)
Table of contents :
(before and after transplantations)
(cancer chemotherapy and some immunosuppressive
drugs)ref1,
ref2,
ref3,
ref4,
ref5
in association with HHV-6
reactivationref1,
ref2,
ref3,
ref4,
ref5
and an increase in proinflammatory cytokines such as
TNF-a, IL-6, and IL-5 (also
transient lymphoid hyperplasia)ref
infectionref
pneumoniaref deficiency
=> urticaria-necrotizing vasculitis /
angioitis;
e.g. Streptococcus
pneumoniae,
Haemophilus
influenzae)
deficiency
=> acquired
angioedema, invasive fungal infections, intracellular bacteria (Salmonella spp., Mycobacterium
spp., viruses
(reactivation of herpesviruses, expecially HHV-1
/
HSV-1, HHV-3
/
VZV, HHV-5
/
CMV)
: in the case of perinatal HIV-1
infection even AMI is compromised due to deficiency of memory
B cells.
; e.g.
Streptococcus
pneumoniae,
Haemophilus
influenzae)
as after splenectomy, gram positive bacteria (Staphylococcus
aureus),
rotavirus and parvovirus (due to decreased IgA
on mucosal surfaces)
and Serratia spp.
or
transfusions (dwarfism, ..), splenomegaly
that look for type
IV
hypersensitivities
after vaccinations or infection and
affect ~ 3-5% of the population with 2/3 of the patients being
women. The site of attack is organ- or tissue-specific or more
systemic : as the self-antigen(s) is usually expressed in more
than one cell type, from an anatomical point of view autoimmune
diseases should more properly be enclosed among the multi-organ failures (MOF).
Anyway, due to common pathogenesis, I prefer to group them
globally among the diseases affecting the immune system : a link
to this page is provided in every page regarding involved organs.
They can be classified as follows according to the main targeted
organ(s) / apparatus(es) :
=> macrophages obstruct
trabeculate, but no lymphocyte infiltration occurs
or panuveitis,
vertigo, nausea
and vomiting,
very deep pain in the eyes => uveitis
(first one eye and in a couple of weeks the other eye may
become affected) with preservation of the choriocapillaris
(thanks to anti-inflammatory products secreted by the
retinal pigment epithelium, including TGF-b and cystatin C
/ retinal pigment epithelial protective protein that
is known to suppress the phagocyte generation of
superoxide) and retina (despite extensive inflammatory
cell infiltration in the choroid) => retinal
detachment
=> rapid vision loss, drowsiness, alopecia areata, autoimmune vitiligo, poliosis, hearing loss, facial
nerve
palsies,
rigidity, walking (gait) disturbance
and cataract.
or interphotoreceptor
retinoid-binding
protein (IRBP).
,
and even prostration, tinnitus (varying from a
whistle to a roar), and deafness. The onset of
symptoms is insidious, usually with a sensation of dullness
or fullness in the ear, and an initial fluctuation in
hearing of 10 to 30 dB, usually in the low tones. The
hearing improves somewhat between attacks, but it continues
to deteriorate as time goes on. There may be increased
sensitivity to sound, or music may sound distorted. Any head
movement aggravates the condition, with the vertigo lasting
several hours. Some patients can have fleeting attacks
lasting several minutes, and still others have attacks
lasting a week or longer and may take months to regain
normal equilibrium.
(isosorbide, an osmotic diuretic), regimen of bed rest,
no smoking, plus inhalation of 5% CO2 + 95% O2
for 30' q.i.d. and 2.75 mg of histamine
diphosphate
in 250 cc of lactated Ringer's solution I.V. b.i.d.
Other drugs, given individually, that are reported to be
effective for an acute attack are 1/150 grain atropine
I.V., diazepam
10 mgm I.V., and fentanyl
citrate + droperidol, which must
be administered in the hospital or by an
anesthesiologist. Vasodilators
are usually ineffective in Meniere's, as are the antivertiginous
drugs.ref1,
ref2
infectionmajor
core
protein lambda 1, tinnitus, nausea and
vomiting,
and sudden hearing loss (SHL) which develop within several
months of each other => bilateral deafness (67%),
and RPR
and/or CT
should be done primarily to rule out cerebellopontine
angle (CPA) tumors. MRI may show enhancement of vestibular
and cochlear structures with gadolinium.
: topical for IK and oral for vestibuloauditory
involvement (prednisone 1 mg/kg for 2-4
weeks)
(?) gene is mapped
approximately at 200 kb telomeric to HLA-A on chromosome 6.
It has 11 SNPs : allele C is in linkage disequilibrium with
HLA-A11 (P<0.00001) and to a lesser extent with HLA-A1
(P<0.01).
,
molecular mimicry is presumed as trigger for this
disease.
/ Charcot's diseaseref
: positive RT-PCR on neuronal cell bodies within
the gray matter of the spinal cord in 88.3% of
patients vs. 3.4% of controlsrefref (OR: 3.2; p = 0.102)ref (OR: 8.4; p = 0.064)ref,
and BDNF,
increased ROS and Glu. Immature (DEC205, CD1a) and
activated/mature (CD83, CD40) DC transcripts are
significantly elevated in ALS ventral horn and corticospinal
tracts. Monocytic/macrophage/microglial transcripts (CD14,
CD18, SR-A, CD68) are increased in ALS spinal cord, and
activated CD68+ cells were demonstrated in close
proximity to motor neurons. mRNA expressions of MCP-1 by
glial cells, which attracts monocytes and mDCs, and of CSF-1 / M-CSF are increased in
ALS tissues. Those patients who progressed most rapidly
expressed significantly more dendritic transcripts than
patients who progressed more slowlyref.
High
titer of IgM anti-GM1 antibodies are detected in
serum of 46% LMND patients, 80% of MN patients, and 18% of
the classical ALS casesref.
=> chronic encephalitis confined to one hemisphere and
contralateral cerebellar hemi-atrophy. In the active phase,
neuronophagia, activated microglial cells (rod cells),
microglial nodules, and perivascular lymphocytic
infiltrates, are present. In the more chronic phase neuronal
loss and gliosis predominate. enteritis
), stiff neck,
and confusion; these are followed by focal seizures,
paralysis, progressively deepening coma, and death. (1 every 1,000 cases) (1 every 4,000-10,000 cases) (1-2 every 1,000,000
immunizations)ref, meningismus, headache, nausea and
vomiting, and drowsiness
progressing to lethargy and coma; disseminated
neurological disease => pyramidal signs, tremor,
cerebellar involvement (expecially in ADEM due to HHV-3 / VZV), seizures,
paralysis, ...
(protidorrachy = 50-150 mg/dL), lymphocytary
pleiocytosis (< 200 cell/mL;
sometimes
higher or with PMN in the first days of disease),
oligoclonal bands
: diffuse symmetric contrast enhancement in white
matter of encephalon and spinal cord,
ACTH,
and plasmapheresis (more cycles if
relapses occur) or more are 40% less likely to
develop MSref.
The link with sunshine may explain why MS is more
common in high latitudes seropositivity is strongly
associated with risk of progressive MS (OR = 7.3) (OR = 2.1) : the risk of MS
increased monotonically with serum titers of IgG
antibodies to VCA or EBNA complexref after 15 years of age (OR =
2.3) after 15 years of age
(OR = 2.8)does not increase the risk of
developing multiple sclerosis or cause exacerbationsref1,
ref2,
ref3,
ref4,
ref5,
ref6,
ref7,
ref8 polarization
(but also Th2) =>
perivenular cuffing by inflammatory cells (BBB is
disrupted but, unlike vasculitis, the vessel wall is
preserved) and necrosis of oligodendrocytes
(sometimes vascular demyelinization) =>
gray-to-pink plaques of demyelination of various sizes
(1-2 mm to many cm) throughout the white matter of the
CNS, sometimes extending into the gray matter, most
commonly in periventricular areas (lateral angles of
lateral ventricles) with a net border between normal and
affected areas => cicatricial gliosis. Survived
oligodendrocytes try to remyelinate some fibers (shadow
plaques) but they are finally desroyed. Hyaluronan
accumulates in demyelinated lesions and inhibits
oligodendrocyte progenitor maturationref.
At least 4 fundamentally different neuropathological
patterns can be discerned. Patterns I and II lesion
pathologies are modeled in the current virus- and
autoimmune-based animal models of encephalomyelitis that
have been established in susceptible rodent strains or
non-human primates. MS is characterized by periodic
relapses correlated with microbial infections, most
commonly URT infections (Influenzaviruses).
Several
possible mechanisms may explain this link :
that are quantitatively related to a reduction in
functional suppression induced during suboptimal T-cell
receptor (TCR) ligation. Of importance, this observation
links a defect in functional peripheral immunoregulation
to an established genetic marker that has been
unequivocally shown to be involved in maintaining immune
tolerance and preventing autoimmune diseases. Diminished
FOXP3 levels thus indicate impaired immunoregulation by Tregs
that may contribute to MS. Future studies will evaluate
the effects of therapies known to influence Treg cell
function and FOXP3 expression, including TCR peptide
vaccination and supplemental estrogenref.
CD4+CD25hi TReg cells
(not diluted by recently activated cells involved in the
ongoing MS-associated immune response) isolated from MS
patients markedly fail to suppress CD4+CD25-
T-cell proliferation and IFN-g
production induced by plate-bound CD3-specific antibodyref.
-W
encoded
viral envelope glycoprotein syncytin
is upregulated in glial cells within acute demyelinating
lesions of multiple sclerosis patients. Syncytin
expression in astrocytes induced the release of redox
reactants, which were cytotoxic to oligodendrocytes.
Syncytin-mediated neuroinflammation and death of
oligodendrocytes, with the ensuing neurobehavioral
deficits, were prevented by the antioxidant ferulic acid
in a mouse model of multiple sclerosis. Thus, syncytin's
proinflammatory properties in the nervous system
demonstrate a novel role for an endogenous retrovirus
protein, which may be a target for therapeutic
interventionref.
Leptin production was
significantly increased in both serum and CSF of
naïve-to-therapy relapsing-remitting multiple sclerosis
(RRMS) patients and correlated with IFN-g secretion in the CSF. T cell
lines against human myelin basic protein (hMBP) produced
immunoreactive leptin and up-regulated the expression of
the leptin receptor (ObR) after activation with hMBP.
Treatment with either anti-leptin or anti-leptin-receptor
neutralizing antibodies inhibited in vitro proliferation
in response to hMBP. Interestingly, in the RRMS patients,
an inverse correlation between serum leptin and percentage
of circulating TRegs was also observed. To
better analyze the finding, we enumerated TRegs
in leptin-deficient (ob/ob) and
leptin-receptor-deficient (db/db) mice and
observed the significant increase in TRegs.
Moreover, treatment of WT mice with soluble ObR fusion
protein (ObR:Fc) increased the percentage of TRegs
and ameliorated the clinical course and progression of
disease in proteolipid protein peptide (PLP139-151)-induced
relapsing-experimental autoimmune encephalomyelitis
(R-EAE), an animal model of RRMS. These findings show an
inverse relationship between leptin secretion and the
frequency of TRegs in RRMS and may have
implications for the pathogenesis of and therapy for
multiple sclerosisref.
(35%) : weakness of the limbs may manifest as loss of
strength or dexterity, fatigue, or a disturbance of
gait. Exercise-induced weakness is a characteristic
symptom of MS. The weakness is of the upper motor
neuron type and is frequently accompanied by other
pyramidal signs such as spasticity, hyperreflexia and
Babinski signs. Occasionally, a tendon reflex may be
lost (simulating a lower motor neuron lesion) if an MS
lesion disrupts the afferent reflex fibers in the
spinal cord.. However, unlike Bell's palsy,
facial weakness in MS is generally not associated
with ipsilateral loss of taste sensation or
retroauricular pain
(37%) (24-32%) (36%) => decreased visus
(2-22.3%; higher in youngs); it regress completely
thanks to resorption of the edema, which initially
is mild. At following attacks regression is only
partial as gliosis is irreversible. It generally
presents as diminished visual acuity, dimness, or
decreased color perception (desaturation) in the
central field of vision. These symptoms may be mild
or may progress to severe visual loss. Rarely, there
is complete loss of light perception. Periorbital
pain (aggravated by eye movement) often precedes or
accompanies the visual loss. An afferent pupillary
defect may be found. Funduscopic examination may be
normal or reveal optic disc swelling (papillitis).
Pallor of the optic disc (optic atrophy) commonly
follows ON. Uveitis is rare and should raise the
possibility of alternative diagnoses. Visual
blurring in MS may result from ON or diplopia.
Visual blurring that resolves when either eye is
covered is due to diplopia. or hyposthenia of extraocular
muscles due to involvement of brainstem nuclei
(expecially rectus lateralis > those innervated
by III or IV cranial nerves) => diplopia (11-15%)
and acquired pendular nystagmus of abduced
eye with a mild oblique deviation (skew
deviation) (0.3%) (1%), hemifacial spasm, and
glossopharyngeal neuralgia can occur when the
demyelinating lesion involves the root entry (or
exit) zone of the fifth, seventh, and ninth cranial
nerve, respectively. Trigeminal neuralgia (tic
douloureux) is a very brief lancinating facial pain
often triggered by an afferent input from the face
or teeth. Most cases of trigeminal neuralgia are not
MS-related. However, the occurrence of atypical
features such as the onset before age 50 years,
bilateral symptoms, objective sensory loss, or
nonparoxysmal pain should raise concerns that a
symptomatic cause such as MS is responsible. (1-1.3%) due to involvement of
brainstem nuclei---CD178 / FasL
interaction-dependent manner. More common in elderlies (5%) (0.59%) (3.6-6%) may appear suddenly and
resemble acute labyrinthitis. A brainstem rather
than end-organ origin is suggested by the presence
of coexisting trigeminal or facial nerve
involvement; vertical nystagmus; or nystagmus that
has no latency to onset, no direction reversal, and
doesn't fatigue. Hearing loss may also occur in MS
but is uncommon. (11%) (3%) (1.6%) (2.6%) (1.6%) (1%) : men report impotence,
less desire, impaired genital sensation, impaired
ejaculation, and inability to achieve/maintain an
erection. Women report genital numbness,
diminished orgasmic response, decreased libido,
unpleasant sensations during intercourse, and
diminished vaginal lubrication. Adductor
spasticity (in women) can also interfere with
intercourse, and urinary incontinence (in either
men or women) can be problematic. (> 90%) : urge
incontinence in weekly or more frequent episodes
(33%), urinary retention, or micturition
exitation (1%) consists of either
persistent rapid flickering contractions of the
facial musculature (especially the lower portion of
the orbicularis oculus) or a contraction that slowly
spreads across the face. It results from lesions of
the corticobulbar tracts or brainstem course of the
facial nerve. (0.3-1%) (50%). Cognitive dysfunction
sufficient to impair activities of daily living
also occurs in 20% can be reactive, endogenous,
or part of the illness itself and can contribute
to fatigue (50-60% along whole course; suicide has
RR = 7.5) (3%) is the electric shock–like
sensation (evoked by neck flexion or other movement)
that radiates down the back into the legs. Rarely,
it radiates into the arms. It is generally
self-limited but may persist for years. Lhermitte's
symptom can also occur with other disorders of the
cervical spine (e.g., cervical spondylosis).has demonstrated bursts of disease
activity 7 to 10 times more frequently than is
clinically apparent. This finding indicates that
there is a large reservoir of subclinical disease
activity in MS, especially during the early stages
of the disease. The triggers causing these bursts
are unknown, although the fact that patients may
experience relapses after nonspecific upper
respiratory infections suggests that either
molecular mimicry between viruses and myelin
antigens or viral superantigens activating
pathogenic T cells may play a role in MS
pathogenesis. Within 15 years from onset, 50%
(the great majority of RRMS ultimately) develop ...
(plaques don't captate : differential diagnosis with
cerebral vasculitides); impaired BBB is seen by
extravasation of Gd-DPTA (sensitivity > 95%);
Gd-enhancement persists for up to 3 months, and the
residual MS plaque remains visible indefinitely as a
focal area of hyperintensity (a lesion) on spin-echo
(T2-weighted) and proton-density images. Lesions are
frequently oriented perpendicular to the ventricular
surface, corresponding to the pathologic pattern of
perivenous demyelination (Dawson's fingers).
Lesions are multifocal within the brain, brainstem,
and spinal cord. Lesions in the anterior corpus
callosum are helpful diagnostically because this site
is usually spared in cerebrovascular disease.
Different criteria for the use of MRI in the diagnosis
of MS have been proposed. The total volume of
T2-weighted signal abnormality (the "burden of
disease") shows a significant (albeit weak)
correlation with clinical disability. Approximately
one-third of T2-weighted lesions appear as hypointense
lesions (black holes) on T1-weighted imaging. Black
holes may be a better marker of irreversible
demyelination and axonal loss than T2
hyperintensities, although even this measure depends
upon the timing of the image acquisition (e.g., most
acute Gd-enhancing T2 lesions are T1 dark). Newer MRI
measures such as brain atrophy, magnetization transfer
ratio (MTR) imaging and proton magnetic resonance
spectroscopic imaging (MRSI) may ultimately serve as
surrogate markers of clinical disability. For example,
MRSI can quantitate molecules such as N-acetyl
aspartate (NAA), which is a marker of axonal
integrity, and MTR may be able to distinguish
demyelination from edema.
: intratechal IgG synthesis (> 2 oligoclonal bands
in 75-90%), mononucleated pleiocytosis > 5 cell/mL (usually < 20/mL, > 50/mL
in myelopathies; improbable when > 75/mL) (> 25%), and
protidorrachy < 100 mg/dL (differential diagnosis
with infections and tumors if higher)
(at least 1 in 80-90%) provide the most information
when the pathways studied are clinically uninvolved.
For example, in a patient with a remitting and
relapsing spinal cord syndrome with sensory deficits
in the legs, an abnormal somatosensory EP following
posterior tibial nerve stimulation provides little new
information. By contrast, an abnormal visual EP in
this circumstance would permit a diagnosis of
clinically definite MS. Abnormalities on one or more
EP modalities occur in 80 to 90% of MS patients. EP
abnormalities are not specific to MS, although a
marked delay in the latency of a specific EP component
(as opposed to a reduced amplitude) is suggestive of
demyelination., IFN-b1band IFN-t)
decrease BBB permeability (once the BBB breaks,
massive infiltration of T cells, augmented
expression of adhesion molecules on endothelial
cell surface, and leakage of inflammatory
cytokines and antibodies will aggravate the MS
lesions)) (mitoxantrone) : 12 mg/m2
in 100 mL (60 gtt/min) every 3 months up to 120
mg/m2 (8-10 doses) in SPMS agonists (methylprednisolone 1 g in 500 mL of slow-drop
physiological solution for 5 consecutive mornings) +
gastric protectants since day before or same day if
i.v. => then decreasing dose (125 mg in p.o.
vials q.d. for 7 days => a.d. for 15 days)ref1, ref2, ref3, rituximab ?) prevents expression of CIITA
in all cell types that need IFN-g to express MHC class
II molecules, including neurons. Further
atorvastatin, but not pravastatin, stabilizes
LFA-1 interactions for 6 months decreases the
number and size of cerebral lesions by around 40%
in a 30-patient clinical trial : it is not clear
if the drug also eased the symptoms of MS, which
commonly include fatigue, tremor and paralysis, as
the study was not designed to assess this, but
prolonged use will help users live a more normal
life. : paralysed mice became
increasingly active just 10 days after receiving the
intravenous injection of 1 million cultured brain
stem cells. Over 40% of them turn into cells that
make myelinref and 4-aminopyridine to improve
conduction blocks) stings along the backref1,
ref2,
ref3,
ref4,
ref5,
ref6,
polyosol and bee pollen provided relief from some of the
painful symptoms of MS, but independent
physiotherapists failed to find hard evidence of
reduced muscle stiffness and disability. However,
new data presented at the annual meeting of the
British Association for the Advancement of Science
in Exeter, UK, indicates that this assessment might
have been premature. Of the patients in the initial
trial, 80% opted to continue cannabinoid treatment
for up to 1 year. In the longer term, there is a
suggestion of a more useful beneficial effect, which
was not clear at the initial stage. Animal studies
have indicated that cannabinoids slow nerve-cell
death-mediated inflammatory
demyelinating disorder of the CNS induced by
immunization of mice and rats with Freund's complete adjuvant
together with ...
heals EAE and worsens MS, while TNF-a
heals MS and worsens EAE. Just before the onset of
disease, the animals' leptin levels double : but in mice
that ate nothing for 48 hours - the equivalent of 7 to
10 days for humans - the leptin surge was smaller.
