Other Behcet issues (sorry,
English only)
The following articles have all been written by Tal
Kinnersly for ABDA's (American Behcet's Disease Association) Boston conference
2001 and for their newsletters.
(C) All rights reserved Tal Kinnersly 2001 and
2002.
Translation into Hebrew is available
upon request for a small fee,
which will help cover the costs of running this site.
- Disclaimer:
- The information in these articles should be
used as a reference only. Always consult your Behcet's Disease specialist
first!
- The articles are provided for information
only. In no way should any of the information found in them be used as a
substitute for professional medical care by a qualified doctor or other
health care professional. Always check with your doctor if you have any
concerns about your condition or treatment.
- The writer of these articles is not
medically trained and is not liable in any way for any of their content.
These articles are not edited by a Medical Doctor, and are in no way a
substitute for medical advice or treatment.
- This writer is not responsible or liable,
directly or indirectly, for any form of damages whatsoever resulting from
the use (or misuse) of information contained in or implied by the content
of these articles.
BD
and vaccines
- With the growing evidence of ineffectiveness
of and even harm caused by vaccines, it is a mystery to me why the
practice of inoculation is so wide spread. Moreover, in the US many
vaccines are given to babies in the first few hours of their life, against
the growing amount of evidence that their efficacy is lower the younger
the child is.
- - Immunity granted by inoculations is often
short lived, as opposed to life-long immunity granted by contracting a
disease.
- - The form of the disease contracted after
being vaccinated against it is usually more severe, and the disease is
difficult to diagnose because of the misguided belief one cannot contract
a disease they were previously vaccinated against.
- - Vaccines contain a lot of additives that
many are allergic to, and other additives that are known to be dangerous
to the neurological system and/ or are carcinogenic.
- - Some vaccines are made using animal and
human parts, posing a moral problem.
- - Many vaccines contain genome altering
substances and can cause various autoimmune diseases and other
malfunctions of the immune system (vaccines have already been linked to MS
, SLE and RA).
- (See bibliography and references for further
reading).
-
- That aside, as Behcet patients we have even
more serious concerns when it comes to certain immunisations.
- Gamma Globulin
- Often recommended to travelers as a
safeguard from hepatitis, this vaccine is known to have caused paralysis
in some BD patients.
- Chicken Pox
- Varicella Zoster, the virus which causes
Chicken-Pox, is of the Herpes family. Herpes viruses and Behcet’s are
closely connected, in a way yet to be understood.
- Influenza (Flu)
- Recommended frequently to those who suffer
lung complications and frequent bouts of pneumonia, but you must weigh the
risks against the benefits very carefully and use your own judgement. Some
BD patients reported getting very sick as a result of the vaccine as well
as being thrown into major flare.
- Others
- If you suffer severe pathergy reaction you
are likely to try and stay away from needles as much as possible. Even if
not, please make sure you carefully weigh the advantages and disadvantages
before you make any decisions.
Avoiding vaccines can be done
legally even in the US.
- Bibliography and reference
Vaccine exemptions in the US
Note: all research was done
online, in order to use the most up-to-date information available.
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Lab differentials between SLE and
BD (Jan 2002)
- Note:
- Before writing this article, as I
was gathering data for it, I turned to several reputable rheumatologists,
requesting their help. I was told in reply that as a non-professional I should
stay out of the subject altogether. When asked if a professional would be
willing to write it instead of me, no reply came at all. I find it regrettable
that I, a patient, should have to write this article, since the medical
profession did not find the time or see the need to put facts already out there
together, for the benefit of patients and doctors alike. It is for that reason
that patients are still being misdiagnosed on a daily basis.
- Any qualified medical
practitioner is welcome to correct this information or contribute further to it.
SLE (Systemic Lupus
Erythematosus) and BD (Behcet’s Disease) can be difficult to distinguish from
each other. As a result, some patients may be misdiagnosed with one or the other
(or both).
Japanese experts believe that in
principal a patient cannot have both diseases, and that double diagnosis in the
US is usually rooted in poor understanding of BD. I do not attempt to take sides
here, merely to remind us all of lab tests which can be of some help in
differential diagnosis between the two diseases. This is by no means a complete
list of tests for either of the diseases discussed, rather of some of the tests
performed which could help tell one from the other.
