Rheumatology

1. Neuro-Rheumatology
Course
Amanda L. Piquet, MD
Assistant Professor of Neurology
Director, Autoimmune Neurology Program
Neuroimmunology, Neuroinfectious Disease and Neurohospitalist
Sections
University of Colorado School of Medicine
Amanda.Piquet@CUAnschutz.edu

2. Disclosures
Dr. Piquet reports grants from University of Colorado
and Rocky Mountain MS Center; consulting fees from
Genentech/Roche and Alexion. Dr. Piquet also receive
honorarium from Medlink and will be receiving
publication royalties from Springer as co-editor of a
textbook.
We will be discussing off-label use of therapies in this
talk.

3. Course Outline
•Part 1: Neurosarcoidosis and CNS Vasculitis
(Dr. Amanda Piquet)
•Part 2: Systemic Lupus Erythematosus, Anti-
Phospholipid Antibody Syndrome (APLS), Behçet’s
disease
(Dr. Shamik Bhattacharyya)

4. Objectives – Part 1
•To provide an overview of neurosarcoidosis with a
review of neurological and radiographical
presentations common in patients with systemic
sarcoidosis
•To provide an overview of CNS vasculitis, review the
differential diagnosis, and discuss a clinical case
example

5. Neurosarcoidosis

6. Sarcoidosis
Inflammatory, multisystem disorder characterized by non-
necrotizing granulomatous inflammation histopathologically
Above: PET scan from patient with biopsy-
proven systemic sarcoidosis
Pathology (right) figure from: Stern BJ, Royal W,
Gelfand JM, et al. Definition and Consensus
Diagnostic Criteria for Neurosarcoidosis: From
the Neurosarcoidosis Consortium Consensus
Group. JAMA Neurol. 2018.
Other granulomatous diseases that are often
considered in the differential include
tuberculosis or other mycobacterial infections,
fungal infections, granulomatosis with
polyangiitis, and chronic granulomatous disease
of combined variable immunodeficiency (CVID)

7. Diagnostic Criteria for Neurosarcoidosis
Definite Probable Possible
Clinical and diagnostic
evidence suggestive of
neurosarcoidosis (MRI, CSF,
and/or EMG/NCS typical of
granulomatous disease) after
rigorous exclusion of other
causes
AND
Nervous system pathology is
consistent with neurosarcoid
Type a) extraneural sarcoidosis is
evident
Type b) No extraneural sarcoid is
evidence (isolated CNS sarcoid)
Clinical and diagnostic evidence
suggestive of neurosarcoidosis
(MRI, CSF, and/or EMG/NCS
typical of granulomatous disease)
after rigorous exclusion of other
causes
AND
Pathologic confirmation of
systemic granulomatous disease
consistent with sarcoidosis
Criteria for
Definite and
Probable not met
but clinical
suspicion for
neurosarcoidosis
remains (no
pathological
confirmation of
granulomatous
disease)
Stern BJ, Royal W, Gelfand JM, et al. Definition and Consensus Diagnostic Criteria for Neurosarcoidosis: From
the Neurosarcoidosis Consortium Consensus Group. JAMA Neurol. 2018;75(12):1546–1553.

8. Neurosarcoidosis
• Central Nervous System Involvement:
• Cranial neuropathies (most common)
• Subacute to chronic meningitis
• Vasculopathy/vasculitis
• Myelopathy/myelitis
• Infiltrative pituitary lesions
• Intraparenchymal mass lesions (rare)
• Peripheral Nervous System Involvement:
• Myopathy
• Neuropathy with axonal sensorimotor polyneuropathy being the
most common type

9. Meningeal Involvement
• An aseptic meningitis, generally with
a lymphocytic pleocytosis, has been
noted in 10-20% of patients.
• Dural thickening (pachymeningitis)
can occur
MacLean HJ, Abdoli M. Neurosarcoidosis as an MS Mimic: The trials and tribulations of making a diagnosis. Mult Scler Relat
Disord. 2015;4(5):414-429.
Figure from: Ginat DT, Dhillon G, Almast J. Magnetic resonance imaging of neurosarcoidosis. J Clin Imaging Sci. 2011;1:15.