Neurons in the brain lesions of diseased mice produce leptin. Mice with a condition
akin to MS that were deprived of food for 48 hours still
developed the disease but had fewer brain lesions and
performed better on tests of walking, balance, weakness
and paralysis. IL-23 produced by CNS-resident
cells controls Th1-cell encephalitogenicity
during the effector phase of EAEref.
SJL mice that express a transgenic TcR specific for PLP
(5B6 TcR-transgenic mice) readily develop spontaneous
EAE, unless on the B10.S background, in which APCs
express lower levels of MHC class II and co-stimulatory
molecules (reversed by TLR9 but not TLR4 agonists)ref.
mediated
disease
and molecules on caudatus and subthalamic nuclei.
(4-8 weeks after < 10% of infections) and molecules on
caudatus and subthalamic nuclei. )
or bilateral involuntary movements that gradually become
severe, affecting all motor activities including gait, arm
movements, and speech, disappearing during sleep. A mild
psychic component is usually present (obsessive-compulsive
disorder
(OCD)).
The disorder may take the form of muscular rigidity (paralytic
chorea).
Westphal's sign : the patellar reflex evokes a
transient maintenance of hyperextension of leg before
falling down (a sign of dystonia). , neuroleptics or
benzodiazepines
can be used for treatment
(some cases)and
bulimia
nervosa,
ACTH
and LHRH
are found
in
75% of affected patients compared to just 16% of those
without eating disorders.
(insect repellent) increases DEET absorption 5-fold
(belief in a threat from biological or chemical weapons)
: b-adrenergic load
potentiates the toxicity of PB. While similar types of
chemical and physiological stressors are present in the
general population, the veteran population received
these stressors in a short time, with greater intensity,
and at a higher percentage exposure than normal for the
general population. Vietnam veterans who experienced
PTSD were 3 times more likely to have an autoimmune
illness (arthritis, psoriasis
or hypothyroidism) or coronary
artery
disease
than veterans not having experienced PTSD. : veterans
with the neurologic symptom complexes were more likely
to have the R allele (heterozygous QR or homozygous R)
than to be homozygous Q for the paraoxonase
/
arylesterase 1 (PON1) gene. Moreover, low activity
of the PON1 type Q (Gln192, formerly
designated type A) arylesterase allozyme distinguished
ill veterans from controls better than just the PON1
genotype or the activity levels of the type R (Arg192,
formerly designated type B) arylesterase allozyme, total
arylesterase, total paraoxonase, or
butyrylcholinesterase. A history of advanced acute
toxicity after taking pyridostigmine was also correlated
with low PON1 type Q arylesterase activity. Type Q is
the allozyme of paraoxonase/arylesterase that most
efficiently hydrolyzes several organophosphates
including sarin, soman, and diazinon. Moreover, sarin
suppresses T cell responses via the autonomic nervous
system and independently of the HPA axis. contained
in some lots of the absorbed anthrax
vaccine used on military personnel
immunized for service in Desert Shield/Desert Storm
during 1990-1991. Squalene is a common component of
"over the counter" performance food supplements like
"Power Bar" and others, usually abused by special
forces. Anti-squalene antibodies (ASA) have
a 100%
sensitivity
and specificity for patients with GWS and
adverse reactions in vaccinated personnel were
similar to symptoms of GWS.
: Lieutenant Colonel Graham Howe, clinical director of
psychiatry with the British forces health service in
Germany describes the case of Lance-Corporal Alex Izett,
who received vaccines, anthrax, botulism, plague and
other unspecified biological agents in anticipation of
war. As the subject was not involved in fighting, the
report states that the common factor linking the
osteoporosis with which he suffers to the high incidence
of osteoporosis in Gulf-war veterans is the vaccines he
received.
autoantibody ref
)
(20-40%; expecially O types 19 and 41, which have
class A, B, or C locusref
able to biosynthetize specific types of the
lipo-oligosaccharides (LOS) mimicking gangliosides
in nervous tissueref
: cross-reactive antibodies between Campylobacter
LOS and gangliosides have been demonstrated in
serum from GBS patientsref.
Ganglioside-mimicking structures are found more
frequently in neuropathy-associated C. jejuni
strains than in strains isolated from patients
with diarrhearef.
An important feature in ganglioside mimicry is the
presence of sialic acid (N-acetylneuraminic
acid) in both LOS and gangliosidesref)
(1 case per about 2,000 infections) (20-50%) (Buzby JC,
Allos BM, Roberts T. 1997. The economic burden
of Campylobacter-associated
Guillain-Barre syndrome. J Infect Dis 176 Suppl
2:S192-7), bulbar palsy,
absent or lessened tendon reflexes, and an increase in the
protein of the cerebrospinal fluid without corresponding
increase in cells. The disease can progress to involve the
respiratory muscles, resulting in dyspnea (=>
respiratory failure).
,
ataxia, and ophthalmoplegia.
These antiganglioside antibodies have been shown to
produce neuromuscular block, and may in part explain
the clinical signs of that disorder.Reports on
cerebellar ataxia and supranuclear oculomotor
derangement in MFS suggested an additional involvement
of the CNS, resembling Bickerstaff's
brainstem
encephalitis (BBE)., which removes plasma and
nerve-damaging antibodies from the blood, is used
during the first few weeks after a severe attack and
may improve the chance of a full recovery => IVIg
are not recommended as they chronicize the
viral infection. Steroid-pulse therapy should be
considered in GBS patients associated with CMV
infection when other conventional treatments are
ineffectiveref
is of great interest because both melanocytes and Schwann
cells derive from neural crest tissue and share common
antigens (gangliosides GM3, GM2, GD3,
and GD2, myelin-associated
glycoprotein
(MAG), other myelin glycoproteins, and
sulfoglucuronyl glycolipids). After some patients with
melanoma receive a therapeutic vaccination with melanoma
lysates, they develop a subacute demyelinating neuropathy.
detect slowed conduction velocities < 80% of the
lower limits of normal (LLN) if the compound muscle
action potential (CMAP) amplitude is greater than 80%
of LLN, and < 70% of LLN if the CMAP amplitude is
less than 80% of LLN (in axon degeneration nerve
conduction velocities rarely fall to less than 80% of
the lower limit of normal, and distal latencies of
F-waves rarely exceed 1.25 times the upper limit of
normal). In patients with demyelination limited to
proximal nerve segments (66%), with or without dropout
of large myelinated axons, routine electrophysiologic
studies might be normal but F-wave latencies are
prolonged unless a sufficient number of large
myelinated fibers remain unaffected. The slowing
in sensory nerves is less than that in motor
nerves.Only 11.7% of patients exhibit temporal
dispersion and 13.3% have conduction block.
Demyelination in proximal regions can result in distal
axon degeneration.ref,
glucocorticoidsref,
tacrolimusref
,
whose genome cross-reacts with histidyl-tRNA
synthetase
/ Jo-1
(the target of autoantibodies in some patients)
=> CHF,
dilated cardiomyopathy,
soft tissues and fasciae, articular contractures,
tuberculosis, pyogenic infections.
(positive sharp waves from splitted fibers) > (azathioprine
and methotrexate)
> IVIg
> cyclosporine
A,
chlorambucil,
cyclophosphamide
or mycophenolate
mofetil,
plasma exchange.
Bisphosphonates,
aluminum hydroxide, probenecid, colchicine, warfarin and
calcium channel
blockers (CCB)
to treat calcinosis
cutis.,
AV block, tachyarrhythmias, myocarditis
=> CHF,
dilated cardiomyopathy
(10%, in 80% of patients with anti-Jo-1 autoantibodies
and 69% of patients without anti-Jo-1 autoantibodies),
LDH, aldolase, SGOT, and Mb (related to muscle mass and
circadian rhythm), up to 50-fold increase in CK (CPKMB
> 12% CPKTOT indicates heart involvement),
myopathic (short and mild) potentials at needle EMG
(positive sharp waves from splitted fibers). Myoglobinuria
in severe conditions. > azathioprine
and methotrexate
> IVIg
> cyclosporine
A,
chlorambucil,cyclophosphamide
or mycophenolate
mofetil ,
plasma exchange
(positive sharp waves from splitted fibers) ,
plasma exchange.
(100% of patients with HLA-DR3 / HLA-DRw6; RR = 20) in
vaccines
incretion => decreased muscle repair after efforts and
increase of [SP]CSF
=> pain; alteration of hypothalamus-hypophysis-adrenal axis
=> decrease of [cortisol]plasma. focal oedema,
mitochondriopathy, =>
lowering
of pain threshold
(10%), no alterations in biohumoral parameters ,
neuropathies. , anorexia =>
weight loss, GCA
(> 50%; however, only a minority of patients with the
disease, who have no evidence of arteritis, ever develop giant
cell arteritis). ,
sideropenic anemia, leukocytosis, gGT, AlkP, biopsy, angiography, and echocolordoppler
(ECD)of
temporal arteries, ophthalmologic visit, high levels of
circulating ICAM-1.
incretion => decreased cortisol and increased ACTH.
High levels of 2',5'-oligoadenylate (2-5A)-dependent
37-kDa form of antiviral RNase L has
been reported in extracts of peripheral blood mononuclear
cells (PBMC), present as a catalytically inactive heterodimer
complex with the RNase L inhibitor (RLI).
(90%) (75%),
... (65%)
(40%),
neuromyasthenia, hypoglicemia, multiple chemicals
hypersensitivity syndrome, chronic candidosis, chronic HHV-4 / EBV infection,
postviral fatigue syndrome. (anna
1 antibodies) (85%) that interfere with the release
of acetylcholine at the motor nerve terminal
(oat-cell carcinoma of the lung; trigger ?). Autonomic
dysfunction (> 50%)
ref
(primarily the a-chain) at the
postsynaptic membrane of the neuromuscular junction =>
neuromuscular exhaustiveness ,
diplopia), 50% has positive autoAb
(10-20%%)
(0-2)
(double-step nerve stimulation => sensitization of
postactivation exhaustion by ischemia => 5 Hz activity
with decrease > 12% in DV registered at deltoid or
fifth finger abductor muscles). It is necessary to test
the repetitive nerve stimulation (PRNS) and intercostal
repetitive nerve stimulation (IRNS) in type II MG patients
regularly
chloride), the patient's eye signs (ptosis and
extraocular muscle abnormalities) markedly decrease
within 2 minutes in cases of myasthenia gravis.
(Prostigmine) test : used in children, and in
adults suspected of having myasthenia gravis but with a
negative Tensilon test; neostigmine methylsulfate mixed
with atropine sulfate is injected intramuscularly;
lessening of myasthenic symptoms is indicative of the
disease
to assess thymic diseases
(p.o. pyridostigmine 2mg/kg/die = 60
mg 3-4 times a day : t1/2 = 10 hr)
0.4 g/kg/die for 5 days
is an important treatment option in MG, especially if a
thymoma is present. It has been proposed as a first-line
therapy in most patients with generalized myasthenia. The
beneficial effect of thymectomy was reported as early as
the 1930s and 1940s in a variety of case reports and small
series. Even though no controlled trial to assess the
efficacy of thymectomy in MG has been reported, thymectomy
has become the standard of care and should be done in all
patients with thymoma and in patients aged 10-55 years
without thymoma but with generalized MG. Thymectomy may
induce remission. This occurs more frequently in young
patients with a short duration of disease, hyperplastic
thymus, and high antibody titer. Remission rate increases
with time: at 7-10 years after surgery, it reaches 40-60%
in all categories of patients except those with thymoma.
(usually remits when the drug is stopped) ,
show sequence homology with some intracellular proteins, and
may persist in connective tissue diseases such as dermatomyositis. Autoantigens :
(97%)
autoantibodies
, estradiol and relaxin
.
with fever, leukocytosis, pleuritis,
and pneumonia
ref
(AIHA) : the antibodies that cause AIHA can be
classified by isotype (IgG, IgM, or IgA) and by the
temperature at which they react maximally with the antigen
on the red cell: warm reacting if that temperature is 37º,
cold reacting if that temperature is less. Much of the
pathophysiology and many of the clinical manifestations are
determined by these characteristics. For the most part, the
isotype and the temperature of reaction coincide: most
frequently, cold-reacting antibodies are IgM and
warm-reacting antibodies are IgG, but important exceptions
exist.|
|
|
|
|
| isotype | IgG | IgM | IgG |
| temperature | 37°C | 4°C | 4°C and 37°C |
| complement fixation | variable | yes | yes |
(e.g. CVID)
antibodies, including IgAref.
It is an ion transporter found in erythrocyte membranes
also shown to be involved in erythrocyte senescence. The
major target of the pathogenic red blood cell (RBC)
autoantibodies in New Zealand black (NZB) mice (which
spontaneously develop AIHAref
: RBC-bound IgG autoantibodies can be detected by direct
antiglobulin test (DAT) from 3 months of age, and the
mice develop signs of anemia from about 6 months of age
onwardref)
is the anion channel protein band 3, and CD4+
T cells from NZB mice respond to band 3 peptide 861-875ref1,
ref2
: nasal administration of different peptides containing
the dominant T-cell epitope can have potentially
detrimental or beneficial effects on the diseaseref
antibodies or non-neoplastic clones
activated during chronic
lymphocytic leukemia
antibodies), that binds to RBCs at
0÷-20°C and induces complement-mediated lysis on
warming at 37°C; it is responsible for hemolysis in a
frigore paroxismal hemoglobinuria (with
anti-i specificity) (with anti-I specificity)
infections and it should
be used only when the simultaneous presence of IgG
antibodies is found. Antibody production can sometimes be
suppressed by chemotherapy, but the rate of proliferation
of benign clones is so small that this is often
ineffective; obviously, if malignancy is present, its
treatment will treat the cold agglutinin problem. More
recently, the use of anti-CD20
(rituximab)
has found some successref
as has the use of fludarabineref.
Some patients appear to benefit by small to moderate doses
of erythropoietin. Plasmapheresis can be used to
remove antibody temporarily but is difficult to maintain
for chronic treatment; great caution is required to be
sure that the blood does not get cold during the procedureref.
(or so it is thought) and was frequently seen in secondary
and tertiary syphilis; this is now rare. It is most
commonly encountered in children as a response to viral illness or immunization,
much like immune
thrombocytopenia in this group; in these cases, it
does not persist, but the clinical syndrome it produces
may be severe enough to cause death. In adults, it is
usually an autoimmune antibody and may be associated with
other evidences of autoimmunityref.
has no place in the regimen as the spleen is not involved
in hemolysis. Prednisone, chemotherapy,
and anti-CD20
(rituximab)
treatment have all been used.
,
expressed primarily on adult RBCs,
expressed primarily on RBCs of fetuses and infants. They
are highly unusual in being encoded by a single VH
gene segment, VH4-34. Although VH4-34
is mandatory, a variety of different D and JH
gene segments, as well as L chains from different
families and isotypes, are used. The I/i Ag is composed
of repetitive N-acetyllactosamine units (Galb1->4GlcNAc) which are linear
in the i structure and branched in I. The strong
association of a single VH gene segment with
specificity for the I/i Ag indicated that the particular
structure formed by the VH4-34-encoded
portion of the Ab is required for I/i binding. The
structural interaction is of an unconventional nature
involving FR1 and therefore independent of the
conventional Ag binding site. These IgM autoantibodies
characteristically will not react with cells at 37°C but
only at lower temperatures. Since the blood temperature
(even in the most peripheral parts of the body) rarely
goes lower than 20°C, only antibodies active at higher
temperatures than this will produce clinical effects. In
the cooler parts of the body (fingers, nose, ears),
agglutination of RBCs by the IgM antibodies will
transiently occur. Hemolysis results indirectly from
attachment of IgM, which in the cooler parts of the
circulation binds and fixes complement. When the RBC
returns to a cooler temperature, the IgM antibody
dissociates, leaving complement on the cell. Lysis, or
destruction, of cells rarely occurs. Rather, C3b present
on the RBCs is recognized by Kupffer cells (which have
receptors for C3b); and red blood cell formation
follows., which,
unlike I and i antigens, are protease sensitive. IgAkref|
|
|
|
|
|
| autoimmune | a-methyl-DOPA, L-DOPA, and mefenamic
acid induce IgG cross-reacting
against Rh Ags |
standard therapeutic dose for 3-6 months | gradual onset of hemolysis, progressive if drug is not discontinued | IgG |
| high-affinity hapten | penicillins, cephalosporins, tetracyclines and tolbutamide
firmly adhere to RBC plasma membrane creating non
self epitopes and inducing drug specific IgGs |
high dosage for days of weeks | subacute extravascular hemolysis for 7-10 days, progressive if drug is not discontinued | IgG |
| low-affinity hapten | quinidine unstably adheres to RBC
plasma membrane inducing Abs that stabilize such a
binding |
standard or low dose for days | rapid onset, sometimes hyperacute with extravascular hemolysis | IgG or IgM |
| nonimmunological proein adsorption | cephalotin damages RBC plasma
membrane allowing many proteins to adhere it and
creating many new non-self epitopes. |
high dosage for days or weeks | clinically not releant | IgG |
interacts with both an IgG antibody and a RBC membrane
epitope probably located on the Band 3 anion channelref
(AIN)
with replacement of 1.0 to 1.5 times the predicted
plasma volume of the patientref
that should be continued until the platelet count is
normalref1,
ref2
or for a minimum of 2 days after the platelet count
returns to normal (>150,000/ml)ref.
This combines plasmapheresis (which may remove circulating
ULVWF multimer-platelet strings, agents that stimulate
endothelial cells to secrete ULVWF multimers, and
autoantibodies against ADAMTS13) and the infusion of
fresh-frozen plasma or cryosupernatant (containing
uninhibited ADAMTS13). Both solvent-detergent–treated
plasmaref1,
ref2
and methylene blue/light-treated plasma (for inactivation
of lipid envelope viruses) also contain active ADAMTS13;
however, protein S activity is below normal in
solvent-detergent plasma. Plasma exchange allows about
80–90% of acquired TTP patients to survive an episode,
usually without persistent overt organ damage. Lower
titers of ADAMTS13 autoantibodies are associated with
better responses to plasma exchange procedures. Plasma
exchange normalizes pattern of vWF polymers and allows
complete remission for 1 weekref.
LDH levels, which reflect tissue ischemia as well as
hemolysisref,
are also a marker of response to treatment. Risks of
plasma exchange should be recognizedref.
In a 9-year cohort study of 206 consecutive patients
treated for thrombotic thrombocytopenic purpura, 5 (2%)
died of complications attributed to the plasma-exchange
treatment (3 from hemorrhage related to the insertion of a
central venous catheter and 2 from catheter-related
sepsis)ref.
53 other patients (26%) had major complications attributed
to plasma-exchange treatment, including systemic
infection, venous thrombosis, and hypotension requiring
dopamineref.
However, given the poor prognosis of untreated TTP, the
benefits of therapy outweigh the risks.
(e.g., 1 to 2 mg/kg of prednisone daily until remission
is achieved; or 1 g of methylprednisolone per day for 3
daysref
administered intravenously)ref1,
ref2
if plasma exchange doesn't work, chronic relapsing TTPref,
plasma-exchange dependence, or relapsing cerebral
ischemia despite normal peripheral blood analysis.
Rituximab is also used for prophylaxis in patients who
experienced at least 2 episodes (at least 1 with
extrahematological symptoms & signs), in complete
remission, failure of at least one first-line therapy,
and ADAMTS < 5%ref1,
ref2.