Assuming you have been through
the list of symptoms (see appendix), and diagnosis is still pending, here are a
few tests to help your doctor decide between BD and SLE (sources of further
information can be found at the end of this article).
- ANA (Anti Nuclear Antibody)-
95%-98% of SLE patients are ANA positive (ANA titer 1:80 or higher).
- BD patients should test negative
for ANA.
- Specifically
- Antibodies to DNA histones
are responsible for the LE (Lupus Erythematosus) cells. They are common in SLE
but are characteristically the only type of ANA observed in patients with
drug-induced lupus due to procainamide or hydralazine.
- LE Prep (Lupus Erythematosus cell
Preparation) is found in 75% of patients with active SLE.
- The test for antibodies to dsDNA
(anti double stranded DNA) is highly
specific for SLE (95%) but has lower sensitivity than ANA (60-70%, depending on
the technique employed). Levels may correlate with disease activity,
particularly with SLE nephritis.
- Anti-Sm
(Anti Smith) is highly specific for SLE. Levels tend to remain stable throughout
the disease course, and its presence is not a definite marker for any specific
manifestation. However, it is observed in less than half of SLE patients.
Different sources suggested anything from 15% to 40% positivity. One source
stated: “The anti-Smith antigen is observed in 25% of patients with SLE
overall, with 10-20% whites and 30-40% blacks and Asians”).
- Antibodies to SSA/Ro and SSB/La
are observed in 15-20% of patients with SLE. They are observed in other
connective tissue diseases also, including Sjogren syndrome, but interest in
them stems from their correlation with certain SLE features, especially subacute
cutaneous lupus rashes. They also are found in the mothers of babies with
neonatal lupus syndromes’ skin rash and congenital heart block, even though
50% of those mothers have no clinical disease. According to a different source,
Anti-Ro is present in about 60% of Lupus patients and is particularly common in
patients with photosensitive rashes and/or arthritis. According to the same
source, Anti-La is present in about 30% of patients who also have anti-Ro
antibodies. (Note: Having both of these together is associated with dry eyes and
mouth (Sjogrens syndome)).
- Antibodies to
ribosomal P protein are uncommon in SLE but do
correlate with the presence of lupus cerebritis.
- Antiphospholipid antibodies
(these include lupus anticoagulant and anticardiolipin antibodies) are
associated with livedo reticularis, arterial and venous thrombosis without
vasculitis or active SLE, an increased incidence of fetal wastage (including
midtrimester and late abortions and stillbirths), and thrombocytopenia.
Different types of antiphospholipid antibodies can be detected by a number of
different laboratory tests. (Notes: 1. False positive Venereal Disease Research
Laboratory (VDRL) is part of the family of antiphospholipid antibodies; 2. In
patients with the lupus anticoagulant, the activated partial thromboplastin time
(aPTT) is prolonged and is not corrected by mixing patient plasma with normal
plasma.)
- Anti-neutrophil cytoplasmic
antibodies (ANCA) and antiphospholipid antibodies are usually negative in BD
patients. (Occasionally, patients are found with positive test results for
perinuclear antineutrophil cytoplasmic (p-ANC) antibody). Although
antiphospholipid antibodies are uncommon in BD, they are said to be worth
pursuing, especially in cases of thrombosis. The best correlation apparently
occurs with retinal vascular lesions. In addition to thrombosis associated with
antiphospholipid antibodies, there have been reports of thombosis in BD
associated with Factor V Leiden mutations, and with prothrombin G20210A
mutations.
- Anticardiolipin antibodies are
present in up to 30% of BD patients.
- Other autoantibodies
may be found in the serum of patients with SLE, including RF (rheumatoid
factor)(30%) and the Coombs antibody.
- RF should be absent in BD
patients.
- Antiendothelial cell antibodies
are detected in diseases with immune-mediated vascular damage and show
significantly increased prevalence in BD.
-
- Genetics-
- HLA
(Human Leukocyte Antigen)
- Years ago SLE was thought to be
associated with HLA-B27. However, this does not seem to be the case any longer.
- HLA class I genes have little to
do with SLE. However, many genes in the HLA class II group are linked to it:
- The combination of the DR3 and
DQ2 variants, or the DR2 and DQ6 variants raise the risk of SLE by a factor of 2
or 3. These genes account for only a small part of the genetic risk for SLE.
