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Systemic Lupus Erythematosus - PPT Presentation

Challenges and Options Grand Rounds Presented by Sumona Kabir DO January 21 st 2015 Overview Case presentation Definition of SLE Pathophysiology Classification Details of each classification ID: 810583

class lupus nephritis renal lupus class renal nephritis sle immune criteria erythematosus positive male year presentation disease case tablet

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Slide1

Systemic Lupus Erythematosus Challenges and Options

Grand RoundsPresented by:Sumona Kabir, DOJanuary 21st, 2015

Slide2

Overview Case presentationDefinition of SLEPathophysiologyClassification Details of each classificationChallenges regarding the current diagnostic criteria Treatments Osteopathic consideration

Slide3

Case presentation – 55 year old male with progressive wasting UE was a 55 yo AA male who presented at GV ED on 12/10/2014 with nonproductive cough, generalized weakness, anorexia, and a general decline of his health. Most of history was obtained from his father. Patient was recently diagnosed with bilateral pneumonia and was placed on Augmentin. His symptoms continued to become worse and he was so weak that he couldn’t get out of bed. On initial presentation, pt had non-productive cough, severe weakness and couldn’t stay awake to talk to the physician. He failed his initial swallow eval. Was febrile, managed with Tylenol. Started on

Zosyn. A foley was placed due to low urine output. Lungs were congested and TB test was initiated. Was admitted to MACU for bilateral pneumonia, hypocalcemia, Severe Protein Calorie malnutrition, and failure to thrive.

Slide4

PMHxBaseline MRDDPsychogenic polydipsiaHyponatremiaHx of seizureChronic constipation and Right internal capsule ischemic strokeAnemia Case presentation –

55 year old male with progressive wasting (Cont) Surgical History:Hip Fracture SurgerySmall intestine Surgery Family History:None noted on file. Social History:Single. Not sexually active. Non-SmokerNo alcohol use

No Drug

use

Allergies/Immunization:

NKA

Slide5

Review Of Systems: Constitutional Symptoms fatigued, generally weak, weight loss and loss of appetite Eyes : negative Ears, Nose, Mouth, Throat : negative Cardiovascular : positive for - dyspnea on exertion, palpitations and shortness of breath

Respiratory : positive for - cough, shortness of breath, sputum changes and wheezing Gastrointestinal : positive for - appetite loss, change in bowel habits and gas/bloating Genitourinary: positive for - change in urinary stream Musculoskeletal : positive for - muscular weakness

Integumentary

: ??

Neurological

: positive for -

confusion, gait disturbance, impaired coordination/balance, memory loss, seizures and weakness

Psychological

: positive for -

disorientation and memory difficulties Endocrine : negative Hematologic / Lymphatic :negative Allergic / Immunologic : negative

Case presentation –

55 year old male with progressive wasting (cont)

Slide6

Medication Amoxicillin-clavulanate (AUGMENTIN) 875-125 mg per tablet Polyethylene glycol (MIRALAX) 17 gram/dose powder Benzonatate (TESSALON) 100 mg capsule Dextromethorphan-guaifenesin (MUCINEX DM) 30-600 mg Tb12 per tablet Albuterol (PROVENTIL HFA; VENTOLIN HFA) 90 mcg/actuation inhaler Ferrous sulfate 325 mg (65 mg iron) tablet Fexofenadine (ALLEGRA ALLERGY) 60 mg tablet

Ciprofloxacin (CIPRO) 250 mg tablet Meclizine (ANTIVERT) 12.5 mg tablet Aspirin 81 mg enteric coated tablet (only medication up untill 12/2014)Case presentation – 55 year old male with progressive wasting (cont)

Slide7

Course of diseasePresented primarily with a lung problem and FTT.Developed aspiration pneumonia. SLE characteristics were identified and tested.Developed petechiae, hemoglobin dropped, fungemia, sepsis.Intubated. Extubated. Improved with steroid.