10. Meningeal Involvement
• The meninges (both
leptomeninges as well as
the dura) can be affected
in 10-20% of patients,
which can manifest as an
inflammatory and
obstructive process in the
CSF
.
• Meningeal enhancement
can be nodular and
diffuse.
MacLean HJ, Abdoli M. Neurosarcoidosis as an MS Mimic: The trials and tribulations of making a diagnosis. Mult Scler Relat
Disord. 2015;4(5):414-429.
Figure from: Ginat DT, Dhillon G, Almast J. Magnetic resonance imaging of neurosarcoidosis. J Clin Imaging Sci. 2011;1:15.

11. Meningeal Involvement
Hydrocephalus can be
seen in 10% of patients.
This can be non-
communicating due to an
obstructive process such
as granuloma formation,
or it can be
communicating, which is
often to due scarring of
the arachnoid villi. This
interferes with proper CSF
reabsorption.
MacLean HJ, Abdoli M. Neurosarcoidosis as an MS Mimic: The trials and tribulations of making a diagnosis. Mult Scler Relat
Disord. 2015;4(5):414-429.
Figure from: Ginat DT, Dhillon G, Almast J. Magnetic resonance imaging of neurosarcoidosis. J Clin Imaging Sci. 2011;1:15.

12. Parenchymal Disease
• Parenchymal disease (noted in 50% of neurosarcoidosis patients),
can manifest as white matter and cortical lesions.
• This presentation can radiographically mimic demyelinating disease
Figure from: MacLean HJ, Abdoli M. Neurosarcoidosis as an MS Mimic: The trials and tribulations of making a diagnosis.
Mult Scler Relat Disord. 2015;4(5):414-429.

13. Hypothalamic Disease
Another important
manifestation of
parenchymal disease to
consider is the invasion of
the hypothalamic/pituitary
regions, which can have
neuroendocrine
consequences on secretion
of ADH, thyroid hormone,
cortisol, and sexual
hormones.
MacLean HJ, Abdoli M. Neurosarcoidosis as an MS Mimic: The trials and tribulations of making a diagnosis. Mult Scler Relat
Disord. 2015;4(5):414-429.
Figure from: Ginat DT, Dhillon G, Almast J. Magnetic resonance imaging of neurosarcoidosis. J Clin Imaging Sci. 2011;1:15.

14. Myelopathy
Involvement of the spinal cord can take place in different radiographic patterns, including patchy
intramedullary lesions, a longitudinally extensive transverse myelitis, intradural/extramedullary
disease, as well as extradural disease.
A B C
D E F
Patient
1
Patient
2
Inflammatory
lesion of the spine:
Sarcoid or
neuromyelitis
optica spectrum
disorder (NMOSD)?
Figure from: Piquet AL, Corboy JR. Neuromyelitis optica . In: Multiple Sclerosis and Related Disorders. second ed. Fox R, Bethoux F, Rae-
Grant A, editors. New York: Springer Publishing Company; 2018. Chapter 38.

15. Myelopathy
Involvement of the spinal cord can take place in different radiographic patterns, including patchy
intramedullary lesions, a longitudinally extensive transverse myelitis, intradural/extramedullary
disease, as well as extradural disease.
A B C
D E F
Patient
1
Patient
2
AQP4+ NMOSD
Sarcoidosis
Inflammatory
lesion of the spine:
Sarcoid or
neuromyelitis
optica spectrum
disorder (NMOSD)?
Figure from: Piquet AL, Corboy JR. Neuromyelitis optica . In: Multiple Sclerosis and Related Disorders. second ed. Fox R, Bethoux F, Rae-
Grant A, editors. New York: Springer Publishing Company; 2018. Chapter 38.