Nevertheless, many studies of class II genes show no links with SLE. However,
when dividing lupus into subtypes, according to the results of various blood
tests, many links between class II genes and lupus subtypes were seen. This
suggests that SLE is not one disease, but several similar diseases.
- Many genes in the HLA class III
group are also linked to SLE:
- The C4A and C2 genes are
discussed below, in the section on "complement genes."
- Certain variants of the TNF
(tumor necrosis factor) genes raise the risk of SLE in some ethnic groups.
- There is an increased percentage
of two histocompatibility antigens in patients with SLE, HLA-DR2 and -DR3. In
addition, there is an increased frequency of the extended haplotype HLA-A1, B8,
DR3.
- HLA-B51 has been linked with BD
but the association is not simple. Generally speaking, countries whose
population has a high occurrence of HLA-B51 also have a high occurrence of BD.
In some of these countries, the prevalence of HLA-B51 is higher in BD patients
than in the general population. For example, the frequency of HLA-B51 is 57% in
Japanese BD patients compared to only 14% in the control group, which equates to
a relative risk of 7.9 for this marker.
- HLA-B51, and in particular its
B101 allele, is significantly associated with BD in Japan, Korea, Turkey,
Israel, Mexico and France, as well as with the ocular manifestations in Britain.
Although HLA-B51 transgenic mice failed to develop any manifestation of BD,
their neutrophils showed excessive function.
- Restriction fragment link
polymorphism studies showed linkage disequilibrium between HLA-B51 locus and
tumor necrosis factor-b gene. This finding may imply that lower levels of tumor
necrosis factor-b may contribute to activation of inflammatory cascade in
Behcet’s disease.
- HLA-B5201 has been associated
with BD in Israeli Arabs and Jews.
- In Japan, an association has been
found between HLA-A26 and Behcet’s disease.
- Sacroiliitis has been described
in HLA-B27 positive BD patients. (HLA-B27-related anterior uveitis also may give
recurrent iridocyclitis with hypopyon, but it is typically unilateral.)
- HLA-DR and -DQ antigens have been
associated with BD in Tunisia, Morocco, Taiwan, Japan and Israel, but studies
pointed at different variants for each region. Findings from the US did not show
any such associations, while findings in Italy and China vary.
- Complement genes
- Complement studies (C3, C4, CH50)
may be useful to determine disease activity in patients known or thought to have
SLE. Complement levels (C3, C4, CH50) may be depressed in patients with active
SLE due to consumption by inflammation induced by active immune complexes. This
is observed in patients with both renal and extra-renal involvement. A low C3
level especially is significant as a marker of ongoing active lupus, especially
lupus nephritis. However, complete or partial congenital deficiency of certain
complement components, especially C4 and C2 (see below), can be associated with
SLE. Thus, a low or very low CH50 in a patient with mild SLE may reflect
congenital deficiency rather than active disease.
- Patients with deficiencies of the
classical pathway components C1qrs, C2, or C4 have been shown to have an
increased likelihood of developing SLE. Homozygous deficiency of C1q has the
highest association with SLE, with a recently quoted prevalence of 93%.
Subsequent components of the classical pathway have a respective prevalence of
57% for C1rs deficiency, 75% association with homozygous C4 deficiencies, and
10% prevalence in patients with C2 deficiencies. (Note: C1q protein is not a
single protein coded by a single gene, rather it is the name for a complex of 3
different types of proteins, called A, B, and C, each made from its own gene on
chromosome 1 . Six copies of A, B, and C group together, meaning that C1q is
actually a complex of 18 individual proteins. Scientists are not sure whether
the A, B, or C gene causes the problem that leads to lupus.)
- Most sources agree that BD
patients may present with elevated complement during acute flares. However, one
source stated: “Serum complement levels are normal, except for just prior to
eye or mucous membrane involvement, at which time they may be decreased.”
- Other genes
- Three studies have scanned the
entire human genome for linkages with SLE. One part of the short arm of
chromosome 1 was positive in all 3 studies. Other parts were positive in two of
three studies. These results were reassuring, because other studies had
identified suspicious genes in precisely these areas of chromosome 1:
- The FCGR2A gene influences how
the body cleans up the results of immune attacks. Certain variants of this gene
raise the risk of kidney disease in African-Americans with lupus.
