azathioprine and cyclosporine were equally effective in preventing disease flares, the primary outcome of the study. Proteinuria, a secondary end point, decreased significantly with both treatments. Blood pressure and creatinine clearance did not change significantly with either treatment; extrarenal manifestations and clinical activity decreased with both treatments (42). Data from this study indicate that cyclosporine and azathioprine are equally effective for maintenance treatment of lupus nephritis and have similar effects on blood pressure and renal function. Tacrolimus, also a calcineurin inhibitor, may be used to treat diffuse proliferative or membranous lupus nephritis. Meta analysis of data from open-label trials, case-control studies, and RCTs showed that tacrolimus may be effective as induction and maintenance therapy for lupus nephritis or in treatment of refractory lupus nephritis with persistent proteinuria (43). Rituximab is a monoclonal antibody directed against CD20, a membrane protein expressed on B-cells. Rituximab depletes B cells from the peripheral blood. Open-label trials indicated improvement of lupus nephritis after B-cell depletion; however RCTs did not show statistically significant response compared with placebo (44-46). Current ACR guidelines propose mycophenolate mofetil or azathioprine as preferred maintenance therapy for proliferative lupus nephritis. Calcineurin inhibitors or rituximab combined with glucocorticoids may be used for patients with inadequate response to cyclophosphamide or mycophenolate mofetil (38). To date, no RCT has directly compared calcineurin inhibitors to mycophenolate mofetil for maintenance treatment of class III or IV lupus nephritis. 76

How should clinicians choose therapy for neuropsychiatric lupus? Treatment relatively empirical IV glucocorticoids, immunoglobulin, cyclophosphamide Relapse may be more common in glucocorticoid vs cyclophosphamide treatment Rituximab may be beneficial, but relapse rate seems high Treatment of serious neuropsychiatric SLE manifestations is relatively empirical and includes IV glucocorticoids, immunoglobulin and cyclophosphamide. An RCT comparing cyclophosphamide to glucocorticoids after 3 days of IV immunoglobulin for treatment of transverse myelitis in lupus showed that relapse was more common in the steroid group. (51). Case reports and small, uncontrolled studies suggest beneficial effect of rituximab in treatment of neuropsychiatric lupus; however, the relapse rate seems to be high. 79

How should clinicians modify treatment for pregnant patients?

Higher flare rate in pregnancy + immediate post-partum Initial presentation with hematologic or renal manifestations during pregnancy not uncommon Consider pregnancy-related abnormalities that mimic SLE (eclampsia, HELLP syndrome) Treat active lupus manifestations Use hydroxychloroquine and prednisone Discontinuation associated with increased flare risk If severe, consider IV glucocorticoids + azathioprine Contraindicated: mycophenolate mofetil, methotrexate, cyclophosphamide Fertility is not significantly affected in SLE; however, SLE flares at a higher rate during pregnancy and the immediate post-partum period. The presence of anti-SSA antibodies may predict adverse pregnancy outcomes, as may other factors, including antiphopsholipid antibodies, renal disease, thrombocytopenia, hypertension, and the use of prednisone. Becoming pregnant during clinical remission correlates with lower frequency and severity of lupus exacerbations. The initial presentation of SLE with hematologic or renal manifestations during pregnancy is not uncommon. Clinicians should also consider pregnancy-related hematologic, vascular and renal abnormalities that mimic SLE manifestations, including eclampsia and the HELLP syndrome (a group of symptoms that occur in pregnant women with hemolysis, elevated liver enzymes, and low platelet count). Antimalarials can be used safely in pregnant SLE patients (63). Active lupus manifestations in pregnancy are usually treated with hydroxychloroquine and prednisone. It is advisable to continue hydroxychloroquine in pregnancy because discontinuation is associated with increased risk for flares and pregnancy is associated with risk for increased disease activity. Hydroxychloroquine may also offer protection against cardiac manifestations of neonatal lupus (65). For severe manifestions, IV glucocorticoids and azathioprine may be considered because azathioprine has not been identified as a human teratogen (64). Mycophenolate mofetil, cyclophosphamide or methotrexate are contraindicated due to potential teratogenicity. 85

Prognosis Poor prognosis if the clients have： high serum creatinine hypertension Myocardial damage associated with cardiac insufficiency Severe NP lupus pneumovax   肺炎疫苗 78

Prognosis Most SLE patients die from infection, probably related to therapy which suppresses immune system Recommend smoking cessation, yearly flu shots, pneumovax q 5years Most SLE patients die from infection, probably related to therapy which suppresses immune system 85% 70% 1year 10 years Survival rate 5 years 20 years 96% 80%

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