In 30-40% of patients with chronic relapsing TTP autoAb
persist during clinical remissionref.,
vincristineref,
or cyclosporineref1,
ref2,
ref3-induced
thrombocytopenia (HIT)|
|
|
|
|
|
|
| heparin (new or remote [> 100 days] exposure) | high | patients undergoing orthopedic surgery | 14 | 3-5 | at baseline and at least every other day from days 4 to 14 of heparin therapy or until heparin discontinued |
| intermediate | adults undergoing cardiac surgery. Children undergoing cardiac surgery | 25-50 | 1-2 | ||
| intermediate | general medical patients, patients with neurological conditions, patients undergoing percutaneous coronary intervention for acute coronary syndrome, patients undergoing acute hemodialysis | 8-20 | 0.8-3.0 | ||
| low to rare | general pediatric patients, pregnant women, patients undergoing chronnic hemodialysis | 0-2.3 | 0-0.1 | not essential | |
| LMWH | intermediate | medical patients patients with neurologic conditions patients undergoing surgical or orthopedic procedures |
2-8 | 0-0.9 | at baseline and every 2 to 4 days after days 4 through 14 of LMWH therapy or until therapy discontinued |
| rare | pregnant women general pediatric population |
unknown | 0-0.1 | routine monitoring not recommended | |
| heparin or LMWH (exposure within 100 days) | unknown | all clinical populations | unknown | unknown | at baseline, within 24 hr, and every other days from days 4 through 14 until heparin is discontinued |
complexes
in their plasma at the time the disease develops. PF4
is a platelet-specific C-X-C chemokine that is
released in high concentrations at sites of platelet
activation. Recent evidence in a transgenic mouse
model suggests a role for PF4 in thrombus formationref. Heparin-PF4 complexes form though an
interaction between the highly sulfated anionic
heparin and a circumferential band of lysine and
arginine residues on PF4. Binding of PF4 to polyanions
appears to expose new antigenic epitopes that lead to
antibody formation. This phenomenon is not
heparin-specific; other negatively charged polyanions
can also induce antigenic sites. Although all major
classes of antibodies have been detected, it appears
that patients with high titer IgG responses
are at greatest risk to develop clinical diseaseref1,
ref2. Anti-heparin-PF4 antibodies also
appear to be more prevalent among individuals
undergoing cardiac surgery with bypass, where high
doses of heparin are used in the setting of intense
platelet activation. Up to 50% of individuals who
undergo cardiac surgery with bypass will become
seropositive. However, at present, there are
no reliable means to predict which seropositive
individuals will develop thrombocytopenia or the
even smaller fraction who will manifest thrombotic
complications. IgG/heparin-PF4 complexes
activate platelets through the platelet FcR, resulting
in further PF4 release and amplification of this
process. In addition, this process results in thrombin
activation, thereby eventuating in a systemic
hypercoagulable state. For reasons that are not clear,
only a minority of heparin-treated patients who form
anti–PF4 (PF4)/heparin antibodies develop
thrombocytopenia, thrombosis, or other sequelae of
HIT. To date, investigators have focused on explaining
this clinical heterogeneity through serologic
differences, such as antibody class, titer, and
platelet-activating propertiesref1,
ref2.
But there are still patients with otherwise typical
"HIT antibodies" who do not develop HIT. A
HIT-mimicking anti-PF4/heparin monoclonal antibody
(named KKO) exhibited greatly increased binding to
human platelets in the presence of added PF4 (maximal
binding at 50 µg/mL), even when heparin was not
present. Similar findings were observed using purified
IgG obtained from patients with HIT. Moreover,
treatment of platelets with chondroitinase, but not
heparanase, greatly reduced antibody binding. Thus, HIT
antigens are formed by stoichiometrically optimal
concentrations of PF4 and platelet surface
chondroitin sulfate. These observations help
explain certain features of HIT, such as
thrombocytopenia that persists for several weeks or
that begins a few days after stopping heparin ("delayed-onset
HIT")ref.
These data might also help account for why thrombotic
risk remains high for a time despite stopping
heparinref
(if no alternative anticoagulant is given), perhaps
because of continuing platelet activation. The
results could also explain the common serologic
finding of heparin-independent platelet activationref1,
ref2.
—a
small
positively charged molecule familiar to clinicians for
its heparin-neutralizing properties—prevented
thrombocytopenia in both FcgRIIA/hPF4low
and FcgRIIA/hPF4high
double-transgenic mice, presumably because protamine
competes with PF4 for binding to platelet surface
chondroitin sulfate. These intriguing results suggest
that protamine should be evaluated in clinical studies
for its potential to reduce HIT antibody–induced
platelet activation 
due to the high incidence of
crossreactivity (although compared with
unfractionated heparin, LMWH therapy is less likely
to result in HIT) appears not to crossreact with
HIT antibodies, but this remains to be tested, such as lepirudin, bivalirudin or argatroban : 2 DTIs
are approved for treatment of HIT in the USA :
argatroban and lepirudin. Argatroban is also
approved for prevention of thrombosis in HIT
patients and for coronary interventions. Danaparoid has been used extensively for
HIT therapy but is not currently available in the
US. Hirsh and colleagues recently published a
critical review on HIT treatmentref. They examined 4 issues: risk of
thrombosis in patients with HIT where heparin was
discontinued in the absence of an alternative
anticoagulant; the efficacy of DTIs in a patients
with HIT (with or without thrombosis); the use of
DTIs in patients with a history of HIT requiring a
coronary intervention; and bleeding risk
associated with this therapy. The criteria for
inclusion were a study design of randomized
controlled trial, prospective cohort study or
retrospective observational study enrolling
patients consecutively; treatment with lepirudin,
argatroban or danaparoid; and a minimum of 30
patients. Of 999 potentially relevant citations
identified, only 9 met these criteria; no studies
using danaparoid met the criteria. There were no
randomized controlled trials comparing treatments.
The incidence of new thromboembolic events in
patients with HIT treated by discontinuing heparin
alone or by heparin withdrawal and initiation of
warfarin in the absence of a DTI ranged from 19%
to 52%. The use of historical controls in the
lepirudin and argatroban trials, together with
differences in trial design, made it difficult to
compare the efficacy of the two drugs directly.
For example, patients in the lepirudin trials were
treated twice as long on average as those in the
argatoban trial. All patients in the lepirudin
trial had a positive test for HIT antibodies,
compared with 65% of those in the argatoban trial.
Even with treatment, mortality ranged from 9% to
22%; 6–18% of patients required amputation or
experienced a new thrombotic event. Neither
outcome was statistically significantly different
from historical controls. However, as Warkentin
and others have pointed outref, using a single endpoint of new
thrombosis (rather than the composite endpoint of
all cause mortality, new thrombosis and limb
amputation) may be a better measure of DTI
efficacy. Amputation of a limb with severe
ischemic injury, for example, might well be
required despite the use of an effective
anticoagulant following the injury. Both drugs
significantly reduced the incidence of new
thromboembolic events. Bleeding rates of 6–18%
were reported for both drugs. The bleeding rate in
coronary inventions was approximately 1%. In the
absence of properly designed drug comparison
trials, the choice of drug is generally based on
differences in their mode of elimination;
lepirudin is renally cleared whereas argatroban is
cleared by the liver. There is no antidote for
either drug. Therefore, in patients with renal
insufficiency, argatroban would be preferred; in
those with liver disease lepirudin would be a
better initial choice. Lepirudin is a recombinant
form of the leech anticoagulant hirudin. Up to 40%
of individuals receiving the drug will develop
antihirudin antibodies, which sometimes prolongs
the drug half-life. There have been a few cases of
fatal anaphylactic reactions in patients
re-exposed to lepirudinref. Either drug should be used
cautiously in critically ill and elderly patients.
For example, because the serum creatinine does not
correlate with the creatinine clearance as well in
the elderly population as it does in younger
individuals, lepirudin may be cleared more slowly
than expected. Argatroban clearance may be
prolonged in ICU patients with normal liver
function tests (LFTs) but compromised hepatic
blood flow due to congestive heart failure or
hemodynamic instability. Bivalirudin has been used in HIT patients
during angioplasty and clinical trials in other
settings are underway. : almost all patients require
oral anticoagulation either because of the
underlying indication for heparin or the risk of
new thromboembolic events due to HIT, which
persists for about a month. Conversion to warfarin
may be accomplished while on the DTI, after there
is evidence of clinical stability and platelet
recovery. Prolongation of the PT is rarely an
issue with lepirudin. This conversion is more
complicated in patients treated with argatroban,
which generally prolongs the INR. Thus, the
observed INR in a patient on argatroban is a
reflection of the effect of both warfarin and
argatroban. A nomogram has been developed by the
manufacturer to assist in this conversion;
however, the effect on the INR depends on both the
argatroban infusion rate and thromboplastin used.
A validation of this nomogram in HIT patients on
concurrent argatroban and warfarin is in progress. : whenever possible, such
surgery should be postponed in patients with
clinical or serologic evidence of HIT. HIT
antibodies are relatively short-lived, and not
all patients develop HIT upon re-exposure to
heparinref. Thus, the generally preferred
strategy is to wait for several weeks and perform
the surgery using unfractionated heparin (UFH)
when serologic tests are negative.
Postoperatively, it is prudent to monitor patients
for the development of HIT antibodies and to have
a low threshold for prophylactic use of a DTI; a
DTI or other non-heparin anticoagulant should be
used for acute coronary syndromes or interventions
requiring anticoagulation. Argatroban is approved for use in HIT
patients requiring percutaneous
coronary
intervention (PCI). The hirudin analog bivalirudin
has also been studied in HIT patients requiring
PCI, and while not FDA-approved, appears to be a
safe and effective alternativeref. If surgery cannot be delayed,
then the approach will depend on the experience of
the institution. Surgery should be performed
"off-pump," if possible, to decrease the
anticoagulant requirement. Alternative approaches
are not FDA-approved, involve off-label use of
available anticoagulants, are based primarily on
anecdotal evidence and involve a significant risk
of bleeding. Lepirudin and bivalirudin have been used successfully in
this setting. However, there is no neutralizing
agent and monitoring drug levels on the pump
optimally requires use of the ecarin clotting time
or chromogenic substrate thrombin assayref. The use of these drugs for
cardiac bypass has recently been reviewed in
detailref. Another alternative is to use
UFH along with prostacyclin to inhibit platelet activationref. Norepinephrine or similar agents must be used
concurrently to counteract the vasodilatory
effects of prostacyclins. are not elevated in patients
with ITP, as they are in patients with thrombocytopenia due to
chemotherapy or aplastic anemiaref1,
ref2,
ref3,
ref4,
ref5,
ref6,
ref7,
ref8;
the mechanism underlying this phenomenon is thought to be
related to clearance of endogenous thrombopoietin by the
megakaryocyte and platelet poolsref1,
ref2.
and IFN-g,
reduced IL-10), and a reduced Th2
response have been recognizedref.
A recent study suggests that CTL-induced lysis of
platelets may be importantref.
Incubation of platelets with anti-CD3-stimulated
autologous CD14–/CD19– blood
mononuclear cells from 6 of 8 patients with active ITP
resulted in significant platelet lysis when compared with
similar studies using cells from normal subjects or ITP
patients in remission. The active cells were CD3+/CD8+
lymphocytes and the lysis was HLA-specific. The authors
also noted increased expression of T cell cytotoxic genes
(Apo-1/Fas, granzyme 1, granzyme 2 and perforin) and genes
involved with the Th1 response (IFN-g
and IL-2RB) while genes from several members of the KIR
receptor family, which downregulate CTLs, were increased
in remission patients when compared to those with active
ITP. Since the number of CTLs is small relative to the
number of platelets produced, the in vivo
importance of this mechanism in ITP remains to be shown.
Cell-mediated cytotoxicity against platelets in patients
with chronic ITP :
,
causing molecular mimicry of antibodies against VZV to
crossreact with platelet antigens, thus causing ITPref.
ITP in some patients has been shown to be due to
production of predominantly self-reactive IgG1ref.-relatedantigen
in
stools
(introduced in 1981; FcR blockade prevents removal of
sensitized platelets by the reticuloendothelial system
in the spleen and liver; 1.0 g/kg/day IV for 2 days).
IVIg drives signaling through activating FcgR in the amelioration of mouse
ITP. The actual administration of IVIg was unnecessary
because as few as 105 IVIg-treated cells
could, upon adoptive transfer, ameliorate ITP. IVIg did
not interact with the inhibitory FcgRIIB
on the initiator cell, although FcgRIIB
does have a role in the late phase of IVIg action.
Notably, only IVIg-treated CD11c+ dendritic
cells could mediate these effects. IVIg forms soluble
immune complexes in vivo that prime
dendritic-cell regulatory activity. In conclusion, the
clinical effects of IVIg in ameliorating ITP seem to
involve the acute interaction of IVIg with activating FcgR on dendritic cellsref.(1.0
g/day
IV for 3 days)
should also be given.
(75 µg/kg) has been suggested as an alternative, although
there is limited experience in the emergency setting.
(1.0 mg/kg/day IV for 2 days) given by continuous infusion
over the 48-hour period, combined with continuous platelet
infusions (1 random unit/hour) until the platelet
count increases.
may be useful in unresponsive patients with uncontrolled
bleedingref.
: early studies from Italy
and Japan reported an increased incidence of H
pylori infection in ITP patients and persistent
partial or complete remissions in 50% patients
following its eradicationref.
A recent prospective study in the USA showed no
increased incidence of H pylori in ITP
patients and no platelet response following its
eradicationref.
A multi-institutional prospective randomized study is
planned that should help define the role of H
pylori in ITP. In the meantime, no
evidence-based recommendations can be made about
whether routine H pylori testing and/or
treatment are indicated in chronic ITP.
(1 mg/kg) and, if a response occurs, taper the dose
slowly with the aim of maintaining safe platelet
counts on doses causing tolerable side effects (<
10–15 mg/day). Response rate = 60-80%, 20-60% are
long-term responders. should be given whenever the
platelet count falls below 25–30,000/µL. This
approach should be continued for ~6 months, if
possible, with the aim of eventually stopping all
treatment. The duration of this approach, prior to
advising splenectomy, must be decided by the patient
and treating physician since there are no data which
establish a definite stopping point. Cooper et alref
reported on 28 Rh+, non-splenectomized
ITP patients who received periodic therapy for
platelet counts < 30,000/µL (68% responded
consistently to anti-D). Patients were treated for
18 months unless they required splenectomy. Of the
28 patients, 12 (43%) are off all treatment (median
16, range 6–33 mos) with either platelet counts of
> 100,000/µL (6 patients) or safe platelet counts
> 30,000/µL (6 patients). Follow-up was obtained
on 21 patients advised for splenectomy after they
failed to attain a stable remission with prednisone.
They decided to postpone splenectomy and continue
treatment, in most cases with either prednisone or
danazol, and their platelet counts eventually
stabilized. 10 had normal platelet counts and 11 had
stable counts > 50,000/µL off all treatment, with
median follow-up of > 8 years.
(introduced in 1916) is recommended if :.
Refractory patients, defined in this manner, often respond
slowly to subsequent treatment, have significant morbidity
from the disease and its therapy, and have a mortality
rate of 10–16%ref1,
ref2.
As reported recentlyref,
there are few randomized, controlled trials to support the
use of any therapy for refractory ITP patients, and
treatment is based on small uncontrolled studies and
physician experience. A recent reportref,
evaluating the long-term outcome of 105 refractory adult
ITP patients (median follow-up, 110 months), showed that
75 patients eventually attained a stable platelet count
> 30,000/µL either
or
(24 patients) (introduced in 1958) : prednisone (1.0 mg/kg/day) is the drug of
choice in refractory patients if "safe" platelet
counts can be maintained on doses acceptable for
long-term use (<= 10 mg/day). Some patients who
require small doses of prednisone, to maintain safe
platelet counts and to avoid steroid side effects,
can be successfully switched to either (0.6 mg BID or TID PO) (75 mg PO daily)
may lead to higher rates of sustained remission.
: a dose of 200 mg QID PO is
given initially with full dose prednisone. Responses
occur slowly and therapy should be continued for 3–6
months before abandoning it. In responding patients,
prednisone is tapered and, if possible, stopped
while danazol is continued at full doses for at
least 1 year and then tapered slowly over several
months. Some patients require danazol maintenance
therapy, with or without low-dose prednisone. (rituximab) : patients who fail
corticosteroids and danazol should receive rituximab
(375 mg/m2 IV q week x 4). Responses are
usually noted within 3–4 weeks after the first
infusion. A stable complete or partial remission
occurs in about one-third of treated patients. Some
patients who relapse will respond to subsequent
courses. CR = 18-54%, sustained > 6 months in
40-49%, to be administered within 3 years; 30-40%
(most PR patients) relapseref.
Weighted means for CR (platelet count >
150,000/ml) and overall response (platelet count
> 50,000/ml) with rituximab were 43.6% and 62.5%,
respectively. Median time to response was 5.5 weeks.
Responses lasted from 2 to 48 months (median 10
months). Nearly all patients had received
corticosteroids, and 53.8% had undergone
splenectomy. Nine patients (2.9%) diedref : the starting dose (150 mg/day
PO) is adjusted to maintain mild neutropenia.
Responses occur within 8–12 weeks and, if the count
normalizes, full doses are given for 3 additional
months and then treatment is stopped. Patients
should drink at least 2 quarts of liquid daily, to
prevent hemorrhagic cystitis, and the blood count
should be monitored each week. : the initial dose of 150 mg/day
PO is adjusted to maintain mild neutropenia.
Responses occur slowly, over 3–6 months, and this
agent is often stopped prematurely. In responding
patients, therapy should be continued at full doses
for 12–18 months and then gradually tapered and
discontinued. : the dose of 1.25–2.5 mg/kg BID
is adjusted based on cyclosporine and creatinine
levels. Of 18 post-splenectomy patients in one
study, 5 complete and 5 partial remissions were
noted; 30% stopped therapy due to side effectsref : few patients have been
studied; responses were noted in 15 of 23 patients
with durations ranging from 1–39 months. Start with
500 mg BID PO and increase to 1,000 mg BID after 2
weeks. Few side effects were notedref : a dose of 1.0–1.5 g/m2
IV is given at 4-week intervals. A high fluid intake
is mandatory and frequent blood counts are required. for treatment of refractory
chronic autoimmune thrombocytopenia : one group
transplanted 14 patients with refractory ITP. Of
these, 6 attained stable platelet counts >
100,000/µL and 2 patients had partial responses
(follow-up 9–42 months). There were no deaths
associated with the procedure and no major
complicationsref.