- The APT1LG1 and ADPRT genes are
part of the body's system that controls the lifespan of cells
("apoptosis"). Similar genes in laboratory mice are linked to SLE, but
more studies of humans are needed.
- Regions on chromosomes 2, 6, 14,
16, and 20 also came up positive in at least two of the whole-genome studies
mentioned above.
- MICA allele is a polymorphic MHC
class I related gene A (MICA) family. MICA6 allele has recently been shown to be
significantly associated with BD (74%), compared with controls (45.6%) in Japan.
The relationship between MICA6 and BD was confirmed in France. However, MICA6
allele is thought to be in linkage disequilibrium with HLA-B51, so more research
is needed.
-
- CIC (Circulating Immune
Complexes)- SLE is associated with the
impaired clearance of circulating immune complexes secondary to: decreased CR1
expression; defective Fc receptor function; deficiencies of early complement
components such as C4A.
- Circulating immune complexes may
also be found in BD patients.
Serum immunoglobulins (IgG, IgA,
IgM)- Most doctors seem to agree that SLE
is frequently associated with elevated IgG, while BD is associated with elevated
IgA, and both can show elevated IgM. However, opinions vary so much about the
results of these tests in either disease, that it is probably not a useful tool
in differential diagnosis between them.
- Skin Biopsy-
Results of skin biopsy can help to diagnose SLE in atypical cases and to
diagnose unusual rashes in patients with SLE. Biopsy of the lupus skin lesions
demonstrates inflammatory infiltrates at the dermoepidermal junction and
vacuolar change in the basal columnar cells.
- A specialist familiar with both
diseases should be able to make a differential diagnosis based on a skin biopsy.
-
- WBC (White Blood Cell count)- Some
sources state that SLE, being an inflammatory disease, shows up high WBC, while
other sources state that since SLE is a collagen-vascular disease, WBC is low.
It should be noted that most sources agree with the latter statement, listing
mild leukopenia (low WBC count) as associated with active SLE in 20-30% of
patients.
- BD patients can have very
elevated WBC during acute flares.
-
- Pathergy- pathergy
reaction is considered unique to Behcet’s disease, and its presence strongly
suggests the diagnosis of BD.
- Higher positivity (84-98%) is
found in Mediterranean and Middle Eastern countries as compared to Far Eastern
countries (40-70%), with Western countries having significantly lower positivity
than either region.
Throughout my search and research
for this article, I found only one source referring to differential diagnosis
between SLE and BD by lab tests. It read: “Systemic lupus erythematosus and
other vasculitic syndromes must be ruled out [for diagnosis with BD] (with
negative antinuclear antibodies and negative antineutrophilic cytoplasmic
antibodies).” (e-medicine, pediatric rheumatology).
- Appendix
- Here is a reminder of the
diagnostic criteria for the two diseases:
SLE The diagnosis of lupus is a
clinical one made by observing symptoms. Lab tests provide only a part of the
picture. The American College of Rheumatology (ACR) has designated 11 criteria
for diagnosis. To receive the diagnosis of lupus, a person must have 4 or more
of these criteria:
- American College of Rheumatology
(ACR) Criteria for the Classification of SLE
- Malar rash
- Discoid rash
- Photosensitivity
(skin)
- Oral ulcers
(oral or nasopharyngeal, usually painless)
- Arthritis
(nonerosive)
- Serositis
(pleurisy, pericarditis)
- Renal involvement
(proteinuria, cellular casts)
- Neurologic disorder
(seizures, psychosis)
- Hematologic disease
(leukopenia, thrombocytopenia, lymphopenia)
- Immunologic disorder
(lupus erythematosus [LE] cells; anti-DNA; anti-Smith [anti-Sm]; biologic
false-positive [BFP] serologic test for syphilis [STS]; antiphospholipid
antibodies)
- ANA
BD Diagnosis of BD is based on
clinical criteria because of the absence of a pathognomonic laboratory test. The
period between the appearance of an initial symptom and a major or minor second
manifestation can be up to a decade long in many cases. Disagreement on the
correct set of diagnostic criteria persists. For the two most commonly
used sets click Japanese,
international.
Sources, reference and further
reading
- SLE related
- BD related
- Other sites
Note: All research was done
online, in order to use the most up-to-date information available.
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East vs.