Acutely bled, reintubated. Renal failure developed. NSTEMI.CVVHD initiated. Initiated cytoxan. Leukopenic, anemic, thrombocytopenic.ARDSCardiac arrest, ROSC, DNR-CC, Passed away.

Slide8

SLE definitionLupus - ˈlo͞opəs/: comes from Latin for wolf, since the 1600sDefinite SLE

After meeting exclusion criteria, anyone meeting 1997 ACR or 2012 SLICC criteria. Probable SLE Doesn’t meet all the ACR/SLICC criteria, less than 4Has other features not included in the guideline: Optic neuritis, aseptic meningitis. Glomerular hematuria, Pneumonitis, pulmonary hemorrhage, or pulmonary hypertension, interstitial lung disease, Myocarditis, verrucous

endocarditis (

Libman

-Sacks

endocarditis), Abdominal vasculitis, Raynaud phenomenon, Elevated

acute phase reactants (

eg

, erythrocyte sedimentation rate [ESR] and C-reactive protein [CRP])

Possible SLE

Meets only 1 criteriaUCTDUndifferentiated connective tissue disease , meets fewer characteristics

Slide9

SLE – Financial burdenMean annual direct costs per patient ranged from US$2,214 - $16,875, and mean annual indirect cost estimates from US$2,239 - $35,540 (year 2010 values). Disease activity and damage, along with poor mental and physical health, were repeatedly reported to predict both reduced HR-QOL and increased costs.

http://www.ncbi.nlm.nih.gov/pubmed/23329592

Slide10

EpidemiologyPrevalence: Ranges from 40/100,000 northern Europeans to >200/100,000 among blacksAge of onset: 30 (females), 40 (Males)Sex: Male to female 1:9Incidence: Estimated 1 to 25 per 100,000 in North America, South America, Europe and Asia.

Incidence has tripled in the last 40 years due to increased detection sensitivity.

Slide11

Pathophysiology Multifactorial and essentially unknown -makes diagnosis hindered and often difficult to identifyProposed mechanisms include:?Autoimmunity with tissue inflammation and damage based on genetic susceptibility and environmental stimuli

? Triggering of the innate immune system by viruses and endogenous ribonucleoprotien - UV light, viral infection, tobacco, drugs like hydralazine and procainamide. - Increased level of estrogen and epigenetic modification of x chromosome

- production of type 1 interferon important in lupus pathogenesis

- autoantibody against nucleic acid and/or nucleic acid binding protein

- immune complex deposition with complement activation, tissue damage

Slide12

Precipitating/ Triggering factors for SLE Possibilities: Genetic or hormonal mileau as predisposing factors

Infections - induce molecular mimicryStress - affect neuroendocrine changes affecting immune cell functionDiet - affecting production of inflammatory mediatorsToxins, drugs – modify cellular responsiveness and immunogenicity of self antigens

Sunlight

– inflammation and tissue damage

Slide13

Drug induced lupus

Slide14

Diagnosing Lupus – what is the issue? ACP Internist weekly newsletter titled “Lupus presentation may be an ‘imitator’” reported the current discussion about re-classifying the 1997 ACR criteria of 4 out of 11 items that defines lupus classification. “ Often begins with fatigue, muscle pain, joint pain and general feeling of being unwell…….”The need for revision includes:Easily classify pts with early diseaseBetter distinguish SLE from non-autoimmune conditions

Slide15

Diagnostic challenges50% of lupus pts. are initially missed diagnosed, most commonly with rheumatic fever, rheumatoid arthritis, and hemolytic anemiaHypocomplementemia is present in three quarters of untreated pts; especially C4 and C1q, these will be more depressed than C3, which suggests complement activation via classical

pathwayImmune complexes in the serum-rises and falls with disease activitywww.jeffkaulfhold.com

Slide16

The presence of 4 or more of the following criteria reflect a 96% sensitivity and specificity for the diagnosis of SLE

Slide17

Slide18

Slide19

SLICC criteriaA criteria for classification Not a criteria for diagnosisWhat is the difference? Up-to-date didn’t differentiate between the two in defining lupus. Necessary for surveillance vs. treatment initiation