agonists
|
|
|
|
|
| prednisone |
1.0 mg/kg PO qd | 1–4 weeks | hypokalemia, gastric upset, sodium and fluid
retention, hyperglycemia, hypertension, myopathy, osteoporosis, infection risk, psychosis |
| colchicine | 0.6 mg PO tid | 4–8 weeks | diarrhea (may limit therapy), nausea, vomiting |
| dapsone |
75–100 mg PO qd | 4–8 weeks | hemolysis, agranulocytosis, aplastic anemia,
exfoliative dermatitis, toxic hepatitis, choleostatic jaundice, peripheral neuropathy. |
| danazol |
200 mg PO qid | 3–6 months | weight gain, fluid retention, seborrhea,
hirsutism, vocal changes, amenorrhea, acne, headache, liver toxicity |
| rituximab |
375 mg/m2 IV q week x 4 | 3–4 weeks | infusional symptoms: (fever, chills, headache,
broncho- spasm), severe B cell reduction and potential for infection |
| cyclophosphamide |
150 mg PO qd | 6–8 weeks | cytopenias, hemorrhagic cystitis, GI symptoms,
sterility, secondary malignancies (lymphoproliferative disorders or acute leukemia have occurred in patients with other disorders receiving these drugs) |
| azathioprine |
150 mg PO qd | 2–10 months | cytopenias, GI symptoms, secondary malignancies (lymphoproliferative disorders or acute leukemia have occurred in patients with other disorders receiving these drugs) |
| cyclosporine
A |
1.25–2.5 mg/kg PO bid | variable | renal insufficiency, hepatotoxicity, hypertension, tremor, hirsutism, gum hyperplasia, hypomagnesemia, secondary malignancies |
| mycophenolate
mofetil |
0.5–1.0 g BID PO | 3–4 weeks | diarrhea, leukopenia, headache, secondary malignancies (lymphoproliferative disorders or acute leukemia have occurred in patients with other disorders receiving these drugs) |
| high-dose cyclophosphamide |
1.0–1.5 g/M2 IV q 4 weeks | 1–4 weeks | cytopenias, hemorrhagic cystitis, GI symptoms,
alopecia, sterility, myocardiopathy, secondary malignancies (acute leukemia or myelodysplasia have resulted from therapy with alkylating agents) |
| combination chemotherapy |
several combinations have been usedref | 1–4 weeks | cytopenias, hemorrhagic cystitis, alopecia,
dermatitis, anaphylaxis, GI symptoms, sterility, myocardiopathy, mucositis, secondary malignancies (acute leukemia or myelodysplasia have resulted from therapy with alkylating agents) |
or HCV
infection antibody antibody antibody
(acquired hemophilia B)
undergoing replacement therapy
antibody
(acquired hemophilia A)ref1,
ref2,
the development of an inhibitor (which occurs in 20-25% of
patients) reduces the response to factor concentrates, but
frequency of bleeds does not increase. These
alloantibodies exhibit type I (logarithmic) kinetics of
inactivation of factor VIII and can be overwhelmed if at
low titer|
|
|
|
|
|
|
| normal plasma alone | 32 | 32 | 36 | 40 | |
| normal plasma + | factor VIII-deficient plasma | 37 | 37 | 41 | 45 |
| weak inhibitor (1 BU) | 37 | 38 | 45 | 53 | |
| moderate inhibitor (5 BU) | 43 | 47 | 55 | 64 | |
| strong inhibitor (20 BU) | 54 | 61 | 77 | 92 | |
, avoid
intramuscular injection and aspirin
(if < 5 BU) or porcine
(if 5-20 BU as it is not recognized by autoantibodies)ref
FVIII to increase FVIII:C > 30-50%/APCC)
500-1,000 U. Response rate = 50-70%,
IVIgG,
plasma exchange,
extracorporeal absorption
bypass autoantibodies and is activated only where TF is
exposed
contains too few FVIII to be an effective replacement
therapy, cyclophosphamide,
azathioprine,
rituximabref1,
ref2
(it shows synergy with cyclophosphamide; selective
depletion of autoIgM-producing plasma cells because they
are short-lived or CD20+ (immature plasma
cells)); relapses are not related to ALC
(200 mg/day to a total dose of 2-3 grams), plus 3) methylprednisolone
(100 mg/day iv. for 1 week and than tapering down
the dose gradually over the next 2 weeks). The
treatment of acute bleeding episodes in the 2 groups
was not different. High purity and ultra-high purity
factor VIII concentrates were used for the ITI. We
performed aPTT and mixing tests before and after 2
hours of incubation, Bethesda inhibitor assay, porcine
FVIII cross-reactivity, FVIII:C before and after FVIII
administration (recovery), 3 times a week. The sex
ratio and mean age (64 years for the ITI group versus
57 years for the controls), the initial and peak
inhibitor titers, and residual FVIII: C values at the
diagnosis were similar in the two groups. Eradication
of the inhibitor occurred in 13/14 patients in the ITI
vs. 4/6 patients in the control group. The main
difference between the 2 groups was in the time needed
for the complete disappearance of the inhibitor (4.6
weeks for ITI vs. 28.3 weeks for controls). In the ITI
group we have observed only 2 relapses during the
relatively long follow-up period (26 months), and in
both cases the same re-induction protocol was
successful again. No bleeding-related mortality
occurred in this group in contrast to that of 33% in
the controls. Apart from the well-known adverse
effects of glucocorticoid therapy, we have observed
only one patient with transient cytopenia. No adverse
event which could be attributed to the use of FVIII
concentrates was seen. The ITI protocol described here
is highly effective for the treatment of acquired
hemophilia, induces quick therapeutic responses and
favorably influences the underlying autoimmune
disorder. This ITI protocol is suitable for the
eradication of idiopathic and autoimmune-associated
FVIII autoantibodies in patients presenting with
severe bleedingref
antibody antibody antibody antibody
who had experienced recurrent pregnancy loss, when mice are
deficient for FcgRs, C4, factor B,
or C5, or after C5aR blockade or neutrophil depletion. ?,
TIA,
amaurosis fugax, epilepsy,
psychosis, untreatable headache,
chorea, chorea gravidarum;
transverse
myelitis)
(> 90%) in every trimester of pregnancy, fetal growth
restriction (FGR; small-for-date foetuses due to multiple
placental thrombi), eclampsia
(25%)=>
leg ulcers
< 1500 cells/mm3
< 100,000 cells/mm3
and cerebrovascular
lesions.
First described in 1965ref,
it comprises about 0.26% of total cerebrovascular cases.
Clearly, no immunological testing to detect
antiphospholipid antibodies in Sneddon’s original
patients was undertaken. In a recently reported case of
Sneddon’s syndrome, repeated attempts to detect
anticardiolipin antibodies failed to give a positive
resultref.
But in another study of 10 cases of Sneddon’s syndrome,
seven had systemic lupus erythematosus, 5 were positive
for the Venereal Disease Research Laboratory (VDRL)
test, and were also positive for lupus anticoagulantref.
6 of these cases had livedo reticularis, all had digital
gangrene, cutaneous ulcers, and superficial
thrombophlebitis; two had pulmonary embolism. There is
little doubt that these cases belonged to the category
of "primary" APS, with or without systemic lupus
erythematosusref,
cerebral and cardiac manifestations.
(100%)
(49%)
=> thrombocytopenia
and fetal loss
if ischemia appears unjustified
to keep 2 < INR < 3 (not immunosuppressants)
in patients with previous thrombosis can reduce the rate
of fetal loss to 25%. Heparins prevent
obstetrical complications in women with APS because they
block activation of complement induced by aPL antibodies
targeted to decidual tissues, rather than by their
anticoagulant effects; treatment with heparin
(unfractionated or low molecular weight) prevent
complement activation in vivo and in vitro
and protected mice from pregnancy complications induced by
aPL antibodies. Neither fondaparinux nor hirudin, other
anticoagulants, inhibited the generation of complement
split products or prevented pregnancy loss, demonstrating
that anticoagulation therapy is insufficient protection
against APS-associated miscarriageref.
with standard chemotherapy led to the complete remission
of a severe hypercoagulable state associated with APAref. expression in
chorion => poorer Ab response => higher NK
cytotoxicity => incomplete placentation (limited to the
decidual region of spiral arteries, not involving myometrial
region : hence arteries can still respond to
vasoconstrictive stimuli). Immunological involvement is
supported by following normal pregnancies in nulliparous,
decreased prevalence after allotransfusion, modifications in
placental vessels mimicking transplant rejection, raised
levels in placenta and maternal blood, increased NK cell and
neutrophil activation =>
(early marker : MPV > 11 fL) => slow disseminated
intravascular
coagulopathy (DIC)
in ...,
retinal hemorrahages or exudates, retinal
detachment)))
=> up-regulation of Flt1 on placenta
=> increase in the levels of circulating sFlt1ref1,
ref2
(mean 4382 pg/ml) => hypertension and proteinuriaref
=> hydropic placentasref1,
ref2
and generalized fetal hydropsref,
which is elevated in the sera of preeclamptic
individuals, correlates with disease severity and falls
after delivery. sEng inhibits formation of capillary
tubes in vitro and induces vascular permeability
and hypertension in vivo. Its effects in pregnant
rats are amplified by coadministration of sFlt1, leading
to severe preeclampsia including the HELLP syndrome and
restriction of fetal growth. sEng impairs binding of
TGF-b1 to its
receptors and downstream signaling including effects on
activation of eNOS and vasodilation, suggesting that
sEng leads to dysregulated TGF-b
signaling in the vasculatureref or nifedipine (10-20 mg
every 30' up to 120 mg /24 hrs)(750-3,00
mg/die
in 3-4 doses) in
hypertensive crises (150-1,200 mg/die p.o in 2-3 doses;
150-300 mg/die i.v. in 4 doses) (gradual
reduction in BP and platelet antiaggregant, too) : not
recommended in patients with COPD, DM, CHF or renal
failure
(minibolus 30 mg)
for DIC
(they cross placenta and may cause loss of variability
of fetal heart rate but are not toxic)(SV)
with segmentary involvements (expecially at vessel
bifurcations) => ischemia of feeded tissues =>
symptoms and signs.
in CSS, anemia,
thrombocytosis
and RF
in CTD-associated vasculitides, CIC in type III
hypersensitivity-like vasculitides, type 2 cryoglobulins
in EMC,
ANCA in type II-hypersensitivity-like vasculitides (no
correlation with disease onset, severity or remission), AECA.-guided)
and MRI
combined with hemorrhages in the lung. , dyspnea ,
hemodialysis,
and prednisone
=> renal failure, pulmonary capillaritis => lung
hemorrhages
> c-ANCA
(70-80%) and cyclophosphamide
allow long-lasting remission in 90%, plasma exchange
infectionref
(30% in 1990ref;
90% in 1991ref),
with
better kits increasing range to 42.3% in 1992ref-66%
in
1993ref;
RNA-HCV measurements range from 63%ref-86%ref1,
ref2,
ref3.
MC is found in 30% to 50% of patients with chronic HCV
infection, with only 10% to 15% of them developing
clinical symptoms of MC overinfection :
a causative role was found in < 5% of patientsref.
Despite 10-25% of HCV patients are also carriers of GBV-C/HGV,
the latter does not play any role in the pathogenesis of
MCref.
)ref.
The production of IgM RF molecules is the most important
event for the emergence of cryoprecipitable immune
complexes. RFs in normal conditions are molecules involved
in the presentation of antigen to T cells within an immune
complex. A postulated hypothesis for the pathogenesis of
HCV-related MC is that HCV initially stimulates the
production of IgM without RF activity; the persistent
antigenic stimulation may induce somatic mutations causing
the acquisition of RF activity. HCV shows a cellular
affinity for lymphocytes. Interaction between the virus
and lymphocytes may occur through the viral envelope
protein E2, which binds human CD81 expressed on both
hepatocytes and lymphocytes. The interaction between HCV
and lymphocytes directly affects B-cell function and may
induce polyclonal activation and expansion of peripheral
CD5+ cellsref.
These cells are considered the major source of IgM RF in
type III cryoglobulinemia. However, monoclonal RF may be
the result of the evolution from polyclonal to oligoclonal
to mono-clonal RF, or may develop de novoref1,
ref2.
Following the initial activation, the emergence of a
single dominant clone producing a monoclonal IgM RF may be
an evolutionary step towards type II mixed
cryoglobulinemia. In the proposed model, the immune
complexes contain HCV core proteins plus specific anticore
IgG, which are bound to IgM with activity of RF. This
large complex reacts with C1q and then binds specifically
to the endothelial cells through the C1qRref.
) => persistent dyschromia,
urticarial lesions, livedo
reticularis, exanthema, acrocyanosis,
and ulcer on renal biopsy. MPGN is
the predominant type of glomerulonephritis caused by
HCV infection in the presence or absence of
cryoglobulinemiaref
after 12-24 months (50%) => acute nephritic
syndrome (20-30%) => acute
renal
failure
(5%)ref1,
ref2,
ref3
(30% of all NHLs in Italy). According to the REAL/WHO
classification, the most frequent histologic subtypes
observed are: lympho-plasmacytic (29%), diffuse large
B-cell (27%), follicular (16%), marginal zone (10%)
and mantle cell (7%) lymphomasref.
These lymphomas are characterized by a high prevalence
of extranodal involvement, especially liver and major
salivary glands. HCV-infected cells in these organs
may act as a reservoir stimulating B-cell
proliferationref.
In our series of 75 patients with HCV-related MC
followed for a median of 62 months (12–163), 5
patients (6.6%) showed malignant evolution: 4 to
lymphoplasmacytic lymphoma and 1 to chronic
lymphocytic leukemiaref.,
increased transaminases (15% at onset => 50%) (used as
immunosuppressant in the pre-HCV eraref); combination with 6-methyl-prednisolone allows faster response and
slower relapse after discontinuation (within 3
months)ref;
PEG-IFN-a2b 1
mg/kg/wk + ribavirin 1 g/day for 12 months confers
81% of clinical responses (1% in genotypes 2 and 3.
In responsive patients, reduction of HCV-RNA usually
heralds the decline of the cryocrit)ref.
Virological, clinical and biochemical response was
sustained in 44% of patientsref.
These authors also set criteria to define the type
of response (complete, partial, no response) of MC
patients to the antiviral approach in terms of: 1)
viral response, i.e., the effect on HCV-RNA; 2)
biochemical response; i.e., the effect on liver
function tests; 3) immune response; i.e., the effect
on RF and cryocrit levels; 4) clinical response;
i.e., the effect on the clinical manifestations of
the disease. The use of IFN-a
in patients with MC is limited by its transient
efficacy and by the peculiar side effects of this
agent (depression, thyroiditis, and neuropathy). In
patients with clinically evident peripheral
neuropathy, nephropathy, or skin ulcers, IFN may
aggravate these manifestationsref1,
ref2.
Antiviral treatment proved effective in splenic
lymphoma
with villous lymphocytes associated with HCV infection
and mixed cryoglobulinemia, resulting in the
clearance of HCV-RNA, remission of lymphoma, and
regression of clinical manifestations of MCref.
These results represent a strong argument in favor
of the etiologic link between HCV infection, MC, and
lymphoma. Interestingly, among B-cell NHL, splenic
marginal zone lymphoma shows a particularly high
incidence (35%) of HCV infectionref.
3 series have recently reported that antiviral
treatment with IFN-a +/-
ribavirin is effective in HCV-associated indolent
and marginal zone lymphoma, most with
cryoglobulinemiaref1,
ref2,
ref3.
In these studies, where the majority of patients had
splenic lymphoma with villous lymphocytes, most
patients achieved a sustained response of lymphoma
with regression of symptoms of MC after clearance of
HCV RNA. A complete remission with IFN + ribavirin
has been also reported in a patient with
HCV-associated mantle cell NHL resistant to
chemotherapy and rituximabref.
If detectable RNA levels 24 weeks after treatment or
<= 2 log10 reduction after 3 months of
treatment (if > 2 log10 continue for 1
year and achieve eradication in 95%) =>ref1,
ref2,
ref3
=> 80% responds after 6 months (reduced purpura,
leg ulcers, morning stiffness, muscle pain, NCV,
proteinuria, IgM, IgG RF, anti-HCV antibodies;
stable arthralgia, muscular strength, livedo
reticularis, creatinine, ALT, and C3; increased C4 but
increased HCV-RNA !); while non-responders
remain monoclonal, responders become monoclonal;
37.5% relapse within 2 years. Rituximab at the
standard dose of 375 mg/m2 IV weekly for
4 weeks was effective and well tolerated, resulting
in a significant and rapid improvement of clinical
signs (purpura, arthralgia, peripheral neuropathy)
and a decline of cryocrit in most patients with MC,
including patients resistant to IFNref1,
ref2,
ref3.
A remission of the underlying malignant
lymphoproliferative disorder was obtainedref.
Rituximab proved to be safe and effective treatment
for cryoglobulinemic nephropathyref.
Complete clinical remission was associated with a
significant reduction of RF activity and anti-HCV
antibody titers. Although an increase of viremia was
observed in responders, no significant variation of
transaminases or deterioration of liver disease was
notedref.
The addition of pegylated IFN and ribavirin after
anti-CD20 treatment has been proposed to eliminate
HCV while maintaining the remission obtained with
rituximabref.
The first dose of rituximab may induce a transient
rise of the cryobulin level that does not indicate
resistance to treatmentref 180 mg/wk
or PEG-IFN-a2b 1.5 mg/kg/wk
+ ribavirin 800-1,200 mg/day + rituximab 375 mg/m2
IV q week x 4.) (low-, high-dose) :
anti-inflammatory, immunosuppressive with cascade filtration (removal
of circulating immune complexes) improves malleolar
ulcersref,
arthritis
on glutei and lower limbs (70%), nausea
and vomiting,
diarrhea, melena, constipation
(70%))
antigens in
20-30% of cases (HCV in 5%) .
(60% : from arteritis or glomerulitis (30%)) => systemic
arterial
hypertension,
nausea
and vomiting,
bleeding) (44%),
AMI,
persisting tachycardia, pericarditis)
(36%) => ulcers) (43%). Those
with wide ulcers have a better prognosis than those
with purpura only.),
arteriography
(mesenteric microaneurysms), neutrophilic leukocytosis,
ACD,
increased ESR,
p-ANCA (< 20%) and cyclophosphamide
allow long-lasting remission in 90%, plasma exchange
polarization.
that becomes confluent and bright red in a
glove-and-sock distribution; the skin becomes
indurated and edematous and desquamates from the
fingers and toes
and fever
without definable cause is an uncommon but important
manifestation : delay in diagnosis and treatment may
be responsible for the high rate of coronary artery
abnormalities that have been reported in patients with
this complicationref
=> coronary artery aneurysms (25% of untreated
cases vs. 4% of patients treated with IVIg
and high dose acetylsalicylic
acid
(ASA).
Serum sodium concentration of <135 mEq/L at the
patient's first visit to hospital may be a predictor
of giant coronary aneurysms due to KDref;
mortality : 0.5-2.8%), myocardium
ischemia,
cardiomegaly;
pericarditis,
myocarditis
: there is no evidence that IVig treatment on day 4 or
earlier has greater efficacy in preventing cardiac
sequelae than treatment on days 5 to 9. In addition,
early treatment is likely to result in a greater
requirement for additional IVGG. However, there is
also no evidence that early treatment increases the
prevalence of cardiac sequelae in a clinical practice
setting, where additional IVGG can be given to those
whose initial treatment failsref.ref,
ophthalmic artery ischemia => ischemic optic
neuritis
=> sudden visual impairment (15% : diplopia,
sight loss, irreversible if untreated), rarely CAD,
lower limb claudication, visceral infarction, aorta
aneurysm. ,
> 3 cm-long temporal artery biopsy (fragmentation of
elastic tunica) or echocolordoppler
(ECD),
anemia.
,
TIA,
stroke,
nausea
and vomiting,
chronic
renal
failure,
CHF),
dizziness,
nausea
and vomiting,
nausea
and vomiting,
thrombocytosis., methotrexate
nasal carrier =>
necrotizing vasculitis of intermediate and small arteries,
arterioles, and venulae. (28%; 10% at onset) (18%; 5% at onset) (18%; 1% at onset) (16%; 6% at onset) (2%; 0% at onset), usually from URT overinfections
(50%; 23% at onset) (6%; 2% at onset) (3%; 1% at onset)
(90%), increased
ESR,
IgA hypergammaglobulinemia, thrombocytosis,
renal biopsy 2
mg/kg/die p.o. => 90% improves symptoms, 75% undergo
complete remission, prednisone, methotrexate,
azathioprine,
TMP/SMZ ,
anterior
uveitis
/ iridocyclitis,
hypopyon,
retinal vasculitis, optic
neuritis=>
blindness
(10%),
colchicine, IFN-a,prednisone, azathioprine,
cyclosporine
A.
The combined cyclosporine and prednisone treatments in
active Behcet uveitis may downregulate the NK-like effector
functions of CD8brightCD56+ T cellsref.
addiction,
psychic disorders, focal neurological defects
infection
infection
1 mg/kg/die p.o.,
immunosuppressive
drugs,
cytotoxic
drugs,
plasmapheresis
(usually monolateral involvement), colchicine,
PABA, vitamin E, relaxin,
plasma exchange, skin massage,
avoid detergents, hydratating creams, warfarin, biofeedback,
surgical sympathectomy (stellate ganglion block), distal
occlusion of ulnar artery in patients with positive Allen
test, symptomatic therapy, no kidney transplant due to
systemic manifestations.
=> claudicatio of calf, foot, forearm, hand
(63%)
=> ischemic
gangrene)
(60% of cases),
hoarseness,
epistaxis,
weakness, malaise. Often associated with type II or
generalized myasthenia gravis or systemic
lupus
erythematosus. These bullae heal without scarring ,
mycophenolate
mofetil,
chlorambucil,
dexamethasone-cyclophosphamide
pulse therapy, immunoablative therapy with
cyclophosphamide, plasmapheresis, and extracorporeal
photochemotherapy.
This combination frequently causes long-term
immunosuppression, the consequences of which are now the
most common cause of death in patients with PVref.
may be considered a first-line agent. This is
primarily because the risk of potentially fatal
adverse effects with this drug is lower than that
associated with other available chemotherapeutic
agents. In patients who are refractory to oral agents,
alternative treatments have been used to prevent
further disease progression.
monotherapy, with a defined protocol, has been reported
to be beneficialref1,
ref2,
to patients who do not have a response to
corticosteroids plus immunosuppressive agents or who
have severe side effects from this therapy. This therapy
is promising since it may allow for discontinuation of
all other therapies, is safe and can produce long-term
remissions. The adverse effects from IVIg therapy are
minimalref
for refractory casesref1,
ref2
: patients with refractory pemphigus vulgaris involving
> 30% of their body-surface area, >= 3 mucosal
sites, or both who had inadequate responses to
conventional therapy and IVIg
were treated with 2 cycles of rituximab (375 mg/m2
of body-surface area) once weekly for 3 weeks and IVIg
(2 g/kg of body weight) in the fourth week. This
induction therapy was followed by a monthly infusion of
rituximab and IVIg for 4 consecutive months. Of 11
patients, 9 had rapid resolution of lesions and a
clinical remission lasting 22 to 37 months (mean, 31.1).
