Download Systemic Lupus Erythematosus Challenges and Options

Grand Rounds
Presented by:
Sumona Kabir, DO
January 21st, 2015
Overview
Case presentation
Definition of SLE
Pathophysiology
Classification
Details of each classification
Challenges regarding the current diagnostic criteria
Treatments
Osteopathic consideration
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.
Case presentation – 55 year old male with progressive wasting (Cont)
PMHx
Baseline MRDD
Psychogenic polydipsia
Hyponatremia
Hx of seizure
Chronic constipation and
Right internal capsule ischemic stroke
Anemia
Surgical History:
Hip Fracture Surgery
Small intestine Surgery
Family History:
None noted on file.
Social History:
Single. Not sexually active.
Non-Smoker
No alcohol use
No Drug use
Allergies/Immunization:
NKA
Case presentation – 55 year old male with progressive wasting (cont)
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)
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)
Course of disease
Presented 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.
ARDS
Cardiac arrest, ROSC, DNR-CC, Passed away.
SLE definition
Lupus - ˈlo͞opəs/: comes from Latin for wolf, since the 1600s
Definite 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 4
Has 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 criteria
UCTD
Undifferentiated connective tissue disease , meets fewer characteristics
SLE – Financial burden
Mean 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
Epidemiology
Prevalence: Ranges from 40/100,000 northern
Europeans to >200/100,000 among blacks
Age of onset: 30 (females), 40 (Males)
Sex: Male to female 1:9
Incidence: 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.
Pathophysiology
Multifactorial and essentially unknown
-makes diagnosis hindered and often difficult to identify
Proposed 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
Precipitating/ Triggering factors for SLE
Possibilities:
Genetic or hormonal mileau as predisposing factors
Infections - induce molecular mimicry
Stress - affect neuroendocrine changes affecting
immune cell function
Diet - affecting production of inflammatory
mediators
Toxins, drugs – modify cellular responsiveness and
immunogenicity of self antigens
Sunlight – inflammation and tissue damage
Drug induced lupus
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:
1.
Easily classify pts with early disease
2. Better distinguish SLE from non-autoimmune conditions
Diagnostic challenges
50% of lupus pts. are initially missed diagnosed, most
commonly with rheumatic fever, rheumatoid arthritis,
and hemolytic anemia
Hypocomplementemia 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 pathway
Immune complexes in the serum-rises and falls with
disease activity
www.jeffkaulfhold.com
The presence of 4 or more of the
following criteria reflect a 96%
sensitivity and specificity for the
diagnosis of SLE
SLICC criteria
A criteria for classification
Not a criteria for diagnosis
What is the difference?
Up-to-date didn’t differentiate between the two in
defining lupus.
Necessary for surveillance vs. treatment initiation
Lets look at the criteria in detail…
Malar rash
Fixed erythema, flat or raised, over the malar
eminences, tending to spare the nasolabial folds
Chronic cutaneous lupus erythematosus:
hyperpigmentation
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
Photosensitivity
Subacute cutaneous lupus
erythematosus.
Red, oval, and annular red
plaques, minimal, scaling in
a 56-year-old women.
Happened after sun exposure.
This is annular type SCLE.
Chronic cutaneous lupus
erythematosus
Oral Ulcers
Nonerosive Arthritis - Involving 2 or more peripheral joints,
characterized by tenderness, swelling, or effusion
Serositis- 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)
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 hemorrhage
Alveolar hemorrhage
The spectrum of severity
Pleuritis or pericarditis
Procedure: Transesophageal Echocardiogram
Assist: None
Dx/Indication: Bacteremia- Rule out endocarditis
Complications: 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 endocarditis
2. No intracardiac masses
3. Mild valvular disease- Mild PI, trace AI, trace TR
4. Trileaflet aortic valve
5. Normal LV systolic function with normal LV wall motion. EF 65%
6. Small PFO identified on bubble study
Cerebral manifestation
EEG report for our pt was negative
For seizures.
No offending drugs
could be indentified
Pt has no psychosis.
Hematologic disorders
Hemolytic anemia with absolute reticulocytosis
Hematologic disorders
Hemolytic anemia with absolute reticulocytosis
Doesn’t have reticulocytosis
Leukopenia
Lymphopenia
Thrombocytopenia
Renal manifestation
Lupus 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 Nephritis
Sudden and unexplained swelling, especially in the extremities (feet,
ankles, legs, fingers, arms) or the eyes
Blood in the urine
Elevated blood pressure
Foamy appearance in urine
Increased urination, especially at night
Renal manifestation
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
Renal US – Our pt
Renal 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 present
UA
Classification of Lupus Nephritis
adopted by International Society of Nephrology.,2003
1. 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 deposits
3. 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 deposits
5. 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
Normal Gomerulus
Class 2: Mesangial Proliferative LN
Class 2: MembranoProliferative LN
Focal (class 3) or Diffuse (Class 4)
Class 5: Membranous LN
Massive subepithelial accumulation of immune deposits
and interdigitating spike formation
www.jeffkaufhold.com
Class 5: Membranous LN
Class 6: Advanced Sclerosing LN
Renal cortex showing almost diffuse, global glomerular sclerosis,
interstitial fibrosis, and vascular sclerosis
www.jeffkaufhold.com
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) + Glucocorticoid
ACR January 6th, 2015 published new data
“ Multidrug Therapy for Induction Treatment of Lupus Nephritis” – A randomized
control trial,
- showing 20.3% more people had remission after at about 6 months with triple
therapy with MMF, Tacrolimus and steroid vs cyclophosphamide + steroid
Tx for Lupus nephritis
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.
www.jeffkaufhold.com
Laboratory Evaluation
A. ANA
Strong positive if >12
2. Low complement level
3. Anti-phospholipid ab
4. Anti Sm ab
5. Direct coombs test in the absence of hemolytic anemia
ANA reliability
Antiphospholipid ab
Antiphospholipid antibodies (LUPUS ANTICOAGULANT)
APA is mostly directed against the beta-2 globulin phospholipidcarrier 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
Activaton of coagulation cascade
Antiphospholipid antibodies –
Anticardiolipins
Antiphosphatidylinositol
Antiphosphatidylglycerol
Antiphosphatidylserine
Skin manifestation
Picture was taken with permission of pt and father at GVH MICU, 12/2014
Skin manifestation
Picture was taken with permission of pt and father at GVH MICU, 12/2014
Skin manifestation
Red-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
Systemic vascular manifestation
Urticarial 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 a
thrombogenic 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.
Case (cont)
What else could have happened?
DIC
Sepsis
TB
ITP
Osteomyelitis
SIADH
Anti-cardiolipin ab crisis
Fungal manifestation in the nervous system
Treatment
Non-biologics – global immunosuppression
NSAIDS – only sx control
Antimalerials
mycophenolate mofetil
azathioprine
methotrexate
cyclophosphamide
cyclosporine
Tacrolimus
Dapsone
Biologics – specific target of the immune system
Rituximab and epratuzumab
Belimumab
Acute Flare up Tx - Glucocorticoid
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
to cause the multiple respiratory failure.
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):321-5
Counterstrain tenderpoints
- Can be used for myalgia similar to fibromyalgia tx
Direct and indirect MFR
Muscle Energy to some extent, if pt can tolerate it, at a
later stage
Percussion Vibrator OMT
Harmonic Healing: A Guide to Facilitated Oscillatory Release and
Other Rhythmic Myofascial Techniques
References
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10.
Up to Date
Primer 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-kidneys
www.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