Slide20

Lets look at the criteria in detail…

Slide21

Malar rashChronic cutaneous lupus erythematosus: hyperpigmentation

Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds

Slide22

Discoid rash Subacute cutaneous lupus erythematosus, an annular polycyclic rash characterized by scaly

erythematous circular plaques with central hypopigmentation. Photo © American College of Physicians.ACP internists weekly bulletin, December 9, 2014

Slide23

Photosensitivity Subacute cutaneous lupus erythematosus. Red, oval, and annular red plaques, minimal, scaling ina 56-year-old women. Happened after sun exposure.

This is annular type SCLE.

Slide24

Chronic cutaneous lupus erythematosus

Slide25

Oral Ulcers

Slide26

Nonerosive Arthritis - Involving 2 or more peripheral joints, characterized by tenderness, swelling, or effusion

Slide27

Serositis- Pleuritis or pericarditis

Possible acute interstitial pneumonitis, severe aspiration

Tx

:

Duoneb

, vest therapy,

Zosyn

+/-

cipro

Slide28

Case presentation – 55 year old male with progressive wasting (cont)

Slide29

Lupus pneumonitis – not an ACR criteria A study with 19 pts with lupus alveolitis:CT scanning revealed an alveolitis (a ground glass appearance) or fibrosis (a honey comb appearance) in all but one patient. Increased uptake on gallium scintigraphy was observed in seven patients.

Analysis of BAL fluid was normal in five patients but showed a lymphocytosis or granulocytosis in seven and six patients, respectively.Acute lupus pneumonitis is an uncommon (1 to 12 percent) manifestation of systemic lupus erythematosus (SLE) Also could be diffuse pulmonary hemorrhageAlveolar hemorrhage

Slide30

The spectrum of severity

Slide31

Pleuritis or pericarditisProcedure: Transesophageal EchocardiogramAssist: NoneDx/Indication: Bacteremia- Rule out endocarditisComplications: None

Consent was obtained from family.The patient tolerated this procedure well without immediate complications. Upon the procedures completion, the patients condition had returned to baseline.Summary:1. No evidence of endocarditis2. No intracardiac masses 3. Mild valvular disease- Mild PI, trace AI, trace TR4. Trileaflet

aortic valve

5. Normal LV systolic function with normal LV wall motion. EF 65%

6. Small PFO identified on bubble study

Slide32

Cerebral manifestationEEG report for our pt was negativeFor seizures.No offending drugs could be indentifiedPt has no psychosis.

Slide33

Hematologic disordersHemolytic anemia with absolute reticulocytosis

Slide34

Hematologic disordersHemolytic anemia with absolute reticulocytosis

Doesn’t have reticulocytosis

Slide35

Leukopenia

Slide36

Lymphopenia

Slide37

Thrombocytopenia

Slide38

Renal manifestationLupus nephritis It’s estimated that as many as 40 percent of all people with lupus, and as many as two-thirds of all children with lupus, will develop kidney complications that require medical evaluation and treatment – Lupus Foundation of America Symptoms of Lupus NephritisSudden and unexplained swelling, especially in the extremities (feet, ankles, legs, fingers, arms) or the eyesBlood in the urineElevated blood pressure

Foamy appearance in urineIncreased urination, especially at night

Slide39

The dominant feature in almost every patient Proteinuria (100%) Nephrotic syndrome (45-65%) Granular casts (30%) Microscopic hematuria (80%) Reduced renal function (40-80%) Hypertension (15-50%) Tubular abnormalities (asymptomatic) (60-80%)

Renal manifestation

Slide40

Renal manifestation Renal US – Our ptRenal US Diffuse heterogeneous appearance of the renal echotexture bilaterally. The finding is nonspecific and of unknown clinical significance given that the kidneys appear normal on the recent noncontrast abdomen/pelvis CT. There is no hydronephrosis presentUA

Slide41

Classification of Lupus Nephritisadopted by International Society of Nephrology.,20031. Minimal mesangial lupus nephritis (class I) – normal glomeruli on LM, mesangial immune deposits by IF

.2. Mesangial proliferative lupus nephritis (class II)- mesangial hypercellularity or expansion of matrix by LM-with mesangial immune deposits3. Focal lupus nephritis (class III)glomerulonephritis

involving less than 50% of all glomeruli, usually with focal

subendothelial

immune deposits

.