16. Myelopathy
Involvement of the spinal cord can take place in different radiographic patterns, including patchy
intramedullary lesions, a longitudinally extensive transverse myelitis, intradural/extramedullary
disease, as well as extradural disease.
A B C
D E F
Patient
1
Patient
2
Inflammatory lesion
of the spine: Sarcoid
or neuromyelitis
optica spectrum
disease (NMOSD)?
AQP4+ NMOSD
Sarcoidosis

17. Myelopathy
Involvement of the spinal cord can take place in different radiographic patterns, including patchy
intramedullary lesions, a longitudinally extensive transverse myelitis, intradural/extramedullary
disease, as well as extradural disease.
A B C
D E F
Patient
1
Patient
2
Inflammatory lesion
of the spine: Sarcoid
or neuromyelitis
optica spectrum
disease (NMOSD)?
AQP4+ NMOSD
Sarcoidosis

18. Other Diagnostic Work up in
Neurosarcoidosis
•CSF findings:* elevated opening pressure, elevated CSF
protein (62%), lymphocytic pleocytosis (57%), positive
oligoclonal bands (19%)
CSF angiotensin-converting enzyme (ACE) is controversial (low
specificity and sensitive)
CSF is normal in ~30% of patients with NS
•Systemic imaging:
Chest imaging in 90% will be abnormal (high resolution chest
CT with contrast)
FDG-PET scan may be helpful to detect extra-pulmonary
sarcoidosis
*Percentages from a group of 42 patients from: Stern BJ, Royal W, Gelfand JM, et al. Definition and
Consensus Diagnostic Criteria for Neurosarcoidosis: From the Neurosarcoidosis Consortium Consensus
Group. JAMA Neurol. 2018;75(12):1546–1553.

19. Neurosarcoidosis and
Treatment
•Intravenous methylprednisolone
followed by a slow, prolonged
prednisone taper is considered
first- line treatment
•Often when there is neurological
involvement, the disease
requires prolonged therapy so
steroid-sparing agents are often
preferred

20. TNF-α Agents: Mechanism
and Reason for Use in
Neurosarcoidosis
• Tumor necrosis factor (TNF)-α is released by macrophages and
plays a critical role in granuloma formation
• Infliximab is a chimeric mouse-human monoclonal IgG1 antibody
directed against TNF-α and induces complement-dependent and
antibody-dependent cytotoxicity and apoptosis ( = inhibiting
granuloma formation).
Remission in 70% (n = 28)
Improvement in 77%
(n= 66)
Two Large Retrospective Studies

21. Central Nervous System
(CNS) Vasculitis

22. CNS Vasculitis
•Often seen clinically as an insidious, progressive,
subacute encephalopathy and strokes
•Broad, heterogeneous group of diseases resulting in
inflammation and destruction of the blood vessels
Primary angiitis of the CNS (PACNS)
Secondary CNS vasculitis
• Systemic inflammatory or infectious process
• Rheumatological diseases/connective tissue disorders

23. Distribution of vessel involvement by
large -, medium-, and small-vessel
vasculitis
Figure from: Jennette JC,
Falk RJ, Bacon PA, et al.
2012 revised International
Chapel Hill Consensus
Conference Nomenclature
of Vasculitides. Arthritis
Rheum. 2013;65(1):1-11.

24. PACNS: Historical
Background
• Initially reported in 1959
as a pathological finding on
autopsies
• Rare: annual incidence rate
is 2.4 cases per one million
person-years
Mean age 50-years-old
Cravioto and Feigin. Noninfectious granulomatous angiitis with a predilection for the nervous system. Neurology 1959.
Salvarani et al. Primary central nervous system vasculitis: analysis of 101 patients. Ann Neurol 2007.
Image from: The Lancet Neurology 2010 9, 1078-1084DOI

25. PACNS: Proposed Diagnostic
Criteria
Calabrese and Mallek. Primary angiitis of the central nervous system. Report of 8 new cases, review of literature and
proposal for diagnostic criteria. Medicine (Baltimore) 1988.
Diagnostic criteria for PACNS
1. The presence of an acquired otherwise unexplained neurological or psychiatric
deficit.
2. The presence of either classic angiographic or histopathological features of
angiitis within the CNS.*
3. No evidence of systemic vasculitis or any disorder that could cause or mimic the
angiographic or pathological features of the disease.
*Gold standard is a pathological diagnosis
The non-specificity of CNS angiograms can results in patients with syndromes of
reversible cerebral vasoconstriction syndrome (RCVS) being misdiagnosed and
treated for PACNS.