All immunosuppressive therapy, including prednisone,
could be discontinued before ending rituximab treatment
in all patients. 2 patients were treated with rituximab
only during recurrences and had sustained remissions.
Titers of IgG4 antikeratinocyte antibodies
correlated with disease activity. Peripheral-blood B
cells became undetectable shortly after initiating
rituximab therapy but subsequently returned to normal
values. Side effects that have been associated with
rituximab were not observed, nor were infectionsref
and burning sensations, sudden onset of tense inflamed
blisters over red base (may appear as collarettes of
blisters) most commonly on genitalia, but also in oral
mucosa (50%), face and perioral skin ,
symmetric annular lesions, papules (may be excoriated and
crusted), vesicles, and bullae on extensor surfaces, elbows,
knees, and buttocks (rarely conjunctiva and oral mucosa)
,
amyloidosis,
ulcerative colitis, and multiple
myeloma
and with D-penicillaminetherapy.
and milia;
onychodystrophy
and lesions of the oral mucosa are often seen. ),
HIV-1,
bacterial infections, stress, and drugs (Li, b-blockers, and antimalarial
drugs)
can aggravate psoriasis. Th1 polarization
and Reiter's disease) or infliximab 5 mg/kg
)
is characterized by the development of pustules in the
flexural areas - the backs of the knees, the insides of
the elbows, the armpits and the groin. These pustules
continue to spread and soon they join to form lakes of
pus. The pustules rupture easily and can become infected.
This condition can be fatal if the patient gets dehydrated
(especially in the elderly), or the infection spreads to
the bloodstream. Generalized pustular psoriasis is often
triggered by stopping topical or oral steroids (pitting
with subungueal keratosis => onycholysis).
(5-10%, expecially males) > knee, hips, ankles,
and wrists
(15-39%) : proximal and distal interphalangeal joints,
metacarpophalangeal, metatarsophalangeal and large
joints ; 1-5% develops arthritis mutilans with
acroosteolysis of capsule => "telescope finger"
; no subcutaneous rheumatoid nodules, 25% has RF.
(50%) + enteritis (30%) (5-40% ; 50-70% has
HLA-B27; RR = 12) : Achilles
calcaneal
tendinitis,
onychodystrophy,
pustulosis, hyperostosis, osteomyelitis (SAPHO)
syndrome
IgG and IgA, AKA IgA, anti-enterobacteria Ab, increased ESR ,
no D-penicillamine
in > 5-10%.
gel
15 mg/wk for >= 1 year (arthropathic and plaque
psoriasis), monitoring ethanolemia, thrombocytopenia,
transaminitis, and pulmonary fibrosis
(psoriasis has a lower incidence at low latitudes and in
sun-tanned people, but there is a risk for nevi) (monitor
hypertriglyceridemia)
3.5 mg/kg/day, monitoring systemic arterial hypetension
(prophylaxis with CCB > b-blockers)
5-10 mg iv (diffuse and refractory forms). Side effect
: tubercular enteritis
25 mg 2 times a week (psoriatic arthritis)
2 mg/kg/wk sc life-long (increase autoimmmunity and ASMA)
in psoriasis patients are actually dangerous. They do
clear up the psoriasis while the patient is taking them,
but after the patient stops, the psoriasis often comes
back even worse.
(AIG)bsubunit (90%) treatment
hepatitis with anti-CYP2E1
autoantibodies are detected in up to 4% of patients
with chronic HCV,
and anti-CYP2A6
autoantibodies are detected in about 2% of these
patients
infections generate anti-UDP- glucuronosyltransferases
(UGT) autoantibodies.
and/or ASMA
with F-actin reactivityref.
About 10% of AIH-2 sera further contain LKM-3
autoantibodies directed against family 1 UGTs+
in 25-50%., ulcerative colitis, and Sjögren's syndrome; or
the disease may progress to cirrhosis and liver failure
(anti-M2 (96%), anti-M4, anti-M8, and anti-M9). Anti-M2 and
anti-M4 reflect disease activity, while anti-M9 antibodies
occur preferentially in early PBC. A progressive course of
PBC can be predicted with high probability even at early
stages of the disease when complement fixing antibodies
against M2, M4 and/or M8 are present in patients' sera. In
contrast, the presence of anti-M2/M9 antibodies heralds a
benign course. In PBC contact persons a strong stimulation
of naturally occurring mitochondrial antibodies (NOMA)
has been observed which was in contrast to the lack of this
antibody type in PBC patients. Considering the generally
accepted role of those antibodies in protecting individuals
from infections, the failure of NOMA production may be a
predisposing factor to acquire PBC more easily. Iflammatory
destruction of the intrahepatic biliary system.
Cirrhosis is actually a late manifestation of the disease.
and MRI.
If they are used early in the course of the disease, both of
these imaging methods demonstrate objective signs of portal
hypertension, hepatomegaly, liver fibrosis, and
lymphadenopathy. The identification of these signs has been
shown to be helpful in the evaluation and surveillance of
patients with primary biliary cirrhosisref
and ASMA
or high frequency of rotavirusref
infections (RR = 1.94 for 1 infection, 3.76 for >= 2
infections) genetically predisposed individuals (obviously
only infection but not autoimmunity can be prevented by
vaccination) : cross reactivity between gliadin and Ad Ags (IgA and IgG)ref
: they may disappear during a gluten-free diet treatmentref.
A peptide recognized by serum immunoglobulins of patients
with active disease, but not by those of patients on a
gluten-free diet, shares homology with the rotavirus major
neutralizing protein VP-7 and with the self-antigens tTG,
HSP60, desmoglein 1, and TLR4. These
antibodies were able to induce increased epithelial cell
permeability evaluated by transepithelial flux of [3H]
mannitol in the T84 human intestinal epithelial cell line.
Finally, the purified antibodies induced monocyte
activation upon binding TLR4ref
markedly upregulates the expression of the cell-surface
receptor NKG2D and the
signal-transduction adaptor molecule DAP10 in
intraepithelial cytotoxic T lymphocytes (CTLs), further
priming the cells to be responsive to NKG2D signalling.
The triggering of NKG2D by its ligand MICA and MICB
which are markedly upregulated on the cell-surface of
intestinal epithelial cells (IECs) by gliadin peptide
p31–49 initiates signalling pathways that lead to the
killing of IECs (in contrast to peripheral blood-derived
CTL clones (which cannot mediate target-cell lysis after
stimulation through NKG2D alone)), and this is coordinated
by IL-15ref1,
ref2ref1,
ref2 and
steatorrhea and/or constipation
producing dehydration and acidosis, which sometimes
occurs in the infantile form of nontropical sprue.
(a gluten-free diet appears to markedly reduce the risk
for lymphoma)
: the tongue was the most frequently affected site in a
series of 128 patients with celiac disease who were
examined for oral mucosal lesions and symptoms, with
29.6% of the patients describing soreness or a burning
sensation and 8.6% having erythema or atrophyref1,
ref2
(9-fold increase in risk)
over extensor surfaces, most common on the elbows, knees
and buttocks. => IgA
depots and microabscesses of papillary cristae
,
schizophrenia, ...) have been reported in up to 26% of
patients with coeliac disease. This is probably an
overestimate, because of the chance associations with
some common neurological conditions such as epilepsy.
The frequency of neurological dysfunction in patients
with DH has not been characterised : they might be
expected to be particularly susceptible to neuronal
damage as some continue to consume gluten when their
dermatological symptoms are controlled by dapsone.
The pathogenesis is speculative but it has been
postulated that : and IL-15 production
often occurs in type 1 RCD despite conventional
treatment. A 4-week amino-acid-based liquid elemental
diet is a therapeutic option that can provide
long-term immunopathologic and clinical improvement of
this difficult conditionref combined with prednisone for 1 yearrefref (0.1
mg/kg/day) intravenously for 5 days, given in 1-3
courses every 6 monthsref
inhibitors polarization.
Up-regulation of TLR2 on monocytes induces higher TNF-a expressionref
,
diarrhea
and rectal bleeding, extraintestinal manifestations (EIMs;
particularly in patients with HLA-B*27, HLA-B*58, and
HLA-DRB1*010 :
and multiple
sclerosis was noted in UC but not Crohn’s disease
patients (unlike another reportref).
The
most common nonintestinal comorbidities identified were
arthritis and asthmaref.
(Jewish race) : increase susceptibility to CD up to 40
times, making
it responsive to bacterial LPS; however, this
induction is deficient in mutant NOD2ref.
Macrophages within the intestinal lamina propria of
CD patients overproduce NF-kB
targets, including the proinflammatory cytokines
TNF-a, IL-1ß and IL-6ref1,
ref2.
Many of the anti-inflammatory drugs used to treat CD
inhibit NF-kB activation,
which suggests it is a key pathogenic factorref1,
ref2.
However, paradoxically, transient transfection
experiments indicate that CD-associated NOD2
variants no longer activate NF-kB
in response to MDPref1,
ref2,
which suggests that defective NF-kB
activation in macrophages facilitates infection of
the lamina propria by enteric bacteria. However Nod2
gene ablation did not cause spontaneous intestinal
infections or colonic inflammationref.
In fact macrophages can activate NF-kB in response to bacteria
also independently of NOD2ref:
PGN itself can also activate NF-kB
through cell-surface TLR2. Despite
an initial report suggested that in this case NOD2
is a negative regulator of TLR2–mediated activation
of NF-kB (particularly by
inhibiting cREL activation : NOD2 deficiency or the
presence of a Crohn disease–like Card15
mutation increases TLR2–mediated activation of NFkB–c-Rel, and Th1
responses are enhanced) and Th1 responsesref,
a following work found no effect of the Nod22939iC
mutation on signaling by TLR2, as coincubation of
macrophages with MDP plus PGN did not reduce the
response to PGNref.
The inhibitory function hypothesis is also
inconsistent with in vivo findings in Nod2
knockout mice, which did not show increased
inflammationref.
Nod22939iC is a
gain-of-function allele, whose product induces
elevated IKK and caspase-1 activation in response to
MDPref.
The gain-of-function hypothesis is consistent with
clinical observations made in CD patientsref1,
ref2.
Recently, TLR signaling and a certain amount of
enteric bacteria were shown to be critical for
maintenance of the intestinal barrier functionref,
a function that was suggested to deteriorate in CD
patientsref.
However, maintenance of barrier function is unlikely
to involve NOD2. By contrast, a unique function of
NOD2, not provided by TLRs, is induction of IL-1ß
processing and release through the N-terminal CARD
domains of NOD2, which may directly interact with
caspase-1 or upstream caspases : in fact Nod22939iC
mice exhibited elevated NF-kB
activation in response to MDP and more efficient
processing and secretion of IL-1ßref.
Given the importance of IL-1ß for the pathology of
DSS-induced colitis in Nod22939iC
mice and the imbalance between IL-1ß and IL-1RA in
CD patientsref,
it would be of interest to critically evaluate its
role in CD pathogenesis. SNPs.
is upregulated by proinflammatory cytokines and
enhanced in inflamed CD lesions. The CX3CR1 T280M
polymorphism appears to influence CD phenotype and
localizationref
has been disproved
and Listeria
spp.,
identified in CD lesions, contribute to the disease.
The disease could be the result of a defect in host
recognition by pathogenic bacterial components that
usually escape the immune response (eg, Yop
molecules), which results in an excessive host
response to these bacteriaref. polarization
=> discontinuous vasculitis necroticans, ulcers
deepened into whole intestinal wall and not
involving all the Ø of the gut, edema => cobblestone
mucosa and wall thickening (garder water tube-like), mesenteric
lymphadenitis,
noncaseating
granulomas
in various tunicae and microgranulomas within mucosa, submucosal
and subserosal fibrosis => single or multiple,
short or long stenoses; rare abscesses; never
perforations despite serositis.
: 15%), upward to ileum (ileitis : 75%; ileocolitis
: 35%), or be limited to terminal ileum (terminal
ileitis or enteritis
: 37%; no melena), stomach (gastritis
: 6%; usually upward after colonotomy), mouth (stomatitis)
and oesophagus (esophagitis :
0.5%).
evacuations / die, postprandial pain in left iliac cavity,
often asymptomatic (even up to age 60 !), weight loss; the
cumulative risk of any fistula was 33% after 10 years and
was 50% after 20 years (perianal, 21% after 10 years and 26%
after 20 years)ref;
psoriasis (11%),
cholesterol gall-stones
due to reduced resorption of biliary acids, enterohepatic
circulation and biliary secretion in ileal disease
shows hyperemia of mesenteric vessels in loop walls (comb
sign)
and echography of the last
small bowel loop (which shows wall thickening, stiffness
of the ileocaecal valve, mesenteric lymphadenitis) is
used only in pediatric patients and for frequent
controls
after > 20 years of disease : the pooled SIR for CRC
was significantly increased (SIR, 1.9, as was the risk
for colon cancer separately (SIR, 2.5)ref
: 5 studies reported SIRs ranging from 3.4 to 66.7, and
the overall pooled estimate was 27.1refref
SNPsacts
on
enteric and parasympathetic nervous systems affecting mucus
composition and inhibiting IL-2 and TNF-a production). :
100%), upward to sigma (proctosigmoiditis) and colon
(left colitis => subtotal colitis => total
colitis or pancolitis), rarely ileum => haustra
disappearance ("tubularization" at Rx). The upper
border of flogosis is well limited and involves all the Ø of
the gut.
(not postprandial), fever, tachycardia, anemia,
fatigue, slimming, tenesmus, mucohemorrhagic diarrhea
(loose discharges of blood, pus, and mucus with scanty fecal
particles)
> 37.5 => admission to hospital
(colitis polyposa) : edematous, inflamed islands
of mucosa between areas of ulceration. Granulation
tissue, cryptitis (PMN infiltrate), muscular and serous
coats are not infiltrated
(6÷10% after 10 years; only if a pancolitis lasting
> 20 years (RR = 32 after 10-20 years of pancolitis
with chronic course; flat instead of polypoid shape
=> surveillance with periodic biopsies and
prophylactic partial
colectomy
if histology detects dysplasia)
=> ileus
(5÷7%)(2%) and uveitis-polarized
immune
responseref
defines grade of activity of the disease
> 6 mg/L. Its short half-life makes CRP a valuable
marker to detect and follow up disease activity in CD. In
contrast, UC has only a modest to absent CRP response
despite active inflammation, and the reason for this is
unknown. In CD, serum levels of CRP correlate well with
disease activity and with other markers of inflammation as
the CDAI, serum amyloid, IL-6 and fecal calprotectin >
60 mg/g. An increased CRP (>45 mg/L) in patients with
IBD predicts with a high certainty the need for colectomy
and this by reflecting severe ongoing and uncontrollable
inflammation in the gut. Finally, trials with anti-TNF and
anti-adhesion molecules have shown that a high CRP
predicts better response to these drugsref.
> 60 mg/g may identify those IBD patients in
remission who are at risk of early relapse. However, a
number of studies have shown that there may be
differences in relapse prediction in patients with
ulcerative colitis (UC) compared to those with CD. For
12 months researchers followed up 79 consecutive
patients with the diagnosis of clinical quiescent IBD
(38 with CD and 41 with UC). However, in addition to
other clinical evaluations and blood tests, at the
beginning of the study a single stool sample was
collected from each patient, and calprotectin
concentration was measured by a commercially available
enzyme-linked immunoassay. The authors found that the
median calprotectin values in CD were 220.1 mg/g in patients who relapsed
during follow-up and 220.5 mg/g
in nonrelapsing patients. However, the median
calprotectin levels in UC were 220 mg/g
in relapsing patients and 67 mg/g
in nonrelapsing patients. Costa and colleagues found a
twofold and a 14-fold increase in the relapse risk,
respectively, in patients with CD and UC in clinical
remission who had fecal calprotectin concentrations
higher than 150 mg/g. Thus,
they concluded that fecal calprotectin levels were a
stronger predictor of clinical relapse in UC than in CD.
This suggests that calprotectin levels can be a
promising noninvasive tool for monitoring and optimizing
therapy especially in patients with UCref.
Most patients were on medical treatment and that
calprotectin may behave differently in patients who are
on no therapy. They emphasize that before this marker is
incorporated into routine practice, larger studies will
be neededref.,
ciprofloxacin,
metronidazole,
macrolides
(clarithromycin,
...), rifabutin,
clofazamine
(prednisone + 5-ASA (ileal CD responds also to diet));
oral budesonide 6 mg/day for 12 months (800 mg tablet) are
significantly more likely to achieve overall
improvement at 6 wk compared to patients treated with
2.4 g/dayref
: azathioprine
is effective for the maintenance of a steroid free
remission in CD. Thiopurine methyltransferase (TPMT) is
important for the metabolism of AZA and influences the
production of active AZA metabolites. AZA dose selection
based on pharmacogenetic testing of TPMT and metabolite
monitoring (MM) may offer a safety and efficacy
advantage over traditional dosing strategies. A decision
analysis was performed to estimate the potential costs
and effectiveness of TPMT screening and MM as disease
management strategies for CD. Strategies applying TPMT
and/or MM to influence treatment decisions were compared
to community care (CC). The impact on toxicity
minimization and improved time to initial and sustained
response was evaluated. A 1-yr model was developed from
the third-party payer perspective for mild to moderately
chronically active, steroid-treated CD patients.
Effectiveness and toxicity defined by time to response
CD activity index (CDAI <150, ± steroids) or time to
sustained response (CDAI <150, off steroids 8
wk) and reduction in leukopenic events, respectively.
One- and two-way sensitivity analyses were conducted to
determine the effect of varying individual estimates
from those used in the base-case analysis. MM, TPMT, and
TPMT + MM strategies as compared to CC achieved an
earlier time to initial response (18.66, 18.96, and
19.10 vs. 22.41 wk, respectively) and sustained response
(39.83, 42.91, and 39.8 vs. 45.36 wk, respectively). The
least costly strategy at 1 yr was TPMT ($3,861) and the
most costly strategy was CC ($7,142). Each alternative
strategy was shown to dominate CC (i.e., less costs and
faster time to response or sustained response). The
cost-effectiveness rankings were robust to sensitivity
analyses on key variables. The addition of alternative
strategies to CC may improve AZA outcomes and reduce the
total cost of care for steroid treated chronically
active CD patients, with TPMT being more beneficial for
initial response to treatment and MM being more
beneficial for sustained response to treatmentref.
Whether the risk of azathioprine
or 6-mercaptopurine associated
lymphoma in IBD is real or relates to the underlying
disease remains unclear. The results of several recent
large well designed population-based studies suggest
that the lymphoma risk associated with azathioprine and
6-mercaptopurine therapy is likely to be of minimal
clinical significance compared to the established and
more frequent risks of myelosuppression and infection,
and is far outweighed by the clinical benefit of
immunomodulator therapy in IBD. While the issue of
lymphoma risk is likely to become more relevant with the
growing number of biologic and immunomodulators being
tested in clinical trials for IBD, early post-marketing
surveillance data on infliximab
suggests that the lymphoma risk may not be any greater
than that associated with azathioprine and
6-mercaptopurineref
in the treatment of 15 patients with moderate to severe
Crohn's disease. No patients had worsening of their
disease. Adverse events were negligible and included
minor injection site reactions and bone pain. Patients
had a significant decrease in mean Crohn's disease
activity index (CDAI) score during treatment
(p<0.0001). After 8 weeks of treatment, mean CDAI had
fallen by 190 points. Overall, 12 patients had a
decrease in CDAI > 100 points, and eight achieved
clinical remission. Retreatment was effective, and
treatment was associated with increased quality-of-life
measures. GM-CSF may offer an alternative to traditional
immunosuppression in treatment of Crohn's diseaseref1,
ref2.
(Geoffrey's method), but it is currently
considered a risk factorref1,
ref2,
ref3
: 5 mg/kg infliximab q8wk improves mucosal healing
(=> reduced hospitalization and surgery), off
steroids, uveitis, migrating arthritis, pyoderma
gangrenosum; premedication with hydrocortisoneref
or azathioprine/6-mercaptopurine to prevent induction of
HACAref.
Adalimumabref
also in subjects with prior loss of response or
intolerance to infliximabref.