West in Behcet Disease (Oct 2001)
Approaches to this disease in
western nations and eastern nations seem to vary largely. Naturally, they also
vary with the doctor you see, but there are general trends in attitude that
depend mostly on geography.
The first such difference becomes
apparent as soon as you visit a doctor and present yourself as a Behcet patient.
“What’s that?” would often be the immediate doctor’s reply in the West,
while in the East (Near and Far East) it may be more like “Oh, I’m afraid I
am not an expert on BD”.
If you are yet to be diagnosed,
the challenge may be even bigger. The likelihood is it would take longer to get
to BD, and longer still to get to diagnosis with it in the West. If you suggest
it yourself you may be told “but you are not Asian” or “but it is too
rare” or in the case of females “but it mostly strikes men”. In the East,
the latter may be more common, and rarity is a subject little mentioned.
But recognising BD is not the end
of the diagnosis problem. While eastern doctors are relatively familiar with the
disease because it is more common in their geographic area (or at least more
frequently diagnosed there), western ones tend to be less informed on average.
This in turn means that once diagnosed with BD, a patient’s medical history is
entirely re-evaluated in the East, and all previous diagnoses looked at from the
point of view of the patient having BD. In most cases this means all or nearly
all previous diagnoses are corrected into the one which incorporates all their
symptoms, Behcet’s Disease. However, in most western countries, particularly
the US and the UK, previous diagnoses remain undisputed. In fact, in that area
of the world, diagnosis of extra diseases keep being made with time, rather than
attributing the new symptoms to Behcet, as is done in eastern countries, such as
Japan.
Whether one carries around
multiple diagnoses or not, a BD patient in the west is much more likely to be
prescribed many more medications, and when one does not work, often more would
be prescribed alongside it, rather than instead of it. In the East, the first
drug may often be either colchicine or minocycline, and steroids would be
normally kept for severe conditions only. It should be noted, though, that in
the last couple of years, steroids are more widely used even in Japan, since
strong drugs which were prescribed here, such as cyclosporine-A for eye
treatment, proved to be potentially very harmful too. In general, different
countries may prefer different medicines, or some drugs may simply not be
available in certain countries. So even within east and west there are
differences between Ｎorth
America and Europe, and in the East between the Far East and the Near East.
Naturally, some drugs may be available under different names, being produced by
different companies.
Lastly, the choice of treatment
may often be influenced by cultural background. China, Japan and Korea, who
still use a lot of their traditional medicines and therapies in everyday life,
tend to implement them in clinics more often than European or North-American
doctors do. Shiatsu and acupuncture, as well as herbal supplements may be
prescribed by the doctor in charge, and the health insurance often pays for
them. Even if alternative treatment is not offered by the large hospitals, most
people would try it anyway, and often seem to benefit from it. In Europe and
North-America efforts are currently being made to incorporate old healing skills
and techniques from various cultures into conventional medicine. The degree of
these efforts depends on the country, as does the treatment offered, but in
general such alternatives are becoming more readily available, although too
often at a very high financial expense.
The two countries that probably
spend the most in resources on BD research are Japan and Turkey. Other countries
commonly involved in research of this disease are Korea, Jordan, Israel, Greece,
Italy, France, Germany ,the UK and the USA.
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Problems
with the current sets of diagnostic criteria (Oct 2001)
Since there is no laboratory test
that clearly indicates or rules out Behcet’s, the diagnosis of this disease is
based on clinical criteria. However, it can take as much as a decade between the
appearance of the first symptom and the next.
The number of different criteria
sets that have been introduced over the past 25-30 years reflects the failure of
any single one to meet clinical demands. This is partly due to the fact that
different regions around the world stress different symptoms, and partly since
most sets of diagnostic criteria are designed to pinpoint classic patients that
can be used in research. Unfortunately, the same sets are later used by doctors
to diagnose new patients, which means some patients may be denied diagnosis,
while others serve to make statistics support the criteria used, as will be
demonstrated soon.
The two sets most widely applied
are the revised criteria of the Japanese group (1987, Shimizu, Table 1) and the
diagnostic criteria of the International Study Group for Behcet Disease (1989,
ISGBD, now ISBD, Table 2). The major limitation of the latter, however, lies in
heavy reliance on recurrent oral ulceration for diagnosis of Behcet disease. Lee
et al give the example of patients with uveitis and genital ulcers without oral
aphthosis not being considered to have Behcet, although this is in fact a
far-advanced form of the disease. They proceed to recommend that the Japanese
criteria be applied concurrently with the ISGBD criteria until a more exact
system is devised.
