)
Table of contents :
(before and after transplantations)
(cancer chemotherapy and some immunosuppressive
drugs)
deficiency => urticaria-necrotizing
vasculitis / angioitis;
e.g. Streptococcus
pneumoniae,
Haemophilus
influenzae)
deficiency => acquired angioedema,
lung
carcinomas),
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.
,
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.
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.,
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%%)
(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
(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 pneumoniaref
(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) : unlike other types of drug-induced
thrombocytopenia, HIT promotes thrombosis rather than bleeding;
therefore HIT should be suspected in patients who experience thrombotic
events despite adequate anticoagulation therapy. Early identification and
treatment of HIT can prevent more serious complications associated with
this disorder (e.g., exacerbation of venous thromboembolism, limb gangrene,
and skin necrosis). Both arterial and venous thrombosis can arise from
a single episode of HIT. Routine assessment of platelet counts is necessary
with heparin therapy, as a decreased platelet level is usually the only
indication of HIT—a
small positively charged molecule familiar to clinicians for its heparin-neutralizing
properties—prevented thrombocytopenia in both FcgRIIA/hPF4low
and FcRIIA/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.
,
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 µg/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)
: 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
: 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.
: one group transplanted 14 patients with refractory ITPref.
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 complications.,
showed a temporary increase in the platelet count in 8 of 12 ITP patients
(5 splenectomy failures) at a dose of 3.0 µg/kg (Bussel JB,
George JN, Kuter DJ, et al. An open-label, dose-finding study evaluating
the safety and platelet response of a novel thrombopoietic factor (AMG
531) in thrombocytopenic adult patients with immune thrombocytopenic purpura
(ITP) [abstract]. Blood. 2003;102:66a)|
|
|
|
|
| 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
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
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. Recently, the use of IVIg
therapy, with a defined protocol, has been reported to be beneficial. This
therapy is promising since it may allow for discontinuation of all other
therapies and is safe. The adverse effects from IVIg therapy are minimalref
for refractory casesref1,
ref2
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-penicillamine
therapy.
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 anti-smooth muscle
antibodies)
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.
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. PT and serum
gGT
increase.
(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 anti-smooth muscle autoantibodies (SMA)
infections : cross reactivity between gliadin and Ad Ags
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,
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)
(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 :
combined with prednisone
for 1 yearrefref
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)
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.
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 | |||||
| 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 adjuvantibus 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)
(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),
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)(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 drugs
(methotrexate
7.5-30 mg/week for 1-2 months (low/moderate effectiveness)
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)
: don't down-regulate anti-citrullin antibody levels
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
(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
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)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
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.
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
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%)
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)
(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%)
(< 5%%)
(50%)(30%)
(5%) => pulmonary
arterial hypertension
(< 5%)
(< 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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