26. PACNS: Clinical Presentation
• Acute presentations with stroke
Recurrent strokes and TIA in 30-50%
ICH (8%)
• Subacute presentations with headaches (63%), encephalopathy
(50%), focal deficit/strokes (40%), seizures (16%), chronic meningitis,
myelopathy (rare)
*PACNS is far less common than secondary causes of vasculitis so a
mimic work up is necessary
*CNS vasculitis must always be considered with strokes of different
ages and in different territories

27. PACNS: Diagnostic work up
• CSF is a vital diagnostic tool
80-90% abnormal: lymphocytic pleocytosis, elevated protein, and
normal glucose
• Imaging often with ischemic infarcts (53% of cases); MRI very sensitive
(almost 100% are abnormal)
Mass lesions (5%), meningeal enhancement (8%), intracranial
hemorrhage (9%)
• Angiogram
Nonspecific pattern of “beading”, aneurysm, circumferential/eccentric
irregularities, multiple occlusions
Sensitivity 40-90%, specificity 30%

28. High Resolution MRI (HR-
MRI)
•Technique that may improve specificity of MRA in
distinguishing PACNS from RCVS by visualizing the
vessel wall

29. Figures from: Mandell et al. Vessel Wall MRI to Differentiate between Reversible Cerebral Vasoconstriction
syndrome and CNS Vasculitis. Stroke 2012.
CNS Vasculitis RCVS

30. Figures from: Mandell et al. Vessel Wall MRI to Differentiate between Reversible Cerebral Vasoconstriction
syndrome and CNS Vasculitis. Stroke 2012.
CNS Vasculitis RCVS

31. Figures from: Mandell et al. Vessel Wall MRI to Differentiate between Reversible Cerebral Vasoconstriction
syndrome and CNS Vasculitis. Stroke 2012.
CNS Vasculitis RCVS

32. Diagnostic Work Up
•Gold standard: Pathologic diagnosis

33. Clinical Case
•81 year old man who presents with cognitive decline,
unsteady gait and visual hallucinations progressive
over 3 weeks.
•Past medical history of seizure and a history of
ruptured RMCA aneurysm with subsequent
encephalomalacia
•Neurological exam: Severe cognitive impairment with
MoCA 5/30, no evidence of focal motor weakness but
due to attention and cognitive deficits he cannot fully
participate in confrontational testing. Visual fields
appear intact. Normal fundoscopic exam.

34. T2/FLAIR
T1 Post-
contrast

35. Biopsy
A-beta related angiitis with evidence of
granulomatous arteritis of leptomeningeal
vessels associated with multinucleated giant
cells and beta amyloid

36. Aβ-related angiitis (ABRA)
• PACNS and cerebral amyloid angiopathy (CAA) are generally
regarded as unrelated disorders  HOWEVER in a minority of
patients ABRA has been described as a distinct clinical-
pathological disorder as a form of CNS vasculitis
Part of a widespread immune reaction to Aβ within the CNS
Aβ immunization in AD = minority of patients with subacute meningo-
encephalitis
Post-mortem studies: severe CAA as well as meningeal and
perivascular inflammation
Check E. Nerve inflammation halts trial for Alzheimer’s drug. Nature 2002.
Ferrer et al. Neuropathology and pathogenesis of encephalitis following amyloid-beta immunization in Alzheimer’s disease.
Brain Pathol 2004.

37. CNS Vasculitis: Treatment
•High dose steroids with a long, slow taper
No validated taper: high dose > 15 mg/day for at
least 3 mo (Ann Rheum Dis 2009)
•Induction: Cyclophosphamide x 6-12 months (dosing
based on EULAR recommendations for small &
medium vessel vasculitis)
•Maintenance therapy: mycophenolate mofetil (1-2 g
daily) (others azathioprine, methotrexate)

38. Moving on to Part
2…
Thank you!
Amanda.Piquet@CUanschutz.edu