The ISGBD set of criteria was
devised purely for the purpose of research, but has been abused ever since it
was written. As a result, statistics in countries where it is used (almost
anywhere outside the Far East) show a rise in patients presenting mouth ulcers.
Of course, anyone not having them will not be diagnosed with Behcet’s under
the new criteria, so eventually all patients show oral aphthosis (Jordan, for
example) and this is in turn used to prove the validity of the criteria in the
first place, which is ridiculous.
For reference, please see the two
sets of diagnostic criteria referred to in this article (Japanese,
international).
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Heredity
(Oct 2001)
I often hear "I am surprised
that so many people in your family have BD. I was told it was not
hereditary."
My family is a classic case for
heredity. No two generations were born or lived in the same country, or in
similar weather patterns. Socio-economic status varies greatly between us, as
does diet, and couples are internationally mixed.
My mother - Born in Iraq, both
her parents were Iraqi Jews. They were very wealthy through her early childhood,
but it did not last past that.
Myself and my brother - Born in
Israel, to a mixed couple. My mother an Iraqi Jew, my father a first generation
Israeli Jew of East-European descent (Poland/Russia/Romania). We were not well
off through my childhood.
My children - Both born in Japan,
lived in Spain for a while. Their mother, myself, mixed all over the place as
you just read, their father a British non-Jew, so there goes the only common
factor so far. When my son was born we were very poor, but we were
financially-comfortable by the time my daughter was born.
My mother (and probably also my
grandmother and most of my mum's six brothers and sisters), my only brother,
both my children and myself have Behcet's.
Dr. Madanat's figures at the
First Convention for patients with Silk-Road (Behcet’s) Disease showed that in
18.6% of Jordanian patients, at least one other member of the family had been
diagnosed with BD. Apparently more siblings are known to share the disease than
are different generations.
It is safe to assume that not all
of us who carry the potential to have the disease actually develop it. The
general belief is that a trigger (or triggers) not agreed upon is responsible
for this difference. This is a subject that deserves its own article but will
not be discussed here.
Many patients I met started off
saying "My children do not have BD, because it is not hereditary", but
after a while said "well, now that you mention it, he/ she does have
aphthae, and skin lesions, and other things". It has been documented that
autoimmune disorders are generally hereditary.
It is also possible that the way
we look at things is partially responsible. Some of us will go as far as seeing
things that do not exist, just because we look too hard. Some may see in others
(children or not) what they have, because they are more aware of it. Others
still would rather not see the disease in others, particularly their own
children, as we do not wish this limiting condition on our family.
Research into the issue of
heredity has its limitations. One problem is the small number of participants in
research, which means the same samples of blood are analyzed again and again.
Another problem stems from the
fundamental view taken by researchers. In order to look for signs of heredity,
scientists normally turn to known familial cases, and take blood samples from
patients in those families in an attempt to find the gene or genes responsible
for Behcet’s disease. However, no research ever attempted to question the
relatives of patients not known to have the disease in their family, in case it
exists there but is misdiagnosed or is not bad enough to call for a doctor’s
attention. I recently attempted to organise such a survey myself, but was
experiencing problems with hospitals, who were not quite sure how to deal with
the ethical complications of interviewing patients’ family members. I am still
working on this subject, though obviously this will take longer than expected.
Below is a summary of genetic
findings made so far:
HLA-B51 or its B101 allele has
been significantly associated with Behcet disease in many countries,
particularly those on the old Silk Road. However, the existence of the antigen
in a person does not imply they will ever develop the disease, while at the same
time a person can have BD and not carry HLA B-51. The connection therefore comes
down mostly to the fact that countries with a higher percentage of BD cases also
show a high percentage of HLA B-51 in their general population.
MICA allele is a polymorphic MHC
(major histocompatibility complex) class I related gene A (MICA) family. MICA6
allele has been shown to be significantly associated with Behcet disease.
However, the MICA6 allele is thought to be in linkage disequilibrium with
HLA-B51 (that is the connection between the two is considered unstable), so the
search for genes related to Behcet disease obviously still has a long way to go.
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