4.

Diffuse lupus nephritis (class IV

)

LN-glomerulonephritis involving >50% of all glomeruli, usually with diffuse subendothelial immune deposits5. Membranous lupus nephritis (class V) - global or segmental subepithelial immune deposits or their morphological sequelae.(can occur in combo with class3 or class4) Reveals advanced sclerosis

6. Advanced

sclerosing

lupus nephritis (class VI

)

>90% of glomeruli

sclerosed

without residual activity

Slide42

Normal Gomerulus

Slide43

Class 2: Mesangial Proliferative LN

Slide44

Class 2: MembranoProliferative LNFocal (class 3) or Diffuse (Class 4)

Slide45

Class 5: Membranous LN

Massive subepithelial accumulation of immune deposits and interdigitating spike formationwww.jeffkaufhold.com

Slide46

Class 5: Membranous LN

Slide47

Renal cortex showing almost diffuse, global glomerular sclerosis, interstitial fibrosis, and vascular sclerosis

Class 6: Advanced Sclerosing LN

www.jeffkaufhold.com

Slide48

Tx for Lupus nephritis Approximately 10 to 30 percent of patients with proliferative lupus nephritis progress to end-stage renal disease (ESRD).Goal is to induce rapid remission and long term maintenance phase Currently most accepted therapy include Cyclophosphamide + Glucocorticoid or

Mycophenolate Mofetil (MMF) + GlucocorticoidACR January 6th, 2015 published new data“ Multidrug Therapy for Induction Treatment of Lupus Nephritis” – A randomizedcontrol trial,

- showing 20.3% more people had remission after at about 6 months with triple

therapy with MMF,

Tacrolimus

and steroid vs cyclophosphamide + steroid

Slide49

Chronic Phase: maintenance therapy Corticosteroids remain the mainstay –doses of usually prednisolone 5-15 mg/day.Daily and alternate-day regimens have not been formally compared in lupus. Meta-analyses are unequivocally in favor of an additional clinical benefit of a cytotoxic agent during the maintenance phase when used in combination with corticosteroids.

Long-term follow-up of the NIH trials have shown less progression of renal scarring at 10-15 years in those groups treated with a cytotoxic agent than in those treated with prednisolone alone.Tx for Lupus nephritis www.jeffkaufhold.com

Slide50

Laboratory Evaluation ANAStrong positive if >12

2. Low complement level3. Anti-phospholipid ab4. Anti Sm ab5. Direct coombs test in the absence of hemolytic anemia

Slide51

ANA reliability

Slide52

Antiphospholipid abAntiphospholipid antibodies (LUPUS ANTICOAGULANT)APA is mostly directed against the beta-2 globulin phospholipid-carrier protein. These antibodies prolong phospholipid-dependent coagulation studies.

APA are detected in one third to one half of pts.APA is associated with renal arterial, venous, and glomerular capillary thrombosis, as well as Libman-Sacks endocarditis and cerebral thrombosis.Prothrombotic risk factors also include depressed release of plasminogen activator, decreased free protein-S levels, and increased von Willebrand factor concentration

www.jeffkaulfhold.com

Slide53

Antiphospholipid antibodies – AnticardiolipinsAntiphosphatidylinositolAntiphosphatidylglycerolAntiphosphatidylserineActivaton

of coagulation cascade

Slide54

Skin manifestationPicture was taken with permission of pt and father at GVH MICU, 12/2014

Slide55

Skin manifestationPicture was taken with permission of pt and father at GVH MICU, 12/2014

Slide56

Skin manifestationRed-to violaceous, well demarcated papules and plaques on the dorsa, sparing the skin overlying the joints. Palmar erythema mainly on the fingertips, this is pathognomonic

Slide57

Systemic vascular manifestationUrticarial or purpuric vasculitis — Vasculitis develops in approximately 11 to 20 percent of patients with SLE.Pathology report of skin biopsy of our pt: These are very interesting and challenging slides.