URTI (22% vs. 18.7%), other infections (> 5%,
expecially sinusitis and UTI), but no increase in TB;
lymphomas incidence = 0.11 vs. 0.06 every 100 patients
per year : azathioprine actually protects from
lymphomas. Only prednisone (neither infliximab nor
immunomodulators) is associated with increased
mortality. Patients with moderate-to-severe active
ulcerative colitis treated with infliximab (5 mg or 10
mg/kg of body weight) intravenously at weeks 0, 2, and 6
and every 8 weeks thereafter were more likely to have a
clinical response at weeks 8, 30, and 54 than were those
receiving placeboref
: induction therapy with natalizumab for Crohn's disease
resulted in small, nonsignificant improvements in
response and remission rates. Patients who had a
response had significantly increased rates of sustained
response and remission if natalizumab was continued
every 4 weeks. The benefit of natalizumab will need to
be weighed against the risk of serious adverse events,
including progressive multifocal leukoencephalopathyref. and examination under
anesthesia (EUA)ref1,
ref2,
usually seen during pregnancy
and thought to be an autoimmune reaction.
/ idiopathic adrenal atrophy.
: they afflict as many as 4 out of 100 women.
SNPs polarization.
Autoantigens :
: the 4th,
5th, 6th extracellular loops and
the beginning of the intracellular tail share homologies
with the other thyroid autoantigens (Tg, TPO and TSH-R)., T4 or both
(32%)
on TSH-R
+
more common on anterior and lateral surfaces of tibia (pretibial mixoedema
(PM) : it may be severe enough to compress the
lymphatics and give superimposed elephantiasis)
but occurs also on other sites (forefoot, hands, ...)
after trauma : orange plaque (hard edema) mimicking
elephantiasis
(< 1%) is tightly associated with thyroid dermopathy,
with loss of all voluntary eye movements, the pupillary
movements and reflex eye movements persisting; seen in
Graves' disease and hysteria.,
TNF, and IL-1 => production of hydrophilic
glycosaminoglycans (GAG) leading to expansion of
extra-ocular muscles, and hypertrophy of the adipose
tissue by adipogenesis => proptosis
/ exophthalmus(38-71%)
=>
lagophthalmos
=> conjunctivitis
(photophobia)
and corneal
ulcer,
diplopia,
lateral
nystagmus
and, in extreme cases, loss of sight due to compression
of the optic nerve. It may precede or follow
thyrotoxicosis by some years (euthyroid eye disease)
(10%)
for 18-24 months (65% of successes in pediatric age)
(when there is cytological suspect of associated
carcinoma (5-10%) : rapid control of hyperthyroidism,
for large goitres or relpase of hyperthyroidism after
ATDT
(80% of successes; 70% as first-option, 15% after
failure of medical or surgical therapy)
10-15 years later
and primary
hyperthyroidism
(chronic
myeloid
leukemia (CML)
and Waldenstrom
macroglobulinemia))
cause a transient release of T4 from
non-thyroid pools (expecially the liver) even when
administered with GR
agonists
in patients with early
stages of Hashimoto's disease, characterized by mild
hypervascularization at thyroid echocolordoppler
(ECD)).
Associated
with idiopathic fibrosis in other organs
(retroperitoneum, mediastinum, biliary ways, lungs, and
orbit)
SNPs
(not fixing complement). TPO–specific T cells, in the
absence of mature B cells and antibodies, spontaneously
infiltrate and destroy the thyroid gland, causing overt
hypothyroidism and obesityref, T4 or both
(IgGs; 20%),
small follicles and germinal centres. .
+ immunosuppression and Th2 CD4+
lymphocytes and histiocytes, extensive neutrophils, fibrin
deposition, and necrosis.
: initial increase in TT3 and TT4
due to release of TBG (normal FT3 and FT4)
=> with progression to liver failure
: initial increase in TT4 and FT4
(normal FT3)
infection : increase in TT3 and TT4
despite weight loss. With conversion to AIDS, TT3
decreases but TSH remains normal
show low TT3 and normal (not increased) rT3
due to increased liver captation.
(T1DM) / growth-onset diabetes / juvenile-onset diabetes
(JOD) / ketosis-prone diabetes / insulin-dependent
diabetes mellitus (IDDM)*R2, IL-4*C,
VDR*C and IGF-I*wt is transmitted more frequently than
expected (67%, Pc=0.015)ref
transcriptional activity. The M55V substitution
resulted in 5.5 times greater NFkB
transcriptional activity and approximately 2 times
greater expression of IL12B, an NFkB-dependent
gene.ref in the lymph
nodes. Disruption of the diabetic process is
irreversible as these T cells cannot then re-enter
the pancreasref
is also the primary replication site of enteroviruses,
enterovirus infections could modify the development of
immune response to dietary insulin in early infancy. IgG
antibodies to BI at 2 years of age are lower in children
with a diabetic mother than in children with a diabetic
father or a sibling, suggesting possible tolerization to
insulin by maternal insulin therapy and
some patients with type 2 diabetes
mellitus)
against autoantigens :
(CD4+ and CD8+
T cell epitope; HLA-B15 and HLA-DR3-associated with RR
< 5) is a key, but not absolutely essential,
autoantigen : despite tolerance to transgenically
overexpressed preproinsulin 2 substantially reduces the
onset and severity of T1DM in NOD mice, some mice still
develop T1DMref.
The oligoclonally expanded T cells from pancreatic lymph
nodes from long-term diabetic patients but not from
control subjects with DR4, a susceptibility allele for
type 1 diabetes, recognized the insulin A 1-15 epitope
restricted by DR4ref.
However this proposed immunological role of insulin may be
undermined by the atypical responses of T cells to the
human insulin fragment that are describedref
: based on avidity of the lymph-node T-cell clones wthat
recognize the insulin A1–15 fragment, would large enough
concentrations of insulin be available in situ for
antigenic stimulation of T cells, given the amount of
peptide required to stimulate the clones and their degree
of responsiveness ?ref. of Langerhans'
islets (endocrine pancreas).,
molecular mimicry (type
II hypersensitivity) is presumed as
trigger for this disease. CBV4 infects insulin-producing b-cells without causing necrosis.
Instead, the stressesd islet cells are phagocytosed by
resident macrophages, which present islet epitopes to
autoreactive T cells in islet-specific TcR-transgenic mice.
These macrophages can induce DM after adoptive transfer to
uninfected mice. Therefore, viral infection can be the last
initiating step in multi-step DM development, requiring the
pre-existence of autoreactive T-cellsref
in response to al teast one of the IA-2 and pro-insulin
peptides, compared to only 7% on non-diabetic control
subjects. However, the PBMCs from non-diabetic controls are
not completely unresponsive to the islet antigens. 64% of them
make an IL-10 response to IA-2 peptides
compared with 29% of diabetic patients. Of the diabetic
patients that make an IL-10 response, almost all also make an
IFN-g
response, whereas control subjects produce IL-10 in the
complete absence of IFN-g.
IL-10 is known to have immunosuppressive functions, so the
T-cells responding to islet antigens in healthy controls might
have a regulatory role. Interestingly, those patients with DM
who produced IL-10 and IFN-g in response to IA-2 or
pro-insulin tend to be older at diagnosis than patients who
produced only IFN-g,
confirming the disease modifying effect of IL-10ref.
. Insulitis =>
production of CXCL9 and CXCL10 from b
cells => infiltration of macrophages and CXCR3+Th1-polarized
lymphocytes.
or simultaneous
pancreas-kidney
(SPK) transplantation
lies in a known NOD susceptibility locus on chromosome 3. -accelerated
diabetes
(CAD) by eliminating various cell populations,
including regulatory cells. There is a greatly expanded pool
of autoreactive peripheral T cells in NOD, and the presence
of T cells autoreactive to a broad repertoire of self Ags.
NOD mouse strain, which is deficient in B7-2 costimulation,
develops a spontaneous autoimmune peripheral polyneuropathy
that has clinical, electrophysiologic, and morphologic
similarities to human CIDP.
Female autoimmune-prone NOD mice have fewer peripheral CD4+
T cells than control strains that do not develop
autoimmunity due to increased levels of IL-21 production,
leading to upregulation of IL-21R expression by T cells, and
clear evidence of increased responsiveness to this cytokine,
which mediates T-cell proliferation but not survival,
failing to upregulate expression of the anti-apoptotic
molecules Bcl-2 or Bcl-XL, leading to low numbers
of long-lived memory T cells -like
toward
Th2 may
prevent disease : targeting autoantigen(s) expression as
transgenes in APCs, pituitary cells, or pancreatic b-cells have been shown to
prevent NOD mice from developing type I diabetes.)
but is tightly dependent on TGF-b.
NKT-cells also participate in the therapeutic effect because
CD1d-/- NOD mice are partially resistant to the
protective effect of OM-85. The question remains of the
specificity of the protective effect of OM-85, which may
include proinflammatory components. It will thus be
important to further characterize the molecular components
that afford protection from type 1 diabetes. LPS is
excluded, but other TLR agonists could be involved because
OM-85 stimulated dendritic cells and induced TGF-b production by splenocytes in a
TLR-2-, TLR-4-, and MyD88-dependent fashionref.
enters the b cell via GLUT2 and causes
alkylation of DNA. DNA damage induces activation of
PARP, a process that is more important for the
diabetogenicity of streptozotocin than DNA damage
itself. Poly ADP-ribosylation leads to depletion of
cellular NAD+ and ATP. Enhanced ATP
dephosphorylation after streptozotocin treatment
supplies a substrate for xanthine
oxidase
resulting in the formation of superoxide radicals.
Consequently, hydrogen peroxide and hydroxyl radicals
are also generated. Furthermore, streptozotocin
liberates toxic amounts of NO. that inhibits
aconitase activity and participates in DNA damage. As a
result of the streptozotocin action, b cells undergo the destruction
by necrosis. antibody syndrome with
hypoglycemia
antibody syndrome ,acanthosis
nigricans
/ early menopause / premature ovarian failure (POF), IL-6, VEGF,
and TNF-a , splenomegaly),
endocrinopathy (E) (type II diabete
mellitus, hypoadrenalism),
skin changes (S) (hyperpigmentation,
dermal thickening, hirsutism, hyperhidrosis),
papilledema, edema, effusions, ascites, thrombocytosis,
hyperprolactinemia => hypogonadism (amenorrhea in
females, gynecomastia and
sexual impotence in males), lymphadenitis,
intracranial
hypertension,peripheral
edema, ascitis, pleural
effusion,
glomerulonephritis,
fever, fatigue, clubbing and
leukonychiaref1,
ref2,
ref3.
Virtually all patients will have either sclerotic bone
lesion(s) or co-existent Castleman’s
disease.
Not all features of the disease are required to make the
diagnosis, and early recognition is important to reduce
morbidity
At a minimum, a patient should have the following: the peripheral neuropathy; osteosclerotic myeloma (i.e., a clonal plasma cell dyscrasia and at least one sclerotic bone lesion) or Castleman disease; and at least one of the other featuresref. Though the majority of patients have osteosclerotic myeloma, these same patients usually have only 5% bone marrow plasma cells or less, and rarely have hypercalcemia or renal insufficiency. These characteristics and the superior median survival differentiate POEMS syndrome from multiple myeloma. The plasma cells are virtually always l restricted. Though the pathophysiologic mechanism is not well understood, there is a correlation between treating the underlying plasmaproliferative disorder (clone) and clinical improvement. Radiation therapy produces substantial improvement of the neuropathy in more than half of the patients who have a single lesion or multiple lesions in a limited area. If there are widespread lesions, conventional chemotherapy or high-dose chemotherapy and peripheral blood support may be helpful. Criteria for the diagnosis of POEMS syndromeref :
| Mayo seriesref | French seriesref | Japanese seriesref | |
| % n=99 | % n=25 | % n=102 | |
| peripheral neuropathy | 100 | 100 | 100 |
| organomegaly | 46 | NS | NS |
| hepatomegaly | 25 | 68 | 78 |
| splenomegaly | 22 | 52 | 35 |
| lymphadenopathy | 26 | 52 | 61 |
| endocrinopathy | 71 (includes gonadal and adrenal abnormalities) | NS | NS |
| diabetes mellitus | 3 | 36 | 25 |
| hypothyroidism | 17 | 36 | |
| monoclonal plasma cell dyscrasia | 100 | 100 | 75 |
| skin changes | 68 | NS | NS |
| hyperpigmentation | 46 | 48 | 93 |
| acrocyanosis and plethora | 19 | NS | NS |
| hemangioma/telangectasia | 9 | 32 | NS |
| hypertrichosis | 26 | 24 | 74 |
| thickening | 5 | 28 | 61 |
| sclerotic bone lesions (of patients with bone lesions) | 97 | 68 | 54 |
| osteosclerotic only | 47 | 41 | 56 |
| mixed sclerotic and lytic | 51 | 59 | 31 |
| lytic only | 2 | 0 | 13 |
| > 1 lesion | 54 | 59 | 45 |
| papilledema | 29 | 40 | 55 |
| extravascular volume overload | 39 | NS | NS |
| peripheral edema | 29 | 80 | 89 |
| ascites | 15 | 32 | 52 |
| pleural effusion | 9 | 24 | 35 |
| Castleman disease | 11 | 24 | 19 |
| other features | |||
| thrombocytosis | 54 | 88 | NS |
| polycythemia | 18 | 12 | 19 |
| clubbing |
5 | 32 | 49 |
| Comment: the percentage for all series uses the total number of patients in the series as the denominator | |||
| characteristic | MGUS | POEMS | multiple myeloma | AL amyloidosis | cryoglobulinemia |
| peripheral neuropathy | ~5% | 100% | 1–8% | 15%–20% | ~25% |
| sensory versus motor predominance | sensory, ataxia (IgM) sensorimotor | predominantly motor | sensory | sensory sensorimotor | predominantly sensory |
| organomegaly | – | ++ | + | ++ | ++ |
| skin involvement | – | ++ | + | + | +++ |
| other symptoms | asymptomatic | edema, fatigue, endocrine abnormalities | bone pain, fatigue, infections | fatigue, edema, cardiomyopathy, nephrosis | purpura, arthralgia, hepatitis, nephritis |
| monoclonal heavy chain | IgM >IgG >IgA | IgG > IgA >IgM | IgG > IgA | IgG > IgA > IgM | IgM >> IgG > IgA |
| monoclonal light chain | k 75% of cases | l > 95% of cases | k 75% of cases | l 75% of cases | k 75% of cases |
| serum M-spike, gm/dL | < 3 | usually < 2 | usually > 3 | usually < 2 | usually < 2 |
| BM plasma cells, % | < 10 | usually < 5 | > 10 | usually < 10 | usually < 5 |
| skeletal lesions | – | +++ (sclerotic, mixed sclerotic & lytic) | +++ (lytic, osteoporotic, or fracture) | – | – |
| thrombocytosis | – | ++ | - | + to ++ | + |
| anemia | - | + | ++ | + | ++ |
| Reprinted with permission from Dispenzieri A. Suarez GA. Kyle RA. POEMS syndrome (osteosclerotic myeloma) In: Dyck PJ. Thomas PK, eds. Peripheral Neuropathy 4th edition. Philadelphia: Elsevier Saunders; 2005:2453–2469 | |||||
ref1,
ref2,
ref3
| treatment |
|
|
|||
|
|
|
|
|
||
| radiation | 70 (64 patients were treated with 70 courses of radiation | 54 | 4 | 16 | 26 |
| melphalan and prednisone | 48 | 44 | 12 | 12 | 31 |
| combination chemotherapy (includes vincristine,
carmustine, melphalan, cyclophosphamide, and
prednisone; vincristine, Adriamycin, and dexamethasone;
cyclophosphamide, Adriamycin, vincristine, and
prednisone; and cyclophosphamide-based chemotherapy) |
15 | 27 | 7 | 33 | 33 |
| cyclosporine or azathioprine | 4 | 0 | 0 | 100 | 0 |
| cyclosporine or azathioprine, + prednisone | 6 | 50 | 0 | 17 | 33 |
| prednisone or dexamethasone | 41 | 15 | 7 | 20 | 59 |
| plasmapheresis | 16 | 0 | 12 | 87 | 0 |
| plasmaphresis + prednisone | 14 | 21 | 0 | 14 | 64 |
| intravenous immunoglobulin | 9 | 0 | 0 | 89 | 11 |
| N | response, % | stable, % | not evaluated, % | |
| Neurologic | 16 | 87 | ... | 13 |
| Subjective | 16 | 87 | ... | 13 |
| Nerve conduction studies (at 1 yr) | 11 | 36 | 9 | 55 |
| Neuropathy impairment score | 16 (1 patient showed borderline worsening at 15 months, but at 24 months, patient reported substantial improvement; no repeat neuropathy impairment score was performed) | 25 | 12 | 56 |
| Hematologic | 16 | 56 | 6 | 37 |
| Non-secretory | 3 | NA | NA | 100 |
| Immunofixation only | 7 | 43 | 14 | 43 |
| Serum protein electrophoresis (SPEP) evaluable | 6 | 100 (2 complete responses, 3 very good partial response, and 1 minimal response) | ... | ... |
| Organ | 11 | 82 | ... | 18 |
| Hepatomegaly | 5 | 60 | ... | 40 |
| Splenomegaly | 10 | 50 | 20 | 30 |
| Lymphadenopathy | 7 | 71 | 29 | 0 |
| Extravascular volume overload | 14 | 79 | ... | 21 |
| Ascites | 6 | 83 | ... | 17 |
| Effusion | 4 | 100 | ... | ... |
| Edema | 14 | 79 | ... | 21 |
| Skin changes | 13 | 54 | 15 | 31 |
| Papilledema | 4 | 50 | ... | 50 |
| Endocrine | 13 | 23 | 8 | 69 |
| Pulmonary | 15 | 20 | ... | 80 |
, ATRA. Therapies
that may be effective in patients with CIDP and
MGUS-associated peripheral neuropathy (intravenous
gammaglobulin and plasmapheresis) are not effective in
patients with POEMS. Instead, the mainstays of therapy for
patients with POEMS include irradiation, corticosteroids, and
alkylator-based therapy, including high-dose chemotherapy with
peripheral blood stem cell transplantation.
with involvement of biliary ways increase the levels of
IgA against dietary antigens
colitis (in addition to mesangial IgA and C3 deposition,
renal histological examination shows glomerular
bleeding, intratubular RBC casts, and acute tubular
necrosis) due
to insertion/deletion polymorphism in intron 16
in 24%, anti-elastin antibodies are present
in all individuals : patients with Peyronie's disease have
higher levels of antibodies to tropoelastin and a-elastin than age-matched
controls, suggesting an increase in elastin synthesis and
breakdown, respectively; complement activation)
and hypercholesterolemia
lead to weakening of the vasculature and its rupture
during coitus
in 25% of the cases),
pain during erection and impotentia coeundi
after intra-cavernous injection of PGE1 to induce erection,
CT,
Gd-MRI and
X-rays ,
and calcium channel
blockers (CCB)injected
directly
into the plaques or delivered under the skin into the
plaque by iontophoresis
(absent in rheumatoid
arthritis)
or anterior
uveitis
/ iridocyclitis
and nephritis
(90%), acute anterior
uveitis
/ iridocyclitis
(20%).
G0/G4 grades => upward spondylitis starting from
lumbar vertebrae, fusion of connective tissue with
periostium, osteitis, alternated pain at right and left
lower limb (weighing sciatica), antalgic loss of
cervical lordosis (reduced neck flexion) and lumbar
lordosis, dorsal hyperkyphosis ("question mark"
posture ; Mennel sign : sacroiliac pain at
spine hyperextension; Forestier sign : when
upright and lying on a wall with the back, the occiput
can't touch the wall; grading with Schober test
(enlengthenment of the imaginary line joining 2 points
10 cm above and 5 cm below lumbosacral joint < 4 cm)
=> gluteal atrophy, decreased chest expansion at
inspiration due to muscle contraction secondary to pain
and flogosis (Øchest at 4th intercostal space or
below mammary gland, VC - Øchest, FRC
< 5 cm) => diaphragmatic inspiration =>
abdominal distension => flexed hip => compensatory
knee flexion. Increased risk of fracture of a
cervical vertebra, cauda equina syndrome
(20-30%) => posterior synechiae, cataract,
glaucomaof
upper
lobes => fungal overinfections,
grade
3
AV block
(10%), aortitis (4%)in
5-10%.,
anemia,
leukocytosis,
thrombocytosis,
hypoalbuminemia,
increased a2-globulins
and IgA, expecially those with
HLA-DR2, HLA-DR3 or HLA-DR4 haplotype
polarization.
