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
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Slide1
Systemic Lupus Erythematosus Challenges and Options
Grand RoundsPresented by:Sumona Kabir, DOJanuary 21st, 2015
Slide2Overview Case presentationDefinition of SLEPathophysiologyClassification Details of each classificationChallenges regarding the current diagnostic criteria Treatments Osteopathic consideration
Slide3Case 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.
Slide4PMHxBaseline 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
Slide5Review 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)
Slide6Medication 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)
Slide7Course 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.
Slide8SLE 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
Slide9SLE – 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
Slide10EpidemiologyPrevalence: 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.
Slide11Pathophysiology 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
Slide12Precipitating/ 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
Slide13Drug induced lupus
Slide14Diagnosing 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
Slide15Diagnostic 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
Slide16The presence of 4 or more of the following criteria reflect a 96% sensitivity and specificity for the diagnosis of SLE
Slide17Slide18Slide19SLICC 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
Slide20Lets look at the criteria in detail…
Slide21Malar rashChronic cutaneous lupus erythematosus: hyperpigmentation
Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds
Slide22Discoid 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
Slide23Photosensitivity 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.
Slide24Chronic cutaneous lupus erythematosus
Slide25Oral Ulcers
Slide26Nonerosive Arthritis - Involving 2 or more peripheral joints, characterized by tenderness, swelling, or effusion
Slide27Serositis- Pleuritis or pericarditis
Possible acute interstitial pneumonitis, severe aspiration
Tx
:
Duoneb
, vest therapy,
Zosyn
+/-
cipro
Case presentation – 55 year old male with progressive wasting (cont)
Slide29Lupus 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
Slide30The spectrum of severity
Slide31Pleuritis 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
Slide32Cerebral manifestationEEG report for our pt was negativeFor seizures.No offending drugs could be indentifiedPt has no psychosis.
Slide33Hematologic disordersHemolytic anemia with absolute reticulocytosis
Slide34Hematologic disordersHemolytic anemia with absolute reticulocytosis
Doesn’t have reticulocytosis
Slide35Leukopenia
Slide36Lymphopenia
Slide37Thrombocytopenia
Slide38Renal 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
Slide39The 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
Slide40Renal 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
Slide41Classification 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
Slide42Normal Gomerulus
Slide43Class 2: Mesangial Proliferative LN
Slide44Class 2: MembranoProliferative LNFocal (class 3) or Diffuse (Class 4)
Slide45Class 5: Membranous LN
Massive subepithelial accumulation of immune deposits and interdigitating spike formationwww.jeffkaufhold.com
Slide46Class 5: Membranous LN
Slide47Renal cortex showing almost diffuse, global glomerular sclerosis, interstitial fibrosis, and vascular sclerosis
Class 6: Advanced Sclerosing LN
www.jeffkaufhold.com
Slide48Tx 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
Slide49Chronic 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
Slide50Laboratory Evaluation ANAStrong positive if >12
2. Low complement level3. Anti-phospholipid ab4. Anti Sm ab5. Direct coombs test in the absence of hemolytic anemia
Slide51ANA reliability
Slide52Antiphospholipid 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
Slide53Antiphospholipid antibodies – AnticardiolipinsAntiphosphatidylinositolAntiphosphatidylglycerolAntiphosphatidylserineActivaton
of coagulation cascade
Slide54Skin manifestationPicture was taken with permission of pt and father at GVH MICU, 12/2014
Slide55Skin manifestationPicture was taken with permission of pt and father at GVH MICU, 12/2014
Slide56Skin 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
Slide57Systemic 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.
Slide58Case (cont)
Slide59What else could have happened? DICSepsisTBITPOsteomyelitisSIADHAnti-cardiolipin ab crisisFungal manifestation in the nervous system
Slide60TreatmentNon-biologics – global immunosuppression NSAIDS – only sx control Antimalerials mycophenolate mofetilazathioprinemethotrexate
cyclophosphamide cyclosporineTacrolimusDapsone Biologics – specific target of the immune systemRituximab and epratuzumabBelimumab
Slide61Acute 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.
Slide62Osteopathic 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
Slide63Percussion Vibrator OMTHarmonic Healing: A Guide to Facilitated Oscillatory Release and Other Rhythmic Myofascial Techniques
Slide64ReferencesUp 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