I do not see evidence of lupus erythematosus in the current biopsy.The primary pathologic process appears to be a vascular injury associated with thrombosis and some inflammation. Since the lesion shows full thickness necrosis of the dermis, it is difficult to make a definitive evaluation of the etiology. Thrombosis raises the possibility that the lesion may represent athrombogenic problem

, but also may be seen proximal or distal to a

vasculitis. The

vasculitisis

not identified in the current biopsy. Further evaluation

for clotting disorders

as well as vasculitis may be helpful in further

evaluating this patient

. I do not see evidence for fungal infections in either biopsy;

however, blood cultures may be helpful and/or tissue cultures if lesions continue to persist.Therefore, the diagnosis will be altered slightly to:A,B) Skin of right hand and right foot (punch biopsies):Epidermal and dermal necrosis associated with vascular thrombosis and inflammation.

GMS stain is negative for fungal organisms.

Slide58

Case (cont)

Slide59

What else could have happened? DICSepsisTBITPOsteomyelitisSIADHAnti-cardiolipin ab crisisFungal manifestation in the nervous system

Slide60

TreatmentNon-biologics – global immunosuppression NSAIDS – only sx control Antimalerials mycophenolate mofetilazathioprinemethotrexate

cyclophosphamide cyclosporineTacrolimusDapsone Biologics – specific target of the immune systemRituximab and epratuzumabBelimumab

Slide61

Acute Flare up Tx - Glucocorticoid

 

Short Acting

Intermediate acting

Long Acting

 

Cortisone

Prednisone

Dexamethasone

 

25

5

1

Mineralocorticoid

XXX

X

None

Glucocorticoid

X

XX

XXX

High dose prednisone = 10 mg

Or

Hydrocortisone = 50 mg

Out

pt

received

Methylprednisone

TID

80 mg for 2 days

60 mg for 20 days

Intermediate attempts to lower dose thought

t

o cause the multiple respiratory failure.

Slide62

Osteopathic Consideration Osteopathic manipulative treatment in conjunction with medication relieves pain associated with fibromyalgia syndrome: results of a randomized clinical pilot project. Gamber et al. J Am Osteopath Assoc. 2002 Jun;102(6):321-5Counterstrain tenderpoints - Can be used for

myalgia similar to fibromyalgia tx Direct and indirect MFRMuscle Energy to some extent, if pt can tolerate it, at a later stage

Slide63

Percussion Vibrator OMTHarmonic Healing: A Guide to Facilitated Oscillatory Release and Other Rhythmic Myofascial Techniques

Slide64

ReferencesUp to DatePrimer on the Rheumatic Diseases, 13th edition. Kippel et al. Chapter 15: 303-327.Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology, 7th edition. Wolff et al. Section 14: 334-343.

Pathologic Basis of Disease, 8th edition. Robbins and Cotran. Kumar et all. The humanistic and economic burden of systemic lupus erythematosus : a systematic review. Pharmacoeconomics. 2013 Jan;31(1):49-61. doi: 10.1007/s40273-012-0007-4.Lupus Foundation of America. How does Lupus affect the renal system? http://www.lupus.org/answers/entry/lupus-and-kidneyswww.jeffkaufhold.com Potency and duration of action of glucocorticoids.

Meikle

AW and Tyler FH.

Am

J of Med 1977;63;200

.

Multidrug therapy for induction of treatment of lupus nephritis. Liu et al. Annals of Internal Medicine.

Voume

162: 18-23. January 6, 2015.

Diagnosis of alveolitis in interstitial lung manifestation in connective tissue diseases: importance of late inspiratory crackles, 67 gallium scan and bronchoalveolar lavage. Witt et al. Lupus. 1996;5(6):606