,
p.o.amoxicillin,
or i.v. ceftriaxone
for 4-6 weeks
(group A b-hemolytic
streptococci), despite 33% of patients doesn't report
tonsillitis : persistence of the organism on pharyngeal
tissues (i.e., the tonsils) is associated with an
increased likelihood of rheumatic fever. RFin
5-10%. and endocarditis accompanying
rheumatic fever. (40-60%) of mitral valve
(and sometimes even aortic valve). Valve failure
(usually mitral
valve
failure) may become clinical even 20
years later. Aschoff
bodies or nodules and => transient subcutaneous
nodules at extensory surfaces of olecranon,
occiput, and back in patients with chronic
pancarditis (< 10%) (< 10%) => Reiter's syndrome (rare) => Reiter's syndrome (differential diagnosis
from disseminated gonococcal infection (DGI) with
involvement of upper limbs, spondylitis, keratoderma
blennorrhagicum
/ keratosis blennorrhagica / palmoplantar
pustulosis, and ex juvantibus
antimicrobial therapy) polarization
and random spondylitis
(from genitourinary infections)
or anterior
uveitis
/ iridocyclitis
: broken vesicles on glans,
distal yellowish pigmentation and/or hypertrophic
hyperkeratosis(from
Chlamydia
trachomatis)
followed by arthritis and bilateral conjunctivitis;
not all symptoms are present in all patients, and there
may also be mucocutaneous manifestations such as keratoderma
blennorrhagicum
/ keratosis blennorrhagica / palmoplantar pustulosis,
circinate balanitis, and stomatitis. It usually affects
young men (male:female ratio 20:1) and runs a
self-limited but relapsing course. (52% at 99mTc
scintigraphy, 4-32% at Rx) in pretibial region of lower
limbs, satellite to targeted joint(s)
(expecially in CD patients)
or osteomalacia
(54%), pericarditis,endocarditis)
(54%)
(75%) (75%)
: symmetric polyarthritis lasting for months (similar to
rheumatoid arthritis but non-erosive), skeleton, tendons, fascias, etc..
(30%; 10% at onset),
uveitis, cataract,
optic
neuritis,
paralysis of extrinsic eye muscles, retinal vasculitis, occlusion
of
retinal vein
(50%; 20% at onset) => ulcers, corneal perforation
=> blindness
(5%),
myocarditis,
conduction disorders, aorta
aneurysms, epilepsy,
stroke, cranial (VI and VII) or peripheral neuropathies),
erythema multiforme,
angioedema/urticaria, livedo
reticularis,
panniculitis(25%), rheumatoid
factor,
ANA; c-ANCA; p-ANCA , immunosuppressive
drugs,
cytotoxic
drugs,
dapsone
, Lactobacillus
delbrueckii
subsp. lactis, and Brucella
melitensis biovar ovis)or
more
are 30% less likely to develop RA : as many people,
particularly the elderly, are vitamin D deficient this
may explain why RA is more common in the elderly polarizationrefagainst
the
following autoantigens :
(50-85% : undetected when of IgA, IgG or IgE isotype; [ ]
relates with severity of extraarticular
symptoms)
(a haplotype of peptidylarginine
deiminase
citrullinating enzyme (PADI) type IV, expressed in
hematological and RA synovial tissues, is associated with
susceptibility to RA that affected stability of
transcripts and is associated with levels of antibody to
citrullinated peptide). ACPA IgG level was found higher in
patients' synovial fluid than in their serum. PC were
detectable in SF and PB, and exhibited high CD95 and CD27
expression. In contrast, SF, but not PB, PC expressed
elevated levels of CD138. SF, but not PB, PC actively
secreted ACPA IgG in cultures, in a linear fashion for at
least 14 days, and CD95-ligation markedly reduced this
activity and provoked PC apoptosisref(32-45%), T4 or both
(26%)by IL-15
and TNF-a
abundant in the peripheral blood and synovial tissue and,
upon ligation of MICA and MICB
on synoviocytes, produce IFN-g.
IL-15
and TNF-a
also prevent NKG2D downmodulation by soluble MIC ligands
shed from cells by proteolysis.
=> fibrous ankylosis => osseous
ankylosis => deformities and morning stiffness for > 1 hr,
improving under effort or psoriatic
arthritis occur), lung (=> pulmonary interstitial
fibrosis), arteriolar walls (=> arteritis => fibrinoid
necrosis => skin ulcers), pleura, meninges.
Granulomas may evolve to cold abscess => fistulae
=> skin draining => infections.,
digital gangrene, visceral infarction (including
myocardial infarction),
interstitial fibrosis, pleuropulmonary nodules
(perforation may cause pneumothorax of bronchopleural
fistulae; Coplan syndrome in patients with
pneumoconioses), pneumonia, arteritis, URT obstruction
due to cricoarythenoideal arthritis or laryngeal
nodules (50%) => rarely cardiac
tamponade)
or cervical myelopathy due to proliferative synovitis
or articular deformity=>scleritis => scleromalacia
perforans (1%)=> hypersplenism
=> ANCA IgG (85-90%) => leukopenia (neutropenia < 1,500 / mL), NK lymphocytosis =>
leukemia; there are usually pigmented spots on
the skin of the lower extremities, and sometimes there
is other evidence of hypersplenism such as anemia or thrombocytopenia
(Hanrahan and Miller, 1932) for patients with severe
infections or associated AIHA =>
neutrophilia (80-90%; transient in 20-30%; mortality =
4.2%)
,
or 99mTc-diphosphonate bone scintigraphy
and CRP
concentration are increased. RA patients have
consistently higher levels of CRP than the healthy
controls throughout the 15 years preceding outward
disease symptoms. The concentration of CRP, however, is
most pronounced, and significant, within the 2 years
before a confirmed diagnosis of RA. Both RF+
and RF- patients show a very similar pattern
of increase in the CRP concentration over time, which
does not indicate a pivotal role for autoantibodies in
the development of inflammation during the preclinical
phase of RA. Rather, the somewhat higher CRP
concentration observed in patients with serologic
abnormalities suggest that the production of
autoantibodies is a phenomenon secondary to an increased
level of inflammation in these patients and C4
concentrations may be decreased (during systemic
vasculitis only), normal or increased
(Fe is sequestered by macrophages) and C4
concentrations are decreased,MMP9, and MMP14 (an
activator of MMP-2) : the former 2 are important in
collagen degradation, through digestion of denatured
collagen (gelatin) generated by thermal denaturation
at body temperature after specific cleavage of the
triple helix of the fibrillar collagen molecules by
collagenases. or
oral/topical GR
agonists
(prednisone < 7.5
mg/die), w3
PUFA-containing diet
(antimalarial drugs and sulfasalazine)
and cytotoxic
xenobiotics
(methotrexate
7.5-30 mg/week for 1-2 months (low/moderate
effectiveness); Syk
inhibitors)
for 1-3 months (low/moderate effectiveness,
hepatotoxicity), azathioprine,
cyclosporine
A
< 5 mg/kg/die)
(infliximab,
adalimumab,
etanercept)
: part of the therapeutic effect might be due to the
restoration of NKG2D downmodulation
: don't down-regulate anti-citrullin antibody levels (rituximab
/
IDEC-C2B8)
: two infusions every 6 months; don't down-regulate
anti-citrullin antibody levels. Incremental
cost-effectiveness ratio is estimated as somewhere between
£12 000 and £30 000 per QALY gained.) : 14 infusions
of abatacept in the first year and 13 thereafter.
Incremental cost-effectiveness ratio is estimated as
somewhere between £37 000–£43 000 per QALY gained.
or gene
therapy conjugated to
Prodaptin® for cell targeting
appears to be a relatively safe salvage treatment in
patients with severe, resistant rheumatoid arthritis (RA)ref
mAb. Anti-4-1BB suppressed serum antibodies to collagen
type II and CD4+ T-cell recall responses to
collagen type II. Crosslinking of 4-1BB evoked an
antigen-specific, active suppression mechanism that
differed from the results of blocking the interaction
between 4-1BB and its ligand, 4-1BBL. Anti-4-1BB
monoclonal antibodies induced massive, antigen-dependent
clonal expansion of CD11c+CD8+ T
cells and accumulation of indoleamine
2,3-dioxygenase (IDO)
in CD11b+ monocytes and CD11c+
dendritic cells. Both anti-IFN-g
and IDO inhibitors reverse the anti-4-1BB effect. The
suppression of collagen-induced arthritis is caused by an
expansion of new CD11c+CD8+ T cells,
and IFN-g
produced by these cells suppresses antigen-specific CD4+
T cells through an indoleamine 2,3-dioxygenase–dependent
mechanismref.
adjuvant arthritis (AA) in
> 10-25% often
accompanied by morbilliform
exanthema,
generalized lymphadenitis,
hepatomegaly, splenomegaly
(resembling adult Felty
syndrome), pleuritis,
pericarditis,
arthritis, and rarely GI tract disease.)
: micrognathia
secondary to condylar erosion from temporomandibular joint
(TJM) arthritis, cervical arthritis => impaired neck
extension, inequal limb length (premature closure or
overgrowth of epiphyses), fixed flexure of lower limbs,
RF
(15%), onset of the joint involvement occurs in large
joints (knees, ankles, or elbows). The small joints of
the hands are spared. Painless swelling of the involved
joint is common. Although fatigue and low grade fever
are occasionally seen, the only significant systemic
manifestation is anterior
uveitis
/ iridocyclitis
(25%, detected with slit lamp examination, without eye
pain, redness, or other clinical signs) => posterior
synechiae that arise from adherence of the iris to the
anterior surface of the lens and result in an irregular
or poorly reactive pupil => 60% have complete
recovery or normal sight, 25% have impaired vision or
unilateral blindness, and 10% are blind+)
polyarthritis (10%) resembles adult rheumatoid
arthritis, female:male ratio > 1, splenomegaly,
and enlargement
of lymph nodes)
in persons infected with bovine
or some other type of nonhuman tuberculosis. of unknown
origin (FUO) (100%), polyarthralgias (90%) or
polyarthritis (65%) myalgia (60%), a pharyngitis (75%), an
evanescent salmon colored maculopapular rash (80%),
leucocytosis (90%), multicentric lymphadenopathy (15%;
paracortical hyperplasia with prominent vascular
proliferation. In the paracortical area, there was a mixed
infiltrate including small-to-medium-sized lymphocytes,
variable numbers of eosinophils, plasma cells, and B
immunoblasts. Differential diagnosis with node-based
peripheral T-cell lymphoma by PCR analysis demonstrating
neither clonal rearrangement of the T-cell receptor
g-chain gene nor immunoglobulin heavy-chain
rearrangement), acute
hepatitis
(25%; fulminant liver failure is rare), splenomegaly
(40%), anemia
(65%), increased ESR
(100%), no RF, transaminitis (65%), and extreme hyperferritinemia
(Yamaguchi and Kahn's criterias, 1992), rarely angioedema and urticaria, disseminated
intravascular
coagulation (DIC)ref
and ARDSref.
Constantly, inflammatory tests are increased and the
rheumatoid factor and the antinuclear antibodies are
negative. The sex ratio is 1.83; the middle age of
intervening from 42 to 45 years. The middle delay for the
diagnosis is 3 to 8 weeks. There are 3 types of evolution:
remission, chronic systemic or chronic articular shape.
AOSD can be subdivided into groups according to their
chronicity: monocyclic systemic, polycyclic systemic, and
chronic destructive type, and are furthermore classified
as non-articular, oligoarticular or polyarticular types
(having arthritis involving 5 or more joints) according to
the extent of articular involvement. Risk factors :
diplotype configuration of S01/S01 in IL-18
gene is a major genetic risk factor (serum concentration
of IL-18 is strikingly high in patients)ref
as 80-100 mg / kg / day (serum salicylate levels should be
maintained between 20 and 30mg/dL) for 6 months 1 mg / kg / day
for brief periods (immediate use in carditis or Coomb+
hemolytic anemia) 1.5-3 mg / kg /
day is frequently more effective in treating individuals
with pauciarticular arthritis of the lower extremities and
ankylosing
spondylitis (AS)
up to 1 mg/kg/week and steroids in various applications
are the drugs of choice for the systemic and polyarticular
courses
(etanercept, infliximab, adalimumab) in patients with
polyarticular involvement, who do not respond to MTXref (rituximab),
cyclosporine
A
(2.5 mg/kg/day), leflunomide and cyclophosphamide
are rarely used.
has been tried as a very last resort but interpretation of
the results is controversial : it induces significant
remission of disease in patients with severe systemic JRA
refractory to conventional therapy, although
treatment-related infections (Legionella
pneumophila,
Staphylococcus
epidermidis,
HHV-3
/
VZV)
and complications (macrophage
activation
syndrome)
are common. 22% experience mild relapses, with
oligoarthritis and sporadic fever, that can be controlled
easily with a 3-month course of low-dose prednisone and
NSAID; 12% are resistant to ASCTref B allele : angiotensin II then binds AT1 receptors on macrophages
leading to up-regulation of
ref,
which in turn extrarenally converts 25-OH-vitamin D3
(produced in liver by CYP27A1
/ steroid 25-hydroxylase) to 1a,25-(OH)2-vitamin D3ref,
independent of body's calcium requirementsref.
This hormone builds to a local concentration sufficient to
catalyze the formation of granuloma (also by inducing
secretion of the monocyte chemokine and growth factor CSF-1 / M-CSF) and prevent
the maturation of dendritic cells into effective
APCs. The negative feedback normally existing (1a,25-(OH)2-vitamin D3-mediated
down-regulation of 1a-hydroxylase
and up-regulation of the catabolyzing enzyme CYP24 / steroid 24-hydroxylase via VDR) apparently
doesn't work.polarizing
cytokines (local CD4+/CD8+ T
lymphocytes ratio is 10:1) : among these IFN-g
further up-regulates 1a-hydroxylase
(reinforcing feedback)
(when necrosis is present it is fibrinoid
necrosis) in
every district of the body (most commonly hili of the lungs),
consisting of Langhans giant cells or foreign body-like cells,
often containing
, fatigue,
malaise, anorexia, dyspnea under effort, dry cough, rarely
hemoptysis, retrosternal pain) +
> subcarinal, anterior mediastinic, posterior
mediastinic, retroperitoneal, and mesenteric
lymphadenitis)
(75-90%) with no ulcerations at lower limbs (25%) (10%) => xerostomia self-limiting in 6-12 months
(75%)
(25-35%) => blindness
(5%) due to hypervitaminosis
D,
direct nerve compression by parotid gland swelling,
proximal demyelination beginning in the
cerebellopontine angle and spreading distally into the
facial canal or a lesion within the facial canal in
light of observations of accompanying taste
disturbance, cataract,
papilledema,
palatal alterations, hearing abnormalities
=> chronic
cor
pulmonale),
no
systemic symptoms
(20%)
=> bullae => pulmonary
aspergillomas
=> death ; sarcoidosic necrotizing granulomatosis
: mainly large lung vessels granulomatous arteritis
=> fibrothorax,
rarely pneumothorax
(20-30%) => cholestasis,
usually asymptomatic
(5-10%) => anemia,
thrombocytopenia=>
increased
calcium intestinal absorption => hypercalcemia
=> hypercalciuria
(1-2%) => nephrocalcinosis
and nephrolithiasis
due to hypervitaminosis
D,
papillary muscles, pericarditis,
heart failure, chronic
cor
pulmonale
(5%)and
nuclear
scans (67Ga uptake and 111In-pentetreotide)
is
important. Lumbar puncture is useful to rule out other
diseases but CSF changes ([monocytes]CSF > 5
/ mL) are not specific. Elevated serum ACE level is also
not a specific diagnosis test. Any part of the CNS can be
involved, but there is predilection for :,
Addison
disease) for at least
6-12 months with 60Co
may be an effective alternative when other treatment
fails or glucocorticoids cause intolerable toxicity.
The recommended dose is between 12 and 30 Gy, divided
into 150-300 cGy/day (30 Gy in 10 sessions) :
radiotherapy is often effective in preventing the
progression of local symptoms from neurosarcoidosis,
but has limited application in reversing established
neurologic deficits; sarcoid meningitis is responsive
to radiotherapy; and radiation dose for the palliation
of symptoms related to neurosarcoidosis is 20 to 25 Gy
for treatment of optic disc swelling in chronic
intracranial hypertension
(sarcoidosis-lymphoma syndrome)ref
in < 5%). The papule is then biopsied and examined
with TEM.
shows hypoperfused segments and high 67Ga
captation in lymph nodes => grading
according to bilateral, symmetrical hilar lymphadenitis
(75-80%), lymphnodal calcifications (5%), parenchymal
alterations (limited or poorly defined peribronchial,
perivascular, scissural or subpleural micronodules),
irregular or consolidation (pseudoalveolar) opacities),
distortion of parenchymal and/or hilar architecture,
bronchiectasias and bronchioloectasias, honeycombing
(rare), emphysema, parahilar retracting conglomerates,
ground-glass, and fibrosis. Staging :
(heterogeneity of parenchymal alterations and anterior
mediastinic lymphnodal involvement) and silicosis
(anamnesis).
]plasma
in 66% (5% are false positives)
(Th-to-Ts ratio = 0.8:1), eosinophilia,
increased ESR 1 mg/kg for 4-6
weeks : but according to the microbial aetiology theory it
would made it even easier for the infection to spread.
antimicrobialsref
(minocycline
> doxycycline(low
penetration
into granulomas)). Side effect : Jarisch-Herxheimer
reaction (JHR) transcription, and the –945G
allele is significantly associated with susceptibility to
systemic sclerosisref
ref
=> increased level of PDGFRref1,
ref2
(agonist antibodies)
=> intimal, adventitial and perivascular fibrosis. When
total RNA is taken from punch biopsies taken from the forearm
and the back, 2776 differentially expressed genes readily
determine diseased from normal tissues. Normal back tissue in
affected individuals gives the same profile of gene expression
as the diseased tissue from the arm, suggesting the means for
early detection of the disease could be normal tissue. Gene
expression profiles in cell lines derived from tissues
constituting normal skin provided explanation for the observed
expression profiles : fibroblast cell lines outgrown from the
biopsies fail to give differential gene expression profiles,
precluding their use for diagnostic purposes. An expression
profile similar to B lymphocytes suggests the involvement of
this inflammatory cell type where previously only T cells were
thought to be present, providing a new direction for research
into the disease
(Erasmus
syndrome / silicoscleroderma : others think it's
just the incidental association, simultaneous or
successive, of silicosis and progressive systemic
sclerosis). When coupled to rheumatoid
arthritis it is a.k.a. Kaplan syndrome., L-Lys, 5-hydroxy-L-Trp
(5-HTP), melatonin
and others.
> 1,000 / mL . PAP esters are absorbed in the
gastrointestinal tract and are distributed and
stored in different organs, particularly in the
liver and brown adipose tissue (BAT). PAP in these
organs showed different patterns of fatty acids,
indicating the ability of the gastrointestinal tract
to modify the fatty acid composition of the parent
PAP. Thus, the fatty acid profile of the PAP esters
found in intestine appears to be related to the type
of oil used as vehicle. Some of these PAP esters,
when a long acyl chain was present in the sn-1
position of the molecule, showed an inhibitory
effect on the PAF synthesis. This is an important
observation in line with the systemic nature of the
disease. and its environmental
metabolite pentachloroanisole (PCA),
cultivated in Almeria
region, in the south-east corner of Spain. The
consequences of the cover-up were appalling. Many died
unnecessarily. Thousands more, children among them,
were left to endure a lifetime of pain and physical
impairment that perhaps could have been avoided if
they had received the care and treatment they needed
as early as possible.
(initially treated for "atypical pneumonia")
=> weight loss
infection. It occurs in association with diabetes
mellitus
in most cases ,
thrombocytopenia,
simvastatin ,
Although muscle strength is unimpaired, myalgia and
arthritis may occur. Sjögren's syndrome and cardiac
abnormalities have been reported and, rarely, aplastic
anemia and thrombocytopenia.
The usual absence of Raynaud's
phenomenon, telangiectasia, and significant visceral
changes (eg, delayed esophageal motility) help distinguish
EF from systemic
in 60% cases
in 100% cases -induced sclerodermiform
acrodermatitis atrophicans
in 100% cases
Ab , Raynaud's
phenomenon, sclerodactyly and teleangectasia (CRST) syndrome /
Thibierge-Weissenbach syndrome, Raynaud's
phenomenon, esophageal
dysfunction, sclerodactyly and teleangectasia (CREST) syndrome
autoantibodies (ACA) (50%).
(70%; 26% of mortality); visceral involvement comes slower
and later in the course of the disease. (<
10%
: average survival 2 years) or primary biliary
cirrhosis (PBC).
Ab (=> increased prevalence in
non-nulliparous females), including GvHD,
systemic
arterial
hypertension and kidney failure
with no proteinuria (7%, higher in American blacks;
12% of mortality), intimal hyperplasia in interlobular
arteries, fibrinoid
necrosis
of afferent arteriolae (including glomerular loops),
and thickening of glomerular basal membrane,
restrictive
cardiomyopathy
(< 10%), chronic pericardial effusion due to renal
failure, fibrinous pericarditis
=> heart failure (30%; 36% of mortality), chronic cor
pulmonale due to pulmonary
arterial
hypertension
(> 15%ref)
or left
ventricular
failure
due to systemic arterial hypertension
autoantibodies (20% of all SSc patients, 40% of
patients with dcSSc) => dyspnea under effort,
dry cough, aerial cysts, bullous emphysema,
bone reabsorption due to ischemia => hooked
hands.
(of chronic diseases, sideropenic, megaloblastic,
microangiopathic)ref
appears to be superior to other techniques in the
detection of myocardial myocardial fibrosis, the
hallmark of cardiac involvement in systemic sclerosis,
which accounts for the majority of cardiac
manifestations in patients with scleroderma. Its
detection and histologic confirmation are difficult
because of an often-asymptomatic course, nonspecific
findings by noninvasive techniques, and patchy
distribution in the myocardiumref.,
immunosuppressive
drugs
and cytotoxic
drugs.
PDGFR inhibitors ?
infection
is presently an exclusion criterion to classify
Sjogren's syndrome; however, there are distinct
clinicopathologic and biologic similarities between
HCV-related and SS-related chronic inflammation of
mucosa-associated lymphoid tissue and
lymphoproliferation that suggest common pathogenetic
pathways. To determine whether a subset of patients
with sicca syndrome and HCV infection may present a
true primary SS rather than a distinct clinicobiologic
entity, 20 consecutive patients with positive anti-HCV
antibodies + heavy subjective dry eye and/or dry mouth
symptoms + positive unstimulated sialometry and/or
Shirmer's test were extensively characterized and
their features were compared with those in HCV-
primary SS controls (classified according to the
latest American-European Consensus Group
Classification Criteria for SS). Of the 20 HCV+
patients with sicca manifestations, 12 (60%) had
positive anti-SSA/SSB antibodies (3/12 by ELISA and
6/12 by immunoblot) and/or positive salivary gland
biopsy (at least 1 focus/4 mm2), which met
the strict classification criteria for SS, as in the
case of HCV- SS controls. Comparing the HCV+
SS subset with HCV-negative SS controls showed similar
female to male ratio (11/1 vs. 46/4), major salivary
gland swelling (17% vs. 26%), positive antinuclear
antibodies (75 vs. 94%) and positive rheumatoid factor
(58 vs. 52%). Significant differences were seen in
mean age (69 vs. 56 years), liver disease (50 vs. 2%),
lung disease (25 vs. 0%), anti-SSA/SSB positivity (25
vs. 90%), and low C3 or C4 (83 vs. 36%). HCV+
SS patients exhibited a trend for more frequent
chronic gastritis (50 vs. 22%), fibromyalgia (33 vs.
14%), peripheral neuropathy (33 vs. 18%), purpura (33
vs. 19%) and cryoglobulinemia (33 vs. 6%). A major
subset of HCV+ patients with definite
subjective sicca symptoms and positive objective tests
may indeed present a true, though peculiar, subset of
SS. There are strict similarities with key clinical,
pathologic and immunologic findings of definite HCV-
SS. Other features appear more characteristic of HCV
infection. When also considering that HCV is
sialotropic and may be treated, HCV-related chronic
sialadenitis represents a unique opportunity to
clarify key pathogenetic events occurring in the large
majority of HCV- SS; and similarities to
typical primary SS, rather than differences, should be
taken into accountref.
The salivary amylase (s-isoamylase) remained high even
after HCV was eradicated. The in situ
hybridization did not show the presence of HCV-RNA in
the salivary gland from patients with chronic
hepatitis C. A protein reacting with anti-HCV-E2
antibodies was found in the cytosol fraction of normal
salivary gland from HCV- cases. Latent
sialadenitis is frequently observed in chronic
hepatitis C, which is not directly related to HCV per
se. The presence of a common epitope between
antigenic protein in the salivary gland and the
HCV-derived protein may be a possible pathogenetic
mechanisms such as molecular mimicryref.
In 86.9% of patients with chronic HCV-infection and
Sjogren's syndrome minor salivary glands were
characterized by mild infiltration and advanced
fibrosis. HCV-RNA was found in the saliva of 57.5%
patients, in minor salivary glands tissue in 39.1%.
HCV-RNA detection in the saliva did not depend on the
degree of viremia, while viral RNA in MSG correlated
with viral load. EBV and HHV-6, HHV-6 only and EBV
were detected only in 18.4%, 26.3% and 15.8% of
patients, respectively. Xerostomia occurred with the
same rate (26.1 and 31.3%) in patients with and
without herpes viruses in the salivaref.
The "dry" syndrome in chronic hepatitis C ran
subclinically in 73.8% patients : the first signs of
SS occurred in 59.5% of patients 2.9 +/- 3.1 years
prior to diagnosis of hepatic disease. The minor
salivary gland in CHC is characterized by fibrosis
prevalence over cell infiltration. 83.3% of chronic
hepatitis C patients had SS and other extrahepatic
lesions : SS was most evident in 28.6% CHC patients
with cryoglobulinemiaref,
HCV, HEV,
and HGV
markers in Russian patients was higher than in donors.
The incidence of serological markers of EBV and HHV-6
was virtually the same in the patients with Sjogren's
disease and donors. EBV DNA was less frequently
detected in patients with Sjogren's disease than in
donors, as was shown by blood and salivary DNA testingref
(50-90%), T4 or both
(50%) (50-90%; 95% of
patients has HLA-DR2/DR3; RR = 17) => leukopenia,
vasculitis expression is
reduced on peripheral B cells of pSS patients through a
post-transcriptional mechanism and could be the consequence of
chronic BAFF increaseref
for > 3 months (42.5%) due to intermitting
monolateral
parotitis or bilateral
parotitis (24% at onset, 60% at anamnesis) => salivary
mucosa-associated
lymphoid tissue (MALT)-type lymphoma
(5%) / fatigue (10%)(14%)
(expecially in SS secondary to SLE),
pulmonary
arterial hypertension or membranoproliferative
glomerulonephritis
only in patients with systemic
vasculitis, essential
mixed
cryoglobulinemia or SLE;
interstial
cystitis, aseptical meningitis, seizures, ...,
pre-existing lymphomas, HCV,
HIV-1,
or sarcoidosis.
and antimalarial drugs.
Called also Mikulicz disease (particularly when
there is lacrimal gland enlargement).QO (40-50%) or FcgRIIIA
which lower affinity for IgG2 or IgG1
and IgG3, respectively => decreased
iccosome clearance => lupus nephritis; FcRgIIbT232,
encoding a single transmembrane amino acid substitution,
is unable to inhibit activatory receptors because it is
excluded from sphingolipid rafts, resulting in the
unopposed proinflammatory signaling thought to promote
SLEref
polymorphism : mutations in the genes encoding CD95 /
Fas / Apo-1
and CD178 / FasL are rare in
classical SLE : activated Th cells are
resistant to anergy and AICD as they upregulate COX-2
expression, which in turn upregulates expression of the
anti-apoptotic protein c-FLIP and decreases signalling
through the Fas apoptotic pathway via enzyme-independent
activity (there is no increased PGE2
production). Inhibition of COX-2 caused apoptosis of the
anergy-resistant lupus T cells by augmenting Fas
signaling and markedly decreasing the survival molecule
c-FLIPref
gene polymorphisms
in naive T lymphocytes-195 bp alleleG138 bp alleleN*2 allele
of serum dilution of 1/40, significantly more of the
children born to a SLE mother are positive for ANA than
controls (27% vs. 7%, respectively; P <
.005). Of the children born to an SLE mother, a
significantly higher proportion of girls are positive
for ANA at the cut off point than boys (36% vs. 13%,
respectively; P < .001). In addition, ANA
positivity was significantly higher in children older
than 3 years than those younger (33% vs. 5%,
respectively; P < .001). Of 44 children
examined more than twice, 10 became positive for ANA at
the second visit, 9 of whom were girls aged 4 to 8
years. No difference was found between children with an
SLE mother and controls in incidence of anti-DNA or antiphospholipid
antibodies. > UVA : 70% has photosensitivity : exposure to
UVB in sunlight induces necrosis of tissues and so
dissequestration of cytoplasmic and nuclear
autoantigens => relapses
=> ANA
in 25-65% => ANA
in 50-100% within few months
develops drug lupus, with rare
anti-dsDNA autoantibodies, rare hypocomplementemia, rare
renal and CNS impairments.
,
30% experience myalgia and arthralgia, > 10% develop
full disease (relapsing fever,
pleuritis,
pulmonary infiltrates, pericarditis,
myocarditis,
increased ESR,
no ANA).
The
coincidence of HLA-DR4 (R = 3.7) and Gm 1;21 (RR = 3.2)
markedly increases the risk of acquiring pseudolupus (RR
6.9)
with immune complex deposition, mesangial or
mesangiocapillary proliferation, and proteinuria)
characteristic of SLE) and worsen the disorder after it
has been established
(before age 20) : patients with SLE have abnormally high
frequencies of EBV-infected cells in their blood, and
this is associated with the occurrence of SLE disease
flares. Although patients with SLE have frequencies of
infected cells comparable to those seen in
immunosuppressed patients, in SLE the effect was
independent of immunosuppressive therapy. Aberrant
expression of viral lytic (BZLF1) and latency (latency
membrane proteins 1 and 2a) genes was also detected in
the blood of SLE patients. The abnormal regulation of
EBV infection in SLE patients reflects the sensitivity
of the virus to perturbation of the immune systemref polarization. B
cells with self specificity for IgGs or DNA are
activated by immunocomplexes containing nucleosomes : DNA
binds both BcR and TLR9(the latter acts as a
coreceptor). The defective production of functional 968-kDa
form of Elf-1
causes the decreased expression of CD3 z-chain. Autoantibodies :
(90-98%; absent in patients with C4AQ0))
(20%) => psychosis
/ depression (30-35%)
=> neonatal lupus (transient cutaneous rash,
rarely congenital
heart
block) from transplacental transfer of
autoantibodies, nephritis. (10-15%)
(50%) => anti-phospholipid
antibody syndrome
(17-30% : SLE-specific !)
(30%)
(23%) (5%) expression is
reduced on peripheral B cells of SLE patients through a
post-transcriptional mechanism and could be the consequence of
chronic BAFF increaseref.
Increased levels of BAFF-R and IL-15ref
in serum. In SLE patients, significant increases of CCR7-,CD27-
and CCR7-,CD27+ and a reduction of CCR7+,CD27+
CD4 memory T cells were found. In vitro stimulation of SLE T
cells showed a stepwise differentiation from naive to CCR7+,CD27+
to CCR7-,CD27+ to CCR7-,CD27-;
telomere length and inducible telomerase decreased in these
subsets in the same progressive sequence. The in vitro
proliferative response of these populations progressively
declined as their susceptibility to apoptosis increased.
Interestingly, a significant reduction in inducible telomerase
was noted in SLE naive and CCR7+,CD27+
CD4+ memory T cells. Additionally, SLE CCR7-,CD27+
and CCR7-, CD27- CD4 memory T cells
proliferated poorly in response to in vitro stimulation
and underwent significantly more apoptosis than their normal
counterparts. Finally, expression of CXCR4 was significantly
reduced in all SLE subsets compared with normal. Together
these data indicate an increased degree of in vivo T
cell stimulation in SLE, resulting in the accumulation of
terminally differentiated memory T cells with a decreased
proliferative capacity and an increased tendency to undergo
apoptosis upon stimulationref.
in
small-diameter arteries and arterioles (26%), anorexia, nausea and
vomiting, weight loss therapy) (40%) on (50%) similar to wolf-bite
(hence the name "lupus") autoAb).
70% of patients has HLA-DR3 (RR = 11).. Only 5% of patients with DLE
develop SLE. DLE-like lesions can be also caused
by 5-fluorouracil
(5-FU) alone or in combination with
tegafur (UFT). (5%))=>
ulcers
and chronic
interstitial
nephritis
(50%, < 10% in drug lupus : 5-10% develops chronic
renal
failure).
CpG-DNA
(but not pI:C RNA or imiquimod) trigger lupus
nephritis in MRL(lpr/lpr) mice (but not in wild-type
mice), support the concept that SLE is triggered by
pathogens that release CpG-rich DNAref (10%) responsive to steroids (25%)secretion due to anti-phospholipid
autoantibodies (< 1%) with no valvular failure (10%; 50%
at necropsy) (8%) due to coronary vasculitis (10%) (30%) => cardiac
tamponade (rarely constrictive
pericarditis) (70%)(15%)
(20%) : cervical and axillary common, may correlate
with disease activity; massive mediastinal
lymphadenopathy rare in patients with SLE alone (< 5%%) (50%) (50%) : common in
patients with SLE, with or without effusion or
friction rub(30%) : mildly exudative
(if not associated with underlying infection);
unilateral or bilateral
: uncommon; presents with fever, nonproductive cough,
infiltrates, hypoxia; cultures are negative; high
mortality rate (5%) => pulmonary
arterial
hypertension (< 5% : insidious
onset of chronic fatigue, weakness, palpitations,
edema; more common in patients with mixed
connective-tissue disease); occurs in patients with
long-standing SLE
: can be difficult to diagnose in patients with SLE;
requires biopsy; responds to corticosteroids : lung
cancer;
lymphoma
more common in patients with SLE (< 5%)
is increased
(75%)ref and C4
concentrations are decreased (75-90% of patients with
lupus nephritis) due to activation of classical activation
pathway of complement cascade by autoantibodies (normal C3
and reduced CH50 in patients with C4AQ0)
is usually normal : it increases only if overinfection
occurs due to immunosuppressive
drugs),
hypocomplementemia, severe CNS impairment, thrombocytopenia, antiphospholipid antibodies, delay
in therapy
rather than to renal failure.
(1-2 mg/kg/alternis diebus)
: mycophenolate
mofetil
is more effective than intravenous cyclophosphamide
in inducing remission of lupus nephritis and has a more
favorable safety profileref
to maintain 2.5 < INR < 3ref1,
ref2
: no reduction in anti-dsDNA, C3 and C4, reduction in
serum Ig (within normal range), no infections; 11/17
develop HACAs
are rarely prescribed for women with SLE, because of
concern about potential negative side effects, but they do
not increase the risk of flare among women with systemic
lupus erythematosus whose disease is stableref.
Anyway global disease activity, maximum SLEDAI score,
incidence of flares, time to first flare, and incidence of
adverse events were similar among women with systemic
lupus erythematosus, irrespective of the type of
contraceptive (combined oral contraceptives,
progestin-only pill or IUD) they were usingref|
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| Harvey AM, Shulman LE, Kaplan D. Systemic lupus erythematosus: review of the literature and clinical analysis of 138 cases. Medicine (Baltimore) 1954;33:291–437 | 1949–54 | 138 | 38 | 15 (39) |
| Ginzler et al, 1978ref | 1966–76 | 223 | 55 | 20 (36) |
| Rosner et al, 1982ref | 1965–78 | 1103 | 222 | 74 (33) |
| Pistiner et al, 1991ref | 1980–89 | 464 | 26 | 5 (19) |
| Janwityanuchit et al, 1993ref | 1980–89 | 537 | 77 | 23 (30) |
| Nossent, 1993ref | 1980–90 | 68 | 22 | 11 (50) |
prophylaxis in a group of patients with SLE in Indiaref.
INH was started in all patients with SLE who were treated
with "long term" corticosteroids. When compared with a
similar historical cohort from some of the same
researchers, the incidence of tuberculosis decreased from
11% to 2%ref1,
ref2.
This study had several limitations. One obvious limitation
is the lack of generalisability of the benefit of INH
prophylaxis in areas in which the prevalence of
tuberculosis differs. In geographical areas such as the
Philippines where the reported prevalence of tuberculosis
in a cohort of patients with SLE was 13.7%
(Victtorio-Navarra STG, Arroyo CG, Torralba T.
Tuberculosis among Filipino patients with systemic lupus
erythematosus. Lupus 1995;4 (suppl 2):89) or in Vietnam
with a prevalence of 27% of clinical tuberculosisref,
a similar strategy may be entertained. Obviously, in other
areas with a high prevalence of tuberculosis, prophylaxis
may also be very beneficial. On the other hand another
study of 451 Greek patients with a variety of connective
tissue disorders, including SLE, recommended that purified
protein derivative screening with INH prophylaxis may not
be necessary in patients with rheumatic syndromes who are
receiving corticosteroids because of the low prevalence of
tuberculosis in that cohort of patientsref.
While there are only isolated cases of tuberculosis in
patients with SLE in Western countries, tuberculosis is
considered to be a growing public health hazard,
especially in areas with a high prevalence of AIDS (Young
LS. Mycobacterial diseases and the compromised host. Clin
Infect Dis 1993;17(suppl 2):436–41). Although prophylaxis
with INH is not commonly practised, it is currently
recommended in patients with positive tuberculin skin
tests requiring high dose prednisone for SLE and other
diseases (American Thoracic Society and Centers for
Disease Control. Recommendations: implementation of
targeted tuberculin testing. Amer J Respir Crit Care Med
2000;161:S233–41). Risk factors for developing
tuberculosis in patients with rheumatic diseases include
the cumulative and mean daily dose of corticosteroids and
a history of pulse corticosteroids treatmentref.
A second limitation of the study by Gaitonde and
colleagues is the lack of monitoring for liver toxicity in
those patients who had no clinical symptoms suggestive of
liver toxicityref.
With estimates of increased liver enzymes in 17% of
patients taking isoniazidref
and the potential for progressive liver damage, this
strategy of INH prophylaxis would not be acceptable in
most Western countries. Obviously, the agents one
considers using for prophylaxis are dependent on the
prevalence of specific diseases in that particular group
of patients. While prophylaxis against tuberculosis in
Western countries may not be as much of a public health
issue as in India, prophylaxis against a variety of other
infectious agents is commonplace. Once previously thought
to be unique to patients with AIDS, Pneumocystis
cariniiis
being
increasingly recognised in patients with SLE and other
inflammatory disordersref.
Most patients who developed Pneumocystis carinii pneumonia
were receiving corticosteroids and other cytotoxic agents
and were lymphopenic at the time of their diagnosisref.
Strategies using a regimen of low dose
trimethaprim/sulfamethoxazole three times weekly, or
inhaled pentamidine monthly, should be considered in
selected patients with active SLE being treated with
immunosuppressive agentsref1,
ref2.
Certainly, patients with SLE who have valvular
abnormalities should receive endocarditis prophylaxis
before invasive dental or genitourinary proceduresref.
Although controversial, others have argued that because of
the high percentage of patients with SLE who have
endothelial damage to the heart valves (as high as 50%) in
patients with SLE, antibiotic treatment should be
considered in all patients with SLE who are undergoing
procedures associated with transient bacteraemia in
accordance with standard regimens suggested by the
American Heart Associationref.
In a small case series of patients with SLE and Neisseria
meningitidis
infections, Mitchell and colleagues suggested the
following possible risk factors: female sex, young age,
renal disease, and persistent hypocomplementaemiaref.
Although it is clear that in children with
haemoglobinopathies and splenic dysfunction who receive
oral penicillin prophylaxis, pneumococcal bacteraemia is
reduced dramaticallyref,
little information supports the use of this strategy in
asplenic adultsref. is
the leading cause of death in patients with MCTD), nonerosive
polyarthritis, renal impairment (25%, mostly membranous
glomerulonephritis), pericarditis
(30%), trigeminal neuropathy, peripheral neuropathy, aseptical
meningitis, lymphadenitis,Sjögren's
syndrome
(SS)
in patients with HLA-DR4
(50%)
(38%)) :
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